Process for preparing novel antibacterial p-oxooxazolidinylbenzene sulfonamides and of pharmaceutical compositions containing the same

Process for the preparation of novel antibacterial p-oxooxazolidinylbenzenesulfonamides and pharmaceutical compositions containing them

Background of the invention

U.S. Patent N^s No. 123,665 to Fugitt et al describes, among others, compounds of formula

<img file="PT75928B_D0001.tif" />

in which

A represents a group of formula R5 (0)_no ;

X represents a chlorine, bromine or fluorine atom;

R represents a C1 -C4 alkyl group; and n represents 0, 1 or 2.

The compounds are described as being useful for the control of plant fungal and bacterial diseases.

British Patent N^s 2OO3^-15, issued to Delande, describes the following compound as an antidepressant:

<img file="PT75928B_D0002.tif" />

<img file="PT75928B_D0003.tif" />

U.S. Patent N^s 4, 34θ.6θ6, issued to Fugitt et al., Discloses antibacterial agents of general formula I. ¹

<img file="PT75928B_D0004.tif" />

in which

R4 represents a group "CH4, -CY4 R6, -CF4" or

-CF₂CF₂H ; and

X represents a group of formula 0R₂·

Summary of the invention

The present invention relates to a process for preparing new compounds of general formula.

<img file="PT75928B_D0005.tif" />

<img file="PT75928B_D0006.tif" />

in which

R2 represents an -NR group₂Rp -R (0R₂) Rg 5 "R3," NHftK₂,

-KX₉, -NR₁₀X, -KXZ or -N = S (0)_noR_gR₉ ;

R₂ and R g independently of each other represent hydrogen, alkyl of 1 to 4 carbon atoms or cycloalkyl of 3 to 3 carbon atoms;

⁰

R -resents a hydrogen atom or a group! ^_u4&lt; ,

0 0 0 il&gt; 1 H '1

-C (CK₉) C-OH, -C-CH = CH-C-OH,

<img file="PT75928B_D0007.tif" />

R 6 represents an aryl or alkyl group of 1 to 12 carbon atoms;

R? represents a hydrogen atom or an alkyl group having from 1 to 5 carbon atoms, -CEL / JH, -CylJSH, aryl or aralkyl;

R 1 and R 2 independently of each other represent an alkyl group of 1 to * + carbon atoms or, taken together, represent a group- (CH „) d dp

R10 represents an alkyl group of 1 to * + carbon atoms;

X represents a chlorine or bromine atom;

Z represents a physiologically acceptable cation;

m represents the number 2 or 3; n represents 0 or 1; and p represents the number 3. * + °^u 5 ;

and their pharmaceutically acceptable salts.

Experimental results indicate that the compounds of formula I may be used to mitigate bacterial infections in mammals. The present invention also relates to

Μ-

<img file="PT75928B_D0008.tif" />

α a process for preparing pharmaceutical compositions containing compounds of formula I and methods of using those compounds to attenuate bacterial infections in mammals.

Preferred compounds because of their high antibacterial activity are those compounds independently of which hydrogen is hydrogen and R3 is amino or methylamino. Especially preferred for its high antibacterial activity is (1) -M-Z '5- (hydroxymethyl) -2-oxooxazoidinyl-3,7-benzenesulfonamide.

The term aryl, used in the definitions of the substituents R 1 and R 6, is intended to encompass all univalent aromatic radicals, whether homocyclic or heterocyclic. Suitable aryl groups comprise radicals of monocyclic compounds such as benzene, pyridine, pyrimidine, pyrazole, furan, triazine, thiophene, imidazole, oxazole, thiazole and pyrrole. Radicals of polycyclic compounds such as biphenyl and terphenyl, as well as condensed polycyclic compounds such as naphthalene, anthracene, phenanthrene, quinoline, isoauinoline, acridine, phenazine, indole, benzothiophene, carbazole and dibenzofuran, are also appropriate.

Any of the aryl groups may optionally include, but are not limited to, at any position but not limited to one or more fluorine, chlorine or bromine, nitro, C1 -C4 alkyl or alkoxy, hydroxy, trifluoromethyl groups , cyano or CC CC-alkyl

C.-C., or groups of formula S (0) CH₇wherein q is 0, 1 or 2. Preferred substituted aryl groups are oiridine, thiophene, furan, pyrrole and benzene, optionally substituted by the atoms and radicals mentioned above.

aralkyl term used in the definition of the group represented by the symbol R? is intended to include an alkyl group of one to four carbon atoms having as a substitute

<img file="PT75928B_D0009.tif" />

te (s), one of the aryl groups described above. The physiologically acceptable cations represented by the symbol Z are alkali metal or alkaline earth metal ions such as K⁺, Mg⁺⁺, Ca⁺⁺, Li⁺ and on⁺. Other suitable ions are known in the art.

Detailed Description of the Invention Synthesis

Compounds of formula I wherein R4 is hydrogen and R4 is -NRgR4 or -KIOR-), quotr. the general formula la may be | prepared in the manner illustrated in scheme 1.

Scheme 1

0

<img file="PT75928B_D0010.tif" />

V_0Y

IV

<img file="PT75928B_D0011.tif" />

HN (OR₂) R₃ or hnr₂r₃

-;&gt; R₃R₂N-S0₂

THF '

<img file="PT75928B_D0012.tif" />

-N 0 ^ 7

OH

Ia (R₂= R₂^{0U 0R}Wherein Y represents an acyl group.

The hydroxy radical of the 5-hydroxymethyl-3-phenyl-2-oxazolidinone (II) is blocked by refluxing this compound with an agent which provides an acyl group, preferably a C1 -C4 alkanoyl halogenated group. Suitable reagents for this purpose are: trifluoroacetic anhydride, dichloroacetyl chloride, dichloroacetic anhydride, trichloroacetyl chloride and trichloroacetic anhydride. The mixture is heated to reflux at a temperature of about 0 ° C to 0 ° C.^OC, preferably between 0 ° and Μ-ΟθΟ. This phase may be carried out in the absence of solvent or with any inert hydrocarbon or chlorinated hydrocarbon solvent. The resulting ester III is reacted with a halogen sulfonic acid such as chlorosulfonic acid or fluoro sulfonic acid at a temperature of about 30 ° C.^and 40 ° C to give the sulfonyl halide of formula IV. This phase can also be performed in the absence of solvent or in a chlorinated hydrocarbon such as CHClyCH₃, CCl₃ or CCL. This product is then dissolved in a solvent, such as tetrahydrofuran, ether, dioxane, 1,2-dimethoxyethane, dimethylformamide, dimethylacetamide or urea, and reacted with the appropriate amine of the formula HHRgR4 or KK ( 0R₂) R₃at a temperature of from about -20 ° C to 30 ° C to give a compound of formula Ia.

Compounds of formula I wherein X is

<img file="PT75928B_D0013.tif" />

A hydroxy group and R 4 is of formula Ib may be prepared by reacting a sulfonyl halide of formula IV with sodium or potassium azide in a mixture of acetone and water as shown in Scheme 2. Suitable solvents are acetone, lower PE ketones such as methyl ethyl ketone, diethyl ketone and cyclopentanone, ethers and dipolar aprotic solvents.

Scheme 2

IV

M₃-ONLY₂· Y-

<img file="PT75928B_D0014.tif" />

The azides of formula Ib as well as the hydrazides of formula Ic according to the present invention may also be prepared according to reaction scheme 3.

Scheme 3

<img file="PT75928B_D0015.tif" />

Ia (R₂= R₃= H)

Sulfonyl halide of formula IV is reacted with

<img file="PT75928B_D0016.tif" />

hydrazine to prepare the hydrazide of formula Ic. The latter may then be reacted with a nitrite such as sodium nitrite in dilute acid solution to obtain the azide of formula Ib. The azide of formula Ib may then be reduced by any of several known methods to obtain the sulfonamide of general formula Ia. Suitable reduction processes include catalytic processes, reaction with sodium borohydride in an alcohol or tetrahydrofuran or reaction with zinc and acetic acid.

The compounds according to the invention, wherein R3 is hydroxy and R3 is -NXZ, -NX₂ or -N = S (O)_noRgR4, can be prepared as illustrated in Scheme M-:

Scheme * +:

<img file="PT75928B_D0017.tif" />

hypohalide (OX _or_ base / Xg

Ia (R₂= R₃= H)

<img file="PT75928B_D0018.tif" />

<img file="PT75928B_D0019.tif" />

Halogen sulfonamide of the general formula Id can easily be prepared by contacting a sulfonamide of general formula Ia with a halogen and a base such as sodium hydroxide or a preformed hypo-halide such as sodium hypochloride. sodium or o:

Calcium hypochlorite. To prepare Ν, Ν-dihalogensulfonamide ί

of formula Ie, the pH is adjusted to:

4 and 3. The adjustment techniques of OH make it possible to add

acetic acid ', carbonic anhydride or an inorganic acid | co diluted. ji

The sulfylimines of formula If can be prepared by reacting the halogen sulfonamide of formula Id with a sulfide; of dialkyl of the general formula -SRgR4, such as dimethyl sulfide, trimethylene sulfide, methyl ethyl sulfide or tetrahydrothiophene, preferably in hydroalcoholic solution. Oxidation of the sulfilimines with, for example, hypochlorite or m-chloro-perbenzoic acid provides the sulfoximines of formula Ig.

The compounds according to the invention wherein R 1 is a group of formula may be prepared as shown in Scheme 5 by reaction with a hyinohalide.

<img file="PT75928B_D0020.tif" />

Scheme 5 '.

R₁₀NHS0

hypohalogenide h₂O

Oh i_Oxnso₂

<img file="PT75928B_D0021.tif" />

V-OH

Oh

Several simple esters of the present invention of formula II as shown in Scheme 6 may be prepared by reacting a compound of formula Ia to Ih with the appropriate acid chloride or anhydride, preferably in the presence of of a base such as pyridine or dimethyl aminopyridine. The preferred solvent is pyridine or other pyridine class solvents, although in many cases no solvent is required.

Scheme 6:

θ ^R1~^ONLY2

NO +

V3

RgCOCl or (RzC0)_O0

Ç

M) H

Ia-Ih

R ^ -30

VOCORz

II

<img file="PT75928B_D0022.tif" />

Many of the single asters may also be prepared by halogen sulfonation of a compound of general formula. ^v as shown in Scheme 7 No solvent is required, but halogen sulfonic acid inert solvents may be used. The resulting sulfonyl halide of formula VI is then reacted with ammonia, with an appropriate amine, azide or hydrazine as indicated in Schemes 1 and 3j pure to give the ester of formula Ij.

Figure 7. ·

<img file="PT75928B_D0023.tif" />

V

<img file="PT75928B_D0024.tif" />

NHNK₂ or

N (0R₂) R₃

Starting compounds of formula V may be prepared from · 5^-hydroxymethyl-3^_phenyl-2-oxazolidinone as shown in Scheme 8.

Scheme 5

II

R / -C

+

Cl base or anhydride

V

<img file="PT75928B_D0025.tif" />

Other esters according to the present invention of formula Ik may be prepared as shown in Scheme 9 by reacting an alcohol of formulas Ia to Ih with an appropriate anhydride:

Scheme 9

<img file="PT75928B_D0026.tif" />

in represents 2 or 3 ·

Suitable solvents are weak pyridine class bases and the appropriate reaction temperature is from about 30 ° to 115 ° C.

The products obtained by the processes described above (Ia to Im) are racemic mixtures, that is, mixtures of (+) and (-) enantiomers at 5θ * · 5θ · The synthesis of optically active compounds can be performed.

<img file="PT75928B_D0027.tif" />

The starting compound in Scheme 1 is 1-hydroxymethyl-3-phenyl-2-oxazolidinone (IIa). This starting compound can be obtained by desulphurizing 1-3-Z (M-methylthio) phenyl-5-hydroxymethyl-2-oxazolidinone (VII) as shown in Scheme 10.

Figure 10

<img file="PT75928B_D0028.tif" />

isomer 1 isomer 1

VII - lia

A preferred process for preparing 1-p-hydroxymethyl-3-phenyl-2-oxazolidinone (IIa) is shown in Scheme 11.

Scheme 11

<img file="PT75928B_D0029.tif" />

1-mandelic acid -&gt;

CHCl ^ or CE-CN

OH

NHCE₂CHCH₂0H

Oh chco₂h base

<img file="PT75928B_D0030.tif" />

Oh nhch₂chch₂oh d-base (5t0)₂C0

Glime K₂co₃

CH ^ ONa

<img file="PT75928B_D0031.tif" />

11 isomer 1 J, .40 $ 00, [

<img file="PT75928B_D0032.tif" />

Aniline is reacted in excess of 2 to 10 with glycidol. Excess aniline is removed by distillation, then distilling (dl) -3'-phenylamino-1,3-propanediol under reduced pressure. This is unfolded by adding it to about 5θ-6θ mol% of 1-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 it with a base. The salt is suspended in water, the suspension is adjusted to pH 8-10, the mixture is saturated with sodium chloride and continuously extracted with dichloromethane. Alternatively, the salt is dissolved in a mixture of alcohol and water and the solution passed through a strongly alkaline ion exchange resin. In either case, the resulting extract or eluted liquid from the column is concentrated to isolate (d) -3'-phenylamino-1,3-propanediol. This product is then reacted with diethyl carbonate (other carbonates such as dimethyl carbonate or diphenyl carbonate may be used) in a polar solvent such as 1,2-dimethoxyethane using potassium carbonate and sodium methoxide. as catalysts. The product is isolated by concentration of the solvent, dilution with water and some acetic acid and washing with water. The product may be purified by recrystallization from 95% ethanol or acetonitrile. If d-mandelic acid is used in this process, isomer d of 5 can be obtained.^-hydroxymethyl-3^-phenyl -2-oxazolidinone.

Another way to obtain optically active compounds according to the invention is to carry out the first reaction of Scheme 11 using optically active glycidol, preferably R-glycidol, to obtain the optically active base directly.

1-5-Hydroxymethyl-3-phenyl-2-oxazolidinone (IIa) also

<img file="PT75928B_D0033.tif" />

may also be prepared from (R) - (+) - 1-benzylglycerol ZTS.Takano, E. Goto, M. Hirama and Ogasawara, Heterocyeles, sp., 3θ1 (lSSlj) following pyridine-p-toluenesulfonyl chloride tosylation; reacting this tosyl ester (S) (VIII) with the potassium salt of N-phenyl-4-methylbenzenesulfonamide in a dipolar aprotic solvent such as dimethylformaraide. The resulting product (IX) is reacted with the anion of the sodium naphthalene radical to yield the product (X) which, when reacting with diethyl carbonate or another carbonate in the presence of a catalytic amount of sodium methoxide. the desired isomer 1. This sequence is illustrated in Scheme 12.

Figure 12

<img file="PT75928B_D0034.tif" />

(S) -isomer

VIII

<img file="PT75928B_D0035.tif" />

<img file="PT75928B_D0036.tif" />

H ^0H · N-EC₂-CH-CH₂0E (R) (d) -isomer (R) -isomer

IX

X

<img file="PT75928B_D0037.tif" />

NaOCH.

-—&gt;

(Et0)₂C0

Amino acid esters according to the present intent wherein R is₅represents a group -C0CE (NH₂) Ry may be prepared by the reaction sequence indicated in Scheme 13:

Esauema 13

- _θ

<img file="PT75928B_D0038.tif" />

^R1°2^s \ -OCO-CHNKCOO-t-Bu

I

<img file="PT75928B_D0039.tif" />

XII - the acid EX r ^ o₂s

<img file="PT75928B_D0040.tif" />

OCG-CH-NH, 1 J ^R7

Im

<img file="PT75928B_D0041.tif" />

An alcohol is reacted with the appropriate blocked amino acid (XI) in the presence of a carbodiimide such as dicyclohexylcarbodiimide. Suitable solvents include dichloromethane, chloroform, tetrahydrofuran and diethyl ether to which a small amount of a weak base such as pyridine may be added. Suitable temperatures are from about 0 ° to 100 ° C. The filtrate (XII) is treated with a volatile acid (e.g. trifluoroacetic acid) at 0 ° -50 ° C. After removal of the acid, for example by vacuum distillation, the ester of formula Im remains as its acid addition salt (e.g. trifluoroacetate). This can be released as an amine by reaction with a base. Treating this amine with an appropriate acid gives the desired salts such as hydrochloride, phosphate, sulfate, acetate and benzoate.

The acid compounds of formula 1k according to the present invention form salts with various inorganic and organic bases whose salts are within the scope of the present invention. These salts comprise alkali metal salts such as sodium and potassium salts, ammonium salts, alkaline earth metal salts such as calcium salts and magnesium salts, salts with organic bases such as lower acyclic amines, benzylamine, dicyclohexylamine, and salts. with basic amino acids like arginine.

Example 1 · + -Z 5- (Hydroxymethyl) -2-oxooxazolidinyl-3 H -benzenesulfonamide (R₁= -NH₂ ; R_?= H)

A solution of 2 * + 7.3g (1.00 mol) of N-phenyl-M-methylbenzenesulfonamide containing 20g of 1,2-diazabicyclo [2] is stirred and heated under nitrogen. Octane (DAECO) in 950 ml of

<img file="PT75928B_D0042.tif" />

dimethylformamide (DMF) while a solution of 70 ml of freshly distilled glycidol in 70 ml of dimethylformamide is added over two hours. It continues to heat for 1 hour and

4-0 minutes and then an additional 35 ml of glycidol in 35 1 of dimethylformamide is added over one hour. Heating is continued for a further 5 hours and 30 minutes. The reaction mixture is poured into 4 liters of cold water (with some ice present) and the product, N- (2,3-dihydroxypropyl) -4-methyl-N-phenylbenzenesulfonamide, crystallizes. This product is filtered off and washed well with cold water to give 34-3g of mp. 91 ° 94- ° C, which after recrystallization from 700 ml of toluene yields 312 g of mp 108.5 ° -10.5 ° C.

250g of 4-00 sodium dispersion in mineral oil is added to a solution of 100g of naphthalene in 1.8 liters of 1,2-dimethoxyethane (Glime) and the mixture is stirred under a nitrogen atmosphere while maintaining a nitrogen atmosphere. temperature between 20 ° and 30 ° C. After all the sodium is added, the mixture is stirred for 20 minutes and then 305g of N- (2.3^-dihydroxypropyl) -4-methyl-N-phenylbenzenesulfonamide through a powder addition funnel while maintaining the temperature of the reaction mass below 35 ° C. After adding all the solid product, the mixture is stirred for one hour. Water is then added until the color of the mixture changes from dark green or black to yellow; Then concentrated hydrochloric acid is added until the solution reacts strongly acid. The mixture is extracted twice with toluene and then three times with hexane, flushed with nitrogen to remove hexane, saturated with sodium chloride and made basic with concentrated ammonium hydroxide solution. The product is extracted with dichloromethane and the extract is dried over potassium carbonate. Filter the extract into dichloromethane and concentrate to give 132.3g of 3^-f^enylamino-1,2-pronanediol

<img file="PT75928B_D0043.tif" />

in the form of a pale yellow oil.

A mixture of 3-phenylamino-1,2-propanediol, 250 ml of 1,2-dimethoxyethane is refluxed under nitrogen. and 61 ml of diethyl carbonate. About 0.5g of solid sodium methoxide is added and refluxing is continued for about 2.5 hours. The mixture is cooled, stirred with water and filtered to give 1.1 g of 5- (hydroxymethyl) -3-phenyl-2-oxazolidinone of mp 122 DEG-12 DEG.¹+^OC. Recrystallize the

4-1.1 g of the product in 100 ml of absolute ethanol to isolate 33 µg of mp 125.5-126 ° C. An additional 25.3g portion of PF 12 product is obtained.¹+, 5 ° -125 ° C from the aqueous filtrate by concentration and recrystallization from ethanol.

The mixture of 25&gt; 3g of 5^-(hydroxymethyl) -3-phenyl-2-oxazolidinone and 100g of trifluoroacetic anhydride. The solid product dissolves completely. The mixture is then concentrated under reduced pressure to give 4-1 g of oil which crystallizes on abandonment. This product is used without further purification.

In a flask under a nitrogen atmosphere, about 250 ml of chlorosulfonic acid is well shaken while the product obtained above is added over 15 minutes. The mixture is not cooled and the temperature remains between 30 ° and 40 ° C. The solid product dissolves with development of heat and gaseous hydrochloric acid. The mixture is stirred at room temperature for one hour and twenty minutes and then quenched on ice, a product, ds (dl) -4- / 55- (trifluoroacetoxyiraethyl) -2-oxooxazolidinyl-3-7-benzene-dichloride. sulfonyl crystallizes and is filtered off, well washed with cold water and dried in a stream of nitrogen. The product is then dissolved in tetrahydrofuran and stirred on ice while 18 ml of concentrated

<img file="PT75928B_D0044.tif" />

ammonium hydroxide, keeping the temperature between 20 ° and 25 ° C. Concentration and filtration give 2 µg of the title compound, mp 154 ° -156 ° C. Recrystallizing this from acetonitrile gives an additional 1.3 g of mp 166-168 ° C.

Example 2

1-4- / 75- (Hydroxymethyl) -2-oxooxazolidinyl-3-7-benzenesulfonamide (^R1 = -NH₂ ; R_? = H)

With stirring, 3θ ° δ of Raney Nickel Catalyst is added to a solution of 4-4g (0.9 mole) of 1-3- / 7- (4-methylthio) phenyl-5-5-hydroxymethyl-2- oxazolidinone in 100 ml of absolute ethanol and the resulting mixture is heated at reflux for one hour. A sample of the reaction mixture is checked by NMR indicating the elimination of the SCH-group. The solution is then filtered and the reaction mixture is repeatedly extracted with boiling ethanol. Combine and concentrate the ethanolic extracts to give 32.5g of 1-5-hydroxymethyl-3-phenyl-2-oxazolidinone, mp 134-136 ° C. This product is recrystallized from 115 ml of absolute ethanol, isolating 32.5 g of white crystals melting at 13-139 ° C._}5 ° C. This product is recrystallized once more from 106 ml of absolute ethanol to give 28.9 g of mp 139⁰“L4o⁰Ç.

A mixture of 23.7 g (0.148 mol) of 1-5-hydroxymethyl-3-phenyl-2-oxazolidinone in 100 ml of trifluoroacetic anhydride is heated at reflux until the solid product is dissolved. This mixture is concentrated under reduced pressure and the resulting oil is added to 200 ml of chlorosulfonic acid while maintaining the mixture below 30 ° C. The mixture is then stirred at room temperature for 2 hours and 15 minutes and then poured over ice. The crystallizing product is separated (1-4- [75- (trifluoroacetoxymethyl) -2-oxooxazolidinyl-3-7-benzenesulfonyl chloride)

<img file="PT75928B_D0045.tif" />

by filtration, wash with water and then add to a mixture of 6θ ml of ammonia concentrated in 300 ml of tetrahydrofuran, keeping the resulting mixture at -10 ° to 0 ° C. The resulting mixture is stirred for 15 minutes at 0 ° C for a further 30 minutes without external cooling. The mixture is then concentrated under reduced pressure to remove tetrahodrofuran and diluted with water. Wash the product with water and filter to give 32.1 g of the title compound, mp 182-188 ° C. (There is a change in crystalline form at 158 ​​° C). After recrystallization from acetonitrile, 2.5 g of Mp 15.5-135 ° C are isolated.

Example 3 (dl) -N, N-Dimethyl and (dl) -N-Methyl-4- [75- (hydroxymethyl) -2-oxooxazolidinyl-3-7-benzenesulfonamide (R3 = or -NHCH3; = H )

Stir at 60 ° C a 2.72g (0.01 mol) solution of (dl) Z5- (hydroxymethyl) -2-oxooxazolidinyl-3-7^-benzene sulfonamide in 50 ml of anhydrous dimethylformamide containing 5 g of anhydrous potassium carbonate while adding 0.62 ml of iodomethane in 10 ml of dimethylformamide. After the addition is complete, the mixture is kept at 60 ° C for one hour and then concentrated under reduced pressure to distill the dimethylformamide. Take up the 3₅7g of residue in dircethyl sulfoxide and chromatographed on silica gel to give a first fraction of 0.65g of (dl) -N, N-dimethyl-4-ZT5- (hydroxymethyl) -2-oxooxazolidinyl-3-7- mp benzene sulfonamide mp 174 ° -176 ° C. A second 1.05 g portion of (dl) -N-methyl-4-Z75 '- (hydroxymethyl) -2-oxooxazolidinyl-3,7-benzenesulfonamide of mp 166-166 ° C is also obtained.

<img file="PT75928B_D0046.tif" />

• Example 4 (dl) -4- [5- (Hydroxymethyl) -2-oxooxazolidinyl-3] benzenesulfonyl azide (^ = -N₃ ; R₅ = H)

A solution of 10 g of sodium azide in 20 ml of water is added to 200 ml of reagent grade acetone and then cooled to -5 ° C. To the solution is added a 19 g portion of (dl) -4- [5- (trifluoroacetoxymethyl) -2-oxooxazolidinyl-3] benzenesulfonyl chloride (prepared in the manner described in example 1) while maintaining the temperature of the mixture below 0 ° C. After stirring the mixture for one hour, it was allowed to stand overnight. Acetone is removed under reduced pressure, water is added, the product is filtered off and washed with water to yield 12.8 g of mp 108 ° -110 ° C. This product is stirred with 250 ml acetonitrile at 25 ° C and filtered to remove any insoluble material present. The solution is concentrated to acetonitrile and filtered to separate the crystallized product. This affords 12.3 g of product which, after recrystallization from ethyl acetate, gives 6.0 g of the title compound mp 112-113 ° C.

Example 5

1-4- [5- (Hydroxymethyl) -2-oxooxazolidinyl-3] benzenesulfonyl azide &lt;* 1 ° -^M3 ’ ^R5 ‘ ^H1

A solution of 5 g of sodium azide in 10 ml of water is added to 100 ml of reagent grade acetone and then cooled to -5 ° C. A 7g portion of 1-4- [5- (trifluoroacetoxymethyl) -2-oxooxazolidinyl-3] benzenesulfonyl chloride (prepared in the manner described in Example 2) is added while maintaining the temperature of the mixture between - 5 ° and 0 ° C. After stirring the mixture for a

<img file="PT75928B_D0047.tif" />

at 0 ° C and standing overnight, acetone is removed under reduced pressure. Water is added, the solid product is filtered off and washed with water, yielding 4.8 g of mp 136-138 ° C. After recrystallization of this solid product from ethyl acetate, 4g of the title compound of mp 137 ° -138 ° C is isolated.

Example 6

1-4- [5- (Hydroxymethyl) -2-oxooxazolidinyl-3] -N-methylbenzenesulfonamide (R = -NHCH₃ ; R, - = H)

A solution of 10 ml of methylamine is stirred in 200 ml of anhydrous tetrahydrofuran while adding 6.3g of 1-4- [5- (trifluoroacetoxymethyl, -2-oxooxazolidinyl-3] benzenesulfonyl chloride. The mixture is at -10 ° C or below during this addition and then allowed to reach room temperature while stirring overnight. After removal of tetrahydrofuran under reduced pressure, water is added, the resulting white solid is filtered off and washed with water, yielding 4.41 g of mp 137-142 ° C. After recrystallization from acetonitrile 3.83 g of the title compound of mp 137 ° -138 ° C

Example 7

According to the technique described in example 6, (1) -4- [5- (hydroxymethyl) -2-oxooxazolidinyl-3] -N-butyl n-benzenesulfonamide (R4 = - NH 4 Cl (H 2 H = H) using 4 ml of butyl

n-amine instead of methylamine.

<img file="PT75928B_D0048.tif" />

Example 8

According to the technique described in example 6, (1) -N, N-dibutyl n.-4- / 75- (hydroxymethyl) -2-oxooxazolidinyl-3-7-benzenesulfonamide may be prepared. -N (C ^ HH ^ n) 2; Rj = H7 using 5_}5th ml of dibutyl n-amine instead of methylamine.

Example 9

1-4 - /) 5- (Hydroxymethyl) -2-oxooxazolidinyl-3-7-N-cyclopropylbenzenesulfonamide (R 1 = -NH; R 5 = h)

A solution of 6 ml of cyclopropylamine in 5 ml of tetrahydrofuran is stirred in an ice bath keeping the temperature below 30 ° C while adding 9.3 g of 1-4-Z5- (trifluoroacetoxymethyl) -2 chloride. -oxooxazolidinyl-3-7-benzenesulfonyl (See Example 2). The mixture is stirred for one hour, the tetrahydrofuran is removed under reduced pressure, the residue is diluted with water and acidified with dilute hydrochloric acid. The solid was filtered off, washed with water and dried to give 7.06 g of the title compound, mp 129-47 ° C. After crystallization from 30 rolls of acetonitrile, 2.0 g of mp 8-16.4 ° C was isolated.

Example 10

1-4- [5- (hydroxymethyl) -2-oxooxazolidinyl-3-7-N-methoxybenzenesulfonamide = -NHOCH 3; = H)

A solution of 3 rolls of methoxyamine (O-methylhydroxylamine) in 50 ml of tetrahydrofuran is stirred and cooled to -5 ° to 10 ° C while a solution is added over 15 minutes. of 4-4-75- (trifluoroacetoxymethyl) -2-oxooxazolidinyl-3'7-benzenesulfonyl chloride (4.4 g of^,7See Example 2) in 20 ml of tetrahydrofuran. A white solid product is separated.

<img file="PT75928B_D0049.tif" />

The mixture is allowed to warm to room temperature, filtered and concentrated to a colorless gum. This gum (1.5g) is chromatographed using Water Co. Prep-100 and eluting with a mixture of 4-5% acetonitrile and 55% dichloromethane. A fifth fraction (1.3g) is crystallized from ethyl acetate to give 1.04 g of the title compound mp 129.6-131.5 ° C. Boiling this compound with 13 mL of ethyl acetate, then cooling and filtering, isolated 0.73 g of the title compound mp 130 ° -132.5 ° C.

Example 11 (dl) -N, K-Dichloro-4-7- (hydroxymethyl) -2-oxooxazclidinyl-3-7^youbenzene sulfonamide (Rf = RNC = Rf = H)

A 2g portion of (dl) -4-ZC5 - (hydroxymethyl) -2-oxooxazolidinyl-3-7-benzene sulfonamide is stirred in an ice bath in a mixture of 10 ml water and 50 ml dichloromethane. and 27 ml of 5.25% sodium hypochlorite (Chlorox) is added. The entire solid product is dissolved and a precipitate forms. The filtered dichloromethane is separated, dried and evaporated to yield 1.5% of the title compound mp 121.5 ° -123 ° C. An additional 1.2 µg of insoluble solid product having the same infrared curve as the previous sample is isolated.

Example 12 (1) -N, N-Dichloro-M-Z75-hydroxymethyl) -2-oxooxazolidinyl-3-7-benzenesulfonamide

A suspension of 1.00 g of (1) -4-Z75- (hydroxymethyl) -2-oxooxazolidinyl-377-benzenesulfonamide in 1 ml water is stirred in an ice bath while 13.5 ml is added. of 5.25% sodium hypochlorite (Chlorox). The solution is slightly acidified by adding acetic acid; The product separates as white crystals (1.24-g) of mp 12.5.5-125.5 ° C.

<img file="PT75928B_D0050.tif" />

Example 13

(Dl) -N-Chloro-5-Z5- (hydroxymethyl) -2-oxooxazolidinyl-3-7-benzenesulfonamide sodium salt (R = -NCINa; = H

Stir in an ice bath 2.0g of (dl) -5- / 35^_(hydroxymethyl) -2-oxooxazoylidinyl-7,7-benzenesulfonamide in 10 mL of water while adding 13.5 mL of 5.25% sodium hypochlorite (Chlorox). The solid product dissolves and separates two crystals. The isolated crystals are filtered off, washed with a small amount of cold water and dried to give 1.97 g of the title compound which decomposes when heated to a temperature above 133 ° C.

Example l5

(1) -N-Chloro-5-Z35- (hydroxymethyl) -2-oxooxazolidinyl-3-benzene sulfonamide sodium salt

1g of (1) -5-3-3- (hydroxymethyl) -2-oxooxazolidinyl-3-7-benzenesulfonatride in 1 ml water is stirred in an ice bath while 6.5 ml is added. of 5.25% sodium hypochlorite (Chlorox). The solid product dissolves and then crystallizes a white solid product. Filter and wash the product once with a small portion of water and ice to give 1.5 g of the title compound mp 165-167 ° C (dec).

Example 15 (dl) -K- ^ 5-3- (5- Hydroxymethyl) -2-oxooxazolidinyl-3-7-phenylsulphonyl-S, 3-dimethylsulphilimine (Rf = -N = S (CH3; Rf = H)

A suspension of 2.00 g of (dl) -5- [35- (hydroxymethyl) -2-oxooxazolidinyl-37-benzenesulfonamide in 10 ml of water is added and 11.5 ml of sodium hypochlorite is added to it. 5.25 $ (Chlorox). Almost all of the initial solid product was dissolved. Filter the solution and add

<img file="PT75928B_D0051.tif" />

25 ml of ethanol and then 10 ml of dimethyl sulfide. The mixture is stirred well for 30 minutes and then concentrated to give a^T,Colorless book. This product is dissolved in acetonitrile and chromatographed using Waters Prep-500 Kplc. This gives 1.7 g of pure title compound of mp 162.5-165.5 ° C (a change in crystalline form is observed at 136 ° C).

Example 16 (dl) -3-ZZ4- (Hydrazosulfonyl) -phenyl-5-5- (hydroxymethyl) -2-oxazolidinone-2 (R1 = -NHKH₂ ; Rf = H)

30g portion of (dl) - '+ - Z'5 chloride is added^_(trifluoroacetoxymethyl) -2-oxooxazolidinyl-3-7-benzenesulfonyl to a solution of ml mL of hydrazine hydrate in 300 mL of tetrahydrofuran maintained at a temperature range of from -10 ° to 0 ° C. After stirring for 30 minutes, the mixture is allowed to reach room temperature. Evaporate tetrahydrofuran in a stream of nitrogen, dilute the residue with water and filter to give 11.3 g of mp 172^O-17 '+ ° C (dec). The product is purified by dissolving it in 30 ml of dimethyl sulfoxide, filtering the resulting solution and diluting with methanol. Thus, 8.6 g of the title compound is isolated from mp 173 ° C (dec.).

Example 17 (dl) 5- (Acetoxymethyl) -2-oxooxazolidinyl-3-7-benzenesulfonamide (R₁ = -NH₂, R_? = -OCR ^)

A mixture of (dl) -5- (hydroxymethyl) -3-phenyl-2-oxazolidinone, 50 ml of acetonitrile, 11 ml of anhydride is refluxed for 30 minutes at reflux for 30 minutes. acetic acid and 0.1g of h-dimethylaminopyridine. This mixture is concentrated under reduced pressure, isolated

<img file="PT75928B_D0052.tif" />

a crude oil which IR and NMR spectra confirm to contain (dl) -5- (hydroxymethyl) -3-phenyl-2-oxooxazolidinone acetate.

The oil is added to 130 ml of chlorosulfonic acid, stirred at room temperature for 2 hours and then poured into three liters of ice. The remaining oil is extracted into methylene chloride and dried over anhydrous sodium sulfate. The extract is concentrated to methylene chloride and the residual oil 10.9 g is added to a mixture of 300 ml of tetrahydrofuran and 60 ml of concentrated ammonium hydroxide solution cooled to -10 ° to 0 ° C. ° C. The tetrahydrofuran is removed under reduced pressure, the residue is diluted with water and filtered, isolating 3.8 g of mp 196.5 ° - 197 ° C. After recrystallization from acetonitrile, 6.3 g of the title compound of mp 199 ° -200 ° C are obtained.

Example 18 1-5-Hydroxymethyl-3-phenyl-2-oxazolidinone

Part A

According to the techniques described by S.Takano, E. Goto,

M. Hirama and Ogasawara in Eeterocycles '', 16,31 (19θ1) θ in the references cited therein, are prepared * + 8g (0.263 mole) of (R) - (+) -1-benzyl glycerol. This is typed according to the standard technique to give 57.3 g of a colorless oil.

A mixture of 37.1 g (0.15 mol) of N-phenyl-4-methylbenzenesulfonamide in 15 ml of anhydrous dimethylformamide is added and 17 g of tert-butoxide is added. of potassium and then 55g of the previously prepared tosylate. The mixture is heated at 95 ° - 100 ° C for 15 hours. The mixture is poured into ice water and the product extracted with ether. Wash the ether extract with water and dry over anhydrous sodium sulfate to give 57.1 g of product. Thin layer chromatographic analysis on silica gel shows three components and some

<img file="PT75928B_D0053.tif" />

of the initial sulfonanilide. The 57.1 g of product is dissolved in 1.5 liters of ether, stirred with 100 ml of 25% aqueous sodium hydroxide solution and filtered through a pad of Celite filter aid. The ethereal filtrate is concentrated to 32.7g of an oil. This is chromatographed on silica gel columns eluting with 90: 10 toluene / ethyl acetate in two steps to give 17.22 g of solid PF 3S ° -: 99.^OC. The product is 4-methyl-N-phenyl-Z72-hydroxy-3- (phenylmethoxy) propyl] -benzenesulfonamide.

A solution of 16.5g (0.049 mol) of 4-methyl-N-phenyl- [72-hydroxy-3- (phenylmethoxy) propyl] -benzenesulfonamide in 100 ml of 1 is stirred under nitrogen. Anhydrous 2-dimethoxyethane while adding a sodium naphthalene radical anion solution (prepared by adding 20 ml of a 40% dispersion of metallic sodium in mineral oil to a solution of 4-Og naphthalene in 100 ral of 1 Anhydrous 2-dimethoxyethane while maintaining the mixture at 25 ° -40 ° C under a nitrogen atmosphere). Addition is continued until the color of the mixture changes from dark green to black. After addition, the temperature is allowed to rise to 40 ° C. After stirring for 3θ minutes, 20 ml of water is added and then 125 ml.^m1 is sulfuric acid at 20%. The temperature is maintained at 30 ° to 40 ° C during acidification. 1,2-Dimethoxyethane is removed by vacuum distillation. Water and the residue are extracted six times with toluene, twice with methylene chloride and a stream of nitrogen is passed to remove methylene chloride. The water is then saturated with sodium chloride and extracted five times with methylene chloride. The extincts are dried over anhydrous potassium carbonate, filtered and concentrated to 6.0 g of a colorless oil consisting of d-3.^_f3^_nylamino-1,2-propanediol.

Collect 6.0g (0.036 mol) of d-3-phenylamino-1,2-pronanediol

<img file="PT75928B_D0054.tif" />

With 10 ml of 1,2-dimethoxyethane and 5 ml of diethyl carbonate and refluxing the boiling solution, add 0.1 g of sodium methoxide. After 10 minutes a solid product is separated and another 5 ml of 1,2-dimethoxyethane is added. Refluxing is continued for 30 minutes, after which 1 ml of acetic acid is added and the mixture is concentrated under reduced pressure to isolate 7.2 g of a solid product. This is extracted with hot acetonitrile and the acetonitrile is concentrated to yield 1.8 g of the title compound mp 136.5-138 ° C. Product optical rotation: Z ^ ó37q25 _ ^ 7₉δ (c = 1 in acetonitrile).

Part B

1820 ml of aniline is heated to 30-85 ° C while stirring under nitrogen. 20 ml of freshly distilled glycidol is slowly added at a rate such that the temperature remains at 85-90Â ° C. After the first α-100 ml of glycidol is added, the external heating source is removed and the reaction temperature is controlled by adding the remaining glycidol and cooling occasionally. After the addition is complete, heat is applied to maintain the temperature at 80-90 ° C for two hours. (Dl) -3-phenylamino-1,3-propanediol is distilled through a short column at a pressure of * +, 0 — M-, 5 mm to remove the aniline which distills the 50 ° -55 ° C (1.5 liters recovered). The product distills to 0.05 mm,

PE 132 ° -135 ° C to give 5S8g of a colorless viscous oil.

Stir a solution of 1201g (7.1 moles) of (di) -3^_phenylamino-1,3-propanediol in 1.9 liters of chloroform and 600.1 g (3.95 moles) of 1-mandelic acid is added. The mixture is refluxed to dissolve the solid product. It is then allowed to cool slowly, separating the salt as crystals. After reaching room temperature the solid product is separated by

<img file="PT75928B_D0055.tif" />

filtration and wash by shaking it three times with chloroform. After drying, 868g of mp (d) -3'-phenylaryl-1,2-propanediol (1) -mandelate of mp 86-37 ° C are isolated. This is recrystallized by heating it to reflux with 2.8 liters of chloroform, cooling slowly, filtering and casting three times with chloroform to give 7% of mp 87-33 ° C.

A suspension of 84-5g of (d) -3'-phenylamino-1,2-propanediol (1) -mandelate in 300 ml of water is stirred in an ice bath while a cold 108g solution is added. of sodium hydroxide in 300 ml of water. The solution is saturated with sodium chloride and then continuously extracted with dichloromethane. The extract is concentrated in vacuo to give 4-4-6.9 g of (d) -3-phenylamino-1,2-propanediol as a colorless oil. Optical rotation of this product:

+ 21 ° (c = 1 in ethanol, read in 200 cm tube).

A mixture of 4-4-1.5g (2.6 mole) of (d) -3-phenylamino-1,2-propanediol, 32% is refluxed for 2 hours. ml diethyl carbonate, 300 ml 1,2-dimethoxyethane, 4-0; potassium carbonate and 1g sodium methoxide. Then another 20 g of potassium carbonate is added and after three and a half hours another 50 ml of diethyl carbonate.

Refluxing is continued for 15 hours. A thin layer chromatogram shows that the reaction is complete. About half of the solvent is removed in vacuo and 50 ml of water and 40 ml of acetic acid are added. Separates the. The white solid is filtered off and washed with water, with 70% ethanol with ether, yielding 4-01.7g of the title compound, mp 137j5 ° - 133.5 ° C. This is crystallized in 1 liter of 95% ethanol._} isolating 368.1 g of MP 13S product, 6 ° -139.1 ° C, which, after recrystallization from 700 ml of acetonitrile, yields 330.4 g of MPF 133.5 ° 139.5 ° C. . Optical Rotation 725-72.0 (c = 1 in acetonitrile).

<img file="PT75928B_D0056.tif" />

Example 19&gt;

(dl) -4- [5-2-benzoyloxymethyl) -2-oxooxazolidinyl-3,7-benzenesulfonamide (R 1 = -NH₂ ; = -OC ^ H ^)

Stir a solution of 5.0 g (13.3 millimoles) of (dl) -4- [1- (hydroxymethyl) -2-oxooxazolidinyl-3-benzenesulfonamide in 50 ml of anhydrous pyridine with cooling at room temperature. a temperature of -3 to 0 ° C while slowly adding 2.3% + ml of benzoyl chloride. A small exotherm is observed. After the addition is complete, the mixture is allowed to warm to 25 ° C and stirred for two hours. Another 0.2 ml of benzoyl chloride is added and the mixture is allowed to stand overnight. The mixture is then poured onto ice and the product is crystallized. Filter, wash the crystals well with water and dry to give 6.72g of product. This is recrystallized by dissolving it in hot diethylene glycol dimethyl ether, concentrating the solution to half its volume and allowing it to stand to isolate 3._}- 5g - product of mp 233 ° ~ 23^l+^OÇ.

Example 20

-----, (dl) -4- / 5- 5- (Propionyloxymethyl) -2-oxooxazolidinyl-3-7-benzene sulfonamide (R1 = -NH₂ ; = -OC ^ H?) I

Stir in an ice bath a solution of J. Og (13.3 mmol) of ('dl) -4- [5-hydroxymethyl) -2-oxooxazolidinyl-3,7-benzenesulfonamide in 50 ml of pyridine anhydrous while adding 1.60 ml of propionyl chloride. The mixture is allowed to warm to room temperature and then left to stand overnight. Pour into 200 ml of water and ice, acidify the water with hydrochloric acid by keeping it cold, filter and wash the crystalline product with cold water to give 3.60 g of the title compound of PF.

<img file="PT75928B_D0057.tif" />

211-212.5 ° C, which upon recrystallization from nitromethane yields 3.32 g of the title compound of MP 212-213.5 ° C.

Example 21

(1-) Butanedioic Acid Mono Ester with h- [7 '- (hydroxymethyl) -2-oxooxazolidinyl-3,7-benzenesulfonamide ⁼ = -c (o) ch₂ce₂coohj7

Stir and heat for 2 hours at 60 ° C a solution of 5.0 g (13.3 millimoles) of (dl) -¹} - ZT5 “(hydroxymethyl) -2-oxooxazolidinyl-3'7-benzenesulfonamide in 50 ml of pyridine and 2.02g of succinic anhydride. The reaction mixture is poured into 100 ml of water and ice and adjusted to pH 3 by the addition of concentrated hydrochloric acid (keeping it cold). Saturate the solution with sodium chloride and extract with tetrahydrofuran. The extract is dried over anhydrous sodium sulfate and concentrated to give 7.9 g of crystals. These are stirred in 50 ml of water and a 20% potassium bicarbonate solution is added to pH 10. The product is filtered off and the filtrate is adjusted to pH 2 with hydrochloric acid.

After filtration and drying, * 0.8 cg of mp 130-170 ° C are obtained. ¹ i

The sodium salt of this product is prepared by suspending 2.2 g of the solid obtained above in 1 ml of water, adding 1 N solution of sodium hydroxide to pH 7, filtering and concentrating in vacuo to give 2 g. .3g of a white solid product.

Similarly, the following semiesters may be prepared:

<img file="PT75928B_D0058.tif" />

3^

Ex. Initial compound

Product Reagent

<img file="PT75928B_D0059.tif" />

CljN- H

<img file="PT75928B_D0060.tif" />

Ny H

<img file="PT75928B_D0061.tif" />

//

H

CH₃NH

CH ^ N0

II c

COj ^ a *

<img file="PT75928B_D0062.tif" />

i

<img file="PT75928B_D0063.tif" />

CH ^ OHNExample 23

L- alamine ester with 1-^_5 '(hydroxymethyl) -2-oxooxazolidinyl-3 H -benzenesulfonamide / R = = -N ^ Rj = -COCH / NH ^) CH ^ _ title compound can be prepared as follows

A solution of b-, 5g ('0.02 mol) of N, N-dicyclohexylsrbodiimide in methylene chloride is added to a solution of 5' (0.02 mole) of β-5- (hydroxyethyl) -2-oxooxazolidinyl. -3-J7^_benzene sulfonamide and 3.3 g (0.02 mol) of K-butoxy tert-carbonyl-L-alamine, 1.2 g of pyridine and 100 ml of dichloromethane. The mixture is stirred at room temperature for one day and the solid precipitate is filtered off. The filtrate is washed successively with 1 M potassium bisulfate solution, water and dilute sodium bicarbonate solution and dried over anhydrous sodium sulfate. The solvent is concentrated and the residue is recrystallized from an appropriate solvent.

The solid product obtained is dissolved in trifluoroacetic acid at 0 ° C, stirred for 15 minutes and poured into ether. A solid precipitate forms which is filtered off and washed with ether. This gives the trifluoroacetate of the ester of

Desired L-alanyl.

Using the technique described above, the following compounds can be prepared:

□

Λ

R₁-0₂5th Ν Ο

<img file="PT75928B_D0064.tif" />

<img file="PT75928B_D0065.tif" />

OR,

Initial Comp

Product

Ex. ^R1

Nt-BOC

Amino acid

H Ph-CH ~ CHCO ~ ​​H t-BOC-NH

<img file="PT75928B_D0066.tif" />

-CCH-CH₉-Ph

NH „(Cl) ^ - H t -BOCNHCH₂CD₂H (Cl) ^ -CCH₂NH „

N₃h (ch₃)₂chchco₂hn₃t-BOC-NH

-cch₂-ch (ch₃)₂

NH „

Ç_noH_çW-H (CHj_OCHCH_CHC0_OHC 'H, W'2 5'3'2-2,22 5 t-BOC-NH' (CH 3)₉S = N- H Ph-CH CHCO₉H t-BOC-NH

-cch₂ch₂ch (ch₃)₂ nh₂

H (CH₃)₂S = N- -CCH-CH_Q-Ph

NH,

CH₃0hN- Η t-BOCNHCH ^ O ^ CH ^ HN--CCH₂NH „

<img file="PT75928B_D0067.tif" />

Dosage forms

Antibacterial agents prepared according to the present invention may be administered by any means that contacts the active agent with the agent's site of action in the body of a mammal. They may be administered by any conventional means suitable for use with pharmaceuticals; either as individual therapeutic agents or in a combination of therapeutic agents. They may be administered alone, but are generally administered with a selected pharmaceutical excipient depending on the route of administration chosen and normal pharmaceutical practice.

The dosage administered, of course, varies with factors known as the pharmacodynamic characteristics of the agent under consideration and its mode and route 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 dosage of active ingredient may be from about 5 to 20 milligrams per kilogram body weight. Usually, when using the most potent compounds prepared by the process according to the present intent, 5 to 15 mg, and preferably 5 to 7.5 mg per kilogram per day, administered in divided doses 2 to 4 times per day as delayed release agents are effective in obtaining the desired results. These drugs may also be administered by^TrI was going parenteral.

* »

Suitable dosage forms (compositions) for internal administration contain from about 1.0 mg to about 500 mg of active ingredient per unit. In these pharmaceutical compositions the active ingredient should generally be present in an amount of from about 0.5 to 95% by weight calculated with respect to weight.

<img file="PT75928B_D0068.tif" />

total composition.

active ingredient may be administered by ^rIt is oral in solid dosage forms such as capsules, tablets and the like, or in liquid dosage forms such as elixirs, syrups and suspensions, and may also be administered parenterally in sterile liquid dosage forms.

Gelatin capsules contain the active ingredient and powdery excipients such as lactose, sucrose, mannitol, starch, cellulose derivatives, magnesium stearate, stearic acid and the like. Analog diluents may be used to prepare tablets. Both tablets and capsules can be manufactured as delayed release products that provide continuous release of the drug for a few hours. The tablets may be sugar coated or film coated to mask any unpleasant taste and protect the tablet from atmospheric air, or be enteric coated tablets for selective disintegration in the gastrointestinal tract.

Liquid dosage forms for oral administration may contain dyes and flavorings to increase patient acceptance.

In general, water, an appropriate oil, saline, aqueous dextrose (glucose) solution and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable excipients for parenteral solutions. Solutions for parenteral administration preferably contain a water-soluble salt of the active ingredient, suitable stabilizing agents and, if necessary, buffer substances. Antioxidants such as sodium bisulfate, sodium sulfite or ascorbic acid, whether alone or in combination, are suitable stabilizing agents. Citric acid may also be used.

<img file="PT75928B_D0069.tif" />

and its salts or sodium EDTA. In addition, parenteral solutions may contain preservatives such as benzalkonium chloride, methyl or propyl paraben, and chlorobutanol.

Suitable pharmaceutical excipients are described in Remington.¹s Pharmaceutical Sciences ,. EW 'Martin, a typical reference text in this field.

Pharmaceutical dosage forms which may be used for administration of the compounds prepared by the process according to the present invention may be illustrated as follows:

Capsules

A large amount of unit capsules are prepared by introducing 75 mg of powdered active ingredient, 150 mg lactose, 2 mg of talc and 3 mg of magnesium stearate into each two-piece hard gelatin capsule.

A mixture of the active ingredient in soybean oil is prepared and injected using a positive gelatin displacement pump to form soft gelatin capsules containing 75 tog of the active ingredient. The capsules are washed in petroleum ether and dried.

»

Ϊ

Pills

A large number of tablets are prepared by conventional techniques so that the dosage unit contains 75 mg active ingredient, 0.2 mg colloidal silicon dioxide, 5 mg magnesium stearate, 250 mg microcrystalline cellulose, 11 mg of cereal starch and 93.8 mg of lactose. Appropriate coatings may be applied to increase their pleasant taste or delay absorption.

4th

<img file="PT75928B_D0070.tif" />

Injectable Solutions

A parenteral composition for administration is prepared by injection by shaking 1.50 by weight of active ingredient in 100 by volume of propylene glycol and water. Make the solution isotonic with sodium chloride and sterilize.

Suspension

An aqueous suspension for oral administration is prepared so that every 5 milliliters contains 75 mg of fine powdered active ingredient, 200 mg of sodium carboxymethyl celluiose, 5 mg of sodium benzoate, 1.0 g of sorbitol solution. USP and 0.025 ml vanillin.

Utility

The experimental results will show that the novel compounds prepared by the process according to the present invention are active against a wide variety of obligatory anaerobic, facultative anaerobic and obligatory anaerobic bacterial isolates including the p-lactamase producing Staphylococcus aureus and Neisseria gonorrhoea strains. Gram-negative enterobacteriaceae and Pseudomonas aeruginosa. 0 antibacterial spectrum of these agents encompasses microorganisms considered to be major human and veterinary pathogens of the respiratory, gastrointestinal, genitourinary and central nervous systems; blood; interstitial fluids, soft tissues; and bones.

A list of analogs exerting an in vitro antibacterial effect is given in Table 1. A microdilution method is used (Conrath, Theodore B., 1972, Handbook of Microtiter Procedures, Dynatech Corporation, Cambridge, Massachusetts) with

<img file="PT75928B_D0071.tif" />

Mueller-Kinton broth to determine 24-hour minimum inhibitory concentrations (MIC) for

Staphylococcus epidermidis and E. coli.

^1

NHL ·

Table -1

Minimum inhibitory concentrations with broth dilution in vitro ^R1°2^s

<img file="PT75928B_D0072.tif" />

O

THE.

K 0

V

OH

Chemical Name (d, 1) -4- / 7 5- (hydroxymethyl) -2-oxooxazolidinyl-3 H-benzene sulfonamide

MIC microdilution broth: µg / ml

S. eoidermidis E. coli

62,5

62,5

HUH₂ (1)-4--/7 5^_(hydroxymethyl) -2-oxooxazolidinyl-3'7-benzenesulfonamide

31,3

31,3

S (CH_)₂ (d, 1) -4- / 5- 5- (hydroxymethyl) -2-oxooxazolidinyl-3-7-N, N-dimethylbenzenesulfonamide

50,0 &gt; 200,0

C-βΝΗ (d, 1) -4 - / 7 5^-(hydroxyethyl) -2-oxooxazolidinyl-3,7-K-methylbenzenesulfonamide

50,0 ^&gt;200,0

CH 2 NH (1) -4 - / 75^-(hydroxymethyl) -2-oxooxazolidinyl-3-7-N-methylbenzenesulfonamide

25,0

200.0 (d, 1) -4 - / 75^-(hydroxymethyl) -2'-oxooxazolidinyl-3-7-benzenesulfonyl azide (1) -4- [5- (5-hydroxymethyl) -2-oxooxazolidinyl-3-7-benzenesulfonyl azide 1,2 +

1,6

12,5

9,4·

<img file="PT75928B_D0073.tif" />

A summary of the in vitro antibacterial spectrum of (1) -4- [5- (hydroxymethyl) -2-oxooxazolidinyl-3] benzenesulfonamide is given in Table 2. The minimum inhibitory concentrations for facultative anaerobic and anaerobic test isolates representing two gram-positive and 11 gram-negative genera were determined by an agar dilution method. The method has been established for the purpose and consists of the following. Mueller-Hinton agar plates containing double concentrations of the compound of 128yzxg / ml and 1.0g / ml are prepared for the susceptibility test of bacterial strains other than Neisseria gonorrhoea and Hemophilus Sp. These latter microorganisms are tested using GC agar with 1% Bacto-Supplement C (Difco Laboratories, Detroit, Michigan) and incubated under 6% CO₂· Agar plates are inoculated with a 0.001 ml calibrated loop of 6-diluted bacterial inoculum containing 5x10 colony forming units (CFG) per ml. After an incubation period of 24 hours at a temperature of 35 ° C, MICs are recorded as the lowest concentration of compound that inhibits macroscopic bacterial development.

The agar dilution method described by AL Barry (The Antimicrobic Susceptibility Test: Principles and Practice ', 1976, Lea and Febiger, Philadelphia, Pennsylvania) was used, with compound concentrations ranging from 32 µg / ml to 0.06 µg / ml to determine. (1) -4- [5- (hydroxymethyl) -2-oxooxazolidinyl-3] benzenesulfonamide inhibitory activity for anaerobic bacteria.

<img file="PT75928B_D0074.tif" />

Table 2

i

In Vitro antibacterial spectrum;

<td>from (1) -4- / 75-</td><td colspan="2">(Hydroxymethyl) -2-oxooxazolidinyl-3-7^- ? -benzenesulfonamide</td>

<td>Trial body</td><td>N⁹ of isolated</td><td>MIC mean: yttg / ml Ϊ</td>

<td>Staphylococci sp.</td><td>3θ</td><td> 22,3 ;·</td>

<td>St reptococci sp.</td><td>ll +</td><td>7.7 j</td>

<td>Ξ coli</td><td> 86</td><td>29.3 Ι</td>

<td>Proteus sp.</td><td> 33</td><td> . . 29,1</td>

<td>Providencia sp.</td><td> 12</td><td> ^1,3</td>

<td>Enterobacter sp.</td><td> 41</td><td> 58,5</td>

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

<td>Shigella sp.</td><td> 9</td><td> 3,0 ' !</td>

<td>Serratia sp.</td><td> 44</td><td>^ Ç6.0 (Range 327123)</td>

<td>Klebsiella sp.</td><td> 50</td><td>i 39 Λ '</td>

<td>Pseudomonas sp.</td><td> 79</td><td>^ 116.8 (Range 3 ^ 123)</td>

<td>iieisseria sp.</td><td> ^3</td><td> 12,3</td>

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

<td>Clostridium sp.</td><td> 5</td><td>l6.3</td>

<td>Fusobacterium sp.</td><td> 4</td><td> 0,9</td>

<td>Bacteroldes sp.</td><td> 23</td><td>^ 15.13 (Range 4 ^ 32) </td>

<td colspan="2">Oram - Anaerobic Cocei 7</td><td> 6,1</td>

MIC: Nun inhibitory concentration by dilution method on β-agar

<img file="PT75928B_D0075.tif" />

The potency of these compounds in vivo is identified by the results summarized in Table 3. · In vivo efficacy determinations are performed by inoculating mice, intraperitoneally, with cultures of the diluted infectious microorganism to produce one;

X.

90-100 $ mortality in control animals within seven days. Os? Diluents used are trypticase soy broth for E. coli, “Proteus sp. and Pseudomonas aeruginosa and 5% pig gastric mucin for infections with Staphylococcus aureus. The compounds, dissolved or suspended in 0.25% methocel®, are administered orally by intubation at the time of infection and again 4 hours after infection. Mortality is recorded daily until the end of the trial and the 50% effective dose of ED is calculated._Q, by the method of Reed-Muench / Reed, LG and Muench,,., A simple method of estimating fifty percent end points, American Journal of Eyelash,

I

27, 4-93-4-97 (1933). i

Table 3

<img file="PT75928B_D0076.tif" />

ji

In vivo efficacy of orally administered compounds on mouse intraperitoneal infections

Chemical Compound 1 (d, 1) -4- [5- (hydroxymethyl) -2-oxooxazolidinyl-3] benzene sulfonamide Chemical Compound 2 · (1) -4- [5- (hydroxymethyl) -2-oxooxazolidinyl-3 ] -benzenesulfonamide f

3 (d, 1) -4- [5- (hydroxymethyl) -2-oxooxazolidinyl-3] benzenesulfonyl azide &lt;RTIgt;

Chemical Compound 4) (1) -4- [5- (Hydroxymethyl-2-oxooxazolidinyl-3] -N-methylbenzenesulfonyl]

I —azida i • í i

Chemical Compound · 5 ^! ί (1) -4- [5- (hydroxymethyl) -2-oxooxazolidinyl-3] -N-methylbenzenesulfonamide

<td rowspan="2"></td><td rowspan="2">Comp.</td><td colspan="4">Infectious bacterial organism</td><td rowspan="2">'Pseudronronas:</td>

<td>Staphylo-</td><td>Escheri-</td><td>Proteus</td><td>Proteus</td>

<td></td><td colspan="2">chemist coccus aureus -so¹</td><td>chia coli °^AND50</td><td>mirabili ^ '^IN50</td><td>Vulgaris^IN50</td><td>fluorescers'^PE50</td>

<td>νή₂</td><td> 1</td><td> 39,1</td><td> 24,9</td><td>NT²</td><td>NT</td><td>t 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 colspan="2">CH₃NH 5</td><td> 15,44</td><td> 39,72</td><td>NT</td><td>NT</td><td>NT</td>

<td>¹IN</td><td> 50^{: Dose}</td><td colspan="2">50% effective mg / kg</td><td></td><td>i t t</td><td></td>

NT: