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WO2003102097A1 - The hydrochloride of (s)-(+)-3-[1-[2-(1-acetyl-2,3-dihydro-1h-indol-3-yl)ethyl]-1,2,3,6-tetrahydropyridin-4-yl]-6-chloro-1h-indole - Google Patents

The hydrochloride of (s)-(+)-3-[1-[2-(1-acetyl-2,3-dihydro-1h-indol-3-yl)ethyl]-1,2,3,6-tetrahydropyridin-4-yl]-6-chloro-1h-indole Download PDF

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WO2003102097A1
WO2003102097A1 PCT/DK2003/000341 DK0300341W WO03102097A1 WO 2003102097 A1 WO2003102097 A1 WO 2003102097A1 DK 0300341 W DK0300341 W DK 0300341W WO 03102097 A1 WO03102097 A1 WO 03102097A1
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hydrochloride
ethyl
dihydro
acetyl
chloro
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WO2003102097A8 (en
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Benny Bang-Andersen
Ole Nielsen
Heidi Lopez De Diego
Gitte Ludvig
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H Lundbeck AS
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H Lundbeck AS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole

Definitions

  • the present invention relates to the hydrochloride of (S)-(+)-3-[l-[2-(l-acetyl-2,3- dihydro-lH-indol-3-yl)ethyl]-l,2,3,6-tetrahydropyridin-4-yl]-6-chloro-lH-indole, a method for the preparation thereof and the use thereof for the preparation of a pharmaceutical composition.
  • WO 98/28293 describes a series of substituted indane and dihydroindole compounds having effect at dopamine D 4 receptors.
  • the compounds described are considered useful for the treatment of a range of psychiatric and neurological disorders, including the positive and negative symptoms of schizophrenia, other psychoses, anxiety disorder, such as generalised anxiety disorder, panic disorder and obsessive compulsive disorder, depression, alcohol abuse, impulse control disorders, aggression, side effects induced by conventional antipsychotic agents, ischaemic disease states, migraine, senile dementia, cardiovascular disorders and for the improvement of sleep.
  • WO 02/089797 describes the use of the above compound for the treatment of attention deficit hyperactivity disorder.
  • WO 98/28293 which is described in WO 98/28293 as a potent dopamine D 4 ligand, may be particularly useful as a pharmaceutical when used in the form of the hydrochloride.
  • the present invention relates to the hydrochloride of (S)-(+)-3-[l-[2-(l-acetyl-2,3 dihydro-lH-indol-3-yl)ethyl]-l,2,3,6-tetrahydropyridin-4-yl]-6-chloro-lH-indole and hydrates and/or solvates thereof.
  • the invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the above hydrochloride together with at least one pharmaceutically acceptable carrier or diluent and the use of the above hydrochloride for the preparation of such a medicament.
  • the invention relates to a method for the treatment of the positive and negative symptoms of schizophrenia, other psychoses, anxiety disorder, such as generalised anxiety disorder, panic disorder and obsessive compulsive disorder, depression, alcohol abuse, impulse control disorders, aggression, side effects induced by conventional antipsychotic agents, ischaemic disease states, migraine, senile dementia, cardiovascular disorders, attention deficit hyperactivity disorder and for the improvement of sleep, in particular the positive and negative symptoms of schizophrenia, other psychoses and depression, comprising administering a pharmaceutically acceptable amount of a hydrochloride as above.
  • the crystalline base of (S)-(+)-3-[l-[2-(l-acetyl-2,3-dihydro-lH-indol-3-yl)ethyl]- l,2,3,6-tetrahydropyridin-4-yl]-6-chloro-lH-indole has a very low solubility and a low intrinsic dissolution rate, which affect the bioavailability of the compound.
  • hydrochloride salt of (S)-(+)-3-[l-[2-(l-acetyl-2,3-dihydro-lH-indol- 3-yl)ethyl]-l,2,3,6-tetrahydropyridin-4-yl]-6-chloro-lH-indole in particular, it was found that when the normal procedure for dissolving a substance in a solvent by heating is used to dissolve the base before adding hydrochloric acid, a mixture of the free base and the hydrochloride is formed.
  • hydrochloride salt of (S)-(+)-3-[l-[2-(l- acetyl-2,3-dihydro-lH-indol-3-yl)ethyl]-l,2,3,6-tetrahydropyridin-4-yl]-6-chloro-lH- indole may be prepared as a stable crystalline salt with improved solubility and dissolution rate, by using a solvent, which is able to dissolve the free base (S)-(+)-3-[l- [2-(l-acetyl-2,3-dihydro-lH-indol-3-yl)ethyl]-l,2,3,6-tetrahydropyridin-4-yl]-6-chloro- IH-indole at room temperature, to dissolve the base before introducing the hydrochloric acid.
  • the aqueous solubility for the hydrochloride salt of the invention is 130 ⁇ g/ml whereas the aqueous solubility of the crystalline free base is 0.2 ⁇ g/ml.
  • the intrinsic dissolution rate, (i.e the amount of substance released in water at 35 °C from a tablet consisting solely of pure compound of formula I) is 0.016 mg/cm 2 min for the hydrochloride and 0.0005 mg/cm 2 min for the free crystalline base.
  • the invention also relates to a method for the preparation of the hydrochloride according to the invention characterized in that the free base of (S)-(+)-3-[l-[2-(l- acetyl-2,3-dihydro-lH-indol-3-yl)ethyl]-l,2,3,6-tetrahydropyridin-4-yl]-6-chloro-lH- indole is dissolved in a solvent capable of dissolving the base at room temperature and the resulting solution is mixed with a solution containing hydrochloric acid, or hydrochloric acid is added as a gas, the solution is cooled or is allowed to cool and the precipitate formed is isolated from the solution.
  • room temperature is meant normal room temperatures, suitable below 35 °C or more suitable below 25 °C.
  • Suitable solvents for the precipitation of the hydrochloride salt are solvents in which the base of (S)-(+)-3-[l-[2-(l-acetyl-2,3-dihydro-lH-indol-3-yl)ethyl]-l, 2,3,6- tetrahydropyridin-4-yl]-6-chloro-lH-indole may be dissolved at room temperature.
  • An example of such a solvent is N,N-dimethylacetamide, or mixtures of N,N- dimethylacetamide and tetrahydrofurane.
  • Acetone may also be used but is less preferred in industrial scale. The person skilled in the art will be able to identify other suitable solvents.
  • alcohols are not suitable as a solvent for the preparation of the hydrochloride of the invention because alkoxy derivatives of the compound of the invention are formed.
  • the solution of ⁇ C1 may suitably be an aqueous solution, an ether solution or a solution of ⁇ C1 in any other solvent. If necessary due to heat evolution, the reaction mixture is cooled during addition of hydrochloric acid and the temperature is suitably kept below 50°C, or more preferably below 35°C .
  • the crystalline hydrochloride formed is suitable isolated by filtration or decanting and thereafter optionally washed and dried.
  • the crystalline free base of (S)-(+)-3-[l-[2-(l-acetyl-2,3-dihydro-lH-indol-3-yl)ethyl]- l,2,3,6-tetrahydropyridin-4-yl]-6-chloro-lH-indole may be prepared as described in example 34 of WO 98/28293.
  • the hydrochloric acid solution was prepared by mixing a saturated solution of hydrochloric acid in diethyl ether (50 ml) with acetone (500 ml)). The crystalline compound formed was collected by filtration and dried in vacuo to give the title compound (24.8 g, 100%).

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

A hydrochloride of (S)-(+)-3-[1-[2-(1-acetyl-2,3-dihydro-1H-indol-3-yl)ethyl]-1,2,3,6-tetrahydropyridin-4-yl]-6-chloro-1H-indole and hydrates and/or solvates thereof, a method for the preparation thereof and the use thereof for the preparation of a pharmaceutical composition.

Description

The hydrochloride of (S)-(+)-3-[l-[2-(l-acetyl-2,3-dihydro-lH-indol-3-yl)ethyl]- l,2,3,6-tetrahydropyridin-4-yl]-6-chloro-l--7-indole
The present invention relates to the hydrochloride of (S)-(+)-3-[l-[2-(l-acetyl-2,3- dihydro-lH-indol-3-yl)ethyl]-l,2,3,6-tetrahydropyridin-4-yl]-6-chloro-lH-indole, a method for the preparation thereof and the use thereof for the preparation of a pharmaceutical composition.
Background of the Invention
WO 98/28293 describes a series of substituted indane and dihydroindole compounds having effect at dopamine D4 receptors. The compounds described are considered useful for the treatment of a range of psychiatric and neurological disorders, including the positive and negative symptoms of schizophrenia, other psychoses, anxiety disorder, such as generalised anxiety disorder, panic disorder and obsessive compulsive disorder, depression, alcohol abuse, impulse control disorders, aggression, side effects induced by conventional antipsychotic agents, ischaemic disease states, migraine, senile dementia, cardiovascular disorders and for the improvement of sleep.
(S)-(+)-3-[l-[2-(l-acetyl-2,3-dihydro-lH-indol-3-yl)ethyl]-l,2,3,6-tetrahydropyridin-4- yl]-6-chloro- IH-indole is described in WO 98/28293 as a crystalline base.
WO 02/089797 describes the use of the above compound for the treatment of attention deficit hyperactivity disorder.
It has now, surprisingly, been found that (S)-(+)-3-[l-[2-(l-acetyl-2,3-dihydro-lH- indol-3-yl)ethyl]-l,2,3,6-tetrahydropyridin-4-yl]-6-chloro-lH-indole having the formula
Figure imgf000003_0001
which is described in WO 98/28293 as a potent dopamine D4 ligand, may be particularly useful as a pharmaceutical when used in the form of the hydrochloride.
Summary of the Invention
Thus, the present invention relates to the hydrochloride of (S)-(+)-3-[l-[2-(l-acetyl-2,3 dihydro-lH-indol-3-yl)ethyl]-l,2,3,6-tetrahydropyridin-4-yl]-6-chloro-lH-indole and hydrates and/or solvates thereof.
The invention also relates to a pharmaceutical composition comprising the above hydrochloride together with at least one pharmaceutically acceptable carrier or diluent and the use of the above hydrochloride for the preparation of such a medicament.
Finally, the invention relates to a method for the treatment of the positive and negative symptoms of schizophrenia, other psychoses, anxiety disorder, such as generalised anxiety disorder, panic disorder and obsessive compulsive disorder, depression, alcohol abuse, impulse control disorders, aggression, side effects induced by conventional antipsychotic agents, ischaemic disease states, migraine, senile dementia, cardiovascular disorders, attention deficit hyperactivity disorder and for the improvement of sleep, in particular the positive and negative symptoms of schizophrenia, other psychoses and depression, comprising administering a pharmaceutically acceptable amount of a hydrochloride as above. Detailed Description of the Invention
The compound (S)-(+)-3-[l-[2-(l-acetyl-2,3-dihydro-lH-indol-3-yl)ethyl]-l,2,3,6- tetrahydro-pyridin-4-yl]-6-chloro- IH-indole was first disclosed in WO 98/28293 as a crystalline base. Salts of (S)-(+)-3-[l-[2-(l-acetyl-2,3-dihydro-lH-indol-3-yl)ethyl]- l,2,3,6-tetrahydropyridin-4-yl]-6-chloro-lH-indol have not been described in the prior art.
The crystalline base of (S)-(+)-3-[l-[2-(l-acetyl-2,3-dihydro-lH-indol-3-yl)ethyl]- l,2,3,6-tetrahydropyridin-4-yl]-6-chloro-lH-indole has a very low solubility and a low intrinsic dissolution rate, which affect the bioavailability of the compound.
Accordingly, another form of the compound, which has greater solubility and a better dissolution rate, had to be identified. It was found that it was very difficult to identify another crystalline form of the compound.
With regard to the hydrochloride salt of (S)-(+)-3-[l-[2-(l-acetyl-2,3-dihydro-lH-indol- 3-yl)ethyl]-l,2,3,6-tetrahydropyridin-4-yl]-6-chloro-lH-indole in particular, it was found that when the normal procedure for dissolving a substance in a solvent by heating is used to dissolve the base before adding hydrochloric acid, a mixture of the free base and the hydrochloride is formed. The hydrochloride of (S)-(+)-3-[l-[2-(l-acetyl-2,3- dihydro-lH-indol-3-yl)ethyl]-l,2,3,6-tetrahydropyridin-4-yl]-6-chloro-lH-indole was therefore not considered suitable for pharmaceutical use.
It has now surprisingly been found, that the hydrochloride salt of (S)-(+)-3-[l-[2-(l- acetyl-2,3-dihydro-lH-indol-3-yl)ethyl]-l,2,3,6-tetrahydropyridin-4-yl]-6-chloro-lH- indole may be prepared as a stable crystalline salt with improved solubility and dissolution rate, by using a solvent, which is able to dissolve the free base (S)-(+)-3-[l- [2-(l-acetyl-2,3-dihydro-lH-indol-3-yl)ethyl]-l,2,3,6-tetrahydropyridin-4-yl]-6-chloro- IH-indole at room temperature, to dissolve the base before introducing the hydrochloric acid. The aqueous solubility for the hydrochloride salt of the invention is 130 μg/ml whereas the aqueous solubility of the crystalline free base is 0.2 μg/ml. The intrinsic dissolution rate, (i.e the amount of substance released in water at 35 °C from a tablet consisting solely of pure compound of formula I) is 0.016 mg/cm2min for the hydrochloride and 0.0005 mg/cm2min for the free crystalline base.
The invention also relates to a method for the preparation of the hydrochloride according to the invention characterized in that the free base of (S)-(+)-3-[l-[2-(l- acetyl-2,3-dihydro-lH-indol-3-yl)ethyl]-l,2,3,6-tetrahydropyridin-4-yl]-6-chloro-lH- indole is dissolved in a solvent capable of dissolving the base at room temperature and the resulting solution is mixed with a solution containing hydrochloric acid, or hydrochloric acid is added as a gas, the solution is cooled or is allowed to cool and the precipitate formed is isolated from the solution.
By room temperature is meant normal room temperatures, suitable below 35 °C or more suitable below 25 °C.
Suitable solvents for the precipitation of the hydrochloride salt are solvents in which the base of (S)-(+)-3-[l-[2-(l-acetyl-2,3-dihydro-lH-indol-3-yl)ethyl]-l, 2,3,6- tetrahydropyridin-4-yl]-6-chloro-lH-indole may be dissolved at room temperature. An example of such a solvent is N,N-dimethylacetamide, or mixtures of N,N- dimethylacetamide and tetrahydrofurane. Acetone may also be used but is less preferred in industrial scale. The person skilled in the art will be able to identify other suitable solvents.
In general, alcohols are not suitable as a solvent for the preparation of the hydrochloride of the invention because alkoxy derivatives of the compound of the invention are formed.
The solution of ΗC1 may suitably be an aqueous solution, an ether solution or a solution of ΗC1 in any other solvent. If necessary due to heat evolution, the reaction mixture is cooled during addition of hydrochloric acid and the temperature is suitably kept below 50°C, or more preferably below 35°C .
The crystalline hydrochloride formed is suitable isolated by filtration or decanting and thereafter optionally washed and dried.
The crystalline free base of (S)-(+)-3-[l-[2-(l-acetyl-2,3-dihydro-lH-indol-3-yl)ethyl]- l,2,3,6-tetrahydropyridin-4-yl]-6-chloro-lH-indole may be prepared as described in example 34 of WO 98/28293.
Example 1
Precipitation of (S)-(+)-3-[l-[2-(l-acetyl-2,3-dihydro-lH-indoIe-3-yl)ethyl]-l ,2,3,6- tetrahydropyridin-4-yl]-6-chloro-l_ -indole hydrochloride with ΗC1 (g)
(S)-(+)-3-[l-[2-(l-acetyl-2,3-dihydro-lH-indol-3-yl)ethyl]-l,2,3,6-tetrahydropyridin-4- yl]-6-chloro- IH-indole (10 g) is slurried in water and filtered. The wet filter cake is dissolved in Dimethylacetamide (18 ml) and TΗF (100 ml) at room temperature. ΗC1- gas (1.1 g) is added and the temperature is kept below 30 °C. (S)-(+)-3-[l-[2-(l-acetyl- 2,3-dihydro-lH-indol-3-yl)ethyl]-l,2,3,6-tetrahydropyridin-4-yl]-6-chloro-lH-indole hydrochloride precipitates and the crystals are collected by filtration. The crystals are washed with water (150 ml) until pΗ is above 3, and then with TΗF (17 ml). The crystals are dried over night in vacuum at 50 °C. Yield: 10.6 g (98%)
Example 2
Precipitation of (S)-(+)-3-[l-[2-(l-acetyl-2,3-dihydro-lH-indol-3-yl)ethyl]-l,2,3,6- tetrahydropyridin-4-yl]-6-chloro-lH-indole hydrochloride with ΗC1 (aq)
(S)-(+)-3-[l-[2-(l-acetyl-2,3-dihydro-lH-indol-3-yl)ethyl]-l,2,3,6-tetrahydroρyridin-4- yl]-6-chloro- IH-indole (1.4 kg) is dissolved in Dimethylacetamide (9.4 kg). A mixture of cone. ΗC1 (0.4 kg) and water (0.2 kg) is added and the solution is cooled to 0-5 °C. S)-(+)-3-[l-[2-(l-acetyl-2,3-dihydro-lH-indol-3-yl)ethyl]-l,2,3,6-tetrahydropyridin-4- yl]-6-chloro- IH-indole hydrochloride is collected by filtration and then slurried in acetone (6.85 kg), filtered and finally dried. Yield: 1.046 kg (69%)
Example 3
Large scale precipitation of S)-(---)-3-[l-[2-(l-acetyl-2,3-dihydro-l//-indoI-3- yl)ethyl]-l,2,3,6-tetrahydropyridin-4-yl]-6-chloro-lH-indole hydrochloride
The wet filtercake of S)-(+)-3-[l-[2-(l-acetyl-2,3-dihydro-lH-indol-3-yl)ethyl]-l,2,3,6- tetrahydropyridin-4-yl]-6-chloro- IH-indole is dissolved in 10 times Tetrahydrofuran and 1.8 times N-N-dimethylacetamid. 1.17 eq. ΗCl-gas is added at a temperature below 35 °C. After stirring at least lh at room temperature, the title compound is collected by filtration. The filtercake of (S)-(+)-3-[l-[2-(l-acetyl-2,3-dihydro-lH-indol-3-yl)ethyl]- l,2,3,6-tetrahydropyridin-4-yl]-6-chloro-lH-indole hydrochloride is washed with water and tetrahydrofuran and finally dried.
Example 4
(S)-(+)-3-[l-[2-(l-acetyl-2,3-dihydro-lH-indol-3-yl)ethyl]-l,2,3,6- tetrahydropyridin-4-yl]-6-chloro-l---f-indole hydrochloride
(S)-(+)-3-[l-[2-(l-acetyl-2,3-dihydro-lH-indol-3-yl)ethyl]-l,2,3,6-tetrahydropyridin-4- yl]-6-chloro- IH-indole (22.9 g, 0.055 mol) was dissolved in hot acetone (1300 ml) and subsequently added a solution of hydrochloric acid in di ethyl ether and acetone until pΗ 2.5. The solution was slowly cooled to room temperature. (The hydrochloric acid solution was prepared by mixing a saturated solution of hydrochloric acid in diethyl ether (50 ml) with acetone (500 ml)). The crystalline compound formed was collected by filtration and dried in vacuo to give the title compound (24.8 g, 100%).

Claims

Patent Claims
1. The hydrochloride of (S)-(+)-3-[l-[2-(l-acetyl-2,3-dihydro-lH-indol-3- yl)ethyl]-l,2,3,6-tetrahydropyridin-4-yl]-6-chloro-lH-indole and hydrates and/or solvates thereof.
2. The hydrochloride of S)-(+)-3-[l-[2-(l-acetyl-2,3-dihydro-lH-indol-3-yl)ethyl]- l,2,3,6-tetrahydropyridin-4-yl]-6-chloro-lH-indole according to claim 1.
3. A pharmaceutical composition comprising a hydrochloride according to claims 1-2 or a hydrate or a solvate thereof together with at least one pharmaceutically acceptable carrier or diluent.
4. A method for the treatment of the positive and negative symptoms of schizophrenia, other psychoses, anxiety disorder, such as generalised anxiety disorder, panic disorder and obsessive compulsive disorder, depression, alcohol abuse, impulse control disorders, aggression, side effects induced by conventional antipsychotic agents, ischaemic disease states, migraine, senile dementia, cardiovascular disorders, attention deficit hyperactivity disorder and for the improvement of sleep comprising administering a pharmaceutically acceptable amount of a hydrochloride according to claims 1-2 or a hydrate or a solvate thereof to an individual in need thereof.
5. The method according to claim 4 wherein the positive and negative symptoms of schizophrenia, other psychoses or depression are treated.
6. The use of a hydrochloride according to claims 1-2 or a hydrate or a solvate thereof for the preparation of a pharmaceutical composition for the treatment of the positive and negative symptoms of schizophrenia, other psychoses, anxiety disorder, such as generalised anxiety disorder, panic disorder and obsessive compulsive disorder, depression, alcohol abuse, impulse control disorders, aggression, side effects induced by conventional antipsychotic agents, ischaemic disease states, migraine, senile dementia, cardiovascular disorders, attention deficit hyperactivity disorder and for the improvement of sleep.
7. The use according to claim 6 wherein the pharmaceutical composition is for the treatment of the positive and negative symptoms of schizophrenia, other psychoses or depression.
8. A method for the preparation of the hydrochloride according to claims 1-2 characterized in that the free base of (S)-(+)-3-[l-[2-(l-acetyl-2,3-dihydro-lH- indol-3-yl)ethyl]-l,2,3,6-tetrahydropyridin-4-yl]-6-chloro-lH-indole is dissolved in a solvent capable of dissolving the base at room temperature, and the resulting solution is mixed with a solution containing hydrochloric acid or hydrochloric acid is added as a gas, the solution is cooled or is allowed to cool and the precipitate formed is isolated from the solution.
PCT/DK2003/000341 2002-05-31 2003-05-22 The hydrochloride of (s)-(+)-3-[1-[2-(1-acetyl-2,3-dihydro-1h-indol-3-yl)ethyl]-1,2,3,6-tetrahydropyridin-4-yl]-6-chloro-1h-indole Ceased WO2003102097A1 (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023201421A1 (en) * 2022-04-19 2023-10-26 Mindset Pharma Inc. Indoline derivatives as serotonergic agents useful for the treatment of disorders related thereto

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998028293A1 (en) * 1996-12-20 1998-07-02 H.Lundbeck A/S Indane or dihydroindole derivatives
WO2001096328A1 (en) * 2000-06-14 2001-12-20 H. Lundbeck A/S Indole derivatives useful for the treatment of cns disorders
WO2002089797A1 (en) * 2001-05-09 2002-11-14 H. Lundbeck A/S Treatment of adhd

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998028293A1 (en) * 1996-12-20 1998-07-02 H.Lundbeck A/S Indane or dihydroindole derivatives
WO2001096328A1 (en) * 2000-06-14 2001-12-20 H. Lundbeck A/S Indole derivatives useful for the treatment of cns disorders
WO2002089797A1 (en) * 2001-05-09 2002-11-14 H. Lundbeck A/S Treatment of adhd

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023201421A1 (en) * 2022-04-19 2023-10-26 Mindset Pharma Inc. Indoline derivatives as serotonergic agents useful for the treatment of disorders related thereto

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AU2003236207A8 (en) 2003-12-19
WO2003102097A8 (en) 2004-12-29

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