P-oxooxazolidinylbenzene sulfonamides as antibacterial agents

(74) Attorney General Tandbergs Patentkontor AS, Oslo.

(30) Priority Requested 04.12.81, 15.09.82, United States, Nos. 327583, 417569.

(54) Designation of the invention

METHOD OF ANALOGUE FOR THE PREPARATION OF THERAPEUTIC ACTIVE P-OXOOXAZOLIDINYLBENZENESULPHONAMIDES.

(57) Summary

Compounds of formula

<img file="NO156751B_D0001.tif" />

wherein R_l is -N (OR₂) R₃, -Nj, -NHNH2, -NX₂, ^_NR10^X' ^{NXZ or} -N = S (O)_nR₈R_g; r_{2 O}g R₃ is H, alkyl of 1-4 carbon atoms or cycloalkyl of 3-8 carbon atoms; Rj is

OOOO 0

H, -CRg, -C (CH₂)_mC-OH, -C-CH = CH-C-OH,

<img file="NO156751B_D0002.tif" />

<img file="NO156751B_D0003.tif" />

or

C-CH-R-;

i · nh₂ is aryl or alkyl of 1 H, alkyl of 1 to 5 carbon atoms, -CH 2 OH, or aralkyl; Rg and R_g are independently alkyl carbon atoms or are together - (CH₂) P; Rae_Q1-4 carbon atoms, X is Cl or Br, Z is or 3, n antibacterial activity.

carbon atoms, R-, 1 CH₂SH, aryl of 1-4 alkyl with physiol or 1, is one is is described.

of acceptable cation, m is and p is 3, 4 or 5

Preparation / of compounds (56) Published publications None.

U.S. Patent 4,128,654 discloses, inter alia, compounds of formula wherein

A = RS (0) ru X = Cl, Br or F, R = C 1 -C 4 alkyl, and n = 0, 1 or 2.

The compounds are described as being useful in the regulation of fungal and bacterial diseases in plants.

British Patent Specification 2003-151 describes the following compound as an anti-depressant:

0H

U.S. Patent 4,340,606 discloses antibacterial agents of general formula

<img file="NO156751B_D0004.tif" />

wherein

R_x = CH₃, C₂H₅, CF₂H, CF₃ or CF₂CF₂H, and X = OR₂.

The present invention relates to a method of analogy for the preparation of therapeutically active compounds of formula:

Ο ^Rr⁰2^S- &lt;§X ^ J '-ORj in which

R_T is -NR₂R₃, -N (OR₂) R₃, -Ν_β, -NHNH₂, -NX₂, -NR- x, ₀ -NXZ or -N = S (0)_nR_gR_g;

R₂ and R₃ is independently H, alkyl of 1-4 carbon atoms or cycloalkyl of 3-8 carbon atoms;

0 0

II II II

R₅ is H, -CRg, -C (CH₂)_mC-OH, ₅ R 1 is phenyl or alkyl of 1 to 12 carbon atoms;

⁵ 6 r and r_o is independently alkyl of 1-4 carbon atoms;

y

R 1 -Q is alkyl of 1-4 carbon atoms;

X is Cl or Br;

Z is a physiologically acceptable cation;

,₀ m is 2 or 3; and n is 0 or 1,

Test results indicate that the compounds of formula I are useful in alleviating bacterial infections in mammals.

,₅ Preferred because of their high antibacterial activity are those compounds wherein independently R_g is H and R 2 = NH₂ or NH-CH3. Particularly preferred because of their high antibacterial activity is the compound (¢,) - 4 [5- (hydroxymethyl) -2-oxooxazolidin-3-yl] benzenesulfonamide.

_i0 Physiologically acceptable cations (Z) include alkali or alkaline earth metal ions such as K +, Mg ++, Ca ++, Li + and Na +. Other suitable ions will be known in the art.

The analogous method of the invention is characterized in that

<img file="NO156751B_D0005.tif" />

wherein Y is a substituent containing an acyl group is contacted with a reactant selected from a suitable amine HNR₂R₃ or HN (OR₂) R₃, azidion N₃, or hydrazine, to form a compound of the formula

<img file="NO156751B_D0006.tif" />

wherein R₃ = NO₂R₃, N (OR₂) R₃, M2 or NHNH₂;

(b) optionally, the product of step (a) wherein R 2 = nh₂ is contacted with a preformed hypohalite or with halogen and a base to form a compound of the formula

<img file="NO156751B_D0007.tif" />

wherein X = Cl or Br;

(c) optionally contacting the product of step (b)

<img file="NO156751B_D0008.tif" />

<img file="NO156751B_D0009.tif" />

<img file="NO156751B_D0010.tif" />

<img file="NO156751B_D0011.tif" />

<img file="NO156751B_D0012.tif" />

<img file="NO156751B_D0013.tif" />

(i) further hypohalite at pH 4 - 8 to form a compound of the formula

<img file="NO156751B_D0014.tif" />

wherein X = Cl or Br; or (ii) a dialkyl sulfide, SRgRg, to form a compound of the formula

<img file="NO156751B_D0015.tif" />

(d) optionally, the product of step (c) (ii) is oxidized to give a compound of the formula

<img file="NO156751B_D0016.tif" />

(e) optionally, the product of step (a) wherein

R ^ = NR₂Rg, R₂= H and R 2 = alkyl of 1-4 carbon atoms, contacted with hypohalite to form the compound

<img file="NO156751B_D0017.tif" />

(f) optionally contacting the product of any of steps (a) - (e) with (i) an acid chloride R 2 COCl or anhydride (R 6 CO)₂O to form a compound of the formula

<img file="NO156751B_D0018.tif" />

(ii) having an anhydride of the formula

II ^A 0 in which _{A =} KH₂&gt;_m, \ cn

and m = 2 or 3, to form a compound of the formula

<img file="NO156751B_D0019.tif" />

The compounds of formula I wherein R 1 = H and R 2 = NR₂R₃, or N (OR₂) R₃represented by Formula Ia can be prepared as illustrated in Scheme 1.

56751

<img file="NO156751B_D0020.tif" />

This year₂= R₂ or OR₂) wherein Y is an acyl group.

The -OH function of 5-hydroxymethyl-3-phenyl-2-oxazolidinone (II) is blocked by refluxing this compound in a reagent which will introduce an acyl group, preferably an alpha-halogenated alkanoyl group. Suitable reagents for this purpose include trifluoroacetic anhydride, dichloroacetyl chloride, dichloroacetic anhydride, trichloroacetyl chloride, and trichloroacetic anhydride. The mixture is refluxed at a temperature in the range of 0 to 150 ° C, preferably 0 to 40 ° C. This step can be carried out in the absence of solvent or with any inert hydrocarbon or chlorinated hydrocarbon solvent. The resulting ester III is contacted with either a halosulfonic acid such as chlorosulfonic acid or fluorosulfonic acid at a temperature of from 30 to 40 ° C to form the sulfonyl halide of formula IV. This step can also be carried out in the absence of solvent or in chlorinated hydrocarbon solvents such as CHCl₃, CH₃CC1₃ or CC1₄. This product is then dissolved in a solvent such as tetrahydrofuran, ether, dioxane, 1,2-dimethoxyethane, dimethylformamide, dime thylacetamide or non-solvents, and is contacted with the appropriate amine, HNI 2 R 2 or HN (OR 2) R₃, at a temperature in the range of -20 to + 30 ° C, to give the compound of formula Ia.

Compounds of Formula I wherein R = H and R 2 - N₃represented by Formula Ib can be prepared by contacting the sulfonyl halide IV with sodium or potassium azide in an acetone-water mixture, as illustrated in Scheme 2. Suitable solvents include acetone, lower boiling ketone solvents such as methyl ethyl ketone, diethyl ketone and cyclopentanone, ether solvents and dipolar solvents.

Reaction Scenario 2:

IV

NaNn or CN, -----

<img file="NO156751B_D0021.tif" />

Ib

The azides Ib as well as the hydrazides Ic can also be prepared according to Scheme 3.

<img file="NO156751B_D0022.tif" />

5675

<img file="NO156751B_D0023.tif" />

<img file="NO156751B_D0024.tif" />

Scheme 3:

IV

H₉NNH₀ —0

<img file="NO156751B_D0025.tif" />

ic

<img file="NO156751B_D0026.tif" />

The sulfonyl halide IV is contacted with hydrazine to produce the hydrazide Ic. This can then be reacted with a nitrite such as sodium nitrite in dilute acid solution to form the azide Ib. The azide Ib can be reduced by any of several known methods to produce sulfonamide Ia. Suitable reduction methods include catalytic methods, reaction with sodium borohydride in an alcohol or in tetrahydrofuran, or reaction with zinc and acetic acid.

Compounds wherein R 2 = H and = NXZ, NX₂ or N = S (O)_nRgR4 can be prepared as illustrated in Scheme 4:

<img file="NO156751B_D0027.tif" />

Scheme 4;

<img file="NO156751B_D0028.tif" />

This year₂= R₃= H)

Θ hypohalite (OX) or________ base / Xj »

<img file="NO156751B_D0029.tif" />

<img file="NO156751B_D0030.tif" />

The halosulfonamide Id can be readily prepared by contacting a sulfonamide Ia L with halogen and a base such as sodium hydroxide, or with a pre-formed hypohalite such as sodium hypochlorite or calcium hypochlorite.

<img file="NO156751B_D0031.tif" />

5675

<img file="NO156751B_D0032.tif" />

<img file="NO156751B_D0033.tif" />

To prepare the Ν, Ν-dihalosulfonamide le, the pH is adjusted to a range of 4 to 8. Methods for adjusting the pH include the addition of acetic acid, carbon dioxide or dilute inorganic acid.

The sulfilimines If can be prepared by contacting the halosulfonamide Id with a dialkyl sulfide SRgR4 such as dimethylsulfide, trimethylene sulfide, methylethylsulfide or tetrahydrothiophene, preferably in a water alcohol solution. Oxidation of the sulfilimines with, for example, hypochlorite or metachloroperbenzoic acid gives the sulfoxymines Ig.

Compounds wherein =

NR 2 qX can be prepared as illustrated in reaction 5, by reaction with a hypohalite.

Scheme 5; _n hypohalite ^

OH

<img file="NO156751B_D0034.tif" />

<img file="NO156751B_D0035.tif" />

ih

Various simple esters represented by Formula I can be prepared as shown in Scheme 6 by reacting a compound of Formula Ia-Lh with the appropriate acid chloride or anhydride, preferably in the presence of a base such as pyridine or 4-dimethylaminopyridine. The preferred solvent is pyridine or other pyridine class solvents, although in many cases no solvent is required.

Reaction core 6:

<img file="NO156751B_D0036.tif" />

RgCOCl or (R_fiC0)₂0

<img file="NO156751B_D0037.tif" />

II

OCORg

Many of the simple esters may also be prepared by halosulfonating a compound of formula V as illustrated in Scheme 7. No solvent is required, but solvents inert to halosulfonic acid may be used. The product, sulfonyl halide VI, is then reacted with airPoniak or a suitable amine or an azide or hydrazine as set forth in Schemes 1, 2 and 3 to give the ester of formula Ij.

<img file="NO156751B_D0038.tif" />

<img file="NO156751B_D0039.tif" />

<img file="NO156751B_D0040.tif" />

<img file="NO156751B_D0041.tif" />

<img file="NO156751B_D0042.tif" />

<img file="NO156751B_D0043.tif" />

<img file="NO156751B_D0044.tif" />

Scheme 7:

<img file="NO156751B_D0045.tif" />

V

<img file="NO156751B_D0046.tif" />

OCOR₆

WE

HNR₂R₃, H₂NNH_2&gt;HN (0R₂) R₃ , or NaN ^ or KN ^

<img file="NO156751B_D0047.tif" />

NHNH₂ or Ij n (or₂) r₃

The starting material V can be prepared from 5hydroxymethyl-3-phenyl-2-oxazolidinone as shown in Scheme 8.

Reaction core 8:

R, -C ^ ♦ base ⁶ X

II ^XC1 S, v or hydride

Other esters of the invention Ik, can be prepared as illustrated in Scheme 9, by contacting an alcohol with a suitable anhydride:

Scheme 9:

<img file="NO156751B_D0048.tif" />

<img file="NO156751B_D0049.tif" />

and m is 2 or 3.

Suitable solvents are weak bases of the pyridine class and a suitable temperature range for the reaction is from 30 to 115 ° C.

The products obtained in the methods described above (Ia - im) are racemic mixtures, i.e. 50:50 mixtures of (+) and (-) enantiomers. The synthesis of optically active compounds can be achieved using as a starting material in Scheme 1, the compound? -5-hydroxymethyl-3-phenyl-2-oxazolidinone (IIa). This starting material can be obtained by desulfurization of β-3 - [(4-methylthio) phenyl] 5-hydroxymethyl-2-oxazolidinone (VII) as shown in reaction 10.

<img file="NO156751B_D0050.tif" />

<img file="NO156751B_D0051.tif" />

<img file="NO156751B_D0052.tif" />

<img file="NO156751B_D0053.tif" />

<img file="NO156751B_D0054.tif" />

<img file="NO156751B_D0055.tif" />

Scheme 10:

<td>-OH</td><td>u Ni (Raney)_K~ Ethanol&gt;</td>

<td>.f-isomer</td><td>2 isomer</td>

<td>VII</td><td>Ila</td>

A preferred process for the preparation of 5-hydroxymethyl-3-phenyl-2-oxazolidinone (Ha) is illustrated in Scheme 11.

Scheme 11:

<img file="NO156751B_D0056.tif" />

base

<img file="NO156751B_D0057.tif" />

OH

NHCH₂CHCH₂0H d-base (EtO), CO ______ ± _____

Glyme '

K₂C0j

CHjONa

<img file="NO156751B_D0058.tif" />

i-isomer IIa, Aniline in 2 to 10 molar excess is reacted with glycidol. The excess aniline is removed by distillation and (di, γ-3-phenylamino-1,3-propanediol is distilled under reduced pressure. It is dissolved by combining it with

60-60 mol% C-mandelic acid in chloroform or acetonitrile.

The desired salt crystallizes and can be purified by recrystallization from chloroform or acetonitrile. (d) -3-Phenylamino-1,3-propanediol can be isolated by contacting a base. The salt is suspended in water, the pH of the mixture is brought to between 8 and 10, the mixture is then saturated with sodium chloride and then extracted continuously with dichloromethane. Alternatively, the salt is dissolved in a water-alcohol mixture and passed over a strongly basic ion-exchange resin. In each case, the resulting extract or column eluate is concentrated to give (d) -3-phenylamino-1,3-propanediol. This product is then reacted with diethyl carbonate (or other carbonates such as dimethyl carbonate or diphenyl carbonate) in a polar solvent such as 1,2-dimethoxyethane using potassium carbonate and sodium methoxide as catalysts. The product is isolated by concentrating the solvent, diluting with water and some acetic acid, and washing with water. The product can be purified by recrystallization from 95% ethanol or acetonitrile. Using d-mandelic acid in this process, the d-isomer of 5-hydroxymethyl-3-phenyl-2-oxazolidinone can be obtained.

Another way to the optically active compounds consists in first conducting the reaction according to the reaction core 11 using optically active glycidol, preferably R-glycidol, to form the optically active base directly.

5-Hydroxymethyl-3-phenyl-2-oxazolidinone (IIa) can also be prepared from (R) - (+) - 1-benzylglycerol [S. Takano, E. Goto, M. Hirama and Ogasawara, Heterocycles, 16, 381 qc (1981)], followed by tosylation with p-toluenesulfonyl chloride in pyridine and reaction of this (S) tosyl ester (Vill) with the potassium salt of N-phenyl. 4-methylbenzenesulfonamide in a dipolar aprotic solvent such as DMF. It results

56751 The decomposing product (IX) is reacted with sodium naphthalene radical anion to give the product (X) which is reacted with diethyl carbonate or other carbonate ester in the presence of a catalytic amount of sodium methoxide, to give the desired β-isomer. This sequence of reactions is illustrated in the reaction nucleus 12:

Scheme 12:

<img file="NO156751B_D0059.tif" />

(S) -isomer VIII

<img file="NO156751B_D0060.tif" />

<img file="NO156751B_D0061.tif" />

(R) (d) -isomer (R) -isomer

IX

NaOCH ------&gt;

Ila (Et0)₂C0

The acidic compounds form salts with various inorganic and organic bases, which salts are within the scope of the invention. Such salts include alkali metal salts such as sodium and potassium salts, ammonium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as the lower aliphatic amines, benzylamine, dicyclohexylamine and salts with basic amino acids such as arginine. Example 1

4- [5-hydroxymethyl) -2-oxooxazolidin-3-yl] benzenesulfonamide (Κ_χ = NH₂, R₅ = H)

A solution of 247.3 g (1.00 mole) of N-phenyl-4methylbenzenesulfonamide containing 20 g of 1,4-diazabicyclo [2.2.2] octane (daBCO) in 950 ml of dimethylformamide (DMF) was stirred and heated under nitrogen and a solution of 70 ml of freshly distilled glycidol in 70 ml of DMF was added over 2 hours. The heating was continued for 1 hour and 40 minutes, and then an additional 35 ml of glycidol in 35 ml of DMF was added over 1 hour. The heating was continued for 5.5 hours. The reaction mixture was poured into 4 liters of cold water (some ice present) and the product, N- (2,3-dihydroxypropyl) -4-methyl-N-phenylbenzenesulfonamide crystallized. This was filtered and washed thoroughly in cold water to give 348 g of m.p. 91 - 94 ° C, and then recrystallized from 700 ml of toluene to give 312 g of mp 108.5 - 109.5 ° C.

56751

250 g of a 40% sodium dispersion in mineral oil was added to a solution of 600 g of naphthalene in 1.8 liters of 1,2-dimethoxyethane (Glyme) stirred under nitrogen and maintained at a temperature between 20 and 30 ° C. of the sodium was added, the mixture was stirred for 20 minutes and 305 g of N- (2,3-dihydroxypropyl) -4-methyl-Nphenylbenzenesulfonamide was added through a powder addition funnel while maintaining the temperature of the reaction mass below 35 ° C. After all of the solid material was added, the mixture was stirred for 1 hour. Water was then added until the color of the mixture fluctuated; from dark green or black to yellow; then concentrated hydrochloric acid was added until the solution was strongly acidic. The mixture was extracted twice with toluene and then three times with hexane, rinsed with nitrogen to remove hexane, saturated with sodium chloride and then basified with concentrated ammonium hydroxide. The product was extracted with dichloromethane and the extract was dried over potassium carbonate. The filtered dichloromethane was concentrated to give 132.3 g of 3-phenylamino-1,2-propanediol, a light yellow oil.

A mixture of 83.6 g (0.5 mole) of 3-phenylamino-1,2-propanediol, 250 ml of 1,2-dimethoxyethane and 61 ml of diethylcarbonate was refluxed under a nitrogen atmosphere. About. 0.15 g of solid sodium methoxide was added and the refluxing was continued for approx. 2.5 hours. The mixture was cooled, stirred with water and filtered to give 41.1 g of 5- (hydroxymethyl) -3-phenyl-2-oxazolidinone, m.p. 122 - 124 ° C. The 41.1 g was recrystallized from 100 ml of absolute ethanol to give 38.0 g of m.p. 125.5 - 126 ° C. An additional mass of 25.3 g (m.p. 124.5 - 125 ° C) was obtained from the aqueous filtrate by concentrated and crystallization from ethanol.

A mixture of 25.3 g of 5- (hydroxymethyl) -3-phenyl2-oxazolidinone and 100 g of trifluoroacetic anhydride was refluxed under nitrogen for 1 hour. All the solid material dissolved. The mixture was then concentrated under reduced pressure to give 41 g of an oil which crystallized on standing. This product was used without further purification.

About. 250 ml of chlorosulfonic acid was stirred thoroughly in a flask under nitrogen, while the above product was added over 15 minutes. The mixture was not cooled and the temperature remained between 30 ° C and 40 ° C. The solid dissolved during the development of heat and hydrogen chloride. The mixture was stirred at ambient temperature for 1 hour and 20 minutes and then poured onto ice. The product, (d 6) -4- [5- (trifluoroacetoxymethyl) -2-oxooxazolidin-3-yl] -benzenesulfonyl chloride, crystallized and was filtered and washed thoroughly with cold water and dried in a stream of nitrogen. The product was then dissolved in tetrahydrofuran and stirred in an ice bath while 18 ml of concentrated ammonium hydroxide was added and the temperature was maintained between 20 and 25 ° C. Concentration and filtration gave 24 g of the title compound, m.p. 154 - 156 ° C. This was recrystallized from acetonitrile to give 15.8 g of m.p. 167 168 ° C.

Example 2 4- [5- (Hydroxymethyl) -2-oxooxazolidin-3-yl] benzenesulfonamide (R₂, R $ = H)

300 g Raney nickel catalyst was added with stirring to a solution of 40.4 g (0.169 mol) of β -3 - [(4-methylthio) phenyl] -5-hydroxymethyl-2-oxazolidinone in 500 ml of absolute ethanol, and the resulting mixture was refluxed for 1 hour. A sample of the reaction mixture was checked by NMR indicating removal of the -SCH 2 group. The solution was then filtered and the reaction mixture was extracted repeatedly with boiling ethanol. The alcohol extracts were combined and concentrated to give 32.5 g of 5 -5-hydroxymethyl-3-phenyl-2-oxazolidinone, m.p.

134 - 136 ° C. This product was recrystallized from 115 ml of absolute ethanol to give 32.5 g of white crystals melting at 138 - 139.5 ° C. This product was recrystallized once more from 106 ml of absolute ethanol to give 28 , 9 g of product with m.p. 139 - 140 ° C.

56751

A mixture of 28.7 g (0.148 mol) of 5 -5-hydroxymethyl-3-phenyl-2-oxazolidinone in 100 ml of trifluoroacetic anhydride was boiled under reflux until the solid was dissolved. This mixture was concentrated under reduced pressure and the resulting oil was added to 200 ml of chlorosulfonic acid while maintaining the mixture at a temperature below 30 ° C. The mixture was stirred at ambient temperature for 2 1/4 hour and then poured over ice. The product which crystallized, (? -4- [5- (trifluoroacetoxymethyl) 2-oxooxarolidin-3-yl] benzenesulfonyl chloride) was filtered and washed with water and then added to a mixture of 60 ml of concentrated ammonia in 300 ml of THF while the temperature of the resulting mixture was kept at -10 ° C. The resulting mixture was stirred for 15 minutes at 0 ° C and for a further 30 minutes without external cooling. The mixture was then concentrated under reduced pressure to remove THF and diluted with water. The product was washed with water and filtered to give 32.1 g of the title compound, m.p. 182 - 184 ° C (A change of the crystal shape was observed at 158 ​​° C.) This was recrystallized from acetonitrile to give 25.5 g, m.p. 184.5 - 185 ° C. Example 3 (d 6) -Ν, Ν-Dimethyl and (dl) -N-methyl-4- [5- (hydroxymethyl) -2oxooxazolidin-3-yl] benzenesulfonamide (R or NHCH₃, R₅ = H)

A solution of 2.72 g (0.01 mol) (d 6) - [5- (hydroxyethyl) -2-oxooxazolidin-3-yl] benzenesulfonamide in 50 ml dry dimethylformamide (DMF) containing portion. 5 g of anhydrous potassium carbonate was stirred at 60 ° C while 0.62 ml of iodomethane in 10 ml of DMF was added. After this addition, the mixture was kept at 60 ° C for 1 hour and then concentrated under reduced pressure to distill out DMF. The residue (3.7 g) was taken up in dimethyl sulfoxide and chromatographed on silica gel to give an early distillate of 0.65 g (d 6) -N, Ndimethyl-4- [5- (hydroxymethyl) -2-oxooxazolidin-3 -yl] benzenesulfonamide, m.p. 174 - 176 ° C. A second distillate of 1.05 g (d d) -N-methyl-4- [5- (hydroxymethyl) -2-oxooxazolidin-3-yl] benzenesulfonamide, m.p. 164 - 166 ° C were also obtained.

Example 4 (d 6) -4- [5- (hydroxymethyl) -2-oxooxazolidin-3-yl] benzenesulfonyl azide (R R = Ng, Rg = H)

A solution of 10 g of sodium azide in 20 ml of water was added to 200 ml of reagent grade acetone and then cooled to -5 ° C. A 19 g portion of (d 6) -4- [5- (trifluoroacetoxymethyl) -2-oxooxazolidine-2 3-yl] benzenesulfonyl chloride (prepared as described in Example 1) was added to the solution keeping the temperature below 0 ° C. After stirring the mixture for 1 hour, it was allowed to stand overnight. The acetone was removed under reduced pressure, water was added and the product was filtered and washed with water to give 12.8 g, m.p. 108-110 ° C. This product was stirred with 250 ml of acetonitrile at 25 ° C and filtered for to remove any insoluble material. The acetonitrile was concentrated and the crystallized product was filtered to give 12.3 g. This product was recrystallized from ethyl acetate to give 6.0 g of the title compound, m.p. 112 - 113 ° C.

Example 5 4- [5- (Hydroxymethyl) -2-oxooxazolidin-3-yl] benzenesulfonyl azide (R (= Ng, Rg = H)

A solution of 5 g of sodium azide in 10 ml of water was added to 100 ml of reagent grade acetone and then cooled to -5 ° C. A 7 g portion of £ -4- [5- (trifluoroacetoxymethyl) -2-oxooxazolidine-2 3-yl] benzenesulfonyl chloride (prepared as described in Example 2) was added while maintaining the temperature of the mixture between -5 and 0 ° C. After stirring the mixture for 1 hour at 0 ° C, it was allowed to stand overnight and the acetone removed under reduced pressure. Water was added and the solid was filtered and washed with water to give 4.8 g of m.p. 136-138 ° C. This solid was recrystallized from ethyl acetate to give 4 g of the title compound, mp 137-138 ° C.

Example 6 4- [5- (Hydroxymethyl) -2-oxoocazolidin-3-yl] -N-methylbenzenesulfonamide (+ = NHCH2 = H)

A solution of 10 ml of methylamine in 200 ml of dry tetrahydrofuran (THF) was stirred while 6.3 g of 4- [5- (trifluoroacetoxymethyl) -2-oxooxazolidin-3-yl] benzenesulfonyl chloride was added. The mixture was kept at a temperature of -10 ° C or lower during this addition and then allowed to warm to room temperature while stirring overnight. After removal of THF under reduced pressure, water was added and a white material was filtered off and washed with water to give 4.41 g of product, m.p. 137 - 142 ° C. Recrystallization from acetonitrile gave 3.83 g of the title compound, m.p. 137 - 138 ° C.

Example 7 4- [5- (Hydroxymethyl) -2-oxooxazolidin-3-yl] -N-cyclopropylbenzenesulfonamide (R_g = H)

A solution of 6 ml of cyclopropylamine in 50 ml of tetrahydrofuran was stirred in an ice bath while the temperature was kept below 30 ° C and while 9.3 g of 4- [5- (trifluoroacetoxymethyl) -2oxooxazolidin-3-yl] benzenesulfonyl chloride (see Example 2) was added. The mixture was stirred for 1 hour, the tetrahydrofuran was removed under reduced pressure and the residue was diluted with water and acidified with dilute hydrochloric acid. The solid was filtered, washed with water and dried. The yield of the title compound was 7.06 g with m.p. 129 - 147 ° C.

This was crystallized from 30 ml of acetonitrile to give 2.0 g of m.p. 161.8 - 163.4 ° C.

Example 8

1- [[5- (hydroxymethyl) -2-oxooxazolidin-3-yl] -N-methoxy] benzenesulfonamide (R R = NHOCH ^, R R = H)

A solution of 3 ml of methoxyamine (O-methylhydroxylamine) in 50 ml of tetrahydrofuran was stirred and cooled to -5 to 10 ° C while a solution of 4.4 g of -4- [5- (trifluoroacetoxymethyl) -2-oxooxazolidine-3 -yl] benzenesulfonyl chloride (see Example 2) in 20 ml of tetrahydrofuran was added over a 15 minute period. A white solid separated. The mixture was allowed to warm to room temperature and filtered and concentrated to give a colorless gum. This (4.5 g) was chromatographed using

Water Co. Prep-500 using a 45% acetonitrile;

% dichloromethane solvent mixture. A fifth mass (1.8 g) was crystallized from ethyl acetate using 1.04 g of the title compound, m.p. 129.6 131.5 ° C. This was boiled with 13 ml of ethyl acetate, cooled o

and filtered to give 0.73 g of m.p. 130 - 132.5 C. Also, sample 9 (d) - N, N-dichloro-4- [5- (hydroxymethyl) -2-oxooxazolidin-3-yl] benzenesulfonamide (R )

A 2 g portion (d 6) -4- [5- (hydroxymethyl) -2oxooxazolidin-3-yl] benzenesulfonamide in a mixture of 10 ml water and 50 ml dichloromethane was stirred in an ice bath and 27 ml 5.25% sodium hydrochlorite (Clorox) was added. All the solid material was dissolved and a precipitate formed. The filtered dichloromethane was separated, dried and evaporated to give 1.54 g of the title compound, mp 121.5 - 123 ° C (decomposition). An additional 1.24 g was an insoluble material and had the same infrared curve as the above sample.

Example 10 (β) -N, N-dichloro-4- [5- (hydroxymethyl) -2-oxooxazolidin-3-yl] benzenesulfonamide

A suspension of 1.00 g (β) -4- [5-hydroxymethyl) -

<img file="NO156751B_D0062.tif" />

<img file="NO156751B_D0063.tif" />

<img file="NO156751B_D0064.tif" />

<img file="NO156751B_D0065.tif" />

<img file="NO156751B_D0066.tif" />

<img file="NO156751B_D0067.tif" />

<img file="NO156751B_D0068.tif" />

2-oxoocazolidin-3-yl] benzenesulfonamide in 1 ml of water was stirred in an ice bath while 13.5 ml of 5.25% sodium hypochlorite (Clorox) was added. The solution was then made slightly acidic by the addition of acetic acid, and the product separated as white crystals (1.24 g), m.p. 124.5 - 125.5 ° C. Example 11 (di) -N-chloro-4- [5- (hydroxymethyl) -2-oxooxazolidin-3-yl] benzenesulfonamide, sodium salt (R = NC1Na, R4 = H)

2.0 g (dJt) -4- [5- (hydroxymethyl) -2-oxooxazolidine

3- yl] benzenesulfonamide was stirred in 10 ml of water on an ice bath while 13.5 ml of 5.25% sodium hypochlorite (Clorox) was added. The solid was dissolved and crystals were then separated. These were filtered and washed with a small amount of cold water and dried. The yield of the title compound was 1.97 g (decomposition upon heating above 138 ° C). Example 12 (i) -N-Chloro-4- [5- (hydroxymethyl) -2-oxooxazolidin-3-yl] benzenesulfonamide, sodium salt g (i) -4- [5- (hydroxymethyl) -2-oxooxazolidin-3yl] benzenesulfonamide in 1 ml of water was stirred in an ice bath while

6.5 ml of sodium hypochlorite (Clorox, 5.25% sodium hypochlorite) was added. The solid was dissolved and then a white solid crystallized. The product was filtered and washed once with a small portion of ice water (1.15 g), mp 165 DEG-167 DEG C. (decomposition). Example 13 (di) -N- {4- [5- (hydroxymethyl) -2-oxooxazolidin-3-yl] phenylsulfonyl} -S, S-dimethylsulfilimine (R 1 = N = S (CH_?)₂, R₅ = H)

A suspension of 2.00 g of (di) -4- [5- (hydroxymethyl) 2-oxooxazolidin-3-yl] benzenesulfonamide in 10 ml of water was stirred and 11.5 ml of 5.25% sodium hypochlorite (Clorox) was added. Practically all of the starting material was dissolved. The solution was filtered and 25 ml of ethanol was added, followed by 10 ml of dimethyl sulfide. The mixture was stirred thoroughly for 30 minutes and then concentrated to a colorless glassy mass. The product was dissolved in acetonitrile and chromatographed using a Waters Prep-500 HpLc. The yield of the pure title compound was 1.74 g with melting point 162.5 - 164.5 ° C (a crystal conversion was observed at 136 ° C).

Example 14 (d 6) -3- [4-Hydrazinosulfonyl) phenyl] -5- (hydroxymethyl) -2oxazolidin-2-one (R ~ NHNH₂, R = H)

A 30 gm percent (d 6) -4- [5- (trifluoroacetoxymethyl) -

2- oxooxazolidin-3-yl] benzenesulfonyl chloride was added to a solution of 6 ml of hydrazine hydrate in 300 ml of tetrahydrofuran maintained at -10 to 0 ° C. After stirring for 30 minutes, the mixture was allowed to warm to ambient temperature. The tetrahydrofuran was evaporated in a stream of nitrogen and the residue was diluted with water and filtered. The yield was 11.81 g, m.p.

172 - 174 ° C (decomposition). The product was purified by dissolving in 30 ml of dimethyl sulfoxide, the solution was filtered and diluted with methanol; yield 8.8 g, m.p. 173 ° C (decomposition).

Example 1.5 (d 6) -4- [5- (Acetoxymethyl) -2-oxooxazolidin-3-Thyl] benzenesulfonamide (R 1 NH 2, R 1 = OCH 2)

A mixture of 19.3 g (0.10 mol) (d 6) -5- (hydroxymethyl) -3-phenyl-2-oxazolidinone, 50 ml acetonitrile, 11 ml acetic anhydride and 0.1 g 4-dimethylaminopyridine was boiled under reflux for 30 minutes. This mixture was concentrated under reduced pressure to give a crude oil which IR and MMR determined contained (d 6) -5- (hydroxymethyl) -

3-phenyl-2-oxooxazolidinone acetate.

The oil was added to 130 ml of chlorosulfonic acid, stirred at ambient temperature for 2 hours and then poured into 3 liters of ice. The remaining oil was extracted into methylene chloride and dried over sodium sulfate. The methylene chloride was concentrated and the remaining oil (10.9 g) was added to a mixture of 300 ml of THF and 60 ml of concentrated ammonium hydroxide cooled to -10 to 0 ° C. THF was removed under reduced pressure and the residue was diluted with water and filtered to give 8.8 g of m.p.

196.5 - 197 ° C. Recrystallization from acetonitrile gave 6.3 g of the title compound, mp 199 - 200 ° C.

Example 16

Preparation of starting material

The l · A ⁵ 48 g (0.263 mol) (R) - (+) - 1-benzylglycerol was prepared by the procedures described by S. Takano, E. Goto, M. Hirama and Ogasawara in Heterocycles, 16, 381 (1981) and references. specified therein. This was tosylated by the indicated procedure to give 57.8 g of a colorless oil.

A mixture of 37.1 g (0.15 mole) of N-phenyl-4-methylbenzenesulfonamide in 150 ml of dry DMF was stirred and 17 g of potassium t-butoxide was added, followed by 55 g of the above tosylate. The mixture was heated to 95 - 100 ° C for 15 hours. The mixture was poured into ice water and the product extracted into ether. The ether was washed back with water and dried over sodium sulfate to give 57.1 g of product. Thin layer analysis on silica gel showed three components and some starting sulfonanilide. 57.1 g of product 20 was dissolved in 1.5 liters of ether, stirred with 100 ml of 25% aqueous sodium hydroxide and filtered through a layer of Celite® filter excipient. The ether was concentrated to give 32.7 g of oil. This was chromatographed on silica gel columns and eluted with 90% toluene: 10% ethyl 25 acetate in two experiments to give 17.02 g of solid product, mp 88-99 ° C. The product is 4-methyl-N-phenyl [2- hydroxy-3- (phenylmethoxy) propyl] benzenesulfonamide.

A solution of 16.5 g (0.049 mol) of 4-methyl-N-phenyl. [2-Hydroxy-3- (phenylmethoxy) propyl] benzenesulfonamide in 100 ml of dry 1,2-dimethoxyethane was stirred under nitrogen while a solution of sodium naphthalene radical anion (prepared by adding 20 ml of a 40% dispersion of sodium metal in mineral oil to a solution of 40 g of naphthalene in 100 ml of dry 1,2-dimethoxyethylene while maintaining the mixture at 25 DEG C. under nitrogen) was added. The addition continued until the color of the mixture changed and was dark green to black. After completion of the addition, the temperature was allowed to rise to 40 ° C. After stirring for 30 minutes, 20 ml of water was added followed by 125 ml of 20% sulfuric acid. The temperature was maintained between 30 and 40 ° C during acidification. 1,2-Dimethoxyethane was removed by vacuum distillation. The water and residue were extracted six times with toluene, twice with methylene chloride and then flushed with nitrogen to remove the methylene chloride. The water was then saturated with sodium chloride and extracted five times with methylene chloride. The extracts were dried over anhydrous potassium carbonate, filtered and concentrated to give 6.0 g of colorless oil. This product is d-3-phenylamino-1,2-propanediol.

6.0 g (0.036 mol) portion of d-3-phenylamino-1,2-propanediol was combined with 10 ml of 1,2-dimethoxyethane and 5 ml of diethyl carbonate and refluxed. To the boiling solution was added 0.1 g of sodium methoxide. After 10 minutes, a solid was separated and 5 ml of additional 1.2 ~ dimethoxyethylene was added. The reflux was continued for 30 minutes, after which 1 ml of acetic acid was added and the mixture was concentrated under reduced pressure to give 7.2 g of solid. This was extracted with hot acetonitrile and the acetonitrile was concentrated to give 1.8 g of the title compound, mp 136.5 - 138 ° C.

the product [aJ_D is -67.1 (C = 1 acetonitrile). Pel B

An 1820 ml portion of aniline was heated with stirring and under nitrogen to 80 - 85 ° C. To this solution was slowly added 265 ml of freshly distilled glycidol at such a rate that the temperature was kept at 85 90 ° C. - 100 ml of glycidol was added, the outer heat source was removed and the reaction temperature was then regulated at the rate of addition and occasional cooling. After the addition was applied, heat was added to maintain the temperature at 80 - 90 ° C for 2 hours. The product (d.) - 3-phenylamino-1,3-propanediol was distilled through a short column at 4.0 - 4.5 mm pressure to remove the aniline which distilled at 50-55 ° C (1.5 liters). was recovered). The product was distilled at 0.05 mm with boiling point 132-135 ° C, yield 588 g of a colorless viscous oil.

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<img file="NO156751B_D0070.tif" />

675

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<img file="NO156751B_D0072.tif" />

A solution of 1201 g (7.18 mol) (dH) -3-phenylamino-1,3-propanediol in 1.9 liters of chloroform was stirred and 600.1 g (3.95 mol) of 1-mandelic acid was added. The mixture was heated to reflux to dissolve the solid. It was then allowed to cool slowly and the salt was precipitated as crystals. After reaching room temperature, the solid was filtered and washed by stirring with chloroform three times. The dry yield was 868 g (d) -3-phenylamino-1,2-propanediol (β) -mandelate, m.p. 86 This was recrystallized by refluxing with 2.8 liters of chloroform, slow cooling and filtration and washing three times with chloroform to give 754 g of m.p. 87-88 ° C.

A suspension of 845 g (d) -3-phenylamino-1,2-propanediol (f) -mandelate in 300 ml of water was stirred on an ice bath while a cold solution of 108 g of sodium hydroxide in 300 ml of water was added. The solution was saturated with sodium chloride and then extracted continuously with dichloromethane. The extract was concentrated in vacuo to give 446.9 g (d) -3-phenylamino-1,2-propanediol, a colorless oil. The optical rotation of the product was [α] 23 = + 21 ° (C = l in ethanol, red in 200 cm tube).

A mixture of 441.5 g (2.60 mol) (d) -3-phenylamino-1,2-propanediol, 325 ml diethyl carbonate, 300 ml 1,2-dimethoxyethane, 40 g potassium carbonate and 1 g sodium methoxide was refluxed for 2 hours. hours. At this time, an additional 20 g of potassium carbonate was added. After 3.5 hours, an additional 50 ml of diethyl carbonate was added.

The refluxing was continued for 15 hours. A thin layer chromatogram showed that the reaction was complete. About. half of the solution needle was removed in vacuo and 500 ml of water and 40 ml of acetic acid were added. The white solid was filtered and washed with water, 70% ethanol and ether to give 401.7 g of the title compound, m.p. 137.5 - 138.5 ° C. This was crystallized from 1 liter of 95% ethanol to give 368.1 g of m.p. 138.6 - 139.1 ° C. This was recrystallized from

700 ml of acetonitrile to give 330.4 g of m.p.

138.5 - 139.5 ° C. The optical rotation of the product [α] + is -72.0 (C = 1 acetonitrile).

Example 17 (d,) -4- [5- (benzoylmethyl) -2-oxooxazolidin-3-yl] benzenesulfonamide (R₂, R ^ = C (O) CgH ^

A solution of 5.0 g (18.3 mmol) (d £) -4- [5- (hydroxymethyl) -2-oxooxazolidin-3-yl] benzenesulfonamide in 50 ml of dry pyridine was stirred with cooling at -8 ° C. to 0 ° C while 2.54 ml of benzoyl chloride was slowly added. A slight exothermic reaction was observed. After the addition was complete, the mixture was allowed to warm to 25 ° C and stirring was continued for 2 hours. An additional 0.2 ml of benzoyl chloride was added and the mixture was allowed to stand overnight. The mixture was then poured over ice and the product crystallized. It was filtered and washed thoroughly with water and dried. The yield was 6.72 g. This was recrystallized by dissolving in hot diethylene glycol dimethyl ether, concentration to half the volume and standing. Yield: 3.55 g with m.p. 233 - 234 ° C.

Example 18 (d 6) -4- [5- (propionyloxymethyl) -2-oxooxazolidin-3-yl] benzenesulfonamide (R₂, R5 - C (O) CH₂CH₃

A solution of 5.0 g (18.3 mmol) of (d £) -4- [5- (hydroxymethyl) -2-oxooxazolidin-3-yl] benzenesulfonamide in 50 ml of dry pyridine was stirred in an ice bath while 1.60 ml of propionyl chloride was added. The mixture was warmed to ambient temperature and allowed to stand overnight. It was then poured into 200 ml of ice-water, the water acidified with hydrochloric acid while kept cold, and the crystalline product filtered and washed with cold water. The yield was 3.60 g, m.p. 211 - 212.5 ° C. This was recrystallized from nitromethane to give 3.32 g of m.p. 212 - 213.5 ° C.

6751

Example 19 (d &amp;) - butanedioic acid, monoester with 4- [5- (hydroxymethyl) -2oxooxazolidin-3-yl] benzenesulfonamide (Ε_χ = NH_?, Rg = C (O) CH₂CH₂COOH) _________________________

A solution of 5.0 g (18.3 mmol) (d 6) -4- [5 (hydroxymethyl) -2-oxooxazolidin-3-yl] benzenesulfonamide in 50 ml of pyridine and 2.02 g of succinic anhydride was stirred and heated in 2 hours at 60 ° C. The reaction mixture was poured into 100 ml of ice-water and the pH was brought to 3 by the addition of concentrated hydrochloric acid (while keeping the mixture cold). The solution was saturated with sodium chloride and extracted with tetrahydrofuran. The extract was dried over sodium sulfate and concentrated to give 7.96 g of crystals. The solid was stirred in 50 ml of water and 20% potassium bicarbonate was added until the pH was equal to 10. The product was then filtered and the filtrate brought back to pH = 2 with hydrochloric acid. The product was filtered and dried to give 4.80 g, mp 167-170 ° C.

The sodium salt of this product was prepared by suspending 2.4 g of the above solid in 50 ml of water, adding 1N NaOH until the pH was 7, filtering and concentrating in vacuo to give 2.35 g of a white solid material.

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• Dosage forms

The antibacterial agents of the invention can be administered in any manner which provides contact between the active agent with the agent's site of action in the body of a mammal. They may be administered by any conventional means available for use in conjunction with pharmaceutical preparations, either as individual therapeutic agents or in combination with therapeutic agents. They can be administered on their own, but administered¹⁰ Generally, a pharmaceutical carrier is selected based on the method of administration chosen and standard pharmaceutical practice.

The dose administered will of course vary depending on known factors such as the pharmacodynamic characteristics of the particular agent and its mode of action and mode of administration; age, health, and weight of the recipient, nature and degree of symptoms, type of concomitant treatment, frequency of treatment and desired effect. Usually, a daily dose of the active ingredient may be from 5 to

20 mg per day kg body weight. When more potent compounds are used, usually 5 to 15, and preferably 5 to 7.5 mg per ml. kg per per day, given in divided doses two to four times per day. day or in an extended release form, be effective in achieving the desired results. These drugs can also be administered parenterally.

Dosage forms (compositions) suitable for interal administration contain from 1.0 mg to 500 mg of active ingredient per day. unit. In these pharmaceutical compositions, the active ingredient will usually be present in an amount of from 0.5 to 95% by weight based on the total weight of the composition.

The active ingredient may be administered orally in solid dosage forms such as capsules, tablets and powders, or in liquid dosage forms such as elixirs, syrups and suspensions, it may also be administered parenterally in sterile liquid dosage forms.

Gelatin capsules contain the active ingredient and powdered carriers such as lactose, sucrose, mannitol, starch, cellulose derivatives, manganese stearate, stearic acid and the like. Similar diluents can be used to make tablets. Both tablets and capsules can be prepared as extended release products to provide a continuous drug release over a period of several hours. Pressed tablets may be sugar-coated or film-coated to mask any unintended taste and protect the tablet from the atmosphere, or enteric coated for selective breakage in the gastrointestinal tract.

Liquid dosage forms for oral administration may contain dyes and flavoring agents to enhance patient confidentiality.

In general, water, suitable oil, saline, aqueous dextrose (glucose) and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions. Preferably, solutions for parenteral administration contain a water-soluble salt of the active ingredient, suitable stabilizers and, if necessary, buffer compounds. Antioxidants such as sodium bisulfate, sodium sulfite or ascorbic acid, either alone or in combination, are suitable stabilizers. Also used are citric acid and its salts and sodium EDTA.

In addition, parenteral solutions may contain preservatives such as benzalkonium chloride, methyl or propylparaben and chlorobutanol.

Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, EW Martin, a standard publication in the art.

Convenience

Test results indicate that the new compounds are active against a wide range of aerobic, facultative anae robe and obligate anaerobic bacterial isolates including beta-lactamase-producing Staphylococcus aureus and Neisseria gonorrhoea strains, members of the Gram-negative Enterobacteriaceae and Pseudomonas aeruginosa. The antibacterial spectrum of these agents comprises organisms recognized as major pathogens within their human mediators and the veterinary medicine of the respiratory system, the gastrointestinal system, the genitourinary system and the central nervous system; blood, interstitial fluids, soft tissues and bones.

A list of analogs exhibiting in vitro antibacterial efficacy is given in Table I. A standard micro-dilution method (Conrath, Theodore,, 1972 Handbook of Microtiter Procedures, Dynatech Corporation, Cambridge, Massachusetts) with Mueller-Hinton nutrient was used for to determine the minimum inhibitory concentration (MIC) for 24 hours for the test strain of Staphylococcus epidermidis and E. coli.

Table I

MIC concentrations in vitro liquid dilution

<img file="NO156751B_D0075.tif" />

<td rowspan="2"> 10</td><td rowspan="2"></td><td rowspan="2">Chemical name S.</td><td colspan="2">Mikrofortynningsvæske</td>

<td>MIC: epidermidis</td><td>pg / ml E. coli</td>

<td> 15</td><td>NH₂</td><td>(D, 1) -4- [5- (hydroxymethyl) -2oxooxazolidin-3-yllbenzensulfonamid</td><td> 62.5</td><td> 62.5</td>

<td></td><td>NH₂</td><td>(I) -4- [5- (hydroxymethyl) -2oxooxazolidin-3-yllbenzerrsulfonamid '</td><td> 31.3</td><td> 31.3</td>

<td> 20</td><td>N (CH₃)₂</td><td>(d, l) -4- [5- (hydroxymethyl) -2-oxooxazolidin-3-yl] -N, Nd imethylbenzenesulfonamide</td><td> 50.0</td><td> &gt;200.0</td>

<td></td><td>CUjNH</td><td>(d, β) -4- [5- (Hydroxymethyl) -2-oxoox azolidin-3-yl] -N-methylbenzenesulfonamide</td><td> 50.0</td><td> &gt;200.0</td>

<td> 25</td><td>CHjNH</td><td>(Β) -4- [5- (hydroxymethyl) -2-oxooxazolidin-3-yl] -N-methylbenzenesulfonamide ·</td><td> 25.0</td><td> 200.0</td>

<td></td><td>^N3</td><td>(d, β) -4- [5- (hydroxymethyl) -2oxooxazolidinyl-yl] benzenesulfonyl azide^f</td><td> 4.2</td><td> 12.5</td>

<td> 30</td><td>^N3</td><td>(£) -4- [5- (hydroxymethyl) -2oxooxazolidin-3-yl] benzenesulfonyl-azidf</td><td> 1.6</td><td> 9.4</td>

A summary of the in vitro antibacterial spectrum of (β) -4- [5- (hydroxymethyl) -2-oxooxazolidin-3-yl] benzenesulfonamide is shown in Table II. The minimum inhibitory concentrations for the aerobic and optionally anaerobic test isolates representing two gram positive and eleven gram negative genera were determined by an agar dilution method. The method is known in the art and is as follows. Mueller-Hinton agar plates were prepared containing double compound concentrations ranging from 128 pg / ml to 1.0 g / ml for the sensitivity testing of the bacterial strains except Neisseria gonorrhoea and Hemophilus sp. The latter organisms were tested using GCagar containing 1% Bakcto-SupplementC (Difco Laboratories, Detroit, Michigan) and incubated below 6% CO₂. The agar plates were inoculated with a 0.001 ml calibrated loop of bacterial inoculum diluted to contain 5 x 10 6 colony forming units (CFU) per ml. ml. After a 24 hour incubation period at 35 ° C, the MIC values ​​were recorded as the lowest compound concentration that inhibits macroscopic bacterial growth.

The agar dilution method described by AL Barry (The Antimicrobic Susceptibility Test: Principles and Practice, 1976, Lea and Febiger, Philadelphia, Pennsylvania) with compound concentrations of 32 µg / ml to 0.06 µg / ml was used to determine the inhibitory activity of (£) 4- [5- (hydroxymethyl) -2-oxooxazolidin-3ryl] benzenesulfonamide for anaerobic bacteria.

<td></td><td>Table II</td>

In vitro antibacterial spectrum of (β) -4- [5- (hydroxymethyl) -2-oxooxazolidin3-yl] benzenesulfonamide

<td colspan="2">Test organism Number of isolates</td><td colspan="2">average MIC^X:</td><td>pg / ml</td>

<td>Staphylococci sp.</td><td> 38</td><td> 22.3</td><td></td><td></td>

<td>Streptococci sp.</td><td> 14</td><td> 7.7</td><td></td><td></td>

<td>E. coli</td><td> 86</td><td> 29.8</td><td></td><td></td>

<td>Proteus sp.</td><td> 88</td><td> 29.1</td><td></td><td></td>

<td>Providencia sp.</td><td> 12</td><td> 41.3</td><td></td><td></td>

<td>Enterobacter sp.</td><td> 41</td><td> 58.5</td><td></td><td></td>

<td>Salmonella sp.</td><td> 6</td><td> 32</td><td></td><td></td>

<td>Shiqella sp.</td><td> 9</td><td> . 8.0</td><td></td><td></td>

<td>Serratia sp.</td><td> 44</td><td> £96.0</td><td>(Area</td><td> 32—&gt;128)</td>

<td>Klebsiella sp.</td><td> 50</td><td> 39.4</td><td></td><td></td>

<td>Pseudomonas sp.</td><td> 79</td><td> £116.8</td><td>(Area</td><td> 8—?128)</td>

<td>Neisseria sp.</td><td> 43</td><td> 12.3</td><td></td><td></td>

<td>Haemophilus sp.</td><td> 4</td><td> 32/</td><td></td><td></td>

<td>Clostridium sp.</td><td> 5</td><td> 16.8</td><td></td><td></td>

<td>Fusobacterium sp.</td><td> 4</td><td> 0.9</td><td></td><td></td>

<td>Bacteroides sp.</td><td> 23</td><td> £15.13</td><td>(Area</td><td> 4—?32)</td>

<td>Gram - Anaerobic Cocci</td><td> 7</td><td> 6.1</td><td></td><td></td>

¹MIC:

Minimum inhibitory concentration by the agar dilution method.

The in vivo power of these compounds is shown by the data summarized in Table III. The in vivo efficacy assays were performed in mice intraperitoneally with cultures of the infecting organics diluted to give 90-100% mortality in the control animals within 7 days. The diluents used were trypticase soy liquid for E. coli, Proteus sp. and Pseudomonas aeruginosa and 5% pig gastric mucin for Staphylococcus aureus infections. The compounds, dissolved or suspended in 0.25% methocelium O, were administered orally by incubation at the time of infection and again 4 hours after infection. Mortality was recorded daily until the end of the test, and the 50% effective dose, EDj-θ, was calculated by the Reed-Muench method (Reed, LG and Muench, H., A simple method of estimating fifty percent end points. American Journal of Hygiene, 27, 1938, 493-497).

Table III

In vivo action of orally administered compounds in mice with intraperitoneal infections

Compound 1 (d, β) -4- [5- (hydroxymethyl) -2-oxooxazolidin-3-yl] benzenformamide

Compound 2 (β) -4- [5- (hydroxymethyl) -2-oxooxazolidin-3-yl) benzenesulfonamide Compound 3 (d, λ) -4- [5- (hydroxymethyl) -2-oxooxazolidin-3-yl] benzenesulfonyl azide

Compound 4 (β) -4- [5- (hydroxymethyl) -2-oxooxazolidin-3-yl] -N-methylbenzenesulfonylazide

Compound 5 (β) -4- [5- (hydroxymethyl) -2-oxooxazolidin-3-yl] -N-methylbenzenesulfonamide

56751

<td></td><td colspan="2">infected</td><td colspan="4">bacterial organisms</td>

<td>D</td><td></td><td colspan="2">Staphylococcus Escherichia</td><td>Proteus</td><td>Proteus</td><td>Pseudomonas</td>

<td> £1</td><td>Comp.</td><td>aureus</td><td>coli</td><td>mirabilis</td><td colspan="2">vulqaris fluorescence</td>

<td></td><td></td><td>ED</td><td>OATH"</td><td>OATH_C„</td><td>OATH"</td><td>OATH_</td>

<td></td><td></td><td> 50</td><td> 50</td><td> 50</td><td> 50</td><td> 50</td>

<td>nh₂</td><td> 1</td><td> 39.1</td><td> 24.9</td><td>NT²</td><td>NT</td><td>NT</td>

<td>nh₂</td><td> 2</td><td> 22.4</td><td> 13.9</td><td> 44.3</td><td> 40.8</td><td> 67.46</td>

<td>^N3</td><td> 3</td><td> 25.99</td><td> 17.89</td><td>NT</td><td>NT</td><td>NT</td>

<td>^N3</td><td> 4</td><td> 26.4</td><td> 14.87</td><td>NT</td><td>NT</td><td>NT</td>

<td>CH, NH</td><td> 5</td><td> 15.44</td><td> 39.72</td><td>NT</td><td>NT</td><td>NT</td>

<td>^OATH50^:</td><td> 50 %</td><td>efficient</td><td>dose: mg / kg</td><td></td><td></td><td></td>

<td>^:NT:</td><td>not</td><td>tested.</td><td></td><td></td><td></td><td></td>