HK1148731B - 5-halogen-substituted oxindole derivatives and their use in the manufacture of a medicament for the treatment of vasopressin-dependent diseases - Google Patents

Description

The present invention relates to new substituted Oxindol derivatives, pharmaceutical products containing them and their use in the manufacture of a medicinal product for the treatment of vasopressin-dependent diseases.

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

The following describes new substituted oxindoles that contain a phenylsulfonyl group at position 1. 1-phenylsulfonyl-1,3-dihydro-2H-indol-2-one has already been described as a ligand of the vasopressin receptor. WO 93/15051, WO 95/18105, WO 98/25901, WO 01/55130, WO 01/55134, WO 01/164668 and WO 01/98295 also describe derivatives that contain arylsulfonyl groups at position 1 of the oxindole aggregate. These compounds differ from the compounds of the invention mainly by the substituents at position 3.

Thus, WO 93/15051 and WO 98/25901 describe 1-phenylsulfonyl-1,3-dihydro-2H-indol-2-one as a ligand of the vasopressin receptors, where the oxindol scaffold is replaced at the 3 position by two alkyl residues which together can also form a cycloalkyl residue (spirover bonding).

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

WO 03/008407 describes 1-phenylsulfonyloxindoles in which pyridylpiperazine is bound to oxindol at the 3-position via a urea, carbamat or 2-oxoethyl group.

The use of 4- ((1-Methy) -piperidine-4-yl) -piperazine-1-carbonic acid-5-chlor-1- ((2,4-dimethoxy-phenylsulfonyl) -3- ((2-methoxy-pyridine-3-yl) -2-oxo-2,3-dihydro-1H-indol-3-yl ester is described in WO 2005/030755 as an example.

The dihydrochloride of 4- ((1-Methylpiperidine-4-yl) -piperazine-1-carbonic acid [5-chlor-1- ((2,4-dimethoxyphenylsulfonyl) -3- ((2-ethoxyphenyl) -2-oxo-2,3-dihydro-1H-indol-3-yl]-amide is described in WO 2006/005609 as example 66.

Err1:Expecting ',' delimiter: line 1 column 440 (char 439)Err1:Expecting ',' delimiter: line 1 column 310 (char 309)The main representatives of the types and subtypes of CYP in the human body are: CYP 1A2, CYP 2C9, CYP 2D6 and CYP 3A4. When used concomitantly with CYP 3A4 inhibitors (e.g. grapefruit juice, cimetidine, erythromycin) and medicinal products that are broken down by this enzyme system, they can compete for the same enzyme binding site, slow down their breakdown and thus increase the undesirable effects and side effects of the administered medicinal product.Err1:Expecting ',' delimiter: line 1 column 232 (char 231)Err1:Expecting ',' delimiter: line 1 column 249 (char 248)

The purpose of the present invention was to provide compounds for use in a procedure for the treatment or prophylaxis of various vasopressin-dependent diseases.The compounds were to exhibit high activity and selectivity, in particular high affinity and selectivity for the vasopressin V1b receptor.In addition, the substance of the invention was to have one or more of the advantages (1) to (8) above.

The problem is solved by compounds of formula I Other In which R1 stands for hydrogen, methoxy or ethoxy;R2 stands for hydrogen or methoxy;R3 stands for hydrogen, methyl, ethyl, n-propyl or isopropyl;R4 stands for ethoxy or isopropoxy;R5 stands for H or methyl;R6 stands for Cl or F;X1 stands for O, NH or CH2; andX2 and X3 stand for N or CH, provided that X2 and X3 do not stand for N at the same time; and their pharmaceutically compatible salts

Err1:Expecting ',' delimiter: line 1 column 139 (char 138)

Err1:Expecting ',' delimiter: line 1 column 399 (char 398)

C1-C4 alkyl represents a linear or branched alkyl residue with 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl, for the purpose of the present invention.

C1-C3-alkoxy is a linear or branched alkyl residue with 1 to 3 carbon atoms bound to an oxygen atom for the purpose of the present invention.

The compounds of the present invention and their pharmacologically compatible salts may also be in the form of solvates or hydrates. Solvates are understood within the scope of the present invention as crystalline forms of the compounds I or their pharmaceutically compatible salts, which contain solvent molecules embedded in the crystal lattice. Preferably, the solvent molecules are embedded in stoichiometric conditions. Hydrates are a special form of solvates; the solvent is water.

The following statements on suitable and preferred features of the invention, in particular on residues R1, R2, R3, R4, R5, R6, X1, X2 and X3 of compound I, as well as on the features of the process and use of the invention, are applicable both on their own and preferably in any combination with each other.

The compounds I are preferably provided in the form of the free base (i.e. according to structural formula I) or in the form of their acid addition salts.

In a preferred embodiment, R1 stands for hydrogen or methoxy.

In a particularly preferred embodiment, R1 and R2 stand for methoxy.

In a preferred embodiment, R3 stands for hydrogen, methyl or ethyl, especially hydrogen or methyl and especially methyl.

In a preferred embodiment, R4 stands for Ethoxy and R5 stands for H.

In an alternative preferred embodiment, R4 stands for ethoxy and R5 stands for methyl.

In an alternative preferred embodiment, R4 stands for isopropoxy and R5 stands for H.

In particular, R4 is preferred for Ethoxy and R5 for H.

In a preferred embodiment, R6 stands for Cl.

In an alternative preferred embodiment, R6 stands for F.

R6 is particularly preferred for Cl.

In a preferred embodiment, X1 stands for NH.

In an alternative embodiment, X1 stands for O.

In an alternative embodiment, X1 stands for CH2.

X1 is particularly preferred for NH or CH2 and in particular for NH.

In a preferred embodiment, one of the variables X2, X3 stands for N and the other for CH.

In a particularly preferred embodiment, X2 stands for N and X3 stands for CH.

In an alternative embodiment, X2 stands for CH and X3 stands for N.

In an alternative preferred embodiment, both variables X2, X3 stand for CH.

A preferred subject matter of the invention is compounds of formula I, in which the R1 is hydrogen or methoxy;R2 is hydrogen or methoxy;R3 is hydrogen, methyl ethyl, n-propyl or isopropyl; preferably hydrogen, methyl or ethyl;R4 is ethoxy;R5 is hydrogen;R6 is Cl;X1 is NH, O or CH2;X2 is N or CH;X3 is N or CH; where X2 and X3 do not simultaneously represent N; and the pharmaceutically compatible salts thereof.

A particularly favourable subject matter of the invention is compounds of formula I, in which the R1 is hydrogen or methoxy;R2 is hydrogen or methoxy;R3 is methyl or ethyl;R4 is ethoxy;R5 is hydrogen;R6 is Cl;X1 is NH,O or CH2;X2 is N or CH;X3 is N or CH; where X2 and X3 do not simultaneously represent N; and the pharmaceutically compatible salts thereof.

A more favourable subject matter of the invention is compounds of formula I, wherein R1Methoxy is;R2Methoxy is;R3Methyl or ethyl is;R4Ethoxy is;R5Hydrogen is;R6Cl is;X1NH is,O or CH2 is;X2N is or CH is;X3N is or CH is; where X2 and X3 do not simultaneously represent N; and the pharmaceutically compatible salts thereof.

The invention is particularly suitable for compounds of formula I, in which the R1Methoxy is;R2Methoxy is;R3Methyl or ethyl is;R4Ethoxy is;R5Hydrogen is;R6Cl is;X1NH is;X2N is or CH is;X3N is or CH is; where X2 and X3 do not simultaneously represent N; and the pharmaceutically compatible salts thereof.

An alternative even more highly preferred subject matter of the invention is compounds of formula I in which the R1Methoxy is;R2Methoxy is;R3Methyl or ethyl is;R4Ethoxy is;R5Hydrogen is;R6Cl is;X1CH2 is;X2N or CH is;X3N or CH is; where X2 and X3 do not simultaneously represent N; and the pharmaceutically compatible salts thereof.

In particular, compounds of formula I are the subject of the invention, in which: R1 is methoxy;R2 is methoxy;R3 is methyl or ethyl;R4 is ethoxy;R5 is hydrogen;R6 is cl;X1 is NH;X2 is N;X3 is CH; and the pharmaceutically compatible salts thereof.

In particular, the invention also covers compounds of formula I, in which R1 is methoxy;R2 is methoxy;R3 is methyl or ethyl;R4 is ethoxy;R5 is hydrogen;R6 is cl;X1 is NH;X2 is CH;X3 is N; and the pharmaceutically compatible salts thereof.

In particular, the invention also covers compounds of formula I, in which R1 is methoxy;R2 is methoxy;R3 is methyl or ethyl;R4 is ethoxy;R5 is hydrogen;R6 is cl;X1 is NH;X2 is CH;X3 is CH; and the pharmaceutically compatible salts thereof.

An alternative preferred subject matter of the invention is compounds of formula I, wherein R1 is hydrogen or methoxy;R2 is hydrogen or methoxy;R3 is hydrogen, methyl ethyl, n-propyl or isopropyl; preferably is hydrogen, methyl or ethyl;R4 is ethoxy;R5 is methyl;R6 is cl;X1 is NH, O or CH2;X2 is N or CH;X3 is N or CH; where X2 and X3 do not simultaneously represent N; and the pharmaceutically compatible salts thereof.

A particularly preferred alternative subject matter of the invention is compounds of formula I, wherein R1 is hydrogen or methoxy;R2 is hydrogen or methoxy;R3 is methyl or ethyl;R4 is ethoxy;R5 is methyl;R6 is cl;X1 is NH,O or CH2;X2 is N or CH;X3 is N or CH; where X2 and X3 do not simultaneously represent N; and the pharmaceutically compatible salts thereof.

An alternative more preferred subject matter of the invention is compounds of formula I, wherein R1Methoxy is;R2Methoxy is;R3Methyl or ethyl is;R4Ethoxy is;R5Methyl is;R6Cl is;X1NH is,O or CH2 is;X2N is or CH is;X3N is or CH is; where X2 and X3 do not simultaneously represent N; and the pharmaceutically compatible salts thereof.

An alternative even more highly preferred subject matter of the invention is compounds of formula I, in which the R1Methoxy is;R2Methoxy is;R3Methyl or ethyl is;R4Ethoxy is;R5Methyl is;R6Cl is;X1NH is;X2N is or CH is;X3N is or CH is; where X2 and X3 do not simultaneously represent N; and the pharmaceutically compatible salts thereof.

An alternative even more highly preferred subject matter of the invention is compounds of formula I, in which the R1Methoxy is;R2Methoxy is;R3Methyl or ethyl is;R4Ethoxy is;R5Methyl is;R6Cl is;X1CH2 is;X2N or CH is;X3N or CH is; where X2 and X3 do not simultaneously represent N; and the pharmaceutically compatible salts thereof.

In particular, compounds of formula I are the subject of the invention, wherein R1 is methoxy;R2 is methoxy;R3 is methyl or ethyl;R4 is ethoxy;R5 is methyl;R6 is cl;X1 is NH;X2 is N;X3 is CH; and the pharmaceutically compatible salts thereof.

In particular, the invention also covers compounds of formula I, in which R1Methoxy is;R2Methoxy is;R3Methyl or ethyl is;R4Ethoxy is;R5Methyl is;R6Cl is;X1NH is;X2CH is;X3N is; and the pharmaceutically compatible salts thereof.

In particular, the invention also covers compounds of formula I, in which R1Methoxy is;R2Methoxy is;R3Methyl or ethyl is;R4Ethoxy is;R5Methyl is;R6Cl is;X1NH is;X2CH is;X3CH is; and the pharmaceutically compatible salts thereof.

The most commonly used is compound I, where R1Methoxy is;R2Methoxy is;R3Methyl is;R4Ethoxy is;R5Hydrogen is is;R6Cl is;X1NH is;X2N is;X3CH is; and the pharmaceutically compatible salts thereof.

Examples of preferred embodiments of the present invention are compounds of formulae I.1 to 1.18 and their pharmaceutically compatible salts, wherein the residues X2, X3, R1, R2 and R3 each assume the meanings given in Table 1 below, per line. Other Tabelle 1:

A-1.	N	CH	Methoxy	Methoxy	Methyl
A-2.	N	CH	Methoxy	H	Methyl
A-3.	N	CH	Ethoxy	H	Methyl
A-4.	N	CH	H	H	Methyl
A-5.	N	CH	H	Methoxy	Methyl
A-6.	N	CH	Ethoxy	Methoxy	Methyl
A-7.	N	CH	Methoxy	Methoxy	Ethyl
A-8.	N	CH	Methoxy	H	Ethyl
A-9.	N	CH	Ethoxy	H	Ethyl
A-10.	N	CH	H	H	Ethyl
A-11.	N	CH	H	Methoxy	Ethyl
A-12.	N	CH	Ethoxy	Methoxy	Ethyl
A-13.	N	CH	Methoxy	Methoxy	n-Propyl
A-14.	N	CH	Methoxy	H	n-Propyl
A-15.	N	CH	Ethoxy	H	n-Propyl
A-16.	N	CH	H	H	n-Propyl
A-17.	N	CH	H	Methoxy	n-Propyl
A-18.	N	CH	Ethoxy	Methoxy	n-Propyl
A-19.	N	CH	Methoxy	Methoxy	Isopropyl
A-20.	N	CH	Methoxy	H	Isopropyl
A-21.	N	CH	Ethoxy	H	Isopropyl
A-22.	N	CH	H	H	Isopropyl
A-23.	N	CH	H	Methoxy	Isopropyl
A-24.	N	CH	Ethoxy	Methoxy	Isopropyl
A-25.	N	CH	Methoxy	Methoxy	H
A-26.	N	CH	Methoxy	H	H
A-27.	N	CH	Ethoxy	H	H
A-28.	N	CH	H	H	H
A-29.	N	CH	H	Methoxy	H
A-30.	N	CH	Ethoxy	Methoxy	H
A-31.	CH	N	Methoxy	Methoxy	Methyl
A-32.	CH	N	Methoxy	H	Methyl
A-33.	CH	N	Ethoxy	H	Methyl
A-34.	CH	N	H	H	Methyl
A-35.	CH	N	H	Methoxy	Methyl
A-36.	CH	N	Ethoxy	Methoxy	Methyl
A-37.	CH	N	Methoxy	Methoxy	Ethyl
A-38.	CH	N	Methoxy	H	Ethyl
A-39.	CH	N	Ethoxy	H	Ethyl
A-40.	CH	N	H	H	Ethyl
A-41.	CH	N	H	Methoxy	Ethyl
A-42.	CH	N	Ethoxy	Methoxy	Ethyl
A-43.	CH	N	Methoxy	Methoxy	n-Propyl
A-44.	CH	N	Methoxy	H	n-Propyl
A-45.	CH	N	Ethoxy	H	n-Propyl
A-46.	CH	N	H	H	n-Propyl
A-47.	CH	N	H	Methoxy	n-Propyl
A-48.	CH	N	Ethoxy	Methoxy	n-Propyl
A-49.	CH	N	Methoxy	Methoxy	Isopropyl
A-50.	CH	N	Methoxy	H	Isopropyl
A-51.	CH	N	Ethoxy	H	Isopropyl
A-52.	CH	N	H	H	Isopropyl
A-53.	CH	N	H	Methoxy	Isopropyl
A-54.	CH	N	Ethoxy	Methoxy	Isopropyl
A-55.	CH	N	Methoxy	Methoxy	H
A-56.	CH	N	Methoxy	H	H
A-57.	CH	N	Ethoxy	H	H
A-58.	CH	N	H	H	H
A-59.	CH	N	H	Methoxy	H
A-60.	CH	N	Ethoxy	Methoxy	H
A-61.	CH	CH	Methoxy	Methoxy	Methyl
A-62.	CH	CH	Methoxy	H	Methyl
A-63.	CH	CH	Ethoxy	H	Methyl
A-64.	CH	CH	H	H	Methyl
A-65.	CH	CH	H	Methoxy	Methyl
A-66.	CH	CH	Ethoxy	Methoxy	Methyl
A-67.	CH	CH	Methoxy	Methoxy	Ethyl
A-68.	CH	CH	Methoxy	H	Ethyl
A-69.	CH	CH	Ethoxy	H	Ethyl
A-70.	CH	CH	H	H	Ethyl
A-71.	CH	CH	H	Methoxy	Ethyl
A-72.	CH	CH	Ethoxy	Methoxy	Methyl
A-73.	CH	CH	Methoxy	Methoxy	n-Propyl
A-74.	CH	CH	Methoxy	H	n-Propyl
A-75.	CH	CH	Ethoxy	H	n-Propyl
A-76.	CH	CH	H	H	n-Propyl
A-77.	CH	CH	H	Methoxy	n-Propyl
A-78.	CH	CH	Ethoxy	Methoxy	n-Propyl
A-79.	CH	CH	Methoxy	Methoxy	Isopropyl
A-80.	CH	CH	Methoxy	H	Isopropyl
A-81.	CH	CH	Ethoxy	H	Isopropyl
A-82.	CH	CH	H	H	Isopropyl
A-83.	CH	CH	H	Methoxy	Isopropyl
A-84.	CH	CH	Ethoxy	Methoxy	Isopropyl
A-85.	CH	CH	Methoxy	Methoxy	H
A-86.	CH	CH	Methoxy	H	H
A-87.	CH	CH	Ethoxy	H	H
A-88.	CH	CH	H	H	H
A-89.	CH	CH	H	Methoxy	H
A-90.	CH	CH	Ethoxy	Methoxy	H

Among the compounds I.1 to 1.18 above, preference is given to compounds of formulae 1.1, I.3, I.5, I.7, I.9, I.11, I.13, I.15 and 1.17, where the residues X2, X3, R1, R2 and R3 have the meanings given in Table 1 for each row, and to compounds of formulae I.1, I.3, I.5, I.7 and I.13 where the residues X2, X3, R1, R2 and R3 have the meanings given in Table 1 for each row.

In particular, preference shall be given to compounds of formula 1.1 where the residues X2, X3, R1, R2 and R3 each have the meanings given in Table 1 in rows A-1, A-2, A-4, A-7, A-31, A-32, A-34, A-37, A-38, A-40, A-61, A-67 and A-85, preferably in rows A-1, A-2, A-4, A-7, A-31, A-37, A-38, A-61 and A-67, and in particular in rows A-1, A-4, A-7, A-31, A-37, A-61 and A-67.

The compounds of formula 1.3 are also of particular preference, where the residues X2, X3, R1, R2 and R3 each have the meanings given in Table 1 in rows A-1, A-7, A-31 and A-37, and preferably in rows A-1 and A-7.

The compounds of formula 1.5 are also of particular preference, where the residues X2, X3, R1, R2 and R3 each have the meanings given in Table 1 in rows A-1, A-7, A-31 and A-37, and preferably in rows A-1 and A-7.

The compounds of formula 1.7 are also of particular preference, where the residues X2, X3, R1, R2 and R3 each take the meanings given in Table 1 in rows A-1, A-4, A-31, A-34, A-37 and A-40 and preferably in row A-1.

The compounds of formula 1.13, wherein the residues X2, X3, R1, R2 and R3 are each those given in Table 1 in rows A-1, A-2, A-4, A-31, A-32 and A-34 and preferably the meanings given in row A-2, are also of particular preference.

Among these particularly favourable compounds, compounds I.1, 1.3, 1.5 and 1.7 are again preferred, with the residues X2, X3, R1, R2 and R3 having the meanings given for the respective compounds.

The compounds of the invention I have a chirality centre at the 3-position of the 2-oxindol ring. The compounds of the invention can therefore be enriched as a 1:1 mixture of enantiomers (racemat) or as a non-racemic mixture of enantiomers in which one of the two enantiomers, either the left-rotating (i.e. minus-rotating) enantiomer (immediate (-) enantiomer) or the right-rotating (i.e. plus-rotating) enantiomer (immediate (+) enantiomer) has a vibrational level, or the enantiomer is essentially enantiomeric, which means that the enantiomer is essentially enantiomeric (+) or the enantiomer is essentially enantiomeric (-) and cannot be defined as an enantiomeric compound, which means that the enantiomer is essentially enantiomeric (+) or that the enantiomer is essentially enantiomeric (-) and therefore no enantiomer can be defined as an enantiomeric compound, which is essentially enantiomeric (+) or enantiomeric (-), and which is essentially enantiomeric in the same enantiomer.

Err1:Expecting ',' delimiter: line 1 column 49 (char 48)

In one embodiment of the invention, the compounds of the invention are present as essentially enantiomeric compounds; in particular, compounds with an enantiomeric surplus of at least 85% ee, more preferably at least 90% ee, more preferably at least 95% ee and in particular at least 98% ee are preferred.

The invention thus covers both pure enantiomers and mixtures thereof, e.g. mixtures in which an enantiomer is present in enriched form, but also the racemates.

The preferred embodiments of the invention are compounds of formula I, as described above, characterized by their presence in optically active form, each of which is the right-rotating (i.e., positive-rotating) enantiomer of the free base of the polarized light oscillating plane of the compound of formula I in question, or a pharmaceutically compatible salt thereof.

In particular, compounds of general formula I and their pharmaceutically compatible salts, as described above, in which the corresponding (+) enantiomer is present in an enantiomeric excess greater than 50% ee, in particular at least 80% ee, more than 90% ee, more than 95% ee and in particular at least 98% ee.

Also preferred embodiments of the invention are compounds of general formula I, as described above, characterized by their presence in optically inactive form, i.e. in the form of the racemate, or in the form of a pharmaceutically compatible salt of the racemate.

The indications of the direction of rotation of the polarized light made in the present invention are preferably those of signs [(+) or (-)] as detected in chloroform as a solvent or in mixtures of solvents containing chloroform, especially in chloroform.

The following are examples of synthetic pathways for the production of the oxindol derivatives of the invention.

The preparation of the compounds of the invention may be carried out using the rules for the synthesis of analogue compounds described in WO 2005/030755 and WO 2006/005609 and is described, for example, in synthesis schemes 1 to 3, in which the variables have the same meanings as in formula I.

3-hydroxy-1,3-dihydroindole-2-one IV can be obtained by adding metallic heterocycles III to the 3-ketogroups of isatine II. The metallic heterocycles, such as the corresponding Grignard (Mg) or organyllithium compound, can be obtained in the usual way from halogen or hydrocarbon compounds. Examples of such formulations are given in Houben-Weyl, Methods of Organic Chemistry, Vol. 13, Chapters 1-2, Mg and Li respectively. Isatine II is either commercially available or has been produced by analogy with the methods described in the literature (Advances in Heterocyclic Chemistry, A.R. Katzky and A.J. Boulton, New York, 1975, J.C. 12, 2001, pp. 27-34; New York, J.C. 18, 2001, pp. 27-32; Academic Press, J.C. 12, 1975).

The 3-hydroxyoxindole IV can be transferred to the compounds V, which carry a flue group LG' in the 3-position, where the flue group LG' is a common starting group, such as chloride or bromide.

The V compounds can then be converted to the sulphonylated product VIII by treatment with sulphonic acid chlorides VII after deprotonation with a strong base such as potassium tert butylate or sodium hydride in DMF. The sulphonic acid chlorides VII used can be either purchased or produced by known processes (e.g. J. Med. Chem. 40, 1149 (1997)).

The preparation of the compounds of general formula I, which have a urea group in the 3-position, can be carried out in a two-step process as described in WO 2005/030755 and WO 2006/005609 and shown in synthesis diagram 1: First, the compounds VIII with chlorophyll phenylester are converted to the corresponding phenylcarbamate IX in the presence of a base, such as pyridine.

The subsequent implementation with amines X, where appropriate at elevated temperature and with the addition of auxiliary bases such as triethylamine or diisopropylethylamine, results in the compounds of the invention of the general formula (I) with urea bridge (X1 = NH). The amines X can either be purchased or produced by methods known in the literature. The representation of the compounds of the invention I with R3 = H can be done by using corresponding Boc-protected amines X (R3 = Boc). The Boc protective group can then be removed, for example by treatment with thorium acids in dichloromethane. Other

The compounds of the invention of general formula I, which contain a carbamat group in the 3-position (X1 = O), can be prepared as described in WO 2006/005609 and shown in synthesis diagram 2: first, the 3-hydroxycompound IV is converted with chloramic acid phenylester to the phenylcarbonate derivatives Xla and/or Xlb. With an excess of X, the carbamat derivatives XII are obtained, which can then be transferred under normal conditions (deprotonation with a strong base, such as sodium or potassium tert-butylate in a suitable solvent, such as DMF, followed by treatment with sulphur chloride) to the invention compounds VII, such as carbamat bridges. Other

The preparation of the compounds of the invention of general formula I, which carry a 2-oxoethyl group in the 3-position (X1 = CH2), can be done as shown in synthesis diagram 3. The introduction of acetic acid grouping can be done in a 4-step sequence as described in WO 2006/005609 (1st substitution of the escape group LG' in V with the sodium salt of dimethylmalonate, 2nd solution of the first ester group, 3rd thermal decarboxylation, 4th solution of the second group). The side chain X can be produced using the standard copper-hydrogenation products known in peptide chemistry, for example, N3-dimethyl (N3-dimethyl) nitrate (N-dimethyl) nitrate (N-dimethyl) nitrate (N-dimethyl) nitrate (N-dimethyl) nitrate) can be treated in a solution such as sulphur dioxide and sulphur nitrate (N-dimethyl nitrate) and can be carried out with a solution of a solvent, for example, sulphur dioxide and sulphur nitrate (N-dimethyl nitrate) and a solution of a sulphuric acid such as sulphur nitrate (N-nitrate) such as sulphate (N-nitrate) and sulphate (N-nitrate) nitrate (N-nitrate) such as in solution, for example, with a solution of sulphenol-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N- Other

The present invention also relates to a pharmaceutical product containing at least one compound of the general formula I and/or a pharmaceutically compatible salt thereof, as described above, and a pharmaceutically compatible carrier.

A further subject matter of the present invention concerns the use of compounds of formula I and/or pharmaceutically compatible salts thereof to manufacture a medicinal product for the treatment and/or prophylaxis of vasopressin-dependent diseases.

Vasopressin-dependent diseases are those in which the course of the disease is at least partially dependent on vasopressin, i. e. diseases that show an increased level of vasopressin that may directly or indirectly contribute to the disease picture.

Err1:Expecting ',' delimiter: line 1 column 513 (char 512)

In another preferred embodiment, the present invention relates to the use of compounds of formula I or pharmaceutically compatible salts thereof to manufacture a medicinal product for the treatment and/or prophylaxis of diseases selected from 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 vasospasmotherapy, renal cortex, hyponemia, necrotic nephropathy, Schwartz-Bartter syndrome, gastrointestinal disorders, gastroesophageal reflux, hepatocytosis, gastroesophageal reflux, and gastroesophageal reflux, and in the case of chemotherapy and chemotherapy of the gastrointestinal tract.

The compounds of formula I or their pharmaceutically compatible salts or the pharmaceutical products of the invention may also be used to treat various vasopressin-dependent disorders that have central nervous causes or changes in the hypothalamic pituitary adrenal axis, for example in affective disorders such as depressive disorders and bipolar disorders, including, for example, dysthymic disorders, phobias, post-traumatic stress disorders, generalized anxiety disorders, panic disorders, seasonal depression and sleep disorders.

The compounds of formula I or their pharmaceutically compatible salts or the pharmaceutical products of the invention may also be used 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.

Furthermore, the compounds of the invention may also be used to treat memory disorders, Alzheimer's disease, psychosis, psychotic disorders, sleep disorders and/or Cushing's syndrome and all stress-related diseases.

Accordingly, another preferred embodiment of the present invention concerns the use of compounds of formula I or pharmaceutically compatible salts thereof in the formulation of a drug for the treatment of mood disorders.

In another preferred embodiment, the present invention relates to the use of compounds of formula I or pharmaceutically compatible salts thereof to manufacture a drug for the treatment of anxiety disorders and/or stress-related anxiety disorders.

In another preferred embodiment, the present invention relates to the use of compounds of formula I or pharmaceutically compatible salts thereof to manufacture a drug for the treatment of memory impairment and/or Alzheimer's disease.

In another preferred embodiment, the present invention relates to the use of compounds of formula I or pharmaceutically compatible salts thereof according to the invention to produce a drug for the treatment of psychosis and/or psychotic disorders.

In another preferred embodiment, the present invention relates to the use of compounds of formula I or pharmaceutically compatible salts thereof to manufacture a drug for the treatment of Cushing's syndrome or other stress-related disorders.

In another preferred embodiment, the present invention relates to the use of compounds of formula I or pharmaceutically compatible salts thereof to produce a drug for the treatment of sleep disorders.

In another preferred embodiment, the present invention relates to the use of compounds of formula I or pharmaceutically compatible salts thereof to manufacture a drug for the treatment of depressive disorders.

Err1:Expecting ',' delimiter: line 1 column 387 (char 386)

In another preferred embodiment, the present invention relates to the use of compounds of formula I or pharmaceutically compatible salts thereof to manufacture a drug for the treatment and/or prophylaxis of drug, drug and/or other-mediated dependencies, for the treatment and/or prophylaxis of stress due to the removal of one or more of the dependent factors, and/or for the treatment and/or prophylaxis of stress-induced relapses into drug, drug and/or other-mediated dependencies.

In another preferred embodiment, the present invention relates to the use of compounds of formula I or pharmaceutically compatible salts thereof according to the invention to manufacture a drug for the treatment and/or prophylaxis of schizophrenia and/or psychosis.

The patient to be treated with the prophylactic or therapeutic procedure is preferably a mammal, such as a human or a non-human mammal or a non-human transgenic mammal.

The compounds of general formula I and their pharmaceutically compatible salts, as described above, may be manufactured by a professional knowledgeable in the technical knowledge of the invention in the form and/or in the analogue version of known steps.

The compounds I and their pharmaceutically compatible salts are characterised by selectivity for the vasopressin receptor subtype V1b to at least one of the closely related vasopressin/oxytocin receptor subtypes (e.g. vasopressin V1a, vasopressin V2 and/or oxytocin).

Alternatively or preferably additionally, the compounds I and their pharmaceutically compatible salts are characterised by improved metabolic stability.

For example, the metabolic stability of a compound can be measured by incubating a solution of this compound with liver microsomes of a particular species (e.g. rat, dog or human) and determining the half-life of the compound under these conditions (RS Obach, Curr Opin Drug Discov Devel. 2001, 4, 36-44). This can be concluded from an observed longer half-life to an improved metabolic stability of the compound.Err1:Expecting ',' delimiter: line 1 column 710 (char 709)

The compounds of the invention have a variety of effects after administration, such as intravenous, intramuscular, subcutaneous, topical, intratracheal, intranasal, transdermal, vaginal, rectal, sublingual, buccal or oral, and are often administered intravenously, intramuscularly or particularly orally.

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

These medicinal products are selected according to the pharmaceutical form and the intended application and are generally known to the professional.

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

The appropriate forms of administration (dose units) include oral forms such as tablets, gelatine capsules, powder, granules and oral solutions or suspensions, sublingual, buccal, intratracheal or intranasal forms, aerosols, implants, subcutaneous, intramuscular or intravenous forms and rectal 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 substance may vary between 0.01 and 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 active substance is mixed with a solid 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 substance with an extender 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 substances together with a sweetener, preferably calorie-free, methyl or propyl parabens as antiseptics, a flavouring and an appropriate colouring.

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

Rectal or vaginal administration is achieved by the use of suppositories prepared with binders that melt at rectal temperature, for example cocoa butter or polyethylene glycols. 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 invention, the products of the invention may contain other active substances which may be useful in the treatment of the disorders or diseases mentioned above.

The present invention thus continues to apply to pharmaceutical products in which several active substances are present together, at least one of which is a compound I or a salt thereof.

The invention is explained in more detail below by means of examples, which are not intended to be exhaustive.

The compounds of the invention may be produced by various synthesis routes. e above-mentioned rules, as described in the synthesis schemes 1, 2 and 3, are only illustratively explained by the examples mentioned, without being limited to the synthesis routes 1, 2 or 3 or analogue rules mentioned.

The experimental part Abbreviations used:

The following information is provided for the purpose of the calculation of the maximum residue levels for the product concerned:

I. Manufacture of the starting compounds (a) 3-hydroxyndol of general formula IV a.1 5-Chlor-3- ((2-Etoxy-Pyridine-3-y) -3-Hydroxy-1,3-Dihydroindol-2-one, whether or not chemically defined

Formation of isatin sodium salt: For 13.9 g (76.5 mmol) of 5-chlorosatin in 300 ml THF, 3.21 g (80.3 mmol) of sodium hydride (60% in mineral oil) was added at 0 °C per serving and stirred for one hour at 0 °C.

Formation of the Grignard reagent: Ethylmagnesium bromide (95.6 mmol, 95.6 ml of 1 M solution in THF) was dripped into a solution of 2-Ethoxy-3-Iodopyridine (20.0 g, 80.3 mmol) in 250 ml THF, maintained at 15 to 22 °C, and the reaction mixture was stirred for 15 min at room temperature.

Grignard addition: The solution of the Grignard reagent was pumped into the ice-cold solution of isatin sodium salt and stirred for three hours at room temperature. The solution was poured into 10% ammonium chloride solution and extracted three times with acetic acid. The combined organic phases were washed with water and saturated saline solution, dried with magnesium sulfate and pressurized under reduced pressure. The crystalline precipitate formed after staying overnight at room temperature was sucked and washed with acetic acid. The following is the list of the isotopes of the IC:

a.2 5-Chlor-3- ((2-Etoxy-5-methylpyridine-3-yl) -3-hydroxy-1,3-dihydroindol-2-one

Formation of isatin sodium salt: For 5.0 g (27.5 mmol) 5-chlorosatin in 100 ml THF, 1.01 g (27.5 mmol) sodium hydride (60% in mineral oil) was added at 0 °C per serving and stirred for one hour at 0 °C.

Formation of the lithium reagent: n-Butyllithium (37.2 mmol, 23.2 ml of a 1.6 M solution in hexane) was dripped into a solution of 3-bromo-2-ethoxy-5-methylpyridine (7.74 g, 35.8 mmol) in 100 ml THF, cooled to -78 °C, kept below 60 °C, and then stirred in the acetone/ dry ice bath for another 15 min.

Addition: The lithiated pyridine solution, cooled to -78 °C, was pumped by transfer needle into the isatin sodium salt solution, which was cooled to -78 °C, and the reaction mixture was stirred for three hours at room temperature. The reaction mixture was poured into 10% ammonium chloride solution and extracted three times with acetic acid. The combined organic phases were washed with water and saturated saline, dried over magnesium sulfate and narrowed under reduced pressure. The following is the list of the isotopes of the IC:

a.3 5-Chlor-3- (((2-Isopropoxy-Pyridine-3-yl) 3-Hydroxy-1,3-Dihydroindol-2-one

The title compound was prepared by analogy with the method in example a.1 using 3-lod-2-isopropoxypyridine.

(b) Amine of general formula X The following substances are to be classified in the same category as the active substance: The following characteristics are specified for the purpose of the above-mentioned equipment:

29.2 g (256 mmol) N-Ethylpiperazine was presented with 50.0 g (256 mmol) tert-butyl 4-oxopiperidin-1 carboxylate (corresponding to 1-Boc-4-piperidone) refrigerated in 800 ml of ethanol. 15.4 g (256 mmol) ice vinegar was added. Then 16.1 g (256 mmol) sodium eluum acetoxyborhydrate was added to the refrigerated reaction mixture in portions. Initially, a slight gas formation and foaming was observed after 2/3 of the reducing agent was added. The reaction mixture was stirred overnight at room temperature. The reaction solution was mixed with 200 ml of 2 N-methyl nitrate to obtain a solution that dissolves the dissolving solvent leaving the ethanol in the refrigerator. The solution was dissolved in water as a vacuum solution containing 53% (14-Ml) methanol and 1-4-methyl methanol (14-Ml) and obtained as a solution containing methanol, methanol, methanol, chloride and magnesium (14-Ml) in the form of a solution containing 10 mg (14-Ml) of methanol (14-Ml) and dissolved in water as a solution containing methanol (14-Ml) and 1-4-methyl methanol (14-Ml) in the form of a solution containing methanol.

The following are to be considered as 'technology' in the context of the 'technology' category:

For the removal of the protective groups, 40 g (135 mmol) tert-butyl 4- ((4-ethylpiperazine-1-yl) piperidine 1-carboxylate of example b.1.1 was introduced in 200 ml of methanol and 1.8 I dichloromethane and added to 100 ml of 5-6 M HCl solution in isopropanol. A suspension was formed, with slight gas development. The solution was stirred for one hour at 40 °C (water bath temperature) and stirred for 48 hours at room temperature. For complete removal, 50 ml of the 5-6 M HCl solution were added to isopropanol and the solution was stirred at 40 °C. The solution was dissolved in ammonium chloride.The reaction mixture was stirred for one hour at the back flow, forming a white suspension with strong gas development, then a thin liquid suspension was formed, which was cooled to room temperature, the precipitate was sucked out and washed with methanol and diethyl ether, and after drying 36 g (117 mmol, 87%) of 1-ethyl-4-piperidine-4-yl-piperazine was isolated as a chloride salt. The test chemical is used to determine the concentration of the active substance in the test chemical.The time of the test is 1 hertz.

Manufacture of racemic compounds of formula I

The compounds I of the invention have been purified in some cases by preparative HPLC, for example by a Prontosil Prep 2012, C18, 125x20 mm, 5 μm column with a solvent gradient of 10% to 100% acetonitrile in water and 0.1% trifluoroacetic acid as a modulator.

Manufacture of racemic compounds of formula I, where X1 stands for NH (examples 1 to 21) The following is the list of the categories of vehicles: (±) 4-methylpiperidine-4-yl) -piperazine-1-carbonic acid [5-chlor-1- (±) 2,4-dimethoxyphenylsulfonyl) 3- (±) 2-ethoxy-pyridine-3-yl) 2-oxo-2,3-dihydro-1H-indol-3-yl]-amide The following shall be added to the list of active substances:

After cooling the reaction mixture to 0 °C, 3.8 ml (52.3 mmol) of thionyl chloride was added. The mixture was stirred at room temperature for one hour and then poured into ice water. After 15 minutes of stirring, the organic phase was separated. The aqueous phase was extracted several times with dichloromethane. The organic phase was dried by combining magnesium, filtered and dissolved. 15.6 g of magnesium was dissolved as a solid without further dissolving in the next step of purification.

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

A refrigerated solution of 47 g (145 mmol) 3.5-dichlor-3-(2-ethoxy-pyridin-3-yl) -1.3-dihydroindol-2-one in 250 ml of dichloromethane was dripped with 104 ml (728 mmol) of 7 N methanol ammonia solution in a nitrogen atmosphere and then stirred overnight at room temperature. The reaction mixture was mixed with 250 ml of water and 250 ml of dichloromethane. After 5 min. stirring, a white solid was released, which was filtered and washed with water and dichloromethane. The following is the list of the substances that are to be used in the test:

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

A solution of 20 g (66 mmol) 3-amino-5-chlor-3- ((2-ethoxy-pyridin-3-yl) -1,3-dihydroindol-2-one in 50 ml anhydrous dimethylformamide was added to a solution of 3.2 g (79 mmol) sodium hydride (60% dispersion in mineral oil) in a nitrogen atmosphere and cooled in an ice bath. The solution was stirred for 10 min at 0 °C, followed by 18.7 g (79 mmol) 2,4-dimethoxy-benzolsulfonyl chloride and stirred for 30 min at room temperature. The reaction mixture was soaked in water and then extracted with an acidic solution. The organic phase was washed with a sodium chloride solution, which dissolved the nitrogen oxide and dissolved the magnesium oxide. The solution was purified in a solution of man-made chloride of about 25% by dissolving the red Magnetic Magnetic Resin. The solution was treated with a white man-made chloride solution (120 to 34 g) and treated with a solution of red man-made chloride. The following information shall be provided for the purpose of the calculation of the sample:

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

The reaction mixture was diluted with dichloromethane and extracted with water. The organic phase was washed with water and saturated saline, dissolved in magnesia sulphate and dried slightly under pressure. The back of the chloroplast narrowed in volume and discharged the six-membered diethylene nitrate. The manopropyl was removed from the liquid as a white liquid, and the manopropyl was washed in the vacuum. The test chemical is a chemical that is used to produce a substance.

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

A mixture of 800 mg (1.28 mmol) [5-Chlor-1-(2,4-dimethoxy-phenylsulfonyl) -3- ((2-ethoxy-pyridine-3-yl) -2-oxo-2,3-dihydro-1H-indol-3-yl) -carbamic acid phenylester, 470 mg (2.56 mmol) 1-methylpiperidine-4-yl) piperazine and 5 ml of dried THF was stirred at room temperature for 24 hours, the reaction mixture was diluted with dichloromethane, washed with water and saturated saline, the organic phase was dried with magnesium sulphate and reduced to a narrow pressure. The residue was chromatographically soluble in silica (12 g red chloroplast, 12% to 12% methanol) in a purified solid of 790 mg titanium methane. The following is the list of the isotopes of the IC: The mean of the measurements of the two samples is given by the mean of the measurements of the two samples.

The compounds of formula I, where X1 stands for NH, as described in examples 2 to 21, may be prepared by using the corresponding 3-hydroxyoxindoles of formula IV, sulphonyl chlorides of formula VII and amines of formula X, analogously to the manufacturing process described in example 1.

The following is the list of the categories of products: 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 (-75oF to -15oF).]

The test chemical is used to determine the concentration of the substance in the test medium.

The following is the list of the categories of products: (±) -4-methylpiperidine-4-yl) -piperazine-1-carbonate [1-phenylsulfonyl-5-chlor-3-(2-ethoxypyridine-3-yl) --2-oxo-2,3-dihydro-1H-indol-3-yl]amide, the salt of trifluoroacetic acid A-977409

The following is the list of the substances that are to be used in the test:

The following is the list of the categories of products: The following substances are to be classified in the immediate vicinity of the test chemical:

The mean of the measurements of the two samples is given by the mean of the measurements of the two samples.

The following is the list of the categories of products: The following substances are to be classified in the immediate vicinity of the test chemical:

The mean of the measurements of the two samples is given by the mean of the measurements of the two samples.

The following is the list of the categories of products: (±) 4-methylpiperazine-1-yl) piperidine-1-carbonate[5-chlorine-3-methyl-2-ethoxy-pyridine-3-yl)-1-methyl-2-phenylsulfonyl) 2-oxo-2,3-dihydro-1H-indol-3-yl]amide, the salt of acetic acid trifluoric acid

The following is the list of the isotopes of the IC:

The following is the list of the categories of products: It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5 and boiling in the range of approximately -15 oC to -15 oC (- 372oF to -157oF).]

The following is the list of the substances that are to be used in the test:

The following is the list of the categories of products: It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

The following is the list of the isotopes of the IC: The mean of the measurements of the two samples is given by the mean of the measurements of the two samples.

The following is the list of the categories of products: (±) 4-Ethylpiperazine-1-yl) piperidine-1-carbonate [5-Chlor-3-Ethyl-2-Ethyoxy-Pyridine-3-yl) 1-Methoxy-Phenylsulfonyl) 2-Oxo-2,3-Dihydro-1H-Indol-3-yl]amide, the salt of acetic acid trifluoride

The following is the list of the substances that are to be used in the test:

The following is the list of the categories of products: 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 (-75oF to -15oF).]

The test chemical is used to determine the concentration of the substance in the test medium.

The following is the list of the categories of products: (±) -[4,4']Bipiperidinyl-1-carbonic acid [5-chlor-1-[2,4-dimethoxyphenylsulfonyl]-3-[2-ethoxypyridine-3-yl) --2-oxo-2,3-dihydro-1H-indol-3-yl]amide, the salt of trifluoroacetic acid

The test chemical is used to determine the concentration of the substance in the test medium.

The following is the list of the categories of products: (±) 1'-Ethyl[4,4']bipiperidinyl-1-carbonic acid [5-chlor-1-[2,4-dimethoxyphenylsulfonyl]-3-[2-ethoxypyridine-3-yl) --2-oxo-2,3-dihydro-1H-indol-3-yl]-amide

The following is the list of the substances that are to be used in the test:

The following is the list of the categories of vehicles: (±) 1'-Methyl-[4,4']bipiperidinyl-1-carbonic acid[5-chlor-1-[2,4-dimethoxyphenylsulfonyl]-3-[2-ethoxypyridine-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]amide

The following is the list of the substances that are to be used in the test: The mean of the measurements of the two samples is given by the following equation:

The following is the list of the categories of vehicles: (±) -4-methylpiperidine-4-yl) -piperazine-1-carbonic acid [5-chlor-1- (±) 2,4-dimethoxyphenylsulfonyl) -3- (±) 2-ethoxy-5-methylpyridine-3-yl) 2-oxo-2,3-dihydro-1H-indol-3-yl]amide, trifluoroacetic acid salt

The following information shall be provided for the purpose of the analysis: The mean of the measurements of the two samples is calculated as the mean of the measurements of the two samples.

The following is the list of the categories of products: (±) -4- (piperidine-4-yl) -piperazine-1-carbonate (piperidine-4-yl) -piperazine-1-carbonate (piperidine-4-yl) -piperazine-1-carbonate (piperidine-4-yl) -piperazine-1-carbonate (piperidine-4-yl) -piperazine-1-carbonate (piperidine-4-yl) -piperazine-1-carbonate (piperidine-4-yl) -piperidine-1-carbonate (piperidine-4-yl) -piperidine-1-carbonate (piperidine-1-carbonate) -piperidine-1-carbonate (piperidine-1-carbonate) -piperidine-1-carbonate (piperidine-1-hydroxy) -piperidine-2-hydroxy) -piperidine-2-hydroxy (piperidine-2-hydroxy) -piperidine-2-hydroxy) -piperidine-2-hydroxy (piperidine-2-hydroxy) -piperidine-2-hydroxy) -piperidine-2-hydroxy (piperidine-2-hydroxy) -piperidine-2-hydroxy (piperidine-2-hydroxy) -piperidine-2-hydroxy) -piperidine-2-hydroxy (piperidine-2-hydroxy) -piperidine-2-hydroxy (piperidine-2-hydroxy) -pipropropy) -piperidine-2-hydroxy (piperidine-2-hydroxy) -piperidine-2-hydroxy (pipropropy) -piperidine-2-hydroxy (pipropropy) -piperidine-2-hydroxy) -pipropropy) -piperidine-dioxide, which is the salt of the salt of the trifluoric acid

The following is the list of the substances that are to be used in the test:

The following is the list of the categories of products: 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 (-75oF to -15oF).]

The following information shall be provided for the purpose of the analysis:

The following is the list of the categories of vehicles: It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5 and boiling in the range of approximately -15 oC to -15 oC (- 372oF to -157oF).]

The following is the list of the isotopes of the IC:

The following is the list of the categories of vehicles: The following substances are to be classified in the immediate vicinity of the test chemical:

The mean of the measurements of the two samples is given by the mean of the measurements of the two samples.

The following is the list of the categories of vehicles: (±) 4- (piperidine-4-yl) -piperazine-1-carbonate [5-chlor-1- (piperidine-2-yl) -dimethoxyphenyl sulphonyl) -3- (piperidine-3-yl) -2-isopropoxy-pyridine-2-oxo-2,3-dihydro-1H-indol-3-yl) -amide

The following is the list of the substances that are to be used in the test:

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

The following information shall be provided for the purpose of the analysis:

The following is the list of the categories of vehicles: It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

The following is the list of the substances that are to be used in the test:

11.2 Production of the racemic compounds of formula I, where X1 stands for O (examples 22 to 27) The following is the list of the categories of products: (±) -4-methylpiperidine-4-yl) -piperazine-1-carbonic acid 5-chlor-1- (±2-dimethoxyphenylsulfonyl) -3- (±2-ethoxypyridine-3-yl) -2-oxo-2,3-dihydro-1H-indol-3-yl ester, trifluoroacetic acid salt It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

A solution of 3.00 g (9.8 mmol) 5-Chlor-3-(2-ethoxypyridin-3-yl) -3-hydroxy-1,3-dihydroindol-2-one from example a.1 was slowly dripped into 10 ml of pyridine to a solution cooled to 0 °C. 2.6 ml (21 mmol) of chlorophyll phenylester was slowly dripped into 10 ml of pyridine and stirred overnight at room temperature. The reaction mixture was diluted with dichloromethane and extracted with water. The organic phase was washed with water and saturated saline, dried over magnesium sulphate and tightly pressed. The residue was removed with diethyl ether. The following is the list of the isotopes of the IC:

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

A mixture of 1.29 g (2.37 mmol) 5-chlor-3-(2-ethoxy-pyridin-3-yl)-2-oxo-3-phenoxycarbonyloxy-2,3-dihydroindol-1-carboxyphenylester, 1.73 g (9.46 mmol) 1-(1-methylpiperidin-4-yl) piperazine and 10 ml of dried THF was stirred at room temperature for 72 hours. The reaction mixture was diluted with dichloromethane and extracted with and saturated saline. The organic phase was dried over magnesium sulfate and tightly inhaled under reduced pressure. The residue was stirred with diethyl ether. 963 mg of the title compound was obtained as a white solid. The test chemical is a chemical that is used to produce a substance.

It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5 and boiling in the range of approximately -15 oC to -15 oC (- 372oF to -157oF).]

To make a solution of 80 mg (0.16 mmol) 4-(1-Methyl-piperidine-4-yl) -piperazine-1-carbonic acid 5-chlor-3-(2-ethoxy-pyridine-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl ester in 2 ml anhydrous dimethylformamide, 7.5 mg (0.19 mmol) sodium hydride (60% dispersion in mineral oil) was added under nitrogen atmosphere and refrigerated in an ice bath. It was stirred for 10 min at 0 °C, then added 44 mg (0.19 mmol) 2,4-dimethoxybenzolesulfonyl chloride and stirred for a further 30 min at room temperature. The reaction mixture was boiled in water and extracted with pre-acidized iron. The organic phase was washed with 0.1 mg of sodium chloride (a solid solution of 78% magnesium sulphate) and purified with 10% of the residual acid, titrated to 125 HP. The solution was purified with a sodium chloride solution of 0.1 mmol, purified in the presence of 5% of magnesium sulphate (PrPrPr18, L) and purified in the presence of 10% of sodium sulphate. The following is the list of the isotopes of the IC: The mean of the measurements of the two samples is calculated as the mean of the measurements of the two samples.

The compounds of formula I, where X1 stands for O, as described in examples 23 to 27, can be prepared by using the corresponding 3-hydroxyoxindoles of formula IV, sulphonyl chlorides of formula VII and amines of formula X, analogously to the manufacturing process described in example 22.

The following is the list of the categories of products: (±) -4-methylpiperidine-4-yl) -piperazine-1-carbonic acid5-chlorine-3-methyl-2-ethoxy-pyridine-3-yl) -2-methyl-phenylsulfonyl-2-oxo-2,3-dihydro-1H-indol-3-yl ester, trifluoroacetic acid salt of which

The following is the list of the isotopes of the IC:

The following is the list of the categories of products: (±) 4-methylpiperidine-4-yl) -piperazine-1-carbonate 1-phenylsulfonyl-5-chloride-3--2-ethoxy-pyridine-3-yl) 2-oxo-2,3-dihydro-1H-indol-3-yl ester, salt of trifluoroacetic acid

The following is the list of the samples of ICs:

The following is the list of the categories of products: (±) 4-methylpiperazine-1-yl) -piperidine-1-carbonate5-chlor-1- (±) 2,4-dimethoxyphenylsulfonyl) -3- (±) 2-ethoxypyridine-3-yl) -2-oxo-2,3-dihydro-1H-indol-3-yl ester, trifluoroacetic acid salt

The following is the list of the isotopes of the IC:

The following is the list of the categories of products: (±) 4-methylpiperazine-1-yl) -piperidine-1-carbonate5-chlorine-3-methyl-2-ethoxy-pyridine-3-yl) -2-methyl-phenylsulfonyl-2-oxo-2,3-dihydro-1H-indol-3-yl ester, trifluoroacetic acid salt of which:

The following is the list of the isotopes of the IC:

The following is the list of the categories of products: (±) 4-methylpiperazine-1-yl) -piperidine-1-carbonate 1-phenylsulfonyl-5-chlor-3--2-ethoxy-pyridine-3-yl) --2-oxo-2,3-dihydro-1H-indol-3-yl ester, trifluoroacetic acid salt of which:

The following is the list of the samples of ICs:

11.3 Production of the racemic compounds of formula I, where X1 stands for CH2 (examples 28 to 33) The following is an example: It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5 and boiling in the range of approximately -15 oC to -15 oC (- 372oF to -157oF).] It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

A suspension of 3.56 g (89 mmol) sodium hydride (60% dispersion in mineral oil) cooled to 10 °C was slowly dripped into 150 ml of dimethylformamide, 11.2 ml (98 mmol) dimethyl malonate and stirred at room temperature for 30 minutes. Then 9.6 g (30 mmol) 3.5-dichlor-3- ((2-ethoxy-pyridine-3-yl) -1.3-dihydroindol-2-one from example were added portion by portion and stirred for 15 min at room temperature. The conversion was stirred to form cold 1N HCl and replaced with dichloromethane. The chloride was separated and the pentahedral phase was extracted. The organic phase was combined with water and sodium chloride via a sodium chloride solution, which was removed from the liquid solution and dissolved in the vacuum to form the mannitol. The following is the list of the isotopes of the IC:

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

The combined organic phase was washed with water and saturated sodium chloride solution, cooled over magnetic magnetic soil and the solvent was removed in a vacuum. The resulting liquid crystallized into a solid (8.41 g/l) at room temperature. The resulting liquid was kept at a vacuum temperature of 5.25 °C. The liquid was then cooled to a temperature of 40 °C. The resulting liquid was kept in a refrigerator at room temperature. The liquid was then cooled to a temperature of 150 °C. The resulting liquid was kept in a vacuum at room temperature. The test chemical is a chemical that is used to produce a substance.

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

The reaction mixture was stirred for 18 hours at room temperature, the solution was set to pH 5 with 1 N hydrochloric acid and then pressed at the rotational evaporation. The residue was taken up in toluene, pressed again to dry, and dried in the vacuum dryer. The product was obtained as 3.75 g raw, which was used in the next step without further cleaning. The test chemical is a chemical that is used to produce a substance.

The value of all the materials of Chapter 9 used does not exceed 20% of the ex-works price of the product

195 mg (1.44 mmol) 1-hydroxybenzotriazole and 276 mg (1.44 mmol) N-dimethylaminopropyl) N-ethylcarbodiimide hydrochloride were added to a solution of 1.00 g [5-Chlor-3- ((2-ethoxypyridine-3-yl) --2-oxo-2,3-dihydro-1H-indol-3-yl] acetic acid in 10 ml dimethylformamide, stirred for 15 minutes and then given 277 mg (1.51 mmol) 1-methylpiperidine-4-yl) piperazine and 1.00 ml (7.41 mmol) triethylamine. The reaction mixture was stirred overnight at room temperature. The solution was then mixed with water and extracted into a white liquid. The solution was mixed with red mannitol (131 mg) extracted from the extracted sodium chloride in a vacuum containing a 70% solution of methanol and magnesium. The following is the list of the isotopes of the IC:

It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5 and boiling in the range of approximately -15 oC to -15 oC (- 372oF to -202oF).]

The reaction mixture was stirred for 10 min at 0 °C, then added 39 mg of 2,4-dimethoxy-benzoyl sulphonyl chloride and stirred for 30 min at room temperature. After the reaction mixture was stirred in water and then extracted with an organic solution of 0.16 mg of mannesia. The solution was purified with a 100% solution of mannesia, a white solution of 5% of mannesia, and a 10% solution of mannesia, a white solution of 5% of mannesia. The following is the list of the substances that are to be used in the test: The mean of the measurements of the two samples is calculated as the mean of the measurements of the two samples.

The compounds of formula I, where X1 stands for CH2, as described in examples 29 to 33, may be prepared by using the corresponding sulphonyl chlorides of formula VII and amines of formula X, analogously to the manufacturing process in example 28.

The following is the list of the categories of products: It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5 and boiling in the range of approximately -15 oC to -15 oC (- 372oF to -157oF).]

The following is the list of the substances that are to be used in the test:

The following is the list of the categories of products: It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5 and boiling in the range of approximately -15 oC to -15 oC (- 372oF to -202oF).]

The following is the list of the substances that are to be used in the test:

The following is the list of the categories of products:

It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5 and boiling in the range of approximately -15 oC to -15 oC (- 372oF to -157oF).]

The following is the list of the substances that are to be used in the test:

The following is the list of the categories of products: It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5 and boiling in the range of approximately -15 oC to -15 oC (- 372oF to -202oF).]

The following is the list of the substances that are to be used in the test:

The following paragraphs shall apply: It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5 and boiling in the range of approximately -15 oC to -15 oC (- 372oF to -157oF).]

The following information shall be provided for the purpose of the calculation of the emission factor:

Manufacture of the chiral compounds of formula I

The separation of racemic compounds of formula I may be carried out, for example, by separation on a preparatory chiral column.

The following information is provided for the purpose of this report: Racetam cleavage of (±) -4- ((1-methylpiperidine-4-yl) -piperazine-1-carbonic acid [5-chlor-1- ((2,4-dimethoxyphenylsulfonyl) -3-)) 2-ethoxypyridine-3-yl) -2-oxo-2,3-dihydro-1H-indol-3-yl]amide

100 mg of racemic 4- ((1-methyl-piperidine-4-yl) -piperazine-1-carbonic acid [5-chlor-1- ((2,4-dimethoxy-phenylsulfonyl) -3- ((2-ethoxy-pyridine-3-yl) -2-oxo-2,3-dihydro-1H-indol-3-yl]amide from example 1 was separated via a chiral preparatory column (Chiralcell OD, flow 55 ml/min) with n-heptane/ethanol (7: 3) as elution agent. yield: 33 mg of the left-spinning enantiomer (example 1A) and 27 mg of the right-spinning enantiomer (example 1B).

The following is the list of the types of vehicles: (-) 4-methylpiperidine-4-yl) -piperazine-1-carbonic acid [5-chlor-1-[2,4-dimethoxyphenylsulfonyl]-3-[2-ethoxypyridine-3-yl) --2-oxo-2,3-dihydro-1H-indol-3-yl]-amide

The following is the list of the substances that are to be used in the test: The mean of the measurements of the two samples is given by the mean of the measurements of the two samples. The test chemical is a mixture of the following: The test chemical is a chemical compound with a specific chemical structure.

The following is the list of the types of vehicles:

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 (-75oF to -15oF).]

The following is the list of the substances that are to be used in the test: The mean of the measurements of the two samples is given by the mean of the measurements of the two samples. The test chemical is a mixture of the following: The test chemical is a chemical compound with a specific chemical structure.

In an analogous manner, the racemates of EXAMPLES 4, 5 and 8 can be separated while maintaining the corresponding enantiomers.

The following is the list of the types of vehicles: 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 (-75oF to -15oF).]

The following is the list of the isotopes of the IC: The mean of the measurements of the two samples is given by the mean of the measurements of the two samples. The test chemical is a mixture of the following: The test chemical is a chemical compound with a specific chemical structure.

The following is the list of the types of vehicles: (-) 4-methylpiperazine-1-yl) -piperidine-1-carbonate [5-chlor-1- (2,4-dimethoxyphenylsulfonyl) -3- (2-ethoxy-pyridine-3-yl) -2-oxo-2,3-dihydro-1H-indol-3-yl) -amide]

The following is the list of the isotopes of the IC: The mean of the measurements of the two samples is given by the mean of the measurements of the two samples. The test chemical is a mixture of the following: The test chemical is a chemical compound with a specific chemical structure.

The following is the list of the types of vehicles: It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

The following is the list of the isotopes of the IC: The mean of the measurements of the two samples is given by the mean of the measurements of the two samples. The test chemical is a mixture of the following: The test chemical is a chemical compound with a specific chemical structure.

The following is the list of the types of vehicles: It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

The following is the list of the isotopes of the IC: The mean of the measurements of the two samples is given by the mean of the measurements of the two samples. The test chemical is a mixture of the following: The test chemical is a chemical compound with a specific chemical structure.

The Commission has not yet adopted a decision on the application of Article 93 (2) of the Treaty. Vasopressin V1b receptor binding test: The following substances:

The test substances were dissolved in DMSO at a concentration of 10-2 M and further diluted in DMSO to 5x10-4 M to 5x10-9 M. This DMSO pre-dilutive series was diluted with test buffer 1:10 in the test approach and the concentration was further diluted to 1:5 in the test approach (2% DMSO in the approach).

The following shall be used for the preparation of the test chemical:

CHO-K1 cells with a stable human vasopressin V1b receptor (clone 3H2) were harvested and homogenised in 50 mM Tris-HCl and in the presence of protease inhibitors (Roche complete Mini # 1836170) with a Polytron homogenizer at the intermediate position for 2x10 seconds and then decentrified for 1h at 40,000 x g.

The test shall be carried out in accordance with the following procedure:

The binding test was performed using the method of Tahara et al. (Tahara et al., British J Pharmacol. 125, 1463-1470 (1998)). The incubation buffer was 50 mM Tris, 10 mM MgCl2, 0.1% BSA, pH 7.4. In the test approach (250 μl), membranes (50 μg/ ml protein in incubation buffer) of CHO-K1 cells with stable human V1b receptors (cell line hV1b_3H2_CHO) were incubated with 1.5 nM 3H-AVP (8-Arg-Vasopressin, PerkinElmer #18479) in incubation buffer (50 mM MgTris, 10 mMMCl2, 0.1% BSA, pH 7.4) (total binding) or with increasing concentrations of test substance (experiment of push-up). The nonspecific binding was performed with 1 MP AVP (Bachemeter # H1780) All determinations were performed as triple-testing. Subsequent incubation was performed at room temperature (60 minutes) using standard vacuum or radiofrequency filtration (Fig.

The following is the evaluation:

The binding parameters were calculated by nonlinear regression in SAS. The program's algorithms work in a manner analogous to the LIGAND evaluation program (Munson PJ and Rodbard D, Analytical Biochem. 107, 220-239 (1980)). The Kd value of 3H-AVP to the recombinant human V1b receptors is 0.4 nM and was used to determine the Ki value.

Vasopressin V1a receptor binding test: The following substances:

The test substances were dissolved in DMSO at a concentration of 10-2 M. Further dilution of these DMSO solutions was carried out in an incubation buffer (50 mM Tris, 10 mM MgCl2, 0.1 % BSA, pH 7.4).

The following shall be used for the preparation of the test chemical:

CHO-K1 cells with a stable human vasopressin V1a receptor (clone 5) were harvested and homogenised in 50 mM Tris-HCl and in the presence of protease inhibitors (Roche complete Mini # 1836170) with a Polytron homogenizer at the intermediate position for 2x10 seconds and then decentrifuged for 1 h at 40,000 x g.

The test shall be carried out in accordance with the following procedure:

The binding test was performed using the method of Tahara et al. (Tahara et al., British J Pharmacol. 125, 1463-1470 (1998)). The incubation buffer was 50 mM Tris, 10 mM MgCl2, 0.1% BSA, pH 7.4. In the test (250 μl) membranes (20 μg/ml protein in incubation buffer) of CHO-K1 cells with stable human V1a receptor expression (cell line hV1a_5_CHO) were incubated with 0.04 nM 125I-AVP (8-Arg-Vasopressin, NEX 128) in incubation buffer (50 mM Tris, 10 mMMCl2, 0.1% BSA, Mg 7.4) (total binding) or with additional increasing concentrations of test substance (expulsion experiment) with non-specific binding determined with 1 μM AVP (Bachem H #1780) and three-fold determination was performed. 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. 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 following is the evaluation:

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

Vasopressin V2 receptor binding test: The following substances:

The test substances were dissolved in DMSO at a concentration of 10-2 M. Further dilution of this DMSO solution was carried out in an incubation buffer (50 mM Tris, 10 mM MgCl2, 0.1 % BSA, pH 7.4).

The following shall be used for the preparation of the test chemical:

CHO-K1 cells with a stable human vasopressin V2 receptor (clone 23) were harvested and homogenised in 50 mM Tris-HCl and in the presence of protease inhibitors (Roche complete Mini # 1836170) with a Polytron homogenizer at the intermediate position for 2x10 seconds and then decentrifuged 1 h at 40,000 x g. The membrane pellet was again homogenised and centrifuged as described and then absorbed in 50 mM Tris-HCl, pH 7.4, homogenised and stored in aliquots at -190°C frozen in liquid nitrogen.

The test shall be carried out in accordance with the following procedure:

The binding test was performed using the method of Tahara et al. (Tahara et al., British J Pharmacol. 125, 1463-1470 (1998)). The incubation buffer was 50 mM Tris, 10 mM MgCl2, 0.1% BSA, pH 7.4. In the test (250 μl) membrane (50 μg/ ml protein in incubation buffer) of CHO-Kl cells with stable human V2 receptor expression (cell line hV2_23_CHO) were incubated with 1-2 nM 3H-AVP (8-Arg-Vasopressin, PerkinElmer #18479) in incubation buffer (50 mM Tris, 10 mM MgCl2, 0.1% BSA, pH 7.4) or with additional increasing concentrations of test substance (expulsion experiment) with incubation of 1 μM 3H-AVP (Bachem # H1780) and triple assay. 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. 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 following is the evaluation:

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

The test is performed on a single test tube. The following substances:

The substances were dissolved in DMSO at a concentration of 10-2 M and diluted with an incubation buffer (50 mM Tris, 10 mM MgCl2, 0.1% BSA, pH 7.4).

The following is the list of active substances:

Confluent HEK-293 cells with transient-expressing recombinant human oxytocin receptors were centrifuged at 750 g at room temperature for 5 minutes. The residue was collected in an ice-cold lysis buffer (50 mM Tris-HCl, 10% glycerin, pH 7.4 and Roche Complete Protease Inhibitor) and osmotically shocked for 20 minutes at 4 °C. The lysified cells were then centrifuged at 750 g at 4 °C for 20 minutes, the residue was collected in an incubation buffer and aliquots of 107 cells/ml were produced. The aliquots were frozen to use at -80 °C.

The test shall be carried out in accordance with the following procedure:

On the day of the experiment, the cells were thawed, diluted with an incubation buffer and homogenised with a multipet Combitip (Eppendorf, Hamburg). The 0.250 ml reaction set consisted of 2 to 5x104 recombinant cells, 3-4 nM 3H oxytocin (PerkinElmer, NET 858) in the presence of test substance (inhibition curve) or only incubation buffer (total binding). The nonspecific binding was determined with 10-6 M oxytocin (Bachem AG, H2510). Triple determinations were made. The bound and free bound cells were separated by vacuum filtration with Whatman GF/B glass filter. The radioactivity of a harvester was determined by a liquid-bound radioactivity measurement in a 2000 m3 or 2200 m3 (CA 2000) or a tricarb cell filter.

The following is the evaluation:

The binding parameters were calculated by non-linear regression analysis (SAS), analogous to the Munson and Rodbard (Analytical Biochem 1980; 107:220-239) LIGAND program.

The following is the calculation of the microsomal half-life:

The metabolic stability of the compounds of the invention was determined in the following test.

The test substances are incubated at a concentration of 0.5 μM as follows: In microtiter plates, 0.5 μM of test substance is pre-incubated in 0.05 μM of potassium phosphate buffer at pH 7.4 at 37 °C for 5 min. The reaction is initiated by the addition of NADPH (1 mg/mL). After 0, 5, 10, 15, 20 and 30 min, 50 μl of aliquots are taken and the reaction is immediately stopped and cooled down with the same volume of acetyltrichloroethylene. The samples are frozen until analysis. The MSMS determines the remaining concentration of non-digested test substance. The test is calculated by increasing the curve of the volume of the test substance/unit of time (LIT/mL) by a factor of 0.01 (Tb/mL) with the mean concentration of the test substance (Tb/mL) being calculated in the order of 1000 mg/mL (Tb/mL) (Tb/mL) (Tb/mL) (Tb/mL) (Tb/mL) (Tb/mL) (Tb/mL) (Tb/mL) (Tb/mL) (Tb/mL) (Tb/mL) (Tb/mL) (Tb/mL) (Tb/mL) (Tb/mL) (Tb/mL) (Tb/mL) (Tb/mL) (Tb/mL) (Tb/mL) (Tb/mL) (Tb/mL) (Tb/mL) (Tb/m (Tb) (Tb/mL) (Tb/mL) (Tb/mL) (Tb/m (Tb) (Tb) (Tb/m (Tb) (Tb/mL) (Tb) (Tb) (Tb) (Tb) (Tb/m (Tb) (Tb) (Tb) (Tb) (Tb) (Tb) (Tb) (Tb (Tb) (Tb) (Tb) (Tb) (Tb (Tb) (Tb) (Tb) (Tb (Tb)

Methods for the in vitro determination of cytochrome P450 (CYP) inhibition "Software" specially designed or modified for the "development" or "production" of equipment specified in 2B001.a. or 2B101.b.

The CYP2C9 CYP2C9 substrate is luciferin H, for CYP3A4 luciferin BE. The reaction is initiated by addition of NADPH. After 30 min incubation in RT, the luciferin detection response is added and the resulting luminescence signal measured (modified according to Promega, Technical Bulletin P450-GLOTM Assays).

Midazolam CYP 3A4 time dependent inhibition

The test consists of two parts: the test substance is pre-incubated with the liver microsomes (with NADPH = pre-incubation, then the substrate is added, in Part 2 the substrate and test substance are added simultaneously = co-incubation).

Pre-incubation:

0.05 mg/ml microsomal protein (human liver microsomes) is incubated with 0-10 μM (or 50 μM) of test substance in 50 mM potassium phosphate buffer for 5 min. The reaction is started with NADPH. After 30 min, 4 μM midazolam (final concentration) is added and incubated for another 10 min. 75 μl of the reaction solution is withdrawn after 10 min and filled with 150 μl acetone solution.

Co-incubation:

0.05 mg/ml microsomal protein (human liver microsomes) is incubated with 4 μM midazolam (final concentration) and 0-10 μM (or 50 μM) of test substance in 50 mM potassium phosphate buffer for 5 min. The reaction is initiated with NADPH. 75 μl of the reaction solution is taken after 10 min and filled with 150 μl acrylonitrile solution. The samples are frozen until MSMS analysis (modified according to literature references: Obdach, Journal of Pharmacology & Experimental Therapeutics, Vol 316, 1, 336-348, 2006; Walsky, Drug Metabolism and Disposition, Vol 32, 6, 647-660, 2004).

Method of determination of water solubility (in mg/ml)

Err1:Expecting ',' delimiter: line 1 column 140 (char 139)

8. results

The results of the receptor binding assays are expressed as receptor binding constants [Ki ((V1b) ] and selectivities [Ki ((V1a) / Ki ((V1b) ] respectively.

In these tests, the compounds of the invention show very high affinities for the V1b receptor (maximum 100 nM, or maximum 10 nM, often < 1 nM), high selectivity for the V1a receptor and good metabolic stability as measured by microsomal clearance.

The results are given in Table 2 and the number of compounds refer to the synthesis samples. Other Tabelle 2

Beispiel
1	+++	+++	+
3	++	++	+++
13	+++	++	+
14	+++	+++	++
15	+++	++	+
16	+++	+	+
17	+++	+	+
24	++	++	++
28	+++	++	+
29	++	+	+++
32	+++	+	++
1B	+++	+++	+++
4B	+++	+++	++
5B	+++	+++	+++
8B	+++	+++	+

Tabelle 2

* h = human

Schlüssel:

			Humane mikrosomale Clearance
+	> 10 - 100 nM	10 - < 25
++	1 - 10 nM	25 - 75
+++	< 1 nM	> 75

Claims (20)

1. Compound of the formula I in which

   R¹ is hydrogen, methoxy or ethoxy;

   R² is hydrogen or methoxy;

   R³ is hydrogen, methyl, ethyl, n-propyl or isopropyl;

   R⁴ is ethoxy or isopropoxy;

   R⁵ is H or methyl;

   R⁶ is Cl or F;

   X¹ is O, NH or CH₂; and

   X² and X³ are N or CH, with the proviso that X² and X³ are not simultaneously N;

   and their pharmaceutically acceptable salts.
2. Compound according to claim 1, in which R¹ is hydrogen or methoxy.
3. Compound according to claim 1, in which R¹ and R² are methoxy.
4. Compound according to any of the preceding claims, in which R³ is hydrogen, methyl or ethyl.
5. Compound according to any of the preceding claims, in which R⁴ is ethoxy and R⁵ is H.
6. Compound according to any of claims 1 to 4, in which R⁴ is ethoxy and R⁵ is methyl.
7. Compound according to any of claims 1 to 4, in which R⁴ is isopropoxy and R⁵ is H.
8. Compound according to any of the preceding claims, in which R⁶ is Cl.
9. Compound according to any of claims 1 to 7, in which R⁶ is F.
10. Compound according to any of the preceding claims, in which X² is N and X³ is CH.
11. Compound according to any of claims 1 to 9, in which X² is CH and X³ is N.
12. Compound according to any of the preceding claims, in which

    R¹ is methoxy;

    R² is methoxy;

    R³ is methyl;

    R⁴ is ethoxy;

    R⁵ is H;

    R⁶ is Cl;

    X¹ is NH;

    X² is N; and

    X³ is CH.
13. Compound according to any of claims 1 to 11, in which

    R¹ is methoxy;

    R² is methoxy;

    R³ is methyl;

    R⁴ is ethoxy;

    R⁵ is methyl;

    R⁶ is Cl;

    X¹ is NH;

    X² is N; and

    X³ is CH.
14. Compound according to any of claims 1 to 11, in which

    R¹ is methoxy;

    R² is methoxy;

    R³ is ethyl;

    R⁴ is ethoxy;

    R⁵ is H;

    R⁶ is Cl;

    X¹ is NH;

    X² is N; and

    X³ is CH.
15. Compound according to any of claims 1 to 11, in which

    R¹ is methoxy;

    R² is methoxy;

    R³ is methyl;

    R⁴ is ethoxy;

    R⁵ is H;

    R⁶ is Cl;

    X¹ is NH;

    X² is CH; and

    X³ is N.
16. Compound according to any of the preceding claims, which is the (+) enantiomer in an enantiomeric purity of at least 90% ee.
17. Compound according to any of claims 1 to 15, which is the racemate.
18. Pharmaceutical composition comprising at least one compound of the formula I as defined in any of the preceding claims and/or at least one pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier.
19. Use of compounds of the formula I as defined in any of claims 1 to 17 or of pharmaceutically acceptable salts thereof for the manufacture of a medicament for the treatment and/or prophylaxis of vasopressin-dependent diseases.
20. Use according to claim 19, for the manufacture of a medicament for the treatment and/or prophylaxis of diseases selected from diabetes, insulin resistance, nocturnal enuresis, incontinence, diseases in which impairments of blood clotting occur, hypertension, pulmonary hypertension, heart failure, myocardial infarction, coronary spasm, unstable angina, PTCA (percutaneous transluminal coronary angioplasty), ischemias of the heart, impairments of the renal system, edemas, renal vasospasm, necrosis of the renal cortex, hyponatremia, hypokalemia, Schwartz-Bartter syndrome, impairments of the gastrointestinal tract, gastritic vasospasm, hepatocirrhosis, gastric and intestinal ulcers, emesis, emesis occurring during chemotherapy, travel sickness, affective disorders, anxiety disorders, stress-dependent anxiety disorders, memory impairments, Alzheimer's disease, psychoses, psychotic disorders, Cushing's syndrome, other stress-dependent diseases, sleep disorders, depressive disorders, preferably childhood onset mood disorders, vasomotor symptoms, thermoregulatory dysfunctions, drug or pharmaceutical dependencies and/or dependencies mediated by other factors; of stress caused by withdrawal of one or more factors mediating the dependence; and/or of stress-induced relapses into drug or pharmaceutical dependencies and/or dependencies mediated by other factors, schizophrenia, and psychosis, and/or for delaying micturition.