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EP1740572A1 - Novel alkyne compounds with an mch-antagonistic action and medicaments containing said compounds - Google Patents

Novel alkyne compounds with an mch-antagonistic action and medicaments containing said compounds

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Publication number
EP1740572A1
EP1740572A1 EP20050716558 EP05716558A EP1740572A1 EP 1740572 A1 EP1740572 A1 EP 1740572A1 EP 20050716558 EP20050716558 EP 20050716558 EP 05716558 A EP05716558 A EP 05716558A EP 1740572 A1 EP1740572 A1 EP 1740572A1
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alkyl
mmol
phenyl
group
molecular
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German (de)
French (fr)
Inventor
Dirk Stenkamp
Stephan Georg Mueller
Philipp Lustenberger
Thorsten Lehmann-Lintz
Leo Thomas
Marcus Schindler
Gerald Jürgen ROTH
Klaus Rudolf
Ralf R. H. Lotz
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Boehringer Ingelheim International GmbH
Boehringer Ingelheim Pharma GmbH and Co KG
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Boehringer Ingelheim International GmbH
Boehringer Ingelheim Pharma GmbH and Co KG
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    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D213/00Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28Radicals substituted by singly-bound oxygen or sulfur atoms
    • C07D213/30Oxygen atoms
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D213/00Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36Radicals substituted by singly-bound nitrogen atoms
    • C07D213/38Radicals substituted by singly-bound nitrogen atoms having only hydrogen, hydrocarbon radicals attached to the substituent nitrogen atom
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D213/00Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with heteroatoms or with carbon atoms having three bonds to hetero atoms, with at the most one to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/61Halogen atoms or nitro radicals
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D405/00Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D409/00Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D409/00Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings

Abstract

The invention relates to alkyne compounds of general formula (I), in which the groups and radicals A, B, W, X, Y, Z, R1 and R2 are defined as cited in claim 1. The invention also relates to medicaments containing at least one inventive alkyne. As a result of the antagonistic action against the MCH-receptor, the inventive medicaments are suitable for treating metabolic disorders and/or eating disorders, in particular adiposity and diabetes.

Description

New alkyne compounds with MGH-antagonistic activity and pharmaceutical compositions containing these compounds

The present invention relates to novel alkyne compounds, their physiologically tolerable salts and their use as MCH antagonists and their use for the preparation of a medicament with for the prophylaxis and / or treatment of symptoms and / or diseases caused by MCH or MCH is available in another causally connected. Another object of this invention relates to the use of a compound of the invention for influencing the eating behavior and for reducing body weight and / or for preventing an increase in 'body weight of a mammal. Further, compositions and medicaments containing a compound of the invention, respectively, as well as processes for their preparation object of this invention. Further objects of this invention relate to methods for preparing the compounds according to the invention.

Background of the Invention The intake of food and its conversion in the body for all living creatures is an essential part of life. Therefore, deviations in the intake and conversion of food generally lead to problems and diseases. The change in human food and dietary habits, particularly in industrialized countries, has (called "obesity", obesity or obesity) favors the formation of morbid overweight in recent decades Obesity leads in those affected directly to restricted mobility and a reduction in the. quality of life. to make matters worse, that .Adipositas often leads to other diseases result such, diabetes, dyslipidemia, hypertension, atherosclerosis and coronary heart disease. In addition, own the high body weight leads to increased stress on the musculoskeletal system, causing chronic pain may lead and diseases such as arthritis or osteoarthritis. Thus, obesity is a serious health problem for society.

The term obesity means an excess of adipose tissue in the body. In this connection, obesity is fundamentally as the increased level seen in body fat content, which leads to a health risk. There is no sharp distinction between normal weight and suffering from obesity individuals, however, associated with obesity health risk increases probably continuously with increasing obesity. For reasons of simplification, in the context of the present invention, individuals with a body weight index (BMI = body mass index), defined (in meters) squared than that measured in kilogram of body weight divided by the height, above the value 25, especially above 30, as viewed from obesity suffering.

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

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

Studies of the function of MCH in animal models provide good indications for a role of the peptide in regulating the energy balance, that is, change in metabolic activity and food intake [1, 2]. For example, the feed intake is increased as compared to control animals after intraventricular administration of MCH in rats. In addition, transgenic rats which produce more MCH react as control animals, after administration of a high fat diet with gaining significantly more weight than animals without an experimentally altered MCH level. It was also determined that a positive correlation between phases of increased desire for food and the quantity of MCH mRNA in the hypothalamus of rats. Of particular significance with regard to the function of MCH but experiments with MCH "knock out" mice. A loss of the neuropeptide are resulting in lean animals with a reduced fat mass, which take significantly less food than control animals. The anorectic effects of MCH are in rodents probably about the G αs - coupled MCH-1R mediated [3-6], daim contrast to primates, ferrets and dogs, so far no second MCH receptor has been demonstrated in rodents loss of the MCH-1R leads to mice to "knock out". a lower fat mass, an increased energy conversion and in high fat diet no weight increase compared with control animals. Another indication of the importance of the MCH system in regulating the energy balance comes from experiments with a receptor antagonist (SNAP-7941) [3]. In long-term experiments, the treated animals significantly this antagonist to lose weight.

In addition to its anorectic effect SNAP-7941 nor more anxiolytic and antidepressant effects are obtained [3] in behavioral experiments on rats with the MCH-1 R antagonist. Therefore, are clear indications that the MCH before-MCH-1 R system is involved not only in regulating the energy balance but also of affectivity.

Literature:

1Q, D., et al., A role for melanin-concentrating hormone in the central regulation of feeding behavior. Nature, 1996. 380 (6571): p. 243-7.

2. Shimada, M., et al., Mice lacking melanin-concentrating hormone are hypophagic and lean. Nature, 1998. 396 (6712): p. 670-4.

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

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

5. Marsh, D., Et al., Melanin-concentrating hormone 1 receptor-deficient mice are lean, hyperactive, and hyperphagic and have altered metabolism. Proc Natl Acad Sci USA, 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 Amili compounds are proposed as MCH antagonists. Thus, in WO 01/21577 are (Takeda) Compounds of formula in which Ar 1 is a cyclic group, X denotes a spacer, Y is a bond or a spacer, Ar 2 are independently H or a hydrocarbon group are an aromatic ring which may be condensed with a non-aromatic ring, R 1 and R wherein R 1 and R 2 together with the adjacent N atom may form an N-containing hetero ring and R2 with Ar may form a spirocyclic ring and R may form an N-containing hetero ring together with the adjacent N atom and Y, as MCH antagonists for the treatment of inter alia obesity.

in WO 01/82925 also be (Takeda) also describes compounds of formula mean in which Ar 1 is a cyclic group, X and Y represent spacer groups, Ar represents an optionally substituted condensed polycyclic aromatic ring, R 1 and R 2 are independently H or a hydrocarbon group, wherein R 1 and R 2 together with the adjacent N atom may form an N-containing heterocyclic ring, and R 2 together with the adjacent N atom and Y may form an N-containing hetero ring, as MCH antagonists for the treatment of obesity, inter alia.

In WO 2004/024702 carboxylic acid amide compounds of formula l

Proposed as MCH antagonists in which Y, A and B form a cyclic group and X, Z, and W may represent bridges or bonds.

In WO 04/039780 A1 alkyne compounds of the formula I

, As MCH antagonists in which Y, A and B form a cyclic group and X, Z, and W may represent bridges or bonds. Among other things, the following substances are called:

(2- {4- [5- (4-chloro-phenyl) -pyridin-2-ylethynyl] -2-methyl-phenoxy} -ethyl) -methyl-prop-2-ynyl amine, (2- {5- [5- (4-chloro-phenyl) -pyridin-2-ylethinyI] indol-1-yl} -ethyl) -cyclopropylmethyl-prop-2-inyI- amine,

{4_ [6- (4-chloro-phenyl) -quinoline-2-ylethynyl] -benzyl} -methyl- (tetrahydro-pyran-4-yl) -amine, allyl (2- {4- [5- (4 -chloro-phenyl) -pyridin-2-ylethynyl] -phenoxy} -ethyl) -cyclopropylmethyl-amine, allyl (2- {4- [5- (4-chloro-phenyl) -pyridin-2-ylethynyl] -2 methyl-phenoxy} -ethyl) -cyclopropylmethyl- amine, allyl (2- {5- [5- (4-chloro-phenyl) -pyridin-2-ylethynyl] -indol-1-yl} -ethyl) -cyclopropylmethyl amine.

In WO 04/039764 A1 amide compounds of the formula I

in which Y, A and B form a cyclic group, and X is an alkylene bridge, Z may represent a bridge or bond, and W is selected from the group consisting of -CR 6a R 6b -O-, -CR 7a = CR 7c -, - CR 6a R 6b -NR 8 -, -CR 7a R 7 -CR 7c R 7d - and -NR 8 -CR 6a R 6b - as MCH antagonists.

OBJECT OF THE INVENTION

The present invention is based on the object to identify new alkyne compounds, particularly those which have a particularly high activity as MCH antagonists. it is an object of this invention is also to provide new alkyne compounds that allow that to influence the eating habits of mammals and achieve particularly in mammals, a reduction in body weight and / or to prevent an increase in body weight.

Further, it is an object of the present invention to provide new pharmaceutical compositions which are suitable for the prophylaxis and / or treatment of symptoms and / or diseases caused by MCH or are otherwise causally connected with MCH. In particular, this invention has for its object, medicines used to treat metabolic disorders, such as to provide obesity and / or diabetes and conditions associated with obesity and diabetes diseases and / or disorders. Other objects of the present invention relate to demonstrating advantageous uses of the compounds according to the invention. Also an object of this invention is to provide a process for the preparation of alkyne compounds of the invention prepared. Other objects of the present invention will become apparent to the skilled man directly from the foregoing and following remarks.

Object of the Invention A first object of the present invention are alkyne compounds of general formula I

in the

R 1 C. 3 6 -AIkenyl, C. 3 6 alkynyl, (hydroxy-Cs-T -cycloalkyO Ci-js-alkyl, oxa-C 4-7 - cycloalkyl, dihydroxy-C 3 7 alkyl, wherein the angegenben groups may be mono- or polysubstituted by substituents. independently selected from the group consisting of halogen, hydroxy, cyano, C ^ alkyl, C 3 7 cycloalkyl, C 3 -. 7 -cycloalkyl-Cι- 3 alkyl, Cι- 4 alkoxy-C 1 - 4 alkyl, C-ι- alkoxy, C ^ alkenyl, C M -alkynyl, amino, Cι- 4 -alkyl-amino and di- (C 1 - alkyl) - amino, wherein the alkyl, alkoxy, Cylcoalkyl groups may have one or more identical or different substituents selected from halogen and hydroxy; and

R 2, independently of R 1 one of the meanings given above for R 1, or R 2 has a meaning selected from the group consisting of H, Cι.8 -alkyl, C. 3 7 cycloalkyl or optionally substituted by identical or different radicals R 20 mono- or polysubstituted and / or by nitro substituted Phenyi- or pyridinyl, wherein said alkyl or cycloalkyl group with identical or different radicals R 11 mono- or polysubstituted can, and wherein a -CH 2 group in position 3 or 4 of a 5-, 6 or 7-gIiedrigen cycloalkyl group by -O-, -S- or -NR 13 - may be replaced, or the radicals R 1, R 2 form together with the N-atom to which they are bonded, a heterocyclic group selected from the meanings - dihydroxy-cyclo-C. 4 7 alkylene-imino, - (hydroxy-C ^ -alky-hydroxy-cyclo-Ca ^ alkylene-imino, - (hydroxy-3 Cι- alkyl) -cyclo-C 3 H 7 alkylene-imino, and in. the last importance Cι- 3 alkyl group is substituted by one or more identical or different Cι- 3 alkyl groups together to form a C 3 - can be connected - 7 -Cyloalkyl group; wherein said heterocyclic mono- groups or can be multiply substituted with substituents independently selected from the group consisting of halogen, hydroxy, cyano, C ^ alkyl, C3. 7, cycloalkyl, Cs-r-cycloalkyl-C-ι- 3 alkyl, Cι- 4 alkoxy Cι- 4 -AlkyI, C M alkoxy, C 1. 4, alkenyl, C-ι- 4 -alkynyl, amino, C ^ -alkyl-amino and di- (C 1 - 4 alkyl) amino, wherein alkyl, alkoxy, Cylcoalkyl groups may have one or more identical or different substituents selected from halogen and hydroxy;

X is a C ^ alkylene bridge, wherein in the significance C. 2 4 alkylene one or two C atoms may be monosubstituted with R 10, or a Cs ^ -alkylene bridge, in which a non-N-with the N-atom of the R 1 R 2 group directly adjacent -CH 2 -CH 2 group by -CH = CH-, - is replaced with the above-stated meanings for X selected a substituent - C≡C-, -CH 2 -O-, -CH 2 -S- or -CH 2 -NR 4 from C. 2 6 alkenyl, C 2 - 6 alkynyl, C. 3 7 cycloalkyl, and C ^ cycloalkyl-C L s-alkyl sowie- independently one, two or three identical or different C ^ may have alkyl substituents, while two alkyl groups to form a 3 to 7-membered alkyl, or a - and an alkenyl group may be bonded together to form a 5 to 7-membered cyclic group, and

W, Z are each independently a single bond or a C - ^ - alkylene bridge, wherein two adjacent C atoms with an additional C ^ alkylene bridge may be joined together, and where one or two C atoms independently of one another by one or two identical or different d-3 alkyl residues can be substituted, wherein two alkyl groups may be joined together to form a carbocyclic ring, and

Y, A are independently selected from the group of. bivalent cyclic groups phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, naphthyl, tetrahydronaphthyl, indolyl, dihydroindolyl, quinolinyl, dihydroquinolinyl, tetrahydroquinolinyl, isoquinolinyl, Dihydroisochinoiinyl, tetrahydro-isoquinolinyl, benzimidazolyl, benzoxazolyl, chromanyl, chromen-4-onyl, thienyl, furanyl, benzothienyl or benzofuranyl, where the cyclic groups mentioned mono- or polysubstituted at one or more C atoms by identical or different radicals R 20, in the case of a phenyl ring may also additionally be monosubstituted by nitro, and / or one or more NH groups with R 21 may be substituted,

B or one of the meanings given for Y, A

Cι.6 alkyl, Ci-e-alkenyl, Cι- 6 alkynyl, C. 3 7 cycloalkyl, C 5-7 cycloalkenyl, C. 3 7 -Cycioalkyl Cι--3 alkyl, Cs-s-cycloalkenyl-Cis alkyl, C 3rd 7 cycloalkyl-Cι- 3 - alkenyl or C. 3 7 cycloalkyl-Cι- 3 alkynyl group, wherein one or more C atoms independently of one another mono- or polysubstituted easily installed by halogen and / or by hydroxy or cyano and / or cyclic groups or polysubstituted by identical or different radicals R 20 may be substituted,

Cy is a carbocyclic 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 one N, O or S atom as heteroatom, - a saturated or unsaturated 5- to 7-membered heterocyclic group having 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 hetero atoms selected from N, O and / or S, wherein the above-mentioned saturated 6 - or 7-membered groups as bridged ring systems with an imino, (C 1 - 4 alkyl) -imino-, methylene, (Cι- 4 alkyl) methylene or di- (C 1 - 4 -atkyl may be present) -methylene bridge, and wherein the previously genann mono- th cyclic groups or, in the case of a phenyl group may also additionally be monosubstituted one or more NH groups may be substituted with R 21 polysubstituted at one or more C atoms by identical or different radicals R 20 by nitro, and / or,

R 4 is H, C ^ alkyl, C 3rd 7 cycloalkyl, or C ^ -cycloalkyl-d-alkyl,

R 10 is hydroxy, ω-hydroxy-C ,.3 alkyl,

R 11 is halogen, C ^ alkyl, C 2nd 6 -alkenyl, C 2 - 6 alkynyl, R 15 -O-, R 15 -O-CO-, R 15 -CO- O-, cyano, R 16 R 17 N-, R 18 R 19 N-CO- or Cy, wherein, in the above-mentioned groups one or more C atoms independently of one another by substituents selected from halogen, OH, CN, CF 3, C-ι- 3 -alkyl, hydroxy-C-ι- 3 alkyl mono- may be mono- or polysubstituted;

R 13 is as defined for R 17,

R 15 is H, d-4 alkyl, C 3rd 7 cycloalkyl, C ^ C ^ -CycIoalkyl-s-alkyl, phenyl, phenyl C-ι- 3 alkyl, pyridinyl or pyridinyl-C-ι- 3 alkyl, R 16 is H, Ci-e--alkyl, C third 7 cycloalkyl, C 3-7 cycloalkyl-d- 3 -alkyl, C. 4 7 cycloalkenyl, C. 4 7 cycloalkenyl-d-3-alkyl, ω-hydroxy-C 2 - 3 -alkyl, ω- (C 1 - 4 alkoxy) - C. 2 3 alkyl, amino-C 2 - 6 alkyl, Cι- 4 alkyl-amino-C. 2 6 alkyl, di (C 1 - 4 alkyl) - amino-C. 2 6 alkyl, or cyclo C 3 - 6 -alkylenimino-C 2 - 6 alkyl,

R 17 is as defined for R 16 or phenyl, phenyl-d- C3 alkyl, pyridinyl, d- alkylcarbonyl, hydroxycarbonyl-d-3-alkyl, Cι- alkoxycarbonyl, C ^^ C ^ alkoxycarbonyl-s- alkyl.d ^ -alkylcarbonylamino-C M-alkyl, N- (C 1-4 -AIkylcarbonyl) -N- (C 1-4 -alkyl) -amino-C 2 - 3 alkyl, C ^ alkylsulfonyl, d- alkylsulfonylamino C. 2 3 -alkyl or N- (. 1 C 4 alkylsulfonyl) -N (-C 1-4 alkyl) amino-C 2 - 3 alkyl;

R 18, R 19 are independently H or Cι- 6 alkyl,

R 20 is halogen, hydroxy, cyano, de-alkyl, C. 2 6 -alkenyl, C. 2 6 alkynyl, C 3 - 7 - cycloalkyl, C 3 - 7 cycloalkyl-d-C3 alkyl, hydroxy-d- 3 alkyl, R -d- 3 alkyl, or one of the meanings given for R 22,

R 21 is C ^ alkyl, ω-hydroxy-C. 2 6 alkyl, ω-C - 4 alkoxy-C. 2 6 alkyl, ω-d- alkyl amino-C 2 - 6 alkyl, ω-di- (C 1-4 -alkyl) -amino-C. 2 6 alkyl, ω-cyclo-C. 3 6 - alkyleneimino-C 2 - 6 alkyl, phenyl, phenyl-d- C3 alkyl, Cι- 4 alkyl-carbonyl, d-4 alkoxy-carbonyl, d- 4 alkylsulfonyl, aminosulfonyl, d - r alkylaminosulfonyl , di-d ^ alkylaminosulfonyl or cyclo-C. 3 6 alkylene- imino-sulfonyl,

R 22 is pyridinyl, phenyl, phenyl-d- 3 alkoxy, cyclo C 3 - 6 -alkylenimino C-2 - - alkoxy, OHC-, HO-N = HC-, C 1 - 4 alkoxy-N = HC -, d- alkoxy, C ^ - alkylthio, carboxy, d- 4 alkylcarbonyl, Cι- 4 alkoxycarbonyl, aminocarbonyl, d ^ alkylaminocarbonyl, di- (C-ι- 4 -a kyl!) -aminocarbonyl, cyclo -C 3 - 6 alkyl-amino-carbonyl, cyclo-C. 3 6 -alkylenimino-carbonyl, phenylaminocarbonyl, cyclo-Cs-e-alkyleneimino-C ^ alkyl-aminocarbonyl, d-4 alkyl-sulfonyl, C ^ alkyl sulfinyl, C ^ alkyl-sulfonylamino, amino, C | - 4 alkylamino, di- (C - alkyl) amino, Cyclo- C. 3 6 -alkylenimino, phenyl-Cι- 3 alkylamino, N- (Cι- 4 alkyl) -phenyl-C. 1 3 alkyl amino, acetylamino, propionylamino, phenylcarbonyl, phenylcarbonylamino, Phenylcarbonylmethylamino, hydroxy-C. 2 3 - alkylaminocarbonyl, (4-morpholinyl) carbonyl, (I-pyrrolidinyl) carbonyl, (1- piperidinyl) carbonyl, (hexahydro-l-azepinyl) carbonyl, (4-methyl-1-piperazinyl) carbonyl, methylenedioxy, aminocarbonylamino or d ^ - alkylaminocarbonylamino, it being possible in the above-mentioned groups and radicals, particularly in W, X, Z, R 4, R 10, R 13 and R 15 to R 22, in each case one or more C atoms may additionally be mono- or polysubstituted by F and / or one or two C atoms independently of one another additionally be monosubstituted by CI or Br and / or in each case one or more phenyl rings independently of one another additionally containing one, two or three substituents selected from the group F, Cl, Br, I, cyano, d- C4 alkyl, C ^ alkoxy, Difiuormethyl-, trifluoromethyl, hydroxy, amino, d- 3 -Aalkylamino-, di- (d- C3 alkyl) amino, acetylamino, aminocarbonyl -, difluoromethoxy, trifluoromethoxy, amino-3 Cι- alkyl, ds-alkylamino-d- C3 alkyl and di- (C 1 3 alkyl.) amino-C 1 - 3 alkyl may have and / or egg n-tuple may be substituted by nitro, and the H atom of any carboxy group or bound to an N atom H atom may each be replaced by a cleaved in vivo radical,

the tautomers, the diastereomers, the enantiomers, the mixtures thereof and

salts

(2- {4- [5- (4-chloro-phenyl) -pyridin-2-ylethynyl] -2-methyl-phenoxy} -ethyl) -methyl-prop-2-ynyl: whereby the following compounds according to the invention are not covered with - amine,

(2- {5- [5- (4-chloro-phenyl) -pyhdin-2-yIethinyl] indol-1-yl} -ethyl) -cyclopropylmethyl-prop-2-ynyl amine,

{4- [6- (4-chloro-phenyl) -quinolin-2-ylethynyl] -benzyl} -methyl- (tetrahydro-pyran-4-yl) -amine, allyl (2- {4- [5- ( 4-chloro-phenyl) -pyridin-2-yIethinyl] -phenoxy} -ethyl) -cyclopropylmethyl-amine,

Allyl (2- {4- [5- (4-chloro-phenyl) -pyridiή-2-ylethynyl] -2-methyl-phenoxy} -ethyl) -cycIopropylmethyl- amine,

Allyl (2- {5- [5- (4-chloro-phenyl) -pyridin-2-ylethynyl] -indol-1-yl} -ethyl) -cyclopropyImethyl-amine.

The compounds according to the present invention, including the physiologically acceptable salts, possess in comparison to known structurally similar compounds, a special effect as antagonists of the MCH receptor, particularly the MCH-1 receptor, and exhibit very good affinities in MCH receptor binding studies. Moreover, the compounds of the invention have a high to very high selectivity to the MCH receptor. In general, the compounds of the invention have a low toxicity, a good oral absorbability and intracerebral transitivity, particularly brain accessibility.

The invention also relates to the compounds in the form of the individual optical isomers, mixtures of the individual enantiomers or racemates, in the form of the tautomers and in the form of the free bases or the corresponding acid addition salts with pharmacologically acceptable acids. Also included in the subject of this invention, the inventive compounds, including their salts, in which one or more hydrogen atoms are replaced by deuterium.

Furthermore, the physiologically acceptable salts of the present invention alkyne compounds described above and below are also an object of this invention.

Also covered by this invention are compositions containing at least one inventive alkyne compound and / or a salt according to the invention optionally together with one or more physiologically acceptable excipients.

Furthermore, medicaments comprising at least one inventive alkyne compound and / or a salt according to the invention optionally together with one or more inert carriers and / or diluents object of the present invention.

Also an object of this invention is the use of at least one alkyne compound according to the invention and / or a salt of the invention for influencing the eating behavior of a mammal.

Furthermore, the use of at least one alkyne compound according to the invention and / or a salt of the invention for reducing body weight and / or for preventing an increase in body weight of a mammal is an object of this invention. Also an object of the present invention is the use of at least one alkyne compound according to the invention and / or a salt according to the invention for preparing a medicament with an MCH receptor-antagonistic activity, in particular antagonistic with MCH-1 receptor activity.

In addition, an object of this invention, the use of at least one alkyne compound according to the invention and / or a salt for preparing a medicament according to the invention, which is for the prophylaxis and / or treatment of symptoms and / or diseases caused by MCH or MCH in a is another causal connection are suitable.

Another object of this invention is 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 nervosa for the prophylaxis and / or treatment of metabolic disorders and / or eating disorders, particularly obesity, bulimia, bulimia, cachexia is, anorexia, anorexia nervosa and hyperphagia, suitable.

Also an object of this invention is the use of at least one alkyne compound according to the invention and / or a salt according to the invention for the manufacture of a medicament for the prophylaxis and / or treatment of conditions associated with obesity diseases and / or disorders, particularly diabetes, especially type II diabetes, diabetic complications, including diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, impaired glucose tolerance, encephalorrhagia, heart failure, cardiovascular disease, especially atherosclerosis and hypertension, arthritis and gonitis is suitable.

Moreover, the present invention has the use of at least one alkyne compound according to the invention and / or a salt according to the invention for the manufacture of a medicament for the prophylaxis 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 is appropriate to the object. Furthermore, an object of this invention is the use of at least one alkyne compound according to the invention and / or a salt according to the invention for preparing a medicament which is for the prophylaxis and / or treatment of micturition disorders such as urinary incontinence, overactive bladder, urgency, nocturia and enuresis suitable ,

Moreover, the present invention has the use of at least one alkyne compound according to the invention and / or a salt according to the invention for preparing a medicament which is suitable for the prophylaxis and / or treatment of dependencies and / or withdrawal symptoms, the subject.

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

Another object of this invention is a pharmaceutical composition containing a first active ingredient which is selected from the novel alkyne compounds and / or the corresponding salts, as well as a second active ingredient which is selected from the group consisting of active substances for the treatment of diabetes, active substances for the treatment of diabetic complications, active substances for the treatment of obesity, preferably other than MCH antagonists, active substances for the treatment of hypertension, agents for the treatment of Dyslipidemia or hyperlipidemia, including arteriosclerosis, active substances for the treatment of arthritis, active substances for

Treatment of anxiety states and active substances for the treatment of depression, optionally together with one or more inert carriers and / or diluents.

Furthermore betriftt an object of this invention is a process for the preparation of alkyne compounds of formula A.5

R 1 R 2 NXYC --CWAB (A.5)

wherein in the formulas A.1, A.2, A.3, A.4 and A.5 R 1, R 2, X, Y, W, A and B have one of the meanings given above and hereinafter, wherein a halogen compound of formula A.1

HO-X-Y-Hal (A.1)

wherein Hal is chlorine, bromine or iodine, preferably bromine or iodine, is with an alkyne compound of formula A.2

HC £ -WAB (A2)

in the presence of a suitable palladium catalyst, a suitable base and copper (I) iodide in a suitable solvent is reacted, and

the compound of formula A.3 obtained

HO-XYC - CWAB (A.3)

with methanesulfonyl chloride (MsCl) is converted to the methanesulphonate derivative A.4,

MsO-XYC- -WAB (A.4)

which is further reacted with an amine of formula H-NR 1 R 2 to the end product A.5.

Another object of this invention is a process for the preparation of alkyne compounds of formula B.5

R 1 R 2 NXYZC --CAB (B.5)

wherein, X, Y, Z, A and B have one of the meanings given hereinbefore and in the formulas B.1, B.2, B.3, B.4 B.5 and R 1, R 2,

wherein a halogen compound of formula B.1

Hal-AB (B.1)

wherein Hal is chlorine, bromine or iodine, preferably bromine or iodine, is with an alkyne compound of formula B.2

HO-XYZC - H (B.2)

in the presence of a suitable palladium catalyst, a suitable base and copper (I) iodide in a suitable solvent is reacted, and

the compound of formula B.3 obtained

HO-XYZC - CAB (B.3)

with methanesulfonyl chloride (MsCl) is converted to the methanesulphonate derivative B.4,

MsO-XYZC - -AB (B.4)

which is further reacted with an amine of formula H-NR 1 R 2 to the end product B.5.

Further, an object of this invention relates to a process for the preparation of alkyne compounds of formula C.3

R 1 R 2 NXYC --CWAB (C.3)

wherein in the formulas C.1, C.2, and C.3 R 1, R 2, X, Y, W, A and B have one of the meanings indicated above and below,

wherein a halogen compound of formula C.1

R 1 R 2 NXY-Hal (C.1)

wherein Hal is chlorine, bromine or iodine, preferably bromine or iodine, is with an alkyne compound of formula C.2

HC - CWAB (C.2)

in the presence of a suitable palladium catalyst, a suitable base and copper (I) iodide is further reacted in a suitable solvent to yield the end product C.3.

Another object of this invention is a process for the preparation of alkyne compounds of formula D.3

R 1 R 2 NXYZC --CAB (D.3)

wherein in the formulas D.1, D.2 and D.3 R 1, R 2, X, Y, Z, A and B have one of the meanings indicated above and below,

wherein a halogen compound of formula D.2

Hal-AB (D.2)

wherein Hal is chlorine, bromine or iodine, preferably bromine or iodine, is with an alkyne compound of formula D.1

R 1 R 2 NXYZC - CH (D.1)

in the presence of a suitable palladium catalyst, a suitable base and copper (I) iodide is reacted in a suitable solvent to yield the end product D.3.

The starting materials and intermediates used in the synthesis according to the invention are also an object of this invention.

Detailed Description of the Invention

Unless otherwise stated the occurring groups, residues and substituents, particularly A, B, W, X, Y, Z, Cy, R 1, R 2, R 4, R 10, R 11, R 13 and R 15 to R 22, the meanings given above and below.

Join groups, residues and / or substituents in a compound more than once, they may have the same or different meanings in each case.

According to a first embodiment, R 1 is selected from the group of C meanings. 3 6 -alkenyl, C. 3 6 alkynyl, (hydroxy-C 3-7 cycloalkyl) -Cι- 3 alkyl, oxa-C. 5 7 - cycloalkyl, dihydroxy-C. 3 7 alkyl, wherein the angegenben groups one or more times may be substituted with substituents which are independently selected from the group consisting of halogen, hydroxy, cyano, d-4 alkyl, C 3rd 7 cycloalkyl, C. 3 7 - cycloalkyl-C-ι- 3 alkyl, Amino, C 1 - 4 - alkyl-amino and di- (C 1 - 4 alkyl) amino, wherein, in the substituents mentioned known alkyl, alkoxy, Cylcoalkyl groups are independently one or more identical or different substituents selected from halogen, may comprise in particular fluorine or chlorine, and hydroxy.

According to this embodiment preferred meanings of the group R 1 are C 3-5 alk-2-enyl, C. 3 5 alk-2-ynyl, (1-hydroxy-C 3 - 6 cycloalkyl) -Cι.3 alkyl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, dihydroxy-C 3-5 alkyl, wherein the angegenben groups may be mono- or polysubstituted as indicated above.

According to this first embodiment, preferred substituents are independently fluorine, chlorine, bromine, hydroxy, cyano, CF 3, d ^ alkyl, C 3 _ 7 cycloalkyl, C 3 - 7 - cycloalkyl Cι- 3 alkyl, d- 4 -alkoxy-C. Alkyl, d ^ alkoxy, amino, Cι- 4 -alkyl-amino and di- (C 1 - 4 - alkyl) amino, wherein the alkyl, Cylcoalkyl groups one or more identical or different substituents selected from fluorine and hydroxy may have.

Particularly preferred substituents are independently fluorine, chlorine, hydroxy, cyano, CF 3, hydroxymethyl, hydroxyethyl, C ^ alkyl, C 3rd 6 cycloalkyl, C 3 - 6 cycloalkyl-methyl, d-jrAlkoxy-ds-alkyl, d-3 alkoxy, amino, Cι- 3 -alkyl-amino and di- (C 1 3 alkyl.) Amino. According to this embodiment particularly preferred meanings of the group R 1 is prop-2-enyl, but-2-enyl, prop-2-ynyl, but-2-ynyl, (1-hydroxy-C 3 - 6 cycloalkyl) -methyl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, 2,3-dihydroxy-C 3-5 alkyl. In this case very particularly preferred meanings are prop-2-enyl, prop-2-ynyl, (l-hydroxy-cyclopropyl) -methyl, tetrahydropyran-4-yl, 2,3-dihydroxypropyl, 2-hydroxy-1 - (hydroxymethyl) ethyl , 1, 1-di (hydroxymethyl) ethyl.

According to this first embodiment, R 2, independently of R 1 one of the meanings given above for R 1, or R 2 has a meaning selected from the group consisting of H, ds-alkyl, C. 3 7 cycloalkyl, or an optionally mono- or with the radical R 20 can be repeatedly and / or by nitro substituted phenyl or pyridinyl group, wherein the alkyl or cycloalkyl group of mono- or independently of one another by identical or different radicals R 11 polysubstituted can, and wherein a -CH 2 group in position 3 or 4 of a 5-, 6 or 7-membered cycloalkyl group, by -O-, -S- or -NR 13 - may be replaced.

Preferred meanings of the group R 11 in this case are F, Cl, Br, d-6 alkyl, C 2 - 6 alkenyl, C. 2 6 - alkynyl, R 15 -O-, cyano, R 16 R 17 N-, C 3 - 7 cycloalkyl, cyclo-C 3 - 6 -alkylenimino-, pyrrolidinyl, N- (d- alkyl) -pyrrolidinyl, piperidinyl, N- (C 1 - 4 alkyl) -piperidinyl, phenyl and pyridyl, wherein in the above-mentioned groups and radicals one or more C-atoms one or more times by F independently of one another, C | - 3 alkyl or hydroxy -d- 3 alkyl, and / or one or two C atoms independently may be monosubstituted with Cl, Br, OH, CF 3 or CN from each other, and wherein the cyclic groups mentioned above one or more times at one or more C -atoms with identical or different radicals R 20, in case of a phenyl group may also additionally be monosubstituted one or more NH groups may be substituted with R 21 by nitro, and / or. If one of the meanings R 11 R 15 -O-, cyano, R 16 R 17 N-, or cyclo C 3 - 6 has -alkylenimino-, is preferably substituted with R 11 C-atom of the alkyl or cycloalkyl group is not directly connected to a heteroatom such as, for example, the group -NX-.

Preferably, the radical R 2 is H, d-6 alkyl, C 3rd 5 alkenyl, C 3-5 alkynyl, C. 3 7 cycloalkyl, hydroxy-C. 3 7 cycloalkyl, C 3 - 7 cycloalkyl-alkyl Cι- 3, (. Hydroxy-C 3 7 cycloalkyl) -Cι- 3 -alkyl, hydroxy-C ^ alkyl, ω-NC-C 2 ,3 alkyl, Cι- 4 -alkoxy-C 2-4 -alkyl, hydroxy-C 1-4 -alkoxy-C 2-4 -alkyl, C 1-4 -alkoxy-carbonyl-4 alkyl Cι- - alkyl-, di- (C 1 - alkyl) amino-C 2 - 4 alkyl, cyclo-Cs-β-alkyleneimino-C ^ alkyl, pyrrolidin-3-yl, N- (C 1 - - alkyl) -pyrrolidin-3-yl, pyrrolidinyl-d- 3 alkyl, N- (C 1-4 -alkyl) -pyrrolidinyl-3 Cι- alkyl, piperidin-3-yl, piperidin-4-yl, N - (C 1 - 4 -AlkyI) -piperidin-3-yl, N- (C 1 - 4 alkyl) -piperidin-4-yl, piperidinyl-Cι.3 alkyl, N- (C 1-4 -alkyl) -piperidinyl-C 1-3 -alkyl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, phenyl, phenyl-d-C3 alkyl, pyridyl or pyridyl-d-3-alkyl, wherein one or more C atoms independently of one another one in the above-mentioned groups and radicals one or more times by F, C-ι- 3 -alkyl or hydroxy-C-ι- 3 alkyl, and / or one or two C atoms may be monosubstituted with Cl, Br, OH, CF 3 or CN, independently of each other, and wherein said phenyl or pyridyl mono- or polysubstituted by identical or different radicals R 20 and / or simply with may be nitro-substituted. Preferred substituents of the above-mentioned phenyl or pyridyl are selected from the group F, Cl, Br, I, cyano, d-4 alkyl, d- 4 alkoxy, difluoromethyl, trifluoromethyl, hydroxy, amino, d - 3 alkylamino, di- (d- C3 alkyl) amino, acetylamino, aminocarbonyl,

Difluoromethoxy, trifluoromethoxy, amino-d-3 alkyl, d-3-alkylamino Cι- 3 -a! Alkyl- and di- (d- C3 alkyl) amino-3 Cι- alkyl, wherein phenyl and can easily be substituted with nitro.

Particularly preferred meanings of the group R 2 are selected from the group consisting of H, d- C4 alkyl, C 3-5 alkenyl, C 3-5 alkynyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl d- 3 - alkyl, ω- (C 1 -C 4 alkoxy.) C 2. 3 alkyl, pyridyl and benzyl, wherein in said radicals (with the exception of H) one or more carbon atoms mono- or independently polysubstituted by F, Cι- 3 alkyl or hydroxy-d-3 alkyl, and / or one or two C atoms independently may be substituted with CI, Br, OH, CF 3 or CN from each other easily.

Very particularly preferred radicals R 2 are selected from the group consisting of H, methyl, ethyl, n-propyl, i-propyl, prop-2-enyl, prop-2-ynyl, 2-methoxyethyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopentylmethyl (l-hydroxy-cyclopropyl) methyl, 2-hydroxyethyl, 3-hydroxypropyl, benzyl and pyridyl.

According to a second embodiment, the radicals form R 1, R 2 together with the N-atom to which they are bonded, a heterocyclic group selected from the meanings dihydroxy- (cyclo-C. 4 7 -alkylene-imino), (hydroxy-d-4 alkyl) -hydroxy-cyclo-C 3 - alkylene-imino, (hydroxy-d- 3 -alkyl) -cyclo-C. 3 7 alkylene-imino, said C 1 in the last Meaning - 3 - alkyl group may be substituted by one or more identical or different C ^ alkyl groups, of which 2 alkyl groups to form a C 3 - 7 -Cyloalkyl- group may be bonded; wherein the heterocyclic groups mentioned may be mono- or polysubstituted with substituents independently selected from the group consisting of halogen, hydroxy, cyano, d-4 alkyl, C 3rd 7 cycloalkyl, d-cycloalkyl-d-alkyl, d- - alkoxy-C ^ alkyl, d- 4 alkoxy, C ^ alkenyl, C 2 - 4 alkynyl, amino, d-4 alkyl-amino and di- (C 1 - 4 - alkyl) -amino, wherein occurring in the said substituents alkyl, alkoxy or cycloalkyl groups one or more C atoms may be mono- or polysubstituted by fluorine times, and wherein in the above substituents occurring alkyl, alkoxy or Cylcoalkyl groups one or more C atoms may be monosubstituted with chloro, bromo or hydroxy.,

According to this second embodiment, preferred heterocyclic groups are 3,4-Dihydroxypyrrolidinyl, 3,4-Dihydroxypiperidinyl, 3,5-Dihydroxypiperidinyl, (hydroxy-d-3 alkyl) - hydroxypyrrolidinyl, (hydroxy-d-3 alkyl) -hydroxy- piperidinyl, (hydroxy-C 3 6 cycloalkyl.) - hydroxypyrrolidinyl, (hydroxy C 3 - 6 cycloalkyl) -hydroxy-piperidinyl, (ds alkyl-hydroxy-methyl) - pyrrolidinyl, (ds alkyl-hydroxy-methyl- -piperidϊnyl, (di-ds-alkyl-hydroxy-methyl-pyrrolidinyl, (di-Ci-s-alkyl-hydroxy-methylJ-piperidinyl, (1-hydroxy-C 3 - 6 cycloalkyl) -pyrrolidinyl, (1-hydroxy - C 3 6 cycloalkyl) piperidinyl, wherein said groups may be substituted as indicated above..

In the above heterocyclic groups the H atom may be replaced by a methyl group in one or two hydroxy groups.

Preferred substituents of the said heterocyclic groups are fluoro, chloro, hydroxy, CF3, Cι.3 alkyl and hydroxy-d-alkyl, in particular methyl, ethyl and CF 3.

According to this second embodiment particularly preferred heterocyclic groups are 3.4-Dihydroxypyrrolidinyl, 3,4-Dihydroxypiperidinyl, 3,5-Dihydroxypiperidinyl (hydroxymethyl) -hydroxy-pyrrolidinyl, (hydroxymethyl) -hydroxy-piperidinyl (1-hydroxyethyl) - hydroxy -pyrrolidinyl, (1 -hydroxyethyl) -hydroxy-piperidinyl, (1-hydroxy-1-methylethyl) -hydroxy-pyrrolidinyl, (1-hydroxy-1-methylethyl) -hydroxy-piperidinyl, (l-hydroxycyclopropyl) -hydroxy-pyrrolidinyl (1 -Hydroxycyclopropyl) -hydroxy-piperidinyl, (1-hydroxy-cyclopröpyl) -pyrrolidinyl, (l-hydroxy-cyclopropyl) piperidinyl, (l-hydroxyethyl) pyrrolidinyl, (l-HydroxyethyΙ) piperidinyl, (1- hydroxy-1-methylethyl) pyrrolidinyl, (1-hydroxy-1-methylethyl) piperidinyl, where the groups indicated have no further substituents or one or two substituents independently selected from fluoro, hydroxy, d-3 alkyl, hydroxy C-ι- having 3 alkyl, CF 3. Most particularly preferred definitions of the heterocyclic groups are

wherein X is as previously defined and more particularly below, and wherein the specified heterocyclic groups R 1 R 2 N- are not further substituted, or

wherein methyl or ethyl mono- by fluorine, di- or may be tri-substituted, and wherein one or more carbon-bonded H atoms of the heterocycle formed by the group R 1 R 2 N- independently of one another by fluorine, chlorine, CN, CF 3, d-3 alkyl, hydroxy-d- 3 alkyl, especially C 3 alkyl or CF 3, preferably methyl, ethyl, CF substituted. 3

According to a first embodiment, the group X is preferably a C 2 --rAlkylen- bridge, particularly preferably ethylene or propylene, where one or two C atoms simple alkyl substituted with hydroxy, hydroxy-C-ι- 3 or d.3 alkoxy, may be substituted in particular hydroxyl, and wherein the alkylene bridge C. 2 6 alkenyl, C. 2 6 alkynyl, C 3 - 6 cycloalkyl, or C. 3 6 -CycloaIkyl-Cι- 3 alkyl mono- and / or independently mono-, di- or trisubstituted 3 alkyl groups may be substituted with same or different Cι-, and wherein two alkyl groups to form a 3- to 7 membered cycloalkyl group, or an alkyl group and an alkenyl group of a 5 to 7-membered cycloalkenyl group may be bonded together to form. In the group X, one or more C atoms may be mono- or polysubstituted by F and / or Cl, preferably F.

According to a second embodiment, the group X is preferably a C 3 - ^ AIkylen- bridge, in which a non with the N-atom of the R 1 R 2 N group immediately adjacent -CH 2 -CH 2 group is replaced by -CH = is substituted, more preferably a -CH 2 -CH = CH-, -CH2-C - CH-, -C≡C-, -CH 2 -O-, -CH 2 -S- or -CH 2 -NR 4 -≡C-, -CH 2 -CH 2 -O-, -CH 2 -CH 2 -S- or -CH 2 - Forwarding CH 2 -NR 4 -B ", wherein the above-indicated selected for X meanings one substituent selected from C 2 6 alkenyl, C 2 6 alkynyl, C 3 7 cycloalkyl, and C 3 -.... -cycloalkyl- Cι-C3 alkyl and / or one, two or three identical or different d-4 alkyl may have substituents, while two alkyl groups to form 3 may be joined together to form a 5 to 7-membered cyclic group of one to 7-membered, or an alkyl and an alkenyl group. can in group X one or more mono- or polysubstituted C atoms substituie with F and / or Cl, preferably F his rt.

Particularly preferred meanings of X are, therefore, ethylene, propylene, -CH 2 -CH = CH-, -CH 2 -C ≡C-, -CH 2 -CH 2 -O-, -CH 2 -CH 2 -S-, or -CH 2 -CH 2 -NR 4 -.

A particularly preferred meaning of X is unsubstituted ethylene or propylene or C M alkylene, especially ethylene or propylene, the one or two identical or different substituents independently selected from fluoro, chloro, hydroxy and Cι- 3 alkyl and / or C 2 - 6 alkenyl having or cyclopropyl substituent, where two alkyl substituents to form a C 3 - 6 cycloalkyl group, or an alkyl and an alkenyl group to form a C. 5 6 cycloalkenyl group may be joined together. Particularly preferably, the alkylene bridge is mono- or disubstituted by identical or different radicals selected from • methyl, ethyl and i-propyl groups, where two alkyl groups may be joined together as indicated to form a cyclic group.

In the meaning of substituted propylene particularly preferred meanings are selected from the group consisting of

Moreover, particularly preferred meanings of X are -CH 2 -CH = CH-, -CH 2 -C≡C-, - CH 2 -CH 2 -O-, -CH 2 -CH 2 -S- or -CH 2 - CH 2 -NR 4 -, in particular -CH 2 -CH = CH-, -CH 2 -CH 2 -O- or -CH 2 -CH 2 -NR 4 -, wherein R 4 is H or d-4 alkyl, wherein the meanings given for X are unsubstituted or one or two same or different substituents independently selected from fluorine and d-3 alkyl and / or a cyclopropyl-substituents, while two alkyl groups to form a C. 3 6 - cycloalkyl group, or if an alkyl group is the radical R 4 may be joined together to form a pyrrolidino or piperidino group. Particularly preferred are as defined above for X are mono- or disubstituted by identical or different radicals selected from substituted methyl, ethyl and i-propyl, while two alkyl groups as indicated to form a cyclic group may be bonded together.

A particularly preferred meaning of X is unsubstituted -CH 2 -CH 2 -O-, or substituted -CH 2 -CH 2 -O- selected from the group consisting of

Also, a particularly preferred Bedetung of X is -CH 2 -CH 2 -NH- or -CH 2 -CH 2 - NCH 3 - or substituted -CH 2 -CH 2 -NCH 3 - selected from the group consisting of

Further, a particularly preferred meaning of X is -CH 2 -CH = CH-, or substituted -CH 2 -CH = CH- selected from the group consisting of

For X in the meaning of substituted alkenylene above given only one of the two possible E / Z configurations. Naturally, the other of the two E / Z configuration according to the invention comprises respectively.

The position of the imino group within the alkylene bridge X is preferably selected so that together with the amino group NR 1 R 2 or another adjacent amino group no Aminalfunktion is formed or two N atoms are not adjacent to each other.

Preferred meanings of the group R> 10 are -OH, methoxy and hydroxymethyl, in particular -OH. According to a third embodiment, the group -CH 2 bridge X is a bridge which is unsubstituted or with one or two identical or different C ^ alkyl substituents and / or a substituent selected from C 2nd 6 alkenyl, C. 2 6 alkynyl, C. 3 6 cycloalkyl, or C. 3 6 - cycloalkyl Cι- alkyl substituted 3, wherein two alkyl substituents may be joined together to form a 3- to 6-membered carbocyclic ring system. According to this embodiment, X is -CH 2 -, preferably unsubstituted or mono- or disubstituted by methyl, wöbe two methyl substituents together to form a cyclopropyl group may be bonded. This third embodiment with respect to X is particularly preferred if Y is a bicyclic group, wherein DER. first ring of the bicyclic group is attached to X and the second ring is connected to Z.

The bridge W preferably represents a single bond or ethylene, particularly preferably a single bond.

The bridge Z preferably represents a single bond or ethylene which may have one or two methyl substituents may be joined together to form a cyclopropyl group. Particularly preferably, Z is a single bond.

The group Y preferably has a meaning 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, chromanyl, chromen-4-onyl, benzothienyl, or benzofuranyl, particularly preferably phenyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl, wherein the cyclic groups mentioned above one or more times at one or more carbon atoms with the same or different radicals R 20, in the case of a phenyl ring may additionally be monosubstituted by nitro, and / or at one or more N atoms with R 21 also easy.

If the group Y is a 6-membered cyclic or heterocyclic group, the bridges X and Z are preferably in the para position linked to the group Y.

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

in particular Y has one of the following meanings

most preferably Y has one of the following meanings

where the cyclic groups listed above once or at one or more C atoms by identical or different radicals R can polysubstituted 20, in the case of a phenyl ring may also additionally be monosubstituted by nitro, and / or one or more NH groups with R 21 be substituted. If the group Y is selected from the group of divalent bicyclic groups

particularly if Y has one of the following meanings

wherein the bicyclic groups listed above once or at one or more C atoms by identical or different radicals R can polysubstituted 20, in the case of a phenyl ring may also additionally be monosubstituted by nitro, and / or one or more NH groups with R 21 may be substituted,

the bridge X is preferably a -CH 2 group which can be substituted with respect to X according to the third embodiment described above.

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

Particularly preferred substituents R 20 of the group Y are selected from the group consisting of fluorine, chlorine, bromine, cyano, nitro, d-4 alkyl, C 2nd 6 alkenyl, hydroxy, ω-hydroxy-3 Cι_ alkyl, C | - 4 alkoxy, trifluoromethyl, trifluoromethoxy, C ^ alkynyl, d-4 alkoxy carbonyl, ω- (C 1 -C 4 alkoxy). -C 1 - alkyl 3, d- alkoxy-carbonylamino, amino, C ^ alkyl amino, di- (C 1 - 4 alkyl) -amino, aminocarbonyl, d ^ alkyl amino-carbonyl and di- (C 1 - alkyl) amino carbonyl.

Very particularly preferred substituents R 20 of the group Y are selected from the group consisting of fluorine, chlorine, bromine, cyano, Cι- 3 alkyl, Cι- 3 alkoxy, d- 4 -

Alkoxycarbonyl, trifluoromethyl, trifluoromethoxy, in the case of a phenyl ring and nitro.

Most preferably the group Y denotes substituted phenylene of ■ 1

Partial formula j (/.) - -, wherein L 1 is one of the above for R 20

meanings indicated, preferably F, CI, Br, I, methyl, ethyl, ethenyl, ethynyl, CF 3, OCH 3, OCF 3, -CO-CH 3, COOCH 3, CN or NO 2 has, or H. Most particularly preferred meanings of the substituent L 1 are H, F, Cl, Br, methyl, ethyl, ethenyl, acetyl or methoxy, especially H or methyl.

Preferably the group A is selected from among the bivalent cyclic

Phenyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, the one or in the case of a phenyl ring may also additionally may be substituted with nitro polysubstituted at one or more C atoms by identical or different radicals R 20, simply.

Very particularly preferably A is one of the groups listed below

especially

most preferably, // V _! _

wherein the groups listed may be substituted as indicated above.

Particularly preferred substituents R 20 of the group A are independently fluorine, chlorine, bromine, CF 3, amino, methoxy and C ^ alkyl.

Preferably the groups A is unsubstituted or monosubstituted by R 20, as indicated.

Preferred definitions of the group B according to a first preferred embodiment are selected from the group consisting of phenyl, pyridyl, thienyl, and furanyl. Particularly preferably the group B is phenyl. The group B in the indicated meanings can be mono- or polysubstituted by identical or different radicals R 20, may additionally also be monosubstituted by nitro phenyl. Preferably, the group B is unsubstituted or mono-, di- or tri-substituted, especially unsubstituted or mono- or disubstituted. In the case of monosubstitution, the substituent is preferably in para-position to the group A.

Preferred substituents R 20 of the group B are selected from the group consisting of fluorine, chlorine, bromine, cyano, nitro, C ^ alkyl, hydroxy, CHF 2, CHF 2 -O-, Cι- hydroxy-3 alkyl, d- 4 alkoxy, trifluoromethyl, trifluoromethoxy, C ^ alkynyl, carboxy, Cι- 4 alkoxycarbonyl, ω- (. C 1 4 alkoxy) -d 3 alkyl, C 1 - alkoxy-carbonylamino, amino -, d- 4 alkyl-amino-, di (C 1 - 4 alkyl) - amino, cyclo-C. 3 6 -alkylenimino-, aminocarbonyl, d- alkyl-amino-carbαnyl- and di- (C 1 - 4 - alkyl) -amino-carbonyl.

Particularly preferred substituents R 20 of the group B are selected from the group consisting of fluorine, chlorine, bromine, cyano, CF 3, C-ι- 3 alkyl, Cι- 4 alkoxy and trifluoromethoxy.

Very particularly preferred substituents R 20 of the group B are selected from the group consisting of chlorine, bromine and methoxy.

According to a second embodiment, the meaning of the group B is preferably selected from d- 6 alkyl, C 2nd 6 -alkenyl, C 2 - 6 alkynyl, C 3-7 cycloalkyl, C. 5 7 cycloalkenyl, C. 3 7 - cycloalkyl-d- alkyl 3 -aIkyl-, C3 7 cycloalkenyl-d-3, C 3 - 7 cycloalkyl-Cι- 3 alkenyl, C. 3 7 - cycloalkyl-d- 3 alkynyl group, wherein one or more carbon atoms in the aforementioned groups for B may be mono- or polysubstituted by fluorine times. In the cyclic groups according to the above-mentioned embodiment, one or more C atoms by identical or different R 20 may be substituted.

Particularly preferred are the groups C 3, according to this embodiment.6 alkyl, C 3rd 6 - alkenyl, C. 3 6 -alkynyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl ,. Cycloheptenyl, cyclopentyl-3 d- alkyl, d-cyclopentenyl-3 ~ alkyl, cyclohexyl-3 d- alkyl, Ci-3 alkyl cyclohexenyl, cycloheptyl-3 Cι- alkyl, Cι-cycloheptenyl - alkyl 3, wherein one or more carbon atoms in the aforementioned groups for B may be mono- or polysubstituted by fluorine times, and may be substituted wherein the cyclic groups in one or more C atoms by identical or different R 20 ,

Is very particularly preferably B according to this second embodiment, cyclohexenyl, which is unsubstituted or 1, 2 or 3 identical or different substituents R 20, in particular methyl, has. Hereinafter, preferred definitions of other substituents according to the invention are given: R 4 is preferably H, C ^ alkyl, C 3 - 6 cycloalkyl, and C. 3 6 -cycloalkyl-methyl, especially H, methyl, ethyl, propyl, i-propyl, n-propyl, Cylcopropyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopentylmethyl, Cyclohexymethyl. Very particularly preferably, R 4 is H or methyl. Preferably the substituent R 13 on one of the meanings given for R 16th Particularly preferably R 13 is H, d-4 alkyl, C 3rd 7 cycloalkyl, d-T-cycloalkyl-d-alkyl, ω-hydroxy-C. 2 3 alkyl, ω- (Cι- alkoxy) C 2 - 3 alkyl. Most particularly preferably R 13 is H or Cι - rAlkyl. The alkyl groups given above can easily be substituted with CI or mono- or poly-F.

Preferred meanings of the substituents R 15 are H, C ^ alkyl, C 3rd 7 cycloalkyl, C 3 - 7 - cycloalkyl-d- 3 alkyl, wherein, as hereinbefore defined, in each case one or additionally, one or more carbon atoms more times independently with F and / or one or two carbon atoms from each other, additionally may be substituted by Cl or Br easy. Particularly preferably R 15 is H, CF 3, methyl, ethyl, propyl or butyl.

The substituent R 16 is preferably H, d- 4 -alkyl, C. 3 7 cycloalkyl, C 3 - 7 cycloalkyl-Cι- 3 - alkyl, ω-hydroxy-C. 2 3 alkyl or ω- (C 1-4 alkoxy) C. 2 3 alkyl, where, as hereinbefore defined, in each case one or more C atoms may additionally be mono- or polysubstituted by F and / or one or two C atoms may additionally be substituted by CI or Br independently of one another easily. Particularly preferably R 16 is H, CF 3, d.3 alkyl, C 3rd 6 cycloalkyl, or C. 3 6 - Cycioalkyl-d- 3 -alkyl.

Preferably the substituent R 17 one of the meanings given for R 16 • as being preferred, or denotes phenyl, phenyl-3 Cι- alkyl, pyridinyl or Cι- 4 -alkylcarbonyl. More preferably, R 17 has one of the meanings given as preferred for R 16th

Preferably, a means or are both of the substituents R 18 and R 19 are independently hydrogen or C 4 alkyl, especially hydrogen. The substituent R 20 is preferably halogen, hydroxy, cyano, Cι- 4 alkyl, C 2-4 alkenyl, C. 2 Alkynyl, C 3-7 cycloalkyl, C. 3 7 cycloalkyl d- 3 alkyl, hydroxy-d ^ alkyl, R 22 -d- 3 alkyl, or one of the meanings given for R 22 as being preferred, wherein, as hereinbefore defined, in each case one or more C-atoms may additionally be mono- or polysubstituted by F and / or one or two C atoms may additionally be substituted by CI or Br independently of one another easily.

Particularly preferred meanings of the group R 20 are halogen, hydroxy, cyano, d- 4 - alkyl, C 3 - 7 cycloalkyl, d-3 alkylcarbonyl and d-4 alkoxy, wherein, as hereinbefore defined, in each case one or more C -atoms may additionally be mono- or polysubstituted by F and / or one or two C atoms may additionally be substituted by CI or Br independently of one another easily. Very particularly preferably, R 20 is F, Cl, Br, I, OH, cyano, methyl, difluoromethyl, trifluoromethyl, ethyl, n-propyl, acetyl, iso-propyl, methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, n-propoxy, or iso- propoxy.

The substituent R 22 is preferably d- 4 alkoxy, C ^ alkylthio, carboxy, Cι- 4 alkylcarbonyl, d- alkoxycarbonyl, aminocarbonyl, d- 4 alkylaminocarbonyl, di- (d- C4 alkyl) aminocarbonyl, C ^ alkyl-sulfonyl, d ^ alkyl sulfinyl, d ^ alkyl-sulfonylamino, amino, d ^ alkylamino, di (C 1-4 alkyl) amino, C ^ alkyl carbonyl-amino, hydroxy-d- 3 - alkylaminocarbonyl, aminocarbonylamino or d ^ alkylaminocarbonyl-amino, wherein, as hereinbefore defined, in each case one or additionally, one or more C atoms polysubstituted by F and / or in each case, one or two C atoms may additionally be substituted by CI or Br independently of one another easily. Most particularly preferred meanings of R 22 are Cι- 4 - alkoxy, d- 3 alkylcarbonyl, amino, d ^ alkylamino, di (C 1 - 4 alkyl) amino, .worin one or more H atoms may be replaced by fluorine.

Preferred meanings of the group R 21 are D--. alkyl, C 1-4 - alkylsulphonyl, -SO 2 -NH 2, -SO 2 -NH-Cι- 3 alkyl, -SO 2 -N (C 1 - 3 alkyl) 2 and cyclo-C. 3 6 -alkylenimino- -sulfonyl, wherein additionally be mono-, as hereinbefore defined, in each case one or more C-atoms or more times by F and / or one or two C atoms may additionally be substituted by CI or Br independently of one another easily. Most particularly preferably R 21 d- 4 alkyl or CF 3.

Cy preferably denotes a C. 3 7 cycloalkyl, particularly a C. 3 6 cycloalkyl group, a C. 5 7 cycloalkenyl group, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl,

Thiomorpholinyl, aryl or heteroaryl, and wherein the cyclic groups mentioned above one or more times at one or more C atoms by identical or different radicals R 20, in case of a phenyl group may also additionally be monosubstituted by nitro, and / or one or more NH groups may be substituted with R 21st Most particularly preferred definitions of the group Cy are C. 3 6 -Cycioalkyl, pyrrolidinyl and piperidinyl which may be substituted as indicated.

The term aryl preferably denotes phenyl or naphthyl, especially phenyl.

The term heteroaryl preferably includes pyridyl, indolyl, quinolinyl and benzoxazolyl.

Those compounds of the invention are preferred in which exhibit one or more of the groups, residues, substituents and / or indices of the meanings defined above as being preferred.

Particularly preferred compounds of the invention can use a general formula IIa, llb, llc, lld, lle, llf, Hg, IIh, in particular lla, llb, He and llf,

are described in the

R 1, R 2, X and Z have one of the preferred meanings given above and

L 1 L 2

L 3, independently of one another have one of the meanings given for R 20, and

m, n, p independently of one another have the values ​​0, 1 or 2, p also has the value 3, mean. In particular, in the formulas Ila, llb, llc, lld, He, IIf, Hg and llh

Z is a single bond,

L 1 is fluorine, chlorine, bromine, cyano, d-3 alkyl, d-3 alkoxy, C ^ alkoxycarbonyl, trifluoromethyl, trifluoromethoxy, nitro,

m is 0 or 1,

L 2 is fluorine, chlorine, bromine, CN, amino, CF 3, methoxy and d- 3 alkyl,

n O breath,

L 3 independently of one another selected from the meanings fluorine, chlorine, bromine, cyano, nitro, d- C4 alkyl, hydroxy, ω-hydroxy-d- 3 alkyl, C ^ alkoxy, trifluoromethyl, trifluoromethoxy, C 2 - 4 - alkynyl, carboxy, C ^ alkoxycarbonyl ω- (d- alkoxy) C 1-3 alkyl, C 1-4 alkoxy-carbonylamino, amino, d ^ -alkyl-amino, di- (C ^ -alky -amino, cyclo-C 3 - 6 -alkylenimino-, aminocarbonyl, C ^ alkyl-amino-carbonyl or di- (C 1 - alkyl) -amino-carbonyl, particularly preferably fluorine , chlorine, bromine, cyano, CF 3, d- C3 alkyl, d-4 alkoxy and trifluoromethoxy, with the proviso that a phenyl ring can only be monosubstituted by nitro, and

p 0, 1, 2 or 3, especially 1 or second

Very particularly preferably in the formulas IIa, IIb, IIc, IId, He, IIf, Hg and IIh

R 1 prop-2-enyl, but-2-enyl, prop-2-ynyl, but-2-ynyl, (1-hydroxy-C 3 6 cycloalkyl.) - methyl, tetrahydropyran-3-yl, tetrahydropyran-4 -yl, 2,3-dihydroxy-C. 3 5 alkyl, and

R 2 is H, d-4 alkyl, C 3rd 5 alkenyl, C. 3 5 alkynyl, C. 3 7 cycloalkyl-C | - - 7 cycloalkyl, C 3 alkyl 3, ω- (C 1 - alkoxy) -C. 2 3 alkyl, pyridyl and benzyl, wherein in said radicals (with the exception of H) one or more carbon atoms mono- or independently polysubstituted by F, Cι- 3 alkyl or hydroxy-d-3 alkyl, and / or one or two C atoms independently may be monosubstituted with Cl, Br, OH, CF 3 or CN from each other, or

R 1, R 2 are joined together to form together with the N-atom to which they are bonded, a heterocyclic group, which is selected from 3,4-Dihydroxypyrrolidinyl, 3,4-Dihydroxypiperidinyl, 3,5-Dihydroxypiperidinyl, ( hydroxymethyl) -hydroxy-pyrrolidinyl, (hydroxymethyl) -hydroxy-piperidinyl, (1 - hydroxyethyl) -hydroxy-pyrrolidinyl, (1-hydroxyethyl) -hydroxy-piperidinyl, (1 - hydroxy-1-methylethyl) -hydroxy-pyrrolidinyl, ( 1-hydroxy-1-methylethyl) -hydroxy-piperidinyl, (l-hydroxycyclopropyl) -hydroxy-pyrrolidinyl, (1-hydroxycyclopropyl) - hydroxy-piperidinyl, (l-hydroxycyclopropyl) -pyrrolidinyΙ, (1-hydroxycyclopropyl) - piperidinyl, (l-hydroxyethyl) pyrrolidinyl, (l-hydroxyethyl) piperidinyl, (1-hydroxy-1-methylethyl) pyrrolidinyl, (1-hydroxy-1-methylethyl) piperidinyl, where the groups indicated no further substituents or having one or two substituents independently selected from fluoro, hydroxy, C 1 -3 alkyl, hydroxy-d. Have 3 alkyl, CF 3,

Having 6 -alkenyl or cyclopropyl substituent, wherein two - X is ethylene or propylene which is unsubstituted or one or two same or different substituents independently selected from fluoro, chloro, hydroxy and Cι- 3 alkyl and / or C 2 alkyl substituents to form a C. 3 e-cycloalkyl group, or an alkyl and an alkenyl group to form a C 5 - 6 cycloalkenyl group may be connected to each other, or

-CH 2 -CH = CH-, -CH 2 -C≡C-, -CH 2 -CH 2 -O- or -CH 2 -CH 2 -NR 4 -, which are unsubstituted or one or two identical or different substituents independently selected from fluorine and d-3 alkyl and / or a cyclopropyl-substituents, while two alkyl groups to form a C 3 - 6 cycloalkyl group with an alkyl group or, if represents the radical R 4, ' form a pyrrolidino or piperidino group may be joined together.

The compounds listed in the experimental section, including the tautomers, the diastereomers, the enantiomers, the mixtures and salts thereof are preferred in the invention. In the following, further defined terms which are used above and hereinafter to describe the compounds of the invention.

The term halogen denotes an atom selected from the group consisting of F, Cl, Br and I, particularly F, Cl and Br.

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

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

The term C 2nd includes n -alkenyl, wherein 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

Double bond. Examples of such groups include vinyl, 1-propenyl, 2-propenyl, iso- propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 3-methyl-2-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl etc ..

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

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

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

The term C 3rd n-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, norbornyl, Norcaryl, adamantyl, etc ..

The term C 5 - n cycloalkenyl denotes a monounsaturated mono-, bi-, tri- or spirocarbocyclic, preferably monocarbocyclic group with 5 to n C atoms. Examples of such groups include cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl, etc ..

The term C 3rd n-cycloalkylcarbonyl denotes a C. 3 n -cycloalkyl-C (= O) group, wherein C. 3 n - cycloalkyl is as defined above.

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

The term cyclo-C. 3 6 -alkylenimino- denotes a 4- to 7-membered ring having 3 to 6 methylene units as well as an imino group, where the bond to the rest of the molecule via the imino group.

The term cyclo-C. 3 6 -alkylenimino-carbonyl denotes a previously defined cyclo-C 3 _ 6 - alkyleneimino ring which is connected via the imino group with a carbonyl group. The term heteroaryl used in this application denotes a heterocyclic, aromatic ring system comprising one or more hetero atoms selected from N, O and / or S in addition to at least one carbon atom. Examples of such groups are furanyl, thiophenyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, 1, 2,3- triazolyl, 1,3,5-triazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1, 2, 3-triazinyl, 1, 2,4-triazinyl, 1, 3,5-triazinyl, 1, 2,3-oxadiazolyl, 1, 2,4-oxadiazolyl, 1, 2,5-oxadiazolyl, 1, 3,4- oxadiazolyl, 1, 2,3-thiadiazolyl, 1, 2,4-thiadiazolyl, 1, 2,5-thiadiazolyl, 1, 3,4-thiadiazolyl, tetrazolyl, thiadiazinyl, indolyl, isoindolyl, benzofuranyl, benzothiophenyl (thianaphthenyl), indazolyl , benzimidazolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, purinyl, quinazolinyl, Chinozilinyl, quinolinyl, isoquinolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, azepinyl, diazepinyl, acridinyl, etc .. the term heteroaryl also comprises the partially hydrogenated heterocyclic, aromatic in particular the ring systems ring systems "listed above. Examples of such partially hydrogenated ring systems are 2,3-di hydrobenzofuranyl, pyrolinyl, pyrazolinyl, indolinyl, oxazolidinyl, oxazolinyl, oxazepinyl, etc .. Particularly preferably, heteroaryl is a heteroaromatic mono- or bicyclic ring system.

Terms such as C 3-7 cycloalkyl-d- n alkyl, aryl-n Cι- alkyl, heteroaryl-C-ι- n-alkyl, etc. denote Ci- n alkyl, as defined above, with a C. 3 7 cycloalkyl, aryl or heteroaryl group is substituted.

Some of the terms given above may be used several times in the definition of a formula or group and have one of the meanings specified in each case independently of one another. So may have the same or different meanings, for example, in the group di-d- to C4 alkyl-amino, the two alkyl groups.

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

As used in this application, "optionally substituted" means 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 the same or different.

The notation used above and hereinafter, in which in a cyclic group a bond of a substituent to the center of this cyclic group is illustrated, denotes, unless otherwise stated, that this substituent bound to any free, carrying an H atom position of the cyclic group can be.

Thus, in the example of the substituent R in the case of s = 1 be bonded to any of the free positions of the phenyl ring; in the case of s = 2 may be R 20 bound to different free positions of the phenyl ring are independently selected substituents.

The H atom of any carboxy group or bound to an N atom H atom (imino or amino group) may be replaced by a cleaved in vivo radical. Under a cleavable by a N-atom in vivo radical is understood to mean, for example, a hydroxy group, an acyl group such as the benzoyl or pyridinoyl group or a C 16 alkanoyl group such as formyl, acetyl, propionyl, butanoyl, pentanoyl or hexanoyl group, an allyloxycarbonyl group, a C 16 alkoxycarbonyl group such as the methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert.butoxycarbonyl, Pentoxycarbonyl-, hexyloxycarbonyl, octyloxycarbonyl, nonyloxycarbonyl, decyloxycarbonyl, Undecyloxycarbonyl- , dodecyloxycarbonyl or Hexadecyloxycarbonylgruppe, a phenyl-Cι.6 alkoxycarbonyl group such as the benzyloxycarbonyl, phenylethoxycarbonyl or Phenylpropoxycarbonylgruppe, a Cι- 3 alkylsulfonyl-C. 2 4 -alkoxycarbonyl, C 1-3 -alkoxy-C 2-4 -alkoxy-C 2-4 -alkoxycarbonyl, or R e CO-O- (R f CR g) -O-CO-group in which

R e is a Cι- 8 alkyl, C. 5 7 cycloalkyl, phenyl or phenyl Cι- 3 alkyl group,

R f is a hydrogen atom, a d.3 alkyl, C 5-7 cycloalkyl or phenyl group and R g represents a hydrogen atom, a C 3 alkyl or R 8 CO-O- (R f CR g) -O- group wherein R e to , R g are defined as mentioned above, showing, in addition, the phthalimido group is an amino group into consideration, the above-mentioned ester residues may be used in vivo into a carboxy group convertible also considered.

The residues and substituents described above may be switched in the manner described or polysubstituted with fluorine. Preferred fluorinated alkyl groups are fluoromethyl, difluoromethyl and trifluoromethyl. Preferred fluorinated alkoxy groups are fluoromethoxy, difluoromethoxy and trifluoromethoxy. Preferred fluorinated alkylsulphinyl and alkylsulphonyl are trifluoromethylsulphinyl and trifluoromethylsulfonyl.

The compounds of general formula I according to the invention may have acid groups, mainly carboxyl groups, and / or basic groups such as 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, sulfuric acid, phosphoric acid, sulphonic acid or organic acids (such as maleic 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 diethylamine, triethylamine, triethanolamine inter alia.

The compounds of the invention may be obtained using the principle known synthetic methods. the compounds according to detail hereinafter described inventive manufacturing method are preferably obtained.

The following two reaction schemes A and B, the synthesis of the compounds according to the invention is represented A.5 and B.5, wherein R 1, R 2, X, Y, Z, W, A and B have one of the meanings described above. Hal represents chlorine, bromine or iodine, in particular bromine or iodine, particularly preferably iodine.

According to Reaction Scheme A, the halogen compound with the alkyne compound A.1 A.2 in a molar ratio of about 1, 5: 1 to 1: 1.5 in the presence of a suitable palladium catalyst, a suitable base and copper under a protective gas atmosphere (l) iodide in a suitable solvent. A preferred amount of this copper (I) iodide is in the range 1 to 15 moI%, particularly from 5 to 10 mol% based on the reactant A.1. Suitable palladium catalysts include Pd (PPh 3), Pd 2 (dba) 3, Pd (OAc) 2, Pd (PPh 3) 2 Cl 2, Pd (CH 3 CN) 2 Cl 2, Pd (dppf) CI 2 , The palladium catalyst is preferably used in an amount of 1 to 15 mol%, in particular 5 to 10 mol%, based on the educt A.1. Suitable bases are, in particular, amines such as triethylamine or

Ethyldiisopropylamine, and Cs 2 CO 3. The base is preferably at least in equimölarer amount based on the educt A.1, used in excess or even as solvent. Further suitable solvents are dimethylformamide or ethers such as tetrahydrofuran, including mixtures thereof. The reaction takes place in a period of about 2 to 24 hours in a temperature range of about 20 to 90 ° C.

The resulting alkyne compound A.3 is reacted directly or after prior purification with methanesulfonyl chloride to methanesulphonate derivative A.4. The case complied reaction conditions are known in the art as such. Advantageous solvents are halogenated hydrocarbons such as dichloromethane. Suitable reaction temperatures are usually in a range of 0 to 30 ° C.

The reaction solution, the methanesulfonate derivative A.4 or containing the purified methanesulfonate Derviat A.4, dissolved in a suitable solvent, is reacted with an amine H-NR R 2 to the end product A.5 and then optionally purified. Has the amine H-NR 1 R 2 is a further primary or secondary amine function, it will be advantageously provided previously with a protecting group that can be cleaved after the reaction using methods known from the literature again. The product thus obtained can be converted, for example by reaction with an appropriate acid in the salt form. A preferred molar ratio of this derivative A.4 to the amine compound is in the range of 1, 5: 1 to 1: 1.5. Suitable solvents are dimethylformamide or ethers, such as tetrahydrofuran, including mixtures thereof. The conversion to product A.5 is advantageously carried out in a temperature range of about 20 to 90 ° C. Chart A:

HO-X-Y-Hal + HC≡CWAB (A.1) (A.2)

Cul [Pd]

HO-C XY ≡CWAB (A.3)

MsCl

MsO-XYC ≡CWAB (A.4)

r -2

R'R XYC≡CWAB N- (A.5)

According to Reaction Scheme B, the halogen compound with the alkyne compound B.1 B.2 in a molar ratio of about 1, 5: 1 to 1: 1.5 in the presence of a suitable palladium catalyst, a suitable base and copper under a protective gas atmosphere (l) iodide in a suitable solvent. Information on suitable reaction conditions, including catalysts, bases and solvents, the notes to Scheme A can be removed.

The resulting alkyne compound B.3 is reacted directly or after prior purification with methanesulfonyl chloride to methanesulphonate derivative B.4. The reaction conditions are to be observed here again refer to what is said to Scheme A. The reaction solution, the methanesulfonate derivative B.4 or containing the purified methanesulfonate Derviat B.4 dissolved in a suitable solvent, is reacted with an amine R 2 H-NR 1 to the end product B.5 and then optionally purified. Again, the models find Scheme A application.

Chart B:

HO-XYZ C≡CH + Hal-AB

(B.1) (B-2)

Cul [Pd]

HO-XYZ C≡CAB (B.3)

MsO-XYZ C≡CAB (B.4)

-1 --- R 2 R'N - XYZ C≡ C -AB (B.5)

According to the further reaction Scheme C, the halogen compound with the alkyne compound C.1 C.2 in a molar ratio of about 1, 5: 1 to 1: 1.5 (in the presence of a suitable palladium catalyst, a suitable base and copper under a protective gas atmosphere I) iodide to form the product C.3 in a suitable solvent. Information on suitable reaction conditions, including catalysts, bases and solvents, the notes to Scheme A can be removed. Reaction Scheme C:

R 1 R 2 N- XY-Hal + HC≡CWAB (C.1) (C.2)

Cul [Pd]

r-, 2 R'R'N- XYC≡CWAB (C.3)

An alternative synthesis is shown in Reaction Scheme D. Hereinafter, the halogen compound with the alkyne compound D.2 D.1 is in a molar ratio of about 1, 5: 1 iodide, 5 in the presence of a suitable palladium catalyst, a suitable base and copper under a protective gas atmosphere (l) in: 1 to 1 a suitable solvent directly converted to the product D.3. Again, the information must be appropriate reaction conditions, including catalysts, bases and solvents, disclosed in the notes to Scheme A.

Chart D:

R 1 R 2 N- XYZ C≡CH + Hal-AB

(D.1) (D.2)

Cul [Pd]

.I R 1 R .2-N- XYZ C≡CAB (D.3)

The reactions of the schemes A, B, C and D are particularly advantageous with the entspechenden iodine compounds A.1, B.2, C.1 perform or D.2. For the case where Hal represents in the compounds A.1, B.2, C.1 D.2 or bromine, it is advantageous to convert these previously into the corresponding iodine compound. A case 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 ), from 14,844 to 14,845). For example, the halogen compound A.1, B.2, C.1 or D.2 with sodium iodide in the presence of Λ /, Λ / '- dimethyl-ethylenediamine and copper (I) iodide in a suitable solvent to the corresponding iodine compound reacted become. A case advantageous molar ratio of the halogen compound to sodium iodide is 1: 1, 8 to 1: 2.3. Λ /, Λ / '- 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 used. Preferred amounts of copper (I) iodide in the range of 5 to 20 mol% based on the halogen compound A.1, B.2, C.1 or D.2. A hiebei suitable solvent is, for example, 1, 4-dioxane. Suitable reaction temperatures are in the range of about 20 to 110 ° C. The reaction is substantially complete in 2 to 72 hours.

The compounds of the invention may advantageously also by the processes described in the following Examples, and these can be combined for this purpose to the skilled worker, for example from the literature-known methods.

Stereoisomeric compounds of formula (I) can in principle be separated by conventional methods. The separation of the diastereomers may be due to their different physicochemical properties, for example by fractional crystallisation from suitable solvents, by high pressure liquid or column chromatography using chiral or preferably non-chiral stationary phases.

The separation of by the general formula (I) falling racemates possible, for example by HPLC on suitable chiral stationary phases (e.g., B. Chiral AGP, Chiralpak AD). Racemates which contain a basic or acidic function can also be separated via the diastereomeric, optically active salts disconnect which upon reaction with an optically active acid, for example (+) - or (-) - tartaric acid, (+) - or (- ) -Diacetylweinsäure, (+) - or (-) - monomethyl or (+) - camphorsulfonic acid, or an optically active base, for example with (f?) - (+) - 1-phenylethylamine, (S) - (-) -1-phenylethylamine or (S) -Brucin arise.

According to a conventional method of separating isomers, the racemate of a compound of general formula (I) is reacted with one of the abovementioned optically active acids or bases in equimolar amounts in a solvent and the resulting crystalline, diastereomeric, optically active salts by utilizing their different solubility separated. This reaction can be carried out in any kind of solvents as long as they have a sufficient difference in solubility of the salts. Preferably, methanol, ethanol or their mixtures, for example in the volume ratio 50:50, are used. Then dissolved of each of the optically active salts in water, carefully neutralized with a base, such as sodium carbonate or potassium carbonate, or with a suitable acid, such as dilute hydrochloric acid or aqueous methanesulphonic acid and in the corresponding free compound in the (+) - or ( -) - obtained form.

Only the (R) - or (S) enantiomer alone or a mixture of two optically active falling under the general formula (I) diastereomeric compounds also characterized, obtained by performing the syntheses described above with a suitable (R ) - or (S) - configured reaction component performs.

WJE mentioned above, the compounds of formula (I) may be converted into salts thereof, particularly for pharmaceutical use, be converted into the physiologically and pharmacologically acceptable salts thereof. These salts may be with organic or inorganic acids on the one hand as physiologically and pharmacologically acceptable acid addition salts of the compounds of formula (I). On the other hand, the compound of formula are converted into physiologically and pharmacologically acceptable salts with alkali or alkaline earth metal cations as counter-ion (I) in the case of acidically bound hydrogen, by reaction with inorganic bases. To prepare the acid addition salts, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid are also suitable. Furthermore, mixtures of the aforementioned acids can be used. For the presentation of the alkali and alkaline earth

Compound of formula (I) with acidically bound hydrogen, are preferably the alkali and alkaline earth metal amides and hydrides into consideration, the hydroxides and hydrides of the alkali metals, particularly of sodium and potassium are preferred and sodium and potassium hydroxide are particularly preferred.

The compounds according to the present invention, including the physiologically acceptable salts thereof, have activity as antagonists of the MCH receptor, particularly the MCH-1 receptor, and exhibit good affinity in MCH receptor binding studies. Pharmacological test systems for MCH-antagonistic properties are described in the following experimental section. As antagonists of the MCH receptor the compounds according to the invention are advantageously suitable as pharmaceutical active substances for the prophylaxis and / or treatment of symptoms and / or diseases caused by MCH or are otherwise causally connected with MCH. In general, the compounds of the invention have a low toxicity, a good oral absorbability and intracerebral transitivity, particularly Himgängigkeit on.

Therefore, MCH antagonists which contain at least one compound of the invention, especially in mammals, such as rats, mice, guinea pigs, rabbits, dogs, cats, sheep, horses, pigs, cattle, monkeys and humans, for the treatment and / or prophylaxis of symptoms and / or diseases caused by MCH or otherwise causally connected with MCH are suitable.

Diseases caused by MCH or are otherwise causally connected with MCH are particularly metabolic disorders such as obesity, and eating disorders such as bulimia, nervosa including bulimia. The indication obesity includes mainly exogenous obesity, hyperinsulinärer obesity, hyperplasmischer obesity, hyperphysealer obesity, hypoplasmischer obesity, hypothyroider obesity, hypothalamic obesity, symptomatic obesity, infantile obesity, upper body obesity, alimentary obesity, hypogonadal obesity and central obesity. Furthermore, be mentioned in this indications also includes cachexia, anorexia and hyperphagia.

Compounds of the invention may be particularly suitable for reducing hunger, curbing appetite, controlling eating behavior and / or inducing a feeling of satiety.

In addition to the diseases caused by MCH or MCH in another causal relationship, hyperlipidemia, cellulitis,

Fat accumulation, malignant mastocytosis, systemic mastocytosis, emotional disorders, affective disorders, depression, anxiety, sleep disorders, reproductive disorders, sexual disorders, memory disorders, epilepsy, forms of dementia and hormonal disorders are. Compounds of the invention are associated also as active ingredients for the prophylaxis and / or treatment of other diseases and / or disorders, particularly those associated with obesity, such as diabetes, diabetes meliitus, especially 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 suitable.

Invention MCH antagonists and formulations can be advantageous in combination with an alimentary therapy, such as an alimentary therapy of diabetes, and exercise can be used.

A further area of ​​indication for which the compounds of the invention are advantageously suitable is the prophylaxis and / or treatment of micturition disorders such as urinary incontinence, overactive bladder, urgency, nycturia, enuresis, wherein the overactive bladder and urinary urgency with or not with benign prostatic hyperplasia in need to connect to stand.

In general, compounds of the invention are potentially suitable, addictions, such as alcohol and / or nicotine addiction, and / or withdrawal symptoms, such as weight gain in smoking cessation in smokers prevent and / or treat. By "dependency" is used herein generally to achieve or to eliminate discomfort understood an irresistible urge to take an addictive substance and / or to perform certain actions, particularly in order either a sense of well-being. In particular, a substance addiction is here under "dependency" understood. By "withdrawal symptoms" here generally understood symptoms that occur or the withdrawal of addictive substances in one or more of these addictive substances dependent patients may occur. The compounds of the invention are particularly potentially as active substances for reducing or ending the use of tobacco, for the treatment or prevention of a nicotine dependency and / or for the treatment or prevention of nicotine withdrawal symptoms, for reducing the craving for tobacco and / or nicotine and generally as a anti-smoking agents suitable. The compounds of the invention may be useful to prevent the typical in smoking cessation in smokers gain weight or reduce it at least. The substances can continue to be useful as agents acting on the request and / or prevent a relapse into a dependency on addictive substances or at least reduce. Examines means not only psycho-motor-active substances such as narcotics or illicit drugs, especially alcohol, nicotine, cocaine, amphetamine, opiates, benzodiazepines and barbiturates are particularly but understood.

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

For this purpose, the compounds of general formula I according to the invention, optionally in combination with other active substances as they are described in detail below, together with one or more inert conventional carriers and / or diluents, eg with corn starch, lactose, sucrose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water / ethanol, water / glycerol, water / sorbitol, water / polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethylcellulose or fatty substances such as hard fat or suitable mixtures thereof, into conventional galenic preparations such as tablets, coated tablets incorporated capsules, lozenges, powders, granules, solutions, emulsions, syrups, inhalation aerosols, ointments or suppositories.

In addition to pharmaceutical compositions, the invention also includes compositions containing at least one inventive alkyne compound and / or a salt according to the invention optionally together with one or more physiologically acceptable excipients. Such compositions can, for example, also foods that can be solid or liquid, be in the compound of the invention is incorporated.

For the combinations mentioned above in particular those as additional active substances which, for example, potentiate the therapeutic effect of an MCH antagonists of the present invention in view of the indications mentioned and / or allow a reduction of the dosage of an MCH antagonist according to the invention. Preferably one or more additional active substances are 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 hypertension, agents for the treatment of hyperlipidemia, including arteriosclerosis, - active substances for the treatment of Dyslipidemia, including arteriosclerosis, active substances for the treatment of arthritis,

- active substances for the treatment of anxiety, drugs used to treat depression.

Subsequently, the drug classes mentioned above are explained in more detail with examples.

Examples of agents for the treatment of diabetes are insulin sensitisers, insulin secretion accelerators, biguanides, insulins, α-glucosidase inhibitors, SS3 Adreno receptor agonists.

Insulin sensitizers 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, GW-1929th

Insulin secretion accelerators include sulfonylureas such as Tolbutamide, Chlorpropamide, Tolzamide, acetohexamide, Glyclopyramide and its ammonium salts, glibenclamide, gliclazide, glimepiride. Further examples of insulin Sektretionsbeschleunigem are repaglinide, nateglinide, mitiglinide (KAD-1229), JTT 608th

Biguanides include metformin, buformin, phenformin. Insulins include from animals, particularly cattle or pigs, insulins derived, semisynthetic human insulins which are synthesized enzymatically from animal-derived insulin, human insulin, by genetic engineering, such as Escherichia coli or yeasts obtained. Further, insulin-zinc (containing 0.45 to 0.9 percent by weight of zinc) and protamine-insulin-zinc obtainable from zinc chloride, protamine sulfate and insulin, understood as insulin. In addition, insulin from insulin fragments or derivatives (for example INS-1, etc.) are obtained. Insulin also different types may include, for example, with respect to the time of occurrence and duration of action ( "ultra immediate action type," "immediate action type," "two phase type", "intermediate type", "prolonged action type", etc.), which are selected depending on the pathological condition of the patients. α-glucosidase inhibitors include acarbose, voglibose, miglitol, emiglitate.

-ß3 Adreno receptor agonists include AJ-9677, BMS-196085, SB-226552, AZ40140.

Other than the aforementioned agents to treat diabetes include ergoset, Pramiintide, leptin, BAY-27-9955 as well as glycogen phosphorylase inhibitors, sorbitol dehydrogenase inhibitors, protein tyrosine phosphatase 1 B inhibitors, dipeptidyl protease inhibitors, glipizide, glyburide.

Drugs for the treatment of diabetic complications include for example aldose reductase inhibitors, glycation inhibitors, protein kinase C inhibitors, DPPIV blockers, GLP-1 or GLP-1 analogs, SGLT-2 inhibitors.

Aldose reductase inhibitors are for example tolrestat, epalrestat, imirestat, zenarestat, SNK-860, zopolrestat, ARI-50Ϊ, AS-3201 each.

An example of a glycation inhibitor is pimagedine.

Protein kinase C inhibitors are for example NGF, LY-333,531th

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

GLP-1 analogues are for example Liraglutide (NN2211) (NovoNordisk), CJC1131 (Conjuchem), Exenatide (Amlyin).

SGLT-2 inhibitors are for example AVE-2268 (Aventis) and T-1095 (Tanabe, Johnson & Johnson). Other than the aforementioned active ingredients for the treatment of diabetic complications include alprostadil, thiapride hydrochloride, cilostazol, mexiletine hydrochloride, ethyl eicosapentate, memantine, pimagedine (ALT-711).

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

A preferred example of a lipase inhibitor is orlistat. Examples of preferred anorectics are phentermine, mazindol, dexfenfluramine, fluoxetine, sibutramine, Baiamine, (S) -Sibutramine, SR-141716, NGD-95-1.

Other than the aforementioned active ingredients for the treatment of obesity include lipstatin.

Further, the anorectic are counted for the purposes of this application the active substance group of anti-obesity agents, wherein the beta 3 agonists, thyromimetic active substances and NPY antagonists should be emphasized. The scope of this coming as the preferred anti-obesity or anorektiöche active substances in question is exemplified by the following additional list: phenylpropanolamine, ephedrine, pseudoephedrine, phentermine, a cholecystokinin-A (hereinafter referred to as CCK-A) agonist, a monoamine reuptake ( reuptake) -lnhibitor (such as sibutramine), a sympathomimetic agent, a serotonergic agent (such as dexfenfluramine, - fenfluramine, or a 5-HT2C agonist such as BVT.933 or APD356, or duloxetine), a dopamine agonist (such as Bromocriptine or pramipexole), a melanocyte-stimulating hormone receptor agonist or mimetic, an analogue of melanocyte-stimulating hormone, a cannabinoid receptor antagonist (rimonabant, Acomplia TM), an MCH antagonist, the OB protein (hereinafter referred to as leptin hereinafter), a leptin analog , a fatty acid synthase (FAS) antagonist, a leptin receptor agonist, a galanin antagonist, a GI lipase inhibitor or reducer (such as orlistat). Other anorectic agents include bombesin agonists, dehydroepiandrosterone or its analogues, glucocorticoid receptor agonists and antagonists, orexin receptor antagonists, urocortin binding protein antagonists, agonists of the Glukogon like peptide-1 receptor such as Exendin, AC 2993, CJC-1131, ZP10 or GRT0203Y, DPPIV inhibitors and ciliary neurotrophic factors such as axokine. In addition, in this context forms of therapy are to mention the lead by increasing fatty acid oxidation in peripheral tissues to weight loss, such as inhibitor of acetyl-CoA carboxylase.

Drugs for the treatment of high blood pressure include inhibitors of angiotensin converting enzyme, calcium antagonists, potassium channel openers, angiotensin II antagonists. Inhibitors of angiotensin converting enzyme inhibitors, captopril, enalapril, alacepril, delapril include (hydrochloride), lisinopril, imidapril, benazepril, cilazapril, temocapril, trandolapril, Manidipine (Hydrochloride).

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

Potassium channel openers include levcromakalim, L-27152, AL0671, NIP-121st

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

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

Fibrate compounds include bezafibrate, clinofibrate, clofibrate, simfibrate.

Drugs for the treatment of Dyslipidemia, including arteriosclerosis, include, for example drugs that increase HDL Speigel, such as nicotinic acid and their derivatives and preparations, such as Niaspan, as well as agonists of the nicotinic acid receptor.

Drugs for the treatment of arthritis include NSAIDs (non-steroidal antiinflammatory drugs), particularly COX2 inhibitors, such as for example meloxicam or ibuprofen. Drugs for the treatment of anxiety disorders include chlordiazepoxide, diazepam, oxazolam, medazepam, Cloxazolam, bromazepam, lorazepam, alprazolam, fludiazepam.

Drugs to treat depression include fluoxetine, fluvoxamine, imipramine, paroxetine, sertraline.

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

In a further embodiment, the invention also relates to the use of at least one alkyne compound according to the invention and / or a salt of the invention for influencing the eating behavior of a mammal. This use is based inter alia that compounds of the invention may be suitable for reducing hunger, curbing appetite, controlling eating behavior and / or inducing a feeling of satiety. The eating behavior is advantageously influenced, that food intake is reduced. Therefore, compounds of the invention are advantageously used for reducing body weight. Another use of the invention is to prevent an increase in body weight, for example in people who had previously taken steps to lose weight and are then interested in maintaining their lower body weight. According to this embodiment it is preferably a non-therapeutic use. Such a non-therapeutic use can be a cosmetic use, for example to alter the external appearance, or an application to improve general health. The compounds of the invention are not used therapeutically, preferably for mammals, particularly humans, which have no diagnosed eating disorders, no diagnosed obesity, bulimia, diabetes and / or no diagnosed micturition disorders, particularly urinary incontinence. Preferably, compounds of the invention for the non-therapeutic use for humans are suitable whose body weight index (BMI = body mass index), defined as the measured in kilogram of body weight divided by height is defined (in meters) squared, is below the value 30, particularly below 25, is located.

The following examples illustrate the invention: Preliminary remarks:

For compounds prepared are provided in a rule, IR, H-NMR and / or mass spectra. Unless otherwise stated, Rf values using, of DC precoated plates Kieselgel 60 F254 (E. Merck, Darmstadt, Item no. 1.05714) without chamber saturation are determined. The R f values obtained under the name Alox are determined using ready-made TLC plates 60 F254 alumina (E. Merck, Darmstadt, Item no. 1.05713) without chamber saturation.

For chromatographic purification, silica gel made by Millipore (MATREX ™, 35-70 my) or Alox (E. Merck, Darmstadt, standardized aluminum oxide 90, 63-200 microns, Reference: 1.01097.9050) is used. The ratios given for the eluants relate to units by volume of the respective solvent.

The units by volume specified for NH3 solutions relate to a concentrated solution of NH 3 in water. Unless otherwise noted, the acid used for working up the reaction solutions, base and salt solutions aqueous systems is surrounded concentrations.

In asymmetric dihydroxylation which are marketed by the company Aldrich

"AD-Mix-Alpha" (Code: 39.275 to 8) and "AD-mix-beta" (Code: 39.276 to 6) is used.

The HPLC data provided are measured using the parameters listed below:

Analytical column: Zorbax column (Agilent Technologies), SB (Stable Bond) C18; 3.5 microns; 4.6 x 75 mm; Column temperature: 30 ° C; Flow: 0.8 mL / min; Injection Volume: 5 ul; Detection at 254 nm (methods A, B, C and D)

Method A:

Analytical columns: Zorbax column (Agilent Technologies), Bonus-RP C14; 3.5 microns; 4.6 x 75 mm; Column temperature: 30 ° C; Flow: 0.8 mL / min; Injection Volume: 5 ul; Detection at 254 nm (Method E) Method E:

Preparative column: Zorbax column (Agilent Technologies), SB (Stable Bond) C18; 3.5 microns; 30 x

100 mm; Column temperature: room temperature; Flow: 30 mL / min; Detection at 254 nm.

In preparative HPLC purifications as a rule the same gradients are used which have been used in collecting the analytical HPLC data.

mass control the collection of products, the product fractions are combined and freeze-dried.

Temperatures are given in degrees Celsius (° C); Periods are generally in

Minutes (min), hours (h) or days (d) specified.

If further details as to the configuration, it remains unclear whether there are pure enantiomers or whether partial or even total racemisation has occurred.

Above and below, the following abbreviations are used: abs. absolute

CDI carbonyldiimidazole

Cyc cyclohexane

DCM dichloromethane

DIPE diisopropyl ether DMF dimethylformamide dppf 1, 1 '-bis (diphenylphosphino) ferrocene

EtOAc ethyl acetate

EtOH ethanol i. vac. MeOH methanol in vacuo

MTBE methyl tert-butyl ether

PE petroleum ether

RT room temperature (approximately 20 ° C)

TBAF tetrabutylammonium fluoride hydrate THF tetrahydrofuran dil. Diluted

→ * denotes the binding site of a residue

Amine A1 (3S, 4R) -4-trifluoromethyl-piperidine-3,4-diol

A1 a 1-benzyl-4-trifluoromethyl-pyridiniurnchlorid

To a solution of 10.0 g (65.94 mmol) of 4-trifluoromethyl-pyridine in 40 mL of acetonitrile, a solution of 7:59 ml (65.94 mmol) of benzyl chloride was added in 10 mL acetonitrile and the mixture stirred for 2 h at 80 ° C. A further 1.5 ml of benzyl chloride are added and the

Mixture 22 h at 80 ° C. The reaction mixture is cooled to RT and treated with MTBE. The precipitate is filtered, washed with MTBE, i. vac. dried and concentrated in

stored desiccator.

Yield: 14:48 g (. 80% of theory) C 13 H 11 F 3 N * CI (M = 273,681) Calc .: molecular peak (M + H) +: 238. Found .: molecular peak (M + H) +: 238

A1 b 1 -benzyl-4-trifluoromethyl-1, 2,3,6-tetrahydro-pyridine

To a solution of 14:48 g (52.91 mmol) of 1-benzyl-4-trifluoromethyl-pyridinium chloride in 100 mL EtOH under strong cooling at 0 ° C in portions 3.0 g (79.36 mmol) of NaBH 4 was added, then the cooling was removed and the reaction mixture 1.5 stirred at 14 ° C. While cooling within 30 min 50 mL of water and then 50 mL of EtOH was added. The reaction mixture is stirred an additional 30 min, the resulting

Suspension filtered and the filtrate i. vac. concentrated. Yield: 11.12 g (92% theory d.)

C 13 H 14 F 3 N (M = 241,252) Calc .: molecular peak (M + H) +: 242. Found .: molecular peak (M + H) +: 242

HPLC-MS: 3.60 min (Method B)

A1c (3S, 4R) -1-benzyl-4-trifluoromethyl-piperidine-3,4-diol

43.80 g of AD-mix-beta is dissolved in 3 L of tert-butanol / water (1: 1) were charged and stirred for 20 min at RT. The mixture is cooled to 0 ° C, 2.97 g (31.25 mmol) of methanesulfonamide and 7:54 g (31.25 mmol) of 1-benzyl-4-trifluoromethyl-1, 2,3,6-tetrahydro-pyridine are added, the cooling bath was removed and 8 d stirred at RT. A further 22 g of AD-mix-beta, and 1.5 g of methanesulfonamide was added and again stirred for 7 d at RT. 11.2 g Nätriumsulfit are added and stirred for 1 h. 200 mL half-saturated NaHCO 3 solution are added and the aqueous phase extracted with DCM exhaustive. The combined organic phases are dried over Na 2 SO 4 i. vac. concentrated. The crude product is purified by MPLC MS (Grom-Sil 120 ODS 4, 10 micron, gradient 00:15% formic acid in water / acetonitrile 90:10 → 10:90 in 10 min.). The eluates are combined, i. vac. concentrated and neutralized 3 solution with 100 mL of half-saturated NaHCO. The aqueous phase is extracted with EtOAc, dried the combined organic phases over Na 2 SO 4 and i. vac. concentrated. - .: Yield: 1:51 g (17% of theory.) C 13 H 16 F 3 NO 2 (M = 275,267) Calc .: molecular peak (M + H) +: 276 Found .: molecular peak (M + H) +: 276 Rf value: 0.40 (silica gel, Cyc / EtOAc 2: 1)

A1d (3S, 4R) -4-trifluoromethyl-piperidine-3,4-diol

A mixture of 1.50g (5:45 mmol) of (3S, 4R) -1-Benzyl-4-trifluoromethyl-piperidine-3,4-diol and

170 mg Pd / C (10%) ϊn 17 mL of MeOH at RT and 3 bar hydrogen pressure for 5 h. Of the

Catalyst is filtered off and the filtrate. vac. concentrated.

Yield: 910 mg (. 90% of theory) C 6 H 10 F 3 NO 2 (M = 185,144) Calc .: molecular peak (M + H) +: 186 Found .: molecular peak (M + H) +: 186

R f value: 0.35 (silica gel, EtOAc / MeOH / NH3 7: 3: 0.3)

amine A2

(3R, 4S) -4-trifluoromethyl-piperidine 3,4-diol

A2a (3R, 4S) -1-Benzyl-4-trifluoromethyl-piperidine-3,4-diol

The product is obtained analogously to 1c starting from 5.8 g (24.04 mmol) of 1-benzyl-4-trifluoromethyl-

1, 2,3,6-tetrahydro-pyridine and AD-mix-alpha obtained. The crude product is purified by HPLC-MS.

Yield: 1.09g (16% theory d.)

C 13 H 16 F 3 NO 2 (M = 275,267) Calc .: molecular peak (M + H) +: 276 Found .: molecular peak (M + H) +: 276

HPLC-MS: 3.70 min (Method A) A2b (3R, 4S) -4-trifluoromethyl-piperidine-3,4-diol

The product is analogous starting A1d from 1.09g (3.96 mmol) of (3R, 4S) -1-benzyl-4- receive trifluoromethyl-piperidine-3,4-diol. Yield: 665 mg (. 91% of theory) C 6 H 10 F 3 NO 2 (M = 185,144) Calc .: molecular peak (M + H) +: 186 Found .: molecular peak (M + H) +: 186 R f value: 12:35 (silica gel, EtOAc / MeOH / NH3 7: 3: 0.3)

Amine A3 - (3R, 4S) -4-methyl-piperidine-3,4-diol OH X> (X

A3a 1-benzyl-4-methyl-1, 2,3,6-tetrahydro-pyridine

The product is b, starting from 10.0 g (45.5 mmol) obtained analogously A1 1-benzyl-4-methyl- pyridinium. Yield: 7.15 g (. 84% of theory) C 13 H 17 N (M = 187,281) Calc .: molecular peak (M + H) +: 188 Found .: molecular peak (M + H) +: 188 R f value: 0.95 (silica gel , EtOAc / MeOH / NH 3 9: 1: 0.1)

A3b (3R, 4S) -1-benzyl-4-methyl-piperidine-3,4-diol

Under nitrogen atmosphere, 14 g of AD-mix alpha in 50 mL water and 50 mL tert-butanol are initially introduced and the mixture stirred for 20 min at RT. The mixture is then cooled to 0 ° C, 0.95 g (10.0 mmol) Methansulfonsäureamid and 1.87 g (10.0 mmol) of 1-benzyl-4-methyl-1, 2,3,6-tetrahydro-pyridine was added, the cooling bath removed and the reaction mixture 24 stirred at RT. To the reaction mixture 3.5 g of sodium sulfite are added and stirred for 1 h. It is mixed with 200 mL DCM and 200 mL of saturated NaHCO 3 solution, the organic phase is separated off and extracted with 100 mL KHSO - solution. The aqueous phase is adjusted with saturated K 2 CO 3 solution alkaline, extracted with 200 mL EtOAc and the organic phase over Na 2 SO 4 dried. purified After the desiccant and solvent the crude product by chromatography is (0.1 silica gel, EtOAc / MeOH / NHs 19: 1). Yield: 1.23 g (. 56% of theory) C 13 H 19 NO 2 (M = 221,296) Calc .: molecular peak (M + H) +: 222. Found .: molecular peak (M + H) +: 222 R f value: 12:56 ( silica gel, EtOAc / MeOH / NH 3 19: 1: 0.1) A3c (3R, 4S) -4-methyl-piperidine-3,4-diol

The product is obtained analogously A1d starting from 1.23 g (5.57 mmol) of (3R, 4S) -1 -benzyl-4-methyl- piperidine-3,4-diol. Yield: 730 mg C (yield quant.) 6 H 13 NO 2 (M = 131,173) Calc .: molecular peak (M + H) +: 132. Found .: molecular peak (M + H) +: 132 HPLC-MS: 0.93 min (method C)

Amin A4

(3S, 4R) -4-methyl-piperidine-3,4-diol

A4a (3S, 4R) -1-benzyl-4-methyl-piperidine-3,4-diol

The product is obtained analogously A3b starting from 5.0 g (26.7 mmol) of 1-benzyl-4-methyl-1, 2,3,6- tetrahydro-pyridine and AD-mix-beta.

Yield: 4.68 g (79% theory d.)

C 13 H 19 NO 2 (M = 221,296) Calc .: molecular peak (M + H) +: 222. Found .: molecular peak (M + H) +: 222

R f value 0.54 (silica gel, EtOAc / MeOH / NH 3 9: 1: 0.1)

A4b (3S, 4R) -4-methyl-piperidine-3,4-diol

The production is analogous A1d starting from 4.68 g (21:14 mmol) of (3S, 4R) -1-benzyl-4-methyl-piperidine-3,4-diol obtained.

Yield: 2:33 g (. 84% of theory) C 6 H 13 NO 2 (M = 131,173) Calc .: molecular peak (M + H) +: 132. Found .: molecular peak (M + H): 132

R f value: 0.05 (silica gel, EtOAc / MeOH / NH 3 9: 1: 0.1)

Amine A5 (3R, 4S) -3-methyl-piperidine-3,4-diol

A5a 1-benzyl-3-methyl-pyridinium chloride

The product is obtained from 41.8 mL (430 mmol) of 3-methylpyridine analogously A1a. Yield: 73.8 g (. 78% of theory) C 13 H 14 N * CI (M = 219,710) Calc .: molecular peak (M) +: 184. Found .: molecular peak (M) +: 184

A5b 1-benzyl-5-methyl-1, 2,3,6-tetrahydro-pyridine

The product is obtained 1-benzyl-3-methyl pyridinium chloride analogously A1b starting from 40.0 g (182 mmol). Yield: 14.9 g (. 44% of theory) C 13 H 17 N (M = 187,281) Calc .: molecular peak (M + H) +: 188 Found .: molecular peak (M + H) +: 188 R f value: 12:32 (silica gel , Cyc / EtOAc 4: 1)

A5c (3R, 4S) -1-Benzyl-3-methyl-piperidine-3,4-diol

The product (40.0 mmol) of 1-benzyl-5-methyl-1, 2,3,6- tetrahydro-pyridine and AD-mix-alpha obtained starting from 7.5 g analogous A3b.

Yield: 5.73 g (65% theory d.)

C 13 H 19 NO 2 (M = 221,296) Calc .: molecular peak (M + H) +: 222. Found .: molecular peak (M + H) +: 222

R f value: 0.63 (silica gel, EtOAc / MeOH / NH 3 9: 1: 0.1)

A5d (3R, 4S) -3-methyl-piperidine-3,4-diol

The product is obtained analogously A1d starting from 5.73 g (25.9 mmol) of (3R, 4S) -1-benzyl-3-methyl-piperidine-3,4-diol.

Yield: 3.4 g C (. Quant yield) 6 H 13 NO 2 (M = 131,173) Calc .: molecular peak (M + H) +: 132. Found .: molecular peak (M + H) +: 132

R f value: 0.05 (silica gel, EtOAc / MeOH / NH 3 9: 1: 0.1)

A6 amine (3S, 4R) -3-methyl-piperidine-3,4-diol

A6a (3S, 4R) -1-benzyl-3-methyl-piperidine-3,4-diol

The product (40.0 mmol) of 1-benzyl-5-methyl-1, 2,3,6- tetrahydro-pyridine and AD-mix-beta obtained starting from 7.5 g analogous A3b. Yield: 7:42 g (. 84% of theory) C 13 H 19 NO 2 (M = 221,296) Calc .: molecular peak (M + H) +: 222. Found .: molecular peak (M + H) +: 222 R r value: 0.63 (silica gel, EtOAc / MeOH / NH 3 9: 1: 0.1)

A6b (3S, 4R) -3-methyl-piperidine-3,4-diol

The product is obtained analogously A1d starting from 8.86 g (40.0 mmol) of (3S, 4R) -1-benzyl-3-methyl-piperidine-3,4-dioi. Yield: 5:03 g (. 96% of theory) C 6 H 13 NO 2 (M = 131,173) Calc .: molecular peak (M + H) +: 132. Found .: molecular peak (M + H) +: 132 R f value: 12:17 ( silica gel, EtOAc / MeOH / NH 3 5: 5: 0.5)

A7 amine (3S, 4R) -4-ethyl-piperidine-3,4-diol

A7a 1-benzyl-4-ethyl-pyridinium chloride

The product is obtained from 100 mL (933 mmol) of 4-ethylpyridine analog A1a. Yield: 143 g (. 66% of theory) C 14 H 16 N * CI (M = 233,736) Calc .: molecular peak (M + H) +: 198 Found .: molecular peak (M + H) +: 198 R f value: 0.12 (silica gel, EtOAc / MeOH / NH 3 9: 1: 0.1)

A7b 1-benzyl-4-ethyl-1, 2,3,6-tetrahydro-pyridine

The product is obtained 1-benzyl-4-ethyl pyridinium chloride analogously A1b starting from 143 g (614 mmol).

Yield: 99 g (80% of theory.)

C 14 H 19 N (M = 201,307) Calc .: molecular peak (M + H) +: 202. Found .: molecular peak (M + H) +: 202

R f value: 0.91 (silica gel, EtOAc / MeOH / NH 3 9: 1: 0.1)

A7c (3S, 4R) -1-benzyl-4-ethyl-piperidine-3,4-diol

The product (71.4 mmol) of 1-benzyl-4-ethyl-1, 2,3,6- tetrahydro-pyridine and AD-mix-beta obtained from 14.37 g analogous A3b.

Yield: 11:46 g (. 68% of theory) C 14 H 21 NO 2 (M = 235,322) Calc .: molecular peak (M + H) +: 236. Found .: molecular peak (M + H) +: 236 R f value: 12:58 ( silica gel, EtOAc / MeOH / NH 3 95: 5: 0.5)

A7d (3S, 4R) -4-ethyl-piperidine-3,4-diol

The product can be obtained analogously A1d, starting from (3S, 4R) -1-benzyl-4-ethyl-piperidine-3,4-diol.

the enantiomer (3R, 4S) -4-ethyl-can piperidine-3,4-diol are obtained analogously to the described sequence.

A8 amine cis-pyrrolidine-3,4-diol OH H H0 τ3

A8a 1-benzyl-2,5-dihydro-1 H-pyrrole To a solution of 10 mL (127 mmol) of 2,5-dihydro-1 H-pyrrole in 100 mL acetonitrile

14.6 mL (127 mmol) of benzyl chloride added dropwise, keeping the reaction mixture heated to 45 ° C. the precipitate after 1.5 h added to the suspension 300 mL MTBE, suction filtered and the filtrate was concentrated. The residue is purified by chromatography (silica gel,

EtOAc / MeOH / NH 3 19: 1: 0.1) to give. Yield: 4.0 g (. 20% of theory) dιH 13 N (M = 159,228) Calc .: molecular peak (M + H) +: 160 Found .: molecular peak (M + H) +: 160

R f value: 0.60 (silica gel, EtOAc / MeOH / NH 3 19: 1: 0.1)

A8b cis-1-benzyl-pyrrolidine-3,4-diol

The product (25.1 mmol) of 1-benzyl-2,5-dihydro-1H-A3b obtained analogously, starting from 4.0 g pyfrol and AD-mix-beta.

Yield: 0.97 g (20% theory d.)

CnH 15 NO 2 (M = 193,242) Calc .: molecular peak (M + H) +: Found 194th. Molecular peak (M + H) +: 194

R f value: 0.15 (silica gel, EtOAc / MeOH / NH 3 9: 1: 0.1)

A8c cis-pyrrolidine-3,4-diol The product is (5:04 mmol) obtained analogously A1d starting from 0.97 g cis-1-benzyl-pyrrolidine-3,4-diol.

Yield: 0.52g (yield quant.) C 4 H 9 NO 2 (M = 103,120) Calc .: molecular peak (M + H) +: 104. Found .: molecular peak (M + H) +: 104 R f value: 0.05 (silica gel, EtOAc / MeOH / NH 3 5: 5: 0.5)

A9 amine (3R, 4S) -piperidine-3,4-diol

A9a (3R, 4S) -1-benzyl-piperidine-3,4-diol

The product (46.17 mmol) of 1-benzyl-1, 2,3,6-tetrahydro-pyridine and AD-mix-alpha obtained starting from 8.0 g analogous A3b. Yield: 6.40 g (. 67% of theory) C 12 H 17 NO 2 (M = 207,269) Calc .: molecular peak (M + H) +: 208. Found .: molecular peak (M + H) +: 208 R f value: 12:24 ( silica gel, EtOAc / MeOH / NH 3 9: 1: 0.1)

A9b (3R, 4S) -piperidine-3,4-diol The product is obtained analogously A1d starting from 6.4 g (30.86 mmol) of (3R, 4S) -1-benzyl-piperidine

3,4-diol obtained.

Yield: 3.83 g (yield quant.)

C 5 HιιNO 2 (M = 117,146) Calc .: molecular peak (M + H) +: 118. Found .: molecular peak (M + H) +: 118 R r value: 0.13 (silica gel, EtOAc / MeOH / NH 3 5: 5 : 0.5)

Amine A10 (3S, 4R) -piperidine-3,4-diol

A10a (3S, 4R) -1-benzyl-piperidine-3,4-diol The product is obtained starting from 8.0 g analogous A3b (46.17 mmol) of 1-benzyl-1, 2,3,6-tetrahydro-pyridine and AD-mix beta received. Yield: 6.13 g (. 64% of theory) Cι 2 H, 7 NO 2 (M = 207,269) Calc .: molecular peak (M + H) +: 208. Found .: molecular peak (M + H) +: 208 R f value: 12:35 (silica gel, EtOAc / MeOH / NH 3 9: 1: 0.1)

A10b (3S, 4R) -piperidine-3,4-diol

The product is obtained analogously A1d starting from 6.13 g (29.56 mmol) of (3S, 4R) -1-benzyl-piperidine-3,4-diol.

Yield: 3.75 g (yield quant.)

C 5 HnNO 2 (M = 117,146) Calc .: molecular peak (M + H) +: 118. Found .: molecular peak (M + H) +: 118

R f value: 0.12 (silica gel, EtOAc / MeOH / NH 3 5: 5: 0.5)

Amin A11

4-hydroxymethyl-piperidin-4-ol

A11 a 1-benzyl-4-hydroxymethyl-piperidin-4-ol The product (16.83 mmol) of 1-benzyl-4-methylene-piperidine and AD-mix-alpha obtained from 3.15 g analogous A3b.

Yield: 2.92 g (79% theory d.)

C 13 H 19 NO 2 (M = 221,296) Calc .: molecular peak (M + H) +: 222. Found .: molecular peak (M + H) +: 222 R r value: 0.12 (silica gel, EtOAc / MeOH / NH 3 9 : 1: 0.1)

A11 b 4-hydroxymethyl-piperidin-4-ol

The product is obtained analogously A1d starting from 2.92 g (13:21 mmol) of 1-benzyl-4-hydroxymethyl-piperidin-4-ol. Yield: 1.88 g (yield quant.) C 6 H 13 NO 2 (M = 131,173) Calc .: molecular peak (M + H) +: 132. Found .: molecular peak (M + H) +: 132 R f value: 0.06 (silica gel, EtOAc / MeOH / NH 3 5: 5: 0.5) amine A12 (S) -1-pyrrolidin-2-yl-cyclopropanol

A12a 1 - ((S) -1-benzyl-pyrrolidin-2-yl) -cyclopropanol To a cooled -15 ° C solution of 5.0 g (21:43 mmol) N-benzyl-L-proline ethyl ester in

80 mL of dry diethyl ether are first slowly 6.91 mL (23:57 mmol) of titanium (IV) - isopropoxide and then 14.3 mL (42. 9 mmol, 3 M in diethyl ether) was added dropwise ethyl magnesium bromide and the reaction mixture stirred for 30 min at this temperature.

Then 10 ° C 5.4 mL (42.9 mmol) of boron trifluoride-diethyl ether complex was added at ca and stirred for a further 75 h at RT. Under cooling is mixed with 50 mL 1 M NaOH,

1 h at RT, combined with 100 mL diethyl ether, the organic phase separated and dried over Na 2 SO 4. After the desiccant and solvent the

Residue purified by chromatography (silica gel, EtOAc).

Yield: 0.745 g (16% theory d.) C 14 H 19 NO (M = 217,307) Calc .: molecular peak (M + H) +: 218. Found .: molecular peak (M + H) +: 218

R r value: 0:17 (silica gel, EtOAc)

A12b (S) -1 -pyrrolidin-2-yl--cyclopropanol The product is obtained analogously A1d starting from 745 mg (3:43 mmol) of 1 - ((S) -1-Benzyl-pyrrolidin

2-yl) -cyclopropanol obtained.

Yield: 350 mg (80% of theory.)

C 7 H 13 NO (M = 127,184) Calc .: molecular peak (M + H) +: 128. Found .: molecular peak (M + H) +: 128 R r value: 0.10 (silica gel, EtOAc / MeOH / NH 3 5: 5: 0.5)

Amine A13 (2S, 4R) -2-hydroxymethyl-pyrrolidin-4-ol HO ,,

/ HO A13a (2S, 4R) -4-hydroxy-2-hydroxymethyl-pyrrolidine-1-carboxylic acid fe / if-butyl ester

To a cooled to 0 ° C solution of 5.0 g (21.62 mmol) of (2S, 4R) -4-Hydroxy-pyrrolidine-1, 2- dicarboxylic acid 1-tert-butyl ester in 25 mL dry THF 54 mL (54.0 mmol) borane-THF complex is added dropwise, the reaction mixture an additional 15 min at 0 ° C and then stirred for 4 h at RT. Is mixed under ice cooling with 60 mL MeOH, stirred for a further 62 h at RT and then concentrated i.vac. on. The residue obtained is purified by chromatography (silica gel, EtOAc / MeOH 19: 1). Yield: 4.53 g (. 96% of theory) C 10 H 19 NO 4 (M = 217,262) Calc .: molecular peak (M + H) 4 ": 218 Found .: molecular peak (M + H) +: 218 R f value: 0.50 (silica gel, EtOAc / MeOH 19: 1)

A13b (2S, 4R) -2-hydroxymethyl-pyrrolidine-4-ol

To a cooled to 0 ° C solution of 4:53 g (20.85 mmol) of (2S, 4R) -4-hydroxy-2-hydroxymethyl-pyrrolidine-1-carboxylic acid fetf-butyl ester in 200 mL DCM 16.0 mL TFA are added and the reaction mixture stirred overnight at RT. It is concentrated dried i. and subjecting the product to freeze-drying. The product is obtained as the trifluoroacetate salt. Yield: 4.73 g (. 96% of theory) C 5 H.πNO 2 * C 2 HF 3 θ 2 (M = 231,170) Calc .: molecular peak (M + H) +: 118. Found .: molecular peak (M + H) + 18: 1 R f value: 0.68 (silica gel, EtOAc / MeOH 9: 1)

example 1

(3S, 4R) -1- (2- {4- [5- (4-chloro-phenyl) -pyridin-2-ylethynyl] -2-methyl-phenoxy} -ethyl) -4-trifluoromethyl-piperidine-3, 4-diol

1 a 2- (4-iodo-2-methyl-phenoxy) -ethanol Under N 2 atmosphere to a cooled to 0 ° C suspension of 0.48g (11 mmol) of NaH in 50 mL THF 2:34 g (10 mmol) of 4 -lod ~ 2-methyl-phenol was added portionwise and stirred an additional 30 min at this temperature. Then 0.85 mL (12 mmol) of 2-bromoethanol, dissolved in 5 mL THF was added dropwise and stirred for 18 h at RT. It is mixed with 5 mL DMF and the reaction mixture heated for 8 h at 70 ° C. The mixture is concentrated i. vac. , the residue taken up in water, exhaustively extracted with EtOAc and dried over Na 2 SO 4. After the desiccant and solvent the residue by chromatography (silica gel, Cyc / EtOAc 7: 3) is cleaned. Yield: 12:39 g (. 14% of theory)

C 9 H 11 IO 2 (M = 278,091) Calc .: molecular peak (M + H) +: 279 Found .: molecular peak (M + H) +: 279

R f value: 0:28 (silica gel, Cyc / EtOAc 2: 1)

1b 2- (2-methyl-4-trimethylsilanylethynyl-phenoxy) -ethanol

To a degassed solution of 2.23 g (8:00 mmol) of 2- (4-iodo-2-methyl-phenoxy) -ethanol, 1.22 mL (8.80 mmol) of trimethylsilylacetylene, 185 mg (0.160 mmol) of tetrakis-triphenylphosphane palladium, and 2:38 mL ( 24.00 mmol) of piperidine in 50 mL THF, under argon, 31 mg (0.160 mmol) Cul were added and the mixture stirred for 1 h at RT. The reaction mixture is diluted with water and the aqueous phase extracted with EtOAc exhaustive. The combined organic phases are washed with saturated NaCl solution and

Na 2 SO dried. After the desiccant and solvent the residue by chromatography (silica gel, Cyc / EtOAc 2: 1) is cleaned. Yield: 1.70 g (86% theory d.)

C 14 H 20 O 2 Si (M = 248,393) Calc .: molecular peak (M + H) +: 249 Found .: molecular peak (M + H) +: 249

R f value: 0:24 (silica gel, Cyc / EtOAc 2: 1)

1c 2- (4-ethynyl-2-methyl-phenoxy) -ethanol

To a solution of 16.8 g (67.6 mmol) of 2- (2-methyl-4-trimethylsilanylethynyl-phenoxy) - ethanol in 500 mL THF at RT (74.4 mmol) of TBAF was added 20.8 g and the mixture stirred for 3 h at RT. The reaction mixture is i. vac. concentrated and the residue dissolved in EtOAc. The organic phase is washed with water and saturated NaCl solution and dried over Na 2 SO 4. After the desiccant and solvent the residue without purification is reacted further. Yield: 12.0 g (quant yield.) CnHι 2 O 2 (M = 176,212) Calc .: molecular peak (M) +: 176 Found .: molecular peak (M) +: 176 R r value: 0:24 (silica gel, Cyc / EtOAc 2 :1)

1 d 2- [4- (5-bromo-pyridin-2-ylethynyl) -2-methyl-phenoxy] -ethanol

To a degassed solution of 11.98 g (68.0 mmol) of 2- (4-ethynyl-2-methyl-phenoxy) -ethanol,

11.16 g (68.0 mmol) of 2,5-dibromopyridine, 0.96 g (1:36 mmol) of bis-triphenylphosphane palladium (II) chloride and 19:22 mL (136.0 mmol) of diisopropylamine in 500 mL THF 00:26 g (1:36 mmol) of Cul were added and the mixture stirred for 4 h at RT. The reaction mixture is i. vac. concentrated and the residue taken up in 800 mL EtOAc. The organic phase is washed with water and saturated NaCl solution and dried for 4 .. After the desiccant and solvent the residue by chromatography (silica gel, gradient DCM / EtOAc 90:10 → 80:20) is purified over Na 2 SO. Yield: 13:20 g (. 58% of theory) C 16 H 14 BrN0 2 (M = 332,192) Calc .: molecular peak (M + H) +: 332/334 (Br) Found .: molecular peak (M + H) +: 332/334 (Br) R f value: 0:39 (silica gel, Cyc / EtOAc 1: 1)

1e 2- {4- [5- (4-chloro-phenyl) -pyridin-2-ylethynyl] -2-methyl-phenoxy} -ethanol

To a suspension of 13.20 g (39.74 mmol) of 2- [4- (5-bromo-pyridin-2-ylethynyl) -2-methyl-phenoxy] -ethanol, 9:32 g (59.60 mmol) 4-chlorophenylboronic acid and 2.30 g (1.99 mmol) of tetrakis-triphenylphosphine-palladium in 400 mL 1, 4-dioxane, 40 mL of 2 N NaHCO 3 - solution and the mixture heated under reflux for 12 h. Additional 4.66 g of 4- chlorophenylboronic acid and 1.14 g of tetrakis-triphenylphosphine-palladium are added and the mixture was again heated for 8 hours under reflux. The reaction mixture is i. vac. concentrated and the residue is stirred with EtOAc and water. The precipitate is filtered, washed with Diethlyether and i. vac. dried. Yield: 10.70 g (. 74% of theory) C 22 H 18 CINO 2 (M = 363,837) Calc .: molecular peak (M + H) +: 364/366 (CI) Found .: molecular peak (M + H) +: 364/366 (CI) R f value 0.47 (silica gel, DCM / EtOAc 2: 1)

1f * methanesulfonic acid 2- {4- [5- (4-chloro-phenyl) -pyridin-2-ylethynyl] -2-methyl-phenoxy} - ethyl ester

To a solution of 10.70 g (29.41 mmol) of 2- {4- [5- (4-chloro-phenyl) -pyridin-2-ylethynyl] -2-methyl-phenoxy} -ethanol and 4:08 mL (29.41 mmol) of triethylamine in 500 mL THF are added dropwise at 0 ° C 2.74 mL (35.29 mmol) of methanesulfonyl chloride and the mixture was stirred then for 2 h at RT. The reaction mixture is filtered and the filtrate i. vac. concentrated. The residue is stirred with diethyl ether and water, and the precipitate filtered off and i. vac. dried. Yield 11.00 g (. 85% of theory) C 23 H 20 CINO 4 S (M = 441,928) Calc .: molecular peak (M + H) +: 442/444 (CI) Found .: molecular peak (M + H) + : 442/444 (CI) R r value: 0.73 (silica gel, DCM / EtOAc 1: 1) 1 g of (3S, 4R) -1 - (2- {4- [5- (4-chloro-phenyl) -pyridine -2-ylethynyl] -2-methyl-phenoxy} - ethyl) -4-trifluoromethyl-piperidine-3,4-diol

A mixture of 82.6 mg (0.187 mmol) of methanesulfonic acid 2- {4- [5- (4-chloro-phenyl) - pyridin-2-ylethynyl] -2-methyl-phenoxy} -ethyl ester, 69.2 mg (0.374 mmol) ( 3S, 4R) -4- trifluoromethyl-piperidine-3,4-diol (amine A1) and 0:13 mL (0.748 mmol) N-ethyldiisopropylamine in 1.7 mL of DMF is shaken at 60 ° C 40 h. Filtration through a syringe filter the raw product via HPLC purified. The fractions containing the product are concentrated by evaporation i. concentrated, the residue was treated with 20 mL EtOAc and 10 mL saturated NaHCO 3 solution by stirring, the organic phase separated and dried over Na 2 SO 4. After the desiccant and solvent the residue is stirred with DIPE, suction filtered and dried.

Yield: 39.2 mg (39% theory d.)

C 28 H 26 CIF 3 N 2 O 3 (M = 530,966) Calc .: molecular peak (M + H) +: 531/533 (CI) Found .: molecular peak (M + H) +: 531/533 (CI) HPLC -MS. 8.2 min (method A)

Analog following Examples are prepared starting from Methansuifonsäure-2- {4- [5- (4-chloro-phenyl) -pyridin-2-ylethynyl] -2-methyl-phenoxy} ethyl ester (Example 1f) was prepared and the corresponding amines:

example 15.1

(S) -3 - [(2- {4- [5- (4-chloro-phenyl) -pyridin-2-ylethynyl] -2-methyl-phenoxy} -ethyl) - cyclopropylmethyl-amino] -propane-1, 2-diol

1.15a (2- {4- [5- (4-chloro-phenyl) -pyridin-2-ylethynyl] -2-methyl-phenoxy} -ethyl) - cyclopropylmethyl-amine A mixture of 1.00 g (2.26 mmol) methanesulfonic acid 2- {4- [5- (4-chloro-phenyl) -pyridin-2- ylethynyl] -2-methyl-phenoxy} -ethyl ester, 0.99 mL (11:32 mmol) C-cyclopropyl-methylamine and 1.92 mL (11:32 mmol) ethyldiisopropylamine in 15 mL DMF is stirred for 72 h at 60 ° C. It is concentrated dried i. and the residue is purified by chromatography (1: 0.1 silica gel, EtOAc / MeOH / NH 3 19) purified.

Yield: 0.27g (29% of theory.) C 26 H 25 CIN 2 O (M = 416,942) Calc .: molecular peak (M + H) +: 417/419 (CI) Found .: molecular peak (M + H) + : 417/419 (CI) R f value: 0:39 (silica gel, DCM / MeOH / NH 3 9: 1: 0.1)

1.15b (S) -3 - [(2- {4- [5- (4-chloro-phenyl) -pyridin-2-ylethynyl] -2-methyl-phenoxy} -ethyl) - cyclopropylmethyl-amino] -propane- 1, 2-diol

A mixture of 70 mg (0.168 mmol) of (2- {4- [5- (4-chloro-phenyl) -pyridin-2-ylethynyl] -2-methyl-phenoxy} -ethyl) (-cyclopropylmethyl-amine, 56 .mu.l 0.672 mmol) (R) -3-chloro-propane-1, 2-diol and 0:12 mL (0.672 mmol) N-ethyldiisopropylamine in 1.7 mL of DMF is shaken for 20 h at 80 ° C. Then, the addition of a further 100 .mu.l (1.12 mmol) (R) is carried -3-chloro-propane-1, 2-diol and keeping the reaction mixture further 6 days at this temperature. It is concentrated dried i. , the residue between 10 mL of half-saturated NaHCO 3 solution and 20 mL

EtOAc, the organic phase is separated and dried over Na 2 SO 4. After the desiccant and solvent the residue is purified by chromatography (silica gel,

DCM / MeOH / NH 3 98: 2: 0.2) to give.

Yield: 10 mg (12% theory d.)

C 29 H 3 ιCIN 2 O 3 (M = 491,021) Calc .: molecular peak (M + H) +: 491/493 (CI) Found .: molecular peak (M + H) +: 491/493 (CI) R f value: 0.30 (silica gel, DCM / MeOH / NH 3 19: 1: 0.1)

example 16.1

(R) -3 - [(2- {4- [5- (4-chloro-phenyl) -pyridin-2-ylethynyl] -2-methyl-phenoxy} -ethyl) - cyclopropylmethyl-amino] -propane-1, 2-diol

The product is obtained analogously to Example 1.15b from 70 mg (0.168 mmol) of (2- {4- [5- (4-chloro-phenyl) -pyridin-2-yiethinyl] -2-methyl-phenoxy} -ethyl) - cyclopropylmethyl-amine and 0.28ml (3.35 mmol) of (S) -3-chloro-propane-1, 2-diol. Yield: 29.6 mg (. 36% of theory) C 29 H 31 CIN 2 θ3 (M = 491,021) Calc .: molecular peak (M + H) +: 491/493 (CI) Found .: molecular peak (M + H) + : 491/493 (CI) R f value: 0:24 (silica gel, DCM / MeOH / NH 3 19: 1: 0.1)

Example 17.1 (2- {4- [5- (4-chloro-phenyl) -pyridin-2-ylethynyl] -2-methyl-phenoxy} -ethyl) -cyclopropylmethyl- prop-2-ynyl-amine

To a solution of 60 mg (0.144 mmol) of (2- {4- [5- (4-chloro-phenyl) -pyridin-2-ylethynyl] -2-methyl-phenoxy} -ethyl) -cyclopropylmethyl-amine in 2 mL DMF is added 3-bromo-propyne 39.8 mg K 2 CO 3 and 17 ul (0:16 mmol, 80% in toluene) and the reaction mixture stirred for 2 h at RT. It is concentrated dried i. , the residue between 20 mL water and 40 mL EtOAc, the organic phase is separated and dried over Na 2 SO 4. After the desiccant and solvent the residue is purified by chromatography (Alox, Cyc / EtOAc 9: 1) is cleaned. Yield: 46.1 mg (. 70% of theory) C 29 H 27 CIN 2 O (M = 454,990) Calc .: molecular peak (M + H) +: 455/457 (CI) Found .: molecular peak (M + H) + : 455/457 (CI) R f value: 0.90 (Alox, Cyc / EtOAc 2: 1)

example 18.1

Allyl (2- {4- [5- (4-chloro-phenyl) -pyridin-2-ylethynyl] -2-methyl-phenoxy} -ethyl) -cyclopentyl-amine

1.18a (2- {4- [5- (4-chloro-phenyl) -pyridin-2-ylethynyl] -2-methyl-phenoxy} -ethyl) - cyclopentyl-amine A mixture 1.33 g (3.0 mmol) methanesulfonic acid 2- {4- [5- (4-chloro-phenyl) -pyridin-2- yiethinyl] -2-methyl-phenoxy} -ethyl ester, 1:49 mL (15.0 mmol) cyclopentylamine and 2:57 mL (15.0 mmol) N-ethyldiisopropylamine in 30 mL of DMF is stirred at 36 h 60 ° C. It is concentrated dried i. , the residue is stirred with water and EtOAc, filtered off with suction, the precipitate is dissolved in DCM, the organic phase washed with half-saturated K 2 CO 3 solution and the organic phase is dried over Na 2 SO. After the desiccant and solvent the residue is triturated, filtered off and dried with diethyl ether. Yield: 0.82 g (63% theory d.) C 27 H 27 CIN 2 O (M = 430,969) Calc .: molecular peak (M + H) +: 431/433 (CI) Found .: molecular peak (M + H) + : 431/433 (CI) R f value: 0:21 (silica gel, DCM / MeOH 9: 1)

1.18b allyl (2- {4- [5- (4-chloro-phenyl) -pyridin-2-ylethynyl] -2-methyl-phenoxy} -ethyl) - cyclopentyl-amine

The product is obtained analogously to Example 1.17 starting from 86.2 mg (0:20 mmol) of (2- {4- [5- (4-

Chloro-phenyl) -pyridin-2-ylethynyl] -2-methyl-phenoxy} -ethyl) -cyclopentyl-amine and 42 ul (0:48 mmol) of 3-bromo-propene produced. Yield: 5.1 mg (5% theory d.)

C 30 H 31 CIN 2 O (M = 471,033) Calc .: molecular peak (M + H) +: 471/473 (CI) Found .: molecular peak (M + H) +: 471/473 (CI) HPLC-MS: 6.4 min (method B)

example 19.1

Allyl (2- {4- [5- (4-chloro-phenyl) -pyridin-2-ylethynyl] -2-methyl-phenoxy} -ethyl) -amine -cyclopentylmethyl-

1.19a (2- {4- [5- (4-chloro-phenyl) -pyridin-2-ylethynyl] -2-methyl-phenoxy} -ethyl) - cyclopentylmethyl-amine

A mixture of 1.33g (3.0 mmol) of methanesulfonic acid 2- {4- [5- (4-chloro-phenyl) -pyridin-2- ylethynyl] -2-methyl-phenoxy} -ethyl ester, 595 mg (6.0 mmol) of cyclopentyl -methylamine and 2:57 mL (15.0 mmol) N-ethyldiisopropylamine in 30 mL DMF is stirred for 20 h at 60 ° C. It is concentrated dried i. , the residue is taken up in half-concentrated K 2 CO 3 solution, the organic phase is separated and dried over Na 2 SO 4. After the desiccant and solvent the residue by chromatography (silica gel, DCM / MeOH 95: 5) is cleaned.

Yield: 0.57g (42% of theory.) C 28 H 29 CIN 2 O (M = 444,995) Calc .: molecular peak (M + H) +: 445/447 (CI) Found .: molecular peak (M + H) + : 445/447 (CI) R f value: 0:21 (silica gel, DCM / MeOH 95: 5)

1.19b allyl (2- {4- [5- (4-chloro-phenyl) -pyridin-2-ylethynyl] -2-methyl-phenoxy} -ethyl) - cyclopentylmethyl-amine The product is prepared analogously to Example 1.17 starting from 89.0 mg (0:20 mmol) of (2- {4- [5- (4-chloro-phenyl) -pyridin-2-ylethynyl] -2-methyl-phenoxy} -ethyl) cyclopentylmethyl-amine and 21 ul (0:24 mmol) 3-bromo-propene produced. Yield: 37.4 mg (. 39% of theory) C 31 H 33 CIN 2 O (M = 485,059) Calc .: molecular peak (M + H) +: 485/487 (CI) Found .: molecular peak (M + H) + : 485/487 (CI) HPLC-MS: 6.6 min (method B)

Example 1.20 allyl (2- {4- [5- (4-chloro-phenyl) -pyridin-2-ylethynyl] -2-methyl-phenoxy} -ethyl) -amine

The product is obtained analogously to Example 1.19a from 400 mg (0.91 mmol) of methanesulfonic acid 2- {4- [5- (4-chloro-ph "enyl) -pyridin-2-ylethynyl] -2-methyl-phenoxy} - ethyl ester and 0.2 mL (2.72 mmol) of allylamine prepared yield:. (. 63% of theory) 228 mg of C 25 H 23 CIN 2 O (M = 402,916) Calc .: molecular peak (M + H) +: 403/405 (CI ) Found .: molecular peak (M + H) +: 403/405 (CI) HPLC-MS: 5.4 min (method B) example 1.21 2- (2- {4- [5- (4-chloro-phenyl) -pyridine -2-ylethynyl] -2-methyl-phenoxy} -ethylamino) propan-1, 3-diol

A mixture of 100 mg (0:23 mmol) of methanesulfonic acid 2- {4- [5- (4-chloro-phenyl) -pyridin-2-ylethynyl] -2-methyl-phenoxy} -ethyl ester, 0.15ml (0.91 mmol) ethyldiisopropylamine and 62 mg (0.68 mmol) 2-amino-propane-1, 3-diol in 2.5 mL of DMF is shaken at 60 ° C for 48 h, after 8 hours with a further 63 mg (0.69 mmol) 2-amino-propan-1 , 3-diol was added. After the reaction, the reaction mixture is purified without workup by HPLC. The fractions containing the product are combined and lyophilized. Yield: 50 mg (. 51% of theory) C 25 H 25 CIN 2 O 3 (M = 436,930) Calc .: molecular peak (M + H) +: 437/439 (CI) Found .: molecular peak (M + H) +: 437/439 (CI) HPLC-MS: 6.9 min (method A)

example 22.1

(3R, 4R) -1- (2- {4- [5- (4-chloro-phenyl) -pyridin-2-ylethynyl] -2-methyl-phenoxy} -ethyl) -pyrrolidin-3,4-diol

A mixture of 83 mg (0:19 mmol) of methanesulfonic acid 2- {4- [5- (4-chloro-phenyl) -pyridin-2- ylethynyl] -2-methyl-phenoxy} -ethyl ester, 0:13 mL (0.75 mmol) ethyldiisopropylamine and 39 mg

Now (0.37 mmol) of (3R, 4R) -pyrrolidine-3,4-diol in 1.7 mL of DMF is shaken for 20 h at 60 ° C.

After the reaction, the reaction mixture is purified without workup by HPLC. The fractions containing the product are combined, approximately 10 ml dried i. concentrated, made alkaline with 3 solution of 5% NaHCO, and extracted with 20 ml of hot EtOAc. The organic phase is separated and dried over Na 2 SO 4. After removing the

Desiccant and solvent the residue is triturated with a little DIPE and suction filtered.

Yield: 26 mg (31% theory d.)

C 26 H 25 CIN 2 O 3 (M = 448,941) Calc .: molecular peak (M + H) +: 449/451 (CI) Found .: molecular peak (M + H) +: 449/451 (CI) HPLC-MS : 4.6 min (method B)

Example 2 (3S, 4R) -1- (2- {4- [5- (4-chloro-phenyl) -pyridin-2-ylethynyl] -phenoxy} -ethyl) -4-trifluoromethyl-piperidine-3,4- diol

2a 2- (4-iodo-phenoxy) -ethanol A suspension of 11 g (50 mmol) of 4-iodophenol, 3.88 mL (55 mmol) of 2-bromoethanol and 8.3 g (60 mmol) K 2 CO 3 in 60 mL of acetone is heated for 24 h under reflux. The solvent is evaporated down. removed, the residue treated with water, exhaustively extracted with EtOAc and the organic phase over Na 2 SO 4 dried. After the desiccant and solvent the residue by chromatography (silica gel, Cyc / EtOAc 7: 3) is cleaned. Yield: 2.9 g (22% of theory.) C 8 H 9 IO 2 (M = 264,064) Calc .: molecular peak (M) +: 264. Found .: molecular peak (M) +: 264 R f value: 0:24 (silica gel, Cyc / EtOAc 2: 1)

2b 2- {4- [5- (4-chloro-phenyl) -pyridin-2-ylethynyl] -phenoxy} -ethanol

Under argon atmosphere, to a solution of 2.9 g (11 mmol) of 2- (4-iodo-phenoxy) - ethanol and 2.35 g (11 mmol) of 5- (4-chloro-phenyl) -2-ethynyl-pyridine in 50 mL piperidine 253 mg (0:22 mmol) of tetrakis-triphenylphosphine-palladium and 42 mg (0:22 mmol) of Cul, and the reaction mixture stirred for 30 min at RT. The solvent is evaporated down. removed, the residue treated with water and stirred with EtOAc. The precipitated product is filtered off and dried. Yield: 2.1 g (. 55% of theory) C 21 H 16 CINO 2 (M = 349,820) Calc .: molecular peak (M + H) +: 350/352 (CI) Found .: molecular peak (M + H) +: 350/352 (CI) R r value: 0.42 (silica gel, Cyc / EtOAc 1: 1) 2c methanesulfonic acid 2- {4- [5- (4-chloro-phenyl) -pyridin-2-ylethynyl] -phenoxy} -ethyl ester

The product is {[5- (4-chloro-phenyl) -pyridin-2-ylethynyl] -phenoxy} -ethanol 4- obtained analogously to Example 1f starting 4.40 g (12:58 mmol) 2-. Yield: 4.50 g (. 84% of theory) C 22 H 18 CINO 4 S (M = 427,901) Calc .: molecular peak (M + H) +: 428/430 (CI) Found .: molecular peak (M + H) + : 428/430 (CI) R f value: 0.88 (silica gel, EtOAc)

2d (3S, 4R) -1- (2- {4- [5- (4-chloro-phenyl) -pyridin-2-ylethynyl] -phenoxy} -ethyl) -4-trifluoromethyl-piperidine-3,4-diol

The product is obtained analogously to Example 1g, starting from 80 mg (0.187 mmol)

Methanesulfonic acid 2- {4- [5- (4-chloro-phenyl) -pyridin-2-ylethynyl] -phenoxy} -ethyl ester and 69.2 mg (0.374 mmol) of (3S, 4R) -4-trifluoromethyl-piperidin-3, 4-diol (amine A1) was prepared.

Yield: 43.6 mg (45% of theory.) C 27 H 24 CIF 3 N 2 O 3 (M = 516,939) Calc .: molecular peak (M + H) +: 517/519 (CI) Found .: molecular peak (M + H) +: 517/519 (CI)

HPLC-MS: 1.1 min (Method A)

Analog following Examples are prepared starting from methanesulfonic acid 2- {4- [5- (4-chloro-phenyl) -pyridin-2-ylethynyl] -phenoxy} -ethyl ester (example 2c) were prepared:

example 14.2

(2- {4- [5- (4-chloro-phenyl) -pyridin-2-ylethynyl] -phenoxy} -ethyl) -cyclopropylmethyl- (tetrahydro- pyran-4-yl) -amine

2.14a (2- {4- [5- (4-chloro-phenyl) -pyridin-2-ylethynyl] -phenoxy} -ethyl) - cyclopropylmethyl-amine

The product is analogous to Example 1.19a from 1.71 g (4.0 mmol)

Methanesulfonic acid 2- {4- [5- pyridin-2-ylethynyl (4-chloro-phenyl)] -phenoxy} -ethyl ester, and 2:02 mL (20.0 mmol) C-cyclopropyl-methylamine.

Yield: 0.70 g (43% theory d.)

C 25 H 23 CIN 2 O (M = 402,916) Calc .: molecular peak (M + H) +: 403/405 (CI) Found .: molecular peak (M + H) +: 403/405 (CI)

HPLC-MS: 5.1 min (method B)

2.14b (2- {4- [5- (4-chloro-phenyl) -pyridin-2-ylethynyl] -phenoxy} -ethyl) - cyclopropylmethyl (tetrahydro-pyran-4-yl) -amine

To a solution of 80.6 mg (0.2 mmol) (2- {4- [5- (4-chloro-phenyl) -pyridin-2-ylethynyl] - phenoxy} -ethyl) -cyclopropylmethyl-amine in 10 mL THF 37 .mu.l (0.4 mmol) tetrahydro-pyran-4-one and 1 drop of glacial acetic acid was added and the reaction mixture stirred for 15 min at RT before the addition of 170 mg (0.8 mmol) of NaBH (OAc) 3 is carried out. Stirring is continued for 16 h at RT, diluted with water, exhaustively extracted with EtOAc and dried over Na 2 SO 4.

After the desiccant and solvent the residue is purified by chromatography

(Silica gel, DCM / MeOH 95: 5). Yield: 9 mg (9% of theory.)

C 30 H 31 CIN 2 O 2 (M = 487,032) Calc .: molecular peak (M + H) +: 487/489 (CI) Found .: molecular peak (M + H) +: 487/489 (CI)

R f value: 0:52 (silica gel, DCM / MeOH 95: 5) Example 15.2 1 - [(2- {4- [5- (4-chloro-phenyl) -pyridin-2-ylethynyl] -phenoxy} -ethylamino) -methyl] -cyclopropanol

The product is obtained analogously to Example 1.19a from 1.71 g (4.0 mmol) of methanesulfonic acid 2- {4- [5- (4-chloro-phenyl) -pyridin-2-ylethynyl] -phenoxy} -ethyl ester and 12:54 g (4.8 mmol) of 1-aminomethyl-cyclopropanol prepared. Yield: 12:55 g (. 33% of theory) C 25 H 23 CIN 2 θ 2 (M = 418,915) Calc .: molecular peak (M + H) +: 419/421 (CI) Found .: molecular peak (M + H) +: 419/421 (CI) R f value: 0:18 (silica gel, EtOAc / MeOH / NH 3 95: 5: 0.5)

HPLC-MS: 4.9 min (Method B)

Example 16.2 1 - {[(2- {4- [5- (4-chloro-phenyl) -pyridin-2-ylethynyl] -phenoxy} -ethyl) - (tetrahydro-pyran-4-yl) - amino] -methyl } -cyclopropanol

The product is obtained analogously to Example 2.14b from 83.8 mg (0.2 mmol) of 1 - [(2- {4- [5- (4-chloro-phenyl) -pyridin-2-ylethynyl] -phenoxy} -ethylamino) -methyl ] -cyclopropanol and 37 .mu.l (0.4 mmol) tetrahydro-pyran-4-one. Yield: 2.1 mg (. 2% of theory) C30H3 1 CIN 2 O 3 (M = 503,032) Calc .: molecular peak (M + H) +: 503/505 (CI) Found .: molecular peak (M + H) +: 503 / 505 (CI) R f value 0.47 (silica gel, DCM / MeOH 9: 1)

[(2- {4- [5- (4-chloro-phenyl) -pyridin-2-ylethynyl] -phenoxy} -ethylamino) -methyl] -cyclopropanol (Example 2.15) prepared - analogously to the following Examples are prepared starting from 1

example 20.2

1 - {[(2- {4- [5- (4-chloro-phenyl) -pyridin-2-ylethynyl] -phenoxy} -ethyl) - (3-hydroxy-propyl) -amino] - methyl} -cyclopropanol

To a solution of 83.8 mg (0.2 mmol) of 1 - [(2- {4- [5- (4-chloro-phenyl) -pyridin-2-ylethynyl] - phenoxy} -ethyl-amino) -methyl] -cyclopropanol (Example 15.2 ) in 2 mL DMF, 55.3 mg (0.4 mmol) K 2 CO 3 and 36 .mu.l (0.4 mmol) of 3-bromo-1-propanol and stirred for 24 h, the reaction mixture at RT. There are again added 36 .mu.l (0.4 mmol) of 3-bromo-1-propanol and heated to the reaction mixture for 8 h at 50 ° C. It is concentrated dried i. , the residue taken up in water, extracted exhaustively with DCM and the combined organic phases over Na 2 SO 4. After the desiccant and solvent the residue by chromatography (5: silica gel, EtOAc / MeOH / NH 3 95 0.5) is cleaned. Yield: 22 mg (23% theory d.) C 28 H 29 CIN 2 O 3 (M = 476,994) Calc .: molecular peak (M + H) +: 478/480 (CI) Found .: molecular peak (M + H) +: 478/480 (CI) R f value: 0:34 (silica gel, EtOAc / MeOH 4: 1)

example 21.2

1 - {[(2- {4- [5- (4-chloro-phenyl) -pyridin-2-ylethynyl] -phenoxy} -ethyl) -propyl-amino] -methyl} - cyclopropanol

The product is obtained analogously to Example 2.20 starting from 83.8 mg (0.2 mmol) of 1 - [(2- {4- [5- (4-

Chloro-phenyl) -pyridin-2-ylethynyl] -phenoxy} -ethylamino) -methyl] -cyclopropanol (example 2.15) and 23 ul (0:25 mmol) of 1-bromo-propane produced.

Yield: 22 mg (24% theory d.)

C 28 H 29 CIN 2 O 2 (M = 460,995) Calc .: molecular peak (M + H) +: 461/463 (CI) Found .: molecular peak (M + H) +: 461/463 (CI)

R f value: 0:56 (silica gel, DCM / MeOH 95: 5)

Example 2.22 2- (2- {4- [5- (4-chloro-phenyl) -pyridin-2-ylethynyl] -phenoxy} -ethyl-amino) -propane-1, 3-diol

The product is obtained analogously to Example 1.21 from 100 mg (0.23 mmol) of methanesulfonic acid 2- {4- [5-

(4-chloro-phenyl) -pyridin-2-ylethynyl ethyl ester and 128 mg (1.40 mmol) 2-amino-propane-1,3-diol obtained] -phenoxy}.

Yield: 48 mg (. 49% of theory) C 24 H 23 CIN 2 O 3 (M = 422,904) Calc .: molecular peak (M + H) +: 423/425 (CI) Found .: molecular peak (M + H) +: 423/425 (CI)

HPLC-MS: 6.6 min (method A) Example 2.23 (3R, 4R) -1- (2- {4- [5- (4-chloro-phenyl) -pyridin-2-ylethynyl] -phenoxy} -ethyl) - pyrrolidine-3,4-diol

The product is obtained analogously to Example 1.22 from 80 mg (0.19 mmol) of methanesulfonic acid 2- {4- [5- (4-chloro-phenyl) -pyridin-2-ylethynyl] -phenoxy} -ethyl ester and 39 mg (0.37 mmol) ( 3R, 4R) - pyrrolidine-3,4-diol obtained. Yield: 34 mg (. 42% of theory) C 25 H 23 CIN 2 θ 3 (M = 434,915) Calc .: molecular peak (M + H) +: 435/437 (CI) Found .: molecular peak (M + H) +: 435/437 (CI) HPLC-MS: 4.4 min (method B)

Example 3 2 - ((E) -3- {4- [5- (4-chloro-phenyl) -pyridin-2-ylethinyI] -phenyl} allylamino) -propan-1, 3-diol

3a 5-bromo-2 - [(tert-butyl-dimethyl-silanyl) ethynyl] pyridine

Under an argon atmosphere to a solution of 49.90 g (201.0 mmol) 2,5-dibromopyridine and 43.0 mL (225.6 mmol) of tert-butyl-ethinyl-dimethyl-silane in 500 ml dry THF and 120 mL of triethylamine at -7 ° C 0.80 g (4.20 mmol) of Cul and 2.90 g (4.13 mmol) of bis triphenylphosphine palladium (II) chloride was added and the mixture stirred for 30 mini at 0 ° C. The reaction mixture is further stirred for 3.5 h, then filtered and the filtrate at RT. vac. concentrated. The residue is dissolved in 1 L EtOAc, the organic phase washed with water and saturated NaCl solution, dried over Na 2 SO 4 and i. vac. concentrated. The crude product is further reacted without purification. Yield: 59.5 g (quant yield.) C 13 H 18 BrNSi (M = 296,278) Calc .: molecular peak (M + H) +: 296/298 (Br) Found .: molecular peak (M + H) +: 296/298 (Br) R f value: 0.75 (silica gel, Cyc / EtOAc 8: 1) 3b 2 - [(tert-butyl-dimethyl-silanyl) ethynyl] -5- (4-chloro-phenyl) -pyridine to a solution of 59.5 g (201.0 mmol) of 5-bromo-2 - [(tert-butyl-dimethyl-silanyl) ethynyl] - pyridine and 36.5 g (233.4 mmol) of 4-chlorophenylboronic acid in 600 mL 1, 4-dioxane, 250 mL MeOH, 220 mL 2 N Na 2 CO 3 solution and 1.80 g (2:46 mmol) of PdCl 2 (dppf) was added and the mixture heated for 1 hour under reflux. The reaction mixture is i. vac. concentrated and diluted with EtOAc. The organic phase is washed with water and half saturated NaHCO 3 - solution, dried over Na 2 SO and i. vac. concentrated. The residue is purified by column chromatography (silica gel, Cyc / EtOAc 9: 1). Yield: 38.5 g (58% theory d.) C 19 H 22 via Cinsi (M = 327,923) .: molecular peak (M + H) +: 328/330 (CI) Found .: molecular peak (M + H) +: 328 / 330 (CI) R f value: 0.60 (silica gel, Cyc / EtOAc 8: 1)

3c 5- (4-chloro-phenyl) -2-ethynyl-pyridine To a solution of 46.50 g (142.0 mmol) of 2 - [(tert-butyl-dimethyl-silanyl) ethynyl] -5- (4-chloro-phenyl ) pyridine in 1 L of DCM at RT, 43.66 g (156.0 mmol) of TBAF was added and the mixture stirred for 2 h. The organic phase is washed with water, dried over Na 2 SO 4 and i. vac. concentrated. The residue is stirred with DIPE, the precipitate was filtered and washed with PE. Yield: 26.0 g (. 86% of theory) C 13 H δ CIN (M = 213,662) Calc .: molecular peak (M + H) +: 214/216 (CI) Found .: molecular peak (M + H) +: 214 / 216 (CI) R f value: 0.30 (silica gel, Cyc / EtOAc 4: 1)

3d (E) -3- (4-iodo-phenyl) -prop-2-en-1-ol

Under nitrogen atmosphere, to a solution of 4.26 g (20.0 mmol) of (E) -3- (4-bromo-phenyl) -prop-2-en-1-ol and 762 mg (4 mmol) of Cul in 20 mL of 1, 4 -dioxane 12.0 g (80.0 mmol) of Nal and 0.85 mL (8.0 mmol) of N, N 'dimethylethylenediamine and the reaction mixture shaken 17 h at 110 ° C. The reaction mixture is cooled to RT, diluted with 200 mL EtOAc and 100 mL half concentrated NH 3 solution, stirred vigorously, the organic phase separated and dried over Na 2 SO 4. After the desiccant and solvent the residue without purification is reacted further. Yield: 4.69 g (90% theory d.) C 9 H 9 IO 2 (M = 260,072) Calc .: molecular peak (M + H) +: 261 Found .: molecular peak (M + H) +: 261 HPLC-MS: 3e 7.9 min (method A) (e) -3- {4- [5- (4-chloro-phenyl) -pyridin-2-ylethynyl] -phenyl} -prop-2-en-1-ol A solution of 3.12 g (12.0 mmol) of (e) -3- (4-iodo-phenyl) -prop-2-en-1-ol, 3.33 g (15.0 mmol) of 5- (4-chloro-phenyl) -2-ethynyl-pyridine and 4.31 mL (24 mmol) of diisopropylamine in 120 mL of dry THF is evacuated three times and then charged with argon. Then the addition of 45 mg is carried out (0:24 mmol) of Cul and 196 mg (0:24 mmol) of PdCl 2 (dppf). The reaction mixture is stirred for 18 h at RT, the solvent i.vac. concentrated, the residue is combined with 100 mL DCM and 50 mL of half-saturated NaHCO 3 solution and stirred vigorously. The precipitate is separated, washed with water and a little DCM, suspended in DIPE, suction filtered again and dried at 50 ° C to constant weight in a circulating air drying cabinet. Yield: 4.23 g C (. Quant yield) 22 H 16 CINO (M = 345,821) Calc .: molecular peak (M + H) +: 346/348 (CI) Found .: molecular peak (M + H) +: 346/348 (CI) R f value: 0:24 (silica gel, Cyc / EtOAc 2: 1)

3f 5- (4-chloro-phenyl) -2- [4 - ((E) -3-chloro-propenyl) phenylethynyl] -pyridine

To a cooled to 0 ° C solution of 6.1 g (17.64 mmol) of (E) -3- {4- [5- (4-chloro-phenyl) - pyridin-2-ylethynyl] -phenyl} -prop-2-ene -1-ol in 80 ml DCM, a solution 2.56 ml (35.28 mmol) of thionyl chloride are added dropwise in 10 mL of DCM slowly and the reaction solution stirred for a further 2 h at 0 ° C and 14 h at RT. It is cooled again to 0 ° C., carefully instilled 150 mL half-saturated NaHCO3 solution, the organic phase is separated off and dried over Na 2 SO 4. After the desiccant and solvent the residue chromätographisch (silica gel, Cyc / EtOAc 4: 1) is cleaned. Yield: 3.2 g (. 50% of theory) C 22 H 15 CI 2 N (M = 364,267) Calc .: molecular peak (M + H) +: 364/366/368 (2CI) -gef .: molecular peak (M + H) +: 364/366/368 (2CI) R f value: 0.60 (silica gel, Cyc / EtOAc 2: 1)

3g 2 - ((E) -3- {4- [5- (4-chloro-phenyl) -pyridin-2-ylethynyl] -phenyl} allylamino) -propan-1, 3-diol A solution of 70 mg ( 0.192 mmol) of 5- (4-chloro-phenyl) -2- [4 - ((e) -3-chloro-propenyl) - phenylethinyfj-pyridine, 70 mg (0.768 mmol) of 2-Aminό-1, 3-propanediol and 00:13 mL (0.768 mmol) N-ethyldiisopropylamine in 1.7 mL of DMF is shaken at 60 ° C 3.5 h. The reaction mixture is filtered through a syringe filter and purified directly via HPLC. Yield: 37.6 mg (. 47% of theory) C 25 H 23 CIN 2 O 2 (M = 418,915) Calc .: molecular peak (M + H) +: 419/421 (CI) Found .: molecular peak (M + H) : 419/421 (CI) HPLC-MS: 4.9 min (method B)

example 3.1

2 - ((E) -3- {4- [5- (4-chloro-phenyl) -pyridin-2-ylethynyl] -phenyl} allylamino) -2-methyl-propan-1, 3- diol

Prepared analogously to Example 3g of 70 mg (0.192 mmol) of 5- (4-chloro-phenyl) -2- [4 - ((E) -3-chloro-propenyl) phenylethynyl] pyridine and 80.7 mg (0.768 mmol) of 2 amino-2-methyl-1, 3-propanediol. Yield: 38.2 mg (46% theory d.) C 26 H 25 CIN 2 O 2 (M = 432,942) Calc .: molecular peak (M + H) +: 433/435 (CI) Found .: molecular peak (M + H) +: 433/435 (CI) HPLC-MS: 4.9 min (method B)

According to the method described in Example 3g the following compounds are prepared:

According to the method described in Example 2.14b following compounds are prepared starting from Example 3:

example 4

(3R, 4S) -1- {5- [5- (4-chloro-phenyl) -pyridin-2-ylethynyl] -benzo [ib] thiophen-2-ylmethyl} -4-methyl-piperidine-3,4- diol

4a 5-iodo-benzo [ό] thiophene-2-carboxylic acid methyl ester

Under Argonatmophäre to a solution of 5.0 g (18.4 mmol) of 5-bromo-benzo [ό] thiophene-2-carboxylic acid methyl ester in 18 mL of 1, 4-dioxane (0.35 g, 1.84 mmol) Cul, 5:53 g (36.88 mmol) NaI and 00:39 mL (3.67 mmol) N, N 'dimethylethylenediamine added and after renewed rinsing with argon, the reaction mixture is heated overnight at 110 ° C. After cooling the reaction mixture with 30% NH 3 solution and water, exhaustively extracted with EtOAc, the combined organic phases washed twice with water and dried over MgSO 4. After the desiccant and solvent the residue is triturated with DIPE and MTBE, suction filtered and dried in air. Yield: 3.4 g (. 58% of theory) C 10 H 7 IO S 2 (M = 318,132) Calc .: molecular peak (M) +: 318. Found .: molecular peak (M) +: 318 HPLC-MS: 6.4 min ( method B)

4b 5- [5- (4-chloro-phenyl) -pyridin-2-ylethynyl] -benzo [ό] thiophene-2-carboxylic acid methyl ester Under Argonatmophäre (10.69 mmol) are added to a solution of 3.4 g of 5-iodo- benzo [ ό] thiophene-2-carboxylic acid methyl ester and 2:48 g (10.69 mmol) of 5- (4-chloro-phenyl) -2-ethynyl-pyridine in 20 mL THF 3.7 mL (26.72 mmol) of triethylamine and evacuated, the reaction mixture three times each with argon fumigated. Then 195 mg (0.267 mmol) of PdCl 2 (dppf) * DCM complex, and 51 mg (0.267 mmol) Cul were added and the reaction mixture stirred 70 h at RT. It is mixed with EtOAc, the precipitated product is filtered off, washed it with a little EtOAc and dried in air. Yield: 3.0 g (. 70% of theory) C 23 H 14 CINO 2 S (M = 403,881) Calc .: molecular peak (M + H) +: 404/406 (CI) Found .: molecular peak (M + H) + : 404/406 (CI) HPLC-MS: 7.3 min (method B)

4c 5- [5- (4-chloro-phenyl) -pyridin-2-ylethynyl] -benzo [b] thiophene-2-carboxylic acid To a suspension of 3.0 g (7:43 mmol) of 5- [5- (4-chloro- phenyl) -pyridin-2-ylethynyl] - benzo [ό] thiophene-2-carboxylic acid methyl ester in 100 mL EtOH is added 22.3 mL of 1 N NaOH and the reaction mixture stirred overnight at RT. The reaction solution is cooled to 0 ° C and dissolved by dropwise addition of 1 N HCI to pH. 6 The precipitated product is filtered off with suction, washed with EtOH and dried in air. Since the product still contained starting material is repeated hydrolysis described above. Yield: 2.7 g (. 93% of theory) C 22 H 12 CINO 2 S (M = 389,855) Calc .: molecular peak (M + H) +: 390/392 (CI) Found .: molecular peak (M + H) + : 390/392 (CI) R f value: 0.89 (silica gel, PE / EtOAc 1: 1)

4d {5- [5- (4-chloro-phenyl) -pyridin-2-ylethynyl] -benzo [ib] thiophen-2-yl} methanol To a suspension of 1.9 g (4.87 mmol) 5- [5- ( 4-chloro-phenyl) -pyridin-2-ylethynyl] - benzo [/ ->] thiophene-2-carboxylic acid in 40 mL of DMF, 2.37 g (14.62 mmol) of CDI was added and the reaction mixture heated overnight at 50 ° C. After cooling to RT, the reaction solution is added to a solution of 552 mg (14.62 mmol) of NaBH 4 water was added in 5 mL of that the temperature does not exceed 30 ° C. It is stirred for 2 h at RT after, treated cautiously with KHSO 4 solution until an acidic reaction is with saturated Na 2 CO 3 - basic solution, exhaustively extracted with DCM, washed the combined organic phases twice with water and dried over MgSO 4. After the desiccant and solvent the residue is triturated with PE, suction filtered and dried in air. Yield: 1.1 g (. 60% of theory) C 22 H 14 cinos (M = 375,871) Calc .: molecular peak (M + H) +: 376/378 (CI) Found .: molecular peak (M + H) +: 376 / 378 (CI) HPLC-MS: 6.2 min 4e (method B) 2- (2-chloromethyl-benzo [-ι] thiophen-5-ylethynyl) -5- (4-chloro-phenyl) -pyridine to a 0 on ° C cooled solution of 1.1 g (2.93 mmol) {5- [5- (4-chloro-phenyl) -pyridin-2- ylethynyl] benzo [jb] thiophene-2-yl} methanol in 20 mL of DCM 1:07 mL (15 mmol) of thionyl chloride and the reaction mixture stirred for 70 h at RT. It is concentrated dried i. , the residue with half-saturated NaHCO 3 solution, exhaustively extracted with DCM, the combined organic phases are washed twice with water and dried over MgSO 4. After the desiccant and solvent the residue by chromatography (silica gel, PE / EtOAc 7: 3) is cleaned. Yield: 0.65 g (56% theory d.)

10. C 22 H 13 Cl 2 NS (M = 394,317) Calc .: molecular peak (M + H) +: 394/396/398 (2CI) Found .: molecular peak (M + H) +: 394/396/398 ( 2CI) HPLC-MS: 7.6 min (method B)

4f (3R, 4S) -1- {5- [5- (4-chloro-phenyl) -pyridin-2-ylethynyl] -benzo [ib] thiophen-2-ylmethyl} -4-

15 methyl-piperidine-3,4-diol To a solution of 60 mg (0.15 mmol) of 2- (2-chloromethyl-benzo [d] thiophen-5-ylethynyl) -5- (4-chloro-phenyl) -pyridine in 2 mL of DMF are added 39.9 mg (0.30 mmol) of (3R, 4S) -4-methyl-piperidine-3,4-diol (amine A3) and the reaction mixture stirred overnight at 70 ° C. Filtration through a syringe filter the reaction mixture is purified by HPLC. 0 Yield: 30 mg (40% of theory.) C 28 H 25 CIN 2 O 2 S (M = 489,029) Calc .: molecular peak (M + H) +: 489/491 (CI) Found .: molecular peak (M + H) +: 489/491 (CI) HPLC-MS: 5.4 min (method A)

25 According to the method described in Example 4f following compounds are prepared:

example 5

(3R, 4S) -1- (2- {4- [5- (4-chloro-phenyl) -3-fluoro-pyridin-2-ylethynyl] -phenoxy} -ethyl) -4-methyl-piperidin-3, 4-diol

5a 2,5-dibromo-3-fluoro-pyridine

To a solution of 6.50 g (25.80 mmol) of 2,5-dibromo-pyridin-3-ylamine and 15 mL of concentrated HCI (180.62 mmol) in 15 mL of water at -5 ° C a solution of 1.78 g (25.80 mmol) of sodium nitrite water is added dropwise in 3.5 mL, and the mixture was stirred for 30 min. At 0 ° C 11:41 mL (77.41 mmol) was added hexafluorophosphoric acid (60% in water) and the mixture stirred 1 h at 0 ° C. The diazonium salt formed is filtered off, washed with cold water, isopropanol and diethyl ether and in the desiccator i. vac. dried. PE (100-140 ° C) is heated to 90 ° C, the diazonium salt is added in portions and the mixture stirred until no more evolution of gas can be observed. The reaction mixture is cooled to RT, placed 3 solution alkaline with saturated Na 2 CO and the aqueous phase extracted with MTBE exhaustive. The combined organic phases are washed with saturated Na 2 CO 3 solution and water, dried over MgSO and i. vac. concentrated. The residue is dissolved in DCM, filtered through silica gel and the filtrate. vac. concentrated. - Yield: 3.30 (51% of theory.) C 5 H 2 Br 2 FN (M = 254,883) Calc .: molecular peak (M + H) +: 253/255/257 (2 Br) Found .: molecular peak (M + H ) +: 253/255/257 (2 Br) R f value: 0.63 (silica gel, PE / EtOAc 9: 1)

5b 5-Bromo-2 - [(tert-butyl-dimethyl-silanyl) ethynyl] -3-fluoro-pyridine

C under an argon atmosphere to a solution of 3.20 g (12:56 mmol) of 2,5-dibromo-3-fluoro-pyridine in 30 mL of dry THF 5.22 mL (37.67 mmol) of triethylamine, 2.62 mL (13.81 mmol) of tert-butyl at 15 ° -ethynyl-dimethyl-silane, 59.8 mg (0.31mmol) and Cul 220.3 mg (0.31mmol) of bis-triphenylphosphine-palladium (II) chloride was added and the mixture stirred for 2 h at RT. Then, 1 mL of tert-butyl-ethinyl-dimethyl-silane were added and stirred for 1 h at RT again. The reaction mixture is i. vac. concentrated and the residue taken up in EtOAc. The organic phase is washed with half saturated NaHCO 3 solution, 5% NH 3 -Lösung.und water and dried over MgSO 4. After the desiccant and solvent the residue by chromatography (silica gel, PE / DCM 9: 1) is cleaned. Yield: 1.62 g (41% theory d.) 3 H Cι about 17 BrFNSi (M = 314,269) .: molecular peak (M + H) +: 314/316 (Br) Found .: molecular peak (M + H) +: 314 / 316 (Br) HPLC-MS: 7.85 min (method B) 5c 2 - [(tert-butyl-dimethyl-silanyl) ethynyl] -5- (4-chloro-phenyl) -3-fluoro-pyridine to a solution of 1.61 g (5.14 mmol) of 5-bromo-2 - [(tert-butyl-dimethyl-silanyl) ethynyl] -3-fluoro-pyridine and 0.90 g (5.65 mmol) 4-chlorophenylboronic acid in 30 mL of 1, 4-dioxane 10 mL MeOH, 10 mL of 2 N Na 2 CO 3 solution and 94 mg (0.13mmol) PdCl 2 (dppf) was added and the mixture heated for 15 min under reflux. The reaction mixture is i. vac. concentrated and diluted with EtOAc. The organic phase is washed with water and half saturated NaHCO 3 solution and dried over Na 2 SO 4. After the desiccant and solvent the residue by chromatography (silica gel, PE / DCM 1: 1) is cleaned. ■ .-. Yield. 1.25 g (. 70% of theory) C 19 H calc ιCIFNSi 2 (M = 345,913) .: molecular peak (M + H) +: 346/348 (CI) Found .: molecular peak (M + H) +: 346/348 (CI) HPLC-MS: 8.83 min (method B)

5d 5- (4-chloro-phenyl) -2-ethynyl-3-fluoro-pyridine

To a solution of 1.25 g (3.61 mmol) of 2 - [(tert-butyl-dimethyl-silanyl) ethynyl] -5- (4-chloro-phenyl) -3-fluoro-pyridine in 30 mL of DCM at RT 1.14g (3.61 mmol) of TBAF was added and the mixture stirred for 2 h. The organic phase is washed with water and dried over Na 2 SO 4. After the desiccant and solvent the residue is triturated with PE, and the precipitate filtered off, washed with PE and dried in air. Yield: 0.72 g (. 86% of theory) C 13 H 7 ClFN (M = 231,653) Calc .: molecular peak (M + H) +: 232/234 (CI) Found .: molecular peak (M + H) +: 232 / 234 (CI) HPLC-MS: 5.81 min (method B)

5e 2- {4- [5- (4-chloro-phenyl) -3-fluoro-pyridin-2-ylethynyl] -phenoxy} -ethanol Under argon atmosphere, to a solution of 0.82 g (3.1 - mmol) 2- (4 -lod-2-methyl-phenoxy) -ethanol, 0.72 g (2.11 mmol) of 5- (4-chloro-phenyl) -2-ethynyl-3-fluoro-pyridine, 57 mg (0.078 mmol) of PdCl 2 (dppf) and 0.86 mL (6.22 mmol) of triethylamine in 20 mL THF 14.8 mg (0.08 mmol) Cul were added and the mixture was stirred for 16 h at RT. The reaction mixture is combined with EtOAc, the precipitate was filtered and washed with EtOAc. The filtrate and the organic. Washings are washed with 5% NH 3 solution and water and dried over MgSO 4. After the desiccant and solvent the residue by chromatography (silica gel, PE / EtOAc 1: 1) is cleaned. (Silica gel, petroleum ether / EtOAc 1: 1) Yield: (. 18% of theory) 0.20g C 21 H 15 CIFNO 2 (M = 367,800) Calc .: molecular peak (M + H) +: 368/370 (CI) Found .: molecular peak (M + H) +: 368/370 (CI) HPLC-MS: 5.9 min (method B)

5f methanesulfonic acid 2- {4- [5- (4-chloro-phenyl) -3-fluoro-pyridin-2-ylethynyl] -phenoxy} - ethyl ester To a solution of 0.20g (0:54 mmol) of 2- {4- [ 5- (4-chloro-phenyl) -3-fluoro-pyridin-2-ylethynyl] - phenoxy} -ethanol and 0:11 mL (0.82 mmol) of triethylamine in 10 mL of DCM is added dropwise at 0 ° C 63 .mu.l (0.82 mmol) of methanesulfonyl chloride and the mixture stirred for 16 h at RT. Additional 0.11 mL (0.82 mmol) of triethylamine and 63 .mu.l (0.82 mmol) of methanesulphonyl chloride are added and the mixture stirred for 8 h. The reaction mixture is diluted with DCM, the organic phase with water and dilute NaHCO3 solution, dried over MgSO 4 and i. vac. concentrated. Yield: 12:24 g (. 99% of theory) C 22 H 17 CIFNO 4 S (M = 445,892) Calc .: molecular peak (M + H) +: 446/448 (CI) Found .: molecular peak (M + H) + : 446/448 (CI) HPLC-MS: 6.2 min (method B)

5g (3R, 4S) -1- (2- {4- [5- (4-chloro-phenyl) -3-fluoro-pyridin-2-ylethynyl] -phenoxy} -ethyl) -4-methyl-piperidin-3 , 4-diol

The product is obtained analogously to Example 4f, starting with 60 mg (0.135 mmol) of methanesulfonic acid 2- {4- [5- (4-chloro-phenyl) -3-fluoro-pyridin-2-ylethynyl] -phenoxy} -ethyl ester and 35.3 receive mg (0.269 mmol) of (3R, 4S) -4-methyl-piperidine-3,4-diol (amine A3). Yield: 47 mg (. 73% of theory) C 2 H26CIFN θ3 2 (M = 480,958) Calc .: molecular peak (M + H) +: 481/483 (CI) Found .: molecular peak (M + H) +: 481 / 483 (CI) HPLC-MS: 5.2 min (method A)

According to the method described in Example 5g following compounds are prepared:

example 5.1

1 - [(S) -1- (2- {4- [5- (4-chloro-phenyl) -3-fluoro-pyridin-2-ylethynyl] -phenoxy} -ethyl) -pyrrolidine-2-yl] - -cyclopropanol

The product is obtained analogously to Example 4f, starting with 60 mg (0.135 mmol) of methanesulfonic acid 2- {4- [5- (4-chloro-phenyl) -3-fluoro-pyridin-2-ylethynyl] -phenoxy} -ethyl ester and 34.2 mg (0.269 mmol) of (S) -1-pyrrolidin-2-yl-cyclopropanol (amine A12) was obtained. Yield: 12 mg (19% theory d.) C 28 H 26 CIFN 2 O 2 (M = 476,969) Calc .: molecular peak (M + H) +: 477/479 (CI) Found .: molecular peak (M + H) +: 477/479 (CI) HPLC-MS: 5.6 min (method A)

example 6

1 - [(S) -1- (2- {2-bromo-4- [5- (4-chloro-phenyl) -3-fluoro-pyridin-2-ylethynyl] -phenoxy} -ethyl) pyrrolidine 2 yl] -cyclopropanol

HO

6a 2- (2-bromo-4-iodo-phenoxy) -ethanol The product is obtained analogously to Example 1a from 30.8 g (103 mmol) 2-bromo-4-iodo-phenol. Yield: 18.5 g (52% theory d.) C 8 H 8 BRLO label 2 (M = 342,956) R f value: 0:18 (silica gel, PE / EtOAc 4: 1) 6b 2- {2-bromo-4- [5- (4 -chloro-phenyl) -3-fluoro-pyridin-2-ylethynyl] -phenoxy} -ethanol The product is obtained analogously to example 5e, starting from 1.5 g (4:37 mmol) phenoxy 2- (2-Bom-4-iodo) ethanol and 1:01 g (4:37 mmol) of 5- (4-chloro-phenyl) -2-ethynyl-3-fluoro-pyridine. Yield: 1.60 g (. 82% of theory) C 2 ιH 14 BrCIFNO 2 (M = 446,697) Calc .: molecular peak (M + H) +: 446/448/450 (BrCI) Found .: molecular peak (M + H) +: 446/448/450 (BrCI) HPLC-MS: 6.4 min (method B)

6c methanesulfonic acid 2- {2-bromo-4- [5- (4-chloro-phenyl) -3-fluoro-pyridin-2-ylethynyl] - phenoxyj-ethyl ester

The product is prepared analogously to Example 5f starting from 1.6 g (3:58 mmol) of 2- {2-bromo-4- [5- (4-chloro-phenyl) -3-fluoro-pyridin-2-ylethynyl] -phenoxy} -ethanol manufactured.

Yield: 1.00 g (. 53% of theory) C 22 H 16 BrCIFNO 4 S (M = 524,788) Calc .: molecular peak (M + H) +: 524/526/528 (BrCI) Found .: molecular peak (M + H ) +: 524/526/528 (BrCI) HPLC-MS: 6.6 min (method B)

6d 1 - [(S) -1 - (2- {2-bromo-4- [5- (4-chloro-phenyl) -3-f luor-pyridin-2-ylethynyl] -phenoxy} -ethyl) - pyrrolidin -2-yl] -cyclopropanol

The product is obtained analogously to Example 4f, starting from 60.0 mg (0.114 mmol) of methanesulfonic acid 2- {2-bromo-4- [5- (4-chloro-phenyl) -3-fluoro-pyridin-2-ylethynyl] -phenoxy} obtained ethyl ester and 29.1 mg (0.229 mmol) of (S) -1-pyrrolidin-2-yl-cyclopropanol (amine A12) -. Yield: 11 mg (17% of theory.) C 28 H 25 BrCIFN 2 O 2 (M = 555,865) Calc .: molecular peak (M + H) +: 555/557/559 (BrCI) Found .: molecular peak (M + H) +: 555/557/559 (BrCI) HPLC-MS: 5.7 min (method A)

Following the procedure described in Example 6d method the following compounds are prepared:

example 7

1 - [(S) -1- (2- {4- [5- (4-chloro-phenyl) -3-fluoro-pyridin-2-ylethynyl] -2-methyl-phenoxy} -ethyl) - pyrrolidin-2 yl] -cyclopropanol

H0

7a 2- (4-iodo-2-methyl-phenoxy) -ethanol

The product is prepared starting from 10 g (42.7 mmol) 4-iodo-2-methyl-phenol analogously to Example 1a.

Yield: 11.4 g (96% theory d.)

C 9 H 11 IO 2 (M = 278,087)

R f value: 0.40 (silica gel, PE / EtOAc 3: 2)

7b 2- {4- [5- (4-chloro-phenyl) -3-fluoro-pyridin-2-ylethynyl] -2-methyl-phenoxy} -ethanol

The product is obtained analogously to Example 5e, starting from 1.5 g (5:39 mmol) of 2- (4-iodo-2-methyl-phenoxy) -ethanol and 1.25 g (5:39 mmol) of 5- (4-chloro-phenyl) -2-ethynyl- 3-fluoro-pyridine.

Yield: 1.40 g (68% of theory.) C 22 H 17 CIFNO 2 (M = 381,827) Calc .: molecular peak (M + H) +: 382/384 (CI) Found .: molecular peak (M + H) +: 382/384 (CI) HPLC-MS: 6.3 min (method B) 7c methanesulfonic acid 2- {4- [5- (4-chloro-phenyl) -3-fluoro-pyridin-2-ylethynyl] -2-methyl- phenoxy} -ethyl ester The product is prepared analogously to example 5f starting from 1.4 g (3.67 mmol) of 2- {4- [5- (4-chloro-phenyl) -3-fluoro-pyridin-2-ylethynyl] -2-methyl- phenoxy} ethanol produced. Yield: 0.77 g (46% of theory.) C 23 H 19 CIFNO 4 S (M = 459,918) Calc .: molecular peak (M + H) +: 460/462 (CI) Found .: molecular peak (M + H) + : 460/462 (CI) HPLC-MS: 6.5 min (method B)

7d 1 - [(S) -1 - (2- {4- [5- (4-chloro-phenyl) -3-fluoro-pyridin-2-ylethynyl] -2-methyl-phenoxy} -ethyl) - pyrrolidine 2-yl] -cyclopropanol The product is obtained analogously to example 4f, starting from 60.0 mg (0.130 mmol) of methanesulfonic acid 2- {4- [5- (4-chloro-phenyl) -3-fluoro-pyridin-2-ylethynyl] - 2-methyl-phenoxy} - ethyl ester and 33.2 mg (0.261 mmol) of (S) -1-pyrrolidin-2-yl-cyclopropanol (amine A12) was obtained. Yield: 22 mg (. 34% of theory) C 29 H 28 CIFN 2 O 2 (M = 490,996) Calc .: molecular peak (M + H) +: 491/493 (CI) Found .: molecular peak (M + H) +: 491/493 (CI) HPLC-MS: 5.8 min (method A)

According to the method described in Example 7d following compounds are prepared:

example 8

(3R, 4S) -1 - ((E) -3- {5- [5- (4-chloro-phenyl) -pyridin-2-ylethynyl] -pyridin-2-yl} -allyl) -4-methyl- piperidine-3,4-diol

8a (E) -3- (5-bromo-pyridin-2-yl) -prop-2-en-1-ol

To a cooled to -5 ° C suspension of 4.1 mL (4.1 mmol, 1 M in THF) of lithium aluminum hydride solution in 20 mL THF was added a solution of 1.0 g (4.71 mmol) of 3- (5-bromo-pyridin-2-yl ) -prop-2-yn-1-ol in 5 mL THF was added dropwise so that the temperature does not exceed 0 ° C. After completion of the addition a further 2 h at 0 ° C. Excess lithium aluminum hydride is decomposed by careful addition of 0.13 mL water, 12:13 mL 15% NaOH, and 0:38 mL of water. The precipitate is filtered and the organic phase dried over MgSO 4. After the desiccant and solvent the residue without cleaning is further reacted. Yield: 0.91 g (63% theory d.) C 8 H calc 8 BrNO (M = 214,059) .: molecular peak (M + H) +: 214/216 (Br) Found .: molecular peak (M + H) +: 214 / 216 (Br) HPLC-MS: 4.2 min (method B)

8b (E) -3- (5-iodo-pyridin-2-yl) -prop-2-en-1-ol

Under argon atmosphere, to a solution of 910 mg (4.25 mmol) (E) -3- (5-bromo-pyridin-2-yl) -prop-2-en-1-ol in 4.5 mL of 1, 4-dioxane 81 mg (0.43 mmol) of CuI, 1.27 g (8.5 mmol) NaI and 90 ul of N, N 'dimethylethylenediamine added and the reaction mixture heated overnight under reflux. After cooling, it is mixed with water, exhaustively extracted with EtOAc and the combined organic phases dried over MgSO 4. After the desiccant and solvent the residue without cleaning is further reacted. Yield: 870 mg (. 78% of theory) C 8 H 8 INO (M = 261,060) Calc .: molecular peak (M + H) +: 262. Found .: molecular peak (M + H) +: 262 HPLC-MS: 4.2 min (method B)

8c (E) -3- {5- [5- (4-chloro-phenyl) -pyridin-2-ylethynyl] -pyridin-2-yl} -prop-2-en-1-ol

A solution of 870 mg (3:33 mmol) of (E) -3- (5-iodo-pyridin-2-yl) -prop-2-en-1-ol, 712 mg (3:33 mmol) of 5- (4-chloro- phenyl) -2-ethynyl-pyridine and 0.97 mL (7.0 mmol) of triethylamine in 10 mL of dry acetonitrile is evacuated three times and then charged with argon. Then the addition of 70 mg is carried out (0:37 mmol) of Cul and 300 mg (0:37 mmol) of PdCl 2 (dppf). The reaction mixture is stirred overnight at RT. The precipitated product is filtered, washed with a little acetonitrile and dried at 50 ° C to constant weight in a circulating air drying cabinet. Yield: 980 mg (85% of theory.) C 2 ιH 15 CIN 2 O (M = 346,809) Calc .: molecular peak (M + H) +: 347/349 (CI) Found .: molecular peak (M + H): 347/349 (CI) HPLC-MS: 5.6 min (method B)

8d (E) -3- {5- [5- (4-chloro-phenyl) -pyridin-2-ylethynyl] -pyridin-2-yl} -allyl) chloride To a cooled -10 ° C solution of 450 mg (1.30 mmol) (e) -3- {5- [5- (4-chloro-phenyl) - pyridin-2-ylethynyl] -pyridin-2-yl} -prop-2-en-1-ol in 25 mL DCM is added a solution of 160 ul of thionyl chloride in 5 mL DCM was added dropwise. The reaction solution is further stirred for 30 min at 0 ° C and overnight at RT. The reaction mixture is treated with 50 mL hälbgesättigter NaHCO3 solution, exhaustively extracted with DCM, the combined organic phases washed twice with water and dried over MgSO 4. After the desiccant and solvent the residue without cleaning is further reacted.

Yield: 450 mg (95% of theory.) C 21 H 14 CI 2 N 2 (M = 365,255) Calc .: molecular peak (M + H) +: 365/367/369 (2 Cl) Found .: molecular peak (M + H) +: 365/367/369 (2 Cl) HPLC-MS: 6.8 min (method B)

According to the method described in Example 3g the following compounds are prepared:

Example 9 (3S, 4R) -1- (2- {4- [5- (4-chloro-phenyl) -pyrazine-2-ylethynyl] -phenoxy} -ethyl) -4-methyl-piperidine

3,4-diol

9a 5- (4-chloro-phenyl) -pyrazine-2-ylamine

To a solution of 8.70 g (174 mmol) of 5-bromo-pyrazin-2-ylamine and 7.98 g (156 mmol) of 4- Chlorphenylborpnsäure in 150 mL 1, 4-dioxane and 50 mL of MeOH, 50 mL of 2 N Na 2 CO 3 - solution and 1.16 g (1.00 mmol) Pd (PPh 3) 4 was added and the reaction mixture 2.5 h heated to 110 ° C. The mixture is concentrated i. vac. a, diluted with EtOAc, the organic phase is separated off, washed with water and dried over Na 2 SO 4. purified: After the desiccant and solvent the residue is purified by chromatography (1 silica gel, gradient DCM to DCM / MeOH 20). Yield: 8.30 g (81% theory d.) C 10 H 8 CIN 3 (M = 205,643) Calc .: molecular peak (M + H) +: 206/208 (CI) Found .: molecular peak (M + H) +: 206/208 (CI) HPLC-MS: 7.2 min (method A)

9b 2- (4-chloro-phenyl) -5-iodo-pyrazin be in a protected against the influence of light flask to a solution of 4.80 g (23.5 mmol) of 5- (4-chloro-phenyl) -pyrazine-2-ylamine in 100 mL of carbon tetrachloride and 50 mL DCM 4.90 mL (40.0 mmol) of tert-butyl nitrite and 7.61 g (30.0 mmol) of iodine added. The mixture is stirred overnight at RT and then combined with 100 mL water. The organic phase is separated, washed twice each with 50 mL 10% sodium thiosulfate solution and 50 mL of water and dried over MgSO 4. After filtration through activated charcoal and removing the solvent, the residue was purified by column chromatography (silica gel, gradient PE to PE / EtOAc 8: 2) is cleaned. Yield: 3:40 g (. 46% of theory) C 10 H 6 CIIN 2 (M = 316,525) Calc .: molecular peak (M + H) +: 317/319 (CI) Found .: molecular peak (M + H) +: 317/319 (CI) R f value: 0:55 (silica gel, PE / EtOAc 9: 1)

9c 2- {4- [5- (4-chloro-phenyl) -pyrazine-2-ylethynyl] -phenoxy} -ethanol

Under argon atmosphere (3.30 mmol) are added to a multi-degassed solution of 535 mg of 2- (4-chloro-phenyl) -5-iodo-pyrazine, 950 mg (3.30 mmol) 2- (4-ethynyl-phenoxy) -ethanol and 0:59 mL (6:00 mmol) of piperidine in 50 mL THF, 49 mg (0.06 mmol) PdCl 2 (dppf) and 11 mg (0.06 mmol) Cul were added and the mixture was stirred for 4 h at RT. The precipitate is filtered off with suction and washed with acetonitrile. The filtrate is concentrated, the resulting precipitate was filtered off and washed with a little acetonitrile. The two precipitates are combined.

Yield: 700 mg (. 67% of theory) C 205 CIN 2 O 2 (M = 350,798) Calc .: molecular peak (M + H) +: 351/353 (CI) Found .: molecular peak (M + H) +: 351/353 (CI) R f value: 0.30 (silica gel, PE / EtOAc 1: 1)

9d methanesulfonic acid 2- {4- [5- (4-chloro-phenyl) -pyrazine-2-ylethynyl] -phenoxy} -ethyl ester To a solution of 700 mg (2.00 mmol) of 2- {4- [5- (4 -chloro-phenyl) -pyrazine-2-ylethynyl] - phenoxy} -ethanol and 0.65 mL (7.98 mmol) of pyridine in 20 mL of DCM at RT (0.62 mL 7.98 mmol) of methanesulfonyl chloride are added dropwise and the mixture stirred then overnight at RT. After adding a further 0.33ml (3.99 mmol) of pyridine and 0:32 mL (12.4 mmol) of methanesulfonyl chloride in an ultrasonic bath, the reaction mixture is stirred for a further 2 h at RT. The solution is diluted with 30 mL DCM, the organic phase separated, washed three times with 60 mL water and dried over MgSO 4. After the desiccant and solvent the residue by chromatography (silica gel, DCM) is cleaned. Yield: 600 mg (70% of theory.) C 21 H 17 CIN 2 O 4 S (M = 428,889). Calcd .: molecular peak (M + H) +: 429/431 (CI) Found .: molecular peak (M + H) +: 429/431 (CI) R f value: 0.30 (silica gel, DCM / MeOH 9: 1)

9e (3S, 4R) -1 - (2- {4- [5- (4-chloro-phenyl) -pyrazine-2-ylethynyl] -phenoxy} -ethyl) -4-methyl-piperidine-3,4-diol a solution of 64 mg (0.15 mmol) of methanesulfonic acid 2- {4- [5- (4-chloro-phenyl) -pyrazine-2-ylethynyl] -phenoxy} -ethyl ester and 59 mg (0.45 mmol) of (3S, 4R) -4-methyl-piperidine-3,4-diol in 1.8 mL of DMF is shaken for 2 hours at 60 ° C and then 65 h at 30 ° C. The reaction mixture is purified by HPLC without further work. The fractions containing the product are combined and lyophilized. Yield: 33 mg (. 47% of theory) C 26 H 26 CIN3O 3 (M = 463,956) Calc .: molecular peak (M + H) +: 464/466 Found .: molecular peak (M + H) +: 464/466 HPLC-MS: 5.3 min (method e)

example 10

(3S, 4R) -1- (2- {4- [5- (4-chloro-phenyl) -pyridin-2-ylethynyl] -phenyl} ethyl) -4-methyl-piperidine-3,4-diol

10a 2- {4- [5- (4-chloro-phenyl) -pyridin-2-ylethynyl] -phenyl} -ethanol

Under argon atmosphere to a multi-degassed solution of 2.0 g (8.06 mmol) of 2- (4-iodo-phenyl) -ethanol, 1.74 g (8:06 mmol) of 5- (4-chloro-phenyl) -2-ethynyl-pyridine and 2.6 mL of triethylamine in 25 mL acetonitrile 79 mg (0.10 mmol) PdCl 2 (dppf) and 18 mg (0.10 mmol) Cul were added and the mixture was stirred for 24 h at RT, forming a precipitate. This is filtered off and washed with a little acetonitrile. The filtrate is extracted with DCM, the organic phase washed with water and added to the above precipitate. It is concentrated dried i. and the residue purified by column chromatography (silica gel, gradient PE to DCM) purified.

Yield: 1.80 g (. 67% of theory) C 2 ιH 16 CINO (M = 333,811) Calc .: molecular peak (M + H) +: 334/336 (CI) Found .: molecular peak (M + H) +: 334 / 336 (CI)

HPLC-MS: 6.0 min (method B)

10b methanesulfonic acid 2- {4- [5- (4-chloro-phenyl) -pyridin-2-ylethynyl] -phenyl} -ethyl ester To a solution of 167 mg (0.50 mmol) of 2- {4- [5- (4 -chloro-phenyl) -pyridin-2-ylethynyl] -phenyl} - ethanol and 81 .mu.l (1.00 mmol) of pyridine in 5 mL DCM at 0 ° C 58 .mu.l (0.75 mmol) of methanesulfonyl chloride are added dropwise and the mixture then 1 h at 0 stirred ° C. This is again treated with pyridine (80 ul) and methanesulfonyl chloride (58 uL) and stirred for 1 h at RT. Then 140 .mu.l (1.00 mmol) of triethylamine was added and diluted by 20 min at RT with ice-water. The organic phase is separated, dried over MgSO 4, filtered and then evaporated down the solvent. away. Yield: 185 mg (. 90% of theory) C 22 H 18 CINO 3 S (M = 411,902) Calc .: molecular peak (M + H) +: 412/414 (CI) Found .: molecular peak (M + H) + : 412/414 (CI) HPLC-MS: 6.3 min (method D)

10c (3S, 4R) -1 - (2- {4- [5- (4-chloro-phenyl) -pyridin-2-ylethynyl] -phenyl} ethyl) -4-methyl-piperidine-3,4-diol a solution of 60 mg (0.15 mmol) of methanesulfonic acid 2- {4- [5- (4-chloro-phenyl) -pyridin-2- ylethynyl] -phenyl} -ethyl ester and 39 mg (0.30 mmol) of (3S, 4R) -4-methyl-piperidine-3,4-diol in 1 mL DMF h at 50 ° C is heated 4, then by 69 mg (0.5 mmol) K 2 CO 3 was added and further 2 h warmed to 50 ° C. The reaction mixture is poured into water and the precipitate filtered. This is washed with a little water and purified by HPLC. Yield: 24 mg (37% of theory.) C 27 H 27 CIN 2 O 2 (M = 446,968) Calc .: molecular peak (M + H) +: 447/449 (CI) Found .: molecular peak (M + H) +: 447/449 (CI) HPLC-MS: 4.5 min (method B)

Subsequently, test methods are described for determining an MCH-receptor antagonistic activity. In addition, other test methods known in the art, for example, mediated by inhibiting the MCH-receptor inhibition of cAMP production as of Hoogduijn M et al. in "melanin-concentrating hormone and its receptor are overexpressed and functional in human skin", Biochem. Biophys. Res Commun. 296 (2002) 698-701 as well as the biosensor measurement of the binding of MCH to the MCH receptor in the presence of antagonistic substances by Piasmonresonanz as described by Karlsson OP and Lofas S. in "Flow-Mediated On-Surface Reconstitution of G-Protein Receptors Coupied for Applications in Surface plasmon Resonance Biosensors ", Anal. Biochem. 300 (2002), are used as described 132-138. Other test methods MCH receptor antagonistic activity are included in the initially cited literature and patent documents, a description of the test methods is hereby incorporated by reference.

MCH-1 receptor binding assay

Method: MCH binding to hMCH-1 R t ansfizierten cells

Species: Human

Test cell: hMCH-1 R stably transfected into CHO / Galpha16 cells Results: IC50 values

Membranes with human hMCH-1 R stably transfected CHO / Galpha16 cells using a syringe resuspended (needle 0.6 x 25 mm) and assay buffer (50 mM HEPES, 10 mM MgCl 2, 2 mM EGTA, pH 7.00; 0.1% bovine serum albumin (protease-free), 0.021% bacitracin, 1 ug / mL aprotinin, diluted 1 ug / mL leupeptin and 1 uM phosphoramidon) to a concentration 5 to 15 ug / mL. 200 microlitres of this membrane fraction (contains 1 to 3 ug protein) are incubated for 60 minutes at room temperature with 100 pM 125 I-tyrosyl melanin concentrating hormone (125 I-MCH commercially obtainable from NEN) and increasing concentrations of the test compound in a final volume of 250 microliters , After incubation, the reaction treated using a cell harvester through 0.5% PEI glass fiber filter (GF / B, Unifilter Packard) is filtered. The membrane-bound radioactivity on the filter retenierte then, after addition of scintillator substance (Packard Microscint 20) in a measuring device determines (TopCount of Packard).

Non-specific binding is defined as bound radioactivity in the presence of 1 micromolar MCH during the incubation period.

The analysis of the concentration binding curve is carried out under the assumption of one receptor binding site. Default:

Unlabeled MCH competes with labeled 125 I-MCH for 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 + mobilization test

Method: Calcium mobilization test with human MCH (FLIPR 384)

Species: Human

Test cell: hMCH-R1 with stably transfected CHO / Galpha 16 cells

Results: 1st measurement:% stimulation of the reference (MCH 10 "6 M) 2nd measurement: pKB value

Reagents: HBSS (10x) (GIBCO) HEPES buffers M) (GIBCO) Pluronic F-127 (Molecular Probes) Fiuo-4 (Molecular Probes) probenecid (Sigma) MCH (Bachem) bovine serum albumin (Serva) (Protease free) DMSO (Serva) Ham's F12 (BioWhittaker) FCS (BioWhittaker) L-Glutamine (GIBCO) hygromycin B (GIBCO) penstrep (BioWhittaker) Zeocin (Invitrogen)

Clonal CHO / Galpha16 hMCH-R1 cells are cultivated in Ham's F12 cell culture medium (with L-glutamine; BioWhittaker; Cat.Nr .: BE12-615F) cultured. This includes 10% FCS, 1% penstrep, 5 mL L-glutamine (200 mM stock solution), per 500 mL 3 mL hygromycin B (50 mg / mL in PBS) and 1.25 ml zeocin (100 ug / ml stock solution). One day before the experiment, cells in 384-well microtiter plate (schwarzwandig with a transparent base, manufactured by Costar). Plated at a density of 2500 cells per cavity and cultivated in the above medium overnight at 37 ° C, 5% CO 2 and cultured 95% relative humidity. On the day of the experiment, the cells with cell culture medium to which 2 mM Fluo-4 and 4.6 mM probenecid is added are incubated 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 is combined with 0.07% Probenicid, washed. The test substances are in Hanks buffer solution, combined with 2.5% DMSO, diluted. 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 FLIPR 384 IPMENT (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 35 minutes to the last washing step the 384-well cell culture plate and the MCH-stimulated fluorescence is then measured in the FLIPR unit 384.

Data analysis:

1. Measurement: Cellular is expressed measured as the peak of the relative fluorescence minus the background and as a percentage of Maximaisignals the reference (MCH 10 "6 M). This measurement serves to identify any possible agonistic effect of a test substance.

2nd measurement: The cellular Ca2 + mobilization is measured as the peak of the relative fluorescence minus the background and as percentage of the maximum signal of the reference (MCH 10 "6 M, signal is standardized to 100%) expressed the EC50 values of the MCH dosage. - effect curve with and without test substance (defined concentration) are prepared by the GraphPad prism 2:01 curve program determined graphically MCH antagonist effect in the generated graphics, a right shift of the MCH stimulation curve the inhibition is expressed as a pKB value: pKB = lθg (EC50 (the test substance.. + Ivich) / EC 5 o (MCH) -1) "Og C (test substance)

The inventive compounds, including their salts, an MCH receptor antagonistic effect in these tests. Using the MCH-1 receptor binding test described above an antagonistic activity in a dose range of about 10 "10 to 10" is 6 M, in particular of 10 "10 to 10" is 7 M was obtained.

The following IC 50 values were determined using the MCH-1 receptor binding test described above:

Compound IC50 value according to Name of example substance No. 2.20. 1 - {[(2- {4- [5- (4-chloro-phenyl) -pyridin-2-ylethynyl] - 13.8 nM phenoxy} -ethyl) - (3- hydroxy-propyl) -amino] - methyl} -cyclopropanol 1.5 (3R, 4S) -1- (2- {4- [5- (4-chloro-phenyl) -pyridin-2 10.9 nM ylethynyl] -2-methyl phenoxy} ethyl) -3-methyl-piperidine-3,4-diol

The following are examples of formulations will be described, wherein the term "active ingredient" one or more compounds according to the invention, including their salts means. In the case of one of the combinations with one or more additional active substances, the term "active substance" also includes the additional active substances.

example A

Capsules for powder inhalation with 1 mq of active ingredient

Composition:

1 capsule for powder inhalation contains:

Active ingredient 1.0 mg

Lactose 20.0 mg

Hard gelatine capsules 50.0 mg 71.0 mα

Method of preparation: The active ingredient is ground to the required particle size inhalants. The ground active ingredient is homogeneously mixed with the lactose. The mixture is filled into hard gelatin capsules.

Example B inhalation solution for Respimat® with 1 mq of active ingredient

Composition:

1 spray contains:

Active ingredient 1.0 mg

Benzalkonium chloride 0.002 mg disodium edetate 0.0075 mg

Water purified ad 15.0 ul

Production method:

The active substance and benzalkonium chloride are dissolved in water and transferred into Respimat®- cartridges.

example C

Inhalationslösunq for nebulisers containing 1 mg active substance Composition: 1 vial contains:

Active ingredient 0.1 g

Sodium chloride 0.18g

Benzalkonium chloride 0.002 g

Water purified ad 20.0 ml

Method of production: active ingredient, sodium chloride and benzalkonium chloride are dissolved in water.

Example D propellant metered dose inhaler having 1 mq of active substance Composition: 1 spray contains: active substance 1.0 mg lecithin 0.1% propellant gas ad 50.0 .mu.l

Method of preparation: The micronised active ingredient is homogeneously suspended in the mixture of lecithin and propellant gas. The suspension is transferred into a pressurized container with 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 ad 0.05 mg purified water 0.1 ml

Method of preparation: The active substance and excipients are dissolved in water and transferred into a corresponding container.

Example F Injectable Solution Containing 5 mg of Active Substance per 5 ml Composition: active substance 5 mg glucose 250 mg human serum albumin 10 mg glycofurol 250 mg water for injections ad 5 ml Preparation:

Glycofurol and glucose in water for injection to dissolve (Wfl); add human serum albumin; dissolve active substance with heating; made up to specified volume with Wfl; transferred into ampoules under nitrogen gassing.

example G

Iniektionslösung with 100 mg of active substance per 20 ml Composition: active substance 100 mg monopotassium dihydrogen phosphate = KH2PO4 12 mg

Disodium hydrogen phosphate = Na2HPθ4-2H θ 2 mg

Sodium chloride 180 mg

Human serum albumin 50 mg polysorbate 80 20 mg water for injections ad 20 ml

production:

Dissolve polysorbate 80, sodium chloride, monopotassium dihydrogen phosphate and disodium hydrogen phosphate in water for injections (Wfl); Human serum albumin admit; dissolve active substance with heating; made up to specified volume with Wfl; transferred into ampoules.

example H

Lvophilisat with 10 mg of active substance Composition:

Active ingredient 10 mg

Mannitol 300 mg

Human serum albumin 20 mg

production:

Mannitol is dissolved in water for injections (Wfl); Human serum albumin admit; dissolve active substance with heating; made up to specified volume with Wfl; transferred into vials; freeze-dry.

Solvent for Lyophilisate:

Polysorbate 80 = Tween 80 20 mg mannitol 200 mg

Water for injections ad 10 ml

production:

Dissolve polysorbate 80 and mannitol in water for injections (Wfl); transferred into ampoules.

example I

Tablets Containing 20 mg of Active substance.

Composition:

Active ingredient 20 mg

Lactose 120 mg

Corn starch 40 mg

Magnesium stearate 2 mg

Povidone K 25 18 mg

Herstellunq:

Active substance, lactose and corn starch are homogeneously mixed; granulated with an aqueous solution of Povidone; mixed with magnesium stearate; compressed in a tablet press; Tablet weight 200 mg.

example J

Capsules Containing 20 mg of Active Substance Composition: active substance 20 mg

Corn starch 80 mg

Highly dispersed silica 5 mg

Magnesium stearate 2.5 mg

Herstellunq:

Active substance, maize starch and silica are homogeneously mixed; mixed with magnesium stearate; Mixture on a capsule filling into hard gelatin capsules Big bottle. 3

Example K Suppositories Containing 50 mg of active substance Composition: active substance 50 mg

Hard fat (Adeps solidus) qs ad 1700 mg

Preparation: Hard fat is melted at about 38 ° C; ground active substance dispersed in the molten hard fat homogeneous; after cooling to about 35 ° C pour into chilled molds.

example L

Iniektionslösung with 10 mg of active substance per 1 ml Composition:

Active ingredient 10 mg

Mannitol 50 mg

Human serum albumin 10 mg

Water for injection ad 1 ml

production:

Mannitol in water for injection to dissolve (Wfl); Human serum albumin admit;

dissolve active substance with heating; made up to specified volume with Wfl; transferred into ampoules under nitrogen gassing.

Claims

claims
1. alkyne compounds of general formula I
R \ 'NXY- -WAB 2 / R in the
RC 3 - 6 alkenyl, C 3 - 6 alkynyl, (hydroxy-Cs -cycloalky -cis-alkyl, oxa-C 4 7 -.. Cycloalkyl, dihydroxy-C 3 7 alkyl, said groups mono- angegenben or more can be substituted with substituents which are independently selected from the group consisting of halogen, hydroxy, cyano, d ^ alkyl, C 3 7 cycloalkyl, C 3 -. -alkyl 7 cycloalkyl-Cι- 3, C 1 -. 4 -alkoxy-Cι- 4 alkyl, C 1 4 alkoxy, C ^ alkenyl, C ^ alkynyl, amino, C ^ -alkyl-amino and di- (Cι- alkyl) - amino, wherein may have one or more identical or different substituents selected from halogen and hydroxy, the alkyl, alkoxy, Cylcoalkyl groups; and
R 2, independently of R 1 one of the meanings given above for R 1, or R 2 has a meaning selected from the group consisting of H, Cι.8 -alkyl, C. 3 7 cycloalkyl or optionally substituted by identical or different radicals R 20 mono- or polysubstituted and / or by nitro substituted phenyl or pyridinyl group, wherein the alkyl or cycloalkyl group with identical or different radicals R 11 mono- or polysubstituted can, and wherein a -CH group in position 3 or 4 of a 5-, 6 or 7-membered cycloalkyl group, by -O-, -S- or -NR 13 - may be replaced, or the radicals R 1, R 2 together form with the N-atom to which they are bonded, a heterocyclic group selected from the meanings - dihydroxy-cyclo-C. 4 7 alkylene-imino, - (hydroxy-C 1 - 4 alkyl) -hydroxy-cyclo-C 3 - 7 alkylene-imino, - (hydroxy-C t - 3 alkyl) -cyclo-C 3 - 7 - alkylene-imino, wherein the Ci-s-alkyl-group in the last importance is substituted by one or more identical or different C t -S-alkyl groups, which together to form a C 3 - 7 connected -Cyloalkyl group could be; wherein the heterocyclic groups mentioned may be mono- or polysubstituted with substituents independently selected from the group consisting of halogen, hydroxy, cyano, C M alkyl, C 3rd 7 cycloalkyl, Cs-Cis cycloalkyl-alkyl, C ^ alkoxy C ^ -alkyl, - rAlkoxy, C ^ alkenyl, C ^ alkynyl, amino, C ^ -alkyl-amino and di- ( C 1-4 alkyl) amino, wherein alkyl, alkoxy, Cylcoalkyl groups may have one or more identical or different substituents selected from halogen and hydroxy;
X is a C ^ alkylene bridge, wherein in the significance C 2 - may be monosubstituted with R 10 alkylene one or two C-atoms, or Cs ^ -alkylene bridge, in which a non with the N atom R 1 R 2 N- group immediately adjacent -CH 2 -CH 2 group is replaced by -CH = CH-, - C≡C-, -CH 2 -O-, -CH 2 -S- or -CH 2 -NR is replaced with the above-stated meanings for X a substituent selected from C 2-4. 6 alkenyl, C 2 - 6 alkynyl, C. 3 May have ^ alkyl substituents 3 alkyl and / or one, two or three identical or different C, while two alkyl groups of one membered 7 to form 3 to - 7 cycloalkyl and C 3 - 7 cycloalkyl-C 1 or an alkyl and an alkenyl group may be bonded together to form a 5 to 7-membered cyclic group, and
W, Z are each independently a single bond or a C-ι- 2 alkylene bridge, wherein two adjacent C atoms with an additional C ^ alkylene bridge may be joined together, and where one or two C atoms independently of one another by one or two identical or different Cι- 3 alkyl residues can be substituted, wherein two alkyl groups may be joined together to form a carbocyclic ring, and
Y, A are independently 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 , chromanyl, chromen-4-onyl, thienyl, furanyl, benzothienyl or benzofuranyl, where the cyclic groups mentioned mono- or polysubstituted at one or more C atoms by identical or different radicals R 20, in the case of a phenyl ring may also additionally be monosubstituted by nitro and / or one or more NH groups with R 21 may be substituted,
B or one of the meanings given for Y, A
Ci-e-alkyl, Ci-e-alkenyl, C-ι- 6 alkynyl, C 3-7 cycloalkyl, C 5-7 cycloalkenyl, C. 3 7 cycloalkyl-Cι.3 alkyl-, C 3-7 cycloalkenyl-C. 1 3 alkyl, C 3 - 7 cycloalkyl-C | -. 3 - alkenyl or C 3. 7 cycloalkyl-Cι- 3 alkynyl group, wherein one or more C atoms independently of one another mono- or polysubstituted easily installed by halogen and / or by hydroxy or cyano and / or cyclic groups or polysubstituted by identical or different radicals R 20 may be substituted,
Cy is a carbocyclic 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 one N, O or S atom as heteroatom, - a saturated or unsaturated 5- to 7-membered heterocyclic group having 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 hetero atoms selected from N, O and / or S, wherein the above-mentioned saturated 6 - or 7-membered groups as .verbrückte ring systems with an imino, (C M -alky -imino-, methylene, (C ^^ alkylene-methylene or di- (Cι- 4 alkyl) methylene may be bridge, and wherein the aforementioned cyclis mono- chen groups or, in the case of a phenyl group may also additionally be monosubstituted one or more NH groups with R 21 may be substituted polysubstituted at one or more C atoms by identical or different radicals R 20 by nitro, and / or,
R 4 is H, C-ι- 4 alkyl, C 3-7 cycloalkyl or Ca-Cis cycloalkyl-alkyl,
R 0 is hydroxy, co-hydroxy-C ^ alkyl, C ^ -alkoxy or C ^ alkoxy-C-ι- 3 alkyl,
R 11 is halogen, C ^ -Alky], C 2 - 6 alkenyl, C 2 - 6 alkynyl, R 15 -O-, R 15 -O-CO-, R 15 -CO- O-, cyano, R 16 R 17 N-, R 18 R 19 N-CO- or Cy, wherein, in the above-mentioned groups one or more C atoms independently of one another by substituents selected from halogen, OH, CN, CF 3, C ^ alkyl, hydroxy 3 -Cι- alkyl may be substituted one or more times;
R 3 is as defined for R 17,
R 15 is H, CM-alkyl, C. 3 7 cycloalkyl, C. 3 7 -CycloaIkyl-Cι- 3 alkyl, phenyl, phenyl Ci 3 alkyl, pyridinyl or pyridinyl-3 Cι- alkyl,
R 16 is H, de-alkyl, C. 3 7 cycloalkyl, C 3 - 7 cycloalkyl-C, -. 3 alkyl, C4. 7 cycloalkenyl, C. 4 7 -cycloalkenyl-3 Cι- alkyl, ω-hydroxy-C. 2 3 alkyl, ω- (C 1 -C 4 alkoxy.) - C2. 3 alkyl, amino-C 2 - 6 -alkyl, C. 1 4 alkyl-amino-C 2 - 6 alkyl, di (C 1 - alkyl) - amino-C. 2 6 alkyl or cyclo-C. 3 6 -alkylenimino-C 2 - 6 alkyl,
R 17 is as defined for R 16 or phenyl, phenyl-C Σ s-alkyl, pyridinyl, d- 4 alkylcarbonyl, hydroxycarbonyl-3 Cι- alkyl, C-ι- 4 alkoxycarbonyl, Cι- 4 -alkoxycarbonyl -Cι- 3 alkyl, C 1-4 alkylcarbonylamino-C 2-3 -alkyl, N- (C 1-4 alkylcarbonyl) -N- (C 1 _ 4 alkyl) amino-C. 2 3 alkyl, d- 4 alkylsulfonyl, d- alkylsulfonylamino-C 2 - 3 alkyl, or N- (C 1-4 -alkylsulphonyl) -N (C 1 4 alkyl.) -amino-C 2. 3 alkyl;
R 18, R 19 are independently H or de-alkyl,
R 20 is halogen, hydroxy, cyano, d-ε--alkyl, C. 2 6 -alkenyl, C. 2 6 -alkynyl, C. 3 7 - cycloalkyl, C 3 - 7 cycloalkyl-Cι- 3 alkyl, hydroxy-Cι- 3 alkyl, R 22 -Cι- 3 alkyl, or one of the meanings given for R 22,
R 21 is C ^ alkyl, ω-hydroxy-C. 2 6 alkyl, ω-d- 4 -alkoxy-C 2 - 6 alkyl, ω-Cι- 4 alkyl amino-C 2 - 6 alkyl, ω-di- (C 1 - alkyl) -amino- C 2 - 6 alkyl, ω-cyclo-C 3 - 6 - alkyIenimino-C 2 - 6 alkyl, phenyl, phenyl-d- C3 alkyl, d-4 alkyl-carbonyl, d-4 alkoxy-carbonyl , C M alkylsulfonyl, aminosulfonyl, d- 4 - alkylaminosulfonyl, di-C ^ alkylaminosulfonyl or cyclo-C. 3 6 -aIkylen- imino-sulfonyl,
R 22 is pyridinyl, phenyl, phenyl-C. 1 3 -alkoxy, cyclo-C. 3 6 -alkylenimino-Qj.4 -. alkoxy, OHC-, HO-N = HC-, C, - 4 alkoxy-N = HC-, C-ι- 4 alkoxy, d- 4 - alkylthio, carboxy, d- 4 alkoxycarbonyl, aminocarbonyl, C ^ alkylaminocarbonyl, di- (d- C4 alkyl) -aminocarbonyl, cyclo-C. 3 6 alkyl-amino-carbonyl, cyclo-C. 3 6 -alkylenimino-carbonyl, phenylaminocarbonyl, cyclo-Cs-β-alkyleneimino-C ^ alkyl-aminocarbonyl, d ^ alkyl-sulfonyl, C ^ -alkyl-sulfinyl, C ^ alkyl-sulfonylamino, amino, Cι- 4 - alkylamino, di- (C 1. 4, alkyl) amino, C ^ alkyl-carbonyl-amino, cyclo C. 3 6 -alkylenimino, phenyl-d- 3 alkylamino, N- (C 1-4 -alkyl) -phenyl-C. 1 3 alkyl amino, acetylamino, propionylamino, phenylcarbonyl, phenylcarbonylamino, Phenylcarbonylmethylamino, hydroxy-C. 2 3 - alkylaminocarbonyl, (4-MorpholinyI) carbonyl, (I-pyrrolidinyl) carbonyl, (1- piperidinyl) carbonyl, (hexahydro-l-azepinyl) carbonyl, (4-methyl-1-piperazinyl) carbonyl, methylenedioxy, aminocarbonylamino or C M - alkylaminocarbonylamino mean
wherein additionally one or in the above-mentioned groups and radicals, particularly in W, X, Z, R 4, R 10, R 13 and R 15 to R 22, in each case one or more C atoms polysubstituted by F and / or in each case one or two C atoms independently of one another additionally be monosubstituted by CI or Br and / or in each case one or more phenyl rings independently of one another additionally containing one, two or three substituents selected from the group F, Cl, Br, I, cyano, d- 4 alkyl, d - 4 - alkoxy, difluoromethyl, trifluoromethyl, hydroxy, amino, ds-alkylamino, di- (C 1 3 alkyl.) amino,
Acetylamino, aminocarbonyl, difluoromethoxy, trifluoromethoxy, amino-d-3 alkyl, Cι- 3 alkylamino-Cι-3-alkyl- and di- (C 1 - 3 alkyl) amino-C 1 - 3 may include alkyl and / or may be monosubstituted by nitro, and
the H atom of any carboxy group or bound to an N atom,
H-atom may be replaced by a cleaved in vivo radical,
the tautomers, the diastereomers, the enantiomers, the mixtures thereof and the salts thereof,
wherein the following compounds are not included:
(2- {4- [5- (4-chloro-phenyl) -pyridin-2-ylethynyl] -2-methyl-phenoxy} -ethyl) -methyl-prop-2-ynyl-amine,
(2- {5- [5- (4-chloro-phenyl) -pyridin-2-ylethynyl] -indol-1-yl} -ethyl) -cyclopropylmethyl- prop-2-ynyl-amine,
{4- [6- (4-chloro-phenyl) -quinoline-2-ylethynyl] -benzyl} -methyl- (tetrahydro-pyran-4-yl) - amine,
Allyl (2- {4- [5- (4-chloro-phenyl) -pyridin-2-ylethynyl] -phenoxy} -ethyl) -cyclopropylmethyl- amine, allyl (2- {4- [5- (4- chloro-phenyl) -pyridin-2-ylethynyl] -2-methyl-phenoxy} -ethyl) - cyclopropylmethyl-amine,
Allyl (2- {5- [5- (4-chloro-phenyl) -pyridin-2-ylethynyl] -indol-1-yl} -ethyl) -cyclopropylmethyl- amine.
2. Alkyne compounds according to claim 1, characterized in that R 1 is selected from the group consisting of the meanings C 3 - 6 alkenyl, C. 3 6 alkynyl, (hydroxy-C 3. 7, cycloalkyl) -d- 3 alkyl, oxa-C. 5 7 cycloalkyl, dihydroxy-C 3 - alkyl, wherein the angegenben groups one or more times may be substituted with substituents which are independently selected from the group consisting of halogen, hydroxy, cyano, C ^ alkyl, C 3rd 7 cycloalkyl, C 3 - 7 cycloalkyl-d- 3 alkyl, C M - alkoxy-Cι - rAlkyl, d- 4 alkoxy, d- 4 alkenyl, C ^ alkynyl, amino, C ^ alkyl amino and di- (C 1-4 alkyl) amino, wherein alkyl, alkoxy, Cylcoalkyl groups may independently have one or more identical or different substituents selected from halogen and hydroxy, and
R 2 has one of the meanings given above for R, independently of R or H d.e alkyl, C 3rd 5 alkenyl, C. 3 5 alkynyl, C. 3 7 cycloalkyl, hydroxy-C 3 - 7 cycloalkyl, C 3 - 7 cycloalkyl-Cι- 3 alkyl, (hydroxy-C 3 - 7 cycloalkyl) -d- 3 -alkyl, hydroxy-C 2 - alkyl, ω-NC-C. 2 3 alkyl-, C 1-4 alkoxy-C. 2 alkyl, hydroxy-d ^ alkoxy-C ^ alkyl, d ^ alkoxy carbonyl-d- alkyl, carboxyl-C ^ alkyl, amino-C Σ ^ alkyl, d ^ - alkyl-amino-C ^ - alkyl, di (C 1 - 4 -alkyl) -amino-C. 2 4 alkyl, cyclo-C 3 - 6 -alkylenimino-C 2-4 -alkyl, pyrrolidine 3-yl, N- (Cι- 4 alkyl) -pyrrolidin-3-yl, pyrrolidinyl-C-ι- 3 alkyl, N- (C 1 - alkyl) -pyrrolidinyl-C. 1 s-alkyl, piperidin-3-yl, piperidin-4-yl, N- (C 1 - 4 alkyl) -piperidin-3-yl, N- (C 1 - 4 alkyl) - piperidin-4-yl, piperidinyl Cι.3 alkyl, N- (C 1-4 alkyl) piperidinyl-3 Cι- alkyl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, phenyl, phenyl-C-ι- 3 alkyl, pyridyl or pyridyl-d- means 3 alkyl, wherein in the above-specified groups and residues one or more C atoms independently of one another mono- or polysubstituted by F, d-3 - alkyl or hydroxy-d-3 alkyl, and / or one or two C atoms independently may be monosubstituted with Cl, Br, OH, CF 3 or CN from each other, and wherein said phenyl or pyridyl mono- or polysubstituted by identical or different radicals R 20 and / or single-nitro may be substituted, and the radicals R and R have the meaning given in claim. 1
3. Alkyne compounds according to claim 1, characterized in that R 1 and R 2 together with the N-atom to which they are bonded form a heterocyclic group selected from the meanings 3,4-Dihydroxypyrrolidinyl, 3, 4-Dihydroxypiperidinyl, 3,5-Dihydroxypiperidinyl, (hydroxy-d-C3 alkyl.) - hydroxypyrrolidinyl, (hydroxy-d-3 alkyl) -hydroxy-piperidinyl, (hydroxy-C 3 H 6 -. cycloalkyl) -hydroxypyrrolidinyl ( hydroxy C 3 - 6 -cycloaIkyl) -hydroxy-piperidinyl, (d- 3 - alkyl-hydroxy-methyl) pyrrolidinyl, (d- C3 alkyl-hydroxy-methyl) piperidinyl, (di-d-3 - alkyl -hydroxy-methyl) pyrrolidinyl, (di-Cι- alkyl 3-hydroxy-methyl) piperidinyl, 1- (hydroxy-C 3 6 cycloalkyl) -pyrrolidinyl, (1-hydroxy-C. 3 - 6 cycloalkyl ) piperidinyl, wherein said heterocyclic groups mentioned may be mono- or polysubstituted with substituents independently selected from the group consisting of halogen, hydroxy, cyano, C ^ alkyl, C 3rd 7 cycloalkyl, C 3 - 7 - cycloalkyl-d- C3 alkyl, Cι- 4 -alkoxy-C 1 - 4 alkyl, C ^ alkoxy, Cι- 4 alkenyl, d- 4 alkynyl, amino, d - 4 alkyl-amino and D (C 1 - 4 alkyl) amino, wherein alkyl, alkoxy, Cylcoalkyl- groups may have one or more identical or different substituents selected from halogen and hydroxy independently of one another.
4. alkyne compounds according to one or more of the preceding claims, characterized in that X is selected from the meanings -CH 2 -, ethylene, propylene, -CH 2 -CH = CH-, -CH 2 -C≡C-, -CH 2 -CH 2 -O-, -CH 2 -CH 2 -S-, -CH 2 -CH 2 -NR 4 -, and
C. 2 4 -Alkyleri having one or two identical or different substituents independently selected from fluoro, chloro, hydroxy, and d.3 alkyl and / or C. 2 Having 6 alkenyl or cyclopropyl substituent, where two alkyl substituents to form a C. 3 6 -CycloalkyI group or an alkyl and an alkenyl group to form a C. 5 6 cycloalkenyl group may be connected to each other, and
-CH 2 -CH = CH-, -CH 2 -C ≡C-, -CH 2 -CH 2 -O-, -CH 2 -CH 2 -S- or -CH 2 -CH 2 -NR 4 -, which one or two identical or different substituents independently selected from fluoro and Cι- alkyl having 3 and / or a cyclopropyl-substituents, while two alkyl groups to form a C. 3 6 cycloalkyl group, or if an alkyl group is the radical R 4 may be joined together to form a pyrrolidino or piperidino group, wherein R 4 is as defined in claim 1, preferably H or Cι- 3 alkyl, having. Alkyne compounds according to one or more of the voherigen claims, characterized in that Z represents a single bond or ethylene, and W is a single bond.
6. alkyne compounds according to one or more of the preceding claims, characterized in that the group Y is selected from among the bivalent cyclic groups, phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, tetrahydronaphthyl, indolyl, dihydroindolyl, quinolinyl, dihydroquinolinyl, tetrahydroquinolinyl , isoquinolinyl, dihydroisoquinolinyl, tetrahydro-isoquinolinyl, benzimidazolyl, benzoxazolyl, chromanyl, chromen-4-onyl, benzothienyl, or benzofuranyl, where the cyclic groups mentioned above one or more times at one or more C atoms by identical or different radicals R 20, in the case of a phenyl ring may also additionally be monosubstituted, it being possible for R 20 and R 21 have the meanings given in claim 1 by nitro, and / or at one or more N atoms with R 21 may be substituted.
7. alkyne compounds according to one or more of the preceding claims, characterized in that the group A is selected from among the bivalent cyclic groups, phenyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, the mono- or polysubstituted at one or more C atoms by identical or different radicals R 20, in the case of a phenyl ring may also additionally may be monosubstituted by nitro, and
R has the meanings given in claim. 1
8. alkyne compounds according to one or more of the preceding claims, characterized in that the group B from the group of phenyl, cyclohexenyl, pyridyl, thienyl, and furanyl is selected, and wherein the cyclic groups mentioned above one or more times at one or more C atoms by identical or different radicals R 20, in case of a phenyl group may also additionally may be monosubstituted by nitro, and R has the meanings given in claim. 1
Alkyne compounds according to one or more of the preceding claims, characterized in that
Y a meaning selected from
A is selected from having a meaning and
B is phenyl, cyclohexenyl, pyridyl, thienyl, and furanyl, preferably phenyl,
wherein Y and A is unsubstituted or monosubstituted by R 20, and B is unsubstituted or mono-, di- or trisubstituted independently of one another by R 20 is substituted, in the case of a phenyl ring may additionally be substituted with nitro also easy, and wherein R 20 has the meaning given in claim. 1
10. Alkyne compounds according to one or more of the preceding claims, characterized, in that
R 20 is F, Cl, Br, I, OH, cyano, amino, methyl, difluoromethyl, trifluoromethyl, ethyl, n-propyl, iso-propyl, acetyl, methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, n-propoxy or iso-propoxy wherein multiple occurrences of the substituents R 20 can have identical or different meanings.
11. Physiologically acceptable salts of the alkyne compounds according to one or more of claims 1 to 10 degrees.
12. A composition comprising 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. A medicament 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 10 and / or a salt according to claim 11 for influencing the eating behavior of a mammal.
15. 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 reducing body weight and / or for preventing an increase in 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 producing a medicament 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 the manufacture of a medicament for the prophylaxis and / or treatment of symptoms and / or diseases caused by MCH or is are otherwise causally connected with MCH are suitable.
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 the manufacture of a medicament for the prophylaxis and / or treatment of metabolic disorders and / or eating disorders, particularly obesity, bulimia , bulimia nervosa, cachexia, anorexia, anorexia nervosa and hyperphagia is suitable.
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 the manufacture of a medicament for the prophylaxis and / or treatment of conditions associated with obesity diseases and / or disorders, particularly diabetes especially type II diabetes is suitable, complications of diabetes including diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, impaired glucose tolerance, encephalorrhagia, heart failure, cardiovascular disease, especially atherosclerosis and hypertension, arthritis and gonitis.
20. 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 the manufacture of a medicament for the prophylaxis and / or treatment of hyperlipidaemia, cellulitis, fat accumulation, malignant mastocytosis, systemic mastocytosis, is suitable 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 the manufacture of a medicament for the prophylaxis and / or treatment of micturition disorders such as urinary incontinence, overactive bladder, urgency, nycturia , is suitable 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 1 1 for the manufacture of a medicament which is suitable for the prophylaxis and / or treatment of dependencies and / or withdrawal symptoms.
23. A method for preparing a composition or a medicament according to one or more of claims 12, 13 and 16 to 22, characterized in that non-chemical method at least one alkyne compound according to one or more of claims 1 to 10 and / or a salt according to claim 11 more inert carriers and / or diluents is incorporated in one or.
24. A pharmaceutical composition comprising a first active ingredient which is selected from the alkyne compounds according to one or more of claims 1 to 10 and / or the salts according to claim 11, and a second active ingredient which is selected from the group consisting of active substances for the treatment of diabetes, active substances for the treatment of diabetic complications, active substances for the treatment of obesity, preferably other than MCH antagonists, active substances for the treatment of hypertension, agents for the treatment of hyperlipidemia, including arteriosclerosis, active substances for the treatment of arthritis, active substances for the treatment of anxiety and agents for the treatment of depression, optionally together with one or more inert carriers and / or diluents.
25. A process for the preparation of alkyne compounds of formula A.5
R 1 R 2 NXYC --CWAB (A.5) wherein in the formulas A.1, A.2, A.3, A.4 and A.5 R 1, R 2, X, 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-X-Y-Hal (A.1) wherein Hal is chlorine, bromine or iodine, preferably bromine or iodine, is with an alkyne compound A.2 of formula HC - -WAB (A.2) in the presence of a suitable palladium catalyst, a suitable base and copper (I) iodide in a suitable solvent is reacted, and the obtained compound of formula A.3
HO-XY-CSG WAB (A.3) with methanesulfonic acid chloride to the methanesulphonate derivative A.4 is reacted (MsCI),
MsO-XYC≡CWAB (A.4) which is further reacted with an amine of formula H-NR 1 R 2 to the end product A.5.
26. A process for the preparation of alkyne compounds of formula B.5 R 1 R 2 NXYZC - CAB (B.5) wherein in the formulas B.1, B.2, B.3, B.4 B.5 and R \ R 2, X, 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-AB (B.1) wherein Hal is chlorine, bromine or iodine, preferably bromine or iodine, is with an alkyne compound of formula B.2
HO-XYZC ≡CH (B.2) in the presence of a suitable palladium catalyst, a suitable base and copper (I) iodide in a suitable solvent is reacted, and the obtained compound of formula B.3
HO-XYZC- £ -AB (B.3) with methanesulfonic acid chloride to the methanesulphonate derivative B.4 is reacted (MsCI),
MsO-XYZC -CAB (B.4) which is reacted with an amine of formula H-NR 1 R 2 to the end product B.5 on.
27. A method for the preparation of alkyne compounds of formula C.3
R 1 R 2 NXYC -CWAB (C.3) wherein in the formulas C.1, C.2, and C.3 R 1, R 2, X, Y, W, A and B one of the claims 1 to 10 have the meanings given, wherein a halogen compound of formula C.1 R 1 R NXY-Hal (C.1) wherein Hal is chlorine, bromine or iodine, preferably bromine or iodine, is with an alkyne compound of formula C.2
HC -WAB (C.2) in the presence of a suitable palladium catalyst, a suitable base and copper (I) iodide is further reacted in a suitable solvent to yield the end product C.3.
28. A method for the preparation of alkyne compounds of formula D.3
R 1 R 2 NXYZC - CAB (D.3) wherein in the formulas D.1, D.2 and D.3 R 1, R 2, X, Y, Z, A and B in one of the claims 1 to have the meanings indicated 10, wherein a halogen compound of formula D.2
Hal-AB (D.2) wherein Hal is chlorine, bromine or iodine, preferably bromine or iodine, is with an alkyne compound of formula D.1
R 1 R 2 NXYZC - CH (D.1) in the presence of a suitable palladium catalyst, a suitable base and copper (I) iodide is reacted in a suitable solvent to yield the end product D.3.
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