WO1993012790A1

WO1993012790A1 - Use of arylindole derivatives for the treatment of psychoses

Info

Publication number: WO1993012790A1
Application number: PCT/DK1992/000390
Authority: WO
Inventors: Jens Kristian Perregaard; Torben Skarsfeldt
Original assignee: H. Lundbeck A/S
Priority date: 1991-12-23
Filing date: 1992-12-21
Publication date: 1993-07-08
Also published as: ZA9210001B; AU668537B2; RU94031165A; SK75794A3; CA2126571A1; EP0618799A1; NO942378L; CZ153994A3; JPH07502517A; DK206591D0; NO942378D0; AU3345293A

Abstract

6-and/or 2-substituted 1-arylindole derivative of general formula (I), where Ar is optionally substituted phenyl or a hetero aromatic group; X and X' are hydrogen, halogen, alkyl, alkoxy, hydroxy, alkylthio, alkylsulfonyl, alkyl- or dialkylamino, cyano, trifluoromethyl, or trifluoromethylthio; or X and X' are linked to constitute a 5-7 membered carbocyclic ring; R1 is hydrogen, or lower alkyl, provided that when X is hydrogen or fluoro, then R1 is not hydrogen; Y is nitrogen or carbon; R is hydrogen, alkyl, alkenyl, cycloalkyl, or cycloalkylmethyl, or R is a substituent of formula (1a) or (1b), wherein n is 2-6; W is oxygen or sulfur; U is nitrogen or carbon; Z is -(CH¿2?)m-, -CH=CH-, -COCH2-, -CSCH2- or 1,2-phenylene; V is oxygen, sulfur, CH2 or NR?2; V1¿ is -O-R?4, -S-R4, -CHR4R5 or -NR4R5; and R3, R4 and R5¿ are hydrogen, alkyl, alkenyl, cycloalkyl, or cycloalkylmethyl; 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.

Description

TREATMENTOFPSYCHOSES

Use of arylindole derivatives for the treatment of psychoses

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.

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 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. Unfortunately, the incidence of severe extrapy- ramidal 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., Neuropharma- cology, 1981 , 20, 1331 -1334).

A few compounds, which do not produce EPS and which are effective in the treat¬ ment 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 compounds in rodents. Clozapine blocks central cholinergic, serotonergic and

SUBSTITUTE SHEET noradrenergic receptors in animal studies.

In recent years several reports have suggested that inhibition of the spontaneous activity of DA neurones in the ventral tegmental area (VTA) in the rat brain upon re- peated treatment with a drug is indicative of the antipsychotic potential of the drug, whereas inhibition of the activity in substantia nigra pars compacta (SNC) should account for 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).

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 D₂- antagonϊstic activity in vivo . Previously, one of the compounds known from said patent, i.e. sertindole, 5-chloro-1-(4-ftuorophenyl)-3-[1-[2-(2-imidazolidinon-1-yl)- ethyl]-4-piperidyI]-1 H-rndole, which is a 5-HT₂ antagonist substantially without DA D₂-antagoπistic 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-HT₂ antagonists known from U.S.Patent No. 4,710,500 do not inhibit the firing of DA neurones.

Our own copending European Patent Application No. 916010055.5 published as 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

SUBSTITUTE SHEET

Ar where 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;

the dotted lines indicate optional bonds;

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 :

-<CH,- V __(CH_2)B_i_c__v, c II

H „ W w 1a. 1 b.

SUBSTITUTE SHEET wherein n is an integer from 2 - 6, inclusive; W is oxygen or sulfur; U is nitrogen or carbon; Z is selected from -(CH₂)_m-, m being 2 or 3, -CH=CH- , -COCH₂- , -CSCH₂-, 1 ,2- phenylene and 1 ,2-phenylene substituted with halogen or trifluoromethyl;

V is selected from oxygen, sulfur, CH₂, 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; and

R4 and R⁵ are independently selected from the R3-substituents.

In pharmacological tests said compounds were found to be highly potent 5-HT₂ antagonists having long duration of action and, accordingly, they were claimed to be useful in the treatment of anxiety, depression, sleep disturbances, migraine, negative symptoms of schizophrenia, and Parkinson^'s disease. Furthermore, they were found to lack dopamine receptor affinity and to be substantially inactive with respect to acute DA antagonistic activity in vivo. The tests used were: a) Inhibition of 3H-ketanserin binding to 5-HT₂ receptors in rat cortex in vitro, which is a test for affinity of drugs for 5-HT₂ receptors in vitro. b) Quipazine antagonism which is a test for 5-HT₂ antagonistic effect in vivo based on the testing of the ability of drugs to inhibit quipazine-induced head twitches in rats. c) Inhibition of 3H-spiperone binding to DA D₂ 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.

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.

SUMMARY OF THE INVENTION

Surprisingly, it has now been found that the 6-substituted and/or 2-alkyl substituted indole and 2,3-dihydroindole derivatives having the above general Formula I inhi¬ bits the firing of DA neurones in 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.

The use of stereoisomers and prodrugs of the 6-substituted or 2-alkyl substituted 2,3-dihydroindole derivatives of Formula I is 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 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.

SUBSTITUTE SHEET 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.

The 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

6-chloro-1 -(4-fluorophenyl)-3-[1 -[2-[3-(2-propyl)-2-imidazolidinon-1 -yl]ethyl]-4- piperidyl]-1 H-indole, Comp. 2 ,

5-chloro-1-(4-fluorophenyl)-2-methyl-3-[1-[2-(2-imidazolidinon-1-yl)ethyl]-4- piperidyl]-1 H-indole, Comp. 3.

As shown by the test for inhibition of pergolide induced rotations in rats with unilate¬ ral 6-OHDA lesions in our prior EP-A2-0465398, 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.

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 neu¬ rones in the SNC area. Since inhibiting effect in the SNC area is indicative of neuro-

SUBSTITUTE SHEET logical 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).

As mentioned above and already shown in our prior EP-A2-0465398 the com¬ pounds used in the present invention have potent central 5-HT₂ antagonistic activi¬ ty. Since such activity is indicative of i.a. effect on negative symptoms of schizo¬ phrenia and on quality of sleep, 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.

Exemplary of such 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. 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.

SUBSTITUTE SH fee; f In the following the invention is further illustrated by way of examples with referen¬ ces to the drawings in which:

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- ϊng of neurones in the VTA and the SNC areas of the brain, respectively.

PHARMACOLOGY

Compounds used in the invention were tested according to a reliable and well known pharmacological method as follows:

Inhibition of DA cell firing in VTA and SNC areas

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.

For further information see Skarsfeldt, T.: Eur. J. Pharmacol. 145, 239-243 (1988) which information is incorporated herein by reference.

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£ & diτXr consist of neurone counts which may be regarded as approximately Poisson distri¬ buted. 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 . In addition Comp. 3 inhibited the firing in VTA by 19% and in SNC by 9% at a dose of 2.2 μmol/kg and by 22% in the VTA and by 3% in the SNC at a dose of 4.4 μmol/kg.

The known substances clozapine and haloperidol were included in the test for com¬ parison purposes. Results for these known substances are shown in Figs. 3-4 , respectively.

Results

As described in our copending EP-A2-0465398 the indole and 2,3-dihydroindole derivatives used according to the invention in general potently bind to 5-HT₂ recep- tors with nanomolar affinities (3H-ketanserin binding test), whereas they have sub¬ stantially no affinity to the DA D₂ receptors (³H-spiperone binding test). The quipa- zine-inhibition test showed that the present indole compounds have potent central 5-HT₂ antagonism in vivo with good oral bioavailability and long duration of action. Furthermore it was found that the compounds have 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 an extremely sensitive test for DA D₂ 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, respective¬ ly showed that the compounds used in the present invention inhibits the firing in the VTA. As seen from Figs. 1-2 and the data for Comp. 3, the compounds tested caused a partial inhibition of the firing in the VTA, whereas they had substantially no activity in the SNC area in relevant doses. From Figs. 3-4 it appears that haloperidol inhibits the firing equipotentiy in both areas whereas clozapine, like the compounds of the invention, inhibits the firing partially and selectively in the VTA, though it is only active in high doses.

SUBSTITUTE SHEET 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:

Magnesium stearate 0.5 mg

2) Tablets containing 5.0 milligrams of Comp. 1 calculated as the free base:

Comp.1 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

3) Syrup containing per milliliter:

SUBSTITUTE SHEET

4) Solution for injection containing per milliliter:

Comp.2 20.0 mg

Acetic acid 17.9 mg Sterile water ad 1 ml

5) Solution for injection containing per milliliter:

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.

Also combinations of the compounds as well as their non-toxic acid salts with other active ingredients, especially other neuroleptics, thymoleptics, tranquilizers, analge¬ sics or the like.fall within the scope of the present invention.

SUBSTITUTE SHEET

Claims

1. Use of a 6- and/or 2-substituted 1-arylindole derivative having the general For- mula I :

where Ar is phenyl, phenyl substituted with one or more substituents selected from halogen, C-|-C₄-alkyl, C-|-C₄-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;

the dotted lines indicate optional bonds;

X is hydrogen, halogen, CrC₄-alkyl, CrC₄-alkoxy, hydroxy, C C₄-alkylthio, Cr C₄-alkylsulfonyl, C C₄-alkyl- or di-(CrC₄)-alkylamino, cyano, trifluoromethyl, or trifluoromethylthio;

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, Cι-C-₄-alkyl or C C₄-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 CrC₄-alkyl, C₂-C₄-alkenyl, cycloalkyl, or cycloalkylmethyl, each

SUBSTITUTE SHEET 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 :

1 b.

5 wherein n is an integer from 2 - 6, inclusive; W is oxygen or sulfur; U is nitrogen or carbon;

Z is selected from -(CH₂)_m-, being 2 or 3, -CH=CH- , -COCH₂- , -CSCH₂-, 1 ,2- phenylene and 1 ,2-phenylene substituted with halogen or trifluoromethyl; 0 V is selected from oxygen, sulfur, CH₂, and NR2 , wherein R2 is hydrogen, C-r C4-alkyl, C2-C4-alkenyl, a cycloalkyl group, a cycloalkylmethyl group, CrC4-alkyl substituted with one or two hydroxy groups, and C₂-C₄-alkenyl substituted with one or two hydroxy groups;

V1 is -0-R4, -S-R4, -CHR4R5 or -NR4R5; 5 R3 is hydrogen, CrC₄-alkyl, C2-C₄-alkenyl, a cycloalkyl group, a cycloalkylmethyl group, CrC4-alkyl substituted with one or two hydroxy groups, and C2-C4-alkenyl substituted with one or two hydroxy groups; and R4 and R⁵ are independently selected from the R3-substituents; or a pharmaceutically acceptable acid addition salt or prodrug thereof, for the manu- o facture of a pharmaceutical composition for the treatment of psychoses in humans.

2. A use according to Claim 1 , characterized in that the compound used is selected from:

6-chloro-1 -(4-fluorophenyl)-3-[1 -[2-(2-imidazolidinon-1 -yl)ethyl]-4-piperidyl]-1 H- indole,

6-chloro-1 -(4-fluorophenyl)-3-[1 -[2-[3-(2-propyl)-2-imidazolidinon-1 -yl]ethyl]-4-piperi- dyl]-1 H-indole, and

5-chloro-1 -(4-fluorophenyl)-2-methyl-3-[1 -[2-(2-imidazolidinon-1 -yl)ethyl]-4- piperidyl]-1 H-indole.

SUBSTITUTE SHEET

3. A method for the treatment of psychoses in humans comprising the step of administering a therapeutically effective amount of a 6- and/or 2-substituted 1 - arylindole 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 comprising the step of ad¬ ministering a therapeutically effective amount of a 6- and/or 2-substituted 1- arylindole derivative as defined in Claim 2 or a pharmaceutically acceptable acid addition salt or prodrug thereof to a patient in need thereof.

fe- Ui BSTITUTE SHEET 1/2

NOT FURNISHED UPON FILING