CA2126571A1 - Use of arylindole derivatives for the treatment of psychoses - Google Patents
Use of arylindole derivatives for the treatment of psychosesInfo
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- CA2126571A1 CA2126571A1 CA002126571A CA2126571A CA2126571A1 CA 2126571 A1 CA2126571 A1 CA 2126571A1 CA 002126571 A CA002126571 A CA 002126571A CA 2126571 A CA2126571 A CA 2126571A CA 2126571 A1 CA2126571 A1 CA 2126571A1
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- alkyl
- hydrogen
- substituted
- alkenyl
- hydroxy
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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- 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
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- 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
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- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Indole Compounds (AREA)
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 -(CH2)m-, -CH=CH-, -COCH2-, -CSCH2- or 1,2-phenylene; V is oxygen, sulfur, CH2 or NR2; V1 is -O-R4, -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.
is nitrogen or carbon; Z is -(CH2)m-, -CH=CH-, -COCH2-, -CSCH2- or 1,2-phenylene; V is oxygen, sulfur, CH2 or NR2; V1 is -O-R4, -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
WO93J12790 2 12 6 5 71 pcT/Dx92~no3~
TREATMENT OF PSYt~O~iE~
Use of aryllndole derivatives for the treatment of psychoses 5 The present invention relates to the use of certain 6- and/or 2-substituted 1-arylindole derivatiYes or salts or prodnJgs thereof for the manufacture of a pharma-ceutical preparation for the treatment of psychoses.
BACKGROIJND OF THE INVENTION
Damping of dopamins (DA) overactivity by the use of DA receptor blocking drugs is today the most important principl~ in ~ha tr~atment of schizophrenia, mDrs particu-larly the positive symptoms thereof. "Classical neuroleptics" such as haloperidol, cis(Z)-flupentixol and chlorprom~zine are believ~d to induce antipsy~hotic effect via 15 DA receptor blockade. Pharmacologically, such compounds antagonize stereoty~
pies induced by dopaminergic compounds (i.e. methylphenidate, apomorphina, 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 ~rsquent 20 in long term treatment with these neuroleptics and causes grsat concern amongclinicians. The EPS a!e difficult to treat, and unsuccessful treatment often leads to poor medication compliance. Some of these neurological side e~fects, which generally involve involuntary movement disorders, have been correlated to the propensity of the drugs to induce catalepsy in rats (Arnt. et al., Neuropharma-25 cology, 1981, 20, 1331-1334).
A fcw compounds, which do not produce EPS and which are effective in ths treat-ment of schizophrenic disorders, are termed ~atypical neurolepticsn. Clozapine is such a drug. Clozapine is an effective antipsychotlc in man but, due to the risk of 30 drug induced agranulocytosis, regular monitoring of blood parameters is required, and its use is theretore costly and restricted. Pharmacologically clozapins induces no catalepsy in rats, neither does it inhibit stereotypies induced by dopaminergic compou~ds in rodents. Clozapine blocks central cholinergic, serotonergic and SUE~StlTtJTE SHEET
WO 93fl2790 PCI'/DK92/00390 ~
noradrenergic receptors in animal studies.
In r~cent years s~veral reports have suggested that inhibition of the spontaneous activity of DA neurones in the ventral t~gmsntal area (VTA3 in the rat brain upon re-s peated treatment with a drug is indicative of the antipsychotic potsntial of the drug,whereas inhibition of the activity in substanfia nigra pars aompacta (SNC) should account for the development of EPS. "Classical neuroleptics" are active in both areas in the same dose range while "atypica! neuroleptics" mainly inactive DA
neurones in the VTA. Clozapine has been shown to be active only in the VTA
10 (Bunney and Grace, Life Sci~nce, 1978, 25,1715-1725, White and Wang, Sa~nc~
19&3, 221,1054-105?, Chiodo and Bunney, J.N~urosci~nce, 1985, 5, 2539-2544, Skarsfeldt, Life SaQnce, 198B, 42,1037-1044).
U.S.Patent No. 4,710,500, corresponding to European Patent No. 0200322, 15 discloses a class of optionally 5-substituted 1-aryl-3-piperidinyl, 1-aryl-3-(1,2,3,6-tetrahydropyridinyl)- or 1-aryl-3-piperæinylindole derivatives having potent 5-HT2 antagonistic activity, and many of them additionally having potent DA D2 antagonistic activity in vivo . Previously, one of the compounds known from saidpatent, i.e. sertindole, 5-chloro-1-(~-fluorophenyl)-3-~ 2-(2-imidazolidinon-1-yl)-20 ethyll-4-piperidyll-1 H-indole, which is a 5-HT2 antagonist substan~ially 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 inhibitthe 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-alkyl substituted indole and 2,3-dihydroindole derivatives having the general Formula I
WO 93/12790 PCI'/DK92~00390 ., 3 2l265 71 ,.:
X'~Y N--R
Ar where Ar is ph~nyl, phenyl substitut~cl with one or rr ore substi~uents sel~ted fr~m halogen, lower alkyl, lower alkoxy, hydroxy, ~nfluor~m~thyl, and cyano, or a hetQro 5 aromatic group sel~ d from 2-thienyl, 3-thienyl, 2-furanyl, 3-furanyl, 2-oxazolyl, 2-imidazolyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl;
the dotted lin~s indicate optional bonds;
10 X iS hydrogen, halogen, lower alkyl, lowar alkoxy, hydroxy, lowe~ alkylthio, low~r alkylsulfonyl, lowcr alkyl- or dialkylamino, cyano, trifluoromethyl, or trifluoromethyl~
thio;
X' is a substitu~nt taken from the X-substituents above; or 15 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, providod that when X is hydrogen or fluoro, th~n R1 is not hydrogen; ~
. . .
20 Y iS nitrogen or ~arbon, provided that when the dotted lins emanating from Y indi-cates a bond, t~ ~n Y is earbon;
:
R is hydrogen, or lower alkyl, lower alkenyl, cycloalkyl, or ~ycloalkylmethyl, each optionally substitut~d with one or two hy~roxy groups, any hydroxy group pr~s~nt25 being optionally esterifi~d with an aliphatic carboxylic acid having from two to twen-tyfour carbon atsms inclusive, or R is a substituent of the formula 1a or lb:
/ \ 13 -(CH2)n-U~ /V --(CH2)n--N--C--Vl U W
w la. lb~
S~UT~ S~I~E~
WO 93/12790 212 ~ !i 7 1 PCl[/DK92/00390 wherein n is an integ~r from 2 - 6, inclusive;
W is oxygen or sulfur; :~
U is nitrogen or oarbon;
5 Z is selected trom -(CH2)m-, m being 2 or 3, -CH=CH-, -COCH2-, -CSCH2-, 1,2-phanylene and 1 ,2-phenylene substitutad with halogen or trifluor~msthyl;
V is selected from oxyg~n, sulfur, CH2, and NR2, wharein R2 is hydrogen, lower alkyl, lower alkenyl, a cycloaikyl group, a cycloalkylmethyl group, lower alkyl substi~
10 tuted with one or two hydroxy groups, and lower alkenyl substituted with one or two hydroxy groups;
V~ is -O-R4, -S-R4, -CHR4R5 or -NR4R5;
~r R3 is hydrogen, lower alkyl, lower alkenyl, a cycloalkyl group, a cycloalkylmethyl group, lower alkyl substituted with one or two hydroxy groups, and lowcr alkenyl 16 substituted with one or two hydroxy groups; and R4 and Rs ar~ independently selected from th~ R3-substituents.
In pharmacological tests said compounds wsre found to be highly potent 5-ffT2 antagonists having long duration of action and, accordingly, they were claimed to 20 be useful in thc treatment of anxiety, depression, sleep disturbances, migraine, negative symptoms of schizophrenia, and Parlcinson s discase. Furthermore, they were found to lack dopamine receptor affinity and to be substantially inactive with respect to acut~ DA antagonistic activi~y in vivo. The tests used were:
a) Inhibition of 3H-ketanserin binding to 5-HT2 rcceptors in rat cortex in vitro, which :`
25 iS a t~st for affinity of drugs for ~HT2 rec~ptors in vitro.
b) Quipazine antagonism which is a test for 5-HT2 antagonistic affect in vivo based on the testing of ths ability of drugs to inhibit quipazine-induced head twitches in rats.
c) Inhibition of 3H-spiperone binding to DA D2 rec~ptors in rat corpus striatum in 30 vitr~ which is a test for afflnity of dnJgs 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 viva.
WO 93J12790 212 6 5 71 P~lDK92/00390 So, in view of the fact that it is known that affinities of antipsychotic drugs tor ~HT2 receptors do not coi relate to ~ffects on pos;tive symptoms of schizophrenia (Perout-ka, S.J. and Snyder,S.H.: Relationship of neuroleptic dn~g effects at brain dopa- -min~, serotonin, alpha-adrenergic, and histamine rec~ptors to clinical potency, Am.
J. Psychiatry, 1980, 137, 1518-1522), th~y were believed to be without antipsy- ~ ;
chotic effects.
SUMMARY C)F THE INVENTION
10 Surprisingly, i~ has now ~en found that the 6-substituted and/or 2^alkyl substituted indole and 2,3~ihydroindole denvatives having the above general Formula I inhi-. bits the firing of DA neurones in VTA in rats.
Accordingly, the present invention provides the us~ of a cornpound havin~ the 15 above defined general Formula I or a pharmaceutically accep~able acid addition sa~ thereof, for the manufacture of a pharrnaceutical cornposition for tha treatment of psychosis in humans. -The use of stereoisomers and prodrug~ of the 6-substituted or 2-alkyl substituted 20 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 bran~ned groups having from one to four carbon atoms ihclu-25 sive. Exemplary of suci groups are methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl-2-prop~yl, 2-methyl-1-propyl, methoxy, ethoxy,1-propoxy, 2-propoxy, methylthio, ethylthio, 1-propylthio, 2-propy~hio, methylsulfonyl, ethylsulF 1yl, ~r ;~
the like. The term lower alkeny refers to such groups having from two to ~our carbon atoms inclusive. ~;
:.
Cycloalkyl is such a group comprising 3 8 carbonatoms, and halogen means `;;
fluoro, chloro, bromo or iodo.
SUBSTITUTE SHEE~ ~;
WO 93/12790 PCI`/DK92/00390 ;
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.
5 An effective daily dose of the compound of the invention, or a pharmac~utically 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 ~nit dos~ of the compound or of the salt thereof is from Q.10 to 200 mg.
The compositions of th~ invention may exist in forms to be administered both orally o or parenterally, for example in the form of tablets, capsules, powders, synJps or solutions for injection ,,,_. :
Prefsrred compounds used according to the invention are:
6-chloro-1-(4-fluorophsnyl)-3-[1-[2-(2-imidazolidinon-1 -yl)ethyl]-4-piperidyl]-1 H-15 indole, Comp. 1, and 6~hloro-1 -(4-fluorophenyl)-3-[1 -[2-[3-(2-propyl)-2-imidazolidinon-1 -yllethyl~-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 pr~or EP-A2-0465398, the compounds used in the pre-sent invention do not show acute antidopaminergic ac~ivity in viv~ and as shown in the 3H-spiperone binding test they havs subst~ntially no affinity for dopamine recep-25 tors in vftro. Accordingly, they were beli~Yed to bs without antipsychotic effecs.
However, they have now unexpectedly been ~ound to inhibit the firing of spontane-ously active DA neurones in the VTA ot the brain upon repeated treatment as mea-sured electrophysiologically, and thus to have antipsychotic potential.
The compounds have been found selectiv~ly and partially to inhibit the firing of the DA neurones in the VTA substantially without inhibiting the firlng of the DA neurones in the SNC area. Since inhibiting effect in the SNC arsa is indica~ive of neuro-SUBSTI~UTE ~lEE-,-W093/~2790 ~12 ~ 71 P~/DK92/00390 logical side effects these compounds are believed to be substantially without suchside effects. So, they have been demonstrated to be very promising drugs for the treatment of psychoses (i.e. positive symptoms of schizophrenia and psychosis ofother genesis).
: -As mentioned above and already shown in our prior EP-A2-0465398 the com-pounds used in the pressnt invention have potent central 5-HT2 antagonistic activi- - ~
ty. Since such activity is indicative of i.a. effect on negative symptoms of schizo- ~i phrenia and on quality of sleep, the compositions of the invention have the further 10 advantage of alleviating or relieving the negative symptoms of schizophrenia and/or improving the,quality of sleep in a schizophrenic p~tient. Such effects are `
_, highly desired in connection with antipsychotic treatment.
The compounds of the general Formula I may be synthesized by methods accor-15 ding to our prior EP-A2-0465398, and specific compounds of Formula I are disclo-sedtherein. -~ ., The pharmaceutically acceptable acid a~dition salts of the compounds may be for-med by reaction with non-toxic organic or inorganic acids in an aqueous miscible20 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, 1umaric, benzoic, ascorbic, ;
25 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 inorganic30 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 saltsl which is well known to the art. ~
.. ..
~5~ri ~JT~
WO 93/lZ790 PCI/DK92/00390 In the following the inv~ntion is further illustrated by way of exampl~s with refer~n-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.
5 Fig. 2: Shows the inhibitin~ effect of Compound No 2 of the invention on the firing of neurones in the VTA and the SNC area~nf th~ brain, respectively.
Fig. 3: Shows the inhibiting effect of the reference compound haloperidol on thefiring of neurones in the VTA and the SNC areas of the brain, respectively.
Fig. 4: Shows the inhibi~ing effect of the reference compound ciozapine on ths fir-10 ing of neurones in the VTA and the SNC ar~as of the brain, respectively.
PHARMACOLOGY
Compounds used in the invention were tested according to a r~liable and well 15 known pharmacological method as follows:
Inhlbition of DA cell firing in VTA an~SNC ~reas This test model is used to ~xamine the effects on spontaneously active DA neuro-20 nes in VTA and SNC upon repeated oral treatment. Inhibition of the number ofactive 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.
25 For further information see Skarsfeldt, T.: Eur. J. Pharmacol. 145, 2390243 (1988) which information is incorporated herein by re~erence.
Rats weighing 250 g at the start of the experiment are used. ARer 21 days of oral treatment with of test compound, the rats are anaesthetized and mounted in a ste-30 reotaxic ~nstrument. Several groups of rats treated with different doses of the testcompound 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 consist of neurone counts which may be r~garded as approximat~ly Poisson distri-butsd. The data are expressed as percent active DA neurones of the number of active neurones in non-treated animals. Results ara shown in Figs. 1-2 . In addition Comp. 3 inhibited the firing in VTA by 19% and in SNC by 9% at a dose o~ 2.2 5 ~lmol/kg and by 22% in the VTA and by 3% in the SNC at a dose of 4.4 ~moUkg.
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 2t3-dihydroindole derivatives used according to the invention in general potently bind to 5-HT2 rece~
15 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 ant~gonism in vivo with good oral bioavailability and long duration of action.
Furthermore it was found that the compounds have no central antidopaminergic 20 activity in vfvo as measured by the inhibition of pergolide-induced rotations in rats with unilateral 6-OHDA l~sions, which test is an extremely sensitive test for DA D2 antagonistic activity in vivo ( Arnt, J. and J. Hyttel, J. Neural. Transm., 1986 ,67, 22~240).
25 The test for inhibition of the firing o1 DA neurones in the VTA and SNC, respective-Iy showed that the cornpounds used in the present invention inhibits the firing in the VTA. As seen from Figs. 1-2 and the data for Comp. 3, the comDounds tested caused a partial inhibition of the firing in the VTA, whereas they ha ;ubstantially no activity in th~ SNC area in relevant doses. From Figs. 3-4 it appQars tha~
30 haloperidol inhibits the firing equipotently in both areas whereas clozapine, like the compounds ot the invention, inhibits the firing partially and selectively in the VTA, though it is only active in high doses.
SUBSTllUTE Sl IEET
Wo 93/1279Q PCI/DK92/00390 FQRMULATiQN 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 frae base:
Comp. 1 0.5 mg Lactose 18mg 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. 1 calcuiated as the free base: :
Comp.1 5.0 mg Lactose 16 mg Potato starch45 mg Saccharose 106 mg Sorbitol 6 mg 2s Talcum 9 mg Gelatine 4 mg Povidone 3 mg Magnesium stearate 0.6 mg 30 3) Syrup oontaining per milliliter:
SUBSTITUTE SHEE~
2l26s7l ' WO 93/12790 PCI'/DK92/00390 1 1 .'' Comp. 2 10.0 mg Sorbitol 500 mg Tragacanth 7 mg Glycerol 50 mg Methyl-paraben1 mg Propyl-paraben0.1 r ~
Ethanol 0.005 ml Water ad ~ ml 4) Solution for injectiDn 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 milliliter:
Comp. 1 50.0 mg Sorbitol 42.9 mg Acetic acid 0.63 mg Sodium hydroxi~e 22 mg Sterile water ad I ml 25 Any other pharmac~utical tableting adjuvants may be us~d provided that they are compatible with the acti~Je ingrsdient, and additional compositions and dosage forms may be similar to those presently used ~or neuroleptics, such as clopenthixol, flupentixol or tluphenazine.
30 Also combinations of the compounds as well as their non-toxic acid salts with othar active ingredients, especial!y other neuroleptics, thymoleptics, tranquilizers, analge-sics or the like,~all within the scope of the present invention.
SUBSTI~UTE SHEE~T
TREATMENT OF PSYt~O~iE~
Use of aryllndole derivatives for the treatment of psychoses 5 The present invention relates to the use of certain 6- and/or 2-substituted 1-arylindole derivatiYes or salts or prodnJgs thereof for the manufacture of a pharma-ceutical preparation for the treatment of psychoses.
BACKGROIJND OF THE INVENTION
Damping of dopamins (DA) overactivity by the use of DA receptor blocking drugs is today the most important principl~ in ~ha tr~atment of schizophrenia, mDrs particu-larly the positive symptoms thereof. "Classical neuroleptics" such as haloperidol, cis(Z)-flupentixol and chlorprom~zine are believ~d to induce antipsy~hotic effect via 15 DA receptor blockade. Pharmacologically, such compounds antagonize stereoty~
pies induced by dopaminergic compounds (i.e. methylphenidate, apomorphina, 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 ~rsquent 20 in long term treatment with these neuroleptics and causes grsat concern amongclinicians. The EPS a!e difficult to treat, and unsuccessful treatment often leads to poor medication compliance. Some of these neurological side e~fects, which generally involve involuntary movement disorders, have been correlated to the propensity of the drugs to induce catalepsy in rats (Arnt. et al., Neuropharma-25 cology, 1981, 20, 1331-1334).
A fcw compounds, which do not produce EPS and which are effective in ths treat-ment of schizophrenic disorders, are termed ~atypical neurolepticsn. Clozapine is such a drug. Clozapine is an effective antipsychotlc in man but, due to the risk of 30 drug induced agranulocytosis, regular monitoring of blood parameters is required, and its use is theretore costly and restricted. Pharmacologically clozapins induces no catalepsy in rats, neither does it inhibit stereotypies induced by dopaminergic compou~ds in rodents. Clozapine blocks central cholinergic, serotonergic and SUE~StlTtJTE SHEET
WO 93fl2790 PCI'/DK92/00390 ~
noradrenergic receptors in animal studies.
In r~cent years s~veral reports have suggested that inhibition of the spontaneous activity of DA neurones in the ventral t~gmsntal area (VTA3 in the rat brain upon re-s peated treatment with a drug is indicative of the antipsychotic potsntial of the drug,whereas inhibition of the activity in substanfia nigra pars aompacta (SNC) should account for the development of EPS. "Classical neuroleptics" are active in both areas in the same dose range while "atypica! neuroleptics" mainly inactive DA
neurones in the VTA. Clozapine has been shown to be active only in the VTA
10 (Bunney and Grace, Life Sci~nce, 1978, 25,1715-1725, White and Wang, Sa~nc~
19&3, 221,1054-105?, Chiodo and Bunney, J.N~urosci~nce, 1985, 5, 2539-2544, Skarsfeldt, Life SaQnce, 198B, 42,1037-1044).
U.S.Patent No. 4,710,500, corresponding to European Patent No. 0200322, 15 discloses a class of optionally 5-substituted 1-aryl-3-piperidinyl, 1-aryl-3-(1,2,3,6-tetrahydropyridinyl)- or 1-aryl-3-piperæinylindole derivatives having potent 5-HT2 antagonistic activity, and many of them additionally having potent DA D2 antagonistic activity in vivo . Previously, one of the compounds known from saidpatent, i.e. sertindole, 5-chloro-1-(~-fluorophenyl)-3-~ 2-(2-imidazolidinon-1-yl)-20 ethyll-4-piperidyll-1 H-indole, which is a 5-HT2 antagonist substan~ially 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 inhibitthe 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-alkyl substituted indole and 2,3-dihydroindole derivatives having the general Formula I
WO 93/12790 PCI'/DK92~00390 ., 3 2l265 71 ,.:
X'~Y N--R
Ar where Ar is ph~nyl, phenyl substitut~cl with one or rr ore substi~uents sel~ted fr~m halogen, lower alkyl, lower alkoxy, hydroxy, ~nfluor~m~thyl, and cyano, or a hetQro 5 aromatic group sel~ d from 2-thienyl, 3-thienyl, 2-furanyl, 3-furanyl, 2-oxazolyl, 2-imidazolyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl;
the dotted lin~s indicate optional bonds;
10 X iS hydrogen, halogen, lower alkyl, lowar alkoxy, hydroxy, lowe~ alkylthio, low~r alkylsulfonyl, lowcr alkyl- or dialkylamino, cyano, trifluoromethyl, or trifluoromethyl~
thio;
X' is a substitu~nt taken from the X-substituents above; or 15 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, providod that when X is hydrogen or fluoro, th~n R1 is not hydrogen; ~
. . .
20 Y iS nitrogen or ~arbon, provided that when the dotted lins emanating from Y indi-cates a bond, t~ ~n Y is earbon;
:
R is hydrogen, or lower alkyl, lower alkenyl, cycloalkyl, or ~ycloalkylmethyl, each optionally substitut~d with one or two hy~roxy groups, any hydroxy group pr~s~nt25 being optionally esterifi~d with an aliphatic carboxylic acid having from two to twen-tyfour carbon atsms inclusive, or R is a substituent of the formula 1a or lb:
/ \ 13 -(CH2)n-U~ /V --(CH2)n--N--C--Vl U W
w la. lb~
S~UT~ S~I~E~
WO 93/12790 212 ~ !i 7 1 PCl[/DK92/00390 wherein n is an integ~r from 2 - 6, inclusive;
W is oxygen or sulfur; :~
U is nitrogen or oarbon;
5 Z is selected trom -(CH2)m-, m being 2 or 3, -CH=CH-, -COCH2-, -CSCH2-, 1,2-phanylene and 1 ,2-phenylene substitutad with halogen or trifluor~msthyl;
V is selected from oxyg~n, sulfur, CH2, and NR2, wharein R2 is hydrogen, lower alkyl, lower alkenyl, a cycloaikyl group, a cycloalkylmethyl group, lower alkyl substi~
10 tuted with one or two hydroxy groups, and lower alkenyl substituted with one or two hydroxy groups;
V~ is -O-R4, -S-R4, -CHR4R5 or -NR4R5;
~r R3 is hydrogen, lower alkyl, lower alkenyl, a cycloalkyl group, a cycloalkylmethyl group, lower alkyl substituted with one or two hydroxy groups, and lowcr alkenyl 16 substituted with one or two hydroxy groups; and R4 and Rs ar~ independently selected from th~ R3-substituents.
In pharmacological tests said compounds wsre found to be highly potent 5-ffT2 antagonists having long duration of action and, accordingly, they were claimed to 20 be useful in thc treatment of anxiety, depression, sleep disturbances, migraine, negative symptoms of schizophrenia, and Parlcinson s discase. Furthermore, they were found to lack dopamine receptor affinity and to be substantially inactive with respect to acut~ DA antagonistic activi~y in vivo. The tests used were:
a) Inhibition of 3H-ketanserin binding to 5-HT2 rcceptors in rat cortex in vitro, which :`
25 iS a t~st for affinity of drugs for ~HT2 rec~ptors in vitro.
b) Quipazine antagonism which is a test for 5-HT2 antagonistic affect in vivo based on the testing of ths ability of drugs to inhibit quipazine-induced head twitches in rats.
c) Inhibition of 3H-spiperone binding to DA D2 rec~ptors in rat corpus striatum in 30 vitr~ which is a test for afflnity of dnJgs 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 viva.
WO 93J12790 212 6 5 71 P~lDK92/00390 So, in view of the fact that it is known that affinities of antipsychotic drugs tor ~HT2 receptors do not coi relate to ~ffects on pos;tive symptoms of schizophrenia (Perout-ka, S.J. and Snyder,S.H.: Relationship of neuroleptic dn~g effects at brain dopa- -min~, serotonin, alpha-adrenergic, and histamine rec~ptors to clinical potency, Am.
J. Psychiatry, 1980, 137, 1518-1522), th~y were believed to be without antipsy- ~ ;
chotic effects.
SUMMARY C)F THE INVENTION
10 Surprisingly, i~ has now ~en found that the 6-substituted and/or 2^alkyl substituted indole and 2,3~ihydroindole denvatives having the above general Formula I inhi-. bits the firing of DA neurones in VTA in rats.
Accordingly, the present invention provides the us~ of a cornpound havin~ the 15 above defined general Formula I or a pharmaceutically accep~able acid addition sa~ thereof, for the manufacture of a pharrnaceutical cornposition for tha treatment of psychosis in humans. -The use of stereoisomers and prodrug~ of the 6-substituted or 2-alkyl substituted 20 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 bran~ned groups having from one to four carbon atoms ihclu-25 sive. Exemplary of suci groups are methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl-2-prop~yl, 2-methyl-1-propyl, methoxy, ethoxy,1-propoxy, 2-propoxy, methylthio, ethylthio, 1-propylthio, 2-propy~hio, methylsulfonyl, ethylsulF 1yl, ~r ;~
the like. The term lower alkeny refers to such groups having from two to ~our carbon atoms inclusive. ~;
:.
Cycloalkyl is such a group comprising 3 8 carbonatoms, and halogen means `;;
fluoro, chloro, bromo or iodo.
SUBSTITUTE SHEE~ ~;
WO 93/12790 PCI`/DK92/00390 ;
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.
5 An effective daily dose of the compound of the invention, or a pharmac~utically 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 ~nit dos~ of the compound or of the salt thereof is from Q.10 to 200 mg.
The compositions of th~ invention may exist in forms to be administered both orally o or parenterally, for example in the form of tablets, capsules, powders, synJps or solutions for injection ,,,_. :
Prefsrred compounds used according to the invention are:
6-chloro-1-(4-fluorophsnyl)-3-[1-[2-(2-imidazolidinon-1 -yl)ethyl]-4-piperidyl]-1 H-15 indole, Comp. 1, and 6~hloro-1 -(4-fluorophenyl)-3-[1 -[2-[3-(2-propyl)-2-imidazolidinon-1 -yllethyl~-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 pr~or EP-A2-0465398, the compounds used in the pre-sent invention do not show acute antidopaminergic ac~ivity in viv~ and as shown in the 3H-spiperone binding test they havs subst~ntially no affinity for dopamine recep-25 tors in vftro. Accordingly, they were beli~Yed to bs without antipsychotic effecs.
However, they have now unexpectedly been ~ound to inhibit the firing of spontane-ously active DA neurones in the VTA ot the brain upon repeated treatment as mea-sured electrophysiologically, and thus to have antipsychotic potential.
The compounds have been found selectiv~ly and partially to inhibit the firing of the DA neurones in the VTA substantially without inhibiting the firlng of the DA neurones in the SNC area. Since inhibiting effect in the SNC arsa is indica~ive of neuro-SUBSTI~UTE ~lEE-,-W093/~2790 ~12 ~ 71 P~/DK92/00390 logical side effects these compounds are believed to be substantially without suchside effects. So, they have been demonstrated to be very promising drugs for the treatment of psychoses (i.e. positive symptoms of schizophrenia and psychosis ofother genesis).
: -As mentioned above and already shown in our prior EP-A2-0465398 the com-pounds used in the pressnt invention have potent central 5-HT2 antagonistic activi- - ~
ty. Since such activity is indicative of i.a. effect on negative symptoms of schizo- ~i phrenia and on quality of sleep, the compositions of the invention have the further 10 advantage of alleviating or relieving the negative symptoms of schizophrenia and/or improving the,quality of sleep in a schizophrenic p~tient. Such effects are `
_, highly desired in connection with antipsychotic treatment.
The compounds of the general Formula I may be synthesized by methods accor-15 ding to our prior EP-A2-0465398, and specific compounds of Formula I are disclo-sedtherein. -~ ., The pharmaceutically acceptable acid a~dition salts of the compounds may be for-med by reaction with non-toxic organic or inorganic acids in an aqueous miscible20 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, 1umaric, benzoic, ascorbic, ;
25 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 inorganic30 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 saltsl which is well known to the art. ~
.. ..
~5~ri ~JT~
WO 93/lZ790 PCI/DK92/00390 In the following the inv~ntion is further illustrated by way of exampl~s with refer~n-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.
5 Fig. 2: Shows the inhibitin~ effect of Compound No 2 of the invention on the firing of neurones in the VTA and the SNC area~nf th~ brain, respectively.
Fig. 3: Shows the inhibiting effect of the reference compound haloperidol on thefiring of neurones in the VTA and the SNC areas of the brain, respectively.
Fig. 4: Shows the inhibi~ing effect of the reference compound ciozapine on ths fir-10 ing of neurones in the VTA and the SNC ar~as of the brain, respectively.
PHARMACOLOGY
Compounds used in the invention were tested according to a r~liable and well 15 known pharmacological method as follows:
Inhlbition of DA cell firing in VTA an~SNC ~reas This test model is used to ~xamine the effects on spontaneously active DA neuro-20 nes in VTA and SNC upon repeated oral treatment. Inhibition of the number ofactive 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.
25 For further information see Skarsfeldt, T.: Eur. J. Pharmacol. 145, 2390243 (1988) which information is incorporated herein by re~erence.
Rats weighing 250 g at the start of the experiment are used. ARer 21 days of oral treatment with of test compound, the rats are anaesthetized and mounted in a ste-30 reotaxic ~nstrument. Several groups of rats treated with different doses of the testcompound 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 consist of neurone counts which may be r~garded as approximat~ly Poisson distri-butsd. The data are expressed as percent active DA neurones of the number of active neurones in non-treated animals. Results ara shown in Figs. 1-2 . In addition Comp. 3 inhibited the firing in VTA by 19% and in SNC by 9% at a dose o~ 2.2 5 ~lmol/kg and by 22% in the VTA and by 3% in the SNC at a dose of 4.4 ~moUkg.
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 2t3-dihydroindole derivatives used according to the invention in general potently bind to 5-HT2 rece~
15 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 ant~gonism in vivo with good oral bioavailability and long duration of action.
Furthermore it was found that the compounds have no central antidopaminergic 20 activity in vfvo as measured by the inhibition of pergolide-induced rotations in rats with unilateral 6-OHDA l~sions, which test is an extremely sensitive test for DA D2 antagonistic activity in vivo ( Arnt, J. and J. Hyttel, J. Neural. Transm., 1986 ,67, 22~240).
25 The test for inhibition of the firing o1 DA neurones in the VTA and SNC, respective-Iy showed that the cornpounds used in the present invention inhibits the firing in the VTA. As seen from Figs. 1-2 and the data for Comp. 3, the comDounds tested caused a partial inhibition of the firing in the VTA, whereas they ha ;ubstantially no activity in th~ SNC area in relevant doses. From Figs. 3-4 it appQars tha~
30 haloperidol inhibits the firing equipotently in both areas whereas clozapine, like the compounds ot the invention, inhibits the firing partially and selectively in the VTA, though it is only active in high doses.
SUBSTllUTE Sl IEET
Wo 93/1279Q PCI/DK92/00390 FQRMULATiQN 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 frae base:
Comp. 1 0.5 mg Lactose 18mg 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. 1 calcuiated as the free base: :
Comp.1 5.0 mg Lactose 16 mg Potato starch45 mg Saccharose 106 mg Sorbitol 6 mg 2s Talcum 9 mg Gelatine 4 mg Povidone 3 mg Magnesium stearate 0.6 mg 30 3) Syrup oontaining per milliliter:
SUBSTITUTE SHEE~
2l26s7l ' WO 93/12790 PCI'/DK92/00390 1 1 .'' Comp. 2 10.0 mg Sorbitol 500 mg Tragacanth 7 mg Glycerol 50 mg Methyl-paraben1 mg Propyl-paraben0.1 r ~
Ethanol 0.005 ml Water ad ~ ml 4) Solution for injectiDn 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 milliliter:
Comp. 1 50.0 mg Sorbitol 42.9 mg Acetic acid 0.63 mg Sodium hydroxi~e 22 mg Sterile water ad I ml 25 Any other pharmac~utical tableting adjuvants may be us~d provided that they are compatible with the acti~Je ingrsdient, and additional compositions and dosage forms may be similar to those presently used ~or neuroleptics, such as clopenthixol, flupentixol or tluphenazine.
30 Also combinations of the compounds as well as their non-toxic acid salts with othar active ingredients, especial!y other neuroleptics, thymoleptics, tranquilizers, analge-sics or the like,~all within the scope of the present invention.
SUBSTI~UTE SHEE~T
Claims (4)
1. Use of a 6- and/or 2-substituted 1-arylindole derivative having the general For-mula I:
I.
where Ar is phenyl, phenyl substituted with one or more substituents selected from halogen, C1-C4-alkyl, C1-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, C1-C4-alkyl, C1-C4-alkoxy, hydroxy, C1-C4-alkylthio, C1-C4-alkylsulfonyl, C1-C4-alkyl- or di-(C1-C4)-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, C1-C4-alkyl or C1-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 C1-C4-alkyl, C2-C4-alkenyl, cycloalkyl, or cycloalkylmethyl, each optionally substituted with one or two hydroxy groups, any hydroxy group presentbeing 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:
1a. lb.
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, C1-C4-alkyl, C2-C4-alkenyl, a cycloalkyl group, a cycloalkylmethyl group, C1-C4-alkyl substituted with one or two hydroxy groups, and C2-C4-alkenyl substituted with one or two hydroxy groups;
V1 is -O-R4, -S-R4, -CHR4R5 or-NR4R5;
R3 is hydrogen, C1-C4-alkyl, C2-C4-alkenyl, a cycloalkyl group, a cycloalkylmethyl group, C1-C4-alkyl substituted with one or two hydroxy groups, and C2-C4-alkenylsubstituted 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-facture of a pharmaceutical composition for the treatment of psychoses in humans.
I.
where Ar is phenyl, phenyl substituted with one or more substituents selected from halogen, C1-C4-alkyl, C1-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, C1-C4-alkyl, C1-C4-alkoxy, hydroxy, C1-C4-alkylthio, C1-C4-alkylsulfonyl, C1-C4-alkyl- or di-(C1-C4)-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, C1-C4-alkyl or C1-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 C1-C4-alkyl, C2-C4-alkenyl, cycloalkyl, or cycloalkylmethyl, each optionally substituted with one or two hydroxy groups, any hydroxy group presentbeing 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:
1a. lb.
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, C1-C4-alkyl, C2-C4-alkenyl, a cycloalkyl group, a cycloalkylmethyl group, C1-C4-alkyl substituted with one or two hydroxy groups, and C2-C4-alkenyl substituted with one or two hydroxy groups;
V1 is -O-R4, -S-R4, -CHR4R5 or-NR4R5;
R3 is hydrogen, C1-C4-alkyl, C2-C4-alkenyl, a cycloalkyl group, a cycloalkylmethyl group, C1-C4-alkyl substituted with one or two hydroxy groups, and C2-C4-alkenylsubstituted 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-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]-1H-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]-1H-indole.
6-chloro-1-(4-fluorophenyl)-3-[1-[2-(2-imidazolidinon-1-yl)ethyl]-4-piperidyl]-1H-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]-1H-indole.
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.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DK912065A DK206591D0 (en) | 1991-12-23 | 1991-12-23 | TREATMENT OF PSYCHOSIS |
| DK2065/91 | 1991-12-23 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2126571A1 true CA2126571A1 (en) | 1993-07-08 |
Family
ID=8109829
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002126571A Abandoned CA2126571A1 (en) | 1991-12-23 | 1992-12-21 | Use of arylindole derivatives for the treatment of psychoses |
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| Country | Link |
|---|---|
| EP (1) | EP0618799A1 (en) |
| JP (1) | JPH07502517A (en) |
| AU (1) | AU668537B2 (en) |
| CA (1) | CA2126571A1 (en) |
| CZ (1) | CZ153994A3 (en) |
| DK (1) | DK206591D0 (en) |
| NO (1) | NO942378L (en) |
| RU (1) | RU94031165A (en) |
| SK (1) | SK75794A3 (en) |
| WO (1) | WO1993012790A1 (en) |
| ZA (1) | ZA9210001B (en) |
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| US5554030A (en) * | 1994-06-30 | 1996-09-10 | Minnesota Mining And Manufacturing Company | Method for bonding non-amalgam restorative materials to dental surfaces |
| IL126063A (en) * | 1996-03-25 | 2002-04-21 | Lilly Co Eli | Pharmaceutical compositions containing olanzapine for treating migraine pain |
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| 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 |
| DK158590D0 (en) * | 1990-07-02 | 1990-07-02 | Lundbeck & Co As H | indole derivatives |
| DK238190D0 (en) * | 1990-10-03 | 1990-10-03 | Lundbeck & Co As H | DEPOT DERIVATIVES |
| DK8492D0 (en) * | 1992-01-23 | 1992-01-23 | Lundbeck & Co As H | TREATMENT OF PSYCHOSIS |
-
1991
- 1991-12-23 DK DK912065A patent/DK206591D0/en not_active Application Discontinuation
-
1992
- 1992-12-21 WO PCT/DK1992/000390 patent/WO1993012790A1/en not_active Application Discontinuation
- 1992-12-21 RU RU94031165/14A patent/RU94031165A/en unknown
- 1992-12-21 EP EP93902096A patent/EP0618799A1/en not_active Ceased
- 1992-12-21 CA CA002126571A patent/CA2126571A1/en not_active Abandoned
- 1992-12-21 SK SK757-94A patent/SK75794A3/en unknown
- 1992-12-21 JP JP5511365A patent/JPH07502517A/en active Pending
- 1992-12-21 AU AU33452/93A patent/AU668537B2/en not_active Ceased
- 1992-12-21 CZ CZ941539A patent/CZ153994A3/en unknown
- 1992-12-23 ZA ZA9210001A patent/ZA9210001B/en unknown
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1994
- 1994-06-22 NO NO942378A patent/NO942378L/en unknown
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| NO942378D0 (en) | 1994-06-22 |
| ZA9210001B (en) | 1994-01-13 |
| RU94031165A (en) | 1996-06-20 |
| EP0618799A1 (en) | 1994-10-12 |
| NO942378L (en) | 1994-06-22 |
| JPH07502517A (en) | 1995-03-16 |
| WO1993012790A1 (en) | 1993-07-08 |
| AU668537B2 (en) | 1996-05-09 |
| CZ153994A3 (en) | 1995-06-14 |
| AU3345293A (en) | 1993-07-28 |
| SK75794A3 (en) | 1995-04-12 |
| DK206591D0 (en) | 1991-12-23 |
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