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

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

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Publication number
US20050070718A1
US20050070718A1 US10/675,300 US67530003A US2005070718A1 US 20050070718 A1 US20050070718 A1 US 20050070718A1 US 67530003 A US67530003 A US 67530003A US 2005070718 A1 US2005070718 A1 US 2005070718A1
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alkyl
phenyl
alkylen
group
alkynyl
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US10/675,300
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Inventor
Wilfried Lubisch
Wilfried Hornberger
Thorsten Oost
Daryl Sauer
Liliane Unger
Wolfgang Wernet
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AbbVie Deutschland GmbH and Co KG
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Abbott GmbH and Co KG
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Priority to US10/675,300 priority Critical patent/US20050070718A1/en
Assigned to ABBOTT GMBH & CO. KG reassignment ABBOTT GMBH & CO. KG ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: SAUER, DARYL RICHARD, UNGER, LILIANE, WERNET, WOLFGANG, LUBISCH, WILFRIED, HORNBERGER, WILFRIED, OOST, THORSTEN K.
Priority to EP12177640A priority patent/EP2546250A1/en
Priority to ES04765719.2T priority patent/ES2547642T3/es
Priority to EP12177644A priority patent/EP2546252A1/en
Priority to TW093129678A priority patent/TW200526640A/zh
Priority to EP12177642A priority patent/EP2546251A1/en
Priority to PCT/EP2004/010940 priority patent/WO2005030755A1/en
Priority to DK04765719.2T priority patent/DK1667993T3/en
Priority to SI200432271T priority patent/SI1667993T1/sl
Priority to US10/574,211 priority patent/US7902379B2/en
Priority to MXPA06003558A priority patent/MXPA06003558A/es
Priority to EP04765719.2A priority patent/EP1667993B1/en
Priority to PL04765719T priority patent/PL1667993T3/pl
Priority to CA002537598A priority patent/CA2537598C/en
Priority to JP2006530059A priority patent/JP4684229B2/ja
Priority to HUE04765719A priority patent/HUE025419T2/en
Publication of US20050070718A1 publication Critical patent/US20050070718A1/en
Priority to US11/440,569 priority patent/US20070021607A1/en
Priority to HK06110531.9A priority patent/HK1090044A1/zh
Priority to US12/839,595 priority patent/US8580842B2/en
Priority to US12/839,612 priority patent/US8350055B2/en
Priority to JP2010236857A priority patent/JP2011102294A/ja
Priority to JP2010236856A priority patent/JP2011088894A/ja
Priority to US14/037,026 priority patent/US9487505B2/en
Priority to HRP20151025TT priority patent/HRP20151025T1/hr
Priority to CY20151100873T priority patent/CY1116730T1/el
Assigned to AbbVie Deutschland GmbH & Co. KG reassignment AbbVie Deutschland GmbH & Co. KG ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: ABBOTT GMBH & CO. KG
Priority to US15/345,204 priority patent/US20170050959A1/en
Abandoned legal-status Critical Current

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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
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    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
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    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • 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
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/32—Alcohol-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/06—Drugs for disorders of the endocrine system of the anterior pituitary hormones, e.g. TSH, ACTH, FSH, LH, PRL, GH
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/38—Drugs for disorders of the endocrine system of the suprarenal hormones
    • 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
    • C07D401/12—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 linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the present invention relates to novel 1,3-dihydroindol-2-one (oxindole) derivatives and to medicaments containing them for the treatment of diseases.
  • vasopressin The role of vasopressin in various pathological states has been the subject of intensive research in recent years, and the selective antagonism of the various vasopressin receptors opens up novel clinical prospects.
  • three receptors V1a, V1b or V3 and V2 by which vasopressin mediates its effect are known.
  • the vasopressin V1b receptor is mainly found in the CNS. This suggests that in particular CNS effects of vasopressin are mediated by the V1b receptor.
  • an antagonist of the V1b receptor shows anxiolytic and antidepressant effects (Griebel et al., PNAS 99, 6370 (2002); Serradeil-Le Gal et al., J. Pharm. Exp. Ther. 300, 1122 (2002)). Since the models used allow a certain forecast of a clinical effect, antagonists of the vasopressin V1b receptor might be useful for the treatment of emotional disturbances, e.g. stress, anxiety and depression.
  • WO 93/15051 and WO 98/25901 have already described 1-phenylsulfonyl-1,3-dihydro-2H-indol-2-ones in which the oxindole framework is substituted in position 3 by two alkyl radicals, which may also be a cycloalkyl radical (spiro linkage), as ligands of vasopressin receptors.
  • alkyl radicals which may also be a cycloalkyl radical (spiro linkage)
  • ligands of vasopressin receptors An alternative possibility is for the spiro ring to contain heteroatoms such as oxygen and nitrogen (optionally with substituents).
  • WO 95/18105 describes 1-phenylsulfonyl-1,3-dihydro-2H-indol-2-ones which have a nitrogen atom in position 3 as ligands of vasopressin receptors. Additionally bonded in position 3 are radicals which may be alkyl, cycloalkyl, phenyl or benzyl radicals (optionally with substituents in each case).
  • the object of the present invention is to provide additional compounds for the treatment or prophylaxis of various vasopressin-dependent or oxytocin-dependent diseases which have high activity.
  • the present application additionally relates to a compound of the formula (II) in which
  • the present invention additionally relates to a compound of the formula (III), in which
  • Novel 1,3-dihydro-2H-indol-2-one derivatives which have heterocycles in position 3 and/or heterocyclic rings in position 1, and their use for the treatment of diseases, are described in the present invention.
  • Rings A and D are preferably selected independently of one another from the group consisting of aromatic heteromonocyclic and aromatic heterobicyclic systems comprising 1 or 2 heteroatoms, where one of the 2 heteroatoms is nitrogen, more preferably from benzothiazole, pyrimidine, pyridine, pyridazine, pyrazine, isoquinoline, quinoline, thiazole, benzimidazole, imidazole, benzoxazole, benzothiophene, thiophene, benzofuran and furan.
  • Rings B and G are preferably selected independently of one another from the group consisting of thiophene, furan, pyrrole, pyrazole, isoxazole, pyridine, pyrimidine, quinoline, isoquinoline, tetrahydroisoquinoline, benzothiophene, benzofuran, indole, imidazole, thiazole, imidazothiazole, benzooxazine and quinoxaline.
  • alkyl alkylene
  • alkenyl alkenylene
  • alkynyl alkynylene
  • alkynylene alkynylene
  • C 1 -C 4 -alkyl as used herein is preferably methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl or t-butyl.
  • C 1 -C 4 -alkylene as used herein is preferably methylene, ethylene, or branched or unbranched propylene or butylene.
  • C 2 -C 4 -alkenyl as used herein is preferably ethenyl, or branched or unbranched propenyl or butenyl.
  • C 2 -C 4 -alkenylene as used herein is preferably ethenylene, or branched or unbranched propenylene or butenylene.
  • C 2 -C 4 -alkynyl as used herein is preferably ethynyl, or branched or unbranched propynyl or butynyl.
  • C 2 -C 4 -alkynylene as used herein is preferably ethynylene, or branched or unbranched propynylene or butynylene.
  • C 1 -C 6 -alkyl as used herein is preferably branched or unbranched hexyl or pentyl, more preferably C 1 -C 4 -alkyl, and in particular methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl or t-butyl.
  • C 1 -C 6 -alkylene as used herein is preferably branched or unbranched hexylene or pentylene, more preferably C 1 -C 4 -alkylene, and in particular methylene, ethylene, or branched or unbranched propylene or butylene.
  • C 2 -C 6 -alkenyl as used herein is preferably branched or unbranched hexenyl or pentenyl, more preferably C 2 -C 4 -alkenyl, and in particular ethenyl, or branched or unbranched propenyl or butenyl.
  • C 2 -C 6 -alkenylene as used herein is preferably branched or unbranched hexenylene or pentenylene, more preferably C 2 -C 4 -alkenylene, and in particular ethenylene, or branched or unbranched propenylene or butenylene.
  • C 2 -C 6 -alkynyl as used herein is preferably branched or unbranched hexynyl or pentynyl, more preferably C 2 -C 4 -alkynyl, and in particular ethynyl, or branched or unbranched propynyl or butynyl.
  • C 2 -C 6 -alkynylene as used herein is preferably branched or unbranched hexynylene or pentynylene, more preferably C 2 -C 4 -alkynylene, and in particular ethynylene, or branched or unbranched propynylene or butynylene.
  • the formulation the “[said] ring may comprise up to two oxo groups” as used herein means that said ring has up to two carbon atoms which are each connected to an oxygen atom via a double bond.
  • Divalent radicals are to be read from the left to the right with respect to their bonds to other substructures of the molecule.
  • “CO—NR 58 ” in the definition of X in R 5 of the compound of formulae (I) to (IIII) is connected to W and Y as follows: (W)—CO—N(R 58 )—(Y)-Z.
  • prodrugs are meant those compounds which are metabolized in vivo to the compounds of the invention.
  • Typical examples of prodrugs are described in C. G. Wermuth (ed.): The Practice of Medicinal Chemistry, Academic Press, San Diego, 1996, p. 671-715. These include, for example, phosphates, carbamates or amino acids, esters and others.
  • the invention further relates to the physiologically tolerated salts of the compounds of the invention which can be obtained by reacting the compounds of the invention with a suitable acid or base.
  • suitable acids and bases are listed for example in Fort suitse der Arzneistoffforschung, 1966, Birkhäuser Verlag. vol. 10, pages 224-285. These include for example hydrochloric acid, citric acid, tartaric acid, lactic acid, phosphoric acid, methanesulfonic acid, acetic acid, formic acid, maleic acid, fumaric acid etc., and sodium hydroxide, lithium hydroxide, potassium hydroxide and 2-amino-2-(hydroxymethyl)-1,3-propanediol (Tris).
  • the invention further relates to the compound of any of general formulae (I) to (III) as therapeutic or prophylactic agent.
  • the invention relates to a medicament comprising the compound of any of general formulae (I) to (III).
  • the compound of any of general formulae (I) to (III) can be used for producing a medicament for the control and/or prophylaxis of various vasopressin-dependent or oxytocin-dependent diseases.
  • the invention further relates to the use of the compound of any of general formulae (I) to (III) for the control and/or prophylaxis of various vasopressin-dependent or oxytocin-dependent diseases.
  • a further aspect of the invention is a method for the therapeutic and/or prophylactic treatment of a mammal requiring a treatment by administering the compound of any of formulae (I) to (III) for the treatment of diseases.
  • the compounds of the invention are effective after administration in various ways, especially orally.
  • the compounds according to the present invention can be useful for the treatment or prevention of various vasopressin-dependent or ocytocin-dependent complaints, such as mental disorders.
  • mental disorders according to the American Psychiatric Association DSM-IV, Diagnostic and Statistical Manual of Mental Disorders, 4th ed., 1994 are attention-deficit and disruptive behavior disorders; delirium, dementia, and amnestic and other cognitive disorders; substance-related disorders, such as alcohol use disorders and alcohol-induced disorders; schizophrenia and other psychotic disorders, such as schizophrenia, schizophreniform disorder, schizoaffective disorder and delusional disorder; mood disorders, such as depressive disorders (major depressive disorder, dysthymic disorder, seasonal affective disorder, premenstrual dysphoric disorder, depressive disorder not otherwise specified), bipolar disorder (bipolar I disorder, bipolar II disorder, cyclothymic disorder, bipolar disorder not otherwise specified, substance-induced mood disorder, mood disorder not otherwise specified); stress-related disorders, such as acute stress disorder; anxiety disorders, such as panic disorder without
  • the present invention also relates to pharmaceutical compositions which comprise an effective dose of a compound of the invention or of a pharmaceutically acceptable salt thereof and suitable pharmaceutical carriers.
  • These pharmaceutical carriers are chosen according to the pharmaceutical form and the desired mode of administration.
  • compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, intratracheal, intranasal, transdermal or rectal administration it is possible to administer the compounds of the formula (I), (II) or (III) or, where suitable, the salts thereof to animals or humans in unitary administration forms, mixed with conventional pharmaceutical carriers, for the prophylaxis or treatment of the above disorders or diseases.
  • the suitable unitary administration forms include forms for oral administration, such as tablets, gelatin capsules, powders, granules and solutions or suspensions for oral intake, forms for sublingual, buccal, intratracheal or intranasal administration, aerosols, implants, forms for subcutaneous, intramuscular or intravenous administration and forms for rectal administration.
  • forms for oral administration such as tablets, gelatin capsules, powders, granules and solutions or suspensions for oral intake, forms for sublingual, buccal, intratracheal or intranasal administration, aerosols, implants, forms for subcutaneous, intramuscular or intravenous administration and forms for rectal administration.
  • the compounds of the invention can be used in creams, ointments or lotions.
  • the dose of the basic active ingredient may vary between 0.01 and 50 mg per kg of bodyweight and per day.
  • Each unit dose may comprise from 0.05 to 5 000 mg, preferably 1 to 1 000 mg, of the active ingredient in combination with a pharmaceutical carrier. This unit dose may be administered 1 to 5 times a day so that a daily dose of from 0.5 to 25 000 mg, preferably 1 to 5 000 mg, is administered.
  • a solid composition is prepared in the form of tablets, the main ingredient is mixed with a pharmaceutical carrier such as gelatin, starch, lactose, magnesium stearate, talc, silica or the like.
  • a pharmaceutical carrier such as gelatin, starch, lactose, magnesium stearate, talc, silica or the like.
  • the tablets may be coated with sucrose, a cellulose derivative or another suitable substance or treated otherwise in order to display persistent or delayed activity and in order to release a predetermined amount of the basic active ingredient continuously.
  • a preparation in the form of gelatin capsules is obtained by mixing the active ingredient with an extender and taking up the resulting mixture in soft or hard gelatin capsules.
  • a preparation in the form of a syrup or elixir or for administration in the form of drops may comprise active ingredients together with a sweetener, which is preferably calorie-free, methylparaben or propylparaben as antiseptics, a flavoring and a suitable color.
  • a sweetener which is preferably calorie-free, methylparaben or propylparaben as antiseptics, a flavoring and a suitable color.
  • the water-dispersible powders or granules may comprise the active ingredients mixed with dispersants or wetting agents, or suspending agents, such as polyvinylpyrrolidones, and sweeteners or masking flavors.
  • Rectal administration is achieved by using suppositories which are prepared with binders which melt at the rectal temperature, for example cocoa butter or polyethylene glycols.
  • Parenteral administration is effected by using aqueous suspensions, isotonic salt solutions or sterile and injectable solutions which comprise pharmacologically acceptable dispersants and/or wetting agents, for example propylene glycol or polyethylene glycol.
  • the basic active ingredient may also be formulated as microcapsules or liposomes, if suitable with one or more carriers or additives.
  • compositions of the invention may comprise other basic active ingredients which may be beneficial for the treatment of the abovementioned disorders or diseases.
  • the present invention thus further relates to pharmaceutical compositions in which a plurality of basic active ingredients are present together, where one of these is the compound of the invention.
  • the compounds of the invention were tested for their activity in the following vasopressin V1b receptor binding assay.
  • Incubation buffer 50 mM Tris, 10 mM MgCl 2 , 0.1% BSA adjusted to pH 7.4 with HCl.
  • Liquid scintillation counting was performed in beta-counters, Tricarb model 2000 or 2200CA (Packard). Dpm were calculated by a programme with standardisation using a standard quench series.
  • Functional activity was determined by testing the effect of the compounds on calcium release in CHO-K 1 cells stably transfected with human V 1b receptor.
  • Cells were seeded into 96-well plates at 50,000 cells/well and grown overnight in tissue culture medium (DMEM/Nut mix F12 Medium with Glutamax I (invitrogen), containing 10% FCS, 100 units/ml Penicillin, 100 ⁇ g/mi Streptomycine, 800 ⁇ g/ml Geneticin) at 37° C. and 5% CO 2 .
  • Cells were loaded with a fluorescent calcium-sensitive dye in the presence of 1% probenicid according to the manufacturers protocol (Ca ++ -Plus-Assay Kit, Molecular Devices).
  • 1,3-dihydroindol-2-ones of the invention can be prepared in various ways, as outlined in synthesis schemes 1-5.
  • the 3-hydroxy-1,3-dihydroindol-2-ones VI can be obtained by addition of metalated heterocycles IV to the 3-keto group of isatins V.
  • metalated heterocycles which can be employed are the corresponding magnesium and lithium compounds.
  • the isatins V were either purchased or prepared by methods described in the literature (Advances in Heterocyclic Chemistry, A. R. Katritzky and A. J. Boulton, Academic Press, New York, 1975, 18, 2-58; J. Brazil. Chem. Soc. 12, 273-324 (2001)).
  • the metalated heterocycles IV were prepared in various ways (see review article by G. Queguiner et al. in Advances in Heterocyclic Chemistry, Vol. 52, ed. A. R.
  • the 3-hydroxy-1,3-dihydroindol-2-ones VI were converted in the next step into compounds VII which bear a leaving group LG in position 3.
  • LG are halides, mesylate and tosylate.
  • the intermediate VII can be prepared by treating the tertiary alcohol VI with thionyl chloride in the presence of a base such as, for example, pyridine.
  • alcohols VI can be activated by conversion into the mesylate using methanesulfonyl chloride in the presence of a base such as, for example, triethylamine.
  • the leaving group LG in the compounds VII can then be replaced by various nucleophiles R5-H, resulting in the compounds VIII which have the radical R5 in position 3.
  • replacement reactions with primary and secondary amines R5-H in the presence of a base such as, for example, N,N-diisopropylethylamine in a solvent such as, for example dichloromethane afford the analogous 3-amino-1,3-dihydroindol-2-ones VIII.
  • the reaction is not confined to nitrogen nucleophiles; it is also possible for oxygen or sulfur nucleophiles R5-H, where appropriate after deprotonation with a suitable base such as, for example, sodium hydride.
  • the 3-urethane derivatives XIII were prepared by initially reacting the 3-hydroxy-1,3-dihydroindol-2-ones VI with heterocyclic sulfonyl chlorides XI under the conditions already described above.
  • Heterocyclic sulfonyl chlorides were either purchased or prepared by standard methods (see, for example, J. Med. Chem. 40, 1149 (1997); J. March, Advanced Organic Chemistry, 1992, 4th ed., Wiley, New York, p 724).
  • a base such as, for example, triethylamine
  • activation with phenyl chloroformate in the presence of a base such as, for example, pyridine and subsequent reaction of the carbonate intermediate with amines L-H, where appropriate at elevated temperature.
  • Heteroaryl-substituted piperidines that can be employed as amines L-H, can be prepared as described in Tetrahedron Let
  • amino derivatives XXII of the invention were prepared from the amines XXI by reaction with customary reagents for derivatizing amino groups, such as, for example, carboxylic acids, carbonyl chlorides, carboxylic anhydrides, sulfonyl chlorides, chloroformates, isocyanates, carbamoyl chlorides by the relevant methods (J. March, Advanced Organic Chemistry, 1992, 4th ed., Wiley, New York, pp. 417-421; 499; 903).
  • customary reagents for derivatizing amino groups such as, for example, carboxylic acids, carbonyl chlorides, carboxylic anhydrides, sulfonyl chlorides, chloroformates, isocyanates, carbamoyl chlorides by the relevant methods (J. March, Advanced Organic Chemistry, 1992, 4th ed., Wiley, New York, pp. 417-421; 499; 903).
  • N-heteroaryl-substituted piperidine carboxylic acids that can be employed as coupling partner for the amines XXI, can be prepared for example as described in J. Med. Chem. 43, 2087 (2000) for 4-carboxy-N-(4-pyridyl)piperidine.
  • the 3-amino group in the compounds XXI can be substituted by treatment with alkylating agents such as, for example, alkyl bromides, iodides or mesylates, and by reaction with aldehydes or ketones in the presence of reducing agents such as, for example, sodium cyanoborohydride in the sense of a reductive amination (J. March, Advanced Organic Chemistry, 1992, 4th ed., Wiley, New York, p. 411; 898).
  • alkylating agents such as, for example, alkyl bromides, iodides or mesylates
  • esters XXIV were prepared by alkylation of the 1,3-dihydroindol-2-ones XXIII with ethyl bromoacetate in the presence of bases such as, for example, potassium carbonate and, where appropriate, potassium iodide. After hydrolysis of the ester function, for example by treatment with lithium hydroxide in a water/THF/methanol mixture, the acids XXV were coupled with amines H—Y-Z employing relevant methods (J. March, Advanced Organic Chemistry, 1992, 4th ed., Wiley, New York, pp. 417-421). Final sulfonylation of the compounds XXVI with sulfonyl chlorides XI afforded the compounds XXVII of the invention.
  • Enantiopure compounds can be obtained for example by carrying out a conventional racemic resolution using suitable optically active acids or bases with compounds of the invention or intermediates which comprise basic or acidic functional groups such as, for example, an amino or carboxyl group.
  • step B The product from step A was mixed with 500 ml of 5-6 M HCl in isopropanol and stirred at room temperature for 4 hours. After cooling to 0° C., the precipitate was filtered off with suction, washed with isopropanol and diethyl ether and dried. 37 g of the desired product were obtained.
  • the diastereomer product was prepared by the method described in the previous paragraph starting from the more polar diastereomer product from step C. Purification by chromatography (silica gel, 5% MeOH in dichloromethane) resulted in Example 2 as a white solid.
  • This diastereomer is the less polar diastereomer from step D.
  • This diastereomer is the more polar diastereomer from step D.
  • the diastereomer product was prepared by the method described in the previous paragraph starting from the less polar diastereomer product from step C. Purification by chromatography (silica gel, 5% MeOH in dichloromethane) and trituration with diethyl ether/hexane resulted in the product as a white solid.
  • reaction mixture was stirred into ammonium chloride solution and extracted several times with ethyl acetate.
  • the combined organic phase was washed four times with water, dried over MgSO 4 and concentrated under reduced pressure.
  • the residue was stirred with isopropanol.
  • the resulting precipitate was filtered off with suction, washed with isopropanol and diethyl ether and dried. 106 g of the desired product were obtained.
  • reaction mixture was stirred into ammonium chloride solution and extracted several times with ethyl acetate.
  • the combined organic phases were washed with saturated brine, dried over MgSO 4 and concentrated under reduced pressure.
  • the residue was stirred with diethyl ether.
  • the resulting precipitate was filtered off with suction, washed with diethyl ether and dried. 26 g of the desired product were obtained.
  • Phenyl chloroformate (0.35 ml, 2.79 mmol) was added dropwise to a solution of example 64 (300 mg, 0.624 mmol) in pyridine (6 ml) while cooling slightly. The reaction mixture was stirred at room temperature overnight. After addition of ice-water, the mixture was extracted with ethyl acetate, and the organic phase was washed several times with dilute citric acid solution and water. The organic phase was dried over magnesium sulfate and concentrated under reduced pressure. The residue was triturated with diethyl ether, and the resulting precipitate was filtered off with suction, washed with diethyl ether and dried. 310 mg of the desired product were obtained.
  • the compounds of the invention bind to the vasopressin V1b receptor.
  • Table 2 the binding affinity of selected examples for the vasopressin V1b receptor is shown.
  • TABLE 2 Binding affinity of selected examples for the vasopressin V1b receptor Binding affinity for the Example # vasopressin V1b receptor 2 +++ 3 +++ 5 +++ 6 ++ 28 +++ 31 +++ 48 +++ 56 +++ 59 + 63 + 65 ++ + indicates binding affinity > 500 nM ++ indicates binding affinity between 50 and 500 nM +++ indicates binding affinity ⁇ 50 nM

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US10/675,300 US20050070718A1 (en) 2003-09-30 2003-09-30 Heteroaryl-substituted 1,3-dihydroindol-2-one derivatives and medicaments containing them
HUE04765719A HUE025419T2 (en) 2003-09-30 2004-09-30 Heteroaryl-substituted 1,3-dihydro-indol-2-one derivatives and medicaments containing them
PL04765719T PL1667993T3 (pl) 2003-09-30 2004-09-30 Heteroarylo-podstawione pochodne 1,3-dihydroindol-2-onu i zawierające je leki
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EP12177644A EP2546252A1 (en) 2003-09-30 2004-09-30 Heteroaryl-substituted 1,3 dihydroindol-2-one derivatives and medicaments containing them
TW093129678A TW200526640A (en) 2003-09-30 2004-09-30 Heteroaryl-substituted 1,3-dihydroindol-2-one derivatives and medicaments containing them
EP12177642A EP2546251A1 (en) 2003-09-30 2004-09-30 Heteroaryl-substituted 1,3 dihydroindol-2-one derivatives and medicaments containing them
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DK04765719.2T DK1667993T3 (en) 2003-09-30 2004-09-30 Heteroberl-substituted 1,3-dihydroindol-2-one derivatives and drugs containing them
SI200432271T SI1667993T1 (sl) 2003-09-30 2004-09-30 Heteroarilno substituirani 1,3-dihidroindol-2-onski derivati in zdravila, ki jih vsebujejo
US10/574,211 US7902379B2 (en) 2003-09-30 2004-09-30 Heteroaryl-substituted 1,3-dihydroindol-2-one derivatives and medicaments containing them
MXPA06003558A MXPA06003558A (es) 2003-09-30 2004-09-30 Derivados de 1,3-dihidroindol-2-ona sustituidos por heteroarilo y medicamentos que los contienen.
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ES04765719.2T ES2547642T3 (es) 2003-09-30 2004-09-30 Derivados de 1,3-dihidroindol-2-ona sustituidos por heteroarilo y medicamentos que los contienen
US11/440,569 US20070021607A1 (en) 2003-09-30 2006-05-25 Heteroaryl-substituted 1,3-dihydroindol-2-one derivatives and medicaments containing them
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US12/839,595 US8580842B2 (en) 2003-09-30 2010-07-20 Heteroaryl-substituted 1,3-dihydroindol-2-one derivatives and medicaments containing them
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JP2010236857A JP2011102294A (ja) 2003-09-30 2010-10-21 ヘテロアリール置換された１，３−ジヒドロインドール−２−オン誘導体および該誘導体を含有する医薬品
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US14/037,026 US9487505B2 (en) 2003-09-30 2013-09-25 Heteroaryl-substituted 1,3-dihydroindol-2-one derivatives and medicaments containing them
HRP20151025TT HRP20151025T1 (hr) 2003-09-30 2015-09-29 Derivati heteroarilom-supstituiranog 1,3-dihidroindol-2-ona i lijekovi koji ih sadrže
CY20151100873T CY1116730T1 (el) 2003-09-30 2015-09-30 Παραγωγα ετεροαρυλ-υποκατεστημενης 1,3-διυδροϊνδολ-2-ονης και φαρμακα που περιεχουν αυτα
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FR2804115B1 (fr) 2000-01-25 2002-03-08 Sanofi Synthelabo Nouveaux derives de 1,3-dihydro-2h-indol-2-one, un procede pour leur preparation et les compositions pharmaceutiques en contenant
FR2804114B1 (fr) 2000-01-25 2002-03-08 Sanofi Synthelabo Nouveaux derives de 1,3-dihydro-2h-indol-2-one, un procede pour leur preparation et les compositions pharmaceutiques en contenant
FR2805536B1 (fr) 2000-02-25 2002-08-23 Sanofi Synthelabo Nouveaux derives de 1,3-dihydro-2h-indol-2-one, un procede pour leur preparation et les compositions pharmaceutiques en contenant
US6448288B1 (en) 2000-05-17 2002-09-10 University Of Massachusetts Cannabinoid drugs
FR2810320B1 (fr) * 2000-06-19 2002-08-23 Sanofi Synthelabo Nouveaux derives de 1,3-dihydro-2h-indol-2-one, un procede pour leur preparation et les compositions pharmaceutiques en contenant
FR2827604B1 (fr) 2001-07-17 2003-09-19 Sanofi Synthelabo Nouveaux derives de 1-phenylsulfonyl-1,3-dihydro-2h-indol-2- one, un procede pour leur preparation et les compositions pharmaceutiques en contenant
US20050070718A1 (en) * 2003-09-30 2005-03-31 Abbott Gmbh & Co. Kg Heteroaryl-substituted 1,3-dihydroindol-2-one derivatives and medicaments containing them
DE102004033834A1 (de) 2004-07-13 2006-02-02 Abbott Gmbh & Co. Kg Substituierte Oxindol-Derivate und diese enthaltende Arzneimittel
JP5125501B2 (ja) 2005-01-28 2013-01-23 大正製薬株式会社 １，３−ジヒドロ−２ｈ−インドール−２−オン化合物、及び芳香族複素環が縮合したピロリジン−２−オン化合物
MX2007011693A (es) 2005-03-24 2008-03-11 Abbott Gmbh & Co Kg Derivados de oxindoles sustituidos, farmacos que contienen dichos derivados y uso de los mismos.
DE102005014904A1 (de) 2005-03-26 2007-02-01 Abbott Gmbh & Co. Kg Substituierte Oxindol-Derivate, diese enthaltende Arzneimittel und deren Verwendung

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