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WO2001036428A1 - Silylated heterocyclic compounds - Google Patents

Silylated heterocyclic compounds Download PDF

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Publication number
WO2001036428A1
WO2001036428A1 PCT/EP2000/011203 EP0011203W WO0136428A1 WO 2001036428 A1 WO2001036428 A1 WO 2001036428A1 EP 0011203 W EP0011203 W EP 0011203W WO 0136428 A1 WO0136428 A1 WO 0136428A1
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Prior art keywords
compound
acid addition
free base
addition salt
salt form
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PCT/EP2000/011203
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German (de)
French (fr)
Inventor
Joachim Nozulak
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Novartis Pharma GmbH Austria
Novartis AG
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Novartis Erfindungen Verwaltungs GmbH
Novartis AG
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Priority to AU23563/01A priority Critical patent/AU2356301A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/0803—Compounds with Si-C or Si-Si linkages
    • C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
    • C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring
    • C07F7/0814—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring said ring is substituted at a C ring atom by Si
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants

Definitions

  • the present invention relates to novel silylated heterocyclic compounds, their preparation, their use as pharmaceuticals and pharmaceutical compositions containing them.
  • X is CH 2 or O
  • Ri is hydrogen, (C 1- )alkyl, (C 3- 5)alkenyl in which the double bond is not adjacent to the nitrogen atom, or benzyl
  • R 2 is hydroxy or (C ⁇ - ) alkoxy
  • R 3 , R 4 and R5, independently, are (C ⁇ - ) alkyl, in free base or acid addition salt form.
  • the above-defined alkyl and alkoxy groups preferably represent methyl and methoxy.
  • X is preferably CH 2 .
  • the invention includes the enantiomers as well as their mixtures, e.g. the diastereo- meric or racemic mixtures which may be present on account of the asymmetrical carbon atoms e.g. in positions 4a and 10a. In said positions the configuration is preferably trans.
  • the invention provides a process for the production of the compounds of formula I and their acid addition salts, whereby in a compound of formula II
  • X, Ri and R 2 are as defined above and R 6 is chlorine, bromine or iodine, the halogen is substituted by a trialkylsilyl group and the compounds of formula I thus obtained are recovered in free base or acid addition salt form.
  • substitution of the halogen by a trialkylsilyl group may be effected using conventional procedures, for example by halogen-metal exchange using n-butyl- lithium, and subsequent reaction with a corresponding trialkyl-halogen-silane, in an aprotic solvent such as tetrahydrofurane.
  • Acid addition salts may be produced from the free bases in known manner, and vice versa. Suitable acid addition salts include the hydrochlorides, the hydrobromines, the hydrogen maleinates and the hydrogen fumarates.
  • the starting compounds of formula II wherein X is CH 2 may be produced from compounds of formula IX according to the following reaction scheme, e.g. as described in steps a) to g) of Example 1.
  • Separation of the isomers from the racemic mixture can be effected according to known methods, for example on the level of the compounds of formula HI, e.g. as described in step f) of the Example.
  • agents of the invention exhibit interesting pharmacological properties when tested in vitro and in animals, and are therefore useful as pharmaceuticals.
  • the agents of the invention behave as partial agonists at the oCi A - adrenoceptor subtype with pECso values from about 5.0 to about 9.0.
  • the agents of the invention on administration of about 1 to about 100 mg/kg p.o. prolong the wakefulness phases and reduce the REM sleep, which is indicative of attention increasing and antidepressive activity.
  • mice Triangle 21, 95-105(1982); Dixon A.K. et al., J.Clin. Psychiatry 55(9), Suppl. B, 4-7(1994)]
  • the agents of the invention at doses of about 0.01 to about 1 mg/kg increase non-social behaviour and social investigation and decrease defensive ambivalence, indicative of attention/vigilance increasing activity, suggesting an antidepressant and anxiolytic profile.
  • MCA middle cerebral artery
  • the agents of the invention are useful in the treatment of depression and related disorders including major depression, bipolar depression/ disorders, manic depression, mania, premenstrual depressive disorders, post-partum depression, post-menopausal depression; anxiety and related disorders including general anxiety disorders, sleep disorders, obsessive compulsive disorders, extreme shyness, social phobia/anxiety, simple phobia, stuttering, agoraphobia, bulimia, eating disorders, obesity, anorexia nervosa, panic disorders, suicidal attempts / ideation; stress and stress-induced disorders including post-traumatic stress disorders, hemorrhagic stress, stress-induced urinary incontinence, stress-induced psychotic episodes; furthermore stroke, post-stroke recovery and head trauma, alcohol abuse/dependency/ withdrawal, drug withdrawal, e.g. nicotine withdrawal, schizophrenia, negative symptoms of schizophrenia, attention deficit hyperactivity disorders (ADHD), sexual dysfunctions, cognitive disorders, memory deficit, senile dementia, Alzheimer's disease, narcole
  • ADHD attention deficit
  • the appropriate dosage will of course vary depending upon, for example, the compound employed, the host, the mode of administration and the nature and severity of the condition being treated. However, in general, satisfactory results in animals are indicated to be obtained at a daily dosage of from about 0.01 to about 100, preferably from about 0.1 to about 50 mg/kg animal body weight. In larger mammals, for example humans, an indicated daily dosage is in the range from 1 to about 500, preferably from about 1 to about 100 mg of an agent of the invention conveniently administered, for example, in divided doses up to four times a day or in sustained release form.
  • the agent of the invention may be administered by any conventional route, in particular enterally, preferably orally, for example in the form of tablets or capsules, or parenterally, for example in the form of injectable solutions or suspensions.
  • enterally preferably orally
  • parenterally for example in the form of injectable solutions or suspensions.
  • the preferred compound is (-)-(4aR,10aR)- 1 ,2,3,4 ,4a,5, 10, 10a-octahydro-9-methoxy-N-methyl-6-trimethylsilyl-benzo[g] quinoline.
  • Said compound has a pECso and intrinsic activity of 5.8 ⁇ 0.2 / 37 ⁇ 2% in the isolated rat vas deferens contraction model, a pECso of 5.97 ⁇ 0.20 / 107 ⁇ 17% in the assay for the 5-HT 1A receptor (calf hippocampus), a pECso of 6.37 ⁇ 0.17 / 97 ⁇ 4% in the assay for the 5-HT 1A receptor (human rec.
  • HeLa cells HeLa cells
  • a pECso of 6.75 ⁇ 0.14 / 70 ⁇ 7% in the assay for the 5-HT IB and 5-HT ID receptors (calf substantia nigra)
  • a pK ⁇ of 7.14 ⁇ 0.14 in the assay for the 5-HT 2A receptor isolated rat aorta
  • a pK ⁇ of 7.03 ⁇ 0.09 in the assay for the 5-HT 2C receptor pig choroid plexus.
  • the sleep/wakefulness cycle at 1 and 3 mg/kg p.o., it induces a long lasting increase of quiet wakefulness and a reduction in REM sleep, the classical sleep phase being mainly unchanged.
  • the intruder test at 0.03, 0.1 and 0.3 mg/kg p.o., it induces a significant increase in non-social behavior and in social investigation, as well as a significant reduction in defensive behavior, which is an index of social withdrawal.
  • the preferred indications are depression and ADHD.
  • the present invention also provides an agent of the invention, for use as a pharmaceutical, e.g. for the treatment of depression and ADHD.
  • the present invention furthermore provides a pharmaceutical composition
  • a pharmaceutical composition comprising an agent of the invention in association with at least one pharmaceutical carrier or diluent.
  • Such compositions may be manufactured in conventional manner.
  • Unit dosage forms contain, for example, from about 0.25 to about 250, preferably from about 0.25 to about 50 mg of a compound according to the invention.
  • the present invention provides the use of an agent of the invention, for the manufacture of a medicament for the treatment of any condition mentioned above.
  • the present invention provides a method for the treatment of any condition mentioned above, in a subject in need of such treatment, which comprises administering to such subject a therapeutically effective amount of an agent of the invention.
  • the starting material may be prepared as follows:
  • a solution of 55 g (0.31 mols) of 8-methoxy-2-tetralone in 100 ml of dimethylformamide is added dropwise to this mixture.
  • the reaction solution is then heated under argon for 4 hours to an internal temperature of 133° and subsequently worked up.
  • the reaction mixture is divided in two and each half is added dropwise to 1.5 litres of 10% hydrochloric acid (ca. -10°). Each portion is then stirred for 30 minutes at -10°.
  • the precipitated 3- carboxy-8-methoxy-2-tetralone is filtered off and washed with one litre of ice water.
  • the starting material is prepared as follows:

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  • Health & Medical Sciences (AREA)
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  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Neurosurgery (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Psychiatry (AREA)
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  • Bioinformatics & Cheminformatics (AREA)
  • Pain & Pain Management (AREA)
  • Pharmacology & Pharmacy (AREA)
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Abstract

The invention provides a compound of formula (I), wherein X and R1 to R5 are as defined in the description, and the preparation thereof. The compounds of formula (I) are useful as pharmaceuticals.

Description

Silylated heterocvclic compounds
The present invention relates to novel silylated heterocyclic compounds, their preparation, their use as pharmaceuticals and pharmaceutical compositions containing them.
More particularly the invention provides compounds of formula I
Figure imgf000002_0001
wherein X is CH2 or O, Ri is hydrogen, (C1- )alkyl, (C3-5)alkenyl in which the double bond is not adjacent to the nitrogen atom, or benzyl, R2 is hydroxy or (Cι- ) alkoxy and R3, R4 and R5, independently, are (Cι- ) alkyl, in free base or acid addition salt form.
The above-defined alkyl and alkoxy groups preferably represent methyl and methoxy. X is preferably CH2.
The invention includes the enantiomers as well as their mixtures, e.g. the diastereo- meric or racemic mixtures which may be present on account of the asymmetrical carbon atoms e.g. in positions 4a and 10a. In said positions the configuration is preferably trans.
In a further aspect, the invention provides a process for the production of the compounds of formula I and their acid addition salts, whereby in a compound of formula II
Figure imgf000003_0001
wherein X, Ri and R2 are as defined above and R6 is chlorine, bromine or iodine, the halogen is substituted by a trialkylsilyl group and the compounds of formula I thus obtained are recovered in free base or acid addition salt form.
The substitution of the halogen by a trialkylsilyl group may be effected using conventional procedures, for example by halogen-metal exchange using n-butyl- lithium, and subsequent reaction with a corresponding trialkyl-halogen-silane, in an aprotic solvent such as tetrahydrofurane.
Working up the reaction mixtures obtained according to the above process and purification of the so obtained compounds may be carried out in accordance to known procedures.
Acid addition salts may be produced from the free bases in known manner, and vice versa. Suitable acid addition salts include the hydrochlorides, the hydrobromines, the hydrogen maleinates and the hydrogen fumarates.
The starting compounds of formula II wherein X is CH2 may be produced from compounds of formula IX according to the following reaction scheme, e.g. as described in steps a) to g) of Example 1.
Figure imgf000003_0002
Figure imgf000004_0001
Figure imgf000004_0002
Halogenation
Figure imgf000004_0003
Separation of the isomers from the racemic mixture, if desired, can be effected according to known methods, for example on the level of the compounds of formula HI, e.g. as described in step f) of the Example.
The starting compounds of formula II wherein X is O as well as the compounds of formula IX and RjCHO are known or may be produced in analogous manner to known procedures. For example the compound of formula II having the trans configuration and wherein X is O, Ri is methyl, R2 is methoxy and Re is iodine, is known from German published application 35 20 104.5 and DE 35 08 263.
Compounds of formula I and their pharmaceutically acceptable acid addition salts, hereinafter referred to as agents of the invention, exhibit interesting pharmacological properties when tested in vitro and in animals, and are therefore useful as pharmaceuticals. In the isolated rat vas deferens contraction model [Honner V. et al., Br. J. Pharmacol 128, 1323-1331(1999)], the agents of the invention behave as partial agonists at the oCiA- adrenoceptor subtype with pECso values from about 5.0 to about 9.0.
In assays for serotonin (5-HT) 1A, 5-HT IB and 5-HT ID receptor-mediated inhibition of forskolin-stimulated adenylate cyclase activity from calf hippocampus, human recombinant HeLa cells and calf substantia nigra [Schoeffter P. et al., Br. J. Pharmacol. 95, 975-985(1988), Neuropharmacology 36, 429-437 (1997) and Naunyn-Schmiedeberg's Arch. Pharmacol. 337,602-608(1988)], the agents of the invention behave as agonists with pECso values from about 5.0 to about 9.0.
In assays for 5-HT 2C receptor-mediated accumulation of inositol phosphates in pig choroid plexus extracts [Hoyer D. et al., Naunyn-Schmiedeberg's Arch. Pharmacol. 339, 252-258 (1989) and in the isolated rat aorta assay for the 5-HT 2A receptor [Kalkman H.O. et al., Pharmacology 53, 351-355(1996)], the agents of the invention behave as antagonists with pKβ values from about 5.0 to about 9.0.
In the sleep/wakefulness cycle in the long-term implanted rat (ECoG recording), the agents of the invention on administration of about 1 to about 100 mg/kg p.o. prolong the wakefulness phases and reduce the REM sleep, which is indicative of attention increasing and antidepressive activity.
In the intruder test in mice [Triangle 21, 95-105(1982); Dixon A.K. et al., J.Clin. Psychiatry 55(9), Suppl. B, 4-7(1994)], the agents of the invention at doses of about 0.01 to about 1 mg/kg increase non-social behaviour and social investigation and decrease defensive ambivalence, indicative of attention/vigilance increasing activity, suggesting an antidepressant and anxiolytic profile.
In the middle cerebral artery (MCA) occlusion model in rats at a dosage of about 1 to about 30 mg/kg/day p.o. [Ta ura A. et al., Cereb. Blood Flow Metabol. 1, 53- 60(1981); Sauter A., Rudin M., Stroke 17, 1228-1234(1986)], the agents of the invention, administered orally each day from the third day after MCA occlusion for three weeks, reduce ischaemia-induced neuronal damage and ensuing symptoms.
In view of the above, the agents of the invention are useful in the treatment of depression and related disorders including major depression, bipolar depression/ disorders, manic depression, mania, premenstrual depressive disorders, post-partum depression, post-menopausal depression; anxiety and related disorders including general anxiety disorders, sleep disorders, obsessive compulsive disorders, extreme shyness, social phobia/anxiety, simple phobia, stuttering, agoraphobia, bulimia, eating disorders, obesity, anorexia nervosa, panic disorders, suicidal attempts / ideation; stress and stress-induced disorders including post-traumatic stress disorders, hemorrhagic stress, stress-induced urinary incontinence, stress-induced psychotic episodes; furthermore stroke, post-stroke recovery and head trauma, alcohol abuse/dependency/ withdrawal, drug withdrawal, e.g. nicotine withdrawal, schizophrenia, negative symptoms of schizophrenia, attention deficit hyperactivity disorders (ADHD), sexual dysfunctions, cognitive disorders, memory deficit, senile dementia, Alzheimer's disease, narcolepsy and chronic fatigue syndrome.
For the above-mentioned indications, the appropriate dosage will of course vary depending upon, for example, the compound employed, the host, the mode of administration and the nature and severity of the condition being treated. However, in general, satisfactory results in animals are indicated to be obtained at a daily dosage of from about 0.01 to about 100, preferably from about 0.1 to about 50 mg/kg animal body weight. In larger mammals, for example humans, an indicated daily dosage is in the range from 1 to about 500, preferably from about 1 to about 100 mg of an agent of the invention conveniently administered, for example, in divided doses up to four times a day or in sustained release form.
The agent of the invention may be administered by any conventional route, in particular enterally, preferably orally, for example in the form of tablets or capsules, or parenterally, for example in the form of injectable solutions or suspensions. For all the above indications the preferred compound is (-)-(4aR,10aR)- 1 ,2,3,4 ,4a,5, 10, 10a-octahydro-9-methoxy-N-methyl-6-trimethylsilyl-benzo[g] quinoline. Said compound has a pECso and intrinsic activity of 5.8 ± 0.2 / 37± 2% in the isolated rat vas deferens contraction model, a pECso of 5.97 ± 0.20 / 107± 17% in the assay for the 5-HT 1A receptor (calf hippocampus), a pECso of 6.37 ± 0.17 / 97± 4% in the assay for the 5-HT 1A receptor (human rec. HeLa cells), a pECso of 6.75 ± 0.14 / 70± 7% in the assay for the 5-HT IB and 5-HT ID receptors (calf substantia nigra), a pKβ of 7.14 ± 0.14 in the assay for the 5-HT 2A receptor (isolated rat aorta) and a pKβ of 7.03 ± 0.09 in the assay for the 5-HT 2C receptor (pig choroid plexus). In the sleep/wakefulness cycle at 1 and 3 mg/kg p.o., it induces a long lasting increase of quiet wakefulness and a reduction in REM sleep, the classical sleep phase being mainly unchanged. In the intruder test at 0.03, 0.1 and 0.3 mg/kg p.o., it induces a significant increase in non-social behavior and in social investigation, as well as a significant reduction in defensive behavior, which is an index of social withdrawal.
The preferred indications are depression and ADHD.
In accordance with the foregoing, the present invention also provides an agent of the invention, for use as a pharmaceutical, e.g. for the treatment of depression and ADHD.
The present invention furthermore provides a pharmaceutical composition comprising an agent of the invention in association with at least one pharmaceutical carrier or diluent. Such compositions may be manufactured in conventional manner. Unit dosage forms contain, for example, from about 0.25 to about 250, preferably from about 0.25 to about 50 mg of a compound according to the invention.
Moreover the present invention provides the use of an agent of the invention, for the manufacture of a medicament for the treatment of any condition mentioned above.
In still a further aspect the present invention provides a method for the treatment of any condition mentioned above, in a subject in need of such treatment, which comprises administering to such subject a therapeutically effective amount of an agent of the invention.
The following examples illustrate the invention. The temperatures are given in degrees Celsius and are uncorrected.
EXAMPLE 1: (-)-(4aR.10aR)-9-methoxy-N-methyl-1.2.3.4.4a.5.10.10a-octahvdro- 6-trimethylsilyl-benzo[g]quinoline
2.4 g (7.7 mmols) of (-)-trans-6-bromo-9-methoxy-N-methyl-l,2,3,4,4a,5,10,10a- octahydro-benzo[g]quinoline are dissolved in 50 ml of absolute tetrahydrofuran. The solution is cooled to -70°, and 14.1 ml (23 mmols) of n-butyllithium (15% solution in hexane) are added under argon. Subsequently, 2 ml (15.4 mmols) of trimethylchlorosilane are added, the mixture is allowed to rise to 0° and stirred for 2 hours. The preparation is washed with a 1 N sodium hydroxide solution and brine. It is extracted with ethyl acetate, and the organic phase dried and concentrated by evaporation . (-) -Trans-9-methoxy-N-methyl-l ,2,3 ,4,4a,5 , 10, 10a-octahydro-6- trimethylsilyl-benzo[g]quinoline is obtained. The corresponding (-)-(4aR,10aR)-9- methoxy-N-methyl-l,2,3,4,4a,5,10,10a-octahydro-6-trimethylsilyl-benzo[g]quinoline hydrogen fumarate is obtained from this, in acetone, with fumaric acid. It has a melting point of 186-187° and the rotation value [α]D 20 =-69° (c = 0.48; methanol); recrystallisation from methanol, acetone, ether. The corresponding (-)-(4aR,10aR)-9- methoxy-N-methyl-l,2,3,4,4a,5,10,10a-octahydro-6-trimethylsilyl-benzo[g]quinoline hydrogen maleinate has a melting point of 152-153° and the rotation value [<X]D 20= -71.2° (c=0.51;methanol).
The starting material may be prepared as follows:
a) 3-Carboxy-8-methoxy-2-tetralone (compound of formula VHI)
13.50 g (0.56 mols) of magnesium ribbons are added to 1.25 litres of methanol and the mixture heated to 50-55° and stirred. After 0.5 hours, a further 20.45 g (0.84 mols) of magnesium ribbons are added and the temperature maintained at 50-55° for a further 1.5 hours. Then, 20.45 g (0.84 mols) of magnesium ribbons are again added and the mixture again maintained at ca. 50° for 1.5 hours. Most of the methanol is subsequently evaporated off, 1.1 litres of dimethylformamide are added to the residue and the mixture is left to stand for 12 hours under argon. Then, carbon dioxide gas is passed into the solution until reaching saturation (ca. 4 hours). A solution of 55 g (0.31 mols) of 8-methoxy-2-tetralone in 100 ml of dimethylformamide is added dropwise to this mixture. The reaction solution is then heated under argon for 4 hours to an internal temperature of 133° and subsequently worked up. The reaction mixture is divided in two and each half is added dropwise to 1.5 litres of 10% hydrochloric acid (ca. -10°). Each portion is then stirred for 30 minutes at -10°. The precipitated 3- carboxy-8-methoxy-2-tetralone is filtered off and washed with one litre of ice water. Then, the crystalline part is stirred for 20 minutes at 0° in 100 ml of methanol, filtered from the methanol by suction, the product washed with 20 ml of ether/petroleum ether (1:1) and the residue dried. 3-Carboxy-8-methoxy-2-tetralone is obtained with a melting point of 114-117° (decomp.).
b) 3-Methoxycarbonyl-8-methoxy-2-tetralone (compound of formula VII)
550 ml of methylene chloride are cooled to 0° and to this are added 49.50 g (0.22 mols) of 3-carboxy-8-methoxy-2-tetralone. 21.11 g (0.22 mols) of chloroformic acid methyl ester are added to this reaction mixture. Then, at an internal temperature of 5°, 34 ml of triethylamine in 50 ml of methylene chloride are added, and stirring is effected for 2 hours at 5°. 125 ml of water are subsequently added dropwise, the organic phase is separated and the solvent is substantially concentrated by evaporation. The residue is mixed with methanol and the product precipitated. After filtering and drying, 3-methoxycarbonyl-8-methoxy-2-tetralone is obtained with a melting point of 106-108°.
c) 3-Methoxycarbonyl-3-(2-cvanoethyl)-8-methoxy-2-tetralone (compound of formula VI)
2.34 g (10 mmols) of 3-methoxycarbonyl-8-methoxy-2-tetralone are dissolved in 50 ml of absolute toluene and 14 ml of absolute methanol. To this are added, under inert gas, 0.81 g (15 mmols) of acrylonitrile and 10 mg of sodium hydride (55% dispersion in oil). Stirring is effected for 20 hours at room temperature. By adding methanolic hydrochloric acid, the reaction mixture is adjusted to pH 1, and then the solvent is concentrated by evaporation. Crude 3-methoxycarbonyl-3-(2-cyanoethyl)-8-methoxy- 2-tetralone is obtained following chromatography (silica gel, methylene chloride with 0.8% methanol) and recrystallisation from acetone/petroleum ether with a melting point of 120-121°.
d) 3-(2-Cvanoethyl)-8-methoxy-2-tetralone (compound of formula V)
5.7 g (20 mmols) of 3-methoxycarbonyl-3-(2-cyanoethyl)-8-methoxγ-2-tetralone are dissolved in 130 ml of hexamethylphosphoric acid triamide at 75°. 1.85 g (44 mmols) of lithium chloride are added and stirring continues for 20 hours at 75°. The reaction product is then poured onto 1 litre of water and the mixture is extracted with ether. The organic phase is washed with water and dried. After concentrating the solvent by evaporation, the resulting oil is chromatographed (silica gel, methylene chloride). 3-(2- cyanoethyl)-8-methoxy-2-tetralone is obtained with a melting point of 68-69°.
e) Trans-9-methoxy-N-methyl-1.2.3,4,4a,5.10.10a-octahvdro-benzo[g]quinoline (compound of formula III)
6.6 g (29 mmols) of 3-(2-cyanoethyl)-8-methoxy-2-tetralone are dissolved in 150 ml of ethanol-chloroform (1:1). 0.6 g of platinum oxide are added and the suspension hydrogenated whilst agitating for 30 seconds at an initial pressure of 40 psi. The reduction mixture is then filtered, concentrated and the residue obtained is extracted in 1 N aqueous sodium bicarbonate solution / methylene chloride. The diastereoisomers of cis- and trans-9-methoxy-l,2,3,4,4a,5,10,10a-octahydro-benzo[g]quinoline are obtained as a crude oil. 1.78 g (8.2 mmols) of this diastereoisomer mixture are dissolved in 1.96 ml of 37% aqueous formaldehyde solution and 1.31 ml of formic acid, and the mixture is heated to 70° under argon and stirred. After 1.5 hours, the mixture is extracted with water/cone, ammonia, water/ice and methylene chloride. The oil obtained after concentrating the solvent by evaporation is chromatographed (silica gel, methylene chloride with 1% methanol and 0.1% ammonia). Trans-9-methoxy-N- methyl-l,2,3,4,4a,5,10,10a-octahydro-benzo[g]quinoline is obtained with a melting point of 85-87°.
As product of the chromatography, cis-9-rnethoxy-N-methyl-l,2,3,4,4a,5, 10,10a- octahydro-benzo[g]quinoline is additionally obtained. 1H-NMR (360 MHz, CDC13): H ClOa = 2.9 ppm (m).
f) (-)-(4aR.10aR)-9-methoxy-N-methyl-1.2.3.4,4a.5.10.10a-octahvdro- benzo[g]quinoline
5.00 g (21.6 mmols) of trans-9-methoxy-N-methyl-l,2,3,4,4a,5,10,10a-octahydro- benzo[g]quinoline are dissolved in 150 ml of acetone. To this is added a solution of 8.73 g (21.6 mmols) of (-)-di-0,0'-p-toluoyl-L-(+)-tartaric acid in 100 ml of acetone. The precipitating salt is stirred for another one hour at room temperature and filtered off. The salt is then recrystallised from methanol/acetone. Thereafter, the salt is taken up in a mixture of ice water/cone, ammonia/methylene chloride. The organic phase is separated and the aqueous phase extracted with methylene chloride. The combined organic phases are dried and concentrated by evaporation. (-)-(4aR,10aR)-9-methoxy- N-methyl-l,2,3,4,4a,5,10,10a-octahydro-benzo[g]quinoline is obtained. [α]ϋ 20 = - 166° (c = 0.5 methylene chloride); melting point: 70°. As the di-0,0'-p-toluoyl-L-(+)- tartrate: melting point: 169-170°.
g) (-)-(4aR.10aR)-6-bromo-9-methoxy-N-methyl-1.2.3.4.4a.5.10.10a-octahvdro- benzo[g]quinoline (compound of formula II)
2.31 g (10 mmols) of (-)-(4aR,10aR)-9-methoxy-N-methyl-l,2,3,4,4a,5,10,10a- octahydro-benzo[g]quinoline are dissolved in a mixture of 50 ml of methylene chloride and 50 ml of carbon tetrachloride, and cooled to 0°. At this temperature, 20 mmols of bromine, dissolved in carbon tetrachloride, are added. The preparation is washed for one hour with a 20% sodium hydrogen sulphite solution and 2 N sodium hydroxide solution, the organic phase is dried and concentrated by evaporation. The residue undergoes flash chromatography (silica gel 60, methylene chloride, 2% methanol, 0.2% cone, ammonia). After crystallisation from methylene chloride/ether, (-)- (4aR,10aR)-6-bromo-methoxy-N-methyl-l,2,3,4,4a,5,10,10a-octahydro-benzo[g]- quinoline is obtained with a decomposition point of 265-267°.
EXAMPLE 2: M-(4aR.10aR)-3.4.4a.5.10.10a-Hexahvdro-6-methoxy-4-methyl-9- trimethylsilyl-2H-naphth[2.3-b]-l,4-oxazine
4.3g (12 mmols) of (-)-(4aR,10aR)-3,4,4a,5,10,10a-hexahydro-9-iodo-6-methoxy-4- methyl-2H-naphth [2,3-b]-l,4-oxazine are dissolved in absolute tetrahydrofuran. The solution is cooled to -70°, and 21.5 ml (36 mmols) of n-butyl-lithium (15% solution in hexane) are added. Subsequently, 2.61 g (24 mmols) of trimethylchlorosilane are added, the mixture is allowed to rise to -10° and stirred. The reaction mixture is poured onto ice, rendered alkaline with a 10% sodium hydroxide solution and extracted with methylene chloride. The organic phase is dried and evaporated. Recrystallisation from ether / petroleum ether yields the title compound. Mp= 146- 147°; [α]D 0= -98° (c=0,5, methylene chloride).
The hydrochloride is obtained from the base using hydrochloric acid in ether. Recrystallisation is effected from methanol / ethyl acetate. Mp= 277-278°; [CX]D 20= -90° (c= 0.5, methanol).
The starting material is prepared as follows:
7.3g (20.3 mmols) of trans-3,4,4a,5,10,10a-hexahydro-9-iodo-6-methoxy-4-methyl- 2H-naphth[2,3-b]-l,4-oxazine are dissolved in acetone. A solution of 8.21 g (20.3 mmols) of (+)-di-0,0'-p-toluene-D-(-)-tartaric acid monohydrate in acetone is added. The solvent is partially evaporated and ethyl acetate and ether are added. The precipitating salt is stirred at room temperature and filtered off. Recrystallisation is effected from methylene chloride / acetone / ethyl acetate. After several recrystallisations the salt is taken up in a mixture of ice water / cone, ammonia / methylene chloride. The organic phase is separated and evaporated. (-)-(4aR,10aR)-3, 4,4a,5 ,10,10a-hexahydro-9-iodo-6-methoxy-4-methyl-2H-naphth [2,3-b]-l ,4-oxazine is obtained as an oil. [(X]D20= -96.8° (c=0.6, methanol).

Claims

CLAIMS :
1. A compounds of formula I,
Figure imgf000015_0001
wherein X is CH2 or O, R] is hydrogen, (C1-4)alkyl, (C3-5)alkenyl in which the double bond is not adjacent to the nitrogen atom, or benzyl, R2 is hydroxy or (Cι- )alkoxy and R3, R and Rs, independently, are (C1-4)alkyl, in free base or acid addition salt form.
2. A compound of formula I as defined in claim I, wherein X is CH2, in free base or acid addition salt form.
3. (-)-(4aR, 1 OaR) -9-methoxy-N-methyl- 1 ,2,3 ,4,4a,5 , 10, 1 Oa-octahydro-6-trimethylsilyl- benzo[g]quinoline in free base or acid addition salt form.
4. A process for preparing a compound of formula I as defined in claim 1 or a salt thereof, which includes the step of substituting the halogen in a compound of formula π,
Figure imgf000015_0002
wherein X is CH2 or O, Rj and R2 are as defined in claim 1 and R6 is chlorine, bromine or iodine, by a trialkylsilyl group, and recovering the thus obtained compound of formula I in free base or acid addition salt form.
5. A compound of any one of claims 1 to 3 in free base or pharmaceutically acceptable acid addition salt form, for use as a pharmaceutical.
6. A compound of any one of claims 1 to 3 in free base or pharmaceutically acceptable acid addition salt form, for use in the treatment of depression and attention deficit hyperactivity disorders.
7. A pharmaceutical composition comprising a compound of any one of claims 1 to 3 in free base or pharmaceutically acceptable acid addition salt form, in association with a pharmaceutical carrier or diluent.
8. The use of a compound of any one of claims 1 to 3 in free base or pharmaceutically acceptable acid addition salt form, as a pharmaceutical for the treatment of depression and attention deficit hyperactivity disorders.
9. The use of a compound of any one of claims 1 to 3 in free base a pharmaceutically acceptable acid addition salt form, for the manufacture of a medicament for the treatment of depression and attention deficit hyperactivity disorders.
10. A method for the treatment of depression and attention deficit hyperactivity disorders, in a subject in need of such treatment, which comprises administering to such subject a therapeutically effective amount of a compound of any one of claims 1 to 3 in free base or pharmaceutically acceptable acid addition salt form.
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US11111263B2 (en) 2019-05-20 2021-09-07 H. Lundbeck A/S Process for the manufacture of (2S,3S,4S,5R,6S)-3,4,5-trihydroxy-6-(((4aR,10aR)-7-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)tetrahydro-2H-pyran-2-carboxylic acid
US11110110B2 (en) 2017-11-24 2021-09-07 H. Lundbeck A/S Catecholamine prodrugs for use in the treatment of Parkinson's disease
US11130775B2 (en) 2019-05-20 2021-09-28 H. Lundbeck A/S Solid forms of (2S,3S,4S,5R,6S)-3,4,5-trihydroxy-6-(((4aR,10aR)-7-hydroxy-1-propyl-1,2,3,4,4A,5,10,10A-octahydrobenzo[g]quinolin-6-yl)oxy)tetrahydro-2H-pyran-2-carboxylic acid
US11168056B2 (en) 2019-05-20 2021-11-09 H. Lundbeck A/S Process for the manufacturing of (6aR,10aR)-7-propyl-6,6a,7,8,9,10,10a,11-octahydro-[1,3]dioxolo[4′,5′:5,6]benzo[1,2-G]quinoline and (4aR,10aR)-1-propyl-1,2,3,4,4a,5,10,10a-octahydro-benzo[G]quinoline-6,7-diol
US12319710B2 (en) 2019-05-21 2025-06-03 H. Lundbeck A/S Catecholamine prodrugs for use in the treatment of Parkinson's diseases
US12384765B2 (en) 2019-05-21 2025-08-12 H. Lundbeck A/S Catecholamine prodrugs for use in the treatment of Parkinson's Disease
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US12398106B2 (en) 2019-05-21 2025-08-26 H. Lundbeck A/S Catecholamine carbamate prodrugs for use in the treatment of parkinson's disease

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