AU2002221576A1 - 3-indoline derivatives useful in the treatment of psychiatric and neurologic disorders - Google Patents

Description

3-INDOLINE DERIVATIVES USEFUL IN THE TREATMENT OF PSYCHIATRIC AND NEUROLOGIC DISORDERS

The present invention relates to a novel class of 3-indoline derivatives having affinity for the dopa ine D₄ receptor. The compounds are useful in the treatment of certain psychiatric and neurologic disorders, in particular psychoses. The compounds also have affinity for the 5-HT_2A receptor.

Background of the Invention

US patent No. 3,751,417 relates to l-acyl-3-[2-(4-phenyl-l-piperazinyl)ethyl]indolines having the general formula

wherein Ri is hydrogen, chloro, bromo, lower alkoxy, nitro, amino, acetamido or dimethylamino, R₂ is hydrogen, lower alkoxy or nitro, or Ri and R₂ taken together is methylenedioxy, R₃ is hydrogen or methyl, * is hydrogen or methyl, R₅ makes the phenyl-ring monosubstituted and is hydrogen, chloro, methoxy, methyl or trifluoromethyl and Y is benzoyl, p-chlorobenzoyl, p-nitrobenzoyl or lower alkanoyl. The compounds herein are said to be useful as tranquillisers and analgesics. It is known from clinical practice, that tranquillisers and analgesics are generally not adequate treatment of psychoses or anxiety disorders.

US 3,751,4 6 relates to similar compounds having a hydrogen in position 1 of the indoline ring These compounds are also described as tranquillisers.

US 5,002,948 relates to compounds having the general formula

wherein Ri is hydrogen, halogen, lower alkyl, lower alkenyl or trifluoromethyl, X is CH, CH₂, NH or CO, the dotted line indicates an optional bond, R₂ is hydrogen, lower alkyl, acyl etc., Y is O or S, Y' is H, O, S or CH₂ and R⁵ is hydrogen, lower alkyl or alkenyl. The compounds are described as 5-HT_1A ligands being useful for the treatment of anxiety, depression, aggression, alcohol abuse and diseases related to the cardiovascular, the gastrointestinal and the renal system.

US 3,900,563 relates to compounds said to be useful for the treatment of psychotic disorders. The compounds disclosed herein have the general formula

wherein Xi is 5,6-dimethoxy or 5,6-methylendioxy, Yi is hydrogen or methyl and _ is hydrogen or methoxy. The compounds are shown in animals at doses of 10 mg/lcg to induce catalepsy predicting extrapyramidal side effects. The compounds of the present invention do not induce catalepsy at doses of 20 mg/kg.

US 4,302,589 relates to substituted cis-2-methyl-3-[(piperazinyl) and (piperidino)ethyl]indolines having the general formula

wherein Ri is fluoro, chloro, trifluoromethyl or methoxy, R₂ is hydrogen, chloro and methoxy, and M and A are carbon or nitrogen. These compounds are described as antipsychotics.

WO 92/22554 relates to certain 4-(phenylalkyl)piperidines having affinity for sigma receptors. Nothing is said about effect at dopamine D₄ receptors. Dopamine D₄ receptors belong to the dopamine D₂ subfamily of receptors, which is considered to be responsible for the antipsychotic effects of neuroleptics. The side effects of neuroleptic drugs which primarily exert their effect via antagonism of D₂ receptors are known to be due to D₂ receptor antagonism in the striatal regions of the brain. However, dopamine D receptors are primarily located in areas of the brain other than striatum, suggesting that antagonists of the dopamine D₄ receptor will be devoid of extrapyramidal side effects. This is illustrated by the antipsychotic clozapine which exerts higher affinity for D₄ than D₂ receptors and is lacking extrapyramidal side effects (Van Tol et al. Nature 1991, 350, 610; Hadley Medicinal Research Reviews 1996, 16, 507- 526 and Sanner Exp . Opin. Ther. Patents 1998, 8, 383-393).

A number of D₄ ligands which were postulated to be selective D₄ receptor antagonists (L-745,879 and U-101958) have been shown to posses antipsychotic potential (Mansbach et al. Psyche-pharmacology 1998, 135, 194-200). However, recently it has been reported that these compounds are partial D₄ receptor agonists in various in vitro efficacy assays (Gazi et al. Br. J. Pharmacol. 1998, 124, 889-896 and Gazi et al. Br. J. Pharmacol. 1999, 128, 613-620). Furthermore, it was shown that clozapine, which is an effective antipsychotic, is a silent antagonists (Gazi et al. Br. J. Pharmacol. 1999, 128, 613-620).

Consequently, D ligands which are partial D₄ receptor agonists or antagonists may have beneficial effects against psychoses.

Dopamine D₄ antagonists may also be useful for the treatment of cognitive deficits (Jentsch et al. Psychopharmacology 1999, 142, 78-84.

It has also been suggested that dopamine D antagonists may be useful to reduce dyskinesia occurring as a result of the treatment of Parkinson's disease with L-dopa (Tahar et al. Eur. J. Pharmacol. 2000, 399, 183-186).

Furthermore, evidence for a genetic association between the "primarily inattentive" subtype of attention deficit hyperactivity disorder and a tandem duplication polymorphism in the gene encoding the dopamine D receptor has been published (McCracken et al. Mol. Psychiat. 2000, 5, 531-536).

This clearly indicates a link between the dopamine D₄ receptor and attention deficit hyperactivity disorder and ligands affecting this receptor may be useful for the treatment of this particular disorder. Various effects are known with respect to compounds which are ligands at the different serotonin receptor subtypes. As regards the 5-HT_2A receptor, which was previously referred to as the 5-HT₂ receptor, the following effects have been reported, e.g.:

Antidepressive effect and improvement of the sleep quality (Meert et al. Drug. Dev. Res. 1989, 18, 119), reduction of the negative symptoms of schizophrenia and of extrapyramidal side effects caused by treatment with classical neuroleptics in schizophrenic patients (Gelders British J. Psychiatry 1989, 155 (suppl. 5), 33). Furthermore, selective 5-HT_2A antagonists could be effective in the prophylaxis and treatment of migraine (Scrip Report; "Migraine - Current trends in research and treatment"; PJB Publications Ltd.; May 1991) and in the treatment of anxiety (Colpart et al Psychopharmacology 1985, 86, 303-305 and Perregaard et al. Current Opinion in Therapeutic Patents 1993, 1, 101-128).

Some clinical studies implicate the 5-HT₂ receptor subtype in aggressive behaviour. Further, atypical serotonin-dopamine antagonist neuroleptics have 5-HT₂ receptor antagonistic effect in addition to their dopamine blocking properties and have been reported to possess anti-aggressive behaviour (Conner et al. Exp. Opin. Ther. Patents. 1998, 8(4), 350-351).

Recently, evidence has also accumulated, which support the rational for selective 5-HT_2A antagonists as drugs capable of treating positive symptoms of psychosis (Leysen et al. Current Pharmaceutical Design 1997, 3, 367-390 and Carlsson Current Opinion in CPNS Investigational Drugs 2000, 2(1), 22-24).

Accordingly, compounds with combined effects at dopamine D and 5-HT_2A receptors may have the further benefit of improved effect on psychiatric symptoms in schizophrenic patients.

Summary of the Invention

The object of the present invention is to provide compounds which are partial agonists or antagonists at the dopamine D₄ receptor, in particular compounds with combined effects at the dopamine D₄ receptor and the 5-HT _A receptor.

Thus, the present invention relates to the use of a compound having the general formula wherein R¹ is acyl, thioacyl, trifluoromethylsulfonyl, or R¹ is a group R^I2SO₂-, R^I2OCO- or R¹²SCO- wherein R¹² is Cι_₆-alkyl, C₂.₆-alkenyl, C₂_₆-alkynyl, C₃_₈-cycloalkyl, C₃_₈-cycloalkyl-Cι_₆-alkyl or aryl, or R¹ is a group R¹³R¹⁴NCO-, R¹³R¹ NCS-, wherein R¹³ and R¹⁴ are independently hydrogen, C₁_₆-allcyl, C₂_₆-alkenyl, C₂_₆-alkynyl, C₃_₈-cycloalkyl, C₃.₈-cycloalkyl-Ci_₆-alkyl or aryl, or R¹³ and R¹⁴ together with the N-atom to which they are linked form a pyrrolidinyl, piperidinyl or perhydroazepin group;

n is 1-6;

X is C, CH or N, and the dotted line emanating from X indicates a bond when X is C and no bond when X is N or CH;

R\ R" and R² are independently selected from hydrogen and Cι_₆-alkyl optionally substituted with a halogen atom; and

R³-R^π are independently selected from hydrogen, halogen, cyano, nitro, Cι.₆-alkyl, C₂_₆-alkenyl, C₂_₆-alkynyl, C₃_₈-cycloa_kyl, C₃.₈-cycloalkyl-Cι_₆-alkyl, amino, Cι_₆-alkylamino, di-(Cι_₆- allcyl)amino, Cι.₆-alkylcarbonyl, aminocarbonyl, Cι_6-alkylaminocarbonyl, di-(Cι_₆- alkyl)aminocarbonyl, Cι_₆-alkoxy, Cι_₆-alkylthio, hydroxy, trifluoromethyl, trifluoromethylsulfonyl and ._δ-alkylsulfonyl;

or a pharmaceutically acceptable acid addition salt thereof, for the manufacture of a medicament useful in the treatment of as positive and negative symptoms of schizophrenia, other psychoses, anxiety disorders, such as generalised anxiety disorder, panic disorder, and obsessive compulsive disorder, depression, aggression, side effects induced by conventional anti-psychotic agents, migraine, cognitive disorders, dyskinesia induced by treatment with L-dopa, attention deficit hyperactivity disorder and in the improvement of sleep quality.

The invention also relates to compounds of formula (I) as defined above, but with the proviso that (i) R⁹may not be hydrogen when R', R", R²-R⁸, R¹⁰-R^π are hydrogen, n is 2 and R¹ is acetyl;

(ii) R⁹ may not be CF₃ or chloro, when R\ R", R²-R⁸, R¹⁰-Rⁿ are hydrogen, X is C or CH, n is 2 and R¹ is acetyl;

(iii) R⁷ or R¹¹ may not be methoxy when X is N, n is 2 or 4 and R¹ is acetyl; and (iv) R⁴may not be methoxy. or a pharmaceutically acceptable acid addition salt thereof.

According to a preferred embodiment, the present invention relates to the S-enantiomer of the compounds of formula (I) and the use thereof.

According to another embodiment, the present invention relates to compounds of formula (I) and the use thereof wherein R⁷ and Rⁿ are hydrogen. In a preferred embodiment, the present invention relates to such compounds of formula (I) and the use thereof wherein R¹⁰ is also hydrogen.

Another preferred group of compounds is that wherein X is CH and the dotted line is a bond.

In a particular preferred embodiment, the present invention relates to compounds wherein at least one of R⁸ and R⁹ is selected from halogen, cyano, nitro, Cι_₆-alkyl, C₂_₆-alkenyl, C₂.₆-alkynyl, C₃_₈- cycloalkyl, C₃.₈-cycloalkyl-Cι_₆-alkyl, amino, Cι-_e-alkylamino, di-(C₁_₆-alkyl)amino, .₆- alkylcarbonyl, aminocarbonyl, Cι_6-alkylaminocarbonyl, di-(Cι_₆-alkyl)aminocarbonyl, C^- alkoxy, Cι_₆-allcylthio, hydroxy, trifluoromethyl, trifluoromethylsulfonyl and C^-alkylsulfonyl.

In particular, R⁸ and R⁹ are identical or R⁸ is hydrogen and R⁹ is as defined above. In particular, R⁸ and R⁹ are identical and selected from halogen or alkyl, in particular methyl.

According to a more specific embodiment, the present invention relates to such compounds of formula (I) and the use thereof, wherein n is 2 or 3, preferably 2, and compounds wherein R¹ is acyl, in particular acetyl.

When R', R" and R² is Cι.₆-alkyl, they are preferably methyl.

R⁴is preferably hydrogen or halogen, in particular fluoro.

In a further embodiment, the present invention relates to compounds of formula (I) above wherein R', R", R², R³, R⁵ and R⁶ are hydrogen. The compounds of the invention are partial agonists or antagonist at the dopamine D₄ receptors. The compounds also have affinity for the 5-HT_2A receptor.

Accordingly, the compounds of the invention are considered useful in the treatment of positive and negative symptoms of schizophrenia, other psychoses, anxiety disorders, such as generalised anxiety disorder, panic disorder and obsessive compulsive disorder, depression, aggression, side effects induced by conventional antipsychotic agents, dyskinesia induced by treatment with L-dopa, migraine, cognitive disorders, attention deficit hyperactivity disorder and in the improvement of sleep quality.

In particular, the compounds of the invention are considered useful in the treatment of positive and negative symptoms of schizophrenia without inducing extrapyramidal side effects.

In another aspect, the present invention provides a pharmaceutical composition comprising at least one compound of formula I as defined above or a pharmaceutically acceptable acid addition salt thereof in a therapeutically effective amount in combination with one or more pharmaceutically acceptable carriers or diluents.

In a further aspect, the present invention provides a method of treating the positive and negative symptoms of schizophrenia, other psychoses, anxiety disorders, such as generalised anxiety disorder, panic disorder, and obsessive compulsive disorder, depression, aggression, side effects induced by conventional anti-psychotic agents, migraine, cognitive disorders, dyskinesia induced by treatment with L-dopa, attention deficit hyperactivity disorder and in the improvement of sleep quality, comprising administration of a therapeutically acceptable amount of a compound of formula (I) as above.

Detailed Description of the Invention

The compounds of general formula I may exist as optical isomers thereof and such optical isomers as well as mixtures thereof are also embraced by the invention.

The term Cι„₆-alkyl refers to a branched or unbranched alkyl group having from one to six carbon atoms inclusive, such as methyl, ethyl, 1-propyl, 2-propyl, 1 -butyl, 2-butyl, 2-methyl-2-propyl and 2-methyl- 1 -propyl. Similarly, C₂_₆-alkenyl and C₂_₆-alkynyl, respectively, designate such groups having from two to six carbon atoms, including one double bond and one triple bond respectively, such as ethenyl, propenyl, butenyl, ethynyl, propynyl and butynyl.

The terms Cι_₆-alkoxy, Cι_₆-alkylthio, Cι.₆-alkylsulfonyl, Cι_₆-alkylamino, Cι_₆-allylcarbonyl and the like designate such groups in which the alkyl group is C .₆ alkyl as defined above.

The term C₃_₈-cycloalkyl designates a monocyclic or bicyclic carbocycle having three to eight C- atoms, such as cyclopropyl, cyclopentyl, cyclohexyl, etc.

Halogen means fluoro, chloro, bromo or iodo.

As used herein the term acyl refers to a formyl, Cι_₆-alkylcarbonyl, arylcarbonyl, aryl-Cι_₆-alkylcarbonyl, C₃_s-cycloalkylcarbonyl or a C₃.₈-cycloallcyl-Cι_₆-alkyl-carbonyl group and the term thioacyl is the corresponding acyl group in which the carbonyl group is replaced with a thiocarbonyl group. In the term C₃_₈-cycloalkyl-Cι.₆-alkyl, C₃.₈-alkyl and C^-alkyl are as defined above.

The term aryl refers to a carbocyclic aromatic group, such as phenyl or naphthyl, in particular phenyl, which may optionally be substituted with Cι_₆-alkyl.

The acid addition salts of the compounds of the invention are pharmaceutically acceptable salts formed with non-toxic acids. Exemplary of such organic salts are those with aleic, fumaric, benzoic, ascorbic, succinic, oxalic, bis-methylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic and theophylline acetic acids, as well as the 8-halotheophyllines, for example 8-bromotheophylline. Exemplary of such inorganic salts are those with hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids.

The pharmaceutical compositions of this invention, or those which are manufactured in accordance with this invention, may be administered by any suitable route, for example orally in the form of tablets, capsules, powders, syrups, etc., or parenterally in the form of solutions for injection. For preparing such compositions, methods well known in the art may be used, and any pharmaceutically acceptable carriers, diluents, excipients or other additives normally used in the art may be used. Conveniently, the compounds of the invention are administered in unit dosage form containing said compounds in an amount of 0.01 to 100 mg.

The total daily dose is usually in the range of 0.05 - 500 mg, and most preferably in the range of 0.1 to 50 mg of the active compound of the invention.

The compounds of the invention may be prepared as follows:

1) Alkylating a piperazine, piperidine or tetrahydropyridine of formula III with an all iating derivative of formula II:

(ii) (πi) wherein R', R", R'-R¹¹, X, n and the dotted line are as previously defined, and L is a leaving group such as e.g. halogen, mesylate or tosylate;

2) Reductive alkylation of an amine of formula III with a reagent of formula IV:

(IV) (HI) wherein R', R", R'-R¹¹, X, n and the dotted line are as previously defined and E is an aldehyde or an activated carboxylic acid;

3) Reducing the double bond in the tetrahydropyridinyl ring in derivatives of formula V:

wherein R', R", R -R and n are as previously defined; or

4) Acylating an amine of formula VI

wherein R', R", R²-R^π, X, n and the dotted line are as previously defined, by the use of a carboxylic acid and a coupling reagent, an activated ester, an acid chloride, an isocyanate or by a two-step procedure by treatment with phosgene followed by addition of an amine; whereupon the compound of formula I is isolated as the free base or a pharmaceutically acceptable acid addition salt thereof.

The allcylation according to method 1) is conveniently performed in an inert organic solvent such as a suitably boiling alcohol or ketone, preferably in the presence of an organic or inorganic base (potassium carbonate, diisopropylethylamine or triethylamine) at reflux temperature. Alternatively, the allcylation can be performed at a fixed temperature, which is different from the boiling point, in one of the above-mentioned solvents or in dimethyl formamide (DMF), dimethylsulfoxide (DMSO) or N-methylpyrrolidin-2-one (ΝMP), preferably in the presence of a base. The alkylating derivatives of formula II have been described in the literature (WO 98/28293), and the amines of formula HI are commercially available or have been described in the literature.

The reductive alkylation according to method 2) is performed by standard literature methods. The reaction can be performed in two steps, e.g. coupling of amines of formula III with reagent of formula IV by standard methods via the carboxylic acid chloride, activated esters or by the use of carboxylic acids in combination with a coupling reagents such as e.g. dicyclohexyl carbodiimide, followed by reduction of the resulting amide with lithium aluminium hydride or alane. The carboxylic acids of formula IV can be prepared by reduction of the corresponding indolecarboxylic acids by standard methods (see e.g. WO 98/28293).

The reduction of the double bond according to method 3) is generally performed by catalytic hydrogenation at low pressure (< 3 arm.) in a Parr apparatus, or by using reducing agents such as diborane or hydroboric derivatives as produced in situ from NaBH₄ in trifluoroacetic acid in inert solvents such as tetrahydrofuran (THF), dioxane or diethyl ether.

The acylation according to method 4) is conveniently performed by standard methods via the carboxylic acid chloride, activated esters or by the use of carboxylic acids in combination with coupling reagents such as e.g. dicyclohexyl carbodiimide. When the acylating reagent is carbamoyl chlorides or isocyanates, the acylation produces urea derivatives. The urea derivatives can also be prepared by a two-step procedure consisting of treatment with phosgene followed by addition of an amine.

The intermediate compounds of formula VI are prepared as described in methods 1) and 2).

Experimental Section

Melting points were determined on a Bϋchi SMP-20 apparatus and are uncorrected. Analytical LC- MS data were obtained on a PE Sciex API 150EX instrument equipped with IonSpray source and Shimadzu LC-8A/SLC-10A LC system. The LC conditions (C18 column 4.6 x 30 mm with a particle size of 3.5 μm) were linear gradient elution with water/acetonitrile/trifluoroacetic acid (90:10:0.05) to water/acetonitrile/trifluoroacetic acid (10:90:0.03) in 4 min at 2 mL/min. Purity was determined by integration of the UV trace (254 nm). The retention times, R_t, are expressed in minutes. Mass spectra were obtained by an alternating scan method to give molecular weight information. The molecular ion, MH+, was obtained at low orifice voltage (5-20V) and fragmentation at high orifice voltage (100-200V).

Preparative LC-MS-separation was performed on the same instrument. The LC conditions (C18 column 20 x 50 mm with a particle size of 5 μm) were linear gradient elution with water/acetonitrile/trifluoroacetic acid (80:20:0.05) to water/acetonitrile/trifluoroacetic acid

(5:95:0.03) in 7 min at 22.7 mL/min. Fraction collection was performed by split-flow MS detection. *H NMR spectra were recorded at 500.13 MHz on a Bruker Avance DRX500 instrument or at 250.13 MHz on a Bruker AC 250 instrument. Deuterated chloroform (99.8%D) or dimethyl sulfoxide (99.9%D) were used as solvents. TMS was used as internal reference standard. Chemical shift values are expressed in ppm-values. The following abbreviations are used for multiplicity of NMR signals: s=singlet, d=doublet, t=triplet, q=quartet, qui=quintet, h=heptet, dd=double doublet, dt=double triplet, dq=double quartet, tt=triplet of triplets, m=multiplet. NMR signals corresponding to acidic protons are generally omitted. Content of water in crystalline compounds was determined by Karl Fischer titration. For column chromatography silica gel of type Kieselgel 60, 230-400 mesh ASTM was used. For ion-exchange chromatography (SCX, 1 g, Varian Mega Bond Elut®, Chrompack cat. no. 220776). Prior use of the SCX-columns was pre-conditioned with 10% solution of acetic acid in methanol (3 mL).

Examples

Preparation of intermediates

A. Amines

4-(3 ,4-Dichlorophenyl)-3 ,6-dihydro-2H-pyridine

A mixture of butyllithium (1.6 M in hexane, 45 mL) and tetrahydrofuran (40 mL) was cooled down to -65-75 °C and subsequently added a solution of 4-bromo-l,2-dichlorobenzene (15 g) in tetrahydrofuran (25 mL). The resulting mixture was stirred at -65-75 °C for 1 h followed by the addition of ethyl 4-oxo-piperidine-l-carboxylate (11.5 g). The resulting mixture was stirred at -65- 75 °C for 1 h followed by another 3 h at room temperature. The mixture was subsequently quenched by the addition of a saturated solution of ammonium chloride in water, and the aqueous phase was extracted with ethyl acetate. The combined organic extracts were dried (MgSO₄), filtered and concentrated in vacuo to give ethyl 4-(3,4-dichlorophenyl)-4-hydroxypiperidine-l-carboxylate (12.6 g). The residue was dissolved in trifluoroacetic acid (100 mL) and stirred at room temperature for 16 h. The solvent was removed in vacuo, and the residue was dissolved in a mixture of 4 M sodium hydroxide and ethanol and subsequently boiled under reflux for 48 h. The mixture was extracted with ethyl acetate, and the combined organic extracts were dried (MgSO₄), filtered and concentrated in vacuo. The residue was purified by flash chromatography on silicagel (eluent: ethyl acetate/4 M ammonia in methanol 1 : 1) to give the title compound (4.1 g).

4-(3,4-Dichlorophenyl)piperidine A mixture of ethyl 4-(3,4-dichlorophenyl)-4-hydroxypiperidine-l-carboxylate (6.0 g), trifluoroacetic acid (50 mL) and triethylsilane (10 mL) was stirred at room temperature for 16 h. The mixture was added water and ethyl acetate, and the phases were separated. The aqueous phase was extracted twice with ethyl acetate, and the combined organic extracts were dried (MgSO₄), filtered and concentrated in vacuo (5.8 g). The residue was dissolved in a mixture of 4 M sodium hydroxide and ethanol and subsequently boiled under reflux for 24 h. The mixture was extracted with ethyl acetate, and the combined organic extracts were dried (MgSO ), filtered and concentrated in vacuo. The residue was purified by flash chromatography on silicagel (eluent: ethyl acetate/4 M ammonia in methanol 1:1) to give the title compound (1.8 g).

Preparation of the compounds of the invention

Example 1

1 a, (+)-l-f2Xl-Acetyl-2, 3-dihydro-lH-indol-3-yl)ethyl]-4-(3, 4- dimethylphenyl)piperazine,hydrochloride. A mixture of l-(3,4-dimethylphenyl)piperazine (1.15 g), (+)-l-[2-(l-acetyl-2,3-dihydro-7H-indol-3- yl)ethylbromide (prepared in WO 98/28293) (1.3 g) and potassium carbonate (0.7 g) in acetonitrile (20 mL) were heated to 85 °C for 6 h. The mixture was cooled to room temperature , silicagel (7 g) added and the mixture evaporated in vacuo to give a white powder. The product was purified by flash chromatography on silicagel using as eluent ethylacetate/triethylamine (99:1). Fractions containing the product were pooled and evaporated in vacuo. The product was dissolved in tetrahydrofuran and converted to its hydrochloride by addition of HC1 in diethylether (1.4 g). Mp 238-240°C. Η MR (DMSO-d₆): 2.00-2.08 (m, IH); 2.15 (s, 3H), 2.20 (s, 6H), 2.30 (m, IH), 3.10- 3.30 (m, 7H), 3.55 (m, IH), 3.60 (m, 2H), 3.75 (m, 2H), 3.85 (m, IH), 4.25 (m, IH), 6.75 (d, IH), 6.83 (s, IH), 7.0 (t, 2H), 7.20 (t, IH), 7.30 (d, IH), 8.05 (d, IH). MS m z: 404 (MH+), 378.1.

The following compounds were prepared in a similar manner:

lb, (+)-l-f2-(l-Acetyl-2,3-dihydro-lH-indol-3-yl)ethγU-4-(4- methylphenyl)piperazine,hydrochloride from 4-(4-methylphenyl)piperazine and (+)-l-[2-(l-acetyl- 2,3-dihydro-7H-indol-3-yl)ethylbromide. Mp 217-220°C. ^!H NMR (DMSO-d₆): 2.00-2.08 (m, IH); 2.17 (s, 3H), 2.23 (s, 3H), 2.30 (m, IH), 3.10-3.30 (m, 7H), 3.55 (m, IH), 3.60 (m, 2H), 3.75 (m, 2H), 3.85 (m, IH), 4.25 (m, IH), 6.90 (d, 2H), 7.05 (m, 3H), 7.20 (t, IH), 7.30 (d, IH), 8.05 (d, IH). MS m/z: 404 (MH+), 364.0. lc, (+)-l-[2-(l-Acetyl-2,3-dihydro-lH-indol-3-yl)ethylf-4-(4-methylphenyl)piperidine from 4-(4-methylphenyl)piperidine and (+)-l-[2-(l-acetyl-2,3-dihydro-liJ-indol-3-yl)ethylbromide. Mp 112-114°C. ^JH NMR (DMSO-d₆): 1.60-1.80 (m, 5H); 2.00 (t, 3H), 2.17 (s, 3H), 2.23 (s, 3H), 2.40 (m, 3H), 3.00 (m, 2H), 3.45 (m, IH), 3.60 (m, 2H), 3.80 (m, IH), 4.20 (m, IH), 7.00 (t, IH), 7.10 (m, 4H), 7.20 (t, IH), 7.30 (d, IH), 8.05 (d, IH). MS m/z: 404 (MH+), 364.1.

Id, (+)-l-[2-(l-Acetyl-2,3-dihydro-lH-indol-3-yl)ethyl]-4-(3,4- dichlorophenyl)piperazine, hydrochloride from 4-(3,4-dichlorophenyl)piperazine and (+)-l-[2-(l- acetyl-2,3-dihydro-7H-indol-3-yl)ethylbromide. Mp 184-186°C. 'H NMR MSO-ds): 2.00-2.08 (m, IH); 2.15 (s, 3H), 2.30 (m, IH), 3.10-3.30 (m, 7H), 3.55 (m, IH), 3.60 (m, 2H), 3.75 (m, 2H), 3.85 (m, IH), 4.25 ( , IH), 7.0 (m, 2H), 7.20 (t, IH), 7.25 (m, IH), 7.30 (d, IH), 7.43 (d, IH), 8.05 (d, IH). MS m/z: 404 (MH+), 417.9.

le, (+)-l-[2-(l-Acetyl-2, 3-dihydro-lH-indol-3-yl)ethyl]-4-(4- bromophenyl)piperazine,hydrochloride from 4-(4-bromophenyl)piperazine, hydrochloride and (+)- l-[2-(l-acetyl-2,3-dihydro-iH-indol-3-yl)ethylbromide.. Η NMR (DMSO-d₆): 2.00-2.08 (m, IH);

2.17 (s, 3H), 2.30 (m, IH), 3.10-3.30 (m, 4H), 3.55 (m, IH), 3.60 (m, 2H), 3.70-4.00 (m, 6H), 4.25

(m, IH), 6.90 (d, 2H), 7.05 (t, IH), 7.20 (t, IH), 7.30 (d, IH), 7.48 (d, 2H), 8.05 (d, IH). MS m/z:

404 (MH+), 427.9.

If, l-[2-(l-Acetyl-2, 3-dihydro-lH-indol-3-yl)ethyl]-4-(3, 4-dichlorophenyl)-3, 6-dihydro-2H- pyridine, hydrochloride. from 4-(3,4-dichlorophenyl)-3,6-dihydro-2H-pyridine and (+)-l-[2-(l-acetyl-2,3-dihydro-ii_^r-indol-

3-yl)ethylbromide. *H NMR (DMSO~d₆): 1.95-2.10 (m, IH); 2.20 (s, 3H); 2.25-2.35 (m, IH); 2.70- 2.80 (m, IH); 2.80-2.95 (m, IH); 3.15-3.30 ( , 3H); 3.45-3.55 (m, IH); 3.60-3.75 (m, IH); 3.75-

3.85 (m, IH); 3.85-3.90 (m, IH); 3.95-4.05 (m, IH); 4.25 (t, IH); 6.35 (s, IH); 7.05 (t, IH); 7.20 (t,

IH); 7.35 (d, IH); 7.50 (d, IH); 7.65 (d, IH); 7.75 (s, IH); 8.05 (d, IH). MS m/z: 415 (MH+).

lg, l-[2-(l-Acetyl-2, 3-dihydro-lH-indol-3-yl)ethyl]-4-(3, 4-dichlorophenyl)piperidine, hydrochloride. from 4-(3,4-dichlorophenyl)piperidine and (+)-l-[2-(l-acetyl-2,3-dihydro-iH-indol-3- yl)ethylbromide. Η NMR (DMSO-fl.): 1.95-2.35 (m, 6H); 2.20 (s, 3H); 2.80-2.95 (m, IH); 2.95- 3.25 (m, 4H); 3.50 (broad s, IH); 3.60 (d, 2H); 3.80-3.90 ( , IH); 4.25 (t, IH); 7.05 (t, IH); 7.20 (t, IH); 7.25 (d, IH); 7.30 (d, IH); 7.50 (s, IH); 7.60 (d, IH); 8.05 (d, IH). MS m/z: 417 (MH+). Pharmacological Testing

The compounds of the invention were tested in well recognised and reliable tests. The tests were as follows:

Inhibition of the binding of [³H]YM-09151-2 to D₄₂ receptors

By this method, the inliibition by drugs of the binding of fH]YM-09151-2 (0.06 nM) to membranes of human cloned dopamine D .₂ receptors expressed in CHO-cells is determined in vitro. The method is modified fromNEN Life Science Products, Inc., technical data certificate PC2533-10/96.

Inhibition of the binding of [³H]Ketanserin to 5-HT_2A receptors

The compounds were tested with respect to their affinity for 5-HT_2A receptors by determining their ability to inhibit binding of fH]Ketanserin (0.50 nM) to membranes from rat brain (cortex) in vitro. Method described in Sanchez et al. DrugDev. Res. 1991, 22, 239-250. In table 1 below, the test results are shown:

Table 1: Binding Data (% inhibition of binding at 5 nM)

The compounds of the invention have been found potently to inhibit the binding of tritiated YM- 09151-2 to dopamine D receptors. Further, the compounds bind potently to 5 -HT_2A receptors.

The compounds have also been tested in a functional assay described by Gazi et al. in Br. J. Pharmacol. 1999, 128, 613-620. In this test, the compounds were shown to be partial agonists or antagonists at the dopamine D receptors. The compounds of the invention have also been tested in the following tests:

Inhibition of the binding of [³H]Spiperone to rat dopamine D₂ receptors

The compounds were tested with respect to affinity for the dopamine D₂ receptor by determining their ability to inhibit the binding of [³H]-spiperone to D₂ receptors by the method of Hyttel et al. J. Neurochem, 1985, 44, 1615.

The compounds were found to have no substantial or only weak affinity for the dopamine D₂ receptor.

The compounds of the invention containing a tetrahydropyridine ring, i.e. compounds wherein X is CH and the dotted line indicates a bond, have particularly good pharmacokinetic properties.

Thus, the compounds of the invention are considered useful in the treatment of positive and negative symptoms of schizophrenia, other psychoses, anxiety disorders, such as generalised anxiety disorder, panic disorder, and obsessive compulsive disorder, depression, side effects induced by conventional antipsychotic agents, migraine, dyskinesia induced by treatment with L-dopa, attention deficit hyperactivity disorder and in the improvement of sleep quality. In particular, the compounds of the invention are considered useful in the treatment of positive and negative symptoms of schizophrenia without inducing extrapyramidal side effects.

Formulation Examples

The pharmaceutical formulations of the invention may be prepared by conventional methods in the art.

For example: Tablets may be prepared by mixing the active ingredient with ordinary adjuvants and/or diluents and subsequently compressing the mixture in a conventional tabletting machine. Examples of adjuvants or diluents comprise: corn starch, potato starch, talcum, magnesium stearate, gelatine, lactose, gums, and the like. Any other adjuvants or additives usually used for such purposes such as colourings, flavourings, preservatives etc. may be used provided that they are compatible with the active ingredients.

Solutions for injections may be prepared by dissolving the active ingredient and possible additives in a part of the solvent for injection, preferably sterile water, adjusting the solution to desired volume, sterilising the solution and filling it in suitable ampules or vials. Any suitable additive conventionally used in the art may be added, such as tonicity agents, preservatives, antioxidants, etc. Typical examples of recipes for the formulation of the invention are as follows:

1) Tablets containing 5.0 mg of a compound of the invention calculated as the free base:

Compound 5.0 mg

Lactose 60 mg

Maize starch 30 mg

Hydroxypropylcellulose 2.4 mg Microcrystalline cellulose 19.2 mg

Croscarmellose Sodium Type A 2.4 mg

Magnesium stearate 0.84 mg

2) Tablets containing 0.5 mg of a compound of the invention calculated as the free base:

Compound 0.5 mg

Lactose 46.9 mg

Maize starch 23.5 mg

Povidone 1.8 mg

Microcrystalline cellulose 14.4 mg

Croscarmellose Sodium Type A 1.8 mg

Magnesium stearate 0.63 mg

3) Syrup containing per millilitre:

Compound 25 mg

Sorbitol 500 mg

Hydroxypropylcellulose 15 mg

Glycerol 50 mg

Methyl-paraben l mg

Propyl-paraben 0.1 mg

Ethanol 0.005 ml

Flavour 0.05 mg

Saccharin sodium 0.5 mg

Water ad 1 ml ) Solution for injection containing per millilitre:

Compound 0.5 mg

Sorbitol 5.1 mg

Acetic Acid 0.05 mg

Saccharin sodium 0.5 mg

Water ad 1 ml

Claims

Claims

1. The use of a compound having the general formula

wherein R¹ is acyl, thioacyl, trifluoromethylsulfonyl, or R¹ is a group R¹²SO₂-, R¹²OCO- or R¹²SCO- wherein R¹² is Cι_₆-alkyl, C₂_₆-alkenyl, C₂.₆-alkynyl, C₃.₈-cycloalkyl, C₃_₈-cycloalkyl-Cι_₆-allcyl or aryl, or R¹ is a group R¹³R¹⁴NCO,- R¹³R¹⁴NCS-, wherein R¹³ and R¹⁴ are independently hydrogen, Ci.6-alkyl, C₂__δ-alkenyl, C₂_₆-alkynyl, C₃_₈-cycloalkyl, C₃_₈-cycloalkyl-Cι.₆-alkyl or aryl, or R¹³ and R¹⁴ together with the N-atom to which they are linked form a pyrrolidinyl, piperidinyl or perhydroazepin group;

n is 1-6;

X is C, CH or N, and the dotted line emanating from X indicates a bond when X is C and no bond when X is N or CH;

R', R" and R² are independently selected from hydrogen and Cι.₆-alkyl optionally substituted with halogen; and

R³-R^π are independently selected from hydrogen, halogen, cyano, nitro, Cι_₆-alkyl, C₂_₆-alkenyl, C₂_ ₆-alkynyl, C₃_₈-cycloalkyl, Ca-s-cycloalkyl- -e-alkyl, amino, Cι-₆-alkylamino, di-(Cι_₆-alkyl)amino, Cι.₆-alkylcarbonyl, aminocarbonyl, Cι_₆-alkylaminocarbonyl, di-(C₁_₆-alkyl)aminocarbonyl, Cι__- alkoxy, Cι_₆-alkylthio, hydroxy, trifluoromethyl, trifluoromethylsulfonyl and Cι_6-alkylsulfonyl;

or a pharmaceutically acceptable acid addition salt thereof, for the manufacture of a medicament useful in the treatment of positive and negative symptoms of schizophrenia, other psychoses, anxiety disorders, such as generalised anxiety disorder, panic disorder, and obsessive compulsive disorder, depression, aggression, side effects induced by conventional anti-psychotic agents, migraine, cognitive disorders, dyskinesia induced by treatment with L-dopa, attention deficit hyperactivity disorder and in the improvement of sleep quality.

2. The use of a compound according to claim 1 which is in the form of the S-enantiomer.

3. The use of a compound according to claims 1 -2 wherein R⁷ and R¹¹ are hydrogen.

4. The use of a compound according to claim 3 wherein R¹⁰ is hydrogen.

5. The compound of any of claims 1 -4 wherein X is CH and the dotted line indicates a bond.

6. The use of a compound according to claims 1-4 wherein at least one of R⁸ and R⁹ are independently selected from halogen, cyano, nitro, Cι_₆-alkyl, C₂_₆-alkenyl, C₂_₆-alkynyl, C₃.₈- cycloalkyl, C₃__s-cycloalkyl-Cι_₆-all_yl, amino, Cι_₆-alkylamino, di-(C₁_₆-allcyl)amino, C ₆- alkylcarbonyl, aminocarbonyl, Cι_₆-alkylaminocarbonyl, di-(Cι_₆-allcyl)aminocarbonyl, Cι_₆-alkoxy, Cι.₆-alkylthio, hydroxy, trifluoromethyl, trifluoromethylsulfonyl and Cι_₆-aTkylsulfonyl.

7. The use of a compound according to claims 1- 6 wherein n is 2 or 3, preferably 2.

8. The use of a compound according to claims 1-7 wherein R¹ is acyl.

9. The use of a compound according to claim 8 wherein R¹ is acetyl.

10. The use of claims 1-9 wherein R⁴ is hydrogen or fluoro.

11. The use of a compound according to claim 1 which is selected from

(+)-l-[2-(l-Acetyl-2,3-dihydro-/H-indol-3-yl)ethyl]-4-(3,4-dimethylphenyl)piperazine,

(+)-l-[2-(l-Acetyl-2,3-dihydro-iH-indol-3-yl)ethyl]-4-(4-methylphenyl)piperazine, (+)-l-[2-(l-Acetyl-2,3-dihydro-2H-indol-3-yl)ethyl]-4-(4-methylphenyl)piperidine, (+)-l-[2-(l-Acetyl-2,3-dihydro-iH-indol-3-yl)ethyl]-4-(3,4-dichlorophenyl)piperazine, (+)-l-[2-(l-Acetyl-2,3-dihydro-7H-indol-3-yl)ethyl]-4-(4-bromophenyl)piperazine, l-[2-(l-Acetyl-2,3-dihydro-lH-indol-3-yl)ethyl]-4-(3,4-dichlorophenyl)-3,6-dihydro-2H-pyridine, and l-[2-(l-Acetyl-2,3-dihydro-lH-indol-3-yl)ethyl]-4-(3,4-dichlorophenyl)piperidine,

or a pharmaceutically acceptable salt thereof.

12. An 3-indoline derivative of the general formula

wherein R¹ is acyl, thioacyl, trifluoromethylsulfonyl, or R¹ is a group R¹²SO₂, R¹²OCO- or R¹²SCO- wherein R¹² is Cι_₆-alkyl, C₂.₆-alkenyl, C₂_₆-alkynyl, C₃_8-cycloalkyl, C₃.₈-cycloalkyl-Cι_₆-alkyl or aryl, or R¹ is a group R¹³R¹⁴NCO,- R¹³R¹⁴NCS-, wherein R¹³ and R¹⁴ are independently hydrogen, Cι-₆-allcyl, C₂__δ-alkenyl, C₂_₆-alkynyl, C₃_₈-cycloalkyl, C₃.₈-cycloalkyl-Cι_6-alkyl or aryl, or R¹³ and R¹⁴ together with the N-atom to which they are linked form a pyrrolidinyl, piperidinyl or perhydroazepin group; and

n is 1-6;

X is C, CH or N, and the dotted line emanating from X indicates a bond when X is C and no bond when X is N or CH;

R', R" and R² are independently selected from hydrogen and Cι_₆-alkyl optionally substituted with halogen;

R³-R^u are independently selected from hydrogen, halogen, cyano, nitro, Cι_₆-alkyl, C₂_₆-alkenyl, C₂_ ₆-allcynyl, C₃_₈-cycloalkyl, C₃_₈-cycloalkyl-Cι_₆-alkyl, amino, Cι_₆-alkylamino, di-(Cι_6-alkyl)amino, Cι_₆-alkylcarbonyl, aminocarbonyl, Cι_₆-alkylaminocarbonyl, di-(Cι.₆-alkyl)aminocarbonyl, Cι_₆- allcoxy, Cι_₆-alkylthio, hydroxy, trifluoromethyl, trifluoromethylsulfonyl and Cι.₆-alkylsulfonyl;

with the proviso that

(i) R^J may not be hydrogen when R' , R", R -R^s, R -R¹ ' are hydrogen, n is 2 and R^J is acetyl

(ii) R^y may not be CF₃ or chloro, when R' , R" , R -R⁸, R -R^{l x} are hydrogen, X is C or CH, n is

2 and R¹ is acetyl;

(i) R⁷ or R¹¹ may not be methoxy when X is N, n is 2 or 4 and R¹ is acetyl; and (iv) R⁴ may not be methoxy;

or a pharmaceutically acceptable acid addition salt thereof.

13. A compound according to claim 12 which is in the form of the S-enantiomer.

14. A compound according to claims 12-13 wherein R⁷ and R¹¹ are hydrogen.

15. A compound according to claim 14 wherein R¹⁰ is hydrogen.

16. A compound of any of claims 12-15 wherein X is CH and the dotted line is a bond.

17. A compound according to claims 12-16 wherein at least one of R⁸ and R⁹ are selected from halogen, cyano, nitro, Cι__s-alkyl, C₂.₆-alkenyl, C₂_₆-alkynyl, C₃_₈-cycloallcyl, C₃„₈-cycloalkyl-Cι-₆- allcyl, amino, Cι_₆-alkylamino, di-(Cι_₆-alkyl)amino, Cι._.-allcylcarbonyl, Cι_.-alkoxy, Cι_₆-alkylthio, hydroxy, trifluoromethyl, trifluoromethylsulfonyl and Cι_₆-alkylsulfonyl.

18. A compound according to claims 12-17 wherein n is 2 or 3, preferably 2.

19. A compound according to claims 12-18 wherein R¹ is acyl.

20. A compound according to claim 19 wherein R¹ is acetyl.

21. A compound according to claims 12-20 wherein R is hydrogen or fluoro and R', R", R², R³, R⁵ and R⁶ are hydrogen.

22. A compound according to claim 12 which is selected from (+)-l-[2-(l-Acetyl-2,3-dihydro-7H-indol-3-yl)ethyl]-4-(3,4-dimethylphenyl)piperazine, (+)-l-[2-(l-Acetyl-2,3-dihydro-iH-indol-3-yl)ethyl]-4-(4-methylphenyl)piperazine, (+)-l-[2-(l-Acetyl-2,3-dihydro-iH-indol-3-yl)ethyl]-4-(4-methylphenyl)piperidine, (+)-l-[2-(l-Acetyl-2,3-dihydro-HEindol-3-yl)ethyl]-4-(3,4-dichlorophenyl)piperazine, (+)-l-[2-(l-Acetyl-2,3-dihydro-7-^£/-indol-3-yl)ethyl]-4-(4-bromophenyl)piperazine, l-[2-(l-Acet^l-2,3-d_hydro-lH-indol-3-yl)ethyl]-4-(3,4-dichlorophenyl)-3,6-dihyα^o-2H-pyr_dine, and l-[2-(l-Acetyl-2,3-dihydro-lH-indol-3-yl)ethyl]-4-(3,4-dichlorophenyl)piperidine, or a pharmaceutically acceptable salt thereof.

23. A pharmaceutical composition characterised in that it comprises a compound of any of claims 12 to 22 in a therapeutically effective amount together with one or more pharmaceutically acceptable carriers or diluents.

24. A method of treating the positive and negative symptoms of schizophrenia, other psychoses, anxiety disorders, such as generalised anxiety disorder, panic disorder, and obsessive compulsive disorder, depression, aggression, side effects induced by conventional anti-psychotic agents, migraine, cognitive disorders, dyskinesia induced by treatment with L-dopa, attention deficit hyperactivity disorder and in the improvement of sleep quality comprising administration of a therapeutically acceptable amount of a compound according to any of claims 12 to 22.