HK1100175B

HK1100175B - Substituted oxindol derivatives and medicaments containing the same

Info

Publication number: HK1100175B
Application number: HK07105667.4A
Authority: HK
Inventors: Wilfried Lubisch; Thorsten Oost; Wolfgang Wernet; Liliane Unger; Wilfried Hornberger; Herve Geneste
Original assignee: 艾伯特有限及两合公司
Priority date: 2004-07-13
Filing date: 2005-07-13
Publication date: 2008-04-11

Description

The present invention relates to new Oxindol derivatives and medicinal products containing them for the treatment of diseases.

Vasopressin is an endogenous hormone that has a wide range of effects on organs and tissues. It is thought that the vasopressin system plays a role in various disease states, such as heart failure and hypertension. Three receptors (V1a, V1b, V3 and V2) are currently known, through which vasopressin exerts its many effects.

This notification describes new substituted oxindoles that carry an aryl sulphonyl group in position 1.1-phenyl sulphonyl-1,3-dihydro-2H-indol-2-ones have already been described as ligands of vasopressin receptors. Derivatives derived from the oxindole scaffolding and carrying aryl sulphonyl groups in position 1 have been described in WO 93/15051, WO 95/18105, WO 98/25901, WO 01/55130, WO 01/55134, WO 01/64668 and WO 01/98295. These compounds differ substantially in substitution in position 3.

In particular, WO 93/15051 and WO 98/25901 describe 1-phenylsulfonyl-1,3-dihydro-2H-indol-2-one as a ligand of the vasopressin receptor, where the oxindol scaffold is replaced in the 3 position by two alkyl radicals, which can also be a cycloalkyl radical (spiral linkage).

WO 95/18105 describes 1-phenylsulfonyl-1,3-dihydro-2H-indol-2-one as a ligand of the vasopressin receptors, which have a nitrogen atom at the 3 position.

Other publications, e.g. WO 01/55130, describe compounds that have nitrogen-containing rings (e.g. proline, homoproline, morpholine, tetrahydroisoquinoline, dihydroindol, each with substituents) bound via their nitrogen atom to the 3 position of the oxindol backbone, but which are replaced by phenylsulfonyl or phenyl groups (optionally with substituents) at both the 1 position and the 3 position on the oxindol ring.

WO 03/008407 describes 1-phenylsulfonyl oxindoles in which pyridylpiperazine is bound to oxindol at position 3 via an oxycarbonyl group and analogous functional groups.

The purpose of the present invention is to provide further compounds for the treatment or prophylaxis of various vasopressin-dependent or oxytocin-dependent diseases, which exhibit high and selective activity.

The problem is solved by a compound or compounds of the general formula (I), Other In which is a 6-10-aryl which can be substituted with up to four R4 residues selected independently from the group consisting of hydrogen, chlorine, bromine, iodine, fluorine, (CH2)0-2-C4-alkyl, CF3, OCF3, CONH2, CONH(C1-C4-alkyl), CONC1-C4-alkyl, NHCHO, NHCONH2, N(C0-C4-alkyl, CONH2, N(C0-C4-alkyl, NHCOCH3, NOCH2, (AC0-22) -OH, O-C1-C6-alkyl, (CH2)0-2-O-C1-C4-alkyl, O-C0-alkyl, C4-C4-alkyl, phenyl, C1-C6-alkyl, C2-C6-alkyl, C2-C6-alkyl, R6-C6-alkyl, R6-C6-alkyl, R6-C6-alkyl, R6-C6-alkyl, R6-C8-alkyl, R6-C6-alkyl, R6-C6-alkyl, R6-C8-alkyl, R6-C6-alkyl, R6-C6-C6-alkyl, R6-C8-alkyl, R6-C6-C6-alkyl, R6-C6-C8-alkyl, R6-C6-C6-alkyl, R6-C8-alkyl, R6-C6-C6-C8-alkyl, R6-C6-C8-alkyl, R6-C6-C6-C8, R6-C8-alkyl, R6-C8-alkyl, R6-C8-alkyl, R6-C8-alkyl, R6-C8-alkyl, R6-C6-C8, R6-C8-alkyl, R6-C8-alkyl, R6-C8-alkyl, R6-C8-alkyl, and the rest of the aromatic substituent may be substituted independently from each other and may be substituted with an aromatic groupThe total value of all the materials of Chapter 9 used does not exceed 20% of the ex-works price of the product and is therefore considered as originating in the country of export, provided that the value of all the materials of Chapter 9 used does not exceed 20% of the ex-works price of the product. Other W is C1-C4-alkyl, (C0-C4-alkyl) O- ((C0-C4-alkyl) or (C0-C4-alkyl) NR15- ((C0-C4-alkyl) wherein R15 is hydrogen or C1-C4-alkyl, X is CO, SO2, (C=NH) or (C=N-CN), and Y a residue selected from the group consisting of is where Y may be additionally substituted by R10 and/or R11, and R10 Hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, OH, O-C1-C4-alkyl, O-C0-C4-alkyl-phenylene, NH2, NH ((C1-C4-alkyl) or N ((C1-C4-alkyl)) is obtained by: R11 Hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, OH, O-C1-C4-alkyl, O-C0-C4-alkyl-phenyl, which is a compound with a molecular weight of less than 0,05 g/cm3The 'C' value is the value of the 'C' value of the 'C' value of the 'C' value of the 'C' value of the 'C' value of the 'C' value of the 'C' value of the 'C' value of the 'C' value of the 'C' value of the 'C' value of the 'C' value of the 'C' value of the 'C' value of the 'C' value of the 'C' value of the 'C' value of the 'C' value of the 'C' value of the 'C' value of the 'C' value of the 'C' value of the 'C' value of the 'C' value of the 'C' value of the 'C' value of the 'C' value of the 'C' value of the 'C' value of the 'C' value of the 'C' value of the 'C' value of the 'C' value of the 'C' value of the 'C' value of the 'C' value of the 'C' value of the 'C' value of the 'C' value of the 'C' value of the 'C' value of the 'C' value of the 'C' value of the 'C' value of the 'C' value of the 'C' value of the 'C' value of the 'C' value of the 'C' value of the 'C' value of the 'C' value of the 'C' value of the 'C' value of the 'C' value of the 'C' value of the 'C' value of the 'C' value of the 'C' value of the 'C' value of the 'C' value of the 'C' value of the 'C' value of the 'C' value of the 'C' value of the 'C' value of the 'C' value of the 'C' value of the 'C' value of the 'C' value of the 'C' value of the 'C' of the 'C' value of the 'C' value of the 'C' value of the 'C' value of the 'C' value of the 'C' value of the 'C' of the 'C' value of the 'C' value of the 'C' value of the 'C' of the 'C' value of the 'C' value of Z a remainder selected from the group consisting of is and Z may be additionally replaced by R12 and/or R13 wherein R12 Hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, OH, O-C1-C4-alkyl, O-C0-C4-alkyl-phenylene, NH2, NH ((C1-C4-alkyl) or N ((C1-C4-alkyl)) is obtained by: R13 Hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, OH, O ((C1-C4-alkyl), O-C0-C4-alkylene-phenyl, NH2, NH ((C1-C4-alkyl) or N ((C1-C4-alkyl)) is obtained by: R14 is hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl or C0-C4-alkylene-phenyl, and their tautomeric, enantiomeric and/or diastereomeric forms, and the physiologically compatible salts of the above compound or compounds.

In a preferred embodiment, in the compounds of general formula (I) A, a phenyl ring may be substituted with up to four residues of R4 and B a phenyl ring may be substituted with the residues of R6, R7, R8 and/or R9.

Furthermore, a compound or compounds of general formula (I) are preferred, in which: A phenyl ring is one that can be substituted with a maximum of two R4 residues, independently selected from the group consisting of hydrogen, chlorine, O-C1-C4-alkyl, (CH2)0-2-O-(CH2)0-2-CH3 and C1-C6-alkyl,Bene is a phenyl ring that can be substituted with the residues R6, R7, R8 and/or R9, wherein R6, R7, R8 and R9 are independently selected from the group consisting of hydrogen, fluorine, chlorine, O-C1-C4-alkyl, (CH2)0-2-O-(CH2)0-2-CH3 and C1-C6-alkyl, wherein OH1 is hydrogen, OH, F, Cl, C1-4-alkyl, O-C1-4-alkyl, O-C1-4-alkyl, (RY2 is hydrogen, (RY2 is oxygen, (RY3) is oxygen, (RY2 is oxygen, (RY3) is oxygen) Other O, CH2NH, W NHCH2, OCH2, CH2O or NH is X is CO, Y a residue selected from the group consisting of Other Is that Z a remainder selected from the group consisting of is where Z may be additionally substituted by R12 and/or R13 where Other R12 is hydrogen or C1-C4-alkyl, R13 is hydrogen or C1-C4-alkyl and R14 is hydrogen, C1-C4-alkyl, C2-C4-alkenyl or C2-C4-alkynyl.

In particular, a compound or compounds of general formula (I) are preferred, in which: Aein is a phenyl ring which can be substituted with a maximum of two residues R4 selected independently from the group consisting of hydrogen, chlorine, O-C1-C4-alkyl, (CH2)0-2-O-(CH2)0-2-CH3 and C1-C6-alkyl,Bene is a phenyl ring which can be substituted with the residues R6 and/or R7, wherein R6 and R7 are independently selected from the group consisting of hydrogen, fluorine, chlorine, O-C1-C4-alkyl and C1-C6-alkyl,R1Hydrogen, F, Cl, CH3, CH2, CH2, CH3, OCH3 or OCH2CH3, wherein CN is a hydrogen, R2H3 (X-W) ((Y-Z) residual, Other W O, CH2 or NH is X is CO, Y a remainder selected from the group Other The and Z a remainder selected from the group Other is where Z may be substituted by R12 and/or R13 where R12 is hydrogen or C1-C4-alkyl, R13 is hydrogen or C1-C4-alkyl and R14 is hydrogen, C1-C4-alkyl, C2-C4-alkenyl or C2-C4-alkynyl.

The general formula (I) compounds, in which the Aein is a phenyl ring which can be substituted with a maximum of two R4 residues, independently selected from the group consisting of hydrogen, chlorine, O-C1-C4-alkyl, (CH2)0-2-O-(CH2)0-2-CH3 and C1-C6-alkyl,Bene is a phenyl ring which can be substituted with the residues R6 and/or R7, wherein R6 and R7 are independently selected from the group consisting of hydrogen, fluorine, chlorine, O-C1-C4-alkyl and C1-C6alkyl,R1Cl, CH3, CN, CH2CH3 or OCH3R2 is a residue, wherein R3 is a (W) -R-X-Y-Z, Other W is CH2, O or NH, X is CO, Y a remainder Other is Z a remainder Other wherein R14 is hydrogen, C1-C4-alkyl, C2-C4-alkenyl or C2-C4-alkynyl.

In addition, a compound or compounds of general formula (I) are particularly preferred, in which: Aein is a phenyl ring which can be substituted with a maximum of two residues R4 selected independently from the group consisting of hydrogen, chlorine, O-C1-C4-alkyl and C1-C4-alkyl,Aine is a phenyl ring substituted with the residues R6 and/or R7, wherein R6 and R7 are independently selected from the group consisting of hydrogen, fluorine, chlorine, O-C1-C4-alkyl and C1-C6-alkyl,R1 is hydrogen, Cl, CH3, CN, CH2CH3, OCH3 or OCH2CH3,R2 is hydrogen,R3 is a residue (W) -X-Y-Z, Other W is CH2, O or NH, X is CO, Y a remainder Other is, and Z a remainder Other is wherein R14 is hydrogen, C1-C4-alkyl, C2-C4-alkenyl or C2-C4-alkynyl.

Err1:Expecting ',' delimiter: line 1 column 56 (char 55)

The variables which characterize the compounds of the invention of formula (I) have the following preferred meanings independently of each other.

A is preferably a phenyl ring that can be substituted with up to four R4 residues, or even more preferably a phenyl ring that can be substituted with up to two R4 residues.

In another embodiment, A is replaced by a substituent. When A is replaced, the substituents R4 are independently selected from the group consisting of hydrogen, chlorine, bromine, iodine, fluorine, (CH2)0-2-CN, CF3, OCF3, CONH2, CONH(C1-C4-alkyl), CONC1-C4-alkyl), NHCHO, NHCONH2, N(C0-C4-alkyl) CONH2, N(C0-C4-alkyl) CONC1-C4-alkyl), NHCO3, 2-CH2, (CH2) 2-OH, NO-C1-C6-alkyl, (CH2) 2-O-C1-C4-alkyl, O-C4-alkyl, O-C4-alkyl, CH4-Cyl, another substituent present in the C1-C4-alkyl, C1-C4-C1-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C

B is preferably a phenyl ring that can be substituted with the residues R6, R7, R8 and/or R9. Preferably, B is substituted with none, one, two, three or four identical or different residues selected from R6, R7, R8 and R9. Even more preferably, B is a phenyl ring that can be substituted with the residues R6 and/or R7. In one embodiment, B is substituted phenyl. In another embodiment, B is substituted with a substituent R6. When B is substituted, the substitutes R6, R7, R8 and/or R9 are independently selected from the group consisting of hydrogen, bromine, fluorine, iodine, CHF (CNF-CF), OCF-CF, OCF-FC, OCF-FC, OCF-FC, OCF-FC, OCF-FC, OCF-FC, OCF-FC, OCF-FC, OCF-FC, OCF-FC, OCF-FC, OCF-FC, OCF-FC, OCF-FC, OCF-FC, OCF-FC, OCF-FC, OCF-FC, OCF-FC, OCF-FC, OCF-FC, OCF-FC, OCF-FC, OCF-FC, OCF-FC, OCF-FC, OCF-FC, OCF-FC, OCF-FC, OCF-FC, OCF-FC, OCF-FC, OCF-FC, OCF-FC, OCF, OCF-FC, OCF, OCF-FC, OCF, OCF-FC, OCF, OCF, OCF-FC, OCF, OCF, OCF, OCF, OCF, OCF, OCF, OCF, OCF, OCF, OCF, OCF, OCF, etc.CONH2, CONH ((C1-C4-alkyl), CON ((C1-C4-alkyl), NHCHO, N ((C1-C4-alkyl), CON ((C1-C4-alkyl), NHCOCH3, NO2, OH, O-C1-C4-alkyl, (CH2)0-2-O-(CH2)0-3-CH3, O-C0-C4-alkyl, phenyl, phenyl, C1-C6-alkyl, C2-C6-alkyl and C2-C6-alkyl, preferably hydrogen, fluorine, chlorine, O-C1-C4-alkyl, (CH2)0-2-O-CH2) phen0-2-CH3 and C1-C6-alkyl, preferably hydrogen, or fluorine, are substitutes, O-C4-alkyl and C1-C6-C6-alkyl. If the substituent is in one, two, four or four substituents, or in two, four or five substituents, the two, four or five substituents are preferable, and the substituents are two, four or five, four or five, four or five, two or four, four or five substituents, and two or four substituents are preferable. R1 is preferably hydrogen, CN, F, Cl, C1-4 alkyl or O- ((C1-4 alkyl),R1 is preferably in the 4-, 5- or 6-position, even more preferably in the 4- or 5-position, most preferably in the 5-position.

R2 is preferably hydrogen.

R3 is a remainder (W) - ((X) - ((Y) -Z, where preferred definitions of R3 are derived from the definitions of W, X, Y and Z, where at least one of the definitions of W, X, Y and Z is any preferred embodiment, as explained below. Preferably, all definitions of W, X, Y and Z are any preferred embodiment. Most preferred is R3 a remainder (W) - ((X) - ((Y) -Z, where all definitions of W, X, Y and Z are the most preferred embodiment.

W is preferably O, (C1-C4-alkyl) NH, NH ((C1-C4-alkyl), O ((C1-C4-alkyl), (C1-C4-alkyl) O or NH, still preferably O, CH2NH, NHCH2, OCH2, CH2O or NH, most preferably CH2, O or NH.

X is preferably CO or SO2, most preferably CO. Y is preferably Other and most preferred Other

R10 is preferably hydrogen or C1-C4 alkyl, where the alkyl group may be in the 2-, 3-, 5- or 6-position, preferably hydrogen or a C1-C4 alkyl group in the 2-position, and particularly preferably hydrogen.

R11 is preferably hydrogen or C1-C4 alkyl, where the alkyl group may be in the 2-, 3-, 5- or 6-position, preferably hydrogen or a C1-C4 alkyl group in the 2-position, and particularly preferably hydrogen.

Z is preferably Other

Even more preferred is Z

In one embodiment, Z is Other

In another embodiment, Z is Other

R12 is preferably hydrogen or C1-C4 alkyl, where the alkyl group may be in the 2-, 3-, 4- or 6-position, preferably hydrogen or a C1-C4 alkyl group in the 2-position, and particularly preferably hydrogen.

R13 is preferably hydrogen or C1-C4 alkyl, where the alkyl group may be in the 2-, 3-, 4- or 6-position, preferably hydrogen or a C1-C4 alkyl group in the 2-position, and particularly preferably hydrogen.

R14 is preferably hydrogen, C1-C4-alkyl, C2-C4-alkenyl or C2-C4-alkynyl, still hydrogen, CH3, CH2CH3, CH2CH2CH3 or CH(CH3) 2 is preferred, most preferably CH3.

R15 is preferably hydrogen or C1-C4-alkyl, preferably hydrogen, CH3, CH2CH3 or CH2CH2CH3, most preferably hydrogen or CH3.

This results in the following particularly favourable groups for R3: Other

Each of these preferred definitions of a variable may be combined with any definitions of the remaining variables.

Err1:CUDA out of memory. Tried to allocate 20.70 GiB (GPU 0; 79.35 GiB total capacity; 27.67 GiB already allocated; 7.44 GiB free; 34.00 GiB reserved in total by PyTorch) If reserved memory is >> allocated memory try setting max_split_size_mb to avoid fragmentation. See documentation for Memory Management and PYTORCH_CUDA_ALLOC_CONF

their tautomeric, enantiomeric and/or diastereomeric forms, and non-saline forms and other physiologically compatible salts of the compound or compounds of the invention.

The compound or compounds of the invention may be present as racemate or as enantiomeric or diastereomeric compounds, preferably as enantiomeric or diastereomeric compounds.

Err1:Expecting ',' delimiter: line 1 column 437 (char 436)

Err1:Expecting ',' delimiter: line 1 column 104 (char 103)

For the purposes of this description, a C1-C4 alkyl is preferably a methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl or t-butyl.

C0-alkyl or (CH2) 0 means a single bond within the meaning of the description.

C1-C4-alkylenes are methylene, ethylene or branched or unbranched propylene or butylene as defined in the specification.

C1-C6-alkyl is, within the meaning of the description, methyl, ethyl or branched or unbranched propyl, butyl, pentyl or hexyl, preferably C1-C4-alkyl, i.e. methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl or t-butyl.

C1-C6-alkylene is, for the purposes of the description, methylene, ethylene or branched or unbranched propylene, butylene, pentylene or hexylene, preferably C1-C4-alkylene, i.e. methylene, ethylene or branched or unbranched propylene or butylene.

The symbol in the chemical formulas of Y and Z indicates the junction points of Y with X and Z and the junction points of Z with Y. In the formulas of Y, each junction point can represent a bond to X or Z.

The compounds of the invention are effective after administration by various routes, in particular oral.

The compounds of the invention show good affinity for, for example, vasopressin receptors of the vasopressin receptor subtypes V1a and V1b. Since the different vasopressin receptors transmit very different effects of vasopressin (M. Thibonnier, Exp. Op. Invest Drugs 1998, 7(5), 729-740; Serradeil-Le Gal, C, et al.; Brain. 2002; 139:197-210), it is of particular importance to obtain effects selectively on, for example, a progression receptor in order to achieve the desired effects without causing significant side effects at the same time. Thus, vasopressin, for example, transmits very different effects on the vasopressin receptors V2, its lower function and its potential for selective treatment of the CNS. Evidence has been obtained that this effect is also very important for improving the selectivity of the vasopressin receptor V1 and, therefore, the specificity of the vasopressin receptor V2 in relation to other receptors.

The present invention also provides for the use of the compounds of the invention to manufacture a medicinal product for the treatment and/or prophylaxis of diseases in which the course of the disease is at least partially dependent on vasopressin, i.e. diseases which show an elevated level of vasopressin or oxytocin which may contribute, indirectly or not, to the disease picture.

The present invention also provides for the use of the compounds of the invention in the manufacture of a medicinal product for the treatment and/or prophylaxis of diseases such as diabetes insipidus, nocturnal enuresis, incontinence, diseases involving blood clotting disorders and/or for the delay of urination.

The present invention also provides for the use of the compounds of the invention in the preparation of a medicinal product for the treatment and/or prophylaxis of the following diseases: hypertension, pulmonary hypertension, heart failure, myocardial infarction, coronary spasm, unstable angina, percutaneous transluminal coronary angioplasty (PTCA), ischaemia of the heart, disorders of the renal system, edema, renal vasospasm, renal cortex necrosis, hyponatremia, hypokalaemia, Schwartz-Bartter syndrome, gastrointestinal disorders, gastritis vasospasm, hepatocirrhosis, stomach and intestinal mucus, eczema, emergent chemotherapy, and on-going necropathy.

The compounds of the invention may also be used to manufacture a medicinal product for the treatment of various vasopressin-dependent or oxytocin-dependent disorders having central venous causes or changes in the hypothalamic pituitary adrenal axis (HPA axis), for example in affective disorders such as depressive disorders and bipolar disorders, including dythymic disorders, phobias, post-traumatic stress disorders, generalized anxiety disorders, panic disorders, seasonal depression and sleep disorders.

The compounds of the invention may also be used to manufacture a medicinal product for the treatment of anxiety disorders and stress-related anxiety disorders, such as generalized anxiety disorders, phobias, post-traumatic anxiety disorders, panic disorders, obsessive-compulsive anxiety disorders, acute stress-related anxiety disorders and social phobia, and may also be used for the treatment of memory disorders, Alzheimer's disease, psychosis, psychotic disorders, sleep disorders and/or Cushing's syndrome.

The present invention also relates to pharmaceutical formulations containing an effective dose of a compound of the invention or a pharmaceutically compatible salt thereof and suitable drug carriers.

These medicinal products are selected according to the pharmaceutical form and the desired application.

The compounds of the invention of generic formula I or, where appropriate, suitable salts thereof, may be used to manufacture pharmaceutical formulations for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, intratracheal, intranasal, transdermal or rectal administration and may be administered to animals or humans in uniform dosage forms, mixed with conventional pharmaceutical media, for the prophylaxis or treatment of the above disorders or diseases.

The appropriate unit dosage forms include oral dosage forms such as tablets, gelatine capsules, powder, granules and oral solutions or suspensions, sublingual, buccal, intratracheal or intranasal dosage forms, aerosols, implants, subcutaneous, intramuscular or intravenous dosage forms and rectal dosage forms.

For topical application, the compounds of the invention may be used in creams, ointments or lotions.

To achieve the desired prophylactic or therapeutic effect, the dose of the active ingredient may vary from 0.01 to 50 mg per kg body weight per day.

Each unit dose may contain 0.05 to 5000 mg, preferably 1 to 1000 mg, of the active substance in combination with a pharmaceutical carrier, which may be administered 1 to 5 times a day, resulting in a daily dose of 0.5 to 25000 mg, preferably 1 to 5000 mg.

If a solid formulation is prepared in the form of tablets, the main ingredient is mixed with a pharmaceutical carrier such as gelatine, starch, lactose, magnesium stearate, talc, silicon dioxide or similar.

The tablets may be coated with sucrose, a cellulose derivative or another suitable substance or otherwise treated to produce sustained or delayed activity and to release a predetermined amount of the active substance continuously.

A gelatine capsule preparation is obtained by mixing the active ingredient with a stretch agent and incorporating the resulting mixture into soft or hard gelatine capsules.

A preparation in the form of a syrup or elixir or for administration in the form of drops may contain active ingredients together with a sweetener, preferably calorie-free, methyl or propyl parabens as antiseptics, a flavouring and an appropriate colouring.

The water-dispersed powder or granules may contain the active ingredients mixed with dispersants, wetting agents or suspensions such as polyvinylpyrrolidone, as well as sweeteners or flavour enhancers.

Rectal administration is achieved by the use of suppositories prepared with binders that melt at rectal temperature, for example cocoa butter or polyethylene glycol. Parenteral administration is achieved by the use of aqueous suspensions, isotonic saline solutions or sterile and injectable solutions containing pharmacologically compatible dispersants and/ or moisturizers, for example propylene glycol or polyethylene glycol.

The active substance may also be formulated as microcapsules or centrosomes, if appropriate with one or more carriers or additives.

In addition to the compounds of the general formula (I) or their pharmaceutically compatible salts, the compositions of the invention may contain other basic active ingredients which may be useful in the treatment of the disorders or diseases mentioned above.

The present invention thus continues to apply to pharmaceutical formulations in which several basic active ingredients are present together, at least one of which is a compound of the invention.

The compounds of the invention are antagonists of the so-called receptors of the vasopressinOxytocin family. Such compounds can be tested in appropriate tests to determine affinity for a receptor, with the affinity constant Ki being a measure of the binding power at the compound receptor and a lower value representing a greater power. For example, the compounds of the invention have been tested for their receptor affinity in the following vasopressin receptor subtype V1b receptor for their affinity.

Vasopressin V1a receptor binding assay

The substances were dissolved in DMSO at a concentration of 10-2 M and further diluted in DMSO at 10-3 M to 10-9 M. These DMSO solutions were diluted with test buffer 1:10 and the substance concentration was again diluted 1:10 in the test approach.

The binding test was performed using the method of Tahara et al. (Tahara A et al., Brit. J. Pharmacol. 125, 1463-1470 (1998)). In the test approach (0.250 ml), membranes (50 ug protein in an incubation buffer (50 mM Tris, 10 mM MgCl2, 0.1% BSA adjusted to pH 7.4 with HCl) were incubated with 0.04 nMJod-AVP (NEX128) in an incubation buffer (total B) or with additional increasing concentrations of 125 (experimental) unsaturated substances. The incubation test was performed with 10 MP-6 tri-fold.

After incubation, 60 minutes at room temperature, the free radio-ligand was filtered by vacuum filtration (Skatron cell harvester 7000) using Wathman GF/B fibre filter mats and transferred to spark-ion vessels.

The liquid sintering measurement was carried out in a Tricarb model 2000 or 2200CA (Packard) apparatus and the cpm measured was converted into dpm using a standard key series.

The binding parameters were calculated by nonlinear regression in SAS. The algorithms of the program work in a similar way to the LIGAND evaluation program (Munson PJ and Rodbard D, Analytical Biochem. 107, 220-239 (1980)).

For the examples of the invention, the above test measured affinities for the human vasopressin receptor V1b and determined affinity constants, with examples 1, 3, 4, 5, 8 and 13 showing Ki values below 100 nM.

Vasopressin V1b receptor binding test:

The substances were dissolved in DMSO at a concentration of 10-2 M and further diluted in DMSO at 10-3 M to 10-9 M. These DMSO solutions were diluted with test buffer 1:10 and the substance concentration was further diluted 1:10 in the test approach.

The binding test was performed using the method of Tahara et al. (Tahara A et al., Brit. J. Pharmacol. 125, 1463-1470 (1998)), in which membranes (58 μ g protein in incubation buffer) of CHO-K1 cells with stable human V1b receptor expression (preparation V1b-3H2, with protease inhibitors, Roche complete Mini # 1836170) were adjusted to 1.5 nM 3H-P (8-Arg-Vasopressin, NETAV 800) in incubation buffer (50 mM Tris, 10 mM MgCl2, 0.1% BSA at pH 7.4 with HCl) (total binding) or with additional concentrations of unconcentrated (sub-experimental incubation) V1b-3H1 cells with 1.5 nM 3H-P (8-Arg-Vasopressin, NETAV 800) in incubation buffer (50 mM Tris, 10 mM MgCl2, 0.1% BSA at pH 7.4) (total binding) or with additional concentrations of unconcentrated (sub-sub-experimental incubation) AVP.

Incubation buffer 50 mM Tris, 10 mM MgCl2, 0.1% BSA adjusted to pH 7.4 with HCl.

After incubation, 60 minutes at room temperature, the free radio-ligand was filtered by vacuum filtration (Skatron cell harvester 7000) using Wathman GF/B fibre filter mats and the filters were transferred to scintillation vessels.

For the examples of the invention, the above test measured affinities for the human vasopressin receptor V1b and determined affinity constants, with examples 2, 6, 10, 16, 17, 23, 24, 26 and 30 showing Ki values below 100 nM.

Effect on vasopressin-induced calcium elevation in cells carrying a cloned human vasopressin receptor

The functional activity of the test substances was studied in CHO-K1 cells that were stably transfected with human V1b receptor. 50,000 cells were sown per 96-penetration microtiter plate and incubated overnight at 37°C in saturated water vapour atmosphere with 5% CO2 in culture medium. The culture medium consisted of DMEM/ Nut Mix F12 with Glutamax I (Fa. invitrogen), 10% calf serum, 100 units/ml penicillin, 100 μg/ml streptomycin and 800 μg/ml genet FL. The cells were washed with culture medium and treated with a fluorescent dye for fluorescent concentrations as specified by the manufacturer (ICLEC Plus/LIC+/V) and the resulting concentration was calculated by using a molecular concentration of 10−50 ± 5 mg/L (Mg/L) in a test chamber with a maximum concentration of 10−50 mg/L (Mg/L) and a concentration of 10−50 mg/L (Mg/L) in the test medium. The cells were then loaded with a fluorescent dye for fluorescent concentrations as specified by the manufacturer (ICLIC+/V).

The following are examples of synthesis pathways for the production of the compounds of the invention.

The production of the oxindoles of the invention can be carried out by various means and is outlined in the synthesis schemes 1 to 4, where the variables have the same meanings as in the general formula (I). Other

The metalized compounds can be obtained from halogen or hydrocarbon compounds. Examples of regulations are contained in Houben-Weiel, Methods for Organic Chemistry, Vol. 13, 1-2, chap. Mg and Li compounds respectively. Isatine IIs are either commercially available or have been produced by analogy to methods described in the literature (Advances in Heterocyclic Chemistry, 1975, J.R. Katz and A.J. Boultzky, New York, Academic Press, J. 12, J. 18, 1975; J. 12, J. 27, 1973).

Alternatively, alcohols III can be obtained by transfer to the mesylate by means of methanoponyl chloride in the presence of a base such as triethylamine. The compounds IV are then converted to amines NH2R15 whereby the analogues are amine Q. For example, the intermediate product IV can be obtained by substitution with analogues of the base in a corresponding way, such as amine N-diethylamine. Alternatively, alcohols III can be obtained by transfer to the mesylate by means of methanoponyl chloride in the presence of a base such as triethylamine.

For the preparation of the compounds XIII, the oxindoles IIIa are first converted to sulphonic acid chlorides XI under the conditions described above. The sulphonic acid chlorides used can be either purchased or produced by analogy to known processes (see, e.g., J. Med. Chem. 40, 1149 (1997)). The compounds XIII are produced by various methods, starting from the sulphonylated compounds XII: (i) transformation with carbamochloridation Z-Y-CO-CI in the presence of a base such as triethenylamine; (ii) activated acids with chloride iron ester in the presence of a base such as pyridine and subsequent transformation with Z-Y-H, as appropriate, can be obtained either at a known temperature or at a known temperature.

The compounds XXII of the invention, which contain a functionalised nitrogen atom in the 3-position (e.g. amides, sulfonamides, carbamates and urea), are produced by the same method as in Scheme 2: 3-amino-oxindoles XII (Q = NR15) are converted by means of reagents for the derivation of amino groups, such as carbon acids, carbon chlorides, carbon hydrides, sulfonic acid, chlorine formate, isocyanates or carbamyl chlorides, and the compounds of the invention are converted by means of substitution, generally using the usual methods (see J. March, Advanced Organic Chemistry, 4th edition, 1992, Wiley, p. 9011-421; New York, p. 4917-4219; Amine hydrides, sulfonic acid, chlorine formate, isocyanate, or carbamyl chloride), and can also be converted by means of substitution agents, such as alkyl acids, such as alkyl acids, or alkyl acids, such as in the case of Wiley, New York, p. 8911-421; or Amine hydrides, such as in the case of Alkyloid, or alkyloid, in the case of NH, or alkyloid, in the case of alkylo, in the case of alkylo, in the case of alkylo, in the case of alkylo.

Alternatively, the components XII can be produced using the two-stage process shown in Synthesis Scheme 3. Other

Sulphonylated isatines XV are obtained by deprotonation of isatines II with a strong base such as sodium hydride or potassium tert-butanolate and then treatment with sulphonic acid chlorides XI. The Xlla compounds are obtained in the second step by addition of metallic compounds I to the 3-ketogroups of sulphonyl isatine XV. The requirements are similar to the above methods.

The reaction can be carried out, for example, in polar solvents such as DMF or THF, with the addition of basic substances, for example NaH, potassium ter-butanolate, sodium tethanolate, trialkylamines or potassium carbonate, at room temperature or at elevated temperatures, such as the sedimentation temperature of the solvent. The analogous reaction of XXIII-indolololone to XXIV-alcohol can be carried out either by reduction of the alcohols of group XXIII-III, or by reduction of the alcohols of group XXIII-indolone to XXIII-alcohol.For example, it can be synthesised with triethyl silane or analogue Mullock, E.B. et al., J.Chem.Soc. C, 1970, 6, 829-833, Ghosal, S. et al., Ind. J.Chem., 1969m 7, 1095-1097 and US 2,759,935. The esters XXIV can be converted with acids such as HCl and H2SO4 or bases such as NaOH, KOH or LiOH into the analogue carbon acids XXV, usually in solvents such as alcohols or THF, with the addition of aqueous acids or bases at room temperature or at temperatures of 25 to 70 °C. These acids XXV can be converted into the derivatives XXVI by converting them, for example, with copper salts under normal conditions of use, such as in Amp R.The introduction of the sulphonic acid residue B-SO2 is carried out in an analogous manner as described above.

The experimental part Example 1 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.] 1a) 5-Chlor-3-hydroxy-3- ((2-methoxyphenyl) indole-2-one

40 g (1.65 mol) magnesium chips were coated with 100 ml of ether, and after adding a little iodine, they were carefully heated until the reaction started. 203 ml (1.65 mol) bromanizol, dissolved in 450 ml of ether, was slowly added to the boiling solution, so that the reaction was carried out under light boiling continuously. Then, under light cooling at 20 °C, 75 g (0.41 mol) 5-chlorosatin was added to 750 ml of anhydrous tetrahydrofuran. Then everything was stirred for another 30 minutes at room temperature.

The following substances are to be classified in the same heading as the active substance:

2 g (18.1 mMol) potassium tert-butanolate was added to 5 g (17.3 mMol) of intermediate 1a in 50 ml anhydrous dimethylformamide and stirred for approximately 60 minutes. Then 3.2 g (18.1 mMol) benzoyl sulphonic acid was rapidly added at 0°C. It was stirred at 0°C for 2 h and then at room temperature for 16 h. The reaction solution was then poured on 250 ml of ice water/K2CO3 solution, precipitating and dissolved in methylene chloride. This organic phase was washed, dried and compacted with NaCl solution. The residual was melted in a vacuum, leaving 2,8 g of the intermediate product crystallised.

The expression 'substances' means substances which are not classified in the same heading as the product.

At 0°C, 4.2 g (26.9 mMol) of chlorophyll phenylacetate was rapidly dripped. It was stirred for another 15 minutes, and then the reaction solution was poured into some 5% potassium carbonate/ice water mixture. The aqueous solution was extracted three times with methyl chloride. The combined organic phases were washed with aqueous potassium carbonate and a naCl solution, dried over MgSO4 and vacuum-dried. The residue was treated with an anthrax, with little oil and oil remaining, and the intermediate product was obtained.

The following substances are to be classified in the same heading as the products of heading 2913:

0.15 g (0.27 mmol) of intermediate 1c and 204 mg (1.1 mmol) 1-methylpiperidine-4-yl) piperazine were stirred in 5 ml of tetrahydrofuran at room temperature for 16 h. The solvent was then removed in a vacuum. The residue was crystallized from 5 ml of methanol to obtain 95 mg of the product. The mean and standard deviation of the mean and standard deviation of the two samples (i.e. the mean and standard deviation) are as follows:

Example 2 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.] The following substances are to be classified in the same heading as the product:

The reaction was carried out by slowly dripping 27,3 g (0.13 mol) 2-propoxy-1-bromobenzene in 100 ml of ether, so that the reaction was continuous under light boiling. Then, under light cooling at 20°C, 7.5 g (42 mMol) 5-methoxyisatin were dripped into 150 ml of anhydrous tetrahydrofuran. Then everything was stirred for another 30 minutes at room temperature. The reaction solution was stirred into a liquid NH4 solution. This was done several times with extra oxygen and the resulting phosphates were mixed with water, with a small amount of water left, and 8,3 g of the liquid was mixed with the liquid, which was produced in a vacuum, in a small amount of water.

The following shall be indicated in the column for the determination of the content of the active substance:

The combined organic phases were washed with water several more times, dried over MgSO4 and compressed in a vacuum. The resulting residue was treated with a small amount of ether, resulting in a solid that was isolated and dried. 3.4 g of the intermediate was obtained.

The following shall be indicated in the column for the product:

3.3 g (7.6 mMol) of intermediate 2b and 5.6 g (30.5 mMol) 1-methylpiperidine-4-yl) piperazine were stirred for 16 h at room temperature in 100 ml of tetrahydrofuran. The solvent was then removed in a vacuum. The residue was distributed between water and acetic acid. The water phase was washed with acetic acid twice more. The combined acetic acid phases were again washed with water, dried and compressed in a vacuum. The residue was stirred with ether, resulting in a solid that was isolated. 2.9 g of the intermediate was obtained.

The following shall be indicated in the column for the product:

To 200 mg (0.38 mMol) of intermediate 2c in 5 ml anhydrous dimethylformamide, 54 mg (0.48 mMol) potassium tert-butanolate was added per serving and stirred for approximately 60 minutes. Then 113 mg (0.48 mMol) 2,4-dimethoxybenzolesulphonic acid chloride was rapidly dripped at 0 °C. Everything was stirred at room temperature for 16 h. The reaction solution was then poured on 1 MOH Na, with precipitation which was isolated. This precipitation was dissolved in 1 ml methanol and mixed with 1 ml of etheric HCl. This solution was kept overnight at 0 °C, with precipitation, and 213 mg of the product was obtained as dihydrochloride. The mean and standard deviation of the mean and standard deviation of the two samples is calculated as follows:

Example 3 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.] The following shall be indicated in the list of substances:

After 100 g (0.345 mol) of intermediate 1a, 56 ml (0.695 mol) pyridine in 1 l of methyl chloride at 0 °C, 38 ml (0.518 mol) of thionyl chloride were slowly added and stirred for about 30 minutes. The reaction mixture was then poured on ice water and the organic phase was separated. This organic phase was washed with water, dried and vacuum-tighted. The residue was treated several times with toluene and the organic solvent was removed in vacuum. 79 g of the raw product was obtained, which was further processed without further purification.

10 g (32.45 mMol) of intermediate 2a were suspended in 100 ml of methylene chloride. After adding 100 ml of 2-molar ethanol ammonia solution, the reaction mixture was stirred for 16 h. Afterwards, everything was poured on ice water and the organic phase was separated. The aqueous phase was cooled, slowly forming a white crystalline acid which was isolated. 5.7 g of the product was obtained.

The following shall be indicated in the column for the product:

0.8 g (2.8 mMol) of intermediate 3b were added to 20 ml of pyridine, 0.38 ml (3.1 mMol) of chlorophyll ethyl ester were added at 0 °C and then stirred for 16 h at room temperature. The solution was then poured on ice water and extracted with acetic acid. The organic phase was washed with water, dried and vacuum-pressed. The resulting residue was dissolved in a small amount of ether and the product was precipitated by careful addition of n-pentane. 1.1 g was obtained.

The following substances are to be classified in the same heading as the product:

1 g (2.4 mMol) of intermediate 3c and 1.8 g (9.8 mMol) 1(1-methylpiperidin-4-yl) piperazine were boiled in 35 ml of anhydrous tetrahydrofuran for 3 h under reflux. The solvent was then removed in a vacuum. The resulting residue was distributed between water and acetic acid, the organic phase was separated, washed with water, dried and vacuum-pressed. The residue was treated with ether/pentane, after which the product was solidified. 0.76 g were obtained.

The following substances are to be classified in the same category as the product:

0.21 g (0.42 mmol) of intermediate 3d in 2 ml of dimethylformamide were given 0.052 mg (0.47 mol) potassium tert-butanolate at 0 °C. Everything was stirred at 0 °C for 1 h. Then 0.11 g (0.47 mol) 2,4-dimethoxybenzolesulfonic acid chloride was added. Then the reaction mixture was stirred for 16 hours at room temperature. The mixture was then poured into a 5% potassium carbonate solution, slowly forming a precipitate. This precipitate was isolated and chromatically cleaned with silica (solvent: methyl methyleneglyceride/ethanol = 1/1) and 0.1 g of the product was obtained. The mean and standard deviation of the mean values of the two samples (i.e. the mean and standard deviation) for the samples (i.e. the mean and standard deviation) are as follows:

The following compounds were produced by analogy with the methodological methods described in examples 1, 2, 3 and 192:

Example 4 4-methyl-piperidine-4-yl) -piperazine-1-carbonic acid-[1-benzoyl-sulfonyl-5-chlor-2-oxo-3-phenyl-2,3-dihydro-1H-indol-3-yl]-ester of dihydrochloride, whether or not containing by weight:

The mean and standard deviation of the mean values of the two samples (i.e. the mean and standard deviation) for the samples (i.e. the mean and standard deviation) are as follows:

Example 5 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

The mean value of the measurements of the test chemical is calculated as the sum of the mean values of the measurements of the test chemical and the mean values of the measurements of the test chemical and the mean values of the measurements of the test chemical and the mean values of the measurements of the test chemical and the mean values of the measurements of the test chemical and the mean values of the measurements of the test chemical and the mean values of the measurements of the test chemical and the mean values of the measurements of the test chemical and the mean values of the measurements of the test chemical and the mean values of the measurements of the test chemical and the mean values of the measurements of the test chemical and the mean values of the measurements of the test chemical and the mean values of the measurements of the test chemical and the mean values of the measurements of the test chemical and the mean values of the measurements of the measurements of the test chemical and the mean values of the measurements of the measurements of the test chemical and the mean values of the measurements of the measurements of the measurements of the measurements of the measurements of the test chemical and the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of

Example 6 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

The mean value of the measurements of the test chemical is calculated as the sum of the mean values of the measurements of the test chemical and the mean values of the measurements of the test chemical and the mean values of the measurements of the test chemical and the mean values of the measurements of the test chemical and the mean values of the measurements of the test chemical and the mean values of the measurements of the test chemical and the mean values of the measurements of the test chemical and the mean values of the measurements of the test chemical and the mean values of the measurements of the test chemical and the mean values of the measurements of the test chemical and the mean values of the measurements of the test chemical and the mean values of the measurements of the test chemical and the mean values of the measurements of the test chemical and the mean values of the measurements of the test chemical and the mean values of the measurements of the measurements of the test chemical and the mean values of the measurements of the measurements of the test chemical and the mean values of the measurements of the measurements of the measurements of the measurements of the test chemical and the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of

Example 7 4- ((Methyl-piperazine-1-yl) -piperidine-1-carbonate-[1-benzolesulfonyl-5-methyl-2-oxo-3-phenyl-2,3-dihydro-1H-indol-3-yl]-ester dihydrochloride] is obtained by the reaction of the following hydrocarbons:

The mean and standard deviation of the mean values of the two samples (i.e. the mean and standard deviation) for the samples (i.e. the mean and standard deviation) is calculated as follows:

Example 8 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

The mean and standard deviation of the mean and standard deviation of the two samples (i.e. the mean and standard deviation) are as follows:

Example 9 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

Example 10 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

The mean of the measurements of the test chemical is calculated as the mean of the measurements of the test chemical in the test chemical.

Example 11 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

The total number of samples of the test chemical is calculated by dividing the total number of samples of the test chemical by the total number of samples of the test chemical.

Example 12 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

The mean and standard deviation of the mean values of the two samples (DMSO) is calculated as follows: δ = 2.0 (DMSO), 2.3 (DMSO), 2.5 (DMSO), 2.7 (DMSO), 2.7 (DMSO), 2.7 (DMSO), 2.7 (DMSO), 2.7 (DMSO), 2.7 (DMSO), 2.7 (DMSO), 2.7 (DMSO), 2.7 (DMSO), 2.7 (DMSO), 2.7 (DMSO), 2.7 (DMSO), 2.7 (DMSO), 2.7 (DMSO), 2.7 (DMSO), 2.7 (DMSO), 2.7 (DMSO), 2.7 (DMSO), 2.7 (DMSO), 2.7 (DMSO), 2.7 (DMSO), 2.7 (DMSO), 2.7 (DMSO), 2.7 (DMSO), 2.7 (DMSO), 2.7 (DMSO), 2.7 (DMSO), 2.7 (DMSO), 2.7 (DMSO), 2.7 (DMSO), 2.3 (DMSO), 2.3 (DMSO), 2.3 (DMSO), 2.3 (DMSO), 2.3 (DMSO), 2.3 (DMSO), 2.3 (DMSO), 2.3 (DMSO), 2.3 (DMSO), 2.3 (DMSO), 2.3 (DMSO), 2.3 (DMSO), 2.3 (DMSO), 2.3 (DMSO), 2.3 (DMSO), 2.3 (DMSO), 2.3 (DMSO), 2.3 (DMSO), 2.3 (DMSO), 2.3 (DMSO), 2.3 (DMSO), 2.3 (DMSO), 2.3 (DMSO), 2.3 (DMSO), 2.3 (DMSO), 2.3 (DMSO), 2.3 (DMSO), 2.3 (DMSO), 2.3 (DMSO), 2.3 (DMSO), 2.3 (DMSO), 2.3 (DMSO), 2.3 (DMSO), 2.3 (DMSO), 2.3 (DMSO), 2.3 (DMSO), 2.3 (DMSO), 2.3 (DMSO), 2.3 (DMSO), 2.3 (DMSO), 2.3 (DMSO), 2.3 (DMSO), 2.3 (DMSO), 2.3 (DMSO), 2.3 (DMSO), 2.3 (DMSO), 2.3 (DMSO), 2.3 (

Example 13 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

Example 14 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

Example 15 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

Example 16 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

Example 17 4-methyl-piperidine-4-yl) -piperazine-1-carbonate-[1-methyl-piperidine-4-yl] -piperidine-1-carbonate-[2-dimethoxybenzolsulfonyl] - 5-methyl-2-oxo-3-methyl-piperidine-2-methyl-phenyl) - 2-dihydro-1H-indol-3-yl] -dihydrochloride ester, whether or not chemically defined

The following are the active substances which may be used in the manufacture of the active substance:

Example 18 The following substances are to be classified in the same heading as the product:

Example 19 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

Example 20 The following substances are to be classified in the same heading as the product:

Example 21 The following substances are to be classified in the same heading as the product:

Example 22 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

Example 23 4-methyl-piperidine-4-yl) -piperazine-1-carbonate-[1-methyl-piperidine-4-yl]-dihydrochloride-[2-dimethoxybenzolsulfonyl]-2-oxo-3-methyl-dihydroxyphenyl]-2,3-dihydro-1H-indol-3-yl]-ester of the dihydrochloride

Example 24 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

Example 25 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

The mean value of the measurements of the test chemical is calculated as the sum of the mean values of the measurements of the test chemical and the mean values of the measurements of the test chemical and the mean values of the measurements of the test chemical and the mean values of the measurements of the test chemical and the mean values of the measurements of the test chemical and the mean values of the measurements of the test chemical and the mean values of the measurements of the test chemical and the mean values of the measurements of the test chemical and the mean values of the measurements of the test chemical and the mean values of the measurements of the test chemical and the mean values of the measurements of the test chemical and the mean values of the measurements of the test chemical and the mean values of the measurements of the test chemical and the mean values of the measurements of the test chemical and the mean values of the measurements of the test chemical and the mean values of the measurements of the measurements of the test chemical and the mean values of the measurements of the measurements of the test chemical and the measurements of the measurements of the measurements of the measurements of the test chemical and the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the test chemical and the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the meas

Example 26 The following substances are to be classified in the same heading as the product:

The mean value of the measurements is calculated as the sum of the measurements of the two samples taken at the same time.

Example 27 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

Example 28 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

Example 29 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

The following table shows the total number of samples of the test chemical in the sample:

Example 30 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

The mean value of the measurements of the test chemical is calculated as the sum of the mean values of the measurements of the test chemical and the mean values of the measurements of the test chemical and the mean values of the measurements of the test chemical and the mean values of the measurements of the test chemical and the mean values of the measurements of the test chemical and the mean values of the measurements of the test chemical and the mean values of the measurements of the test chemical and the mean values of the measurements of the test chemical and the mean values of the measurements of the test chemical and the mean values of the measurements of the test chemical and the mean values of the measurements of the test chemical and the mean values of the measurements of the test chemical and the mean values of the measurements of the test chemical and the mean values of the measurements of the test chemical and the mean values of the measurements of the test chemical and the mean values of the measurements of the measurements of the test chemical and the mean values of the measurements of the measurements of the test chemical and the measurements of the measurements of the measurements of the measurements of the measurements of the test chemical and the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the

Example 31 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

The mean concentration of the active substance in the test chemical is calculated as the sum of the following:

Example 32 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

Example 33 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

The mean and standard deviation of the mean values of the measurements of the two samples is calculated as follows:

Example 34 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

Example 35 The following substances are to be classified in the same heading as the product:

Example 36 4-methyl-piperidine-4-yl) -piperazine-1-carbonic acid-[1-benzolesulfonyl-5-methyl-2-oxo-3-phenyl-2,3-dihydro-1H-indol-3-yl]-ester dihydrochloride, whether or not containing by weight:

The mean concentration of the active substance in the test chemical is calculated as the following:

Example 37 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

Example 38 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

Example 39 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

The mean and standard deviation of the mean values of the two samples (D2O, δ = 1.9-2.1 ((2H), 2.4-2.6 ((2H), 2.7 ((3H), 2.9 ((3H), 3.1-3.3 ((2H), 3.3 ((1H), 3.3-3.6 ((7H), 3.6-3.75 ((4H), 3.8 ((3H), 3.9 ((3H), 3.9 ((4.2 ((2H), 6.9 ((1H), 7.0 ((1 H), 7.1 ((2H), 7.45 ((1 H), 7.5 ((2H), 7.7 ((1 H), 7.8 ((1 H) and 8.3 ppm) are as follows:

Example 40 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

Example 41 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

Example 42 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

The mean concentration of CDCl3 in the human blood is approximately 0.05% (see section 4.8).

Example 43 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

Example 44 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

The concentration of the substance in the test chemical is calculated by adding the following elements to the total concentration of the test chemical:

Example 45 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

Example 46 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

The mean and standard deviation of the mean and standard deviation of the two samples is calculated as follows:

Example 47 The following substances are to be classified in the same heading as the product:

The total number of samples of the test chemical is calculated by dividing the total concentration of the test chemical by the total number of samples of the test chemical.

Example 48 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

Example 49 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

Example 50 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

Example 51 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

Example 52 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

Example 53 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

Example 54 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

Example 55 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

Example 56 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

Example 57 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5 and boiling in the range of approximately -15oC to -15oC (-70oF to -15oF).]

Example 58 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5 and boiling in the range of approximately -15oC to -15oC (- 37oF to -15oF).]

Example 59 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

Example 60 The following substances are to be classified in the same heading as the product:

Example 61 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

Example 62 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

Example 63 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

Example 64 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.] Example 65 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

Example 66 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

Example 67 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

Example 68 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5 and boiling in the range of approximately -15oC to -15oC (- 37oF to -15oF).]

The total number of ppm of the test chemical in the sample is calculated by dividing the total dose by the total dose of the test chemical in the sample.

Example 69 The following substances are to be classified in the same heading as the product: Example 70 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

Example 71 The following substances are to be classified in the same heading as the product:

Example 72 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

Example 73 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

Example 74 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

The total number of samples of the test chemical is calculated by dividing the total concentration of the test chemical by the total concentration of the test chemical.

Example 75 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

Example 76 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

Example 77 The following substances are to be classified in the same heading as the product:

Example 78 4-methyl-piperidine-4-yl) -piperazine-1-carbonate-{5-methoxy-1-(2-methoxy-benzolsulfonyl) -3-[2-methoxy-ethyl) -phenyl]-2-oxo-2,3-dihydro-1H-indol-3-yl}-amide dihydrochloride, whether or not containing by weight more than 5% of sulphonylurea

The mean concentration of the active substance in the test chemical is calculated as the following: δ = 2.05 (< 2H), 2.3 (< 2H), 2.7 (< 3H), 2.85 (< 3.2H), 3.25 (< 3.7H), 3.25 (< 3.7H), 3.75 (< 3.75H), 3.85 (< 3H), 3.85 (< 3H), 3.85 (< 3H), 3.25 (< 1H), 4.25 (< 1H), 6.5 (< 1H), 6.9 (< 1H), 7.25 (< 1H), 7.4 (< 1H), 7.75 (< 2H), 7.9 (< 1H), 10.S (< N+H) and 11.7 (< N+H) ppm).

Example 79 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

The mean concentration of the substance in the test chemical is calculated as the sum of the concentrations of the active substance in the test chemical and the total concentration of the active substance in the test chemical.

Example 80 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

Example 81 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

Example 82 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

The mean and standard deviation of the mean values of the NOECs for the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of samples of the samples of the samples of the samples of samples of the samples of samples of the samples of samples of the samples of samples of samples of samples of samples of samples of samples of samples of samples of samples of samples of samples of samples of samples of samples of samples of samples of samples of samples of samples of samples of samples of samples of samples of samples of samples of samples of samples of samples of samples of samples of samples of samples of samples of samples of

Example 83 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

The mean concentration of CDCl3 in the human body is approximately 0.05% (see section 4.8).

Example 84 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

Example 85 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

Example 86 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

The mean concentration of CDCl3 in the human body is approximately 0.8 μg/l, and the mean concentration of CDCl3 in the human body is approximately 0.8 μg/l.

Example 87 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

The mean concentration of CDCl3 in the blood is approximately 0.8 μg/l, and the mean concentration of CDCl3 in the blood is approximately 0.8 μg/l.

Example 88 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

Example 89 The following shall be indicated in the column 'C' of the column 'C' of the table:

Example 90 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

Example 91 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

The mean concentration of CDCl3 in the human blood is approximately 0.85 (< 0.85), 1.0-1.9 (< 0.6H), 2.25 (< 0.25), 2.25 (< 0.7H), 2.9 (< 0.7H), 2.9 (< 0.1H), 3.55 (< 0.3H), 3.65 (< 0.65), 3.75 (< 0.3H), 3.75 (< 0.3H), 3.75 (< 0.3H), 3.75 (< 0.3H), 3.75 (< 0.3H), 3.75 (< 0.3H), 3.75 (< 0.3H), 3.75 (< 0.3H), 3.75 (< 0.3H), 3.75 (< 0.3H), 3.75 (< 0.3H), 3.75 (< 0.3H), 3.75 (< 0.3H), 3.75 (< 0.7H), 3.75 (< 0.7H), 3.75 (< 0.7H), 3.75 (< 0.7H), 3.75 (< 0.7H), 3.75 (< 0.7H), 3.75 (< 0.7H), 3.75 (< 0.7H), 3.75 (< 0.7H), 3.75 (< 0.7H), 3.75 (< 0.7H), 3.75 (< 0.7H), 3.75 (< 0.7 (< 0.7H), 3.65 (< 0.7H), 3.65 (< 0.7 (< 0.7H), 3.65 (< 0.8H), 3.65 (< 0.8 (< 0.8H), 3.65 (< 0.8 (< 0.8H) and 0.8 (< 0.6H) H) H) H) ppm).

Example 92 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.] Example 93 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

Example 94 4-methyl-piperidine-4-yl) -piperazine-1-carbonate-[3-methyl-ethoxy-phenyl]-5-fluoro-1-methyl-benzoyl sulphonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-ester of dihydrochloride, whether or not containing by weight:

Example 95 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

Example 96 4-methyl-piperidine-4-yl) -piperazine-1-carbonate-[5-chlorine-3-[2-ethoxyphenyl) -4-methyl-benzolsulfonyl) -2-oxo-2,3-dihydro-1H-indol-3-yl] ester of dihydrochloride

Example 97 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

Example 98 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

Example 99 The following substances are to be classified in the same heading as the product:

The mean and standard deviation of the mean values of the NOECs for the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of samples of the samples of the samples of the samples of samples of the samples of the samples of samples of the samples of samples of the samples of samples of samples of samples of samples of samples of samples of samples of samples of samples of samples of samples of samples of samples of samples of samples of samples of samples of samples of samples of samples of samples of samples of samples of samples of samples of samples of samples of samples of samples of samples of samples of samples of samples of samples of samples of samples of samples

Example 100 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.] Example 101 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

Example 102 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

Example 103 The following substances are to be classified in the same heading as the product:

Example 104 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

Example 105 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

Example 106 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

Example 107 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

Example 108 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

Example 109 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

Example 110 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

Example 111 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

Example 112 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

Example 113 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

Example 114 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

Example 115 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

Example 116 4-methylpiperidine-4-yl) -piperazine-1-carbonic acid-[1-benzoylsulfonyl-5-cyano-3-[2-ethoxyphenyl) --2-oxo-2,3-dihydro-1H-indol-3-yl]amide dihydrochloride, whether or not containing by weight:

Example 117 The following substances are to be classified in the same heading as the product:

Example 118 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

Example 119 The following substances are to be classified in the same heading as the product:

Example 120 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

Example 121 The following substances are to be classified in the same heading as the product:

Example 122 The following substances are to be classified in the same heading as the product:

Example 123 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

The mean of the measurements of the 1H-NMR (D6-DMSO) is given by: δ = 1.15 (< 3H), 1.5 (< 2H), 2.05 (< 2H), 2.6 (< 2H), 2.8 (< 3H), 3.2-3.8 (< 11H), 3.85 (< 4H), 3.95 (< 1H), 6.95 (< 2H), 7.1 (< 2H), 7.15 (< 2H), 7.3 (< 1H), 7.4 (< 1H), 7.7 (< 1H), 7.75 (< 1H), and 7.95 (< 2H) ppm.

Example 124 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

Example 125 The following substances are to be classified in the same group as the product:

The mean concentration of CDCl3 in the blood is approximately 1 μg/l, and the mean concentration of CDCl3 in the blood is approximately 1 μg/l.

Example 126 The following substances are to be classified in the same heading as the product:

The mean and standard deviation of the mean values of the two samples (CDCl3) are: δ = 1.4-1.6 ((5H), 1.7 ((2H), 1.9 ((2H), 2.2-2.3 ((4H), 2.45 ((4H), 3.55 ((3H), 4.1 to 4.3 ((2H), 6.75 to 7.15 ((7H), 7.25 ((1H), 7.5 ((1H), 7.9 ((1H) and 8.15 ((1H) ppm.

Example 127 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

The following is a list of the active substances that may be used in the preparation of the active substance:

Example 128 The following substances are to be classified in the same heading as the product:

Example 129 (-) - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -

Example 130 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

Example 131 (-) - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -

Example 132 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

Example 133 The following substances are to be classified in the same heading as the product:

The mean and standard deviation of the mean values of the two samples (CDCl3) are: δ = 1.35 (H), 1.5 (H), 1.85 (H), 2.25 (H), 2.8 (H), 2.14 (H), 3.7 (H), 2.11 (H), 4.1 (H), 4.2 (H), 6.5, 6.1, 6.9, 6.2, 7.5, 7.3, 7.5, 7.7, 8.5, 8.5, 8.1 (H) and 8.15 (H) ppm.

Example 134 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

Example 135 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

Example 136 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

The total number of patients with a history of renal failure in the first three years of life was estimated at approximately 10 to 150.

Example 137 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

Example 138 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

Example 139 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

Example 140 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

The mean and standard deviation of the mean and standard deviation of the two samples is calculated by dividing the mean and standard deviation by the mean values of the samples.

Example 141 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.] Example 142 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

Example 143 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

Example 144 The following substances are to be classified in the same heading as the product:

Example 145 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

Example 146 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

The mean and standard deviation of the mean values of the NOECs for the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of samples of the samples of the samples of the samples of samples of samples of the samples of samples of samples of the samples of samples of samples of samples of the samples of samples of samples of samples of samples of samples of samples of samples of samples of samples of samples of samples of samples of samples of samples of samples of samples of samples of samples of samples of samples of samples of samples of samples of samples of samples of samples of samples of samp

Example 147 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

Example 148 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.] Example 149 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

Example 150 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.] Example 151 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.] Example 152 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

Example 153 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

Example 154 The following substances are to be classified in the same heading as the product:

Example 155 The following substances are to be classified in the same heading as the product:

The mean value of the measurements of the test chemical is calculated as the sum of the mean values of the measurements of the test chemical and the mean values of the measurements of the test chemical and the mean values of the measurements of the test chemical and the mean values of the measurements of the test chemical and the mean values of the measurements of the test chemical and the mean values of the measurements of the test chemical and the mean values of the measurements of the test chemical and the mean values of the measurements of the measurements of the test chemical and the mean values of the measurements of the measurements of the test chemical and the mean values of the measurements of the measurements of the test chemical and the mean values of the measurements of the measurements of the measurements of the test chemical and the mean values of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements

Example 156 The following substances are to be classified in the same group as the product:

Example 157 The following substances are to be classified in the same heading as the product:

The total number of patients with a history of renal failure (including renal failure) is estimated at approximately 1 in 100 patients with a history of renal failure (including renal failure).

Example 158 4- ((Isopropyl-piperazine-1-yl) -piperidine-1-carbonic acid-[5-cyano-1- ((2,4-dimethoxybenzolsulfonyl) -3- ((2-ethoxyphenyl) -2-oxo-2,3-dihydro-1H-indol-3-yl) -amide dihydrochloride) is obtained by the addition of a mixture of the following substances:

Example 159 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

Example 160 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

Example 161 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

Example 162 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

Example 163 The following substances are to be classified in the same heading as the product:

Example 164 The following substances are to be classified in the same heading as the product:

Example 165 The following substances are to be classified in the same heading as the product:

Example 166 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

The mean concentration of CDCl3 in the human blood is approximately 0.4 μg/l, and the mean concentration of CDCl3 in the human blood is approximately 0.4 μg/l.

Example 167 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

Example 168 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

The mean and standard deviation of the mean and standard deviation of the two samples (DMSO) is calculated as the mean and standard deviation of the two samples (DMSO) in the sample.

Example 169 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

Example 170 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

Example 171 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

Example 172 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

Example 173 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

Example 174 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

The mean concentration of CDCl3 in the human blood is approximately 0.01% (see section 4.8).

Example 175 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

The total number of samples of the active substance (s) is calculated by dividing the total number of samples of the active substance (s) by the total number of samples of the active substance (s) taken into account.

Example 176 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

Example 177 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

Example 178 The following substances are to be classified in the same heading as the product:

Example 179 The following substances are to be classified in the same heading as the product:

Example 180 The following substances are to be classified in the same heading as the product:

Example 181 The following substances are to be classified in the same heading as the product:

Example 182 The following substances are to be classified in the same heading as the product:

Example 183 The following substances are to be classified in the same heading as the product:

The mean concentration of CDCl3 in the human blood is approximately 0.9 μg/l, and the mean concentration of CDCl3 in the human blood is approximately 0.9 μg/l.

Example 184 The following substances are to be classified in the same heading as the product:

The mean concentration of the active substance in the test chemical is calculated as the following: δ = 0.9 (< 3H), 1.25 (< 1.4 (< 5H), 1.4-1.65 (< 5H), 1.75 (< 2H), 2.25 (< 2.8)), 2.25 (< 2.8)), 3.7 (< 2H), 4.7 (< 1H), 6.35 (< 1H), 6.8 (< 2H), 7.1 (< 7.2)), 7.3 (< 1H), 7.45 (< 1H), 7.6 (< 1H), 8.05 (< 1H) and 8.1 (< 8.1H) ppm.

Example 185 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

Example 186 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

Example 187 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

The total number of samples of the test chemical is calculated by dividing the total sample by the total number of samples of the test chemical.

Example 188 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

Example 189 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

The mean concentration of CDCl3 in the blood is approximately 0.9 μg/l, and the mean concentration of CDCl3 in the blood is approximately 0.9 μg/l.

Example 190 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

Example 191 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

The mean concentration of CDCl3 in the blood is approximately 0.4 μg/l, and the mean concentration of CDCl3 in the blood is approximately 0.4 μg/l.

Example 192 The following substances are to be classified in the same heading as the product: (a) 4- (4-Propylpiperazine-1-yl) -piperidine-1-carbonate butyl ester

The reaction mixture was concentrated in a vacuum and then distributed between acetic acid and 1 M NaOH. The organic phase was separated, washed, dried and dissolved in a vacuum with 1 M NaOH, H2O and NaCl. The residue was chromatographically purified using a silicon chromatograph (CHF: 1/152H/Cl2 = 43,6 MCl of the product).

(b) 1-piperidine-4-yl-4-propylpiperazine trihydrochloride

After 30 minutes, the gas evolution was completed, 50 ml of 5-6M isopropanol HCl were added again and everything stirred for 1 hour at 40°C. The product was allowed to cool and isolated. 34 g of the product was obtained.

(c) 3- (β-ethoxyphenyl) 3-hydroxy-5-iodine-1,3-dihydro-indol-2-one

8.0 g (1.65 mol) of magnesium were coated with 40 ml of ether, and after a little iodine was added, the reaction was heated until the reaction started. To the boiling solution, 66.3 g (0.33 mol) of 2-bromo-1-ethoxybenzole, dissolved in 200 ml of ether, were slowly added so that the reaction was carried out under light boiling continuously. Then, under light cooling at 20 °C, 30 g (0.11 mol) of 5-iododine were added to 800 ml of anhydrous hydrofuran. Then everything was stirred for another 30 minutes at room temperature. The reaction solution was dried in a water-based NH4Cl solution under stirring. This water was boiled four times and the extracted phosphates were combined with concentrated water, which was then dried in a vacuum and extracted from a solid body of water containing 33,6 g of isophthalic acid.

(d) 3- (β-ethoxyphenyl) 3-hydroxy-2-oxo-2,3-dihydro-1H-indol-5-carboxy nitrile

37 g (94 mMol) of the intermediate 192c and 11 g (94 mMol) of zinc cyanide were given in 300 ml DMF and everything was heated rapidly to 90-95°C. Afterwards, 1.6 g (1.4 mMol) Pd[Ph3P]4 were added in two servings within 20 minutes. After another 30 minutes, the reaction mixture was poured on ice water and extracted with acetic acid. The organic phase was isolated with water and saturated NaCl solution, washed, dried and vacuumed.

(e) 3-Chlor-3- ((2-Etoxyphenyl)-2-Oxo-2,3-Dihydro-1H-Indol-5-Carboxylic Acid Nitryl

10 g (34 mMol) of the intermediate product 192d and 5.6 ml (68 mMol) of pyridine were dissolved in 120 ml CH2Cl2. Afterwards, everything was cooled to 0 °C and 3.7 ml (51 mMol) SOCl2 was added. The reaction mixture was stirred for 1 hour. Then everything was carefully placed in ice water, the organic phase was separated, washed several times with H2O, dried and vacuumed. The resulting residue was treated with n-pentane and the resulting solid was isolated to obtain 9.9 of the product.

(f) 2-[5-Cyano-3- ((2-Etoxyphenyl) 2-Oxo-2,3-Dihydro-1H-Indol-3-yl]-malonic acid dimethyl ester

3.8 g (96 mMol) NaH(60%) were gently added to 200 ml of anhydrous DMF. At 10°C, 12 ml (105 mMol) of malonic dimethyl ester was added slowly. Everything was stirred for 30 minutes at room temperature. Then 10 g (32 mMol) of the intermediate product was added in the 192nd serving and the reaction mixture was stirred for 15 minutes. This mixture was gently stirred in 1 M HCl and then cooled, with precipitation occurring, which was isolated and decrystallized from CH2Cl2/pentan.

(g) [5-cyano-3- ((2-ethoxyphenyl) 2-oxo-2,3-dihydro-1H-indol-3-yl] acetic acid methyl ester

10.7 g (26 mMol) of intermediate 192f were dissolved in 10 ml of ethanol. 100 ml of 2M sodium salt was added and stirred for 1 h at room temperature. The reaction solution was stirred in 1 M HCl, precipitation was initiated, which was isolated and dried. This solid was transferred to a 1 L vessel and heated to 150 °C, the latter foaming up by gas development.

(h) [5-cyano-3- ((2-ethoxyphenyl) 2-oxo-2,3-dihydro-1H-indol-3-yl] acetic acid

36 ml 2M NaOH were added to 5.9 g (16.8 mMol) of the intermediate 192g in 25 ml ethanol and stirred at room temperature for 3 h. The reaction mixture was then acidified with 6 ml acetic acid and diluted with water. Overnight a solid was released which was isolated and dried.

The following shall be added to the list of active substances:

1.8 g (16.3 mMol) t-BuOK were gently added at 0°C to 1.9 g (5.4 mMol) of intermediate 192b in 25 ml of anhydrous DMF, followed by 2 g (5.4 mMol) of intermediate 192h, 0.8 g (5.4 mMol) HOBT, 2.9 ml (20.9 mMol) Et3N and finally 1.1 g (5.4 mMol) EDAC, each serving. The mixture was then stirred at room temperature for 16 h. This mixture was then introduced into a 5% K2CO3 solution, precipitating, which was isolated and dried. 2.6 g of the product was dried.

0.2 g (0.38 mmol) of intermediate 192i in 4 ml DMF was given as 47 mg (0.42 mMol) t-BuOK at 0°C. Everything was stirred at 0°C for 1 h. Then 86 mg (0.42 mMol) 4-methoxybenzolesulfonyl chloride was added at 0°C in portions and stirred for 16 h. The solution was stirred in 1 M NaOH and the precipitate was isolated. The total number of samples of the test chemical is calculated by dividing the total number of samples of the test chemical by the total number of samples of the test chemical.

Example 193 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

The total number of patients with a history of renal failure (including renal failure) is estimated at approximately 100 patients per day.

Example 194 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

Example 195 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

Example 196 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

Example 197 The following substances are to be classified in the same heading as the product:

Example 198 The following substances are to be classified in the same heading as the product:

Example 199 The following substances are to be classified in the same heading as the product:

The mean concentration of the active substance in the test chemical is calculated as the following: δ = 1.05 (H), 1.35 (H), 1.5 (H), 1.5 (H), 1.75 (H), 2.3 (H), 2.3 (H), 2.5 (H), 2.8 (H), 2.11 (H), 3.7 (H), 3.85 (H), 3.8 (H), 4.0, 4.2, 6.5, 6.5, 7.5, 7.5, 7.5, 7.5, 7.5, 7.5, 7.5, 7.5, 7.5, 7.5, 7.5, 7.5, 7.5, 7.5, 7.5, 7.5, 8.5, 8.5, 8.5, 8.5, 8.5, 8.5, 8.5, 8.5, 8.5, 8.5, 8.5, 8.5, 8.5, 8.5, 8.5, 8.5, 8.5, 8.5, 8.5, 8.5, 8.5, 8.5, 8.5, 8.5, 8.5, 8.5, 8.5, 8.5, 8.5, 8.5, 8.5, 8.5, 8.5, 8.5, 8.5, 8.5, 8.5, 8.5, 8.5, 8.5, 8.5, 8.5, 8.5, 8.5, 8.5, 8.5, 8.5, 8.5, 8.5, 8.5, 8.5, 8.5, 8.5, 8.5, 8.5, 8.5, 8.5, 8.5, 8.5, 8.5, 8.5, 8.5, 8.5, 8.5, 8.5, 8.5, 8.5, 8.6, 8.6, 8.6, 8.6, 8.7, 8.8, 8.9, 8.9, 8.9, 8.9, 8.9, 8.9, 8.9, 9.9, 9.9, 9.9, 9.9, 9.9, 9.9, 9.9, 9.9, 9.9, 9.9, 9.9, 9.9, 9.9, 9.9, 9.9, 9.9, 9.9, 9.9, 9.9, 9.9, 9.9, 9.9, 9.9, 9.9, 9.9, 9.9, 9.9, 9.9, 9.9, 9.9, 9.9, 9.9, 9.9, 9.9, 9.9, 9.9, 9.9, 9.9, 9.9, 9.9, 9.9, 9.9, 9.9, 9.9, 9.9, 9.9, 9.9, 9.9, 9.9, 9.9, 9.9, 9.9, 9.9, 9.9, 9.9, 9.9, 9.9, 9.9, 9.9, 9.9, 9.9, 9.9, 9.9, 9.9, 9.9, 9.9, 9.9, 9.9, 9.9, 9.9, 9.9, 9.9, 9.9, 9.9, 9.9, 9.9, 9.9, 9.9, 9.9, 9.9, 9.9, 9.9, 9.9, 9.9, 9.9, 9.9, 9.9, 9.9, 9.9, 9.9, 9.9, 9.9, 9.9, 9.9, 9.9, 9.9, 9.9, 9.9, 9.9, 9.9, 9.9, 9.9, 9.9, 9.9, 9.9, 9.9, 9.9, 9.9, 9.9, 9.9, 9.9, 9.9, 9.9, 9.9, 9.9,

Example 200 The following substances are to be classified in the same heading as the product:

Example 201 The following substances are to be classified in the same heading as the product:

Example 202 The following substances are to be classified in the same heading as the product:

Example 203 The following substances are to be classified in the same heading as the product:

Example 204 The following substances are to be classified in the same heading as the product:

Example 205 The following substances are to be classified in the same heading as the product:

Example 206 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

Example 207 The following substances are to be classified in the same heading as the product:

Example 208 The following substances are to be classified in the same heading as the product:

Claims

Compound or compounds of the general formula (I) wherein
A is C_6-10-aryl which can be substituted by a maximum of four radicals R⁴ which are chosen independently of one another from the group consisting of hydrogen, chlorine, bromine, iodine, fluorine, (CH₂)_0-2-CN, CF₃, OCF₃, CONH₂, CONH(C₁-C₄-alkyl), CON(C₁-C₄-alkyl)(C₁-C₄-alkyl), NHCHO, NHCONH₂, N(C₀-C₄-alkylene)CONH₂, N(C₀-C₄-alkylene)CONH(C₁-C₄-alkyl), NHCOCH₃, NO₂, (CH₂)_0-2-OH, O-C₁-C₆-alkyl, (CH₂)_0-2-O-C₁-C₄-alkyl, O-C₀-C₄-alkylene-phenyl, phenyl, C₁-C₆-alkyl, C₂-C₆-alkenyl and C₂-C₆-alkynyl,

B is an aromatic or partly aromatic C_6-10-mono- or -bicyclic radical, which can be substituted by the radicals R⁶, R⁷, R⁸ and/or R⁹, wherein R⁶, R⁷, R⁸ and R⁹ are chosen independently of one another from the group consisting of hydrogen, chlorine, bromine, iodine, fluorine, (CH₂)_0-2-CN, CF₃, OCF₃, CONH₂, CONH (C₁-C₄-alkyl), CON (C₁-C₄alkyl) (C₁-C₄-alkyl), NHCHO, N (C₀-C₄-alkylene) CONH (C₁-C₄-alkyl), NHCOCH₃, NO₂, OH, O-C₁-C₄-alkyl, (CH₂)_0-2-O-(CH₂)_0-3-CH₃, O-C₀-C₄-alkylene-phenyl, phenyl, C₁-C₆-alkyl, C₂-C₆-alkenyl and C₂-C₆-alkynyl,

R¹ is hydrogen, C₁-C₆-alkyl, OH, O- (C₁-C₄-alkyl), N(C₁-C₄-alkyl)(C₁-C₄-alkyl), CN, CONH₂, OCF₃, CF₃, Br, F, Cl, I, NO₂, NHCHO, NHCO(C₁-C₄-alkyl) or NHCONH₂,

R² is hydrogen, C₁-C₄-alkyl, O-(C₁-C₄-alkyl), Cl or F,

R³ is a radical (W)-(X)-(Y)-Z, wherein
W is C₁-C₄-alkylene, (C₀-C₄-alkylene) -O- (C₀-C₄-alkylene) or (C₀-C₄-alkylene)-NR¹⁵-(C₀-C₄-alkylene), wherein R¹⁵ is hydrogen or C₁-C₄-alkyl,

X is CO, SO₂, (C=NH) or (C=N-CN) and

Y is a radical chosen from the group consisting of
wherein Y can additionally be substituted by R¹⁰ and/or R¹¹, wherein

R¹⁰ is hydrogen, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, OH, O-C₁-C₄-alkyl, O-C₀-C₄-alkylene-phenyl, NH₂, NH(C₁-C₄-alkyl) or N(C₁-C₄-alkyl) (C₁-C₄-alkyl),

R¹¹ is hydrogen, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, OH, O-C₁-C₄-alkyl, O-C₀-C₄-alkylene-phenyl, NH₂, NH (C₁-C₄-alkyl) or N (C₁-C₄-alkyl) (C₁-C₄-alkyl), and

Z is a radical chosen from the group consisting of wherein Z can additionally be substituted by R¹² and/or R¹³, wherein
R¹² is hydrogen, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, OH, O-C₁-C₄-alkyl, O-C₀-C₄-alkylene-phenyl, NH₂, NH (C₁-C₄-alkyl) or N(C₁-C₄-alkyl) (C₁-C₄-alkyl),

R¹³ is hydrogen, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, OH, O (C₁-C₄-alkyl) , O-C₀-C₄-alkylene-phenyl, NH₂, NH(C₁-C₄-alkyl) or N(C₁-C₄-alkyl) (C₁-C₄-alkyl),

R¹⁴ is hydrogen, C₁-C₄-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl or C₀-C₄-alkylene-phenyl, and
their tautomeric, enantiomeric and/or diastereomeric forms, and the physiologically acceptable salts of the abovementioned compound or compounds.
Compound or compounds according to claim 1, wherein A is a phenyl ring which can be substituted by a maximum of four radicals R⁴, and B is a phenyl ring which can be substituted by the radicals R⁶, R⁷, R⁸ and/or R⁹, wherein the radicals R⁴, R⁶, R⁷, R⁸ and R⁹ are intended to have the meanings mentioned in claim 1, and their tautomeric, enantiomeric and/or diastereomeric forms, and the physiologically acceptable salts of the abovementioned compound or compounds.
Compound or compounds according to claim 1, wherein
A is a phenyl ring which can be substituted by a maximum of two radicals R⁴ which are chosen independently of one another from the group consisting of hydrogen, chlorine, O-C₁-C₄-alkyl, (CH₂)_0-2-O-(CH₂)_0-2-CH₃ and C₁-C₆-alkyl,

B is a phenyl ring which can be substituted by the radicals R⁶, R⁷, R⁸ and/or R⁹, wherein R⁶, R⁷, R⁸ and R⁹ are chosen independently of one another from the group consisting of hydrogen, fluorine, chlorine, O-C₁-C₄-alkyl, (CH₂)_0-2-O-(CH₂)_0-2-CH₃ and C₁-C₆-alkyl,

R¹ is hydrogen, CN, F, Cl, C_1-4-alkyl, OH or O-(C_1-4-alkyl),

R² is hydrogen,

R³ is a radical (W)-(X)-(Y)-Z, wherein
W is 0, CH₂NH, NHCH₂, OCH₂, CH₂O or NH,

X is CO,

Y is a radical chosen from the group consisting of

Z is a radical chosen from the group consisting of wherein Z can additionally be substituted by R¹² and/or R¹³, wherein
R¹² is hydrogen or C₁-C₄-alkyl,

R¹³ is hydrogen or C₁-C₄-alkyl and wherein

R¹⁴ is hydrogen, C₁-C₄-alkyl, C₂-C₄-alkenyl or C₂-C₄-alkynyl,

and their tautomeric, enantiomeric and/or diastereomeric forms, and the physiologically acceptable salts of the abovementioned compound or compounds.
Compound or compounds according to claim 1, wherein
A is a phenyl ring which can be substituted by a maximum of two radicals R⁴ which are chosen independently of one another from the group consisting of hydrogen, chlorine, O-C₁-C₄-alkyl, (CH₂)_0-2-O-(CH₂)_0-2-CH₃ and C₁-C₆-alkyl,

B is a phenyl ring which can be substituted by the radicals R⁶ and/or R⁷, wherein R⁶ and R⁷ are chosen independently of one another from the group consisting of hydrogen, fluorine, chlorine, O-C₁-C₄-alkyl and C₁-C₆-alkyl,

R¹ is hydrogen, F, Cl, CH₃, CN, CH₂CH₃, OCH₃ or OCH₂CH₃,

R² is hydrogen,

R³ is a radical (W)-(X)-(Y)-Z, wherein
W is O, CH₂ or NH,

X is CO,

Y is a radical chosen from the group consisting of

Z is a radical chosen from the group consisting of wherein Z can be substituted by R¹² and/or R¹³, wherein
R¹² is hydrogen or C₁-C₄-alkyl,

R¹³ is hydrogen or C₁-C₄-alkyl and

R¹⁴ is hydrogen, C₁-C₄-alkyl, C₂-C₄-alkenyl or C₂-C₄-alkynyl,

and their tautomeric, enantiomeric and/or diastereomeric forms, and the physiologically acceptable salts of the abovementioned compound or compounds.
Compound or compounds according to claim 1, wherein
A is a phenyl ring which can be substituted by a maximum of two radicals R⁴ which are chosen independently of one another from the group consisting of hydrogen, chlorine, O-C₁-C₄-alkyl, (CH₂)_0-2-O- (CH₂)_0-2-CH₃ and C₁-C₆-alkyl,

B is a phenyl ring which can be substituted by the radicals R⁶ and/or R⁷, wherein R⁶ and R⁷ are chosen independently of one another from the group consisting of hydrogen, fluorine, chlorine, O-C₁-C₄-alkyl, and C₁-C₆-alkyl,

R¹ is Cl, CH₃, CN, CH₂CH₃ or OCH₃,

R² is hydrogen,

R³ is a radical (W) - (X) - (Y) -Z, wherein
W is CH₂, O or NH,

X is CO,

Y is a radical

Z is a radical wherein
R¹⁴ is hydrogen, C₁-C₄-alkyl, C₂-C₄-alkenyl or C₂-C₄-alkynyl,

and their tautomeric, enantiomeric and/or diastereomeric forms, and the physiologically acceptable salts of the abovementioned compound or compounds.
Compound or compounds according to claim 1, wherein
A is a phenyl ring which can be substituted by a maximum of two radicals R⁴ which are chosen independently of one another from the group consisting of hydrogen, chlorine, O-C₁-C₄-alkyl and C₁-C₄-alkyl,

B is a phenyl ring which is substituted by the radicals R⁶ and/or R⁷, wherein R⁶ and R⁷ independently of one another are chosen from the group consisting of hydrogen, fluorine, chlorine, O-C₁-C₄-alkyl and C₁-C₆-alkyl,

R¹ is hydrogen, Cl, CH₃, CN, CH₂CH₃, OCH₃ or OCH₂CH₃,

R² is hydrogen,

R³ is a radical (W)-(X)-(Y)-Z, wherein
W is CH₂, 0 or NH,

X is CO,

Y is a radical and

Z is a radical
wherein
R¹⁴ is hydrogen, C₁-C₄-alkyl, C₂-C₄-alkenyl or C₂-C₄-alkynyl,
and their tautomeric, enantiomeric and/or diastereomeric forms, and the physiologically acceptable salts of the abovementioned compound or compounds.
Medicament comprising at least one compound according to one of claims 1 to 6 and optionally conventional pharmaceutical auxiliary substances.
Use of at least one compound according to one of claims 1 to 6 for the preparation of a medicament for treatment and/or prophylaxis of vasopressin-dependent or oxytocin-dependent diseases.
Use of at least one compound according to one of claims 1 to 6 for the preparation of a medicament for treatment and/or prophylaxis of at least one disease chosen from the group consisting of diabetes insipidus, enuresis nocturna, incontinence, diseases with which blood clotting disorders occur, and/or for delaying micturition.
Use of at least one compound according to one of claims 1 to 6 for the preparation of a medicament for treatment and/or prophylaxis of at least one disease chosen from the group consisting of hypertension, pulmonary hypertension, cardiac insufficiency, myocardial infarction, coronary spasm, unstable angina, PTCA (percutaneous transluminal coronary angioplasty), ischaemias of the heart, disorders of the renal system, oedemas, renal vasospasm, necrosis of the renal cortex, hyponatraemia, hypokalaemia, Schwartz-Bartter syndrome, disorders of the gastrointestinal tract, gastritic vasospasm, hepatocirrhosis, gastric and intestinal ulcer, emesis, emesis occurring with chemotherapy, and/or travel sickness.
Use of at least one compound according to one of claims 1 to 6 for the preparation of a medicament for treatment of diseases.
Use of at least one compound according to one of claims 1 to 6 for the preparation of a medicament for treatment of affective disorders.
Use of at least one compound according to one of claims 1 to 6 for the preparation of a medicament for treatment of anxiety disorders and/or stress-related anxiety disorders.
Use of at least one compound according to one of claims 1 to 6 for the preparation of a medicament for treatment of memory performance disorders and/or Alzheimer's disease.
Use of at least one compound according to one of claims 1 to 6 for the preparation of a medicament for treatment of psychoses and/or psychotic disorders.
Use of at least one compound according to one of claims 1 to 6 for the preparation of a medicament for treatment of Cushing's syndrome.
Use of at least one compound according to one of claims 1 to 6 for the preparation of a medicament for treatment of sleep disorders.
Compound or compounds according to one of claims 1 to 6 for use as medicaments.
Process for the preparation of a compound according to the general formula (I) wherein the radicals R¹, R², R³, A and B have the meanings mentioned in one of claims 1 to 6, characterized in that according to process variant (A) the isatin or isatin derivative, which are known per se, substituted by the radicals R¹ and R² is reacted by procedures known per se by introduction of the radical A into the 3-position to give the corresponding 3-hydroxy-oxindole derivative, followed by introduction of the B-SO₂ radical on the ring nitrogen and exchange of the radical R³ for the 3-hydroxyl group or another suitable leaving group or according to process variant (B) the isatin or isatin derivative, which are known per se, substituted by the radicals R¹ and R² is first substituted by procedures known per se by introduction of the radical B-SO₂ on the ring nitrogen and reacted by subsequent introduction of the radical A into the 3-position to give the corresponding 3-hydroxy-oxindole derivative, followed by exchange of the radical R³ for the 3-hydroxyl group or another suitable leaving group.