SK86394A3 - 3-arylindole and 3-arylindazole derivatives and their use - Google Patents

Abstract

3-Arylindole or 3-arylindazole derivatives having general formula (I) wherein Ar is optionally substituted phenyl or a hetero aromatic group; R<1>-R<4> are hydrogen, halogen, alkyl, alkoxy, hydroxy, alkylthio, alkylsulfonyl, alkyl- or dialkylamino, cyano, trifluoromethyl, or trifluoromethylthio; X is N, CR<6>, R<6> being H, halogen, trifluoromethyl or alkyl, or CH2; Y is N, CH or C; R<5> is H, alkyl, alkenyl, cycloalkyl, or cycloalkylalkyl, or R<5> 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 -(CH2)m-, -CH=CH-, phenylene, -COCH2-, or -CSCH2-; V is O, S, CH2 or NR<7> wherein R<7> is H, alkyl, alkenyl, cycloalkyl or cycloalkylalkyl; U<1> is O, S, CH2 or NR<8>; and V<1> is NR<9>R<10>, OR<11>, SR<12> or CR<13>R<14>R<15>, where each of R<8>-R<15> are as defined for R<7>; inhibit the firing of spontaneously active dopamine neurones in the ventral tegmental area of the brain and are thus useful for the treatment of psychoses in humans.

Description

The invention relates to the use of certain 3-arylindole and 3-arylindazole derivatives and their salts for the manufacture of pharmaceutical compositions for the treatment of psychoses in humans.

BACKGROUND OF THE INVENTION

The inhibition of too high dopamine DA activity by using DA receptor blocking agents is nowadays the most important principle in the treatment of schizophrenia, and in particular its positive symptoms. Classical neuroleptics such as haloperidol, cis (Z) -flupentixol, or chlorpromazine induce an antipsychotic effect, probably by blocking the DA receptor. From a pharmacological point of view, these agents antagonize the stereotypic reactions induced by dopaminergic compounds such as methylphenidate, apomorphine or amphetamine in mice or rats, and also inhibit the particular behavior that can be induced by perolid in rats with unilateral 6-OHDA damage. Unfortunately, long-term treatment with these neuroleptics very often has severe extrapyramidal EPS side effects such as dystonia, akathisia and parkinsonism, which are clinically very serious. These side effects of EPS are very difficult to treat and the patient often refuses treatment. Some of these neurological side effects, which usually involve movement disorders, independently of will, correlate with the ability of the compounds to induce catalepsy in rats, as described in Arnt et al., Neuropharmacology, 1981, 20,

1331 to 1334.

A few compounds that do not induce EPS and are also effective in the treatment of schizophrenic disorders are referred to as atypical neuroleptics. One of these agents is cloozapine, which is an effective antipsychotic agent in humans, but because of the risk of agranulocytosis, blood counts should be regularly monitored and treatment is therefore costly and limited. From a pharmacological point of view, it does not induce catalepsy in rats or inhibit the dopaminergic-induced stereotyping in rodents. In animal experiments, this compound inhibits central cholinergic, serotonergic and noradrenergic receptors.

In recent years, there have been reports that inhibition of spontaneous DA neuronal activity in the ventral tegmental area of VTA in rat brain after repeated drug administration may be indicative of the antipsychotic potential of this agent, but inhibition of activity in substantia nigra pars compacta SNC is indicative of EPS development. Classical neuroleptics are effective in both areas at the same dose range, but atypical neuroleptics cause mostly inactivation of DA neurons in VTA. Clozapine has been shown to be effective only in the VTA region according to Bunney and Grace, Life Science, 1978, 25, 1715-1725, Vhite and Vang, Science, 1983, 221, 1054-1057, Chiodo and Bunney, J. Neuroscience, 1985 5, 2539-2544, Skarsfeldt, Life Science, 1988, 42, 1937-1044.

U.S. Pat. No. 4,710,500, which corresponds to European patent specification no. 200,322 describes a group of optionally 5-substituted 1-aryl-3-piperidinyl-, 1-aryl-3 (1,2,3,6-tetrahydropyridinyl) - or 1-aryl-3-piperazinylindole derivatives having a strong 5-HT ₂ and, in addition, many of these compounds have a potent DA D ₂ antagonist effect in vivo. It has previously been unexpectedly found that one of the compounds described in said patent is sertindole, i.e. 5-chloro-1- (4-fluorophenyl) -3- [1- [2- (2-imidazolidinon-1-yl) ethyl] -4-piperidyl] -1H-indole, which is a 5-HT ₂ -antagonist substantially free of the DA D ₂ -antagonist effect in vivo, inhibits DA-neurone irritation in the VTA region in the brain, as also described in European Patent Application Ser. . 392,959 (Lundbeck). However, this patent also demonstrates that other, highly related substances, which are 5-HT 2 -antagonists, are described in U.S. Pat. No. 4,710,500 cannot inhibit DA neurons.

European patent application no. No. 91610058.9, published no. EP 470 039 (Lundbeck) describes a group of 3-arylindole or 3-arylindazole derivatives of the general formula I

Ar is phenyl, optionally substituted with at least one of 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,

R ¹ to R ⁴ are independently selected from hydrogen, halogen, lower alkyl, lower alkoxy, hydroxy, nitro, lower alkylthio, lower alkylsulfonyl, lower alkylamino, lower dialkylamino, cyano, trifluoromethyl and trifluoromethylthio, propyl; a bond, wherein when the dashed line based on X is a double bond, X is a nitrogen atom or a CR 6 group where it is hydrogen, halogen, trifluoromethyl or lower alkyl, and when the dashed line is not a double bond, means

X is a CH 2 group, when the dotted line based on Y is different from the double bond,

Y is nitrogen or CH and when the dotted line is a double bond, Y is carbon, r5 is hydrogen, cycloalkyl, cycloalkylalkyl, lower alkyl or lower alkenyl, or two hydroxy groups of groups Ia and Ib optionally substituted with one or one of

where is an integer from 2 to 6, represents an oxygen or sulfur atom, represents a nitrogen atom or a CH group,

Z is - (CH 2) _m in which m is an integer or 3 or is 1,2-phenylene optionally substituted by halogen or trifluoromethyl or -CH = CH-, -COCH 2 - or -CSCH 2 -,

V represents an oxygen or sulfur atom, a CH2 or NR group in which R represents a hydrogen atom, a lower alkyl, a lower alkenyl, a cycloalkyl or a cycloalkylalkyl, optionally substituted by one or two hydroxy groups;

NR, wherein R ° is hydrogen, lower alkyl, lower alkenyl, cycloalkyl or cycloalkylalkyl, optionally substituted with one or two hydroxy groups, and is NR 1 R 1 -O, OR ³ , SR ³² or CR ³ R ³ R ³ R ³ R ³ where R @ 9 to R @ ¹³ independently have the meaning given for R @, provided that R @ ³ has a meaning different from the methyl group when R ^{@ 1} to R @ ⁴ are hydrogen, X and Y are CH and Ar; means phenyl.

In European patent specification no. No. 470,039, compounds of formula I are described as having 5-HT2-antagonistic activity with a long duration of action in pharmacological trials and have therefore been described as useful for the treatment of anxiety, depression, sleep disorders, migraine, negative symptoms of schizophrenia and Parkinson's disease. In addition, it has been shown that said compounds have substantially no affinity for DA D ₂ -receptors in vitro and are substantially devoid of acute dopamine antagonistic effect in vivo. The following tests were used to demonstrate:

and

a) Inhibition of H-ketanserin binding to 5-HT 2 -receptors in rat cerebral cortex is an assay for the affinity of substances for these receptors in vitro.

b) The Quipazine Antagonism Test, which monitors the ability of the compounds to inhibit Quipazine-induced head twitch in rats, is an in vivo 5-HT ₂ -antagonistic effect assay.

and

c) Inhibition of H-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) The Pergolide-Induced Behavioral Antagonist Assay in rats having unilateral 6-OHDA damage is a ring walk and the assay is very sensitive to the in vivo acute central antagonist effect of DA.

Since it is known that the affinity of antipsychotic agents for 5-HT 2 -receptors is not consistent with the effect of these agents on the positive symptoms of schizophrenia according to Peroutka S.J. and Snyder S. H., Relationship of neuro-leptic drug effects at brain dopamine, serotonin, alpha-adrenergic, and histamine receptors to clinical potency, Am. J. Psychiatry, 1980, 137, 1518-1522, said compounds were considered to have no antipsychotic effects.

SUMMARY OF THE INVENTION

It has now been unexpectedly found that the 3-arylindole or 3-arylindazole derivatives of the above formula I inhibit the activation of DA-neurons in the VTA region in rats.

The present invention relates to the use of the 3-arylindole and 3-arylindazole derivatives of the formula I or their acid addition salts, which are pharmaceutically acceptable, for the production of pharmaceutical compositions for the treatment of psychoses in humans.

The invention also encompasses the use of stereoisomers and prodrugs of the 3-arylindole or 3-arylindazole derivatives of Formula I.

In the present description, in formula I the terms lower alkyl, lower alkoxy, lower alkylthio and lower alkylsulfonyl are straight or branched chain groups having 1 to 4 carbon atoms. Examples of these 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, ethylsulfonyl and the like.

Lower alkenyl means an alkenyl group having 2 to 4 carbon atoms, for example, ethenyl, 1-propenyl, 2-butenyl and the like.

Cycloalkyl is a group of 3 to 8 carbon atoms, cycloalkylalkyl is cycloalkyl, substituted with lower alkyl, halogen is fluorine, chlorine, bromine or iodine.

The groups -COCH ₂ - and -CSCH ₂ - in the meaning of Z can be assigned to the ring structure Ia in both directions.

The psychoses that can be treated are psychoses related to schizophrenia and other psychoses and related disorders (such as mania and the like).

The effective daily dosage of the compounds of the invention or their pharmaceutically acceptable salts is 0.01 to 10.0 mg / kg. The daily dose is administered in one or more sub-doses, and depending on this, the individual dose of the compound or salt thereof may range from 0.10 to 200 mg.

The pharmaceutical compositions of the invention may be administered orally or parenterally, for example in the form of tablets, capsules, powders, syrups or injectable solutions.

Preferred compounds are:

3- (4-fluórfény1) -5-methyl- [1- [2- [3- (2-propyl) imidazolidin

2-on-1-yl] ethyl] -4-piperidyl] -4-indole, compound 1

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

3- (4-fluorophenyl) -1- [1- [2- (imidazolidin-2-on-1-yl) ethyl] -1,2,3,6-tetrahydropyridin-4-yl] -5-trifluoromethyl-1 H indole, compound 3 and 1- [1- [2- (1,3-dimethyl-1-ureido) ethyl] -4-piperidyl] -5-fluoro-3- (4-fluorophenyl) -1H-indole, compound 4, melting point as the hydrochloride is 255-257 ° C.

Further examples of compounds of formula I which can be used according to the invention can be found in EP 470 039.

As demonstrated in the rotation inhibition test induced in rats with unilateral 6-OHDA injury following pergolide administration according to EP 470 039, the compounds of the invention do not have acute antidopaminergic activity in vivo and, as evidenced by the 3H-spiperone binding assay, no affinity for dopamine receptors in vivo. For these reasons, they have hitherto been considered as having no antipsychotic effect.

However, it has now been unexpectedly shown that these agents can inhibit the spontaneously active DA-neurons in the VTA region of the brain after repeated administration, as can be measured electrophysiologically and therefore have antipsychotic effects.

It has been shown that said compounds can cause selective and partial inhibition of DA-neurons in said region without inhibiting DA-neurons in the SNC region. Since the inhibitory effect in the SNC region demonstrates neurological side effects, these substances are substantially devoid of side effects of this type and could therefore be very promising substances for the treatment of psychoses of other origin.

As mentioned above and as shown in EP 470 039, the compounds of the invention have a potent central 5-HT 2 antagonistic effect. Since this effect demonstrates, inter alia, an effect on schizophrenia and sleep quality, the compounds of the invention have the additional advantage of alleviating the negative symptoms of schizophrenia and improving sleep quality in schizophrenic patients. These effects are very valuable during the treatment of psychoses.

Compounds of formula (I) may be prepared as disclosed in EP 470 039.

Pharmaceutically acceptable acid addition salts of said compounds may be formed by reaction with non-toxic organic or organic acids in water miscible solvents such as acetone or ethanol followed by isolation of the salt by concentration of the solution and cooling or reaction with an excess of acid in a water-immiscible solvent. ethyl ether or chloroform, the salt precipitates directly from these solvents.

Examples of suitable organic salts are those with maleic, fumaric, benzoic, ascorbic, embonic, succinic, oxalic, bis-methylenesalicylic, methanesulfonic, ethanesulfonic, acetic, propionic, tartar, salicylic, citric, gluconic, lactic, malic, malic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic and theophylline acetic acids, 8-halo-thiophylenes, for example 8-bromo-thiophyline, are also useful. Examples of inorganic salts are those with hydrochloric, hydrobromic, sulfuric, sulfonic, phosphoric and nitric acids. These salts can also be prepared by conventional methods, for example by double decomposition of the corresponding salts, as is generally known in the art.

Pharmacological tests

The compounds used according to the invention were subjected to conventional pharmacological tests.

Inhibition of DA-neuron irritation in the VTA and SNC regions

This model is used to monitor the effect of spontaneously active DA-neurons in the VTA and SNC regions after repeated oral administration. Inhibition of the number of active DA-neurons in the VTA region demonstrates the antipsychotic effect of the compound, whereas inhibition of active DA-neurons in the SNC region indicates the likelihood of neurological side effects of the metals.

For further information, reference may be made to Skarsfeldt T., Eur. J. Pharmacol., 1988, 145, 239-243.

Rats weighing 250 g were used at the start of the experiment. The test substance was administered orally for 21 days, after which the rats were anesthetized and fixed in a stereotaxic apparatus. Several groups of rats were used, and various doses of test substances were administered. A 3x3 mm hole was drilled in the skull. Monitoring of DA-neuron activity was performed with a glass electrode. The electrode was introduced at eight sites in the VTA and SNC regions. Numbers of active neurons that approximate the Poisson distribution were obtained. The data obtained are reported as a percentage of active DA-neurons compared to active neurons of untreated animals. The results obtained are shown in FIG. 1 to 4.

Known substances such as clozapine and haloperidol were also included for comparison. The results for these substances are shown in FIG. 5 and 6.

The results •

As described in EP 470 039, the arylindole or β-arylindazole derivatives used according to the invention are capable of binding to 5-HT ₂ -receptors with an affinity in the nanomol α region (H-ketanserin binding assay) while a very low affinity has been demonstrated for DA D2-receptors ( ³ H-spiperone binding assay). The compounds have been shown to be potent 5-HT 2 -antagonists in vivo with good oral bioavailability and long-term efficacy as demonstrated by the quipazine inhibition assay. In addition, it has been shown that the compounds have essentially no central anti-dopaminergic effect in vivo in measuring inhibition of rotation in rats with unilateral 6-OHDA injury following pergolide administration, an extremely sensitive DA D ₇ -agonist in vivo test according to the publication Arnt J. and J. Hyttel, J. Neural, Transm., 1986, 67, 225-240.

An assay for inhibiting DA-neuron activity in the VTA and SNC regions showed inhibition in the VTA region. As shown in FIG. 1 to 4, the compounds caused inhibition in the VTA region, but had essentially no effect on the SNC region. FIG. 5 and 6, it is evident that haloperidol causes inhibition in both regions, while clozapine, as well as the compounds used in the invention, causes partial selective inhibition in the VTA region, although it is only effective at high doses.

The invention will be explained by the following examples in connection with the accompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

In FIG. 1 to 4 show the inhibitory effect of compounds no. 1-4 for neuronal irritation in the VTA and SNC regions of the brain. Compound 1 was used as oxalate and 4 as hydrochloride. In FIG. 5 shows the inhibitory effect of the reference compound clozapine on neuronal irritation in the VTA and SNC regions of the brain. In FIG. 6 shows the inhibitory effect of the comparator haloperidol on neuronal irritation in the VTA and SNC regions of the brain.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

Tablets containing 0.5 mg of Compound 1, converted to the free base component amount in mg of Compound 1

Lacquer potato starch

0,5 sucrose58 sorbitol3 talc5 gelatin2 polyvinylpyrrolidone1 magnesium stearate0,5

Example 2

Tablets containing 5.0 mg of Compound 4, converted to the free base component amount in mg

Compound 1 5.0 lactose 16 Potato starch 45 sucrose 106 sorbitol 6 talc 9 gelatin 4 polyvinylpyrrolidone 3 magnesium stearate 0.6

Example 3

syrup

The syrup contains the following ingredients in 1 ml of the final product:

compound 3 10,0 mg sorbitol 500.0 mg tragakant 7.0 glycerol 50.0 mg metylpyrabén 1.0 mg propyl 0.1 mg ethanol 0,005 ml water to 1.0 ml

Example 4

Solution for injection Compound 2 Acetic acid sterile water into

20.0 mg

17.9 mg

1.0 ml

Example 5

Solution for injection in compound 1 sorbitol acetic acid

50.0 mg

42.9 mg

0.63 mg sterile water to

1.0 ml

Other excipients may be used in the manufacture of the pharmaceutical compositions, provided that they are compatible with the active ingredient used and other pharmaceutical compositions and other dosage forms similar to those currently used for other neuroleptics, such as clopentixol, may be prepared. , flupentixol or flufenazine.

It is also within the scope of the invention to combine the said compounds and their non-toxic acid addition salts with other active ingredients, in particular other neuroleptics, thymoleptics, tranquilizers, analgesics and the like.

Claims (4)

Use of the 3-arylindole and 3-arylindazole derivatives of the general formula I Ar is phenyl, optionally substituted with at least one of 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, R ³ to R ⁴ are independently selected from hydrogen, halogen, lower alkyl, lower alkoxy, hydroxy, nitro, lower alkylthio, lower alkylsulfonyl, lower alkylamino, lower dialkylamino, cyano, trifluoromethyl and trifluoromethylthio; a line means a double bond, if any, where the dashed line is based on the symbol X represents a double bond, X represents a nitrogen atom or a Cr6 group where it represents a hydrogen atom, a halogen atom, trifluoromethyl or lower alkyl, and in the case where the dashed line does not represent a double bond, X represents CH2 if the dashed line starting from symbol Y, is different from a double bond, Y is a nitrogen atom or a CH group, and when the dotted line is a double bond, Y is a carbon atom. r5 represents a hydrogen atom, a cycloalkyl, a cycloalkylalkyl, a lower alkyl or a lower alkenyl, optionally substituted by one or two hydroxy groups, or is one of the groups Ia and Ib - (CH ₂ ) _n - II W or - (CH 2) n - U c - V ¹ II W where n is an integer from 2 to 6, V is an oxygen or sulfur atom, U represents a nitrogen atom or a CH group, Z is - (CH 2) _m wherein m is an integer 2 or 3 or is a 1,2-phenylene group optionally substituted by a halogen atom or a trifluoromethyl group or a group -CH = CH-, -COCH 2 - or -CSCH 2 -, V is oxygen or sulfur, CH2 or NR in which R represents a hydrogen atom, a lower alkyl, a lower alkenyl, a cycloalkyl or a cycloalkylalkyl, optionally substituted by one or two hydroxy groups, hydrox represents an oxygen or sulfur atom, a CH2 group or O Q NR, wherein R is H, lower alkyl, lower alkenyl, cycloalkyl or cycloalkylalkyl, optionally substituted by one or two hydroxy groups and a is NR ^ R ^ θ, OR h, SR _{^7, and} JL ^ _{e t>} Cr13r14r15 wherein R R @ 1 to R @ 2 independently have the meaning given for R @, provided that R @ ³ has a meaning different from the methyl group when R ^{@ 1} to R @ ⁴ are hydrogen, X and Y are CH and Ar is phenyl, as well as pharmaceutically acceptable acid addition salts or precursors thereof for the manufacture of pharmaceutical compositions for the treatment of psychoses in humans. Use according to claim 1, wherein the compounds used are: 3- (4-fluorophenyl) -5-methyl- [1- [2- [3- (2-propyl) imidazolidin 2-on-1-yl] ethyl] -4-piperidyl] -4-indole, 3- (4-fluorophenyl) -1- [1- [2- (imidazolidin-2-one-1-yl) ethyl] -4-piperidyl] -5-methyl-1H-indole, 3- (4-fluorophenyl) -1- [1- [2- (imidazolidin-2-one-1-yl) ethyl] -1,3,3,6-tetrahydropyridin-4-yl] -5-trifluoromethyl- 1H-indole and 1- (1- (2- (1,3-dimethyl-ureido) ethyl] -4-piperidyl] -5-fluór3- (4-fluorophenyl) indole--ΙΗ. 3. A method for treating psychoses in humans, comprising administering an effective amount of a 3-arylindole or 3-arylindazole derivative of the Formula I as claimed in claim 1 or a pharmaceutically acceptable acid addition salt or prodrug thereof. 4. A method of treating psychoses in humans, comprising administering an effective amount of a 3-arylindole or 3-arylindazole derivative of the formula I as claimed in claim 2 or a pharmaceutically acceptable acid addition salt or prodrug thereof.