WO1993014758A1

WO1993014758A1 - Use of 3-arylindole and 3-arylindazole derivatives for the treatment of psychoses

Info

Publication number: WO1993014758A1
Application number: PCT/DK1993/000021
Authority: WO
Inventors: Kim Andersen; Torben Skarsfeldt
Original assignee: H Lundbeck AS
Current assignee: H Lundbeck AS
Priority date: 1992-01-23
Filing date: 1993-01-22
Publication date: 1993-08-05
Anticipated expiration: 1994-07-23
Also published as: AU3449493A; DK8492D0; JPH07503240A; NO942686D0; EP0621781A1; RU94035658A; SK86394A3; NO942686L; CA2128699A1; ZA93491B; CZ176494A3; AU670063B2

Abstract

3-Arylindole or 3-arylindazole derivatives having general formula (I) wherein Ar is optionally substituted phenyl or a hetero aromatic group; R1-R4 are hydrogen, halogen, alkyl, alkoxy, hydroxy, alkylthio, alkylsulfonyl, alkyl- or dialkylamino, cyano, trifluoromethyl, or trifluoromethylthio; X is N, CR6, R6 being H, halogen, trifluoromethyl or alkyl, or CH¿2?; Y is N, CH or C; R?5¿ is H, alkyl, alkenyl, cycloalkyl, or cycloalkylalkyl, or R5 is a substituent of formula (1a) or (1b), wherein n is 2 - 6; W is O or S; U is N or CH; Z is -(CH¿2?)m-, -CH=CH-, phenylene, -COCH2-, or -CSCH2-; V is O, S, CH2 or NR?7¿ wherein R7 is H, alkyl, alkenyl, cycloalkyl or cycloalkylalkyl; U1 is O, S, CH¿2? or NR?8; and V1 is NR9R10, OR11, SR12 or CR13R14R15¿, where each of R8-R15 are as defined for R7; 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

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 3- arylindazoie 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 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. 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., Neuropharmacology, 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 cholinergϊc, serotonergic and noradrenergic receptors in animal studies.

In recent years several reports have suggested that inhibition of the spontaneous ac- tivity 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 substaπtia 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 neuro- nes 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 Da- antagonistic activity in vivo . Previously, one of the compounds known from said patent, i.e. sertindoie, 5-chloro-1-(4-fluorophenyl)-3-[1-[2-(2-imidazolidinon-1-yl)- ethyl]-4-piperϊdyl]-1 H-indole, which is a 5-HT2 antagonist substantially without DA D₂-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-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. 91610058.9 published as EP-A2-0 470 039 discloses a class of 3-arylindole or 3-aryiindazole derivatives having the general Formula I

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, 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 ;

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 :

wherein n is an integer from 2 - 6, inclusive; 5 is O or S; U is N or CH ;

Z is -(CH₂)_m-. rn being 2 or 3, or Z is 1 ,2-phenylene optionally substituted with halogen or trifluoromethyl or Z is -CH=CH- , -COCH₂- or -CSCH₂-;

V is O, S, CH₂, 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, CH₂ or a group NR^β, wherein R^β 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^β-substituents; provided that R5 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-HT₂ 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 D₂ 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-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 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.

Since it is known that affinities of antipsychotic drugs for 5-HT₂ 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, 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 deriva¬ tives having the above general Formula I inhibits the firing of DA neurones in the VTA in rats.

o 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 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 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, and halogen means fluoro, chloro, bromo or iodo.

The Z groups -COCH₂- and -CSCH₂- 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.

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.

Preferred compounds used according to the invention are:

3-(4-FIuorophenyl)-5-methyl-1 -[1 -[2-[3-(2-propyl)imidazolidin-2-on-1 -yl]ethyl]-4- piperidyl]- 7H-indoie, Comp. 1 ,

3-(4-Fluorophenyl)-1 -[1 -[2-(imidazolidin-2-on-1 -yl)ethyl]-4-piperidyl]-5-methyl- 1H- indole, Comp. 2, 3-(4-Fluorophenyl)-1 -[1 -[2-(imidazolidin-2-on-1 -yl)ethyl]-1 ,2,3,6-tetrahydropyridin-4- yl]-5-trifluoromethyl-7H-indole, Comp. 3, and

1 -[1 -[2-(1 ,3-Dimethyl-1 -ureido)ethyl]-4-piperidyl]-5-fluoro-3-(4-f luorophenyl)-

7H-indole, Comp. 4 (mp: 255-57°C as hydrochloride).

Further examples of compounds of Formula I used according to the invention are listed in our prior EP-A2-0470039.

As found by the test for inhibition of pergolide induced rotations in rats with unilate¬ ral 6-OHDA lesions in our prior EP-A2-0 470 039, 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 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.

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 (i.e. positive symptoms of schizophrenia and psychosis of other genesis).

As mentioned above and already shown in our prior EP-A2-0 470 039 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 schizophre¬ nia and on quality of sleep, 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.

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, 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. 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 referen¬ ces 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 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.

PHARMACOLOGICAL TEST METHODS The compounds used in the invention were tested according to reliable and well known pharmacological methods 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 is believed to account for the development of neurological side effects.

For further information see Skarsfeldt, T.: Eur. J. Pharmacol. 1988, 145, 239-243, 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 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 known substances clozapine and haloperidol were included in the test fo comparison purposes. Results for these known substances are shown in Figs. 5-6 respectively.

Results

As described in our copending European Patent publication EP-A2-0 470 039, the 3 arylindole or 3-arylindazoie derivatives used according to the present inventio potently bind to 5-HT₂ 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-HT₂ antagonism in vivo with good oral bioavailability and lon duration of action (quipazine-inhibition test). Furthermore it was found that 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).

The test for inhibition of the firing of DA neurones in the VTA and SNC, respectivel showed that the compounds used in the present invention inhibits the firing in th VTA. As seen from Figs. 1-4 the exemplifying compounds blocked the firin 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 bot 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:

Magnesium stearate 0.5 mg

2) Tablets containing 5.0 milligrams of Comp. 4 calculated as the free base:

Magnesium stearate 0.6 mg 3) Syrup containing per milliliter:

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 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.

Claims

1. Use of a 3-arylindole or 3-arylindazole derivatives having the general Formula I

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 CH₂ ;

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, cycloalkyl-lower-alkyl, lower alkyl or lower alkenyl, optionally substituted with one or two hydroxy groups, or R5 is a group taken from structures 1a and 1b :

1b.

wherein n is an integer from 2 - 6, inclusive; W is O or S; U is N or CH ;

Z is -(CH )_m-, m being 2 or 3, or Z is 1 ,2-phenylene optionally substituted with halogen or trifluoromethyl or Z is -CH=CH- , -COCH₂- or -CSCH -;

V is O, S, CH₂, or NR7, wherein fV is H, lower alkyl, lower alkenyl, cycloalkyl or cycloalkyl-lower-alkyl optionally substituted with one or two hydroxy groups; W- is O, S, CH₂ or a group NR^β, wherein R^β is H, lower alkyl, lower alkenyl, cycloalkyl or cycloalkyl-lower-alkyl 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^β-substituents; provided that Rs may not be methyl when R1-R4 each are H, X and Y are CH and Ar is phenyl; or a pharmaceutically acceptable acid addition salt or a prod rug thereof, for the manufacture of a pharmaceutical composition for the treatment of psychoses in humans.

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

3-(4-Fluorophenyl)-5-methyl-1 -[1 -[2-[3-(2-propyl)imidazolidin-2-on-1 -yl]ethyl]-4- piperidyl]-7H-indole, 3-(4-Fluorophenyl)-1 -[1 -[2-(imidazolidin-2-on-1 -yl)ethyl]-4-piperidyl]-5-methyl- 1H- indole,

3-(4-Fluorophenyl)-1-[1-[2-(imidazolidin-2-on-1-yl)ethyl]-1 ,2,3,6-tetrahydropyridin-4- yl]-5-trifluoromethyl- 7H-indole, and

1 -[1 -[2-(1 ,3-Dimβthyl-1 -ureido)ethyl]-4-piperidyl]-5-fluoro-3-(4-fluorophenyl)- 1H- nόo\e. 3. A method for the treatment of psychoses in humans 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 comprising the step of ad¬ ministering a therapeutically effective amount of a 3-arylindole or 3-arylindazoie derivative as defined in Claim 2 or a pharmaceutically acceptable acid addition salt or prodrug thereof to a patient in need thereof.