EP1368335A2 - Novel amino dicarboxylic acid derivatives with pharmaceutical properties - Google Patents

Abstract

The invention relates to the use of compounds of formula (I) and of their salts and stereoisomers for producing medicaments used in the treatment of cardiovascular diseases.

Description

Novel aminodicarboxylic acid derivatives with pharmaceutical properties

The present invention relates to new chemical compounds which also stimulate soluble guanylate cyclase via a novel mode of action which does not involve the heme group of the enzyme, their production and their use as medicaments, in particular as medicaments for the treatment of cardiovascular diseases.

Cyclic guanosine monophosphate (cGMP) is one of the most important cellular transmission systems in mammalian cells. Together with nitrogen monoxide (NO), which is released from the endothelium and transmits hormone-like and mechanical signals, it forms the NO / cGMP system. The guanylate cyclases catalyze the biosynthesis of cGMP from guanosine triposphate (GTP). The previously known representatives of this family can be divided into two groups according to structural features and the type of ligand: the particulate guanylate cyclases that can be stimulated by natriuretic peptides and the soluble guanylate cyclases that can be stimulated by NO. The soluble guanylate cyclases consist of two subunits and most likely contain one heme per heterodimer, which is part of the regulatory center. This is of central importance for the activation mechanism. NO can bind to the iron atom of the heme and thus significantly increase the activity of the enzyme. Hem-free preparations, on the other hand, cannot be stimulated by NO. CO is also able to attack the central iron atom of the heme, whereby the stimulation by CO is significantly less than that by NO.

Due to the formation of cGMP and the resulting regulation of phosphodiesterases, ion channels and protein kinases, guanylate cyclase plays a decisive role in different physiological processes, in particular in the relaxation and proliferation of smooth muscle cells, platelet aggregation and adhesion and neuronal signal transmission as well as in diseases , which are based on a disturbance of the above-mentioned processes. Under pathophysiological conditions, the NO / cGMP system can be suppressed, which leads to Examples include high blood pressure, platelet activation, increased cell proliferation, endothelial dysfunction, atherosclerosis, angina pectoris, heart failure, thrombosis, stroke and myocardial infarction.

A NO-independent treatment option for such diseases aimed at influencing the cGMP signal path in organisms is a promising approach due to the expected high efficiency and few side effects.

To date, only compounds such as organic nitrates have been used for the therapeutic stimulation of soluble guanylate cyclase, the effect of which is based on NO. This is formed by bioconversion and activates the soluble guanylate cyclase by attacks on the iron central atom of the heme. In addition to the side effects, the development of tolerance is one of the decisive disadvantages of this type of treatment.

In recent years, some substances have been described which directly soluble guanylate cyclase, i.e. stimulate without prior release of NO, such as, for example, 3- (5'-hydroxymethyl-2'-furyl) -l-benzylindazole (YC-1, Wu et al., Blood 84 (1994), 4226; Mülsch et al., Br J. Pharmacol. 120 (1997), 681), fatty acids (Goldberg et al, J. Biol. Chem. 252 (1977), 1279), diphenyliodonium hexafluorophosphate (Pettibone et al., Eur. J. Pharmacol. 116 ( 1985), 307), isoliquiritigenin (Yu et al., Brit. J. Pharmacol. 114 (1995), 1587) and various substituted pyrazole derivatives (WO 98/16223, WO 98/16507 and WO 98/23619).

The previously known stimulators of soluble guanylate cyclase stimulate the enzyme either directly via the heme group (carbon monoxide, nitrogen monoxide or diphenyliodonium hexafluorophosphate) by interaction with the iron center of the heme group and a resulting conformational change that leads to an increase in enzyme activity (Gerzer et al., FEBS Lett. 132 (1981), 71), or via a heme-dependent mechanism that is independent of NO, but too potentiates the stimulating effect of NO or CO (e.g. YC-1, Hoenicka et al., J. Mol. Med. (1999) 14; or that in WO 98/16223, WO 98/16507 and WO 98/23619 described pyrazole derivatives).

The stimulating effects of isoliquiritigenin and of which are claimed in the literature

Fatty acids such as B. arachidonic acid, prostaglandin endoperoxides and fatty acid hydroperoxides on the soluble guanylate cyclase could not be confirmed (see e.g. Hoenicka et al., J. Mol. Med. 77 (1999), 14).

If the heme group is removed from the soluble guanylate cyclase, the enzyme still shows a detectable catalytic basal activity, i.e. cGMP is still formed. The remaining catalytic basal activity of the heme-free enzyme cannot be stimulated by any of the known stimulators mentioned above.

A stimulation of heme-free soluble guanylate cyclase by protoporphyrin IX has been described (Ignarro et al., Adv. Pharmacol. 26 (1994), 35). However, protoporphyrin IX can be regarded as facial expressions for the NO-heme adduct, which is why the addition of protoporphyrin IX to the soluble guanylate cyclase should lead to the formation of a structure of the enzyme corresponding to the soluble guanylate cyclase which is stimulated by NO. This is also through the

The fact proves that the stimulating effect of protoporphyrin IX is increased by the above-described NO-independent but heme-dependent stimulator YC-1 (Mülsch et al., Naunyn Schmiedebergs Arch. Pharmacol. 355, R47).

So far, no compounds have been described which can stimulate the soluble guanylate cyclase independently of the heme group present in the enzyme.

It was the object of the present invention to provide medicaments for the treatment of cardiovascular diseases or others by influencing the cGMP

Develop signaling pathways in organisms treatable diseases. The above object is achieved by the use of compounds for the production of medicaments which are capable of stimulating the soluble guanylate cyclase independently of NO and of the heme group present in the enzyme.

Surprisingly, it was found that there are compounds which can also stimulate the soluble guanylate cyclase independently of the heme group present in the enzyme. The biological activity of these stimulators is based on a completely new mechanism for stimulating soluble guanylate cyclase. in the

In contrast to the compounds described above and known from the prior art as stimulators of soluble guanylate cyclase, the compounds according to the invention are able to stimulate both the heme-containing and the heme-free form of the soluble guanylate cyclase. The stimulation of the enzyme with these new stimulators is via a heme-independent path, which is also demonstrated by the fact that the new stimulators on the heme-containing enzyme on the one hand show no synergistic effect with NO and on the other hand the effect of these new stimulators is not affected by Hem-dependent inhibitor of soluble guanylate cyclase, lH-l, 2,4-oxadiazol- (4,3a) -quinoxalin-l-one (ODQ).

This represents a new therapeutic approach for the treatment of cardiovascular diseases and other diseases that can be treated in organisms by influencing the cGMP signaling pathway.

EP-A-0 345 068 describes, inter alia, the aminoalkanecarboxylic acid (1) as an intermediate in the synthesis of GABA antagonists:

WO 93/00359 describes the aminoalkanecarboxylic acid (2) as an intermediate in peptide synthesis and its use as an active ingredient for treating diseases of the central nervous system:

However, neither of these two publications describes that such aminoalkane carboxylic acids can have a stimulating effect on soluble guanylate cyclase which is independent of the heme group present in the enzyme.

Substances structurally similar to the compounds according to the invention are also known from WO 01/19776, WO 01/19355, WO 01/19780 and WO 01/19778.

According to the present invention, the heme contained in the enzyme

Group-independent stimulation of soluble guanylate cyclase aminoalkane carboxylic acids of formula (I) used: embedded image in which

Z for a phenyl ring which has a saturated, partially unsaturated or aromatic carba- or heterocycle with up to 3 heteroatoms from the

Row S, N and / or O is fused, or a partially unsaturated or aromatic heterocycle having 1 to 9 carbon atoms and up to 3

Heteroatoms from the series S, N and / or O,

V is absent, O, NR ⁴ , NR ⁴ CONR ⁴ , NR ⁴ CO, NR ⁴ SO ₂ , COO, CONR ⁴ or S (O) ₀ ,

embedded image in which

R independently of any further radical R which may be present

Is hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms, cycloalkyl having 3 to 8 carbon atoms, aryl having 6 to 10 carbon atoms or arylalkyl having 7 to 18 carbon atoms, the aryl radical in turn being used one or more times by halogen, alkyl, alkoxy with bis can be substituted to 6 carbon atoms,

o means 0, 1 or 2,

Q is missing, straight chain or branched alkylene, straight chain or branched

Means alkenediyl or straight-chain or branched alkynediyl each having up to 12 carbon atoms, each of which has one or more groups from O, S (O) _p , NR ⁵ , CO, NR ⁵ SO ₂ or CONR ^{5 can} contain, and can be substituted one or more times by halogen, hydroxy or alkoxy with up to 4 carbon atoms, optionally any two atoms of the above chain to form a three- to eight-membered ring can be connected to one another,

embedded image in which

R ⁵ denotes hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms or cycloalkyl having 3 to 8 carbon atoms, which can be substituted by halogen or alkoxy having up to 4 carbon atoms,

0, 1 or 2 means

Represents hydrogen, NR ⁸ R ⁹ , aryl having 6 to 10 carbon atoms, an aromatic or saturated heterocycle having 1 to 9 carbon atoms and up to 3 heteroatoms from the series S, N and or O or straight-chain or branched cycloalkyl having 3 to 8 carbon atoms, which can also be bonded via N, where the cyclic radicals are each one to three times by straight-chain or branched alkyl, straight-chain or branched alkenyl, straight-chain or branched alkynyl, straight-chain or branched alkoxy, straight-chain or branched alkoxyalkoxy, straight-chain or branched haloalkyl, straight-chain or branched haloalkoxy each with up to 8 carbon atoms, straight-chain or branched cycloalkyl with 3 to 8 carbon atoms, halogen, hydroxy, CN, SR ⁶ , NO ₂ , NR ⁸ R ⁹ , NR ⁷ COR ¹⁰ , NR ⁷ CONR ⁷ R ¹⁰ or CONR ^π R ¹² can be substituted,

wherein R ^{6 is} hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms, straight-chain or branched haloalkyl having up to 8 carbon atoms or cycloalkyl having 3 to 8 carbon atoms,

R ^7, independently of any further radical R ^{7 which may} be present, denotes hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms or cycloalkyl having 3 to 8 carbon atoms,

R ⁸ , R ⁹ , R ¹¹ and R ¹² independently of one another are hydrogen, straight-chain or branched alkyl, straight-chain or branched alkenyl having up to 8 carbon atoms, aryl having 6 to 10 carbon atoms, an aromatic heterocycle having 1 to 9 carbon atoms and up to 3 heteroatoms from the series S, N and / or O, arylalkyl with 8 to 18

Are carbon atoms, cycloalkyl having 3 to 8 carbon atoms or a radical of the formula SO ₂ R ¹³ , the aryl radical in turn being used one or more times by halogen, hydroxy, CN, NO ₂ , NH ₂ , NHCOR ⁷ , alkyl, alkoxy, haloalkyl or haloalkoxy can be substituted with up to 6 carbon atoms, or two substituents from R ⁸ and R ⁹ or R ¹¹ and R ¹² can be connected to one another to form a five- or six-membered ring which may contain O or N,

wherein

1 "

R denotes straight-chain or branched alkyl having up to 4 carbon atoms or aryl having 6 to 10 carbon atoms, the aryl radical in turn can be substituted one or more times by halogen, CN, NO ₂ , alkyl, alkoxy, haloalkyl or haloalkoxy having up to 6 carbon atoms,

R ^{10 is} hydrogen, straight-chain or branched alkyl having up to 12 carbon atoms, straight-chain or branched alkenyl having up to 12 carbon atoms, aryl having 6 to 10 carbon atoms, an aromatic heterocycle having 1 to 9 carbon atoms and up to 3 heteroatoms from the series S, N and or denotes O or cycloalkyl having 3 to 8 carbon atoms, which may optionally further be substituted by halogen, hydroxy, CN, NO ₂ , NH ₂ , NHCOR ⁷ , alkyl, alkoxy, haloalkyl or haloalkoxy having up to 6 carbon atoms;

and / or the cyclic radicals in each case one to three times by aryl with 6 to 10 carbon atoms, a saturated carbocycle with 6 to 10 carbon atoms, an aromatic or saturated heterocycle with 1 to 9 carbon atoms and up to 3 heteroatoms from the series S, N and / or O can be substituted, which can also be bonded via N, which is directly or via a group from O, S, SO, SO ₂ , NR ⁷ , SO ₂ NR ⁷ , CON, straight-chain or branched alkylene, straight-chain or branched alkenediyl , straight-chain or branched alkyloxy, straight-chain or branched oxyalkyloxy, straight-chain or branched sulfonylalkyl, straight-chain or branched thioalkyl, each with up to 8

Carbon atoms can be bonded and one to three times by straight-chain or branched alkyl, straight-chain or branched alkoxy, straight-chain or branched alkoxyalkoxy, straight-chain or branched haloalkyl, straight-chain or branched haloalkoxy, carbonylalkyl or straight-chain or branched alkenyl, each with up to 6 Carbon atoms, halogen, SR ⁶ , CN, NO ₂ , NR ⁸ R ⁹ , CONR ¹⁵ R ¹⁶ or NR ¹⁴ COR ¹⁷ can be substituted,

embedded image in which

R ¹⁴ denotes hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms or cycloalkyl having 3 to 8 carbon atoms,

R ¹⁵ , R ¹⁶ independently of one another are hydrogen, straight-chain or branched

Alkyl with up to 8 carbon atoms, cycloalkyl with 3 to 8 carbon atoms, aryl with 6 to 10 carbon atoms or a radical of the formula SO ₂ R ¹⁸ , the aryl radical in turn being used one or more times by halogen, hydroxy, CN, NO ₂ , NH ₂ , NHCOR ⁷ , alkyl, alkoxy, haloalkyl or haloalkoxy with up to 6

Carbon atoms can be substituted

embedded image in which

R ¹⁸ denotes straight-chain or branched alkyl having up to 4 carbon atoms or aryl having 6 to 10 carbon atoms, the aryl radical in turn being used one or more times by halogen, hydroxy, CN, NO ₂ , NH ₂ , NHCOR ⁷ , alkyl, alkoxy, haloalkyl or Haloalkoxy can be substituted with up to 6 carbon atoms,

and

R ^{17 is} hydrogen, straight-chain or branched alkyl with up to 12

Carbon atoms, straight-chain or branched alkenyl with up to 12 carbon atoms, aryl with 6 to 10 carbon atoms, an aromatic heterocycle with 1 to 9 carbon atoms and up to 3 heteroatoms from the series S, N and or O or cycloalkyl with 3 to 8 carbon atoms, which may be further substituted by halogen, hydroxy, CN , NO ₂ , NH ₂ , NHCOR ⁷ , alkyl, alkoxy,

Haloalkyl or haloalkoxy can be substituted with up to 6 carbon atoms;

and / or the cyclic radicals can be fused with an aromatic or saturated carbocycle with 1 to 10 carbon atoms or an aromatic or saturated heterocycle with 1 to 9 carbon atoms and up to 3 heteroatoms from the series S, N and / or O,

Hydrogen, halogen, straight-chain or branched alkyl, optionally one or more substituents from the group consisting of

C ₆ - alkoxy, NR ¹⁹ R ²⁰ , cycloalkyl with 3 to 8 carbon atoms, can carry, straight-chain or branched haloalkyl, straight-chain or branched alkoxy, or alkoxycarbonyl with up to 4 carbon atoms each, CN, NO ₂ , NR ¹⁹ R ²⁰ , SR ¹⁷ , SO ₂ R ¹⁷ , cycloalkyl with 3 to 8 carbon atoms, haloalkoxy haloalkoxy with up to 6 carbon atoms,

Cycloalkoxy with up to 14 carbon atoms, CONH ₂ , CONR ¹⁷ R ¹⁷ , SO ₂ NH ₂ , SO ₂ NR ¹⁷ R ¹⁷ , alkoxyalkoxy with up to 12 carbon atoms, NHCOOR ¹⁷ , NHCOR ¹⁷ , NHSO ₂ R ¹⁷ , NHCONH ₂ , OCONR ¹⁷ R ¹⁷ , OSO ₂ R ¹⁷ , C ₂ -i ₂ -alkenyl or Cι.i ₂ -alkynyl means

wherein

R ¹⁹ and R ²⁰ independently of one another are hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms or cycloalkyl having 3 to 8 carbon atoms, m represents an integer from 1 to 4,

W denotes straight-chain or branched alkylene with up to 6 carbon atoms or straight-chain or branched alkenediyl with up to 6 carbon atoms, each of which can contain a group from O, S (O) _q , NR ²¹ , CO or CONR ²¹ , or CO, NHCO or OCO means

embedded image in which

q represents 0, 1 or 2,

R ²¹ denotes hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms or cycloalkyl having 3 to 8 carbon atoms,

U denotes straight-chain or branched alkyl having up to 4 carbon atoms,

A is aryl with 6 to 10 carbon atoms or an aromatic heterocycle with 1 to 9 carbon atoms and up to 3 heteroatoms from the series S, N and / or O, which may be one to three times by halogen, straight-chain or branched alkyl, straight-chain or branched Haloalkyl, straight-chain or branched alkoxy, haloalkoxy or alkoxycarbonyl with up to 4 carbon atoms, CN, NO ₂ or NR ²² R ²³ can be substituted, in which

99 9 ^

R and R each independently represent hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms or cycloalkyl having 3 to 8 carbon atoms, carbonylalkyl or sulfonylalkyl. R ^{2 means} tetrazolyl, COOR ²⁴ or CONR ²⁵ R ²⁶ ,

embedded image in which

R ^{24 is} hydrogen, alkyl of 1 to 8 carbon atoms or cycloalkyl of 3 to 8 carbon atoms

R ²⁵ and R ²⁶ each independently represent hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms, cycloalkyl having 3 to 8 carbon atoms or a radical of the formula SO ₂ R ²⁷ , or R ²⁵ and R ²⁶ together represent a five- or six-membered ring form, which can contain N or O,

wherein

R ²⁷ denotes straight-chain or branched alkyl having up to 4 carbon atoms or aryl having 6 to 10 carbon atoms, the aryl radical in turn being one or more times by halogen, CN, NO ₂ , alkyl, alkoxy, haloalkyl or haloalkoxy having up to 6

Carbon atoms can be substituted

X denotes straight-chain or branched alkylene with up to 12 carbon atoms or straight-chain or branched alkenediyl with up to 12 carbon atoms, each of one to three groups from O, S (O) _r , NR ²⁸ , CO or

CONR ²⁹ may contain aryl or aryloxy having 6 to 10 carbon atoms, the aryl radical in turn being able to be substituted one or more times by halogen, CN, NO, alkyl, alkoxy, haloalkyl or haloalkoxy having up to 6 carbon atoms, optionally two random atoms of the above chains are connected to one another by an alkyl chain to form a three- to eight-membered ring, embedded image in which

r represents 0, 1 or 2,

R ^{28 represents} hydrogen, alkyl having 1 to 8 carbon atoms or cycloalkyl having 3 to 8 carbon atoms,

R ²⁹ denotes hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms or cycloalkyl having 3 to 8 carbon atoms,

n represents 1 or 2;

R ^{1 means} tetrazolyl, COOR ³⁰ or CONR ³¹ R ³² ,

wherein

R ^{30 is} hydrogen, alkyl of 1 to 8 carbon atoms or cycloalkyl of 3 to 8 carbon atoms

R ³¹ and R ³² each independently represent hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms, cycloalkyl having 3 to 8 carbon atoms or a radical of the formula SO ₂ R ³³ ,

wherein

R means straight-chain or branched alkyl having up to 4 carbon atoms or aryl having 6 to 10 carbon atoms, the aryl radical in turn can be substituted one or more times by halogen, CN, NO ₂ , alkyl, alkoxy, haloalkyl or haloalkoxy having up to 6 carbon atoms,

and their stereoisomers and salts.

Preferred compounds of the formula (I) are

embedded image in which

for a cyclic radical from the group consisting of

the radicals V and W can be bonded to any carbon atom or to any nitrogen atom of a ring which may be present;

V is absent, O, NR ⁴ , NR ⁴ CONR ⁴ , NR ⁴ CO, NR ⁴ SO ₂ , COO, CONR ⁴ or S (O) ₀ ,

embedded image in which

R ^4, independently of any further radical R ^{4 which may} be present, denotes hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms, cycloalkyl having 3 to 8 carbon atoms, aryl having 6 to 10 carbon atoms or arylalkyl having 7 to 18 carbon atoms, the aryl radical can in turn be substituted one or more times by halogen, alkyl, alkoxy having up to 6 carbon atoms,

0, 1 or 2 means Q is absent, straight-chain or branched alkylene, straight-chain or branched alkenediyl or straight-chain or branched alkynediyl each having up to 12 carbon atoms, each of which means one or more groups of O, S (O) _p , NR ⁵ , CO, NR ⁵ SO ₂ or CONR ^{5 can} contain, and can be substituted one or more times by halogen, hydroxy or alkoxy with up to 4 carbon atoms, optionally any two atoms of the above chain can be connected to form a three- to eight-membered ring,

wherein

R ^{5 is} hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms or cycloalkyl having 3 to 8 carbon atoms, which can be substituted by halogen or alkoxy having up to 4 carbon atoms,

p means 0, 1 or 2,

Y is hydrogen, NR ⁸ R ⁹ , aryl with 6 to 10 carbon atoms, an aromatic or saturated heterocycle with 1 to 9 carbon atoms and up to 3 heteroatoms from the series S, N and / or O or straight-chain or branched cycloalkyl with 3 to 8 carbon atoms, which can also be bonded via N, the cyclic radicals in each case one to three times by straight-chain or branched alkyl, straight-chain or branched alkenyl, straight-chain or branched alkynyl, straight-chain or branched alkoxy, straight-chain or branched alkoxyalkoxy, straight-chain or branched Haloalkyl, straight-chain or branched haloalkoxy each having up to 8 carbon atoms, straight-chain or branched cycloalkyl having 3 to 8 carbon atoms, halogen, hydroxy, CN, SR ⁶ , NO ₂ , NR ⁸ R ⁹ , NR ⁷ COR ¹⁰ ,

NR ⁷ CONR ⁷ R ¹⁰ or CONR ^π R ¹² can be substituted, embedded image in which

R ⁶ denotes hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms, straight-chain or branched haloalkyl having up to 8 carbon atoms or cycloalkyl having 3 to 8 carbon atoms,

R ^7, independently of any further radical R ^{7 which may} be present, denotes hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms or cycloalkyl having 3 to 8 carbon atoms,

R ⁸ , R ⁹ , R ¹¹ and R ¹² independently of one another are hydrogen, straight-chain or branched alkyl, straight-chain or branched alkenyl with up to

8 carbon atoms, aryl with 6 to 10 carbon atoms, an aromatic heterocycle with 1 to 9 carbon atoms and up to 3 heteroatoms from the series S, N and / or O, arylalkyl with 8 to 18 carbon atoms, cycloalkyl with 3 to 8 carbon atoms or a radical of the formula SO ₂ R ¹³ , where the aryl radical in turn can be substituted one or more times by halogen, hydroxy, CN, NO ₂ , NH ₂ , NHCOR ⁷ , alkyl, alkoxy, haloalkyl or haloalkoxy having up to 6 carbon atoms, or two Substituents from R ⁸ and R ⁹ or R ¹¹ and R ¹² can be connected to one another to form a five- or six-membered ring which can contain O or N,

embedded image in which R ¹³ denotes straight-chain or branched alkyl having up to 4 carbon atoms or aryl having 6 to 10 carbon atoms, the aryl radical in turn being used one or more times by halogen, CN, NO ₂ , alkyl, alkoxy, haloalkyl or haloalkoxy having up to 6 carbon atoms can be substituted

R ^{10 is} hydrogen, straight-chain or branched alkyl having up to 12 carbon atoms, straight-chain or branched alkenyl having up to

12 carbon atoms, aryl with 6 to 10 carbon atoms, an aromatic heterocycle with 1 to 9 carbon atoms and up to 3 heteroatoms from the series S, N and / or O or cycloalkyl with 3 to 8 carbon atoms, which may be further substituted by halogen, hydroxy, CN, NO ₂ , NH ₂ , NHCOR ⁷ , alkyl, alkoxy,

Haloalkyl or haloalkoxy can be substituted with up to 6 carbon atoms;

and / or the cyclic radicals in each case one to three times by aryl having 6 to 10 carbon atoms, an aromatic or saturated heterocycle

1 to 9 carbon atoms and up to 3 heteroatoms from the series S, N and / or O can be substituted, which can also be bonded via N, which directly or via a group from O, S, SO, SO ₂ , NR ⁷ , SO ₂ NR ⁷ , CONR ⁷ , straight-chain or branched alkylene, straight-chain or branched alkenediyl, straight-chain or branched alkyloxy, straight-chain or branched oxyalkyloxy, straight-chain or branched sulfonylalkyl, straight-chain or branched thioalkyl each having up to 8 carbon atoms and can be bound up to three times by straight-chain or branched alkyl, straight-chain or branched alkoxy, straight-chain or branched alkoxyalkoxy, straight-chain or branched

Haloalkyl, straight-chain or branched haloalkoxy, carbonylalkyl or straight-chain or branched alkenyl having in each case up to 6 carbon atoms, halogen, SR ^6, CN, NO _2, NR ⁸ R ^9, CONR ^l5 R ¹⁶ or NR ¹⁴ COR ¹⁷ may be substituted,

embedded image in which

R ¹⁴ denotes hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms or cycloalkyl having 3 to 8 carbon atoms,

R ¹⁵ , R ¹⁶ independently of one another are hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms, cycloalkyl having 3 to 8 carbon atoms or a radical of the formula SO ₂ R ¹⁸ ,

wherein

R ¹⁸ denotes straight-chain or branched alkyl having up to 4 carbon atoms or aryl having 6 to 10 carbon atoms, the aryl radical in turn being substituted one or more times by halogen, CN, NO ₂ , alkyl, alkoxy, haloalkyl or haloalkoxy having up to 6 carbon atoms can

and

R ^{17 is} hydrogen, straight-chain or branched alkyl with up to 12

Carbon atoms, straight-chain or branched alkenyl with up to

12 carbon atoms, aryl with 6 to 10 carbon atoms, an aromatic heterocycle with 1 to 9 carbon atoms and up to

3 heteroatoms from the series S, N and / or O or cycloalkyl with 3 is up to 8 carbon atoms, which may optionally be further substituted by halogen, CN, NO ₂ , alkyl, alkoxy, haloalkyl or haloalkoxy having up to 6 carbon atoms;

and / or the cyclic radicals with an aromatic or saturated

Carbocycle with 1 to 10 carbon atoms or an aromatic or saturated heterocycle with 1 to 9 carbon atoms and up to 3 heteroatoms from the series S, N and / or O can be fused,

R ³ denotes hydrogen, halogen, straight-chain or branched alkyl, straight-chain or branched haloalkyl or straight-chain or branched alkoxy each having up to 4 carbon atoms,

m represents an integer from 1 to 4,

W denotes straight-chain or branched alkylene or straight-chain or branched alkenediyl each having up to 4 carbon atoms,

U -CH ₂ - means

A is phenyl or an aromatic heterocycle having 1 to 9 carbon atoms and up to 3 heteroatoms from the series S, N and / or O, which may be one to three times by halogen, straight-chain or branched alkyl, straight-chain or branched haloalkyl or straight-chain or branched alkoxy with up to 4 carbon atoms, can be substituted,

R ^{2 means} COOR ²⁴

wherein R ²⁴ denotes hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms,

X denotes straight-chain or branched alkylene with up to 8 carbon atoms or straight-chain or branched alkenediyl with up to 8 carbon atoms, each of one to three groups from phenyl, phenyloxy, O, CO

9Q or CONR can contain

embedded image in which

R ²⁹ denotes hydrogen, straight-chain or branched alkyl having up to 6 carbon atoms or cycloalkyl having 3 to 6 carbon atoms,

n represents 1 or 2;

R ^{1 means} COOR ³⁰ ,

embedded image in which

R, 30 is hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms.

Compounds of the formula (I) are particularly preferred

embedded image in which

Z for a cyclic radical from the group consisting of

the radicals V and W can be bonded to any carbon atom or to any nitrogen atom of a ring which may be present;

V is absent, O, S or NR ⁴ means

embedded image in which

R represents hydrogen or methyl,

is absent, means straight-chain or branched alkylene with up to 9 carbon atoms or straight-chain or branched alkenediyl or straight-chain or branched alkynediyl with up to 4 carbon atoms, which can be simply substituted by halogen,

Y H, NR R, cyclohexyl, phenyl, naphthyl or a heterocycle from the group

means which can also be bonded via N, where the cyclic radicals are each one to three times by straight-chain or branched alkyl, straight-chain or branched alkenyl, straight-chain or branched alkynyl, straight-chain or branched alkoxy, straight-chain or branched alkoxyalkoxy, straight-chain or branched haloalkyl, straight-chain or branched haloalkoxy each having up to 4 carbon atoms, straight-chain or branched cycloalkyl having 3 to 6 carbon atoms, F, CI, Br, I, NO ₂ , SR ⁶ , NR ⁸ R ⁹ , NR ⁷ COR ¹⁰ or CONR ^π R ¹² substituted could be,

embedded image in which

R denotes hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms, or straight-chain or branched haloalkyl having up to 4 carbon atoms,

R ⁷ denotes hydrogen, or straight-chain or branched alkyl having up to 4 carbon atoms,

R ⁸ , R ⁹ , R ¹¹ and R ¹² independently of one another are hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms, or phenyl, where the phenyl radical is monosubstituted to triple by F, CI Br, hydroxy, methyl, ethyl, n - Propyl, i-propyl, n-butyl, s-butyl, i-butyl, t-butyl, Methoxy, ethoxy, amino, acetylamino, NO ₂ , CF ₃ , OCF ₃ or CN may be substituted, or two substituents from R ⁸ and R ⁹ or R ¹¹ and R ^{12 may be} linked to form a five- or six-membered ring, which can be interrupted by O or N,

R 10 is hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms, or phenyl, where the phenyl radical is monosubstituted to triple by F, Cl Br, hydroxy, methyl, ethyl, n-propyl, i-propyl, n-butyl, see -Butyl, i-butyl, t-butyl, methoxy, ethoxy, amino, acetylamino, NO ₂ , CF ₃ , OCF ₃ or CN;

and / or the cyclic radicals in each case one to three times by phenyl or a heterocycle from the group

can be substituted, which directly or via a group from O, S, SO, SO ₂ , NR ⁴ , SO ₂ NR ⁷ ,

CONR, straight-chain or branched alkylene, straight-chain or branched alkenediyl, straight-chain or branched alkyloxy, straight-chain or branched oxyalkyloxy, straight-chain or branched sulfonylalkyl, straight-chain or branched thioalkyl, each having up to 4 carbon atoms, and can be bonded one to three times by straight-chain or branched alkyl, straight-chain or branched alkoxy, branched or branched alkoxy straight-chain or branched haloalkyl or straight-chain or branched alkenyl each having up to 4 carbon atoms, F, CI, Br, I, CN, SCH ₃ , OCF ₃ , NO ₂ , NR ⁸ R ⁹ or NR ¹⁴ COR ¹⁷ can be substituted,

embedded image in which

R ¹⁴ denotes hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms or cycloalkyl having 3 to 8 carbon atoms,

and

R ^{17 is} hydrogen, straight-chain or branched alkyl having up to 12 carbon atoms, straight-chain or branched alkenyl having up to

12 carbon atoms, aryl with 6 to 10 carbon atoms, an aromatic heterocycle with 1 to 9 carbon atoms and up to 3 heteroatoms from the series S, N and / or O or cycloalkyl with 3 to 8 carbon atoms, which may also be represented by F, CI Br , Hydroxy, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-

Butyl, i-butyl, t-butyl, methoxy, ethoxy, amino, acetylamino, NO ₂ , CF ₃ , OCF ₃ or CN may be substituted;

and / or the cyclic radicals having an aromatic or saturated carbocycle having 1 to 10 carbon atoms or an aromatic or saturated heterocycle with 1 to 9 carbon atoms and up to 3 heteroatoms from the series S, N and or O can be fused,

R ^{3 represents} hydrogen, methyl or fluorine,

m represents an integer from 1 to 4,

W denotes CH ₂ , -CH ₂ CH ₂ -, CH ₂ CH ₂ CH ₂₎ CH = CHCH ₂ ,

U -CH ₂ - means

A is phenyl, pyridyl, thienyl or thiazolyl, which is optionally one to three times by methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, CF ₃ , methoxy, Ethoxy, F, CI, Br can be substituted,

R ^{2 means} COOR ²⁴

embedded image in which

R ^{24 is} hydrogen or straight-chain or branched alkyl with up to 4

Carbon atoms means

X denotes straight-chain or branched alkylene with up to 8 carbon atoms or straight-chain or branched alkenediyl with up to 8 carbon atoms, each of which may contain one to three groups from phenyl, phenyloxy, O, CO or CONR ³⁰ ,

embedded image in which R ³⁰ denotes hydrogen, straight-chain or branched alkyl having up to 6 carbon atoms or cycloalkyl having 3 to 6 carbon atoms,

n represents 1 or 2;

R ^{1 means} COOR ³⁵ ,

embedded image in which

R ^{35 is} hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms.

Compounds of the formula (I) are very particularly preferred here:

embedded image in which

for a cyclic radical from the group consisting of

the radicals V and W can be bonded to any carbon atom or to any nitrogen atom of a ring which may be present;

O means

straight-chain or branched alkylene with up to 9 carbon atoms or straight-chain or branched alkenediyl or straight-chain or branched Alkynediyl having up to 4 carbon atoms, which can be simply substituted by halogen,

Y H, cyclohexyl, phenyl or a heterocycle from the group

means, the cyclic radicals in each case one to three times by straight-chain or branched alkyl, straight-chain or branched alkenyl, straight-chain or branched alkynyl, straight-chain or branched alkoxy, straight-chain or branched alkoxyalkoxy, straight-chain or branched haloalkyl, straight-chain or branched haloalkoxy with in each case up to 4 carbon atoms, straight-chain or branched cycloalkyl with 3 to 6 carbon atoms, F, CI, Br, I, NO ₂ , SR ⁶ , NR ⁸ R ⁹ , NR ⁷ COR ¹⁰ or CONR ⁿ R ¹² can be substituted, embedded image in which

R ⁶ denotes hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms, or straight-chain or branched haloalkyl having up to 4 carbon atoms,

R ⁷ denotes hydrogen, or straight-chain or branched alkyl having up to 4 carbon atoms,

R ⁸ , R ⁹ , R ¹¹ and R ¹² independently of one another are hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms, or phenyl, where the phenyl radical is monosubstituted to triple by F, CI Br, hydroxy, methyl, ethyl, n - Propyl, i-propyl, n-butyl, s-butyl, i-butyl, t-butyl,

Methoxy, ethoxy, amino, acetylamino, NO ₂ , CF ₃ , OCF ₃ or CN may be substituted, or two substituents from R ⁸ and R ⁹ or R ¹¹ and R ^{12 may be} linked to form a five- or six-membered ring, which can be interrupted by O or N,

R ^{10 is} hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms, or phenyl, where the phenyl radical is monosubstituted to triple by F, Cl Br, hydroxy, methyl, ethyl, n-propyl, i-propyl, n-butyl, see -Butyl, i-butyl, t-butyl,

Methoxy, ethoxy, amino, acetylamino, NO ₂ , CF ₃ , OCF ₃ or CN may be substituted;

and / or the cyclic radicals in each case one to three times by phenyl or a heterocycle from the group

Can be substituted, which are directly or via a group of O, S, SO, SO ₂ , straight-chain or branched alkylene, straight-chain or branched alkenediyl, straight-chain or branched alkyloxy, straight-chain or branched oxyalkyloxy, straight-chain or branched sulfonylalkyl, straight-chain or branched thio each can have up to 4 carbon atoms bonded and one to three times by straight-chain or branched alkyl, straight-chain or branched alkoxy, straight-chain or branched alkoxyalkoxy, straight-chain or branched haloalkyl or straight-chain or branched alkenyl each having up to 4 carbon atoms, F, CI, Br, I, CN, SCH ₃ , OCF ₃ , NO ₂ , NR ⁸ R ⁹ or NR ^I4 COR ¹⁷ can be substituted,

Wonn

R 14 denotes hydrogen, straight-chain or branched alkyl having up to 6 carbon atoms or cycloalkyl having 3 to 6 carbon atoms, and

R ^{17 is} hydrogen, straight-chain or branched alkyl having up to 6 carbon atoms, straight-chain or branched alkenyl having up to

6 carbon atoms, aryl with 6 to 10 carbon atoms, an aromatic heterocycle with 1 to 9 carbon atoms and up to 3 heteroatoms from the series S, N and or O or cycloalkyl with 3 to 6 carbon atoms, which may also be represented by F, CI Br, Hydroxy, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-

Butyl, i-butyl, t-butyl, methoxy, ethoxy, amino, acetylamino, NO ₂ , CF ₃ , OCF ₃ or CN may be substituted;

and / or the cyclic radicals can be fused with an aromatic or saturated carbocycle with 1 to 10 carbon atoms or an aromatic or saturated heterocycle with 1 to 9 carbon atoms and up to 3 heteroatoms from the series S, N and / or O,

R represents hydrogen, methyl or fluorine,

m represents an integer from 1 to 2,

W -CH ₂ - or -CH ₂ CH ₂ - means

U -CH ₂ - means

A is phenyl, which is optionally one to three times by methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, CF ₃ , methoxy, ethoxy, F, CI, Br can be substituted

R ^{2 means} COOR ²⁴ embedded image in which

R ²⁴ denotes hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms,

means straight-chain or branched alkylene with up to 6 carbon atoms or straight-chain or branched alkenediyl with up to 6 carbon atoms, each of which may contain one to three groups from phenyloxy, O, CO or CONR ³⁰ ,

embedded image in which

R ³⁰ denotes hydrogen, straight-chain or branched alkyl having up to 6 carbon atoms or cycloalkyl having 3 to 6 carbon atoms,

n represents 1 or 2;

R ^{1 means} COOR ³⁵ ,

embedded image in which

R ^{35 is} hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms.

According to the invention, particular preference is given to compounds of the formula (I) in which R ¹ and R ^{2 are} each COOH.

According to the present invention, compounds in which for a cyclic radical from the group consisting of

the radicals V and W can be bonded to any carbon atom or to any nitrogen atom of a ring which may be present;

V O means

Q means CH ₂

Y is phenyl which is substituted by a radical selected from the group consisting of 2-phenylethyl, cyclohexyl, 4-chlorophenyl, 4-methoxyphenyl,

4-trifluoromethylphenyl, 4-cyanophenyl, 4-chlorophenoxy, 4-methoxyphenoxy, 4-trifluoromethylphenoxy, 4-cyanophenoxy, 4-methylphenyl is selected,

R ^{3 represents} hydrogen, methyl or fluorine,

m represents an integer from 1 to 2,

W -CH ₂ CH ₂ - means

U -CH ₂ - means

A means phenyl

R ² means COOH, where R ^{2 is} in the 4-position to the rest U,

X means (CH ₂ )

R ¹ means COOH. Also particularly preferred according to the present invention are compounds in which

Z for a cyclic radical from the group consisting of

the radicals V and W can be bonded to any carbon atom or to any nitrogen atom of a ring which may be present;

V is missing,

Q means CH ₂ O which is bonded to Z via its carbon atom,

Y is phenyl which is substituted by a radical selected from the group consisting of 2-phenylethyl, cyclohexyl, 4-chlorophenyl, 4-methoxyphenyl, 4-trifmormethylphenyl, 4-cyanophenyl, 4-chlorophenoxy, 4-methoxyphenoxy, 4-trifluoromethylphenoxy, 4-cyanophenoxy, 4-methylphenyl, 4-tert-butylphenyl, 4-carboxyphenyl, 4-fluorophenyl, 3-methoxyphenyl, 2,4-dichlorophenyl is selected,

R ^{3 represents} hydrogen, methyl or fluorine,

m represents an integer from 1 to 2,

W -CH ₂ CH2- means

U -CH ₂ - means

A means phenyl

R means COOH, where _{R2 is arranged} in 4 position to the rest U,

X means (CH ₂ ) ₄ ,

R ¹ means COOH. The compounds of the general formula (I) according to the invention can also be present in the form of their salts. In general, salts with organic or inorganic bases or acids may be mentioned here.

Physiologically acceptable salts are preferred in the context of the present invention. Physiologically acceptable salts of the compounds according to the invention can be salts of the substances according to the invention with mineral acids, carboxylic acids or sulfonic acids. For example, particular preference is given to Salts with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid.

Physiologically acceptable salts can also be metal or ammonium salts of the compounds according to the invention which have a free carboxyl group.

For example, particular preference is given to Sodium, potassium, magnesium or calcium salts, as well as ammonium salts derived from ammonia, or organic amines such as ethylamine, di- or triethylamine, di- or triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine or ethylenediamine.

The compounds according to the invention can exist in stereoisomeric forms which either behave like image and mirror image (enantiomers) or do not behave like image and mirror image (diastereomers). The invention relates both to the enantiomers or diastereomers and to their respective mixtures. Like the diastereomers, the racemic forms can be separated into the stereoisomerically uniform constituents in a known manner, for example by racemate resolution or chromatographic separation. Double bonds present in the compounds according to the invention can be in the eis or trans configuration (Z or E form). In the context of the present invention, unless otherwise stated, the substituents generally have the following meaning:

Alkyl generally represents a straight-chain or branched hydrocarbon radical having 1 to 20 carbon atoms. For example, methyl, ethyl, propyl,

Isopropyl, butyl, isobutyl, pentyl, isopentyl, hexyl, isohexyl, heptyl, isoheptyl, octyl and isooctyl, nonyl, decyl, dodeyl, eicosyl.

Alkylene generally stands for a straight-chain or branched hydrocarbon bridge with 1 to 20 carbon atoms. For example, methylene, ethylene,

Propylene, α-methylethylene, ß-methylethylene, α-ethylethylene, ß-ethylethylene, butylene, α-methylpropylene, ß-methylpropylene, γ-methylpropylene, α-ethylpropylene, ß-ethylpropylene, γ-ethylpropylene, pentylene, hexylene, heptylene, Called octylene, nonylene, decylene, dodeylene and eicosylene.

Alkenyl generally represents a straight-chain or branched hydrocarbon radical having 2 to 20 carbon atoms and one or more, preferably one or two, double bonds. Examples include allyl, propenyl, isopropenyl, butenyl, isobutenyl, pentenyl, isopentenyl, hexenyl, isohexenyl, heptenyl, isoheptenyl, octenyl and isooctenyl.

Alkynyl generally represents a straight-chain or branched hydrocarbon radical having 2 to 20 carbon atoms and one or more, preferably with one or two triple bonds. Examples include ethynyl, 2-butynyl, 2-pentynyl and 2-hexynyl.

Alkenediyl generally represents a straight-chain or branched hydrocarbon bridge with 2 to 20 carbon atoms and one or more, preferably with one or two, double bonds. For example, ethene-1,2-diyl, propene-1,3-diyl, propene-1,2-diyl, 1-butene-1,4-diyl, 1-butene-1,3-diyl, 1-butene- l, 2-diyl, 2-butene

1, 4-diyl, 2-butene-l, 3-diyl, 2-butene-2,3-diyl called. Alkindiyl generally represents a straight-chain or branched hydrocarbon bridge with 2 to 20 carbon atoms and one or more, preferably with one or two triple bonds. Examples include ethyne-1,2-diyl, propyne-1,3-diyl, l-butyne-1,4-diyl, l-butyne-1,3-diyl, 2-butene-1,4-diyl.

Acyl generally represents straight-chain or branched lower alkyl having 1 to 9 carbon atoms, which is bonded via a carbonyl group. Examples include: acetyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, butylcarbonyl and isobutylcarbonyl.

Alkoxy generally represents a straight-chain or branched hydrocarbon radical having 1 to 14 carbon atoms which is bonded via an oxygen atom. Examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentoxy, isopentoxy, hexoxy, isohex oxy, heptoxy, isoheptoxy, octoxy or iso-octoxy. The terms "alkoxy" and "alkyloxy" are used synonymously.

Alkoxyalkyl generally represents an alkyl radical having up to 8 carbon atoms which is substituted by an alkoxy radical having up to 8 carbon atoms.

Alkoxycarbonyl can, for example, by the formula

- C - O alkyl

II O are shown.

Alkyl here generally represents a straight-chain or branched hydrocarbon radical having 1 to 13 carbon atoms. Examples include the following alkoxycarbonyl radicals: methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl or isobutoxycarbonyl. Cycloalkyl generally represents a cyclic hydrocarbon radical having 3 to 8 carbon atoms. Cyclopropyl, cyclopentyl and cyclohexyl are preferred. Examples include cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

Cycloalkoxy in the context of the invention is an alkoxy radical whose hydrocarbon radical is a cycloalkyl radical. The cycloalkyl radical generally has up to 8 carbon atoms. Examples include: cyclopropyloxy and cyclohexyloxy. The terms "cycloalkoxy" and "cycloalkyloxy" are used synonymously.

Aryl generally represents an aromatic radical having 6 to 10 carbon atoms. Preferred aryl radicals are phenyl and naphthyl.

Halogen in the context of the invention represents fluorine, chlorine, bromine and iodine.

In the context of the invention, heterocycle generally represents a saturated, unsaturated or aromatic 3- to 10-membered, for example 5- or 6-membered, heterocycle which can contain up to 3 heteroatoms from the series S, N and or or and which in the case of a nitrogen atom can also be bound via this. Examples include: oxadiazolyl, thiadiazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, furyl, pyrrolyl, pyrrolidinyl, piperazinyl,

Tetrahydropyranyl, tetrahydrofuranyl, 1,2,3 triazolyl, thiazolyl, oxazolyl, imidazolyl, morpholinyl or piperidyl. Thiazolyl, furyl, oxazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidinyl, pyridazinyl and tetrahydropyranyl are preferred. The term "heteroaryl" (or "hetaryl") stands for an aromatic heterocyclic radical.

In the heterocycle structures shown in the present application, only one bond to the neighboring group is indicated, for example in the heterocycle structures which are suitable for Y, the bond to the unit Q. Independently of this, however, these heterocycle structures can carry further substituents as indicated. The present invention further relates to a process for the preparation of the compounds of the formula (I), characterized in that

[A] Compounds of Formula (11)

with compounds of the formula (HI)

E-X-R (HI)

implements,

embedded image in which

Z, R, 1, r R> 2, V, Q, Y, W, X, U, A and m have the same meanings as defined above,

E either represents a leaving group which is substituted in the presence of a base or is an optionally activated hydroxy function;

or

[B] Compounds of Formula (IV)

with compounds of formula (V)

implements,

embedded image in which

Z, R ¹ , R ² , R ³ , V, Q, Y, W, X, U, A and m have the same meanings as defined above,

E either represents a leaving group which is substituted in the presence of a base or is an optionally activated hydroxy function;

or

[C] compounds of the formula (VI)

with compounds of the formula (VE)

Implements E-U-A-R '(VE),

embedded image in which

Z, R ¹ , R ² , R ³ , V, Q, Y, W, X, U, A and m have the same meanings as defined above,

E either represents a leaving group which is substituted in the presence of a base or is an optionally activated hydroxy function;

or

[D] compounds of the formula (VHI),

wherein Va stands for O or S and

Z, R ¹ , R ² , R ³ , Y, Q, W, U, A, X and m have the meaning given above

with compounds of formula (D)

^Y (IX) implements

embedded image in which

Q, Y have the same meanings as defined above,

E either represents a leaving group which is substituted in the presence of a base or is an optionally activated hydroxy function:

or

[E] compounds of the formula (X),

embedded image in which Z, R ³ , V, Q, Y, W, X, U, A and m have the same meanings as defined above,

R ^ and R ² _b each independently represent CN or COO Alk, where Alk represents a straight-chain or branched alkyl radical having up to 6 carbon atoms,

converted into the corresponding free carboxylic acids with aqueous solutions of strong acids or strong bases.

or

[F] Compounds of Formula (XI)

embedded image in which

Z, R, R> 2, R, V, Q, X, W, U, A and m have the same meanings as defined above,

represents Br, I or the group CF SO ₂ -O,

with compounds of the formula (XU)

MZ '(XII) embedded image in which

M represents an aryl or heteroaryl radical, a straight-chain or branched alkyl, alkenyl or alkynyl radical or cycloalkyl radical or an arylalkyl, an arylalkenyl or an arylalkynyl radical,

Z 'represents the groupings -B (OH) ₂ , -CH≡CH, -CH = CH ₂ or -Sn (nBu) ₃

in the presence of a palladium compound, optionally additionally in the presence of a reducing agent and other additives and in the presence of a base;

or

[G] compounds of the formula (XIII)

Ar represents an aryl or heteroaryl radical,

E represents a leaving group which is substituted in the presence of a base according to process D with compounds of the formula (VTfl) and the compounds of the formula (XIV) thus obtained

hydrogenated with hydrogen in the presence of a catalyst.

The processes according to the invention for the preparation of compounds of the formula (I) are illustrated below using exemplary, non-limiting embodiments:

Example of reaction sequence according to method A / E:

Example of reaction sequence according to method D / E:

Example of reaction sequence according to method B / E:

Example of reaction sequence according to method C / E:

Preferably R = t-Bu

Example of reaction sequence according to method D / F / E

Example of reaction sequence according to method D / G / E

hydrogenation

Alternatively, the compounds of the formula (I) can also be prepared on a solid phase, such as a polystyrene resin, particularly preferably a commercially available Wang polystyrene resin. The resin is initially dissolved in a swollen like dimethylformamide (DMF). The corresponding carboxylic acid serving as the starting compound is then bound to the resin by standard methods. For example, the carboxylic acid can be bound to the resin in the presence of a base such as pyridine or 4-dimethylaminopyridine (DMAP) and a reagent which activates the carboxyl unit, such as an acid halide, for example dichlorobenzoyl chloride, in a solvent such as dimethylformamide (DMF). However, other reagents conventionally used for this purpose can also be used. The reaction mixture is left to stir for at least 2 hours, preferably 12 hours, particularly preferably about 24 hours, at room temperature and normal pressure, the carboxylic acid being used in excess, preferably in a two to three-fold excess, with respect to the loading of the solid phase.

After removal of any unreacted reagents, the carboxylic acid bound to the resin can be derivatized without having to be separated from the resin beforehand. For example, a corresponding 4-aminobenzoic acid or 4-formylbenzoic acid derivative can be attached to the resin, then via successive reductive amination reactions, as described below for the preparation of the compounds of the formula (II), (IV) and (VI) a compound of the formula (VUI) are reacted, which can then be converted into the target compounds on the solid phase analogously to process [D].

The resin is split off after the desired structure of the target compound on the solid phase in a conventional manner in an acidic environment. The product separated from the resin can, after removal of any solvents which may be present, be purified by known purification processes, such as, for example, chromatographic processes. The following schemes illustrate possible solid-phase syntheses of compounds of the formula (I), although other synthetic routes known to the person skilled in the art or known from the literature are also possible:

Example A for solid phase synthesis:

Wang stands for a Wang polystyrene resin. Example B for solid phase synthesis:

2 ⁾ r _Z 1 * Br ^ 1 ^ P ^y r ^ »- V (- Z) = _c 0 ^ → l ^Z ) ^ OH - / ^* OH έ AICI3 _ -o DIBAH _ ^ ₀

Lett, 1996 37 4819

Wang stands for a Wang polystyrene resin.

Preferred solvents for the processes according to the invention are conventional organic solvents which do not change under the reaction conditions or water. For the process according to the invention, ethers such as diethyl ether, butyl methyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, or hydrocarbons such as benzene, toluene, xylene or petroleum ether, or amides such as dimethylformamide or hexamethylphosphorium triamide, or 1,3-dimethyl-2-imidazole are preferably used for the process according to the invention -on, 1, 3-dimethyl-tetrahydro- pyrimidin-2-one, acetonitrile, ethyl acetate or dimethyl sulfoxide can be used. It is of course also possible to use mixtures of the abovementioned solvents.

The bases preferred for the processes according to the invention comprise basic compounds conventionally used for basic reactions. Alkali metal hydrides such as sodium hydride or potassium hydride, or alkali metal alcoholates such as sodium methoxide, sodium ethanolate, potassium methoxide, potassium ethanolate or potassium t-butoxide, or carbonates such as sodium carbonate, cesium carbonate or potassium carbonate or amides such as sodium amide or lithium diisopropylamide, or organolith such as phenyllithium, butyllithium or methyl lithium or sodium hexamethyldisilazane can be used.

Processes A to C according to the invention can preferably be carried out in acetonitrile in each case by reaction of the compounds (II) and (UT), (TV) and (V) or (VI) and (VII) in the presence of a base such as sodium carbonate, Et ₃ N, DABCO , K ₂ CO ₃ , KOH, NaOH or NaH can be carried out. The reaction can generally be carried out in a temperature range from -20 ° C. to + 90 ° C., preferably from 0 ° C. to + 70 ° C. The reaction can be carried out at normal pressure, elevated or reduced pressure (for example in a range from 0.5 to 5 bar). In general, the reaction is carried out at normal pressure.

In processes A to C according to the invention, a compound of the formula (I) is replaced by nucleophilic substitution of a leaving group E in one of the compounds of the

Formula (HI), (V) or (VII) represented by the amine function of one of the compounds of formula (II), (IV) or (VI). The following leaving groups E are, for example: halogen, tosylate, mesylate, or a hydroxyl function activated by reagents such as diisopropylazodicarboxylate / PPh ₃ (Mitsonobu reaction). Process D according to the invention can preferably be carried out in acetonitrile by reaction of the compounds (VTH) and (IX) in the presence of a base such as sodium carbonate, potassium carbonate, Et ₃ N, DABCO, K ₂ CO ₃ , KOH, NaOH or NaH. The reaction can generally be carried out in a temperature range from -20 ° C. to + 90 ° C., preferably from 0 ° C. to + 90 ° C. The reaction can be carried out at normal pressure, elevated or reduced pressure (for example in a range from 0.5 to 5 bar). In general, the reaction is carried out at normal pressure.

In process D according to the invention, a compound of the formula (I) is prepared by nucleophilic substitution of a leaving group E in the compound of the formula (LX) by the hydroxyl or thiol function of the compound of the formula (Viπ). The following leaving groups E are, for example: halogen, tosylate, mesylate, or a hydroxyl function activated by reagents such as diisopropylazodicarboxylate / PPh ₃ (Mitsonobu reaction).

In process E according to the invention, a compound of the formula (I) in which R ¹ and R ² each represent a free carboxyl function is obtained by converting ester and / or nitrile functions of the compound (X) into the corresponding free carboxyl functions. This reaction can be carried out, for example, by adding aqueous solutions of strong acids such as HC1 or H ₂ SO ₄ , or strong bases such as NaOH, KOH or LiOH. The reaction can be carried out in one of the abovementioned organic solvents, in water or in mixtures of organic solvents or in mixtures of organic solvents with water. According to the invention, for example, is preferred

Carrying out the reaction in a mixture of water and methanol or dioxane. The reaction can generally be carried out in a temperature range from -20 ° C. to + 90 ° C., preferably from 0 ° C. to + 90 ° C. The reaction can be carried out at normal pressure, elevated or reduced pressure (for example in a range from 0.5 to 5 bar). In general, the reaction

Normal pressure executed. In process F according to the invention, a compound of the formula (I) is reacted by reacting a compound of the formula (XI) which contains a substitutable group L with a compound of the group (XII) in the presence of a palladium compound and, if appropriate, a reducing agent and other additives represented in basic medium. The reaction formally represents a reductive coupling of the compounds of the formulas (XI) and (XII), as described, for example, in LS Hegedus, Organometallics in Synthesis, M. Schlosser, Ed., Wiley & Sons, 1994.

As the substitutable group L in the compounds of the formula (XI), for example a halogen radical such as Br or I or a conventional leaving group such as a triflate radical can be used.

The compounds of formula (XH) contain a reactive group Z, which can be selected from the group consisting of -B (OH) ₂ , -CH≡CH, -CH = CH ₂ or -Sn (nBu) ₃ .

A palladium (II) compound such as Cl ₂ Pd (PPh ₃ ) ₂ or Pd (OAc) ₂ or a palladium (O) compound such as Pd (PPh ₃ ) ₄ or Pd ₂ (dba) ₃ can be used as the palladium compound become. If necessary, a reducing agent such as triphenylphosphine or other additives such as Cu (I) Br, NBu ₄ NCl, LiCl or Ag ₃ PO ₄ can also be added to the reaction mixture (cf. T Jeffery, Tetrahedron lett. 1985, 26, 2667-2670; T. Jeffery, J. Chem. Soc, Chem. Commun. 1984, 1287-1289; S. Bräse, A. deMejiere in "Metal-catalyzed cross-coupling reactions", Ed. F. Diederich, PJ Stang , Wiley-VCH,

Weinheim 1998, 99-166).

The reaction is carried out in the presence of a conventional base such as Na ₂ CO ₃ , NaOH or triethylamine. Suitable solvents are the organic solvents mentioned above, ethers such as dimethoxyethane being particularly preferred. The reaction can generally be in one Temperature range from -20 ° C to + 90 ° C, preferably from 0 ° C to + 90 ° C. The reaction can be carried out at normal pressure, elevated or reduced pressure (for example in a range from 0.5 to 5 bar). In general, the reaction is carried out at normal pressure.

In process G according to the invention, compounds of the formula (I) are obtained by reacting compounds of the formula (XIH) which contain a leaving group E with compounds of the formula (VIII) according to the process D according to the invention and the compounds of the formula (XIV ) then hydrogenated.

The first step of process G thus proceeds analogously to process D, with compounds of the formula (XIH) being reacted with the alcohols or thiols of the formula (XIII) here instead of the compounds of the formula (IX). The unsaturated compounds of the formula (XIV) are thus obtained, which can be converted into the compounds of the formula (I) by conventional hydrogenation processes.

The hydrogenation of the compounds of the formula (XIV) with hydrogen in the presence of a catalyst such as, for example, Pd carbon or PtO _{2 is} preferred.

Process G can be carried out in one of the above-mentioned organic solvents. Ethyl acetate is preferred. The reaction can generally be carried out in a temperature range from -20 ° C. to + 90 ° C., preferably from 0 ° C. to + 90 ° C. The reaction can be carried out at normal pressure, elevated or reduced pressure (for example in a range from 0.5 to 5 bar). In general, the reaction is carried out at normal pressure.

The new compounds of the formula II, IV and VI can be obtained in a generally known manner by the following methods: by reaction of amines of the formulas (XV), (XVI) and (XVπ)

NH ₂ (XVI)

^* A— R '

NR, (XVII)

X

^* R '

where the radicals R ² , R ³ , m, V, Q, U, W, X, Y and A have the meanings given above;

with carbonyl compounds of the formulas (XVm), (XIX), (XX)

(XVIII)

in which

Ua, Wa and Xa have the meaning of U, W and X, but are shortened by one carbon unit, and

T represents hydrogen or a -CC alkyl function, which can also be linked to Ua or Xa to form a cycle, and the other radicals are as defined above,

first converted to a Schiff base and then reduced with common reducing agents such as NaBH, H ₂ / Pd / C etc. or directly under the conditions of reductive alkylation in the presence of a reducing agent such as H ₂ / PαVC, NaCNBH ₃ , NaH (OAc) ₃ (cf. Patai, Ed., The Chemistry of the Carbon-Nitrogen Double Bond, pp. 276-293 and the literature cited therein);

b) by reacting amines of the formulas (XV), (XVI) and (XVII) with compounds of the formulas (ET), (V), (VE) (see, for example, J. March, Advanced Organic Chemistry, fourth edition, Wiley , 1992, page 411 and the literature cited therein).

Amines of the formula (inter alia) or compounds of the formula (VHI),

where Va is O or S,

can be obtained in a generally known manner according to the following reaction scheme:

(XXIII) (Ha)

"E-Q-Y (IX), base alkylation

(XXII) _{1 1} cleavage -PGo O or S protective group

(XVa) (XVIII)

E-X-R1 (III), base alkylation

(VIII) (XXI) In the above scheme, PGo stands for a common phenol or thiophenol protecting group, such as CH ₃ , CH ₂ Ph, CH ₂ CH = CH ₂ , CH ₂ OCH ₃ , CH ₂ OCH ₂ SiMe ₃ , SiMe ₃ , PGn an amine protecting group, such as, for example, tBuOCO, T for hydrogen or a C ₁ -C 6 -alkyl function, which can also be linked to form a cycle with Ua, and Ua has the meaning of U, but is shortened by one CH ₂ group. The other residues are as defined above.

(Ilb) is obtained, for example, by first reacting (XVa) with (XVIII) to form a Schiff base and then reducing it with common reducing agents, such as NaBH, H ₂ / Pd / C etc., or directly under the conditions of a reductive one

Alkylation in the presence of a reducing agent, such as H ₂ / Pd / C, NaCNBH ₃ or NaH (OAc) ₃ . The compound (üb) can be converted into a compound of the formula by reaction with a compound of the formula (DI) in the presence of a base

(XXI) are transferred (cf. Method A).

An O or S protective group in (Hb) or (XXI) can be split off with a suitable reagent (cf. TW Greene, PGM Wuts, Protective Groups in Organic Synthesis, second edition, New York, 1991). If, for example in formula (IIb) or (XXI) -Va-PGo, stands for -O-CH ₃ , the methyl group can be formed at -70 to 20 ° C. with the formation of the phenol by boron tribromide in methylene chloride

Remove trimethylsilyl iodide in chloroform at 25-50 ° C or by sodium ethyl thiolate in DMF at 150 ° C.

A compound of formula (XXIII) can be obtained from the compound of formula (IIc) thus obtained by protecting the amino function (see also T.W. Greene, P.G.M.

Wuts, Protective Groups in Organic Synthesis, second edition, New York, 1991) and subsequent implementation of the amine-protected compound of the formula thus obtained

(XXII) with a compound of formula (IX) obtained (see. Method D).

An N-protecting group as in (XXII) can be introduced and removed using standard methods (cf. TW Greene, PGM Wuts, Protective Groups in Organic Synthesis, second edition, New York, 1991). For example, in formula (XXII) PGn stands for fßuOCO, the protective group can be introduced by reacting the amine with tert-butyl pyrrocarbonate in polar or non-polar solvents at 0 ° C to 25 ° C. The protecting group can be split off to (Ila) using numerous acids, such as, for example, HC1, H ₂ SO ₄ or CF ₃ COOH, at from 0 ° to 25 ° C. (cf. literature cited above).

Substances of the formulas (III) are commercially available, known from the literature or can be synthesized by processes known from the literature (cf. e.g. J. Chem. Soc. 1958, 3065).

Substances of the formulas (V) are known from the literature or can be synthesized analogously to processes known from the literature (cf., for example, J. Med. Chem. 1989, 32, 1757; Indian J. Chem. Sect. B 1985, 24, 1015; Recl. Trav.Chim.Pays-Bas 1973, 92, 1281; Terahedron Lett. 1986, 37, 4327).

Substances of the formula (VII) are commercially available, known from the literature, or can be synthesized analogously to processes known from the literature (cf., for example, J. Org. Chem. 1959, 24, 1952; Collect Czech. Chem. Commun 1974, 39, 3527; Helv Chim. Acta 1975, 58, 682; Liebigs Ann. Chem. 1981, 623).

Substances of the formula (IX) are commercially available, known from the literature, or can be synthesized analogously to processes known from the literature (cf., for example, J. Prakt. Chem. 1960, 341; Farmaco Ed. Sei. 1956, 378; Eur. J. Med. Chem. Chim. Ther. 1984, 19, 205; Bull. Soc. Chim. Fr. 1951, 97. Liebigs Ann. Chem. 1954, 586,

52; EP-A-0 334 137). In particular, 4-chloromethylbiphenyl compounds which carry a further substituent in the 4'-position can be obtained by coupling 4- (B (OH) ₂ - Ph-CHO with the corresponding bromophenyl compounds substituted in the 4-position in the presence of palladium catalysts, such as for example Pd (PPh ₃ ) or PdCl ₂ (PPh3) 2 and sodium carbonate to the corresponding biphenyl Compounds and subsequent reduction to alcohol with NaBH ₄ and conversion to the corresponding chloride with SOCl ₂ are prepared.

If in formulas (III), (V), (VII) and (IX) E is halogen, the compounds can also be prepared by generally known methods, e.g. by reacting an alcohol with a chlorination reagent, e.g. Thionyl chloride or sulfuryl chloride can be produced (see e.g. J. March, Advanced Organic Chemistry, fourth edition, Wiley, 1992, page 1274 or the literature cited therein).

Amines of the formula (XV) are commercially available, known from the literature, or can be synthesized analogously to processes known from the literature (cf., for example, Tetrahedron 1997, 53, 2075; J. Med. Chem. 1984, 27, 1321; WO97 / 29079; J. Org. Chem. 1982, 47, 5396). For example, these compounds can be selected from the corresponding halide compounds and in particular chloride compounds in which a W'-Hal group is used instead of the W-NH ₂ radicals of the compounds of the formula (XV), where W 'is a radical W shortened by one C atom, by substitution of the halide residue by a cyano group to obtain the corresponding nitrile compounds and reduction of the nitrile group or by reaction of corresponding aldehyde compounds in which instead of the residues W-NH _{2 of} the compounds of the formula (XV) there is a group W'-CHO, where W represents a radical W shortened by one carbon atom, can be obtained with nitromethane and subsequent reduction. A few exemplary synthetic routes for the amines of the formula (XV) are listed below, the reagents indicated generally representing only one of several possibilities. For example, a reduction reaction from aldehyde to alcohol groups, substitution of alcohol groups by halogen groups, substitution of halogen functions by nitrile groups, or reductions of nitrile groups to corresponding amino groups can be carried out with all reactants conventionally used for such reactions (cf. e.g. the corresponding chapter in March, Advanced Organic Chemistry, Wiley, 3 ^, ed., 1985). In the exemplary synthetic routes listed below, the radicals given have the same meaning as defined above.

Synthesis: g a):

Synthesis route b):

LiAIH ₄ or BH ₃

This synthetic route can be used, for example, starting from commercially available or known hydroxycarboxylic acids:

Synthesis route c):

LiAIH ₄ or BH ₃

In the synthesis routes a) to d), the corresponding hydroxycarboxylic acids or hydroxycarnonic esters can also be used instead of the hydroxyaldehydes become. Furthermore, in these synthetic routes, the conversion of the primary hydroxyl group into the nitrile group can also be carried out via the corresponding bromide, mesylate, tosylate or acetate instead of via the corresponding halide.

Synthetic route d):

LiAIH ₄ or BH ₃ CH OC1

This process can be used, for example, starting from 2-hydroxynaphth-1-aldehyde, 1-hydroxymethyl-2-methoxynaphthalene or one of the following commercially available or literature-known hydroxyaldehydes:

Synthesis route e):

Synthesis route f):

LiAIH, / AICI,

Synthesis route g)

KCN

The 2-cyanomethyl-3-hydroxypyridine is also according to Desideri et al, J. Heterocycl.

Chem. 1988, 333-335.

Synthesis route h):

Amines of the formula (XVI) are commercially available, known from the literature, or can be synthesized analogously to processes known from the literature (cf., for example, J. Am. Chem. Soc. 1982, 104, 6801; Chem. Lett. 1984, 1733; J. Med Chem. 1998, 41, 5219; DE-2059922).

Amines of the formula (XVII) are commercially available, known from the literature, or can be synthesized analogously to processes known from the literature (see, for example, J. Org. Chem. 1968, 33, 1581; Bull. Chem. Soc. Jpn. 1973, 46, 968 ; J. Am. Chem. Soc. 1958, 80, 1510; J. Org. Chem. 1961, 26, 2507; Synth. Commun. 1989, 19, 1787).

Amines of the formulas (XV), (XVI) and (XVII) can also be according to generally known

Methods, e.g. by the reduction of a corresponding nitrile, the reaction of a corresponding halide with phthalimide and subsequent reaction with hydrazine or the rearrangement of acylazides in the presence of water (see, for example, J. March, Advanced Organic Chemistry, fourth edition, Wiley, 1992, page 1276 or the literature cited there).

Carbonyl compounds of the formula (XVIII) are commercially available, known from the literature, or can be synthesized analogously to processes known from the literature (see e.g. J. Med. Chem. 1989, 32, 1277; Chem. Ber. 1938, 71, 335; Bull. Soc. Chim. Fr. 1996, 123, 679).

Carbonyl compounds of the formula (XIX) are commercially available, known from the literature, or can be synthesized in analogy to processes known from the literature,

(see e.g. WO96 / 11902; DE-2209128; Synthesis 1995, 1135; Bull. Chem. Soc. Jpn. 1985, 58, 2192).

Carbonyl compounds of the formula (XX) are commercially available, known from the literature, or can be synthesized analogously to processes known from the literature

(see e.g. Synthesis 1983, 942; J. Am. Chem. Soc. 1992, 114, 8158).

Carbonyl compounds of the formulas (XVIII), (XIX) and (XX) can also be prepared by generally known methods, e.g. by oxidation of alcohols, the reduction of acid chlorides, or the reduction of nitriles (see e.g. J.

March, Advanced Organic Chemistry, fourth edition, Wiley, 1992, page 1270 or the literature cited therein).

Compounds of the formula (XII) are commercially available, known from the literature, or can be synthesized analogously to processes known from the literature (see, for example, for aromatic boronic acids: J.Chem.Soc.C 1966, 566. J.Org.Chem., 38, 1973 , 4016; or for tributyltin compounds: Tetrahedron Lett. 31, 1990, 1347).

Compounds of the formula (XIII) are commercially available, known from the literature, or can be synthesized analogously to processes known from the literature (cf. e.g.

J. Chem. Soc. Chem. Commun., 17, 1994, 1919).

The compounds according to the invention, in particular the compounds of the general formula (I), show an unforeseeable, valuable spectrum of pharmacological activity. The compounds according to the invention, in particular the compounds of the general formula (I), lead to vascular relaxation, platelet aggregation inhibition and to a reduction in blood pressure and to an increase in the coronary blood flow. These effects are mediated by direct stimulation of soluble guanylate cyclase and an intracellular increase in cGMP.

They can therefore be used in medicines for the treatment of cardiovascular diseases such as, for example, for the treatment of high blood pressure and heart failure, stable and unstable angina pectoris, peripheral and cardiac vascular diseases, of arrhythmias, for the treatment of thromboembolic diseases and ischemia such as myocardial infarction, stroke, transistoric and Ischemic attacks, peripheral circulatory disorders, prevention of restenoses such as after thrombolysis therapies, percutaneous transluminal angioplasties (PTA), percutaneous transluminal coronary angioplasties (PTCA), bypass and for the treatment of arteriosclerosis, fibrotic diseases such as liver fibrosis and diseases of the pulmonary fibrosis or pulmonary fibrosis system, for example, of the uterine fibrosis or pulmonary fibrosis system, for example, of the asthma or pulmonary fibrosis system Prostate hypertrophy, erectile dysfunction, female sexual dysfunction and incontinence as well as for the treatment of glaucoma.

The compounds described in the present invention, in particular the compounds of the general formula (I), are also active compounds for combating diseases in the central nervous system which are characterized by disorders of the NO / cGMP system. In particular, they are suitable for eliminating cognitive deficits, for improving learning and memory and for treating Alzheimer's disease. They are also suitable for the treatment of diseases of the central nervous system such as anxiety, tension and depression, central nervous system-related sexual dysfunctions and sleep disorders, as well as for the regulation of pathological disorders in the intake of food, beverages and addictive substances. The active ingredients are also suitable for regulating cerebral blood flow and are therefore effective means of combating migraines.

They are also suitable for the prophylaxis and control of the consequences of cerebral infarction (apoplexia cerebri) such as stroke, cerebral ischemia and the skull.

Him trauma. The compounds according to the invention, in particular the compounds of the general formula (I), can likewise be used to combat painful conditions.

In addition, the compounds according to the invention have anti-inflammatory activity and can therefore be used as anti-inflammatory agents.

Vascular relaxant effect in vitro

Rabbits are anesthetized or killed by intravenous injection of thiopental sodium (approx. 50 mg / kg,) and exsanguinated. The saphenous artery is removed and divided into 3 mm wide rings. The rings are individually mounted on a triangular pair of hooks made of 0.3 mm special wire (Remanium®) that is open at the end. Each ring is placed in 5 ml organ baths with 37 ° C warm, carbogen-gassed Krebs-Henseleit solution of the following composition (mM): NaCl: 119; KC1: 4.8; CaCl ₂ x 2 H ₂ O: 1; MgSO ₄ x 7 H ₂ O: 1.4; KH ₂ PO ₄ : 1.2; _NaHCO3: 25; Glucose: 10; Bovine serum albumin: 0.001%. The contraction force is recorded with Statham UC2 cells, amplified and digitized via A / D converter (DAS-1802 HC, Keithley Instruments Munich), and recorded in parallel on line recorders. Contractions are induced by adding phenylephrine.

After several (generally 4) control cycles, the substance to be examined is added in increasing doses in each further run and the level of the contraction achieved under the influence of the test substance is compared with the level of the contraction achieved in the last previous run. From this, the concentration is calculated, which is necessary to achieve the contraction achieved in the pre-control Reduce 50% (IC ₅₀ ). The standard application volume is 5 μl. The DMSO proportion in the bath solution corresponds to 0.1%.

The results are shown in Table 1:

Table 1: Vascular relaxation effects in vitro

Stimulation of recombinant soluble guanylate cyclase (sGC) in vitro

The investigations into the stimulation of the recombinant soluble guanylate cyclase (sGC) and the compounds according to the invention with and without sodium nitroprusside and with and without the heme-dependent sGC inhibitor lH-1,2,4-oxadiazole- (4,3a) -quinoxalin-1- on (ODQ) were carried out according to the method described in detail in the following literature: M. Hoenicka, EM Becker, H. Apeler, T. Sirichoke, H. Schroeder, R. Gerzer and J.-P. Stasch: Purified soluble guanylyl cyclase expressed in a baculovirus / Sf9 System: Stimulation by YC-1, nitric oxide, and carbon oxide. J. Mol. Med. 77 (1999): 14-23.

The heme-free guanylate cyclase was obtained by adding Tween 20 to the sample buffer (0.5% in the final concentration). The activation of the sGC by a test substance is given as n-fold stimulation of the basal activity.

The present invention includes pharmaceutical preparations which, in addition to non-toxic, inert pharmaceutically suitable excipients, include the inventive

Contains compounds, especially the compounds of general formula (I), and processes for the preparation of these preparations.

The active ingredient can optionally also be present in microencapsulated form in one or more of the carriers mentioned above.

The therapeutically active compounds, in particular the compounds of the general formula (I), should be present in the pharmaceutical preparations listed above in a concentration of about 0.1 to 99.5, preferably about 0.5 to 95% by weight of the total mixture to be available.

In addition to the compounds according to the invention, in particular the compounds of the general formula (I), the pharmaceutical preparations listed above can also contain further active pharmaceutical ingredients.

In general, it has proven to be advantageous in both human and veterinary medicine to use the active ingredient (s) according to the invention in total amounts of about 0.5 to about 500, preferably 5 to 100 mg / kg of body weight per 24 hours, optionally in the form multiple doses to achieve the desired results. A single dose contains the one or more according to the invention

Active ingredients preferably in amounts of about 1 to about 80, in particular 3 to 30 mg / kg body weight.

The present invention is illustrated below with the aid of non-restrictive preferred examples. Unless otherwise stated, all quantities refer to percentages by weight. Examples

Abbreviations

RT: room temperature

EE: ethyl acetate

BABA: n-butyl acetate / n-butanol / glacial acetic acid / phosphate buffer pH 6

(50: 9: 25.15; original phase)

Eluents for thin layer chromatography:

T 1 E 1: toluene - ethyl acetate (1: 1)

Tl EtOHl: toluene - methanol (1: 1)

C 1 E 1: cyclohexane - ethyl acetate (1: 1) C 1 E2: cyclohexane - ethyl acetate (1: 2)

starting compounds

Example I [4- (Chloromethyl) -2,5-dimethyl-3-thienyl] acetonitrile

A solution of 2.98 g (14.24 mmol) of 3,4-bis (chloromethyl) -2,5-dimethylthiophene (Gärtner et al., J. Amer. Chem. Soc, 73, 1951, 5872) in 30 ml of dry acetonitrile is slowly added dropwise with 1.9 ml (14.24 mmol) of trimethylsilyl cyanide and 12.96 ml (14.42 mmol) of a 1-N-tetra-n-butylammonium fluoride solution in THF and stirred overnight at room temperature. Then the approach to dryness rotated in and the crude product obtained is purified by column chromatography (cyclohexane ethyl acetate 10: 1). 0.82 g (4.1 mmol, 28% yield) of a colorless oil are obtained. R _f (cyclohexane / ethyl acetate 2: 1): 0.39. 1H-NMR (200 MHz, CDC1 ₃ , δ / ppm): 4.58 (2H, s), 3.64 (2H, s), 2.42 (3H, s), 2.39

(3H, s). MS (DCI, NH ₃ ): 234 (M + N ₂ H ₇ ⁺ ), 217 (M + NH ₄ ⁺ ).

Example II {4 [(4-bromophenoxy) methyl] -2,5-dimethyl-3-thienyl} acetonitrile

A solution of 800 mg (4.33 mmol) [4- (chloromethyl) -2,5-dimethyl-3-thienyl] acetonitrile from Example I and 840 mg (4.83 mmol) 4-bromophenol in 20 ml acetonitrile 830 mg (6.04 mmol) of anhydrous potassium carbonate are added and the mixture is heated to reflux under argon for 12 h. After cooling and removing the solvent, the crude product obtained is purified by preparative HPLC and 1.149 g (3.42 mmol, 85% yield) of a colorless solid is obtained. R _f (cyclohexane / ethyl acetate 2: 1): 0.45.

Η NMR (300 MHz, DMSO-d ₆ , δ / ppm): 7.48 (2H, d), 7.01 (2H, d), 4.98 (2H, s), 3.81 (2H, s), 2.38 (3H, s), 2.36 (3H, s). MS (DCI, NH ₃ ): 353.1 (M + NH ₄ ⁺ ). Example III

2- {4 - [(4-bromophenoxy) methyl] -2,5-dimethyl-3-thienyl} ethylamine

557 mg (4.18 mmol) of aluminum trichloride are dissolved in 10 ml of THF, cooled to 0 ° C. under argon and slowly mixed with 2.81 ml of a lithium aluminum hydride solution (IM in THF). A solution of 937 mg (2.79 mmol) {4 [(4-bromophenoxy) methyl] -2,5-dimethyl-3-thienyl} acetonitrile from Ex. Π in 10 ml THF is slowly added dropwise to the reaction solution. After stirring for 2 h at room temperature, the reaction solution is cooled to 0 ° C. and quenched with ice water, made basic with sodium hydroxide solution, extracted with ethyl acetate and dried over magnesium sulfate. After removing the solvent, the crude product obtained is purified by preparative HPLC and 693 mg (2.04 mmol, 73% yield) of a colorless oil are obtained.

R _f (dichloromethane methanol 10: 1): 0.26.

Η NMR (300 MHz, DMSO-d ₆ , δ / ppm): 7.48 (2H, d), 7.0 (2H, d), 4.86 (2H, s), 3.3

(2H, broad s), 2.65-2.52 (4H, m), 2.32 (3H, s), 2.29 (3H, s).

MS (DCI, NH ₃ ): 680.9 [2M + H ⁺ ], 340.1 (M + H ⁺ ). Example IV

Methyl 4 - {[(2- {4 - [(4-bromophenoxy) methyl] -2,5-dimethyl-3-thienyl} ethyl) - amino] methyl} benzoate

A solution of 640 mg (1.88 mmol) 2- {4 - [(4-bromophenoxy) methyl] -2,5-dimethyl-3-thienyl} ethylamine from Ex. M and 308 g (1.88 mmol ) 4-Formylbenzoic acid methyl ester in 5 ml of ethanol is heated to reflux for 2 hours. The solvent is then stripped off in vacuo and the residue obtained is dissolved in 5 ml of methanol. In portions, a total of 142 mg (3.76 mmol) become firmer

NaBH ₄ added. After stirring for two hours at room temperature, the mixture is poured into water and extracted with ethyl acetate. The organic extract is washed with saturated sodium chloride solution and dried over Na ₂ SO ₄ . After filtration, the solvent is removed in vacuo and the crude product obtained is purified by preparative HPLC. 897 mg (1.84 mmol, 97% yield) of a colorless oil are obtained. R _f (cyclohexane / ethyl acetate, 1: 1): 0.57.

1H-NMR (300 MHz, DMSO-d ₆ , δ / ppm): 8.01 (2H, d), 7.59 (2H, d), 7.42 (2H, d), 6.88 (2H, d), 4.81 (2H, s), 4.23 (2H, pt, including 1H, broad), 3.89 (3H, s), 3.05-2.90 (2H, m), 2, 89-2.77 (2H, m), 2.34 (3H, s), 2.31 (3H, s).

MS (DCI, NH ₃ ): 488.1 (M + H ⁺ ). Example V

3 - [(4-bromobenzyl) oxy] -5,6,7,8-tetrahydro-2-naphthoic acid-methylester

A solution of 20 g (96.97 mmol) of 3-hydroxy-5,6,7,8-tetrahydro-2-naphthalenecarboxylic acid methyl ester (CAS 52888-73-0) and 25.45 g (101.8 mmol ) 4-Bromo-benzyl bromide in 600 ml of anhydrous acetonitrile is mixed with 16.1 g (116.4 mmol) of potassium carbonate and heated to reflux. After 20 hours, the majority of the solvent is spun off and the residue between diethyl ether and

Phosphate buffer (pH 5.5) distributed. The organic phase is separated off and dried over anhydrous sodium sulfate. After filtration and spinning in, a crude product is obtained which is purified by crystallization from ether. 20.2 g (56% yield) of a colorless solid are obtained. R _f (cyclohexane / ethyl acetate 5: 1): 0.49.

1H-NMR (200 MHz, DMSO-d ₆ , δ / ppm): 1.71 (dd, 4H), 2.63-2.77 (m, 4H), 3.78 (s, 3H), 5, 12 (s, 2H), 6.91 (s, 1H), 7.43 (s, 1H), 7.46 (d, 2H), 7.60 (d, 2H). MS (ESI): 375 and 377 (M + H ⁺ ), 397 and 399 (M + Na ⁺ ). Example VI

{3 - [(4-bromobenzyl) oxy] -5,6,7,8-tetrahydro-2-naphthyl} methanol

Under argon and at -78 ° C, a solution of 20.0 g (53.3 mmol) of 3 - [(4-bromobenzyl) oxy] -5,6,7,8-tetrahydro-2-naphthalenecarboxylic acid methyl ester in 250 ml of water-free diethyl ester with 40 ml (40 mmol) of a one-molar LiAlH ₄ solution in ether. The mixture is allowed to come to room temperature overnight. Then it is carefully adjusted to pH 1-2 with 2 molar hydrochloric acid and extracted with ether.

The organic phase is separated off and dried over anhydrous sodium sulfate. After filtration and spinning in, 16.4 g (89% yield) of a colorless solid are obtained. R _f (cyclohexane / ethyl acetate 5: 1): 0.20. 1H-NMR (200 MHz, DMSO-d ₆ , δ / ppm): 1.69 (dd, 4H), 2.60-2.68 (m, 4H), 4.47 (d,

2H), 4.90 (t, 1H), 5.03 (s, 2H), 6.67 (s, 1H), 7.03 (s, 1H), 7.40 (d, 2H), 7, 59 (d. 2H). MS (DCI, NH ₃ ): 364 and 366 (M + NH ₄ ⁺ ). Example VII

6 - [(4-bromobenzyl) oxy] -7- (chloromethyl) -l, 2,3,4-tetrahydronaphthalene

A solution of 16.4 g (47.23 mmol) {3 - [(4-bromobenzyl) oxy] -5,6,7,8-tetrahydro-2-naphthyl methanol in 35 ml dichloromethane is mixed with 35 ml (473 mmol ) freshly distilled thionyl chloride. After adding a drop of DMF, the mixture is heated to reflux for one hour. The solvent and excess thionyl chloride are then distilled off. The residue is made of ether with little

Recrystallized cyclohexane. 17.2 g (99% yield) of a yellow solid are obtained. R _f (cyclohexane / ethyl acetate 1: 1): 0.78. 1H-NMR (300 MHz, DMSO-d ₆ , δ / ppm): 1.69 (dd, 4H), 2.60-2.70 (m, 4H), 4.67 (s, 2H), 5, 10 (s, 2H), 6.77 (s, 1H), 7.07 (s, 1H), 7.43 (d, 2H), 7.60 (d, 2H).

MS (DCI, NH ₃ ): 382 (M + NH ₄ ⁺ ). Example VIII

{3 - [(4-bromobenzyl) oxy] -5,6,7,8-tetrahydro-2-naphthyl} acetonitrile

A solution of 17.3 g (47.31 mmol) of 6 - [(4-bromobenzyl) oxy] -7- (chloromethyl) - 1,2,3,4-tetrahydronaphthalene in 850 ml of dimethylformamide is mixed with 2.78 g ( 56.77 mmol) of sodium cyanide were added and the mixture was stirred at room temperature overnight. Then water is added and the mixture is extracted with ether. The organic phase is dried over anhydrous sodium sulfate. After filtration and

Spinning in gives 13.89 g (82% yield) of product. R _f (cyclohexane / ethyl acetate 3: 1): 0.51.

1H NMR (200 MHz, DMSO-d ₆ , δ / ppm): 1.69 (dd, 4H), 2.61-2.70 (, 4H), 3.80 (s, 2H), 5.10 (s, 2H), 6.80 (s, 1H), 7.01 (s, 1H), 7.46 (d, 2H), 7.59 (d, 2H). MS (DCI, NH ₃ ): 373 and 375 (M + NH ₄ ⁺ ).

Example IX

2- {3 - [(4-bromobenzyl) oxy] -5,6,7,8-tetrahydro-2-naphthyl} ethylamine

A solution of 13.5 g (37.89 mmol) of {3 - [(4-bromobenzyl) oxy] -5,6,7,8-tetrahydro-2-naphthyl} acetonitrile in 300 ml of anhydrous tetrahydrofuran (THF) is mixed with 38 ml of a 2 molar solution of borane-dimethyl sulfide complex in THF were added. The

The mixture is heated to reflux for five hours. After cooling, it is acidified with dilute hydrochloric acid and briefly heated again (5 minutes). Then it is made alkaline with sodium hydroxide solution and extracted with ether. The organic extract is dried over anhydrous sodium sulfate. After filtering and spinning in, 14.2 g of a yellow waxy solid are obtained, which is only approx.

92% is pure, but is still used in the next stage without cleaning. R _f (cyclohexane / ethyl acetate 3: 1): 0.81.

Η NMR (200 MHz, DMSO-d ₆ , δ / ppm): 1.68 (dd, 4H), 2.03 (broad s, 2H), 2.57-2.70 (m, 8H), 5 , 01 (s, 2H), 6.67 (s, 1H), 6.80 (s, 1H), 7.40 (d, 2H), 7.59 (d, 2H). MS (DCI, NH ₃ ): 360 and 362 (M + H ⁺ ).

Example X

4 - {[(2- {3 - [(4-bromobenzyl) oxy] -5,6,7,8-tetrahydro-2-naphthyl} ethyl) amino] - methyl} benzoic acid methyl ester

A solution of 14.84 g (41.18 mmol) of 2- {3 - [(4-bromobenzyl) oxy] -5,6,7,8-tetra-hydro-2-naphthyl} ethylamine and 6.08 g ( 37.06 mmol) of methyl 4-formylbenzoate in 300 ml of toluene is heated to reflux on a water separator for 30 minutes.

The toluene is then removed on a tot evaporator and the residue is taken up in methanol. The methanolic solution is mixed with ice cooling with 2.34 g (61.77 mmol) of solid sodium borohydride. After stirring for 30 minutes at room temperature, the mixture is neutralized with 5% sodium dihydrogenphosphate solution, diluted with water and extracted with ether. The organic phase is over

Dried sodium sulfate. The crude product obtained after filtering and spinning in is purified by flash chromatography on silica gel using cyclohexane / ethyl acetate 2: 1 as the eluent. 5.62 g (27% yield) are obtained. R _f (cyclohexane / ethyl acetate 1: 1): 0.26. Η NMR (300 MHz, DMSO-d ₆ , δ / ppm): 1.68 (dd, 4H), 2.56-2.68 (m, 8H), 3.74 (s,

2H), 3.83 (s, 3H), 4.99 (s, 2H), 6.66 (s, 1H), 6.79 (s, 1H), 7.33 (d, 2H), 7, 41 (d, 2H), 7.53 (d, 2H), 7.87 (d, 2H). MS (ESI): 508 and 510 (M + H ⁺ ).

Example XI

4 - {[(2- {3 - [(4-bromobenzyl) oxy] -5,6,7,8-tetrahydro-2-naphthyl} ethyl) (5-methoxy-5-oxopentyl) amino] methyl} benzoic acid- methylester

2.3 g (4.52 mmol) 4 - {[(2- {3 - [(4-bromobenzyl) oxy] -5,6,7,8-tetrahydro-2-naphthyl} ethyl) amino] methyl} Methyl benzoate, 1.06 g (5.43 mmol) methyl bromvalerate and 0.75 g (5.43 mmol) potassium carbonate are heated to reflux in 150 ml butyronitrile. The reaction is complete after 48 hours. It is evaporated to dryness. The residue is then taken up in ethyl acetate and washed with water. The organic phase is dried over sodium sulfate. After filtration and spinning in, the crude product is purified by flash chromatography on silica gel using cyclohexane / ethyl acetate 6: 1 as the eluent. 622 mg (60% yield) of a colorless oil are obtained. R _f (cyclohexane / ethyl acetate 1: 1): 0.53.

1H-NMR (300 MHz, DMSO-d ₆ , δ / ppm): 1.32-1.47 (m, 4H), 1.67 (dd, 4H), 2.17 (t, 2H), 2, 39 (t, 2H), 2.50-2.69 (m, 8H), 3.54 (s, 3H), 3.58 (s, 2H), 3.82 (s, 3H), 4.92 (s, 2H), 6.63 (s, 1H), 6.75 (s, 1H), 7.31 (d, 2H), 7.36 (d, 2H), 7.52 (d, 2H) , 7.82 (d, 2H). MS (ESI): 622 and 624 (M + H ⁺ ).

Example XII

{3 - [(4-bromobenzyl) oxy] -6-methyl-2-pyridinyl} methanol

A solution of 3.86 g (37.73 mmol) of 2- (hydroxymethyl) -6-methyl-3-pyridinol and 8.32 g (33.27 mmol) of 4-bromobenzyl bromide in 50 ml of acetonitrile is mixed with 9.58 g (69.31 mmol) of anhydrous potassium carbonate were added and the mixture was heated to reflux under argon for 12 h. After cooling and removing the solvent, the crude product obtained is purified by column chromatography (cyclohexane / ethyl acetate 2/1) and 7.205 g (23.38 mmol, 82% yield) of a colorless solid is obtained.

1H-NMR (300 MHz, DMSO-d ₆ , δ / ppm): 7.59 (2H, d), 7.42 (2H, d), 7.35 (1H, d), 7.1 (1H, d), 5.14 (2H, s), 4.79 (1H, t), 4.55 (2H, d), 2.4 (3H, s). MS (DCI, NH ₃ ): 308/310 (M + H ⁺ ).

Example XIII

3 - [(4-bromobenzyl) oxy] -2- (bromomethyl) -6-methylpyridine

A solution of 9.2 g (35.07 mmol) triphenylphosphine and 11.63 g (35.07 mmol) tetrabromomethane in 320 ml THF is mixed with a solution of 7.205 g (23.38 mmol) {3 - [(4- Bromobenzyl) oxy] -6-methyl-2-pyridinyl} methanol in 160 ml of THF. After 5 hours of stirring at room temperature, a further 3.066 g of triphenylphosphine and 3.877 g of tetrabromomethane (0.5 equivalents each) are added in solid form. After 12 hours, the mixture is evaporated to dryness, taken up in ether, filtered through diatomaceous earth, the organic phase is evaporated and the product obtained is isolated by flash chromatography (silica gel, dichloromethane). 2.028 g (5.46 mmol, 23% yield) of a colorless solid are obtained. R _f (cyclohexane / ethyl acetate 1: 1): 0.35.

1H-NMR (400 MHz, DMSO-d ₆ , δ / ppm): 7.61 (2H, d), 7.46 (2H, d), 7.43 (1H, d), 7.19 (1H, d), 5.21 (2H, s), 4.64 (2H, s), 2.38 (3H, s). MS (DCI, NH ₃ ): 370/372 (M + H ⁺ ).

Example XIV

{3 - [(4-bromobenzyl) oxy] -6-methyl-2-pyridinyl} acetonitrile

2.99 ml (22.45 mmol) are added to a solution of 5.55 g (14.97 mmol) of 3 - [(4-bromobenzyl) oxy] -2- (bromomethyl) - 6-methylpyridine in 350 ml of dry acetonitrile. Trimethylsilyl cyanide and 22.45 ml (22.45 mmol) of a 1-N-tetra-n-butylammonium fluoride solution in THF are slowly added dropwise and the mixture is stirred overnight at room temperature. The mixture is then evaporated to dryness and the crude product obtained is purified by column chromatography (cyclohexane / ethyl acetate 1.5: 1). 4.29 g (13.53 mmol, 90% yield) of a colorless oil are obtained. R _f (cyclohexane / ethyl acetate 2: 1): 0.21.

Η NMR (200 MHz, CDC1 ₃ , δ / ppm): 7.59 (2H, d), 7.45 (2H, d), 7.42 (1H, d), 7.29 (1H, d) , 5.19 (2H, s), 4.09 (2H, s), 2.4 (3H, s). MS (DCI, NH ₃ ): 632.7 / 634.8 (2M + H ⁺ ), 317 (M + H ⁺ ).

Example XV

2- {3 - [(4-bromobenzyl) oxy] -6-methyl-2-pyridinyl} ethylamine

In a solution of 3.25 g (10.25 mmol) {3 - [(4-bromobenzyl) oxy] -6-methyl-2-pyridinyl} acetonitrile in 50 ml THF at 0 ° C slowly add 525 μl (30, 76 mmol) of a borane-dimethyl sulfide complex solution were added dropwise. After thawing and stirring for two hours at room temperature, the reaction solution is cooled to 0 ° C. and quenched with a 1N HCl solution. Then the approach to

Dried in dry, taken up in ethyl acetate and made basic with sodium hydroxide solution. The organic phase is dried over magnesium sulfate and after

Removing the solvent, the crude product obtained is purified by column chromatography (dichloromethane / methanol acetic acid 100: 10: 1.5) and 325 mg (1.01 mmol, 10% yield) of a colorless oil are obtained.

R _f (dichloromethane / methanol 10: 1): 0.05.

LC-MS: Rt = 1.524 min, MS (ESI): 321 (M + H ⁺ ).

LC-MS method: column: Symmetry C 18; 21 mm x 150 mm; 5 μm

Ionization: ESI positive / negative

Oven temperature: 70 ° C

Solvent A: acetonitrile

Solvent B: 0.3g HC1 (30%) / ll water gradient: A / B 2/98 to 95/5 within 2.5 min

Flow: 0.9 ml / min to 1.2 ml / min within 2 min

MS (DCI, NH ₃ ): 321.1 / 323.1 (M + H ⁺ ). Example XVI

4- {[(2- {3 - [(4-bromobenzyl) oxy] -6-methyl-2-pyridinyl) ethyl) amino] methyl} ■ methyl benzoate

A solution of 675 mg (2.10 mmol) of 2- {3 - [(4-bromobenzyl) oxy] -6-methyl-2-pyridinyljethylamine and 345 mg (2.10 mmol) of methyl 4-formylbenzoate in 5 ml of ethanol is heated to reflux for two hours. The solvent is then stripped off in vacuo and the residue obtained is dissolved in 5 ml of methanol. A total of 159 mg (4.21 mmol) of solid NaBH are added in portions. After stirring for two hours at room temperature, the mixture is poured into water and extracted with ethyl acetate. The organic extract is washed with saturated sodium chloride solution and dried over Na ₂ SO ₄ . After filtration, the solvent is removed in vacuo and the crude product obtained is purified by preparative HPLC. 351 mg (0.75 mmol, 35% yield) of a colorless oil are obtained.

Η NMR (200 MHz, DMSO-d ₆ , δ / ppm): 7.90 (2H, d), 7.56 (2H, d), 7.46 (2H, d), 7.37 (2H, d), 7.29 (1H, d), 7.02 (1H, d), 5.08 (2H, s), 3.80 (3H, s), 3.41-3.12 (2H, s broad), 2.99-2.71 (4H m), 2.36 (3H, s). MS (ESI): 469 (M + H ⁺ ).

Example XVII

4 - {[(2- {3 - [(4-bromobenzyl) oxy] -6-methyl-2-pyridinyl} ethyl) (5-ethoxy-5-oxopentyl) amino] methyl} benzoic acid methyl ester

A solution of 298 mg (0.63 mmol) of methyl 4 - {[(2- {3 - [(4-bromobenzyl) oxy] -6-methyl-2-pyridinyl} ethyl) amino] methyl} -benzoate and 150 μl (0.95 mmol) methyl 5-bromovalerate in 3 ml acetonitrile is mixed with 134 mg (1.27 mmol) anhydrous sodium carbonate and heated under reflux for 12 hours.

The mixture is then evaporated, taken up with ethyl acetate and with

Washed water. After drying over Na ₂ SO, filtration and concentration, this becomes

Product purified by preparative HPLC. 293 mg (0.49 mmol, 77% yield) of a colorless oil are obtained.

1H-NMR (300 MHz, DMSO-d ₆ , δ / ppm): 7.83 (2H, d), 7.54 (2H, d), 7.39-7.22 (5H, m), 7, 0 (1H, d), 5.02 (2H, s), 3.99 (2H, q), 3.61 (2H, s), 3.29 (3H, s), 2.92-2.81 (2H,), 2.76-2.64 (2H, m), 2.39 (2H, t), 2.32 (3H, s), 2.12 (2H, t), 1.42-1 , 26 (4H, m),

1.18 (3H, t). LC-MS: Rt = 3.45 min; MS (ESIpos): 597/599 (M ⁺ ).

LC-MS method:

Device type HPLC: HP 1100

UV detector DAD: 208-400 nm

Column: Symmetry C18; 50 mm x 2.1 mm; 3.5 μm ionization: ESI positive / negative

Oven temperature: 40 ° C

Solvent A: CH CN + 0.1% formic acid

Solvent B: H ₂ O + 0.1% formic acid gradient

Time A% B% flow

0.00 10.0 90.0 0.50

4.00 90.0 10.0 0.50

6.00 90.0 10.0 0.50

6.10 10.0 90.0 1.00

7.50 10.0 90.0 0.50

synthesis Examples

example 1

Methyl 4 - {[(2- {4 - [(4-bromophenoxy) methyl] -2,5-dimethyl-3-thienyl} ethyl) (5-ethoxy-5-oxopentyl) amino] methyl} benzoate

A solution of 842 mg (1.72 mmol) of methyl 4 - {[(2- {4 - [(4-bromophenoxy) methyl] - 2,5-dimethyl-3-thienyl} ethyl) amino] methyl} benzoate Ex. IV and 409 µl

(2.59 mmol) of methyl 5-bromovalerate in 10 ml of acetonitrile is mixed with 365 mg (3.45 mmol) of anhydrous sodium carbonate and heated to reflux for 12 hours. The mixture is then evaporated, taken up in ethyl acetate and washed with water. After drying over Na ₂ SO ₄ , filtration and concentration, the product is purified by preparative HPLC. It will

Obtained 1.058 g (1.71 mmol, 93% yield) of a colorless oil. R _f (cyclohexane / ethyl acetate 2: 1): 0.44.

1H-NMR (200 MHz, DMSO-d ₆ , δ / ppm): 7.99 (2H, d), 7.67 (2H, d), 7.43 (2H, d), 6.91 (2H, d), 4.83 (2H, s), 4.46 (2H, s), 4.03 (2H, q), 3.89 (3H, s), 3.18-2.78 (6H, m ), 2.34 (3H, s), 2.27 (3H, s), 2.16 (2H, t), 1.72-1.51 (2H, m), 1.49-1.29 ( 2H, m), 1.19

(3H, t). MS (ESI): 616 (M + H ⁺ ). Example 2

Methyl-4- {[[2- (4 - {(2 ', 4' -dichloro-1, 1 '-biphenyl-4-yl) oxy] methyl} -2,5-dimethyl-3-thienyl) ethyl] (5-ethoxy-5-oxopentyl) amino] methyl} benzoate

120 mg (0.19 mmol) methyl-4 - {[(2- {4 - [(4-bromophenoxy) methyl] -2,5-dimethyl-3-thienyl} ethyl) (5-ethoxy-5-oxopentyl) amino] methyl} benzoate from Example 1 are dissolved in 2 ml of 1,2-dimethoxyethane and under argon with 44 mg (0.23 mmol) of 2,4-dichlorophenylboronic acid, 7 mg (0.01 mmol) of bis (triphenylphoshin) palladium (II) - chloride and mixed with 215 μl of a 2 molar Na ₂ CO ₃ solution in water. The reaction mixture is then stirred under reflux for 12 h. The mixture is then cooled and filtered through 1 g of extrelute, washed with dichloromethane and evaporated. The product obtained is purified by preparative HPLC. 73 mg (0.11 mmol, 53% yield) of a colorless oil are obtained.

R _f (cyclohexane / ethyl acetate 2: 1): 0.51.

1H-NMR (300 MHz, DMSO-d ₆ , δ / ppm): 8.01 (2H, d), 7.71 (1H, d), 7.64 (2H, d), 7.49 (1H, dd), 7.41 (1H, s), 7.36 (2H, d), 7.00 (2H, d), 4.89 (2H, s), 4.47 (2H, s), 4, 00 (2H, q), 3.84 (3H, s), 3.21-2.71 (6H, m), 2.37 (3H, s), 2.28 (3H, s), 2.14 (2H, t), 1.69-1.51 (2H, m), 1.48-1.31 (2H,), 1.13 (3H, t).

MS (ESI): 681.9 (M + H ⁺ ). Example 3

4 - ({(4-Carboxybutyl) [2- (4 - {[(2 ', 4'-dichloro-l, l' -biphenyl-4-yl) oxy] methyl} -2,5-dimethyl-3- thienyl) ethyl] amino} methyl) benzoic acid

A solution of 68 mg (0.1 mmol) methyl-4 - {[[2- (4 - {(2 ', 4'-dichloro-l, l'-biphenyl-4-yl) oxy] methyl} -2 , 5-dimethyl-3-thienyl) ethyl] (5-ethoxy-5-oxopentyl) amino] meth-yl} benzoate from Example 2 in 4.0 ml of dioxane and 2 ml of water is mixed with 500 .mu.l

45% solution of NaOH in water was added and the mixture was stirred at 90 ° C. for 2 hours. After cooling, the dioxane is drawn off and the aqueous phase is adjusted to pH 4 to 5 with 1 molar hydrochloric acid. The product precipitates, which is filtered off, washed with water and dried. 47 mg (0.07 mmol, 72% yield) of a white solid are obtained.

R _f (ethyl acetate / methanol, 7: 3): 0.22.

Η NMR (200 MHz, DMSO-d ₆₎ δ / ppm): 12.4 (2H, broad), 7.84 (2H, d), 7.70 (1H, d), 7.53-7, 29 (6H, m), 7.03 (2H, d), 4.82 (2H, s), 3.61 (2H, s), 2.71-2.38 (6H, m, partially masked by DMSO ), 2.35 (3H, s), 2.18 (3H, s), 2.08 (2H, t)), 1.48-1.28 (4H, m).

MS (ESI): 639.9 (M + H ⁺ ). The following were produced in an analogous manner:

Example: Formula analytical data

Η-NMR ^ ppm] (DMSO-d ₆ ):

(from 1 and 4- 12.31 (1H, broad), 9.99 (1H, trifluoro-broad), 8.08-7.91 (2H, m), 7.89-methyl-7.72 (6H , m), 7.67 (2H, d), 7.08 phenyl- (2H, d), 4.89 (2H, s), 3.45 (2H, boronic acid s), 3.22-2.88 (4H, m), 2.60-2.00 and then (10H, m, therein 2.39 (3H, s), 2.27 analogous to Ex. 2 (3H, s), 2.08 (2H, t)), 1.76-1.49 and 3) (2H, m), 1.48-1.29 (2H, m). (200 MHz)

Η NMR: δ [ppm] (DMSO-d ₆ ):

(from 1 and 4- 12.4 (2H, broad), 7.53 (6H, dd), methoxy- 6.98 (6H, d), 4.81 (2H, s), 3.79 phenyl- ( 3H, s), 3.60 (2H, s), 2.71-2.02 boronic acid (16H, m, partially masked by and then DMSO, therein 2.37 (3H, s), 2.21 analogous to Ex. 2 (3H, s), 2.09 (2H, t)), 1.48-1.28 and 3) (4H, m). (200 MHz)

Η NMR: δ [ppm] (DMSO-d ₆ ):

(from 1 and 12.2 (2H, broad), 7.82 (2H, d), 4-chloro-7.61 (4H, t), 7.49 (2H, d), 7.35 phenyl- ( 2H, d), 7.03 (2H, d), 4.71 (2H, boronic acid s), 3.60 (2H, s), 2.71-2.37 (6H, and then m, partially obscured by analogous to Ex. 2 DMSO), 2.35 (3H, s), 2.19 (3H, and 3) s), 2.08 (2H, t)), 1.46-1.31 (4H, m) , (200 MHz)

Example 11

4 - {[(2- {3 - [(4'-methoxy-l, l'-biphenyl-4-yl) methoxy] -5,6,7,8-tetrahydro-2-naphthyl} ethyl) (5th methoxy-5-oxopentyl) amino] methyl} benzoic acid methylester

A solution of 200 mg (0.32 mmol) of 4 - {[(2- {3 - [(4-bromobenzyl) oxy] -5,6,7,8-tetrahydro-2-naphthyl} ethyl) (5-methoxy -5-oxopentyl) amino] methyl} methyl benzoate and 11.1 mg (3 mol%) tetrakis (triphenylphosphine) palladium- (0) in 10 ml dimethoxyethane (DME) is mixed with 56.5 mg (0.35 mmol) 4-methoxyphenyl boronic acid and 0.48 ml of a 2 molar sodium carbonate solution in water. It is refluxed under argon for three hours. Then pH5 phosphate buffer and ether are added. The phases are separated. The aqueous phase is extracted with ether. The combined ether phases are dried over sodium sulfate, filtered and evaporated. The product is isolated by flash chromatography on silica gel with cyclohexane / ethyl acetate 8: 1 as the eluent. 160 mg (77% yield) of a pale yellow oil are obtained. R _f (cyclohexane / ethyl acetate 5: 1): 0.10.

1H-NMR (400 MHz, DMSO-d ₆ , δ / ppm): 1.58-1.72 (m, 8H), 2.16 (t, 2H), 2.41 (t, 2H), 2, 55-2.59 (m, 4H), 2.63-2.69 (m, 4H), 3.52 (s, 3H), 3.60 (s, 2H), 3.81 (s, 6H) , 5.00 (s, 2H), 6.69 (s, 1H), 6.77 (s, 1H), 7.02 (d, 2H), 7.37 (d, 2H), 7.41 ( d, 2H), 7.58 (2 d, 4H), 7.83 (d, 2H). MS (ESI): 650 (M + H ⁺ ).

Example 12

4- ({(5-methoxy-5-oxopentyl) [2- (3- {[4 '- (trifluoromethyl) - 1, 1' -biρhenyl-4-yl] methoxy} -5,6,7,8 -tetrahydro-2-naphthyl) ethyl] amino} methyl) benzoic acid methyl ester

In an analogous manner to that described for synthesis example 11, 200 mg (0.32 mmol) of 4 - {[(2- {3 - [(4-bromobenzyl) oxy] -5,6,7,8-tetrahydro -2-naphthyl} - ethyl) (5-methoxy-5-oxopentyl) amino] methyl} methyl benzoate, 11.1 mg (3 mol%) tetrakis (triphenylphosphine) palladium- (0), 70.6 mg (0.35 mmol) 4- (Trifluoromethyl) phenylboronic acid and and 0.48 ml of a 2 molar sodium carbonate solution in 10 ml DME after flash chromatography on silica gel (cyclohexane / ethyl acetate 10: 1) 170 mg (67% yield) of a light yellow oil. R _f (cyclohexane / ethyl acetate 5: 1): 0.16.

1H-NMR (200 MHz, DMSO-d ₆ , δ / ppm): 1.61-1.72 (m, 8H), 2.13 (t, 2H), 2.40 (t, 2H), 2, 50-2.70 (m, 4H, partially covered by DMSO signal), 3.50 (s, 3H), 3.60 (s, 2H), 3.79 (s, 3H), 5.03 (s , 2H), 6.69 (s, IH), 6.78 (s, IH), 7.36 (d, 2H), 7.49 (d, 2H), 7.71 (d, 2H), 7 , 79-7.86 (m, 6H). MS (ESI): 688 (M + H ^.

Example 13

4 - {[(4-carboxybutyl) (2- {3 - [(4 * -methoxy-l, r-biphenyl-4-yl) methoxy] -5,6,7,8-tetrahydro-2-naphthyl} ethyl ) amino] methyl} benzoic acid

A solution of 140 mg (0.22 mmol) 4 - {[(2- {3 - [(4'-methoxy-l, l'-biphenyl-4-yl) methoxy] -5,6,7,8- tetrahydro-2-naphthyl} ethyl) (5-methoxy-5-oxopentyl) amino] - methyl} benzoic acid methyl ester in 4 ml of tetrahydrofuran and 4 ml of methanol is mixed with 8 ml of 2 molar sodium hydroxide solution and heated to reflux. When the reaction has ended, the mixture is diluted with a little water and extracted with ether. The watery The phase is adjusted to pH 5 with 2 molar hydrochloric acid and extracted with ethyl acetate.

The ethyl acetate extract is evaporated to dryness. The residue is boiled up with ether and filtered after cooling. 85 mg (63% yield) of a light beige solid are obtained.

Melting point:> 240 ° C.

R _f (ethyl acetate): <0.05.

1H-NMR (400 MHz, DMSO-d ₆ , δ / ppm): 1.39-1.47 (m, 4H), 1.67-1.70 (m, 4H), 2.11

(t, 2H), 2.44 (m, 2H), 2.57 (m, 4H), 2.65 (m, 4H), 3.62 (s wide, 2H), 3.80 (s, 3H) )

5.00 (s, 2H), 6.69 (s, IH), 6.78 (s, IH), 7.01 (d, 2H), 7.37 (d, 2H), 7.41 (d , 2H), 7.58

(2 d, 4H), 7.83 (d, 2H), 12.38 (broad, 2H).

MS (ESI): 622 (M + H).

Example 14

4- ({(4-Carboxybutyl) [2- (3- {[4 '- (trifluoromethyl) -l, 1' -biphenyl-4-yl] methoxy} -5,6,7,8-tetrahydro-2- naphthyl) ethyl] amino} methyl) benzoic acid

Analogously to that described in Synthesis Example 13, 140 mg of 4 - ({(5-methoxy-5-oxopentyl) [2- (3 - {[4 '- (tri fluoromethyl) - 1, 1' -biphenyl-4-yl] methoxy} - 5,6,7,8-tetrahydro-2-naphthyl) ethyl] amino} methyl) benzoic acid methyl ester 79 mg (56% yield) of a white solid were obtained. 1H-NMR (300 MHz, DMSO-d ₆ , δ / ppm): 1.42 (m, 4H), 1.68 (m, 4H), 2.10 (dd, 2H),

2.42 (dd, 2H), 2.59 (m, 4H) 2.68 (m, 4H), 3.61 (s, 2H), 5.02 (s, 2H), 6.69 (s, IH)

6.78 (s, IH), 7.33 (d, 2H), 7.49 (d, 2H), 7.71 (d, 2H), 7.78-7.88 (m, 6H), 12 , 27 (wide,

2H).

MS (ESI): 660 (M + H ⁺ ).

Example 15

4 - ({(5-ethoxy-5-oxopentyl) [2- (6-methyl-3 - {[4 '- (trifluoromethyl) -l, l ^, -biphenyl-4-yl] methoxy} -2-pyridinyl) ethyl] amino} methyl) methyl benzoate

134 mg (0.22 mmol) 4 - {[(2- {3 - [(4-bromobenzyl) oxy] -6-methyl-2-pyridinyl} ethyl) (5-ethoxy-5-oxopentyl) amino] methyl} methyl benzoate are dissolved in 2 ml of 1,2-dimethoxyethane and under argon with 51 mg (0.27 mmol) of 4-trifluoromethyl-phenylboronic acid, 8 mg (0.01 mmol) of bis (triphenylphoshin) palladium (II) chloride and mixed with 250 ul of a 2 molar Na ₂ CO ₃ solution in water. The reaction mixture is then stirred under reflux for 12 h. The mixture is then cooled and filtered through 3 g of extrelute, washed with dichloromethane and evaporated. The product obtained is purified by column chromatography (dichloromethane / methanol, 100: 5). 135 mg (0.20 mmol, 91% yield) of a colorless oil are obtained. R _f (cyclohexane / ethyl acetate 2: 1): 0.28. 1H NMR (200 MHz, DMSO-d ₆ , δ / ppm): 7.92-7.42 (10H, m), 7.39-7.23 (3H, m), 7.01

(IH, d), 5.11 (2H, s), 3.98 (2H, q), 3.59 (2H, s), 3.32 (3H, s), 2.99-2.81 ( 2H, m),

2.79-2.62 (2H, m), 2.39 (2H, t), 2.33 (3H, s), 2.09 (2H, t), 1.48-1.21 (4H, m), 1.1

(3H, t).

MS (ESI): 663 (M + H ⁺ ).

Example 16

4- ({(4-Carboxybutyl) [2- (6-methyl-3- {[4 '- (trifluoromethyl) - 1, 1'-biphenyl-4-yl] methoxy} -2-pyridinyl) ethyl] amino} methyl) benzoic acid

A solution of 125 mg (0.19 mmol) of 4 - ({(5-ethoxy-5-oxopentyl) [2- (6-methyl-3- {[4 '- (trifluoromethyl) -l, -biphenyl-4- yl] methoxy} -2-pyridinyl) ethyl] amino} methyl) - benzoic acid methyl ester in 1.0 ml of dioxane and 1 ml of water is mixed with 51 ul of a 45% solution of NaOH in water and for 4 hours at 60 ° C stirred. After cooling, the dioxane is drawn off and the aqueous phase is adjusted to pH 4 to 5 with 1 molar hydrochloric acid. The product precipitates, which is filtered off, washed with water and dried. 83 mg (0.13 mmol, 89% yield) of a white solid are obtained.

Η NMR (300 MHz, DMSO-d ₆ , δ / ppm): 12.4 (2H, broad), 7.93-7.78 (4H, m), 7.72 (2H, d), 7, 68-7.46 (6H, m), 7.33 (IH, d), 7.03 (IH, d), 5.13 (2H, s), 3.75-3.52 (2H, s, broad), 3.04-2.88 (2H, m), 2.87-2.66 (2H, m), 2.57-2.49 (2H, m, partially masked by DMSO), 2.32 (3H, s), 2.11 (2H, t), 1.51-1.29 (4H, m). MS (ESI): 621 (M + H *).

Claims

claims

1. Compounds of formula (I)

embedded image in which

Z for a phenyl ring fused with a saturated, partially unsaturated or aromatic carba- or heterocycle with up to 3 heteroatoms from the series S, N and / or O, or a partially unsaturated or aromatic heterocycle with 1 to 9 carbon atoms and is up to 3 heteroatoms from the series S, N and / or O,

V is missing, O, NR ⁴ , NR ⁴ CONR ⁴ , NR ⁴ CO, NR ⁴ SO ₂ , COO, CONR ⁴ or

S (O) ₀ means

wherein

R regardless of any other, if any

Radical R ^{4 is} hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms, cycloalkyl having 3 to 8 carbon atoms, aryl having 6 to 10 carbon atoms or arylalkyl having 7 to 18 carbon atoms, the aryl radical in turn being one or more times by halogen, alkyl,

Alkoxy can be substituted with up to 6 carbon atoms, o means 0, 1 or 2,

Q is absent, straight-chain or branched alkylene, straight-chain or branched alkenediyl or straight-chain or branched alkynediyl each having up to 12 carbon atoms, each of which means one or more groups of O, S (O) _p , NR ⁵ , CO, NR ⁵ SO ₂ or CONR ^{5 can} contain, and can be substituted one or more times by halogen, hydroxy or alkoxy with up to 4 carbon atoms, optionally any two atoms of the above chain can be connected to form a three- to eight-membered ring,

embedded image in which

R ^{5 is} hydrogen, straight-chain or branched alkyl with up to 8

Means carbon atoms or cycloalkyl having 3 to 8 carbon atoms, which can be substituted by halogen or alkoxy having up to 4 carbon atoms,

p means 0, 1 or 2,

Y is hydrogen, NR ⁸ R ⁹ , aryl with 6 to 10 carbon atoms, an aromatic or saturated heterocycle with 1 to 9 carbon atoms and up to 3 heteroatoms from the series S, N and / or O or straight-chain or branched cycloalkyl with 3 to 8 carbon atoms means, which can also be bound via N, the cyclic radicals in each case one to three times by straight-chain or branched alkyl, straight-chain or branched alkenyl, straight-chain or branched alkynyl, straight-chain or branched alkoxy, straight-chain or branched haloalkyl, straight-chain or branched Haloalkoxy with up to 8 carbon Substance atoms, straight-chain or branched cycloalkyl with 3 to 8 carbon atoms, halogen, hydroxy, CN, SR ⁶ , NO ₂ , NR ⁸ R ⁹ , NR ⁷ COR ¹⁰ , NR ⁷ CONR ⁷ R ¹⁰ or CONR ⁿ R ¹² can be substituted,

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R ^{6 is} hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms, straight-chain or branched haloalkyl having up to 8 carbon atoms or cycloalkyl having 3 to 8 carbon atoms,

R ^7, independently of any further radical R ^{7 which may} be present, denotes hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms or cycloalkyl having 3 to 8 carbon atoms,

R ⁸ , R ⁹ , R ¹¹ and R ¹² independently of one another, hydrogen, straight-chain or branched alkyl, straight-chain or branched alkenyl having up to 8 carbon atoms, aryl having 6 to 10 carbon atoms, an aromatic heterocycle having 1 to

9 carbon atoms and up to 3 heteroatoms from the series S, N and / or O, arylalkyl having 8 to 18 carbon atoms, cycloalkyl having 3 to 8 carbon atoms or a radical of the formula SO ₂ R ¹³ , the aryl radical in turn being one or more by

Halogen, hydroxy, CN, NO ₂ , NH ₂ , NHCOR ⁷ , alkyl, alkoxy, haloalkyl or haloalkoxy with up to 6 carbon atoms can be substituted, or two substituents from R ⁸ and R ⁹ or R ^{1 1} and R ¹² with each other may be linked to form a five- or six-membered ring which may contain O or N, Wonn

R ¹³ denotes straight-chain or branched alkyl having up to 4 carbon atoms or aryl having 6 to 10 carbon atoms, the aryl radical in turn being substituted one or more times by halogen, CN, NO ₂ , alkyl, alkoxy, haloalkyl or haloalkoxy having up to 6 carbon atoms can

R ^{10 is} hydrogen, straight-chain or branched alkyl having up to 12 carbon atoms, straight-chain or branched alkenyl having up to 12 carbon atoms, aryl having 6 to 10 carbon atoms, an aromatic heterocycle having 1 to 9

Carbon atoms and up to 3 heteroatoms from the series S, N and or O or cycloalkyl having 3 to 8 carbon atoms, which optionally further by halogen, hydroxy, CN, NO ₂ , NH ₂ , NHCOR ⁷ , alkyl, alkoxy, haloalkyl or haloalkoxy can be substituted with up to 6 carbon atoms;

and / or the cyclic radicals in each case one to three times by aryl with 6 to 10 carbon atoms, a saturated carbocycle with 6 to 10 carbon atoms, an aromatic or saturated heterocycle with 1 to 9 carbon atoms and up to 3 heteroatoms from the series S, N and / or O may be substituted, which may also be bonded via N, which may be direct or via a group of O, S, SO, SO ₂ , NR ⁷ , SO ₂ NR ⁷ , CONR ⁷ , straight-chain or branched alkylene, straight-chain or branched Alkenediyl, straight chain or mixed branched alkyloxy, straight-chain or branched oxyalkyloxy, straight-chain or branched sulfonylalkyl, straight-chain or branched thioalkyl, each having up to 8 carbon atoms, and one to three times by straight-chain or branched alkyl, straight-chain or branched alkoxy, straight-chain or branched alkoxyalkoxy, straight-chain or branched straight-chain or branched haloalkoxy, carbonylalkyl or straight-chain or branched alkenyl each having up to 6 carbon atoms, halogen, SR ⁶ , CN, NO ₂ , NR ⁸ R ⁹ , CONR ¹⁵ R ¹⁶ or NR ¹⁴ COR ¹⁷ can be substituted,

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R ¹⁴ denotes hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms or cycloalkyl having 3 to 8 carbon atoms,

R ¹⁵ and R ¹⁶ independently of one another, hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms, cycloalkyl having 3 to 8 carbon atoms, aryl having 6 to 10

Are carbon atoms or a radical of the formula SO ₂ R ¹⁸ , the aryl radical in turn being substituted one or more times by halogen, hydroxy, CN, NO ₂ , NH ₂ , NHCOR ⁷ , alkyl, alkoxy, haloalkyl or haloalkoxy having up to 6 carbon atoms can

Wonn

R 1 X denotes straight-chain or branched alkyl having up to 4 carbon atoms or aryl having 6 to 10 carbon atoms, the aryl radical in turn may be substituted one or more times by halogen, hydroxy, CN, NO ₂ , NH ₂ , NHCOR ⁷ , alkyl, alkoxy, haloalkyl or haloalkoxy having up to 6 carbon atoms,

and

R ^{17 is} hydrogen, straight-chain or branched alkyl having up to 12 carbon atoms, straight-chain or branched alkenyl having up to 12 carbon atoms, aryl having 6 to 10

Carbon atoms, an aromatic heterocycle having 1 to 9 carbon atoms and up to 3 heteroatoms from the series S, N and / or O or cycloalkyl having 3 to 8 carbon atoms, which may also be halogen, hydroxyl, CN, NO ₂ , NH ₂ , NHCOR ⁷ , alkyl, alkoxy,

Haloalkyl or haloalkoxy can be substituted with up to 6 carbon atoms;

and / or the cyclic radicals can be fused with an aromatic or saturated carbocycle with 1 to 10 carbon atoms or an aromatic or saturated heterocycle with 1 to 9 carbon atoms and up to 3 heteroatoms from the series S, N and / or O,

Hydrogen, halogen, straight-chain or branched alkyl, which can optionally carry one or more substituents from the group consisting of Cl-6-alkoxy, NR ¹⁹ R ²⁰ , cycloalkyl having 3 to 8 carbon atoms, straight-chain or branched haloalkyl, straight-chain or branched Alkoxy, or alkoxycarbonyl each having up to 4 carbon atoms, CN, NO ₂ , NR ¹⁹ R ²⁰ , SR ¹⁷ ,

SO ₂ R ¹⁷ , cycloalkyl of 3 to 8 carbon atoms, haloalkoxy Haloalkoxy with up to 6 carbon atoms, cycloalkoxy with up to 14 carbon atoms, CONH ₂ , CONR ¹⁷ R ¹⁷ , SO ₂ NH ₂ , SO ₂ NR ¹⁷ R ¹⁷ , alkoxyalkoxy with up to 12 carbon atoms, NHCOOR ¹⁷ , NHCOR ¹⁷ , NHSO ₂ R ¹⁷ , NHCONH ₂ , OCONR ^{, 7} R ¹⁷ , OSO ₂ R ¹⁷ , C ₂ -i ₂ alkenyl or C ₂ . ₁₂ -alkynyl means

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R ¹⁹ and R ²⁰ independently of one another, hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms or

Mean cycloalkyl having 3 to 8 carbon atoms,

m represents an integer from 1 to 4,

W denotes straight-chain or branched alkylene with up to 6 carbon atoms or straight-chain or branched alkenediyl with up to 6 carbon atoms, each of which can contain a group from O, S (O) _q , NR ²¹ , CO or CONR ²¹ , or CO, NHCO or OCO means

wherein

q represents 0, 1 or 2,

R ^{21 is} hydrogen, straight-chain or branched alkyl with up to 8

Means carbon atoms or cycloalkyl having 3 to 8 carbon atoms,

U denotes straight-chain or branched alkyl having up to 4 carbon atoms, A is aryl with 6 to 10 carbon atoms or an aromatic heterocycle with 1 to 9 carbon atoms and up to 3 heteroatoms from the series S, N and or O, which may be one to three times by halogen, straight-chain or branched alkyl, straight-chain or branched haloalkyl straight-chain or branched alkoxy, haloalkoxy or alkoxycarbonyl with up to 4 carbon atoms, CN, NO ₂ or NR ²² R ²³ can be substituted,

wherein

R ²² and R ²³ each independently of one another represent hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms or cycloalkyl having 3 to 8 carbon atoms, carbonylalkyl or sulfonylalkyl,

R ^{2 means} tetrazolyl, COOR ²⁴ or CONR ²⁵ R ²⁶ ,

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R ^{24 is} hydrogen, alkyl of 1 to 8 carbon atoms or cycloalkyl of 3 to 8 carbon atoms

R ²⁵ and R ²⁶ each independently of one another, hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms,

Are cycloalkyl having 3 to 8 carbon atoms or a radical of the formula SO ₂ R ²⁷ ,

or R ²⁵ and R ²⁶ together form a five- or six-membered ring which may contain N or O,

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R ²⁷ denotes straight-chain or branched alkyl having up to 4 carbon atoms or aryl having 6 to 10 carbon atoms, the aryl radical in turn being substituted one or more times by halogen, CN, NO ₂ , alkyl, alkoxy, haloalkyl or

Haloalkoxy can be substituted with up to 6 carbon atoms,

straight-chain or branched alkylene with up to 12 carbon atoms or straight-chain or branched alkenediyl with up to 12

Means carbon atoms, each of which can contain one to three groups of O, S (O) _r , NR ²⁸ , CO or CONR ²⁹ , aryl or aryloxy having 6 to 10 carbon atoms, the aryl radical in turn being used one or more times by halogen, CN, NO ₂ , alkyl, alkoxy, haloalkyl or haloalkoxy can be substituted with up to 6 carbon atoms, any two atoms of the above chains being connected to one another by an alkyl chain to form a three- to eight-membered ring,

wherein

r represents 0, 1 or 2,

R ^{28 represents} hydrogen, alkyl having 1 to 8 carbon atoms or cycloalkyl having 3 to 8 carbon atoms, R ²⁹ denotes hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms or cycloalkyl having 3 to 8 carbon atoms,

n represents 1 or 2;

R ^{1 means} tetrazolyl, COOR ³⁰ or CONR ³¹ R ³² ,

wherein

R ^{30 is} hydrogen, alkyl of 1 to 8 carbon atoms or cycloalkyl of 3 to 8 carbon atoms

R ³¹ and R ³² each independently of one another, hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms,

Are cycloalkyl having 3 to 8 carbon atoms or a radical of the formula SO ₂ R ³³ ,

Wonn

R ³³ denotes straight-chain or branched alkyl having up to 4 carbon atoms or aryl having 6 to 10 carbon atoms, the aryl radical in turn being used one or more times by halogen, CN, NO ₂ , alkyl, alkoxy, haloalkyl or

Haloalkoxy can be substituted with up to 6 carbon atoms,

and their stereoisomers and salts.

2. Compounds according to claim 1, embedded image in which

for a cyclic radical from the group consisting of

the radicals V and W can be bonded to any carbon atom or to any nitrogen atom of a ring which may be present;

V is missing, O, NR ⁴ , NR ⁴ CONR ⁴ , NR ⁴ CO, NR ⁴ SO ₂ , COO, CONR ⁴ or

S (O) ₀ means

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R ^{4 is} independent of any other one that may be present

Radical R ^{4 is} hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms, cycloalkyl having 3 to 8 carbon atoms, aryl having 6 to 10 carbon atoms or arylalkyl having 7 to 18 carbon atoms, the aryl radical in turn being one or more times by halogen, alkyl,

Alkoxy can be substituted with up to 6 carbon atoms,

o means 0, 1 or 2,

Q is absent, straight-chain or branched alkylene, straight-chain or branched alkenediyl or straight-chain or branched alkynediyl each having up to 12 carbon atoms, each of which means one or more groups of O, S (O) _p , NR ⁵ , CO, NR ⁵ SO ₂ or CONR ^{5 can} contain, and can be substituted one or more times by halogen, hydroxy or alkoxy with up to 4 carbon atoms, optionally any two atoms of the above chain can be connected to form a three- to eight-membered ring,

wherein R ⁵ denotes hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms or cycloalkyl having 3 to 8 carbon atoms, which can be substituted by halogen or alkoxy having up to 4 carbon atoms,

p means 0, 1 or 2,

Hydrogen, NR ⁸ R ⁹ , aryl with 6 to 10 carbon atoms, an aromatic or saturated heterocycle with 1 to 9 carbon atoms and up to 3 heteroatoms from the series S, N and / or O or straight-chain or branched cycloalkyl with 3 to 8 Means carbon atoms, which can also be bonded via N, the cyclic radicals in each case one to three times by straight-chain or branched alkyl, straight-chain or branched alkenyl, straight-chain or branched alkynyl, straight-chain or branched alkoxy, straight-chain or branched alkoxyalkoxy, straight-chain or branched haloalkyl , straight-chain or branched haloalkoxy each having up to 8 carbon atoms, straight-chain or branched cycloalkyl having 3 to 8 carbon atoms, halogen, hydroxy, CN, SR ⁶ , NO ₂ , NR ⁸ R ⁹ , NR ⁷ COR ¹⁰ ,

NR ⁷ CONR ⁷ R ¹⁰ or CONR ^u R ¹² can be substituted,

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R ^{6 is} hydrogen, straight-chain or branched alkyl with up to 8

Is carbon atoms, straight-chain or branched haloalkyl having up to 8 carbon atoms or cycloalkyl having 3 to 8 carbon atoms,

R ^{7 is} independent of any other one that may be present

R radical is hydrogen, straight-chain or branched alkyl means up to 8 carbon atoms or cycloalkyl with 3 to 8 carbon atoms,

R ⁸ , R ⁹ , R ¹¹ and R ¹² independently of one another, hydrogen, straight-chain or branched alkyl, straight-chain or branched

Alkenyl with up to 8 carbon atoms, aryl with 6 to 10 carbon atoms, an aromatic heterocycle with 1 to 9 carbon atoms and up to 3 heteroatoms from the series S, N and / or O, arylalkyl with 8 to 18 carbon atoms, cycloalkyl with 3 to 8 Carbon atoms or a residue of

Formula mean SO ₂ R ¹³ , where the aryl radical in turn can be substituted one or more times by halogen, hydroxy, CN, NO ₂ , NH ₂ , NHCOR ⁷ , alkyl, alkoxy, haloalkyl or haloalkoxy with up to 6 carbon atoms, or two substituents from R ⁸ and R ⁹ or R ¹¹ and R ¹² can be bonded to one another to form a five- or six-membered ring which can contain O or N,

wherein

R denotes straight-chain or branched alkyl having up to 4 carbon atoms or aryl having 6 to 10 carbon atoms, the aryl radical in turn being repeated one or more times

Halogen, CN, NO ₂ , alkyl, alkoxy, haloalkyl or haloalkoxy with up to 6 carbon atoms can be substituted,

R ^{1 is} hydrogen, straight-chain or branched alkyl with up to

12 carbon atoms, straight-chain or branched alkenyl with up to 12 carbon atoms, aryl with 6 to 10 carbon atoms, an aromatic heterocycle with 1 to 9 carbon atoms and up to 3 heteroatoms from the series S, N and or O or cycloalkyl with 3 to 8 carbon atoms, which may furthermore mean by

Halogen, hydroxy, CN, NO ₂ , NH ₂ , NHCOR ⁷ , alkyl, alkoxy, haloalkyl or haloalkoxy with up to 6 carbon atoms can be substituted;

and / or the cyclic radicals each one to three times by using aryl

6 to 10 carbon atoms, an aromatic or saturated heterocycle having 1 to 9 carbon atoms and up to 3 heteroatoms from the series S, N and or O can be substituted, which can also be bonded via N, which directly or via a group from O, S, SO, SO ₂ , NR ⁷ ,

SO ₂ NR ⁷ , CONR ⁷ , straight-chain or branched alkylene, straight-chain or branched alkenediyl, straight-chain or branched alkyloxy, straight-chain or branched oxyalkyloxy, straight-chain or branched sulfonylalkyl, straight-chain or branched thioalkyl each having up to 8 carbon atoms and can be bound up to three times by straight-chain or branched alkyl, straight-chain or branched alkoxy, straight-chain or branched alkoxyalkoxy, straight-chain or branched haloalkyl, straight-chain or branched haloalkoxy, carbonylalkyl or straight-chain or branched alkenyl each having up to 6 carbon atoms, halogen, SR ⁶ , CN, NO ₂ , NR ⁸ R ⁹ , CONR ¹⁵ R ¹⁶ or NR ¹⁴ COR ¹⁷ can be substituted,

embedded image in which R ¹⁴ denotes hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms or cycloalkyl having 3 to 8 carbon atoms,

R ¹⁵ and R ¹⁶ independently of one another are hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms, cycloalkyl having 3 to 8 carbon atoms or a radical of the formula SO ₂ R ¹⁸ ,

wherein

R ¹⁸ denotes straight-chain or branched alkyl having up to 4 carbon atoms or aryl having 6 to 10 carbon atoms, the aryl radical in turn being repeated one or more times

Halogen, CN, NO ₂ , alkyl, alkoxy, haloalkyl or haloalkoxy with up to 6 carbon atoms can be substituted,

and

R ^{17 is} hydrogen, straight-chain or branched alkyl having up to 12 carbon atoms, straight-chain or branched alkenyl having up to 12 carbon atoms, aryl having 6 to 10 carbon atoms, an aromatic heterocycle having 1 to

9 carbon atoms and up to 3 heteroatoms from the series S, N and or O or cycloalkyl having 3 to 8 carbon atoms, which may also be halogen, CN, NO ₂ , alkyl, alkoxy, haloalkyl or halogenoalkoxy having up to 6 carbon atoms can be substituted; and / or the cyclic radicals can be fused with an aromatic or saturated carbocycle with 1 to 10 carbon atoms or an aromatic or saturated heterocycle with 1 to 9 carbon atoms and up to 3 heteroatoms from the series S, N and / or O,

R, 3 is hydrogen, halogen, straight-chain or branched alkyl, which can optionally carry one or more substituents from the group consisting of C 1-6 alkoxy, NR ¹⁹ R ²⁰ , cycloalkyl having 3 to 8 carbon atoms, straight-chain or branched haloalkyl , straight-chain or branched alkoxy, or alkoxycarbonyl with up to 4 carbon atoms, CN, NO ₂ , NR ¹⁹ R ²⁰ , SR ¹⁷ , SO ₂ R ¹⁷ , cycloalkyl with 3 to 8 carbon atoms, haloalkoxy haloalkoxy with up to 6 Carbon atoms, cycloalkoxy with up to 14 carbon atoms, CONH ₂ , CONR ¹⁷ R ¹⁷ , SO ₂ NH ₂ , SO ₂ NR ¹⁷ R ¹⁷ , alkoxyalkoxy with up to 12 carbon atoms, NHCOOR ¹⁷ , NHCOR ¹⁷ , NHSO ₂ R ¹⁷ , NHCONH ₂ , OCONR ¹⁷ R ¹⁷ ,

C ₂ -ι ₂ - alkenyl or C ₂ -ι ₂ alkynyl,

m represents an integer from 1 to 4,

W denotes straight-chain or branched alkylene or straight-chain or branched alkenediyl each having up to 4 carbon atoms,

U -CH ₂ - means

A is phenyl or an aromatic heterocycle having 1 to 9 carbon atoms and up to 3 heteroatoms from the series S, N and or O, which may optionally be mono- to trisubstituted by halogen, straight-chain or branched alkyl, straight-chain or branched haloalkyl or straight-chain or branched alkoxy having up to 4 carbon atoms,

R ^{2 means} COOR ²⁴

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R ²⁴ denotes hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms,

X denotes straight-chain or branched alkylene with up to 8 carbon atoms or straight-chain or branched alkenediyl with up to 8 carbon atoms, each of which consists of one to three groups

Can contain phenyl, phenyloxy, O, CO or CONR ²⁹ ,

embedded image in which

R ^{29 is} hydrogen, straight-chain or branched alkyl with up to 6

Means carbon atoms or cycloalkyl having 3 to 6 carbon atoms,

n represents 1 or 2;

R ^{1 means} COOR ³⁰ ,

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R is hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms. Compounds according to claim 1,

embedded image in which

for a cyclic radical from the group consisting of

the radicals V and W can be bonded to any carbon atom or to any nitrogen atom of a ring which may be present;

V is absent, O, S or NR ⁴ means

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R> 4 denotes hydrogen or methyl,

is absent, means straight-chain or branched alkylene with up to 9 carbon atoms or straight-chain or branched alkenediyl or straight-chain or branched alkynediyl with up to 4 carbon atoms, which can be simply substituted by halogen,

H, NR8n R9, cyclohexyl, phenyl, naphthyl or a heterocycle from the group

means which can also be bonded via N, where the cyclic radicals are each one to three times by straight-chain or branched alkyl, straight-chain or branched alkenyl, straight-chain or branched alkynyl, straight-chain or branched alkoxy, straight-chain or branched alkoxyalkoxy, straight-chain or branched haloalkyl, straight-chain or branched haloalkoxy each having up to 4 carbon atoms, straight-chain or branched cycloalkyl having 3 to 6 carbon atoms, F, CI, Br, I, NO ₂ , SR ⁶ , NR ⁸ R ⁹ , NR ⁷ COR ¹⁰ or CONR ^π R ¹² substituted can be what R ⁶ denotes hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms, or straight-chain or branched haloalkyl having up to 4 carbon atoms,

R ⁷ denotes hydrogen, or straight-chain or branched alkyl having up to 4 carbon atoms,

R ⁸ , R ⁹ , R ¹¹ and R ¹² independently of one another are hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms, or phenyl, the phenyl radical being mono- to triple by F, CI Br, hydroxyl, methyl, ethyl, n - Propyl, i-propyl, n-butyl, s-butyl, i-butyl, t-butyl, methoxy, ethoxy, amino, acetylamino, NO ₂ , CF ₃ , OCF or CN can be substituted, or two substituents from R ⁸ and R ⁹ or R ¹¹ and R ¹² can be connected to one another to form a five- or six-membered ring which can be interrupted by O or N,

R ^{10 is} hydrogen, straight-chain or branched alkyl with up to 4

Carbon atoms, or phenyl, the phenyl radical being one to three times by F, CI Br, hydroxy, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl, t-butyl, methoxy , Ethoxy, amino, acetylamino, NO ₂ , CF, OCF3 or CN may be substituted;

and / or the cyclic radicals in each case one to three times by phenyl or a heterocycle from the group

May be substituted, which are directly or via a group of O, S, SO, SO ₂ , NR ⁴ , SO ₂ NR ⁷ , CONR ⁷ , straight-chain or branched alkylene, straight-chain or branched alkenediyl, straight-chain or branched alkyloxy, straight-chain or branched oxyalkyloxy , straight-chain or branched sulfonylalkyl, straight-chain or branched thioalkyl, each having up to 4 carbon atoms, and one to three times by straight-chain or branched alkyl, straight-chain or branched alkoxy, straight-chain or branched alkoxyalkoxy, straight-chain or branched haloalkyl or straight-chain or branched alkenyl or branched up to 4 carbon atoms, F, CI, Br, I, CN, SCH ₃ , OCF ₃ , NO ₂ , NR ⁸ R ⁹ or NR ¹⁴ COR ¹⁷ can be substituted,

wherein R ¹⁴ denotes hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms or cycloalkyl having 3 to 8 carbon atoms,

and

R ^{17 is} hydrogen, straight-chain or branched alkyl having up to 12 carbon atoms, straight-chain or branched alkenyl having up to 12 carbon atoms, aryl having 6 to 10 carbon atoms, an aromatic heterocycle having 1 to

9 carbon atoms and up to 3 heteroatoms from the series S, N and / or O or cycloalkyl having 3 to 8 carbon atoms, which may also be represented by F, CI Br, hydroxy, methyl, ethyl, n-propyl, i-propyl, n Butyl, s-butyl, i-butyl, t-butyl, methoxy, ethoxy, amino, acetylamino, NO ₂ , CF ₃ , OCF ₃ or CN;

and / or the cyclic radicals can be fused with an aromatic or saturated carbocycle with 1 to 10 carbon atoms or an aromatic or saturated heterocycle with 1 to 9 carbon atoms and up to 3 heteroatoms from the series S, N and / or O,

R represents hydrogen, methyl or fluorine,

m represents an integer from 1 to 2,

W denotes CH ₂ , -CH ₂ CH ₂ -, CH2CH2CH2, CH = CHCH ₂ ,

U -CH ₂ - means A is phenyl, pyridyl, thienyl or thiazolyl, which may be mono- to triple by methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, CF ₃ , methoxy, Ethoxy, F, CI, Br can be substituted,

R ^{2 means} COOR ²⁴

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R ²⁴ denotes hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms,

X denotes straight-chain or branched alkylene with up to 8 carbon atoms or straight-chain or branched alkenediyl with up to 8 carbon atoms, each of which consists of one to three groups

Can contain phenyl, phenyloxy, O, CO or CONR ³⁰ ,

embedded image in which

R ^{30 is} hydrogen, straight-chain or branched alkyl with up to 6

Means carbon atoms or cycloalkyl having 3 to 6 carbon atoms,

n represents 1 or 2;

R ^{1 means} COOR ³⁵ ,

embedded image in which

R> 35 is hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms. Compounds according to claim 1,

embedded image in which

Z for a cyclic radical from the group consisting of

the radicals V and W can be bonded to any carbon atom or to any nitrogen atom of a ring which may be present;

V O means

means straight-chain or branched alkylene with up to 9 carbon atoms or straight-chain or branched alkenediyl or straight-chain or branched alkynediyl with up to 4 carbon atoms, which can be simply substituted by halogen,

H, cyclohexyl, phenyl or a heterocycle from the group

means, the cyclic radicals in each case one to three times by straight-chain or branched alkyl, straight-chain or branched alkenyl, straight-chain or branched alkynyl, straight-chain or branched alkoxy, straight-chain or branched alkoxyalkoxy, straight-chain or branched haloalkyl, straight-chain or branched haloalkoxy with in each case up to 4 carbon atoms, straight-chain or branched cycloalkyl with 3 to 6 carbon atoms, F, CI, Br, I, NO ₂ , SR ⁶ , NR ⁸ R ⁹ , NR ⁷ COR ¹⁰ or CONR ^π R ¹² can be substituted,

Wonn R ⁶ denotes hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms, or straight-chain or branched haloalkyl having up to 4 carbon atoms,

R ⁷ denotes hydrogen, or straight-chain or branched alkyl having up to 4 carbon atoms,

R ⁸ , R ⁹ , R ¹¹ and R ¹² independently of one another are hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms, or phenyl, the phenyl radical being mono- to triple by F, CI Br, hydroxyl, methyl, ethyl, n - Propyl, i-propyl, n-butyl, s-butyl, i-butyl, t-butyl, methoxy, ethoxy, amino, acetylamino, NO2, CF ₃ , OCF ₃ or CN can be substituted, or two substituents from R ⁸ and R ⁹ or R ¹¹ and R ¹² can be connected to one another to form a five- or six-membered ring which can be interrupted by O or N,

R ^{10 is} hydrogen, straight-chain or branched alkyl with up to 4

Carbon atoms, or phenyl, the phenyl radical being one to three times by F, CI Br, hydroxy, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl, t-butyl, methoxy , Ethoxy, amino, acetylamino, NO ₂ , CF ₃ , OCF ₃ or CN may be substituted;

and or the cyclic radicals in each case one to three times by phenyl or a heterocycle from the group

Can be substituted, which are directly or via a group of O, S, SO, SO ₂ , straight-chain or branched alkylene, straight-chain or branched alkenediyl, straight-chain or branched alkyloxy, straight-chain or branched oxyalkyloxy, straight-chain or branched sulfonyl-alkyl, straight-chain or branched Thioalkyl each having up to 4 carbon atoms and can be bonded one to three times by straight-chain or branched alkyl, straight-chain or branched alkoxy, straight-chain or branched alkoxyalkoxy, straight-chain or branched haloalkyl or straight-chain or branched alkenyl each having up to 4 carbon atoms, F, CI, Br, I, CN, SCH ₃ , OCF ₃ , NO ₂ , NR ⁸ R ⁹ or NR ¹⁴ COR ¹⁷ can be substituted,

wherein

R 14 is hydrogen, straight-chain or branched alkyl having up to 6 carbon atoms or cycloalkyl having 3 to 6 carbon atoms. and

R ^{17 is} hydrogen, straight-chain or branched alkyl having up to 6 carbon atoms, straight-chain or branched alkenyl having up to 6 carbon atoms, aryl having 6 to 10 carbon atoms, an aromatic heterocycle having 1 to 9 carbon atoms and up to 3 heteroatoms from the series S, N and / or O or cycloalkyl having 3 to 6 carbon atoms, which may also be represented by F, CI

Br, hydroxy, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl, t-butyl, methoxy, ethoxy, amino, acetylamino, NO ₂ , CF ₃ , OCF or CN substituted could be;

and / or the cyclic radicals can be fused with an aromatic or saturated carbocycle with 1 to 10 carbon atoms or an aromatic or saturated heterocycle with 1 to 9 carbon atoms and up to 3 heteroatoms from the series S, N and / or O,

R »3 denotes hydrogen, methyl or fluorine,

m represents an integer from 1 to 2,

W -CH ₂ - or -CH ₂ CH ₂ - means

U -CH ₂ - means

A is phenyl, which is optionally one to three times by methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, CF ₃ ,

Methoxy, ethoxy, F, CI, Br can be substituted, R ^{2 means} COOR ²⁴

embedded image in which

R ²⁴ denotes hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms,

X straight-chain or branched alkylene with up to 6 carbon atoms or straight-chain or branched alkenediyl with up to 6

Means carbon atoms, each of which can contain one to three groups of phenyloxy, O, CO or CONR ³⁰ ,

embedded image in which

R ³⁰ denotes hydrogen, straight-chain or branched alkyl having up to 6 carbon atoms or cycloalkyl having 3 to 6 carbon atoms,

n represents 1 or 2;

R ^{1 means} COOR ³⁵ ,

embedded image in which

R ^{35 is} hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms.

5. Compounds according to claim 1,

embedded image in which for a cyclic radical from the group consisting of

the radicals V and W can be bonded to any carbon atom or to any nitrogen atom of a ring which may be present;

V O means

means straight-chain or branched alkylene with up to 9 carbon atoms or straight-chain or branched alkenediyl or straight-chain or branched alkynediyl with up to 4 carbon atoms, which can be simply substituted by halogen,

Y H, cyclohexyl, phenyl or a heterocycle from the group

means where the cyclic radicals are each one to three times by straight-chain or branched alkyl, straight-chain or branched alkenyl, straight-chain or branched alkynyl, straight-chain or branched alkoxy, straight-chain or branched alkoxyalkoxy, straight-chain or branched haloalkyl, straight-chain or branched haloalkoxy, each with up to 4 carbonalkoxy straight-chain or branched cycloalkyl having 3 to 6 carbon atoms, F, CI, Br, I, NO ₂ , SR ⁶ , NR ⁸ R ⁹ , NR ⁷ COR ¹⁰ or CONR ^π R ¹² can be substituted,

embedded image in which

R ⁶ denotes hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms, or straight-chain or branched haloalkyl having up to 4 carbon atoms,

R ⁷ denotes hydrogen, or straight-chain or branched alkyl having up to 4 carbon atoms,

R ⁸ , R ⁹ , R ¹¹ and R ¹² independently of one another are hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms, or phenyl, the phenyl radical being mono- to triple by F, CI Br, hydroxyl, methyl, ethyl, n Propyl, i-propyl, n-butyl, s-butyl, i-butyl, t-butyl, methoxy, ethoxy, amino, acetylamino, NO ₂ , CF ₃ ,

OCF or CN can be substituted, or two substituents from R ⁸ and R ⁹ or R ¹¹ and R ¹² can be connected to one another to form a five- or six-membered ring which can be interrupted by O or N, R lo represents hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms, or phenyl, where the phenyl radical is mono- to triple by F, CI Br, hydroxy, methyl, ethyl, n-propyl, i-propyl, n-butyl, see -Butyl, i-butyl, t-butyl, methoxy, ethoxy, amino, acetylamino, NO ₂ , CF ₃ , OCF ₃ or CN may be substituted;

and / or the cyclic radicals in each case one to three times by phenyl or a heterocycle from the group

Can be substituted, which are directly or via a group of O, S, SO, SO ₂₎ straight-chain or branched alkylene, straight-chain or branched alkenediyl, straight-chain or branched alkyloxy, straight-chain or branched oxyalkyloxy, straight-chain or branched sulfonylalkyl, straight-chain or branched Thioalkyl, each having up to 4 carbon atoms, can be bonded one to three times by straight-chain or branched alkyl, straight-chain or mixed branched alkoxy, straight-chain or branched alkoxyalkoxy, straight-chain or branched haloalkyl or straight-chain or branched alkenyl each having up to 4 carbon atoms, F, CI, Br, I, CN, SCH ₃ , OCF ₃ , NO ₂ , NR ⁸ R ⁹ or NR ¹⁴ COR ¹⁷ can be substituted,

embedded image in which

R ¹⁴ denotes hydrogen, straight-chain or branched alkyl having up to 6 carbon atoms or cycloalkyl having 3 to 6 carbon atoms,

and

R ^{17 is} hydrogen, straight-chain or branched alkyl with up to 6

Carbon atoms, straight-chain or branched alkenyl with up to 6 carbon atoms, aryl with 6 to 10 carbon atoms, an aromatic heterocycle with 1 to 9 carbon atoms and up to 3 heteroatoms from the series S, N and / or O or cycloalkyl with 3 to 6 carbon atoms , which may also be represented by F, CI Br, hydroxy, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl, t-butyl, methoxy, ethoxy, amino, acetylamino, NO ₂ , CF ₃ , OCF ₃ or CN may be substituted;

and / or the cyclic radicals can be fused with an aromatic or saturated carbocycle with 1 to 10 carbon atoms or an aromatic or saturated heterocycle with 1 to 9 carbon atoms and up to 3 heteroatoms from the series S, N and or O, R ^{3 represents} hydrogen, methyl or fluorine,

m represents an integer from 1 to 2,

W -CH ₂ - or -CH ₂ CH ₂ - means

U -CH ₂ - means

A is phenyl, which is optionally one to three times by methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, CF ₃ ,

Methoxy, ethoxy, F, CI, Br can be substituted,

R ² means COOH,

X denotes straight-chain or branched alkylene with up to 6 carbon atoms or straight-chain or branched alkenediyl with up to 6 carbon atoms, each of which can contain one to three groups of phenyloxy, O, CO or CONR ³⁰ ,

wherein

R ³⁰ denotes hydrogen, straight-chain or branched alkyl having up to 6 carbon atoms or cycloalkyl having 3 to 6 carbon atoms,

n represents 1 or 2;

R ¹ means COOH.

Compounds according to claim 1, wherein for a cyclic radical from the group consisting of

the radicals V and W can be bonded to any carbon atom or to any nitrogen atom of a ring which may be present;

V O means

Q means CH ₂

Y is phenyl which is substituted by a radical selected from the group consisting of 2-phenylethyl, cyclohexyl, 4-chlorophenyl, 4-

Methoxyphenyl, 4-trifluoromethylphenyl, 4-cyanophenyl, 4-chlorophenoxy, 4-methoxyphenoxy, 4-trifluoromethylphenoxy, 4-cyanophenoxy, 4-methylphenyl is selected,

R ^{3 represents} hydrogen, methyl or fluorine,

m represents an integer from 1 to 2,

W -CH ₂ CH ₂ - means

U -CH ₂ - means

A means phenyl

R means COOH, where _{R2 is} in the 4-position to the rest U,

X means (CH ₂ ) ₄ ,

R ¹ means COOH.

7. Compounds according to claim 1, wherein for a cyclic radical from the group consisting of

the radicals V and W can be bonded to any carbon atom or to any nitrogen atom of a ring which may be present;

V is missing,

Q means CH ₂ O which is bonded to Z via its carbon atom,

Y is phenyl which is substituted by a radical selected from the group consisting of 2-phenylethyl, cyclohexyl, 4-chlorophenyl, 4-

Methoxyphenyl, 4-trifluoromethylphenyl, 4-cyanophenyl, 4-chlorophenoxy, 4-methoxyphenoxy, 4-trifluoromethylphenoxy, 4-cyanophenoxy, 4-methylphenyl, 4-tert-butylphenyl, 4-carboxyphenyl, 4-fluorophenyl, 3- Methoxyphenyl, 2,4-dichlo henyl is selected,

R ^{3 represents} hydrogen, methyl or fluorine,

m represents an integer from 1 to 2,

W -CH ₂ CH ₂ - means

U -CH ₂ - means

A means phenyl

R ² means COOH, where _{R2 is arranged} in the 4-position to the rest U,

X means (CH ₂ ) ₄ ,

R ¹ means COOH. Process for the preparation of compounds of general formula (I), characterized in that

[A] compounds of the formula (IT)

with compounds of the formula (HI)

E-X-R '(HI)

implements,

wherein

Z, R ¹ , R ² , R ³ , V, Q, Y, W, X, U, A and m have the same meanings as defined above,

E either means a leaving group which in the presence of a

Base is substituted, or is an optionally activated hydroxy function;

or

[B] Compounds of Formula (IV)

with compounds of formula (V)

implements,

embedded image in which

Z, R ¹ , R ² , R ³ , V, Q, Y, W, X, U, A and m have the same meanings as defined above,

E is either a leaving group which is substituted in the presence of a base or an optionally activated one

Is hydroxy function;

or

[C] compounds of the formula (VI)

with compounds of the formula (VH)

E-U-A-R '(VH)

implements,

embedded image in which

Z, R ¹ , R, RV, Q, Y, W, X, U, A and m have the same meanings as defined above,

E is either a leaving group which is substituted in the presence of a base or an optionally activated one

Is hydroxy function;

or

[D] compounds of the formula (VIH),

embedded image in which Va stands for O or S and

Z, R ¹ , R ² , R ³ , Y, Q, W, U, A, X and m have the meaning given above

with compounds of formula (IX)

, Q.

Υ (IX)

implements,

embedded image in which

Q, Y have the same meanings as defined above,

E either means a leaving group which in the presence of a

Base is substituted, or is an optionally activated hydroxy function;

or

[E] compounds of the formula (X),

embedded image in which

Z, R ³ , V, Q, Y, W, X, U, A and m have the same meanings as defined above,

R ^! _b and R each independently represent CN or COOAlk, where Alk represents a straight-chain or branched alkyl radical having up to 6 carbon atoms,

converted into the corresponding free carboxylic acids with aqueous solutions of strong acids or strong bases.

or

[F] Compounds of Formula (XI)

embedded image in which

Z, R, R, R, V, Q, X, W, U, A and m have the same meanings as defined above,

L represents Br, I or the group CF ₃ SO ₂ -O, with compounds of the formula (XII)

M-Z '(XU)

wherein

M represents an aryl or heteroaryl radical, a straight-chain or branched alkyl, alkenyl or alkynyl radical or cycloalkyl radical or an arylalkyl, an arylalkenyl or an arylalkynyl radical,

Z 'represents the groupings -B (OH) ₂ , -CH≡CH, -CH = CH ₂ or -Sn (nBu) ₃

in the presence of a palladium compound, optionally additionally in

In the presence of a reducing agent and other additives and in the presence of a base;

or

[G] compounds of the formula (XIH)

wherein Ar represents an aryl or heteroaryl radical,

E represents a leaving group which is substituted in the presence of a base.

reacted with compounds of the formula (Vm) by process D and the compounds of the formula (XIV) thus obtained

hydrogenated with hydrogen in the presence of a catalyst.

9. Medicament containing at least one compound of the general formula (1) according to one of the preceding claims.

10. Use of compounds of formula (I) according to one of the preceding claims for the manufacture of a medicament for the treatment of cardiovascular diseases.

11. Use of compounds of general formula (I) according to any one of the preceding claims for the manufacture of medicaments for the treatment of angina pectoris, ischemia and heart failure.

12. Use of compounds of general formula (I) according to one of the preceding claims for the manufacture of medicaments for the treatment of hypertension, thromboembolic disorders, arteriosclerosis and venous disorders.

13. Use of compounds of general formula (I) according to one of the preceding claims for the manufacture of medicaments for the treatment of fibrotic diseases.

14. Use according to claim 16, characterized in that the fibrotic

Liver fibrosis disease.