The subject of the invention constitutes new derivatives of N- [(phenoxy)ethoxy]alkylaminoalkanols, which according to the invention possess pharmacological activity, in particular in therapy and/or prophylaxis of disorders and symptoms with neurological etiology.

Among most frequent disorders of neurological system there are epilepsy and neuropathic pain. Epilepsy is defined as occurrence without identifiable cause recurrent epileptic seizures, while neuropathic pain is connected with abnormal function of neurons. Common pathomechanisms of those two disorders, i.e. pathological changes occurring within nervous system enable simultaneous development of drugs for those kind of disorders. Both epilepsy and neuropathic pain, despite available pharmacotherapy, remain insufficiently treated in significant groups of patients. It is estimated that about 30% of epilepsy patients still suffer from seizures, while among patients experiencing partial seizures (simple, complex, and secondarily generalized) the percentage is even higher and reaches 40%. Neuropathic pain is insufficiently treated in about 50% of patients. [Banerjee, P .N.; Filippi, D.; Allen Hauser, W. The descriptive epidemiology of epilepsy-a review. Epilepsy Res. 2009, 85, 31-45; Waszkielewicz A. M., Gunia A., Sloczynska K ., Marona H. : Evaluation of anticonvulsants for possible use in neuropathic pain. Curr Med Chem. 2011, 18, 4344-4358; Brodie, M.J. Management strategies for refractory localization-related seizures. Epilepsia 2001, 42 Suppl 3, 27-30],

Currently used antiepileptic drugs can be divided into following chemical groups: hydantoin derivatives, barbituric acid derivatives, 2,5-pyrrolidinedione derivatives, iminostilbene derivatives, 1,4- and 1,5-benzodiazepines derivatives, valproic acid derivatives, oxazolidinone derivatives, acetylurea derivatives, sulfonamide derivatives, GABA-analogues and other drugs with various structures.

Patent EP1809273 lists several various drugs available for the treatment of epileptic seizures. There are older drugs such as phenytoin (diphenylhydantoin), sodium valproate, and carbamazepine, as well as newer drugs such as felbamate (derivative of carbamic acid), gabapentin and pregabalin (derivatievs of carboxylic acid), topiramate, and tiagabin.

To that group of drugs belong also derivatives of alkanolamides and alkanolamines.

Alkanolamide derivatives of cinnamic acid were described in patent application PL401500.

Patent PL211939 describes buthylmethylaminoethyltiazophenols.

Patent US41 1851 1A describes aryloxyaminobutanols.

Aminoalkanols, for example l-isopropylamino-3-(naphtyloxy)-2-propanol [J. W. Black, et al., Lancet, 1, 1080 (1964)] acting as potent β-inhibitor, or alkyl ethers of 3-amino-l-phenoxy-2- propanol showing stimulating effect on central nervous system were described in [J W. Black, et al ., Lancet, 1, 1080 (1964)].

There are also known derivatives of 1,2-aminoalkanols [H. Marona, L. Antkiewicz-Michaluk, Acta Pol. Pharm., 1998, vol. 55, nr 6, str. 487-498] and derivatives of aryloxyacetamides and aryloxyethylamines [H. Marona, A.M. Waszkielewicz, E. Szneler, Acta Pol. Pharm., 2005, vol. Vol. 62, nr 5, str. 345-353].

Patent PL212489 describes phenoxyalkylaminoalkanols. Those compounds influence the stabilization of functional membrane potential of cells possessing their own electrical function, including nervous cells, what results in possessing potential activity in nervous system disorders.

It was unexpectedly shown, especially according to very beneficial results of in vivo pharmacological tests, that incorporating ether moiety between phenoxy and alkylaminoalkanol groups of phenoxyalkylaminoalkanols significantly improved the specificity of mechanism of action of the last. The derivatives obtained according to the invention of N- [(phenoxy)ethoxy]alkylaminoalkanols similary to phenoxyalkylaminoalkanols are characterized by beneficial pharmacological properties, especially in the treatment and/or prophylaxis of disorders and symptoms with neurological etiology, such as epilepsy and pain. They possess significantly more selective binding to sigma receptors when compared to other tested receptors. Such properties correlate with safer usage of the drugs in pharmacotherapy and decreased number of adverse effects.

The main subject of the solution presented within current invention constitutes N- [(phenoxy)ethoxy]alkylaminoalkanols with general structure 1.

In which Rl is

. 2,6-(CH ₃ ) ₂

. 2,3-(CH ₃ ) ₂

. 2,4-(CH ₃ ) ₂

. 2,4,6-(CH ₃ ) ₃

. 2-Cl, 6-CH ₃

And R2 is aminoalkanol selected from the following: (R,S)-2-aminopropan-l-ol; (R)-2- aminopropan-l-ol; (S)-2-aminopropan-l-ol; (R, S)-2-aminobutan- 1 -ol, (R)-2-aminobutan-l-ol, (S)- 2-aminobutan-l-ol, trans-(D,L)-2-aminocyclohexanol; trans-4-aminocyclohexanol; (R,S)-2-amino- 1-phenyloethanol; 4-hydroxypiperidine, and their accepted for usage in pharmacotherapy salts and pro-drugs. Compounds selected according to present invention are presented in Table 1 below.

Table 1.

Another solution according to the invention is also the usage of N- [(phenoxy)ethoxy]alkylaminoalkanols with general structure 1, in which Rl constitutes (CH ₃ ) ₂ , (CH ₃ ) ₃ , or CI and CH ₃ , and R2 constitutes aminoalkanol selected from the following: (R,S)-2- aminopropan-l-ol, (R)-2-aminopropan-l-ol, (S)-2-aminopropan-l-ol, (R, S)-2-aminobutan- 1 -ol, (R)-2-aminobutan-l-ol, (S)-2-aminobutan-l-ol, trans-(D,L)-2-aminocyclohexanol, trans-4- aminocyclohexanol, (R,S)-2-aminol-phenylethanol, 4-hydroxypiperidine, and their possible salts accepted for the usage in pharmacotherapy, for the preparation of drug used in the treatment and prophylaxis of disorders or symptoms with neurological etiology, especially epilepsy and/or pain.

Example 1. The detailed description of synthesis of intermediate products and subject compounds.

The reactions of synthesis of appropriate N-[(phenoxy)ethoxy]alkylaminoalkanols were carried out by means of N-alkylation of appropriate aminoalkanols by bromide of appropriate [(phenoxy)ethoxy]alkyl. Some compounds were characterized as hydrochlorides, and the solution of HC1 in ethanol was used for the conversion.

To obtain compounds as racemates, enantiomers or achiral structures commercially available reagents (phenols, aminoalkanols) were used, with the exception of trans-D,L-2- aminocyclohexanol, which was obtained by means of know methods.

Example 1.1. Synthesis of 2,6-dimethyl-; 2,3-dimethyl-; 2,4-dimethyl-; 2,4,6,-trimethyl-; 2- chlor-6-methyl- phenoxyethoxyethanol.

In the three-neck round-bottom flask of 750 mL there was prepared a reaction mixture containing 200 mL acetone, 0.6 mole anhydrous K2CO3, 0.5 mole 2-(2-chlorethoxy)ethanol and 0.2 mole of appropriate phenol: 2,6-dimethylphenol, 2,3-dimethylphenol, 2,4-dimethylphenol, 2,4,6- trimethylphenol, or 2-chlor-6-methylphenol. The mixture was being heated and refluxed for over a dozen hours, then the reaction mixture was filtered, and a filtrate was evaporated under reduced pressure to obtain oily residue, which was afterwards diluted with 200 mL of water and alkalified with 10% NaOH under the control of universal indicator paper. The product was extracted with toluene, the organic phase was washed with 5% NaOH, water and dried over anhydrous NaiSOzt. After evaporation of solvent the crude product was obtained, which was used in further reactions without purification.

Example 1.2. Synthesis of 2,6-dimethyl-; 2,3-dimethyl-; 2,4-dimethyl-; 2,4,6,-trimethyl-; 2- chlor-6-methyl- phenoxyethoxyethyl bromides.

In the round-bottom flask of 500 mL there were placed 0.15 mole of appropriate 2,6-dimethyl-; 2,3- dimethyl-; 2,4-dimethyl-; 2,4,6,-trimethyl-; or 2-chlor-6-methyl- [(phenoxy)ethoxy] ethanol and 0.75 mole PBr ₃ was added in small portions. The reagents were heated and refluxed in water bath for 1.5 hour. Then, the reagents were poured into a beaker with ice and neutralized with 15% of NaHC0 ₃ , then the mixture was extracted with toluene. After drying the organic layer over anhydrous Na ₂ S0 ₄ the solvent was evaporated, and oily residue was obtained.

Example 1.3. Synthesis of the subject compounds.

In the round-bottom flask of 250 mL there was placed 0.015 mole of appropriate 2,6-dimethyl-; 2,3- dimethyl-; 2,4-dimethyl-; 2,4,6,-trimethyl-; 2-chlor-6-methyl- [(phenoxy)ethoxy]ethyl bromide, 0.12 mole appropriate aminoalkanol, and 0.2 mole anhydrous K2CO ₃ . The mixture was being heated and refluxed in 50 mL of toluene for about 5 hours, then the reaction mixture was left to cool down, silica gel was added, and the mixture was again brought to boil. Then the reaction mixture was filtered, and filtrate was evaporated under reduced pressure to obtain oily residue, then 50 mL of water and 10% HC1 were added to obtain acidic pH under the control of universal indicator paper and activated charcoal was added afterwards. The mixture was refluxed for a while. Then the mixture was filtered, and the filtrate was alkalified with 10% NaOH to obtain crude base, which was afterwards extracted with toluene. Organic layer was dried over anhydrous Na ₂ S0 ₄ , and the organic solvent was evaporated to obtain oily residue, from which product was crystallized by means of «-hexane. Some compounds were converted into hydrochlorides using the ethanol solution of HC1. Hydrochlorides were crystallized with acetone.

Example 2. Physicochemical data of selected compounds according to the invention

For selected compounds according to the invention, using standard analytical technics, there were found parameters such as: melting point (M.p.), elemental analysis of carbon, nitrogen, and hydrogen content, ^: H NMR spectrum, specific rotation [a] for enantiomers. H- 16/ 10 - R,S-2-({2- [2-(2,6-Dimethylphenoxy)ethoxy] ethyl} mino)propan- l-ol

M.p =46-48°C; C _calc /C _f0 und 67.38/67.21; H _ca i _c /H _found 9.42/9.66; N _ca i _c /N _f0 und 5.24/5.12

¾NMR (CDC1 ₃ ): δ ppm 7.00 (d, J=7.4; 2H, Ar-H3), 6.92 (dd, J=8.1; J=6.2; IH, Ar-H4), 3.98-3.92 (m, 2H, Ar-0-CH ₂ ), 3.84-3.78 (m, 2H, A1--O-CH2-CH2), 3.74-3.67 (m, 2H, 0-CH ₂ -CH ₂ -NH), 3.61 (dd, J=10.5; J=3.7; IH, CHH-OH), 3.30 (dd, J=11.2; J=7.2; IH, CHH-OH), 3.06-2.96 (m, IH, O- CH ₂ -CHH-NH), 2.91-2.74 (m, IH, 0-CH ₂ -CHH-NH), 2.91-2.74 (m, IH, NH-CH), 2.41 (bs, 2H, OH, NH), 2 29 (s, 6H, Ar-CH ₃ ), 1.09 (d, J=6 7; 3H, CH-CH ₃ )

H-21/10 - R(-)-2-({2-[2-(2,6-Dimethylphenoxy)ethoxy]ethyl}amino)propan -l-ol

M.p =46-48°C; C _C aic/Cf ₀ und 67.38/67.31; H _calc /H _found 9.42/9.70; N _ca ic/Nf ₀ und 5.24/5.04

¾ NMR (CDCI ₃ ): δ ppm 7.00 (d, J=7.4; 2H, Ar-H3), 6.92 (dd, J=8.1; J=6.2; IH, Ar-H4), 3.98-3.92 (m, 2H, Ar-0-CH ₂ ), 3.84-3.78 (m, 2H, A1--O-CH2-CH2), 3.74-3.67 (m, 2H, 0-CH ₂ -CH ₂ -NH), 3.61 (dd, J=10.5; J=3.7; IH, CHH-OH), 3.30 (dd, J=11.2; J=7.2; IH, CHH-OH), 3.06-2.96 (m, IH, O- CH ₂ -CHH-NH), 2.91-2.74 (m, IH, 0-CH ₂ -CHH-NH), 2.91-2.74 (m, IH, NH-CH), 2.41 (bs, 2H, OH, NH), 2.29 (s, 6H, Ar-CH ₃ ), 1.09 (d, J=6.7; 3H, CH-CH ₃ ). [a _D ²⁰ ]= -13.250.

H-50/09 - R(-)-2-({2-[2-(2,6-Dimethylphenoxy)ethoxy]ethyl}amino)propan -l-ol hydrochloride

M.p =98-100°C; C _ca i _c /C _found 59.29/58.98; H _calc /H _found 8.63/8.68; N _ca i _c /N _found 4.53/4.59

¾ NMR (DMSO-d ₆ ): δ ppm 8.50 (bs, 2H, NH ₂ ⁺ ), 7.01-6.99 (m, 2H, Ar-H), 6.92-6.87 (m, IH, Ar- H), 5.36 (t, J=5.1; IH, OH); 3.89-3.86 (m, 2H, Ar-0-CH ₂ ), 3.79-3.74 (m, 4H, Ar-0-CH ₂ -CH ₂ -0- CH ₂ -CH ₂ -NH), 3.64-3.58 (m, IH, CHH-OH), 3.52-3.44 (m, IH, CHH-OH), 3.32-3.23 (m, IH, NH- CH), 3.14 (t, 2H, J=5.6; 0-CH ₂ -CH ₂ -NH), 2.20 (s, 6H, Ar-CH ₃ ), 1.70 (d, J=6.7; 3H, CH-CH ₃ ).

H-19/10 - S(+)-2-({2-[2-(2,6-Dimethylphenoxy)ethoxy]ethyl}amino)propan -l-ol

M.p =46-48°C; C _calc /C _found 67.38/67.23; H _ca i _c /H _found 9.42/9.75; N _ca i _c /N _found 5.24/4.99

¾ NMR (CDCI ₃ ): δ ppm 7.00 (d, J=7.4; 2H, Ar-H3), 6.92 (dd, J=8.1; J=6.2; IH, Ar-H4), 3.98-3.92 (m, 2H, Ar-0-CH ₂ ), 3.84-3.78 (m, 2H, Ar-0-CH ₂ -CH ₂ ), 3.74-3.67 (m, 2H, 0-CH ₂ -CH ₂ -NH), 3.61 (dd, J=10.5; J=3.7; IH, CHH-OH), 3.30 (dd, J=11.2; J=7.2; IH, CHH-OH), 3 06-2.96 (m, IH, O- CH ₂ -CHH-NH), 2.91-2.74 (m, IH, 0-CH ₂ -CHH-NH), 2.91-2.74 (m, IH, NH-CH), 2.41 (bs, 2H, OH, NH), 2.29 (s, 6H, Ar-CH ₃ ), 1.09 (d, J=6.7; 3H, CH-CHj). [a _D ²⁰ ]=13.067.

H-23/10 - S(+)-2-({2-[2-(2,6-Dimethylphenoxy)ethoxy]ethyl}amino)propan -l-ol hydrochloride

M.p =97-99°C; C _calc /C _found 59.29/59.34; H _ca i _c /H _found 8.63/8.80; N _ca i _c /N _found 4.53/4.60

XH NMR (DMSO-de): δ ppm 8.77 (bs, IH, NHH ⁺ ), 8.54 (bs, IH, NHH ), 7.00 (d, J=7.4; IH, Ar- H3), 6.89 (dd, J=8.5; J=6.5; IH, Ar-H4), 5.37 (t, J=5.3; IH, OH); 3.90-3.87 (m, 2H, Ar-0-CH ₂ ), 3.81-3.74 (m, 4H, Ar-0-CH ₂ -CH ₂ -0-CH ₂ -CH ₂ -NH), 3.63 (dt, J=11.8; J=4.3; IH, 0-CH ₂ -CHH- NH), 3.50 (dt, J=11.8; J=5.4; 0-CH ₂ -CHH-NH), 3.28 (bs, IH, NH-CH), 3.15 (bs, 2H, CH ₂ -OH), 2.21 (s, 6H, A1--CH3), 1.19 (d, J=6.7; 3H, CH-CH3).

H-22/10 - R,S-2-({2-[2-(2,6-Dimethylphenoxy)ethoxy]etylo}amino)butan-l -ol

M.p =48-50°C; C _calc /Cfound 68.29/68.40; H _ca i _c /H _found 9.67/10.07; N _ca i _c /Nf ₀ und 4.98/4.88

¾ NMR (CDCI ₃ ): δ ppm 7.00 (d, J=7.6; 2H, Ar-H3), 6.92 (dd, J=8.6; J=6.5; IH, Ar-H4), 3.96-3.92 (m, 2H, Ar-0-CH ₂ ), 3.86-3.81 (m, 2H, Ar-0-CH ₂ -CH ₂ ), 3.76 (t, J=4.9; 2H, 0-CH ₂ -CH ₂ -NH), 3.71 (dd, J=11.4; J=4.0; IH, CHH-OH), 3.43 (dd, J=l l. l; J=6.5; IH, CHH-OH), 3.05 (dt, J=12.0; J=5.5; IH, 0-CH ₂ -CHH-NH), 2.90 (dt, J=12.9; J=4.6; IH, 0-CH ₂ -CHH-NH), 2.76-2.66 (m, IH, NH-CH), 2.58 (bs, 2H, OH, NH), 2.29 (s, 6H, Ar-CH ₃ ), 1.64-1.45 (m, 2H, CH-CH ₂ -CH ₃ ), 0.95 (t, J=7.7; 3H, CH-CH ₂ -CH ₃ ) H-61/10 - R(-)-2-({2-[2-(2,6-Dimethylphenoxy)ethoxy]ethyl}amino)butan- l-ol

M.p =50-52°C; C _calc /C _f ound 68.29/68.14; H _ca i _c /H _found 9.67/9.66; N _ca i _c /N _f0 und 4.98/4.91

XH NMR (CDC1 ₃ ): δ ppm 7.05-6.97 (m, 2H, Ar-H3), 6.96-6.87 (m, IH, Ar-H4), 3.97-3.91 (m, 2H, A1--O-CH2), 3.83-3.77 (m, 2H, Ar-0-CH ₂ -CH2j, 3.72-3.64 (m, 2H, O-CH2-CH2-NH), 3.61 (dd, J=10.6; J=4.0; IH, CHH-OH), 3.29 (dd, J=10.8; J=6.4; IH, CHH-OH), 2.99-2.88 (m, IH, 0-CH ₂ - CHH-NH), 2.81-2.71 (m, IH, 0-CH ₂ -CHH-NH), 2.62-2.51 (m, IH, NH-CH), 2.29 (s, 6H, Ar-C¾), 1.56-1.36 (m, 2H, CH-CH2-CH3), 0.92 (t, J=7.4; 3H, CH-CH ₂ -CH ₂ ) [a _D ²⁰ ]= -11.719.

H-32/10 - S(+)-2-({2-[2-(2,6-Dimethylphenoxy)ethoksy]ethyl}amino)butan -l-ol

M.p =51-53°C; C _C aic/Cf ₀ und 68.29/67.83; H _calc /H _found 9.67/9.78; N _ca ic/Nf ₀ und 4.98/4.91

¾ NMR (CDCI ₃ ): δ ppm 7.00 (d, J=7.6; 2H, Ar-H3), 6.92 (dd, J=8.6; J=6.5; IH, Ar-H4), 3.96-3.92 (m, 2H, Ar-0-CH ₂ ), 3.86-3.81 (m, 2H, Ar-O-CHj-Cfb), 3.72 (t, J=4.9; 2H, 0-CH ₂ -CH ₂ -NH), 3.67 (dd, J=11.4; J=4.0; IH, CHH-OH), 3.37 (dd, J=1 1.2; J=6.7; IH, CHH-OH), 3.00 (m, IH, 0-CH ₂ - CHH-NH), 2.90 (dt, 7=12.5; 7=4.5; IH, 0-CH ₂ -CHH-NH), 2.76-2.66 (m, IH, NH-CH), 2.58 (bs, 2H, OH, NH), 2.29 (s, 6H, Ar-CH ₃ ), 1.64-1.45 (m, 2H, CH-CH2-CH ₃ ), 0.95 (t, 7=8.2; 3H, CH-CH ₂ -

H-58/10 - trans-(D,L)-2-({2-[2-(2,6-Dimethylphenoxy)ethoxy]ethyl}amino )cyclohexanol

M.p =47-49°C; C _calc /C _found 70.32/70.98; H _ca i _c /H _found 9.51/9.53; N _ca i _c /N _found 4.56/4.51

XH NMR (CDCI3): 7.01-6.89 (m, 3H, Ar-H), 3.95-3.92 (m, 2H, Ar-0-CH ₂ ), 3.81-3.79 (m, 2H, Ar- O-CH2-CH2), 3.69-3.66 (m, 2H, CH2-CH2-NH), 3.18-3.12 (m, IH, CH-OH), 3.12-3.03 (m, IH, CHH-NH), 2.72-2.65 (m, IH, 0-CH ₂ -CHH-NH), 2.29 (s, 6H, Ar-CH ₃ ), 2.27-2.19 (m, IH, NH), 2.11-2.02 (m, 2H, cyclohex.), 1.74-1.69 (m, 2H, cyclohex), 1.24-1.29 (m, 4H, cyclohex).

H-66/10 - (R,S)-2-({2-[2-(2,6-Dimethylphenoxy)ethoxy]ethyl}amino)-l-ph enylethanol

M.p =110-112°C; C _ca i _c /C _foiind 72.92/72.52; H _ca i _c /H _found 8.26/8.07; N _ca i _c /N _foiind 4.25/4.21.

XH NMR (CDCI ₃ ): δ ppm 7.40-7.25 (m, 5H, Ar-H), 7.03-6.89 (m, 3H, Ar-H), 4.70 (dd, 7=9.2; 7=3.6; IH, Ar-CH-OH), 3.97-3.92 (m, 2H, Ar-0-CH ₂ ), 3 82-3.78 (m, 2H, Ar-O-CHz-CTb), 3.86 (t, 7=4.9; 2H, CH2-CH2-NH), 2.98-2.87 (m, 3H, NH-CHH-CH-Ar + CH ₂ -CH NH), 2.72 (dd, 7=12.3; 7=9.2; IH, NH-CHH-CH-Ar), 2.28 (s, 6H, Ar-CH ₃ ).

H- 101/10 - l-{2-[2-(2,6-Dimethylphenoxy)ethoxy]ethyl}-4-hydroxypiperidy ne

M.p =51-53°C; C _calc /C _found 69.59/69.41; H _ca i _c /H _found 9.28/9.23; N _ca i _c /N _found 4.77/4.75

XH NMR (CDCI ₃ ): δ ppm 7.02-6.97 (m, 2H, Ar-H3), 6.94-6.88 (m, IH, Ar-H4), 3.96-3.89 (m, 2H, Ar-0-CH ₂ ), 3.81-3.76 (m, 2H, Ar-O-CHz-CHj), 3.70 (t, 7=5.7; CHH-CH ₂ -NH), 3.72-3.68 (m, IH, CH-OH), 2.91-2.79 (m, 2H, N-CH ₂ (pip)), 2.64 (t, 2H, 7=5.7; CH2-CH2-NH), 2.28 (s, 6H, Ar-CH ₃ ), 2.27-2.17 (m, 2H, N-CH ₂ (pip)), 1.96-1.84 (m, 2H, CH ₂ (pip)), 1.69-1.53 (m, 2H, CH ₂ (pip)).

H-l 11/10 - R,S-2-({2-[2-(2-Chloro-6-methylphenoxy)ethoxy] ethyl} amino)butan-l-ol

M.p =34-36°C; C _calc /C _found 59.69/59.61; H _ca i _c /H _found 8.02/8.21; N _ca i _c /N _found 4.64/4.57

XH NMR (CDC1 ₃ ): δ ppm 7.22-6.90 (m, 3H, Ar-H), 4.14-4.08 (m, 2H, Ar-0-CH ₂ ), 3.86-3.80 (m, 2H, Ar-0-CH ₂ -CH2), 3.70-3.58 (m, 3H, CH ₂ -CH ₂ -NH + CHH-OH), 3.35-3.25 (m, IH, CHH-OH), 2.98-2.88 (m, IH, CH ₂ -CHH-NH), 2.80-2.70 (m, IH, CH ₂ -CHH-NH), 2.60-2.52 (m, IH, NH-CH), 2.33 (s, 3H, Ar-CH ₃ ), 1.55-1.35 (m, 2H, CH CH ₃ ), 0.90 (t, 7=7.4; 3H, CH2-CH ₃ ).

H-86/10 - R(-)-2-({2-[2-(2-Chloro-6-methylphenoxy)ethoxy]ethyl}amino)b utan-l-ol

M.p =40-42°C; C _cal 7C _found 59.69/59.57; H _ca i _c /H _found 8.02/8.08; N _ca i _c /N _found 4.64/4.59 ^X H NMR (CDCI ₃ ): δ ppm 7.20 (d, J=7.9; IH, Ar-H), 7.07 (d, J=7.9; IH, Ar-H), 6.94 (t, J=7.9; IH, Ar-H4), 4.10 (t, J=4.6; 2H, Ar-0-CH ₂ ), 3.88-3.80 (m, 2H, Ar-0-CH ₂ -CH ₂ ), 3.70-3.65 (m, 2H, CH ₂ - CH ₂ -NH), 3.60 (dd, 7=12.0; 7=4.1; IH, CHH-OH), 3.30 (dd, 7=10.5; 7=6.4; IH, CHH-OH), 2.98- 2.88 (m, IH, CH ₂ -CHH-NH), 2.80-2.72 (m, IH, CH ₂ -CHH-NH), 2.60-2.52 (m, IH, NH-CH), 2.33 (s, 3H, Ar-CH ₃ ), 1.58-1.35 (m, 2H, CH ₂ -CH ₃ ), 0.92 (t, 7=7.4; 3H, CH ₂ -CH ₃ ). [a _D ²⁰ ]= -5.728.

H-33/10 - S-(+)-2-({2-[2-(2-Chloro-6-methylphenoxy)ethoxy]ethyl}amino) butan-l-ol

M.p =40-42°C; C _calc /C _found 59.69/59.34; H _ca i _c /H _found 8.02/8.21; N _ca i _c /N _found 4.64/4.47

XH NMR (CDCI ₃ ): δ ppm 7.20 (d, 7=8.2; IH, Ar-H), 7.07 (d, 7=7.5; IH, Ar-H), 6.95 (t, 7=7.5; IH, Ar-H4), 4.13-4.07 (m, 2H, Ar-0-CH ₂ ), 3.89-3.84 (m, 2H, Ar-0-CH ₂ -CH ₂ ), 3.78 (t, 7=5.2; 2H, CH ₂ - CH ₂ -NH), 3.72 (dd, 7=11.3; 7=3.7; IH, CHH-OH), 3.45 (dd, 7=11.3; 7=6.1; IH, CHH-OH), 3.06 (dt, 7=12.5; 7=5.7; IH, CH ₂ -CHH-NH), 2.92 (dd, 7=12.5; 7=4.7; IH, CH ₂ -CHH-NH), 2.78-2.69 (m, IH, NH-CH), 2.54 (bs, 2H, NH, OH), 2.33 (s, 3H, Ar-CH ₃ ), 1.58-1.35 (m, 2H, CH ₂ -CH ₃ ), 0.92 (t, 7=7.4; 3H, CH ₂ -CH ₃ ).

H-78/ 10 - R,S-2-({2- [2-(2-Chloro-6-methylphenoxy)ethoxy] ethyl}amino)-4-hydroxypiperidine

M.p =52-54°C, C _C ai7Cfound 61.24/61.25; H _calc /H _found 7.71/7.68; N _ca ic Nf ₀ un _d 4.46/4.43

XH NMR (CDCI ₃ ): δ ppm 7.22-6.82 (m, 3H, Ar-H), 4.08 (t, 7=4.6; 2H, Ar-0-CH ₂ ), 3.82 (t, 7=4.6; 2H, Ar-0-CH ₂ -CH ₂ ), 3.75 (t, 7=5.8; 2H, 0-CH CH ₂ -N + bs, IH, CH-OH), 2.90-2.86 (m, 2H, pip ), 2.69 (t, 7=5.8; 2H, 0-CH ₂ -CH N), 2.34-2.32 (m, 2H, pip.), 2.32 (s, 3H, Ar-CH ₃ ), 1.98-1.93 (m, 2H, pip ), 1.72-1.61 (m, 2H, pip ).

H-79/10 - R,S-2-({2-[2-(2-Chloro-6-methylphenoxy)ethoxy]ethyl}amino)-l -phenylethanol

T=100-102°C; C _ca ic/Cf ₀ und 65.23/65.06; H _calc /Hf _0U n _d 6.91/6.83; N _ca i _c /Nf ₀ und 4.00/4.00

'H NMR (DMSO-d ₆ ): δ ppm 7.35-7.32 (m, 2H, Ar-H), 7.31-7.29 (m, 2H, Ar-H), 7.28-7.26 (m, IH, Ar-H), 7.23-7.19 (m, IH, Ar-H), 7.19-7.16 (m, IH, Ar-H), 7.03 (dd, 7=7.8; 7=7.6; IH, Ar-H), 5.23 (d, 7 =4.4, IH, OH), 4.62-4.58 (m, IH, Ar-CH-OH ), 4.00 (t, 7=4.8; 2H, Ar-0-CH ₂ ), 3.70 (t, 7=4.8; 2H, Ar-0-CH ₂ -CH ₂ ), 3 53 (t, 7=5 5; 2H, CH CH ₂ -NH), 2.71 (t, 7=5.5; 2H, CH NH), 2.68-2.61 (m, IH, NH-CHH-CH-Ar), 2.26 (s, 3H, Ar-CH ₃ ), 1.78 (bs, 2H, NH).

H-59/ 10 - R,S-2-({2- [2-(2,4,6-Trimethylphenoxy)ethoxy] ethyl} amino)propan- l-ol

M.p =53-55°C; C _calc /C _found 68.29/68.29; H _ca i _c /H _found 9.67/9.61; N _ca i _c /N _found 4.98/4.86

^ NMR CDCls): δ ppm 6.81 (s, 2H, Ar-H), 3.97-3.86 (m, 2H, Ar-0-CH ₂ ), 3.83-3.75 (m, 2H, Ar- O-CH ₂ -CH ₂ ), 3.72-3.63 (m, 2H, O-CH -CH ₂ -NH), 3.58 (dd, 7=10.5; 7=4.1; IH, CHH-OH), 3.25 (dd, 7=10.6; 7=6.8; IH, CHH-OH), 3.05-2.89 (m, IH, 0-CH ₂ -CHH-NH), 2.86-2.68 (m, 2H, 0-CH ₂ - CHH-NH + CH-CH ₂ -OH), 2.25 (s, 6H, Ar-CH ₃ ), 2.23 (s, 3H, Ar-CH ₃ ), 1.05 (d, 7=6.7; 3H, CH- CH ₃ ).

H-l 16/10 - trans-D,L-2-({2-[2-(2,4,6-Trimethylphenoxy)ethoxy]ethyl}amin o)cyclohexanol

M.p =54-56°C; C _calc /C _found 70.93/70.90; H _ca i _c /H _found 9.72/9.53; N _ca i _c /N _found 4.36/4.35

¾ NMR (CDC1 ₃ ): 6.81 (s, 2H, Ar-H), 3.94-3.87 (m, 2H, Ar-0-CH ₂ ), 3.81-3.75 (m, 2H, Ar-0-CH ₂ - CH ₂ ), 3.70-3.62 (m, 2H, O-CH ₂ -CH ₂ -NH), 3.44 (bs, IH, NH), 3.23-3 11 (m, IH, CH-OH), 3.11- 3.00 (m, IH, O-CH ₂ -CHH-NH), 2.67 (dt, 7=12.2; 7=4.6; IH, 0-CH ₂ -CHH-NH), 2.25 (s, 6H, Ar- CH ₃ ), 2.23 (s, 3H, Ar-CH ₃ ), 2.22-2.16 (m, IH, CH-NH), 2.12-1.98 (m, 2H, cyclohex ), 1.77-1.66 (m, 2H, cyclohex.), 1.35-1.17 (m, 3H, cyclohex.), 1.06-0 91 (m, IH, cyclohex.)

H-30/11 - R,S-2-({2-[2-(2,3-Dimethylphenoxy)ethoxy]ethyl}amino)propan- l-ol

M.p =50-52°C; C _calc /C _fo und 67.38/67.42; H _calc /H _found 9.42/9.36; N _ca i _c /N _fou nd 5.24/5.11 ^X H NMR (CDCI ₃ ): δ ppm 7.04 (t, J=7.7; 1H, Ar-H5), 6.78 (d, J=7.4; 1H, Ar-H4), 6.72 (d, 7=8.2, 1H, Ar-H6), 4.11 (d, J=4.6; 2H, Ar-0-CH ₂ ), 3.87-3.82 (m, 2H, Ar-0-CH ₂ -CH ₂ ), 3.72-3.65 (m, 2H, O-CH ₂ -CH ₂ -NH), 3.58 (dd, J=10.5; J=4.1; 1H, CHH-OH), 3.22 (dd, J=10.5; J=6.7; 1H, CHH-OH), 2.99-2.90 (m, 1H, 0-CH ₂ -CHH-NH), 2.82-2.68 (m, 2H, 0-CH ₂ -CHH-NH + NH-CH), 2.27 (s, 3H, A1--CH ₃ ), 2.16 (s, 3H, Ar-C¾), 1.05 (d, J=6.7; 3H, CH-CH ₃ ).

H-52/12 - trans-D,L-2-({2-[2-(2,3-Dimethylphenoxy)ethoxy]ethyl}amino)c yclohexanol

M.p =84-85°C; C _ca ic/Cfoun _d 70.32/69.94; H _ca i _c /H _found 9.51/9.79; N _ca ic Nfound 4.56/4.55

XH NMR (CDCI ₃ ): δ ppm 7.03 (t, 7=7.8; 1H, Ar-H5), 6.78 (d, 7=7.4; 1H, Ar-H4), 6.71 (d, 7=8 2, 1H, Ar-H6), 4.12-4.09 (m, 2H, Ar-0-CH ₂ ), 3.85-3.81 (m, 2H, Ar-O-CTt-CEb), 3.69-3.65 (m, 2H, 0-CH ₂ -CH ₂ -NH), 3.40 (bs, 1H, OH), 3.18- 3.10 (m, 1H, CH-OH), 3.07-2.99 (m, 1H, 0-CH ₂ -CHH- NH), 2.68-2.61 (m, 1H, 0-CH ₂ -CHH-NH), 2.67 (s, 3H, Ar-CH ₃ ), 2.23-2.17 (m, 1H, CH-NH), 2.16 (s, 3H, A1--CH ₃ ), 2.08-2.00 (m, 2H, cyclohex.), 1.72-1.69 (m, 2H, cyclohex.), 1.34-1.18 (m, 3H, cyclohex.), 1.02-0.94 (m, 1H, cyclohex.)

H-78/12 - trans-4-({2-[2-(2,3-Dimethylphenoxy)ethoxy]ethyl}amino)cyclo hexanol

M.p =68-70°C; C _calc /C _found 70.32/70.69; H _ca i _c /H _found 9.50/9.12; N _ca i _c /N _found 4.56/4.33

XH NMR (DMSO-d ₆ ): δ ppm 7.07 (dd, J=8.1; J=7.5; 1H, Ar-H5), 6.78 (d, J=8.1; 1H, Ar-H6), 6.75 (d, J=7.5; 1H, Ar-H4), 4.43 (bs, 1H, -OH), 4.04 (ddd, J=6.2; 7=4.7; J=3.2; 2H, Ar-0-CH ₂ ), 3.71 (ddd, J=6.2; J=4.7; J=3.2; 2H, Ar-0-CH ₂ -CH ₂ ), 3.51 (t, J=5.7; 2H, 0-CH CH ₂ -NH), 3.36- 3.30 (m, 1H, CH-OH), 2.66 (t, J=5.7; 2H, 0-CH ₂ -CH ₂ -NH), 2.29 (tt, J=10.6; J=3.5; 1H, CH-NH), 2.20 (s, 3H, A1--CH3), 2.07 (s, 3H, Ar-CH ₃ ), 1.80-1.73 (m, 4H, cyclohex.), 1.40 (bs, 1H, -NH), 1.16-1.07 (m, 2H, cyclohex.), 1.01-0.92 (m, 2H, cyclohex.).

H-79/12 - l-{2-[2-(2,3-Dimethylphenoxy)ethoxy]ethyl}-4-hydroxypiperidi ne hydrochloride

M.p =138-140°C; Cc _a ic Cf _0ll nd 61.90/61.58; H _ca i _c /H _foimd 8.55/8.29; N _ca i _c /Nf _0ll nd 4.25/4.21

XH NMR (DMSO-de): δ ppm 10.67 (bs, 1H, NH ⁺ ), 7.00 (dd, J=8.2; J=7.4; 1H, Ar-H5), 6.78 (d, J=8.2; 1H, Ar-H6), 6.75 (d, J=7.4; 1H, Ar-H4), 4.79 (bs, 1H, OH); 4.10 (ddd, J=6.1; J=4.7; J=3.3 ; 2H, Ar-0-CH ₂ ), 3.91 (t, J=5.2; 2H, 0-CH ₂ -CH ₂ -NH), 3.88 (bs, 1H, CH-OH), 3.80 (ddd, 7=6.1; 7=4.7; 7=3.3; 2H, Ar-0-CH ₂ -CH ₂ -), 3.65 (bs, 2H, N-CH ₂ (pip)), 3.41 (bs, 2H, N-CH ₂ (pip)), 1.98 (bs, 2H, CH ₂ (pip)), 1.74 (bs, 2H, CH ₂ (pip)), 3.22 (t, 7=5.2; 2H, 0-CH ₂ -CH ₂ -NH), 2.21 (s, 3H, Ar-CH ₃ ),

H-89/12 - R,S-2-({2-[2-(2,4-Dimethylphenoxy)ethoxy]ethyl}amino)propan- l-ol

M.p =46-48°C; C _calc /C _f0U n _d 67.38/66.92; H _ca i _c /H _found 9.42/9.42; N _ca i _c /N _f0U n _d 5.24/5.05

^X H NMR (CDCI ₃ ): δ ppm 6.95-6.71 (m, 3H, Ar-H), 4.12-4.08 (m, 2H, Ar-0-CH ₂ ), 3.85-3.80 (m,

2H, Ar-0-CH ₂ -CH ₂ ), 3.70-3.65 (m, 2H, 0-CH ₂ -CH ₂ -NH), 3.58 (dd, 7=10.5; 7=4.1; 1H, CHH-OH),

3.25 (dd, 7=10.6; 7=6.9; 1H, CHH-OH), 3.00-2.90 (m, 1H, 0-CH ₂ -CHH-NH), 2.85-2.68 (m, 2H, O-

CH ₂ -CHH-NH + CH-CH2-OH), 2.25 (s, 3H, Ar-CH ₃ ), 2.20 (s, 3H, Ar-CH ₃ ), 1.05 (d, 7=6.4; 3H,

CH-CH ₃ ).

Evaluation of pharmacological activity of compounds according to the invention was performed at National Institutes of Health in Rockville, USA within Antiepileptic Drug Development (ADD) Program. Pharmacological tests were performed according to published procedures, which previously served for identification of biological activity of currently used antiepileptic and/or analgesic drugs. The research were conducted to provoke in tested animals some states corresponding with clinical symptoms observed in humans in the course of neurological disorders such as epilepsy or pain. For example, maximal electroshock (MES) test described below conducted in rodents corresponds with tonic-clonic seizures in epilepsy in humans. Activity in the chemical test of subcutaneous pentetrazole (scMet) forecasts the activity of the compound in absence seizures in humans. 6-Hz test belongs to the animal models of resistant seizures, and activity shown in that test is considered as good predictor for efficacy in psychomotor and focal seizures in humans. The activity on 6-Hz test means moreover possible activity in inhibition of so called epileptogenesis, which is development of epilepsy as a disorder. Activity in pilocarpine test corresponds with prevention of status epilepticus. Activity in formalin test corresponds with inhibition of pain with neurogenic etiology (first phase) and/or pain with inflammatory etiology (second phase) [Bialer, M; White, H. S. Key factors in the discovery and development of new antiepileptic drugs. Nature Rev Drug Discov. 2010,9, 68-82; Loscher, W. Critical review of current animal models of seizures and epilepsy used in the discovery and development of new antiepileptic drugs. Seizure 201 1, 20, 359-368].

Screening tests

In the subject invention the first phase of evaluation of activity constituted screening in MES and scMet tests. Additionally evaluation of neurotoxicity was conducted in order to establish possible adverse effects from nervous system caused by tested substances. The tests were performed in Carworth Farms 1 mice (intraperitoneal administration, i.p.) and Spague-Dawley rats (oral administration, p.o. and intraperitoneal administration, i.p)

[http://www.ninds.nih.gov/research/asp/testdesc.htm; White, H. S.; Woodhead, J. H.; Wilcox, K. S.; Stables, J. P.; Kupferberg, H. J.; Wolf, H. H. D. Discovery and preclinical development of antiepileptic drugs. W: Antiepileptic Drugs Fifih Edition; Levy, R. H.; Mattson, R. H.; Mel drum, B. S.; Perucca, E., Eds.; Lippincott Williams & Wilkins: Philadelphia, 2002; p. 36-48].

Neurotoxicity evaluation

In mice the test of rotating rod (rotorod test) was performed. In the test the knurled plastic rod rotating 6 times per minute was used. In normal conditions mice are able to remain on rod for long time. If the animal is not able to remain on the rod in every of 3 trials of 1 minute duration it is assumed that the substance caused neurotoxicity.

In rats the neurotoxicity was scored according to observations of the behaviour. As symptoms of neurotoxicity there are considered among others impaired movement ability ('zig-zag', circle), ataxia, abnormal placement of limb and abnormal posture, tremors, hyperactivity, somnolence, stupor, loss of cognitive activity, catalepsy [http://www.ninds.nih.gov/research/asp/testdesc.htm; White, H. S.; Woodhead, J. H.; Wilcox, K. S.; Stables, J. P.; Kupferberg, H. J.; Wolf, H. H. D. Discovery and preclinical development of antiepileptic drugs. W: Antiepileptic Drugs Fifih Edition; Levy, R. H.; Mattson, R. H.; Meldrum, B. S.; Perucca, E., Eds.; Lippincott Williams & Wilkins: Philadelphia, 2002; p. 36-48].

Maximal electroshock test (MES)

In the MES test for provoking the seizures electric current was used at 60 Hz and 50 mA (in mice) or 150 mA (in rats) and delivered for 0.2 s via corneal electrodes. The compound is classified as active when it protects from occurring of characteristic hindlimb extension. It is generally accepted that MES test enables verification of anticonvulsant activity in tonic-clonic generalized seizures [http://www.ninds.nih.gov/research/asp/testdesc.htm; White, H. S.; Woodhead, J. H.; Wilcox, K. S.; Stables, J. P.; Kupferberg, H. J.; Wolf, H. H. D. Discovery and preclinical development of antiepileptic drugs. W: Antiepileptic Drugs Fifth Edition; Levy, R. H.; Mattson, R. H.; Mel drum, B. S.; Perucca, E., Eds.; Lippincott Williams & Wilkins: Philadelphia, 2002; p. 36-48].

Pentetrazole test (scMet)

In the test for provoking the seizures subcutaneously administered pentetrazole was used at the dose of 85 mg/kg (mice) or 70 mg/kg (rats). The tested animal is placed in separate cage and observed for 30 min. The activity of the compound is scored according to absence of occurring of even a single episode of seizures [http://www.ninds.nih.gov/research/asp/testdesc.htm; White, H. S.; Woodhead, J. H.; Wilcox, K. S.; Stables, J. P.; Kupferberg, H. J.; Wolf, H. H. D. Discovery and preclinical development of antiepileptic drugs. W: Antiepileptic Drugs Fifth Edition; Levy, R. H.; Mattson, R. H.; Meldrum, B. S.; Perucca, E., Eds.; Lippincott Williams & Wilkins: Philadelphia, 2002; p. 36-48].

6-Hz test

6-Hz test is conducted in mice. For the provoking the seizures electric current at frequency of 6 Hz and 22, 32, or 44 mA delivered for 3 s via corneal electrodes is used. Protection is defined as remaining the normal activity for 10 s after stimulation [http://www.ninds.nih.gov/research/asp/testdesc.htm; White, H. S.; Woodhead, J. H.; Wilcox, K. S.; Stables, J. P.; Kupferberg, H. J.; Wolf, H. H. D. Discovery and preclinical development of antiepileptic drugs. W: Antiepileptic Drugs Fifth Edition; Levy, R. H.; Mattson, R. H.; Meldrum, B. S.; Perucca, E , Eds.; Lippincott Williams & Wilkins: Philadelphia, 2002; p. 36-48],

Formalin test

Formalin test is conducted in mice. The test covers the administration of formalin to hindlimb of the animal, what causes the licking of the place of administration. The total time of licking is considered as corresponding to the intensity of pain sensation experienced by the animal. It is characteristic, that there are two phases of the test. The first phase (acute) is about 10 minutes long and corresponds to the direct stimulation of peripheral sensor and pain neurons The second phase (inflammatory) develops as the response of liberation of inflammatory mediators from impaired tissues and nerves' endings. The activity in that phase corresponds with beneficial effect in neuropathic pain. Simultaneously control tests are performed which involve administration to other animals solvent alone (e.g. methylcellulose). The shortening of the time of hindlimb licking is scored as analgesic activity [http://www.ninds.nih.gov/research/asp/testdesc.htm; White, H. S.; Woodhead, J. H.; Wilcox, K. S.; Stables, J. P.; Kupferberg, H. J.; Wolf, H. H. D. Discovery and preclinical development of antiepileptic drugs. W: Antiepileptic Drugs Fifth Edition; Levy, R. H.; Mattson, R. H.; Meldrum, B. S.; Perucca, E., Eds.; Lippincott Williams & Wilkins: Philadelphia, 2002; p. 36-48; Capone, F ; Aloisi, A. M. Refinement of pain evaluation techniques. The formalin test. Annali dell'Istituto Superiore di Sanitd 2004, 40, 223-229] .

The results of performed testes are presented in tables below.

Results of activity in MES and scMet tests and neurotoxicity evaluation conducted in mice after intraperitoneal administration of the tested compounds. Table 2.

)Number of animals protected/numer of animals tested in MES or scMet displaying signs of neurotoxicity/numer of animals tested in rotarod test;„-"- the compound was not tested incertain conditions; the number in parentheses indicates the number of observed deaths

Results of activity in MES and scMet tests as well as in neurotoxicity assessment in rats after oral administration of tested compounds

Table 3.

Compound's Dose Activity ³ '

Test

symbol [mg/kg] 0.25 h 0.5 h l .O h 2.0 h 4.0 h

MES 30 0/4 0/4 0/4 0/4 0/4

H-19/10

TOX 30 0/4 0/4 0/4 0/4 0/4

MES 30 0/4 0/4 0/4 0/4 0/4

H-23/10

TOX 30 0/4 0/4 0/4 0/4 0/4

MES 30 0/4 0/4 1/4 0/4 0/4

H-58/10

TOX 30 0/4 0/4 0/4 0/4 0/4

MES 30 0/4 0/4 0/4 0/4 0/4

H-32/10

TOX 30 0/4 0/4 0/4 0/4 0/4

MES 30 0/4 0/4 1/4 0/4 0/4

H-86/10

TOX 30 0/4 0/4 0/4 0/4 0/4

Screening tests in rats after intraperitoneal administration Table 4.

Compound' s Dose Activity ³ '

Test

symbol [mg/kg] 0.25 h 0.5 h l .O h 2.0 h 4.0 h

MES 30 4/4 4/4 3/4 0/4 0/4

H-19/10

TOX 30 0/4 0/4 0/4 0/4 0/4

MES 30 4/4 4/4 3/4 0/4 0/4

H-23/10

TOX 30 0/4 0/4 0/4 0/4 0/4 Results of quantitative evaluation

Table 5.

The ED50 and TD50 values obtained in tests in mice after intraperitoneal administration of tested compounds

Results of screening in 6-Hz test after intraperitoneal administration of the tested compounds

Table 6.

Results of formalin test for compound H-50/09

Table 7

Dose Area Under Curve (AUC)

Test phase

[mg/kg] Control H-50/09 % of Control S E.M P Value

13.0 Acute 237.47 130.39 54.9 11.52 < 0,05

13.0 Inf amatory 819.6 665.07 81.14 10.43 > 0,05