SK6412000A3 - Biphenyl derivatives as pharmaceuticals - Google Patents

Abstract

Compounds of formula (I) wherein R1, R2, R3, R4 and R5 are as defined in the description, are useful as pharmaceuticals.

Description

Technical field

The present invention relates to novel biphenyl derivatives, to a process for their preparation, to their use as medicaments and to pharmaceutical compositions containing them.

SUMMARY OF THE INVENTION

More specifically, the present invention provides a compound of formula I

R ³ where

R ¹ and R ² are each independently hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, halogen, trifluoromethyl, trifluoromethoxy, cyano or alkanoyl 2 to 5 carbon atoms,

R ³ is hydrogen, hydroxyl, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 3 -C 6 cycloalkyloxy, halogen, cyano, C 2 -C 5 alkanoyl, carbamoyl , (1-4C) alkylsulfonyloxy or trifluoromethylsulfonyloxy,

R ⁴ is a hydrogen atom, a hydroxyl group or an alkoxy group having 1 to 4 carbon atoms, and

R ⁵ is a group of formula (a), (b), (c) or (d)

(a) (b) (c)

R ⁷ —X — N ^Z (d) where

R ⁶ is an alkyl group having 1 to 4 carbon atoms,

X is a straight or branched alkylene chain containing from 1 to 4 carbon atoms; and

R ⁷ and R ⁸ are each independently hydrogen, C 1 -C 4 alkyl, C 2 -C 4 hydroxyalkyl or C 1 -C 4 phenylalkyl or together with the nitrogen atom to which they are attached are bound, pyrrolidinyl, piperidino, piperazinyl or morpholino or a group of formula (e)

R ¹³ R ¹⁴ (e) wherein Z is O, CH ₂ or CH ₂ -CH ₂ and R ⁹ ,

R ¹⁰ , R ¹¹ , R ¹² , R ¹³ and R ¹⁴ are each independently hydrogen, halogen, C 1 -C 4 alkyl or C 1 -C 4 alkoxy, in free base form or in acid addition form salt.

Since asymmetric carbon atoms may be present in the compounds of formula I or salts thereof, the compounds may exist in optically active form or in the form of mixtures of optical isomers, for example in the form of racemic mixtures. All optical isomers and mixtures thereof, including racemic mixtures, form part of the present invention

The halogen atom is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, preferably a fluorine atom and a chlorine atom.

Any alkyl, alkoxy and alkylthio group preferably has a straight chain. Preferably it contains 1 to 3 carbon atoms, more preferably methyl, methoxy and methylthio.

The following meanings and combinations thereof are preferred:

R ( ¹⁾ and R ( ²⁾ independently of one another are hydrogen, (C1-C4) -alkyl, (C1-C4) -alkoxy, halogen or trifluoromethyl,

R ³ is hydrogen or para to the phenyl substituent is hydroxyl, C 1 -C 4 alkoxy, C 3 -C 6 cycloalkyloxy, cyano or carbamoyl,

R ⁴ is a hydrogen atom,

R ⁵ is a group of formula (a) or (d).

When R ⁵ is a group of formula (a), R ⁶ is preferably a methyl group or a propyl group.

When R ⁵ is a group of formula (d), R ⁷ 'and R ⁸ are preferably hydrogen, C 1 -C 4 alkyl and, together with the nitrogen atom to which they are attached, form a group of formula (e).

When R ⁷ and R ⁸ together with the nitrogen atom to which they are attached form a group of formula (e), Z is preferably an oxygen atom and R ⁹ to R ¹⁴ independently of one another are preferably a hydrogen atom or a methyl group.

In one group of compounds of formula I, R ¹ , R ² , R ³ and R ⁴ are as defined above and R ⁵ is a group of formula (a), (b) or (c).

In another group of compounds of formula I, R ¹ , R ² , R ³ and R ⁴ are as defined above and R ⁵ is a group of formula (d).

According to another embodiment, the present invention provides a process for the preparation of compounds of formula I and salts thereof, wherein the compound of formula II

Y

wherein R ³ , R ⁴ and R ⁵ are as defined above and Y is a halogen atom or a trifluoromethylsulfonate group, reacts with a compound of formula III

R 2

wherein R ¹ and R ² are as defined above, and the obtained compound is isolated in the form of the free base or in the form of an acid addition salt.

The reaction can be carried out in a known manner, preferably by transition metal catalyzed aryl-aryl condensation, as described for example in Example 1. Hal is preferably a bromine atom or an iodine atom, especially an iodine atom.

Alternatively, the compounds of formula (I) may be obtained by another well known method of aryl-aryl condensation using, for example, an arylstannyl, -zinc, -halide precursor or Grignard precursor.

For the preparation of compounds of formula I wherein R ⁵ is a group of formula (c), the nitrogen atom in the group of formula (c) may be protected, for example by an alkoxycarbonyl group which may be removed after reaction with a compound of formula III by known methods , see for example Example 11.

To obtain compounds of formula I wherein R ⁵ is a group of formula (b), a compound of formula I can be prepared as described above, but R ⁵ is 3-pyridyl, and the pyridyl group can then be converted by known methods to the desired tetrahydropyridyl group via a pyridinium salt, for example, pyridinium iodide as described in Example 1.

To obtain compounds of formula I wherein R ⁵ is a group of formula (a), the corresponding compound wherein R ⁵ is a group of formula (b) may first be prepared, and then hydrogenation may be carried out according to known procedures, such as described in Example 5.

The compounds of formula I in optically pure form can be obtained from the corresponding racemates by known methods as described in Examples 9 and 10. Alternatively, optically pure starting materials can be used as described in Examples 28 and 29.

The acid addition salts may be prepared in known manner from the free base forms and vice versa. Suitable pharmaceutically acceptable acid addition salts for use in the present invention include, for example, hydrochloride, hydrogen maleate, hydrogen fumarate and hydrogen malonate.

The starting compounds of the formula II are known or can be prepared by halogenating the compounds of the formula IV

(IV) where R ³ , R ⁴ and R ⁵ have already been defined using known procedures

The starting compounds of the formulas III and IV are known or can be prepared in an analogous manner to known compounds, for example as described in the examples.

The compounds of formula I and their pharmaceutically acceptable acid addition salts, hereinafter referred to as the "agents of the present invention, are characterized by pharmacological activity and are therefore suitable as pharmaceuticals.

The agents of the present invention provide long-lasting protection against convulsions induced by maximum electroshock in mice at doses of 1 to 100 mg / kg p.o. and about 0.32 to 32 mg / kg i.p. [E. A. Swinyard, J. Am. Pharm. Assoc. Scient. Ed., 38, 201 (1949) and J. Pharmacol. Exptl. Therap., 106, 319 (1952)].

The agents of the present invention are therefore suitable for the treatment of epilepsy and other seizures, such as high pressure neurological syndrome.

The agents of the present invention further reduce neuronal damage induced by ischemia and the resulting symptoms of midbrain artery occlusion in the rat model at doses of 1 to mg / kg i.p., i.v. and p.o. [A. Tamura et al., J. Cereb. Blood

Flow Metabol., 1, 53-60 (1981); A. Sauter, M. Rudin, Stroke, 17,

1228-1234 (1986)].

The agents of the present invention are further suitable for the treatment of any clinical condition involving a component of cerebral anoxia, hypoxia and / or ischemia, for example, gray and white brain mass, stroke, reperfusion injury, subarachnoid bleeding, brain or spinal cord injury / injury, high intracranial pressure multi-infarct dementia or vascular dementia; and any surgical procedures potentially associated with cerebral anoxia, hypoxia and / or ischemia (e.g., cardiac bypass surgery, surgery on extracerebral vessels).

The agents of the invention are characterized by binding to a veratridine-sensitive sodium channel at an IC _{50 of} 0.1 to 100 μΜ. The coupling procedure is described, for example, in JB Brown., Journal of Neuroscience, 6, 2064-2070 (1986). They block veratridine-induced glutamate release in rat hippocampus sectional preparations at concentrations of 0.1 to 1 mM. The experiment was performed according to MJ Leách et al., Epilepsy 27, 490-497 (1986) and Stroke, 24, 1063-1067 (1993) using exogenous glutamate.

Thus, the agents of the present invention are for use in the treatment of any disease, disorder or clinical condition involving glutamate release in its etiology, including psychiatric disorders (such as schizophrenia, depression, anxiety, panic attacks, lack of attention and cognitive disorders, social rejection), hormonal conditions (excess GH secretion (for example, in the treatment of diabetes mellitus, angiopathy and acromegaly) or LH (prostate hypertrophy, menopausal syndrome), corticosterone secretion under stress), brain damage induced by metabolic (hypoglycemia, non-ketotic hyperglycemia, hepatic encephalopathy associated with liver failure), emesis, convulsions, tinnitus, pain (such as pain caused by cancer or arthritis), and drug abuse and withdrawal (ethanol, opiates (including form-like synthetics) (such as petidin, methadone, etc.), cocaine, amphetamine, barbiturates and other sedatives (benzodiazepines).

Further, the agents of the present invention are indicated for use in the treatment of any disease involving neuronal damage, for example neurodegenerative diseases such as Alzheimer's disease, Huntington's disease or Parkinson's disease, virus-induced neurodegeneration (including HIV), amyotrophic lateral sclerosis (ALS), supranuclear olivopontocerebral atrophy (OPCA) and environmental exogenous neurotoxins.

In the above indications, the appropriate dosage will vary depending upon, for example, the compound employed, the patient, the mode of administration, and the nature and severity of the disease being treated. In general, however, satisfactory results were obtained in animals at a daily dose of 0.1 to 100, preferably 0.5 to 100 mg / kg animal body weight. In higher mammals such as man, the indicated daily dose will be between 1 to 500, preferably 1 to 300 mg, of an agent of the invention, usually administered, for example, in divided doses up to four times a day or in a slow release form.

The agent of the present invention may be administered by any route, particularly enterally, preferably orally, for example in the form of tablets or capsules, or parenterally, for example in the form of injectable solutions or suspensions.

Accordingly, the present invention also provides an agent of the invention for use as a medicament, for example, for the treatment of epilepsy, stroke and brain or spinal cord injury.

The present invention further provides a pharmaceutical composition comprising an agent of the present invention in association with at least one pharmaceutical carrier or diluent. These compositions may be prepared in conventional manner. A unit dosage form contains, for example, 0.25 to 150, preferably 0.25 to 25 mg, of a compound of the present invention.

Further, the present invention provides the use of an agent of the present invention for the preparation of a medicament for the treatment of any of the above conditions, for example epilepsy, stroke and brain or spinal cord injury.

Yet another object of the present invention is to provide a method of treating any of said conditions, for example epilepsy, stroke and brain or spinal cord injury, in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of an agent of the invention.

The following examples illustrate the invention. Temperatures are given in degrees Celsius and are not corrected.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

3- (4-Methoxy-4'-trifluoromethylbiphenyl-3-yl) -1-methyl-1,2,5,6-tetrahydropyridine

A. 3- (5-Bromo-2-methoxyphenyl) pyridine

A solution of bromine (12.2 g, 3.9 mL, 0.076 mol) in glacial acetic acid (40 mL) was added dropwise over 15 minutes to a solution of 3- (2-methoxyphenyl) pyridine (14.0 g, 0.076 mol) and anhydrous sodium acetate (6.8 g, 0.083 mol) in glacial acetic acid (140 mL), maintaining the temperature between 15-20 ° C. A precipitate is formed which gradually dissolves as the suspension is stirred. The suspension was allowed to stir for 18 hours at room temperature to give a clear orange solution. The acetic acid was removed under reduced pressure and the residue was taken up in ethyl acetate (250 mL). The extract was washed with water (150 mL), saturated aqueous sodium bicarbonate (100 mL), and brine (75 mL), dried over magnesium sulfate and evaporated to give the product as an orange oil. TLC (silica gel, toluene-ethanol-ammonium hydroxide 85: 15: 1) _Rf = 0.5.

B. 3- (4-Methoxy-4'-trifluoromethylbiphenyl-3-yl) pyridine

A mixture of 3- (5-bromo-2-methoxyphenyl) pyridine (19.0 g, 0.072 mol), 4-trifluoromethylphenylboronic acid (14.3 g, 0.076 mol), palladium acetate (520 mg, 0.0023 mol), three -o-tolylphosphine (2.1 g, 0.0069 mol), 2M aqueous sodium carbonate solution (39 ml, 0.077 mol), methanol (80 ml) and toluene (350 ml) were heated under argon for 18 hours to reflux. The mixture was allowed to cool, filtered through Hyflo (diatomaceous earth), diluted with water (100 mL) and the phases were separated. The aqueous phase was extracted with toluene (150 ml) and the combined organic phases were washed with water (100 ml) and brine (100 ml), dried over magnesium sulfate, treated with activated carbon (1 g), filtered through Hyflo and evaporated to give a yellow oil. This oil was dissolved in ethanol (50 mL) and treated with a 3N solution of hydrogen chloride in ethanol (25 mL). The hydrochloride precipitated upon addition of ether (20 g, 76%), mp 229-231 ° C. TLC (silica gel, toluene-ethanol-ammonium hydroxide 85: 15: 1) Rf = 0.55.

C. 3- (4-Methoxy-4'-trifluoromethylbiphenyl-3-yl) -1-methylpyridinium iodide

A solution of methyl iodide (9.4 g, 66 mmol) in acetone (25 mL) was added dropwise to a cold (15 ° C) solution of 3- (4-methoxy-4'-trifluoromethylbiphenyl-3-yl) pyridine (10 mL) over 15 min. 9 g, mmol) in acetone (100 mL). The reaction mixture was then heated at reflux for 2 h, then a second portion of methyl iodide (1 mL, 2.2 g, 15 mmol) was added and the mixture was heated at reflux for an additional 1.5 h. . Evaporation of the solvent gave the title compound as a yellow solid which was used directly in the next reaction. TLC (silica gel, toluene-ethanol-ammonium hydroxide 85: 15: 1) Rf = 0-0.02.

D. 3- (4-Methoxy-4'-trifluoromethylbiphenyl-3-yl) -1-methyl-

1,2,5,6-tetrahydropyridine

A solution of sodium hydroxide (1.5 g, 36 mmol) in water (100 mL) was added to a solution of 3- (4-methoxy-4'-trifluoromethylbiphenyl-3-yl) -1-methylpyridinium iodide in methanol (150 mL). Sodium borohydride (2.5 g, 66 mmol) was added portionwise over 30 minutes and the mixture was allowed to stir at room temperature for 60 hours. The mixture was filtered through Hyflo and the filtrate was evaporated to approximately 100 mL, whereupon a yellow oil separated. Extract the mixture with ethyl acetate (3 x 125 mL), wash the combined organic extracts with brine (75 mL), dry over magnesium sulfate, and evaporate to afford the title compound as a tan oil. TLC (silica gel, toluene-ethanol-ammonium hydroxide 85: 15: 1) _Rf = 0.4. The hydrogen maleate has a melting point

123-125 ° C (EtOH / Et ₂ O).

The following compounds of formula I were prepared in an analogous manner to that described in Example 1:

Example 2

3- (4-Methoxybiphenyl-3-yl) -1-methyl-1,2,5,6-tetrahydropyridine

The hydrochloride melts at 187-194 ° C.

Example 3

3- (2'-Chloro-4-methoxybiphenyl-3-yl) -1-methyl-1,2,5,6-tetrahydropyridine

Hydrogen oxalate has a melting point of 137-142 ° C.

Example 4

3- (4-Methoxy-4'-trifluoromethylbiphenyl-3-yl) -1-propyl-1,2,5,6-tetrahydropyridine

The compound is obtained as a yellow oil. TLC (silica gel, toluene-ethanol-ammonium hydroxide 85: 15: 1) _Rf = 0.25.

Example 5

3- (4-methoxy-4'-trifluoromethyl-biphenyl-3-yl) -1-methylpiperidine

Palladium on charcoal (10%, 700 mg) was added to a degassed solution of 3- (4-methoxy-4'-trifluoromethylbiphenyl-3-yl) -1-methyl-1,2,5, β-tetrahydropyridine (obtained according to Example 1). 1) (5.3 g, 15.9 mmol) in glacial acetic acid (75 mL) and the mixture was hydrogenated in a Parr hydrogenation reactor for 18 hours at room temperature and 50 psi hydrogen pressure, consuming 70 mL of hydrogen. The catalyst was filtered off and fresh catalyst (800 mg) was added and the mixture was further hydrogenated for 18 hours at 45 ° C and 507 kPa of hydrogen, consuming 400 ml of hydrogen. The suspension is then filtered, the solid is washed with acetic acid and the filtrate is evaporated. The residue was treated with a saturated aqueous potassium carbonate solution until the solution remained basic and then extracted with ethyl acetate. The organic extracts were washed with brine (30 mL), dried over magnesium sulfate and evaporated to give the product as a light brown oil. The hydrogen maleate has a melting point of 93-96 ° C (EtOH / Et ₂ O, with decomposition).

The following compounds of formula I were prepared in an analogous manner to that described in Example 5:

Example 6

3- (4-Methoxy-3-yl) -1-methylpiperidine

The hydrochloride melts at 254-262 ° C.

Example 7

3- (2-Chloro-4-methoxy-biphenyl-3-yl) -1-methylpiperidine

The hydrochloride melts at 237-247 ° C.

Example 8

3- (4-methoxy-4'-trifluoromethyl-biphenyl-3-yl) -1-propyl-

Racemic hydrogen fumarate has a melting point of 178-180 ° C (EtOH / Et 2 O, with decomposition).

The racemate is separated into the enantiomers by high pressure liquid chromatography (HPLC) on a Chiracel OJ column, 25 x 0.46 cm, mobile phase: hexane-ethanol 9: 1 with 0.1% TFA. flow rate: 1 ml / min. The first enantiomer elutes at a retention time of 8.35 minutes and the second at 10.25 minutes. The enantiomers crystallize in the form of a fumarate, the first having [α] _D ²⁰ = +24.4 (c = 1.0, MeOH) and the second [α] _D ²⁰ = -24.3 (c = 1.0, MeOH) .

Example 9 (-) - 3- (4-Methoxy-4'-trifluoromethylbiphenyl-3-yl) -1-methylpiperidine

A solution of 3- (4-methoxy-4'-trifluoromethylbiphenyl-3-yl) -1-methylpiperidine (obtained according to Example 5) (7.7 g, 22 mmol) and (-) -2,3-di-o hydrate toluyltartaric acid (8.9 g, 22 mmol) in hot (70 ° C) ethanol (100 mL) was allowed to cool to room temperature and allowed to stand for 18 hours. The resulting crystals are filtered off and recrystallized from 100 ml of ethanol to give crystals of m.p. 155-156 ° C; [α] _D ²⁰ = -77.8 (c = 1.0, MeOH). The free base (oil) is obtained from the crystals thus prepared; [α] _D ²⁰ = -9.3 (c = 0.95, MeOH). These crystals were recrystallized from ethanol (80 mL) to give crystals of m.p. 159-160 ° C; [α] D ²⁰ = -83.0 (c = 1.0, MeOH); free base (oil); [α] D ²⁰ = -12.5 (c = 0.9, MeOH). The hydrogen maleate has a melting point of 124-126 ° C (EtOH / Et 2 O); [α] _D ²⁰ = -6.2 (c = 1.0, MeOH).

Example 10 (+) - 3- (4-Methoxy-4‘-trifluoromethylbiphenyl-3-yl) -1-methylpiperidine

The mother liquors of Example 9 are stored and the free base is prepared by reaction with saturated aqueous potassium carbonate solution and extraction with ethyl acetate. The free base obtained from the first mother liquors (2.4 g, 6.88 mmol) is reacted with (+) - 2,3-di-o-toluyltartaric acid hydrate (2.6 g, 6.88 mmol) in boiling ethanol ( 40 ml) and upon cooling, crystals are obtained which are recrystallized from ethanol (25 ml) to give colorless crystals of m.p. 164-165 ° C; [<x] _D ²⁰ = +81.1 (c = 1.1,

MeOH), where the free base has [α] _D ²⁰ = +11.3 (c = 1.0, MeOH). The free base from the combined second and third mother liquors (3.6 g, 10.3 mmol) is reacted with (+) - 2,3-di-o-toluyltartaric acid hydrate (3.9 g, 10.3 mmol) in boiling ethanol (50 mL). After crystallization is complete, the crystals are recrystallized from ethanol (45 ml) to give crystals with [α] D ²⁰ = +85.2 (c = 1.0, MeOH), the free base having [α] D ²⁰ = +9 1.8 (c = 1.4, MeOH), and further recrystallized from ethanol (30 mL) to give crystals of m.p. 164-165 ° C; [α] _D ²⁰ = +87.3 (c = 1.0, MeOH), with the free base having [α] _D ²⁰ = +11.3 (c = 1.0, MeOH). Hydrogen maleate has a melting point of 125-127 ° C (EtOH / Et 2 O); [a] _D ²⁰ = + 5.4 (c = 1.1, MeOH).

Example 11

3- (4-methoxy-4'-trifluoromethyl-biphenyl-3-yl) -1-methylpyrrolidine

A. 1-Ethoxycarbonyl-3- (2-methoxyphenyl) pyrrolidine

A solution of ethyl chloroformate (0.61 mL, 673 mg, 6.21 mmol) in dichloromethane (3 mL) was added dropwise to the cold over 10 min.

(0-5 ° C) ice bath) of a solution of N-ethyl-N, N-diisopropylamine (1.3 ml, 911 mg, 7.01 mmol) and 3- (2-methoxyphenyl) pyrrolidine (1.00 g, 5.65 mmol) in dichloromethane (15 mL). Yellow reaction mixture

The mixture was allowed to stir for 3.5 hours at room temperature, then washed with 1N hydrochloric acid (15 ml), saturated aqueous sodium bicarbonate solution (15 ml) and brine (10 ml), dried over magnesium sulphate and the solvent was evaporated. to give the product as a yellow oil. TLC (silica gel, toluene-ethanol-ammonium hydroxide 85: 15: 1) Rf = 0.6.

B. 1-Ethoxycarbonyl-3- (5-bromo-2-methoxyphenyl) pyrrolidine

A solution of bromine (835 mg, 5.22 µg) in glacial acetic acid (3 mL) was added dropwise to a solution of 1-ethoxycarbonyl-3- (2-methoxyphenyl) pyrrolidine (1.300 g, 5.22 mmol) and sodium acetate (470 mg). , 5.70 mmp1) in glacial acetic acid (15 mL) and the mixture was allowed to stir at room temperature for 18 hours. The mixture was filtered through Hyflo and the solvent was evaporated. The residue was taken up in ethyl acetate (30 mL) and the solution was washed with water (20 mL), saturated aqueous sodium carbonate solution (20 mL), and brine (15 mL). The aqueous phase was extracted with ethyl acetate (25 mL) and the combined extracts were dried over magnesium sulphate and evaporated to give the product as a yellow-brown oil [TLC (silica gel, toluene-ethanol-ammonium hydroxide 85: 15: 1) _Rf = 0.6], which is used directly in the next reaction.

C. 1-Ethoxycarbonyl-3- (4-methoxy-4'-trifluoromethylbiphenyl-3-yl) -pyrrolidine.

It is obtained from 1-ethoxycarbonyl-3- (5-bromo-2-methoxyphenyl) pyrrolidine and 4-trifluoromethylphenylboronic acid by palladium catalyzed condensation in an analogous manner to that described in Example IB. TLC (silica gel, toluene-ethanol-ammonium hydroxide 85: 15: 1) Rf = 0.78. The crude product was used directly in the next reaction.

D. 3- (4-Methoxy-4'-trifluoromethylbiphenyl-3-yl) -1-methylpyrrolidine

The crude product obtained in Step C (2.00 g) was dissolved in tetrahydrofuran (15 mL) and added dropwise over 15 minutes to a cold (0-5 ° C) suspension of lithium aluminum hydride (350 mg, 9.2 mmol) in tetrahydrofuran (25 mL). ml). The reaction mixture was allowed to stir at room temperature for 1 hour and then heated at reflux for 18 hours, allowed to cool to room temperature and worked up by careful addition of saturated aqueous sodium sulfate solution (2 mL), 2N ammonium hydroxide. (2 mL) and diethyl ether (50 mL). The mixture was stirred vigorously for 1 hour at room temperature and the precipitate was filtered off. The precipitate was further washed with diethyl ether-tetrahydrofuran (1: 1, 30 mL) and the combined filtrates were dried over magnesium sulfate and evaporated to give a red oil.

The crude product was dissolved in diethyl ether (50 mL) and extracted with 2N hydrochloric acid (2 x 15 mL). The combined acidic phases were further extracted with diethyl ether (20 mL), cooled in an ice bath, pH adjusted to alkaline with saturated aqueous potassium carbonate solution and extracted with diethyl ether (50 mL). The ether extracts were washed with brine (30 mL), dried over magnesium sulfate and evaporated to give the product as a red oil. TLC (silica gel, toluene-ethanol-ammonium hydroxide 85: 15: 1) _Rf = 0.1. The hydrogen fumarate has a melting point of 176-180 ° C (with decomposition).

Example 12

2- (4'-trifluoromethyl-biphenyl-3-yl) ethylamine

A mixture of 3- (bromophenyl) ethylamine (1.400 g, 7.0 mmol), acid

4-trifluoromethylphenyl boronic acid (1.33 g, 7.0 mmol), tris-o-toluylphosphine (212 mg, 0.70 mmol), palladium acetate (160 mg, 0.7 mmol), aqueous sodium carbonate solution (2M, 3 (5 mg, 0.7 mL), methanol (2 mL) and toluene (25 mL) were refluxed under argon for 18 h. The mixture was allowed to cool to room temperature and the phases were separated. The aqueous phase was extracted with toluene (25 mL). The combined organic phases were washed with water (25 ml) and brine (30 ml), dried over magnesium sulphate and evaporated. The residue is purified by chromatography (silica gel, toluene-ethanol-ammonium hydroxide (85: 15: 1) to give the product as a yellow oil. TLC (silica gel, toluene-ethanol-ammonium hydroxide 85: 15: 1) _Rf = 0.30.

Example 13

N, N-Dimethyl- [2- (4'-trifluoromethylbiphenyl-3-yl) ethyl] amine

It is obtained in an analogous manner to that described in Example 12. The hydrogen maleate has a melting point of 150-153 ° C (EtOH / Et 2 O).

The compound can also be obtained by dimethylating the compound of Example 12 according to known procedures, for example by Eschweiler-Clark methylation.

Example 14

2- (6-methoxy-4'-trifluoromethyl-biphenyl-3-yl) ethylamine

It was obtained in a similar manner to that described in Example 12 as a yellow oil. TLC (silica gel, toluene-ethanol-ammonium hydroxide 85: 15: 1) Rf = 0.30.

Example 15

N, N-Dimethyl- [2- (6-methoxy-4'-trifluoromethyl-biphenyl-3-yl) etyljamín

It is obtained in an analogous manner to that described in the example

12. The hydrochloride has a melting point of 210-212 ° C (EtOH / Et 2 O).

The compound can also be obtained by Eschweiler-Clark methylation of the compound of Example 14.

Example 16

2- (4-Methoxy-4'-trifluoromethylbiphenyl-3-yl) ethylamine

It is obtained in an analogous manner to that described in the example

12. The hydrogen maleate has a melting point of 157-160 ° C (EtOH).

Example 17

N, N-Dimethyl-2- [2- (4-methoxy-4'-trifluoromethyl-biphenyl-3-yl) -ethyl] -amine

It is obtained in an analogous manner to that described in the example

12. Hydrogen maleate has a melting point of 136-137 ° C (EtOH).

The compound can also be prepared by Eschweiler-Clark methylation of the compound of Example 16.

Example 18

N-propyl- [2- (4-methoxy-4'-trifluoromethyl-biphenyl-3-yl) -ethyl] -amine

It is obtained in an analogous manner to that described in Example 12. The hydrogen maleate has a melting point of 178-180 ° C (EtOH / Et 2 O).

Example 19

1- [2- (4-methoxy-4'-trifluoromethyl-biphenyl-3-yl) ethyl] pyrrolidine

It is obtained in an analogous manner to that described in Example 12. The hydrogen maleate has a melting point of 131-133 ° C (EtOH / Et 2 O).

The compound can also be prepared as follows:

A. 1- [2- (4-Methoxy-4'-trifluoromethylbiphenyl-3-yl) ethyl] pyrrolidine-

-2,5-dione

A solution of 2- (4-methoxy-4'-trifluoromethylbiphenyl-3-yl) ethylamine (1.4 g, 4.74 mmol) and succinic anhydride (475 mg, 4.74 mmol) in tetrahydrofuran (60 mL) was heated. for 18 hours at reflux. The solution was then evaporated to dryness and the residue heated to 190 ° C to give an oil which crystallized on standing. Recrystallization from diethyl ether gave the product, m.p. 116-120 ° C.

B. 1- [2- (4-Methoxy-4'-trifluoromethylbiphenyl-3-yl) ethyl] pyrrolidine

A solution of 1- [2- (4-methoxy-4'-trifluoromethylbiphenyl-3-yl) ethyl] pyrrolidine-2,5-dione (1.3 g, 3.45 mmol) in tetrahydrofuran (10 mL) was added over 10 minutes dropwise to a suspension of lithium aluminum hydride (262 mg, 6.9 mmol) in tetrahydrofuran (15 mL), maintaining the temperature between 0-10 ° C. After the addition was complete, the mixture was allowed to warm to room temperature and stirred for 1 hour, then heated at reflux for 18 hours. After cooling, the reaction mixture was treated successively with a saturated aqueous sodium sulfate solution (2 mL) and an aqueous sodium hydroxide solution (2N, 1 mL). After addition of diethyl ether (25 ml), the resulting mixture was stirred for 1 hour and then filtered. The precipitate was washed with diethyl ether and the wash was mixed with the filtrate. The diethyl ether solution was dried over magnesium sulfate and evaporated to give a yellow oil which was purified by crystallisation as the hydrogen maleate.

Example 20 (1 S *, 2 S *, 6 R * _f * R) -4- [2- (4-methoxy-4'-trifluoromethyl-biphenyl-3-yl) ethyl] -10-oxa-4-tricyclo [5.2. 1.0 (2,6)] decane

It is obtained analogously to Example 12. The hydrogen maleate has a melting point of 163-164 ° C (EtOH / Et 2 O). The compound can also be prepared as follows:

A. (1S *, 2S *, 6R *, 1R *) -4- [2- (4-methoxy-4'-trifluoromethylbiphenyl-3-yl) ethyl] -10-oxa-4-azatricyclo [5.2.1.0 &lt; 2,7 &gt; 1.0 (2,6)] decane-3,5-dione

A solution of 2- (4-methoxy-4'-trifluoromethylbiphenyl-3-yl) ethylamine (1.4 g, 4.74 mmol) and (1S *, 2S *, 6R *, 7R *) - 4,10-dioxatricyclo- [5,2,1,0 (2,6)] - Decane-3,5-dione (850 mg, 5.1 mmol) in tetrahydrofuran (60 mL) was heated at reflux for 18 h in a similar manner as described in Example 8A to give the product with a melting point of 166-168 ° C.

B. (1S *, 2S *, 6R *, 7R *) -4- [2- (4-methoxy-4 ' -trifluoromethylbiphenyl-3-)

yl) ethyl] -10-oxa-4-tricyclo [5,2,1,0 (2,6)] decane

The product of Example 20A was reduced with lithium aluminum hydride in tetrahydrofuran to give the product as a brown oil which was recrystallized as hydrogen maleate.

Example 21 (1S *, 2S *, 6R *, 7R *) -4- [2- (4-methoxy-4'-trifluoromethyl-biphenyl-3-yl) -ethyl] -10-oxa-4-aza-2,6 -dimetyltricyklo [5,2,1,0 (2,6)] decane

It is obtained in an analogous manner to that described in the example

12. The hydrochloride has a melting point of 229-231 ° C. The compound can also be prepared as follows:

A. (1S *, 2S *, 6R *, 6R *) - 4- [2- (4-methoxy-4'-trifluoromethylbiphenyl-3-yl) ethyl] -10-oxa-4-aza-2,6 -dimetyltricyklo [5,2,1,0 (2,6)] decane-3,5-dione

It was obtained in a similar manner to that described in Example 20A of the

2- (4-methoxy-4'-trifluoromethylbiphenyl-3-yl) ethylamine; and (1S *, 2S *, 6R * _f 1 R *) -2,6-dimethyl-4,10-dioxatricyclo [5.2.1.0 &lt; 2,7 &gt; O (2,6)] decane-3,5-dione. Melting point 115-117 ° C (Et ₂ O / hexane).

B. (1S *, 2S *, 6R *, 7R *) -4- [2- (4-Methoxy-4'-trifluoromethylbiphenyl-3-yl) ethyl] -10-oxa-4-aza-2,6- dimetyltricyklo [5,2,1,0 (2,6)] decane

Obtained in a similar manner as described in Example 20B by reduction of (1S *, 2S *, 6R *, 7R *) -4- [2- (4-methoxy-4'-trifluoromethylbiphenyl-3-yl) ethyl] -10 oxa-4-aza-2,6-dimetyltricyklo- [5,2,1,0 (2,6)] decane-3,5-dione.

Example 22

2- (4'-Isopropyl-4-methoxy-biphenyl-3-yl) ethylamine

Is obtained in an analogous manner to that described in example 12. TLC (ethyl acetate-methanol-ammonium hydroxide 80: 20: 2) _Rf = 0.22.

Example 23

N, N-dimethyl-2- (4'-isopropyl-4-methoxy-biphenyl-3-yl) ethylamine

It is obtained in an analogous manner to that described in Example 12. The hydrogen maleate has a melting point of 123-124 ° C (EtOH / Et ₂ O).

The compound can also be prepared by Eschweiler-Clark methylation of the compound of Example 22.

Example 24

2- (2-chloro-4-methoxy-biphenyl-3-yl) ethylamine

It is obtained in an analogous manner to that described in the example

12. The hydrochloride has a melting point of 191-205 ° C.

Example 25

N, N-dimethyl-2- (2-chloro-4-methoxy-biphenyl-3-yl) ethylamine

It is obtained in an analogous manner to that described in Example 12. The hydrochloride has a melting point of 151-159 ° C.

The compound can also be prepared by Eschweiler-Clark methylation of the compound of Example 24.

Example 26 (2'-Chloro-4-methoxybiphenyl-3-ylmethyl) -N, N-dimethylamine

It is obtained in an analogous manner to that described in Example 12. The hydrogen oxalate has a melting point of 145-159 ° C.

Example 27

N, N-dimethyl-2- (2-chloro-4-methoxy-biphenyl-3-yl) -1-methylethylamine

It was obtained in an analogous manner to that described in Example 12. The hydrochloride had a melting point of 141-145 ° C.

Example 28 (+) - [2- (4-Methoxy-4'-trifluoromethylbiphenyl-3-yl) -1-methylethyl] -N, N-dimethylamine

A. (Z) -1-Methoxy-2- (2-nitropropenyl) benzene

A solution of 10 g of 2-methoxybenzaldehyde, 6.07 g of nitroethane, 0.8 ml

Of 1-butylamine and 30 ml of ethanol are refluxed for three days, the ethanol is evaporated and the remaining reaction mixture is dissolved in ethyl acetate. After extraction with water and brine, the solvent is evaporated and the residue is distilled over a short path (Kugelrohr). The fractions distilling at 120-170 ° C / 100 Pa are purified on silica gel, eluting with dichloromethane / cyclohexane 1: 1 to give the title compound as yellow plates, mp 39-42 ° C.

B. rac -2- (2-Methoxyphenyl) -1-methylethylamine

A solution of 45.01 g (233 mmol) of (Z) -1-methoxy-2- (2-nitropropenyl) -benzene in 250 ml of ether is slowly added dropwise to a flask equipped with a mechanical stirrer, a thermometer and a reflux condenser containing 40.84 g of LiAlH _4. in 600 ml diethyl ether. The exothermic reaction is ice-cooled and the temperature is maintained between 5-10 ° C. The mixture was stirred overnight at room temperature, 330 ml of 2M sodium carbonate was added, the resulting suspension was filtered, and the ether phase was extracted with 2M hydrochloric acid. The pH of the acidic aqueous phase is made alkaline with 1.2 equivalents of concentrated ammonia and extracted with diethyl ether. The ether phase was washed with brine, dried over sodium sulfate and evaporated to give the title compound as a yellow oil. ¹ H-NMR (360 MHz, CDCl 3):

7.2 t, 1H; 7.1 d, 1H; 7.0 - 6.8 m, 2H; 3.9 s, 3H; 3.2 m, 1H; 2.8 m, 1H; 2.6 m, 1H; 1.1 d, 3H.

Further purification is accomplished by converting the compound to the naphthalene-1,5-disulfonate salt.

C. 1 (-) - 2- (2-Methoxyphenyl) -1-methylethylamine

To 19.16 rac-2- (2-methoxyphenyl) -1-methylethylamine dissolved in 300 ml of methanol is added a solution of 17.49 g of D - (-) - tartaric acid in 334 ml of methanol and the mixture is kept at a temperature of 3 hours Low: 14 ° C. The solid is filtered off, the mother liquors are discarded and the filter cake is washed with ice-cold methanol and recrystallized twice from methanol until the optical rotation remains constant. 11.11 g of (-) - 2- (2-methoxyphenyl) -1-methylethylamine D-tartaric acid salt are obtained in the form of fine white flakes, m.p. 144-149 ° C. The free base is characterized by a specific rotation of [α] 539 = -35.4 ° (c = 1, MeOH). According to analytical chiral capillary electrophoresis of the free base, the optical purity is> 98%.

C. 2 (+) - 2- (2-Methoxyphenyl) -1-methylethylamine

The first mother liquors obtained in the preparation of the (-) - enantiomer C.I are evaporated and the residue is released from the tartrate by reaction with concentrated ammonia and ethyl acetate. After evaporation of the organic layer, 11.14 g of a yellow oil is obtained and combined with 10.12 g of L - (+) - tartaric acid in a total volume of 140 ml of methanol. After 3 hours at 4 ° C, the solid formed is collected, washed with ice-cold methanol and recrystallized from methanol until the specific rotation remains constant. 11.92 g of L-tartaric acid salt of (+) - 2- (2-methoxyphenyl) -1-methylethylamine are obtained in the form of white flakes. The free base has a specific rotation [α] 539 = + 37.7 ° (c = 1, MeOH). According to analytical chiral capillary electrophoresis of the free base, the optical purity is> 98%.

D. (-) - [2- (2-Methoxyphenyl) -1-methylethyl] -N, N-dimethylamine

11.8 g of the tartaric acid salt of (+) - 2- (2-methoxyphenyl) -1-methylethylamine are liberated with concentrated ammonia in ethyl acetate and the oil obtained is dissolved in 56 ml of methanol. To this solution was added 22.3 mL of a 36.5% aqueous formaldehyde solution, the mixture was cooled to 3 ° C and treated in small portions with 10.66 g of NaCNBH 3. After stirring at room temperature for 22 hours, the solvent was evaporated and the residue was partitioned between ethyl acetate and water. The organic phase is washed with water and brine, dried over sodium sulphate, evaporated and the residue is purified on silica gel, eluting with a toluene / ethyl acetate / methanol / conc. ammonia 60: 30: 10: 1 to give 5.02 g of the title compound as a yellow oil. [α] 539 = -19.9 ° (c = 1, MeOH). ¹ H-NMR (360 MHz, CDCl 3): 7.2 dxt, 1H; 7.1 dxd, 1H; 7.0 - 6.8 m, 2H; 3.85 s, 3H; 3.1-3.0 m, 1H; 2.95 - 2.85 m, 1H; 2.4 br s, 7H; 0.95 d, 3H.

E. (+) - [2- (5-Bromo-2-methoxyphenyl) -1-methylethyl] -N, N-dimethylamine

To a mixture of 4.47 g of (-) - [2- (2-methoxyphenyl) -1-methylethyl] -N, N-dimethylamine, 2.09 g of sodium acetate and 40 ml of glacial acetic acid in a mechanically stirred flask at 20 ° C. 1.19 ml of bromine in 8.5 ml of glacial acetic acid was added dropwise to 30 ° C. The reaction mixture was stirred for 16 hours, neutralized with concentrated ammonia and extracted with ethyl acetate. After working up the organic phase with brine and sodium sulfate, the solvent is evaporated and the residue is purified by chromatography on silica gel, eluting with toluene / ethyl acetate / methanol / conc. ammonia 60: 30: 10: 1 to give 4.32 g of the title compound as a brown oil. [α] ₅₈₉ = + 1.5 ° (c = 1.01 MeOH). ¹ H-NMR (360 MHz, CDCl ₃ ): 7.2-7.0 m, 2H; 6.6 d, 1H; 3.7 s, 3H;

2.95 - 2.75 m, 2H; 2.3-2.2 m + s, 7H; 0.85 d, 3H.

F. (+) - [2- (4-Methoxy-4'-trifluoromethylbiphenyl-3-yl) -1-methyl-ethyl] -N, N-dimethylamine

A 500 mL flask was charged with 140 mL of toluene and 28 mL of 2M sodium carbonate and charged with argon for 1 hour. Then, 3.94 g of (+) - [2- (5-bromo-2-methoxyphenyl) -1-methylethyl] -N, N-dimethylamine,

4.95 g of 4-trifluoromethylphenylboronic acid and 374 mg of tetrakis- (triphenylphosphine) palladium are added and the mixture is refluxed for 12 hours. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine, dried over sodium sulfate and evaporated to give a brown oil. After the preparation of the naphthalene-1,5-disulfonate salt of this oil and liberation of the free base, the product is recrystallized in the form of hydrochloride hydrochloride in diethyl ether. Recrystallization from ethanol / ether gave the title compound hydrochloride as white slices, mp 155-163 ° C.

The free base solidifies and has a melting point of 36-37 ° C and is characterized by a specific rotation of [α] 539 = + 13.0 ° (c = 0.995 MeOH). According to analytical chiral HPLC (Chiracel OJ), the optical purity is> 98%. ^X H-NMR (360 MHz, CDCl3): 7.7 s, 4H; 7.45 dxd, 1H; 7,4 d,

1 H; 6.95 d, 1H; 3.9 s, 3H; 3.25-3.20 m, 1H; 3.0-2.9 m, 1H;

2.55-2.45 m, 1H; 2.40 s, 6H; 1.0 d, 1H.

Example 29 (-) - [2- (4-Methoxy-4'-trifluoromethylbiphenyl-3-yl) -1-methylethyl] -N, N-dimethylamine

A. (+) - [2- (2-Methoxyphenyl) -1-methylethyl] -N, N-dimethylamine

The product prepared according to the procedure described in Example 28C.1 was reduced with NaCNBH ₃ and formaldehyde according to the procedure described in Example 28D to give the title compound as a yellow oil. [a] ₅ 89 = + 21.6 ° (c = 1.03 MeOH).

B. (-) - (2- (5-Bromo-2-methoxyphenyl) -1-methylethyl] -N, N-dimethylamine

The product prepared in Step A was brominated according to the procedure described in Example 28E to give the title compound as a yellow oil. [α] D89 = -1.0 ° (c = 1.05 MeOH).

C. (-) - [2- (4-Methoxy-4'-trifluoromethylbiphenyl-3-yl) -1-methyl-ethyl] -N, N-dimethylamine

The product prepared according to Step B is aryl-acid

4-trifluoromethylphenyl borate according to the procedure described in Example 28F to give the title compound hydrochloride as white plates, mp 148-163 ° C.

The free base solidifies and has a melting point of 31 ° C and a specific rotation of [α] 589 = -12.8 ° (c = 1.0 MeOH). According to analytical chiral HPLC (Chiracel OJ), the optical purity is> 99%.

Example 30 [1- (4-Methoxy-4'-trifluoromethylbiphenyl-3-ylmethyl) propyl] -N, N-dimethylamine

A. 1-Methoxy-2- (2-nitrobut-1-enyl) benzene

A solution of 2.72 g of 2-methoxybenzaldehyde, 1.96 g of 1-nitropropane,

0.4 ml of 1-butylamine and 10 ml of toluene are heated to reflux for 16 hours. Toluene was evaporated and the residue was dissolved in ethyl acetate and extracted with water and brine. Evaporation of the organic phase affords the title compound as a yellow oil which is sufficiently pure for the next step. ¹ H-NMR (360 MHz, CDCl 3): 8.6 s (olefinic H E-isomer);

8.2 s (olefinic H-Z isomer).

B. 1- (2-Methoxybenzyl) propylamine

A solution of 3.79 g of 1-methoxy-2- (2-nitrobut-1-enyl) benzene in 15 ml of diethyl ether is added dropwise at 0-5 ° C to a mixture of 2.28 g of L1AlH4 and 35 ml of diethyl ether stirred with a magnetic stirrer. The mixture is stirred overnight at room temperature, 20 ml of 2M sodium carbonate are added, the suspension obtained is filtered and the organic phase is extracted with 2M hydrochloric acid. The pH of the acidic aqueous phase was made alkaline with 2M sodium hydroxide and extracted with tert-butyl methyl ether. The organic phase was washed with brine, dried over sodium sulfate and evaporated to give the title compound as a yellow oil. ¹ H-NMR (360 MHz, CDCl 3): 7.2-7.0 m, 2H; 6.9 - 6.7 m, 2H; 3.8 s, 3H; 2.9 m, 1H;

2.8 dxd, 1H; 2.4 dxd, 1H; 1.5 m, 1H; 1.3 m, 1H; 0.9 t, 3H.

C. 1- (5-Bromo-2-methoxybenzyl) propylamine

To a mixture of 2.25 g of 1- (2-methoxybenzyl) propylamine, 1.13 g of sodium acetate and 57 ml of glacial acetic acid in a magnetically stirred flask is added dropwise 0.65 ml of bromine in 3 ml of glacial acid at 20-30 ° C. acid. The reaction mixture was stirred for 4 hours, evaporated and the residue was partitioned between water and ethyl acetate. The organic phase is extracted with 2M acetic acid and the pH of the combined aqueous acidic phases is made alkaline with concentrated ammonia. Extraction with ethyl acetate, drying of the organic phase over sodium sulfate and evaporation affords the title compound as a colorless powder. ^X H-NMR (360 MHz, CDCl3):

7.2 d, 1 H; 7.1 s, 1H; 6.7 d, 1H; 3.8 s, 3H; 2.9 m, 1H; 2.7 m, 1 H; 2.5 m, 1H; 1.6 - 1.3 m, 2H; 1.0 t, 3H.

D. [1- (4-Methoxy-4'-trifluoromethyl-biphenyl-3-ylmethyl) -propyl] -amine

A mixture of 1.91 g of 1- (5-bromo-2-methoxybenzyl) propylamine, 0.3 g of tetrakis (triphenylphosphine) palladium, 2.61 g of 4-trifluoromethylphenylboronic acid, 24 ml of 2M sodium carbonate and 25 ml of toluene was added for 7 hours. heated to reflux. After extraction of the aqueous phase with diethyl ether, the organic phases are combined, dried over sodium sulfate and evaporated to give the title compound as a brown oil, eluting with 85: 15: 1.

which on silica gel en / ethanol / concentrated ammonia CDC1 _3): 7.65 s, 4H; 7.5 dxd, 1H;

is ^{ethyl; H-NMR} purified Toluol (360 MHz,

7.4 d, 1H; 7.0 d, 1H;

3.9 s, 3H;

3.1 m, 1H; 2.9 dxd, 1H; 2.6 dxd, 1H; 1.6 m, 1H; 1.4 m, 1H; 1.1t, 3H.

E. [1- (4-Methoxy-4'-trifluoromethyl-biphenyl-3-ylmethyl) -propyl] -N, N-dimethylamine hydrochloride

To a mixture of 1.25 g of [1- (4-methoxy-4'-trifluoromethyl-biphenyl-3-ylmethyl) -propyl] -amine, 2.5 ml of 36.5% formalin and 10 ml of methanol under argon at 3 ° C for several 1.66 g of NaCNBH 3 are added in portions. After stirring overnight at room temperature, the solvent was evaporated and the residue was partitioned between ethyl acetate and water. The organic phase was washed with water and brine and evaporated to give the crude product which was reacted with hydrogen chloride in diethyl ether. The solid obtained is filtered and recrystallized from acetone / diethyl ether to give the title compound as white needles, mp 155-172 ° C.

Example 31

1- [2- (4-methoxy-4'-trifluoromethyl-biphenyl-3-yl) -1-methyl-ethyl] -piperidin

A. 2- (5-Bromo-2-methoxyphenyl) -1-methylethylamine

A mixture of 6.54 g of 2- (2-methoxyphenyl) -1-methylethylamine (free base prepared according to the procedure described in Example 28B), 3.56 g of sodium acetate and 180 ml of glacial acetic acid was treated with 6.31 g of bromine according to the procedure described in Example 30C to give the title compound as a yellow oil. ^T H-NMR (360 MHz, CDCl 3): 7.4 to 7.2 m, 2H; 6.7 d, 1H; 3.8 s, 3H; 3.2 hex, 1H; 2.8-2.5 m, 2H; 1.1 d, 3H.

B. 2- (4-Methoxy-4'-trifluoromethylbiphenyl-3-yl) -1-methylethylamine hydrochloride

A mixture of 7.62 g of 2- (5-bromo-2-methoxyphenyl) -1-methylethylamine, 0.71 g of tetrakis (triphenylphosphine) palladium, 7.98 g of 4-trifluoromethylphenylboronic acid, 24 ml of 2M sodium carbonate, 40 ml of toluene and Ethanol (10 ml) was refluxed for 9 hours under argon. After treatment according to Example 30D, the crude oil was purified by conversion to the hydrochloride, which was obtained as white slices. ¹ H-NMR (360 MHz, DMSO-d 6): 7.90-7.75 dxd, 4H; 7.65 dxd, 1H; 7.60 d, 1 H; 7.15 d, 1H; 3.85 s, 3H; 3.5 m, 1H; 3.1-2.8 m, 2H; 1.15 d, 3H.

C. 4- [2- (4-Methoxy-4'-trifluoromethylbiphenyl-3-yl) -1-methylethylcarbamoyl] butanoic acid

The base is released from 1.1 g of 2- (4-methoxy-4'-trifluoromethylbiphenyl-3-yl) -1-methylethylamine hydrochloride and reacted with 0.37 g of glutaric anhydride in tetrahydrofuran for 20 hours at reflux temperature. reflux condenser. The solvent was evaporated and the residue was dissolved in ethyl acetate. Extraction of the organic phase 1M with hydrochloric acid, water and brine, drying over sodium sulfate and evaporation affords the title compound as a white powder, m.p. 88 ° C (dec.).

D. 1- [2- (4-Methoxy-4'-trifluoromethylbiphenyl-3-yl) -1-methylethyl] -

-piperidine-2,6-dione

A mixture of 1.02 g of the carboxylic acid obtained in Step C and 4.3 g of acetyl chloride in 20 ml of chloroform is heated at reflux for 17 hours, then cooled, extracted with water and 2M sodium carbonate. The organic phase is dried over sodium sulfate, the solvent is evaporated and the residue is purified on silica gel, eluting with ethyl acetate / cyclohexane 1: 2 to give the title compound as a pale yellow oil which solidifies in a refrigerator. ^X H-NMR (360 MHz, CDC1 _3):

7.6 - 7.5 m, 4H; 7.4 dxd, 1H; 7.2 d, 1H; 6.8 d, 1H; 5.2 m, 1H;

3.8 s, 3H; 3.2-3.0 m, 2H; 2.4-2.3 m, 4H; 1.5 br m, about 2H (+ HOD); 1.35 d, 3H.

E. 1- [2- (4-Methoxy-4'-trifluoromethylbiphenyl-3-yl) -1-methylethyl] piperidine hydrochloride

A solution of 0.3 g of 1- [2- (4-methoxy-4'-trifluoromethylbiphenyl-3-yl) -1-methylethyl] piperidine-2 is added dropwise under a argon atmosphere to a suspension of 0.054 g of LiAlH4 in 6 ml of diethyl ether. 6-dione in 2 ml diethyl ether. After stirring for 30 minutes, 0.5 ml of 2M sodium carbonate is added, the mixture is filtered and the filtrate is acidified and extracted with 1M hydrochloric acid. The pH of the aqueous phase is made alkaline with concentrated ammonia and extracted with diethyl ether. The organic phase is dried over sodium sulphate, evaporated and the residue is treated with hydrogen chloride in diethyl ether to give the title compound as colorless flakes, m.p. 185 ° C (dec.).

Example 32

N, N-Diethyl- [2- (4-methoxy-4'-trifluoromethylbiphenyl-3-yl) -1-methylethyl] amine

Obtained by reductive alkylation of 2- (4-methoxy-4'-trifluoromethylbiphenyl-3-yl) -1-methylethylamine (obtained according to the procedure described in Example 31B) with acetaldehyde over 10% palladium on carbon in ethyl acetate. The hydrochloride has a melting point of 105-107 C.

Claims (10)

First Compound of Formula I? IN R ³ where R ¹ and R ² are each independently hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, halogen, trifluoromethyl, trifluoromethoxy, cyano or alkanoyl 2 to 5 carbon atoms, R ³ is hydrogen, hydroxyl, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 3 -C 6 cycloalkyloxy, halogen, cyano, C 2 -C 5 alkanoyl, carbamoyl , (1-4C) alkylsulfonyloxy or trifluoromethylsulfonyloxy, R ⁴ is a hydrogen atom, a hydroxyl group or an alkoxy group having 1 to 4 carbon atoms, and R ⁵ is a group of formula (a), (b), (c) or (d) (b) —X — Ν ^Ζ x R ⁷ R 8 (d) wherein R ⁶ is an alkyl group having 1 to 4 carbon atoms, X is a straight or branched alkylene chain containing 1 to 5 carbon atoms; 4 carbon atoms a R ⁷ and R ⁸ together with the nitrogen atom to which they are attached form a group of formula (e) R13 R ¹⁴ (e) wherein Z is O, CH ₂ or CH ₂ -CH ₂ and R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ and R ¹⁴ are each independently hydrogen, halogen, alkyl containing 1-4 carbon atoms or a C1-4 alkoxy group, in free base or acid addition salt form. A compound of formula I according to claim 1, wherein R ¹ , R ² , R ³ and R ⁴ are as defined in claim 1 and R ⁵ is a group of the formula (a), (b) or (c) as defined in claim 1, in the form of the free base or in the form of an acid addition salt. A compound of formula I according to claim 1, wherein R ¹ , R ² , R ³ and R ⁴ are as defined in claim 1 and R ⁵ is a group of the formula (d) as defined in claim 1, in free base or acid form. addition salt. A compound according to claim 1 selected from the group consisting of: (+) - 3- (4-methoxy-4'-trifluoromethylbiphenyl-3-yl) -1-propylpiperidine, (-) -3- (4-methoxy-4) 1-Trifluoromethylbiphenyl-3-yl) -1-propylpiperidine, (-) -3- (4-methoxy-4'-trifluoromethylbiphenyl-3-yl) -1-methylpiperidine, (+) - 3- (4-methoxy-4) 1-Trifluoromethylbiphenyl-3-yl) -1-methylpiperidine, (1S *, 2S *, 6R *, 7F *) -4- [2- (4-methoxy-4'-trifluoromethylbiphenyl-3-yl) ethyl] - 10-oxa-4-azatricyclo [ 5,2,1,0 (2,6)] decane, in the form of the free base or in the form of an acid addition salt. 5th process preparation compound of the formula I according to claim 1 vo a free base; or in shape an acid addition salt, v y z n and no u j ú c i s a t ý m that general compound of formula II R ³ - in Λ (II) * ⁵ where R ³ , R ⁴ a R ⁵ are as defined in claim 1 and Y is a halogen atom or trifluoro- methylsulfonate group, reacts with the compound of formula III (III) wherein R ¹ and R ² are as defined in claim 1, and the resulting compound is isolated in the form of the free base or in the form of an acid addition salt. A compound according to any one of claims 1 to 4 in free base or pharmaceutically acceptable acid addition salt form for use as a medicament. A compound according to any one of claims 1 to 4 in free base or pharmaceutically acceptable acid addition salt form for use in the treatment of epilepsy, stroke and brain or spinal cord injury. A pharmaceutical composition comprising a compound according to any one of claims 1 to 4 in the form of the free base or in the form of a pharmaceutically acceptable acid addition salt, together with a pharmaceutically acceptable carrier or diluent. Use of a compound according to any one of claims 1 to 4 in free base or pharmaceutically acceptable acid addition salt form for the preparation of a medicament for the treatment of epilepsy, stroke and brain and spinal cord injury. A method of treating epilepsy, stroke and brain or spinal cord injury in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound according to any one of claims 1 to 4 as a free base or a pharmaceutically acceptable acid addition salt. .