GB2025931A - Methane-sulfonamide derivatives - Google Patents

Abstract

Methane-sulfonamide derivatives of the formula: <IMAGE> wherein R1, is a hydrogen or halogen atom, R2 and R3 are each independently a hydrogen atom or a straight or branched chain alkyl group having from 1 to 3 carbon atoms, and one of X and Y is a carbon atom and the other is a nitrogen atom, provided that the group: -CH2SO2NR2R3 is bonded to the carbon atom of either of X and Y, and the alkali metal salts thereof, and a process for their preparation. These compounds possess anticonvulsant activity and are useful as anticonvulsants for controlling convulsions and seizures in patients with epilepsy.

Description

SPECIFICATION Methane sulfonamide derivatives The present invention relates to novel methane-sulfonamide derivatives. The present invention provides a compound of the formula:

wherein R1 is a hydrogen or halogen atom, R2 and R3 are each independently a hydrogen atom or an alkyl group having from 1 to 3 carbon atoms, and one of X and Y is a carbon atom and the other is a nitrogen atom, provided that the group: -CH2SO2NR2R3 is bonded to the carbon atom of either of X ane Y, or an alkali metal salt thereof.

The term "halogen atom" denotes fluorine, chlorine and bromine atoms, and the term "alkyl" denotes a straight or branched alkyl group having 1 to- 3 carbon atoms, such as methyl, ethyl, propyl or isopropyl. The term "alkali metal salt" includes sodium and potassium salts.

The compounds of formula (I) includes the following two types of compounds:

In the course of intensive studies on sulfamoyl-alkyl derivatives of various benzazoles it has been found that when the sulfamoylmethyl group is introduced at the 3-position of 1 ,2-benzisoxazoles or at the 2-position of benzoxazoles, the resulting compounds possess excellent anticonvulsant activity.

Although some 3-sulfamoylmethylindole derivatives are disclosed in United States Patent Specification No. 3,833,608, the compounds of formula (I) of the present invention are clearly different from the indole derivatives disclosed in this patent specification both in their chemical structure and pharmacological properties.

Preferred compounds of the present invention are the compounds,of the formula (I) wherein R1 is hydrogen atom or a halogen atom at the 5- or 6-position of the ring and R2 and R3 are each independently a hydrogen atom or a methyl group. Particularly preferred compounds are the compounds of formula (I) wherein R, is a hydrogen atom or a 5- or 6-halogen atom and R2 and R3 are both hydrogen atoms. Examples are as follows, of which the first three compounds are particularly preferred.

3-Sulfamoylmethyl- 1 ,2 -benzisoxazole 5-FI uoro-3-sulfamoylmethyl 1 ,2-benzisoxazole 2-Sulfamoylmethylbenzoxazole 5-Chloro-3-sulfamoylmethyl 1 ,2-benzisoxazole 5-Bromo-3-sulfamoylmethyl-1 ,2-benzisoxazole 6-Fluoro-3-sulfamoylmethyl- 1 ,2-benzisoxazole The compounds of the formula (I) may be prepared by reacting a compound of the formula:

wherein R1, X and Y are as defined above, and Z is a halogen atom (e.g. chlorine or bromine), with an amine of the formula: wherein R2 andR3 are as defined above.

I he reaction of the compound of the formula (II) with the amine of the formula (III) may be carried out in the absence of a solvent, but is preferably be carried out in the presence of an inert solvent. The inert solvent may be water, an alcohol (e.g. ethanol or isopropanol), an aromatic hydrocarbon (e.g.

toluene or xylene), an ether (e.g. diethyl ether, tetrahydrofuran or dioxane), an ester (e.g. ethyl acetate), or a mixture of two or more thereof. Preferred solvents are ethers and esters.

The reaction is preferably carried out in the presence of a base as a dehydrohalogenating agent.

The base may be, for example, an alkali metal bicarbonate (e.g. sodium bicarbonate or potassium bicarbonate), an alkali metal carbonate (e.g. sodium carbonate or potassium carbonate), or an organic amine (e.g. triethylamine). Instead of using a specific base, an excess amount of the amine of formula (III) may be used, this amine acting as a reactant and also as a dehydrohalogenating agent.

The amine of the formula (III) is usually used in an amount of from 1 to 4 moles to 1 mole of the compound of the formula (II), but may be used in a large excess amount. The reaction temperature is not critical, but the reaction is usually carried out at a temperature in the range of from 0 C to 350C. The desired compound of the formula (I) can be isolated from the reaction mixture and purified in a conventional manner.

The starting compound of the formula (II) is prepared by reacting a halogenomethyl derivative of the formula:

wherein R1,X and Y are as defined above, and Hal is a halogen atom (e.g. chlorine, bromine or iodine), which is prepared by the similar process to that disclosed in Chem. Pharm. Bull. (Tokyo), Vol. 24, page 632 (1976) and Belgian Patent No. 624,463, with sodium sulfite in an inert solvent (e.g. aqueous methanol or aqueous ethanol) at a temperature of from 40CC to 800C to give a sodium methanesulfonate of the formula:

wherein R, X and Y are as defined above, and then reacting the resulting sodium methanesulfonate of the formula (V) with a halogenating agent (e.g. phosphorus oxychloride or phosphorus oxybromide).

The compound of the formula (I) wherein either one or both of R2 and R3 are hydrogen atoms may be reacted with an alkali metal compound in a conventional manner to give an alkali metal salt of the compound of the formula (I). The alkali metal compound may be, for example, an alkali metal hydroxide (e.g. sodium hydroxide or potassium hydroxide) or an alkali metal alcoholate (e.g. sodium ethylate).

The compounds of formula (I) and their alkali metal salts of the. present invention possess good anticonvulsant activity. Pharmacological test data for representative compounds of the present invention areigiven below together with the date for commercially available anticonvulsants.

(1) anti-maximal electroshock seizure activity in mice Male mice of STD-ddY strain were used. The test compounds were orally administered to the test animals (each group: 10 mice) in the form of a homogeneous suspension in a 0.5% tragacanth solution.

Maximal electroshock seizures (MES) were induced by the method of Swinyard [cf. J. Amer.

Pharm. Assoc., Vol. 38, page 201(1949)]. The animals were subjected to 60 Hz current of 25 mA for 0.2 second delivered through cornea electrodes after administration of the test compounds. Median effective dose (ED,), i.e. the dose which prevents hindlimb tonic extensor components of seizures in 50% of animals, was calculated by the method of lNitchfield and Wilcoxon [cf. J. Pharmacol. Exp. Ther., Vol. 96, page 99 11947)].

The EDso at peak effect time of the compounds is shown in Tables 1 a and 1 b.

TABLE la

Test compound ED50 (mg/kg, p.o.) No. R1 R2 R3 1 H H H 19.6 2 H H CH3 22.3 3 H H C2H5 38.9 A H H CH(CH3)2 56.0 5 H CH3 CH3 37.2 6 5-Cl H H 14.2 7 5-CI H CH3 ca. 20 8 5-Cl H C2Hs 21.3 9 5-Cl CH3 CH3 56.2 10 5-F H H 14.5 11 5-F H CH3 34.5 12 5-F H C2H5 31.6 13 5-F CH3 CH3 32.0 14 | 5-Br H H 13.5 15 5-Br H CH3 15.0 16 5-Br H C2H5 18.3 17 5-Br H CH(CH3)2 22.3 18 6-F H H 18.9 TABLE ib

Test compound No. R1 R2 R3 ED50 (mg/kg, p.o.) 19 H H H 12.0 20 H H CH3 17.2 21 H CH3 CH3 34.0 22 H H (CH2)2CH3 31.2 23 5-Cl H H 30.3 Diphenylhydantoin 7.6 Carbamazepine 13.2 Primidone 21.7 Phenacemide 61.2 [Note]: Diphenylhydantoin: 5,5-di phenyl-2,4imidazol idinedione Carbamezepine: 5H-dibenz[b,f]azepine-5-carboxamide Primidone; 5-ethyl-5-phenylhexahydropyrimidine-4,6-dione Phenacemide: phenylacetylurea The anti-MES activities of the compounds of this invention were more poterit than that of phenacemide, while less than that of diphenylhydantoin. The activities of some compounds of this invention were almost equal to or more potent than those of carbamazepine and primidone.

(2) Effect on coordinated motor movements in mice Mice trained to continue coordinated motor.movements for 100 seconds or more on a rotarod apparatus (2.5 cm in diameter at 11 RPM) were used [J. Amer. Pharm.Assoc., Sci. Ed., Vol 46, page 208(1957)]. impairment of coordinated motor movements was defined as the inability of the animals to stay on the rotarod for a 100 second test period. After oral administration of the test compounds the rotarod performance was tested at intervals of 1 hour for 6 hours. The median neutrotoxic dose (NTD50), i.e. the dose which caused 50% of the animals to fall from the rotarod was calculated by the method of Litchfield and Wilcoxon.

The NTD50 at peak effect time of the test compounds is shown in Table 2. The protective indices (NTD50/ED50 of anti-MES) of the test compounds were calculated and are also shown in the same table.

TABLE 2

NTD50 Test compound *1 (mg/kg, p.o.) Protective index) 1 292 (2) *2 14.9 10 154 (2) 10.6 19 168 (2) 14.0 Diphenylhydantoin 72 (6) 9.5 Carbamazepine 141 (1) 10.7 [Note]: *1) The test compounds 1, 10 and 19 are as defined in Tables la and 1b: *2) Figures in parentheses represent peak effect time in hours.

The neurotoxic effects of the compounds of this invention were about one-half to about onequarter as potent as that induced by diphenylhydantoin. The protective indices of the compounds of this invention were higher than that of diphenylhydantoin and were almost equal to or higher than that of carbamazepine. Therefore, the compounds of this invention have a wide separation of therapeutic effects from acute neurotoxic effects.

(3) Acute toxicity in mice Male mice of STDddY strain weighing 2022 g were used. The test compounds were orally administered to the test animals (each group: 10 mice) in the form of a homogeneous suspension in 0.5% tragacanth solution. The mortality wds observed for 7 days. The median lethal dose (LD60), i.e. the dose which causes death in 50% of animals, was calculated by Probit method.

The LD, of the test compounds is shown in Table 3. The safety index (LD50/ED50 of anti-MES) of each comp6und was calculated and is also shown in the same table.

TABLE 3

LD50 Test compound* (mg/kg, p.o.) Safety index 1 1829 93.3 10 1 1257 86.7 19 ca. 1800 Diphenylhydantoin 363 47.8 Carbamazepine 1700 129 [Note]: *) The test compounds 1,10 and 19 are as defined in Tables la and ib.

The acute lethal toxicities of the compounds of this invention were fairly weak compared with that of diphenylhydrantoin. The safety indices of the compounds of this invention were about twice as high as that of diphenylhydantoin, while their indices were somewhat lower than that of carbamazepine. The compounds of this invention have large safety margins as compared to di-phenylhydantoin.

As is clearfrom the above test results, the compounds of the formula (I) and their alkali metal salts of the present invention possess good anticonvulsant activity and have a low toxicity, and hence, these compounds are useful as anticonvulsants for controlling convulsions and seizures in patients with epilepsy.

The compounds of the present invention can be administered by an oral, parenteral or intrarectal route. The dosage of these compounds may vary in accordance with the particular compound the administration route, the age of the patient and the degree of the therapeutic effect desired, but is usually in the range of 1 to 100 mg/kg/day, preferably 3 to 50 mg/kg/day, which may be administered in a single dose or in divided doses.

The compounds of the present invention are usually administered in the form of a pharmaceutical composition which contains them in admixture with a pharmaceutical carrier. The pharmaceutical composition may be in dosage forms such as tablets, capsules, granules, fine granules, powders, syrups, suppositories or injections. These preparations can be prepared by conventional methods.

The carriers useful for these preparations include all organic or inorganic carrier materials which are usually used for pharmaceutical preparations and are inert to the active ingredient. Examples of carriers suitable for the preparation of tablets capsules, granules and fine granules are diluents such as lactose, starch, sucrose, D-mannitol, calcium sulfate, or microcrystalline cellulose; disintegrants such as sodium carboxymethylcellulose, modified starch, or calcium carboxymethylcellulose; binders such as methylceilulose, gelatin, acacia, ethylcellulose, hydroxypropylcellulose, or polyvinylpyrrolidone; lubricants such as light anhydrous silicic acid, magnesium stearate, talc, or hydrogenated oil.When formed into tablets, they may be coated in a conventional manner by using the conventional coating agents such as calcium phosphate, carnauba wax, hydroxypropyl methylcellulose, macrogol, hydroxypropyl methylphthalate, cellulose acetate phthalate, titanium dioxide or sorbitan fatty acid ester.

Examples of carriers suitable for the preparation of syrups are sweetening agents such as sucrose, glucose, fructose, or D-sorbitol; suspending agents such as acacia, tragacanth, sodium carboxymethylcellulose, methylcellulose, sodium alginate, microcrystalline cellulose, or veegum; dispersing agents such as sorbitan fatty acid ester, sodium lauryl sulfate, or polysorbate 80. When formed into syrups, conventional flavoring agents, aromatic substances or preservatives may optionally be added thereto. The syrups may be in the form of a dry syrup which is dissolved or suspended before use.

Examples of bases used for the preparation of suppositories are cacao butter, glycerin saturated fatty acid ester, glycerogelatin or macrogol.

When formed into suppositories, conventional surface active agents or preservatives optionally be admixed therewith.

When prepared for injection, the alkali metal salt of the compound is dissolved in distilled water for injection, to which may optionally be added conventional solubilizers, buffering or pH adjusting agents, isotonic agents preservatives and other suitable substances. The compositions may be in the form of solid dry preparations which are dissolved before injection.

The pharmaceutical compositions usually contain the compounds of formula (I) or their alkali metal salts as the active ingredient in an amount of 0.5% by weight or more, preferably 10 to 70% by weight, based on the total weight of the composition. These compositions may optionally contain other therapeutically active compounds.

The present invention is illustrated by the following Examples, but is not limited thereto. In Examples, the compounds were identified by elementary analysis, mass spectrum, IR spectrum, NMR spectrum, or the like.

EXAMPLE 1 1 ,2-Benzisoxazole-3-methanesulfonyl chloride: To a solution of 8.0 g of 3-bromomethyl-1 ,2-benzisoxazole (m.p. 64--660C) in 130 ml of methanol was added a solution of 8.1 g of sodium sulfite in 130 ml of water. The mixture was heated with stirring at 500C for 4 hours and concentrated under reduced pressure. The crystalline residue was dissolved in 250 ml of methanol with warming and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure and the crystalline residue was washed with diethyl ether to give crude sodium 1 ,2-benzisoxazole-3-methanesulfonate (1 0.5 g).

To 100 ml of phosphorus oxychloride was added 10.5 g of the above-mentioned sodium salt and the mixture was heated under reflux for 3 hours. The excess of phosphorus oxychloride was distilled off under reduced pressure. The residue was dissolved in 200 ml of ethyl acetate and the removal of the insoluble material by filtration gave the solution of the desired product.

EXAMPLE 2 The following compounds were prepared in substantially the same manner as in Example 1: 5-Fluroo-1 ,2-benzisoxazole3-methanesulfonyl chloride; 5-Chloro-1 ,2-benzisoxazole-3-methanesulfonyl chloride; -5-Bromo-1 ,2-benzisoxazole-3-methanesulfonyl chloride; 6-Fluorn1 ,2-benzisoxazole3-methanesulfonyl chloride.

EXAMPLE 3 3-Sulfamoyl methyl- 1 ,2-benzisoxazole: The solution of 1 ,2-benzisoxazole-3-methanesulfonyl chloride in ethyl acetate, which was prepared in Example 1, was cooled on an ice bath, saturated with dry ammonia gas, and allowed to stand at room temperature for one hour. After the removal of the insoluble material by filtration, the filtrate was concentrated to yield a crystalline solid, which was washed with a small amount of ethyl acetate and recrystallized from ethyl acetate to give the desired product (5.2 g), m.p. 1 60-1 630C.

EXAMPLE 4 5-FI uoro-3-sulfamoylmethyl-1 ,2-benzisoxazole: Sixty six grams of sodium 5-fluoro-1 ,2-benzisoxazole-3-sulfonate, which was prepared in substantially the same manner as described in the first paragraph of Example 1, was dissolved in 500 ml of phosphorus oxychloride and the solution was heated under reflux for 4 hours. After the removal of the remaining phosphorus oxychloride by distillation, the residue was dissolved in 500 mi of benzene and then filtered. The filtrate was concentrated under reduced pressure and the residue was dissolved in 500 ml of diethyl ether. The resulting solution was saturated with dry ammonia gas under cooling on an ice bath and allowed to stand at room temperature for 30 minutes. The solvent was evaporated under reduced pressure and the residue was extracted with ethyl acetate.The ethyl acetate layer was concentrated to a volume of about 100 ml under reduced pressure. The crystalline precipitate was collected and washed with benzene to give the desired product (32 g), m.p. 182--1850C.

EXAMPLE 5 Various compounds of the formula:

as listed in the following Table 4 were prepared in substantially the same manner as in Examples 3 and 4.

TABLE 4

R1 R2 R3 Melting point ( C) H H CH3 113 - 115 H H C2H5 76 - 78 H H (CH2)2 CH3 86 - 88 H H CH(CH3)2 114 - 117 H CH3 CH3 105 - 107 OF H OH3 141 - 144 5-F H C2H5 114 - 117 5-F H CH(CH3 )2 127 - 130 5-F CH3 CH3 145 - 148 6-F H H 187 - 190 5-CI H H 192 - 195 5-CI H CH3 148 - 151 5-CI H C2H5 150 - 152 5-CI H CH(CH3)2 114 - 116 5-Cl CH3 CH3 176 - 179 5-Br H H 221 - 225 5-Br H CH3 152 - 154 5-Br H C2H5 144 - 147 5-Br H CH(CH3)2 | 95 - 97 5-Br CH3 w CH3 -183 - 185 EXAMPLE 6 Benzoxazole-2-methanesulfonyl chloride:: To a solution of 3.0 g of 2-bromomethylbenzoxazole [prepared according to the procedures described in Belgian Patent No. 624,463] in 40 ml of methanol was added a solution of 1.9 g of sodium sulfite in 40 ml of water The mixture was heated with stirring at 600C for 6 hours and concentrated under reduced pressure to give crude sodium benzoxazole-2-methanesulfonate (4.5 g). To the sodium salt was added 1 5 ml of phosphorus oxychloride and the mixture was heated under reflux for one hour.

The removal of the remaining phosphorus oxychloride by distillation under reduced pressure gave the desired product as an oil.

EXAMPLE 7 2-Sulfamoylmethylbenzoxazole: The benzoxazole-2-methanesulfonyl chloride, which was prepared in Example 6, was dissolved in 100 ml of ethyl acetate, saturated with dry ammonia gas under cooling on an ice bath, and allowed to stand at room temperature for 30 minutes. Evaporation of the solvent under reduced pressure gave an oily residue, which was chromatographed on silica gel with 3% methanol-chloroform as eluent. The eluate was concentrated to dryness and the crystalline residue was recrystallized from ethyl acetate to give the desired product (0.4 g), m.p. 166-169 C.

EXAMPLE 8 5-Chlorobenzoxazole-2-methanesulfonyl chloride was prepared in substantially the same manner as in Example 6.

EXAMPLE 9 Various compounds of the formula:

as listed in the following Table 5 were prepared in substantially the same manner as in Example 7.

TABLE 5

R, R2 R3 Melting point (C) H H CH3 139 - 142 H CH3 CH3 109 - 111 H H (CH2)2 CH3 146 - 149 5-CI H H 188 - 191 EXAMPLE 10 Sodium salt of 3-sulfamoylmethyl- 1 ,2-benzisoxazole: To a solution of 7.0 g of 3-sulfamoylmethyl-1 ,2-benzisoxazole in 300 ml of ethanol was added a solution of sodium ethylate which was prepared from 0.76 g of sodium and 40 ml of ethanol.The mixture was allowed to stand at room temperature for a while and evaporated to one-fifth of its original volume under reduced pressure. The concentrated solution was cooled and the crystalline precipitate was collected, washed with ethanol and dried to give the desired product (6.5 g), m.p. 225-2300C (decompsotion).

EXAMPLE 11 The following compounds were prepared in substantially the same manner as in Example 10: Sodium salt of 5-fluoro-3-sulfåmoylmethyl-1,2-benzisoxazole, m.p. 240--2430C (decomposition); Sodium salt of 2-sulfamoylmethylbenzoxazole, m.p. 265-267 C (decomposition).

EXAMPLE 12 per 1,000 tablets 3-Sulfamoylmethyl-1 ,2-benzisoxazole 100 g Lactose 35 g Corn starch 17 g Microcrystalline cellulose 40 g Polyvinylpyrrolidone 6g Light anhydrous silicic acid 1.g Magnesium stearate 1g The above components were blended, granulated and made into tablets by a conventional method. 1,000 tablets each weight 200 mg were formed.

EXAMPLE 13 3-Sulfamoylmethyl-1 ,2-benzisoxazole 200 g Lactose 779 g Hydroxypropylcellulose 20 g Light anhydrous silicic acid 1g The above components were blended and made into fine granules by a conventional method.

EXAMPLE 14 The same procedures as in Examples 12 and 13 were repeated except that 5-fluoro-3- sulfamoylmethy!-1,2-benzisoxazole or 2-sulfamoylmethylbenzoxazoleSwas used instead of 3 sulfamoylmethyl-1 ,2-benzisoxazole. Thus, tablets and fine granules of each compound were prepared respectively.

Claims (16)

1. A compound of the formula:

wherein R1 is a hydrogen or halogen atom, R2 and R3 are each independently a hydrogen atom or an alkyl group having from 1 to 3 carbon atoms, and one of X and Y is a carbon atom and the other is a nitrogen atom, provided that the group: -CH2S02NR2R3 is bonded to the carbon atom of either of X and Y, or an alkali metal salt thereof.

2. A compound of the formula:

wherein R, is a hydrogen or halogen atom, and R2 and R3 are each independently a hydrogen atom or an alkyl group having from 1 to 3 carbon atoms, or an alkali metal salt thereof.

3. A compound of the formula:

wherein R1 is a hydrogen or halogen atom, and R and R3 are each independently a hydrogen atom or an alkyl group having from 1 to 3 carbon atoms, or an alkali metal salt thereof.

4. A compound as claimed in any one of the preceding claimsbwherein R1 is a hydrogen atom or a halogen atom at the 5- Br 6-position of the ring, or an alkali metal salt thereof.

5. A compound as claimed in claim 4, wherein R2 and R3 are each independently a hydrogen atom or a methyl group, or an alkali metal salt thereof.

6. A compound as claimed in claim 5, wherein R2 and R3 are both hydrogen atoms, or an alkali metal salt thereof.

7. 3-Sulfamoylmethyl-1 ,2-benzisoxazole or an alkali metal salt thereof.

8.5-Fluoro-3-sulfamoylmethyl-1,2-benzisoxazole or an alkali metal salt thereof.

9. 5-Chloro-3-sulfamoylmethyl-1 ,2-benzisoxazole or an alkali metal salt thereof.

10. 5-Bromo-3-sulfamoylmethyl-1 ,2-benzisoxazole or an alkali metal salt thereof.

11. 6-Fluoro-3-sulfamoylmethyl-1 ,2-benzisoxazole or an alkali metal salt thereof.

1 2. 2-Sulfamoylmethylbenzoxazole or an alkali metal salt thereof.

13. A process for the preparation of a compound of the formula:

wherein R1, R2, R3, X and Y are as defined in claim 1, which process comprises reacting a compound of the formula:

wherein R1, X and Y are as defined above and Xis a halogen atom, with an amine of the formula

wherein R2 and R3 are as defined above, and when either or both of R2 and R3 are hydrogen atoms, optionally converting the resulting compound into an alkali metal salt thereof.

14. A process as claimed in claim 13 wherein the group Z in formula (II) is a chlorine or bromine atom.

1 5. A process as claimed in claim 1 3 substantially as hereinbefore described with reference to any one of the foregoing Examples.

16. A compound as claimed in claim 1 whenever prepared by a process as claimed in any one of claims 13 to 15.

1 7. A pharmaceutical composition comprising as an active ingredient a compound of the formula:

as claimed in any one of claims 1 to 12, or claim 16 or an alkali metal salt thereof and a pharmaceutically acceptable carrier.