IL45776A - Thiamphenicol derivatives their manufacture and pharmaceutical compositions containing them - Google Patents

Abstract

1433977 Sulphones F HOFFMANN-LA ROCHE & CO AG 21 Nov 1974 [22 Nov 1973] 50447/74 Heading C2C Novel compounds (I) (including salts thereof) where R is H or a glycyl group, are made by reacting (II) with difluoroacetic acid or a functional derivative thereof and, if desired, esterifying (I) obtained (R is H) to give the glycyl ester. D - Threo - 1 - [(p - methylsulphonyl)phenyl]- 2 - (2,2 - difluoroacetamido) - 1,3 - propanediol 3 - (N - tert - butyolxycarbonyl) - glycyl ester is obtained by reacting the 1,3-propanediol with N-tert-butyloxycarbonyl-glycine. Pharmaceutical preparations active against gram-positive and -negative micro-organisms contain (I) as active ingredient. Administration is orally, parenterally or topically. [GB1433977A]

Description

45776/2 jniR c»1?'»3an nmpn »T03rn !Ehiamphenicol derivatives, their inanufacture and pharmaceutical compositions containing them SPARAMK ICA A.G. 4410/87 The present invention relates to acyl derivatives.

More particularly, the invention is concerned with acyl derivatives, a process for the manufacture thereof and pharmaceutical preparations containing same.

The acyl derivatives provided by the present invention are compounds of the general formula , wherein R represents a hydrogen atom or a glycyl group, and acid addition salts of those compounds in whic R represents a glycyl group.

Since the compounds of formula I and their salts contain two asymmetric carbon atoms, they can be present in four etereoisomeric forms or as racemates= Preferred compounds of formula I are D-threo~l-C(p- -met ylsulphonyl )-phenyl]-2-(2 ,2-difluoroacetamido )-l , 5~ -propanediol (fluorthiemphenicol) and the corresponding 5--glycyl ester.

According to the process provided by the present invention, the acyl derivatives aforesaid (i.e. the compounds of formula I and acid addition salts of those compounds in which R represents a glycyl group) are manufactured by reacting a compound of the formula OH H or an acid addition salt thereof with difluoroacetic acid or a reactive functional derivative thereof and, if desired, esterifying a resulting compound of formula I in which R represents a hydrogen atom to give the corresponding glycyl ester and, also if desired, converting a glycyl ester obtained into an acid addition salt.

Examples of reactive functional derivatives of difluoroacetic acid include esters (e.g. the methyl or ethyl ester), halides (i.e. the chloride, bromide and fluoride), azides, anhydrides, especially mixed anhydrides with strong acids, amides (e.g. imidazolides) and the like.

The reaction of a compound of formula II with difluoroacetic acid or a reactive functional derivative thereof can be carried out in a manner known per se.

Thus, for example, difluoroacetic acid itself can be reacted with a compound of formula II in the presence of a condensation agent (e.g. a carbodiimide such as dicyclo-hexylcarbodiimide) in an inert solvent (e.g. ethyl acetate, acetonitrile, dioxane, chloroform, methylene chloride, -ethyl-5-phenyl-isoxazolium 3 ' -sulphonate) can be used as the condensation agent in place of carbodiimides.

In another embodiment, a salt of a compound of formula II (e.g. the hydrochloride) can be reacted with a reactive functional derivative of difluoroacetic acid in a solvent, expediently a polar solvent such as a lower alkanol (e.g. methanol) .

The reaction of a compound of formula II with difluoroacetic acid or a reactive functional derivative thereof can be expediently carried out at temperatures between about room temperature and the reflux temperature of the reaction mixture.

The esterification of a compound of formula I in which R represents a hydrogen atom to give the corresponding ester in which R represents a glycyl group can be carried out in a manner known per se. Thus, for example, fluorthiamphenicol can be reacted with glycine, the amino group of which is present in protected form (e.g. N-t-butyloxycarbonyl-glycine) , in the presence of a condensation agent (e.g. a carbodiimide such as dicyclohexylcarbodiimide) in an inert solvent (e.g. acetonitrile) at a temperature between about +5°C and -10°C (e.g. at about 0°C) and the protecting group can subsequently be cleaved off by treatment with a dilute acid (e.g. a mixture of hydrochloric acid and glacial acetic acid).

The compounds of formula I in which R represents a glycyl group are bases and can be converted into acid addition acid, hydrobromic acid, sulphuric acid, phosphoric acid and the like and with organic acids such as acetic acid, tartaric acid, maleic acid, fumaric acid, citric acid, oxalic acid, toluenesulphonic acid and the like.

Optically active compounds of formula I can be manufactured not only from the corresponding antipodes of formula II but also by resolution of a racemate. Thus, for example, a racemate of formula I in which R represents a glycyl group can be resolved using an optically active acid (e.g. an antipode of camphorsulphonic acid, tartaric acid or the like).

The compound of formula II is a known compound and can be prepared in a manner known per se.

The compounds of formula I, in particular those having the D-threo form, and acid addition salts of those compounds in which R represents a glycyl group possess antibiotic activity. They have a wide spectrum of activity against gram-positive and gram-negative microorganisms, especially against Proteus and Pseudomonas aeruginosa. The compounds of formula I and pharmaceutically acceptable acid addition salts of those compounds in which R represents a glycyl group can be used as therapeutics and disinfectants.

Individual dosages of ca 1 g are appropriate for adults.

While fluorthiamphenicol is especially suitable for oral administration, its 3-glycyl ester hydrochloride is especially suitable for parenteral administration because of its The latter is h drol ticall The acute toxicity in mg/kg) of fluorthiamphenicol and its 3-glycyl ester hydrochloride upon intravenous, subcutaneous and oral administration to mice as well as the activity in mg kg) of these two substances against Pseudomonas aeruginosa upon oral administration to mice are given in the following Table: Table The two threo compounds of formula (I) herein in which R is hydrogen are encompassed by the generic formula disclosed in British Patent Specification No. 745,900.

This publication does not, however, specifically disclose any of the compounds of the present invention which are surprisingly superior to the closest prior art compound, thiamphenicol , in their water-solubility, lower toxicity and higher antibiotic activity.

Pharmaceutical preparations can contain the compounds of formula I and pharmaceutically acceptable acid addition salts of those compounds in which R represents a glycyl group in association with a compatible pharmaceutical carrier.

This carrier can be an organic or inorganic, inert carrier material suitable for enteral, especially oral, or parenteral administration such as, for example, water, gelatine, gum arabic, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkyleneglycols, petroleum jelly, etc. The pharmaceutical preparations can be made up in a solid form (e.g. as tablets, drag^es, suppositories or capsules), in a semi-solid form (e.g. as ointments) or in a liquid form (e.g. as solutions, suspensions or emulsions). The pharmaceutical preparations may be sterilised and/or may contain adjuvants o such as preservatives, stabilisers, wetting agents, emulsifiers, salts for varying the osmotic pressure or buffers.

The following Examples illustrate the process provided by the present invention: Example 1 Manufacture of D-threo-l-[(p-meth.ylsulphonyl )phenyl 3 -2--(2 ,2-difluoroacetamido)-l , 5-propanediol 5.64 g of D-threo-l-[(p-methylsulphonyl)phenylJ-2-amino--1 , 3-propanediol hydrochloride in 100 ml of methanol are brought into solution by means of 2.76 ml of triethylamine and treated with 5 · 35 g of difluoroacetic acid methyl ester. The mixture is heated under reflux for 10 minutes and then evaporated under reduced pressure. The oily residue is dissolved in the minimum amount of water and extracted twice with ethyl acetate. The combined ethyl acetate extracts are dried over magnesium sulphate and concentrated under reduced pressure, the desired compound crystallising out in a pure state. The colourless crystallisate is filtered off under a vacuum, washed with diethyl ether and with petroleum ether and dried at 30°C under reduced pressure. The desired product is obtained in a yield of 4.15 g and has a melting point of 152°-15 °C; CaJ^0 = +14.2° (c = 1.610 in methanol).

Example 2 Manufacture of D-threo-l-[(p-methylsulphonyl)phenyl]-2--C2 , 2-difluoroacetamido)-l, 3-propanediol 5-glycyl ester hydrochloride carbonyl-gl cine and 2.4 g of pyridine are dissolved in 150 ml of acetonitrile. This solution is treated at 0°C with a solution of 6.15 g of dicyclohexyl-carbodiimide in 0 ml of acetonitrile. The mixture is left to stand for 0. hour at 0°C and then for 20 hours at 20°C. After filtration of the dicyclohexyl-urea, the filtrate is evaporated under reduced pressure. The resulting residue is dissolved in ethyl acetate and washed successively, with the addition of ice, with 1-N sulphuric acid and with a 10% sodium bicarbonate solution. The ethyl acetate solution is then dried over magnesium sulphate and evaporated under reduced pressure.

The light foam remaining as the residue (12.5 g) is chromatographed on a silica gel column with ethyl acetate as the eluant; .05 g of D-threo-l-[(p-methylsulphonyl)phenyl]--2-(2,2-difluoroacetamido)-1 , 3-propanediol 3-(N-t-butyloxy-carbonyl)-glycyl ester being obtained in pure form as a colourless foam. 4.0 g of D-threo-l-[(p-methylsulphonyl)phenyl]-2-(2,2--difluoroacetamido)-l , 3-propanediol 3-(N-t-butyloxycarbonyl)--glycyl ester are dissolved in 1 0 ml of a 1.4-N hydrochloric acid glacial acetic acid solution and left to stand for 0. hour. The mixture is concentrated under reduced pressure and treated with diethyl ether, the desired product precipitating. This is then re-precipitated from ethanol/ diethyl ether, filtered off under a vacuum, washed with ether and dried at 20°C under reduced pressure. There are obtained 3.25 g of amorphous, pure product as a colourless powder 20 having a melting point above 120°C (decomposition); Ca]p = ° = than l .

The following Examples illustrate typical pharmaceutical preparations containing the acyl derivatives provided by the present invention: Example A An interlocking gelatine capsule containing the following ingredients is manufactured in the usual manner: Fluorthiamphenicol 500 mg Luviskol (water-soluble polyvinylpyrrolidone) 20 mg Mannitol 20 mg Talc 15 mg Magnesium stearate 2 mg Example B A lyophilisate of the following composition is manufactured in the usual manner: Fluorthiamphenicol 3-glycyl ester hydrochloride 1 J0 mg p-Hydroxybenzoic acid methyl ester 2 mg p-Hydroxybenzoic acid propyl ester 0.2 mg This lyophilisate is filled into an ampoule. Such an ampoule contains the lyophilised active ingredient for 5· 3 m of ready-for-use injection solution. For the manufacture of .5 ml of ready-for-use injection solution, ml of distilled water are added to the lyophilisate.

Claims (13)

Having now particularly described and ascertained the nature of our said invention and in what manner the same is to be performed, we declare that what we claim is:

1. A process for the manufacture of acyl derivatives of the general formula wherein R represents a hydrogen atom or a glycyl group, and of acid addition salts of those compounds in which R represents a glycyl group, which process comprises reacting a compound of the formula OH H or an acid addition salt thereof with difluoroacetic acid or a reactive functional derivative thereof and, if desired, esterifying a resulting compound of formula I,in which R represents a hydrogen atomfto give the corresponding glycyl ester and, also if desired, converting a glycyl ester obtained into an acid addition salt.

2. A process according to claim 1, wherein D-threo-1-[ (p-methylsulphonyl)phenyl]-2-amino-l,3-propanediol hydrochloride is used as the startin material of formula II.

3. A process for the manufacture of the acyl derivatives claimed in claim 1, substantially as hereinbefore described with reference to Example 1 or Example 2.

4. A process for the manufacture of preparationshaving pharmaceutical properties, characterized in that a compound of the general formula wherein R represents a hydrogen atom or a glycyl group, or a pharmaceutically utilizable acid addition salt of such a compound, in which R represents a glycyl group, is mixed, as active substance, with nontoxic, inert, therapeutically compatible solid or liquid carriers, commonly used in such preparations, and/or excipients.

5. Compositions having pharmaceutical properties, containing a compound of the general formula wherein R represents a hydrogen atom or a glycyl group, or a pharmaceutically utilizable salt of such a compound, in which R represents a glycyl group, and a carrier.

6. Racemic or optically active compounds of the general formula wherein R represents a hydrogen atom or a glycyl group, and acid addition salts of those compounds in which R represents a glycyl group, whenever prepared by the process as claimed in any one of claims 1-3 or by an obvious chemical equivalent thereof.

7. compound according to claim 6, namely D-threo-1-[ (p-methylsulphonyl)phenyl]-2-(2 ,2-difluoroacetamido)-1,3-propanediol, whenever prepared by the process as claimed in any one of claims 1-3 or by an obvious chemical equivalent thereof.

8. Compounds according to claim 6, namely D-threo-1-[ (p-meth lsulphonyl)phenyl]-2-( 2 , 2-difluoroacetamido )-l,3-propanediol 3-glycyl ester and acid addition salts thereof, whenever prepared b the process as claimed in any one of claims 1-3 or by an obvious chemical equivalent thereof.

9. A compound according to claim 6 or 8, namely D-threo-l-[ (p-methylsulphonyl)phenyl]-2- (2, 2-difluoroacetamido )-1,3-propanediol 3-glycyl ester hydrochloride, whenever prepared obvious chemical equivalent thereof.

10. Racemic or optically active compounds general formula wherein R represents a hydrogen atom or a glycyl group, and acid addition salts of those compounds in which R represents a glycyl group.

11. A compound according to claim 10, namely D-threo-1-[ (p-methyIsulphonyl)phenyl]-2- ( 2 , 2-difluoroacetamido )-1, 3-propanediol.

12. Compounds according to claim 10, namely D-threo-1-[ (p-methyIsulphonyl)phen l]-2- (2 , 2-difluoroacetamido )-1, 3-propanediol 3-glycyl ester and acid addition salts thereof.

13. compound according to claim 10 or 12, namely D-threo-l-[ (p-methyIsulphonyl)phenyl]-2-(2,2-difluoroacetamido) 1,3-propanediol 3-glycyl ester hydrochloride.