JPH075467B2 - Cefalolidine preparation with reduced side effects - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION It is known that cephalosporin-type antibiotic cephaloridine exhibits excellent antibacterial action. However, nephrotoxicity is generally observed when high doses of it are injected intravenously or intramuscularly.

Therefore, the present inventors have completed the present invention as a result of intensive studies to reduce renal toxicity.

The present invention comprises compounding the cephalosporin antibiotic cephaloridine with an amino acid derivative.

The amino acid derivative of the present invention is represented by the following formula.

In the formula, R represents an acyl group, an alkoxycarbonyl group or an aralkyloxycarbonyl group.

X represents an alkylene group which may have a substituent.

In the general formula (I), when R represents an acyl group, for example, acetyl, propionyl, n-butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl and the like having 1 to 18 carbon atoms. Aliphatic saturated acyl groups each having 5 or preferably 5 to 8; for example, acryloyl, methacryloyl, crotonoyl,
Aliphatic unsaturated acyl groups having 3 to 8 carbon atoms, preferably 3 to 4 carbon atoms, such as propioloyl; for example, benzoyl, 4-toluoyl, 3-toluoyl,
2-toluoyl, 4-n-butylbenzoyl, 4-hydroxybenzoyl, 3-hydroxybenzoyl, 2-hydroxybenzoyl, 4-methoxybenzoyl, 3-methoxybenzoyl, 2-methoxybenzoyl, 4-n-
Butoxybenzoyl, 4-aminobenzoyl, 3-aminobenzoyl, 2-aminobenzoyl, 4-chlorobenzoyl, 3-fluorobenzoyl, 2-bromobenzoyl, 3-sulfobenzoyl, naphthoyl, 3-hydroxy-2-naphthoyl, 1- Aryl moieties such as hydroxy-2-naphthoyl are the same or different and have 1 to 5 substituents, preferably 1 to 3 substituents, preferably C _1-4 alkyl, hydroxy, C _1-4 alkoxy, amino, sulfo and halogen.
Or may have, and the aryl moiety has 6 to 14 carbon atoms.
Aromatic acyl groups having 1, preferably 6 to 10, for example cyclopropanecarbonyl, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, 1-methyl-1-cyclohexanecarbonyl,
The cycloalkane moiety such as 1-phenyl-1-cyclopropanecarbonyl, 1-phenyl-1-cyclopentanecarbonyl, 1-phenyl-1-cyclohexanecarbonyl has C _1-4 alkyl, phenyl as a substituent Also, the cycloalkane moiety has 3 to 8 carbon atoms,
An alicyclic acyl group having preferably 3 to 6 groups; for example, phenylacetyl, (2-phenyl-2-methyl) acetyl, (2-phenyl-2-ethyl) acetyl, (2,2-diphenyl) acetyl, (2-phenyl-
2-cyclopentyl) acetyl, 3-phenylpropionyl, 4-phenylbutyryl, 4-tolylacetyl, 4
-Aryl moieties such as hydroxyphenylacetyl, 4-aminophenylacetyl, 4-methoxyphenylacetyl, 3-sulfophenylacetyl and 4-chlorophenylacetyl are the same or different and are C _1-4 alkyl, hydroxy, C _1-4 alkoxy. , Amino, sulfo, halogen may have 1 to 5, preferably 1 to 3 as a substituent, and the alkylene moiety may be substituted with phenyl or C _3-6 cycloalkyl, and aryl The portion has 6 to 14 carbon atoms, preferably 6 to 10 carbon atoms,
Aroaliphatic acyl group whose alkylene moiety has 1 to 4 carbon atoms; for example, nicotinyl, 2-thiophenecarbonyl, 2-furoyl, 2-pyrazinecarbonyl, 2-piperidinecarbonyl, N'-methylnicotinyl, 6-hydroxyl. The same or different nitrogen atoms in the ring, such as nicotinyl,
From a saturated or unsaturated 5- to 6-membered ring having 1 to 3 sulfur atoms and 1 to 3 oxygen atoms, and optionally having 1 to 3 substituents which are the same or different and are C _1-4 alkyl and hydroxy A heterocyclic acyl group;

When R represents an alkoxycarbonyl group, it has 2 to 7 carbon atoms in total such as methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, t-butoxycarbonyl and pentyloxycarbonyl. The group which it has can be mentioned.

When R represents an aralkyloxycarbonyl group, for example, benzyloxycarbonyl, α-methylbenzyloxycarbonyl, phenethyloxycarbonyl, 3-phenylpropoxycarbonyl, 4-tolyloxycarbonyl, 4-hydroxybenzyloxycarbonyl, 4-methoxybenzyloxy. Aryl moieties such as carbonyl and 4-aminobenzyloxycarbonyl are the same or different and have 1 to 5 substituents, preferably 1 to 3 substituents, such as C _1-4 alkyl, hydroxy, amino and C _1-4 alkoxy.
And the aralkyl moiety may have 7 to 9 carbon atoms.

R is preferably an aliphatic saturated acyl group having 5 to 8 carbon atoms; aryl moieties having the same or different and having 1 to 3 C _1-4 alkyl and C _1-4 alkoxy as substituents Also, an aromatic acyl group whose aryl moiety has 6 to 10 carbon atoms; an alicyclic acyl group whose cycloalkane moiety has 3 to 6 carbon atoms; C _1-4 alkyl in which the aryl moieties are the same or different, C _1-4 alkoxy as substitution 1
3 to 3, optionally an aryl moiety having 6 to 10 carbon atoms and an alkylene moiety having 1 to 4 carbon atoms; a nitrogen atom, a sulfur atom or oxygen in the ring. Saturated or unsaturated 5 to 6 having one atom
Heterocyclic acyl group consisting of member rings; alkoxycarbonyl group having 2 to 7 carbon atoms as a whole; 1 to 3 C _1-4 alkyl and C _1-4 alkoxy having the same or different aryl moieties as substituents The aralkyl moiety may be an aralkyloxycarbonyl group having 7 to 9 carbon atoms.

R is optimally an aryl part which may have one C _1-4 alkyl as a substituent, and an aryl part has an aromatic acyl group having 6 to 10 carbon atoms; a cycloalkane part has 3 carbon atoms. An alicyclic acyl group having from 1 to 6; an aryl portion is phenyl and an alkylene portion has 1 to 4 carbon atoms.
Examples thereof include an araliphatic acyl group having 4 to 6 carbon atoms; an alkoxycarbonyl group having 4 to 6 carbon atoms as a whole; and an aralkyloxycarbonyl group having an aralkyl portion having 7 to 9 carbon atoms.

When R represents an acyl group, the meaning of the acyl group also includes those described below.

That is, the aforementioned acyl, alkoxycarbonyl, or aralkyloxycarbonyl is bonded to an amino acid residue to have an acid amide bond in the group, for example, an acyl group such as N-benzoylglycyl or N-benzoylglycylglycyl, Is included.

Therefore, the compound having the general formula (I) also includes oligopeptide compounds such as N-benzoylglycylglycine and N-benzoylglycylglycylglycine.

In the general formula (I), when X represents an alkylene group, for example, methylene, ethylidene, ethylene, propylidene, 1-methylethylidene, 1-methylethylene, trimethylene, butylidene, 2-methylpropylidene, 1
-Methylpropylidene, 1,2-dimethylethylene, 1-
Ethylethylene, 1-methyltrimethylene, 2-methyltrimethylene, tetramethylene, pentylidene, 3-methylbutylidene, 2-methylbutylidene, 2,2-dimethylpropylidene, 1-ethylpropylidene, 1,2- Dimethylpropylidene, 1-propylethylene, 1- (1-
Methylethyl) ethylene, 1-ethyl-2-methylethylene, 1-ethyltrimethylene, 2-ethyltrimethylene, 1,3-dimethyltrimethylene, 1-methyltetramethylene, 2-methyltetramethylene, pentamethylene,
Hexylidene, 4-methylpentylidene, 3-methylpentylidene, 2-methylpentylidene, 1-methylpentylidene, 2-ethylbutylidene, 1-ethylbutylidene, 1,3-dimethylbutylidene, 1,2- Dimethylbutylidene, 3,3-dimethylbutylidene, 2,3-dimethylbutylidene, 1-butylethylene, 1-methyl-2-propylethylene, 1,2-diethylethylene, 1-methyl-1-propylethylene, 2-propyltrimethylene, 1-ethyl-3-methyltrimethylene, 1-ethyltetramethylene, 2-ethyltetramethylene, 1,3-dimethyltetramethylene, 1-methylpentamethylene, 2-methylpentamethylene, 3- Methyl pentamethylene, hexamethylene, heptylidene, 5-methylhexylidene, 4-methylhexylidene, 3-methyl Hexylidene, 1-Methylhexylidene, 3-Ethylpentylidene, 1-Ethylpentylidene, 4,4-Dimethylpentylidene, 2,4-Dimethylpentylidene, 1,2-Dimethylpentylidene, 1-Propylbutylidene , 2-ethyl-1-methylbutylidene, 1-ethyl-2-methylbutylidene, 1,2,2-trimethylbutylidene, 1,2,3-trimethylbutylidene, 1
-Pentylethylene, 1-butyl-2-methylethylene, 1-ethyl-2-propylethylene, 1-butyl-
1-methylethylene, 1-ethyl-1-propylethylene, 1-butyltrimethylene, 2-butyltrimethylene, 1,3-diethyltrimethylene, 1-methyl-3-propyltrimethylene, 1-propyltetramethylene, Two
-Propyltetramethylene, 1-ethyl-4-methyltetramethylene, 3-ethyl-1-methyltetramethylene, 1-ethylpentamethylene, 3-ethylpentamethylene, 1,3-dimethylpentamethylene, 1-methylhexamethylene , 3-methylhexamethylene, heptamethylene, octylidene, 6-methylheptylidene, 4-methylheptylidene, 2-methylheptylidene, 1-methylheptylidene, 4-ethylhexylidene, 3-ethyl. Hexylidene, 2-ethylhexylidene, 1-ethylhexylidene, 3,5-dimethylhexylidene, 4,5-dimethylhexylidene, 2,4-dimethylhexylidene, 1,5-dimethyl Hexylidene, 1,4-dimethylhexylidene, 2-
Propylpentylidene, 1-Propylpentylidene, 2
-Ethyl-4-methylpentylidene, 3-ethyl-2-
Methylpentylidene, 3-ethyl-1-methylpentylidene, 1-ethyl-3-methylpentylidene, 3-methyl-1-propylbutylidene, 2-methyl-1-propylbutylidene, 1-ethyl-2, 3-dimethylbutylidene, 1,2-diethylbutylidene, 1-hexylethylene, 1-methyl-2-pentylethylene, 1-butyl-
2-ethylethylene, 1,2-dipropylethylene, 1-
Pentyl trimethylene, 2-pentyl trimethylene, 1
-Butyl-3-methyltrimethylene, 1-butyl-2-
Methyl trimethylene, 1-ethyl-3-propyltrimethylene, 1,2-dimethyl-3-propyltrimethylene,
1-butyltetramethylene, 1-methyl-4-propyltetramethylene, 1-propylpentamethylene, 3-propylpentamethylene, 2-ethyl-4-methylpentamethylene, 1-ethylhexamethylene, 3-ethylhexamethylene, Examples thereof include alkylene groups having 1 to 8 carbon atoms, preferably 1 to 5 carbon atoms, such as 1,3-dimethylhexamethylene, 1-methylheptamethylene, 4-methylheptamethylene, and octamethylene.

The above alkylene groups may be the same or different and may have 1 to 4, preferably 1 to 2 substituents, and these substituents include, for example, a hydroxy group; C _1- such as methoxy and ethoxy. ₄ alkyl-substituted hydroxy group; C _6-14 aryl-substituted hydroxy group such as phenoxy, 4-tolyloxy, 4-hydroxyphenoxy, 4-aminophenoxy, 4-methoxyphenoxy (1-5 aryl groups are the same or different, Preferably substituted with 1 to 3 C _1-4 alkyl, hydroxy, amino, C _1-4 alkoxy); benzyloxy, 4-methylbenzyloxy, 4
A C _7-9 aralkyl-substituted hydroxy group such as -hydroxybenzyloxy, 4-aminobenzyloxy, 4-methoxybenzyloxy (the aryl part is the same or different and is 1 to 5, preferably 1 to 3 C _{1 -4} alkyl,
Hydroxy, amino, optionally substituted with C _1-4 alkoxy); mercapto group; C such as methylthio, ethylthio
_1-4 alkyl-substituted mercapto group; C _6-14 such as phenylthio, 4-tolylthio, 4-hydroxyphenylthio, 4-aminophenylthio, 4-methoxyphenylthio
Aryl-substituted mercapto group (aryl groups may be the same or different and may be substituted with 1 to 5, preferably 1 to 3, C _1-4 alkyl, hydroxy, amino, C _1-4 alkoxy); benzylthio C _7-9 aralkyl-substituted mercapto group such as 4-methylbenzylthio, 4-hydroxybenzylthio, 4-aminobenzylthio, 4-methoxybenzylthio (1 to 5 aryl groups are the same or different, preferably 1 to 3, C _1-4 alkyl,
Hydroxy, amino, optionally substituted by C _1-4 alkoxy); Carboxy-C _1-4 alkyl-substituted mercapto group such as carboxymethylthio, carboxyethylthio; Amino group; Mono such as methylamino, dimethylamino Or a di-C _1-4 alkyl-substituted amino group; a mono- or di-C _6-14 aryl-substituted amino such as phenylamino, 4-tolylamino, 4-hydroxyphenylamino, 4-aminophenylamino, 4-methoxyphenylamino A group (the aryl part may be the same or different and may be substituted with 1 to 5, preferably 1 to 3, C _1-4 alkyl, hydroxy, amino, C _1-4 alkoxy); benzylamino, 4 -Methylbenzylamino, 4-hydroxybenzylamino, 4-aminobenzylamino, 4-methoxybenzylamino Una mono- or di -C _7-9 aralkyl substituted amino group (the aryl portion is one to five identical or different, preferably 1 to 3, the C _1-4 alkyl,
Hydroxy, amino, optionally substituted with C _1-4 alkoxy); an amino group mono- or di-substituted with a group having the same meaning as R above; phenyl, 4-tolyl, 4-hydroxyphenyl,
C such as 4-aminophenyl, 4-methoxyphenyl
_6-14 aryl group (aryl moieties may be the same or different and may be substituted with 1 to 5, preferably 1 to 3, C _1-4 alkyl, hydroxy, amino, C _1-4 alkoxy); Carboxyl group; Like methylsulfinyl, ethylsulfinyl
C _1-4 alkylsulfinyl group; C _1-4 such as methylsulfonyl and ethylsulfonyl
Alkylsulfonyl group; pyrrolyl, imidazolyl, pyrazolyl, pyridyl,
And a heterocyclic group such as pyrazinyl, pyrimidinyl, pyridazinyl, indoridinyl, indolyl, indazolyl; and the like.

X is preferably an alkylene group having 1 to 5 carbon atoms, and the alkylene groups are the same or different and are 1 to 2
May have a substituent, as the substituent, a hydroxy group; C _1-4 alkyl-substituted hydroxy group; C
_6-14 aryl-substituted hydroxy group (aryl part may be the same or different and may be substituted with 1 to 3 C _1-4 alkyl, hydroxy, amino, C _1-4 alkoxy); C _7-9
Aralkyl-substituted hydroxy group (aryl moieties may be the same or different and may be substituted with 1 to 3 C _1-4 alkyl, hydroxy, amino, C _1-4 alkoxy); mercapto group; C _1-4 alkyl substitution Mercapto group; C _6-14 aryl-substituted mercapto group (aryl moieties are the same or different
To 3 C _1-4 alkyl, hydroxy, amino, C _1-4 alkoxy may be substituted); C _7-9 aralkyl-substituted mercapto group (aryl moieties are the same or different and are 1 to 3 C _1-4 alkyl, hydroxy, amino, optionally substituted with C _1-4 alkoxy); carboxy-C _1-4 alkyl-substituted mercapto group; amino group; mono- or di-C
_1-4 alkyl-substituted amino group; mono- or di-C _6-14 aryl-substituted amino group (aryl groups are the same or different and are substituted with 1 to 3 C _1-4 alkyl, hydroxy, amino, C _1-4 alkoxy) _Optional ); mono or di-C _7-9
Aralkyl-substituted amino groups (aryl moieties are the same or different and are 1 to 3 C _1-4 alkyl, hydroxy, amino,
C _1-4 alkoxy may be substituted); an amino group mono- or di-substituted with a group having the same meaning as R described above; C _6-14
Aryl group (aryl groups are the same or different and are 1 to 3
C _1-4 alkyl, hydroxy, amino, C _1-4 alkoxy may be substituted); carboxyl group; heterocyclic group.

X is optimally an alkylene group having 1 to 5 carbon atoms, and the alkylene groups are the same or different and are 1 to 2
May have one substituent, and these substituents include a hydroxy group; a C _1-4 alkyl-substituted hydroxy group; a mercapto group; a C _1-4 alkyl-substituted mercapto group; an amino group; a mono- or di- C _1-4 alkyl-substituted amino group; amino group mono- or di-substituted with a group having the same meaning as R described above; C
_6-14 Aryl group (Aryl moieties are the same or different 1
To 3 C _1-4 alkyl, hydroxy, amino, C _1-4 alkoxy may be substituted); carboxyl group;
A heterocyclic group can be mentioned.

In the amino acid derivative having the general formula (I), glycine, β-alanine, 4-aminobutanoic acid, 5-aminovaleric acid, 6-aminohexanoic acid,
8-aminooctanoic acid, alanine, 2-aminobutanoic 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-diaminobutanoic acid, ornithine,
Lysine, hydroxylysine, arginine, N ^[delta] - dimethyl-ornithine, N ^[delta] - methyl lysine, cysteine,
Methionine, ethionine, S-carboxymethyl cystine, S-benzyl cystine, methionine sulfoxide, ethionine sulfoxide, methionine sulfone, cysteic acid, serine, O-methylserine, threonine,
O-methyl threonine, homoserine, ethoxynin, 3
-Methoxyvaline, 3-phenylserine, 3-methylphenylalanine, histidine, tryptophan, 2-methylalanine, 2-methylserine, 2-hydroxyisoleucine, 2-methylmethionine, 2-ethylphenylglycine, 3-aminobutanoic acid, 3- Examples thereof include amino-4-methylvaleric acid, 3-amino-3-phenylpropionic acid, 3-amino-2-hydroxypropionic acid, and 4-amino-3-hydroxybutanoic acid derivatives.

More optimally, glycine, β-alanine, 4-aminobutanoic acid, 5-aminovaleric acid, 6-aminohexanoic acid, 8-aminooctanoic acid, alanine, norvaline, valine, leucine, isoleucine, norleucine, phenylglycine, phenylalanine. , Ornithine, lysine,
N ^δ -dimethylornithine, methionine, ethionine,
O-methylserine, O-methylthreonine, ethoxynin, 3-methoxyvaline, 3-phenylserine, 3-methylphenylalanine, histidine, 2-methylalanine, 2-methylserine, 2-hydroxyisoleucine,
2-ethylphenylglycine, 3-aminobutanoic acid, 3
-Amino-4-methylvaleric acid, 3-amino-3-
Examples thereof include phenylpropionic acid derivatives.

More particularly optimally, β-alanine, 4-aminobutanoic acid, 5-aminovaleric acid, 6-aminohexanoic acid,
Examples thereof include derivatives of alanine, valine, leucine, norleucine, phenylglycine, phenylalanine, methionine and histidine.

When the amino acid derivative having the general formula (I) is an oligopeptide compound such as a dipeptide type or a tripeptide type, these are preferably β-alanine, 4-
A compound in which amino acids consisting of aminobutanoic acid, 5-aminovaleric acid, 6-aminohexanoic acid, alanine, valine, leucine, norleucine, phenylglycine, phenylalanine, methionine and histidine are appropriately combined (for example, leucylglycine, glycyl-β-alanine). ,
Glycylalanine, valylalanine, leucylalanine, glycylvaline, alanylvaline, leucylvaline, valylleucine, phenylalanylleucine, histidylleucine, glycylphenylalanine, alanylphenylalanine, leucylphenylalanine, glycylmethionine, valylmethionine, gly Silhistidine, alanyl valyl glycine, glycyl alanyl valine, glycyl phenylalanyl leucine, glycyl glycyl histidine, etc.) can be mentioned.

Examples of the amino acid derivative having the general formula (I) of the present invention include the following compounds.
Although these compounds have D-form, L-form, DL-form, etc., any of them can be used.

1. Glycine derivative 1-1. N-hexanoylglycine 2. N-heptanoylglycine 3. N-octanoylglycine 4. N-nonanoylglycine 5. N-decanoylglycine 6. N- (4-toluoyl) Glycine 7. N- (4-methoxybenzoyl) glycine 8. N- (1-naphthoyl) glycine 9. N- (1-phenyl-1-cyclohexanecal
Bonyl) glycine 10. N-[(2,2-diphenyl) acetyl] glycy
N 11. N-[(2-phenyl-2-cyclopentyl
A) acetyl] glycine 12. N-n-butoxycarbonylglycine 13. N-octanoylleucylglycine 14. N-benzoylleucylglycine 15. Nn-butoxycarbonylleucylglycine
16. N-octanoylalanylvalylglycine 17. N-benzoylalanylvalylglycine 18. N-cyclohexanecarbonylalanylvalyl
Luglycine 19. Nn-butoxycarbonylalanylvalyl
Glycine 2. β-alanine derivative 2-1. N-hexanoyl-β-alanine 2. N-heptanoyl-β-alanine 3. N-octanoyl-β-alanine 4. N-nonanoyl-β-alanine 5. N- ( 4-toluoyl) -β-alanine 6. N- (4-methoxybenzoyl) -β-alani
7. N- (3-hydroxy-2-naphthoyl) -β
-Alanine 8. N- (1-phenyl-1-cyclopentanecal
Bonyl) -β-alanine 9. N-[(2,2-diphenyl) acetyl] -β-
Alanine 10. N- (3-phenylpropionyl) -β-a
Lanine 11. N- (4-phenylbutyryl) -β-alani
12.N- (4-methoxyphenylacetyl) -β
-Alanine 13.Nt-butoxycarbonyl-β-alanine 14.N-benzyloxycarbonyl-β-alani
15. N- (4-methoxybenzyloxycarbonyl)
) -Β-alanine 16. N- (4-methylbenzyloxycarboni
) -Β-alanine 17. N- (α-methylbenzyloxycarboni
) -Β-alanine 18. N-benzoylglycyl-β-alanine 19. N- (1-naphthoyl) glycyl-β-ara
Nin 20. N-cyclohexanecarbonylglycyl-β
-Alanine 21. N-benzyloxycarbonylglycyl-β
-Alanine 22. N-benzoyl-β-alanine 3. 4-aminobutanoic acid derivative 3-1. N-hexanoyl-4-aminobutanoic acid 2. N-heptanoyl-4-aminobutanoic acid 3. N-benzoyl-4-aminobutanoic acid 4. N- (4-toluoyl) -4-aminobutanoic acid 5. N- (3-methoxybenzoyl) -4-amino
Butanoic acid 6. N-cyclopentanecarbonyl-4-aminobutane
Tanoic acid 7. N-cyclohexanecarbonyl-4-aminobutane
Tanoic acid 8. N- (1-phenyl-4-cyclopropanal
Bonyl) -4-aminobutanoic acid 9. N- (1-phenyl-1-cyclopentanecal
Bonyl) -4-aminobutanoic acid 10.N-phenylacetyl-4-aminobutanoic acid 11.N- (3-phenylpropionyl) -4-a
Minobutanoic acid 12. N- (4-tolylacetyl) -4-aminobu
Tanoic acid 13. N-nicotinyl-4-aminobutanoic acid 14. Nn-butoxycarbonyl-4-aminobutanoic acid
Tanoic acid 15. N-benzyloxycarbonyl-4-amino
Butanoic acid 16. N- (3-phenylpropoxycarbonyl)
-4-Aminobutanoic acid 17. N- (α-methylbenzyloxycarbonyl
) -4-Aminobutanoic acid 18. N- (1-naphthoyl) -4-aminobutane
Acid 4. 5-Aminovalerianic acid derivative 4-1. Nn-butyryl-5-aminovalerianic acid 2. N-isobutyryl-5-aminovalerianic acid 3. N-valeryl-5-aminovalerianic acid 4. N- Isovaleryl-5-aminovalerianic acid 5. N-hexanoyl-5-aminovalerianic acid 6. N-benzoyl-5-aminovalerianic acid 7. N- (3-toluoyl) -5-aminovaleria
Acid 8. N- (2-methoxybenzoyl) -5-amino
Valerianic acid 9. N-cyclopentanecarbonyl-5-aminova
Lerianic acid 10. N-cyclohexanecarbonyl-5-amino
Valerian acid 11. N- (1-phenyl-1-cyclopropaneca
Rubonyl) -5-aminovalerianic acid 12. N- (1-phenyl-1-cyclohexaneca)
Lubonyl) -5-aminovalerianic acid 13. N-phenylacetyl-5-aminovaleria
Acid 14. N-[(2-phenyl-2-methyl) acetyl
] -5-Aminovalerianic acid 15.N-nicotinyl-5-aminovaleric acid 16.N- (2-thiophenecarbonyl) -5-a
Minovalerianic acid 17. N- (2-Furoyl) -5-aminovaleria
Acid 18. N-isopropoxycarbonyl-5-amino
Valerian acid 19. N-pentyloxycarbonyl-5-amino
Valerian acid 20. N-benzyloxycarbonyl-5-amino
Valerian acid 21. N- (4-methoxybenzyloxycarbonyl
) -5-Aminovalerianic acid 22. N- (4-methylbenzyloxycarbonyl)
) -5-Aminovalerianic acid 23. N- (4-hydroxyphenylacetyl)-
5-Aminovalerianic acid 24. N- (N'-methylnicotinyl) -5-ami
Novarelian acid 5. 6-aminohexanoic acid derivative 5-1. N-acetyl-6-aminohexanoic acid 2. N-propionyl-6-aminohexanoic acid 3. Nn-butyryl-6-aminohexanoic acid 4. N-isobutyryl-6-aminohexanoic acid 5. N-isovaleryl-6-aminohexanoic acid 6. N-hexanoyl-6-aminohexanoic acid 7. N-acryloyl-6-aminohexanoic acid 8. N-methacryloyl-6- Aminohexanoic acid 9. N-crotonoyl-6-aminohexanoic acid 10. N-propioroyl-6-aminohexanoic acid 11. N-benzoyl-6-aminohexanoic acid 12. N- (2-toluoyl) -6-aminohexahexa
Acid 13. N- (4-methoxybenzoyl) -6-ami
Nohexanoic acid 14. N- (4-aminobenzoyl) -6-amino
Hexanoic acid 15. N- (1-naphthoyl) -6-aminohexa
Acid 16. N-cyclobutanecarbonyl-6-amino
Xanthic acid 17. N-cyclopentanecarbonyl-6-amino
Hexanoic acid 18. N-cyclohexanecarbonyl-6-amino
Hexanoic acid 19. N-phenylacetyl-6-aminohexane
Acid 20. N- (3-phenylpropionyl) -6-a
Minohexanoic acid 21. N-nicotinyl-6-aminohexanoic acid 22. N- (2-thiophenecarbonyl) -6-a
Minohexanoic acid 23. N-methoxycarbonyl-6-aminohexa
Acid 24. N-ethoxycarbonyl-6-aminohexa
Acid 25. Nn-butoxycarbonyl-6-amino
Xanthic acid 26. N-pentyloxycarbonyl-6-amino
Hexanoic acid 27. N-benzyloxycarbonyl-6-amino
Hexanoic acid 28. N-phenethyloxycarbonyl-6-ami
Nohexanoic acid 29. N- (3-phenylpropoxycarbonyl)
-6-Aminohexanoic acid 30. N- (4-methoxybenzyloxycarbonyl)
) -6-Aminohexanoic acid 31. N- (4-methylbenzyloxycarbonyl)
) -6-Aminohexanoic acid 32. N- (α-methylbenzyloxycarbonyl)
) -6-Aminohexanoic acid 33. N- (N'-methylnicotinyl) -6-ami
Noxanoic acid 34. N- (4-chlorophenylacetyl) -6-
Aminohexanoic acid 6. 8-aminooctanoic acid derivative 6-1. N-acetyl-8-aminooctanoic acid 2. N-valeryl-8-aminooctanoic acid 3. N-benzoyl-8-aminooctanoic acid 4. N- (3-Hydroxybenzoyl) -8-ami
Nooctanoic acid 5. N- (3-sulfobenzoyl) -8-amino
Cutanic acid 6. N-Cyclopropanecarbonyl-8-amino
Cutanic acid 7. N- (4-aminophenylacetyl) -8-a
Minooctanoic acid 8. N-methoxycarbonyl-8-aminooctane
Acid 9. N-n-propoxycarbonyl-8-amino
Cutanic acid 10. N-isopropoxycarbonyl-8-amino
Octanoic acid 11. N-benzyloxycarbonyl-8-amino
Octanoic acid 12. N- (4-hydroxybenzyloxycarbo
Nyl) -8-aminooctanoic acid 13.N- (N'-methylnicotinyl) -8-ami
Nooctanoic acid 14. N- (6-hydroxynicotinyl) -8-a
Minooctanoic acid 7. Alanine derivative 7-1. N-valeryl alanine 2. N-hexanoyl alanine 3. N-benzoyl alanine 4. N- (4-methoxybenzoyl) alanine 5. N- (1-naphthoyl) alanine 6 .N- (1-phenyl-1-cyclopropanecal
Bonyl) alanine 7. N-phenylacetylalanine 8. Nn-butoxycarbonylalanine 9. N-benzyloxycarbonylalanine 10. N- (α-methylbenzyloxycarbonyl)
Ru) alanine 11. N-octanoylglycylalanine 12. N-benzoylglycylalanine 13. Nn-butoxycarbonylglycylalani
14. N-benzoylvalylalanine 15. N- (4-toluoyl) valylalanine 16. N-cyclopentanecarbonylvalylalani
N 17. N-cyclohexanecarbonylvalylalani
18. N-benzyloxycarbonyl valylalani
N. N-benzoyl leucyl alanine 20. N- (4-methoxybenzoyl) leucyl a
Lanine 21. Nn-butoxycarbonylleucylalani
22. N-benzyloxycarbonyl leucylara
Nin 23. N- (2-bromobenzoyl) alanine 8. 2-Aminobutanoic acid derivative 8-1. N-pivaloyl-2-aminobutanoic acid 2. N-hexanoyl-2-aminobutanoic acid 3. N-heptanoyl-2-aminobutane Acid 4. N-benzoyl-2-aminobutanoic acid 5. N- (4-toluoyl) -2-aminobutanoic acid 6. N- (1-phenyl-1-cyclopentanecal
Bonyl) -2-aminobutanoic acid 7. N-[(2,2-diphenyl) acetyl] -2-
Aminobutanoic acid 8. N-ethoxycarbonyl-2-aminobutanoic acid 9. N-benzyloxycarbonyl-2-aminobutanoic acid
Tanoic acid 10. N- (4-methoxybenzyloxycarbonic acid
) -2-Aminobutanoic acid 9. Norvaline derivative 9-1. N-valeryl norvaline 2. N-decanoyl norvaline 3. N-benzoyl norvaline 4. N- (3-toluoyl) norvaline 5. N- ( 3-Sulfobenzoyl) norvaline 6. N-cyclohexanecarbonylnorvaline 7. N- (1-phenyl-1-cyclohexanecal)
Bonyl) norvaline 8. N-[(2-phenyl-2-ethyl) acetyl
L] norvaline 9. N- (4-methoxyphenylacetyl) norva
Phosphorus 10. N- (2-Pyrazincarbonyl) norvaline 11. N-Benzyloxycarbonylnorvaline 12. N- (4-Methylbenzyloxycarbonyl)
Le) norvaline 10. valine derivative 10-1. N-propionylvaline 2. N-n-butyrylvaline 3. N-isobutyrylvaline 4. N-valerylvaline 5. N-acryloylvaline 6. N-methacryloylvaline 7. N -Crotonoylvaline 8. N-propioloylvaline 9. N- (2-methoxybenzoyl) valine 10. N- (4-n-butoxybenzoyl) valine 11. N-cyclopentanecarbonylvaline 12.N-cyclohexanecarbonyl. Valine 13. N- (1-phenyl-1-cyclopentaneca
Lubonyl) valine 14.N-phenylacetylvaline 15.N-nicotinylvaline 16.N- (2-piperidinecarbonyl) valine 17.N-ethoxycarbonylvaline 18.N-isopropoxycarbonylvaline 19.Nt-butoxycarbonylvaline. 20. N-pentyloxycarbonylvaline 21. N-benzyloxycarbonylvaline 22. N- (4-tolylacetyl) valine 23. N-benzoylglycylvaline 24. N- (4-toluoyl) glycylvaline 25. N- ( 1-naphthoyl) glycylvaline 26. N-cyclopentanecarbonylglycylvally
27. N-n-butoxycarbonylglycylvaline 28. N-octanoylalanylvaline 29. N-benzoylalanylvaline 30. N- (4-toluoyl) alanylvaline 31.N- (4-aminobenzoyl) alanylvalin
32. N- (1-naphthoyl) alanylvaline 33.N-cyclohexanecarbonylalanylvalin
34. N-phenylacetylalanylvaline 35. N-benzyloxycarbonylalanyl valin
36. N-benzoylleucylvaline 37. N-benzoylglycylalanylvaline 38. N- (4-toluoyl) glycylalanylvaline
Phosphorus 39. N- (1-naphthoyl) glycylalanilva
Phosphorus 40. N-cyclopentanecarbonylglycylara
Nilvaline 41. Nn-butoxycarbonylglycylalani
Luvaline 42. N-benzyloxycarbonylglycylara
Nilvaline 43. N- (N'-methylnicotinyl) valine 44. N- (3-fluorobenzoyl) valine 45. N-benzoylvaline 46. Nt-butoxycarbonylvaline 11. Leucine derivative 11-1. N- n-butyryl leucine 2. N-isovaleryl leucine 3. N-benzoyl leucine 4. N- (4-n-butylbenzoyl) leucine 5. N- (2-hydroxybenzoyl) leucine 6. N- (3- Sulfobenzoyl) leucine 7. N-cyclopentanecarbonylleucine 8. N-cyclohexanecarbonylleucine 9. N- (1-phenyl-1-cyclopropanecal
Bonyl) leucine 10. N-phenylacetyl leucine 11. N-nicotinyl leucine 12. N-ethoxycarbonyl leucine 13. N-benzyloxycarbonyl leucine 14. N- (4-hydroxyphenylacetyl) ro
Isine 15. N-benzoylvalylleucine 16. N-ethoxycarbonylvalylleucine 17. N-benzoylphenylalanylleucine 18. N-phenylacetylphenylalanylleucine.
Syn 19. N-benzyloxycarbonyl phenylara
Nylleucine 20. N-benzoylhistidylleucine 21. N- (4-toluoyl) histidylleucine 22. N- (4-hydroxybenzoyl) histidi
Leleucine 23. N- (1-naphthoyl) histidyl leucine 24. N-benzoylglycylphenylalanylro
Isin 25. N- (4-methoxybenzoyl) glycyl sulf
Phenylalanyl leucine 26. N-phenylacetylglycyl phenylara
Nylleucine 27. Nt-butoxycarbonylleucine 12. Isoleucine derivative 12-1. N-valeryl isoleucine 2. N-pivaloyl isoleucine 3. N-octanoyl isoleucine 4. N-benzoyl isoleucine 5. N- (3 -Hydroxybenzoyl) isoleucine
6. N-cyclopentanecarbonyl isoleucine 7. N-cyclohexanecarbonyl isoleucine 8. N- (1-phenyl-1-cyclopentacarbo
Nyl) isoleucine 9. N-phenylacetylisoleucine 10. N-methoxycarbonylisoleucine 11. N-n-propoxycarbonylisoleucine 12. N-isopropoxycarbonylisoleucine 13. N-benzyloxycarbonylisoleucine 13. Norleucine derivative 13-1. N-propionyl norleucine 2. N-valeryl norleucine 3. N-pivaloyl norleucine 4. N-nonanoyl norleucine 5. N-benzoyl norleucine 6. N- (4-hydroxybenzoyl) -norleucine
Syn 7. N-cyclohexanecarbonylnorleucine 8. N- (1-phenyl-1-cyclopropanecal
Bonyl) norleucine 9. N-[(2-phenyl-2-ethyl) acetyl
Norleucine 10.N-ethoxycarbonylnorleucine 11.Nn-propoxycarbonylnorleucine 12.Nt-butoxycarbonylnorleucine 13.N-benzyloxycarbonylnorleucine 14.phenylglycine derivative 14-1.N -Propionylphenylglycine 2.N-n-butyrylphenylglycine 3.N-isobutyrylphenylglycine 4.N-valerylphenylglycine 5.N-hexanoylphenylglycine 6.N-heptanoylphenylglycine 7.N -Octanoylphenylglycine 8. N-nonanoylphenylglycine 9. N-decanoylphenylglycine 10. N-crotonoylphenylglycine 11. N- (4-toluoyl) phenylglycine 12. N- (4-hydroxybenzoyl) Phenyl
Glycine 13. N- (4-methoxybenzoyl) phenyl group
Lysine 14. N- (4-aminobenzoyl) phenyl glycol
Syn 15. N- (4-sulfobenzoyl) phenyl glycol
Syn 16.N- (1-naphthoyl) phenylglycine 17.N-Cyclopropanecarbonylphenylglyc
Syn 18. N-cyclohexanecarbonylphenylglycine
Syn 19. N-nicotinylphenylglycine 20. N- (2-thiophenecarbonyl) phenyl
Glycine 21. N- (2-furoyl) phenylglycine 22. N-methoxycarbonylphenylglycine 23. N-ethoxycarbonylphenylglycine 24. Nn-butoxycarbonylphenylglycine
25. N-benzyloxycarbonylphenyl glycol
Syn 26. N- (4-methoxybenzyloxycarbonyl)
27) N- (4-chlorobenzoyl) phenylglycine
Syn 28. N-acetylphenylglycine 29. N-benzoylphenylglycine 15. Phenylalanine derivative 15-1. N-propylonylphenylalanine 2. N-n-butyrylphenylalanine 3. N-isobutylphenylalanine 4. N-valeryl Phenylalanine 5. N-hexanoylphenylalanine 6. N-heptanoylphenylalanine 7. N-octanoylphenylalanine 8. N-nonanoylphenylalanine 9. N-decanoylphenylalanine 10. N-crotonoylphenylalanine 11. N- (4- Toluoyl) phenylalanine 12. N- (4-hydroxybenzoyl) phenyl
Alanine 13. N- (4-methoxybenzoyl) phenyla
Lanine 14. N- (4-aminobenzoyl) phenylara
Nin 15. N- (4-sulfobenzoyl) phenylara
Nin 16. N- (1-naphthoyl) phenylalanine 17. N-Cyclopropanecarbonylphenylalan
Nin 18. N-cyclohexanecarbonylphenylara
Nin 19. N-nicotinylphenylalanine 20. N- (2-thiophenecarbonyl) phenyl
Alanine 21. N- (2-furoyl) phenylalanine 22. N-methoxycarbonylphenylalanine 23. N-ethoxycarbonylphenylalanine 24. Nn-butoxycarbonylphenylalani
25. N-benzyloxycarbonylphenylara
Nin 26. N- (4-methoxybenzyloxycarbonyl)
) Phenylalanine 27.N-benzoylglycyl Phenylalanine 28.N- (4-hydroxybenzoyl) glycyl
Phenylalanine 29. N- (1-naphthoyl) glycylphenyla
Lanine 30. N-ethoxycarbonylglycylphenylene
Lanine 31. N-benzyloxycarbonylglycylphe
Nylalanine 32. N-benzoylalanine Phenylalanine 33. N- (4-toluoyl) alanylphenylene
Lanine 34. N- (4-hydroxybenzoyl) alanyl
Phenylalanine 35. N- (4-aminobenzoyl) alanylfe
Nylalanine 36. N- (1-naphthoyl) alanylphenylene
Lanine 37. N-benzyloxycarbonylalanylfe
Nylalanine 38. N-benzoylleucyl Phenylalanine 39. N- (4-hydroxybenzoyl) leucyl
Phenylalanine 40. N-cyclohexanecarbonylleucylphe
Nylalanine 41. N-benzyloxycarbonyl leucylphe
Nylalanine 42. N-acetylphenylalanine 43. N-benzoylphenylalanine 16. Tyrosine derivative 16-1. N-benzoyltyrosine 2. N- (3-methoxybenzoyl) tyrosine 3. N-cyclohexanecarbonyltyrosine 4. N-benzyloxycarbonyl Tyrosine 5. N-phenethyloxycarbonyl tyrosine 17. O-methyl tyrosine derivative 17-1. N-acetyl-O-methyl tyrosine 2. N-propioroyl-O-methyl tyrosine 3. N-benzoyl-O-methyl tyrosine 4. N- (4-aminobenzoyl) -O-methylthio
Rosin 5. N- (1-phenyl-1-cyclopentanecal
Bonyl) -O-methyltyrosine 6. N- (1-phenyl-1-cyclohexanecal
Bonyl) -O-methyltyrosine 7. N-methoxycarbonyl-O-methyltyrosine 8. N-benzyloxycarbonyl-O-methylthio
Rosin 9. N-phenethyloxycarbonyl-O-methyl
Tyrosine 18. Aspartic acid derivative 18-1. N-heptanoyl aspartic acid 2. N-decanoyl aspartic acid 3. N- (4-hydroxybenzoyl) asparagi
Acid 4. N- (3-hydroxy-2-naphthoyl) as
Paraginic acid 5. N- (1-phenyl-1-cyclopentanecal
Bonyl) aspartic acid 6. N- (1-phenyl-1-cyclohexanecal
Bonyl) aspartic acid 7. N-benzyloxycarbonyl aspartic acid 8. N- (4-methoxybenzyloxycarbonyl)
A) Aspartic acid 19. Glutamic acid derivative 19-1. N-nonanoylglutamic acid 2. N- (4-methoxybenzoyl) glutamic acid 3. N- (1-naphthoyl) glutamic acid 4. N- (1-phenyl-1-cyclo) Pentancal
Bonyl) glutamic acid 5. N-benzyloxycarbonyl glutamic acid 6. N-benzoylglutamic acid 20. 4-carboxyglutamic acid derivative 20-1. N-heptanoyl-4-carboxyglutamine
Acid 2. N- (4-methoxybenzoyl) -4-carbo
Xyglutamic acid 3. N- (1-naphthoyl) -4-carboxyglut
Tamamic acid 4. N- (1-hydroxy-2-naphthoyl) -4
-Carboxyglutamic acid 5. N-phenylacetyl-4-carboxygluta
Minic acid 21.3-Methylaspartic acid derivative 21-1. N-octanoyl-3-methylaspartic acid 2. N- (4-methoxybenzoyl) -3-methyl
Aspartic acid 3. N-[(2-phenyl-2-cyclopentyl)
Acetyl] -3-methylaspartic acid 22. 2-aminoadipic acid derivative 22-1. N-hexanoyl-2-aminoadipic acid 2. N-benzoyl-2-aminoadipic acid 3. N- (4-toluoyl)- 2-aminoadipine
Acid 4. N- (1-naphthoyl) -2-aminoadipine
Acid 5. N- (4-phenylbutyryl) -2-aminoa
Dipic acid 6. N-Phenylacetyl-2-aminoadipic acid 7. N-Ethoxycarbonyl-2-aminoadipine
Acid 23. 2-Aminopimelic acid derivative 23-1. N-valeryl-2-aminopimelic acid 2. N-benzoyl-2-aminopimelic acid 3. N- (3-phenylpropionyl) -2-ami
Nopimelic acid 4. N-methoxycarbonyl-2-aminopimelin
Acid 5. N-ethoxycarbonyl-2-aminopimelin
Acid 6. N-benzyloxycarbonyl-2-aminopi
Melinic acid 24. 2-Aminosuberic acid derivative 24-1. Nn-butyryl-2-aminosuberic acid 2. N-benzoyl-2-aminosuberic acid 3. N- (1-naphthoyl) -2-aminosuberin
Acid 4. N- (2-phenyl-2-cyclopentyl)-
2-Aminosuberic acid 5. N-methoxycarbonyl-2-aminosuberine
Acid 6. N-n-propoxycarbonyl-2-aminos
Berylic acid 25. 3-Hydroxyaspartic acid derivative 25-1. N- (1-naphthoyl) -3-hydroxyas
Paraginic acid 2. N- (1-phenyl-1-cyclohexanecal
Bonyl) -3-hydroxyaspartic acid 3. N-[(2-phenyl-2-ethyl) acetyl
] -3-Hydroxyaspartic acid 26. 3-Hydroxyglutamic acid derivative 26-1. N- (1-naphthoyl) -3-hydroxyglutate
Tamamic acid 2. N- (1-phenyl-1-cyclohexanecal
Bonyl) -3-hydroxyglutamic acid 3. N-[(2,2-diphenyl) acetyl] -3-
Hydroxyglutamic acid 27. 2,3-diaminopropionic acid 27-1. N^α-Hexanoyl-2,3-diaminopropio
Acid 2. N^α-(4-n-Butylbenzoyl) -2,3-
Diaminopropionic acid 3. N^α, N^β-Dibenzoyl-2,3-diaminopro
Pionic acid 4. N^α-(1-phenyl-1-cyclopentanker
Rubonyl) -2,3-diaminopropionic acid 5.N^α-[(2-Phenyl-2-ethyl) acetyl
] -2,3-Diaminopropionic acid 28.2,4-Diaminobutanoic acid derivative 28-1.N^α-(1-naphthoyl) -2,4-diaminobu
Tanoic acid 2. N^α, N^γ-Dibenzoyl-2,4-diaminobutane
Acid 3. N^α-(1-Phenyl-1-cyclopetancal
Bonyl) -2,4-diaminobutanoic acid 4. N^α-[(2-Phenyl-2-ethyl) acetyl
] -2,4-Diaminobutanoic acid 29. Ornithine derivative 29-1. N^α-Benzyloxycarbonyl ornithine 2. N^α-(4-methoxybenzyloxycarboni
Le) Ornithine 3. N^α, N^δ-Dibenzyloxycarbonyl orni
Chin 4. N^α, N^δ-Di (4-methoxybenzyloxyca
Lubonyl) Ornithine 5. N^α-Valeryl ornithine 6. N^α, N^δ-Dihexanoyl ornithine 7. N^α, N^δ-Dibenzoylornithine 8. N^α-Cyclohexane carbonyl ornithine 9. N^α, N^δ-Di-t-butoxycarbonyl orni
Chin 30. Lysine derivative 30-1. N^α-Benzyloxycarbonyl lysine 2. N^α-(4-methoxybenzyloxycarboni
Le) Lysine 3. N^α, N^ε-Dibenzyloxycarbonyl lysine 4. N^α, N^ε-Di (4-methoxybenzyloxyca
Lubonyl) lysine 5. N^α, N^ε-Dioctanoyl lysine 6. N^α-Benzoyl lysine 7. N^α, N^ε-Dicyclopropane carbonyl lysine 8. N^α, N^ε-Diethoxycarbonyl lysine 9. N^α, N^ε-Dibenzoyl lysine 31.5-hydroxylysine derivative 31-1. N^α-(4-Toluoyl) -5-hydroxyl
Jin 2. N^α, N^δ-Dibenzoyl-5-hydroxylidi
N 3. N^α-(1-phenyl-1-cyclopentanker
Lubonyl) -5-hydroxylysine 4. N^α-[(2-Phenyl-2-cyclopentyl
L) acetyl] -5-hydroxylysine 5. N^α-(1-phenyl-1-cyclopentanker
Lubonyl) -5-hydroxylysine 6. N^α-[(2-Phenyl-2-cyclopentyl
) Acetyl] -5-hydroxylysine 32. Arginine derivative 32-1. N^α-Heptanoyl arginine 2. N^α-(2-Methoxybenzoyl) arginine 33. N^δ-Dimethylornithine derivative 33-1. N^α-Hivaloyl-N^δ-Dimethylornithine 2. N^α-Octanoyl-N^δ-Dimethyl ornithic
N 3. N^α-Acryloyl-N^δ-Dimethyl ornithic
N 4. N^α-Benzoyl-N^δ-Dimethylornithine 5. N^α-(4-hydroxybenzoyl) -N^δ−
Dimethyl ornithine 6. N^α-Cyclohexanecarbonyl-N^δ-Jime
Cilornithine 7. N^α-[(2-Phenyl-2-methyl) acetyl
] -N^δ-Dimethylornithine 8. N^α-Ethoxycarbonyl-N^δ-Dimethylo
Lunitine 9. N^α-N-butoxycarbonyl-N^δ-Zimechi
Luornithine 10. N^α-Benzyloxycarbonyl-N^δ-J
Methyl ornithine 34. N^ε-Methyllysine derivative 34-1. N^α-Hexanoyl-N^ε-Methyllysine 2. N^α-Nonanoyl-N^ε-Methyllysine 3.N^α-Acryloyl-N^ε-Methyllysine 4. N^α-Benzoyl-N^ε-Methyllysine 34-5. N^α-(4-n-Butoxybenzoyl) -N^ε
-Methyllysine 6. N^α-(3-Sulfobenzoyl) -N^ε-Met
Luridine 7. N^α-Cyclobutanecarbonyl-N^ε-Methyl
Lysine 8. N^α-Cyclohexanecarbonyl-N^ε-Met
Luridine 9. N^α-Phenylacetyl-N^ε-Methyllysine 10. N^α-N-propoxycarbonyl-N^ε-M
Tyridine 11.N^α-Isopropoxycarbonyl-N^ε-M
Tyridine 12. N^α-Benzyloxycarbonyl-N^ε-M
Tyryridine 35. Cysteine derivative 35-1. N-phenylacetylcysteine 36. Methionine derivative 36-1. N-valerylmethionine 2. N-acryloylmethionine 3. N-methacryloylmethionine 4. N-benzoylmethionine 5. N- ( 4-toluoyl) methionine 36-6. N- (4-methoxybenzoyl) methionine 7. N- (4-aminobenzoyl) methionine 8. N-cyclopentanecarbonylmethionine 9. N-cyclohexanecarbonylmethionine 10. N- (1 -Phenyl-1-cyclohexane carbonate
Lubonyl) methionine 11. N-phenylacetylmethionine 12. N-[(2-phenyl-2-methyl) acetyl
Methionine 13. N-methoxycarbonylmethionine 14. N-ethoxycarbonylmethionine 15. N-n-butoxycarbonylmethionine 16. N-benzyloxycarbonylmethionine 17. N- (4-methylbenzyloxycarbonyl)
) Methionine 18. N-benzoylglycylmethionine 19. N- (4-methoxybenzoyl) glycylme
Thionine 20. N-benzyloxycarbonylglycylmethyi
Onine 21. N-benzoylvalylmethionine 22. N-Cyclopentanecarbonylvalylmethionine
Nin 23. N-ethoxycarbonylvalylmethionine 37. Ethionine derivative 37-1. Nn-butyrylethionine 2. N-benzoylethionine 3. N- (4-toluoyl) ethionine 4. N- (3-toluoyl) Ethionine 5. N- (4-n-Butylbenzoyl) ethionine 6. N- (4-Hydroxybenzoyl) ethionine 7. N- (4-Aminobenzoyl) ethionine 8. N- (3-Sulfobenzoyl) ethionine 9.N -(1-Phenyl-1-cyclopropanecal
Bonyl) ethionine 10. N-phenylacetylethionine 11. N-methoxycarbonylethionine 12. N-ethoxycarbonylethionine 13. N-benzyloxycarbonylethionine 14. N- (4-methoxybenzyloxycarbonyl)
Le) ethionine 15. N-cyclohexanecarbonylethionine 38. S-carboxymethylene cysteine derivative 38-1. N-propionyl-S-carboxymethyl cis
Thein 2. N-acryloyl-S-carboxymethyl cis
Thein 3. N-benzoyl-S-carboxymethyl system
In 4. N- (4-toluoyl) -S-carboxymethyi
Lucysteine 5. N- (4-methoxybenzoyl) -S-carbo
Xymethyl cysteine 6. N- (4-n-butoxybenzoyl) -S-carb
Ruboxymethyl cysteine 7. N-cyclohexanecarbonyl-S-carboxy
Cimethyl cysteine 8. N- (1-phenyl-1-cyclopentanecar
Bonyl) -S-carboxymethyl cysteine 9. N- (^α-Methylbenzyloxycarbonyl)
-S-carboxymethyl cysteine 39. S-benzyl cysteine derivative 39-1. N-benzoyl-S-benzyl cysteine 2. N- (4-hydroxybenzoyl) -S-ben
Dilcysteine 3. N- (3-sulfobenzoyl) -S-benzyl
Cysteine 4. N-cyclopropanecarbonyl-S-benzyl
Cysteine 5. N-methoxycarbonyl-S-benzyl system
In 39-6. N-ethoxycarbonyl-S-benzyl system
In 7. Nn-propoxycarbonyl-S-benzyl
Cysteine 8. N- (4-hydroxybenzyloxycarboni
) -S-benzyl cysteine 40 methionine sulfoxide derivative 40-1. N- (4-toluoyl) -methionine sulfoxide
Sid 2. N-pentyloxycarbonylmethionine sulfone
Foxoxide 3. N-benzyloxycarbonylmethionine sulphate
Phoxide 41. Ethionine sulfoxide derivative 41-1. N-benzoylethionine sulfoxide 2. N-benzyloxycarbonylethionine sulfone
Phoxide 42. Methionine sulfone derivative 42-1. N- (1-naphthoyl) methionine sulfone 2. N-cyclohexanecarbonylmethionine sulfone
Phone 3. N-pentyloxycarbonylmethionine sulfone
Hong 43. Cysteine acid derivative 43-1. N- (4-toluoyl) cysteic acid 2. N- (1-naphthoyl) cysteic acid 3. N- (3-hydroxy-2-naphthoyl) cis
Teynic acid 4. N- (1-phenyl-1-cyclohexanecal
Bonyl) cysteic acid 44. Serine derivative 44-1. N-octanoylserine 2. N-benzoylserine 3. N- (3-toluoyl) serine 4. N- (4-methoxybenzoyl) serine 5. N- (1 -Naphthoyl) serine 6. N- (1-phenyl-1-cyclopentanecar
Bonyl) serine 7. N-benzyloxycarbonyl serine 8. N- (^α-Methylbenzyloxycarbonyl)
Serine 45. O-methylserine derivative 45-1. N-valeryl-O-methylserine 2. N-benzoyl-O-methylserine 3. N-cyclohexanecarbonyl-O-methylserine
Phosphorus 4. N-phenylacetyl-O-methylserine 5. N-[(2-phenyl-2-methyl) acetyl
] -O-Methylserine 6. N- (3-phenylpropionyl) -O-methyl
Lucerin 7. N-phenethyloxycarbonyl-O-methyl
Serine 46. Threonine derivative 46-1. N-hexanoylthreonine 2. N-nonanoylthreonine 3. N-benzoylthreonine 4. N- (3-hydroxy-2-naphthoyl) tre
Onine 5. N-cyclohexanecarbonylthreonine 6. N-[(2,2-diphenyl) acetyl] threo
Nin 7. Nn-butoxycarbonylthreonine 8. N-benzyloxycarbonylthreonine 9. N- (4-methoxybenzyloxycarbonyl)
) Threonine 47. O-methyl threonine derivative 47-1. Nn-butyryl-O-methyl threonine 2. N- (4-methoxybenzoyl) -O-methyl
Threonine 3. N- (1-naphthoyl) -O-methylthreoni
4. N- (1-phenyl-1-cyclopentanecal
Bonyl) -O-methylthreonine 5. N-ethoxycarbonyl-O-methylthreoni
6. N- (3-phenylpropoxycarbonyl)-
O-Methylthreonine 48. Homoserine derivative 48-1. N-heptanoylhomoserine 2. N-benzoylhomoserine 3. N- (3-methoxybenzoyl) homoserine 4. N-[(2-phenyl-2-cyclopentyl)
Acetyl] homoserine 5. N- (4-hydroxybenzyloxycarbonyl
) Homoserine 6. N- (4-methylbenzyloxycarbonyl)
Homoserine 49. Ethoxynin derivative 49-1. N-benzoylethoxynyl 2. N- (4-n-butoxybenzoyl) ethoxy
Nin 3. N-cyclohexanecarbonylethoxynin 4. N-methoxycarbonylethoxynin 50. 3-methoxyvaline derivative 50-1. N-isovaleryl-3-methoxyvaline 2. N- (4-toluoyl) -3-methoxyvaline 3. N- (1-naphthoyl) -3-methoxyvaline 4. N-cyclopentanecarbonyl-3-methoxy
Valine 5. N-cyclohexanecarbonyl-3-methoxy
Valine 6. N-methoxycarbonyl-3-methoxyvaline 7. N-ethoxycarbonyl-3-methoxyvaline 51. 3-phenylserine derivative 51-1. N-propionyl-3-phenylserine 2. N- (4-amino Benzoyl) -3-phenyl
Serine 3. N- (1-naphthoyl) -3-phenylserine 4. N-benzoyl-3-phenylserine 5. N-cyclohexanecarbonyl-3-phenyl
Serine 6. N-phenylacetyl-3-phenylserine 7. N-methoxycarbonyl-3-phenylserine 8. Nn-butoxycarbonyl-3-phenylserine
Phosphorus 9. N-benzyloxycarbonyl-3-phenyl
Serine 10. N- (^α-Methylbenzyloxycarboni
) -3-Phenylserine 52.3-Methylphenylalanine derivative 52-1. N-acetyl-3-methylphenylalanine 2. N-hexanoyl-3-methylphenylalani
3.N-benzoyl-3-methylphenylalanine 4.N- (4-aminobenzoyl) -3-methylphenone
Phenylalanine 5. N- (3-sulfobenzoyl) -3-methylphosphine
Phenylalanine 6. N-cyclobutanecarbonyl-3-methylphene
Nylalanine 7. N-cyclopentanecarbonyl-3-methylphosphine
Phenylalanine 8. N-phenylacetyl-3-methylphenylene
Lanine 9. N-isopropoxycarbonyl-3-methylphosphine
Phenylalanine 10. Nn-butoxycarbonyl-3-methylphenyl
Phenylalanine 11. N- (4-aminobenzyloxycarboni
) -3-Methylphenylalanine 53. Histidine derivative 53-1. N-acetylhistidine 2. N-hexanoylhistidine 3. N-acryloylhistidine 4. N-methacryloylhistidine 5. N-benzoylhistidine 6. N- (4) -Toluoyl) histidine 7. N- (4-methoxybenzoyl) histidine 8. N- (4-n-butoxybenzoyl) histidi
9. N-cyclopentanecarbonylhistidine 10. N-cyclohexanecarbonylhistidine 11. N- (1-phenyl-1-cyclopentaneca
Lubonyl) histidine 12.N-phenylacetylhistidine 13.N-[(2-phenyl-2-cyclopentyl
) Acetyl] histidine 14. N- (4-methoxybenzyloxycarbonyl)
Histidine 15. N-benzoylglycyl Histidine 16. N- (4-n-butylbenzoyl) glycyl
Histidine 17. N-phenylacetylglycyl histidine 18. N-Ethoxycarbonylglycyl histidine 19. N-benzyloxycarbonylglycyl histidine
Tidine 20. N-benzoylglycylglycyl histidine 21. N-ethoxycarbonylglycylglycyl histidine
Stidine 22. N-benzyloxycarbonylglycylglycyl
Silhistidine 23. Nt-butoxycarbonylhistidine 54. Tryptophan derivative 54-1. N- (4-hydroxybenzoyl) tryptoph
Anne 2. N-benzyloxycarbonyltryptophan 55.2-Methylalanine derivative 55-1. N-propionyl-2-methylalanine 2. N-benzoyl-2-methylalanine 3. N- (3-toluoyl) -2- Methylalanine 4. N- (3-methoxybenzoyl) -2-methyl
Alanine 5. N-cyclobutanecarbonyl-2-methylara
Nin 6. N-phenylacetyl-2-methylalanine 7. N-phenethyloxycarbonyl-2-methyl
Alanine 56. 2-Methylserine derivative 56-1. N-valeryl-2-methylserine 2. N-octanoyl-2-methylserine 3. N-benzoyl-2-methylserine 4. N- (2-toluoyl) -2-methylserine 5 .N- (4-methoxybenzoyl) -2-methyl
Serine 6. N- (1-naphthoyl) -2-methylserine 7. N-Cyclopentanecarbonyl-2-methylserine
Phosphorus 8. N-[(2,2-diphenyl) acetyl] -2-
Methylserine 9. N-pentyloxycarbonyl-2-methylseline
Phosphorus 57. 2-hydroxyisoleucine derivative 57-1. N-valeryl-2-hydroxyisoleucine 2. N-heptanoyl-2-hydroxyisoleucine
3. N-benzoyl-2-hydroxyisoleucine 4. N- (4-n-butylbenzoyl) -2-hydr
Roxyisoleucine 5. N- (3-hydroxy-2-naphthoyl) -2
-Hydroxyisoleucine 6. N-Cyclohexanecarbonyl-2-hydroxy
Cysoleucine 7. N-phenylacetyl-2-hydroxyisolo
Isine 58. 2-Methylmethionine derivative 58-1. N-hexanoyl-2-methylmethionine 2. N-benzoyl-2-methylmethionine 3. N- (4-hydroxybenzoyl) -2-methyi
Lumethionine 4. Nn-Bropoxycarbonyl-2-methylmeth
Thionine 5. N-isopropoxycarbonyl-2-methylmeth
Thionine 59.2-Ethylphenylglycine derivative 59-1. N-acetyl-2-ethylphenylglycine 2. N-n-butyryl-2-ethylphenylglycy
3. N- (3-sulfobenzoyl) -2-ethyl sulfone
Phenylglycine 4. N-ethoxycarbonyl-2-ethylphenyl
Glycine 5. N-n-propoxycarbonyl-2-ethyl sulfone
Phenylglycine 60 3-Aminobutanoic acid derivative 60-1. N-hexanoyl-3-aminobutanoic acid 2. N-benzoyl-3-aminobutanoic acid 3. N- (4-methoxybenzoyl) -3-amino
Butanoic acid 4. N- (3-sulfobenzoyl) -3-aminobutane
Tanoic acid 5. N- (1-naphthoyl) -3-aminobutanoic acid 6. N-Cyclopropanecarbonyl-3-aminobutane
Tanoic acid 7. N-[(2,2-diphenyl) acetyl] -3-
Aminobutanoic acid 8. N- (4-phenylbutyl) -3-aminobutanoic acid
Acid 9. N- (^α-Methylbenzyloxycarbonyl)
-3-Aminobutanoic acid 61. 3-Amino-4-methylvaleric acid derivative 61-1. N-valeryl-3-amino-4-methylvaleri
Anoic acid 2. N-isovaleryl-3-amino-4-methylva
Lerianic acid 3. N-heptanoyl-3-amino-4-methylva
Lerianic acid 4. N-benzoyl-3-amino-4-methylvale
Lianic acid 5. N- (3-toluoyl) -3-amino-4-me
Tylvalerian acid 6. N- (3-sulfobenzoyl) -3-amino-
4-Methylvaleric acid 7. N- (1-naphthoyl) -3-amino-4-me
Tylvaleric acid 8. N-phenylacetyl-3-amino-4-methyi
Luvalerian acid 9. N- (3-phenylpropionyl) -3-ami
No-4-methylvalerianic acid 10. N-n-butoxycarbonyl-3-amino-
4-Methylvalerianic acid 11. N- (4-methylbenzyloxycarbonic acid
) -3-Amino-4-methylvaleric acid 62. 3-Amino-3-phenylpropionic acid derivative 62-1. Nn-butyryl-3-amino-3-phenyl
Propionic acid 2. N-valeryl-3-amino-3-phenylpro
Pionic acid 3. N-benzoyl-3-amino-3-phenylpropionate
Ropionic acid 4. N- (4-aminobenzoyl) -3-amino-
3-phenylpropionic acid 5. N-cyclopropanecarbonyl-3-amino-
3-Phenylpropionic acid 6. N-Cyclobutanecarbonyl-3-amino-3
-Phenylpropionic acid 7. N-Cyclopentanecarbonyl-3-amino-
3-Phenylpropionic acid 8. N-methoxycarbonyl-3-amino-3-fluoro
Phenylpropionic acid 9. Nn-propoxycarbonyl-3-amino-
3-Phenylpropionic acid 10. Nn-butoxycarbonyl-3-amino-
3-Phenylpropionic acid 11. N- (4-aminobenzyloxycarbonic acid
) -3-Amino-3-phenylpropionic acid 63. 3-Amino-2-hydroxypropionic acid derivative 63-1. N-valeryl-3-amino-2-hydroxypropionate
Ropionic acid 2. N-heptanoyl-3-amino-2-hydroxy
Cipropionic acid 3. N-benzoyl-3-amino-2-hydroxy
Propionic acid 4. N- (3-methoxybenzoyl) -3-amino
2-Hydroxypropionic acid 5. N-cyclohexanecarbonyl-3-amino-
2-Hydroxypropionic acid 6. N-benzyloxycarbonyl-3-amino-
2-Hydroxypropionic acid 7. N- (3-phenylpropoxycarbonyl)-
3-Amino-2-hydroxypropionic acid 64.4-Amino-3-hydroxybutanoic acid derivative 64-1. N-isobutyryl-4-amino-3-hydroxy
Cibutanoic acid 2. N-decanoyl-4-amino-3-hydroxy
Butanoic acid 3. N-benzoyl-4-amino-3-hydroxy
Butanoic acid 4. N- (2-toluoyl) -4-amino-3-hi
Droxybutanoic acid 5. N- (3-aminobenzoyl) -4-amino-
3-hydroxybutanoic acid 6. N- (1-phenyl-1-cyclohexanecal
Bonyl) -4-amino-3-hydroxybutanoic acid 7. N-[(2-phenyl-2-methyl) acetyl
] -4-Amino-3-hydroxybutanoic acid 8. N- (4-methoxybenzyloxycarbonic acid
) -4-Amino-3-hydroxybutanoic acid Also, the amino acid derivative having the general formula (I) is
It can also be used as a pharmacologically acceptable salt. like this
Examples of the salt include alkali such as sodium and potassium
Metal salts, alkaline earth metal salts such as calcium, and
Magnesium salt, aluminum salt, iron salt, zinc salt, copper
Metal salts such as salt, nickel salt and cobalt salt;
Nium salts; organic acids such as glucosamine and galactosamine
Mint salt can be given.

The preparation of the present invention is manufactured by a conventional method. That is, the amino acid derivative having the general formula (I) itself has low solubility in water. Therefore, in the dispersion liquid of the amino acid derivative having the general formula (I), a metal compound such as sodium hydroxide or potassium hydroxide or a pharmaceutically usable amine derivative (for example, amino sugar such as ammonia, glucosamine, or galactosamine) is added. Add an aqueous solution to pH 6 ~
Adjust within the range of 9 and dissolve. The desired formulation is obtained by adding the cephalosporin type antibiotic cephaloridine to this solution. The formulation may further be lyophilized if desired. When the amino acid derivative having the general formula (I) is added to cephaloridine,
The amount is not particularly limited, but is preferably 1/10 to 4 by weight ratio.
Double. In addition, the administration method is usually preferably intravenous administration.

Next, the present invention will be described in more detail with reference to Examples and Experimental Examples, but the present invention is not limited thereto.

Example 1 5 g of N ^ε -benzoylaminocaproic acid was weighed and then dispersed in 80 ml of water. A 1N-sodium hydroxide aqueous solution was gradually added to this dispersion to dissolve N ^ε -benzoylaminocaproic acid. The pH at this time was 7-8. Then, cephaloridine [(6R-trans) -1-
{[2-Carboxy-8-oxo-7-[(2-thienylacetyl) amino] -5-thia-1-azabicyclo [4.2.0] oct-2-en-3-yl] methyl} pyridinium hydroxide After dissolving 5 g, the total amount was 100 ml.

Example 2 Using cephaloridine and other amino acid derivatives having the above general formula (I) and using the same procedure as in Example 1, the desired formulations shown in Table 2 were obtained.

Experimental Example 1 3 ml / kg of the preparation obtained in Example 1 was added to a rabbit (body weight: about 3 kg).
The amount (that is, cephaloridine 150 mg / kg + N ^ε -benzoylaminocaproic acid 150 mg / kg) was infused through the ear vein. For comparison, a preparation containing no N ^ε -benzoylaminocaproic acid in Example 1 was obtained, and this preparation was injected into rabbits as described above. As a result of autopsy of the kidneys of both rabbits one week later, the rabbits to which the formulation without N ^ε -benzoylaminocaproic acid was administered showed tissue changes in the kidney, but the formulation with N ^ε -benzoylaminocaproic acid was administered. The rabbits showed no histological changes in the kidney.

Experimental Example 2 Similar experiments were carried out on formulations using cephaloridine and other amino acid derivatives having the general formula (I). The results are shown in Table 2.

In addition, each symbol in the column of effects of Table 2 is: improved to the extent that no tissue change in the kidney is observed: improved to the extent that there is almost no tissue change in the kidney +: tissue change in the kidney Shows a significant improvement.

As is clear from Table 2, when the amino acid derivative having the above general formula (I) was blended, a markedly better effect was exhibited than when it was not blended.

Claims (1)

[Claims] 1. Cephaloridine has the formula (In the formula, R represents an acyl group, an alkoxycarbonyl group or an aralkyloxycarbonyl group. X represents an alkylene group which may have a substituent.)
An antibacterial cephaloridine preparation with reduced nephrotoxicity, which comprises blending an amino acid derivative having