EP1861392A2 - Derives d'oxindole substitues, medicaments contenant ces derives et leur utilisation - Google Patents

Derives d'oxindole substitues, medicaments contenant ces derives et leur utilisation

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Publication number
EP1861392A2
EP1861392A2 EP06723672A EP06723672A EP1861392A2 EP 1861392 A2 EP1861392 A2 EP 1861392A2 EP 06723672 A EP06723672 A EP 06723672A EP 06723672 A EP06723672 A EP 06723672A EP 1861392 A2 EP1861392 A2 EP 1861392A2
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European Patent Office
Prior art keywords
alkyl
group
general formula
hydrogen
independently
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP06723672A
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German (de)
English (en)
Inventor
Thorsten Oost
Wilfried Lubisch
Wolfgang Wernet
Wilfried Hornberger
Liliane Unger
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Abbott GmbH and Co KG
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Abbott GmbH and Co KG
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Priority claimed from DE200510014628 external-priority patent/DE102005014628A1/de
Priority claimed from DE200510015957 external-priority patent/DE102005015957A1/de
Application filed by Abbott GmbH and Co KG filed Critical Abbott GmbH and Co KG
Publication of EP1861392A2 publication Critical patent/EP1861392A2/fr
Withdrawn legal-status Critical Current

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    • 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
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    • 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

Definitions

  • novel substituted oxindoles which carry a (hetero) aryl-sulfonyl group in the 1-position.
  • 1-phenylsulfonyl-1,3-dihydro-2H-indol-2-ones have already been described as ligands of vasopressin receptors.
  • WO 93/15051 WO95 / 18105, WO 98/25901, WO 01/55130, WO
  • R A 5 , R A ⁇ , R A 9 are independently of one another and independently of their occurrence selected from the group consisting of hydrogen, C 1 -C 4 alkyl and C 1 -C ⁇ haloalkyl; R A 8 is selected from the group consisting of the respective individual radicals
  • R Y 3 is selected from the group consisting of hydrogen, C 1 -C 4 alkyl and C 1 -C 4 haloalkyl;
  • a preferred embodiment relates to compounds of the general formula (I), wherein the variables independently of one another have the following meanings:
  • R A 8 is independently of its occurrence selected from the group consisting of the respective individual residues
  • R Y 2 is selected from the group consisting of hydrogen, phenyl, Ci-C ⁇ alkyl, and C 3 -C 7 cycloalkyl,
  • R Y 21 and R Y 22 independently of their respective occurrence, may also together with the nitrogen atom to which they are attached form a 4-, 5- or 6-membered, saturated or unsaturated N-heterocyclic ring,
  • a further preferred embodiment relates to compounds of the general formula (I) in which the variables independently of one another have the following meanings:
  • A is a cyclic radical selected from the group consisting of phenyl, thienyl, pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl, which is substituted by the radical RA 1 and additionally lent with one or two radicals R A 11 and / or RA 12 , independently of one another and independently of their occurrence, are selected from the group consisting of hydrogen, chlorine, methoxy, ethoxy, propoxy, methyl, ethyl and propyl;
  • RA 1 R A 2 is - (C 1 -C 4 -alkylene) -RA 4
  • RA is selected 2 from the group consisting of O, CH 2 -O, NR A 5, CH 2 - NR A 5, A NR 5 -CO, CH 2 -NR 5 -CO and A is a single bond;
  • RA 5 , RA 9 are independently of one another and independently of their occurrence selected from the group consisting of hydrogen and C 1 -C 4 alkyl;
  • RA 8 is selected from the group consisting of the respective individual residues
  • R Y 1 is selected from the group consisting of
  • R Y 2 is selected from the group consisting of hydrogen, phenyl and C 1 -C 4 alkyl;
  • R Y 1 and R Y 2 together with the atoms to which they are attached, can form a 5- or 6-membered, saturated or unsaturated ring, which instead of a C atom as a ring member and a heteroatom selected from Group, consisting of O and NR Y 5 , may have as another ring member, wherein R Y s independently of its respective occurrence of hydrogen, C 1 -C 4 alkyl, or CO-C 1 -C 4 alkyl may stand, and wherein the ring may have one or two substituents R Y 6 and / or R Y 7 which are selected independently of one another and independently of their respective occurrence from the group consisting of the radicals hydrogen,
  • R Y 6 and R Y 7 independently of their occurrence, together with the C atoms to which they are attached, can also form a fused phenyl ring (benzo ring);
  • R Y 3 is selected from the group consisting of hydrogen and methyl
  • R Y 4 is CO-NR Y 21 R Y 22 , wherein
  • R Y 21 , R Y 22 are independently selected from the group consisting of hydrogen and C 1 -C 4 alkyl;
  • R Y 21 and R Y 22, independently of their occurrence, may also form, together with the nitrogen atom to which they are attached, a 4-, 5- or 6-membered, saturated or unsaturated N-heterocyclic ring;
  • a further preferred embodiment relates to compounds of the general formula (I) in which the variables independently of one another have the following meanings:
  • A is a radical selected from the group consisting of the respective individual radicals
  • R A 11 is independently selected from the group consisting of hydrogen, chlorine, methoxy and ethoxy;
  • R A 1 is a radical selected from the group consisting of the respective individual radicals
  • R B is a cyclic radical selected from the group consisting of phenyl, pyridyl, thienyl and quinolinyl, each of which may be substituted with 1 or 2 radicals R B 1 and / or R B 2 , wherein R B is 1 and
  • R B 2 are independently selected from the group consisting of hydrogen, chlorine, fluorine, CN, methyl and methoxy;
  • R 1 is selected from the group consisting of hydrogen, chlorine, fluorine, CN, methoxy and methyl; is selected from the group consisting of hydrogen and chlorine;
  • R Y 4 is CO-N R Y 21 R Y 22 , wherein R Y 21 and R Y 22 are independently selected from the group consisting of hydrogen, methyl and ethyl;
  • R Y 21 and R Y 22, independently of their respective occurrence, may also form, together with the nitrogen atom to which they are attached, a 4-, 5- or 6-membered, saturated or unsaturated or partially unsaturated N-heterocyclic ring;
  • R Y 5 is selected from the group consisting of the radicals hydrogen, C 1 -C 4 alkyl, and CO-C 1 -C 4 alkyl;
  • R Y 6 is selected from the group consisting of the radicals hydrogen, fluorine, OH and OC 1 -C 4 -alkyl,
  • a further preferred embodiment relates to compounds of the general formula (I) in which the variables independently of one another have the following meanings:
  • A is phenyl which, in addition to the radical R A 1, has another, among Cl and C 1 -
  • C 4 alkoxy may carry selected radical R A 11 , which is preferably in ortho position to the point of attachment of the phenyl ring to the rest of the
  • Molecule is bound, z. B. a radical selected from the
  • a radical is independent of its respective occurrence selected from the group consisting of the respective individual radicals
  • cyclic radical selected from the group consisting of phenyl, pyridyl, thienyl and quinolinyl, each of which may carry one or two radicals R B ⁇ RB 2 , where B is in particular one of the radicals:
  • R B 1 and R B 2 are independently and independently selected from the group consisting of hydrogen, chlorine, fluorine, CN, methyl and methoxy;
  • R 1 is selected from the group consisting of chlorine, methoxy and CN;
  • R 2 is hydrogen
  • Me CH 3 their tautomeric, enantiomeric and diastereomeric forms, and their prodrugs, as well as the physiologically acceptable salts of said compounds.
  • a further preferred embodiment relates to compounds of the general formula (I) in which the variables independently of one another have the following meanings.
  • R A 1 is a radical, regardless of its occurrence, selected from the group consisting of the respective individual radicals
  • B is a cyclic radical selected from the group consisting of the respective individual radicals
  • R 1 is chlorine
  • R 2 is hydrogen
  • Y is a radical selected from the group consisting of the respective individual radicals
  • a further preferred embodiment relates to compounds of the general formula (I) in which the variables independently of one another have the following meanings:
  • A is a radical selected from the group consisting of the respective individual radicals
  • R A 1 is a residue, independently of its occurrence, selected from the group consisting of the respective individual residues
  • B is a cyclic radical selected from the group consisting of the respective individual radicals
  • R 1 is chlorine
  • R 2 is hydrogen
  • Me CH 3 , their tautomeric, enantiomeric and diastereomeric forms, and their prodrugs, as well as the physiologically acceptable salts of said compounds.
  • a further preferred embodiment relates to compounds of the general formula (I) in which the variables independently of one another have the following meanings:
  • R A 1 is a radical selected from the group consisting of the respective individual radicals
  • B is a cyclic radical selected from the group consisting of the respective individual radicals
  • R 1 is chlorine
  • R 2 is hydrogen
  • Y is selected from the group consisting of the respective individual radicals
  • a further preferred embodiment relates to compounds of the general formula (I) in which the radical R 1 is bonded to the 5-position of the oxindole ring skeleton.
  • a further preferred embodiment relates to compounds of the general formula (I), wherein the compound of the general formula (I) is an enriched optically active isomer having an optical purity of greater than 50% based on the optically inactive mixture of the isomer mixture the plane of polarized light turns to the left ("negative rotation").
  • a further preferred embodiment relates to compounds of the general formula (I), where the optically active isomer is an enantiomeric enriched diastereomer.
  • a further preferred embodiment relates to compounds of the general formula (I) in which the property "negative rotation" is based on the free base.
  • a further preferred embodiment relates to compounds of the general formula (I) which have a binding affinity Ki to the vasopressin receptor subtype V1b of less than about 100 nM, preferably not more than 10 nM, in particular not more than 1 nM and especially not more than 0.1 nM, e.g. , From 0.01 to less than 100nM, or from 0.1 to less than 100nM or from 1 to less than 100nM, or from 10 to less than 100nM or from 0.01 to 10nM, or from 0.1 to 10nM or from 1 to 10nM.
  • a further preferred embodiment relates to compounds of the general formula (I) which have a selectivity to the vasopressin receptor subtype V1b over the vasopressin receptor subtype V1a, the quotient of Ki (VIa) / Ki (V1b) being greater than 1.
  • a further preferred embodiment relates to compounds of the general formula (I) which have a selectivity to the vasopressin receptor subtype V1b over the vasopressin receptor subtype V2, the quotient of Ki (V2) / Ki (V1b) being greater than 1.
  • a further preferred embodiment relates to compounds of the general formula (I) which have a selectivity to the vasopressin receptor subtype V1b in relation to the oxytocin (OT) receptor, the quotient of Ki (OT) / Ki (V1b) being greater than 1.
  • a further preferred embodiment relates to compounds of the general formula (I) which have a binding affinity Ki to the vasopressin receptor subtype V1b of less than 100 nM, preferably not more than 10 nM, in particular not more than 1 nM and especially not more than 0.1 nM, eg. From 0.01 to less than 100nM, or from 0.1 to less than 100nM or from 1 to less than 100nM or from 10 to less than 100nM or from 0.01 to
  • a further preferred embodiment relates to compounds of the general formula (I) which have a binding affinity Ki to the vasopressin receptor subtype V1b of less than 100 nM, preferably not more than 10 nM, in particular not more than 1 nM and especially not more than 0.1 nM, eg.
  • a further preferred embodiment relates to compounds of the general formula (I) which have a binding affinity Ki to the vasopressin receptor subtype V1b of less than 100 nM, preferably not more than 10 nM, in particular not more than 1 nM and especially not more than 0.1 nM, eg.
  • vasopressin 0.01 to less than 100 nM, or 0.1 to less than 100 nM or 1 to less than 100 nM or 10 to less than 100 nM or 0.01 to 10 nM, or 0.1 to 10 nM or 1 to 10 nM, and a selectivity to vasopressin Have receptor subtype V1b to the oxytocin (OT) receptor, wherein the quotient of Ki (OT) / Ki (V1b) is greater than 1.
  • a further preferred embodiment relates to compounds of the general formula (I) which have a binding affinity Ki to the vasopressin receptor subtype V1b of less than 100 nM, preferably not more than 10 nM, in particular not more than 1 nM and especially not more than 0.1 nM, eg.
  • vasopressin receptor subtype V1b 0.01 to less than 100 nM, or 0.1 to less than 100 nM or 1 to less than 100 nM or 10 to less than 100 nM or 0.01 to 10 nM, or 0.1 to 10 nM or 1 to 10 nM, and selectivities to the vasopressin receptor subtype V1b to the vasopressin receptor subtype V1a and the vasopressin receptor subtype V2, wherein the quotients of Ki (VIa) / Ki (V1b) and Ki (V2) / Ki (V1b) are each greater than one.
  • a further preferred embodiment relates to compounds of the general formula (I) which have a binding affinity Ki to the vasopressin receptor subtype V1b of less than 100 nM, preferably not more than 10 nM, in particular not more than 1 nM and especially not more than 0.1 nM, eg.
  • vasopressin Receptor subtype V1b 0.01 to less than 100 nM, or 0.1 to less than 100 nM or 1 to less than 100 nM or 10 to less than 100 nM or 0.01 to 10 nM, or 0.1 to 10 nM or 1 to 10 nM, and simultaneous selectivities to vasopressin Receptor subtype V1b to the vasopressin receptor subtype V1a and the oxytocin (OT) receptor, wherein the quotients of Ki (VIa) / Ki (V1b) and Ki (OT) / Ki (V1b) are each greater than 1.
  • a further preferred embodiment relates to compounds of the general formula (I) which have a binding affinity Ki to the vasopressin receptor subtype V1b of less than 100 nM, preferably not more than 10 nM, in particular not more than 1 nM and especially not more than 0.1 nM, eg. From 0.01 to less than 100nM, or from 0.1 to less than 100nM or from 1 to less than 100nM or from 10 to less than 100nM or from 0.01 to
  • Ki (V2) / Ki (V1b) and Ki (OT) / Ki (V1b) are each greater than 1 are provided.
  • a further preferred embodiment relates to compounds of the general formula (I) which have a binding affinity Ki to the vasopressin receptor subtype V1b of less than 100 nM, preferably not more than 10 nM, in particular not more than 1 nM and especially not more than 0.1 nM, eg.
  • vasopressin Receptor subtype V1b 0.01 to less than 100 nM, or 0.1 to less than 100 nM or 1 to less than 100 nM or 10 to less than 100 nM or 0.01 to 10 nM, or 0.1 to 10 nM or 1 to 10 nM, and simultaneous selectivities to vasopressin Receptor subtype V1b to the vasopressin receptor subtype V1a, the vasopressin receptor subtype V2 and the oxytocin (OT) receptor, wherein the quotients of Ki (VI a) / Ki (V1b), Ki (V2) / Ki (V1b) and Ki (OT) / Ki (V1b) are each greater than 1.
  • Another aspect of the present invention relates to compounds of general formula (I) for use as pharmaceuticals.
  • Another aspect of the present invention relates to a pharmaceutical composition containing at least one compound of general formula (I).
  • Another aspect of the present invention relates to the use of at least one compound of the general formula (I) for the treatment and / or prophylaxis of at least one vasopressin-dependent and / or oxytocin-dependent disease and / or for the manufacture of a medicament for the treatment and / or Prophylaxis of at least one of the mentioned diseases.
  • Another aspect of the present invention relates to the use of at least one compound of the general formula (I) for the treatment and / or prophylaxis of at least one disease selected from the group consisting of diabetes insipidus, nocturnal enuresis, incontinence, diseases in which blood coagulation disorders occur and / or delay the voiding and / or for the manufacture of a medicament for the treatment and / or prophylaxis of at least one of said diseases.
  • a disease selected from the group consisting of diabetes insipidus, nocturnal enuresis, incontinence, diseases in which blood coagulation disorders occur and / or delay the voiding and / or for the manufacture of a medicament for the treatment and / or prophylaxis of at least one of said diseases.
  • Another aspect of the present invention relates to the use of at least one compound of the general formula (I) for the treatment and / or prophylaxis of mood disorders and / or for the preparation of a medicament for the treatment of mood disorders.
  • Another aspect of the present invention relates to the use of at least one compound of the general formula (I) for the treatment and / or prophylaxis of anxiety disorders and / or stress-dependent anxiety disorders and / or for the manufacture of a medicament for the treatment of anxiety disorders and / or stress-dependent anxiety disorders.
  • Another aspect of the present invention relates to the use of at least one compound of general formula (I) for the treatment and / or prophylaxis of insomnia and / or for the manufacture of a medicament for the treatment and / or prophylaxis of insomnia.
  • Another aspect of the present invention relates to the use of at least one compound of the general formula (I) for the treatment and / or prophylaxis of depressive disorders and / or for the production of a medicament for the treatment and / or prophylaxis of depressive disorders.
  • Halogen is, in the sense of the description, unless otherwise stated, a halogen atom selected from fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine, more preferably fluorine or chlorine.
  • radicals and groups in the meaning of the description may preferably be mono- or polysubstituted, more preferably mono-, di- or trisubstituted, most preferably
  • the expression "in each case optionally substituted” is intended to make clear that not only the directly following radical but also all the radicals mentioned in the respective group may be substituted.
  • aromatic, heteroaromatic, partially aromatic or partially heteroaromatic mono- or bicyclic ring in the sense of the description, unless otherwise stated, means a mono- or bicyclic ring of C atoms ("aromatic” or “partially aromatic") or a combination of C and heteroatoms (“heteroaromatic” or “partially heteroaromatic”) is in each case constructed as ring members and an aromatic number of double bonds in the ring ("monocyclic") or in the two rings (“bicyclic") ) (“Aromatic” or "heteroaromatic") or only in one of the rings (“partially aromatic” or “partially heteroaromatic")
  • Aromatic and heteroaromatic rings include in particular 5- or 6-membered monocycles and bicyclic systems of two condensed 5 or 6-membered monocycles.
  • saturated or completely or partially unsaturated carbocyclic ring or “saturated or unsaturated carbocyclic ring” in the sense of the description, unless otherwise stated, mean a ring formed from C atoms or formed ring system which does not have a double bond ( "Saturated") or one or more conjugated or unconjugated or partially conjugated double bonds (“partially or completely unsaturated” or “unsaturated”) .
  • the carbocyclic ring may be a mono-, bi- or tricyclic ring
  • saturated carbocyclic may, unless stated otherwise, be a bicycloalkyl or tricycloalkyl radical having 5 to 10 carbon atoms
  • the ring system may preferably contain 5 to 10, more preferably 6 to 10, carbon atoms
  • Tricycloalkyl radical preferably contains the ring system from 6 to 10 more preferably 7 to 10 carbon atoms. Examples of a bicycloalkyl
  • the compounds according to the invention show good affinity for vasopressin receptors, in particular for the vasopressin receptor subtype V1b. Since the various vasopressin receptors transmit very different effects of the vasopressin (M. Thibonnier, Exp.Opin., Invest Drugs 1998, 7 (5), 729-740; Seradeil-Le GaI, C, et al., Prog Brain Res. 2002; 139: 197-210), it is of particular importance to selectively obtain effects on, for example, a vasopressin receptor so as to obtain the desired effect without at the same time causing significant side effects.
  • the suitable unitary administration forms include forms for oral administration such as tablets, gelatin capsules, powders, granules and oral solutions or suspensions, forms for sublingual, buccal, intratracheal or intranasal administration, aerosols, implants, forms of subcutaneous, intramuscular or intravenous administration and Forms of rectal administration.
  • the dose of the active principle may vary between 0.01 and 50 mg per kg of body weight per day.
  • a preparation in the form of gelatin capsules is obtained by mixing the active ingredient with an extender and incorporating the resulting mixture into 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 agent and a suitable coloring matter.
  • a sweetener which is preferably calorie-free, methylparaben or propylparaben as antiseptics, a flavoring agent and a suitable coloring matter.
  • compositions according to the invention may contain other active principles which may be useful for the treatment of the above-mentioned disorders or diseases.
  • the present invention thus further relates to pharmaceutical compositions in which several active principles are present together, at least one of which is a compound of the invention.
  • the compounds according to the invention are antagonists of the so-called receptors of the vasopressin oxytocin family. Such compounds can be tested in suitable assays which detect the affinity for a receptor, the affinity constant Ki being a measure of the potency of the compounds and a smaller value represents a greater potency.
  • the compounds according to the invention were, for example, tested for affinity for their receptor affinity in the following vasopressin receptor subtype V1b receptor.
  • the 3-hydroxyoxindoles VI can be prepared by adding lithium organic or Grignard compounds to the 3-keto group of the substituted isatin V in an ethereal solvent such as tetrahydrofuran (THF).
  • THF tetrahydrofuran
  • the lithium species can be obtained from the iodo-aryl compound IV by treatment with organolithium reagents, such as n-butyllithium, in THF at low temperatures.
  • organolithium reagents such as n-butyllithium
  • the corresponding Grignard compound may be prepared by treatment with magnesium in an ethereal solvent such as THF.
  • metallated hetero aromatics carrying a protected formyl group can be prepared in an analogous manner (protecting the formyl function as a cyclic acetal followed by lithium-halogen exchange or insertion of magnesium into the heteroaryl-halogen bond), for example from commercially available 2-bromo 4-formyl-3-methoxypyridine, 6-bromo-2-formylpyridine, 5-bromo-3-formylpyridine, 2-bromo-4-formylpyridine, 2-bromo-5-formylpyridine, 4-Bromo-2-formylthiophene , 3-bromo-2-formylthiophene, 5-bromo-2-formylthiophene or 3-bromo-4-formylthiophene.
  • the compounds VII are then in the presence of a base, such as N, N-diisopropylethylamine, with primary or secondary amines YH, such as (S) -pyrrolidine-2-carboxylic acid dimethylamide (H-PrO-NMe 2 ), (2S, 4R ) -4-hydroxypyrrolidine-2-carboxylic acid dimethylamide (H-Hyp-NMe 2 ) or (S) -N, N-dimethyl-2-methylaminopropionamide (H-MeAl-NMe 2 ), in a solvent, such as dichloromethane, converted to the corresponding 3-Aminooxindolen VIII.
  • a base such as N, N-diisopropylethylamine
  • primary or secondary amines YH such as (S) -pyrrolidine-2-carboxylic acid dimethylamide (H-PrO-NMe 2 ), (2S, 4R ) -4-hydroxypyrrolidine-2
  • the resulting aldehyde IX may be combined with primary or secondary amines in the presence of a reducing agent such as sodium cyanoborohydride or solid phase-bound triacetoxyborohydride in a solvent such as THF Amines X (Reductive Amination: J.March, Advanced Organic Chemistry, 1992, 4th edition, Wiley, New York, p.411, 898).
  • a reducing agent such as sodium cyanoborohydride or solid phase-bound triacetoxyborohydride in a solvent such as THF Amines X (Reductive Amination: J.March, Advanced Organic Chemistry, 1992, 4th edition, Wiley, New York, p.411, 898).
  • the products of the reductive amination were purified by preparative reversed-phase HPLC (eluent: gradient of 10% to 80% acetonitrile in water, 0.1% trifluoroacetic acid) and fall accordingly as trifluoroacetic acid salts.
  • the dropping rate was slowed down so that the reaction mixture just continued to boil.
  • the reaction mixture was then stirred for a further 20 minutes and then cooled to room temperature.
  • the resulting Grignard solution was added to an ice-cooled solution of the 5-chloroisatin sodium salt [prepared by treating a solution of 5-chloroisatin (13.1 g, 72 mmol) in THF (400 mL) with one equivalent of sodium hydride for one hour 0 ° C] and then stirred for 5 hours at room temperature.
  • the reaction solution was mixed with aqueous ammonium chloride solution while stirring, and the reaction was extracted twice with ethyl acetate.
  • reaction mixture is allowed to warm to room temperature and stirred for a further hour.
  • the reaction solution was added with stirring with aqueous ammonium chloride solution and the batch was extracted with ethyl acetate.
  • the combined organic phase was washed with water and brine, dried over magnesium sulfate and concentrated under reduced pressure. Chromatographic purification over silica gel (eluent 10-30% gradient of ethyl acetate in dichloromethane) gave 3.8 g (41%) of the desired addition product.
  • step 34D To a solution of the reaction product according to step 34D (574 mg, 0.76 mmol) in THF (10 mL) at 0 ° C was added a solution of tetra-n-butylammonium fluoride in THF (1.0 M, 10 mL, 10 mmol). After 30 minutes, water was added to the reaction and extracted several times with ethyl acetate. The combined organic phase was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (eluent gradient 70-100% ethyl acetate in dichloromethane). Yield: 376 mg (83%).
  • Examples 40 to 68 below can be prepared in an analogous manner according to Synthetic Scheme 1.
  • test substances were dissolved in a concentration of 10 -2 M in DMSO (dimethyl sulfoxide) and further diluted in DMSO to 5 ⁇ 10 -4 M to 5 ⁇ 10 -9 M. This DMSO predilution series was diluted 1:10 with assay buffer. In the test mixture, the substance concentration was again diluted 1: 5 (2% DMSO in the batch).
  • DMSO dimethyl sulfoxide
  • CHO-K1 cells stably expressed with 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) with a Polytron homogenizer at medium position 2x10 seconds and then centrifuged for 1 h at 40,000 xg. The membrane pellet was again homogenized as described and centrifuged and then taken up in 50 mM Tris-HCl, pH 7.4, homogenized and stored in aliquots frozen at -190 ° C in liquid nitrogen.
  • protease inhibitors Roche complete Mini # 1836170
  • Binding test The binding test was carried out in accordance with the method of Tahara et al. (Tahara A et al., Brit. J. Pharmacol. 125, 1463-1470 (1998)). Incubation buffer was: 50mM Tris, 10mM 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) with 1.5 nM 3 H-AVP (8-Arg vasopressin, Perkin Elmer # 18479) in incubation buffer (50 mM Tris, 10 mM MgCl 2 , 0.1% BSA, pH 7.4) (total binding) or additionally incubated with increasing concentrations of test substance (displacement experiment).
  • Non-specific binding was determined with 1 ⁇ M AVP (Bachern # H1780). All determinations were made in triplicate.
  • the free radioligand was filtered by vacuum filtration (Skatron cell harvester 7000) over Wathman GF / B glass fiber filter mats and the filters transferred to scintillation vials.
  • the liquid scintillation measurement was carried out in a Tricarb Model 2000 or 2200CA (Packard). The conversion of the measured cpm into dpm was carried out using a standard quench series.
  • the binding parameters were calculated by nonlinear regression in SAS.
  • the algorithms of the program work analogously to the LIGAND evaluation program (Munson PJ and Rodbard D, Analytical Biochem., 107, 220-239 (1980)).
  • the Kd value of 3 H-AVP to the recombinant hV2 receptors is 0.4 nM and was used to determine the Ki value.
  • Vasopressin V1a receptor binding test substances:
  • test substances were dissolved in a concentration of 10 -2 M in DMSO.
  • concentration of 10 -2 M in DMSO was carried out in incubation buffer (50 mM Tris, 10 mM MgCl 2 , 0.1% BSA, pH 7.4).
  • CHO-K1 cells stably expressed with human vasopressin V1a receptor were harvested and homogenized in 50 mM Tris-HCl and in the presence of protease inhibitors (Roche complete Mini # 1836170) with a Polytron homogenizer at a median position of 2x10 seconds and then centrifuged for 1 h at 40,000 xg. The membrane pellet was homogenized again as described and centrifuged and then taken up in 50 mM Tris-HCl, pH 7.4, homogenized and stored in aliquots frozen at -190 ° C in liquid nitrogen.
  • protease inhibitors Roche complete Mini # 1836170
  • the binding test was performed according to the method of Tahara et al. (Tahara A et al., Brit. J. Pharmacol. 125, 1463-1470 (1998)).
  • Incubation buffer was: 50mM Tris, 10mM MgCl 2 , 0.1% BSA, pH 7.4.
  • membranes (20 ⁇ g / ml protein in incubation buffer) of CHO-K1 cells with stably expressed human V1a receptors (cell line hV1a_5_CHO) were incubated with 0.04 nM 125 I-AVP (8-arg-vasopressin, NEX 128).
  • the free radioligand was filtered by vacuum filtration (Skatron cell harvester 7000) over Wathman GF / B glass fiber filter mats and the filters transferred to scintillation vials.
  • the liquid scintillation measurement was carried out in a Tricarb Model 2000 or 2200CA (Packard). The conversion of the measured cpm into dpm was carried out using a standard quench series.
  • the binding parameters were calculated by nonlinear regression in SAS.
  • the algorithms of the program work analogously to the LIGAND evaluation program (Munson PJ and Rodbard D, Analytical Biochem., 107, 220-239 (1980)).
  • the Kd value of 125 I -AVP to the recombinant hV1a receptors was determined in saturation experiments.
  • a Kd value of 1.33 nM was used to determine the ki value.
  • test substances were dissolved in a concentration of 10 -2 M in DMSO. Further dilution of this DMSO solution was carried out in incubation buffer (50 mM Tris, 10 mM MgCl 2 , 0.1% BSA, pH 7.4).
  • CHO-K1 cells stably expressed with 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) with a Polytron homogenizer at a mean 2x10 sec Centrifuged at 40,000 xg for 1 h. The membrane pellet was homogenized again as described and centrifuged and then taken up in 50 mM Tris-HCl, pH 7.4, homogenized and stored in aliquots frozen at -190 ° C in liquid nitrogen.
  • the binding test was performed according to the method of Tahara et al. (Tahara A et al., Brit. J. Pharmacol. 125, 1463-1470 (1998)).
  • Incubation buffer was: 50mM Tris, 10mM 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) with 1-2 nM 3 H-AVP (8-Arg vasopressin, Perkin Elmer # 18479) in incubation buffer (50 mM Tris, 10 mM MgCl 2 , 0.1% BSA, pH 7.4) (total binding) or additionally incubated with increasing concentrations of test substance (displacement experiment).
  • total binding 50 mM Tris, 10 mM MgCl 2 , 0.1% BSA, pH 7.4
  • the free radioligand was filtered by vacuum filtration (Skatron cell harvester 7000) over Wathman GF / B glass fiber filter mats and the filters transferred to scintillation vials.
  • the liquid scintillation measurement was carried out in a Tricarb Model 2000 or 2200CA (Packard). The conversion of the measured cpm into dpm was carried out using a standard quench series.
  • the binding parameters were calculated by nonlinear regression in SAS.
  • the algorithms of the program work analogously to the LIGAND evaluation program (Munson PJ and Rodbard D, Analytical Biochem., 107, 220-239 (1980)).
  • the Kd value of 3 H-AVP to the recombinant hV2 receptors is 2.4 nM and was used to determine the Ki value.
  • the substances were dissolved in DMSO at a concentration of 10 -2 M and diluted with incubation buffer (50 mM Tris, 10 mM MgCl 2 , 0.1% BSA, pH 7.4).
  • Confluent HEK-293 cells with transiently expressed recombinant human oxytocin receptors were centrifuged at 750 xg for 5 minutes at room temperature. 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 osmotic shock for 20 minutes at 4 ° C. Thereafter, the lysed cells were centrifuged at 750 xg for 20 minutes at 4 ° C, the residue taken up in incubation buffer and made aliquots of 10 7 cells / ml. The aliquots were frozen at -80 ° C until use.
  • ice-cold lysis buffer 50 mM Tris-HCl, 10% glycerol, pH 7.4 and Roche Complete Protease Inhibitor
  • the binding parameters were calculated by non-linear regression analysis (SAS), analogous to the program LIGAND by Munson and Rodbard (Analytical Biochem 1980, 107: 220-239).
  • SAS non-linear regression analysis
  • the Kd value of 3 H-oxytocin to the recombinant hOT receptors is 7.6 nM and was used to determine the Ki value.
  • the functional activity of the test substances was investigated on CHO-K1 cells stably transfected with the human V1b receptor.
  • CHO-K1 cells stably transfected with the human V1b receptor.
  • 50,000 cells were seeded and incubated overnight at 37 ° C in saturated steam atmosphere with 5% CO 2 in culture medium.
  • the culture medium consisted of DMEM / Nut Mix F12 with Glutamax I (from Invitrogen), 10% fetal calf serum, 100 units / ml penicillin, 100 ⁇ g / ml streptomycin and 800 ⁇ g / ml geneticin.
  • the next day, the cells were washed with culture medium and loaded with a fluorescent dye for calcium according to the manufacturer's instructions (Ca ++ Plus Assay Kit, Molecular Devices).
  • the loading of the cells was carried out in the presence of Probenzid (1 vol%).
  • the test substances were diluted with culture medium (final concentration of 10 -10 to 10 -5 M) and at room temperature for 15 minutes with the dye-loaded cells incubated. Thereafter, arg-vasopressin (10 -8 M) was added and the maximum fluorescence signal was determined with a FLIPR-96 meter (Molecular Devices).
  • the affinities for the human vasopressin receptor V1b were measured in accordance with the above tests and the affinity constants (Ki) were determined.
  • Table 1 below shows the V1b receptor affinity of selected compounds (+++ means ⁇ 1 nM, ++ means 1-10 nM and + means 10-100 nM).
  • the affinities for further vasopressin receptors or their subtypes such as e.g. V1a and V2, and the oxytocin (OT) receptor.
  • the available quotients of the corresponding Ki values ie, "Ki (V1a) / Ki (V1b)", “Ki (V2) / Ki (v1b)” and / or "Ki (OT) Ki (VIb ) "can serve as a measure of a possible selectivity of the compounds according to the invention with regard to a particular vasopressin or oxytocin receptor or one of its subtypes, such as, for example, V1b.
  • the compounds of the invention showed a surprisingly high affinity for the human V1b receptor, often less than or equal to 1 nM and in some cases even less than or equal to 0.1 nM.
  • a number of compounds of the invention act as a functional antagonist of the human vasopressin V1b receptor, e.g. B. Example 2. Due to the greatly increased affinity of the compounds according to the invention for the human V1b receptor, they will already cause the therapeutic effects mediated by V1b receptors at lower concentrations / efficacy levels. Low levels of effect are generally desirable because it reduces the likelihood of side effects not caused by interaction with human V1b receptors.

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Abstract

La présente invention concerne de nouveaux dérivés d'oxindole de formule générale (I), dans laquelle les substituants R<SUP>1</SUP>, R<SUP>2</SUP>, A, B et Y sont tels que définis dans la revendication 1. L'invention concerne également des médicaments contenant ces dérivés et leur utilisation en prévention et/ou traitement de maladies liées à la vasopressine et/ou à l'oxytocine.
EP06723672A 2005-03-24 2006-03-23 Derives d'oxindole substitues, medicaments contenant ces derives et leur utilisation Withdrawn EP1861392A2 (fr)

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US66475905P 2005-03-24 2005-03-24
DE200510014628 DE102005014628A1 (de) 2005-03-26 2005-03-26 Substituierte Oxindol-Derivate, diese enthaltende Arzneimittel und deren Verwendung
DE200510015957 DE102005015957A1 (de) 2005-03-31 2005-03-31 Substituierte Oxindol-Derivate, diese enthaltende Arzneimittel und deren Verwendung
PCT/EP2006/002685 WO2006100082A2 (fr) 2005-03-24 2006-03-23 Derives d'oxindole substitues, medicaments contenant ces derives et leur utilisation

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