CA2504207C - New amide compounds having mch-antagonistic activity and medicaments comprising these compounds - Google Patents

New amide compounds having mch-antagonistic activity and medicaments comprising these compounds Download PDF

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Publication number
CA2504207C
CA2504207C CA2504207A CA2504207A CA2504207C CA 2504207 C CA2504207 C CA 2504207C CA 2504207 A CA2504207 A CA 2504207A CA 2504207 A CA2504207 A CA 2504207A CA 2504207 C CA2504207 C CA 2504207C
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alkyl
phenyl
chloro
group
amino
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CA2504207A
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French (fr)
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CA2504207A1 (en
Inventor
Dirk Stenkamp
Stephan Georg Muller
Gerald Jurgen Roth
Philipp Lustenberger
Klaus Rudolf
Thorsten Lehmann-Lintz
Kirsten Arndt
Ralf R. H. Lotz
Martin Lenter
Heike-Andrea Wieland
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Boehringer Ingelheim Pharma GmbH and Co KG
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Boehringer Ingelheim Pharma GmbH and Co KG
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07C233/24—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
    • C07C233/29—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
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Abstract

The present invention relates to amide compounds of general formula I (See Formula I) wherein A, B and Y are carbo- or heterocyclic groups; b is 0 or 1; X is an alkylene bridge; W is alkylene, alkenylene, alkyloxy, alkylamino, etc.; Z is a bond or alkyiene bridge; R1, R2 and R3 are hydrogen, alkyl, cycloalkyl, etc., or R1 and R2 form an alkylene bridge. Moreover the invention relates to pharmaceutical compositions containing at least one amide according to the invention. In view of the MCH receptor-antagonistic activity the pharmaceutical compositions according to the invention are suitable for the treatment of metabolic disorders and/or eating disorders, particularly obesity, bulimia, anorexia, hyperphagia and diabetes.

Description

DEMANDES OU BREVETS VOLUMINEUX
LA PRESENTE PARTIE DE CETTE DEMANDE OU CE BREVETS
COMPREND PLUS D'UN TOME.
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JUMBO APPLICATIONS / PATENTS

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THAN ONE VOLUME.

NOTE: For additional volumes please contact the Canadian Patent Office.

Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 if New amide compounds having MCH-antagonistic activity and medicaments comprising these compounds The present invention relates to new amide compounds, the physiologically acceptable salts thereof as well as their use as MCH antagonists and their use in preparing a pharmaceutical preparation which is suitable for the prevention and/or treatment of symptoms and/or diseases caused by MCH or causally connected with MCH in some other way. The invention also relates to the use of a compound according to the invention for influencing eating behaviour and for reducing body weight and/or for preventing any increase in body weight in a mammal. It further relates to compositions and medicaments containing a compound according to the invention and processes for preparing them.

Background to the Invention The intake of food and its conversion in the body is an essential part of life for all living creatures. Therefore, deviations in the intake and conversion of food generally lead to problems and also illness. The changes in the lifestyle and nutrition of humans, particularly in industrialised countries, have promoted obesity in recent decades. In affected people, obesity leads directly to restricted mobility and a reduction in the quality of life. There is the additional factor that obesity often leads to other diseases such as, for example, diabetes, dyslipidaemia, high blood pressure, arteriosclerosis and coronary heart disease. Moreover, high body weight alone puts an increased strain on the support and mobility apparatus, which can lead to chronic pain and diseases such as arthritis or osteoarthritis. Thus, 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 seen as the increased level of fatness which leads to a health risk. In the last analysis it is not precisely possible to draw a Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 if distinction between normal individuals and those suffering from obesity, but the health risk accompanying obesity is presumed to rise continuously as the level of fatness increases. For simplicity's sake, in the present invention, individuals with a Body Mass Index (BMI), which is defined as the body weight measured in kilograms divided by the height (in metres) squared, above a value of 25 and more particularly above 30 are preferably regarded as suffering from obesity.

Apart from physical activity and a change in nutrition, there is currently no convincing treatment option for effectively reducing body weight. However, as obesity is a major risk factor in the development of serious and even life-threatening diseases, it is all the more important to have access to pharmaceutical active substances for the prevention and/or treatment of obesity. One approach which has been proposed very recently is the therapeutic use of MCH antagonists (cf. inter alia WO 01/21577, WO
01/82925).

Melanin-concentrating hormone (MCH) is a cyclic neuropeptide consisting of 19 amino acids. It is synthesised predominantly in the hypothalamus in mammals and from there travels to other parts of the brain by the projections of hypothalamic neurones. Its biological activity is mediated in humans through two different G-protein-coupled receptors (GPCRs) from the family of rhodopsin-related GPCRs, namely the MCH receptors 1 and 2 (MCH-1 R, MCH-2R).

Investigations into the function of MCH in animal models have provided good indications for a role of the peptide in regulating the energy balance, i.e.
changing metabolic activity and food intake [1,2]. For example, after intraventricular administration of MCH in rats, food intake was increased compared with control animals. Additionally, transgenic rats which produce more MCH than control animals, when given a high-fat diet, responded by gaining significantly more weight than animals without an experimentally altered MCH level. It was also found that there is a positive correlation between phases of increased desire for food and the quantity of MCH mRNA

Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 if in the hypothalamus of rats. However, experiments with MCH knock-out mice are particularly important in showing the function of MCH. Loss of the neuropeptide results in lean animals with a reduced fat mass, which take in significantly less food than control animals.

The anorectic effects of MCH are mediated in rodents through the Gds-coupled MCH-1 R [3-6]. Unlike primates, ferrets and dogs, no second receptor has hitherto been found in rodents. After losing the MCH-1 R, knock-out mice have a lower fat mass, an increased energy conversion and, when fed on a high fat diet, do not put on weight, compared with control animals. Another indication of the importance of the MCH-MCH-1 R system in regulating the energy balance results from experiments with a receptor antagonist (SNAP-7941) [3]. In long term trials the animals treated with the antagonist lose significant amounts of weight.

In addition to its anorectic effect, the MCH-1 R antagonist SNAP-7941 also achieves additional anxiolytic and antidepressant effects in behavioural experiments on rats [3]. Thus, there are clear indications that the MCH-MCH-1 R system is involved not only in regulating the energy balance but also in affectivity.

Literature:
1. Qu, D., et al., A role for melanin-concentrating hormone in the central regulation of feeding behaviour. Nature, 1996. 380(6571): p. 243-7.
2. Shimada, M., et al., Mice lacking melanin-concentrating hormone are hypophagic and lean. Nature, 1998. 396(6712): p. 670-4.
3. Borowsky, B., et al., Antidepressant, anxiolytic and anorectic effects of a melanin-concentrating hormone-1 receptor antagonist. Nat Med, 2002.
8(8): p. 825-30.
4. Chen, Y., et al., Targeted disruption of the melanin-concentrating hormone receptor-1 results in hyperphagia and resistance to diet-induced obesity. Endocrinology, 2002. 143(7): p. 2469-77.

Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 ff 5. Marsh, D.J., et al., Melanin-concentrating hormone 1 receptor-deficient mice are lean, hyperactive, and hyperphagic and have altered metabolism. Proc Nab Acad Sci U S A, 2002. 99(5): p. 3240-5.
6. Takekawa, S., et al., T-226296: A novel, orally active and selective melanin-concentrating hormone receptor antagonist. Eur J Pharmacol, 2002. 438(3): p. 129-35.

In the patent literature certain amine compounds are proposed as MCH
antagonists. Thus, WO 01/21577 (Takeda) describes compounds of formula R
Ar- X-Ar-Y-N-wherein Ar' denotes a cyclic group , X denotes a spacer, Y denotes a bond or a spacer, Ar denotes an aromatic ring which may be fused with a non-aromatic ring, R1 and R2 independently of one another denote H or a hydrocarbon group, while R1 and R2 together with the adjacent N atom may form an N-containing hetero ring and R2 with Ar may also form a spirocyclic ring, R together with the adjacent N atom and Y may form an N-containing hetero ring, as MCH antagonists for the treatment of obesity.

Moreover WO 01/82925 (Takeda) also describes compounds of formula R
Ar'-X-Ar-Y-N
\R2 wherein Ar' denotes a cyclic group , X and Y represent spacer groups, Ar denotes an optionally substituted fused polycyclic aromatic ring, R1 and R2 independently of one another represent H or a hydrocarbon group, while R' and R2 together with the adjacent N atom may form an N-containing heterocyclic ring and R2 together with the adjacent N atom and Y may form an N-containing hetero ring, as MCH antagonists for the treatment of obesity, inter alia.

In EP 073 016 Al (Boehringer Ingelheim) 1-aryloxy-3-alkylamino-2-propanols of general formula Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 ff CN

R- CO-N OH

R
wherein R, may represent aryloxyalkylene, inter alia, are proposed for use as cardiac or coronary therapeutic agents or for lowering blood pressure.
However, there is no mention of these compounds having an MCH-antagonistic activity.

US 3,994,900 mentions inter alia n-(4-alkoxy-phenyl)-3-phenyl-acrylamides, n-(4-alkylthio-phenyl)-3-phenyl-acrylamides, n-(4-alkylsulphinyl-phenyl)-3-phenyl-acrylamidse and n-(4-alkylsulphonyl-phenyl)-3-phenyl-acrylamides as starting materials for synthesising dihydroquinolinone derivatives.

DE 1088955 lists inter alia the compounds N-[4-(2-diethylamino-ethoxy)-phenyl]-3-phenyl-acrylamide and N-[4-(2-diethylamino-ethoxy)-phenyl]-3-phenyl-propionamide.

WO 00/06153, which proposes compounds with a CCR5 receptor activity, mentions inter alia the compound 3-(3,4-dichloro-phenyl)-N-[3-(2-diisopropylamino-ethoxy)-4-methoxy-phenyl]-acrylamide.
FR 1176918 mentions the compounds (N-[4-(2-morpholin-4-ylethoxy)-phenyl]-3-phenyl-propionamide) and N-[4-(2-diethylamino-ethoxy)-phenyl]-3-phenyl-propionamide.

In the article by A. P. Tamiz et al., J. Med. Chem. 42 (17), 1999, 3412-3420, the compound (3-(4-chloro-phenyl)-N-{2-[4-(2-diethylamino-ethoxy)-phenyl]-ethyl}-acryl amide) is mentioned.

In DE 3016827, which relates to compounds having an effect on the cardiovascular system, the compounds N-{2-[3-(4-{2-[2-(4-chloro-phenoxy)-acetylamino]-ethyl}-phenoxy)-2-hydroxy-propylamino]-ethyl}-isobutyramide, Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 if cyclopentanecarboxylic acid {2-[3-(4-{2-[2-(4-chloro-phenoxy)-acetylamino]-ethyl}-phenoxy)-2-hydroxy-propylamino]-ethyl}-amide and 2-(4-chloro-phenoxy)-N-(2-{4-[2-hydroxy-3-(2-phenylacetylamino-ethylamino)-propoxy]-phenyl}-ethyl)-acetamide inter alia are mentioned on page 55.

Aim of the invention The aim of the present invention is to discover new amide compounds, particularly those which have an activity as MCH antagonists.

A further aim of the invention is to provide new amide compounds which make it possible to influence the eating behaviour of mammals and in particular achieve a reduction in body weight and/or prevent an increase in body weight in mammals.

The present invention further sets out to provide new pharmaceutical compositions which are suitable for the prevention and/or treatment of symptoms and/or diseases caused by MCH or otherwise causally connected to MCH. In particular, the aim 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 which are associated with obesity and diabetes. Other objectives of the present invention are concerned with demonstrating advantageous uses of the compounds according to the invention. The invention also sets out to provide a process for preparing the amide compounds according to the invention. Other aims of the present invention will be immediately apparent to the skilled man from the foregoing remarks and those that follow.

Subject matter of the invention A first object of the present invention comprises amide compounds of general formula I

Amide compounds of general formula I

Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 if R O
RZiN-X-Y- Z -N-C-W-A4B ~b I

wherein R1, R2 independently of one another denote H, a C1.8-alkyl or C3_7-cycloalkyl group optionally substituted by the group R11, while a -CH2- group in position 3 or 4 of a 5-, 6- or 7-membered cycloalkyl group may be replaced by -0-, -S-, -NH-, -N(C1.4-alkyl)- or -N(CO-O-C1.-alkyl)-, or a phenyl or pyridinyl group optionally mono- or polysubstituted by the group R12 and/or monosubstituted by nitro, or R1 and R2 form a C2_8-alkylene bridge wherein - one or two -CH2- groups may be replaced independently of one another by -CH=N- or -CH=CH- and/or - one or two -CH2- groups may be replaced independently of one another by -0-, -S-, -SO-, -(SO2)-, -C=N-O-R18-, -CO-, -C(=CH2)- or -NR13- in such a way that heteroatoms are not directly connected to one another, while in the above-defined alkylene bridge one or more H atoms may be replaced by R14, and while the above-defined alkylene bridge may be substituted by one or two identical or different carbo- or heterocyclic groups Cy in such a way that the bond between the alkylene bridge and the group Cy is formed - via a single or double bond, - via a common C atom forming a spirocyclic ring system, - via two common, adjacent C and/or N atoms forming a fused bicyclic ring system or Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 ff - via three or more C and/or N atoms forming a bridged ring system, R3 denotes H, C1-6-alkyl, C3-7-cycloalkyl or C3-7-cycloalkyl-C1 -alkyl , X denotes a C1-8-alkylene bridge wherein - a -CH2- group may be replaced by -CH=CH- or -C-=C- and/or - one or two -CH2- groups may be replaced independently of one another by -0-, -S-, -(SO)-, -(SO2)-, -CO- or -NR4- in such a way that in each case two 0, S or N atoms or an 0 and an S atom are not directly connected to one another, while the bridge X may be attached to R' including the N atom attached to R1 and X forming a heterocyclic group, while the bridge X may additionally also be attached to R2 , including the N-atom attached to R2 and X , forming a heterocyclic group, and two C atoms or one C and one N atom of the alkylene bridge may be joined together by an additional C1-4-alkylene bridge, and a C atom may be substituted by R10 and/or one or two C atoms in each case may be substituted with one or two identical or different substituents selected from C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C3-7-cycloalkyl, C3-7-cycloalkyl-C1-3-alkyl, C4-7-cycloalkenyl and C4-7-cycloalkenyl-C1_3-alkyl, while two alkyl and/or alkenyl substituents may be joined together, forming a carbocyclic ring system, and W is selected from among -CR6aR6b-O-, -CR7a=CR7c-, -CR6aR6b-NR8-, -CR7aR7b-CR7CR7d- and -NR8-CR6aR6b_ Z denotes a single bond, C1-1-alkylene, wherein two adjacent C
atoms may be joined together with an additional C1.4-alkylene bridge, Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 ff while a C atom of the alkylene bridge may be substituted with R10 and/or one or two C atoms independently of one another may be substituted with one or two identical or different C1-6-alkyl groups, while two alkyl groups may be joined together, forming a carbocyclic ring, and Y denotes one of the meanings given for Cy, while R1 may be attached to Y including the group X and the N
atom attached to R1 and X , forming a heterocyclic group fused to Y, and/or X may be attached to Y forming a carbo- or heterocyclic group fused to Y, and A denotes one of the meanings given for Cy, B denotes one of the meanings given for Cy, b denotes the value 0 or 1, Cy denotes a carbo- or heterocyclic group selected from one of the following meanings a saturated 3- to 7-membered carbocyclic group, an unsaturated 4- to 7-membered carbocyclic group, a phenyl group, a saturated 4- to 7-membered or unsaturated 5- to 7-membered heterocyclic group with an N, 0 or S atom as heteroatom, a saturated or unsaturated 5- to 7-membered heterocyclic group with two or more N atoms or with one or two N atoms and an 0 or S atom as heteroatoms, Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 ff - an aromatic heterocyclic 5- or 6-membered group with one or more identical or different heteroatoms selected from N, 0 and/or S, while the above-mentioned 4-, 5-, 6- or 7-membered groups may be attached via two common, adjacent C atoms fused to a phenyl or pyridine ring, and in the above-mentioned 5-, 6- or 7-membered groups one or two non-adjacent -CH2- groups may be replaced independently of one another by a -CO-, -C(=CH2)-, -(SO)- or -(SO2)- group, and the above-mentioned saturated 6- or 7-membered groups may also be present as bridged ring systems with an imino, N-(Ct.4-alkyl)-imino, methylene, C1-4-alkyl-methylene or di-(C1-4-alkyl)-methylene bridge, and the above-mentioned cyclic groups may be mono- or polysubstituted at one or more C atoms with R20, in the case of a phenyl group they may also additionally be monosubstituted with nitro, and/or one or more NH groups may be substituted with R21, R4 has one of the meanings given for R17, C2-6-alkenyl or C3-6-alkynyl, R6a R6b denotes H, C1-4-alkyl or CF3, R7a R7b R7o, R7d denotes H, F, C1-4-alkyl or CF3, R8 denotes H, C1-4-alkyl, C3-7-cycloalkyl or C3-7-cycloalkyl-C1-3-alkyl, Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 if R10 denotes hydroxy, w-hydroxy-Cl-3-alkyl, C1-4-alkoxy, w-(C1.4-alkoxy)-C1_3-alkyl, carboxy, C1.4-alkoxycarbonyl, amino, C1-4-alkyl-amino, di-(C1-a-alkyl)-amino, cyclo-C3_6-alkyleneimino, amino-C1.3-alkyl, C1-4-alkyl-amino-Cl.3-alkyl, di-(C1-a-alkyl)-amino-Cl-3-alkyl, cyclo-C3.6-alkyleneimino-C1.3-alkyl, amino-C1_3-alkoxy, C1-1-alkyl-amino-C1.3-alkoxy, di-(C1_4-alkyl)-amino-C1.3-alkoxy or cyclo-C3.6-alkyleneimino-C1.3-alkoxy, aminocarbonyl, C1.4-alkyl-aminocarbonyl, di-(C1-4-alkyl)-aminocarbonyl or cyclo-C3-,,-alkyleneimino-carbonyl, R11 denotes C2_6-alkenyl, C2_6-alkynyl, R15-O, Rt5-O-CO, R15-CO-O, R16R17N, R18R19N-CO or Cy, R12 has one of the meanings given for R20, R13 has one of the meanings given for R17, with the exception of carboxy, R14 denotes halogen, C1.6-alkyl, C2_6-alkenyl, C2_6-alkynyl, R15-O, R15-O-CO, R15-CO, R15-CO-O, R16R17N, R18R19N-CO, R15-O-C1.3-alkyl, R15-O-CO-C1.3-alkyl, R15-O-CO-NH, R15-SO2-NH, R15-O-CO-NH-C1_ 3-alkyl-, R15-SO2-NH-C1.3-alkyl-, R15-CO-C1.3-alkyl, R15-CO-O-C1.3-alkyl, R16R17N-C1.3-alkyl, R18R19N-CO-C1.3-alkyl or Cy-C1.3-alkyl, R15 denotes H, C1_4-alkyl, C3_7-cycloalkyl, C3_7-cycloalkyl-C1.3-alkyl, phenyl, phenyl-C1.3-alkyl, pyridinyl or pyridinyl-C1.3-alkyl, R16 denotes H, C1_6-alkyl, C3_7-cycloalkyl, C3_7-cycloalkyl-C1_3-alkyl, C4_7-cycloalkenyl, C4_7-cycloalkenyl-C1.3-alkyl, w-hydroxy-C2_3-alkyl, w-(C1-4-alkoxy)-C2_3-alkyl, amino-C2-6-alkyl, C1.4-alkyl-amino-C2-6-alkyl, di-(C1-4-alkyl)-amino-C2_6-alkyl or cyclo-C3.6-alkyleneimino-C2.6-alkyl, Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 ff R17 has one of the meanings given for R16 or denotes phenyl, phenyl-C1.3-alkyl, pyridinyl, dioxolan-2-yl, -CHO, C1.4-alkylcarbonyl, carboxy, hydroxycarbonyl-C1.3-alkyl, C1.4-alkoxycarbonyl, C1.4-alkoxycarbonyl-C1_3-alkyl, C1-4-alkylcarbonylamino-C2.3-alkyl, N-(C1-4-alkylcarbonyl)-N-(C1-4-alkyl)-amino-C2.3-alkyl, C1-4-alkylsulphonyl, C1.4-alkylsulphonylamino-C2_3-alkyl or N-(C1-4-alkylsulphonyl)-N(C1.4-alkyl)-amino-C2_3-alkyl R18, R19 independently of one another denote H or C1.6-alkyl, R20 denotes halogen, hydroxy, cyano, C1.6-alkyl, C2.6-alkenyl, C2-6-alkynyl, C3.7-cycloalkyl, C3_7-cycloalkyl-C1.3-alkyl, hydroxy-C1 -alkyl, R22-C1.3-alkyl or one of the meanings given for R22, R21 denotes C1.4-alkyl, w-hydroxy-C2_3-alkyl, w-C1.4-alkoxy-C2.6-alkyl, w-C1_4-alkyl-amino-C2.6-alkyl, w-di-(C1.4-alkyl)-amino-C2_6-alkyl, w-cyclo-C3_6-alkyleneimino-C2_6-alkyl, phenyl-C1.3-alkyl, C1-4-alkyl-carbonyl, C1-4-alkoxy-carbonyl or C14-alkylsulphonyl, R22 denotes phenyl-C1.3-alkoxy, OHC, HO-N=HC, C1-4-alkoxy-N=HC, C1.4-alkoxy, C1.4-alkylthio, carboxy, C1-4-alkylcarbonyl, C1.4-alkoxycarbonyl, aminocarbonyl, C1-4-alkylaminocarbonyl, di-(C1_4-alkyl)-aminocarbonyl, cyclo-C8_6-alkyl-amino-carbonyl, cyclo-C3_6-alkyleneimino-carbonyl, cyclo-C3-6-alkyleneimino-C24-alkyl-aminocarbonyl, phenyl-amino-carbonyl, C1.4-alkyl-sulphonyl, C14-alkyl-sulphinyl, C1.4-alkyl-sulphonylamino, amino, C1_4-alkylamino, di-(C1.4-alkyl)-amino, C1_4-alkyl-carbonyl-amino, cyclo-C3_6-alkyleneimino, phenyl-C1.3-alkylamino or N-(C1.4-alkyl)-phenyl-C1.3-alkylamino, acetylamino, propionylamino, phenylcarbonylamino, phenylcarbonylmethylamino, hydroxy-alkylaminocarbonyl, (4-morpholinyl)carbonyl, (1-pyrrolidinyl)-Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 if carbonyl, (1-piperidinyl)carbonyl, (hexahydro-1-azepinyl)carbonyl, (4-methyl-1-piperazinyl)carbonyl, methylenedioxy, aminocarbonyl-amino or alkylaminocarbonylamino, while in the above-mentioned groups and residues, especially in A, B, W, X, Y, Z, R' to Ra Rsa, R6b R'a, R7b, R'0, R'd, R8, R10 to R22, in particular, in each case one or more C atoms may additionally be mono- or polysubstituted by F
and/or in each case one or two C atoms may additionally be monosubstituted by Cl or Br independently of one another and/or in each case one or more phenyl rings may additionally, independently of one another, have one, two or three substituents selected from among F, Cl, Br, I, C1-4-alkyl, C1-4-alkoxy, difluoromethyl, trifluoromethyl, hydroxy, amino, C1-3-alkylamino, di-(C1_3-alkyl)-amino, acetylamino, aminocarbonyl, cyano, difluoromethoxy, trifluoromethoxy, amino-C1_3-alkyl, C1.3-alkylamino-C1.3-alkyl- and di-(C1.3-alkyl)-amino-C1_3-alkyl and/or may be monosubstituted by nitro, and the H atom of any carboxy group present or an H atom bonded to an N atom may each be replaced by a group which can be cleaved in vivo, the tautomers, the diastereomers, the enantiomers, the mixtures thereof and the salts thereof, with the following provisos (Ml), (M2) and (M3) (Ml) in the event that Y denotes phenylene substituted with -CN, X denotes -CH2-CH(OH)-CH2-O-, Z denotes a single bond, R' denotes a straight-chain or branched alkyl group with 1 to 10 C atoms and R2 and R3 represent H, then W does not represent -CR6aR6b-O-, (M2) in the event that W denotes -CH=CH- and Y denotes a phenylene group and Z is a single bond, then the bridges X and Z at the phenylene ring of the group Y are in the para position to one another and at least one of the following conditions is met:
(a) the group Y meaning phenylene is at least monosubstituted, (b) b has the value 0 and the group A is at least disubstituted, (c) b has the value 1;

(M3) the following individual compounds are not included:
N-[4-(2-diethylamino-ethoxy)-phenyl]-3-phenyl-propionamide, N-[4-(2-morpholin-4-ylethoxy)-phenyl]-3-phenyl-propionamide, 3-(4-chloro-phenyl)-N-{2-[4-(2-diethylamino-ethoxy)-phenyl]-ethyl}-acrylamide, N-{2-[3-(4-{2-[2-(4-ch loro-phenoxy)-acetylam ino]-ethyl}-phenoxy)-2-hydroxy-propylamino]-ethyl}-isobutyramide, cyclopentanecarboxylic acid {2-[3-(4-{2-[2-(4-chloro-phenoxy)-acetylamino]-ethyl}-phenoxy)-2-hydroxy-propylamino]-ethyl}-amide, 2-(4-chloro-phenoxy)-N-(2-{4-[2-hydroxy-3-(2-phenylacetylamino-ethylamino)-propoxy]-phenyl}-ethyl)-acetamide.
The invention also relates to the compounds in the form of the individual optical isomers, mixtures of the individual enantiomers or racemates, in the form of the tautomers and in the form of the free bases or the corresponding acid addition salts with pharmacologically safe acids. The subject of the invention also includes the compounds according to the invention, including the salts thereof, wherein one or more hydrogen atoms are replaced by deuterium.

In an aspect, there is provided compound of formula I
R\ I

R2,- N-X-Y-Z-N-C-W-A--E BI b wherein 14a R1, R2 independently of one another denote H, a C1_8-alkyl or C3_7-cycloalkyl group optionally substituted by the group R11, wherein a -CH2-group in position 3 or 4 of a 5-, 6- or 7-membered cycloalkyl group may be replaced by -0-, -S- or -NR13-, or a phenyl or pyridinyl group optionally mono- or polysubstituted by the group R12 and/or monosubstituted by nitro, with the proviso that at least one of the groups R1, R2 has a meaning other than H, or R1 and R2 form a C2_8-alkylene bridge wherein - one or two -CH2- groups may be replaced independently of one another by -CH=N- or -CH=CH- and/or - one or two -CH2- groups may be replaced independently of one another by -0-, -S-, -SO-, -(SO2)-, -C=N-0-R18-, -CO-, -C(=CH2)- or -NR13- in such a way that heteroatoms are not directly connected to one another, wherein in the above-defined alkylene bridge one or more H atoms may be replaced by R14, and wherein the above-defined alkylene bridge may be substituted by one or two identical or different carbo- or heterocyclic groups Cy in such a way that the bond between the alkylene bridge and the group Cy is formed - via a single or double bond, - via a common C atom forming a spirocyclic ring system, - via two common, adjacent C and/or N atoms forming a fused bicyclic ring system or - via three or more C and/or N atoms forming a bridged ring system, R3 denotes H, C1-6-alkyl, C3_7-cycloalkyl or C3_7-cycloalkyl-C1_4-alkyl, X denotes an unbranched C14-alkylene bridge and 14b if the group Y is connected to X via a C atom, it may also denote -CH2-CH=CH-, -CH2-C=C-, C2.4-alkylenoxy or C2_4-alkylene-NR4-, wherein the bridge X may be attached to R' including the N atom attached to R1 and X forming a heterocyclic group, wherein the bridge X may additionally also be attached to R2, including the N-atom attached to R2 and X, forming a heterocyclic group, and a C atom may be substituted by R10 and/or one or two C atoms may each be substituted with one or two identical or different substituents selected from among C1_6-alkyl, C2_6-alkenyl, C2_6-alkynyl, C3_7-cycloalkyl, C3_7-cycloalkyl-C1_3-alkyl, C4_7-cycloalkenyl and C4_7-cycloalkenyl-C1_3-alkyl, wherein two alkyl and/or alkenyl substituents may be joined together, forming a carbocyclic ring system, with the proviso that the group X denoting C24-alkylenoxy does not contain a hydroxy substitutent; and W denotes -CR6aR6b_O-, -CR7a=CR7c , -CR6aR6b-NR8_, -OR7ap7b-CR7cR71_ or -NR8-CR6aR6b_, Z denotes a single bond or C14-alkylene, wherein two adjacent C atoms may be joined together with an additional C1.4-alkylene bridge, wherein a C atom of the alkylene bridge may be substituted with R1 and/or one or two C atoms independently of one another may be substituted with one or two identical or different C1_6-alkyl groups, wherein two alkyl groups may be joined together, forming a carbocyclic ring, and Y is selected from among the bivalent cyclic groups N
N ~~N

14c N
N

and wherein the above-mentioned cyclic groups may be mono- or polysubstituted by R20 at one or more C atoms, and in the case of a phenyl group may also additionally be monosubstituted by nitro, and/or the hydrogen in an NH
group may be replaced by R21, and A denotes one of the meanings given for Cy, B denotes one of the meanings given for Cy, b denotes the value 0 or 1, Cy denotes a carbo- or heterocyclic group selected from one of the following meanings - a saturated 3- to 7-membered carbocyclic group, - an unsaturated 4- to 7-membered carbocyclic group, - a phenyl group, - a saturated 4- to 7-membered or unsaturated 5- to 7-membered heterocyclic group with an N, 0 or S atom as heteroatom, - a saturated or unsaturated 5- to 7-membered heterocyclic group with two or more N atoms or with one or two N atoms and an 0 or S atom as heteroatoms, and 14d - an aromatic heterocyclic 5- or 6-membered group with one or more identical or different heteroatoms selected from N, 0 and/or S, wherein in the above-mentioned Cy, 4-, 5-, 6- or 7-membered groups may be attached via two common, adjacent C atoms fused to a phenyl or pyridine ring, and in the above-mentioned Cy, in 5-, 6- or 7-membered groups one or two non-adjacent -CH2- groups may be replaced independently of one another by a -CO-, -C(=CH2)-, -(SO)- or -(SO2)- group, and the above-mentioned Cy, saturated 6- or 7-membered groups may also be present as bridged ring systems with an imino, N-(C1_4-alkyl)-imino, methylene, C1-4-alkyl-methylene or di-(C1_4-alkyl)-methylene bridge, and the above-mentioned cyclic groups may be mono- or polysubstituted at one or more C atoms with R20, in the case of a phenyl group they may also additionally be monosubstituted with nitro, and/or one or more NH groups may be substituted with R21, R4 denotes H, C1.6-alkyl or C2_6-alkenyl, Rea, R6b denotes H, C1_4-alkyl or CF3, R7a, R7b, R7C, R7d denotes H, F, Cl, C1_4-alkyl or CF3, R8 denotes H, C1.4-alkyl, C3_7-cycloalkyl or C3_7-cycloalkyl-C1_3-alkyl, R10 denotes hydroxy, w-hydroxy-C1.3-alkyl, C1_4-alkoxy, w-(C1.4-alkoxy)-C1_3-alkyl, carboxy, C1.4-alkoxycarbonyl, amino, C1_4-alkyl-amino, di-(C1.4-alkyl)-amino, cyclo-C3_6-alkyleneimino, amino-C1_3-alkyl, C1-4-alkyl-amino-C1.3-alkyl, di-(C1.4-alkyl)-amino-C1_3-alkyl, cyclo-C3_6-alkyleneimino-C1_3-alkyl, amino-C1_3-alkoxy, C1-4-alkyl-amino-C1_3-alkoxy, di-(C1_4-alkyl)-amino-C1_3-alkoxy, cyclo-C3_6-alkyleneimino-C1_3-alkoxy, aminocarbonyl, C14-alkyl-aminocarbonyl, di-(C1.4-alkyl)-aminocarbonyl or cyclo-C3.6-alkyleneimino-carbonyl, 14e R" denotes C2_6-alkenyl, C2_6-alkynyl, R15-O, R15-O-CO, R15-CO-O, R16R17N, R18R19N-CO or Cy, R12 has one of the meanings given for R20, R13 has one of the meanings given for R17, with the exception of carboxy, R14 denotes halogen, C1_6-alkyl, C2_6-alkenyl, C2_6-alkynyl, R15-O, R15-O-CO, R15-CO, R15-CO-O, R16R17N, R'8R19N-CO, R15-O-C1-3-alkyl, R15-O-CO-C1_3-alkyl, R15-O-CO-NH, R15-SO2-NH, R15-O-CO-NH-C1.3-alkyl, R'5-S02-NH-C1_3-alkyl-, R15-CO-C1.3-alkyl, R15-CO-O-C1.3-alkyl, R16R17N-C1.3-alkyl, R'8R19N-CO-C1_3-alkyl or Cy-C1_3-alkyl, R15 denotes H, C1_4-alkyl, C3.7-cycloalkyl, C3_7-cycloalkyl-C1_3-alkyl, phenyl, phenyl-C1_3-alkyl, pyridinyl or pyridinyl-C1.3-alkyl, R16 denotes H, C1-6-alkyl, C3_7-cycloalkyl, C3_7-cycloalkyl-Cl.3-alkyl, C4_7-cycloalkenyl, C4_7-cycloalkenyl-C1_3-alkyl, u-hydroxy-C2_3-alkyl, w-(C1-4-alkoxy)-C2_3-alkyl, amino-C2_6-alkyl, C1_4-alkyl-amino-C2-6-alkyl, di-(C1-4-alkyl)-amino-C2_6-alkyl or cyclo-C3_6-alkyleneimino-C2 6-alkyl, R17 has one of the meanings given for R16 or denotes phenyl, phenyl-C1_3-alkyl, pyridinyl, dioxolan-2-yl, -CHO, C1-4-alkylcarbonyl, carboxy, hydroxycarbonyl-Cl-3-alkyl, C1-4-alkoxycarbonyl, C1-4-alkoxycarbonyl-Cl-3-alkyl, C1_4-alkylcarbonylamino-C2.3-alkyl, N-(C1_4-alkylcarbonyl)-N-(C1-4-alkyl)-amino-C2_3-alkyl, C1-4-alkylsulphonyl, C1-4-alkylsulphonylamino-C2_3-alkyl or N-(C1_4-alkylsulphonyl)-N(C1-4-alkyl)-amino-C2_3-alkyl, R18, R19 independently of one another denote H or C1-6-alkyl, R20 denotes halogen, hydroxy, cyano, C1_6-alkyl, C2_6-alkenyl, C2_6-alkynyl, C3_7-cycloalkyl, C3_7-cycloalkyl-C1_3-alkyl, hydroxy-CI.4-alkyl, R22-C 1.3-alkyl or one of the meanings given for R, 14f R21 denotes C1.4-alkyl, co-hydroxy-C2_3-alkyl, co-C1 -alkoxy-C2_6-alkyl, w-C1_4-alkyl-amino-C2_6-alkyl, w-di-(C1-4-alkyl)-amino-C2_6-alkyl, w-cyclo-C3.-alkyleneimino-C2-6-alkyl, phenyl-C1_3-alkyl, C1_4-alkylcarbonyl, C1-4-alkoxy-carbonyl or C1-4-alkylsulphonyl, R22 denotes phenyl-C1_3-alkoxy, OHC, HO-N=HC, C14-alkoxy-N=HC, C1-4-alkoxy, C1_4-alkylthio, carboxy, C14-alkylcarbonyl, C1-4-alkoxycarbonyl, aminocarbonyl, C1-4-alkylaminocarbonyl, di-(C1-4-alkyl)-aminocarbonyl, cyclo-C3.6-alkyl-amino-carbonyl, cyclo-C3.6-alkyleneimino-carbonyl, cyclo-C3_6-alkyleneimino-C2_4-alkyl-aminocarbonyl, phenyl-amino-carbonyl, C1_4-alkyl-sulphonyl, C1.4-alkyl-sulphinyl, C1.4-alkyl-sulphonylamino, amino, C1_4-alkylamino, di-(C1.4-alkyl)-amino, C1_4-alkyl-carbonyl-amino, cyclo-C3.6-alkyleneimino, phenyl-C1_3-alkylamino, N-(C1.4-alkyl)-phenyl-CI_3-alkylamino, acetylamino, propionylamino, phenylcarbonylamino, phenylcarbonylmethylamino, hydroxy-alkylaminocarbonyl, (4-morpholinyl)carbonyl, (1-pyrrolidinyl)-carbonyl, (1-piperidinyl)carbonyl, (hexahydro-1-azepinyl)carbonyl, (4-methyl-1-piperazinyl)carbonyl, methylenedioxy, aminocarbonylamino or alkylaminocarbonylamino, wherein in the above-mentioned groups and residues in A, B, W, X, Y, Z, R1 to R4, R6a, Rsb, R7a, R7b, 7C R7d, R8, R10 to R22, one or more C atoms in each case may additionally be mono- or polysubstituted by F and/or one or two C
atoms in each case may additionally be monosubstituted by Cl or Br independently of one another and/or one or more phenyl rings in each case may additionally, independently of one another, have one, two or three substituents selected from among F, Cl, Br, I, C1.4-alkyl, C1_4-alkoxy, difluoromethyl, trifluoromethyl, hydroxy, amino, C1_3-alkylamino, di-(C1_3-alkyl)-amino, acetylamino, aminocarbonyl, cyano, difluoromethoxy, trifluoromethoxy, amino-C1_3-alkyl, C1_3-alkylamino-C1_3-alkyl and di-(C1_3-alkyl)-amino-C1_3-alkyl and/or may be monosubstituted by nitro, and the H atom of any carboxy group present or an H atom bonded to an N atom may each be replaced by a group which can be cleaved in vivo, 14g a tautomer, diastereomer or enantiomer thereof, a mixture thereof or a salt thereof, with the following provisos (M2) and (M3) (M2) in the event that W denotes -CH=CH- and Y denotes a phenylene group and Z is a single bond, then the bridges X and Z at the phenylene ring of the group Y are in the para position to one another and at least one of the following conditions is met:

(a) the group Y meaning phenylene is at least monosubstituted, (b) b has the value 0 and the group A is at least disubstituted, and (c) b has the value 1;

(M3) the following individual compounds are not included:
N-[4-(2-diethylamino-ethoxy)-phenyl]-3-phenyl-propionamide, N-[4-(2-morpholin-4-ylethoxy)-phenyl]-3-phenyl-propionamide, 3-(4-chloro-phenyl)-N-{2-[4-(2-diethylamino-ethoxy)-phenyl]-ethyl}-acrylamide, N-{2-[3-(4-{2-[2-(4-ch loro-phenoxy)-acetylamino]-ethyl}-phenoxy)-2-hydroxy-propylamino]-ethyl}-isobutyramide, cyclopentanecarboxylic acid {2-[3-(4-{2-[2-(4-chloro-phenoxy)-acetylamino]-ethyl}-phenoxy)-2-hydroxy-propylamino]-ethyl}-amide, and 2-(4-chloro-phenoxy)-N-(2-{4-[2-hydroxy-3-(2-phenylacetylamino-ethylam ino)-propoxy]-phenyl}-ethyl)-acetamide.

This invention also includes the physiologically acceptable salts of the amide compounds according to the invention as described above and hereinafter.

14h This invention also relates to compositions containing at least one amide compound according to the invention and/or a salt according to the invention optionally together with one or more physiologically acceptable excipients.

Also covered by this invention are pharmaceutical compositions containing at least one amide compound according to the invention and/or a salt according to the invention optionally together with one or more inert carriers and/or diluents.

Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 ff This invention also relates to the use of at least one amide compound according to the invention and/or a salt according to the invention, including the compounds excluded by provisos (Ml), (M2) and (M3) , for influencing the eating behaviour of a mammal.

The invention further relates to the use of at least one amide compound according to the invention and/or a salt according to the invention, including the compounds excluded by provisos (Ml), (M2) and (M3) , for reducing the body weight and/ or for preventing an increase in the body weight of a mammal.

The invention also relates to the use of at least one amide compound according to the invention and/or a salt according to the invention, including the compounds excluded by provisos (Ml), (M2) and (M3), for preparing a pharmaceutical composition with an MCH receptor-antagonistic activity, particularly with an MCH-1 receptor-antagonistic activity.

This invention also relates to the use of at least one amide compound according to the invention and/or a salt according to the invention, including the compounds excluded by provisos (Ml), (M2) and (W), for preparing a pharmaceutical composition which is suitable for the prevention and/or treatment of symptoms and/or diseases which are caused by MCH or are otherwise causally connected with MCH.

A further object of this invention is the use of at least one amide compound according to the invention and/or a salt according to the invention, including the compounds excluded by provisos (Ml), (M2) and (M3) , for preparing a pharmaceutical composition which is suitable for the prevention and/or treatment of metabolic disorders and/or eating disorders, particularly obesity, bulimia, bulimia nervosa, cachexia, anorexia, anorexia nervosa and hyperphagia Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 ff The invention also relates to the use of at least one amide compound according to the invention and/or a salt according to the invention, including the compounds excluded by provisos (M1), (M2) and (M3) , for preparing a pharmaceutical composition which is suitable for the prevention and/or treatment of diseases and/or disorders associated with obesity, particularly diabetes, especially type II diabetes, complications of diabetes including diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, pathological glucose tolerance, encephalorrhagia, cardiac insufficiency, cardiovascular diseases, particularly arteriosclerosis and high blood pressure, arthritis and gonitis.

In addition the present invention relates to the use of at least one amide compound according to the invention and/or a salt according to the invention, including the compounds excluded by provisos (Ml), (M2) and (M3) , for preparing a pharmaceutical composition which is suitable for the prevention and/or treatment of hype rlipidaemia, cellulitis, fat accumulation, malignant mastocytosis, systemic mastocytosis, emotional disorders, affective disorders, depression, anxiety, sleep disorders, reproductive disorders, sexual disorders, memory disorders, epilepsy, forms of dementia and hormonal disorders.

The invention also relates to the use of at least one amide compound according to the invention and/or a salt according to the invention, including the compounds excluded by provisos (Ml), (M2) and (M3) , for preparing a pharmaceutical composition which is suitable for the prevention and/or treatment of urinary problems, such as for example urinary incontinence, overactive bladder, urgency, nycturia and enuresis.

The invention further relates to processes for preparing for preparing a pharmaceutical composition according to the invention, characterised in that at least one amide compound according to the invention and/ or a salt according to the invention is incorporated in one or more inert carriers and/or diluents by a non-chemical method.

Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 if The invention also relates to a pharmaceutical composition containing a first active substance which is selected from the amide compounds according to the invention and/or the corresponding salts, including the compounds excluded by provisos (Ml), (M2) and (M3), 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 other than MCH antagonists, active substances for the treatment of high blood pressure, active substances for the treatment of hyperlipidaemia, including arteriosclerosis, active substances for the treatment of arthritis, active substances for the treatment of anxiety states and active substances for the treatment of depression, optionally together with one or more inert carriers and/or diluents.

Detailed Description of the invention Unless otherwise specified the groups, residues and substituents, particularly A, B, W, X, Y, Z, R' to Ra R 6a, R6b, R7a R7b R7c R7d R8 R10 to R22, and index b, have the meanings given hereinbefore.

According to one embodiment the groups R1, R2, X, Z, b, R10, R14, R15, R17, R20, R21, R22 have the following meanings:

R', R2 independently of one another denote H, a C1-8-alkyl or C3_7-cycloalkyl group optionally substituted by the group R11, or a phenyl group optionally mono- or polysubstituted by the group R12 and/or monosubstituted by nitro, or R1 and R2 form a C2_8-alkylene bridge wherein - one or two -CH2- groups independently of one another may be replaced by -CH=N- or -CH=CH- and/or - one or two -CH2- groups independently of one another may be replaced by -0-, -S-, -CO-, -C(=CH2)-or -NR13- so that heteroatoms are not directly connected to one another, Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 if while in the alkylene bridge defined above one or more H atoms may be replaced by R14, and while the alkylene bridge defined hereinbefore may be substituted with one or two identical or different carbo- or heterocyclic groups Cy so that the bond between the alkylene bridge and the group Cy is made - via a single or double bond, - via a common C atom forming a spirocyclic ring system, - via two common adjacent C and/or N atoms forming a fused bicyclic ring system or - via three or more C and/or N atoms forming a bridged ring system, X denotes a C1_8-alkylene bridge wherein - a -CH2- group may be replaced by -CH=CH- or -C=C- and/or - one or two -CH2- groups may be replaced independently of one another by -0-, -S-, -(SO)-, -(SO2)-, -CO- or -NR4- in such a way that in each case two O, S or N atoms or an 0 and an S atom are not directly joined together, while the bridge X may be connected to R1 including the N
atom attached to R1 and X forming a heterocyclic group, and two C atoms or a C and an N atom of the alkylene bridge may be joined together by an additional C1-a-alkylene bridge, and a C atom may be substituted by R10 and/or one or two C atoms in each case may be substituted by one or two identical or different C1-6-alkyl groups, and Z denotes a single bond, C1_4-alkylene, wherein two adjacent C
atoms may be joined together by an additional C1-4-alkylene Boehringer ingelheim CA 02504207 2005-04-28 Case 1-1407 if bridge, while a C atom of the alkylene bridge may be substituted by R10 and/or one or two C atoms independently of one another may be substituted by one or two identical or different C1-6-alkyl groups, and b has the value 0, R10 denotes hydroxy, w-hydroxy-Cl.3-alkyl, C1-4-alkoxy, w-(C1_4-alkoxy)-C1.3-alkyl, amino, C1-4-alkyl-amino, di-(C1-4-alkyl)-amino, cyclo-C3_6-alkyleneimino, amino-C1.3-alkyl, C14-alkyl-amino-Cl.3-alkyl, di-(C1-4-alkyl)-amino-Cl.3-alkyl, cyclo-C3_6-alkyleneimino-C1.3-alkyl, amino-Cl.3-alkoxy, C1_4-alkyl-amino-C1_3-alkoxy, di-(C1.4-alkyl)-amino-Cl.3-alkoxy or cyclo-C3.6-alkyleneimino-C1.3-alkoxy, R14 denotes halogen, C1.6-alkyl, R15-O, R15-O-CO, R15-CO, R15-CO-O R16R17N R18R19N-CO, R15-O-C1.3-alkyl- , R15-O-CO-C1-3-alkyl, R15-CO-C1.3-alkyl, R15-CO-O-C1.3-alkyl, R16R17N-C1.3-alkyl, R18R19N-CO-C1.3-alkyl or Cy-C1.3-alkyl, R15 denotes H, C1.4-alkyl, C3_7-cycloalkyl, C3_7-cycloalkyl-C13-alkyl, phenyl or phenyl-Cl.3-alkyl, R17 has one of the meanings given for R16 or denotes phenyl, phenyl-C1.3-alkyl, C1-4-alkylcarbonyl, hydroxycarbonyl-C1.3-alkyl, C1.4-alkylcarbonylamino-C2_3-alkyl, N-(C1-4-alkylcarbonyl)-N-(C1-4-alkyl)-amino-C2.3-alkyl, C1-4-alkylsulphonyl, C1_4-alkylsulphonylamino-C2.3-alkyl or N-(C1.4-alkylsulphonyl)-N(C1_4-alkyl)-amino-C2.3-alkyl, Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 if R20 denotes halogen, hydroxy, cyano, C1-6-alkyl, C3_7-cycloalkyl, C3_7-cycloalkyl- C1.3-alkyl, hydroxy-C1 -alkyl, R22-C1.3-alkyl or one of the meanings given for R22, R21 denotes C1.4-alkyl, w-hydroxy-C2.3-alkyl, w-C1-4-alkoxy-C2-6-alkyl, w-C1.4-alkyl-amino-C2-6-alkyl, w-di-(C1-4-alkyl)-amino-C2_6-alkyl, w-cyclo-C3.6-alkyleneimino-C2-6-alkyl, phenyl, phenyl-C1.3-alkyl, C1.4-alkyl-carbonyl, carboxy, C1-4-alkoxy-carbonyl or C1.4-alkylsulphonyl, R22 denotes phenyl, phenyl-C1.3-alkoxy, C1.4-alkoxy, C1-4-alkylthio, carboxy, C1-4-alkylcarbonyl, C1-4-alkoxycarbonyl, aminocarbonyl, C1.4-alkylaminocarbonyl, di-(C1_4-alkyl)-aminocarbonyl, cyclo-C3.6-alkyleneimino-carbonyl, C1-4-alkyl-sulphonyl, C1-4-alkyl-sulphinyl, C1.4-alkyl-sulphonylamino, amino, C,.4-alkylamino, di-(C1-4-alkyl)-amino, cyclo-C3_6-alkyleneimino, phenyl-C1.3-alkylamino or N-(C1.4-alkyl)-phenyl-C1_3-alkylamino, acetylamino, propionylamino, phenylcarbonylamino, phenylcarbonylmethylamino, hydroxyalkylaminocarbonyl, (4-morpholinyl)carbonyl, (1-pyrrolidinyl)carbonyl, (1-piperidinyl)carbonyl, (hexahydro-1-azepinyl)carbonyl, (4-methyl-l-piperazinyl)carbonyl, methylenedioxy, aminocarbonylamino or alkylaminocarbonylamino, while the groups and residues R3 Ra R6a, R6b R7a, R7b R7o R7a R8, R11 R12, R16, R18, R19, W, Y, A, Cy have the meanings given hereinbefore.
Preferably the group R3 denotes H or C1.4-alkyl, particularly preferably H or methyl, particularly H.

If R1 and R2 are not joined together via an alkylene bridge, R1 and R2 independently of one another preferably represent a C1_8-alkyl or C3_7-cycloalkyl group optionally substituted by the group R11, while a -CH2- group Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 if in position 3 or 4 of a 5-, 6- or 7-membered cycloalkyl group may be replaced by -0-, -S- or -NH-, -N(C1-4-alkyl)- or -N(CO-O-C1-4-alkyl)-, or a phenyl or pyridinyl group optionally mono- or polysubstituted by the group R12 and/or monosubstituted by nitro, and one of the groups R' and R2 may also represent H.

Preferably the groups R1, R2 independently of one another represent H, C1.6-alkyl, C3-7-cycloalkyl, C3_7-cycloalkyl-C1.3-alkyl, w-hydroxy-C2.3-alkyl, w-(C1.4-alkoxy)-C2_3-alkyl, C1.a-alkoxy-carbonyl-C1.4-alkyl, carboxyl-C1_4-alkyl, amino-C2_4-alkyl, C1-4-alkyl-amino-C2-4-alkyl, di-(C1.4-alkyl)-amino-C2.4-alkyl, cyclo-C3.6-alkyleneimino-C2_4-alkyl, pyrrolidin-3-yl, N-(C1-4-alkyl)-pyrrolidinyl, pyrrolidinyl-C1.3-alkyl, N-(C1.4-alkyl)-pyrrolidinyl-C1.3-alkyl, piperidinyl, N-(C1.4-alkyl)-piperidinyl, piperidinyl-C1_3-alkyl, N-(C1.4-alkyl)-piperidinyl-C1.3-alkyl, phenyl, phenyl-C1_3-alkyl, pyridyl or pyridyl-Cl.3-alkyl, while in the above-mentioned groups and residues one or more C atoms may be mono- or polysubstituted by F and/or one or two C atoms may independently of one another be monosubstituted by Cl or Br, and the phenyl or pyridyl group may be mono- or polysubstituted by the group R12 as hereinbefore defined and/or may be monosubstituted by nitro. Preferred substituents of the above-mentioned phenyl or pyridyl groups are selected from the group F, Cl, Br, I, cyano, C1.4-alkyl, C1-4-alkoxy, difluoromethyl, trifluoromethyl, hydroxy, amino, C1_3-alkylamino, di-(C1_3-alkyl)-amino, acetylamino, aminocarbonyl, difluoromethoxy, trifluoromethoxy, amino-C1_3-alkyl, C1_3-alkylamino-C1.3-alkyl-and di-(C1.3-alkyl)-amino-C1_3-alkyl, while a phenyl group may also be monosubstituted by nitro.

Particularly preferred definitions of the groups R1 and/or R2 are selected from among C1-6-alkyl, C3_7-cycloalkyl, C3_7-cycloalkyl-C1.3-alkyl, w-hydroxy-C2_3-alkyl, w-(C1-4-alkoxy)-C2.3-alkyl, C1-4-alkoxy-carbonyl-C14-alkyl, carboxyl-C14-alkyl, while one of the groups R1 and R2 may also represent H.
Particularly preferably, at least one of the groups R', R2, and most preferably both groups, has a meaning other than H.

Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 if If R1 and R2 form an alkylene bridge, it is preferably a C3_7-alkylene bridge wherein - a -CH2- group not adjacent to the N atom of the R'R2N group may be replaced by -CH=N- or -CH=CH- and/or - a -CH2- group which is preferably not adjacent to the N atom of the R'R2N
group, may be replaced by -0-, -S-, -C(=N-0-R18)-, -CO-, -C(=CH2)- or -NR13-, most preferably by -0-, -S- or -NR13-, in such a way that heteroatoms are not directly connected to one another, while in the alkylene bridge defined above one or more H atoms may be replaced by R14, and the alkylene bridge defined hereinbefore may be substituted by a carbo- or heterocyclic group Cy in such a way that the bond between the alkylene bridge and the group Cy is made - via a single or double bond, - via a common C atom forming a spirocyclic ring system, - via two common adjacent C and/or N atoms forming a fused bicyclic ring system or - via three or more C and/or N atoms forming a bridged ring system.

Also preferably, R1 and R2 form an alkylene bridge in such a way that R'R2N-denotes a group selected from azetidine, pyrrolidine, piperidine, azepan, 2,5-dihydro-1 H-pyrrole, 1,2,3,6-tetrahydro-pyridine, 2,3,4,7-tetrahydro-1 H-azepine, 2,3,6,7-tetrahydro-1 H-azepine, piperazine, wherein the free imine function is substituted by R13, piperidin-4-one, piperidin-4-one-oxime, piperidin-4-one-O-C1_4-alkyl-oxime, morpholine and thiomorpholine, while according to the general definition of R1 and R2 one or more H atoms may be replaced by R14, and/ or the above-mentioned groups may be substituted by one or two identical or different carbo- or heterocyclic groups Cy in a manner specified according to the general definition of R1 and R2. Particularly preferred groups Cy are C3_7-cycloalkyl, aza-C4.7- cycloalkyl, particularly cyclo-C3_6-alkyleneimino, as well as 1-C1-4-alkyl-aza-C4_7-cycloalkyl.

Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 ff The C2.8-alkylene bridge formed by R' and R2 wherein -CH2- groups may be replaced as specified may be substituted by one or two identical or different carbo- or heterocyclic groups Cy as described.

If the alkylene bridge is linked to a group Cy via a single bond, Cy is preferably selected from among C3-7-cycloalkyl, cyclo-C3_6-alkyleneimino, 1 H-imidazol, thienyl and phenyl.

If the alkylene bridge is linked to a group Cy via a common C atom forming a spirocyclic ring system, Cy is preferably selected from among C3.7-cycloalkyl, aza-C4.8-cycloalky, oxa-C4-8-cycloalkyl, 2, 3-dihydro-1 H-quinazolin-4-one.

If the alkylene bridge is linked to a group Cy via two common adjacent C
and/or N atoms forming a fused bicyclic ring system, Cy is preferably selected from among C4-7-cycloalkyl, phenyl, thienyl.

If the alkylene bridge is linked to a group Cy via three or more C and/or N
atoms forming a bridged ring system, Cy preferably denotes C4-8-cycloalkyl or aza-C4-8-cycloalkyl.

X
R'-N~
Preferably, the group is defined according to one of the following partial formulae N-X- ON -X CN -X

CNXH
C
N-X- CN-XH

Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 if N-X aN N-X-;
N R1 O, N-X-; N- N-X
0 N-X-, N-X--I N-X

S\--/ -X~ N
, N-X-;
2R?N N-X- N-X
Rz1iN
CN N-X- CN N-X

N-X N-X!;
ON
N-X--T
NN-X-+ N-X--T
N N~~

Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 if N
N-X

N R21N N-X~
N-X

R2\
N N-X
N :Dc R21 i N-X

N-X-' Rz~ N N-X-T

OJON-X-R_-N--X"-4 R? N R? N
X"
X' R? N R? N
X
X' N
N NI N
x1l X

Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 if wherein one or more H atoms of the heterocycle formed by the group R'R2N-may be replaced by R14 and the ring attached to the heterocycle formed by the group R'R2N- may be mono- or polysubstituted by R20 at one or more C
atoms, and in the case of a phenyl ring it may also additionally be monosubstituted by nitro and X', X" independently of one another denote a single bond or C1_3-alkylene and if the group Y is linked to X or X" via a C atom, may also denote -C1_3-alkylene-O-, -C1-3-alkylene-NH- or -C1-3-alkylene-N(C1-3-alkyl)-, and X" may additionally also denote -O-C1.3-alkylene-, -NH-C1-3-alkylene-or -N(C1_3-alkyl)-C1-3-alkylene- and if the group Y is linked to X" via a C atom, may also denote -NH-, -N(C1-3-alkyl)- or -0-, while in the definitions given hereinbefore for X', X" in each case a C atom may be substituted by R10, preferably by a hydroxy, c0-hydroxy-C1_3-alkyl, w-(C1-4-alkoxy)-C1.3-alkyl and/or C1-4-alkoxy group, and/or one or two C atoms in each case may be substituted by one or two identical or different substituents selected from C1.6-alkyl, C2_6-alkenyl, C2-6-alkynyl, C3.7-cycloalkyl, C3-7-cycloalkyl-C1_3-alkyl, C4-7-cycloalkenyl and C4-7-cycloalkenyl-C1-3-alkyl, while two alkyl and/or alkenyl substituents may be joined together forming a carbocyclic ring system, and in X, X" independently of one another 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 independently of one another may be Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 if monosubstituted by Cl or Br and wherein R2, R10, R13, R14, R18, R20, R21 and X have the meanings given hereinbefore and hereinafter.

In the preferred and particularly preferred definitions of R'R2N listed above the following definitions of the substituent R14 are preferred: C14-alkyl, C2-4-alkenyl, C24-alkynyl, C3-7-cycloalkyl, C8_7-cycloalkyl-C1_3-alkyl, hydroxy, c.0-hydroxy-C1.3-alkyl, C1.4-alkoxy, w-(C1.4-alkoxy)-C1-3-alkyl, C1-4-alkyl-carbonyl, carboxy, C1.4-alkoxycarbonyl, hydroxy-carbonyl-C1_3-alkyl, C1_4-alkoxycarbonyl-C1.3-alkyl, C1_4-alkoxy-carbonylamino, C1-4-alkoxy-carbonylamino-C1.3-alkyl, amino, C1-4-alkyl-amino, C3.7-cycloalkyl-amino, N-(C3_7-cycloalkyl)-N-(C1.4-alkyl)-amino, di-(C1-4-alkyl)-amino, amino-C1_3-alkyl, C1_4-alkyl-amino-C1.3-alkyl, C3_7-cycloalkyl-amino-C1.3-alkyl, N-(C3-7-cycloalkyl)-N-(C1-4-alkyl)-amino-C1_3-alkyl, di-(C1-4-alkyl)-amino-C1 3-alkyl, cyclo-C3-6-alkyleneimino-C1.3-alkyl, aminocarbonyl, C1-4-alkyl-amino-carbonyl, C3_7-cycloalkyl-amino-carbonyl, N-(C$_7-cycloalkyl)-N-(C1-4-alkyl)-amino-carbonyl, di-(C1.4-alkyl)-amino-carbonyl, pyridinyl-oxy, pyridinyl-amino, pyridinyl-C1_3-alkyl-amino.

Most particularly preferred definitions of the substituent R14 are C1.4-alkyl, hydroxy, w-hydroxy-Cl.3-alkyl, C14-alkoxy, w-(C1.4-alkoxy)-C1_3-alkyl, amino-C1_3-alkyl, C1.4-alkyl-amino-C1_3-alkyl, C3_7-cycloalkyl-amino-C1-3-alkyl, N-(C3-7-cycloalkyl)-N-(C1-4-alkyl)-amino-C1.3-alkyl, di-(C1-4-alkyl)-amino-Cl-3-alkyl-and cyclo-C3_6-alkyleneimino-C1_3-alkyl.

Preferably X denotes a C1-6-alkylene bridge wherein - a -CH2- group not adjacent to the N atom of the R1R2N group may be replaced by -CH=CH- or -C-C- and/or - a -CH2- group not adjacent to the N atom of the R'R2N group may be replaced by -0-, -S-, -CO- or -NR 4_' particularly preferably by -0-, -S- or -NR4-, in such a way that in each case two 0, S or N atoms or an 0 and an S atom are not directly joined together, Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 ff while R4 and Y may be joined together forming a heterocyclic ring system, while the bridge X may be connected to R1 including the N atom attached to R1 and X, forming a heterocyclic group, while the bridge X may additionally also be connected to R2 including the N atom attached to R2 and X, forming a heterocyclic group, and two C atoms or a C and an N atom of the alkylene bridge may be joined together by an additional Ci_4-alkylene bridge, and a C atom may be substituted by R10 and/or one or two C atoms in each case may be substituted by one or two identical or different substituents selected from C1.6-alkyl, C2_6-alkenyl, C2_6-alkynyl, C3-7-cycloalkyl, C3_7-cycloalkyl-C1.3-alkyl, C4_7-cycloalkenyl and C4_7-cycloalkenyl-C1_3-alkyl, while two alkyl and/or alkenyl substituents may be joined together, forming a carbocyclic ring system, particularly a cyclopropyl, cyclobutyl or cyclopentyl group.

Preferably in the group X a -CH2- group immediately adjacent to the group R1R2N- is not replaced by -0, -S, -(SO), -(SO2), -CO or -NR4-.

If in the group X a -CH2- group of the alkylene bridge is replaced according to the invention, this -CH2- group is preferably not directly connected to a heteroatom, a double or triple bond.

Preferably the alkylene bridge X, X or X" has no or not more than one imino group. The position of the imino group within the alkylene bridge X, X or X"
is preferably such that no aminal function is formed together with the amino group NR1R2 or another adjacent amino group or two N atoms are not adjacent to one another.

Preferably X denotes an unbranched Ci_4-alkylene bridge and if the group Y is linked to X via a C atom, it may also denote Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 ff -CH2-CH=CH-, -CH2-C-C-, C2-4-alkylenoxy or C2-4-alkylene-NR4, while R4 and Y may be joined together forming a heterocyclic ring system, while the bridge X may be connected to R1 including the N atom attached to R1 and X, forming a heterocyclic group, and in X a C atom may be substituted by R10 and/or one or two C atoms in each case may be substituted by one or two identical or different substituents selected from C1-6-alkyl, C2_6-alkenyl, C2.6-alkynyl, C3_7-cycloalkyl, C3_7-cycloalkyl-C1.3-alkyl, C4_7-cycloalkenyl and C4-7-cycloalkenyl-C1_3-alkyl-, while two alkyl and/or alkenyl substituents may be joined together, forming a carbocyclic ring system and in the above-mentioned groups and residues one or more C atoms may be mono- or polysubstituted by F and/or one or two C atoms independently of one another may be monosubstituted by Cl or Br and wherein R1, R4 and R10 are defined as hereinbefore and hereinafter.
Particularly preferably, X denotes -CH2-, -CH2-CH2-, -CH2-CH2-CH2- or -CH2-CH2-NR4-CO- and if the group Y is linked to X via a C atom, it also denotes -CH2-CH=CH-, -CH2-C=C-, -CH2-CH2-O-, -CH2-CH2-CH2-O- or -CH2-CH2-NR4- or -CH2-CH2-CH2-NR4-, while R4 and Y may be joined together, forming a heterocyclic ring system, while the bridge X may be connected to R1 including the N atom attached to R' and X, forming a heterocyclic group, and in X a C atom may be substituted by R10, preferably a hydroxy, Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 ff w-hydroxy-C1.3-alkyl, w-(C1-4-alkoxy)-C1.3-alkyl and/or C1.4-alkoxy group, and/or one or two C atoms independently of one another may each be substituted by one or two identical or different C1.4-alkyl groups, while two alkyl groups may be joined together, forming a carbocyclic ring system , 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 independently of one another be monosubstituted by Cl or Br.

Most particularly preferably, if the group Y is linked to X via a C atom, X
denotes -CH2-CH2-O-, which may be substituted as specified hereinbefore.
If R4 is linked to Y forming a heterocyclic ring system, Y preferably has the meaning phenyl and R4 preferably has the meaning C2_6-alkyl or C2.6-alkenyl.
Preferred heterocyclic ring systems are indole, dihydroindole, dihydroquinoline and tetrahydroquinoline.

The group R4 preferably only represents vinyl if R4 is attached to Y, forming a heterocyclic ring system.

The group X preferably has no carbonyl group.

Advantageously, the group X with the meaning C2-4-alkyleneoxy, particularly -CH2-CH2-CH2-O-, has no hydroxy substituents.

If a C atom is substituted in X, X or X", the preferred substituents are selected from among the C1-4-alkyl, C2.4-alkenyl, C2_4-alkynyl, C3_7-cycloalkyl, C8_7-cycloalkyl-C1_3-alkyl, hydroxy, w-hydroxy-C1_3-alkyl, w-(C1_4-alkoxy)-C1_3-alkyl-and C1_4-alkoxy groups. Moreover, in X, X or X" , a C atom may be disubstituted and/or one or two C atoms may be mono- or disubstituted, while preferred substituents are selected from among C1-4-alkyl, C2_4-alkenyl, C2-4-alkynyl, C3_7-cycloalkyl and C3_7-cycloalkyl-Cl-3-alkyl, and two C1-4-alkyl and/or Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 if C2.4-alkenyl substituents may also be joined together forming a saturated or monounsaturated carbocyclic ring.

Most particularly preferred substituents for one or two C atoms in X, Xor X"
are selected from methyl, ethyl, n-propyl, i-propyl, cyclopropyl, cyclopropylmethyl, while two alkyl substituents on a C atom may also be joined together, forming a carbocyclic ring.

If Y denotes a fused bicyclic ring system, a preferred definition of the group X
is -CH2-, -CH2-CH2- and -CH2-CH2-CH2-, particularly -CH2- or -CH2-CH2-, which may be substituted as specified.

If in the group X, X or X" one or more C atoms is or are substituted by a hydroxy and/or C1-4-alkoxy group, the substituted C atom is preferably not directly adjacent to another heteroatom.

Preferably Z is a single bond, -CH2- or -CH2-CH2-, while one or two C atoms independently of one another may be mono- or disubstituted by F, CH3 or CF3 and/or monosubstituted by Cl.

Particularly preferred definitions of the group Z are a single bond, -CH2- or -CH2-CH2-, particularly a single bond.

According to a first embodiment the compounds according to the invention have a bridge W, which is selected from the group -CR6aR6b-O-, -CR6aR6b_ NR8-, -CR7aR7b-CR7cR7d_ and -NRa-CR6aR6b_ According to a second embodiment the compounds according to the invention have a bridge W, which denotes -CR7a=CR7o-.

W preferably denotes -CH2-O, -CH2-NR8-, -CH2-CH2- or -CH=CH-, while in the last two meanings in each case one or two C atoms may be substituted independently of one another by F, Cl, CH3 or CF3. In the above definitions Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 if -CH2-O- and -CH2-NR8- the group A is advantageously attached to the bridge W via a C atom.

Preferred definitions of the substituent R8 are H and methyl.

Particularly preferred definitions of the group W are -CH2-O-, -CH2-NH-, -CH2-NCH3- and -CH2-CH2, particularly -CH2-O-.

If the group W has the above meaning of an optionally substituted -CH=CH-bridge, the group Z is preferably a single bond.

Preferred embodiments of this invention therefore comprise compounds which may each be described by the following formulae Ia, Ib, Ic and Id:

la R2/N-X-Y- Z -N-C-CH2-O -A+B lb 11 lb R \ 0 R2/N-X-Y- z -N-C-CH 2 CH2 A+B ]b R O IC
- C-CH=CH-A+B ]b R
R\ 0 2/N-X-Y- Z -N-C-CH 2-NR8 A-f -B ,b Id wherein R1, R2, X, Y, Z, R3, R8, A, B and b are defined as hereinbefore and hereinafter, particularly have the meanings given as being preferred, while R8 preferably denotes H or methyl.

Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 if The group Y preferably has a meanings selected from among the bivalent cyclic groups phenyl, pyridinyl, naphthyl, tetrahydronaphthyl, indolyl, dihydroindolyl, quinolinyl, dihydroquinolinyl, tetrahydroquinolinyl, isoquinolinyl, dihydroisoquinolinyl or tetrahydro-isoquinolinyl, while the above-mentioned cyclic groups may be mono- or polysubstituted by R20 at one or more C atoms and in the case of a phenyl group may also additionally be monosubstituted by nitro, and/or by R21 at one or more N atoms. R1 may be attached to Y
and/or X may be attached to Y as specified hereinbefore.

particularly preferably, one definition of the group Y is selected from the following bivalent cyclic groups 1 , -N
N~P
N

N
and particularly Y has one of the following definitions:

N

Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 ff N and N
while the cyclic groups listed above may be mono- or polysubstituted by R20 at one or more C atoms, and in the case of a phenyl group may also additionally be monosubstituted by nitro, and/or one or more NH groups may be substituted by R21.

The group Y is preferably unsubstituted or mono- or disubstituted.

Particularly preferred substituents R20 of the group Y are selected from among fluorine, chlorine, bromine, cyano, nitro, C1-4-alkyl, C2.6-alkenyl, hydroxy, w-hydroxy-C1.3-alkyl, C14-alkoxy, trifluoromethyl, trifluoromethoxy, C2_4-alkynyl, C14-alkoxycarbonyl, w-(C1-4-alkoxy)-C1-3-alkyl, C1-4-alkoxy-carbonylamino, amino, C1-4-alkyl-amino, di-(C1_4-alkyl)-amino, aminocarbonyl, C1-4-alkyl-amino-carbonyl, di-(C1_4-alkyl)-amino-carbonyl, -CH=N-OH and -CH=N-O-C1_4-alkyl.

Most particularly preferred substituents R20 of the group Y are selected from among fluorine, chlorine, bromine, cyano, C1_3-alkyl, C1.3-alkoxy, trifluoromethyl, trifluoromethoxy, and, in the case of a phenyl ring, nitro as well.

If Y is a phenyl or pyridinyl group, the phenyl or pyridinyl group is at least monosubstituted, particularly if the group W denotes optionally substituted -CH=CH- or -CH2-CH2-.

Most particularly preferably, the group Y denotes substituted phenylene of the Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 if L
partial formula f wherein L' has one of the meanings given hereinbefore for R20 , preferably F, Cl, Br, I, CH3, CF3, OCH3, OCF3, CN or NO2, or denotes H.

The group Y preferably denotes monosubstituted phenylene according to the above partial formula, if the bridge W denotes -CH=CH-.

A preferred meaning of the group A is aryl or heteroaryl.

Preferably the group A is selected from among the cyclic groups phenyl, pyridinyl or naphthyl, which may be mono- or polysubstituted by R20 at one or more C atoms, in the case of a phenyl ring may also additionally be monosubstituted by nitro.

If b has the value 0, the group A is preferably mono-, di or trisubstituted.
If b has the value 1, the group A is preferably unsubstituted or mono- or disubstituted.

Most particularly preferably, A is one of the following groups B lb , B Jb , N

B 1b while the groups listed may be mono- or polysubstituted by R20 as specified.
The definitions phenyl and pyridyl given for the group A are preferred when b has the value 1.

Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 if Particularly preferred substituents R20 for the group A are selected from among fluorine, chlorine, bromine, cyano, C1-0-alkyl, C2_6-alkenyl, -CHO, hydroxy, 0o-hydroxy-C1_3-alkyl, C1-4-alkoxy, trifluoromethyl, trifluoromethoxy, C2_4-alkynyl, carboxy, C1-4-alkoxycarbonyl, w-(C1_4-alkoxy)-C1.3-alkyl, C1-4-alkoxy-carbonylamino, amino, C1-4-alkyl-amino, di-(C1_4-alkyl)-amino, cyclo-C3_6-alkyleneimino, aminocarbonyl, C1-4-alkyl-amino-carbonyl, di-(C1-4-alkyl)-amino-carbonyl, -CH=N-OH and -CH=N-O-C1.4-alkyl.

Most particularly preferred substituents R20 for the group A are selected from among fluorine, chlorine, bromine, cyano, C14-alkyl, C1_4-alkoxy, trifluoromethyl, trifluoromethoxy, carboxy, C1-4-alkoxycarbonyl, C1-4-alkyl-amino, di-(C1.4-alkyl)-amino, If b has the value 0, a particularly preferred meaning of the group A is substituted phenyl of the partial formula (L2)4 wherein L2 has one of the meanings given for R20 or denotes H, preferably F, Cl, Br, 1, CH3, CF3, OCH3, OCF3, CN or NO2, L3 has one of the meanings given for R20 or denotes H, preferably F, Cl, Br, I, CF3, OCF3, CN, NO2, C14-alkyl, C3_7-cycloalkyl, C3_7-cycloalkyl-C1_3-alkyl, C1-4-alkoxy, C3.7-cycloalkyl-O, C3_7-cycloalkyl-C1_3-alkoxy, -COO-C1.4-alkyl or -COOH, Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 if q has the value 0, 1 or 2, with the proviso that the phenyl and naphthyl group may be at most only monosubstituted by nitro.

Particularly preferably, A is substituted phenyl according to the above partial formula in which q denotes 1 or 2 and/or at least one substituent L2 is in the meta position to the substituent L3.

The group A preferably denotes substituted phenyl according to the above partial formula, while q has the value I or 2 if the bridge W represents -CH=CH, the group Y denotes phenyl and b has the value 0.

Another preferred partial formula for A, particularly if b has the value 0, is , wherein the bond to the group W is made via the C
atom with position number 2 or 3.

If b has the value 1, a preferred meaning for the group B is aryl or heteroaryl, which may be substituted as specified.

Preferred definitions of the group B are selected from among phenyl, pyridyl, thienyl and furanyl. Particularly preferably, the group B denotes phenyl. The group B with the meanings given above may be mono- or polysubstituted by R20, and a phenyl group may additionally also be monosubstituted by nitro.
Preferably the group B is mono-, di- or trisubstituted, particularly mono- or disubstituted. In the event of a monosubstitution the substituent is preferably in the para position to the group A.

Particularly preferred substituents R20 for the group B are selected from among fluorine, chlorine, bromine, cyano, nitro, C1_q-alkyl, hydroxy, Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 ff c)-hydroxy-C13-alkyl, C14-alkoxy, trifluoromethyl, trifluoromethoxy, C2-4-alkynyl, carboxy, C1-4-alkoxycarbonyl, o-(C14-alkoxy)-C1.3-alkyl, C1_4-alkoxy-carbonylamino, amino, C14-alkyl-amino, di-(C1.4-alkyl)-amino, cyclo-C3.6-alkyleneimino, aminocarbonyl, C1-4-alkyl-amino-carbonyl- and di-(C1.4-alkyl)-amino-carbonyl.

Most particularly preferred substituents R20 for the group B are selected from among fluorine, chlorine, bromine, cyano, CF3, C,.3-alkyl, C1-4-alkoxy and trifluoromethoxy.

The group B preferably denotes an at least monosubstituted phenyl ring, if the bridge W denotes -CH=CH-, the group Y denotes phenyl and b has the value 1.

R4 has one of the meanings given for R17, preferably one of the meanings given for R16.

Particularly preferred meanings of the substituent R4 are H, C1.6-alkyl and C3_6-alkenyl. If R4 is attached to Y, forming a heterocyclic ring system, particularly preferred meanings for R4 are C2-6-alkyl and C2_6-alkenyl.

The groups R6a R6b represent H, C1-4-alkyl or CF3, preferably H or methyl, particularly H.

The groups R7a R7b R7c R7d represent H, F, C1-4-alkyl or CF3, preferably H or methyl, particularly H.

The group R8 preferably denotes H or methyl.

If R11 is a C2_6-alkenyl or C2-6-alkynyl group, the definitions -CH=CH2, -CH=CH(CH3), -CH=C(CH3)2 and -C-CH, -C=C-CH3 are preferred.

The substituent R2 preferably has none of the following structural elements:

Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 if a) -CO-aryl or -CO-heteroaryl, particularly -CO-phenyl, wherein heteroaryl, aryl and phenyl may be substituted, b) -C(=NH)-NH-, wherein the H atoms may be substituted and/or c) -NH-CO-NH-, wherein the H atoms may be substituted.

Preferred definitions of the group R20 are halogen, hydroxy, cyano, C1-4-alkyl, C3_7-cycloalkyl and C1_4-alkoxy. Particularly preferably R20 denotes F, Cl, Br, I, OH, cyano, methyl, difluoromethyl, trifluoromethyl, ethyl, n-propyl, iso-propyl, methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, n-propoxy or iso-propoxy.
Preferred definitions of the group R21 are C1.4-alkyl, C1-4-alkylcarbonyl, C1-alkylsulphonyl, -S02-NH2, -SO2-NH-C1_3-alkyl, -SO2-N(C1_3-alkyl)2 and cyclo-C8_6-alkyleneimino-sulphonyl.

Cy preferably denotes a C3_7-cycloalkyl, particularly a C5_7-cycloalkyl group, a Cb_7-cycloalkenyl group, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, aryl or heteroaryl, while aryl or heteroaryl preferably denotes a monocyclic or fused bicyclic ring system, and the above-mentioned cyclic groups may be mono- or polysubstituted by R20 at one or more C atoms, and in the case of a phenyl group may also additionally be monosubstituted by nitro, and/or one or more NH groups may be substituted by R21.

Preferred compounds according to the invention are those wherein one or more of the groups, residues, substituents and/or indices have one of the meanings given as being preferred.

Particularly preferred compounds according to the invention are those wherein Y denotes phenyl, 1H-indolyl, 2,3-dihydro-1 H-indolyl or 1,2,3,4-tetrahydroquinoline according to the definition described above as being preferred, particularly with phenyl substituted by L1 according to the partial formula given hereinbefore and/or Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 if A denotes phenyl substituted by L2 and L3 according to the partial formula given hereinbefore.

Most particularly preferred compounds according to the invention are those wherein A, X, Y, Z, R', R2, R3 and W independently of one another have one or more of the above-mentioned preferred meanings.

Preferred groups of compounds according to this invention can be described by the following formulae I L1 1P [ R20~r la.1 R\N-C Z -N-C-CH -O B }
R2i 13 2 \ Jb R Q

[Li] P [R21r la.2 -CH2 \ / lb -O 4B R2i 13 R Q

[ L1 ]p [ R20~r la.3 -CH2-O 4 B lb RZR Q

[ L1 ]p [R21 r la.4 R21 N-CH2 -CH 2 Z -N3 C-CH2 O B Jb R Q

Boehringer Ingelheim Case 1-1407 if R4 [L1] p [R21 r la.5 R2/N-CH2 CH2 N Z -Ns C-CH2 O B ~b R Q

R4 [Li] {R2Jr la.6 R2/N-CH2-CH2-CH2- Z -N3 C-CH2-O B Jb R Q
[Li] p [R21r la.7 Ri 0 R2/N-CH2-CH2-CH2- Z -N3 C-CH2-O B Jb R Q

a [Lii p [R21r la.8 R
R~ 0 R2/N-CH2-CH2-N-CO Z -N3 -C-CH 2-0 4B Jb R Q
R [ L' lp [R21r la.9 R2/N-CH2-CH=C Z -N3 C-CH2-O B 1b R Q

[Li] p [R21Jr la.10 R\ O 11 R2"N-CH2-C C Z -N3 C-CH2-O B Jb R Q

Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 if Ia.11 [ L ]p {R21 r R /N-C2 Z -N-C-CH=C 4B lb [LI]p {R2Ir la.12 R\N-CH 2 -CH 2 \ / Z -N-C-CH=CW- 4 B l R13 ~ / Jb R Q

[Li]p [R21r la.13 R /N-CH 2 -C 2 Z -N-C-CH2 / -NR JB ]lb R Q
wherein R1, R2, Z, R3, R4, R8, R20, B and b have the meanings given hereinbefore and Z preferably denotes a single bond or -CH2-CH2-, R3 preferably denotes H or methyl, R4 preferably denotes H, C,_6-alkyl or C2_6-alkenyl, while R4 may be attached to Y forming a heterocyclic ring system, particularly preferably forming an indole, dihydroindole, dihydroquinoline or tetrahydroquinoline group, Q denotes CH or N, while CH may be substituted by R20, B preferably denotes aryl or heteroaryl, particularly preferably denotes phenyl, pyridyl, furanyl or thienyl, while B may be mono- or polysubstituted by R, Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 if L1 preferably denotes fluorine, chlorine, bromine, cyano, nitro, C1_3-alkyl, C1.3-alkoxy, trifluoromethyl, trifluoromethoxy or nitro, p has the value 0 or 1, R20 preferably denotes fluorine, chlorine, bromine, cyano, C1.4-alkyl, C2-6-alkenyl, -CHO, hydroxy, c0-hydroxy-C1.3-alkyl, C1-4-alkoxy, trifl uorom ethyl, trifluoromethoxy, C2_4-alkynyl, carboxy, C1.4-alkoxy-carbonyl, w-(C1_4-alkoxy)-C1_3-alkyl, C1-4-alkoxy-carbonylamino, amino, C1_4-alkyl-amino, di-(C14-alkyl)-amino, cyclo-C3-6-alkyleneimino, aminocarbonyl, C1-4-alkyl-amino-carbonyl, di-(C1-4-alkyl)-amino-carbonyl, -CH=N-OH and -CH=N-O-C1-4-alkyl, r has the value 1, 2 or 3 and, if b has the value 1, r may also denote 0 and the compounds according to provisos (Ml), (M2) and (M3) are not included.
The following individual compounds are particularly preferred:

F
(1) H cl ~JFF
CI N-O
ON~-~0 0 N-[3-ch loro-4-(2-piperid in-l -yl-ethoxy)-phenyl]-2-(2-chloro-4-trifluoromethyl-phenoxy)-acetamide F
CIF
( 2) N
F
\ aO
H3Cl N~
H3C~N,/,O 0 Boehringer ingelheim Case 1-1407 ff 2-(2-ch loro-4-trifluoromethyl-phenoxy)-N-[3-cyano-4-(2-diethylam ino-ethoxy)-phenyl]-acetamide N CI
(3) N/ N
F

-5-7~
F F
2-(2-chloro-4-trifluoromethyl-phenoxy)-N-[1-(2-diethylamino-ethyl)-2,3-dihydro-1 H-indol-5-yl]-acetamide F
CI ::::: F F Z:zl (4) H3C CI 0 H3C ~N 0 N-[3-chloro-4-(3-diethylamino-prop-1 -ynyl)-phenyl]-2-(2-chloro-4-trifluoromethyl-phenoxy)-acetamide (5) CI
CH3 H O_( \ F
/
F F

2-(2-chloro-4-trifluoromethyl-phenoxy)-N-[1-(2-diethylamino-ethyl)-2, 3-dimethyl-1 H-indol-5-yi]-acetamide (6) N~iN CI
CH O \ F

F F

2-(2-chloro-4-trifluoromethyl-phenoxy)-N-[1-(2-diethylamino-ethyl)-1 H -i ndol-5-yl]-acetam ide Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 ff . CH3 (7) H3CN^" O Ci H,C
F
F F

2-(2-chloro-4-trifluoromethyl-phenoxy)-N-[4-(2-diethylamino-ethoxy)-3-methoxy-phenyl]-acetamide cl H3C'N~` 0 Cl (8) H3CJ

2-(3-chloro-biphenyl-4-yloxy)-N-[3-chloro-4-(2-diethylamino-ethoxy)-phenyl]-acetamide cl H,C^N ' I \ 0 Cl (9) H3C / N,O I \
FI / F
F
F

N-[3-chloro-4-(2-diethylamino-ethoxy)-phenyl]-2-(2-chloro-4-trifluoromethyl-phenoxy)-acetamide cl H,C 0 CI
N(10) H3C H'O

2-(4-tert.-butyl-2-chloro-phenoxy)-N-[3-chloro-4-(2-diethylam ino-ethoxy)-phenyl]-acetamide Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 ff CI
11 H3CN^' 0 Cl H I\
H3C -(/No '(f~/ / `CH

O

methyl 3-chloro-4-{[3-ch loro-4-(2-d iethylamino-ethoxy)-phenylcarbamoyl]-methoxy}-benzoate cl 12 H3C'N'---( ) tL 0 Br H3C) H~O I \\

'Br N-[3-chloro-4-(2-d iethyla mino-ethoxy)-phenyl]-2-(2,4-dibromo-phenoxy)-acetamide cl (13) H3CN---- 61- O CI
H3C" H11 / Br 2-(4-bromo-2-ch loro-phenoxy)-N-[3-chloro-4-(2-diethylamino-ethoxy)-phenyl]-acetamide (14) H3C cl -r`
H3C~N -.. I / 0 CH3 N-[3-ch loro-4-(2-d iet hyla m i no-et hoxy)-phenyl]-2-(4-iod o-2-methyl-phenoxy)-acetamide CH3 cl (15) cl CI

Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 ff methyl (2-{2-chloro-4-[2-(2,4-dichloro-phenoxy)-acetylamino]-phenoxy}-ethylamino)-acetate F
( CI / F
16) CI N I F
o o o /

N-[3-ch loro-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-2-(2-chloro-4-trifluoromethyl-phenoxy)-acetamide F
CI / F
(17) /CH Cl N~0 \ I F

H3Cf N-{3-ch loro-4-[2-(ethyl-propyl-amino)-ethoxy]-phenyl}-2-(2-chloro-4-trifluoromethyl-phenoxy)-acetamide F
CI F
(18) CH CI N~O F
N,-,-, O 0 N-{3-ch loro-4-[2-(ethyl-methyl-am ino)-ethoxy]-phenyl}-2-(2-chloro-4-trifluoromethyl-phenoxy)-acetamide (19) H N`CH3 H3C CI N-trO
H3C~N~~O 0 Cl N-[3-ch loro-4-(2-d iethyla m ino-ethoxy)-phenyl]-2-(2-chloro-4-dimethylamino-phenoxy)-acetamide Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 ff F
H cl / F
(20) H3C` CI / N \ \ F
H3C~N~~O \ I 0 (E)-N-[3-chloro-4-(2-diethylam ino-ethoxy)-phenyl]-3-(2-ch loro-4-trifluoromethyl-phenyl)-acrylamide F
F
(21) H F
H3C cl rir N'N \I
H
H3C~N - 0 0 CI

N-[3-ch loro-4-(2-diethylamino-ethoxy)-phenyl]-2-(2-ch loro-4-trifluoromethyl-phenylamino)-acetamide (22) H3CN0 ~~ 0 CI
H3C CI' H' I \

N-[3-chloro-4-(2-diethylamino-ethoxy)-phenyl]-2-(2-chloro-4-f uran-2-yl-phenoxy)-acetamide H3CN0 0 cI
(23) HCJ CI v bsx N-[3-chloro-4-(2-diethylamino-ethoxy)-phenyl]-2-(2-chloro-4-thiophen-2-yl-phenoxy)-acetamide H3CN---0 \ 0 CI
(24) H3C CI H0 ~ ~N

Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 ff N-[3-ch Ioro-4-(2-d iethyla m i n o-eth oxy)-phenyl]-2-(2-chloro-4-pyrid i n-3-yl-phenoxy)-acetamide CH, Cl CH3 / N \
/ F
F F

2-(2-bromo-4-trifluoromethyl-phenoxy)-N-[3-chloro-4-(2-diethylamino-ethoxy)-phenyl]-acetamide (26) /'\N---.- O cl H
F
F F

N-{3-chloro-4-[2-(2,5-dihydro-pyrrol-1-yl)-ethoxy]-phenyl}-2-(2-chloro-4-trifluoromethyl-phenoxy)-acetamide cl (27) ~, I \ 0 cl (27) H~C~O / N~O \
O H I / F
F F

ethyl 1-(2-{2-chloro-4-[2-(2-chloro-4-trifluoromethyl-phenoxy)-acetyla m i no]-phenoxy}-ethyl)-pi perid ine-4-carboxylate H'C\ cl (28) H,CvN 0 0 CI
H 0 -(\
/ F
~FF

N-[3-chloro-4-(3-diethyla mino-propoxy)-phenyl]-2-(2-chloro-4-trifluoromethyl-phenoxy)-acetamide Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 ff N HZ
CI
(29) N~~O O CI
/ N~0 \
H F
F F

N-{4-[2-(2-aminomethyl-pyrrolidin-1-yl)-ethoxy]-3-chloro-phenyl}-2-(2-chloro-4-trifluoromethyl-phenoxy)-acetamide (30) N-CH, CI
Ni 0 Cl Nflo \
H i / F
F F

N-{3-chloro-4-[2-(2-dimethylaminomethyl-pyrrolidin-1-yl)-ethoxy]-phenyl}-2-(2-chloro-4-trifluoromethyl-phenoxy)-acetamide 0 O Cl (31) H3C N0 H3C Br \

F F

N-[3-bromo-4-(2-d iethylamino-ethoxy)-phenyl]-2-(2-chloro-4-trifluoromethyl-phenoxy)-acetamide cl N\ (Of CI
(32) HC- 'Nlo H
/ F
F F

N-{3-chloro-4-[2-(4-methoxy-piperidin-1-yl)-ethoxy]-phenyl}-2-(2-chloro-4-trifluoromethyl-phenoxy)-acetam ide Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 ff cl (33)\ O cl HO / H~ -':\
/ F
F F

N-{3-chloro-4-[2-(4-hydroxy-piperidin-1-yl)-ethoxy]-phenyl}-2-(2-chloro-4-trifluoromethyl-phenoxy)-acetam ide O.N"o (34) H,C~N""-' / IOI cl H3C" I H~O -'\
/ F
FF

2-(2-chloro-4-trifluoromethyl-phenoxy)-N-[4-(2-diethylam ino-ethoxy)-3-nitro-phenyl]-acetamide H,CN 0 H CI
(35) H,c cI H " I \

F+F

N-[3-chloro-4-(2-d iethyla mi no-ethoxy)-phenyl]-2-(2-ch loro-4-trifluoromethoxy-phenylamino)-acetamide CH, cl (36) I ~0 N F
C H3 H I \
/ F
F F

N-[3-ch loro-4-(2-d iethyla mi no-ethoxy)-phenyl]-2-(2-fluoro-4-trifluoromethyl-phenylamino)-acetamide Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 ff cl H C
(37) 0 Br / F
F F

2-(2-bromo-4-trifluoromethyl-phenyiamino)-N-[3-chloro-4-(2-diethylamino-ethoxy)-phenyl]-acetamide 0"--a O
(38) H
Cl (E)-3-(4'-chloro-biphenyl-4-yl)-N-(4-piperidin-l-ylmethyl-phenyl)-acrylamide cl (39) ~ 3 _ CI 0 N / \ N~O \ / F

N-[3-chloro-4-(2-diethylamino-ethylamino)-phenyl]-2-(2-chloro-4-trifluoromethyl-phenoxy)-acetamide ~J H CI
I / Ho \
(40) H 3 I / c `~ NO CI
F
F
F

N-{3-chloro-4-[2-(4-methyl-piperidin-1-yl)-ethylamino]-phenyl}-2-(2-ch loro-4-trifluoromethyl-phenoxy)-acetam ide /IcI
(41) ~ N \ I /

I / O
HC N

Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 ff (E)-3-(4'-chloro-biphenyl-4-yl)-N-(4-dimethylaminomethyl-phenyl)-acrylamide CI
(42) N IN
ON I / O

(E)-3-[5-(4-chloro-phenyl)-pyridin-2-yl]-N-(4-piperidin-1 -ylmethyl-phenyl)-acrylamide H CI
(43) /~N~i / I O CI

F
F
F

(E)-N-{3-chloro-4-[2-(4-methyl-piperidin-1-yl)-ethylamino]-phenyl}-3-(2-chloro-4-trifluoromethyl-phenyl)-acrylamide cl (44) ~N o cl H3C ~ H
F
F
F

(E)-N-[3-chloro-4-(4-methyl-piperidin-1 -ylmethyl)-phenyl]-3-(2-chloro-4-trifluoromethyl-phenyl)-acrylamide (45) H3C N~-`O O
J I
H I

/ F
F F

2-(2-chloro-4-trifluoromethyl-phenoxy)-N-[4-(2-diethylamino-ethoxy)-3-methyl-phenyl]-acetam ide Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 ff (46) H3C J '-0 1 0 cl H3C H / I \
F
F F

(E)-3-(2-chloro-4-trifluoromethyl-phenyl)-N-[4-(2-diethylamino-ethoxy)-3-methyl-phenyl]-acrylamide 0, CH3 (47) H 3C^N ' 0 CI
H3C/ I / N / \
H
F
FF

(E)-3-(2-chloro-4-trifluoromethyl-phenyl)-N-[4-(2-diethylamino-ethoxy)-3-methoxy-phenyl]-acrylamide H3C`
(48) H3Cl-~N CI

O CI
'\ N / \
H
F
F
F

(E)-N-[3-chloro-4-(2-diethylamino-ethyl)-phenyl]-3-(2-chloro-4-trifluoromethyl-phenyl)-acrylamide H3C\
(qg) H3C N
cI
/ I0J a ~ NO \
/ F
H F
F
N-[3-chloro-4-(2-diethylamino-ethyl)-phenyl]-2-(2-chloro-4-trifluoromethyl-phenoxy)-acetamide Boehringer Ingelheim Case 1-1407 if H,c`^
(50) N
ci o / CI
I
~ N~O bF
F
N-{3-chloro-4-[2-(4-methyl-piperidin-1-yl)-ethyl]-phenyl}-2-(2-chloro-4-trifluoromethyl-phenoxy)-acetamide including the salts thereof.

Some expressions used hereinbefore and below to describe the compounds according to the invention will now be defined more fully.

The term halogen denotes an atom selected from among F, Cl, Br and I, particularly F, Cl and Br.

The term C1_n-alkyl, where n has a value of 3 to 8, denotes a saturated, branched or unbranched hydrocarbon group with 1 to n C atoms. Examples of such groups include methyl, ethyl, n-propyl, iso-propyl, butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, neo-pentyl, tert-pentyl, n-hexyl, iso-hexyl, etc.

The term C1_n-alkylene, where n may have a value of 1 to 8, denotes a saturated, branched or unbranched hydrocarbon bridge with 1 to n C atoms.
Examples of such groups include methylene (-CH2-), ethylene (-CH2-CH2-), 1-methyl-ethylene (-CH(CH3)-CH2-), 1,1-dimethyl-ethylene (-C(CH3)2-CH2-), n-prop-1,3-ylene (-CH2-CH2-CH2-), 1 -methyl prop- 1, 3-ylene (-CH(CH3)-CH2-CH2-), 2-methylprop- 1,3-ylene (-CH2-CH(CH3)-CH2-), etc., as well as the corresponding mirror-symmetrical forms.

The term C2_n-alkenyl, where n has a value of 3 to 6, denotes a branched or unbranched hydrocarbon group with 2 to n C atoms and at least one C=C-Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 ff double bond. Examples of such groups include vinyl, 1-propenyl, 2-propenyl, iso-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 3-methyl-2-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl etc.

The term C2_õ-alkynyl, where n has a value of 3 to 6, denotes a branched or unbranched hydrocarbon group with 2 to n C atoms and a C=C triple bond.
Examples of such groups include ethynyl, 1-propynyl, 2-propynyl, iso-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 2-methyl-1-propynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 3-methyl-2-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl etc.

The term C1_n-alkoxy denotes a C1_n-alkyl-O- group, wherein C1_n-alkyl is defined as above. Examples of such groups include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, iso-pentoxy, neo-pentoxy, tert-pentoxy, n-hexoxy, iso-hexoxy etc.
The term C1_n-alkylthio denotes a C1-n-alkyl-S- group, wherein C1_n-alkyl is defined as above. Examples of such groups include methylthio, ethylthio, n-propylthio, iso-propylthio, n-butylthio, iso-butylthio, sec-butylthio, tert-butylthio, n-pentylthio, iso-pentylthio, neo-pentylthio, tert-pentylthio, n-hexylthio, iso-hexylthio, etc.

The term C1_n-alkylcarbonyl denotes a C1_n-alkyl-C(=O)- group, wherein C-alkyl is defined as above. Examples of such groups include methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, iso-propylcarbonyl, n-butylcarbonyl, iso-butylcarbonyl, sec-butylcarbonyl, tert-butylcarbonyl, n-pentylcarbonyl, iso-pentylcarbonyl, neo-pentylcarbonyl, tert-pentylcarbonyl, n-hexylcarbonyl, iso-hexylcarbonyl, etc.

The term C3_n-cycloalkyl denotes a saturated mono-, bi-, tri- or spirocarbocyclic group with 3 to n C atoms. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 ff cyclononyl, cyclododecyl, bicyclo[3.2.1.]octyl, spiro[4.5]decyl, norpinyl, norbonyl, norcaryl, adamantyl, etc.

The term C5_n-cycloalkenyl denotes a monounsaturated mono-, bi-, tri- or spirocarbocyclic group with 5 to n C atoms. Examples of such groups include cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl, etc.
The term C3_n-cycloalkylcarbonyl denotes a C3-n-cycloalkyl-C(=O) group, wherein C3_n-cycloalkyl is defined as above.

The term aryl denotes a carbocyclic, aromatic ring system, such as for example phenyl, biphenyl, naphthyl, anthracenyl, phenanthrenyl, fluorenyl, indenyl, pentalenyl, azulenyl, biphenylenyl, etc. A particularly preferred meaning of "aryl" is phenyl.

The term cyclo-C3_7-alkyleneimino denotes a 4- to 7-membered ring which has 3 to 7 methylene units as well as an imino group, the bond to the rest of the molecule being made via the imino group.

The term cyclo-C3_7-alkyleneimino-carbonyl denotes a cycIo-C3_7-alkyleneimino ring as defined hereinbefore which is linked to a carbonyl group via the imino group.

The term heteroaryl used in this application denotes a heterocyclic, aromatic ring system which comprises in addition to at least one C atom one or more heteroatoms selected from N, 0 and/or S. Examples of such groups are furanyl, thiophenyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, 1,2,3-triazolyl, 1,3,5-triazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, tetrazolyl, thiadiazinyl, indolyl, isoindolyl, benzofuranyl, benzothiophenyl (thianaphthenyl), indazolyl, benzimidazolyl, benzthiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, purinyl, quinazolinyl, quinozilinyl, quinolinyl, Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 if isoquinolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, azepinyl, diazepinyl, acridinyl, etc. The term heteroaryl also comprises the partially hydrogenated heterocyclic, aromatic ring systems, particularly those listed above. Examples of such partially hydrogenated heterocycles are 2,3-dihydrobenzofuranyl, pyrolinyl, pyrazolinyl, indolinyl, oxazolidinyl, oxazolinyl, oxazepinyl, etc. Particularly preferably, heteroaryl denotes a heteroaromatic mono- or bicyclic ring system.

Terms such as aryl-C,_n-alkyl, heteroaryl-C1_n-alkyl, etc. refer to C1_n-alkyl, as defined above, which is substituted with an aryl or heteroaryl group.

Many of the terms given above may be used repeatedly in the definition of a formula or group and in each case have one of the meanings given above, independently of one another.

The term "unsaturated", e.g. in "unsaturated carbocyclic group" or "unsaturated heterocyclic group", as used particularly in the definition of the group Cy, comprises, in addition to the mono- or polyunsaturated groups, the corresponding totally unsaturated groups, but particularly the mono- and diunsaturated groups.

The term "optionally substituted" used in this application indicates that the group thus designated is either unsubstituted or mono- or polysubstituted by the substituents specified. If the group in question is polysubstituted, the substituents may be identical or different.

The H atom of any carboxy group present or an H atom (imino or amino group) bonded to an N atom may in each case be replaced by a group which can be cleaved in vivo. By a group which can be cleaved in vivo from an N
atom is meant for example a hydroxy group, an acyl group such as the benzoyl or pyridinoyl group or a C1_16-alkanoyl group such as the formyl, acetyl, propionyl, butanoyl, pentanoyl or hexanoyl group, an allyloxycarbonyl group, a C1_16-alkoxycarbonyl group such as the methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 ff tert.butoxycarbonyl, pentoxycarbonyl, hexyloxycarbonyl, octyloxycarbonyl, nonyloxycarbonyl, decyloxycarbonyl, undecyloxycarbonyl, dodecyloxycarbonyl or hexadecyloxycarbonyl group, a phenyl-C1_6-alkoxycarbonyl group such as the benzyloxycarbonyl, phenylethoxycarbonyl or phenylpropoxycarbonyl group, a C1_3-alkylsulphonyl-C2-4-alkoxycarbonyl, C1.3-alkoxy-C2.4-alkoxy-C2_4-alkoxycarbonyl or ReCO-O-(RfCRg)-O-CO group wherein Re denotes a C1.8-alkyl, C5_7-cycloalkyl, phenyl or phenyl- C1_3-alkyl group, Rf denotes a hydrogen atom, a CI-3-alkyl, C5_7-cycloalkyl or phenyl group and R9 denotes a hydrogen atom, a C1.3-alkyl or ReCO-O-(RfCRg)-O group wherein Re to R. are as hereinbefore defined, while additionally the phthalimido group is a possibility for an amino group, and the above-mentioned ester groups may also be used as groups which can be converted into a carboxy group in vivo.

The residues and substituents described above may be mono- or polysubstituted by fluorine as described. Preferred fluorinated alkyl groups are fluoromethyl, difluoromethyl and trifluoromethyl. Preferred fluorinated alkoxy groups are fluoromethoxy, difluoromethoxy and trifluoromethoxy. Preferred fluorinated alkylsulphinyl and alkylsulphonyl groups are trifluoromethylsulphinyl and trifluoromethylsulphonyl.

The compounds of general formula I according to the invention may have acid groups, predominantly carboxyl groups, and/or basic groups such as e.g.
amino functions. Compounds of general formula I may therefore be present as internal salts, as salts with pharmaceutically useable inorganic acids such as hydrochloric acid, sulphuric acid, phosphoric acid, sulphonic acid or organic acids (such as for example maleic acid, fumaric acid, citric acid, Boehringer Ingelheim Case 1-1407 if tartaric acid or acetic acid) or as salts with pharmaceutically useable bases such as alkali or alkaline earth metal hydroxides or carbonates, zinc or ammonium hydroxides or organic amines such as e.g. diethylamine, triethylamine, triethanolamine inter alia.

The compounds according to the invention may be obtained using methods of synthesis which are known in principle. Preferably the compounds are obtained analogously to the methods of preparation described more fully hereinafter, which are also a subject of this invention. Abbreviations used hereinafter are defined in the introduction to the experimental section or are familiar to those skilled in the art. The term alkyl used in reaction plans A, B
and C denotes Cl-4-alkyl, unless otherwise stated.

If the starting materials or intermediate products listed below contain groups R', R2, R3, X, Y, Z, A or B with amine functions, these are preferably used in protected form, for example with a Boc, Fmoc or Cbz protective group, and liberated at the end of the reactions by standard methods.

According to general reaction plan A an alkyl haloacetate (A-1), preferably optionally substituted ethyl bromoacetate, is reacted with a hydroxy compound (A-2), for example a phenol, in a molar ratio of 1:1 to 2:1 in a suitable solvent in the presence of a suitable base. Suitable bases are particularly tertiary amines such as triethylamine or HUnig base as well as alkali metal carbonates, for example potassium carbonate. The reactions are carried out in a suitable solvent, while DMF is preferably used.
The reaction takes place in a period of from 4 to 24 hours in a temperature range from RT to 120 C, preferably from 60 C to 100 C.

The alkyl aryloxy-acetates (A-3) thus obtained, after being purified, are hydrolysed to form the corresponding aryloxy-acetic acids (A-4). The reaction is preferably carried out in ethanol-water mixtures in the presence of an excess of alkali metal hydroxides, for example 2-5 equiv. sodium hydroxide.
The reaction is carried out over a period of from 1 to 4 hours in a temperature range from RT to 80 C.

Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 ff The aryloxy-acetic acids (A-4) after purification are coupled with an aniline (A-5) to form the amide (A-6). The necessary activation of the acetic acid is preferably carried out using a mixed anhydride or using coupling reagents.
The mixed anhydride of the relevant aryloxy-acetic acid (A-4) is preferably prepared by reacting the acetic acid with an excess of alkyl chloroformate, preferably isopropyl chloroformate, in a molar ratio of 1:1 to 1:1.2. The bases used are preferably tertiary amines, for example N-methylmorpholine, used in equimolar amounts to the alkyl chloroformate in question.
The reaction is carried out in a suitable solvent such as THE at temperatures between -10 C and -5 C and takes place over a period of 10 to 30 minutes.
The mixed anhydride thus obtained is preferably reacted with an amine compound (A-5), for example an aniline, without further purification. The aniline is used in excess relative to the particular acetic acid (A-4), preferably 5-10 mol%,.

The reaction is carried out for example at RT over a period of 1 to 4 hours.
Another preferred reaction yields the amide (A-6) by coupling the aniline (A-5) to the corresponding aryloxy-acetic acid (A-4) with the aid of peptide coupling reagents in a suitable solvent using a suitable base. The aryloxy-acetic acid (A-4) and an aniline (A-5) are preferably used in a molar ratio of from 1.5:1 to 1:1.5. The peptide coupling reagent used is TBTU, for example, used in an equimolar amount or in excess, preferably from equimolar to a 50 mol%
excess. Alternatively, the reaction may also be carried out in the presence of an amount of HOBt equimolar to the TBTU. Preferred solvents are THE and DMF in a temperature range from RT to 80 C, preferably from RT to 40 C.
The bases used are preferably tertiary amines such as triethylamine or Hunig base.

Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 if Reaction plan A: (W representing -CH2-O-) O
AlkyI,,O,~,Hal + HO-A413 1b (A-1) (A-2) O
Alkyl,, O)L""O-A4B ]b (A-3) O
HO'~v O-A4B 1, (A-4) R\ H
R2/N-X-Y- Z -N3 (A-5) R
O

R N-X-Y- Z -N O-A L B lb (A-6) R
According to general reaction plan B an alkyl haloacetate (B-1), preferably ethyl bromoacetate, is reacted with an amine compound (B-2), for example an aniline, in an excess, preferably in a molar ratio of 1:1 to 1.2:1, in a suitable solvent in the presence of a suitable base. Suitable bases are, in particular, tertiary amines such as Hunig base.

The solvent used is preferably Hunig base, DMF or the mixtures thereof.

Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 ff The reaction is carried out over a period of 4 to 48 hours in a temperature range from 90 C to 130 C. The further reaction of the ethyl arylamino-acetate (B-3) was carried out analogously to the general reaction plan A by hydrolysis to form the arylamino-acetic acid (B-4). The amide (B-6) is preferably prepared from the acetic acid (B-4) and the aniline (B-5) using TBTU and a suitable base in a suitable solvent. The aryloxy-acetic acid (B-4) and the aniline (B-5) are preferably used in a molar ratio of 1.5:1 to 1:1.5.
The peptide coupling reagent used is TBTU, for example, which is used in an equimolar amount or in excess, preferably from equimolar to a 50 mol%
excess. The preferred solvent is DMF in a temperature range from RT to 80 C, preferably from RT to 40 C. The bases used are preferably tertiary amines such as HUnig base.

Reaction plan B: (W representing -CH2-NR8- with R$ = H in this instance) Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 ff O
Alkyl.,,O,,~,Hal + H2N-A-{-B ~b (B-1) (B-2) O
Alkyl 0 -A-{-B Jb (B-3) O
HO NH--A-+B (B-4) R H
R2/N-X-Y- Z -N3 (B-5) R
O

RN-X_Y- Z -N'K,N--A-+B lb (B-6) R2' 13 R
According to reaction plan C an acrylic acid ester (C-3), e.g. an optionally substituted ethyl phenylacrylate, is prepared by palladium-catalysed reaction of an alkyl acrylate (C-1) and a (hetero)aryl halide (C-2). Preferably (hetero)arylbromide and (hetero)aryliodide (C-2) are added to the reaction in excess in relation to the acrylic acid, preferably in a molar ratio of 1:1 to 1:1.5.
The solvent used may be for example acetonitrile at 80 C. The palladium catalyst used is preferably palladium(II)acetate (1 mol%) combined with tri-o-tolylphosphine (3 to 4 mol%). Suitable bases are tertiary amines such as triethylamine.

Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 ff After purification, the acrylic acid ester (C-3) is hydrolysed to form the corresponding acrylic acid (C-4). The reaction is preferably carried out in ethanol-water mixtures in the presence of alkali metal hydroxides such as sodium hydroxide (200-300 mol%).
The reaction takes place over a period of 1 to 4 hours at ambient temperature.
After purification, the acrylic acid compound (C-4) is coupled to an amine compound (C-5), for example an aniline, to form the acrylamide (C-6). The necessary activation of the acrylic acid (C-4) takes place analogously to general reaction plan A, preferably via a mixed anhydride or using coupling reagents such as TBTU or TBTU in combination with HOBt.

Reaction plan C: (W representing -CH=CH-) Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 if O
C1-2-Alkyl,,,,O + Hal-A-f -B lb (C-1) (C-2) O
C'-2-Alkyl,,O,-~~A-+B lb (C-3) HO v A~B lb (C-4) R\ H
RZ/N-X-Y- Z -N3 (C-5) R
R\ (C-6) RZ/ N-X-Y- Z -Ns R
The compounds according to the invention may advantageously also be obtained using methods described in the following Examples, which may also be combined with methods known to the skilled man from the literature, for example.

Stereoisomeric compounds of formula (I) may be separated in principle by conventional methods. The diastereomers may be separated on the basis of their different physico-chemical properties, e.g. by fractional crystallisation Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 ff from suitable solvents, by high pressure liquid or column chromatography, using chiral or preferably non-chiral stationary phases.

Racemates covered by general formula (I) may be separated for example by HPLC on suitable chiral stationary phases (e.g. Chiral AGP, Chiralpak AD).
Racemates which contain a basic or acidic function can also be separated via the diastereomeric, optically active salts which are produced on reacting with an optically active acid, for example (+) or (-)-tartaric acid, (+) or (-)-diacetyl tartaric acid, (+) or (-)-monomethyl tartrate or (+)-camphorsulphonic acid, or an optically active base, for example with (R)-(+)-1-phenylethylamine, (S)-(-)-1-phenylethylamine or (S)-brucine.

According to a conventional method of separating isomers, the racemate of a compound of general formula (I) is reacted with one of the above-mentioned optically active acids or bases in equimolar amounts in a solvent and the resulting crystalline, diastereomeric, optically active salts thereof are separated using their different solubilities. This reaction may be carried out in any type of solvents provided that they show sufficient differences in terms of the solubility of the salts. Preferably, methanol, ethanol or mixtures thereof, for example in a ratio by volume of 50:50, are used. Then each of the optically active salts is dissolved in water, carefully neutralised with a base such as sodium carbonate or potassium carbonate, or with a suitable acid, e.g. with dilute hydrochloric acid or aqueous methanesulphonic acid, and in this way the corresponding free compound is obtained in the (+) or (-) form.

The (R) or (S) enantiomer alone or a mixture of two optically active diastereomeric compounds covered by general formula I may also be obtained by performing the syntheses described above with a suitable reaction component in the (R) or (S) configuration.

As already mentioned, the compounds of formula (I) may be converted into the salts thereof, particularly for pharmaceutical use into the physiologically and pharmacologically acceptable salts thereof. These salts may be present on the one hand as physiologically and pharmacologically acceptable acid Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 if addition salts of the compounds of formula (I) with inorganic or organic acids.
On the other hand, in the case of acidically bound hydrogen, the compound of formula (I) may also be converted by reaction with inorganic bases into physiologically and pharmacologically acceptable salts with alkali or alkaline earth metal cations as counter-ion. The acid addition salts may be prepared, for example, using hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid, toluenesulphonic acid, benzenesuIphonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.
Moreover, mixtures of the above mentioned acids may be used. To prepare the alkali and alkaline earth metal salts of the compound of formula (I) with acidically bound hydrogen the alkali and alkaline earth metal hydroxides and hydrides are preferably used, while the hydroxides and hydrides of the alkali metals, particularly sodium and potassium are preferred and sodium and potassium hydroxide are most preferred.

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

As antagonists of the MCH receptor the compounds according to the invention are advantageously suitable as pharmaceutical active substances for the prevention and/or treatment of symptoms and/or diseases caused by MCH or causally connected with MCH in some other way. Generally the compounds according to the invention have low toxicity, they are well absorbed by oral route and have an intracerebral transitivity, particularly brain accessibility.

Therefore, MCH antagonists which contain at least one compound according to the invention, are particularly suitable in mammals, such as for example rats, mice, guinea pigs, hares, dogs, cats, sheep, horses, pigs, cattle, monkeys and also humans, for the treatment and/or prevention of symptoms Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 ff and/or diseases which are caused by MCH or are otherwise causally connected with MCH.

Diseases caused by MCH or otherwise causally connected with MCH are particularly metabolic disorders, such as for example obesity, and eating disorders, such as for example bulimia, including bulimia nervosa. The indication obesity includes in particular exogenic obesity, hyperinsulinaemic obesity, hyperplasmic obesity, hyperphyseal adiposity, hypoplasmic obesity, hypothyroid obesity, hypothalamic obesity, symptomatic obesity, infantile obesity, upper body obesity, alimentary obesity, hypogonadal obesity and central obesity. This range of indications also includes cachexia, anorexia and hyperphagia.

Compounds according to the invention may, in particular, be suitable for reducing hunger, curbing appetite, controlling eating behaviour and/or promoting a feeling of satiety.

In addition, the diseases caused by MCH or otherwise causally connected with MCH also include hyperlipidaemia, cellulitis, fat accumulation, malignant mastocytosis, systemic mastocytosis, emotional disorders, affectivity disorders, depression, anxiety states, sleep disoreders, reproductive disorders, sexual disorders, memory disorders, epilepsy, forms of dementia and hormonal disorders.

Compounds according to the invention are also suitable as active substances for the prevention and/or treatment of other illnesses and/or disorders, particularly those which accompany obesity, such as, for example, diabetes, diabetes mellitus, especially type li diabetes, hyperglycaemia, particularly chronic hyperglycaemia, complications of diabetes including diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, etc., insulin resistance, pathological glucose tolerance, encephalorrhagia, cardiac insufficiency, cardiovascular diseases, particularly arteriosclerosis and high blood pressure, arthritis and gonitis.

Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 if MCH antagonists and formulations according to the invention may advantageously be used in combination with a dietary therapy, such as for example a dietary diabetes treatment, and exercise.

Another range of indications for which the compounds according to the invention are advantageously suitable is the prevention and/or treatment of urinary disorders, such as for example urinary incontinence, overactive bladder, urgency, nycturia and enuresis, while the Harninkontinenz, uberaktiver Harnblase, Harndrang, Nykturie, Enuresis, while the overactive bladder and urgency may or may not be connected with benign prostatic hyperplasia.

The dosage required to achieve such an effect is conveniently, by intravenous or subcutaneous route, 0.001 to 30 mg/kg of body weight, preferably 0.01 to 5 mg/kg of body weight, and by oral or nasal route or by inhalation, 0.01 to 50 mg/kg of body weight, preferably 0.1 to 30 mg/kg of body weight, in each case once to three times a day.

For this purpose, the compounds of formula I prepared according to the invention may be formulated, optionally together with other active substances as described hereinafter, together with one or more inert conventional carriers and/or diluents, e.g. with corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethylcellulose or fatty substances such as hard fat or suitable mixtures thereof, to produce conventional galenic preparations such as plain or coated tablets, capsules, powders, granules, solutions, emulsions, syrups, aerosols for inhalation, ointments or suppositories.

In addition to pharmaceutical compositions the invention also covers compositions containing at least one amide compound according to the invention and/ or a salt according to the invention optionally together with one or more physiologically acceptable excipients. Such compositions may also Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 if be foods, for example, which may be solid or liquid, in which the compound according to the invention is incorporated.

For the above mentioned combinations it is possible to use as additional active substances particularly those which for example potentiate the therapeutic effect of an MCH antagonist according to the invention in terms of one of the indications mentioned above and/or which make it possible to reduce the dosage of an MCH antagonist according to the invention.
Preferably one or more additional active substances are selected from among 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 MCH
antagonists, active substances for the treatment of high blood pressure, active substances for the treatment of hyperlipidaemia, including arteriosclerosis, active substances for the treatment of arthritis, active substances for the treatment of anxiety states, active substances for the treatment of depression.

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

Examples of active substances for the treatment of diabetes are insulin sensitisers, insulin secretion accelerators, biguanides, insulins, a-glucosidase inhibitors, (33 adreno-receptor agonists.

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

Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 ff Insulin secretion accelerators include sulphonylureas, such as for example tolbutamide, chloropropamide, tolzamide, acetohexamide, glyclopyramide and its ammonium salts, glibenclamide, gliclazide, glimepiride. Further examples of insulin secretion accelerators are repaglinide, nateglinide, mitiglinide (KAD-1229) and JTT-608.

Biguanides include metformin, buformin and phenformin.

Insulins include those obtained from animals, particularly cattle or pigs, semisynthetic human insulins which are synthesised enzymatically from insulin obtained from animals, human insulin obtained by genetic engineering, e.g. from Escherichia coli or yeasts. Moreover, the term insulin also includes insulin-zinc (containing 0.45 to 0.9 percent by weight of zinc) and protamine-insulin-zinc obtainable from zinc chloride, protamine sulphate and insulin. Insulation may also be obtained from insulin fragments or derivatives (for example INS-1, etc.).

Insulin may also include different kinds, e.g. with regard to the onset time and duration of effect ("ultra immediate action type", "immediate action type", "two phase type", "intermediate type", "prolonged action type", etc.), which are selected depending on the pathological condition of the patient.

a-Glucosidase inhibitors include acarbose, voglibose, miglitol, emiglitate.
R3 Adreno receptor agonists include AJ-9677, BMS-1 96085, SB-226552, AZ40140.

Active substances for the treatment of diabetes other than those mentioned above include ergoset, pramlintide, leptin, BAY-27-9955 as well as glycogen phosphorylase inhibitors, sorbitol dehydrogenase inhibitors, protein tyrosine phosphatase 1 B inhibitors, dipeptidyl protease Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 if inhibitors, glipizid, glyburide.

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

Aldose reductase inhibitors are for example tolrestat, epalrestat, imirestat, zenarestat, SNK-860, zopolrestat, ARI-50i, AS-3201.
An example of a glycation inhibitor is pimagedine.

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

Active substances other than those mentioned above for the treatment of diabetic complications include alprostadil, thiapride hydrochloride, cilostazol, mexiletine hydrochloride, ethyl eicosapentate, memantine, pimagedine (ALT-71 1).

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

A preferred example of a lipase inhibitor is orlistat.

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

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

Moreover for the purposes of this application the active substance group of anti-obesity active substances also includes the anorectics, of which the Ra agonists, thyromimetic active substances and NPY antagonists Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 ff should be emphasised. The scope of the anti-obesity or anorectic active substances which are preferred here is indicated by the following additional list, by way of example: phenylpropanolamine, ephedrine, pseudoephedrine, phentermine, a cholecystokinin-A (hereinafter referred to as CCK-A) agonist, 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 (such as for example bromocriptine), a melanocyte-stimulating hormone receptor agonist or mimetic, an analogue of 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 galanine antagonist, a GI lipase inhibitor or reducer (such as for example orlistat). Other anorectics include bombesin agonists, dehydroepiandrosterone or its analogues, glucocorticoid receptor agonists and antagonists, orexin receptor antagonists, urocortin binding protein antagonists, agonists of the Glucagon-like Peptide-1 receptor, such as for example exendin and ciliary neurotrophic factors, such as for example axokine.

Active substances for the treatment of high blood pressure include inhibitors of angiotensin converting enzyme, calcium antagonists, potassium channel openers and angiotensin 11 antagonists.

Inhibitors of angiotensin converting enzyme include captopril, enalapril, alacepril, delapril (hydrochloride), lisinopril, imidapril, benazepril, cilazapril, temocapril, trandolapril, manidipine (hydrochloride).

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

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

Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 ff Angiotensin II antagonists include telmisartan, losartan, candesartan cilexetil, valsartan, irbesartan, CS-866, E4177.

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

Fibrate compounds include bezafibrate, clinofibrate, clofibrate and simfibrate.

Active substances for the treatment of arthritis include ibuprofen.
Active substances for the treatment of anxiety states include chlordiazepoxide, diazepam, oxazolam, medazepam, cloxazolam, bromazepam, lorazepam, aiprazolam, fludiazepam.

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

The dosage for these active substances is conveniently 1/5 of the lowest normal recommended dose up to 1/1 of the normal recommended dose.

In another embodiment the invention also relates to the use of at least one amide compound according to the invention and/or a salt according to the invention for influencing the eating behaviour of a mammal. This use is based particularly on the fact that compounds according to the invention may be suitable for reducing hunger, curbing appetite, controlling eating behaviour and/or promoting a feeling of satiety. The eating behaviour is advantageously influenced in such a way as to reduce food intake. Therefore, the compounds according to the invention are advantageously used for reducing body weight. A further use according to the invention is the prevention of Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 if increases in body weight, for example in people who have previously taken steps to reduce their weight and are then interested in maintaining their reduced body weight. According to this embodiment it is preferably a non-therapeutic use. Such a non-therapeutic use may be a cosmetic use, for example for altering the outer appearance, or an application for improving the general feeling of wellbeing. The compounds according to the invention are preferably used in a non-therapeutic capacity for mammals, particularly humans, who have no diagnosed disorders of eating behaviour, no diagnosed obesity, bulimia, diabetes and/ or no diagnosed urinary problems, particularly urinary incontinence. Preferably the compounds according to the invention are suitable for non-therapeutic use in humans whose body mass index (BMI =
body mass index), which is defined as the body weight measured in kilograms divided by the height (in metres) squared, is less than 30, particularly less than 25.

The Examples that follow are intended to illustrate the invention:

Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 ff Preliminary remarks:

As a rule, IR, 1 H-NMR and/or mass spectra have been obtained for the compounds prepared. Unless otherwise stated the Rf values are determined using ready-made silica gel 60 TLC plates F254 (E. Merck, Darmstadt, Item no. 1.05714) without chamber saturation. The Rf values obtained under the name Alox are determined using ready-made aluminium oxide 60 F254 TLC
plates (E. Merck, Darmstadt, Item no. 1.05713) without chamber saturation.
The ratios given for the eluants relate to units by volume of the solvent in question. The units by volume for NH3 relate to a concentrated solution of NH3 in water. Silica gel made by Millipore (MATREXTM, 35-70 my) is used for chromatographic purification. Alox (E. Merck, Darmstadt, aluminium oxide 90 standardised, 63-200 pm, Item no. 1.01097.9050) is used for chromatographic purification. The HPLC data given are measured under the following parameters:
Analytical columns: Zorbax column (Agilent Technologies), SB (Stable Bond) -C18; 3.5 pm; 4.6 x 75 mm; column temperature: 30 C; flow: 0.8 mL / min;
injection volume: 5 pL; detection at 254 nm (methods A and B) Symmetry 300 (Waters), 3.5 pm; 4.6 x 75 mm; column temperature: 30 C;
flow: 0.8 mL / min; injection volume: 5 pL; detection at 254 nm (method C) method A: water:acetonitrile:formic acid 9:1:0.01 to 1:9:0.01 over 9 min method B: water:acetonitrile:formic acid 9:1:0.01 to 1:9:0.01 over 4 min, then 6 min 1:9:0.01 method C: water:acetonitrile:formic acid 9:1:0.01 to 1:9:0.01 over 4 min, then 6 min 1:9:0.01 Preparative column: Zorbax column (Agilent Technologies), SB (Stable Bond) - C18; 3.5 pm; 30 x 100 mm; column temperature: ambient temperature; flow:
30 mL / min; detection at 254 nm.
In preparative HPLC purifications, as a rule, the same gradients are used as were used to raise the analytical HPLC data.
The products are collected under mass control, the fractions containing product are combined and freeze-dried.

Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 if If there is no specific information as to the configuration, it is not clear whether there are pure enantiomers or whether partial or even total racemisation has taken place.

The following abbreviations are used above and hereinafter:
abs. absolute Boc tert-butoxycarbonyl Cbz benzyloxycarbonyl CDI N,N'-carbonyldiimidazole CDT 1,1'-carbonyldi(1,2,4-triazole) DMF N,N-dimethylformamide ether diethyl ether EtOAc ethyl acetate EtOH ethanol Fmoc 9-fluorenylmethoxycarbonyl sat. saturated semiconc. semiconcentrated HCI hydrochloric acid HOAc acetic acid HOBt 1 -hyd roxybenzotriazo le-hyd rate HUnig base N-ethyldiisopropylamine HV high vacuum i. vac. in vacuo (in vacuo) KOH potassium hydroxide conc. concentrated MeOH methanol MTBE methyl-tert-butylether NaCl sodium chloride NaOH sodium hydroxide org. organic Ph phenyl RT ambient temperature (ca. 20 C) TBTU 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium-tetrafluoroborate Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 if TEBAC triethylbenzylammonium chloride TFA trifluoroacetic acid THE tetrahydrofuran -~* denotes the binding site of a group Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 if Synthesis of intermediate products Intermediate product 1:

C1 N ~7 Br H-Br Z1a) [2-(2-chloro-4-nitro-phenoxy)-ethyl)-diethyl-amine-hydrobromide 40.00 g (1.00 mol) of potassium carbonate was added to a solution of 50.00 g (0.288 mol) of 2-chloro-4-nitro-phenol and 60.23 g (0.350 mol) of (2-chloro-ethyl)-diethyl-amine in 700 mL DMF and the mixture was stirred for16 hours at 80 C. The reaction mixture was evaporated down i. vac., the residue was combined with water and the aqueous phase was exhaustively extracted with EtOAc. The combined org. extracts were washed with water, dried over magnesium sulphate and evaporated down i. vac. The crude product was recrystallised from EtOAc and the mother liquor evaporated down i. vac.
Purification of the residue by column chromatography (silica gel, gradient dichloromethane / MeOH 10:0 - 9:1) yielded the desired product.
Yield: 29.00 g (37 % of theory) C12H17CIN203 (M= 272.734) Calc.: molpeak (M+H)+: 273/275 Found: molpeak (M+H)+: 273/275 (CI) Z1 b) 3-chloro-4-(2-diethylamino-ethoxy)-phenylamine A solution of 100 mL of conc. aqueous HCI in 100 mL EtOH was added dropwise to a suspension of 20.00 g (358 mmol) of iron powder and 20 g (73.33 mmol) of [2-(2-chloro-4-nitro-phenoxy)-ethyl)-diethyl-amine in 200 mL
EtOH, while the temperature was kept below 20 C by cooling with ice. The reaction mixture was stirred for 30 minutes, neutralised with 10% aqueous sodium bicarbonate solution and was exhaustively extracted with EtOAc. The combined org. extracts were dried over magnesium sulphate and evaporated down i. vac. The product was stored under a nitrogen atmosphere.

Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 if Yield: 17.40 g (98 % of theory) C12H19CIN2O (M= 242.751) Calc.: molpeak(M+H)+:243/245 Found: molpeak (M+H)+: 243/245 (CI) Rf value: 0.6 (silica gel, dichloromethane / MeOH / conc. aqueous ammonia 90:10:1) Z1 c) 2-bromo-N-[3-chloro-4-(2-diethylamino-ethoxy)-phenyl]-acetamide-hydrobromide A solution of 1.86 mL (21.00 mmol) of bromoacetylbromide in 10 mL of dichloromethane was added dropwise to a solution of 5.00 g (21.00 mmol) of 3-chloro-4-(2-diethylamino-ethoxy)-phenylamine in 100 mL of dichloromethane at 0 C and the mixture was stirred for 20 minutes at 0 C.
The precipitate formed was filtered off, washed with dichloromethane and MTBE and dried i. vac. at 40 C.
Yield: 8.20 g (89 % of theory) C14H21BrCIN2O2 * Br (M= 444.597) Calc.: molpeak(M+H)+:363/365/367 Found: molpeak (M+H)+: 363/365/367 (BrCI) HPLC-MS: 4.2for 5 min. (Stable Bond C18; 3.5 pm; water:acetonitrile:formic acid 9:1:0.01 -> 1:9:0.01 over 9 min) Intermediate product 2:

0 ci HO
~O
/ F
F
F

Z2a) ethyl (2-chloro-4-trifluoromethyl-phenoxy)-acetate 28.19 g (0.204 mol) of potassium carbonate was added to a solution of 20.00 g (0.102 mol) of 2-chloro-4-trifluoromethyl-phenol and 11.36 mL (0.102 mol) of ethyl bromo-acetate in 300 mL of DMF and the mixture was stirred for 7 hours at 60 C and for 16 hours at RT. The reaction mixture was evaporated down i. vac. and the residue combined with EtOAc. The org. phase was Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 ff washed with water, dried over magnesium sulphate and evaporated down i.
vac.
Yield: 23.79 g (83% of theory) C11H10CIF303 (M= 282.649) Calc.: molpeak(M+Na)+:305/307 Found: molpeak (M+Na)+: 305/307 (CI) Rf value: 0.58 (silica gel, petroleum ether / EtOAc 4:1) Z2b) (2-chloro-4-trifluoromethyl-phenoxy)-acetic acid 84 mL of 2 M aqueous NaOH was added to a solution of 23.97 g (0.084 mol) of ethyl (2-chloro-4-trifluoromethyl-phenoxy)-acetate in 200 mL EtOH and the mixture was refluxed for 1 hour. EtOH was concentrated by evaporation i.
vac., the residue was diluted with ice water and acidified with 2 M aqueous HCI. The precipitate formed was filtered off, washed with water and dried at 70 C i. vac.
Yield: 12.33 g (58 % of theory) C9H6CIF303 (M= 254.595) Calc.: molpeak(M-H)-:253/255 Found: molpeak (M-H)-: 253/255 (CI) Rf value: 0.04 (silica gel, petroleum ether /EtOAc 3:2) Intermediate product 3:

O CI
H1~1O / O CI
\ I N'~'O \
/ F
F
F

Z3a) 2-chloro-1-(2,2-diethoxy-ethoxy)-4-nitrobenzene 26.56 g (0.150 mol) of 2-chloro-4-nitrophenol and 24.25 mL (0.150 mol) of 2-bromo-1,1-diethoxy-ethane was added to a suspension of 22.80 g (0.165 mol) of potassium carbonate in 250 mL DMF and the mixture was heated to 140 C
for 24 hours. The reaction mixture was diluted with 1 L water and exhaustively extracted with MTBE. The combined org. extracts were washed with water, Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 if dried over magnesium sulphate and evaporated down i. vac. Yield: 32.10 g (74 % of theory) C12H16CINO5 (M= 289.718) Rf value: 0.7 (silica gel, dichloromethane / cyclohexane / EtOAc 1:4:1) Z3b) 3-chloro-4-(2,2-diethoxy-ethoxy)-phenylamine 30 g (0.104 mol) of 2-chloro-1-(2,2-diethoxy-ethoxy)-4-nitrobenzene was added to a suspension of 1.50 g Pd/C (10 %) in 500 mL EtOAc and the mixture was hydrogenated for 2 hours at 20 psi. The catalyst was filtered off and the filtrate evaporated down i. vac.
Yield: 27.00 g (quantitative yield) C12H18CINO3 (M= 259.735) Calc.: molpeak(M+H)+:260/262 Found: molpeak (M+H)+: 260/262 (Cl) Rf value: 0.75 (silica gel, dichloromethane / MeOH 9:1) Z3c) N-[3-chloro-4-(2,2-diethoxy-ethoxy)-phenyl]-2-(2-chloro-4-trifluoromethyl-phenoxy)-acetamide 4.495 g (0.028 mol) of CDI was added to a solution of 6.365 g (0.025 mol) of (2-chloro-4-trifluoromethyl-phenoxy)-acetic acid (intermediate product 2b) in 100 mL abs. THE and the mixture was stirred for 30 minutes at 50 C. 6.494 g (0.025 mol) of 3-chloro-4-(2,2-diethoxy-ethoxy)-phenylamine was added and the mixture was stirred for 16 hours at RT. The reaction mixture was poured into ice water and stirred for 1 hour. The precipitate formed was filtered off, washed with water and dried at 50 C.
Yield: 11.40 g (92 % of theory) C21 H22C12F3NO5 (M= 496.314) Calc.: molpeak(M-H)":494/496/498 Found: molpeak (M-H)-: 494/496/498 (CI2) Rf value: 0.73 (silica gel, petroleum ether /EtOAc 3:2) Z3d) N-[3-chloro-4-(2-oxo-ethoxy)-phenyl]-2-(2-chloro-4-trifluoromethyl-phenoxy)-acetamide Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 ff 40 mL water and 130 mL TFA was added to a solution of 11.40 g (0.023 mol) of N-[3-chloro-4-(2,2-diethoxy-ethoxy)-phenyl]-2-(2-chloro-4-trifluoromethyl-phenoxy)-acetamide in 130 mL chloroform at 0 C and the mixture was stirred for 3.5 hours at 0 C and for 48 hours at RT. The reaction mixture was neutralised with sat. aqueous sodium carbonate solution and exhaustively extracted with dichloromethane. The combined org. extracts were washed with water, dried over magnesium sulphate and evaporated down i. vac.
Yield: 8.40g (86 % of theory) C17H12CI2F3NO4(M= 422.191) CaIc.: molpeak(M-H) 421/423/425 Found: molpeak (M-H)-: 421/423/425 (CI2) Rf value: 0.14 (silica gel, petroleum ether /EtOAc 3:2) Intermediate product 4:

Hl-v O O CI
H
CI

Z4a) N-[3-chloro-4-(2,2-diethoxy-ethoxy)-phenyl]-2-(2,4-dichloro-phenoxy)-acetamide At 0 C a solution of 0.57 g (2.38 mmol) of (2,4-dichloro-phenoxy)-acetylchloride in 4 mL dichloromethane was added dropwise to a solution of 0.50 g (2.16 mmol) of 3-chloro-4-(2,2-diethoxy-ethoxy)-phenylamine (intermediate product Z3b) and 0.74 mL (4.32 mmol) of ethyl-diisopropylamine in 10 mL dichloromethane and the mixture was stirred for 1 hour at 0 C.
MeOH was added and the precipitated product was filtered off. The product was washed with MeOH and dried i. vac.
Yield: 0.74 g (79% of theory) C18H18CI3NO5 (M= 434.70) Calc.: molpeak(M-H)-:432/434/436 Found: molpeak (M-H)-: 432/434/436 (CI3) HPLC-MS: 5.00 Min. (Devosil RPAqueous; 30-100% water / acetonitrile 70:30 0:100 in for 5 min.) Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 if Z4b) N-[3-chloro-4-(2-oxo-ethoxy)-phenyl]-2-(2,4-dichloro-phenoxy)-acetamide At O C 2 mL TFA and 0.15 mL water was added to a solution of 50 mg (0.011 mmol) of N-[3-chloro-4-(2,2-diethoxy-ethoxy)-phenyl]-2-(2,4-dichloro-phenoxy)-acetamide in 2 mL dichloromethane and the mixture was stirred for 3.5 hours. 200 ml of 2 M aqueous sodium carbonate solution was added and exhaustively extracted with dichloromethane. The combined org. extracts were dried over magnesium sulphate, evaporated down i. vac. and the residue was purified by column chromatography (silica gel, EtOAc / hexane 1:1).
Yield: 40 mg (89 % of theory) C16H12C13NO4 (M= 388.63) Calc.: molpeak(M-H)":386/388/390 Found: molpeak (M-H)-: 386/388/390 (Cl3) Rf value: 0.25 (silica gel, hexane / EtOAc 3:2) HPLC-MS: 4.56 Min. (Devosil RPAqueous; 5-100% water / acetonitrile 70:30 -a 0:100 in for 5 min.) Intermediate product 5:

J aNHZ
Z5a) Diethyl-[2-(4-nitro-phenoxy)-ethyl]-amine 2.07 g (15.0 mmol) of potassium carbonate was added to a solution of 1.04 g (7.5 mmol) of 4-nitrophenol in 20 mL DMF under an argon atmosphere and the mixture was stirred for 20 minutes at 80 C. 1.72 g (10.0 mmol) of (2-chloro-ethyl)-diethyl-amine-hydrochloride was added and the mixture was stirred for 8 hours at 90 C. 100 ml of 2 M aqueous sodium carbonate solution was added and exhaustively extracted with ether. The combined org. extracts were dried over magnesium sulphate and evaporated down i. vac. The crude product was used in the next reaction step without further purification.
Yield: 1.59 g (89% of theory) Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 ff C12H18N2O3 (M= 238.28) Calc.: molpeak(M+H)+:239 Found: molpeak (M+H)+: 239 Rf value: 0.2 (silica gel, EtOAc) Z5b) 4-(2-Diethylamino-ethoxy)-phenylamine 2.6 g (10.9 mmol) of diethyl-[2-(4-nitro-phenoxy)-ethyl]-amine was added to a suspension of 130 mg Pd/C (10 %) in 20 mL MeOH and the mixture was hydrogenated for 4 hours. The catalyst was filtered off and the filtrate evaporated down i. vac.
Yield: 2.19 g (96% of theory) C12H2ON2O (M= 208.30) Calc.: molpeak(M+H)+:209 Found: molpeak (M+H)+: 209 Rf value: 0.2 (silica gel, dichloromethane / MeOH 9:1) Intermediate product 6:

Z6a) Diethyl-[2-(2-methoxy-4-nitro-phenoxy)-ethyl]-amine The product was obtained analogously to intermediate product Z5a starting from 1.27 g (7.5 mmol) of 2-methoxy-4-nitro-phenol and 1.72 g (10.0 mmol) of (2-chloro-ethyl)-diethyl-amine-hydrochloride.
Yield: 1.01 g (50 % of theory) C13H2ON2O4 (M= 268.31) Calc.: molpeak(M+H)+:269 Found: molpeak (M+H)+: 269 Rf value: 0.2 (silica gel, EtOAc) Z6b) 4-(2-Diethylamino-ethoxy)-3-methoxy-phenylamine Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 ff 0.77 g (2.87 mmol) of diethyl-[2-(2-methoxy-4-nitro-phenoxy)-ethyl]-amine was added to a suspension of 1.00 g (17.9 mmol) of iron powder in 7 mL
EtOH and the mixture was stirred for 10 minutes at RT. 6.6 mL of conc.
aqueous HCI was added dropwise within 15 minutes and the mixture was stirred for 1 hour. 100 ml of 2 M sodium carbonate solution was added and the mixture was exhaustively extracted with EtOAc. The combined org.
extracts were dried over magnesium sulphate and evaporated down i. vac.
Yield: 0.62 g (92 % of theory) C13H22N202 (M= 238.33) CaIc.: molpeak(M+H)+:269 Found: molpeak (M+H)+: 269 Rf value: 0.05 (silica gel, dichloromethane / MeOH 9:1) Intermediate product 7:

0 o Z7a) methyl 2-(2-diethylamino-ethoxy)-5-nitro-benzoate The product was obtained analogously to intermediate product Z5a starting from 1.48 g (7.5 mmol) of methyl 2-hydroxy-5-nitro-benzoate and 1.72 g (10.0 mmol) of (2-chloro-ethyl)-diethyl-amine-hydrochloride.
Yield: 0.81 g (40 % of theory) C14H20N205 (M= 296.32) Calc.: molpeak(M+H)+:297 Found: molpeak (M+H)+: 297 Rf value: 0.1 (silica gel, EtOAc / MeOH 9:1) Z7b) methyl 5-amino-2-(2-diethylamino-ethoxy)-benzoate The product was obtained analogously to intermediate product Z5b starting from 400 mg (1.35 mmol) of methyl 2-(2-diethylamino-ethoxy)-5-nitro-benzoate.
Yield: 0.35 g (97 % of theory) Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 if C14H22N203 (M= 266.34) Calc.: molpeak(M+H)+:267 Found: molpeak (M+H)+: 267 Rf value: 0.2 (silica gel, EtOAc / McOH 9:1) Intermediate product 8:

F

Z8a) diethyl-[2-(2-fluoro-4-nitro-phenoxy)-ethyll-amine The product was obtained analogously to intermediate product Z5a starting from 1.18 g (7.5 mmol) of 2-fluoro-4-nitro-phenol and 1.72 g (10.0 mmol) of (2-chloro-ethyl)-diethyl-amine-hydrochloride obtained.
Yield: 1.65 g (86 % of theory) C12H17FN203 (M= 256.27) Calc.: molpeak(M+H)+:257 Found: molpeak (M+H)+: 257 Rf value: 0.1 (silica gel, EtOAc) Z8b) 4-(2-diethylamino-ethoxy)-3-fluoro-phenylamine The product was obtained analogously to intermediate product Z6b starting from 0.68 g (2.65 mmol) of diethyl-[2-(2-fluoro-4-nitro-phenoxy)-ethyl]-amine.
Yield: 0.60 g (quantitative yield) C12H19FN2O (M= 226.29) Calc.: molpeak(M+H)-:227 Found: molpeak (M+H)+: 227 Rf value: 0.1 (silica gel, dichioromethane / MeOH 9:1) Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 if Intermediate product 9:

N

Z9a) tert.butyl (3-diethyl aminomethyl-4-hydroxy-phenyl)-carbaminate At 80 C a solution of 0.90 g (4.11 mmol) of Boc-anhydride in 20 mL THE was added to a solution of 1.00 g (3.74 mmol) of 4-amino-2-diethylaminomethyl-phenol and 0.52 mL (3.74 mmol) of triethylamine in 20 mL abs. THE and the mixture was refluxed for 24 hours. 100 ml of 2 M aqueous sodium carbonate solution was added and the mixture was exhaustively extracted with ether.
The combined org. extracts were dried over magnesium sulphate, evaporated down i. vac. and the residue was purified by column chromatography (silica gel, EtOAc).
Yield: 1.03 g (94 % of theory) C16H26N203 (M= 294.39) CaIc.: molpeak(M+H)-:295 Found: molpeak (M+H)+: 295 Rf value: 0.3 (silica gel, EtOAc) Z9b) tert.butyl [4-(2-diethylamino-ethoxy)-3-diethylaminomethyl-phenyl]-carbaminate The product was obtained analogously to intermediate product Z5a starting from 2.21 g (7.5 mmol) of tert.butyl (3-diethylaminomethyl-4-hydroxy-phenyl)-carbaminate and 1.72 g (10.0 mmol) of (2-chloro-ethyl)-diethyl-amine-hydrochloride.
Yield: 0.88 g (30 % of theory) C22H39N303 (M= 393.56) Calc.: molpeak(M+H)+:394 Found: molpeak (M+H)+: 394 Rf value: 0.05 (silica gel, dichioromethane / MeOH 9:1) Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 ff Z9c) 4-(2-diethylamino-ethoxy)-3-diethylaminomethyl-phenylamine 5 mL TFA was added to a solution of 0.18 g (0.457 mmol) of tert.butyl [4-(2-diethylamino-ethoxy)-3-diethylaminomethyl-phenyl]-carbaminate in 5 mL
chloroform and the mixture was stirred for 1 hour at RT. 100 ml of 2 M
aqueous sodium carbonate solution was added and exhaustively extracted with ether. The combined org. extracts were dried over magnesium sulphate and evaporated down i. vac.
Yield: 0.13 g (97 % of theory) C17H31N3O (M= 293.45) Calc.: molpeak(M+H)+:294 Found: molpeak (M+H)+: 294 Rf value: 0.05 (silica gel, dichloromethane / MeOH 4:1) Intermediate product 10:

NH, Z10) 4-(2-piperidin-1-yl-ethoxy)-phenylamine 15.4 g (111.00 mmol) of potassium carbonate was added to a solution of 4.0 g (27.86 mmol) of 4-amino-2-chlorophenol and 5.1 g (27.86 mmol) of 1-(2-chloro-ethyl)-piperidine in 50 mL acetonitrile and the mixture was stirred for hours at RT. The solvent was evaporated off i. vac., the residue was combined with water and the aqueous phase was exhaustively extracted with EtOAc. The combined org. extracts were washed with water, dried over magnesium sulphate, evaporated down i. vac. and the residue was purified by column chromatography (silica gel, dichloromethane / MeOH / conc. aqueous ammonia 90:10:1).
Yield: 77 mg (61 % of theory) C13H19CIN2O (M= 254.762) Calc.: molpeak(M+H)+:255/257 Found: molpeak (M+H)+: 255/257 (Cl) Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 if Intermediate product 11:

N

Z11 a) 2-hydroxy-5-nitro-benzonitrile At 45-50 C a solution of 36.0 mL of 65% aqueous nitric acid in 50 mL conc.
acetic acid was added dropwise to a solution of 50 g (0.416 mol) of 2-hydroxy-benzonitrile in 150 mL conc. acetic acid and the mixture was stirred for 1 hour at 50 C. The reaction mixture was cooled to RT, diluted with 400 mL water and the precipitate formed was filtered off (mixture of o- and p-substituted product). The mother liquor was diluted with 1 L ice water and the precipitate formed was filtered off (product). The product mixture was dissolved in dichloromethane / MeOH and purified by column chromatography (silica gel, gradient dichloromethane / MeOH 10:0 -> 4:1).
Yield: 25.22 g (37 % of theory) C7H4N203 (M= 164.122) Calc.: molpeak(M-H)-:163 Found: molpeak (M-H)-: 163 Rf value: 0.35 (silica gel, dichioromethane / MeOH 9:1) Z11 b) 5-amino-2-hydroxy-benzonitrile 4.50 g (27.00 mmol) of 2-hydroxy-5-nitro-benzonitrile was added to a suspension of 0.45 g Pd/C (10 %) in 45 mL EtOAc and the mixture was hydrogenated for 1.5 hours under 3 bar H2 atmosphere. The catalyst was filtered off and the residue dried i. vac.
Yield: 3.40 g (94 % of theory) C7H6N20 (M= 134.139) Calc.: molpeak(M-H)-:133 Found: molpeak (M-H) 133 Rf value: 0.3 (silica gel, dichloromethane / MeOH 9:1) Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 ff Z11c) 5-amino-2-(2-diethylamino-ethoxy)-benzonitrile 11.06 g (0.080 mol) of potassium carbonate was added to a solution of 2.683 g (0.020 mol) of 5-amino-2-hydroxy-benzonitrile and 3.786 g (0.022 mol) of N,N-diethylamino-ethylchoride-hydrochloride in 100 mL abs. acetonitrile and the mixture was stirred for 48 hours at RT. The solvent was evaporated off i.
vac. and the residue was combined with water. The aqueous phase was exhaustively extracted with EtOAc, the combined org. extracts were washed with water, dried over magnesium sulphate and evaporated down i. vac. The residue was purified by column chromatography (silica gel, dichloromethane /
MeOH / conc. aqueous ammonia 90:10:1).
Yield: 0.80 g (17 % of theory) C13H19N3O (M= 233.316) CaIc.: molpeak(M+H)+:234 Found: molpeak (M+H)+: 234 Rf value: 0.15 (silica gel, dichloromethane / MeOH / conc. aqueous ammonia 90:10:1) Intermediate product 12:

Z12a) diethyl-[2-(5-nitro-2,3-dihydro-indol-1-yl)-ethyl]-amine 1.00 g (7.262 mmol) of potassium carbonate was added to a solution of 0.477 g (2.905 mmol) of 5-nitro-2,3-dihydro-1 H-indole and 0.500 g (2.905 mmol) of N,N-diethylamino-ethylchoride-hydrochloride in 5 mL DMF and the mixture was stirred for 16 hours at 90 C. The reaction mixture was diluted with water and exhaustively extracted with EtOAc. The combined org. phases were dried over magnesium sulphate and evaporated down i. vac. The residue was purified by column chromatography (silica gel, EtOAc).
Yield: 0.14 g (18 % of theory) C141-121 N302 (M= 263.342) Calc.: molpeak(M+H)+:264 Found: molpeak (M+H)+: 264 Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 if Rf value: 0.26 (silica gel, EtOAc / MeOH 9:1) Z12b) 1-(2-diethylamino-ethyl)-2,3-dihydro-1 H-indol-5-ylamine 140 mg (0.532 mmol) of diethyl-[2-(5-nitro-2,3-dihydro-indol-1-yl)-ethyl]-amine was added to a suspension of 50 mg of Raney-Ni in 5 mL MeOH and the mixture was hydrogenated for 1 hour at RT under 20 psi of H2 atmosphere.
The catalyst was filtered off and the filtrate evaporated down i. vac. The crude product was reacted immediately without any further purification (cf. Example 12).
Yield: 80 mg (64 % of theory) Intermediate product 13:

J \ a NHZ

Z13a) [3-(2-chloro-4-nitro-phenyl)-prop-2-ynyl]-diethyl-amine Under a nitrogen atmosphere 12.5 mL (0.090 mol) of 3-N,N-diethylamino-propyne was added to 25.00 g (0.106 mol) of 4-bromo-3-chloro-nitrobenzene, 43.7 mL (0.315 mol) of triethylamine, 10.40 g (0.009 mol) of tetra kis[triphenylphosphine]-palladium(II) and 1.71 g (0.009 mol) of copper(l)-iodide in 250 mL acetonitrile and the mixture was refluxed for 18 hours. The reaction mixture was evaporated down i. vac., combined with EtOAc and the organic phase was washed with water. The org. phase was evaporated down i. vac. and the residue was purified by column chromatography (silica gel, petroleum ether/ EtOAc 10:0 -* 4:1) followed by column chromatography (silica gel, dichloromethane).
Yield: 15.0 g (62 % of theory) C13H15CIN202 (M= 266.730) Calc.: molpeak(M+H)+:267/269 Found: molpeak (M+H)+: 267/269 (CI) Z13b) 3-chloro-4-(3-diethylamino-prop-1-ynyl)-phenylamine Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 ff A solution of 15 mL of conc. aqueous HCI in 15 mL EtOH was added to a suspension of 4.189 g (75.00 mmol) of iron powder and 2.00 g (7.50 mmol) of [3-(2-chloro-4-nitro-phenyl)-prop-2-ynyl]-diethyl-amine in 20 mL of EtOH with vigorous stirring and the mixture was stirred for 30 minutes. The reaction mixture was neutralised with 200 mL of 10 % aqueous sodium carbonate solution and exhaustively extracted with EtOAc. The combined org. phases were dried over magnesium sulphate, evaporated down i. vac. and the residue was purified by column chromatography (silica gel, gradient dichloromethane / 10 % conc. aqueous ammonia in MeOH 100:0 -* 5:95).
Yield: 0.45 g (25 % of theory) C13H17CIN2 (M= 236.747) CaIc.: molpeak(M+H)+:237/239 Found: molpeak (M+H)+: 237/239 (Cl) Intermediate product 14:

NHZ

Z14a) [2-(2,3-dimethyl-5-nitro-indol-1-yl)-ethyl]-diethyl-amine 1.00 g (7.262 mmol) of potassium carbonate was added to a solution of 0.553 g (2.905 mmol) of 2,3-dimethyl-5-nitro-1 H-indole and 0.500 g (2.905 mmol) of N,N-diethylamino-ethylchoride-hydrochloride in 5 mL DMF and the mixture was stirred for 16 hours at 90 C. The reaction mixture was diluted with water and exhaustively extracted with EtOAc. The combined org. phases were dried over magnesium sulphate and evaporated down i. vac. The residue was purified by column chromatography (silica gel, EtOAc / MeOH 9:1).
Yield: 0.15 g (18 % of theory) C16H23N302 (M= 289.3812) Calc.: molpeak(M+H)+:290 Found: molpeak (M+H)+: 290 Rf value: 0.54 (silica gel, EtOAc / MeOH 9:1) Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 ff Z14b) 1-(2-diethylamino-ethyl)-2,3-dimethyl-1 H-indol-5-ylamine 150 mg (0.518 mmol) of [2-(2,3-dimethyl-5-nitro-indol-1-yl)-ethyl]-diethyl-amine was added to a suspension of 100 mg of Raney-Ni in 5 mL MeOH and the mixture was hydrogenated for 1 hour at RT under 20 psi H2 atmosphere.
The catalyst was filtered off and the filtrate evaporated down i. vac. The crude product was reacted immediately without further purification (see Example 5).
Yield: 100 mg (74 % of theory) Intermediate product 15:

CI

Z15) 3-chloro-4-(3-diethylamino-propyl)-phenylamine 2.00 g (7.498 mmol) of 3-chloro-4-(3-diethylamino-prop-1-ynyl)-phenylamine (intermediate product Z13b) was added to a suspension of 0.50 g Raney-Ni in 50 mL abs. MeOH and the mixture was hydrogenated for 2.5 hours at RT and 50 psi H2 atmosphere. The catalyst was filtered off, the filtrate evaporated down i. vac. and the residue was purified by column chromatography (silica gel, gradient dichloromethane / 10 % conc. aqueous ammonia in MeOH 100:0 -* 5:95).
Yield: 0.90 g (50 % of theory) C13H21CIN (M= 240.779) Calc.: molpeak(M+H)+:241/243 Found: molpeak (M+H)+: 241/243 (CI) Intermediate product 16:

F
F F
J
NHZ

Z16a) diethyl-[2-(4-nitro-2-trifluoromethyl-phenoxy)-ethyl]-amine Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 ff 5.60 g (40.00 mmol) of potassium carbonate was added to a solution of 4.10 g (20.00 mmol) of 4-nitro-2-trifluoromethyl-phenol (J. Org. Chem. 1962, 27, 4660-4662.) in 40 mL DMF and the mixture was heated to 80 C. A solution of 3.5 g (20.00 mmol) of N,N-diethylamino-ethylchoride-hydrochloride in 10 mL
DMF was added dropwise and the mixture was stirred for a further 3 hours at 80 C. The reaction mixture was diluted with 100 mL sat. aqueous NaCl solution and exhaustively extracted with EtOAc. The combined org. extracts were washed with 10 % aqueous sodium carbonate solution, dried over magnesium sulphate and evaporated down i. vac.
Yield: 7.5 g (80 % of theory) C13H17F3N2O3 (M= 306.287) CaIc.: molpeak(M+H)+:307 Found: molpeak (M+H)+: 307 Z16b) 4-(2-diethylamino-ethoxy)-3-trifluoromethyl-phenylamine 7.0 g (22.854 mmol) of 4-(2-diethylamino-ethoxy)-3-trifluoromethyl-phenylamine was added to a suspension of 0.50 g Pd/C (10 %) in EtOAc and the mixture was hydrogenated for 6 hours at 50 C and 50 psi H2 atmosphere.
The catalyst was filtered off and the filtrate evaporated down i. vac. MTBE
was added and the org. phase was washed several times with water, dried over magnesium sulphate, filtered through activated charcoal and evaporated down i. vac.
Yield: 4.40 g (70 % of theory) C13H19F3N2O (M= 276.304) Calc.: molpeak(M+H)+:277 Found: molpeak (M+H)+: 277 Intermediate product 17:

CI CI

J i NH2 Z17) 3-chloro-4-((Z)-1-chloro-3-diethylamino-propenyl)-phenylamine Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 ff A solution of 15 mL conc. aqueous HCI in 15 mL EtOH was added to a suspension of 2.20 g (75.00 mmol) of iron powder and 2.20 g (8.25 mmol) of [3-(2-chloro-4-nitro-phenyl)-prop-2-ynyl]-diethyl-amine (intermediate product Z13a) in 20 mL EtOH with vigorous stirring and the mixture was stirred for 2 hours at 80 C. The reaction mixture was neutralised with 200 mL 10 %
aqueous sodium carbonate solution and exhaustively extracted with EtOAc.
The combined org. phases were dried over magnesium sulphate and evaporated down i. vac.
Yield: 1.70 g (75 % of theory) C13H18CI2N2 (M= 273.208) Calc.: molpeak(M+H)+:273/275/277 Found: molpeak (M+H)+: 273/275/277 (Cl2) Rf value: 0.71 (silica gel, EtOAc / MeOH / conc. aqueous ammonia 90:10:1) Intermediate product 18:

" NH2 Z18a) diethyl-[2-(5-nitro-indol-1-yl)-ethyl]-amine 1.00 g (7.262 mmol) of potassium carbonate was added to a solution of 0.47 g (2.905 mmol) of 5-nitro-1 H-indole and 0.50 g (2.905 mmol) of N,N-diethylamino-ethylchoride-hydrochloride in 5 mL DMF and the mixture was stirred for 3 hours at 80 C. The reaction mixture was diluted with water and exhaustively extracted with EtOAc. The combined org. phases were dried over magnesium sulphate and evaporated down i. vac.
Yield: 0.65g (86 % of theory) C141-119N302 (M= 261.326) CaIc.: molpeak(M+H)+:262 Found: molpeak (M+H)+: 264 Z18b) 1-(2-diethylamino-ethyl)-1 H-indol-5-ylamine 650 mg (2.487 mmol) of diethyl-[2-(5-nitro-indol-1-yl)-ethyl]-amine was added to a suspension of 200 mg Raney-Ni in 10 mL MeOH and the mixture was Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 if hydrogenated for 2 hours at RT under 20 psi H2 atmosphere. The catalyst was filtered off and the filtrate evaporated down i. vac.
Yield: 520 mg (90 % of theory) C14H21 N3 (M= 231.344) CaIc.: molpeak(M+H)+:232 Found: molpeak (M+H)+: 232 Intermediate product 19:

H
-N-,,/N \ NHZ

Z19a) N'-(2-chloro-4-nitro-phenyl)-N, N-diethyl-ethane-1,2-diamine 25 mL of 50 % aqueous KOH solution was added to a solution of 1.00 g (5.795 mmol) of 2-chloro-4-nitro-phenylamine, 2.995 g (17.384 mmol) of (2-chloro-ethyl)-diethyl-amine and 0.66 g (2.898 mmol) of TEBAC in 50 mL
toluene and the mixture was refluxed for 5 days. The reaction mixture was cooled to RT and exhaustively extracted with EtOAc. The combined org.
phases were dried over magnesium sulphate, evaporated down i. vac. and the residue was purified by column chromatography (silica gel, dichloromethane / MeOH 4:1).
Yield: 1.2 g (76 % of theory) C12H18CIN302 (M= 271.749) Calc.: molpeak(M+H)+:272/274 Found: molpeak (M+H)+: 272/274 (CI) Z19b) N-(2-diethylamino-ethyl)-benzene-1,4-diamine 1.20 mg (4.416 mmol) of N'-(2-chloro-4-nitro-phenyl)-N,N-diethyl-ethane-1,2-diamine was added to a suspension of 200 mg Raney-Ni in 20 mL MeOH and the mixture was hydrogenated for 2 hours at RT under 20 psi H2 atmosphere.
The catalyst was filtered off and the filtrate evaporated down i. vac.
Yield: 800 mg (87 % of theory) C12H21N3 (M= 207.321) CaIc.: molpeak(M+H)+:207 Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 if Found: molpeak (M+H)+: 207 Intermediate product 20:

CI

Z20a) N-(2-chloro-4-nitro-phenyl)-N',N'-diethyl-N-methyl-ethane-l,2-diamine 1.00 mL (6.181 mmol) of N,N-diethyl-N'-methyl-ethane-l,2-diamine was added to a solution of 1.085 g (6.181 mmol) of 2-chloro-1-fluoro-4-nitrobenzene and 1.03 mL (7.417 mmol) of triethylamine in 20 mL THE and the mixture was stirred for 48 hours at RT. The reaction mixture was combined with sat. aqueous sodium bicarbonate solution and exhaustively extracted with EtOAc. The combined org. extracts were dried over magnesium sulphate and evaporated down i. vac.
Yield: 1.60 mg (91 % of theory) C13H2OCIN3O2 (M= 285.776) CaIc.: molpeak(M+H)+:286/288 Found: molpeak (M+H)+: 286/288 (CI) Z20b) 2-chloro-N'-(2-diethylamino-ethyl)-N'-methyl-benzene-1,4-diamine 1.60 mg (5.599 mmol) of N-(2-chIoro-4-nitro-phenyl)-N',N'-diethyl -N-methyl-ethane-1,2-diamine was added to a suspension of 200 mg Raney-Ni in 20 mL
MeOH and the mixture was hydrogenated for 2 hours at RT under 20 psi H2 atmosphere. The catalyst was filtered off and the filtrate evaporated down i.
vac.
Yield: 1.30 mg (91 % of theory) C13H22CIN3 (M= 255.793) Calc.: molpeak(M+H)+:256/258 Found: molpeak (M+H)+: 256/258 Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 if Intermediate product 21:

Z21a) N-[1-(2-di ethyl am ino-ethyl)-1,2,3,4-tetrahydro-quinolin-6-yl]-2,2,2-trifluoro-acetamide 50 mL of 50 % aqueous KOH solution was added to a solution of 3.00 g (12.284 mmol) of 6-nitro-1,2,3,4-tetrahydro-quinoline, 6.342 g (36.852 mmol) of (2-chloro-ethyl)-diethyl-amine and 1.68 g (7.370 mmol) of TEBAC in 100 mL toluene and the mixture was stirred for 1 hour at 80 C. The reaction mixture was cooled to RT and exhaustively extracted with EtOAc. The combined org. phases were dried over magnesium sulphate, evaporated down i. vac. and the residue was purified by column chromatography (silica gel, EtOAc / McOH 9:1).
Yield: 0.75 g (18 % of theory) C17H24F3N3O (M= 343.396) CaIc.: molpeak(M+H)+:344 Found: molpeak (M+H)+: 344 Z21 b) 1-(2-diethylamino-ethyl)-1,2,3,4-tetrahydro-quinolin-6-ylamine 1.1 mL 6 M aqueous NaOH solution was added to a solution of 0.75 g (2.184 mmol) of N-[l -(2-diethylamino-ethyl)-1,2,3,4-tetrahydro-quinolin-6-yl]-2,2,2-trifluoro-acetamide in 5 mL MeOH at 0 C and the mixture was stirred for 15 minutes at 0 C and for 1 hour at RT. The reaction mixture was evaporated down i. vac., sat. aqueous sodium bicarbonate solution was added and the mixture was exhaustively extracted with EtOAc. The combined org. extracts were dried over magnesium sulphate, evaporated down i. vac. and the residue was purified by column chromatography (silica gel, dichloromethane /
MeOH / conc. aqueous ammonia 90:10:1).
Yield: 220 mg (41 % of theory) C15H25N3 (M= 247.387) CaIc.: molpeak(M+H)+:248 Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 if Found: molpeak (M+H)+: 248 Intermediate product 22:

o=s=o N

I / N

Z22a) N-(4-nitro-phenyl)-methanesulphonic acid amide 27.60 g (0.20 mol) of 4-nitroaniline was dissolved in 100 mL pyridine. At 0 C
16.3 mL (0.21 mol) of methanesulphonic acid chloride were added dropwise so that the reaction temperature did not exceed 20-25 C. Then the mixture was stirred for 2.5 hours at RT. The reaction mixture was added to 800 mL ice water with stirring and stirred for 30 minutes. The precipitated solid was filtered off, washed with 500 mL water and 100 mL EtOH and dried.
Yield: 41.00 g (95 % of theory) melting point: 183-184 C
Rf value: 0.50 (silica gel, dichloromethane / EtOAc = 90:10) Z22b) N-(2-dimethylamino-ethyl)-N-(4-nitro-phenyl)-methanesulphonic acid amide 36.00 g (0.166 mol) of N-(4-nitro-phenyl)-methanesulphonic acid amide was dissolved in 2000 mL acetone. The solution was combined with 47.8 g (0.332 mol) of 1-chloro-2-dimethylaminoethane * HCI, 68.8 g (0.498 mol) of potassium carbonate, 5.0 g (0.033 mol) of sodium iodide and 50 mL water. It was refluxed for 16 hours with stirring. After the addition of another 23.9 g (0.166 mol) of 1-chloro-2-dimethylaminoethane * HCl, 45.9 g (0.332 mol) of potassium carbonate and 5.0 g (0.033 mol) of sodiumiodide, the mixture was refluxed for 5 hours with stirring. At RT the inorganic salts were filtered off.
The filtrate was evaporated down i. vac. and the residue dissolved in EtOAc.
The org. phase was washed 2x with semisat. aqueous sodium chloride solution, dried over magnesium sulphate, filtered and evaporated down i. vac.
Yield: 30.57 g (64 % of theory) Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 ff C11H17N3O4S (M= 287.340) CaIc.: molpeak(M+H)+:288 Found: molpeak (M+H)+: 288 Rf value: 0.60 (silica gel, dichloromethane / MeOH / conc. aqueous ammonia = 90:10:1) Z22c) N-(4-amino-phenyl)-N-(2-dimethylamino-ethyl)-methanesulphonic acid amide 9.00 g (31.3 mmol) of N-(2-dimethylamino-ethyl)-N-(4-nitro-phenyl)-methanesulphonic acid amide were dissolved in 120 mL MeOH. After the addition of 1.0 g of 10% palladium/charcoal the mixture was hydrogenated for 1 hour at RT and 50 psi H2 atmosphere. The reaction mixture was filtered and the filtrate evaporated down i. vac. The residue was stirred with ether/petroleum ether = 1:1. The solid was filtered off, washed with ether/petroleum ether = 1:1 and dried.
Yield: 7.65 g (95 % of theory) melting point: 151-152 C
Rf value: 0.40 (silica gel, dichloromethane / MeOH / conc. aqueous ammonia = 90:10:1) Intermediate product 23:

NCH
H

Z23a) ethyl 4-cyanomethyl-benzoate A solution of 500 g (2.057 mol) of ethyl 4-bromomethyl-benzoate in 1000 ml of ethanol is added dropwise to a solution of 147.5 g (2.263 mol) of potassium cyanide in 250 mL of hot water. The reaction mixture is refluxed for one hour and stirred for 12 hours at RT. A further 73.7 g (0.5 mol) of potassium cyanide are added and the mixture is refluxed for two hours. The solid present in the reaction mixture is filtered off and the filtrate is filtered through a mixture of Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 if silica gel and activated charcoal. The filtrate obtained is evaporated down and the residue is poured onto 1000 mL of water. The aqueous solution is extracted with MTBE and the organic phase is extracted three times with water. Then the organic phase is dried over magnesium sulphate and the solvent is distilled off using the rotary evaporator. The product is purified by column chromatography on silica gel (petroleum ether/ ethyl acetate 8:2).
Yield: 164.46 g (42.2 % of theory) C1 1 H1 1 N02 (M= 189.216) Calc.: molpeak (M+H)+: 190 Found: molpeak (M+H)+: 190 Rf value: 0.3 (silica gel, petroleum ether/EtOAc 8:2) Z23b) 4-cyanomethyl-benzoic acid A solution of 10 g (53 mol) of ethyl 4-cyanomethyl-benzoate and 2.02 mL of a 1 M sodium hydroxide solution in 100 mL of ethanol is refluxed for one hour.
Then the reaction solution is evaporated down and the residue is combined with ice water. Concentrated hydrochloric acid is added dropwise to the reaction solution until no more precipitate is formed. The precipitate is filtered off, washed twice with water and dried.
Yield: 4.7 g (55 % of theory) C9H7NO2 (M= 161,162) Calc.: molpeak (M-H)-: 160 Found: molpeak (M-H)-: 160 Z23c) (4-hydroxymethyl-phenyl)-acetonitrile 5.17 g (32 mol) of CDI are added to a solution of 4.7 g (29 mol) of 4-cyanomethyl-benzoic acid in 250 mL of tetrahydrofuran and stirred until no more gas is given off. This reaction mixture is added dropwise to a solution of 3.29 g (87 mol) of sodium borohydride in 200 mL of water in such a way that the temperature does not exceed 30 C. The mixture is stirred for two hours and the reaction mixture is adjusted to pH 3-4 with potassium hydrogen sulphate solution. Then it is extracted with EtOAc, the organic phase is dried Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 if over magnesium sulphate and the solvent is separated off using the rotary evaporator.
Yield: 2.6 g (60.9 % of theory) C9H9NO (M= 147.178) Calc.: molpeak(M-H)-: 146 Found: molpeak (M-H)-: 146 Z23d) (4-bromomethyl-phenyl)-acetonitrile 0.86 mL (9 mmol) of phosphorus tribromide are added dropwise to a solution of 2.6 g (17.66 mmol) of (4-hydroxymethyl-phenyl)-acetonitrile in 25 mL MTBE
at 0 C. After the reaction has ended the reaction mixture is combined with water at RT, the organic phase is separated off and these are extracted successively with sodium hydrogen carbonate solution and water. The organic phase is dried over magnesium sulphate and the solvent is distilled off using the rotary evaporator.
Yield: 2.9 g (78.1 % of theory) C9H8BrN (M= 210.075) Calc.: molpeak(M+H)+:209/211 Found: molpeak (M+H)+: 209/211 Z23e) (4-pyrrolidin-1-ylmethyl-phenyl)-acetonitrile 0.446 mL (5.44 mmol) of pyrrolidine and 1.366 g (9.882 mmol) of potassium carbonate are added to 20 mL of dimethylformamide. 1.038 g (4.941 mmol) of (4-bromomethyl-phenyl)-acetonitrile are added with stirring and the mixture is stirred for 12 hours at RT. The reaction mixture is evaporated down in the rotary evaporator and the residue is extracted with EtOAc and water. The organic phase is dried over magnesium sulphate and the solvent is removed using the rotary evaporator.
Yield: 0.732 g (74 % of theory) C13H16N2 (M= 200,286) Calc.: molpeak(M+H)+:201 Found: molpeak (M+H)+: 201 Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 if Rf value: 0.5 (silica gel, dichloromethane / MeOH / conc. aqueous ammonia 90:10:1) Z23f) 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 Raney nickel in 25 mL of methanolic ammonia solution is hydrogenated for 9 hours at 50 C under 3 bar hydrogen.
Yield: 0.72 g (96.4 % of theory) C13H2ON2 (M= 204.31) Calc.: molpeak(M+H)+:205 Found: molpeak (M+H)+: 205 Rf value: 0.23 (silica gel, dichloromethane / MeOH / conc. aqueous ammonia 90:10:1) Intermediate product 24 /--GN
N H
H

Z24a) (4-piperidin-1-ylmethyl-phenyl)-acetonitrile Prepared analogously to Example Z23e from piperidine and (4-bromomethyl-phenyl)-acetonitrile.
Yield: 1.6 g (39 % of theory) C14H18N2(M= 214.31) CaIc.: molpeak(M+H)+:215 Found: molpeak (M+H)+: 215 Rf value: 0.4 (silica gel, cyclohexane/EtOAc 1:1) Z24b) 2-(4-piperidin-1-ylmethyl-phenyl)-ethylamine Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 if Prepared analogously to Example Z23f from (4-piperidin-1 -ylmethyl-phenyl)-acetonitrile Yield: 1.4 g (85.9 % of theory) C14H22N2 (M= 218.34) Calc.: molpeak(M+H)+:219 Found: molpeak (M+H)+: 219 Rf value: 0.2 (silica gel, dichloromethane/ethanol/ammonia 20:1:0.1) Intermediate product 25:

Z25a) Ethyl 5-hydroxy-2-nitrobenzoate A solution of 5.00 g (27.304 mmol) 5-hydroxy-2-nitrobenzoic acid was refluxed in 200 mL ethanolic HCI for 5 h and then stirred for 48 h at RT. The reaction mixture was evaporated down i. vac. and diluted with EtOAc. The org. phase was washed with water, dried over magnesium sulphate and evaporated down i. vac.. The crude product was used in the next reaction step without any further purification.
Yield: 5.00 g (87% of theory) C9H9NO5 (M= 211,176) Calc.: molpeak (M-H)-: 210 Found: molpeak (M-H)-: 210 Z25b) Ethyl 2-nitro-5-(2-diethylamino-ethoxy)-benzoate Prepared analogously to intermediate product Z5a from ethyl 5-hydroxy-2-nitrobenzoate and (2-chloroethyl)-diethyl-amine-hydrochloride Yield: 6.30 g (85% of theory) C15H22N205 (M= 310,353) Calc.: molpeak (M+H)+: 311 Found: molpeak (M+H)+: 311 Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 if Z25c) ethyl 2-amino-5-(2-diethylamino-ethoxy)-benzoate Prepared analogously to intermediate product Z5b from ethyl 2-nitro-5-(2-diethylamino-ethoxy)-benzoate. Column chromatography (silica gel, EtOAc/MeOH/ammonia 90:10:1) yielded the product.
Yield: 4.00 g (71 % of theory) C15H24N203 (M= 280,370) Calc.: molpeak (M+H)+: 281 Found: molpeak (M+H)+: 281 Intermediate product 26: ethyl (4-bromo-2-chloro-phenoxy)-acetate 0 ci Br Z26) 14.5 mL (83.242 mmol) Honig base was added to a solution of 7.800 g (37.222 mmol) 4-bromo-2-chlorophenol and 4.70 mL (41.537 mmol) ethyl bromoacetate in 100 mL DMF and the mixture was stirred for 4 h at 100 C.
The reaction mixture was combined with water and exhaustively extracted with EtOAc. The combined org. phases were washed with saturated aqueous sodium bicarbonate, water and saturated aqueous NaCl, dried over sodium sulphate and evaporated down i. vac. . The crude product was used in the next reaction step without any further purification.
Yield: 11.36 g (quant. yield) C10H10BrCIO3 (M= 293.546) Rf value: 0.65 (silica gel, dichloromethane) Intermediate product 27:

Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 if Z27a) [2-(3-chloro-4-nitro-phenoxy)-ethyl]-diethyl-amine Prepared analogously to intermediate product Z5a starting from 3-chloro-4-nitro-phenol and (2-chloro-ethyl)-diethyl-amine.
Yield: 1.25 g (79% of theory) C12H17CIN2O3 (M= 272.734) Calc.: molpeak (M+H)+: 273/275 Found: molpeak (M+H)+: 273/275 (CI) Rf value: 0.44 (silica gel, dichloromethane / MeOH 9:1).
Z27b) 2-chloro-4-(2-diethylamino-ethoxy)-phenylamine A suspension of 1.24 g (4.547 mmol) [2-(3-chloro-4-nitro-phenoxy)-ethyl]diethyl-amine (Z27a) and 300 mg Raney nickel in EtOAc was hydrogenated at RT and 3 bar. The catalyst was filtered off and the filtrate evaporated down i. vac. .
Yield: 1.10 g (quant. yield) C12H19CIN2O (M= 242.751) Calc.: molpeak (M+H)+: 243/245 Found: molpeak (M+H)+: 243/245 (CI) Rf value: 0.41 (silica gel, dichloromethane / MeOH 9:1).
Intermediate product 28:

ci er~~ \ 0 CI
H
F
F
F

Z28a) N-(3-chloro-4-hydroxy-phenyl)-2-(2-chloro-4-trifluoromethyl-phenoxy)-acetamide 17.31 mL (98.510 mmol) Honig base was added at RT to a solution of 7.600 g (29.850 mmol) (2-chloro-4-trifluoromethyl-phenoxy)-acetic acid (Z2b), 4.370 g (29.850 mmol) 4-amino-2-chloro-phenol and 10.56 g (32.840 mmol) TBTU in 550 mL as. THE and the mixture was stirred for 48 h. The reaction mixture Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 if was evaporated down i. vac. and diluted with EtOAc. The org. phase was washed with water, saturated aqueous sodium bicarbonate and saturated aqueous NaCl, dried over sodium sulphate and evaporated down i. vac. .
Column chromatography (silica gel, gradient dichloromethane / MeOH 99:1 ->
19:1) yielded the product.
Yield: 4.200 g (37% of theory) C15H10CI2F3NO3 (M= 380.153) CaIc.: molpeak (M+H)+: 380/382/384 Found: molpeak (M+H)+: 380/382/384 (CI2) Rf value: 0.58 (silica gel, dichloromethane / MeOH 19:1).

Z28b) N-[4-(2-bromo-ethoxy)-3-chloro-phenyl]-2-(2-chloro-4-trifluoromethyl-phenoxy)-acetamide A solution of 3.66 mL (41.56 mmol) 1,2-dibromoethane in 5 mL DMF was slowly added at RT to a suspension of 1.580 g (4.156 mmol) N-(3-chloro-4-hydroxy-phenyl)-2-(2-chloro-4-trifluoromethyl-phenoxy)-acetamide and 2.880 g (8.310 mmol) potassium carbonate in 20 mL DMF and the mixture was stirred for 2.5 h. The reaction mixture was evaporated down i. vac. and diluted with EtOAc. The org. phase was washed with water and saturated aqueous NaCl, dried over magnesium sulphate and evaporated down i. vac. .
Column chromatography (silica gel, petroleum ether --- dichloromethane) yielded the product.
Yield: 1.120 g (55% of theory) C17H13BrCI2F3NO3 (M= 487.103) CaIc.: molpeak (M+H)+: 486/488/490/492 Found: molpeak (M+H)+: 486/488/490/492 (BrC12) Rf value: 0.72 (silica gel, dichloromethane / MeOH 49:1).
Intermediate product 29:

ci NHZ

Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 if Z29a) [2-(2-chloro-4-nitro-phenoxy)-propyl]-diethyl-amine At 0 C 1.60 g (33.000 mmol) NaH (50% in oil) was added to a solution of 5.30 g (30.000 mmol) 3-chloro-4-fluoro-nitrobenzene and 4.30 g (33.000 mmol) 3-diethylamino-propanol in 50 mL abs. DMF and the mixture was stirred for 2 h at 0 C and for 1 h at RT. The reaction mixture was evaporated down i. vac. and diluted with EtOAc. The org. phase was washed with water, dried over sodium sulphate and evaporated down i. vac. . Column chromatography (silica gel, dichloromethane / EtOH / conc. aqueous ammonia 90:10:0.1) yielded the product.
Yield: 8.00 g (93% of theory) C13H19CIN2O3 (M= 286.761) Rf value: 0.30 (silica gel, dichloromethane / MeOH / conc. aqueous ammonia 90:10:0.1).

Z29b) 3-chloro-4-(3-diethylamino-propoxy)-phenylamine A suspension of 8.00 g (27.900 mmol) [2-(2-chloro-4-nitro-phenoxy)-propyl]-diethyl-amine (Z29a) and 0.80 g Raney nickel in 170 mL MeOH was hydrogenated for 8 h at RT and 50 psi. The catalyst was filtered off and the filtrate evaporated down i. vac. .
Yield: 6.70 g (93% of theory) C13H21CIN2O (M= 256.778) CaIc.: molpeak (M+H)+: 257/259 Found: molpeak (M+H)+: 257/259 (CI) Rf value: 0.40 (silica gel, dichloromethane / MeOH / conc. aqueous ammonia 50:10:0.1).

Intermediate product 30:

Br Z30a) [2-(2-bromo-4-nitro-phenoxy)-ethyl]-diethyl-amine Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 if Prepared analogously to Intermediate product Z29a starting from 2-bromo-1-fluoro-4-nitro-benzene and 2-diethylamino-ethanol.
Yield: 0.790 g (83% of theory) C12H17BrN2O3 (M= 317.185) Calc.: molpeak (M+H)+: 317/319 Found: molpeak (M+H)+: 317/319 (Br) Rf value: 0.48 (silica gel, dichloromethane / MeOH 9:1).
Z30b) 3-bromo-4-(2-diethylamino-ethoxy)-phenylamine Prepared analogously to Intermediate product Z29b starting from [2-(2-bromo-4-nitro-phenoxy)-ethyl]-diethyl-amine (Z30a).
Yield: 0.670 g (96% of theory) C12H19BrN2O (M= 287.202) Calc.: molpeak (M+H)+: 287/289 Found: molpeak (M+H)+: 287/289 (Br) Rf value: 0.30 (silica gel, dichloromethane / MeOH 9:1).
Intermediate product 31:

o. ..o N

NH, Z31 a) N-[4-(2-diethylamino-ethoxy)-3-nitro-phenyl]-acetamide 0.737 g (7.286 mmol) potassium nitrate was added batchwise at -10 C to a solution of 1.520 g (6.072 mmol) N-[4-(2-diethylamino-ethoxy)-phenyl]-acetamide in 25 mL conc. sulphuric acid and the mixture was stirred for 1 h at -10 C. The reaction mixture was poured onto a mixture of ice and conc.
aqueous ammonia and the aqueous phase was exhaustively extracted with EtOAc. The combined org. phases were dried over sodium sulphate and evaporated down i. vac. .
Yield: 1.8 g (quant. yield) C14H21N304 (M= 295.341) Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 if Calc.: molpeak (M+H)+: 296 Found: molpeak (M+H)+: 296 Rf value: 0.51 (Alox, dichloromethane / MeOH 39:1).
Z31 b) 4-(2-diethylamino-ethoxy)-3-nitro-phenylamine A solution of 1.85 g (6.264 mmol) N-[4-(2-diethylamino-ethoxy)-3-nitro-phenyl]-acetamide (Z31 a) in semiconc. aqueous HCI was stirred for 2 h at 100 C, cooled to RT, made basic with ice and conc. aqueous ammonia and the aqueous phase was exhaustively extracted with EtOAc. The combined org.
phases were washed with water and dried over sodium sulphate.
Yield: 1.38 g (87% of theory) C12H19N303 (M= 253.304) Calc.: molpeak (M+H)+: 254 Found: molpeak (M+H)+: 254 Rf value: 0.68 (Alox, dichloromethane / MeOH 39:1).
Intermediate product 32:

ci ci \ o ci / N~O \
H
/ F
F
F

Z32a) N-(3-chloro-4-hydroxymethyl-phenyl)-2-(2-chloro-4-trifluoromethyl-phenoxy)-acetamide 0.55 mL (4.200 mmol) of isopropyl chloroformate was slowly added dropwise at -5 C to a solution of 1.018 g (4.000 mmol) of (2-chloro-4-trifluoromethyl-phenoxy)-acetic acid (Z2b) and 0.46 mL (4.200 mmol) N-methylmorpholine in mL abs. DMF and the mixture was stirred for another 5 min.. 0.662 g (4.200 mmol) (4-amino-2-chloro-phenyl)-methanol was added at -5 C, the mixture was stirred for 2 h at RT and then the reaction mixture was poured onto ice water. The precipitate was filtered off, washed with water and dried in HV.
Yield: 1.360 g (83% of theory) Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 ff C16H12CI2F3NO3 (M= 394.180) Rf value: 0.50 (silica gel, dichioromethane / MeOH 19:1).

Z32b) N-(3-chloro-4-chloromethyl-phenyl)-2-(2-chloro-4-trifluoromethyl-phenoxy)-acetamide 1.12 mL (16.440 mmol) thionyl chloride was added to a solution of 1.620 g (4.110 mmol) N-(3-chloro-4-hydroxymethyl-phenyl)-2-(2-chloro-4-trifluoromethyl-phenoxy)-acetamide (Z32a) in 30 mL toluene and the mixture was stirred for 2 h at 80 C. The reaction mixture was evaporated down i. vac.
and the residue recrystallised from ether/petroleum ether. The precipitate was filtered off, washed with petroleum ether and dried in a HV.
Yield: 1.100 g (65% of theory) C16H11C13F3NO2 (M= 412.626) Calc.: molpeak (M+H)+: 412/414/416/418 Found: molpeak (M+H)+: 412/414/416/418 (CI3) Rf value: 0.69 (silica gel, petroleum ether / EtOAc 3:1).
Intermediate product 33:

'~1oN

Z33a) tert-butyl methyl-(4-nitro-benzyl)-carbaminate 17.68 g (81.00 mmol) Boc-anhydride was slowly added at 0 C to a solution of 13.40 g (81.00 mmol) methyl-(4-nitro-benzyl)-amine in 25 mL EtOAc and the mixture was stirred for 3 h at RT. The org. phase was washed with water, dried over sodium sulphate and evaporated down i. vac. .
Yield: 21.36 g (99% of theory) C13H18N204 (M= 266.299) Rf value: 0.60 (silica gel, petroleum ether / EtOAc 3:7).
Z33b) tert-butyl (4-amino-benzyl)-methyl-carbaminate Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 if A suspension of 23.00 g (86.00 mmol) tert-butyl methyl-(4-nitro-benzyl)-carbaminate (Intermediate product Z33a) and 2.30 g Raney nickel in 460 mL
EtOH/EtOAc (1:1) was hydrogenated at RT and 3 bar. The catalyst was filtered off, the filtrate evaporated down i. vac. and the residue purified by column chromatography (silica gel, petroleum ether/ EtOAc 1:1).
Yield: 9.23 g (45% of theory) C13H2ON202 (M= 236.317) Calc.: molpeak (M+H)+: 237 Found: molpeak (M+H)+: 237 Rf value: 0.40 (silica gel, petroleum ether / EtOAc 1:1).
Intermediate product 34:

O
HO
N

CI

Z34a) ethyl (E)-3-[5-(4-chloro-phenyl)-pyridin-2-yl]-acrylate 2.000 g (5.560 mmol) (ethoxycarbonylmethylene)-triphenylphosphorane was added at RT to a solution of 1.100 g (5.050 mmol) 5-(4-chloro-phenyl)-pyridine-2-carbaldehyde in 50 mL abs. THE and the mixture was stirred for 4 h at RT. The reaction mixture was evaporated down i. vac. and the residue purified by column chromatography (Alox, neutral, act. II-III, petroleum ether /
EtOAc 5:1). Recrystallisation from petroleum ether yielded the product.
Yield: 1.200 g (83% of theory) C16H14CIN02 (M= 287.748) Calc.: molpeak (M+H)+: 288/290 Found: molpeak (M+H)+: 288/290 (CI) Rf value: 0.60 (silica gel, petroleum ether/ EtOAc 5:1).
Z34b) (E)-3-[5-(4-chloro-phenyl)-pyridin-2-yl]-acrylic acid 12.6 mL aqueous NaOH (1 M) was added at RT to a suspension of 1.200 g (4.200 mmol) ethyl (E)-3-[5-(4-chloro-phenyl)-pyridin-2-yl]-acrylate (Z34a) in Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 if 50 mL EtOH and the mixture was stirred for 1 h . 12.6 mL aqueous HCI (1 M) was added at 0 C. The precipitate formed was filtered off, washed with water and dried i. vac. at 100 C.
Yield: 1.000 g (92% of theory) C14H10CIN02 (M= 259.694) Calc.: molpeak (M+H)+: 260/262 Found: molpeak (M+H)+: 260/262 (Cl) Rf value: 0.40 (silica gel, dichloromethane / MeOH 9:1).
Intermediate product 35:

Cl NHZ

Z35a) (2-chloro-4-nitro-benzyl)-diethyl-amine 0.80 g (3.883 mmol) 2-chloro-1-chloromethyl-4-nitro-benzene was added to a solution of 2.60 mL (25.000 mmol) diethylamine in 50 mL THE and the mixture was refluxed for 8 h. The reaction mixture was evaporated down i. vac. and the residue was taken up in EtOAc. The org. phase was washed with water, dried over sodium sulphate and evaporated down i. vac. .
Yield: 0.750 g (80% of theory) C11H15CIN2O2 (M= 242.707) Calc.: molpeak (M+H)+: 243/245 Found: molpeak (M+H)+: 243/245 (CI) Rf value: 0.50 (Alox, petroleum ether).

Z35b) 3-chloro-4-diethylaminomethyl-phenylamine A suspension of 0.700 g (2.884 mmol) (2-chloro-4-nitro-benzyl)-diethyl-amine (Z35a) and 0.400 g Raney nickel in 20 mL THE was hydrogenated for 7.5 h at RT and 25 psi. The catalyst was filtered off and the filtrate was evaporated Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 ff down i. vac. . The crude product was purified by column chromatography (Alox, neutral, act. I1-111, petroleum ether / EtOAc 4:1).
Yield: 0.510 g (83% of theory) C11H17CIN2 (M= 212.725) CaIc.: molpeak (M+H)+: 213/215 Found: molpeak (M+H)+: 213/215 (CI) Rf value: 0.58 (Alox, petroleum ether / EtOAc 3:1).
Intermediate product 36:

ci N

Z36a) 1-(2-chloro-4-nitro-benzyl)-4-methyl-piperidine 1.00 g (4.854 mmol) 2-chloro-1-chloromethyl-4-nitro-benzene was slowly added at RT to 2.00 mL (16.223 mmol) 4-methylpiperidine and the mixture was stirred for a further 15 min.. EtOAc was added, the org. phase was washed with water, dried over sodium sulphate and evaporated down i. vac. .
C13H17CIN202 (M= 268.746) CaIc.: molpeak (M+H)+: 269/271 Found: molpeak (M+H)+: 269/271 (CI) Rf value: 0.40 (Alox, petroleum ether).

Z36b) 3-chloro-4-(4-methyl-piperidin-1-ylmethyl)-phenylamine Prepared analogously to Intermediate product Z35b starting from 1-(2-chioro-4-nitro-benzyl)-4-methyl-piperidine (Z36a). The crude product was purified by column chromatography (Alox, neutral, act. II-III, gradient petroleum ether /
EtOAc 6:1 -- 3:1).
Yield: 0.930 g (80% of theory) C13H19CIN2 (M= 238.763) Caic.: molpeak (M+H)+: 239/241 Found: molpeak (M+H)+: 239/241 (CI) Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 if Rf value: 0.58 (Alox, petroleum ether / EtOAc 3:1).
Intermediate product 37:

0 ci HO
F
F
F

Z37a) ethyl (E)-3-(2-chloro-4-trifluoromethyl-phenyl)-acrylate 0.157 g (0.686 mmol) palladium(II)acetate, 0.800 g (2.550 mmol) tri-o-tolylphosphine and 23.94 mL (171.73 mmol) triethylamine was added to 21.48 g (68.69 mmol) 2-chloro-1-iodo-4-trifluoromethyl-benzene and 10.45 mL
(96.17 mmol) ethyl acrylate in 100 mL acetonitrile and the mixture was refluxed for 6 h. The reaction mixture was evaporated down i. vac. and the residue triturated with EtOAc. The precipitate was filtered off and dried in a HV. The crude product was used in the next reaction step without any further purification.
Yield: 19.1 g (quant. yield) C12H10CIF3O2 (M= 278.661) Rf value: 0.65 (silica gel, petroleum ether / EtOAc 6:1).
Z37b) (E)-3-(2-chloro-4-trifluoromethyl-phenyl)-acrylic acid A solution of 5.80 g (145.00 mmol) NaOH in 30 mL water was slowly added to a solution of 19.1 g (68.61 mmol) (E)-3-(2-chloro-4-trifluoromethyl-phenyl)-acrylate ethyl (Z37a) in 100 mL EtOH and the mixture was stirred for 1 h at RT. EtOH was concentrated by evaporation i. vac., the aqueous phase was washed with EtOAc and acidified to pH 1with semiconc. aqueous HCI. The precipitate was filtered off, washed with water and dried in a HV.
Yield: 15.80 g (92% of theory) C10H6CIF3O2 (M= 250.606) Calc.: molpeak (M+H)+: 249/250 Found: molpeak (M+H)+: 249/250 (CI) Rf value: 0.50 (silica gel, petroleum ether / EtOAc 3:1).

Boehringer Ingeiheim CA 02504207 2005-04-28 Case 1-1407 if Intermediate product 38:

CI o N
N

CI

Z38a) (E)-3-[5-(4-chloro-phenyl)-pyridin-2-yl]-N-(4-hydroxymethyl-phenyl)-acrylamide 90 pL (0.720 mmol) isobutyl chloroformate was added dropwise at -6 C to a solution of 0.180 g (0.690 mmol) (E)-3-[5-(4-chloro-phenyl)-pyridin-2-yll-acrylic acid (Z34b) and 80 pL (0.720 mmol) N-methylmorpholine in 5 mL abs. DMF
and the mixture was stirred for 5 min.. 90 mg (0.720 mmol) 4-amino-benzylalcohol was added and the mixture was stirred for 2 h. The reaction mixture was poured onto water and the precipitate was filtered off. The precipitate was suspended in toluene, concentrated by evaporation i. vac., then stirred with ether and dried i. vac. at 80 C .
Yield: 0.210 g (83% of theory) C21H CIN2O2 (M= 364.835) Calc.: molpeak (M+H)+: 365/367 Found: molpeak (M+H)+: 365/367 (CI) Rf value: 0.30 (silica gel, dichloromethane / MeOH / HOAC 90:10:0.1).

Z38b) (E)-N-(4-chloromethyl-phenyl)-3-[5-(4-chloro-phenyl)-pyridin-2-yl]-acrylamide 50 pL (0.680 mmol) thionyl chloride was added to a suspension of 0.190 g (0.520 mmol) (E)-3-[5-(4-chloro-phenyl)-pyridin-2-yl]-N-(4-hydroxymethyl-phenyl)-acrylamide (Z38a) in 20 mL dichloromethane and the mixture was stirred for 2 h at RT . Another 50 pL thionyl chloride were added and the mixture was again stirred for 3 h. The solvent was concentrated by evaporation i. vac., the residue taken up twice in toluene and concentrated by evaporation i. vac.. The crude product was obtained as the HCI salt and used in the next reaction step without any further purification.

Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 if Yield: 0.132 g (60% of theory) C21 H16C12N2O * HCI (M= 419.741) Calc.: molpeak (M+H)+: 383/385/387 Found: molpeak (M+H)+: 383/385/387 (CI2) Rf value: 0.90 (silica gel, dichloromethane / MeOH / conc. aqueous ammonia 90:10:0.1).

Intermediate product 39:

Z39a) diethyl-[2-(2-methyl-4-nitro-phenoxy)-ethyl]-amine At 0 C 0.92 g (19.2 mmol) sodium hydride (50% in oil) was added to a solution of 2.70 g (17.4 mmol) 2-fluoro-5-nitro-toluene and 2.54 mL (19.2 mmol) 2-diethylaminoethanol in 50 mL DMF under an argon atmosphere and the mixture was stirred for 2 hours at 0 C and for 1 hour at ambient temperature. The solvent was removed, the residue was taken up in ethyl acetate and extracted with water. The organic phase was dried over sodium sulphate and evaporated down i. vac. . Then it was purified by silica gel column chromatography with dichloromethane/methanol 9:1 as eluant.
Yield: 3.1 g (71% of theory) C13H20N2O3 (M= 252.31) Calc.: molpeak (M+H)+: 253 Found: molpeak (M+H)+: 253 Rf value: 0.60 (silica gel, dichloromethane / McOH 9:1) Z39b) 4-(2-diethylamino-ethoxy)-3-methyl-phenylamine 3.10 g (12.3 mmol) diethyl-[2-(2-methyl-4-nitro-phenoxy)-ethyl]-amine were dissolved in 250 mL ethyl acetate, 0.55 g Raney nickel was added and the mixture was hydrogenated for 36 hours at 50 psi and ambient temperature.
The catalyst was filtered off and the filtrate evaporated down i. vac. .
Yield: 2.70 g (99% of theory) Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 if C13H22N20 (M= 222.33) Calc.: molpeak (M+H)+: 223 Found: molpeak (M+H)+: 223 Rf value: 0.35 (silica gel, dichloromethane/methanol 9:1) Intermediate product 40:

O CI
ONO

Z40a) N-tert.butoxycarbonyl-N-methyl-[2-(2-chloro-4-nitro-phenoxy)-ethyl]-amine The product was obtained analogously to Intermediate product 29a starting from 2.00 g (11.4 mmol) 3-chloro-4-fluoro-nitrobenzene, 2.10 g (12.0 mmol) N-tert.butoxycarbonyl-N-methyl-aminoethanol and 820 mg (17.1 mmol) sodium hydride (50% in oil).
Yield: 3.77 g (100 % of theory) C14H19CIN205 (M= 330.77) Rf value: 0.35 (silica gel, petroleum ether/ethyl acetate 4:1) Z40b) 4-(N-tert.butoxycarbonyl-2-methylamino-ethoxy)-3-chloro-phenylamine The product was obtained analogously to Intermediate product 29b starting from 4.19 g (12.7 mmol) N-tert.butoxycarbonyl-N-methyl-[2-(2-chloro-4-nitro-phenoxy)-ethyl]-amine by hydrogenation with 500 mg Raney nickel at 3 bar.
Yield: 3.68 g (94 % of theory) C14H21CIN2O3 (M= 300.78) CaIc.: molpeak (M+H)+: 301/303 Found: molpeak (M+H)+: 301/303 Rf value: 0.60 (silica gel, dichloromethane/methanol 19:1) Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 if Intermediate product 41:

0 N-'-""O
H
NHz Z41a) N-tert.butoxycarbonyl-[2-(2-chloro-4-nitro-phenoxy)-ethyl]-amine The product was obtained analogously to Intermediate product 29a starting from 2.00 g (11.4 mmol) 3-chloro-4-fluoro-nitrobenzene, 1.85 mL (12.0 mmol) N-tert.butoxycarbonyl-aminoethanol and 820 mg (17.1 mmol) sodium hydride (50% in oil).
Yield: 2.25 g (62 % of theory) C13H17CIN205 (M= 316.74) Caic.: molpeak (M-H)-: 315/317 Found: molpeak (M-H) 315/317 Rf value: 0.45 (silica gel, petroleum ether/ethyl acetate 4:1) Z41 b) 4-(N-tert.butoxycarbonyl-2-amino-ethoxy)-3-chloro-phenylamine The product was obtained analogously to Intermediate product 29b starting from 2.25 g (7.10 mmol) N-tert. butoxycarbonyl-[2-(2-chloro-4-nitro-phenoxy)-ethyl]-amine by hydrogenation with 500 mg Raney nickel at 3 bar.
Yield: 1.95 g (81 % of theory) C13H19C1N203 (M= 286.76) Calc.: molpeak (M+H)+: 287/289 Found: molpeak (M+H)+: 287/289 Rf value: 0.55 (silica gel, dichloromethane/methanol 19:1) Intermediate product 42:

ci H

Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 ff Z42a) M-(2-chloro-4-nitro-phenyl)-N,N-diethyl-ethane-1,2-diamine 9.440 g (34.120 mmol) potassium carbonate was added to a solution of 4.96 mL (34.160 mmol) N',N'diethyl-ethane-1,2-diamine in 64 mL DMF and the mixture was stirred for for 15 min. at RT. 6.120 g (68.240 mmol) 2-chloro-1-fluoro-4-nitro-benzene was added and the resulting mixture was stirred for 16 h at RT. The reaction mixture was poured onto ice water, the precipitate was filtered off and purified by column chromatography (Alox, neutral, act. II-III, dichloromethane / MeOH 49:1).
Yield: 9.20 g (99 % of theory) C12H18CIN302 (M= 271.749) Calc.: molpeak (M+H)+: 272/274 Found: molpeak (M+H)+: 272/274 Rf value: 0.72 (Alox, dichloromethane/methanol 49:1) Z42b) 2-chloro-N' (2-diethylamino-ethyl)-benzene-1,4-diamine A suspension of 8.850 g (32.570 mmol) N-(2-chloro-4-nitro-phenyl)-N,N-diethyl-ethane-1,2-diamine and 4.00 g Raney nickel in 200 mL THE was hydrogenated for 7 h at 20 psi hydrogen pressure. The catalyst was filtered off, the filtrate evaporated down i. vac. and the residue purified by column chromatography (Alox, neutral, act. II-III, gradient dichloromethane / MeOH
100:0-+24:1).
Yield: 6.150 g (78 % of theory) C12H20CIN3 (M= 241.766) Calc.: molpeak (M+H)+: 242/244 Found: molpeak (M+H)+: 242/244 Rf value: 0.62 (Alox, dichloromethane/methanol 49:1) Intermediate product 43:

CI
H

N~\/N
NHZ

Z43a) tert-butyl [2-(4-methyl-piperidin-1-yl)-ethyl]-carbaminate Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 ff A solution of 10.00 g (43.280 mmol) tert-butyl (2-bromo-ethyl)-carbaminate and 11.60 mL (96.000 mmol) 4-methyl-piperidine in 100 mL dichloromethane was stirred for 16 h at RT. The crude product was filtered through Alox (neutral, act. II-III, dichloromethane / MeOH 49:1) and the filtrate was evaporated down i. vac. .
Yield: 6.150 g (78 % of theory) C13H26N202 (M= 242.364) CaIc.: molpeak (M+H)+: 243 Found: molpeak (M+H)+: 243 Rf value: 0.65 (Alox, dichloromethane/methanol 19:1) Z43b) 2-(4-methyl-piperidin-1-yl)-ethylamine-bis-trifluoroacetate 11.56 mL (150 mmol) TFA was added at RT to a solution of 8.500 g (35.070 mmol) tert-butyl [2-(4-methyl-piperidin-1-yl)-ethyl]-carbaminate in 100 mL
dichloromethane and the mixture was stirred for 16 h at RT. The reaction mixture was evaporated down i. vac. and the residue stirred with ether. The precipitate was filtered off, washed with ether and dried in a HV. The product was obtained as the bis-trifluoroacetate salt.
Yield: 12.10 g (93 % of theory) C81-118N2 * 2 C2HF3O2 (M= 370.295) CaIc.: molpeak (M+H)+: 143 Found: molpeak (M+H)+: 143 Z43c) (2-chloro-4-nitro-phenyl)-[2-(4-methyl-piperidin-1-yl)-ethyl]-amine Prepared analogously to Intermediate product Z42a starting from 12.02 g (32.450 mmol) 2-(4-methyl-piperidin-1-yl)-ethylamine-bis-trifluoroacetate, 5.810 g (32.450 mmol) 2-chloro-1-fluoro-4-nitro-benzene and 17.94 g (129.64 mmol) potassium carbonate.
Yield: 8.85 g (92% of theory) C14H2OCIN3O2 (M= 297.787) Calc.: molpeak (M+H)+: 298/300 Found: molpeak (M+H)+: 298/300 Z43d) 2-chloro-N' [2-(4-methyl-piperidin-1-yl)-ethyl]-benzene-1,4-diamine Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 ff Prepared analogously to Intermediate product Z42b starting from 8.715 g (29.270 mmol) (2-chloro-4-nitro-phenyl)-[2-(4-methyl-piperidin-1-yl)-ethyl]-amine.
Yield: 7.00 g (89 % of theory) C14H22CIN3 (M= 267.805) Calc.: molpeak (M+H)+: 268/280 Found: molpeak (M+H)+: 268/280 (CI) Rf value: 0.60 (Alox, dichloromethane/methanol 49:1) Intermediate product 44:

ci /N

Z44a) (2-chloro-4-nitro-phenyl)-acetyl-chloride A suspension of 8.100 g (37.571 mmol) (2-chloro-4-nitro-phenyl)-acetic acid in 40 mL thionyl chloride was refluxed for 2 h, cooled to RT and evaporated down i. vac. . The crude product was used in the next reaction step without any further purification.
Yield: 8.80 g (quant. yield) C8H5C12NO3 (M= 234.040) Z44b) 2-(2-chloro-4-nitro-phenyl)-N,N-diethyl-acetamide At 0 C a solution of 3.20 g (13.673 mmol) (2-chloro-4-nitro-phenyl)-acetyl-chloride in 50 mL EtOAc was slowly added dropwise to a solution of 5.67 mL
(54.000 mmol) diethylamine in 50 mL EtOAc, then the cooling bath was removed and the mixture was stirred for 2 h at RT. The reaction mixture was diluted with EtOAc, the org. phase was washed with water and saturated aqueous NaCl solution, dried over sodium sulphate and evaporated down i.
vac..
Yield: 3.70 g (quant. yield) C12H15CIN2O3 (M= 270.718) Calc.: molpeak (M+H)+: 271/273 Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 if Found: molpeak (M+H)+: 271/273 (Cl) Rf value: 0.45 (silica gel, petroleum ether / EtOAc 1:1) Z44c) [2-(2-chloro-4-nitro-phenyl)-ethyl]-diethyl-amine 65 mL (65.000 mmol) borane (1 M in THF) was added at RT to a solution of 3.702 g (13.673 mmol) 2-(2-chloro-4-nitro-phenyl)-N,N-diethyl-acetamide in 130 mL THE and the mixture was stirred for 4 h . The reaction mixture was evaporated down i. vac. , the residue was combined with 15 mL MeOH and 15 mL semiconc. aqueous HCI and heated to 100 Cfor 15 min.. Water was added, the mixture was made basic with aqueous sodium carbonate solution and the aqueous phase was extracted with EtOAc. The combined org.
phases were washed with water and saturated aqueous NaCl solution, dried over sodium sulphate and evaporated down i. vac. . The crude product was purified by column chromatography (Alox, neutral, act. II-III, gradient petroleum ether/ EtOAc 8:1 --* 4:1).
Yield: 2.10 g (60% of theory) C12H17CIN202 (M= 256.734) Rf value: 0.63 (Alox, petroleum ether / EtOAc 3:1) Z44d) 3-chloro-4-(2-diethylamino-ethyl)-phenylamine A suspension of 2.00 g (7.790 mmol) [2-(2-chloro-4-nitro-phenyl)-ethyl]-diethyl-amine and 0.80 g Raney nickel in THE was hydrogenated for 2.5 h at RT and 25 psi hydrogen pressure. The catalyst was filtered off and the filtrate evaporated down i. vac. .
Yield: 3.70 g (quant, yield) C12H19CIN2 (M= 226.752) Calc.: molpeak (M+H)+: 227/229 Found: molpeak (M+H)+: 227/229 (Cl) Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 if Intermediate product 45:

ci Br 0 ci H

F
F F

Z45a) 3-(2-chloro-4-nitro-phenyl)-prop-2-yn-1-ol 1.059 mL (18.000 mmol) propargylalcohol was added under argon to 5.013 g (21.200 mmol) 4-bromo-3-chloronitrobenzene, 8.72 mL (63.000 mmol) triethylamine, 1.265 g (1.800 mmol) bis(triphenylphosphine)-palladium(II)dichloride and 0.343 g (1.800 mmol) copper(I)iodide in 50 mL
acetonitrile and the mixture was refluxed for 4 h. The reaction mixture was filtered through Celite and the filtrate was evaporated down i. vac. . The residue was dissolved in EtOAc, the org. phase was washed with water, dried over sodium sulphate and evaporated down i. vac. . The crude product was purified by column chromatography (silica gel, petroleum ether / EtOAc 3:1) and by trituration with petroleum ether.
Yield: 2.550 g (67% of theory) C9H6CINO3 (M= 211.606) Calc.: molpeak (M+H)+: 211/213 Found: molpeak (M+H)+: 211/213 (CI) Rf value: 0.38 (silica gel, dichloromethane / MeOH 50:1) Z45b) 3-(2-chloro-4-nitro-phenyl)-propan-1-ol A suspension of 1.25 g (6.808 mmol) 3-(2-chloro-4-nitro-phenyl)-prop-2-yn-1-ol and 1.00 g Raney nickel in 50 mL THE was hydrogenated for 12 h at RT
and 25 psi hydrogen pressure. The catalyst was filtered off and the filtrate was evaporated down i. vac. .
Yield: 1.26 g (quant. yield) C9H12CINO (M= 185.655) CaIc.: molpeak (M+H)+: 186/188 Found: molpeak (M+H)+: 186/188 (Cl) Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 ff Rf value: 0.33 (silica gel, dichloromethane / MeOH 19:1) Z45c) (E)-N-[3-chloro-4-(3-hydroxy-propyl)-phenyl]-3-(2-chloro-4-trifluoromethyl-phenyl)-acrylamide Prepared analogously to Intermediate product Z32a starting from (E)-3-(2-chloro-4-trifluoromethyl-phenyl)-acrylic acid (Z37b) and 3-(2-chloro-4-nitro-phenyl)-propan-1-ol. The crude product was purified by column chromatography (silica gel, petroleum ether / EtOAc 1:1).
Yield: 1.800 g (63% of theory) C19H16CI2F3NO2 (M= 418.246) Calc.: molpeak (M+H)+: 418/420/422 Found: molpeak (M+H)+: 418/420/422 (C12) Z45d) (E)-N-[4-(3-bromo-propyl)-3-chloro-phenyl]-3-(2-chloro-4-trifluoromethyl-phenyl)-acrylamide 0.577 g (2.200 mmol) triphenylphosphine was added batchwise to a suspension of 0.836 g (2.000 mmol) (E)-N-[3-chloro-4-(3-hydroxy-propyl)-phenyl]-3-(2-chloro-4-trifluoromethyl-phenyl)-acrylamide and 0.730 g (2.200 mmol) tetrabromomethane in 10 mL dichloromethane and the mixture was stirred for 48 h at RT. The reaction mixture was purified by column chromatography (silica gel, dichloromethane) and the residue was triturated with petroleum ether.
Yield: 0.620 g (64% of theory) C19H15BrCI2F3NO (M= 481.143) CaIc.: molpeak (M+H)+: 480/482/484/486 Found: molpeak (M+H)+: 480/482/484/486 (BrC12) Rf value: 0.81 (silica gel, dichloromethane) Intermediate product 46:

N ci NH, Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 ff Z46a) 2-(2-chloro-4-nitro-phenyl)-1-(4-methyl-piperidin-1-yl)-ethanone Prepared analogously to Intermediate product Z44b starting from (2-chloro-4-nitro-phenyl)-acetyl-chloride (Z44a) and 4-methylpiperidine.
Yield: 1.050 g (77% of theory) C14H17CIN2O3 (M= 296.756) Rf value: 0.51 (silica gel, petroleum ether / EtOAc 1:1) Z46b) 1-[2-(2-chloro-4-nitro-phenyl)-ethyl]-4-methyl-piperidine Prepared analogously to Intermediate product Z44c starting from (2-chloro-4-nitro-phenyl)-1-(4-methyl-piperidin-1-yl)-ethanone. The crude product was purified by column chromatography (Alox, neutral, act. II-111, gradient petroleum ether / EtOAc 8:1-- 6:1).
Yield: 0.820 g (57% of theory) C14H19CIN2O2 (M= 282.773) Rf value: 0.73 (silica gel, petroleum ether / EtOAc 2:1) Z46c) 3-chloro-4-[2-(4-methyl-piperidin-1-yl)-ethyl]-phenylamine Prepared analogously to Intermediate product Z44d starting from 1-[2-(2-chloro-4-nitro-phenyl)-ethyl]-4-methyl-piperidine.
Yield: 0.820 g (57% of theory) C14H21CIN2 (M= 252.790) Calc.: molpeak (M+H)+: 253/255 Found: molpeak (M+H)+: 253/255 (CI) Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 if General working method I (TBTU coupling):

Triethylamine (1.5 eq.) or N-ethyldiisopropylamine (1.5eq.) and TBTU (1.0-1.5 eq.) are added successively to a solution of carboxylic acid (1.0 eq.) in THE
or DMF. Depending on the carboxylic acid the mixture is stirred for 10 minutes -12 hours between ambient temperature and 40 C before the amine (1.0 eq.) is added. The reaction is stirred for 30 minutes - 24 hours between ambient temperature and 40 C, before semisaturated NaHCO3 solution is added. After extraction of the aqueous phase with EtOAc the organic phase is dried over magnesium sulphate. The solvent is removed using the rotary evaporator;
further purification is carried out by column chromatography or crystallisation.
The reaction may also be carried out in a Chemspeed automatic synthesiser.
The following compounds were prepared according to general working method I:

CI
CI
HBO o / + R1.,NH Rte p 6__t:
\ I F H H F F
F (educt) F
F

while in the Table that follows the products are defined by the partial formula R'-NH- and the associated carboxylic acid educts are defined by reference to the corresponding Example number of the intermediate product.

Exa- R 'NH- Educt Empirical formula Mass Rf Yield (%) m le spectrum value 1 Z 10 C22H23C12F3N203 491/493 0.45 44 H
2 ~"~ Z11b C22H23C1F3N3O3 470/472 0.36 64 0 [M+H]+ (A) H

Boehringer ingelheim CA 02504207 2005-04-28 Case 1-1407 ff 3 N I Z 12b C23H27C1F3N3O2 470/472 0.22 44 [M+H] + (A) N-' H
4 Z13b C22H21C12F3N2O2 473/475/47 0.42 21 { N' 7 [M+H]+ (A) H
Z14b C25H29C1F3N3O2 496/498 0.30 48 N' H
6 Lit. C21H24C1F3N2O2 429/431 0.33 36 ~" \ { [M+H]+ (A) H
7 GN Z24b C23H26CIF3N2O2 455/457 0.46 50 [M+H]+ (A) H
8 ~JN { Z23f C22H24C1F3N2O2 441/443 0.37 46 H [M+H]+ (A) 9 Z15 C22H25C12F3N2O2 477/479/48 0.22 31 H
F F Z16b C22H23C!F6N2O3 513/515 0.27 39 [M+H]+ (A) We H
11 _ Z17 C22H22C13F3N2O2 509/11/13/ 0.48 1 \ N .
[M+H]+ (A) H
12 N RI Z 18b C23H25C1F3N3O2 468/470 0.63 1 N [M+H]+ (A) H
13 Z19b C21H25C1F3N3O2 444/446 0.35 35 {N [M+H]+ (A) H
14 4 Z20b C22H26C12F3N3O2 492/494/49 0.46 49 J { N 6 [M+H]+ (A) H

Boehringer ingelheim CA 02504207 2005-04-28 Case 1-1407 ff 15 N Z21 b C24H29C1F3N302 484/486 0.86 42 \ I [M+H]+ (B) N
H

Lit.: known from the literature Eluant: A) dichloromethane / MeOH / conc. aqueous ammonia = 90:10:1 B) EtOAc / MeOH / conc. aqueous ammonia = 90:10:1 General working method l l:

A solution of 1.0 eq. acid chloride in THE is slowly added dropwise to a solution of 1.0 eq. of 3-chloro-4-(2-diethylamino-ethoxy)-phenylamine and 4.5-6.0 eq. of triethylamine in THE at 5 C. The reaction mixture is stirred for 3 hours at 25-30 C, filtered off and washed with THF. The filtrate is evaporated down i. vac. and the residue purified by column chromatography. The intermediate product is dissolved in acetonitrile, acidified with ethereal HCI
and precipitated with ether. Further purification is carried out by recrystallisation.

According to general working method II the following compounds were prepared:

YO _R1 CI (educt) CI CI Ko while in the Table that follows the products are defined by means of the group R'-. The associated amino educts are commercially available and/or known from the literature.

I Examp R Empirical formula Melting Yield (%) Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 if le point 16 i I a C20H23C13N203 x 186-188 C 63 HCI
CI
17 GI C20H24C12N203 x 171-172 C 62 18 C20H24C12N203 x 183-185 C 63 HCl CI

Example 19:

F
F
/ I F
\1 O \ NO \
19) 2-(2-chloro-4-trifluoromethyl-phenoxy)-N-[4-(2-diethylamino-ethoxy)-3-methoxy-phenyl]-acetamide 171 mg (0.82 mmol) of CDI was added to a solution of 185 mg (0.73 mmol) of (2-chloro-4-trifluoromethyl-phenoxy)-acetic acid (cf intermediate product Z2b) in 5 mL tetrahydrofuran and the reaction mixture was stirred for 30 minutes at 50 C. Then 0.1 mL (0.73 mmol) of triethylamine and 200 mg (0.73 mmol) of 4-(2-diethylamino-ethoxy)-3-methoxy-phenylamine (see intermediate product Z6b) were added and the solution was stirred for 16 hours at RT. The reaction solution was added to water and stirred for 45 minutes at RT. After filtration the residue was dried in the circulating air dryer.
Yield: 170 mg (49 % of theory) C22H26CIF3N204 (M= 474.912) Calc.: Molpeak(M+H)+:475/477 Found: Molpeak (M+H)+: 475/477 (Cl) Rf value: 0.30 (silica gel, dichloromethane / MeOH / conc. aqueous ammonia 90:10:1).

Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 if Example 20:

O CI
N" v O
H
CI
20) 2-(2,4-dichloro-phenoxy)-N-[4-(2-diethylamino-ethoxy)-3-methoxy-phenyl]-acetamide A solution of 70 mg (0.290 mmol) of (2,4-dichloro-phenoxy)-acetylchloride in 0.5 mL dichloromethane was added to a solution of 66 mg (0.278 mmol) of 4-(2-diethylamino-ethoxy)-3-methoxy-phenylamine (intermediate product Z6b) and 96 pL (0.56 mmol) of ethyl-diisopropylamine in 1.5 mL abs.
dichloromethane and the mixture was stirred for 15 hours at RT. The reaction mixture was evaporated down i. vac. and the residue was purified by column chromatography (silica gel, dichloromethane / MeOH 9:1).
Yield: 77 mg (61 % of theory) C21 1-12602N204 (M= 441.358) Calc.: Molpeak(M+H)+:441/443/445 Found: Molpeak (M+H)+: 441/443/445 Rf value: 0.32 (silica gel, dichloromethane / MeOH 9:1) The following compounds were prepared analogously to Example 20:

CI1~1C / I + educt R,N~O
H
CI CI

while in the Table that follows the products are defined by means of the group R and the associated educts are defined by reference to the corresponding Example number of the intermediate product or are given as known from the literature (Lit.).

Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 if Exa R Educt Empirical formula Mass Rf Yield mpl spectrum valu (%) e e 21 1 Lit. C22H27CI2N303 452/454/457 0.12 65 %
/N

[M+H]+ (A) ON
22 Lit. C201-12402N202 395/397/399 0.38 46 %
[M+HI+ (A) 23 Lit. C21H26C12N203 425/427/429 0.31 69 %
[M+H]+ (A) 24 F Z8b C20H23Cl2FN203 429/431/433 0.34 66 %

) 1 [M+H]+ (A) 25 O O1, Z7b C221-12602N205 469/471/473 0.30 40 %
[M+Hl+ (A) J ~.
26 Z5b C20H24C12N203 411/413/415 0.33 89%
[M+H]+ (A) 27 o Lit. C21H25C12N303 438/440/442 0.28 52 %
".~N [M+H]+ (A) Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 if 28 1 Z23c C19H23C12N3O4S 460/462 0.40 36 %
o=s=o " I [M+H]+ (A) 29 ( Z9c C25H39C12N3O3 496/498/500 0.21 84%
[M+H]+ (A) J
30 ~\N Lit. C191-122C12N202 381/383 0.48 35 %
[M+H]+ (A) 31 Lit. C20H23C12N3O2 408/410/412 0.35 40 %
N ., [M+H]+ (A) Rf value: A= (silica gel, dichloromethane / MeOH 9:1) B= (silica gel, EtOAc) Example 32:

CI

/ N' H
32) 2-(3-chIoro-biphenyl-4-yloxy)-N-[3-chloro-4-(2-diethyl amino-ethoxy)-phenyl]-acetamide 65 mg (0.47 mmol) of potassium carbonate was added to a solution of 70 mg (0.159 mmol) of 2-bromo-N-[3-chloro-4-(2-diethylamino-ethoxy)-phenyl]-acetamide-hydrobromide (intermediate product Z1c) and 64 mg (0.314 mmol) of 3-chloro-biphenyl-4-ol in 1 mL of abs. DMF and the mixture was stirred for 1 hour at 40 C and for 15 hours at RT. The reaction mixture was diluted with dichloromethane, the org. phase was washed with sat. aqueous sodium Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 if bicarbonate solution and water and dried over magnesium sulphate. Column chromatography (silica gel, dichloromethane / MeOH 9:1) yielded the product.
Yield: 51 mg (67 % of theory) C26HY8C12N2O3 (M= 487.431) Calc.: Molpeak(M+H)+:487/489/491 Found: Molpeak (M+H)+: 487/489/491 (CI2) Rf value: 0.43 (silica gel, dichloromethane / MeOH 9:1) The following compounds were prepared analogously to Example 32:
CI CI

0 + educt 0 J H-Br l N" v Br N'~-'0,R

while in the Table that follows the products are defined by means of the group R and the associated educts are commercially available.

Exa R Empirical formula Mass Rf Yield (%) mpl spectrum value e 33 CI C21 H23C12F3N2O3 479/481/483 0.34 67 %
F [M+Hl+ (A) F
F
34 C' C24H32C12N2O3 467/469/471 0.31 63 %
[M+H]+ (A) 35 C' C22H26C12N2O5 469/471/473 0.30 80 %

[M+H]+ (A) 36 Br C20H23Br2CIN2O3 533/535/537 0.31 82 %
\ I [M+H]+ (A) Br Boehringer Ingelheim Case 1-1407 if 37 c' C20H23BrCI2N2O3 489/491/495/4 0.25 74 %
95 [M+H]+ (A) B
38 Br C24H26BrCIN2O3 505/507/509 0.36 80 %
[M+H]+ (A) 39 Ci C21H26C12N204 441/443/445 0.38 60%
[M+H]+ (A) 40 C21 H26C12N203 425/427/429 0.31 85%
&cl [M+H]+ (A) 41 Br C20H23BrCI2N2O3 489/491/493/4 0.32 57 %
[M+H](A) ~cj 95 42 C24H27CIN203 427/429 0.31 78 %
[M+HI+ (A) 43 C22H29CIN203 405/407 0.30 73 %
[M+H]+ (A) 44 F C20H23C12FN203 429/431/433 0.26 74 %
[M+H]+ (A) ci 45 c' C21H26CIZN203 425/427/429 0.19 54 %
= [M+H]+ (A) 46 C26H34C12N203 493/495/497 0.24 62 %

[M+H]+ (A) ci 47 0 C22H26C12N205 469/471/473[ 0.25 68 %
M+H]+ (A) ci 48 oll C21H26C12N204 441/443/445 0.31 80%
[M+H]+ (A) ci 49 = , 1c, C20H23C13N203 445/447/449/4 0.26(A) 66 %
c~ 51 [M+H]+

Boehringer Ingeiheim CA 02504207 2005-04-28 Case 1-1407 ff 50 i I C271-130C12N203 501/503/505[ 0.36 93 %
M+H]+ (A) 51 C261-12602N203 487/489/491[ 0.36 83 %

M+H]+ (A) 52 CI C20H23C12FN2O3 429/431/433[ 0.36 64 %
M+H]+ (A) 53 C241-1270 N203 427/429 0.32 84 %

[M+H]+ (A) 54 0 C21 H25C12N3O4 454/456/458[ 0.08 72 %
M+H]+ (A) CI
55 o H C27H29C12N3O4 530/532/534[ 0.23 48 %
M+H]+ (A) ci Rf value: A= (silica gel, dichloromethane / MeOH 9:1) General working method III (phenol alkylation 11 Phenol (2.0 eq.) and potassium carbonate (3.0-5.0 eq.) are added successively to a solution of the alkyl bromide (see intermediate product Z1c) (1.0 eq.) in DMF. The mixture is stirred for 48-72 hours at RT under a nitrogen atmosphere, before being added to water. After extraction of the aqueous phase with EtOAc the organic phase is dried over magnesium sulphate. The solvent is removed using the rotary evaporator; further purification is carried out by column chromatography or crystallisation.

Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 if According to general working method III the following compounds were prepared-H
I
~~~p \ I N Br + RI CI / i N~O.R1 O ,,N~~oi 0 ,Br H H
(edict) while in the Table that follows the products are defined by means of the group R1 and the associated educts are commercially available.

Examp R1 Empirical formula Mass Rf Yield le spectrum value (%) 56 C21H26C11N203 517/519 0.32 (A) 47 [M+H]+
57 ` C24H26BrC1N2O3 505/507/509 0.42 (A) 20 [M+H]
58 C21H27BrC1N2O3 469/471/473 0.33 (A) 49 [M+H]+
59 F F C21H24C!F3N203 445/447 0.32 (A) 56 F
[M+H]+
60 C23H29C1N204 433/435 0.37 (A) 23 [M+H]+
61 C21H26C12N203 425/427/429 0.42 (A) 24 [M+H]+
62 NT C22H2702N304 468/470/472 0.26 (A) 21 [M+H]+
63 C22H28BrC1N2O3 483/485/487 0.32 (A) 48 [M+H]+

Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 if 64 C23H26C1N303 428/430 0.23 (A) 12 [M+H]+
Eluant: A) dichloromethane / MeOH / ammonia = 90:10:1 General working method IV (phenolalkylation III

Bromoacetylbromide (1.0 eq.) in dioxane is added dropwise to a solution of the aniline (see intermediate product Z1 b) (1.0 eq.) in DMF at -10 C. Then the mixture is heated to RT and phenol (1.0 eq.) in DMF and potassium-tert-butoxide (2.0 eq.) in tert-butanol are added successively. The mixture is heated to 80 C for 4 hours. DMF is eliminated in vacuo and the residue is dissolved in EtOAc. The ethyl acetate solution is washed 1x with 10 % K2CO3 solution, then 2x with water. The EtOAc is eliminated in vacuo. Further purification is carried out by column chromatography.
According to general working method IV the following compounds were prepared:

H
CI N H

H I
N Br R1 + ~Br + O' i 0 HBr O H
(educt) while in the Table that follows the products are defined by means of the group R1 and the associated educts are commercially available.

Examp R1 Empirical formula Mass Rf Yield (%) le spectrum value 65 F C2)H23C1F3N305 490/492 0.24 (A) 6 i \ F [M+H]+

0 a Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 ff 66 N; C20H23C12N305 456/458/460 0.28 (A) 7 [M+H]+
CI
67 r C24H25Br2C1N2O5 583/85/87/89 0.50 (A) 7 Br [M+H]
68 C25H29C!N204 455/457 0.24 (A) 13 [M+H]
69 C20H22C14N203 479/81/83/85/ 0.28 (A) 10 CI 87 [M+H]+
CI
70 Br C2oH22BrC13N2O3 521/23/25/27 0.28 (A) 10 "( CI [M+H]+

CI
71 I CI C20H22C14N203 477/79/81/83 0.23 (A) 8 [M+H]+
CI
72 C22H27C1N204 419/421 0.25 (A) 5 H [M+H]+
73 C22H27C13N203 473/75/77/79 0.31 (A) 8 [M+H]+
CI
74 r C21H25BrCl2N2O3 503/05/07/09 0.28 (A) 8 [M+H]+
CI

Eluant: A) dichloromethane / MeOH / ammonia = 90:10:1 Example 75:

CI
1~I O CI
O H \ N'~_'O
H
\ CI
75) methyl (2-{2-chloro-4-[2-(2,4-dichloro-phenoxy)-acetylamino]-phenoxy}-ethylamino)-acetate Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 ff 75 pL (0.54 mmol) of triethylamine and 70 mg (0.18 mmol) of N-[3-chloro-4-(2-oxo-ethoxy)-phenyl]-2-(2,4-dichloro-phenoxy)-acetamide was added to a suspension of 45 mg (0.36 mmol) of methyl amino-acetate hydrochloride in 2 mL dichloromethane / THE (1:1). 114 mg (0.54 mmol) of sodium triacetoxyborohydride was added and the mixture was stirred for 3 hours at RT. 100 mL of 2 N aqueous sodium carbonate solution was added and the aqueous phase was exhaustively extracted with chloroform. The combined org. extracts were dried over magnesium sulphate, evaporated down i. vac.
and purified by column chromatography (silica gel, EtOAc / MeOH 9:1).
Yield: 71 mg (78 % of theory) C19H19C13N2O5 (M= 461.733) Calc.: Molpeak(M+H)+:461/463/465/467 Found: Molpeak (M+H)+: 461/463/465/467 (03) Rf value: 0.32 (silica gel, EtOAc) The following compounds were prepared analogously to Example 75:

H'~_' C 0 Cl R"""O 0 CI
+ educt CI I CI

while in the Table that follows the products are defined by means of the group R and the associated educts are commercially available.

Exa R Empirical formula Mass Rf Yield mpI spectrum value (%) e 76 , = C21H23C13N2O3 457/459/461/463 0.30 66 %
IM+HI+ (A) 77 GN C20H21C13N2O3 443/445/447/449 0.28 70 %
[M+H]+ (A) Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 if 78 , = C20H21C13N204 459/461/463/465 0.18 72%
of [M+H] + (B) 79 C28H29C13N2O3 547/549/551/553 0.19 52 %
[M+H]+ (B) 80 C21 H24C13N3O3 472/474/476/478 0.31 66%
"J [M+H]+ (A) 81 i C20H24C13N3O3 460/462/464/466 0.19 42 %
[M+H]+ (A) 82 C25HP3C13N2O3 505/507/509/511 0.61 78 %
" [M+H]+ (B) 83 C22H25C13N2O3 471/473/475/477 0.41 64 %
[M+H]+ (B) 84 C23H21C13N2O3 479/481/483/485 0.16 69 %
\ NH [M+H]+ (B) 85 C28H30C13N2O3 583/585/587/589 0.51 56 %
[M+H]+ (B) 86 C27H28C13N3O3 548/550/552/554 0.10 82 %
" [M+H]+ (B) 87 C22H19C13N2O3 465/467/469/471 0.51 58%
[M+H]+ (C) Rf value: A= (silica gel, dichloromethane / MeOH 9:1) B= (silica gel, EtOAc) C= (silica gel, EtOAc / hexane 1:1) General working method V (reductive amination):

Conc. hydrochloric acid (2.0 eq.) is added to a solution of the aldehyde (see intermediate product Z3d) (1.0 eq.) and amine (2.0 eq.) in THE or the pH is Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 ff adjusted to between 4-6 with glacial acetic acid. The mixture is stirred for minutes at RT and then sodium cyanoborohydride (2.0 eq.) in THE or sodium triacetoxyborohydride (2.0 eq.) is added. The reaction mixture is stirred for minutes - 24 hours at RT to 60 C, depending on the amine, before adding sat. aqueous sodium bicarbonate solution. After extraction of the aqueous phase with ether the organic phase is dried over magnesium sulphate. The solvent is removed using the rotary evaporator; further purification is carried out by column chromatography or crystallisation.
According to general working method V the following compounds were prepared:

F F
F
H CI F H CI / F
I /` I i CI / N~O \ R1, H CI N \
H~0 \ I 0 + R2 R I f 0 0 (educt) while in the Table that follows the products are defined by means of the group R1R2N- and the associated educts are commercially available or known from the literature.

Examp R R N- Empirical Mass Rf Yield (%) le formula spectrum value 88 CN __ = C21 H21 C12F3N203 477/479/481 0.13 (A) 27 [M+H]+
89 C22H25C12F3N203 493/495/497 0.26 (B) 8 [M+H]+
90 N C20H21C12F3N203 465/67/69 0.25 (B) 4 [M+H]+
91 C24H28C12F3N3O3 534/536 [M+H]+ 0.10 (B) 30 92 Y C2oH21Cl2F3N203 465/467/469 0.28 (B) 9 H [M+H]+

Boehringer ingelheim CA 02504207 2005-04-28 Case 1-1407 ff 93 C26H25C12F3N203 541/543/545 0.80 (B) 10 [M+H]+
94 / C26H23C12F3N203 539/541/543 0.35 (B) 19 N [M+H]+
95 C22H25C12F3N204 509/511/513 0.37 (B) 7 [M+H]+
96 C23H28C12F3N303 522/524/526 0.18 (B) 8 [M+H]+
97 C29H36C12F3N305 634/636/638 0.32 (B) 6 ~N [M+H]+
0yN
98 N C24H21C12F3N203 513/515/517 0.47 (C) 27 Cj~-,H' [M+H]+
99 C25H29C12F3N203 533/535/537 0.37 (C) 1 [M+H]+
100 N__ C21H21C12F3N204 493/495 [M+H]+ 0.33 (B) 13 101 Nom` C25H24C12F3N303 542/544/546 0.35 (B) 10 [M+H]+
102 _N N C22H24C12F3N303 506/508/510 0.15 (B) 1 SI
[M+H] +
103 ~0 C26H30C12F3N305 592/594/596 0.55 (B) 21 "u [M+H]+
104 /`\ 9N C29H29C12F3N203 581/583/585 0.55 (B) 18 [M+H]+
105 C23H27C12F3N203 507/509/511 0.65 (B) 6 [M+H]+
Eluant: A) dichloromethane / MeOH I conc. aqueous ammonia = 95:5:0.5 B) dichloromethane / MeOH / conc. aqueous ammonia = 90:10:1 C) dichloromethane / MeOH = 9:1 Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 ff Example 106:

GI \ N~O \
0 Cl 106) 3-chloro-4-{[3-chloro-4-(2-diethylamino-ethoxy)-phenylcarbamoyl]-methoxy}-benzoic acid A solution of 1.8 g (3.835 mmol) of methyl 3-chloro-4-{[3-chloro-4-(2-diethylamino-ethoxy)-phenylcarbamoyl]-methoxy}-benzoate (from Example 35) and 2 ml of 2 M aqueous NaOH solution in 20 mL MeOH was refluxed for 1 hour. The reaction solution was evaporated down i. vac., diluted with water and acidified weakly with HCI. After 3 days at RT the solution was evaporated down i. vac. The residue was triturated with cold EtOH and the precipitate was filtered off.
Yield: 230 mg (13 % of theory) C21 H24C12N2O5 (M= 455.342) Cale.- Molpeak(M+H)+:454/456/458 Found: Molpeak (M+H)+: 454/456/458 (CI2) Rf value: 0.05 (silica gel, dichioromethane / MeOH / conc. aqueous ammonia 90:10:1).

General working method VI:

A solution of 1.0 eq. of 3-chloro-4-{[3-chloro-4-(2-diethylamino-ethoxy)-phenylcarbamoyl]-methoxy}-benzoic acid (from Example 106) and 1.07 eq. of TBTU in DMF is placed at RT. After the addition of 1.07 eq. triethylamine the mixture is stirred for 10 minutes. Then 7.0 eq. amine are added and the mixture is stirred for 16 hours at RT. The reaction mixture is combined with water or 5% sodium carbonate solution. The precipitated solid is filtered off, washed with water and dried i. vac.
According to general working method VI the following compounds were prepared:

Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 if Ni R
O H,, IR' CI N z Cl N O N ~p R
1 I/ CI R' O CI

while in the Table that follows the products are defined by means of the group R'R2N- and the associated educts are commercially available or known from the literature.

Examp R R N- Empirical Mass Rf Yield (%) le formula spectrum value 107 C21H2502F3N304 454/456/458 0.37 (A) 59 [M+H]+
aus (NH4)2CO3 108 C22H27C12F3N304 468/470/472 0.38 (A) 57 [M+H]+
109 C23H29C12F3N304 482/484/486 0.38 (A) 55 [M+H]+
Eluant: A) dichloromethane / MeOH / conc. aqueous ammonia = 90:10:1 General working method VII (Suzuki coupling):

Boric acid (2.0 eq.) and tetrakis-(triphenylphosphine)-palladium (0.1 eq.) are added successively to a solution of the iodide (1.0 eq.; see Example 56) in toluene and 2M sodium carbonate solution (4.0 eq.) and stirred overnight at 80 C. The reaction solution is combined with 10 % aqueous Na2CO3 solution and the aqueous phase is extracted with EtOAc. The organic phases are combined and the solvent is eliminated in vacuo. Further purification is carried out by column chromatography.

Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 if According to general working method VII the following compounds were prepared:

H
CI / I N`r- 0 + HO, R1 CI / I N~O
41 O O OH \/N~/ `O \ 0 O

while in the Table that follows the products are defined by means of the group R1 and the associated educts are commercially available or known from the literature.

Examp R1 Empirical Mass Rf Yield le formula spectrum value (%) 110 1 C27H30C12N203 501/503/505 0.30 (A) 4 [M+H]+
111 C271-13002N203 501/503/505 0.30 (A) 4 ci [M+H]+
112 C27H30C12N203 501/503/505 0.30 (A) 6 [M+H]+
113 C28H33C1N204 497/499/501 0.27 (A) 8 [M+H]+
114 C28H33C1N204 481/483 0.6 (B) 21 [M+H]+
Eluant: A) dichloromethane / MeOH / conc. aqueous ammonia = 90:10:1 B) EtOAc / MeOH / conc. aqueous ammonia = 90:10:1 Example 115:

Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 ff 115) N-[3-chloro-4-(2-piperazin-1-yl-ethoxy)-phenyl]-2-(2-chloro-4-F
F
CI / F
0 NO \
N
C"J:/-ON,O
trifluoromethyl-phenoxy)-acetamide 0.200 g (0.338 mmol) of tert.butyl 4-(2-{2-chloro-4-[2-(2-chloro-4-trifluoromethyl-phenoxy)-acetylamino]-phenoxy}-ethyl)-piperazin-1-carboxylate (from Example 103) were dissolved in 5.0 mL dichioromethane.
After the addition of 0.5 mL (6.760 mmol) of trifluoroacetic acid the mixture was stirred for 2 hours at RT. The reaction solution was evaporated down i.
vac. and the residue combined with sat. aqueous sodium hydrogen carbonate solution. The aqueous phase was extracted with EtOAc. The org. phase was dried over magnesium sulphate, filtered and evaporated down i. vac. Further purification was carried out by column chromatography.
Yield: 0.032 g (16 % of theory) C21 H22Cl2F3N303 * 2 CH202 (M= 584.381) Caic.: Molpeak(M+H)+: 492/494/496 (CI2) Found: Molpeak (M+H)+: 492/494/496 (CI2) Rf value: 0.22 (silica gel, dichioromethane / MeOH / conc. aqueous ammonia 90:10:1).

Example 116:

F
F
CI F
CI \ NY__O
N O I /
116) N-{3-chloro-4-[2-(ethyl-pipe ridin-4-yl-amino)-ethoxy]-phenyl}-2-(2-chloro-4-trifluoromethyl-phenoxy)-acetamide 0.180 g (0.284 mmol) of tert.butyl 4-[(2-{2-chloro-4-[2-(2-chloro-4-trifluoromethyl-phenoxy)-acetylamino]-phenoxy}-ethyl)-ethyl-amino]-piperidine-1-carboxylate (from Example 97) were dissolved in 5.0 mL

Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 if dichloromethane. After the addition of 0.44 mL (5.680 mmol) of trifluoroacetic acid the mixture was stirred for 2 hours at RT. The reaction solution was evaporated down i. vac. and the residue combined with sat. aqueous sodium hydrogen carbonate solution. The aqueous phase was extracted with EtOAc.
The org. phase was dried over magnesium sulphate, filtered and evaporated down i. vac. Further purification was carried out by column chromatography.
Yield: 0.011 g (6 % of theory) C24H28C12F3N303 * 2 CH202 (M= 626.462) Calc.: Molpeak(M+H)+: 534/536/538 (C12) Found: Molpeak (M+H)+: 534/536/538 (012) Rf value: 0.25 (silica gel, dichloromethane / MeOH / conc. aqueous ammonia 90:10:1).

Example 117:

CI N-Trl~ 0 CI
\/N-~/-O I / 0 CI H
117) N-[3-chloro-4-(2-diethylamino-ethoxy)-phenyl]-2-(2-chloro-4-dimethylamino-phenoxy)-acetamide 94.7 mg (0.200 mmol) of 2-(4-amino-2-chloro-phenoxy)-N-[3-chloro-4-(2-diethylamino-ethoxy)-phenyl]-acetamide (from Example 118), 0.149 mL (37%, 2.000 mmol) of formaldehyde solution and 62.8 mg (1.000 mmol) of sodium cyanoborohydride was placed in 5.0 mL acetonitrile at RT. The pH was adjusted to 4-5 with glacial acetic acid with stirring. After 1 hour the reaction mixture was acidified with 12 % HCI and stirred for 10 minutes. Then it was made slightly alkaline with 20 % potassium carbonate solution. The aqueous phase was extracted with EtOAc. The org. phase was dried over magnesium sulphate, filtered and evaporated down i. vac. The residue was purified by column chromatography (silica gel; EtOAc / 10 % conc. aqueous ammonia in MeOH 100:0 -* 5:95). The oily residue was combined with ethereal HCI, evaporated down i. vac. and dissolved in 10 mL isopropanol. The precipitate formed was filtered off and dried i. vac.

Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 ff Yield: 0.035 g (36 % of theory) C22H29CI2N303 * HCI (M= 490.862) Calc.: Molpeak(M+H)+: 454/456/458 (CI2) Found: Molpeak (M+H)+: 454/456/458 (CI2) Rf value: 0.40 (silica gel, dichloromethane / MeOH / conc. aqueous ammonia 90:10:1) Example 118:

N
CI N O r~y 118) 2-(4-amino-2-chloro-phenoxy)-N-[3-chloro-4-(2-diethylamino-ethoxy)-phenyl]-acetamide 0.310 g (0.679 mmol) of N-[3-chloro-4-(2-diethylamino-ethoxy)-phenyl]-2-(2-chloro-4-nitro-phenoxy)-acetamide (from Example 66) was dissolved in 10.0 mL of EtOAc. After the addition of 0.030 g Pt/C (5%) the mixture was hydrogenated at RT under 15 psi H2 atmosphere for 5 hours. The reaction mixture was filtered and the filtrate was evaporated down i. vac. The residue was dissolved with a little EtOH. The precipitate formed was filtered off and dried i. vac.
Yield: 0.050 g (17 % of theory) C20H25C12N303 (M= 426.347) Caic.: Molpeak(M+H)+: 426/428/430 (CI2) Found: Molpeak (M+H)+: 426/428/430 (CI2) Rf value: 0.24 (silica gel, dichloromethane / MeOH / conc. aqueous ammonia 90:10:1).

Example 119:

F
CI
CI /
HH I F
\/NCO I 0 Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 ff 119) (E)-N-[3-chloro-4-(2-diethylamino-ethoxy)-phenyl]-3-(2-chloro-4-trifluoromethyl-phenyl)-acrylamide 0.29 mL (2.10 mmol) of triethylamine was added to a solution of 0.28 g (1.00 mmol) of 3-chloro-4-(2-diethylamino-ethoxy)-phenylamine-hydrochloride (intermediate product Z1 b), 0.25 g (1.00 mmol) of (E)-3-(2-chloro-4-trifluoromethyl-phenyl)-acrylic acid (Z37b) and 0.34 g (1.05 mmol) of TBTU in mL abs. THE and the mixture was stirred for 1 hour at RT. The reaction mixture was evaporated down i. vac. and the residue was combined with dichloromethane and water. The org. phase was separated off, washed with sat. aqueous sodium bicarbonate solution and water and evaporated down i.
vac. The residue was purified by column chromatography (silica gel, gradient dichloromethane / 10 % conc. aqueous ammonia in MeOH 100:0 -a 5:95).
Yield: 150 mg (32 % of theory) C22H23C12F3N2O2 (M= 475.342) Calc.: Molpeak(M+H)+:475/477/479 Found: Molpeak (M+H)+: 475/477/479 (CI2) Rf value: 0.2 (silica gel, dichloromethane / MeOH / conc. aqueous ammonia 95:5:1) Example 120:

F
F
CI N F
~ II H
120) N-[3-chloro-4-(2-diethylamino-ethoxy)-phenyl]-2-(2-chloro-4-trifluoromethyl-phenylamino)-acetamide A solution of 0.228 g (0.511 mmol) of 2-bromo-N-[3-chloro-4-(2-diethylamino-ethoxy)-phenyl]-acetamide-hydrobromide (intermediate product Z1 c) and 0.200 g (1.023 mmol) of 2-chloro-4-trifluoromethyl-phenylamine in 5 mL DMF
was stirred for 16 hours at 90 C and then for 24 hours at 120 C. The reaction mixture was cooled to RT, diluted with water and exhaustively Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 ff extracted with EtOAc. The combined org. extracts were dried over magnesium sulphate and evaporated down i. vac. The residue was dissolved in DMF and purified by HPLC-MS (Stable Bond C18; 3.5 m;
water:acetonitrile:formic acid 9:1:0.01 -> 1:9:0.01 over 9 min).
Yield: 11 mg (5 % of theory) 021 H24C12F3N3O2 (M= 478.346) Calc.: Molpeak(M+H)+:478/480/482 Found: Molpeak (M+H)+: 478/480/482 (C12) Rf value: 0.24 (silica gel, dichloromethane / MeOH / conc. aqueous ammonia 90:10:1).

Example 121:

F
CI
F
CI N F
121 a) 3-(2-chloro-4-trifluoromethyl-phenyl)-propionic acid 2.00 g (7.981 mmol) of (E)-3-(2-chloro-4-trifluoromethyl-phenyl)-acrylic acid (Z37b) was added at RT to a suspension of 0.500 g Raney nickel in abs.
MeOH and the mixture was hydrogenated for 4 hours at 50 psi H2 atmosphere. The catalyst was filtered off and the filtrate evaporated down i.
vac.
Yield: 1.90 g (94 % of theory) C10H8CIF3O2 (M= 252.622) Calc.: Molpeak(M-H)-:251/253 Found: Molpeak (M+H)+: 251/253 (Cl) 121b) N-[3-chloro-4-(2-diethylamino-ethoxy)-phenyl]-3-(2-chloro-4-trifluoromethyl-phenyl)-propionamide The product was obtained analogously to Example 119 starting from 0.400 g (1.433 mmol) of 3-chloro-4-(2-diethylamino-ethoxy)-phenylamine-Boehringer Ingelheim Case 1-1407 if hydrochloride (intermediate product Z1 b) and 0.362 g (1.433 mmol) of 3-(2-chloro-4-trifluoromethyl-phenyl)-propionic acid.
Yield: 340 mg (50% of theory) C22H25C12F3N202 (M= 477.358) Calc.: Molpeak(M-H)":477/479/481 Found: Molpeak (M+H)+: 477/479/481 (Cl2) Rf value: 0.30 (silica gel, dichloromethane / MeOH / conc. aqueous ammonia 90:10:1) Example 122:

F
CI / F
H CI / N` F

122a) ethyl 2-(2-chloro-4-trifluoromethyl-phenoxy)-propionate 10.00 g (50.87 mmol) of 2-chloro-4-trifluoromethyl-phenol, 7.11 mL (55.00 mmol) of ethyl 2-bromopropionate and 7.60 g (55 mmol) of potassium carbonate in 100 mL DMF was stirred for 16 hours at 50 C and then filtered.
The filtrate was evaporated down i. vac., combined with water and exhaustively extracted with EtOAc. The combined org. extracts were washed with 10% aqueous sodium carbonate solution and water, dried over sodium sulphate and evaporated down i. vac.
Yield: 14.10 g (93 % of theory) C121-112C1F303 (M= 296.676) Calc.: Molpeak(M+Na)+:319/321 Found: Molpeak (M+Na)+: 319/321 (Cl) Rf value: 0.6 (silica gel, EtOAc / petroleum ether 4:1) 122b) 2-(2-chloro-4-trifluoromethyl-phenoxy)-propionic acid 50 mL (0.100 mol) of 2 M aqueous NaOH solution was added to a solution of 14.00 g (0.047 mol) of ethyl 2-(2-chloro-4-trifluoromethyl-phenoxy)-propionate in 100 mL EtOH and the mixture was refluxed for 1 hour. EtOH was Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 if evaporated off i. vac., the residue was diluted with ice water and acidified with 2 M aqueous HCI. The precipitate formed was filtered off, washed with water and dried at 70 C i. vac.
Yield: 12.10 g (96 % of theory) C10H5CIF3O3 (M= 268.622) Calc.: Molpeak(M-H)":267/269 Found: Molpeak (M-H)-: 267/269 (CI) 122c) N-[3-chloro-4-(2-diethylamino-ethoxy)-phenyl]-2-(2-chloro-4-trifluoromethyl-phenoxy)-propionamide-hydrochloride 0.342 mL (2.000 mmol) of ethyl-diisopropylamine was added to a solution of 0.364 g (1.500 mmol) of 3-chloro-4-(2-diethylamino-ethoxy)-phenylamine (intermediate product Z1 b), 0.403 g (1.500 mmol) of 2-(2-chloro-4-trifluoromethyl-phenoxy)-propionic acid and 0.562 g (1.750 mmol) of TBTU in mL abs. THE and the mixture was stirred for 1 hour at RT. The reaction mixture was evaporated down i. vac. and the residue combined with dichloromethane and water. The org. phase was separated off, washed with sat. aqueous sodium bicarbonate solution and water and evaporated down i.
vac. The residue was purified by column chromatography (silica gel, gradient dichloromethane / 10 % conc. aqueous ammonia in MeOH 100:0 -). 5:95).
Yield: 450 mg (57 % of theory) C22H25C12F3N2O3 * HCI (M= 529.818) Calc.: Molpeak(M+H)+:493/495/497 Found: Molpeak (M+H)+: 493/495/497 (Cl2) Rf value: 0.30 (silica gel, dichloromethane / MeOH / conc. aqueous ammonia 95:5:0.5).

Example 123:

CI CI
CI N
_ ~~0 / 0 Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 if 123) N-[3-chloro-4-(2-diethylamino-ethoxy)-phenyl]-3-(2,4-dichloro-phenyl)-propionamide A solution of 0.271 g (1.236 mmol) of (3-(2,4-dichloro-phenyl)-propionic acid in 3.00 mL thionyl chloride was stirred for 2 hours at RT, evaporated down i.
vac. and dissolved in 10 mL dichloromethane. This solution of the acid chloride was slowly added dropwise, while cooling with ice, to a solution of 0.300 (1.236 mmol) of 3-chloro-4-(2-diethylamino-ethoxy)-phenylamine (intermediate product Z1b) and 0.32 mL (1.854 mmol) of ethyl-diisopropylamine in 10 mL dichloromethane and the mixture was stirred for 16 hours at RT. The reaction mixture was washed with sat. aqueous sodium bicarbonate solution, dried over magnesium sulphate and evaporated down i.
vac. The residue was dissolved in EtOAc and purified by column chromatography (silica gel, EtOAc / MeOH / conc. aqueous ammonia 90:10:1).
Yield: 60 mg (11 % of theory) C21H25CI3N2O2 (M= 443.) Cale.: Molpeak(M-Na)":441/443/445 Found: Molpeak (M-Na)-: 441/443/445 (CI2) Rf value: 0.27 (silica gel, dichloromethane / MeOH / conc. aqueous ammonia 90:10:1) Example 124:

CI
CI NYN
H
N,-/,, O - 0 CI

124) 1-[3-chloro-4-(2-diethylamino-ethoxy)-phenyl]-3-(2,4-dichloro-benzyl)-urea 203 mg (1.236 mmol) of CDT in 4 mL DMF was added to a solution of 345 mg (1.236 mmol) of 3-chloro-4-(2-diethylamino-ethoxy)-phenylamine-hydrochloride (intermediate product Z1 b) and 0.56 mL (4.000 mmol) of triethylamine in 40 mL THE and the mixture was stirred for 2 hours at RT. 176 Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 ff mg (1.236 mmol) of 2,4-dichloro-benzylamine was added, the reaction mixture was refluxed for 4 hours and then evaporated down i. vac. The residue was purified by column chromatography (silica gel, dichloromethane / MeOH /
conc. aqueous ammonia 80:20:1) and the product was triturated with diisopropylether.
Yield: 300 mg (55 % of theory) C20H24C13N302 (M= 444.792) Calc.: Molpeak(M+H)+:444/446/448 Found: Molpeak (M+H)+: 444/446/448 (CI3) Rf value: 0.73 (silica gel, dichloromethane / MeOH / conc. aqueous ammonia 80:20:1) Example 125:

F
CI / F
CI \ N1O \ I F
~~O / 0 125a) tert.butyl [3-chloro-4-(2-diethylamino-ethoxy)-phenyl]-carbaminate 0.31 mL (2.266 mmol) of triethylamine was added to a solution of 0.500 g (2.06 mmol) of 3-chloro-4-(2-diethylamino-ethoxy)-phenylamine and 0.495 g (2.266 mmol) of Boc-anhydride in 10 mL dichloromethane at RT and the mixture was stirred for 48 hours. The reaction mixture was diluted with dichloromethane and the org. phase was washed with sat. aqueous sodium bicarbonate solution. The combined org. extracts were dried over magnesium sulphate and evaporated down i. vac. Column chromatography (silica gel, dichloromethane / MeOH / conc. aqueous ammonia 90:10:1) yielded the product.
Yield: 500 mg (71 % of theory) C17H27CIN203 (M= 342.869) Calc.: Molpeak(M+H+:343/345 Found: Molpeak (M+H)+: 343/345 (Cl) Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 if 125b) [3-chloro-4-(2-diethylamino-ethoxy)-phenyl]-methyl-amine Under a nitrogen atmosphere a solution of 500 mg (1.458 mmol) of tert.butyl [3-chloro-4-(2-diethylamino-ethoxy)-phenyl]-carbaminate in 10 mL THE was slowly added dropwise to a suspension of 165 mg (4.374 mmol) of lithium aluminium hydride in 20 mL abs. THE and the mixture was stirred for 16 hours at RT. 165 pL of water, 165 pL of 15% aqueous NaOH solution and a further 495 pL water was added and the precipitate formed was filtered off. The filtrate was dried over magnesium sulphate, evaporated down i. vac. and the residue was purified by column chromatography (silica gel, EtOAc / MeOH /
conc. aqueous ammonia 90:10:1).
Yield: 180 mg (48 % of theory) C13H21CIN2O (M= 256.778) Calc.: Molpeak(M+H)+:257/259 Found: Molpeak (M+H)+: 257/259 (Cl) Rf value: 0.61 (silica gel, EtOAc / MeOH / conc. aqueous ammonia 90:10:1) 125c) N-[3-chloro-4-(2-diethylamino-ethoxy)-phenyl]-2-(2-chloro-4-trifluoromethyl-phenoxy)-N-methyl-acetamide 293 mg (0.911 mmol) of TBTU and 123 mg (0.911 mmol) of HOBT were added to a suspension of 231 mg (0.911 mmol) of (2-chloro-4-trifluoromethyl-phenoxy)-acetic acid (intermediate product Z2b) in 5 mL abs. THE and the mixture was stirred for 10 minutes at RT. 180 mg (0.701 mmol) of [3-chloro-4-(2-diethylamino-ethoxy)-phenyl]-methyl-amine and 0.18 mL (1.051 mmol) of ethyl-diisopropylamine were added, the mixture was stirred for 16 hours at RT
and evaporated down i. vac. The residue was purified by column chromatography (silica gel, silica gel, dichloromethane / MeOH / conc.
aqueous ammonia 85:15:1).
Yield: 150 mg (43 % of theory) C22H25C12F3N2O3 (M= 493.357) Calc.: Molpeak(M+H)+:493/495/497 Found: Molpeak (M+H)+: 493/495/497 (CI2) Rf value: 0.416 (silica gel, dichloromethane / MeOH / conc. aqueous ammonia 90:10:1).

Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 if aN'~ O

CI
Example 126: F
126) N-{3-chloro-4-[2-(ethyl-phenyl-amino)-ethoxy]-phenyl}-2-(2-chloro-4-trifluoromethyl-phenoxy)-acetamide The product was obtained according to general working method V starting from 0.422 g (0.616 mmol) N-[3-chloro-4-(2-oxo-ethoxy)-phenyl]-2-(2-chloro-4-trifluoromethyl-phenoxy)-acetamide (Z3d) and 0.094 mL (0.739 mmol) N-ethylaniline.
Yield: 20 mg (6.2% of theory) C25H23Cl2F3N203 (M= 527.375) Cale.: molpeak (M-H)-: 525/527/529 Found: molpeak (M-H)-: 525/527/529 (Cl2) Rf value: 0.94 (silica gel, EtOAc) Example 127:

CI
O `
F
F F
ethyl 2-[2-(2-chloro-4-trifluoromethyl-phenoxy)-acetylamino]-5-(2-diethylamino-ethoxy)-benzoate The product was obtained according to general working method I starting from 1.00 g (3.567 mmol) (2-chloro-4-trifluoromethyl-phenoxy)-acetic acid (Z2b) and 0.908 g (3.567 mmol) ethyl 2-amino-5-(2-diethylamino-ethoxy)-benzoate (Z25c).
Yield: 1.700 g (92% of theory) C24H28CIF3N205 (M= 516.949) Cale.: molpeak (M-H)-: 515/517 Found: molpeak (M-H) 515/517 (Cl) Rf value: 0.35 (silica gel, EtOAc / MeOH / conc. aqueous ammonia 90:10:1).

Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 if Example 128:

OH
N
CI

O F
F F
128) 2-[2-(2-chIoro-4-trifluoromethyl-phenoxy)-acetylamino]-5-(2-diethyl amino-ethoxy)-benzoic acid mL aqueous NaOH (1N) was added to a solution of 0.900 g (1,741 mmol) ethyl 2-[2-(2-chloro-4-trifluoromethyl-phenoxy)-acetylamino]-5-(2-diethylamino-ethoxy)-benzoate (Example 127) in 30 mL EtOH and the mixture was stirred for 2 h at RT . The reaction mixture was acidified with 10 mL
aqueous HCI (1 M) and treated with ultrasound for 30 min.. The precipitate was filtered off, washed with water and dried at 50 C i. vac..
Yield: 0.640 g (75% of theory) C22H24CIF3N205 (M= 488.895) Calc.: molpeak (M-H)-: 487/489 Found: molpeak (M-H)-: 487/489 (CI) Example 129:

CI )Cr N /N\~_O 0 129) 2-(biphenyl-4-yloxy)-N-[3-chloro-4-(2-diethylamino-ethoxy)-phenyl]-acetamide The product was prepared according to general working method I from (biphenyl-4-yloxy)-acetic acid and 3-chloro-4-(2-diethylamino-ethoxy)-phenylamine.
Yield: 0.560 g (58% of theory) C26H29CIN203 (M= 452.986) Calc.: molpeak (M+H)+: 453/455 Found: molpeak (M+H)+: 453/455 (CI) Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 if Rf value: 0.76 (silica gel, dichloromethane / MeOH / cyclohexane / conc.
aqueous ammonia 75:15:15:1).

Example 130:

i o 130a) ethyl (2-chloro-4-furan-2-yl-phenoxy)-acetate 3.5 mL aqueous sodium carbonate solution (1 M) was added to a solution of 1.00 g (3.407 mmol) ethyl (4-bromo-2-chloro-phenoxy)-acetate (Z26), 0.784 g (6.800 mmol) 2-furanboric acid and 0.196 g (0.170 mmol) tetrakis-triphenylphosphine-palladium in 65 mL dioxane and the mixture was refluxed for 4 h. The reaction mixture was cooled to RT, evaporated down i. vac. , diluted with water and exhaustively extracted with EtOAc. The combined org.
phases were washed with saturated aqueous sodium bicarbonate, water and saturated aqueous NaCl, dried over sodium sulphate and evaporated down i.
vac. . Column chromatography (silica gel, petroleum ether / EtOAc 3:1) yielded the product.
Yield: 0.800 g (84% of theory) C14H13CIO4 (M= 280.710) Calc.: molpeak (M+H)+: 281/283 Found: molpeak (M+H)+: 281/283 (Cl) Rf value: 0.56 (silica gel, petroleum ether / EtOAc 3:1).
130b) (2-chloro-4-furan-2-yl-phenoxy)-acetic acid 0.40 g (10.00 mmol) NaOH in 5 mL water was added to a solution of 0.280 g (2.672 mmol) ethyl (2-chloro-4-furan-2-yl-phenoxy)-acetate (130a) in 20 mL
abs. EtOH and the mixture was stirred for 16 h at RT. The reaction mixture was diluted with water and acidified to pH 1 with semiconc. aqueous HCl.
The precipitate was filtered off, washed with water and dried in a HV.
Yield: 0.630 g (93% of theory) C12H9CIO4 (M= 252.656) Calc.: molpeak (M-H)-: 251/253 Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 ff Found: molpeak (M-H)-: 251/253 (Cl) 130c) N-[3-chloro-4-(2-diethyl amino-ethoxy)-phenyl]-2-(2-chloro-4-furan-2-yl-phenoxy)-acetamide The product was prepared according to general working method I from 2-chloro-4-furan-2-yl-phenoxy)-acetic acid (130b) and 3-chloro-4-(2-diethylamino-ethoxy)-phenylamine (Z1 b).
Yield: 0.380 g (79% of theory) C24H26C12N2O4 (M= 477.392) Calc.: molpeak (M+H)+: 477/479/481 Found: molpeak (M+H)+: 477/479/481 (C12) Rf value: 0.70 (Alox, dichloromethane / MeOH 30:1).
Example 131:

O
N~
H

131a) ethyl (2-ch loro-4-th i ophe n-2-yl -p hen oxy)-acetate Prepared analogously to Example 130a from ethyl (4-bromo-2-chloro-phenoxy)-acetate (Z26) and thiophene-2-boric acid.
Yield: 0.730 g (72% of theory) C14H13CI03S (M= 296.775) Calc.: molpeak (M+H)+: 297/299 Found: molpeak (M+H)+: 297/299 (CI) Rf value: 0.60 (silica gel, petroleum ether/ EtOAc 3:1).
131 b) (2-chloro-4-thiophen-2-yl-phenoxy)-acetic acid Prepared analogously to Example 130b from ethyl (2-chloro-4-thiophen-2-yl-phenoxy)-acetate (131 a).
Yield: 0.600 g (95% of theory) C12H9CI03S (M= 268.721) Calc.: molpeak (M+H)+: 267/269 Found: molpeak (M+H)+: 267/269 (Cl) Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 ff 131c) N-[3-chloro-4-(2-diethylamino-ethoxy)-phenyl]-2-(2-chloro-4-thiophen-2-yl-phenoxy)-acetamide The product was prepared according to general working method I from 2-chloro-4-thiophen-2-yl-phenoxy)-acetic acid (131 b) and 3-chloro-4-(2-diethylamino-ethoxy)-phenylamine (Z1 b).
Yield: 0.410 g (83% of theory) C24H26C12N203S (M= 493.456) Calc.: molpeak (M+H)+: 491/493/495 Found: molpeak (M+H)+: 491/493/495 (012) Rf value: 0.64 (Alox, dichloromethane / MeOH 30:1).
Example 132:

Br CI \ N ~( 0 \ I

132a) ethyl 2-(4-bromo-2-methoxy-phenoxy)-acetate Prepared analogously to Intermediate product Z2a from ethyl bromo-acetate and 2-methoxy-4-bromophenol.
Yield: 3.600 g (83% of theory) C11H13BrO4 (M= 289.128) Calc.: molpeak (M+H)+: 289/291 Found: molpeak (M+H)+: 289/291 (Br).

132b) 2-(4-bromo-2-methoxy-phenoxy)-acetic acid Prepared analogously to Example 130b from ethyl 2-(4-bromo-2-methoxy-phenoxy)-acetate (132a).
Yield: 3.250 g (quant. yield) C9HgBrO4 (M= 289.128) CaIc.: molpeak (M+H)+: 261/263 Found: molpeak (M+H)+: 261/263 (Br).

Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 if 132c) 2-(4-bromo-2-methoxy-phenoxy)-N-[3-chloro-4-(2-diethylamino-ethoxy)-phenyl]-acetamide The product was prepared according to general working method I from 2-(4-bromo-2-methoxy-phenoxy)-acetic acid (132b) and 3-chloro-4-(2-diethylamino-ethoxy)-phenylamine (Z1 b).
Yield: 0.050 g (20% of theory) C21H26BrCIN2O4 (M= 485.809) Calc.: molpeak (M+H)+: 485/487/489 Found: molpeak (M+H)+: 485/487/489 (BrCI) Rf value: 0.55 (silica gel, dichloromethane / MeOH 9:1).
Example 133:
F

F
H F
~( O
/N~/\ a-,-IOI N
O
133) 2-(2-amino-4-trifluoromethyl-phenoxy)-N-[3-chloro-4-(2-diethylamino-ethoxy)-phenyl]-acetamide A suspension of 0.280 g (0.570 mmol) 2-(2-amino-4-trifluoromethyl-phenoxy)-N-[3-chloro-4-(2-diethylamino-ethoxy)-phenyl]-acetamide (Example 65) and 50 mg Raney nickel in 10 mL MeOH was hydrogenated for 5 h at 50 psi. The catalyst was filtered off and the filtrate evaporated down i. vac. . Column chromatography (Alox, N, act. II-III, gradient dichioromethane / MeOH 49:1 19:1) yielded the product.
Yield: 0.180 g (69% of theory) C21H25CIF3N303 (M= 459.900) Ca1c.: molpeak (M+H)+: 460/462 Found: molpeak (M+H)+: 460/462 (CI) Rf value: 0.42 (Alox, dichioromethane / MeOH 19:1).
Example 134:

Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 ff O

'Cl 134a) ethyl (3,2'-dichloro-biphenyl-4-yloxy)-acetate Prepared analogously to Example 130a from ethyl (4-bromo-2-chloro-phenoxy)-acetate (Z26) and 2-chlorophenylboric acid.
Yield: 1.070 g (97% of theory) C16Hf4C12O3 (M= 325.194) Rf value: 0.58 (silica gel, petroleum ether/ EtOAc 3:1).
134b) (3,2'-dichloro-biphenyl-4-yloxy)-acetic acid Prepared analogously to Example 130b from ethyl (3,2'-dichloro-biphenyl-4-yloxy)-acetate (1 34a).
Yield: 0.900 g (92% of theory) C14HIOC12O3 (M= 297.140) Caic.: molpeak (M-H) 295/297/299 Found: molpeak (M-H)-: 295/297/299 (CI2) 134c) N-[3-chloro-4-(2-diethylamino-ethoxy)-phenyl]-2-(3,2'-dichloro-biphenyl-4-yloxy)-acetamide The product was prepared according to general working method I from (3,2'-dichloro-biphenyl-4-yloxy)-acetic acid (134b) and 3-chloro-4-(2-diethylamino-ethoxy)-phenylamine (Z1 b).
Yield: 0.250 g (48% of theory) C26H27C13N2O3 (M= 521.876) Calc.: molpeak (M+H)+: 521/523/525/527 Found: molpeak (M+H)+: 521/523/525/527 (C13) Rf value: 0.65 (Alox, dichloromethane / MeOH 30:1).
Example 135:

Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 if DaNlj~ 0 CI

135a) ethyl (3,4'-dichloro-biphenyl-4-yloxy)-acetate Prepared analogously to Example 130a from ethyl (4-bromo-2-chloro-phenoxy)-acetate (Z26) and 4-chlorophenylboric acid.
Yield: 0.430 g (68% of theory) C161-114C1203 (M= 325.194) Rf value: 0.62 (silica gel, petroleum ether / EtOAc 3:1).
135b) (3,4'-dichloro-biphenyl-4-yloxy)-acetic acid Prepared analogously to Example 130b from ethyl (3,4'-dichloro-biphenyl-4-yloxy)-acetate (1 35a).
Yield: 0.299 g (76% of theory) C14H10C1203 (M= 297.140) Calc.: molpeak (M-H)-: 295/297/299 Found: molpeak (M-H)-: 295/297/299 (CI2) 135c) N-[3-chloro-4-(2-diethylamino-ethoxy)-phenyl]-2-(3,4'-dichloro-biphenyl-4-yloxy)-acetamide The product was prepared according to general working method I from (3,4'-dichloro-biphenyl-4-yloxy)-acetic acid (135b) and 3-chloro-4-(2-diethylamino-ethoxy)-phenylamine (Z1 b).
Yield: 0.280 g (60% of theory) C26H27C13N203 (M= 521.876) Calc.: molpeak (M+H)+: 521/523/525/527 Found: molpeak (M+H)+: 521/523/525/527 (CI3) Rf value: 0.48 (Alox, dichloromethane / MeOH 50:1).
Example 136:

Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 if \N~/ I \ O CI
C, -HJ/

N

136a) ethyl (2-chloro-4-pyridin-3-yl-phenoxy)-acetate Prepared analogously to Example 130a from ethyl (4-bromo-2-chloro-phenoxy)-acetate (Z26) and pyridine-3-boric acid.
Yield: 0.420 g (58 % of theory) C16H14CIN03 (M= 291.737) Rf value: 0.45 (silica gel, petroleum ether / EtOAc 1:3).
136b) (2-chloro-4-pyridin-3-yi-phenoxy)-acetic acid 250 mg (6.250 mmol) NaOH in 10 mL water was added to a solution of 0.400 g (1.371 mmol) ethyl (2-chloro-4-pyridin-3-yl-phenoxy)-acetate in 40 mL abs.
EtOH and the mixture was stirred for 1 h at RT. The reaction mixture was acidified with aqueous HCI (1 M) to pH 7.5, the precipitate was filtered off and washed with water.
Yield: 0.269 g (74 % of theory) C13H10CIN03 (M= 263.683) Calc.: molpeak (M+Na)+: 264/266 Found: molpeak (M+Na)+: 264/266 (CI3) 136c) N-[3-chloro-4-(2-diethylamino-ethoxy)-phenyl]-2-(2-chloro-4-pyridin-3-yl-phenoxy)-acetamide The product was prepared according to general working method I from (2-chloro-4-pyridin-3-yl-phenoxy)-acetic acid (1 36b) and 3-chloro-4-(2-diethylamino-ethoxy)-phenylamine (Z1 b).
Yield: 0.328 g (75% of theory) C25H27C12N303 (M= 488.418) Calc.: molpeak (M+H)+: 488/490/492 Found: molpeak (M+H)+: 488/490/492 (C12) Rf value: 0.47 (Alox, dichloromethane / MeOH 30:1).

Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 if Example 137:

oocI

137a) (4'-chloro-biphenyl-4-yloxy)-acetic acid 1.5 mL TFA was added to a solution of 0.750 g (2.000 mmol) tert-butyl (4'-chloro-biphenyl-4-yloxy)-acetate in 20 mL dichloromethane and the mixture was stirred for 16 h at RT. The reaction mixture was evaporated down i. vac.
and diluted with 1 M aqueous NaOH and EtOAc. The precipitate was filtered off and dried at 80 C i. vac..
Yield: 0.522 g (quant. yield) C141-111003 (M= 262.695) Calc.: molpeak (M-H)-: 261/263 Found: molpeak (M-H)-: 261/263 (Cl) 137b) 2-(4'-chloro-biphenyl-4-yloxy)-N-(4-piperidin-1-ylmethyl-phenyl)-acetamide The product was prepared according to general working method I from (4'-chloro-biphenyl-4-yloxy)-acetic acid (137a) and 4-piperidin-ylmethyl-phenylamine.
Yield: 0.140 g (40% of theory) C26H27CIN202 (M= 434.970) Calc.: molpeak (M+H)+: 435/437 Found: molpeak (M+H)+: 435/437 (Cl) Rf value: 0.40 (silica gel, dichloromethane / McOH 9:1).
Example 138:

a--- ~O CI
N" v \
H

F
138a) ethyl (3-chloro-4'-fluoro-biphenyl-4-yloxy)-acetate Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 if Prepared analogously to Example 130a from ethyl (4-bromo-2-chloro-phenoxy)-acetate (Z26) and 4-fl uoro-phenylboric acid.
Yield: 0.850 g (81 % of theory) C16H14CIF03 (M= 308.740) Calc.: molpeak (M+H)+: 309/311 Found: molpeak (M+H)+: 309/311 (Cl) Rf value: 0.45 (silica gel, petroleum ether 1 EtOAc 3:1).
138b) (3-chloro-4'-fluoro-biphenyl-4-yloxy)-acetic acid Prepared analogously to Example 130b from ethyl (3-chloro-4'-fluoro-biphenyl-4-yloxy)-acetate (1 38a).
Yield: 0.520 g (67% of theory) C14H10CIF03 (M= 280.685) Calc.: molpeak (M-H) 279/281 Found: molpeak (M-H)-: 279/281 (Cl) 138c) N-[3-chloro-4-(2-diethylamino-ethoxy)-phenyl]-2-(3-chloro-4'-fluoro-biphenyl-4-yloxy)-acetamide The product was prepared according to general working method I from (3-chloro-4'-fluoro-biphenyl-4-yloxy)-acetic acid (138b) and 3-chloro-4-(2-diethylamino-ethoxy)-phenylamine (Z1 b).
Yield: 0.440 g (87% of theory) C2SH27C12FN203 (M= 505.421) Calc.: molpeak (M+H)+: 505/507/509 Found: molpeak (M+H)+: 505/507/509 (CI2) Rf value: 0.46 (Alox, dichloromethane / MeOH 50:1).
Example 139:

~~N^~ I O Br O
\
F
F F
139a) ethyl (2-bromo-4-trifluoromethyl-phenoxy)-acetate Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 if A solution of 2.650 g (11.000 mmol) 2-bromo-4-trifluoromethyl-phenol and 1.47 mL 13.20 mmol) ethyl bromo-acetate in 20 mL Hunig base was stirred for h at 120 C. The reaction mixture was diluted with EtOAc and the org.
phase was washed with water, saturated aqueous sodium bicarbonate and saturated aqueous NaCl, dried over magnesium sulphate and evaporated down i. vac. . Column chromatography (silica gel, gradient dichioromethane /
MeOH 100:0 -- 19:1) yielded the product.
Yield: 2.80 g (78% of theory) C11 H10BrF3O3 (M= 327.100) Calc.: molpeak (M+H)+: 327/329 Found: molpeak (M+H)+: 327/329 (Br) Rf value: 0.85 (silica gel, dichioromethane).

139b) (2-bromo-4-trifluoromethyl-phenoxy)-acetic acid Prepared analogously to Example 130b from ethyl (2-bromo-4-trifluoromethyl-phenoxy)-acetate (1 39a).
Yield: 2.150 g (84% of theory) C9H6BrF3O3 (M= 299.046) Calc.: molpeak (M-H)-: 297/299 Found: molpeak (M-H)-: 297/299 (Br) Rf value: 0.35 (silica gel, dichioromethane / MeOH 49:1).

139c) 2-(2-bromo-4-trifluoromethyl-phenoxy)-N-[3-chloro-4-(2-diethylamino-ethoxy)-phenyl]-acetamide The product was prepared according to general working method I from (2-bromo-4-trifluoromethyl-phenoxy)-acetic acid (139b) and 3-chloro-4-(2-diethylamino-ethoxy)-phenylamine (Z1 b).
Yield: 0.450 g (86% of theory) C2,H23BrCIF3N2O3 (M= 523.781) Calc.: molpeak (M+H)+: 523/525/527 Found: molpeak (M+H)+: 523/525/527 (BrCl) Rf value: 0.45 (silica gel, dichloromethane / MeOH 9:1).

Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 if Example 140:

C-Da H" v F
/
\ F
CI
F
140a) 1-(2-chloro-4-nitro-benzyl)-pyrrolidine 10.50 g (74.452 mmol) potassium carbonate was added to a solution of 7.400 g (29.543 mmol) of 1-bromomethyl-2-chloro-4-nitro-benzene and 5.00 mL
(59.300 mmol) pyrrolidine in 150 mL acetonitrile and the mixture was stirred for 16 h at RT. The reaction mixture was diluted with 200 mL
dichloromethane, filtered and the filtrate evaporated down i. vac. . The residue was taken up in EtOAc, the org. phase was washed with water, dried over magnesium sulphate and evaporated down i. vac. . The crude product was used in the next reaction step without any further purification.
Yield: 6.100 g (86% of theory) C111-113CIN202 (M= 240.691) Calc.: molpeak (M+H)+: 241/243 Found: molpeak (M+H)+: 241/243 (Cl) Rf value: 0.38 (silica gel, petroleum ether/ EtOAc 2:1).
140b) 3-chloro-4-pyrrolidin-1-ylmethyl-phenylamine A suspension of 1.00 g (4.155 mmol) 1-(2-chloro-4-nitro-benzyl)-pyrrolidine (140a) and 100 mg Raney nickel in 30 mL MeOH were hydrogenated at RT
and 10 psi. The catalyst was filtered off and the filtrate evaporated down i.
vac..
Yield: 0.840 g (96% of theory) C11H15CIN2 (M= 210.709) Calc.: molpeak (M+H)+: 211/213 Found: molpeak (M+H)+: 211/213 (Cl) Rf value: 0.78 (silica gel, dichloromethane / MeOH / cyclohexane / conc.
aqueous ammonia 75:15:15:1).

140c) N-(3-chloro-4-pyrrolidin-1-ylmethyl-phenyl)-2-(2-chloro-4-trifluoromethyl-phenoxy)-acetamide Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 ff The product was prepared according to general working method I from (2-chloro-4-trifluoromethyl-phenoxy)-acetic acid (Z2b) and 3-chloro-4-pyrrolidin-1 -ylmethyl-phenylamine (140b).
Yield: 0.360 g (51 % of theory) C20H19CI2F3N202 (M= 447.288) Calc.: molpeak (M+H)+: 447/449/451 Found: molpeak (M+H)+: 447/449/451 (C12) Rf value: 0.58 (silica gel, dichloromethane / EtOAc / MeOH / conc. aqueous ammonia 350:75:75:10).

Example 141:

W' / 0 CI
O
H
F
F

141 a) N,N,N'-trimethyl-N'-(4-nitro-phenyl)-ethane-1,2-diamine 3.600 g (25.514 mmol) 1-fluoro-4-nitrobenzene and 8.00 mL (62.948 mmol) N,N,N'-trimethyl-ethylene-1,2-diamine were stirred for 1 h at 100 C and then cooled to RT. The reaction mixture was diluted with water and exhaustively extracted with ether. The combined org. phases were dried over sodium sulphate and evaporated down i. vac. .
Yield: 5.771 g (quant. yield) C11H17N302 (M= 223.277) Calc.: molpeak (M+H)+: 224 Found: molpeak (M+H)+: 224 Rf value: 0.32 (silica gel, EtOAc / EtOH / conc. aqueous ammonia 50:10:1).
141 b) N-(2-dimethylamino-ethyl)-N-methyl benzene- l,4-diamine A suspension of 5.770 g (25.842 mmol), N,N'-trimethyl-N'-(4-nitro-phenyl)-ethane-1,2-diamine (141a) and 0.60 g Pd/C (10%) in EtOH was hydrogenated for 4.5 h at 50 psi. The catalyst was filtered off and the filtrate evaporated down i. vac. . The crude product was further reacted immediately.
Yield: 3.162 g (63% of theory) Boehringer Ingelheim Case 1-1407 if C11H19N3 (M= 1943.294) 141 c) 2-(2-chloro-4-trifluoromethyl-phenoxy)-N-{4-[(2-dimethylamino-ethyl)-methyl-amino]-phenyl}-acetamide The product was prepared according to general working method I from (2-chloro-4-trifluoromethyl-phenoxy)-acetic acid (Z2b) and N-(2-dimethylamino-ethyl)-N-methylbenzene- 1,4-diamine (141 b).
Yield: 0.110 g (37% of theory) C20H23CIF3N302 (M= 429.873) Calc.: molpeak (M+H)+: 430/432 Found: molpeak (M+H)+: 430/432 (Cl) Rf value: 0.37 (silica gel, dichloromethane / MeOH / conc. aqueous ammonia 90:10:1).

Example 142:

F
F F

142a) N-(2-dimethylamino-ethyl)-N-(4-nitro-phenyl)-acetamide A solution of 50 g (0.239 mol) N,N-dimethyl-N'-(4-nitro-phenyl)-ethane-1,2-diamine in 500 mL acetic anhydride was stirred for 3.5 h at 130 C, then evaporated down i. vac. and neutralised with saturated aqueous sodium bicarbonate. The residue was exhaustively extracted with EtOAc, the combined org. phases were dried over sodium sulphate and evaporated down i. vac. .
Yield: 58.36 g (97% of theory) C12H17N303 (M= 251.288) Calc.: molpeak (M+H)+: 252 Found: molpeak (M+H)+: 252 Rf value: 0.55 (silica gel, dichloromethane / MeOH / conc, aqueous ammonia 90:10:1).

Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 if 142b) N-(4-amino-phenyl)-N-(2-dimethylamino-ethyl)-acetamide Prepared analogously to Example 141 b starting from -(2-dimethylamino-ethyl)-N-(4-nitro-phenyl)-acetamide) (142a).
Yield: 50.66 g (99% of theory) C12H19N30 (M= 221.305) Calc.: molpeak (M+H)+: 222 Found: molpeak (M+H)+: 222 Rf value: 0.50 (silica gel, dichloromethane / MeOH / conc. aqueous ammonia 90:10:1).

142c) N-{4-[acetyl-(2-dimethylamino-ethyl)-amino]-phenyl}-2-(2-chloro-4-trifluoromethyl-phenoxy)-acetamide The product was prepared according to general working method I from (2-chloro-4-trifluoromethyl-phenoxy)-acetic acid (Z2b) and N-(4-amino-phenyl)-N-(2-dimethylamino-ethyl)-acetamide (142b).
Yield: 0.200 g (64% of theory) C21 H23CIF3N3O3 (M= 457.884) Calc.: molpeak (M+H)+: 458/460 Found: molpeak (M+H)+: 458/460 (CI) Rf value: 0.64 (Alox, dichloromethane / MeOH 19:1).
Example 143:

\N~~ 0 CI
H~ O
CI F
F

143) N-[2-chloro-4-(2-diethylamino-ethoxy)-phenyl]-2-(2-chloro-4-trifluoromethyl-phenoxy)-acetamide 0.141 mL (1.080 mmol) chloroformic acid-isopropylester was added dropwise at -10 C to a solution of 0.254 g (0.982 mmol) (2-chloro-4-trifluoromethyl-phenoxy)-acetic acid (Z2b) and 0.119 mL (1.080 mmol) N-methylmorpholine in 20 mL abs. THE and the mixture was stirred for a further 10 min.. 0.250 g Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 if (1.031 mmol) 2-chloro-4-(2-diethylamino-ethoxy)-phenylamine (Z27b) was added, the mixture was stirred for 1 h at RT and then evaporated down i. vac.
Water was added and the aqueous phase was exhaustively extracted with dichloromethane. The combined org. phases were dried over sodium sulphate, evaporated down i. vac. and the residue stirred with ether. The precipitate was filtered off, washed with ether and dried in a HV.
Yield: 0.210 g (45% of theory) C21 H23C12F3N2O3 (M= 479.330) Cale.: molpeak (M+H)+: 479/481/483 Found: molpeak (M+H)+: 479/481/483 (CI2) Rf value: 0.67 (Alox, dichloromethane / MeOH 39:1).
Example 144:

N yN
O G
N 11 p F
F

144) 2-(2-chloro-4-trifluoromethyl-phenoxy)-N-[4-(2-dimethylamino-acetylamino)-phenyl]-acetamide Prepared analogously to Example 143 starting from (2-chloro-4-trifluoromethyl-phenoxy)-acetic acid (Z2b) and N-(4-amino-phenyl)-2-dimethylamino-acetamide.
Yield: 0.270 g (64% of theory) C19H19CIF3N3O3 (M= 429.830) Cale.: molpeak (M+H)+: 430/432 Found: molpeak (M+H)+: 430/432 (Cl) Rf value: 0.82 (Alox, dichloromethane / MeOH 39:1).
Example 145:

Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 ff CI
GN/ v I \ CI

H

F

145) N-{3-chloro-4-[2-(2,5-dihydro-pyrrol-1-yl)-ethoxy]-phenyl}-2-(2-chloro-4-trifluoromethyl-phenoxy)-acetamide A solution of 0.145 g (0.300 mmol) of N-[4-(2-bromo-ethoxy)-3-chloro-phenyl]-2-(2-chloro-4-trifluoromethyl-phenoxy)-acetamide (Z28b) and 30.6 pL
(0.400 mmol) 2,5-dihydro-1 H-pyrrole in 2 mL HUnig base was stirred for 3h at 80 C and then evaporated down i. vac. . Column chromatography (Alox, neutral, act. II-III, gradient dichloromethane / MeOH 20:0 --- 19:1) yielded the product.
Yield: 85 mg (60% of theory) C21H19Cl2F3N203 (M= 475.298) Cale.: molpeak (M+H)+: 475/477/479 Found: molpeak (M+H)+: 475/477/479 (CI2) Rf value: 0.35 (Alox, dichioromethane / MeOH 19:1).
Example 146:
CI
N~~ I \ O CI
H
F
O

F
146) ethyl 1-(2-{2-chloro-4-[2-(2-chloro-4-trifluoromethyl-phenoxy)-acetyl amino]-p henoxy}-ethyl)-piperidine-4-carboxylate Prepared analogously to Example 145 starting from N-[4-(2-bromo-ethoxy)-3-chloro-phenyl]-2-(2-chloro-4-trifluoromethyl-phenoxy)-acetamide (Z28b) and ethyl piperidine-4-carboxylate.
Yield: 190 mg (82% of theory) C25H27Cl2F3N2O5 (M= 563.406) Cale.: molpeak (M+H)+: 563/565/567 Found: molpeak (M+H)+: 563/565/567 (CI2) Rf value: 0.52 (silica gel, dichioromethane / MeOH 9:1).

Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 if Example 147:

CI
=X
H
\\~-(N~~
I
O
H
H
F
F

147) tert-butyl [1-(2-{2-chloro-4-[2-(2-chloro-4-trifluoromethyl-phenoxy)-acetylamino]-phenoxy}-ethyl)-pyrrolidin-3-yl]-carbaminate Prepared analogously to Example 145 starting from N-[4-(2-bromo-ethoxy)-3-chloro-phenyl]-2-(2-chloro-4-trifluoromethyl-phenoxy)-acetamide (Z28b) and tert-butyl pyrrolidin-3-yl-carbaminate.
Yield: 230 mg (95% of theory) C26H30C12F3N305 (M= 592.447) Calc.: molpeak (M+H)+: 592/594/596 Found: molpeak (M+H)+: 592/594/596 (C12) Rf value: 0.55 (silica gel, dichloromethane / MeOH 19:1).
Example 148:
CI
H,N~N O CI
H O
F
F

148) N-{4-[2-(3-amino-pyrrolidin-1-yl)-ethoxy]-3-chloro-phenyl}-2-(2-chloro-4-trifluoromethyl-phenoxy)-acetamide 0.80 mL (10.380 mmol) TFA was added at RT to a solution of 0.230 g (0.340 mmol) tert-butyl [1-(2-{2-chloro-4-[2-(2-chloro-4-trifluoromethyl-phenoxy)-acetylamino]-phenoxy}-ethyl)-pyrrolidin-3-yl]-carbaminate (Example 147) in 2 mL dichloromethane and the mixture was stirred for 16 h. The reaction mixture was evaporated down i. vac. and the residue triturated with ether.

Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 if The precipitate was filtered off, washed with ether and dried in a HV. The product was obtained as the bis-trifluoroacetate salt.
Yield: 230 mg (94% of theory) C21H22Cl2F3N3O3* 2 C2HF302 (M= 720.378) Calc.: molpeak (M+H)+: 492/494/496 Found: molpeak (M+H)+: 492/494/496 (CI2) Rf value: 0.45 (Alox, dichloromethane / MeOH 19:1).
Example 149:
CI

O CI
HO N I /O
N
H

F
149) 1-(2-{2-chloro-4-[2-(2-chloro-4-trifluoromethyl-phenoxy)-acetylamino]-phenoxy}-ethyl)-piperidin-4-carboxylic acid 2 mL aqueous NaOH (1 M) was added at RT to a solution of 150 mg (0.270 mmol) ethyl 1-(2-{2-chloro-4-[2-(2-chloro-4-trifluoromethyl-phenoxy)-acetyl amino]-p henoxy}-ethyl)-piperidine-4-carboxylate (Example 146) in 4 mL
EtOH and the mixture was stirred for 16 h. The reaction mixture was neutralised with 2 mL aqueous HCI (1 M), evaporated down i. vac. and the crude product was purified by column chromatography (silica gel, dichloromethane / MeOH 4:1).
Yield: 100 mg (69% of theory) C23H23C12F3N205 (M= 535.351) Calc.: molpeak (M+H)+: 535/537/539 Found: molpeak (M+H)+: 535/537/539 (CI2) Rf value: 0.35 (silica gel, dichloromethane / MeOH 4:1).
Example 150:

Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 ff O CI

N~~ ~ ~ O CI
H
F
F

150) ethyl (S)-1-(2-{2-chloro-4-[2-(2-chloro-4-trifluoromethyl-phenoxy)-acetylamino]-phenoxy}-ethyl)-pyrrolidine-2-carboxylate Prepared analogously to Example 145 starting from N-[4-(2-bromo-ethoxy)-3-chloro-phenyl]-2-(2-chloro-4-trifluoromethyl-phenoxy)-acetamide (Z28b) and ethyl (S)-pyrrolidine-2-carboxylate Yield: 200 mg (89% of theory) C24H25C12F3N205 (M= 549.378) Calc.: molpeak (M+H)+: 549/551/553 Found: molpeak (M+H)+: 549/551/553 (CI2) Rf value: 0.53 (Alox, dichloromethane / MeOH 49:1).
Example 151:
OH
O CI
N^/O O CI

H
F
F

151) (S)-1-(2-{2-chloro-4-[2-(2-chloro-4-trifluoromethyl-phenoxy)-acetylamino]-phenoxy}-ethyl)-pyrrolidine-2-carboxylic acid Prepared analogously to Example 149 starting from ethyl (S)-1-(2-{2-chloro-4-[2-(2-chloro-4-trifluoromethyl-phenoxy)-acetylamino]-phenoxy}-ethyl)-pyrrolidine-2-carboxylate (Example 150).
Yield: 114 mg (30% of theory) C22H21C12F3N205 (M= 521.324) Calc.: molpeak (M+H)+: 521/523/525 Found: molpeak (M+H)+: 521/523/525 (CI2).

Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 if Example 152:

CI
~~ IN\~~O O CI
O

F
F

152) N-[3-chloro-4-(3-diethylamino-propoxy)-phenyl]-2-(2-chloro-4-trifluoromethyl-phenoxy)-acetamide Prepared analogously to Example 145 starting from N-[4-(2-bromo-ethoxy)-3-chloro-phenyl]-2-(2-chloro-4-trifluoromethyl-phenoxy)-acetamide (Z28b) and 3-chloro-4-(3-diethylamino-propoxy)-phenylamine (Z29b).
Yield: 330 mg (68% of theory) C22H25C12F3N203 (M= 493.357) Ca1c.: molpeak (M+H)+: 493/495/497 Found: molpeak (M+H)+: 493/495/497 (CI2).
Rf value: 0.30 (silica gel, dichloromethane / MeOH / conc. aqueous ammonia 90:10:0.1).

Example 153:
O
o~
NH
CI

O CI
NI t:~N~~O
H
F
F F

153) tert. butyl [1-(2-{2-chloro-4-[2-(2-chloro-4-trifluoromethyl-phenoxy)-acetylamino]-phenoxy}-ethyl)-pyrrolidin-2-ylmethyl]-carbaminate Prepared analogously to Example 143 starting from N-[4-(2-bromo-ethoxy)-3-chloro-phenyl]-2-(2-chloro-4-trifluoromethyl-phenoxy)-acetamide (Z28b) and tert-butyl pyrrolidin-2-ylmethyl-carbaminate.
Yield: 280 mg (quant. yield) C27H32C12F3N3O5 (M= 606.474) Calc.: molpeak (M-H)-: 604/606/608 Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 if Found: molpeak (M-H)-: 604/606/608 (CI2).
Rf value: 0.85 (Alox, dichloromethane / MeOH 19:1).
Example 154:
NHi CI
O
N/~~ I \ 0 CI

F
154) N-{4-[2-(2-aminomethyl-pyrrolidin-1-yl)-ethoxy]-3-chloro-phenyl}-2-(2-chloro-4-trifluoromethyl-phenoxy)-acetamide Prepared analogously to Example 148 starting from tert. butyl [1-(2-{2-chloro-4-[2-(2-chloro-4-trifluoromethyl-phenoxy)-acetylamino]-phenoxy}-ethyl)-pyrrolidi n-2-ylmethyl]-carbaminate (Example 153).
Yield: 280 mg (quant. yield) C22H24C12F3N303 * C2HF302 (M= 734.405) Calc.: molpeak (M-H)-: 504/506/508 Found: molpeak (M-H)-: 504/506/508 (CI2).
Rf value: 0.14 (Alox, dichloromethane / MeOH 19:1).
Example 155:

EN------ CI

I O
H
F
F
155) N-{3-chloro-4-[2-(2-dimethylaminomethyl-pyrrolidin-1-yl)-ethoxy]-phenyl}-2-(2-chloro-4-trifluoromethyl-phenoxy)-acetamide 0.46 mL (6.080 mmol) formaldehyde (37% in water) was added to a solution of 250 mg (0.340 mmol) N-{4-[2-(2-aminomethyl-pyrrolidin-1-yl)-ethoxy]-3-chloro-phenyl}-2-(2-chloro-4-trifluoromethyl-phenoxy)-acetamide (Example 154) in 7 mL MeOH and the mixture was stirred for 1 h at RT. 103 mg (2.720 Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 if mmol) sodium borohydride was added batchwise and the mixture was stirred for a further 16 h at RT. The reaction mixture was evaporated down i. vac.
and the residue was taken up in dichloromethane. The org. phase was washed with saturated aqueous sodium bicarbonate, dried over sodium sulphate and evaporated down i. vac. . Column chromatography (silica gel, dichloromethane / MeOH 49:1) yielded the product.
Yield: 170 mg (94% of theory) C24H28C12F3N3O3 (M= 534.410) Calc.: molpeak (M+H)+: 534/536/538 Found: molpeak (M+H)+: 534/536/538 (Cl2).
Rf value: 0.58 (Alox, dichloromethane / MeOH 19:1).
Example 156:

CI
J 6r \ H
F
F

156) N-[3-bromo-4-(2-diethylamino-ethoxy)-phenyl]-2-(2-chloro-4-trifluoromethyl-phenoxy)-acetamide Prepared analogously to Example 143 starting from (2-chloro-4-tri fluoromethyl-phenoxy)-acetic acid (Z2b) and 3-bromo-4-(2-diethylamino-ethoxy)-phenylamine (Z30b).
Yield: 0.310 g (60% of theory) C21 H23BrCIF3N2O3 (M= 523.781) Calc.: molpeak (M+H)+: 523/525/527 Found: molpeak (M+H)+: 523/525/527 (BrCI).
Rf value: 0.64 (Alox, dichloromethane / MeOH 39:1).
Example 157:

Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 ff CI

\O r N---~- O CI
/1~\/JI / /llll\./O \

F F

157) N-{3-chIoro-4-[2-(4-methoxy-piperidin-1-yl)-ethoxy]-phenyl}-2-(2-chloro-4-trifl uoromethyl-phenoxy)-acetamide Prepared analogously to Example 145 starting from N-[4-(2-bromo-ethoxy)-3-chloro-phenyl]-2-(2-chloro-4-trifluoromethyl-phenoxy)-acetamide (Z28b) and 4-methoxy-piperidine.
Yield: 0.200 g (94% of theory) C23H25C12F3N2O4 (M= 521.368) Calc.: molpeak (M+H)+: 521/523/525 Found: molpeak (M+H)+: 521/523/525 (C12).
Rf value: 0.75 (Alox, dichloromethane / MeOH 49:1).
Example 158:
CI
r N I ~ O CI
/1I \/J' / /1I Il\
HO FI
/
F

158) N-{3-chloro-4-[2-(4-hydroxy-piperidin-1-yl)-ethoxy]-phenyl}-2-(2-chloro-4-trifluoromethyl-phenoxy)-acetamide Prepared analogously to Example 145 starting from N-[4-(2-bromo-ethoxy)-3-chloro-phenyl]-2-(2-chloro-4-trifluoromethyl-phenoxy)-acetamide (Z28b) and 4-hydroxy-piperidine.
Yield: 0.190 g (91 % of theory) C22H23C12F3N204 (M= 507.341) Calc.: molpeak (M+H)+: 507/509/511 Found: molpeak (M+H)+: 507/509/511 (C12).
Rf value: 0.55 (Alox, dichloromethane / MeOH 19:1).

Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 if Example 159:
O'~ N;o O CI
O
H l\

F F
159) 2-(2-chloro-4-trifluoromethyl-phenoxy)-N-[4-(2-diethylamino-ethoxy)-3-nitro-phenyl]-acetamide Prepared analogously to Example 143 starting from (2-chloro-4-trifluoromethyl-phenoxy)-acetic acid (Z2b) and 4-(2-diethylamino-ethoxy)-3-nitro-phenylamine (Z31a).
Yield: 0.410 g (45% of theory) C21H23CIF3N3O5 (M= 489.883) Calc.: molpeak (M+H)+: 490/492 Found: molpeak (M+H)+: 490/492 (Cl).
Rf value: 0.46 (silica gel, dichloromethane / MeOH 9:1).
Example 160:

NH0 \N~~ I 0 CI
H
F
F

160) N-[3-amino-4-(2-diethylamino-ethoxy)-phenyl]-2-(2-chloro-4-trifluoromethyl-phenoxy)-acetamide A suspension of 330 mg (0.674 mmol) 2-(2-chloro-4-trifluoromethyl-phenoxy)-N-[4-(2-diethylamino-ethoxy)-3-nitro-phenyl]-acetamide (Example 160) and 200 mg Raney nickel was hydrogenated at RT and 3 bar. The catalyst was filtered off and the filtrate evaporated down i. vac. .
Yield: 0.310 g (quant. yield) C21H25CIF3N3O3 (M= 459.900) Calc.: molpeak (M+H)+: 460/462 Found: molpeak (M+H)+: 460/462 (Cl).
Rf value: 0.45 (silica gel, dichloromethane / McOH 9:1).

Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 if Example 161:

HNLO
\N~~ ( 0 CI
O
J H ~\
F
F F

161) N-[3-acetylamino-4-(2-di ethyl am ino-ethoxy)-phenyl]-2-(2-chloro-4-trifluoromethyl-phenoxy)-acetamide A solution of 100 mg (0.217 mmol) N-[3-amino-4-(2-diethylamino-ethoxy)-phenyl]-2-(2-chloro-4-trifluoromethyl-phenoxy)-acetamide (Example 160) in 10 mL acetic anhydride was stirred for 3 h at 100 C and then evaporated down i.
vac. . The residue was combined with saturated aqueous sodium bicarbonate and exhaustively extracted with EtOAc. The combined org. phases were dried over sodium sulphate, evaporated down i. vac. and the residue was stirred with ether. The precipitate was filtered off, washed with ether and dried in a HV.
Yield: 0.108 g (quant. yield) C23H27CIF3N304 (M= 501.938) Calc.: molpeak (M+H)+: 502/504 Found: molpeak (M+H)+: 502/504 (Cl).
Rf value: 0.42 (silica gel, dichloromethane / MeOH 9:1).
Example 162:
O
`sue HNC \\
O
\N~~ I 0 CI
\
H

F F
162) 2-(2-chloro-4-trifluoromethyl-phenoxy)-N-[4-(2-diethylamino-ethoxy)-3-methanesul phonylami no-phenyl]-acetamide Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 if A solution of 100 mg (0.217 mmol) N-[3-amino-4-(2-diethylamino-ethoxy)-phenyl]-2-(2-chloro-4-trifluoromethyl- phenoxy)-acetamide (Example 160) in 5 mL pyridine was added at 0 C to 18 pL (0.239 mmol) of methanesulphonylchloride, the mixture was slowly heated to RT and stirred for 3 h at RT. The reaction mixture was poured onto ice water and the aqueous phase was exhaustively extracted with EtOAc. The combined org.
phases were dried over sodium sulphate and evaporated down i. vac. . The residue was lyophilised.
Yield: 0.080 g (87% of theory) C22H27CIF3N3O5S (M= 537.990) Calc.: molpeak (M+H)+: 538/540 Found: molpeak (M+H)+: 538/540 (Cl).
Rf value: 0.40 (silica gel, dichloromethane / MeOH 9:1).
Example 163:

N O
H I \
I
CI
163a) 2-(4-bromo-phenylamino)-N-(4-dimethylaminomethyl-phenyl)-acetamide The product was prepared according to general working method I from (4-bromo-phenylamino)-acetic acid and 4-dimethylaminomethyl-phenylamine.
Yield: 1.340 g (28% of theory) C17H2OBrN3O (M= 362.272) Calc.: molpeak (M+H)+: 362/364 Found: molpeak (M+H)+: 362/364 (Cl).
Rf value: 0.68 (Alox, dichloromethane / MeOH 19:1).

163b) 2-(4'-chloro-biphenyl-4-ylamino)-N-(4-dimethylaminomethyl-phenyl)-acetamide Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 if Prepared analogously to Example 130a starting from 2-(4-bromo-phenylamino)-N-(4-dimethylaminomethyl-phenyl)-acetamide (Example 163a) and 4-chloro-phenyl-boric acid.
Yield: 0.160 g (41 % of theory) C23H24CIN3O (M= 393.920) Calc.: molpeak (M+H)+: 394/396 Found: molpeak (M+H)+: 394/396 (Cl).
Rf value: 0.48 (silica gel, dichloromethane / MeOH / conc. aqueous ammonia 90:10:1).

Example 164:
F

F
F
CI H
-C"

164a) (2-chloro-4-trifluoromethyl-phenyl)-methyl-amine 7.04 mL (59.059 mmol) N,N-dimethyl-formamide-dimethylacetal was added to a solution of 2.100 g (10.738 mmol) 2-chloro-4-trifluoromethoxy-phenylamine in 10 mL DMF under a nitrogen atmosphere and the mixture was stirred for 5 h at 60 C and for 16 h at RT. 1.421 g (37.583 mmol) sodium borohydride was added and the mixture was stirred for another 3 h at 60 C. Saturated aqueous sodium bicarbonate was added and the mixture was extracted with EtOAc. The org. phase was dried over sodium sulphate and evaporated down i. vac. at 30 C. Column chromatography (silica gel, petroleum ether) yielded the product.
Yield: 1.100 g (49% of theory) C$H7CIF3N (M= 209.600) Calc.: molpeak (M+H)+: 210/212 Found: molpeak (M+H)+: 210/212 (CI).
Rf value: 0.75 (silica gel, petroleum ether / EtOAc 9:1).

164b) N-[3-chloro-4-(2-diethylamino-ethoxy)-phenyl]-2-[(2-chloro-4-trifluoromethyl-phenyl)-methyl-amino]-acetamide Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 if A solution of 0.200 g (0.450 mmol) 2-bromo-N-[3-chloro-4-(2-diethylamino-ethoxy)-phenyl]-acetamide-hydrobromide and 0.141 g (0.675 mmol) (2-chioro-4-trifluoromethyl-phenyl)-methyl-amine (Example 164a) in 2 mL DMF was heated to 100 C for 2 h in the microwave. The reaction mixture was evaporated down i. vac. , diluted with 3 mL DMF and purified by HPLC-MS
(Stable Bond C18; 3.5 pm; water:acetonitrile:formic acid 9:1:0.01 -* 1:9:0.01 over 9 min) . The product was obtained as the formate salt.
Yield: 36 mg (15% of theory) C22H26C12F3N302 * CH202 (M= 538.399) Calc.: molpeak (M+H)+: 492/494/496 Found: molpeak (M+H)+: 492/494/496 (C12).
Rf value: 0.69 (silica gel, EtOAc / MeOH / conc. aqueous ammonia 90:10:1).
Example 165:

\N~~~ I \ 0 CI
JIB N
J CI / H~ V I \

O
F F F

165a) ethyl (2-chloro-4-trifluoromethoxy-phenyl-amino)-acetate 0.566 mL (5.000 mmol) ethyl bromoacetate was added at RT to a solution of 0.95 g (4.266 mmol) (2-chloro-4-trifluoromethyl-phenyl)-methyl-amine in 10 mL Hunig base and the mixture was refluxed for 4 h. Water was added and the aqueous phase was exhaustively extracted with EtOAc. The combined org. phases were washed with water, saturated aqueous sodium bicarbonate and saturated aqueous NaCl, dried over sodium sulphate and evaporated down i. vac. . The crude product was used in the next reaction step without any further purification.
Yield: 1.200 g (57% of theory) C11Ht1CIF3N03 (M= 297.663) Rf value: 0.68 (silica gel, petroleum ether/ EtOAc 3:1).

165b) (2-chloro-4-trifluoromethoxy-phenyl-amino)-acetic acid Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 ff Prepared analogously to Intermediate product Z2b starting from ethyl [(2-chloro-4-trifluoromethyl-phenyl)-methyl-amino]-acetate (Example 165a).
Yield: 0.630 g (97% of theory) C9H7CIF3NO3 (M= 209.600) Calc.: molpeak (M+H)+: 210/212 Found: molpeak (M+H)+: 210/212 (CI).
Rf value: 0.75 (silica gel, petroleum ether / EtOAc 9:1).

165c) N-[3-chloro-4-(2-diethylamino-ethoxy)-phenyl]-2-(2-chloro-4-trifluoromethoxy-phenylamino)-acetamide The product was prepared according to general working method I from (2-chloro-4-trifluoromethoxy-phenyl-amino)-acetic acid (Example 165b) and 3-chloro-4-(2-diethylamino-ethoxy)-phenylamine (Z1 b).
Yield: 0.220 g (44% of theory) C21H24C12F3N3O3 (M= 494.345) CaIc.: molpeak (M-H) 492/494/496 Found: molpeak (M-H) 492/494/496 (CI).
Rf value: 0.48 (Alox, dichloromethane / MeOH 30:1).
Example 166:

N~~ I O F

F
F F

166a) ethyl (2-fluoro-4-trifluoromethyl-phenylamino)-acetate Prepared analogously to Example 165a starting from 2-fluoro-4-trifluoromethyl-phenylamine and ethyl bromoacetate. The crude product was purified by column chromatography (silica gel, gradient dichloromethane /
MeOH 20:0 ---),19:1).
Yield: 0.980 g (82% of theory) Cõ H11 F4NO2 (M= 265.209) Calc.: molpeak (M+H)+: 266 Found: molpeak (M+H)+: 266 Boehringer Ingelheim CA 02504207 2005-04-28 Case 1-1407 if Rf value: 0.72 (silica gel, petroleum ether / EtOAc 3:1).
166b) (2-fluoro-4-trifluoromethyl-phenylamino)-acetic acid Prepared analogously to Intermediate product Z2b starting from ethyl (2-fluoro-4-trifluoromethyl-phenylamino)-acetate (Example 166a). The crude product was purified by column chromatography (silica gel, gradient dichloromethane / MeOH 20:0 -- 19:1).
Yield: 0.670 g (79% of theory) C9H7F4NO2 (M= 237.155) CaIc.: molpeak (M-H) 236 Found: molpeak (M-H)-: 236.

166c) N-(3-chloro-4-(2-diethylamino-ethoxy)-phenyl]-2-(2-fluoro-4-trifluoromethyl-phenylamino)-acetamide The product was obtained according to general working method I starting from (2-fluoro-4-trifluoromethyl-phenylamino)-acetic acid (Example 166b) and 3-chloro-4-(2-diethylamino-ethoxy)-phenylamine (Z1 b).
Yield: 0.150 g (32% of theory) C21H24CIF4N302 (M= 461.891) CaIc.: molpeak (M+H)+: 462/464 Found: molpeak (M+H)+: 462/464 (CI) Example 167:
CI
o Br F
F

167a) ethyl (2-bromo-4-trifluoromethyl-phenylamino)-acetate Prepared analogously to Example 166a starting from 2-bromo-4-trifluoromethyl-phenylamine and ethyl bromoacetate.
Yield: 1.200 g (36% of theory) C11H11BrF3NO2 (M= 326.115) Rf value: 0.72 (silica gel, petroleum ether / EtOAc 3:1).

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COMPREND PLUS D'UN TOME.

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Claims (32)

CLAIMS:
1. Compound of formula I

wherein R1, R2 independently of one another denote H, a C1-8-alkyl or C3-7-cycloalkyl group optionally substituted by the group R11, wherein a -CH2-group in position 3 or 4 of a 5-, 6- or 7-membered cycloalkyl group may be replaced by -O-, -S- or -NR13-, or a phenyl or pyridinyl group optionally mono- or polysubstituted by the group R12 and/or monosubstituted by nitro, with the proviso that at least one of the groups R1, R2 has a meaning other than H, or R1 and R2 form a C2-8-alkylene bridge wherein - one or two -CH2- groups may be replaced independently of one another by -CH=N- or -CH=CH- and/or - one or two -CH2- groups may be replaced independently of one another by -O-, -S-, -SO-, -(SO2)-, -C=N-O-R18-, -CO-, -C(=CH2)- or -NR13- in such a way that heteroatoms are not directly connected to one another, wherein in the above-defined alkylene bridge one or more H atoms may be replaced by R14, and wherein the above-defined alkylene bridge may be substituted by one or two identical or different carbo- or heterocyclic groups Cy in such a way that the bond between the alkylene bridge and the group Cy is formed - via a single or double bond, - via a common C atom forming a spirocyclic ring system, - via two common, adjacent C and/or N atoms forming a fused bicyclic ring system or - via three or more C and/or N atoms forming a bridged ring system, R3 denotes H, C1-6-alkyl, C3-7-cycloalkyl or C3-7-cycloalkyl-C1-4-alkyl, X denotes an unbranched C1-4-alkylene bridge and if the group Y is connected to X via a C atom, it may also denote -CH2-CH=CH-, -CH2-C=C-, C2-4-alkylenoxy or C2-4-alkylene-NR4-, wherein the bridge X may be attached to R1 including the N atom attached to R1 and X forming a heterocyclic group, wherein the bridge X may additionally also be attached to R2, including the N-atom attached to R2 and X, forming a heterocyclic group, and a C atom may be substituted by R10 and/or one or two C atoms may each be substituted with one or two identical or different substituents selected from among C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C3-7-cycloalkyl, C3-7-cycloalkyl-C1-3-alkyl, C4-7-cycloalkenyl and C4-7-cycloalkenyl-C1-3-alkyl, wherein two alkyl and/or alkenyl substituents may be joined together, forming a carbocyclic ring system, with the proviso that the group X denoting C2-4-alkylenoxy does not contain a hydroxy substitutent; and W denotes -CR6a R6b-O-, -CR7a=CR7c-, -CR6a R6b-NR8-, -OR7a p7b-CR7c R7d- or -NR8-CR6a R6b-, Z denotes a single bond or C1-4-alkylene, wherein two adjacent C atoms may be joined together with an additional C1-4-alkylene bridge, wherein a C atom of the alkylene bridge may be substituted with R10 and/or one or two C atoms independently of one another may be substituted with one or two identical or different C1-6-alkyl groups, wherein two alkyl groups may be joined together, forming a carbocyclic ring, and Y is selected from among the bivalent cyclic groups wherein the above-mentioned cyclic groups may be mono- or polysubstituted by R20 at one or more C atoms, and in the case of a phenyl group may also additionally be monosubstituted by nitro, and/or the hydrogen in an NH
group may be replaced by R21, and A denotes one of the meanings given for Cy, B denotes one of the meanings given for Cy, b denotes the value 0 or 1, Cy denotes a carbo- or heterocyclic group selected from one of the following meanings - a saturated 3- to 7-membered carbocyclic group, - an unsaturated 4- to 7-membered carbocyclic group, - a phenyl group, - a saturated 4- to 7-membered or unsaturated 5- to 7-membered heterocyclic group with an N, O or S atom as heteroatom, - a saturated or unsaturated 5- to 7-membered heterocyclic group with two or more N atoms or with one or two N atoms and an O or S atom as heteroatoms, and - an aromatic heterocyclic 5- or 6-membered group with one or more identical or different heteroatoms selected from N, O and/or S, wherein in the above-mentioned. Cy, 4-, 5-, 6- or 7-membered groups may be attached via two common, adjacent C atoms fused to a phenyl or pyridine ring, and in the above-mentioned Cy, in 5-, 6- or 7-membered groups one or two non-adjacent -CH2- groups may be replaced independently of one another by a -CO-, -C(=CH2)-, -(SO)- or -(SO2)- group, and the above-mentioned Cy, saturated 6- or 7-membered groups may also be present as bridged ring systems with an imino, N-(C1-4-alkyl)-imino, methylene, C1-4-alkyl-methylene or di-(C1-4-alkyl)-methylene bridge, and the above-mentioned cyclic groups may be mono- or polysubstituted at one or more C atoms with R20, in the case of a phenyl group they may also additionally be monosubstituted with nitro, and/or one or more NH groups may be substituted with R21, R4 denotes H, C1-6-alkyl or C2-6-alkenyl, R6a, R6b denotes H, C1-4-alkyl or CF3, R7a, R7b, R7c , R7d denotes H, F, Cl, C1-4-alkyl or CF3, R8 denotes H, C1-4-alkyl, C3-7-cycloalkyl or C3-7-cycloalkyl-C1-3-alkyl, R10 denotes hydroxy, .omega.-hydroxy-C1-3-alkyl, C1-4-alkoxy, .omega.-(C1-4-alkoxy)-C1-3-alkyl, carboxy, C1-4-alkoxycarbonyl, amino, C1-4-alkyl-amino, di-(C1-4-alkyl)-amino, cyclo-C3-6-alkyleneimino, amino-C1-3-alkyl, C1-4-alkyl-amino-C1-3-alkyl, di-(C1-4-alkyl)-amino-C1-3-alkyl, cyclo-C3-6-alkyleneimino-C1-3-alkyl, amino-C1-3-alkoxy, C1-4-alkyl-amino-C1-3-alkoxy, di-(C1-4-alkyl)-amino-C1-3-alkoxy, cyclo-C3-6-alkyleneimino-C1-3-alkoxy, aminocarbonyl, C1-4-alkyl-aminocarbonyl, di-(C1-4-alkyl)-aminocarbonyl or cyclo-C3-6-alkyleneimino-carbonyl, R11 denotes C2-6-alkenyl, C2-6-alkynyl, R15-O, R15-O-CO, R15-CO-O, R16R17N, R18R19N-CO or Cy, R12 has one of the meanings given for R20, R13 has one of the meanings given for R17, with the exception of carboxy, R14 denotes halogen, C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, R15-O, R15-O-CO, R15-CO, R15-CO-O, R16R17N, R18R19N-CO, R15-O-C1-3-alkyl, R15-O-CO-C1-3-alkyl, R15-O-CO-NH, R15-SO2-NH, R15-O-CO-NH-C1-3-alkyl, R15-SO2-NH-C1-3-alkyl-, R15-CO-C1-3-alkyl, R15-CO-O-C1-3-alkyl, R16R17N-C1-3-alkyl, C1-3-alkyl or Cy-C1-3-alkyl, R15 denotes H, C1-4-alkyl, C3-7-cycloalkyl, C3-7-cycloalkyl-C1-3-alkyl, phenyl, phenyl-C1-3-alkyl, pyridinyl or pyridinyl-C1-3-alkyl, R16 denotes H, C1-6-alkyl, C3-7-cycloalkyl, C3-7-cycloalkyl-C1-3-alkyl, C4-7-cycloalkenyl, C4-7-cycloalkenyl-C1-3-alkyl, .omega.-hydroxy-C2-3-alkyl, .omega.-(C1-4-alkoxy)-C2-3-alkyl, amino-C2-6-alkyl, C1-4-alkyl-amino-C2-6-alkyl, di-(C1-4-alkyl)-amino-C2-6-alkyl or cyclo-C3-6-alkyleneimino-C2-6-alkyl, R17 has one of the meanings given for R16 or denotes phenyl, phenyl-C1-3-alkyl, pyridinyl, dioxolan-2-yl, -CHO, C1-4-alkylcarbonyl, carboxy, hydroxycarbonyl-C1-3-alkyl, C1-4-alkoxycarbonyl, C1-4-alkoxycarbonyl-C1-3-alkyl, C1-4-alkylcarbonylamino-C2-3-alkyl, N-(C1-4-alkylcarbonyl)-N-(C1-4-alkyl)-amino-C2-3-alkyl, C1-4-alkylsulphonyl, C1-4-alkylsulphonylamino-C2-3-alkyl or N-(C1-4-alkylsulphonyl)-N(C1-4-alkyl)-amino-C2-3-alkyl, R18, R19 independently of one another denote H or C1-6-alkyl, R20 denotes halogen, hydroxy, cyano, C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C3-7-cycloalkyl, C3-7-cycloalkyl-C1-3-alkyl, hydroxy-C1-4-alkyl, R22-C1-3-alkyl or one of the meanings given for R22, R21 denotes C1-4-alkyl, .omega.-hydroxy-C2-3-alkyl, .omega.-C1-4-alkoxy-C2-6-alkyl, .omega.-C1-4-alkyl-amino-C2-6-alkyl, .omega.-di-(C1-4-alkyl)-amino-C2-6-alkyl, .omega.-cyclo-C3-6-alkyleneimino-C2-6-alkyl, phenyl-C1-3-alkyl, C1-4-alkylcarbonyl, C1-4-alkoxy-carbonyl or C1-4-alkylsulphonyl, R22 denotes phenyl-C1-3-alkoxy, OHC, HO-N=HC, C1-4-alkoxy-N=HC, C1-4-alkoxy, C1-4-alkylthio, carboxy, C1-4-alkylcarbonyl, C1-4-alkoxycarbonyl, aminocarbonyl, C1-4-alkylaminocarbonyl, di-(C1-4-alkyl)-aminocarbonyl, cyclo-alkyl-amino-carbonyl, cyclo-C3-6-alkyleneimino-carbonyl, cyclo-C3-6-alkyleneimino-C2-4-alkyl-aminocarbonyl, phenyl-amino-carbonyl, C1-4-alkyl-sulphonyl, C1-4-alkyl-sulphinyl, C1-4-alkyl-sulphonylamino, amino, C1-4-alkylamino, di-(C1-4-alkyl)-amino, C1-4-alkyl-carbonyl-amino, cyclo-C3-6-alkyleneimino, phenyl-C1-3-alkylamino, N-(C1-4-alkyl)-phenyl-C1-3-alkylamino, acetylamino, propionylamino, phenylcarbonylamino, phenylcarbonylmethylamino, hydroxy-alkylaminocarbonyl, (4-morpholinyl)carbonyl, (1-pyrrolidinyl)-carbonyl, (1-piperidinyl)carbonyl, (hexahydro-1-azepinyl)carbonyl, (4-methyl-1-piperazinyl)carbonyl, methylenedioxy, aminocarbonylamino or alkylaminocarbonylamino, wherein in the above-mentioned groups and residues in A, B, W, X, Y, Z, R1 to R4, R6a, R6b, R7a, R7b R7C, R7d, R8, R10 to R22, one or more C atoms in each case may additionally be mono- or polysubstituted by F and/or one or two C
atoms in each case may additionally be monosubstituted by Cl or Br independently of one another and/or one or more phenyl rings in each case may additionally, independently of one another, have one, two or three substituents selected from among F, Cl, Br, I, C1-4-alkyl, C1-4-alkoxy, difluoromethyl, trifluoromethyl, hydroxy, amino, C1-3-alkylamino, di-(C1-3-alkyl)-amino, acetylamino, aminocarbonyl, cyano, difluoromethoxy, trifluoromethoxy, amino-C1-3-alkyl, C1-3-alkylamino-C1-3-alkyl and di-(C1-3-alkyl)-amino-C1-3-alkyl and/or may be monosubstituted by nitro, and the H atom of any carboxy group present or an H atom bonded to an N atom may each be replaced by a group which can be cleaved in vivo, a tautomer, diastereomer or enantiomer thereof, a mixture thereof or a salt thereof, with the following provisos (M2) and (M3) (M2) in the event that W denotes -CH=CH- and Y denotes a phenylene group and Z is a single bond, then the bridges X and Z at the phenylene ring of the group Y are in the para position to one another and at least one of the following conditions is met:

(a) the group Y meaning phenylene is at least monosubstituted, (b) b has the value 0 and the group A is at least disubstituted, and (c) b has the value 1;

(M3) the following individual compounds are not included:
N-[4-(2-diethylamino-ethoxy)-phenyl]-3-phenyl-propionamide, N-[4-(2-morpholin-4-ylethoxy)-phenyl]-3-phenyl-propionamide, 3-(4-chloro-phenyl)-N-{2-[4-(2-diethylamino-ethoxy)-phenyl]-ethyl}-acrylamide, N-{2-[3-(4-{2-[2-(4-chloro-phenoxy)-acetylamino]-ethyl}-phenoxy)-2-hydroxy-propylamino]-ethyl}-isobutyramide, cyclopentanecarboxylic acid {2-[3-(4-{2-[2-(4-chloro-phenoxy)-acetylamino]-ethyl}-phenoxy)-2-hydroxy-propylamino]-ethyl}-amide, and 2-(4-chloro-phenoxy)-N-(2-{4-[2-hydroxy-3-(2-phenylacetylamino-ethylamino)-propoxy]-phenyl}-ethyl)-acetamide.
2. Compound according to claim 1, a tautomer, diastereomer or enantiomer thereof, a mixture thereof or a salt thereof, wherein R1, R2 independently of one another denote H, a C1-8-alkyl or C3-7-cycloalkyl group optionally substituted by the group R11, or a phenyl group optionally mono- or polysubstituted by the group R12 and/or monosubstituted by nitro, with the proviso that at least one of the groups R1, R2 has a meaning other than H, or R1 and R2 form a C2-8-alkylene bridge wherein - one or two -CH2- groups independently of one another may be replaced by -CH=N- or -CH=CH- and/or - one or two -CH2- groups independently of one another may be replaced by -O-, -S-, -CO-, -C(=CH2)- or -NR13- so that heteroatoms are not directly connected to one another, wherein in the alkylene bridge defined above one or more H atoms may be replaced by R14, and wherein the alkylene bridge defined hereinbefore may be substituted with one or two identical or different carbo- or heterocyclic groups Cy so that the bond between the alkylene bridge and the group Cy is made - via a single or double bond, - via a common C atom forming a spirocyclic ring system, - via two common adjacent C and/or N atoms forming a fused bicyclic ring system or - via three or more C and/or N atoms forming a bridged ring system, X denotes an unbranched C1-4-alkylene bridge and if the group Y is connected to X via a C atom, it may also denote -CH2-CH=CH-, -CH2-C.ident.C-, C2-4-alkylenoxy or C2-4-alkylene-NR4-, wherein the bridge X may be connected to R1 including the N atom attached to R1 and X forming a heterocyclic group, and a C atom may be substituted by R10 and/or one or two C atoms in each case may be substituted by one or two identical or different C1-6-alkyl groups, with the proviso that the group X denoting C2-4-alkylenoxy does not have a hydroxy substituent;
and Z denotes a single bond, C1-4-alkylene, wherein two adjacent C atoms may be joined together by an additional C1-4-alkylene bridge, wherein a C atom of the alkylene bridge may be substituted by R10 and/or one or two C atoms independently of one another may be substituted by one or two identical or different C1-6-alkyl groups, and b has the value 0, R10 denotes hydroxy, .omega.-hydroxy-C1-3-alkyl, C1-4-alkoxy, .omega.-(C1-4-alkoxy)-C1-3-alkyl, amino, C1-4-alkyl-amino, di-(C1-4-alkyl)-amino, cyclo-C3-6-alkyleneimino, amino-C1-3-alkyl, C1-4-alkyl-amino-C1-3-alkyl, di-(C1-4-alkyl)-amino-C1-3-alkyl, cyclo-C3-6-alkyleneimino-C1-3-alkyl, amino-C1-3-alkoxy, C1-4-alkyl-amino-C1-3-alkoxy, di-(C1-4-alkyl)-amino-C1-3-alkoxy or cyclo-C3-6-alkyleneimino-C1-3-alkoxy, R14 denotes halogen, C1-6-alkyl, R15-O, R15-O-CO, R15-CO, R15-CO-O, R16R17N, R18R19N-CO, R15-O-C1-3-alkyl-, R15-O-CO-C1-3-alkyl, R15-CO-C1-3-alkyl, R15-CO-O-C1-3-alkyl, R16R17N-C1-3-alkyl, R18R19N-CO-C1-3-alkyl or Cy-C1-3-alkyl, R15 denotes H, C1-4-alkyl, C3-7-cycloalkyl, C3-7-cycloalkyl-C1-3-alkyl, phenyl or phenyl-C1-3-alkyl, R17 has one of the meanings given for R16 or denotes phenyl, phenyl-C1-3-alkyl, C1-4-alkylcarbonyl, hydroxycarbonyl-C1-3-alkyl, C1-4-alkylcarbonylamino-C2-3-alkyl, N-(C1-4-alkylcarbonyl)-N-(C1-4-alkyl)-amino-C2-3-alkyl, C1-4-alkylsulphonyl, C1-4-alkylsulphonylamino-C2-3-alkyl or N-(C1-4-alkylsulphonyl)-N-(C1-4-alkyl)-amino-C2-3-alkyl, R20 denotes halogen, hydroxy, cyano, C1-6-alkyl, C3-7-cycloalkyl, C3-7-cycloalkyl-C1-3-alkyl, hydroxy-C1-4-alkyl, R22-C1-3-alkyl or one of the meanings given for R22, R21 denotes C1-4-alkyl, .omega.-hydroxy-C2-3-alkyl, .omega.-C1-4-alkoxy-C2-6-alkyl, .omega.-C1-4-alkyl-amino-C2-6-alkyl, .omega.-di-(C1-4-alkyl)-amino-C2-6-alkyl, .omega.-cyclo-C3-6-alkyleneimino-C2-6-alkyl, phenyl, phenyl-C1-3-alkyl, C1-4-alkyl-carbonyl, carboxy, C1-4-alkoxy-carbonyl or C1-4-alkylsulphonyl, R22 denotes phenyl, phenyl-C1-3-alkoxy, C1-4-alkoxy, C1-4-alkylthio, carboxy, C1-4-alkylcarbonyl, C1-4-alkoxycarbonyl, aminocarbonyl, C1-4-alkylaminocarbonyl, di-(C1-4-alkyl)-aminocarbonyl, cyclo-C3-6-alkyleneimino-carbonyl, C1-4-alkyl-sulphonyl, C1-4-alkyl-sulphinyl, C1-4-alkyl-sulphonylamino, amino, C1-4-alkylamino, di-(C1-4-alkyl)-amino, cyclo-C3-6-alkyleneimino, phenyl-C1-3-alkylamino or N-(C1-4-alkyl)-phenyl-C1-3-alkylamino, acetylamino, propionylamino, phenylcarbonylamino, phenylcarbonylmethylamino, hydroxyalkylaminocarbonyl, (4-morpholinyl)carbonyl, (1-pyrrolidinyl)carbonyl, (1-piperidinyl)carbonyl, (hexahydro-1-azepinyl)carbonyl, (4-methyl-1-piperazinyl)carbonyl, methylenedioxy, aminocarbonylamino or alkylaminocarbonylamino.
3. Compound according to claim 1 or 2, a tautomer, diastereomer or enantiomer thereof, a mixture thereof or a salt thereof, wherein R1, R2 independently of one another denote H, C1-6-alkyl, C3-7-cycloalkyl, C3-7-cycloalkyl-C1-3-alkyl, .omega.-hydroxy-C2-3-alkyl, .omega.-(C1-4-alkoxy)-C2-3-alkyl, C1-4-alkoxy-carbonyl-C1-4-alkyl, carboxyl-C1-4-alkyl, amino-C2-4-alkyl, C1-4-alkyl-amino-C2-4-alkyl, di-(C1-4-alkyl)-amino-C2-4-alkyl, cyclo-C3-6-alkyleneimino-C2-4-alkyl, pyrrolidinyl, N-(C1-4-alkyl)-pyrrolidinyl, pyrrolidinyl-C1-3-alkyl, N-(C1-4-alkyl)-pyrrolidinyl-C1-3-alkyl, piperidinyl, N-(C1-4-alkyl)-piperidinyl, piperidinyl-C1-3-alkyl, N-(C1-4-alkyl)-piperidinyl-C1-3-alkyl, phenyl, phenyl-C1-3-alkyl, pyridyl or pyridyl-C1-3-alkyl, wherein in the above-mentioned groups and residues one or more C atoms may be mono- or polysubstituted by F and/or one or two C atoms may independently of one another be monosubstituted by Cl or Br, and the phenyl or pyridyl group may be mono- or polysubstituted by the group R12 and/or may be monosubstituted by nitro, with the proviso that at least one of the groups R1, R2 has a meaning other than H.
4. Compound according to claim 1 or 2, a tautomer, diastereomer or enantiomer thereof, a mixture thereof or a salt thereof, wherein R1 and R2 form an alkylene bridge such that R1R2N- denotes a group selected from azetidine, pyrrolidine, piperidine, azepan, 2,5-dihydro-1H-pyrrole, 1,2,3,6-tetrahydro-pyridine, 2,3,4,7-tetrahydro-1H-azepine, 2,3,6,7-tetrahydro-1H-azepine, piperazine, wherein the free imine function is substituted by R13, piperidin-4-one-oxime, piperidin-4-one-O-C1-4-alkyl-oxime, morpholine and thiomorpholine, wherein one or more H atoms may be replaced by R14, and/or may be substituted in the manner indicated in claim 1 by one or two identical or different carbo- or heterocyclic groups Cy.
5. Compound according to claim 1, a tautomer, diastereomer or enantiomer thereof, a mixture thereof or a salt thereof, wherein the group is defined according to one of the following partial formulae wherein one or more H atoms of the heterocycle formed by the group R1R2N- may be replaced by R14 and the ring attached to the heterocycle formed by the group R1R2N- may be mono- or polysubstituted by R20 at one or more C
atoms, and in the case of a phenyl ring it may also additionally be monosubstituted by nitro and X', X" independently of one another denote a single bond or C1-3-alkylene and if the group Y is linked to X' or X" via a C atom, may also denote -C1-3-alkylene-O-, -C1-3-alkylene-NH- or -C1-3-alkylene-N(C1-3-alkyl)-, and wherein in the definitions given hereinbefore for X', X" in each case a C atom may be substituted by R10, and/or one or two C atoms may each be substituted by one or two identical or different substituents selected from C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C3-7-cycloalkyl, C3-7-cycloalkyl-C1-3-alkyl, C4-7-cycloalkenyl and C4-7-cycloalkenyl-C1-3-alkyl, wherein two alkyl and/or alkenyl substituents may be joined together forming a carbocyclic ring system, and in X', X" independently of one another one or more C atoms may be mono- or polysubstituted by F and/or one or two C atoms independently of one another may each be monosubstituted by Cl or Br.
6. Compound according to claim 1 or 2, a tautomer, diastereomer or enantiomer thereof, a mixture thereof or a salt thereof, wherein X denotes -CH2-, -CH2-CH2- or -CH2-CH2-CH2-, and if the group Y is linked to X via a C atom, it also denotes -CH2-CH=CH-, -CH2-C.ident.C-, -CH2-CH2-O-, -CH2-CH2-CH2-O-, -CH2-CH2-NR4- or -CH2-CH2-CH2-NR4-, wherein the bridge X may be connected to R1 including the N atom attached to R1 and X, forming a heterocyclic group, and in X a C atom may be substituted by a hydroxy, .omega.-hydroxy-C1-3-alkyl, .omega.-(C1-4-alkoxy)-C1-3-alkyl and/or C1-4-alkoxy group, and/or one or two C
atoms may each be substituted by one or two identical or different substituents selected from among C1-6-alkyl, C3-7-cycloalkyl and C3-7-cycloalkyl-C1-3alkyl, wherein two alkyl substituents may be joined together, forming a carbocyclic ring system, and one or more C atoms may each be mono- or polysubstituted by F
and/or one or two C atoms may each independently of one another be monosubstituted by Cl or Br and with the proviso that the group X denoting C2-4-alkylenoxy does not have a hydroxy substituent.
7. Compound according to any one of claims 1 to 6, a tautomer, diastereomer or enantiomer thereof, a mixture thereof or a salt thereof, wherein Z is a single bond, -CH2- or -CH2-CH2-, wherein one or two C atoms independently of one another may be mono- or disubstituted by F, CH3 or CF3 and/or monosubstituted by Cl.
8. Compound according to any one of claims 1 to 7, a tautomer, diastereomer or enantiomer thereof, a mixture thereof or a salt thereof, wherein W denotes -CH2-O-, -CH2-NR8-, -CH2-CH2- or -CH=CH-, wherein in each case one or two C atoms may be substituted independently of one another by F, CH3 or CF3.
9. Compound according to any one of claims 1 to 8, a tautomer, diastereomer or enantiomer thereof, a mixture thereof or a salt thereof, wherein the group A denotes phenyl, pyridinyl or naphthyl, wherein the above-mentioned cyclic groups may be mono- or polysubstituted by R20 at one or more C atoms, and in the case of a phenyl group may also additionally be monosubstituted by nitro, and/or the hydrogen in an NH

group may be replaced by R.
10. Compound according to any one of claims 1 to 9, a tautomer, diastereomer or enantiomer thereof, a mixture thereof or a salt thereof, wherein b has the value 0.
11. Compound according to any one of claims 1 to 9, a tautomer, diastereomer or enantiomer thereof, a mixture thereof or a salt thereof, wherein b has the value 1 and B has a meaning selected from among phenyl, furanyl, thienyl and pyridyl, wherein the above-mentioned cyclic groups may be mono- or polysubstituted by R20 at one or more C atoms, and in the case of a phenyl group may also additionally be monosubstituted by nitro.
12. Compound according to any one of claims 1 to 8, a tautomer, diastereomer or enantiomer thereof, a mixture thereof or a salt thereof, wherein the group A denotes phenyl, pyridinyl or naphthyl, wherein the above-mentioned cyclic groups may be mono- or polysubstituted by R20 at one or more C atoms, and in the case of a phenyl group may also additionally be monosubstituted by nitro, and/or the hydrogen in an NH
group may be replaced by R21;

B has a meaning selected from among phenyl, furanyl, thienyl and pyridyl, wherein the above-mentioned cyclic groups may be mono- or polysubstituted by R20 at one or more C atoms, and in the case of a phenyl group may also additionally be monosubstituted by nitro; and b has the value 0 or 1.
13. Compound according to claim 12, a tautomer, diastereomer or enantiomer thereof, a mixture thereof or a salt thereof, wherein R1, R2 independently of one another denote H, C1-6-alkyl, C3-7-cycloalkyl, C3-7-cycloalkyl-C1-3-alkyl, .omega.-hydroxy-C2-3-alkyl, .omega.-(C1-4-alkoxy)-C2-3-alkyl, C1-4-alkoxy-carbonyl-C1-4-alkyl, carboxyl-C1-4-alkyl, amino-C2-4-alkyl, C1-4-alkyl-amino-C2-4-alkyl, di-(C1-4-alkyl)-amino-C2-4-alkyl, cyclo-C3-6-alkyleneimino-C2-4-alkyl, pyrrolidinyl, N-(C1-4-alkyl)-pyrrolidinyl, pyrrolidinyl-C1-3-alkyl, N-(C1-4-alkyl)-pyrrolidinyl-C1-3-alkyl, piperidinyl, N-(C1-4-alkyl)-piperidinyl, piperidinyl-C1-3-alkyl, N-(C1-4-alkyl)-piperidinyl-C1-3-alkyl, phenyl, phenyl-C1-3-alkyl, pyridyl or pyridyl-C1-3-alkyl, wherein in the above-mentioned groups and residues one or more C atoms may be mono- or polysubstituted by F and/or one or two C atoms may independently of one another be monosubstituted by Cl or Br, and the phenyl or pyridyl group may be mono- or polysubstituted by the group R12 and/or may be monosubstituted by nitro, with the proviso that at least one of the groups R1, R2 has a meaning other than H;

X denotes -CH2-, -CH2-CH2- or -CH2-CH2-CH2-, and if the group Y is linked to X via a C atom, it also denotes -CH2-CH=CH-, -CH2-C.ident.C-, -CH2-CH2-O-, -CH2-CH2-CH2-O-, -CH2-CH2-NR4- or -CH2-CH2-CH2-NR4-, wherein the bridge X may be connected to R1 including the N atom attached to R1 and X, forming a heterocyclic group, and in X a C atom may be substituted by a hydroxy, co-hydroxy-C1-3-alkyl, .omega.-(C1-4-alkoxy)-C1-3-alkyl and/or C1-4-alkoxy group, and/or one or two C
atoms may each be substituted by one or two identical or different substituents selected from among C1-6-alkyl, C3-7-cycloalkyl and C3-7-cycloalkyl-C1-3alkyl, wherein two alkyl substituents may be joined together, forming a carbocyclic ring system, and one or more C atoms may each be mono- or polysubstituted by F
and/or one or two C atoms may each independently of one another be monosubstituted by Cl or Br and with the proviso that the group X denoting C24-alkylenoxy does not have a hydroxy substituent;

W denotes -CH2-O-, -CH2-NR8-, -CH2-CH2- or -CH=CH-, wherein in each case one or two C atoms may be substituted independently of one another by F, CH3 or CF3; and Z is a single bond, -CH2- or -CH2-CH2-, wherein one or two C atoms independently of one another may be mono- or disubstituted by F, CH3 or CF3 and/or monosubstituted by Cl.
14. Compound according to claim 12, a tautomer, diastereomer or enantiomer thereof, a mixture thereof or a salt thereof, wherein R1 and R2 form an alkylene bridge such that R1R2N- denotes a group selected from azetidine, pyrrolidine, piperidine, azepan, 2,5-dihydro-1H-pyrrole, 1,2,3,6-tetrahydro-pyridine, 2,3,4,7-tetrahydro-1H-azepine, 2,3,6,7-tetrahydro-azepine, piperazine, wherein the free imine function is substituted by R13, piperidin-4-one-oxime, piperidin-4-one-O-C14-alkyl-oxime, morpholine and thiomorpholine, wherein one or more H atoms may be replaced by R14, and/or may be substituted in the manner indicated in claim 1 by one or two identical or different carbo- or heterocyclic groups Cy;

X denotes -CH2-, -CH2-CH2- or -CH2-CH2-CH2-, and if the group Y is linked to X via a C atom, it also denotes -CH2-CH=CH-, -CH2-C.ident.C-, -CH2-CH2-O-, -CH2-CH2-CH2-O-, -CH2-CH2-NR4- or -CH2-CH2-CH2-NR4-, wherein the bridge X may be connected to R1 including the N atom attached to R1 and X, forming a heterocyclic group, and in X a C atom may be substituted by a hydroxy, .omega.-hydroxy-C1-3-alkyl, .omega.-(C1-4-alkoxy)-C1-3-alkyl and/or C1-4-alkoxy group, and/or one or two C
atoms may each be substituted by one or two identical or different substituents selected from among C1-6-alkyl, C3-7-cycloalkyl and C3-7-cycloalkyl-C1-3alkyl, wherein two alkyl substituents may be joined together, forming a carbocyclic ring system, and one or more C atoms may each be mono- or polysubstituted by F
and/or one or two C atoms may each independently of one another be monosubstituted by Cl or Br and with the proviso that the group X denoting C2-4-alkylenoxy does not have a hydroxy substituent;

W denotes -CH2-O-, -CH2-NR8-, -CH2-CH2- or -CH=CH-, wherein in each case one or two C atoms may be substituted independently of one another by F, CH3 or CF3; and Z is a single bond, -CH2- or -CH2-CH2-, wherein one or two C atoms independently of one another may be mono- or disubstituted by F, CH3 or CF3 and/or monosubstituted by Cl.
15. Compound according to any one of claims 1 to 14, a tautomer, diastereomer or enantiomer thereof, a mixture thereof or a salt thereof, wherein R20 denotes F, Cl, Br, I, OH, cyano, C1-4-alkyl, C1-4-alkoxy, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, amino, C1-3-alkyl-amino, di-C1-3-alkyl-amino, carboxy or C1-4-alkoxy-carbonyl, wherein each substituent R20 has the same or different meanings.
16. The compound:

(1) N-[3-chloro-4-(2-piperidin-1-yl-ethoxy)-phenyl]-2-(2-chloro-4-trifluoromethyl-phenoxy)-acetamide;

(2) 2-(2-chloro-4-trifluoromethyl-phenoxy)-N-[3-cyano-4-(2-diethylamino-ethoxy)-phenyl]-acetamide;

(3) 2-(2-chloro-4-trifluoromethyl-phenoxy)-N-[1-(2-diethylaminoethyl)-2,3-dihydro-1H-indol-5-yl]-acetamide;

(4) N-[3-chloro-4-(3-diethylamino-prop-1-ynyl)-phenyl]-2-(2-chloro-4-trifluoromethyl-phenoxy)-acetamide;

(5) 2-(2-chloro-4-trifluoromethyl-phenoxy)-N-[1-(2-diethylaminoethyl)-2,3-dimethyl-1H-indol-5-yl]-acetamide;

(6) 2-(2-chloro-4-trifluoromethyl-phenoxy)-N-[1-(2-diethylaminoethyl)-1H-indol-5-yl]-acetamide;

(7) 2-(2-chloro-4-trifluoromethyl-phenoxy)-N-[4-(2-diethylaminoethoxy)-3-methoxy-phenyl]-acetamide;

(8) 2-(3-chloro-biphenyl-4-yloxy)-N-[3-chloro-4-(2-diethylaminoethoxy)-phenyl]-acetamide;

(9) N-[3-chloro-4-(2-diethylamino-ethoxy)-phenyl]-2-(2-chloro-4-trifluoromethyl-phenoxy)-acetamide;

(10) 2-(4-tert.-butyl-2-chloro-phenoxy)-N-[3-chloro-4-(2-diethylamino-ethoxy)-phenyl]-acetamide;

(11) methyl 3-chloro-4-{[3-chloro-4-(2-diethylamino-ethoxy)-phenylcarbamoyl]-methoxy}-benzoate;

(12) N-[3-chloro-4-(2-diethylamino-ethoxy)-phenyl]-2-(2,4-dibromo-phenoxy)-acetamide;

(13) 2-(4-bromo-2-chloro-phenoxy)-N-[3-chloro-4-(2-diethylamino-ethoxy)-phenyl]-acetamide;

(14) N-[3-chloro-4-(2-diethylamino-ethoxy)-phenyl]-2-(4-iodo-2-methyl-phenoxy)-acetamide;

(15) methyl (2-{2-chloro-4-[2-(2,4-dichloro-phenoxy)-acetylamino]-phenoxy}-ethylamino)-acetate;

(16) N-[3-chloro-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-2-(2-chloro-4-trifluoromethyl-phenoxy)-acetamide;

(17) N-{3-chloro-4-[2-(ethyl-propyl-amino)-ethoxy]-phenyl}-2-(2-chloro-4-trifluoromethyl-phenoxy)-acetamide;

(18) N-{3-chloro-4-[2-(ethyl-methyl-amino)-ethoxy]-phenyl}-2-(2-chloro-4-trifluoromethyl-phenoxy)-acetamide;

(19) N-[3-chloro-4-(2-diethylamino-ethoxy)-phenyl]-2-(2-chloro-4-dimethylamino-phenoxy)-acetamide;

(20) (E)-N-[3-chloro-4-(2-diethylamino-ethoxy)-phenyl]-3-(2-chloro-4-trifluoromethyl-phenyl)-acrylamide;

(21) N-[3-chloro-4-(2-diethylamino-ethoxy)-phenyl]-2-(2-chloro-4-trifluoromethyl-phenylamino)-acetamide;

(22) N-[3-chloro-4-(2-diethylamino-ethoxy)-phenyl]-2-(2-chloro-4-furan-2-yl-phenoxy)-acetamide;

(23) N-[3-chloro-4-(2-diethylamino-ethoxy)-phenyl]-2-(2-chloro-4-thiophen-2-yl-phenoxy)-acetamide;

(24) N-[3-chloro-4-(2-diethylamino-ethoxy)-phenyl]-2-(2-chloro-4-pyridin-3-yl-phenoxy)-acetamide;

(25) 2-(2-bromo-4-trifluoromethyl-phenoxy)-N-[3-chloro-4-(2-diethylamino-ethoxy)-phenyl]-acetamide;

(26) N-{3-chloro-4-[2-(2,5-dihydro-pyrrol-1-yl)-ethoxy]-phenyl}-2-(2-chloro-4-trifluoromethyl-phenoxy)-acetamide;

(27) ethyl 1-(2-{2-chloro-4-[2-(2-chloro-4-trifluoromethyl-phenoxy)-acetylamino]-phenoxy}-ethyl)-piperidine-4-carboxylate;

(28) N-[3-chloro-4-(3-diethylamino-propoxy)-phenyl]-2-(2-chloro-4-trifluoromethyl-phenoxy)-acetamide;

(29) N-{4-[2-(2-aminomethyl-pyrrolidin-1-yl)-ethoxy]-3-chloro-phenyl}-2-(2-chloro-4-trifluoromethyl-phenoxy)-acetamide;

(30) N-{3-chloro-4-[2-(2-dimethylaminomethyl-pyrrolidin-1-yl)-ethoxy]-phenyl}-2-(2-chloro-4-trifluoromethyl-phenoxy)-acetamide;
(31) N-[3-bromo-4-(2-diethylamino-ethoxy)-phenyl]-2-(2-chloro-4-trifluoromethyl-phenoxy)-acetamide;

(32) N-{3-chloro-4-[2-(4-methoxy-piperidin-1-yl)-ethoxy]-phenyl}-2-(2-chloro-4-trifluoromethyl-phenoxy)-acetamide;
(33) N-{3-chloro-4-[2-(4-hydroxy-piperidin-1-yl)-ethoxy]-phenyl}-2-(2-chloro-4-trifluoromethyl-phenoxy)-acetamide;
(34) 2-(2-chloro-4-trifluoromethyl-phenoxy)-N-[4-(2-diethylamino-ethoxy)-3-nitro-phenyl]-acetamide;

(35) N-[3-chloro-4-(2-diethylamino-ethoxy)-phenyl]-2-(2-chloro-4-trifluoromethoxy-phenylamino)-acetamide;

(36) N-[3-chloro-4-(2-diethylamino-ethoxy)-phenyl]-2-(2-fluoro-4-trifluoromethyl-phenylamino)-acetamide;

(37) 2-(2-bromo-4-trifluoromethyl-phenylamino)-N-[3-chloro-4-(2-diethylamino-ethoxy)-phenyl]-acetamide;

(38) (E)-3-(4'-chloro-biphenyl-4-yl)-N-(4-piperidin-1-ylmethyl-phenyl)-acrylamide;

(39) N-[3-chloro-4-(2-diethylamino-ethylamino)-phenyl]-2-(2-chloro-4-trifluoromethyl-phenoxy)-acetamide;

(40) N-{3-chloro-4-[2-(4-methyl-piperidin-1-yl)-ethylamino]-phenyl}-2-(2-chloro-4-trifluoromethyl-phenoxy)-acetamide;

(41) (E)-3-(4'-chloro-biphenyl-4-yl)-N-(4-dimethylaminomethyl-phenyl)-acrylamide;

(42) (E)-3-[5-(4-chloro-phenyl)-pyridin-2-yl]-N-(4-piperidin-1-ylmethyl-phenyl)-acrylamide;

(43) (E)-N-{3-chloro-4-[2-(4-methyl-piperidin-1-yl)-ethylamino]-phenyl}-3-(2-chloro-4-trifluoromethyl-phenyl)-acrylamide;

(44) (E)-N-[3-chloro-4-(4-methyl-piperidin-1-ylmethyl)-phenyl]-3-(2-chloro-4-trifluoromethyl-phenyl)-acrylamide;

(45) 2-(2-chloro-4-trifluoromethyl-phenoxy)-N-[4-(2-diethylamino-ethoxy)-3-methyl-phenyl]-acetamide;

(46) (E)-3-(2-chloro-4-trifluoromethyl-phenyl)-N-[4-(2-diethylamino-ethoxy)-3-methyl-phenyl]-acrylamide;

(47) (E)-3-(2-chloro-4-trifluoromethyl-phenyl)-N-[4-(2-diethylamino-ethoxy)-3-methoxy-phenyl]-acrylamide;

(48) (E)-N-[3-chloro-4-(2-diethylamino-ethyl)-phenyl]-3-(2-chloro-4-trifluoromethyl-phenyl)-acrylamide;

(49) N-[3-chloro-4-(2-diethylamino-ethyl)-phenyl]-2-(2-chloro-4-trifluoromethyl-phenoxy)-acetamide; or (50) N-{3-chloro-4-[2-(4-methyl-piperidin-1-yl)-ethyl]-phenyl}-2-(2-chloro-4-trifluoromethyl-phenoxy)-acetamide, or a salt thereof.
17. Physiologically acceptable salt of the compound as defined in claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15, a tautomer, diastereomer or enantiomer thereof, or a mixture thereof, or the compound as defined in claim 16.
18. Composition, comprising at least one compound as defined in claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15, a tautomer, diastereomer or enantiomer thereof, a mixture thereof or a salt thereof, compound or salt as defined in claim 16, and/or salt as defined in claim 17, together with one or more physiologically acceptable excipients.
19. Medicament, comprising at least one compound as defined in claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15, a tautomer, diastereomer or enantiomer thereof, a mixture thereof or a salt thereof, compound or salt as defined in claim 16, and/or salt as defined in claim 17, together with one or more inert carriers and/or diluents.
20. Non-therapeutic use of at least one compound as defined in claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15, a tautomer, diastereomer or enantiomer thereof, a mixture thereof or a salt thereof, compound or salt as defined in claim 16, and/or salt as defined in claim 17, including the compounds excluded by provisos (M2) and (M3) according to claim 1, for influencing the eating behaviour of a mammal by reducing hunger, reining in appetite, controlling eating behaviour and/or producing a feeling of satiation.
21. Non-therapeutic use of at least one compound as defined in claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15, a tautomer, diastereomer or enantiomer thereof, a mixture thereof or a salt thereof, compound or salt as defined in claim 16, and/or salt as defined in claim 17, including the compounds excluded by provisos (M2) and (M3) according to claim 1, for reducing the body weight and/or for preventing an increase in the body weight of a mammal.
22. Use of at least one compound as defined in claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15, a tautomer, diastereomer or enantiomer thereof, a mixture thereof or a salt thereof, compound or salt as defined in claim 16, and/or salt as defined in claim 17, including the compounds excluded by provisos (M2) and (M3) according to claim 1, for preparing a medicament with an MCH receptor-antagonistic activity.
23. Use of at least one compound as defined in claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15, a tautomer, diastereomer or enantiomer thereof, a mixture thereof or a salt thereof, compound or salt as defined in claim 16, and/or salt as defined in claim 17, including the compounds excluded by provisos (M2) and (M3) according to claim 1, for the prevention and/or treatment of symptoms and/or diseases caused by MCH or causally connected with MCH in some other way.
24. Use of at least one compound as defined in claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15, a tautomer, diastereomer or enantiomer thereof, a mixture thereof or a salt thereof, compound or salt as defined in claim 16, and/or salt as defined in claim 17, including the compounds excluded by provisos (M2) and (M3) according to claim 1, for the prevention and/or treatment of a metabolic disorder and/or eating disorder.
25. Use of at least one compound as defined in claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15, a tautomer, diastereomer or enantiomer thereof, a mixture thereof or a salt thereof, compound or salt as defined in claim 16, and/or salt as defined in claim 17, including the compounds excluded by provisos (M2) and (M3) according to claim 1, for the prevention and/or treatment of obesity, bulimia, bulimia nervosa, cachexia, anorexia, anorexia nervosa or hyperphagia.
26. Use of at least one compound as defined in claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15, a tautomer, diastereomer or enantiomer thereof, a mixture thereof or a salt thereof, compound or salt as defined in claim 16, and/or salt as defined in claim 17, including the compounds excluded by provisos (M2) and (M3) according to claim 1, for the prevention and/or treatment of an illness and/or disorder which accompanies obesity.
27. Use of at least one compound as defined in claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15, a tautomer, diastereomer or enantiomer thereof, a mixture thereof or a salt thereof, compound or salt as defined in claim 16, and/or salt as defined in claim 17, including the compounds excluded by provisos (M2) and (M3) according to claim 1, for the prevention and/or treatment of diabetes, complications of diabetes or a cardiovascular disease.
28. Use of at least one compound as defined in claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15, a tautomer, diastereomer or enantiomer thereof, a mixture thereof or a salt thereof, compound or salt as defined in claim 16, and/or salt as defined in claim 17, including the compounds excluded by provisos (M2) and (M3) according to claim 1, for the prevention and/or treatment of type II diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, pathological glucose tolerance, cardiac insufficiency, arteriosclerosis or high blood pressure, arthritis or gonitis.
29. Use of at least one compound as defined in claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15, a tautomer, diastereomer or enantiomer thereof, a mixture thereof or a salt thereof, compound or salt as defined in claim 16, and/or salt as defined in claim 17, including the compounds excluded by provisos (M2) and (M3) according to claim 1, for the prevention and/or treatment of hyperlipidaemia, fat accumulation, an emotional disorder, an affective disorder, depression or anxiety.
30. Medicament, comprising a first active substance, which is at least one compound as defined in claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15, a tautomer, diastereomer, or enantiomer thereof, a mixture thereof or a salt thereof, compound or salt as defined in claim 16, and/or salt as defined in claim 17, including the compounds excluded by provisos (M2) and (M3) according to claim 1; and a second active substance selected from the group consisting of active substances for the treatment of diabetes, active substances for the treatment of diabetic complications, active substances for the treatment of obesity, active substances for the treatment of high blood pressure, active substances for the treatment of hyperlipidaemia, active substances for the treatment of arthritis, active substances for the treatment of anxiety states and active substances for the treatment of depression, optionally together with one or more inert carriers and/or diluents.
31. Medicament according to claim 30, comprising as second active substance a substance for the treatment of obesity which is other than MCH
antagonist.
32. Medicament according to claim 30, comprising as second active substance a substance for the treatment of arteriosclerosis.
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CN1708476A (en) 2005-12-14
AU2003285306A1 (en) 2004-05-25
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