NO174958B - Analogous process for the preparation of therapeutically active tetralin derivatives - Google Patents

Description

The present invention relates to the production of new 1,2,3,4-tetrahydro-2-naphthylamines.

In depressed patients, signs indicate that the neurotransmission in the central nervous system (CNS) may be disturbed. These disturbances include the neurotransmitters norepinephrine (NA) and 5-hydroxytryptamine (5-HT). The drugs most often used in the treatment of depression are considered to work by improving the neurotransmission of one or both of these physiological agents. Available data suggest that the increase in 5-HT neurotransmission will primarily improve depressed mood and anxiety, while the increase in norepinephrine neurotransmission will improve retardation symptoms that occur in depressed patients. In recent years, great efforts have been made to develop new drugs with high selectivity for improving 5-HT neurotransmission in the CNS.

The mechanism of action for the drugs that are generally used today in the therapy for mental depression is generally believed to be indirect, as the drugs work by blocking the reuptake of neurotransmitters, NA and/or 5-HT, which are released from nerve terminals in the CNS, which increases the concentration of these transmitters in the synaptic cleft and restores adequate neurotransmission. For example, the clinically documented antidepressant medication, zimelidine (dimethylamino-1-(4-bromophenyl)-1-(3-pyridyl)propene) acts as such a reuptake inhibitor with high selectivity for 5-HT neurons.

A fundamentally different way to improve neurotransmission in the central 6-HT neurons would be to use a 5-HT receptor agonist that acts directly on the 5-HT receptors, and in particular the 5-HT 2 receptor. To minimize unwanted side effects, a high selectivity for this type of receptor would be necessary.

Clinically, 5-HT1A agonists have also shown anxiolytic properties. The drug, "Buspirone" is the only currently available, marketed 5-HT 2 agonist that has anxiolytic activity. This compound antagonizes dopamine receptors at the same dose as it stimulates 5-HT^A receptors. A similar drug, "Gepirone" also has dopamine antagonistic properties. However, these dopamine antagonist properties reduce the clinical applicability of these compounds, because long-term treatment with dopamine antagonists causes tardive dyskinesia.

The search for new CNS-active compounds is focused on finding compounds with selective 5-HT 2 A ~ receptor antagonist effects without adversely affecting central dopamine receptors.

Medicines that act on central dopamine transmission,

are clinically effective in the treatment of a number of central nervous system diseases such as parkinsonism, schizophrenia and manic-depressive illness. In parkinsonism, for example, the nigro-neostriatal hypofunction can be restored by an increase in postsynaptic dopamine receptor stimulation. In schizophrenia, the condition can be normalized by achieving a reduction in postsynaptic dopamine receptor stimulation. Classic antipsychotics directly block the postsynaptic dopamine receptor. The same effect can be achieved by inhibiting intraneuronal, presynaptic events that are essential for maintaining adequate neurotransmission, transport mechanism and transmitter synthesis.

In recent years, a large body of pharmacological, biochemical and electrophysical discoveries have provided considerable support in favor of the existence of a specific population of central autoregulatory dopamine receptors located within the dopaminergic neuron itself. These receptors are part of a homeostatic mechanism that modulates nerve impulse flow and transmitter synthesis and regulates the amount of dopamine released from the nerve endings.

Direct dopamine receptor agonists, such as apomorphine, are able to activate the dopamine autoreceptors as well as the postsynaptic dopamine receptors. The effects of autoreceptor stimulation appear to predominate when apomorphine is administered in low doses, while the impairment of dopamine transmission at higher doses is offset by the increase in postsynaptic receptor stimulation. The antipsychotic and antidyskinetic effects in humans of low doses of apomorphine are probably caused by the autoreceptor-stimulator properties of this dopamine receptor agonist. This knowledge indicates that dopamine receptor stimulants with a high selectivity for central nerve dopamine autoreceptors will be valuable in the treatment of psychiatric diseases.

The following documents may be important when examining this application.

Derwent 12191K (Belgium 893 917) describes indanyl-substituted imidazole derivatives and tetralylimidazole derivatives where the aromatic ring in the indanyl and tetralyl groups may be substituted with various groups including halogen, alkyl (C^-Cg), trihaloalkyl, alkoxy and alkylthio. The compounds are useful for the treatment of atherosclerosis.

GB patent 1 377 356 describes 8-hydroxy- and 8-methoxy-substituted 1,1-dialkyl-2-aminotetralins in which the amino group is unsubstituted or substituted with an alkyl C]_~cg* These compounds are useful as analgesics.

Derwent 40378A/23 (GB 1 597 140) describes, among other compounds, 2-aminotetralines which are substituted on

the aromatic ring with halogen, dichloro and additionally hydroxy or an alkanoyloxy group. These compounds are useful in the treatment of heart conditions and/or Parkinson's disease.

CH 637 363 (Derwent 729 386) and CH 637 364 describe, among other compounds, 2-aminotetralins which are substituted on the aromatic ring with halogen, dichloro and, in addition, hydroxy, alkyl or other functional groups. These compounds are stimulants for α- and β-adrenergic and dopamine receptors which make them useful in the treatment of heart diseases, heart attacks, hypertension and Parkinson's disease.

DE 2 333 847 (Derwent 7633V) describes a very wide range of compounds which may comprise aminotetralines and aminoindanes substituted on the aromatic ring with alkoxy or halogen and in addition hydroxy, aralkyloxy or acyloxy. These compounds are water softeners and corrosion inhibitors in lubricants as well as CNS depressants and antiarrhythmic agents.

EP 272 534-A (Derwent) describes 2-aminotetralins which are substituted in the 8-position by halogen (fluorine, chlorine, bromine or iodine) among many other compounds within a broad description. These compounds are useful serotonin antagonists or agonists with high affinity for cerebral S-HT 2 receptors making them useful in the treatment of CNS diseases, cognitive deficits, Alzheimer's disease, cardiovascular diseases, pain and intestinal diseases.

DE 2 803 582 (Derwent 58274B) describes 2-aminotetralins in which the amino group is substituted with, among other things, alkyl, or cycloalkyl, and in which the aromatic ring is substituted with, among other things, alkyl, halogen, dichloro and additionally with hydroxy or an alkanoyloxy group. These compounds have a stimulating effect on α- and β-adrenoreceptors and on dopamine receptors and are useful in the treatment of heart diseases, heart attacks, high blood pressure and Parkinson's disease.

Wikström, H., et al., J. Med. Chem. 30, 1115 (1987) describes 4-hydroxy- and 4-methoxy-2-aminoindanes in which the amino part is unsubstituted or substituted with dimethyl or di-n-propyl, 5-hydroxy-2-dimethylaminoindan and 7-hydroxy-2-aminotetralin in which the amino moiety is substituted with dimethyl or di-n-propyl. This work focuses on the structural analysis of the compounds in relation to their central dopaminergic effects.

J. G. Canon, et al., J. Med. Chem. 25, 1442-1446

(1982) and J. Med. Chem. 28, 515-518 (1985) describes, among other things, 4-hydroxy- and 5-hydroxy-2-di-n-propylindane in an investigation concerning structural analysis of a series of 2-aminoindanes.

Seeman, et al., Molecular Pharmacology 28, 291-299

(1985) included a number of known hydroxy-substituted and methoxy-substituted aminotetralins and aminoindanes in a D₂ receptor binding affinity assay.

THAT. Dren, et al., J. Pharm. Pollock. 67, 880-882 (1978) describes, among other compounds, 2-aminotetralin in which the amino group is mono-substituted with cyclopropylmethyl or cyclopropyl and the aromatic ring is substituted with methoxy in the 5- or 6-position. These compounds were tested for local anesthetic activity. THE. Ames, et al., J. Chem. Soc. 2636 (1965) describes the synthesis of various di-alkoxy-substituted aminotetralins in which the alkoxy groups have from 1 to 4 carbon atoms. 6-methoxy-2-aminotetralin is also described. LAUGH. Arvidsson, J. Med. Chem. 27, 45-51 (1984) describes a series of 2-aminotetralins in which the amine is substituted with one or two lower alkyl groups with 1-4 carbon atoms, octyl or benzyl, and the aromatic ring is substituted in the 5- and/or 8-position with hydroxy or lower alkoxy. These compounds were tested as dopamine and 5-hydroxy-tryptamine receptor agonists. LAUGH. Arvidsson, et al., J. Med. Chem. 24, 921-923

(1981) describe 8-methoxy-2-aminotetralins in which the amino moiety

is substituted with n-propyl, benzyl or di-n-propyl and 2-di-n-propyl-aminotetralins in which the aromatic ring is substituted in the 5-, 6-, 7- or 8-position with hydroxy. These compounds were evaluated in connection with their effect on dopaminergic and oc-adrenergic receptors.

J. D. McDermed/. et al., J. Med. Chem. 19, 547-549

(1976) describe 5,6-dihydroxy- and 5r, 6- and 7-hydroxy-2-di-n-propylaminotetralins in a study of their dopaminergic activity.

J. D. McDermed, et al., J. Med. Chem. 18, 362-367

(1975) describe a large series of 2-aminotetralins in which it

aromatic ring is mono- or di-substituted with hydroxy, methyl or lower alkoxy and the amine part is unsubstituted or substituted with lower alkyl, benzyl, alkoxyalkyl or forms part of a monocyclic heterocyclic group. These compounds were assessed for their dopaminergic activity. L. E. Arvidsson, J. Med. Chem. 30, 2105-2109 (1987) evaluates the 5-HT receptor agonist activity of 1-methyl-2-di-n-propylaminotetralins substituted in the 8-position with hydroxy or methoxy. D. B. Rusterholz, et al., J. Med. Chem. 19, 99-102

(1976) describe 5- and/or 8-substituted-2-aminotetralins in which the 5- or 8-position is substituted with methyl, hydroxy or methoxy. The effect of these compounds on prolactin release has been assessed.

J. G. Cannon, et al., J. Med. Chem. 28, 515 (1985) describes the resolution of 4-hydroxy-2-(di-n-propyl)aminoindane, a synthetic precursor of a potent dopaminergic agonist.

An object of the invention is to provide compounds for therapeutic use, in particular compounds with a therapeutic activity in the central nervous system. Another object is to provide compounds with an effect on 5-HT -

IA

the receptor's mammals including man. A further object of the invention is to provide compounds with an effect on the subclass of dopamine receptors known as the D2 receptor.

The present invention relates to an analogous method for the preparation of therapeutically active compound of formula I and pharmaceutically acceptable acid addition salts thereof,

wherein -YRX is a substituent in the 8-position of the aromatic ring, and is 0Rlr wherein Rx is (C^Cg)-alkyl,

R3 is -CH2-(C3-C8)-cycloalkyl,

R4 is (C1-C8)-alkyl, -CH2-(C3-C4)-cycloalkyl or -(CH2)m-R5,

m is 0-2,

R5 is optionally substituted with lower alkoxy phenyl, 2-thiophene or 3-thiophene, with the proviso that when R3 contains more than 4 carbon atoms and R4 is alkyl, said alkyl contains from 1 to 3 carbon atoms.

The compounds produced according to the invention have selective pharmacological properties and are applicable in the treatment of central nervous system diseases including antidepressant symptoms, anxiolytic symptoms, panic attacks, obsessive-compulsive disorder, senile dementia, emotional disturbances related to dementia diseases and stimulation of sexual activity. The compounds according to the invention are also useful for suppressing aggressive behavior, confused, unclear states and impotence. Certain compounds according to the present invention also have blood pressure-lowering effects. Particularly preferred compounds are 8-methoxy-2-(N-cyclopropylmethyl-N-n-propylamino)tetralin and 8-methoxy-2-(N,N-dicyclopropylmethylamino)tetralin.

The compounds produced according to the invention are identified in two ways: by the descriptive name and the reference to labeled structures contained in appropriate plates. In appropriate situations, the correct stereochemistry is also shown in the plates.

In this document, the bracketed expression (Cn-Cm) is inclusive so that a compound with (C-^-Cg) will include compounds with 1 to 8 carbon atoms and their isomeric forms. The different carbon parts are defined as follows: Alkyl refers to an aliphatic hydrocarbon radical and includes branched or unbranched forms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neo-pentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl and n-octyl.

Alkoxy as represented by -OR, when R, is (C,-C0)

i i lo alkyl, refers to an alkyl radical attached to the rest of the molecule by oxygen and includes branched or linear forms such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy, n-pentoxy, isopentoxy, neo-pentoxy, n-hexoxy, isohexoxy, n-heptoxy, isoheptoxy and n-octoxy.

It will be clear to the person skilled in the art that compounds prepared according to the invention may contain chiral centers. The scope of this invention includes the preparation of all enantiomeric or diastereomeric forms of compounds of formula I either in pure form or as mixtures of enantiomers or diastereomers. The compounds of formula I contain two asymmetric carbon atoms in the aliphatic ring part, including the ring carbon atoms near the nitrogen atom. The compounds' therapeutic properties may depend to a greater or lesser extent on the stereochemistry of a particular compound. Pure enantiomers as well as enantiomers or diastereomeric mixtures are included

of the invention.

Both organic and inorganic acids can be used to prepare non-toxic, pharmaceutically acceptable acid addition salts of the compounds according to the invention. Illustrative acids are sulfuric acid, nitric acid, phosphoric acid, hydrochloric acid, citric acid, acetic acid, lactic acid, tartaric acid, palmic acid, ethanedisulfonic acid, sulfamic acid, succinic acid, cyclohexylsulfamic acid, fumaric acid, maleic acid and benzoic acid. These salts are easily produced using known methods in the field.

The analog method according to the invention is characterized by the fact that a compound of formula

dissolved in a solvent, acylated with a suitable alkyl, cycloalkyl, phenyl (optionally substituted) or thiophene carboxylic acid, separated as an organic layer to form an amide, which is then reduced with dichloroethane, tetrabutylammonium, BH4, LiAlH4 or a combination thereof, and the amine product is washed and separated, and optionally converted to a hydrochloride salt.

A compound of the formula, C-1, can be converted to a compound of the formula I when R x and R 4 are equal, by alkylating the nitrogen and oxygen atoms with a suitable alkylating agent. The compound of formula C-1 can be treated with an alkyl halide or tosylate of the formula RaX, when Ra is alkyl or cycloalkyl, and when X is Cl, Br, I or TsO, in an organic solvent such as acetonitrile or acetone and in the presence of a base like for example. potassium carbonate or sodium hydroxide.

Alternatively, the compounds according to the invention can be obtained from a compound with the formula C-2 by alkylating the hydroxy part with a suitable alkylating agent. The starting compound, C-2, can be treated with an alkyl halide or tosylate RtøX, when is alkyl, alkenyl, cycloalkyl or benzyl, when X is Cl, Br, I or TsO, in an organic solvent such as e.g. acetonitrile or acetone and the presence of a base such as potassium carbonate or sodium hydroxide.

In addition, a compound of formula C-3 can be converted into a compound of formula I, by alkylating the nitrogen atom with a suitable alkylating agent. The starting compound can be treated with an alkyl halide or tosylate RCX, when Rc is alkyl, cycloalkyl, heterocyclic alkyl, ethylalkyloxy or ethylthiaalkyl, when X is Cl, Br, I or TsO, in an organic solvent such as e.g. acetonitrile or acetone and in the presence of a base such as e.g. potassium carbonate or sodium hydroxide, or the starting compound, C-3, can be treated with a complex of carboxylic acid and sodium borohydride, when the carboxylic acid is HOOC-(C1-C7)alkyl, HOOC-(C3-Cg)cycloalkyl, HOOC-(CH2)p-R5 or HOOC-CH2-X-(CH2)n~CH3, when p is 1 or 2, n is zero or 3 and X is oxygen or sulfur. Alternatively, the starting compound, C-3, can be dissolved in methanol and treated with an aldehyde and sodium cyanoborohydride, when the aldehyde is HOC-(C1-C7)alkyl, HOC-(C^-C8)cycloalkyl, HOC-(CH2)p-R5 or HOC-CH2-X-(CH2)n-CH3 when p is 1 or 2, n is zero to 3 and X is oxygen or sulfur.

In addition, an amide of the formula C-4, when R 1 is (C 1 -C 6 ) alkyl, (C 3 -C 8 )cycloalkyl, (CH 2 ) p -R 5 or

-CH2-X-(CH2)n-CH3, when p is 1 or 2, n is zero to 3 and X is oxygen or sulphur, is reduced with a hydride-reducing agent such as e.g. lithium aluminum hydride in ether or tetrahydrofuran, diborane in tetrahydrofuran or QBH3 (where Q represents tetrabutylammonium ion) in a mixture of dichloromethane and dichloroethane, to give a compound of formula I. Compounds of the invention where R^Y is -S (C^-C3) alkyl, can be prepared from a compound corresponding to a C-4 compound in which OR^ is replaced by a hydroxy group by converting the hydroxy group to an amine which is then converted to bromine via a Sandmeyer reaction. The bromine-substituted intermediate is lithiated using n-butyllithium in THF or ether and

treated with (C^C-j) alkyl-SS-alkyl ( C^ C^ to the alkylthio-substituted compounds.

Starting materials for the compounds C-1 to C-4 can be obtained by methods described below or by methods according to the state of the art.

The known or commercially available ketone, C-5, when alkyl, alkenyl, cycloalkyl or benzyl, reacts with hydroxylamine in the presence of base to give the intermediate oxime which is reduced by catalytic hydrogenation to a compound of formula C-6. To obtain the secondary amine, a compound of formula C-6 is acylated with a carboxylic acid chloride in the presence of triethylamine and then reduced with a hydride reducing agent such as lithium aluminum hydride in ether or tetrahydrofuran, diborane in tetrahydrofuran or QBH4 (where Q represents tetrabutylammonium ion) in a mixture of dichloromethane and dichloroethane. Alternatively, the ketone, C-5, can be converted directly to the secondary amine, C-6, by reacting the ketone with a primary amine of the formula R^NH^, in which R is alkyl, cycloalkyl, heterocyclic alkyl, ethylalkoxy or ethylthiaalkyl, with sodium cyanoborohydride in methanol that has been acidified to approx. pH 5 with the addition of a few drops of concentrated acetic acid.

The preparation of the compounds with an alkyl group in the 1-position of the aliphatic ring is achieved by alkylating a compound of formula C-7, either via the enamine or by direct alkylation of the ketone, C-7, under basic conditions, to give a compound of the formula C-5, converting the compound C-5 to the secondary amine using methods already described, separating the cis and trans isomers formed and finally converting the secondary amine to the tertiary amine using methods already described .

A pure enantiomer of compound C-3 can be prepared by converting the cis-secondary amine, C-3, to (-)-O-methyl-mandelic acid amide, C-8, followed by chromatographic separation of the two diastereomers and resolution by subsequent reaction with potassium tert-butoxide in tetrahydrofuran with traces of water and methyllithium. The secondary amine can be converted to the tertiary amine using methods already described.

In clinical practice, the compounds according to the present invention will normally be administered orally, rectally or by injection, in the form of pharmaceutical preparations comprising the active ingredient either as a free base or as a pharmaceutically acceptable, non-toxic acid addition salt, such as e.g. the hydrochloride, the lactate, the acetate and the sulfamate, in association with a pharmaceutically acceptable carrier. The use and administration to a patient to be treated in the hospital will be easy for a person skilled in the art to decide.

In therapeutic treatment, the appropriate daily doses of the compounds according to the invention are 1-2000 mg for oral application, preferably 50-500 mg, and 0.1-100 mg for parenteral application, preferably 0.5-50 mg.

The compounds where -0^ is in the 8-position of the aromatic ring are highly selective 5-HT1A receptor agonists with little or no dopaminergic activity. In vitro binding data for the IC50 ratio between dopamine D2 and 5-HT1A appears in Table 1 for a compound according to the invention, 8-methoxy-2-(N,N-dicyclopropylmethyl)-tetralin, and shows the selectivity for the 5-HT1a receptor . These compounds are particularly effective anxiolytics and anti-depressants. Other uses for these compounds include panic attacks, obsessive-compulsive disorder, and senile dementia, particularly the emotional disturbances that occur with dementia. In addition, central 5-HT receptor activation is believed to be involved in influencing sexual behavior. These compounds will be useful for stimulating sexual activity and preventing impotence.

The compounds where -0^ is in the 5-, 6- or 7-position show selective affinity for D2 receptors. These compounds are particularly effective in the treatment of psychoses, manic-depressive disorders and parkinsonism.

The compounds have also been shown to have high oral potency and a long duration of action. Both of these features are useful for effective clinical treatment.

The utility of the compounds to treat central nervous system diseases is demonstrated by behavioral and biochemical activity in rats pretreated with reserpine.

Antagonism of the reserpine-induced "neuroleptic syndrome" in rats (visible behavior).

Depletion of the monoamine stores with reserpine causes a "neuroleptic syndrome" which is characterized by hypomotility, catalepsy, muscle stiffness, hunchbacked posture as well as a number of other central and peripheral signs of monoamine depletion. All or part of this syndrome can be reversed by the administration of drugs that stimulate dopamine or 5-HT receptors directly or indirectly.

Stimulation of the dopamine receptors, e.g. with apomorphine, causes both movement and stereotyped behavior such as sniffing, gnawing and jumping. On the other hand, stimulation of the 5-HT receptors with 5-hydroxytryptophan (5-HTP) combined with, for example, MAO inhibitors, causes a very different behavior. The animals lie flat on the cage floor and exhibit forward locomotion with outstretched forepaws pawing, "playing the piano" and moving their hind legs to the side, occasionally with a slight tremor in the forebody and with Straub tail, stiff outstretched tail.

In-vivo determination of rat brain tyrosine and tryptophan hydroxylation after pretreatment with reserpine (biochemically controlled dopamine and 5-HT receptor activity).

The compounds to be investigated were tested biochemically for central dopamine and 5-HT receptor (pre- and/or postsynaptic)-stimulating activity. The idea of this biochemical research method is that a dopamine or 5-HT receptor agonist will stimulate the receptor and, by regulatory feedback systems, cause a decrease in tyrosine or tryptophan hydroxylating activity, respectively, and a subsequent decrease in the synthesis rate for dopamine and 5-HT in the presynaptic neuron. Dopamine and 5-HTP formation, as determined after in-vivo inhibition of the aromatic L-amino acid decarboxylase with NSD 1015 (3-hydroxybenzylhydrazine hydrochloride) are taken as indirect measures of dopamine-

and 5-HT synthesis rates.

Analogous conditions probably also exist for central NA neurons. Effects on dopamine formation in the NA-dominated, hemispheric parts (mainly the cortex) can thus be considered to reflect NA receptor-mediated changes.

Trial procedures.

Rats (150 - 300 g) pretreated with reserpine (5 mg/kg, 18 hours before) were administered the test compounds. Observations of visible behavior (changes in motility, lateral movement of the hind legs, etc.) were carried out. Subsequent administration of NSD 1015, decapitation, brain dissection (corpora striata, forebrain and remaining hemisphere parts (mainly cortex) or rat brain), homogenization, late centrifugation, ion exchange chromatography and spectrofluorimetric measurements (all as described in detail by Wikstrom, et al. ,

J. Med. Chem., 21, 864-867, 1979 and reference cited therein), or by HPLC/EC, yielded actual dopamine and 5-HTP levels. Multiple doses (n = 4 - 6) were tested for each compound and brain region. The dose of a compound which produces 50% of the maximum reduction of the %-HTP level in the rat iron part was then determined. These ED50 values appear in Table I.

All of the compounds in Table 1 were both behaviorally and biochemically active, and produced the above-mentioned effects indicative of either central dopamine or 5-HT receptor stimulation. The absence of significant decreases in dopamine levels in the hemispheric brain parts suggests that none of the compounds have central NA receptor stimulatory effects at the current dosage.

Certain compounds according to the invention also exhibit blood pressure-lowering effects, e.g. the compounds of Examples 12, 13 and 17 after measurement in spontaneously hypertensive rats as described by Grodin, et al., J. Pharm. Pharmacol. 37,

263-265 (1984). Without further elaboration, it is considered that the person skilled in the art can carry out the present invention to its full extent by using the preceding description. The following detailed examples describe how the various compounds are to be prepared and/or the various methods are to be carried out according to the invention and are only to be regarded as illustrative, and not to limit the description in any way whatsoever. The person skilled in the art will clearly be able to vary the methods both in terms of reactants and reaction conditions and techniques.

Example 1

8-Methoxy-2-(N-cyclopropylmethylamino)tetralin

8-Methoxy-2-aminotetralin hydrochloride (0.5 g, 2.35 mmol) is dissolved in dichloromethane (50 mL), and triethylamine (3 mL) and cyclopropane carboxylic acid chloride (0.95 mL) are added. The reaction is stopped after 2 hours by adding 10% sodium carbonate (50 ml). The organic layer is separated, washed with water (50 ml), dried over sodium carbonate, filtered and the solvent evaporated to give the amide as an oil (0.85 g). The amide is dissolved in dichloromethane (25 ml) and reduced by the addition of dichloroethane (25 ml) and QBH 4 (2.5 g) (where Q_ denotes tetrabutylammonium ion) under reflux for 6 hours. The reaction is stopped by adding 10% sodium carbonate (100 ml) and dichloromethane (2 x 100 ml). The organic layer is separated, washed with water (50 ml), dried (sodium carbonate), filtered and the solvent evaporated in the amine (95% purity by GC analysis) as an oil (0.47 g). This amine is converted to the hydrochloride salt by means of hydrochloric acid-saturated methanol and evaporation. Recrystallization from ethanol/ether gives white crystals (0.38 g) melting at 214° C. GC/MS shows M<+> as base peak at m/e = 231.10. Other prominent peaks appear at m/e = 161.05 (m-cyclopropylmethylamine, 48.8%), m/e = 160.05

(53.2%) and m/e = 159.05 (37.3%) .

Example 2

8-Methoxy-2-(N,N-dicyclopropylmethylamino)tetralin

8-Methoxy-2-(N-cyclopropylmethylamino)tetralin hydrochloride (0.36 g, 1.35 mmol) is dissolved in dichloromethane (50 mL), and triethylamine (1 mL) and cyclopropanecarboxylic acid chloride (0.35 mL) are added. The reaction is stopped after 2 hours by adding 10% sodium carbonate (50 ml). The organic layer is separated, washed with water (50 ml), dried (sodium carbonate), filtered and the solvent evaporated to leave the amide as an oil (0.47 g), which is dissolved in dichloromethane (25 ml) and reduced by the addition of dichloroethane (25 ml) and QBH^ (2.5 g) (where Q denotes tetrabutylammonium ion) under reflux for 2 hours. The reaction is not complete at this point according to GC analysis, and additional QBH4 (2.5 g) and dichloro-

ethane (25 mL). The reaction is stopped after refluxing for 1 night by adding 10% sodium carbonate (100 ml) and dichloromethane (2 x 100 ml). The organic layer is separated, washed with water (50 ml), dried (sodium carbonate), filtered and the solvent evaporated to give the amine as an oil (0.40 g). The amine is chromatographed (silica gel, 40 g) by first eluting with petroleum ether:ether (3:1) and then with ether. The fractions containing the pure product are collected and the solvent is evaporated. The remaining amine is converted to the hydrochloride by addition of hydrochloric acid-saturated ethanol and evaporation. Recrystallization from ethyl acetate/ether gives white crystals (114 mg) melting at 174 - 176° C. GC/MS shows M<+> at m/e = 285.25 (54.8%), the base peak at m/e = 136.10. Other important peaks appear at m/e = 244.15 (m-cyclopropyl, 25.0%), m/e = 161.05 (m-(di-cyclopropylmethylamine), 63.5%).

The remaining fractions are pooled and the solvent evaporated to give 150 mg of an oil containing 70% of the intermediate amide. The oil is dissolved in dry ether (10 ml) and reduced with lithium aluminum hydride and converted to the hydrochloride salt as described above, and recrystallization as above gives 126 mg of white crystals with the same properties as those obtained first.

Example 3

cis-5-methoxy-1-methyl-2-(N-cyclopropylmethylamino)-tetralin To a solution of 5-methoxy-1-methyl-2-tetralone (2.0

g) in absolute ethanol (50 ml) add acetic acid (1.9 g), cyclopropylmethylamine (2.0 g) and 4 Å molecular sieves. The mixture

heated in a closed flask at 80° C for 1 hour. The molecular sieves ) are filtered off and the solution is hydrogenated (Pt02) at atmospheric pressure. The catalyst is filtered off (Celite), and the volatile substances are evaporated. Dilute hydrochloric acid (50 ml) is added to the solid residue. The resulting acidic solution is washed with ether, basified with 5% sodium hydroxide and extracted twice

> times with ether. The ether extracts are combined, dried (sodium sulfate) and evaporated. The resulting crude base is eluted through an aluminum oxide column with ether-light petroleum (1:4).

Example 4

cis-5-methoxy-1-methyl-2-(N,N-dicyclopropylmethylamino)-tetralin hydrochloride

Cyclopropanecarboxylic acid chloride (0.49 g) in dry ether (10 ml) is added to a solution of cis-5-methoxy-1-methyl-2-(N-cyclopropylmethylamino)tetralin (400 mg) and triethylamine (0.49 g) in dry ether (80 ml). After 30 minutes at room temperature, the reaction mixture is filtered and the ether is evaporated. The resulting crude amide is passed through an aluminum oxide column eluted with ether. The purified amide dissolved in dry THF (20 ml) is added to a suspension of lithium aluminum hydride (1.0 g)

in dry THF (30 mL) under N2. After stirring under reflux for 3 hours, the reaction mixture is hydrolysed, the precipitate is filtered off and the solvent is evaporated. The oily residue is chromatographed on an aluminum oxide column with ether-light petroleum (1:1). The hydrochloride is prepared and recrystallized from ethanol-ether to give the title compound.

Example 5

(+)- and (-)-cis-5-methoxy-1-methyl-2-(N,N-dicyclopropylmethyl-amino)tetralin hydrochloride

(-)-cis-5-methoxy-1-methyl-2-(N,N-dicyclopropylmethylamino)-tetralin hydrochloride

R-(-)-O-methylmandelic acid chloride (4.1 g), prepared from R-(-)-O-methylmandelic acid by treatment with thionyl chloride at 20° C. for 10 hours, dissolved in 5 ml of dichloromethane, is added at room temperature to a stirred mixture of (+)-cis-5-methoxy-1-methyl-2-(N-cyclopropylamino)tetralin (3.0 g), dichloromethane

(25 ml), water (25 ml) and 5% aqueous sodium hydroxide (12 ml). After stirring for 1.5 hours, the phases are separated, and the organic phase is washed once with water, then dried (magnesium sulfate), filtered and evaporated. 15 ml of ether is added to the residue, and one of the diastereomeric amides is precipitated (1.2 g). The precipitate is collected by filtration and then recrystallized from acetone to give 1.0 g of one of the diastereomers. The filtrates from the treatment with ether and acetone are combined and evaporated. This oily residue is chromatographed on a silica gel column with ether/light petroleum (50:50). The fractions containing one of the dia-

the stereomers eluting first are combined and the solvent evaporated to give 0.6 g of one of the diastereomeric amides. This diastereomer turns out to be the same diastereomeric amide (TLC) isolated by precipitation from ether (see above). The diastereomeric amide (1.6 g) is dissolved in dry tetrahydrofuran (40 ml) and kept at -8° C. under nitrogen. Potassium tert-butoxide (21.1 g) and water 1 (0.60 ml) are added to this solution, dividing the addition into seven portions over 12 days.

13 days after the first addition of the reagents, ice, water and ether are added to the reaction mixture until two layers are formed. The phases are separated, and the organic layer is washed with 1M hydrochloric acid, saturated aqueous sodium bicarbonate, dried (magnesium sulfate), filtered and evaporated. The residue, dissolved in ether-light petroleum (50:50), is passed through a silica gel column and eluted first with ether-light petroleum (50:50) and then with ether, to give a solid (0.55 g) after evaporation. To this solid (0.56 g), dissolved in dry tetrahydrofuran (40 ml) at -8° C and under nitrogen, methyllithium (0.0054 mol) is added with stirring. The mixture is stirred for 10 minutes and then extracted with saturated aqueous NH 2 Cl. The phases are separated, and the organic layer is extracted with 5M hydrochloric acid. The combined aqueous layers are basified with 5M sodium hydroxide and extracted with ether. The organic layer is dried (sodium sulfate) and filtered. Hydrochloric acid-saturated ether is added to give a precipitate which is recrystallized to give (-)-cis-5-methoxy-1-methyl-2-(N-cyclopropylmethylamino)tetralin hydrochloride.

Cyclopropanecarboxylic acid chloride (0.28 g) in dry ether (5 ml) is added slowly at 5° C. to a solution of (-)-cis-5-methoxy-1-methyl-2-(N-cyclopropylmethylamino)tetralin (0.35 g), triethylamine (0.31 g) and dry ether (45 ml). The mixture is stirred at room temperature for 1 hour, the formed triethylammonium chloride is filtered off and the solvent is evaporated. The residue (0.40 g) dissolved in dry tetrahydrofuran (10 ml) is added to a suspension of lithium aluminum hydride (0.80 g) in dry tetrahydrofuran (40 ml) under nitrogen. After stirring under reflux for 5 hours, the mixture is hydrolysed, the precipitate is filtered off and the solvent is evaporated. The residue is passed through an alumina column with ether/light petroleum (20:80), and the amine is precipitated as the hydrochloride and recrystallized from ethanol-ether to give (-)-cis-5-methoxy-1-methyl-2-(N,N -dicyclopropylmethylamino)tetralin hydrochloride.

Example 6

(+)-cis-7-methoxy-1-methyl-2-(N-cyclopropylmethylamino)-tetralin

To a solution of 7-methoxy-1-methyl-2-tetralone

(2.0 g) in absolute ethanol (50 ml) is added acetic acid (1.85 g, 31.5 mmol), cyclopropylmethylamine (1.85 g) and 4 Å molecular sieves. The mixture is refluxed for 3.5 hours. The molecular sieves are filtered off, and the solution is hydrogenated with 0.3 g of PtC^ in a Parr apparatus. The catalyst is filtered off (Celite), and the volatile substances are evaporated. The resulting crude base is eluted through a silica gel column with methanol to give an oil of 80% isomeric purity (GC). The hydrochloride is prepared and recrystallized twice from methanol-ether.

Example 7

(+)-cis-7-methoxy-1-methyl-2-(N,N-dicyclopropylmethylamino)-tetralin

Sodium borohydride (0.41 g, 10.1 mmol) is added portionwise to a stirred solution of cyclopropane carboxylic acid chloride (2.4 g) in dry benzene (20 ml) under N 2 , while the temperature is maintained below 20° C. After 2 hours (+)-cis-7-methoxy-1-methyl-2-(cyclopropylmethylamino)tetralin (0.5 g) is added, and the mixture is refluxed for 4 hours and then treated with 10% sodium bicarbonate solution. The benzene layer is dried (sodium sulfate), and the solvent is evaporated. The hydrochloride salt is prepared and recrystallized from methanol-ether.

Example 8

( + )-R-8-methoxy-2-(di-cyclopropyl —-methylamino)tetralin

The dissolution is carried out on 8-methoxy-2-(benzylamino)-tetralin using (-)-di-p-toluoyltartaric acid according to Karlsson, et al., Acta Chem. Scand., B 42, 231-236 (1988). The enantiomers of 8-methoxy-2-(benzylamino)tetralin are debenzylated, giving the corresponding enantiomers of 8-methoxy-2-aminotetralin, i.e. R-(+)- and S-(-)-8-methoxy-2 -aminotetralin.

The primary amine (+)-R-8-methoxy-2-aminotetralin (3.29 g) is acylated with cyclopropanecarboxylic acid chloride (1.8 mL), and the prepared amide (3.63 g) is reduced with QBH4 as described above, to to give the secondary amine, which is again acylated in the same manner with cyclopropanecarboxylic acid chloride (3.2 mL).

The prepared amide (3.57 g) is dissolved in dry THF (25 ml) and reduced with LiAlH 2 at room temperature. Usual work-up gives the crude tertiary amine product (2.9 g) which is chromatographed (SiO 2 , elution with CH 2 Cl 2 :MeOH (19:1)); to give the pure product (2.1 g) as an oil, which is converted to its hydrochloride with HCl-saturated EtOH and evaporation of the solvent and excess acid. No crystals are obtained in an attempt to crystallize the product. The optical rotation is: aD =+68° (c 1.0, MeOH).

GC/MS shows M<+> at m/e = 285 (61%) and the base peak at m/e = 136. Other important peaks appear at m/e = 244 (30%), 161 (72%) and m /e = 160 (42%).

Example 9

(-)-R-8-methoxy-2-(di-cyclopropylmethylamino)tetralin

The primary amine (-)-R-8-methoxy-2-aminotetralin (5.0 g) is converted to the secondary amine (-)-R-8-methoxy-2-(cyclopropylmethylamino)tetralin, which is further converted to the tertiary amine (-)-R-8-methoxy-2-(di-cyclopropylmethylamino)-tetralin (2.42 g) as described for the corresponding (+)-enantiomer in Example 3 above. The optical rotation is: a. 22 =-166° (c 1.0, MeOH).

GC/MS shows M at m/e = 285 (83%) and the base peak at m/e = 136. Other important peaks appear at m/e = 244' (33%), 161 (67%) and m/e = 160 (40%).

Example 1. 0-8-methoxy-2-(N-cyclopropylmethyl-N-ethylamino)tetralin 8-methoxy-2-(cyclopropylmethylamino)tetralin (200 mg) is dissolved in CH2C12 (25 ml), and the solution is made basic by adding of Et^N (3 mL) . Acetyl chloride (150) is added and the reaction mixture is stirred for 3 hours. 10% Na 2 CO 3 is added and the crude amide product is extracted into the organic layer, which is dried and filtered. The organic solvent is removed by evaporation to give 210 mg of the amide as an oil, which dissolve in dry ether Q.0 ml) . This solution is added to a suspension of LiAlH4 (0.3 g) in dry ether (10 ml), and the temperature is maintained at approx. 0° C with an ice bath. Usual work-up (0.3 ml water, 0.3 ml 15% NaOH, 0.9 ml water, filtration and ether extraction) gives 188 mg of an oil which is chromatographed (200 g SiC^, eluting with CH 2 Cl 2 : MeOH (19:1 )), to give the product as an oil (66 mg).

GC/MS shows M<+> at m/e = 259 (70%) and the base peak at m/e = 161. Other important peaks appear at m/e = 244 (33%) and m/e = 160 (30 %) .

Example 11

8-Methoxy-2-(N-cyclopropylmethyl-N-n-propylamino)tetralin

8-Methoxy-2-(n-propylamino)tetralin (350 mg) is dissolved in CH 2 Cl 2 (20 mL) and Et 2 N (1 mL), and the cyclopropanecarboxylic acid chloride (0.5 mL) is added. Workup gives the amide (0.6 g) as an oil. The amide is dissolved in dry ether and reduced with LiAlH^ (0.9 g). The reaction is stopped after 2 hours in the usual way (0.9 ml H 2 O, 0.9 ml 15% NaOH and 2.7 ml H 2 O) and work-up in an oil, which is chromatographed on SiO 2 (70 g), eluting with petroleum ether:ether (1:1). The fractions containing pure product are collected and the solvent is evaporated to

give an oil (210 mg) which is converted to the hydrochloride with HCl-saturated EtOH and evaporation of the solvent. Crystals

(170 mg) is obtained from acetone: ether and they melt at 143 - 145°C.

GC/MS shows M<+> at m/e = 273.15 (24.5%) and the base peak at m/e = 161.05. Other important peaks appear at m/e = 245.05 (14.3%), m/e = 244.05 (87.1%) and m/e = 162.05 (18.8%).

Example 12

7-methoxy-2-(N-cyclopropylmethyl-N-n-propylamino)tetralin 7-methoxy-2-(n-propylamino)tetralin (500 mg) is dissolved in CH2CI2 (25 ml), and the solution is made basic by adding Et3N (3 ml). Cyclopropanecarboxylic acid chloride (195 µl) is added and the reaction mixture is stirred for 4 hours. 10% Na2C03 add-

and the crude amide product is extracted into the organic layer, which is dried and filtered. The organic solvent is removed by evaporation to give 500 mg of the amide (GC/MS shows M<+> at m/e = 287.15 (0.3%) and the base peak at m/e = 160.10) as an oil , which is dissolved in 1,2-dichloroethane (50 ml). To this solution is added QBH 4 (where Q stands for tetrabutylammonium) (5.0 g) dissolved in Cl 2 Cl 2 (50 ml). The react ion mixture is refluxed for 36 hours and cooled to room temperature and extracted several times with water. The solvents in the organic phase are evaporated and ether is added to the residue. The ether phase is washed with water several times, separated, dried (Na 2 SO 4 ), filtered and the solvent evaporated to give 453 mg of an oil which is chromatographed (200 g SiC^J eluting with petroleum ether:ether (9:1)) to give the product like an oil. This oil is converted to the hydrochloride with HCl-saturated EtOH and evaporation to give an oil (436 mg).

GC/MS shows M<+> at m/e = 273.15 (27.1%) and the base peak at m/e = 244.15. Another important peak appears at m/e = 161.10 (76.9

Example 13.

8-Methoxy-2-(N-cyclopropylmethyl-N-(2-thiophenethyl)amino)-tetralin

8-methoxy-2-aminotetralin (800 mg) is stirred in a two-phase system (10% Na 2 CO 3 and CH 2 Cl 2 )/ and 2-thiopheneacetic acid chloride (1 g) is added. The reaction mixture is stirred for 2 hours, and the organic phase is then separated, dried (Na2SO4)

and filtered. The solvent is evaporated to give the amide as an oil (1.5 g). The amide is reduced with QBH 4 (1 g) in a refluxing (8 h) mixture of CH 2 Cl 2 (50 mL) and 1,2-dichloroethane (50 mL). The reaction mixture is cooled to room temperature, and the organic layer is washed several times with water. The organic layer is separated and the solvents evaporated to give an oil, which is treated with EtOAc and water. This mixture is acidified with HCl (10%) and stirred for 30 minutes, and the mixture is made basic. The organic layer is separated, dried (Na 2 SO 4 ) and filtered. The solvent is evaporated to give the amide as an oil (900 mg). This oil (400 mg)

is dissolved in CH 2 Cl 2 (25 mL) and Et^N (1 mL) and cyclopropanecarboxylic acid chloride (1.0 mL) is added, and the reaction mixture is stirred for 1 hour. 10% Na^O^ is added, and the crude amide product is extracted into the organic layer, which is dried and filtered.

The organic solvent is removed by evaporation to give 600 mg of the amide as an oil, which is chromatographed (SiO 2 and elution with petroleum ether:ether (2:1)) to give 270 mg of the pure amide. This amide (270 mg) is dissolved in 1,2-dichloroethane (20 ml). To this solution is added

QBH4 (where Q stands for tetraethylammonium) (1.0 g) dissolved in

CH 2 Cl 2 (20 mL). The reaction mixture is refluxed in

12 hours and then cooled to room temperature and extracted with water several times. The solvents in the organic phase are evaporated, and EtOAc (20 ml) is added to the residue. The organic phase is washed with water several times, separated, dried (Na 2 SO 4 ), filtered, and the solvent evaporated to give 220 mg of an oil, which is chromatographed (20 g SiO 2 , elution with petroleum ether: ether (1:1)), to give the product as an oil (160 mg). This oil is converted to the hydrochloride with HCl-saturated EtOH and evaporation of the solvent to give an oil (170 mg).

GC/MS shows M<+> at m/e = 340.20 (0.1%), m/e = 341.10 (0.1%), and the base peak at m/e = 161.10. Other important peaks appear at m/e = 245.20 (11.6%) and m/e = 244.20 (63.8%).

Example 14

5-methoxy-2-(cyclopropylmethylamino)tetralin

5-methoxy-2-aminotetralin (972 mg) is dissolved in

CH 2 Cl 2 (20 mL), and Et 2 N (3 mL) are added along with cyclopropanecarboxylic acid chloride (550 µl). The reaction mixture is stirred for 1 hour. 10% Na2CT\,2 is added, and the crude amide product is extracted into the organic layer, which is dried and filtered. The organic solvent is removed by evaporation to give 1.16 g of the amide as an oil, which is chromatographed (SiO 2 and eluting with CH 2 Cl 2 :MeOH (45.1)) to give 0.98 mg of the pure amide (GC/ MS shows m<+> at m/e = 245 (61%) and the ba-s ice peak at m/e = 160. Other important peaks appear at m/e = 159 (26%),

m/e = 145 (19%) and m/e = 129 (18%)). This amide (0.98 g) is dissolved in 1,2-dichloroethane (30 ml). To this solution is added QBH 4 (where Q stands for tetrabutylammonium) (2.0 g) dissolved in CH 2 Cl 2 (30 ml). The reaction mixture is refluxed for 24 hours and then cooled to room temperature and extracted with water several times. The solvents in the organic phase evaporate,

and EtOAc (20 mL) is added to the residue. The organic phase is washed with water several times, separated, dried (Na 2 SO 4 ), filtered and the solvent evaporated to give 800 mg of an oil, which is chromatographed (200 g SiO 2 ; elution with CH 2 Cl 2 :MeOH (19:1)) to give give the product as an oil (800 mg).

GC/MS shows M<+> as the base peak at m/e = 231. Other important peaks appear at m/e = 161 (62%), m/e = 160 (83%), m/e = 159 (64 %) and m/e = 104 (92%) .

Example 15

5-Methoxy-2-(dicyclopropylmethylamino)tetralin

5-Methoxy-2-(cyclopropylmethylamino)tetralin (410 mg) is dissolved in CH 2 Cl 2 (20 mL) and Et 2 N (3 mL) is added along with cyclopropanecarboxylic acid chloride (400 µl). The reaction mixture is stirred for 48 hours. 10% Na2C03 is added, and the crude amide product is extracted into the organic layer, which is dried and filtered. The organic solvent is removed by evaporation to give 520 mg of the amide as an oil. This crude amide (520 mg) is dissolved in dry THF (15 mL), and this solution is added dropwise to a suspension of LiAlH2 (0.5 g) in dry THF (10 mL). The reaction mixture is stirred at room temperature for 1 hour, and usual work-up gives 385 mg of the desired product as an oil (GC/MS shows M<+> at m/e = 285.20 (40%), base peak at m/e = 136 .05. Other important peaks appear at m/e = 244.10 (30.1%), m/e = 161.05 (37.9%, m/e=), m/e = 160.15 ( 30.2%) and m/e = 159.05 (13.2%). The product is converted to a crystalline hydrochloride,

and crystals melting at 150-153°C are obtained from EtOH:ether.

Example i6

5-Methoxy-2-(N-cyclopropylmethyl-N-n-propylamino)tetralin

5-Methoxy-2-(cyclopropylmethylamino)tetralin (390 mg) is dissolved in CH 2 Cl 2 (20 mL) and Et 2 N (3 mL) is added along with propionic acid chloride (300 µl). The reaction mixture is stirred for 5 hours. 10% Na-^CO^ is added, and the crude amide product is extracted into the organic layer, which is dried and filtered. The organic

solvent is removed by evaporation to give 469 mg of the amide as an oil. This crude amide (469 mg) is dissolved in dry ether (15 ml), and this solution is added dropwise to a suspension of LiAlH4 (0.45 g) in dry ether (10 ml). The reaction mixture is stirred at room temperature for 1 hour, and usual workup gives 324 mg of the desired product as an oil, which is chromatographed (SiO 2 and elution with CH 2 Cl 2 :MeOH (19:1)) to give 201 mg of the desired product as an oil. GC/MS shows M<+> at m/e = 273.20 (25.0%) , base peak at m/e = 244.25. Other important peaks appear at m/e = 245.25 (18.6%), m/e = 244.05 (87.1%) and m/e = 161.15 (75.3%).

Example 17

(+)-cis-1S,2R-5-methoxy-1-methyl-2-(N-cyclopropylmethyl-N-n-propylamino)tetralin

(+)-cis-1S,2R-5-methoxy-1-methyl-2-(n-propylamino)-tetralin (500 mg) dissolved in CH 2 Cl 2 (20 ml) and Et 3 N (3 ml) is added together with cyclopropanecarboxylic acid chloride (300 ul). The reaction mixture is stirred for 1 hour. 10% Na 2 CO 3 is added, and the crude amide product is extracted into the organic layer, which is dried and filtered. The organic solvent is removed by evaporation to give 550 mg of the amide as an oil. This crude amide (550 mg) is dissolved in dry ether (15 ml), and this solution is added dropwise to a suspension of LiAlH^ (0.60 g) in dry ether (10 ml). The reaction mixture is stirred at room temperature and usual workup gives 483 mg of the desired product as an oil which is chromatographed (100 g SiO 2 and eluting with hexane:ether (3:1)) to give the desired product as an oil (280 mg ). This oil is converted to the hydrochloride salt, but no crystals are obtained.

GC/MS shows M<+> at m/e = 287.15 (25.8%) and the base peak at m/e = 258.15. Other important peaks appear at m/e = 259.15 (19.5%), m/e = 176.10 (12.4%), m/e = 175.10 (88.6%) and m/ e = 174.20 (17.4%). The optical rotation is measured and found to be: ctp<22> = +38° (c 1.0, MeOH).

Example 18

(+)-cis-1S,2R-5-methoxy-1-methyl-2-(cyclopropylmethylamino)-tetralin

(+)-cis-1S,2R-5-methoxy-1-methyl-2-aminotetralin

(970 mg) is dissolved in CH 2 Cl 2 (20 mL), and Et 2 N (3 mL) is added along with cyclopropanecarboxylic acid chloride (500 µl). The reaction mixture is stirred for 1 hour. 10% Na 2 CO 3 is added, and the crude amide product is extracted into the organic layer, which is dried and filtered. The organic solvent is removed by evaporation to give 1.0 mg of the amide as an oil. This crude amide (1.0 mg) is dissolved in 1,2-dichloroethane (60 mL). To this solution is added QBH 4 (where Q stands for tetrabutylammonium) (1.4 g) dissolved in CH 2 Cl 2 (69 ml). The reaction mixture is refluxed for 48 hours and then cooled to room temperature and extracted with water several times. The solvents in the organic phase are evaporated, and trichlorethylene is added to the residue. The organic phase is washed several times with water, separated, dried (Na 2 SO 4 ), filtered and the solvent evaporated to give 840 mg of an oil, which is converted to the hydrochloride with HCl-saturated EtOH and evaporated to give crystals (750 mg) which melt at 212°C.

GC/MS shows M<+> at m/e = 245.15 (53.5%) and the base peak at m/e = 148.10. Other important peaks appear at m/e = 190.20 (15.6%), m/e = 175.10 (18.2%), m/e = 174.10

(44.8%), m/e = 173.20 (10.3%) and m/e = 159.10 (45.9%).

The optical rotation is measured and found to be: aD 22 = +49.1

(c 1.0, MeOH).

Example 19

(+)-cis-1S,2R-5-methoxy-1-methyl-2-(N-cyclopropylmethyl-N-(3-methoxyphenylethyl)amino)tetralin

(+)-cis-1S,2R-5-methoxy-1-methyl-2-(cyclopropyl-methylamino)tetralin (50 mg) was dissolved in CH 2 Cl 2 (5 mL), and 10% NaOH (5 mL) was added together with 3-methoxyphenylacetic acid chloride (50 µl) • The reaction mixture was stirred for 1 hour. The crude amide product was extracted into the organic layer, which was dried and filtered. The organic solvent was removed by evaporation to give 60 mg of the amide as an oil. This crude amide (60 mg) was dissolved in 1,2-dichloroethane (10 mL). To this solution was added QBH4 (where Q stands for tetraethylammonium)

(200 mg) dissolved in CH 2 Cl 2 (30 ml). The reaction mixture was refluxed overnight and then cooled to room temperature and extracted with water several times, separated,

dried (Na 2 SO 4 ), filtered and the solvent evaporated to give 60 mg of the desired product as an oil, which was chromatographed (15 g SiO 2 and eluting with hexane:ether (3:1)) to give the desired product as an oil (20 mg). This oil was converted to the hydrochloride salt, but no crystals were obtained.

GC/MS shows M<+> at m/e = 379.20 (0.1%) and the base peak at m/e = 258.20. Other important peaks appeared at m/e = 259.20 (19.0%), m/e = 176.10 (8.6%) and m/e = 175.10 (65.3%). The optical rotation was measured and found to be αD<22> = +35° (c 1.0, MeOH).

Example 20

(+)-R-8-methoxy-2-(N-cyclopropylmethyl-N-(3-methoxyphenylethyl)-amino)tetralin

(+)-R-8-methoxy-1-methyl-2-(cyclopropylmethylamino)-tetralin (250 mg) was dissolved in CH 2 Cl 2 (25 mL), and 10% NaOH

(25 mL) was added along with a 3-methoxyphenylacetic acid chloride (0.4 g). The reaction mixture was stirred for 2 days. The crude amide product was extracted into the organic layer, which was dried and filtered. The organic solvent was removed by evaporation to give 400 mg of the amide as an oil. This crude amide was chromatographed (SiO 2 and elution with petroleum ether: ether (3:1)). The fractions containing pure product were pooled and the solvent was evaporated to give an oil (250 mg). The amido oil (250 mg) was dissolved in dry ether (10 mL). To this solution was added LiAlH^ (100 mg). Usual workup gave the desired product as an oil (100 mg).

GC/MS showed M-1 at m/e = 364.15 (0.1%) and the base peak at m/e = 161.00. Other important peaks appeared at m/e = 245.05 (16.2%) and m/e = 244.05 (87.2%).

Example 21

7-methylthio-2-(N-cyclopropylmethyl-N-n-propylamino)tetralin

7-Bromo-2-(di-n-propylamino)tetralin HCl (600 mg) was basified with 10% Na 2 O 2 and extracted with CH 2 Cl 2 . The organic layer was dried and filtered, and the solvent

was evaporated under reduced pressure. The residual oil was dissolved

in dry THF (40 mL) and poured into a flask equipped with an N-( ) inlet, a dropping funnel, a thermometer, and septum for syringe injections of reagents and sample collection. This flask was cooled to

-78°C, and n-BuLi in hexane (1.4M, 3 mL) was injected through the septum. The reaction mixture was stirred for 0.5 hour in order for the halogen-lithium exchange to take place. It was checked with a small sample completely in water and GC analysis. Dimethyl sulfide (0.5 mL) was added dropwise from the funnel over 30 minutes at -78° C. CO., the (s) bath was removed, and the temperature was brought to room temperature before the reaction was quenched with water. Extractive work-up gave an oil (700 mg) containing 2-(di-n-propylamino)tetralin and the desired product in an approximate ratio of 45:55. This crude oil was chromatographed, and they

fractions containing pure product were pooled and the solvent evaporated to give 110 mg of the product as an oil, which was used in the next step without further purification. The oil (95 mg) was dissolved in CH 2 Cl 2 (10 mL) and excess Br 2 (35 uD) was added. The organic phase was extracted with 10% Na 2 CO 3 and separated. Excess Br 2 was removed by addition of anisole

(1 ml). The product in the organic phase was then extracted with 10% HCl, and the acidic organic phase (containing the brominated anisoles) was discarded. The acidic water was made alkaline

(10% Na 2 CO 3 ) and extracted with ether, dried (Na 2 CO 3 ), filtered and the solvent evaporated to give 40 mg of an oil.

GC/MS showed M<+> at m/e = 235 (60%) and the base peak at m/e = 129. Other important peaks appeared at m/e = 206

(52%), m/e = 192 (20%), m/e = 177 (45%), m/e = 176 (30%), m/e = 175 (15%), m/e = 151 (25%), m/e = 150 (35%) and

m/e = 130 (50

The resulting secondary amine (40 mg, 0.17 mmol) was dissolved in CH 2 Cl 2 (5 mL) and N-acylated with cyclopropanecarboxylic acid chloride (23 µL) in the presence of Et 3 N (50 µL). After 30 minutes the reaction mixture was washed with 10% Na 2 CO 3 < and the organic phase was separated, dried (Na 2 CO 3 ), filtered and the solvent was evaporated to give 55 mg of an oil.

GC/MS showed M<+> at m/e = 303 (1%) and the base peak

at m/e = 176. Other important peaks appeared at m/e = 175

(15%), m/e = 129 (45%) and m/e = 128 (25%).

The amide (55 mg) was dissolved in dry ether (10 mL) and reduced by addition of LiAlH2 (75 mg). Usual work-up gave the crude product as an oil (29 mg) which was chromatographed (SiC 4 and elution with petroleum ether:ether (3:1)). This fraction containing the desired pure 7-methylthio-2-N-cyclopropylmethyl~N-n-propylamine)tetralin was collected and the solvent evaporated to give 14 mg of an oil.

GC/MS showed M<+> at m/e = 289 (35%) and the base peak at m/e = 260. Other important peaks will appear at m/e = 261 (20%), m/e = 324 ( 10%), m/e = 177 (25%), m/e = 176 (10%), m/e = 151 (10%), m/e = 130 (40%), m/e = 129 ( 45%) , m/e = 124 (20%) and m/e = 84 (15%) .

Example 22

(+)-R-8-methoxy-2-(N-cyclopropylmethyl-N-ethylamino)tetralin

(+)-R-8-methoxy-2-(cyclopropylmethylamino)tetralin (500 mg) was dissolved in CH 2 Cl 2 (25 mL) and 10% Na 2 CO 3 (25 mL) was added along with acetyl chloride (0.4 g). The reaction mixture was stirred for 2 hours. The crude amide product was extracted into the organic layer, which was dried and filtered. The organic solvent was removed by evaporation to give the amide as an oil. This crude amide was chromatographed (SiO 2 and elution with petroleum ether:ether (3.1)). The fractions containing pure product were pooled and the solvent was evaporated to give an oil (324 mg). The amido oil (324 mg) was dissolved in dry ether (10 mL). LiAlH2 was added to this solution

(300 ml). Usual workup gave the desired product as an oil (290 mg) which was chromatographed (SiO 2 and eluting with CH 2 Cl 2 :MeOH (19:1)). The fractions containing pure product were pooled and the solvent was evaporated to give an oil (153 mg).

GC/MS showed M<+> at m/e = 259.15 (70.9%) and the base peak at m/e = 161.05. Other important peaks appeared at m/e =260.15 (14.2%), m/e = 244.15 (32.9%), m/e = 218.15 (17.3%), m/ e = 160.05 (29.7%), m/e = 159.05 (14.9%) and m/e = 110.05 (80.4%). The optical rotation was measured and found to be o<D<22> = +64.9° (c 1.0, MeOH).

Claims (3)

1. Analogy process for the preparation of therapeutically active compound of formula I and pharmaceutically acceptable acid addition salts thereof, wherein -YRX is a substituent in the 8-position of the aromatic ring, and is 0Rlr wherein Rx is (C 1 -C 8 )-alkyl, R3 is -CH2-(C3-C8)-cycloalkyl, R4 is (C1-C8)-alkyl, -CH2-(C3-C4)-cycloalkyl or -(CH2)m-R5, m is 0-2, R5 is optionally substituted with lower alkoxy phenyl, 2-thiophene or 3-thiophene, with the proviso that when R3 contains more than 4 carbon atoms and R4 is alkyl, said alkyl contains from 1 to 3 carbon atoms, characterized in that a compound of formula dissolved in a solvent, acylated with a suitable alkyl, cycloalkyl, phenyl (optionally substituted) or thiophene carboxylic acid, separated as an organic layer to form an amide, which is then reduced with dichloroethane, tetrabutylammonium, BH4, LiAlH4 or a combination thereof, and the amine product is washed and separated, and optionally converted into a hydrochloride salt• 2. Method according to claim 1, for the production of 8-methoxy-2-(N-cyclopropylmethyl-N-n-propylamino)tetralin, characterized in that corresponding starting materials are used. 3. Method according to claim 1, for the production of 8-methoxy-2-(N,N-dicyclopropylmethylamino)tetralin, characterized in that corresponding starting materials are used.