KR100478405B1 - Pyridylalkene- and pyridylalkyne-acidamides as cytostatic and immunosuppressive agents - Google Patents

Abstract

The present invention relates to novel pyridyl alkanes and pyridyl alkyne acid amides according to general formula (I), also to their production methods, to drugs containing these compounds and also to their pharmaceutical use, in particular for the treatment of tumors or for immunosuppression It is about.

Description

Pyridyl alkenes and pyridyl alkyne-acid amides as cell division inhibitors and immunosuppressants

The present invention relates to novel pyridine compounds, methods for their preparation, drugs containing these compounds and their use, in particular the treatment of cell division inhibitors or immunosuppressants and / or cancer states.

Strong demand for cell division inhibitory therapies that provide new drugs and / or drugs that have strong activity and exhibit reduced side effects as compared to many classic cancer suppressors, while providing broad access to the treatment of as many cancers as possible. Has been. Furthermore, efficient cell division inhibitors for efficient treatment should be available. Active ingredients of this type are also referred to for combination therapy involving other cell division inhibitors or radiotherapy (e.g., X-rays, radioactive elements such as cobalt, or linear accelerators), surgical procedures and heat therapy. Exceptions shall be made to the instructions given.

In this regard, there has also been a strong need to enhance cancer treatment, for example as new compounds to inhibit or overcome resistance.

This object has been successfully solved by a very surprising method using pyridyl alkane acid amide derivatives as defined below.

Various pyridine compounds substituted by specific methods are known to be pharmaceutically useful but have properties that lie in completely different indications.

Thus, ω-pyridyl alkane and / or alkene amides having anti-allergic activity have 5-lipoxygenase-inhibitory and anti-histamine actions and amides of these compounds The components are disclosed in EP 0 210 782 which has a piperizine or homopiperizine ring and is cited that the pyridine ring can be linked together in the 2-, 3- or 4-position. JP 63,179,869 further discloses pyridyl amides, ω-pyridyl alkanes and alkenamides as anti-allergic active substances containing substituted piperidine rings in the amine component. Compounds with the same properties were found in Chem. Pharm. Bull 37, 100-105 (1989) and J. Med. Chem. 1989, 583-593.

Pyridyl carbonamides, pyridyl urea and pyridyl thioureas, in which the amide moiety is bonded to the piperidine ring or piperazine ring via an aryl substituted alkyl chain, For example EP-A-0 428 434 or EP-A-0 512 902 are described as antagonists of neurokinin receptors and substance P. Furthermore, pyridyl (alkyl) carbonamides, pyridyl (alkyl) sulfonamides and analogues urea, in which the amide moiety is bonded to the piperidine ring via an alkyl chain, are described in EP-A-0 479 601. It is disclosed as an active ingredient with anti-arrhythimic properties.

In WO 91/15485, the production of pyridine-3,5-dicarboxylic acid esters and amides and their use for the treatment of cancer states are disclosed. These compounds differ in the very important structural features described below from the compounds according to the invention, for example the absence of hydrocarbon chains between the pyridine ring and the amide grouping or the dicarboxyl group on the pyridine ring. . Compounds disclosed in WO 89/07443 in the form of optically pure R (-)-Ni-guldifine and further like dihydropyridines with cytotoxic activity have greater structural differences. Compared with these existing compounds, the compounds according to the invention have a wide range of action which can function with unexpected good activity despite large structural differences.

Structurally closely related compounds have been represented as piperidine compounds disclosed in EP-A-0 330 026. However, no 3-pyridyl derivatives are described in detail, except for a single compound which will be detailed below, and no specific examples are disclosed in that publication. These conventional compounds are distinguished by anti-cholinesterase activity, anti- forgetfulness activity and activity against hyperkinesia, senile dementia, mania and Alzheimer's disease.

From the point of view of the art, the discovery that the compounds according to formula (I) as defined below had activity which can be applied in the treatment of cancer diseases in a particularly good way was completely unexpected. The pharmaceutical discovery that the compounds according to the invention have the property of immunosuppression in addition to the activity of cell division inhibition is also considered very surprising.

Specific cancer indications and binding possibilities, as well as the results of the pharmaceutical test from which this conclusion is to be derived, are detailed and illustrated later in this specification.

Thus, the main subject of the present invention is the following compound of formula (I), also stereoisomers and / or mixtures thereof and (E) -3- (3-pyridyl) -N- [2- (1-benzylpiperidine Pharmaceutically acceptable acid addition salts except for -4-yl) ethyl] -2-propenamide hydrochloride.

Wherein R ¹ is hydrogen, halogen, cyano, trifluoromethyl, hydroxy, benzyloxy, aminocarbonyl, carboxyl, phenyl, phenoxy, phenylthio, pyridyloxy, pyridylthio, alkyl (especially carbon number) Is 1 to 6 alkyl), alkenyl (especially alkenyl having 3 to 6 carbon atoms), alkynyl (especially alkynyl having 3 to 6 carbon atoms), hydroxyalkyl (especially Hydroxyalkyl having 1 to 6 carbon atoms, alkoxy (especially alkoxy having 1 to 6 carbon atoms), alkenyloxy (especially alkenyloxy having 3 to 6 carbon atoms), alkynyloxy (Particularly alkynyloxy having 3 to 6 carbon atoms), alkanoyloxy (particularly alkanoyloxy having 1 to 7 carbon atoms), alkoxycarbonyloxy (particularly alkoxycarbonyl having 2 to 7 carbon atoms) Oxy), alkylthio (especially alkylthio having 1 to 6 carbon atoms), alkenylthio (especially 3 to 6 carbon atoms) Alkenylthio), alkynylthio (particularly alkynylthio having 3 to 6 carbon atoms), cycloalkyl (particularly cycloalkyl having 3 to 8 carbon atoms), cycloalkyloxy (particularly 3 carbon atoms) To 8 cycloalkyloxy), cycloalkylthio (especially cycloalkylthio having from 3 to 8 carbon atoms), alkoxycarbonyl (especially alkoxycarbonyl having 2 to 7 carbon atoms), alkylaminocarbonyl (Particularly alkylaminocarbonyl having 2 to 7 carbon atoms), dialkylaminocarbonyl (particularly dialkylaminocarbonyl having 3 to 13 carbon atoms) or NR ⁵ R ⁶ :

In this case, R ⁵ and R ⁶ are independently of each other hydrogen, alkyl (particularly one to six carbon atoms), alkenyl (particularly three to six carbon atoms) and alkynyl (particularly three to six carbon atoms) ) Is selected from

R ² is hydrogen, halogen, cyano, hydroxy, trifluoromethyl, benzyloxy, alkyl (particularly one to six carbon atoms), alkoxy (particularly one to six carbon atoms) or alkanoyloxy (particularly 1 to 7 carbon atoms)

When R ¹ and R ² are adjacent to each other, an optically formed bridge is selected from the following.

-(CH ₂ ) ₄ -,-(CH = CH) _2- , and -CH ₂ O-CR ⁷ R ⁸ -O-:

R ⁷ and R ⁸ are each independently hydrogen or an alkyl (particularly one to six carbon atoms) group.

R ³ is hydrogen, halogen, alkyl (particularly one to six carbon atoms), trifluoromethyl or hydroxyalkyl (particularly one to six carbon atoms),

R ⁴ is hydrogen, hydroxy, benzyloxy, alkyl (especially one to six carbon atoms), alkenyl (especially three to six carbon atoms), alkynyl (especially three to six carbon atoms), cyclo Alkyl (especially three to six carbon atoms) or alkoxy (especially one to six carbon atoms),

k is 0 or 1,

A is optionally selected from two to six alkenylene, optionally substituted one to three times by C ₁ -C ₃ -alkyl, hydroxy, C ₁ -C ₃ -alkoxy, fluorine, cyano or phenyl Alkenylene comprising;

Alkadienylene, especially including at least 4 carbon atoms, especially including 4 to 6 alkadienylene, optionally substituted by C ₁ -C ₃ -alkyl, fluorine, cyano or phenyl;

1,3,5-hexatrienylene optionally substituted by C ₁ -C ₃ -alkyl, fluorine, cyano or phenyl and

Selected from ethinylene.

D is optionally substituted one or two times with alkylene (particularly one to six carbon atoms), hydroxy or alkoxy (particularly one to six carbon atoms), especially one to ten carbon atoms ;

Optionally substituted once or twice with alkyl (especially from 1 to 6 carbon atoms), hydroxy or alkoxy (especially from 1 to 6 carbon atoms), and a double bond may also cyclize E; Alkenylene, especially including alkenylene from dog to 10, having at least two carbon atoms;

Especially containing 3 to 10 carbon atoms, optionally substituted once or twice with alkyl (especially from 1 to 6 carbon atoms), hydroxy or alkoxy (especially from 1 to 6 carbon atoms); Alkynylene having at least three carbon atoms; And

Alkylene (particularly one to ten carbon atoms), at least two of which may be substituted isomericly with one to three methylene units, respectively, O, S, NR ⁹ , CO, SO or SO ₂ Selected from alkenylene with carbon atoms (especially from 2 to 10 carbon atoms) or alkinylene with at least 3 carbon atoms (especially from 3 to 10 carbon atoms),

R ⁹ is hydrogen, alkyl (particularly one to six carbon atoms), alkenyl (particularly three to six carbon atoms), alkynyl (particularly three to six carbon atoms), acyl (particularly one carbon atom) To up to 6) or alkylsulfonyl (especially from 1 to 6 carbon atoms).

E is

or

Wherein the heterocyclic ring also optionally has a double bond,

n and p are independently of each other 0, 1, 2, or 3 (where n + p ≦ 4),

q is 2 or 3,

R ¹⁰ is hydrogen, alkyl (particularly one to six carbon atoms), hydroxy, hydroxymethyl, carboxy or alkoxycarbonyl (particularly two to seven carbon atoms) having at least two carbon atoms,

R ¹¹ is hydrogen, alkyl (especially one to six carbon atoms) or oxo group adjacent to a nitrogen atom,

Wherein R ¹⁰ and R ¹¹ optionally together form an alkylene bridge (particularly a C ₁ -C ₃ -alkylene bridge under the formation of a bicyclic ring system) with 1, 2, 3, 4 or 5 carbon atoms,

G is selected from hydrogen, G ₁ , G ₂ , G ₃ , G ₄ and G ₅ ,

Where G ₁ is the residue

-(CH ₂ ) r- (CR ¹³ R ¹⁴ ) sR ¹² (G1)

Indicates

R is an integer from 1 to 3 or 0,

S is 0 or 1,

R ¹² represents hydrogen, alkyl (particularly C ₁ -C ₆ ), alkenyl having at least three carbon atoms (particularly C ₃ -C ₆ ), alkynyl having at least three carbon atoms (particularly C ₃ -C ₆₎ ), Cycloalkyl having at least three carbon atoms (especially C ₃ -C ₈ ),

5- to 7-membered heterocycles which are saturated and may comprise one or two hetero-atoms from groups N and / or S and / or O,

Benzyl or phenyl,

Monocyclic aromatic pentacyclic or 6, which may contain up to three hetero-atoms in one of the groups of group N and / or S and / or O and is directly bonded or bonded through a methylene group Ring heterocycles,

Analyzed non-rings having from 8 to 16 ring atoms and at least one aromatic ring, where linkage can occur on aromatic or hydrated rings and can occur directly or through methylene groups And tricyclic aromatic or partially hydrated carbocyclic ring systems,

Having 8 to 16 ring atoms and at least one aromatic ring, one to three ring atoms may be selected from N and / or S and / or O, and the bond may occur on an aromatic or hydrated ring And is selected from analytical non- and tricyclic aromatic or aliphatic hydrated heterocyclic ring systems that can occur directly or through a methylene group,

R ¹³ has the same meaning as R ¹² , but is independently selected from

R ¹⁴ is hydrogen, hydroxyl, methyl, benzyl, phenyl,

5- or 6-membered monocyclic aromatic heterocycle, which may include three to one heteroatom selected from group N and / or S and / or O and is bonded directly or through a methylene group,

Analyzed non- and tricyclic aromatics or partially having 8 to 16 ring atoms and at least one aromatic ring, wherein the bond can occur on an aromatic or hydrated ring and can occur directly or through a methylene group Hydrated carbocyclic ring systems,

Having 8 to 16 ring atoms and at least one aromatic ring, one or three ring atoms can be selected from N and / or S and / or O, and the bond can take place on an aromatic or hydrated ring Selected from analyzed non- and tricyclic aromatic or partially hydrated heterocyclic ring systems that can occur directly or through a methylene group,

G2 is residue

or

Is

Wherein the substituents R ¹² and R ¹⁴ may have the meanings mentioned above or the group-NR ¹² R ¹⁴ may also optionally contain one or two or more from groups N and / or S and / or O, except for essential nitrogen atoms. Nitrogen heterocycles selected from saturated or unsaturated 4- to 8-ring monocyclic heterocycles which may be selected from heteroatoms and bonded via nitrogen atoms or

Saturated or unsaturated non-or having 8 to 16 ring atoms and optionally containing one or two or more heteroatoms selected from the group N and / or S and / or O, except for essential nitrogen atoms Tricyclic, analyzed or bridged heterocycles,

G3 is a residue

-SO _2- (CH ₂ ) _r R ¹² (G3)

Is,

C4 is a residue

Is,

Ar ¹ and Ar ² are independently selected from phenyl, pyridyl or naphthyl,

G5 is a residue

-COR ¹⁵ (G5)

Wherein R ¹⁵ is selected from trifluoromethyl, alkoxy (particularly C ₁ -C ₆ ), alkenyloxy (particularly C ₃ -C ₆ ) or benzyloxy,

Wherein any aryl moiety and / or aromatic ring system at the substituents R ¹ , R ² , R ⁴ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , Ar ¹ and Ar ² and / or the ring system-NR ¹² R ¹⁴ Are independently of each other halogen, cyano, alkyl (particularly C ₁ -C ₆ ), trifluoromethyl, cycloalkyl (particularly C ₃ -C ₈ ), phenyl, benzyl, hydroxy, alkoxy (particularly C ₁ -C ₆ ), alkoxy substituted in whole or in part by fluorine, substituted alkoxy (particularly C ₁ -C ₆ ), benzyloxy, phenoxy, mercapto, alkylthio (particularly C ₁ -C ₆ ), carboxy, alkoxycar Carbonyl (especially C ₁ -C ₆ ), benzyloxycarbonyl, nitro, amino, monoalkylamino (especially mono-C ₁ -C ₆ -alkylamino), dialkylamino (especially di- (C ₁ -C _6- Alkyl) -amino) and one to three identical or different residues selected from methylenedioxy for two adjacent groups on an aromatic or ring system. Which may be substituted, wherein in the substituents R ¹ to R ¹³ , residue alkyl, alketyl, alkynyl, hydroxyalkyl, alkoxy, alkenyloxy, alkynyloxy, alkanoyloxy, alkoxycarbonyl, alkoxycarbonyloxy, Each of alkylthio, alkenylthio, alkynylthio, alkylene, acyl, alkylsulfonyl, alkenylene, alkynylene, cycloalkyl, cycloalkyloxy, alkoxycarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl 1 to 2 or 4, 6, 8, 10 or 12 carbon atoms and / or 2 or 3 to 5, 7, 9, 11, or 13 and / or 15 carbon atoms or 4, 5, 6 depending on the structure , 7, 8, 9, 10, 11, 12, 13, 14 or 15 carbon atoms.

Preferred embodiments according to the invention are compounds of formula (I), their stereoisomers and / or mixtures thereof, and (E) -3- (3-pyridyl) -N- [2- (1-benzyl Pharmaceutically acceptable acid addition salts with the exception of piperidin-4-yl) ethyl] -2-propenamide hydrochloride.

At this time,

R ¹ is hydrogen, halogen, cyano, C ₁ -C ₆ -alkyl, C ₃ -C ₆ -alkenyl, C ₃ -C ₆ -alkynyl, trifluoromethyl, C ₃ -C ₈ -cycloalkyl, C ₁ -C ₆ -hydroxyalkyl, hydroxy, C ₁ -C ₆ -alkoxy, C ₃ -C ₆ -alkenyloxy, C ₃ -C ₆ -alkynyloxy, benzyloxy, C ₁ -C _7- Alkanoyloxy, C ₂ -C ₇ -alkoxycarbonyloxy, C ₁ -C ₆ -alkylthio, C ₃ -C ₆ -alkenylthio, C ₃ -C ₆ -alkynylthio, C ₃ -C _8- Cycloalkyloxy, C ₃ -C ₈ -cycloalkylthio, C ₂ -C ₇ -alkoxycarbonyl, aminocarbonyl, C ₂ -C ₇ -alkylaminocarbonyl, C ₃ -C ₁₃ -dialkylaminocarbonyl , Carboxy, phenyl, phenoxy, phenylthio, pyridyloxy, pyridylthio or NR ⁵ R ⁶ , wherein

With R ⁵

R ⁶ are independently of each other selected from hydrogen, C ₁ -C ₆ -alkyl, C ₃ -C ₆ -alkenyl and C ₃ -C ₆ -alkynyl,

R ² is hydrogen, halogen, cyano, C ₁ -C ₆ -alkyl, trifluoromethyl, hydroxy, C ₁ -C ₆ -alkoxy, benzyloxy or C ₁ -C ₇ -alkanoyloxy,

Wherein R ¹ and R ² are optionally selected from bridge members of — (CH ₂ ) ₄ — and — (CH═CH) ₂ — and —CH ₂ O—CR ⁷ R ⁸ —O— when they are adjacent; , Where

R ⁷ and

R ⁸ is independently of each other hydrogen or C ₁ -C ₆ -alkyl,

R ³ is hydrogen, halogen, C ₁ -C ₆ -alkyl, trifluoromethyl or C ₁ -C ₆ -hydroxyalkyl, and

R ⁴ is hydrogen, C ₁ -C ₆ - alkyl, C ₃ -C ₆ - alkenyl, C ₃ -C ₆ - alkynyl, C ₃ -C ₆ - cycloalkyl, hydroxy, C ₁ -C ₆ - alkoxy Or benzyloxy,

k is 0 or 1,

A is C ₂ -C ₆ -alkenylene, optionally substituted one to three times with C ₁ -C ₃ -alkyl, hydroxy, C ₁ -C ₃ -alkoxy, fluorine, cyano or phenyl,

C ₄ -C ₆ -alkadienylene, optionally substituted once or twice with C ₁ -C ₃ -alkyl, fluorine, cyano or phenyl,

1,3,5-hexatrienylene, and ethinylene, optionally substituted by C ₁ -C ₃ -alkyl, fluorine, cyano or phenyl,

D is C ₁ -C ₁₀ -alkylene optionally substituted once or twice by C ₁ -C ₆ -alkyl, hydroxy or C ₁ -C ₆ -alkoxy,

Optionally substituted once or twice by C ₁ -C ₆ -alkyl, hydroxy or C ₁ -C ₆ -alkoxy, wherein the double bond may also cyclize E (C ₂ -C ₁₀ -alkenylene) alkenylene),

C ₃ -C ₁₀ -alkinylene optionally substituted once or twice by C ₁ -C ₆ -alkyl, hydroxy or C ₁ -C ₆ -alkoxy, and

C ₁ -C ₁₀ -alkylene, C ₂ -C ₁₀ -alkenylene or C ₃ -C, wherein one to three methylene units are each replaced isotropically by O, S, NR ⁹ , CO, SO or SO _{2 16} -alkynylene, wherein

R ⁹ is hydrogen, C ₁ -C ₆ -alkyl, C ₃ -C ₆ -alkenyl, C ₃ -C ₆ -alkynyl, C ₁ -C ₆ -acyl or C ₁ -C ₆ -alkylsulfonyl,

E is

or

Wherein the heterocyclic ring optionally has a double bond,

n and p are independently of each other 0, 1, 2 or 3, provided that n + p ≦ 4,

q is 2 or 3,

R ¹⁰ is hydrogen, C ₁ -C ₆ -alkyl, hydroxy, hydroxymethyl, carboxy or C ₂ -C ₇ -alkoxycarbonyl,

R ¹¹ is hydrogen, C ₁ -C ₆ -alkyl or an oxo group adjacent to a nitrogen atom, wherein R ¹⁰ and R ¹¹ are optionally taken together together with C ₁ -C ₃ -alkyl in the formation of a non-cyclic ring system Form a Ren bridge,

G is hydrogen,

Choose from G1, G2, G3, G4, and G5, where

G1 is a residue

-(CH ₂ ) r- (CR ¹³ R ¹⁴ ) sR ¹² (G1)

, Where

r is an integer from 1 to 3 or 0,

s is 0 or 1,

R ¹² is hydrogen, C ₁ -C ₆ -alkyl, C ₃ -C ₆ -alkenyl, C ₃ -C ₆ -alkynyl, C ₃ -C ₈ -cycloalkyl,

Saturated 5 to 7 ring heterocycles, which may include one or two hetero atoms selected from group N and / or S and / or 0,

Benzyl or phenyl,

5- or 6-membered monocyclic aromatic heterocycles which may include three heteroatoms in one of groups N and / or S and / or O, which are bonded directly or through a methylene group,

Analyzed non- and tricyclic aromatics or partials having from 8 to 16 ring atoms and at least one aromatic ring, wherein the bond can occur on the aromatic or hydrated ring and can occur directly or through a methylene group Hydrated carbocyclic ring systems,

Having from eight to sixteen ring atoms and at least one aromatic ring, one to three ring atoms may be selected from N and / or S and / or O, and a bond may occur on an aromatic ring or a hydrated ring Analyzed non- and tricyclic aromatic or partially hydrated heterocyclic ring systems, which can be generated directly or through a methylene group,

R ¹³ has the same meaning as R ¹² , but can be selected independently.

R ¹⁴ is hydrogen, hydroxy, methyl, benzyl, phenyl,

5- or 6-membered monocyclic aromatic heterocycles comprising three heteroatoms in one of groups N and / or S and / or O, bonded directly or through a methylene group,

Analyzed non- and tricyclic aromatic or partially hydrated having from 8 to 16 ring atoms and at least one aromatic ring, wherein the bond occurs on the aromatic or hydrated ring and can occur directly or through a methylene group Carbocyclic ring systems,

Having from eight to sixteen ring atoms and at least one aromatic ring, one to three ring atoms may be selected from N and / or S and / or O, and a bond may occur on an aromatic ring or a hydrated ring Selected from the analyzed non- and tricyclic aromatic or partially hydrated heterocyclic ring systems, which can be and can occur directly or through a methylene group.

G2 is residue

or

, Where

Substituents R ¹² and R ¹⁴ may have the meanings mentioned above,

Tribal

-NR ¹² R ¹⁴

May also optionally contain one or two or more heteroatoms selected from the group N and / or S and / or O, except for essential nitrogen atoms, and may be a four to eight ring saturated or fluorinated monocyclic heterocycle. field,

Aside from the essential nitrogen atoms, it may optionally contain one or two or more heteroatoms selected from the group N and / or S and / or O, and saturated or unsaturated non-s having 8 to 16 ring atoms. Or a nitrogen heterocycle which is bonded via a nitrogen atom, selected from tricyclic, analyzed or bridged heterocycles.

G3 is residue

-SO _2- (CH ₂ ) rR ¹² (G3)

Is,

G4 is a residue

, Where

Ar ¹ and Ar ² are each independently selected from phenyl, pyridyl or naphthyl,

G5 is a residue

-COR ¹⁵ (G5)

, Where

R ¹⁵ is trifluoromethyl, C ₁ -C ₆ -alkoxy, C ₃ -C ₆ -alkenyloxy or benzyloxy,

Wherein the substituents R ¹ , R ² , R ⁴ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , Ar ¹ and Ar ² , and / or the aromatic ring systems of the ring system—NR ¹² R ¹⁴ are independently of each other halogen, Cyano, C ₁ -C ₆ -alkyl, trifluoromethyl, C ₃ -C ₈ -cycloalkyl, phenyl, benzyl, hydroxy, C ₁ -C, which may be optionally substituted in whole or in part by fluorine ₆ -alkoxy, benzyloxy, phenoxy, mercapto, C ₁ -C ₆ -alkylthio, carboxy, C ₁ -C ₆ -alkoxycarbonyl, benzyloxycarbonyl, nitro, amino, mono-C ₁ -C ₆ - alkylaminocarbonyl or di - (C ₁ -C ₆ - alkyl) - may be substituted from one to three of the same or different residues selected from amino and aromatic ring or methylenedioxy for two adjacent groups on the ring system .

More preferred embodiments according to the invention include substituents R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹² , R ¹³ , R ¹⁴ and R ¹⁵ Compounds of the invention in which A and D have the following meanings in relation to given substitutions according to the following formulae, usually also when the heterocycle itself is substituted or in the free hydroxy-, mercapto- and / or amino groups Tautomeres in ring systems analyzed by, and, if applicable, cis / trans-isomers, endo / exo-isomers, enantiomers, which are pure isomers or mixtures and / or racemic mixtures. Optical isomers, stereoisomers such as diastereomers and pharmaceutically acceptable acid addition salts with inorganic or organic acids,

Hydrochloride, hydrobromide, hydroiodide, sulfate, and phosphate are preferred salts of addition salts with suitable inorganic acids. Acetate, benzoate, citrate, fumarate, gluconate, malates, maleates ), Methanesulfonate, lactate, oxalate, succinate, tartrates and tosylates are preferred salts of addition of organic acids:

At this time,

Halogen is fluorine, chlorine, bromine or iodine,

C ₁ -C ₆ -alkyl may be straight chain or branched, preferably methyl-, ethyl-, propyl-, isopropyl-, butyl-, isobutyl-, secondary butyl-, tertiary butyl-, cyclopropyl Methyl-, pentyl-, isopentyl-, tertiary pentyl-, neopentyl-, cyclopropylethyl-, cyclobutylmethyl- or hexyl group,

Alkylene is for example methylene, ethylene, propylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene, nonamethylene or decamethylene,

C ₃ -C ₆ -alkenyl may be straight chain or branched, preferably allyl-, 2-butenyl-, 3-butenyl-, 2-methyl-2-propenyl-, 2- Pentenyl-, 4-pentenyl-, 2-methyl-2-butenyl-, 3-methyl-2-butenyl-, 2-hexenyl-, 5-hexenyl-, 4-methyl-3-pentenyl Or a 2,2-dimethyl-3-butenyl group,

Alkenylene is, for example, ethenylene, propylene, butenylene, pentenylene, hexenylene, hexathenylene, heptenylene, octenylene, nonenylene or decenylene,

C ₃ -C ₆ -alkynyl may be straight chain or branched, preferably propargyl-, 2-butynyl-, 3-butynyl-, 4-pentynyl-, 5-hexyl Nil- or 4-methyl-2-pentynyl group,

Alkynylene is, for example, propynylene, butynylene, pentynylene, hexynylene, heptynylene, octinylene, noninylene or decinylene,

C ₃ -C ₈ -cycloalkyl is preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl,

C ₁ -C ₆ -hydroxyalkyl comprises a hydroxy group at one of the C ₂ -C ₆ -alkyl moieties named above, in particular in the form of hydroxymethyl- and hydroxyethyl groups,

At this time,

C ₁ -C ₆ -alkoxy, C ₃ -C ₆ -alkenyloxy, C ₃ -C ₆ -alkynyloxy, except for the oxygen atom, are each named C ₁ -C ₆ -alkyl-, C ₃ -C Methoxy-, ethoxy-, isopropoxy-, tertiary butoxy-, allyloxy- and propargyl, including one of the ₆ -alkenyl- and / or C ₃ -C ₆ -alkynyl groups Oxy groups are preferred and are understood to be, for example, difluoromethoxy, trifluoromethoxy or 2,2,2-trifluoroethoxy among C ₁ -C ₆ -alkoxy, which is wholly or partially substituted with fluorine. ,

C ₁ -C ₆ -alkylthio, C ₃ -C ₆ -alkenylthio, C ₃ -C ₆ -alkynylthio are each C ₁ -C ₆ -alkyl-, C _3- C ₆ -alkenyl- or C ₃ -C ₆ -alkynyl groups, in particular one of methylthio-, ethylthio-, isopropylthio- and tertiary butylthio groups,

C ₃ -C ₈ -cycloalkyloxy and C ₃ -C ₈ -cycloalkylthio are preferably cyclopentyloxy- and cyclopentylthio- and / or cyclohexyloxy- and cyclohexylthio groups,

C ₁ -C ₇ -alkanoyloxy groups include aliphatic acyl residues having 1 to 7 carbon atoms, in particular acetoxy-, propionyloxy- and pivaloyloxy groups, except for oxygen atoms ,

The C ₂ -C ₇ -alkoxycarbonyl groups are _{one of the} aforementioned C ₁ -C ₆ -alkoxy groups, in particular methoxycarbonyl-, ethoxycarbonyl-, isopropoxy, except for the carbonyl group. Carbonyl-, isobutoxycarbonyl- and tert-butoxycarbonyl groups,

The C ₂ -C ₇ -alkoxycarbonyloxy groups are one of the aforementioned C ₂ -C ₇ -alkoxycarbonyl residues, in particular methoxycarbonyloxy-, ethoxycarbonyloxy-, except for the oxygen atom. Isopropoxycarbonyloxy-, isobutoxycarbonyloxy- and tertiary butoxycarbonyl groups and allyloxycarbonyloxy groups,

C ₂ -C ₇ -alkylaminocarbonyl and C ₃ -C ₁₃ -dialkylaminocarbonyl groups include alkylamino- and / or dialkylamino moieties except carbonyl groups, and their C ₁ -C ₆ -Alkyl groups have the above meaning, wherein dimethylaminocarbonyl-, diethylaminocarbonyl- and diisopropylaminocarbonyl groups are preferred, except for the unsubstituted amino group, the following C _1- C ₆ -alkylamino groups and / or di- (C ₁ -C ₆ -alkyl) amino groups are understood under the amino groups of this formula NR ⁵ R ⁶ ,

C ₁ -C ₆ -alkylamino is one of the aforementioned C ₁ -C ₆ -alkyl groups, in particular methylamino-, ethylamino-, propylamino-, isopropylamino-, butylamino- and tertiary butylamino In the form of groups,

Di- (C ₁ -C ₆ -alkyl) amino represents the same or different two of the previously named C ₁ -C ₆ -alkyl groups on the nitrogen atom, in particular dimethylamino-, diethylamino, dipropylamino-, diisopropyl Carries in the form of amino-, isopropylmethylamino-, dibutylamino- or tertiary butylmethylamino groups,

C ₁ -C ₆ -acyl is an aliphatic saturated or unsaturated straight chain, branched or cyclic carboxylic acid residue, in particular formyl-, acetyl-, propionyl-, acryloil-, butyryl-, iso Butyryl-, methacryloyl-, cyclopropylcarbonyl-, pentanoyl-, pivaloyl-, cyclobutylcarbonyl-, hexanoyl- and dimethylacryloyl groups,

C ₁ -C ₆ -alkanesulfonyl is preferably a methanesulfonyl-, ethanesulfonyl-, propanesulfonyl-, butanesulfonyl-, pentanesulfonyl- and hexanesulfonyl groups,

Saturated 5- to 7-membered heterocycles having one or two hetero atoms are in particular tetrahydrofuryl, tetrahydrothienyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, hexahydroazinyl, piperazinyl , Hexahydrodiazepinyl or morpholinyl,

5- or 6-membered monocyclic aromatic heterocycles having one to three heteroatoms are in particular furyl, thienyl, pyrroyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, Oxadiazolyl, thiadiazolyl, triazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl or triazinyl,

Analyzed non- and tricyclic aromatic or partially hydrated carbocyclic ring systems having 8 to 16 ring atoms and at least one aromatic ring are preferably benzocyclobutyl, indanyl, indenyl, naph Methyl, dihydronaphthyl, tetrahydronaphthyl, biphenylenyl, fluorenyl, anthryl, dihydroanthryl, phenanthryl, dihydrophenanthryl, dibenzocyclohep Tenyl, dihydrodibenzocycloheptenyl, dihydrodibenzocyclooctenyl or tetrahydrodibenzocyclooctenyl, wherein the mono- or dioxo- derivatives are indanone, tetralone, anthrone, anthra Residues of quinones, fluorenones, phenanthrones, dibenzocycloheptenones, dihydrodibenzocycloheptenones or tetrahydrodibenzocyclooctenones are for example partially hydrated cyclic Is understood to Dudley system,

Analyzed non- and tricyclic aromatic or partially hydrated heterocyclic ring systems having 8 to 16 ring atoms and at least one aromatic ring are for example imidazothiazolyl, benzofuryl, di Hydrobenzofuryl, benzothienyl, dihydrobenzothienyl, indolyl, indolinyl, benzimidazolyl, indazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzoisothiazolyl, Benzofurazanyl, benzothiadiazolyl, benzotriazolyl, oxazoropyridyl, thiazopyridyl, isothiazolopyridyl, imidazopyridyl, pyrazoropyridyl, thienopyrimidinyl ), Chromanyl, benzopyranyl, quinolyl, isoquinolyl, dihydroquinolyl, tetrahydroquinolyl, benzodioxanyl, quinoxalinyl, quinazolinyl, naphthyridinyl, carbazolyl, tetrahydro Carbazolyl, Lidoindolyl, acridinyl, phenothiazinyl, dihydrodibenzoxepinyl, benzocycloheptathienyl, dihydrothienobenzothiepinyl, dihydrodibenzothiepinyl, octahydrodibenzothiepinyl , Dihydrodibenzazepinyl, octahydrodibenzazepinyl, benzocycloheptapyridyl, dihydropyridobenzodiazepinyl, dihydrodibenzoxazepinyl, dihydropyridobenzoxepinyl, dihydropyridobenzoxazepi Nil, dihydrodibenzothiazepinyl or dihydropyridobenzothiazepinyl, of which their mono- or dioxo-derivatives and / or optionally their possible tautomers are also partially hydrated heterocyclic ring systems, For example indolinone, isatin, benzoxazoron and / or its tautomer hydroxybenzoxazoles, benzisoxazorone, benzothiazoron, benzoisothiazoron and benzimidazorone and / or their tautomers, Hydroxybenzisoxazole, hydroxybenzothiazole, hydroxybenzoisothiazole and residues of hydroxybenzimidazole, residues of indazolinone, residues of oxazolopyridinone, thiazolopyridinone, pyrazolopyridinone and already Dazopyridinone and / or their tautomer hydroxyoxazolopyridine, hydroxythiazolopyridine, hydroxypyrazolopyridine and hydroxyimidazopyridine, chromanone, chromone, quinolinone, dihydroquinolinone, Tetrahydrocarbazolone, residues of acridon, dihydrodibenzoxepinone, benzocycloheptathiophenone, dihydrothienobenzothiepionone, dihydrodibenzothiepone, dihydrodibenzoazinone, Is understood as residues of benzocycloheptapyridinone, dihydropyridobenzoxazepineone, dihydrodibenzothiazepinone and dihydropyridobenzothiazepinone,

Saturated and unsaturated monocyclic, tetracyclic to octacyclic heterocycles are groups that may optionally contain one or two additional heteroatoms selected from N and / or S and / or O, except for the necessary nitrogen atoms. It represents -NR ¹² R ¹⁴ as, for example, azetidine, pyrrolidine, piperidine, (1H) tetrahydropyridine, hexahydroazepine, (1H) tetrahydroazepine, octahydroazocin, pyra Zolidine, piperazine, hexahydrodiazepine, morpholine, hexahydrooxazepine, thiomorpholine or thiomorpholine-1,1-dioxide,

Saturated and unsaturated non- or tricyclic, analyzed or bridged heterocycles have 8 to 16 ring atoms and one or two selected from N and / or S and / or O, except for essential nitrogen atoms. -NR ¹² R ¹⁴ as a group optionally containing two additional hetero atoms, for example 5-aza-bicyclo [2.1.1] hexane, 2-aza-bicyclo [2,2.1] heptane, 7 -Aza-bicyclo [2.2.1] heptane, 2,5-diaza-bicyclo [2.2.1] heptane, 2-aza-bicyclo [2.2.2] octane, 8-aza-bicyclo [3.2. 1] octane, 2,5-diaza-bicyclo [2.2.2] octane, 9-aza-bicyclo [3.3.1] nonane, indolin, isoindolin, (1H) -dihydroquinoline, (1H ) -Tetrahydroquinoline, (2H) -tetrahydroisoquinoline, (1H) -tetrahydroquinoxaline, (4H) -dihydrobenzoxazine, (4H) -dihydrobenothiazine, (1H)- Tetrahydrobenzo [b] azepine, (1H) -tetrahi Robenzo [c] azepine, (1H) -tetrahydrobenzo [d] azepine, (5H) -tetrahydrobenzo [b] oxazepine, (5H) -tetrahydrobenzo [b] thiazepine, 1,2 , 3,4-tetrahydro-9H-pyrido [3,4-b] indole, (10H) -dihydroacridine, 1,2,3,4-tetrahydroacridanone, (10H) -phenoxazine , (10H) -phenothiazine, (5H) -dibenzazepine, (5H) -dihydrodibenzazepine, (5H) -octahydrodibenzazepine, (5H) -dihydrodibenzodiazepines, (11H)- Dihydrodibenzo [b, e] oxazepine, (11H) -dihydrodibenzo [b, e] thiazepine, (10H) -dihydrodibenzo [b, f] oxazepine, (10H) -dihydro Dibenzo [b, f] thiazepine or (5H) -tetrahydrodibenzagoxycin.

Particular preference is given to compounds in which the substituents represented in formula (I) have the following meanings:

R ¹ is hydrogen, halogen, cyano, C ₁ -C ₆ -alkyl, trifluoromethyl, C ₃ -C ₆ -cycloalkyl, C ₁ -C ₄ -hydroxyalkyl, hydroxy, C ₁ -C ₄ -Alkoxy, benzyloxy, C ₁ -C ₄ -alkanoyloxy, C ₁ -C ₄ -alkylthio, C ₂ -C ₅ -alkoxycarbonyl, aminocarbonyl, C ₃ -C ₉ -dialkylaminocarbonyl , Carboxy, phenyl, phenoxy, pyridyloxy or NR ⁵ R ^6, wherein

R ⁵ and

R ⁶ are independently of each other selected from hydrogen and C ₁ -C ₆ -alkyl,

R ² is hydrogen, halogen, C ₁ -C ₆ -alkyl, trifluoromethyl or hydroxy, wherein

R ¹ and R ² are a bridge selected from the group of bridge members — (CH ₂ ) ₄ — and — (CH═CH) ₂ —CH ₂ O—CR ⁷ R ⁸ —O, where they are adjacent. Is optionally formed, where

R ⁷ and

R ⁸ may be independently of each other hydrogen and C ₁ -C ₆ -alkyl,

R ³ is selected from hydrogen, halogen and C ₁ -C ₆ -alkyl,

R ⁴ is selected from hydrogen, C ₁ -C ₆ -alkyl, C ₃ -C ₆ -alkenyl, hydroxy, C ₁ -C ₆ -alkoxy and benzyloxy,

k is 0 or 1,

A is C ₂ -C ₆ -alkenylene, optionally substituted one to three times with C ₁ -C ₃ -alkyl, hydroxy, fluorine, cyano, or phenyl;

C ₄ -C ₆ -alkadienylene, optionally substituted once or twice with C ₁ -C ₃ -alkyl, fluorine, cyano, or phenyl,

1,3,5-hexatrienylene optionally substituted with C ₁ -C ₃ -alkyl, fluorine or cyano, also

Ethynylene,

D is C ₁ -C ₃ - once or twice C ₁ -C ₁₀ optionally being substituted with alkyl or hydroxy-alkylene,

Optionally substituted once or twice with C ₁ -C ₃ -alkyl or hydroxy, wherein the double bond is also C ₂ -C ₁₀ -alkenylene, which may be for ringing E,

Selected from C ₃ -C ₁₀ -alkynylene which is optionally substituted once or twice with C ₁ -C ₃ -alkyl or hydroxy, and also

C ₁ -C ₁₀ -alkylene, C ₂ -C ₁₀ -alkenylene, or C ₃ -C, wherein one to three methylene units are stereoisomerically replaced with O, S, NR ⁹ , CO, SO or SO _{2 10} -alkynylene, wherein,

R ⁹ is hydrogen, C ₁ -C ₃ -alkyl, C ₁ -C ₆ -acyl or methanesulfonyl,

E is

or

Wherein the heterocyclic ring optionally has a double bond

n and p may be 0, 1, 2 or 3, independently of each other, provided that n + p ≦ 4,

q is 2 or 3,

R ¹⁰ is selected from hydrogen, C ₁ -C ₃ -alkyl, hydroxy, hydroxymethyl, carboxy or C ₂ -C ₇ -alkoxycarbonyl,

R ¹¹ is selected from hydrogen or oxo group adjacent to a nitrogen atom,

G is hydrogen,

Selected from G1, G2, G3, G4 and G5, wherein

G1 is the residue

-(CH ₂ ) _r- (CR ¹³ R ¹⁴ ) _s -R ¹² (G1)

At this time

r is 0, 1 or 2,

s is 0 or 1,

R ¹² is hydrogen, C ₁ -C ₆ - alkyl, C3-C ₆ - alkenyl, C ₃ -C ₆ - alkynyl, C ₃ -C ₈ - cycloalkyl,

Benzyl, phenyl,

Monocyclic aromatic five- or six-membered heterocycles containing one to three heteroatoms from groups N and / or S and / or O and bonded directly or via a methylene group,

Analyzed non- and tricyclic aromatic or partially hydrated carbons having from 8 to 16 ring atoms and at least one aromatic ring, wherein the bond occurs via an aromatic or hydrated ring and can occur directly or via a methylene group Bocyclic ring system,

Having from 8 to 16 ring atoms and at least one aromatic ring, wherein one to three ring atoms can be selected from the groups N and / or S and / or O, wherein the bond occurs via an aromatic or hydrated ring and directly Or an analyzed non- and tricyclic aromatic or partially hydrated heterocyclic ring which may occur via a methylene group,

R ¹³ has the same meaning as R ¹² , but is selected independently of it,

R ¹⁴ is hydrogen, hydroxy, methyl, benzyl or phenyl,

Monocyclic aromatic cyclic or hexacyclic heterocycles which may contain one to three heteroatoms from groups N and / or S and / or O, and which are bonded directly or via a methylene group,

Analyzed non- and tricyclic aromatic or partially hydrated carbons having from 8 to 16 ring atoms and at least one aromatic ring, wherein the bond occurs via an aromatic or hydrated ring and can occur directly or via a methylene group Bocyclic ring system,

Having from 8 to 16 ring atoms and at least one aromatic ring, wherein one to three ring atoms can be selected from the groups N and / or S and / or O, the bond taking place via an aromatic or hydrated ring and directly Or an analyzed non- and tricyclic aromatic or partially hydrated heterocyclic ring which may occur via a methylene group,

G2 is the next residue

And

Wherein the substituents R ¹² and R ¹⁴ may have the above meanings, or

-NR ¹² R ¹⁴

Is also bonded via a nitrogen atom,

Saturated or unsaturated monocyclic tetracyclic to octacyclic heterocycles, which may optionally contain one or two additional heteroatoms selected from N and / or S and / or O, except essential nitrogen atoms, or

Saturated or unsaturated non- or optionally containing one or two additional heteroatoms selected from N and / or S and / or O, with the exception of the necessary nitrogen atoms, and having from 8 to 16 ring atoms Nitrogen heterocycle selected from tricyclic analyzed or bridged heterocycles,

G3 is the next residue

-SO _2- (CH ₂ ) _r R ¹² (G3),

G4 is the next residue

At this time

Ar ¹ and

Ar ² is independently selected from phenyl, pyridyl or naphthyl,

G5 is the residue

-COR ¹⁵ (G5)

At this time

R ¹⁵ is trifluoromethyl, C ₁ -C ₆ -alkoxy, C ₃ -C ₆ -alkenyloxy or benzyloxy,

In the substituents R ¹ , R ² , R ⁴ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , Ar ¹ and / or Ar ² and / or in the ring system, -NR ¹² R ¹⁴ are independently of each other a series halogen, Furnace, C ₁ -C ₆ -alkyl, trifluoromethyl, C ₃ -C ₈ -cycloalkyl, phenyl, benzyl, hydroxy, C ₁ -C ₆ -alkoxy, which may be optionally substituted, in whole or in part, with fluorine, Benzyloxy, phenoxy, mercapto, C ₁ -C ₆ -alkylthio, carboxy, C ₁ -C ₆ -alkoxycarbonyl, benzyloxycarbonyl, nitro, amino, mono-C ₁ -C ₆ -alkylamino, di - (C ₁ -C ₆ - alkyl) - group can be from one to three same or have a different substituent (carry) carry, on the aromatic ring, or two adjacent ring system from amino methylenedioxy bridge (a methylenedioxy bridge) Aromatic ring systems capable of forming additional rings via

Particular preference is given to compounds in which the substituents represented in formula (I) have the following meanings:

R ¹ is hydrogen, halogen, cyano, methyl, trifluoromethyl, hydroxy, C ₁ -C ₄ -alkoxy, ethylthio, methoxycarbonyl, tert-butoxycarbonyl, aminocarbonyl, Carboxy and phenoxy,

R ² is hydrogen, halogen, trifluoromethyl or hydroxy,

R ³ is hydrogen or halogen,

R ⁴ is selected from hydrogen, C ₁ -C ₃ -alkyl, hydroxy and C ₁ -C ₃ -alkoxy,

k is 0 or 1,

A is C ₂ -C ₆ -alkenylene optionally substituted once or twice with C ₁ -C ₃ -alkyl, hydroxy or fluorine, or

C ₄ -C ₆ -alkadienylene, optionally substituted with C ₁ -C ₃ -alkyl or 1 or 2 fluorine atoms,

1,3,5-hexatrienylene optionally substituted with fluorine,

D is C ₁ -C ₈ -alkylene optionally substituted once or twice with methyl or hydroxy,

C ₂ -C ₈ -alkenylene, which may be optionally substituted once or twice with methyl or hydroxy, wherein the double bond may also be for ringing E

C ₃ -C ₈ -alkynylene, optionally substituted once or twice with methyl or hydroxy

By one to three methylene units are stereoisomeric qualitative O, S, NH, N ( CH 3), N (COCH 3), N (SO 2 CH 3), CO, C 1 to be replaced by SO or SO ₂ -C ₈ -alkylene, C ₂ -C ₈ -alkenylene, or C ₃ -C ₈ -alkynylene,

E is

or

Wherein the heterocyclic ring optionally has a double bond

n and

p may be 0, 1, 2 or 3, independently of each other, provided that n + p ≦ 3,

q is 2 or 3,

R ¹⁰ is selected from hydrogen, C ₁ -C ₃ -alkyl, hydroxy, hydroxymethyl,

R ¹¹ is selected from hydrogen or oxo group adjacent to a nitrogen atom,

G is hydrogen or

G1, G2, G3, G4 and G5, where

G1 is the residue

-(CH ₂ ) _r- (CR ¹³ R ¹⁴ ) _s -R ¹² (G1)

At this time

r is 0, 1 or 2,

s is 0 or 1,

R ¹² is hydrogen, C ₁ -C ₆ -alkyl, C ₃ -C ₈ -cycloalkyl, benzyl or phenyl,

Benzocyclobutyl, indanyl, indenyl, oxoindanyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, oxotetrahydronaphthyl, biphenylenyl, bonded directly or via a methylene group , Fluorenyl, oxofluorenyl, anthryl, dihydroanthryl, oxodihydroanthryl, dioxodihydroanthryl, phenanthryl, dihydrophenanthryl, oxodihydrophenanthryl , Dibenzocycloheptenyl, oxodibenzocycloheptenyl, dihydrodibenzocycloheptenyl, oxodihydrodibenzocycloheptenyl, dihydrodibenzocyclooctenyl, tetrahydrodibenzocyclooctenyl and oxotetrahydro Dibenzocyclooctenyl,

Furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imida, bonded directly or via a methylene group Zolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazineyl, imidazothiazolyl, benzofuryl, dihydrobenzofuryl, benzothienyl, dihydrobenzo Thienyl, indolyl, indolinyl, oxoindolinyl, dioxoindolinyl, benzoxazolyl, oxobenzoxazolinyl, benzisoxazolyl, oxobenzisoxazolyl, benzothiazolyl, oxthiazolyl, oxobenz Thiazolinyl, benzoisothiazolyl, oxobenzoisothiazolinyl, benzimidazolyl, oxobenzimidazolinyl, indazolyl, oxoindazolinyl, benzofurazanyl, benzothiadiazolyl, benzotria Zolyl, oxazolopyridyl, oxodihydrooxazolopyridyl , Thiazolopyridyl, oxodihydrothiazolopyridyl, isothiazolopyridyl, imidazopyridyl, oxodihydroimidazopyridyl, pyrazolopyridyl, oxodihydropyrazolopyridyl, thienopyrimi Thienopyrimidinyl, Chromanyl, Chromanonyl, Benzopyranyl, Chromonyl, Quinolyl, Isoquinolyl, Dihydroquinolyl, Oxodihydroquinolinyl, Tetrahydroquinolyl, Oxotetrahydro Quinolinyl, benzodioxyl, quinoxalinyl, quinazolinyl, naphthyridinyl, carbazolyl, tetrahydrocarbazolyl, oxotetrahydrocarbazolyl, pyridoindoleyl, acridinyl, oxo Dihydroacridinyl, phenothiazineyl, dihydrodibenzoxepinyl, oxodihydrodibenzoxepinyl, benzocycloheptathienyl, oxobenzocycloheptathienyl, dihydrothienobenzothiefinyl (dihydrothienobenx othiepinyl), oxodihydrothienobenzothiepinyl, dihydrodibenzothiepinyl, oxodihydrodibenzothiepinyl, octahydrodibenzothiepinyl, dihydrodibenzazepinyl, oxodihydrodibenzazepinyl, Octahydrodibenzazepinyl, benzocycloheptapyridyl, oxobenzocycloheptapyridyl, dihydropyridobenzodiazepinyl, dihydrodibenzoxazepinyl, dihydropyridobenzoxepinyl, dihydropyridobenzoxepinyl, dihydropyridobenzoxepinyl From dobenoxazinpinyl, oxodihydropyridobenzoxazinyl, dihydrodibenzothiazepinyl, oxodihydrodibenzothiazepinyl, dihydropyridobenzothiazepinyl, oxodihydropyridobenzothiazepinyl Selected,

R ¹³ has the same meaning as R ¹² , but is selected independently of it,

R ¹⁴ is hydrogen, hydroxy, methyl, benzyl or phenyl,

Indanyl, indenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazine, bonded directly or via a methylene group Zolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazinyl, benzofuryl, benzothienyl, indolyl, indolinyl, benzoxazolyl , Benzothiazolyl, benzimidazolyl, chromanyl, quinolyl or tetrahydroquinolyl,

G2 is the next residue

And

Wherein the substituents R ¹² and R ¹⁴ may have the above meanings, or

-NR ¹² R ¹⁴

The group may also include azetidine, pyrrolidine, piperidine, (1H) tetrahydropyridine, hexahydroazepine, (1H) tetrahydroazepine, octahydroazocine , Pyrazolidine, piperazine, hexhydrodiazepine, morpholine, hexahydrooxazepine, thiomorpholine, thiomorpholine-1,1-dioxide, 5-aza-bi-cyclo [2.1.1] hexane, 2-aza-bicyclo [2.2.1] heptane, 7-aza-bicyclo [2.2.1] heptane, 2,5-diaza-bicyclo [2.2.1] heptane, 2-aza-bicyclo [2.2 .2] octane, 8-aza-bicyclo [3.2.1] octane, 2,5-diazabicyclo [2.2.2] octane, 9-azabicyclo [3.3.1] nonane, indolin, isoindolin, (1H) -dihydroquinoline, (1H) -tetrahydroquinoline, (2H) -tetrahydroisoquinoline, (1H) -tetrahydroquinoxaline, (4H) -dihydrobenzoxazine, (4H)- -Dihydrobenzothiazine, (1H) -tetrahydrobenzo [b] azepine, (1H) -te Lahydrobenzo [c] azepine, (1H) -tetrahydrobenzo [d] azepine, (5H) -tetrahydrobenzo [b] oxazepine, (5H) -tetrahydrobenzo [b] thiazepine, 1, 2,3,4-tetrahydro-9H-pyrido [3,4-b] indole, (10H) -dihydroacridine, 1,2,3,4-tetrahydroacridanone, (10H ) -Phenoxazine, (10H) -phenothiazine, (5H) -dibenzazepine, (5H) -dihydrodibenzazepine, (5H) -octahydrodibenzazepine, (5H) -dihydrodibenzodiazepines, (11H) -dihydrodibenzo [b, e] oxazepine, (11H) -dihydrodibenzo [b, e] thiazepine, (10H) -dihydrodibenzo [b, f] oxazepine, (10H To a nitrogen-bonded ring atom of) -dihydrodibenzo [b, f] thiazepine or (5H) -tetrahydrodibenzagine;

G3 is the next residue

-SO _2- (CH ₂ ) _r R ¹² (G3),

G4 is the next residue,

At this time

Ar ¹ and

Ar ² is independently selected from phenyl, pyridyl or naphthyl,

G5 is the residue

-COR ¹⁵ (G5)

At this time

R ¹⁵ is trifluoromethyl, C ₁ -C ₆ -alkoxy, C ₃ -C ₆ -alkenyloxy or benzyloxy,

Substituents independently of one another are halogen series, cyano, C ₁ -C ₆ -alkyl, trifluoromethyl, C ₃ -C ₈ -cycloalkyl, phenyl, benzyl, hydroxy, C ₁ -C ₆ -alkoxy, wholly or From C ₁ -C ₆ -alkoxy which may be partially substituted with fluorine and may be substituted with one to three same or other substituents, benzyloxy, phenoxy, mercapto, C ₁ -C ₆ -alkylthio, carboxy, C ₁ -C ₆ - alkoxycarbonyl, benzyloxycarbonyl, nitro, amino, mono -C ₁ -C ₆ - alkylamino, di - (C ₁ -C ₆ - alkyl) - can (carry) carrying this amino And an aromatic ring system in which two adjacent groups on an aromatic ring or ring system can form additional rings with methylenedioxy bridges.

Another preferred embodiment of the invention is a compound in which the substituents indicated in formula (I) have the following meanings:

R ¹ is hydrogen, halogen, cyano, methyl, trifluoromethyl, hydroxy, methoxy or methoxycarbonyl,

R ² is hydrogen or halogen,

R ³ is hydrogen,

R ⁴ is selected from hydrogen, C ₁ -C ₃ -alkyl or hydroxy,

k is 0 or 1,

A is C ₂ -C ₆ -alkylene optionally substituted once or twice with hydroxy or fluorine, or

C ₂ -C ₆ -alkenylene, optionally substituted once or twice with hydroxy or fluorine,

C ₄ -C ₆ -alkadienylene optionally substituted with 1 or 2 fluorine atoms, or

1,3,5-hexatrienylene,

D is C ₂ -C ₈ -alkylene optionally substituted with methyl or hydroxy,

C ₂ -C ₈ -alkenylene, which may be optionally substituted with methyl or hydroxy, wherein the double bond may also be for ringing E

C ₂ -C ₈ -alkylene, wherein one to three methylene units can be stereoisomerically replaced with O, NH, N (CH ₃ ), N (COCH ₃ ), N (SO ₂ CH ₃ ) or CO, C ₂ -C ₈ -alkenylene,

E is the residue

or

Wherein the heterocyclic ring optionally has a double bond

n and p may be 0, 1, 2 or 3, independently of each other, provided that n + p ≦ 3,

q is 2,

R ¹⁰ is hydrogen, methyl or hydroxy,

R ¹¹ is hydrogen or an oxo group adjacent to a nitrogen atom,

G is hydrogen, C ₃ -C ₈ -cycloalkyl, methoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, trifluoroacetyl, diphenylphosphinoyl or the following residues

And

And

And

Selected from

r is 0, 1 or 2,

s is 0 or 1,

R ¹² is hydrogen, methyl, benzyl or phenyl,

Indanyl, indenyl, oxoindanyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, oxotetrahydronaphthyl, fluorenyl, oxofluorenyl, anthryl, di, bonded directly or via a methylene group Hydroanthryl, oxodihydroanthryl, dioxodihydroanthryl, dibenzocycloheptenyl, oxodibenzocycloheptenyl, dihydrodibenzocycloheptenyl, oxodihydrodibenzocycloheptenyl,

Furyl, thienyl, pyrroyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, thiadiazoleyl, triazolyl, pyridyl, bonded directly or via a methylene group , Pyrazinyl, pyridazinyl, pyrimidinyl, imidazothiazolyl, benzofuryl, dihydrobenzofuryl, benzothienyl, dihydrobenzothienyl, indolyl, indolinyl, oxoindolinyl, dioxoindolin 1, benzoxazolyl, oxobenzoxazolinyl, benzisoxazolyl, oxobenzisoxazolyl, benzothiazolyl, oxobenzthiazolinyl, benzoisothiazolyl, oxobenzoisothiazolinyl, benzimidazolyl, Oxobenzimidazolinyl, benzofurazyl, benzothiadiazolyl, benzotriazolyl, oxazolopyridyl, oxodihydrooxazolopyridyl, thiazolopyridyl, oxodihydrothiazolopyridyl, isothiazolopyrid Dill, imidazopyridyl, oxodihydride Leumidazopyridyl, pyrazolopyridyl, thienopyrimidinyl, chromanyl, chromonyl, benzopyranyl, chromonyl, quinolyl, isoquinolyl, dihydroquinolyl, oxodihydroquinolinyl, tetrahydro Quinolyl, oxotetrahydroquinolinyl, benzodioxanyl, quinoxalinyl, quinazolinyl, naphthyridinyl, carbazolyl, tetrahydrocarbazolyl, oxotetrahydrocarbazolyl, pyridoindoleyl, acry Dinyl, oxodihydroacridinyl, phenothiazineyl, dihydrodibenzoxepinyl, benzocycloheptathienyl, oxobenzocycloheptathienyl, dihydrothienobenzothiepinyl, oxodihydrothienobenzothipinyl, di Hydrodibenzothiepinyl, oxodihydrodibenzothiepinyl, dihydrodibenzazepinyl, oxodihydrodibenzazepinyl, octahydrodibenzazepinyl, benzocycloheptapyridyl, oxobenzocycloheptapyridyl, dihydro And Ben Lido jokse sulfinyl, dihydro dibenzothiazyl claim sulfinyl, oxo-dihydro-dibenzothiazyl claim sulfinyl,

R ¹³ is hydrogen, methyl, benzyl or phenyl,

R ¹⁴ is hydrogen, hydroxy, methyl, benzyl, phenyl,

Naphthyl, furyl, thienyl, oxazolyl, thiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, thidiazolyl, pyridyl, benzofuryl, benzothienyl, indolyl, bonded directly or via a methylene group, Indolinyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, chromanyl, quinolyl or tetrahydroquinolyl,

At this time, in the formula (I)

-NR ¹² R ¹⁴ also contains pyrrolidine, piperidine, (1H) tetrahydropyridine, hexahydroazepine, octahydroazocin, piperazine, hexhydrodiazepine, morpholine, hexahydrooxazepine, 2- Azabicyclo [2.2.1] heptane, 7-azabicyclo [2.2.1] heptane, 2,5-diazabicyclo [2.2.1] heptane, 8-azabicyclo [3.2.1] octane, 2,5-dia Zacyclocyclo [2.2.2] octane, indolin, isoindolin, (1H) -dihydroquinoline, (1H) -tetrahydroquinoline, (2H) -tetrahydroisoquinoline, (1H) -tetrahydroquinoxaline, (4H) -dihydrobenzoxazine, (4H) -dihydrobenzothiazine, (1H) -tetrahydrobenzo [b] azepine, (1H) -tetrahydrobenzo [d] azepine, (5H)- Tetrahydrobenzo [b] oxazepine, (5H) -tetrahydrobenzo [b] thiazepine, 1,2,3,4-tetrahydro-9H-pyrido [3,4-b] indole, (10H)- Dihydroacridine, 1,2,3,4-tetrahydroacridanone, (5H) -dihydrodibenzazepine, (5H) -dihydro Benzodiazepines, (11H) -dihydrodibenzo [b, e] oxazepine, (11H) -dihydrodibenzo [b, e] thiazepine, (10H) -dihydrodibenzo [b, f] oxazepine or It can be selected from (5H) -tetrahydrodibenzazocin.

Very particular preference is given to compounds in which the substituents represented in formula (I) have the following meanings:

R ¹ is hydrogen, fluorine, chlorine, bromine, methane, trifluoromethyl or hydroxy,

R ² and

R ³ is hydrogen,

R ⁴ is hydrogen or hydroxy,

k is 0 or 1,

A is selected from C ₂ -C ₄ -alkylene optionally substituted with fluorine,

D is C ₂ -C ₆ - alkylene, C ₂ -C ₆ double bond, which can also be for making a ring E - the alkenylene group, and a methylene unit in stereoisomeric qualitative O, NH, N (CH ₃₎ Or CO may be replaced, or the ethylene group may be stereoisomerically replaced with NH-CO and / or CO-NH, or the e or propylene group is stereoisomerically NH-CO-O and / or O-CO- C ₂ -C ₆ -alkylene, C ₂ -C ₆ -alkenylene, which may be replaced by NH,

E is selected from pyrrolidine, piperidine, 1,2,5,6-tetrahydropyridine, hexahydroazepine, morpholine and hexahydro-1,4-oxazepine, which is selective to the nitrogen atom Adjacent heterocyclic rings may be substituted with an oxo group,

G is hydrogen, tert-butoxycarbonyl, diphenylphosphinoyl or the following residues

And

And

And

Is selected from one of the following

r is 0 or 1,

s is 0 or 1,

R ¹² is hydrogen, methyl, benzyl or phenyl,

Indenyl, oxoindanyl, naphthyl, tetrahydronaphthyl, fluorenyl, oxofluorenyl, anthryl, dihydroanthryl, oxodihydroanthryl, dioxodihydro, bonded directly or via a methylene group Anthryl, dibenzocycloheptenyl, dihydrodibenzocycloheptenyl,

Furyl, thienyl, oxazolyl, thiazolyl, imidazolyl, oxdiazolyl, thiadiazoleyl, pyridyl, pyrazinyl, pyrimidinyl, imidazothiazolyl, benzofuryl, benzo, bonded directly or via a methylene group Thienyl, indolyl, oxoindolinyl, dioxoindolinyl, benzoxazolyl, oxobenzoxazolinyl, benzothiazolyl, oxobenzthiazolinyl, benzimidazolyl, oxobenzimidazolinyl, benzo Furazanyl, benzotriazolyl, oxazolopyridyl, oxodihydrooxazolopyridyl, thiazolopyridyl, oxodihydrothiazolopyridyl, chromanyl, chromanyl, benzopyranyl, chromoyl, quinolyl, iso Quinolyl, oxodihydroquinolinyl, tetrahydroquinolyl, oxotetrahydroquinolinyl, benzodioxanyl, quinazolinyl, acridinyl, oxodihydroacridinyl, phenothiazineyl, dihydrodibenzoxepinyl, Benzocycloheptathienyl, dihydro Thienobenzothiepinyl, dihydrodibenzothiepinyl, oxodihydrodibenzothiepinyl, dihydrodibenzazepinyl, oxodihydrodibenzazepinyl, octahydrodibenzazepinyl, benzocycloheptapyridyl, oxobenzocyclohepta Pyridyl, dihydrodibenzothiazepinyl,

R ¹³ is hydrogen, methyl, benzyl or phenyl,

R ¹⁴ is hydrogen, hydroxy, methyl, benzyl or phenyl,

Naphthyl, furyl, thienyl, pyridyl, benzofuryl, benzothienyl, indolyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, chromanyl, quinolyl or tetrahydro, bonded directly or via a methylene group Quinolyl,

At this time, in the chemical formula

-NR ¹² R ¹⁴ is pyrrolidine, piperidine, hexahydroazepine, morpholine, 2,5-diazabicyclo [2.2.1] heptane, indolin, isoindolin, (1H) -dihydroquinoline , (1H) -tetrahydroquinoline, (2H) -tetrahydroisoquinoline, (1H) -tetrahydrobenzo [b] azepine, (1H) -tetrahydrobenzo [d] azepine, (5H) -tetrahydro Benzo [b] oxazepine, (5H) -tetrahydrobenzo [b] thiazepine, 1,2,3,4-tetrahydroacridanone, (5H) -dihydrodibenzazepine, (11H) -dihydro Dibenzo [b, e] oxazepine or (11H) -dihydrodibenzo [b, e] thiazepine,

The aromatic ring systems at the substituents independently of one another are halogen series, cyano, C ₁ -C ₆ -alkyl, trifluoromethyl, C ₃ -C ₈ -cycloalkyl, phenyl, benzyl, hydroxy, C ₁ -C _6- Alkoxy, which may be substituted with one to three same or different substituents from C ₁ -C ₆ -alkoxy which may be optionally substituted with fluorine, wholly or partly, benzyloxy, phenoxy, mercapto, C ₁ -C _6- With alkylthio, carboxy, C ₁ -C ₆ -alkoxycarbonyl, benzyloxycarbonyl, nitro, amino, mono-C ₁ -C ₆ -alkylamino or di- (C ₁ -C ₆ -alkyl) -amino It may be carried, and two adjacent groups on the aromatic ring or ring system may cross the methylenedioxy bridge to form an additional ring.

Very particular preference is given to compounds in which the substituents represented in formula (I) have the following meanings:

R ¹ is hydrogen, fluorine, methyl, trifluoromethyl or hydroxy,

R ² and

R ³ is hydrogen,

R ⁴ is hydrogen or hydroxy,

k is 0,

A is ethylene (vinylene) or 1,3-butadiene ylene,

D is C ₂ -C ₆ -alkylene or C ₂ -C ₆ -alkenylene, wherein the double bond may also be for ringing E;

E is selected from pyrrolidine, piperidine, hexahydroazepine or morpholine,

G is benzyl, phenethyl, fluorenylmethyl, anthrylmethyl, diphenylmethyl, fluorenyl e or dihydrodibenzocycloheptenyl,

Furylmethyl, thienylmethyl, thiazolylmethyl, pyridylmethyl, benzothienylmethyl, quinolylmethyl, phenyl-thienylmethyl, phenyl-pyridylmethyl, dihydrodibenzoxepinyl, dihydrodibenzothipinyl,

Acetyl, pivaloyl, phenylacetyl, diphenylacetyl, diphenylpropionyl, naphthylacetyl, benzoyl, naphthoyl, anthrylcarbonyl, oxofluorenylcarbonyl, oxodihydroantryl Carbonyl or dioxodihydroanthrylcarbonyl,

Proyl, pyridylcarbonyl, chromoylcarbonyl, quinolylcarbonyl,

Naphthylaminocarbonyl, dibenzylaminocarbonyl, benzylphenylaminocarbonyl, diphenylaminocarbonyl, indolinyl-1-carbonyl, dihydrodibenzazepine-N-carbonyl, tetrahydroquinolinyl-N -Carbonyl, tetrahydrobenzo [b] azinyl-N-carbonyl,

Methanesulfonyl, phenylsulfonyl, p-toluenesulfonyl, naphthylsulfonyl, quinolinesulfonyl and

Diphenylphosphinoyl,

At this time, the aromatic ring systems are independently of each other halogen series, cyano, C ₁ -C ₆ -alkyl, trifluoromethyl, C ₃ -C ₈ -cycloalkyl, phenyl, benzyl, hydroxy, C ₁ -C ₆ -Alkoxy, C ₁ -C ₆ -alkoxy, benzyloxy, phenoxy, mercapto, C ₁ -C ₆ -alkylthio, carboxy, C ₁ -C ₆ -alkoxycarbonyl which may be wholly or partially substituted by fluorine , Benzyloxycarbonyl, nitro, amino, mono-C ₁ -C ₆ -alkylamino or di- (C ₁ -C ₆ -alkyl) -amino can be substituted with one to three same or different substituents, and Two adjacent groups of the ring or ring system may then form an additional ring via the methylenedioxy bridge.

Exemplary series of compounds according to each substituent definition are listed in Table 1 below to represent the invention without limiting the scope of the compounds according to the invention.

TABLE 1

Examples of Compounds of Formula (I) According to the Invention

Synthetic Method

Another aspect of the invention is analogous to the process for the production of compounds of formula (I) according to the invention.

Method (A):

Compound of formula (I)

(a) obtained by reacting a carboxylic acid of formula (II),

Wherein R ¹ , R ² , R ³ , A and k have the above meanings or their reaction derivatives react with the compound of formula (III),

Wherein D, E, G and R ⁴ also have this meaning.

Reactive derivatives of compound (II) can be, for example, active esters, anhydrides, acid halides (particularly acid chlorides) or simple lower alkyl esters. Suitable active esters are, for example, p-nitrophenyl esters, 2,4,6-trichlorophenyl esters, pentachlorophenyl esters, cyanomethyl esters, N-hydroxyphthalimide of N-hydroxysuccinimides. And an ester such as 2-hydroxypyridine or 2-mercaptopyridine of N-hydroxypiperidine, 1-hydroxybenzotriazole, and the like. Anhydrides can be symmetric anhydrides or mixed with, for example, pivaloyl chloride or chloroformate as they are obtained. Aromatic (eg chloroformic acid phenyl ester), araliphatic (eg chloroformic acid benzyl ester) or aliphatic chloroformate (eg chloroformic acid methyl ester, -ethyl ester or -isobutyl ester) Can be used as

The reaction of compound (II) with compound (III) can also be carried out by dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, N, N'-carbonyldiimidazole, It can be carried out in the presence of condensation agents such as 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline and the like. If carbodiimide is used as a condensing agent, it may be desirable to add samples such as N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxybenzotriazole, N-hydroxypiperidine and the like. Can be.

The compounds of formula III can be used in the reaction as free bases and in the form of their acid addition salts. For this purpose, salts of inorganic acids, ie hydrochloride, hydrobromide or sulfate salts, are preferred.

The reaction of compound (II) or their reaction derivatives with compound (III) is generally carried out in a suitably inert solvent. Aromatic hydrocarbons such as benzene, toluene, xylene, halogenated hydrocarbons (e.g. dichloromethane, chloroform, 1,2-dichloroethane, trichloroethylene), ethers (e.g. diethyl ether, tetrahydrofuran, Dioxane, glycol dimethyl ether), ethyl acetate, acetonitrile or polar aprotic solvents such as, for example, dimethylsulfoxide, dimethylformamide or N-methylpyrrolidone. Pure solvents and mixtures of two or more may also be used.

The reaction is optionally carried out in the presence of an auxiliary base. Suitable examples of such auxiliary bases are alkali metal carbonates (sodium carbonate, potassium carbonate), alkali metal hydrogen carbonates (sodium bicarbonate, potassium hydrogen carbonate), or triethylamine, ethyl diisopropylamine, tributylamine, Organic bases such as N-methylmorpholine or pyridine. Appropriate excess of compound (III) can also be used as the base. If compound (III) is used in the form of their acid addition salts, it is appropriate to consider the amount of auxiliary bases used equivalently.

The reaction temperature can vary widely-depending on the reactivity of the extracts. In general, the reaction is carried out at temperatures between −40 ° C. and 180 ° C., preferably at −10 ° C. and 130 ° C., especially at the boiling point of the solvent used.

Starting compounds (II) and (III) are known or can be produced according to known methods in a similar manner. Moreover, the production of representative examples is further described below.

Compound of formula (I)

(b) can be produced by the reaction of a compound of formula (I) with a compound of formula (IV), wherein G is hydrogen, and which itself has the activity found according to the invention,

L-G (Ⅳ)

Where G has the meaning given above, except for hydrogen, and L represents a suitable nucleoofuge or reactor. The form of the nucleofuge or reactor (L) and the conditions of the reaction depend on the nature of the residue G.

Compounds of formula (I) in which G has the meaning of (G1) in accordance with the definitions above except for hydrogen are also excluded with method (a)

(c) can be produced by reaction of a compound of formula (I) wherein G is hydrogen with a suitable alkylating and / or arylating agent of formula (IV), wherein in formula (IV) G is alkyl-, alkenyl- , Alkynyl-, cycloalkyl-, allyl-, aralkyl-, heteroaryl- or heteroaralkyl moiety, and the leaving group (L) is for example chlorine, bromine or iodine A reactive derivative of an alcohol such as a halogen atom or methanesulfonyloxy-trifluoromethanesulfonyloxy-, ethanesulfonyloxy-, benzenesulfonyloxy-, p-toluenesulfonyloxy -sulfonic acid esters such as p-bromobenzenesulfonyloxy- or m-nitrobenzenesulfonyloxy moiety or the reactive group L in which the reaction takes place during addition may also be an epoxide group.

The reaction of compounds (I) and (IV), wherein G is hydrogen, is usually carried out in a suitable inert solvent. Solvents of this type include aromatic hydrocarbons (benzene, toluene, xylene), ethers (e.g. tetrahydrofuran, dioxane, glycol dimethyl ether), ethyl acetate, acetonitrile, ketones (acetone, ethyl methyl ketone), alcohols Polar protic solvents such as (ethanol, isopropanol, butanol, glycol monomethyl ether) or polar aprotic solvents such as, for example, dimethylsulfoxide, dimethylformamide or N-methylpyrrolidone can be contemplated. Pure solvents and mixtures of two or more may also be used. Preferably, the reaction is carried out in the presence of a base, which base can be used as used in method (a) above. If chloride or bromide is used as compound (IV), the reaction can be accelerated by the addition of alkali metal iodide (sodium iodide, potassium iodide). The reaction temperature may vary between 0 ° C. and 180 ° C., depending on the reactivity of the extract, but is preferably between 20 ° C. and 130 ° C.

Compounds of formula (I) wherein G represents an acyl moiety, carbamoyl moiety, sulfonyl moiety or phosphinoyl moiety in accordance with the above definitions, also include, except for method (a) above,

(a) can be produced by reaction of a compound of formula (I) wherein G is hydrogen with a carboxylic acid, carbamic acid, sulfonic acid and / or phosphinic acid of formula (V),

HO-G (Ⅴ)

Wherein G is an acyl moiety, a carbamoyl moiety, a sulfonyl moiety or a phosphinoyl moiety, or a derivative capable of reacting according to the above definition. Preferred derivatives of carboxylic acids and / or sulfonic acids (V) capable of reacting are symmetric or asymmetric carboxylic anhydrides and / or sulfonic anhydrides or acyl- and / or sulfonyl halides, in particular acyl- and / or sulfonyl chlorides to be. Preferably, the derivatives of carbamate and / or phosphinic acid that can be reacted are carbamoyl halides and / or phosphinyl halides, in particular carbamyl and / or phosphinyl chlorides. The reaction of said acids (V) and / or their reactive derivatives with compounds (I), wherein G is hydrogen, preferably takes place in the presence of an auxiliary base in a solvent and under the conditions as described in method (a).

G represents a carbamoyl residue according to definition (G2b) under the condition that r = 0;

Compounds of formula (I), except for methods (a) and (d),

(e) Intermediate product is formed by reaction of a compound of formula (I) in which G is hydrogen and a carbonyl group transmitter, followed by direct reaction with a primary or secondary amine of formula (VI) Can be

H-NR ¹² R ¹⁴ (Ⅵ)

Wherein R ¹² and R ¹⁴ and / or the group —NR ¹² R ¹⁴ have the meaning according to the above definition without purification or separation of the intermediate product. Bis-trichloromethyl carbonate (triphosgene) and carbonyldiimidazole have been particularly demonstrated as reactive carbonyl group carriers. The reaction of a compound of formula (I), wherein G is hydrogen, with triphosgene and / or carbonyldiimidazole is generally carried out in an absolute, inert solvent in the presence of a tertiary organic amine as auxiliary base. This is done by slowly pouring the solution of (I) and the auxiliary base into a solution of an equivalent amount of carbonyl group carrier. In that regard, the reaction requires a molar ratio of 1: 1 for the reaction of compound (I) with carbonyldiimidazole and, on the contrary, a ratio of 1: 0.35 for the use of triphosgene. After completion of the reaction from the constituent components to the intermediate product, compound (VI) is added in stoichiometric amounts or in excess as a solution or solid and the reaction is generally completed at elevated temperature. Suitable inert solvents are, for example, hexane, heptane, benzene, toluene, xylene, chlorinated hydrocarbons (eg dichloromethane, chloroform, 1,2-dichloroethane, trichloroethylene), ethers (eg diethyl ether, Tetrahydrofuran, dioxane), esters such as ethyl acetate, butyl acetate, acetonitrile or formamide or polar aprotic solvents such as dimethylformamide. Pure solvents and mixtures may also be used in various ways. It is sometimes desirable to run the first partial reaction in a low viscosity, high volatility solvent at low temperatures, an intermediate is formed, then remove the solvent and replace it with a high boiling point solvent.

Amines such as, for example, triethylamine, ethyl diisopropylamine, tributylamine, N-methylmorpholine or pyridine are suitable as auxiliary bases. If compound (I) or (VI) is used as a salt, the amount of auxiliary base will be increased accordingly. The reaction temperature is between -40 ° C and 50 ° C for the first partial reaction, preferably between 0 ° C and 30 ° C and between 0 ° C and 150 ° C for the second partial reaction, preferably between 20 ° C and 120 ° C. Can be placed on.

Represents a carbamoyl residue according to definition (G2b) under the condition that G is r = 0 and R ¹⁴ = hydrogen

Compounds of formula (I) except for methods (a), (d) and (e)

(f) can be produced by reaction of a compound of formula (I), wherein G is hydrogen, and an isocyanate salt of formula (VIII) in which R ¹² has the meaning according to the above definition

O = C = NR ¹² (iii).

The reaction of a compound of formula (I), wherein G is hydrogen, with an isocyanate salt of formula (VIII) is carried out in a completely inert solvent, which solvent is a hydrocarbon such as pentane, hexane, heptane, benzene, toluene or xylene, chlorination Hydrocarbons (dichloromethane, chloroform, 1,2-dichloroethane, trichloroethylene, etc.), ethers (eg, diethyl ether, tetrahydrofuran, dioxane), esters such as ethyl acetate, butyl acetate, or formamide Or a polar aprotic solvent such as dimethylformamide. Mixtures of various solvents may also be used. Accordingly, the reaction temperature may vary in the range from -20 ° C to 150 ° C, but may preferably be placed at 20 ° C to 100 ° C.

As already mentioned, the compound of formula (I), wherein G is hydrogen, is itself a compound having tumor growth inhibitory ability and / or cell division inhibitory and immunosuppressive effects. However, irrespective of therapeutic adaptation, they also represent intermediate compounds useful for the production of many other compounds according to the invention corresponding to (c) to (f).

These compounds can in principle be produced by reacting the carboxylic acid of formula (II) with the amine of formula (III) in which G is hydrogen as described above according to method A. However, since the compounds of formula (III), wherein G is hydrogen, represent α, ω-diamines, the formation of the production mixture always takes place in the reaction with carboxylic acid (II) or their reactive derivatives which then require separation. Excluded.

In contrast, compounds of formula (I), wherein G is hydrogen, are more preferably produced essentially from other compounds of formula (I), which are groups that are selectively cleavable under conditions where G is not demanding, ie corresponding to nitrogen protecting groups.

Among the compounds according to formula (I) having tumor growth inhibitory ability and / or cell division inhibition and immunosuppressive effects, G is 4-methoxybenzyl group, triphenylmethyl group, methoxy and / or ethoxycarbonyl group, tert-butoxy There is a compound showing a carbonyl group, allyloxycarbonyl group or trifluoroacetyl group. Thus, compounds of formula (I) in which G is a 4-methoxybenzyl group are converted to compounds of formula (I) in which G is hydrogen by selective oxidation, for example, to ammonium-cerium (IV) -nitrate. Simple alkoxycarbonyl groups, such as methoxy- or ethoxycarbonyl groups, which are G in the compound of formula (I), also cleavage of trifluoroacetyl groups do not cleave the A and D linked amide function. And by alkaline hydrolysis under conditions that are not demanding. This is appropriately effective for the cleavage of triphenylmethyl and tertiary-butoxycarbonyl groups, which are G in the compound of formula (I), which cleavage takes place in acidic media under conditions that are not demanding. Finally, compounds of formula (I), in which G is an allyloxycarbonyl group, can be converted to G in hydrogen in the natural medium using a palladium catalyst. All of these methods are well known to those skilled in the art and are further documented in monographs (see Greene, Wuts, Protective Groups in Organic Synthesis, New York, 1991).

Compounds of formula (I) wherein R ⁴ is an alkyl, alkenyl, alkynyl or cycloalkyl moiety according to the above definitions also include, except for methods (a) and (b),

(g) can be produced by reaction of a compound of formula (I) wherein R ⁴ is hydrogen with an alkylating agent of formula (VIII)

LR ⁴ (Ⅷ)

Wherein R ⁴ is an alkyl, alkenyl, alkynyl or cycloalkyl moiety according to the above definition and L is a suitable nucleofuge, ie a sulfonic acid ester of an alcohol or a halogen atom such as for example chlorine, bromine or iodine. Preferred sulfonic acid esters are methylsulfonyloxy residue, trifluoromethanesulfonyloxy-, p-toluenesulfonyloxy-, p-bromobenzenesulfonyloxy- or m-nitrobenzenesulfonyloxy residue as L It contains.

Following amide alkylation in the presence of tertiary amino groups, the reaction requires the use of strong auxiliary bases such as potassium-tert-butylate, sodium hydride, potassium hydride or butyl lithium in the protic inert solvent. Such solvents are for example aliphatic or aromatic hydrocarbons (pentane, hexane, heptane, benzene, toluene), ethers (e.g. tetrahydrofuran, dioxane) or dimethyl sulfoxide, dimethylformamide or N-methylpyrroli It may be a polar solvent such as money. Depending on the reactivity of the extract, the reaction temperature may be between -40 ° C and 140 ° C, preferably between -20 ° C and 80 ° C.

Compounds of formula (I) produced according to methods (a) to (g) may be subjected to known methods, for example, by distilling off the solvent followed by partitioning, extraction, reprecipitation or recrystallization of the residues or other purification methods. By separation and purification. For this purpose, column chromatography or purification on a suitable support, preferred, middle or high pressure liquid chromatography is preferred.

In general, compounds (I) are first obtained in the form of their free base or hydrate or solvates, depending on the type of separation and purification. Their addition salts with pharmaceutically suitable acids are obtained by the typical method of changing the base to the desired acid in a suitable solvent. Depending on the number of basic centers of compound (I), more than one equivalent of acid per mole of base may be bound.

Suitable solvents include, for example, chlorinated hydrocarbons such as dichloromethane or chloroform; Ethers such as diethyl ether, dioxane or tetrahydrofuran; Acetonitrile; Ketones such as acetone or ethyl methyl ketone; Esters such as methyl acetate or ethyl acetate or low molecular alcohols such as methanol, ethanol or isopropanol; And water. Pure solvents and mixtures of two or more solvents may also be used. Salts can be separated by crystallization, precipitation or evaporation of the solvent. Thereby, the salts optionally accumulate as hydrates or solvates.

The base can be recovered from the salt, for example by alkalizing with an aqueous ammonia solution, alkali carbonate or dilute sodium hydroxide solution.

If not already specifically labeled, the compounds listed below and / or their pharmaceutically acceptable salts are particularly preferred.

N- [4- (1-methylsulfonylpiperidin-4-yl) -butyl] -3- (pyridin-3-yl) -acrylamide,

N- {4- [1- (2-naphthylsulfonyl) -piperidin-4-yl] -butyl} -3- (pyridin-3-yl) -acrylamide,

N- {4- [1- (2-naphthylsulfonyl) -piperidin-4-yl] -butyl} -5- (pyridin-3-yl) -2,4-pentadienoic acid amide ,

N- {4- [1- (1-naphthylaminocarbonyl) -piperidin-4-yl] -butyl} -3- (pyridin-3-yl) -acrylamide,

N- [4- (1-diphenylaminocarbonyl-piperidin-4-yl) -butyl] -3- (pyridin-3-yl) -acrylamide,

N- [4- (1-diphenylaminocarbonyl-piperidin-4-yl) -butyl] -5- (pyridin-3-yl) -2,4-pentadienoic acid amide,

N- {4- [1- (10,11) -Dihydrodibenzo [b, f] azepin-5-yl-carbonyl) -piperidin-4-yl] -butyl} -3- (pyridine -3-yl) -acrylamide,

N- [4- (1-diphenylphosphinoyl-piperidin-4-yl) -butyl] -3- (pyridin-3-yl) -acrylamide,

N- [4- (1-acetylpiperidin-4-yl) -butyl] -3- (pyridin-3-yl) -acrylamide,

N- [4- (1-diphenylacetyl-piperidin-4-yl) -butyl] -3- (pyridin-3-yl) -acrylamide,

N- {4- [1- (3,3-Diphenylpropionyl-piperidin-4-yl] -butyl} -3- (pyridin-3-yl) -acrylamide,

N- [4- (1-benzoylpiperidin-4-yl) -butyl] -3- (pyridin-3-yl) -acrylamide,

N- [4- (1-benzoylpiperidin-4-yl) -butyl] -5- (pyridin-3-yl) -2,4-pentadienoic acid amide,

N- {4- [1- (9-Oxo-9H-fluoro-4-yl-carbonyl) -piperidin-4-yl] -butyl} -3- (pyridin-3-yl) -acrylamide ,

N- {4- [1- (phenylpyridin-3-yl-methyl) -piperidin-4-yl] -butyl} -3- (pyridin-3-yl) -acrylamide,

N- {4- [1- (phenylpyridin-4-yl-methyl) -piperidin-4-yl] -butyl} -3- (pyridin-3-yl) -acrylamide,

N- {4- [1- (6,11-Dihydrodibenzo [b, e] oxepin-11-yl) -piperidin-4-yl] -butyl} -3- (pyridin-3-yl ) -Acrylamide,

N- {4- [1- (6,11-Dihydrodibenzo [b, e] thipin-11-yl) -piperidin-4-yl] -butyl} -3- (pyridin-3-yl ) -Acrylamide,

N- [7- (1-diphenylmethylpiperidin-4-yl) -heptyl] -3- (pyridin-3-yl) -acrylamide,

N- [8- (1-diphenylmethylpiperidin-4-yl) -octyl] -3- (pyridin-3-yl) -acrylamide,

N- [3- (1-diphenylmethylpiperidin-4-yloxy) -propyl] -3- (pyridin-3-yl) -acrylamide,

N- [3- (1-benzylpiperidin-4-yloxy) -propyl] -3- (pyridin-3-yl) -acrylamide,

N- [2- (1-diphenylmethylpiperidin-4-yl) -ethyl] -5- (pyridin-3-yl) -2,4-pentadienoic acidamide,

N- [4- (1-diphenylmethylpiperidin-4-yl) -butyl] -5- (pyridin-3-yl) -2,4-pentadienoic acidamide,

N- [5- (1-diphenylmethylpiperidin-4-yl) -pentyl] -5- (pyridin-3-yl) -2,4-pentadienoic acidamide or

N- [6- (1-Diphenylmethylpiperidin-4-yl) -hexyl] -5- (pyridin-3-yl) -2,4-pentadienoic acidamide.

For the final product of the invention according to formula (I)

Synthetic Example

In the following production examples for the final product, the abbreviations represent the following terms:

MP = melting point,

RT = room temperature,

THF = tetrahydrofuran,

DMF = dimethylformamide,

CDI = carbonyldiimidazole,

abs = complete

EDC = N- (3-dimethylaminopropyl) -N'-ethyl-carbodiimide hydrochloride,

HOBT = 1-hydroxybenzotriazole,

TEA = triethylamine.

¹ H-NMR-spectrum = proton resonance spectrum, used at 100 MHz Chemical shifts are given in ppm relative to TMS as reference (δ = 0.0),

s = singlet,

d = doublet,

t = triplet,

dt = doublet-triplet,

m = multiplet,

ar = aromatic

py = pyridine.

Example 1

N- {4- [1- (diphenylaminocarbonyl) -piperidin-4-yl] -butyl} -3- (pyridin-3-yl) -acrylamide (substance 199)

6.5 g (18.0 mmol) of N- [4- (piperidin-4-yl) -butyl] -3- (pyridin-3-yl) -acrylamide dihydrochloride (K22.142) and 5.77 ml (41.4 mmol) TEA is placed in 70 ml of absolute dichloromethane and cooled to about 0 ° C. with dehumidification. 4.58 g (19.8 mmol) of N, N-diphenylcarbamic acid chloride are dissolved in 20 ml of complete dichloromethane and added dropwise. The mixture is no longer cooled and stirred overnight at room temperature. 4 ml (28.7 mmol) of TEA are added and the red suspension is stirred for another 2 hours at room temperature. The batch is then washed with 80 ml of water. The organic phase is dried over sodium sulfate and the solvent is removed in vacuo. The residue is purified by chromatography on silica gel with CHCl ₃ / CH ₃ OH (98/2), and after removing the solvent, it is crystallized twice from 60 ml of acetic acid ethyl ester each. Beige crystals with an MP of 132-134 ° C .; Yield: 5.3 g (60%).

C ₃₀ H ₃₄ N ₄ O ₂ (482.6)

IR-Spectrum (KBr): ν (NH) 3300 cm ^-1

ν (C = 0) 1660 cm ^-1

1 H-NMR-spectrum (CDCl ₃ ): 0.60-1.75 (11H, m, piperidine, piperidine- (CH ₂ ) ₃ )

2.40-2.85 (2H, m, piperidine)

3.33 (2H, dt, CONHC H ₂ , J = 6.5 Hz, J = 12.7 Hz)

3.85-4.20 (2H, m, piperidine)

5.95-6.20 (1H, m, NH)

6.42 (1H, doublet, CH = C H CO, J = 15.7 Hz)

6.90-7.45 (11H, m, ar, py)

7.59 (1H, doublet, C H = CHCO, J = 15.7 Hz)

7.65-7.90 (1H, m, py)

8.45-8.60 (1H, m, py)

8.65-8.85 (1H, m, py)

Example 2

N- [4- (1-Diphenylacetyl-piperidin-4-yl) -butyl] -3- (pyridin-3-yl) -acrylamide (substance 150)

It is produced similarly to Example 1. However, no TEA is added next.

Batch Size: 5.0 g (13.9 mmol) of N- [4- (piperidin-4-yl) -butyl] -3- (pyridin-3-yl) -acrylamide dihydrochloride (Material 14 as dihydrochloride) ), 5.8 ml (41.6 mmol) of TEA and 3.9 g (15.2 mmol) of diphenylacetic acid chloride.

In tablets, this is washed twice with 50 ml of water each. Chromatographic purification is carried out with CHCl ₃ / CH ₃ OH (97/3 to 95/5). The residue is first crystallized twice from 15 ml acetic acid ethyl ester and then from 18 ml ethanol / diethyl ether (5/1). Colorless crystals have an MP of 161 ° C; Yield: 3.6 g (53%).

C ₃₁ H ₃₅ N ₃ O ₂ (481.6)

IR-Spectrum (KBr): ν (NH) 3280 cm ^-1

ν (C = 0) 1665, 1530 cm ^-1

ν (C = C) 1615 cm ^-1

¹ H-NMR-spectrum (CDCl ₃ ): 0.50-1.85 (1H, m, piperidine, piperidine- (CH ₂ ) ₃ )

                          2.40-3.10 (2H, m, piperidine)

3.32 (2H, dt, CONHC H ₂ , J = 6.5Hz, J = 12.6Hz)

                          3.80-4.05 (1H, m, piperidine)

                          4.55-4.80 (1H, m, piperidine)

5.23 (1H, Ar ₂ CH)

                          6.10-6.35 (1H, m, NH)

6.44 (1H, doublet, CH = C H CO, J = 15.7 Hz)

                          7.10-7.45 (1H, m, ar, py)

7.59 (1H, doublet, C H = CHCO, J = 15.7 Hz)

                          7.60-7.85 (1H, m, py)

                          8.50-8.65 (1H, m, py)

                          8.65-8.80 (1H, m, py)

Example 3

N- {4- [1- (2-naphthyl-sulfonyl) -piperidin-4-yl] -butyl} -3- (pyridin-3-yl) -acrylamide (substance 219)

It is produced similarly to Example 2.

Batch Size: 6.0 g (16.6 mmol) of N- [4- (piperidin-4-yl) -butyl] -3- (pyridin-3-yl) -acrylamide dihydrochloride (di in 70 ml complete dichloromethane Material 14) as hydrochloride, 5.6 ml (40.0 mmol) of TEA and 2.5 g (11.0 mmol) of naphthalin-2-sulfonic acid chloride.

In practice, it is washed twice with 70 ml of water each. Chromatographic purification is carried out with CHCl ₃ / CH ₃ OH (95/5 to 94/6). The residue is crystallized from 30 ml of acetic acid ethyl ester. Chromatographic purification is repeated with CHCl ₃ / CH ₃ OH (95/5). Yield: 2.7 g (57%); Amorphous solid with MP of 85-87 ° C.

C ₂₇ H ₃₁ N ₃ O ₃ S (477.5)

IR-Spectrum (KBr): ν (NH) 3320 cm ^-1

ν (C = 0) 1690, 1560 cm ^-1

ν (C = C) 1640 cm ^-1

¹ H-NMR-spectrum (CDCl ₃ ): 0.90-1.95 (1H, m, piperidine, piperidine- (CH ₂ ) ₃ )

                       2.10-2.50 (2H, m, piperidine)

3.34 (2H, dt, CONHC H ₂ , J = 6.5 Hz, J = 12.5 Hz)

                       3.65-4.00 (2H, m, piperidine)

                       5.85-6.15 (1H, m, NH)

6.46 (1H, doublet, C H = CHCO, J = 15.7 Hz)

7.15-8.10 (9H, m, ar, py, C H = CHCO)

                       8.33 (1H, s, Ar)

                       8.50-8.65 (1H, m, py)

                       8.65-8.80 (1H, m, py)

Example 4

N- {4- [1- (1-naphthylaminocarbonyl) -piperidin-4-yl] -butyl} -3- (pyridin-3-yl) -acrylamide (substance 195)

2.35 g (13.9 mmol) of 1-naphthyl isocyanate is dissolved in 10 ml of complete THF and 4.0 g (13.9 mmol) of N- [4- (piperidin-4-yl)-in 30 ml of complete THF A solution of butyl-3- (pyridin-3-yl) -acrylamide (material 14) is added dropwise at room temperature with moisture removed. After about an hour a white precipitate is formed and the suspension is stirred overnight at room temperature. The solid is removed, purified by chromatography on silica gel with CHCl ₃ / CH ₃ OH (95/5 to 93/7) and crystallized from isopropanol after removing the solvent. Colorless crystals have an MP of 198-200 ° C .; Yield: 2.2 g (34%).

C ₂₈ H ₃₂ N ₄ O ₂ (456.6)

IR-Spectrum (KBr): ν (NH) 3240 cm ^-1

ν (C = 0) 1660, 1560 cm ^-1

ν (C = C) 1615 cm ^-1

¹ H-NMR-spectrum (CDCl ₃ ): 1.00-1.95 (1H, m, piperidine, piperidine- (CH ₂ ) ₃ )

                        2.75-3.15 (2H, m, piperidine)

3.37 (2H, dt, CONHC H ₂ , J = 6.5 Hz, J = 12.7 Hz)

                        3.95-4.25 (2H, m, piperidine)

                        5.75-6.05 (1H, m, NH)

6.42 (1H, doublet, CH = C H CO, J = 15.6 Hz)

                        6.70 (1H, s, NH)

7.20-8.00 (10H, m, ar, py, C H = CHCO)

                        8.50-8.65 (1H, m, py)

                        8.65-8.80 (1H, m, py)

Example 5

N- {4- [1- (6,11-Dihydro-dibenzo [b, e] thien-11-yl) -piperidin-4-yl] -butyl} -3- (pyridine-3- Yl) -acrylamide (substance 136)

7.02 g (21.5 mmol) of N- [4- (piperidin-4-yl) -butyl-3- (pyridin-3-yl) -acrylamide (substance 14 as dihydrochloride) is 100 ml of complete dichloromethane Suspended in and added to 7.08 g (70.0 mmol) of TEA. The mixture was cooled to about 0 ° C. with dehumidification and a solution of 5.30 g (21.5 mmol) of 11-chloro-6,11-dihydro-dibenzo [b, e] thiefine in 10 ml of complete dichloromethane It is added dropwise. The mixture is stirred at room temperature for 24 hours without further cooling. The batch is then washed with 50 ml of 10% sodium hydroxide solution and 30 ml of water. The organic phase is dried over sodium sulfate and the solvent is removed in vacuo. The reddish brown residue is purified by chromatography three times on silica gel using CHCl ₃ / CH ₃ OH (100/0 to 97/3, and 96/4 to 94/6). Subsequently, further purification takes place by MPLC with CHCl ₃ / CH ₃ OH (98/2). Yield: 0.5 g (5%) of brittle glassy solids with MP of 89-91 ° C.

C ₃₁ H ₃₅ N ₃ OS (497.7)

IR-Spectrum (KBr): ν (NH) 3280 cm ^-1

ν (C = O) 1660, 1550 cm ^-1

ν (C = C) 1620 cm ^-1

¹ H-NMR-spectrum (CDCl ₃ ): 0.90-2.00 (13H, m, piperidine, piperidine- (CH ₂ ) ₃ )

                       2.55-2.95 (2H, m, piperidine)

3.20-3.60 (3H, m, CONHC H ₂ , SCH ₂ )

4.03 (1H, Ar ₂ CH)

                       6.10-6.35 (1H, m, NH)

5.95-6.30 (1H, m, SCH ₂ )

6.44 (1H, doublet, CH = C H CO, J = 15.7 Hz)

                       6.85-7.40 (9H, m, ar, py)

7.61 (1H, doublet, C H = CHCO, J = 15.7 Hz)

                       7.65-7.85 (1H, m, py)

                       8.50-8.65 (1H, m, py)

                       8.65-8.80 (1H, m, py)

Example 6

N- [4- (1-Diphenylmethyl-piperidin-4-yl) -butyl] -5- (pyridin-3-yl) -2,4-pentadienoic acid amide (substance 70)

Add 3 drops of pyridine, and then 3.85 g (22 mmol) of 5- (3-pyridyl) -2.4-pentadienoic acid is suspended in 90 ml of complete dichloromethane and in a bath of ice without moisture. Cool down to 0 ° C. 3.8 g (30.0 mmol) of oxalyl chloride are added dropwise and the mixture is stirred overnight at room temperature. The solvent and excess oxalyl chloride are then removed by distillation in a rotary evaporator. The residue is dried for 2 hours in a high-vacuum state to completely remove the oxalyl chloride. The acid chloride obtained in this way is suspended in 50 ml of complete dichloromethane and then cooled to about 0 ° C. in an ice bath with the exclusion of moisture. 6.44 g (20.0 mmol) of 4- (1-diphenylmethyl-piperidin-4-yl) -butylamine are dissolved in 40 ml of complete dichloromethane and added dropwise into this suspension. After the addition is complete, the ice bath is removed and the reaction stirred for another 2 hours at room temperature. The mixture is then washed with 10% sodium hydroxide solution. The organic phases are each washed twice with 40 ml of water and dried by sodium sulfate, and the solvent is removed in vacuo. The residue is purified by chromatography on silica gel with CHCl ₃ / CH ₃ OH (98/2 to 95/5) to remove the solvent and then crystallized twice from 250 ml to 200 ml acetonitrile. Beige crystals with an MP of 164-166 ° C .; Yield: 4.7 g (49%).

C ₃₂ H ₃₇ N ₃ O (479.6)

IR-Spectrum (KBr): ν (NH) 3280 cm ^-1

ν (C = O) 1650, 1550 cm ^-1

ν (C = C) 1600 cm ^-1

¹ H-NMR-spectrum (CDCl ₃ ): 1.00-2.00 (13H, m, piperidine, piperidine- (CH ₂ ) ₃ )

                       2.70-3.00 (2H, m, piperidine)

3.34 (2H, dt, CONHC H ₂ , J = 6.6 Hz, J = 12.8 Hz)

4.21 (1H, s, Ar ₂ CH)

                       5.50-5.75 (1H, m, NH)

                       6.44 (1H, doublet, CH = CH, J = 14.7 Hz)

                       6.75-6.95 (2H, m, CH = CH)

                       7.05-7.50 (12H, m, ar, py, CH = CH)

                       7.65-7.85 (1H, m, py)

                       8.45-8.55 (1H, m, py)

                       8.60-8.75 (1H, m, py)

Example 7

N- [4- (1-benzoylpiperidin-4-yl) -butyl] -3- (pyridin-3-yl) -acrylamide (substance 159)

5.1 g (36.2 mMo1) of benzoyl chloride is dissolved in 150 ml of complete dichloromethane and cooled to about 0 ° C. without moisture. 10.4 g (36.2 mmol) N- [4- (piperidin-4-yl) -butyl] -3- (pyridin-3-yl) -acrylamide (material 14) is dissolved in 50 ml of complete dichloromethane It is added dropwise in an ice cooling state. The mixture is stirred overnight at room temperature without further cooling. The suspension is then added to 60 ml of 2M sodium hydroxide and extracted twice with 80 ml of dichloromethane each. The combined organic phases are each washed twice with 60 ml of water, dried by sodium sulphate and the solvent is removed in vacuo. The residue is purified by chromatography on silica gel using CHCl ₃ / CH ₃ OH (97/3 to 95/5) and recrystallized from 75 ml of acetonitrile. Colorless crystals with an MP of 100-102 ° C .; Yield: 9.8 g (69%)

C ₂₄ H ₂₉ N ₃ O ₂ (391.5)

IR-Spectrum (KBr): ν (NH) 3280 cm ^-1

ν (C = O) 1670, 1545 cm ^-1

ν (C = C) 1630 cm ^-1

¹ H-NMR-spectrum (CDCl ₃ ): 0.80-2.00 (11H, m, piperidine, piperidine- (CH ₂ ) ₃ )

2.55-4.00 (5H, m, piperidine, CONHC H ₂ )

                        4.40-4.90 (1H, piperidine)

                        6.00-6.25 (1H, m, NH)

6.48 (1H, doublet, CH = C H CO, J = 15.7 Hz)

7.15-7.95 (8H, m, ar, py, C H = CHCO)

                        8.50-8.65 (1H, m, py)

                        8.65-8.80 (1H, m, py)

Example 8

N- (1-diphenylmethyl-azetin-3-ylmethyl) -3- (pyridin-3-yl) -acrylamide (substance 1)

Production is similar to Example 6.

Batch size: 4.3 g (28.7 mmol) 3- (3-pyridyl) -acrylic acid, 6.7 ml (78.4 mmol) oxalyl chloride, and 6.6 g (26.1 mmol) of (1-diphenylmethyl-azetidine- 3-ylmethyl) -amine

In practice, the reaction mixture is washed with 10% sodium hydroxide solution. The aqueous phase is extracted twice with 50 ml of dichloromethane each. The combined organic phases are dried by sodium sulphate and the solvent is removed in vacuo. The residue is preliminarily purified by chromatography on silica gel using CHCl ₃ / CH ₃ OH (98/2 to 95/5), followed by 2 using CHCl ₃ / CH ₃ OH (99/1 to 95/5). Purified by flash-chromatography. After the solvent was removed, an amorphous solid with MP of 72-74 ° C. was left; Yield: 0.75 g (7%).

C ₂₅ H ₂₅ N ₃ O (383.5)

IR-Spectrum (KBr): ν (NH) 3320 cm ^-1

ν (C = O) 1680, 1570 cm ^-1

ν (C = C) 1640 cm ^-1

¹ H-NMR-spectrum (CDCl ₃ ): 2.40-2.80 (1H, m, azetidine)

                          2.80-3.10 (2H, m, Azetidine)

                          3.10-3.40 (2H, m, Azetidine)

3.60 (2H, doublet of CONHC H ₂ , J = 5.7 Hz)

4.36 (1H, Ar ₂ CH)

                          6.45-6.75 (1H, m, NH)

6.50 (1H, doublet, CH = C H CO, J = 15.7 Hz)

                          7.00-7.50 (11H, m, ar, py)

7.62 (1H, doublet, C H = CHCO, J = 15.7 Hz)

                          7.65-7.90 (1H, m, py)

                          8.50-8.70 (1H, m, py)

                          8.70-8.85 (1H, m, py)

Example 9

N- (4-Diphenylmethyl-morpholin-2-ylmethyl) -3- (pyridin-3-yl) -acrylamide (substance 250)

Production is similar to Example 6.

Batch Size: 2.3 g (15.6 mmol) of 3- (3-pyridyl) -acrylic acid, 5.4 g (42.5 mmol) of oxalyl chloride, and 3.6 g (14.7 mmol) of 2-aminomethyl-4-diphenylmethyl Morpholine.

In practice, 40 ml of 10% sodium hydroxide solution is added to the reaction solution. The aqueous phase is extracted with 15 ml of dichloromethane. The combined organic phases are each washed twice with 15 ml of water, dried by sodium sulphate and the solvent is removed in vacuo. The residue is purified three times by chromatography on silica gel using CHCl ₃ / CH ₃ OH (95/5, 90/10, and 90/10). After the solvent was removed, an amorphous solid with an MP of 71-74 ° C. was left; Yield: 0.8 g (13%).

C ₂₆ H ₂₇ N ₃ O ₂ (413.5)

IR-Spectrum (KBr): ν (NH) 3270 cm ^-1

ν (C = O) 1655, 1540 cm ^-1

ν (C = C) 1620 cm ^-1

¹ H-NMR-spectrum (CDCl ₃ ): 1.70-2.30 (2H, m, morpholine)

                        2.55-2.90 (2H, m, morpholine)

                        3.00-3.35 (1H, m, morpholine)

3.50-4.00 (4H, m, CONHC H ₂ , morpholine)

4.20 (1H, Ar ₂ CH)

                        6.00-6.25 (1H, m, NH)

6.47 (1H, doublet, CH = C H CO, J = 15.7 Hz)

                        7.00-7.55 (11H, m, ar, py)

7.60 (1H, doublet, C H = CHCO, J = 15.7 Hz)

                        7.65-7.90 (1H, m, py)

                        8.50-8.70 (1H, m, py)

                        8.70-8.80 (1H, m, py)

Example 10

N- {4- [1- (9-Oxo-9H-fluoren-4-yl-carbonyl) -piperidin-4-yl] -butyl} -3- (pyridin-3-yl) -acrylamide (Material 178)

5.0 g (20.0 mmol) of 95% 9-fluorenone-4-carboxylic acid chloride was added to 70 ml of complete dichloromethane and 6.5 g (18.2 mmol) of N- [4- (piperidin-4-yl] -butyl ] -3- (pyridin-3-yl) -acrylamide dihydrochloride (Material 14 as dihydrochloride) is added The mixture is cooled to about 0 ° C. without moisture and dissolved in 10 ml of complete dichloromethane. 4.0 g (40.0 mmol) of TEA are added dropwise, the batch is stirred overnight at room temperature without further cooling, in which 150 ml of 10% sodium hydroxide solution is added to the reaction solution which is shaken and extracted. The organic phase is washed with 100 ml of water, dried over sodium sulphate and the solvent is removed in vacuo The residue is preliminarily purified on silica gel using CHCl ₃ / CH ₃ OH (96/4 to 95/5) and then CHCl _By attribute-chromatography with ₃ / CH ₃ OH (99/5) After removal of the solvent, a yellow vitreous solid product with MP of 80-82 ° C. remains; yield: 2.3 g (25%).

C ₃₁ H ₃₁ N ₃ O ₃ (493.6)

IR-Spectrum (KBr): ν (NH) 3320 cm ^-1

ν (C = O) 1730, 1640 cm ^-1

ν (C = C) 1620 cm ^-1

¹ H-NMR-spectrum (CDCl ₃ ): 0.70-2.05 (1H, m, piperidine, piperidine- (CH ₂ ) ₃ )

2.60-3.80 (5H, m, piperidine, CONHC H ₂ )

                         4.70-5.05 (1H, piperidine)

                         5.85-6.20 (1H, m, NH)

6.47 (1H, doublet, CH = C H CO, J = 15.7 Hz)

7.15-7.90 (10H, m, ar, py. C H = CHCO)

                         8.50-8.65 (1H, m, py)

                         8.65-8.85 (1H, m, py)

Example 11

N- [3- (1-Benzyl-piperidin-4-yloxy) -propyl] -3- (pyridin-3-yl) -acrylamide (substance 39)

2.4 g (16.2 mmol) of 3- (3-pyridyl) -acrylic acid and 2.3 ml (16.2 mmol) of TEA are suspended in 50 ml of complete toluene and 1.5 ml (15.5 mmol) of ethyl chloroformate in 20 ml of complete toluene The ester solution is added dropwise with mild cooling in the absence of moisture. This yellow suspension is stirred at room temperature for 2 hours and then added by dropwise addition of 3.5 g (14.1 mmol) 3- (1-benzylpiperidin-4-yloxy) -propylamine in 20 ml of complete toluene. do. The mixture is stirred at room temperature for 2 hours and extracted by shaking three times by heating with 10 ml of water, 2 M sodium hydroxide, and again with water. The organic phase is concentrated in vacuo and the orange oily residue is purified on silica gel using CHCl ₃ / CH ₃ OH / NH ₄ OH (90/9/1 and 95/5/0 to 90/10/0). Purified twice by chromatography and crystallized from 10 ml acetic acid ethyl ester.

Colorless crystals with MP of 100-102 ° C. remain; Yield: 1.9 g (35%).

C ₂₃ H ₂₉ N ₃ O ₂ (379.5)

IR-Spectrum (KBr): ν (NH) 3290 cm ^-1

ν (C = O) 1650, 1530 cm ^-1

ν (C = C) 1610 cm ^-1

¹ H-NMR-spectrum (CDCl ₃ ): 1.50-2.45 (8H, m, piperidine, C-CH ₂ -C)

                       2.70-3.00 (2H, m, piperidine)

3.25-3.80 (7H, m, piperidine, CONHC H ₂ , Ar-CH ₂ , O-CH ₂ )

6.54 (1H, doublet, CH = C H CO, J = 15.7 Hz)

                      6.70-6.95 (1H, m, NH)

                      7.25-7.50 (6H, m, ar, py)

7.69 (1H, doublet, C H = CHCO, J = 15.7 Hz)

                      7.80-8.00 (1H, m, py)

                      8.60-8.75 (1H, m, py)

                      8.75-8.90 (1H, m, py)

Example 12

N- [6- (1-Diphenylmethyl-piperidin-3-yl-carbonyl-amineo) -hexyl] -3- (pyridin-3-yl) -acrylamide (substance 103)

1.79 g (12.0 mmol) of 3- (3-pyridyl) -acrylic acid and 4.0 g (39.5 mmol) of TEA are suspended in 80 ml of complete dichloromethane and cooled to about 0 ° C. without moisture. 2.2 g (14.3 mmol) of 88% HOBT and 2.76 g (14.4 mmol) of EDC are added and the mixture is stirred for 30 minutes on ice. 5.6 g (12.0 mmol) of 1-diphenylmethyl-piperidine-3-carboxylic acid- (6-amino-hexyl) -amide dihydrochloride are added and the mixture is stirred overnight at room temperature without cooling. The batch is then washed twice with sodium hydroxide and with 50 ml of 2 M sodium hydroxide solution and with 70 ml of water. The organic phase is dried by sodium sulfate and the solvent is removed in vacuo. The residue is purified by chromatography on silica gel using CHCl ₃ / CH ₃ OH (96/4 to 95/5) and crystallized from 70 ml acetonitrile. Colorless crystals with an MP of 129-131 ° C. remain; Yield: 3.9 g (62%).

C ₃₃ H ₄₀ N ₄ O ₂ (524.7)

IR-Spectrum (KBr): v (NH) 3300 cm ^-1

v (C = O) 1640, 1540 cm ^-1

ν (C = C) 1620 cm ^-1

¹ H-NMR-spectrum (CDCl ₃ ): 1.20-2.95 (17H, m, piperidine, C- (CH ₂ ) ₄ -C)

3.15-3.55 (4H, m, CONHC H ₂ )

4.24 (1H, Ar ₂ CH)

                          6.30-6.55 (1H, m, NH)

6.57 (1H, doublet, CH = C H CO, J = 15.7 Hz)

                          7.05-7.45 (11H, m, ar, py)

7.62 (1H, doublet, C H = CHCO, J = 15.7 Hz)

                          7.65-8.00 (2H, m, py. NH)

                          8.50-8.60 (1H, m, py)

                          8.65-8.80 (1H, m, py)

Example 13

N- [4- (1-Diphenylphosphinyl-piperidin-4-yl) -butyl] -3- (pyridin-3-yl) -acrylamide (substance 232)

1.06 ml (5.55 mmol) of diphenylphosphinic acid chloride are dissolved in 20 ml of complete THF and cooled to about 0 ° C. without moisture. 2.0 g (5.55 mmol) N- [4-piperidin-4-yl) -butyl] -3- (pyridin-3-yl) -acrylamide dihydrochloride (material 14 which is dihydrochloride) and 2.3 ml (16.6 mmol) of TEA is suspended in 90 ml of complete THF and added dropwise under ice-cooling. The mixture is stirred for 4 days at room temperature without further cooling. The solvent is then removed in vacuo and the residue is taken up in 70 ml of 10% sodium hydroxide solution and extracted twice with 100 ml of CHCl ₃ , respectively. The combined organic phase is washed with saturated NaCl solution and dried by sodium sulfate, and the solvent is removed in vacuo. Moieties _{CHCl 3 / CH 3 OH (90/10} ) and the pre-purified on silica gel using, then _{CHCl 3 / CH 3 OH (90/10} ) by using the attribute-and further purified by chromatography of the acetate 30ml Crystallized from ethyl ester. Colorless crystals with an MP of 154-155 ° C. remain; Yield: 1.04 g (30%).

C ₂₉ H ₃₄ N ₃ O ₂ P (487.6)

IR-Spectrum (KBr): ν (NH) 3260 cm ^-1

ν (C = O) 1650, 1550 cm ^-1

ν (C = C) 1610 cm ^-1

¹ H-NMR-spectrum (CDCl ₃ ): 0.90-1.80 (11H, m, piperidine, pyriridine- (CH ₂ ) ₃ )

                       2.55-2.95 (2H, m, piperidine)

3.10-3.55 (4H, m, piperidine, CONHC H ₂ )

6.59 (1H, doublet, CH = C H CO, J = 15.7 Hz)

                       6.55-6.80 (1H, m, NH)

7.15-8.00 (13H, m, ar, py. C H = CHCO)

                       8.50-8.60 (1H, m, py)

                       8.60-8.80 (1H, m, py)

Example 14

N- [4- (1-Benzyl-piperidin-3-yl) -butyl] -3- (pyridin-3-yl) -acrylamide (substance 40)

Production is similar to Example 6.

Batch Size: 2.6g (17.4mmol) of 3- (3-pyridyl) -acrylic acid, 1.6ml (19.0mmol) of oxalyl chloride, and 3.9g (15.8mmol) of 100ml of complete dichloromethane Benzyl-piperidin-3-yl) -butylamine.

The reaction time is extended to 6 hours at room temperature. In practice, the batch is washed with 50 ml of 1 M sodium hydroxide solution and the aqueous phase is extracted with 50 ml of dichloromethane. The combined organic phases are concentrated in vacuo and the residue is prepurified twice by chromatography on silica gel using CHCl ₃ / CH ₃ OH (93/7 to 95/5), followed by CHCl ₃ / CH ₃ OH (95 / 5 to 97/3), and further purified by flash-chromatography and crystallized from 5 ml of acetic acid ethyl ester. Colorless crystals with an MP of 80-82 ° C. remain; Yield: 0.9 g (15%).

C ₂₄ H ₃₁ N ₃ O (377.5)

IR-Spectrum (KBr): ν (NH) 3300 cm ^-1

ν (C = O) 1650, 1530 cm ^-1

ν (C = C) 1610 cm ^-1

¹ H-NMR-spectrum (CDCl ₃ ): 1.00-2.10 (13H, m, piperidine, piperidine- (CH ₂ ) ₃ )

                       2.65-2.95 (2H, m, piperidine)

3.37 (2H, dt, CONHC H ₂ , J = 6.5 Hz, J = 12.7 Hz)

3.50 (2H, s, Ar-CH ₂ )

                       5.65-5.95 (1H, m, NH)

6.46 (1H, doublet, CH = C H CO, J = 15.6 Hz)

                       7.10-7.40 (6H, m, ar, py)

7.62 (1H, doublet, C H = CHCO, J = 15.6 Hz)

                       7.65-7.90 (1H, m, py)

                       8.50-8.65 (1H, m, py)

                       8.70-8.80 (1H, m, py)

Example 15

N- [4- (1-tert-butoxycarbonylpiperidin-4-yl) -butyl] -3- (pyridin-3-yl) -acrylamide (substance 242)

Production is similar to Example 6. In addition, TEA is added dropwise with addition of the amine.

Batch Size: 16.4 g (110 mmol) 3- (3-pyridyl) -acrylic acid, 18.9 g (150 mmol) oxalyl chloride, 25.6 g (100 mmol) 4- (tert-butoxycarbonyl-piperidine- 4-yl) -butylamine, and 10.1 g (100 mmol) of TEA in 300 mmol of dichloromethane.

In practice, 100 ml of 10% sodium hydroxide solution is added to the reaction solution. The aqueous phase is extracted with 30 ml of dichloromethane. The combined organic phases are washed twice with 25 ml of water each and the solvent is removed in vacuo. The residue is dissolved in CHCl ₃ / CH ₃ OH (90/10) and filtered through a thin layer of silica gel. After the solvent is removed, red oil (44 g) remains as an initial product. For purification, it is chromatographed with CHCl ₃ / CH ₃ OH (95/5) in silica gel. Yield: 26.5 g (68%) of yellow viscous oil.

C ₂₂ H ₃₃ N ₃ O ₃ (387.50)

IR-Spectrum (KBr): ν (NH) 3250 cm ^-1

ν (C = O) 1670, 1540 cm ^-1

ν (C = C) 1600 cm ^-1

¹ H-NMR-spectrum (CDCl ₃ ): 0.80-1.90 (20H, m, piperidine, piperidine- (CH ₂ ) ₃ ,

                       Tertiary, butyl)

                        2.30-2.90 (2H, m, piperidine)

                        3.10-3.60 (2H, m, piperidine)

3.80-4.30 (2H, m, CONHC H ₂ )

                        6.15-6.55 (1H, m, NH)

6.43 (1H, doublet, CH = C H CO, J = 15.6 Hz)

                        7.05-7.85 (2H, m, py)

7.51 (1H, d, C H = CHCO, J = 15.6 Hz)

                        8.35-8.55 (1H, m, py)

                        8.55-8.70 (1H, m, py)

Example 16

N- [4- (piperidin-4-yl) -butyl] -3- (pyridin-3-yl) -acrylamide dihydrochloride (substance 14 being dihydrochloride)

44.0 g (<113.5 mmol) initial N- {4- {N- (tert-butoxycarbonyl) -piperidin-4-yl] -butyl} -3- (pyridin-3-yl) -acrylamide (Material 242) is dissolved in 400 ml of ethanol and added to 26.0 ml of concentrated hydrochloric acid. The mixture is heated to boil for 3 hours, cooled, and then the solvent is removed in vacuo. Yellow residue is crystallized from 500 ml of isopropanol. Beige colored crystals with an MP of 178-188 ° C. remain; Yield: 32.6 g (90%).

C ₁₇ H ₂₅ N ₃ O2HCl (360.3)

IR-Spectrum (KBr): ν (NH) 3260 cm ^-1

ν (C = O) 1670, 1545 cm ^-1

ν (C = C) 1630 cm ^-1

¹ H-NMR-spectrum (D ₂ O) 0.95-1.95 (11H, m, piperidine, piperidine- (CH ₂ ) ₃ )

                       2.60-3.00 (2H, m, piperidine)

3.00-3.40 (4H, m, piperidine, CONHC H ₂ )

6.73 (1H, doublet, CH = C H CO, J = 15.9 Hz)

7.41 (1H, doublet, C H = CHCO, J = 15.9 Hz)

                       7.80-8.00 (1H, m, py)

                       8.50-8.65 (2H, m, py)

                       8.65-8.90 (1H, m, py)

The invention is illustrated in more detail by the synthetic examples listed in Table 2 below, which are not intended to limit the invention.

TABLE 2

Compound prepared by formula (I)

Table comment

¹ MeOH = Methanol

  EE = ethyl acetate

  iPrOH = isopropanol

  MeCN = acetonitrile

  EtOH = ethanol

Et ₂ O = diethyl ether

  BuCl = 1-chlorobutane

  MTBE = methyl tert-butyl ether

^{As 2} dihydrochloride

Purification by ^Three Column Chromatography

Some examples of the production of starting compounds are described below to better represent the final product.

Synthesis of Starting Compound

Example 1A

4- (1-tert-butoxycarbonyl-piperidin-4-yl) -butan-1-ol

100 g (458 mmol) 4-piperidin-4-yl-butan-1-ol hydrochloride is dissolved in 120 ml of water, added to 216 ml (1550 mmol) of TEA and cooled to about 5-10 ° C. 122 g (559 mmol) of di-tert-butyl dicarbonate are dissolved in 400 ml of THF and added dropwise within 4 hours with further cooling. The mixture is left overnight at room temperature without further cooling. Subsequently, THF is removed in vacuo and the residue is extracted twice with 300 ml and 200 ml CHCl ₃ , respectively, and the combined organic phases are washed twice with 20 ml of water each. The solvent is removed in vacuo. The residue is dried in high vacuum and further processed without further purification. Yield: 136 g (102%).

Example 2A

2- [4- (1-tert-butoxycarbonylpiperidin-4-yl) -butyl] -isoindole-1,3-dione

136 g (<528 mmol) 4- [1-tert-butoxycarbonylpiperidin-4-yl) -butan-1-ol (initial product), 135.3 g (516 mmol) triphenylphosphine, and 75.9 g (516 mmol) of phthalimide was suspended in 1800 ml of THF and 89.9 g (516 mmol) of azodicarboxylic acid diethyl ester was added for 3 hours in a protective atmosphere and under mild cooling (at about 15 ° C.). It is added dropwise within. The mixture remains overnight at room temperature without further cooling. The solvent is then removed in vacuo and the oily residue is dissolved in 500 ml of acetic acid ethyl ester and kept at 0 ° C. overnight. The sinking precipitate is filtered off and discarded. The solution is concentrated in vacuo and the oily residue is purified by chromatography on silica gel using CHCl ₃ , the solvent is removed and crystallized from 200 ml of isopropanol. Colorless crystals with MP of 100-102 ° C. remain; Yield: 108.5 g (57%).

Example 3A

4- (1-tert-butoxycarbonylpiperidin-4-yl) -butylamine

113.0 g (292 mmol) of 2- [4- (1-tert-butoxycarbonylpiperidin-4-yl) -butyl] -isoindole-1,3-dione are dissolved in 600 ml of ethanol, 29.3 g (585 mmol) of hydrazine hydrate was added and boiled for 3 hours. After cooling the solution, the mixture is filtered and the filtrate is concentrated in vacuo. The residue is dispersed between 500 ml of toluene and 500 ml of 10% sodium hydroxide solution under heating (about 50 ° C.). The organic phase is washed once with 50 ml of 10% sodium hydroxide solution and twice with 50 ml of water each. The solvent is removed in vacuo and the residue is dried at 70 ° C. under high vacuum to be further processed without further purification. Yield of colorless oil: 64.0 g (85%).

Example 4A

(1-diphenylmethyl-azetidin-3-ylmethyl) -amine

A solution of 10.0 g (40 mmol) of 1-diphenylmethyl-azetidine-3-carbonitrile in 20 ml of complete THF was added dropwise to a suspension of 3.1 g (80 mmol) of lithium aluminum hydride in 80 ml of complete THF. And stirred overnight. The batch is carefully added to 2 ml of ethanol and filtered. The filtrate is concentrated in vacuo and dispersed between CHCl ₃ and water. The aqueous phase is extracted twice with 50 ml of CHCl ₃ each, the combined organic phases are dried by sodium sulphate and the solvent is removed in vacuo. The residue is purified by chromatography on silica gel using CHCl ₃ / CH ₃ OH / NH ₄ OH (90/10/0 to 90/10/1). Yield: 5.6 g (55%) of resin cured slowly.

Example 5A

3- (1-benzylpiperidin-4-yloxy) -propylamine

10.0 g (40.9 mmol) of 3- (1-benzylpiperidin-4-yloxy) -propionitrile is dissolved in 100 ml of ethanol and placed on Raney-Nickel's spatula tip Is added. The mixture is stirred at room temperature in a hydrogen atmosphere until the theoretical amount of hydrogen is absorbed (about 2 days). The mixture is filtered from the catalyst and the solvent is removed in vacuo. The residue is distilled off in a bulb tube apparatus. Yield of colorless oil: 7.5 g (73%).

Example 6A

1-diphenylmethyl-piperidine-3-carboxylic acid hydrochloride

15.7 g (100 mmol) of piperidine-3-carboxylic acid ethyl ester and 30.4 g (220 mmol) of potassium carbonate are placed in 100 ml of DMF and 24.1 g of diphenyl methyl bromide and added dropwise. The mixture is stirred overnight at room temperature and then filtered. The filtrate is concentrated in vacuo and the residue is taken up with 150 ml of acetic acid ethyl ester and extracted twice with 50 ml of 10% hydrochloric acid, respectively. The organic phase is discarded and the combined aqueous phases are basic with 10% sodium hydroxide solution and extracted twice with 50 ml of acetic acid ethyl ester each. The combined organic phases are cooled to about 0 ° C. and the precipitated solids are removed and dried. Yield: 20.5 g (63%) of compound 1-diphenylmethyl-piperidine-3-carboxylic acid ethyl ester with MP at 166-168 ° C. The compound is boiled by heating for 8 hours with 24 ml of 20% hydrochloric acid in 100 ml water. After cooling, the precipitate is filtered off and crystallized from 70 ml methanol. Yield: 15.6 g (74%).

Example 7A

1-diphenylmethylpiperidine-3-carboxylic acid- (6-aminenohexyl) -amide

10.0 g (33.8 mmol) of 1-diphenylmethylpiperidine-3-carboxylic acid hydrochloride reacts with 8.6 g (68 mmol) of oxalyl chloride to form an acid chloride similarly to Example 6. It is suspended in complete dichloromethane and added to 6.64 g (30.7 mmol) of N- (tert-butoxycarbonyl) -hexanediamine and 3.1 g (30.7 mmol) of TEA and stirred overnight at room temperature. The mixture is then concentrated and taken up in CHCl ₃ and washed once with 50 ml of 10% sodium hydroxide solution and twice with 30 ml of water each. The organic phase is dried over sodium sulfate and the solvent is removed in vacuo. The residue is purified by chromatography on silica gel using CHCl ₃ / CH ₃ OH (100/0 to 98/2) and dissolved in 80 ml of ethanol. After adding 6 ml of concentrated hydrochloric acid, the mixture is heated and boiled for 5 hours. After cooling, the solvent is removed in vacuo and the residues are dehydrated by azeotropically dehydrating twice with 30 ml of toluene each and then dried in high vacuum. The resin is further treated without further purification. Yield: 6.8 g (71%).

Example 8A

4- (1-benzylpiperidine-3-ylidene) -butyronitrile

77.3 g (188.3 mmol) of 3-cyanopropyl-triphenylphosphonium bromide are suspended in 300 ml of toluene and added to 22.0 g (191.9 mmol) of potassium tert-butylate. The mixture is cooled to about 0 ° C. in the absence of moisture and 34.6 g (182.8 mmol) of 1-benzyl-3-piperidone solution in 50 ml of toluene are added dropwise under cooling. The batch is left overnight at about 0 ° C. and then diluted with 200 ml of toluene and washed twice with 100 ml of water each. The organic phase is extracted with about 150 ml of concentrated hydrochloric acid. The aqueous phase is then basic with 200 ml of 10% sodium hydroxide solution and extracted twice with 250 ml of toluene each. The solvent is removed in vacuo and the residue is purified by chromatography on silica gel using CHCl ₃ / CH ₃ OH (97/3). After the solvent is taken off, a light brown oil is left, which is further processed without further purification. Yield 47.4 g (90%).

Example 9A

4- (1-benzylpiperidin-3-yl) -butylamine

8.0 g (33.3 mmol) of 4- (1-benzylbenzylpiperidin-3-yldene) -butylonitrile are dissolved in 80 ml of ethanol and added to Raney-Nickel's spatula tip. The mixture is stirred at about 50 ° C. (about 5 days) in a hydrogen atmosphere until the theoretical amount of hydrogen is absorbed. The mixture is filtered from the catalyst and the solvent is removed in vacuo. The residue is purified twice by chromatography on silica gel using CHCl ₃ / CH ₃ OH / NH ₄ OH (90/10/1). After removal of the solvent, colorless oil is left, which is further processed without further purification. Yield: 3.9 g (47%).

The active ingredients according to the invention are in the form of acid addition salts, hydrates, or solvates, respectively, optionally with the addition of other active ingredients for indication tumor treatment or immunosuppression. Furnaces or combinations thereof with one another may be treated with the desired drug. When the active ingredients according to the invention are combined with other pharmaceutical forms, these ingredients may also optionally be adjoined with one another in a pharmaceutical packaging, eg tablets, next to the viles, as desired. Each may be present.

Therefore, another aspect of the present invention is a method of treating a human or animal body, wherein a compound or complex mixture according to formula (I), in which the substituents have the above meanings, for the treatment of tumors and / or cytostatic agents, cancer It is taken as an antiproliferative agent, an immunosuppressive agent, or optionally in combination with another cytostatic or immunosuppressive active ingredient or other active ingredient suitable for the indicated indication.

The invention also provides a compound according to formula (I) for use in therapy in which the treatment is carried out in association with one or more medical indications for tumors or for immunosuppression, optionally in combination with another medicament suitable for the indicated indication. Or a complex mixture.

(E) -3- (3-pyridyl) -N- [2-benzylpyridin-4-yl) ethyl] -2-propenamide hydrochloride, for producing a drug for human or animal body therapy The use of one or more compounds according to formula (I) or in the corresponding diagnostics, in particular with respect to one or more medical indications for the treatment of tumors or for immunosuppression, optionally in combination with additional agents suitable for these indications. The use of the compounds according to (I) shows examples according to the invention.

Each suitable tumor indication is shown at the end of the section describing the pharmacological test results.

The drug is taken with one or more compounds according to formula (I) in an amount suitable for treating these active ingredients, with each suitable pharmaceutically acceptable carriers and adjuvants for the finished pharmaceutical form. The method of production is likewise within the protection scope of the present invention.

Depending on the medical indication to be considered, each suitable pharmaceutical form is selected for the appropriate therapeutic application.

The present invention also provides for the treatment of these indications, (E) -3- (3-pyridyl) -N- [2- (1-benzylpiperidin-4-yl) ethyl] -2-propenamide hydro It relates to the use of compounds according to formula (I) comprising chloride.

To better understand the present invention, the production of each suitable drug as well as a series of pharmaceutical forms is described below.

Therapeutic dosage forms

Producing a drug in the amount of one or more compounds according to the invention and / or using the drugs according to the invention is by conventional methods using conventional pharmaceutical techniques. To this end, the active ingredient as it is or in salt form is treated with suitable and pharmaceutically acceptable auxiliaries and carriers to form a pharmaceutical form suitable for a variety of indications and types of application. In this way, the drug can be produced in such a way that each desired release rate is obtained, for example with a rapid floating effect and / or with a sustained or depot effect.

Drug preparation for parenteral use, including injections and infusions, is one of the most important drugs used systematically for the treatment of tumors as well as other indications.

Preferably, the injection is administered for the treatment of the tumor. It is prepared in the form of a vial or in the form of so-called injection preparations which can be used immediately, for example in addition to a variety of dispensing perforation bottles, or ready-to-use syringes or disposable syringes. Injection preparations can be administered in subcutaneous (s.c.), intramuscular (i.m.), intravenous (i.v.), or intracutaneous (i.c.) forms. Each suitable injectable form can be produced in particular in solution, crystalline suspensions, nanoparticles, or colloid-disperse systems such as, for example, hydrosols.

Injectable formulations can also be produced in concentrates which have an aqueous isotonic diluent and can be adjusted to the desired active ingredient dosage. In addition, the formulations can also be produced as powders such as lyophilisate, which are dissolved or dispersed just prior to application with a suitable diluent. Infusions can be formulated in the form of liquids based on mixed colloids such as isotonic solutions, fat emulsions, liposome formulations, microemulsions, and phospholipids. As in the preparation of injectable solutions, the injectable formulation may also be prepared in the form of a diluted concentrate. Injectable formulations are also applicable in the form of continuous infusion in inpatient and outpatient treatments, such as, for example, mini-pumps.

Albumin, plasma extenders, surface active compounds, organic solvents, pH enhancing compounds, complex forming compounds, or polymeric compounds are particularly useful as substances for enhancing the absorption of the active ingredient into proteins or polymers, or where the active substance may It may be added to parenteral pharmaceutical forms for the purpose of reducing absorption into injection devices or packaging materials.

The active ingredient may be bound to nanoparticles of pharmaceuticals for parenteral use, for example to finely dispersed particles based on poly (meth) acrylates, polyacetates, polyglycolates, polyamino acids or polyether urethanes. have. Parenteral formulations can also be carried out, for example, on the multiple unit principle, where the active ingredient is contained in the finest distribution and / or dispersion and suspended form, or as a crystalline suspension, or after the active ingredient is for example Structural modifications are possible from single unit principles contained in pharmaceutical forms, such as infused tablets or seeds, to depot preparations. Often, these implants or depot drugs in single and multi-unit pharmaceutical forms consist of what are called biodegradable polymers, which include polyether urethanes of lactic and glycolic acids, polyether urethanes, polyamino acids, poly (meth) ) Acrylates or polysaccharides.

Sterile water such as organic and inorganic acids or bases and substances that affect the pH value such as their salts, buffer materials for setting the pH value such as sodium chloride, monosodium carbonate, glucose and fructose and Isotonic agents, such as isotonic and / or surface active substances and for example partial fatty acid esters of polyoxyethylene sorbitan (Tween ^® ) or fatty acid esters of polyoxyethylene for example (Cremophor ^® ) And emulsifiers such as, for example, fatty oils such as peanut oil, soybean oil, castor oil, and synthetic fatty acid esters such as ethyl oleate, isopropyl myristate and neutral oil (Miglyol ^® ), Also, for example, polymer aids such as gelatin, dextran, polyvinylpyrrolidone, for example propylene glycol, ethanol, N, N-dimethylacetamide, Soluble organic solvent additives such as propylene glycol or complex forming compounds such as, for example, citrate and urea, such as hydroxypropyl benzoate and preservatives such as hydroxymethyl benzoate, benzyl alcohol ), For example, antioxidants such as sodium sulfite, and stabilizers such as, for example, EDTA, are suitable as adjuvants or carriers in pharmaceutical production for parenteral use.

In suspension, thickening agents are constantly added to prevent the active ingredient from sinking in tensides and peptizers and to ensure the ability of the precipitate to shake, or complexes such as EDTA Complex formers are added continuously. It can also be obtained in various polymeric complexes such as, for example, polyethylene glycol, polystyrene, carboxymethylcellulose, Pluronics ^® or polyethylene glycol sorbitan fatty acid esters. The active ingredient can also be incorporated into liquid formulations in the form of inclusion compounds, for example in cyclodextrins. As another adjuvant, dispersants are also suitable. For the production of lyophilisates, builders such as mannite, dextran, saccharose, human albumin, lactose, PVP, or gelatin variants are also used.

Unless the active ingredients are incorporated into liquid pharmaceutical formulations in the form of bases, these active ingredients are used in the form of acid addition salts, hydrates, or solvates in pharmaceuticals for parenteral use.

Another important line of application is tablets, hard or soft gelatin capsules, coated tablets, powders, pellets, microcapsules, oval compresses, granules, chewable tablets, lozenges, gums Or orally as a small sachet. Oral administration of such solids may also be formulated as a sustained action and / or depot system. Among these are one or more micronized active ingredients, erosion forms and diffusion agents based on the matrix, for example by using fat, waxy and / or polymeric compounds, or so-called reservoir systems. There are drugs with diffusions. As retarding agents and / or controlled release agents, for example films such as ethylcellulose, hydroxypropylmethylcellulose, poly (meth) acrylate derivatives (e.g. Eudragit ^® ), hydroxypropylmethylcellulose phthalate or The matrix forming material is suitable in organic solution and in aqueous dispersion form. In this regard, the residence time in the body can be increased by the preparation of so-called bio-adhesives and by strong contact with the mucous membranes of the body. An example of a mucoadhesive polymer is the Carbomers ^® group.

For sublingual applications, compacts, for example, oval, non-degradable tablets of slow release and appropriate size of the active ingredient are particularly suitable. For the release of the active ingredient in various parts of the gastrointestinal system, mixtures of pellets which are released in various places are suitable, for example pellet mixtures which are soluble in gastric juice and in the small intestine and / or insoluble in the large intestine without dissolving in gastric juice. The same objective to release in various parts of the gastrointestinal system can also be devised for tablets produced in thin slices with nuclei, wherein the coating of the agent is released quickly from the gastric juice and the nucleus of the drug is released slowly from the middle of the small intestine. do. Controlling to be released from various parts of the gastrointestinal system may also consist of a multilayer tablet. Pellet mixtures with different release agents may be filled into hard gelatin capsules.

Anti-stick and lubricants and separators, dispersants such as flame dispersed silicone dioxide, disintegrants such as various starch types, waxes based on PVC, Eudragit ^® and / or or a granule forming agent (granulating agent) or retardant cellulose esters, cellulose or Cremophor ^® as such as a polymer compound, for example, a tablet, hard or soft gelatin capsules, and for compressing the water produced, such as coated tablets and granules It is used as another supplement.

Antioxidants, for example sweetening agents such as saccharose, zirite or mannite, masking flavors, aromatics, preservatives, coloring agents, buffering agents, direct-tableting agents such as microcrystalline cellulose, starch and starch Degradation products (e.g., Celutab ^® ), lactose, polyethylene glycol, polyvinylpyrrolidone and dicalcium phosphate, lubricants, fillers such as lactose or starch, binders in the form of lactose, wheat or corn and / Or starch variants such as rice starch, for example cellulose derivatives such as methylcellulose, hydroxypropylcellulose or silica, talc powders, for example stearates such as magnesium stearate, aluminum stearate, calcium stearate, talc Siliconized talc, stearic acid, acetyl alcohol, and hydrated fats are used.

In this regard, mention will also be made of oral treatment systems, in particular composed of osmotic principals, such as gastrointestinal therapeutic systems (GIT) or oral osmotic systmes (OROS).

Both tablets or effervescent tablets are orally administered compresses in the form of ready-to-use medicaments that are quickly dissolved or suspended in water and ready for immediate drinking. Among the oral dosage forms are also solutions such as, for example, drops, juices, suspensions, which may be produced by any of the above methods, may contain preservatives and are readily ingested to increase stability. It may optionally include aromatics, and may include colorants, antioxidants, and / or vitamins, and sweeteners such as sugars or artificial sweeteners to make them easier to distinguish. This also applies to concentrated juices formulated with water prior to ingestion. Ion exchange resins in combination with one or more active ingredients will also be mentioned with respect to producing ingestible liquid forms.

Special release forms are formulated in the form of so-called floating medicines, for example tablet-based fillets, which generate gas when contacted with liquids in the body and thus float on the surface of the gastric juice. In addition, so-called electronically controlled release systems can also be formulated, whereby the active ingredient release can optionally be tailored to individual needs.

Another group of lineage doses and, optionally, a pharmaceutical form with a topical effect are represented as drugs that are rectally applicable. Among these are suppository and enema formulations. Enema formulations may be formulated based on tablets with aqueous solvents to produce such dosage forms. Rectal capsules are also available based on gelatin or other carriers.

Cured fats such as Witepsol ^® , Massa Estarinum ^® , Novata ^® , coconut fat, glycerol-gelatin chunks, glycerol-soap-gel and polyethylene glycols are suitable as bases.

For long term application of systemic active ingredient release up to several weeks, pressed implants are preferably formulated based on so-called biodegradable polymers.

As another important group of lineage active drugs, the transdermal system is also highlighted, which distinguishes it from the rectal forms mentioned above by avoiding the liver circulatory system and / or liver metabolic problems. These plasters may be formulated in transdermal systems capable of releasing the active ingredient in a controlled manner over a long period of time, in particular based on different layers and / or mixtures of suitable auxiliaries and carriers. Apart from suitable auxiliaries and carriers such as solvents and polymer urea, for example based on Eudragit ^® , oleic acid, Azone ^® , adipicic acid, derivatives, ethanol, urea, propylglycol Membrane penetration enhancers such as and / or penetration promoters are suitable for the production of this type of transdermal system for the purpose of improving and / or accelerating penetration.

For the administration of drugs locally, locally, or locally, the following are suitable for special formulations: emulsions, creams, foam tablets, depot implants, eggs or urethra that are applicable to the vagina or genitals Transurethral Administration Penetration Solutions In ophthalmological applications, highly bactericidal ointments, solutions and / or drops or creams and emulsions are suitable.

Likewise, the corresponding otological drops, ointments or creams may be marked for application to the ear. In the above-mentioned applications, administration of semi-solid formulations such as gels, for example, based on Carbopols ^® and other polymer compounds such as polyvinylpyrrolidone and cellulose derivatives, is also possible. It is possible.

Generally, ordinary emulsions, gels, ointments, creams or mixed phase and / or amphiphilic emulsion systems for application to the skin or mucus membrane. (Oil / water-water / oil mixed phase), liposomes and transfersomes can be named. Gel builders for the production of suitable foundations or cellulose derivatives, such as sodium algenate as gel builders such as guar or xanthene viscous rubber, for example aluminum hydroxide or bentonite (thixotropic gel builder la called) and the inorganic gel builders, and, for example, Carbopols ^®, polyvinylpyrrolidone, microcrystalline cellulose or polyacrylate derivatives adjuvant (adjuvents) and / or carriers, such as carboxymethyl cellulose, such as ( carriers). Also suitable are phospholipids as well as affinity-friendly low molecular and high molecular weight compounds. The gel may be present as a hydrogel based on water or as a hydrophobic organogels based on a mixture of low molecular and polymeric paraffinic hydrocarbons and petrolatum, for example.

Anionic, cationic or neutral tensides are emulsifiers such as alkaline soaps, methyl soaps, amine soaps, sulfonated compounds, cationic soaps, high fatty alcohols, eg Lanette type sorbitan and polyoxyethylene sorbitan fatty acid esters, fleece wax, lanolin, or other synthetic products for oil / water and water / oil emulsion production.

Hydrophilic organogels can be embodied, for example, on the basis of polymeric polyethylene glycols. This gel-like form is washable. Petrolatum, natural or synthetic waxes, fatty acids, fatty alcohols, for example fatty acid esters such as single-, double-, or triglycerides, paraffin oils or vegetable oils, hardened castor oils or coconut oils, pork fats, for example Softisan ^® and Synthetic fats based on acrylic, caprinic, lauric and stearic acids, or triglyceride mixtures such as Miglyol ^® can be used to produce ointments, creams or emulsions. And / or as lipids in the form of waxy components.

Osmotically effective acids and bases such as, for example, hydrochloric acid, citric acid, sodium hydroxide solution, calcium hydroxide solution, monosodium carbonate, for example citrate, Buffer systems such as phosphate, Tris-buffer or triethanolamine are used to adjust the pH value.

Preservatives such as methyl- or propyl benzoate (parabenes or sorbic acid) may be added to increase stability.

Pastes, powders or solutions are referred to as locally applicable form. The paste contains mainly lipophilic and hydrophilic auxiliary agents, which consist of very large amounts of fatty substances, such as a consistency-giving base.

Powders or locally applicable powders may include starch varieties, for example wheat or rice starch, silicon dioxide or silica dioxide in which the flame is dispersed, and the starch varieties are agglomerates. It also acts as a diluent to increase the smoothness and flowability.

Nasal drops or nasal sprays serve as a nasal application form. In this regard, nebulizers or nose creams or ointments may be used.

In addition, controlled dosage aerosols as well as nasal sprays or dry powder formulations are suitable for systematic administration of the active ingredient.

Such pressure and / or controlled dose aerosol and powder formulations may be inhaled or insufflated. This type of dosage form is certainly important for direct and local application to the lungs or bronchus and larynx. Thus, the powder component may be formulated, for example, as an active ingredient-soft pellets, ie an active ingredient-pellet mixture with a suitable carrier, for example an active ingredient pellet mixture such as lactose and / or glucose. have. For inhalation or inflation, ordinary applicators suitable for the treatment of the nose, mouth and / or pharynx are suitable. The active ingredient is also applicable by an ultrasonic nebulizer. As aerosol spray formulations and / or controlled dosage aerosols as propellant gases, tetrafluoroethane or HFC 134a and / or heptafluoropropane or HFC 227 are suitable and are in gaseous form at normal pressure and room temperature. For example, non-fluorinated hydrocarbons such as propane, butane or dimethyl ether or other propellants may be selected. Instead of a controlled dose aerosol, a manual pump system without propellant may be used.

Propellant aerosols also have surfaces such as, for example, isopropyl myristate, polyoxyenthylene sorbitan fatty acid esters, sorbitan trioleate, lecithins or soya lecithin. It may contain an active adjuvant appropriately.

For local application in situ, a solution for infiltration, for example a solution for transurethral administration of bladder tumors or genital tumors or for profusion of liver or other organ carcinoma Solution is suitable.

Each suitable medical form may be generated according to procedures and prescriptions based on pharmaceutical-physical principles as described, for example, in the following handbook, and the present invention relates to the production of each suitable medicaments. Included in the gist of:

Physical Pharmacy (A.N. Martin, J. Swarbrick, A. Cammarata), 2nd Ed., Philadelphia Pennsylvania, (1970), German version: Physikalische Pharmazie, (1987), 3rd edition, Stuttgart;

R. Voigt, M. Bornschein, Lehrbuch der pharmazeutischen Technologie, Verlag Chemie, Weinheim, (1984), 5th edition;

P.H. List, Arzneimformenlehre, Wissenschaft mbH, Stuttgart, (1985), 4th edition;

H. Sucker, P. Fuchs, P. Speiser, Pharmazeutische Technologie, Georg Thieme Verlag, Stuttgart-New York, (1991), 2nd edition;

A.T. Florence, D. Attwood, Physicochemical Principles of Pharmacy, The Maximillan Press Ltd., Hong Kong, (1981);

L.A. Trissel, Handbook on Injectable Drugs, American Society of Hospital Pharmacists, (1994), 8th edition;

Y. W Chien, Transdermal Controlled Systemic Medications, Marcel Dekker Inc., New York-Basel, (1987);

K.E. Avis, L. Lachmann, H.A. Liebermann, Pharmaceutical Dosage Forms: Parenteral Medications, volume 2, Marcel Dekker Inc., New York-Basel, (1986);

B.W. Muller, Controlled Drug Delivery, Paperback APV, volume 17, Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart, (1987);

H. Asch, D. Essig, P.C. Schmidt, Technologie von Salben, Suspensionen und Emulsionen, Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart, (1984);

H.A. Liebermann, L. Lachman, J.B. Schwartz, Pharmaceutical Desage forms: Tablets, Volume 1, Marcel Dekker Inc., New York, 2nd Edition (1989);

D. Chulin, M. Deleuil, Y. Pourcelot, Powder Technology and Pharmaceutical Processes, in J.C. Williams, T. Allen, Handbook of Powder Technology, Elsevier Amsterdam-London-New York-Tokyo, (1994);

J.T. Carstensen, Pharmaceutical Principles of Solid Dosage Forms, Technomic Publishing Co., Inc., Lancaster-Basel, (1993).

Production Example

1. Injection Therapy

a) Parental Solution

5.000 g of active ingredient used according to the invention

Acid sodium phosphate 5.000 g

Sodium Tartarate 12.000 g

7.500 g of benzyl alcohol

Up to 1000.000 ml of water for injection

The solution is produced, sterilized according to the usual method and filled in 10 ml vials. One vial contains 50 mg of the compound according to the invention.

b) Penteral solution

1.000 g of active ingredient used according to the invention

Hydrochloric acid, dilute 5.000 g

Sodium chloride 6.000 g

7.500 g of benzyl alcohol

Up to 1000.000 ml of water for injection

The solution is produced by stirring according to the usual method, the drug form is adjusted to the appropriate pH value by acid addition, then filled into 100 ml vials and sterilized. The vial contains 100 mg of the compound according to the invention.

c) Parental Dispersion

10.000 g of active ingredient used according to the invention

20.000 g of soya lecithin

100.000 g of saturated triglycerides

7.650 g sodium hydroxide

Up to 1000.000 ml of water for injection

The active ingredient used according to the invention is dispersed in saturated triglycerides. Then, upon stirring, soya lecithin is added, followed by the addition of aqueous sodium hydroxide solution with subsequent homogenization. The dispersed components are sterilized and filled in 10 ml vials. The vial contains 50 mg of the compound according to the invention.

d) Biodegradable Parenteral Depot Medicinal Form

10.000 g of active ingredient used according to the invention

Polylactic acid /

70.000 g of polygycolic acid polymer

0.200 g of polyvinylpyrrolidine

2.000 g of gelatin

2.000 g of soya lecithin

Up to 1000.000 ml of sodium chloride

First, the active ingredient is mixed into a biodegradable polymer comprising polylactic acid and polyglycolic acid by suitable methods (spray drying, solvent-evaporation or phase separation) and then enters the sterilization process. The particles enter a pre-made two-syringe syringe filled with the auxiliary solution produced in a sterile manner. Biodegradable microparticles are mixed with a dispersant just prior to application and dispersion. The resulting syringe contains 200 mg of the active compound according to the invention.

e) Parental Dispersion for Subcutaneous Installation

25,000 g of active ingredient used according to the invention

25,000 g of soya lecithin

Peanut oil 400,000 g

50,000 g benzyl alcohol

Miglyole ^{® up to} 1000,000 g

The active ingredient is dispersed together with soya lecithin and peanut oil. Benzyl alcohol is dissolved in Miglyole ^® and added to the dispersant. The whole dispersant is sterilized and then filled into vials with a 2 ml content. The vial contains 50 mg of active ingredient.

f) parenteral spray solution

The solution named in example b) can also be used, for example, for sparging the liver.

If desired, instead of ampules of injectable solutions, so-called perforation bottles (vials) which can be optionally preserved and infusion solutions with the amount of one or more active ingredients according to the invention are added to the above indicators. In combination with a suitable additional agent, the most suitable pH value for the physiological pH value and / or isotonicity and / or euhydria and optional additional required nutrients, namely vitamins, amino acids, stabilizers and The addition of buffer substances for the adjustment of other necessary auxiliaries can be made available in the usual way.

2. Solid, Peroral Administration Medicaments

a) Tablets

10,000 g of active ingredient used according to the invention

5,200 g lactose

Starch, 1,800 g

Hydroxypropylmethylcellulose

(hydroxypropylmethylcellulose) 900 g

100 g of magnesium stearate

The components are mixed with each other and compressed in a conventional manner, at which time a tablet weight of 180 mg is set. Each tablet contains 100 mg of active ingredient. If necessary, the tablet obtained in this manner is coated to provide a film coating and / or enterically coated.

b) coated tablet cores

10,000 g of active ingredient used according to the invention

500 g of flame-dispersed silicon dioxide

2,250 g of grain starch

Stearic acid 350 g

Ethanol 3.01

900 g of gelatin

Purified water 10.01

300 g of talcum

180 g of magnesium stearate

In this component granules are produced which are preferably compressed into a coated tablet core. Each core contains 50 mg of active ingredient. The core may be further processed in a conventional manner on the coated tablet. If desired, gastric fluid resistant or retarding film coats may be applied in a known manner.

c) drink suspension of vials

0.050 g of active ingredient used according to the invention

Glycerin 0.500 g

Sorbite, 0.500 g of 70% solution

0.010 g of sodium saccharinate

0.040 g of methyl-p-hydroxybenzoate

Fragrance q.s.

Sterile Wasser q.s. Up to 5 ml

The above-mentioned ingredients are mixed in suspension in the usual way and filled into a suitable beverage bottle having a content of 5 ml.

d) Poorly Soluble Sublingual Tablets

0.030 g of active ingredient used according to the invention

0.100 g of lactose

0.004 g of stearic acid

Talcum purum 0.015 g

Sweetener q.s.

Fragrance q.s.

Rice starch q.s. Up to 0.500 g

The active ingredient is compressed into a tablet under the tongue, preferably oblong, with an adjuvant at high pressure.

e) soft gel capsules

0.050 g of active ingredient used according to the invention

Fatty acid glyceride mixtures (Miglyole ^® ) qs up to 0.500 g

The active ingredient is filled into a resilient, soft gelatin capsule that is glued together with a fluid carrier mixture and mixed with additional auxiliaries suitable for encapsulation.

f) hard gelatin capsules

0.150 g of active ingredient used according to the invention

0.100 g of microcrystalline cellulose

Hydroxypropylmethylcellulose

(hydroxypropylmethylcellulose) 0.030 g

0.100 g of mannite

0.050 g of ethyl cellulose

0.010 g of triethyl citrate

The active ingredient is mixed with adjuvant, microcrystalline cellulose, hydroxypropylmethylcellulose and manite, moistened into granules and formed into pellets. They are then coated with ethylcellulose and triethyl citrate solutions in an organic solvent of a fluidized-bed device. Hard gelatin capsules contain 150 mg of active ingredient.

3. locally administrable pharmaceutical forms

a) hydrophilic ointment

0.500 g of active ingredient used according to the invention

Eucerinum ^® anhydricum 60.000 g

15.000 g of microcrystalline wax

Petrolatum oil q.s. Up to 100.000 g

The adjuvant mentioned above is dissolved and further treated as an ointment with the active ingredient in the usual manner.

b) lipophilic ointment

10.000 g of active ingredient used according to the invention

50.000 g of propylene glycol

Paraffin, 100.000 g of liquid

100.000 g of paraffin wax

Up to 1000.000 ml of petroleum jelly

The active ingredient used according to the invention is dissolved in propylene glycol at about 60 ° C. At the same time, the lipophilic component is dissolved at 60-70 ° C. and then combined with the active ingredient solution. The ointment is first oiled at 60-70 ° C. and then cooled to 35-40 ° C. under constant emulsification and filled into 10 g tubes. One tube contains 100 mg of the compound according to the invention.

4. Inhalation Therapeutic

A further subject is a pharmaceutical formulation characterized by containing the active ingredient used according to the invention as a base or physiologically acceptable salt and as a carrier and / or diluent accompanying it.

With regard to the production of medicaments, in particular the physiologically acceptable suitable salts of the active ingredient are, for example, hydrochloride, hydrobromide, sulfate, phosphate, maleate, tartarate, citrate, Benzoate, 4-methoxybenzoate, 2- or 4-hydroxybenzoate, 4-chlorobenzoate, p-tosylate, methaneosulfonate, ascorbate, salicylate, Derived from inorganic or organic acids such as acetate, formate, succinate, lactate, glutarate, gluconate or tricarballyate Acid addition salt.

Administration of the active ingredient used in the present invention by inhalation occurs in accordance with the invention in a customary and customary manner for this type of administration, for example in combination with a spacer or with the form of a conventional controlled dose aerosol. In controlled dose aerosols, a metering valve is supplied and the dose of the composition is administered accordingly. For spraying, the present compositions may be formulated, for example, as an aqueous solution or suspension and administered by an atomizer. Aerosols in which the active ingredient is suspended as a carrier and / or diluent with one or two stabilizers of the propellant or suspended with, for example, tetrafluoroethane or HFC 134a and / or heptafluoropropane or HFC 227. Spray formulations may be used equally, but non-fluorinated hydrocarbons or other propellants may be selected, such as propane, butane, or dimethyl ether in gaseous form at normal pressure and room temperature. Thus, a propellant-free manual pump system or powder system as described below can also be used.

Suitably the propellant aerosol may also contain surface active aids such as, for example, isopropyl, myristate, polyoxyethylene sorbitan fatty acid esters, sorbitan trioeate, lecithin, oleic acid.

In administration by inhalation and / or insufflation, a medicament having an amount of the compound according to the invention may also be in the form of a powder composition, for example an active ingredient-soft pellet or a suitable carrier such as, for example, lactose and / or glucose. It can be formulated into an active ingredient-powder mixture with. The powder composition may be formulated and administered in a single dose or in multiple doses.

The compounds according to the invention are preferably administered by controlled dose aerosol or in the form of a powder dosage formulation, the powder dosage formulation preferably containing glucose and / or lactose as carrier material.

Applicators for inhalation of pharmaceutical formulations containing one or more of the active ingredients used according to the invention, for example for inhalation in the nose, mouth and / or pharynx or for inhalation in the nose, mouth and / or pharynx. As such, all applicators suitable for controlled dosage aerosol and / or powder dosage formulations are generally suitable, such as devices which persist in the propellant gas phase of the spray (adjusted dosage aerosol or powder dosage formulation).

Another embodiment may consist of an aqueous solution of the active ingredient used according to the invention, said aqueous solution optionally containing additives and / or additional active ingredients applied by an ultrasonic nebulizer.

In Examples a) and b) the micronized active ingredient is predispersed in a small amount of stabilizer and then placed in a suspension vessel with a large amount of propellant gas solution. The suspension is dispersed by a suitable stirring system (eg high performance mixer or ultrasound mixer) until ultra-fine dispersion occurs. The suspension is then retained in the flux of the filling device suitable for cold propellants or pressure fillings. In addition, the suspension can be produced in a suitable cold stable solution of HFC 134a / 227.

Examples c) to d) illustrate the composition and production of a dosage powder formulation.

In example c), the active ingredient is formulated into pellets having MMAD between 0.1 and 0.3 mm diameter after micronization following addition of steam and used in a multi-dose powder applicator.

In Examples d) and e) the active ingredient is micronized and the bulk material is then mixed with lactose in a constant amount and then filled into a multi-dose powder inhaler.

In all the embodiments described above, the active ingredient or medicinal agent in the form of each suitable pharmaceutically acceptable salt and / or acid addition salt may be present in each case so long as no base is selected.

In the following, the results of the pharmaceutical tests obtained in connection with newly discovered indications based on new compounds specifically structured in a representative manner are described.

Pharma experiment part

1. Inhibition of Growth of Human Tumor Cells

The tumor growth inhibitory activity of the substances on human tumor cells in a standardized in vitro test system was determined. In the screening test, the materials provided IC ₅₀ -values in the concentration range from 0.1 nM to 10 μMdml.

Example

HepG2 cells were plated at a density of 20,000 cells / ml in 12-well plastic dishes. Incubation occurs in Richters IMEM-ZO nutrient medium with 5% fetal calf serum (FCS) in a tissue culture incubator with a gas mixture of 5% CO ₂ and 95% air at a temperature of 37 ° C. did. One day after plating, the culture medium was aspirated from the cells and replaced with fresh medium containing each concentration of test substance. For control and individual concentrations without test material, three batches were performed for each. Three days after the start of treatment, the medium was regenerated with the test compound. After 6 days of material incubation, the test was terminated and the amount of protein in the individual wells was determined by the sulfohodamin-B-method (according to P. Skehan et al .: new color-based cell destruction assay for anti-cancer drug screening) New Colorimetric Cytotoxicity Assay for Anticancer-Drug Screening.J. Natl. Cancer Inst. 82: 1107-1112, 1990). IC ₅₀ -values (defined as concentrations at which 50% cell growth was inhibited) were obtained from dose-response curves and provided as a comparative measure for the activity of the test compound.

The following results were obtained.

2. Indications

The compounds of formula (I) and salts thereof allow for therapeutic use in malignant diseases of humans and animals through good inhibition of tumor cell growth. The anti-neoplastic activity of the materials described is prophylactic, adjunct, temporary suppressive and curative of solid tumors, leukemias and lymphomas. It can be used for treatment and to reduce or prevent the formation of metastasis in humans and animals. Therapeutic use is for example possible in the following diseases: gynocological tumors of the uterus or vagina, ovarian carcinoma, testicular tumor, prostate carcinoma, skin cancer, kidney cancer, bladder tumor, esophageal cancer, gastric cancer, rectal cancer, Pancreatic cancer, thyroid cancer, adrenal tumor, leukemia and lymphoma, Hodgkin's disease, tumor disease of the CNS, soft-tissue sarcoma, bone sarcomas, benign and malignant mesotheliomas, especially intestinal cancer (intestine cancer), liver cancer, breast cancer, bronchial and lung carcinoma, melanoma, acute and chronic leukemia. Benign papillomatosis tumors are also contemplated for treatment with named substances.

Classification of new structures of compounds has activity profiles that are independent in their effectiveness against various tumor types. Thus, for example, tumors that withstand inhibitory to habitual cellular activity may respond to these substances as a whole. Also, on the basis of independent properties, combinations of new compounds and known chemotherapeutic used pharmaceuticals or other therapeutic methods are contemplated while the properties are supplemented in an appropriate manner. The integration of the compounds currently used in therapeutic compositions with their specific structures has good results, for example with one or more substances in the following classification: anti-metabolites (eg cytarabine, 5-fluorouracil, 6-mercaptopurine, methotrexart), alkylating agents (e.g. busulfan, carmustine, cisplatin, carboplatin, cyclophosphamide, dacarbazine, melphalane , Thiotepa), DNA-inserting substances and topoisomerase inhibitors (eg actinomycin D, daunorubicin, doxorubicin, mitomycin C) Mitoxantrone, etoposide, teniposide, teniposide, topotecan, irinotecan, spindle spindles (e.g. vincristine, Navelbin, taxol, Taxoter), hormonal activators (e.g. tamoxifen, flutamide, formestan, goserelin) or other cellular inhibitors composed of multiple modes of action (e.g. L-asparaginase, bleomycin, hydroxyurea). Resistant tumor cells may again be reacted with a new compound and a mechanism of resistance to common cell activity inhibitors (eg P-glycoprotein, MRP, glutathione-S-transferase, metallothionein). It can be made sensitive. For example, combinations with radiation therapy, hyperthermia or immunotherapy are also applicable.

3. Immunosuppressive Activity

Many anticancer agents have a cytotoxic effect on tumor cells as well as a cytotoxic effect on the blood cell system. This leads to a weakening of immune defense, which can be used in particular in alternation, for example, to suppress rejection after organ transplantation. Thus, the use of major compounds that selectively bind with other compounds effective for these indications is suitable for diseases such as psoriasis or autoimmune diseases. To test the therapeutic utility in this type of disease, material activity was tested on newly isolated lymphocytes as follows.

The spleen of Swiss tm mice served as a lymphocyte source. Lymphocyte populations were isolated from spleen cell suspensions on ficoll gradients and taken up in IMEM-ZO culture medium consisting of 70,000 dextran 70,000 and 2% fetal calf serum. The cells were plated at a density of about 500,000 cells / well / ml in a 12-well dish and the 1 ml double concentrated test substance solution was transferred to the pipette in wells, followed by 37 ° C. and 5% CO ₂ in a tissue culture incubator. Were incubated. After 2 days, 1 ml-aliquot consisting of 5 μl of fluorescent solution propidium iodide (8 mg / ml) and 3.3′-dihexiloxacarbosyanin iodide (40 μg / ml) Each was added in wells and incubated for 3 minutes at room temperature. Subsequently, 10,000 cells were measured for each sample on a flow-through cytometer and the percentage amount of organ cells in the population was determined. The IC ₅₀ -values used in the following table for the properties of the individual materials were calculated by dose action curves.

Independent classification of the compounds used according to the invention also allows for efficient combination with known immunosuppressive agents such as, for example, cyclosporin A, tactolimus, rapamycin, azathiopyrine and glucocorticoids.

The present invention relates to each active ingredient concentration, dosage, combination of one or more cytostatic agents, tumor suppressors, cancerostatic agents, immunosuppressants or certain specific signs or treatments or immune diseases specifically named herein It is not limited to additional agents suitable for the type of tumor.

Claims (35)

(E) -3- (3-pyridyl) -N- [2- (1-benzylpiperidin-4-yl) ethyl] -2-propenamide hydrochloride according to formula (I) Pharmaceutically acceptable acid addition with tautomers and stereoisomers and / or mixtures thereof in the case of ring systems in which heterocyclics are substituted or analyzed by compounds with free hydroxy, mercapto and / or amino groups Salts: (Wherein R ¹ is hydrogen, halogen, cyano, C ₁ -C ₆ -alkyl, trifluoromethyl, C ₃ -C ₈ -cycloalkyl, C ₁ -C ₄ -hydroxyalkyl, hydroxy, C ₁ -C ₄ -Alkoxy, benzyloxy, C ₁ -C ₄ -alkanoyloxy, C ₁ -C ₄ -alkylthio, C ₂ -C ₅ -alkoxycarbonyl, aminocarbonyl, C ₃ -C ₉ -dialkylaminocarbonyl , Carboxy, phenyl, phenoxy, pyridyloxy and NR ⁵ R ⁶ , wherein R ⁵ and R ⁶ are independently of each other selected from hydrogen and C ₁ -C ₆ -alkyl, R ² is selected from hydrogen, halogen, C ₁ -C ₆ -alkyl, trifluoromethyl and hydroxy, Wherein R ¹ and R ² are, when they are adjacent, a bridge selected from the group of the bridge members — (CH ₂ ) ₄ — and — (CH═CH) ₂ — and CH ₂ O—CR ⁷ R ⁸ —O— optionally forms a bridge, wherein R ⁷ and R ⁸ are independently of each other hydrogen or C ₁ -C ₆ -alkyl, R ³ is selected from hydrogen, halogen and C ₁ -C ₆ -alkyl, R ⁴ is selected from hydrogen, C ₁ -C ₆ -alkyl, C ₃ -C ₆ -alkenyl, hydroxy, C ₁ -C ₆ -alkoxy and benzyloxy, k is 0 or 1, A is C ₂ -C ₆ -alkenylene, optionally substituted one to three times with C ₁ -C ₃ -alkyl, hydroxy, fluorine, cyano, or phenyl; C ₄ -C ₆ -alkadienylene, optionally substituted once or twice with C ₁ -C ₃ -alkyl, fluorine, cyano, or phenyl, 1,3,5-hexatrienylene optionally substituted with C ₁ -C ₃ -alkyl, fluorine or cyano, and Selected from ethynylene, D is C ₁ -C ₃ - once or twice C ₁ -C ₁₀ optionally being substituted with alkyl or hydroxy-alkylene, C ₂ -C ₁₀ -alkenylene, optionally substituted once or twice with C ₁ -C ₃ -alkyl or hydroxy, wherein the double bond is optionally for ringing E, C ₃ -C ₁₀ -alkynylene, optionally substituted once or twice with C ₁ -C ₃ -alkyl or hydroxy, and C ₁ -C ₁₀ -alkylene, C ₂ -C ₁₀ -alkenylene and C ₃ -C _10- , wherein one to three methylene units are isomericly replaced by O, S, NR ⁹ , CO, SO or SO ₂ Is selected from the group consisting of alkynylene, wherein R ⁹ is selected from hydrogen, C ₁ -C ₃ -alkyl, C ₁ -C ₆ -acyl and methanesulfonyl, E is or Wherein the heterocyclic ring optionally has a double bond n and p are each independently 0, 1, 2 or 3 under the condition that n + p ≦ 4, q is 1 or 2, R ¹⁰ is selected from hydrogen, C ₁ -C ₃ -alkyl, hydroxy, hydroxymethyl, carboxy and C ₂ -C ₇ -alkoxy carbonyl, R ¹¹ is hydrogen or an oxo group adjacent to a nitrogen atom, G is hydrogen, Selected from G1, G2, G3, G4 and G5, wherein G1 is the residue At this time r is 0, 1 or 2, s is 0 or 1, R ¹² is hydrogen, C ₁ -C ₆ -alkyl, C ₃ -C ₆ -alkenyl, C ₃ -C ₆ -alkynyl, C ₃ -C ₈ -cycloalkyl, Benzyl, phenyl, A group consisting of monocyclic aromatic five- or six-membered heterocycles containing one to three heteroatoms selected from N, S and O and bonded directly or via a methylene group, Analyzed non- and tricyclic aromatic or partially hydrogenated carbocyclic having from 8 to 16 ring atoms and at least one aromatic ring, wherein the bond occurs via an aromatic or hydrogenated ring and occurs directly or via a methylene group A group consisting of a ring system, and Analyzes having 8 to 16 ring atoms and at least one aromatic ring, wherein one to three ring atoms are selected from N, S and O, and the bond occurs via an aromatic or hydrogenated ring and occurs directly or via a methylene group Selected from the group consisting of non- and tricyclic aromatic or partially hydrogenated heterocyclic ring systems, R ¹³ has the same meaning as R ¹² , but is selected independently of it, R ¹⁴ is hydrogen, hydroxy, methyl, benzyl, phenyl, A group consisting of monocyclic aromatic pentacyclic and hexacyclic heterocycles containing one to three heteroatoms selected from N, S and O and bonded directly or via a methylene group, Analyzed non- and tricyclic aromatic or partially hydrogenated carbocyclic having from 8 to 16 ring atoms and at least one aromatic ring, wherein the bond occurs via an aromatic or hydrogenated ring and occurs directly or via a methylene group Groups leading to the ring system, and Analyzes having 8 to 16 ring atoms and at least one aromatic ring, wherein one to three ring atoms are selected from N, S and O, and the bond occurs via an aromatic or hydrogenated ring and occurs directly or via a methylene group Selected from the group leading to non- and tricyclic aromatic or partially hydrogenated heterocyclic rings, G2 is the next residue And Wherein the substituents R ¹² and R ¹⁴ have the above meanings, or -NR ¹² R ¹⁴ silver A group consisting of saturated and unsaturated monocyclic tetracyclic to octacyclic heterocycles optionally containing one or two additional heteroatoms selected from N, S and O, except for the necessary nitrogen atoms, and Saturated and unsaturated non- or tricyclic analyzed or bridges, optionally containing one or two additional heteroatoms selected from N, S and O, with the exception of the necessary nitrogen atoms and having from 8 to 16 ring atoms A nitrogen-containing heterocycle bond selected from the group consisting of heterocycles spanning, G3 is the next residue G4 is the next residue At this time Ar ¹ and Ar ² is independently selected from phenyl, pyridyl or naphthyl, G5 is the residue At this time R ¹⁵ is selected from trifluoromethyl, C ₁ -C ₆ -alkoxy, C ₃ -C ₆ -alkenyloxy and benzyloxy, Wherein at the substituents R ¹ , R ² , R ⁴ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , Ar ¹ and Ar ² and the ring system -NR ¹² R ¹⁴ , the aromatic ring system is optionally halogen, cyano, C C ₁ -C ₆ -alkoxy, benzyloxy, phenoxy optionally substituted with _1- C ₆ -alkyl, trifluoromethyl, C ₃ -C ₈ -cycloalkyl, phenyl, benzyl, hydroxy, wholly or partially fluorine , Mercapto, C ₁ -C ₆ -alkylthio, carboxy, C ₁ -C ₆ -alkoxycarbonyl, benzyloxycarbonyl, nitro, amino, mono-C ₁ -C ₆ -alkylamino, and di- (C Independently carry one to three substituents independently selected from _1- C ₆ -alkyl) -amino, and two adjacent groups of an aromatic ring or ring system are optionally via an methylenedioxy bridge to further ring To form). The method of claim 1, R ¹ is hydrogen, halogen, cyano, methyl, trifluoromethyl, hydroxy, C ₁ -C ₄ -alkoxy, ethylthio, methoxycarbonyl, tert-butoxycarbonyl, aminocarbonyl, carboxy and phenoxy Is chosen from the city, R ² is selected from hydrogen, halogen, trifluoromethyl and hydroxy, R ³ is hydrogen or halogen, R ⁴ is selected from hydrogen, C ₁ -C ₃ -alkyl, hydroxy and C ₁ -C ₃ -alkoxy, k is 0 or 1, A is C ₂ -C ₆ -alkenylene, optionally substituted once or twice with C ₁ -C ₃ -alkyl, hydroxy or fluorine, C ₄ -C ₆ -alkadienylene optionally substituted with C ₁ -C ₃ -alkyl or 1 or 2 fluorine atoms, and Selected from 1,3,5-hexatrienylene optionally substituted with fluorine, D is C ₁ -C ₈ -alkylene optionally substituted once or twice with methyl or hydroxy, C ₂ -C ₈ -alkenylene, which is optionally substituted once or twice with methyl or hydroxy, wherein the double bond is optionally for ringing E, C ₃ -C ₈ -alkynylene, optionally substituted once or twice with methyl or hydroxy, and By one to three methylene units are stereoisomeric qualitative O, S, NH, N ( CH 3), N (COCH 3), N (SO 2 CH 3), CO, C 1 to be replaced by SO or SO ₂ -C ₈ -alkylene, C ₂ -C ₈ -alkenylene, and C ₃ -C ₈ -alkynylene, E is or Wherein the heterocyclic ring optionally has a double bond n and p is 0, 1, 2 or 3, independently of each other, under the condition that n + p ≦ 3, q is 1 or 2, R ¹⁰ is selected from hydrogen, C ₁ -C ₃ -alkyl, hydroxy, and hydroxymethyl, R ¹¹ is hydrogen or an oxo group adjacent to a nitrogen atom, G is hydrogen, Selected from G1, G2, G3, G4 and G5, wherein G1 is the residue At this time r is 0, 1 or 2, s is 0 or 1, R ¹² is hydrogen, C ₁ -C ₆ -alkyl, C ₃ -C ₈ -cycloalkyl, benzyl or phenyl, Benzocyclobutyl, indanyl, indenyl, oxoindanyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, oxotetrahydronaphthyl, biphenylenyl, bonded directly or via a methylene group , Fluorenyl, oxofluorenyl, anthryl, dihydroanthryl, oxodihydroanthryl, dioxodihydroanthryl, phenanthryl, dihydrophenanthryl, oxodihydrophenanthryl , Dibenzocycloheptenyl, oxodibenzocycloheptenyl, dihydrodibenzocycloheptenyl, oxodihydrodibenzocycloheptenyl, dihydrodibenzocyclooctenyl, tetrahydrodibenzocyclooctenyl and oxotetrahydro A group consisting of dibenzocyclooctenyl, and Furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imida, bonded directly or via a methylene group Zolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazineyl, imidazothiazolyl, benzofuryl, dihydrobenzofuryl, benzothienyl, dihydrobenzo Thienyl, indolyl, indolinyl, oxoindolinyl, dioxoindolinyl, benzoxazolyl, oxobenzoxazolinyl, benzisoxazolyl, oxobenzisoxazolyl, benzothiazolyl, oxthiazolyl, oxobenz Thiazolinyl, benzoisothiazolyl, oxobenzoisothiazolinyl, benzimidazolyl, oxobenzimidazolinyl, indazolyl, oxoindazolinyl, benzofurazanyl, benzothiadiazolyl, benzotria Zolyl, oxazolopyridyl, oxodihydrooxazolopyridyl , Thiazolopyridyl, oxodihydrothiazolopyridyl, isothiazolopyridyl, imidazopyridyl, oxodihydroimidazopyridyl, pyrazolopyridyl, oxodihydropyrazolopyridyl, thienopyrimi Thienopyrimidinyl, Chromanyl, Chromanonyl, Benzopyranyl, Chromonyl, Quinolyl, Isoquinolyl, Dihydroquinolyl, Oxodihydroquinolinyl, Tetrahydroquinolyl, Oxotetrahydro Quinolinyl, benzodioxyl, quinoxalinyl, quinazolinyl, naphthyridinyl, carbazolyl, tetrahydrocarbazolyl, oxotetrahydrocarbazolyl, pyridoindoleyl, acridinyl, oxo Dihydroacridinyl, phenothiazineyl, dihydrodibenzoxepinyl, oxodihydrodibenzoxepinyl, benzocycloheptathienyl, oxobenzocycloheptathienyl, dihydrothienobenzothiefinyl (dihydrothienobenx othiepinyl), oxodihydrothienobenzothiepinyl, dihydrodibenzothiepinyl, oxodihydrodibenzothiepinyl, octahydrodibenzothiepinyl, dihydrodibenzazepinyl, oxodihydrodibenzazepinyl, Octahydrodibenzazepinyl, benzocycloheptapyridyl, oxobenzocycloheptapyridyl, dihydropyridobenzodiazepinyl, dihydrodibenzoxazepinyl, dihydropyridobenzoxepinyl, dihydropyridobenzoxepinyl, dihydropyridobenzoxepinyl Dobenoxazinpinyl, oxodihydropyridobenzoxazinyl, dihydrodibenzothiazepinyl, oxodihydrodibenzothiazepinyl, dihydropyridobenzothiazepinyl, and oxodihydropyridobenzothiazepinyl Selected from the group consisting of R ¹³ has the same meaning as R ¹² , but is selected independently of it, R ¹⁴ is hydrogen, hydroxy, methyl, benzyl, phenyl, and Indanyl, indenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazine, bonded directly or via a methylene group Zolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazinyl, benzofuryl, benzothienyl, indolyl, indolinyl, benzoxazolyl , Benzothiazolyl, benzimidazolyl, chromanyl, quinolyl and tetrahydroquinolyl, G2 is the next residue And Wherein the substituents R ¹² and R ¹⁴ have the above meanings, or -NR ¹² R ¹⁴ Azetidine, pyrrolidine, piperidine, (1H) tetrahydropyridine, hexahydroazepine, (1H) tetrahydroazepine, octahydroazocine, pyra bound across nitrogen atoms Zolidine, piperazine, hexahydrodiazepine, morpholine, hexahydrooxazepine, thiomorpholine, thiomorpholine-1,1-dioxide, 5-aza-bi-cyclo [2.1.1] hexane, 2- Aza-bicyclo [2.2.1] heptane, 7-aza-bicyclo [2.2.1] heptane, 2,5-diaza-bicyclo [2.2.1] heptane, 2-aza-bicyclo [2.2.2 ] Octane, 8-aza-bicyclo [3.2.1] octane, 2,5-diazabicyclo [2.2.2] octane, 9-azabicyclo [3.3.1] nonane, indolin, isoindolin, (1H ) -Dihydroquinoline, (1H) -tetrahydroquinoline, (2H) -tetrahydroisoquinoline, (1H) -tetrahydroquinoxaline, (4H) -dihydrobenzoxazine, (4H) -dihydro Benzothiazine, (1H) -tetrahydrobenzo [b] azepine, (1H) -tetrahydrate Benzo [c] azepine, (1H) -tetrahydrobenzo [d] azepine, (5H) -tetrahydrobenzo [b] oxazepine, (5H) -tetrahydrobenzo [b] thiazepine, 1,2, 3,4-tetrahydro-9H-pyrido [3,4-b] indole, (10H) -dihydroacridine, 1,2,3,4-tetrahydroacridanone, (10H)- Phenoxazine, (10H) -phenothiazine, (5H) -dibenzazepine, (5H) -dihydrodibenzazepine, (5H) -octahydrodibenzazepine, (5H) -dihydrodibenzodiazepines, (11H ) -Dihydrodibenzo [b, e] oxazepine, (11H) -dihydrodibenzo [b, e] thiazepine, (10H) -dihydrodibenzo [b, f] oxazepine, (10H)- A nitrogen-containing heterocycle selected from the group consisting of dihydrodibenzo [b, f] thiazepine and (5H) -tetrahydrodibenzazocin, G3 is the next residue G4 is the next residue At this time Ar ¹ and Ar ² is independently selected from phenyl, pyridyl and naphthyl, G5 is the residue At this time R ¹⁵ is selected from trifluoromethyl, C ₁ -C ₆ -alkoxy, C ₃ -C ₆ -alkenyloxy and benzyloxy, wherein the aromatic ring system is optionally halogen, cyano, C ₁ -C ₆ -Alkyl, trifluoromethyl, C ₃ -C ₈ -cycloalkyl, phenyl, benzyl, hydroxy, C ₁ -C ₆ -alkoxy, C ₁ -C ₆ -alkoxy, benzyloxy, wholly or partially substituted by fluorine , Phenoxy, mercapto, C ₁ -C ₆ -alkylthio, carboxy, C ₁ -C ₆ -alkoxycarbonyl, benzyloxycarbonyl, nitro, amino, mono-C ₁ -C ₆ -alkylamino, and di - (C ₁ -C ₆ - alkyl) - being independently selected from each other from the group consisting of substituted amino with one to three substituents selected independently, Wherein the two adjacent groups of the ring or ring system optionally form an additional ring with a methylene deoxy bridge. The method according to claim 1 or 2, R ¹ is selected from hydrogen, halogen, cyano, methyl, trifluoromethyl, hydroxy, methoxy and methoxycarbonyl, R ² is hydrogen or halogen, R ³ is hydrogen, R ⁴ is selected from hydrogen, C ₁ -C ₃ -alkyl and hydroxy, k is 0 or 1, A is C ₂ -C ₆ -alkylene optionally substituted once or twice with hydroxy or fluorine, C ₄ -C ₆ -alkadienylene, optionally substituted with one or two fluorine atoms, and 1,3,5-hexatrienylene, D is C ₂ -C ₈ -alkylene optionally substituted with methyl or hydroxy, C ₂ -C ₈ -alkenylene, optionally substituted with methyl or hydroxy, wherein the double bond is optionally for ringing E, and C ₂ -C ₈ -alkylene, wherein one to three methylene units can be stereoisomerically replaced with O, NH, N (CH ₃ ), N (COCH ₃ ), N (SO ₂ CH ₃ ) or CO and Selected from the group consisting of C ₂ -C ₈ -alkenylene, E is the residue or Wherein the heterocyclic ring optionally has a double bond n and p are each independently 0, 1, 2 or 3, provided that n + p ≦ 3, q is 1 or 2, R ¹⁰ is selected from hydrogen, methyl and hydroxy, R ¹¹ is hydrogen or an oxo group adjacent to a nitrogen atom, G is hydrogen, C ₃ -C ₈ -cycloalkyl, methoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, trifluoroacetyl, diphenylphosphinoyl and the following residues And And And Selected from r is 1 or 2, s is 0 or 1, R ¹² is hydrogen, methyl, benzyl, phenyl, Indanyl, indenyl, oxoindanyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, oxotetrahydronaphthyl, fluorenyl, oxofluorenyl, anthryl, di A group consisting of hydroanthryl, oxodihydroanthryl, dioxodihydroanthryl, dibenzocycloheptenyl, oxodibenzocycloheptenyl, dihydrodibenzocycloheptenyl, oxodihydrodibenzocycloheptenyl, and Furyl, thienyl, pyrroyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, thiadiazoleyl, triazolyl, pyridyl, bonded directly or via a methylene group , Pyrazinyl, pyridazinyl, pyrimidinyl, imidazothiazolyl, benzofuryl, dihydrobenzofuryl, benzothienyl, dihydrobenzothienyl, indolyl, indolinyl, oxoindolinyl, dioxoindolin 1, benzoxazolyl, oxobenzoxazolinyl, benzisoxazolyl, oxobenzisoxazolyl, benzothiazolyl, oxobenzthiazolinyl, benzoisothiazolyl, oxobenzoisothiazolinyl, benzimidazolyl, Oxobenzimidazolinyl, benzofurazyl, benzothiadiazolyl, benzotriazolyl, oxazolopyridyl, oxodihydrooxazolopyridyl, thiazolopyridyl, oxodihydrothiazolopyridyl, isothiazolopyrid Dill, imidazopyridyl, oxodihydride Leumidazopyridyl, pyrazolopyridyl, thienopyrimidinyl, chromanyl, chromonyl, benzopyranyl, chromonyl, quinolyl, isoquinolyl, dihydroquinolyl, oxodihydroquinolinyl, tetrahydro Quinolyl, oxotetrahydroquinolinyl, benzodioxanyl, quinoxalinyl, quinazolinyl, naphthyridinyl, carbazolyl, tetrahydrocarbazolyl, oxotetrahydrocarbazolyl, pyridoindoleyl, acry Dinyl, oxodihydroacridinyl, phenothiazineyl, dihydrodibenzoxepinyl, benzocycloheptathienyl, oxobenzocycloheptathienyl, dihydrothienobenzothiepinyl, oxodihydrothienobenzothipinyl, di Hydrodibenzothiepinyl, oxodihydrodibenzothiepinyl, dihydrodibenzazepinyl, oxodihydrodibenzazepinyl, octahydrodibenzazepinyl, benzocycloheptapyridyl, oxobenzocycloheptapyridyl, dihydro Lido is selected from Ben jokse sulfinyl, dihydro dibenzothiazyl the sulfinyl and oxo-dihydro-di-benzothiazepine day group consisting of, R ¹³ is selected from hydrogen, methyl, benzyl and phenyl R ¹⁴ is hydrogen, hydroxy, methyl, benzyl, phenyl, and Naphthyl, furyl, thienyl, oxazolyl, thiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, thidiazolyl, pyridyl, benzofuryl, benzothienyl, indolyl, bonded directly or via a methylene group, Indolinyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, chromanyl, quinolyl and tetrahydroquinolyl, wherein in -NR ¹² R ¹⁴ is optionally pyrrolidine, piperidine, (1H) -tetrahydropyridine, hexahydroazepine, octahydroazocin, piperazine, hexyhydrodiazepine, morpholine, hexahydrooxazepine, 2-azabicyclo [2.2.1] heptane, 7-azabicyclo [2.2.1] heptane, 2,5-diazabicyclo [2.2.1] heptane, 8-azabicyclo [3.2.1] octane, 2,5 Diazabicyclo [2.2.2] octane, indolin, isoindolin, (1H) -dihydroquinoline, (1H) -tetrahydroquinoline, (2H) -tetrahydroisoquinoline, (1H) -tetrahydroquinoxol Saline, (4H) -dihydrobenzoxazine, (4H) -dihydrobenzothiazine, (1H) -tetrahydrobenzo [b] azepine, (1H) -tetrahydrobenzo [d] azepine, (5H ) -Tetrahydrobenzo [b] oxazepine, (5H) -tetrahydrobenzo [b] thiazepine, 1,2,3,4-tetrahydro-9H-pyrido [3,4-b] indole, (10H ) -Dihydroacridine, 1,2,3,4-tetrahydroacridanone, (5H) -dihydrodibenzazepine, (5H) -di Drodibenzodiazepines, (11H) -dihydrodibenzo [b, e] oxazepine, (11H) -dihydrodibenzo [b, e] thiazepine, (10H) -dihydrodibenzo [b, f] oxa A compound selected from zepin and (5H) -tetrahydrodibenzazocin. The method according to claim 1 or 2, R ¹ is selected from hydrogen, fluorine, chlorine, bromine, methyl, trifluoromethyl and hydroxy, R ² and R ³ is hydrogen, R ⁴ is hydrogen or hydroxy, k is 0 or 1, A is C ₂ -C ₄ -alkylene optionally substituted with fluorine, D is C ₂ -C ₆ - alkylene group, the double bond optionally is for making the E by the ring C ₂ -C ₆ - is alkenylene, and methylene units in stereoisomeric qualitative O, NH, N (CH ₃₎ Or CO can be replaced, or ethylene groups can be stereoisomerically replaced with NH-CO or CO-NH, or propylene groups can be stereoisomerically replaced with NH-CO-O or O-CO-NH. with C ₂ -C ₆ - it is selected from the group consisting of alkenylene, - C ₂ -C ₆ alkylene and E is selected from pyrrolidine, piperidine, 1,2,5,6-tetrahydropyridine, hexahydroazepine, morpholine and hexahydro-1,4-oxazepine, wherein a heterocyclic ring Is optionally substituted with an oxo group adjacent to a nitrogen atom, G is hydrogen, tert-butoxycarbonyl, diphenylphosphinoyl and the following residues And And And Is selected from one of the following r is 0 or 1, s is 0 or 1, R ¹² is hydrogen, methyl, benzyl, phenyl, Indenyl, oxoindanyl, naphthyl, tetrahydronaphthyl, fluorenyl, oxofluorenyl, anthryl, dihydroanthryl, oxodihydroanthryl, dioxodihydro, bonded directly or via a methylene group A group consisting of anthryl, dibenzocycloheptenyl and dihydrodibenzocycloheptenyl, and Furyl, thienyl, oxazolyl, thiazolyl, imidazolyl, oxdiazolyl, thiadiazoleyl, pyridyl, pyrazinyl, pyrimidinyl, imidazothiazolyl, benzofuryl, benzo, bonded directly or via a methylene group Thienyl, indolyl, oxoindolinyl, dioxoindolinyl, benzoxazolyl, oxobenzoxazolinyl, benzothiazolyl, oxobenzthiazolinyl, benzimidazolyl, oxobenzimidazolinyl, benzo Furazanyl, benzotriazolyl, oxazolopyridyl, oxodihydrooxazolopyridyl, thiazolopyridyl, oxodihydrothiazolopyridyl, chromanyl, chromanyl, benzopyranyl, chromoyl, quinolyl, iso Quinolyl, oxodihydroquinolinyl, tetrahydroquinolyl, oxotetrahydroquinolinyl, benzodioxanyl, quinazolinyl, acridinyl, oxodihydroacridinyl, phenothiazineyl, dihydrodibenzoxepinyl, Benzocycloheptathienyl, dihydro Thienobenzothiepinyl, dihydrodibenzothiepinyl, oxodihydrodibenzothiepinyl, dihydrodibenzazepinyl, oxodihydrodibenzazepinyl, octahydrodibenzazepinyl, benzocycloheptapyridyl, oxobenzocyclohepta Selected from the group consisting of pyridyl and dihydrodibenzothiazepinyl, R ¹³ is selected from hydrogen, methyl, benzyl and phenyl, R ¹⁴ is hydrogen, hydroxy, methyl, benzyl, phenyl, and Naphthyl, furyl, thienyl, pyridyl, benzofuryl, benzothienyl, indolyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, chromanyl, quinolyl and tetrahydro, bonded directly or via a methylene group Selected from the group consisting of quinolyl, wherein in -NR ¹² R ¹⁴ is optionally pyrrolidine, piperidine, hexahydroazepine, morpholine, 2,5-diazabicyclo [2.2.1] heptane, indolin, isoindolin, (1H) -di Hydroquinoline, (1H) -tetrahydroquinoline, (2H) -tetrahydroisoquinoline, (1H) -tetrahydrobenzo [b] azepine, (1H) -tetrahydrobenzo [d] azepine, (5H)- Tetrahydrobenzo [b] oxazepine, (5H) -tetrahydrobenzo [b] thiazepine, 1,2,3,4-tetrahydroacridanone, (5H) -dihydrodibenzazepine, (11H)- Dihydrodibenzo [b, e] oxazepine and (11H) -dihydrodibenzo [b, e] thiazepine, At this time, the aromatic ring systems are optionally independently of each other halogen, cyano, C ₁ -C ₆ -alkyl, trifluoromethyl, C ₃ -C ₈ -cycloalkyl, phenyl, benzyl, hydroxy, C ₁ -C ₆ -alkoxy, C ₁ -C ₆ -alkoxy, benzyloxy, phenoxy, mercapto, C ₁ -C ₆ -alkylthio, carboxy, C ₁ -C ₆ -alkoxycarbonyl, wholly or partially substituted by fluorine, Substituted with one to three substituents independently selected from the group consisting of benzyloxycarbonyl, nitro, amino, mono-C ₁ -C ₆ -alkylamino and di- (C ₁ -C ₆ -alkyl) -amino, Two adjacent groups on an aromatic ring or ring system, optionally via an methylenedioxy bridge, to form an additional ring. The method according to claim 1 or 2, R ¹ is selected from hydrogen, fluorine, methyl, trifluoromethyl and hydroxy, R ² and R ³ is hydrogen, R ⁴ is hydrogen or hydroxy, k is 0, A is ethenylene (vinylene) or 1,3-butadieneylene, D is C ₂ -C ₆ -alkylene or C ₂ -C ₆ -alkenylene, wherein the double bond may also be for ringing E E is selected from pyrrolidine, piperidine, hexahydroazepine or morpholine, G is benzyl, phenethyl, fluorenylmethyl, anthrylmethyl, diphenylmethyl, fluorenyl, dihydrodibenzocycloheptenyl, furylmethyl, thienylmethyl, thiazolylmethyl, pyridylmethyl, benzothienyl Methyl, quinolylmethyl, phenyl-thienylmethyl, phenyl-pyridylmethyl, dihydrodibenzoxepinyl, dihydrodibenzothiepinyl, Acetyl, pivaloyl, phenylacetyl, diphenylacetyl, diphenylpropionyl, naphthylacetyl, benzoyl, naphthoyl, anthrylcarbonyl, oxofluorenylcarbonyl, oxodihydroantryl Carbonyl, dioxodihydroantrylcarbonyl, Furoyl, pyridylcarbonyl, chromoylcarbonyl, quinolylcarbonyl, Naphthylaminocarbonyl, dibenzylaminocarbonyl, benzylphenylaminocarbonyl, diphenylaminocarbonyl, indolinyl-1-carbonyl, dihydrodibenzazepine-N-carbonyl, tetrahydroquinolinyl-N -Carbonyl, tetrahydrobenzo [b] azinyl-N-carbonyl, Methanesulfonyl, phenylsulfonyl, p-toluenesulfonyl, naphthylsulfonyl, quinolinesulfonyl and Diphenylphosphinoyl, Wherein the aromatic ring system is optionally halogen, cyano, C ₁ -C ₆ -alkyl, trifluoromethyl, C ₃ -C ₈ -cycloalkyl, phenyl, benzyl, hydroxy, C ₁ -C ₆ -alkoxy, C ₁ -C ₆ -alkoxy, benzyloxy, phenoxy, mercapto, C ₁ -C ₆ -alkylthio, carboxy, C ₁ -C ₆ -alkoxycarbonyl, benzyloxycarbonyl, wholly or partially substituted by fluorine Are independently substituted with one to three substituents independently selected from the group consisting of nitro, amino, mono-C ₁ -C ₆ -alkylamino and di- (C ₁ -C ₆ -alkyl) -amino, and When two adjacent groups of said ring or ring system optionally form an additional ring via a methylenedioxy bridge. The method according to claim 1 or 2, N- [4- (1-methylsulfonylpiperidin-4-yl) -butyl] -3- (pyridin-3-yl) -acrylamide, N- {4- [1- (2-naphthylsulfonyl) -piperidin-4-yl] -butyl} -3- (pyridin-3-yl) -acrylamide, N- {4- [1- (2-naphthylsulfonyl) -piperidin-4-yl] -butyl} -5- (pyridin-3-yl) -2,4-pentadienoic acid amide , N- {4- [1- (1-naphthylaminocarbonyl) -piperidin-4-yl] -butyl} -3- (pyridin-3-yl) -acrylamide, N- [4- (1-diphenylaminocarbonyl-piperidin-4-yl) -butyl] -3- (pyridin-3-yl) -acrylamide, N- [4- (1-diphenylaminocarbonyl-piperidin-4-yl) -butyl] -5- (pyridin-3-yl) -2,4-pentadienoic acid amide, N- {4- [1- (10,11-Dihydrodibenzo [b, f] azepin-5-yl-carbonyl) -piperidin-4-yl] -butyl} -3- (pyridine- 3-yl) -acrylamide, And N- [4- (1-diphenylphosphinoyl-lipridin-4-yl) -butyl] -3- (pyridin-3-yl) -acryl amide Or pharmaceutically acceptable acid addition salts thereof. The method according to claim 1 or 2, N- [4- (1-acetylpiperidin-4-yl) -butyl] -3- (pyridin-3-yl) -acrylamide, N- [4- (1-diphenylacetyl-piperidin-4-yl) -butyl] -3- (piperidin-3-yl) -acrylamide, N- {4- [1- (3,3-Diphenylpropionyl) -piperidin-4-yl] -butyl} -3- (pyridin-3-yl) -acrylamide, N- [4- (1-benzoylpiperidin-4-yl) -butyl] -3- (pyridin-3-yl) -acrylamide, N- [4- (1-benzoylpiperidin-4-yl) -butyl] -5- (pyridin-3-yl) -2,4-pentadienoic acid amide, and N- {4- [1- (9-Oxo-9H-fluoren-4-yl-carbonyl) -piperidin-4-yl] -butyl} -3- (pyridin-3-yl) -acrylamide , Or a pharmaceutically acceptable acid addition salt thereof. The method according to claim 1 or 2, N- {4- [1- (phenylpyridin-3-yl-methyl) -piperidin-4-yl] -butyl} -3- (pyridin-3-yl) -acrylamide, N- {4- [1- (phenylpyridin-4-yl-methyl) -piperidin-4-yl] -butyl} -3- (pyridin-3-yl) -acrylamide, N- {4- [1- (6,11-Dihydrodibenzo [b, e] oxepin-11-yl) -piperidin-4-yl] -butyl} -3- (pyridin-3-yl ) -Acrylamide and N- {4- [1- (6,11-Dihydrodibenzo [b, e] thipin-11-yl) -piperidin-4-yl] -butyl} -3- (pyridin-3-yl ) -Acrylamide, Or pharmaceutically acceptable acid addition salts thereof. The method according to claim 1 or 2, N- [7- (1-diphenylmethylpiperidin-4-yl) -heptyl] -3- (pyridin-3-yl) -acrylamide, N- [8- (1-diphenylmethylpiperidin-4-yl) -octyl] -3- (pyridin-3-yl) -acrylamide, N- [3- (1-Diphenylmethylpiperidin-4-yloxy) -propyl] -3- (pyridin-3-yl) -acrylamide, and N- [3- (1-benzylpiperidin-4-yloxy) -propyl] -3- (pyridin-3-yl) -acrylamide, Or pharmaceutically acceptable acid addition salts thereof. The method according to claim 1 or 2, N- [2- (1-diphenylmethylpiperidin-4-yl) -ethyl] -5- (pyridin-3-yl) -2,4-pentadienoic acidamide, N- [4- (1-diphenylmethylpiperidin-4-yl) -butyl] -5- (pyridin-3-yl) -2,4-pentadienoic acidamide, N- [5- (1-diphenylmethylpiperidin-4-yl) -pentyl] -5- (pyridin-3-yl) -2,4-pentadienoic acidamide and N- [6- (1-diphenylmethylpiperidin-4-yl) -hexyl] -5- (pyridin-3-yl) -2,4-pentadienoic acidamide, Or pharmaceutically acceptable acid addition salts thereof. A method for preparing a compound according to claim 1 or 2, (a) Carboxylic Acids of Formula (II) Wherein R ¹ , R ² , R ³ , A and k have the above meanings or their reaction derivatives react with the compound of formula (III), Wherein D, E, G and R ⁴ have the meanings given in claims 1 to 5, or (b) a compound of formula (I), wherein G is hydrogen, reacts with a compound of formula (IV), Wherein G has the meaning given in claims 1 to 5, except for hydrogen, L represents a suitable nucleoofuge or reactor, and the form and reaction of the nucleofuge or reactor (L) The condition depends on the nature of the residue G, or (c) a compound of formula (I), wherein G is hydrogen, reacts with a suitable alkylating or arylating agent of formula (IV) according to variant (b), wherein in formula (IV) G represents G1 and Alkyl-, alkenyl-, alkynyl-, cycloalkyl-, allyl-, aralkyl-, heteroaryl- or heteroaralkyl moieties according to claim 4, nucleofuge L is a reaction derivative of an alcohol, chlorine , Bromine, iodine, methanesulfonyloxy-, trifluoromethanesulfonyloxy-, ethanesulfonyloxy-, benzenesulfonyloxy-, p-toluenesulfonyloxy-, p-bromobenzenesulfonyloxy- or m-nitrobenzenesulfonyloxy moiety or an epoxide group, (d) a compound of formula (I) wherein G is hydrogen is a carboxylic acid, carbamic acid, sulfonic acid or phosphinic acid of formula (V) Wherein G is an acyl residue, carbamoyl residue, sulfonyl residue or phosphinoyl residue, or Reacting with derivatives thereof that can react to carboxyl symmetric or asymmetric carboxylic anhydrides, sulfonic anhydrides, acyl- or sulfonyl halides, preferably acyl- or sulfonyl chlorides, carbamoyl halides or phosphinic acids The reaction of the acid (V) or their reaction derivatives with compound (I), wherein G is hydrogen, is used as a preferred derivative of acid or sulfonic acid (V), as described in the presence of auxiliary bases in the solvent and in variant (a). Preferably under conditions as described above, or (e) A compound of formula (I), wherein G is hydrogen, reacts with a carbonyl group transmitter to form an intermediate product, which is then reacted with a primary or secondary amine of formula (VI) without purification or prior separation. and Wherein R ¹² and R ¹⁴ and the group —NR ¹² R ¹⁴ have the meaning according to claims 1 to 4, wherein bis- (trichloromethyl) carbonate (triphosgen) and carbonyldiimidazole are particularly reactive carbonyl groups The reaction of a compound of formula (I) with triphosphene or carbonyldiimidazole, which is used as a carrier and G is hydrogen, is carried out in an absolute, inert solvent in the presence of a tertiary organic amine as an auxiliary base. The solution of (I) and the auxiliary base are preferably carried out by the slow addition of the same amount of solution of the carbonyl group carrier, or (f) a compound of formula (I) wherein G is hydrogen, reacts with an isocyanate salt of formula (VII) wherein R ¹² has the meaning according to claims 1 to 4, The reaction between the compound of formula (I), wherein G is hydrogen, and the isocyanate salt of formula (i) are pentane, hexane, heptane, benzene, toluene, dichloromethane, chloroform, 1,2-dichloroethane, trichloroethylene, Occurs in diethyl ether, tetrahydrofuran, dioxane, ethyl acetate, butyl acetate, formamide, dimethylformamide or mixtures thereof and the reaction temperature may vary in the range from -20 ° C to 150 ° C, but preferably 20 Can vary from 100 ° C. to 100 ° C. (g) a compound of formula (I) wherein R ⁴ is hydrogen is reacted with an alkylating agent of formula (VII) Wherein R ⁴ is an alkyl, alkenyl, alkynyl or cycloalkyl moiety and L is a sulfonic acid ester of chlorine, bromine, iodine or alcohol and the sulfonic acid ester of formula (VIII) is preferably methylsulfonyl jade as nucleotype L Period, trifluoromethanesulfonyloxy-, p-toluenesulfonyloxy-, p-bromobenzenesulfonyloxy- or m-nitrobenzenesulfonyloxy group, and the amide alkylation is pentane, in the presence of a tertiary amino group. Is carried out under the use of potassium tert-butylate, sodium hydride, potassium hydride or butyl lithium in hexane, heptane, benzene, toluene, tetrahydrofuran, dioxane, dimethyl sulfoxide, dimethylformamide, N-methylpyrrolidone and , The reaction temperature is between -40 ° C and 140 ° C, preferably between -20 ° C and 80 ° C. 12. The reaction derivatives of compound (II) according to claim 11, as their activated esters, anhydrides, acid halides, acid chlorides, p-nitrophenyl esters 2,4,6-trichlorophenyl esters, Pentachlorophenyl ester, cyano methyl ester, N-hydrosuccinimide, N-hydroxyphthalimide, 1-hydroxybenzotriazole, N-hydroxypiperidine, 2-hydroxypyridine or 2-meth An ester of captopyridine is used according to method variant (a), chloroformic acid phenyl ester, chloroformic acid benzyl ester, chloroformic acid methyl ester, ethyl ester or isobutyl ester is used as an anhydride, compound (II) and compound ( The reaction of III) optionally comprises dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylraminopropyl) -carbodiimide hydrochloride, N, N'-carbonyldiimidazole or 1-ethoxycarb Bonil In the presence of 2-ethoxy-1,2-dihydroquinoline, In the case of carbodiimide as a thickening agent, N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxybenzotriazole, or N-hydroxypiperidine is preferably added, Compounds of formula (III) which are free of base or in the form of acid addition salts of compounds preferably react in the form of salts of acids selected from hydrochlorides, hydrobromides and sulfates, and optionally in the form of their reactive derivatives ( The reaction of the compound of II) is preferably benzene, toluene, xylene, dichloromethane, chloroform, 1,2-dichloromethane, trichloroethylene, diethyl ether, tetrahydrofuran, dioxane, glycol dimethyl ether, ethyl Is carried out with compound (III) in acetate, acetonitrile, dimethylsulfoxide, dimethylformamide or N-methylpyrrolidone, The reaction is optionally carried out in the presence of sodium carbonate, potassium carbonate, sodium hydrocarbon, potassium potassium, triethylamine, ethyldiisopropylamine, tributylamine, N-methylmorpholine, or feedridine, and the appropriate extra formula ( The compound of III) is optionally used as a base, and when using a compound of formula III in the form of an acid addition salt, the amount of auxiliary base is equally considered, and The reaction temperature is between -40 ° C and 180 ° C, preferably between -10 ° C and 130 ° C, preferably at the boiling point of the solvent used. 12. The reaction according to claim 11, wherein, according to the method of variant (b), the reaction of compound (I) with a compound according to formula (IV), wherein G is hydrogen, optionally comprises benzene, toluene, xylene, tetrahydrofuran, dioxane, It is carried out in glycol dimethyl ether, ethyl acetate, acetonitrile, acetone, ethyl methyl ketone, ethanol, isopropanol, butanol, glycol monomethyl ether, dimethyl sulfoxide, dimethylformamide or N-methylpyrrolidone and mixtures of two or more thereof As well as pure solvents are used and the reaction is optionally carried out in the presence of a base, optionally in the presence of such as according to the method of variant (a) according to claim 12, iodide for chloride or bromide as compound (IV) The addition of sodium or potassium iodide occurs and the reaction temperature varies between 0 ° C and 180 ° C. Is a compound according to formula (I), wherein G is hydrogen and the remaining substituents have the meanings given in claims 1-4: A pharmaceutical composition for treating cancer comprising a pharmaceutically acceptable carrier and a toxicologically stable adjuvant in combination with a compound according to claim 1 or optionally with other active ingredients. A pharmaceutical composition for the treatment of cell division inhibition or immunosuppression comprising a pharmaceutically acceptable carrier and a toxicologically stable adjuvant in combination with a compound according to claim 1 or optionally with other active ingredients. 17. The method according to claim 15 or 16, optionally in a sustained action or in the form of a fluid-resistive substance, in the form of an oral dosage form of solids such as tablets, capsules, coated tablets, or, optionally, a sustained action or gastric fluid of the stomach- A pharmaceutical composition that is a liquid oral solution, suspension, or effervescent tablet in the form of tabs or sachets in the form of a resist. 17. The method of claim 15 or 16, optionally in a sustained action form, together with a suitable pharmaceutically acceptable carrier and adjuvant, in the form of a suitable injection or infusion preparation or as a parenteral depot pharmaceutical form or implant, or concentrated. Pharmaceutical compositions in the form of water, powder or lyophilisate. The pharmaceutical composition according to claim 15 or 16, which is in the form of a spray in the form of an inhalation therapy, optionally with a suitable pharmaceutically acceptable propellant, carrier and adjuvant. 17. The pharmaceutical composition according to claim 15 or 16 in the form of a transdermal treatment system for systematic treatment. The pharmaceutical composition according to claim 15 or 16 in the form of a gastrointestinal treatment system for systematic treatment. 17. The pharmaceutical composition according to claim 15 or 16, in the form of a salve, suspension, emulsion, balm or plaster or in the form of an externally applicable solution. The pharmaceutical composition according to claim 15 or 16, which is for administration by controlled dose aerosol or in the form of a dry powder dosage formulation. The pharmaceutical composition of claim 15 or 16 in the form of a rectal, genital or transurethral administration emulsion, solution, liposome solution, implant, suppository or capsule. A pharmaceutical composition according to claim 15 or 16 in the form of a nasal, otologic or ophthalmologic composition. The pharmaceutical composition according to claim 15 or 16, which is in orally administrable form. The pharmaceutical composition according to claim 15 or 16, wherein the dosage unit for one administration contains 0.01 to 2.0 mg or 0.1 to 10 or 20 mg of the active ingredient according to claim 1 or 2. The pharmaceutical composition of claim 19, wherein the pharmaceutically acceptable carrier is a propellant aerosol. 29. The pharmaceutical composition of claim 28, wherein the propellant aerosol is tetrafluoroethane, heptafluoropropane, propane, butane or dimethyl ether or mixtures thereof. The pharmaceutical composition of claim 28, wherein the propellant aerosol contains a surface active adjuvant. A pharmaceutical composition according to claim 15 which contains glucose and / or lactose as powder dosage. The pharmaceutical composition according to claim 15 or 16, which is optionally present in the form of a separate dosage unit of the pharmaceutical package in combination with an additional cytostatic or immunosuppressive agent. N- (4-Diphenylmethyl-morpholin-2-ylmethyl) -3- (pyridin-3-yl) -acrylamide. A compound according to claim 1 or 2 and (E) -3- (3-pyridyl) -N- [2- (1-benzylpiperidin-4-yl) ethyl] -2-propenamide hydro A pharmaceutical composition for treating cancer and / or inhibiting cell division or immunosuppression comprising chloride and a pharmaceutically acceptable carrier or adjuvant and optionally one or more additional active ingredients. (E) -3- (3-pyridyl) -N- [2- (1-benzylpiperidin-4-yl) ethyl] -2-propenamide hydrochloride and a pharmaceutically acceptable carrier or adjuvant A pharmaceutical composition for treating cancer and / or inhibiting cell division or immunosuppression, optionally comprising one or more additional active ingredients.