DE102005015957A1 - New substituted oxindole derivatives are vasopressin receptor binders useful to treat e.g. diabetes insipidus, enuresis nocturna, incontinence, hypertonia, heart failure, myocardial infarction, coronary spasm and renal disorders - Google Patents

Abstract

Substituted oxindole derivatives (I) and their tautomers, enantiomers, diastereomers, prodrugs and salts, are new. Substituted oxindole derivatives of formula (I) and their tautomers, enantiomers, diastereomers, prodrugs and salts, are new. A : (hetero)aromatic or partially-(hetero)aromatic 2-10C mono- or bicyclic ring comprising 0-4 N atoms or 0-2 of O-atoms and 0-2 of S-atoms and substituted with R a 1> and with 1-3 residues of R a 1> 1>, R a 1> 2> or R a 1> 3>; R a 1> 1>, R a 1> 2>, R a 1> 3>H, Cl, Br, I, F, CN, CF 3, OCF 3, OCNF 2, CO-NH 2, CO-NH (1-4C alkyl), CO-N-(1-4C alkyl) (1-4C alkyl), NH 2, NH (1-4C alkyl), N(1-4C alkyl)(1-4C alkyl), NHCHO, NH-CO-NH 2, NH-CO (1-4C alkyl), NO 2, OH, O-1-4C alkyl, O-(0-4C alkylene)-phenyl, phenyl, 1-6C alkyl, 1-6C haloalkyl, 2-6C alkenyl or 2-6C alkynyl; R a 1>R a 2>-(1-4C alkylene)-R a 4>; R a 2>(0-4C-alkylene)-O, (0-4C alkylene)-NR a 5>, (0-4C alkylene)-S, (0-4C-alkylene)-SO, (0-4C-alkylene)-SO 2, (0-4C-alkylene)-CO, (0-4C-alkylene)-NR a 5>-CO, (0-4C-alkylene)-CO-NR a 5>, (0-4C-alkylene)-CO-O, (0-4C-alkylene)-NR a 5>-SO 2, (0-4C alkylene)-SO 2-NR a 5>, (0-4C-alkylene)-NR a 5>-CO-NR a 6>, (0-4C-alkylene)-O-CO-NR a 5>, (0-4C-alkylene)-NR a 5>-CO-O or single bond; R a 4>NH 2, NH(1-4C-alkyl), N(1-4C-alkyl)(1-4C-alkyl), NH(1-4C-alkylene-O-1-4C-alkyl), N(1-4C-alkyl) (1-4C-alkylene-O-1-4C-alkyl), NH-CHO, N(1-4C-alkyl)-CHO, NH-CO-NH 2, N(1-4C alkyl)-CO-NH 2, NH-CO-1-4C-alkyl, N(1-4C-alkyl)-CO-1-4C-alkyl, NH-SO 2-1-4C-alkyl, N(1-4C-alkyl)-SO 2-1-4C-alkyl or ring R a 8>; R a 5>, R a 6>, R a 9>H, 1-4C-alkyl or 1-4C-haloalkyl; R a 8>e.g. -azetidine, -pyrrolidine, -piperidine, -morpholine or -thiomorpholine; B 1>2-10C (hetero)aromatic or partially-(hetero)aromatic mono- or bicyclic ring comprising 0-4 N atoms, 0-2 O atoms and/or 0-2 S atoms and 1-3 residues of R b 1>, R b 2> or R b 3>; R b 1>-R b 3>F, CN, CF 3, OCF 3, OCHF 2, CO-NH 2, CO-NH (1-4C-alkyl), CO-N(1-4C-alkyl), H, Cl, Br, I, (1-4C-alkyl), NH 2, NH (1-4C-alkyl), N(1-4C-alkyl) (1-4C-alkyl), NH-CHO, NH-CO-NH 2, NN-CO-1-4C-alkyl, NO 2, OH, O-1-4C-alkyl, O-CO-4C-alkylene-phenyl, phenyl, 1-6C-alkyl, 1-6C-haloalkyl, 2-6C-alkenyl or 2-6C-alkynyl; R 1>H, Cl, Br, I, F, CN, CF 3, OCF 3, OCHF 2, CO-NH 2, CO-NH (1-4C-alkyl), CO-N(1-4C-alkyl) (1-4C-alkyl), NH 2, NH(1-4C-alkyl), N(1-4C-alkyl) (1-4C-alkyl), NH-CHO, NH-CO-NH 2, NH-CO-(1-4C-alkyl), NO 2, OH, O-(1-4C-alkyl), O-(0-4C-alkylene)-phenyl, phenyl, 1-6C-alkyl, 1-6C-haloalkyl, 2-6C-alkenyl or 2-6C-alkynyl; R 2>H, 1-4C-alkyl, O-1-4C-alkyl, Cl or F; Y 1>-N(R y 1>)(C(R y 2>)(R y 3>)(R y 4>)); either R y 1>H, 1-4C-alkyl or 1-4C-haloalkyl; and R y 2>H or phenyl (optionally substituted with 1-5 residues of R ph 1>-R ph 5>); or R y 1>+R y 2>4-7 membered optionally saturated carbocyclic ring (where the C atom in the ring is substituted with heteroatoms of O, S or NR y 5>) substituted with R y 6> and R y 7>; R ph 1>-R ph 5>H, halo, 1-6C-alkyl or 1-6C-alkoxy, 1-6C-alkyl, 3-7C-cycloalkyl or 1-6C-haloalkyl; R y 5>H, 1-4C-alkyl or CO-1-4C-alkyl; either R y 6>, R y 7>F, CN, H, Cl, Br, I, CF 3, OCF 3, OCHF 2, CO-NH 2, CO-NH (1-4C-alkyl), CO-N(1-4C-alkyl) (1-4C-alkyl), NH 2, NH(1-4C-alkyl), N(1-4C-alkyl)(1-4C-alkyl), NH-CHO, NH-CO-NH 2, NH-CO-(1-4C-alkyl), OH, O-1-4C-alkyl, O-CO-1-4C-alkyl, O(CH 2) 0 - 2-phenyl, phenyl or 1-6C-alkyl; or CR y 6>, CR y 7>condensed phenyl ring or 5-6 membered aromatic heterocyclic group comprising 1-4 heteroatoms of N, O or S; R y 3>H, 1-4C-alkyl or 1-4C-haloalkyl; R y 4>CO-NR y 2> 1>R y 2> 2>, H, CO-1-4C-alkyl, COOH or CO-O-1-4C-alkyl; and either R y 2> 1>, R y 2> 2>H, 1-4C-alkyl or 1-4C-haloalkyl; or R y 2> 1>+R y 2> 2>4-6 membered optionally saturated carbocyclic ring. An independent claim is included for the preparation of (I). [Image] ACTIVITY : Antidiabetic; Uropathic; Cardiant; Vasotropic; Antianginal; Nephrotropic; Antiinflammatory; Antidiuretic; Cardiovascular-Gen.; Gastrointestinal-Gen.; Hepatotropic; Antiulcer; Antiemetic; Antidepressant; Tranquilizer; Nootropic; Neuroprotective; Neuroleptic; Endocrine-Gen.; Hypnotic; Antiaddictive. MECHANISM OF ACTION : Vasopressin receptor binder; Oxytoxin receptor binder. The affinity of (I) to bind human vasopressin subtype VIb was tested using biological assays. The results showed that binding affinity constant (Ki) of (S)-1-[5-chloro-1-(2,4-dimethoxy-benzenesulfonyl)-3-(2-methoxy-4-pyrrolidin-1-ylmethyl-phenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-pyrrolidin-2-carboxylic acid dimethylamide was less than 1 nM.

Description

The present invention relates to novel substituted oxindole derivatives, these containing drugs and their use for treatment of diseases.

vasopressin is an endogenous hormone, the most diverse effects on organs and tissues. In various disease states one suspects that that Vasopressin system plays a role such as heart failure and hypertension. Currently there are three receptors (V1a, V1b or V3 and V2), via the vasopressin mediates its numerous effects. Therefore, be Antagonists of these receptors as possible new therapeutic approaches for the treatment of diseases (M. Thibonnier, Exp. Invest. Drugs 1998, 7 (5), 729-740).

oxytocin is one formed in neurosecretory neurons of the hypothalamus and - bound to Neurophysins - to Pituitary posterior lobes transported and stored there hormone. Oxytocin stimulates the contraction of the uterine muscles and the myoepithelial Cells of the mammary gland (Milk injection) on; the contractile readiness of the uterus becomes by estrogens (promoting Effect) and gestagens (inhibitory effect) varies. The removal of Oxytocin is produced by the enzyme oxytocinase. Oxytocin is used in obstetrics (for example, for labor induction, in postpartum uterine atony) (cited from: Roche Lexicon Medicine 5th Edition).

In the present application describes novel substituted oxindoles, which carry an aryl-sulfonyl group in the 1-position. 1-phenylsulfonyl-1,3-dihydro-2H-indol-2-one have already been described as ligands of vasopressin receptors. In WO 93/15051, WO 95/18105, WO 98/25901, WO 01/55130, WO 01/55134, WO 01/164668 and WO 1/98295 have described derivatives derived from Oxindole structure are derived and carry in the 1-position Arylsulfonlygruppen. These Compounds differ significantly in the substitution in 3-position.

Especially WO 93/15051 and WO 98/25901 disclose 1-phenylsulfonyl-1,3-dihydro-2H-indole-2-ones described as ligands of vasopressin receptors in which the Oxindole structure in the 3-position is substituted by two alkyl radicals, which is also a cycloalkyl radical (Spiro linkage) could be. Alternatively, the spiro ring may contain heteroatoms, such as oxygen and Nitrogen (optionally with substituents) included.

The WO 95/18105 describes 1-phenylsulfonyl-1,3-dihydro-2H-indole-2-ones as ligands of vasopressin receptors containing a nitrogen atom in own the 3-position. additionally are attached in the 3-position radicals, the alkyl, cycloalkyl, Phenyl or benzyl radicals (each optionally with Substituent).

Other Publications, For example, WO 01/55130 describe compounds which are nitrogen containing rings (e.g., proline, homoproline, morpholine, Tetrahydroisoquinoline, dihydroindole; each optionally with substituents), the above their nitrogen atom bound to the 3-position of the oxindole skeleton but which are substituted by phenylsulfonyl or phenyl groups (optionally with substituents) in both the 1-position and the 3-position substituted on the oxindole ring.

In WO 03/008407 describes 1-phenylsulfonyl-oxindoles in which in 3 position pyridylpiperazines over an oxycarbonyl group is attached to the oxindole.

task The present invention is further compounds for treatment or prophylaxis of various vasopressin-dependent or dependent oxytocin Diseases available to provide a high and selective activity.

worin
A ein aromatischer, heteroaromatischer, teil-aromatischer oder teil-heteroaromatischer mono- oder bicyclischer Ring ist, der aus 2, 3, 4, 5, 6, 7, 8, 9 oder 10 Kohlenstoff-Atomen sowie 0, 1, 2, 3 oder 4 Stickstoff-Atomen und/oder 0, 1 oder 2 Sauerstoff-Atomen und/oder 0, 1 oder 2 Schwefel-Atomen besteht, und der mit dem Rest R_A ¹ substituiert ist und ausserdem zusätzlich mit 1, 2 oder 3 Resten R_A ¹¹, R_A ¹² und/oder R_A ¹³ substituiert sein kann, die unabhängig voneinander und unabhängig von ihrem jeweiligen Auftreten ausgewählt sind aus der Gruppe, bestehend aus Wasserstoff, Chlor, Brom, Iod, Fluor, CN, CF₃, OCF₃, OCHF₂, CO-NH₂, CO-NH(C₁-C₄-Alkyl), CO-N(C₁-C₄-Alkyl)(C₁-C₄-Alkyl), NH₂, NH(C₁-C₄-Alkyl), N(C₁-C₄-Alkyl)(C₁-C₄-Alkyl), NHCHO, NH-CO-NH₂, NH-CO(C₁-C₄-Alkyl), NO₂, OH, O-C₁-C₄-Alkyl, O-C₀-C₄-Alkylen-Phenyl, Phenyl, C₁-C₆-Alkyl, C₁-C₆-Halogenalkyl, C₂-C₆-Alkenyl und C₂-C₆-Alkinyl,
worin
R_A ¹ R_A ²-(C₁-C₄-Alkylen)-R_A ⁴ ist,
R_A ² ausgewählt ist aus der Gruppe, bestehend aus (C₀-C₄-Alkylen)-O, (C₀-C₄-Alkylen)-NR_A ⁵, (C₀-C₄-Alkylen)-S, (C₀-C₄-Alkylen)-SO, (C₀-C₄-Alkylen)-SO₂, (C₀-C₄-Alkylen)-CO, (C₀-C₄-Alkylen)-NR_A ⁵-CO, (C₀-C₄-Alkylen)-CO-NR_A ⁵, (C₀-C₄-Alkylen)-CO-O, (C₀-C₄-Alkylen)-NR_A ⁵-SO₂, (C₀-C₄-Alkylen)-SO₂-NR_A ⁵, (C₀-C₄-Alkylen)-NR_A ⁵-CO-NR_A ⁶, (C₀-C₄-Alkylen)-O-CO-NR_A ⁵, (C₀-C₄-Alkylen)-NR_A ⁵-CO-O und Einfachbindung,
R_A ⁴ ausgewählt ist aus der Gruppe, bestehend aus NH₂, NH(C₁-C₄-Alkyl), N(C₁-C₄-Alkyl)(C₁-C₄-Alkyl), NH(C₁-C₄-Alkylen-O-C₁-C₄-Alkyl), N(C₁-C₄-Alkyl)(C₁-C₄-Alkylen-O-C₁-C₄-Alkyl), NH-CHO, N(C₁-C₄-Alkyl)-CHO, NH-CO-NH₂, N(C₁-C₄-Alkyl)-CO-NH₂, NH-CO-C₁-C₄-Alkyl, N(C₁-C₄-Alkyl)-CO-C₁-C₄-Alkyl, NH-SO₂-C₁-C₄-Alkyl, N(C₁-C₄-Alkyl)-SO₂-C₁-C₄-Alkyl und Ring R_A ⁸,
R_A ⁵, R_A ⁶, R_A ⁹ unabhängig voneinander und unanhängig von ihrem jeweiligen Auftreten ausgewählt sind aus der Gruppe, bestehend aus Wasserstoff, C₁-C₄-Alkyl und C₁-C₄-Halogenalkyl;
R_A ⁸ ausgewählt ist aus der Gruppe, bestehend aus den jeweiligen einzelnen Resten

B ein aromatischer, heteroaromatischer, teil-aromatischer oder teil-heteroaromatischer mono- oder bicyclischer Ring ist, der aus 2, 3, 4, 5, 6, 7, 8, 9 oder 10 Kohlenstoff-Atomen sowie 0, 1, 2, 3 oder 4 Stickstoff-Atomen und/oder 0, 1 oder 2 Sauerstoff-Atomen und/oder 0, 1 oder 2 Schwefel-Atomen besteht, und der mit 1, 2 oder 3 Resten R_B ¹, R_B ² und/oder R_B ³ substituiert sein kann, wobei R_B ¹, R_B ² und R_B ³ unabhängig voneinander und unabhängig von ihrem jeweiligen Auftreten ausgewählt sind aus der Gruppe, bestehend aus Wasserstoff, Chlor, Brom, Iod, Fluor, CN, CF₃, OCF₃, OCHF₂, CO-NH₂, CO-NH(C₁-C₄-Alkyl), CO-N(C₁-C₄-Alkyl)(C₁-C₄-Alkyl), NH₂, NH(C₁-C₄-Alkyl), N(C₁-C₄-Alkyl)(C₁-C₄-Alkyl), NH-CHO, NH-CO-NH₂, NH-CO-C₁-C₄-Alkyl, NO₂, OH, O-C₁-C₄-Alkyl, O-C₀-C₄-Alkylen-Phenyl, Phenyl, C₁-C₆-Alkyl, C₁-C₆-Halogenalkyl, C₂-C₆-Alkenyl und C₂-C₆-Alkinyl;
R¹ ausgewählt ist aus der Gruppe, bestehend aus Wasserstoff, Chlor, Brom, Iod, Fluor, CN, CF₃, OCF₃, OCHF₂, CO-NH₂, CO-NH(C₁-C₄-Alkyl), CO-N(C₁-C₄-Alkyl)(C₁-C₄-Alkyl), NH₂, NH(C₁-C₄-Alkyl), N(C₁-C₄-Alkyl)(C₁-C₄-Alkyl), NH-CHO, NH-CO-NH₂, NH-CO-C₁-C₄-Alkyl, NO₂, OH, O-C₁-C₄-Alkyl, O-C₀-C₄-Alkylen-Phenyl, Phenyl, C₁-C₆-Alkyl, C₁-C₆-Halogenalkyl, C₂-C₆-Alkenyl und C₂-C₆-Alkinyl,
R² ausgewählt ist aus der Gruppe, bestehend aus Wasserstoff, C₁-C₄-Alkyl, O-C₁-C₄-Alkyl, Chlor und Fluor,
Y einen Rest

bedeutet, worin
R_Y ¹ ausgewählt ist aus der Gruppe, bestehend aus Wasserstoff, C₁-C₄-Alkyl und C₁-C₄-Halogenalkyl;
R_Y ² ausgewählt ist aus der Gruppe, bestehend aus Wasserstoff; Phenyl; Phenyl subsituiert mit 1, 2, 3, 4 oder 5 Resten R_Ph ¹, R_Ph ², R_Ph ³, R_Ph ⁴ und/oder R_Ph ⁵, welche unabhängig voneinander ausgewählt sind aus der Gruppe bestehend aus Wasserstoff, Halogen, C₁-C₆-Alkyl und C₁-C₆-Alkoxy; C₁-C₆-Alkyl; C₃-C₇-Cycloalkyl und C₁-C₆-Halogenalkyl;
worin R_Y ¹ und R_Y ² auch gemeinsam einen 4-, 5-, 6- oder 7-gliedrigen, gesättigten oder ungesättigten carbocyclischen Ring bilden können, der anstelle eines Ring-C-Atoms auch ein Heteroatom, ausgewählt aus der Gruppe, bestehend aus O, S und NR_Y ⁵, als Ringglied aufweisen kann, wobei R_Y ⁵ unabhängig von seinem jeweiligen Auftreten für Wasserstoff, C₁-C₄-Alkyl oder CO-C₁-C₄-Alkyl stehen kann, und wobei der Ring ein oder zwei Substituenten R_Y ⁶ und R_Y ⁷ aufweisen kann, die unabhängig voneinander und unabhängig von ihrem jeweiligen Auftreten ausgewählt sind aus der Gruppe, bestehend aus den Resten Wasserstoff, Chlor, Brom, Iod, Fluor, CN, CF₃, OCF₃, OCHF₂, CO-NH₂, CO-NH(C₁-C₄-Alkyl), CO-N(C₁-C₄- Alkyl)(C₁-C₄-Alkyl), NH₂, NH(C₁-C₄-Alkyl), N(C₁-C₄-Alkyl)(C₁-C₄-Alkyl), NH-CHO, NH-CO-NH₂, NH-CO-C₁-C₄-Alkyl, OH, O-C₁-C₄-Alkyl, O-CO-C₁-C₄-Alkyl, O-(CH₂)_0-2-Phenyl, Phenyl, C₁-C₆-Alkyl,
oder
R_Y ⁶ und R_Y ⁷ unabhängig von ihrem jeweiligen Auftreten gemeinsam mit den C-Atomen, an die sie gebunden sind, auch einen kondensierten Phenylring oder einen kondensierten 5- oder 6-gliedrigen, aromatischen Heterocyclus bilden können, der neben C-Atomen als Ringglieder 1, 2, 3 oder 4 gleiche oder verschiedene Heteroatome als Ringglieder aufweist, die unabhängig voneinander ausgewählt sein können aus der Gruppe bestehend aus Stickstoff, Sauerstoff und Schwefel,
R_Y ³ ausgewählt ist aus der Gruppe, bestehend aus Wasserstoff, C₁-C₄-Alkyl und C₁-C₄-Halogenalkyl;
R_Y ⁴ ausgewählt ist aus der Gruppe, bestehend aus Wasserstoff, CO-NR_Y ²¹R_Y ²², CO-C₁-C₄-Alkyl, COOH und CO-O-C₁-C₄-Alkyl,
R_Y ²¹, R_Y ²² unabhängig voneinander und unabhängig von ihrem jeweiligen Auftreten ausgewählt sind aus der Gruppe, bestehend aus Wasserstoff, C₁-C₄-Alkyl und C₁-C₄-Halogenalkyl;
oder R_Y ²¹ und R_Y ²² unabhängig von ihrem jeweiligen Auftreten auch gemeinsam einen 4-, 5- oder 6-gliedrigen, gesättigten oder ganz oder teilweise ungesättigten carbocyclischen Ring bilden können,
bedeuten,
ihre tautomeren, enantiomeren und diastereomeren Formen, und ihre Prodrugs, sowie die physiologisch verträglichen Salze der genannten Verbindungen, bereitgestellt.The object is achieved by at least one compound of the general formula (I),

wherein
A is an aromatic, heteroaromatic, partially aromatic or partially heteroaromatic mono- or bicyclic ring consisting of 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms and 0, 1, 2, 3 or 4 nitrogen atoms and / or 0, 1 or 2 oxygen atoms and / or 0, 1 or 2 sulfur atoms, and which is substituted by the radical R _A ¹ and additionally with 1, 2 or 3 radicals R _A ¹¹ , R _A ¹² and / or R _A ¹³ may be substituted independently of one another and independently of their occurrence from the group consisting of hydrogen, chlorine, bromine, iodine, fluorine, CN, CF ₃ , OCF ₃ , OCHF ₂ , CO-NH ₂ , CO-NH (C ₁ -C ₄ -alkyl), CO-N (C ₁ -C ₄ -alkyl) (C ₁ -C ₄ -alkyl), NH ₂ , NH (C C ₁ -C ₄ -alkyl), N (C ₁ -C ₄ -alkyl) (C ₁ -C ₄ -alkyl), NHCHO, NH-CO-NH ₂ , NH-CO (C ₁ -C ₄ -alkyl), NO ₂ , OH, OC ₁ -C ₄ -alkyl, OC ₀ -C ₄ -alkylene-phenyl, phenyl, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -haloalkyl, C ₂ -C ₆ -alkenyl and C C ₂ -C ₆ alkynyl,
wherein
R _A ¹ R _A ^{2 is} - (C ₁ -C ₄ -alkylene) -R _A ⁴ ,
R _A ^{2 is} selected from the group consisting of (C ₀ -C ₄ -alkylene) -O, (C ₀ -C ₄ -alkylene) -NR _A ⁵ , (C ₀ -C ₄ -alkylene) -S, ( C ₀ -C ₄ -alkylene) -SO, (C ₀ -C ₄ -alkylene) -SO ₂ , (C ₀ -C ₄ -alkylene) -CO, (C ₀ -C ₄ -alkylene) -NR _A ⁵ - CO, (C ₀ -C ₄ -alkylene) -CO-NR _A ⁵ , (C ₀ -C ₄ -alkylene) -CO-O, (C ₀ -C ₄ -alkylene) -NR _A ⁵ -SO ₂ , ( C ₀ -C ₄ -alkylene) -SO ₂ -NR _A ⁵ , (C ₀ -C ₄ -alkylene) -NR _A ⁵ -CO-NR _A ⁶ , (C ₀ -C ₄ -alkylene) -O-CO- NR _A ⁵ , (C ₀ -C ₄ -alkylene) -NR _A ⁵ -CO-O and single bond,
R _A ^{4 is} selected from the group consisting of NH ₂ , NH (C ₁ -C ₄ -alkyl), N (C ₁ -C ₄ -alkyl) (C ₁ -C ₄ -alkyl), NH (C ₁ - C ₄ -alkylene-OC ₁ -C ₄ -alkyl), N (C ₁ -C ₄ -alkyl) (C ₁ -C ₄ -alkylene-OC ₁ -C ₄ -alkyl), NH-CHO, N (C ₁ C ₄ alkyl) -CHO, NH-CO-NH ₂ , N (C ₁ -C ₄ alkyl) -CO-NH ₂ , NH-CO-C ₁ -C ₄ alkyl, N (C ₁ -C _4- alkyl) -CO-C ₁ -C ₄ -alkyl, NH-SO ₂ -C ₁ -C ₄ -alkyl, N (C ₁ -C ₄ -alkyl) -SO ₂ -C ₁ -C ₄ -alkyl and Ring R _A ⁸ ,
R _A ⁵ , R _A ⁶ , R _A ⁹ independently of one another and independently of their occurrence, are selected from the group consisting of hydrogen, C ₁ -C ₄ -alkyl and C ₁ -C ₄ -haloalkyl;
R _A ^{8 is} selected from the group consisting of the respective individual radicals

B is an aromatic, heteroaromatic, partially aromatic or partially heteroaromatic mono- or bicyclic ring which consists of 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms and 0, 1, 2, 3 or 4 nitrogen atoms and / or 0, 1 or 2 oxygen atoms and / or 0, 1 or 2 sulfur atoms, and with 1, 2 or 3 radicals R _B ¹ , R _B ² and / or R _B ³ may be substituted, wherein R _B ¹ , R _B ² and R _B ^{3 are} independently and independently of their occurrence selected from the group consisting of hydrogen, chlorine, bromine, iodine, fluorine, CN, CF ₃ , OCF ₃ , OCHF ₂ , CO-NH ₂ , CO-NH (C ₁ -C ₄ -alkyl), CO-N (C ₁ -C ₄ -alkyl) (C ₁ -C ₄ -alkyl), NH ₂ , NH (C C ₁ -C ₄ -alkyl), N (C ₁ -C ₄ -alkyl) (C ₁ -C ₄ -alkyl), NH-CHO, NH-CO-NH ₂ , NH-CO-C ₁ -C ₄ -alkyl , NO ₂ , OH, OC ₁ -C ₄ -alkyl, OC ₀ -C ₄ -alkylene-phenyl, phenyl, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -haloalkyl, C ₂ -C ₆ -alkenyl and C ₂ -C ₆ alkynyl;
R ^{1 is} selected from the group consisting of hydrogen, chlorine, bromine, iodine, fluorine, CN, CF ₃ , OCF ₃ , OCHF ₂ , CO-NH ₂ , CO-NH (C ₁ -C ₄ -alkyl), CO -N (C ₁ -C ₄ -alkyl) (C ₁ -C ₄ -alkyl), NH ₂ , NH (C ₁ -C ₄ -alkyl), N (C ₁ -C ₄ -alkyl) (C ₁ -C _4- alkyl), NH-CHO, NH-CO-NH ₂ , NH-CO-C ₁ -C ₄ -alkyl, NO ₂ , OH, OC ₁ -C ₄ -alkyl, OC ₀ -C ₄ -alkylene-phenyl , Phenyl, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -haloalkyl, C ₂ -C ₆ -alkenyl and C ₂ -C ₆ -alkynyl,
R ^{2 is} selected from the group consisting of hydrogen, C ₁ -C ₄ -alkyl, OC ₁ -C ₄ -alkyl, chlorine and fluorine,
Y a rest

means, in which
R _Y ^{1 is} selected from the group consisting of hydrogen, C ₁ -C ₄ alkyl and C ₁ -C ₄ haloalkyl;
R _Y ^{2 is} selected from the group consisting of hydrogen; phenyl; Phenyl substituted with 1, 2, 3, 4 or 5 radicals R _Ph ¹ , R _Ph ² , R _Ph ³ , R _Ph ⁴ and / or R _Ph ⁵ , which are independently selected from the group consisting of hydrogen, halogen, C C ₁ -C ₆ -alkyl and C ₁ -C ₆ -alkoxy; C ₁ -C ₆ alkyl; C ₃ -C ₇ cycloalkyl and C ₁ -C ₆ haloalkyl;
wherein R _Y ¹ and R _Y ^{2 may} also together form a 4-, 5-, 6- or 7-membered, saturated or unsaturated carbocyclic ring, which instead of a ring C atom and a heteroatom selected from the group consisting from O, S and NR _Y ⁵ , may have as ring member, wherein R _Y ⁵ independently of its respective occurrence of hydrogen, C ₁ -C ₄ alkyl or CO-C ₁ -C ₄ alkyl may be, and wherein the ring may have one or two substituents R _Y ⁶ and R _Y ⁷ independently of one another and independently of their occurrence selected from the group consisting of the radicals hydrogen, chlorine, bromine, iodine, fluorine, CN, CF ₃ , OCF ₃ , OCHF _2, CO-NH _2, CO-NH (C ₁ -C ₄ alkyl), CO-N (C ₁ -C ₄ - alkyl) (C ₁ -C ₄ alkyl), NH _2, NH (C C ₁ -C ₄ -alkyl), N (C ₁ -C ₄ -alkyl) (C ₁ -C ₄ -alkyl), NH-CHO, NH-CO-NH ₂ , NH-CO-C ₁ -C ₄ -alkyl , OH, OC ₁ -C ₄ -alkyl, O-CO-C ₁ -C ₄ alkyl, O- (CH _{2) 0-2} -phenyl, phenyl, C ₁ -C ₆ alkyl,
or
R _Y ⁶ and R _Y ^7, regardless of their respective occurrence together with the C atoms to which they are attached, can also form a fused phenyl ring or a fused 5- or 6-membered aromatic heterocycle which, in addition to C atoms as Ring members 1, 2, 3 or 4 identical or different heteroatoms as ring members, which may be independently selected from the group consisting of nitrogen, oxygen and sulfur,
R _Y ^{3 is} selected from the group consisting of hydrogen, C ₁ -C ₄ alkyl and C ₁ -C ₄ haloalkyl;
R _Y ^{4 is} selected from the group consisting of hydrogen, CO-NR _Y ²¹ R _Y ²² , CO-C ₁ -C ₄ -alkyl, COOH and CO-OC ₁ -C ₄ -alkyl,
R _Y ²¹ , R _Y ^{22 are} independently of one another and independently of their occurrence selected from the group consisting of hydrogen, C ₁ -C ₄ alkyl and C ₁ -C ₄ haloalkyl;
or R _Y ²¹ and R _Y ^{22 can} also together form a 4-, 5- or 6-membered, saturated or completely or partially unsaturated carbocyclic ring, regardless of their respective occurrence,
mean,
their tautomeric, enantiomeric and diastereomeric forms, and their prodrugs, as well as the physiologically acceptable salts of said compounds.

B ein aromatischer oder heteroaromatischer mono- oder bicyclischer carbocyclischer Ring mit 2, 3, 4, 5, 6, 7, 8, 9 oder 10 C-Atomen als Ringgliedern ist, der zusätzlich 1, 2 oder 3 gleiche oder verschiedene Heteroatome, unabhängig voneinander ausgewählt aus der Gruppe, bestehend aus Stickstoff, Sauerstoff und Schwefel, als Ringglieder enthalten kann und der mit einem, zwei oder drei Resten R_B ¹, R_B ² und/oder R_B ³ substituiert sein kann, wobei R_B ¹, R_B ² und R_B ³ unabhängig voneinander und unabhängig von ihrem jeweiligen Auftreten ausgewählt sind aus der Gruppe, bestehend aus Wasserstoff, Chlor, Brom, Fluor, CN, CF₃, OCF₃, OCHF₂, O-C₁-C₄-Alkyl, C₁-C₄-Alkyl und C₁-C₄-Halogenalkyl;
R¹ ausgewählt ist aus der Gruppe, bestehend aus Wasserstoff, Brom, Chlor, Fluor, CN, CF₃, OCF₃, O-C₁-C₄-Alkyl, C₁-C₄-Alkyl, C₁-C₄-Halogenalkyl und C₂-C₄-Alkinyl,
R² ausgewählt ist aus der Gruppe, bestehend aus Wasserstoff, C₁-C₄-Alkyl, C₁-C₄-Halogenalkyl, O-C₁-C₄-Alkyl, Chlor und Fluor,
Y einen Rest

bedeutet, worin
R_Y ¹ ausgewählt ist aus der Gruppe, bestehend aus Wasserstoff und C₁-C₄-Alkyl;
R_Y ² ausgewählt ist aus der Gruppe, bestehend aus Wasserstoff, Phenyl, C₁-C₆-Alkyl, und C₃-C₇-Cycloalkyl,
worin R_Y ¹ und R_Y ² auch gemeinsam einen 4-, 5-, 6- oder 7-gliedrigen, gesättigten oder ungesättigten carbocyclischen Ring bilden können, der anstelle eines C-Atoms als Ringglied auch ein Heteroatom, ausgewählt aus der Gruppe, bestehend aus O und NR_Y ⁵, als Ringglied aufweisen kann, wobei R_Y ⁵ unabhängig von seinem jeweiligen Auftreten für Wasserstoff, C₁-C₄-Alkyl, C₁-C₄-Halogenalkyl oder CO-C₁-C₄-Alkyl stehen kann, und wobei der Ring ein oder zwei Substituenten R_Y ⁶ und/oder R_Y ⁷ aufweisen kann, die unabhängig voneinander und unabhängig von ihrem jeweiligen Auftreten ausgewählt sind aus der Gruppe, bestehend aus den Resten Wasserstoff, Fluor, CN, OH, O-C₁-C₄-Alkyl, O-CO-C₁-C₄-Alkyl, O-(CH₂)_0-2-Phenyl, Phenyl und C₁-C₄-Alkyl;
oder
R_Y ⁶ und R_Y ⁷ unabhängig von ihrem jeweiligen Auftreten gemeinsam mit den C-Atomen, an die sie gebunden sind, auch einen kondensierten Phenylring (Benzo-Ring) bilden können;
R_Y ³ ausgewählt ist aus der Gruppe, bestehend aus Wasserstoff und Methyl,
R_Y ⁴ ausgewählt ist aus der Gruppe, bestehend aus CO-NR_Y ²¹R_Y ²², CO-C₁-C₄-Alkyl und CO-O-C₁-C₄-Alkyl,
R_Y ²¹, R_Y ²² unabhängig voneinander und unabhängig von ihrem jeweiligen Auftreten ausgewählt sind aus der Gruppe, bestehend aus Wasserstoff und C₁-C₄-Alkyl;
oder
R_Y ²¹ und R_Y ²² unabhängig von ihrem jeweiligen Auftreten auch gemeinsam einen 4-, 5- oder 6-gliedrigen, gesättigten oder ungesättigten carbocyclischen Ring bilden können,
bedeuten,
ihre tautomeren, enantiomeren und diastereomeren Formen, und ihre Prodrugs, sowie die physiologisch verträglichen Salze der genannten Verbindungen, bereitgestellt.According to a preferred embodiment, at least one compound of general formula (I) as described above, wherein
A is an aromatic or heteroaromatic monocyclic ring having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms as ring members, which additionally additionally 0, 1, 2 or 3 identical or different heteroatoms, independently selected from the group consisting of nitrogen, oxygen and sulfur, may contain as ring members and is substituted with the radical R _A ¹ and may also be substituted by one, two or three radicals R _A ¹¹ , R _A ¹² and / or R _A ¹³ which are independently of one another and independently of their occurrence selected from the group consisting of hydrogen, chlorine, fluorine, OC ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkyl and C ₁ -C ₄ -haloalkyl,
wherein
R _A ¹ R _A ^{2 is} - (C ₁ -C ₄ alkylene) -R _A ⁴ ;
R _A ^{2 is} selected from the group consisting of (C ₀ -C ₄ -alkylene) -O, (C ₀ -C ₄ -alkylene) -NR _A ⁵ , (C ₀ -C ₄ -alkylene) -S, ( C ₀ -C ₄ -alkylene) -SO, (C ₀ -C ₄ -alkylene) -SO ₂ , (C ₀ -C ₄ -alkylene) -CO, (C ₀ -C ₄ -alkylene) -NR _A ⁵ - CO, (C ₀ -C ₄ -alkylene) -CO-NR _A ⁵ , (C ₀ -C ₄ -alkylene) -CO-O and single bond;
R _A ^{4 is} selected from the group consisting of NH ₂ , NH (C ₁ -C ₄ -alkyl), N (C ₁ -C ₄ -alkyl) (C ₁ -C ₄ -alkyl), N (C ₁ -) C ₄ alkyl) (C ₁ -C ₄ alkylene-OC ₁ -C ₄ alkyl) and ring R _A ⁸ ;
R _A ⁵ , R _A ^{9 are} independently of one another and independently of their occurrence selected from the group consisting of hydrogen and C ₁ -C ₄ alkyl;
R _A ^{8 is} independently of its occurrence selected from the group consisting of the respective individual residues

B is an aromatic or heteroaromatic monocyclic or bicyclic carbocyclic ring having 2, 3, 4, 5, 6, 7, 8, 9 or 10 C atoms as ring members which additionally has 1, 2 or 3 identical or different heteroatoms, independently of one another selected from the group consisting of nitrogen, oxygen and sulfur, which may be ring members and which may be substituted with one, two or three R _B ¹ , R _B ² and / or R _B ³ radicals, wherein R _B ¹ , R _B ² and R _B ^{3 are} independently of one another and independently of their occurrence selected from the group consisting of hydrogen, chlorine, bromine, fluorine, CN, CF ₃ , OCF ₃ , OCHF ₂ , OC ₁ -C ₄ alkyl, C ₁ C ₄ alkyl and C ₁ -C ₄ haloalkyl;
R ^{1 is} selected from the group consisting of hydrogen, bromine, chlorine, fluorine, CN, CF ₃ , OCF ₃ , OC ₁ -C ₄ alkyl, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl and C ₂ -C ₄ alkynyl,
R ^{2 is} selected from the group consisting of hydrogen, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -haloalkyl, OC ₁ -C ₄ -alkyl, chlorine and fluorine,
Y a rest

means, in which
R _Y ^{1 is} selected from the group consisting of hydrogen and C ₁ -C ₄ alkyl;
R _Y ^{2 is} selected from the group consisting of hydrogen, phenyl, C ₁ -C ₆ -alkyl, and C ₃ -C ₇ -cycloalkyl,
wherein R _Y ¹ and R _Y ^{2 may} also together form a 4-, 5-, 6- or 7-membered, saturated or unsaturated carbocyclic ring, which instead of a C atom as a ring member and a heteroatom selected from the group consisting from O and NR _Y ⁵ , may have as ring member, wherein R _Y ⁵ independently of its respective occurrence of hydrogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl or CO-C ₁ -C ₄ alkyl stand and wherein the ring may have one or two substituents R _Y ⁶ and / or R _Y ⁷ , which are independently of one another and independently of their occurrence selected from the group consisting of the radicals hydrogen, fluorine, CN, OH, OC ₁ -C ₄ alkyl, O-CO-C ₁ -C ₄ alkyl, O- (CH _{2) 0-2} -phenyl, phenyl and C ₁ -C ₄ alkyl;
or
R _Y ⁶ and R _Y ^7, independently of their occurrence, together with the C atoms to which they are attached, can also form a fused phenyl ring (benzo ring);
R _Y ^{3 is} selected from the group consisting of hydrogen and methyl,
R _Y ^{4 is} selected from the group consisting of CO-NR _Y ²¹ R _Y ²² , CO-C ₁ -C ₄ -alkyl and CO-OC ₁ -C ₄ -alkyl,
R _Y ²¹ , R _Y ^{22 are} independently of one another and independently of their occurrence selected from the group consisting of hydrogen and C ₁ -C ₄ alkyl;
or
R _Y ²¹ and R _Y ^{22 can} also together form a 4-, 5- or 6-membered, saturated or unsaturated carbocyclic ring, regardless of their respective occurrence,
mean,
their tautomeric, enantiomeric and diastereomeric forms, and their prodrugs, as well as the physiologically acceptable salts of said compounds.

B ein aromatischer oder heteroaromatischer mono- oder bicyclischer Ring mit 2, 3, 4, 5, 6, 7, 8, 9 oder 10 C-Atomen als Ringgliedern ist, der 1, 2 oder 3 gleiche oder verschiedene Heteroatome, unabhängig voneinander ausgewählt aus der Gruppe, bestehend aus Stickstoff, Sauerstoff und Schwefel, als Ringglied enthalten kann und der mit ein oder zwei Resten R_B ¹ und/oder R_B ² substituiert sein kann, wobei R_B ¹ und R_B ² unabhängig voneinander ausgewählt sind aus der Gruppe, bestehend aus Wasserstoff, Chlor, Fluor, CN, O-C₁-C₄-Alkyl und C₁-C₄-Alkyl;
R¹ ausgewählt ist aus der Gruppe, bestehend aus Wasserstoff, Chlor, Fluor, CN, Methoxy und Methyl;
R² ausgewählt ist aus der Gruppe, bestehend aus Wasserstoff, Chlor und Methyl;
Y einen Rest

bedeutet, worin
R_Y ¹ ausgewählt ist aus der Gruppe, bestehend aus Wasserstoff und C₁-C₄-Alkyl;
R_Y ² ausgewählt ist aus der Gruppe, bestehend aus Wasserstoff, Phenyl und C₁-C₄-Alkyl;
wobei R_Y ¹ und R_Y ² auch gemeinsam einen 5- oder 6-gliedrigen, gesättigten oder ungesättigten carbocylischen Ring bilden können, der anstelle eines C-Atoms als Ringglied auch ein Heteroatom, ausgewählt aus der Gruppe, bestehend aus O und NR_Y ⁵, als Ringglied aufweisen kann, wobei R_Y ⁵ unabhängig von seinem jeweiligen Auftreten für Wasserstoff, C₁-C₄-Alkyl, oder CO-C₁-C₄-Alkyl stehen kann, und wobei der Ring ein oder zwei Substituenten R_Y ⁶ und/oder R_Y ⁷ aufweisen kann, die unabhängig voneinander und unabhängig von ihrem jeweiligen Auftreten ausgewählt sind aus der Gruppe, bestehend aus den Resten Wasserstoff, Fluor, OH und O-C₁-C₄-Alkyl,
oder
R_Y ⁶ und R_Y ⁷ unabhängig von ihrem jeweiligen Auftreten gemeinsam mit den C-Atomen, an die sie gebunden sind, auch einen kondensierten Phenylring (Benzo-Ring) bilden können;
R_Y ³ ausgewählt ist aus der Gruppe, bestehend aus Wasserstoff und Methyl;
R_Y ⁴ CO-NR_Y ²¹R_Y ²² ist,
worin
R_Y ²¹, R_Y ²² unabhängig voneinander ausgewählt sind aus der Gruppe, bestehend aus Wasserstoff und C₁-C₄-Alkyl;
oder
R_Y ²¹ und R_Y ²² unabhängig von ihrem jeweiligen Auftreten auch gemeinsam einen 4-, 5- oder 6-gliedrigen, gesättigten oder ungesättigten carbocyclischen Ring bilden können;
bedeuten,
ihre tautomeren, enantiomeren und diastereomeren Formen, und ihre Prodrugs, sowie die physiologisch verträgliche Salze der genannten Verbindungen, bereitgestellt.According to a further preferred embodiment, at least one compound of general formula (I) as described above, wherein
A is a ring selected from the group consisting of benzene, thiophene, pyridine, pyrimidine, pyrazine and pyridazine and which is substituted with the radical R _A ¹ and additionally with one or two radicals R _A ¹¹ and / or R _A ¹² may be substituted independently of one another and independently of their occurrence selected from the group consisting of hydrogen, chlorine, methoxy, ethoxy, propoxy, methyl, ethyl and propyl;
wherein
R _A ¹ R _A ^{2 is} - (C ₁ -C ₄ -alkylene) -R _A ⁴ ,
wherein
R _A ^{2 is} selected from the group consisting of O, CH ₂ -O, NR _A ⁵ , CH ₂ -NR _A ⁵ , NR _A ⁵ -CO, CH ₂ -NR _A ⁵ -CO and a single bond;
R _A ^{4 is} selected from the group consisting of NH ₂ , NH (C ₁ -C ₄ -alkyl), N (C ₁ -C ₄ -alkyl) (C ₁ -C ₄ -alkyl), N (C ₁ -) C ₄ alkyl) (C ₁ -C ₄ alkylene-OC ₁ -C ₄ alkyl) and ring R _A ⁸ ;
R _A ⁵ , R _A ^{9 are} independently of one another and independently of their occurrence selected from the group consisting of hydrogen and C ₁ -C ₄ alkyl;
R _A ^{8 is} selected from the group consisting of the respective individual radicals

B is an aromatic or heteroaromatic mono- or bicyclic ring having 2, 3, 4, 5, 6, 7, 8, 9 or 10 C atoms as ring members, the 1, 2 or 3 identical or different heteroatoms, independently selected from the group consisting of nitrogen, oxygen and sulfur, may contain as ring member and which may be substituted by one or two radicals R _B ¹ and / or R _B ² , wherein R _B ¹ and R _B ^{2 are} independently selected from the group consisting of hydrogen, chlorine, fluorine, CN, OC ₁ -C ₄ alkyl and C ₁ -C ₄ alkyl;
R ^{1 is} selected from the group consisting of hydrogen, chlorine, fluorine, CN, methoxy and methyl;
R ^{2 is} selected from the group consisting of hydrogen, chlorine and methyl;
Y a rest

means, in which
R _Y ^{1 is} selected from the group consisting of hydrogen and C ₁ -C ₄ alkyl;
R _Y ^{2 is} selected from the group consisting of hydrogen, phenyl and C ₁ -C ₄ alkyl;
wherein R _Y ¹ and R _Y ^{2 may} also together form a 5- or 6-membered, saturated or unsaturated carbocyclic ring, which instead of a C atom as a ring member and a heteroatom selected from the group consisting of O and NR _Y ⁵ , as ring member, where R _Y ^{5 are} independently of each occurrence hydrogen, C ₁ -C ₄ alkyl, or CO-C ₁ -C ₄ -alkyl, and which ring one or two substituents R ⁶ _Y and / or R _Y ⁷ may be selected independently of one another and independently of their respective occurrence from the group consisting of the radicals hydrogen, fluorine, OH and OC ₁ -C ₄ -alkyl,
or
R _Y ⁶ and R _Y ^7, independently of their occurrence, together with the C atoms to which they are attached, can also form a fused phenyl ring (benzo ring);
R _Y ^{3 is} selected from the group consisting of hydrogen and methyl;
R _Y ^{4 is} CO-NR _Y ²¹ R _Y ²² ,
wherein
R _Y ²¹ , R _Y ^{22 are} independently selected from the group consisting of hydrogen and C ₁ -C ₄ alkyl;
or
R _Y ²¹ and R _Y ^22, independently of their respective occurrence, may also together form a 4-, 5- or 6-membered, saturated or unsaturated carbocyclic ring;
mean,
their tautomeric, enantiomeric and diastereomeric forms, and their prodrugs, as well as the physiologically acceptable salts of said compounds.

worin
R_A ¹¹ unabhängig von seinem jeweiligen Auftreten ausgewählt ist aus der Gruppe, bestehend aus Wasserstoff, Chlor, Methoxy und Ethoxy;
R_A ¹ ein Rest ist ausgewählt aus der Gruppe, bestehend aus den jeweiligen einzelnen Resten

B ein Ring ist ausgewählt aus der Gruppe, bestehend aus Benzen, Pyridin, Thiophen und Chinolin, welche jeweils mit 1 oder 2 Resten R_B ¹ und/oder R_B ² substituiert sein können, wobei R_B ¹ und R_B ² unabhängig voneinander ausgewählt sind aus der Gruppe, bestehend aus Wasserstoff, Chlor, Fluor, CN, Methyl und Methoxy;
R¹ ausgewählt ist aus der Gruppe, bestehend aus Wasserstoff, Chlor, Fluor, CN, Methoxy und Methyl;
R² ausgewählt ist aus der Gruppe, bestehend aus Wasserstoff und Chlor;
Y ein Rest ist ausgewählt aus der Gruppe, bestehend aus den jeweiligen einzelnen Resten

R_Y ⁴ CO-NR_Y ²¹R_Y ²² ist, wobei R_Y ²¹ und R_Y ²² unabhängig voneinander ausgewählt sind aus der Gruppe, bestehend aus Wasserstoff, Methyl und Ethyl;
oder
R_Y ²¹ und R_Y ²² unabhängig von ihrem jeweiligen Auftreten auch gemeinsam einen 4-, 5- oder 6-gliedrigen, gesättigten oder ungesättigten oder teilweise ungesättigten carbocyclischen Ring bilden können;
R_Y ⁵ ausgewählt ist aus der Gruppe, bestehend aus den Resten Wasserstoff, C₁-C₄-Alkyl, und CO-C₁-C₄-Alkyl;
R_Y ⁶ ausgewählt ist aus der Gruppe, bestehend aus den Resten Wasserstoff, Fluor, OH und O-C₁-C₄-Alkyl,
bedeuten,
ihre tautomeren, enantiomeren und diastereomeren Formen, und ihre Prodrugs, sowie die physiologisch verträgliche Salze der genannten Verbindungen, bereitgestellt.According to a further preferred embodiment, at least one compound of general formula (I) as described above, wherein
A is a radical selected from the group consisting of the respective individual radicals

wherein
R _A ^{11 is} independently selected from the group consisting of hydrogen, chlorine, methoxy and ethoxy;
R _A ^{1 is} a radical selected from the group consisting of the respective individual radicals

B is a ring selected from the group consisting of benzene, pyridine, thiophene and quinoline, each weils with 1 or 2 radicals R _B ¹ and / or R _B ² may be substituted, wherein R _B and R ¹ _B ² are independently selected from the group consisting of hydrogen, chlorine, fluorine, CN, methyl and methoxy;
R ^{1 is} selected from the group consisting of hydrogen, chlorine, fluorine, CN, methoxy and methyl;
R ^{2 is} selected from the group consisting of hydrogen and chlorine;
Y is a radical selected from the group consisting of the respective individual radicals

R _Y ^{4 is} CO-NR _Y ²¹ R _Y ²² , wherein R _Y ²¹ and R _Y ^{22 are} independently selected from the group consisting of hydrogen, methyl and ethyl;
or
R _Y ²¹ and R _Y ^22, independently of their respective occurrence, may also together form a 4-, 5- or 6-membered, saturated or unsaturated or partially unsaturated carbocyclic ring;
R _Y ^{5 is} selected from the group consisting of the radicals hydrogen, C ₁ -C ₄ alkyl, and CO-C ₁ -C ₄ alkyl;
R _Y ^{6 is} selected from the group consisting of the radicals hydrogen, fluorine, OH and OC ₁ -C ₄ -alkyl,
mean,
their tautomeric, enantiomeric and diastereomeric forms, and their prodrugs, as well as the physiologically acceptable salts of said compounds.

R_A ¹ ein Rest ist unabhängig von seinem jeweiligen Auftreten ausgewählt aus der Gruppe, bestehend aus den jeweiligen einzelnen Resten

B ein Ring ist ausgewählt aus der Gruppe, bestehend aus den jeweiligen einzelnen Resten

worin
R_B ¹ und R_B ² unabhängig voneinander und unabhängig von ihrem jeweiligen Auftreten ausgewählt sind aus der Gruppe, bestehend aus Wasserstoff, Chlor, Fluor, CN, Methyl und Methoxy;
R¹ ausgewählt ist aus der Gruppe, bestehend aus Chlor, Methoxy und CN;
R² Wasserstoff ist,
Y ausgewählt ist aus der Gruppe, bestehend aus den jeweiligen einzelnen Resten

ihre tautomeren, enantiomeren und diastereomeren Formen, und ihre Prodrugs, sowie die physiologisch verträgliche Salze der genannten Verbindungen, bereitgestellt.According to a further preferred embodiment, at least one compound of general formula (I) as described above, wherein
A is selected from the group consisting of the respective individual radicals

R _A ^{1 is} a radical regardless of its occurrence selected from the group consisting of the respective individual radicals

B is a ring selected from the group consisting of the respective individual radicals

wherein
R _B ¹ and R _B ^{2 are} independently and independently selected from the group consisting of hydrogen, chlorine, fluorine, CN, methyl and methoxy;
R ^{1 is} selected from the group consisting of chlorine, methoxy and CN;
R ^{2 is} hydrogen,
Y is selected from the group consisting of the respective individual radicals

their tautomeric, enantiomeric and diastereomeric forms, and their prodrugs, as well as the physiologically acceptable salts of said compounds.

,worin
R_A ¹ ein Rest ist unabhängig von seinem jeweiligen Auftreten ausgewählt aus der Gruppe, bestehend aus den jeweiligen einzelnen Resten

B ein Ring ist ausgewählt aus der Gruppe, bestehend aus den jeweiligen einzelnen Resten

R¹ Chlor ist;
R² Wasserstoff ist;
Y Ein Rest ist ausgewählt aus der Gruppe, bestehend aus den jeweiligen einzelnen Resten

,ihre tautomeren, enantiomeren und diastereomeren Formen, und ihre Prodrugs, sowie die physiologisch verträgliche Salze der genannten Verbindungen, bereitgestellt.According to a further preferred embodiment, at least one compound of the general formula (I) as described above, in which
A is selected from the group consisting of the respective individual radicals

,wherein
R _A ^{1 is} a radical regardless of its occurrence selected from the group consisting of the respective individual radicals

B is a ring selected from the group consisting of the respective individual radicals

R ^{1 is} chlorine;
R ^{2 is} hydrogen;
Y A radical is selected from the group consisting of the respective individual radicals

, their tautomeric, enantiomeric and diastereomeric forms, and their prodrugs, as well as the physiologically acceptable salts of said compounds.

R_A ¹ ein Rest ist unabhängig von seinem jeweiligen Auftreten ausgewählt aus der Gruppe, bestehend aus den jeweiligen einzelnen Resten

B Ein Ring ist ausgewählt aus der Gruppe, bestehend aus den jeweiligen einzelnen Resten

R¹ Chlor ist;
R² Wasserstoff ist;
Y ein Rest ist ausgewählt aus der Gruppe, bestehend aus den jeweiligen einzelnen Resten

,ihre tautomeren, enantiomeren und diastereomeren Formen, und ihre Prodrugs, sowie die physiologisch verträgliche Salze der genannten Verbindungen, bereitgestellt.According to a further preferred embodiment, at least one compound of the general formula (I) as described above, in which
A is a radical selected from the group consisting of the respective individual radicals

R _A ^{1 is} a radical regardless of its occurrence selected from the group consisting of the respective individual radicals

B A ring is selected from the group consisting of the respective individual residues

R ^{1 is} chlorine;
R ^{2 is} hydrogen;
Y is a radical selected from the group consisting of the respective individual radicals

, their tautomeric, enantiomeric and diastereomeric forms, and their prodrugs, as well as the physiologically acceptable salts of said compounds.

worin
R_A ¹ ein Rest ist ausgewählt aus der Gruppe, bestehend aus den jeweiligen einzelnen Resten

B ein Ring ist ausgewählt aus der Gruppe, bestehend aus den jeweiligen einzelnen Resten

R¹ Chlor ist,
R² Wasserstoff ist,
Y ausgewählt ist aus der Gruppe, bestehend aus den jeweiligen einzelnen Resten

,ihre tautomeren, enantiomeren und diastereomeren Formen, und ihre Prodrugs, sowie die physiologisch verträgliche Salze der genannten Verbindungen, bereitgestellt.According to a further preferred embodiment, at least one compound of the general formula (I) as described above, in which
A is a ring selected from the group consisting of the respective individual radicals

wherein
R _A ^{1 is} a radical selected from the group consisting of the respective individual radicals

B is a ring selected from the group consisting of the respective individual radicals

R ^{1 is} chlorine,
R ^{2 is} hydrogen,
Y is selected from the group consisting of the respective individual radicals

, their tautomeric, enantiomeric and diastereomeric forms, and their prodrugs, as well as the physiologically acceptable salts of said compounds.

According to one another preferred embodiment is at least one compound of the general formula (I), as described above, characterized in that the radical R1 is attached to the 5-position of the oxindole ring skeleton.

According to one another preferred embodiment is at least one compound of the general formula (I), as described above, characterized in that it is to an enriched optically active isomer with an optical Purity of more than 50% is based on the optically inactive mixture of the isomer mixture, which rotates the plane of polarized light to the left ("negative rotation").

According to one another preferred embodiment is at least one compound of the general formula (I), as described above, characterized in that it is at the optically active isomer is an enantiomerically enriched diastereomer acted.

According to one another preferred embodiment is at least one compound of the general formula (I), as described above, characterized in that the property "negative Rotation "on the free base is provided.

According to one another preferred embodiment is at least one compound of the general formula (I), as as described above, characterized in that it has a binding affinity Ki to the vasopressin receptor subtype V1b of less than or equal to about 100 nM, preferably in the range between including about 10 nM and including about 100 nM, especially preferably in the range between about 1 nM inclusive and inclusive about 10 nM, most preferably less than or equal to about 1 nM provided.

According to a further preferred embodiment, at least one compound of general formula (I) as described above, characterized in that it has a selectivity to the vasopressin receptor subtype V1b against the vasopressin receptor subtype V1a, so the quotient Ki (V1a) / Ki (V1b) is at least greater than 1, provided.

According to one another preferred embodiment is at least one compound of the general formula (I), as described above, characterized in that it has a selectivity to the vasopressin receptor subtype V1b opposite vasopressin receptor subtype V2, ie the quotient of Ki (V2) / Ki (V1b) at least greater than 1 is provided.

According to one another preferred embodiment is at least one compound of general formula (I) as above described, characterized in that it has a selectivity to the vasopressin receptor subtype V1b opposite the oxytocin (OT) receptor, ie the quotient of Ki (OT) / Ki (V1b) at least greater than 1 is provided.

According to one another preferred embodiment is at least one compound of the general formula (I), as as described above, characterized in that it has a binding affinity Ki to the vasopressin receptor subtype V1b of less than or equal to about 100 nM, preferably in the range between including about 10 nM and including about 100 nM, especially preferably in the range between about 1 nM inclusive and inclusive about 10 nM, most preferably less than or equal to about 1 nM, and selectivity to the vasopressin receptor subtype V1b over the vasopressin receptor subtype V1a, ie the quotient of Ki (V1a) / Ki (V1b) is at least greater than 1 is provided.

According to one another preferred embodiment is at least one compound of general formula (I) as above , characterized in that it has a binding affinity Ki to the vasopressin receptor subtype V1b of less than or equal to about 100 nM, preferably in the range between including about 10 nM and including about 100 nM, especially preferably in the range between about 1 nM inclusive and inclusive about 10 nM, most preferably less than or equal to about 1 nM, and selectivity to the vasopressin receptor subtype V1b over the vasopressin receptor subtype V2, ie the quotient of Ki (V2) / Ki (V1b) is at least greater than 1 is provided.

According to one another preferred embodiment is at least one compound of the general formula (I), as as described above, characterized in that it has a binding affinity Ki to the vasopressin receptor subtype V1b of less than or equal to about 100 nM, preferably in the range between including about 10 nM and including about 100 nM, especially preferably in the range between about 1 nM inclusive and inclusive about 10 nM, most preferably less than or equal to about 1 nM, and selectivity to the vasopressin receptor subtype V1b versus the oxytocin (OT) receptor ie, the quotient of Ki (OT) / Ki (V1b) is at least greater than 1 is provided.

According to one another preferred embodiment is at least one compound of the general formula (I), as as described above, characterized in that it has a binding affinity Ki to the vasopressin receptor subtype V1b of less than or equal to about 100 nM, preferably in the range between including about 10 nM and including about 100 nM, more preferably in the range between about including 1 nM and including about 10 nM very particularly preferred from less than or equal to about 1 nM, and selectivities to the vasopressin receptor subtype V1b opposite the vasopressin receptor subtype V1a and the vasopressin receptor subtype V2, that is the quotients from Ki (V1a) / Ki (V1b) and Ki (V2) / Ki (V1b) each at least greater than 1 are provided.

According to one another preferred embodiment is at least one compound of the general formula (I), as as described above, characterized in that it has a binding affinity Ki to the vasopressin receptor subtype V1b of less than or equal to about 100 nM, preferably in the range between including about 10 nM and including about 100 nM, especially preferably in the range between about 1 nM inclusive and inclusive about 10 nM, most preferably less than or equal to about 1 nM, and simultaneous selectivities to the vasopressin receptor subtype V1b opposite the vasopressin receptor subtype V1a and the oxytocin (OT) receptor , ie the quotients of Ki (V1a) / Ki (V1b) and Ki (OT) / Ki (V1b) each at least greater than 1 are provided.

According to a further preferred embodiment, at least one compound of the general formula (I) as described above is characterized in that it has a binding affinity Ki to the vasopressin receptor subtype V1b of less than or equal to about 100 nM, preferably in the range between and including about 10 nM including about 100 nM, more preferably ranging between about 1 nM inclusive and including about 10 nM, most preferably less than or equal to about 1 nM, and simultaneous selectivities to vasopressin receptor subtype V1b over vasopressin-Re zeptorsubtyp V2 and the oxytocin (OT) receptor, ie the quotients of Ki (V2) / Ki (V1b) and Ki (OT) / Ki (V1b) are each at least greater than 1, provided.

According to one another preferred embodiment is at least one compound of the general formula (I), as as described above, characterized in that it has a binding affinity Ki to the vasopressin receptor subtype V1b of less than or equal to about 100 nM, preferably in the range between including about 10 nM and including about 100 nM, especially preferably in the range between about 1 nM inclusive and inclusive about 10 nM, most preferably less than or equal to about 1 nM, and simultaneous selectivities to the vasopressin receptor subtype V1b opposite the vasopressin receptor subtype V1a, the vasopressin receptor subtype V2 and the oxytocin (OT) receptor, ie the quotients Ki (V1a) / Ki (V1b), Ki (V2) / Ki (V1b) and Ki (OT) / Ki (V1b) each at least greater than 1 are provided.

According to one Another aspect of the present invention will be at least one Compound of general formula (I) as described above for use as a drug.

According to one Another aspect of the present invention is at least one pharmaceutical containing at least one compound of general formula (I), as described above.

According to one Another aspect of the present invention is the use of at least one compound of general formula (I), such as described above, for the treatment and / or prophylaxis of at least a vasopressin-dependent and / or oxytocin-dependent Illness and / or for the manufacture of a medicament for treatment and / or prophylaxis of at least one of said diseases provided.

According to one Another aspect of the present invention is the use of at least one compound of general formula (I), such as described above, for the treatment and / or prophylaxis of at least a disease selected from the group consisting of diabetes insipidus, enuresis nocturna, Incontinence, diseases in which blood coagulation disorders occur and / or to delay the Voiding and / or for the manufacture of a medicament for treatment and / or prophylaxis of at least one of said diseases, provided.

According to one Another aspect of the present invention is the use of at least one compound of general formula (I), such as described above, for the treatment and / or prophylaxis of at least a disease selected from the group consisting of hypertension, pulmonary hypertension, Heart failure, myocardial infarction, coronary spasm, unstable Angina, PTCA (percutaneous transluminal coronary angioplasty), Ischemia of the heart, disorders of the renal system, edema, renal vasospasm, necrosis of the renal cortex, hyponatraemia, hypokalemia, Schwartz-Bartter Syndrome, disorders of the Gastrointestinal tract, gastric vasospasm, hepatocirrhosis, Stomach and intestinal sulcus, vomiting, vomiting during chemotherapy, and / or motion sickness and / or for the manufacture of a medicament for the treatment and / or prophylaxis of at least one of said Diseases, provided.

According to one Another aspect of the present invention is the use of at least one compound of general formula (I), such as described above, for the treatment and / or prophylaxis of affective disorders and / or for the manufacture of a medicament for the treatment of affective disorders, provided.

According to one Another aspect of the present invention is the use of at least one compound of general formula (I), such as described above, for the treatment and / or prophylaxis of anxiety disorders and / or stress-related anxiety disorders and / or for the manufacture of a medicament for the treatment of anxiety disorders and / or stress dependent Anxiety disorders, provided.

According to one Another aspect of the present invention is the use of at least one compound of general formula (I), such as described above, for the treatment and / or prophylaxis of memory impairment and / or Morbus Alzheimer and / or for the manufacture of a medicament for Treatment and / or prophylaxis of memory impairment and / or Alzheimer's disease, provided.

According to a further aspect of the present invention, the use of at least one compound of general formula (I), as described above, for the treatment and / or prophylaxis psychosis and / or psychotic disorders and / or for the manufacture of a medicament for the treatment and / or prophylaxis of psychosis and / or psychotic disorders.

According to one Another aspect of the present invention is the use of at least one compound of general formula (I) as above described, for the treatment and / or prophylaxis of Cushing's syndrome and / or for the manufacture of a medicament for the treatment and / or prophylaxis of Cushing's syndrome.

According to one Another aspect of the present invention is the use of at least one compound of general formula (I), such as described above, for the treatment and / or prophylaxis of sleep disorders and / or for the manufacture of a medicament for the treatment and / or prophylaxis of sleep disorders, provided.

According to one Another aspect of the present invention is the use of at least one compound of general formula (I), such as described above, for the treatment and / or prophylaxis of depressive Diseases and / or for the manufacture of a medicament for treatment and / or prophylaxis of depressive disorders.

According to one Another aspect of the present invention is a method for Treatment and / or prophylaxis of at least one disease selected from the group consisting of diabetes insipidus, enuresis nocturna, Incontinence, diseases in which blood coagulation disorders occur and to the delay the micturition in a patient, characterized in that the Patients an effective amount of at least one compound of the general Formula (I) as described above.

According to one Another aspect of the present invention is a method for Treatment and / or prophylaxis of at least one disease selected from the group consisting of hypertension, pulmonary hypertension, heart failure, Myocardial infarction, coronary spasm, unstable angina, PTCA (percutaneous transluminal coronary angioplasty), ischemia of the heart, disorders of the heart renal system, edema, renal vasospasm, necrosis of the renal cortex, hyponatraemia, hypokalemia, Schwartz-Bartter syndrome, disorders of the gastrointestinal tract, gastric vasospasm, hepatocirrhosis, Stomach and intestinal sulcus, vomiting, vomiting during chemotherapy, and motion sickness in a patient, characterized in that the patient an effective amount of at least one compound of general formula (I) as described above will be provided.

According to one Another aspect of the present invention is a method for Treatment and / or prophylaxis of mood disorders in a patient characterized in that the patient an effective amount at least a compound of general formula (I), as described above, administered.

According to one Another aspect of the present invention is a method for Treatment of anxiety disorders and / or stress dependent anxiety disorders in a patient, characterized in that the patient a effective amount of at least one compound of the general formula (I) administered as described above.

According to one Another aspect of the present invention is a method for Treatment of memory impairment and / or Alzheimer's disease in a patient, characterized in that the Patients an effective amount of at least one compound of the general Formula (I) as described above.

According to one Another aspect of the present invention is a method for Treatment of psychosis and / or psychotic disorders in a patient, characterized in that the patient a effective amount of at least one compound of the general formula (I) administered as described above.

According to one Another aspect of the present invention is a method for Treatment of Cushing's Syndrome in a Patient, characterized that the patient an effective amount of at least one compound of general formula (I) as described above will be provided.

According to one Another aspect of the present invention is a method for Treatment of sleep disorders in a patient, characterized in that the patient a effective amount of at least one compound of the general formula (I) administered as described above.

According to one Another aspect of the present invention is a method for Treatment of depressive disorders in a patient, thereby characterized in that the patient an effective amount at least a compound of general formula (I), as described above, administered.

According to one preferred embodiment the methods described above are characterized by that the patient is a mammal, preferably a human or a nonhuman or a nonhuman transgenic mammal is.

According to one Another aspect of the present invention is a method for Preparation of at least one compound of the general formula (I), as described above, characterized in that they through execution and / or in analogous implementation from the competent Skilled in known process steps can be produced, provided.

each These preferred definitions of a variable may be given any definitions the remaining variables are combined.

According to a further embodiment, at least one compound of the invention according to the general formula (I) is selected from the group consisting of the examples 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67 and 68, as well as their tautomeric, enantiomeric and diastereomeric forms, and their prodrugs, as well as non-salt forms and other physiologically acceptable salts of the abovementioned compounds, provided:
The compounds according to the invention can be present as racemates or as enantiomerically pure or diastereomerically pure or enantiomerically pure diastereomeric compounds. The compounds are preferably present as enantiomerically pure or enantiomerically pure diastereomeric compounds.

Physiologically acceptable salts in the sense of the description, unless stated otherwise, can be formed, for example, with the following anions:
Chloride, bromide, phosphate, carbonate, nitrate, perchlorate, sulfate, citrate, lactate, tartrate, maleate, fumarate, mandelate, benzoate, ascorbate, cinnamate, glycollate, methanesulfonate, formate, malonate, naphthalene-2-sulfonate, tosylates, salicylate, Trifluoroacetate and / or acetate. Other suitable acids are listed, for example, in "Fortschritt der Arzneimittelforschung", 1966, Birkhauser Verlag, Vol. 10, p.224-285.

in the Meaning of the present description, unless otherwise stated, include the terms "alkyl", "cycloalkyl", "alkoxy", "haloalkyl", "alkenyl", "alkynyl" or "alkylene" and derivatives thereof Radicals are always both unbranched and branched "alkyl", "cycloalkyl", "alkoxy", "haloalkyl", "alkenyl", "alkynyl" or "alkylene".

C ₀ -alkylene or (CH ₂ ) ₀ or similar expressions in the sense of the description, unless otherwise stated, denote a single bond or hydrogen.

The terms C ₁ -C ₆ -alkyl and C ₁ -C ₄ -alkyl, in the sense of the description, unless otherwise stated, mean a straight-chain or branched saturated hydrocarbon chain with the respectively indicated number of carbon atoms of 1 to 6 or of 1 to 4 carbon atoms such as methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1,1- Dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, 1-methylpentyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethylbutyl, 2-ethylbutyl or 1-ethyl-2-methylpropyl, preferably methyl, ethyl, propyl, n-butyl or i butyl. C ₁ -C ₄ -alkyl in the sense of the description, unless stated otherwise, is preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or t-butyl.

The term "C ₁ -C ₆ -alkoxy" in the sense of the description, unless stated otherwise, means an oxygen-bonded C ₁ -C ₆ -alkyl group which is as defined above.

The terms C ₁ -C ₆ -alkylene and C ₁ -C ₄ -alkylene (with C ₀ -alkylene = single bond) in the sense of the description, unless otherwise stated, mean an alkyl group having 1 to 6 or 0 to 4C -Atomen, which is as defined above, in which a hydrogen atom is replaced by a bond. In particular, methylene, eth-1,2-ylene, prop-1,2-ylene, prop-1,3-ylene, but-1,2-ylene, but-1,3-ylene, but-2,3- ylene, but-1,4-ylene, 2-methylprop-1,3-ylene, pent-1,2-ylene, pent-1,3-ylene, pent-1,4-ylene, pent-1,5- ylene, pent-2,3-ylene, pent-2,4-ylene, 1-methylbut-1,4-ylene, 2-methylbut-1,4-ylene, 2-methylbut-1,3-ylene, 2- Ethylprop-1,3-ylene, hex-3,4-ylene, 3-methylpent-2,4-ylene, hept-3,5-ylene, 2-ethylpent-1,3-ylene, 3-ethylhept-3, 5-ylene, etc., preferably methylene, eth-1,2-ylene and prop-1,2-ylene, for example

The term C ₃ -C ₇ -cycloalkyl in the sense of the description, unless stated otherwise, means a saturated hydrocarbon ring having 3 to 7, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

C ₁ -C ₆ -haloalkyl or C ₁ -C ₄ -haloalkyl is, in the context of the description, unless otherwise stated, a C ₁ -C ₆ -alkyl or C ₁ -C ₄ -alkyl, as defined above, in one, several or all hydrogen atoms have been replaced by identical or different halogen atoms as defined below.

The term C ₂ -C ₆ -alkenyl, in the sense of the description, unless otherwise stated, means a branched or unbranched hydrocarbon chain containing at least one double bond having 2 to 6 carbon atoms. Preferably, C ₂ -C ₆ alkenyl contains one or two double bonds, most preferably one double bond. Examples of the alkenyl groups are those as mentioned above for alkyl, which groups contain one or two double bonds, such as vinyl, 2-propenyl, 2-butenyl, 3-butenyl, 1-methyl-2-propenyl, 2-methyl 2-propenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-methyl-3-butenyl, 2 Methyl 3-butenyl, 3-methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-2-propenyl, 2-hexenyl, 3-hexenyl , 4-hexenyl, 5-hexenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 3-methyl-3-pentenyl, 4 Methyl 3-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-enenyl, 4-methyl-4-pentenyl, 1,1-dimethyl-2-butenyl, 1 , 1-dimethyl-3-butenyl, 1,2-dimethyl-2-butenyl, 1,2-dimethyl-3-butenyl, 1,3-dimethyl-2-butenyl, 1,3-dimethyl-3-butenyl, 2 , 2-Dimethyl-3-butenyl, 2,3-dimethyl-2-butenyl, 2,3-dimethyl-3-butenyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 2-ethyl-2 -butenyl , 2-ethyl-3-butenyl, 1,1,2-trimethyl-2-propenyl, 1-ethyl-1-methyl-2-propenyl and 1-ethyl-2-methyl-2-propenyl, in particular 2-propenyl, 2-butenyl, 3-methyl-2-butenyl or 3-methyl-2-pentenyl.

The term C ₂ -C ₆ -alkynyl in the sense of the description, unless otherwise stated, means a branched or unbranched hydrocarbon chain containing at least one triple bond having 2 to 6 carbon atoms. Preferably, C ₂ -C ₆ alkynyl contains one or two triple bonds, most preferably a triple bond. Examples of the alkynyl groups are those as mentioned above for alkyl, which groups contain one or two triple bonds, such as ethynyl, 1-propynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-3-butynyl , 2-methyl-3-butynyl, 1-methyl-2-butynyl, 1,1-dimethyl-2-propynyl, 1-ethyl-2-propynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl , 1-methyl-2-pentynyl, 1-methyl-2-pentynyl, 1-methyl-3-pentynyl, 1-methyl-4-pentynyl, 2-methyl-3-pentynyl, 2-methyl-4-pentynyl, 3 Methyl 4-pentynyl, 4-methyl-2-pentynyl, 1,1-dimethyl-2-butynyl, 1,1-dimethyl-3-butynyl, 1,2-dimethyl-3-butynyl, 2,2-dimethyl 3-butynyl, 1-ethyl-2-butynyl, 1-ethyl-3-butynyl, 2-ethyl-3-butynyl and 1-ethyl-1-methyl-2-propynyl, preferably ethynyl, 1-propynyl, 1-butyl, 2-propynyl, 2-butynyl, 1-methyl-2-propynyl or 1-methyl-2-butynyl.

The Terms "3- to 10-membered carbocycle "or" 4 to 7-membered carbocyclic ring "or" carbocyclic ring with 2 to 10 C atoms "in the sense the description, unless otherwise stated, a saturated or completely or partially unsaturated Hydrocarbon ring having 3 to 10 carbon atoms or 4 to 7 C atoms or 2-10 C atoms as ring atoms, such as Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexy, cycloheptyl, cyclooctyl, Cyclononyl or cyclodecanyl. As far as explicitly stated, the Carbocyclic ring also contain heteroatoms as ring atoms. So far otherwise stated is, can the heteroatom ring members optionally both in place of the C atom ring members or additionally be included to the C-atom ring members.

halogen is in the sense of the description, unless otherwise stated, a halogen atom is selected from fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or Bromine, more preferably fluorine or chlorine.

The terms "C ₁ -C ₆ -haloalkyl" or "C ₁ -C ₄ -haloalkyl" in the sense of the description, unless stated otherwise, denote an alkyl radical as defined above which is partially or completely free dig is substituted by one or more identical or different radicals independently selected from the group consisting of fluorine, chlorine, bromine and iodine, eg CH ₂ F, CHF ₂ , CF ₃ , CH ₂ Cl, 2-fluoroethyl, 2-chloroethyl 2,2,2-trifluoroethyl.

Provided this by using the term "substituted" accordingly is described, the Remains and groups in the sense of the description, as far as nothing else accomplished is preferably one or more times, more preferably one, two or trisubstituted, most preferably monosubstituted or disubstituted be. The expression "each optionally substituted "should clarify that not only the directly following rest but all radicals mentioned in the respective group be substituted can.

Examples of suitable substituents in the meaning of the description, unless stated otherwise, include: halogen, CN, CF ₃ , CHF ₂ , OCF ₃ , OCHF ₂ , NO ₂ , NH ₂ , OH, COOH, in each case branched or unbranched, optionally substituted C ₁ -C ₆ -alkyl, C ₃ -C ₇ -cycloalkyl, C ₁ -C ₆ -alkylene-OC ₁ -C ₆ -alkyl or C ₁ -C ₆ -thioalkyl, OC ₁ -C ₄ -alkyl, N ( C ₁ -C ₄ -alkyl) ₂ , NH (C ₁ -C ₄ -alkyl), aryl, -O-aryl, C ₁ -C ₄ -alkylene-O-aryl, NHCO-C ₁ -C ₄ -alkyl, NH-SO ₂ -C ₁ -C ₄ -alkyl, CO-C _1-4 -alkyl, SO ₂ -C ₁ -C ₄ -alkyl, in the aryl radical optionally substituted NHCO-aryl, NHSO ₂ -aryl, CONH ₂ , SO ₂ NH ₂ , SO ₂ -aryl, SO-C ₁ -C ₄ -alkyl, SO-aryl, N-pyrrolidinyl, N-piperidinyl, and N-morpholinyl. Preferred substituents are F, Cl, CF ₃ , OCF ₃ , NH ₂ , NO ₂ , OH, COOH, C ₁ -C ₄ alkyl, methoxy, acetyl, NH-acetyl and SO ₂ NH ₂ .

For the purposes of the description, parenthesized expressions with subscripts are understood to mean, unless otherwise stated, that the meanings of the radicals in parentheses may be the same or different. For example, N (C ₁ -C ₄ -alkyl) ₂ in the sense of the description is N (C ₁ -C ₄ -alkyl) (C ₁ -C ₄ -alkyl), where the two radicals are (C ₁ -C ₄ -alkyl ) may be the same or different.

By the symbol (*) in the chemical formulas of R1, R2, A, B and Y in the general formula (I) in the sense of the description, unless stated otherwise is, the junctures the radicals mentioned with the oxindole ring skeleton or one connected to the oxindole ring skeleton Group shown.

By the symbol (_) is used in the sense of the description, as far as nothing else accomplished is, a single bond represented, which, if necessary, to a chiral center bound -, should mean that the corresponding compound either as about 1: 1 mixture (racemate, (R / S) form) of the two enantiomeric forms in relation to the chiral center or as separate enantiomers (R) and / or (S) in Referring to the center of chirality.

The Symbol -SO- means in the sense of the description, as far as nothing else accomplished is a sulfoxide group (-S (= O) -).

The Symbol -SO2- means in the sense of the description, as far as nothing else accomplished is, optionally a remainder selected from the group consisting of the sulfone (- (O = S = O) -) and the sulfinic acid group (- (S = O) -O-), the meaning of the sulfonic group being preferably meant is.

Of the Expression "aromatic, heteroaromatic, partially aromatic or partially heteroaromatic mono- or bicyclic ring "means in the sense of the description, unless stated otherwise a mono or bicylic ring of C atoms ("aromatic" or "partially aromatic") or a combination from C and hetero atoms ("heteroaromatic" or "partially heteroaromatic") in each case as ring members is constructed and an aromatic number of double bondings in the ring ("monocyclic") or in the two Ringing ("bicyclic") ("aromatic" or "heteroaromatic") or only in one of the rings ("partially aromatic" or "partially heteroaromatic").

Examples for aromatic Rings are phenyl, biphenyl, naphthyl, tetrahydronaphthyl, fluorenyl, Indenyl and phenanthrenyl, more preferably phenyl and naphthyl, such as 1-naphthyl or 2-naphthyl. Most preferred is phenyl.

Examples of heteroaromatic rings are 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-thiazolyl, 4-thiazolyl, 5 Thiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, 6-pyrimidyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 3-isothiazolyl, 4-isothiazolyl , 5-isothiazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, thiadiazolyl, oxadiazolyl, triazinyl , Indolinyl, benzothienyl, naphthothienyl, benzofuranyl, chromenyl, indolyl, isoindolyl, indazolyl, quinolyl, isoquinolyl, phthalazinyl, quinoxa linyl, benzimidazolyl and benzoxazolyl, 2,3-dihydro-1,4-benzodioxinyl, 1,3-benzodioxolyl, 2,1,3-benzothiadiazolyl.

The Expressions "saturated or wholly or partially unsaturated carbocyclic ring "or" saturated or unsaturated carbocyclic ring " in the sense of the description, unless stated otherwise one of C atoms and optionally one or more heteroatoms formed ring or formed ring system that does not lie in the ring Double bond ("saturated") or one or several conjugated or not or only partially conjugated with each other Double bonds ("partial or completely unsaturated or unsaturated). The carbocyclic Ring may be a mono-, bi or tricyclic ring. A bi- or tricyclic, more saturated Carbocycle may be used in the sense of the description, as far as nothing else accomplished is a Bicycloalkyl- or Tricycloalkylrest having 2 to 10 carbon atoms be. In a bicycloalkyl radical, the ring system may preferably 5 to 10, more preferably 6 to 10 carbon atoms, In the case of a tricycloalkyl radical the ring system is preferably 6 to 10, more preferably 6 to 10 Carbon atoms. Examples of a bicycloalkyl radical include Indanyl, camphyl and norbornyl. Examples of a tricycloalkyl radical include adamantyl.

Of the Expression "im Meaning of the description " the present application in its entirety, ie in particular the description, the claims, the drawings and the abstract.

The Compounds of the invention are after administration in various ways (for example intravenously, intramuscularly, oral), especially oral.

The Compounds of the invention show good affinity to vasopressin receptors, for example, the vasopressin receptor subtypes V1a and V1b. Because the different vasopressin receptors very different effects of the vasopressin (M. Thibonnier, Exp. Olpin Invest. Drugs 1998, 7 (5), 729-740; Serradeil-Le Gal, C, et al .; Prog Brain Res. 2002; 139: 197-210), it is special Meaning, effects selective on, for example, a vasopressin receptor to get the desired one Achieve effect without significant side effects to cause. For example, Vasopressin mediates on the Receptor V2, effects on the kidney and its function and this would be at a possible treatment undesirable from CNS disorders. Special significance therefore has besides the actual affinity at the target receptor also the selectivity across from the other vasopressin receptors. The compounds of the invention show the advantage of very good affinities for the desired receptors how to have the vasopressin receptors V1b and V1a and at the same time an improved selectivity across from to show the other receptors like V2.

The The present invention also provides the use of the compounds of the invention for the treatment and / or prophylaxis of diseases in which the disease process depends at least in part on vasopressin, i. Diseases that increased one Vasopressin or oxytocin levels show, indirectly or indirectly contribute to the clinical picture, including the fact that vasopressin-dependent Effects also due to a pathologically increased density of vasopressin receptors in certain parts of the body (especially brain) can be caused.

Farther the present invention provides the use of the compounds of the invention ready for the treatment and / or prophylaxis of diseases such as Example diabetes insipidus, nocturnal enuresis, incontinence, diseases, where blood clotting disorders occur and / or delay the micturition.

The The present invention also provides the use of the compounds of the invention for the treatment and / or prophylaxis of the following diseases available: Hypertension, pulmonary hypertension, heart failure, myocardial infarction, Coronary spasm, unstable angina, PTCA (percutaneous transluminal coronary angioplasia), ischemia of the heart, disorders of the renal system, edema, renal Vasospasm, necrosis of the renal cortex, hyponatremia, hypokalaemia, Schwartz-Bartter Syndrome, disorders of the gastrointestinal tract, gastric vasospasm, hepatocirrhosis, Stomach and intestinal ulcer, vomiting, vomiting during chemotherapy, and motion sickness.

The compounds of the present invention may also be used to treat various vasopressin-dependent or oxytocin-dependent disorders having central nervous causes or changes in the hypothalamic pituitary adrenal axis (HPA), for example, affective disorders such as depressive disorders and bipolar disorders disorders. These include, for example, dythymous disorders, phobias, posttraumatic stress disorders, general anxiety disorders, panic disorders, sai mental depression and sleep disorders.

As well can the compounds of the invention for treatment of anxiety disorders and stress dependent anxiety disorders be used, such as generalized anxiety disorders, Phobias, post-traumatic anxiety disorders, panic anxiety disorders, obsessive compulsive anxiety disorders, acute stress dependent anxiety disorders and social phobia. Furthermore you can the compounds of the invention also for the treatment of memory disorders, Alzheimer's disease, psychosis, psychotic disorders, sleep disorders and / or Cushing syndrome.

The the present invention also relates to pharmaceutical compositions, the one effective dose of a compound of the invention or a pharmaceutical acceptable Salt thereof and suitable excipients included.

These excipients be according to the pharmaceutical form and desired Application type selected.

The Compounds of the invention of the general formula I or, if appropriate, suitable salts thereof Connections can for the preparation of pharmaceutical compositions for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, intratracheal, intranasal, transdermal or rectal administration be used and animals or humans in unitary administration forms, mixed with conventional pharmaceutical carriers, for the prophylaxis or treatment of the above disorders or diseases become.

The suitable uniform administration forms include forms for oral administration, such as tablets, gelatin capsules, powders, granule and solutions or suspensions for oral administration, forms for sublingual, buccal, intratracheal or intranasal administration, aerosols, Implants, forms of subcutaneous, intramuscular or intravenous administration and forms of rectal administration.

to topical administration can the compounds of the invention in creams, ointments or lotions.

Around the wished To achieve prophylactic or therapeutic effect, the Dose of the active principle between 0.01 and 50 mg per kg body weight and vary per day.

each Unit dose may be 0.05 to 5000 mg, preferably 1 to 1000 mg, of the active ingredient in combination with a pharmaceutical carrier contain. This unit dose can be administered 1 to 5 times a day be, so a daily Dose of 0.5 to 25000 mg, preferably 1 to 5000 mg.

If a solid composition is prepared in the form of tablets, becomes the main ingredient with a pharmaceutical carrier, such as Gelatin, starch, Lactose, magnesium stearate, talc, silica or the like, mixed.

The Tablets can with sucrose, a cellulose derivative or another suitable one Substance can be coated or otherwise treated to a persistent or delayed activity and a predetermined amount of the active principle continuously release.

A Preparation in the form of gelatin capsules is achieved by mixing the active Component with an extender and picking up the resulting Blend into soft or hard gelatin capsules.

A Preparation in the form of a syrup or elixir or for administration In the form of drops can be active ingredients together with one Sweetener, which is preferably calorie-free, methylparaben or propylparaben as antiseptics, a flavoring agent and a suitable dye contain.

The water-dispersible powders or granules may be the active ingredients, mixed with dispersants, wetting agents or suspending agents, such as polyvinylpyrrolidones, as well as sweeteners or flavoring agents, contain.

Rectal administration is achieved by using suppositories prepared with binders which melt at rectal temperature, for example cocoa butter or polyethylene glycols. A Parenteral administration is effected using aqueous suspensions, isotonic saline solutions or sterile and injectable solutions containing pharmacologically acceptable dispersants and / or wetting agents, for example, propylene glycol or polyethylene glycol.

Of the active basic ingredient can also be called microcapsules or centrosomes, if appropriate with one or more carriers or additives become.

In addition to the compounds of general formula (I) or their pharmaceutically compatible salts can the compositions of the invention contain other active ingredients that are used to treat the above mentioned disturbances or diseases useful could be.

The The present invention thus further relates to pharmaceutical compositions, where several basic active ingredients are present together, wherein at least one of these is a compound of the invention is.

The Compounds of the invention represent antagonists of the so-called receptors of the vasopressin oxytocin family Such compounds can be obtained in suitable tests containing the affinity to determine a receptor, examine the affinity constant Ki is a measure of potency of connections and a smaller value represents a greater power represents. The compounds of the invention For example, they were based on their receptor affinity in the following vasopressin receptor subtype V1b receptor on her affinity checked.

MANUFACTURING THE INVENTION OF THE INVENTION LINKS

in the The following are exemplary synthetic routes for the preparation of Compounds of the invention described.

Verbindungen, in denen eine Aminogruppe R_A ⁴ über eine Methylengruppe an den Ring A gebunden ist, können in der in Syntheseschema 1 gezeigten Weise synthetisiert werden. Die 3-Hydroxy-oxindole VI können durch Addition von Lithium-organischen oder Grignard-Verbindungen an die 3-Ketogruppe der substituierten Isatine V in einem etherischen Lösungsmittel, wie zum Beispiel THF, hergestellt werden. Zum Beispiel (R_A ¹¹ = OCH₃) lässt sich die Lithium-Spezies aus der Iod-aryl-Verbindung IV durch Behandlung mit Organolithium-Reagenzien, wie z.B. n-Butyllithium, in THF bei tiefen Temperaturen erhalten. Alternativ kann aus IV die entsprechende Grignard-Verbindung durch Behandlung mit Magnesium in einem etherischen Lösungsmittel, wie z.B. THF, hergestellt werden. Das cyclische Acetal IV kann in zwei Stufen (Methylierung des Phenol-Sauerstoffs gefolgt von Schützung des Aldehyds als Acetal) aus kommerziell verfügbarem 3-Hydroxy-4-iodbenzaldehyd (II) hergestellt werden. In analoger Weise lässt sich aus käuflichem 3-Brom-4-methoxybenzaldehyd der isomere Baustein (geschützte Aldehyd-Funktion para zur Methoxygruppe) gewinnen. Für die Synthese der Verbindungen mit R_A ¹¹ = H kann man käufliche Grignard- Verbindungen, z.B. (3-(1-Pyrrolidinylmethyl)phenyl)magnesiumbromid oder (4-(1-Pyrrolidinylmethyl)phenyl)magnesiumbromid mit den Isatinen V umsetzen.The preparation of the oxindoles according to the invention can be carried out, for example, in the way outlined in Synthetic Scheme 1. In the synthesis scheme 1, the variables have the same meanings as in the general formula (I) SYNTHESIS SCHEME 1 (R _A ¹¹ = OCH ₃ , R ² = N)

Compounds in which an amino group R _A ⁴ is bonded to Ring A via a methylene group can be synthesized in the manner shown in Synthetic Scheme 1. The 3-hydroxy-oxindoles VI can be prepared by adding lithium-organic or Grignard compounds to the 3-keto group of the substituted isatins V in an ethereal solvent such as THF. For example (R _A ¹¹ = OCH ₃ ), the lithium species can be prepared from the iodo-aryl compound IV by treatment with organolithium reagents en, such as n-butyllithium, obtained in THF at low temperatures. Alternatively, from IV, the corresponding Grignard compound may be prepared by treatment with magnesium in an ethereal solvent such as THF. The cyclic acetal IV can be prepared in two stages (methylation of phenol-oxygen followed by protection of the aldehyde as acetal) from commercially available 3-hydroxy-4-iodobenzaldehyde (II). In an analogous manner, the isomeric building block (protected aldehyde function para to the methoxy group) can be obtained from commercially available 3-bromo-4-methoxybenzaldehyde. Commercially available Grignard compounds, for example (3- (1-pyrrolidinylmethyl) phenyl) magnesium bromide or (4- (1-pyrrolidinylmethyl) phenyl) magnesium bromide, can be reacted with the isatynes V for the synthesis of the compounds with R _A ¹¹ = H.

In the case, that A is an aromatic heterocycle, metalated heteroaromatics, the one protected Bear formyl group, in an analogous manner (protecting the formyl function as cyclic acetal followed by lithium-halogen exchange or insertion of magnesium into the heteroaryl-halogen bond) be prepared, e.g. from commercially available 2-bromo-4-formyl-3-methoxypyridine, 6-bromo-2-formylpyridine, 5-bromo-3-formylpyridine, 2-bromo-4-formylpyridine, 2-bromo-5-formylpyridine, 4-bromo-2-formylthiophene, 3-bromo-2-formylthiophene, 5-bromo-2-formylthiophene or 3-bromo-4-formylthiophene.

The 3-hydroxy-oxindoles VI can be converted into the compounds VII which carry a leaving group LG in the 3-position, it being possible for the leaving group LG to be customary leaving groups, for example halides, mesylate or tosylate. Thus, for example (LG = chlorine), the intermediate VII can be prepared by treating the alcohol VI with thionyl chloride in the presence of a base such as pyridine in a solvent such as dichloromethane. The compounds VII are then reacted in the presence of a base, such as N, N-diisopropylethylamine, with primary or secondary amines YH in a solvent, such as dichloromethane, to give the 3-aminooxindoles VIII. After cleavage of the acetal protecting group, eg by treatment with aqueous hydrochloric acid in acetone, the resulting aldehyde IX may be combined with primary or secondary amines in the presence of a reducing agent such as sodium cyanoborohydride or solid phase bound triacetoxyborohydride in a solvent such as THF to form the amines X. (Reductive amination: J. March, Advanced Organic Chemistry, 1992, 4th edition, Wiley, New York, p.411, 898). Sulfonylation of the oxindole nitrogen can be accomplished by treating X with sulfonyl chlorides B-SO ₂ Cl after deprotonation with a strong base such as potassium tert-butylate or sodium hydride in a solvent such as DMF or THF.

The cyano group as radical R ¹ can be introduced starting from the corresponding compounds with R ¹ = iodine, for example by heating compound X or XI (where R ¹ = I) with zinc cyanide in DMF in the presence of catalytic amounts of palladium tetrakis ( triphenylphosphine) or by heating with potassium cyanide and catalytic amounts of palladium tetrakis (triphenylphosphine) in THF (J. Med. Chem. 1996, 39, 5072-5082).

SYNTHESIS SCHEME 2 (R _A ¹¹ = OCH ₃ , R ² = H)

In the manner shown in Synthetic Scheme 2, compounds can be synthesized in which an amino group R _A ⁴ is bonded via an O-alkyl group to the ring A. The 3-hydroxy-oxindoles XII can be prepared by adding lithium-organic or Grignard compounds to the 3-keto group of the substituted isatins V. For example (R _A ¹¹ = OCH ₃ ) can be prepared from 4-bromo-3-methoxyphenol after protection of the phenolic oxygen function with a suitable protecting group PG, such as triisopropylsilyl, by treatment with organolithium reagents, such as n-butyllithium, in an ethereal solvent, such as THF, at low temperatures, the corresponding lithium species are obtained. Introduction of the LG vanishing group, substitution of the LG leaving group with amines YH and sulfonylation of the oxindole nitrogen was carried out as described previously (synthesis scheme 1) and afforded the protected compound XV. After removal of the protective group PG, in the case of PG = triisopropylsilyl, for example with tetrabutylammonium fluoride in THF, the phenolic oxygen function can be alkylated with alkyl halides containing substituted amino groups R _A ⁴ , eg by heating the phenol XVI with the alkylating agent R _A ⁴ - (C ₂ -C ₄ alkyl) -Cl in DMF in the presence of a base such as potassium carbonate in the microwave.

The The invention is explained below with reference to examples, without limited to the examples to be.

EXPERIMENTAL PART

EXAMPLE 1

(S) -1- [5-chloro-1- (2,4-dimethoxy-benzenesulfonyl) -3- (2-methoxy-4-pyrrolidin-1-ylmethyl-phenyl) -2-oxo-2,3-dihydro -1H-indol-3-yl] -pyrrolidine-2-carboxylic acid dimethylamide, trifluoroacetic salt

A) 2- (4-iodo-3-methoxyphenyl) -5,5-dimethyl- [1,3] dioxane

To an ice-cooled solution of 3-hydroxy-4-iodobenzaldehyde (5.00 g, 20.2 mmol) in DMF (20 mL) was added sodium hydride (887 mg, 60% dispersion in mineral oil, 22.2 mmol) and stirred at 0 ° C for 60 min. To the solution of phenolate was added dropwise iodomethane (3.15 mL, 22.2 mmol) and the reaction mixture was stirred for 4 hrs. At room temperature. The reaction was diluted with ethyl acetate and washed with ice-water and saturated brine. After drying over magnesium sulfate, the organic phase was concentrated under reduced pressure. The residue (6.32 g) was dissolved in toluene (150 mL), and after addition of neopentyl glycol (2.76 g, 26.5 mmol) and Amberlyst-15 (400 mg), the reaction mixture was refluxed on a water trap for 3 h. After filtration, the reaction solution was concentrated under reduced pressure and the residue was purified by chromatography on silica gel (eluent gradient 10-25% ethyl acetate in dichloromethane). Yield: 6.83 g (77%) of a yellowish oil. MS (API-ES, pos) m / z = 349 [M + H] ⁺ 2- (3-bromo-4-methoxyphenyl) -5,5-dimethyl- [1,3] dioxane was passed through in an analogous manner Acetalization of commercially available 3-bromo-4-methoxybenzaldehyde prepared with neopentyl glycol. Yield: 6.13 g (88%) of a white solid. MS (API-ES, pos) m / z = 301, 303 [M + H] ⁺

B) 5-Chloro-3- [4- (5,5-dimethyl- [1,3] dioxan-2-yl) -2-methoxyphenyl] -3-hydroxy-1,3-dihydro-indole-2 -one

To a solution of 2- (4-iodo-3-methoxy-phenyl) -5,5-dimethyl- [1,3] dioxane (3.00 g, 8.62 mmol) in THF (100 mL) became slow at -78 ° C a solution of n-butyllithium in hexane (1.6 M, 5.52 mL, 8.83 mmol) was added dropwise. After 15 minutes, a solution of the 5-chloroisatin sodium salt [prepared by treating a solution of 5-chloroisatin (1.21 g, 6.64 mmol) in THF with one equivalent of sodium hydride for one hour at 0 ° C] to the organo-lithium species solution dripped. The reaction mixture is allowed to warm to room temperature and stirred for a further hour. The reaction solution was added with stirring with aqueous ammonium chloride solution and the batch was extracted with ethyl acetate. The combined organic phase was washed with water and brine, dried over magnesium sulfate and concentrated under reduced pressure. The desired product crystallizes when standing in the cold. Yield: 1.42 g (53%) of a white solid. MS (API-ES, pos) m / z = 404 [M + H] ⁺

C) (S) -1- {5-Chloro-3- [4- (5,5-dimethyl- [1,3-dioxan-2-yl) -2-methoxyphenyl] -2-oxo-2,3- dihydro-1H-indol-3-yl} -pyrrolidine-2-carboxylic acid dimethylamide

A solution of the reaction product according to step B) (2.84 g, 7.02 mmol) in dichloromethane (20 mL) was added under ice-cooling with pyridine (0.68 mL, 8.43 mmol) and thionyl chloride (0.61 mL, 8.43 mmol) and at 0 ° C for 15 min touched. The reaction solution was quenched with water with stirring and the reaction extracted with dichloromethane. The organic phase was washed with water and saturated brine dried over magnesium sulfate and concentrated under reduced pressure. To a solution of the thus obtained 3-chloro-oxindole intermediate in dichloromethane (20 mL) were added N, N-diisopropylethylamine (3.32 mL, 19.1 mmol) and (S) -pyrrolidine-2-carboxylic acid dimethylamide (1.00 g, 7.01 mmol) and the reaction mixture stirred for 18 hrs. At room temperature. After dilution with dichloromethane, the reaction was washed with water and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (eluent gradient 1-5% methanol in dichloromethane). Yield: 3.08 g (79%) of a mixture of diastereomers. MS (API-ES, pos) m / z = 528 [M + H] ⁺

D) (S) -1- [5-Chloro-3- (4-formyl-2-methoxy-phenyl) -2-oxo-2,3-dihydro-1H-indol-3-yl] -pyrrolidine-2 dimethylcarboxamide

A solution of the reaction product according to step C) (1.00 g, 1.89 mmol) in a mixture of acetone (15 mL), dichloromethane (2 mL) and 2 N aqueous hydrochloric acid (10 mL) was stirred at room temperature for 72 h. To complete the reaction was heated to 50 ° C for 45 min. The reaction mixture was diluted with dichloromethane and neutralized by the addition of sodium bicarbonate solution. The organic phase was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. Yield: 650 mg (78%) of a white solid. MS (API-ES, pos) m / z = 442 [M + H] ⁺

E) (S) -1- {5-Chloro-3- (2-methoxy-4-pyrrolidin-1-ylmethylphenyl) -2-oxo-2,3-dihydro-1H-indol-3-yl] - pyrrolidine-2-carboxylic acid dimethylamide, linksdrehendes

diastereomer

A solution of the reaction product according to step D) (650 mg, 1.47 mmol) in THF (5 mL) was treated with pyrrolidine (0.15 mL, 1.77 mmol) and MP triacetoxyborohydride resin (Argonaut, 2.04 g, f = 1.8 mmol / g, 3.68 mmol) and shaken for 16 hrs. At room temperature. The solid phase reagent was filtered off, washed with THF and the filtrate concentrated under reduced pressure. The residue was purified by chromatography on silica gel (eluent gradient 5-25% methanol in dichloromethane). Yield: 156 mg (21%) of the earlier eluting diastereomer, MS (API-ES, pos) m / z = 497 [M + H] ⁺ , [⎕] _D -124 (c 0.1, CHCl ₃ , 20 ° C) ; 87 mg of the later eluting diastereomer, MS (API-ES, pos) m / z = 497 [M + H] ⁺ .

F) (S) -1- [5-Chloro-1- (2,4-dimethoxy-benzenesulfonyl) -3- (2-methoxy-4-pyrrolidin-1-ylmethyl-phenyl) -2-oxo-2,3 dihydro-1H-indol-3-yl] -pyrrolidine-2-carboxylic acid dimethylamide, trifluoroacetic Salt (Example 1)

A solution of the reaction product according to step E) (30 mg of the previously eluting levorotatory diastereomer, 0.06 mmol) in DMF (2 mL) was treated at 0 ° C with sodium hydride (3 mg, 60% dispersion in mineral oil, 0.08 mmol). After 30 min, 2,4-dimethoxybenzenesulfonyl chloride (15 mg, 0.06 mmol) was added to the reaction solution and stirred at room temperature for a further 30 min. The batch was mixed with sodium bicarbonate solution and extracted with ethyl acetate. The combined organic phase was washed with water and brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC (mobile phase gradient 10-100% acetonitrile in water + 0.1% trifluoroacetic acid). Yield: 20 mg (48%), MS (API-ES, pos) m / z = 697 [M + H] ⁺ .

On Analogously, the following compounds 1 to 33 were prepared:

EXAMPLE 2

(S) -1- [5-chloro-1- (4-methoxy-benzenesulfonyl) -3- (2-methoxy-4-pyrrolidin-1-ylmethyl-phenyl} -2-oxo-2,3-dihydro-1 H indol-3-yl] -pyrrolidine-2-carboxylic acid dimethylamide, trifluoroacetic salt

• MS (API-ES, pos) m / z = 667 [M + H] ⁺ .

EXAMPLE 3

(S) -1- [5-chloro-1- (4-fluoro-benzenesulfonyl) -3- (2-methoxy-4-pyrrolidin-1-ylmethyl-phenyl) -2-oxo-2,3-dihydro-1 H indol-3-yl] -pyrrolidine-2-carboxylic acid dimethylamide, trifluoroacetic salt

• MS (API-ES, pos) m / z = 655 [M + H] ⁺ .

EXAMPLE 4

(S) -1- [5-chloro-1- (4-chloro-benzenesulfonyl) -3- (2-methoxy-4-pyrrolidin-1-ylmethyl-phenyl) -2-oxo-2,3-dihydro-1 H indol-3-yl] -pyrrolidine-2-carboxylic acid dimethylamide, trifluoroacetic salt

• MS (API-ES, pos) m / z = 671 [M + H] ⁺ .

EXAMPLE 5

(S) -1- [5-chloro-1- (4-cyano-benzenesulfonyl) -3- (2-methoxy-4-pyrrolidin-1-ylmethyl-phenyl) -2-oxo-2,3-dihydro-1 H indol-3-yl] -pyrrolidine-2-carboxylic acid dimethylamide, trifluoroacetic salt

• MS (API-ES, pos) m / z = 662 [M + H] ⁺ .

EXAMPLE 6

(2S, 4R) -1- [5-chloro-1- (2,4-dimethoxy-benzenesulfonyl) -2-oxo-3- (4-pyrrolidin-1-ylmethyl-phenyl) -2,3-dihydro-1 H indol-3-yl] -4-hydroxy-pyrrolidine-2-carboxylic acid dimethylamide

• MS (API-ES, pos) m / z = 683 [M + H] ⁺ .

EXAMPLE 7

(S) -1- [5-chloro-1- (2,4-dimethoxy-benzenesulfonyl) -3- (4-dimethylaminomethyl-2-methoxy-phenyl) -2-oxo-2,3-dihydro-1H-indole -3-yl] -pyrrolidine-2-carboxylic acid dimethylamide

• MS (API-ES, pos) m / z = 671 [M + H] ⁺ .

EXAMPLE 8

(S) -1- [5-chloro-1- (2,4-dimethoxy-benzenesulfonyl) -3- (2-methoxy-4-piperidin-1-ylmethyl-phenyl) -2-oxo-2,3-dihydro -1H-indol-3-yl] -pyrrolidine-2-carboxylic acid dimethylamide

• MS (API-ES, pos) m / z = 711 [M + H] ⁺ .

EXAMPLE 9

(S) -1- {5-chloro-1- (2,4-dimethoxy-benzenesulfonyl) -3- [2-methoxy-4- (4-methyl-piperazin-1-ylmethyl) phenyl] -2-oxo -2,3-dihydro-1H-indol-3-yl} -pyrrolidine-2-carboxylic acid dimethylamide

• MS (API-ES, pos) m / z = 726 [M + H] ^+.

EXAMPLE 10

(S) -1- [5-chloro-1- (2,4-dimethoxy-benzenesulfonyl) -3- (2-methoxy-4-morpholin-4-ylmethyl-phenyl) -2-oxo-2,3-dihydro -1H-indol-3-yl] -pyrrolidine-2-carboxylic acid dimethylamide

• MS (API-ES, pos) m / z = 713 [M + H] ⁺ .

EXAMPLE 11

(S) -1- [3- [4- (4-Acetyl-piperazin-1-ylmethyl) -2-methoxy-phenyl] -5-chloro-1- (2,4-dimethoxy-benzenesulfonyl) -2-oxo -2,3-dihydro-1H-indol-3-yl) pyrrolidine-2-carboxylic acid dimethylamide

• MS (API-ES, pos) m / z = 754 [M + H] ⁺ .

EXAMPLE 12

(S) -1- [5-chloro-1- (2,4-dimethoxy-benzenesulfonyl) -3- (4 - {[(2-dimethylaminoethyl) -methyl-amino] -methyl} -2-methoxy-phenyl) -2-oxo-2,3-dihydro-1H-indol-3-yl] -pyrrolidine-2-carboxylic acid dimethylamide

• MS (API-ES, pos) m / z = 728 [M + H] ⁺ .

EXAMPLE 13

(S) -2 - {[5-chloro-1- (2,4-dimethoxy-benzenesulfonyl) -3- (4-dimethylaminomethyl-2-methoxy-phenyl) -2-oxo-2,3-dihydro-1H- indol-3-yl] -methyl-amino} -N, N-dimethyl-propionamide

• MS (API-ES, pos) m / z = 659 [M + H] ⁺ .

EXAMPLE 14

(S) -2 - {[5-chloro-1- (2,4-dimethoxy-benzenesulfonyl) -3- (2-methoxy-4-pyrrolidin-1-ylmethyl-phenyl) -2-oxo-2,3- dihydro-1H-indol-3-yl) methyl-amino} -N, N-dimethyl-propionamide

• MS (API-ES, pos) m / z = 685 [M + H] ⁺ .

EXAMPLE 15

(S) -2 - ({5-chloro-1- (2,4-dimethoxy-benzenesulfonyl) -3- [2-methoxy-4- (4-methyl-piperazin-1-ylmethyl) phenyl] -2- oxo-2,3-dihydro-1H-indol-3-yl} -methyl-amino) -N, N-dimethyl-propionamide

• MS (API-ES, pos) m / z = 714 [M + H] ⁺ .

EXAMPLE 16

(2S, 4R) -1- [5-chloro-1- (2,4-dimethoxy-benzenesulfonyl) -3- (3-dimethylaminomethyl-phenyl) -2-oxo-2,3-dihydro-1H-indol-3 yl] -4-hydroxy-pyrrolidine-2-carboxylic acid

• MS (API-ES, pos) m / z = 657 [M + H] ⁺ .

EXAMPLE 17

(S) -1- [5-chloro-3- (5-dimethylaminomethyl-2-methoxy-phenyl) -1- (4-methoxy-benzenesulfonyl) -2-oxo-2,3-dihydro-1H-indol-3 -yl] -pyrrolidine-2-carboxylic acid dimethylamide, trifluoroacetic salt

• MS (API-ES, pos) m / z = 641 [M + H] ⁺ .

EXAMPLE 18

(S) -1- [5-chloro-1- (4-methoxy-benzenesulfonyl) -3- (2-methoxy-5-pyrrolidin-1-ylmethyl-phenyl) -2-oxo-2,3-dihydro-1 H indol-3-yl] -pyrrolidine-2-carboxylic acid dimethylamide, trifluoroacetic salt

• MS (API-ES, pos) m / z = 667 [M + H] ⁺ .

EXAMPLE 19

(S) -1- [5-chloro-1- (4-methoxy-benzenesulfonyl) -3- (2-methoxy-5-piperidin-1-ylmethyl-phenyl) -2-oxo-2,3-dihydro-1 H indol-3-yl] -pyrrolidine-2-carboxylic acid dimethylamide, trifluoroacetic salt

• MS (API-ES, pos) m / z = 681 [M + H] ⁺ .

EXAMPLE 20

(S) -1- {5-chloro-1- (4-methoxy-benzenesulfonyl) -3- [2-methoxy-5- (4-methyl-piperazin-1-ylmethyl) phenyl] -2-oxo-2 , 3-dihydro-1H-indol-3-yl} -pyrrolidine-2-carboxylic acid dimethylamide, trifluoroacetic salt

• MS (API-ES, pos) m / z = 696 [M + H] ⁺ .

EXAMPLE 21

(S) -1- [5-chloro-1- (4-methoxy-benzenesulfonyl) -3- (2-methoxy-5-morpholin-4-ylmethyl-phenyl) -2-oxo-2,3-dihydro-1 H indol-3-yl] -pyrrolidine-2-carboxylic acid dimethylamide, trifluoroacetic salt

• MS (API-ES, pos) m / z = 683 [M + H] ⁺ .

EXAMPLE 22

(S) -1- [5-chloro-3- (5 - {[(2-dimethylamino-ethyl) -methyl-amino] -methyl} -2-methoxy-phenyl) -1- (4-methoxy-benzenesulfonyl) -2-oxo-2,3-dihydro-1 H-indol-3-yl] -pyrrolidine-2-carboxylic acid dimethylamide, trifluoroacetic acid salt

• MS (API-ES, pos) m / z = 698 [M + H] ⁺ .

EXAMPLE 23

(S) -1- [5-chloro-3- (5 - {[(3-dimethylamino-propyl) -methyl-amino] -methyl} -2-methoxy-phenyl) -1- (4-methoxy-benzenesulfonyl) -2-oxo-2,3-dihydro-1H-indol-3-yl] -pyrrolidine-2-carboxylic acid dimethylamide, trifluoroacetic salt

• MS (API-ES, pos) m / z = 712 [M + H] ⁺ .

EXAMPLE 24

(S) -1- [5-chloro-1- (2,4-dimethoxy-benzenesulfonyl) -3- (5-dimethylaminomethyl-2-methoxy-phenyl) -2-oxo-2,3-dihydro-1H-indole -3-yl] -pyrrolidine-2-carboxylic acid dimethylamide, trifluoroacetic salt

• MS (API-ES, pos) m / z = 671 [M + H] ⁺ .

EXAMPLE 25

(S) -1- [5-chloro-1- (2,4-dimethoxy-benzenesulfonyl) -3- (2-methoxy-5-pyrrolidin-1-ylmethyl-phenyl) -2-oxo-2,3-dihydro -1H-indol-3-yl] -pyrrolidine-2-carboxylic acid dimethylamide, trifluoroacetic salt

• MS (API-ES, pos) m / z = 697 [M + H] ⁺ .

EXAMPLE 26

(S) -1- [5-chloro-1- (2,4-dimethoxy-benzenesulfonyl) -3- (2-methoxy-5-piperidin-1-ylmethyl-phenyl) -2-oxo-2,3-dihydro -1H-indol-3-yl] -pyrrolidine-2-carboxylic acid dimethylamide trifluoroacetic salt

• MS (API-ES, pos) m / z = 711 [M + H] ⁺ .

EXAMPLE 27

(S) -1- {5-chloro-1- (2,4-dimethoxy-benzenesulfonyl) -3- [2-methoxy-5- (4-methyl-piperazin-1-ylmethyl) phenyl] -2-oxo -2,3-dihydro-1H-indol-3-yl} -pyrrolidine-2-carboxylic acid dimethylamide, trifluoroacetic salt

• MS (API-ES, pos) m / z = 726 [M + H] ⁺ .

EXAMPLE 28

(S) -1- [5-chloro-1- (2,4-dimethoxy-benzenesulfonyl) -3- (2-methoxy-5-morpholin-4-ylmethyl-phenyl) -2-oxo-2,3-dihydro -1H-indol-3-yl] -pyrrolidine-2-carboxylic acid dimethylamide, trifluoroacetic salt

• MS (API-ES, pos) m / z = 713 [M + H] ⁺ .

EXAMPLE 29

(S) -1- [5-chloro-1- (2,4-dimethoxy-benzenesulfonyl) -3- (5 - {[(2-dimethylaminoethyl) -methyl-amino] -methyl} -2-methoxy-phenyl) -2-oxo-2,3-dihydro-1H-indol-3-yl] -pyrrolidine-2-carboxylic acid dimethylamide, trifluoroacetic salt

• MS (API-ES, pos) m / z = 728 [M + H] ⁺ .

EXAMPLE 30

(S) -1- [5- chloro-1- (2,4-dimethoxy-benzenesulfonyl) -3- (5 - {[(3-dimethylaminopropyl) -methyl-amino] -methyl} -2-methoxy-phenyl) -2-oxo-2,3-dihydro-1H-indol-3-yl] -pyrrolidine-2-carboxylic acid dimethylamide, trifluoroacetic salt

• MS (API-ES, pos) m / z = 742 [M + H] ^+.

EXAMPLE 31

(S) -1- [5-chloro-1- (2,4-dimethoxy-benzenesulfonyl) -3- (2-methoxy-4 - {[(2-methoxy-ethyl) -methyl-amino] -methyl} - phenyl) -2-oxo-2,3-dihydro-1H-indol-3-yl] -pyrrolidine-2-carboxylic acid dimethylamide

• MS (API-ES, pos) m / z = 715 [M + H] ⁺ .

EXAMPLE 32

(S) -1- [5-chloro-1- (4-methoxy-benzenesulfonyl) -3- (2-methoxy-5 - {[(2-methoxy-ethyl) -methyl-amino) -methyl} -phenyl) -2-oxo-2,3-dihydro-1H-indol-3-yl] -pyrrolidine-2-carboxylic acid dimethylamide, trifluoroacetic salt

• MS (API-ES, pos) m / z = 685 [M + H] ⁺ .

EXAMPLE 33

(S) -1- [5-chloro-1- (2,4-dimethoxy-benzenesulfonyl) -3- (2-methoxy-5 - {[(2-methoxy-ethyl) -methyl-amino] -methyl} - phenyl) -2-oxo-2,3-dihydro-1H-indol-3-yl] -pyrrolidine-2-carboxylic acid dimethylamide, trifluoroacetic salt

• MS (API-ES, pos) m / z = 715 [M + H] ⁺ .

Farther Examples 34 to 39 below are analogous according to the synthesis scheme 2 available.

EXAMPLE 34

(S) -1- {5-chloro-1- (4-cyano-benzenesulfonyl) -3- [2-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) -phenyl] -2-oxo-2 , 3-dihydro-1H-indol-3-yl} -pyrrolidine-2-carboxylic acid dimethylamide, trifluoroacetic salt

EXAMPLE 35

(S) -1- {5-chloro-1- (4-cyano-benzenesulfonyl) -3- [4- (2-dimethylamino-ethoxy) -2-methoxy-phenyl] -2-oxo-2,3-dihydro -1H-indol-3-yl} -pyrrolidine-2-carboxylic acid dimethylamide, trifluoroacetic salt

EXAMPLE 36

(S) -1- {5-chloro-1- (4-cyano-benzenesulfonyl) -3- [2-methoxy-4- (2-morpholin-4-yl-ethoxy) -phenyl] -2-oxo-2 , 3-dihydro-1H-indol-3-yl} -pyrrolidine-2-carboxylic acid dimethylamide, trifluoroacetic salt

EXAMPLE 37

(S) -1- {5-chloro-1- (4-cyano-benzenesulfonyl) -3- [2-methoxy-4- (3-piperidin-1-yl-propoxy) -phenyl] -2-oxo-2 , 3-dihydro-1H-indol-3-yl} -pyrrolidine-2-carboxylic acid dimethylamide, trifluoroacetic salt

EXAMPLE 38

(S) -1- {5-chloro-1- (4-cyano-benzenesulfonyl) -3- [4- (3-dimethylamino-propoxy) -2-methoxy-phenyl] -2-oxo-2,3-dihydro -1H-indol-3-yl} -pyrrolidine-2-carboxylic acid dimethylamide, trifluoroacetic salt

EXAMPLE 39

(S) -1- (5-chloro-1- (4-cyano-benzenesulfonyl) -3- {2-methoxy-4- [3- (4-methyl-piperazin-1-yl) propoxy] phenyl} -2-oxo-2,3-dihydro-1H-indol-3-yl) pyrrolidine-2-carboxylic acid dimethylamide

Farther Examples 40 to 68 below are analogous according to the synthesis scheme 1 available.

EXAMPLE 40

(S) -1- [5-chloro-3- (2-methoxy-4-pyrrolidin-1-ylmethyl-phenyl) -2-oxo-1- (pyridine-2-sulfonyl) -2,3-dihydro-1 H indol-3-yl] -pyrrolidine-2-carboxylic acid dimethylamide

EXAMPLE 41

(S) -1- [5-chloro-3- (2-methoxy-4-pyrrolidin-1-ylmethyl-phenyl) -1- (5-methyl-pyridine-2-sulfonyl) -2-oxo-2,3 dihydro-1H-indol-3-yl] -pyrrolidine-2-carboxylic acid dimethylamide

EXAMPLE 42

(S) -1- [5-chloro-1- (5-chloro-pyridin-2-sulfonyl) -3- (2-methoxy-4-pyrrolidin-1-ylmethyl-phenyl) -2-oxo-2,3 dihydro-1H-indol-3-yl] -pyrrolidine-2-carboxylic acid dimethylamide

EXAMPLE 43

(S) -1- [5-chloro-3- (2-methoxy-4-pyrrolidin-1-ylmethyl-phenyl)-oxo-1- -2 (thiophene-2-sulfonyl) -2,3-dihydro-1 H indol-3-yl] -pyrrolidine-2-carboxylic acid dimethylamide

EXAMPLE 44

(S) -1 - [(5-chloro-3- (2-methoxy-4-pyrrolidin-1-ylmethyl-phenyl) -2-oxo-1- (thiophene-3-sulfonyl) -2,3-dihydro- 1H-indol-3-yl] -pyrrolidine-2-carboxylic acid dimethylamide

EXAMPLE 45

(S) -1- [5- chloro-3- (2-methoxy-4-pyrrolidin-1-ylmethyl-phenyl) -2-oxo-1- (quinoline-8-sulfonyl) -2,3-dihydro-1 H indol-3-yl] -pyrrolidine-2-carboxylic acid dimethylamide

EXAMPLE 46

(2S, 4R) -1- [5-Cyano-1- (4-methoxy-benzenesulfonyl) -3- (2-methoxy-4-pyrrolidin-1-ylmethyl-phenyl) -2-oxo-2,3-dihydro -1H-indol-3-yl] -4-hydroxy-pyrrolidine-2-carboxylic acid dimethylamide

EXAMPLE 47

(2S, 4R) -1- [5-chloro-1- (4-methoxy-benzenesulfonyl) -3- (2-methoxy-4-pyrrolidin-1-ylmethyl-phenyl) -2-oxo-2,3-dihydro -1H-indol-3-yl] -4-fluoro-pyrrolidine-2-carboxylic acid dimethylamide

EXAMPLE 48

(S) -1- [5-chloro-1- (4-methoxy-benzenesulfonyl) -3- (2-methoxy-4-pyrrolidin-1-ylmethyl-phenyl) -2-oxo-2,3-dihydro-1 H indol-3-yl] piperidine-2-carboxylic acid dimethylamide

EXAMPLE 49

(S) -2- [5-chloro-1- (4-methoxy-benzenesulfonyl) -3- (2-methoxy-4-pyrrolidin-1-ylmethyl-phenyl) -2-oxo-2,3-dihydro-1 H indole-3-ylamino] -N, N-dimethyl-propionamide

EXAMPLE 50

(S) -1- [5-cyano-3- (2-methoxy-4-pyrrolidin-1-ylmethyl-phenyl) -2-oxo-1- (pyridine-2-sulfonyl) -2,3-dihydro-1 H indol-3-yl] -pyrrolidine-2-carboxylic acid dimethylamide

EXAMPLE 51

(S) -1- [5-cyano-3- (2-methoxy-4-pyrrolidin-1-ylmethyl-phenyl) -1- (5-methyl-pyridine-2-sulfonyl) -2-oxo-2,3 dihydro-1H-indol-3-yl] -pyrrolidine-2-carboxylic acid dimethylamide

EXAMPLE 52

(S) -1- [5-cyano-1- (5-chloro-pyridin-2-sulfonyl) -3- (2-methoxy-4-pyrrolidin-1-ylmethyl-phenyl) -2-oxo-2,3 dihydro-1H-indol-3-yl] -pyrrolidine-2-carboxylic acid dimethylamide

EXAMPLE 53

(S) -1- [5-cyano-3- (2-methoxy-4-pyrrolidin-1-ylmethyl-phenyl) -2-oxo-1- (thiophene-2-sulfonyl) -2,3-dihydro-1 H indol-3-yl] -pyrrolidine-2-carboxylic acid dimethylamide

EXAMPLE 54

(S) -1 - [(5-cyano-3- (2-methoxy-4-pyrrolidin-1-ylmethyl-phenyl) -2-oxo-1- (thiophene-3-sulfonyl) -2,3-dihydro- 1H-indol-3-yl] -pyrrolidine-2-carboxylic acid dimethylamide

EXAMPLE 55

(S) -1- [5-cyano-3- (2-methoxy-4-pyrrolidin-1-ylmethyl-phenyl) -2-oxo-1- (quinoline-8-sulfonyl) -2,3-dihydro-1 H indol-3-yl] -pyrrolidine-2-carboxylic acid dimethylamide

EXAMPLE 56

(S) -1- [5-Cyano-1- (4-methoxy-benzenesulfonyl) -3- (2-methoxy-4-pyrrolidin-1-ylmethyl-phenyl) -2-oxo-2,3-dihydro-1 H indol-3-yl] -pyrrolidine-2-carboxylic acid dimethylamide

EXAMPLE 57

(2S, 4R) -1- [5-Cyano-1- (4-methoxy-benzenesulfonyl) -3- (2-methoxy-4-pyrrolidin-1-ylmethyl-phenyl) -2-oxo-2,3-dihydro -1H-indol-3-yl] -4-hydroxy-pyrrolidine-2-carboxylic acid dimethylamide

EXAMPLE 58

(2S, 4R) -1- (5-Cyano-1- (4-methoxy-benzenesulfonyl) -3- (2-methoxy-4-pyrrolidin-1-ylmethyl-phenyl) -2-oxo-2,3-dihydro -1H-indol-3-yl] -4-fluoro-pyrrolidine-2-carboxylic acid dimethylamide

EXAMPLE 59

(S) -1- (5-Cyano-1- (4-methoxy-benzenesulfonyl) -3- (2-methoxy-4-pyrrolidin-1-ylmethyl-phenyl) -2-oxo-2,3-dihydro-1 H indol-3-yl] piperidine-2-carboxylic acid dimethylamide

EXAMPLE 60

(S) -2- [5-Cyano-1- (4-methoxy-benzenesulfonyl) -3- (2-methoxy-4-pyrrolidin-1-ylmethyl-phenyl) -2-oxo-2,3-dihydro-1 H indole-3-ylamino] -N, N-dimethyl-propionamide

EXAMPLE 61

(S) -1- [5-cyano-3- (5-dimethylaminomethyl-2-methoxy-phenyl) -1- (4-methoxy-benzenesulfonyl) -2-oxo-2,3-dihydro-1H-indol-3 yl] -pyrrolidine-2-carboxylic acid

EXAMPLE 62

(S) -1- [5-Cyano-1- (4-methoxy-benzenesulfonyl) -3- (2-methoxy-5-pyrrolidin-1-ylmethyl-phenyl) -2-oxo-2,3-dihydro-1 H indol-3-yl] -pyrrolidine-2-carboxylic acid dimethylamide

EXAMPLE 63

(S) -1- [5-Cyano-1- (4-methoxy-benzenesulfonyl) -3- (2-methoxy-5-piperidin-1-ylmethyl-phenyl) -2-oxo-2,3-dihydro-1 H indol-3-yl] -pyrrolidine-2-carboxylic acid dimethylamide

EXAMPLE 64

(S) -1- {5-Cyano-1- (4-methoxy-benzenesulfonyl) -3- [2-methoxy-5- (4-methyl-piperazin-1-ylmethyl) phenyl] -2-oxo-2 , 3-dihydro-1H-indol-3-yl} -pyrrolidine-2-carboxylic acid dimethylamide

EXAMPLE 65

(S) -1- [5-Cyano-1- (4-methoxy-benzenesulfonyl) -3- (2-methoxy-5-morpholin-4-ylmethyl-phenyl) -2-oxo-2,3-dihydro-1 H indol-3-yl] -pyrrolidine-2-carboxylic acid dimethylamide

EXAMPLE 66

(S) -1- [5-cyano-3- (5 - {[(2-dimethylamino-ethyl) -methyl-amino] -methyl} -2-methoxy-phenyl) -1- (4-methoxy-benzenesulfonyl) -2-oxo-2,3-dihydro-1 H-indol-3-yl] -pyrrolidine-2-carboxylic acid dimethylamide

EXAMPLE 67

(S) -1- [5-cyano-3- (5 - {[(3-dimethylamino-propyl) -methyl-amino] -methyl} -2-methoxy-phenyl) -1- (4-methoxy-benzenesulfonyl) -2-oxo-2,3-dihydro-1H-indol-3-yl] -pyrrolidine-2-carboxylic acid dimethylamide

EXAMPLE 68

(S) -1- [5-Cyano-1- (4-methoxy-benzenesulfonyl) -3- (2-methoxy-5 - {[(2-methoxy-ethyl) -methyl-amino] -methyl} -phenyl) -2-oxo-2,3-dihydro-1H-indol-3-yl] -pyrrolidine-2-carboxylic acid dimethylamide

Methods for determination the biological activity

Vasopressin V1b Receptor Binding Test:

substances:

The test substances were dissolved in DMSO at a concentration of 10 ^-2 M and further diluted in DMSO to 5 × 10 ^-4 M to 5 × 10 ^-9 M. This DMSO predilution series was diluted 1:10 with assay buffer. In the test mixture, the substance concentration was again diluted 1: 5 (2% DMSO in the batch).

Membrane preparation:

CHO-K1 Cells with stably expressed human vasopressin V1b receptor (Clone 3H2) were harvested and dissolved in 50 mM Tris-HCl and in the presence of protease inhibitors (Roche complete Mini # 1836170) with a Homogenize Polytron Homogenizer at medium position for 2 × 10 seconds and subsequently 1 h at 40,000 × g centrifuged. The membrane pellet was again described as homogenized and centrifuged and then in 50 mM Tris-HCl, pH 7.4, homogenized and frozen in aliquots at -190 ° C in liquid nitrogen kept.

Binding Assay:

The binding test was performed according to the method of Tahara et al. (Tahara A et al., Brit. J. Pharmacol. 125, 1463-1470 (1998)). Incubation buffer was: 50mM Tris, 10mM MgCl ₂ , 0.1% BSA, pH 7.4.

In the assay (250 μl), membranes (50 μg / ml protein in incubation buffer) of CHO-K1 cells with stably expressed human V1b receptors (hV1b_3H2_CHO cell line) were immunized with 1.5 nM ³ H-AVP (8-Arg vasopressin, Perkin Elmer # 18479) in incubation buffer (50 mM Tris, 10 mM MgCl ₂ , 0.1% BSA, pH 7.4) (total binding) or additionally incubated with increasing concentrations of test substance (displacement experiment). Non-specific binding was determined with 1 μM AVP (Bachem # H1780). All determinations were made in triplicate. After incubation (60 minutes at room temperature), the free radioligand was filtered by vacuum filtration (Skatron cell harvester 7000) over Wathman GF / B glass fiber filter mats and the filters transferred to scintillation vials. The liquid scintillation measurement was carried out in a Tricarb Model 2000 or 22000A (Packard). The conversion of the measured cpm into dpm was carried out using a standard quench series.

Evaluation:

The binding parameters were calculated by nonlinear regression in SAS. The algorithms of the program work analogously to the LIGAND evaluation program (Munson PJ and Rodbard D, Analytical Biochem., 107, 220-239 (1980)). The Kd value of ³ H-AVP to the recombinant hV2 receptors is 0.4 nM and was used to determine the Ki value.

Vasopressin V1a receptor binding test:

substances:

The test substances were dissolved in a concentration of 10 ^-2 M in DMSO.

The further dilution of these DMSO solutions was carried out in incubation buffer (50 mM Tris, 10 mM MgCl ₂ , 0.1% BSA, pH 7.4).

Membrane preparation:

CHO-K1 Cells with stably expressed human vasopressin V1a receptor (Clone 5) were harvested and in 50 mM Tris-HCl and in the presence of protease inhibitors (Roche complete Mini # 1836170) with a Homogenize Polytron Homogenizer at medium position for 2 × 10 seconds and subsequently 1 h at 40,000 × g centrifuged. The membrane pellet was again described as homogenized and centrifuged and then in 50 mM Tris-HCl, pH 7.4, homogenized and frozen in aliquots at -190 ° C in liquid nitrogen kept.

Binding Assay:

The binding test was performed according to the method of Tahara et al. (Tahara A et al., Brit. J. Pharmacol. 125, 1463-1470 (1998)). Incubation buffer was: 50mM Tris, 10mM MgCl ₂ , 0.1% BSA, pH 7.4.

In the assay (250 μl), membranes (20 μg / ml protein in incubation buffer) of CHO-K1 cells with stably expressed human V1a receptors (hVia_5_CHO cell line) were incubated with 0.04 nM ¹²⁵ I-AVP (8-arg-vasopressin, NEX 128). in incubation buffer (50 mM Tris, 10 mM MgCl ₂ , 0.1% BSA, pH 7.4) (total binding) or additionally incubated with increasing concentrations of test substance (displacement experiment). Non-specific binding was determined with 1 μM AVP (Bachem # H1780). Triple determinations were made.

To Incubation (60 minutes at room temperature), became the free radioligand by vacuum filtration (Skatron cell harvester 7000) via Wathman GF / B glass fiber filter mats filtered and transferred the filters in scintillation vials. The liquid scintillation took place in a Tricarb device Model 2000 or 22000A (Packard). The conversion of the measured cpm in dpm was performed using a standard quench series.

Evaluation:

The binding parameters were calculated by nonlinear regression in SAS. The algorithms of the program work analogously to the LIGAND evaluation program (Munson PJ and Rodbard D, Analytical Biochem., 107, 220-239 (1980)). The Kd of ¹²⁵ I-AVP to the recombinant hV1a receptors was determined in saturation experiments. A Kd value of 1.33 nM was used to determine the Ki value.

Vasopressin V2 Receptor Binding Test:

substances:

The test substances were dissolved in a concentration of 10 ^-2 M in DMSO. The further dilution of this DMSO solution can be carried out in incubation buffer (50 mM Tris, 10 mM MgCl ₂ , 0.1% BSA, pH 7.4).

Membrane preparation:

CHO-K1 Cells with stably expressed human vasopressin V2 receptor (clone 23) were harvested and dissolved in 50 mM Tris-HCl and in the presence of Protease Inhibitors (Roche complete Mini # 1836170) with a Polytron Homogenizer homogenized on middle position for 2 × 10 seconds and subsequently 1 h at 40,000 × g centrifuged. The membrane pellet was again described as homogenized and centrifuged and then in 50 mM Tris-HCl, pH 7.4, homogenized and frozen in aliquots at -190 ° C in liquid nitrogen kept.

Binding Assay:

The binding test was performed according to the method of Tahara et al. (Tahara A et al., Brit. J. Pharmacol. 125, 1463-1470 (1998)). Incubation buffer was: 50mM Tris, 10mM MgCl ₂ , 0.1% BSA, pH 7.4.

In the assay (250 μl), membranes (50 μg / ml protein in incubation buffer) of CHO-K1 cells were stably expressed with human V2 receptors (hV2_23_CHO cell line) with 1-2 nM ³ H-AVP (8-Arg vasopressin, Perkin Elmer # 18479) in incubation buffer (50 mM Tris, 10 mM MgCl ₂ , 0.1% BSA, pH 7.4) (total binding) or additionally incubated with increasing concentrations of test substance (displacement experiment). Non-specific binding was determined with 1 μM AVP (Bachem # H1780). Triple determinations were made.

To Incubation (60 minutes at room temperature), became the free radioligand by vacuum filtration (Skatron cell harvester 7000) via Wathman GF / B glass fiber filter mats filtered and transferred the filters in scintillation vials. The liquid scintillation took place in a Tricarb device Model 2000 or 22000A (Packard). The conversion of the measured cpm in dpm was performed using a standard quench series.

Evaluation:

The binding parameters were calculated by nonlinear regression in SAS. The algorithms of the program work analogously to the LIGAND evaluation program (Munson PJ and Rodbard D, Analytical Biochem., 107, 220-239 (1980)). The Kd value of ³ H-AVP to the recombinant hV2 receptors is 2.4 nM and was used to determine the Ki value.

Oxytocin Receptor Binding Test

substances:

The substances were dissolved in DMSO at a concentration of 10 ^-2 M M and diluted with incubation buffer (50 mM Tris, 10 mM MgCl ₂ , 0.1% BSA, pH 7.4).

Cell Preparation:

Confluent HEK-293 cells with transiently expressed recombinant human oxytocin receptors were centrifuged at 750 x g for 5 minutes at room temperature. The residue was taken up in ice-cold lysis buffer (50 mM Tris-HCl, 10% glycerol, pH 7.4 and Roche Complete Protease Inhibitor) and subjected to osmotic shock for 20 minutes at 4 ° C. Thereafter, the lysed cells were centrifuged at 750 x g for 20 minutes at 4 ° C, the residue taken up in incubation buffer and aliquots of 10 ⁷ cells / ml prepared. The aliquots were frozen at -80 ° C until use.

Binding Assay:

On the day of the experiment, the cells were thawed, diluted with incubation buffer and homogenized with a Multipette Combitip (Eppendorf, Hamburg). The reaction mixture of 0.250 ml was composed of 2 to 5 × 10 ⁴ recombinant cells, 3-4 nM ³ H-oxytocin (PerkinElmer, NET 858) in the presence of test substance (inhibition curve) or only incubation buffer (total binding). The non-specific binding was determined with 10 ^-6 M oxytocin (Bachem AG, H2510). Triplicate determinations were made. Bound and free radioligand were separated by filtration under vacuum with Whatman GF / B glass fiber filters using a Skatron Cell Harvester 7000. The bound radioactivity was measured by liquid scintillation in a Tricarb Beta Counter, Model 2000 or 22000A (Packard).

Evaluation:

The binding parameters were calculated by nonlinear regression analysis (SAS), analogous to the program LIGAND by Munson and Rodbard (Analytical Biochem 1980, 107: 220-239). The Kd value of ³ H-oxytocin to the recombinant hOT receptors is 7.6 nM and was used to determine the Ki value.

Effect on vasopressin-induced Calcium increase in cells carrying a cloned human vasopressin receptor wear

The functional activity of the test substances was investigated on CHO-K1 cells stably transfected with the human V1b receptor. Per well of a 96 well microtiter plate 50,000 cells were seeded and incubated overnight at 37 ° C in saturated steam atmosphere with 5% CO ₂ in culture medium. The culture medium consisted of DMEM / Nut Mix F12 with Glutamax I (Invitrogen), 10% fetal calf serum, 100 units / ml penicillin, 100 μg / ml streptomycin and 800 μg / ml geneticin. The next day, the cells were washed with culture medium and loaded with a fluorescent dye for calcium according to the manufacturer's instructions (Ca ⁺⁺ Plus Assay Kit, Molecular Devices). The loading of the cells was carried out in the presence of Probenzid (1 vol%). The test substances were diluted with culture medium (final concentration of 10 ^-10 to 10 ^-5 M) and at room temperature for 15 minutes with the dye-loaded cells incubated. Thereafter, arg-vasopressin (10 ^-8 M) was added and the maximum fluorescence signal was determined with a FLIPR-96 meter (Molecular Devices). Concentration action curves were generated using nonlinear regression algorithms (GraphPad Prism 3.0). Kb values were calculated from IC50 values according to Cheng and Prusoff (Kb = IC50 / 1 + L / EC50).

For the compounds of the invention were according to the above Tests the affinities to the human vasopressin receptor V1b and the affinity constants (Ki) determined. In Table 1 below, the V1b receptor affinity of selected compounds listed (+++ means <1 nM, ++ means 1-10 nM and + means 10-100 nM).

Table 1:

Furthermore can according to the above Tests the affinities to other vasopressin receptors or their subtypes, e.g. V1a and V2, and the oxytocin (OT) receptor. The available Quotients of the corresponding Ki values, ie "Ki (V1a) / Ki (V1b)", "Ki (V2) / Ki (V1b)" and / or "Ki (OT) Ki (V1b)", can be used as a measure of a possible selectivity of the compounds of the invention with respect to a particular vasopressin or oxytocin receptor or one of their subtypes, e.g. V1b, serve.

• – eine verbesserte Affinität zum V1b- Rezeptor und/oder
• – eine verbesserte Selektivität zum V1b-Rezeptor im Vergleich zu einem, zwei oder drei Rezeptoren ausgewählt aus der Gruppe bestehend aus dem V1a-, V2- und Oxytocin(OT)-Rezeptor.

The advantages of the compounds according to the invention can be, for example:

• An improved affinity for the V1b receptor and / or
• An improved selectivity to the V1b receptor compared to one, two or three receptors selected from the group consisting of the V1a, V2 and oxytocin (OT) receptor.

Claims (46)

Compounds of the general formula (1),

wherein A is an aromatic, heteroaromatic, partially aromatic or partially heteroaromatic mono- or bicyclic ring which consists of 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms and 0, 1, 2, 3 or 4 nitrogen atoms and / or 0, 1 or 2 oxygen atoms and / or 0, 1 or 2 sulfur atoms, and which is substituted with the radical R _A ¹ and additionally with 1, 2 or 3 radicals R _A ¹¹ , R _A ¹² and / or R _A ¹³ may be substituted independently of one another and independently of their occurrence selected from the group consisting of hydrogen, chlorine, bromine, iodine, fluorine, CN, CF ₃ , OCF ₃ , OCHF ₂ , CO-NH ₂ , CO-NH (C ₁ -C ₄ -alkyl), CO-N (C ₁ -C ₄ -alkyl) (C ₁ -C ₄ -alkyl), NH ₂ , NH ( C ₁ -C ₄ -alkyl), N (C ₁ -C ₄ -alkyl) (C ₁ -C ₄ -alkyl), NHCHO, NH-CO-NH ₂ , NH-CO (C ₁ -C ₄ -alkyl) , NO ₂ , OH, OC ₁ -C ₄ -alkyl, OC ₀ -C ₄ -alkylene-phenyl, phenyl, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -haloalkyl, C ₂ -C ₆ -alkenyl and C ₂ -C ₆ alkynyl wherein R _A ¹ R _A ² - (C C ₁ -C ₄ -alkylene) -R _A ⁴ , R _A ^{2 is} selected from the group consisting of (C ₀ -C ₄ -alkylene) -O, (C ₀ -C ₄ -alkylene) -NR _A ⁵ , (C ₀ -C ₄ -alkylene) -S, (C ₀ -C ₄ -alkylene) -SO, (C ₀ -C ₄ -alkylene) -SO ₂ , (C ₀ -C ₄ -alkylene) -CO, ( C ₀ -C ₄ -alkylene) -NR _A ⁵ -CO, (C ₀ -C ₄ -alkylene) -CO-NR _A ⁵ , (C ₀ -C ₄ -alkylene) -CO-O, (C ₀ - C ₄ -alkylene) -NR _A ⁵ -SO ₂ , (C ₀ -C ₄ -alkylene) -SO ₂ -NR _A ⁵ , (C ₀ -C ₄ -alkylene) -NR _A ⁵ -CO-NR _A ⁶ , (C ₀ -C ₄ -alkylene) -O-CO-NR _A ⁵ , (C ₀ -C ₄ -alkylene) -NR _A ⁵ -CO-O and single bond, R _A ^{4 is} selected from the group consisting of NH ₂ , NH (C ₁ -C ₄ -alkyl), N (C ₁ -C ₄ -alkyl) (C ₁ -C ₄ -alkyl), NH (C ₁ -C ₄ -alkylene-OC ₁ -C ₄ -alkyl ), N (C ₁ -C ₄ -alkyl) (C ₁ -C ₄ -alkylene-OC ₁ -C ₄ -alkyl), NH-CHO, N (C ₁ -C ₄ -alkyl) -CHO, NH- CO-NH ₂ , N (C ₁ -C ₄ -alkyl) -CO-NH ₂ , NH-CO-C ₁ -C ₄ -alkyl, N (C ₁ -C ₄ -alkyl) -CO-C ₁ - C ₄ alkyl, NH-SO ₂ C ₁ -C ₄ alkyl, N (C ₁ -C ₄ alkyl) -SO ₂ C ₁ -C ₄ alkyl and ring R _A ⁸ , R _A ⁵ , R _A ⁶ , R _A ⁹ independently and, regardless of their occurrence, are selected from the group consisting of hydrogen, C ₁ -C ₄ alkyl and C ₁ -C ₄ haloalkyl; R _A ^{8 is} selected from the group consisting of the respective individual radicals

B is an aromatic, heteroaromatic, partially aromatic or partially heteroaromatic mono- or bicyclic ring which consists of 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms and 0, 1, 2, 3 or 4 nitrogen atoms and / or 0, 1 or 2 oxygen atoms and / or 0, 1 or 2 sulfur atoms, and with 1, 2 or 3 radicals R _B ¹ , R _B ² and / or R _B ³ may be substituted, wherein R _B ¹ , R _B ² and R _B ^{3 are} independently and independently of their occurrence selected from the group consisting of hydrogen, chlorine, bromine, iodine, fluorine, CN, CF ₃ , OCF ₃ , OCHF ₂ , CO-NH ₂ , CO-NH (C ₁ -C ₄ -alkyl), CO-N (C ₁ -C ₄ -alkyl) (C ₁ -C ₄ -alkyl), NH ₂ , NH (C C ₁ -C ₄ -alkyl), N (C ₁ -C ₄ -alkyl) (C ₁ -C ₄ -alkyl), NH-CHO, NH-CO-NH ₂ , NH-CO-C ₁ -C ₄ -alkyl , NO ₂ , OH, OC ₁ -C ₄ -alkyl, OC ₀ -C ₄ -alkylene-phenyl, phenyl, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -haloalkyl, C ₂ -C ₆ -alkenyl and C ₂ -C ₆ alkynyl; R ^{1 is} selected from the group consisting of hydrogen, chlorine, Bram, iodine, fluorine, CN, CF ₃ , OCF ₃ , OCHF ₂ , CO-NH ₂ , CO-NH (C ₁ -C ₄ alkyl), CO -N (C ₁ -C ₄ -alkyl) (C ₁ -C ₄ -alkyl), NH ₂ , NH (C ₁ -C ₄ -alkyl), N (C ₁ -C ₄ -alkyl) (C ₁ -C _4- alkyl), NH-CHO, NH-CO-NH ₂ , NH-CO-C ₁ -C ₄ -alkyl, NO ₂ , OH, OC ₁ -C ₄ -alkyl, OC ₀ -C ₄ -alkylene-phenyl , Phenyl, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -haloalkyl, C ₂ -C ₆ -alkenyl and C ₂ -C ₆ -alkynyl, R ^{2 is} selected from the group consisting of hydrogen, C ₁ -C ₄ alkyl, OC ₁ -C ₄ alkyl, chlorine and fluorine, Y is a radical

wherein R _Y ^{1 is} selected from the group consisting of hydrogen, C ₁ -C ₄ alkyl and C ₁ -C ₄ haloalkyl; R _Y ^{2 is} selected from the group consisting of hydrogen; phenyl; Phenyl substituted with 1, 2, 3, 4 or 5 radicals R _Ph ¹ , R _Ph ² , R _Ph ³ , R _Ph ⁴ and / or R _Ph ⁵ , which are independently selected from the group consisting of hydrogen, halogen, C C ₁ -C ₆ -alkyl and C ₁ -C ₆ -alkoxy; C ₁ -C ₆ alkyl; C ₃ -C ₇ cycloalkyl and C ₁ -C ₆ haloalkyl; wherein R _Y ¹ and R _Y ^{2 may} also together form a 4-, 5-, 6- or 7-membered, saturated or unsaturated carbocyclic ring, which instead of a ring C atom and a heteroatom selected from the group consisting from O, S and NR _Y ⁵ , may have as ring member, wherein R _Y ⁵ independently of its respective occurrence of hydrogen, C ₁ -C ₄ alkyl or CO-C ₁ -C ₄ alkyl may be, and wherein the ring may have one or two substituents R _Y ⁶ and R _Y ⁷ independently of one another and independently of their occurrence selected from the group consisting of the radicals hydrogen, chlorine, bromine, iodine, fluorine, CN, CF ₃ , OCF ₃ , OCHF ₂ , CO-NH ₂ , CO-NH (C ₁ -C ₄ -alkyl), CO-N (C ₁ -C ₄ -alkyl) (C ₁ -C ₄ -alkyl), NH ₂ , NH (C C ₁ -C ₄ -alkyl), N (C ₁ -C ₄ -alkyl) (C ₁ -C ₄ -alkyl), NH-CHO, NH-CO-NH ₂ , NH-CO-C ₁ -C ₄ -alkyl , OH, OC ₁ -C ₄ -alkyl, O-CO-C ₁ -C ₄ -alkyl, O- (CH ₂ ) _0-2- phenyl, phenyl, C ₁ -C ₆ -alkyl, or R _Y ⁶ and R _Y ⁷ independent v on their respective occurrence, together with the C atoms to which they are attached, can also form a fused phenyl ring or a fused 5- or 6-membered aromatic heterocycle which, in addition to C atoms, is ring members 1, 2, 3 or 4 having identical or different heteroatoms as ring members, which may be independently selected from the group consisting of nitrogen, oxygen and sulfur, R _Y ^{3 is} selected from the group consisting of hydrogen, C ₁ -C ₄ alkyl and C ₁ -C ₄ -haloalkyl; R _Y ^{4 is} selected from the group consisting of hydrogen, CO-NR _Y ²¹ R _Y ²² , CO-C ₁ -C ₄ alkyl, COOH and CO-OC ₁ -C ₄ alkyl, R _Y ²¹ , R _Y ²² independently of one another and independently of their occurrence, are selected from the group consisting of hydrogen, C ₁ -C ₄ -alkyl and C ₁ -C ₄ -haloalkyl; or R _Y ²¹ and R _Y ^22, independently of their respective occurrence, can also together form a 4-, 5- or 6-membered, saturated or completely or partially unsaturated carbocyclic ring, their tautomeric, enantiomeric and diastereomeric forms, and their prodrugs , as well as the physiologically acceptable salts of the compounds mentioned. Compounds of the general formula (I) according to Claim 1, in which A is an aromatic or heteroaromatic monocyclic ring having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms as ring members, which additionally contains 0, 1 , 2 or 3 identical or different heteroatoms, independently selected from the group consisting of nitrogen, oxygen and sulfur, may contain as ring members and is substituted with the radical R _A ¹ and also with one, two or three radicals R _A ¹¹ , R _A ¹² and / or R _A ¹³ may be substituted, which are independently of one another and independently of their occurrence selected from the group consisting of hydrogen, chlorine, fluorine, OC ₁ -C ₄ alkyl, C ₁ -C ₄ - Alkyl and C ₁ -C ₄ -haloalkyl wherein R _A ¹ R is _A ² - (C ₁ -C ₄ -alkylene) -R _A ⁴ ; R _A ^{2 is} selected from the group consisting of (C ₀ -C ₄ -alkylene) -O, (C ₀ -C ₄ -alkylene) -NR _A ⁵ , (C ₀ -C ₄ -alkylene) -S, ( C ₀ -C ₄ -alkylene) -SO, (C ₀ -C ₄ -alkylene) -SO ₂ , (C ₀ -C ₄ -alkylene) -CO, (C ₀ -C ₄ -alkylene) -NR _A ⁵ - CO, (C ₀ -C ₄ -alkylene) -CO-NR _A ⁵ , (C ₀ -C ₄ -alkylene) -CO-O and single bond; R _A ^{4 is} selected from the group consisting of NH ₂ , NH (C ₁ -C ₄ -alkyl), N (C ₁ -C ₄ -alkyl) (C ₁ -C ₄ -alkyl), N (C ₁ -) C ₄ alkyl) (C ₁ -C ₄ alkylene-OC ₁ -C ₄ alkyl) and ring R _A ⁸ ; R _A ⁵ , R _A ^{9 are} independently of one another and independently of their occurrence selected from the group consisting of hydrogen and C ₁ -C ₄ alkyl; R _A ^{8 is} independently of its occurrence selected from the group consisting of the respective individual residues

B is an aromatic or heteroaromatic monocyclic or bicyclic carbocyclic ring having 2, 3, 4, 5, 6, 7, 8, 9 or 10 C atoms as ring members which additionally has 1, 2 or 3 identical or different heteroatoms, independently of one another selected from the group consisting of nitrogen, oxygen and sulfur, which may be ring members and which may be substituted with one, two or three R _B ¹ , R _B ² and / or R _B ³ radicals, wherein R _B ¹ , R _B ² and R _B ^{3 are} independently of one another and independently of their occurrence selected from the group consisting of hydrogen, chlorine, bromine, fluorine, CN, CF ₃ , OCF ₃ , OCHF ₂ , OC ₁ -C ₄ alkyl, C ₁ C ₄ alkyl and C ₁ -C ₄ haloalkyl; R ^{1 is} selected from the group consisting of hydrogen, bromine, chlorine, fluorine, CN, CF ₃ , OCF ₃ , OC ₁ -C ₄ alkyl, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl and C ₂ -C ₄ alkynyl, R ^{2 is} selected from the group consisting of hydrogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, OC ₁ -C ₄ alkyl, chlorine and fluorine, Y a rest

wherein R _Y ^{1 is} selected from the group consisting of hydrogen and C ₁ -C ₄ alkyl; R _Y ^{2 is} selected from the group consisting of hydrogen, phenyl, C ₁ -C ₆ -alkyl, and C ₃ -C ₇ -cycloalkyl, wherein R _Y ¹ and R _Y ^{2 are} also together a 4-, 5-, 6 - or 7-membered, saturated or unsaturated carbocyclic ring can form, which instead of a C atom as a ring member and a heteroatom selected from the group consisting of O and NR _Y ^{5 may have} as a ring member, wherein R _Y ^{5 is} independent of may each be hydrogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl or CO-C ₁ -C ₄ alkyl, and wherein the ring has one or two substituents R _Y ⁶ and / or R _Y ⁷ , which are selected independently of one another and independently of their occurrence from the group consisting of the radicals hydrogen, fluorine, CN, OH, OC ₁ -C ₄ alkyl, O-CO-C ₁ -C ₄ alkyl , O- (CH ₂ ) _0-2 -phenyl, phenyl and C ₁ -C ₄ -alkyl; or R _Y ⁶ and R _Y ^7, independently of their respective occurrence together with the C atoms to which they are attached, can also form a fused phenyl ring (benzo ring); R _Y ^{3 is} selected from the group consisting of hydrogen and methyl, R _Y ^{4 is} selected from the group consisting of CO-NR _Y ²¹ R _Y ²² , CO-C ₁ -C ₄ -alkyl and CO-OC ₁ - C ₄ alkyl, R _Y ²¹ , R _Y ^{22 are} independently of one another and independently of their occurrence selected from the group consisting of hydrogen and C ₁ -C ₄ alkyl; or R _Y ²¹ and R _Y ^22, independently of their respective occurrence, may also together form a 4-, 5- or 6-membered, saturated or unsaturated carbocyclic ring, their tautomeric, enantiomeric and diastereomeric forms, and their prodrugs, and Physiologically acceptable salts of the compounds mentioned. Compounds of the general formula (I) according to claim 1 or 2, wherein A is a ring selected from the group consisting of benzene, thiophene, pyridine, pyrimidine, pyrazine and pyridazine and which is substituted with the radical R _A ¹ and may additionally be additionally substituted by one or two radicals R _A ¹¹ and / or R _A ¹² , which are selected independently of one another and independently of their respective occurrence from the group consisting of hydrogen, chlorine, methoxy, ethoxy, propoxy, methyl, Ethyl and propyl; wherein R _A ¹ R _A ² - (C ₁ -C ₄ alkylene) -R _A ⁴ , wherein R _A ^{2 is} selected from the group consisting of O, CH ₂ -O, NR _A ⁵ , CH ₂ -NR _A ⁵ , NR _A ⁵ -CO, CH ₂ -NR _A ⁵ -CO and a single bond; R _A ^{4 is} selected from the group consisting of NH ₂ , NH (C ₁ -C ₄ -alkyl), N (C ₁ -C ₄ -alkyl) (C ₁ -C ₄ -alkyl), N (C ₁ -) C ₄ alkyl) (C ₁ -C ₄ alkylene-OC ₁ -C ₄ alkyl) and ring R _A ⁸ ; R _A ⁵ , R _A ^{9 are} independently of one another and independently of their occurrence selected from the group consisting of hydrogen and C ₁ -C ₄ alkyl; R _A ^{8 is} selected from the group consisting of the respective individual radicals

B is an aromatic or heteroaromatic mono- or bicyclic ring having 2, 3, 4, 5, 6, 7, 8, 9 or 10 C atoms as ring members, the 1, 2 or 3 identical or different heteroatoms, independently selected from the group consisting of nitrogen, oxygen and sulfur, may contain as ring member and which may be substituted by one or two radicals R _B ¹ and / or R _B ² , wherein R _B ¹ and R _B ^{2 are} independently selected from the group consisting of hydrogen, chlorine, fluorine, CN, OC ₁ -C ₄ alkyl and C ₁ -C ₄ alkyl; R ^{1 is} selected from the group consisting of hydrogen, chlorine, fluorine, CN, methoxy and methyl; R ^{2 is} selected from the group consisting of hydrogen, chlorine and methyl; Y a rest

wherein R _Y ^{1 is} selected from the group consisting of hydrogen and C ₁ -C ₄ alkyl; R _Y ^{2 is} selected from the group consisting of hydrogen, phenyl and C ₁ -C ₄ alkyl; wherein R _Y ¹ and R _Y ^{2 may} also together form a 5- or 6-membered, saturated or unsaturated carbocyclic ring, which instead of a C atom as a ring member and a heteroatom selected from the group consisting of O and NR _Y ⁵ , as ring member, where R _Y ^{5 are} independently of each occurrence hydrogen, C ₁ -C ₄ alkyl, or CO-C ₁ -C ₄ -alkyl, and which ring one or two substituents R ⁶ _Y and / or R _Y ⁷ may be selected independently of one another and independently of their respective occurrence from the group consisting of the radicals hydrogen, fluorine, OH and OC ₁ -C ₄ -alkyl, or R _Y ⁶ and R _Y ⁷ regardless of their occurrence together with the carbon atoms to which they are attached, they can also form a fused phenyl ring (benzo ring); R _Y ^{3 is} selected from the group consisting of hydrogen and methyl; R _Y ^{4 is} CO-NR _Y ²¹ R _Y ²² , wherein R _Y ²¹ , R _Y ^{22 are} independently selected from the group consisting of hydrogen and C ₁ -C ₄ alkyl; or R _Y ²¹ and R _Y ^22, independently of their respective occurrence, may also together form a 4-, 5- or 6-membered, saturated or unsaturated carbocyclic ring; their tautomeric, enantiomeric and diastereomeric forms, and their prodrugs, as well as the physiologically acceptable salts of said compounds. Compounds of general formula (I) according to any one of claims 1 to 3, wherein A is a radical selected from the group consisting of the respective individual radicals

wherein R _A ^{11 is} independently selected from the group consisting of hydrogen, chlorine, methoxy and ethoxy; R _A ^{1 is} a radical selected from the group consisting of the respective individual radicals

B is a ring selected from the group consisting of benzene, pyridine, thiophene and quinoline, each of which may be substituted by 1 or 2 radicals R _B ¹ and / or R _B ² , wherein R _B ¹ and R _B ^{2 are} independently selected are selected from the group consisting of hydrogen, chlorine, fluorine, CN, methyl and methoxy; R ^{1 is} selected from the group consisting of hydrogen, chlorine, fluorine, CN, methoxy and methyl; R ^{2 is} selected from the group consisting of hydrogen and chlorine; Y is a radical selected from the group consisting of the respective individual radicals

R _Y ^{4 is} CO-NR _Y ²¹ R _Y ²² , wherein R _Y ²¹ and R _Y ^{22 are} independently selected from the group consisting of hydrogen, methyl and ethyl; or R _Y ²¹ and R _Y ^22, independently of their respective occurrence, can also together form a 4-, 5- or 6-membered, saturated or unsaturated or partially unsaturated carbocyclic ring; R _Y ^{5 is} selected from the group consisting of the radicals hydrogen, C ₁ -C ₄ alkyl, and CO-C ₁ -C ₄ alkyl; R _Y ^{6 is} selected from the group consisting of the radicals hydrogen, fluorine, OH and OC ₁ -C ₄ alkyl, their tautomeric, enantiomeric and diastereomeric forms, and their prodrugs, and the physiologically acceptable salts of said compounds. Compounds of general formula (I) according to any one of claims 1 to 4, wherein A is selected from the group consisting of the respective individual radicals

R _A ^{1 is} a radical regardless of its occurrence selected from the group consisting of the respective individual radicals

B is a ring selected from the group consisting of the respective individual radicals

wherein R _B ¹ and R _B ^{2 are} independently and independently selected from the group consisting of hydrogen, chlorine, fluorine, CN, methyl and methoxy; R ^{1 is} selected from the group consisting of chlorine, methoxy and CN; R ^{2 is} hydrogen, Y is selected from the group consisting of the respective individual radicals

their tautomeric, enantiomeric and diastereomeric forms, and their prodrugs, as well as the physiologically acceptable salts of said compounds. Compounds of general formula (I) according to any one of claims 1 to 5, wherein A is selected from the group consisting of the respective individual radicals

in which R _A ^{1 is} a radical, regardless of its occurrence, selected from the group consisting of the respective individual radicals

B is a ring selected from the group consisting of the respective individual radicals

R ^{1 is} chlorine; R ^{2 is} hydrogen; Y A radical is selected from the group consisting of the respective individual radicals

their tautomeric, enantiomeric and diastereomeric forms, and their prodrugs, as well as the physiologically acceptable salts of said compounds. Compounds of the general formula (I) according to any one of claims 1 to 6, wherein A is a radical selected from the group consisting of the respective individual radicals

R _A ^{1 is} a radical regardless of its occurrence selected from the group consisting of the respective individual radicals

B A ring is selected from the group consisting of the respective individual residues

R ^{1 is} chlorine; R ^{2 is} hydrogen; Y is a radical selected from the group consisting of the respective individual radicals

, their tautomeric, enantiomeric and diastereomeric forms, and their prodrugs, and the physiologically acceptable salts of said compounds. Compounds of general formula (I) according to any one of claims 1 to 7, wherein A is a ring selected from the group consisting of the respective individual radicals

wherein R _A ^{1 is} a radical selected from the group consisting of the respective individual radicals

B is a ring selected from the group consisting of the respective individual radicals

R ^{1 is} chloro, R ^{2 is} hydrogen, Y is selected from the group consisting of the respective individual radicals

their tautomeric, enantiomeric and diastereomeric forms, and their prodrugs, as well as the physiologically acceptable salts of said compounds. At least one compound of the general formula (I) according to any one of claims 1 to 8, characterized in that the remainder R1 to the 5-position of the oxindole ring skeleton is bound. At least one compound of the general formula (I) according to any one of claims 1 to 9, characterized in that it is an enriched optically active isomer with an optical purity of greater than 50% is based on the optically inactive mixture of the isomer mixture, which turns the plane of polarized light to the left ("negative Rotation "). At least one compound of the general formula (I) according to any one of claims 1 to 10, characterized in that it is the optically active Isomer is an enantiomerically-enriched diastereomer. At least one compound of the general formula (I) according to any one of claims 1 or 11, characterized in that the property "negative Rotation "on the free base is related. Compounds according to one of claims 1 to 12, characterized in that it has a binding affinity Ki to Vasopressin receptor subtypes V1b of less than or equal to about 100 nM, preferably in the range between including about 10 nM and including about 100 nM, more preferably in the range between about including 1 nM and including about 10 nM very particularly preferred from less than or equal to about 1 nM. Compounds according to one of claims 1 to 12, characterized in that it has a selectivity to vasopressin receptor subtype V1b across from have the vasopressin receptor subtype V1a, so the quotient of Ki (V1a) / Ki (V1b) is at least greater than 1. Compounds according to one of claims 1 to 12, characterized in that it has a selectivity to vasopressin receptor subtype V1b across from vasopressin receptor subtype V2, ie the quotient Ki (V2) / Ki (V1b) at least greater than 1 is. Compounds according to one of claims 1 to 12, characterized in that it has a selectivity to vasopressin receptor subtype V1b across from have the oxytocin (OT) receptor, ie the quotient of Ki (OT) / Ki (V1b) at least greater than 1 is. Compounds according to one of claims 1 to 12, characterized in that it has a binding affinity Ki to Vasopressin receptor subtypes V1b of less than or equal to about 100 nM, preferably in the range between including about 10 nM and including about 100 nM, more preferably in the range between about including 1 nM and including about 10 nM very particularly preferred from less than or equal to about 1 nM, and selectivity to the vasopressin receptor subtype V1b opposite have the vasopressin receptor subtype V1a, so the quotient of Ki (V1a) / Ki (V1b) is at least greater than 1. Compounds according to one of claims 1 to 12, characterized in that it has a binding affinity Ki to Vasopressin receptor subtypes V1b of less than or equal to about 100 nM, preferably in the range between including about 10 nM and including about 100 nM, more preferably in the range between about including 1 nM and including about 10 nM very particularly preferred from less than or equal to about 1 nM, and selectivity to the vasopressin receptor subtype V1b opposite vasopressin receptor subtype V2, ie the quotient Ki (V2) / Ki (V1b) at least greater than 1 is. Compounds according to one of claims 1 to 12, characterized in that it has a binding affinity Ki to Vasopressin receptor subtypes V1b of less than or equal to about 100 nM, preferably in the range between including about 10 nM and including about 100 nM, more preferably in the range between about including 1 nM and including about 10 nM very particularly preferred from less than or equal to about 1 nM, and selectivity to the vasopressin receptor subtype V1b opposite have the oxytocin (OT) receptor, ie the quotient of Ki (OT) / Ki (V1b) at least greater than 1 is. Compounds according to one of claims 1 to 12, characterized in that it has a binding affinity Ki to Vasopressin receptor subtypes V1b of less than or equal to about 100 nM, preferably in the range between including about 10 nM and including about 100 nM, more preferably in the range between about including 1 nM and including about 10 nM very particularly preferred from less than or equal to about 1 nM, and selectivities to the vasopressin receptor subtype V1b opposite vasopressin receptor subtype V1a and vasopressin receptor subtype V2 ie the quotients of Ki (V1a) / Ki (V1b) and Ki (V2) / Ki (V1b) each at least greater than 1 are. Compounds according to one of claims 1 to 12, characterized in that it has a binding affinity Ki to Vasopressin receptor subtypes V1b of less than or equal to about 100 nM, preferably in the range between including about 10 nM and including about 100 nM, more preferably in the range between about including 1 nM and including about 10 nM very particularly preferred from less than or equal to about 1 nM, and simultaneous selectivities to Vasopressin receptor subtype V1b versus the vasopressin receptor subtype V1a and the oxytocin (OT) receptor, ie the quotients from Ki (V1a) / Ki (V1b) and Ki (OT) / Ki (V1b) in each case at least greater than 1 are. Compounds according to one of claims 1 to 12, characterized in that it has a binding affinity Ki to Vasopressin receptor subtypes V1b of less than or equal to about 100 nM, preferably in the range between including about 10 nM and including about 100 nM, more preferably in the range between about including 1 nM and including about 10 nM very particularly preferred from less than or equal to about 1 nM, and simultaneous selectivities to Vasopressin receptor subtype V1b versus the vasopressin receptor subtype V2 and the oxytocin (OT) receptor, ie the quotients from Ki (V2) / Ki (V1b) and Ki (OT) / Ki (V1b) in each case at least greater than 1 are. Compounds according to one of claims 1 to 12, characterized in that it has a binding affinity Ki to Vasopressin receptor subtypes V1b of less than or equal to about 100 nM, preferably in the range between including about 10 nM and including about 100 nM, more preferably in the range between about including 1 nM and including about 10 nM very particularly preferred from less than or equal to about 1 nM, and simultaneous selectivities to Vasopressin receptor subtype V1b versus the vasopressin receptor subtype V1a, the vasopressin receptor subtype V2 and the oxytocin (OT) receptor, ie the quotients from Ki (V1a) / Ki (V1b), Ki (V2) / Ki (V1b) and Ki (OT) / Ki (V1b) in each case at least greater than 1 are. At least one compound of the general formula (I) according to any one of claims 1 to 23 for use as a medicine. Medicament containing at least one compound of the general formula (I) according to one of claims 1 to 23. Use of at least one compound of the general Formula (I) according to a the claims 1 to 23 for the treatment and / or prophylaxis of at least one Vasopressin-dependent and / or oxytocin-dependent Illness and / or for the manufacture of a medicament for treatment and / or prophylaxis of at least one of said diseases. Use of at least one compound of the general Formula (I) according to a the claims 1 to 23 for the treatment and / or prophylaxis of at least one Disease selected from the group consisting of diabetes insipidus, enuresis nocturna, Incontinence, diseases in which blood coagulation disorders occur and / or for delay micturition and / or for the manufacture of a medicament for treatment and / or prophylaxis of at least one of said diseases. Use of at least one compound of the general Formula (I) according to a the claims 1 to 23 for the treatment and / or prophylaxis of at least one Disease selected from the group consisting of hypertension, pulmonary hypertension, Heart failure, myocardial infarction, coronary spasm, unstable Angina, PTCA (percutaneous transluminal coronary angioplasty), Ischemia of the heart, disorders of the renal system, edema, renal vasospasm, necrosis of the renal cortex, hyponatraemia, hypokalemia, Schwartz-Bartter Syndrome, disorders of the gastrointestinal tract, gastric vasospasm, hepatocirrhosis, Stomach and intestinal sulcus, vomiting, vomiting during chemotherapy, and / or motion sickness and / or for the manufacture of a medicament for the treatment and / or prophylaxis of at least one of said Diseases. Use of at least one compound of the general Formula (I) according to a the claims 1 to 23 for the treatment of affective disorders and / or for production a medicine for the treatment of mood disorders. Use of at least one compound of the general Formula (I) according to a the claims 1 to 23 for the treatment of anxiety disorders and / or stress-related anxiety disorders and / or for the manufacture of a medicament for the treatment of anxiety disorders and / or stress-related Anxiety disorders. Use of at least one compound of the general Formula (I) according to a the claims 1 to 23 for the treatment of memory impairment and / or Morbus Alzheimer and / or for the manufacture of a medicament for Treatment of memory impairment and / or Alzheimer's disease. Use of at least one compound of the general Formula (I) according to a the claims 1 to 23 for the treatment of psychosis and / or psychotic disorders and / or for the manufacture of a medicament for the treatment of psychosis and / or psychotic disorders. Use of at least one compound of the general Formula (I) according to a the claims 1 to 23 for the treatment of Cushing's syndrome and / or for the production of a Drug for the treatment of Cushing's syndrome. Use of at least one compound of the general Formula (I) according to a the claims 1 to 23 for the treatment of sleep disorders and / or for production a drug for the treatment of sleep disorders. Use of at least one compound of the general Formula (I) according to a the claims 1 to 23 for the treatment of depressive disorders and / or Preparation of a medicament for the treatment of depressive disorders. Method for the treatment and / or prophylaxis of at least one disease selected from the group from diabetes insipidus, nocturnal enuresis, incontinence, diseases, where blood clotting disorders occur and delay the micturition in a patient, characterized in that the Patients an effective amount of at least one compound of the general Formula (I) according to one of claims 1 to 23 is administered. Method for the treatment and / or prophylaxis of at least one disease selected from Group consisting of hypertension, pulmonary hypertension, heart failure, myocardial infarction, coronary spasm, unstable angina, PTCA (percutaneous transluminal coronary angioplasty), ischemia of the heart, renal disorders, edema, renal vasospasm, renal cortex necrosis, hyponatraemia, hypokalaemia, black -Bartner syndrome, disorders of the gastrointestinal tract, gastric vasospasm, hepatocirrhosis, gastric and intestinal ulcer, emesis, emesis occurring in chemotherapy, and motion sickness in a patient, characterized in that the patient an effective amount of at least one compound of general formula (I) according to any one of claims 1 to 23 is administered. Method for the treatment and / or prophylaxis of affective disorders in a patient, characterized in that the patient a effective amount of at least one compound of the general formula (I) according to one the claims 1 to 23 is administered. Method of treating anxiety disorders and / or stress-related anxiety disorders in a patient, characterized in that the patient a effective amount of at least one compound of the general formula (I) according to one the claims 1 to 23 is administered. Method for the treatment of memory impairment and / or Alzheimer's disease in a patient, characterized in that the patient an effective amount of at least one compound of general formula (I) according to a the claims 1 to 23 is administered. Method of treating psychosis and / or psychotic disorders in a patient, characterized in that the patient a effective amount of at least one compound of the general formula (I) according to one the claims 1 to 23 is administered. Method for the treatment of Cushing's syndrome in a patient, characterized in that the patient a effective amount of at least one compound of the general formula (I) according to one of claims 1 to 23 is administered. Method for the treatment of sleep disorders in a patient, characterized in that the patient a effective amount of at least one compound of the general formula (I) according to one of claims 1 to 23 is administered. Method for the treatment of depressive disorders in a patient, characterized in that the patient a effective amount of at least one compound of the general formula (I) according to one the claims 1 to 23 is administered. Method according to one of Claims 36 to 44, characterized that the patient is a mammal, preferably one Human or a nonhuman or a nonhuman transgenic mammal is. Process for the preparation of compounds of the general Formula (I) according to a of claims 1 to 23, characterized in that they by implementation and / or in analogous implementation from the competent It is possible to produce a process step known to those skilled in the art.