Note: Descriptions are shown in the official language in which they were submitted.
YO 93/14758 21 2 8 6 9 9 PCT/DK93/00021
Use of 3-arylindole and 3-arylindazol~ derivatives for
the treatment of psychoses.
FIELD OF TH EINV ENTIO N
- The present invention relates to the use of a certain class of 3-arylindole and 3-
arylindazole derivatives or salts thersof 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 rQceptor 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,
5 cis(Z)-flupentixol or chlorpromæin~ are believed to induc~ antipsychotic effect via
DA receptsr 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 b~havior in
rats with unilateral 6-OHDA lesions. Unfortunately, the incidence of severe extrapy-
ramidal side ~ffects (EPS) (dystonia, akathisia and parkinsonism) is very frcquent inlong term treatment with thcse neuroleptics and causes great concern among
clinicians. The EPS are difficult to treat, and unsuccessful treatment o~ten leads to
poor medication compliance. Some o~ these nsurological side effects, which
~enerally involve involuntary movement disorders, have been corr~lated to the
2s propensity of the drugs to induce catalepsy in rats (Arnt. et al., Neuropharmacology,
1981, 20, 1331-133~).
A few compounds, which do not produce EPS and which are effective in the treat-
ment of schizophrenic disorders, are termad Uatypical neuroleptics". Clozapine is
30 such a drug. Clozapine is an effective antipsychotic in man but, due to the risk of
drug induced agranuloGytosis, regular monitoring of blood parameters is required,
and its use is ther~fore costly and restricted. Pharmacologically, clozapine induces
no catalepsy in rats, neither does it inhibit stereotypies induced by dopaminergic
WO 93/14758 PCI /DK93/0
2128699 2 i
compounds in rodents. Clozapine blocks central cholinergic, serotonergic and
noradrenergic receptors in animal studies.
In recent years several ~eports have suggested that inhibition of the spontaneous ac-
5 tivity of DA neurones in the ventral tegmentaJ ar~a (VTA) in the rat brain upon re-
peated treatment with a drug is indicative of the antipsychotic potential of the dnJg,
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 Uatypical neuroleptics" rnainly inactive DA neuro-
10 nes in the VTA. Clozapine has been shown to be active only in the VTA (Bunneyand Grace, Life Saence, 1978, 25, 1715-1725, White and Wang, Science, 1983,
221, 1054-1057, Chiodo and Bunney, J.Nsuroscience, 1985, 5, 2539-2544,
Skarsfeldt, Life Science, 1988, 42, 1037-1044).
15 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-ar,vl-3-(1,2,3,6-
tetrahydropyridinyl~- or 1-aryl-3-piperazinylindole derivatives having potent 5-HT2
anta~onistic activity, and many of them additionally having potent DA D2-
antagonistic activity in vivo . Previously, one of the cornpounds known from said
20 patent, i.e. sertindole, 5-chloro-1-(4-fluorophenyl)-3-[1-[2-(2-imidazolidinon-1-yl)-
ethyll-4-piperidyl]-1H-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). Howeverl said
patent publication also shows that other very closely related 5-HT2 antagonists
25 kno~-n from U.S.Patent No. 4,710,500 do not inhibit the firing of DA neurones.
Our own copending European Patent Application No. 91610058.g published as
EP-A2-0 470 û39 discloses a class of 3-ar,vlindole or 3-arylindazole derivativeshaving the general Formula I
NO 93/14758 PCr/DK93/00021
212869~
Rl
Ar
R3X~X
R4 ~Y~,
wherein Ar is phenyl optionally substituted with one or more substituents seleoted
from halogen, low~r 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 indepsndently selected from hydrogen, halogen, iower 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 groupCR6 wherein R6 is hydrogen, halogen, trifiuoromethyl 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;
Rs is hydrogen, or eycloalkyl, cycloalky!alkyl, lower alkyl or lower alkenyl, optionally
20 substituted with one or two hydroxy groups, or Rs is a group taken from structur~s
1a and:lb:
' i /Z\ ~ (CH2)n~U1--C~Vl
-(CH2)n-U~ /v or w
c
U 1a. lb.
wherein n is an intsger from 2 - 6, inclusiYe;
25 WisO:orS;
.
WO ~3/147~8 PCI`/DK93/000
U is N ~ 8~99
Z is -(CH2)m-, m being 2 or 3, or Z is 1,2-phenylene optionally substituted withhalogen or trifluoromethyl or Z is -CH=CH-, -CC)CH2- or -CSCH2-;
V is O, S, CH2, or NR7, wherein R7 is hydrogen, lower alkyl, low~r alkenyl, cyclo-
5 alkyl or cycloalkylalkyl optionally substituted with one or two hydroxy groups;U1 is O, S, CH2 or a group NR8, wherein;R8 is H, lower alkyl, lower alkenyl,
cycloalkyl or cycloalkylalkyl optionally substltuted with one or two hydroxy groups;
and
V1 is NR9R10, OR11, SR12 or CR13Rl4R1s~ where each of R9-R15 may be indepen-
10 dently s~lected among the P~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
15 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 ~ubstantially without
affinity tor DA D2 receptors in vitro and to be substantially inactive with respect to
20 acute dopamine antagonistic effect in vivo. The tests used were:
a) Inhibition of 3H-ketanserin binding to 5-HT2 receptors in rat cortex in vltro, which
is a test for affinity ot drugs for 5-HT2 r~ceptors in vitro.
b~ Quipazine antagonism which is a test for 5-HT2 antagonistic eHect in vivo based
on testing ot the ability of drugs to inhibit quipazine-induced head twitches in rats.
25 C) Inhibition of 3H-spiperone binding to DA D2 receptors in rat corpus striatum in
vitro which is a lest tor affinity of drL gs tor DA D2 receptors jn vitro.
d) Antagonism of pergolide-induced circiing 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 affiniti~s of antipsychotic drugs tor 5-~tT2 receptors do not
correlate to effects on positive symptoms of schizophrenia (Peroutka, S.J. and
Snyder,S.H.: Relationship ot neuroleptic drug effects at brain dopamine, serotonin,
WO ~3/14758 ~ 1 2 8 ~ 9 9 PCr/DK93/00021
alpha-adrenergic, and histamine receptors to clinical potency, Am. J. Psychia~
~980 ,137, 1518-15~2) they were found to be withou~ antipsychotic effects.
- SUMMARY OF THE INVENTION
Surprisingly, it has now been found that the 3-arylindole or 3-arylindazol~ d~riva-
tives having the above general Formula I inhibits the firing of DA neurones in ~he
VTA in ra~s.
10 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 ~or the tr~atment of
psychosis in humans. -
15 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
20 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,1-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-pr~penyl, 2-butenyl, etc.
Cycloalkyl is such a group comprising 3 8 carbon atoms, cycloalkylalkyl is cyclo-
30 alkyl-lower-alkyl, and halogen means fluoro, chloro, bromo or iodo.
The Z groups -COCH2- and -CSCH2- may be incorpQrated in the ring of the
structure la in bo~h directions.
WO 93/14758 PCr/DK93/001
212~69~ 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. -
5An effective daily dose of the com~ound of the invention, or a pharmaceuticallyacceptable 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 forrn of tablets, capsules, powders, syrùps orsolutions for injection.
15 Preferred compounds used according to the invention are:
3-(4-Fluorophenyl)-5-methyl-1-[1 -l2-[3-(2-propyl)imidazolidin-2-on-1 -yl]ethyl]-4-
piperidyl]- lH-indole, Comp. 1,
3-(4-Fluorophenyl)-1-[1-[2-(imidazolidin-2-on-1-yl)ethyl]-4-piperidyl]-5-methyl- 1H- -
indole, Comp. 2,
20 3-(4-Fluorophenyl)-1-~1-[2-(imidazolidin-2-on-1-yl)ethyl]-1,2,3,6-tetrahydropyridin-4-
yl]-5-trifluoromethyl- 1H-indole, Comp. 3, and
1-[1-[2-(1 ,3-Dime~hyl-1 -ureido)ethyl]-4-piperidyl]-5-fluoro-3-(4-fluorophenyl)-
l~indole, Comp. 4 (mp: 255-57C as hydrochloride).
25 Further examples of compounds of Formula I used according to the invention are
listed in our prior EP-A2-0 470 039
I
As found by the test for inhibition ot pergolide induced rotstions in rats with unilate-
ral 6-OHDA lesions in our prior EP-A2-0 470 039, the compounds used in the pre-
30 sent invention do not show acute antidopaminergic activity in vivo and as shown inthe 3H-spiperone binding test they have substantially no affinity for dopamine recep-
tors in vitro. Accordingly, they were believed to be without antipsychotic effects.
WO 93/14758 21 2 ~ 6 9 4 PCr/DK93/00021
However, they have now unexpectedly been found to inhibit the firing of spontane-
ously active DA neurones in the VTA of the brain upon repealed treatment as mea-sured electrophysiologically, and thUs to have antipsychotic poten~ial.
5 In particular, the compounds have been found selectively and partially to inhibit the
firing of the DA neurones in the vrA substantially without inhibiting the firing of the
DA neurones in the SNC area. Since inhibiting effe~ in the SNC area is indicative
of neurological side eftects these compounds are beiieved to be substantially
without such side sffects. So, they have be~n demonstrated to be very promising
10 dnugs for the treatment of psychoses (i.e. positive symptoms of schizophrenia and
psychosis of other genesis).
,~ r~ -
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-
5 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 o~ schizophrenia andlor impro-
ving the qua!ity of sleep in a schizophrenic patient. Such e~fects are highly desir~d
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 pharmaceuticaily acceptable acid addition salts of the compounds may be
25 formed by reaction with non-toxic organic or inorganic acids in an aqueous miscible
solvent, such as acstone or ethanol, and subsequent isolation of the salt by
concentratiQn and cooling or by reaction with an excess of the acid in aqu~ous
immiscible solvent, such as ethyi 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,
W093/14758 2~2~6 pcr/DK93/ooo2
cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-amino-benzoic,
glutamic, benzene sulfonic and theophylline acetic acids as well ~s thé 8-
halo~h~ophyllines, lor example 8-bromo-theophylline. Exemplary of such inorganicsalts are those with hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and
5 nitric acids. Of course, these salts may also be prepared by the classical method ot
double decomposition of appropriate salts, which is well known to the art.
In the following the invention is turther illustra~ed by way ot examples with referen-
ces to the drawings in which: -
10 Fi~ 4: Show the inhibiting effect o~ Compounds Nos 1 - 4, respectively, of th~
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 hydro-
chloride salt.
Fig. 5: Shows the inhibiting eftect of the reference compound clozapine on the
15 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 thefiring of neurones in the VTA and the SNC areas of the brain, respectively.
PHARMACOLOGICALTESTMETHODS
20 The compounds used in the invention were tested according to reliable and well
known phannaco~ogical methods as follows:
Inbibi~ion ot DA cell ffring in VTA and SNC areas
25 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, whileinhibition of the number ot active DA neurones in SNC is believed to account for the
development of nsurological side effects.
~o :
For further information see Skarsfeldt, T.: Eur. J. Pharmacol. 1988, 145, 239-243,
which information is incorporated herein by reference.
212~699 "
~'10 ~3/14758 PCI /~DK93/00021
Rats weighing 250 9 at the start of the expenment are used. After 21 days of oral
treatment with test compound, the rats are anaesthetized and m~unted in a
stereotaxic instrument. Several groups of rats treated with different doses of test
compound are used. A hole (3 x 3 mm) is drill~d in the skull. Recording of l:)A
5 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 percant active DA neurones of the number
of active neurones in non-treated animals. Results are shown in Figs. 1~ .
The known substances clozap~ne and haloperidol were included in the test for
eomparison purposes. Results for these known substances are shown in Figs. 5-6,
respectively.
15 F~e~
As described in our copending European Patent publication EP-A2-0 470 039, the 3-
arylindole or 3-arylindazole derivatives used according to the present inventionpotently bind to 5-HT2 receptors with affinities in the nanomolar range (31~-
20 ketanserin binding test), whereas they were found to have very low affinity for theDA D-2 receptors (3H-spiperone binding test). The compounds were found to have
potent central 5-HT2 antagonism in vivo with good oral bioavailability and long
duration of action (quipazine-inhibition test). Furthermore it was tound that the
compounds have substantially no central antidopaminergic activity ~n vivo as
25 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. N~ur~l. Transm., 1986, 67, 225-240).
The test for inhibition of the firing of DA neurones in the VTA and SNC, respectively
30 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 ths 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
WO 93/14758 PCI`/DK93/000~ -
2128699 10
areas whereas clozapine, like the compounds used according to the invention,
blocks the firing partially and sslectively in ~he VTA, though it is only active in high
doses. :
FORMULATION EXAMPLES
Typical ~xamples of formulas ~or cornpositions manufactured according to th~
invention, are as follows:
~:
1 ) Tablets containing 0~5 milligrams of Comp. 1 caiculated as the free base: :
~_. Comp. 1 0.5mg
Lactose 18 mg
Potato starch 27 mg
Saccharose 58 mg
Sorbitol 3 mg
Talcum 5 mg
Gelatine 2 mg
Povidone 1 mg
20 Magnesium stearate 0.~ mg
2) Tablets containing 5.0 milligrams of Comp. 4 calculated as the ~ree base:
Comp. 4 5.0 mg
Lactose 1 B mg
Potato starch45 mg
Saccharose106 mg
Sorbitol 6 mg
Talcurn 9 mg
Gelatine 4 mg
Povidone 3 mg
Magnesium stearate 0.6 mg
~3 93/14758 PCr/DK93/00021
1 1 2128699
3) Syrup containing per milliliter:
Comp. 3 10.0 mg
Sorbitol . 500 mg
- Tragacanth 7 mg
Glycerol 50mg
Methyl-paraben 1 mg
Propyl-parab~n 0.1 mg
Ethanol 0.00~ ml
Water adlml
4) Solution for injection containing per milliliter:
Comp. 2 20.0 mg
Acetic acid 17.9 mg
15 Sterile water ad 1 ml
5) Solution for injection containing per millilit~r:
Comp. 1 50.0mg
Sorbitol 42.9 mg
Acetic acid 0.63 mg
Sodium hydroxide22 mg
Steriie water ad I ml
Any other pharmaceutical adjuvants may be used provided that they are compatible25 with the active ingredient, and additional cornpositions 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 thcir non-toxic acid salts with other
30 active ingredients, especially other neuroleptics, thymoleptics, tranquilizers,
analgesics or the like,fall within the scope of the prssent invention.
