Composition containing a penem or carbapenem antibiotic and the use of the same

US 4,757,066 A
Filed: 10/10/1986
Issued: 07/12/1988
Est. Priority Date: 10/15/1984
Status: Expired due to Term

First Claim

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1. An antibiotic composition comprising:

an antibiotic selected from the group consisting of penem antibiotics and carbapenem antibiotics having renal toxicity; and

a pharmaceutically acceptable N-acylated derivative of an amino acid wherein the amino group and the carboxylic acid group are attached to a saturated aliphatic carbon chain or carbon atom, or a salt thereof in an amount at least sufficient to reduce or eliminate said renal toxicity.

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Abstract

Administration of an N-acylated amino acid in association with a penem or carbapenem antibiotic relieves or eliminates the renal problems associated with administration of the antibiotic alone. The amino acid derivative and antibiotic may be formulated together as a composition or administered separately, either simultaneously or sequentially.

186 Citations

117 Claims

1. An antibiotic composition comprising:
- an antibiotic selected from the group consisting of penem antibiotics and carbapenem antibiotics having renal toxicity; and
  
  a pharmaceutically acceptable N-acylated derivative of an amino acid wherein the amino group and the carboxylic acid group are attached to a saturated aliphatic carbon chain or carbon atom, or a salt thereof in an amount at least sufficient to reduce or eliminate said renal toxicity.
- View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19)
- - 2. A composition as claimed in claim 1, wherein the weight ratio of said N-acylated amino acid to said antibiotic is from about 0.1:
    - 1 to 4;
      
      1.
  - 3. A composition as claimed in claim 2, wherein said amino acid is a compound of formula (II):
    - space="preserve" listing-type="equation">H.sub.2 N--X--COOH (II)
      wherein X represents a C₁ -C₁₀ alkylene group or a C₁ -C₁₀ alkylene group having at least one substituent selected from the group consisting of hydroxy groups, C₁ -C₄ alkoxy groups, C₆ -C₁₄ aryloxy groups, substituted C₆ -C₁₄ aryloxy groups, C₇ -C₉ aralkyloxy groups, substituted C₇ -C₉ aralkyloxy groups, mercapto groups, C₁ -C₄ alkylthio groups, C₆ -C₁₄ arylthio groups, substituted C₆ -C₁₄ arylthio groups, C₇ -C₉ aralkylthio groups, substituted C₇ -C₉ aralkylthio groups, C₂ -C₅ carboxyalkylthio groups, amino groups, amino groups having one or two substituents selected from the group consisting ofC₁ -C₄ alkyl groups, C₆ -C₁₄ aryl groups, substituted C₆ -C₁₄ aryl groups, C₇ -C₉ aralkyl groups, substituted C₇ -C₉ aralkyl groups and carboxylic acyl groups.C₆ -C₁₄ aryl groups, substituted C₆ -C₁₄ aryl groups, carboxy groups, amidino groups, sulfo groups, C₁ -C₄ alkylsulfinyl groups, C₁ -C₄ alkylsulfonyl groups and heterocyclic groups having from 5 to 14 ring atoms of which from 1 to 5 are hetero-atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms, said substituted aryloxy, aralkyloxy, arylthio, aralkylthio, aryl and aralkyl groups having at least one substituent selected from the group consisting of C₁ -C₄ alkyl groups, hydroxy groups, amino groups and C₁ -C₄ alkoxy groups,or a pharmaceutically acceptable salt thereof.
  - 4. A composition as claimed in claim 3, wherein the N-acyl group is selected from the group consisting of:
    - C₁ -C₁₈ alkanoyl groups;
      
      C₃ -C₈ alkenoyl groups;
      
      C₃ -C₈ alkynoyl groups;
      
      aromatic acyl groups wherein the aryl part is C₆ -C₁₄ carbocyclic aryl and is unsubstituted or has from 1 to 5 substituents is selected from the group consisting of C₁ -C₄ alkyl groups, hydroxy groups, C₁ -C₄ alkoxy groups, amino groups, sulfo groups and halogen atoms;
      
      cycloalkanecarbonyl groups where the cycloalkane part is C₃ -C₈ and is unsubstituted or has at least one substituent selected from the group consisting of C₁ -C₄ alkyl groups and phenyl groups;
      
      araliphatic acyl groups in which the aryl ring is a carbocyclic ring having from 6 to 14 carbon atoms and which is unsubstituted or has from 1 to 5 substituents selected from the group consisting of C₁ -C₄ alkyl groups, hydroxy groups, C₁ -C₄ alkoxy groups, amino groups, sulfo groups and halogen atoms, and in which the alkyl moiety has from 1 to 4 carbon atoms;
      
      heterocyclic acyl groups which have saturated or unsaturated ring systems, the rings having 5 or 6 ring atoms, of which from 1 to 3 are hetero-atoms independently selected from the group consisting of nitrogen, sulfur and oxygen atoms and the ring being unsubstituted or having from 1 to 3 substituents selected from the group consisting of C₁ -C₄ alkyl groups and hydroxy groups;
      
      C₂ -C₇ alkoxycarbonyl groups;
      
      aralkyloxycarbonyl groups where the aralkyl part has from 7 to 9 carbon atoms and is unsubstituted or has from 1 to 5 substituents selected from the group consisting of amino groups, C₁ -C₄ alkyl groups, C₁ -C₄ alkoxy groups and hydroxy groups; and
      
      acyl groups derived from an amino acid by removal of OH from the carboxylic acid group and N-acylation of the amino group with at least one of the above-mentioned acyl groups.
  - 5. A composition as claimed in claim 3, wherein the N-acyl group is selected from the group consisting of:
    - saturated aliphatic acyl groups having from 1 to 8 carbon atoms;
      
      aromatic acyl groups in which the aryl moiety has from 6 to 10 ring carbon atoms and is unsubstituted or has from 1 to 3 substituents independently selected from the group consisting of C₁ -C₄ alkyl groups and C₁ -C₄ alkoxy groups;
      
      alicyclic acyl groups in which the cycloalkane ring has from 3 to 6 carbon atoms;
      
      araliphatic acyl groups in which the aryl ring has from 6 to 10 ring carbon atoms and the alkyl group has from 1 to 4 carbon atoms, the aryl ring being unsubstituted or having from 1 to 3 substituents independently selected from the group consisting of C₁ -C₄ alkyl groups and C₁ -C₄ alkoxy groups;
      
      heterocyclic acyl groups in which the heterocyclic ring is saturated or unsaturated and has 5 or 6 ring atoms of which one is a nitrogen, sulfur or oxygen hetero-atom;
      
      alkoxycarbonyl groups having a total of from 2 to 7 carbon atoms;
      
      aralkyloxycarbonyl groups in which the aralkyl moiety has from 7 to 9 carbon atoms and the aryl ring is unsubstituted or has from 1 to 3 substituents independently selected from the group consisting of C₁ -C₄ alkyl groups and C₁ -C₄ alkoxy groups; and
      
      acyl groups derived from an amino acid by removal of OH from the carboxylic acid group and N-acylation of the amino group with at least one of the above-mentioned acyl groups.
  - 6. A composition as claimed in claim 3, wherein the N-acyl group is selected from the group consisting of:
    - aromatic acyl groups in which the aryl ring has from 6 to 10 ring atoms and which is unsubstituted or has a single substituent selected from the group consisting of C₁ -C₄ alkyl groups, C₁ -C₄ alkoxy groups, hydroxy groups and amino groups;
      
      alicyclic acyl groups in which the cycloalkane moiety has from 3 to 6 carbon atoms;
      
      phenylaliphatic acyl groups in which the phenyl group is unsubstituted or has a single C₁ -C₄ alkyl substituent, and in which the alkyl part has from 1 to 4 carbon atoms;
      
      alkoxycarbonyl groups having a total of from 4 to 6 carbon atoms;
      
      aralkyloxycarbonyl groups in which the aralkyl part has from 7 to 9 carbon atoms and has 0 or 1 substituent selected from the group consisting of C₁ -C₄ alkyl groups and C₁ -C₄ alkoxy group; and
      
      acyl groups derived from an amino acid by removal of OH from the carboxylic acid group and N-acylation of the amino group with at least one of the above-mentioned acyl groups.
  - 7. A composition as claimed in claim 3, wherein the N-acyl group is selected from the group consisting of:
    - acetyl, benzoyl, cyclohexanecarbonyl, cyclopropanecarbonyl, hexanoyl, isobutyryl, crotonyl, ethoxycarbonyl, 4-hydroxybenzoyl, anisoyl, 4-aminobenzoyl, naphthoyl, toluoyl, benzyloxycarbonyl and 4-methoxybenzyloxycarbonyl groups.
  - 8. A composition as claimed in claim 3, wherein X represents a C₁ -C₅ alkylene group which is unsubstituted or has one or two substituents independently selected from the group consisting of:
    - hydroxy groups;
      
      C₁ -C₄ alkoxy groups;
      
      aryloxy groups wherein the aryl ring has from 6 to 14 ring carbon atoms and which is unsubstituted or has from 1 to 3 substituents independently selected from the group consisting of C₁ -C₄ alkyl groups, hydroxy groups, amino groups and C₁ -C₄ alkoxy groups;
      
      C₇ -C₉ aralkyloxy groups, wherein the aryl moiety is unsubstituted or has from 1 to 3 substituents independently selected from the group consisting of C₁ -C₄ alkyl groups, hydroxy groups, amino groups and C₁ -C₄ alkoxy groups, mercapto groups;
      
      C₁ -C₄ alkylthio groups;
      
      arylthio groups wherein the aryl ring has from 6 to 14 ring carbon atoms and which is unsubstituted or has from 1 to 3 substituents independently selected from the group consisting of C₁ -C₄ alkyl groups, hydroxy groups, amino groups and C₁ -C₄ alkoxy groups;
      
      C₇ -C₉ aralkylthio groups wherein the aryl ring is unsubstituted or has from 1 to 3 substituents independently selected from the group consisting of C₁ -C₄ alkyl groups, hydroxy groups, amino groups and C₁ -C₄ alkoxy groups;
      
      carboxyalkylthio groups in which the alkyl part has from 1 to 4 carbon atoms;
      
      amino groups, amino groups having one or two C₁ -C₄ alkyl substituents;
      
      amino groups having one or two aryl substituents in which the aryl ring has from 6 to 14 ring carbon atoms and is unsubstituted or has from 1 to 3 substituents independently selected from the group consisting of C₁ -C₄ alkyl groups, hydroxy groups, amino groups and C₁ -C₄ alkoxy groups;
      
      amino groups having one or two C₇ -C₉ aralkyl substituents in which the aryl part is unsubstituted or has from 1 to 3 substituents selected from the group consisting of C₁ -C₄ alkyl groups, hydroxy groups, amino groups and C₁ -C₄ alkoxy groups;
      
      amino groups having one or two carboxylic acyl substituents;
      
      aryl groups having from 6 to 14 ring carbon atoms and being unsubstituted or having from 1 to 3 substituents selected from the group consisting of C₁ -C₄ alkyl groups, hydroxy groups, amino groups and C₁ -C₄ alkoxy groups;
      
      carboxy groups; and
      
      heterocyclic groups having from 5 to 9 ring atoms, of which from 1 to 3 are hetero-atoms selected from the group consisting of nitrogen, oxygen and sulfur hetero-atoms.
  - 9. A composition as claimed in claim 3, wherein X represents a C₁ -C₅ alkylene group which is unsubstituted or has 1 or 2 substituents independently selected from the group consisting of:
    - hydroxy groups;
      
      C₁ -C₄ alkoxy groups;
      
      mercapto groups;
      
      C₁ -C₄ alkylthio groups;
      
      amino groups;
      
      amino groups having one or two C₁ -C₄ alkyl substituents;
      
      amino groups having one or two carboxylic acyl substituents;
      
      aryl groups having from 6 to 14 carbon atoms wherein the aryl ring is unsubstituted or has from 1 to 3 substituents selected from the group consisting of C₁ -C₄ alkyl groups, hydroxy groups, amino groups and C₁ -C₄ alkoxy groups;
      
      carboxy groups; and
      
      heterocyclic groups having from 5 to 9 ring atoms, of which from 1 to 3 are hetero-atoms selected from the group consisting of nitrogen and oxygen hetero-atoms.
  - 10. A composition as claimed in claim 2, wherein said amino acid is glycine, β
    - -alanine, 4-aminobutyric acid, 5-aminovaleric acid, 6-aminohexanoic acid, 8-aminooctanoic acid, alanine, 2-aminobutyric acid, norvaline, valine, leucine, isoleucine, norleucine, phenylglycine, phenylalanine, tyrosine, O-methyltyrosine, aspartic acid, glutamic acid, 4-carboxyglutamic acid, 3-methylaspartic acid, 2-aminoadipic acid, 2-aminopimelic acid, 2-aminosuberic acid, 3-hydroxyaspartic acid, 3-hydroxyglutamic acid, 2,3-diaminopropionic acid, 2,4-diaminobutyric acid, ornithine, lysine, 5-hydroxylysine, arginine, N.sup.δ
      
      ,N.sup.δ
      
      -dimethylornithine, N.sup.ε
      
      -methyllysine, cysteine, methionine, ethionine, S-carboxymethylcysteine, S-benzylcysteine, methionine S-oxide, ethionine S-oxide, methionine S,S-dioxide, cysteic acid, serine, O-methylserine, threonine, O-methylthreonine, homothreonine, ethoxinine, 3-methoxyvaline, 3-phenylserine, 3-methyl-3-phenylalanine, histidine, tryptophan, 2-methylalanine, 2-methylserine, 2-hydroxyisoleucine, 2-methylmethionine, 2-ethyl-2-phenylglycine, 3-aminobutyric acid, 3-amino-4-methylvaleric acid, 3-amino-3-phenylpropionic acid, 3-amino-2-hydroxypropionic acid or 4-amino-3-hydroxybutyric acid.
  - 11. A composition as claimed in claim 2, wherein said amino acid is glycine, β
    - -alanine, 4-aminobutyric acid, 5-aminovaleric acid, 6-aminohexanoic acid, 8-aminooctanoic acid, alanine, norvaline, valine, leucine, isoleucine, norleucine, N.sup.δ
      
      ,N.sup.δ
      
      -dimethylornithine, methionine, ethionine, O-methylserine, O-methylthreonine, ethoxinine, 3-methoxyvaline, 3-phenylserine, 3-methyl-3-phenylalanine, histidine, 2-methylalanine, 2-methylserine, 2-hydroxyisoleucine, 2-ethylphenylglycine, 3-aminobutyric acid, 3-amino-4-methylvaleric acid, 3-amino-3-phenylpropionic acid, ornithine, lysine, phenylalanine or phenylglycine.
  - 12. A composition as claimed in claim 2, wherein said amino acid is β
    - -alanine, 4-aminobutyric acid, 5-aminovaleric acid, 6-aminohexanoic acid, alanine, valine, leucine, norleucine, methionine, histidine, ornithine, glycine, phenylalanine or phenylglycine.
  - 13. A composition as claimed in claim 2, wherein said amino acid is leucylglycine, glycyl-β
    - -alanine, glycylalanine, valylalanine, leucylalanine, glycylvaline, alanylvaline, leucylvaline, valylleucine, phenylalanylleucine, histidylleucine, glycylphenylalanine, alanylphenylalanine, leucylphenylalanine, glycylmethionine, valylmethionine, glycylhistidine, alanylvalylglycine, glycylalanylvaline, glycylphenylalanylleucine or glycylglycylhistidine.
  - 14. A composition as claimed in claim 2, wherein said amino acid is glycine, β
    - -alanine, 4-aminobutyric acid, 5-aminovaleric acid, 6-aminohexanoic acid, 8-aminooctanoic acid, alanine, norvaline, valine, leucine, isoleucine, norleucine, N.sup.δ
      
      ,N.sup.δ
      
      -dimethylornithine, methionine, ethionine, O-methylserine, O-methylthreonine, ethoxinine, 3-methoxyvaline, 3-phenylserine, 3-methyl-3-phenylalanine, histidine, 2-methylalanine, 2-methylserine, 2-hydroxyisoleucine, 2-ethylphenylglycine, 3-aminobutyric acid, 3-amino-4-methylvaleric acid, 3-amino-3-phenylpropionic acic, ornithine, lysine, phenylalanine or phenylglycine, and is N-acylated with an N-acyl group selected from the group consisting of;
      
      aromatic acyl groups in which the aryl ring has from 6 to 10 ring atoms and which is unsubstituted or has a single C₁ -C₄ alkyl substituent;
      
      alicyclic acyl groups in which the cycloalkane moiety has from 3 to 6 carbon atoms;
      
      phenylaliphatic acyl groups in which the phenyl group is unsubstituted or has a single C₁ -C₄ alkyl substituent, and in which the alkyl part has from 1 to 4 carbon atoms;
      
      alkoxycarbonyl groups having a total of from 4 to 6 carbon atoms;
      
      aralkyloxycarbonyl groups in which the aralkyl part has from 7 to 9 carbon atoms; and
      
      acyl groups derived from an amino acid by removal of OH from the carboxylic acid group and N-acylation of the amino group with at least one of the above-mentioned acyl groups.
  - 15. A composition as claimed in claim 2, wherein said N-acylated amino acid is selected from the group consisting of:
    - N-(p-toluoyl)-β
      
      -alanineN-(4-methoxybenzoyl)-β
      
      -alanineN-(3-hydroxy-2-naphthoyl)-β
      
      -alanineN-benzoylglycyl-β
      
      -alanineN-benzoyl-β
      
      -alanineN-benzoyl-5-aminovaleric acidN-benzoyl-6-aminohexanoic acidN-cyclohexanecarbonyl-6-aminohexanoic acidN-(N-methylnicotinoyl)-6-aminohexanoic acidN-benzoyl-8-aminooctanoic acidN-benzoylalanineN-(1-naphthoyl)alanineN-benzoylvalylalanineN-benzoyl-2-aminobutyric acidN-benzoylnorvalineN-valerylvalineN-benzoylalanylvalineN-benzoylvalineN-benzoylleucineN-benzoylglycylphenylalanylleucineN-benzoylnorleucineN⁶⁰,N.sup.δ
      
      -dibenzoylornithineN.sup.α
      
      ,N.sup.δ
      
      -dicyclopropanecarbonylornithineN.sup.α
      
      ,N.sup.δ
      
      -dicyclohexanecarbonylornithineN.sup.α
      
      -benzoyl-N.sup.δ
      
      -cyclohexanecarbonylornithineN.sup.α
      
      -benzoyl-N.sup.δ
      
      -acetylornithineN.sup.α
      
      -cyclohexanecarbonyl-N.sup.δ
      
      -acetylornithineN.sup.α
      
      ,N.sup.ε
      
      -dibenzoyllysineN.sup.α
      
      ,N.sup.ε
      
      -dicyclopropanecarbonyllysineN.sup.α
      
      ,N.sup.ε
      
      -dicyclohexanecarbonyllysineN.sup.α
      
      -benzoyl-Nε
      
      -cyclohexanecarbonyllysineN.sup.α
      
      -benzoyl-N.sup.ε
      
      -acetyllysineN.sup.α
      
      ,N.sup.ε
      
      -dianisoyllysineN.sup.α
      
      -cyclohexanecarbonyl-N.sup.ε
      
      -acetyllysineN-benzoylphenylalanineN-(4-methoxybenzoyl)phenylalanineN-hexanoylphenylalanineN-cyclopropanecarbonylphenylalanineN-cyclohexanecarbonylphenylalanineN-anisoylphenylalanineN-benzoylglycylphenylalanineN-benzoylalanylphenylalanineN-cyclohexanecarbonylleucylphenylalanineN-benzoylphenylglycineN-cyclopropanecarbonylphenylglycineN-cyclohexanecarbonylphenylglycineN-anisoylphenylglycineN-(4-methoxybenzoyl)phenylglycineN-benzoyl-O-methyltyrosineN-benzoylmethionineN-phenylacetylmethionineN-benzoylvalylmethionineN-benzoylethionineN-(4-methoxybenzyloxycarbonyl)ethionineN-benzoylthreonineN-benzoylhistidineN-(p-toluoyl)histidineN-(4-methoxybenzoyl)histidineN-(4-methoxybenzoyl)-3-aminobutyric acid andN-butyryl-3-amino-3-phenylpropionic acid.
  - 16. A composition as claimed in claim 2, wherein said antibiotic is selected from the group consisting of compounds of formula (I):
    - ##STR102## in which;
      
      Y represents a sulfur atom, a methylene group or a methylene group having 1 or 2 substituents selected from the group consisting of methyl and methoxy groups; and
      
      R¹ represents a C₁ -C₆ alkyl group, a C₁ -C₆ alkyl group having at least one substituent selected from the group consisting of substituents (i) or a heterocyclic group having from 4 to 14 ring atoms of which from 1 to 5 are hetero-atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms where said heterocyclic group is unsubstituted or has at least one substituent selected from the group consisting of substituents (ii);
      
      substituents (i);
      
      halogen atoms, amino groups, amino groups having at least one substituents selected from the group consisting of substituents (iii), C₁ -C₄ alkylideneamino groups, C₁ -C₄ aminoalkylideneamino groups, amidino groups, amidino groups having from 1 to 3 substituents selected from the group consisting of substituents (iii), heterocyclic groups having from 4 to 14 ring atoms of which from 1 to 5 are hetero-atoms selected from the group consisting of nitrogen, oxygen and sulfur hetero-atoms wherein said heterocyclic group is unsubstituted or has at least one substituent selected from the group consisting of substituents (ii), imino groups, cyano groups, carbamoyl groups and carbamoyl groups having at least one substituent selected from the group consisting of C₁ -C₄ alkyl groups and C₁ -C₄ alkoxy groups;
      
      substituents (ii);
      
      C₁ -C₆ alkanimidoyl groups, C₁ -C₆ alkyl groups, alkoxyalkyl groups where the alkoxy and alkyl parts are each C₁ -C₄, carbamoyl groups, carbamoyl groups having at least one substituent selected from the group consisting of C₁ -C₄ alkyl groups and C₁ -C₄ alkoxy groups, C₁ -C₄ haloalkyl groups, heterocyclic acrylimidoyl groups where the heterocyclic part has from 5 to 9 ring atoms of which from 1 to 3 are hetero-atoms selected from the group consisting of nitrogen, oxygen and sulfur hetero-atoms, amidino groups, amidino groups having from 1 to 3 substituents selected from the group consisting of substituents (iii), imino groups, oxygen atoms, C₁ -C₆ alkanoyl groups, C₁ -C₆ alkanesulfonyl groups, C₁ -C₆ alkanesulfinyl groups, hydroximino groups, C₁ -C₄ alkoximino groups, carbamoyloxy groups, carbamoyloxy groups having at least one substituent selected from the group consisting of C₁ -C₄ alkyl groups and C₁ -C₄ alkoxy groups, carbamoyloxyalkyl groups where the alkyl part is C₁ -C₄ and the carbamoyl part is unsubstituted or has at least one substituent selected from the group consisting of C₁ -C₄ alkyl groups and C₁ -C₄ alkoxy groups and C₁ -C₄ iminoalkyl groups;
      
      substituents (iii);
      
      C₁ -C₆ alkyl groups, C₂ -C₆ alkenyl groups, C₂ -C₆ alkynyl groups, oxygen atoms and said alkyl, alkenyl and alkynyl groups having at least one substituent selected from the group consisting of halogen atoms, carbamoyloxy groups and carbamoyloxy groups having at least one substituent selected from the group consisting of C₁ -C₄ alkyl groups and C₁ -C₄ alkoxy groups;
      
      and pharmaceutically acceptable salts thereof.
  - 17. A composition as claimed in claim 16, wherein Y represents a sulfur atom, a methylene group, or the group CH₁₃ --CH<
    - , CH₃ O--CH<
      
      or (CH₃)₂ C<
      
      .
  - 18. A composition as claimed in claim 17, wherein R¹ represents an ethyl, 2-fluoroethyl, 2-(aminomethyleneamino)ethyl, N¹,N¹ -dimethylamidinomethyl, N¹,N¹,N² -trimethylamidinomethyl, 3-pyrrolidinyl, 1-formimidoyl-3-pyrrolidinyl, 1-acetimidoyl-3-pyrrolidinyl, 1-propionimidoyl-3-pyrrolidinyl, 2-methyl-1,4,5,6-tetrahydro-5-pyrimidinyl, 2-methoxymethyl-1,4,5,6-tetrahydro-5-pyrimidinyl, 3-azetidinyl, 1-acetimidoyl-3-azetidinyl, N¹ -methyl-N¹ -(2-propynyl)amidinomethyl, N¹ -(2-fluoroethyl)-N¹ -methylamidinomethyl, N¹ -(3-fluoropropyl)-N¹ -methylamidinomethyl, N¹ -methyl-N¹ -(2,2,2-trifluoroethyl)amidinomethyl, 1-(3-azetidinyl)ethyl, 1-(1-acetimidoyl-3-azetidinyl)ethyl, 1,4,5,6-tetrahydro-2-pyrimidinylmethyl, 1-(4,5-dihydro-2-thiazolyl)ethyl, 5-carbamoyl-3-pyrrolidinyl, 1-acetimidoyl-5-carbamoyl-3-pyrrolidinyl, 2-chloromethyl-1,4,5,6-tetrahydro-5-pyrimidinyl, 1-butyrimidoyl-3-pyrrolidinyl, 1-nicotinimidyl-3-pyrrolidinyl, N¹,N¹ -diallylamidinomethyl, N¹ -methyl-N¹ -(2-propynyl)amidino, N¹ -(2-fluoroethyl)-N¹ -methylamidino, N¹ -(3-fluoropropyl)-N¹ -methylamidino, N¹ -methyl-N¹ -(2,2,2-trifluoroethyl)amidino, N¹ -allyl-N¹ -methylamidinomethyl, cyanomethyl, 2-cyanoethyl, 1-cyanoethyl, 2-cyano-1-methylethyl, 2-aminoethyl, 1-carbamoylethyl, 2-(1-aminoethylideneamino)ethyl, 1-amidino-3-pyrrolidinyl, 2-methyl-1,3-diazabicyclo[3.3.0]oct-2-en-7-yl, 2-methoxymethyl-1,3-diazabicyclo[3.3.0]oct-2-en-7-yl, 5-imino-2-pyrrolidinyl, 2-imino-5-piperidinyl, 1-acetimidoyl-5-methylcarbamoyl-3-pyrrolidinyl, 1-acetimidoyl-5-methoxycarbamoyl-3-pyrrolidinyl, 2-imino-2-(S-oxothiomorpholino)ethyl, 2-imino-2-(1,1-dioxo-1,3-thiazolidin-3-yl)ethyl, 2-imino-2-(S,S-dioxothiomorpholino)ethyl, 2-imino-2-(3,5-dioxo-1-piperazinyl)ethyl, 2-imino-2-(4-methyl-3,5-dioxo-1-piperazinyl)ethyl, 2-imino-2-(3-oxo-1-piperazinyl)ethyl, 2-imino-2-(4-methyl-3-oxo-1-piperazinyl)ethyl, 2-imino-2-(4-acetyl-3-oxo-1-piperazinyl)ethyl, 2-imino-2-(4-methanesulfonyl-3-oxo-1-piperazinyl)ethyl, N¹ -(2-carbamoyloxyethyl)-N¹ -methylamidinomethyl, 2-(3-hydroximino-1-pyrrolidinyl)-2-iminoethyl, 2-imino-2-(3-methoximino-1-pyrrolidinyl)ethyl, 2-(4-hydroximinopiperidino)-2-iminoethyl, 2-imino-2-(4-methoximinopiperidino)ethyl, 2-(3-carbamoyloxy-1-pyrrolidinyl)-2-iminoethyl, 2-imino-2-(3-oxo-1-piperazinyl)ethyl, 2-(3-carbamoylpiperidino)-2-iminoethyl, 2-(3-carbamoyloxypiperidino)-2-iminoethyl, 2-(2-carbamoyloxy-1-pyrrolidinyl)-2-iminoethyl, 2-(2-carbamoyloxymethyl-1-pyrrolidinyl)-2-iminoethyl, 2-(4-carbamoyloxypiperidino)-2-iminoethyl, 2-(4-formyl-1-piperazinyl)-2-iminoethyl, 2-(4-acetyl-1-piperazinyl)-2-iminoethyl, 1-formyl-3-azetidinyl, 1-iminomethyl-3-azetidinyl, 1-methyl-4-piperidyl, 1-acetimidoyl-4-piperidyl or 1-acetyl-3-pyrrolidinyl group.
  - 19. A composition as claimed in claim 16, wherein said antibiotic is selected from the group consisting of:
    - (5R,6S)-2-{2-[(aminomethylene)amino]ethylthio}-6-[1(R)-hydroxyethyl]-2-carbapenem-3-carboxylic acid(5R,6S)-2-[(3S)-1-acetimidoylpyrrolidin-3-ylthio]-6-[1(R)-hydroxyethyl]-2-carbapenem-3-carboxylic acid(5R,6S)-2-[(3R)-1-acetimidoylpyrrolidin-3-ylthio]-6-[1(R)-hydroxyethyl]-2-carbapenem-3-carboxylic acid(5R,6S)-2-[(3R)-1-acetimidoylpyrrolidin-3-ylthio]-6-[1(R)-hydroxyethyl]-1(S)-methyl-2-carbapenem-3-carboxylic acid(5R,6S)-2-[(3S)-1-acetimidoylpyrrolidin-3-ylthio]-6-[1(R)-hydroxyethyl]-1(R)-methyl-2-carbapenem-3-carboxylic acid(5R,6S)-2-[(3S)-1-acetimidoylpyrrolidin-3-ylthio]-6-[1(R)-hydroxyethyl]-1(S)-methyl-2-carbapenem-3-carboxylic acid and(5R,6S)-2-[(3S)-1-acetimidoyl-5(S)-carbamoylpyrrolidin-3-ylthio]-6-[1(R)-hydroxyethyl]-2-carbapenem-3-carboxylic acid.

20. An antibiotic composition comprising:
- (a) an N-acylated amino acid selected from the group consisting of N-acylated derivatives of compounds of formula (II);
  space="preserve" listing-type="equation">H.sub.2 N--X--COOH (II)
  where X represents a C₁ -C₁₀ alkylene group or a C₁ -C₁₀ alkylene group having at least one substituent selected from the group consisting of hydroxy groups, C₁ -C₄ alkoxy groups, C₆ -C₁₄ aryloxy groups, substituted C₆ -C₁₄ aryloxy groups, C₇ -C₉ aralkyloxy groups, substituted C₇ -C₉ aralkyloxy groups, mercapto groups, C₁ -C₄ alkylthio groups, C₆ -C₁₄ arylthio groups, substituted C₆ -C₁₄ arylthio groups, C₇ -C₉ aralkylthio groups, substituted C₇ -C₉ aralkylthio groups, C₂ -C₅ carboxyalkylthio groups, amino groups, amino groups having one or two substituents selected from the group consisting ofC₁ -C₄ alkyl groups, C₆ -C₁₄ aryl groups, substituted C₆ -C₁₄ aryl groups, C₇ -C₉ aralkyl groups, substituted C₇ -C₉ aralkyl groups and carboxylic acyl groups, C₆ -C₁₄ aryl groups, substituted C₆ -C₁₄ aryl groups, carboxy groups, amidino groups, sulfo groups, C₁ -C₄ alkylsulfinyl groups, C₁ -C₄ alkylsulfonyl groups and heterocyclic groups having from 5 to 14 ring atoms of which from 1 to 5 are hetero-atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms, said substituted aryloxy, aralkyloxy, arylthio, aralkylthio, aryl and aralkyl groups having at least one substituent selected from the group consisting of C₁ -C₄ alkyl groups, hydroxyl groups, amino groups and C₁ -C₄ alkoxy groups; and
  
  pharmaceutically acceptable salt thereof; and
  
  (b) an antibiotic selected from the group consisting of compounds of formula (I);
  
  ##STR103## in which;
  
  Y represents a sulfur atom, a methylene group or a methylene group having 1 or 2 substituents selected from the group consisting of methyl and methoxy groups; and
  
  R¹ represents a C₁ -C₆ alkyl group, a C₁ -C₆ alkyl group having at least one substituent selected from the group consisting of substituents (i) or a heterocyclic group having from 4 to 14 ring atoms of which from 1 to 5 are hetero-atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms where said heterocyclic group is unsubstituted or has at least one substituent selected from the group consisting of substituents (ii);
  
  substituents (i);
  
  halogen atoms, amino groups, amino groups having at least one substituent selected from the group consisting of substituents (iii), C₁ -C₄ alkylideneamino groups, C₁ -C₄ aminoalkylideneamino groups, amidino groups, amidino groups having from 1 to 3 substituents selected from the group consisting of substituents (iii), heterocyclic groups having from 4 to 14 ring atoms of which from 1 to 5 are hetero-atoms selected from the group consisting of nitrogen, oxygen and sulfur hetero-atoms wherein said heterocyclic group is unsubstituted or has at least one substituent selected from the group consisting of substituents (ii), imino groups, cyano groups, carbamoyl groups and carbamoyl groups having at least one substituent selected from the group consisting of C₁ -C₄ alkyl groups and C₁ -C₄ alkyl groups;
  
  substituents (ii);
  
  C₁ -C₆ alkanimidoyl groups, C₁ -C₆ alkyl groups, alkoxyalkyl groups where the alkoxy and alkyl parts are each C₁ -C₄, carbamoyl groups, carbamoyl groups having at least one substituent selected from the group consisting of C₁ -C₄ alkyl groups and C₁ -C₄ alkoxy groups, C₁ -C₄ haloalkyl groups, heterocyclic acylimidoyl groups where the heterocyclic part has from 5 to 9 ring atoms of which from 1 to 3 are hetero-atoms selected from the group consisting of nitrogen, oxygen and sulfur hetero-atoms, amidino groups, amidino groups having from 1 to 3 substituents selected from the group consisting of substituents (iii), imino groups, oxygen atoms, C₁ -C₆ alkanoyl groups, C₁ -C₆ alkanesulfonyl groups, C₁ -C₆ alkanesulfinyl groups, hydroximino groups, C₁ -C₄ alkoximino groups, carbamoyloxy groups, carbamoyloxy groups having at least one substituent selected from the group consisting of C₁ -C₄ alkyl groups and C₁ -C₄ alkoxy groups, carbamoyloxyalkyl groups where the alkyl part is C₁ -C₄ and the carbamoyl part is unsubstituted or has at least one substituent selected from the group consisting of C₁ -C₄ alkyl groups and C₁ -C₄ alkoxy groups and C₁ -C₄ iminoalkyl groups;
  
  substituents (iii);
  
  C₁ -C₆ alkyl groups, C₂ -C₆ alkenyl groups, C₂ -C₆ alkynyl groups, oxygen atoms and said alkyl, alkenyl and alkynyl groups having at least one substituent selected from group consisting of halogen atoms, carbamoyloxy groups and carbamoyloxy groups having at least one substituent selected from the group consisting of C₁ -C₄ alkyl groups and C₁ -C₄ alkoxy groups;
  
  and pharmaceutically acceptable salts thereof;
  
  said antibiotic (b) having renal toxicity and said amino acid (a) being in an amount at least sufficient to reduce or eliminate said renal toxicity.
- View Dependent Claims (21, 22, 23, 24, 25, 26, 27, 29, 32, 33, 34, 35)
- - 21. A composition as claimed in claim 20, wherein the weight ratio of said N-acylated amino acid to said antibiotic is from about 0.1:
    - 1 to 4;
      
      1.
  - 22. A composition as claimed in claim 21, wherein the N-acyl group is selected from the group consisting of:
    - saturated aliphatic acyl groups having from 1 to 8 carbon atoms;
      
      aromatic acyl groups in which the aryl moiety has from 6 to 10 ring carbon atoms and is unsubstituted or has from 1 to 3 substituents independently selected from the group consisting of C₁ -C₄ alkyl groups and C₁ -C₄ alkoxy group;
      
      alicyclic acyl groups in which the cycloalkane ring has from 3 to 6 carbon atoms;
      
      araliphatic acyl groups in which the aryl ring has from 6 to 10 ring carbon atoms and the alkyl group has from 1 to 4 carbon atoms, the aryl ring being unsubstituted or having from 1 to 3 substituents independently selected from the group consisting of C₁ -C₄ alkyl groups and C₁ -C₄ alkoxy groups;
      
      heterocyclic acyl groups in which the heterocyclic ring is saturated or unsaturated and has 5 or 6 ring atoms of which one is a nitrogen, sulfur or oxygen hetero-atom;
      
      alkoxycarbonyl groups having a total of from 2 to 7 carbon atoms;
      
      aralkyloxycarbonyl groups in which the aralkyl moiety has from 7 to 9 carbon atoms and the aryl ring is unsubstituted or has from 1 to 3 substituents independently selected from the group consisting of C₁ -C₄ alkyl groups and C₁ -C₄ alkoxy groups; and
      
      acyl groups derived from an amino acid by removal of OH from the carboxylic acid group and N-acylation of the amino group with at least one of the above-mentioned acyl groups.
  - 23. A composition as claimed in claim 21, wherein the N-acyl group is selected from the group consisting of:
    - aromatic acyl groups in which the aryl ring has from 6 to 10 ring atoms and which is unsubstituted or has a single substituent selected from the group consisting of C₁ -C₄ alkyl groups, C₁ -C₄ alkoxy group, hydroxy groups and amino groups;
      
      alicyclic acyl groups in which the cycloalkane moiety has from 3 to 6 carbon atoms;
      
      phenylaliphatic acyl groups in which the phenyl group is unsubstituted or has a single C₁ -C₄ alkyl substituent, and in which the alkyl part has from 1 to 4 carbon atoms;
      
      alkoxycarbonyl groups having a total of from 4 to 6 carbon atoms;
      
      aralkyloxycarbonyl groups in which the aralkyl part has from 7 to 9 carbon atoms and has 0 or 1 substituent selected from the group consisting of C₁ -C₄ alkyl groups and C₁ -C₄ alkoxy groups; and
      
      acyl groups derived from an amino acid by removal of OH from the carboxylic acid group and N-acylation of the amino group with at least one of the above-mentioned acyl groups.
  - 24. A composition as claimed in claim 21, wherein the N-acyl group is selected from the group consisting of:
    - acetyl, benzoyl, cyclohexanecarbonyl, cyclopropanecarbonyl, hexanoyl, isobutyryl, crotonoyl, ethoxycarbonyl, 4-hydroxybenzoyl, anisoyl, 4-aminobenzoyl, napththoyl, toluoyl, benzyloxycarbonyl and 4-methoxybenzyloxycarbonyl groups.
  - 25. A composition as claimed in claim 21, wherein X represents a C₁ -C₅ alkylene group which is unsubstituted or has 1 to 2 substituents independently selected from the group consisting of:
    - hydroxy groups;
      
      C₁ -C₄ alkoxy group;
      
      mercapto groups;
      
      C₁ -C₄ alkylthio groups;
      
      amino groups;
      
      amino groups having one or two C₁ -C₄ alkyl substituents;
      
      amino groups having one or two carboxylic acyl substituents;
      
      aryl groups having from 6 to 14 carbon atoms wherein the aryl ring is unsubstituted or has from 1 to 3 substituents selected from the group consisting of C₁ -C₄ alkyl groups, hydroxy groups, amino groups and C₁ -C₄ alkoxy groups;
      
      carboxy groups; and
      
      heterocyclic groups having from 5 to 9 ring atoms, of which from 1 to 3 are hetero-atoms selected from the group consisting of nitrogen and oxygen hetero-atoms.
  - 26. A composition as claimed in claim 21, wherein said amino acid is glycine, β
    - -alanine, 4-aminobutyric acid, 5-aminovaleric acid, 6-aminohexanoic acid, 8-aminooctanoic acid, alanine, 2-aminobutyric acid, norvaline, valine, leucine, isoleucine, norleucine, phenyglycine, phenylalanine, tyrosine, O-methyltyrosine, aspartic acid, glutamic acid, 4-carboxyglutamic acid, 3-methylaspartic acid, 2-aminoadipic acid, 2-aminopimelic acid, 2-aminosuberic acid, 3-hydroxyaspartic acid, 3-hydroxyglutamic acid, 2,3-diaminopropionic acid, 2,4-diaminobutyric acid, ornithine, lysine, 5-hydroxylysine, arginine, N.sup.δ
      
      ,N.sup.δ
      
      -dimethylornithine, N.sup.δ
      
      -methyllysine, cysteine, methionine, ethionine, S-carboxymethylcysteine, S-benzylcysteine, methionine S-oxide, ethionine S-oxide, methionine S,S-dioxide, cysteic acid, serine, O-methylserine, threonine, O-methylthreonine, homothreonine, ethoxinine, 3-methoxyvaline, 3-phenylserine, 3-methyl-3-phenylalanine, histidine, tryptophan, 2-methylalanine, 2-methylserine, 2-hydroxyisoleucine, 2-methylmethionine, 2-ethyl-2-phenylglycine, 3-aminobutyric acid, 3-amino-4-methylvaleric acid, 3-amino-3-phenylpropionic acid, 3-amino-2-hydroxypropionic acid or 4-amino-3-hydroxybutyric acid.
  - 27. A composition as claimed in claim 21, wherein said amino acid is β
    - -alanine, 4-aminobutyric acid, 5-aminovaleric acid, 6-aminohexanoic acid, alanine, valine, leucine, norleucine, methionine, histidine, ornithine, glycine, phenylalanine or phenylglycine.
  - 29. A composition as claimed in claim 21, wherein said N-acylated amino acid is selected from the group consisting of:
    - N-(p-toluoyl)-β
      
      -alanineN-(4-methoxybenzoyl)-β
      
      -alanineN-(3-hydroxy-2-naphthoyl)-β
      
      -alanineN-benzoylglycyl-β
      
      -alanineN-benzoyl-β
      
      -alanineN-benzoyl-5-aminovaleric acidN-benzoyl-6-aminohexanoic acidN-cyclohexanecarbonyl-6-aminohexanoic acidN-(N-methylnicotinoyl)-6-aminohexanoic acidN-benzoyl-8-aminooctanoic acidN-benzoylalanineN-(1-naphthoyl)alanineN-benzoylvalylalanineN-benzoyl-2-aminobutyric acidN-benzoylnorvalineN-valerylvalineN-benzoylalanylvalineN-benzoylvalineN-benzoylleucineN-benzoylglycylphenylalanylleucineN-benzoylnorleucineN.sup.α
      
      ,N.sup.δ
      
      -dibenzoylornithineN.sup.α
      
      ,N.sup.δ
      
      -dicyclopropanecarbonylornithineN.sup.α
      
      ,N.sup.δ
      
      -dicyclohexanecarbonylornithineN.sup.α
      
      -benzoyl-N.sup.δ
      
      -cyclohexanecarbonylornithineN.sup.α
      
      -benzoyl-N.sup.δ
      
      -acetylornithineN.sup.α
      
      -cyclohexanecarbonyl-N.sup.δ
      
      -acetylornithineN.sup.α
      
      ,N.sup.ε
      
      -dibenzoyllysineN.sup.α
      
      ,N.sup.ε
      
      -dicyclopropanecarbonyllysineN.sup.α
      
      ,N.sup.ε
      
      -dicyclohexanecarbonyllysineN.sup.α
      
      -benzoyl-N.sup.ε
      
      -cyclohexanecarbonyllysineN.sup.α
      
      -benzoyl-N.sup.ε
      
      -acetyllysineN.sup.α
      
      ,N.sup.ε
      
      -dianisoyllysineN.sup.α
      
      -cyclohexanecarbonyl-N.sup.ε
      
      -acetyllysineN-benzoylphenylalanineN-(4-methoxybenzoyl)phenylalanineN-hexanoylphenylalanineN-cyclopropanecarbonylphenylalanineN-cyclohexanecarbonylphenylalanineN-anisoylphenylalanineN-benzoylglycylphenylalanineN-benzoylalanylphenylalanineN-cyclohexanecarbonylleucylphenylalanineN-benzoylphenyglycineN-cyclopropanecarbonylphenylglycineN-cyclohexanecarbonylphenylglycineN-anisoylphenylglycineN-(4-methoxybenzoyl)phenylglycineN-benzoyl-O-methyltyrosineN-benzoylmethionineN-phenylacetylmethionineN-benzoylvalylmethionineN-benzoylethionineN-(4-methoxybenzyloxycarbonyl)ethionineN-benzoylthreonineN-benzoylhistidineN-(p-toluoyl)histidineN-(4-methoxybenzoyl)histidineN-(4-methoxybenzoyl)-3-aminobutyric acid andN-butyryl-3-amino-3-phenylpropionic acid.
  - 32. A composition as claimed in claim 21, wherein said antibiotic is selected from the group consisting of:
    - (5R,6S)-2-{2-[(aminomethylene)amino]ethylthio}-6-[1(R)-hydroxyethyl]-2-carbapenem-3-carboxylic acid(5R,6S)-2-[(3S)-1-acetimidoylpyrrolidin-3-ylthio]-6-[1(R)-hydroxyethyl]-2-carbapenem-3-carboxylic acid(5R,6S)-2-[(3R)-1-acetimidoylpyrrolidin-3-ylthio]-6-[1(R)-hydroxyethyl]-2-carbapenem-3-carboxylic acid(5R,6S)-2-[(3R)-1-acetimidoylpyrrolidin-3-ylthio]-6-[1(R)-hydroxyethyl]-1(S)-methyl-2-carbapenem-3-carboxylic acid(5R,6S)-2-[(3S)-1-acetimidoylpyrrolidin-3-ylthio]-6-[1(R)-hydroxyethyl]-1(R)-methyl-2-carbapenem-3-carboxylic acid(5R,6S)-2-[(3S)-1-acetimidoylpyrrolidin-3-ylthio]-6-[1(R)-hydroxyethyl]-1(S)-methyl-2-carbapenem-3-carboxylic acid and(5R,6S)-2-[(3S)-1-acetimidoyl-5(S)-carbamoylpyrrolidin-3-ylthio]-6-[1(R)-hydroxyethyl]-2-carbapenem-3-carboxylic acid.
  - 33. A composition as claimed in claim 32, wherein said amino acid is glycine, β
    - -alanine, 4-aminobutyric acid, 5-aminovaleric acid, 6-aminohexanoic acid, 8-aminooctanoic acid, alanine, 2-aminobutyric acid, norvaline, valine, leucine, isoleucine, norleucine, phenylglycine, phenylalanine, tyrosine, O-methyltyrosine, aspartic acid, glutamic acid, 4-carboxyglutamic acid, 3-methylaspartic acid, 2-aminoadipic acid, 2-aminopimelic acid, 2-aminosuberic acid, 3-hydroxyaspartic acid, 3-hydroxyglutamic acid, 2,3-diaminopropionic acid, 2,4-diaminobutyric acid, ornithine, lysine, 5-hydroxylysine, arginine, N.sup.δ
      
      ,N.sup.δ
      
      -dimethylornithine, N.sup.ε
      
      -methyllysine, cysteine, methionine, ethionine, S-carboxymethylcysteine, S-benzylcysteine, methionine S-oxide, ethionine S-oxide, methionine S,S-dioxide, cysteic acid, serine, O-methylserine, threonine, O-methylthreonine, homothreonine, ethoxinine, 3-methoxyvaline, 3-phenylserine, 3-methyl-3-phenylalanine, histidine, tryptophan, 2-methylalanine, 2-methylserine, 2-hydroxyisoleucine, 2-methylmethionine, 2-ethyl-2-phenylglycine, 3-aminobutyric acid, 3-amino-4-methylvaleric acid, 3-amino-3-phenylpropionic acid, 3-amino-2-hydroxypropionic acid or 4-amino-3-hydroxybutyric acid.
  - 34. A composition as claimed in claim 32, wherein said amino acid is β
    - -alanine, 4-aminobutyric acid, 5-aminovaleric acid, 6-aminohexanoic acid, alanine, valine, leucine, norleucine, methionine, histidine, ornithine, glycine, phenylalanine or phenylglycine.
  - 35. A composition as claimed in claim 32, wherein said amino acid is leucylglycine, glycyl-β
    - -alanine, glycylalanine, valylalanine, leucylalanine, glycylvaline, alanylvaline, leucylvaline, valylleucine, phenylalanylleucine, histidylleucine, glycylphenylalanine, alanylphenylalanine, leucylphenylalanine, glycylmethionine, valylmethionine, glycylhistidine, alanylvalylglycine, glycylalanylvaline, glycylphenylalanylleucine or glycylglycylhistidine.

28. A composition as claimed in clsim 21, wherein said amino acid is leucylglycine, glycyl-β
- -alanine, glycylalanine, valylalanine, leucylalanine, glycylvaline, alanylvaline, leucylvaline, valylleucine, phenylalanylleucine, histidylleucine, glycylphenylalanine, alanylphenylalanine, leucylphenylalanine, glycylmethionine, valylmethionine, glycylhistidine, alanylvalylglycine, glyclylalanylvaline, glycylphenylalanylleucine, or glycylglycylhistidine.

30. A composition as claimed in 21 wherein Y represents a sulfur atom, a methylene group, or the group CH₃ --CH<
- , CH₃ O--CH<
  
  or (CH₃)₂ C<
  
  .
- View Dependent Claims (31)
- - 31. A composition as claimed in claim 30, wherein R¹ represents an ethyl, 2-fluoroethyl, 2-(aminomethyleneamino)ethyl, N¹,N¹ -dimethylamidinomethyl, N¹,N¹,N² -trimethylamidinomethyl, 3-pyrrolidinyl, 1-formimidoyl-3-pyrrolidinyl, 1-acetimidoyl-3-pyrrolidinyl, 1-propionimidoyl-3-pyrrolidinyl, 2-methyl-1,4,5,6-tetrahydro-5-pyrimidinyl, 2-methoxymethyl-1,4,5,6-tetrahydro-5-pyrimidinyl, 3-azetidinyl, 1-acetimidoyl-3-azetidinyl, N¹ -methyl-N¹ -(2-propynyl)amidinomethyl, N¹ -(2-fluoroethyl)-N¹ -methylamidinomethyl, N¹ -(3-fluoropropyl)-N¹ -methylamidinomethyl, N¹ -methyl-N¹ -(2,2,2-trifluoroethyl)amidinomethyl, 1-(3-azetidinyl)ethyl, 1-(1-acetimidoyl-3-azetidinyl)ethyl, 1,4,5,6-tetrahydro-2-pyrimidinylmethyl, 1-(4,5-dihydro-2-thiazolyl)ethyl, 5-carbamoyl-3-pyrrolidinyl, 1-acetimidoyl-5-carbamoyl-3-pyrrolidinyl, 2-chloromethyl-1,4,5,6-tetrahydro-5-pyrimidinyl, 1-butyrimidoyl-3-pyrrolidinyl, 1-nicotinimidoyl-3-pyrrolidinyl, N¹,N¹ -diallylamidinomethyl, N¹ -methyl-N¹ -(2-propynyl)amidino, N¹ -(2-fluoroethyl)-N¹ -methylamidino, N¹ -(3-fluoropropyl)-N¹ -methylamidino, N¹ -methyl-N¹ -(2,2,2-trifluoroethyl)amidino, N¹ -allyl-N¹ -methylamidinomethyl, cyanomethyl, 2-cyanoethyl, 1-cyanoethyl, 2-cyano-1-methylethyl, 2-aminoethyl, 1-carbamoylethyl, 2-(1-aminoethylideneamino)ethyl, 1-amidino-3-pyrrolidinyl, 2-methyl-1,3-diazabicyclo-[3.3.0]oct-2-en-7-yl, 2-methoxymethyl-1,3-diazabicyclo[3.3.0]oct-2-en-7-yl, 5-imino-2-pyrrolidinyl, 2-imino-5-piperidinyl, 1-acetimidoyl-5-methylcarbamoyl-3-pyrrolidinyl, 1-acetimidoyl-5-methoxycarbamoyl-3-pyrrolidinyl, 2-imino-2-(S-oxothiomorpholino)ethyl, 2-imino-2-(1,1-dioxo-1,3-thiazolidin-3-yl)ethyl, 2-imino-2-(S,S-dioxothiomorpholino)ethyl, 2-imino-2-(3,5-dioxo-1-piperazinyl)ethyl, 2-imino-2-(4-methyl-3,5-dioxo-1-piperazinyl)ethyl, 2-imino-2-(3-oxo-1-piperazinyl)ethyl, 2-imino-2-(4-methyl-3-oxo-1-piperazinyl)ethyl, 2-imino-2-(4-acetyl-3-oxo-1-piperazinyl)ethyl, 2-imino-2-(4-methanesulfonyl-3-oxo-1-piperazinyl)ethyl, N¹ -(2-carbamoyloxyethyl)-N¹ -methylamidinomethyl, 2-(3-hydroximino-1-pyrrolidinyl)-2-iminoethyl, 2-imino-2-(3-methoximino-1-pyrrolidinyl)ethyl, 2-(4-hydroximinopiperidino)-2-iminoethyl, 2-imino-2-(4-methoximinopiperidino)ethyl, 2-(3-carbamoyloxy-1-pyrrolidinyl)-2-iminoethyl, 2-imino-2-(3-oxo-1-piperazinyl)ethyl, 2-(3-carbamoylpiperidino)-2-iminoethyl, 2-(3-carbamoyloxypiperidino)-2-iminoethyl, 2-(2-carbamoyloxy-1-pyrrolidinyl)-2-iminoethyl, 2-(2-carbamoyloxymethyl-1-pyrrolidinyl)-2-iminoethyl, 2-(4-carbamoyloxypiperidino)-2-iminoethyl, 2-(4-formyl-1-piperazinyl)-2-iminoethyl, 2-(4-acetyl-1-piperazinyl)-2-iminoethyl, 1-formyl-3-azetidinyl, 1-iminomethyl-3-azetidinyl, 1-methyl-4-piperidyl, 1-acetimidoyl-4-piperidyl or 1-acetyl-3-pyrrolidinyl group.

36. An antibiotic composition comprising:
- an antibiotic selected from the group consisting of penem antibiotics and carbapenem antibiotics having renal toxicity; and
  
  a pharmaceutically acceptable N-acylated derivative of an amino acid wherein said derivative is selected from the group consisting of N-benzoylvaline and N-benzoyl-β
  
  -alanine in an amount at least sufficient to reduce or eliminate said renal toxicity.
- View Dependent Claims (37, 38, 39, 40, 41)
- - 37. A composition as claimed in claim 36, wherein the weight ratio of said N-acylated amino acid to said antibiotic is from about 0.1:
    - 1 to 4;
      
      1.
  - 38. A composition as claimed in claim 37, wherein said antibiotic is selected from the group consisting of compounds of formula (I):
    - ##STR104## in which;
      
      Y represents a sulfur atom, a methylene group or a methylene group having 1 or 2 substituents selected from the group consisting of methyl and methoxy groups; and
      
      R¹ represents a C₁ -C₆ alkyl group, a C₁ -C₆ alkyl group having at least one substituent selected from the group consisting of substituents (i) or a heterocyclic group having from 4 to 14 ring atoms of which from 1 to 5 are hetero-atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms where said heterocyclic group is unsubstituted or has at least one substituent selected from the group consisting of substituents (ii);
      
      substituents (i);
      
      halogen atoms, amino groups, amino groups having at least one substituent selected from the group consisting of substituents (iii), C₁ -C₄ alkylideneamino groups, C₁ -C₄ aminoalkylideneamino groups, amidino groups, amidino groups having from 1 to 3 substituents selected from the group consisting of substituents (iii), heterocyclic groups having from 4 to 14 ring atoms of which from 1 to 5 are hetero-atoms selected from the group consisting of nitrogen, oxygen and sulfur hetero-atoms wherein said heterocyclic group is unsubstituted or has at least one substituent selected from the group consisting of substituents (ii), imino groups, cyano groups, carbamoyl groups and carbamoyl groups having at least one substituent selected from the group consisting of C₁ -C₄ alkyl groups and C₁ -C₄ alkoxy groups;
      
      substituents (ii);
      
      C₁ -C₆ alkanimidoyl groups, C₁ -C₆ alkyl groups, alkoxyalkyl groups where the alkoxy and alkyl parts are each C₁ -C₄, carbamoyl groups, carbamoyl groups having at least one substituent selected from the group consisting of C₁ -C₄ alkyl groups and C₁ -C₄ alkoxy groups, C₁ -C₄ haloalkyl groups, heterocyclic acylimidoyl groups where the heterocyclic part has from 5 to 9 ring atoms of which from 1 to 3 are hetero-atoms selected from the group consisting of nitrogen, oxygen and sulfur hetero-atoms, amidino groups, amidino groups having from 1 to 3 substituents selected from the group consisting of substituents (iii), imino groups, oxygen atoms, C₁ -C₆ alkanoyl groups, C₁ -C₆ alkanesulfonyl groups, C₁ -C₆ alkanesulfinyl groups, hydroximino groups, C₁ -C₄ alkoximino groups, carbamoyloxy groups, carbamoyloxy groups having at least one substituent selected from the group consisting of C₁ -C₄ alkyl groups and C.sub. 1 -C₄ alkoxy groups, carbamoyloxyalkyl groups where the alkyl part is C₁ -C₄ and the carbamoyl part is unsubstituted or has at least one substituent selected from the group consisting of C₁ -C₄ alkyl groups and C₁ -C₄ alkoxy groups and C₁ -C₄ iminoalkyl groups;
      
      substituents (iii);
      
      C₁ -C₆ alkyl groups, C₂ -C₆ alkenyl groups, C₂ -C₆ alkynyl groups, oxygen atoms and said alkyl, alkenyl and alkynyl groups having at least one substituent selected from the group consisting of halogen atoms, carbamoyloxy groups and carbamoyloxy groups having at least one substituent selected from the group consisting of C₁ -C₄ alkyl groups and C₁ -C₄ alkoxy groups;
      
      and pharmaceutically acceptable salts thereof.
  - 39. A composition as claimed in claim 38, wherein Y represents a sulfur atom, a methylene group, or the group CH₃ --CH<
    - , CH₃ O--CH<
      
      or (CH₃)₂ C<
      
      .
  - 40. A composition as claimed in claim 39, wherein R¹ represents an ethyl, 2-fluoroethyl, 2-(aminomethyleneamino)ethyl, N¹,N¹ -dimethylamidinomethyl, N¹,N¹,N² -trimethylamidinomethyl, 3-pyrrolidinyl, 1-formimidoyl-3-pyrrolidinyl, 1-acetimidoyl-3-pyrrolidinyl, 1-propionimidoyl-3-pyrrolidinyl, 2-methyl-1,4,5,6-tetrahydro-5-pyrimidinyl, 2-methoxymethyl-1,4,5,6-tetrahydro-5-pyrimidinyl, 3-azetidinyl, 1-acetimidoyl-3-azetidinyl, N¹ -methyl-N¹ -(2-propynyl)amidinomethyl, N¹ -(2-fluoroethyl)-N¹ -methylamidinomethyl, N¹ -(3-fluoropropyl)-N¹ -methylamidinomethyl, N¹ -methyl-N¹ -(2,2,2-trifluoroethyl)amidinomethyl, 1-(3-azetidinyl)ethyl, 1-(1-acetimidoyl-3-azetidinyl)ethyl, 1,4,5,6-tetrahydro-2-pyrimidinylmethyl, 1-(4,5-dihydro-2-thiazolyl)ethyl, 5-carbamoyl-3-pyrrolidinyl, 1-acetimidoyl-5-carbamoyl-3-pyrrolidinyl, 2-chloromethyl-1,4,5,6-tetrahydro-5-pyrimidinyl, 1-butyrimidoyl-3-pyrrolidinyl, 1-nicotinimidoyl-3-pyrrolidinyl, N¹,N¹ -diallylamidinomethyl, N¹ -allyl-N¹ -methylamidinomethyl, cyanomethyl, 2-cyanoethyl, 1-cyanoethyl, 2-cyano-1-methylethyl, 2-aminoethyl or 1-carbamoylethyl group.
  - 41. A composition as claimed in claim 37, wherein said antibiotic is selected from the group consisting of:
    - (5R,6S)-2-{2-[(aminomethylene)amino]ethylthio}-6-[1(R)-hydroxyethyl]-2-carbapenem-3-carboxylic acid(5R,6S)-2-[(3S)-1-acetimidoylpyrrolidin-3-ylthio]-6-[1(R)-hydroxyethyl]-2-carbapenem-3-carboxylic acid(5R,6S)-2-[(3R)-1-acetimidoylpyrrolidin-3-ylthio]-6-[1(R)-hydroxyethyl]-2-carbapenem-3-carboxylic acid(5R,6S)-2-[(3R)-1-acetimidoylpyrrolidin-3-ylthio]-6-[1(R)-hydroxyethyl]-1(S)-methyl-2-carbapenem-3-carboxylic acid(5R,6S)-2-[(3S)-1-acetimidoylpyrrolidin-3-ylthio]-6-[1(R)-hydroxyethyl]-1(R)-methyl-2-carbapenem-3-carboxylic acid(5R,6S)-2-[(3S)-1-acetimidoylpyrrolidin-3-ylthio]-6-[1(R)-hydroxyethyl]-1(S)-methyl-2-carbapenem-3-carboxylic acid and(5R,6S)-2-[(3S)-1-acetimidoyl-5(S)-carbamoylpyrrolidin-3-ylthio]-6-[1(R)-hydroxyethyl]-2-carbapenem-3-carboxylic acid.

42. An antibiotic composition comprising:
- an antibiotic selected from the group consisting of penem antibiotics and carbapenem antibiotics having renal toxicity; and
  
  a pharmaceutically acceptable N-acylated amino acid wherein the amino acid is selected from the group consisting of ornithine, lysine, phenylglycine and phenylalanine and salts thereof in an amount at least sufficient to reduce or eliminate said renal toxicity.
- View Dependent Claims (43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54)
- - 43. A composition as claimed in claim 42, wherein the weight ratio of said N-acylated amino acid to said antibiotic is from about 0.1:
    - 1 to 4;
      
      1.
  - 44. A composition as claimed in claim 43, wherein said N-acylated amino acid is a compound of formula (IV):
    - space="preserve" listing-type="equation">R.sup.4 --NH--(CH.sub.2).sub.n --CH(COOH)--NHR.sup.3 (IV)
      wherein;
      
      n is 3 or 4; and
      
      R³ and R⁴ are independently selected from the group consisting of hydrogen atoms and carboxylic acyl groups, provided that R³ and R⁴ are not both hydrogen;
      
      or a pharmaceutically acceptable salt thereof.
  - 45. A composition as claimed in claim 44, wherein R³ and R⁴ are independently selected from the group consisting of:
    - hydrogen atoms;
      
      C₁ -C₁₈ alkanoyl groups;
      
      C₃ -C₈ alkenoyl groups;
      
      C₃ -C₈ alkynoyl groups;
      
      aromatic acyl groups wherein the aryl part is C₆ -C₁₄ carbocyclic aryl and is unsubstituted or has from 1 to 5 substituents selected from the group consisting of C₁ -C₄ alkyl groups, hydroxy groups, C₁ -C₄ alkoxy groups, amino groups and sulfo groups;
      
      cycloalkanecarbonyl groups where the cycloalkane part is C₃ -C₈ ;
      
      C₂ -C₇ alkoxycarbonyl groups; and
      
      aralkyloxycarbonyl groups where the aralkyl part has from 7 to 9 carbon atoms and is unsubstituted or has from 1 to 5 substituents selected from the group consisting of amino groups, C₁ -C₄ alkyl groups, C₁ -C₄ alkoxy groups and hydroxy groups;
      
      provided that R³ and R⁴ are not both hydrogen.
  - 46. A composition as claimed in claim 44, wherein R³ and R⁴ are independently selected from the group consisting of hydrogen atoms and acetyl, benzoyl, cyclohexanecarbonyl, cyclopropanecarbonyl, hexanoyl, isobutyryl, crotonoyl, ethoxycarbonyl, 4-hydroxybenzoyl, anisoyl, 4-aminobenzoyl, naphthoyl, toluoyl, benzyloxycarbonyl and 4-methoxybenzyloxycarbonyl groups, provided that R³ and R⁴ are not both hydrogen atoms.
  - 47. A composition as claimed in claim 44, wherein at least one of R³ and R⁴ represents an acyl group selected from the group consisting of acetyl and benzoyl groups.
  - 48. A composition as claimed in claim 43, wherein said N-acylated amino acid is a compound of formula (V):
    - space="preserve" listing-type="equation">Ph--(CH.sub.2).sub.m --CH(COOH)--NHR.sup.2 (V)
      wherein;
      
      Ph represents a phenyl group;
      
      m is 0 or 1; and
      
      R² represents a carboxylic acyl group;
      
      or a pharmaceutically acceptable salt thereof.
  - 49. A composition as claimed in claim 48, wherein R² is selected from the group consisting of:
    - C₁ -C₁₈ alkanoyl groups;
      
      C₃ -C₈ alkenoyl groups;
      
      C₃ -C₈ alkynoyl groups;
      
      aromatic acyl groups wherein the aryl part is C₆ -C₁₄ carbocyclic aryl and is unsubstituted or has from 1 to 5 substituents selected from the group consisting of C₁ -C₄ alkyl groups, hydroxy groups, C₁ -C₄ alkoxy groups, amino groups and sulfo groups;
      
      cycloalkanecarbonyl groups where the cycloalkane part is C₃ -C₈ ;
      
      C₂ -C₇ alkoxycarbonyl groups; and
      
      aralkyloxycarbonyl groups where the aralkyl part has from 7 to 9 carbon atoms and is unsubstituted or has from 1 to 5 substituents selected from the group consisting of amino groups, C₁ -C₄ alkyl groups, C₁ -C₄ alkoxy groups and hydroxy groups.
  - 50. A composition as claimed in claim 48, wherein R² is selected from the group consisting of acetyl, benzoyl, cyclohexanecarbonyl, cyclopropanecarbonyl, hexanoyl, isobutyryl crotonoyl, ethoxycarbonyl, 4-hydroxybenzoyl, anisoyl, 4-aminobenzoyl, naphthoyl, toluoyl, benzyloxycarbonyl and 4-methoxybenzyloxycarbonyl groups.
  - 51. A composition as claimed in claim 48, wherein R² represents an acyl group selected from the group consisting of acetyl and benzoyl groups.
  - 52. A composition as claimed in claim 43, wherein said N-acylated amino acid is selected from the group consisting of:
    - N.sup.α
      
      ,N.sup.δ
      
      -DibenzoylornithineN.sup.α
      
      ,N.sup.δ
      
      -DicyclohexanecarbonylornithineN.sup.α
      
      -Benzoyl-N.sup.δ
      
      -cyclohexanecarbonylornithineN.sup.α
      
      -Benzoyl-N.sup.δ
      
      -acetylornithineN.sup.α
      
      ,N.sup.ε
      
      -DibenzoyllysineN.sup.α
      
      ,N.sup.ε
      
      -DicyclohexanecarbonyllysineN.sup.α
      
      -Benzoyl-N.sup.ε
      
      -cyclohexanecarbonyllysineN.sup.α
      
      -Benzoyl-N.sup.ε
      
      -acetyllysineN-BenzoylphenylglycineN-BenzoylphenylalanineN-CyclohexanecarbonylphenylglycineN-CyclohexanecarbonylphenylalanineN.sup.α
      
      -Cyclohexanecarbonyl-N.sup.ε
      
      -acetyllysine andN.sup.α
      
      -Cyclohexanecarbonyl-N.sup.δ
      
      -acetylornithine.
  - 53. A composition as claimed in claim 43, wherein said antibiotic is selected from the group consisting of compounds of formula (I):
    - ##STR105## wherein;
      
      Y represents a sulfur atom, a methylene group, or a methylene group having 1 or 2 methyl substituents; and
      
      R¹ represents an ethyl, 2-fluoroethyl, 2-(aminoethyleneamino)ethyl, N¹,N¹ -dimethylamidinomethyl, N¹,N¹,N² -trimethylamidinomethyl, 3-pyrrolidinyl, 1-formimidoyl-3-pyrrolidinyl, 1-acetimidoyl-3-pyrrolidinyl, 1-propionimidoyl-3-pyrrolidinyl, 2-methyl-1,4,5,6-tetrahydro-5-pyrimidinyl, 2-methoxymethyl-1,4,5,6-tetrahydro-5-pyrimidinyl, 3-azetidinyl, 1-acetimidoyl-3-azetidinyl, N¹ -methyl-N¹ -(2-propynyl)amidinomethyl, N¹ -(2-fluoroethyl)N¹ -methylamidinomethyl, N¹ -(3-fluoropropyl)N¹ -methylamidinomethyl, N¹ -methyl-N¹ -(2,2,2-trifluoroethyl)amidinomethyl, 1-(3-azetidinyl)ethyl, 1-(1-acetimidoyl-3-azetidinyl)ethyl, 1,4,5,6-tetrahydro-2-pyrimidinylmethyl, 1-(4,5-dihydro-2-thiazolyl)ethyl, 5-carbamoyl-3-pyrrolidinyl, 1-acetimidoyl-5-carbamoyl-3-pyrrolidinyl, 2-chloromethyl-1,4,5,6-tetrahydro-5-pyrimidinyl, 1-butyrimidoyl-3-pyrrolidinyl, 1-nicotinimidoyl-3-pyrrolidinyl, N¹,N¹ -diallylamidinomethyl, N¹ -methyl-N¹ -(2-propynyl)amidino, N¹ -(2-fluoroethyl)-N¹ -methylamidino, N¹ -(3-fluoro-propyl)-N¹ -methylamidino, N¹ -methyl-N¹ -(2,2,2-trifluoroethyl)amidino, N¹ -allyl-N¹ -methylamidinomethyl, cyanomethyl, 2-cyanoethyl, 1-cyanoethyl, 2-cyano-1-methylethyl, 2-aminoethyl or 1-carbamoylethyl group.
  - 54. A composition as claimed in claim 53, wherein said antibiotic is selected from the group consisting of:
    - (5R,6S)-2-{2-[(aminomethylene)amino]ethylthio}-6-[1(R)-hydroxyethyl]-2-carbapenem-3-carboxylic acid(5R,6S)-2-[(3S)-1-acetimidoylpyrrolidin-3-ylthio]-6-[1(R)-hydroxyethyl]-2-carbapenem-3-carboxylic acid(5R,6S)-2-[(3R)-1-acetimidoylpyrrolidin-3-ylthio]-6-[1(R)-hydroxyethyl]-2-carbapenem-3-carboxylic acid(5R,6S)-2-[(3R)-1-acetimidoylpyrrolidin-3-ylthio]-6-[1(R)-hydroxyethyl]-1(S)-methyl-2-carbapenem-3-carboxylic acid(5R,6S)-2-[(3S)-1-acetimidoylpyrrolidin-3-ylthio]-6-[1(R)-hydroxyethyl]-1(R)-methyl-2-carbapenem-3-carboxylic acid(5R,6S)-2-[(3S)-1-acetimidoylpyrrolidin-3-ylthio]-6-[1(R)-hydroxyethyl]-1(S)-methyl-2-carbapenem-3-carboxylic acid and(5R,6S)-2-[(3S)-1-acetimidoyl-5(S)-carbamoylpyrrolidin-3-ylthio]-6[1(R)-hydroxyethyl]-2-carbapenem-3-carboxylic acid.

55. An antibiotic composition comprising:
- (a) an N-acylated amino acid selected from the group consisting of compounds of formula (IV);
  space="preserve" listing-type="equation">R.sup.4 --NH--(CH.sub.2).sub.n --CH(COOH)--NHR.sup.3 (IV)
  wherein;
  
  n is 3 or 4; and
  R³ and R₄ are independently selected from the group consisting of hydrogen atoms and carboxylic acyl groups, provided that R³ and R⁴ are not both hydrogen, and compounds of formula (V);
  space="preserve" listing-type="equation">Ph--(CH.sub.2).sub.m --CH(COOH)NHR.sup.2 (V)
  wherein;
  
  Ph represents the phenyl group;
  
  m is 0 or 1; and
  
  R² represents a carboxylic acyl group;
  
  or a pharmaceutically acceptable salt thereof; and
  
  (b) an antibiotic selected from the group consisting of compounds of formula (I);
  
  ##STR106## wherein;
  
  Y represents a sulfur atom, a methylene group, or a methylene group having 1 or 2 methyl substituents; and
  
  R¹ represents an ethyl, 2-fluoroethyl, 2-(aminomethyleneamino)ethyl, N¹,N¹ -dimethyl-amidinomethyl, N¹,N¹,N² -trimethylamidinomethyl, 3-pyrrolidinyl, 1-formimidoyl-3-pyrrolidinyl, 1-acetimidoyl-3-pyrrolidinyl, 1-propionimidoyl-3-pyrrolidinyl, 2-methyl-1,4,5,6-tetrahydro-5-pyrimidinyl, 2-methoxymethyl-1,4,5,6-tetrahydro-5-pyrimidinyl, 3-azetidinyl, 1-acetimidoyl-3-azetidinyl, N¹ -methyl-N¹ -(2-propynyl)amidinomethyl, N¹ -(2-fluoroethyl)N¹ -methylamidinomethyl, N¹ -(3-fluoropropyl)N¹ -methylamidinomethyl, N¹ -methyl-N¹ -(2,2,2-trifluoroethyl)amidinomethyl, 1-(3-azetidinyl)ethyl, 1-(1-acetimidoyl-3-azetidinyl)ethyl, 1,4,5,6-tetrahydro-2-pyrimidinylmethyl, 1-(4,5-dihydro-2-thiazolyl)ethyl, 5-carbamoyl-3-pyrrolidinyl, 1-acetimidoyl-5-carbamoyl-3-pyrrolidinyl, 2-chloromethyl-1,4,5,6-tetrahydro-5-pyrimidinyl, 1-butyrimidoyl-3-pyrrolidinyl, 1-nicotinimidoyl-3-pyrrolidinyl, N¹,N¹ -diallyl-amidinomethyl, N¹ -methyl-N¹ -(2-propynyl)amidino, N¹ -(2-fluoroethyl)-N¹ -methylamidino, N¹ -(3-fluoropropyl)-N¹ -methylamidino, N¹ -methyl-N¹ -(2,2,2-trifluoroethyl)amidino, N¹ -allyl-N¹ -methylamidinomethyl, cyanomethyl, 2-cyanoethyl, 1-cyanoethyl, 2-cyano-1-methylethyl, 2-aminoethyl or 1-carbamoylethyl group and pharmaceutically acceptable salts thereof;
  
  said antibiotic (b) having renal toxicity and said amino acid (a) being in an amount at least sufficient to reduce or eliminate said renal toxicity.
- View Dependent Claims (56, 57, 58, 59, 60, 61, 62, 63)
- - 56. The composition as claimed in claim 55, wherein the weight ratio of said N-acylated amino acid to said antibiotic is about from 0.1:
    - 1 to 4;
      
      1.
  - 57. A composition as claimed in claim 56, wherein R³ and R⁴ are independently selected from the group consisting of:
    - hydrogen atoms;
      
      C₁ -C₁₈ alkanoyl groups;
      
      C₃ -C₈ alkenoyl groups;
      
      C₃ -C₈ alkynoyl groups;
      
      aromatic acyl groups wherein the aryl part is C₆ -C₁₄ carbocyclic aryl and is unsubstituted or has from 1 to 5 substituents selected from the group consisting of C₁ -C₄ alkyl groups, hydroxy groups, C₁ -C₄ alkoxy groups, amino groups and sulfo groups;
      
      cycloalkanecarbonyl groups where the cycloalkane part is C₃ -C₈ ;
      
      C₂ -C₇ alkoxycarbonyl groups; and
      
      aralkyloxycarbonyl groups where the aralkyl part has from 7 to 9 carbon atoms and is unsubstituted or has from 1 to 5 substituents selected from the group consisting of amino groups, C₁ -C₄ alkyl groups, C₁ -C₄ alkoxy groups and hydroxy groups;
      
      provided that R³ and R⁴ are not both hydrogen.
  - 58. A composition as claimed in claim 56, wherein R³ and R⁴ are independently selected from the group consisting of hydrogen atoms and acetyl, benzoyl, cyclohexanecarbonyl, cyclopropanecarbonyl, hexanoyl, isobutyryl, crotonoyl, ethoxycarbonyl, 4-hydroxybenzoyl, anisoyl, 4-aminobenzoyl, naphthoyl, toluoyl, benzyloxycarbonyl and 4-methoxybenzyloxycarbonyl groups, provided that R³ and R⁴ are not both hydrogen atoms.
  - 59. A composition as claimed in claim 56, wherein at least one of R³ and R⁴ represents an acyl group selected from the group consisting of acetyl and benzoyl groups.
  - 60. A composition as claimed in claim 56, wherein R² is selected from the group consisting of:
    - C₁ -C₁₈ alkanoyl groups;
      
      C₃ -C₈ alkenoyl groups;
      
      C₃ -C₈ alkynoyl groups;
      
      aromatic acyl groups wherein the aryl part is C₆ -C₁₄ carbocyclic aryl and is unsubstituted or has from 1 to 5 substituents selected from the group consisting of C₁ -C₄ alkyl groups, hydroxy groups, C₁ -C₄ alkoxy groups, amino groups and sulfo groups;
      
      cycloalkanecarbonyl groups where the cycloalkane part is C₃ -C₈ ;
      
      C₂ -C₇ alkoxycarbonyl groups; and
      
      aralkyloxycarbonyl groups where the aralkyl part has from 7 to 9 carbon atoms and is unsubstituted or has from 1 to 5 substituents selected from the group consisting of amino groups, C₁ -C₄ alkyl groups, C₁ -C₄ alkoxy groups and hydroxy groups.
  - 61. A composition as claimed in claim 56, wherein R² is selected from the group consisting of acetyl, benzoyl, cyclohexanecarbonyl, cyclopropanecarbonyl, hexanoyl, isobutyryl, crotonoyl, ethoxycarbonyl, 4-hydroxybenzoyl, anisoyl, 4-aminobenzoyl, naphthoyl, toluoyl, benzyloxycarbonyl and 4-methoxybenzyloxycarbonyl groups.
  - 62. A composition as claimed in claim 56, wherein R² represents an acyl group selected from the group consisting of acetyl and benzoyl groups.
  - 63. A composition as claimed in claim 56, wherein said N-acylated amino acid is selected from the group consisting of:
    - N.sup.α
      
      ,N.sup.δ
      
      -DibenzoylornithineN.sup.α
      
      ,N.sup.δ
      
      -DicyclohexanecarbonylornithineN.sup.α
      
      -Benzoyl-N.sup.δ
      
      -cyclohexanecarbonylornithineN.sup.α
      
      -Benzoyl-N.sup.δ
      
      -acetylornithineN.sup.α
      
      ,N.sup.ε
      
      -DibenzoyllysineN.sup.α
      
      ,N.sup.ε
      
      -DicyclohexanecarbonyllysineN.sup.α
      
      -Benzoyl-N.sup.ε
      
      -cyclohexanecarbonyllysineN.sup.α
      
      -Benzoyl-N.sup.ε
      
      -acetyllysineN-BenzoylphenylglycineN-BenzoylphenylalanineN-CyclohexanecarbonylphenylglycineN-CyclohexanecarbonylphenylalanineN.sup.α
      
      -Cyclohexanecarbonyl-N.sup.ε
      
      -acetyllysine andN.sup.α
      
      -Cyclohexanecarbonyl-N.sup.ε
      
      -acetylornithineand said antibiotic is selected from the group consisting of;
      
      (5R,6S)-2-{2-[(aminomethylene)amino]ethylthio}-6-[1(R)-hydroxyethyl]-2-carbapenem-3-carboxylic acid(5R,6S)-2-[(3S)-1-acetimidoylpyrrolidin-3-ylthio]-6-[1(R)-hydroxyethyl]-2-carbapenem-3-carboxylic acid(5R,6S)-2-[(3R)-1-acetimidoylpyrrolidin-3-ylthio]-6-[1(R)-hydroxyethyl]-2-carbapenem-3-carboxylic acid(5R,6S)-2-[(3R)-1-acetimidoylpyrrolidin-3-ylthio]-6-[1(R)-hydroxyethyl]-1(S)-methyl-2-carbapenem-3-carboxylic acid(5R,6S)-2-[(3S)-1-acetimidoylpyrrolidin-3-ylthio]-6-[1(R)-hydroxyethyl]-1(R)-methyl-2-carbapenem-3-carboxylic acid(5R,6S)-2-[(3S)-1-acetimidoylpyrrolidin-3-ylthio]-6-[1(R)-hydroxyethyl]-1(S)-methyl-2-carbapenem-3-carboxylic acid and(5R,6S)-2-[(3S)-1-acetimidoyl-5(S)-carbamoylpyrrolidin-3-ylthio]-6-[1(R)-hydroxyethyl]-2-carbapenem-3-carboxylic acid.

64. The antibiotic composition comprising:
- (a) (5R,6S)-2-[(3S)-1-acetimidoylpyrrolidin-3-ylthio]-6-[1(R)hydroxyethyl]-2-carbapenem-3-carboxylic acid; and
  
  (b) N-benzoyl-valine, wherein the weight ratio of (a) to (b) is from about 1;
  
  0.1 to 1;
  
  4.
- View Dependent Claims (65)
- - 65. A composition as claimed in claim 64, wherein said weight ratio is about 1:
    - 1.

66. An antibiotic composition comprising:
- (a) (5R,6S)-2-[(3S)-1-acetimidoylpyrrolidin-3-ylthio]-6-[1(R)hydroxyethyl]-2-carbapenem-3-carboxylic acid; and
  
  (b) an amount of N-benzoyl-β
  
  -alanine at least sufficient to reduce or eliminate renal toxicity of said carbapenem.
- View Dependent Claims (67, 68)
- - 67. A composition as claimed in claim 66, wherein the weight ratio of (a) to (b) is from about 1:
    - 0.1 to 1;
      
      4.
  - 68. A composition as claimed in claim 67, wherein said weight ratio is about 1:
    - 1.

69. A method of treating a mammal suffering from a bacterial infection by administering to said mammal:
- an antibiotic selected from the group consisting of penem antibiotics and carbapenem antibiotics capable of causing renal damage in an amount effective to treat said bacterial infection; and
  
  an amount of a pharmaceutically acceptable N-acylated derivative of an amino acid wherein the amino group and the carboxylic acid group are attached to a saturated aliphatic carbon chain or carbon atom, or a salt thereof at least sufficient to reduce, alleviate or prevent said renal damage;
  
  said antibiotic and said amino acid derivative being administered to said mammal sufficiently closely in time to each other that the amino acid derivative has a suitable concentration in the blood while said antibiotic is in the blood to reduce, alleviate or prevent said renal damage.
- View Dependent Claims (70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 90, 91, 92, 93, 94, 95, 97, 99, 100, 101, 103, 104, 105)
- - 70. The method as claimed in claim 69, wherein said antibiotic and said N-acylated derivative of an amino acid are administered concurrently.
  - 71. The method as claimed in claim 70, wherein the weight ratio of said N-acylated amino acid to said antibiotic is from about 0.1:
    - 1 to 4;
      
      1.
  - 72. The method as claimed in claim 69, wherein the weight ratio of said N-acylated amino acid to said antibiotic is from about 0.1:
    - 1 to 4;
      
      1.
  - 73. A method as claimed in claim 72, wherein said amino acid is a compound of formula (II):
    - space="preserve" listing-type="equation">H.sub.2 N--X--COOH (II)
      wherein X represents a C₁ -C₁₀ alkylene group or a C₁ -C₁₀ alkylene group having at least one substituent selected from the group consisting of hydroxy groups, C₁ -C₄ alkoxy groups, C₆ -C₁₄ aryloxy groups, substituted C₆ -C₁₄ aryloxy groups, C₇ -C₉ aralkyloxy groups, substituted C₇ -C₉ aralkyloxy groups, mercapto groups, C₁ -C₄ alkylthio groups, C₆ -C₁₄ arylthio groups, substituted C₆ C₁₄ arylthio groups, C₇ -C₉ aralkylthio groups, substituted C₇ -C₉ aralkylthio groups, C₂ -C₅ carboxyalkylthio groups, amino groups, amino groups having one or two substituents selected from the group consisting ofC₁ -C₄ alkyl groups, C₆ -C₁₄ aryl groups, substituted C₆ -C₁₄ aryl groups, C₇ -C₉ aralkyl groups, substituted C₇ -C₉ aralkyl groups and carboxylic acyl groups,C₆ -C₁₄ aryl groups, substituted C₆ -C₁₄ aryl groups, carboxy groups, amidino groups, sulfo groups, C₁ -C₄ alkylsulfinyl groups, C₁ -C₄ alkylsulfonyl groups and heterocyclic groups having from 5 to 14 ring atoms of which from 1 to 5 are hetero-atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms, said substituted aryloxy, aralkyloxy, arylthio, aralkylthio, aryl and aralkyl groups having at least one substituent selected from the group consisting of C₁ -C₄ alkyl groups, hydroxy groups, amino groups and C₁ -C₄ alkoxy groups, or a pharmaceutically acceptable salt thereof.
  - 74. A method as claimed in claim 73, wherein the N-acyl group is selected from the group consisting of:
    - saturated aliphatic acyl groups having from 1 to 8 carbon atoms;
      
      aromatic acyl groups in which the aryl moiety has from 6 to 10 ring carbon atoms and is unsubstituted or has from 1 to 3 substituents independently selected from the group consisting of C₁ -C₄ alkyl groups and C₁ -C₄ alkoxy groups;
      
      alicyclic acyl groups in which the cycloalkane ring has from 3 to 6 carbon atoms;
      
      araliphatic acyl groups in which the aryl ring has from 6 to 10 ring carbon atoms and the alkyl group has from 1 to 4 carbon atoms, the aryl ring being unsubstituted or having from 1 to 3 substituents independently selected from the group consisting of C₁ -C₄ alkyl groups and C₁ -C₄ alkoxy groups;
      
      heterocyclic acyl groups in which the heterocyclic ring is saturated or unsaturated and has 5 or 6 ring atoms of which one is a nitrogen, sulfur or oxygen hetero-atom;
      
      alkoxycarbonyl groups having a total of from 2 to 7 carbon atoms;
      
      aralkyloxycarbonyl groups in which the aralkyl moiety has from 7 to 9 carbon atoms and the aryl ring is unsubstituted or has from 1 to 3 substituents independently selected from the group consisting of C₁ -C₄ alkyl groups and C₁ -C₄ alkoxy groups; and
      
      acyl groups derived from an amino acid by removal of OH from the carboxylic acid group and N-acylation of the amino group with at least one of the above-mentioned acyl groups.
  - 75. A method as claimed in claim 73, wherein the N-acyl group is selected from the group consisting of:
    - aromatic acyl groups in which the aryl ring has from 6 to 10 ring atoms and which is unsubstituted or has a single substituent selected from the group consisting of C₁ -C₄ alkyl groups, C₁ -C₄ alkoxy groups, hydroxy groups and amino groups;
      
      alicyclic acyl groups in which the cycloalkane moiety has from 3 to 6 carbon atoms;
      
      phenylaliphatic acyl groups in which the phenyl group is unsubstituted or has a single C₁ -C₄ alkyl substituent, and in which the alkyl part has from 1 to 4 carbon atoms;
      
      alkoxycarbonyl groups having a total of from 4 to 6 carbon atoms;
      
      aralkyloxycarbonyl groups in which the aralkyl part has from 7 to 9 carbon atoms and has 0 to 1 substituent selected from the group consisting of C₁ -C₄ alkyl groups and C₁ -C₄ alkoxy groups; and
      
      acyl groups derived from an amino acid by removal of OH from the carboxylic acid group and N-acylation of the amino group with at least one of the above-mentioned acyl groups.
  - 76. A method as claimed in claim 73, wherein the N-acyl group is selected from the group consisting of:
    - acetyl, benzoyl, cyclohexanecarbonyl, cyclopropanecarbonyl, hexanoyl, isobutyryl, crotonoyl, ethoxycarbonyl, 4-hydroxybenzoyl, anisoyl, 4-aminobenzoyl, napththoyl, toluoyl, benzyloxycarbonyl and 4-methoxybenzyloxycarbonyl groups.
  - 77. A method as claimed in claim 73, wherein X represents a C₁ -C₅ alkylene group which is unsubstituted or has 1 or 2 substituents independently selected from the group consisting of:
    - hydroxy groups;
      
      C₁ -C₄ alkoxy groups;
      
      mercapto groups;
      
      C₁ -C₄ alkylthio groups;
      
      amino groups;
      
      amino groups having one or two C₁ -C₄ alkyl substituents;
      
      amino groups having one or two carboxylic acyl substituents;
      
      aryl groups having from 6 to 14 carbon atoms wherein the aryl ring is unsubstituted or has from 1 to 3 substituents selected from the group consisting of C₁ -C₄ alkyl groups, hydroxy groups, amino groups and C₁ -C₄ alkoxy groups;
      
      carboxy groups; and
      
      heterocyclic groups having from 5 to 9 ring atoms, of which from 1 to 3 are hetero-atoms selected from the group consisting of nitrogen and oxygen hetero-atoms.
  - 78. A method as claimed in claim 72, wherein said amino acid is glycine, β
    - -alanine, 4-aminobutyric acid, 5-aminovaleric acid, 6-aminohexanoic acid, 8-aminooctanoic acid, alanine, 2-aminobutyric acid, norvaline, valine, leucine, isoleucine, norleucine, phenylglycine, phenylalanine, tyrosine, O-methyltyrosine, aspartic acid, glutamic acid, 4-carboxyglutamic acid, 3-methylaspartic acid, 2-aminoadipic acid, 2-aminopimelic acid, 2-aminosuberic acid, 3-hydroxyaspartic acid, 3-hydroxyglutamic acid, 2,3-diaminopropionic acid, 2,4-diaminobutyric acid, ornithine, lysine, 5-hydroxylysine, arginine, N.sup.δ
      
      ,N.sup.δ
      
      -dimethylornithine, N.sup.ε
      
      -methyllysine, cysteine, methionine, ethionine, S-carboxymethylcysteine, S-benzylcysteine, methionine S-oxide, ethionine S-oxide, methionine S,S-dioxide, cysteic acid, serine, O-methylserine, threonine, O-methylthreonine, homothreonine, ethoxinine, 3-methoxyvaline, 3-phenylserine, 3-methyl-3-phenylalanine, histidine, tryptophan, 2-methylalanine, 2-methylserine, 2-hydroxyisoleucine, 2-methylmethionine, 2-ethyl-2-phenylglycine, 3-aminobutyric acid, 3-amino-4-methylvaleric acid, 3-amino-3-phenylpropionic acid, 3-amino-2-hydroxypropionic acid or 4-amino-3-hydroxybutyric acid.
  - 79. A method as claimed in claim 72, wherein said amino acid is β
    - -alanine, 4-aminobutyric acid, 5-aminovaleric acid, 6-aminohexanoic acid, alanine, valine, leucine, norleucine, methionine, histidine, ornithine, glycine, phenylalanine or phenylglycine.
  - 80. A method as claimed in claim 72, wherein said amino acid is leucylglycine, glycyl-β
    - -alanine, glycylalanine, valylalanine, leucylalanine, glycylvaline, alanylvaline, leucylvaline, valylleucine, phenylalanylleucine, histidylleucine, glycylphenylalanine, alanylphenylalanine, leucylphenylalanine, glycylmethionine, valylmethionine, glycylhistidine, alanylvalylglycine, glycylalanylvaline, glycylphenylalanylleucine or glycylglycylhistidine.
  - 81. A method as claimed in claim 72, wherein said antibiotic is selected from the group consisting of compounds of formula (I):
    - ##STR107## in which;
      
      Y represents a sulfur atom, a methylene group or a methylene group having 1 or 2 substituents selected from the group consisting of methyl and methoxy groups; and
      
      R¹ represents a C₁ -C₆ alkyl group, a C₁ -C₆ alkyl group having at least one substituent selected from the group consisting of substituents (i) or a heterocyclic group having from 4 to 14 ring atoms of which from 1 to 5 are hetero-atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms where said heterocyclic group is unsubstituted or has at least one substituent selected from the group consisting of substituents (ii);
      
      substituents (i);
      
      halogen atoms, amino groups, amino groups having at least one substituent selected from the group consisting of substituents (iii), C₁ -C₄ alkylideneamino groups, C₁ -C₄ aminoalkylideneamino groups, amidino groups, amidino groups having from 1 to 3 substituents selected from the group consisting of substituents (iii), heterocyclic groups having from 4 to 14 ring atoms of which from 1 to 5 are hetero-atoms selected from the group consisting of nitrogen, oxygen and sulfur hetero-atoms wherein said heterocyclic group is unsubstituted or has at least one substituent selected from the group consisting of substituents (ii), imino groups, cyano groups, carbamoyl groups and carbamoyl groups having at least one substituent selected from the group consisting of C₁ -C₄ alkyl groups and C₁ -C₄ alkoxy groups;
      
      substituents (ii);
      
      C₁ -C₆ alkanimidoyl groups, C₁ -C₆ alkyl groups, alkoxyalkyl groups where the alkoxy and alkyl parts are each C₁ -C₄, carbamoyl groups, carbamoyl groups having at least one substituent selected from the group consisting of C₁ -C₄ alkyl groups and C₁ -C₄ alkoxy groups, C₁ -C₄ haloalkyl groups, heterocyclic acylimidoyl groups where the heterocyclic part has from 5 to 9 ring atoms of which from 1 to 3 are hetero-atoms selected from the group consisting of nitrogen, oxygen and sulfur hetero-atoms, amidino groups, amidino groups having from 1 to 3 substituents selected from the group consisting of substituents (iii), imino groups, oxygen atoms, C₁ -C₆ alkanoyl groups, C₁ -C₆ alkanesulfonyl groups, C₁ -C₆ alkanesulfinyl groups, hydroximino groups, C₁ -C₄ alkoximino groups, carbamoyloxy groups, carbamoyloxy groups having at least one substituent selected from the group consisting of C₁ -C₄ alkyl groups and C₁ -C₄ alkoxy groups, carbamoyloxyalkyl groups where the alkyl part is C₁ -C₄ and the carbamoyl part is unsubstituted or has at least one substituent selected from the group consisting of C₁ -C₄ alkyl groups and C₁ -C₄ alkoxy groups and C₁ -C₄ iminoalkyl groups;
      
      substituents (iii);
      
      C₁ -C₆ alkyl groups, C₂ -C₆ alkenyl groups, C₂ -C₆ alkynyl groups, oxygen atoms and said alkyl, alkenyl and alkynyl groups having at least one substituent selected from the group consisting of halogen atoms, carbamoyloxy groups and carbamoyloxy groups having at least one substituent selected from the group consisting of C₁ -C₄ alkyl groups and C₁ -C₄ alkoxy groups;
      
      and pharmaceutically acceptable salts thereof.
  - 82. A method as claimed in claim 81, wherein Y represents a sulfur atom, a methylene group, or the group CH₃ --CH<
    - , CH₃ O--CH<
      
      or (CH₃)₂ C<
      
      .
  - 83. A method as claimed in claim 82, wherein R¹ represents an ethyl, 2-fluoroethyl, 2-(aminomethyleneamino)ethyl, N¹,N¹ -dimethylamidinomethyl, N¹,N¹,N² -trimethylamidinomethyl, 3-pyrrolidinyl, 1-formimidoyl-3-pyrrolidinyl, 1-acetimidoyl-3-pyrrolidinyl, 1-propionimidoyl-3-pyrrolidinyl, 2-methyl-1,4,5,6-tetrahydro-5-pyrimidinyl, 2-methoxymethyl-1,4,5,6-tetrahydro-5-pyrimidinyl, 3-azetidinyl, 1-acetimidoyl-3-azetidinyl, N¹ -methyl-N¹ -(2-propynyl)amidinomethyl, N¹ -(2-fluoroethyl)-N¹ -methylamidinomethyl, N¹ -(3-fluoropropyl)-N¹ -methylamidinomethyl, N¹ -methyl-N¹ -(2,2,2-trifluoroethyl)amidinomethyl, 1-(3-azetidinyl)ethyl, 1-(1-acetimidoyl-3-azetidinyl)ethyl, 1,4,5,6-tetrahydro-2-pyrimidinylmethyl, 1-(4,5-dihydro-2-thiazolyl)ethyl, 5-carbamoyl-3-pyrrolidinyl, 1-acetimidoyl-5-carbamoyl-3-pyrrolidinyl, 2-chloromethyl-1,4,5,6-tetrahydro-5-pyrimidinyl, 1-butyrimidoyl-3-pyrrolidinyl, 1-nicotinimidoyl-3-pyrrolidinyl, N¹,N¹ -diallylamidinomethyl, N¹ -methyl-N¹ -(2-propynyl)amidino, N¹ -(2-fluoroethyl)-N¹ -methylamidino, N¹ -(3-fluoropropyl)-N¹ -methylamidino, N¹ -methyl-N¹ -(2,2,2-trifluoroethyl)amidino, N¹ -allyl-N¹ -methylamidinomethyl, cyanomethyl, 2-cyanoethyl, 1-cyanoethyl, 2-cyano-1-methylethyl, 2-aminoethyl, 1-carbamoylethyl, 2-(1-aminoethylideneamino)ethyl, 1-amidino-3-pyrrolidinyl, 2-methyl-1,3-diazabicyclo[3.3.0]oct-2-en-7-yl, 2-methoxymethyl-1,3-diazabicyclo[3.3.0]oct-2-en-7-yl, 5-imino-2-pyrrolidinyl, 2-imino-5-piperidinyl, 1-acetimidoyl-5-methylcarbamoyl-3-pyrrolidinyl, 1-acetimidoyl-5-methoxycarbamoyl-3-pyrrolidinyl, 2-imino-2-(S-oxothiomorpholino)ethyl, 2-imino-2-(1,1-dioxo-1,3-thiazolidin-3-yl)ethyl, 2-imino-2-(S,S-dioxothiomorpholino)ethyl, 2-imino-2-(3,5-dioxo-1-piperazinyl)ethyl, 2-imino-2-(4-methyl-3,5-dioxo-1-piperazinyl)ethyl, 2-imino-2-(3-oxo-1-piperazinyl)ethyl, 2-imino-2-(4-methyl-3-oxo-1-piperazinyl)ethyl, 2-imino-2-(4-acetyl-3-oxo-1-piperazinyl)ethyl, 2-imino-2-(4-methanesulfonyl-3-oxo-1-piperazinyl)ethyl, N¹ -(2-carbamoyloxyethyl)-N¹ -methylamidinomethyl, 2-(3-hydroximino-1-pyrrolidinyl)-2-iminoethyl, 2-imino-2-(3-methoximino-1-pyrrolidinyl)ethyl, 2-(4-hydroximinopiperidino)-2-iminoethyl, 2-imino-2-(4-methoximinopiperidino)ethyl, 2-(3-carbamoyloxy-1-pyrrolidinyl)-2-iminoethyl, 2-imino-2-(3-oxo-1-piperazinyl)ethyl, 2-(3-carbamoylpiperidino)-2-iminoethyl, 2-(3-carbamoyloxypiperidino)-2-iminoethyl, 2-(2-carbamoyloxy-1-pyrrolidinyl)-2-iminoethyl, 2-(2-carbamoyloxymethyl-1-pyrrolidinyl)-2-iminoethyl, 2-(4-carbamoyloxypiperidino)-2-iminoethyl, 2-(4-formyl-1-piperazinyl)-2-iminoethyl, 2-(4-acetyl-1-piperazinyl)-2-iminoethyl, 1-formyl-3-azetidinyl, 1-iminomethyl-3-azetidinyl, 1-methyl-4-piperidyl, 1-acetimidoyl-4-piperidyl or 1-acetyl-3-pyrrolidinyl group.
  - 84. A method as claimed in claim 82, wherein said N-acylated derivative of an amino acid is selected from the group consisting of N-benzoylvaline and N-benzoyl-β
    - -alanine.
  - 85. A method as claimed in claim 81, wherein said antibiotic is selected from the group consisting of:
    - (5R,6S)-2-{2-[(aminomethylene)amino]ethylthio}-6-[1(R)-hydroxyethyl]-2-carbapenem-3-carboxylic acid(5R,6S)-2-[(3S)-1-acetimidoylpyrrolidin-3-ylthio]-6-[1(R)-hydroxyethyl]-2-carbapenem-3-carboxylic acid(5R,6S)-2-[(3R)-1-acetimidoylpyrrolidin-3-ylthio]-6-[1(R)-hydroxyethyl]-2-carbapenem-3-carboxylic acid(5R,6S)-2-[(3R)-1-acetimidoylpyrrolidin-3-ylthio]-6-[1(R)-hydroxyethyl]-1(S)-methyl-2-carbapenem-3-carboxylic acid(5R,6S)-2-[(3S)1-acetimidoylpyrrolidin-3-ylthio]-6-[1(R)-hydroxyethyl]-1(R)-methyl-2-carbapenem-3-carboxylic acid(5R,6S)-2[(3S)-1-acetimidoylpyrrolidin-3-ylthio]-6-[1(R)-hydroxyethyl]-1(S)-methyl-2-carbapenem-3-carboxylic acid and(5R,6S)-2-[(3S)-1-acetimidoyl-5(S)-carbamoylpyrrolidin-3-ylthio]-6-[1(R)-hydroxyethyl]-2-carbapenem-3-carboxylic acid and said N-acylated amino acid is selected from the group consisting of;
      
      N-(p-toluoyl)-β
      
      -alanineN-(4-methoxybenzoyl)-β
      
      -alanineN-(3-hydroxy-2-naphthoyl)-β
      
      -alanineN-benzoylglycyl-β
      
      -alanineN-benzoyl-β
      
      -alanineN-benzoyl-5-aminovaleric acid N-benzoyl-6-aminohexanoic acidN-cyclohexanecarbonyl-6-aminohexanoic acidN-(N-methylnicotinoyl)-6-aminohexanoic acidN-benzoyl-8-aminooctanoic acidN-benzoylalanineN-(1-naphthoyl)alanineN-benzoylvalylalanineN-benzoyl-2-aminobutyric acidN-benzoylnorvalineN-valerylvalineN-benzoylalanylvalineN-benzoylvalineN-benzoylleucineN-benzoylglycylphenylalanylleucineN-benzoylnorleucineN.sup.α
      
      ,N.sup.δ
      
      -dibenzoylornithineN.sup.α
      
      ,N.sup.δ
      
      -dicyclopropanecarbonylornithineN.sup.α
      
      ,N.sup.δ
      
      -dicyclohexanecarbonylornithineN.sup.α
      
      -benzoyl-N.sup.δ
      
      -cyclohexanecarbonylornithineN.sup.α
      
      -benzoyl-N.sup.δ
      
      -acetylornithineN.sup.α
      
      -cyclohexanecarbonyl-N.sup.δ
      
      -acetylornithineN.sup.α
      
      ,N.sup.ε
      
      -dibenzoyllysineN.sup.α
      
      ,N.sup.ε
      
      -dicyclopropanecarbonyllysineN.sup.α
      
      ,N.sup.ε
      
      -dicyclohexanecarbonyllysineN.sup.α
      
      -benzoyl-N.sup.ε
      
      -cyclohexanecarbonyllysineN.sup.α
      
      -benzoyl-N.sup.ε
      
      -acetyllysineN.sup.α
      
      ,N.sup.ε
      
      -dianisoyllysineN.sup.α
      
      -cyclohexanecarbonyl-N.sup.ε
      
      -acetyllysineN-benzoylphenylalanineN-(4-methoxybenzoyl)phenylalanineN-hexanoylphenylalanineN-cyclopropanecarbonylphenylalanineN-cyclohexanecarbonylphenylalanineN-anisoylphenylalanineN-benzoylglycylphenylalanineN-benzoylalanylphenylalanineN-cyclohexanecarbonylleucylphenylalanineN-benzoylphenylglycineN-cyclopropanecarbonylphenylglycineN-cyclohexanecarbonylphenylglycineN-anisoylphenylglycineN-(4-methoxybenzoyl)phenylglycineN-benzoyl-O-methyltyrosineN-benzoylmethionineN-phenylacetylmethionineN-benzoylvalylmethionineN-benzoylethionineN-(4-methoxybenzyloxycarbonyl)ethionineN-benzoylthreonineN-benzoylhistidineN-(p-toluoyl)histidineN-(4-methoxybenzoyl)histidineN-(4-methoxybenzoyl)-3-aminobutyric acid andN-butyryl-3-amino-3-phenylpropionic acid.
  - 86. A method as claimed in claim 81, wherein said N-acylated derivative of an amino acid is selected from the group consisting of N-benzoylvaline and N-benzoyl-β
    - -alanine.
  - 87. A method as claimed in claim 86, wherein said antibiotic and said N-acylated derivative of an amino acid are administered together.
  - 88. A method as claimed in claim 86, wherein said antibiotic and said N-acylated derivative of an amino acid are administered sequentially within 1 hour of each other.
  - 90. The method as claimed in claim 86, wherein said antibiotic and said N-acylated derivatives of an amino acid are administered concurrently.
  - 91. A method as claimed in claim 72, wherein said N-acylated derivative of an amino acid is selected from the group consisting of N-benzoylvaline and N-benzoyl-β
    - -alanine.
  - 92. A method as claimed in claim 69, wherein said antibiotic and said N-acylated derivative of an amino acid are administered together.
  - 93. The method as claimed in claim 91, wherein the weight ratio of said N-acylated amino acid to said antibiotic is from about 0.1:
    - 1 to 4;
      
      1.
  - 94. A method as claimed in claim 69, wherein said antibiotic and said N-acylated derivative of an amino acid are administered sequentially within 1 hour of each other.
  - 95. The method as claimed in claim 93, wherein the weight ratio of said N-acylated amino acid to said antibiotic is from about 0.1:
    - 1 to 4;
      
      1.
  - 97. A method as claimed in claim 95, wherein the weight ratio of said N-acylated amino acid to said antibiotic is from about 0.1:
    - 1 to 4;
      
      1.
  - 99. A method as claimed in claim 97, wherein R³ and R⁴ are independently selected from the group consisting of:
    - hydrogen atoms;
      
      C₁ -C₁₈ alkanoyl groups;
      
      C₃ -C₈ alkenoyl groups;
      
      C₃ -C₈ alkynoyl groups;
      
      aromatic acyl groups wherein the aryl part is C₆ -C₁₄ carbocyclic aryl and is unsubstituted or has from 1 to 5 substituents selected from the group consisting of C₁ -C₄ alkyl groups, hydroxy groups, C₁ -C₄ alkoxy groups, amino groups and sulfo groups;
      
      cycloalkanecarbonyl group where the cycloalkane part is C₃ -C₈ ;
      
      C₂ -C₇ alkoxycarbonyl groups; and
      
      aralkyloxycarbonyl groups where the aralkyl part has from 7 to 9 carbon atoms and is unsubstituted or has from 1 to 5 substituents selected from the group consisting of amino groups;
      
      C₁ -C₄ alkyl groups, C₁ -C₄ alkoxy groups and hydroxyl groups;
      
      provided that R³ and R⁴ are not both hydrogen.
  - 100. A method as claimed in claim 97, wherein R³ and R⁴ are independently selected from the group consisting of hydrogen atoms and acetyl, benzoyl, cyclohexanecarbonyl, cyclopropanecarbonyl, hexanoyl, isobutyryl, crotonoyl, ethoxycarbonyl, 4-hydroxybenzoyl, anisoyl, 4-aminobenzoyl, naphthoyl, toluoyl, benzyloxycarbonyl and 4-methoxybenzyloxycarbonyl groups, provided that R³ and R⁴ are not both hydrogen atoms.
  - 101. A method as claimed in claim 97, wherein at least one of R³ and R⁴ represents an acyl group selected from the group consisting of acetyl and benzoyl groups.
  - 103. A method as claimed in claim 101, wherein R² is selected from the group consisting of:
    - C₁ -C₁₈ alkanoyl groups;
      
      C₃ -C₈ alkenoyl groups;
      
      C₃ -C₈ alkynoyl groups;
      
      aromatic acyl groups wherein the aryl part is C₆ -C₁₄ carbocyclic aryl and is unsubstituted or has from 1 to 5 substituents selected from the group consisting of C₁ -C₄ alkyl groups, hydroxy groups, C₁ -C₄ alkoxy groups, amino groups and sulfo groups;
      
      cycloalkanecarbonyl groups where the cycloalkane part is C₃ -C₈ ;
      
      C₂ -C₇ alkoxycarbonyl groups; and
      
      aralkyloxycarbonyl groups where the aralkyl part has from 7 to 9 carbon atoms and is unsubstituted or has from 1 to 5 substituents selected from the group consisting of amino groups, C₁ -C₄ alkyl groups, C₁ -C₄ alkoxy groups and hydroxy groups.
  - 104. A method as claimed in claim 101, wherein R² is selected from the group consisting of acetyl, benzoyl, cyclohexanecarbonyl, cyclopropanecarbonyl, hexanoyl, isobutyryl, crotonoyl, ethoxycarbonyl, 4-hydroxybenzoyl, anisoyl, 4-aminobenzoyl, naphthoyl, toluoyl, benzyloxycarbonyl and 4-methoxybenzyloxycarbonyl groups.
  - 105. A method as claimed in claim 101, wherein R² represents an acyl group selected from the group consisting of acetyl and benzoyl groups.

89.

96. A method of treating a mammal suffering from a bacterial infection by administering to said mammal:
- (a) an antibiotic in an amount effective to treat said bacterial infection, said antibiotic selected from the group consisting of penem antibiotics and carbapenem antibiotics having renal toxicity; and
  
  (b) an amount of pharmaceutically acceptable N-acylated derivative of an amino acid selected from the group consisting of ornithine, lysine, phenylglycine and phenylalanine at least sufficient to reduce or eliminate said renal toxicity;
  
  said antibiotic and said amino acid derivative being administered sequentially within one hour of each other.
- View Dependent Claims (98, 102, 106, 107, 108, 109, 110, 112, 115, 116, 117)
- - 98. A method as claimed in claim 96, wherein said N-acylated amino acid is a compound of formula (IV):
    - space="preserve" listing-type="equation">R.sup.4 --NH--(CH.sub.2).sub.n --CH(COOH)--NHR.sup.3 (IV)
      wherein;
      
      n is 3 or 4; and
      
      R³ and R⁴ are independently selected from the group consisting of hydrogen atoms and carboxylic acyl groups, provided that R³ and R⁴ are not both hydrogen;
      
      or a pharmaceutically acceptable salt thereof.
  - 102. A method as claimed in claim 96, wherein said N-acylated amino acid is a compound of formula (V):
    - space="preserve" listing-type="equation">Ph--(CH.sub.2).sub.m --CH(COOH)--NHR.sup.2 (V)
      wherein;
      
      Ph represents a phenyl group;
      
      m is 0 or 1; and
      
      R² represents a carboxylic acyl groups;
      
      or a pharmaceutically acceptable salt thereof.
  - 106. A method as claimed in claim 96, wherein said N-acylated amino acid is selected from the group consisting of:
    - N.sup.α
      
      ,N.sup.δ
      
      -DibenzoylornithineN.sup.α
      
      ,N.sup.δ
      
      -DicyclohexanecarbonylornithineN.sup.α
      
      -Benzoyl-N.sup.δ
      
      -cyclohexanecarbonylornithineN.sup.α
      
      -Benzoyl-Nδ
      
      -acetylornithineN.sup.α
      
      ,N.sup.ε
      
      -DibenzoyllysineN.sup.α
      
      ,Nε
      
      -DicyclohexanecarbonyllysineN.sup.α
      
      -Benzoyl-N.sup.ε
      
      -cyclohexanecarbonyllysineN.sup.α
      
      -Benzoyl-N.sup.ε
      
      -acetyllysineN-BenzoylphenylglycineN-BenzoylphenylalanineN-CyclohexanecarbonylphenylglycineN-CyclohexanecarbonylphenylalanineN.sup.α
      
      -Cyclohexanecarbonyl-N.sup.ε
      
      -acetyllysine andN.sup.α
      
      -Cyclohexanecarbonyl-N.sup.δ
      
      -acetylornithine.
  - 107. A method as claimed in claim 96, wherein said antibiotic is a compound of formula (I):
    - ##STR108## wherein;
      
      Y represents a sulfur atom, a methylene group, or a methylene group having 1 or 2 methyl substituents; and
      
      R¹ represents an ethyl, 2-fluoroethyl,2-(aminomethyleneamino)ethyl, N¹,N¹ -dimethylamidinomethyl, N¹,N¹,N² -trimethylamidinomethyl, 3-pyrrolidinyl, 1-formimidoyl-3-pyrrolidinyl, 1-acetimidoyl-3-pyrrolidinyl, 1-propionimidoyl-3-pyrrolidinyl, 2-methyl-1,4,5,6-tetrahydro-5-pyrimidinyl, 2-methoxymethyl-1,4,5,6-tetrahydro-5-pyrimidinyl, 3-azetidinyl, 1-acetimidoyl-3-azetidinyl, N¹ -methyl-N¹ -(2-propynyl)amidinomethyl, N¹ -(2-fluoroethyl)-N¹ -methylamidinomethyl, N¹ -(3-fluoropropyl)-N¹ -methylamidinomethyl, N¹ -methyl-N¹ -(2,2,2-trifluoroethyl)amidinomethyl, 1-(3-azetidinyl)ethyl, 1-(1-acetimidoyl-3-azetidinyl)ethyl, 1,4,5,6-tetrahydro-2-pyrimidinylmethyl, 1-(4,5-dihydro-2-thiazolyl)ethyl, 5-carbamoyl-3-pyrrolidinyl, 1-acetimidoyl-5-carbamoyl-3-pyrrolidinyl, 2-chloromethyl-1,4,5,6-tetrahydro-5-pyrimidinyl, 1-butyrimidoyl-3-pyrrolidinyl, 1-nicotinimidoyl-3-pyrrolidinyl, N¹,N¹ -diallyl-amidinomethyl, N¹ -methyl-N¹ -(2-propynyl)amidino, N¹ -(2-fluoroethyl)-N¹ -methylamidino, N¹ -(3-fluoro-propyl)-N¹ -methylamidino, N¹ -methyl-N¹ -(2,2,2-trifluoroethyl)amidino, N¹ -allyl-N¹ -methylamidinomethyl, cyanomethyl, 2-cyanoethyl, 1-cyanoethyl, 2-cyano-1-methylethyl, 2-aminoethyl or 1-carbamoylethyl groupand pharmaceutically acceptable salts thereof.
  - 108. A method as claimed in claim 106, wherein said antibiotic is selected from the group consisting of:
    - (5R,6S)-2-{2-[(aminomethylene)amino]ethylthio}-6-[1(R)-hydroxyethyl]-2-carbapenem-3-carboxylic acid(5R,6S)-2-[(3S)-1-acetimidoylpyrrolidin-3-ylthio]-6-[1(R)-hydroxyethyl]-2-carbapenem-3-carboxylic acid(5R,6S)-2-[(3R)-1-acetimidoylpyrrolidin-3-ylthio]-6-[1(R)-hydroxyethyl]-2-carbapenem-3-carboxylic acid(5R,6S)-2-[(3R)-1-acetimidoylpyrrolidin-3-ylthio]-6-[1(R)-hydroxyethyl]-1(S)-methyl-2-carbapenem-3-carboxylic acid(5R,6S)-2-[(3S)-1-acetimidoylpyrrolidin-3-ylthio]-6-[1(R)-hydroxyethyl]-1(R)-methyl-2-carbapenem-3-carboxylic acid(5R,6S)-2-[(3S)-1-acetimidoylpyrrolidin-3-ylthio]-6-[1(R)-hydroxyethyl]-1(S)-methyl-2-carbapenem-3-carboxylic acid and(5R,6S)-2-[(3S)-1-acetimidoyl-5(S)-carbamoylpyrrolidin-3-ylthio]-6-[1(R)-hydroxyethyl]-2-carbapenem-3-carboxylic acid.
  - 109. A method as claimed in claim 96, wherein said antibiotic and said N-acylated derivative of an amino acid are administered together.
  - 110. A method as claimed in claim 96, wherein said antibiotic and said N-acylated derivative of an amino acid are administered sequentially within 1 hour of each other.
  - 112. The method as claimed in claim 110, wherein the weight ratio of (a) to (b) is from about 1:
    - 0.1 to 1;
      
      4.
  - 115. The method as claimed in claim 110, wherein (a) and (b) are administered concurrently.
  - 116. The method as claimed in claim 110, wherein (a) and (b) are administered sequentially within one hour of each other.
  - 117. The method as claimed in claim 110, wherein (a) and (b) are administered together.

111. The method of treating a mammal suffering from a bacterial infection by administering to said mammal:
- (a) (5R,6S)-2-[(3S)-1-acetimidoylpyrrolidin-3-ylthio]-6-[1(R)-hydroxyethyl]-2-carbapenem-3-carboxylic acid in an amount effective to treat said bacterial infection; and
  
  (b) N-benzoyl-β
  
  -alanine in an amount sufficient to reduce or eliminate renal toxicity of said carbapenem; and
  
  said carbapenem and said alanine being administered to said mammal sufficiently closely in time to each other that concentration in the blood while said antibiotic is in the blood, is sufficient to reduce or eliminate said renal toxicity.
- View Dependent Claims (113, 114)
- - 113. The method as claimed in claim 111, wherein said weight ratio is about 1:
    - 1.
  - 114. The method as claimed in claim 111, wherein (a) and (b) are administered together.

Specification

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Litigation Campaign Assessment

Current Assignee
Sankyo Company Limited (Daiichi Sankyo Company Limited)
Original Assignee
Sankyo Company Limited (Daiichi Sankyo Company Limited)
Inventors
Shiokari, Takashi, Ueda, Seigo, Kawahara, Yukinori, Iwata, Masayuki
Primary Examiner(s)
GRIFFIN, RONALD

Application Number

US06/917,793
Time in Patent Office

641 Days
Field of Search

514/210, 540/350, 424/85
US Class Current

514/192
CPC Class Codes

A61K 2300/00   Mixtures or combinations of...

A61K 31/40   having five-membered rings ...

A61K 31/43   Compounds containing 4-thia...

Composition containing a penem or carbapenem antibiotic and the use of the same

First Claim

1 Assignment

0 Petitions

Accused Products

Abstract

186 Citations

117 Claims

Specification

Solutions

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Composition containing a penem or carbapenem antibiotic and the use of the same

First Claim

1 Assignment

Subscription Required

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0 Petitions

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Accused Products

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Abstract

186 Citations

117 Claims

Specification

Subscription Required

Solutions

Use Cases

Quick Links