US20050070718A1

US20050070718A1 - Heteroaryl-substituted 1,3-dihydroindol-2-one derivatives and medicaments containing them

Info

Publication number: US20050070718A1
Application number: US10/675,300
Authority: US
Inventors: Wilfried Lubisch; Wilfried Hornberger; Thorsten Oost; Daryl Sauer; Liliane Unger; Wolfgang Wernet
Original assignee: Abbott GmbH and Co KG
Current assignee: AbbVie Deutschland GmbH and Co KG
Priority date: 2003-09-30
Filing date: 2003-09-30
Publication date: 2005-03-31
Also published as: US20110071156A1; EP1667993A1; CA2537598A1; ES2547642T3; DK1667993T3; HK1090044A1; CA2537598C; US8350055B2; US7902379B2; TW200526640A; MXPA06003558A; EP2546252A1; WO2005030755A1; EP1667993B1; US20070021607A1; JP2007507456A; JP4684229B2; SI1667993T1; EP2546251A1; HUE025419T2

Abstract

The present invention relates to novel 1,3-dihydroindol-2-one (oxindole) derivatives of the formula (I)

in which

- A, R³, R⁴, R⁵, R⁶and R⁷are defined according to claim 1, and to medicaments containing them for the treatment of diseases. In particular, the novel oxindole derivaties can be used for the control and/or prophylaxis of various vasopressin-dependent or oxytocin-dependent diseases.

Description

The present invention relates to novel 1,3-dihydroindol-2-one (oxindole) derivatives and to medicaments containing them for the treatment of diseases.

BACKGROUND OF THE INVENTION

The role of vasopressin in various pathological states has been the subject of intensive research in recent years, and the selective antagonism of the various vasopressin receptors opens up novel clinical prospects. At present, three receptors (V1a, V1b or V3 and V2) by which vasopressin mediates its effect are known. In contrast to the other two receptors, the vasopressin V1b receptor is mainly found in the CNS. This suggests that in particular CNS effects of vasopressin are mediated by the V1b receptor. Thus, it has also been found that an antagonist of the V1b receptor shows anxiolytic and antidepressant effects (Griebel et al., PNAS 99, 6370 (2002); Serradeil-Le Gal et al., J. Pharm. Exp. Ther. 300, 1122 (2002)). Since the models used allow a certain forecast of a clinical effect, antagonists of the vasopressin V1b receptor might be useful for the treatment of emotional disturbances, e.g. stress, anxiety and depression.
WO 93/15051 and WO 98/25901 have already described 1-phenylsulfonyl-1,3-dihydro-2H-indol-2-ones in which the oxindole framework is substituted in position 3 by two alkyl radicals, which may also be a cycloalkyl radical (spiro linkage), as ligands of vasopressin receptors. An alternative possibility is for the spiro ring to contain heteroatoms such as oxygen and nitrogen (optionally with substituents).
WO 95/18105 describes 1-phenylsulfonyl-1,3-dihydro-2H-indol-2-ones which have a nitrogen atom in position 3 as ligands of vasopressin receptors. Additionally bonded in position 3 are radicals which may be alkyl, cycloalkyl, phenyl or benzyl radicals (optionally with substituents in each case).
Other publications describe compounds which have nitrogen-containing rings (e.g. proline, homoproline, morpholine, tetrahydroisoquinoline, dihydroindole; optionally with substituents in each case) bonded via their nitrogen atom to position 3 of the oxindole framework, but which have phenylsulfonyl or phenyl radicals (optionally with substituents) both in position 1 and position 3 on the oxindole ring.
The object of the present invention is to provide additional compounds for the treatment or prophylaxis of various vasopressin-dependent or oxytocin-dependent diseases which have high activity.

SUMMARY OF THE INVENTION

The object has been achieved by a compound of the formula (I)

in which

- A is an aromatic heteromonocyclic, or an aromatic or partially aromatic heterobicyclic ring,
  - where the heterocycles are 5- or 6-membered rings and comprise up to 4 heteroatoms selected from the group consisting of N, O and S, and up to 2 oxo groups, where not more than one of the heteroatoms is an oxygen atom,
  - and A may be substituted by radicals R¹¹, R¹²and/or R¹³,
  - where
  - R¹¹, R¹²and R¹³are selected independently of one another from the group consisting of chlorine, bromine, iodine, fluorine, CN, CF₃, OCF₃, NO₂, OH, O—C₁-C₄-alkyl, O-phenyl, O—-C₁-C₄-alkylen-phenyl, phenyl, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, NH₂, NH(C₁-C₄-alkyl) and N(C₁-C₄-alkyl)₂,
- R³and R⁴are selected independently of one another from the group consisting of hydrogen, chlorine, bromine, iodine, fluorine, CN, CF₃, OCF₃, NO₂, OH, O—C₁-C₄-alkyl, O-phenyl, O—C₁-C₄-alkylen-phenyl, phenyl, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, NH₂, NH(C₁-C₄-alkyl) and N(C₁-C₄-alkyl)₂, or
- R³and R⁴are connected to give —CH═CH—CH═CH—, —(CH₂)₄— or —(CH₂)₃—,
- R⁵is a radical (W)—(X)—(Y)-Z, where
  - W is selected from the group consisting of C₁-C₄-alkylen, C₂-C₄-alkenylen, C₂-C₄-alkynylen, O, O—(C₁-C₄-alkylen), S, S—(C₁-C₄-alkylen), NR⁵⁴, NR⁵⁴—(C₁-C₄-alkylen) and a bond,
  - X is selected from the group consisting of CO, CO—O, SO₂, NR⁵⁴, NR⁵⁴—CO, NR⁵⁴—SO₂, CO—NR⁵⁸and a bond,
  - Y is C₁-C₆-alkylen, C₂-C₆-alkenylen, C₂-C₆-alkynylen, or a bond,
  - Z is selected from the group consisting of hydrogen, E, O—R⁵², NR⁵¹R⁵², S—R⁵²,
  - where
  - E is an unsaturated, saturated or partially unsaturated mono-, bi- or tricyclic ring having a maximum of 14 carbon atoms and 0 to 5 nitrogen atoms, 0 to 2 oxygen atoms and/or 0 to 2 sulfur atoms, said ring may comprise up to two oxo groups, and may be substituted by radicals R⁵⁵, R⁵⁶, R⁵⁷, and/or up to three radicals R⁵³,
  - R⁵¹is selected from the group consisting of hydrogen, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, phenyl and C₁-C₄-alkylen-phenyl, where the phenyl ring may be substituted by up to two radicals R⁵³,
  - R⁵²is selected from the group consisting of hydrogen, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, E and C₁-C₄-alkylen-E,
  - R⁵³is selected from the group consisting of chlorine, bromine, iodine, fluorine, CN, CF₃, OCF₃, NO₂, OH, O—C₁-C₄-alkyl, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, NH₂, NH(C₁-C₄-alkyl) and N(C₁-C₄-alkyl)₂,
  - R⁵⁴is selected from the group consisting of hydrogen, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, phenyl and C₁-C₄-alkylen-phenyl, where the phenyl ring may be substituted by up to two radicals R⁵⁹,
  - R⁵⁵is selected from the group consisting of C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, phenyl, C₁-C₄-alkylen-phenyl, where the ring may be substituted by up to two radicals R⁶⁰, and OH, O—C₁-C₄-alkyl, O-phenyl, O—C₁-C₄-alkylen-phenyl, NH₂, NH(C₁-C₄-alkyl) and N(C₁-C₄-alkyl)₂,
  - R⁵⁶is a group Q¹-Q²-Q³, where
  - Q¹is selected from the group consisting of a bond, C₁-C₄-alkylen, C₂-C₄-alkenylen, C₂-C₄-alkynylen, C₁-C₄-alkylen-N(C₁-C₄-alkyl), N(C₁-C₄-alkyl), C₁-C₄-alkylen-NH, NH, N(C₁-C₄-alkyl)-C₁-C₄-alkylen, NH—C₁-C₄-alkylen, O, C₁-C₄-alkylen-O, O—C₁-C₄-alkylen, CO—NH, CO—N(C₁-C₄-alkyl), NH—CO, N(C₁-C₄-alkyl)-CO, CO, SO₂, SO, S, O, SO₂—NH, SO₂—N(C₁-C₄-alkyl), NH—SO₂, N(C₁-C₄-alkyl)-SO₂, O—CO—NH, O—CO—N(C₁-C₄-alkyl), NH—CO—O, N(C₁-C₄-alkyl)-CO—O, N(C₁-C₄-alkyl)-CO—N(C₁-C₄-alkyl), NH—CO—N(C₁-C₄-alkyl), N(C₁-C₄-alkyl)-CO—NH, and NH—CO—NH,
  - Q²is selected from the group consisting of C₁-C₄-alkylen, C₂-C₄-alkenylen, C₂-C₄-alkynylen, and a bond,
  - Q³is a hydrogen or an unsaturated, saturated or partially unsaturated mono-, bi- or tricyclic ring having a maximum of 14 carbon atoms and 0 to 5 nitrogen atoms, 0 to 2 oxygen atoms and/or 0 to 2 sulfur atoms, which may comprise up to two oxo groups and may be substituted by the radicals R⁶³, R⁶⁴and/or R⁶⁵,
  - R⁵⁷is selected from the group consisting of C₁-C₆-alkyl, phenyl, C₁-C₄-alkylen-phenyl, COOH, CO—O—C₁-C₄-alkyl, CONH₂, CO—NH—C₁-C₄-alkyl, CO—N(C₁-C₄-alkyl)₂, CO—C₁-C₄-alkyl, CH₂—NH₂, CH₂—NH—C₁-C₄-alkyl and CH₂—N(C₁-C₄-alkyl)₂,
  - R⁵⁸is selected from the group consisting of hydrogen, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, phenyl and C₁-C₄-alkylen-phenyl, where the phenyl ring may be substituted by up to two radicals R⁶²,
  - R⁵⁹, R⁶⁰and R⁶²are selected independently of one another from the group consisting of chlorine, bromine, iodine, fluorine, CN, CF₃, OCF₃, NO₂, OH, O—C₁-C₄-alkyl, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, NH₂, NH(C₁-C₄-alkyl) and N(C₁-C₄-alkyl)₂,
  - R⁶³, R⁶⁴and R⁶⁵are selected independently of one another from the group consisting of chlorine, bromine, iodine, fluorine, CN, CF₃, OCF₃, NO₂, OH, O—C₁-C₄-alkyl, O-phenyl, O—C₁-C₄-alkylen-phenyl, phenyl, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, NH₂, NH(C₁-C₄-alkyl) and N(C₁-C₄-alkyl)₂,
- R⁶and R⁷are selected independently of one another from the group consisting of hydrogen, chlorine, bromine, iodine, fluorine, CN, CF₃, OCF₃, NO₂, OH, O—C₁-C₄-alkyl, O-phenyl, O—C₁-C₄-alkylen-phenyl, phenyl, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, NH₂, NH(C₁-C₄-alkyl) and N(C₁-C₄-alkyl)₂,
- and their tautomeric forms, enantiomeric and diastereomeric forms, and prodrugs thereof.

The present application additionally relates to a compound of the formula (II)

in which

- B is selected from the group consisting of thiophene, furan, pyrrole, pyridine, quinoline, tetrahydroquinoline, isoquinoline, tetrahydroisoquinoline, benzothiophene, benzofuran, dihydrobenzofuran, indole, dihydroisoindole,
- an aromatic heteromonocyclic and an aromatic or partially aromatic heterobicyclic ring,
  - where the heterocycles are 5- or 6-membered rings and comprise 2 to 4 heteroatoms selected from the group consisting of N, O and S, and up to 2 oxo groups, and
  - B may be substituted by the radicals R²¹, R²²and/or R²³,
  - R²¹, R²²and R²³are selected independently of one another from the group consisting of chlorine, bromine, iodine, fluorine, CN, CF₃, OCF₃, NO₂, OH, O—C₁-C₄-alkyl, O-phenyl, O—C₁-C₄-alkylen-phenyl, phenyl, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, NH₂, NH(C₁-C₄-alkyl) and N(C₁-C₄-alkyl)₂, morpholin-4-yl, pyrrolidin-1-yl, piperidin-1-yl, 4-piperazin-1-yl, 4-(Cl-C₄-alkyl)-piperazin-1-yl,
- R³and R⁴are selected independently of one another from the group consisting of hydrogen, chlorine, bromine, iodine, fluorine, CN, CF₃, OCF₃, NO₂, OH, O—C₁-C₄-alkyl, O-phenyl, O—C₁-C₄-alkylen-phenyl, phenyl, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, NH₂, NH(C₁-C₄-alkyl) and N(C₁-C₄-alkyl)₂, or
- R³and R⁴are connected to give —CH═CH—CH═CH—, —(CH₂)₄— or —(CH₂)₃—,
- R⁵is a radical (W)—(X)—(Y)-Z, where
  - W is selected from the group consisting of C₁-C₄-alkylen, C₂-C₄-alkenylen, C₂-C₄-alkynylen, O, O—(C₁-C₄-alkylen), S, S—(C₁-C₄-alkylen), NR⁵⁴, NR⁵⁴-(C₁-C₄-alkylen) and a bond,
  - X is selected from the group consisting of CO, CO—O, SO₂, NR⁵⁴, NR⁵⁴—CO, NR⁵⁴—SO₂, CO—NR⁵⁸and a bond,
  - Y is C₁-C₆-alkylen, C₂-C₆-alkenylen, C₂-C₆-alkynylen, or a bond,
  - Z is selected from the group consisting of hydrogen, E, O—R⁵², NR⁵¹R⁵², S—R⁵²,
  - where
  - E is an unsaturated, saturated or partially unsaturated mono-, bi- or tricyclic ring having a maximum of 14 carbon atoms and 0 to 5 nitrogen atoms, 0 to 2 oxygen atoms and/or 0 to 2 sulfur atoms, said ring may comprise up to two oxo groups, and may be substituted by radicals R⁵⁵, R⁵⁶, R⁵⁷and/or up to three radicals R⁵³and,
  - R⁵¹is selected from the group consisting of hydrogen, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, phenyl and C₁-C₄-alkylen-phenyl, where the phenyl ring may be substituted by up to two radicals R⁵³,
  - R⁵²is selected from the group consisting of hydrogen, C₁-C₆-alkyl, C₂-C₆-alkenyl,
  - C₂-C₆-alkynyl, E and C₁-C₄-alkylen-E,
  - R⁵³is selected from the group consisting of chlorine, bromine, iodine, fluorine, CN, CF₃, OCF₃, NO₂, OH, O—C₁-C₄-alkyl, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, NH₂, NH(C₁-C₄-alkyl) and N(C₁-C₄-alkyl)₂,
  - R⁵⁴is selected from the group consisting of hydrogen, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, phenyl and C₁-C₄-alkylen-phenyl, where the phenyl ring may be substituted by up to two radicals R⁵⁹,
  - R⁵⁵is selected from the group consisting of C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, phenyl, C₁-C₄-alkylen-phenyl, where the ring may be substituted by up to two radicals R⁶⁰, and OH, O—C₁-C₄-alkyl, O-phenyl, O—C₁-C₄-alkylen-phenyl, NH₂, NH(C₁-C₄-alkyl) and N(C₁-C₄-alkyl)₂,
  - R⁵⁶is a group Q¹-Q²-Q³, where
  - Q¹is selected from the group consisting of a bond, C₁-C₄-alkylen, C₂-C₄-alkenylen, C₂-C₄-alkynylen, C₁-C₄-alkylen-N(C₁-C₄-alkyl), N(C₁-C₄-alkyl), C₁-C₄-alkylen-NH, NH, N(C₁-C₄-alkyl)-C₁-C₄-alkylen, NH—C₁-C₄-alkylen, O, C₁-C₄-alkylen-O, O—C₁-C₄-alkylen, CO—NH, CO—N(C₁-C₄-alkyl), NH—CO, N(C₁-C₄-alkyl)-CO, CO, SO₂, SO, S, O, SO₂—NH, SO₂—N(C₁-C₄-alkyl), NH—SO₂, N(C₁-C₄-alkyl)-SO₂, O—CO—NH, O—CO—N(C₁-C₄-alkyl), NH—CO—O, N(C₁-C₄-alkyl)-CO—O, N(C₁-C₄-alkyl)-CO—N(C₁-C₄-alkyl), NH—CO—N(C₁-C₄-alkyl), N(C₁-C₄-alkyl)-CO—NH, and NH—CO—NH,
  - Q²is selected from the group consisting of C₁-C₄-alkylen, C₂-C₄-alkenylen, C₂-C₄-alkynylen, and a bond,
  - Q³is a hydrogen or an unsaturated, saturated or partially unsaturated mono-, bi- or tricyclic ring having a maximum of 14 carbon atoms and 0 to 5 nitrogen atoms, 0 to 2 oxygen atoms and/or 0 to 2 sulfur atoms, which may comprise up to two oxo groups and may be substituted by the radicals R⁶³, R⁶⁴and/or R⁶⁵,
  - R⁵⁷is selected from the group consisting of C₁-C₆-alkyl, phenyl, C₁-C₄-alkylen-phenyl, COOH, CO—O—C₁-C₄-alkyl, CONH₂, CO—NH—C₁-C₄-alkyl, CO—N(C₁-C₄-alkyl)₂, CO—C₁-C₄-alkyl, CH₂—NH₂, CH₂—NH—C—C₄-alkyl and CH₂—N(C₁-C₄-alkyl)₂,
  - R⁵⁸is selected from the group consisting of hydrogen, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, phenyl and C₁-C₄-alkylen-phenyl, where the phenyl ring may be substituted by up to two radicals R⁶²,
  - R⁵⁹, R⁶⁰and R⁶²are selected independently of one another from the group consisting of chlorine, bromine, iodine, fluorine, CN, CF₃, OCF₃, NO₂, OH, O—C₁-C₄-alkyl, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, NH₂, NH(C₁-C₄-alkyl) and N(C₁-C₄-alkyl)₂,
  - R⁶³, R⁶⁴and R⁶⁵are selected independently of one another from the group consisting of chlorine, bromine, iodine, fluorine, CN, CF₃, OCF₃, NO₂, OH, O—C₁-C₄-alkyl, O-phenyl, O—C₁-C₄-alkylen-phenyl, phenyl, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, NH₂, NH(C₁-C₄-alkyl) and N(C₁-C₄-alkyl)₂,
- R⁶and R⁷are selected independently of one another from the group consisting of hydrogen, chlorine, bromine, iodine, fluorine, CN, CF₃, OCF₃, NO₂, OH, O—C₁-C₄-alkyl, O-phenyl, O—C₁-C₄-alkylen-phenyl, phenyl, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, NH₂, NH(C₁-C₄-alkyl) and N(C₁-C₄-alkyl)₂,
- and their tautomeric forms, enantiomeric and diastereomeric forms, and prodrugs thereof.

The present invention additionally relates to a compound of the formula (III),

in which

- D is an aromatic heteromonocyclic, or an aromatic or partially aromatic heterobicyclic ring,
  - where the heterocycles are 5- or 6-membered rings and comprise up to 4 heteroatoms selected from the group consisting of N, O and S, and up to 2 oxo groups,
  - and D may be substituted by radicals R²¹, R²²and/or R²³,
- G is an aromatic heteromonocyclic, aromatic or partially aromatic heterobicyclic ring,
  - where the heterocycles are 5- or 6-membered rings and comprise up to 4 heteroatoms selected from the group consisting of N, O and S, and up to 2 oxo groups and
  - G may be substituted by radicals R⁷¹, R⁷²and/or R⁷³,
  - R²¹, R²², R²³, R⁷¹, R⁷²and R⁷³are selected independently of one another from the group consisting of chlorine, bromine, iodine, fluorine, CN, CF₃, OCF₃, NO₂, OH, O—C₁-C₄-alkyl, O-phenyl, O—C₁-C₄-alkylen-phenyl, phenyl, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, NH₂, NH(C₁-C₄-alkyl) and N(C₁-C₄-alkyl)₂, morpholin-4-yl, pyrrolidin-1-yl, piperidin-1-yl, 4-piperazin-1-yl, 4-(C₁-C₄-alkyl)-piperazin-1-yl,
- R³and R⁴are selected independently of one another from the group consisting of hydrogen, chlorine, bromine, iodine, fluorine, CN, CF₃, OCF₃, NO₂, OH, O—C₁-C₄-alkyl, O-phenyl, O—C₁-C₄-alkylen-phenyl, phenyl, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, NH₂, NH(C₁-C₄-alkyl) and N(C₁-C₄-alkyl)₂, or
- R³and R⁴are connected to give —CH═CH—CH═CH—, —(CH₂)₄— or —(CH₂)₃—,
- R⁵is a radical (W)—(X)—(Y)-Z, where
  - W is selected from the group consisting of C₁-C₄-alkylen, C₂-C₄-alkenylen, C₂-C₄-alkynylen, O, O—(C₁-C₄-alkylen), S, S—(C₁-C₄-alkylen), NR^54,NR⁵⁴—(C₁-C₄-alkylen) and a bond,
  - X is selected from the group consisting of CO, CO—O, SO₂, NR⁵⁴, NR⁵⁴—CO, NR⁵⁴—SO₂, CO—NR⁵⁸and a bond,
  - Y is C₁-C₆-alkylen, C₂-C₆-alkenylen, C₂-C₆-alkynylen, or a bond,
  - Z is selected from the group consisting of hydrogen, E, O—R⁵², NR⁵¹R⁵², S—R⁵²,
  - where
  - E is an unsaturated, saturated or partially unsaturated mono-, bi- or tricyclic ring having a maximum of 14 carbon atoms and 0 to 5 nitrogen atoms, 0 to 2 oxygen atoms and/or 0 to 2 sulfur atoms, which may comprise up to two oxo groups, and E may be substituted by radicals R⁵⁵, R⁵⁶, R⁵⁷and/or up to three radicals R⁵³,
  - R⁵¹is selected from the group consisting of hydrogen, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, phenyl and C₁-C₄-alkylen-phenyl, where the phenyl ring may be substituted by up to two radicals R⁵³,
  - R⁵²is selected from the group consisting of hydrogen, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, E and C₁-C₄-alkylen-E,
  - R⁵³is selected from the group consisting of chlorine, bromine, iodine, fluorine, CN, CF₃, OCF₃, NO₂, OH, O—C₁-C₄-alkyl, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, NH₂, NH(C₁-C₄-alkyl) and N(C₁-C₄-alkyl)₂,
  - R⁵⁴is selected from the group consisting of hydrogen, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, phenyl and C₁-C₄-alkylen-phenyl, where the phenyl ring may be substituted by up to two radicals R⁵⁹,
  - R⁵⁵is selected from the group consisting of C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, phenyl, C₁-C₄-alkylen-phenyl, where the ring may be substituted by up to two radicals R⁶⁰, and OH, O—C₁-C₄-alkyl, O-phenyl, O—C₁-C₄-alkylen-phenyl, NH₂, NH(C₁-C₄-alkyl) and N(C₁-C₄-alkyl)₂,
  - R⁵⁶is a group Q¹-Q²-Q³, where
  - Q¹is selected from the group consisting of a bond, C₁-C₄-alkylen, C₂-C₄-alkenylen, C₂-C₄-alkynylen, C₁-C₄-alkylen-N(C₁-C₄-alkyl), N(C₁-C₄-alkyl), C₁-C₄-alkylen-NH, NH, N(C₁-C₄-alkyl)-C₁-C₄-alkylen, NH—C₁-C₄-alkylen, O, C₁-C₄-alkylen-O, O—C₁-C₄-alkylen, CO—NH, CO—N(C₁-C₄-alkyl), NH—CO, N(C₁-C₄-alkyl)-CO, CO, SO₂, SO, S, O, SO₂—NH, SO₂—N(C₁-C₄-alkyl), NH—SO₂, N(C₁-C₄-alkyl)-SO₂, O—CO—NH, O—CO—N(C₁-C₄-alkyl), NH—CO—O, N(C₁-C₄-alkyl)-CO—O, N(C₁-C₄-alkyl)-CO—N(C₁-C₄-alkyl), NH—CO—N(C₁-C₄-alkyl), N(C₁-C₄-alkyl)-CO—NH, and NH—CO—NH,
  - Q²is selected from the group consisting of C₁-C₄-alkylen, C₂-C₄-alkenylen, C₂-C₄-alkynylen, and a bond,
  - Q³is a hydrogen or an unsaturated, saturated or partially unsaturated mono-, bi- or tricyclic ring having a maximum of 14 carbon atoms and 0 to 5 nitrogen atoms, 0 to 2 oxygen atoms and/or 0 to 2 sulfur atoms, which may comprise up to two oxo groups and may be substituted by the radicals R⁶³, R⁶⁴and/or R⁶⁵,
  - R⁵⁷is selected from the group consisting of C₁-C₆-alkyl, phenyl, C₁-C₄-alkylen-phenyl, COOH, CO—O—C₁-C₄-alkyl, CONH₂, CO—NH—C₁-C₄-alkyl, CO—N(C₁-C₄-alkyl)₂, CO—C₁-C₄-alkyl, CH₂—NH₂, CH₂—NH—C₁-C₄-alkyl and CH₂—N(C₁-C₄-alkyl)₂,
  - R⁵⁸is selected from the group consisting of hydrogen, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, phenyl and C₁-C₄-alkylen-phenyl, where the phenyl ring may be substituted by up to two radicals R⁶²,
  - R⁵⁹, R⁶⁰and R⁶²are selected independently of one another from the group consisting of chlorine, bromine, iodine, fluorine, CN, CF₃, OCF₃, NO₂, OH, O—C₁-C₄-alkyl, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, NH₂, NH(C₁-C₄-alkyl) and N(C₁-C₄-alkyl)₂,
  - R⁶³, R⁶⁴and R⁶⁵are selected independently of one another from the group consisting of chlorine, bromine, iodine, fluorine, CN, CF₃, OCF₃, NO₂, OH, O—C₁-C₄-alkyl, O-phenyl, O—C₁-C₄-alkylen-phenyl, phenyl, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, NH₂, NH(C₁-C₄-alkyl) and N(C₁-C₄-alkyl)₂,
- and their tautomeric forms, enantiomeric and diastereomeric forms, and prodrugs thereof.

Novel 1,3-dihydro-2H-indol-2-one derivatives which have heterocycles in position 3 and/or heterocyclic rings in position 1, and their use for the treatment of diseases, are described in the present invention.

DETAILED DESCRIPTION OF THE INVENTION

Preferred embodiments of the present invention are explained below.
Rings A and D are preferably selected independently of one another from the group consisting of aromatic heteromonocyclic and aromatic heterobicyclic systems comprising 1 or 2 heteroatoms, where one of the 2 heteroatoms is nitrogen, more preferably from benzothiazole, pyrimidine, pyridine, pyridazine, pyrazine, isoquinoline, quinoline, thiazole, benzimidazole, imidazole, benzoxazole, benzothiophene, thiophene, benzofuran and furan.
Rings B and G are preferably selected independently of one another from the group consisting of thiophene, furan, pyrrole, pyrazole, isoxazole, pyridine, pyrimidine, quinoline, isoquinoline, tetrahydroisoquinoline, benzothiophene, benzofuran, indole, imidazole, thiazole, imidazothiazole, benzooxazine and quinoxaline.
The terms “alkyl”, “alkylene”, “alkenyl”, “alkenylene”, “alkynyl” and “alkynylene” as use herein always include unbranched or branched “alkyl”, “alkylene”, “alkenyl”, “alkenylene”, “alkynyl” or “alkynylene”.
C₁-C₄-alkyl as used herein is preferably methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl or t-butyl.
C₁-C₄-alkylene as used herein is preferably methylene, ethylene, or branched or unbranched propylene or butylene.
C₂-C₄-alkenyl as used herein is preferably ethenyl, or branched or unbranched propenyl or butenyl.
C₂-C₄-alkenylene as used herein is preferably ethenylene, or branched or unbranched propenylene or butenylene.
C₂-C₄-alkynyl as used herein is preferably ethynyl, or branched or unbranched propynyl or butynyl.
C₂-C₄-alkynylene as used herein is preferably ethynylene, or branched or unbranched propynylene or butynylene.
C₁-C₆-alkyl as used herein is preferably branched or unbranched hexyl or pentyl, more preferably C₁-C₄-alkyl, and in particular methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl or t-butyl.
C₁-C₆-alkylene as used herein is preferably branched or unbranched hexylene or pentylene, more preferably C₁-C₄-alkylene, and in particular methylene, ethylene, or branched or unbranched propylene or butylene.
C₂-C₆-alkenyl as used herein is preferably branched or unbranched hexenyl or pentenyl, more preferably C₂-C₄-alkenyl, and in particular ethenyl, or branched or unbranched propenyl or butenyl.
C₂-C₆-alkenylene as used herein is preferably branched or unbranched hexenylene or pentenylene, more preferably C₂-C₄-alkenylene, and in particular ethenylene, or branched or unbranched propenylene or butenylene.
C₂-C₆-alkynyl as used herein is preferably branched or unbranched hexynyl or pentynyl, more preferably C₂-C₄-alkynyl, and in particular ethynyl, or branched or unbranched propynyl or butynyl.
C₂-C₆-alkynylene as used herein is preferably branched or unbranched hexynylene or pentynylene, more preferably C₂-C₄-alkynylene, and in particular ethynylene, or branched or unbranched propynylene or butynylene.
The formulation the “[said] ring may comprise up to two oxo groups” as used herein means that said ring has up to two carbon atoms which are each connected to an oxygen atom via a double bond.
Divalent radicals are to be read from the left to the right with respect to their bonds to other substructures of the molecule. Thus, for example “CO—NR⁵⁸” in the definition of X in R⁵of the compound of formulae (I) to (IIII) is connected to W and Y as follows: (W)—CO—N(R⁵⁸)—(Y)-Z.
By prodrugs are meant those compounds which are metabolized in vivo to the compounds of the invention. Typical examples of prodrugs are described in C. G. Wermuth (ed.): The Practice of Medicinal Chemistry, Academic Press, San Diego, 1996, p. 671-715. These include, for example, phosphates, carbamates or amino acids, esters and others.
The invention further relates to the physiologically tolerated salts of the compounds of the invention which can be obtained by reacting the compounds of the invention with a suitable acid or base. Suitable acids and bases are listed for example in Fortschritte der Arzneimittelforschung, 1966, Birkhäuser Verlag. vol. 10, pages 224-285. These include for example hydrochloric acid, citric acid, tartaric acid, lactic acid, phosphoric acid, methanesulfonic acid, acetic acid, formic acid, maleic acid, fumaric acid etc., and sodium hydroxide, lithium hydroxide, potassium hydroxide and 2-amino-2-(hydroxymethyl)-1,3-propanediol (Tris).
The invention further relates to the compound of any of general formulae (I) to (III) as therapeutic or prophylactic agent.
Furthermore, the invention relates to a medicament comprising the compound of any of general formulae (I) to (III).
The compound of any of general formulae (I) to (III) can be used for producing a medicament for the control and/or prophylaxis of various vasopressin-dependent or oxytocin-dependent diseases.
The invention further relates to the use of the compound of any of general formulae (I) to (III) for the control and/or prophylaxis of various vasopressin-dependent or oxytocin-dependent diseases.
A further aspect of the invention is a method for the therapeutic and/or prophylactic treatment of a mammal requiring a treatment by administering the compound of any of formulae (I) to (III) for the treatment of diseases.
Furthermore, the compound of any of formulae (I) to (III) can be used for the treatment of:

- depressions and/or bipolar disorders such as, for example, dysthymic disorders, subsyndromal depression, seasonal affected disorders, premenstrual dysphoric disorders and/or psychotic disorders;
- anxiety and/or stress-related disorders such as, for example, general anxiety disorders, panic disorders, obsessive-compulsive disorders, post-traumatic disorders, acute stress disorders and/or social phobia;
- memory disorders and/or Alzheimer's disease;
- psychoses and/or psychotic disorders; and/or
- Cushing's syndrome.

The compounds of the invention are effective after administration in various ways, especially orally.
The compounds according to the present invention can be useful for the treatment or prevention of various vasopressin-dependent or ocytocin-dependent complaints, such as mental disorders. Examples of such mental disorders according to the American Psychiatric Association DSM-IV, Diagnostic and Statistical Manual of Mental Disorders, 4th ed., 1994 are attention-deficit and disruptive behavior disorders; delirium, dementia, and amnestic and other cognitive disorders; substance-related disorders, such as alcohol use disorders and alcohol-induced disorders; schizophrenia and other psychotic disorders, such as schizophrenia, schizophreniform disorder, schizoaffective disorder and delusional disorder; mood disorders, such as depressive disorders (major depressive disorder, dysthymic disorder, seasonal affective disorder, premenstrual dysphoric disorder, depressive disorder not otherwise specified), bipolar disorder (bipolar I disorder, bipolar II disorder, cyclothymic disorder, bipolar disorder not otherwise specified, substance-induced mood disorder, mood disorder not otherwise specified); stress-related disorders, such as acute stress disorder; anxiety disorders, such as panic disorder without agoraphobia, panic disorder with agoraphobia, agoraphobia without history of panic disorder, specific phobia, social phobia, obsessive-compulsive disorder, posttraumatic stress disorder, acute stress disorder, generalized anxiety disorder, substance-induced anxiety disorder; somatoform disorders, such as somatization disorder, undifferentiated somatoform disorder, conversion disorder, pain disorder; eating disorders; sleep disorders, such as primary sleep disorders (dyssomnias, parasomnias), sleep disorders related to another mental disorder. Furthermore, compounds according to the present invention can be useful for the treatment of Cushing syndrome.
The present invention also relates to pharmaceutical compositions which comprise an effective dose of a compound of the invention or of a pharmaceutically acceptable salt thereof and suitable pharmaceutical carriers.
These pharmaceutical carriers are chosen according to the pharmaceutical form and the desired mode of administration.
With the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, intratracheal, intranasal, transdermal or rectal administration it is possible to administer the compounds of the formula (I), (II) or (III) or, where suitable, the salts thereof to animals or humans in unitary administration forms, mixed with conventional pharmaceutical carriers, for the prophylaxis or treatment of the above disorders or diseases.
The suitable unitary administration forms include forms for oral administration, such as tablets, gelatin capsules, powders, granules and solutions or suspensions for oral intake, forms for sublingual, buccal, intratracheal or intranasal administration, aerosols, implants, forms for subcutaneous, intramuscular or intravenous administration and forms for rectal administration.
For topical administration, the compounds of the invention can be used in creams, ointments or lotions.
In order to achieve the desired prophylactic or therapeutic effect, the dose of the basic active ingredient may vary between 0.01 and 50 mg per kg of bodyweight and per day.
Each unit dose may comprise from 0.05 to 5 000 mg, preferably 1 to 1 000 mg, of the active ingredient in combination with a pharmaceutical carrier. This unit dose may be administered 1 to 5 times a day so that a daily dose of from 0.5 to 25 000 mg, preferably 1 to 5 000 mg, is administered.
If a solid composition is prepared in the form of tablets, the main ingredient is mixed with a pharmaceutical carrier such as gelatin, starch, lactose, magnesium stearate, talc, silica or the like.
The tablets may be coated with sucrose, a cellulose derivative or another suitable substance or treated otherwise in order to display persistent or delayed activity and in order to release a predetermined amount of the basic active ingredient continuously.
A preparation in the form of gelatin capsules is obtained by mixing the active ingredient with an extender and taking up the resulting mixture in soft or hard gelatin capsules.
A preparation in the form of a syrup or elixir or for administration in the form of drops may comprise active ingredients together with a sweetener, which is preferably calorie-free, methylparaben or propylparaben as antiseptics, a flavoring and a suitable color.
The water-dispersible powders or granules may comprise the active ingredients mixed with dispersants or wetting agents, or suspending agents, such as polyvinylpyrrolidones, and sweeteners or masking flavors.
Rectal administration is achieved by using suppositories which are prepared with binders which melt at the rectal temperature, for example cocoa butter or polyethylene glycols. Parenteral administration is effected by using aqueous suspensions, isotonic salt solutions or sterile and injectable solutions which comprise pharmacologically acceptable dispersants and/or wetting agents, for example propylene glycol or polyethylene glycol.
The basic active ingredient may also be formulated as microcapsules or liposomes, if suitable with one or more carriers or additives.
In addition to the compounds of the general formula (I) or their pharmaceutically acceptable salts, the compositions of the invention may comprise other basic active ingredients which may be beneficial for the treatment of the abovementioned disorders or diseases.
The present invention thus further relates to pharmaceutical compositions in which a plurality of basic active ingredients are present together, where one of these is the compound of the invention.
The compounds of the invention were tested for their activity in the following vasopressin V1b receptor binding assay.
Vasopressin V1b Receptor binding Assay:
Dissolution of Compounds:
Compounds were dissolved in a concentration of 10⁻²M or 10⁻³M in DMSO. Further dilutions were performed with water
Binding Assays:
The procedure for the binding assay was based on the method of Tahara et al. (Tahara A et al., Brit. J. Pharmacol. 125, 1463-1470 (1998)). Assays (0.250 ml) consisted of membranes (58 μg protein) from CHO-K1 cells permanently expressing human V1b receptors (preparation V1b-3H2, containing protease inhibitors, Roche complete Mini #1836170), 1.5 nM ³H-AVP (8-Arg-vasopressin, NET 800) in incubation buffer (total binding) and different concentrations of test compound (displacement). Non-specific binding was defined with 10⁻⁶M AVP. Assays were performed in triplicate.
Incubation buffer: 50 mM Tris, 10 mM MgCl₂, 0.1% BSA adjusted to pH 7.4 with HCl.
After incubation, 60 min at room temperature, bound and free radioligand was separated by filtration under vacuum through Whatman GF/B glass fibre mats using a Skatron cell havester 7000.
Liquid scintillation counting was performed in beta-counters, Tricarb model 2000 or 2200CA (Packard). Dpm were calculated by a programme with standardisation using a standard quench series.
Evaluation:
Evaluation of binding parameters was performed by non-linear regression analysis with SAS. The strategy of this program is similar to the program LIGAND described by Munson and Rodbard (Munson P J and Rodbard D, Analytical Biochem. 107, 220-239 (1980)).
Functional Assay for the Human V1b Receptor
Functional activity was determined by testing the effect of the compounds on calcium release in CHO-K₁cells stably transfected with human V_1breceptor. Cells were seeded into 96-well plates at 50,000 cells/well and grown overnight in tissue culture medium (DMEM/Nut mix F12 Medium with Glutamax I (invitrogen), containing 10% FCS, 100 units/ml Penicillin, 100 μg/mi Streptomycine, 800 μg/ml Geneticin) at 37° C. and 5% CO₂. Cells were loaded with a fluorescent calcium-sensitive dye in the presence of 1% probenicid according to the manufacturers protocol (Ca⁺⁺-Plus-Assay Kit, Molecular Devices). Serial compound dilutions (final concentrations 10⁻¹⁰to 10⁻⁵M) were added to the cells either alone or in the presence of Arg-vasopressin (10⁻⁸M) and the maximum calcium response was determined using a FLIPR-96 instrument (Molecular Devices). Concentration-response curves were fitted using a three-parameter logistic equation (GraphPad Prism 3.0). Kb values were calculated from IC50 values according to Cheng & Prusoff (Kb=IC50/1+L/EC50).
The synthesis of the compounds of the invention is described below.
The 1,3-dihydroindol-2-ones of the invention can be prepared in various ways, as outlined in synthesis schemes 1-5.
The 3-hydroxy-1,3-dihydroindol-2-ones VI can be obtained by addition of metalated heterocycles IV to the 3-keto group of isatins V. Examples of metalated heterocycles which can be employed are the corresponding magnesium and lithium compounds. The isatins V were either purchased or prepared by methods described in the literature (Advances in Heterocyclic Chemistry, A. R. Katritzky and A. J. Boulton, Academic Press, New York, 1975, 18, 2-58; J. Brazil. Chem. Soc. 12, 273-324 (2001)). The metalated heterocycles IV were prepared in various ways (see review article by G. Queguiner et al. in Advances in Heterocyclic Chemistry, Vol. 52, ed. A. R. Katritzky, Academic Press, 1991, 187-304.: J. Heterocyclic Chem. 37, 615 (2000); Heterocyles 37, 2149, (1994)): (i) reaction of heteroaryl halides with magnesium affords in certain cases (for example 2-bromo-3-methylthiophene) the corresponding Grignard compounds (M=Mg); (ii) reaction of heteroaryl bromides and iodides with alkyllithium reagents such as, for example, n-butyllithium, tert-butyllithium or mesityllithium at low temperatures affords in certain cases (for example 5-bromo-2,4-dimethoxypyrimidine) the lithiated heterocycles by halogen-lithium exchange; (iii) reaction of substituted heterocycles with the aforementioned alkyllithium reagents and lithium bases such as, for example, lithium diisopropylamide or lithium tetramethylpiperidylamide likewise affords in certain cases (for example 2-methoxypyrazine) the lithiated heterocycles, especially when the hetero-aromatic system is substituted by ortho-directing groups such as, for example, a methoxy group.
The 3-hydroxy-1,3-dihydroindol-2-ones VI were converted in the next step into compounds VII which bear a leaving group LG in position 3. Examples for LG are halides, mesylate and tosylate. Thus, for example, in the case where LG is chlorine the intermediate VII can be prepared by treating the tertiary alcohol VI with thionyl chloride in the presence of a base such as, for example, pyridine. Alternatively, alcohols VI can be activated by conversion into the mesylate using methanesulfonyl chloride in the presence of a base such as, for example, triethylamine. The leaving group LG in the compounds VII can then be replaced by various nucleophiles R5-H, resulting in the compounds VIII which have the radical R5 in position 3. For example, replacement reactions with primary and secondary amines R5-H in the presence of a base such as, for example, N,N-diisopropylethylamine in a solvent such as, for example dichloromethane afford the analogous 3-amino-1,3-dihydroindol-2-ones VIII. The reaction is not confined to nitrogen nucleophiles; it is also possible for oxygen or sulfur nucleophiles R5-H, where appropriate after deprotonation with a suitable base such as, for example, sodium hydride. Final sulfonylation by treating the compounds VIII with the sulfonyl chlorides IX after deprotonation with a strong base such as, for example, potassium tert-butoxide or sodium hydride in a solvent such as, for example, DMF affords the compounds X of the invention.
The 3-urethane derivatives XIII were prepared by initially reacting the 3-hydroxy-1,3-dihydroindol-2-ones VI with heterocyclic sulfonyl chlorides XI under the conditions already described above. Heterocyclic sulfonyl chlorides were either purchased or prepared by standard methods (see, for example, J. Med. Chem. 40, 1149 (1997); J. March, Advanced Organic Chemistry, 1992, 4th ed., Wiley, New York, p 724). The compounds XIII of the invention were prepared in various ways starting from the sulfonylated compounds XII: (i) reaction with isocyanates L=C═O (L contains nitrogen); (ii) reaction with carbamoyl chlorides L-CO—Cl (L contains nitrogen) in the presence of a base such as, for example, triethylamine; (iii) activation with phenyl chloroformate in the presence of a base such as, for example, pyridine and subsequent reaction of the carbonate intermediate with amines L-H, where appropriate at elevated temperature. Heteroaryl-substituted piperidines, that can be employed as amines L-H, can be prepared as described in Tetrahedron Lett. 34, 5287 (1993) and Bioorg. Med. Chem. Left. 11, 2213 (2001) for 4-(4′-piperidinyl)-pyridine.
Compounds XXII of the invention bearing a functionalized nitrogen atom in position 3 (e.g. amides, sulfonamides, carbamates and ureas) were prepared as described in synthesis scheme 3. The 3-amino-1,3-dihydroindol-2-ones XX were prepared for example by reacting compounds VII (LG is a leaving group such as, for example, chloride or mesylate) with primary amines R⁵⁴—NH₂in the presence of a base such as, for example, N,N-diisopropylethylamine in suitable solvents such as, for example, dichloromethane. Treatment of compounds XX with sulfonyl chlorides XI after deprotonation with a strong base such as, for example, potassium tert-butoxide or sodium hydride in a solvent such as, for example, DMF afforded the 3-amino-1,3-dihydroindol-2-ones XXI sulfonylated in position 1. The amino derivatives XXII of the invention were prepared from the amines XXI by reaction with customary reagents for derivatizing amino groups, such as, for example, carboxylic acids, carbonyl chlorides, carboxylic anhydrides, sulfonyl chlorides, chloroformates, isocyanates, carbamoyl chlorides by the relevant methods (J. March, Advanced Organic Chemistry, 1992, 4th ed., Wiley, New York, pp. 417-421; 499; 903).
N-heteroaryl-substituted piperidine carboxylic acids, that can be employed as coupling partner for the amines XXI, can be prepared for example as described in J. Med. Chem. 43, 2087 (2000) for 4-carboxy-N-(4-pyridyl)piperidine.
In addition, the 3-amino group in the compounds XXI can be substituted by treatment with alkylating agents such as, for example, alkyl bromides, iodides or mesylates, and by reaction with aldehydes or ketones in the presence of reducing agents such as, for example, sodium cyanoborohydride in the sense of a reductive amination (J. March, Advanced Organic Chemistry, 1992, 4th ed., Wiley, New York, p. 411; 898).
Compounds XXVII of the invention in which X—Y-Z radicals are linked via an alkylene bridge W to position 3 of the 1,3-dihydroindol-2-one framework were prepared for example by alkylation of the deoxygenated compounds XXIII and, where appropriate, derivatized further. An example for the preparation of compounds of the XXVII type in which W is a methylene group and X is a carbonyl group is described in synthesis scheme 4: Deoxygenation of the 3-hydroxy-1,3-dihydroindol-2-ones VI took place with triethylsilane in trifluoroacetic acid. The esters XXIV were prepared by alkylation of the 1,3-dihydroindol-2-ones XXIII with ethyl bromoacetate in the presence of bases such as, for example, potassium carbonate and, where appropriate, potassium iodide. After hydrolysis of the ester function, for example by treatment with lithium hydroxide in a water/THF/methanol mixture, the acids XXV were coupled with amines H—Y-Z employing relevant methods (J. March, Advanced Organic Chemistry, 1992, 4th ed., Wiley, New York, pp. 417-421). Final sulfonylation of the compounds XXVI with sulfonyl chlorides XI afforded the compounds XXVII of the invention.
Compounds of the invention in which X—Y-Z radicals are linked via an oxygen atom (W═O) to position 3 of the 1,3-dihydroindol-2-one framework were prepared for example by alkylation of the 1-sulfonyl-3-hydroxy-1,3-dihydroindol-2-ones XII with alkylating agents such as, for example, aralkyl bromides, iodides or mesylates after deprotonation of the tertiary hydroxyl group with bases such as, for example, sodium hydride.
Enantiopure compounds can be obtained for example by carrying out a conventional racemic resolution using suitable optically active acids or bases with compounds of the invention or intermediates which comprise basic or acidic functional groups such as, for example, an amino or carboxyl group.

EXAMPLES

(2S, 4R)-4-Hydroxypyrrolidine-2-carboxylic acid dimethylamide hydrochloride

A) BOP (172 g, 0.389 mol) was added in portions to a solution of (2S, 4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (90 g, 0.398 mol) in dichloromethane (450 ml) and DIPEA (68 ml, 0.523 mol) at 0° C. and stirred at 0° C. for 1 hour. Then a 2 M solution of dimethylamine in THF (800 ml, 1.6 mol) was added dropwise at 0° C., and the mixture was stirred at room temperature overnight. The reaction mixture was stirred into ice-water, and the mixture was extracted several times with dichloromethane. The collected organic phase was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure.
B) The product from step A was mixed with 500 ml of 5-6 M HCl in isopropanol and stirred at room temperature for 4 hours. After cooling to 0° C., the precipitate was filtered off with suction, washed with isopropanol and diethyl ether and dried. 37 g of the desired product were obtained.

Example 1 and Example 2

(2S, 4R)-1-[3-Benzothiazol-2-yl-5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxypyrrolidine-2-carboxylic acid dimethylamide

A) 3-Benzothiazol-2-yl-5-chloro-3-hydroxy-1,3-dihydroindol-2-one

A 1.6 M solution of n-butyllithium in hexane (35 ml, 56 mmol) was added dropwise to a solution of benzothiazole (6.2 ml, 56 mmol) in THF (100 ml) at −78° C. After stirring at −78° C. for 1.5 h, the solution of the lithiated benzothiazole was transferred via a needle into an ice-cold suspension of 5-chloroisatin (3.63 g, 20 mmol) in THF (70 ml). The reaction mixture was stirred at 0° C. for 1 h and then saturated ammonium chloride solution was added. The mixture was extracted three times with ethyl acetate and the combined organic layers were washed with saturated brine. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure, during which the product starts to crystallize. Filtration and drying yielded 4.47 g of the product as yellow crystalline solid.

B) 3-Benzothiazol-2-yl-3,5-dichloro-1,3-dihydroindol-2-one

Pyridine (0.57 ml) and thionyl chloride (0.42 ml) were successively added to an ice-cooled solution of the product from step A (1.27 g, 4.0 mmol) in dichloromethane (40 ml). The reaction mixture was stirred at 0° C. for 1 h and then saturated ammonium chloride solution was added. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was rapidly employed without further purification in the next step.

C) (2S, 4R)-1-(3-Benzothiazol-2-yl-5-chloro-2-oxo-2,3-dihydro-1 H-indol-3-yl)-4hydroxy-pyrrolidine-2-carboxylic acid dimethylamide

(2S, 4R)-4-hydroxypyrrolidine-2-carboxylic acid dimethylamide hydrochloride (0.78 g, 4.0 mmol) was added to a solution of the product from step B in a mixture of dichloromethane (9 ml), THF (2 ml) and DIPEA (2 ml). The reaction mixture was stirred at room temperature for 48 h. After addition of water, the mixture was extracted four times with ethyl acetate. The combined organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The less polar diastereomer, as judged by thin-layer-chromatography using 5% MeOH in dichloromethane, precipitated on concentration and was filtered off. Purification by chromatography (silica gel, 5% MeOH in dichloromethane) resulted in 0.28 g of the less polar diastereomer.
Purification by chromatography (silica gel, 5% MeOH in dichloromethane) of the mother liquor resulted in 0.36 g of the more polar diastereomer.

Example 1

(+)-(2S, 4R)-1-[3-Benzothiazol-2-yl-5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxypyrrolidine-2-carboxylic acid dimethylamide

Sodium hydride (12 mg of 60% dispersion in mineral oil, 0.3 mmol) was added to an ice-cold solution of the less polar diastereomer product from step C (115 mg, 0.25 mmol) in DMF (1.5 ml). The reaction mixture was stirred at 0° C. for 1 h and then 2,4-dimethyoxyphenylsufonyl chloride (71 mg, 0.3 mmol) was added. After the reaction mixture had been stirred at room temperature for one hour, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over magnesium sulfate. Purification by chromatography (silica gel, 5% MeOH in dichloromethane) resulted in 93 mg of Example 1 as a white solid.

Example 2

(−)-(2S, 4R)-1-[3-Benzothiazol-2-yl-5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxypyrrolidine-2-carboxylic acid dimethylamide

The diastereomer product was prepared by the method described in the previous paragraph starting from the more polar diastereomer product from step C. Purification by chromatography (silica gel, 5% MeOH in dichloromethane) resulted in Example 2 as a white solid.

Example 3 and Example 4

(2S, 4R)-1-[5-Chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2,4-dimethoxypyrimidin-5-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxypyrrolidine-2-carboxylic acid dimethylamide

A) 5-Chloro-3-(2,4-dimethoxypyrimidin-5-yl)-3-hydroxy-1,3-dihydroindol-2-one

A 1.6 M solution of n-butyllithium in hexane (10 ml, 16 mmol) was added dropwise to a solution of 5-bromo-2,4-dimethoxypyrimidine (3.29 g, 15 mmol) in THF (50 ml) at −78° C. After stirring at −78° C. for 0.5 h, a suspension of 5-chloroisatin (1.27 g, 7.0 mmol) in THF (50 ml) was added dropwise. The reaction mixture was allowed to warm to room temperature and then saturated ammonium chloride solution was added. The mixture was extracted three times with ethyl acetate, and the combined organic layers were washed with saturated brine. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification by chromatography (silica gel, 50% ethyl acetate in dichloromethane) resulted in 0.97 g of the product.

B) 3,5-Dichloro-3-(2,4-dimethoxypyrimidin-5-yl)-1,3-dihydroindol-2-one

Pyridine (0.28 ml) and thionyl chloride (0.18 ml) were added successively to an ice-cold solution of the product from step A (0.64 g, 2.0 mmol) in dichloromethane (20 ml). The reaction mixture was stirred at 0° C. for 1 h and then saturated ammonium chloride solution was added. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was rapidly employed without further purification in the next step.

C) (2S, 4R)-1-[5-Chloro-3-(2,4-dimethoxypyrimidin-5-y)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxypyrrolidine-2-carboxylic acid dimethylamide

(2S, 4R)-4-Hydroxypyrrolidine-2-carboxylic acid dimethylamide hydrochloride (0.39 g, 2.0 mmol) was added to a solution of the product from step B in a mixture of dichloromethane (4 ml), THF (1 ml) and DIPEA (1 ml). The reaction mixture was stirred at room temperature for 18 h. After addition of water, the mixture was extracted four times with ethyl acetate. The combined organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification by chromatography (silica gel, 7% MeOH in dichloromethane) resulted in 0.45 g of the mixture of diastereomers (ratio about 2:1).

D) (2S, 4R)-1-[5-Chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2,4-dimethoxypyrimidin-5-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxypyrrolidine-2-carboxylic acid dimethylamide

Sodium hydride (12 mg of 60% dispersion in mineral oil, 0.3 mmol) was added to an ice-cold solution of the mixture of diastereomers from step C (139 mg, 0.30 mmol) in DMF (1.5 ml). The reaction mixture was stirred at 0° C. for 0.5 h and then 2,4-dimethoxyphenylsulfonyl chloride (71 mg, 0.3 mmol) was added. After the reaction mixture had been stirred at room temperature for one hour, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over magnesium sulfate. Purification by chromatography (silica gel, 5% MeOH in dichloromethane) resulted in 63 mg of the less polar diastereomer ((−) isomer) and 25 mg of the more polar diastereomer ((+) isomer) as colorless waxes.

Example 3

(−)-(2S, 4R)-1-[5-Chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2,4-dimethoxypyrimidin-5-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxypyrrolidine-2-carboxylic acid dimethylamide

This diastereomer is the less polar diastereomer from step D.

Example 4

(+)-(2S, 4R)-1-[5-Chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2,4-dimethoxypyrimidin-5-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxypyrrolidine-2-carboxylic acid dimethylamide

This diastereomer is the more polar diastereomer from step D.

Example 5 and Example 6

(2S, 4R)-1-[5-Chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-methoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxypyrrolidine-2-carboxylic acid dimethylamide

A) 5-Chloro-3-(2-methoxypyridin-3-yl)-3-hydroxy-1,3-dihydroindol-2-one

A 1.7 M solution of tert-butyllithium in pentane (28.9 ml, 49.1 mmol) was added to THF (100 ml) at −78° C. 2-Bromomesitylene (3.6 ml, 23.4 mmol) was added dropwise and the mixture stirred at −78° C. for 1 h. 2-Methoxypyridine (1.92 ml, 18 mmol) was added at −78° C. and then the mixture was stirred at 0° C. for 1 h and at ambient temperature for 0.5 h. A suspension of 5-chloroisatin (1.27 g, 9.0 mmol) in THF (50 ml) was added dropwise at −78° C. The reaction mixture was allowed to warm to room temperature and then saturated ammonium chloride solution was added. The mixture was extracted three times with ethyl acetate, and the collected extracts were washed with saturated brine.
The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification by crystallization from dichloromethane yielded 1.1 g of the product.

B) 3,5-Dichloro-3-(2-methoxypyridin-3-yl)-1,3-dihydroindol-2-one

Pyridine (0.33 ml) and thionyl chloride (0.30 ml) were added successively to an ice-cold solution of the product from step A (1.1 g, 3.44 mmol) in dichloromethane (10 ml). The reaction mixture was stirred at 0° C. for 1 h and then saturated ammonium chloride solution was added. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was rapidly employed without further purification in the next step.

C) (2S, 4R)-1-[5-Chloro-3-(2-methoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxypyrrolidine-2-carboxylic acid dimethylamide

(2S, 4R)-4-Hydroxypyrrolidine-2-carboxylic acid dimethylamide hydrochloride (0.67 g, 3.44 mmol) was added to a solution of the product from step B in a mixture of dichloromethane (10 ml), THF (2 ml) and DIPEA (1.6 ml). The reaction mixture was stirred at room temperature for 18 h. After addition of water, the mixture was extracted four times with ethyl acetate. The combined organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification by chromatography (silica gel, 5% MeOH in dichloromethane) resulted in 0.58 g of the more polar diastereomer, 0.2 g of the less polar diastereomer and 0.4 g of a mixture of diastereomers (ratio about 1:1).

Example 5

(−)-(2S, 4R)-1-[5-Chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-methoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxypyrrolidine-2-carboxylic acid dimethylamide

Sodium hydride (14.4 mg of 60% dispersion in mineral oil, 0.36 mmol) was added to an ice-cold solution of the more polar diastereomer product from step C (150 mg, 0.35 mmol) in DMF (3.2 ml). The reaction mixture was stirred at 0° C. for 1 h and then 2,4-dimethoxyphenylsulfonyl chloride (86.2 mg, 0.364 mmol) was added. After the reaction mixture had been stirred at room temperature for one hour, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine and dried over magnesium sulfate. Purification by chromatography (silica gel, 5% MeOH in dichloromethane) and trituration with diethyl ether (6 ml) and hexane (6 ml) resulted in 130 mg of the (−) diastereomer as a white solid.

Example 6

(+)-(2S, 4R)-1-[5-Chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-methoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxypyrrolidine-2-carboxylic acid dimethylamide

The diastereomer product was prepared by the method described in the previous paragraph starting from the less polar diastereomer product from step C. Purification by chromatography (silica gel, 5% MeOH in dichloromethane) and trituration with diethyl ether/hexane resulted in the product as a white solid.
The following compounds can be prepared in analogy to the preparation of examples 1 to 6 employing the synthetic route that is outlined in synthesis scheme 1:

Example 7

(2S, 4R)-1-[5-Chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-methylpyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxypyrrolidine-2-carboxylic acid dimethylamide

Example 8

(2S, 4R)-1-[5-Chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-chloropyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxypyrrolidine-2-carboxylic acid dimethylamide

Example 9

(2S, 4R)-1-[5-Chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(3-methoxypyridin-2-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxypyrrolidine-2-carboxylic acid dimethylamide

Example 10

(2S, 4R)-1-[5-Chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(4-methoxypyridin-3-yl)-2oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxypyrrolidine-2-carboxylic acid dimethylamide

Example 11

(2S, 4R)-1-[5-Chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(4-methylpyridin-3-yl)-2oxo-2,3-dihydro-1H-indol-3-yl]4-hydroxypyrrolidine-2-carboxylic acid dimethylamide

Example 12

(2S, 4R)-1-[5-Chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-pyrazin-2-yl-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxypyrrolidine-2-carboxylic acid dimethylamide

Example 13

(2S, 4R)-1-[5-Chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(3-methoxypyrazin-2-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxypyrrolidine-2-carboxylic acid dimethylamide

Example 14

(2S, 4R)-1-[5-Chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(3,6-dimethoxypyridazin-4-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxypyrrolidine-2-carboxylic acid dimethylamide

Example 15

(2S, 4R)-1-[5-Chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(isoquinolin-4-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxypyrrolidine-2-carboxylic acid dimethylamide

Example 16

(2S, 4R)-1-[5-Chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(quinolin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxypyrrolidine-2-carboxylic acid dimethylamide

EXAMPLE17

(2S, 4R)-1-[5-Chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(thiazol-2-yl)-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxypyrrolidine-2-carboxylic acid dimethylamide

Example 18

(2S, 4R)-1-[5-Chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(1-methyl-1H-benzimidazol-2-yl)-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxypyrrolidine-2-carboxylic acid dimethylamide

Example 19

(2S, 4R)-1-[5-Chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(1-methyl-1H-imidazol-2-yl)-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxypyrrolidine-2-carboxylic acid dimethylamide

Example 20

(2S, 4R)-1-[5-Chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(benzoxazol-2-yl)-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxypyrrolidine-2-carboxylic acid dimethylamide

Example 21

(2S, 4R)-1-[5-Chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(3-methylbenzo[b]thiophen-2-yl)-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxypyrrolidine-2-carboxylic acid dimethylamide

EXAMPLE22

(2S, 4R)-1-[5-Chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(3-methylthiophen-2-yl)-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxypyrrolidine-2-carboxylic acid dimethylamide

Example 23

(2S, 4R)-1-[5-Chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(benzo[b]thiophen-7-yl)-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxypyrrolidine-2-carboxylic acid dimethylamide

Example 24

(2S, 4R)-1-[5-Chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(benzofuran-7-yl)-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxypyrrolidine-2-carboxylic acid dimethylamide

Example 25

(2S, 4R)-1-[5-Chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(benzofuran-2-yl)-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxypyrrolidine-2-carboxylic acid dimethylamide

Example 26

(2S, 4R)-1-[5-Chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(3-methylfuran-2-yl)-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxypyrrolidine-2-carboxylic acid dimethylamide

Example 27

(2S, 4R)-1-[5-Chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-furan-3-yl-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxypyrrolidine-2-carboxylic acid dimethylamide

Example 28

(2S, 4R)-1-[5-Chloro-3-(2-methoxyphenyl)-2-oxo-1-(quinoline-8-sulfonyl)-2,3-dihydro-1H-indol-3-yl]-4-hydroxypyrrolidine-2-carboxylic acid dimethylamide

A) 5-Chloro-3-hydroxy-3-(2-methoxyphenyl)-1,3-dihydroindol-2-one

Magnesium turnings (40 g, 1.65 mol) are introduced into diethyl ether (100 ml) and, while stirring, a solution of 2-bromoanisole (206 ml, 1.65 mol) in diethyl ether (450 ml) is added dropwise. The reaction can be initiated if necessary by adding iodine crystals. During the addition, the reaction mixture should boil gently. After the addition, the mixture was stirred at room temperature for 1 hour. A suspension of 5-chloroisatin (75 g, 0.41 mol) in THF (750 ml) was added to the Grignard solution while cooling slightly (temperature 18-24° C.), and the mixture was stirred at room temperature for 30 min. The reaction mixture was stirred into ammonium chloride solution and extracted several times with ethyl acetate. The combined organic phase was washed four times with water, dried over MgSO₄and concentrated under reduced pressure. The residue was stirred with isopropanol. The resulting precipitate was filtered off with suction, washed with isopropanol and diethyl ether and dried. 106 g of the desired product were obtained.

B) (2S, 4R)-1-[5-Chloro-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxypyrrolidine-2-carboxylic acid dimethylamide

Pyridine (56 ml) and thionyl chloride (38 ml) were successively added dropwise to an ice-cold solution of the product from step A (100 g, 0.345 mol) in dichloromethane (1 000 ml). The reaction mixture was stirred at 0° C. for 30 min and then stirred into ice-water. The organic phase was separated, and the aqueous phase was extracted once more with dichloromethane. The combined organic phase was washed several times with water, dried over MgSO₄and concentrated under reduced pressure. The residue was stirred with hot toluene. The resulting crystals were filtered off with suction in the cold, washed with toluene and pentane and dried. 79 g of the desired 3-chloro intermediate were obtained.
(2S, 4R)-4-Hydroxypyrrolidine-2-carboxylic acid dimethylamide hydrochloride (12.6 g, 65 mmol) was added to a solution of the 3-chloro intermediate (20.0 g, 65 mmol) in dichloromethane (400 ml) and DIPEA (28 ml, 162 mmol). The solution was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane and washed with dilute sodium bicarbonate and several times with water. The organic phase was dried over MgSO₄and concentrated under reduced pressure. The residue was recrystallized from acetone. 6.5 g of the less polar (+)-diastereomer were obtained. The mother liquor was concentrated under reduced pressure. Purification of the residue by chromatography (silica gel, 7% MeOH in dichloromethane) resulted in 1.0 g of the less polar (+)-diastereomer and 17.3 g of the more polar (−)-diastereomer.

C) (−)-(2S,4R)-1-[5-Chloro-3-(2-methoxyphenyl)-2-oxo-1-(quinoline-8-sulfonyl)-2,3-dihydro-1H-indol-3-yl]-4-hydroxypyrrolidine-2-carboxylic acid dimethylamide

Potassium tert-butoxide (38 mg, 0.34 mmol) was added to an ice-cold solution of the more polar (−)-diastereomer product from step B (150 mg, 0.34 mmol) in DMF (3 ml), and the mixture was stirred at 0° C. for 30 min. After addition of 8-quinolinesulfonyl chloride (79 mg, 0.34 mmol), the reaction mixture was left to stir at room temperature for 3 hours. After this, water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer washed with water and saturated brine and dried over magnesium sulfate. Purification by chromatography (silica gel, 7% MeOH in dichloromethane) resulted in 159 mg of the product.
The following products can be prepared in analogy to example 28 using product 28B (more polar diastereomer) as starting material in the sulfonylation reaction:

Example 29

(2S, 4R)-1-[5-Chloro-1-(thiophene-2-sulfonyl)-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxypyrrolidine-2-carboxylic acid dimethylamide

Example 30

(2S, 4R)-1-[5-Chloro-1-(thiophene-3-sulfonyl)-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxypyrrolidine-2-carboxylic acid dimethylamide

Example 31

(2S, 4R)-1-[5-Chloro-1-(5-chlorothiophene-2-sulfonyl)-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxypyrrolidine-2-carboxylic acid dimethylamide

Example 32

(2S, 4R)-1-[5-Chloro-1-(3-bromo-5-chlorothiophene-2-sulfonyl)-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxypyrrolidine-2-carboxylic acid dimethylamide

Example 33

(2S, 4R)-1-[5-Chloro-1-(4-bromo-5-chlorothiophene-2-sulfonyl)-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxypyrrolidine-2-carboxylic acid dimethylamide

Example 34

(2S, 4R)-1-[5-Chloro-1-(5-methylthiophene-2-sulfonyl)-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxypyrrolidine-2-carboxylic acid dimethylamide

Example 35

(2S, 4R)-1-[5-Chloro-1-(4,5-dichlorothiophene-2-sulfonyl)-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxypyrrolidine-2-carboxylic acid dimethylamide

Example 36

(2S, 4R)-1-[5-Chloro-1-(3-methylbenzo[b]thiophene-2-sulfonyl)-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxypyrrolidine-2-carboxylic acid dimethylamide

Example 37

(2S, 4R)-1-[5-Chloro-1-(benzo[b]thiophene-2-sulfonyl)-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxypyrrolidine-2-carboxylic acid dimethylamide

Example 38

(2S, 4R)-1-[5-Chloro-1-(5-chloro-3-methylbenzo[b]thiophene-2-sulfonyl)-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxypyrrolidine-2-carboxylic acid dimethylamide

Example 39

(2S, 4R)-1-[5-Chloro-1-(1-methyl-1H-imidazole-4-sulfonyl)-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxypyrrolidine-2-carboxylic acid dimethylamide

Example 40

(2S, 4R)-1-[5-Chloro-1-(1,2-dimethyl-1H-imidazole-4-sulfonyl)-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxypyrrolidine-2-carboxylic acid dimethylamide

Example 41

(2S, 4R)-1-[5-Chloro-1-(5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonyl)-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxypyrrolidine-2-carboxylic acid dimethylamide

Example 42

(2S, 4R)-1-[5-Chloro-1-(1,3,5-trimethyl-1H-pyrazole-4-sulfonyl)-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxypyrrolidine-2-carboxylic acid dimethylamide

Example 43

(2S, 4R)-1-[5-Chloro-1-(5-methyl-1-phenyl-1H-pyrazole-4-sulfonyl)-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxypyrrolidine-2-carboxylic acid dimethylamide

Example 44

(2S, 4R)-1-[5-Chloro-1-(3,5-dimethylisoxazole-4-sulfonyl)-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxypyrrolidine-2-carboxylic acid dimethylamide

Example 45

(2S, 4R)-1-[5-Chloro-1-(2,4-dimethylthiazole-5-sulfonyl)-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxypyrrolidine-2-carboxylic acid dimethylamide

Example 46

(2S, 4R)-1-[5-Chloro-1-(6-chloroimidazo[2,1-b]thiazole-5-sulfonyl)-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxypyrrolidine-2-carboxylic acid dimethylamide

Example 47

(2S, 4R)-1-[5-Chloro-1-(pyridine-2-sulfonyl)-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxypyrrolidine-2-carboxylic acid dimethylamide

Example 48

(2S, 4R)-1-[5-Chloro-1-(5-bromopyridine-2-sulfonyl)-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxypyrrolidine-2-carboxylic acid dimethylamide

Example 49

(2S, 4R)-1-[5-Chloro-1-(5-trifluoromethylpyridine-2-sulfonyl)-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxypyrrolidine-2-carboxylic acid dimethylamide

Example 50

(2S, 4R)-1-[5-Chloro-1-(5-methoxypyridine-2-sulfonyl)-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxypyrrolidine-2-carboxylic acid dimethylamide

Example 51

(2S, 4R)-1-[5-Chloro-1-(5-methylpyridine-2-sulfonyl)-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxypyrrolidine-2-carboxylic acid dimethylamide

Example 52

(2S, 4R)-1-[5-Chloro-1-(5-chloropyridine-2-sulfonyl)-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxypyrrolidine-2-carboxylic acid dimethylamide

Example 53

(2S, 4R)-1-[5-Chloro-1-(5-bromo-3-methylpyridine-2-sulfonyl)-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-2,3-dihydro-1H-indol-3-yl]-4-hydroxypyrrolidine-2-carboxylic acid dimethylamide

Example 54

(2S, 4R)-1-[5-Chloro-1-(3,5-dimethylpyridine-2-sulfonyl)-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxypyrrolidine-2-carboxylic acid dimethylamide

Example 55

(2S, 4R)-1-[5-Chloro-1-(pyridine-3-sulfonyl)-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxypyrrolidine-2-carboxylic acid dimethylamide

Example 56

(2S, 4R)-1-[5-Chloro-1-(6-morpholino-4-yl-pyridine-3-sulfonyl)-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxypyrrolidine-2-carboxylic acid dimethylamide

Example 57

(2S, 4R)-1-[5-Chloro-1-(6-phenoxypyridine-3-sulfonyl)-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]4-hydroxypyrrolidine-2-carboxylic acid dimethylamide

Example 58

(2S, 4R)-1-[5-Chloro-1-(6-methoxypyridine-3-sulfonyl)-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxypyrrolidine-2-carboxylic acid dimethylamide

Example 59

(2S, 4R)-1-[5-Chloro-1-(5-bromo-6-chloropyridine-3-sulfonyl)-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxypyrrolidine-2-carboxylic acid dimethylamide

Example 60

(2S, 4R)-1-[5-Chloro-1-(4-methyl-3,4-dihydro-2H-benzo[1,4]oxazine-7-sulfonyl)-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxypyrrolidine-2-carboxylic acid dimethylamide

Example 61

(2S, 4R)-1-[5-Chloro-1-(1,2,3,4-tetrahydro-isoquinoline-7-sulfonyl)-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxypyrrolidine-2-carboxylic acid dimethylamide

Example 62

5-Chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-hydroxy-3-(3-methylthiophen-2-yl)-1,3-dihydroindol-2-one

A) 5-Chloro-3-hydroxy-3-(3-methylthiophen-2-yl)-1,3-dihydroindol-2-one

Magnesium turnings (6.8 g, 0.27 mmol) are introduced into diethyl ether (30 ml), and, while stirring, a solution of 2-bromo-3-methylthiophene (50 g, 0.282 mol) in diethyl ether (100 ml) is added dropwise. The reaction can be initiated if necessary by adding iodine crystals. During the addition, the reaction mixture should boil gently. After the addition the mixture was stirred at room temperature for 1 hour. A suspension of 5-chloroisatin (19 g, 0.1 05 mol) in THF (200 ml) was added to the Grignard solution while cooling slightly (temperature 18-24° C.) and the mixture was stirred at room temperature for 30 min. The reaction mixture was stirred into ammonium chloride solution and extracted several times with ethyl acetate. The combined organic phases were washed with saturated brine, dried over MgSO₄and concentrated under reduced pressure. The residue was stirred with diethyl ether. The resulting precipitate was filtered off with suction, washed with diethyl ether and dried. 26 g of the desired product were obtained.

B) 5-Chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-hydroxy-3-(3-methylthiophen-2-yl)-1,3-dihydroindol-2-one

Potassium tert-butoxide (1.21 g, 10.8 mmol) was added to an ice-cold solution of the product from step A (3.00 g, 10.8 mmol) in DMF (30 ml), and the mixture was stirred at 0° C. for 30 min. After addition of 2,4-dimethoxyphenylsulfonyl chloride (2.5 g, 10.8 mmol), the reaction mixture was left to stir at 0° C. for 1 hour. Further addition of 0.2 equivalent each of potassium tert-butoxide and sulfonyl chloride led to no further advance in the reaction according to thin-layer chromatography. The reaction mixture was stirred into dilute potassium carbonate solution, and the resulting precipitate was filtered off. The precipitate was taken up in ethyl acetate, and the extract was washed with saturated brine and dried over MgSO₄. Purification by chromatography (silica gel, gradient 30% to 50% ethyl acetate in heptane) and recrystallization from diethyl ether resulted in 0.96 g of the desired product.

Example 63

5-Chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(3-methylthiophen-2-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl (4-chlorophenyl)carbamate

4-Chlorophenyl isocyanate (32 mg, 0.208 mmol) and DMAP (5 mg) were successively added to a solution of example 62 (100 mg, 0.21 mmol) in toluene (20 ml) and stirred at 90° C. for 30 min. The solvent was removed under reduced pressure, and the residue was taken up in ethyl acetate. The organic phase was washed with dilute citric acid solution and saturated sodium chloride solution, dried over MgSO₄and concentrated under reduced pressure. Recrystallization from methanol resulted in 80 mg of the desired product.

Example 64

5-Chloro-3-hydroxy-3-(2-methoxyphenyl)-1-(quinoline-8-sulfonyl)-1,3-dihydroindol-2-one

Potassium tert-butoxide (0.81 g, 7.25 mmol) was added to an ice-cold solution of product 28A (2.00 g, 6.90 mmol) in DMF (24 ml), and the mixture was stirred at 0° C. for 60 min. After addition of 8-quinolinesulfonyl chloride (1.65 g, 7.25 mmol), the reaction mixture was left to stir at 0° C. for 2 hours and then at room temperature overnight. The reaction mixture was stirred into dilute potassium carbonate solution, and the resulting precipitate was filtered off, washed with water and dried. Purification by chromatography (silica gel, 10% MeOH in dichloromethane) resulted in 1.8 g of the product.

Example 65

5-Chloro-3-(2-methoxyphenyl)-2-oxo-1-(quinoline-8-sulfonyl)-2,3-dihydro-1H-indol-3-yl piperidine-1-carboxylate

A) 5-Chloro-3-(2-methoxyphenyl)-2-oxo-1-(quinoline-8-sulfonyl)-2,3-dihydro-1H-indol-3-yl phenoxy-1-carboxylate

Phenyl chloroformate (0.35 ml, 2.79 mmol) was added dropwise to a solution of example 64 (300 mg, 0.624 mmol) in pyridine (6 ml) while cooling slightly. The reaction mixture was stirred at room temperature overnight. After addition of ice-water, the mixture was extracted with ethyl acetate, and the organic phase was washed several times with dilute citric acid solution and water. The organic phase was dried over magnesium sulfate and concentrated under reduced pressure. The residue was triturated with diethyl ether, and the resulting precipitate was filtered off with suction, washed with diethyl ether and dried. 310 mg of the desired product were obtained.

B) 5-Chloro-3-(2-methoxyphenyl)-2-oxo-1-(quinoline-8-sulfonyl)-2,3-dihydro-1H-indol-3-yl piperidine-1-carboxylate

Piperidine (0.132 ml, 1.33 mmol) was added to a solution of the product from step A (200 mg, 0.33 mmol) in THF (10 ml), and the reaction solution was stirred overnight. 2 M sodium hydroxide solution was added to the reaction mixture, which was then extracted with dichloromethane. The organic phase was washed three times with water and concentrated under reduced pressure. Recrystallization from dichloromethane/diethyl ether resulted in 112 mg of the desired product.
The following products can be prepared in analogy to example 65:

Example 66

5-Chloro-3-(2-methoxyphenyl)-2-oxo-1-(quinoline-8-sulfonyl)-2,3-dihydro-1H-indol-3-yl 4-pyridin-4-ylpiperazine-1-carboxylate

Example 67

5-Chloro-3-(2-methoxyphenyl)-2-oxo-1-(quinoline-8-sulfonyl)-2,3-dihydro-1H-indol-3-yl 3,4,5,6-tetrahydro-2H-[4,4′]bipyridinyl-1-carboxylate

Example 68

5-Chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2,4-dimethoxypyrimidin-5-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4-pyridin-2-ylpiperazine-1-carboxylate

Example 69

5-Chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-methoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4-pyridin-2-ylpiperazine-1-carboxylate

Example 70

5-Chloro-3-(2,4-dimethoxypyrimidin-5-yl)-2-oxo-1-(quinoline-8-sulfonyl)-2,3-dihydro-1H-indol-3-yl 4-pyridin-2-ylpiperazine-1-carboxylate

Example 71

5-Chloro-3-(2,4-dimethoxypyrimidin-5-yl)-2-oxo-1-(quinoline-8-sulfonyl)-2,3-dihydro-1H-indol-3-yl 4-pyridin-4-ylpiperazine-1-carboxylate

Example 72

5-Chloro-3-(2-methoxypyridin-3-yl)-2-oxo-1-(quinoline-8-sulfonyl)-2,3-dihydro-1H-indol-3-yl 4-pyridin-2-ylpiperazine-1-carboxylate

Example 73

5-Chloro-3-(2-methoxypyridin-3-yl)-2-oxo-1-(quinoline-8-sulfonyl)-2,3-dihydro-1H-indol-3yl 4-pyridin-4-ylpiperazine-1-carboxylate

Example 74

5-Chloro-3-(2-methoxypyridin-3-yl)-2-oxo-1-(quinoline-8-sulfonyl)-2,3-dihydro-1H-indol-3-yl 3,4,5,6-tetrahydro-2H-[4,4′]bipyridinyl-1-carboxylate

Example 75

5-Chloro-3-(2-methoxyphenyl)-2-oxo-1-(quinoline-8-sulfonyl)-2,3-dihydro-1H-indol-3-yl 4-(1-methylpiperidin-4-yl)-piperazine-1-carboxylate

Example 76

5-Chloro-3-(2-methoxypyridin-3-yl)-2-oxo-1-phenylsulfonyl-2,3-dihydro-1H-indol-3-yl 4-(1-methylpiperidin-4-yl)-piperazine-1-carboxylate

Additional examples were prepared employing synthetic methods that are outlined in synthetic scheme 3:

Example 77

N-[5-Chloro-3-(2-methoxyphenyl)-2-oxo-1-(quinoline-8-sulfonyl)-2,3-dihydro-1H-indol-3-yl]-acetamide

Example 78

3,4,5,6-Tetrahydro-2H-[1,4′]bipyridinyl4-carboxylic acid [5-Chloro-3-(2-methoxyphenyl)-2-oxo-1-(quinoline-8-sulfonyl)-2,3-dihydro-1H-indol-3-yl]-amide

Example 79

3,4,5,6-Tetrahydro-2H-[1,4′]bipyridinyl-4-carboxylic acid [5-Chloro-3-(2-methoxypyridin-3-yl)-2-oxo-1-(quinoline-8-sulfonyl)-2,3-dihydro-1H-indol-3-yl]-amide

In the following Table 1 characteristic mass-spectroscopic data are shown for selected examples.

TABLE 1


Characteristic mass-spectroscopic data for selected examples
(ESI, positive mode)

	Example #	Molecular ion peak

	1	657
	2	657
	3	662
	4	662
	5	631
	6	631
	9	631
	10	631
	13	632
	28	621
	29	576
	30	576
	31	610
	32	690
	33	690
	35	646
	37	626
	38	674
	39	574
	40	588
	41	622
	42	602
	43	650
	44	589
	45	605
	46	650
	47	571
	48	649
	53	663
	54	599
	55	571
	56	656
	57	663
	59	684
	60	641
	61	625
	62	480
	63	633
	64	481
	65	592
	66	670
	68	711
	70	702
	75	690

The compounds of the invention bind to the vasopressin V1b receptor. In the following Table 2 the binding affinity of selected examples for the vasopressin V1b receptor is shown.

TABLE 2


Binding affinity of selected examples for the vasopressin V1b receptor

		Binding affinity for the
	Example #	vasopressin V1b receptor

	2	+++
	3	+++
	5	+++
	6	++
	28	+++
	31	+++
	48	+++
	56	+++
	59	+
	63	+
	65	++

	+ indicates binding affinity > 500 nM
	++ indicates binding affinity between 50 and 500 nM
	+++ indicates binding affinity < 50 nM

Claims

1. A compound of the formula (I)

in which

A is an aromatic heteromonocyclic, or an aromatic or partially aromatic heterobicyclic ring,

where the heterocycles are 5- or 6-membered rings and comprise up to 4 heteroatoms selected from the group consisting of N, O and S, and up to 2 oxo groups, where not more than one of the heteroatoms is an oxygen atom,

and A may be substituted by radicals R¹¹, R¹²and/or R¹³,

where

R¹¹, R¹²and R¹³are selected independently of one another from the group consisting of chlorine, bromine, iodine, fluorine, CN, CF₃, OCF₃, NO₂, OH, O—C₁-C₄-alkyl, O-phenyl, O—C₁-C₄-alkylen-phenyl, phenyl, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, NH₂, NH(C₁-C₄-alkyl) and N(C₁-C₄-alkyl)₂,

R³and R⁴are selected independently of one another from the group consisting of hydrogen, chlorine, bromine, iodine, fluorine, CN, CF₃, OCF₃, NO₂, OH, O—C₁-C₄-alkyl, O-phenyl, O-C₁-C₄-alkylen-phenyl, phenyl, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, NH₂, NH(C₁-C₄-alkyl) and N(C₁-C₄-alkyl)₂, or

R³and R⁴are connected to give —CH═CH—CH═CH—, —(CH₂)₄— or —(CH₂)₃—,

R⁵is a radical (W)—(X)—(Y)-Z, where

W is selected from the group consisting of C₁-C₄-alkylen, C₂-C₄-alkenylen, C₂-C₄-alkynylen, O, O—(C₁-C₄-alkylen), S, S—(C₁-C₄-alkylen), NR⁵⁴, NR-⁵⁴—(C₁-C₄-alkylen) and a bond,

X is selected from the group consisting of CO, CO—O, SO₂, NR⁵⁴, NR⁵⁴—CO, NR⁵⁴—SO₂, CO—NR⁵⁸and a bond,

Y is C₁-C₆-alkylen, C₂-C₆-alkenylen, C₂-C₆-alkynylen, or a bond,

Z is selected from the group consisting of hydrogen, E, O—R⁵², NR⁵¹R⁵², S—R⁵²,

where

E is an unsaturated, saturated or partially unsaturated mono-, bi- or tricyclic ring having a maximum of 14 carbon atoms and 0 to 5 nitrogen atoms, 0 to 2 oxygen atoms and/or 0 to 2 sulfur atoms, said ring may comprise up to two oxo groups, and may be substituted by radicals R⁵⁵, R⁵⁶, R⁵⁷, and/or up to three radicals R⁵³,

R⁵¹is selected from the group consisting of hydrogen, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, phenyl and C₁-C₄-alkylen-phenyl, where the phenyl ring may be substituted by up to two radicals R⁵³,

R⁵²is selected from the group consisting of hydrogen, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, E and C₁-C₄-alkylen-E,

R⁵³is selected from the group consisting of chlorine, bromine, iodine, fluorine, CN, CF₃, OCF₃, NO₂, OH, O—C₁-C₄-alkyl, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, NH₂, NH(C₁-C₄-alkyl) and N(C₁-C₄-alkyl)₂,

R⁵⁴is selected from the group consisting of hydrogen, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, phenyl and C₁-C₄-alkylen-phenyl, where the phenyl ring may be substituted by up to two radicals R⁵⁹,

R⁵⁵is selected from the group consisting of C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, phenyl, C₁-C₄-alkylen-phenyl, where the ring may be substituted by up to two radicals R⁶⁰, and OH, O—C₁-C₄-alkyl, O-phenyl, O—C₁-C₄-alkylen-phenyl, NH₂, NH(C₁-C₄-alkyl) and N(C₁-C₄-alkyl)₂,

R⁵⁶is a group Q¹-Q²-Q³, where

Q¹is selected from the group consisting of a bond, C₁-C₄-alkylen, C₂-C₄-alkenylen, C₂-C₄-alkynylen, C₁-C₄-alkylen-N(C₁-C₄-alkyl), N(C₁-C₄-alkyl), C₁-C₄-alkylen-NH, NH, N(C₁-C₄-alkyl)-C₁-C₄-alkylen, NH—C,-C₄-alkylen, O, C₁-C₄-alkylen-O, O—C₁-C₄-alkylen, CO—NH, CO—N(C₁-C₄-alkyl), NH—CO, N(C₁-C₄-alkyl)-CO, CO, SO₂, SO, S, O, SO₂—NH, SO₂—N(C₁-C₄-alkyl), NH—SO₂, N(C₁-C₄-alkyl)-SO₂, O—CO—NH, O—CO—N(C₁-C₄-alkyl), NH—CO—O, N(C₁-C₄-alkyl)-CO—O, N(C₁-C₄-alkyl)-CO—N(C₁-C₄-alkyl), NH—CO—N(C₁-C₄-alkyl), N(C₁-C₄-alkyl)-CO—NH, and NH—CO—NH,

Q²is selected from the group consisting of C₁-C₄-alkylen, C₂-C₄-alkenylen, C₂-C₄-alkynylen, and a bond,

Q³is a hydrogen or an unsaturated, saturated or partially unsaturated mono-, bi- or tricyclic ring having a maximum of 14 carbon atoms and 0 to 5 nitrogen atoms, 0 to 2 oxygen atoms and/or 0 to 2 sulfur atoms, which may comprise up to two oxo groups and may be substituted by the radicals R⁶³, R⁶⁴and/or R⁶⁵,

R⁵⁷is selected from the group consisting of C₁-C₆-alkyl, phenyl, C₁-C₄-alkylen-phenyl, COOH, CO—O—C₁-C₄-alkyl, CONH₂, CO—NH—C₁-C₄-alkyl, CO—N(C₁-C₄-alkyl)₂, CO—C₁-C₄-alkyl, CH₂—NH₂, CH₂—NH—C₁-C₄-alkyl and CH₂—N(C₁-C₄-alkyl)₂,

R⁵⁸is selected from the group consisting of hydrogen, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, phenyl and C₁-C₄-alkylen-phenyl, where the phenyl ring may be substituted by up to two radicals R⁶²,

R⁵⁹, R⁶⁰and R⁶²are selected independently of one another from the group consisting of chlorine, bromine, iodine, fluorine, CN, CF₃, OCF₃, NO₂, OH, O—C₁-C₄-alkyl, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, NH₂, NH(C₁-C₄-alkyl) and N(C₁-C₄-alkyl)₂,

R⁶³, R⁶⁴and R⁶⁵are selected independently of one another from the group consisting of chlorine, bromine, iodine, fluorine, CN, CF₃, OCF₃, NO₂, OH, O—C₁-C₄-alkyl, O-phenyl, O—C₁-C₄-alkylen-phenyl, phenyl, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, NH₂, NH(C₁-C₄-alkyl) and N(C₁-C₄-alkyl)₂,

R⁶and R⁷are selected independently of one another from the group consisting of hydrogen, chlorine, bromine, iodine, fluorine, CN, CF₃, OCF₃, NO₂, OH, O—C₁-C₄-alkyl, O-phenyl, O—C₁-C₄-alkylen-phenyl, phenyl, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, NH₂, NH(C₁-C₄-alkyl) and N(C₁-C₄-alkyl)₂,

and their tautomeric forms, enantiomeric and diastereomeric forms, and prodrugs thereof.

2. A compound of the formula (II)

in which

B is selected from the group consisting of thiophene, furan, pyrrole, pyridine, quinoline, tetrahydroquinoline, isoquinoline, tetrahydroisoquinoline, benzothiophene, benzofuran, dihydrobenzofuran, indole, dihydroisoindole,

an aromatic heteromonocyclic and an aromatic or partially aromatic heterobicyclic ring,

where the heterocycles are 5- or 6-membered rings and comprise 2 to 4 heteroatoms selected from the group consisting of N, O and S, and up to 2 oxo groups, and

B may be substituted by the radicals R²¹, R²²and/or R²³,

R²¹, R²²and R²³are selected independently of one another from the group consisting of chlorine, bromine, iodine, fluorine, CN, CF₃, OCF₃, NO₂, OH, O—C₁-C₄-alkyl, O-phenyl, O—C₁-C₄-alkylen-phenyl, phenyl, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, NH₂, NH(C₁-C₄-alkyl) and N(C₁-C₄-alkyl)₂, morpholin-4-yl, pyrrolidin-1-yl, piperidin-1-yl, 4-piperazin-1-yl, 4-(C₁-C₄-alkyl)-piperazin-1-yl,

R³and R⁴are selected independently of one another from the group consisting of hydrogen, chlorine, bromine, iodine, fluorine, CN, CF₃, OCF₃, NO₂, OH, O—C₁-C₄-alkyl, O-phenyl, O—C₁-C₄-alkylen-phenyl, phenyl, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, NH₂, NH(C₁-C₄-alkyl) and N(C₁-C₄-alkyl)₂, or

R⁵is a radical (W)—(X)—(Y)-Z, where

W is selected from the group consisting of C₁-C₄-alkylen, C₂-C₄-alkenylen, C₂-C₄-alkynylen, O, O—(C₁-C₄-alkylen), S, S—(C₁-C₄-alkylen), NR⁵⁴, NR⁵⁴—(C₁-C₄-alkylen) and a bond,

Y is C₁-C₆-alkylen, C₂-C₆-alkenylen, C₂-C₆-alkynylen, or a bond,

where

E is an unsaturated, saturated or partially unsaturated mono-, bi- or tricyclic ring having a maximum of 14 carbon atoms and 0 to 5 nitrogen atoms, 0 to 2 oxygen atoms and/or 0 to 2 sulfur atoms, said ring may comprise up to two oxo groups, and may be substituted by radicals R⁵⁵, R⁵⁶, R⁵⁷and/or up to three radicals R⁵³and,

R⁵⁶is a group Q¹-Q²-Q³, where

Q¹is selected from the group consisting of a bond, C₁-C₄-alkylen, C₂-C₄-alkenylen, C₂-C₄-alkynylen, C₁-C₄-alkylen-N(C₁-C₄-alkyl), N(C₁-C₄-alkyl), C₁-C₄-alkylen-NH, NH, N(C₁-C₄-alkyl)-C₁-C₄-alkylen, NH—C₁-C₄-alkylen, O, C₁-C₄-alkylen-O, O—C₁-C₄-alkylen, CO—NH, CO—N(C₁-C₄-alkyl), NH—CO, N(C₁-C₄-alkyl)-CO, CO, SO₂, SO, S, O, SO₂—NH, SO₂—N(C₁-C₄-alkyl), NH—SO₂, N(C₁-C₄-alkyl)-SO₂, O—CO—NH, O—CO—N(C₁-C₄-alkyl), NH—CO—O, N(C₁-C₄-alkyl)-CO—O, N(C₁-C₄-alkyl)-CO—N(C₁-C₄-alkyl), NH—CO—N(C₁-C₄-alkyl), N(C₁-C₄-alkyl)-CO—NH, and NH—CO—NH,

3. A compound of the formula (III),

in which

D is an aromatic heteromonocyclic, or an aromatic or partially aromatic heterobicyclic ring,

where the heterocycles are 5- or 6-membered rings and comprise up to 4 heteroatoms selected from the group consisting of N, O and S, and up to 2 oxo groups,

and D may be substituted by radicals R²¹, R²²and/or R²³,

G is an aromatic heteromonocyclic, aromatic or partially aromatic heterobicyclic ring,

where the heterocycles are 5- or 6-membered rings and comprise up to 4 heteroatoms selected from the group consisting of N, O and S, and up to 2 oxo groups and

G may be substituted by radicals R⁷¹, R⁷²and/or R⁷³,

R²¹, R²², R²³, R⁷¹, R⁷²and R⁷³are selected independently of one another from the group consisting of chlorine, bromine, iodine, fluorine, CN, CF₃, OCF₃, NO₂, OH, O—C₁-C₄-alkyl, O-phenyl, O—C₁-C₄-alkylen-phenyl, phenyl, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, NH₂, NH(C₁-C₄-alkyl) and N(C₁-C₄-alkyl)₂, morpholin-4-yl, pyrrolidin-1-yl, piperidin-1-yl, 4-piperazin-1-yl, 4-(C₁-C₄-alkyl)-piperazin-1-yl,

R⁵is a radical (W)—(X)—(Y)-Z, where

Y is C₁-C₆-alkylen, C₂-C₆-alkenylen, C₂-C₆-alkynylen, or a bond,

where

E is an unsaturated, saturated or partially unsaturated mono-, bi- or tricyclic ring having a maximum of 14 carbon atoms and 0 to 5 nitrogen atoms, 0 to 2 oxygen atoms and/or 0 to 2 sulfur atoms, which may comprise up to two oxo groups, and E may be substituted by radicals R⁵⁵, R⁵⁶, R⁵⁷and/or up to three radicals R⁵³,

R⁵⁵is a group Q¹-Q²-Q³, where

Q¹is selected from the group consisting of a bond, C₁-C₄-alkylen, C₂-C₄-alkenylen, C₂-C₄-alkynylen, C₁-C₄-alkylen-N(C₁-C₄-alkyl), N(C₁-C₄-alkyl), C₁-C₄-alkylen-NH, NH, N(C₁-C₄-alkyl)-C₁-C₄-alkylen, NH—C, —C₄-alkylen, O, C₁-C₄-alkylen-O, O—C₁-C₄-alkylen, CO—NH, CO—N(C₁-C₄-alkyl), NH—CO, N(C₁-C₄-alkyl)-CO, CO, SO₂, SO, S, O, SO₂—NH, SO₂—N(C₁-C₄-alkyl), NH—SO₂, N(C₁-C₄-alkyl)-SO₂, O—CO—NH, O—CO—N(C₁-C₄-alkyl), NH—CO—O, N(C₁-C₄-alkyl)-CO—O, N(C₁-C₄-alkyl)-CO—N(C₁-C₄-alkyl), NH—CO—N(C₁-C₄-alkyl), N(C₁-C₄-alkyl)-CO—NH, and NH—CO—NH,

R⁵⁷is selected from the group consisting of C₁-C₆-alkyl, phenyl, C₁-C₄-alkylen-phenyl, COOH, CO—O—C₁-C₄-alkyl, CONH₂, CO—NH—C₁-C₄-alkyl, CO—N(C₁-C₄-alkyl)₂, CO—C₁-C₄-alkyl, CH₂—NH₂, CH₂—NH—C₁-C₄-alkyl and CH₂-N(C₁-C₄-alkyl)₂,

R⁶³, R⁵⁴and R⁶⁵are selected independently of one another from the group consisting of chlorine, bromine, iodine, fluorine, CN, CF₃, OCF₃, NO₂, OH, O—C₁-C₄-alkyl, O-phenyl, O—C₁-C₄-alkylen-phenyl, phenyl, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, NH₂, NH(C₁-C₄-alkyl) and N(C₁-C₄-alkyl)₂,

4. A medicament comprising a compound as claimed in claim 1.

5. The use of a compound as claimed in claim 1 for the control and/or prophylaxis of various vasopressin-dependent or oxytocin-dependent diseases.

6. A method for the therapeutic and/or prophylactic treatment of a mammal requiring a treatment by administering a compound as claimed in claim 1 for the treatment of diseases.

7. The use of a compound as claimed in claim 1 for the treatment of depressions and/or bipolar disorders such as, for example, dysthymic disorders, subsyndromal depression, seasonal affected disorders, premenstrual dysphoric disorders and/or psychotic disorders.

8. The use of a compound as claimed in claim 1 for the treatment of anxiety and/or stress-related disorders such as, for example, general anxiety disorders, panic disorders, obsessive-compulsive disorders, post-traumatic disorders, acute stress disorders and/or social phobia.

9. The use of a compound as claimed in claim 1 for the treatment of memory disorders and/or Alzheimer's disease.

10. The use of a compound as claimed in claim 1 for the treatment of psychoses and/or psychotic disorders.

11. The use of a compound as claimed in claim 1 for the treatment of Cushing's syndrome.