HK1109622A - Tetrahydropyridin-4-yl indoles with a combination of affinity for dopamine-d2 receptors and serotonin reuptake sites - Google Patents

Description

For dopamine-D2Tetrahydropyridin-4-yl indoles with combined affinity for receptor and 5-hydroxytryptamine reuptake site

The present invention relates to a group of novel tetrahydropyridin-4-yl indoles with a dual mode of action: i.e. inhibition of 5-hydroxytryptamine reuptake and dopamine-D₂The receptors have affinity, to processes for the preparation of these compounds and to novel intermediates useful in the synthesis of said tetrahydropyridin-4-yl indoles. The invention also relates to the use of a compound disclosed herein for the preparation of a medicament having a beneficial effect. Such benefits are disclosed herein or will be apparent to those skilled in the art from the specification and general knowledge in the art. The invention also relates to the use of a compound of the invention for the preparation of a medicament for the treatment or prevention of a disease or condition. More particularly, the present invention relates to a novel use for the treatment or prevention of a disease or condition, such use having been herein describedAre disclosed in or are obvious to one skilled in the art from the specification or from common general knowledge in the art. In an embodiment of the invention, the use of a particular compound disclosed herein for the preparation of a medicament for the treatment of dopamine-D₂Drugs that are disorders of the receptor and the site of 5-hydroxytryptamine reuptake, or which disorders can be treated by acting on the above targets.

WO 00/023441 and WO 00/069424 disclose dopamine-D₂The dual action tetrahydropyridin-4-yl indole derivatives of antagonists and 5-hydroxytryptamine reuptake inhibitors, Van Hes et al (Bioorganic and Medicinal Chemistry Letters, 13(3), 405-408, 2003) further describe candidate compounds of these patents having clinical potential. In the literature published by Timms et al (Bioorganic and Medicinal Chemistry Letters, 14(10), 2469-2472, 2004), it is described 5-HT of 5-hydroxytryptamine_1DTetrahydropyridin-4-yl indole derivatives with dual action as antagonists and 5-hydroxytryptamine reuptake inhibitors, and some compounds in this group have also been shown to have dopamine-D activity₂Antagonistic activity. WO 2004/020437 describes a dopamine-D as a dopamine₄Specific compounds of antagonists and 5-hydroxytryptamine reuptake inhibitors: s- (+) -3- {1- [2- (2, 3-dihydro-1H-indol-3-yl) ethyl]-3, 6 dihydro-2H-pyridin-4-yl } -6-chloro-1H-indole. It is not disclosed that the compound has dopamine-D₂Affinity c.q. activity.

It is an object of the present invention to provide other compounds having dopamine-D₂Antagonist and 5-hydroxytryptamine reuptake inhibitor.

A novel group of 1, 2, 3, 6-tetrahydropyridin-4-yl indoles of formula (I) has surprisingly been found

And a method of producing the sameTautomers, stereoisomers, prodrugs, N-oxides, pharmacologically acceptable salts, hydrates and solvates have potent dopamine-D₂Antagonist activity and potent 5-hydroxytryptamine reuptake inhibitor activity.

Wherein:

-R₁is hydrogen, halogen, alkyl (C)_1-3) Or alkoxy (C)_1-3) CN or CF₃，

-R₂Is hydrogen or alkyl (C)_1-3)，

-R₃Is hydrogen or alkyl (C)_1-3)，

Z is hydrogen or alkyl (C)_1-3) Alkoxy (C)_1-3) Or alkylthio (C)_1-3)，

A is hydrogen or alkyl (C)_1-3) Or is or

-A and Z together form a saturated or (partially) unsaturated five-or six-membered ring, which may be substituted by halogen, alkyl (C)_1-3) Or phenyl substitution, wherein ring Z represents carbon, sulfur or nitrogen.

Alkyl (C) in the above substituents_1-3) Meaning methyl, ethyl, n-propyl or isopropyl.

Prodrugs of the above compounds are also included within the scope of the present invention. A prodrug is a drug that is not active by itself, but may be converted to one or more active metabolites. Prodrugs are bioreversible derivatives of drug molecules that overcome some of the obstacles to the use of the parent drug molecule. These obstacles include, but are not limited to, solubility, permeability, stability, pre-system metabolism and targeting limitations (Medicinal Chemistry: Principles and Practice, 1994, ISBN0-85186 494-5, Ed., F.D. King, p.215; J.Stella, "Prodrugs therapeutics,Expert Opin.Ther.Patents， 14(3) 277-280, 2004; ettmayer et al, "letters from marked and linked structural precursors", J.Med.chem., 47, 2393-. A prodrug form of a compound of formula (I),i.e. compounds which are metabolized to compounds of formula (1) when administered by any known route, are encompassed by the present invention. In particular, it relates to compounds having primary or secondary amines or hydroxyl groups. These compounds can be reacted with organic acids to give compounds containing the structure of formula (1) wherein the additional groups present are easily removed after administration, such as, but not limited to, amidines, enamines, Mannich bases, hydroxy-methylene derivatives, O- (acyloxymethylene carbamate) derivatives, carbamates, esters, amides or enaminones.

N-oxides of the above compounds are included in the scope of the present invention. Tertiary amines may or may not produce N-oxide metabolites. The degree of N-oxidation that occurs varies from trace to near quantitative conversion. The activity of the N-oxide may be higher or lower than that of the corresponding tertiary amine. At the same time, N-oxides are readily reduced chemically to the corresponding tertiary amines, but to a different extent in the human body. Some N-oxides are reduced almost quantitatively to the corresponding tertiary amines, while in other cases the conversion is only a minor reaction or even no reaction at all. (M.H.Bickel:The pharmacology and Biochemistry of N-oxides″， Pharmacological Reviews， 21(4)，325-355，1969)。

preferably the compounds of the invention have the formula (I) wherein R₁Is hydrogen or halogen, R₂Is hydrogen, R₃Is CH₃Z is SCH₃And A is CH₃Or Z + A may be formed by CH₃、C₂H₅Or i-C₃H₇Substituted (partially) unsaturated six-membered rings.

Particular preference is given to compounds having the structure of formula (I) in which R₁＝R₂＝H，R₃Is CH₃Z + A together represent C (CH)₃) CH-CH ═ CH-, and salts thereof.

Compounds of the invention have been found to be useful for dopamine D₂The receptor and the 5-hydroxytryptamine reuptake site show high affinity. The combination is useful for the treatment of schizophrenia and the likeIt is a psychiatric disorder that allows more complete treatment of all disease symptoms (e.g., positive and negative).

Some compounds having the structure of formula (I) show partial agonist activity at dopamine receptors, which makes them particularly suitable for the treatment of parkinson's disease.

These compounds are shown to be dopamine D₂Receptor antagonists are active because they potentially antagonize apomorphine-induced mouse climbing behavior. These compounds also show activity as 5-hydroxytryptamine reuptake inhibitors, as they potentiate 5-HTP-induced behavior in mice.

These compounds are active in therapeutic models sensitive to clinically useful neuroleptics (e.g., the benzodiazepine response; Van der Heyden & Bradford, Behav. Bra in Res., 1988, 31: 61-67) and antidepressants or anxiolytics (stress-induced voidation; Van der Poel et al, Psycho-pharmacology, 1989, 97: 147-148).

Dopamine D for clinical application₂In contrast to receptor antagonists, the compounds have a lower propensity to cause rodent catalepsy and, thus, cause fewer extrapyramidal side effects than existing neuroleptics.

Intrinsic 5-hydroxytryptamine reuptake inhibition activity may be responsible for the efficacy of these compounds in behavioral models sensitive to antidepressants or anxiolytics.

These compounds are useful in the treatment of mood disorders or disorders of the central nervous system caused by disorders of the dopaminergic or 5-hydroxytryptamine systems, such as: aggression, anxiety disorders, autism, vertigo, depression, cognitive or memory disorders, parkinson's disease, in particular schizophrenia, and other psychotic disorders.

Summary of The Invention

Compounds having the structure of formula (I) can be prepared by reacting compounds of formula (II)

With compounds of the formula (III)

Prepared by reaction

Wherein

R₁、R₂、R₃Z and A have the aforementioned meanings, and L is a so-called leaving group, such as halogen or methylsulfonyl.

The reaction is preferably carried out in an organic solvent such as acetonitrile, triethylamine or K₂CO₃And KI in the presence of KI at reflux temperature.

The starting compounds for the synthesis of formula (II) can be obtained by reacting optionally substituted indole derivatives with 4-piperidones by methods known per se.

The starting compounds having the structure of formula (III) can be obtained by known methods for the synthesis of analogous compounds.

The choice of a particular synthetic method depends on factors known to those skilled in the art, such as the compatibility of the reactant functionality with the reagents used, the possibility of using protecting groups, catalysts, activators and coupling agents, and the final structural characteristics in the final product prepared.

Pharmaceutically acceptable salts can be prepared using standard procedures well known in the art, for example by mixing a compound of the invention with a suitable acid, for example an inorganic acid such as hydrochloric acid, or an organic acid.

Pharmaceutical preparation

The compounds of the invention may be brought into a form suitable for administration by conventional means using excipients such as liquid or solid carrier materials. The pharmaceutical compositions of the present invention may be administered enterally, orally, parenterally (intramuscularly or intravenously), rectally or topically. They may be administered in the form of solutions, powders, tablets, capsules (including microcapsules), ointments (creams or gels) or suppositories. Suitable excipients for these preparations are pharmaceutically customary liquid or solid fillers and admixtures, solvents, emulsifiers, lubricants, flavorings, colorants and/or buffer substances. Frequently used adjuvants which may be mentioned are magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, milk protein, gelatin, starch, cellulose and its derivatives, animal and vegetable oils (e.g. cod liver oil, sunflower seed, peanut or sesame oil), polyethylene glycols and solvents (e.g. sterile water and mono-or polyhydric alcohols such as glycerol).

The compounds of the present invention are generally administered in the form of pharmaceutical compositions which are important and novel embodiments of the present invention due to the presence of these compounds, particularly the specific compounds disclosed herein. Types of pharmaceutical compositions can include, but are not limited to, tablets, chewable tablets, capsules, solutions, parenteral solutions, suppositories, suspensions, and other dosage forms disclosed herein or apparent to one of skill in the art in light of the specification and general knowledge in the art. In an embodiment of the invention, a pharmaceutical assembly or kit is provided comprising one or more containers filled with one or more of the ingredients of the pharmaceutical composition of the invention. Various written materials such as instructions for use, or instructions in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals, may be contained with such container(s) which reflect approval by the governmental agency obtaining manufacture, use or sale of pharmaceuticals for human or livestock.

Pharmacological methods

In vitro for dopamine-D₂Affinity of receptor

Compounds for dopamine-D₂The affinity of the receptor is determined by receptor binding assays described in the following references: creese, r.schneider and s.h.snyder: "2³H]Spiroperidol labels dopamin receptors in ratitupituity and brain ", Eur.J.Pharmacol., 46, 377-381, 1977.

Affinity for 5-hydroxytryptamine reuptake site in vitro

The affinity of a compound for the 5-hydroxytryptamine reuptake site is determined by the receptor binding assay described in: e.haber t et al: "Characterisation of³H]-parooxetine binding to rat diagnostic membranes ", Eur.J. Pharmacol, 118, 107-.

Dosage form

Compounds of the invention for dopamine-D₂The affinity of the receptor and the 5-hydroxytryptamine reuptake site was determined by the method described above. The theoretical lowest effective dose can be estimated from the binding affinities measured for a given compound of formula (1). When the concentration of the compound is equal to the determined K_iAt twice the value, it is likely that 100% of the receptors will be occupied by the compound. Given the ideal bioavailability, converting this concentration to mg of compound per kg of patient would result in the theoretical lowest effective dose. Pharmacokinetic, pharmacodynamic and other factors may alter the actual dose administered above or below the above values. Conveniently, the dose is 0.001-1000mg/kg, preferably 0.1-100mg/kg, of patient body weight.

Treatment of

The term "treatment" as used herein refers to any treatment of a condition or disease in a mammal, preferably a human, including: (1) preventing a disease or disorder in a subject who may have a predisposition to develop but has not yet been diagnosed with the disease (2) inhibiting the disease or disorder, i.e., arresting its development, (3) alleviating the disease or disorder, i.e., reducing the disorder, or (4) alleviating the disorder caused by the disease, i.e., arresting the symptoms of the disease.

The preparation of the compounds having the structure of formula (I) is described in detail in the following examples.

Examples

Example 1: materials and methods

¹H and¹³c NMR spectra were recorded by Bruker Avance DRX600 instrument (600MHz), Varian UN400 instrument (400MHz) or Varian VXR200instrument (200MHz) using DMSO-D₆Or CDCl₃As solvent, tetramethylsilane was used as internal standard. Chemical shifts are given in ppm (delta ratio) in terms of the low field of tetrasilane. The coupling constants (J) are expressed in Hz. Flash chromatography was performed using silica gel 60(0.040-0.063 mmMerck). Chromatography was performed with gel 60(0.063-0.200mm Merck). Melting points were recorded by a B ü chi B-545 melting point apparatus. Mass spectra were recorded by a Micromass QTOF-2 instrument with MassLynx application software to obtain and reconstruct the data. Using excimer ions [ M + H]⁺The exact molecular weight was determined.

Example 2: synthesis of specific Compounds

Compound 26

a) 5-fluoro-3- (1, 2, 3, 6, -tetrahydropyridin-4-yl) indole.

To a solution of sodium (60g, 2.6 mol) in 1000ml of methanol was added 5-fluoroindole (49g, 0.36mol) and 4-piperidone₂HCl (170g, 1.11 mol). The mixture was heated at reflux for 18h, then concentrated, water was added and extracted with ethyl acetate. The organic layers were combined and dried over sodium sulfate, then concentrated. The resulting solid was dissolved in methanol (about 200ml) and then diluted with water (about 1000 and 1500 ml). The precipitate was collected, washed with water and petroleum ether and then dried under vacuum at 60 ℃. 74g (95%) of a yellow solid are obtained.

b)3- (2-chloroethyl) -2, 9-dimethyl-4H-pyrido [1, 2-a]Of (4-pyrimidineones) Preparation of

To a solution of 2-amino-3-methylpyrimidine (3.3g, 30mmol) in phosphorus oxychloride (11ml) was added 2-acetylbutyrolactone (3.25ml, 30 mmol). The mixture was heated at 100 ℃ for 18 hours, cooled, poured onto ice, basified with 2N sodium hydroxide solution and extracted with ethyl acetate. The organic layer was separated, dried, concentrated and purified by silica gel column chromatography (dichloromethane/methanol-95/5). 2.5g (35%) of a white solid are obtained.

c)3- [2- [4- (5-fluoro-1H-indol-3-yl) -1, 2, 3, 6-tetrahydro-pyridin-1-yl]Second step Base of]-2, 9-dimethyl-4H-pyrido [1, 2-a]Preparation of pyrimidin-4-one.

A solution of 5-fluoro-3- (1, 2, 3, 6-tetrahydropyridin-4-yl) indole (5.5g, 0.025mol), 3- (2-chloroethyl) -2, 9-dimethyl-4H-pyrido [1, 2-a ] pyrimidin-4-one (7.2g, 0.030mol), diisopropylamine (5ml) and potassium iodide (1g) in acetonitrile (100ml) was heated under reflux for 24H. After cooling, the precipitate was collected and washed with acetonitrile (20ml), isopropanol (3X 20ml) and petroleum ether (25ml) respectively. This gave 7.13g (67%) of a pale yellow solid. M.p.: 229 ℃ and 230 ℃.

Free base of Compound 22

a) Preparation of 3- (1, 2, 3, 6-tetrahydropyridin-4-yl) indole.

To a solution of sodium methoxide (450ml, 30% in methanol, 2.5mol) in 1000ml of methanol was added indole (50g, 0.427mol) and 4-piperidone H₂HCl (162g, 1.05 mol). The mixture was heated to reflux for 18h to form a yellow precipitate. The mixture was concentrated and water (1000ml) was added. The precipitate was collected, washed with water and petroleum ether and then dried in a vacuum oven at 50 ℃. 77g (91%) of a pale yellow solid are obtained.

b)3- [2- [4- (1H-indol-3-yl) -1, 2, 3, 6-tetrahydropyridin-1-yl]-B Base of]-2, 9-dimethyl-4H-pyrido [1, 2-a]Preparation of pyrimidin-4-one.

A solution of 3- (1, 2, 3, 6-tetrahydropyridin-4-yl) indole (25g, 0.126mol), 3- (2-chloroethyl) -2, 9-dimethyl-4H-pyrido [1, 2-a ] pyrimidin-4-one (33g, 0.139mol) and potassium carbonate (17.5g, 0.127mol) in acetonitrile (500ml) and water (100ml) was heated to reflux for 18H. After cooling, the precipitate was collected and washed with water, isopropanol and petroleum ether, respectively, to give 38g (76%) of a pale yellow solid. M.p.: 210 ℃ and 212 ℃.

Compound 12

a) Preparation of 2-thio-5- (2-hydroxyethyl) -6-methyluracil.

To a solution of sodium (55.6g, 2.4mol) in ethanol (1000ml) was added 2-acetylbutyrolactone (155g, 1.2mol) slowly followed by thiourea (128g, 1.65mol) in small portions. The mixture was heated to reflux for 16h, then concentrated, water (800ml) was added and acidified slowly with concentrated hydrochloric acid (200 ml). The precipitate was collected and washed with water, isopropanol and petroleum ether. 125g (56%) of a white solid are obtained.

b) Preparation of 2-methylthio-5- (2-hydroxyethyl) -6-methyl-3H-pyrimidin-4-one.

To a suspension of 2-thio-5- (2-hydroxyethyl) -6-methyluracil (50g, 0.26mol) in DMF (320ml) was slowly added one equivalent of sodium hydride. One equivalent of methyl iodide (16.6ml) was then added slowly. The mixture was stirred at 30 ℃ for two hours, followed by addition of water (800 ml). The precipitate was collected and washed with water, isopropanol and petroleum ether. Yield 34.4g (64%).

c) Preparation of 2-methylthio-5- (2-hydroxyethyl) -3, 6-dimethyl-3H-pyrimidin-4-one.

To a suspension of 2-methylsulfanyl-5- (2-hydroxyethyl) -6-methyl-3H-pyrimidin-4-one (34g, 0.17mol) in DMF (300ml) was slowly added one equivalent of sodium hydride (55%, 7.4 g). One equivalent of methyl iodide (10.5ml) was then added slowly. The mixture was stirred at 50 ℃ for two hours, followed by removal of most of the DMF in vacuo. Water was added and the mixture was extracted with ethyl acetate. The organic layers were combined and dried over sodium sulfate, then concentrated and purified by flash chromatography (eluent: diethyl ether followed by diethyl ether/methanol-9/1). Yield 20.3g (56%), mp.117-118 ℃.

d) 2-methylthio-5- (2-chloroethyl)) Preparation of (E) -3, 6-dimethyl-3H-pyrimidin-4-one.

To a solution of 2-methylsulfanyl-5- (2-hydroxyethyl) -3, 6-dimethyl-3H-pyrimidin-4-one (20.3g, 0.095mol) in chloroform (200ml) was added one equivalent of pyridine (7.6ml) followed by three equivalents of thionyl chloride (21ml) slowly. After stirring for 15 min, the mixture was concentrated and water (300ml) was added. The precipitate was collected and washed with water, isopropanol and petroleum ether. Yield 34.4g (64%). Yield 20.3g (92%). Mp.135-137 deg.C.

e)5- [2- [4- (1H-indol-3-yl) -1, 2, 3, 6-tetrahydropyridin-1-yl]-B Base of]Preparation of (E) -2-methylthio-3, 6-dimethyl-3H-pyrimidin-4-one.

To a solution of 3- (1, 2, 3, 6-tetrahydropyridin-4-yl) indole (1.0g, 5mmol) in acetonitrile (30ml) was added 2-methylsulfanyl-5- (2-chloroethyl) -3, 6-dimethyl-3H-pyrimidin-4-one (1.42g, 6.1mmol), potassium iodide (0.84g, 5mmol) and triethylamine (1.4ml, 10 mmol). The mixture was heated at 80 ℃ for 8h, cooled, concentrated and purified by flash chromatography (dichloromethane/methanol/ammonia-95/4.5/0.5). Yield: yellow compound 1.83g (92%). Mp.245-246 ℃.

Compound 18

a) Preparation of 2-methoxy-5- (2-hydroxyethyl) -6-methyl-3H-pyrimidin-4-one.

To a solution of O-methylisourea hydrogen sulfate (17.2g, 0.1mol) in water (90ml) was added calcium hydroxide (8.14g, 0.11mol), followed by a solution of 2-acetylbutyrolactone (10.7ml, 0.1mol) in ethanol (70 ml). The mixture was stirred at room temperature for two days, filtered and washed with ethanol. The filtrate was concentrated in vacuo and purified by flash chromatography (dichloromethane/methanol-95/5). 2.6g (14%) of a white solid are obtained.

b) Preparation of 2-methoxy-5- (2-hydroxyethyl) -3, 6-dimethyl-3H-pyrimidin-4-one.

To a suspension of 2-methoxy-5- (2-hydroxyethyl) -6-methyl-3H-pyrimidin-4-one (2.6g, 0.014mol) in DMF (25ml) was added one equivalent of sodium hydride (55%, 0.6 g). After stirring for 0.5h, iodomethane (0.81ml, 0.014mol) was added and the mixture was heated at 50 ℃ for 5 h. After cooling, most of the DMF was removed in vacuo. Water was added and the mixture was extracted with ethyl acetate. The organic layers were combined and dried over sodium sulfate and then concentrated. This gave 2.0g (71%) of a yellow oil.

c) 2-methoxy-5- (2-methylsulfonyloxyethyl) -3, 6-dimethyl-3H-pyrimidine-4- And (3) preparing ketone.

To a solution of 2-methoxy-5- (2-hydroxyethyl) -3, 6-dimethyl-3H-pyrimidin-4-one (2.0g, 0.01mol) in dry ethyl acetate (100ml) was added triethylamine (2.7 ml). After cooling in ice water, methanesulfonyl chloride (0.9ml, 0.011mol) was added slowly. After stirring at room temperature for 16h, the precipitate was filtered off and the filtrate (70ml) was used without further purification.

d)5- [2- [4- (1H-indol-3-yl) -1, 2, 3, 6-tetrahydropyridin-1-yl]-B Base of]Preparation of (E) -2-methoxy-3, 6-dimethyl-3H-pyrimidin-4-one.

To the above filtrate (35ml, ca. 5mmol) were added 3- (1, 2, 3, 6-tetrahydropyridin-4-yl) indole (1.0g, 5mmol), triethylamine (2ml), potassium iodide (0.84g, 5mmol) and acetonitrile (50 ml). The mixture was heated at 80 ℃ for 16h, then concentrated and purified by flash chromatography (eluent: dichloromethane/methanol/ammonia ═ 95/4.5/0.5). Yield 0.5g (26%), mp.209-211 ℃.

The compounds of formula (I) listed in the following table were prepared according to the methods of examples 1-4.

No	R1	R2	R3	Z	A	(Z+A)Z A	Salts or free bases	Melting Point (. degree.C.)
									1	H	H	CH3	-	-	-CH＝CH-CH＝CH-	HCl	205 (decomposition)
2	7-Cl	H	CH3	-	-	-CH＝CH-CH＝CH-	fb	232-3
									3	5-CH3	H	CH3	-	-	-CH＝CH-CH＝CH-	fb	206-7
4	6-Cl	H	CH3	-	-	-CH＝CH-CH＝CH-	fb	246-8
									5	5-Cl	H	CH3	-	-	-CH＝CH-CH＝CH-	fb	Amorphous form
6	5-CN	H	CH3	-	-	-CH＝CH-CH＝CH-	fb	Amorphous form
									7	5-F	H	CH3	-	-	-CH＝CH-CH＝CH-	fb	226-7(d.)
8	5-Br	H	CH3	-	-	-CH＝CH-CH＝CH-	HCl	Amorphous form
									9	H	H	CH3	-	-	-CH＝CH-C(CH3)＝CH-	HCl	Amorphous form
10	H	H	CH3	-	-	-S-CH2-CH2-	HCl	Amorphous form
									11	H	H	CH3	-	-	-S-CH＝CH-	HCl	Amorphous form
12	H	H	CH3	SCH3	CH3	-	fb	245-6
									13	7-CH3	H	CH3	-	-	-CH＝CH-CH＝CH-	fb	226-7
14	H	H	CH3	SCH3	H	-	fb	Amorphous form
									15	H	H	CH3	-	-	-CH＝C(CH3)-CH＝CH-	HCl	261-4
16	H	H	CH3	-	-	-S-CH＝C(C6H5)-	fb	220-3
									17	H	H	CH3	-	-	-NH-(CH2)3-	fb	249-52
18	H	H	CH3	OCH3	CH3	-	HCl	209-11
									19	5-F	H	CH3	SCH3	CH3	-	fb	229 (decomposition)
20	H	CH3	CH3	SCH3	CH3	-	HCl	Amorphous form
									21	5-F	H	CH3	-	-	-CH＝C(CH3)-CH＝CH-	fb	Glass body
22	H	H	CH3	-	-	-C(CH3)＝CH-CH＝CH-	CH3SO3H	242-6
									23	H	H	CH3	-	-	-CH＝CH-CH＝C(CH3)-	fb	207-9
24	5-F	H	CH3	-	-	-CH＝C(C2H5)-CH＝CH-	fb	198-201
									25	H	H	CH3	-	-	-CH＝C(C2H5)-CH＝CH-	fb	203-7
26	5-F	H	CH3	-	-	-C(CH3)＝CH-CH＝CH-	fb	229-30
									27	H	H	CH3	-	-	-CH＝C(C6H5)-CH＝CH-	fb	211-24
28	5-F	H	CH3	-	-	-CH＝C(i-C3H7)-CH＝CH-	fb	Amorphous form
									29	H	H	CH3	-	-	-CH＝C(i-C3H7)-CH＝CH-	fb	202-4
30	5-Cl	H	C2H5	H	CH3	-	fb	204-7
									31	5-Br	H	C2H5	H	CH3	-	fb	205-8
32	5-CN	H	C2H5	H	CH3	-	fb	227-30
									33	5-F	H	CH3	H	CH3	-	fb	234-5(d.)

Example 3: formulation of Compound 22 in animal studies

For oral (p.o.) administration: a quantity of glass beads was added to the desired amount (0.5-5mg) of solid compound 22 in a glass tube and the solid was rotary milled for 2 minutes. After addition of 1ml of 1% aqueous methylcellulose and 2% (v/v) Poloxamer 188(Lutrol F68), the mixture was spun for 10 minutes to form a suspension of the compound. A few drops of aqueous NaOH (0.1N) were used to adjust the pH to 7. The remaining particles were further suspended using an ultrasonic bath.

For intraperitoneal (i.p.) administration: a quantity of glass beads was added to the desired amount (0.5-15mg) of solid compound 22 in a glass tube and the solid was rotary milled for 2 minutes. After adding 1ml of 1% methylcellulose and 5% mannitol aqueous solution, the compound was suspended by rotation for 10 minutes. Finally the pH was adjusted to 7.

Example 4: results of pharmacological tests

dopamine-D obtained according to the above experimental method₂And 5-hydroxytryptamine reuptake receptor affinity data are shown in the table below.

TABLE 2 in vitro affinity of the Compounds of the invention

	Affinity in vitro
				dopamine-D2	5-HT reuptake
Compound (I)	pKi	pKi
1	7.7	8.8
			7	7.8	9.5
10	7.8	8.8
			11	8.0	8.6
14	7.0	7.3
			15	8.1	8.4
18	7.5	9.1
			19	8.2	7.6
20	7.0	8.1
			21	7.5	9.8
22	8.1	8.8
			24	8.0	8.1
27	7.2	9.5
			33	7.3	8.5

Claims (10)

1. Tetrahydropyridin-4-yl indole derivatives of formula (I):

and tautomers, stereoisomers, prodrugs, N-oxides, pharmacologically acceptable salts, hydrates and solvates thereof,

wherein:

-R₁is hydrogen, halogen, alkyl (C)_1-3) Or alkoxy (C)_1-3)、CNOr CF₃，

-R₂Is hydrogen or alkyl (C)_1-3)，

-R₃Is hydrogen or alkyl (C)_1-3)，

Z is hydrogen or alkyl (C)_1-3) Alkoxy (C)_1-3) Or alkylthio (C)_1-3)，

A is hydrogen or alkyl (C)_1-3) Or is or

-A and Z together form a saturated or (partially) unsaturated five-or six-membered ring, which may be substituted by halogen, alkyl (C)_1-3) Or phenyl substitution, wherein ring Z represents carbon, sulfur or nitrogen.

2. The compound of claim 1, wherein R is selected from the group consisting of tautomers, stereoisomers, prodrugs, N-oxides, pharmacologically acceptable salts, hydrates and solvates thereof₁Is hydrogen or halogen, R₂Is hydrogen, R₃Is CH₃Z is SCH₃And A is CH₃Or Z + A may be formed by CH₃、C₂H₅Or i-C₃H₇Substituted (partially) unsaturated six-membered rings.

3. The compound of claim 1, wherein R is selected from the group consisting of tautomers, stereoisomers, prodrugs, N-oxides, pharmacologically acceptable salts, hydrates and solvates thereof₁＝R₂＝H，R₃Is CH₃And Z + A together represent-C (CH)₃)＝CH-CH＝CH-。

4. The compound of claim 1, selected from:

R₁ R₂ R₃ Z A (Z+AlZA H H CH₃ - - -CH＝CH-CH＝CH- 7-Cl H CH₃ - - -CH＝CH-CH＝CH- 5-CH₃ H CH₃ - - -CH＝CH-CH＝CH- 6-Cl H CH₃ - - -CH＝CH-CH＝CH- 5-Cl H CH₃ - - -CH＝CH-CH＝CH- 5-CN H CH₃ - - -CH＝CH-CH＝CH- 5-F H CH₃ - - -CH＝CH-CH＝CH- 5-Br H CH₃ - - -CH＝CH-CH＝CH- H H CH₃ - - -CH＝CH-C(CH₃)＝CH- H H CH₃ - - -S-CH₂-CH₂- H H CH₃ - - -S-CH＝CH- H H CH₃ SCH₃ CH₃ - 7-CH₃ H CH₃ - - -CH＝CH-CH＝CH- H H CH₃ SCH₃ H - H H CH₃ - - -CH＝C(CH₃)-CH＝CH- H H CH₃ - - -S-CH＝C(C₆H₅)- H H CH₃ - - -NH-(CH₂)₃- H H CH₃ OCH₃ CH₃ - 5-F H CH₃ SCH₃ CH₃ - H CH₃ CH₃ SCH₃ CH₃ - 5-F H CH₃ - - -CH＝C(CH₃)-CH＝CH- H H CH₃ - - -C(CH₃)＝CH-CH＝CH- H H CH₃ - - -CH＝CH-CH＝C(CH₃)- 5-F H CH₃ - - -CH＝C(C₂H₅)-CH＝CH- H H CH₃ - - -CH＝C(C₂H₅)-CH＝CH- 5-F H CH₃ - - -C(CH₃)＝CH-CH＝CH- H H CH₃ - - -CH＝C(C₆H₅)-CH＝CH- 5-F H CH₃ - - -CH＝C(i-C₃H₇)-CH＝CH- H H CH₃ - - -CH＝C(i-C₃H₇)-CH＝CH- 5-Cl H C₂H₅ H CH₃ - 5-Br H C₂H₅ H CH₃ - 5-CN H C₂H₅ H CH₃ - 5-F H CH₃ H CH₃ -

and tautomers, stereoisomers, prodrugs, N-oxides, pharmacologically acceptable salts, hydrates and solvates thereof.

5. The process for preparing a compound according to claim 1, wherein the compound having the structure of formula (II) is reacted under basic conditions

With a compound having the structure of formula (III)

Wherein the symbols have the meaning given in claim 1 and L is a so-called leaving group.

6. A pharmaceutical composition comprising, as active ingredient, at least one compound according to claim 1 or a salt thereof, in addition to a pharmaceutically acceptable carrier and/or at least one pharmaceutically acceptable adjuvant.

7. A process for preparing a composition according to claim 6, characterized in that a compound according to claim 1 is brought into a form suitable for administration.

8. A compound according to any one of claims 1 to 4, or a salt thereof, for use as a medicament.

9. Use of a compound according to any one of claims 1-4 for the preparation of a pharmaceutical composition for the treatment of CNS disorders.

10. Use according to claim 9, characterized in that the CNS disorder is aggression, anxiety disorders, autism, vertigo, depression, cognitive or memory disorders, schizophrenia and other psychotic disorders.