CA2559237A1 - Novel alkyne compounds having an mch-antagonistic effect and medicaments containing said compounds - Google Patents

Abstract

The invention relates to alkyne compounds of general formula (I), in which groups and residues A, B, W, X, Y, Z, R1 and R2 have the meanings cited in Claim 1. The invention also relates to medicaments containing at least one inventive alkyne. The MCH receptor antagonistic effect renders the inventive medicaments suitable for treating metabolic disorders and/or eating disorders, in particular, obesity and diabetes.

Description

WO 2005/103028' ~ PCT/EP2005/003684 86982pct Novel alkyne compounds having an MCH-antagonistic effect and medicaments containing said compounds The present invention relates to new alkyne 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 1o 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. Other aspects of this invention relate to processes for preparing the compounds according to the invention.
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 morbid overweight (also known as corpulence or 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.
3o The term obesity means an excess of adipose tissue in the body. In this connection, obesity is fundamentally to be seen as the increased level of fatness which leads to a health risk. There is no sharp 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 (BM/), 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 1o 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, 2o 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 3o MCH mRNA 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 presumably mediated in rodents through the Gds-coupled MCH-1 R [3-6], as, unlike primates, ferrets and dogs, no second MCH
receptor subtype 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 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.

5. Marsh, D.J., et al., Melanin-concentrating hormone 1 receptor-deficient mice are lean, hyperactive, and hyperphagic and have altered metabolism. Proc Natl Acad Sci U S A, 2002. 99(5): p. 3240-5.

6. Takekawa, S., et al., T-226296: A novel, orally active and selective melanin-concentrating hormone receptor antagonist. Eur J Pharmacol, 2002. 438(3): p.
129-35.

In the patent literature certain amine compounds are proposed as MCH
antagonists.
Thus, WO 01/21577 (Takeda) describes compounds of formula R
Ar1 X-Ar-Y-N

wherein Ar1 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 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 Ar'-X-Ar-Y-N~ R

wherein Ar1 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 R1 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.
WO 2004/024702 proposes carboxylic acid amide compounds of formula I
O
1 ,X~
R-N Y N A-f -W--~B

wherein Y, A and B may represent cyclic groups and X, Z and W may denote bridges or bonds, as MCH-antagonists.
WO 04/039780 A1 describes alkyne compounds of formula I

R' R2~N-X-Y- Z W-A-B I
wherein Y, A and B may denote cyclic groups and X, Z and W may denote bridges or bonds, as MCH-antagonists.
WO 04/039764 A1 describes amide compounds of formula I
R~ O
R2~N X Y Z N3 C W A-~B,b I
R
wherein Y, A and B may denote cyclic groups and X denotes an alkylene bridge, Z
denotes a bridge or bond and W is selected from the group comprising -CR6aRsb-O-, -CR'a=CR'°-, -CR6aRsb-NR$-, -CR7aR'b-CR''R'd- and -NR$-CR6aRsb-, as MCH-1o antagonists.
Aim of the invention The aim of the present invention is to identify new alkyne compounds, particularly those which are especially effective as MCH antagonists. The invention also sets out to provide new alkyne compounds which can be used to influence the eating habits of mammals and achieve a reduction in body weight, particularly in mammals, and/or prevent an increase in body weight.
2o 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 3o follow.

Object of the invention In a first aspect the present invention relates to alkyne compounds of general formula I
R' R2~N- Y- Z W-A-B I
wherein R', R2 independently of one another denote H, C~_8-alkyl, C3_~-cycloalkyl or a phenyl or pyridinyl group optionally mono- or polysubstituted by identical or different groups R2° and/or monosubstituted by vitro, while the alkyl or cycloalkyl group may be mono- or polysubstituted by identical or different groups R", and a -CH2- group in position 3 or 4 of a 5-, 6- or 7-membered cycloalkyl group may be replaced by -O-, -S or -NR'3-, or R' and R2 form a C3_8-alkylene bridge, wherein a -CH2- group not adjacent to the N atom of the R'R2N group may be replaced -CH=N-, -CH=CH-, -O-, -S-, -SO-, -(S02)-, -CO-, -C(=CH2)- or -NR'3-, while in the alkylene bridge defined hereinbefore one or more H atoms may be replaced by identical or different groups R'4, and the alkylene bridge defined hereinbefore 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 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;
W, Z independently of one another denote a single bond or a C~_2-alkylene bridge, while two adjacent C atoms may be joined together with an additional C~_4-alkylene bridge, and one or two C atoms independently of one another may be substituted 1o by one or two identical or different C~_3-alkyl groups, while two alkyl groups may be joined together to form a carbocyclic ring, and Y is selected from the definitions of the partial formulae Y1 to Y9 ,, M~, w ~ ~L
N K
Ni M , '~N K~L
N, K~L
N M ,, K~L
M '' ' ~K~L
N

WO 2005/103029 $ PCT/EP2005/003684 , N M

N K~L
N M~, ~L
N K
N M , O K,L
, N M , K,L
wherein the groups M, K and L represent a CH group, while one of the groups M, K, L may also represent an N atom, and in the partial formulae Y1 to Y9 one or more C atoms may be substituted independently of one another by R2°, and in the partial formulae Y5 and Y6 an NH group may be substituted by C~_ 4-a I kyl , A is selected from among the bivalent cyclic groups phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, naphthyl, tetrahydronaphthyl, indolyl, dihydroindolyl, quinolinyl, dihydroquinolinyl, tetrahydroquinolinyl, isoquinolinyl, dihydroisoquinolinyl, tetrahydro-isoquinolinyl, benzimidazolyl, benzoxazolyl, thienyl, furanyl, benzothienyl or benzofuranyl, while the above-mentioned cyclic groups may be mono-or polysubstituted at one or more C atoms by identical or different groups R2°, or in the case of a phenyl ring may also additionally be monosubstituted by nitro, and/or one or more NH groups may be 2o substituted by R2~, WO 2005/103029 g PCT/EP2005/003684 B has one of the meanings given for A or denotes C~_6-alkyl, C~_6-alkenyl, C~_6-alkynyl, C3_7-cycloalkyl, C5_~-cycloalkenyl, C3_~-cycloalkyl-C~_3-alkyl, C3_~-cycloalkenyl-C~_3-alkyl, C3_~-cycloalkyl-C~_3-alkenyl or C3_~-cycloalkyl-C~_3-alkynyl, wherein one or more C atoms independently of one another may be mono- or polysubstituted by halogen and/ or monosubstituted by hydroxy or cyano and/ or cyclic groups may be mono- or polysubstituted by identical or 1o different groups R2°, 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 2o two or more N atoms or with one or two N atoms and an O or S atom as heteroatoms, - an aromatic heterocyclic 5- or 6-membered group with one or more identical or different heteroatoms selected from N, O and/or S, while the above-mentioned saturated 6- or 7-membered groups may also be present as bridged ring systems with an imino, (C~_4-alkyl)-imino, methylene, (C~_4-alkyl)-methylene or di-(C~_4-alkyl)-methylene bridge, and 3o while the above-mentioned cyclic groups may be mono- or polysubstituted at one or more C atoms by identical or different groups R2°, or in the case of a phenyl group may also additionally be monosubstituted by nitro, and/or one or more NH groups may be WO 2005/103029 ~ Q PCT/EP2005/003684 substituted by R21, R11 denotes halogen, C1_6-alkyl, C2_6-alkenyl, C2_6-alkynyl, R15-O-, R15-O-CO-R'5-CO-O-, cyano, R16R17N, R1sR19N-CO- or Cy, while in the above-mentioned groups one or more C atoms may be substituted independently of one another by substituents selected from halogen, OH, CN, CF3, C1_3-alkyl, hydroxy-C1_3-alkyl;
R13 has one of the meanings given for R17, R14 denotes halogen, cyano, C1_6-alkyl, C2_6-alkenyl, C2_6-alkynyl, R15-O-, R16-O-CO-, R15-CO-, R15-CO-O-, R16R17N, R18R1sN-CO-, R1s-O-C1_3_ alkyl , R15-O-CO-C1_3-alkyl, R15-S02-NH, R15-O-CO-NH-C1_3-alkyl, R15-S02-NH-C1_3-alkyl, R15-CO-C1_3-alkyl, R15-CO-O-C1_3-alkyl, R16R17N-C1_ 3-alkyl, R18R1sN-CO-C1_3-alkyl or Cy-C1_3-alkyl, R15 denotes H, C1_4-alkyl, C3_~-cycloalkyl, C3_7-cycloalkyl-C1_3-alkyl, phenyl, phenyl-C1_3-alkyl, pyridinyl or pyridinyl-C1_3-alkyl, 2o R16 denotes H, C1_6-alkyl, C3_7-cycloalkyl, C3_~-cycloalkyl-C1_3-alkyl, C4_7-cycloalkenyl, C4_~-cycloalkenyl-C1_3-alkyl, w-hydroxy-C2_3-alkyl, ar(C1_ 4-alkoxy)-C2_3-alkyl, amino-Cz_6-alkyl, C1_4-alkyl-amino-C2_6-alkyl, di-(C1_4-alkyl)-amino-CZ_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, C1_4-alkyicarbonyl, hydroxycarbonyl-C1_3-alkyl, C~_4-alkoxycarbonyl, C1_4-alkoxycarbonyl-C~_3-alkyl, C1_4-alkylcarbonylamino-CZ_3-alkyl, N-(C1_4-alkylcarbonyl)-N-(C1_4-alkyl)-amino-C2_3-alkyl, C1_4-alkylsulphonyl, 3o C1_4-alkylsulphonylamino-C2_3-alkyl or N-(C1_4-alkylsulphonyl)-N(-C1_ 4-alkyl )-a m ino-C2_3-a Ikyl;

R'$, R'9 independently of one another denote H or C~_s-alkyl, R2° denotes halogen, hydroxy, cyano, C~_s-alkyl, C2_s-alkenyl, C2_s-alkynyl, C3_~-cycloalkyl, C3_~-cycloalkyl-C~_3-alkyl, hydroxy-C~_3-alkyl, R22-C~-3-alkyl or has one of the meanings given for R2z, R2' denotes C~_4-alkyl, w-hydroxy-C2_s-alkyl, ~-C~_4-alkoxy-Cz_s-alkyl, c~-C~_a-alkyl-amino-C2_s-alkyl, w-di-(C~_4-alkyl)-amino-C2_s-alkyl, c°-cyclo-C3_s-alkyleneimino-C2_s-alkyl, phenyl, phenyl-C~_3-alkyl, C~_4-alkyl-carbonyl, 1o C~_4-alkoxy-carbonyl, C~_4-alkylsulphonyl, aminosulphonyl, C~_4-alkylaminosulphonyl, di-C~_4-alkylaminosulphonyl or cyclo-C3_s-alkylene-imino-sulphonyl, R22 denotes pyridinyl, phenyl, phenyl-C~_3-alkoxy, cyclo-C3_s-alkyleneimino-C2_4-alkoxy, OHC-, HO-N=HC-, C~_4-alkoxy-N=HC-, C~_4-alkoxy, C~_a-alkylthio, carboxy, C~_4-alkylcarbonyl, C~_4-alkoxycarbonyl, aminocarbonyl, C~_4-alkylaminocarbonyl, di-(C~_4-alkyl)-aminocarbonyl, cyclo-C3_s-alkyl-amino-carbonyl, cyclo-C3_s-alkyleneimino-carbonyl, phenylaminocarbonyl, cyclo-C3_s-alkyleneimino-C2_4-alkyl-2o aminocarbonyl, C~_4-alkyl-sulphonyl, C~_4-alkyl-sulphinyl, C~_4-alkyl-sulphonylamino, amino, C~_4-alkylamino, di-(C~_4-alkyl)-amino, C~_4-alkyl-carbonyl-amino, cyclo-C3_s-alkyleneimino, phenyl-C~_3-alkylamino, N-(C~_ 4-alkyl)-phenyl-C~_3-alkylamino, acetylamino, propionylamino, phenylcarbonyl, phenylcarbonylamino, phenylcarbonylmethylamino, hydroxy-C2_3-alkylaminocarbonyl, (4-morpholinyl)carbonyl, (1-pyr-rolidinyl)carbonyl, (1-piperidinyl)carbonyl, (hexahydro-1-azepinyl)carbonyl, (4-methyl-1-piperazinyl)carbonyl, methylenedioxy, aminocarbonylamino or C~_4-alkylaminocarbonylamino, 3o while in the above-mentioned groups and radicals, particularly in W, Z, R'3 to R22, 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 independently of one another may additionally be monosubstituted by CI or Br and/or in each WO 2005/103029 ~ 2 PCT/EP2005/003684 case one or more phenyl rings may additionally comprise independently of one another one, two or three substituents selected from the group F, CI, Br, I, cyano, C~_4-alkyl, C~_4-alkoxy, difluoromethyl, trifluoromethyl, hydroxy, amino, C~_3-Aalkylamino, di-(C~_3-alkyl)-amino, acetylamino, aminocarbonyl, difluoromethoxy, trifluoromethoxy, amino-C~_3-alkyl, C~_3-alkylamino-Ci_3-alkyl-and di-(C~_3-alkyl)-amino-C~_3-alkyl and/or may be monosubstituted by vitro, and the H atom of any carboxy group present or an H atom bound to an N atom 1o may in each case be replaced by a group which can be cleaved in vivo, the tautomers, the diastereomers, the enantiomers, the mixtures thereof and the salts thereof.
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 corresponding acid addition salts with pharmacologically acceptable acids. The subject of the invention also includes the compounds according to the invention, including their salts, wherein one or more 2o hydrogen atoms are replaced by deuterium.
This invention also includes the physiologically acceptable salts of the alkyne compounds according to the invention as described above and hereinafter.
Also covered by this invention are compositions containing at least one alkyne 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 alkyne compound according to the invention and/ or a salt according to the invention optionally together with one or more inert carriers and/or diluents.

This invention also relates to the use of at least one alkyne compound according to the invention and/or a salt according to the invention for influencing the eating behaviour of a mammal.
The invention further relates to the use of at least one alkyne compound according to the invention and/or a salt according to the invention 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 alkyne compound according to 1o the invention and/or a salt according to the invention for preparing a pharmaceutical composition with an MCH receptor-antagonistic activity, particularly with an receptor-antagonistic activity.
This invention also relates to the use of at least one alkyne compound according to 15 the invention and/or a salt according to the invention 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 alkyne compound according 2o to the invention and/or a salt according to the invention 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.
25 The invention also relates to the use of at least one alkyne compound according to the invention and/or a salt according to the invention for 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 3o 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 alkyne compound according to the invention and/or a salt according to the invention for preparing a pharmaceutical composition which is suitable for the prevention and/or treatment of hyperlipidaemia, 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 alkyne compound according to 1o the invention and/or a salt according to the invention 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 the use of at least one alkyne compound according to the invention and/ or a salt according to the invention for preparing a pharmaceutical composition which is suitable for the prevention and/or treatment of dependencies and/or withdrawal symptoms.
2o The invention further relates to processes for preparing for preparing a pharmaceutical composition according to the invention, characterised in that at least one alkyne 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.
The invention also relates to a pharmaceutical composition containing a first active substance which is selected from the alkyne compounds according to the invention and/or the corresponding salts as well as a second active substance which is selected from the group consisting of active substances for the treatment of diabetes, active 3o 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 dyslipidaemia or hyperlipidaemia, including arteriosclerosis, active substances for the WO 2005!103029 15 PCT/EP2005/003684 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.
Moreover, in one aspect, the invention relates to a process for preparing alkyne compounds of formula A.5 R'R2N-Y-C=C-W-A-B (A.5) 1o while in formulae A.1, A.2, A.3, A.4 and A.5 R~, R2, Y, W, A and B have one of the meanings given hereinbefore and hereinafter, wherein a halogen compound of formula A.1 HO-Y-Hal (A.1 ) wherein Hal denotes chlorine, bromine or iodine, preferably bromine or iodine, is reacted with an alkyne compound of formula A.2 2o H-C=C-W-A-B (A.2) in the presence of a suitable palladium catalyst, a suitable base and copper(I)iodide in a suitable solvent, and the compound of formula A.3 obtained HO-Y-C=C-W-A-B (A.3) is reacted with a suitable halogenating agent to form the halide derivative A.4 in which 3o Hal' denotes CI, Br or I, Hal'-Y-C=C-W-A-B (A.4) which is further reacted with an amine of formula H-NR'R2 to form the end product A.S.
This invention further relates to a process for preparing alkyne compounds of formula B.5 R'R2N-Y-Z-C=C-A-B (B.5) 1o while in formulae B.1, B.2, B.3, B.4 and B.5 R', R2, Y, Z, A and B have one of the meanings given hereinbefore and hereinafter, wherein a halogen compound of formula B.1 Hal-A-B (B.1 ) wherein Hal denotes chlorine, bromine or iodine, preferably bromine or iodine, is reacted with an alkyne compound of formula B.2 2o HO-Y-Z-C=C-H (B.2) in the presence of a suitable palladium catalyst, a suitable base and copper(I)iodide in a suitable solvent, and the resulting compound of formula B.3 HO-Y-Z-C=C-A-B (B.3) is reacted with a suitable halogenating agent to form the halide derivative B.4 in which 3o Hal' denotes CI, Br or I, Hal'-Y-Z-C=C-A-B (B.4) which is reacted further with an amine of formula H-NR~R2 to form the end product B.S.
In addition, the invention relates to a process for preparing alkyne compounds of formula C.3 R~R2N-Y-C=C-W-A-B (C.3) while in formulae C.1, C.2 and C.3 R', R2, Y, W, A and B have one of the meanings 1o given hereinbefore and hereinafter, wherein a halogen compound of formula C.1 R' R2N-Y-Hal (C.1 ) wherein Hal denotes chlorine, bromine or iodine, preferably bromine or iodine, is further reacted with an alkyne compound of formula C.2 H-C=C-W-A-B (C.2) in the presence of a suitable palladium catalyst, a suitable base and copper(I)iodide in a suitable solvent to yield the end product C.3.
In another aspect the invention relates to a process for preparing alkyne compounds of formula D.3 R~R2N-Y-Z-C=C-A-B (D.3) while in formulae D.1, D.2 and D.3 R~, R2, Y, Z, A and B have one of the meanings 3o given hereinbefore and hereinafter, wherein a halogen compound of formula D.2 WO 2005/103029 1$ PCT/EP2005/003684 Hal-A-B (D.2) wherein Hal denotes chlorine, bromine or iodine, preferably bromine or iodine, is reacted with an alkyne compound of formula D.1 R'R2N-Y-Z-C=C-H (D.1 ) in the presence of a suitable palladium catalyst, a suitable base and copper(I)iodide in a suitable solvent to form the end product D.3.
The starting materials and intermediate products used in the synthesis according to the invention are also a subject of this invention.
Detailed description of the invention Unless otherwise specified, the groups, residues and substituents, particularly A, B, W, Y, Z, Cy, R', R2, R", R'3 to R22, M, K and L, have the meanings given hereinbefore.
2o If groups, residues and/or substituents occur more than once in a compound, they may have the same or different meanings in each case.
If R' and R2 are not joined together via an alkylene bridge, R' and R2 independently of one another preferably denote a C~_8-alkyl or C3_~-cycloalkyl group mono-or polysubstituted by identical or different groups R", while a -CH2- group in position 3 or 4 of a 5-, 6- or 7-membered cycloalkyl group may be replaced by -O-, -S- or -NR'3-, or a phenyl or pyridinyl group optionally mono- or polysubstituted by identical or different groups R2° and/or monosubstituted by nitro, while one or both of the groups R' and R2 may also represent H.
Preferred meanings of the group R" are F, CI, Br, C~_6-alkyl, C2_6-alkenyl, C2_6-alkynyl, R'S-O-, cyano, R'6R'~N, C3_~-cycloalkyl, cyclo-C3_6-alkyleneimino, pyrrolidinyl, N-(C~_4-alkyl)-pyrrolidinyl, piperidinyl, N-(Ci_4-alkyl)-piperidinyl, phenyl and pyridyl, while in the WO 2005/103029 ~ g PCT/EP2005/003684 above-mentioned groups and radicals one or more C atoms may be mono- or polysubstituted independently of one another by F, C~_3-alkyl or hydroxy-C~_3-alkyl, and/or one or two C atoms may be monossubstituted independently of one another by CI, Br, OH, CF3 or CN, and the above-mentioned cyclic groups may be mono- or polysubstituted at one or more C atoms by identical or different radicals R2°, or 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 R2'. If R" has one of the meanings R'S-O-, cyano, R'6R"N or cyclo-C3_6-alkyleneimino, the C atom of the alkyl or cycloalkyl group substituted by R" is preferably not directly connected to a heteroatom, such 1o as for example the group -N-X-.
Preferably the groups R', R2 independently of one another represent H, C~_6-alkyl, C3_5-alkenyl, C3_5-alkynyl, C3_~-cycloalkyl, hydroxy-C3_~-cycloalkyl, C3_~-cycloalkyl-C~_3-alkyl, (hydroxy-C3_~-cycloalkyl)-C~_3-alkyl, hydroxy-C2_4-alkyl, c°-NC-C2_3-alkyl, C~_4-alkoxy-C2_4-alkyl, hydroxy-C~_4-alkoxy-C2~-alkyl, C~_4-alkoxy-carbonyl-C~_4-alkyl, carboxyl-C~_4-alkyl, amino-C2_4-alkyl, C~_4-alkyl-amino-C2_4-alkyl, di-(C~_4-alkyl)-amino-C2_4-alkyl, cyclo-C3_6-alkyleneimino-C2_4-alkyl, pyrrolidin-3-yl, N-(C~_4-alkyl)-pyrrolidin-3-yl, pyrrolidinyl-C~_3-alkyl, N-(C~_4-alkyl)-pyrrolidinyl-C~_3-alkyl, piperidin-3-yl, piperidin-4-yl, N-(C~_4-alkyl)-piperidin-3-yl, N-(C~_4-alkyl)-piperidin-4-yl, piperidinyl-C~_3-alkyl, 2o N-(C~_4-alkyl)-piperidinyl-C~_3-alkyl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, tetrahydrofuran-2-ylmethyl, tetrahydrofuran-3-ylmethyl, phenyl, phenyl-C~_3-alkyl, pyridyl or pyridyl-C~_3-alkyl, while in the above-mentioned groups and radicals one or more C atoms independently of one another may be mono- or polysubstituted by F, C~_3-alkyl or hydroxy-C~_3-alkyl, and/or one or two C atoms independently of one another may be monosubstituted by CI, Br, OH, CF3 or CN, and the above-mentioned cyclic groups may be mono- or polysubstituted at one or more C atoms by identical or different radicals R2°, in the case of a phenyl group may also additionally be monosubstituted by vitro, and/or one or more NH groups may be substituted by R2'.
Preferred substituents of the above-mentioned phenyl or pyridyl groups are selected 3o from the group F, CI, Br, I, cyano, C~_4-alkyl, C~_4-alkoxy, difluoromethyl, trifluoromethyl, hydroxy, amino, C~_3-alkylamino, di-(C~_3-alkyl)-amino, acetylamino, aminocarbonyl, difluoromethoxy, trifluoromethoxy, amino-Ci_3-alkyl, Ci_3-alkylamino-C~_3-alkyl and di-(C~_3-alkyl)-amino-C~_3-alkyl, while a phenyl group may also be monosubstituted by nitro.
Particularly preferred definitions of the groups R~ and/or R2 are selected from the group consisting of H, C~~-alkyl, hydroxy-C~_4-alkyl, C3_5-alkenyl, C3_5-alkynyl, C3_~-cycloalkyl, hydroxy-C3_~-cycloalkyl, dihydroxy-C3_6-alkyl, C3_~-cycloalkyl-C~_3-alkyl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, tetrahydrofuran-2-ylmethyl, tetrahydrofuran-3-ylmethyl, (hydroxy-C3_~-cycloalkyl)-C~_3-alkyl, c~-(C~_4-alkoxy)-CZ_3-alkyl, di-(Ci_3-alkyl)amino-C2_3-alkyl, pyrrolidin-N-yl-C2_3-alkyl, piperidin-N-yl-1o C2_3-alkyl, pyridyl and benzyl, while an alkyl, cycloalkyl or cycloalkyl-alkyl group may additionally be mono- or disubstituted by hydroxy and/or hydroxy-C~_3-alkyl, and/or mono- or polysubstituted by F or C~_3-alkyl and/or monosubstituted by CF3, Br, CI or CN.
Most particularly preferred groups R' and/or R2 are selected from the group consisting of H, methyl, ethyl, n-propyl, i-propyl, prop-2-enyl, but-2-enyl, prop-2-ynyl, but-2-ynyl, 2-methoxyethyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopentylmethyl, hydroxy-C3_7-cycloalkyl, (hydroxy-Ci_3-alkyl)-hydroxy-C3_~-cycloalkyl, dihydroxy-C3_5-alkyl, 2-hydroxy-1-(hydroxymethyl)-ethyl, 1,1-di(hydroxymethyl)-ethyl, (1-hydroxy-C3_6-cycloalkyl)-methyl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, tetrahydrofuran-2-ylmethyl, tetrahydrofuran-3-ylmethyl, hydroxyethyl, 3-hydroxypropyl, di-(C~_3-alkyl)aminoethyl, pyrrolidin-N-yl-ethyl, piperidin-N-ylethyl, benzyl and pyridyl, while the above-mentioned groups may be mono- or polysubstituted by F and/or C~_3-alkyl, and the phenyl and pyridyl rings may be substituted as specified.
Examples of most particularly preferred groups R~ and/or R2 are therefore H, methyl, ethyl, n-propyl, i-propyl, prop-2-enyl, prop-2-ynyl, 2-methoxyethyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopentylmethyl, hydroxy-cyclopentyl, 3o hydroxy-cyclohexyl, (hydroxymethyl)-hydroxy-cyclopentyl, (hydroxymethyl)-hydroxy-cyclohexyl, 2,3-dihydroxypropyl, (1-hydroxy-cyclopropyl)-methyl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, tetrahydrofuran-2-ylmethyl, tetrahydrofuran-3-ylmethyl, hydroxyethyl, 3-hydroxypropyl, dimethylaminoethyl, benzyl and pyridyl.

Particularly preferably, at least one of the groups R', R2 has a meaning other than H.
If R' and R2 form an alkylene bridge, this is preferably a C3_~-alkylene bridge or a C3_~-alkylene bridge, wherein a -CH2- group not adjacent to the N atom of the R'R2N
group is replaced by -CH=N-, -CH=CH-, -O-, -S-, -CO- or -NR'3-, while in the alkylene bridge defined hereinbefore one or more H atoms may be replaced by identical or different groups R'4, and the alkylene bridge defined hereinbefore may be substituted with 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.
2o Preferably also, R' and R2 form an alkylene bridge such that R'R2N- denotes a group which is selected from azetidine, pyrrolidine, piperidine, azepan, 2,5-dihydro-pyrrole, 1,2,3,6-tetrahydro-pyridine, 2,3,4,7-tetrahydro-1 H-azepine, 2,3,6,7-tetrahydro-1 H-azepine, piperazine in which the free imine function is substituted by R'3, piperidin-4-one, morpholine and thiomorpholine, is particularly preferably selected from pyrrolidine, piperidine, piperazine in which the free imine function is substituted by R'3, and morpholine, while according to the general definition of R' and R2 one or more H atoms may be 3o replaced by identical or different groups R'4, 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 R' and R2, while the group Cy may be mono- or polysubstituted by R2°.

Particularly preferred groups Cy are C3_~-cycloalkyl, aza-C4_~-cycloalkyl, particularly cyclo-C3_s-alkyleneimino, as well as 1-C~_4-alkyl-aza-C4_~-cycloalkyl, while the group Cy may be mono- or polysubstituted by R2o.
The C3_8-alkylene bridge formed by R' and R2, wherein -CH2- groups may be replaced as specified, may be substituted, as described, by one or two identical or different carbo- or heterocyclic groups Cy, which may be substituted as specified hereinbefore.
1o In the event that the alkylene bridge is linked to a group Cy through a single bond, Cy is preferably selected from the group consisting of C3_~-cycloalkyl, cyclo-C3_s-alkyleneimino, 1 H-imidazol, thienyl and phenyl.
In the event that the alkylene bridge is linked to a group Cy via a common C
atom forming a spirocyclic ring system, Cy is preferably selected from the group consisting of C3_~-cycloalkyl, aza-C4_$-cycloalkyl, oxa-C4_$-cycloalkyl, 2,3-dihydro-1 H-quinazolin-4-one.
In the event that the alkylene bridge is linked to a group Cy via two common adjacent 2o C and/or N atoms forming a fused bicyclic ring system, Cy is preferably selected from the group consisting of C4_~-cycloalkyl, phenyl, thienyl.
In the event that 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.
In the event that the heterocyclic group R'R2N- is substituted by a group Cy, the group Cy is preferably linked to the group R'R2N- through a single bond, while Cy is preferably selected from the group consisting of C3_~-cycloalkyl and cyclo-C3_s-3o alkyleneimino, while these groups may be substituted as specified, preferably by fluorine, C~_3-alkyl, hydroxy-C~_3-alkyl and hydroxy.

/', Particularly preferably the group R

is defined according to one of the following partial formulae N . N . N
, . , N-r N
N , ~ I . , . , R' 3 N N
I N~ ~ N-~ , N
~ , N ~ , N , , N
N-~ -N .
Rz~
S N~- \N
U , N ' Rz, N N . N
-.
, R2~~N , ~ .
N N-; N N
' , Rz~ N
N
.
N . N
-, -.
N ' N ' -\
N . N
N N ~~
Rz~
\N
v , -T
N ' ' Rz~
N Rz ~ N \v%~N -~-v -T
N ' R2' \ N N vN-T
' Rz~ i N
N ~ Rz'- N N
v . ~ I v ' \ N ' ' / ~ N
S~ ' WO 2005/103029 25 PCTlEP2005/003684 N ' \N-'. N-~;
N ~, wherein one or more H atoms of the heterocycle formed by the group R'R2N- may be replaced by identical or different groups R'4, and the heterocycle formed by the group R'R2N- may be substituted by one or two, preferably one C3_~-cycloalkyl group, while the cycloalkyl group may be mono-or polysubstituted by R2°, and the ring attached to the heterocycle formed by the group R'R2N- may be mono-or 1o polysubstituted at one or more C atoms by R2°, or in the case of a phenyl ring may also additionally be monosubstituted by nitro and wherein R'3, R'4, R2°, R2' have the meanings given hereinbefore and hereinafter.
~5 If the heterocycle formed by the group R'R2N- is substituted as specified by one or two cycloalkyl groups mono- or polysubstituted by R2°, the substituents R2o independently of one another preferably denote C~_4-alkyl, C~_4-alkoxy-C~_3-alkyl, hydroxy-C~_3-alkyl, hydroxy, fluorine, chlorine, bromine or CF3, particularly hydroxy.
%', Most particularly preferably the group R

is defined according to one of the following partial formulae N~ ~NT N
. ~ .
\ , I N-~.
N-~ ' , O N-J R's N N i U , , U
.N , N
/ \ ' ~
, particularly , ~
,N-r-N
where R'3 has the meanings given above and hereinafter, and the heterocycle formed by the group R'R2N- may be substituted by C3_6-cycloalkyl, hydroxy-C3_6-cycloalkyl or (hydroxy-C3_6-cycloalkyl)-C~_3-alkyl, and the heterocycle formed by the group R'R2N- may be mono-, di- or trisubstituted by identical or different groups R'4. The substituents R'4 preferably denote independently of one another F, CI, Br, OH, C~_4-alkyl, C~_4-alkoxy, C~_4-alkoxy-C~_3-alkyl, hydroxy-C~_ 4-alkyl or CF3, particularly hydroxy, C~_3-alkyl, CF3 or hydroxy-C~_3-alkyl.
If the partial formulae shown above are substituted as specified, the following definitions of the group R'R2N are particularly preferred:
hydroxypyrrolidinyl, hydroxypiperidinyl, 3,4-dihydroxypyrrolidinyl, 3,4-dihydroxypiperidinyl, 3,5-dihydroxypiperidinyl, (hydroxymethyl)-pyrrolidinyl, (hydroxymethyl)-piperidinyl, (hydroxymethyl)-hydroxy-pyrrolidinyl, (hydroxymethyl)-hydroxy-piperidinyl, while in the groups mentioned a hydroxymethyl group may be mono- or disubstituted at the C atom by methyl, while two methyl substituents may be joined together, forming a cyclopropyl group, and in one or two hydroxy groups the H atom may be replaced by a methyl group, and the groups mentioned have no further substituents or have one or two substituents selected independently of one another from fluorine, hydroxy, C~_3-alkyl, hydroxy-C~_3-alkyl, CF3.
The following partial formulae are most particularly preferred definitions of the R' N~' heterocyclic group R specified above:
N ~ ~~~~N
~N ~ , v v ~ v HO NT HO N ; HO N-r > > ~
HO--~/~
v O N-=-' , HO , HO HO HO
N-' HO \N~ ' N~ ' HO ' HO
HO HO HO
HO N ' HO N~ ' HO N~ ' FsC ~/

WO 2005/103029 2$ PCT/EP2005/003684 HO
\ , \ , N--1 N-' , , , HO N-~
HO -O
HO HO HO
, N-1 N . N
, HO ~ HO HO
HO
v , N ' HO
v . v , v N-T N-T- N
, , . , , HO HO HO
N-~ N . N
, r r HO HO ' Ho '~
wherein the groups mentioned are not further substituted, or wherein methyl or ethyl groups may be mono-, di- or trisubstituted by fluorine, and wherein one or more H atoms of the heterocycle formed by the group R~R2N-which are bound to carbon may be substituted independently of one another by fluorine, chlorine, CN, CF3, C~_3-alkyl, hydroxy-C~_3-alkyl, particularly C~_3-alkyl or CF3, preferably methyl, ethyl, CF3.
Among the above-mentioned preferred and particularly preferred meanings of R'R2N, 1o the following definitions of the substituent R'4 are preferred: F, CI, Br, cyano, C~_4-alkyl, C2_4-alkenyl, C2_4-alkynyl, C3_~-cycloalkyl, C3_~-cycloalkyl-C1_3-alkyl, hydroxy, hydroxy-C~_3-alkyl, C~_4-alkoxy, c~-(C~_4-alkoxy)-C~_3-alkyl, C~_4-alkyl-carbonyl, carboxy, C~_4-alkoxycarbonyl, hydroxy-carbonyl-C~_3-alkyl, C'_4-alkoxycarbonyl-C~_3-alkyl, C~_ 4-alkoxy-carbonylamino, C~_4-alkoxy-carbonylamino-C~_3-alkyl, amino, C~_4-alkyl-amino, C3_~-cycloalkyl-amino, N-(C3_~-cycloalkyl)-N-(C~_4-alkyl)-amino, di-(C~_4-alkyl)-amino, cyclo-C3_6-alkyleneimino, amino-C~_3-alkyl, C~_4-alkyl-amino-C,_3-alkyl, C3_~-cycioaikyl-amino-C,_3-alkyl, N-(C3_~-cycloalkyl)-N-(C~_4-alkyl)-amino-CI_3-alkyl, di-(C~_a-alkyl)-amino-C~_3-alkyl, cyclo-C3_6-alkyleneimino-C~_3-alkyl, aminocarbonyl, C1_4-alkyl-amino-carbonyl, C3_~-cycloalkyl-amino-carbonyl, N-(C3_~-cycloalkyl)-N-(C~_4-alkyl)-1o amino-carbonyl, di-(C,_4-alkyl)-amino-carbonyl, pyridinyl-oxy, pyridinyl-amino, pyridinyi-C~_3-alkyl-amino.
Particularly preferred meanings of the substituent R'4 are F, CI, Br, C~_4-alkyl, hydroxy, hydroxy-C~_3-alkyl, C~_4-alkoxy, ur(C~_4-alkoxy)-C~_3-alkyl, amino-C~_3-alkyl, C~_4-alkyl-amino-C~_3-alkyl, C3_~-cycloalkyl-amino-C~_3-alkyl, N-(C3_7-cycloalkyl)-N-(C~_a-alkyl)-amino-C~_3-alkyl, di-(C~_4-alkyl)-amino-C~_3-alkyl, cyclo-C3_6-alkyleneimino-C~_3-alkyl, aminocarbonyl and pyridylamino.
In the above-mentioned preferred meanings of R~4 in each case one or more C
atoms 2o may additionally be mono- or polysubstituted by F and/or in each case one or two C
atoms may independently of one another additionally be monosubstituted by CI
or Br.
Thus, preferred meanings of R'4 also include, for example, -CF3, -OCF3, CF3-CO-and CF3-CHOH-.
Most particularly preferred meanings of the substituent R'4 are C~_3-alkyl, hydroxy-C~_ 3-alkyl, methoxymethyl, hydroxy, CF3, CF3-CHOH-, particularly hydroxy, methyl, ethyl, CF3 and hydroxymethyl.
The bridge W preferably denotes a single bond or ethylene, particularly preferably a 3o single bond.

WO 2005/103029 3p PCT/EP2005/003684 The bridge Z preferably denotes a single bond or ethylene which may have one or two methyl substituents which may be joined together, forming a cyclopropyl group.
Particularly preferably Z denotes a single bond.
In the group Y the groups K, L and M preferably denote CH, while one or more CH
groups may be substituted independently of one another by R2°
According to another embodiment one of the groups K, L and M preferably denotes an N atom, while the other two groups selected from K, L and M denote a CH
group 1o which may be substituted independently of one another by R2°
Preferred definitions of the group Y are selected from the partial formulae M , N K' Ni M ,,, '~N K~L
N M ,, / I ~ Y6 ~L
N K
wherein the groups M, K and L represent a CH group, while one of the groups M, K, L
may also represent an N atom, and in the partial formulae Y1, Y2, Y6 one or more CH groups may be substituted independently of one another by R2°, and 2o in partial formula Y6 an NH group may be substituted by C~_4-alkyl.
Most particularly preferably the group Y denotes quinoline according to partial formula Y1, while K, L and M denote a CH group, the quinoline group is preferably WO 20051103029 3~ PCTIEP2005/003684 unsubstituted or one or more CH groups of the quinoline group are substituted independently of one another by R2°.
The group Y is preferably unsubstituted or mono- or disubstituted.
A most particularly preferred definition of the group Y is quinoline, which may be substituted, particularly in the 4 position. Therefore Y preferably denotes R2o ~ ~ ~ and w N ~~, N
where R2° is defined as below, and particularly denotes C~_3-alkyl, and most 1 o particularly methyl.
Particularly preferred substituents R2° of the group Y are selected from among fluorine, chlorine, bromine, cyano, vitro, C~_4-alkyl, C2_6-alkenyl, hydroxy, w-hydroxy-C~_3-alkyl, C~_4-alkoxy, trifluoromethyl, trifluoromethoxy, C2_4-alkynyl, C~_ 4-alkoxycarbonyl, c~-(C~_4-alkoxy)-C~_3-alkyl, C~_4-alkoxy-carbonylamino, amino, C~_a-alkyl-amino, di-(C~_4-alkyl)-amino, aminocarbonyl, C~_4-alkyl-amino-carbonyl and di-(C~_4-alkyl)-amino-carbonyl.
Most particularly preferred substituents R2° of the group Y are selected from among 2o fluorine, chlorine, bromine, cyano, C~_3-alkyl, C2_3-alkenyl, C2_3-alkynyl, C~_3-alkoxy, C~_ 4-alkoxycarbonyl, trifluoromethyl, trifluoromethoxy, or in the case of a phenyl ring vitro as well. Examples of most particularly preferred meanings of the substituent R2° are F, CI, Br, methyl, ethyl, acetyl or methoxy.
Preferably the group A is selected from among the bivalent cyclic groups phenyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, which may be mono- or polysubstituted at one or more C atoms by identical or different groups R2°, or in the case of a phenyl ring may also additionally be monosubstituted by vitro.

Most particularly preferably A is one of the following groups , -N N-\ ~ , N
-N N-, / , N N
\ / .
N-N
/ ~ , . , particularly ; . or ~ \ / ;
N-N
most particularly preferably while the groups listed may be substituted as specified hereinbefore.
Particularly preferred substituents RZ° of the group A are, independently of one another, fluorine, chlorine, bromine, amino, CF3, methoxy and C~_3-alkyl.
1o Preferably the group A is unsubstituted or monosubstituted by R2°, as specified.
Preferred definitions of the group B according to a first preferred embodiment are selected from the group comprising phenyl, pyridyl, thienyl and furanyl.
Particularly preferably the group B denotes phenyl. The group B with the meanings given may be mono- or polysubstituted by identical or different groups R2°, while a phenyl group may additionally also be monosubstituted by nitro. Preferably the group B is WO 2005/103029 33 PCTlEP20051003684 unsubstituted or mono-, di- or trisubstituted, particularly unsubstituted or mono- or disubstituted. In the case of a monosubstitution the substituent is preferably in the para position to the group A.
Preferred substituents R2° of the group B are selected from the group comprising fluorine, chlorine, bromine, cyano, nitro, C,_4-alkyl, hydroxy, CHF2, CHF2-O-, hydroxy-C~_3-alkyl, C~_4-alkoxy, trifluoromethyl, trifluoromethoxy, C2_4-alkynyl, carboxy, C~_4-alkoxycarbonyl, w-(C~_4-alkoxy)-C~_3-alkyl, C,_4-alkoxy-carbonylamino, amino, C~_ 4-alkyl-amino, di-(C~_4-alkyl)-amino, cyclo-C3_s-alkyleneimino, aminocarbonyl, C,_4-1o alkyl-amino-carbonyl and di-(C,_4-alkyl)-amino-carbonyl.
Particularly preferred substituents R2° of the group B are selected from the group comprising fluorine, chlorine, bromine, cyano, CF3, C~_3-alkyl, C~_4-alkoxy and trifluoromethoxy.
Most particularly preferred substituents R2° of the group B are selected from the group comprising chlorine, bromine and methoxy.
According to a second embodiment the meaning of the group B is preferably selected 2o from C,_s-alkyl, C2_s-alkenyl, C2_s-alkynyl, Cs_7-cycloalkyl, C5_~-cycloalkenyl, C3_~-cycloalkyl-C~_3-alkyl, C3_~-cycloalkenyl-C~_3-alkyl, C3_~-cycloalkyl-C~_3-alkenyl, Cs_~-cycloalkyl-C~_3-alkynyl, while one or more C atoms in the groups mentioned for B
hereinbefore may be mono- or polysubstituted by fluorine. In the cyclic groups according to the above-mentioned embodiment one or more C atoms may be substituted by R2°.
Particularly preferred according to this embodiment are the groups C3_s-alkyl, C3_s-alkenyl, C3_s-alkynyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclopentyl-C~_3-alkyl, cyclopentenyl-C~_3-alkyl, cyclohexyl-3o C~_3-alkyl, cyclohexenyl-C~_3-alkyl, cycloheptyl-C~_3-alkyl, cycloheptenyl-C~.3-alkyl, while one or more C atoms in the groups mentioned for B hereinbefore may be mono-or polysubstituted by fluorine, and in cyclic groups one or more C atoms may be substituted by identical or different R2°.

Most particularly preferably, according to this second embodiment B denotes cyclohexenyl which is unsubstituted or comprises 1, 2 or 3 identical or different substituents R2°, particularly methyl.
The following are preferred definitions of other substituents according to the invention:
Preferably the substituent R'3 has one of the meanings given for R'6.
Particularly preferably R'3 denotes H, C~_4-alkyl, C3_~-cycloalkyl, C3_~-cycloalkyl-C~_3-alkyl, 1o c°-hydroxy-C2_3-alkyl, w-(C~_4-alkoxy)-CZ_3-alkyl. Most particularly preferably R'3 denotes H or C~_4-alkyl. The alkyl groups mentioned hereinbefore may be monosubstituted by CI or mono- or polysubstituted by F.
Preferred meanings of the substituent R'S are H, C~_4-alkyl, C3_~-cycloalkyl, C3_~-cycloalkyl-C~_3-alkyl, while, as defined hereinbefore, 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 independently of one another may additionally be monosubstituted by CI
or Br. Particularly preferably R'S denotes H, CF3, methyl, ethyl, propy! or butyl.
2o The substituent R'6 preferably denotes H, C~_4-alkyl, C3_~-cycloalkyl, C3_~-cycloalkyl-C~_3-alkyl, c°-hydroxy-C2_3-alkyl or w-(C~_4-alkoxy)-Cz_3-alkyl, while, as hereinbefore defined, 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 independently of one another may additionally be monosubstituted by CI or Br. Particularly preferably R'6 denotes H, CF3, C~_3-alkyl, C3_6-cycloalkyl or C3_6-cycloalkyl-C~_3-alkyl.
Preferably the substituent R" has one of the meanings given for R'6 as being preferred or denotes phenyl, phenyl-C~_3-alkyl, pyridinyl or C,_4-alkylcarbonyl.
Particularly preferably R" has one of the meanings given for R'6 as being preferred.
Preferably one or both of the substituents R'$ and R'9 independently of one another denotes hydrogen or C~_4-alkyl, particularly hydrogen.

The substituent R2° preferably denotes halogen, hydroxy, cyano, C,_4-alkyl, CZ_4-alkenyl, CZ_4-alkynyl, C3_~-cycloalkyl, C3_~-cycloalkyl- C,_3-alkyl, hydroxy-C,_4-alkyl, R22-C~_3-alkyl or has one of the meanings given for R22 as being preferred, while, as hereinbefore defined, 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 independently of one another may additionally be monosubstituted by CI or Br.
Particularly preferred definitions of the group R2° are halogen, hydroxy, cyano, C~_a-alkyl, C,_4-alkylcarbonyl, C3_~-cycloalkyl and C,_4-alkoxy, while, as hereinbefore 1o defined, 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 independently of one another may additionally be monosubstituted by CI or Br. Most particularly preferably R2° denotes F, CI, Br, I, OH, cyano, methyl, difluoromethyl, trifluoromethyl, ethyl, n-propyl, iso-propyl, acetyl, methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, n-propoxy or iso-propoxy.
The substituent R22 preferably denotes C~_4-alkoxy, C~_4-alkylthio, carboxy, C,_4-alkylcarbonyl, C~_4-alkoxycarbonyl, aminocarbonyl, C~_4-alkylaminocarbonyl, di-(C~_4-alkyl)-aminocarbonyl, C,_4-alkyl-sulphonyl, C~_4-alkyl-sulphinyl, C,_4-alkyl-2o sulphonylamino, amino, C,_4-alkylamino, di-(C~_4-alkyl)-amino, C~_4-alkyl-carbonyl-amino, hydroxy-C~_3-alkylaminocarbonyl, aminocarbonylamino or C»-alkylaminocarbonyl-amino, while, as hereinbefore defined, 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 independently of one another may additionally be monosubstituted by CI or Br. Most particularly preferred meanings for R22 are C~_4-alkoxy, C~_a-alkylcarbonyl, amino, C,_4-alkylamino, di-(C~_4-alkyl)-amino, wherein one or more H
atoms may be replaced by fluorine.
Preferred definitions of the group Rz' are C~_a-alkyl, C~_4-alkylcarbonyl, C~_4-3o alkylsulphonyl, -S02-NH2, -SOZ-NH-C~_3-alkyl, -S02-N(C~_3-alkyl)2 and cyclo-C3_s-alkyleneimino-sulphonyl, while, as hereinbefore defined, 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 independently of one another may additionally be monosubstituted by CI
or Br. Most particularly preferably Rz' denotes C~_4-alkyl or CF3.
Cy preferably denotes a C3_~-cycloalkyl, particularly a C3_6-cycloalkyl group, a C5_~-cycloalkenyl group, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, aryl or heteroaryl, and the above-mentioned cyclic groups may be mono- or polysubstituted at one or more C atoms by identical or different groups R2°, or in the case of a phenyl group may also additionally be monosubstituted by vitro, and/or one or more NH groups may be substituted by R2'. Most particularly preferred definitions of the group Cy are C3_6-cycloalkyl, pyrrolidinyl and piperidinyl, which may be substituted as specified.
The term aryl preferably denotes phenyl or naphthyl, particularly phenyl.
The term heteroaryl preferably comprises pyridyl, indolyl, quinolinyl and benzoxazolyl.
Preferred compounds according to the invention are those wherein one or more of the groups, radicals, substituents and/or indices have one of the meanings given hereinbefore as being preferred.
Particularly preferred compounds according to the invention may be described by a general formula Ila, Ilb, Ilc and Ild, particularly Ila and Ilb, ~Lz)n _ ~L3)P
R\ N / \ z - \ / \ / Ila N ~ N
Rzi ~Lz)n \L3)P
R~ N / \ z - \T/ \ Ilb N ~ N
Rzi \L2)n ~L3~P
N ~~ Z- N~ ~'~ IIC
R\~N
Rzi ~Lz)n ~L3)P
N ~ ~ Z - N ~ ~ Ild R\~N
Rzi wherein the quinoline and benzimidazole groups are unsubstituted or mono- or disubstituted by L', while a quinoline group is preferably unsubstituted or monosubstituted in the 4 position by R2°, particularly C~_3-alkyl, most particularly methyl, and R', R2 and Z have one of the above-mentioned meanings and L' , L2.
1o L3, independently of one another have one of the meanings given for R2°, and n, p independently of one another represent the values 0, 1 or 2, and p also denotes the value 3.
In particular in formulae Ila, Ilb, Ilc and Ild, preferably Ila and Ilb, Z denotes a single bond, L' denotes fluorine, chlorine, bromine, cyano, C~_3-alkyl, C~_3-alkoxy, C~-a-2o alkoxycarbonyl, trifluoromethyl, trifluoromethoxy, nitro, particularly C~_3-alkyl, WO 20051103029 3$ PCT/EP20051003684 L2 denotes fluorine, chlorine, bromine, CN, amino, CF3, methoxy and C~_3-alkyl, n denotes 0 or 1, L3 are selected independently of one another from the meanings fluorine, chlorine, bromine, cyano, nitro, C~_4-alkyl, hydroxy, w-hydroxy-C~_3-alkyl, C~_4-alkoxy, trifluoromethyl, trifluoromethoxy, C2_4-alkynyl, carboxy, C~_ 1o a-alkoxycarbonyl, ar(C~_4-alkoxy)-C~_3-alkyl, C~_4-alkoxy-carbonylamino, amino, C,_4-alkyl-amino, di-(C~_a-alkyl)-amino, cyclo-C3_s-alkyleneimino, aminocarbonyl, C~_4-alkyl-amino-carbonyl or di-(C~_4-alkyl)-amino-carbonyl, particularly preferred are fluorine, chlorine, bromine, cyano, CF3, C,_3-alkyl, C~_4-alkoxy and trifluoromethoxy, with the proviso that a phenyl ring may only be monosubstituted by nitro, and p denotes 0, 1, 2 or 3, particularly 1 or 2.
Most particularly preferably in formulae Ila, Ilb, Ilc, Ild, particularly Ila and Ilb, R', R2 independently of one another denote C~_4-alkyl, hydroxy-C~_4-alkyl, C3-alkenyl, C3_5-alkynyl, C3_~-cycloalkyl, hydroxy-C3_~-cycloalkyl, dihydroxy-C3_ 6-alkyl, C3_~-cycloalkyl-C~_3-alkyl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, tetrahydrofuran-2-ylmethyl, tetrahydrofuran-3-ylmethyl, (hydroxy-C3_~-cycloalkyl)-C~_3-alkyl, w-(C~_4-alkoxy)-C2_3-alkyl, di-(C~_3-alkyl)amino-Cz_3-alkyl, pyrrolidine-N-yl-C2_3-alkyl, piperidin-N-yl-C2_3-alkyl, pyridyl or benZyl, while an alkyl, cycloalkyl or cycloalkyl-alkyl group may additionally be mono- or disubstituted by hydroxy and/or hydroxy-C~_3-alkyl, and/or mono- or polysubstituted by F or C,_3-alkyl and/or monosubstituted by CF3, 3o Br, CI or CN, and one or both, preferably one of the groups R' and R2 may also represent H, and phenyl and pyridyl rings may be mono- or polysubstituted by identical or different groups R2°, and phenyl may also be monosubstituted by nitro, or R', R2 are joined together and form together with the N atom to which they are bound a heterocyclic group which is selected from pyrrolidine, piperidine, piperazine, wherein the free imine function is substituted by R'3, and morpholine, wherein one or more H atoms may be replaced by identical or different groups R'4, and 1o the heterocyclic group defined hereinbefore may be substituted via a single bond by a carbo- or heterocyclic group Cy, while Cy is selected from the group comprising C3_~-cycloalkyl and cyclo-C3_6-alkyleneimino, while Cy may be mono- or polysubstituted by identical or different groups R2°, where R2° is as hereinbefore defined and is preferably selected from fluorine, CF3, C~_3-alkyl, hydroxy-C~_3-alkyl and hydroxy, and R'4 is selected from F, CI, Br, C~_4-alkyl, hydroxy, hydroxy-C~_3-alkyl, C~_ 4-alkoxy, w-(C~_4-alkoxy)-C~_3-alkyl, amino-C~_3-alkyl, C~_4-alkyl-amino-C~_3-alkyl, C3_~-cycloalkyl-amino-C~_3-alkyl, N-(C3_~-cycloalkyl)-N-(C~_4-alkyl)-2o amino-C~_3-alkyl, di-(C~_4-alkyl)-amino-C~_3-alkyl, cyclo-C3_6-alkyleneimino-C~_3-alkyl, aminocarbonyl and pyridylamino, while in the above-mentioned meanings 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 independently of one another may additionally be monosubstituted by CI or B r.
The compounds listed in the experimental section, including the tautomers, the diastereomers, the enantiomers, the mixtures thereof and the salts thereof, are preferred according to the invention.
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, CI, Br and I, particularly F, CI and Br.
The term C~_~-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 C~_"-alkylene, where n may have a value of 1 to 8, denotes a saturated, 1o 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-), 1-methylprop-1,3-ylene (-CH(CH3)-CH2-CH2-), 2-methylprop-1,3-ylene (-CH(CH3)-CH2-), etc., as well as the corresponding mirror-symmetrical forms.
The term C2_"-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-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_~-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.
3o The term C~_~-alkoxy denotes a C~_~-alkyl-O- group, wherein C~_~-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 C~_~-alkylthio denotes a C~_~-alkyl-S- group, wherein C~_~-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 C~_~-alkylcarbonyl denotes a C~_~-alkyl -C(=O)- group, wherein C~_n-alkyl is defined as above. Examples of such groups include methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, iso-propylcarbonyl, n-butylcarbonyl, iso-butylcarbonyl, sec-1o butylcarbonyl, tert-butylcarbonyl, n-pentylcarbonyl, iso-pentylcarbonyl, neo-pentylcarbonyl, tert-pentylcarbonyl, n-hexylcarbonyl, iso-hexylcarbonyl, etc.
The term C3_~-cycloalkyl denotes a saturated mono-, bi-, tri- or spirocarbocyclic, preferably monocarbocyclic group with 3 to n C atoms. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclododecyl, bicyclo[3,2,1]octyl, spiro[4,5]decyl, norpinyl, norbonyl, norcaryl, adamantyl, etc.
The term C5_~-cycloalkenyl denotes a monounsaturated mono-, bi-, tri- or 2o spirocarbocyclic, preferably monocarboxylic group with 5 to n C atoms.
Examples of such groups include cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl, etc.
The term C3_~-cycloalkylcarbonyl denotes a C3_~-cycloalkyl-C(=O) group, wherein C3_n-cycloalkyl is as hereinbefore defined.
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_6-alkyleneimino denotes a 4- to 7-membered ring which comprises 3 to 6 methylene units as well as an imino group, while the bond to the residue of the molecule is made via the imino group.

The term cyclo-C3_s-alkyleneimino-carbonyl denotes a cyclo-C3_s-alkyleneimino ring as hereinbefore defined 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, O and/or S. Examples of such groups are furanyl, thiophenyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, 1,2,3-triazolyl, 1,3,5-triazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, tetrazofyl, thiadiazinyl, indolyl, isoindolyl, benzofuranyl, benzothiophenyl (thianaphthenyl), indazolyl, benzimidazolyl, benzthiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, purinyl, quinazolinyl, quinozilinyl, quinolinyl, isoquinolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, azepinyl, diazepinyl, acridinyl, etc. The term heteroaryl alsa comprises the partially hydrogenated heterocyclic, aromatic ring systems, particularly those listed above. Examples of such partially hydrogenated ring systems are 2,3-dihydrobenzofuranyl, pyrolinyl, pyrazolinyl, indolinyl, oxazolidinyl, oxazolinyl, oxazepinyl, etc.
Particularly preferably 2o heteroaryl denotes a heteroaromatic mono- or bicyclic ring system.
Terms such as C3_~-cycloalkyl-C~_~-alkyl, heteroaryl-C~_~-alkyl, etc. refer to C~_~-alkyl, as defined above, which is substituted with a C3_~-cycloalkyl, 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. Thus, for example, in the group di-C~_4-alkyl-amino, the two alkyl groups may have the same or different meanings.
3o The term "unsaturated", for example 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 style used hereinbefore and hereinafter, according to which in a cyclic group a bond of a substituent is shown towards the centre of this cyclic group, indicates unless otherwise stated that this substituent may be bound to any free position of the 1o cyclic group carrying an H atom.
R2ols Thus in the exampl Je fi the substituent R2° where s = 1 may be bound to any of the free positions of the phenyl ring; where s = 2 selected substituents R2° may independently of one another be bound to different free positions of the phenyl ring.
The H atom of any carboxy group present or an H atom bound to an N atom (imino or amino group) 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 C,_~6-alkanoyl group such as the formyl, acetyl, propionyl, butanoyl, pentanoyl or hexanoyl group, an allyloxycarbonyl group, a C~_~s-alkoxycarbonyl group such as the methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert.butoxycarbonyl, pentoxycarbonyl, hexyloxycarbonyl, octyloxycarbonyl, nonyloxycarbonyl, decyloxycarbonyl, undecyloxycarbonyl, dodecyloxycarbonyl or hexadecyloxycarbonyl group, a phenyl-C~_6-alkoxycarbonyl group such as the benzyloxycarbonyl, phenylethoxycarbonyl or phenylpropoxycarbonyl group, a C1_3-alkylsulphonyl-C2_4-alkoxycarbonyl, C~_3-alkoxy-Cz_4-alkoxy-CZ_4-alkoxycarbonyl or ReCO-O-(RfCRg)-O-CO- group wherein Re denotes a C~_8-alkyl, C5_7-cycloalkyl, phenyl or phenyl- C~_3-alkyl group, Rf denotes a hydrogen atom, a C~_3-alkyl, C5_~-cycloalkyl or phenyl group and Rg denotes a hydrogen atom, a C~_3-alkyl or ReCO-O-(RfCR9)-O group wherein Re to R9 are as hereinbefore defined, while the phthalimido group is an additional possibility for an amino group, and the 1o above-mentioned ester groups may also be used as a group which can be converted in vivo into a carboxy group.
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.
2o The compounds of general formula 1 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 malefic acid, fumaric acid, citric acid, 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 aiia.
3o 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 explained more fully hereinafter.

The two reaction plans A and B that follow show the synthesis of the compounds A.5 and B.5 according to the invention, while R', R2, X, Y, Z, W, A and B have one of the meanings described hereinbefore. Hal denotes chlorine, bromine or iodine, particularly bromine or iodine, particularly preferably iodine.
According to reaction plan A the halogen compound A.1 is reacted with the alkyne compound A.2 in a molar ratio of about 1.5 : 1 to 1 : 1.5 under a protective has atmosphere in the presence of a suitable palladium catalyst, a suitable base and copper(I)iodide in a suitable solvent.
1o A preferred amount of copper(I)iodide is in the range from 1 to 15 mol°l°, particularly 5 to 10 mol% based on the educt A.1.
Suitable palladium catalysts are for example Pd(PPh3)4, Pd2(dba)3, Pd(OAc)2, Pd(PPh3)2C12, Pd(CH3CN)2CI2, Pd(dppf)CI2. The palladium catalyst is preferably used in an amount from 1 to 15 mol°lo, particularly 5 to 10 mol°lo based on the educt A.1.
Suitable bases are particularly amines, such as for example triethylamine or ethyldiisopropylamine, as well as CszC03. The base is preferably used in an at least equimolar amount based on the educt A.1, in excess or as the solvent.
Moreover, suitable solvents are dimethylformamide or ether, such as for example tetrahydrofuran, including the mixtures thereof. The reaction takes place over a period of about 2 to 24 hours in a temperature range of about 20 to 90°C.
The alkyne compound A.3 obtained is reacted directly or after prior purification with a suitable halogenating agent to obtain the halide derivative A.4, wherein Hal' denotes chlorine, bromine or iodine. Suitable halogenating agents include for example or N(butyl)4Br with P205. The reaction conditions required are known to the skilled man as such. Suitable reaction temperatures are usually in the range from 15 to 150°C.
The reaction solution containing the halide derivative A.4 or the purified halide 3o derivative A.4, dissolved in a suitable solvent, is reacted with an amine H-NR'R2 to yield the end product A.5 and then optionally purified. If the amine H-NR'Rz has another primary or secondary amino function, this is advantageously provided with a protective group beforehand, which can be cleaved again after the reaction has ended, using methods known from the literature. The product thus obtained may for example be converted into the salt form by reaction with a corresponding acid.
A
preferred molar ratio of the derivative A.4 to the amine compound is in the range from 1.5 : 1 to 1 : 1.5. Suitable solvents are dimethylformamide or ether, such as for example tetrahydrofuran, including the mixtures thereof.
The reaction to form the product A.5 is advantageously carried out in a temperature range from about 20 to 90°C.
Reaction plan A:
HO-X-Y-Hal + H-C=C-W-A-B
(A.1) (A.2) Cul [Pd]
HO-X-Y-C!C-W-A-B (A.3) MsCI
Ms0-X-Y-C=C-W-A-B (A.4) HNR'R2 R'R2N- X-Y-C-C-W-A-B (A.5) According to reaction plan B the halogen compound B.2 is reacted with the alkyne compound B.1 in a molar ratio of about 1.5 : 1 to 1 : 1.5 under a protective gas atmosphere in the presence of a suitable palladium catalyst, a suitable base and copper(I)iodide in a suitable solvent. Information on suitable reaction conditions, including catalysts, bases and solvents, may be found in the explanations of reaction plan A.
The alkyne compound B.3 obtained is reacted directly or after prior purification with a suitable halogenating agent to obtain the halide derivative B.4, wherein Hal' denotes chlorine, bromine or iodine. The reaction conditions to be respected can again be found in the remarks accompanying Diagram A.
1o The reaction solution containing the halide derivative B.4 or the purified halide derivative B.4, dissolved in a suitable solvent, is reacted with an amine H-NR'R2 to yield the end product B.5 and then optionally purified. Here again, the remarks concerning Diagram A apply.

WO 2005/103029 4$ PCT/EP2005/003684 Reaction plan B:
HO-X-Y-Z- C=C-H + Hal-A-B
(B.1) (B.2) Cul [Pd]
HO-X-Y-Z- C-C-A-B (B.3) MsCI
Ms0-X-Y-Z-C=C-A-B (B.4) HNR~R2 R1R2N-X-Y-Z-C-C-A-B (B.5) According to the other reaction plan C the halogen compound C.1 is reacted with the alkyne compound C.2 in a molar ratio of about 1.5 : 1 to 1 : 1.5 under a protective gas atmosphere in the presence of a suitable palladium catalyst, a suitable base and copper(I)iodide in a suitable solvent to form the product C.3 directly.
Information on suitable reaction conditions, including catalysts, bases and solvents, may be found in 1 o the explanatory remarks accompanying reaction plan A.

WO 2005/103029 4g PCT/EP2005/003684 Reaction plan C:
R'R2N-X-Y-Hal + H-C=C-W-A-B
(C.1 ) (C.2) Cul [Pd]
R'R2N- X-Y-C-C-W-A-B (C.3) An alternative method of synthesis to this is shown in reaction plan D.
According to this, the halogen compound D.2 is reacted with the alkyne compound D.1 in a molar ratio of about 1.5 : 1 to 1 : 1.5 under a protective gas atmosphere in the presence of a suitable palladium catalyst, a suitable base and copper(I)iodide in a suitable solvent to 1o form the product D.3 directly. Once again, information on suitable reaction conditions, including catalysts, bases and solvents, may be found in the explanatory remarks accompanying reaction plan A.
Reaction plan D:
R'R2N-X-Y-Z- C-C-H + Hal-A-B
(D.1 ) (D.2) Cul [Pd]
R'R2N-X-Y-Z- C-C-A-B (D.3) The reactions according to plans A, B, C and D are particularly advantageously 2o carried out with the corresponding iodine compounds A.1, B.2, C.1 and D.2.
In the event that Hal denotes bromine in compounds A.1, B.2, C.1 or D.2, it is advantageous to convert it into the corresponding iodine compound beforehand. One particularly advantageous method is the Aryl-Finkelstein reaction (Klapars, Artis;
Buchwald, Stephen L.. Copper-Catalyzed Halogen Exchange in Aryl Halides: An Aromatic Finkelstein Reaction. Journal of the American Chemical Society (2002), 124(50), 14844-14845). Thus, for example, the halogen compound A.1, B.2, C.1 or D.2 may be reacted with sodium iodide in the presence of N,N'-dimethyl-ethylenediamine and copper(I)iodide in a suitable solvent to form the corresponding iodine compound. An advantageous molar ratio of the halogen compound to sodium iodide is 1 : 1.8 to 1 2.3. N,N'-dimethyl-ethylenediamine is advantageously used in a molar ratio of 10 to 30 mol% based on the halogen compound A.1, B.2, C.1 or D.2. Preferred amounts of copper(I)iodide are in the range from 5 to 20 mol% based on the halogen compound A.1, B.2, C.1 or D.2. A suitable solvent is for example 1,4-dioxane. Suitable reaction temperatures are in the range from about 20 to 110°C. The reaction is substantially complete after 2 to 72 hours.
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 explained more fully in the experimental section.
Stereoisomeric compounds of formula (I) may chiefly be separated by conventional methods. The diastereomers are separated on the basis of their different physico-chemical properties, e.g. by fractional crystallisation 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.

WO 2005/103029 5~ PCT/EP2005/003684 According to a conventional method of separating isomers, the racemate of a compound of 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 solvent provided that it is sufficiently different 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 1o 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 of 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 2o pharmacologically acceptable salts thereof. These salts may be present on the one hand as physiologically and pharmacologically acceptable acid 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, benzenesulphonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or malefic acid. Moreover, mixtures of the 3o 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 WO 2005/103029 ~2 PCT/EP2005/003684 hydroxides and hydrides of the alkali metals, particularly of 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.
1o As antagonists of the MCH receptor the compounds according to the invention are advantageously suitable as pharmaceutical active substances for the prevention andlor 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 good intracerebral 15 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 humans, for the 2o treatment andlor prevention of symptoms 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 25 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, central obesity. This range of indications also includes 3o cachexia, anorexia and hyperphagia.

WO 2005/103029 53 PCTlEP2005/003684 Compounds according to the invention may be particularly suitable for reducing hunger, curbing appetite, controlling eating behaviour and/or inducing a feeling of satiation.
In addition, the diseases caused by MCH or otherwise causally connected with MCH
also include hyperlipidaemia, cellulitis, fatty accumulation, malignant mastocytosis, systemic mastocytosis, emotional disorders, affectivity disorders, depression, anxiety states, 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, particularly type II 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.
2o MGH 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 micturition disorders, such as for example urinary incontinence, hyperactive bladder, urgency, nycturia, enuresis, while the hyperactive bladder and urgency may or may not be connected with benign prostatic hyperplasia.
3o Generally speaking, the compounds according to the invention are potentially suitable for preventing and/or treating dependencies, such as for example alcohol and/or nicotine dependency, and/or withdrawal symptoms, such as for example weight gain in smokers coming off nicotine. By "dependency" is generally meant here an WO 2005/103029 54 PC~JEP2005/003684 irresistible urge to take an addictive substance and/or to perform certain actions, particularly in order to either achieve a feeling of wellbeing or to eliminate negative emotions. In particular, the term "dependency" is used here to denote a dependency on an addictive substance. By "withdrawal symptoms" are meant here, in general, symptoms which occur or may occur when addictive substances are withdrawn from patients dependent on one or more such substances. The compounds according to the invention are potentially suitable particularly as active substances for reducing or ending tobacco consumption, for the treatment or prevention of a nicotine dependency and/or for the treatment or prevention of nicotine withdrawal symptoms, 1o for reducing the craving for tobacco and/or nicotine and generally as an anti-smoking agent. The compounds according to the invention may also be useful for preventing or at least reducing the weight gain typically seen when smokers are coming off nicotine. The substances may also be suitable as active substances which prevent or at least reduce the craving for and/or relapse into a dependency on addictive substances. The term addictive substances refers particularly but not exclusively to substances with a psycho-motor activity, such as narcotics or drugs, particularly alcohol, nicotine, ***e, amphetamine, opiates, benzodiazepines and barbiturates.
The dosage required to achieve such an effect is conveniently, by intravenous or sub-2o cutaneous 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 1 to 3 x daily.
For this purpose, the compounds prepared according to the invention may be formulated, optionally in conjunction 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 ceNulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethylene glycol, propylene glycol, cetylstearyl alcohol, 3o carboxymethylcellulose or fatty substances such as hard fat or suitable mixtures thereof, to produce conventional galenic preparations such as plain or coated tablets, capsules, lozenges, powders, granules, solutions, emulsions, syrups, aerosols for inhalation, ointments or suppositories.

In addition to pharmaceutical compositions the invention also includes compositions containing at least one alkyne 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 be for example foodstuffs 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 1o 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 15 - 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, 20 - active substances for the treatment of hyperlipidaemia, including arteriosclerosis, active substances for the treatment of dyslipidaemia, 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, 3o insulin secretion accelerators, biguanides, insulins, a-glucosidase inhibitors, X33 adreno-receptor agonists.

Insulin sensitisers include glitazones, particularly 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 and GW-1929.
Insulin secretion accelerators include sulphonylureas, such as for example tolbutamide, chloropropamide, tolazamide, 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 Escherichi 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. Insulin may also 2o 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.
(33 Adreno receptor agonists include AJ-9677, BMS-196085, SB-226552, 3o 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 inhibitors, glipazide, glyburide.
Active substances for the treatment of diabetic complications include for example aldose reductase inhibitors, glycation inhibitors and protein kinase C
inhibitors, DPPIV
blockers, GLP-1 or GLP-2 analogues and SGLT-2 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.
DPPIV blockers are for example LAF237 (Novartis), MK431 (Merck) as well as 815541, 823093 and 825964 (all GIaxoSmithkline).
GLP-1 analogues are for example Liraglutide (NN2211 ) (NovoNordisk), CJC1131 (Conjuchem), Exenatide (Amylin).
SGLT-2 inhibitors are for example AVE-2268 (Aventis) and T-1095 (Tanabe, Johnson&Johnson).
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-711 ).
Active substances for the treatment of obesity, preferably other than MCH
3o antagonists, include lipase inhibitors and anorectics.
A preferred example of a lipase inhibitor is orlistat.

WO 2005/103029 5$ PCTlEP2005/003684 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 (33 agonists, thyromimetic active substances and NPY antagonists should be 1o emphasised. The range of substances which may be considered as preferred anti-obesity or anorectic active substances 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 manoamine reuptake inhibitor (such as for example 15 sibutramine), a sympathomimetic active substance, a serotonergic active substance (such as for example dexfenfluramine, fenfluramine, a 5-HT2C
agonist such as BVT.933 or APD356, or duloxetine), a dopamine antagonist (such as for example bromocriptine or pramipexol), a melanocyte-stimulating hormone receptor agonist or mimetic, an analogue of melanocyte-stimulating 2o hormone, a cannabinoid receptor antagonist (Rimonabant, ACOMPLIA TM), an MCH antagonist, the OB protein (hereinafter referred to as leptin), a leptin analogue, a fatty acid synthase (FAS) antagonist, a leptin receptor agonist, a galanine antagonist, a GI lipase inhibitor or reducer (such as for example orlistat). Other anorectics include bombesin agonists, dehydroepiandrosterone 25 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, AC 2993, CJC-1131, ZP10 or GRT0203Y, DPPIV inhibitors and ciliary neurotrophic factors, such as for example axokines. In this context mention should also be made of 3o the forms of therapy which produce weight loss by increasing the fatty acid oxidation in the peripheral tissue, such as for example inhibitors of acetyl-CoA
carboxylase.

WO 2005/103029 5g PCT/EP2005/003684 Active substances for the treatment of high blood pressure include inhibitors of angiotensin converting enzyme, calcium antagonists, potassium channel openers and angiotensin II 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, 1o nicardipine.
Potassium channel openers include levcromakalim, L-27152, AL0671, NIP-121.
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.
2o HMG-CoA reductase inhibitors include pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, lipantil, cerivastatin, itavastatin, ZD-4522 and their salts.
Fibrate compounds include bezafibrate, clinofibrate, clofibrate and simfibrate.
Active substances for the treatment of dyslipidaemia, including arteriosclerosis, include e.g. medicaments which raise the HDL level, such as e.g. nicotinic acid and derivatives and preparations thereof, such as e.g. niaspan, as well as agonists of the nicotinic acid receptor.
3o Active substances for the treatment of arthritis include NSAIDs (non-steroidal antiinflammatory drugs), particularly C07C2 inhibitors, such as for example meloxicam or ibuprofen.

Active substances for the treatment of anxiety states include chlordiazepoxide, diazepam, oxozolam, medazepam, cloxazolam, bromazepam, lorazepam, alprazolam, fludiazepam.
Active substances for the treatment of depression include fluoxetine, fluvoxamine, imipramine, paroxetine, sertraline.
The dosage 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 alkyne compound according to the invention and/ or a salt according to the invention for influencing the eating behaviour of a mammal. This use is particularly based on the fact that compounds according to the invention may be suitable for reducing hunger, curbing appetite, controlling eating behaviour and/or inducing a feeling of satiety. The eating behaviour is advantageously influenced so as to reduce food intake.
Therefore, the compounds according to the invention are advantageously used for reducing body weight. Another use according to the invention is the prevention of increases in body weight, for example in people who had previously taken steps to lose weight and are interested in maintaining their lower body weight.
According to this embodiment it is preferably a non-therapeutic use. Such a non-therapeutic use might be a cosmetic use, for example to alter the external appearance, or an application to improve general health. The compounds according to the invention are preferably used non-therapeutically for mammals, particularly humans, not suffering from any diagnosed eating disorders, no diagnosed obesity, bulimia, diabetes and/or no diagnosed micturition disorders, particularly urinary incontinence.
Preferably, the compounds according to the invention are suitable for non-therapeutic use in people whose BMI (body mass index), defined as their body weight in kilograms divided by their height (in metres) squared, is below a level of 30, particularly below 25.

WO 2005!103029 61 PCT/EP2005/003684 The Examples that follow are intended to illustrate the invention:
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 were 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 heading Alox were determined using ready-made aluminium oxide 60 TLC plates F254 (E. Merck, Darmstadt, Item no. 1.05713) without chamber saturation. For chromatographic purifications silica gel 1o made by Messrs Millipore (MATREXTM, 35-70 my) or Alox (E. Merck, Darmstadt, standardised aluminium oxide 90, 63-200 Nm, Item no. 1.01097.9050) is used.
The ratios specified for the eluants are based on units by volume of the solvents in question. The units by volume specified in the case of NH3 relate to a concentrated solution of NH3 in water. Unless otherwise stated the acid, base and salt solutions used for working up the reaction solutions are aqueous systems of the concentrations specified.
The HPLC data specified were measured under the parameters indicated below:
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).
Method A:
time (min) percent by volume of waterpercent by volume of acetonitrile (with 0.1 % formic acid) (with 0.1 % formic acid) Method B:
time (min) percent by volume of waterpercent by volume of acetonitrile (with 0.1 % formic acid) (With 0.1 % formic acid) Analytical columns: Zorbax column (Agilent Technologies), Bonus RP - C14; 3.5 Nm;
4.6 x 75 mm; column temperature: 30°C; flow: 0.8 mL l min; injection volume: 5 NL;
5 detection at 254 nm (method C) Method C:
time (min) percent by volume of waterpercent by volume of acetonitrile (with 0.1 t formic acid) (with 0.1 % formic acid) Preparative column: Zorbax column (Agilent Technologies), SB (Stable Bond) -C18;
10 3.5 Nm; 30 x 100 mm; column temperature: ambient temperature; flow: 30 mL l min;
detecttion at 254 nm.
In preparative HPLC purification, as a rule the same gradients are used which were used when obtaining the analytical HPLC data.
The products are collected under mass control, the fractions containing the product are combined and freeze-dried.
Temperatures are given in degrees Celsius (°C) ; times are generally given in minutes (min), hours (h) or days (d). 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 Cyc cyclohexane DCM dichloromethane DIPE diisopropylether DMF dimethylformamide dppf 1,1 '-bis(diphenylphosphino)ferrocene EtOAc ethyl acetate EtOH ethanol i. vac. in vacuo MeOH methanol MTBE methyl-tent-butylether NMP N-methylpyrrolidinane PE petroleum ether RT ambient temperature (approx. 20C) TBAF tetrabutylammonium fluoride-hydrate THF tetrahydrofuran dil. dilute -~* denotes the bonding site of a group Example 1 {6-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-4-methyl-quinolin-2-yl}-methyl-amine c~
1 a N-(4-bromo-phenyl)-3-oxo-butyramide A solution of 25.72 mL (336 mmol) diketene in 100 mL toluene is added dropwise at 90°C to a solution of 51.0 g (288 mmol) 4-bromoaniline in 200 mL
toluene and the WO 2005/103029 64 PCTlEP20051003684 reaction mixture is kept for 5 h at this temperature. The reaction solution is cooled in the ice bath, the precipitate formed is filtered and then washed with toluene until the product is virtually colourless. Subsequently it is dried at 50°C in the circulating air dryer until the weight is constant.
Yield: 50.0 g (68% of theoretical) C~oH~oBrN02 (M= 256.096) Calc.: molpeak (M+H)+: 256/258 (Br) Found: molpeak (M+H)+: 256/258 (Br) HPLC-MS: 4.7 min (method B) 1 b 6-bromo-4-methyl-1 H-quinolin-2-one A solution of 50.0 g (195 mmol) N-(4-bromo-phenyl)-3-oxo-butyramide in 217 mL
concentrated sulphuric acid is heated to 120°C for 1 h. After cooling to RT the reaction solution is added to 1.5 L of ice water, stirred for 30 min, the precipitate formed is filtered and washed again with 4 L water. Subsequently it is dried at 35°C in the circulating air dryer until the weight is constant.
Yield: 24.0 g (52% of theoretical) C~oH8BrN0 (M= 238.081 ) Calc.: molpeak (M+H)+: 2381240 (Br) Found: molpeak (M+H)+: 238/240 (Br) HPLC-MS: 4.8 min (method B) 1 c 6-iodo-4-methyl-1 H-quinolin-2-one A mixture of 5.0 g (21.0 mmol) 6-bromo-4-methyl-1 H-quinolin-2-one and 400 mg (2.1 mmol) Cul in 21 mL 1,4-dioxane is evacuated and gassed with argon. Then 6.3 g (42.0 mmol) Nal and 0.45 mL (4.2 mmol) N,N'-dimethylethylenediamine are added, the mixture is evacuated again and gassed with argon before being heated overnight to 110°C. HPLC analysis of the mixture shows approx 20% reaction.
Therefore another 400 mg (2.1 mmol) Cul, 6.3 g (42.0 mmol) Nal, 0.45 mL (4.2 mmol) N,N'-dimethylethylenediamine and 21 mL 1,4-dioxane are added and the mixture is heated overnight again to 110°C. To complete the reaction the above procedure is repeated 3o another three times. After cooling the suspension is combined with 10% NH3 solution and water and the precipitated product is filtered off. This is then washed with 10%
NH3 solution, water, isopropanol, DIPE, EtOAc and DCM and dried overnight in the air. The product, which still contains approx. 20% educt, is further reacted without purification.
Yield: 3.0 g (40% of theoretical) C~oH$INO (M= 285.081 ) Calc.: molpeak (M+H)+: 286 Found: molpeak (M+H)+: 286 HPLC-MS: 5.0 min (method B) 1 d 5-bromo-2-[(tent-butyl-dimethyl-silanyl)-ethynyl]-pyridine Under an argon atmosphere 0.80 g (4.20 mmol) Cul and 2.90 g (4.13 mmol) bis 1o triphenylphosphane-palladium(II)-chloride are added to a solution of 49.90 g (201.0 mmol) 2,5-dibromopyridine and 43.0 mL (225.6 mmol) tert-butyl-ethynyl-dimethyl silane in 500 mL dry THF and 120 mL triethylamine at -7 °C and the mixture is stirred for 30 min at 0 °C. The reaction mixture is stirred for a further 3.5 h at RT, then filtered and the filtrate is evaporated down i. vac. . The residue is dissolved in 1 L
EtOAc, the organic phase is washed with water and saturated NaCI solution, dried over Na2S04 and evaporated down i. vac. . The crude product is further reacted without purification.
Yield: 59.5 g (quant. Yield) C~3H~$BrNSi (M= 296.278) 2o Calc.: molpeak (M+H)+: 296/298 (Br) Found: molpeak (M+H) : 296/298 (Br) Rf value: 0.75 (silica gel, Cyc/EtOAc 8:1 ) 1 a 2-[(tert-butyl-dimethyl-silanyl)-ethynyl]-5-(4-chloro-phenyl)-pyridine 250 mL MeOH, 220 mL 2 N Na2C03 solution and 1.80 g (2.46 mmol) PdCl2(dppf) are added to a solution of 59.5 g (201.0 mmol) 5-bromo-2-[(tert-butyl-dimethyl-silanyl)-ethynyl]-pyridine and 36.5 g (233.4 mmol) 4-chlorophenylboric acid in 600 mL
1,4-dioxane and the mixture is refluxed for 1 h. The reaction mixture is evaporated down i.
vac. and diluted with EtOAc . The organic phase is washed with water and semisaturated NaHC03 solution, dried over Na2S04 and evaporated down i. vac. .
3o The residue is purified by column chromatography (silica gel, Cyc/EtOAc 9:1 ).
Yield: 38.5 g (58% of theoretical) C~9H22CINSi (M= 327.923) Calc.: molpeak (M+H)+: 328/330 (CI) Found: molpeak (M+H)+: 328/330 (CI) WO 2005/103029 gg PCTlEP20051003684 Rf value: 0.60 (silica gel, Cyc/EtOAc 8:1 ) 1f 5-(4-chloro-phenyl)-2-ethynyl-pyridine 43.66 g (156.0 mmol) TBAF are added at RT to a solution of 46.50 g (142.0 mmol) 2-[(tert-butyl-dimethyl-silanyl)-ethynyl)-5-(4-chloro-phenyl)-pyridine in 1 L
DCM and the mixture is stirred for 2 h. The organic phase is washed with water, dried over Na2S04 and evaporated down i. vac. . The residue is stirred with DIPE, the precipitate is filtered off and washed with PE.
Yield: 26.0 g (86% of theoretical) 1o C~3H8CIN (M= 213.662) Calc.: molpeak (M+H)+: 214/216 (CI) Found: molpeak (M+H)+: 214!216 (CI) Rf value: 0.30 (silica gel, Cyc/EtOAc 4:1 ) 1 g 6-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-4-methyl-1 H-quinolin-2-one 1.8 g (8.42 mmol) 5-(4-chloro-phenyl)-2-ethynyl-pyridine and 2.34 mL (16.84 mmol) triethylamine are added to a suspension of 3.0 g (8.42 mmol) 6-iodo-4-methyl-1 H-quinolin-2-one in 20 mL DMF and the mixture is evacuated three times and gassed with argon. Then 40.1 mg (0.21 mmol) Cul and 153.9 mg (0.21 mmol) PdCl2(dppf)-2o DCM complex are added and the mixture is evacuated again and gassed with argon.
The reaction mixture is stirred overnight at RT, combined with EtOAc, the precipitated product is filtered off and with washed EtOAc. The residue is stirred with a THF/water mixture (1:1 ), filtered, washed with THF and dried in the circulating air dryer at 50°C
until the weight is constant.
Yield: 3.10 g (99% of theoretical) C23H~5CIN2O (M= 370.831 ) Calc.: molpeak (M+H)+: 371/373 (CI) Found: molpeak (M+H)+: 371/373 (CI) 1 h 2-chloro-6-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-4-methyl-quinoline 3.0 g (8.09 mmol) 6-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-4-methyl-1 H-quinolin-2-one are added batchwise to 37.1 mL phosphorus oxychloride and refluxed fort h.
After cooling the reaction mixture is slowly poured onto 500 mL 10% NH3 solution and stirred for 30 min in the ice bath. The mixture is extracted exhaustively with EtOAc, the combined organic phases are washed with water and dried over MgS04. After the desiccant and solvent have been eliminated the residue is reacted further without purification.
Yield: 1.40 g (44% of theoretical) C23H14C12N2 (M= 389.276) Calc.: molpeak (M+H)+: 389/391/393 (2C1) Found: molpeak (M+H)+: 389/391/393 (2C1) 1 i 2-bromo-6-[5-(4-chloro-phenyl)-pyridin-2-ylethynylJ-4-methyl-quinoline 478 mg (1.48 mmol) tetrabutylammonium bromide and 493 mg (3.37 mmol) phosphorus pentoxide are added to a suspension of 500 mg (1.21 mmol) 6-[5-(4-chloro-phenyl)-pyridin-2-ylethynylJ-4-methyl-1 H-quinolin-2-one in 10 mL
toluene and the reaction mixture is heated to 95°C for 1.5 h. After cooling the organic phase is decanted off, the residue is treated twice with toluene in the ultrasound bath, the combined organic phases are washed with semisaturated NaHC03 solution and water and dried over MgS04. After the desiccant and solvent have been eliminated the residue is dried and reacted further without purification.
Yield: 120 mg (18% of theoretical) C23H~aBrCIN2 (M= 433.730) 2o Calc.: molpeak (M+H)+: 433/435/437 (BrCI) Found: molpeak (M+H)+:

(BrCI) 1 k {6-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-4-methyl-quinolin-2-yl)-methyl-amine 19.1 mg (0.617 mmol) methylamine are added to a solution of 60 mg (0.154 mmol) chloro-6-[5-(4-chloro-phenyl)-pyridin-2-ylethynyfJ-4-methyl-quinoline in 5 mL
1,4-dioxane and the reaction mixture is heated to 130°C for 70 h in the sealed vessel.
The mixture is evaporated down i.vac., the residue is triturated with a little isopropanol, filtered and washed with isopropanol, EtOAc and DIPE. The residue is 3o dissolved in DCM, filtered to remove insoluble ingredients, evaporated down and dried.
Yield: 28 mg (47% of theoretical) C24H~$CIN3 (M= 383.873) WO 2005/103029 6$ PCT/EP2005/003684 Calc.: molpeak (M+H)+: 384/386 (CI) Found: molpeak (M+H)+: 384/386 (CI) HPLC-MS: 5.7 min (method A) The following Examples are prepared analogously, starting from 60 mg of 2-chloro-6-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-4-methyl-quinoline (Example 1 h) and the corresponding amines:
ci ExampleR Yield Empirical Mass HPLC
(%) formula spectrumretention time in min (method) 1.1 ~ , 60 C25H2oCIN3 398/400 5.9 (A) [M+H]+

H

1.2 * 24 CZSHZOCIN3 409/411 4.9 (B) ~, v [M+H]+

1.3 1 52 C28H2~CINa 453/455 5.2 (A) ~ +

[M+H]

1.4 ~ * 5 C27H22C1N3 424/426 6.3 (A) N ~ [M+H]+

H

1.5 ~ 10 C28H24CIN3 438/440 6.5 (A) i [M+H]+

H

WO 2005/103029 6g PCT/EP2005/003684 1.6 12 C3~H3oCIN3 480/482 7.2 (A) [M+Hl+

N
I
H

1.7 4 C3~H3oCIN3 480/482 7.2 (A) [M+H]+

~,. N ~
I
H

Analogously to Example 1 k the following Examples may be prepared starting from 2-chloro-6-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-4-methyl-quinoline (Example 1h) or 2-bromo-6-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-4-methyl-quinoline (Example 1 i) and the corresponding amines:
Examples 1.8-1.9, 1.11, 1.15-1.21, 1.23 and 1.28 were prepared by heating in NMP
in the microwave (300W, 190°C; 30-60 min).
Example 1.13 was prepared by heating in DMF in the microwave (150W, 170°C; 10 1o min). Example 1.51 was obtained as a by-product.

Exa Structure Yield Mass HPLC

mple (%) spectrum retention time (method) 1,g / I c~ 4 414/416 I \ ~M+H~+
\

~N

HO~ I /
N /
N

H

1,g / 34 428/430 5.4 min c~

\ I IM+Hl+ (C) \

i ~N

\

HO~ I /
N /
N

H

1.10 / c \
I

J
~N

\ \

HO~
N N

H

1.11 / 29 442/444 5.9 min c' \ I IM+Hl+ (C) \

~N

O /
/

N N

H

1.12 / I c' 18 410/412 4.79 min w IM+Hl+ C B ) ~N
N
H
1.13 / I c' 17 452/454 6.64 min w w IM+Hl+ CC) i 'N
N N
H
1.14 / I c' IJ
~N
F N N /
F I
F H
1.15 / I c' 20 440/442 6.5 min ~ ~ IM+Hl+ CC) ~N
N N
I
H
1.16 / I c' 27 454/456 6.8 min w w CM+Hl+ CC) i ~N
N N
I
H

1.17 / I c' 17 426/428 6.0 min \ \ ~M+H~+
(C) J

N

, , N N

1.18 / 9 426/428 6.2 min c' I CM+Hl+ (C) \ \

~N

/ /

N N

H

1.19 / I c' 12 454/456 6.7 min \ \ IM+Hl+ (C) ~N

~~~ / /
N
H

1.20 / I c' 35 474/476 6.9 min I ~M H~ (C) \

I/ i N

\

/ /
N N

H

1.21 / I c~ 16 475/477 6.3 min I \ \ IM+H~+ (C) \ i I ~ N
N /

\ \

/ /
N N

H

WO 2005/103029 73 PCTlEP2005/003684 1.22 \ \

r J

I , ~ N

, , N N

H

1.23 / g 424/426 6.11 min c' l I fM+Hl+ (C) \ \

~N

/ /
H N

1.24 / I

\ \

~J
~N

\ \

HO
N
H

1.25 / I c' \ \

~J
~N

~ ~ / /
N N
H

1.26 / I c \ \

IJ
~N

\ \

N N

H

1.27 /

\

\ , NJ
N~ \ \

/ /
N N

H

1.28 / I c' 3 444/446 5.4 min I \ \ ~M+H~+
(C) J

% N
HO

\ \

HO~
N N

H

1.29 /

\
I

J
~N

HO~ ~ / /
N N

1.30 / c \I
~

J
~N

\

/ /
N

1.31 /

\
~

J
~N

\ \

~N

N

1.32 \
I

J
~N

i /

N N

H

1.33 \i NJ

I

, /
N N

H

1.34 /

\I
I

J
~N

\

i /
N N

H

1.35 , I
\ \
I

J
~N

\
/ /

N N

H

1.36 / I o~

\ \
I

J
~N

\ \
~ / /

N N

H

1.37 i I \ ci \

N

N N

H

1.38 / I F

\ \ F

N

\ \
~ / /

N N

H

1.39 /

F \ \
I

J
~N

\ \

N N

H

1.40 i ci \ \

IJ
~N

\ \

N N

H

Example 1.41 6-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-4-methyl-2-pyrrolidin-1-yl-quinoline <°

77 pL (0.925 mmol) pyrrolidine are added to a solution of 90 mg (0.231 mmol) 2-chloro-6-(5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-4-methyl-quinoline in 5 mL
1,4-dioxane and the reaction mixture is refluxed overnight. It is evaporated down i.vac., the residue is taken up in DMF and purified by HPLC-MS. The fractions containing the product are combined, evaporated down and freeze-dried. The product is dissolved in DCM, evaporated down, the residue is triturated with a little EtOAc, filtered, washed again with a little EtOAc and dried at 50°C in the circulating air dryer.
Yield: 39 mg (39% of theoretical) C27H22CIN3 (M= 423.936) 1o Calc.: molpeak (M+H)+: 424/426 (CI) Found: molpeak (M+H)+: 424/426 (CI) HPLC-MS: 5.8 min (method A) Example 1.42 6-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-4-methyl-2-pyrrolidin-1-yl-quinoline ci HzN
A mixture of 200 mg (0.514 mmol) 2-chloro-6-[5-(4-chloro-phenyl)-pyridin-2-ylethyny!]-4-methyl-quinoline, 607 mg (10.28 mmol) acetamide and 355 mg (2.57 mmol) K2C03 are heated to 200°C for 7 h in a melt. After cooling water is added, the mixture is exhaustively extracted with EtOAc, the combined organic phases are extracted twice 2o with semisaturated NaHC03 solution and dried over MgSOa. After the desiccant and solvent have been eliminated the residue is dissolved in DMF, filtered and purified by HPLC-MS.
Yield: 4 mg (2% of theoretical) C23H~6CIN3 (M= 369.846) Calc.: molpeak (M+H)+: 370/372 (CI) Found: molpeak (M+H)+: 370/372 (CI) HPLC-MS: 5.5 min (method A) WO 2005/103029 7$ PCT/EP2005/003684 Example 1.43 6-[5-(4-chloro-phenyl)-pyridin-2-yfethynyl]-4-methyl-2-(4-methyl-piperidin-1-yi)-quinoline 1.43a 6-bromo-2-chloro-4-methyl-quinoline 25 mL phosphorus oxychloride are added to 2.7 g (11.34 mmol) 6-bromo-4-methyl-1 H-quinolin-2-one (Example 1 b) and the reaction mixture is refluxed fort h.
After cooling the mixture is added batchwise to 250 mL 10% NH3 solution, the precipitate formed is filtered off, washed with water and dried in the circulating air dryer at 30°C.
Yield: 2.7 g (93% of theoretical) C~oH~BrCIN (M= 256.526) Calc.: molpeak (M+H)*: 256/258/260 (BrCI) Found: molpeak (M+H)*: 256/258/260 (BrCI) Rf value: 0.95 (silica gel, DCM/MeOH 9:1 ) 1.43b 6-bromo-4-methyl-2-(4-methyl-piperidin-1-yl)-quinoline 0.24 mL (2.0 mmol) 4-methylpiperidine and 0.28 mL (2.0 mmol) triethylamine are added to a solution of 0.51 g (2.0 mmol) 6-bromo-2-chloro-4-methyl-quinoline in 15 mL 1,4-dioxane and the reaction mixture is refluxed overnight. After cooling the 2o precipitate is filtered off, the filtrate is evaporated down, the residue is combined with acetonitrile and MTBE, filtered to remove insoluble ingredients and the filtrate is evaporated down again.
Yield: 0.69 g (100°l0 of theoretical) C~6H~gBrN2 (M= 319.240) Calc.: molpeak (M+H)*: 319/321 (Br) Found: molpeak (M+H)*: 319/321 (Br) HPLC-MS: 4.7 min (method B) WO 2005/103029 7g PCT/EP2005/003684 1.43c 6-iodo-4-methyl-2-(4-methyl-piperidin-1-yl)-quinoline Under an argon atmosphere 39 mg (0.2 mmol) Cul, 0.6 g (4.0 mmol) Nal and 43 NL
N,N~-dimethylethylenediamine are added to a solution of 0.69 g (2.0 mmol) 6-bromo-4-methyl-2-(4-methyl-piperidin-1-yl)-quinoline in 2 mL 1,4-dioxane and the reaction mixture is shaken for 14 h at 110°C. After cooling it is combined with 60 mL EtOAc, the organic phase is washed twice with 20 mL 5% NH3 solution and dried over MgS04. After the desiccant and solvent have been eliminated the residue is reacted further without purification.
Yield: 0.65 g (88% of theoretical) 1o C~6H~sIN2 (M= 366.240) Calc.: molpeak (M+H)+: 367 Found: molpeak (M+H)+: 367 HPLC-MS: 7.0 min (method A) 1.43d 6-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-4-methyl-2-(4-methyl-piperidin-1-yl)-quinoline A solution of 293 mg (0.8 mmol) 6-iodo-4-methyl-2-(4-methyl-piperidin-1-yl)-quinoline, 184 mg (0.8 mmol, 93% purity) 5-(4-chloro-phenyl)-2-ethynyl-pyridine and 158 pL (1.6 mmol) piperidine in 4 mL 1,4-dioxane is evacuated three times and gassed with argon. After the addition of 3 mg (0.016 mmol) Cul and 13 mg (0.016 2o mmol) PdCl2(dppf)-DCM complex the reaction mixture is stirred for 4 h at RT. It is combined with 10 mL EtOAc, the precipitate is filtered off, washed with a little EtOAc and MeOH and dried in the air.
Yield: 240 mg (66% of theoretical) C2sH2sCIN3 (M= 451.990) Calc.: molpeak (M+H)+: 452/454 (CI) Found: molpeak (M+H)+: 452/454 (CI) HPLC-MS: 6.1 min (method B) WO 20051103029 $Q PCT/EP2005/003684 Example '1.44 {6-[5-(4-chloro-phenyl)-pyridin-2-yiethynyl]-4-methyl-quinolin-2-yl)-isopropyl-amine Prepared analogously in a sequence analogous to Example 1.43 b (with 0.3 g 6-bromo-2-chloro-4-methyl-quinoline; 61 % yield), 1.43c (with 0.2 g (6-bromo-4-methyl-quinolin-2-yl)-isopropyl-amine; 60% yield) and 1.43d (with 0.16 g (6-iodo-4-methyl-quinolin-2-yl)-isopropyl-amine; 8% yield).
C26H22CIN3 (M= 411.926) Calc.: molpeak (M+H)+: 412/414 (CI) Found: molpeak (M+H)+: 412!414 (CI) 1o HPLC-MS: 5.6 min (method B) The following Examples are prepared analogously to Example 1 k starting from 90 mg 2-chloro-6-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-4-methyl-quinofine (Example 1 h) and the corresponding amines:
ci WO 2005/103029 $~ PCT/EP2005/003684 Example R Yield Empirical Mass HPLC
(%) formula spectrumretention time in min (method) 1.45 H 11 C26H22CIN30 428/430 5.5 (C) * [M+H]+
~

N

1.46 ~ 9 C28H24CIN30 454/456 5.7 (C) [M+H]+

1.47 * 13 Cz8H2~CIN4 455/457 4.5 (C) ~N ~
[M+H]+

/N~

1.48 ~~H 36 C28H24CIN30 454/456 5.1 (B) [M+H]+

GNP

The following products are prepared from 100 mg 2-chloro-6-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-4-methyl-quinoline (Example 1 h) and the corresponding amines by heating in NMP in the microwave (60 min 300 W, 190°C):
ci R

WO 2005/103029 $2 PCT/EP2005/003684 ExampleR Yield Empirical Mass HPLC
(%) formula spectrum retention time in min (method) 1.49 * 17 C28H24CIN30 454/456 5.9 (C) ~
N

[M+H]+
~

H

1.50 H. 9 C26H22CIN30 428/430 7.8 (C) ~ ~

N [M+H]

-o Example 1.51 {6-[5-(4-chloro-phenyl )-pyrid in-2-ylethynyl]-4-m ethyl-quinol in-2-yl}-d i methyl-a mine ci \N
By-product of the preparation of Example 1.13.
Yield: 61 mg (50 % of theoretical based on 2-chloro-6-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-4-methyl-quinoline) 1o C25H2pCIN3 (M= 397.899) Calc.: molpeak (M+H)+: 398/400 (CI) Found: molpeak (M+H)+: 398/400 (CI) HPLC-MS: 5.6 min (method C).

WO 2005/103029 $3 PCT/EP2005/003684 Example 2.1 5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-pyrrolidin-1-yl-1 H-benzimidazole-ditrifluoroacetate f 2.1 a 5-bromo-1,3-dihydro-benzimidazol-2-one 4.29 g (26.46 mmol) carbonyldiimidazole (CD/) are added to a solution of 4.5 g (24.05 mmol) 4-bromo-benzene-1,2-diamine in 95 ml DMF and the reaction mixture is stirred for 5 hours at 80°C. Then the reaction mixture is poured onto water and the 1 o precipitate formed is filtered off. The precipitate is washed three times with water and dried in the circulating air dryer at 60°C.
Yield: 4.6 g (90 % of theoretical) C~H5BrN20 (M= 213.03) Cafc.: molpeak (M+H)+: 213/215 Found: molpeak (M+H)+: 213/215 Rf value: 0.5 (silica gel, DCM/MeOH 10:1 ).
2.1 b 2,5-dibromo-1 H-benzimidazole 4.5 g (21.12 mmol) 5-bromo-1,3-dihydro-benzimidazol-2-one are added batchwise at 60°C to a melt of 30.27 g (105,6 mmol) phosphorus oxybromide and the reaction 2o mixture is stirred for 5 hours at 110°C. Then the reaction mixture is poured onto water and the precipitate formed is filtered off. The precipitate is stirred with DIPE/acetone (4:1 ) and the solid is filtered off. The solid is dried in the circulating air dryer at 50°C .
Yield: 3.4 g (58 % of theoretical) C~H4Br2N2 (M= 275.92) Calc.: molpeak (M+H)+: 27512771279 Found: molpeak (M+H)+: 275/277/279 Rr value: 0.6 (silica gel, DCM/MeOH 10:1 ).

WO 2005/103029 $4 PCT/EP2005/003684 2.1c 5-bromo-2-pyrrolidin-1-yl-1H-benzimidazole A suspension of 1 g (3.6 mmol) 2,5-dibromo-1 H-benzimidazole and 0.85 ml (10.18 mmol) pyrrolidine in 45 ml acetonitrile is heated for 2 h at 150°C in the microwave.
The reaction mixture is poured onto water and extracted with EtOAc . The organic phase is washed three times with water and dried over Na2S04 . The solvent is distilled off, the residue is stirred with DIPE and the solid is filtered off.
Yield: 0.43 g (45 % of theoretical) C»H~2BrN3 (M= 266.13) Calc.: molpeak (M-H)-: 264/266 Found: molpeak (M-H)-: 264/266 1o Rf value: 0.5 (silica gel, DCM/MeOH 10:1 ).
2.1 d 5-iodo-2-pyrrolidin-1-yl-1 H-benzimidazole 0.48 g (1.8 mmol) 5-bromo-2-pyrrolidin-1-yl-1H-benzimidazole and 34 mg (0.18 mmol) Cul are placed in a round flask. The reaction vessel is flushed with argon.
Then 0.54 g (3.6 mmol) Nal, 32 mg (0.36 mmof) dimethylenediamine and 3 mL 1,4-dioxane are added under argon. The reaction mixture is stirred for 14 h at 110°C.
Subsequently, the cooled reaction mixture is combined with concentrated ammonia solution, diluted with water and the precipitate formed is filtered off. The solid is stirred with methanol and again filtered.
2o Yield: 0.3 g (53 % of theoretical) C»H~2IN3 (M= 313.13) Calc.: molpeak (M+H)+: 314 Found: molpeak (M)+: 314 2.1.e 5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-pyrrolidin-1-yi-1H-benzimidazole-ditrifluoroacetate 0.2 g (0.64 mmol) 5-iodo-2-pyrrolidin-1-yl-1H-benzimidazole, 0.62 g (1.92 mmol) caesium carbonate, 0.036 g (0,03 mmol) tetrakistriphenylphosphine palladium and 0.012 g (0.06 mmol) Cul are suspended in 20 ml absolute THF and the reaction mixture is degassed and ventilated with argon. Then 0.273 g (1.28 mmol) 5-(4-chloro-3o phenyl)-2-ethynyl-pyridine are added at RT under argon and the reaction mixture is stirred for 16 h. The reaction mixture is poured into a 2 N NH3 solution and the precipitate formed is filtered off. The solid is washed with water. Then the solid is WO 2005/103029 $5 PCT/EP2005/003684 dissolved in DMF/trifluoroacetic acid and purified by HPLC (solvent:
acetonitrile/
water/0.5% trifluoroacetic acid).
Yield: 40 mg (10 % of theoretical) CzøH~9CIN4x 2 C2HF302 (M= 626.93) melting point: 179-180°C
Calc.: molpeak (M+H)+: 399/401 Found: molpeak (M+H)+: 399/401 The following compounds may be prepared analogously to Example 2.1:
Exam- Structure YieldMass retention in ple % spectrumtime HPLC

(method) ~' 9 401 3.1 (C) 2.2 .~ \ ~M+H~+
I I

J
~N

N
N~/

N /

CI
/ I

2.3 \ \

I
-N

N \
N \/

N /

/ CI
I

2.4 I \
w ~N

N
N~/ /

N

/ CI

2.5 I

~N

~N
~N~/ L

O /
N

WO 2005/103029 $6 PCT/EP2005/003684 ci 2.6 H
'N

Oi~ ~~ \
N

N

CI

2.7 I
\

~N

N \
O I~~~N~/

N

CI

2.8 I
w ~N

0~~~ N \
~
N~/

-\
~/
H N N

H

CI

2.9 I
\

~N

F N \
F-~~~N~/ I

F N /

CI
I

2.10 \
\

I ~N

N
O N ~~
I

U N /

/ CI
( 2.11 I
\

~N

N
-N N-~/
I

U N /

WO 2005/703029 $7 PCTIEP2005/003684 / CI
\ I
2.12 I w -N
N
N--~r I
N /
/ CI
2.13 \ I
I i -N
N
N-~r N /
/ CI
\ I
2.14 \
'J
~N
~N \
N ~ I
H N
/ CI
2.15 I \ ~/
-N
,N \
N~J\r I
H N
/ CI
2.16 N~
N \
N---~r H N /

WO 20051103029 $$ PCT/EP2005/003684 CI
/I
2.17 I w N'r ~N
N ~
N /
CI
I
2.18 -N
N
N--C~
H N
CI
2.19 ~ w N \ / N
N-<~ I
H N
CI
2.20 N \ ~ N
N-~~ I
H N
CI
2.21 I
N ~ / N
N-~r H N
/ CI
~I
2.22 N/
~N
N
H N

WO 2005/103029 $g PCTIEP2005/003684 c1 I

2.23 I J

~N
N

~
N /

N /

CI
/I

2.24 \ \
I

J
N \ ~ ,N

N
N ~/

/ /
N

/ CI
I

2.25 ~

H_0 /
~N

N \
/

~ /
N
N

/ CI

2.26 I \

-o, ~N

N
/

~ /
N
H N

/ CI

2.27 I \

F
~ N
~

F \
N
/

F /N~ /
N

/ CI
I

2.28 I \ \

N

N \
/

N ~ /
/
H N

CI
/I

. I J

'N

N
/

. N-~ /
H N

CI

\
2.30 I \

N

N \
/

N~ /
H N

CI
/I

2.31 I \ \

~ N

N \
/

N ~ /
N

CI
/I

2.32 I \ \

~ N

N \
N ~/

N /

/ CI
I

2.33 I ~ ~

N

\ N
N~/

N /

CI

2.34 N~

N
~

N-~
N

WO 2005/103029 g~ PCT/EP2005/003684 ci 2.35 ( N
N
N r r CI
I
2.36 _N
~ ~N
N /
N
CI
r/
2.37 ~N
~ ~N
N ~
N r CI
r I
2.38 J
_N
~N
N ~
N
O
r CI
I
2.39 N
N
N--~r N r -O

m WO 2005/103029 g2 PCT/EP2005/003684 c1 I

2.40 \

~N

N
N ~/

N

CI
I

2.41 \
I ~

N

N
N ~/

N

CI
I

2.42 \
I

r -N

H ~N \

H N

/ G

2.43 H / wN
O N

N

F N /
F

F

CI

2.44 i N

N
~N--~/

N

CI

2.45 -N
N

N--~r i N

WO 2005/103029 g3 PCT/EP2005/003684 F

\
2.46 I

~N

\N \
N ~

N

F

2.47 ~N

~N \
N ~

N ~ .

F
( 2.48 \

N

N \
~

~
N
H N

I

2.49 ~ \

~N

.N \
N~/\~

N

2.50 \ \
I

J
~N

,N \
N~J I
~

\
N

2.51 ~ \
I

J
~N

N \
~

~
N
H N

F F

2.52 \

~N

N \
N~/ I

N /

F F

2.53 I ~F

N

,N \
N~/\/

N /

F
F

2.54 \

~N

N \
I

N--~ I
N /

/ O\

2.55 I
\

N

\N \
N /

N /

/ O\

2.56 I
\

N

N \
N \/

N /

/ O\

\
2.57 I I

N

N \
/

N~ /
N

WO 2005/103029 g5 PCT/EP2005/003684 / 85 415/4170.21 c' 2.58 I ~M+H~ (Rr I \

~ N silica gel \ , N~ I

~ EtOAc/PE

1:1) / ci \
2.59 ~ w' N

N \
N~/

CI

2.60 I \

N

N \
N ~/

N

CI

2.61 I \

N

N \
O~N~/

H

/ CI

\
2.62 H
~N
O

,~ ~~
~~N I

~
~J N

c1 \
2.63 I
\

~N

H N \
O_~~N~/

N

CI

2.64 ~N

0 N \
N--~/

H N\ ~ /

H

CI
/

2.65 I
\

i ~N

F N \
F- ~~~N ~/ I

F N

/ CI
I

2.66 I \

~N

N
O N---C~
I

N /

/ CI

2.67 I \
\I

N

N \
-N N---~/
I

U N /

/ CI

\
2.68 \ I

( ~N

N \
/

N \
H ~ /

WO 2005/103029 g7 PCT/EP2005/003684 c1 I
2.69 ( N
N
N--~r H
CI
\ I
2.70 I ~ a N
~N \
N ~
H
CI
\ I
2.71 I
N
N \
N--~r H
Cl ~I
2.72 I w N
N
N--~r H
CI
2.73 ~N
N
N-~r ~
H

WO 2005/103029 g$ PCTIEP2005/003684 / c1 I

2.74 I ~

N

N
N~/

H ~ /

/ CI

2.75 I

N \ ~ \N
/

N--~ I

/ Ct 2.76 I

N \ ~ \N
/

N \ /
H ~

/ CI

2.77 I

N \ ~ ~N

N~/

H ~ /

/ CI

2.78 I

N
N
/

~ I
N /
H ~

/ CI

2.79 I
w N
N
/

N \ /
H ~

WO 2005/103029 gg PCT/EP2005/003684 ci 2.80 I
w N \ / N

N N~/ I

H

CI

2.81 I
w H-O
~N

N \
/

N /
H

~

/ CI
I

2.82 I \
w -o, ~N

N \
/

~ I
N /
H

~

/ CI

2.83 I v \Y

F
~N
~

F \
N
/

F /N \ /
H

~

/ CI

2.84 I

N

N \
/

N~
H

CI

2.85 w I

N

N
~

C
N
/ /
H

/ CI
I

2.86 \
I w N

N
/

N ~
H ~ /

/ CI

2.87 I \C ~

N

N
~

NC
I
H
/

~

Ct 2.88 I \ \

~N

C CN \
N ~

N

/ CI

2.89 I w N

N
N

N /

CI
~I
2.90 I \ \
N~
N \
N r N
CI
2.91 ~J
~N
,N N /
CI
2.92 I
N
~ ~N
N r I
N
CI
2.93 I ~ a N
N \
N--~r N
CI
\ I
2.94 I
N
N \
N--~r N
O

WO 2005/703029 'J Q2 PCT/EP2005/003684 CI
I

2.95 \ \
I

J
~N

N \
/
N

\
N /

-O I

CI

2.96 -N

~N
N ~

N

CI
I

2.97 \
I w N/

N
N--~/ I

N "

/ CI

2.98 I w' N

H N \
N~/ I

H ~ /

/ CI

2.99 ~ w ~N

O ~N \
,N /

N /
I

CI
2.100 O N \ ~ .N
~N-~r N
CI
2.101 j \ ~ I
° IJ
N
N
N-~r N
CI
~I
2.102 ~N
N
N~r N
CI
~I
2.103 ~N
C ~N , N r N
CI
2.104 I \
N
N \
N~r N

/ CI

2.105 N

N
~

N--~
H N

Some test methods for determining an MCH-receptor antagonistic activity will now be described. In addition, other test methods known to the skilled man may be used, e.g.
by inhibiting the MCH-receptor-mediated inhibition of CAMP production, as described by Hoogduijn M et al. in "Melanin-concentrating hormone and its receptor are expressed and functional in human skin", Biochem. Biophys. Res Commun. 296 (2002) 698-701 and by biosensory measurement of the binding of MCH to the MCH
receptor in the presence of antagonistic substances by plasmon resonance, as 1o described by Karlsson OP and Lofas S. in "Flow-Mediated On-Surface Reconstitution of G-Protein Coupled Receptors for Applications in Surface Plasmon Resonance Biosensors", Anal. Biochem. 300 (2002), 132-138. Other methods of testing antagonistic activity to MCH receptors are contained in the references and patent documents mentioned hereinbefore, and the description of the test methods used is hereby incorporated in this application.
MCH-1 receptor binding test Method: MCH binding to hMCH-1 R transfected cells Species: Human 2o Test cell: hMCH-1 R stably transfected into CHO/Galpha16 cells Results: IC50 values Membranes from CHO/Galpha16 cells stably transfected with human hMCH-1 R are resuspended using a syringe (needle 0.6 x 25 mm) and diluted in test buffer (50 mM
HEPES, 10 mM MgCl2, 2 mM EGTA, pH 7.00; 0.1 % bovine serum albumin (protease-free), 0.021 % bacitracin, 1 pg/ml aprotinin, 1 pg/ml leupeptin and phosphoramidone) to a concentration of 5 to 15 Ng/ml.

200 microlitres of this membrane fraction (contains 1 to 3 Ng of protein) are incubated for 60 minutes at ambient temperature with 100 pM of '251-tyrosyl melanin concentrating hormone ('251-MCH commercially obtainable from NEN) and increasing concentrations of the test compound in a final volume of 250 microlitres.
After the incubation the reaction is filtered using a cell harvester through 0.5% PEI
treated fibreglass filters (GF/B, Unifilter Packard). The membrane-bound radioactivity retained on the filter is then determined after the addition of scintillator substance (Packard Microscint 20) in a measuring device (TopCount of Packard).
The non-specific binding is defined as bound radioactivity in the presence of 1o micromolar MCH during the incubation period.
The analysis of the concentration binding curve is carried out on the assumption of one receptor binding site.
Standard:
Non-labelled MCH competes with labelled '251-MCH for the receptor binding with an IC50 value of between 0.06 and 0.15 nM.
The KD value of the radioligand is 0.156 nM.
MCH-1 receptor-coupled Ca2+ mobilisation test 2o Method: Calcium mobilisation test with human MCH (FLIPR384) Species: Human Test cells: CHO/ Galpha 16 cells stably transfected with hMCH-R1 Results: 1 st measurement:: % stimulation of the reference (MCH 10-6M) 2nd measurement: pKB value Reagents: HBSS (10x) (GIBCO) HEPES buffer (1 M) (GIBCO) Pluronic F-127 (Molecular Probes) Fluo-4 (Molecular Probes) Probenecid (Sigma) MCH (Bachem) bovine serum albumin (Serva) (protease-free) DMSO (Serva) Ham's F12 (BioWhittaker) FCS (Biotahittaker) L-Glutamine (GIBCO) Hygromycin B (GIBCO) PENStrep (BioWhittaker) Zeocin (Invitrogen) Clonal CHO/Galpha16 hMCH-R1 cells are cultivated in Ham's F12 cell culture medium (with L-glutamine; BioWhittaker; Cat.No.: BE12-615F). This contains per ml 10% FCS, 1 % PENStrep, 5 ml L-glutamine (200 mM stock solution), 3 ml hygromycin B (50 mg/ml in PBS) and 1.25 ml zeocin (100 Ng/ml stock solution).
One day before the experiment the cells are plated on a 384-well microtitre plate (black-walled with a transparent base, made by Costar) in a density of 2500 cells per cavity and cultivated in the above medium overnight at 37°C, 5% C02 and 95%
relative humidity. On the day of the experiment the cells are incubated with cell culture 1o medium to which 2 mM Fluo-4 and 4.6 mM Probenicid have been added, at 37°C for 45 minutes. After charging with fluorescent dye the cells are washed four times with Hanks buffer solution (1 x HBSS, 20 mM HEPES), which has been combined with 0.07% Probenicid. The test substances are diluted in Hanks buffer solution, combined with 2.5% DMSO. The background fluorescence of non-stimulated cells is measured in the presence of substance in the 384-well microtitre plate five minutes after the last washing step in the FLIPR384 apparatus (Molecular Devices; excitation wavelength:
488 nm; emission wavelength: bandpass 510 to 570 nm). To stimulate the cells MCH
is diluted in Hanks buffer with 0.1 % BSA, pipetted into the 384-well cell culture plate 35 minutes after the last washing step and the MCH-stimulated fluorescence is then 2o measured in the FLIPR384 apparatus.

Data analysis:
1 st measurement: The cellular Ca2+ mobilisation is measured as the peak of the relative fluorescence minus the background and is expressed as the percentage of the maximum signal of the reference (MCH 10-6M). This measurement serves to identify any possible agonistic effect of a test substance.
2nd measurement: The cellular Ca2+ mobilisation is measured as the peak of the relative fluorescence minus the background and is expressed as the percentage of the maximum signal of the reference (MCH 10-6M, signal is standardised to 100%).
The EC50 values of the MCH dosage activity curve with and without test substance (defined concentration) are determined graphically by the GraphPad Prism 2.01 curve program. MCH antagonists cause the MCH stimulation curve to shift to the right in the graph plotted.
The inhibition is expressed as a pKB value:
pKB=IOg(EC50(testsubstance+MCH) ~ EC50(MCH) -1 ) -IOg C(testsubstance) The compounds according to the invention, including their salts, exhibit an MCH-receptor antagonistic activity in the tests mentioned above. Using the MCH-1 receptor binding test described above an antagonistic activity is obtained in a dosage range 2o from about 10-'° to 10-5 M, particularly from 10-9 to 10-6 M.
The following IC50 values were determined using the MCH-1 receptor binding test described above:
Compound ~ ~ IC50 value according to ~ Name of substance Example no.
1.44 ~ {6-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-4- ~ 6.8 nM
methyl-quinolin-2-yl}-isopropyl-amine 1.43 ~ 6-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-4- ~ 246 nM
methyl-2-(4-methyl-piperidin-1-yl)-quinoline Some examples of formulations will be described hereinafter, wherein the term "active substance" denotes one or more compounds according to the invention, including their salts. In the case of one of the combinations with one or more active substances described, the term "active substance" also includes the additional active substances.
Example A
Capsules for powder inhalation containing 1 ma active substance 1o Composition:
1 capsule for powder inhalation contains:
active substance 1.0 mg lactose 20.0 mg hard gelatine capsules 50.0 ma 71.0 mg Method of preparation:
The active substance is ground to the particle size required for inhalation.
The ground active substance is homogeneously mixed with the lactose. The mixture is packed into hard gelatine capsules.
Example B
Inhalable solution for Respimat~ containing 1 ma active substance Composition:

1 spray contains:

active substance 1.0 mg benzalkonium chloride 0.002 mg disodium edetate 0.0075 mg 3o purified water ad 15.0 NI

Method of preparation:
The active substance and benzalkonium chloride are dissolved in water and packed into Respimat~ cartridges.
Example C
Inhalable solution for nebulisers containing 1 my active substance Composition:

1 vial contains:

active substance 0.1 g sodium chloride 0.18 g benzalkonium chloride 0.002 g purified water ad 20.0 ml Method of preparation:
The active substance, sodium chloride and benzalkonium chloride are dissolved in water.
2o Example D
Propellant type metered dose aerosol containing 1 ma active substance Composition:
1 spray contains:
active substance 1.0 mg lecithin 0.1 propellant gas ad 50.0 Nl Method of preparation:
3o The micronised active substance is homogeneously suspended in the mixture of lecithin and propellant gas. The suspension is transferred into a pressurised container with a metering valve.

Example E
Nasal spray containing 1 mg active substance Composition:

active substance 1.0 mg sodium chloride 0.9 mg benzalkonium chloride 0.025 mg disodium edetate 0.05 mg purified water ad 0.1 ml Method of preparation:
The active substance and the excipients are dissolved in water and transferred into a corresponding container.
Example F
Injectable solution containing 5 mgi of active substance per 5 ml Composition:

active substance 5 mg 2o glucose 250 mg human serum albumin 10 mg glycofurol 250 mg water for injections ad 5 ml Preparation:
Glycofurol and glucose are dissolved in water for injections (Wfl); human serum albumin is added; active ingredient is dissolved with heating; made up to specified volume with Wfl; transferred into ampoules under nitrogen gas.

Exam~~le G
Injectable solution containing 100 ma of active substance per 20 ml Composition:
active substance 100 mg monopotassium dihydrogen phosphate = KH2P04 12 mg disodium hydrogen phosphate = Na2HP04~2H20 2 mg sodium chloride 180 mg 1o human serum albumin 50 mg Polysorbate 80 20 mg water for injections ad 20 ml Preparation:
Polysorbate 80, sodium chloride, monopotassium dihydrogen phosphate and disodium hydrogen phosphate are dissolved in water for injections (Wfl); human serum albumin is added; active ingredient is dissolved with heating; made up to specified volume with Wfl; transferred into ampoules.
2o Example H
Lyophilisate containing 10 mp of active substance Composition:
Active substance 10 mg Mannitol 300 mg human serum albumin 20 mg Preparation:
3o Mannitol is dissolved in water for injections (Wfl); human serum albumin is added;
active ingredient is dissolved with heating; made up to specified volume with Wfl;
transferred into vials; freeze-dried.

Solvent for lyophilisate:
Polysorbate 80 = Tween 80 20 mg mannitol 200 mg water for injections ad 10 ml Preparation:
Polysorbate 80 and mannitol are dissolved in water for injections (Wfl);
transferred into ampoules.
Example I
Tablets containing 20 ma of active substance Composition:
active substance 20 mg lactose 120 mg maize starch 40 mg magnesium stearate 2 mg Povidone K 25 1 8 mg 2o Preparation:
Active substance, lactose and maize starch are homogeneously mixed; granulated with an aqueous solution of Povidone; mixed with magnesium stearate;
compressed in a tablet press; weight of tablet 200 mg.
Example J
Capsules containing 20 mg active substance Composition:
3o active substance 20 mg maize starch 80 mg highly dispersed silica 5 mg magnesium stearate 2.5 mg Preparation:
Active substance, maize starch and silica are homogeneously mixed; mixed with magnesium stearate; the mixture is packed into size 3 hard gelatine capsules in a capsule filling machine.
Example K
Suppositories containinct 50 mg of active substance Composition:
active substance 50 mg hard fat (Adeps solidus) q.s. ad 1700 mg Preparation:
Hard fat is melted at about 38°C; ground active substance is homogeneously dispersed in the molten hard fat; after cooling to about 35°C it is poured into chilled moulds.
2o Example L
Iniectable solution containing 10 mgi of active substance per 1 ml Composition:
active substance 10 mg mannitol 50 mg human serum albumin 10 mg water for injections ad 1 ml Preparation:
Mannitol is dissolved in water for injections (Wfl); human serum albumin is added;
active ingredient is dissolved with heating; made up to specified volume with Wfl;
transferred into ampoules under nitrogen gas.

Claims (28)

1. Alkyne compounds of general formula I

wherein R1, R2 independently of one another denote H, C1-8-alkyl, C3-7-cycloalkyl or a phenyl or pyridinyl group optionally mono- or polysubstituted by identical or different groups R20 and/or monosubstituted by nitro, while the alkyl or cycloalkyl group may be mono- or polysubstituted by identical or different groups R11, and 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 R1 and R2 form a C3-8-alkylene bridge, wherein a -CH2- group not adjacent to the N atom of the R1R2N group may be replaced -CH=N-, -CH=CH-, -O-, -S-, -SO-, -(SO2)-, -CO-, -C(=CH2)- or -NR13-, while in the alkylene bridge defined hereinbefore one or more H atoms may be replaced by identical or different groups R14, and the alkylene bridge defined hereinbefore 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 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;

W, Z independently of one another denote a single bond or a C1-2-alkylene bridge, while two adjacent C atoms may be joined together with an additional C1-4-alkylene bridge, and one or two C atoms independently of one another may be substituted by one or two identical or different C1-3-alkyl groups, while two alkyl groups may be joined together to form a carbocyclic ring, and Y is selected from the definitions of the partial formulae Y1 to Y9 wherein the groups M, K and L represent a CH group, while one of the groups M, K, L may also represent an N atom, and in the partial formulae Y1 to Y9 one or more C atoms may be substituted independently of one another by R20, and in the partial formulae Y5 and Y6 an NH group may be substituted by C1-4-alkyl, A is selected from among the bivalent cyclic groups phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, naphthyl, tetrahydronaphthyl, indolyl, dihydroindolyl, quinolinyl, dihydroquinolinyl, tetrahydroquinolinyl, isoquinolinyl, dihydroisoquinolinyl, tetrahydro-isoquinolinyl, benzimidazolyl, benzoxazolyl, thienyl, furanyl, benzothienyl or benzofuranyl, while the above-mentioned cyclic groups may be mono-or polysubstituted at one or more C atoms by identical or different groups R20, or in the case of a phenyl ring may also additionally be monosubstituted by nitro, and/or one or more NH groups may be substituted by R21, B has one of the meanings given for Y, A or denotes C1-6-alkyl, C1-6-alkenyl, C1-6-alkynyl, C3-7-cycloalkyl, C5-7-cycloalkenyl, C3-7-cycloalkyl-C1-3-alkyl, C3-7-cycloalkenyl-C1-3-alkyl, C3-7-cycloalkyl-C1-3-alkenyl or C3-7-cycloalkyl-C1-3-alkynyl, wherein one or more C atoms independently of one another may be mono- or polysubstituted by halogen and/or monosubstituted by hydroxy or cyano and/or cyclic groups may be mono- or polysubstituted by identical or different groups R20, 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, - an aromatic heterocyclic 5- or 6-membered group with one or more identical or different heteroatoms selected from N, O and/or S, while the above-mentioned saturated 6- or 7-membered groups may also be present as bridged ring systems with an imino, (C1-44-alkyl)-imino, methylene, (C1-4-alkyl)-methylene or di-(C1-4-alkyl)-methylene bridge, and while the above-mentioned cyclic groups may be mono- or polysubstituted at one or more C atoms by identical or different groups R20, or 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, R11 ~denotes halogen, C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, R15-O-, R15-O-CO-,R15-CO-O-, cyano, R16R17N, R18R19N-CO- or Cy, while in the above-mentioned groups one or more C atoms may be substituted independently of one another by substituents selected from halogen, OH, CN, CF3, C1-3-alkyl, hydroxy-C1-3-alkyl;

R13 ~has one of the meanings given for R17, R14 ~denotes halogen, cyano, 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-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, .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, C1-4-alkylcarbonyl, 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 denoted halogen, hydroxy, cyano, C1-6-alkyl, C2-6-alkenyl, C2-6-alkenyl, C2-6-alkynyl, C3-7-cycloalkyl, C3-7-cycloalkyl-C1-3-alkyl, hydroxy-C1-3-alkyl, R22-C1-3-alkyl or has one of the meanings given for R22, R21 denotes C1-4-alkyl, .omega.-hydroxy-C2-6-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, C1-4-alkoxy-carbonyl, C1-4-alkylsulphonyl, aminosulphonyl, C1-4-alkylaminosulphonyl, di-C1-4-alkylaminosulphonyl or cyclo-C3-6-alkylene-imino-sulphonyl, R22 denotes pyridinyl, phenyl, phenyl-C1-3-alkoxy, cyclo-C3-6-alkyleneimino-C2-4-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-C3-6-alkyl-amino-carbonyl, cyclo-C3-6-alkyleneimino-carbonyl, phenylaminocarbonyl, cyclo-C3-6-alkyleneimino-C2-4-alkyl-aminocarbonyl, 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, phenylcarbonyl, phenylcarbonylamino, phenylcarbonylmethylamino, hydroxy-C2-3-alkylaminocarbonyl, (4-morpholinyl)carbonyl, (1-pyr-rolidinyl)carbonyl, (1-piperidinyl)carbonyl, (hexahydro-1-azepinyl)carbonyl, (4-methyl-1-piperazinyl)carbonyl, methylenedioxy, aminocarbonylamino or C1-4-alkylaminocarbonylamino, while in the above-mentioned groups and radicals, particularly in W, Z, R13 to R22, 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 independently of one another may additionally be monosubstituted by Cl or Br and/or in each case one or more phenyl rings may additionally comprise independently of one another one, two or three substituents selected from the group F, Cl, Br, I, cyano, C1-4-alkyl, C1-4-alkoxy, difluoromethyl, trifluoromethyl, hydroxy, amino, C1-3-Aalkylamino, 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 and/or may be monosubstituted by nitro, and the H atom of any carboxy group present or an H atom bound to an N atom may in each case be replaced by a group which can be cleaved in vivo, the tautomers, the diastereomers, the enantiomers, the mixtures thereof and the salts thereof.

2. Alkyne compounds according to claim 1, characterised in that the groups R1, R2 are selected independently of one another from the group comprising H, C1-6-alkyl, C3-5-alkenyl, C3-5-alkynyl, C3-7-cycloalkyl, hydroxy-C3-7-cycloalkyl, C3-7-cycloalkyl-C1-3-alkyl, (hydroxy-C3-7-cycloalkyl)-C1-3-alkyl, hydroxy-C2-4-alkyl, .omega.-NC-C2-3-alkyl, C1-4-alkoxy-C2-4-alkyl, hydroxy-C1-4-alkoxy-C2-4-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, pyrrolidin-3-yl, N-(C1-4-alkyl)-pyrrolidin-3-yl, pyrrolidinyl-C1-3-alkyl, N-(C1-4-alkyl)-pyrrolidinyl-C1-3-alkyl, piperidin-3-yl, piperidin-4-yl, N-(C1-4-alkyl)-piperidin-3-yl, N-(C1-4-alkyl)-piperidin-4-yl, piperidinyl-C1-3-alkyl, N-(C1-4-alkyl)-piperidinyl-C1-3-alkyl, tetrahydropyran-

3-yl, tetrahydropyran-4-yl, tetrahydrofuran-2-ylmethyl, tetrahydrofuran-3-ylmethyl, phenyl, phenyl-C1-3-alkyl, pyridyl or pyridyl-C1-3-alkyl, while in the above-mentioned groups and radicals one or more C atoms may be mono- or polysubstituted independently of one another by F, C1-3-alkyl or hydroxy-C1-3-alkyl, and/or one or two C atoms independently of one another may be monosubstituted by Cl, Br, OH, CF3 or CN, and the phenyl or pyridyl group may be mono- or polysubstituted by identical or different groups R20, or in the case of a phenyl group may also additionally be monosubstituted by nitro, and the group R20 has the meanings given in claim 1.
3. Alkyne compounds according to claim 1, characterised in that R1 and R2 together with the N atom to which they are bound form a heterocyclic group which is selected from the meanings pyrrolidine, piperidine, piperazine, wherein the free imine function is substituted by R13, and morpholine, while one or more H atoms may be replaced by identical or different groups R14, and/ or the heterocyclic groups specified 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 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;
and the groups R13, R14 and the group Cy are defined as in claim 1.

4. Alkyne compounds according to one or more of the preceding claims, characterised in that Z denotes a single bond or ethylene and W denotes a single bond.

5. Alkyne compounds according to one or more of the preceding claims, characterised in that the group Y is selected from among the partial formulae wherein the groups M, K and L represent a CH group, while one of the groups M, K, L may also represent an N atom, and in the partial formulae Y1, Y2, Y6 one or more CH groups may be substituted independently of one another by R20, and in the partial formula Y6 a NH group may be substituted by C1-4-alkyl, while R20 is defined as in claim 1.

6. Alkyne compounds according to claim 5, characterised in that the group Y
denotes a quinoline group according to partial formula Y1, wherein the groups M, K and L denote a CH group, and in the quinoline group one or more CH
groups may be substituted independently of one another by R20, where R20 is defined as in claim 1.

7. Alkyne compounds according to one or more of the preceding claims, characterised in that the group A is selected from among the bivalent cyclic groups phenyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, which may be mono- or polysubstituted at one or more C atoms by identical or different groups R20, or in the case of a phenyl ring may also additionally be monosubstituted by nitro, and R20 has the meaning given in claim 1.

8. Alkyne compounds according to one or more of the preceding claims, characterised in that the group B is selected from phenyl, cyclohexenyl, pyridyl, thienyl and furanyl, and the above-mentioned cyclic groups may be mono- or polysubstituted at one or more C atoms by identical or different groups R20, or in the case of a phenyl group may also additionally be monosubstituted by nitro, and R20 has the meanings given in claim 1.

9. Alkyne compounds according to one or more of the preceding claims, characterised in that Y denotes A has a meaning selected from B denotes phenyl, cyclohexenyl, pyridyl, thienyl and furanyl, preferably phenyl, while Y and A are unsubstituted or monosubstituted by R20, and B is unsubstituted or mono-, di- or trisubstituted independently of one another by R20, or in the case of a phenyl ring may also additionally be monosubstituted by nitro, and wherein R20 has the meaning given in claim 1.

10. Alkyne compounds according to one or more of the preceding claims, characterised in that R20 denotes F, Cl, Br, I, OH, cyano, methyl, difluoromethyl, trifluoromethyl, ethyl, n-propyl, iso-propyl, amino, acetyl, methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, n-propoxy or iso-propoxy, while substituents R20 which occur several times may have identical or different meanings.

11. Physiologically acceptable salts of the alkyne compounds according to one or more of claims 1 to 10.

12. Composition, containing at least one alkyne compound according to one or more of claims 1 to 10 and/ or a salt according to claim 11, optionally together with one or more physiologically acceptable excipients.

13. Pharmaceutical compositions, containing at least one alkyne compound according to one or more of claims 1 to 10 and/ or a salt according to claim 11, optionally together with one or more inert carriers and/or diluents.

14. Use of at least one alkyne compound according to one or more of claims 1 to and/ or a salt according to claim 11 for influencing the eating behaviour of a mammal.

15. Use of at least one amide compound according to one or more of claims 1 to and/or a salt according to claim 11, for reducing the body weight and/ or for preventing an increase in the body weight of a mammal.

16. Use of at least one alkyne compound according to one or more of claims 1 to 10 and/or a salt according to claim 11 for preparing a pharmaceutical composition with an MCH-receptor-antagonistic activity.

17. Use of at least one alkyne compound according to one or more of claims 1 to 10 and/or a salt according to claim 11 for preparing a pharmaceutical composition which is suitable for preventing and/or treating symptoms and/or diseases which are caused by MCH or are otherwise causally connected with MCH.

18. Use of at least one alkyne compound according to one or more of claims 1 to 10 and/or a salt according to claim 11 for preparing a pharmaceutical composition which is suitable for preventing and/or treating metabolic disorders and/or eating disorders, particularly obesity, bulimia, bulimia nervosa, cachexia, anorexia, anorexia nervosa and hyperphagia.

19. Use of at least one alkyne compound according to one or more of claims 1 to 10 and/or a salt according to claim 11 for preparing a pharmaceutical composition which is suitable for preventing and/or treating 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.

20. Use of at least one alkyne compound according to one or more of claims 1 to and/or a salt according to claim 11 for preparing a pharmaceutical composition which is suitable for preventing and/or treating hyperlipidaemia, 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.

21. Use of at least one alkyne compound according to one or more of claims 1 to 10 and/or a salt according to claim 11 for preparing a pharmaceutical composition which is suitable for preventing and/or treating micturition disorders, such as for example urinary incontinence, hyperactive urinary bladder, urgency, nycturia and enuresis.

22. Use of at least one alkyne compound according to one or more of claims 1 to 10 and/or a salt according to claim 11 for preparing a pharmaceutical composition which is suitable for preventing and/or treating dependencies and/or withdrawal symptoms.

23. Process for preparing a composition or a pharmaceutical composition according to one or more of claims 12, 13 and 16 to 22, characterised in that at least one alkyne compound according to one or more of claims 1 to 10 and/or a salt according to claim 11 is incorporated in one or more inert carriers and/or diluents by a non-chemical method.

24. Pharmaceutical composition, containing a first active substance which is selected from the alkyne compounds according to one or more of claims 1 to 10 and/or a salt according to claim 11, 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, 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.

25. Process for preparing alkyne compounds of formula A.5 R1R2N-Y-C.ident.C-W-A-B (A.5) while in formulae A.1, A.2, A.3, A.4 and A.5 R1, R2, Y, W, A and B have one of the meanings given in claims 1 to 10, wherein a halogen compound of formula A.1 HO-Y-Hal (A.1) wherein Hal denotes chlorine, bromine or iodine, preferably bromine or iodine, is reacted with an alkyne compound of formula A.2 H-C.ident.C-W-A-B (A.2) in the presence of a suitable palladium catalyst, a suitable base and copper(I)iodide in a suitable solvent, and the compound of formula A.3 obtained HO-Y-C.ident.C-W-A-B (A.3) is reacted with a suitable halogenating agent to form the halide derivative A.4 in which Hal' denotes Cl, Br or I, Hal'-Y-C=C-W-A-B (A.4) which is further reacted with an amine of formula H-NR1R2 to form the end product A.5.

26. Process for preparing alkyne compounds of formula B.5 R1R2N-Y-Z-C.ident.C-A-B (B.5) while in formulae B.1, B.2, B.3, B.4 and B.5 R1, R2, Y, Z, A and B have one of the meanings given in claims 1 to 10, wherein a halogen compound of formula B.1 Hal-A-B (B.1) wherein Hal denotes chlorine, bromine or iodine, preferably bromine or iodine, is reacted with an alkyne compound of formula B.2 HO-Y-Z-C.ident.C-H (B.2) in the presence of a suitable palladium catalyst, a suitable base and copper(I)iodide in a suitable solvent, and the resulting compound of formula B.3 HO-Y-Z-C.ident.C-A-B (B.3) is reacted with a suitable halogenating agent to form the halide derivative B.4 in which Hal' denotes Cl, Br or I, Hal'-Y-Z-C.ident.C-A-B (B.4) which is reacted further with an amine of formula H-NR'R2 to form the end product B.5.

27. Process for preparing alkyne compounds of formula C.3 R1R2N-Y-C.ident.C-W-A-B (C.3) while in formulae C.1, C.2 and C.3 R1, R2, Y, W, A and B have one of the meanings given in claims 1 to 10, wherein a halogen compound of formula C.1 R1R2N-Y-Hal (C.1) wherein Hal denotes chlorine, bromine or iodine, preferably bromine or iodine, is further reacted with an alkyne compound of formula C.2 H-C.ident.C-W-A-B (C.2) in the presence of a suitable palladium catalyst, a suitable base and copper(I)iodide in a suitable solvent to yield the end product C.3.

28. Process for preparing alkyne compounds of formula D.3 R1R2N-Y-Z-C=C-A-B (D.3) while in formulae D.1, D.2 and D.3 R1, R2, Y, Z, A and B have one of the meanings given in claims 1 to 10, wherein a halogen compound of formula D.2 Hal-A-B (D.2) wherein Hal denotes chlorine, bromine or iodine, preferably bromine or iodine, is reacted with an alkyne compound of formula D.1 R1R2N-Y-Z-C=C-H (D.1) in the presence of a suitable palladium catalyst, a suitable base and copper(I)iodide in a suitable solvent to form the end product D.3.