WO1993014758A1 - Utilisation de derives de 3-arylindole et de 3-arylindazole dans le traitement de psychoses - Google Patents

Utilisation de derives de 3-arylindole et de 3-arylindazole dans le traitement de psychoses Download PDF

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Publication number
WO1993014758A1
WO1993014758A1 PCT/DK1993/000021 DK9300021W WO9314758A1 WO 1993014758 A1 WO1993014758 A1 WO 1993014758A1 DK 9300021 W DK9300021 W DK 9300021W WO 9314758 A1 WO9314758 A1 WO 9314758A1
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WO
WIPO (PCT)
Prior art keywords
alkyl
cycloalkyl
trifluoromethyl
optionally substituted
halogen
Prior art date
Application number
PCT/DK1993/000021
Other languages
English (en)
Inventor
Kim Andersen
Torben Skarsfeldt
Original Assignee
H. Lundbeck A/S
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by H. Lundbeck A/S filed Critical H. Lundbeck A/S
Priority to EP93903188A priority Critical patent/EP0621781A1/fr
Priority to AU34494/93A priority patent/AU670063B2/en
Priority to SK863-94A priority patent/SK86394A3/sk
Priority to JP5512865A priority patent/JPH07503240A/ja
Publication of WO1993014758A1 publication Critical patent/WO1993014758A1/fr
Priority to NO942686A priority patent/NO942686D0/no

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives

Definitions

  • the present invention relates to the use of a certain class of 3-arylindole and 3- arylindazoie derivatives or salts thereof for the manufacture of a pharmaceutical preparation for the treatment of psychoses.
  • DA receptor blocking drugs Damping of dopamine (DA) overactivity by the use of DA receptor blocking drugs is today the most important principle in the treatment of schizophrenia, more particu ⁇ larly the positive symptoms thereof.
  • "Classical neuroleptics" such as haioperidol, cis(Z)-flupentixol or chlorpromazine are believed to induce antipsychotic effect via DA receptor blockade.
  • Pharmacologically, such compounds antagonize stereoty- pies induced by dopaminergic compounds (i.e. methylphenidate, apomorphine, amphetamine) in mice or rats and they inhibit pergolide-induced circling behavior in rats with unilateral 6-OHDA lesions.
  • EPS extrapy- ramidal side effects
  • Clozapine is such a drug. Clozapine is an effective antipsychotic in man but, due to the risk of drug induced agranulocytosis, regular monitoring of blood parameters is required, and its use is therefore costly and restricted. Pharmacologically, clozapine induces no catalepsy in rats, neither does it inhibit stereotypies induced by dopaminergic compounds in rodents. Clozapine blocks central cholinerg ⁇ c, serotonergic and noradrenergic receptors in animal studies.
  • Clozapine has been shown to be active only in the VTA (Bunney and Grace, Life Science, 1978, 25, 1715-1725, White and Wang, Science, 1983, 221, 1054-1057, Chiodo and Bunney, J.Neuroscience, 1985, 5, 2539-2544, Skarsfeldt, Life Science, 1988, 42, 1037-1044).
  • U.S. Patent No. 4,710,500 corresponding to European Patent No. 0200322, discloses a class of optionally 5-substituted 1-aryl-3-piperidinyl, 1-aryl-3-(1 ,2,3,6- tetrahydropyridinyl)- or 1-aryl-3-piperazinylindole derivatives having potent 5-HT 2 antagonistic activity, and many of them additionally having potent DA Da- antagonistic activity in vivo .
  • one of the compounds known from said patent i.e.
  • EP-A2-0 470 039 discloses a class of 3-arylindole or 3-aryiindazole derivatives having the general Formula I
  • Ar is phenyl optionally substituted with one or more substituents selected from halogen, lower alkyl, lower alkoxy, hydroxy, trifluoromethyl, and cyano, or Ar is 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl;
  • R1-R4 are independently selected from hydrogen, halogen, lower alkyl, lower alkoxy, hydroxy, nitro, lower alkylthio, lower alkylsulphonyl, lower alkylamino, di- lower-alkylamino, cyano, trifluoromethyl, and trifluoromethylthio;
  • the dotted lines designate optional double bonds; when the dotted line emanating from X indicates a double bond, X is N or a group CR6 wherein R6 is hydrogen, halogen, trifluoromethyl or lower alkyl; and when the dotted line indicates no double bond, X is CH ;
  • Y when the dotted line emanating from the Y do not indicate a double bond, Y is N or CH; and when it indicates a double bond, then Y is C;
  • R5 is hydrogen, or cycloalkyl, cycloalkylalkyl, lower alkyl or lower alkenyl, optionally o substituted with one or two hydroxy groups, or R5 is a group taken from structures 1a and 1b :
  • n is an integer from 2 - 6, inclusive; 5 is O or S; U is N or CH ;
  • V is O, S, CH 2 , or NR7, wherein R? is hydrogen, lower alkyl, lower alkenyl, cycio- alkyl or cycloalkylalkyl optionally substituted with one or two hydroxy groups;
  • W- is O, S, CH 2 or a group NR ⁇ , wherein R ⁇ is H, lower alkyl, lower alkenyl, cycloalkyl or cycloalkylalkyl optionally substituted with one or two hydroxy groups; and
  • VI is NR9R10, OR11, SR12 or CR13R R15, where each of R9-R15 may be indepen- dently selected among the R ⁇ -substituents; provided that R5 may not be methyl when R1-R4 each are hydrogen, X and Y are CH and Ar is phenyl.
  • the compounds having the above general Formula I were disclosed as highly potent 5-HT 2 antagonists having a long duration of action in pharmacological tests and accordingly, as useful in the treatment of anxiety, depres ⁇ sion, sleep disturbances, migraine, negative symptoms of schizophrenia, and Parkinson ' s disease. Furthermore, they were found to be substantially without affinity for DA D 2 receptors in vitro and to be substantially inactive with respect to acute dopamine antagonistic effect in vivo.
  • the tests used were: a) Inhibition of 3H-ketanserin binding to 5-HT 2 receptors in rat cortex in vitro, which is a test for affinity of drugs for 5-HT 2 receptors in vitro.
  • the present invention provides the use of a compound having the above defined general Formula I or a pharmaceutically acceptable acid addition salt thereof, for the manufacture of a pharmaceutical composition for the treatment of psychosis in humans.
  • lower alkyl, lower alkoxy, lower alkylthio and lower alkylsulfonyl designate such o straight chained or branched groups having from one to four carbon atoms inclu ⁇ sive.
  • exemplary of such groups are methyl, ethyl, 1-propyl, 2-propyl, 1 -butyl, 2- butyl, 2-methyl-2-propyl, 2-methyl-1-propyl, methoxy, ethoxy.l-propoxy, 2-propoxy, methylthio, ethylthio, 1-propylthio, 2-propylthio, methylsulfonyl, ethylsulphonyl, or the like. 5
  • Lower alkenyl is intended to mean an alkenyl group containing from 2 to 4 carbon atoms, for example ethenyl, 1-propenyl, 2-butenyl, etc.
  • Cycloalkyl is such a group comprising 3-8 carbon atoms
  • cycloalkylalkyl is cycio- 0 aikyl-lower-alkyl
  • halogen means fluoro, chloro, bromo or iodo.
  • the Z groups -COCH 2 - and -CSCH 2 - may be incorporated in the ring of the structure 1a in both directions.
  • the psychoses to be treated are psychosis in connection with schizophrenia (positive symptoms of schizophrenia) and other psychoses and related disorders, such as mania etc.
  • An effective daily dose of the compound of the invention, or a pharmaceutically acceptable salt thereof is from 0.01 to 10.0 mg/kg.
  • the daily dose is administered in one or more subdoses and, accordingly, a unit dose of the compound or of the salt thereof is from 0.10 to 200 mg.
  • compositions of the invention may exist in forms to be administered orally or parenterally, for example in the form of tablets, capsules, powders, syrups or solutions for injection.
  • Preferred compounds used according to the invention are:
  • the compounds used in the pre- sent invention do not show acute antidopaminergic activity in vivo and as shown in the 3 H-spiperone binding test they have substantially no affinity for dopamine recep ⁇ tors in vitro. Accordingly, they were believed to be without antipsychotic effects. However, they have now unexpectedly been found to inhibit the firing of spontane ⁇ ously active DA neurones in the VTA of the brain upon repeated treatment as mea ⁇ sured electrophysiologically, and thus to have antipsychotic potential.
  • the compounds have been found selectively and partially to inhibit the firing of the DA neurones in the VTA substantially without inhibiting the firing of the DA neurones in the SNC area. Since inhibiting effect in the SNC area is indicative of neurological side effects these compounds are believed to be substantially without such side effects. So, they have been demonstrated to be very promising drugs for the treatment of psychoses (i.e. positive symptoms of schizophrenia and psychosis of other genesis).
  • the compositions of the invention have the further advan ⁇ tage of alleviating or relieving the negative symptoms of schizophrenia and/or impro ⁇ ving the quality of sleep in a schizophrenic patient. Such effects are highly desired in connection with antipsychotic treatment.
  • the compounds of the general Formula I may be synthesized by methods accord ⁇ ing to our prior EP Patent publication EP-A2-0 470 039.
  • the pharmaceutically acceptable acid addition salts of the compounds may be formed by reaction with non-toxic organic or inorganic acids in an aqueous miscible solvent, such as acetone or ethanol, and subsequent isolation of the salt by concentration and cooling or by reaction with an excess of the acid in aqueous immiscible solvent, such as ethyl ether or chloroform, with the desired salt separat ⁇ ing directly.
  • an aqueous miscible solvent such as acetone or ethanol
  • organic salts are those with maleic, fumaric, benzoic, ascorbic, embonic, succinic, oxalic, bis methylene-salicylic, methanesulfonic, ethane- disulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-amino-benzoic, glutamic, benzene sulfonic and theophylline acetic acids as well as the 8- halotheophyllines, for example 8-bromo-theophylline.
  • inorganic salts are those with hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids.
  • these salts may also be prepared by the classical method of double decomposition of appropriate salts, which is well known to the art.
  • Fig. 1 - 4 Show the inhibiting effect of Compounds Nos 1 - 4, respectively, of the invention on the firing of neurones in the VTA and the SNC areas of the brain, respectively.
  • Compounds 1 was given as the oxaiate salt and Comp. 4 as the hydro- chloride salt.
  • Fig. 5 Shows the inhibiting effect of the reference compound clozapine on the firing of neurones in the VTA and the SNC areas of the brain, respectively.
  • Fig. 6 Shows the inhibiting effect of the reference compound haloperidol on the firing of neurones in the VTA and the SNC areas of the brain, respectively.
  • This test model is used to examine the effects on spontaneously active DA neuro ⁇ nes in VTA and SNC upon repeated oral treatment. Inhibition of the number of active DA neurones in VTA indicates an antipsychotic effect of a compound, while inhibition of the number of active DA neurones in SNC is believed to account for the development of neurological side effects.
  • Rats weighing 250 g at the start of the experiment are used. After 21 days of oral treatment with test compound, the rats are anaesthetized and mounted in a stereotaxic instrument. Several groups of rats treated with different doses of test compound are used. A hole (3 x 3 mm) is drilled in the skull. Recording of DA neurone activity is performed with a single barrel glass electrode. Eight electrode penetrations are made through VTA and SNC, respectively. Data from the experi ⁇ ments consist of neurone counts which may be regarded as approximately Poisson distributed. The data are expressed as percent active DA neurones of the numbe of active neurones in non-treated animals. Results are shown in Figs. 1-4 .
  • the 3 arylindole or 3-arylindazoie derivatives used according to the present inventio potently bind to 5-HT 2 receptors with affinities in the nanomolar range (3H ketanserin binding test), whereas they were found to have very low affinity for th DA D-2 receptors (3H-spiperone binding test).
  • the compounds were found to hav potent central 5-HT 2 antagonism in vivo with good oral bioavailability and lon duration of action (quipazine-inhibition test).
  • th compounds have substantially no central antidopaminergic activity in vivo a measured by the inhibition of pergolide-induced rotations in rats with unilateral 6 OHDA lesions, which test is a extremely sensitive test for DA D-2 antagonisti activity in vivo ( Arnt, J. and J. Hyttel, J. Neural. Transm., 1986, 67, 225-240).
  • compositions and dosage forms may be similar to those presently used for neuroleptics, such as clopenthixol, flupentixol or fluphenazine.

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  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Organic Chemistry (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Anesthesiology (AREA)
  • Psychiatry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Indole Compounds (AREA)

Abstract

Dérivés de 3-arylindole ou de 3-arylindazole répondant à la formule générale (I) dans laquelle Ar représente un groupe phényle éventuellement substitué ou un groupe hétéro aromatique; R1-R4 représentent hydrogène, halogène, alkyle, alcoxy, hydroxy, alkylthio, alkylsulfonyle, alkyl- ou dialkylamino, cyano, trifluorométhyle ou trifluorométhylthio; X représente N, CR6, R6 représentant halogène, trifluorométhyle ou alkyle, ou CH¿2?; Y représente N, CH ou C; R?5¿ représente H, alkyle, alcényle, cycloalkyle, ou cycloalkylalkyl, ou R5 représente un substituant de la formule 1a ou 1b dans lesquelles n vaut 2 - 6; W représente O ou S; U représente N ou CH; Z représente -(CH¿2?)m-, -CH=CH-, phénylène, -COCH2- ou -CSCH2-; V représente O, S, CH2 ou NR?7, R7¿ représentant H, alkyle, alcényle, cycloalkyle ou cycloalkylalkyle; U1 représente O, S, CH¿2? ou NR?8; et V1¿ représente NR?9R10, OR11, SR12 ou CR13R14R15, R8-R15¿ représentant chacun les mêmes éléments que R7. Ces dérivés inhibent l'activation de neurones de dopamine à activité spontanée dans la région de la calotte ventrale du cerveau, et permettent ainsi de traiter des psychoses chez les humains.
PCT/DK1993/000021 1992-01-23 1993-01-22 Utilisation de derives de 3-arylindole et de 3-arylindazole dans le traitement de psychoses WO1993014758A1 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
EP93903188A EP0621781A1 (fr) 1992-01-23 1993-01-22 Utilisation de derives de 3-arylindole et de 3-arylindazole dans le traitement de psychoses
AU34494/93A AU670063B2 (en) 1992-01-23 1993-01-22 Use of 3-arylindole and 3-arylindazole derivatives for the treatment of psychoses
SK863-94A SK86394A3 (en) 1992-01-23 1993-01-22 3-arylindole and 3-arylindazole derivatives and their use
JP5512865A JPH07503240A (ja) 1992-01-23 1993-01-22 ３‐アリールインドールおよび１‐アリールインダゾール誘導体の精神病の治療のための使用
NO942686A NO942686D0 (no) 1992-01-23 1994-07-18 Anvendelse av 3-arylindol- og 3-arylindazolderivater ved behandling av psykoser

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DK0084/92 1992-01-23
DK9284A DK8492D0 (da) 1992-01-23 1992-01-23 Behandling af psykoser

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WO1993014758A1 true WO1993014758A1 (fr) 1993-08-05

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EP (1) EP0621781A1 (fr)
JP (1) JPH07503240A (fr)
AU (1) AU670063B2 (fr)
CA (1) CA2128699A1 (fr)
CZ (1) CZ176494A3 (fr)
DK (1) DK8492D0 (fr)
NO (1) NO942686D0 (fr)
RU (1) RU94035658A (fr)
SK (1) SK86394A3 (fr)
WO (1) WO1993014758A1 (fr)
ZA (1) ZA93491B (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6258825B1 (en) 1997-05-30 2001-07-10 Banyu Pharmaceutical Co., Ltd. 2-oxoimidazole derivatives
US7973069B2 (en) 2004-07-14 2011-07-05 Ptc Therapeutics, Inc. Methods for treating hepatitis C

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DK206591D0 (da) * 1991-12-23 1991-12-23 Lundbeck & Co As H Behandling af psykoser

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4710500A (en) * 1985-04-10 1987-12-01 H. Lundbeck A/S 1-(4'-fluorophenyl)-3,5-substituted indoles useful in the treatment of psychic disorders and pharmaceutical compositions thereof
EP0392959A2 (fr) * 1989-04-11 1990-10-17 H. Lundbeck A/S Utilisation de sertindole pour le traitement de la schizophrénie
EP0470039A2 (fr) * 1990-07-30 1992-02-05 H. Lundbeck A/S Dérivés de 3-arylindole et 3-arylindazole

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4710500A (en) * 1985-04-10 1987-12-01 H. Lundbeck A/S 1-(4'-fluorophenyl)-3,5-substituted indoles useful in the treatment of psychic disorders and pharmaceutical compositions thereof
EP0392959A2 (fr) * 1989-04-11 1990-10-17 H. Lundbeck A/S Utilisation de sertindole pour le traitement de la schizophrénie
EP0470039A2 (fr) * 1990-07-30 1992-02-05 H. Lundbeck A/S Dérivés de 3-arylindole et 3-arylindazole

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6258825B1 (en) 1997-05-30 2001-07-10 Banyu Pharmaceutical Co., Ltd. 2-oxoimidazole derivatives
US7973069B2 (en) 2004-07-14 2011-07-05 Ptc Therapeutics, Inc. Methods for treating hepatitis C

Also Published As

Publication number Publication date
DK8492D0 (da) 1992-01-23
NO942686L (no) 1994-07-18
SK86394A3 (en) 1995-04-12
NO942686D0 (no) 1994-07-18
CZ176494A3 (en) 1995-04-12
AU670063B2 (en) 1996-07-04
EP0621781A1 (fr) 1994-11-02
CA2128699A1 (fr) 1993-08-05
JPH07503240A (ja) 1995-04-06
ZA93491B (en) 1993-08-23
AU3449493A (en) 1993-09-01
RU94035658A (ru) 1996-06-20

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