WO1999041229A1

WO1999041229A1 - Halogenated phenyl alcohol amides (ligands of gabab receptor) having an anticonvulsant activity

Info

Publication number: WO1999041229A1
Application number: PCT/MX1999/000004
Authority: WO
Inventors: Guillermo Carvajal Sandoval; Sergio Enrique Meza Toledo
Original assignee: Guillermo Carvajal Sandoval; Sergio Enrique Meza Toledo
Priority date: 1998-02-11
Filing date: 1999-02-11
Publication date: 1999-08-19

Abstract

New anticonvulsant compounds have been synthesized with a chlorine or fluorine atom in the position para of the phenyl ring. These compounds include DL-2-hydroxy-2-(4'-chlorophenyl)butyramide, DL-2-hydroxy-2-(4'-fluorophenyl)butyramide, DL-3-hydroxy-3-(4'-chlorophenyl)pentanamide, DL-3-hydroxy-3-(4'-fluorophenyl)pentanamide, DL-4-hydroxy-4-(4'-chlorophenyl)hexanamide and DL-4-hydroxy-4-(4'-fluorophenyl)hexanamide. Said compounds have a rather significant anticonvulsant activity against convulsions produced by pentylene tetrazol, as well as unexpected properties in particular a high affinity to the GABAB receptor in addition to a sustained anticonvulsant activity. The invention also relates to methods for the synthesis of halogenated phenyl alcohol amides such as indicated in the examples given in the disclosure.

Description

one

PHENYL ALCOHOL HALOGENATED AMIDAS (GABAB RECEIVER LIGANDS) THAT PRESENT ANTI-CONVULSIONING ACTIVITY

TECHNICAL FIELD

The present invention relates to novel ligands of the GABA _B receptor (γ-aminobutytic acid), particularly hydroxyamides, which exhibit anticonvulsant activity, and methods for the preparation of such compounds.

BACKGROUND OF THE INVENTION Compounds (±) -4-hιdroxι-4-fenιlhexanamιda (DL-HEPB), (±) -3-hιdroxι-3- phenylpentanamide (DL-HEPP) and (±) -2-hιdroxι-2- fenιlbutιramιda (DL-HEPA), have a broad spectrum of anticonvulsant activity They protect mice against seizures caused by pentylenotetrazol bicuculin, 4-amιnopιrιdιna, thiosemicarbazide and maximum electric shock See Carvajal y cois, Biochem Pharma 13 (1964), Pérez-de-la-Mora and cois, Biochem Pharmacol 22, 2635 (1973) and Meza-Toledo and cois, Arzneim Forsch 40 (II), 1289 (1990) Both DL-HEPB and DL-HEPP they also protect cats and rats against hippocampal kindling See Solis and cois, Neurobiology, International Symposium, pp 83-94, (1979) and Solís and cois, Arch Neurocien (Mex) 1, 99 (1996) In addition, the DL-HEPP protects rats against γ-aminobutmco acid withdrawal syndrome (GABA), this is a model of focal epilepsy, which has shown a extraordinary resistance to classical antiepileptics See Brailowsky and cois, Epilepsy Res 11, 167 (1992) DL-HEPP also produces a significant decrease in focal discharges in the congenital model of epilepsy type absences in the Strasbourg rat (GAERS), this one It is a model of generalized non-convulsive epilepsy, in which antagonists towards GABA _B receptors have anticonvulsant activity See Brailowsky and cois, cited above, Liu, and cois, Neurosa 48, 87 (1992), Marescaux and cois, Pharmacol Commun 2 , 57 (1992) and Froestl and cois, J Med Chem 38, 3313 (1995) In the search for new compounds with a high anticonvulsant activity, a new sene of halogenated hydroxyamides was synthesized, which presented a high affinity towards the GABA receptor _{B in} addition to a fairly significant anticonvulsant activity DETAILED DESCRIPTION Compounds with a chlorine or fluorine atom were synthesized at the para position of the phenyl ring of a homologous series of phenyl alcohol amides. The prepared compounds are named as DL-2-hιdroxι-2- (4'-chlorophenyl) butιramιda (DL - CI-HEPA, 1), DL-2-hιdroxι-2- (4'-fluorofenιl) butιramιda (DL-F-HEPA, 2), DL-3- hιdroxι-3- (4 ^' -chlorophenιl) pentanamιda (DL -CI-HEPP, 3), DL-3-hιdroxι-3- (4'-fluoro-fen ⁱ l) pentanamide (DL-F-HEPP, 4), DL-4-hιdroxι-4- (4'-chlorophenιl ) hexanamιda (DL-CI-HEPB, 5), and DL-4-hιdroxι-4- (4'-fluorophenιl) hexanamide (DL-F-HEPB _, 6) The compounds mentioned showed unexpected differences in anticonvulsant activity with respect to non-halogenated compounds The pentylenetetrazole test was used to evaluate the anticonvulsant activity of each compound. As can be seen in Table 1, compounds 1, 3 and 5 had an unusually high anticonvulsant activity, being greater than two to three times with respect to the activity that the non-halogenated compounds exhibited. In Example 4 at the bottom, it was observed that compounds 2, 4 and 6 also presented unexpected differences in the duration of their anticonvulsant activity, with respect to the activity of the non-halogenated compounds As can be seen in Table 2, at times 4 h after 6 hours, compounds 2, 4 and 6 showed an anticonvulsant activity two to three times higher with respect to the activity of the non-halogenated compounds The foregoing was particularly unexpected based on the nature of those compounds, and demonstrates that there are substantial unexpected differences in the activity of the aforementioned compounds Based on the protective effect of the compounds of the invention against seizures produced by pentylenetetrazole, can be expected to be effective in the treatment of epilepsy type absences the phenyl alcohol amides, the inhibition of the specific binding of R- [ ³ H] -baclofen to GABA _B receptors in crude synaptic membranes of rat brain was evaluated. As observed in Table 1, the phenyl alcohol amides showed a high affinity towards the GABA _B receptor Compounds 1 and 3 were as potent as GABA and R-baclofen and were the most potent of the compounds evaluated. DL-HEPA compounds, 3

DL-HEPP and DL-HEPB were as potent as DL-baclofen. Compounds 2, 4 and 6 were less active than DL-2-hιdroxιsaclofen. Compound 5 was the least active of all the studied senes. A linear relationship was found. between the pKi values, in mol / 1, and the pDE ₅₀ values, in mol kg ^"1 for the anticonvulsant activity of the DL-HEPA DL-HEPP, DL-HEPB amides and for compounds 1 and 3 The equation obtained pKi = 4 55 + 0 72 pDE ₅₀ , r ² = 0 92 For compounds 2, 4, 5 and 6, no relationship was observed between pKi values and pDE ₅₀ values for anticonvulsant activity Additionally, the R-baciophen (a GABA _B receptor agonist) very efficiently antagonized the anticonvulsant activity of DL-HEPP and compound 3 (Fig 5) The above results, as well as the protective activity of DL-HEPP in the GAERS epilepsy model , support the notion that some of the phenyl alcohol anticonvulsant amides they are antagonists of the GABA _B receptor See Liu, and cois, Neurosa 48, 87 (1992), Marescaux and cois, Pharmacol Commun 2, 57 (1992) and Brailowsky, and cois, cited above To date, only a number have been synthesized reduced antagonists towards GABA _B receptors that penetrate the blood brain barrier, therefore its therapeutic potential has not been fully evaluated The main known antagonists towards GABA _B receptors have in their structure the main GABA chain which is linked to hydrophobic substituents Additionally , some of them contain isostéπcas substitutions of the GABA carboxylate group with phosphate, phosphoπlos or sulfate groups that are bound to hydrophobic substituents See Kerr and cois, Med Res Rev 12, 593 (1992), Bowery, Ann Rev Pharmacol Toxicol 33, 109 ( 1993) and Froestl and cois, J Med Chem 38, 3313 (1995) The compounds of this invention are not structurally related to the main known antagonists towards the GABA _B receptors, and consequently they represent a new family of antagonists towards the GABA _B receptors which possess anticonvulsant activity in vivo by the foregoing, the compounds of the invention possess a novel mechanism of action that explains their anticonvulsant activity

In the following examples, the melting points were determined in an Electrothermal apparatus and are not corrected. Infrared spectra were obtained. 4

on a Perkin Elmer 1310 spectrometer. The hydrogen nuclear magnetic resonance spectra were performed on a Vahan EM 360-L spectrometer. Chemical shift values are indicated in δ (ppm); CDCI ₃ and DMSO-dβ were used as solvents and TMS as internal standard.

5 The elemental analyzes were performed by the Galbraith, Inc. laboratories of Knoxville, TN (USA) and the differences obtained with respect to the theoretical values were ± 0.5%, with the exception of some indicated values.

EXAMPLE 1 Preparation of DL-2-hydroxy-2- (4'-chlorophenyl) butyramide, DL-CI-HEPA (1) 0 Compound 1 was obtained by condensation between 4'-chloropropyrophenone and cyanide. sodium in acidic medium (Fig. 1). Caution: Hydrogen cyanide is released! To a stirred mixture containing: 4'-chloropropyrophenone (22.61 g, 0.1342 moles), sodium cyanide (16.4 g, 0.3347 moles), ethyl ether (80 mL) and water (100 mL), HCI was added to the

15 37% (28 mi, 0.34 moles). The temperature was maintained between 2 and 5 ° C during the addition which required 2 h. Subsequently, stirring was continued for an additional 5 h at a temperature of 10 to 15 ° C. Then, the ether phase was separated and water (20 ml) was added to dissolve the salts. Then, the aqueous solution was extracted with 3 50 ml portions of ether. Extracts

20 combined ethers were concentrated under reduced pressure of 20-30 mm Hg. The residual oil was cooled, 37% HCI (32 ml) was added and it was saturated at 5-10 ° C with HCI (g), kept at room temperature for 18 h, a precipitate appearing. The excess HCI was removed by flowing air through the solution. The precipitate was filtered and recrystallized with benzene.

25 obtaining 15.1 g (52.7%) of 1, mp 122-123 ° C; ¹ H NMR (CDCI ^ DMSO-de) δ: 0.9 (t, 3H, -CH ₃ ), 2.1 (m, 2H, -CH ₂ -), 5.4 (s, 1 H, -OH), 6.6 (bs , 1 H, -NH-), 7.1 (bs, 1H, -NH-), 7.3 (d, 2H, H phenyl), 7.6 (d, 2H, H phenyl); IR (KBr): 3470, 3280, 1661 cm Anal. (Cι ₀ Hι ₂ NO ₂ CI): C, H, N, O, Cl.

EXAMPLE 2

Preparation ³⁰ DL-2-hydroxy-2- (4'-fluorophenyl) butyramide, DL-F-HEPA (2) Compound 2 was obtained by condensation between the 4'- fluoropropiophenone and sodium cyanide in acid medium (Fig. 1). 5

Caution: Hydrogen cyanide is released! To a stirred mixture containing: 4'-fluoropropyrophenone (101.84 g, 0.67 mol), sodium cyanide (82 g, 1.67 mol), ethyl ether (80 ml) and water (100 ml), 37% HCI ( 140 mi, 1.7 moles). The temperature was maintained between 2 and 5 ° C during the addition which required 2.5 h. Subsequently, stirring was continued for an additional 5 h at a temperature of 10 to 15 ° C. Then, the ether phase was separated and water (100 ml) was added to dissolve the salts. Then, the aqueous solution was extracted with 4 50 ml portions of ether. The combined ether extracts were concentrated under reduced pressure of 20-30 mm Hg. The residual oil was cooled, 37% HCi (160 ml) was added and it was saturated at 5-10 ° C with HCI _(g) , keeping at room temperature for 18 h, a precipitate appearing. The excess HCI was removed by flowing air through the solution. The precipitate was filtered and recrystallized with benzene to obtain 66.2 g (50.2%) of 2, mp 109-110 ° C; 1 H NMR (CDCIs / DMSO-de) δ: 0.9 (t, 3H, -CH ₃ ), 2.1 (q, 2H, -CHr), 5.2 (s, 1H, -OH), 6.2 (bs, 1H, - NH-), 6.9- 7.3 (bs, 1 H, -NH-), 6.9-7.3 (m, 2H, H phenyl), 7.5-7.9 (m, 2H, H phenyl); IR (KBr): 3350, 3160, 1650 cm ^"1. Anal. (C10H12NO2F): C, H, N, O, F.

EXAMPLE 3 Preparation of DL-3-hydroxy-3- (4'-cloiOfenH) pentanamide, DL-CI-HEPP (3) Compound 3 was prepared by condensation between ethyl bromoacetate and 4 ^, -chloropropyrophenone, in presence of zinc, forming hydroxy ester 3a, which when treated with ammonium hydroxide led to amide 3 (Fig. 2). A. Preparation of ethyl DL-3-hydroxy-3- (4'-chlorophenyl) pentanoate (Za) To a stirred solution containing: 4'-chloropropyrophenone (50.55 g, 0.3 mol), ethyl bromoacetate (34.3 g, 0.206 mol), benzene (40 ml) and ethyl ether (10 ml), activated zinc (20.92 g, 0.32 mol) was added over a period of 1.5 h and refluxed for 5 h. The reaction mixture was hydrolyzed with 10% H ₂ SO ₄ (200 mL) and the organic layer was washed successively with: 5% H ₂ SO ₄ (100 mL), 10% Na ₂ CO ₃ (25 mL) , H ₂ SO ₄ at 5% (25 mi) and water (50 mi). The organic layer was separated and the combined acid solutions were extracted with two 50 ml portions of ethyl ether each. The ether extracts and the initially separated organic layer were combined, dried over MgSO ₄ , 6

filtered and concentrated. The residue was fractionally distilled under reduced pressure to obtain 51.2 g (96.9%) of 3a, e.g. 164-165 ° C / 18 mm Hg; 1 H NMR (CDCI ₃ ) δ: 0.8 (t, 3H, -CH ₃ ), 1.2 (q, 3H, -COO-CH ₂ CH ₃ ), 1.8 (q, 2H, - CH ₂ Me), 3.0 (m , 2H, -CH ₂ -), 4.1 (q, 2H, -COOCH ₂ Me), 4.4. (s, 1 H, -OH), 7 4 (d,

5H, phenyl H), 7.9 (d, 1H, phenyl H); IR (CHCI ₃ ) 3465, 1708 crn ^"1. B. Preparation of DL-3-Hydroxy-3- (4'-chlorophenyl) pentanamide (3) A mixture containing: compound 4a (49 g, 0.191 mol), ethanol (200 ml) and 28% ammonium hydroxide (200 ml) was cooled to 0 ° C and saturated with gaseous ammonia, the flask was covered with a rubber stopper and held at

10 room temperature for 27 days. Then, the reaction mixture was cooled, solid NaCl (15 g) was added and extracted with four 150 ml portions of ethyl ether. The combined ether extracts were dried with Na ₂ SO ₄ , filtered and concentrated to dryness. The obtained residue was washed with n-hexane and recrystallized with water to obtain 19.2 g (44.2%) of 3, mp 99-

15 100 ° C; ¹ H NMR (CDCI3) δ: 0.8 (t, 3H, -CH ₃ ), 1.7 (q, 4H, -CH ₂ Me), 2.7 (s, 2H, - CH ₂ -CO-), 4.3 (s, 1 H, -OH), 5.9 (bs, 2H, -NH ₂ ), 7.2 (s, 4H, H phenyl); IR (KBr): 3440, 3140, 1661 cm ^{~ 1} . Anal. (CnH ₁₄ NO ₂ CI): C, H, N, O, Cl.

EXAMPLE 4 Preparation of DL-3-hydroxy-3- (4'-fluorophenyl) pentanamide, DL-F-HEPP (4) 0 Compound 4 was prepared by condensation between sodium acetonitrile and 4'-fluoropropiophene, forming nitrile 4a, which when treated with hydrogen peroxide in alkaline medium produced 4 (Fig. 3). A. Preparation of DL-3-Hydroxy-3- (4'-fluorophenyl) pentanonitrile (a) To a stirred mixture containing sodamide (23.4 g, 0.6 mol) in liquid ammonia (200 ml) (prepared from sodium (13.8 g, 0.6 mol)), a solution of acetonitrile (24.6 g, 0.6 mol) dissolved in tetrahydrofuran (600 ml) was added over a period of 20 min and stirring was continued for an additional 35 min. Subsequently, 4'-fluoropropyrophenone (91.2 g, 0.6 mol) solubilized in tetrahydrofuran (600 ml) was added and stirred for 20 min.

Then the reaction mixture was poured into a suspension of ammonium chloride (80 g) in liquid ammonia (200 ml). The ammonia was allowed to evaporate and the solid residue was treated with 3N HCI (400 mL) and extracted with two portions of 150 ml of tetrahydrofuran each. Then, the combined organic extracts were dried and concentrated. The residue was recrystallized with hexane to obtain 69.5 g (60%) of -4a, mp 76-77 ° C; ¹ H NMR (CDCI ₃ ) δ: 0.8 (t, 3H, -CH ₃ ), 2.0 (q, 2H, -CH ₂ Me), 2.6 (s, 1 H, -CH ₂ CN), 2.8 (s, 1 H, -OH), 6.9-7.2 (m,

5H, phenyl H), 7.2-7.4 (m, 2H, phenyl H); IR (KBr) 3410, 2240 cm ^"1. B. Preparation of DL-3-Hydroxy-3- (4'-fluorOphenyl) pentanamide (4) Compound 4a (57.9 g, 0.3 mol), 18.1% hydrogen peroxide (315 ml, 1,669 moles), absolute ethanol (150 ml) and 6N NaOH (15 ml), mixed thoroughly and stirred for 10 h keeping the temperature between

10 40-50 ° C. The reaction mixture was then neutralized with 5% H ₂ SO ₄ and extracted with four 50 ml portions of ethyl ether each. The combined ether extracts were concentrated to dryness and the residue was recrystallized with benzene to obtain 49.1 g (77.6%) of 4, mp 86-87 ° C; ¹ H NMR (CDCI ₃ ) δ: 0.8 (t, 3H, -CH ₃ ), 1.8 (q, 4H, -CH ₂ Me), 2.7 (s, 2H, -CH ₂ -CO-), 5.0 (s , 1 H, -OH),

5.7 (bs, 1H, -NH-), 6.9-7.2 (bs, 1H, -NH-), 6.9-7.6 (m, 4H, H phenyl); IR (KBr): 3340, 3160, 1645 cm ^"1. Anal. (CnH ₁₄ NO ₂ F): C, H, N, O, F.

EXAMPLE 5 Preparation of DL-4-hydroxy-4- (4'-chlorophenyl) hexanamide, DL-CI-HEPB (5) Compound 5 be prepared? by a condensation between the 4'-

Chloropropyrophenone and diethyl succinate, in the presence of sodium hydride, followed by cyclization under acidic conditions to produce DL-5-ethyl-5- (4'-chlorophenyl) butyrolactone (5a). The treatment of this with ammonia under pressure produced 5 (Fig. 4). A. Preparation of DL-5-ethyl ~ 5- (4'-chlorophenyl) butyrolactone (5a)

To a solution containing: 4'-chloropropyrophenone (25.27 g, 0.15 mol), benzene (150 ml), diethyl succinate (78.3 g, 0.45 mol), under a nitrogen atmosphere, sodium hydride (10.8 g, 0.45 mol) and absolute ethanol (2.2 mi). The reaction mixture was stirred for 2.5 h in an ice bath. After it was acidified with acetic acid (42 ml), it was diluted with water (70 ml)

30 and extracted with four 50 ml portions of ethyl ether each. The organic phase was separated and the aqueous solution was extracted with 4 50 ml portions of ethyl ether. The combined organic phases were washed with a solution of Na ₂ CO ₃ at 5%. The alkaline solution was acidified with 98% H ₂ SO ₄ and extracted with two 50 ml portions of ethyl ether each. The ethereal fraction of the acid phase was combined with that extracted from the alkaline phase, dried over anhydrous Na ₂ SO ₄ , filtered and evaporated to dryness. The oily residue obtained (42 g), is mainly composed of condensation products. This oily product, glacial acetic acid (120 ml), 48% HBr (80 ml) and water (40 ml), were refluxed for 26 h. Then, the reaction mixture was concentrated under reduced pressure, diluted with water (100 π) and extracted with 4 portions of 50 ml of ethyl ether each. The combined organic phases were washed with a 5% NaHCO ₃ solution and the ether phase was stored. The alkaline phase was acidified with 98% H ₂ SO and extracted with two 50 ml portions of ethyl ether each. The combined organic phases were concentrated and the obtained residue was treated again with HBr as previously mentioned. The ether fraction of this second treatment was combined with the ether solution initially separated from the original reaction. These were washed with a saturated aqueous solution of NaCl, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was fractionally distilled under reduced pressure to obtain 21.5 g (63.9 ^' %) ^' of 5a, e.g. 192-193 ° C / 15 mm Hg; NMR-1H (CDCJ ₃ ) δ: 0.8 (t, 3H, -CH ₃ ), 1.9 (q, 2H, -CH ₂ Me), 2.5 (m, 4H, -CH ₂ -CH2-), 7.3 ( _Sι 4H , H phenyl); IR (CHCI3): 1765 cm ^'1 .

B. Preparation of DL-4-hydroxy-4- (4'-cloiOphenyl) hexanamide (5) A mixture of 5a (20 g, 0.0891 mol) and liquid ammonia (100 ml), was heated in a Parr pump at 100 -105 ° C (68 at) for 2 h. The excess ammonia was removed and the solid residue was recrystallized with water to obtain 7.0 g (32.5%) of 5, mp 106-107 ° C; ¹ H NMR (CDC / DMSO-dβ) δ: 0.8 (t, 3H, -CH ₃ ), 1.9 (q, 2H, -CH ₂ Me), 2.1 (s, 4H, -CH2-CH2-), 4.9 (s, 1H, -OH), 6.1 (bs, 1 H, -NH-), 6.7 (bs, 1H, -NH-), 7.4 (s, 4H, H phenyl); IR (KBr). 3320, 3150, 1675 cm ^"1. Anal. (C ₁₂ Hι ₆ NO ₂ CI): C, H, N, Cl (calculated 13.24%, found 13.93%).

EXAMPLE 6 Preparation of DL-4-hydroxy-4- (4'-fluorophenyl) hexanamide, DL-F-HEPB (6) Compound 6. Was prepared by condensation between 4-fluoropropyrophenone and diethyl succinate, in presence of sodium hydride, followed by cyclization under acidic conditions to produce DL-5-ethyl-5- Y

(4'-fluorophenyl) butyrolactone (6a). The treatment of this with ammonia under pressure produced 6 (Fig. 4).

A. Preparation of DL-5-ethyl-5- (4'-fluorophenyl) butyrolactone (6a)

To a solution containing: 4'-fluoropropyrophenone (15.2 g, 0.1 mol), benzene (100 ml), diethyl succinate (52.2 g, 0.3 mol), under a nitrogen atmosphere, sodium hydride (7.2 g) was added , 0.3 moles) and absolute ethanol (1.5 mi). The reaction mixture was stirred for 2.5 h in an ice bath. It was then acidified with acetic acid (21 ml), diluted with water (50 ml) and extracted with four 50 ml portions of ethyl ether each. The organic phase was separated and the aqueous solution was extracted with 4 50 ml portions of ethyl ether. The combined organic phases were washed with a 5% Na ₂ CO ₃ solution. The alkaline solution was acidified with 98% H ₂ SO ₄ and extracted with two 50 ml portions of ethyl ether each. The ethereal fraction of the acid phase was combined with that extracted from the alkaline phase, dried over anhydrous Na ₂ SO ₄ , filtered and evaporated to dryness. The oily residue obtained (23.2 g), is mainly composed of condensation products. This oily product, glacial acetic acid (80 ml), 48% HBr (53 ml) and water (27 ml), were refluxed for 26 h. Then, the reaction mixture was concentrated under reduced pressure, diluted with water (100 ml) and extracted with 4 portions of 50 ml of ethyl ether each. The combined organic phases were washed with a 5% NaHCO ₃ solution and the ether phase was stored. The alkaline phase was acidified with 98% H ₂ SO ₄ and extracted with two 50 ml portions of ethyl ether each. The combined organic phases were concentrated and the obtained residue was treated again with HBr as previously mentioned. The ether fraction of this second treatment was combined with the ether solution initially separated from the original reaction. These were washed with saturated aqueous NaCl, dried over Na SO-t _Σ anhydrous, filtered and concentrated. The residue was fractionally distilled under reduced pressure to obtain 16.5 g (79.3%) of 6a, e.g. 164-165 ° C / 7 mm Hg; ¹ H NMR (CDCI ₃ ) δ: 0.8 (t, 3H, - CH ₃ ), 2.0 (q, 2H, -CH ₂ Me), 2.5 (s, 4H, -CH ₂ -CH ₂ -), 6.9- 7.5 (m, 4H, H phenyl); IR (CHCI ₃ ): 1760 cm ^"1. B. Preparation of DL-4-hydrox 4- (4'-fluorophenyl) hexanamide (S) A mixture of 6a (104 g, 0.5 mol) and liquid ammonia (200 ml) was heated in a Parr pump at 100-105 ° C (68 atm) for 2 h. Excess ammonia was removed and the solid residue was recrystallized with water to obtain 73 _. 9 g (65.7%) of 6, mp 97-98 ° C; 1H-NMR (CDC / DMSO-de) _δ:. 0.8 (t, ^"3H, -CH _3), September 1 (m, 6H, -CH ₂ Me and -CH ₂ -CH ₂ -), 5.0 (s, 1H, -OH), 6.8 (bs, 1H, -NH-), July 7-7 (bs, 1H, -NH-), 7-7.7 (m, 4H, _phenyl). IR (KBr) : 3310, 3150, 1660 cm ^"1 . Anal. (C ₁₂ H ₁₆ NO ₂ F): C, H, N, F.

EXAMPLE 7 Anticonvulsant activity A. General methods

Male albino mice of strain CD-1 (National Institute of Virology, Mexico City), weighing 18 to 25 g, were used, which were placed in cages in groups of 20. The mice were kept at room temperature (20- 24 ° C), with water and croquettes (Blue Bonnet brand) ad libitum, with a 12-h light-dark cycle (the light was turned on at 6.00 am). Compounds 2, 4, 6, DL-HEPA, DL-HEPP and DL-HEPB, were dissolved in water, while compounds 1, 3 and 5 were dissolved in a solution of polyethylene glycol 400 at 30% in water. The route of administration of all the compounds was intraperitoneal (ip). The dose of pentylenetetrazole that produced seizures and death was determined in 100% of the mice (CD100) and this was used in the evaluations performed. The CD100 value obtained for pentylenetetrazole was 100 mg kg ^"1. For each compound, the optimal anticonvulsant activity time was evaluated before determining dose-response curves. For the latter, pentylenetetrazole was administered via ip, 100 mg kg ^"1 , to 5 groups of 10-20 mice that had previously received the compounds, and the suppression of clonic seizures and death was considered the end point of the evaluation. The vehicle was inactive in all the tests performed. The ED50 and 95% confidence intervals were calculated by the Litchfield and Wilcoxon method (Table 1). See Litchfield et al., J. Pharmacol. Exp. Ther. 96, 99 (1949). Table 1

COMPOUND OFso mg kg ^"1 ) Ki ± SEM ^b) PTZ ^a) μmol / l

DL-CI-HEPA, 1 16 (12-20) ° '0 030 ± 0 001

DL-F-HEPA, 2 49 (43-56) 15 38 1 1 742

DL-HEPA 61 (55-68) 0 075 ± 0 010

DL-CI-HEPP, 3 20 (19-22) 0 031 ± 0 007

DL-F-HEPP, 4 43 (34-54) 7 297 1 0 730

DL-HEPP 54 (48-61) 0 082 1 0 005

DL-CI-HEPB, 5 26 (23-31) 20 92 1 2 351

DL-F-HEPB, 6 46 (41-51) 7 578 1 1 758

DL-HEPB 56 (51-61) 0 099 1 0 020

GABA - 0 045 1 0 007

R-Baclofen - 0 070 1 0 009

DL-Baclofen - 0 124 1 0 015

DL-2-Hιdroxι-saclofen - 2 814 1 0 546 a) Attacks caused by pentylenetetrazol (PTZ) in mice b) Inhibition constants 1 standard errors of the means c) 95% confidence intervals β Duration of anticonvulsant activity

Groups of 15 to 30 mice were administered compounds 2, 4, 6, DL-HEPA, DL-HEPP and DL-HEPB (100 mg kg ^"1 ip) and protection against seizures and death was evaluated at different times caused by pentylenetetrazole, at a dose of 100 mg kg ^"1 ip Table 2

% Protection * ⁰

Compound 0 5 h 1 h 2 h 3 h 4 h 6 h

DL-HEPA 93 + 7 65 + 7 67111 50 + 0 35 + 7 25 + 7

DL-F-HEPA, 2 100 + 0 10010 9111 9616 9010 70114

DL-HEPP 95 + 6 88 910 60 111 5517 40114 b)

DL-F-HEPP, 4 100 + 0 b) 7814 71 + 2 7517 b)

DL-HEPB 95 ± 7 7010 40 + 14 33 ± 9 25 + 7 15 + 7

DL-F-HEPB, 6 10010 100 + 0 7517 81.8 + 0 4517 50 + 14

a) Average 1 SD b) Not evaluated

C Antagonism of R-baclofen hydrochloride on the anticonvulsant activity of compound 3 and DL-HEPP

Three groups of 10 peaks were administered separately either compound 3 (25 mg kg ^"1 ip) or DL-HEPP (100 mg kg ^{" 1} ip), and then each group was injected with R hydrochloride -baclofen at different doses (5-25 mg kg ^"1 ip) The protection against seizures and death caused by pentylenetetrazole (100 mg kg ¹ ip) was evaluated at 30 min (Fig 5) 12

Three control groups of 10 mice were administered separately either hydrochloride R-baclofen (25 mg kg ^"1 ip), the DL-HEPP (100 mg ^{kg" 1} _i. P.) Or compound 3 (25 mg kg ^"1 ip), and after 30 min, the protection against seizures and death caused by pentiienotetrazole (100 mg kg ^{" 1} ip) was evaluated (Fig. 5). In the pharmacological evaluations carried out, R-baclofen hydrochloride did not show anticonvulsant activity, at a dose of 25 mg kg ^"1 , against seizures and death caused by pentylenetetrazole. Mortality was determined in three control groups of 10 mice to which they were administered separately the combinations of either DL-HEPP (100 mg kg ^"1 ip) or compound 3 (25 mg kg ^{" 1} ip), with R-baclof-ence hydrochloride (25 mg Kg ^"1 ip) No death was observed in the control groups of mice, to which the combinations of R-baclofen hydrochloride with compound 3 or with DL-HEPP were administered.

EXAMPLE 8 Binding experiments with R-fHJ-baclofen

A. General methods

Male Wistar rats (CINVESTAV-IPN, Mexico D. F), weighing 120 to 180 g, were used, which were placed in cages in groups of 20. The rats were kept at room temperature (20-24 ° C), with water and croquettes (Purina Chow brand) ad libitum, with a 12-h light-dark cycle (the light was turned on at 7.00 a.m.). Both the phenyl alcohol amides and the standard compounds used in the assay were dissolved in a solution of Tris-HCI 50 mmol / l-CaCfe 2.5 mmol / l, pH 7.4. β. Inhibition by phenyl alcohol amides of the specific binding of R-fbi] - baclofen, to GABAB receptors, from rat brain synaptic membranes

Raw synaptic membranes were prepared from rat brain and binding experiments were performed in triplicate according to essentially the previously published method. See Bowery et al., Br. J. Pharmacol. 78, 191 (1983). The concentration of each compound that reduced 50% of the specific binding of R- [ ³ H] -baclofen (IC ₅₀ ) was determined. The results of the data of either 2 or 3 independent experiments performed in triplicate were analyzed. IC ₅₀ values were obtained at from the displacement curves using a non-linear regression analysis See PRISMA program, version 1 0, Graph Pad Software Inc, San Diego, CA (USA _/ ¹ Possibly, the JC50 values were used to calculate the inhibition constants (Ki ) (Table 1) See Cheng et al Biochem Pharmacol 22, 3099 (1973) and Bowery et al, cited both

Since the patent law in Mexico does not allow patenting the use of new compounds with pharmacological activity, the use of phenyl alcohol amides as anticonvulsants is included in the claims of the present patent application. It is understood that the foregoing description preferably exemplifies most important of the invention, and that the invention is not limited to the specific forms shown. For example, various derivatives of the illustrated compounds can be made by the methods described. These and other modifications can be made from the invention without departing from the sphere of application thereof, as expressed in the appended claims

Claims

1 DL-2-hιdroxι-2- (4'-chlorophenιl) butιramιda

2 DL-2-hιdroxι-2- (4'-fluorophenιl) butιramιda

3 DL-3-hιdroxι-3- (4'-chlorophenιl) pentanamιda 5 4 DL-3-hιdroxι-3- (4'-fluorofenιl) pentanamιda

5 DL-4-hιdroxι-4- (4'-chlorophenιl) hexanamιda

6 DL-4-hιdroxι-4- (4'-fluorophenιl) hexanamιda

7 A method for inhibiting seizures in a subject, which comprises administering to a subject an effective amount of DL-2-hιdroxι-2- (4 -

10 chlorophenyl) butιramιda of claim 1

A method of inhibiting seizures in a subject, which comprises administering to a subject an effective amount of the DL-2-hιdroxι-2- (4-fluorophenyl) butιramιda of claim 2

A method for inhibiting seizures in a subject, which comprises administering to a subject an effective amount of the DL-3-hydroxy-3- (4'-chlorophenyl) pentanamide of claim 3

A method of inhibiting seizures in a subject, which comprises administering to a subject an effective amount of the DL-3-hydroxy-3- (4-fluorophenol) pentanamide of claim 4

A method for inhibiting seizures in a subject, which comprises administering to a subject an effective amount of the DL-4-hydroxy-4- (4'-chlorophenyl) hexanamide of claim 5

12 A method for inhibiting seizures in a subject, which comprises administering to a subject an effective amount of DL-4-hιdroxι-4- (4'-

25 fluorophenyl) hexanamide of claim 6

13 A homologous phenyl alcohol amides that bind to the GABA _B receptor

14 A compound known as DL-2-hιdroxι-2-fenιlbutιramιda that binds to the GABA _B receptor

15 A compound known as DL-3-hιdroxι-3-fenιlpentanamιda that binds 30 to the GABA _B receptor

16 A compound known as DL-4-hιdroxι-4-fenιlhexanamιda that binds to the GABA _B receptor fifteen

17. A compound known as DL-2-hydroxy-2- (4'-chlorophenyl) butyramide of claim 1 that binds to the GABA _B receptor.

18. A compound known as DL-2-hydroxy-2- (4'-fluorophenyl) butyramide of claim 2 that binds to the GABA _B receptor.

19. A compound known as DL-3-hydroxy-3- (4'-chlorophenyl) pentanamide of claim 3 that binds to the GABA _B receptor.

20. A compound known as DL-3-hydroxy-3- (4'-fluorophenyl) pentanamide of claim 4 that binds to the GABA _B receptor.

21. A compound known as DL-4-hydroxy-4- (4'-chlorophenyl) hexanamide of claim 5 that binds to the GABA _B receptor.

22. A compound known as DL-4-hydroxy-4- (4'-fluorophenyl) hexanamide of claim 6 that binds to the GABA _B receptor.

23. A method for the synthesis of DL-2-hydroxy-2- (4'-chloro or 4'-fluoro phenyl) butyramides which comprises:

A) Reaction between 4'-fluo ^' ropropiophenone or 4'-chloropropyrophenone with a cyanide salt under acidic conditions to form a nitrile; and B) transforming the nitrile -CN group into a -NH ₂ group to form the DL-2-hydroxy-2- (4'-chloro or 4'-fluoro phenyl) butyramides. 25. A method for the synthesis of DL-3-hydroxy-3- (4'-fluorophenyl) pentanamide which comprises:

A) Reaction between 4'-fluoropropyrophenone with sodium acetonitrile to obtain DL-3-hydroxy-3- (4'-fluorophenyl) pentanonitrile; Y

B) transform the -CN group of the mentioned pentanonitrile into a -NH ₂ group to form the DL-3-hydroxy-3- (4'-fluorophenyl) pentanamide.

A method for the synthesis of DL-3-hydroxy-3- (4'-chlorophenyl) pentanamide which comprises:

A) Reaction between 4'-chloropropyrophenone with ethyl bromoacetate, in the presence of zinc, to obtain ethyl DL-3-hydroxy-3- (4'-chlorophenyl) pentanoate; and 30 B) transforming the mentioned pentanoate ester group into a -NH ₂ group to obtain the DL-3-hydroxy-3- (4'-chlorophenyl) pentanamide.

27. A method for the synthesis of DL-4-hydroxy-4- (4'-chloro or 4'-fluoro phenyl) hexanamides which comprises: A) Reaction between 4'-fluoropropyrophenone or 4'-chloropropyrophenone with diethyl succinate in the presence of sodium hydride, followed by cyclization under acidic conditions to ^" produce lactones; and

B) transformation of the lactones with ammonia under pressure in the DL-4- hydroxι-4- (4'-chloro or 4'-fluoro phenyl) hexanamides