WO1993012790A1 - Use of arylindole derivatives for the treatment of psychoses - Google Patents

Use of arylindole derivatives for the treatment of psychoses Download PDF

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Publication number
WO1993012790A1
WO1993012790A1 PCT/DK1992/000390 DK9200390W WO9312790A1 WO 1993012790 A1 WO1993012790 A1 WO 1993012790A1 DK 9200390 W DK9200390 W DK 9200390W WO 9312790 A1 WO9312790 A1 WO 9312790A1
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WO
WIPO (PCT)
Prior art keywords
alkyl
hydrogen
substituted
alkenyl
hydroxy groups
Prior art date
Application number
PCT/DK1992/000390
Other languages
English (en)
French (fr)
Inventor
Jens Kristian Perregaard
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 EP93902096A priority Critical patent/EP0618799A1/en
Priority to AU33452/93A priority patent/AU668537B2/en
Priority to SK757-94A priority patent/SK75794A3/sk
Priority to JP5511365A priority patent/JPH07502517A/ja
Publication of WO1993012790A1 publication Critical patent/WO1993012790A1/en
Priority to NO942378A priority patent/NO942378L/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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • 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

Definitions

  • the present invention relates to the use of certain 6- and/or 2-substituted 1- arylindole derivatives or salts or prodrugs thereof for the manufacture of a pharma ⁇ ceutical 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 haloperidol, cis(Z)-flupentixol and 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 cholinergic, serotonergic and
  • VTA ventral tegmental area
  • SNC substantia nigra pars compacta
  • 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-HT2 antagonistic activity, and many of them additionally having potent DA D 2 - antagon ⁇ stic activity in vivo .
  • one of the compounds known from said patent i.e.
  • EP-A2-0465398 discloses a class of 6-substituted and/or 2-aIkyl substituted indole and 2,3-dihydroindole derivatives having the general Formula I
  • Ar is phenyl, phenyl substituted with one or more substituents selected from halogen, lower alkyl, lower alkoxy, hydroxy, trifluoromethyl, and cyano, or a hetero aromatic group selected from 2-thienyl, 3-thienyl, 2-furanyl, 3-furanyl, 2-oxazolyl, 2- imidazolyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl;
  • X is hydrogen, halogen, lower alkyl, lower alkoxy, hydroxy, lower alkylthio, lower alkylsulfonyl, lower alkyl- or dialkylamino, cyano, trifluoromethyl, or trifluoromethyl ⁇ thio;
  • X ' is a substituent taken from the X-substituents above; or X and X ' are linked to constitute a 5-7 membered carbocyclic ring;
  • R1 is hydrogen, lower alkyl or lower alkyl substituted with one or two hydroxy groups, provided that when X is hydrogen or fluoro, then R1 is not hydrogen;
  • Y is nitrogen or carbon, provided that when the dotted line emanating from Y indi ⁇ cates a bond, then Y is carbon;
  • R is hydrogen, or lower alkyl, lower alkenyl, cycloalkyl, or cycloalkylmethyl, each optionally substituted with one or two hydroxy groups, any hydroxy group present being optionally esterified with an aliphatic carboxylic acid having from two to twen- tyfour carbon atoms inclusive, or R is a substituent of the formula 1a or 1b :
  • V is selected from oxygen, sulfur, CH 2 , and NR2 , wherein R2 is hydrogen, lower alkyl, lower alkenyl, a cycloalkyl group, a cycloalkylmethyl group, lower alkyl substi- tuted with one or two hydroxy groups, and lower alkenyl substituted with one or two hydroxy groups;
  • VI is -0-R4 -S-R4, -CHR4R5 or -NR4R5;
  • R3 is hydrogen, lower alkyl, lower alkenyl, a cycloalkyl group, a cycloalkylmethyl group, lower alkyl substituted with one or two hydroxy groups, and lower alkenyl substituted with one or two hydroxy groups;
  • R4 and R 5 are independently selected from the R3-substituents.
  • TfUT SHEET So in view of the fact that it is known that affinities of antipsychotic drugs for 5-HT receptors do not correlate to effects on positive symptoms of schizophrenia (Perout- ka, S.J. and Snyder.S.H.: Relationship of neuroleptic drug effects at brain dopa ⁇ mine, serotonin, alpha-adrenergic, and histamine receptors to clinical potency, Am. J. Psychiatry, 1980, 137, 1518-1522), they were believed to be without antipsy ⁇ chotic effects.
  • 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 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.
  • the term lower alkeny refers to such groups having from two to four carbon atoms inclusive.
  • Cycloalkyl is such a group comprising 3-8 carbonatoms, and halogen means fluoro, chloro, bromo or iodo.
  • the psychoses to be treated are psychosis in connection with schizophrenia (posi ⁇ tive symptoms of schizophrenia) and other psychoses and related deseases 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 both 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: 6-chloro-1-(4-fluorophenyl)-3-[1 -[2-(2-imidazolidinon-1 -yl)ethyl]-4-piperidylJ-1 H- indole, Comp. 1 , and
  • the compounds used in the pre ⁇ sent invention do not show acute antidopaminergic activity in vivo and as shown in the 3H-spiperone binding test they have substantially no affinity for dopamine recep- tors in vitro. Accordingly, they were believed to be without antipsychotic effecs.
  • 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 neu ⁇ rones in the SNC area. Since inhibiting effect in the SNC area is indicative of neuro-
  • the compositions of the invention have the further advantage of alleviating or relieving the negative symptoms of schizophrenia and/or improving 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 accor- ding to our prior EP-A2-0465338, and specific compounds of Formula I are disclo ⁇ sed therein.
  • the pharmaceutically acceptable acid addition salts of the compounds may be for ⁇ med 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 concen ⁇ tration 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 separating 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, mandel- ic, 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 Shows the inhibiting effect of Compound No 1 of the invention on the firing of neurones in the VTA and the SNC areas of the brain, respectively.
  • Fig. 2 Shows the inhibiting effect of Compound No 2 of the invention on the firing of neurones in the VTA and the SNC areas of the brain, respectively.
  • Fig. 3 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.
  • Fig. 4 Shows the inhibiting effect of the reference compound clozapine on the fir- ⁇ ng 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 accounts for the develop ⁇ ment of neurological side effects.
  • Rats weighing 250 g at the start of the experiment are used. After 21 days of oral treatment with of test compound, the rats are anaesthetized and mounted in a ste- reotaxic instrument. Several groups of rats treated with different doses of the test compound are used. A hole (3 x 3 mm) is drilled in the skull. Recording of DA neu ⁇ rone activity is performed with a single barrel glass electrode. Eight electrode pene ⁇ trations are made through VTA and SNC, respectively. Data from the experiments
  • SUBSTiTUT£ & di ⁇ Xr consist of neurone counts which may be regarded as approximately Poisson distri ⁇ ubbed. The data are expressed as percent active DA neurones of the number of active neurones in non-treated animals. Results are shown in Figs. 1-2 .
  • Comp. 3 inhibited the firing in VTA by 19% and in SNC by 9% at a dose of 2.2 ⁇ mol/kg and by 22% in the VTA and by 3% in the SNC at a dose of 4.4 ⁇ mol/kg.
  • the indole and 2,3-dihydroindole derivatives used according to the invention in general potently bind to 5-HT 2 recep- tors with nanomolar affinities (3H-ketanserin binding test), whereas they have sub ⁇ stantially no affinity to the DA D 2 receptors ( 3 H-spiperone binding test).
  • the quipa- zine-inhibition test showed that the present indole compounds have potent central 5-HT 2 antagonism in vivo with good oral bioavailability and long duration of action.
  • any other pharmaceutical tableting adjuvants may be used provided that they are compatible with the active ingredient, and additional compositions and dosage forms may be similar to those presently used for neuroleptics, such as clopenthixol, flupentixol orfluphenazine.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Psychiatry (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Indole Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
PCT/DK1992/000390 1991-12-23 1992-12-21 Use of arylindole derivatives for the treatment of psychoses WO1993012790A1 (en)

Priority Applications (5)

Application Number Priority Date Filing Date Title
EP93902096A EP0618799A1 (en) 1991-12-23 1992-12-21 Use of arylindole derivatives for the treatment of psychoses
AU33452/93A AU668537B2 (en) 1991-12-23 1992-12-21 Use of arylindole derivatives for the treatment of psychoses
SK757-94A SK75794A3 (en) 1991-12-23 1992-12-21 Arylindole derivatives
JP5511365A JPH07502517A (ja) 1991-12-23 1992-12-21 精神病の治療のためのアリールインドールの使用
NO942378A NO942378L (no) 1991-12-23 1994-06-22 Anvendelse av arylindolderivater for behandling av psykoser

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DK912065A DK206591D0 (da) 1991-12-23 1991-12-23 Behandling af psykoser
DK2065/91 1991-12-23

Publications (1)

Publication Number Publication Date
WO1993012790A1 true WO1993012790A1 (en) 1993-07-08

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ID=8109829

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Application Number Title Priority Date Filing Date
PCT/DK1992/000390 WO1993012790A1 (en) 1991-12-23 1992-12-21 Use of arylindole derivatives for the treatment of psychoses

Country Status (11)

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EP (1) EP0618799A1 (enrdf_load_stackoverflow)
JP (1) JPH07502517A (enrdf_load_stackoverflow)
AU (1) AU668537B2 (enrdf_load_stackoverflow)
CA (1) CA2126571A1 (enrdf_load_stackoverflow)
CZ (1) CZ153994A3 (enrdf_load_stackoverflow)
DK (1) DK206591D0 (enrdf_load_stackoverflow)
NO (1) NO942378L (enrdf_load_stackoverflow)
RU (1) RU94031165A (enrdf_load_stackoverflow)
SK (1) SK75794A3 (enrdf_load_stackoverflow)
WO (1) WO1993012790A1 (enrdf_load_stackoverflow)
ZA (1) ZA9210001B (enrdf_load_stackoverflow)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5554030A (en) * 1994-06-30 1996-09-10 Minnesota Mining And Manufacturing Company Method for bonding non-amalgam restorative materials to dental surfaces
EP0932407A4 (en) * 1996-03-25 2002-04-24 Lilly Co Eli TECHNIQUE FOR TREATING MIGRAINE PAIN

Citations (4)

* 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 (en) * 1989-04-11 1990-10-17 H. Lundbeck A/S Use of sertindole for the treatment of schizophrenia
EP0465398A2 (en) * 1990-07-02 1992-01-08 H. Lundbeck A/S Novel indole derivatives
WO1992006089A1 (en) * 1990-10-03 1992-04-16 H. Lundbeck A/S Sertindole prodrugs

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DK8492D0 (da) * 1992-01-23 1992-01-23 Lundbeck & Co As H Behandling af psykoser

Patent Citations (4)

* 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 (en) * 1989-04-11 1990-10-17 H. Lundbeck A/S Use of sertindole for the treatment of schizophrenia
EP0465398A2 (en) * 1990-07-02 1992-01-08 H. Lundbeck A/S Novel indole derivatives
WO1992006089A1 (en) * 1990-10-03 1992-04-16 H. Lundbeck A/S Sertindole prodrugs

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5554030A (en) * 1994-06-30 1996-09-10 Minnesota Mining And Manufacturing Company Method for bonding non-amalgam restorative materials to dental surfaces
EP0932407A4 (en) * 1996-03-25 2002-04-24 Lilly Co Eli TECHNIQUE FOR TREATING MIGRAINE PAIN

Also Published As

Publication number Publication date
CZ153994A3 (en) 1995-06-14
RU94031165A (ru) 1996-06-20
CA2126571A1 (en) 1993-07-08
AU668537B2 (en) 1996-05-09
DK206591D0 (da) 1991-12-23
NO942378L (no) 1994-06-22
SK75794A3 (en) 1995-04-12
ZA9210001B (en) 1994-01-13
AU3345293A (en) 1993-07-28
NO942378D0 (enrdf_load_stackoverflow) 1994-06-22
JPH07502517A (ja) 1995-03-16
EP0618799A1 (en) 1994-10-12

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