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US20160362394A1 - Carbamate-substituted oxindole derivatives and use thereof for the treatment of vasopressin-dependent diseases - Google Patents

Carbamate-substituted oxindole derivatives and use thereof for the treatment of vasopressin-dependent diseases Download PDF

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US20160362394A1
US20160362394A1 US15/244,283 US201615244283A US2016362394A1 US 20160362394 A1 US20160362394 A1 US 20160362394A1 US 201615244283 A US201615244283 A US 201615244283A US 2016362394 A1 US2016362394 A1 US 2016362394A1
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methoxy
ethoxypyridin
cyano
indol
dihydro
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US15/244,283
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Astrid Netz
Thorsten Oost
Hervé Geneste
Wilfried Braje
Wolfgang Wernet
Liliane Unger
Wilfried Hornberger
Wilfried Lubisch
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AbbVie Deutschland GmbH and Co KG
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AbbVie Deutschland GmbH and Co KG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • Vasopressin is an endogenous hormone which exerts various effects on organs and tissues. It is suspected that the vasopressin system is involved in various pathological states such as, for example, heart failure and high blood pressure. At present, three receptors (V1a, V1b or V3 and V2) via which vasopressin mediates its numerous effects are known. Antagonists of these receptors are therefore being investigated as possible new therapeutic approaches for the treatment of diseases (M. Thibonnier, Exp. Opin. Invest. Drugs 1998, 7(5), 729-740).
  • Novel substituted oxindoles having a phenylsulfonyl group in position 1 are described herein.
  • 1-Phenylsulfonyl-1,3-dihydro-2H-indol-2-ones have previously been described as ligands of vasopressin receptors.
  • 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 having arylsulfonyl groups in position 1 of the oxindole structure. These compounds differ from the compounds of the invention essentially through the substituents in position 3.
  • WO 95/18105 describes 1-phenylsulfonyl-1,3-dihydro-2H-indol-2-ones having a nitrogen atom in position 3 as ligands of vasopressin receptors.
  • radicals selected from optionally substituted alkyl, cycloalkyl, phenyl or benzyl radicals are bonded in position 3.
  • WO 03/008407 describes 1-phenylsulfonyloxindoles in which pyridylpiperazines are linked via an oxycarbonyl group to the oxindole in position 3.
  • WO 2005/030755 describes as example 108 the 2-methoxypyridin-3-yl carbamate compound 5-cyano-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-methoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate (according to IUPAC nomenclature: 5-Cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-methoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(1-methylpiperidin-4-yl)piperazin-1-carboxylate).
  • a selectivity for the vasopressin V1b receptor compared with the vasopressin V1a receptor i.e. the quotient of the binding affinity for the V1a receptor (Ki(V1a) (determined in the unit “nanomolar (nM)”) and the binding affinity for the V1b receptor (Ki(V1b)) (determined in the unit “nanomolar (nM)”).
  • Ki(V1a)/Ki(V1b) means a greater V1b selectivity
  • a selectivity for the vasopressin V1b receptor compared with the vasopressin V2 receptor i.e.
  • cytochrome P450 (CYP) is the name for a superfamily of heme proteins having enzymatic activity (oxidase).
  • CYP 1A2 The principal representatives of the types and subtypes of CYP in the human body are: CYP 1A2, CYP 2C9, CYP 2D6 and CYP 3A4. If CYP 3A4 inhibitors (e.g.
  • grapefruit juice, cimetidine, erythromycin are used at the same time as medicinal substances which are degraded by this enzyme system and thus compete for the same binding site on the enzyme, the degradation thereof may be slowed down and thus effects and side effects of the administered medicinal substance may be undesirably enhanced; 6.) a suitable solubility in water (in mg/ml); 7.) suitable pharmacokinetics (time course of the concentration of the compound of the invention in plasma or in tissue, for example brain).
  • the pharmacokinetics can be described by the following parameters: half-life, volume of distribution, plasma clearance, AUC (area under the curve, area under the concentration-time curve), oral bioavailability, the so-called brain-plasma ratio; 8.) a suitable portion of the active substance is bound to plasma proteins (drug-plasma protein binding (PPB) value); 9.) no or only low blockade of the hERG channel: compounds which block the hERG channel may cause a prolongation of the QT interval and thus lead to serious disturbances of cardiac rhythm (for example so-called “torsade de pointes”).
  • the potential of compounds to block the hERG channel can be determined by means of the displacement assay with radiolabelled dofetilide which is described in the literature (G. J.
  • IC50 in this dofetilide assay means a greater probability of potent hERG blockade.
  • the blockade of the hERG channel can be measured by electrophysiological experiments on cells which have been transfected with the hERG channel, by so-called whole-cell patch clamping (G. J. Diaz et al., Journal of Pharmacological and Toxicological Methods, 50 (2004), 187-199).
  • the compounds were intended to have a high activity and selectivity, especially a high affinity and selectivity vis-à-vis the vasopressin V1b receptor.
  • the substance of the invention was intended to have one or more of the aforementioned advantages 1.) to 9.).
  • the present invention relates to compounds of the formula I (also “compounds I” hereinafter) and the pharmaceutically acceptable salts of the compounds I and the prodrugs of the compounds I.
  • the pharmaceutically acceptable salts of compounds of the formula I which are also referred to as physiologically tolerated salts, are ordinarily obtainable by reacting the free base of the compounds I of the invention (i.e. of the compounds I according to structural formula I) with suitable acids.
  • suitable acids are listed in “Fort Whitneye der Arzneistoffforschung”, 1966, Birkhäuser Verlag, vol. 10, pp. 224-285. These include for example hydrochloric acid, citric acid, tartaric acid, lactic acid, phosphoric acid, methanesulfonic acid, acetic acid, formic acid, maleic acid and fumaric acid.
  • prodrugs means compounds which are metabolized in vivo to the compounds I of the invention. Typical examples of prodrugs are described in C. G. Wermeth (editor): The Practice of Medicinal Chemistry, Academic Press, San Diego, 1996, pages 671-715. These include for example phosphates, carbamates, amino acids, esters, amides, peptides, ureas and the like. Suitable prodrugs in the present case may be for example compounds I in which the outer nitrogen atom of the outer piperidine/piperazine ring forms an amide/peptide linkage by this nitrogen atom being substituted by a C 1 -C 4 -alkylcarbonyl group, e.g.
  • alkylcarbonyloxyalkyl carbamates in which the outer nitrogen atom of the outer piperidine/piperazine ring has in the position of the radical R 3 a group of the formula —C( ⁇ O)—O—CHR a —O—C( ⁇ O)—R b in which R a and R b are independently of one another C 1 -C 4 -alkyl.
  • Such carbamates are described for example in J. Alexander, R. Cargill, S. R. Michelson, H. Schwam, J. Medicinal Chem. 1988, 31(2), 318-322. These groups can then be eliminated under metabolic conditions and result in compounds I in which R 3 is H.
  • C 1 -C 4 -Alkyl is in the context of the present invention a linear or branched alkyl radical having 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl.
  • C 1 -C 3 -Alkoxy is in the context of the present invention a linear or branched alkyl radical linked via an oxygen atom and having 1 to 3 carbon atoms. Examples are methoxy, ethoxy, n-propoxy and isopropoxy.
  • the compounds of the invention of the formula I, their pharmacologically acceptable salts and their prodrugs may also be present in the form of solvates or hydrates.
  • Solvates mean in the context of the present invention crystalline forms of the compounds I or of their pharmaceutically acceptable salts or prodrugs thereof which comprise solvent molecules incorporated in the crystal lattice.
  • the solvent molecules are preferably incorporated in stoichiometric ratios.
  • Hydrates are a specific form of solvates; the solvent in this case is water.
  • 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.
  • R 1 is hydrogen or methoxy.
  • R 1 and R 2 are both H.
  • R 1 is methoxy and R 2 is H.
  • R 1 is H and R 2 is methoxy.
  • R 1 and R 2 are both methoxy.
  • R 3 is hydrogen, methyl or ethyl.
  • one of the variables X 1 , X 2 is N and the other is CH.
  • X 1 is CH and X 2 is N.
  • the invention preferably relates to compounds of the formula I in which
  • the invention particularly preferably relates to compounds of the formula I in which
  • the invention alternatively particularly preferably relates to compounds of the formula I in which
  • the invention further particularly preferably relates to compounds of the formula I in which
  • the invention particularly relates to compounds of the formula I in which
  • the invention furthermore preferably relates to compounds of the formula I in which
  • the invention furthermore particularly relates to compounds of the formula I in which
  • the invention furthermore particularly relates to compounds of the formula I in which
  • the invention furthermore particularly relates to compounds of the formula I in which
  • the invention furthermore particularly relates to compounds of the formula I in which
  • Examples of preferred embodiment of the present invention are compounds of the formula I and the pharmaceutically acceptable salts and prodrugs thereof, in which the radicals X 1 , X 2 , R 1 , R 2 and R 3 assume in each case the meanings mentioned in each line in the following table 1.
  • the compounds I of the invention have a center of chirality in position 3 of the 2-oxindole ring.
  • the compounds of the invention may therefore be in the form of a 1:1 mixture of enantiomers (racemate) or of a nonracemic mixture of enantiomers in which one of the two enantiomers, either the enantiomer which rotates the plane of vibration of linearly polarized light to the left (i.e. minus rotation) (hereinafter ( ⁇ ) enantiomer) or the enantiomer which rotates the plane of vibration of linearly polarized light to the right (i.e.
  • Preferred embodiments of the invention are compounds of the formula I as detailed above which are characterized in that they are in optically active form, and the enantiomer of the relevant compound of the formula I is the one which rotates the plane of vibration of polarized light to the left (i.e. minus rotation), in the form of a free base, or a pharmaceutically acceptable salt or a prodrug thereof.
  • the enantiomers with levorotation or minus rotation of the compounds I are also referred to hereinafter as ( ⁇ ) enantiomers.
  • This configuration is also referred to hereinafter as the “preferred configuration”.
  • Examples of particularly preferred compounds I are the compounds listed in following table 2 with the example numbers 1 to 90B, and the pharmaceutically acceptable salts and prodrugs thereof.
  • examples 1 to 90 correspond to the racemate of the respective compounds
  • the examples with an appended letter “A” (1A, 2A, . . . to 90A) correspond to the dextrorotatory (+) enantiomer
  • the examples with an appended letter “B” (1B, 2B, . . . to 90B) correspond to the levorotatory ( ⁇ ) enantiomer of the respective compound 1 to 90.
  • the naming of the compounds corresponds to the naming generated by the ACD-Labs version 8.00 release product version 8.05.
  • the oxindoles of the invention can be prepared in various ways, and the preparation is outlined in synthesis schemes 1 and 2.
  • the variables in these synthetic schemes have the same meanings as in formula I.
  • the 3-hydroxy-1,3-dihydroindol-2-ones IV can be obtained by addition of metallated heterocycles III onto the 3-keto group of the isatins II.
  • the metallated heterocycles such as, for example, the corresponding Grignard (Mg) or organyllithium compound, can be obtained in any conventional way from halogen or hydrocarbon compounds. Examples of methods are present in Houben-Weyl, Methoden der Organischen Chemie, vol. 13, 1-2, chapter on Mg and Li compounds.
  • the isatins II are either commercially available or can be prepared in analogy to methods described in the literature (Advances in Heterocyclic Chemistry, A. R. Katritzky and A. J. Boulton, Academic Press, New York, 1975, 18, 2-58; J. Brazil. Chem. Soc. 12, 273-324, 2001).
  • the hydroxy group in the compound IV is then derivatized, for example with phenyl chloroformate, to give the compounds Va and/or Vb.
  • LG can have as leaving group OPh in the compounds Va and/or Vb which is derived from reaction of IV with phenyl chloroformate in the presence of a base such as, for example, pyridine.
  • amines VI can be either purchased or prepared by methods known from the literature.
  • Compounds such as VII can then be converted by treatment with sulfonyl chlorides VIII after deprotonation with a strong base such as, for example, potassium tert-butoxide or sodium hydride in dimethylformamide (DMF) into the compounds of the invention.
  • a strong base such as, for example, potassium tert-butoxide or sodium hydride in dimethylformamide (DMF)
  • the employed sulfonyl chlorides VIII can either be purchased or prepared in an analogous manner to known processes (see, for example, J. Med. Chem. 40, 1149 (1997)).
  • the compounds I of the invention can be prepared according to synthesis scheme 2 in the shown three-stage process analogous to synthesis scheme 1 with alteration of the sequence.
  • the 3-hydroxyoxindoles IV are sulfonylated by deprotonation with a strong base such as, for example, sodium hydride or potassium tert-butoxide and subsequent treatment with sulfonyl chlorides VIII in DMF.
  • a strong base such as, for example, sodium hydride or potassium tert-butoxide
  • derivatization of the hydroxy group in IX follows to give the compound X by treatment for example with phenyl chloroformate.
  • the compounds I of the invention are generated in an excess of amine VI or else with the assistance of an auxiliary base.
  • R 3 in the amine VI is represented by the reaction of amines with aldehydes or ketones in the presence of reducing agents such as, for example, sodium cyanoborohydride or sodium acetoxyborohydride in the manner of a reductive amination (J. March, Advanced Organic Chemistry, 1992, 4th edition, Wiley, New York, pages 411; 898).
  • reducing agents such as, for example, sodium cyanoborohydride or sodium acetoxyborohydride in the manner of a reductive amination
  • a further aspect of the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising at least one compound of the general formula I and/or a pharmaceutically acceptable salt or a prodrug thereof as detailed above, and a pharmaceutically acceptable carrier.
  • Suitable carriers depend inter alia on the dosage form of the composition and are known in principle to the skilled worker. Some suitable carriers are described hereinafter.
  • a further aspect of the present invention relates to the use of compounds of the formula I and/or of pharmaceutically acceptable salts or prodrugs thereof for the manufacture of a medicament for the treatment and/or prophylaxis of vasopressin-dependent diseases.
  • the present invention relates to the use of compounds of the invention of the formula I or of pharmaceutically acceptable salts or prodrugs thereof for the manufacture of a medicament for the treatment and/or prophylaxis of diseases selected from diabetes, insulin resistance, nocturnal enuresis, incontinence and diseases in which impairments of blood clotting occur, and/or for delaying micturition.
  • diabetes means all types of diabetes, especially diabetes mellitus (including type I and especially type II), diabetes renalis and in particular diabetes insipidus.
  • the types of diabetes are preferably diabetes mellitus of type II (with insulin resistance) or diabetes insipidus.
  • the present invention relates to the use of compounds of the invention of the formula I or of pharmaceutically acceptable salts or prodrugs thereof for the manufacture of a medicament for the treatment and/or prophylaxis of diseases selected from 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, and travel sickness.
  • diseases selected from hypertension, pulmonary hypertension, heart failure, myocardial infarction, coronary spasm, unstable angina, PTCA (percutaneous transluminal coronary angioplasty), isch
  • the compounds of the invention of the formula I or their pharmaceutically acceptable salts or their prodrugs or the pharmaceutical composition of the invention can also be used for the treatment of various vasopressin-dependent complaints which have central nervous causes or alterations in the HPA axis (hypothalamic pituitary adrenal axis), for example for affective disorders such as depressive disorders and bipolar disorders. These include for example dysthymic disorders, phobias, post-traumatic stress disorders, general anxiety disorders, panic disorders, seasonal depression and sleep disorders.
  • the compounds of the invention of the formula I and their pharmaceutically acceptable salts or their prodrugs or the pharmaceutical composition of the invention can likewise be employed for the treatment of anxiety disorders and stress-dependent anxiety disorders, such as, for example, generalized anxiety disorders, phobias, post-traumatic anxiety disorders, panic anxiety disorders, obsessive-compulsive anxiety disorders, acute stress-dependent anxiety disorders and social phobia.
  • anxiety disorders and stress-dependent anxiety disorders such as, for example, generalized anxiety disorders, phobias, post-traumatic anxiety disorders, panic anxiety disorders, obsessive-compulsive anxiety disorders, acute stress-dependent anxiety disorders and social phobia.
  • the compounds of the invention can furthermore also be employed for the treatment of memory impairments, Alzheimer's disease, psychoses, psychotic disorders, sleep disorders and/or Cushing's syndrome, and all stress-dependent diseases.
  • a further preferred embodiment of the present invention relates to the use of compounds of the invention of the formula I or of pharmaceutically acceptable salts or prodrugs thereof for the manufacture of a medicament for the treatment of affective disorders.
  • the present invention relates to the use of compounds of the invention of the formula I or of pharmaceutically acceptable salts or prodrugs thereof for the manufacture of a medicament for the treatment of anxiety disorders and/or stress-dependent anxiety disorders.
  • the present invention relates to the use of compounds of the invention of the formula I or of pharmaceutically acceptable salts or prodrugs thereof for the manufacture of a medicament for the treatment of memory impairments and/or Alzheimer's disease.
  • the present invention relates to the use of compounds of the invention of the formula I or of pharmaceutically acceptable salts or prodrugs thereof for the manufacture of a medicament for the treatment of psychoses and/or psychotic disorders.
  • the present invention relates to the use of compounds of the invention of the formula I or of pharmaceutically acceptable salts or prodrugs thereof for the manufacture of a medicament for the treatment of Cushing's syndrome or other stress-dependent diseases.
  • the present invention relates to the use of compounds of the invention of the formula I or of pharmaceutically acceptable salts or prodrugs thereof for the manufacture of a medicament for the treatment of sleep disorders.
  • the present invention relates to the use of compounds of the invention of the formula I or of pharmaceutically acceptable salts or prodrugs thereof for the manufacture of a medicament for the treatment of depressive disorders.
  • depressive disorders are so-called childhood onset mood disorders, i.e. depressive moods having their onset in childhood.
  • the present invention relates to the use of compounds of the invention of the formula I or of pharmaceutically acceptable salts or prodrugs thereof for the manufacture of a medicament for the treatment of vasomotor symptoms and/or thermoregulatory dysfunctions such as, for example, the hot flush symptom.
  • the present invention relates to the use of compounds of the invention of the formula I or of pharmaceutically acceptable salts or prodrugs thereof for the manufacture of a medicament for the treatment and/or prophylaxis of drug or pharmaceutical dependencies and/or dependencies mediated by other factors, for the treatment and/or prophylaxis of stress caused by withdrawal of one or more factors mediating the dependence and/or for the treatment and/or prophylaxis of stress-induced relapses into drug or pharmaceutical dependencies and/or dependencies mediated by other factors.
  • the present invention relates to the use of compounds of the invention of the formula I or of pharmaceutically acceptable salts or prodrugs thereof for the manufacture of a medicament for the treatment and/or prophylaxis of schizophrenia and/or psychosis.
  • a further aspect of the invention relates to a method for the treatment and/or prophylaxis of vasopressin-dependent diseases, in which an effective amount of at least one compound of the invention of the formula I or of at least one pharmaceutically acceptable salt or one prodrug thereof or of a pharmaceutical composition of the invention is administered to a patient.
  • the method of the invention serves for the treatment and/or prophylaxis of disorders selected from diabetes, insulin resistance, nocturnal enuresis, incontinence and diseases in which impairments of blood clotting occur, and/or for delaying micturition.
  • disorders selected from diabetes, insulin resistance, nocturnal enuresis, incontinence and diseases in which impairments of blood clotting occur, and/or for delaying micturition.
  • the method of the invention serves for the treatment and/or prophylaxis of disorders selected from 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, and travel sickness.
  • disorders selected from 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
  • the method of the invention serves for the treatment and/or prophylaxis of affective disorders.
  • the method of the invention serves for the treatment and/or prophylaxis of anxiety disorders and/or stress-dependent anxiety disorders.
  • the method of the invention serves for the treatment and/or prophylaxis of memory impairments and/or Alzheimer's disease.
  • the method of the invention serves for the treatment and/or prophylaxis of psychoses and/or psychotic disorders.
  • the method of the invention serves for the treatment and/or prophylaxis of Cushing's syndrome.
  • the method of the invention serves for the treatment and/or prophylaxis of sleep disorders in a patient.
  • the method of the invention serves for the treatment and/or prophylaxis of depressive disorders.
  • depressive disorders specific mention is also to be made of childhood onset mood disorders, i.e. depressive moods having their onset in childhood.
  • the method of the invention serves for the treatment and/or prophylaxis of vasomotor symptoms and/or thermoregulatory dysfunctions, such as, for example, the hot flush symptom.
  • the method of the invention serves for the treatment and/or prophylaxis of drug or pharmaceutical dependencies and/or dependencies mediated by other factors, for the treatment and/or prophylaxis of stress caused by withdrawal of one or more factors mediating the dependence, and/or for the treatment and/or prophylaxis of stress-induced relapses into drug or pharmaceutical dependencies and/or dependencies mediated by other factors.
  • the patient to be treated prophylactically or therapeutically with the method of the invention is preferably a mammal, for example a human or a nonhuman mammal or a nonhuman transgenic mammal. Specifically it is a human.
  • the compounds I or their prodrugs and/or their pharmaceutically acceptable salts are distinguished by having a selectivity for the vasopressin V1b receptor subtype vis-à-vis at least one of the closely related vasopressin/oxytocin receptor subtypes (for example vasopressin V1a, vasopressin V2 and/or oxytocin).
  • the compounds I or their prodrugs and/or their pharmaceutically acceptable salts are distinguished by having an improved metabolic stability.
  • the metabolic stability of a compound can be measured for example by incubating a solution of this compound with liver microsomes from particular species (for example rat, dog or human) and determining the half-life of the compound under these conditions (R S Obach, Curr Opin Drug Discov Devel. 2001, 4, 36-44). It is possible in this connection to conclude from an observed longer half-life that the metabolic stability of the compound is improved.
  • the stability in the presence of human liver microsomes is of particular interest because it makes it possible to predict the metabolic degradation of the compound in the human liver. Compounds with increased metabolic stability (measured in the liver microsome test) are therefore probably also degraded more slowly in the liver.
  • the slower metabolic degradation in the liver may lead to higher and/or longer-lasting concentrations (active levels) of the compound in the body, so that the elimination half-life of the compounds of the invention is increased.
  • Increased and/or longer-lasting active levels may lead to a better activity of the compound in the treatment or prophylaxis of various vasopressin-dependent diseases.
  • an improved metabolic stability may lead to an increased bioavailability after oral administration, because the compound is subject, after absorption in the intestine, to less metabolic degradation in the liver (so-called first pass effect).
  • An increased oral bioavailability may, owing to an increased concentration (active level) of the compound, lead to a better activity of the compound after oral administration.
  • the compounds I or their prodrugs and/or their pharmaceutically acceptable salts are distinguished by having an improved pharmacological activity, compared with the oxindole compounds known from the prior art, in patients or relevant animal models which enable prognostic statements for use in the treatment.
  • the present invention also relates to pharmaceutical compositions which comprise an effective dose of a compound I of the invention, of a pharmaceutically acceptable salt or of a prodrug thereof and suitable pharmaceutical carriers (drug carriers).
  • These drug carriers are chosen according to the pharmaceutical form and the desired mode of administration and are known in principle to the skilled worker.
  • the compounds of the invention of the formula I or optionally suitable salts of these compounds can be used to produce pharmaceutical compositions for oral, sublingual, buccal, subcutaneous, intramuscular, intravenous, topical, intratracheal, intranasal, transdermal, vaginal or rectal administration, and be administered to animals or humans in uniform administration forms, mixed with conventional pharmaceutical carriers, for the prophylaxis or treatment of the above disorders or diseases.
  • the suitable administration forms include forms for oral administration such as tablets, gelatin capsules, powders, granules and solutions or suspensions for oral intake, forms for sublingual, buccal, intratracheal or intranasal administration, aerosols, implants, forms of subcutaneous, intramuscular or intravenous administration and forms of rectal administration.
  • the compounds of the invention can be used in creams, ointments or lotions for topical administration.
  • a solid composition is prepared in the form of tablets, the active ingredient is mixed with a solid pharmaceutical carrier such as gelatin, starch, lactose, magnesium stearate, talc, silicon dioxide or the like.
  • a solid pharmaceutical carrier such as gelatin, starch, lactose, magnesium stearate, talc, silicon dioxide or the like.
  • a preparation in the form of gelatin capsules is obtained by mixing the active ingredient with an extender and including the resulting mixture in soft or hard gelatin capsules.
  • a preparation in the form of a syrup or elixir or for administration in the form of drops may contain active ingredients together with a sweetener, which is preferably calorie-free, methylparaben or propylparaben as antiseptics, a flavoring and a suitable coloring substance.
  • a sweetener which is preferably calorie-free, methylparaben or propylparaben as antiseptics, a flavoring and a suitable coloring substance.
  • Rectal or vaginal administration is achieved by using suppositories which are prepared with binders which melt at rectal temperature, for example cocoa butter or polyethylene glycols.
  • Parenteral administration is effected by using aqueous suspensions, isotonic saline solutions or sterile and injectable solutions which comprise pharmacologically acceptable dispersants and/or wetting agents, for example propylene glycol or polyethylene glycol.
  • compositions of the invention may, in addition to the compounds of the invention, comprise other active ingredients which may be beneficial for the treatment of the disorders or diseases indicated above.
  • the present invention thus further relates to pharmaceutical compositions in which a plurality of active ingredients are present together, where at least one of these is a compound I of the invention, salt or a prodrug thereof.
  • the compounds of the invention can be prepared by various synthetic routes.
  • the methods mentioned, as described accordingly in synthesis schemes 1 and 2, are explained in greater detail merely by way of example using the given examples without being exclusively restricted to synthesis routes 1 or 2 or analogous methods.
  • the reaction solution was worked up by adding 200 ml of 2N of sodium hydroxide solution while cooling, distilling out the solvent ethanol and diluting the remaining reaction mixture with water. It was extracted with diethyl ether (2 ⁇ ) and was washed with saturated sodium chloride solution (1 ⁇ ), and the combined organic phases were dried over magnesium sulfate and filtered, and the solvent was removed in vacuo.
  • the crude title compound was obtained as a yellow oil which was then chromatographed on a 4 l suction funnel filled with silica gel using dichloromethane and 10% methanol as eluent. In total, 40 g (135 mmol, 53%) of tert-butyl 4-(4-ethylpiperazin-1-yl)piperidine-1-carboxylate were obtained.
  • the protective group was removed by introducing 40 g (135 mmol) of tert-butyl 4-(4-ethylpiperazin-1-yl)piperidine-1-carboxylate from example a.1 into 200 ml of methanol and 1.8 l of dichloromethane and adding 100 ml of 5-6M HCl solution in isopropanol. A suspension resulted, and slight gas evolution was also observable.
  • the reaction mixture was stirred at 40° C. (water bath temperature) for one hour and then stirred at room temperature for 48 hours. For complete deprotection, 50 ml of the 5-6M HCl solution in isopropanol were again added and the reaction mixture was stirred at 40° C.
  • the dichloromethane was distilled out in a rotary evaporator. 200 ml of methanol and 30 ml of the 5-6M HCl solution in isopropanol were again added. The reaction mixture was stirred under reflux for one hour, during which a white suspension formed with strong evolution of gas. A mobile suspension then resulted and was cooled to room temperature. The precipitate was filtered off with suction and washed with methanol and diethyl ether. After drying, 36 g (117 mmol, 87%) of 1-ethyl-4-piperidin-4-ylpiperazine were isolated as chloride salt.
  • the solution of the pyridine Grignard was then added to the solution, cooled in an ice bath, of the 5-iodoisatin sodium salt at a temperature between 5 and 18° C. over a period of 5-10 minutes. After addition of the pyridine Grignard was complete, the ice bath was removed. The reaction mixture was stirred at room temperature for 2 hours. An excess of saturated ammonium chloride solution was added, followed by ethyl acetate, the mixture being stirred for 5 minutes. The aqueous phase was separated off and extracted with ethyl acetate (2 ⁇ ). The combined organic phases were washed with water (2 ⁇ ), and the solvent was removed in vacuo.
  • reaction mixture was allowed to thaw to room temperature and was stirred at room temperature overnight. After conversion was complete, the reaction mixture was poured into 10 ml of ice-water and initially neutralized and then adjusted to pH 9 with 2 ml of 1 N sodium hydroxide solution. A precipitate separated out and was washed with water and dried in a vacuum drying oven to result in 68 mg of dry solid. In order to remove the slight impurities, the solid was stirred in 3 ml of diethyl ether. After leaving to stand overnight, the solid was again filtered off and washed with a little diethyl ether and dried.
  • the compounds I of the invention can also be purified as an alternative to crystallization by conventional normal-phase column chromatography (such as, for example, NP SiO 2 cartridge, Chromabond and dichloromethane/methanol as eluent) and/or by preparative HPLC (RP, eluent acetonitrile/water, 0.1% TFA or 0.1% acetic acid).
  • Compounds I then result where appropriate as trifluoroacetic acid salt, bis(trifluoroacetic acid) salt or acetic acid salt.
  • the compounds of the formula I according to examples 2 to 90 can be prepared using the appropriate starting compounds in analogy to the process for preparing example 1.
  • Racemic compounds of the formula I can be resolved for example by separation on a preparative chiral column.
  • the enantiomer eluted first (example 1A) with positive rotation (rotation determined in chloroform) could be isolated in a yield of 20 mg (0.028 mmol, 29%), and the subsequent enantiomer (example 1B) with negative rotation (rotation determined in chloroform) could be isolated in a yield of 17 mg (0.024 mmol, 25%).
  • racemates of examples 2 to 90 can be resolved in an analogous manner to result in the corresponding (+) enantiomers 2A, 3A, 4A, 5A, 6A, 7A, 8A, 9A, 10A, 11A, 12A, 13A, 14A, 15A, 16A, 17A, 18A, 19A, 20A, 21A, 22A, 23A, 24A, 25A, 26A, 27A, 28A, 29A, 30A, 31A, 32A, 33A, 34A, 35A, 36A, 37A, 38A, 39A, 40A, 41A, 42A, 43A, 44A, 45A, 46A, 47A, 48A, 49A, 50A, 51A, 52A, 53A, 54A, 55A, 56A, 57A, 58A, 59A, 60A, 61A, 62A, 63A, 64A, 65A, 66A, 67A, 68A, 69A, 70A, 71A, 72A, 73
  • the (+) enantiomer of the formula I and the ( ⁇ ) enantiomer of the formula I can also be prepared using enantiopure precursors and intermediates for example in analogy to synthesis scheme 1 or 2, preferably in accordance with synthesis scheme 2.
  • the enantiomer separation is to be explained in detail in relation to intermediate IV, racemic 5-cyano-3-hydroxy-3-(2-ethoxypyridin-3-yl)-1,3-dihydroindol-2-one, without being restricted thereto. Resolution of the racemate into the enantiomers can take place by preparative chiral chromatography.
  • the enantiomer separation conditions were a preparative chiral column (Chiralpak AD 20 micron 5 cm ID ⁇ 500 cm) with the eluents hexane/ethanol/methanol in the ratio 80/10/10 and a flow rate of 80 ml/min.
  • Example 4B illustrates by way of example the synthesis route in analogy to synthesis scheme 2.
  • Examples 37B and 40B can be prepared using the appropriate starting compounds in analogy to the process for preparing example 4B.
  • (+)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-indol-3-yl 4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate, example 4A can be obtained in analogy to example 4B starting from enantiopure (+)-5-cyano-3-hydroxy-3-(2-ethoxypyridin-3-yl)-1,3-dihydroindol-2-one (enantiomer with plus rotation [rotation determined in chloroform]) and according to process stages 4B.1) to 4B.3) as enantiomer 4A.
  • the compound of example 40A can be prepared using the appropriate starting compounds in analogy to the process for preparing example 4A.
  • test substances were dissolved in a concentration of 10 ⁇ 2 M in DMSO and further diluted to 5 ⁇ 10 ⁇ 4 M to 5 ⁇ 10 ⁇ 9 M. These serial DMSO predilutions were diluted 1:10 with assay buffer. The substance concentration was further diluted 1:5 in the assay mixture (2% DMSO in the mixture).
  • CHO-K1 cells with stably expressed human vasopressin V1b receptor were harvested and homogenized in 50 mM Tris-HCl and in the presence of protease inhibitors (Roche complete Mini #1836170) using a Polytron homogenizer at intermediate setting for 2 ⁇ 10 seconds, and subsequently centrifuged at 40 000 ⁇ g for 1 h. The membrane pellet was again homogenized and centrifuged as described and subsequently taken up in 50 mM Tris-HCl, pH 7.4, homogenized and stored in aliquots frozen in liquid nitrogen at ⁇ 190° C.
  • the binding assay was carried out by the method based on that of Tahara et al. (Tahara A et al., Brit. J. Pharmacol. 125, 1463-1470 (1998)).
  • the incubation buffer was: 50 mM Tris, 10 mM MgCl 2 , 0.1% BSA, pH 7.4.
  • membranes 50 ⁇ g/ml protein in incubation buffer
  • CHO-K1 cells with stably expressed human V1b receptors cell line hV1b_3H2_CHO
  • 1.5 nM 3 H-AVP 8-Arg-vasopressin, PerkinElmer #18479
  • incubation buffer 50 mM Tris, 10 mM MgCl 2 , 0.1% BSA, pH 7.4
  • total binding or additionally with increasing concentrations of test substance (displacement experiment).
  • the nonspecific binding was determined with 1 ⁇ M AVP (Bachem # H1780). All determinations were carried out as triplicate determinations.
  • the binding parameters were calculated by nonlinear regression in SAS.
  • the algorithms of the program operate in analogy to the LIGAND analysis program (Munson P J and Rodbard D, Analytical Biochem. 107, 220-239 (1980)).
  • the Kd of 3 H-AVP for the recombinant human V1b receptors is 0.4 nM and was used to determine the Ki.
  • CHO-K1 cells with stably expressed human vasopressin V1a receptor were harvested and homogenized in 50 mM Tris-HCl and in the presence of protease inhibitors (Roche complete Mini #1836170) using a Polytron homogenizer at intermediate setting for 2 ⁇ 10 seconds, and subsequently centrifuged at 40 000 ⁇ g for 1 h. The membrane pellet was again homogenized and centrifuged as described and subsequently taken up in 50 mM Tris-HCl, pH 7.4, homogenized and stored in aliquots frozen in liquid nitrogen at ⁇ 190° C.
  • the binding assay was carried out by the method based on that of Tahara et al. (Tahara A et al., Brit. J. Pharmacol. 125, 1463-1470 (1998)).
  • the incubation buffer was: 50 mM Tris, 10 mM MgCl 2 , 0.1% BSA, pH 7.4.
  • the binding parameters were calculated by nonlinear regression in SAS.
  • the algorithms of the program operate in analogy to the LIGAND analysis program (Munson P J and Rodbard D, Analytical Biochem. 107, 220-239 (1980)).
  • the Kd of 125 I-AVP for the recombinant hV1a receptors was determined in saturation experiments.
  • a Kd of 1.33 nM was used to determine the Ki.
  • test substances were dissolved in a concentration of 10 ⁇ 2 M in DMSO. Further dilution of these DMSO solutions took place in incubation buffer (50 mM Tris, 10 mM MgCl 2 , 0.1% BSA, pH 7.4).
  • the binding assay was carried out by the method based on that of Tahara et al. (Tahara A et al., Brit. J. Pharmacol. 125, 1463-1470 (1998)).
  • the incubation buffer was: 50 mM Tris, 10 mM MgCl 2 , 0.1% BSA, pH 7.4.
  • membranes 50 ⁇ g/ml protein in incubation buffer
  • CHO-K1 cells with stably expressed human V2 receptors cell line hV2_23_CHO
  • 1-2 nM 3 H-AVP 8-Arg-vasopressin, PerkinElmer #18479
  • incubation buffer 50 mM Tris, 10 mM MgCl 2 , 0.1% BSA, pH 7.4
  • total binding 50 mM Tris, 10 mM MgCl 2 , 0.1% BSA, pH 7.4
  • the nonspecific binding was determined with 1 ⁇ M AVP (Bachem # H1780). Triplicate determinations were carried out.
  • the binding parameters were calculated by nonlinear regression in SAS.
  • the algorithms of the program operate in analogy to the LIGAND analysis program (Munson P J and Rodbard D, Analytical Biochem. 107, 220-239 (1980)).
  • the Kd of 3 H-AVP for the recombinant hV2 receptors is 2.4 nM and was used to determine the Ki.
  • the substances were dissolved in a concentration of 10 ⁇ 2 M in DMSO and diluted with incubation buffer (50 mM Tris, 10 mM MgCl 2 , 0.1% BSA, pH 7.4).
  • Confluent HEK-293 cells with transiently expressing recombinant human oxytocin receptors were centrifuged at 750 ⁇ g at room temperature for 5 minutes. The residue was taken up in ice-cold lysis buffer (50 mM Tris-HCl, 10% glycerol, pH 7.4 and Roche complete protease inhibitor) and subjected to an osmotic shock at 4° C. for 20 minutes. The lyzed cells were then centrifuged at 750 ⁇ g at 4° C. for 20 minutes, the residue was taken up in incubation buffer, and aliquots of 10 7 cells/ml were prepared. The aliquots were frozen at ⁇ 80° C. until used.
  • ice-cold lysis buffer 50 mM Tris-HCl, 10% glycerol, pH 7.4 and Roche complete protease inhibitor
  • the binding parameters were calculated by nonlinear regression analysis (SAS) in analogy to the LIGAND program of Munson and Rodbard (Analytical Biochem 1980; 107: 220-239).
  • SAS nonlinear regression analysis
  • the Kd of 3 H-oxytocin for the recombinant hOT receptors is 7.6 nM and was used to determine the Ki.
  • the metabolic stability of the compounds of the invention was determined in the following assay.
  • test substances were incubated in a concentration of 0.5 ⁇ M as follows:
  • test substance 0.5 ⁇ M test substance are preincubated together with liver microsomes from different species (from rat, human or other species) (0.25 mg of microsomal protein/ml) in 0.05 M potassium phosphate buffer of pH 7.4 in microtiter plates at 37° C. for 5 min.
  • the reaction is started by adding NADPH (1 mg/mL). After 0, 5, 10, 15, 20 and 30 min, 50 ⁇ l aliquots are removed, and the reaction is immediately stopped and cooled with the same volume of acetonitrile. The samples are frozen until analyzed. The remaining concentration of undegraded test substance is determined by MSMS.
  • the half-life (T1 ⁇ 2) is determined from the gradient of the signal of test substance/unit time plot, it being possible to calculate the half-life of the test substance, assuming first order kinetics, from the decrease in the concentration of the compound with time.
  • 150 ⁇ l of rat or human plasma to which 1 or 10 ⁇ M of test substance was added is pipetted on one side of the 96-well dialysis chambers, and 150 ⁇ l of PPS buffer are pipetted on the other side.
  • the chambers are separated by a dialysis membrane with a cut-off of 6-8000 daltons.
  • the 96-well dialysis chambers are covered and shaken gently overnight.
  • 10 ⁇ l of plasma are removed and diluted with 90 ⁇ l of PPS buffer, and the protein is precipitated with 200 ⁇ l of acetonitrile.
  • the precipitated protein is centrifuged down and 100 ⁇ l of the supernatant is used for the MSMS analysis. 100 ⁇ l are removed from the buffer side for MSMS analysis. See also the following reference: Banker, Journal of Pharmaceutical Sciences Vol, 92, 5, 967-974, 2003.
  • 0.4 mg/ml human liver microsomes are preincubated with the test substances to be investigated (0-20 ⁇ M), the CYP-specific substrates, in 0.05 M potassium phosphate buffer of pH 7.4 at 37° C. for 10 min.
  • the Cyp-specific substrate for CYP 2C9 is luciferin H
  • for CYP 3A4 is luciferin BE.
  • the reaction is started by adding NADPH. After incubation at RT for 30 min, the luciferin detection reagent is added, and the resulting luminescence signal is measured (modified from reference: Promega, Technical Bulletin P450-GLOTM Assays).
  • microsomal protein human liver microsomes
  • 0-10 ⁇ M (or 50 ⁇ M) test substance in 50 mM potassium phosphate buffer for 5 min.
  • the reaction is started with NADPH. After 30 min 4 ⁇ M midazolam (final concentration) are added, and incubation is continued for 10 min. 75 ⁇ l of the reaction solution are removed after 10 min, and stopped with 150 ⁇ l of acetonitrile solution.
  • microsomal protein human liver microsomes
  • 4 ⁇ M midazolam final concentration
  • 0-10 ⁇ M or 50 ⁇ M test substance
  • 50 mM potassium phosphate buffer 50 mM potassium phosphate buffer
  • the reaction is started with NADPH.
  • 75 ⁇ l of the reaction solution are removed after 10 min and stopped with 150 ⁇ l of acetonitrile solution.
  • the samples are frozen until the MSMS analysis (modified from references: Obdach, Journal of Pharmacology & Experimental Therapeutics, Vol 316, 1, 336-348, 2006; Walsky, Drug Metabolism and Disposition Vol 32, 6, 647-660, 2004).
  • the solubility in water of the compounds of the invention can be determined for example by the so-called shake flask method (as specified in ASTM International: E 1148-02 , Standard test methods for measurement of aqueous solubility, Book of Standards Volume 11.05.).
  • This entails an excess of the solid compound being put into a buffer solution with a particular pH (for example phosphate buffer of pH 7.4), and the resulting mixture being shaken or stirred until equilibrium has been set up (typically 24 or 48 hours, sometimes even up to 7 days).
  • the undissolved solid is then removed by filtration or centrifugation, and the concentration of the dissolved compound is determined by UV spectroscopy or high pressure liquid chromatography (HPLC) by means of an appropriate calibration plot.
  • HPLC high pressure liquid chromatography
  • the results of the receptor binding investigations are expressed as receptor binding constants [K i (V1b), K i (V1a), K i (V2), K i (OT)].
  • the results of the investigation of the metabolic stability are indicated as microsomal clearance (mCl).
  • the compounds of the invention show very high affinities for the V1b receptor in these assays (maximally 100 nM, or maximally 50 nM, frequently ⁇ 10 nM).
  • the compounds also show high selectivities vis-à-vis the V1a, V2 and/or OT receptor and a good metabolic stability, measured as microsomal clearance.

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Abstract

The present invention relates to novel carbamate-substituted oxindole derivatives, pharmaceutical compositions comprising them, and their use for the treatment of vasopressin-dependent disorders.

Description

  • The present invention relates to novel substituted oxindole derivatives, pharmaceutical compositions comprising them, and their use for the treatment of vasopressin-dependent disorders.
  • Vasopressin is an endogenous hormone which exerts various effects on organs and tissues. It is suspected that the vasopressin system is involved in various pathological states such as, for example, heart failure and high blood pressure. At present, three receptors (V1a, V1b or V3 and V2) via which vasopressin mediates its numerous effects are known. Antagonists of these receptors are therefore being investigated as possible new therapeutic approaches for the treatment of diseases (M. Thibonnier, Exp. Opin. Invest. Drugs 1998, 7(5), 729-740).
  • Novel substituted oxindoles having a phenylsulfonyl group in position 1 are described herein. 1-Phenylsulfonyl-1,3-dihydro-2H-indol-2-ones have previously been described as ligands of vasopressin receptors. 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 having arylsulfonyl groups in position 1 of the oxindole structure. These compounds differ from the compounds of the invention essentially through the substituents in position 3.
  • Thus, WO 93/15051 and WO 98/25901 describe 1-phenylsulfonyl-1,3-dihydro-2H-indol-2-ones, in which the oxindole structure is substituted in position 3 by two alkyl radicals which may also together form a cycloalkyl radical (spiro linkage), as ligands of vasopressin receptors. As alternative, the spiro ring may comprise heteroatoms such as oxygen and nitrogen (optionally with substituents).
  • WO 95/18105 describes 1-phenylsulfonyl-1,3-dihydro-2H-indol-2-ones having a nitrogen atom in position 3 as ligands of vasopressin receptors. In addition, radicals selected from optionally substituted alkyl, cycloalkyl, phenyl or benzyl radicals are bonded in position 3.
  • WO 03/008407 describes 1-phenylsulfonyloxindoles in which pyridylpiperazines are linked via an oxycarbonyl group to the oxindole in position 3.
  • WO 2005/030755 describes as example 108 the 2-methoxypyridin-3-yl carbamate compound 5-cyano-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-methoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate (according to IUPAC nomenclature: 5-Cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-methoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(1-methylpiperidin-4-yl)piperazin-1-carboxylate).
  • WO 2006/005609 describes the 2-ethoxyphenyl carbamate compounds 1-(2,4-dimethoxy-1-benzenesulfonyl)-5-cyano-2-oxo-3-(2-ethoxyphenyl)-2,3-dihydro-1H-indol-3-yl 4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate (example 63) and 5-cyano-1-(2,4-dimethoxybenzenesulfonyl)-3-(2-ethoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(4-methylpiperazin-1-yl)piperidine-1-carboxylate dihydrochloride (example 172).
  • Besides the binding affinity for the vasopressin V1b receptor, further properties may be advantageous for the treatment and/or prophylaxis of vasopressin-dependent disorders, such as, for example:
  • 1.) a selectivity for the vasopressin V1b receptor compared with the vasopressin V1a receptor, i.e. the quotient of the binding affinity for the V1a receptor (Ki(V1a) (determined in the unit “nanomolar (nM)”) and the binding affinity for the V1b receptor (Ki(V1b)) (determined in the unit “nanomolar (nM)”). A larger quotient Ki(V1a)/Ki(V1b) means a greater V1b selectivity;
    2.) a selectivity for the vasopressin V1b receptor compared with the vasopressin V2 receptor, i.e. the quotient of the binding affinity for the V2 receptor (Ki(V2) (determined in the unit “nanomolar (nM)”) and the binding affinity for the V1b receptor (Ki(V1b)) (determined in the unit “nanomolar (nM)”). A larger quotient Ki(V2)/Ki(V1b) means a greater V1b selectivity;
    3.) a selectivity for the vasopressin V1b receptor compared with the oxytocin OT receptor, i.e. the quotient of the binding affinity for the OT receptor (Ki(OT) (determined in the unit “nanomolar (nM)”) and the binding affinity for the V1b receptor (Ki(V1b)) (determined in the unit “nanomolar (nM)”). A larger quotient Ki(OT)/Ki(V1b) means a greater V1b selectivity.
    4.) the metabolic stability, for example determined from the half-lives, measured in vitro, in liver microsomes from various species (e.g. rat or human);
    5.) no or only low inhibition of cytochrome P450 (CYP) enzymes: cytochrome P450 (CYP) is the name for a superfamily of heme proteins having enzymatic activity (oxidase). They are also particularly important for the degradation (metabolism) of foreign substances such as drugs or xenobiotics in mammalian organisms. The principal representatives of the types and subtypes of CYP in the human body are: CYP 1A2, CYP 2C9, CYP 2D6 and CYP 3A4. If CYP 3A4 inhibitors (e.g. grapefruit juice, cimetidine, erythromycin) are used at the same time as medicinal substances which are degraded by this enzyme system and thus compete for the same binding site on the enzyme, the degradation thereof may be slowed down and thus effects and side effects of the administered medicinal substance may be undesirably enhanced;
    6.) a suitable solubility in water (in mg/ml);
    7.) suitable pharmacokinetics (time course of the concentration of the compound of the invention in plasma or in tissue, for example brain). The pharmacokinetics can be described by the following parameters: half-life, volume of distribution, plasma clearance, AUC (area under the curve, area under the concentration-time curve), oral bioavailability, the so-called brain-plasma ratio;
    8.) a suitable portion of the active substance is bound to plasma proteins (drug-plasma protein binding (PPB) value);
    9.) no or only low blockade of the hERG channel: compounds which block the hERG channel may cause a prolongation of the QT interval and thus lead to serious disturbances of cardiac rhythm (for example so-called “torsade de pointes”). The potential of compounds to block the hERG channel can be determined by means of the displacement assay with radiolabelled dofetilide which is described in the literature (G. J. Diaz et al., Journal of Pharmacological and Toxicological Methods, 50 (2004), 187-199). A smaller IC50 in this dofetilide assay means a greater probability of potent hERG blockade. In addition, the blockade of the hERG channel can be measured by electrophysiological experiments on cells which have been transfected with the hERG channel, by so-called whole-cell patch clamping (G. J. Diaz et al., Journal of Pharmacological and Toxicological Methods, 50 (2004), 187-199).
  • It was therefore an object of the present invention to provide compounds for the treatment or prophylaxis of various vasopressin-dependent diseases. The compounds were intended to have a high activity and selectivity, especially a high affinity and selectivity vis-à-vis the vasopressin V1b receptor. In addition, the substance of the invention was intended to have one or more of the aforementioned advantages 1.) to 9.).
  • The object is achieved by compounds of the formula I
  • Figure US20160362394A1-20161215-C00001
  • in which
    • R1 is hydrogen, methoxy or ethoxy;
    • R2 is hydrogen or methoxy;
    • R3 is hydrogen, methyl, ethyl, n-propyl or isopropyl;
    • X1 and X2 are N or CH, with the proviso that X1 and X2 are not simultaneously N;
      and by their pharmaceutically acceptable salts and prodrugs thereof.
  • Accordingly, the present invention relates to compounds of the formula I (also “compounds I” hereinafter) and the pharmaceutically acceptable salts of the compounds I and the prodrugs of the compounds I.
  • The pharmaceutically acceptable salts of compounds of the formula I, which are also referred to as physiologically tolerated salts, are ordinarily obtainable by reacting the free base of the compounds I of the invention (i.e. of the compounds I according to structural formula I) with suitable acids. Examples of suitable acids are listed in “Fortschritte der Arzneimittelforschung”, 1966, Birkhäuser Verlag, vol. 10, pp. 224-285. These include for example hydrochloric acid, citric acid, tartaric acid, lactic acid, phosphoric acid, methanesulfonic acid, acetic acid, formic acid, maleic acid and fumaric acid.
  • The term “prodrugs” means compounds which are metabolized in vivo to the compounds I of the invention. Typical examples of prodrugs are described in C. G. Wermeth (editor): The Practice of Medicinal Chemistry, Academic Press, San Diego, 1996, pages 671-715. These include for example phosphates, carbamates, amino acids, esters, amides, peptides, ureas and the like. Suitable prodrugs in the present case may be for example compounds I in which the outer nitrogen atom of the outer piperidine/piperazine ring forms an amide/peptide linkage by this nitrogen atom being substituted by a C1-C4-alkylcarbonyl group, e.g. by acetyl, propionyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl or tert-butylcarbonyl (pivaloyl), by benzoyl, or by an amino acid residue linked via CO, e.g. glycine, alanine, serine, phenylalanine and the like linked via CO, in the position of the radical R3. Further suitable prodrugs are alkylcarbonyloxyalkyl carbamates in which the outer nitrogen atom of the outer piperidine/piperazine ring has in the position of the radical R3 a group of the formula —C(═O)—O—CHRa—O—C(═O)—Rb in which Ra and Rb are independently of one another C1-C4-alkyl. Such carbamates are described for example in J. Alexander, R. Cargill, S. R. Michelson, H. Schwam, J. Medicinal Chem. 1988, 31(2), 318-322. These groups can then be eliminated under metabolic conditions and result in compounds I in which R3 is H.
  • C1-C4-Alkyl is in the context of the present invention a linear or branched alkyl radical having 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl.
  • C1-C3-Alkoxy is in the context of the present invention a linear or branched alkyl radical linked via an oxygen atom and having 1 to 3 carbon atoms. Examples are methoxy, ethoxy, n-propoxy and isopropoxy.
  • The compounds of the invention of the formula I, their pharmacologically acceptable salts and their prodrugs may also be present in the form of solvates or hydrates. Solvates mean in the context of the present invention crystalline forms of the compounds I or of their pharmaceutically acceptable salts or prodrugs thereof which comprise solvent molecules incorporated in the crystal lattice. The solvent molecules are preferably incorporated in stoichiometric ratios. Hydrates are a specific form of solvates; the solvent in this case is water.
  • The statements made hereinafter concerning suitable and preferred features of the invention, especially concerning the variables R1, R2, R3, X1 and X2 in the compound I, but also concerning the features of the process of the invention and of the use according to the invention apply both taken on their own and preferably in any possible combination with one another.
  • 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 is hydrogen or methoxy.
  • In a particularly preferred embodiment, R1 and R2 are both H.
  • In an alternatively preferred embodiment, R1 is methoxy and R2 is H.
  • In an alternatively particularly preferred embodiment, R1 is H and R2 is methoxy.
  • In an alternatively particularly preferred embodiment, R1 and R2 are both methoxy.
  • In a further preferred embodiment, R3 is hydrogen, methyl or ethyl.
  • In a further preferred embodiment, one of the variables X1, X2 is N and the other is CH.
  • In a particularly preferred embodiment in this connection, X1 is N and X2 is CH.
  • In an alternatively particularly preferred embodiment, X1 is CH and X2 is N.
  • The invention preferably relates to compounds of the formula I in which
    • R1 is hydrogen or methoxy;
    • R2 is hydrogen or methoxy;
    • R3 is hydrogen, methyl, ethyl, n-propyl or isopropyl, preferably hydrogen, methyl or ethyl;
    • X1 is N or CH;
    • X2 is N or CH;
      where X1 and X2 are not simultaneously N;
      and the pharmaceutically acceptable salts and prodrugs thereof.
  • In a particular embodiment, one of the variables X1 or X2 is N and the other is CH.
  • The invention particularly preferably relates to compounds of the formula I in which
    • R1 is hydrogen or methoxy;
    • R2 is hydrogen or methoxy;
    • R3 is hydrogen, methyl or ethyl;
    • X1 is N;
    • X2 is CH;
      and the pharmaceutically acceptable salts and prodrugs thereof.
  • The invention alternatively particularly preferably relates to compounds of the formula I in which
    • R1 is hydrogen or methoxy;
    • R2 is hydrogen or methoxy;
    • R3 is hydrogen, methyl or ethyl;
    • X1 is CH;
    • X2 is N;
      and the pharmaceutically acceptable salts and prodrugs thereof.
  • The invention further particularly preferably relates to compounds of the formula I in which
    • R1 is hydrogen or methoxy;
    • R2 is hydrogen or methoxy;
    • R3 is hydrogen, methyl or ethyl;
    • X1 is CH;
    • X2 is CH;
      and the pharmaceutically acceptable salts and prodrugs thereof.
  • The invention particularly relates to compounds of the formula I in which
    • R1 is methoxy;
    • R2 is methoxy;
    • R3 is hydrogen, methyl or ethyl, preferably methyl or ethyl;
    • X1 is CH;
    • X2 is N;
      and the pharmaceutically acceptable salts and prodrugs thereof.
  • The invention furthermore particularly relates to compounds of the formula I in which
    • R1 is hydrogen;
    • R2 is methoxy;
    • R3 is hydrogen, methyl or ethyl, preferably methyl or ethyl;
    • X1 is CH;
    • X2 is N;
      and the pharmaceutically acceptable salts and prodrugs thereof.
  • The invention furthermore particularly relates to compounds of the formula I in which
    • R1 is methoxy;
    • R2 is hydrogen;
    • R3 is hydrogen, methyl or ethyl, preferably methyl or ethyl;
    • X1 is CH;
    • X2 is N;
      and the pharmaceutically acceptable salts and prodrugs thereof.
  • The invention furthermore preferably relates to compounds of the formula I in which
    • R1 is hydrogen;
    • R2 is hydrogen;
    • R3 is hydrogen, methyl or ethyl, preferably methyl or ethyl;
    • X1 is CH;
    • X2 is N;
      and the pharmaceutically acceptable salts and prodrugs thereof.
  • The invention furthermore particularly relates to compounds of the formula I in which
    • R1 is methoxy;
    • R2 is methoxy;
    • R3 is hydrogen, methyl or ethyl, preferably methyl or ethyl;
    • X1 is N;
    • X2 is CH;
      and the pharmaceutically acceptable salts and prodrugs thereof.
  • The invention furthermore particularly relates to compounds of the formula I in which
    • R1 is hydrogen;
    • R2 is methoxy;
    • R3 is hydrogen, methyl or ethyl, preferably methyl or ethyl;
    • X1 is N;
    • X2 is CH;
      and the pharmaceutically acceptable salts and prodrugs thereof.
  • The invention furthermore particularly relates to compounds of the formula I in which
    • R1 is methoxy;
    • R2 is hydrogen;
    • R3 is hydrogen, methyl or ethyl, preferably methyl or ethyl;
    • X1 is N;
    • X2 is CH;
      and the pharmaceutically acceptable salts and prodrugs thereof.
  • The invention furthermore particularly relates to compounds of the formula I in which
    • R1 is hydrogen;
    • R2 is hydrogen;
    • R3 is hydrogen, methyl or ethyl, preferably methyl or ethyl;
    • X1 is N;
    • X2 is CH;
      and the pharmaceutically acceptable salts and prodrugs thereof.
  • Examples of preferred embodiment of the present invention are compounds of the formula I and the pharmaceutically acceptable salts and prodrugs thereof, in which the radicals X1, X2, R1, R2 and R3 assume in each case the meanings mentioned in each line in the following table 1.
  • TABLE 1
    Example No. X1 X2 R1 R2 R3
    1 N CH Methoxy Methoxy Methyl
    2 N CH Methoxy H Methyl
    3 N CH Ethoxy H Methyl
    4 N CH H H Methyl
    5 N CH H Methoxy Methyl
    6 N CH Ethoxy Methoxy Methyl
    7 N CH Methoxy Methoxy Ethyl
    8 N CH Methoxy H Ethyl
    9 N CH Ethoxy H Ethyl
    10 N CH H H Ethyl
    11 N CH H Methoxy Ethyl
    12 N CH Ethoxy Methoxy Ethyl
    13 N CH Methoxy Methoxy n-Propyl
    14 N CH Methoxy H n-Propyl
    15 N CH Ethoxy H n-Propyl
    16 N CH H H n-Propyl
    17 N CH H Methoxy n-Propyl
    18 N CH Ethoxy Methoxy n-Propyl
    19 N CH Methoxy Methoxy Isopropyl
    20 N CH Methoxy H Isopropyl
    21 N CH Ethoxy H Isopropyl
    22 N CH H H Isopropyl
    23 N CH H Methoxy Isopropyl
    24 N CH Ethoxy Methoxy Isopropyl
    25 N CH Methoxy Methoxy H
    26 N CH Methoxy H H
    27 N CH Ethoxy H H
    28 N CH H H H
    29 N CH H Methoxy H
    30 N CH Ethoxy Methoxy H
    31 CH N Methoxy Methoxy Methyl
    32 CH N Methoxy H Methyl
    33 CH N Ethoxy H Methyl
    34 CH N H H Methyl
    35 CH N H Methoxy Methyl
    36 CH N Ethoxy Methoxy Methyl
    37 CH N Methoxy Methoxy Ethyl
    38 CH N Methoxy H Ethyl
    39 CH N Ethoxy H Ethyl
    40 CH N H H Ethyl
    41 CH N H Methoxy Ethyl
    42 CH N Ethoxy Methoxy Ethyl
    43 CH N Methoxy Methoxy n-Propyl
    44 CH N Methoxy H n-Propyl
    45 CH N Ethoxy H n-Propyl
    46 CH N H H n-Propyl
    47 CH N H Methoxy n-Propyl
    48 CH N Ethoxy Methoxy n-Propyl
    49 CH N Methoxy Methoxy Isopropyl
    50 CH N Methoxy H Isopropyl
    51 CH N Ethoxy H Isopropyl
    52 CH N H H Isopropyl
    53 CH N H Methoxy Isopropyl
    54 CH N Ethoxy Methoxy Isopropyl
    55 CH N Methoxy Methoxy H
    56 CH N Methoxy H H
    57 CH N Ethoxy H H
    58 CH N H H H
    59 CH N H Methoxy H
    60 CH N Ethoxy Methoxy H
    61 CH CH Methoxy Methoxy Methyl
    62 CH CH Methoxy H Methyl
    63 CH CH Ethoxy H Methyl
    64 CH CH H H Methyl
    65 CH CH H Methoxy Methyl
    66 CH CH Ethoxy Methoxy Methyl
    67 CH CH Methoxy Methoxy Ethyl
    68 CH CH Methoxy H Ethyl
    69 CH CH Ethoxy H Ethyl
    70 CH CH H H Ethyl
    71 CH CH H Methoxy Ethyl
    72 CH CH Ethoxy Methoxy Ethyl
    73 CH CH Methoxy Methoxy n-Propyl
    74 CH CH Methoxy H n-Propyl
    75 CH CH Ethoxy H n-Propyl
    76 CH CH H H n-Propyl
    77 CH CH H Methoxy n-Propyl
    78 CH CH Ethoxy Methoxy n-Propyl
    79 CH CH Methoxy Methoxy Isopropyl
    80 CH CH Methoxy H Isopropyl
    81 CH CH Ethoxy H Isopropyl
    82 CH CH H H Isopropyl
    83 CH CH H Methoxy Isopropyl
    84 CH CH Ethoxy Methoxy Isopropyl
    85 CH CH Methoxy Methoxy H
    86 CH CH Methoxy H H
    87 CH CH Ethoxy H H
    88 CH CH H H H
    89 CH CH H Methoxy H
    90 CH CH Ethoxy Methoxy H
  • The compounds I of the invention have a center of chirality in position 3 of the 2-oxindole ring. The compounds of the invention may therefore be in the form of a 1:1 mixture of enantiomers (racemate) or of a nonracemic mixture of enantiomers in which one of the two enantiomers, either the enantiomer which rotates the plane of vibration of linearly polarized light to the left (i.e. minus rotation) (hereinafter (−) enantiomer) or the enantiomer which rotates the plane of vibration of linearly polarized light to the right (i.e. plus rotation) (hereinafter (+) enantiomer), is enriched, or of substantially enantiopure compounds, that is to say of substantially enantiopure (−) enantiomer or (+) enantiomer. Since the compounds of the invention have a single center of asymmetry and no axis/plane of chirality, a nonracemic mixture can also be defined as a mixture of enantiomers in which either the R or the S enantiomer predominates. Substantially enantiopure compounds can accordingly also be defined as substantially enantiopure R enantiomer or substantially enantiopure S enantiomer.
  • “Substantially enantiopure compounds” means in the context of the present invention those compounds having an enantiomeric excess (ee; % ee=(R−S)/(R+S)×100 or (S−R)/(S+R)×100) of at least 80% ee, preferably at least 85% ee, more preferably at least 90% ee, even more preferably at least 95% ee and in particular at least 98% ee.
  • In one embodiment of the invention, the compounds of the invention are in the form of substantially enantiopure compounds. Particularly preferred compounds have an enantiomeric excess of at least 85% ee, more preferably of at least 90% ee, even more preferably of at least 95% ee and in particular of at least 98% ee.
  • The invention thus relates both to the pure enantiomers and to mixtures thereof, e.g. mixtures in which one enantiomer is present in enriched form, but also to the racemates. The invention also relates to the pharmaceutically acceptable salts and the prodrugs of the pure enantiomers of compounds I, and the mixtures of enantiomers in the form of the pharmaceutically acceptable salts and prodrugs of compounds I.
  • Preferred embodiments of the invention are compounds of the formula I as detailed above which are characterized in that they are in optically active form, and the enantiomer of the relevant compound of the formula I is the one which rotates the plane of vibration of polarized light to the left (i.e. minus rotation), in the form of a free base, or a pharmaceutically acceptable salt or a prodrug thereof. The enantiomers with levorotation or minus rotation of the compounds I are also referred to hereinafter as (−) enantiomers.
  • The statements made in the context of the present invention concerning the direction of rotation of polarized light relate preferably to the signs [(+) or (−)] as determined in chloroform as solvent or in chloroform-containing solvent mixtures, in particular in chloroform.
  • Preferred embodiments of the invention are those compounds of the formula I as detailed above which are characterized in that they are in optically active form, with the absolute configuration at the chiral C-3 ring carbon atom of the oxindole structure corresponding to the absolute configuration at C-3 of the (−) enantiomer of the compound 5-cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate (=compound of example 1) in the form of the free base. This configuration is also referred to hereinafter as the “preferred configuration”.
  • Particular preference is given to compounds of the general formula I, pharmaceutically acceptable salts and their prodrugs as detailed above in which the corresponding (−) enantiomer is present in an optical purity (enantiomeric excess, ee) of more than 50% ee, particularly preferably of at least 80% ee, more preferably of at least 90% ee and even more preferably of at least 95% ee and in particular of at least 98% ee.
  • Particular preference is alternatively given to compounds of the general formula I, their pharmaceutically acceptable salts and their prodrugs in which the enantiomer displaying the preferred absolute configuration at the C-3 ring carbon atom is present in with an optical purity (enantiomeric excess, ee) of more than 50% ee, preferably of at least 80% ee, more preferably of at least 90% ee, even more preferably of at least 95% ee and in particular of at least 98% ee.
  • Likewise preferred embodiments of the invention are compounds of the general formula I as detailed above which are characterized in that they are in optically inactive form, i.e. in the form of the racemate, or in the form of a pharmaceutically acceptable salt or of a prodrug of the racemate.
  • Examples of particularly preferred compounds I are the compounds listed in following table 2 with the example numbers 1 to 90B, and the pharmaceutically acceptable salts and prodrugs thereof. In this connection, examples 1 to 90 correspond to the racemate of the respective compounds, the examples with an appended letter “A” (1A, 2A, . . . to 90A) correspond to the dextrorotatory (+) enantiomer and the examples with an appended letter “B” (1B, 2B, . . . to 90B) correspond to the levorotatory (−) enantiomer of the respective compound 1 to 90. The naming of the compounds corresponds to the naming generated by the ACD-Labs version 8.00 release product version 8.05.
  • TABLE 2
    Example
    No. X1 X2 R1 R2 R3 IUPAC Name
     1 N CH Methoxy Methoxy Methyl (±)-5-Cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-
    2,3-dihydro-1H-indol-3-yl 4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate
     1A N CH Methoxy Methoxy Methyl (+)-5-Cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-
    2,3-dihydro-1H-indol-3-yl 4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate
     1B N CH Methoxy Methoxy Methyl (−)-5-Cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-
    2,3-dihydro-1H-indol-3-yl 4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate
     2 N CH Methoxy H Methyl (±)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulfonyl]-2-oxo-2,3-
    dihydro-1H-indol-3-yl 4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate
     2A N CH Methoxy H Methyl (+)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulfonyl]-2-oxo-2,3-
    dihydro-1H-indol-3-yl 4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate
     2B N CH Methoxy H Methyl (−)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulfonyl]-2-oxo-2,3-
    dihydro-1H-indol-3-yl 4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate
     3 N CH Ethoxy H Methyl (±)-5-Cyano-1-[(2-ethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-
    dihydro-1H-indol-3-yl 4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate
     3A N CH Ethoxy H Methyl (+)-5-Cyano-1-[(2-ethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-
    dihydro-1H-indol-3-yl 4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate
     3B N CH Ethoxy H Methyl (−)-5-Cyano-1-[(2-ethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-
    dihydro-1H-indol-3-yl 4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate
     4 N CH H H Methyl (±)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-
    indol-3-yl 4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate
     4A N CH H H Methyl (+)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-
    indol-3-yl 4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate
     4B N CH H H Methyl (−)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-
    indol-3-yl 4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate
     5 N CH H Methoxy Methyl (±)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulfonyl]-2-oxo-2,3-
    dihydro-1H-indol-3-yl 4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate
     5A N CH H Methoxy Methyl (+)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulfonyl]-2-oxo-2,3-
    dihydro-1H-indol-3-yl 4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate
     5B N CH H Methoxy Methyl (−)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulfonyl]-2-oxo-2,3-
    dihydro-1H-indol-3-yl 4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate
     6 N CH Ethoxy Methoxy Methyl (±)-5-Cyano-1-[(2-ethoxy-4-methoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-
    oxo-2,3-dihydro-1H-indol-3-yl 4-(1-methylpiperidin-4-yl)piperazine-1-
    carboxylate
     6A N CH Ethoxy Methoxy Methyl (+)-5-Cyano-1-[(2-ethoxy-4-methoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-
    oxo-2,3-dihydro-1H-indol-3-yl 4-(1-methylpiperidin-4-yl)piperazine-1-
    carboxylate
     6B N CH Ethoxy Methoxy Methyl (−)-5-Cyano-1-[(2-ethoxy-4-methoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-
    oxo-2,3-dihydro-1H-indol-3-yl 4-(1-methylpiperidin-4-yl)piperazine-1-
    carboxylate
     7 N CH Methoxy Methoxy Ethyl (±)-5-Cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-
    2,3-dihydro-1H-indol-3-yl 4-(1-ethylpiperidin-4-yl)piperazine-1-carboxylate
     7A N CH Methoxy Methoxy Ethyl (+)-5-Cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-
    2,3-dihydro-1H-indol-3-yl 4-(1-ethylpiperidin-4-yl)piperazine-1-carboxylate
     7B N CH Methoxy Methoxy Ethyl (−)-5-Cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-
    2,3-dihydro-1H-indol-3-yl 4-(1-ethylpiperidin-4-yl)piperazine-1-carboxylate
     8 N CH Methoxy H Ethyl (±)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulfonyl]-2-oxo-2,3-
    dihydro-1H-indol-3-yl 4-(1-ethylpiperidin-4-yl)piperazine-1-carboxylate
     8A N CH Methoxy H Ethyl (+)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulfonyl]-2-oxo-2,3-
    dihydro-1H-indol-3-yl 4-(1-ethylpiperidin-4-yl)piperazine-1-carboxylate
     8B N CH Methoxy H Ethyl (−)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulfonyl]-2-oxo-2,3-
    dihydro-1H-indol-3-yl 4-(1-ethylpiperidin-4-yl)piperazine-1-carboxylate
     9 N CH Ethoxy H Ethyl (±)-5-Cyano-1-[(2-ethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-
    dihydro-1H-indol-3-yl 4-(1-ethylpiperidin-4-yl)piperazine-1-carboxylate
     9A N CH Ethoxy H Ethyl (+)-5-Cyano-1-[(2-ethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-
    dihydro-1H-indol-3-yl 4-(1-ethylpiperidin-4-yl)piperazine-1-carboxylate
     9B N CH Ethoxy H Ethyl (−)-5-Cyano-1-[(2-ethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-
    dihydro-1H-indol-3-yl 4-(1-ethylpiperidin-4-yl)piperazine-1-carboxylate
    10 N CH H H Ethyl (±)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-
    indol-3-yl 4-(1-ethylpiperidin-4-yl)piperazine-1-carboxylate
    10A N CH H H Ethyl (+)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-
    indol-3-yl 4-(1-ethylpiperidin-4-yl)piperazine-1-carboxylate
    10B N CH H H Ethyl (−)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-
    indol-3-yl 4-(1-ethylpiperidin-4-yl)piperazine-1-carboxylate
    11 N CH H Methoxy Ethyl (±)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulfonyl]-2-oxo-2,3-
    dihydro-1H-indol-3-yl 4-(1-ethylpiperidin-4-yl)piperazine-1-carboxylate
    11A N CH H Methoxy Ethyl (+)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulfonyl]-2-oxo-2,3-
    dihydro-1H-indol-3-yl 4-(1-ethylpiperidin-4-yl)piperazine-1-carboxylate
    11B N CH H Methoxy Ethyl (−)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulfonyl]-2-oxo-2,3-
    dihydro-1H-indol-3-yl 4-(1-ethylpiperidin-4-yl)piperazine-1-carboxylate
    12 N CH Ethoxy Methoxy Ethyl (±)-5-Cyano-1-[(2-ethoxy-4-methoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-
    oxo-2,3-dihydro-1H-indol-3-yl 4-(1-ethylpiperidin-4-yl)piperazine-1-carboxylate
    12A N CH Ethoxy Methoxy Ethyl (+)-5-Cyano-1-[(2-ethoxy-4-methoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-
    oxo-2,3-dihydro-1H-indol-3-yl 4-(1-ethylpiperidin-4-yl)piperazine-1-carboxylate
    12B N CH Ethoxy Methoxy Ethyl (−)-5-Cyano-1-[(2-ethoxy-4-methoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-
    oxo-2,3-dihydro-1H-indol-3-yl 4-(1-ethylpiperidin-4-yl)piperazine-1-carboxylate
    13 N CH Methoxy Methoxy n-Propyl (±)-5-Cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-
    2,3-dihydro-1H-indol-3-yl 4-(1-propylpiperidin-4-yl)piperazine-1-carboxylate
    13A N CH Methoxy Methoxy n-Propyl (+)-5-Cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-
    2,3-dihydro-1H-indol-3-yl 4-(1-propylpiperidin-4-yl)piperazine-1-carboxylate
    13B N CH Methoxy Methoxy n-Propyl (−)-5-Cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-
    2,3-dihydro-1H-indol-3-yl 4-(1-propylpiperidin-4-yl)piperazine-1-carboxylate
    14 N CH Methoxy H n-Propyl (±)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulfonyl]-2-oxo-2,3-
    dihydro-1H-indol-3-yl 4-(1-propylpiperidin-4-yl)piperazine-1-carboxylate
    14A N CH Methoxy H n-Propyl (+)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulfonyl]-2-oxo-2,3-
    dihydro-1H-indol-3-yl 4-(1-propylpiperidin-4-yl)piperazine-1-carboxylate
    14B N CH Methoxy H n-Propyl (−)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulfonyl]-2-oxo-2,3-
    dihydro-1H-indol-3-yl 4-(1-propylpiperidin-4-yl)piperazine-1-carboxylate
    15 N CH Ethoxy H n-Propyl (±)-5-Cyano-1-[(2-ethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-
    dihydro-1H-indol-3-yl 4-(1-propylpiperidin-4-yl)piperazine-1-carboxylate
    15A N CH Ethoxy H n-Propyl (+)-5-Cyano-1-[(2-ethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-
    dihydro-1H-indol-3-yl 4-(1-propylpiperidin-4-yl)piperazine-1-carboxylate
    15B N CH Ethoxy H n-Propyl (−)-5-Cyano-1-[(2-ethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-
    dihydro-1H-indol-3-yl 4-(1-propylpiperidin-4-yl)piperazine-1-carboxylate
    16 N CH H H n-Propyl (±)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-
    indol-3-yl 4-(1-propylpiperidin-4-yl)piperazine-1-carboxylate
    16A N CH H H n-Propyl (+)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-
    indol-3-yl 4-(1-propylpiperidin-4-yl)piperazine-1-carboxylate
    16B N CH H H n-Propyl (−)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-
    indol-3-yl 4-(1-propylpiperidin-4-yl)piperazine-1-carboxylate
    17 N CH H Methoxy n-Propyl (±)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulfonyl]-2-oxo-2,3-
    dihydro-1H-indol-3-yl 4-(1-propylpiperidin-4-yl)piperazine-1-carboxylate
    17A N CH H Methoxy n-Propyl (+)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulfonyl]-2-oxo-2,3-
    dihydro-1H-indol-3-yl 4-(1-propylpiperidin-4-yl)piperazine-1-carboxylate
    17B N CH H Methoxy n-Propyl (−)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulfonyl]-2-oxo-2,3-
    dihydro-1H-indol-3-yl 4-(1-propylpiperidin-4-yl)piperazine-1-carboxylate
    18 N CH Ethoxy Methoxy n-Propyl (±)-5-Cyano-1-[(2-ethoxy-4-methoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-
    oxo-2,3-dihydro-1H-indol-3-yl 4-(1-propylpiperidin-4-yl)piperazine-1-
    carboxylate
    18A N CH Ethoxy Methoxy n-Propyl (+)-5-Cyano-1-[(2-ethoxy-4-methoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-
    oxo-2,3-dihydro-1H-indol-3-yl 4-(1-propylpiperidin-4-yl)piperazine-1-
    carboxylate
    18B N CH Ethoxy Methoxy n-Propyl (−)-5-Cyano-1-[(2-ethoxy-4-methoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-
    oxo-2,3-dihydro-1H-indol-3-yl 4-(1-propylpiperidin-4-yl)piperazine-1-
    carboxylate
    19 N CH Methoxy Methoxy Isopropyl (±)-5-Cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-
    2,3-dihydro-1H-indol-3-yl 4-(1-isopropylpiperidin-4-yl)piperazine-1-carboxylate
    19A N CH Methoxy Methoxy Isopropyl (+)-5-Cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-
    2,3-dihydro-1H-indol-3-yl 4-(1-isopropylpiperidin-4-yl)piperazine-1-carboxylate
    19B N CH Methoxy Methoxy Isopropyl (−)-5-Cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-
    2,3-dihydro-1H-indol-3-yl 4-(1-isopropylpiperidin-4-yl)piperazine-1-carboxylate
    20 N CH Methoxy H Isopropyl (±)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulfonyl]-2-oxo-2,3-
    dihydro-1H-indol-3-yl 4-(1-isopropylpiperidin-4-yl)piperazine-1-carboxylate
    20A N CH Methoxy H Isopropyl (+)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulfonyl]-2-oxo-2,3-
    dihydro-1H-indol-3-yl 4-(1-isopropylpiperidin-4-yl)piperazine-1-carboxylate
    20B N CH Methoxy H Isopropyl (−)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulfonyl]-2-oxo-2,3-
    dihydro-1H-indol-3-yl 4-(1-isopropylpiperidin-4-yl)piperazine-1-carboxylate
    21 N CH Ethoxy H Isopropyl (±)-5-Cyano-1-[(2-ethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-
    dihydro-1H-indol-3-yl 4-(1-isopropylpiperidin-4-yl)piperazine-1-carboxylate
    21A N CH Ethoxy H Isopropyl (+)-5-Cyano-1-[(2-ethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-
    dihydro-1H-indol-3-yl 4-(1-isopropylpiperidin-4-yl)piperazine-1-carboxylate
    21B N CH Ethoxy H Isopropyl (−)-5-Cyano-1-[(2-ethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-
    dihydro-1H-indol-3-yl 4-(1-isopropylpiperidin-4-yl)piperazine-1-carboxylate
    22 N CH H H Isopropyl (±)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-
    indol-3-yl 4-(1-isopropylpiperidin-4-yl)piperazine-1-carboxylate
    22A N CH H H Isopropyl (+)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-
    indol-3-yl 4-(1-isopropylpiperidin-4-yl)piperazine-1-carboxylate
    22B N CH H H Isopropyl (−)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-
    indol-3-yl 4-(1-isopropylpiperidin-4-yl)piperazine-1-carboxylate
    23 N CH H Methoxy Isopropyl (±)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulfonyl]-2-oxo-2,3-
    dihydro-1H-indol-3-yl 4-(1-isopropylpiperidin-4-yl)piperazine-1-carboxylate
    23A N CH H Methoxy Isopropyl (+)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulfonyl]-2-oxo-2,3-
    dihydro-1H-indol-3-yl 4-(1-isopropylpiperidin-4-yl)piperazine-1-carboxylate
    23B N CH H Methoxy Isopropyl (−)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulfonyl]-2-oxo-2,3-
    dihydro-1H-indol-3-yl 4-(1-isopropylpiperidin-4-yl)piperazine-1-carboxylate
    24 N CH Ethoxy Methoxy Isopropyl (±)-5-Cyano-1-[(2-ethoxy-4-methoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-
    oxo-2,3-dihydro-1H-indol-3-yl 4-(1-isopropylpiperidin-4-yl)piperazine-1-
    carboxylate
    24A N CH Ethoxy Methoxy Isopropyl (+)-5-Cyano-1-[(2-ethoxy-4-methoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-
    oxo-2,3-dihydro-1H-indol-3-yl 4-(1-isopropylpiperidin-4-yl)piperazine-1-
    carboxylate
    24B N CH Ethoxy Methoxy Isopropyl (−)-5-Cyano-1-[(2-ethoxy-4-methoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-
    oxo-2,3-dihydro-1H-indol-3-yl 4-(1-isopropylpiperidin-4-yl)piperazine-1-
    carboxylate
    25 N CH Methoxy Methoxy H (±)-5-Cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-
    2,3-dihydro-1H-indol-3-yl 4-piperidin-4-ylpiperazine-1-carboxylate
    25A N CH Methoxy Methoxy H (+)-5-Cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-
    2,3-dihydro-1H-indol-3-yl 4-piperidin-4-ylpiperazine-1-carboxylate
    25B N CH Methoxy Methoxy H (−)-5-Cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-
    2,3-dihydro-1H-indol-3-yl 4-piperidin-4-ylpiperazine-1-carboxylate
    26 N CH Methoxy H H (±)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulfonyl]-2-oxo-2,3-
    dihydro-1H-indol-3-yl 4-piperidin-4-ylpiperazine-1-carboxylate
    26A N CH Methoxy H H (+)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulfonyl]-2-oxo-2,3-
    dihydro-1H-indol-3-yl 4-piperidin-4-ylpiperazine-1-carboxylate
    26B N CH Methoxy H H (−)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulfonyl]-2-oxo-2,3-
    dihydro-1H-indol-3-yl 4-piperidin-4-ylpiperazine-1-carboxylate
    27 N CH Ethoxy H H (±)-5-Cyano-1-[(2-ethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-
    dihydro-1H-indol-3-yl 4-piperidin-4-ylpiperazine-1-carboxylate
    27A N CH Ethoxy H H (+)-5-Cyano-1-[(2-ethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-
    dihydro-1H-indol-3-yl 4-piperidin-4-ylpiperazine-1-carboxylate
    27B N CH Ethoxy H H (−)-5-Cyano-1-[(2-ethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-
    dihydro-1H-indol-3-yl 4-piperidin-4-ylpiperazine-1-carboxylate
    28 N CH H H H (±)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-
    indol-3-yl 4-piperidin-4-ylpiperazine-1-carboxylate
    28A N CH H H H (+)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-
    indol-3-yl 4-piperidin-4-ylpiperazine-1-carboxylate
    28B N CH H H H (−)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-
    indol-3-yl 4-piperidin-4-ylpiperazine-1-carboxylate
    29 N CH H Methoxy H (±)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulfonyl]-2-oxo-2,3-
    dihydro-1H-indol-3-yl 4-piperidin-4-ylpiperazine-1-carboxylate
    29A N CH H Methoxy H (+)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulfonyl]-2-oxo-2,3-
    dihydro-1H-indol-3-yl 4-piperidin-4-ylpiperazine-1-carboxylate
    29B N CH H Methoxy H (−)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulfonyl]-2-oxo-2,3-
    dihydro-1H-indol-3-yl 4-piperidin-4-ylpiperazine-1-carboxylate
    30 N CH Ethoxy Methoxy H (±)-5-Cyano-1-[(2-ethoxy-4-methoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-
    oxo-2,3-dihydro-1H-indol-3-yl 4-piperidin-4-ylpiperazine-1-carboxylate
    30A N CH Ethoxy Methoxy H (+)-5-Cyano-1-[(2-ethoxy-4-methoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-
    oxo-2,3-dihydro-1H-indol-3-yl 4-piperidin-4-ylpiperazine-1-carboxylate
    30B N CH Ethoxy Methoxy H (−)-5-Cyano-1-[(2-ethoxy-4-methoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-
    oxo-2,3-dihydro-1H-indol-3-yl 4-piperidin-4-ylpiperazine-1-carboxylate
    31 CH N Methoxy Methoxy Methyl (±)-5-Cyano-1-[(2-ethoxy-4-methoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-
    oxo-2,3-dihydro-1H-indol-3-yl 4-piperidin-4-ylpiperazine-1-carboxylate
    31A CH N Methoxy Methoxy Methyl (+)-5-Cyano-1-[(2-ethoxy-4-methoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-
    oxo-2,3-dihydro-1H-indol-3-yl 4-piperidin-4-ylpiperazine-1-carboxylate
    31B CH N Methoxy Methoxy Methyl (−)-5-Cyano-1-[(2-ethoxy-4-methoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-
    oxo-2,3-dihydro-1H-indol-3-yl 4-piperidin-4-ylpiperazine-1-carboxylate
    32 CH N Methoxy H Methyl (±)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulfonyl]-2-oxo-2,3-
    dihydro-1H-indol-3-yl 4-(4-methylpiperazin-1-yl)piperidine-1-carboxylate
    32A CH N Methoxy H Methyl (+)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulfonyl]-2-oxo-2,3-
    dihydro-1H-indol-3-yl 4-(4-methylpiperazin-1-yl)piperidine-1-carboxylate
    32B CH N Methoxy H Methyl (−)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulfonyl]-2-oxo-2,3-
    dihydro-1H-indol-3-yl 4-(4-methylpiperazin-1-yl)piperidine-1-carboxylate
    33 CH N Ethoxy H Methyl (±)-5-Cyano-1-[(2-ethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-
    dihydro-1H-indol-3-yl 4-(4-methylpiperazin-1-yl)piperidine-1-carboxylate
    33A CH N Ethoxy H Methyl (+)-5-Cyano-1-[(2-ethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-
    dihydro-1H-indol-3-yl 4-(4-methylpiperazin-1-yl)piperidine-1-carboxylate
    33B CH N Ethoxy H Methyl (−)-5-Cyano-1-[(2-ethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-
    dihydro-1H-indol-3-yl 4-(4-methylpiperazin-1-yl)piperidine-1-carboxylate
    34 CH N H H Methyl (±)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-
    indol-3-yl 4-(4-methylpiperazin-1-yl)piperidine-1-carboxylate
    34A CH N H H Methyl (+)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-
    indol-3-yl 4-(4-methylpiperazin-1-yl)piperidine-1-carboxylate
    34B CH N H H Methyl (−)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-
    indol-3-yl 4-(4-methylpiperazin-1-yl)piperidine-1-carboxylate
    35 CH N H Methoxy Methyl (±)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulfonyl]-2-oxo-2,3-
    dihydro-1H-indol-3-yl 4-(4-methylpiperazin-1-yl)piperidine-1-carboxylate
    35A CH N H Methoxy Methyl (+)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulfonyl]-2-oxo-2,3-
    dihydro-1H-indol-3-yl 4-(4-methylpiperazin-1-yl)piperidine-1-carboxylate
    35B CH N H Methoxy Methyl (−)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulfonyl]-2-oxo-2,3-
    dihydro-1H-indol-3-yl 4-(4-methylpiperazin-1-yl)piperidine-1-carboxylate
    36 CH N Ethoxy Methoxy Methyl (±)-5-Cyano-1-[(2-ethoxy-4-methoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-
    oxo-2,3-dihydro-1H-indol-3-yl 4-(4-methylpiperazin-1-yl)piperidine-1-
    carboxylate
    36A CH N Ethoxy Methoxy Methyl (+)-5-Cyano-1-[(2-ethoxy-4-methoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-
    oxo-2,3-dihydro-1H-indol-3-yl 4-(4-methylpiperazin-1-yl)piperidine-1-
    carboxylate
    36B CH N Ethoxy Methoxy Methyl (−)-5-Cyano-1-[(2-ethoxy-4-methoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-
    oxo-2,3-dihydro-1H-indol-3-yl 4-(4-methylpiperazin-1-yl)piperidine-1-
    carboxylate
    37 CH N Methoxy Methoxy Ethyl (±)-5-Cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-
    2,3-dihydro-1H-indol-3-yl 4-(4-ethylpiperazin-1-yl)piperidine-1-carboxylate
    37A CH N Methoxy Methoxy Ethyl (+)-5-Cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-
    2,3-dihydro-1H-indol-3-yl 4-(4-ethylpiperazin-1-yl)piperidine-1-carboxylate
    37B CH N Methoxy Methoxy Ethyl (−)-5-Cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-
    2,3-dihydro-1H-indol-3-yl 4-(4-ethylpiperazin-1-yl)piperidine-1-carboxylate
    38 CH N Methoxy H Ethyl (±)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulfonyl]-2-oxo-2,3-
    dihydro-1H-indol-3-yl 4-(4-ethylpiperazin-1-yl)piperidine-1-carboxylate
    38A CH N Methoxy H Ethyl (+)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulfonyl]-2-oxo-2,3-
    dihydro-1H-indol-3-yl 4-(4-ethylpiperazin-1-yl)piperidine-1-carboxylate
    38B CH N Methoxy H Ethyl (−)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulfonyl]-2-oxo-2,3-
    dihydro-1H-indol-3-yl 4-(4-ethylpiperazin-1-yl)piperidine-1-carboxylate
    39 CH N Ethoxy H Ethyl (±)-5-Cyano-1-[(2-ethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-
    dihydro-1H-indol-3-yl 4-(4-ethylpiperazin-1-yl)piperidine-1-carboxylate
    39A CH N Ethoxy H Ethyl (+)-5-Cyano-1-[(2-ethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-
    dihydro-1H-indol-3-yl 4-(4-ethylpiperazin-1-yl)piperidine-1-carboxylate
    39B CH N Ethoxy H Ethyl (−)-5-Cyano-1-[(2-ethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-
    dihydro-1H-indol-3-yl 4-(4-ethylpiperazin-1-yl)piperidine-1-carboxylate
    40 CH N H H Ethyl (±)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-
    indol-3-yl 4-(4-ethylpiperazin-1-yl)piperidine-1-carboxylate
    40A CH N H H Ethyl (+)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-
    indol-3-yl 4-(4-ethylpiperazin-1-yl)piperidine-1-carboxylate
    40B CH N H H Ethyl (−)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-
    indol-3-yl 4-(4-ethylpiperazin-1-yl)piperidine-1-carboxylate
    41 CH N H Methoxy Ethyl (±)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulfonyl]-2-oxo-2,3-
    dihydro-1H-indol-3-yl 4-(4-ethylpiperazin-1-yl)piperidine-1-carboxylate
    41A CH N H Methoxy Ethyl (+)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulfonyl]-2-oxo-2,3-
    dihydro-1H-indol-3-yl 4-(4-ethylpiperazin-1-yl)piperidine-1-carboxylate
    41B CH N H Methoxy Ethyl (−)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulfonyl]-2-oxo-2,3-
    dihydro-1H-indol-3-yl 4-(4-ethylpiperazin-1-yl)piperidine-1-carboxylate
    42 CH N Ethoxy Methoxy Ethyl (±)-5-Cyano-1-[(2-ethoxy-4-methoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-
    oxo-2,3-dihydro-1H-indol-3-yl 4-(4-ethylpiperazin-1-yl)piperidine-1-carboxylate
    42A CH N Ethoxy Methoxy Ethyl (+)-5-Cyano-1-[(2-ethoxy-4-methoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-
    oxo-2,3-dihydro-1H-indol-3-yl 4-(4-ethylpiperazin-1-yl)piperidine-1-carboxylate
    42B CH N Ethoxy Methoxy Ethyl (−)-5-Cyano-1-[(2-ethoxy-4-methoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-
    oxo-2,3-dihydro-1H-indol-3-yl 4-(4-ethylpiperazin-1-yl)piperidine-1-carboxylate
    43 CH N Methoxy Methoxy n-Propyl (±)-5-Cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-
    2,3-dihydro-1H-indol-3-yl 4-(4-propylpiperazin-1-yl)piperidine-1-carboxylate
    43A CH N Methoxy Methoxy n-Propyl (+)-5-Cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-
    2,3-dihydro-1H-indol-3-yl 4-(4-propylpiperazin-1-yl)piperidine-1-carboxylate
    43B CH N Methoxy Methoxy n-Propyl (−)-5-Cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-
    2,3-dihydro-1H-indol-3-yl 4-(4-propylpiperazin-1-yl)piperidine-1-carboxylate
    44 CH N Methoxy H n-Propyl (±)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulfonyl]-2-oxo-2,3-
    dihydro-1H-indol-3-yl 4-(4-propylpiperazin-1-yl)piperidine-1-carboxylate
    44A CH N Methoxy H n-Propyl (+)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulfonyl]-2-oxo-2,3-
    dihydro-1H-indol-3-yl 4-(4-propylpiperazin-1-yl)piperidine-1-carboxylate
    44B CH N Methoxy H n-Propyl (−)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulfonyl]-2-oxo-2,3-
    dihydro-1H-indol-3-yl 4-(4-propylpiperazin-1-yl)piperidine-1-carboxylate
    45 CH N Ethoxy H n-Propyl (±)-5-Cyano-1-[(2-ethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-
    dihydro-1H-indol-3-yl 4-(4-propylpiperazin-1-yl)piperidine-1-carboxylate
    45A CH N Ethoxy H n-Propyl (+)-5-Cyano-1-[(2-ethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-
    dihydro-1H-indol-3-yl 4-(4-propylpiperazin-1-yl)piperidine-1-carboxylate
    45B CH N Ethoxy H n-Propyl (−)-5-Cyano-1-[(2-ethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-
    dihydro-1H-indol-3-yl 4-(4-propylpiperazin-1-yl)piperidine-1-carboxylate
    46 CH N H H n-Propyl (±)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-
    indol-3-yl 4-(4-propylpiperazin-1-yl)piperidine-1-carboxylate
    46A CH N H H n-Propyl (+)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-
    indol-3-yl 4-(4-propylpiperazin-1-yl)piperidine-1-carboxylate
    46B CH N H H n-Propyl (−)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-
    indol-3-yl 4-(4-propylpiperazin-1-yl)piperidine-1-carboxylate
    47 CH N H Methoxy n-Propyl (±)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulfonyl]-2-oxo-2,3-
    dihydro-1H-indol-3-yl 4-(4-propylpiperazin-1-yl)piperidine-1-carboxylate
    47A CH N H Methoxy n-Propyl (+)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulfonyl]-2-oxo-2,3-
    dihydro-1H-indol-3-yl 4-(4-propylpiperazin-1-yl)piperidine-1-carboxylate
    47B CH N H Methoxy n-Propyl (−)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulfonyl]-2-oxo-2,3-
    dihydro-1H-indol-3-yl 4-(4-propylpiperazin-1-yl)piperidine-1-carboxylate
    48 CH N Ethoxy Methoxy n-Propyl (±)-5-Cyano-1-[(2-ethoxy-4-methoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-
    oxo-2,3-dihydro-1H-indol-3-yl 4-(4-propylpiperazin-1-yl)piperidine-1-
    carboxylate
    48A CH N Ethoxy Methoxy n-Propyl (+)-5-Cyano-1-[(2-ethoxy-4-methoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-
    oxo-2,3-dihydro-1H-indol-3-yl 4-(4-propylpiperazin-1-yl)piperidine-1-
    carboxylate
    48B CH N Ethoxy Methoxy n-Propyl (−)-5-Cyano-1-[(2-ethoxy-4-methoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-
    oxo-2,3-dihydro-1H-indol-3-yl 4-(4-propylpiperazin-1-yl)piperidine-1-
    carboxylate
    49 CH N Methoxy Methoxy Isopropyl (±)-5-Cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-
    2,3-dihydro-1H-indol-3-yl 4-(4-isopropylpiperazin-1-yl)piperidine-1-carboxylate
    49A CH N Methoxy Methoxy Isopropyl (+)-5-Cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-
    2,3-dihydro-1H-indol-3-yl 4-(4-isopropylpiperazin-1-yl)piperidine-1-carboxylate
    49B CH N Methoxy Methoxy Isopropyl (−)-5-Cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-
    2,3-dihydro-1H-indol-3-yl 4-(4-isopropylpiperazin-1-yl)piperidine-1-carboxylate
    50 CH N Methoxy H Isopropyl (±)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulfonyl]-2-oxo-2,3-
    dihydro-1H-indol-3-yl 4-(4-isopropylpiperazin-1-yl)piperidine-1-carboxylate
    50A CH N Methoxy H Isopropyl (+)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulfonyl]-2-oxo-2,3-
    dihydro-1H-indol-3-yl 4-(4-isopropylpiperazin-1-yl)piperidine-1-carboxylate
    50B CH N Methoxy H Isopropyl (−)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulfonyl]-2-oxo-2,3-
    dihydro-1H-indol-3-yl 4-(4-isopropylpiperazin-1-yl)piperidine-1-carboxylate
    51 CH N Ethoxy H Isopropyl (±)-5-Cyano-1-[(2-ethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-
    dihydro-1H-indol-3-yl 4-(4-isopropylpiperazin-1-yl)piperidine-1-carboxylate
    51A CH N Ethoxy H Isopropyl (+)-5-Cyano-1-[(2-ethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-
    dihydro-1H-indol-3-yl 4-(4-isopropylpiperazin-1-yl)piperidine-1-carboxylate
    51B CH N Ethoxy H Isopropyl (−)-5-Cyano-1-[(2-ethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-
    dihydro-1H-indol-3-yl 4-(4-isopropylpiperazin-1-yl)piperidine-1-carboxylate
    52 CH N H H Isopropyl (±)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-
    indol-3-yl 4-(4-isopropylpiperazin-1-yl)piperidine-1-carboxylate
    52A CH N H H Isopropyl (+)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-
    indol-3-yl 4-(4-isopropylpiperazin-1-yl)piperidine-1-carboxylate
    52B CH N H H Isopropyl (−)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-
    indol-3-yl 4-(4-isopropylpiperazin-1-yl)piperidine-1-carboxylate
    53 CH N H Methoxy Isopropyl (±)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulfonyl]-2-oxo-2,3-
    dihydro-1H-indol-3-yl 4-(4-isopropylpiperazin-1-yl)piperidine-1-carboxylate
    53A CH N H Methoxy Isopropyl (+)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulfonyl]-2-oxo-2,3-
    dihydro-1H-indol-3-yl 4-(4-isopropylpiperazin-1-yl)piperidine-1-carboxylate
    53B CH N H Methoxy Isopropyl (−)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulfonyl]-2-oxo-2,3-
    dihydro-1H-indol-3-yl 4-(4-isopropylpiperazin-1-yl)piperidine-1-carboxylate
    54 CH N Ethoxy Methoxy Isopropyl (±)-5-Cyano-1-[(2-ethoxy-4-methoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-
    oxo-2,3-dihydro-1H-indol-3-yl 4-(4-isopropylpiperazin-1-yl)piperidine-1-
    carboxylate
    54A CH N Ethoxy Methoxy Isopropyl (+)-5-Cyano-1-[(2-ethoxy-4-methoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-
    oxo-2,3-dihydro-1H-indol-3-yl 4-(4-isopropylpiperazin-1-yl)piperidine-1-
    carboxylate
    54B CH N Ethoxy Methoxy Isopropyl (−)-5-Cyano-1-[(2-ethoxy-4-methoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-
    oxo-2,3-dihydro-1H-indol-3-yl 4-(4-isopropylpiperazin-1-yl)piperidine-1-
    carboxylate
    55 CH N Methoxy Methoxy H (±)-5-Cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-
    2,3-dihydro-1H-indol-3-yl 4-piperazin-1-ylpiperidine-1-carboxylate
    55A CH N Methoxy Methoxy H (+)-5-Cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-
    2,3-dihydro-1H-indol-3-yl 4-piperazin-1-ylpiperidine-1-carboxylate
    55B CH N Methoxy Methoxy H (−)-5-Cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-
    2,3-dihydro-1H-indol-3-yl 4-piperazin-1-ylpiperidine-1-carboxylate
    56 CH N Methoxy H H (±)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulfonyl]-2-oxo-2,3-
    dihydro-1H-indol-3-yl 4-piperazin-1-ylpiperidine-1-carboxylate
    56A CH N Methoxy H H (+)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulfonyl]-2-oxo-2,3-
    dihydro-1H-indol-3-yl 4-piperazin-1-ylpiperidine-1-carboxylate
    56B CH N Methoxy H H (−)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulfonyl]-2-oxo-2,3-
    dihydro-1H-indol-3-yl 4-piperazin-1-ylpiperidine-1-carboxylate
    57 CH N Ethoxy H H (±)-5-Cyano-1-[(2-ethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-
    dihydro-1H-indol-3-yl 4-piperazin-1-ylpiperidine-1-carboxylate
    57A CH N Ethoxy H H (+)-5-Cyano-1-[(2-ethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-
    dihydro-1H-indol-3-yl 4-piperazin-1-ylpiperidine-1-carboxylate
    57B CH N Ethoxy H H (−)-5-Cyano-1-[(2-ethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-
    dihydro-1H-indol-3-yl 4-piperazin-1-ylpiperidine-1-carboxylate
    58 CH N H H H (±)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-
    indol-3-yl 4-piperazin-1-ylpiperidine-1-carboxylate
    58A CH N H H H (+)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-
    indol-3-yl 4-piperazin-1-ylpiperidine-1-carboxylate
    58B CH N H H H (−)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-
    indol-3-yl 4-piperazin-1-ylpiperidine-1-carboxylate
    59 CH N H Methoxy H (±)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulfonyl]-2-oxo-2,3-
    dihydro-1H-indol-3-yl 4-piperazin-1-ylpiperidine-1-carboxylate
    59A CH N H Methoxy H (+)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulfonyl]-2-oxo-2,3-
    dihydro-1H-indol-3-yl 4-piperazin-1-ylpiperidine-1-carboxylate
    59B CH N H Methoxy H (−)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulfonyl]-2-oxo-2,3-
    dihydro-1H-indol-3-yl 4-piperazin-1-ylpiperidine-1-carboxylate
    60 CH N Ethoxy Methoxy H (±)-5-Cyano-1-[(2-ethoxy-4-methoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-
    oxo-2,3-dihydro-1H-indol-3-yl 4-piperazin-1-ylpiperidine-1-carboxylate
    60A CH N Ethoxy Methoxy H (+)-5-Cyano-1-[(2-ethoxy-4-methoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-
    oxo-2,3-dihydro-1H-indol-3-yl 4-piperazin-1-ylpiperidine-1-carboxylate
    60B CH N Ethoxy Methoxy H (−)-5-Cyano-1-[(2-ethoxy-4-methoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-
    oxo-2,3-dihydro-1H-indol-3-yl 4-piperazin-1-ylpiperidine-1-carboxylate
    61 CH CH Methoxy Methoxy Methyl (±)-5-Cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-
    2,3-dihydro-1H-indol-3-yl 1′-methyl-4,4′-bipiperidine-1-carboxylate
    61A CH CH Methoxy Methoxy Methyl (+)-5-Cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-
    2,3-dihydro-1H-indol-3-yl 1′-methyl-4,4′-bipiperidine-1-carboxylate
    61B CH CH Methoxy Methoxy Methyl (−)-5-Cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-
    2,3-dihydro-1H-indol-3-yl 1′-methyl-4,4′-bipiperidine-1-carboxylate
    62 CH CH Methoxy H Methyl (±)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulfonyl]-2-oxo-2,3-
    dihydro-1H-indol-3-yl 1′-methyl-4,4′-bipiperidine-1-carboxylate
    62A CH CH Methoxy H Methyl (+)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulfonyl]-2-oxo-2,3-
    dihydro-1H-indol-3-yl 1′-methyl-4,4′-bipiperidine-1-carboxylate
    62B CH CH Methoxy H Methyl (−)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulfonyl]-2-oxo-2,3-
    dihydro-1H-indol-3-yl 1′-methyl-4,4′-bipiperidine-1-carboxylate
    63 CH CH Ethoxy H Methyl (±)-5-Cyano-1-[(2-ethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-
    dihydro-1H-indol-3-yl 1′-methyl-4,4′-bipiperidine-1-carboxylate
    63A CH CH Ethoxy H Methyl (+)-5-Cyano-1-[(2-ethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-
    dihydro-1H-indol-3-yl 1′-methyl-4,4′-bipiperidine-1-carboxylate
    63B CH CH Ethoxy H Methyl (−)-5-Cyano-1-[(2-ethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-
    dihydro-1H-indol-3-yl 1′-methyl-4,4′-bipiperidine-1-carboxylate
    64 CH CH H H Methyl (±)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-
    indol-3-yl 1′-methyl-4,4′-bipiperidine-1-carboxylate
    64A CH CH H H Methyl (+)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-
    indol-3-yl 1′-methyl-4,4′-bipiperidine-1-carboxylate
    64B CH CH H H Methyl (−)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-
    indol-3-yl 1′-methyl-4,4′-bipiperidine-1-carboxylate
    65 CH CH H Methoxy Methyl (±)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulfonyl]-2-oxo-2,3-
    dihydro-1H-indol-3-yl 1′-methyl-4,4′-bipiperidine-1-carboxylate
    65A CH CH H Methoxy Methyl (+)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulfonyl]-2-oxo-2,3-
    dihydro-1H-indol-3-yl 1′-methyl-4,4′-bipiperidine-1-carboxylate
    65B CH CH H Methoxy Methyl (−)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulfonyl]-2-oxo-2,3-
    dihydro-1H-indol-3-yl 1′-methyl-4,4′-bipiperidine-1-carboxylate
    66 CH CH Ethoxy Methoxy Methyl (±)-5-Cyano-1-[(2-ethoxy-4-methoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-
    oxo-2,3-dihydro-1H-indol-3-yl 1′-methyl-4,4′-bipiperidine-1-carboxylate
    66A CH CH Ethoxy Methoxy Methyl (+)-5-Cyano-1-[(2-ethoxy-4-methoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-
    oxo-2,3-dihydro-1H-indol-3-yl 1′-methyl-4,4′-bipiperidine-1-carboxylate
    66B CH CH Ethoxy Methoxy Methyl (−)-5-Cyano-1-[(2-ethoxy-4-methoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-
    oxo-2,3-dihydro-1H-indol-3-yl 1′-methyl-4,4′-bipiperidine-1-carboxylate
    67 CH CH Methoxy Methoxy Ethyl (±)-5-Cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-
    2,3-dihydro-1H-indol-3-yl 1′-ethyl-4,4′-bipiperidine-1-carboxylate
    67A CH CH Methoxy Methoxy Ethyl (+)-5-Cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-
    2,3-dihydro-1H-indol-3-yl 1′-ethyl-4,4′-bipiperidine-1-carboxylate
    67B CH CH Methoxy Methoxy Ethyl (−)-5-Cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-
    2,3-dihydro-1H-indol-3-yl 1′-ethyl-4,4′-bipiperidine-1-carboxylate
    68 CH CH Methoxy H Ethyl (±)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulfonyl]-2-oxo-2,3-
    dihydro-1H-indol-3-yl 1′-ethyl-4,4′-bipiperidine-1-carboxylate
    68A CH CH Methoxy H Ethyl (+)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulfonyl]-2-oxo-2,3-
    dihydro-1H-indol-3-yl 1′-ethyl-4,4′-bipiperidine-1-carboxylate
    68B CH CH Methoxy H Ethyl (−)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulfonyl]-2-oxo-2,3-
    dihydro-1H-indol-3-yl 1′-ethyl-4,4′-bipiperidine-1-carboxylate
    69 CH CH Ethoxy H Ethyl (±)-5-Cyano-1-[(2-ethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-
    dihydro-1H-indol-3-yl 1′-ethyl-4,4′-bipiperidine-1-carboxylate
    69A CH CH Ethoxy H Ethyl (+)-5-Cyano-1-[(2-ethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-
    dihydro-1H-indol-3-yl 1′-ethyl-4,4′-bipiperidine-1-carboxylate
    69B CH CH Ethoxy H Ethyl (−)-5-Cyano-1-[(2-ethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-
    dihydro-1H-indol-3-yl 1′-ethyl-4,4′-bipiperidine-1-carboxylate
    70 CH CH H H Ethyl (±)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-
    indol-3-yl 1′-ethyl-4,4′-bipiperidine-1-carboxylate
    70A CH CH H H Ethyl (+)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-
    indol-3-yl 1′-ethyl-4,4′-bipiperidine-1-carboxylate
    70B CH CH H H Ethyl (−)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-
    indol-3-yl 1′-ethyl-4,4′-bipiperidine-1-carboxylate
    71 CH CH H Methoxy Ethyl (±)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulfonyl]-2-oxo-2,3-
    dihydro-1H-indol-3-yl 1′-ethyl-4,4′-bipiperidine-1-carboxylate
    71A CH CH H Methoxy Ethyl (+)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulfonyl]-2-oxo-2,3-
    dihydro-1H-indol-3-yl 1′-ethyl-4,4′-bipiperidine-1-carboxylate
    71B CH CH H Methoxy Ethyl (−)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulfonyl]-2-oxo-2,3-
    dihydro-1H-indol-3-yl 1′-ethyl-4,4′-bipiperidine-1-carboxylate
    72 CH CH Ethoxy Methoxy Ethyl (±)-5-Cyano-1-[(2-ethoxy-4-methoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-
    oxo-2,3-dihydro-1H-indol-3-yl 1′-ethyl-4,4′-bipiperidine-1-carboxylate
    72A CH CH Ethoxy Methoxy Ethyl (+)-5-Cyano-1-[(2-ethoxy-4-methoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-
    oxo-2,3-dihydro-1H-indol-3-yl 1′-ethyl-4,4′-bipiperidine-1-carboxylate
    72B CH CH Ethoxy Methoxy Ethyl (−)-5-Cyano-1-[(2-ethoxy-4-methoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-
    oxo-2,3-dihydro-1H-indol-3-yl 1′-ethyl-4,4′-bipiperidine-1-carboxylate
    73 CH CH Methoxy Methoxy n-Propyl (±)-5-Cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-
    2,3-dihydro-1H-indol-3-yl 1′-propyl-4,4′-bipiperidine-1-carboxylate
    73A CH CH Methoxy Methoxy n-Propyl (+)-5-Cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-
    2,3-dihydro-1H-indol-3-yl 1′-propyl-4,4′-bipiperidine-1-carboxylate
    73B CH CH Methoxy Methoxy n-Propyl (−)-5-Cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-
    2,3-dihydro-1H-indol-3-yl 1′-propyl-4,4′-bipiperidine-1-carboxylate
    74 CH CH Methoxy H n-Propyl (±)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulfonyl]-2-oxo-2,3-
    dihydro-1H-indol-3-yl 1′-propyl-4,4′-bipiperidine-1-carboxylate
    74A CH CH Methoxy H n-Propyl (+)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulfonyl]-2-oxo-2,3-
    dihydro-1H-indol-3-yl 1′-propyl-4,4′-bipiperidine-1-carboxylate
    74B CH CH Methoxy H n-Propyl (−)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulfonyl]-2-oxo-2,3-
    dihydro-1H-indol-3-yl 1′-propyl-4,4′-bipiperidine-1-carboxylate
    75 CH CH Ethoxy H n-Propyl (±)-5-Cyano-1-[(2-ethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-
    dihydro-1H-indol-3-yl 1′-propyl-4,4′-bipiperidine-1-carboxylate
    75A CH CH Ethoxy H n-Propyl (+)-5-Cyano-1-[(2-ethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-
    dihydro-1H-indol-3-yl 1′-propyl-4,4′-bipiperidine-1-carboxylate
    75B CH CH Ethoxy H n-Propyl (−)-5-Cyano-1-[(2-ethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-
    dihydro-1H-indol-3-yl 1′-propyl-4,4′-bipiperidine-1-carboxylate
    76 CH CH H H n-Propyl (±)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-
    indol-3-yl 1′-propyl-4,4′-bipiperidine-1-carboxylate
    76A CH CH H H n-Propyl (+)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-
    indol-3-yl 1′-propyl-4,4′-bipiperidine-1-carboxylate
    76B CH CH H H n-Propyl (−)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-
    indol-3-yl 1′-propyl-4,4′-bipiperidine-1-carboxylate
    77 CH CH H Methoxy n-Propyl (±)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulfonyl]-2-oxo-2,3-
    dihydro-1H-indol-3-yl 1′-propyl-4,4′-bipiperidine-1-carboxylate
    77A CH CH H Methoxy n-Propyl (+)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulfonyl]-2-oxo-2,3-
    dihydro-1H-indol-3-yl 1′-propyl-4,4′-bipiperidine-1-carboxylate
    77B CH CH H Methoxy n-Propyl (−)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulfonyl]-2-oxo-2,3-
    dihydro-1H-indol-3-yl 1′-propyl-4,4′-bipiperidine-1-carboxylate
    78 CH CH Ethoxy Methoxy n-Propyl (±)-5-Cyano-1-[(2-ethoxy-4-methoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-
    oxo-2,3-dihydro-1H-indol-3-yl 1′-propyl-4,4′-bipiperidine-1-carboxylate
    78A CH CH Ethoxy Methoxy n-Propyl (+)-5-Cyano-1-[(2-ethoxy-4-methoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-
    oxo-2,3-dihydro-1H-indol-3-yl 1′-propyl-4,4′-bipiperidine-1-carboxylate
    78B CH CH Ethoxy Methoxy n-Propyl (−)-5-Cyano-1-[(2-ethoxy-4-methoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-
    oxo-2,3-dihydro-1H-indol-3-yl 1′-propyl-4,4′-bipiperidine-1-carboxylate
    79 CH CH Methoxy Methoxy Isopropyl (±)-5-Cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-
    2,3-dihydro-1H-indol-3-yl 1′-isopropyl-4,4′-bipiperidine-1-carboxylate
    79A CH CH Methoxy Methoxy Isopropyl (+)-5-Cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-
    2,3-dihydro-1H-indol-3-yl 1′-isopropyl-4,4′-bipiperidine-1-carboxylate
    79B CH CH Methoxy Methoxy Isopropyl (−)-5-Cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-
    2,3-dihydro-1H-indol-3-yl 1′-isopropyl-4,4′-bipiperidine-1-carboxylate
    80 CH CH Methoxy H Isopropyl (±)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulfonyl]-2-oxo-2,3-
    dihydro-1H-indol-3-yl 1′-isopropyl-4,4′-bipiperidine-1-carboxylate
    80A CH CH Methoxy H Isopropyl (+)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulfonyl]-2-oxo-2,3-
    dihydro-1H-indol-3-yl 1′-isopropyl-4,4′-bipiperidine-1-carboxylate
    80B CH CH Methoxy H Isopropyl (−)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulfonyl]-2-oxo-2,3-
    dihydro-1H-indol-3-yl 1′-isopropyl-4,4′-bipiperidine-1-carboxylate
    81 CH CH Ethoxy H Isopropyl (±)-5-Cyano-1-[(2-ethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-
    dihydro-1H-indol-3-yl 1′-isopropyl-4,4′-bipiperidine-1-carboxylate
    81A CH CH Ethoxy H Isopropyl (+)-5-Cyano-1-[(2-ethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-
    dihydro-1H-indol-3-yl 1′-isopropyl-4,4′-bipiperidine-1-carboxylate
    81B CH CH Ethoxy H Isopropyl (−)-5-Cyano-1-[(2-ethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-
    dihydro-1H-indol-3-yl 1′-isopropyl-4,4′-bipiperidine-1-carboxylate
    82 CH CH H H Isopropyl (±)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-
    indol-3-yl 1′-isopropyl-4,4′-bipiperidine-1-carboxylate
    82A CH CH H H Isopropyl (+)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-
    indol-3-yl 1′-isopropyl-4,4′-bipiperidine-1-carboxylate
    82B CH CH H H Isopropyl (−)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-
    indol-3-yl 1′-isopropyl-4,4′-bipiperidine-1-carboxylate
    83 CH CH H Methoxy Isopropyl (±)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulfonyl]-2-oxo-2,3-
    dihydro-1H-indol-3-yl 1′-isopropyl-4,4′-bipiperidine-1-carboxylate
    83A CH CH H Methoxy Isopropyl (+)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulfonyl]-2-oxo-2,3-
    dihydro-1H-indol-3-yl 1′-isopropyl-4,4′-bipiperidine-1-carboxylate
    83B CH CH H Methoxy Isopropyl (−)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulfonyl]-2-oxo-2,3-
    dihydro-1H-indol-3-yl 1′-isopropyl-4,4′-bipiperidine-1-carboxylate
    84 CH CH Ethoxy Methoxy Isopropyl (±)-5-Cyano-1-[(2-ethoxy-4-methoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-
    oxo-2,3-dihydro-1H-indol-3-yl 1′-isopropyl-4,4′-bipiperidine-1-carboxylate
    84A CH CH Ethoxy Methoxy Isopropyl (+)-5-Cyano-1-[(2-ethoxy-4-methoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-
    oxo-2,3-dihydro-1H-indol-3-yl 1′-isopropyl-4,4′-bipiperidine-1-carboxylate
    84B CH CH Ethoxy Methoxy Isopropyl (−)-5-Cyano-1-[(2-ethoxy-4-methoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-
    oxo-2,3-dihydro-1H-indol-3-yl 1′-isopropyl-4,4′-bipiperidine-1-carboxylate
    85 CH CH Methoxy Methoxy H (±)-5-Cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-
    2,3-dihydro-1H-indol-3-yl 4,4′-bipiperidine-1-carboxylate
    85A CH CH Methoxy Methoxy H (+)-5-Cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-
    2,3-dihydro-1H-indol-3-yl 4,4′-bipiperidine-1-carboxylate
    85B CH CH Methoxy Methoxy H (−)-5-Cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-
    2,3-dihydro-1H-indol-3-yl 4,4′-bipiperidine-1-carboxylate
    86 CH CH Methoxy H H (±)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulfonyl]-2-oxo-2,3-
    dihydro-1H-indol-3-yl 4,4′-bipiperidine-1-carboxylate
    86A CH CH Methoxy H H (+)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulfonyl]-2-oxo-2,3-
    dihydro-1H-indol-3-yl 4,4′-bipiperidine-1-carboxylate
    86B CH CH Methoxy H H (−)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulfonyl]-2-oxo-2,3-
    dihydro-1H-indol-3-yl 4,4′-bipiperidine-1-carboxylate
    87 CH CH Ethoxy H H (±)-5-Cyano-1-[(2-ethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-
    dihydro-1H-indol-3-yl 4,4′-bipiperidine-1-carboxylate
    87A CH CH Ethoxy H H (+)-5-Cyano-1-[(2-ethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-
    dihydro-1H-indol-3-yl 4,4′-bipiperidine-1-carboxylate
    87B CH CH Ethoxy H H (−)-5-Cyano-1-[(2-ethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-
    dihydro-1H-indol-3-yl 4,4′-bipiperidine-1-carboxylate
    88 CH CH H H H (±)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-
    indol-3-yl 4,4′-bipiperidine-1-carboxylate
    88A CH CH H H H (+)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-
    indol-3-yl 4,4′-bipiperidine-1-carboxylate
    88B CH CH H H H (−)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-
    indol-3-yl 4,4′-bipiperidine-1-carboxylate
    89 CH CH H Methoxy H (±)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulfonyl]-2-oxo-2,3-
    dihydro-1H-indol-3-yl 4,4′-bipiperidine-1-carboxylate
    89A CH CH H Methoxy H (+)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulfonyl]-2-oxo-2,3-
    dihydro-1H-indol-3-yl 4,4′-bipiperidine-1-carboxylate
    89B CH CH H Methoxy H (−)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulfonyl]-2-oxo-2,3-
    dihydro-1H-indol-3-yl 4,4′-bipiperidine-1-carboxylate
    90 CH CH Ethoxy Methoxy H (±)-5-Cyano-1-[(2-ethoxy-4-methoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-
    oxo-2,3-dihydro-1H-indol-3-yl 4,4′-bipiperidine-1-carboxylate
    90A CH CH Ethoxy Methoxy H (+)-5-Cyano-1-[(2-ethoxy-4-methoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-
    oxo-2,3-dihydro-1H-indol-3-yl 4,4′-bipiperidine-1-carboxylate
    90B CH CH Ethoxy Methoxy H (−)-5-Cyano-1-[(2-ethoxy-4-methoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-
    oxo-2,3-dihydro-1H-indol-3-yl 4,4′-bipiperidine-1-carboxylate
  • Among these, particular preference is given to the racemates (i.e. compounds 1, 2, . . . 90) and their physiologically tolerated salts, and their prodrugs. Also particularly preferred are the (−) enantiomers (i.e. compounds 1B, 2B, . . . 90B) and their physiologically tolerated salts, and their prodrugs. The aforementioned compounds are provided in particular in the form of their free base or in the form of their acid addition salts.
  • Examples of synthetic routes for preparing the oxindole derivatives of the invention are described below.
  • The oxindoles of the invention can be prepared in various ways, and the preparation is outlined in synthesis schemes 1 and 2. The variables in these synthetic schemes have the same meanings as in formula I.
  • The 3-hydroxy-1,3-dihydroindol-2-ones IV can be obtained by addition of metallated heterocycles III onto the 3-keto group of the isatins II. The metallated heterocycles, such as, for example, the corresponding Grignard (Mg) or organyllithium compound, can be obtained in any conventional way from halogen or hydrocarbon compounds. Examples of methods are present in Houben-Weyl, Methoden der Organischen Chemie, vol. 13, 1-2, chapter on Mg and Li compounds. The isatins II are either commercially available or can be prepared in analogy to methods described in the literature (Advances in Heterocyclic Chemistry, A. R. Katritzky and A. J. Boulton, Academic Press, New York, 1975, 18, 2-58; J. Brazil. Chem. Soc. 12, 273-324, 2001).
  • The 3-hydroxyoxindoles IV which contain for example in position 5 an iodine as radical Ra in the 6-membered aromatic can be converted with KCN or Zn(CN)2 with Pd(0) catalysis in solvents such as dimethylformamide or tetrahydrofuran and, where appropriate also with the addition of bases such as K2CO3 or other carbonates or amines, at elevated temperature into the analogous cyan-containing 3-hydroxyoxindole IV. It is possible to take as Pd(0) salts for example transition metal complexes prepared in situ from PdCl2 or PdOAc2 by adding phosphines such as tris(ortho-tolyl)phosphine. Commercial palladium complexes such as, for example, the catalyst tetrakis(triphenylphosphine)palladium(0) and/or additions of phosphine ligands can likewise be employed.
  • The hydroxy group in the compound IV is then derivatized, for example with phenyl chloroformate, to give the compounds Va and/or Vb. This consequently takes place by reaction with reagents such as, for example, carboxylic acids, carbonyl chlorides, carbonic anhydrides, chloroformates, isocyanates or carbamoyl chlorides into the compounds V of the invention, using generally customary methods (see J. March, Advanced Organic Chemistry, 1992, 4th edition, Wiley, New York, pages 417-421; 499; 903). For example, LG can have as leaving group OPh in the compounds Va and/or Vb which is derived from reaction of IV with phenyl chloroformate in the presence of a base such as, for example, pyridine.
  • Subsequent reaction with excess amines VI, where appropriate at elevated temperature and/or with the addition of auxiliary bases such as, for example, triethylamine or diisopropylethylamine, leads to the compounds VII. The amines VI can be either purchased or prepared by methods known from the literature.
  • Compounds such as VII can then be converted by treatment with sulfonyl chlorides VIII after deprotonation with a strong base such as, for example, potassium tert-butoxide or sodium hydride in dimethylformamide (DMF) into the compounds of the invention. The employed sulfonyl chlorides VIII can either be purchased or prepared in an analogous manner to known processes (see, for example, J. Med. Chem. 40, 1149 (1997)).
  • Figure US20160362394A1-20161215-C00002
  • Alternatively, the compounds I of the invention can be prepared according to synthesis scheme 2 in the shown three-stage process analogous to synthesis scheme 1 with alteration of the sequence.
  • In this case firstly the 3-hydroxyoxindoles IV are sulfonylated by deprotonation with a strong base such as, for example, sodium hydride or potassium tert-butoxide and subsequent treatment with sulfonyl chlorides VIII in DMF. In the next step, derivatization of the hydroxy group in IX follows to give the compound X by treatment for example with phenyl chloroformate. Finally, the compounds I of the invention are generated in an excess of amine VI or else with the assistance of an auxiliary base.
  • Figure US20160362394A1-20161215-C00003
  • A further preparation possibility and derivatization by R3 in the amine VI is represented by the reaction of amines with aldehydes or ketones in the presence of reducing agents such as, for example, sodium cyanoborohydride or sodium acetoxyborohydride in the manner of a reductive amination (J. March, Advanced Organic Chemistry, 1992, 4th edition, Wiley, New York, pages 411; 898).
  • A further aspect of the present invention relates to a pharmaceutical composition comprising at least one compound of the general formula I and/or a pharmaceutically acceptable salt or a prodrug thereof as detailed above, and a pharmaceutically acceptable carrier. Suitable carriers depend inter alia on the dosage form of the composition and are known in principle to the skilled worker. Some suitable carriers are described hereinafter.
  • A further aspect of the present invention relates to the use of compounds of the formula I and/or of pharmaceutically acceptable salts or prodrugs thereof for the manufacture of a medicament for the treatment and/or prophylaxis of vasopressin-dependent diseases.
  • Vasopressin-dependent diseases are those in which the progress of the disease is at least partly dependent on vasopressin, i.e. diseases which show an elevated vasopressin level which may contribute directly or indirectly to the pathological condition. In other words, vasopressin-dependent diseases are those which can be influenced by modulating the vasopressin receptor, for example by administration of a vasopressin receptor ligand (agonist, antagonist, partial antagonist/agonist, inverse agonist etc.).
  • In a preferred embodiment, the present invention relates to the use of compounds of the invention of the formula I or of pharmaceutically acceptable salts or prodrugs thereof for the manufacture of a medicament for the treatment and/or prophylaxis of diseases selected from diabetes, insulin resistance, nocturnal enuresis, incontinence and diseases in which impairments of blood clotting occur, and/or for delaying micturition. The term “diabetes” means all types of diabetes, especially diabetes mellitus (including type I and especially type II), diabetes renalis and in particular diabetes insipidus. The types of diabetes are preferably diabetes mellitus of type II (with insulin resistance) or diabetes insipidus.
  • In a further preferred embodiment, the present invention relates to the use of compounds of the invention of the formula I or of pharmaceutically acceptable salts or prodrugs thereof for the manufacture of a medicament for the treatment and/or prophylaxis of diseases selected from 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, and travel sickness.
  • The compounds of the invention of the formula I or their pharmaceutically acceptable salts or their prodrugs or the pharmaceutical composition of the invention can also be used for the treatment of various vasopressin-dependent complaints which have central nervous causes or alterations in the HPA axis (hypothalamic pituitary adrenal axis), for example for affective disorders such as depressive disorders and bipolar disorders. These include for example dysthymic disorders, phobias, post-traumatic stress disorders, general anxiety disorders, panic disorders, seasonal depression and sleep disorders.
  • The compounds of the invention of the formula I and their pharmaceutically acceptable salts or their prodrugs or the pharmaceutical composition of the invention can likewise be employed for the treatment of anxiety disorders and stress-dependent anxiety disorders, such as, for example, generalized anxiety disorders, phobias, post-traumatic anxiety disorders, panic anxiety disorders, obsessive-compulsive anxiety disorders, acute stress-dependent anxiety disorders and social phobia.
  • The compounds of the invention can furthermore also be employed for the treatment of memory impairments, Alzheimer's disease, psychoses, psychotic disorders, sleep disorders and/or Cushing's syndrome, and all stress-dependent diseases.
  • Accordingly, a further preferred embodiment of the present invention relates to the use of compounds of the invention of the formula I or of pharmaceutically acceptable salts or prodrugs thereof for the manufacture of a medicament for the treatment of affective disorders.
  • In a further preferred embodiment, the present invention relates to the use of compounds of the invention of the formula I or of pharmaceutically acceptable salts or prodrugs thereof for the manufacture of a medicament for the treatment of anxiety disorders and/or stress-dependent anxiety disorders.
  • In a further preferred embodiment, the present invention relates to the use of compounds of the invention of the formula I or of pharmaceutically acceptable salts or prodrugs thereof for the manufacture of a medicament for the treatment of memory impairments and/or Alzheimer's disease.
  • In a further preferred embodiment, the present invention relates to the use of compounds of the invention of the formula I or of pharmaceutically acceptable salts or prodrugs thereof for the manufacture of a medicament for the treatment of psychoses and/or psychotic disorders.
  • In a further preferred embodiment, the present invention relates to the use of compounds of the invention of the formula I or of pharmaceutically acceptable salts or prodrugs thereof for the manufacture of a medicament for the treatment of Cushing's syndrome or other stress-dependent diseases.
  • In a further preferred embodiment, the present invention relates to the use of compounds of the invention of the formula I or of pharmaceutically acceptable salts or prodrugs thereof for the manufacture of a medicament for the treatment of sleep disorders.
  • In a further preferred embodiment, the present invention relates to the use of compounds of the invention of the formula I or of pharmaceutically acceptable salts or prodrugs thereof for the manufacture of a medicament for the treatment of depressive disorders. A particular form of depressive disorders are so-called childhood onset mood disorders, i.e. depressive moods having their onset in childhood.
  • In a further preferred embodiment, the present invention relates to the use of compounds of the invention of the formula I or of pharmaceutically acceptable salts or prodrugs thereof for the manufacture of a medicament for the treatment of vasomotor symptoms and/or thermoregulatory dysfunctions such as, for example, the hot flush symptom.
  • In a further preferred embodiment, the present invention relates to the use of compounds of the invention of the formula I or of pharmaceutically acceptable salts or prodrugs thereof for the manufacture of a medicament for the treatment and/or prophylaxis of drug or pharmaceutical dependencies and/or dependencies mediated by other factors, for the treatment and/or prophylaxis of stress caused by withdrawal of one or more factors mediating the dependence and/or for the treatment and/or prophylaxis of stress-induced relapses into drug or pharmaceutical dependencies and/or dependencies mediated by other factors.
  • In a further preferred embodiment, the present invention relates to the use of compounds of the invention of the formula I or of pharmaceutically acceptable salts or prodrugs thereof for the manufacture of a medicament for the treatment and/or prophylaxis of schizophrenia and/or psychosis.
  • A further aspect of the invention relates to a method for the treatment and/or prophylaxis of vasopressin-dependent diseases, in which an effective amount of at least one compound of the invention of the formula I or of at least one pharmaceutically acceptable salt or one prodrug thereof or of a pharmaceutical composition of the invention is administered to a patient.
  • Concerning the definition of vasopressin-dependent diseases, reference is made to the above statements.
  • In a preferred embodiment of the invention, the method of the invention serves for the treatment and/or prophylaxis of disorders selected from diabetes, insulin resistance, nocturnal enuresis, incontinence and diseases in which impairments of blood clotting occur, and/or for delaying micturition. Concerning the definition of diabetes, reference is made to the above statements.
  • In a further preferred embodiment, the method of the invention serves for the treatment and/or prophylaxis of disorders selected from 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, and travel sickness.
  • In a further preferred embodiment, the method of the invention serves for the treatment and/or prophylaxis of affective disorders.
  • In a further preferred embodiment, the method of the invention serves for the treatment and/or prophylaxis of anxiety disorders and/or stress-dependent anxiety disorders.
  • In a further preferred embodiment, the method of the invention serves for the treatment and/or prophylaxis of memory impairments and/or Alzheimer's disease.
  • In a further preferred embodiment, the method of the invention serves for the treatment and/or prophylaxis of psychoses and/or psychotic disorders.
  • In a further preferred embodiment, the method of the invention serves for the treatment and/or prophylaxis of Cushing's syndrome.
  • In a further preferred embodiment, the method of the invention serves for the treatment and/or prophylaxis of sleep disorders in a patient.
  • In a further preferred embodiment, the method of the invention serves for the treatment and/or prophylaxis of depressive disorders. In the case of depressive disorders, specific mention is also to be made of childhood onset mood disorders, i.e. depressive moods having their onset in childhood.
  • In a further preferred embodiment, the method of the invention serves for the treatment and/or prophylaxis of vasomotor symptoms and/or thermoregulatory dysfunctions, such as, for example, the hot flush symptom.
  • In a further preferred embodiment, the method of the invention serves for the treatment and/or prophylaxis of drug or pharmaceutical dependencies and/or dependencies mediated by other factors, for the treatment and/or prophylaxis of stress caused by withdrawal of one or more factors mediating the dependence, and/or for the treatment and/or prophylaxis of stress-induced relapses into drug or pharmaceutical dependencies and/or dependencies mediated by other factors.
  • In a further preferred embodiment, the method of the invention serves for the treatment and/or prophylaxis of schizophrenia and/or psychosis.
  • The patient to be treated prophylactically or therapeutically with the method of the invention is preferably a mammal, for example a human or a nonhuman mammal or a nonhuman transgenic mammal. Specifically it is a human.
  • The compounds of the general formula I, their pharmaceutically acceptable salts and prodrugs as detailed above can be prepared by a skilled worker with knowledge of the technical teaching of the invention in implementing and/or in analogous implementation of process steps known per se.
  • The compounds I or their prodrugs and/or their pharmaceutically acceptable salts are distinguished by having a selectivity for the vasopressin V1b receptor subtype vis-à-vis at least one of the closely related vasopressin/oxytocin receptor subtypes (for example vasopressin V1a, vasopressin V2 and/or oxytocin).
  • Alternatively, or preferably in addition, the compounds I or their prodrugs and/or their pharmaceutically acceptable salts are distinguished by having an improved metabolic stability.
  • The metabolic stability of a compound can be measured for example by incubating a solution of this compound with liver microsomes from particular species (for example rat, dog or human) and determining the half-life of the compound under these conditions (R S Obach, Curr Opin Drug Discov Devel. 2001, 4, 36-44). It is possible in this connection to conclude from an observed longer half-life that the metabolic stability of the compound is improved. The stability in the presence of human liver microsomes is of particular interest because it makes it possible to predict the metabolic degradation of the compound in the human liver. Compounds with increased metabolic stability (measured in the liver microsome test) are therefore probably also degraded more slowly in the liver. The slower metabolic degradation in the liver may lead to higher and/or longer-lasting concentrations (active levels) of the compound in the body, so that the elimination half-life of the compounds of the invention is increased. Increased and/or longer-lasting active levels may lead to a better activity of the compound in the treatment or prophylaxis of various vasopressin-dependent diseases. In addition, an improved metabolic stability may lead to an increased bioavailability after oral administration, because the compound is subject, after absorption in the intestine, to less metabolic degradation in the liver (so-called first pass effect). An increased oral bioavailability may, owing to an increased concentration (active level) of the compound, lead to a better activity of the compound after oral administration.
  • Alternatively, or preferably in addition, the compounds I or their prodrugs and/or their pharmaceutically acceptable salts are distinguished by having an improved pharmacological activity, compared with the oxindole compounds known from the prior art, in patients or relevant animal models which enable prognostic statements for use in the treatment.
  • The compounds of the invention are effective after administration by various routes. Possible examples are intravenous, intramuscular, subcutaneous, topical, intratracheal, intranasal, transdermal, vaginal, rectal, sublingual, buccal or oral administration, and administration is frequently intravenous, intramuscular or, in particular, oral.
  • The present invention also relates to pharmaceutical compositions which comprise an effective dose of a compound I of the invention, of a pharmaceutically acceptable salt or of a prodrug thereof and suitable pharmaceutical carriers (drug carriers).
  • These drug carriers are chosen according to the pharmaceutical form and the desired mode of administration and are known in principle to the skilled worker.
  • The compounds of the invention of the formula I or optionally suitable salts of these compounds can be used to produce pharmaceutical compositions for oral, sublingual, buccal, subcutaneous, intramuscular, intravenous, topical, intratracheal, intranasal, transdermal, vaginal or rectal administration, and be administered to animals or humans in uniform administration forms, mixed with conventional pharmaceutical carriers, for the prophylaxis or treatment of the above disorders or diseases.
  • The suitable administration forms (dose units) include forms for oral administration such as tablets, gelatin capsules, powders, granules and solutions or suspensions for oral intake, forms for sublingual, buccal, intratracheal or intranasal administration, aerosols, implants, forms of subcutaneous, intramuscular or intravenous administration and forms of rectal administration.
  • The compounds of the invention can be used in creams, ointments or lotions for topical administration.
  • In order to achieve the desired prophylactic or therapeutic effect, the dose of the active ingredient can vary between 0.01 and 50 mg per kg of body weight and per day.
  • Each unit dose may comprise from 0.05 to 5000 mg, preferably 1 to 1000 mg, of the active ingredient in combination with a pharmaceutical carrier. This unit dose can be administered once to 5 times a day, so that a daily dose of from 0.5 to 25 000 mg, preferably 1 to 5000 mg, is administered.
  • If a solid composition is prepared in the form of tablets, the active ingredient is mixed with a solid pharmaceutical carrier such as gelatin, starch, lactose, magnesium stearate, talc, silicon dioxide or the like.
  • The tablets can be coated with sucrose, a cellulose derivative or another suitable substance or be treated otherwise in order to display a sustained or delayed activity and to release a predetermined amount of the active ingredient continuously.
  • A preparation in the form of gelatin capsules is obtained by mixing the active ingredient with an extender and including the resulting mixture in soft or hard gelatin capsules.
  • A preparation in the form of a syrup or elixir or for administration in the form of drops may contain active ingredients together with a sweetener, which is preferably calorie-free, methylparaben or propylparaben as antiseptics, a flavoring and a suitable coloring substance.
  • Water-dispersible powders or granules may comprise the active ingredients mixed with dispersants, wetting agents or suspending agents, such as polyvinylpyrrolidones, and sweeteners or masking flavors.
  • Rectal or vaginal administration is achieved by using suppositories which are prepared with binders which melt at rectal temperature, for example cocoa butter or polyethylene glycols. Parenteral administration is effected by using aqueous suspensions, isotonic saline solutions or sterile and injectable solutions which comprise pharmacologically acceptable dispersants and/or wetting agents, for example propylene glycol or polyethylene glycol.
  • The active ingredient may also be formulated as microcapsules or centrosomes, if suitable with one or more carriers or additives.
  • The compositions of the invention may, in addition to the compounds of the invention, comprise other active ingredients which may be beneficial for the treatment of the disorders or diseases indicated above.
  • The present invention thus further relates to pharmaceutical compositions in which a plurality of active ingredients are present together, where at least one of these is a compound I of the invention, salt or a prodrug thereof.
  • The invention is explained in more detail below by means of examples, but the examples are not to be understood to be restrictive.
  • The compounds of the invention can be prepared by various synthetic routes. The methods mentioned, as described accordingly in synthesis schemes 1 and 2, are explained in greater detail merely by way of example using the given examples without being exclusively restricted to synthesis routes 1 or 2 or analogous methods.
    • EXPERIMENTAL SECTION Abbreviations
    • THF: tetrahydrofuran
    • DMSO: dimethyl sulfoxide
    • TFA: trifluoroacetic acid
    • p: pseudo (for example pt pseudo triplet)
    • b: broad (for example bs broad singlet)
    • s: singlet
    • d: doublet
    • t: triplet
    • m: multiplet
    • dd: doublet of doublets
    • dt: doublet of triplets
    • tt: triplet of triplets
    I. Preparation of the Starting Compound VI a) 1-Ethyl-4-piperidin-4-yl-piperazine a.1) tert-Butyl 4-(4-ethylpiperazin-1-yl)piperidine-1-carboxylate
  • 29.2 g (256 mmol) of N-ethylpiperazine were introduced with 50.0 g (256 mmol) of tert-butyl 4-oxopiperidine-1-carboxylate (corresponds to 1-Boc-4-piperidone) into 800 ml of ethanol while cooling in ice. 15.4 g (256 mmol) of glacial acetic acid were added. Then 16.1 g (256 mmol) of sodium acetoxyborohydride were added in portions to the cooled reaction mixture. Initially slight gas formation was observed and, after addition of ⅔ of the reducing agent, foam formation was observed. The reaction mixture was stirred at room temperature overnight. The reaction solution was worked up by adding 200 ml of 2N of sodium hydroxide solution while cooling, distilling out the solvent ethanol and diluting the remaining reaction mixture with water. It was extracted with diethyl ether (2×) and was washed with saturated sodium chloride solution (1×), and the combined organic phases were dried over magnesium sulfate and filtered, and the solvent was removed in vacuo. The crude title compound was obtained as a yellow oil which was then chromatographed on a 4 l suction funnel filled with silica gel using dichloromethane and 10% methanol as eluent. In total, 40 g (135 mmol, 53%) of tert-butyl 4-(4-ethylpiperazin-1-yl)piperidine-1-carboxylate were obtained.
    • a.2) 1-Ethyl-4-piperidin-4-ylpiperazine as chloride salt
  • The protective group was removed by introducing 40 g (135 mmol) of tert-butyl 4-(4-ethylpiperazin-1-yl)piperidine-1-carboxylate from example a.1 into 200 ml of methanol and 1.8 l of dichloromethane and adding 100 ml of 5-6M HCl solution in isopropanol. A suspension resulted, and slight gas evolution was also observable. The reaction mixture was stirred at 40° C. (water bath temperature) for one hour and then stirred at room temperature for 48 hours. For complete deprotection, 50 ml of the 5-6M HCl solution in isopropanol were again added and the reaction mixture was stirred at 40° C. The dichloromethane was distilled out in a rotary evaporator. 200 ml of methanol and 30 ml of the 5-6M HCl solution in isopropanol were again added. The reaction mixture was stirred under reflux for one hour, during which a white suspension formed with strong evolution of gas. A mobile suspension then resulted and was cooled to room temperature. The precipitate was filtered off with suction and washed with methanol and diethyl ether. After drying, 36 g (117 mmol, 87%) of 1-ethyl-4-piperidin-4-ylpiperazine were isolated as chloride salt.
  • 1H-NMR (D2O, 400 MHz) δ[ppm]=3.74-3.47 (m, 11H), 3.28 (q, 2H, J=7.3 Hz), 3.06 (dt, 2H, J=2.2 Hz, J=13.2 Hz), 2.38 (m, 2H, J=13.6 Hz), 1.89 (dq, 2H, J=4.1 Hz, J=13.3 Hz), 1.30 (t, 3H, J=7.3 Hz).
    • II. Preparation of the Racemic Compounds of the Formula I Example 1 (±)-5-Cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate 1.1 (±)-3-(2-Ethoxypyridin-3-yl)-3-hydroxy-5-iodo-1,3-dihydro-2H-indol-2-one
  • 3.22 g (80.50 mmol, 60% w/w) of sodium hydride were added in portions to 20.86 g (76.40 mmol) of 5-iodoisatin in 400 ml of anhydrous tetrahydrofuran (THF) while stirring and cooling in an ice bath, keeping the temperature at between 0-10° C. The resulting suspension was stirred while cooling in an ice bath for one hour. To prepare the pyridine Grignard 20 g (80.30 mmol) of 2-ethoxy-3-iodopyridine were dissolved in 400 ml of anhydrous THF at room temperature. 95.6 ml (1 M solution in THF, 95.60 mmol) of ethylmagnesium bromide were added to this solution while cooling at a temperature between 22 and 15° C. over a period of 5-10 minutes. The solution was stirred for 20 minutes, during which it became a pale yellowish color from colorless.
  • The solution of the pyridine Grignard was then added to the solution, cooled in an ice bath, of the 5-iodoisatin sodium salt at a temperature between 5 and 18° C. over a period of 5-10 minutes. After addition of the pyridine Grignard was complete, the ice bath was removed. The reaction mixture was stirred at room temperature for 2 hours. An excess of saturated ammonium chloride solution was added, followed by ethyl acetate, the mixture being stirred for 5 minutes. The aqueous phase was separated off and extracted with ethyl acetate (2×). The combined organic phases were washed with water (2×), and the solvent was removed in vacuo. During this, unreacted 5-iodoisatin precipitated first from the still dilute solution and was separated off. After further concentration, finally the title compound also crystallized. The suspension was stored in a refrigerator at 5° C. for 2 hours. The precipitated, pale yellow solid was then filtered off and washed with a little ethyl acetate. After drying at 40° C., (±)-3-(2-ethoxypyridin-3-yl)-3-hydroxy-5-iodo-1,3-dihydro-2H-indol-2-one (17.1 g, 43.16 mmol, 57%) was isolated.
  • ESI-MS [M+H+]=397.05 calculated for C15H13IN2O3=396.19.
    • 1.2 (±)-5-Cyano-3-hydroxy-3-(2-ethoxypyridin-3-yl)-1,3-dihydroindol-2-one
  • 7.1 g (17.92 mmol) of (±)-3-(2-ethoxypyridin-3-yl)-3-hydroxy-5-iodo-1,3-dihydro-2H-indol-2-one from example 1.1 were stirred in 100 ml of anhydrous THF under a nitrogen atmosphere at room temperature. 2.1 g (17.92 mmol) of zinc cyanide were added, followed by 0.51 g (0.45 mmol) of the catalyst tetrakis(triphenylphosphine)palladium(0). The reaction mixture was immediately placed in a preheated oil bath at a temperature of 100° C. The mixture was stirred at 100° C. (oil-bath temperature) and, after 30 minutes, a further 0.51 g (0.45 mmol) of the catalyst was added. The mixture was stirred for a total of 2 hours. The reaction mixture was allowed to cool to room temperature and an excess of water was added. It was subsequently extracted with ethyl acetate (3×), and the combined organic phases were washed with water (3×). The solvent was evaporated to dryness in vacuo, and the residue was slurried with a small volume of ethyl acetate. A pale yellow solid could be filtered off and was washed with ethyl acetate and dried in a vacuum drying oven. 3.7 g (12.44 mmol, 69.4%) of 5-cyano-3-hydroxy-3-(2-ethoxypyridin-3-yl)-1,3-dihydroindol-2-one were obtained.
  • ESI-MS [M+H+]=296.05 calculated for C16H13N3O3=295.30.
    • 1.3 (±)-Phenyl 5-cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-3-[(phenoxycarbonyl)oxy]indoline-1-carboxylate
  • 4.63 ml (36.98 mmol) of phenyl chloroformate were slowly added dropwise, undiluted, at the preset temperature to a suspension, cooled to 0° C., of 5.20 g (17.61 mmol) of (±)-5-cyano-3-hydroxy-3-(2-ethoxypyridin-3-yl)-1,3-dihydroindol-2-one from example 1.2 in 100 ml of pyridine. After the reaction mixture had thawed to room temperature it was stirred for 2 hours. The progress of the reaction was followed by thin-layer chromatography (silica gel, dichloromethane/methanol 9:1). Excess pyridine was removed in vacuo, and the residue was poured into 200 ml of ice-water and extracted with ethyl acetate (3×). The organic phase was washed with water (2×). Traces of pyridine were still present in the phase. The organic phase was dried over sodium sulfate. After removal of the ethyl acetate in vacuo, the remaining pyridine was driven off by addition of toluene and removal in vacuo several times. The residue was dried under high vacuum. 8.20 g (15.31 mmol, 87%) of phenyl 5-cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-3-[(phenoxycarbonyl)-oxy]indoline-1-carboxylate were obtained.
  • ESI-MS [M+H+]=536.25 calculated for C30H21N3O7=535.52.
    • 1.4 (±)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate
  • 2.74 g (14.94 mmol) of 1-(1-methylpiperidin-4-yl)piperazine were added to a solution of 1.60 g (2.89 mmol) of (±)-phenyl 5-cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-3-[(phenoxycarbonyl)oxy]indoline-1-carboxylate from example 1.3 in 50 ml of THF. During this, initially a slight turbidity formed and eventually a precipitate separated out. After stirring at room temperature for 2 hours, the reaction was complete (checked by thin-layer chromatography (silica gel, dichloromethane/methanol 9:1)). The mixture was stirred overnight. The precipitate was filtered off with suction and washed with THF and diethyl ether. 0.923 g (1.829 mmol, 61%) of 5-cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate was obtained. The title compound was pure according to MS and HPLC. The mother liquor contained only traces of the title compound plus the byproduct phenyl 4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate.
  • ESI-MS [M+H+]=505.25 calculated for C27H32N6O4=504.59.
    • 1.5 (±)-5-Cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate
  • 24.47 mg (0.22 mmol) of potassium tert-butoxide were added undiluted to a solution of 100 mg (0.20 mmol) of (±)-5-cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate in 2 ml of absolute dimethylformamide while cooling at 0° C. The reaction mixture was stirred at 0° C. for one hour. A clear colorless solution formed. At 0° C., 51.6 mg (0.22 mmol) of 2,4-dimethoxybenzenesulfonyl chloride were added. The reaction mixture was allowed to thaw to room temperature and was stirred at room temperature overnight. After conversion was complete, the reaction mixture was poured into 10 ml of ice-water and initially neutralized and then adjusted to pH 9 with 2 ml of 1 N sodium hydroxide solution. A precipitate separated out and was washed with water and dried in a vacuum drying oven to result in 68 mg of dry solid. In order to remove the slight impurities, the solid was stirred in 3 ml of diethyl ether. After leaving to stand overnight, the solid was again filtered off and washed with a little diethyl ether and dried. 40 mg (0.06 mmol, 29%) of (±)-5-cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate were obtained.
  • ESI-MS [M+H+]=705.4 calculated for C35H40N6O8S=704.81.
  • 1H-NMR ([d6]-DMSO, 500 MHz) δ [ppm]=8.22-8.10 (m, 2H), 7.96 (d, 1H, J=8.0 Hz), 7.92 (d, 1H, J=8.3 Hz), 7.85 (d, 1H, J=8.7 Hz), 7.65 (s, 1H), 7.13 (m, 1H), 6.67-6.63 (m, 2H), 4.08 (m, 2H), 3.84 (s, 3H), 3.67-3.45 (m, 3H), 3.51 (s, 3H), 3.04 (m, 2H), 2.74 (pd, 2H, J=9.4 Hz), 2.46 (m, 1H), 2.28 (m, 2H), 2.14 (m, 1H), 2.10 (s, 3H), 1.79 (pt, 2H, J=10.3 Hz), 1.61 (pd, 2H, J=10.2 Hz), 1.36 (m, 2H), 0.99 (t, 3H, J=6.4 Hz).
  • The compounds I of the invention can also be purified as an alternative to crystallization by conventional normal-phase column chromatography (such as, for example, NP SiO2 cartridge, Chromabond and dichloromethane/methanol as eluent) and/or by preparative HPLC (RP, eluent acetonitrile/water, 0.1% TFA or 0.1% acetic acid). Compounds I then result where appropriate as trifluoroacetic acid salt, bis(trifluoroacetic acid) salt or acetic acid salt.
    • Examples 2 to 90
  • The compounds of the formula I according to examples 2 to 90 can be prepared using the appropriate starting compounds in analogy to the process for preparing example 1.
    • Example 2 (±)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulfonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate
  • ESI-MS [M+H+]=675.15 calculated for C34H38N6O7S=674.78.
    • Example 4 (±)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-indol-3-yl 4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate
  • ESI-MS [M+H+]=645.20 calculated for C33H36N6O6S=644.76.
  • 1H-NMR ([d6]-DMSO, 500 MHz) δ[ppm]=8.18-8.15 (m, 2H), 8.05 (d, 2H, J=7.5 Hz), 7.97 (d, 1H, J=8.6 Hz), 7.93 (dd, 1H, J=1.7 Hz, J=8.6 Hz), 7.79 (pt, 1H, J=7.5 Hz), 7.70 (pd, 1H, J=1.6 Hz), 7.66 (pt, 2H, J=7.9 Hz), 7.15 (dd, 1H, J=5.1 Hz, J=7.5 Hz), 4.05 (m, 1H), 3.88 (m, 1H), 3.55 (m, 2H), 3.03 (m, 2H), 2.97 (m, 2H), 2.47-2.21 (m, 10H), 1.74 (m, 2H), 1.51 (m, 2H), 0.89 (t, 3H, J=7.1 Hz).
    • Example 5 (±)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulfonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate
  • ESI-MS [M+H+]=675.15 calculated for C34H38N6O7S=674.78.
    • Example 10 (±)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-indol-3-yl 4-(1-ethylpiperidin-4-yl)piperazine-1-carboxylate, trifluoroacetic acid salt
  • 4 μl (0.06 mmol) of acetaldehyde were added dropwise to 50 mg (0.06 mmol) of 5-cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-indol-3-yl 4-piperidin-4-ylpiperazine-1-carboxylate in the form of the bis(trifluoroacetic acid) salt from example 28 in 5 ml of dimethylformamide. The mixture was stirred for 5 minutes. To this suspension were added firstly 41.3 mg (0.29 mmol) of sodium sulfate and then 10 μl (0.12 mmol) of glacial acetic acid, and the mixture was stirred for one hour. 18.5 mg (0.09 mmol) of sodium acetoxyborohydride were introduced in one portion, whereupon an almost clear solution formed within 15 minutes. The progress of the reaction was followed by LC-MS (RP, acetonitrile/water as eluent and 0.1% TFA). After conversion was complete, the mixture was diluted with water and adjusted to pH 10 with 2N sodium hydroxide solution. After removal of the organic phase, the aqueous phase was extracted again with dichloromethane (2×), the combined organic phase was dried over magnesium sulfate and filtered, and the solvent was removed in vacuo. 35 mg of the crude title compound were isolated and were purified by preparative HPLC on a chromolith column (normal phase, from Merck) with the eluents dichloromethane and methanol (gradient 0-5% by volume of methanol within 15 min). Since byproduct (the desulfonylated analog of the product) was detectable in addition to the title compound, it was purified again by preparative HPLC (RP, eluent acetonitrile/water, 0.1% TFA). 19 mg (0.027 mmol, 45%) of 5-cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-indol-3-yl 4-(1-ethylpiperidin-4-yl)piperazine-1-carboxylate, trifluoroacetic acid salt were isolated.
  • ESI-MS [M+H+]=659.3 calculated for C34H38N6O6S=658.78.
    • Example 25 (±)-5-Cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4-piperidin-4-ylpiperazine-1-carboxylate as bis(trifluoroacetic acid) salt
  • 0.159 mg (1.391 mmol) of trifluoroacetic acid was added dropwise to a solution of 0.220 g (0.278 mmol) of 5-cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl-4-[1-(tert-butoxycarbonyl)piperidine-4-yl]piperazine-1-carboxylate (prepared in analogy to example 1, process stage 1.1) to 1.5)) in 3 ml of dichloromethane. The reaction mixture was stirred at room temperature for one hour, monitoring the reaction by thin-layer chromatography (dichloromethane/methanol 9:1). The solvent was removed in vacuo, and the residue (304 mg) was then purified by preparative HPLC (RP, eluent acetonitrile/water, 0.1% TFA), with 20 mg (0.022 mol, 8%) of 5-cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4-piperidin-4-ylpiperazine-1-carboxylate as bis(trifluoroacetic acid) salt being isolated.
  • ESI-MS [M+H+]=691.25 calculated for C34H38N6O8S=690.78.
    • Example 28 (±)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-indol-3-yl 4-piperidin-4-ylpiperazine-1-carboxylate as bis(trifluoroacetic acid) salt
  • ESI-MS [M+H+]=631.20 calculated for C32H34N6O6S=630.73.
    • Example 31 (±)-5-Cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(4-methylpiperazin-1-yl)piperidine-1-carboxylate
  • ESI-MS [M+H+]=705.25 calculated for C35H40N6O8S=704.81.
    • Example 32 (±)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulfonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(4-methylpiperazin-1-yl)piperidine-1-carboxylate
  • ESI-MS [M+H+]=675.15 calculated for C34H38N6O7S=674.78.
    • Example 34 (±)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-indol-3-yl 4-(4-methylpiperazin-1-yl)piperidine-1-carboxylate
  • ESI-MS [M+H+]=645.15 calculated for C33H36N6O6S=644.76.
    • Example 35 (±)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulfonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(4-methylpiperazin-1-yl)piperidine-1-carboxylate
  • ESI-MS [M+H+]=675.25 calculated for C34H38N6O7S=674.78.
    • Example 37 (±)-5-Cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(4-ethylpiperazin-1-yl)piperidine-1-carboxylate
  • ESI-MS [M+H+]=719.30 calculated for C36H42N6O8S=718.84.
  • 1H-NMR ([d6]-DMSO, 500 MHz) δ[ppm]=8.19 (dd, 1H, J=1.6 Hz, J=4.9 Hz, 8.15 (dd, 1H, J=1.6 Hz, J=7.6 Hz), 7.97 (m, 2H), 7.87 (d, 1H, J=8.7 Hz), 7.69 (m, 1H), 7.16 (dd, 1H, J=5.0 Hz, J=7.6 Hz), 6.72-6.68 (m, 2H), 4.19 (m, 1H), 4.10 (m, 2H), 3.86 (s, 3H), 3.74 (m, 2H), 3.52 (s, 3H), 3.58-3.50 (m, 2H), 3.08-2.44 (m, 11H), 1.57 (m, 3H), 1.18 (m, 3H), 1.01 (t, 3H, J=6.8 Hz).
    • Example 40 (±)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-indol-3-yl 4-(4-ethylpiperazin-1-yl)piperidine-1-carboxylate
  • ESI-MS [M+H+]=659.30 calculated for C34H38N6O6S=658.78.
  • 1H-NMR ([d6]-DMSO, 500 MHz) δ[ppm]=8.19-8.17 (m, 2H), 8.07 (d, 2H, J=7.7 Hz), 7.99 (d, 1H, J=8.6 Hz), 7.95 (m, 1H, J=8.4 Hz), 7.81 (t, 1H, J=7.5 Hz), 7.73 (d, 1H, J=32.5 Hz), 7.67 (pt, 2H, J=7.8 Hz), 7.17 (dd, 1H, J=5.0 Hz, J=7.6 Hz), 4.18-4.04 (m, 2H), 3.92 (m, 1H), 3.43 (m, 2H), 3.01 (m, 1H), 2.62 (m, 1H), 2.45-2.25 (m, 11H), 1.79 (m, 1H), 1.61 (m, 1H), 1.36 (m, 1H), 1.09 (m, 1H), 0.97 (m, 3H), 0.92 (t, 3H, J=7.1 Hz).
    • Example 55 5-Cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4-piperazin-1-ylpiperidine-1-carboxylate as bis(trifluoroacetic acid) salt
  • ESI-MS [M+H+]=691.25 calculated for C34H38N6O8S=690.78.
    • III. Preparation of Chiral Compounds of the General Formula I A.) Racemate Resolution of Compounds of the Formula I
  • Racemic compounds of the formula I can be resolved for example by separation on a preparative chiral column.
    • Example 1A and Example 1B (+)-5-Cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate (example 1A) and (−)-5-cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate (example 1B)
  • 68 mg (0.096 mmol) of the racemic 5-cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate from example 1 were resolved on a preparative chiral column (Chiracel OD, flow rate 55 ml/min) with n-heptane/ethanol (700:300) as eluent. The enantiomer eluted first (example 1A) with positive rotation (rotation determined in chloroform) could be isolated in a yield of 20 mg (0.028 mmol, 29%), and the subsequent enantiomer (example 1B) with negative rotation (rotation determined in chloroform) could be isolated in a yield of 17 mg (0.024 mmol, 25%).
    • Example 1A (+)-5-Cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate
  • ESI-MS [M+H+]=353.4 (½ mass) calculated for C35H40N6O8S=704.81.
  • HPLC (Chiracel OD 0.46 cm×25 cm; n-heptane/ethanol 7:3) Rf=9.10 min.
  • Rotation α (22° C., 589 nm, CHCl3, 1 mg/ml)=plus rotation
  • 1H-NMR ([d6]-DMSO, 500 MHz) δ[ppm]=8.16 (dd, 1H, J=1.7 Hz, J=4.9 Hz), 8.12 (dd, 1H, J=1.7 Hz, J=7.6 Hz), 7.97-7.91 (m, 2H), 7.85 (pd, 1H, J=8.8 Hz), 7.66 (d, 1H, J=36.9 Hz), 7.13 (dd, 1H, J=5.0 Hz, J=7.6 Hz), 6.66 (m, 2H), 4.15 (m, 1H), 4.09 (q, 2H, J=6.9 Hz), 3.84 (s, 3H), 3.53-3.48 (m, 1H), 3.50 (s, 3H), 2.97 (pt, 1H, J=12.1 Hz), 2.62 (pt, 1H, J=12.6 Hz), 2.40-2.25 (m, 9H), 2.11 (s, 3H), 1.74 (m, 1H), 1.58 (m, 1H), 1.37-1.26 (m, 1H), 1.04 (m, 1H), 1.00 (t, 3H, J=7.1 Hz).
    • Example 1B (−)-5-Cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate
  • ESI-MS [M+H+]=353.45 (½ mass) calculated for C35H40N6O8S=704.81.
  • HPLC (Chiracel OD 0.46 cm×25 cm; n-heptane/ethanol 7:3) Rf=15.91 min.
  • Rotation α (22° C., 589 nm, CHCl3, 1 mg/ml)=minus rotation
  • 1H-NMR ([d6]-DMSO, 500 MHz) δ[ppm]=8.17 (dd, 1H, J=1.7 Hz, J=4.9 Hz), 8.12 (dd, 1H, J=1.7 Hz, J=7.6 Hz), 7.97-7.91 (m, 2H), 7.84 (pd, 1H, J=8.5 Hz), 7.66 (d, 1H, J=37.5 Hz), 7.14 (dd, 1H, J=5.0 Hz, J=7.6 Hz), 6.66 (m, 2H), 4.15 (m, 1H), 4.08 (q, 2H, J=6.9 Hz), 3.84 (s, 3H), 3.51 (s+m, 4H), 2.98 (pt, 1H, J=12.0 Hz), 2.62 (pt, 1H, J=11.1 Hz), 2.47-2.21 (m, 9H), 2.12 (s, 3H), 1.74 (m, 1H), 1.57 (m, 1H), 1.40-1.23 (m, 1H), 1.04 (m, 1H), 1.00 (t, 3H, J=7.1 Hz).
  • The racemates of examples 2 to 90 can be resolved in an analogous manner to result in the corresponding (+) enantiomers 2A, 3A, 4A, 5A, 6A, 7A, 8A, 9A, 10A, 11A, 12A, 13A, 14A, 15A, 16A, 17A, 18A, 19A, 20A, 21A, 22A, 23A, 24A, 25A, 26A, 27A, 28A, 29A, 30A, 31A, 32A, 33A, 34A, 35A, 36A, 37A, 38A, 39A, 40A, 41A, 42A, 43A, 44A, 45A, 46A, 47A, 48A, 49A, 50A, 51A, 52A, 53A, 54A, 55A, 56A, 57A, 58A, 59A, 60A, 61A, 62A, 63A, 64A, 65A, 66A, 67A, 68A, 69A, 70A, 71A, 72A, 73A, 74A, 75A, 76A, 77A, 78A, 79A, 80A, 81A, 82A, 83A, 84A, 85A, 86A, 87A, 88A, 89A and 90A
  • and the corresponding (−) enantiomers 2B, 3B, 4B, 5B, 6B, 7B, 8B, 9B, 10B, 11B, 12B, 13B, 14B, 15B, 16B, 17B, 18B, 19B, 20B, 21B, 22B, 23B, 24B, 25B, 26B, 27B, 28B, 29B, 30B, 31B, 32B, 33B, 34B, 35B, 36B, 37B, 38B, 39B, 40B, 41B, 42B, 43B, 44B, 45B, 46B, 47B, 48B, 49B, 50B, 51B, 52B, 53B, 54B, 55B, 56B, 57B, 58B, 59B, 60B, 61B, 62B, 63B, 64B, 65B, 66B, 67B, 68B, 69B, 70B, 71B, 72B, 73B, 74B, 75B, 76B, 77B, 78B, 79B, 80B, 81B, 82B, 83B, 84B, 85B, 86B, 87B, 88B, 89B and 90B.
    • Example 2A (+)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulfonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate
  • ESI-MS [M+H+]=675.20 calculated for C34H38N6O7S=674.78.
  • HPLC (Chiracel OD 0.46 cm×25 cm; n-heptane/ethanol 7:3) Rf=10.10 min.
  • Rotation α (22° C., 589 nm, CHCl3, 1 mg/ml)=plus rotation
    • Example 2B (−)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulfonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate
  • ESI-MS [M+H+]=675.20 calculated for C34H38N6O7S=674.78.
  • HPLC (Chiracel OD 0.46 cm×25 cm; n-heptane/ethanol 7:3) R1=12.73 min. (ee=80%)
  • Rotation α (22° C., 589 nm, CHCl3, 1 mg/ml)=minus rotation
    • B.) Synthesis of the (+) and (−) Enantiomers of the Compound of the Formula I Using Enantiopure Precursors and Intermediates
  • The (+) enantiomer of the formula I and the (−) enantiomer of the formula I can also be prepared using enantiopure precursors and intermediates for example in analogy to synthesis scheme 1 or 2, preferably in accordance with synthesis scheme 2. The enantiomer separation is to be explained in detail in relation to intermediate IV, racemic 5-cyano-3-hydroxy-3-(2-ethoxypyridin-3-yl)-1,3-dihydroindol-2-one, without being restricted thereto. Resolution of the racemate into the enantiomers can take place by preparative chiral chromatography.
  • Resolution of racemic 5-cyano-3-hydroxy-3-(2-ethoxypyridin-3-yl)-1,3-dihydroindol-2-one:
  • After chromatographic separation of 10.0 g (33.86 mmol) of the racemic 5-cyano-3-hydroxy-3-(2-ethoxypyridin-3-yl)-1,3-dihydroindol-2-one from example 1.2, 4.85 g (16.42 mmol) of 5-cyano-3-hydroxy-3-(2-ethoxypyridin-3-yl)-1,3-dihydroindol-2-one eluting first (minus rotation, rotation determined in chloroform) were isolated with an enantiomeric excess (e.e.) of >99% and 4.66 g (15.78 mmol) of 5-cyano-3-hydroxy-3-(2-ethoxypyridin-3-yl)-1,3-dihydroindol-2-one eluting last (plus rotation, rotation determined in chloroform) were isolated with an enantiomeric excess (e.e.) of 99%. The enantiomer separation conditions were a preparative chiral column (Chiralpak AD 20 micron 5 cm ID×500 cm) with the eluents hexane/ethanol/methanol in the ratio 80/10/10 and a flow rate of 80 ml/min.
  • Enantiomer 1 of 5-cyano-3-hydroxy-3-(2-ethoxypyridin-3-yl)-1,3-dihydroindol-2-one:
  • ESI-MS [M+H+]=296.15 calculated for C16H13N3O3=295.30.
  • HPLC (Chiralpak AD 4.6 mmID×25 cm; hexane/ethanol/methanol 80/10/10) Rf=4.61 min.
  • Rotation α (22° C., 589 nm, CHCl3, 1 mg/ml)=minus rotation
  • Enantiomer 2 of 5-cyano-3-hydroxy-3-(2-ethoxypyridin-3-yl)-1,3-dihydroindol-2-one:
  • ESI-MS [M+H+]=296.15 calculated for C16H13N3O3=295.30.
  • HPLC (Chiralpak AD 4.6 mmID×25 cm; hexane/ethanol/methanol 80/10/10) Rf=6.43 min.
  • Rotation α (22° C., 589 nm, CHCl3, 1 mg/ml)=plus rotation
  • Example 4B illustrates by way of example the synthesis route in analogy to synthesis scheme 2.
    • Example 4B (−)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-indol-3-yl 4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate 4B.1) 3-(2-Ethoxypyridin-3-yl)-3-hydroxy-2-oxo-1-(phenylsulfonyl)indoline-5-carbonitrile
  • 2.50 g (7.79 mmol) of (−)-5-cyano-3-hydroxy-3-(2-ethoxypyridin-3-yl)-1,3-dihydroindol-2-one (prepared as in example 1.2 and racemate resolution into the corresponding enantiomers as described above) were dissolved in 30 ml of dimethylformamide, resulting in a yellow solution. After cooling to 0° C., 1.00 g (8.94 mmol) of potassium tert-butoxide was added in portions so that the temperature was kept between 0° C. and 5° C. The solution changed in color from yellow to dark yellow. It was stirred for 30 minutes and, at 0° C., 1.07 ml (8.20 mmol) of benzenesulfonyl chloride were slowly added dropwise. The solution became turbid and pale orange in color. It was stirred while cooling in ice for one hour. The progress of the reaction was followed by thin-layer chromatography (dichloromethane/methanol 9:1). For working up, the reaction mixture was added dropwise to ice-water. During this, a precipitate separated out and was, after stirring for 5 minutes, filtered off and washed with water. The title compound (2.65 g, 6.09 mmol, 78%) was dried in a vacuum drying oven at 40° C. and used for the next reaction without further purification.
  • ESI-MS [M+H+]=436.05 calculated for C22H17N3O5S=435.46.
    • 4B.2) 5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-indol-3-yl phenyl carbonate
  • 2.65 g (6.09 mmol) of optically active 3-(2-ethoxypyridin-3-yl)-3-hydroxy-2-oxo-1-(phenylsulfonyl)indoline-5-carbonitrile from example 4B.1 were dissolved in 4.9 ml of pyridine and 6.0 ml of dichloromethane while cooling at 0° C. in ice, the solution becoming brown in color. At this temperature, 1.24 g (7.91 mmol) of phenyl chloroformate were slowly added dropwise. The reaction mixture was stirred in an ice bath for 2 hours. After conversion was complete, the reaction mixture was further diluted with dichloromethane and poured into ice-water. The phases were separated, and the organic phase was washed again with saturated sodium chloride solution (1×) and water (1×). The solvent was evaporated in vacuo, and excess pyridine was removed by codistillation with toluene. 50 ml of diisopropyl ether were added to precipitate the product, and, after the solid had been filtered off with suction and washed with diisopropyl ether, a total of 2.16 g (3.89 mmol, 64%) of the optically active 5-cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-indol-3-yl phenyl carbonate was isolated. Further purification of the mother liquor by normal-phase chromatography with dichloromethane as mobile phase resulted in 800 mg of the optically active 5-cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-indol-3-ylphenyl carbonate.
  • ESI-MS [M+H+]=556.15 calculated for C29H21N3O7S=555.57.
    • 4B.3) (−)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-indol-3-yl 4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate
  • 1.29 g (7.02 mmol) of 1-(1-methylpiperidin-4-yl)piperazine were added to a solution of 1.30 g (2.34 mmol) of optically active 5-cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-indol-3-yl phenyl carbonate from example 4B.2 in 10 ml of dry tetrahydrofuran (dried over molecular sieves). The reaction mixture was initially stirred at room temperature for one hour, then again heated to 40° C. until complete conversion was achieved in the reaction. The solvent was removed in vacuo, and the residue was again dissolved in 100 ml of dichloromethane and extracted with water (4×). Saturated sodium chloride solution was added dropwise to improve phase separation. The combined organic phase was dried over magnesium sulfate and filtered, and the solvent was removed in vacuo. 1.5 g of a yellow-brown foam were obtained and were again mixed with 1 ml of dichloromethane and 30 ml of diethyl ether. Stirring resulted in a solid precipitate which was filtered off with suction. The crystals were purified by column chromatography on a preparative MPLC (ISCO Companion, 12 g NP cartridge) with dichloromethane/methanol as eluent. In total, 0.547 g (0.848 mmol, 36%) of (−)-5-cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-indol-3-yl 4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate was obtained. The mother liquor likewise contained product which was also purified by crystallization and chromatography.
  • In order to obtain the product also as mesylate salt, 18.41 mg (0.19 mmol) of methanesulfonic acid were added to a solution of 130 mg (0.20 mmol) of (−)-5-cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-indol-3-yl 4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate in 5 ml of dichloromethane. The reaction mixture was stirred for one hour. The solvent was evaporated in vacuo and the residue was dried over a nitrogen atmosphere. Last traces of solvent were removed by drying in a vacuum drying oven at 35° C. In total, 142 mg (0.19 mmol) of the optically active 5-cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-indol-3-yl 4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate mesylate were obtained.
  • ESI-MS [M+H+]=645.25 calculated for C33H36N6O6S=644.76.
  • Rotation α (22° C., 589 nm, CHCl3, 1 mg/ml)=minus rotation
  • 1H-NMR ([d6]-DMSO, 500 MHz) δ[ppm]=8.18 (m, 2H), 8.07 (d, 2H, J=7.5 Hz), 7.99 (d, 1H, J=8.6 Hz), 7.94 (dd, 1H, J=1.7 Hz, J=8.6 Hz), 7.79 (t, 1H, J=7.5 Hz), 7.71 (d, 1H, J=1.5 Hz), 7.66 (t, 2H, J=7.9 Hz), 7.15 (dd, 1H, J=5.6 Hz, J=7.0 Hz), 4.06 (m, 1H), 3.91 (m, 1H), 3.57 (m, 2H), 2.98 (m, 2H), 2.78 (pd, 2H, J=11.3 Hz), 2.47 (m, 2H), 2.29 (m, 2H), 2.18-2.11 (m, 1H), 2.14 (s, 3H), 1.85 (pt, 2H, J=11.3 Hz), 1.64 (pd, 2H, J=11.7 Hz), 1.39 (m, 2H), 0.92 (t, 3H, J=7.1 Hz).
  • The compounds of examples 37B and 40B can be prepared using the appropriate starting compounds in analogy to the process for preparing example 4B.
    • Example 37B (−)-5-Cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(4-ethylpiperazin-1-yl)piperidine-1-carboxylate
  • ESI-MS [M+H+]=719.25 calculated for C36H42N6O8S=718.84.
  • HPLC (Chiracel OD 0.46 cm×25 cm; n-heptane/ethanol 7:3) Rf=11.65 min. (ee=80%)
    • Example 40B (−)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-indol-3-yl 4-(4-ethylpiperazin-1-yl)piperidine-1-carboxylate
  • ESI-MS [M+H+]=659.25 calculated for C34H38N6O6S=658.78.
  • 1H-NMR ([d6]-DMSO, 500 MHz) δ[ppm]=8.24-8.19 (m, 2H), 8.10 (d, 2H, J=7.7 Hz), 8.03 (d, 1H, J=8.6 Hz), 7.97 (m, 1H, J=8.5 Hz), 7.83 (t, 1H, J=7.5 Hz), 7.75 (d, 1H, J=31.6 Hz), 7.70 (pt, 2H, J=7.9 Hz), 7.20 (dd, 1H, J=5.1 Hz, J=7.5 Hz), 4.21-4.08 (m, 2H), 3.97 (m, 1H), 3.44 (m, 2H), 3.05 (m, 1H), 2.64 (m, 1H), 2.48-2.28 (m, 11H), 1.83 (m, 1H), 1.65 (m, 1H), 1.41 (m, 1H), 1.13 (m, 1H), 1.01 (m, 3H), 0.97 (t, 3H, J=7.1 Hz).
  • (+)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-indol-3-yl 4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate, example 4A, can be obtained in analogy to example 4B starting from enantiopure (+)-5-cyano-3-hydroxy-3-(2-ethoxypyridin-3-yl)-1,3-dihydroindol-2-one (enantiomer with plus rotation [rotation determined in chloroform]) and according to process stages 4B.1) to 4B.3) as enantiomer 4A.
    • Example 4A (+)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-indol-3-yl 4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate as trifluoroacetic acid salt
  • ESI-MS [M+H+]=645.25 calculated for C33H36N6O6S=644.76.
  • The compound of example 40A can be prepared using the appropriate starting compounds in analogy to the process for preparing example 4A.
    • Example 40A (+)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-indol-3-yl 4-(4-ethylpiperazin-1-yl)piperidine-1-carboxylate as trifluoroacetic acid salt
  • ESI-MS [M+H+]=659.25 calculated for C34H38N6O6S=658.78.
    • IV. Determination of the Biological Activity 1. Vasopressin V1b Receptor Binding Assay: Substances:
  • The test substances were dissolved in a concentration of 10−2 M in DMSO and further diluted to 5×10−4 M to 5×10−9 M. These serial DMSO predilutions were diluted 1:10 with assay buffer. The substance concentration was further diluted 1:5 in the assay mixture (2% DMSO in the mixture).
    • Membrane Preparation:
  • CHO-K1 cells with stably expressed human vasopressin V1b receptor (clone 3H2) were harvested and homogenized in 50 mM Tris-HCl and in the presence of protease inhibitors (Roche complete Mini #1836170) using a Polytron homogenizer at intermediate setting for 2×10 seconds, and subsequently centrifuged at 40 000×g for 1 h. The membrane pellet was again homogenized and centrifuged as described and subsequently taken up in 50 mM Tris-HCl, pH 7.4, homogenized and stored in aliquots frozen in liquid nitrogen at −190° C.
    • Binding Assay:
  • The binding assay was carried out by the method based on that of Tahara et al. (Tahara A et al., Brit. J. Pharmacol. 125, 1463-1470 (1998)).
  • The incubation buffer was: 50 mM Tris, 10 mM MgCl2, 0.1% BSA, pH 7.4.
  • In the assay mixture (250 μl), membranes (50 μg/ml protein in incubation buffer) from CHO-K1 cells with stably expressed 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 Tris, 10 mM MgCl2, 0.1% BSA, pH 7.4) (total binding) or additionally with increasing concentrations of test substance (displacement experiment). The nonspecific binding was determined with 1 μM AVP (Bachem # H1780). All determinations were carried out as triplicate determinations. After incubation (60 minutes at room temperature), the free radioligand was filtered off by vacuum filtration (Skatron cell harvester 7000) through Wathman GF/B glass fiber filter mats, and the filters were transferred into scintillation vials. The liquid scintillation measurement took place in a model 2000 or 2200CA Tricarb instrument (Packard). Conversion of the measured cpm into dpm was carried out with the aid of a standard quench series.
    • Analysis:
  • The binding parameters were calculated by nonlinear regression in SAS. The algorithms of the program operate in analogy to the LIGAND analysis program (Munson P J and Rodbard D, Analytical Biochem. 107, 220-239 (1980)). The Kd of 3H-AVP for the recombinant human V1b receptors is 0.4 nM and was used to determine the Ki.
    • 2. Vasopressin Via Receptor Binding Assay: Substances:
  • The test substances were dissolved in a concentration of 10−2 M in DMSO. Further dilution of these DMSO solutions took place in incubation buffer (50 mM Tris, 10 mM MgCl2, 0.1% BSA, pH 7.4).
    • Membrane Preparation:
  • CHO-K1 cells with stably expressed human vasopressin V1a receptor (clone 5) were harvested and homogenized in 50 mM Tris-HCl and in the presence of protease inhibitors (Roche complete Mini #1836170) using a Polytron homogenizer at intermediate setting for 2×10 seconds, and subsequently centrifuged at 40 000×g for 1 h. The membrane pellet was again homogenized and centrifuged as described and subsequently taken up in 50 mM Tris-HCl, pH 7.4, homogenized and stored in aliquots frozen in liquid nitrogen at −190° C.
    • Binding Assay:
  • The binding assay was carried out by the method based on that of Tahara et al. (Tahara A et al., Brit. J. Pharmacol. 125, 1463-1470 (1998)).
  • The incubation buffer was: 50 mM Tris, 10 mM MgCl2, 0.1% BSA, pH 7.4.
  • In the assay mixture (250 μl), membranes (20 μg/ml protein in incubation buffer) from CHO-K1 cells with stably expressed human V1a receptors (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 mM MgCl2, 0.1% BSA, pH 7.4) (total binding) or additionally with increasing concentrations of test substance (displacement experiment). The nonspecific binding was determined with 1 μM AVP (Bachem # H1780). Triplicate determinations were carried out.
  • After incubation (60 minutes at room temperature), the free radioligand was filtered off by vacuum filtration (Skatron cell harvester 7000) through Wathman GF/B glass fiber filter mats, and the filters were transferred into scintillation vials.
  • The liquid scintillation measurement took place in a model 2000 or 2200CA Tricarb instrument (Packard). Conversion of the measured cpm into dpm was carried out with the aid of a standard quench series.
    • Analysis:
  • The binding parameters were calculated by nonlinear regression in SAS. The algorithms of the program operate in analogy to the LIGAND analysis program (Munson P J and Rodbard D, Analytical Biochem. 107, 220-239 (1980)). The Kd of 125I-AVP for the recombinant hV1a receptors was determined in saturation experiments. A Kd of 1.33 nM was used to determine the Ki.
    • 3. Vasopressin V2 Receptor Binding Assay: Substances:
  • The test substances were dissolved in a concentration of 10−2 M in DMSO. Further dilution of these DMSO solutions took place in incubation buffer (50 mM Tris, 10 mM MgCl2, 0.1% BSA, pH 7.4).
    • Membrane Preparation:
  • CHO-K1 cells with stably expressed human vasopressin V2 receptor (clone 23) were harvested and homogenized in 50 mM Tris-HCl and in the presence of protease inhibitors (Roche complete Mini #1836170) using a Polytron homogenizer at intermediate setting for 2×10 seconds, and subsequently centrifuged at 40 000×g for 1 h. The membrane pellet was again homogenized and centrifuged as described and subsequently taken up in 50 mM Tris-HCl, pH 7.4, homogenized and stored in aliquots frozen in liquid nitrogen at −190° C.
    • Binding Assay:
  • The binding assay was carried out by the method based on that of Tahara et al. (Tahara A et al., Brit. J. Pharmacol. 125, 1463-1470 (1998)).
  • The incubation buffer was: 50 mM Tris, 10 mM MgCl2, 0.1% BSA, pH 7.4.
  • In the assay mixture (250 μl), membranes (50 μg/ml protein in incubation buffer) from CHO-K1 cells with stably expressed human V2 receptors (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) (total binding) or additionally with increasing concentrations of test substance (displacement experiment). The nonspecific binding was determined with 1 μM AVP (Bachem # H1780). Triplicate determinations were carried out.
  • After incubation (60 minutes at room temperature), the free radioligand was filtered off by vacuum filtration (Skatron cell harvester 7000) through Wathman GF/B glass fiber filter mats, and the filters were transferred into scintillation vials.
  • The liquid scintillation measurement took place in a model 2000 or 2200CA Tricarb instrument (Packard). Conversion of the measured cpm into dpm was carried out with the aid of a standard quench series.
    • Analysis:
  • The binding parameters were calculated by nonlinear regression in SAS. The algorithms of the program operate in analogy to the LIGAND analysis program (Munson P J and Rodbard D, Analytical Biochem. 107, 220-239 (1980)). The Kd of 3H-AVP for the recombinant hV2 receptors is 2.4 nM and was used to determine the Ki.
    • 4. Oxytocin Receptor Binding Assay Substances:
  • The substances were dissolved in a concentration of 10−2 M in DMSO and diluted with incubation buffer (50 mM Tris, 10 mM MgCl2, 0.1% BSA, pH 7.4).
    • Cell Preparation:
  • Confluent HEK-293 cells with transiently expressing recombinant human oxytocin receptors were centrifuged at 750×g at room temperature for 5 minutes. The residue was taken up in ice-cold lysis buffer (50 mM Tris-HCl, 10% glycerol, pH 7.4 and Roche complete protease inhibitor) and subjected to an osmotic shock at 4° C. for 20 minutes. The lyzed cells were then centrifuged at 750×g at 4° C. for 20 minutes, the residue was taken up in incubation buffer, and aliquots of 107 cells/ml were prepared. The aliquots were frozen at −80° C. until used.
    • Binding Assay:
  • On the day of the experiment, the cells were thawed, diluted with incubation buffer and homogenized using a Multipette Combitip (Eppendorf, Hamburg). The reaction mixture of 0.250 ml was composed of 2 to 5×104 recombinant cells, 3-4 nM 3H-oxytocin (PerkinElmer, NET 858) in the presence of test substance (inhibition plot) or only incubation buffer (total binding). The nonspecific binding was determined with 10−6 M oxytocin (Bachem AG, H2510). Triplicate determinations were set up. Bound and free radioligand were separated by filtration under vacuum with Whatman GF/B glass fiber filters with the aid of a Skatron cell harvester 7000. The bound radioactivity was determined by liquid scintillation measurement in a Tricarb Beta counter, model 2000 or 2200CA (Packard).
    • Analysis:
  • The binding parameters were calculated by nonlinear regression analysis (SAS) in analogy to the LIGAND program of Munson and Rodbard (Analytical Biochem 1980; 107: 220-239). The Kd of 3H-oxytocin for the recombinant hOT receptors is 7.6 nM and was used to determine the Ki.
    • 5. Determination of the Microsomal Half-Life:
  • The metabolic stability of the compounds of the invention was determined in the following assay.
  • The test substances were incubated in a concentration of 0.5 μM as follows:
  • 0.5 μM test substance are preincubated together with liver microsomes from different species (from rat, human or other species) (0.25 mg of microsomal protein/ml) in 0.05 M potassium phosphate buffer of pH 7.4 in microtiter plates at 37° C. for 5 min. The reaction is started by adding NADPH (1 mg/mL). After 0, 5, 10, 15, 20 and 30 min, 50 μl aliquots are removed, and the reaction is immediately stopped and cooled with the same volume of acetonitrile. The samples are frozen until analyzed. The remaining concentration of undegraded test substance is determined by MSMS. The half-life (T½) is determined from the gradient of the signal of test substance/unit time plot, it being possible to calculate the half-life of the test substance, assuming first order kinetics, from the decrease in the concentration of the compound with time. The microsomal clearance (mCl) is calculated from mCl=In2/T½/(content of microsomal protein in mg/ml)×1000 [ml/min/mg] (modified from references: Di, The Society for Biomoleculur Screening, 2003, 453-462; Obach, D M D, 1999 vol 27. N 11, 1350-1359).
    • 6. Determination of the Plasma Protein Binding (PPB) by Equilibrium Dialysis:
  • 150 μl of rat or human plasma to which 1 or 10 μM of test substance was added is pipetted on one side of the 96-well dialysis chambers, and 150 μl of PPS buffer are pipetted on the other side. The chambers are separated by a dialysis membrane with a cut-off of 6-8000 daltons. The 96-well dialysis chambers are covered and shaken gently overnight. The next morning, 10 μl of plasma are removed and diluted with 90 μl of PPS buffer, and the protein is precipitated with 200 μl of acetonitrile. The precipitated protein is centrifuged down and 100 μl of the supernatant is used for the MSMS analysis. 100 μl are removed from the buffer side for MSMS analysis. See also the following reference: Banker, Journal of Pharmaceutical Sciences Vol, 92, 5, 967-974, 2003.
    • 7. Methods for In Vitro Determination of the Cytochrome P450 (CYP) Inhibition Luminescent Substrates for 2C9 and 3A4:
  • 0.4 mg/ml human liver microsomes are preincubated with the test substances to be investigated (0-20 μM), the CYP-specific substrates, in 0.05 M potassium phosphate buffer of pH 7.4 at 37° C. for 10 min. The Cyp-specific substrate for CYP 2C9 is luciferin H, and for CYP 3A4 is luciferin BE. The reaction is started by adding NADPH. After incubation at RT for 30 min, the luciferin detection reagent is added, and the resulting luminescence signal is measured (modified from reference: Promega, Technical Bulletin P450-GLO™ Assays).
    • Midazolam CYP 3A4 Time-Dependent Inhibition
  • The assay consists of 2 parts. Firstly, the test substance is preincubated with the liver microsomes (with NADPH=preincubation, then addition of the substrate; in the second part the substrate and the test substance are added simultaneously=coincubation.
    • Preincubation:
  • 0.05 mg/ml microsomal protein (human liver microsomes) are preincubated with 0-10 μM (or 50 μM) 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) are added, and incubation is continued for 10 min. 75 μl of the reaction solution are removed after 10 min, and stopped with 150 μl of acetonitrile solution.
    • Coincubation:
  • 0.05 mg/ml microsomal protein (human liver microsomes) are preincubated with 4 μM midazolam (final concentration) and 0-10 μM (or 50 μM) test substance in 50 mM potassium phosphate buffer for 5 min. The reaction is started with NADPH. 75 μl of the reaction solution are removed after 10 min and stopped with 150 μl of acetonitrile solution. The samples are frozen until the MSMS analysis (modified from references: Obdach, Journal of Pharmacology & Experimental Therapeutics, Vol 316, 1, 336-348, 2006; Walsky, Drug Metabolism and Disposition Vol 32, 6, 647-660, 2004).
    • 8. Method for Determining the Solubility in Water (in Mg/Ml)
  • The solubility in water of the compounds of the invention can be determined for example by the so-called shake flask method (as specified in ASTM International: E 1148-02, Standard test methods for measurement of aqueous solubility, Book of Standards Volume 11.05.). This entails an excess of the solid compound being put into a buffer solution with a particular pH (for example phosphate buffer of pH 7.4), and the resulting mixture being shaken or stirred until equilibrium has been set up (typically 24 or 48 hours, sometimes even up to 7 days). The undissolved solid is then removed by filtration or centrifugation, and the concentration of the dissolved compound is determined by UV spectroscopy or high pressure liquid chromatography (HPLC) by means of an appropriate calibration plot.
    • 9. Results
  • The results of the receptor binding investigations are expressed as receptor binding constants [Ki(V1b), Ki(V1a), Ki(V2), Ki(OT)]. The results of the investigation of the metabolic stability are indicated as microsomal clearance (mCl).
  • The compounds of the invention show very high affinities for the V1b receptor in these assays (maximally 100 nM, or maximally 50 nM, frequently <10 nM). The compounds also show high selectivities vis-à-vis the V1a, V2 and/or OT receptor and a good metabolic stability, measured as microsomal clearance.
  • The results are listed in table 3.
  • TABLE 3
    Human
    microsomal
    Ki(h-V1b)* Ki(h-V1a)/ Ki(h-OT)/ clearance
    Example [nM] Ki(h-V1b)* Ki(h-V1b)* [μl min−1 mg−1]
     1 +++ +++ +++ +
     2 +++ +++ +++ +
     2B +++ +++ +++ +
     4 +++ +++ +++ +++
     4B +++ +++ +++ +++
     5 +++ +++ ++ +
    10 +++ +++ +++ +++
    25 +++ +++ + ++
    28 ++ ++ +++ +++
    32 ++ ++ +++ +
    35 +++ ++ ++ +
    37 +++ +++ +++ +
    40 +++ ++ +++ ++
    55 +++ ++ + +
    Ki(V1a)/ Ki(OT)/ Human microsomal
    Key: Ki(V1b) Ki(V1b) Ki(V1b) clearance
    + >50-100 nM  15-25  15-25 >75-200 μl min−1 mg−1
    ++ 10-50 nM >25-75 >25-45 50-75 μl min−1 mg−1
    +++ <10 nM >75 >45 <50 μl min−1 mg−1
    *h = human

Claims (33)

1. A compound of the formula I
Figure US20160362394A1-20161215-C00004
in which
R1 is hydrogen, methoxy or ethoxy;
R2 is hydrogen or methoxy;
R3 is hydrogen, methyl, ethyl, n-propyl or isopropyl;
X1 and X2 are N or CH, with the proviso that X1 and X2 are not simultaneously N;
and their pharmaceutically acceptable salts and prodrugs thereof.
2. A compound as claimed in claim 1, in which R1 is hydrogen or methoxy.
3. A compound as claimed in any of the preceding claims, in which R3 is hydrogen, methyl or ethyl.
4. A compound as claimed in any of the preceding claims, in which X1 is N and X2 is CH.
5. A compound as claimed in any of claims 1 to 3, in which X1 is CH and X2 is N.
6. A compound as claimed in any of claims 1 to 3, in which X1 is CH and X2 is CH.
7. A compound as claimed in any of claims 1 to 3 and 5, in which
R1 is methoxy;
R2 is methoxy;
R3 is methyl or ethyl;
X1 is CH; and
X2 is N.
8. A compound as claimed in any of claims 1 to 3 and 5, in which
R1 is methoxy;
R2 is H;
R3 is methyl or ethyl;
X1 is CH; and
X2 is N.
9. A compound as claimed in any of claims 1 to 3 and 5, in which
R1 is H;
R2 is methoxy;
R3 is methyl or ethyl;
X1 is CH; and
X2 is N.
10. A compound as claimed in any of claims 1 to 3 and 5, in which
R1 is H;
R2 is H;
R3 is methyl or ethyl;
X1 is CH; and
X2 is N.
11. A compound as claimed in any of claims 1 to 4, in which
R1 is methoxy;
R2 is methoxy;
R3 is methyl or ethyl;
X1 is N; and
X2 is CH.
12. A compound as claimed in any of claims 1 to 4, in which
R1 is methoxy;
R2 is H;
R3 is methyl or ethyl;
X1 is N; and
X2 is CH.
13. A compound as claimed in any of claims 1 to 4, in which
R1 is H;
R2 is methoxy;
R3 is methyl or ethyl;
X1 is N; and
X2 is CH.
14. A compound as claimed in any of claims 1 to 4, in which
R1 is H;
R2 is H;
R3 is methyl or ethyl;
X1 is N; and
X2 is CH.
15. A compound as claimed in any of the preceding claims, which is the (−) enantiomer in an enantiomeric purity of at least 50% ee.
16. A compound as claimed in claim 15, where the (−) enantiomer has an enantiomeric purity of at least 90% ee.
17. A compound as claimed in any of claims 1 to 14, which is the racemate.
18. A 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 or prodrug thereof and at least one pharmaceutically acceptable carrier.
19. The use of compounds of the formula I as defined in any of claims 1 to 17 or of pharmaceutically acceptable salts or prodrugs thereof for the manufacture of a medicament for the treatment and/or prophylaxis of vasopressin-dependent diseases.
20. The use of compounds of the formula I as defined in any of claims 1 to 17 or of pharmaceutically acceptable salts or prodrugs thereof for the manufacture of a medicament for the treatment and/or prophylaxis of diseases selected from diabetes, insulin resistance, nocturnal enuresis, incontinence and diseases in which impairments of blood clotting occur, and/or for delaying micturition.
21. The use of compounds of the formula I as defined in any of claims 1 to 17 or of pharmaceutically acceptable salts or prodrugs thereof for the manufacture of a medicament for the treatment and/or prophylaxis of diseases selected from 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, and travel sickness.
22. The use of compounds of the formula I as defined in any of claims 1 to 17 or of pharmaceutically acceptable salts or prodrugs thereof for the manufacture of a medicament for the treatment and/or prophylaxis of diseases selected from affective disorders.
23. The use of compounds of the formula I as defined in any of claims 1 to 17 or of pharmaceutically acceptable salts or prodrugs thereof for the manufacture of a medicament for the treatment and/or prophylaxis of diseases selected from anxiety disorders and stress-dependent anxiety disorders.
24. The use of compounds of the formula I as defined in any of claims 1 to 17 or of pharmaceutically acceptable salts or prodrugs thereof for the manufacture of a medicament for the treatment and/or prophylaxis of diseases selected from memory impairments and Alzheimer's disease.
25. The use of compounds of the formula I as defined in any of claims 1 to 17 or of pharmaceutically acceptable salts or prodrugs thereof for the manufacture of a medicament for the treatment and/or prophylaxis of diseases selected from psychoses and psychotic disorders.
26. The use of compounds of the formula I as defined in any of claims 1 to 17 or of pharmaceutically acceptable salts or prodrugs thereof for the manufacture of a medicament for the treatment and/or prophylaxis of diseases selected from Cushing's syndrome and other stress-dependent diseases.
27. The use of compounds of the formula I as defined in any of claims 1 to 17 or of pharmaceutically acceptable salts or prodrugs thereof for the manufacture of a medicament for the treatment and/or prophylaxis of diseases selected from sleep disorders.
28. The use of compounds of the formula I as defined in any of claims 1 to 17 or of pharmaceutically acceptable salts or prodrugs thereof for the manufacture of a medicament for the treatment and/or prophylaxis of diseases selected from depressive disorders.
29. The use as claimed in claim 28 for the treatment and/or prophylaxis of childhood onset mood disorders.
30. The use of compounds of the formula I as defined in any of claims 1 to 17 or of pharmaceutically acceptable salts or prodrugs thereof for the manufacture of a medicament for the treatment and/or prophylaxis of vasomotor symptoms and/or thermoregulatory dysfunctions.
31. The use of compounds of the formula I as defined in any of claims 1 to 17 or of pharmaceutically acceptable salts or prodrugs thereof for the manufacture of a medicament for the treatment and/or prophylaxis of 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.
32. The use of compounds of the formula I as defined in any of claims 1 to 17 or of pharmaceutically acceptable salts or prodrugs thereof for the manufacture of a medicament for the treatment and/or prophylaxis of diseases selected from schizophrenia and psychosis.
33. A method for treating disorders defined as in any of claims 19 to 32, in which an effective amount of at least one compound of the formula I as defined in any of claims 1 to 17 or of at least one pharmaceutically acceptable salt or a prodrug thereof or of a pharmaceutical composition as claimed in claim 18 is administered to a patient.
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