AU670063B2 - Creation of Inventions and Patents with Artificial Intelligence

AU670063B2 – Use of 3-arylindole and 3-arylindazole derivatives for the treatment of psychoses
– Google Patents

AU670063B2 – Use of 3-arylindole and 3-arylindazole derivatives for the treatment of psychoses
– Google Patents
Use of 3-arylindole and 3-arylindazole derivatives for the treatment of psychoses

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AU670063B2

AU670063B2
AU34494/93A
AU3449493A
AU670063B2
AU 670063 B2
AU670063 B2
AU 670063B2
AU 34494/93 A
AU34494/93 A
AU 34494/93A
AU 3449493 A
AU3449493 A
AU 3449493A
AU 670063 B2
AU670063 B2
AU 670063B2
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Prior art keywords
cycloalkyl
ethyl
alkyl
treatment
trifluoromethyl
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1992-01-23
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AU3449493A
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Kim Andersen
Torben Skarsfeldt
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H Lundbeck AS

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H Lundbeck AS
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1992-01-23
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1993-01-22
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1996-07-04

1993-01-22
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1993-09-01
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1996-07-04
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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

Description

OPI DATE 01/09/93 APPLN. ID AOJP DATE 28/10/93 PCT NUMBER 34494/93 111111 I 1111I PCT/DK93/00021 liltP II 1111i1111111111liii111111111ii AU9334494 (51) International Patent Classification 5 (11) International Publication Number: WO 93/14758 A61K 31/445, 31/505 Al (43) International Publication Date: 5 August 1993 (05.08,93) (21) International Application Number: PCT/DK93/00021 (81) Designated States: AT, AU, BB, BG. BR. CA. CH. CZ.
DE, Di(, ES, F1, GB. HU, JP, KP. KR. LK. LU. MIG.
(22) International Filing Date: 22 January 1993 (22.01.93) MN, MW, NL, NO, NZ, PL, PT, RO, RU, SD, SE. SK.
UA, US, European patent (AT, BE, CH, DE. DK. ES, FR, GB, GR, IE, IT. LU, MC, NL, PT, SE). OAPI pa- Priority data: tent (BF, BJ, CF, CG, CI, CM, GA, GN. ML. MR. SN.
0084/92 23 January 1992 (23.01.92) DK TD, TG).
(71) Applicant (for all designated States except US): H. LUND- Published BECK A/S [DK/DK]; Ottiliavej 9, DK-2500 Copenhag- With international search report.
en-Valby (DK).
(72) Inventors; and Inventors/Applicants (for US only) ANDERSEN, Kim [DK/DK]; Minervavej 11, DK-2610 Rodovre SKARSFELDT, Torben [DK/DK]; D, GI.Koge Landevet, DK-2660 Brondby Strand (DK).
(74) Agent: MEIDAHL PETERSEN, John; H. Lundbeck A/S, 9, Ottiliavej, DK-2500 Copenhagen-Valby (DK).
(54)Title: USE OF 3-ARYLINDOLE AND 3-ARYLINDAZOLE DERIVATIVES FOR THE TREATMENT OF PSY-
CHOSES
-(CH
2
C
I
(1a) (CH2)n-U! 1
-C-V
1 11 w (ib) ±4
CN
(57) Abstract 3-Arylindole or 3-arylindazole derivatives having general formula wherein Ar is optionally substituted phenyl or a hetero aromatic group; R’-R- 4 are hydrogen, halogen, alkyl, alkoxy, hydroxy, alkylthio, alkylsulf’onyl, alkyl- or dialkylamino, cyano, trifluoromethyl, or trifluoromethylthio; X is N, CR 6
R
6 being H, halogen, trifluoromethyl or alkyl, or Y is N, CH or C; R 5 is H, alkyl, alkenyl, cycloalkyl, or cycloalkylalkyl, or R 5 is a substituent of formula (I a) or (I wherein n is 2 6; W isO0 or S; U is N or CH; Z is -(CH 2 phenylene, .COCH 2 or -CSCH 2 V isO0, S, CH 2 or NR 7 wherein R 7 is H, alkyl, alkenyl, cycloalkyl or cycloalkylalkyl; Ul is 0, S, CH 2 or NR 8 and V1 is NR 9 R’1 0 OR1I, SR 12 or CR13RI 4 RIS, where each of R 8
-R’
5 are as defined for R 7 inhibit the firing of spontaneously active dopamine neurones in the ventral tegmental area of the brain and are thus useful for the treatment of psychoses in humans.
WO 93/14758 PCT/DK93/00021 Use of 3-arylindole and 3-arylindazole derivatives for the treatment of psychoses.
FIELD OF THE INVENTION The present invention relates to the use of a certain class of 3-arylindole and 3arylindazole derivatives or salts thereof for the manufacture of a pharmaceutical preparation for the treatment of psychoses.
BACKGROUND OF THE INVENTION 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 particularly the positive symptoms thereof. “Classical neuroleptics” such as haloperidol, is cis(Z)-flupentixol or chlorpromazine are believed to induce antipsychotic effect via DA receptor blockade. Pharmacologically, such compounds antagonize stereotypies induced by dopaminergic compounds methylphenidate, apomorphine, amphetamine) in mice or rats and they inhibit pergolide-induced circling behavior in rats with unilateral 6-OHDA lesions. Unfortunately, the incidence of severe extrapyramidal side effects (EPS) (dystonia, akathisia and parkinsonism) is very frequent in long term treatment with these neuroleptics and causes great concern among clinicians. The EPS are difficult to treat, and unsuccessful treatment often leads to poor medication compliance. Some of these neurological side effects, which generally involve involuntary movement disorders, have been correlated to the propensity of the drugs to induce catalepsy in rats (Arnt. et al., Neuropharmacology, 1981, 20,1331-1334).
A few compounds, which do not produce EPS and which are effective in the treatment of schizophrenic disorders, are termed “atypical neuroleptics”. 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 WO 93/14758 PCT/DK93/0021 2 compounds in rodents. Clozapine blocks central cholinergic, serotonergic and noradrenergic receptors in animal studies.
In recent years several reports have suggested that inhibition of the spontaneous acs tivity of DA neurones in the ventral tegmental area (VTA) in the rat brain upon repeated treatment with a drug is indicative of the antipsychotic potential of the drug, whereas inhibition of the activity in substantia nigra pars compacta (SNC) is indicative of the development of EPS. “Classical neuroleptics” are active in both areas in the same dose range while “atypical neuroleptics” mainly inactive DA neurones in the VTA. 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).
1s 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-(1,2,3,6tetrahydropyridinyl)- or 1-aryl-3-piperazinylindole derivatives having potent 5-HT 2 antagonistic activity, and many of them additionally having potent DA D 2 antagonistic activity in vivo Previously, one of the compounds known from said patent, i.e. sertindole, 5-chloro-1-(4-fluorophenyl)-3-[1-[2-(2-imidazolidinon-1-yl)ethyl]-4-piperidyl]-1H-indole, which is a 5-HT 2 antagonist substantially without DA
D
2 -antagonistic activity in vivo, was surprisingly found to inhibit the firing of DA neurones in the VTA og the brain (cf. our own EP-A1-0392959). However, said patent publication also shows that other very closely related 5-HT 2 antagonists known from U.S.Patent No. 4,710,500 do not inhibit the firing of DA neurones.
i1 Our own copending European Patent Application No. 91610058.9 published as 470 039 discloses a class of 3-arylindole or 3-arylindazole derivatives having the general Formula I r i; I i WO 93114758 PCT/DK93/00021 wherein Ar is phenyl optionally substituted with one or more substituents selected from halogen, lower alkyl, lower alkoxy, hydroxy, trifluoromethyl, and cyano, or Ar is s 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, dilower-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 2 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; Rs is hydrogen, or cycloalkyl, cycloalkylalkyl, lower alkyl or lower alkenyl, optionally substituted with one or two hydroxy groups, or Rs is a group taken from structures la and Ib z\ -(CH2)n-Ul /V
C
H
W w (CH2)n-U1-C-V 1
II
W
wherein n is an integer from 2 6, inclusive; WisOorS; c Ii WO 93/14758 PCT/DK93/00021 4 U is N or CH Z is m being 2 or 3, or Z is 1,2-phenylene optionally substituted with halogen or trifluoromethyl or Z is -CH=CH- -COCH 2 or -CSCH 2 SV is O, S, CH 2 or NR7, wherein R7 is hydrogen, lower alkyl, lower alkenyl, cyclos alkyl or cycloalkylalkyl optionally substituted with one or two hydroxy groups; U1 is O, S, CH 2 or a group NR8, wherein R8 is H, lower alkyl, lower alkenyl, cycloalkyl or cycloalkylalkyl optionally substituted with one or two hydroxy groups; and is NR9Rio, ORlI, SR12 or CR13R14R15, where each of R9-Ris may be independently selected among the R 8 -substituents; provided that Rs may not be methyl when R1-R4 each are hydrogen, X and Y are CH and Ar is phenyl.
In our EP-A2-0 470 039 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, depression, 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.
b) Quipazine antagonism which is a test for 5-HT 2 antagonistic effect in vivo based on testing of the ability of drugs to inhibit quipazine-induced head twitches in rats.
c) Inhibition of 3 H-spiperone binding to DA D 2 receptors in rat corpus striatum in vitro which is a test for affinity of drugs for DA D2 receptors in vitro.
d) Antagonism of pergolide-induced circling behavior in rats with unilateral 6-OHDA lesions which is an extremely sensitive test for acute central DA antagonistic effect in vivo.
Since it is known that affinities of antipsychotic drugs for 5-HT 2 receptors do not correlate to effects on positive symptoms of schizophrenia (Peroutka, S.J. and Snyder,S.H.: Relationship of neuroleptic drug effects at brain dopamine, serotonin, i WO 93/14758 PCT/DK93/00021 alpha-adrenergic, and histamine receptors to clinical potency, Am. J. Psychiatry, 1980 ,137, 1518-1522) they were found to be without antipsychotic effects.
SUMMARY OF THE INVENTION Surprisingly, it has now been found that the 3-arylindole or 3-arylindazole derivatives having the above general Formula I inhibits the firing of DA neurones in the VTA in rats.
Accordingly, 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 s -ei3.w ao, o~iVe. y rpva-s is The use of stereoisomers and prodrugs of the 3-arylindole or 3-arylindazole derivatives of Formula I are also embraced by this invention.
In the context of the present invention and the definition of Formula I the terms lower alkyl, lower alkoxy, lower alkylthio and lower alkylsulfonyl designate such straight chained or branched groups having from one to four carbon atoms inclusive. Exemplary of such groups are methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2butyl, 2-methyl-2-propyl, 2-methyl-l-propyl, methoxy, ethoxy,l-propoxy, 2-propoxy, methylthio, ethylthio, 1-propylthio, 2-propylthio, methylsulfonyl, ethylsulphonyl, or the like.
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 cycloalkyl-lower-alkyl, and halogen means fluoro, chloro, bromo or iodo.
The Z groups -COCH 2 and -CSCH 2 may be incorporated in the ring of the T structure la in both directions.
i i i u3 WO 93/14758 PCT/DK93/00021 6 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 S-It thereof is from 0.10 to 200 mg.
The 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.
is Preferred compounds used according to the invention are: 3-(4-Fluorophenyl)-5-methyl-1-[1 [23-(2-propyl)imidazolidin-2-on-1-yl]ethyl]-4piperidyl]- 1H-indole, Comp. 1, 3-(4-Fluorophenyl)-1 -[2-(imidazolidin-2-on-1 -yl)ethyl]-4-piperidyl]-5-methyl- 1Hindole, Comp. 2, 3-(4-Fluorophenyl)-1-[1-[2-(imidazolidin-2-on-1-yl)ethyl]-1,2,3,6-tetrahydropyridin-4yl]-5-trifluoromethyl-1H-indole, Comp. 3, and 1-[1 -[2-(1,3-Dimethyl-1 -ureido)ethyll4-piporidyl]-5-fluoro-3-(4-fluorphenyl)- 1H-indole, Comp. 4 (mp: 255-57 0 C as hydrochloride).
Further examples of compounds of Formula I used according to the invention are fj listed in our prior EP-A2-0 470 039.
As found by the test for inhibition of pergolide induced rotations in rats with unilateral 6-OHDA lesions in our prior EP-A2-0 470 039, the compounds used in the present 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 receptors in vitro. Accordingly, they were believed to be without antipsychotic effects.
i i WO 93/14758 PCT/DK93/00021 7 However, they have now unexpectedly been found to inhibit the firing of spontaneously active DA neurones in the VTA of the brain upon repeated treatment as measured electrophysiologically, and thus to have antipsychotic potential.
s In particular, 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 p:,itive symptoms of schizophrenia and psychosis of other genesis).
As mentioned above and already shown in our prior EP-A2-0 470 039 the compounds used in the present invention have potent central 5-HT 2 antagonistic activity. Since such activity is indicative of i.a. effect on negative symptoms of schizophrenia and on quality of sleep, the compositions of the invention have the further advantage of alleviating or relieving the negative sv’,ptoms 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 according 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 separating directly.
Exemplary of such organic salts are those with maleic, fumaric, benzoic, ascorbic, embonic, succinic, oxalic, bis methylene-salicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, citic, gluconic, lactic, malic, mandelic, c; 1 -e p I- O W03/14758 PCT/DK93/00021 8 cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-amino-benzoic, glutamic, benzene sulfonic and theophylline acetic acids as well as the 8halotheophyllines, for example 8-bromo-theophylline. Exemplary of such inorganic salts are those with hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids. Of course, these salts may also be prepared by the classical method of double decomposition of appropriate salts, which is well known to the art.
In the following the invention is further illustrated by way of examples with references to the drawings in which: 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 oxalate salt and Comp. 4 as the hydrochloride 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.
PHARMACOLOGICAL TEST METHODS The compounds used in the invention were tested according to reliable and well known pharmacological methods as follows: Inhibition of DA ell firing in VTA and SNC areas This test model is used to examine the effects on spontaneously active DA neurones 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.
i For further information see Skarsfeldt, Eur. J. Pharmacol. 1988, 145, 239-243, which information is incorporated herein by reference.
i WO 93/14758 PCT/DK93/00021 9 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 experiments consist of neurone counts which may be regarded as approximately Poisson distribute0 The data are expressed as percent active DA neurones of the number of active neurones in non-treated animals. Results are shown in Figs. 1-4 The known substances clozapine and haloperidol were included in the test for comparison purposes. Results for these known substances are shown in Figs. 5-6, respectively.
is Results As described in our copendi;g European Patent publication EP-A2-0 470 039, the 3arylindole or 3-arylindazole derivatives used according to the present invention potently bind to 5-HT 2 receptors with affinities in the nanomolar range (3Hketanserin binding test), whereas they were found to have very low affinity for the DA D-2 receptors 3 H-spiperone binding test). The compounds were found to have potent central 5-HT 2 antagonism in vivo with good oral bioavailability and long duration of action (quipazine-inhibition test). Frthermore it was found that the compounds have substantially no central antidopaminergic activity in vivo as 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 antagonistic activity in vivo Arnt, J. and J. Hyttel, J. Neural. Transm., 1986, 67, 225-240).
The test for inhibition of the firing of DA neurones in the VTA and SNC, respectively showed that the compounds used in the present invention inhibits the firing in the VTA. As seen from Figs. 1-4 the exemplifying compounds blocked the firing partially in the VTA, whereas they had substantially no activity in the SNC area.
From Figs. 5-6 it appears that haloperidol blocks the firing equipotently in both 1\
F-
WO 93/14758 PCT/DK93/00021 areas whereas clozapine, like the compounds used according to the invention, blocks the firing partially and selectively in the VTA, though it is only active in high doses.
FORMULATION EXAMPLES Typical examples of formulas for compositions manufactured according to the invention, are as follows: 1) Tablets containing 0.5 milligrams of Comp. 1 calculated as the free base: Comp. 1 0.5 mg Lactose 18 mg Potato starch 27 mg Saccharose 58 mg Sorbitol 3 mg Talcum 5 mg Gelatine 2 mg Povidone 1 mg Magnesium stearate 0.5 mg 2) Tablets containing 5.0 milligrams of Comp. 4 calculated as the free base: Comp. 4 5.0 mg Lactose 16 mg Potato starch 45 mg Saccharose 106 mg Sorbitol 6 mg Talcum 9 mg Gelatine 4 mg Povidone 3 mg Magnesium stearate 0.6 mg L i: I i -uC jrii~L -i i- WO 93/14758 PCI/DK93/00021 11 3) Syrup containing per milliliter: Comp. 3 10.0 mg Sorbitol 500 mg Tragacanth 7 mg Glycerol 50 mg Methyl-paraben 1 mg Propyl-paraben 0.1 mg Ethanol 0.005 ml Water ad 1 ml 4) Solution for injection containing per milliliter: Comp. 2 20.0 mg Acetic acid 17.9 mg is Sterile water ad 1 ml Solution for injection containing per milliliter: Comp. 1 50.0 mg Sorbitol 42.9 mg Acetic acid 0.63 mg Sodium hydroxide 22 mg Sterile water ad I ml Any other pharmaceutical 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 or fluphenazine.
Also combinations of the compounds as well as their non-toxic acid salts with other active ingredients, especially other neuroleptics, thymoleptics, tranquilizers, analgesics or the like,fall within the scope of the present invention.
IL.- I Id. N A;P I I- ii.L I 7

Claims (3)

1. A method for the treatment of human psychoses comprising the administration, to a human suffering from the positive symptoms of schizophrenia, of a therapeutically effective amount of a 3-arylindole or

3-arylindazole derivatives having the general Formula I: R 1 Ar R 3 N’ (I) R 4 6 9N a R wherein 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, 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 Salkylamino, di-lower-alkylamino, cyano, trifluoromethyl, and trifluoromethylthio; the dotted lines designate optional double bonds; when the dotted line emanating form 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 2 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; is hydrogen, or cycloalkyl, cycloalkyl-lower-alkyl, lower alkyl or lower Salkenyl, optionally substituted with one or two hydroxy groups, or R5 is a group taken from structures la and 1b: Z -(CH2)n-U-C-V -(CH2)n-U V or W C W la. Ib, I I 1- I F-

4-. 4*4# 4 4 4 13 wherein n Is an integer from 2 6, inclusive; W is 0or S; U is N or CH; Z is mn being 2 or 3, or Z is 1 ,2-phenylene optionally substituted with halogen or trifluoromethyl or Z is -CH=CH-, -COCH 2 OR -CSCH 2 V is 0, S, OH 2 or NR7, wherein R7 is H, lower alkyl, lower alkenyl, cycloalkyl or cycloalkyl-lower-alkyl optionally substituted with one or two hydroxy groups; U1 is 0, S, OH 2 or a group NR8, wherein Rl8 is H, lower alkyl, lower alkenyl, cycloalkyl or cycloalkyl-lower-alkyl optionally substituted with one or two hydroxy groups; and V1 is NR9R1O, OR”l, SR12 or CR13R14R15, where each of R9-R15 may be independently selected among the R8-substituents; provided that R5 may not be methyl when Rl1-R4 each are H, X and Y are OH and Ar is phenyl; or a pharmaceutically acceptable acid addition salt or a prodrug thereof. 2. A method of treatment according to Claim 1, characterized in that the compound used is selected from: 3-(4-Fluorophenyl)-5-methyl-1 -[2-[3-(2-propyl)imidazolidi n-2-on-1 -yl]ethyl]-4- piperidyl]- 1H-indole, 3-(4-Fluorophenyl)-1 [1 -[2-(imidazolidin-2-on-1 -yl)ethyl]-4-p iperidyl]-5-m ethyl- 1 H-i ndole, 3-(4-Fluorophenyl)-l-[1 midazolidi n-2-on-1 -yl)ethyl]-1 ,2,3,6-tetrahydro- pyridi n-4-yl]-5-trifluoromethyl-l1H-i ndole, and 1 1 (1 ,3-Dim ethyl -1 -u reido)ethyl]-4-pi pe ridylI]-5-f luo ro-3-(4 -flIuoroph enyl) 1 H- indole. 4 14 3. A method for the treatment of psychoses in humans suffering from the positive symptoms of schizophrenia comprising the step of administering a therapeutically effective amount of a 3-arylindole or 3-arylindazole derivative having the general Formula I as defined in claim 1 or a pharmaceutically acceptable acid addition salt or prodrug thereof to a patient in need thereof. 4. A method for the treatment of psychoses in humans suffering from the positive symptoms of schizophrenia comprising the step of administering a therapeutically effective amount of a 3-arylindole or 3-arylindazole derivative as defined in claim 2 or a pharmaceutically acceptable acid addition salt or prodrug thereof to a patient in need thereof. eDATED this 7th day of May, 1996. H. LUNDBECK A/S t 4 S” WATERMARK PATENT TRADEMARK ATTORNEYS 290 BURWOOD ROAD HAWTHORN VICTORIA 3122 AUSTRALIA IAS:SI:JL:JZ VAX doc 06 AU3449493.WPC ‘ll 5 .1 XL ~–LU

AU34494/93A
1992-01-23
1993-01-22
Use of 3-arylindole and 3-arylindazole derivatives for the treatment of psychoses

Ceased

AU670063B2
(en)

Applications Claiming Priority (3)

Application Number
Priority Date
Filing Date
Title

DK9284A

DK8492D0
(en)

1992-01-23
1992-01-23

TREATMENT OF PSYCHOSIS

DK084/92

1992-01-23

PCT/DK1993/000021

WO1993014758A1
(en)

1992-01-23
1993-01-22
Use of 3-arylindole and 3-arylindazole derivatives for the treatment of psychoses

Publications (2)

Publication Number
Publication Date

AU3449493A

AU3449493A
(en)

1993-09-01

AU670063B2
true

AU670063B2
(en)

1996-07-04

Family
ID=8089556
Family Applications (1)

Application Number
Title
Priority Date
Filing Date

AU34494/93A
Ceased

AU670063B2
(en)

1992-01-23
1993-01-22
Use of 3-arylindole and 3-arylindazole derivatives for the treatment of psychoses

Country Status (11)

Country
Link

EP
(1)

EP0621781A1
(en)

JP
(1)

JPH07503240A
(en)

AU
(1)

AU670063B2
(en)

CA
(1)

CA2128699A1
(en)

CZ
(1)

CZ176494A3
(en)

DK
(1)

DK8492D0
(en)

NO
(1)

NO942686L
(en)

RU
(1)

RU94035658A
(en)

SK
(1)

SK86394A3
(en)

WO
(1)

WO1993014758A1
(en)

ZA
(1)

ZA93491B
(en)

Families Citing this family (3)

* Cited by examiner, † Cited by third party

Publication number
Priority date
Publication date
Assignee
Title

DK206591D0
(en)

1991-12-23
1991-12-23
Lundbeck & Co As H

TREATMENT OF PSYCHOSIS

ATE276242T1
(en)

1997-05-30
2004-10-15
Banyu Pharma Co Ltd

2-OXOIMIDAZOLE DERIVATIVES

US7781478B2
(en)

2004-07-14
2010-08-24
Ptc Therapeutics, Inc.
Methods for treating hepatitis C

Family Cites Families (3)

* Cited by examiner, † Cited by third party

Publication number
Priority date
Publication date
Assignee
Title

IE58370B1
(en)

1985-04-10
1993-09-08
Lundbeck & Co As H
Indole derivatives

GB8908085D0
(en)

1989-04-11
1989-05-24
Lundbeck & Co As H
New therapeutic use

DK181190D0
(en)

1990-07-30
1990-07-30
Lundbeck & Co As H

3-ARYL-INDOL OR 3-ARYL-INDAZOL DERIVATIVES

1992

1992-01-23
DK
DK9284A
patent/DK8492D0/en
not_active
Application Discontinuation

1993

1993-01-22
JP
JP5512865A
patent/JPH07503240A/en
active
Pending

1993-01-22
AU
AU34494/93A
patent/AU670063B2/en
not_active
Ceased

1993-01-22
ZA
ZA93491A
patent/ZA93491B/en
unknown

1993-01-22
WO
PCT/DK1993/000021
patent/WO1993014758A1/en
not_active
Application Discontinuation

1993-01-22
CA
CA002128699A
patent/CA2128699A1/en
not_active
Abandoned

1993-01-22
SK
SK863-94A
patent/SK86394A3/en
unknown

1993-01-22
CZ
CZ941764A
patent/CZ176494A3/en
unknown

1993-01-22
EP
EP93903188A
patent/EP0621781A1/en
not_active
Withdrawn

1994

1994-07-18
NO
NO942686A
patent/NO942686L/en
unknown

1994-07-22
RU
RU94035658/14A
patent/RU94035658A/en
unknown

Also Published As

Publication number
Publication date

WO1993014758A1
(en)

1993-08-05

CZ176494A3
(en)

1995-04-12

ZA93491B
(en)

1993-08-23

NO942686D0
(en)

1994-07-18

NO942686L
(en)

1994-07-18

CA2128699A1
(en)

1993-08-05

JPH07503240A
(en)

1995-04-06

SK86394A3
(en)

1995-04-12

DK8492D0
(en)

1992-01-23

RU94035658A
(en)

1996-06-20

EP0621781A1
(en)

1994-11-02

AU3449493A
(en)

1993-09-01

Contact information