WO1999040067A2 - Benzisoxazole derivatives having d4-antagonistic activity - Google Patents

Benzisoxazole derivatives having d4-antagonistic activity Download PDF

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WO1999040067A2
WO1999040067A2 PCT/EP1999/000852 EP9900852W WO9940067A2 WO 1999040067 A2 WO1999040067 A2 WO 1999040067A2 EP 9900852 W EP9900852 W EP 9900852W WO 9940067 A2 WO9940067 A2 WO 9940067A2
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amino
sulfonyl
group
compound
dialkyl
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WO1999040067A3 (en
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Jacobus A. J. Den Hartog
Gerben M. Visser
Bartholomeus J. Van Steen
Martinus T. M. Tulp
Eric Ronken
Cornelis G. Kruse
Josephus H. M. Lange
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Duphar International Research BV
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Priority to DK99914450T priority Critical patent/DK1054885T3/en
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Priority to AU33273/99A priority patent/AU3327399A/en
Priority to DE69936572T priority patent/DE69936572T2/en
Priority to CA002320120A priority patent/CA2320120C/en
Priority to JP2000530498A priority patent/JP4627882B2/en
Priority to EP99914450A priority patent/EP1054885B1/en
Publication of WO1999040067A2 publication Critical patent/WO1999040067A2/en
Publication of WO1999040067A3 publication Critical patent/WO1999040067A3/en
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    • 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
    • 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
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a group of novel benzisoxazole derivatives, to a method for the preparation of these compounds, and to pharmaceutical compositions containing one or more of these compounds as an active component.
  • - (R ) n represents 0, 1 or 2 substituents, which can be the same or different, from the group C ⁇ -alkyl or alkoxy, halogen, trifluoromethyl, nitro, amino, mono- or dialkyl (C 1.2 )-amino, sulfonyl-(C 1 ⁇ 3 )alkyl or -alkoxy, sulfonyl trifluoromethyl, sulfonyl amino, and sulfonyl mono- or dialkyl (C 1 . 2 )-amino,
  • - X is O, S, NH or NCH 3
  • - Y represents CH 2 or (CH 2 ) 2
  • (R 2 ) m represents 0, 1 , or 2 substituents, which can be the same or different, from the group methyl and ethyl, or (R 2 ) m is a methylene bridge or ethylene bridge,
  • - A is a group -CH 2 -(CRH) P - wherein R is hydrogen or methyl and p is 0 or 1 , and
  • - B represents 2- or 3-indolyl or 2-benzimidazolyl, which groups may be substituted at carbon with 1 or 2 substituents from the group C- ⁇ -alkyl or alkoxy, halogen, trifluoromethyl, nitro, amino, mono- or dialkyl (C 1 . 2 )amino, sulfonyKC ⁇ alkyl or -alkoxy, sulfonyl trifluoromethyl, sulfonyl amino, and sulfonyl mono- or dialkyl (C 1-2 )-amino, are potent and selective antagonists of the dopamine D4-receptor.
  • the compounds according to the invention are suitable for use in the treatment of psychiatric disorders such as psychosis, anxiety, depression, attention deficits and memory disorders, neurological disorders such as Parkinson's disease and ischaemia and other CNS-diseases involving dopaminergic neurotransmission.
  • psychiatric disorders such as psychosis, anxiety, depression, attention deficits and memory disorders
  • neurological disorders such as Parkinson's disease and ischaemia and other CNS-diseases involving dopaminergic neurotransmission.
  • the affinity of the compounds of the invention for dopamine D4 receptors was determined using CHO-K1 cells which are stably transfected to express the human recombinant dopamine receptor, D4.2 subtype (Van Tol et al, Nature 350, 610, 1991 ) and using [3H]-Spiperone as the ligand. After incubation of a freshly prepared cellmembrane preparation with the [3H]-ligand, with or without addition of compounds of the invention, separation of bound and free ligand was performed by filtration over glassfiberfilters (Research Biochemicals International protocol, Catalog No. D-177). Radioactivity on the filter was measured by liquid scintillation counting. Results are expressed as IC50 values and transformed into inhibitory constants (Ki).
  • the dopamine D4 antagonistic activity of compounds of the invention was determined by functional studies using CHO-K1 ceils stably expressing the human dopamine D4.4 receptor (Van Tol et al, Nature 358, 149, 1992).These cells were fitted with a construct encoding a truncated form of alkaline phosphatase, causing it to get secreted by the cells. Expression of this secretable alkaline phosphatase (SeAP) is under direct control of cellular cyclic AMP (Berger et al, Gene, 66, 1 , 1988). SeAP measurements were done with p-nitrophenylphosphate (pNPP) as the substrate using colorimetric readout at 450 nm.
  • pNPP p-nitrophenylphosphate
  • Dopamine D4 antagonist activity was determined by co-incubation of cells with prostaglandin PGE1 (1 ⁇ M) and quinpirole (1 ⁇ M), with or without addition of compounds of the invention, for receptor-mediated stimulation of adenylate cyclase and for maximal dopamine D4 receptor-mediated suppression, respectively.
  • the antagonistic effect of compounds of the invention against agonist dependant attenuation of dopamine D4 receptor mediated SeAP formation was quantified, yielding estimates of intrinsic activity and potency (pA2 values). Clozapine and spiperone were used as reference dopamine antagonists.
  • Dopamine D4 antagonist properties and absence of dopamine D4 agonist properties of selected compounds of the invention were further confirmed using radioactive measurements of cAMP formation according to Salomon et al. (Anal Biochem, 58, 541 , 1974) as modified by Weiss et al. (J Neurochem 45, 869, 1985).
  • the selectivity of the compounds of the invention with regard to the dopamine D2 receptor was determined by measuring the affinity for dopamine D2 receptors using rat brain homogenates and [3H]-Spiperone as the ligand (Leysen et al, Biochem Pharmacol 27, 307, 1978). After incubation of a freshly prepared cellmembrane preparation with the [3H]- ligand, with or without addition of compounds of the invention, separation of bound and free ligand was performed by filtration over glassfiberfilters. Radioactivity on the filter was measured by liquid scintillation counting. Results are expressed as IC50 values and transformed into inhibitory constants (Ki).
  • the dopamine D2 (ant)agonistic activity of compounds of the invention was determined by functional studies based on radioactive measurements of cAMP formation according to Salomon et al.( Anal Biochem, 58, 541 ,
  • CHO cells stably expressing human dopamine D2L receptors ( Grandy et al, Proc Natl Acad Sci USA, 86, 9762, 1989).
  • Suitable acids with which the compounds can form pharmaceutically acceptable acid addition salts are for example hydrochloric acid, sulphuric acid, phosphoric acid, nitric acid, and organic acids such as citric acid, fumaric acid, maleic acid, tartaric acid, acetic acid, benzoic acid, p-toluene sulphonic acid, methane sulphonic acid and naphthalene sulphonic acid.
  • the compounds of the invention can be brought into forms suitable for administration by means of usual processes using auxiliary substances and/or liquid or solid carrier materials.
  • the compounds of the invention having formula (I) can be obtained according to methods known for the synthesis of structurally related compounds.
  • a suitable synthesis for the compounds according to the present invention is the following:
  • This reaction is carried out in a polar aprotic solvent such as dimethylformamide in the presence of an equivalent amount of a base such as sodiumhydride at 20 - 120°C.
  • a base such as sodiumhydride
  • Part B To a solution of 25.6 g (83 mmol) of 3-(4-oxo-1-benzyl-piperidino)- benzisoxazole in 1 ,2-dichloroethane (200 ml) a solution of 1-chloroethyl chloroformate ( 13.6 ml, 125 mmol, 1.5 equivalent) was added dropwise under ice cooling. The mixture was stirred at 0 °C for 1/2 hr, at room temperature for 1 hr, refluxed for 2 hrs and subsequently cooled to room temperature. After concentration in vacuo , methanol (200 ml) was added and the resulting mixture was refluxed for 2 hrs.
  • Part C A quantity of 9.7 g (60 mmol) of commercially available indole-2- carboxyiic acid and 9.8 g (60 mmol) of commercially available 1 ,1 '- carbonyldiimidazole were dissolved in dry tetrahydrofuran (300 ml) , the reaction mixture was refluxed under nitrogen for 1 hr and subsequently cooled in ice.
  • Part D To a solution of 18.4 g (50 mmol) of 3-(4-oxo-[1-(2-carboxy- indolyl)piperidino])benzisoxazole and 9.5 g (250 mmol, 5 equivalent) of sodium borohydride in dry 1 ,1-dimethoxyethane (400 ml) under nitrogen, a solution of 14.3 ml (250 mmol) acetic acid in dry 1 ,2-dimethoxyethane (100 ml) was added dropwise in 1/2 hr. The mixture was refluxed for 1 hr. After cooling of the reaction mixture in ice, subsequent dropwise addition was carried out of: 1 ).

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Abstract

The present invention relates to a group of novel benzisoxazole derivatives which are potent and selective antagonists of the dopamine D4-receptor. The compounds have general formula (I) wherein (R1)n represents 0, 1, or 2 substituents, which can be the same or different, from the group C1-3-alkyl or alkoxy, halogen, trifluoromethyl, nitro, amino mono- or dialkyl (C1-2)-amino, sulfonyl-(C1-3)alkyl or -alkoxy, sulfonyl trifluoromethyl, sulfonyl amino, and sulfonyl mono- or dialkyl (C1-2)-amino, X is O, S, NH or NCH3, Y represents CH2 or (CH2)2, (R2)m represents 0, 1, or 2 substituents, which can be the same or different, from the group methyl and ethyl, or (R2)m is a methylene bridge or ethylene bridge, A is a group -CH2-(CRH)p- wherein R is hydrogen or methyl and p is 0 or 1, and B represents 2- or 3-indolyl or 2-benzimidazolyl, which groups may be substituted at carbon with 1 or 2 substituents from the group C-1-3-alkyl or alkoxy, halogen, trifluoromethyl, nitro, amino, mono- or dialkyl (C1-2)amino, sulfonyl-(C1-3)alkyl or -alkoxy, sulfonyl trifluoromethyl, sulfonyl amino, and sulfonyl mono- or dialkyl (C1-2)-amino.

Description

Benzisoxazole derivatives having D4-antagonistic activity
The present invention relates to a group of novel benzisoxazole derivatives, to a method for the preparation of these compounds, and to pharmaceutical compositions containing one or more of these compounds as an active component.
It has surprisingly been found that the compounds and salts thereof of the formula (I)
Figure imgf000003_0001
wherein
- (R )n represents 0, 1 or 2 substituents, which can be the same or different, from the group C^-alkyl or alkoxy, halogen, trifluoromethyl, nitro, amino, mono- or dialkyl (C1.2)-amino, sulfonyl-(C1^3)alkyl or -alkoxy, sulfonyl trifluoromethyl, sulfonyl amino, and sulfonyl mono- or dialkyl (C1.2)-amino,
- X is O, S, NH or NCH3, - Y represents CH2 or (CH2)2
- (R2)m represents 0, 1 , or 2 substituents, which can be the same or different, from the group methyl and ethyl, or (R2)m is a methylene bridge or ethylene bridge,
- A is a group -CH2-(CRH)P- wherein R is hydrogen or methyl and p is 0 or 1 , and
- B represents 2- or 3-indolyl or 2-benzimidazolyl, which groups may be substituted at carbon with 1 or 2 substituents from the group C-^-alkyl or alkoxy, halogen, trifluoromethyl, nitro, amino, mono- or dialkyl (C1.2)amino, sulfonyKC^alkyl or -alkoxy, sulfonyl trifluoromethyl, sulfonyl amino, and sulfonyl mono- or dialkyl (C1-2)-amino, are potent and selective antagonists of the dopamine D4-receptor. Compounds having formula (I) wherein A is the group CH2, Y is CH2, X is O, NH or NCH3 and m and n are 0, and B has the above meaning, and salts thereof are preferred.
Due to the potent and selective D4 antagonistic activity the compounds according to the invention are suitable for use in the treatment of psychiatric disorders such as psychosis, anxiety, depression, attention deficits and memory disorders, neurological disorders such as Parkinson's disease and ischaemia and other CNS-diseases involving dopaminergic neurotransmission.
The affinity of the compounds of the invention for dopamine D4 receptors was determined using CHO-K1 cells which are stably transfected to express the human recombinant dopamine receptor, D4.2 subtype (Van Tol et al, Nature 350, 610, 1991 ) and using [3H]-Spiperone as the ligand. After incubation of a freshly prepared cellmembrane preparation with the [3H]-ligand, with or without addition of compounds of the invention, separation of bound and free ligand was performed by filtration over glassfiberfilters (Research Biochemicals International protocol, Catalog No. D-177). Radioactivity on the filter was measured by liquid scintillation counting. Results are expressed as IC50 values and transformed into inhibitory constants (Ki).
The dopamine D4 antagonistic activity of compounds of the invention was determined by functional studies using CHO-K1 ceils stably expressing the human dopamine D4.4 receptor (Van Tol et al, Nature 358, 149, 1992).These cells were fitted with a construct encoding a truncated form of alkaline phosphatase, causing it to get secreted by the cells. Expression of this secretable alkaline phosphatase (SeAP) is under direct control of cellular cyclic AMP (Berger et al, Gene, 66, 1 , 1988). SeAP measurements were done with p-nitrophenylphosphate (pNPP) as the substrate using colorimetric readout at 450 nm. Dopamine D4 antagonist activity was determined by co-incubation of cells with prostaglandin PGE1 (1 μM) and quinpirole (1 μM), with or without addition of compounds of the invention, for receptor-mediated stimulation of adenylate cyclase and for maximal dopamine D4 receptor-mediated suppression, respectively. The antagonistic effect of compounds of the invention against agonist dependant attenuation of dopamine D4 receptor mediated SeAP formation was quantified, yielding estimates of intrinsic activity and potency (pA2 values). Clozapine and spiperone were used as reference dopamine antagonists.
Absence of dopamine D4 agonistic activity was confirmed using the same assay, but leaving out the standard dopamine D4 agonist quinpirole, by determination of the concentration-dependant attenuation of the dopamine D4 receptor mediated SeAP formation by compounds of the invention.
Dopamine D4 antagonist properties and absence of dopamine D4 agonist properties of selected compounds of the invention were further confirmed using radioactive measurements of cAMP formation according to Salomon et al. (Anal Biochem, 58, 541 , 1974) as modified by Weiss et al. (J Neurochem 45, 869, 1985).
The selectivity of the compounds of the invention with regard to the dopamine D2 receptor, was determined by measuring the affinity for dopamine D2 receptors using rat brain homogenates and [3H]-Spiperone as the ligand (Leysen et al, Biochem Pharmacol 27, 307, 1978). After incubation of a freshly prepared cellmembrane preparation with the [3H]- ligand, with or without addition of compounds of the invention, separation of bound and free ligand was performed by filtration over glassfiberfilters. Radioactivity on the filter was measured by liquid scintillation counting. Results are expressed as IC50 values and transformed into inhibitory constants (Ki).
The dopamine D2 (ant)agonistic activity of compounds of the invention was determined by functional studies based on radioactive measurements of cAMP formation according to Salomon et al.( Anal Biochem, 58, 541 ,
1974), as modified by Weiss et al. (J Neurochem, 45, 869, 1985), using
CHO cells, stably expressing human dopamine D2L receptors ( Grandy et al, Proc Natl Acad Sci USA, 86, 9762, 1989).
Suitable acids with which the compounds can form pharmaceutically acceptable acid addition salts are for example hydrochloric acid, sulphuric acid, phosphoric acid, nitric acid, and organic acids such as citric acid, fumaric acid, maleic acid, tartaric acid, acetic acid, benzoic acid, p-toluene sulphonic acid, methane sulphonic acid and naphthalene sulphonic acid.
The compounds of the invention can be brought into forms suitable for administration by means of usual processes using auxiliary substances and/or liquid or solid carrier materials.
The compounds of the invention having formula (I) can be obtained according to methods known for the synthesis of structurally related compounds.
A suitable synthesis for the compounds according to the present invention is the following:
Step l
Reaction of a compound having formula (II)
Figure imgf000006_0001
with a compound of the formula (III)
Figure imgf000006_0002
This reaction is carried out in a polar aprotic solvent such as dimethylformamide in the presence of an equivalent amount of a base such as sodiumhydride at 20 - 120°C. The protecting benzyl group is then removed from the obtained product.
Step 2
When B is the group 2- or 3-indolyl, the thus obtained deprotected compound having formula (IV)
Figure imgf000007_0001
is reacted with an optionally substituted 2- or 3-indolyl carboxylic acid derivative of the formula B-A'-COOH, wherein A' is the group -(CRH)P-, wherein R is hydrogen or methyl and p has the value 0 or 1. This reaction is carried out in the presence of an equivalent amount of 1 ,1 '- carbonyldiimidazole in an aprotic solvent such as tetrahydrofuran.
Step 3
The keto group in the obtained compound of the formula (V)
Figure imgf000007_0002
is reduced to CH2 in a manner known per se, e.g. by means of an excess of sodium borohydride in the presence of acetic acid in a solvent such as dimethoxyethane under an atmosphere of nitrogen to give the desired compound having formula (I).
To prepare a compound having formula (I) wherein B is the group 2- benzimidazolyl, the compound having formula (IV) is reacted with an optionally substituted 2-halomethyl benzimidazole derivative of the formula B-A-Z, wherein A has the above meaning and Z is Cl or Br. This reaction is carried out in the presence of a base such as triethylamine in a polar aprotic solvent such as acetonitrile at 20 - 80°C.
The preparation of the compounds is illustrated in the following examples.
Example I
3-(4-Oxo-[1-(2-methylindolyl)piperidino])-benzisoxazole.hydrochloride Part A: A quantity of 19.1 g (100 mmol) of commercially available, dry 4- hydroxy-1-benzyl-piperidine was dissolved in dimethylformamide (150 ml) and 6.4 g (55% quality; 100 mmol) sodiumhydride was added. After stirring at 80 °C for 1 hr the mixture was cooled to room temperature and 15.4 g (100 mmol) of 3-chloro-benzisoxazole ((H. Boshagen, Chem. Ber. 1967, 100, pg 3326) was added in portions. After stirring at room temperature for 1 hr and at 80 °C for 3 hr, the mixture was cooled to room temperature and water (300 ml) was added. The solution was extracted with dichloromethane (three times 150 ml), the organic layer was subsequently washed with water (three times 40 mi), dried over magnesium sulphate and concentrated in vacuo. The product was purified applying flash- chromatography over silicagel using dichloromethane/methanol 99:1 as the eluent. After concentration in vacuo a total of 25.6 g of 3-(4-oxo-1-benzyl- piperidino)-benzisoxazole was obtained (83% yield)
Part B: To a solution of 25.6 g (83 mmol) of 3-(4-oxo-1-benzyl-piperidino)- benzisoxazole in 1 ,2-dichloroethane (200 ml) a solution of 1-chloroethyl chloroformate ( 13.6 ml, 125 mmol, 1.5 equivalent) was added dropwise under ice cooling. The mixture was stirred at 0 °C for 1/2 hr, at room temperature for 1 hr, refluxed for 2 hrs and subsequently cooled to room temperature. After concentration in vacuo , methanol (200 ml) was added and the resulting mixture was refluxed for 2 hrs. The precipitate obtained after subsequent cooling to 0°C was collected by filtration, washed with petroleum-ether (40-60) and dried in vacuo. In this way 14.5 g of 3-(4-oxo- piperidino)-benzisoxazole.hydrochloride was obtained as a pink solid (69 % yield).
Part C: A quantity of 9.7 g (60 mmol) of commercially available indole-2- carboxyiic acid and 9.8 g (60 mmol) of commercially available 1 ,1 '- carbonyldiimidazole were dissolved in dry tetrahydrofuran (300 ml) , the reaction mixture was refluxed under nitrogen for 1 hr and subsequently cooled in ice.
Meanwhile the obtained 14.5 g (57 mmol) of 3-(4-oxo-piperidino)- benzisoxazole.hydrochloride was dissolved in a sodium hydroxide solution in water (2N, 200 ml) and extracted with dichloromethane (three times 100 ml). The combined organic layers were dried over sodium sulphate, concentrated in vacuo and dissolved in dry tetrahydrofuran (70 ml). The obtained solution of 3-(4-oxo-piperidino)-benzisoxazole was added to the solution of activated indole-2-carboxyiic acid and the resulting reaction mixture was refluxed for 2 hrs. After concentration in vacuo, water (200 ml) was added. After washing with dichloromethane (three times 70 ml) the combined organic layers were washed with water (three times 40 ml), dried over sodium sulphate and concentrated in vacuo. The resulting yellow solid was suspended under stirring in diisopropylether (300 ml). After 40 hrs the precipitate was collected by filtration, washed with diisopropylether (two times 150 ml) and dried in vacuo. A quantity of 18.4 g of 3-(4-oxo-[1-(2-carboxy-indolyl)piperidino])benzisoxazole was obtained as a white solid (89 % yield).
Part D: To a solution of 18.4 g (50 mmol) of 3-(4-oxo-[1-(2-carboxy- indolyl)piperidino])benzisoxazole and 9.5 g (250 mmol, 5 equivalent) of sodium borohydride in dry 1 ,1-dimethoxyethane (400 ml) under nitrogen, a solution of 14.3 ml (250 mmol) acetic acid in dry 1 ,2-dimethoxyethane (100 ml) was added dropwise in 1/2 hr. The mixture was refluxed for 1 hr. After cooling of the reaction mixture in ice, subsequent dropwise addition was carried out of: 1 ). a mixture of water (9.5ml) and 1 ,2-dimethoxyethane (100ml), 2). water (90ml) and 3). a solution of sodiumhydroxide in water (2N, 15 ml). The reaction mixture was refluxed for 2 hrs. The precipitate obtained after cooling to room temperature was removed by filtration. To the filtrate water (300 ml) and ethylacetate (50 ml) were added, the water layer was further extracted with ethylacetate (two times 150 mi) and the combined organic layers were washed with water ( three times 70 ml), dried over sodium sulphate and concentrated in vacuo. The residual yellow oil was dissolved in absolute ethanol (200 ml), heated to 70°C and a solution of 1.83 g hydrochloride (50 mmol) in absolute ethanol (15 ml) was added. After stirring for 1/2 hr at 70°C .subsequent cooling and stirring at room temperature for 2 hrs, the resulting precipitate was collected by filtration, washed with absolute ethanol (two times 25 ml) and dried in vacuo. In this way 15.2 g of 3-(4-oxo-[1-(2-methylindolyl)piperidino])- benzisoxazole.hydrochloride was obtained as a white solid (79% yield) with a melting point of 225°C.
In an analogous manner the compounds having formula (I) listed below have been prepared: Table
Figure imgf000010_0001

Claims

Claims:
1. A compound of formula (I) or a salt thereof
Figure imgf000011_0001
wherein
- (R - represents 0, 1 or 2 substituents, which can be the same or different, from the group C^-alkyl or alkoxy, halogen, trifluoromethyl, nitro, amino mono- or dialkyl (C,.2)-amino, sulfonyl-(C1.3)alkyl or -alkoxy, sulfonyl trifluoromethyl, sulfonyl amino, and sulfonyl mono- or dialkyl (C,_2)-amino,
- X is O, S, NH or NCH3,
- Y represents CH2 or (CH2)2 - (R2)m represents 0, 1 , or 2 substituents, which can be the same or different, from the group methyl and ethyl, or (R2)m is a methylene bridge or ethylene bridge,
- A is a group -CH2-(CRH)p- wherein R is hydrogen or methyl and p is 0 or 1 , and - B represents 2- or 3-indolyl or 2-benzimidazolyl, which groups may be substituted at carbon with 1 or 2 substituents from the group C-Lg-alkyl or alkoxy, halogen, trifluoromethyl, nitro, amino, mono- or dialkyl (C^amino, sulfonyKC^alkyl or -alkoxy, sulfonyl trifluoromethyl, sulfonyl amino, and sulfonyl mono- or dialkyl (C.,.2)-amino.
2. A compound as claimed in claim 1 , wherein A is CH2, Y is CH2, X is O, NH or NCH3, m and n are 0, and B has the meanings given in claim 1.
3. Pharmaceutical compositions containing at least one compound as claimed in 1 as an active component.
4. A method of preparing pharmaceutical compositions characterized in that a composition as claimed in 3 is prepared by bringing a compound as claimed in claim 1 in a form suitable for administration.
5. A method for the preparation of benzisoxazole derivatives, characterized in that a compound claimed in claim 1 is prepared by reaction of a compound of the formula (IV)
Figure imgf000012_0001
a) with an optionally substituted 2- or 3-indolyi carboxylic acid derivative of the formula B-A'-COOH, wherein A' has the meaning (CRH)P wherein R is hydrogen or methyl, and p is 0 or 1 , followed by reduction of the keto group in the obtained compound of the formula (V):
Figure imgf000012_0002
or b) with an optionally substituted 2-halomethyl benzimidazole derivative of the formula B-A-Z, wherein B is the 2-benzimidazolyl group, A has the meaning given in claim 1 , and Z is chloro or bromo.
6. A method of treating psychiatric disorders such as psychosis, anxiety, depression, attention deficits and memory disorders, neurological disorders such as Parkinson's disease and ischaemia and other CNS-diseases involving dopaminergic neurotransmission, characterized in that a compound as claimed in claim 1 is used.
PCT/EP1999/000852 1998-02-09 1999-02-05 Benzisoxazole derivatives having d4-antagonistic activity Ceased WO1999040067A2 (en)

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DK99914450T DK1054885T3 (en) 1998-02-09 1999-02-05 Benzisoxazole derivatives with D4 antagonistic effect
US09/601,795 US6335326B1 (en) 1998-02-09 1999-02-05 Benzisoxazole derivatives having d4-antagonistic activity
AU33273/99A AU3327399A (en) 1998-02-09 1999-02-05 Benzisoxazole derivatives having d4-antagonistic activity
DE69936572T DE69936572T2 (en) 1998-02-09 1999-02-05 Benzoxazole derivatives with D4-antagonistic activity
CA002320120A CA2320120C (en) 1998-02-09 1999-02-05 Benzisoxazole derivatives having d4-antagonistic activity
JP2000530498A JP4627882B2 (en) 1998-02-09 1999-02-05 Benzisoxazole derivatives having D4-antagonist activity
EP99914450A EP1054885B1 (en) 1998-02-09 1999-02-05 Benzisoxazole derivatives having d4-antagonistic activity

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Cited By (7)

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WO1999040067A3 (en) * 1998-02-09 1999-11-25 Duphar Int Res Benzisoxazole derivatives having d4-antagonistic activity
WO2001019833A1 (en) * 1999-09-14 2001-03-22 Aventis Pharmaceuticals, Inc. Thienoisoxazolyl- and thienylpyrrazolyl-phenoxy substituted propyl derivatives useful as d4 antagonists
WO2001019821A1 (en) * 1999-09-14 2001-03-22 Aventis Pharmaceuticals Inc. Benzisoxazolyl-, pyridoisoxazolyl- and benzthienyl-phenoxy derivatives useful as d4 antagonists
JP2003509431A (en) * 1999-09-14 2003-03-11 アベンティス・ファーマスーティカルズ・インコーポレイテツド Thienoisoxazolephenoxy unsubstituted ethyl and propyl derivatives useful as D4 antagonists
US7091199B1 (en) 1999-09-14 2006-08-15 Aventis Pharmaceuticals Inc. Thienoisoxazole phenoxy unsubstituted ethyl and propyl derivatives useful as d4 antagonists
US7125903B1 (en) 1999-09-14 2006-10-24 Aventis Pharmaceuticals Inc. Thienoisoxazolyl-and thienylpyrrazolyl-phenoxy substituted propyl derivatives useful as D4 antagonists
US7253165B2 (en) 1999-09-14 2007-08-07 Aventis Pharmaceuticals Inc. Benzisoxazolyl-, pyridoisoxazolyl-and benzthienyl-phenoxy derivatives useful as D4 antagonists

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US6747029B2 (en) 2001-03-12 2004-06-08 The Mclean Hospital Corporation Dopamine D4 receptor antagonists as treatment for attention deficit-hyperactivity disorder
EP1856114B1 (en) * 2005-02-25 2014-08-20 Pfizer Inc. Benzisoxazole derivatives
JP5502733B2 (en) * 2007-07-26 2014-05-28 エフ．ホフマン−ラ ロシュ アーゲー Dual modulators of 5-HT2A and D3 receptors
US8877778B2 (en) 2010-12-15 2014-11-04 Hoffmann-La Roche Inc. Benzofurane compounds
US8921397B2 (en) 2011-05-04 2014-12-30 Hoffmann-La Roche Inc. Benzofurane-piperidine compounds

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999040067A3 (en) * 1998-02-09 1999-11-25 Duphar Int Res Benzisoxazole derivatives having d4-antagonistic activity
US6335326B1 (en) 1998-02-09 2002-01-01 Duphar International Research B.V. Benzisoxazole derivatives having d4-antagonistic activity
WO2001019833A1 (en) * 1999-09-14 2001-03-22 Aventis Pharmaceuticals, Inc. Thienoisoxazolyl- and thienylpyrrazolyl-phenoxy substituted propyl derivatives useful as d4 antagonists
WO2001019821A1 (en) * 1999-09-14 2001-03-22 Aventis Pharmaceuticals Inc. Benzisoxazolyl-, pyridoisoxazolyl- and benzthienyl-phenoxy derivatives useful as d4 antagonists
JP2003509431A (en) * 1999-09-14 2003-03-11 アベンティス・ファーマスーティカルズ・インコーポレイテツド Thienoisoxazolephenoxy unsubstituted ethyl and propyl derivatives useful as D4 antagonists
JP2003509432A (en) * 1999-09-14 2003-03-11 アベンティス・ファーマスーティカルズ・インコーポレイテツド Thienoisoxazolyl- and thienylpyrazolyl-phenoxy-substituted propyl derivatives useful as D4 antagonists
US7091199B1 (en) 1999-09-14 2006-08-15 Aventis Pharmaceuticals Inc. Thienoisoxazole phenoxy unsubstituted ethyl and propyl derivatives useful as d4 antagonists
US7125903B1 (en) 1999-09-14 2006-10-24 Aventis Pharmaceuticals Inc. Thienoisoxazolyl-and thienylpyrrazolyl-phenoxy substituted propyl derivatives useful as D4 antagonists
US7253165B2 (en) 1999-09-14 2007-08-07 Aventis Pharmaceuticals Inc. Benzisoxazolyl-, pyridoisoxazolyl-and benzthienyl-phenoxy derivatives useful as D4 antagonists
JP4847662B2 (en) * 1999-09-14 2011-12-28 アベンティスユービー・セカンド・インコーポレイテッド Thienoisoxazolyl- and thienylpyrazolyl-phenoxy-substituted propyl derivatives useful as D4 antagonists

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CA2320120A1 (en) 1999-08-12
DE69936572D1 (en) 2007-08-30
DE69936572T2 (en) 2008-06-19
JP4627882B2 (en) 2011-02-09
JP2002502842A (en) 2002-01-29
DK1054885T3 (en) 2007-10-15
AU3327399A (en) 1999-08-23
WO1999040067A3 (en) 1999-11-25
ATE367389T1 (en) 2007-08-15
EP1054885B1 (en) 2007-07-18
PT1054885E (en) 2007-10-03
CA2320120C (en) 2009-08-11
EP1054885A2 (en) 2000-11-29
ES2291023T3 (en) 2008-02-16
US6335326B1 (en) 2002-01-01

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