Anticonvulsant Compounds

Abstract

Compounds having anticonvulsant and anti-pain activity are provided. Specifically, for example, compounds represented by formula 1 are useful for regulating voltage-gated sodium channel activity. TIFF2023011585000075.tif3350

Description

[Technical field]

[0001] The present invention relates to compounds with anticonvulsant and anti-pain activity, which are useful in modulating voltage-gated sodium channel activity and are therefore useful in the treatment of epilepsy and chronic or acute pain. [Background technology]

[0002] Anticonvulsant compounds are now widely used to treat a variety of conditions and diseases, including epilepsy. Epilepsy is a neurological condition that affects the nervous system, causing affected individuals to suffer from seizures. These seizures can be conceptualized as inappropriately synchronized brain activity, caused by proper electrical communication between neurons in the brain. Seizures are often seen on an electroencephalogram (EEG) as high amplitude neural discharges occurring across brain regions. This brain activity is accompanied by behavioral disturbances, such as loss of balance, muscle movement spasms, visual disturbances, and loss of consciousness. It is estimated that approximately 0.5% of the world's population suffers from some form of epilepsy. Epilepsy is a lifelong condition with a very low return rate and is rarely fatal. People with uncontrolled epilepsy are often unemployed or underemployed.

[0003] All these factors combine to make epilepsy one of the most expensive healthcare burdens in the world. In North America alone, the cost of epilepsy in direct medical costs and lost economic activity is estimated to be several billion dollars annually. There is no known cure for epilepsy. Summary of the Invention [Problem to be solved by the invention]

[0004] Control of epileptic seizures remains an unmet medical challenge. Current drug therapies control seizures by targeting many sites in the central nervous system (CNS). Although effective, these drugs often cause unwanted side effects that reduce compliance and therefore efficacy. Reportedly, approximately 30% of epilepsy patients do not respond to current therapies, including both drug and brain stimulation therapies. Thus, there is a need to develop new anticonvulsant drugs to provide effective options for these individuals.

[0005] Similarly, management of acute and chronic pain is an ongoing problem. Millions of people live with various forms of chronic pain. Blockade of sodium channel function is one of many treatments. [Means for solving the problem]

[0006] Summary of the invention In one embodiment, the present invention provides a therapeutically effective amount of a compound of formula (I): [ka] [In the formula, R1=R2=CH3 or R1=H and R2=aryl, where aryl is selected from the group consisting of: Phenyl unsubstituted or substituted with one or two compounds selected from the group consisting of CH3, OH, OCH3, SO2CH3, SO2Ph, F, Cl, CF3, CN; 1- or 2-naphthyl; 2-, 3-, or 4-pyridyl, unsubstituted or substituted with one or two compounds selected from the group consisting of CH3, OCH3, SO2CH3, SO2Ph, F, Cl, CF3, CN; 2- or 3-furyl, unsubstituted or substituted with one or two compounds selected from the group consisting of CH3, OCH3, SO2CH3, SO2Ph, F, Cl, CF3, CN; or 2- or 3-thienyl, unsubstituted or substituted with one or two compounds selected from the group consisting of CH3, OCH3, SO2CH3, SO2Ph, F, Cl, CF3, CN; R3=H; C(O)R5, where R5 = H, CH3, C2H5, CH(CH3)2, CHCH3CN, or aryl; C(O)-O-R6, where R6=a pharma- ceutically acceptable salt, H, C1-C6 alkyl (straight or branched chain), CH2C6H5, or CH(CH2)n, where n=2-5; C(O)NH2, C(O)NHR6 or C(O)NR7R8, where R7 and R8 are independently =C1-C6 alkyl (straight or branched chain), CH2C6H5, aryl, or R7 and R8 together are =(CH2)n, where n=3-5; OH, OCH3, or OCH2C6H5; S-CH3, S-C6H5, S(O)CH3, S(O)C6H5, SO2CH3, or SO2C6H5; NO2, NH2, NHR6, NR7R8, or a pharma- ceutically acceptable salt thereof; or C≡CC(O)CH3, C≡CC(O)CH(CH3)2, C≡CC(O)C2H5, C≡CC(O)C6H5, C≡CC(O)-OH, or C≡CC(O)-O - a pharma- ceutically acceptable salt of CN; and R4 = one or two compounds selected from the group consisting of H, CH3, OH, OCH3, SO2CH3, SO2Ph, F, Cl, CF3, or CN. The present invention relates to a method of eliminating or reducing convulsive activity or the severity of epileptic seizures by administering to a subject a compound of the formula:

[0007] In another embodiment, the method comprises administering to a subject a therapeutically effective amount of a compound of the formula: [ka] The method includes administering to a subject a compound represented by the formula:

[0008] In yet another embodiment, the present specification provides a therapeutically effective amount of a compound of formula (II): [ka] [In the formula, R1=R2=CH3 or R1=H and R2=aryl; and R3=C1-C6 alkyl (straight or branched), CH(CH2)n, where n=3-5, or aryl; CH2SC6H5, or CH2SO2C6H5; S-C6H5, S(O)C6H5, or SO2C6H5; CH=CHC(O)CH3, CH=CHC(O)C6H5, CH=CHC(O)-O-CH3, CH=CHC(O)-O-C2H5, CH=CHC(O)-O-CH(CH3)2, CH=CHC(O)-O-C4H9, or CH=CHC(O)-O-C6H5; CH=CHCN; or CH=CHSO2CH3, CH=CHSO2C6H5] The present invention relates to a method of eliminating or reducing convulsive activity or the severity of epileptic seizures by administering to a subject a compound of the formula:

[0009] In another aspect, the present invention relates to a pharmaceutical composition comprising a compound of formula (I), or a pharma- ceutically acceptable salt or solvate thereof, in association with a pharma- ceutically acceptable excipient.

[0010] In another embodiment, the composition has the following formula: [ka] The present invention includes compounds represented by the formula:

[0011] In yet another embodiment, the present invention relates to a pharmaceutical composition comprising a compound of formula (II) or a pharma- ceutically acceptable salt or solvate thereof, in association with a pharma- ceutically acceptable excipient.

[0012] In order that the invention may be more clearly understood, a preferred embodiment thereof will now be described in detail, by way of example only, with reference to the accompanying drawings, in which: [Brief description of the drawings]

[0013] [Figure 1] Graph showing reduction in circuit activation of certain exemplary compounds in accordance with the present invention. [Diagram 2] Graph showing the efficacy of the compound of Example 1 at 10 pM to 10 μM. [Diagram 3] Graph showing the recovery rate of sodium channel activity before and after application of 100 pM of the compound of Example 1. [Figure 4] Summary of data showing prevention of stage 5 seizures by the compound of Example 1 at a dose of 20 mg / kg in an animal model of partial complex seizures using the amygdala kindling model of epilepsy. [Diagram 5] Graph showing that pretreatment of rats (20 mg / kg) undergoing an amygdala kindling procedure prevents the development of stage 5 seizures. [Figure 6] Electronic recordings of activity from the amygdala of a rat following traumatic brain injury and stress (tail pinch). The graph below shows the frequency and amplitude of the electrophysiological response. [Figure 7] Graph showing detection of the compounds of Examples 1 and 2 in rat blood following oral or intravenous administration of the compound of Example 1. [Figure 8] Graph showing the time it takes for compound of Example 1 to be converted to compound of Example 2 in vivo. [Figure 9] Graph showing the stability of the compound of Example 2 in human plasma, converted from the compound of Example 1. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] Description of the Preferred Embodiments Certain compounds described herein have been found to be voltage-gated sodium channel inhibitors with anticonvulsant activity. Voltage-gated sodium channels are found in neurons of the central and peripheral nervous system and are responsible for initiating the rapid rise of action potentials. They are essential for the nervous system's ability to initiate and propagate electrical signals.

[0015] The compounds of formula (I) and formula (II) are inhibitors of voltage-gated sodium channel activity and are useful for treating epileptic seizures and pain. Preferred compounds of the present invention are the compounds listed in the Examples below and their pharma- ceutically acceptable salts and solvates.

[0016] Epileptic seizures are caused by disturbances in brain electrical activity. In particular, excessive brain electrical activity is a hallmark of epileptic seizures. Brain electrical activity is primarily mediated by voltage-gated sodium channels. Thus, attenuating voltage-gated sodium channel activity is a common goal for controlling epileptic disorders.

[0017] The present invention also provides a method for eliminating or reducing the severity of convulsive activity or epileptic seizures by administering to a subject a therapeutically effective amount of a compound of Formula (I) or Formula (II), or a pharma- ceutically acceptable salt or solvate thereof, together with a pharma- ceutically acceptable excipient.

[0018] The present invention further provides a method for the prophylactic treatment or prevention of epileptogenesis caused by traumatic brain injury by administering to a subject a therapeutically effective amount of a compound of Formula (I) or Formula (II), or a pharma- ceutically acceptable salt or solvate thereof, together with a pharma- ceutically acceptable excipient.

[0019] The compounds of the invention may be administered orally, parenterally or topically. For the treatment of pain, topical administration is preferred.

[0020] The compounds of the present invention can be prepared by the following procedures: According to the first procedure, preferred compounds of formula (I) can be prepared according to the following methodology, illustrated by the general reaction sequence below.

[0021] General Procedure A In this sequence, cyclic 1,3-diketones such as dimedone are converted in situ to their p-toluenesulfonate esters by reaction with p-toluenesulfonyl chloride in the presence of potassium carbonate in a dioxane-water mixture. To the reaction mixture thus obtained, an arylboronic acid and a catalytic amount of tetrakis(triphenylphosphine)palladium(0) are added. The resulting mixture is heated to reflux for 2 h or until the reaction is complete, while being monitored by analytical thin-layer chromatography. Once the reaction is complete, the mixture is extracted with EtOAc (3x10 mL), the combined organic extracts are dried over MgSO4, filtered, and the solvent is evaporated on a rotary evaporator. The products are isolated by column chromatography and characterized by 1H and 13C NMR and sometimes high-resolution mass spectrometry (HRMS).

[0022] Scheme A [ka] EXAMPLES

[0023] [ka] To a mixture of dimedone (935 mg, 6.67 mmol) and potassium carbonate (2.31 g, 16.7 mmol) in 1,4-dioxane (16 mL) and water (8 mL) in a 2:1 ratio, p-toluenesulfonyl chloride (1.65 g, 8.67 mmol) was added. The mixture was stirred at room temperature for 2 h. 4-Methoxycarbonylphenylboronic acid (1.35 g, 8.56 mmol) and tetrakis(triphenylphosphine)palladium(0) (231 mg, 0.20 mmol) were added and the mixture was heated to reflux for 4 h. The resulting reaction mixture was extracted with EtOAc (3x10 mL). The extract was dried over MgSO4, filtered and evaporated on a rotary evaporator. Example 1 was isolated by column chromatography and then crystallized from 9:1 (diethyl ether:hexane) as light yellow crystals. Yield: 0.71 g, 41%. 1 H NMR (400 MHz, CDCl3)δ, ppm:8.09-8.00(m, 2H), 7.63-7.48(m, 2H), 6.44(t, J=1.40 Hz, 1H), 3.93(s, 3H), 2.66(d, J=1.40 Hz, 2H), 2.36(s, 2H), 1.14(s, 6H). 13 C NMR(100 MHz, CDCl3)δ, ppm:199.77, 166.42, 156.23, 143.42, 131.14, 129.93(2C), 126.10(2C), 125.72, 52.27, 50.90, 42.27, 33.79, 28.35(2C) HRMS:C 16 H 18 Calculated value for O3: 258.1256; Measured value: 258.1233 EXAMPLES

[0024] [ka] Methyl 3',3'-dimethyl-5'-oxo-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-4-carboxylate (compound 1) (50 mg, 0.19 mmol) was dissolved in methanol (4 mL) and 5% aqueous sodium hydroxide was added (1 mL). The mixture was stirred at room temperature until disappearance of the starting material was observed by TLC. Approximately half of the methanol solvent was evaporated using a rotary evaporator and water (5 mL) was added. The mixture was extracted with EtOAc (3x5 mL) and the organic extract was discarded. The aqueous phase was treated with 5% aqueous hydrochloric acid (1 mL) and the mixture was extracted with EtOAc (3x5 mL). The second organic phase was dried over MgSO4 and evaporated to give the compound of Example 2 as a white solid. (40 mg, 86%). 1 H NMR(400 MHz, CDCl3)δ, ppm:8.15(d, J=8.49 Hz, 2H), 7.62(d, J=8.51 Hz, 2H), 6.47(t, J=1.31 Hz, 1H), 2.67(d, J=1.31 Hz, 2H), 2.38(s, 2H), 1.15(s, 6H). 13 C NMR(100 MHz, MeOH-D4)δ, ppm:201.15, 167.71, 158.33, 143.32, 131.82, 129.76(2C), 126.08(2C), 124.63, 50.29, 41.69, 33.33, 27.02(2C) HRMS:C 15 H 16 Calculated value for O3: 244.1099; Measured value: 244.1095 EXAMPLES

[0025] [ka] 3',3'-Dimethyl-5'-oxo-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-4-carboxylic acid (compound 1) (0.1 g, 0.41 mmol) was dissolved in dichloromethane (10 mL) at room temperature. Sodium bis(trimethylsilyl)amide 1M (0.41 mL, 0.41 mmol) was added dropwise and a white precipitate was quickly observed. All the solvent was evaporated using a rotary evaporator and diethyl ether (10 mL) was added to the mixture. After filtering the suspension, the sodium salt compound of Example 3 was obtained as a beige fine powder. (96.5 mg, 88%) 1 H NMR (400 MHz, MeOH-D4)δ, ppm:7.97(d, J=8.19 Hz, 2H), 7.60(d, J=8.20 Hz, 2H), 6.39(s, 1H), 2.73(s, 2H), 2.33(s, 2H), 1.11(s, 6H). 13 C NMR(100 MHz, MeOH-D4)δ, ppm:202.85, 174.01, 160.76, 142.17, 140.15, 130.77(2C), 126.96(2C), 125.14, 51.76, 43.20, 34.75, 28.48(2C) EXAMPLES

[0026] [ka] 3',3'-Dimethyl-5'-oxo-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-4-carboxylic acid (compound 1) (100 mg, 0.41 mmol) was dissolved in dichloromethane (10 mL). A solution of 2-dimethylaminoethanol (36.5 mg, 0.41 mmol) in 1 mL of dichloromethane was added and the mixture was stirred for 10 minutes. The solvent was completely evaporated and diethyl ether (10 mL) was added to the mixture. The observed precipitated salt was filtered to give the ammonium salt compound of Example 4 as a fine white powder. (103 mg, 75%) 1H NMR (400 MHz, CDCl3)δ, ppm:8.08(d, J=8.41 Hz, 2H), 7.55(d, J=8.40 Hz, 2H), 6.44(t, J=1.23 Hz, 1H), 4.00-3.91(m, 2H), 3.12-3.05(m, 2H), 2.80(s, 6H), 2.67(d, J=1.32 Hz, 2H), 2.35(s, 2H), 1.14(s, 6H). 13 C NMR(100 MHz, MeOH-D4)δ, ppm:202.82, 173.85, 160.69, 142.34, 139.77, 130.79(2C), 12 7.00(2C), 125.20, 60.65, 57.08, 51.76, 43.88(2C), 43.20, 34.75, 28.48(2C). EXAMPLES

[0027] [ka] As described in General Procedure A, p-toluenesulfonyl chloride (1.77 g, 9.27 mmol), dimedone (1.00 g, 7.13 mmol) and potassium carbonate (2.46 g, 17.8 mmol) were reacted in a 2:1 ratio of 1,4-dioxane (14 mL) and water (7 mL). To this mixture, 2,4-difluorophenylboronic acid (1.35 g, 8.56 mmol) and tetrakis(triphenylphosphine)palladium(0) (247 mg, 0.21 mmol) were added and the mixture was heated to reflux for 3 hours. Usual workup and purification by silica gel chromatography gave 0.73 g (43%) of the compound of Example 5 as a beige solid. 1 H NMR (400 MHz, CDCl3)δ, ppm:7.31(dt, J=8.62, 6.36 Hz, 1H), 6.96-6.82(m, 2H), 6.24(s, 1H), 2.60(t, J=1.61 Hz, 2H), 2.34(s, 2H), 1.12(s, 6H). 13C NMR (100 MHz, CDCl3) δ, ppm: 199.58, 163.40, 160.15, 153.86, 129.92, 127.89, 124.29, 111.81, 104.79, 51.00, 43.67, 34.15, 28.17 (2C). EXAMPLES

[0028] [ka] According to the general procedure, p-toluenesulfonyl chloride (1.42 g, 7.42 mmol), dimedone (800 mg, 5.71 mmol), potassium carbonate (1.97 g, 14.3 mmol) in a 2:1 ratio of 1,4-dioxane (12 mL) and water (6 mL), followed by 4-fluorophenylboronic acid (1.08 g, 6.85 mmol) and tetrakis(triphenylphosphine)palladium(0) (197 mg, 0.17 mmol) according to general procedure A gave, after purification, 0.71 g (57%) of the compound of example 6 as a light brown solid. 1 H NMR (400 MHz, CDCl3)δ, ppm:7.56-7.43(m, 2H), 7.13-6.97(m, 2H), 6.33(t, J=1.39 Hz, 1H), 2.59(d, J=1.45 Hz, 2H), 2.30(s, 2H), 1.10(s, 6H). 13 C NMR (100 MHz, CDCl3) δ, ppm: 199.87, 164.98, 162.49, 156.25, 135.05, 128.04, 124.21, 115.89, 115.67, 50.80, 42.35, 33.71, 28.37 (2C). HRMS:C 14 HH 15 Calculated value for FO: 218.1107; Measured value: 218.1091 EXAMPLES

[0029] [ka] To a mixture of dimedone (140.2 mg, 1.0 mmol) and potassium carbonate (345 mg, 2.5 mmol) in 1,4-dioxane (4 mL) and water (2 mL) in a 2:1 ratio, p-toluenesulfonyl chloride (247.8 mg, 1.3 mmol) was added. The mixture was stirred at room temperature for 1 h. 4-Methoxyphenylboronic acid (182.4 mg, 1.2 mmol) and tetrakis(triphenylphosphine)palladium(0) (34.7 mg, 0.03 mmol) were added and the mixture was heated to reflux for 2 h. The resulting mixture was extracted with EtOAc (3x10 mL). The extract was dried over MgSO4, filtered, and the solvent was evaporated on a rotary evaporator. The compound of Example 7 was isolated by column chromatography to give 130 mg (56%) of white crystals. 1 H NMR (400 MHz, CDCl3)δ, ppm:7.51-7.40(m, 2H), 6.89-6.84(m, 2H), 6.32(s, 1H), 3.77(s, 3H), 2.55(d, J=1.25 Hz, 2H), 2.25(s, 2H), 1.06(s, 6H). 13 C NMR (100 MHz, CDCl3)δ, ppm: 199.94, 161.03, 156.92, 130.72, 127.48(2C), 122.24, 113.93(2C), 55.14, 50.59, 41.79, 33.38, 28.21(2C). HRMS:C 15 H 18 Calculated value for O2: 230.1307; Measured value: 230.1323 EXAMPLES

[0030] [ka] A mixture of p-TsCl (1.6 eq., 440 mg, 2.31 mmol), 1-3-cyclohexanedione (1.2 eq., 200 mg, 1.78 mmol) and potassium carbonate (2.5 eq., 511 mg, 3.7 mmol) in 1,4-dioxane (10 mL) and water (5 mL) was stirred until deemed complete by TLC. 225 mg of 4-methoxyphenylboronic acid and 8.55 mg of Pd(PPh4)4 were added and the reaction mixture was refluxed at 100° C. for 1.5 h. The usual workup described in General Procedure A, followed by flash column chromatography eluting with EtOAc / Hexane (15-35%), gave Example 8 as white crystals in 67% yield. 1 H NMR (400 MHz, CDCl3)δ ppm:7.51(dt, J=9.9, 2.6 Hz, 2H), 6.92(dt, J=9.9, 2.6 Hz, 2H), 6.39(t, J=1.3 Hz, 1H), 3.84(s, 3H), 2.75(td, J=9.1, 1.3 Hz, 2H), 2.46(t, J=6.7 Hz, 2H), 2.13(m, J=6.4 Hz, 2H). 13 C NMR (100 MHz, CDCl3) δ ppm: 199.91, 161.24, 159.11, 130.84, 127.64, 123.74, 114.16, 55.40, 37.21, 27.88, 22.79 HRMS:C 13 H 14 Calculated value for O2: 202.0994; Measured value: 202.0997 EXAMPLES

[0031] [ka] A mixture of p-TsCl (1.6 eq., 371.8 mg, 1.95 mmol), 1-3-cyclohexanedione (1.2 eq., 168.2 mg, 1.5 mmol) and potassium carbonate (2.5 eq., 431.9 mg, 3 mmol) in 1,4-dioxane (10 mL) and water (5 mL) was stirred at room temperature until deemed complete by TLC. 225 mg of 4-methoxycarbonylphenylboronic acid and 7.22 mg of Pd(PPh4)4 were added and the reaction mixture was refluxed at 100° C. for 1.5 h. The usual workup followed by flash chromatography with EtOAc / Hexane (15-30%) gave Example 9 as white crystals (31%). 1 H NMR(400 MHz, CDCl3)δ ppm:8.06(dt, J=8.6, 1.9 Hz, 2H), 7.58(dt, J=8.6, 1.9 Hz, 2H), 6.44(t, J=1.5 Hz, 1H), 3.93(s, 3H), 2.78(td, J=6.0, 1.5 Hz, 2H), 2.50(t, J=6.7 Hz, 2.17(m, J=5.4 Hz, 2H). 13 C NMR (100 MHz, CDCl3) δ ppm: 199.55, 166.44, 158.38, 143.20, 131.19, 129.95(2C), 126.78(2C), 126.04, 52.29, 37.23, 28.08, 22.73 HRMS:C 14 H 14 Calculated value for O3: 230.0943; Measured value: 230.0975 EXAMPLES

[0032] [ka] The ester compound of Example 2 (1 eq., 20 mg, 0.087 mmol) was added to a solution of 1 mL of 5% NaOH in 4 mL of methanol. The solution was kept at room temperature overnight. The reaction mixture was diluted with 20 mL of EtOAc. To the separated aqueous layer, 5% HCl solution was added until the solution was acidic. The mixture was extracted with 20 mL of EtOAc. The organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure to give Example 10 as a copper-colored solid (10 mg, 0.046 mmol, 53%). 1 H NMR(400 MHz, CDCl3)δ ppm:8.07(d, J=8.5 Hz, 2H), 7.72(d, J=8.5 Hz, 2H), 6.44(s, 1H), 2.87(td, J=6.0, 1.2 Hz, 2H), 2.50(t, J=6.7 Hz, 2H), 2.18(m, J=6.3 Hz, 2H) 13 C NMR (100 MHz, CDCl3) δ ppm: 201.07, 167.72, 160.63, 143.12, 131.77, 129.74, 127.72, 126.00, 38.16, 36.63, 30.29, 27.69, 22.43 EXAMPLES

[0033] [ka] 3',3'-Dimethyl-5'-oxo-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-4-carboxylic acid (Example 2) (0.1 g, 0.41 mmol) was added to dichloromethane (15 mL). Thionyl chloride (81.9 mg, 0.69 mmol) was added and the mixture was refluxed for 3 h. The solvent and excess thionyl chloride were evaporated using a rotary evaporator. The flask was closed with a septum and the mixture was dissolved in benzene (15 mL) at 0 °C. Piperidine (70.0 mg, 0.82 mmol) and triethylamine (82.8 mg, 0.82 mmol) were added simultaneously very slowly and the mixture was stirred at 0 °C for 5 min. The reaction was quenched by adding water and an aqueous solution of NH4Cl. The mixture was extracted with EtOAc (3x10 mL), dried over MgSO4 and filtered. The extract was treated with 5% aqueous sodium hydroxide solution. The amide compound of Example 11 was obtained as a white fine powder in 70% yield. 1 H NMR (400 MHz, CDCl3)δ, ppm:7.59-7.52(m, 2H), 7.46-7.41(m, 2H), 6.42(t, J=1.45 Hz, 1H), 3.78-3.66(br, 2H), 3.43-3.28(br, 2H), 2.64(d, J=1.42 Hz, 2H), 2.35(s, 2H), 1.72-1.61(m, 4H), 1.57-1.49(m, 2H), 1.13(s, 6H). 13 C NMR(100 MHz, CDCl3)δ, ppm:199.90, 169.43, 156.61, 140.05, 137.88, 127.27(2C), 12 6.24(2C), 124.96, 50.92(2C), 42.30(2C), 33.77(2C), 28.38(2C), 24.54(2C) HRMS:C 20 H 25 Calculated value for NO2: 311.1885; Measured value: 311.1863 EXAMPLES

[0034] [ka] 3',3'-Dimethyl-5'-oxo-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-4-carboxylic acid (Example 2) (75 mg, 0.31 mmol) was added to dichloromethane (15 mL). Thionyl chloride (62.1 mg, 0.52 mmol) was added and the mixture was refluxed for 3 h. The solvent and excess thionyl chloride were evaporated using a rotary evaporator. The flask was closed with a septum and the mixture was dissolved in benzene (15 mL) at 0° C. Isopropylamine (72.7 mg, 1.23 mmol) and triethylamine (124 mg, 1.23 mmol) were added simultaneously very slowly and the mixture was stirred at 0° C. for 5 min. The reaction was quenched by adding water and an aqueous solution of NH4Cl. The mixture was extracted with EtOAc (3×10 mL), dried over MgSO4, filtered and the ethyl acetate layer was washed with 5% sodium hydroxide. The amide compound of Example 12 was isolated by column chromatography as a fine white powder in 57% yield (50 mg). 1 H NMR (400 MHz, CDCl3)δ, ppm:7.79(d, J=8.37 Hz, 2H), 7.57(d, J=8.37 Hz, 2H), 6.42(s, 1H), 5.95(d, J=6.25 Hz, 1H), 4.30(qd, J=13.30, 6.56 Hz, 1H), 2.65(d, J=1.15 Hz, 2H), 2.35(s, 2H), 1.28(d, J=6.55 Hz, 6H), 1.14(s, 6H). 13 C NMR(100 MHz, CDCl3)δ, ppm: 199.84, 165.78, 156.34, 141.81, 136.00, 127.28 (2C) , 126.24(2C), 125.30, 50.89, 42.23, 42.03, 33.77, 28.36(2C), 22.80(2C) EXAMPLES

[0035] [ka] 3',3'-Dimethyl-5'-oxo-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-4-carboxylic acid (Example 2) (100 mg, 0.41 mmol) was added to dichloromethane (15 mL). Thionyl chloride (82.7 mg, 0.70 mmol) was added and the mixture was refluxed for 3 h. The solvent and excess thionyl chloride were evaporated using a rotary evaporator. The flask was closed with a septum and the mixture was dissolved in benzene (15 mL) at 0 °C. Aniline (152 mg, 1.64 mmol) and triethylamine (166 mg, 1.64 mmol) were added simultaneously very slowly and the mixture was stirred at 0 °C for 5 min. The reaction was quenched by adding water and an aqueous solution of NH4Cl. The mixture was extracted with EtOAc (3x10 mL), dried over MgSO4 and filtered. The extract was treated with 5% aqueous sodium hydroxide solution. Column chromatography afforded the anilide compound of Example 13 as a fine white powder (50 mg) in 38% yield. 1 H NMR (400 MHz, CDCl3)δ, ppm:7.95-7.90(m, 2H), 7.83(br, 1H), 7.68-7.61(m, 4H), 7.42-7.36(m, 2H), 7.21-7.15(m, 1H), 6.45(t, J=1.44 Hz, 1H), 2.67(d, J=1.45 Hz, 2H), 2.37(s, 2H), 1.16(s, 3H). 13 C NMR(100 MHz, CDCl3)δ, ppm:199.85, 164.81, 156.14, 142.47, 137.75, 135.99, 129.18(2C), 12 7.52(2C), 126.56(2C), 125.61, 124.81, 120.24(2C), 50.94, 42.29, 33.84, 28.41(2C) EXAMPLES

[0036] [ka] 3',3'-Dimethyl-5'-oxo-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-4-carboxylic acid (Example 2) (100 mg, 0.41 mmol) was added to dichloromethane (15 mL). Thionyl chloride (82.7 mg, 0.70 mmol) was added and the mixture was refluxed for 3 h. The solvent and excess thionyl chloride were evaporated using a rotary evaporator. The flask was closed with a septum and the mixture was dissolved in benzene (15 mL) at 0 °C. Benzylamine (175 mg, 1.64 mmol) and triethylamine (166 mg, 1.64 mmol) were added simultaneously very slowly and the mixture was stirred at 0 °C for 5 min. The reaction was quenched by adding water and an aqueous solution of NH4Cl. The mixture was extracted with EtOAc (3x10 mL), dried over MgSO4 and filtered. The extract was treated with 5% aqueous sodium hydroxide solution. Example 14 was isolated by column chromatography to give a fine beige powder (70 mg, 51%). 1 H NMR (400 MHz, CDCl3)δ, ppm:7.85-7.81(m, 2H), 7.60-7.55(m, 2H), 7.38-7.28(m, 5H), 6.49-6.43(m, 1H), 6.42(t, J=1.44 Hz, 1H), 4.66(d, J=5.64 Hz, 2H), 2.64(d, J=1.43 Hz, 2H), 2.35(s, 2H), 1.14(s, 6H). 13 C NMR(100 MHz, CDCl3)δ, ppm:199.82, 166.43, 156.21, 142.18, 137.94, 135.35, 128.86(2C), 127.9 7(2C), 127.76, 127.40(2C), 126.37(2C), 125.46, 50.91, 44.26, 42.26, 33.80, 28.38(2C) EXAMPLES

[0037] [ka] 3',3'-Dimethyl-5'-oxo-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-4-carboxylic acid (Example 2) (100 mg, 0.41 mmol) was added to dichloromethane (15 mL). Thionyl chloride (82.7 mg, 0.70 mmol) was added and the mixture was refluxed for 3 h. The solvent and excess thionyl chloride were evaporated using a rotary evaporator. The flask was closed with a septum and the mixture was dissolved in benzene (15 mL) at 0 °C. N-Methylaniline (175 mg, 1.64 mmol) and triethylamine (166 mg, 1.64 mmol) were added simultaneously very slowly and the mixture was stirred at 0 °C for 5 min. The reaction was quenched by adding water and an aqueous solution of NH4Cl. The mixture was extracted with EtOAc (3x10 mL), dried over MgSO4 and filtered. The extract was treated with 5% aqueous sodium hydroxide solution. The tertiary amide compound of Example 15 was isolated by column chromatography to give a fine beige powder (60 mg, 44%). 1 H NMR (400 MHz, CDCl3)δ, ppm:7.33(s, 4H), 7.28-7.22(m, 2H), 7.19-7.14(m, 1H), 7.07-7.03(m, 2H), 6.32(t, J=1.48 Hz, 1H), 3.51(s, 3H), 2.55(d, J=1.47 Hz, 2H), 2.30(s, 2H), 1.09(s, 6H). 13 C NMR(100 MHz, CDCl3)δ, ppm:199.83, 169.67, 156.34, 144.64, 140.02, 137.23, 129.32(2C), 129.1 7(2C), 126.89(2C), 126.76, 125.49(2C), 124.99, 50.88, 42.07, 38.46, 33.66, 28.36(2C) EXAMPLES

[0038] [ka] 4-Bromophenol (4.33 g, 25 mmol) and imidazole (2.21 g, 32.5 mmol) were dissolved in a 1:1 ratio mixture of tetrahydrofuran (15 mL) and dimethylformamide (15 mL). tert-Butyldimethylsilyl chloride (4.15 g, 27.5 mmol) and 4-dimethylaminopyridine (trace amount) were added and the reaction was stirred at room temperature for 12 h. The mixture was diluted with water (30 mL) and ether (40 mL) and then extracted with EtOAc (3x20 mL). The organic extracts were dried over MgSO4, filtered and evaporated with. The silyl-protected intermediate was isolated by column chromatography (5.63 g, 68%). The silyl-protected intermediate (320 mg, 0.97 mmol) was dissolved in EtOAc (25 mL) and aqueous 5% sodium hydroxide solution (25 mL) was added. The aqueous phase was retained and treated with aqueous 10% hydrochloric acid solution (15 mL). The mixture was extracted with EtOAc (3x10 mL) and the organic extracts were dried over MgSO4, filtered and evaporated to give Example 16 as a beige solid (150 mg, 71%). Total synthetic yield = 48% 1 H NMR (300 MHz, MeOH-D4)δ, ppm:7.57-7.48(m, 2H), 6.94-6.73(m, 2H), 6.34(t, J=1.39 Hz, 1H), 2.70(d, J=1.36 Hz, 2H), 2.32(s, 2H), 1.12(s, 6H). 13 C NMR(100 MHz, MeOH-D4)δ, ppm:201.62, 159.83, 159.79, 129.37, 127.78(2C), 120.58, 115.26(2C), 50.18, 41.44, 33.13, 27.10(2C) HRMS:C 14 H 16 Calculated value for O2: 216.1150; Measured value: 216.1174 EXAMPLES

[0039] [ka] 4'-Hydroxy-5,5-dimethyl-5,6-dihydro-[1,1'-biphenyl]-3(4H)-one (50 mg, 0.23 mmol) was dissolved in dichloromethane (10 mL) and 4-dimethylaminopyridine (trace amount) was added. Acetic anhydride (27.7 mg, 0.46 mmol) and triethylamine (70.1 mg, 0.69 mmol) were added and the solution was stirred at room temperature for 30 minutes. The reaction mixture was then poured into a flask containing a saturated aqueous solution of NaHCO3 and extracted with dichloromethane (3x10 mL). The organic extract was dried over MgSO4, filtered and evaporated. The acetate compound of Example 17 was isolated by column chromatography in 42% yield as a light beige solid. 1 H NMR (400 MHz, CDCl3)δ, ppm:7.59-7.50(m, 2H), 7.20-7.06(m, 2H), 6.38(s, 1H), 2.62(d, J=1.25 Hz, 2H), 2.33(s, 2H), 2.31(s, 3H), 1.12(s, 6H). 13 C NMR(100 MHz, CDCl3)δ, ppm:199.93, 169.20, 156.45, 151.89, 136.62, 127.36(2C), 124.43, 121.95(2C), 50.87, 42.32, 33.76, 28.38(2C), 21.10

[0040] General Scheme B [ka] EXAMPLES

[0041] [ka] 3-Methoxy-5,5-dimethylcyclohex-2-enone (1.0 g, 6.48 mmol) was dissolved in anhydrous THF at 0° C. under nitrogen atmosphere. n-Butyllithium 2.5 M (6.7 mL, 114.93 mmol) was slowly added and the solution was stirred at 0° C. for 20 min. The mixture was quenched with aqueous NH4Cl solution and extracted with EtOAc (3×10 mL). The resulting extract was dried over MgSO4, filtered and evaporated. Example 18 compound, 3-butyl-5,5-dimethylcyclohex-2-en-1-one, was isolated by column chromatography in 32% yield as a colorless oil (370 mg). 1 H NMR (400 MHz, CDCl3)δ, ppm: 5.87(s, 1H), 2.18(m, 6H), 1.47(m, 2H), 1.33(qd, J=14.36, 7.15 Hz, 2H), 1.02(s, 6H), 0.91(t, J=7.28 Hz, 3H). 13 C NMR (50 MHz, CDCl3)δ, ppm:200.0, 164.2, 124.4, 51.0, 43.8, 37.6, 33.5, 28.9, 28.2, 22.2, 13.7 EXAMPLES

[0042] [ka] Magnesium turnings (0.30 g, 12.3 mmol) are added to the flask and placed under nitrogen atmosphere. A solution of bromobenzene (1.50 g, 9.55 mmol) in anhydrous diethyl ether (10 mL) is added and the mixture is gently refluxed until all magnesium turnings are consumed. A solution of 3-methoxy-5,5-dimethylcyclohex-2-enone (0.50 g, 3.24 mmol) in diethyl ether (10 mL) is added at room temperature and the mixture is refluxed again for 30 min. The reaction is quenched with water and a saturated aqueous solution of NH4Cl. The mixture is extracted with EtOAc, dried over MgSO4, filtered, evaporated and after silica gel chromatography, the compound of Example 19, 3-phenyl-5,5-dimethylcyclohex-2-en-1-one, is obtained as a white solid (260 mg, 40%). 1 H NMR(400 MHz, CDCl3)δ, ppm:7.54(ddd, J=4.48, 2.39, 1.40 Hz, 2H), 7.43-7.40(m, 3H), 6.42(t, J=1.50, 1.50 Hz, 1H), 2.66(d, J=1.46 Hz, 2H), 2.35(s, 2H), 1.14(s, 6H); 13 C NMR (100 M Hz, CDCl3)δ, ppm:199.7, 157.4, 138.9, 129.8, 128.6, 126.0, 124.3, 51.0, 42.4, 33.9, 28.5 HRMS:C 14 H 16 Calculated for O: 200.1201; Found = 200.1187 EXAMPLES

[0043] [ka] Magnesium turnings (0.43 g, 17.9 mmol) are added to the flask and placed under nitrogen atmosphere. A solution of bromocyclohexane (2.91 g, 17.9 mmol) in anhydrous diethyl ether (10 mL) is added and the mixture is gently refluxed until all magnesium turnings are consumed. A solution of 3-ethoxy-5,5-dimethylcyclohex-2-enono (1.0 g, 5.95 mmol) in diethyl ether (10 mL) is added at room temperature and the mixture is refluxed again for 30 minutes. The reaction is quenched with water and an aqueous solution of NH4Cl. The mixture is extracted with EtOAc, dried over MgSO4, filtered, evaporated and after silica gel chromatography, the compound of Example 20, 3-cyclohexyl-5,5-dimethylcyclohex-2-en-1-one, is obtained as a white solid (290 mg, 24%). 1 H NMR (400 MHz, CDCl3)δ, ppm:5.84(d, J=0.69 Hz, 1H), 2.19(s, 2H), 2.17(d, J=0.86 Hz, 2H), 2.05-1.94(m, 1H), 1.84-1.65(m, 5H), 1.35-1.11(m, 5H), 1.00(s, 6H). 13 C NMR(100 MHz, CDCl3)δ, ppm:200.56, 168.67, 122.92, 51.26, 46.05, 42.58, 33.58, 30.78(2C), 28.18(2C), 26.21(2C), 26.02 EXAMPLES

[0044] [ka] A mixture of 5-5-dimethyl-1,3-cyclohexanedione (1 eq, 4 g, 28.5 mmol), p-TsCl (1 eq, 5.44 g, 28.5 mmol) and potassium carbonate (2.5 eq, 9.85 g, 71.25 mmol) in 60 mL of acetone was stirred at room temperature for 18 h. The mixture was filtered and concentrated under reduced pressure. The crude mass was purified by flash column chromatography eluting with EtOAc / Hexane (20-25%) to give 5.85 g of the intermediate sulfonate ester (70%) as a light brown oil. 1 H NMR (400 MHz, CDCl3)δ ppm:7.79(dt, J=8.6, 1.9 Hz, 2H), 7.35(dq, J=8.6, 1.5 Hz, 2H), 5.75(t, J=1.3, 1H), 2.44(s, 3H), 2.35(d, J=1.3 Hz, 2H), 2.17(s, 2H), 1.00(s, 6H)

[0045] Methyl phenyl sulfone (2 eq., 212 mg, 1.36 mmol) dissolved in 1 mL of anhydrous THF was added to a solution of LDA (2 eq., 0.68 mL, 1.36 mmol) dissolved in 15 mL of anhydrous THF kept at -78°C under nitrogen. The mixture was stirred for 15 min. Compound 8 (1 eq., 200 mg, 0.68 mmol) was dissolved in anhydrous THF and added dropwise and the solution was kept at low temperature for 1 h. The reaction mixture was warmed to room temperature, diluted with 20 mL of saturated NH4CL solution and extracted with 2x20 mL of EtOAc. The organic extracts were combined, washed with water (2x5 mL), dried over anhydrous MgSO4 and concentrated under reduced pressure. The crude mass was purified by flash column chromatography eluting with EtOAc / Hexane (40%) to give 0.1 g, 53% of Example 21 (70%) as a yellow oil. 1 H NMR (400 MHz, CDCl3)δ ppm:7.82(d, J=7.2 Hz, 2H), 7.63(m, 1H), 7.52(t, J=7.7 Hz, 2H), 5.55(s, 1H), 3.89(s, 2H), 2.38(d, J=1.0 Hz, 2H), 2.14(s, 2H), 0.98(s, 6H) 13C NMR (100 MHz, CDCl3) δ ppm: 198.68, 148.35, 138.01, 134.33, 131.52, 129.37, 128.23, 63.88, 50.71, 43.85, 33.63, 28.08 EXAMPLES

[0046] [ka] Thiophenol (3.77 g, 34.2 mmol), 5,5-dimethylcyclohexane-1,3-dione (4.0 g, 28.5 mmol) and anhydrous ferrous chloride (0.93 g, 5.71 mmol) were added to the flask and stirred at room temperature for 5 hours. The mixture was dissolved in dichloromethane (30 mL) and washed with 10% sodium hydroxide solution in an extraction funnel. The aqueous phase was treated with bleach to remove the strong thiophenol odor. The organic phase was dried over MgSO4, filtered and concentrated on a rotary evaporator. Example 22 compound, 3-(phenylthio)cyclohex-2-enone, was isolated by column chromatography (1.78 g, 30%). 1 H NMR (400 MHz, CDCl3)δ, ppm: 7.48-7.34(m, 5H), 5.45(t, J=1.14 Hz, 1H), 2.50(dd, J=8.76, 3.48 Hz, 2H), 2.35(dd, J=8.23, 4.93 Hz, 2H), 2.01(m, 2H) EXAMPLES

[0047] [ka] 5,5-Dimethyl-3-(phenylthio)cyclohex-2-enone (1.09 g, 4.69 mmol) was dissolved in dichloromethane (15 mL) and the solution was cooled to 0° C. mCPBA was dissolved in a small amount of dichloromethane and added dropwise. The mixture was stirred at 0° C. for 30 min, then warmed to room temperature and stirred for an additional 1 h. The reaction was quenched with a 10% aqueous solution of sodium carbonate. The mixture was extracted with dichloromethane (2×10 mL) and finally washed with a solution of brine (20 mL). The organic extract was dried over MgSO4, filtered and concentrated on a rotary evaporator. The sulfoxide compound of Example 23 was isolated using column chromatography to give a clear yellow oil (550 mg, 47%). 1 H NMR (400 MHz, CDCl3)δ, ppm:7.66-7.60(m, 2H), 7.55-7.49(m, 3H), 6.74(t, J=1.59 Hz, 1H), 2.26(d, J=1.27 Hz, 2H), 2.06(dq, J=17.76, 1.54 Hz, 2H), 0.91(s, 3H), 0.85(s, 3H) EXAMPLES

[0048] [ka] 5,5-Dimethyl-3-(phenylthio)cyclohex-2-enone (1.09 g, 4.69 mmol) was dissolved in dichloromethane (15 mL) and the solution was cooled to 0° C. mCPBA was dissolved in a small amount of dichloromethane and added dropwise. The mixture was stirred at 0° C. for 30 min, then warmed to room temperature and stirred for an additional 1 h. The reaction was quenched with a 10% aqueous solution of sodium carbonate. The mixture was extracted with dichloromethane (2×10 mL) and finally washed with a solution of brine (20 mL). The organic extract was dried over MgSO4, filtered and concentrated on a rotary evaporator. The sulfone compound of Example 24 was isolated using column chromatography to give a clear yellow oil (300 mg, 24%). 1H NMR(400 MHz, CDCl3)δ, ppm:7.90(ddd, J=7.22, 2.93, 1.67 Hz, 2H), 7.70(m, 1H), 7.62-7.57(m, 2H), 6.72(t, J=1.73 Hz, 1H), 2.39(d, J=1.75 Hz, 2H), 2.27(s, 2H), 0.96(s, 6H) EXAMPLES

[0049] [ka] Lithium diisopropylamide 2M (3.87 mL, 7.74 mmol) was added to anhydrous THF (25 mL) at -78 °C under nitrogen atmosphere. Propionitrile (0.06 mL, 7.74 mmol) was added dropwise and the solution was stirred at -78 °C for 15 min. 3',3'-Dimethyl-5'-oxo-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-4-carboxylic acid (100 mg, 0.387 mmol) was added dropwise and the solution was stirred for 30 min. The reaction was quenched by transferring the mixture to a beaker containing aqueous NH4Cl solution. The mixture was then warmed to room temperature, diluted with water, and then extracted with EtOAc (3x10 mL). The extract was dried over MgSO4, filtered, and concentrated on a rotary evaporator.

[0050] Hydroxyl intermediate was isolated by column chromatography, dissolved in toluene, and p-toluenesulfonic acid (50 mg, catalytic) was added. The mixture was refluxed for 3 hours, and the reaction was quenched by adding aqueous NaHCO3 solution. The mixture was extracted with EtOAc (3x10 mL), and the extract was dried over MgSO4, filtered, and concentrated on a rotary evaporator. Example 25 was isolated by column chromatography (30 mg, 28%). 1H NMR(400 MHz, CDCl3)δ, ppm: 8.07-7.98(m, 2H), 7.71-7.61(m, 2H), 6.45(s, 1H), 4.36(q, J=7.18 Hz, 1H), 2.65(d, J=1.53 Hz, 2H), 2.36(d, J=5.96 Hz, 2H), 1.65(d, J=7.14 Hz, 3H), 1.14(s, 6H) EXAMPLES

[0051] [ka] Thiophenol (3.77 g, 34.2 mmol), 5,5-dimethylcyclohexane-1,3-dione (4.0 g, 28.5 mmol) and anhydrous ferrous chloride (0.93 g, 5.71 mmol) were added to the flask and stirred at room temperature for 5 hours. The mixture was dissolved in dichloromethane (30 mL) and washed with 10% sodium hydroxide solution in an extraction funnel. The aqueous phase was treated with bleach to remove the strong thiophenol odor. The organic phase was dried over MgSO4, filtered and concentrated on a rotary evaporator. The compound of Example 26, i.e., 5,5-dimethyl-3-(phenylthio)cyclohex-2-enone, was isolated by column chromatography (1.47 g, 22%). 1 H NMR (400 MHz, CDCl3)δ, ppm: 7.45(tdt, J=3.93, 2.51, 1.89 Hz, 5H), 5.48(s, 1H), 2.40(s, 2H), 2.23(s, 2H), 1.08(s, 6H)

[0052] The compounds described in the Examples above demonstrate activity in in vitro and in vivo assays that track electrical activity in the brain. The first assay is performed using voltage-sensitive dye imaging. This is performed on isolated rat brain slices that are viable in artificial cerebrospinal fluid (ACSF). Electrically stimulating the slices activates the neural tissue within them. A voltage-sensitive dye, such as di-4-ANEPPS, is incubated with the brain slices for 1 hour in an appropriate solution that facilitates penetration of the dye into the tissue. The dye responds to changes in voltage across the cell membranes of neurons in the brain slices. The Example compounds are added to ACSF at known concentrations between 50 and 200 nM. The brain slices are then subjected to electrical stimulation which activates neurons within the slices, and the dye responds to changes in voltage which can be observed and quantified to assess the extent to which brain activation is attenuated by the presence of the example compounds.

[0053] The compound of Example 1 exemplified above can suppress the activation of brain slice activity by 29±5 and 48±5% at concentrations of 50nM and 200nM, respectively.The compound of Example 1 reduces both the amplitude and duration of the response, indicating the ability of the compound to suppress brain activity.

[0054] Figure 1 shows a summary of the activity of certain example compounds assayed in this manner. Many, but not all, compounds show greater activity at higher frequencies of brain activity than at lower frequencies. This is a desirable attribute since excessive activity is a hallmark of seizure activity. The compound of Example 1 is a particularly preferred example; there is little or no activity at a stimulation frequency of 20 pulses / sec, while there is a 48% reduction in activity at 60 pulses / sec.

[0055] In another assay, inhibition of voltage-gated sodium channel activity by the example compounds is determined using patch clamp electrophysiology. This analysis is performed on cultured cortical neurons isolated from rats. As shown in Figure 2, the potency of the example compound was tested from 10 pM to 10 μM. This was done by assessing the inhibition of voltage-gated sodium channel activity 16 ms after the test pulse.

[0056] The compounds of the examples increase the time required for voltage-gated sodium channels to recover from the normally occurring inactive state induced by depolarization. At high levels (frequency) of sodium channel activity, these compounds are more effective at suppressing activity than at low (non-seizure) levels of activity. Thus, the compounds of the examples tend to suppress abnormal brain behavior to a greater extent than normal brain behavior.

[0057] As shown in Figure 3, the compound of Example 1 slows down the recovery of sodium channel inactivation. These data were obtained using patch clamp techniques in cultured rat cortical neurons. Under control conditions, recovery occurs at a rate of about 13 ms. In the presence of 100 pM of the compound of Example 1, recovery slows down to a rate of about 26 ms, and recovery is essentially complete after about 50 ms. Furthermore, Figure 3 shows that recovery from inactivation is 100%. Thus, the compound of Example 1 does not cause partial inactivation of sodium channels at rest. This is a desirable property for an anti-seizure compound, as it reduces high-frequency (epileptic) activity while causing little or no block of normal function.

[0058] As shown in Figure 4, the compound of Example 1 reduces seizures in a rodent kindling model of epilepsy. This model produces partial complex seizures similar to the temporal lobe seizures experienced by humans. Oral administration (20mg / kg) in a rodent model of amygdala stimulation kindling prevents the occurrence of stage 5 seizures.

[0059] Furthermore, as shown in Figure 5, the compound of Example 1 is shown to prevent the onset of epileptogenic seizures in the kindling model. Pre-prophylactic administration of the compound of Example 1 prevents the onset of seizures in the kindling model. Thus, the compounds of the present invention, such as the compound of Example 1, can be used for the prophylactic treatment or prevention of epileptogenesis.

[0060] As shown in Figure 6, the compound of Example 1 prevents the induction of seizure activity in a rodent model of traumatic brain injury / stress. After moderate traumatic brain injury under control conditions, stress induces epileptiform activity in the amygdala. This activity is shown on the left side of Figure 6, where the stressor induces an increase in activity. The fast Fourier transform sliding window spectrograph shown below the electrical response shows that this activity spans a frequency range up to 500 Hz (light gray / white indicates high amplitude power, dark gray / black indicates low amplitude power). On the right side of Figure 6, it is clear that the compound of Example 1 is particularly effective in preventing the induction of this response and reducing high frequency activity (i.e., >250 Hz) that is considered epileptogenic. This electrophysiological response in control traumatic brain injury rats was accompanied by stage 2 to 3 seizures (Racine scale: mean 2.0±0.5, n=6 rats). These behavioral responses were blocked in traumatic brain injury rats treated with the compound of Example 1.

[0061] As shown in Figures 7-9, there is data indicating that a prodrug / drug relationship exists between the compounds of Example 1 and Example 2. As shown in Figure 7, injection or oral absorption of the compound of Example 1 is only detectable as the free acid (compound of Example 2). All rats were dosed orally or intravenously with the compound of Example 1. The compound of Example 2 was the only molecule detected in significant amounts over a 24-hour period. These data indicate that there is a prodrug-drug relationship between the compounds of Example 1 and Example 2. In vitro screening of the compound of Example 2 showed similar efficacy to the compound of Example 1, indicating that the in vivo effects of the compound of Example 1 are likely mediated by the compound of Example 2.

[0062] As shown in FIG. 8, the time course of conversion of compound of Example 1 to compound of Example 2 is essentially complete within 1 hour of dosing in rats dosed with 20 mg / kg of compound of Example 1.

[0063] As shown in FIG. 9, the compound of Example 2 is stable and is not converted to further molecules in the plasma of humans administered the compound of Example 1.

[0064] Thus, the compound of Example 1 is likely converted to the compound of Example 2 in vivo, mediating the observed activity of the compound of Example 1. The compound of Example 1 may be useful as a prodrug, as it may have favorable bioavailability when administered orally.

[0065] Many embodiments of the invention have been described herein. Nevertheless, it will be understood that various modifications may be made without departing from the scope of the invention as set forth in the claims that follow.

Claims

1. Formula (I): 【Chemistry 1】 (I) [In the formula, R 1 =R 2 =CH 3 ; R 3 = C(O)R 5 , where R 5 =H, CH 3 , C 2 H 5 , CH(CH 3 ) 2 , C.H.H. 3 CN, or unsubstituted or CH 3 , O.H., O.C.H. 3 , S.O. 2 CH 3 , S.O. 2 Ph, F, Cl, CF 3 phenyl substituted with one or two selected from C(O)-O - , or C(O)-OR 6 , where R 6 is H, straight or branched C1-C6 alkyl, CH 2 C 6 H 5 or C3-C6 cycloalkyl; C(O)NH 2 , C(O)NHR 6、 C(O)N(H)phenyl, C(O)N(H)CH 2 Phenyl, C(O)N(CH 3 ) phenyl, or C(O)NR 7 R 8 , where R 7 and R 8 are each independently a straight or branched C1-C6 alkyl, CH 2 C 6 H 5 or unsubstituted or CH 3 , O.H., O.C.H. 3 , S.O. 2 CH 3 , S.O. 2 Ph, F, Cl, CF 3 phenyl substituted with one or two selected from 7 and R 8 Let's get together =(CH 2 ) m, where m is an integer from 3 to 5; OH, OCH 2 C 6 H 5 or OC(O)CH 3 ; S-CH 3 , S.C. 6 H 5 , S(O)CH 3 , S(O)C 6 H 5 , S.O. 2 CH 3 , or SO 2 C 6 H 5 ; NO 2 , N.H. 2 , N.H.R. 6 , or N.R. 7 R 8 ; C≡CC(O)CH 3 、C≡CC(O)CH(CH 3 ) 2 、C≡CC(O)C 2 H 5 、C≡CC(O)C 6 H 5 、C≡CC(O)-OH、またはC≡CC(O)-O - ;または CN; and R 4 =H, CH 3 , O.H., O.C.H. 3 , F, Cl, CF 3 , or CN; however, R 3 and R 4 cannot both be OH; R 4 If H, then R 3 OH, CO 2 H, CO 2 CH 3 , CO 2 C 2 H 5 , C(O)H, C(O)CH 3 , N.H. 2 , CN or NO 2 cannot be; and R 4 CH 3 If R 3 CO 2 CH 3 It is not possible. or a pharma- ceutically acceptable salt thereof.

2. R 3 = C(O)R 5 , where R 5 , H, CH 3 , C 2 H 5 , CH(CH 3 ) 2 , C.H.H. 3 CN, or unsubstituted or CH 3 , O.H., O.C.H. 3 , S.O. 2 CH 3 , S.O. 2 Ph, F, Cl, CF 3 phenyl substituted with one or two selected from C(O)-O - , or C(O)-OR 6 , where R 6 is H, straight or branched C1-C6 alkyl, CH 2 C 6 H 5 or C3-C6 cycloalkyl; C(O)NH 2 , C(O)NHR 6 or C(O)NR 7 R 8 , where R 7 and R 8 are independently straight or branched C1-C6 alkyl, CH 2 C 6 H 5 , unsubstituted or CH 3 , O.H., O.C.H. 3 , S.O. 2 CH 3 , S.O. 2 Ph, F, Cl, CF 3 phenyl substituted with one or two selected from 7 and R 8 Together, =(CH 2 ) ｍ and where m is an integer from 3 to 5; or OH, or OCH 2 C 6 H 5 2. The compound of claim 1, wherein: 【Request 3】 【Chemistry 2】 2. The compound of claim 1 selected from the group consisting of:

4. Formula (II): 【Chemistry 3】 (II) [In the formula, R 1 =R 2 =CH 3 ; R 3 =C4 or C5 cycloalkyl; CH 2 SC 6 H 5 ; CH=CHC(O)C 6 H 5 、CH=CHC(O)-O-CH(CH 3 ) 2 、CH=CHC(O)-OC 4 H 9 、またはCH=CHC(O)-OC 6 H 5 ; CH=CHCN; or CH=CHSO 2 CH 3 , or CH=CHSO 2 C 6 H 5 ] A compound represented by the formula:

5. R 3 is CH 2 SC 6 H 5 , CH=CHC(O)C 6 H 5 , CH=CHC(O)-O-CH(CH 3 ) 2 , CH=CHC(O)-OC 4 H 9 , or CH=CHC(O)-OC 6 H 5 5. The compound of claim 4,

6. The following formula: 【Chemistry 4】 The compound according to claim 1, which is a compound represented by the formula:

7. Formula (I): 【Chemistry 5】 (I) [In the formula, R 1 =R 2 =CH 3 or H; R 3 =H; F； C(O)R 5 , where R 5 =H, CH 3 , C 2 H 5 , CH(CH 3 ) 2 , C.H.H. 3 CN, or unsubstituted or CH 3 , O.H., O.C.H. 3 , S.O. 2 CH 3 , S.O. 2 Ph, F, Cl, CF 3 phenyl substituted with one or two selected from C(O)-O - , or C(O)-OR 6 , where R 6 is H, straight or branched C1-C6 alkyl, CH 2 C 6 H 5 or C3-C6 cycloalkyl; C(O)NH 2 , C(O)NHR 6、 C(O)N(H)phenyl, C(O)N(H)CH 2 Phenyl, C(O)N(CH 3 ) phenyl, or C(O)NR 7 R 8 , where R 7 and R 8 are each independently a straight or branched C1-C6 alkyl, CH 2 C 6 H 5 , unsubstituted or CH 3 , O.H., O.C.H. 3 , S.O. 2 CH 3 , S.O. 2 Ph, F, Cl, CF 3 phenyl substituted with one or two selected from 7 and R 8 Let's get together =(CH 2 ) m, where m is an integer from 3 to 5; OH、AND 3 ,AND 2 C 6 H 5 or OC(O)CH 3 ; S-CH 3 , S.C. 6 H 5 , S(O)CH 3 , S(O)C 6 H 5 , S.O. 2 CH 3 , or SO 2 C 6 H 5 ; NO 2 , N.H. 2 , N.H.R. 6 , or N.R. 7 R 8 ; C≡CC(O)CH 3 、C≡CC(O)CH(CH 3 ) 2 、C≡CC(O)C 2 H 5 、C≡CC(O)C 6 H 5 、C≡CC(O)-OH、またはC≡CC(O)-O - ;または CN; and R 4 =H, CH 3 , O.H., O.C.H. 3 , S.O. 2 CH 3 , S.O. 2 Ph, F, Cl, CF 3 , or CN] or a pharma- ceutical composition comprising a compound represented by the formula: (a) eliminating or reducing the severity of seizure activity or epileptic seizures; or (b) treating or preventing epileptogenesis; A pharmaceutical composition for use in treating

8. R 1 =R 2 =CH 3 and R 3 =H; C(O)R 5 , where R 5 =H, CH 3 , C 2 H 5 , CH(CH 3 ) 2 , C.H.H. 3 CN, or unsubstituted or CH 3 , O.H., O.C.H. 3 , S.O. 2 CH 3 , S.O. 2 Ph, F, Cl, CF 3 phenyl substituted with one or two selected from C(O)-O - , or C(O)-OR 6 , where R 6 is H, straight or branched C1-C6 alkyl, CH 2 C 6 H 5 or C3-C6 cycloalkyl; C(O)NH 2 , C(O)NHR 6 or C(O)NR 7 R 8 , where R 7 and R 8 are independently straight or branched C1-C6 alkyl, CH 2 C 6 H 5 , unsubstituted or CH 3 , O.H., O.C.H. 3 , S.O. 2 CH 3 , S.O. 2 Ph, F, Cl, CF 3 phenyl substituted with one or two selected from 7 and R 8 Together, =(CH 2 ) ｍ where m is an integer from 3 to 5; or OH, OCH 3 , or OCH 2 C 6 H 5 The pharmaceutical composition according to claim 7,

9. The compound of formula (I) 【Chemistry 6】 【Chemistry 7】 【Chemistry 8】 8. The pharmaceutical composition of claim 7, wherein the compound is selected from the group consisting of:

10. Formula (II): 【Chemistry 9】 (II) [In the formula, R 1 =R 2 =CH 3 or H; R 3 = straight or branched chain C1-C6 alkyl, or C4-C6 cycloalkyl, or unsubstituted or CH 3 , O.H., O.C.H. 3 , S.O. 2 CH 3 , S.O. 2 Ph, F, Cl, CF 3 phenyl substituted with one or two selected from CH 2 SC 6 H 5 , or C.H. 2 SO 2 C 6 H 5 ; SC 6 H 5 , S(O)C 6 H 5 , or SO 2 C 6 H 5 ; C(O)CH(CN)CH 3 ; CH=CHC(O)CH 3 、CH=CHC(O)C 6 H 5 、CH=CHC(O)-O-CH 3 、CH=CHC(O)-OC 2 H 5 、CH=CHC(O)-O-CH(CH 3 ) 2 、CH=CHC(O)-OC 4 H 9 、またはCH=CHC(O)-OC 6 H 5 ; CH=CHCN; or CH=CHSO 2 CH 3 , or CH=CHSO 2 C 6 H 5 ] or a pharma- ceutical composition comprising a compound represented by the formula: (a) eliminating or reducing the severity of seizure activity or epileptic seizures; or (b) treating or preventing epileptogenesis; A pharmaceutical composition for use in treating

11. R 1 =R 2 =CH 3 and R 3 is a straight or branched chain C1-C6 alkyl, or a C4-C6 cycloalkyl, or a phenyl; CH 2 SC 6 H 5 , or C.H. 2 SO 2 C 6 H 5 ; SC 6 H 5 , S(O)C 6 H 5 , or SO 2 C 6 H 5 ;or CH=CHC(O)CH 3 , CH=CHC(O)C 6 H 5 , CH=CHC(O)-O-CH 3 , CH=CHC(O)-OC 2 H 5 , CH=CHC(O)-O-CH(CH 3 ) 2 , CH=CHC(O)-OC 4 H 9 , or CH=CHC(O)-OC 6 H 5 The pharmaceutical composition of claim 10,

12. The compound of formula (II) 【Chemistry 10】 【Chemistry 11】 The pharmaceutical composition of claim 10, selected from the group consisting of:

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