WO2006061373A2 - Tetrahydropyridin-4-yl indoles with a combination of affinity for dopamine-d2 receptors and serotonin reuptake sites - Google Patents
Tetrahydropyridin-4-yl indoles with a combination of affinity for dopamine-d2 receptors and serotonin reuptake sites Download PDFInfo
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- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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- C07D513/04—Ortho-condensed systems
Abstract
The present invention relates to a group of novel tetrahydropyridin-4-yl indoles with a dual mode of action: serotonin reuptake inhibition and affinity for dopamine -D2 receptors, to methods for the preparation of these compounds and to novel intermediates useful for the synthesis of said tetrahydropyridin-4-yl indoles. The invention also relates to the use of a compound disclosed herein for the manufacture of a medicament giving a beneficial effect. The invention relates to novel tetrahydropyridin -4-yl indoles of the formula (I) and tautomers, stereoisomers, prodrugs, N -oxides, pharmacologically acceptable salts, hydrates and solvates thereof , wherein: - R1 is hydrogen, halogen, alkyl (C1-3) or alkoxy(C1-3), CN or CF3, - R2 is hydrogen or alkyl (C1-3), R3 is hydrogen or alkyl (C1-3), - Z is hydrogen or alkyl (C1-3), alkoxy(C1-3) or alkylthio(C1-3), - A is hydrogen or alkyl (C1-3), or - A and Z together form a saturated or (partly) unsaturated 5 - or 6- membered ring which may be substituted with halogen, alkyl (C1-3) or phenyl, in which ring Z represents carbon, sulfur of nitrogen .
Description
TETRAHYDROPYRIDIN -4-YL INDOLES WITH A COMBINATION OF AFFINITY FOR DOPAMINE-D2 RECEPTORS AND SEROTONIN REUPTAKE SITES
The present invention relates to a group of novel tetrahydropyridin-4-yl indoles with a dual mode of action: serotonin reuptake inhibition and affinity for dopamine-D2 receptors, to methods for the preparation of these compounds and to novel intermediates useful for the synthesis of said tetrahydropyridin-4-yl indoles. The invention also relates to the use of a compound disclosed herein for the manufacture of a medicament giving a beneficial effect. A beneficial effect is disclosed herein or apparent to a person skilled in the art from the specification and general knowledge in the art. The invention also relates to the use of a compound of t he invention for the manufacture of a medicament for treating or preventing a disease or condition. More particularly, the invention relates to a new use for the treatment of a disease or condition disclosed herein or apparent to a person skilled in the art from the specification and general knowledge in the art. In embodiments of the invention specific compounds disclosed herein are used for the manufacture of a medicament useful in the treatment of disorders in which dopamine -D2 receptors and serotonin reuptake sites are involved, or that can be treated via manipulation of those targets.
Tetrahydropyridin-4-yl indole derivatives with a dual action as dopamine -D2 antagonists and serotonin reuptake inhibitors are known from WO 00/023441 and WO 00/069424, and a promising clinical candidate disclosed in these patent applications was further described by Van Hes et al. (Bioorganic and Medicinal Chemistry Letters, 13(3), 405-408, 2003). In a publication by Timms et al., (Bioorganic and Medicinal Chemistry Letters, 14(10), 2469-2472, 2004) tetrahydropyridin-4-yl indole derivatives with a dual action as serotonin 5 -HT10 antagonists and serotonin reuptake inhibitors are described, and also in this group of compounds some were shown to possess dopamine -D2 antagonistic activity. In WO 2004/020437 one specific compound is described as dopamine -D4 antagonist and serotonin reuptake inhibitor: S-(+)-3-{1 -[2-(2,3-dihydro-1H-indol-3-yl)ethyl]- 3,6dihydro-2H-pyridin-4-yl}-6-chloro-1 H-indole. Of this compound no dopamine -D2 affinity c.q. activity was disclosed.
The goal of the present invention was to provide further compounds with a dual action as dopamine-D2 antagonists and serotonin reuptake inhibitors.
Surprisingly, potent dopamine-D2 antagonistic activity combined with potent serotonin reuptake inhibitory activity was found in a group of novel 1, 2, 3, 6-tetrahydropyridin- 4-yl indoles of the formula (I)
(I)
and tautomers, stereoisomers, prodrugs, N -oxides, pharmacologically acceptable salts, hydrates and solvates thereof,
wherein :
R1 is hydrogen, halogen, alkyl (Ci-3) or alkoxy(Ci-3), CN or CF3,
- R2 is hydrogen or alkyl (Ci-3),
- R3 is hydrogen or alkyl (Ci-3),
- Z is hydrogen or alkyl (Ci-3), alkoxy(Ci-3) or alkylthio(Ci-3),
- A is hydrogen or alkyl (Ci-3), or
- A and Z together form a saturated or (partly) unsaturated 5- or 6- membered ring which may be substituted with halogen, alkyl (Ci-3) or phenyl, in which ring Z represents carbon, sulfur of nitrogen .
In the description of the substituents the abbreviation al kyl(Ci-3) means methyl, ethyl, n-propyl or isopropyl .
Prodrugs of the compounds mentioned above are in the scope of the present invention. Prodrugs are therapeutic agents which are inactive per se but are transformed into one or more active metabolites. Prodrugs are bioreversible derivatives of drug molecules used to overcome some barriers to the utility of the parent drug molecule. These barriers include, but are not limited to, solubility, permeability, stability, presystemic metabolism and targeting limitations (Medicinal Chemistry: Principles and Practice, 1994, ISBN 0-85186-494-5, Ed.: F. D. King, p.
215; J. Stella, "Prodrugs as therapeutics", Expert Opin. Ther. Patents, 14(3), 277-
280, 2004; P. Ettmayer et al., "Lessons learned from marketed and investigational
prodrugs", J.Med.Chem., 47, 2393-2404, 2004). Pro-drugs, i.e. compounds which when administered to humans by any known route, are metabolised to compounds having formula (1), belong to the invention. In particular this relates to compounds with primary or secondary amino or hydroxy groups. Such compounds can be reacted with organic acids to yield compounds having formula (1) wherein an additional group is present which is easily removed after administration, for instance, but not limited to amidine, enamine, a Mannich base, a hydroxyl -methylene derivative, an O-(acyloxymethylene carbamate) derivative, carbamate, ester, amide or enaminone.
N-oxides of the compounds mentioned above are in the scope of the present invention. Tertiary amines may or may not give rise to N -oxide metabolites. The extend to what N -oxidation takes place varies from trace amounts to a near quantitative conversion. N-oxides may be more active than their corresponding tertiary amines or less active. Whilst N-oxides are easily reduced to their corresponding tertiary amines by chemical means, in the human body this happens to varying degrees. Some N-oxides undergo nearly quantitative reductive conversion to the corresponding tertiary amines, in other cases the conversion is a mere t race reaction or even completely absent. (M. H. Bickel: " The pharmacology and Biochemistry of N-oxides", Pharmacological Reviews, £1(4), 325 - 355, 1969).
Preferred compounds of the invention are compounds having formu Ia (I) wherein R1 is hydrogen or halogen, R2 is hydrogen, R3 is CH3, Z is SCH3 and A is CH3, or Z+A from a (partly) unsaturated 6-membered ring which may be substituted with CH3, C2H5 or i-C3H7.
Especially preferred is the compounds having formula (I) wherein Ri=R2=H, R3 is CH3 and Z+A together represent C(CH3)=CH-CH=CH-, and the salts thereof.
It has been found that the compounds according to the invention show high affinity for both the dopamine D2 receptor and the serotonin reuptake site. This combinat ion is useful for the treatment of schizophrenia and other psychotic disorders which enables a more complete treatment of all disease symptoms (e.g. positive symptoms and negative symptoms).
Some of the compounds having formula (I) show partial agonist activity at dopamine receptors making them particularly suitable for the treatment of Parkinson's disease.
The compounds show activity as antagonists at dopamine D2 receptors as they potentially antagonize apomorphine -induced climbing behaviour in mice. The compounds also show activity as inhibitors of serotonin reuptake, as they potentiate 5 - HTP induced behaviour in mice.
The compounds are active in therapeutic models sensitive to clinically relevant antipsychotics (e.g. the conditioned avoidance response; Van der Heyden & Bradford, Behav. Brain Res., 1988, 31:61 -67) and antidepressants or anxiolytics (e.g. suppression of stress -induced vocalization; van der Poel et al., Psycho-pharmacology, 1989, 97: 147-148).
In contrast to clinically relevant dopamine D2 receptor antagonists the described compounds have a low propensity to induce catalepsy in rodents and as such are likely to induce less extrapyramidal side effects than existing antipsychotic agents.
The inhibitory activity of serotonin reuptake inherent in these compounds may be responsible for the therapeutic effects observed in behavioural models sensitive to either antidepressants or anxiolytics.
The compounds can be used for the treatment of affections or diseases of the central nervous system caused by disturbances in either the dopaminergic or serotonergic systems, for example: aggression, anxiety disorders, autism, vertigo, depression, disturbances of cognition or memory, Parkinson's disease, and in particular schizophrenia and other psychotic di sorders.
GENERALASPECTSOFSYNTHESES
The compounds having formula (I) can be prepared by reaction of a compound of the formula
(H)
with a compound of the formula
("I")
wherein the symbols Ri, R2, R3, Z and A have the above meanings, an d L is a so- called leaving group, for example halogen or mesyl group.
This reaction is preferably carried out in an organic solvent such as acetonitrile in the precence of triethylamine or K2CO3 and Kl at reflux temperature.
The starting compounds for this synthesis of the formula (II) can be obtained in a manner known per se by reacting an optionally substituted indole derivative with 4 - piperidone.
The staring compounds having formula (III) can be obtained according to methods known for the synthesis of analogous compounds.
The selection of the particular synthetic procedures depends on factors known to those skilled in the art such as the compatibility of functional groups with the reagents used, the possibility to use protecting groups, catalysts, activating and coupling reagents and the ultimate structural features present in the final compound being prepared.
Pharmaceutically acceptable salts may be obtained using standard procedures well known in the art, for example by mixing a compound of the present invention with a suitable acid, for instance an inorganic acid such as hydrochloric acid, or with an organic acid.
PHARMACEUTICAL PREPARATIONS
The compounds of the invention can be brought into forms suitable for administration by means of usual processes using auxiliary substances such as liquid or solid carrier material. The pharmaceutical compositions of the invention may be administered enterally, orally, parenterally (intramuscularly or intravenously), rectally or locally (topically). They can be administered in the form of solutions, powders, tablets, capsules (including microcapsules), ointments (creams or gel) or suppositories. Suitable excipients for such formulations are the pharmaceutically customary liquid or solid fillers and extenders , solvents, emulsifiers, lubricants, flavorings, colorings and/or buffer substances. Frequently used auxiliary substances which may be mentioned are magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, lactoprotein, gelatin, starch, cellulose and its derivatives, animal and vegetable oils such as fish liver oil, sunflower, groundnut or sesame oil, polyethylene glycol and solvents such as, for example, sterile water and mono- or polyhydric alcohols such as glycerol.
Compounds of the present invention are generally administered as pharmaceutical compositions which are important and novel embodiments of the invention because of the presence of the compounds, more particularly specific compounds disclosed herein. Types of pharmaceuti cal compositions that may be used include but are not limited to tablets, chewable tablets, capsules, solutions, parenteral solutions, suppositories, suspensions, and other types disclosed herein or apparent to a person skilled in the art from the specification and general knowledge in the art. In embodiments of the invention, a pharmaceutical pack or kit is provided comprising one or more containers filled with one or more of the ingredients of a pharmaceutical composition of the invention. Associated with such container(s) can be various written materials such as instructions for use, or a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals products, which notice reflects approval by the agency of manufacture, use, or sale for human or veterinary administration.
PHARMACOLOGICAL METHODS
In vitro affinity for dopamine -D2 receptors
Affinity of the compounds for dopamine-D2 receptor s was determined using the receptor binding assay described by I. Creese, R. Schneider and S. H. Snyder: "[3H]- Spiroperidol labels dopamine receptors in rat pituitary and brain", Eur.J. Pharmacol., 46, 377 - 381 , 1977.
In vitro affinity for serotonin reuptake sites
Affinity of the compounds for serotonin reuptake sites was determined using the receptor binding assay described by E. Habert et a/.,: "Characterisation of [3H]- paroxetine binding to rat cortical membranes", Eur.J. Pharmacol., 118, 107 - 114, 1985.
DOSAGES
The affinity of the compounds of the invention for dopamine-D2 receptors and serotonine reuptake sites was determined as described above. From the binding affinity measured for a given compound of formula (1), one can estimate a theoretical lowest effective dose. At a concentration of the compound equal to twice the measured Krvalue, 100% of the receptors likely will be occupied by the compound. Converting that concentration to mg of compound per kg of patient yields a theoretical lowest effective dose, assuming ideal bioavailability. Pharmacokinetic, pharmacodynamic, and other considerations may alter the dose actually administered to a higher or lower value. The dosage expediently administered is 0.001 - 1000 mg/kg, preferably 0.1 -100 mg/kg of patient's bodyweight. TREATMENT
The term "treatment" as used herein refers to any treatment of a mammalian, preferably human condition or disease, and includes: (1) preventing the disease or condition from occurring in a subject which may be predisposed to the disease but has not yet been diagnosed as having it, (2) inhibiting the disease or condition, i.e., arresting its development, (3) relieving the disease or condition, i.e., causing
regression of the condition, or (4) relieving the conditions caused by the disease, i.e., stopping the symptoms of the disease.
The preparation of the compounds having formula (I) will now be described in more detail in the following Examples.
EXAMPLES
EXAMPLE 1 : MATERIALS AND METHODS
1H and 13C NMR spectra were recorded on a Bruker Avance DRX600 instrument
(600 MHz), Varian UN400 instrument (400 MHz) or on a Varian VXR200 instrument (200 MHz) using DMSO-D6 or CDCI3 as solvents with tetramethylsilane as an internal standard. Chemical shifts are given in ppm ( δ scale) downfield from tetramethylsilane. Coupling constants (J) are expressed in Hz. Flash chromatography was performed using silica gel 60 (0.040-0.063 mm, Merck). Column chromatography was performed using silica gel 60 (0.063 -0.200 mm, Merck). Melting points were recorded on a Bϋchi B-545 melting point apparatus. Mass spectra were recorded on a Micromass QTOF-2 instrument with MassLynx application software for acquisition and reconstruction of the data. Exact mass measurement was done of the quasimolecular ion [M+H]+.
EXAMPLE 2: SYNTHESES OF SPECIFIC COMPOUNDS
compound No. 26
a) Preparation of 5-fluoro-3- (1 , 2, 3. 6,-tetrahvdropyridin-4-yl) indole.
To a solution of sodium (60 g, 2.6 mol) in 1000 ml of methanol was added 5- fluoroindole (49 g, 0.36 mol) and 4-piperidone.H2O.HCI (170 g, 1.11 mol). The mixture was heated under reflux for 18h, then concentrated , water was added and extracted with ethyl acetate. The combined organic layer was dried over sodium sulfate and then concentrated. The resulting solid was dissolved in methanol (about 200 ml) and then diluted with water (about 1000-1500 ml). The precipitate was collected, washed with water and petroleum ether and then dried in a vacuum oven at 600C. Yield 74 g (95%) of a yellow solid.
b) Preparation of 3- (2-chloroethyl)-2, 9-dimethyl-4H-pyrido H, 2-al- Pyrimidin-4-one.
To a solution of 2-amino-3-picoline (3.3 g, 30 mmol) in phosphorus oxychloride (11 ml) was added 2-acetylbutyrolactone (3.25 ml, 30 mmol). The mixture was heated at 1000C for 18 hours, cooled, poured on ice, made basic with a 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). Yield 2.5 g (35%) of white solid.
c) Preparation of 3-r2-r4-(5-fluoro-1 H-indol-3-yl)-1 ,2,3,6-tetrahydro- pyridin-1 -yl1ethvπ-2.9-dimethyl-4H-pyridori .2-a1pyrimidin-4-one.
A solution of 5-fluoro-3-(1 ,2,3,6-tetrahydropyridin-4-yl)indole (5.5 g, 0.025 mol), 3-(2- chloroethyl)-2,9-dimethyl-4H-pyrido[1 ,2-a]pyrimidin-4-one (7.2 g, 0.030 mol), diisopropylamine (5 ml) and potassium iodide (1 g) in acetonitrile (100 ml) was heated under reflux for 24h. After cooling the precipitate was collected and washed with acetonitrile (20 ml), isopropyl alcohol (3x 20 ml) and petroleum ether (25 ml) respectively. Yield 7.13 g (67%) of a pale yellow solid. M.p.: 229 -2300C.
Free base of compound No. 22
a) Preparation of 3-(1.2.3.6-tetrahydropyridin-4-yl)indole.
To a solution of sodium methoxide (450 ml , 30% in methanol, 2.5 mol) in 1000 ml of methanol was added indole (50 g, 0.427 mol) and 4-piperidone.H2O.HCI (162 g, 1.05 mol). The mixture was heated under reflux for 18h forming a yellow precipitate. The mixture was concentrated and water (1000 ml) was added. The precipitate was collected, washed with water and petroleum ether and then dried in a vacuum oven at 500C. Yield 77 g (91%) of a pale yellow solid.
b) Preparation of 3-[2-[4-(I H-indol-3-yl)-1 ,2,3,6-tetrahydropyridin-1 -yll- ethvπ-2,9-dimethyl-4H-pyridori,2-a1pyrimidin-4-one.
A solution of 3-(1 ,2,3,6-tetrahydropyridin-4-yl)indole (25 g, 0.126 mol), 3 -(2- chloroethyl)-2,9-dimethyl-4H-pyrido[1 ,2-a]pyrimidin-4-one (33 g, 0.139 mol) and potassium carbonate (17.5 g, 0.127 mol) in acetonitrile (500 ml) and water (100 ml) was heated under reflux for 18h. After cooling the precipitate was collected and washed with water, isopropyl alcohol and petroleum ether respectivel y. Yield 38 g (76%) of a pale yellow solid. M.p.: 210-2120C.
Compound No.12
a) Preparation of 2-thio-5-(2-hvdroxyethyl)-6-methyluracil.
To a solution of sodium (55.6 g, 2.4 mol) in ethanol (1000 ml) was added slowly 2- acetylbutyrolactone 155 g, 1.2 mol) after which thiourea (128 g, 1.65 mol) was added in small portions. The mixture was heated under reflux for 16h , then concentrated, water (800 ml) was added and acidified slowly with concentrated hydrochloric acid (200 ml). The precipitate was collected and washed with water, isopropyl alcohol and petroleum ether. Yield 125 g (56%) of a white solid.
b) Preparation of 2-methylthio-5-(2-hvdroxyethyl)-6-methyl-3H- pyrimidin-4-one.
To a suspension of 2-thio-5-(2-hydroxyethyl)-6-methyluracil (50 g, 0.26 mol) in DMF (320 ml) was added slowly one equivalent of sodium hydride. Next was added slowly one equivalent of methyl iodide (16.6 ml). The mixture was stirred for two hours at 30°C, after which water (800 ml) was added. The precipitate was collected and washed with water, isopropyl alcohol and petroleum ether. Yield 34.4 g (64%).
c) Preparation of 2-methylthio-5-(2-hvdroxγethyl)-3.6-dimethyl-3H- Pyrimidin-4-one
To a suspension of 2-methylthio-5-(2-hydroxyethyl)-6-methyl-3H-pyrimidin-4-one (34 g, 0.17 mol) in DMF (300 ml) was added slowly one equivalent of sodium hydride (55%, 7.4 g). Next was added slowly one equivalent of methyl iodide (10.5 ml). The mixture was stirred for two hours at 50 °C, after which most of the DMF was removed in vaccuum. Water was added and the mixture was extracted with ethyl acetate. The combined organic layer was dried over sodium sulfate and then concentrated and purified by flash chromatografy (eluens: ether followed by ether/methanol=9/1). Yield 20.3 g (56%), mp. 117-118°C.
d) Preparation of 2-methylthio-5-(2-chloroethyl)-3.6-dimethyl-3H- Pyrimidin-4-one.
To a solution of 2-methylthio-5-(2-hydroxyethyl)-3,6-dimethyl-3H-pyrimidin-4-one (20.3 g, 0.095 mol) in chloroform (200 ml) was added one equivalent of pyridine (7.6 ml), followed by slow addition of three equivalents of thionyl chloride (21 ml). After stirring for 15 minutes, the mixture was concentrated and water (300 ml) was added. The precipitate was collected and washed with water, isopropyl alcohol and petroleum ether. Yield 34.4 g (64%). Yield 20.3 g (92%). Mp. 135-137°C.
e) Preparation of 5-[2-[4-M H-indol-3-ylH .2.3.6-tetrahvdropyridin-i -yll ethyll-2-methylthio-3,6-dimethyl-3H-pyrimidin-4-one.
To a solution of 3-(1 ,2,3,6-tetrahydropyridin-4-yl)indole (1.0 g, 5 mmol) in acetonitrile (30 ml) was added 2-methylthio-5-(2-chloroethyl)-3,6-dimethyl-3H-pyrimidin-4-one (1.42 g, 6.1 mmol), potassium iodide (0.84 g, 5 mmol) and triethylamine (1.4 ml , 10 mmol). The mixture was heated at 800C for 8 hours , cooled , concentrated and purified by flash chromatografy (dichloromethane /methanol/ammonia=95/4.5/0.5) Yield: 1.83 g (92%) of a yellow compound. Mp. 245-246°C.
Compound No.18
a) Preparation of 2-methoxy-5-(2-hvdroxyethyl)- 6-methyl-3H-pyrimidin- 4 -one.
To a solution of O-methylisourea hydrogen sulfate (17.2 g, 0.1 mol) in water (90 ml) was added calcium hydroxide (8.14 g , 0.11 mol) followed by a solution of 2 - acetylbutyrolactone (10.7 ml, 0.1 mol) in ethanol (70 ml). The mixture was stirred at room temperature for two days, filtered and washed with ethanol. The filtrate was concentrated in vaccuum and purified by flash chromatografy (dichloromethane/methanol=95/5). Yield 2.6 g (14%) of a white solid.
b) Preparation of 2-methoxy-5-(2-hvdroxyethyl)-3, 6-dimethyl-3H- pyrimidin-4-one.
To a suspension of 2-methoxy-5-(2-hydroxyethyl)-6-methyl-3H-pyrimidin-4-one (2.6 g, 0.014 mol) in DMF (25 ml) was added one equiva lent of sodium hydride (55%, 0.6 g). After stirring for 0.5 hr. methyl iodide (0.81 ml , 0.014 mol) was added and the mixture was heated at 50 °C for five hours. After cooling , most of the DMF was removed in vaccuum. Water was added and the mixture was extracted with ethyl acetate. The combined organic layer was dried over sodium sulfate and then concentrated. Yield 2.0 g (71%) of a yellow oil.
c) Preparation of 2-methoxy-5-(2-mesyloxyethyl)-3. 6 -dimethyl -3H- pyrimidin-4-one.
To a solution of 2-methoxy-5-(2-hydroxyethyl)-3, 6-dimethyl-3H-pyrimidin-4-one (2.0 g, 0.01 mol) in dry ethyl acetate (100 ml) was added triethylamine (2.7 ml). After cooling in icewater, mesylchloride (0.9 ml, 0.011 mol) was added slowly. After stirring for 16 hours at room temperature the precipitate was filtered off and the filtrate (70 ml) was used without further purification.
d) Preparation of 5-[2-[4-(I H-indol-3-yl)-1 ,2,3,6-tetrahydropyridin-1 -yli ethvn-2-methoxy-3,6-dimethyl-3H-pyrimidin-4-one.
To the above mentioned filtrate (35 ml .about 5 mmol) was added 3-(1 ,2,3,6- tetrahydropyridin-4-yl)indole (1.0 g, 5 mmol), triethylamine (2 ml), potassium iodide (0.84 g, 5 mmol) and acetonitrile (50 ml). The mixture was heated at 80 °C for 16 hours and then concentrated and purified by flash chromatografy (eluens: dichloromethane/methanol/ammonia =95/4.5/0.5). Yield 0.5 g (26%) , mp. 209-2110C.
The compounds with formula (I) listed in the table below have been prepared according to the methods of Examples 1 to 4.
(I)
For oral (p.o.) administration : to the desired quantity (0.5-5 mg) of the solid compound 22 in a glass tube, some glass beads were added and the solid was milled by vortexing for 2 minutes. After addition of 1 ml of a solution of 1% methylcellulose in water and 2% (v/v) of Poloxamer 188 (Lutrol F68), the compound was suspended by vortexing for 10 minutes. The p H was adjusted to 7 with a few drops of aqueous NaOH (0.1 N). Remaining particles in the suspension were further suspended by using an ultrasonic bath.
For intraperitoneal (Lp.) administration : to the desired quantity (0.5-15 mg) of the solid compound 22 in a glass tube, some glass beads were added and the solid was milled by vortexing for 2 minutes. After addition of 1 ml of a solution of 1% methylcellulose and 5% mannitol in water, the compound was suspended by vortexing for 10 minutes. Finally the pH was adjusted to 7.
EXAMPLE 4: PHARMACOLOGICAL TESTRESULTS
Dopamine-D2 and serotonin reuptake receptor affinity data obtained according to the protocols given above are shown in the table below.
Table 2. In vitro affinities of compounds of the invention
Claims
1. Tetrahydropyridin-4-yl indoles derivatives of the formula (I):
wherein:
R1 is hydrogen, halogen, alkyl (Ci-3) or alkoxy(d-3), CN or CF3,
R2 is hydrogen or alkyl (Ci-3),
R3 is hydrogen or alkyl (Ci-3),
Z is hydrogen or alkyl (Ci-3), alkoxy(Ci-3) or alkylthio(Ci-3), - A is hydrogen or alkyl (Ci-3), or
A and Z together form a saturated or (partly) unsaturated 5- or 6- membered ring which may be substituted with halogen, alkyl (Ci-3) or phenyl, in which ring Z represents carbon, sulfur of nitrogen,
2. A compound as claimed in claim 1 , and tautomers, stereoisomers, prodrugs, N-oxides, pharmacologically acceptable salts, hydrates and solvates thereof, wherein Ri is hydrogen or halogen, R2 is hydrogen, R3 is CH3, Z is SCH3 and A is CH3, or Z+A from a (partly) unsaturated 6 -membered ring which may be substituted with CH3, C2H5 or J-C3H7.
3. A compound as claimed in claim 1 , and tautomers, stereoisomers, prodrugs, N-oxides, pharmacologically acceptable salts, hydrates and solvates thereof, wherein Ri=R2=H, R3 is CH3 and Z+A together represent -C(CH3)=CH- CH=CH-. A compound as claimed in claim 1 , selected from the group:
5. Method for the preparation of compounds as claimed in claim 1 , characterised in that a compound having formula (II)
(H)
is reacted under basic conditions with a compound having formula (III)
(Hi)
in which formulae the symbols having the meanings given in claim 1 , and L is a so-called leaving group.
6. A pharmaceutical composition comprising, in addition to a pharmaceuti-cally acceptable carrier and/or at least one pharmaceutically acceptable auxiliary substance, a pharmacologically active amount of at least one compound as claimed in claim 1 , or a salt thereof, as an active ingredient.
7. A method of preparing a composition as claimed in claim 6, characterised in that a compound of claim 1 is brought into a form suitable for administration.
8. A compound as claimed in any of the claims 1 -4, or a salt thereof, for use as a medicament
9. Use of a compound as claimed in any of the claims 1 -4 for the preparation of a pharmaceutical composition for the treatment of CNS disorders.
10. Use as claimed in claim 9, characterized in that said CNS disorders are aggression, anxiety disorders, autism, vertigo, depression, disturbances of cognition or memory, schizophrenia and other psychotic disorders.
Priority Applications (8)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| BRPI0518465-7A BRPI0518465A2 (en) | 2004-12-07 | 2005-12-06 | compound, method for the preparation of compound, pharmaceutical composition, method of preparing a composition, and use of a compound |
| CA002587936A CA2587936A1 (en) | 2004-12-07 | 2005-12-06 | Tetrahydropyridin-4-yl indoles with a combination of affinity for dopamine-d2 receptors and serotonin reuptake sites |
| AU2005313387A AU2005313387A1 (en) | 2004-12-07 | 2005-12-06 | Tetrahydropyridin-4-yl indoles with a combination of affinity for dopamine-D2 receptors and serotonin reuptake sites |
| MX2007006757A MX2007006757A (en) | 2004-12-07 | 2005-12-06 | Tetrahydropyridin-4-yl indoles with a combination of affinity for dopamine-d2 receptors and serotonin reuptake sites. |
| EP05817509A EP1828168A2 (en) | 2004-12-07 | 2005-12-06 | Tetrahydropyridin-4-yl indoles with a combination of affinity for dopamine-d2 receptors and serotonin reuptake sites |
| JP2007544893A JP2008523027A (en) | 2004-12-07 | 2005-12-06 | Tetrahydropyridin-4-ylindoles with a combination of affinity for the dopamine-D2 receptor and a serotonin resorption site |
| IL183202A IL183202A0 (en) | 2004-12-07 | 2007-05-15 | Tetrahydropyridin-4-yl indoles with a combination of affinity for dopamine -d2 receptors and serotonin reuptake sites |
| NO20073389A NO20073389L (en) | 2004-12-07 | 2007-07-02 | Tetrahydropyridin-4-ylndoles with a combination of affinity for dopamine D2 receptors and serotonin reuptake sites |
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US63343904P | 2004-12-07 | 2004-12-07 | |
| EP04106351 | 2004-12-07 | ||
| US60/633,439 | 2004-12-07 | ||
| EP04106351.2 | 2004-12-07 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| WO2006061373A2 true WO2006061373A2 (en) | 2006-06-15 |
| WO2006061373A3 WO2006061373A3 (en) | 2006-09-21 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/EP2005/056501 WO2006061373A2 (en) | 2004-12-07 | 2005-12-06 | Tetrahydropyridin-4-yl indoles with a combination of affinity for dopamine-d2 receptors and serotonin reuptake sites |
Country Status (14)
| Country | Link |
|---|---|
| EP (1) | EP1828168A2 (en) |
| JP (1) | JP2008523027A (en) |
| KR (1) | KR20070091009A (en) |
| CN (1) | CN101072770A (en) |
| AR (1) | AR052146A1 (en) |
| AU (1) | AU2005313387A1 (en) |
| BR (1) | BRPI0518465A2 (en) |
| CA (1) | CA2587936A1 (en) |
| MX (1) | MX2007006757A (en) |
| RU (1) | RU2007125692A (en) |
| SA (1) | SA05260388B1 (en) |
| TW (1) | TW200626575A (en) |
| WO (1) | WO2006061373A2 (en) |
| ZA (1) | ZA200704155B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20100311969A1 (en) * | 2008-02-05 | 2010-12-09 | Watson Pharma Private Limited | Process For Preparation of Paliperidone |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0378255A2 (en) * | 1989-01-09 | 1990-07-18 | Janssen Pharmaceutica N.V. | 2-Aminopyrimidinone derivatives |
| WO2000069424A2 (en) * | 1999-05-12 | 2000-11-23 | Solvay Pharmaceuticals B.V. | Method of treating psychotic disorders |
| WO2004020437A1 (en) * | 2002-08-29 | 2004-03-11 | H. Lundbeck A/S | S-(+)-3-{1-[2-(2,3-dihydro-1h-indol-3-yl)ethyl]-3,6-dihydro-2h-pyridin-4-yl}-6-chloro-1h-indole and acid addition salts thereof |
-
2005
- 2005-12-06 RU RU2007125692/04A patent/RU2007125692A/en not_active Application Discontinuation
- 2005-12-06 TW TW094142934A patent/TW200626575A/en unknown
- 2005-12-06 EP EP05817509A patent/EP1828168A2/en not_active Withdrawn
- 2005-12-06 JP JP2007544893A patent/JP2008523027A/en not_active Withdrawn
- 2005-12-06 KR KR1020077015615A patent/KR20070091009A/en not_active Application Discontinuation
- 2005-12-06 SA SA5260388A patent/SA05260388B1/en unknown
- 2005-12-06 CN CNA2005800419599A patent/CN101072770A/en active Pending
- 2005-12-06 MX MX2007006757A patent/MX2007006757A/en active IP Right Grant
- 2005-12-06 AU AU2005313387A patent/AU2005313387A1/en not_active Abandoned
- 2005-12-06 AR ARP050105089A patent/AR052146A1/en not_active Application Discontinuation
- 2005-12-06 BR BRPI0518465-7A patent/BRPI0518465A2/en not_active IP Right Cessation
- 2005-12-06 WO PCT/EP2005/056501 patent/WO2006061373A2/en active Application Filing
- 2005-12-06 CA CA002587936A patent/CA2587936A1/en not_active Abandoned
-
2007
- 2007-05-22 ZA ZA200704155A patent/ZA200704155B/en unknown
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0378255A2 (en) * | 1989-01-09 | 1990-07-18 | Janssen Pharmaceutica N.V. | 2-Aminopyrimidinone derivatives |
| WO2000069424A2 (en) * | 1999-05-12 | 2000-11-23 | Solvay Pharmaceuticals B.V. | Method of treating psychotic disorders |
| WO2004020437A1 (en) * | 2002-08-29 | 2004-03-11 | H. Lundbeck A/S | S-(+)-3-{1-[2-(2,3-dihydro-1h-indol-3-yl)ethyl]-3,6-dihydro-2h-pyridin-4-yl}-6-chloro-1h-indole and acid addition salts thereof |
Non-Patent Citations (2)
| Title |
|---|
| TIMMS G H ET AL: "SAR development of a selective 5-HT1D antagonist/serotonin reuptake inhibitor lead using rapid parallel synthesis" BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, OXFORD, GB, vol. 14, no. 10, 17 May 2004 (2004-05-17), pages 2469-2472, XP004841222 ISSN: 0960-894X * |
| VAN HES ROLF ET AL: "SLV310, a novel, potential antipsychotic, combining potent dopamine D2 receptor antagonism with serotonin reuptake inhibition." BIOORGANIC AND MEDICINAL CHEMISTRY LETTERS, vol. 13, no. 3, 10 February 2003 (2003-02-10), pages 405-408, XP002331578 ISSN: 0960-894X * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20100311969A1 (en) * | 2008-02-05 | 2010-12-09 | Watson Pharma Private Limited | Process For Preparation of Paliperidone |
Also Published As
| Publication number | Publication date |
|---|---|
| CA2587936A1 (en) | 2006-06-15 |
| AU2005313387A1 (en) | 2006-06-15 |
| RU2007125692A (en) | 2009-01-20 |
| BRPI0518465A2 (en) | 2008-11-18 |
| JP2008523027A (en) | 2008-07-03 |
| TW200626575A (en) | 2006-08-01 |
| KR20070091009A (en) | 2007-09-06 |
| SA05260388B1 (en) | 2009-06-09 |
| CN101072770A (en) | 2007-11-14 |
| MX2007006757A (en) | 2007-11-09 |
| ZA200704155B (en) | 2008-08-27 |
| WO2006061373A3 (en) | 2006-09-21 |
| AR052146A1 (en) | 2007-03-07 |
| EP1828168A2 (en) | 2007-09-05 |
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