KR20010031699A - Biphenyl Derivatives as Pharmaceuticals - Google Patents

Abstract

Compounds of formula I useful as medicaments.

<Formula I>

Wherein R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are as defined in the specification.

Description

Biphenyl Derivatives as Pharmaceuticals

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

More specifically, the present invention provides a compound of formula I in the form of a free base or an acid addition salt.

Where

R ₁ and R ₂ are independently hydrogen, (C _1-4 ) alkyl, (C _1-4 ) alkoxy, (C _1-4 ) alkylthio, halogen, trifluoromethyl, trifluoromethoxy, cyano or (C _2-5 ) alkanoyl,

R ₃ is hydrogen, hydroxy, (C _1-4 ) alkyl, (C _1-4 ) alkoxy, (C _3-6 ) cycloalkyloxy, halogen, cyano, (C _2-5 ) alkanoyl, carba Moly, (C _1-4 ) alkylsulfonyloxy or trifluoromethylsulfonyloxy,

R ₄ is hydrogen, hydroxy or (C _1-4 ) alkoxy,

R ₅ is a chemical formula or Where is

R ₆ is (C _1-4 ) alkyl,

X is straight or branched chain alkylene having 1 to 4 carbon atoms,

R ₇ and R ₈ are independently hydrogen, (C _1-4 ) alkyl, hydroxy (C _2-4 ) alkyl or phenyl (C _1-4 ) alkyl, or pyrrolidinyl together with the nitrogen atom to which they are attached , Piperidino, piperazinyl or morpholino groups or chemical formulas groups of (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 independently H, halogen, (C _{1- 4} ) alkyl or (C _1-4 ) alkoxy).

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

Halogen is fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.

Optional alkyl, alkoxy and alkylthio groups are preferably linear groups. These preferably have 1 to 3 carbon atoms, more preferably methyl, methoxy and methylthio groups.

The following meanings and combinations thereof are preferred:

R ₁ and R ₂ are independently hydrogen, (C _1-4 ) alkyl, (C _1-4 ) alkoxy, halogen or trifluoromethyl,

R ₃ is hydrogen or hydroxy, (C _1-4 ) alkoxy, (C _3-6 ) cycloalkyloxy, cyano or carbamoyl in the para position relative to the phenyl substituent,

R ₄ is H,

R ₅ is a group of formula (a) or (d).

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

When R ₅ is a group of formula (d), R ₇ and R ₈ are preferably hydrogen, (C _1-4 ) alkyl or 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 O and R ₉ to R ₁₄ are independently preferably hydrogen or methyl.

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 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 (d).

In another aspect, the present invention provides a process for preparing a compound of formula I and salts thereof comprising reacting a compound of formula II with a compound of formula III and recovering the resulting compound in free base form or in acid addition salt form.

Wherein R ₁ to R ₅ are as defined above and Y is halogen or trifluoromethyl sulfonate.

This reaction takes place by known methods, preferably by aryl-aryl coupling by transition metal-catalyst (eg as described in Example 1). Halogen is preferably bromine or iodine, in particular iodine.

The compounds of the invention can also be obtained by the aryl-aryl coupling method by other known metal-catalysts using, for example, aryl-stannyl, -zinc, -halide or Grignard precursors.

In the preparation of compounds of formula (I) wherein R ₅ is a group of formula (c), the nitrogen in the group of formula (c) can be protected by, for example, an alkoxycarbonyl group, which alkoxycarbonyl group is It can be removed after reaction with the compound of III. See, for example, Example 11.

In preparing compounds of formula (I) wherein R ₅ is a group of formula (b), compounds of formula (I) wherein R ₅ is a 3-pyridyl group are first prepared as described above for compounds of formula (I) and then known pyridyl groups According to the method it can be converted to the desired tetrahydropyridyl via the corresponding pyridinium salt (eg, via pyridinium iodide as described in Example 1).

R ₅ is in the manufacture of a resulting compound of formula (I) of formula (a), R ₅ is in accordance with known methods, such as prepare a corresponding compound of formula (b) first and then for as example, as described in Example 5 Hydrogenation can be carried out.

From the corresponding racemates, compounds of formula (I) in optically pure form can be obtained, for example, according to known methods as described in Examples 9 and 10. Alternatively, optically pure starting materials can be used as described in Examples 28 and 29.

Acid addition salts can be prepared from the free base form by known methods and vice versa. Pharmaceutically acceptable acid addition salts suitable for use according to the invention are, for example, hydrochlorides, maleates, fumarates and malonates.

Starting materials of formula (II) are known or can be prepared by halogenating the compounds of formula (IV) according to known methods.

Wherein R ₃ , R ₄ and R ₅ are as defined above.

Starting materials of the formulas (III) and (IV) are known or can be prepared analogously to known methods, for example as described in the Examples.

Compounds of formula (I) and pharmaceutically acceptable acid addition salts thereof (hereinafter collectively referred to as `` drugs of the invention '') exhibit pharmacological activity and are therefore useful as medicaments.

The medicament of the present invention provides continuous protection against convulsions by maximal electroshock at doses of about 1 to 100 mg / kg oral and about 0.32 to 32 mg / kg intraperitoneal administration in mice (EA Swinyard, J. Am. Pharm. Assoc. Scient.Ed. 38, 201 (1949) and J. Pharmacol. Exptl. Therap. 106, 319 (1952).

Thus, the medicaments of the present invention are useful for the treatment of epilepsy and other convulsive symptoms such as hypertensive neurological syndrome.

In addition, the agents of the present invention reduce neuronal damage and subsequent symptoms in the middle cerebral artery (MCA) occlusion model due to ischemia at 1-50 mg / kg parenteral, intravenous and oral dosages in rats (A Tamura et al., J. Cereb. Blood Flow Metabol. 1, 53-60 (1981), A. Sauter, M. Rudin, Stroke 17, 1228-1234 (1986)).

Thus, the medicaments of the present invention are useful for cerebral oxygen deficiency, hypoxia and / or ischemia such as ischemic damage to gray and white matter, stroke, reperfusion injury, subarachnoid hemorrhage, brain and spinal cord injury / trauma, high intracranial pressure, Any clinical procedure involving one component of multiinfarct dementia or vascular dementia and any surgical method potentially associated with cerebral oxygen deficiency, hypoxia and / or ischemia (eg, heart bypass, extracerebral vascular surgery) It is useful for the treatment of symptoms.

The medicament of the present invention exhibits a binding to veratridine-sensitive sodium channel having an IC ₅₀ of about 0.1 to about 100 μM. For a binding process see, eg, JB Brown, Journal of Neuroscience 6, 2064-2070 (1986). They block glutamate release by veratridine in the hippocampus slice formulations of rats at a concentration of about 0.1-1 mM. This experiment is performed using foreign glutamate according to MJ Leach et al. In Epilpepsia 27, 490-497 (1986) and Stroke 24, 1063-1067 (1993).

Thus, the medicaments of the present invention may be used in psychiatric diseases (e.g., schizophrenia, depression, anxiety, panic attacks, attention deficit and cognitive impairment, social breakaway symptoms), hormonal diseases (excess GH [e.g. diabetes mellitus, vasculature) In the treatment of diseases and acromegaly] or LH [prostate hypertrophy, postmenopausal syndrome] secretion, corticosterone secretion under stress), brain injury by metabolism (hypoglycemia, nonketomic hyperglycineemia [glycine brain disease], sulfite oxidase deficiency) , Brain diseases caused by liver associated with liver failure), vomiting, convulsions, tinnitus, pain (eg cancer pain, arthritis) and drugs (ethanol, sedatives [synthetic agents with effects such as soothing agents, eg pettidine , Methadone, and the like], any disease, disorder associated with glutamate release in etiology, including cocaine, amphetamine, barbiturate and other sedatives, benzodiazepines) abuse and withdrawal, or It has been shown to be useful for the treatment of clinical symptoms.

In addition, the medicaments of the present invention can be used for neurological injuries, such as neurodegenerative diseases such as Alzheimer's disease, Huntington's disease or Parkinson's disease, viruses (including HIV) -induced neurodegeneration, amyotrophic lateral sclerosis (ALS), nuclear paralysis, olive It has been shown to be used for the treatment of glioblastoma cortical atrophy (OPCA) and any disease, including the action of the environment, exogenous neurotoxins.

In the directions described above, of course suitable dosages depend, for example, on the compound used, the recipient, the method of administration and the symptoms and severity of the disease being treated. However, in general, a daily dose of about 0.1 to about 100, preferably about 0.5 to about 100 mg / kg animal body weight, results in satisfactory results in the animal. In larger mammals, such as humans, the indicated daily dosage is typically divided up to four times a day into a daily dosage of about 1 to about 500, preferably about 1 to about 300 mg of the medicament of the invention. Amount or sustained release.

The agents of the present invention may be administered by any conventional route, in particular in the intestine, preferably orally, for example in the form of tablets or capsules or parenterally, for example in the form of injectable solutions or suspensions.

As noted above, the present invention also provides a medicament of the invention for use as a medicament, for example for the treatment of epilepsy, stroke and brain or spinal cord trauma.

The present invention also provides a pharmaceutical composition comprising a medicament of the invention together with one or more pharmaceutical carriers or diluents. Such compositions may be prepared according to conventional methods. The unit dosage contains, for example, about 0.25 to about 150, preferably 0.25 to about 25 mg of the compound according to the invention.

The present invention also provides the use of a medicament of the invention for the preparation of a medicament for the treatment of the conditions described above, such as epilepsy, stroke and brain or spinal cord trauma.

Further, further features of the present invention include administering a therapeutically effective amount of a medicament of the invention to a patient in need of treatment of any of the conditions described above, such as epilepsy, stroke and brain or spinal cord trauma. Provide a method for treating symptoms.

The following examples illustrate the invention. The temperature is in degrees Celsius and does not change.

Example 1: 3- (4-methoxy-4'-trifluoromethyl-biphenyl-3-yl) -1-methyl-1,2,5,6-tetrahydropyridine

A. 3- (5-Bromo-2-methoxy-phenyl) -pyridine

A solution of bromine (12.2 g, 3.9 ml, 0.076 mol) in glacial acetic acid (40 ml) was added 3- (2-methoxyphenyl) -pyridine (14.0 g, 0.076 mol) and glacial acetic acid (6.8 g) in glacial acetic acid (140 ml). , 0.083 mol) was added dropwise for 15 minutes, and the temperature was maintained at 15 to 20 ° C. If a precipitate was observed, the suspension was slowly dissolved by stirring. This suspension was stirred for 18 hours at room temperature before a clear orange solution was obtained. Acetic acid was removed under reduced pressure and the residue was dissolved in EtOAc (250 ml). The extract was washed with water (150 ml), saturated aqueous NaHCO ₃ (100 ml) and brine (75 ml), dried (MgSO ₄ ) and evaporated to give the product as an orange oil. TLC (silica gel, toluene-EtOH-NH ₄ OH 85: 15: 1) Rf = 0.5

B. 3- (4-methoxy-4'-trifluoromethyl-biphenyl-3-yl) -pyridine

3- (5-Bromo-2-methoxy-phenyl) -pyridine (19.0 g, 0.072 mol), 4-trifluoromethylphenylboronic acid (14.3 g, 0.076 mol), palladium (II) acetate (520 mg, 0.0023 mol), a mixture of tri-o-toluylphosphine (2.1 g, 0.0069 mol), 2M aqueous Na ₂ CO ₃ (39 ml, 0.077 mol), MeOH (80 ml) and toluene (350 ml) in an argon atmosphere Under reflux for 18 hours. The mixture was cooled, filtered through Hyflo, diluted with water (100 ml) and the phases separated. The aqueous phase is extracted with toluene (150 ml) and the combined organic phases are washed with water (100 ml) and brine (100 ml), dried (MgSO ₄ ), treated with activated charcoal (1 g), filtered through hyflo and evaporated. To give a yellow oil. This oil was dissolved in EtOH (50 ml) and treated with 3N ethanol HCl (25 ml). Hydrochloride salt precipitated (20 g, 76%) upon ether addition. Melting point 229-231 ° C. TLC (silica gel, toluene-EtOH-NH ₄ OH 85: 15: 1) Rf = 0.55.

C. 3- (4-methoxy-4'-trifluoromethyl-biphenyl-3-yl) -1-methyl-pyridinium iodide

A solution of methyl iodide (9.4 g, 66 mmol) in acetone (25 ml) was added to 3- (4-methoxy-4'-trifluoromethyl-biphenyl-3-yl)-in acetone (100 ml). To a cold (15 ° C.) solution of pyridine (10.9 g, 33 mmol) was added dropwise for 15 minutes. The reaction mixture was then heated to reflux for 2 hours before the second portion of methyl iodide (1 ml, 2.2 g, 0.015 mmol) was added and the mixture was refluxed for an additional 1.5 hours. After evaporation of the solvent, the title compound was obtained as a yellow solid which was used directly in the next reaction. TLC (silica gel, toluene-EtOH-NH ₄ OH 85: 15: 1) Rf = 0-0.02

D. 3- (4-methoxy-4'-trifluoromethyl-biphenyl-3-yl) -1-methyl-1,2,5,6-tetrahydro-pyridine

A solution of sodium hydroxide (1.5 g, 36 mmol) in water (100 ml) was added 3- (4-methoxy-4'-trifluoromethyl-biphenyl-3-yl) -1- in MeOH (150 ml). To a solution of methyl-pyridinium iodide. To the resulting mixture was added sodium borohydride (2.5 g, 66 mmol) in portions for 30 minutes and the mixture was stirred at room temperature for 60 hours. The mixture was filtered through Hiflo and the filtrate was concentrated to about 100 ml to separate the yellow oil. This mixture was extracted with EtOAc (3 x 125 ml). The combined organic extracts were washed with brine (75 ml), dried (MgSO ₄ ) and evaporated to afford the title compound as a tan oil. TLC (silica gel, toluene-EtOH-NH ₄ OH 85: 15: 1) Rf = 0.4. The melting point of maleate was 123-125 ° C. (EtOH / Et ₂ O).

The following compounds of formula I were prepared in a similar manner to Example 1:

Example 2: 3- (4-methoxy-biphenyl-3-yl) -1-methyl-1,2,5,6-tetrahydro-pyridine

The melting point of the hydrochloride salt was 187-194 ° C.

Example 3: 3- (2'-Chloro-4-methoxy-biphenyl-3-yl) -1-methyl-1,2,5,6-tetrahydro-pyridine

The melting point of the oxalate was 137-142 ° C.

Example 4: 3- (4-methoxy-4'-trifluoromethyl-biphenyl-3-yl) -1-propyl-1,2,5,6-tetrahydro-pyridine

The compound was obtained as a yellow oil. TLC (silica gel, toluene-EtOH-NH ₄ OH 85: 15: 1) Rf = 0.25

Example 5: 3- (4-methoxy-4'-trifluoromethyl-biphenyl-3-yl) -1-methyl-piperidine

Palladium on carbon (10%, 700 mg) in 3- (4-methoxy-4'-trifluoromethyl-biphenyl-3-yl)-(obtained according to example 1) in glacial acetic acid (75 ml)- To a degassed solution of 1-methyl-1,2,5,6-tetrahydropyridine (5.3 g, 15.9 mmol) and the mixture was hydrogenated over 18 hours at room temperature and 5 atm hydrogen pressure on a Parr hydroreactor. 70 ml of hydrogen was used during this time. The catalyst was then filtered and fresh catalyst added (0.800 g) and the mixture was hydrogenated at 45 ° C. and 5 atm hydrogen pressure for an additional 18 hours, during which time 400 ml of hydrogen was used. The suspension was then filtered, the solid was washed with AcOH and the filtrate was evaporated. The residue was treated with saturated aqueous K ₂ CO ₃ until a basic solution was obtained and extracted with EtOAc. The organic extract was washed with brine (30 ml), dried (MgSO ₄ ) and evaporated to afford the product as a light brown oil. The melting point of maleate was 93-96 ° C. (EtOH / Et ₂ O, decomposition).

The following compounds of formula I were prepared in a similar manner to Example 5:

Example 6: 3- (4-methoxy-biphenyl-3-yl) -1-methyl-piperidine

The melting point of the hydrochloride salt was 254-262 ° C.

Example 7: 3- (2'-Chloro-4-methoxy-biphenyl-3-yl) -1-methyl-piperidine

The melting point of the hydrochloride salt was 237-247 ° C.

Example 8: 3- (4-methoxy-4'-trifluoromethyl-biphenyl-3-yl) -1-propyl-piperidine

The melting point of the fumarate of racemate was 178-180 ° C. (EtOH / Et ₂ O, decomposition).

Racemates were separated on their enantiomers using 0.1% TFA on Chiralcel OJ (column 25 × 0.46 cm, mobile phase: hexane-EtOH 9: 1). Flow rate: 1 ml / min. The first enantiomer was eluted with a residence time of 8.35 minutes and the second enantiomer was 10.25 minutes. The enantiomer was crystallized with its corresponding fumarate, [α] _D ²⁰ = +24.4 (c = 1.0, MeOH) of the first crystal and [α] _D ²⁰ = -24.3 (c = 1.0, of the second crystal). MeOH).

Example 9: (-)-3- (4-methoxy-4'-trifluoromethyl-biphenyl-3-yl) -1-methyl-piperidine

3- (4-methoxy-4'-trifluoromethyl-biphenyl-3-yl) -1-methyl-pi in warmed (70 ° C.) EtOH (100 ml) (obtained according to example 5) A solution of ferridine (7.7 g, 22 mmol) and (-)-2,3-di-o-toluyltartaric acid hydrate (8.9 g, 22 mmol) was cooled to room temperature and left for 18 hours. The resulting crystals were filtered and recrystallized from 100 ml EtOH to give crystals having a melting point of 155-156 ° C; [a] _D ² ° = -77.8 (c = 1.0 MeOH). A free base was formed from the obtained crystals (oil; [α] _D ²⁰ = -9.3 (c = 0.95, MeOH) .These crystals were again recrystallized from EtOH (80 ml) to obtain crystals having a melting point of 159-160 ° C. [a] _D ²⁰ = -83.0 (c = 1.0, MeOH); free base (oil): [α] _D ²⁰ = -12.5 (c = 0.9, MeOH) The melting point of maleate was 124-126 ° C ( EtOH / Et ₂ O): [α] _D ²⁰ = −6.2 (c = 1.0, MeOH).

Example 10: (+)-3- (4-methoxy-4'-trifluoromethyl-biphenyl-3-yl) -1-methyl-piperidine

The mother liquor of Example 9 was stored and each treated with saturated aqueous K ₂ CO ₃ and extracted with EtOAc to prepare a free base. The free base (2.4 g, 6.88 mmol) obtained from the first mother liquor was treated with (+)-2,3-di-o-toluyltartaric acid hydrate (2.6 g, 6.88 mmol) in boiling EtOH (40 ml) and cooled The obtained crystals were recrystallized from EtOH (25 ml) to obtain colorless crystals having a melting point of 164-165 ° C. from a free base having [α] _D ²⁰ of +11.3 (c = 1.0, MeOH), [α] _D ²⁰ = +81.1 (c = 1.1, MeOH). Free base (3.6 g, 10.3 mmol) from the combined second and third mother liquors with (+)-2,3-di-o-toluyltartaric acid hydrate (3.9 g, 10.3 mmol) in boiling EtOH (50 ml) Combined. After complete crystallization, the crystals were recrystallized from EtOH (45 ml) [α] D 20 is +9.8 (c = 1.4, MeOH) from which the free base [α] _D ²⁰ is +85.2 (c = 1.0, MeOH) of Crystals were obtained and further recrystallized from EtOH (30 ml) to give crystals having a melting point of 164-165 ° C; [α] _D ²⁰ = +87.3 (c = 1.0, MeOH) from the free base [α] _D ²⁰ is +11.3 (c = 1.0, MeOH). The melting point of maleate is 125-127 ° C. (EtOH / Et ₂ O); [a] _D ² ° = +5.4 (c = 1.1, MeOH).

Example 11: 3- (4-methoxy-4'-trifluoromethyl-biphenyl-3-yl) -1-methyl-pyrrolidine

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

CH ₂ Cl ₂ (3 ml) ethyl chloroformate (0.61 ml, 673 mg, 6.21 mmol) was added to CH ₂ Cl ₂ (15 ml) of N- ethyl -N, N- diisopropylamine in a (1.3 ml , 911 mg, 7.01 mmol) and 3- (2-methoxyphenyl) -pyrrolidine (1.00 g, 5.65 mmol) were added dropwise to the cold (0-5 ° C, ice bath) solution for 10 minutes. The yellow reaction mixture was stirred at rt for 3.5 h, then washed with 1N HCl (15 ml), saturated aqueous NaHCO ₃ (15 ml) and brine (10 ml), dried (MgSO ₄ ) and the solvent evaporated to a yellow oil. To give the product. TLC (silica gel, toluene-EtOH-NH ₄ OH 85: 15: 1) Rf = 0.6.

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

A solution of bromine (835 mg, 5.22 mmol) in glacial acetic acid (3 ml) was added 1-ethoxycarbonyl-3- (2-methoxyphenyl) -pyrrolidine (1.300 g, 5.22 mmol) in glacial acetic acid (15 ml) and To the solution of sodium acetate (470 mg, 5.70 mmol) was added dropwise and stirred for 18 hours at room temperature. The mixture was filtered through hiflo and the solvent was evaporated. The residue was dissolved in ethyl acetate (30 ml) and the solution was washed with water (20 ml), saturated aqueous Na ₂ CO ₃ (20 ml) and brine (15 ml). The aqueous phase was extracted with EtOAc (25 ml) and the combined organic extracts were dried (MgSO ₄ ) and evaporated to afford the product as a tan oil [TLC (silica gel, toluene-EtOH-NH ₄ OH 85: 15: 1) Rf = 0.6 Used directly in the next reaction.

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

1-ethoxycarbonyl-3- (5-bromo-2-methoxyphenyl) -pyrrolidine and 4-trifluoromethylphenyl-boronic acid in a palladium-catalyzed coupling in a similar manner to Example 1B Obtained from. TLC (silica gel, toluene-EtOH-NH ₄ OH 85: 15: 1) Rf = 0.78. The crude product was used directly for the next reaction.

D. 3- (4-methoxy-4'-trifluoromethyl-biphenyl-3-yl) -1-methyl-pyrrolidine

The crude product (2.00 g) obtained in C was dissolved in THF (15 ml) and added dropwise to a cold (0-5 ° C.) suspension of lithium aluminum hydride (350 mg, 9.2 mmol) in THF (25 ml) for 15 minutes. The reaction mixture was stirred at room temperature for 1 hour, heated to reflux for 18 hours, then cooled to room temperature and carefully watched with saturated aqueous Na ₂ SO ₄ (2 ml), 2N NaOH (2 ml), and Et ₂ O (50 ml). Treatment was added gently. The mixture was vigorously stirred at rt for 1 h and the precipitate was filtered off. The precipitate was further washed with Et ₂ O-THF (1: 1 30 ml) and the combined filtrates were dried (MgSO ₄ ) and evaporated to give a reddish oil. This crude product was dissolved in Et ₂ O (50 ml) and extracted with 2N HCl (2 × 15 ml). The combined acid phases were further extracted with Et ₂ O (20 ml), cooled (ice bath), alkalined with saturated aqueous K ₂ CO ₃ and extracted with Et ₂ O (50 ml). The ether extract was washed with brine (30 ml), dried (MgSO ₄ ) and evaporated to afford the product as a reddish oil. TLC (silica gel, toluene-EtOH-NH ₄ OH 85: 15: 1) Rf = 0.1. The melting point of fumarate was 176-180 ° C. (decomposition).

Example 12: 2- (4'-trifluoromethyl-biphenyl-3-yl) ethylamine

3- (bromophenyl) -ethylamine (1.400 g, 7.0 mmol), 4-trifluoromethylphenylboronic acid (1.33 g, 7.0 mmol), tris- (ortho-toluyl) phosphine (212 mg, 0.70 mmol) ), A mixture of palladium (II) acetate (160 mg, 0.70 mmol), aqueous sodium carbonate solution (2M, 3.5 ml), MeOH (2 ml) and toluene (25 ml) was heated to reflux under argon for 18 hours. The mixture was then cooled to room temperature and the phases 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 (MgSO ₄ ) and evaporated. The residue was chromatographed (silica gel, toluene-ethanol-NH ₄ OH 85: 15: 1) to give the product as a light yellow oil. TLC (silica gel, toluene-ethanol-NH ₄ OH 85: 15: 1) Rf = 0.30.

Example 13: N, N-dimethyl- [2- (4'-trifluoromethyl-biphenyl-3-yl) ethyl] amine

Obtained in a similar manner to Example 12. The melting point of maleate was 150-153 ° C. (EtOH / Et ₂ O).

The compounds may also be obtained by dimethylation of the compounds of Example 12 according to known methods, for example Eschweiler-Clarke methylation.

Example 14 2- (6-methoxy-4'-trifluoromethyl-biphenyl-3-yl) ethylamine

Obtained as a yellow oil in a similar manner as in Example 12. TLC (silica gel, toluene-EtOH-NH ₄ OH 85: 15: 1) Rf = 0.30.

Example 15 N, N-dimethyl- [2- (6-methoxy-4'-trifluoromethyl-biphenyl-3-yl) ethyl] amine

Obtained in a similar manner to Example 12. The melting point of the hydrochloride salt was 210-212 ° C. (EtOH / Et ₂ O).

Compounds may also be obtained according to Eschweiler-Clark methylation of the compounds of Example 14.

Example 16: 2- (4-methoxy-4'-trifluoromethyl-biphenyl-3-yl) ethylamine

Obtained in a similar manner to Example 12. The melting point of maleate was 157-160 ° C. (EtOH).

Example 17 N, N-Dimethyl-2-[(4-methoxy-4'-trifluoromethyl-biphenyl-3-yl) ethyl] amine

Obtained in a similar manner to Example 12. The melting point of maleate was 136-137 ° C. (EtOH).

Compounds may also be obtained following Eschweiler-Clark methylation of the compounds of Example 16.

Example 18 N-propyl-2- [4-methoxy-4'-trifluoromethyl-biphenyl-3-yl)] ethylamine

Obtained in a similar manner to Example 12. The melting point of maleate was 178-180 ° C. (EtOH / Et ₂ O).

Example 19: 1- [2- (4-methoxy-4'-trifluoromethyl-biphenyl-3-yl) ethyl] pyrrolidine

Obtained in a similar manner to Example 12. The melting point of maleate was 131-133 ° C. (EtOH / Et ₂ O).

The compound can be obtained as follows:

A. 1- [2- (4-methoxy-4'-trifluoroethyl-biphenyl-3-yl) -ethyl-pyrrolidine-2,5-dione

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 THF (60 ml) Heated to reflux for 18 h. The solution was then evaporated to dryness and the residue heated to 190 ° C. to make an oil which was then left to crystallize and recrystallized (Et ₂ O) to give the product, melting point 116-120 ° C.

B. 1- [2- (4-methoxy-4'-trifluoroethyl-biphenyl-3-yl) -ethyl] pyrrolidine

1- [2- (4-methoxy-4'-trifluoromethyl-biphenyl-3-yl) -ethyl-pyrrolidine-2,5-dione (1.3 g, 3.45 mmol) in THF (10 ml) ) Was added dropwise to a suspension of lithium aluminum hydride (262 mg, 6.9 mmol) in THF (15 ml) for 10 minutes and maintained at 0-10 ° C. The addition was complete and the mixture was allowed to warm to rt, stirred for 1 h and then heated to reflux for 18 h. After cooling the reaction mixture was treated sequentially with saturated aqueous Na ₂ SO ₄ (2 ml) and aqueous NaOH (2N, 1 ml). After addition of Et ₂ O (25 ml) the resulting mixture was stirred for 1 h and filtered. The precipitate was washed with Et ₂ O and the wash was combined with the filtrate. The Et ₂ O solution was dried (MgSO ₄ ) and evaporated to give a yellow oil which was purified by crystallization to give maleate.

Example 20: (1S ^* , 2S ^* , 6R ^* , 7R ^* )-4- [2- (4-methoxy-4'-trifluoromethyl-biphenyl-3-yl) -ethyl] -10- Oxa-4-aza-tricyclo [5.2.1.0 (2,6)] decane

Obtained in a similar manner to Example 12. The melting point of maleate was 163-164 ° C. (EtOH / Et ₂ O). In addition, the compound can be obtained as follows:

A. (1S ^* , 2R ^* , 6S ^* , 7R ^* )-4- [2- (4-methoxy-4'-trifluoromethyl-biphenyl-3-yl) -ethyl] -10-oxa- 4-aza-tricyclo [5.2.1.0 (2,6)] decane-3,5-dione

2- (4-methoxy-4'-trifluoromethyl-biphenyl-3-yl) -ethylamine (1.4 g, 4.74 mmol) in THF (60 ml) and (1S ^* , 2R ^* , 6S ^* , A solution of 7R ^* )-4,10-dioxa-tricyclo [5.2.1.0 (2,6)] decane-3,5-dione (850 mg, 5.1 mmol) for 18 hours in a similar manner to Example 8A The product was heated to reflux to obtain a product having a melting point of 166-168 占 폚.

B. (1S ^* , 2S ^* , 6R ^* , 7R ^* )-4- [2- (4-methoxy-4'-trifluoromethyl-biphenyl-3-yl) -ethyl] -10-oxa- 4-aza-tricyclo [5.2.1.0 (2,6)] decane

The product from Example 20A was reduced with lithium aluminum hydride in THF to give the product as a brown oil and crystallized with maleate.

Example 21: (1S ^* , 2S ^* , 6R ^* , 7R ^* )-4- [2- (4-methoxy-4'-trifluoromethyl-biphenylyl-3-yl) -ethyl] -10- Oxa-4-aza-2,6-dimethyl-tricyclo [5.2.1.0 (2,6)] decane

Obtained in a similar manner to Example 12. The melting point of the hydrochloride salt was 229-231 ° C. The compound may also be obtained as follows:

A. (1S ^* , 2R ^* , 6S ^* , 7R ^* )-4- [2- (4-methoxy-4'-trifluoromethyl-biphenyl-3-yl) -ethyl] -10-oxa- 4-aza-2,6-dimethyl-tricyclo [5.2.1.0 (2,6)] decane-3,5-dione

In a similar manner as in Example 20A, 2- (4-methoxy-4'-trifluoromethyl-biphenyl-3-yl) -ethylamine and (1R ^* , 2S ^* , 6R ^* , 7S ^* )-2, Obtained from 6-dimethyl-4,10-dioxa-tricyclo [5.2.1.0 (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'-trifluoromethyl-biphenyl-3-yl) -ethyl] -10-oxa- 4-aza-2,6-dimethyl-tricyclo [5.2.1.0 (2,6)] decane

In a similar manner as in Example 20B, (1R ^* , 2S ^* , 6R ^* , 7S ^* )-4- [2- (4-methoxy-4'-trifluoromethyl-biphenyl-3-yl) -ethyl] Obtained from -10-oxa-4-aza-2,6-dimethyl-tricyclo [5.2.1.0 (2,6)] decane-3,5-dione.

Example 22: 2- (4'-Isopropyl-4-methoxy-biphenyl-3-yl) -ethylamine

Obtained in a similar manner to Example 12. TLC (silica gel, EtOAc-NH ₄ OH 0: 20: 2) Rf = 0.22.

Example 23 N, N-dimethyl-2- (4'-isopropyl-4-methoxy-biphenyl-3-yl) -ethylamine

Obtained in a similar manner to Example 12. The melting point of maleate was 123-124 ° C. (EtOH / Et ₂ O).

The compounds can also be obtained according to Eschweiler-Clark methylation of the compounds of Example 22.

Example 24: 2- (2'-Chloro-4-methoxy-biphenyl-3-yl) -ethylamine

Obtained in a similar manner to Example 12. The melting point of the hydrochloride salt was 191-205 ° C.

Example 25 N, N-dimethyl-2- (2'-chloro-4-methoxy-biphenyl-3-yl) -ethylamine

Obtained in a similar manner to Example 12. The melting point of the hydrochloride salt was 151-159 ° C.

Compounds may also be obtained following Eshweiler-Clark methylation of the compounds of Example 24.

Example 26: (2'-Chloro-4-methoxy-biphenyl-3-yl-methyl) -N, N-dimethylamine

Obtained in a similar manner to Example 12. The melting point of the oxalate was 145-159 ° C.

Example 27 N, N-dimethyl-2- (2'-chloro-4-methoxy-biphenyl-3-yl) -1-methyl-ethylamine

Obtained in a similar manner to Example 12. The melting point of the hydrochloride salt was 141-145 ° C.

Example 28: (+)-[2- (4-methoxy-4'-trifluoromethyl-biphenyl-3-yl) -1-methyl-ethyl] -N, N-dimethyl-amine

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

A solution of 10 g of 2-methoxybenzaldehyde and 6.07 g of nitroethane in 0.8 ml of 1-butylamine and 30 ml of ethanol was refluxed for 3 days, ethanol was evaporated and the remaining mixture was dissolved in ethyl acetate. After extraction with water and brine, the solvent was evaporated and the remaining bulb was inflated to evaporate. Fractions evaporated at 120-170 ° C./0.01 mbar were purified by eluting with 1: 1 methylene chloride / cyclohexane on silica gel to give the title compound as a yellow plate, melting point 39-42 ° C.

B. rac-2- (2-methoxy-phenyl) -1-methyl-ethylamine

A solution of 45.01 g (233 mmol) of Z-1-methoxy-2- (2-nitropropenyl) -benzene in 250 ml of ether was loaded with a mechanical stirrer, thermometer and reflux condenser and LiAlH ₄ 40.84 in 600 ml of diethyl ether. It was slowly added dropwise to the flask containing g. The exothermic reaction was cooled with ice and kept between 5-10 ° C. After stirring overnight at room temperature 330 ml of 2M Na ₂ CO ₃ were added, the resulting suspension was filtered and the ether phase was extracted with 2M HCl. The acidic aqueous phase was alkalined with 1.2 equivalents of concentrated ammonia and extracted with diethyl ether. The ether phase was washed with brine, dried over Na ₂ SO ₄ and concentrated to give the title compound as a yellow oil. ¹ H-NMR (360 MHz, CDCl ₃ ): 7.2 t, 1H; 7.1 d, 1 H; 7.0-6.8 m, 2 H; 3.9 s, 3 H; 3.2 m, 1H; 2.8 m, 1 H; 2.6 m, 1H; 1.1 d, 3 H.

Further purification was performed by converting the compound to naphthalene-1,5-disulfonate.

C.1 (-)-2- (2-methoxy-phenyl) -1-methyl-ethylamine

To 19.16 g of rac-2- (2-methoxy-phenyl) -1-methyl-ethylamine dissolved in 300 ml of methanol was added a solution of 17.49 g of D-(-)-tartaric acid in 334 ml of methanol and the mixture was stirred at 4 ° C. Hold for 3 hours. The solid was filtered, the mother liquor was stored and the filter kit was washed with ice cold methanol and recrystallized twice from methanol until the optical rotation was constant. 11.11 g of (-)-2- (2-methoxy-phenyl) -1-methyl-ethylamine D-tartarate was obtained as a fine white plate, and the melting point was 144-149 ° C. The free base exhibited an intrinsic light rotation of [α] ₅₈₉ = -35.4 ° (c = 1, MeOH). Analytical chiral capillary electrophoresis of the free base showed optical purity greater than 98%.

C.2 (+)-2- (2-methoxy-phenyl) -1-methyl-ethylamine

The first mother liquor obtained in the preparation of the (-)-enantiomer of C.1 was concentrated and the residue liberated from tartrate was treated with concentrated ammonia and ethyl acetate. After evaporating the organic layer, 11.14 g of a yellow oil was obtained and combined with 10.12 g of L-(+)-tartaric acid in 140 ml of total volume of methanol. After 3 hours at 4 ° C., the resulting solid was collected, washed with ice-cold methanol and recrystallized from methanol until the natural light rotation was constant. 11.92 g of (+)-2- (2-methoxy-phenyl) -1-methyl-ethylamine-L-tartrate was obtained as a white plate. The free base showed an intrinsic light rotation of [α] ₅₈₉ = + 37.7 ° (c = 1, MeOH). Analytical chiral capillary electrophoresis showed optical purity of over 98%.

D. (-)-[2- (2-methoxy-phenyl) -1-methyl-ethyl] -N, N-dimethyl-amine

11.8 g of tartarate of (+)-2- (2-methoxy-phenyl) -1-methyl-ethylamine were liberated with concentrated ammonia in ethyl acetate and the oil obtained was dissolved in 56 ml of methanol. To this solution was added 22.3 ml of a 36.5% aqueous formaldehyde solution and the mixture was cooled to 3 ° C. and treated slightly with 10.66 g of NaCNBH ₃ . After stirring for 22 hours 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, dried over Na ₂ SO ₄ , concentrated and the residue was eluted with 60: 30: 10: 1 toluene / ethyl acetate / methanol / conc. Ammonia on silica gel [α] ₅₈₉ = -19.9 ° (c = 1, MeOH) to give the title compound. ¹ H-NMR (360 MHz, CDCl ₃ ): 7.2 dxt, 1H; 7.1 dxd, 1 H; 7.0-6.8 m, 2 H; 3.85 s, 3 H; 3.1-3.0 m, 1 H; 2.95-2.85 m, 1 H; 2.4 br s, 7H; 0.95 d, 3 H.

E. (+)-[2- (5-Bromo-2-methoxy-phenyl) -1-methyl-ethyl] -N, N-dimethyl-amine

A mixture of 4.47 g of (-)-[2- (2-methoxy-phenyl) -1-methyl-ethyl] -dimethyl-amine, 2.09 g of sodium acetate and 40 ml of glacial acetic acid in a flask mechanically stirred at 20-30 ° C To this was added dropwise 1.19 ml of bromine in 8.5 ml of glacial acetic acid. The reaction mixture was stirred for 16 h, neutralized with concentrated ammonia and extracted with ethyl acetate. The organic layer was dried over brine and Na ₂ SO ₄ , the solvent was evaporated, and the residue obtained on silica gel was purified with 60: 30: 10: 1 toluene / ethyl acetate / methanol / condensed ammonia [α] ₅₈₉ = + 1.5 ° (c = 1.01, MeOH) gave 4.32 g of the title compound. ¹ H-NMR (360 MHz, CDCl ₃ ): 7.2-7.0 m, 2H; 6.60 d, 1 H; 3.70 s, 3 H; 2.95-2.75 m, 2H; 2.3-2.2 m + s, 7H; 0.85 d, 3 H.

F. (+)-[2- (4-methoxy-4'-trifluoromethyl-biphenyl-3-yl) -1-methyl-ethyl] -N, N-dimethyl-amine

The 500 ml flask was filled with 140 ml of toluene and 28 ml of 2M Na ₂ CO ₃ and treated with argon gas for 1 hour. Then 3.94 g of (+)-[2- (5-bromo-2-methoxy-phenyl) -1-methyl-ethyl] -dimethyl-amine, 4.95 g of 4-trifluoromethyl-phenylboronic acid and tetra 374 mg of kiss (triphenylphosphine) palladium were added and the mixture was refluxed for 12 hours. The aqueous layer was extracted with ethyl acetate and the combined organic phases were washed with brine, dried over Na ₂ SO ₄ and concentrated to give a brown oil. Naphthalene-1,5-disulfonate of this oil was formed and the free base was liberated to crystallize the product from HCl in diethyl ether to a hydrochloride salt. Recrystallization from ethanol / ether gave the hydrochloride salt of the title compound in a fine white plate, melting point 155-163 ° C.

The free base solidified (melting point 36-37 ° C.) and exhibited an intrinsic light rotation rate of [α] ₅₈₉ = + 13.0 ° (c = 0.995, MeOH). Analytical chiral HPLC (chiralcel OJ) showed optical purity greater than 99%. ¹ H-NMR (360 MHz, CDCl ₃ ): 7.70 s, 4H; 7.45 dxd, 1 H; 7.40 d, 1 H; 6.95 d, 1 H; 3.90 s, 3 H; 3.25-3.20 m, 1 H; 3.0-2.9 m, 1 H; 2.55-2.45 m, 1 H; 2.40 s, 6 H; 1.00 d, 1 H.

Example 29: (-)-[2- (4-methoxy-4'-trifluoromethyl-biphenyl-3-yl) -1-methyl-ethyl] -N, N-dimethyl-amine

A. (+)-[2- (2-methoxy-phenyl) -1-methyl-ethyl] -N, N-dimethyl-amine

The product prepared as described in Example 28C.1 was reduced with NaCNBH ₃ and formaldehyde according to the description of Example 28D to give the title compound as a yellow oil, [α] ₅₈₉ = + 21.6 ° (c = 1.03, MeOH). ).

B. (-)-[2- (5-Bromo-2-methoxy-phenyl) -1-methyl-ethyl] -N, N-dimethyl-amine

The product prepared in A was brominated as described in Example 28E to give the title compound as a yellow oil, [a] ₅₈₉ = -1.0 ° (c = 1.05, MeOH).

C. (-)-[2- (4-methoxy-4'-trifluoromethyl-biphenyl-3-yl) -1-methyl-ethyl] -N, N-dimethyl-amine

The product prepared in B was arylated with 4-trifluoromethyl-phenylboronic acid according to Example 28F to give the hydrochloride salt of the title compound as a white plate, melting point 148-163 °.

The free base solidified (melting point 31 ° C.) and exhibited an intrinsic light rotation of [α] ₅₈₉ = -12.8 ° (c = 1.0, MeOH). Analytical chiral HPLC (chiralcel OJ) showed optical purity greater than 99%.

Example 30: [1- (4-methoxy-4'-trifluoromethyl-biphenyl-3-ylmethyl) -propyl] -N, N-dimethyl-amine

A. 1-methoxy-2- (2-nitro-but-1-enyl) -benzene

A solution of 2.72 g of 2-methoxybenzaldehyde and 1.96 g of 1-nitropropane in 0.4 ml of 1-butylamine and 10 ml of toluene was refluxed for 16 hours. Toluene was evaporated and the residue was dissolved in ethyl acetate and extracted with water and brine. The organic phase was concentrated to give the title compound as a yellow oil, which was pure enough for the next step. ¹ H-NMR (360 MHz, CDCl ₃ ): 8.6 s (olefinic H of E-isomer); 8.2 s (olefinic H of Z-isomer).

B. 1- (2-methoxybenzyl) -propylamine

3.79 g of 1-methoxy-2- (2-nitro-but-1-enyl) -benzene in 15 ml of diethyl ether in a mechanically stirred mixture of 2.28 g of LiAlH ₄ in 35 ml of diethyl ether at 0-5 ° C. Solution was added dropwise. After stirring at room temperature overnight, 20 ml of 2M Na ₂ CO ₃ was added and the resulting suspension was filtered and the organic phase was extracted with 2M HCl. The acidic aqueous phase was alkalized with 2M NaOH and extracted with methyl-t-butyl ether. The organic phase was washed with brine, dried over Na ₂ SO ₄ and concentrated 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, 3 H; 2.9 m, 1 H; 2.8 dxd, 1 H; 2.4 dxd, 1 H; 1.5 m, 1 H; 1.3 m, 1H; 0.9 t, 3 H.

C. 1- (5-Bromo-2-methoxy-benzyl) -propylamine

0.65 ml of bromine in 3 ml of glacial acetic acid was added dropwise 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 flask mechanically stirred at 20-30 ° C. The reaction mixture was stirred for 4 hours, concentrated and the residue obtained was partitioned between water and ethyl acetate. The organic phase was extracted with 2M acetic acid and the combined acidic aqueous phases were alkalized with concentrated ammonia. Re-extract with ethyl acetate and dry the organic phase with Na ₂ SO ₄ and concentrate to give the title compound as a colorless powder. ¹ H-NMR (360 MHz, CDCl ₃ ): 7.2 d, 1H; 7.1 s, 1 H; 6.7 d, 1 H; 3.8 s, 3 H; 2.9 m, 1 H; 2.7 m, 1 H; 2.5 m, 1H; 1.6-1.3 m, 2H; 1.0 t, 3 H.

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

1.91 g of 1- (5-bromo-2-methoxy-benzyl) -propylamine, 0.3 g of tetrakis (triphenylphosphine) palladium, 2.61 g of 4-trifluoromethyl-phenylboronic acid, 2M Na ₂ CO A mixture of ₃ 24 ml and 25 ml of toluene was refluxed under argon for 7 hours. The aqueous phase was extracted with diethyl ether, then the organic phases were combined, dried over Na ₂ SO ₄ and concentrated to afford the title compound as a brown oil which was purified by eluting with 85: 15: 1 toluene / ethanol / conc. Ammonia on silica gel. ¹ H-NMR (360 MHz, CDCl ₃ ): 7.65 s, 4H; 7.5 dxd, 1 H; 7.4 d, 1 H; 7.0 d, 1 H; 3.9 s, 3 H; 3.1 m, 1 H; 2.9 dxd, 1 H; 2.6 dxd, 1 H; 1.6 m, 1 H; 1.4 m, 1 H; 1.1 t, 3 H.

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

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

Example 31: 1- [2- (4-methoxy-4'-trifluoromethyl-biphenyl-3-yl) -1-methyl-ethyl] -piperidine

A. 2- (5-Bromo-2-methoxy-phenyl) -1-methyl-ethylamine

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

B. 2- (4-methoxy-4'-trifluoromethyl-biphenyl-3-yl) -1-methyl-ethylamine-hydrochloride

7.62 g of 2- (5-bromo-2-methoxy-phenyl) -1-methyl-ethylamine, 0.71 g of tetrakis (triphenylphosphine) palladium, 7.98 g of 4-trifluoromethyl-phenylboronic acid, A mixture of 24 ml 2M Na ₂ CO ₃ , 40 ml toluene and 10 ml ethanol was refluxed under argon for 9 hours. After performing similarly to Example 30D, the crude oil was purified by conversion to hydrochloride salt to give in the form of a white plate. ¹ H-NMR (360 MHz, CDCl ₃ ): 7.90-7.75 dxd, 4H; 7.65 dxd, 1 H; 7.60 d, 1 H; 7.15 d, 1 H; 3.85 s, 3 H; 3.5 m, 1H; 3.1-2.8 m, 2H; 1.15 d, 3 H.

C. 4- [2- (4-methoxy-4'-trifluoromethyl-biphenyl-3-yl) -1-methyl-ethyl-carbamoyl] butyric acid

1.1 g of 2- (4-methoxy-4'-trifluoromethyl-biphenyl-3-yl) -1-methyl-ethylamine hydrochloride was liberated and glutaric anhydride in THF under reflux for 20 hours Reacted with 0.37 g. The solvent was evaporated and the residue dissolved in ethyl acetate. The organic phase was extracted with 1M HCl, water and brine, dried over Na ₂ SO ₄ and evaporated to afford the title compound as a white powder, melting point 88 ° C. (decomposition).

D. 1- [2- (4-Methoxy-4'-trifluoromethyl-biphenyl-3-yl) -1-methyl-ethyl] -piperidine-2,6-dione

A mixture of 1.02 g of carboxylic acid and 4.3 g of acetyl chloride obtained in C in 20 ml of chloroform was refluxed for 17 hours, cooled and extracted with water and 2M Na ₂ CO ₃ . The organic phase was dried over Na ₂ SO ₄ and then the solvent was evaporated and the residue was purified by eluting with 1: 2 ethyl acetate / cyclohexane on silica gel to give the title compound as a light yellow oil and solidified in the refrigerator. ¹ H-NMR (360 MHz, CDCl ₃ ): 7.6-7.5 m, 4H; 7.4 dxd, 1 H; 7.2 d, 1 H; 6.8 d, 1 H; 5.2 m, 1H; 3.8 s, 3 H; 3.2-3.0 m, 2H; 2.4-2.3 m, 4H; 1.5 br m about 2H (+ HCD); 1.35 d, 3 H.

E. 1- [2- (4-Methoxy-4′-trifluoromethyl-biphenyl-3-yl) -1-methyl-ethyl] -piperidine hydrochloride

To argon suspension of 0.054 g of LiAlH ₄ in 6 ml of diethyl ether under argon, 1- [2- (4-methoxy-4'-trifluoromethyl-biphenyl-3-yl) -1- in 2 ml of diethyl ether. A solution of 0.3 g of methyl-ethyl] -piperidine-2,6-dione was added dropwise under slight cooling. After stirring for 30 minutes 0.5 ml of 2M Na ₂ CO ₃ was added and the resulting mixture was filtered, the filtrate was acidified and extracted with 1M HCl. The aqueous phase was alkalized with concentrated ammonia and extracted with diethyl ether. The organic phase was dried over Na ₂ SO ₄ and concentrated and the residue was treated with a solution of HCl in diethyl ether to give the title compound as a colorless plate, melting point 185 ° C. (decomposition).

Example 32: N, N-diethyl- [2- (4-methoxy-4'-trifluoromethyl-biphenyl-3-yl) -1-methyl-ethyl] -amine

2- (4-methoxy-4'-trifluoromethyl-biphenyl-3-yl) -1-methyl-ethylamine (obtained as described in Example 31B) was diluted with 10% Pd / C in ethyl acetate. Obtained by acetaldehyde reductive alkylation on a bed. The melting point of the hydrochloride was 105-107 ° C.

Claims (10)

Compound of formula I in free base or acid addition salt form. <Formula I> Where R ₁ and R ₂ are independently hydrogen, (C _1-4 ) alkyl, (C _1-4 ) alkoxy, (C _1-4 ) alkylthio, halogen, trifluoromethyl, trifluoromethoxy, cyano or (C _2-5 ) alkanoyl, R ₃ is hydrogen, hydroxy, (C _1-4 ) alkyl, (C _1-4 ) alkoxy, (C _3-6 ) cycloalkyloxy, halogen, cyano, (C _2-5 ) alkanoyl, carba Moly, (C _1-4 ) alkylsulfonyloxy or trifluoromethylsulfonyloxy, R ₄ is hydrogen, hydroxy or (C _1-4 ) alkoxy, R ₅ is a chemical formula or Where is R ₆ is (C _1-4 ) alkyl, X is straight or branched chain alkylene having 1 to 4 carbon atoms, R ₇ and R ₈ are independently hydrogen, (C _1-4 ) alkyl, hydroxy (C _2-4 ) alkyl or phenyl (C _1-4 ) alkyl, or pyrrolidinyl together with the nitrogen atom to which they are attached , Piperidino, piperazinyl or morpholino groups or chemical formulas groups of (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 independently H, halogen, (C _{1- 4} ) alkyl or (C _1-4 ) alkoxy). The compound of formula (a), (b) or (c) according to claim ₁ , wherein R ₁ , R ₂ , R ₃ and R ₄ are as defined in claim 1 and R ₅ is as defined in claim 1. The compound of formula I in the form of a free base or acid addition salt. The free base or acid addition salt form of 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 formula (d) as defined in claim ₁ . Of compounds of formula (I). The method of claim 1, (+)-3- (4-methoxy-4'-trifluoromethyl-biphenyl-3-yl) -1-propyl-piperidine, (-)-3- (4-methoxy-4'-trifluoromethyl-biphenyl-3-yl) -1-propyl-piperidine, (-)-3- (4-methoxy-4'-trifluoromethyl-biphenyl-3-yl) -1-methyl-piperidine, (+)-3- (4-methoxy-4'-trifluoromethyl-biphenyl-3-yl) -1-methyl-piperidine, (1S ^* , 2S ^* , 6R ^* , 7R ^* )-4- [2- (4-methoxy-4'-trifluoromethyl-biphenyl-3-yl) -ethyl] -10-oxa-4- Aza-tricyclo [5.2.1.0 (2,6)] decane, (+)-[2- (4-methoxy-4'-trifluoromethyl-biphenyl-3-yl) -1-methyl-ethyl] -N, N-dimethyl-amine, Free base or acid addition selected from (-)-[2- (4-methoxy-4'-trifluoromethyl-biphenyl-3-yl) -1-methyl-ethyl] -N, N-dimethyl-amine Compound in salt form. A process for preparing a compound of formula I in free base form or in acid addition salt form by reacting a compound of formula II with a compound of formula III and recovering the resulting compound in free base form or in acid addition salt form. <Formula II> <Formula III> Wherein R ₁ to R ₅ are as defined in claim 1 and Y is halogen or trifluoromethyl sulfonate. 5. The compound according to claim 1, in the form of a free base or a pharmaceutically acceptable acid addition salt for use as a medicament. The compound according to any one of claims 1 to 4 in the form of a free base or pharmaceutically acceptable acid addition salt for use in the treatment of epilepsy, stroke and brain or spinal cord trauma. A pharmaceutical composition comprising the compound of any one of claims 1-4 in free base or pharmaceutically acceptable acid addition salt form together with a pharmaceutical carrier or diluent. Use of a compound of 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 or spinal cord trauma. A method of treating said disease comprising administering to a patient with epilepsy, stroke and brain or spinal cord trauma a therapeutically effective amount of a compound of any one of claims 1 to 4 in free base or pharmaceutically acceptable acid addition salt form. .