COMPOSITION CONTAINING A PENEM OR CARBAPENEM ANTIBIOTIC

Abstract: Administration of an N-acylated amino acid (ornithine, lysine, phenylglycine or phenylalanine) in association with a penem or carbapenem antibiotic relieves or eliminates the renal problems associated with administration of the antibiotic alone. The amino acid and antibiotic may be formulated together as a composition or administered separately, either simultaneously or sequentially. A phar­ maceutical composition may be prepared simply by mixing the two components.

Description: The present invention relates to a novel composition comprising a penem or carbapenem antibiotic in association with an amino acid derivative. The invention also provides these compounds for treating bacterial infections by administering them to the patient, simultaneously or sequentially. The class of compounds known as "penem and carbapenem antibiotics" is, of course, very well-known and is potentially of great value for the treatment of bacterial infections. Although, as a group, these penem and carbapenem antibiotics exhibit excellent anti-bacterial activity and a variety of other properties which render them highly suitable for pharmaceutical use, they do have a number of disadvantages. One of the problems of these antibiotics is that, in general, they exhibit a degree of renal toxicity, and some degree of kidney damage is a frequent side effect of their use; accordingly, such penem and carbapenem antibiotics should not be used for the treatment of patients with actual or suspected impaired renal function. As a result, the penem and carbapenem antibiotics cannot be used for many patients for whom otherwise they would be the antibiotic of choice. The problem of renal toxicity is particularly acute when the antibiotics are administered by intravenous or intramuscular injection in a high dose. We have now surprisingly found that the concurrent, or effectively concurrent, administration, with the penem or carbapenem antibiotic, of one or more of a certain limited class of acylated amino acid derivatives significantly reduces this renal toxicity. Accordingly, in one aspect, the present invention provides a composition comprising: (a) an antibiotic which is a penem antibiotic or a carbapenem antibiotic; and (b) a pharmaceutically acceptable N -acylated amino acid, in which the amino acid is ornithine, lysine, phenylglycine or phenylalanine, and the acyl group is a C₁-C₁₈ alkanoyl group, a C₃-C₈ alkenoyl group, a C₃-C₈ alkynoyl group, an aromatic acyl group wherein the aryl part is C₆-C₁₄ carbocyclic aryl and is unsubstituted or has from 1 to 5 C₁-C₄ alkyl, hydroxy, C₁-C₄ alkoxy, amino or sulphonyl substituents, a cycloalkanecarbonyl group where in the cycloalkane part is C₃-C₈, a C₂-C₇ alkoxycarbonyl group, or an aralkyloxycarbonyl group where in the aralkyl part has from 7 to 9 carbon atoms and is unsubstituted or has from 1 to 5 amino, C₁₋C₄ alkyl, C₁-C₄ alkoxy or hydroxy substituents; or a pharmaceutically acceptable salt thereof; and wherein the amount of said N -acylated amino acid is sufficient to alleviate any renal toxicity of said antibiotic, preferably in a weight ratio of from 0.1:1 to 4:1. In another aspect, the invention provides the use of: (a) an antibiotic which is a penem antibiotic or a carbapenem antibiotic; and (b) a pharmaceutically acceptable N -acylated derivative of an amino acid, in which the amino acid is ornithine, lysine, phenylglycine or phenylalanine, wherein the acyl group and amount are as defined above, for the manufacture of a one-part or two-part medicament for the treatment of bacterial infections. The invention also provides a two-part pharmaceutical preparation comprising, in one part, (a) and, in the other part, (b). There is no particular limitation on the nature of the penem or carbapenem antibiotic to which the present invention can be applied and it is believed that the beneficial effects of the concurrent or effectively concurrent administration of an acylated amino acid derivative will be achieved regardless of the particular antibiotic chosen. However, the antibiotics which are currently of most actual or potential interest may be represented by the general formula I: in which: X represents a sulphur atom, a methylene group or a methylene group having 1 or 2 methyl substituents; and R¹ represents a group of formula: The invention may also be applied to pharmaceutically acceptable salts and esters of such antibiotics. Specific examples of compounds of general formula I which may be employed in the present invention are those in which R¹ and X are as defined below. The penem and carbapenem compounds are hereinafter, where appropriate, identified by the numbers assigned to them in this list. Of the compounds listed above, we particularly prefer those which have the same configuration as thienamycin, i.e. (5 R ,6 S )-6-[1( R )-hydroxyethyl]. In particular, the following compounds are preferred: (5 R ,6 S )-2-{2-[(aminomethylene)amino]ethylthio}-6-[1( R )-hydroxyethyl]-2-carbapenem-3-carboxylic acid (isomer of Compound No. 1) (5 R ,6 S )-2-[(3 S )-1-acetimidoylpyrrolidin-3-ylthio]-6-[1( R )-hydroxyethyl]-2-carbapenem-3-carboxylic acid (isomer of Compound No. 6) (5 R ,6 S )-2-[(3 R )-1-acetimidoylpyrrolidin-3-ylthio]-6-[1( R )-hydroxyethyl]-2-carbapenem-3-carboxylic acid (isomer of Compound No. 7) (5 R ,6 S )-2-[(3 R )-1-acetimidoylpyrrolidin-3-ylthio]-6-[1( R )-hydroxyethyl]-1( S )-methyl-2-carbapenem-3-carboxylic acid (isomer of Compound No. 23) (5 R ,6 S )-2-[(3 S )-1-acetimidoylpyrrolidin-3-ylthio]-6-[1( R )-hydroxyethyl]-1( R )-methyl-2-carbapenem-3-carboxylic acid (isomer of Compound No. 24) (5 R ,6 S )-2-[(3 S )-1-acetimidoylpyrrolidin-3-ylthio]-6-[1( R )-hydroxyethyl]-1( S )-methyl-2-carbapenem-3-carboxylic acid (isomer of Compound No. 27) (5 R ,6 S )-2-[(3 S )-1-acetimidoyl-5( S )-carbamoylpyrrolidin-3-ylthio]-6-[1( R )-hydroxyethyl]-2-carbapenem-3-carboxylic acid (isomer of Compound No. 28) The above compounds may likewise be employed in the form of their pharmaceutically acceptable salts or esters, examples of which are well-known to those skilled in the art and which are given, for example, in EP-A-00 72710. N -acylated derivatives of ornithine and lysine may be represented by the general formula II: R²-NH-(CH₂) n -CH(COOH)NH-R³ (II) and phenylalanine and phenylglycine derivatives may be represented by the general formula III: Ph-(CH₂) m -CH(COOH)-NHR⁴ (III) In the above formulae, n represents the integer 3 or 4, whilst m represents the cypher 0 or the integer 1. Ph represents the phenyl group. R² and R³ are the same or different and each represents a hydrogen atom or a carboxylic acyl group as defined, provided that R² and R³ are not simultaneously hydrogen atoms. R⁴ represents a carboxylic acyl group. Examples of carboxylic acyl groups which may be represented by R², R³ and R⁴ include: alkanoyl groups having from 1 to 18, preferably from 2 to 5, carbon atoms, for example the acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, octanoyl, nonanoyl and decanoyl groups; alkenoyl and alkynoyl groups having from 3 to 8, more preferably 3 or 4, carbon atoms, for example the acryloyl, methacryloyl, crotonoyl or propioloyl groups; aromatic acyl groups in which the aryl ring is a carbocyclic ring having from 6 to 14, preferably 6 to 10, carbon atoms and optionally having from 1 to 5, more preferably from 1 to 3, C₁-C₄ alkyl, hydroxy, alkoxy, amino or sulphonyl substituents, for example the benzoyl and naphthoyl groups and the benzoyl and naphthoyl groups having one or more of the above substituents; alicyclic acyl groups in which the carbocyclic ring has from 3 to 8 carbon atoms, more preferably 3 or 6 carbon atoms, for example the cyclopropanecarbonyl and cyclohexanecarbonyl groups; alkoxycarbonyl groups having a total of from 2 to 7 carbon atoms, for example the methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl and pentyloxycarbonyl groups; and aralkyloxycarbonyl groups in which the aralkyl moiety has from 7 to 9 carbon atoms and is unsubstituted or has from 1 to 5, more preferably from 1 to 3, amino, C₁-C₄ alkyl, C₁-C₄ alkoxy or hydroxy substituents, for example the benzyloxycarbonyl, phenethyloxycarbonyl, 3-phenylpropoxycarbonyl, 4-methoxybenzyloxycarbonyl, 4-hydroxybenzyloxycarbonyl, p -tolyloxycarbonyl and 4-aminobenzyloxycarbonyl groups. Of the groups exemplified above, the following are preferred: acetyl, benzoyl, cyclohexanecarbonyl, cyclopropanecarbonyl, hexanoyl, isobutyryl, crotonoyl, ethoxycarbonyl, 4-hydroxybenzoyl, anisoyl, 4-aminobenzoyl, naphthoyl, toluoyl, benzyloxycarbonyl and 4-methoxybenzyloxycarbonyl groups, of which the acetyl and benzoyl, particularly benzoyl, groups are most preferred. Specific examples of the amino acid compounds which may be employed in the present invention are given in the following list. It should, of course, be appreciated that these compounds can exist in the D -, L - and DL - forms and that any of these forms can be employed in the present invention. The compounds are hereinafter referred to by the numbers appended to them in this list. In the case of the mono-acylated derivatives of ornithine, the acyl group can be present on either the N α - or the N δ -position, whilst, in the case of mono-acylated derivatives of lysine, the acyl group can be present on either the N α - or N ε -position. Of course, the respective individual mono-acylated derivatives or a mixture of the N α and N δ or N α and N ε derivatives may be used. When the compounds of the invention are hereinafter referred to by the numbers appended to them in the following list, the N α isomer is identified by the appropriate number followed by the character "α", the N δ isomer is identified by the number followed by "δ" and the N ε isomer is identified by the number followed by "ε". Where the number alone is given, a mixture is meant. Where the compound is identified by the number followed by "α/δ" or "α/ε", this defines specifically the three options: the isolated N α isomer; the isolated N δ isomer or N ε isomer; or a mixture of these two isomers. 1. N -Acetylornithine 2. N -Propionylornithine 3. N -Butyrylornithine 4. N -Isobutyrylornithine 5. N -Valerylornithine 6. N -Hexanoylornithine 7. N -Heptanoylornithine 8. N -Octanoylornithine 9. N -Nonanoylornithine 10. N -Decanoylornithine 11. N -Crotonoylornithine 12. N -Benzoylornithine 13. N -Cyclopropanecarbonylornithine 14. N -Cyclohexanecarbonylornithine 15. N α , N δ -Diacetylornithine 16. N α , N δ -Dipropionylornithine 17. N α , N δ -Dibutyrylornithine 18. N α , N δ -Diisobutyrylornithine 19. N α , N δ -Divalerylornithine 20. N α , N δ -Diisovalerylornithine 21. N α , N δ -Dihexanoylornithine 22. N α , N δ -Diheptanoylornithine 23. N α , N δ -Dioctanoylornithine 24. N α , N δ -Dinonanoylornithine 25. N α , N δ -Didecanoylornithine 26. N α , N δ -Dicrotonoylornithine 27. N α , N δ -Dibenzoylornithine 28. N α , N δ -Dicyclopropanecarbonylornithine 29. N α , N δ -Dicyclohexanecarbonylornithine 30. N α -Isobutyryl- N δ -benzoylornithine 31. N α -Crotonoyl- N δ -benzoylornithine 32. N α -Cyclopropanecarbonyl- N δ -isobutyrylornithine 33. N α -Cyclohexanecarbonyl- N δ -crotonoylornithine 34. N α -Benzoyl- N δ -isobutyrylornithine 35. N α -Benzoyl- N δ -crotonoylornithine 36. N α -Benzoyl- N δ -cyclopropanecarbonylornithine 37. N α -Benzoyl- N δ -cyclohexanecarbonylornithine 38. N α -Benzoyl- N δ -acetylornithine 39. N α -Benzoyl- N δ -propionylornithine 40. N -Methoxycarbonylornithine 41. N -Ethoxycarbonylornithine 42. N -Butoxycarbonylornithine 43. N α , N δ -Dimethoxycarbonylornithine 44. N α , N δ -Diethoxycarbonylornithine 45. N α , N δ -Dibutoxycarbonylornithine 46. N α -Methoxycarbonyl- N δ -ethoxycarbonylornithine 47. N α -Methoxycarbonyl- N δ -butoxycarbonylornithine 48. N α -Ethoxycarbonyl- N δ -methoxycarbonylornithine 49. N α -Butoxycarbonyl- N δ -ethoxycarbonylornithine 50. N α -Ethoxycarbonyl- N δ -butyrylornithine 51. N α -Ethoxycarbonyl- N δ -crotonoylornithine 52. N α -Ethoxycarbonyl- N δ -cyclopropanecarbonylornithine 53. N α -Ethoxycarbonyl- N δ -benzoylornithine 54. N α -Propionyl- N δ -ethoxycarbonylornithine 55. N α -Benzoyl- N δ -ethoxycarbonylornithine 56. N -Acetyllysine 57. N -Propionyllysine 58. N -Butyryllysine 59. N -Isobutyryllysine 60. N -Valeryllysine 61. N -Hexanoyllysine 62. N -Heptanoyllysine 63. N -Octanoyllysine 64. N -Nonanoyllysine 65. N -Decanoyllysine 66. N -Crotonoyllysine 67. N -Benzoyllysine 68. N -Cyclopropanecarbonyllysine 69. N -Cyclohexanecarbonyllysine 70. N α , N ε -Diacetyllysine 71. N α , N ε -Dipropionyllysine 72. N α , N ε -Dibutyryllysine 73. N α , N ε -Diisobutyryllysine 74. N α , N ε -Divaleryllysine 75. N α , N ε -Diisovaleryllysine 76. N α , N ε -Dihexanoyllysine 77. N α , N ε -Diheptanoyllysine 78. N α , N ε -Dioctanoyllysine 79. N α , N ε -Dinonanoyllysine 80. N α , N ε -Didecanoyllysine 81. N α , N ε -Dicrotonoyllysine 82. N α , N ε -Dibenzoyllysine 83. N α , N ε -Dicyclopropanecarbonyllysine 84. N α , N ε -Dicyclohexanecarbonyllysine 85. N α -Isobutyryl- N ε -crotonoyllysine 86. N α -Isobutyryl- N ε -benzoyllysine 87. N α -Crotonoyl- N ε -benzoyllysine 88. N α -Cyclopropanecarbonyl- N ε -isobutyryllysine 89. N α -Cyclohexanecarbonyl- N ε -crotonoyllysine 90. N α -Cyclopropanecarbonyl- N ε -cyclohexanecarbonyllysine 91. N α -Cyclohexanecarbonyl- N ε -benzoyllysine 92. N α -Benzoyl- N ε -isobutyryllysine 93. N α -Benzoyl- N ε -crotonoyllysine 94. N α -Benzoyl- N ε -cyclopropanecarbonyllysine 95. N α -Benzoyl- N ε -cyclohexanecarbonyllysine 96. N α -Benzoyl- N ε -acetyllysine 97. N α -Benzoyl- N ε -propionyllysine 98. N -Methoxycarbonyllysine 99. N -Ethoxycarbonyllysine 100. N -Butoxycarbonyllysine 101. N α , N ε -Dimethoxycarbonyllysine 102. N α , N ε -Diethoxycarbonyllysine 103. N α , N ε -Dibutoxycarbonyllysine 104. N α -Methoxycarbonyl- N ε -ethoxycarbonyllysine 105. N α -Methoxycarbonyl- N ε -butoxycarbonyllysine 106. N α -Ethoxycarbonyl- N ε -methoxycarbonyllysine 107. N α -Butoxycarbonyl- N ε -ethoxycarbonyllysine 108. N α -Ethoxycarbonyl- N ε -propionyllysine 109. N α -Ethoxycarbonyl- N ε -crotonoyllysine 110. N α -Ethoxycarbonyl- N ε -cyclohexanecarbonyllysine 111. N α -Ethoxycarbonyl- N ε -benzoyllysine 112. N α -Isobutyryl- N ε -ethoxycarbonyllysine 113. N α -Benzoyl- N ε -ethoxycarbonyllysine 114. N -Acetylphenylglycine 115. N -Benzoylphenylglycine 116. N -Acetylphenylalanine 117 N -Benzoylphenylalanine 118. N -Propionylphenylglycine 119. N -Butyrylphenylglycine 120. N -Isobutyrylphenylglycine 121. N -Valerylphenylglycine 122. N -Hexanoylphenylglycine 123. N -Heptanoylphenylglycine 124. N -Octanoylphenylglycine 125. N -Nonanoylphenylglycine 126. N -Decanoylphenylglycine 127. N -Crotonoylphenylglycine 128. N -Cyclopropanecarbonylphenylglycine 129. N -Cyclohexanecarbonylphenylglycine 130. N -Methoxycarbonylphenylglycine 131. N -Ethoxycarbonylphenylglycine 132. N -Butoxycarbonylphenylglycine 133. N -Propionylphenylalanine 134. N -Butyrylphenylalanine 135. N -Isobutyrylphenylalanine 136. N -Valerylphenylalanine 137. N -Hexanoylphenylalanine 138. N -Heptanoylphenylalanine 139. N -Octanoylphenylalanine 140. N -Nonanoylphenylalanine 141. N -Decanoylphenylalanine 142. N -Crotonoylphenylalanine 143. N -Cyclopropanecarbonylphenylalanine 144. N -Cyclohexanecarbonylphenylalanine 145. N -Methoxycarbonylphenylalanine 146. N -Ethoxycarbonylphenylalanine 147. N -Butoxycarbonylphenylalanine 148. N -(4-Hydroxybenzoyl)lysine 149. N -Anisoyllysine 150. N -(4-Aminobenzoyl)lysine 151. N -Naphthoyllysine 152. N -(4-Sulphonylbenzoyl)lysine 153. N -Toluoyllysine 154. N -Benzyloxycarbonyllysine 155. N -(4-Methoxybenzyloxycarbonyl)lysine 156. N α , N ε -Di(4-hydroxybenzoyl)lysine 157. N α , N ε -Dianisoyllysine 158. N α , N ε -Di(4-aminobenzoyl)lysine 159. N α , N ε -Dinaphthoyllysine 160. N α -Cyclohexanecarbonyl- N ε -acetyllysine 161. N α , N ε -Ditoluoyllysine 162. N α , N ε -Dibenzyloxycarbonyllysine 163. N α , N ε -Di(4-methoxybenzyloxycarbonyl)lysine 164. N -(4-Hydroxybenzoyl)ornithine 165. N -Anisoylornithine 166. N -(4-Aminobenzoyl)ornithine 167. N -Naphthoylornithine 168. N -(4-Sulphonylbenzoyl)ornithine 169. N -Toluoylornithine 170. N -Benzyloxycarbonylornithine 171. N -(4-Methoxybenzyloxycarbonyl)ornithine 172. N α , N δ -Di(4-hydroxybenzoyl)ornithine 173. N α , N δ -Dianisoylornithine 174. N α , N δ -Di(4-aminobenzoyl)ornithine 175. N α , N δ -Dinaphthoylornithine 176. N α -Cyclohexanecarbonyl- N δ -acetylornithine 177. N α , N δ -Ditoluoylornithine 178. N α , N δ -Dibenzyloxycarbonylornithine 179. N α , N δ -Di(4-methoxybenzyloxycarbonyl)ornithine 180. N -(4-Hydroxybenzoyl)phenylglycine 181. N -Anisoylphenylglycine 182. N -(4-Aminobenzoyl)phenylglycine 183. N -Naphthoylphenylglycine 184. N -(4-Sulphonylbenzoyl)phenylglycine 185. N -Toluoylphenylglycine 186. N -Benzyloxycarbonylphenylglycine 187. N -(4-Methoxybenzyloxycarbonyl)phenylglycine 188. N -(4-Hydroxybenzoyl)phenylalanine 189. N -(4-Sulphonylbenzoyl)phenylalanine 190. N -(4-Aminobenzoyl)phenylalanine 191. N -Naphthoylphenylalanine 192. N -Anisoylphenylalanine 193. N -Toluoylphenylalanine 194. N -Benzyloxycarbonylphenylalanine 195. N -(4-Methoxybenzyloxycarbonyl)phenylalanine Of the amino acid derivatives listed above, the following are particularly preferred: Compounds No. 27, 29, 37, 38, 82, 84, 95, 96, 115, 117, 129, 144, 160 and 176. The amino acid derivatives employed in the present invention are acids and, as such, are capable of forming salts; any pharmaceutically acceptable salt of these amino acids may be employed. Examples of such salts include: alkali metal salts such as the sodium or potassium salts; alkaline earth metal salts, such as the calcium salt; other metal salts, such as the magnesium, aluminium, iron, zinc, copper, nickel and cobalt salts; the ammonium salt; and salts with amino sugars, such as glucosamine and galactosamine. The compositions of the invention may be prepared by any suitable method which involves mixing the antibiotic with the amino acid derivative and the invention is not intended to be limited by any particular method of preparation. Since the amino acid derivatives employed in this invention have, in general, very limited solubility in water, it is preferred that they should first be dispersed in water and then converted to a suitable salt by adding an aqueous solution of an appropriate base, for example: a metal compound, such as sodium hydroxide or potassium hydroxide; ammonia; or an amino sugar, such as glucosamine or galactosamine. Sufficient of the base is added to adjust the pH of the mixture to a value within the range from 6 to 9. The penem or carbapenem antibiotic is then added to the resulting solution. The mixed solution thus obtained may be employed as such or it may first be lyophilized to give a powdery mixture, which may be subsequently formulated into an appropriate dosage form suitable for the chosen route of administration, either by the manufacturer or prior to use. Although it is convenient to administer the antibiotic and the amino acid derivative simultaneously to a patient in a single composition, it is, of course, clear that the two compounds may be administered separately, provided that they are administered sufficiently closely in time to each other that the amino acid derivative has a suitable concentration in the blood for all or most of the time that the antibiotic is present. Normally, it is anticipated that this will be achieved if the two compounds are administered within one hour of each other. The composition of the invention is particularly suitable for use by intravenous administration. There is no particular restriction on the relative proportions of the amino acid derivative and the penem or carbapenem antibiotic; in general, we have found that proportions of amino acid derivative to antibiotic of from 0.1:1 to 4:1 give good results, but equally proportions outside this range may successfully be employed. The invention is further illustrated by the following Examples and Activity Tests. In the following, the penem or carbapenem antibiotics are referred to by the numbers appended to them in the foregoing list and are identified as "Penem Cpd No." whilst the amino acid derivatives are also identified by the numbers appended to them in the foregoing list and are referred to as "Amino Acid Cpd No." EXAMPLE 1 5 g of N α , N ε -dibenzoyllysine were weighed out and dispersed in 80 ml of water. A 1N aqueous solution of sodium hydroxide was slowly added to this dispersion, and the N α , N ε -dibenzoyllysine dissolved when the pH of the solution reached a value of 7-8. Then, 5 g of (5 R ,6 S )-2-[(3 S )-1-acetimidoylpyrrolidin-3-ylthio]-6-[1( R )-hydroxyethyl]-2-carbapenem-3-carboxylic acid (Penem Compound No. 6) were dissolved in this solution, to give a total volume of 100 ml. EXAMPLE 2 Similar procedures to those described in Example 1 were carried out, using the other penem or carbapenem antibiotic substances and the other ornithine, lysine phenylglycine or phenylalanine derivatives shown in the following Table, in the amounts shown in that Table. In this Table, where the amino acid derivatives are not specified as being D - or L -, then they are the DL -form. ACTIVITY TESTS The preparation obtained by the procedure described in Example 1 was injected into the ear vein of a rabbit (about 3 kg body weight) in an amount of 3 ml/kg [that is 150 mg/kg of the penem Compound No. 6 + 150 mg/kg of N α , N ε -dibenzoyllysine (amino acid Compound No. 82)]. A preparation which had been obtained by the same procedure as that described in Example 1 but not including the N α , N ε -dibenzoyllysine was injected into another rabbit, as a control, in a similar manner to the above. After one week, the kidneys of both rabbits were excised and examined. A change was observed in the renal tissue of the rabbits to which had been administered the preparation without the N α , N ε -dibenzoyllysine, but no such change was observed at all in the renal tissue of rabbits to which had been administered the preparation containing the N α, N ε -dibenzoyllysine. Similar experiments were carried out on other preparations which were prepared from other penem or carbapenem antibiotic substances and other amino acid derivatives. The Table also shows the results of these experiments. The observed change in the renal tissue of the control rabbits was a degenerative necrosis of the proximal renal tubules in the region of the renal cortex. In the following Table, where the proportion of the total area of this region which exhibited such necrosis was from 0 to 25%, this is shown as +++. Where the area is less than 50% this is shown as ++ and where it is less than 75% this is shown as +. Where different animals within each test group exhibited different responses, this is shown as e.g. +++ - ++ or ++ - +. It should be noted that, whenever penem or carbapenem antibiotic substances which were not combined with amino acid derivatives were administered, a change in the renal tissue was observed.

Claims: Claims for the following Contracting States: BE, CH, DE, FR, GB, IT, LI, NL, SE A composition comprising: (a) an antibiotic which is a penem antibiotic or a carbapenem antibiotic; and (b) a pharmaceutically acceptable N -acylated amino acid, in which the amino acid is ornithine, lysine, phenylglycine or phenylalanine, and the acyl group is a C₁-C₁₈ alkanoyl group, a C₃-C₈ alkenoyl group, a C₃-C₈ alkynoyl group, an aromatic acyl group wherein the aryl part is C₆-C₁₄ carbocyclic aryl and is unsubstituted or has from 1 to 5 C₁-C₄ alkyl, hydroxy, C₁-C₄ alkoxy, amino or sulphonyl substituents, a cycloalkanecarbonyl group wherein the cycloalkane part is C₃-C₈, a C₂-C₇ alkoxycarbonyl group, or an aralkyloxycarbonyl group wherein the aralkyl part has from 7 to 9 carbon atoms and is unsubstituted or has from 1 to 5 amino, C₁-C₄ alkyl, C₁-C₄ alkoxy or hydroxy substituents; or a therapeutically acceptable salt thereof; and wherein the amount of said N -acylated amino acid is sufficient to alleviate any renal toxicity of said antibiotic, preferably in a weight ratio of from 0.1:1 to 4:1. A composition as claimed in Claim 1, wherein said N -acylated amino acid is a compound of general formula II: R²-NH-(CH₂) n -CH(COOH)-NHR³ (II) wherein: n is 3 or 4; and R² and R³ are the same or different and each represents a hydrogen atom or a carboxylic acyl group, provided that R² and R³ are not both hydrogen atoms; wherein the carboxylic acyl group is a C₁-C₁₈ alkanoyl group, a C₃-C₈ alkenoyl group, a C₃-C₈ alkynoyl group, an aromatic acyl group wherein the aryl part is C₆-C₁₄ carbocyclic aryl and is unsubstituted or has from 1 to 5 C₁-C₄ alkyl, hydroxy, C₁-C₄ alkoxy, amino or sulphonyl substituents, a cycloalkanecarbonyl group wherein the cycloalkane part is C₃-C₈, a C₂-C₇ alkoxycarbonyl group, or an aralkyloxycarbonyl group wherein the aralkyl part has from 7 to 9 carbon atoms and is unsubstituted or has from 1 to 5 amino, C₁-C₄ alkyl, C₁-C₄ alkoxy or hydroxy substituents; or a pharmaceutically acceptable salt thereof. A composition as claimed in Claim 2, wherein R² and R³ are the same or different and each represents a hydrogen atom or an acetyl, benzoyl, cyclohexanecarbonyl, cyclopropanecarbonyl, hexanoyl, isobutyryl, crotonoyl, ethoxycarbonyl, 4-hydroxybenzoyl, anisoyl, 4-aminobenzoyl, naphthoyl, toluoyl, benzyloxycarbonyl or 4-methoxybenzyloxycarbonyl group, provided that R² and R³ are not both hydrogen atoms. A composition as claimed in Claim 2, wherein at least one of R² and R³ represents an acetyl and/or benzoyl group. A composition as claimed in Claim 1, wherein said N -acylated amino acid is a compound of general formula III: Ph-(CH₂) m -CH(COOH)-NHR⁴ (III) wherein: Ph represents a phenyl group; m is 0 or 1; and R⁴ represents a carboxylic acyl group as defined; or a pharmaceutically acceptable salt thereof. A composition as claimed in Claim 5, wherein R⁴ represents an acetyl, benzoyl, cyclohexanecarbonyl, cyclopropanecarbonyl, hexanoyl, isobutyryl, crotonoyl, ethoxycarbonyl, 4-hydroxybenzoyl, anisoyl, 4-aminobenzoyl, naphthoyl, toluoyl, benzyloxycarbonyl or 4-methoxybenzyloxycarbonyl group. A composition as claimed in Claim 5, wherein R⁴ represents an acetyl or benzoyl group. A composition as claimed in Claim 1, wherein said N -acylated amino acid is: N α , N δ -Dibenzoylornithine N α , N δ -Dicyclohexanecarbonylornithine N α -Benzoyl- N δ -cyclohexanecarbonylornithine N α -Benzoyl- N δ -acetylornithine N α , N ε -Dibenzoyllysine N α , N ε -Dicyclohexanecarbonyllysine N α -Benzoyl- N ε -cyclohexanecarbonyllysine N α -Benzoyl- N ε -acetyllysine N -Benzoylphenylglycine N -Benzoylphenylalanine N -Cyclohexanecarbonylphenylglycine N -Cyclohexanecarbonylphenylalanine N α -Cyclohexanecarbonyl- N ε -acetyllysine or N α -Cyclohexanecarbonyl- N δ -acetylornithine. A composition as claimed in any one of Claims 1 to 8, wherein said antibiotic is a compound of general formula I: wherein: X represents a sulphur atom, a methylene group, or a methylene group having 1 or 2 methyl substituents; and R¹ represents a group of formula: or a pharmaceutically acceptable salt thereof. A composition as claimed in Claim 9, wherein said antibiotic is: (5 R ,6 S )-2-{2-[(aminomethylene)amino]ethylthio}-6-[1( R )-hydroxyethyl]-2-carbapenem-3-carboxylic acid (5 R ,6 S )-2-[(3 S )-1-acetimidoylpyrrolidin-3-ylthio]-6-[1( R )-hydroxyethyl]-2-carbapenem-3-carboxylic acid (5 R ,6 S )-2-[(3 R )-1-acetimidoylpyrrolidin-3-ylthio]-6-[1( R )-hydroxyethyl]-2-carbapenem-3-carboxylic acid (5 R ,6 S )-2-[(3 R )-1-acetimidoylpyrrolidin-3-ylthio]-6-[1( R )-hydroxyethyl]-1( S )-methyl-2-carbapenem-3-carboxylic acid (5 R ,6 S )-2-[(3 S )-1-acetimidoylpyrrolidin-3-ylthio]-6-[1( R )-hydroxyethyl]-1( R )-methyl-2-carbapenem-3-carboxylic acid (5 R ,6 S )-2-[(3 S )-1-acetimidoylpyrrolidin-3-ylthio]-6-[1( R )-hydroxyethyl]-1( S )-methyl-2-carbapenem-3-carboxylic acid or (5 R ,6 S )-2-[(3 S )-1-acetimidoyl-5( S )-carbamoylpyrrolidin-3-ylthio]-6-[1( R )-hydroxyethyl]-2-carbapenem-3-carboxylic acid A composition as claimed in any one of Claims 1 to 10, wherein the weight ratio of said N -acylated amino acid to said antibiotic is from 0.1:1 to 4:1. The use of: (a) a penem antibiotic or a carbapenem antibiotic; and (b) a pharmaceutically acceptable N -acylated derivative of an amino acid, the amino acid being ornithine, lysine, phenylglycine and phenylalanine, wherein the acyl group and amount are as defined in claim 1, for the manufacture of a one-part or two-part medicament for the treatment of bacterial infections. The use as claimed in Claim 12, wherein said N -acylated amino acid is as defined in any one of Claims 2 to 8. The use as claimed in Claim 12 or Claim 13, wherein said antibiotic is as defined in any one of Claims 9 and 10. The use as claimed in any one of Claims 12 to 14, wherein the weight ratio of said N -acylated amino acid to said antibiotic is from 0.1:1 to 4:1. A packaged pharmaceutical preparation for treating a mammal suffering from a bacterial infection, comprising: (a) in one part, a penem antibiotic or a carbapenem antibiotic; and (b) in another part, a pharmaceutically acceptable N -acylated derivative of an amino acid, the amino acid being ornithine, lysine, phenylglycine and phenylalanine, and wherein the acyl group and amount are as defined in claim 1. A preparation as claimed in Claim 16, wherein said N -acylated amino acid is as defined in any one of Claims 2 to 10. A preparation as claimed in Claim 16 or Claim 17, wherein said antibiotic is as defined in any one of Claims 9 and 10. A preparation as claimed in any one of Claims 16 to 18, wherein the weight ratio of said N -acylated amino acid to said antibiotic is from 0.1:1 to 4:1. Claims for the following Contracting State: AT A method of making a pharmaceutical composition by mixing: (a) an antibiotic which is a penem antibiotic or a carbapenem antibiotic; and (b) a pharmaceutically acceptable N -acylated amino acid, in which the amino acid is ornithine, lysine, phenylglycine or phenylalanine, and the acyl group is a C₁-C₁₈ alkanoyl group, a C₃-C₈ alkenoyl group, a C₃-C₈ alkynoyl group, an aromatic acyl group wherein the aryl part is C₆-C₁₄ carbocyclic aryl and is unsubstituted or has from 1 to 5 C₁-C₄ alkyl, hydroxy, C₁-C₄ alkoxy, amino or sulphonyl substituents, a cycloalkanecarbonyl group wherein the cycloalkane part is C₃-C₈, a C₂-C₇ alkoxycarbonyl group, or an aralkyloxycarbonyl group wherein the aralkyl part has from 7 to 9 carbon atoms and is unsubstituted or has from 1 to 5 amino, C₁-C₄ alkyl, C₁-C₄ alkoxy or hydroxy substituents; or a pharmaceutically acceptable salt thereof; and wherein the amount of said N -acylated amino acid is sufficient to alleviate any renal toxicity of said antibiotic, preferably in a weight ratio of from 0.1:1 to 4:1. A method as claimed in Claim 1, wherein said N -acylated amino acid is a compound of general formula II: R²-NH-(CH₂) n -CH(COOH)-NHR³ (II) wherein: n is 3 or 4; and R² and R³ are the same or different and each represents a hydrogen atom or a carboxylic acyl group, provided that R² and R³ are not both hydrogen atoms; wherein the carboxylic acyl group is a C₁-C₁₈ alkanoyl group, a C₃-C₈ alkenoyl group, a C₃-C₈ alkynoyl group, an aromatic acyl group wherein the aryl part is C₆-C₁₄ carbocyclic aryl and is unsubstituted or has from 1 to 5 C₁-C₄ alkyl, hydroxy, C₁-C₄ alkoxy, amino or sulphonyl substituents, a cycloalkanecarbonyl group wherein the cycloalkane part is C₃-C₈, a C₂-C₇ alkoxycarbonyl group, or an aralkyloxycarbonyl group wherein the aralkyl part has from 7 to 9 carbon atoms and is unsubstituted or has from 1 to 5 amino, C₁-C₄ alkyl, C₁-C₄ alkoxy or hydroxy substituents; or a pharmaceutically acceptable salt thereof. A method as claimed in Claim 2, wherein R² and R³ are the same or different and each represents a hydrogen atom or an acetyl, benzoyl, cyclohexanecarbonyl, cyclopropanecarbonyl, hexanoyl, isobutyryl, crotonoyl, ethoxycarbonyl, 4-hydroxybenzoyl, anisoyl, 4-aminobenzoyl, naphthoyl, toluoyl, benzyloxycarbonyl or 4-methoxybenzyloxycarbonyl group, provided that R² and R³ are not both hydrogen atoms. A method as claimed in Claim 2, wherein at least one of R² and R³ represents an acetyl and/or benzoyl group. A method as claimed in Claim 1, wherein said N -acylated amino acid is a compound of general formula III: Ph-(CH₂) m -CH(COOH)-NHR⁴ (III) wherein: Ph represents a phenyl group; m is 0 or 1; and R⁴ represents a carboxylic acyl group as defined; or a pharmaceutically acceptable salt thereof. A method as claimed in Claim 5, wherein R⁴ represents an acetyl, benzoyl, cyclohexanecarbonyl, cyclopropanecarbonyl, hexanoyl, isobutyryl, crotonoyl, ethoxycarbonyl, 4-hydroxybenzoyl, anisoyl, 4-aminobenzoyl, naphthoyl, toluoyl, benzyloxycarbonyl or 4-methoxybenzyloxycarbonyl group. A method as claimed in Claim 5, wherein R⁴ represents an acetyl or benzoyl group. A method as claimed in Claim 1, wherein said N -acylated amino acid is: N α , N δ -Dibenzoylornithine N α , N δ -Dicyclohexanecarbonylornithine N α -Benzoyl- N δ -cyclohexanecarbonylornithine N α -Benzoyl- N δ -acetylornithine N α , N ε -Dibenzoyllysine N α , N ε -Dicyclohexanecarbonyllysine N α -Benzoyl- N ε -cyclohexanecarbonyllysine N α -Benzoyl- N ε -acetyllysine N -Benzoylphenylglycine N -Benzoylphenylalanine N -Cyclohexanecarbonylphenylglycine N -Cyclohexanecarbonylphenylalanine N α -Cyclohexanecarbonyl- N ε -acetyllysine or N α -Cyclohexanecarbonyl- N δ -acetylornithine. A method as claimed in any one of Claims 1 to 8, wherein said antibiotic is a compound of general formula I: wherein: X represents a sulphur atom, a methylene group, or a methylene group having 1 or 2 methyl substituents; and R¹ represents a group of formula: or a pharmaceutically acceptable salt thereof. A method as claimed in Claim 9, wherein said antibiotic is: (5 R ,6 S )-2-{2-[(aminomethylene)amino]ethylthio}-6-[1( R )-hydroxyethyl]-2-carbapenem-3-carboxylic acid (5 R ,6 S )-2-[(3 S )-1-acetimidoylpyrrolidin-3-ylthio]-6-[1( R )-hydroxyethyl]-2-carbapenem-3-carboxylic acid (5 R ,6 S )-2-[(3 R )-1-acetimidoylpyrrolidin-3-ylthio]-6-[1( R )-hydroxyethyl]-2-carbapenem-3-carboxylic acid (5 R ,6 S )-2-[(3 R )-1-acetimidoylpyrrolidin-3-ylthio]-6-[1( R )-hydroxyethyl]-1( S )-methyl-2-carbapenem-3-carboxylic acid (5 R ,6 S )-2-[(3 S )-1-acetimidoylpyrrolidin-3-ylthio]-6-[1( R )-hydroxyethyl]-1( R )-methyl-2-carbapenem-3-carboxylic acid (5 R ,6 S )-2-[(3 S )-1-acetimidoylpyrrolidin-3-ylthio]-6-[1( R )-hydroxyethyl]-1( S )-methyl-2-carbapenem-3-carboxylic acid or (5 R ,6 S )-2-[(3 S )-1-acetimidoyl-5( S )-carbamoylpyrrolidin-3-ylthio]-6-[1( R )-hydroxyethyl]-2-carbapenem-3-carboxylic acid A method as claimed in any one of Claims 1 to 10, wherein the weight ratio of said N -acylated amino acid to said antibiotic is from 0.1:1 to 4:1. The use of: (a) a penem antibiotic or a carbapenem antibiotic; and (b) a pharmaceutically acceptable N -acylated derivative of an amino acid, the amino acid being ornithine, lysine, phenylglycine and phenylalanine, wherein the acyl group and amount are as defined in claim 1, for the manufacture of a one-part or two-part medicament for the treatment of bacterial infections. The use as claimed in Claim 12, wherein said N -acylated amino acid is as defined in any one of Claims 2 to 8. The use as claimed in Claim 12 or Claim 13, wherein said antibiotic is as defined in any one of Claims 9 and 10. The use as claimed in any one of Claims 12 to 14, wherein the weight ratio of said N -acylated amino acid to said antibiotic is from 0.1:1 to 4:1.

Inventors: IWATA, MASAYUKI PRODUCT DEVELOPMENT LAB., SHIOGARI, TAKASHI PRODUCT DEVELOPMENT LAB., UEDA, SEIGO PRODUCT DEVELOPMENT LAB.
Applicants: SANKYO COMPANY LIMITED
Application year: 1985
Main classification: A61K31
IPC codes: A61K31