IE45460B1 - D-threo-1-phenyl-2-trifluoroacetmido-1-3-propanediol derivatives - Google Patents

Abstract

The compounds of the annexed formula in which R stands for CH3S- or CH3O2S- and R1 stands for hydrogen or, if R denotes CH3O2S-, for an acyl radical of an aliphatic carboxylic acid having 15-17 C atoms or aminoacetic acid, are prepared by reaction of a compound of the annexed formula with free trifluoroacetic acid or a functional derivative thereof. The corresponding esters, if R stands for CH3O2S-, are obtained by subsequent esterification to give the corresponding compound in which R1 is an acyl radical. The compound of the formula Ia in which R denotes CH3O2S and R1 denotes hydrogen is also prepared by oxidation of the corresponding methylmercapto compound using a peroxide compound. The esters of aminoacetic acid of the formula Ia can be converted into the corresponding therapeutically utilisable acid addition salts. The compounds obtained show a broad antibiotic spectrum of action and are highly suitable for use in human medicine.

Description

The invention relates to derivatives of D-threo-1phenyl-2-trifluoroacetamido-1,3-propanediol, processes for the preparation of such derivatives and pharmaceutical preparations containing such derivatives.

The invention provides a D-threo-l-phenyl-2-trifluoroacetamido-1,3-propanediol derivative of the general formula D-threo wherein either R represents a CH^S group and represents a hydrogen atom or R represents a CHjSO2 group and R^ repre10 sents a hydrogen atom, an aliphatic acyl group having from 15 to 17 oarbon atoms or a glycyl group.

The invention further provides a therapeutically accept able acid addition salt of the derivative of the general formula I wherein R represents a CHjSOj group and R^ repre15 sents a glycyl group.

Derivatives according to the invention possess wide spectrum antibiotic activity with good results in human therapy.

D-threo-1-(£-methylmeroaptophenyl)-2-trifluoroacetamido 20 1,3-propanediol 6 θ - 3 (I; R = CH^S. R^=H) may be prepared from D-threo-1-(p-methylmercaptophenyl)-2-amino-lz3-propanedicl by reacting the latter with trifluoroacetic acid or a reactive derivative thereof.

If the reaction is with trifluoroacetic acid, it is preferably carried out in the presence of a condensing agent, suitably a carbodiimide, for example dicyclohexylcarbodiimide. If the reaction is with a reactive derivative of trifluoroacetic acid, the reactive derivative is preferably an ester, amide, halide, anhydride or azide thereof. Methyl trifluoroacetate is the preferred reactive derivative. The reaction is preferably carried out in the presence of an inert organic solvent such as methanol.

D-threo-1-(p-methylsulphonylphenyl)-2-trifluorcacetamido1,3-propanediol (I? R = CH^SO^, R^ = H) may be prepared from D-threo-1- (pmethylmercaptophenyl)-2-trifluoroacetamido-l,3~propanediol, prepared as above described, by reacting the latter with a peroxidic oxidizing agent. The peroxidic oxidising agent is suitably hydrogen peroxide, a peracid, ammonium persulphate or potassium persulphate. Hydrogen peroxide is the preferred peroxidic oxidizing agent.

D-threo-I-(p-methyisulphonylphenyl)-2~tri£luoroacetamido1,3-propanediol (I: R - CH-^SOj, R^ ~ H) may alternatively be prepared from Dthreo-1- (p-methylmercaptophenyl)-2-amino-l,3-propanediol by reacting the latter with a peroxidic oxidizing agent and reacting the resultant D-threo-1-(p-methylsulphonylphenyl)2-amino-l,3-propanediol with trifluoroacetic acid or a reactive derivative thereof. The preferred conditions and reagents for these two reactions are identical to those described for the corresponding reactions above; this alterna4 Β -1 β Ο tive preparation simply reverses the order in which the 2amino and 1-(p-methylmercaptophenyl) groups of the D-threo1- (£-methylmercaptophenyl)-2-amino-l,3-propanediol are converted to 2-trifluoroacetamido and 1-(p>-methylsulphonyl5 phenyl) groups respectively.

D-threo-1-(p-methylsulphonylphenyl)-2-trifluoroacetamido 3-(C15_1?)acyloxy-1-propanols (I; R = CH3SO2, = (c15_17)·' acyl) may be prepared from D-threo-(l-£-methylsulphonylphenyl) 2- trifluoroacetamido-1,3-propanediol, prepared by either of 10 the methods above described, by reacting the latter with a • stoichiometric excess of an aliphatic carboxylic acid having from 15 to 17 carbon atoms or an active derivative thereof in the presence of an inert organic solvent and in the further presence of a base at a temperature of from 10°C to 50°C. The reaction conditions ensure that the 1-hydroxy group is -. esterified and not the 3-hydroxy group. The stoichiometric excess is preferably a slight excess. The preferred bases are hydroxides and carbonates of alkali metals, hydroxides and carbonates of alkaline earth metals, pyridine, tri20 alkylamines, N-aIky1-anilines and N,N-dialkylanilines. If an active derivative of the carboxylic acid is used, it is preferably a chloride, bromide or anhydride of the carboxylic acid. Most preferably, an acid chloride is employed in the presence of pyridine. The esters provided by this process are water-insoluble and can be recovered from the reaction mixture by addition of water, whereupon they precipitate and may be filtered off. The esters may be recrystallised from a suitable solvent, for essample, ethanol.

D-threo-1-(p-methylsulphonylphenyl)-2-trifluoroacetamido30 3-glycyloxy-l-propanol (I? R = CH^SO^, R^ = glycyl) may be prepared from D-threo-1-(n-methylsulphonylphenyl)-2-trifluoroΰ 1 6 0 acetamido-1,3-propanediol, prepared by either of the methods described above, by reacting the latter with an amino-group protected glycine or an amino-group protected derivative of glycine and removing the amino protecting group. The reaction is preferably carried out in the presence of a condensing agent, suitably a carbodiimide, for example dicyclohexylcarbodiimide. If an aasino-group protected derivative of glycine is used in the reaction, it is preferably an aminogroup protected mixed anhydride of glycine.

D-threo-1-(p-methylsulphonylphenyl)-2-trifluoroacetamido3-glycyloxy-l-propanol (I; R = CHgSOg, R^ = glycyl) may alternatively be prepared from D-three-1-(p-methylsuIphonylphenyl)-2-trifluoroacetamido-1-3-propanediol, prepared by either of the methods described above by reacting the latter with monochloroacetyl chloride, reacting the resultant product with hexamethylenetetramine and hydrolysing the resultant hexamethylenetetramine salt with a strong mineral acid. The strong mineral acid is preferably hydrochloric acid. The glycyl ester provided by this process or by the last described process is water soluble. It may be transformed into its acid addition salts by treatment with the acid corresponding to the salt which is desired, working according to known methods.

All the above described processes are included within the scope of the invention.

Derivatives according to the invention have been studied to evaluate both their toxicity characteristics and their antibiotic properties.

In the following Tables the names of the various derivatives have been abbreviated for simplicity as follows; ΰ 16 Ο - 6 Ζ 2100 = D - (+) - threo - 1 - (ρ - methylsulphonylphenyl)2 - trifluoroacetamido - 1,3 - propanediol Ζ 2109 = D - (-) - threo - 1 - (£ - methylmeroaptopheriyl)2 - trifluoroacetamido - 1,3 - propanediol S Z 2112 = D - (+) - threo - 1 - (p - methylsulphonylphenyl) - 3trifluoroacetamido - 3 - palmitoyloxy - 1 - propanol Z 2117 = D - (+) - threo - 1 - (£- methylsulphonylphenyl)2 - trifluoroacetamido - 3 - glycyloxy - 1 - propanol.

The determination of LDgQ values in the mouse by using oral and subcutaneous administration shows that the compounds under examination have good tolerability (Table 1) The mice were observed for; over one week for administration and no sign of suffering was apparent.

The antibacterial activity spectrum has been studied by the method of agar dilutions in a double series. The M.I C. (minimum inhibitory concentration) was tested against grampositive and gram-negative microorganisms as well as proteus. The two derivatives having the alcoholic function esterified (Z 2112 and Z 2117) are quickly hydrolized in the animal organism and show the same activity as Z 2100. The results obtained from the tests carried out in vitro are listed in Table 2.

Furthermore, the compounds of the invention show a bacterial activity, both in vitro and in the presence of rabbit serum, in respect of some microorganism strains resistant against thiamphenicol (D (+)-threo-l-(4-methylsulphonyl)1,3—-propanediol? see Merck Index ninth edition, 9034) as appears from the following results: - 7 ά ΰ 4 ti Ο Thiamphen ico 1 (MIC mcg/ml) Z.2100 * Streptococcus faecalis z 61 160 80 * II K Z 20 160 40 * Staphylococcus albus 1238 160 40 * Staphylococcus aureus 4180 160 40 A* Pseudomonas aeruginosa 50541 160 80 ** Streptococcus Faecalis 320 80 * = Tests in vitro; AA = tests carried out in oulture broth, in the presence of rabbit serum.

The study of the antibiotic activity of the derivatives of the present invention was completed by the determination of in experimental infections from multocide NCTC 10722 pasteuralla induced in the mouse by· intraperitoneal inoculation of a bacterial amount equal to about 100 times the lethal amount at 50%. The determination of PD^0 relating to the examined derivatives was carried out according to the method of Spearman-Karber (L. CavalliSforza Analisi statistica per mediei e biologi e analisi del dosaggio biologico— Ed.

Universitatrie Boringhieri — Torino — 1961, pages 173—175). The results obtained from the tests carried out in vivo are listed in Table 3.

TABLE I Compound Admin is tration per os (mg/kg) subcutaneous (mg/kg Z 2100 5000 5000 Z 2109 5000 Not determined Z 2112 5000 Not determined Z 2117 5000 5000 - 8 TABLE 2 ORGANISM TEST MIC (mcg/ml) Z 2100 3 2109 S. aureus Oxford 16 32 Proteus morgani N 520 8 4 Salmonella Typhi M-VI 32 64 E. Coli Κχ2 64 16 Strept. Faecalis ATCC 10541 8 32 Past, multocide NCTC 10722 2 4 Shighella Boydii 4 8 32 Strept . Agalactiae 4 b 16 64 TABLE 3 Compound Administration Treatment (day) mg^Sg Z 2100 per os 5 19 Z 2109 per os 5 16.6 Z 2112 per os 5 21 Z 2117 subcutaneous 5 14.3 The invention further provides compositions comprising compounds according to the invention in admixture with a therapeutically acceptable carrier or diluent.

This carrier or diluent may be an inorganic or inert organic material rendering the composition suitable for oral, rectal or parenteral administration such as water, gelatine, gum arabic, lactose, starch, magnesium stearate, talc, vege10 table oils and polyalkylene glycols. The composition can be made up in a solid form (for example as tablets, suppositories or capsules) or in a liquid form (for example as solutions, suspensions or emulsions). The compositions may be sterilised and may contain adjuvants such as preservatives, stabilizers, Λΰ-3 60 - 9 wetting agents, emulsifiers, salts for varying the osmotic pressure and buffers. Typical pharmaceutical preparations are: Gelatine capsule for oral administration D-(+)-threo-I-(p-raethylsulphonylphenyl)-2-trifluoroacetamido-l,3-propanediol 250 mg Lactose 50 mg Talc 5 mg Magnesium stearate 5 mg Vial for parenteral administration Lyophilised D-{+)-threo-1- (js-methylsulphonylphenyl)-2-trifluoroacetamido-l,3-propanediol 500 mg Solvent vial (physiological solution) sodium chloride 45 mg Ready-for-use-injection water q.s. 5 mg The following Examples illustrate the invention.

EXAMPLE 1.

Preparation of D-{+)-threo-1-(p-methylsulphonylphenyl)-2trifluoroacetamido-1,3-propanediol g (0.0612 mol) of D-(-)-threo-1-(p-methylsulphonylphenyl) -2-amino-l, 3-propanediol, 45 ml of methanol and 12.7 g (0.0992 mol) of methyl trifluoroacetate were refluxed for 4 hours. The solvent was evaporated off under vacuum and the resulting residue was crystallized from aqueous ethanol (50% V/V). g of 2> (+)-threo-1-(£-methylsulphonylphenyl)-2-trifluoroacetamido-l, 3-propanediol were obtained, m.p. = 180°—181°C? [ci]20 = + 7.7° (l%Me0H). - 10 EXAMPLE 2.

Preparation of D- (-)-threo-1-(p-methylmercaptophenyl)-2trifluoroacetamido-1,3-propanediol g (0.234 mol) of D-(-)-threo-1-(jc-methylmeroapto5 phenyl)-2-amino-l,3-propanediol, 150 ml of methanol and 45 g (0.351 mol) of methyl trifluoroacetate were refluxed for 4 hours. The solvent was evaporated off under vacuum and the resulting residue was crystallized from aqueous ethanol (50% V/V). 52.3 g of D-(-)-threo-1-(p-methylmercaptophenyl)-2-trifluoro acetamido-1,3-propanediol were obtained, b.p. = 117°—118°C? [a]2° = -7.15° (l%MeCH).

EXAMPLE 3.

Preparation of D-{+)-threo-1-(p-methylsulEwnylphenyl)-215 trifluoroacetamido-1,3-propanediol To a solution of 21.1 g of 130 vol. ydrogen peroxide, g (0.0647 mol) of D-(-)-threo-1-(p-methylmercaptophenyl)2-trifluoroacetamido-1,3-propanediol were ,:lowly added, at 40°C. After the addition the whole was kept under these conditions for 30 minutes and then 21.7 g 0.211 mol) of acetic anhydride were slowly added at 40°C After 3 hours at 40°C the whole was cooled to -10°C, and the precipitate which formed was filtered off, washed with icy water and dried. 15.5 g of D-(+)-threo-1-(ρ-methyls’ lphonylphenyl)-225 trifluoroacetamido-1,3-propanediol were ob·. ined. m.p. = 179°—180°C. The product crystallized fro'-, aqueous ethanol (50% V/V) showed a m.p. of 180°—181°C? [a]p°= + 7.7°C (1% MeOH).

EXAMPLE 4.

Preparation of D-(+)-threo-1-(p-methvlsulphonvlphenyl)-2trifluoroacetamido-3-qlvevloxv-l-propa'iol hydrochloride 19.2 g (0.0562 mol) of D-(x)-threo-?-(p-methylsulphonylphenyl)-2-trifluoroacetamido-1,3-propanediol were »»!3 4 6 0 - 11 dissolved in 22.5 ml of N,N-dimethylformamide containing 4.52 g (0.0569 mol) of pyridine. To the solution cooled to 0°C, 6.42 g (0.0569 mol) of monochloroacetyl chloride were added slowly and under stirring. After the end of the addition the solution was stirred for a further 1 hour at 0°C and then was poured under stirring into a mixture of ice and water. Crude D-(+)-threo-l-(£-methylsulphonylphenyl)-2-trifluorcscetamido-3-chloroacetoxy-l-propanol was precipitated. After filtration off and drying it weighed 19.8 g. The product was purified by crystallization from ethanol, m.p. 168°—169°C; [uj2° = + 10.4° (l%Me0H). g (0.0215 mol) of D“(+)--threo-l-(£-methylsulphonylphenyl)-2-trifluoroacetamido-3-chloroacetoxy-l-propanol, prepared as described above, 36.5 ml of acetonitrile and 3.02 g (0.0215 mol) of hexamethylenetetramine were stirred for two hours at 40°—45°C and then were left overnight at room temperature. The whole was evaporated to dryness under vacuum and the residue was treated at 20°c under stirring with a solution of 27.5 ml of ethanol containing 5.5 ml of concentrated hydrochloric acid. The whole was left under stirring at 30°C overnight and then was evaporated to dryness under vacuum. The residue obtained was treated with 20 ml of N,N-dimethylformamide and the resulting clear solution was poured into 150 ml of dichloromethane. 4.2 g of D - (+) - threo - 1 - (£- methylsulphonylphenyl)-2trifluoroacetamido-3-glycyloxy-l-propanol hydrochloride precipitated. The product was purified by crystallization from ethanol. m p. = 190°—191°Cf [a] 20 = + 20.5 (1% MeOH).

. Ci - 12 EXAMPLE 5.

Preparation of D-(+)-threo-l-(p-methylsulphonylphenyl)-2trifluoroacetaniiao-3-palmitoyloxy-1-propanol 9.6 g (0.0281 mol) of D-(+)-threo-1-(p-methylsulphonyl5 phenyl)-2-trifluoroacetamido-l,3-propanol were dissolved in 13.5 ml of N.N-Simethylformamide containing 2.66 g (0.0336 mol) of pyridine. To the resultant solution 8 5g (0.0309 mol.) of palmitoyl chloride were slowly added at 10—15°C vzhile stirring. The solution was then heated to 35—40°C and was left under stirring for 30 minutes. After this period of time, 60 ml of vzater were poured into the solution kept under stirring and the mixture was cooled to 0°C. D-(+) threo-1-(p-methylsulphonylphenyl)-2-trifluoroacetamido-3palmitoyloxy-l-propanol precipitated. It was filtered off and weighed (15.25 g). The product was purified by crystallisation from toluene and successive washing with petroleum ether.

Claims (5)

1. CIAIMS:1. A D-threo-l-phenyl-2-trifluoroaoetamido-l,3propanediol derivative of the general formula I as herein defined, or when R represents CI^SO^ and R^ represents a glycyl group, a therapeutically acceptable acid addition salt thereof.

2. D-(+)-threc-1-(p-methylsulphonylphenyl)-2-trifluoroacetamido-1,3-propanediol.

3. D-(-)-threo-1-(p-methylmercaptophenyl)-2-trifluoroacetamido-1,3-propanediol.

4. D-(+)-threo-1-(p-methylsulphonylphenyl)-2-trifluoroacetamido-3-palmitoyloxy-1-propanol. 5 D-(+)-threo-1-(p-methylsulphonylphenyl)-2-trifluoroacetamido-3-glycyloxy-l-propanol or its hydrochloride. 6. A process for the preparation of D-threo-1-(pmethylmercaptophenyl)-2-trifluoroacetamido-1,3-propanediol, the proeess comprising reacting D-threo-1-(p-methylmercaptophenyl) -2-amino-l, 3-propanediol with trifluoroacetic acid or a reactive derivative thereof. 7. A process according to claim 6 in whioh the reaction is carried out with trifluoroacetio acid in the presence of a carbodiimide condensing agent. 8. A process according to claim 7 in which the carbodiimide condensing agent is dicyclohexylcarbodiimide 9. A process according to claim 6 in which the reaction is carried out with an ester, amide, halide, anhydride or azide or trifluoroacetio acid. 10. D-threo-1-(p-methylmercaptophenyl)-2-trifluoroacetamido-1, 3-propanediol prepared by a process according to any of claims 6 to 9. 4SjdOU - 14 11. A process for the preparation of D-threo-l-(pmethylsulphonylphenyl)-2-trifluoroacetamido-1,3-propanediol, the process comprising reacting a compound according to claim 10 with a peroxidic oxidising agent. 5 12. A process according to claim 11 in which the peroxidic oxidising agent is hydrogen peroxide, a peraeid, ammonium persulphate or potassium persulphate. 13. D-threo-1-(p-methylsulphonylphenyl)-2-trifluoroacetamido-1, 3-propar.ediol prepared by a process according 10 to claim 11 or claim 12. 14. A process for the preparation of D-threo-1-(pmethylsulphonylphenyl)-2-trifluoroacetamido-1,3-propanediol, the process comprising reacting D-threo-l-(p-methy1mereaptophenyl)-2-amino-l 3-propanediol with a peroxidic 15 oxidizing agent and reacting the resultant D-threo-1-(pmethylsulphonylphenyl)-2-amino-l,3-propanediol with trifluoroacetic acid or a reactive derivative thereof. 15. A process according to claim 14 in which the peroxidic oxidizing agent is hydrogen peroxide, a peraoid, 20 ammonium persulphate or potassium persulphate. 16. A process according to claim 14 or claim 15 in which the reaction of the D-threo-J-(p-methylsulphonylphenyl)-2-amino-l,3-propanediol is carried out with trifluoroacetic acid in the presence of a carbodiimide condensing 25 agent. 17. A process according to olaim 16 in whieh the carbodiimide condensing agent is dicyclohexylcarbodiimide. 18. A process according to claim 14 or claim 15 in which the reaotion of the D-threo-1-(p-methylsulphonyl30 phenyl)-2-amino-l,3-propanediol is carried out with an ester, i 3 4 6 ΰ amide, halide, anhydride of azide or trifluoroacetic acid. 19. D-threo-1-(p-methylsulphonylphenyl)-2-trifluoroacetamido-1,3-propanediol prepared by a process according to any of claims 14 to 18. 20. X process for the preparation of a D-threo-1-(£methylsulphonylphenyl)-2-trifluoroacetamido-3-acyloxy-lpropanol in which the 3-acyloxy group is aliphatic and has from 15 to 17 carbon atoms, the process comprising reacting a compound according to claim 13 or claim 19 with a stoichiometric excess of an aliphatic carboxylic acid having from 15 to 17 carbon atoms or with an active derivative thereof in the presence of an inert organic solvent and in the further presence of a base at a temperature of from 10°C to 50°C. 21. A process according to claim 20 in which the base is a hydroxide or carbonate of an alkali metal, a hydroxide or a carbonate of an alkaline earth metal, pyridine, a trialkylamine, an N-alkyl-aniline or an N,N-dialkylaniline. 22. A process according to claim 20 or claim 21 in which the reaction is carried out with a chloride, bromide or anhydride of the carboxylic acid. 23. D - threo-l-(p-methylsulphonylphenyl)-2-trifluoroacetamido-3-acyloxy-l-propanol in which the 3-acyloxy group is aliphatic and has from 15 to 17 carbon atoms prepared by a process according to any of claims 20 to 22. 24. A process for the preparation of D-threo-l-(pmethylsulphonylphenyl)-2-trifluoroacetamido-3-glycyloxy-lpropanol, the process comprising reacting a compound according to claim 13 or claim 19 with an amino-group protected glycine or an amino-group protected derivative of glycine and removing the amino protecting group. - 16 «55460 25. A process according to claim 24 in which the reaction is carried out in the presence of a carbodiimide condensing agent. 26. A process according to claim 25 in which the 5 carbodiimide condensing agent is dicyclohexylcarbodiimide. 27. A process according to any of claims 24 to 26 in which the reaction is carried out with an amino-group protected mixed anhydride of glycine. 28. D-threo-1-(p-methylsulphonylphenyl)-2-trifluoro10 acetamido-3-glycycloxy-l-propanol prepared by a process according to any of claims 24 to 27. 29. A process for the preparation of D-threo-1-(ρίπε thylsulphonylphenyU-a-trifluoroacetamido-S-glycyloxy-Ipropanol, the process comprising reacting a compound 15 according to claim 13 or claim 19 with monochloroacetyl chloride, reacting the resultant product with hexamethylenetetramine and hydrolysing the resultant hexamethylenetetramine salt with a strong mineral acid. 30. A process according to claim 29 in which the 20 strong mineral acid is hydrochloric acid. 31 D - threo-1-(p-methylsulphonylphenyl)-2-trifluoroacetamido-3-glycyloxy-l-propanol prepared by a process according to claim 29 or claim 30. 32. A process for the preparation of an acid addition 25 salt of D-threo-1-(p-methylsulphonylphenyl)-2-trifluoroacetamido-3-glycyloxy-l-propanol, the process comprising treating a compound according to claim 28 or claim 31 with an acid. 33. An acid addition salt of D-threo-1-(p-methyl30 sulphonylph.enyl-2-trifluoroaoetamido-3-glycyloxy-l-propanol - 17 prepared by a method according to claim 32. 34. A process for the preparation of a compound according to claim 1, the process being substantially as described herein with reference to any of the Examples.

5. 35. A composition comprising a compound according to any of claims 1 to 5, 10, 13, 19, 23, 28, 31 or 33 in admixture with a therapeutically acceptable carrier or diluent.