JPS6193117A - Penem-or carbapenem-type antibiotic preparation having mitigated side effect - Google Patents

Abstract

PURPOSE:To prepare the titled drug preparation having mitigated side effects such as renal toxicity, by compounding a penem-type or carbapenem-type antibiotic substance with an ornithine or lysine derivative. CONSTITUTION:The penem-type or carbapenem-type antibiotic substance such as the compound of formula I [X is CH2, S, -C(CH3)H-, etc.; R<1> is -CH2CH3, -CH2CH2F, group of formula II, etc.] is compounded with an ornithine or lysine derivative such as the compound of formula III (n is 3 or 4; R<2> and R<3> are H, acyl or alkoxycarbonyl; R<2> and R<3> are not H at the same time) to obtain the titled drug preparation having mitigated side effect. The amount of the ornithine or lysine derivative is preferably 1/10-4pts.wt. per 1pt. of the antibiotic substance. The renal toxicity of the substance can be mitigated remarkably.

Description

DETAILED DESCRIPTION OF THE INVENTION R nem type and carbapenem type antibiotics are known to exhibit excellent antibacterial activity. However, nephrotoxicity is commonly observed when these high doses are injected intravenously or intramuscularly.

Therefore, the present inventors completed the present invention as a result of intensive research to reduce nephrotoxicity.

The present invention consists of incorporating an ornithine or lysine derivative into a penem or carbapenem antibiotic.

The penem- or carbapenem-type antibiotic of the present invention is represented by the following formula, for example.

vinegar.

R1 is -CH2CHs --CH2CHzF t ~
N=C-NH2.

Specific examples of the compound having the formula (1) include the following compounds.

Examples of the ornithine or lysine derivatives of the present invention include compounds of the following formula.

During the ceremony.

n represents an integer of 3 or 4.

R2 and R3 are the same or different and represent a hydrogen atom, an acyl group, or an alkoxycarbonyl group (however, this excludes the case where R2 and R3 are both hydrogen atoms).

When R2 and/or R3 represent an acyl group, for example an aliphatic saturated acyl group such as acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, piparoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl; acryloyl, methacryloyl.

Aliphatic unsaturated acyl groups such as crotonoyl, propioloyl; alkyl, hydroxy, alkoxy, amino,
benzoyl optionally having sulfone as a substituent;
Aromatic acyl groups such as naphthoyl; cyclopropanecarbnyl.

Examples include alicyclic acyl groups such as cyclohexanecal.

When R2 and/or R3 represents an alkoxycarzanyl group, for example, methoxycargonyl, ethoxycardenyl, n-propoxycargonyl.

Examples include impropoxycarboxyl, butoxycarbonyl, and pentoxycarbonyl.

Specific examples of compounds having the formula (10) include the following compounds.These compounds include 0-form, 5-form, and DL-form, but any of them can be used. .

1 Acetyl ornithine 2 Propionyl I 3 Butyryl 〃 4 Inbutyryl 〃 5 Valeryl 〃 6 Hexanoyl 〃 7 Heptanoyl ornithine 8 Octanoyl 1 9 Nonanoyl 1 10 Decanoyl 1 11 Crotonoyl 1 12 Benzoyl 1 13 Cyclopronoyl Nyl I°14 Cyclohexanecarbunyl 115 α,δ-Diacetyl 1 16 α,δ-Dideropionyl I 17 α,δ-dibutyryl 1 18 α,δ-diisobutyryl 1 19 α,δ-dipareryl I 20 α,δ-diisovaleryl 1 21 α,δ-dihexanoyl I 22 α , δ-diheptanoyl 1 23 α, δ-dioctanoyl I 24 α, δ-dinonanoyl I 25 α, δ-didecanoyl I 26 α, δ-dicrotonoyl I 27 α, δ-dibenzoylornithine 28 α,
δ-Dicyclopropanecargonyl I29 α, δ-
Dicyclohexanecargonyl I30 α-isobutyryl-δ-benzoyl I31 α-crotonoyl-δ-benzoyl 32 α-cycμpropanecargonyl-δ-inbutyryl 1 33 α-cyclohexanecarbinyl-δ-crotonoyl I 34 α-benzoyl-δ- Isobutyryl I35
α-benzoyl-δ-crotonoyl I36 α-
Pensoyl-δ-cycloprono9cargonyl 〃 37 α-Pensoyl-δ-cyclohexanecargonyl 〃 38 α-Benzoyl-a-acetyl I39 α
-Pensoyl-δ-propionyl 〃Chrysanthemum Methoxycar is L I 41 Ethoxycarbonyl 1 42 Butoxycarbonyl l 43 α,δ-Dimethoxycar is Nyl ornithine 44
α, δ-jetoxylic? Nil I45 α, δ
-Dipoxycargonyl 146 α-methoxycargenyl-δ-ethoxycal? Nyl 1 47 α-Methoxycardenyl-δ-butoxycargonyl 1 48 α-Ethoxycargenyl-δ-Methoxycargenyl 1 49 α-Ptoxycargenyl-δ-Ethoxycargenyl l α-Ethoxycargonyl-δ- Butyryl I51
α-ethoxycarbonyl-δ-crotonoyl I 52 α-ethoxycarbonyl-δ-cyclodeppancalyl 1 α-ethoxycarbonyl-δ-benzoyl I54
α-Glopionyl-δ-ethoxycargonyl I 55 α-pensoyl-δ-ethoxycargonyl I
56 Acetyl Lysine 57 Propionyl 58 Butyryl 59 Isobutyryl I ■ Valeryl 61 Hexanoyl 62 Heptanoyl 63 Octanoyl 64 Nonanoyl 65 Decanoyl 66 Crotonoyl 67 Benzoyl 1 68 cyclopropanecarbonyl I69 cyclohexanecarbonyl I70 αμm diacetyl I 71 α , 1-diglopionyl I 72 αμmdibutyryl 1 73 α,e-diisobutyryl I 74 α,S-dipareryl I 75 α,C-diisovaleryl 1 76 α,ε-dihexanoyl lysine 77 αμm
Diheptanoyl 1 78 αμm dioctanoyl 1 79 α,C-dinonanoyl 1 80 α,ε-zodecanoyl 1 81 α,6-dicrototuyl 1 82 α,C-dibenzoyl I 83 α,g + 9 cyclopronocarboxylic acid
I84 α,g-zocyclohexanecal is L 18
5 α-isobutyryl-ε-crotonoyl 186
α-Inbutyryl-8-benzoyl I87 α-
Crotonoyl-C-benzoyl 188 α-cyclozolonone carbinyl-6-inbutyryl 1 89 α-7 Chlohexanecal? Nyl-i-/rotonoyl 1 90 α-cyclopronocargonyl-e-cyclohexanecargenyl 〃 91 α-cyclohexanecargonyl? Ni-C-benzoyl 1 92 α-benzoyl-C-isobutyryl lysine 93
α-pensoyl-1-crotonoyl I94 α
-pensoyl-ε-kuku EI7'rono arm noncarnyl
〃 95 α-benzoyl-C-cyclohexanecarganyl 〃 96 α-pensoyl-ε-acetyl I97 α
-hensoyl-t-7'ropionyl I98 Methoxycar♂yl 1 99 Ethoxycar? Nyl 1 100 Butoxycaryl 1 101 α,I-dimethoxycarbonyl 1102
αμm Jetoxical? Nil I103 α, e-
Diptoxycargonyl I104 α-Methoxycarbonyl-6-nitoxycargonyl 1 105 α-Methoxycar is nyl e-Butoxycar is nil 1 106 α-Ethoxycar? Niru C-Methoxylic? Niru 〃 107 Is α-butoxycal Nilu C-ethoxycal? Nillysine 108 α-ethoxycargenyl-ε-propionyl 1 109 α-ethoxycargenyl-e-crotonoyl 1 110 α-ethoxycargonyl-e-cyclohexanecargonyl 〃 111 α-ethoxycardenyl-ε-pensoyl 1
112 α-isobutyryl-e-ethoxycarbonyl 1 113 α-peycyyl-8-ethoxycarbonyl In the compound having the general formula (II), n preferably represents an integer of 3 or 4, and R2 and R3 are One side represents a hydrogen atom and the other side represents an acyl group or an alkoxycarbonyl group, or R
2 and R3 are the same or different acyl groups or the same or different alkoxy groups are particularly preferably compounds in which n represents an integer of 3 or 4, and R2 and R3 are the same acyl group or alkoxy A compound that exhibits a carbonyl group.

The formulation of the present invention is manufactured according to conventional methods. That is, ornithine or rinone derivatives themselves have low solubility in water. Therefore, an aqueous solution of an alkali metal compound such as sodium hydroxide, potassium hydroxide or a pharmaceutically usable amine derivative (for example an amino sugar such as ammonia, glucosamine or galactosamine) is added to a dispersion of ornithine or a lysine derivative. - Adjust and dissolve in the range of 6 to 9. A penem-type or carbapenem-type antibiotic is added to this solution, and when the ornithine or rinone derivative is added to the penem-type or carbapenem-type antibiotic, the amount thereof is not particularly limited, but it is preferably 1/10 to 4 in weight ratio. It's double. Furthermore, intravenous administration is usually preferred.

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

Example 1 5 tons of α,C-dibenzoylridine was weighed, and then 8 tons of water was added.
Dispersed over 0m. To this dispersion was gradually added an aqueous solution of IN-sodium hydroxide.

ε-dibenzoyl lysine was dissolved. - at this time is 7~
It was 8. Then, (5R168,8B)-
2-((38)-1-acetoylvirolinone-3
After dissolving 5 t of -ylthio)-6-(1-hydroxyethyl)-2-carbapenem-3-carboxylic acid (compound number 6), the total amount was adjusted to 100+d.

Example 2 Example 1 was repeated using other penem or carbapenem antibiotics and other ornithine or lysine derivatives to obtain the desired formulations listed in Table 2.

In addition, in the table, ornithine or rinone derivatives without any description of D- or L- indicate DL-integrated.

Experimental Example 1 The preparation obtained in Example 1 was administered to domestic rabbits (weight: 3 YU) by smt.
Ay* (i.e. Compound No. 6 antibiotic 150”I/
kll + ct, g-dibenzoylridine 150
9) was injected into the ear vein at 11q/. As a comparison, a preparation without α,ε-dibenzoylridine was obtained in Example 1, and this was injected into rabbits in the same manner as above.

As a result of autopsy of the kidneys of both rabbits one week later, histological changes were observed in the kidneys of the rabbits administered the preparation without α,e-dibenzoylrisine, but those treated with the preparation containing α,ε-nopenzoylrisine. No tissue changes were observed in the kidneys of the rabbits treated with the drug.

Experimental Example 2 Similar experiments were conducted with formulations using other penem- or carbapenem-type antibiotics and other ornithine or lysine derivatives.

The results are shown in Table 2. In addition, penem-type or carbapenem-type antibiotics 5 that do not contain ornithine or lysine derivatives
Tissue changes in the kidneys were observed in all cases where t was administered.

In addition, each sign in the effect column of Table 2 is +1+: Improved to the point that no tissue changes were observed in the kidney. +: Improved to the extent that almost no tissue changes were observed in the kidney. As is clear from Table 2, in which tissue changes in the kidney were greatly improved, when ornithine or Rino/derivatives were blended, the effects were significantly better than when they were not blended.

Patent Issue Hachisankyo Co., Ltd.

Claims (1)

[Claims] An antibiotic preparation with reduced side effects, characterized in that an ornithine or lysine derivative is blended with a penem-type or carbapenem-type antibiotic.