JPS6042399A - Mycoplanecin derivative - Google Patents

Abstract

NEW MATERIAL:A compound shown by the formula (R is amino acid residue or peptide residue containing both at least one liberated basic group, and at least one carboxyl group or protected carboxyl group). EXAMPLE:L-Aspartylneomycoplanecin. USE:An antitubercular agent. PREPARATION:An amino acid or peptide having a basic group or carboxyl group which is protected in case of necessity is condensed with neomycoplanecin to give a neomycoplanecin derivative the amino acid or peptide having a basic group or carboxyl group which is protected in case of necessity is further condensed with the prepared neomycoplanecin, and the protecting group of the basic group or carboxyl group is optionally removed. The condensation process can be carried out by ordinary peptide synthesis (e.g., DCC process, mixed acid anhydride method).

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel mycoplanesin derivatives and pharmacologically acceptable salts thereof.

Conventionally, examples of compounds such as "Mycobranesina l" include:
Formula (wherein R1 represents an α-ketobutyryl-N-methylvalyl group, a hydrogen atom, or an α-hydroxybutyryl-N-methylvalyl group, an yr-1o ``tJmethyl6'' group, or an ethyl group. R represents an isobutyl group or Compounds having a pentyl group (1°) are known (Sho 54-160302, Sho 56-65853, Sho 5).
6-140957 and 56-142250).

However, the above compound is 91m fat-soluble in ether, ethyl acetate, etc.

The present inventors have discovered that the mycoplanesin derivatives shown below are highly active in vivo when they are water-soluble or water-soluble substances in vivo. completed. That is, the feature of the present invention lies in the discovery of a water-bathable mycoplanesin fatty acid. The mycoplanesin attractant of the present invention has strong antibacterial activity against bacteria, especially Mycobacterium tuberculosis. Consequently, the compound No. 4 developed herein can be used for the prevention or treatment of human and animal diseases caused by these bacteria.

The present invention relates to mycoplanesin derivatives having the general formula and their morally acceptable salts.

In the formula, R represents an amino acid residue or a peptide residue having both at least 1111.1 of free basic groups and at least one carboxyl group or a placed carboxyl group.

In addition, the pharmacologically acceptable compounds that can tolerate π1 are monoacid, image plane, inorganic acids such as nitric acid, organic acids such as acetic acid, trifluoroacetic acid, and hydrofluoric acid, sodium, potassium, and calcium. It is possible to open the joints, etc.

The mycoplanesin inducer of the present invention is a product 1 of the present invention.
It is a water-soluble substance that has a monobasic group and a carboxyl group (H holding (may be -!), or is converted into a water-soluble substance in vivo, and is thus water-soluble in conventional mycoplanesin compounds. Compared to the previous mycobrane compound, which imparts sex to PC, it has 1 l of bile compared to the IFi compound.
JF is less likely to be excreted, and therefore its use in the body has become even more difficult.

In the compound of the above formula (Ill fL), R represents at least one free basic group and a small number of carboxyl groups or conjugated carboxyl groups.
If it is an amino acid residue or a peptide paper hexadecimal that has +, there is no special traction.

Here's one! the amino acid or peptide used i,'l
'i-amino acid] (Amino acids include α-amino acid, β-amino acid,
Amino acids, including r-amino acids, are used without particular limitation.

For example, aliphatic amino acids such as glycine, alanine, valine, leucine, monoamino monocarboxylic acid amino 6 such as -soleucine, β-aminopropion, and γ-amine; .

Sulfur-containing amino acids such as cysteine, cystine, and methionine, amphoteric amino acids such as monoaminodicarboxylic acids such as asparachynic acid and glutamine, and bases of monocarboxylic acids having diamino or amine and guanido groups such as lysine and arginine. amino acids, diaminodicarboxylic acids such as alpha, epsilon-diaminopimelic acid,
Aminoffi+ with an aromatic nucleus! Finally, phenylglycine, phenylalanine, tyrosine, and histidine, tryptophan, proline, and oxyproline 7 can be identified as amino acids that have the amino acids.

In particular, monoaminocarboxylic acids such as glycine and valine, sulfur-containing amino acids such as cysteine, monoaminodicarboxylic acids such as asparagine and curtamine, diaminocarboxylic acids such as lysine and arginine,
Amino acids selected from monocarboxylic acids having amine and quanide groups, amino acids having an aromatic nucleus such as phenylalanine, complex amino acids such as liptophan) are preferred as the amino acids of the peptide constituents. Yes.

In addition, when R is amino 1, one carboxyl group is neomycoplanen (item 1 (note 2)), R1 is a hydrogen atom, upper (2 is an ethyl group, R is (Isobutyl group compound (hereinafter the same)), it must be an amino acid with at least two carboxyl groups.When R is a peptide residue, one of the peptide components At least 2 amino acids i+b+
Any amino acid having a carboxyl group may be used.

The following compounds can be selected as target compounds of J according to the present invention.

1 L-aspartyl neomycoplanesin 2, D-glutamyl neomycoplanesin 3 α, ε-diaminohimeryl neomycoplanesin 4 β-methyl-L-aspartyl neomycoplanesin 5 β-benzyl-D- Aspartyl neomycoplanesin 6 β-L-Aspartyl neomycobranesin O 1-D-glutamyl neomycoplanesin 8 α-Methyl-β-L-aspartyl neomycoplanesin 9 α-Benzyl-γ-D-cure Tamyl neomycoplanesin 10, L-glycyl-L-aspartyl neomycoplanesin 1, 1. D-75nyl-D-glutamyl neomycoplanesin +2. L-valyl-β-L-aspartyl-omycoplanesin 13, L-leucyl-γ-methyl-L-glutamyl neomycoplanesin/14, L-inleucyl-α-methyl-β-L-aspartyl neomycoplanesin 15. TJ-seryl-L-aspartyl neomycoplanesin +6. L-threonyl-D-glutamyl neomycoplanesin 17, L-methy3-β-L-aspartyl neomycoplanesin 18, L-ornithine-γ-benzy-L-glutamyl neomycoplanesin 19, L-glycyl α-methyl -β-L-aspartylneomycoplanesin 20, L-phenylalanyl-L-aspartylneomycoplanesin 21, L-tyrosyl-β-L-aspartylneomycobranesin 72, L-histidyl -L-aspartylneomycosilanesin 23, L-tritophil-L-glutamylneomycoplanesin 74, L-fluoryl-L-aspartylneomycobranesin 25, L-oxyfluoryl-L-gluta Tamirneomycogranesin 2B. D-Aspartyl-D-IJ Silneomycobranesin 27,'l-butyloxycarbonyl-1)-Aspartyl-D-IJ Silneomycobranesin 28
β-D-7 subaltyl~lLI7 silneme mycoplanesin 29, t-phthyloxy carbonyl-alpha-pivaloyloxymethyl-β~D-aspartyl-D-lysylneomycobranesin 30, t-phthyloxycarbonyl-β-y' h)ly
-D-aspartyl-D-lysylneomycoplanesin/31, D-phenylcrisyl-D~aspartylneomycoplanesin 32, t-phthyloxycarbonyl-D-phenylcrisyl-D-aspartylneomycoplanesin Syn 33 D-phenylcrisyl-β-methyl-D-aspartyl neomycoplanesin 34, D-phenylcrisyl-β-D-aspartyl neomycoplanesin 35, D-arginyl-D-aspartyl neomycoplanesin Mycoplanesin 36, N-α-trifluoroacetyl-D-arginyl-D-aspartyl neomygobranesin 37, N-α-trifluoroacetyl-D-arginyl-β-benzyl-D-aspartylneomyco Planesin 38, N-α-trifluoroacetyl-1]-alkynyl-//-D-aspartylneomycoplanesin 39, L-aspartyl-N-methyl-L-valylneomycoplanesin 40 β-benzyl- L-aspartyl-N-methyl-
L-valylneomycobranesin/41 β-L-aspartyl-N-methyl-L-valylneomycoplanesin 42, α-L-glutamyl-N-methyl-L-noculylneomycobranesin 43, r-methyl- α-L-glucumyl-N-methyl-L-valylneomycoplanesin 44.7-L-glutami/L, -N-methy/l/-L-no<liluneomycofranesin 45 α, and monodiaminobimeli L-N-methyl to L-valylneomycoplanesin 46 L-asparty)b -D-phenylglycylneomycoplanesin/4T, β-benzyl-L-aspartyl-D-phenylglycylneomycoplanesin 48 β -L-aspartyl-D-phenylcrysyl neomycoplanesin/49 α-methyl-β-L-aspartyl-D-phenylglycylneomycoplanesin 150, D-aspartyl-D-)liftophilneomycoplanesin 51, β -benzyl-D-aspartyl-D-trigtophylneomycoplanesin 52 β-1) -7 spartyl-D, -)liftophilneomycoplanesin 53, L-aspartyl-L-histidylneomycoplanesin Syn54.8-(glutathione-8')-I,-7steinyl neomycobranesin 55, Nt-butyloxycarbonyl-S-(glutathione-8)-L-cysteinyl neomycobranesin 56 , D-phenylalanyl-L-phenylalanylcrisyl-D-arginyl-D-aspartylneomycoplanesin 5γ, D-valyl-L-lysyl-yinleufluor-
D-tyrosyl-D-noenylglycyl L-7 subalthylneomycoplanene 7no5B, L-alanyl-b-seryl-D-glutamylneomycoplanesin 59.1)-floryl-L-ornithine-L-threonyl-L -cysteinyl-D-7 Subarthyl neomycoplanesin 60, L-leucyl-L-driftyl-L-glutamyl neomycoplanesin 61, t-fluoroxycarbonyl-D-phenylgrin-D-aspartyl-139 Silneomycofuranesin 62 t-butyloxycarbonyl-I-hybaloyloxycarbonyl-α-D-aspardyl-D-ridyliomycobranesi/e3. t-Butyloxycarbonyl-γ-pivaloyloxy7methyl-α-L-curl-myl-D-lysyl neomycoplanesin 64, penzyloxycarbonyl-α-pivaloyloxymethyl-γ-D-glutamyl-L-lysyl neo Mycoplanesin and these drugs JJli 1st revised answer 1 in one corner.

For example, mycoplanesin sieve d-1 of the present invention can be produced by the following method.

That is, (1) a step of condensing neomycobranesin with an amino acid with a basic group and a carboxyl group preserved as desired, or a tJ dipeptide; Step 9 of condensing amino acids or peptides with protected basic groups and carboxyl groups, step 9 of removing the protecting groups of basic groups or carboxyl groups as necessary; By combining them arbitrarily! 6 will be completed.

In detail, the above-mentioned (1) and (2) are converted into IjkL by a conventional condensation reaction. In the amino acids or peptides used in the condensation step, it is generally desirable to retain reactive groups other than carboxyl groups or amino groups that are open to the reaction. Here, J, H^ basic groups are set as 119 groups, or 1 or 11 are benzyloxycarbonyl, t-
Butyloxycarbonyl, biphenylpropyloxycarbonyl, and 'TNcf-nido groups can be used as nitro, tosyl, and hinoki group h1 → formyl groups.

For example, methyl, ethyl, t-butyl, benzyl, pivaloyloxymethyl, etc. can be substituted for the carboxyl group.

In particular, pivaloyloxymethyl is a preferred 6ψ group because it is easily removed in vivo.

The reaction in the condensation step is carried out according to a conventional method.For example, a method using dicyclohexylcarbodiimide, a method using a mixed acid anhydride, a condensation method using a l1lt silicate Amaru system, etc. i! These include a method in which an i-no-lide is added every 1 month, a raw ester method in which a 4-dimethylaminopyridine cloth is added every 4 months, and the like. For example, by a condensation method using dicyclohexylcarbodiimide, in the presence of agent M, neomycoplanesin or uneomycoplanesin fatty conductor care amino sulfur-coated peptide and dicyclohexylcarbodiimide are cooled with water. The reaction is carried out at lower to room temperature. Reaction A! %-Jf,
When the reaction mixture is processed according to a t'-layer method, such as column noromatography, the desired product is obtained (4).

Next, the reaction to remove the protecting group of the basic group as necessary is as follows:
Although it depends on the type of protecting group, all iLs are carried out according to conventional methods. For example, benzyloxydicarbonyl can be prepared by catalytic evacuation using a palladium-carbon catalyst.
-Butyloxycarbonyl can be produced by contacting with 1) and 2, such as hydrochloric acid, formic acid, trifluoroacetic acid, or anhydrous hydrogen fluoride; tosyl can be produced by contacting with an acid such as anhydrous hydrogen fluoride. Achieved.

Next, if necessary, the reaction of removing the carboxyl group from the base group 1h is completed by the retention group Schiff [1].

For example, endogroups that can be removed in vivo, such as pivaloyloxy/methyl and methyl, do not need to be removed in advance. All reactions for removing the binding group are carried out according to conventional methods. For example, methyl, ethyl, and pivaloyloxy/methyl can be saponified with dichloromethane, t-butyl can be contacted with a salt υ, and rTj, such as trifluoro-11toic acid. Accordingly, benzyl I'11 can be achieved by catalytic reduction using a palladium-carbon catalyst or by contacting with an acid such as anhydrous hydrogen fluoride. The target compound C thus obtained is For example, it can be prepared using conventional methods such as column chromatography, thin layer chromatography, and extraction.

The myco)lanecin conductor of the present invention is used as an anti-1-4 drug, FA nucleating agent, for bacterial infectious diseases. Anti-tuberculosis therapy is administered orally or parenterally. +11. '
Parenteral administration of +hayashi is preferred. Dosage form! For example, tablets, capsules, powders, granules, or especially y
RR pulse or intramuscular injection is given. The symptoms, age, body, 1
It is a good idea to drop the island in 200 to 2241 times per day or in several times per day.

According to the necessity of this administration, 111. '-ni', I really can.

Next, embodiments of the present invention will be described in detail, but the present invention is not limited to these embodiments.

Example I L-Aspartylneomania F5 Ne.
Syn hydrochloride 1) Neomycoplanesin 1. Or(1mno/ri, t
-Butyloxycarbonyl-β-benzyl-L-aspartic acid succinimide ester 0855f (2
mmo6) and 4-dimethylaminopyridine 0.2
5f (2 mmol) f dichlorodimethane 5 m 11
kL (d M'f1 you, 3 hours at room temperature 4.i'
;j, stirred. The resulting reaction f 11111 order 10%
After drying, the bath agent was distilled off from the reaction solution, and 1 ton of residual water was removed. The product was subjected to column chromatography using silica gel and purified with chloroform-methanol (20:1).Then, it was reprecipitated with ether-n-hexane to give t-butyloxycarbonyl-β-benzyl- L-Aspartyl neomycobranetsuno 1.25F (95.5%) was introduced.

Melting point 141-150℃, [α] -56.1° (C1
, methanol) 2) t++ dilated t-butyloxycarbonyl-β-/
<Njiru L-Aspartyl neomycoplanesin 0.
3 & (0,232 mmo/ ) to tetrahedron +=+7
Run 30 m4*; After j'l'N, catalytic reduction (10%
Using palladium-carbon 0.11, 40°C, 90 Kq
/, rtn' for 3H) to carry out the debenzylation reaction. Is it dim? After concentrating the lk, the t-butylmexycarbonyl reaction was carried out by stirring in 3N hydrochloric acid/dioxane for 2 hours.Then, the bath agent was distilled off from the reaction solution, and the r41 white ib ethyl-petroleum Using ether, the combination of 41 precipitation $12 i and Table d1! 13 no 1 o,
zr (75,7%) was tricked'#, 0 melting point 117
~178℃, [α) -53,0° (C1, methanol) Elemental analysis value Cs s %z N 1o 013・H'
Theoretical value as L-g 2H20 C, 5627: H, C33: tv, tt93:
cl.

3.02 Actual value C, 56, 30: H, 835: 1111.67
:C/.

3.24 In Example 1, L-aspartyl neomycoplanesin trifluoro(g' [= e
The det-butyloxycarbonyl reaction was carried out in the presence of trifluoroacetic acid to give the title compound.

Melting point 175-176°C Example 3 μm methyl-b-aspartylneomycobranetsuno') 4.4 Example 1 Succinimide yielding Q t-phytyloxycarbonyl-β-benzyl-L-asparagine at kc Using t-butyloxycarbonyl-β-methyl-L-aspartic acid succinimide ester in place of the ester, t-butyloxycarbonyl- Oxycarbonyl-A-methyl-L-aspartylneomycoplanesin (oxycarbonyl-A-methyl-L-aspartyl neomycoplanesin)
1. Ta.

141i+ point 158-160℃, [α'11 -sa
, eo (C1, methanol) 2) Obtained ft-, t-butyloxycarbonyl-β-
Methyl-L-aspartyl neomycobrane was subjected to a t-butyloxycarbonyl-removal reaction according to the method of Example 1-2), and a compound indicated as 1- was obtained.

Melting point 157-1so℃, [α:] -53,7° (cl
, methanol) Elemental analysis value C56N94 N1+I O12” 2o
Theoretical value C, 59, 39: H, 8,! 15;N,
1237 actual measurement value C, 59, 37: H, 8B1: N
, 12.18 Actual Ta Example 4 β-L-Aspartylneomycoplanesin 1) In Example 1, t-butyloxycarbonyl-
Penzyloxycarbonyl-α-t-phthyroome-aspartate succinimide ester was added to β-benzyl-L-aspartic acid succinimide ester once a month, according to the method of Jika I 9111-1). 1t
In the ri reaction, benzyloxycarbonyl-
α-t-j Chiru β-L ~ Aspartyl neomycoplanezino is 1t and buhi.

Melting point 144-148℃, [ ] 59.0' (C1
, 7' ta■] nor) 2) (?/uretabenzyloxycarbonyl=(χ-t
JIQ t-butyl anti-L1. Carbonyl-β-L-aspartylneomycoplanesin was used.

Direction 169-111℃, [α] D-50.6° (C
1, methanol) 6) Conducting the obtained benzyloxycarbonyl-β-L-aspartyl neomycoplanesin 1'/111''
By applying the method of 2), only one compound 11 was prepared without contacting the debenzyloxycarbonyl reaction.

Melting point 183-185℃ Elemental analysis value C5, H22N1oO46・4H20! c: City jl#', C, 56, 29: H, 8, 5
9: N, 11.49 lol 11111 nL C, s 1
47e He8.36: N, 11.60'J Example 5
N-t-butyloxycarbonyl-s-(glutathione~5)-L-cysteinylneomycoplanesin 1) t-butylmexylcarbonyl-5-(3-nitro-
2 pyridine sulfenyl)-L-cystine dicyclohexylamine 41. tr(1,013mu)(,+
/ ) in 40 ml of ethyl acetate.1. -After 1
Add 0% citric acid and mix together.

After drying over anhydrous sodium sulfate, the t(I agent) was distilled off.The resulting residue was diluted with 40 ml of acetonitrile.
W (after that, synchhexylcarbodiimide 0.41
F (1,99 mmol) and neomycoplanesin 1.1 (1,013 mmol) were added at Kakuhaido, and further 4-dimethylaminopyridine (1,1"?
0.82 mmol) was added. The reaction solution was stirred at room temperature for 3 hours on JW and then reacted overnight. Distill the bath agent from the reaction solution/
After ζ, add ethyl acetate, then add +(+1) to 10%
It was washed with citric acid and water, and the anhydrous sulfur was dried over sodium chloride. The solvent was distilled off from the reaction solution, and... ! fref f? : The residue was poured onto a silica gel plate and separated with chloroporum-methanol (C9:1). In history, C1 ``One substance ethyl-petroleum ether ke (11 sediments d and t-
Butyloxycarbonyl-8-(3-nitro-2-pyridinesulfenyl)-L-cysteinylneomycoplanesin 0.355' (25,7%) or f41/and.

Melting point 158-161°C, (α:l] -19,s'
(C1, methanol) 2) Obtained t-butyloxy7carbonyl, 5-(3
-Nitro-2-hi IJ Synsulfenyl-I, -cysteinyl neomycoplanesin 0,31 (0.2 2
4mmo/)k After dissolving 20mdK in methanol,
Glutathione 0.0 8-2 1/ (0.2 6
An i%y solution dissolved in a 150% methanol aqueous solution was added under stirring at room temperature. The reaction solution was stirred at room temperature for 30 minutes, the insoluble tube was filtered off, and then subjected to column chromatography using Sephadex LH-20 and eluted with methanol. The indicated compound was eluted earlier than the by-produced yellow (7)3-=)l:I-2-mercagtoviridine. Distill the soln fill from the eluate, add vinegar 11' ethyl-petroleum ether to 11+ precipitate, and the indicated compound is 0.32.
r (96chi) was obtained as 161 white bodies.

Melting point 112-114°C, [α)D-113.4° (C1
．． Methanol) Bovine analysis 1ftj. C69 He1s 1'++3
0+9 82・H2O as y)) Logical value C, 5
4.78: H, 7.79: N, 12.04: B
,,4.24 Actual measurement c, 54.70:H, 7.97:N, C
2. oo;S.

j1 Example 6 S-(glutathione-S)-L-cysteinyl neomycoplanesin 1) Tet-butyloxycarbonyl-8-(3-nitro-2) obtained in Example 5-1) − H+)
Synsulfenyl)-L-cysteinylneomycoplanesin was treated with trifluoroacetic acid according to the method of Example 1-2). #5p t-butyloxycarbonyl reaction by contacting Bl+ with Ta.

Melting point 151-155t, [αJ -19.2°(C
1, me1+tanol) 2) The prepared S-(3-nitro-2-pyridinesulfenyl)-L-cysteinylneomycoplanesin was treated with glutathione according to the method of Example 5-2). When reacted, the indicated compound is produced! I was beaten.

la'! Point 182-184℃, [α'] -84,4
'(CI', Medtanol) Elemental analysis value 064H107N13°17S2° Horse 0 and 11 Logical value C,5441; H,7,78:N,
12.89:S, 4.54 Practical Confession C, 5469:H, 804:N, 12.
63:S, 4.33 Example 7 α-L-glutamyl-N-methyl-L-valylneomycoplanesin 1) lII-benzyl-N-methyl-L-valine.tm
After dissolving 0.4 V (1,8 nmo/) of the acid salt in 40 ml of acetonitrile, 0.4 V (1,94
mmol) and neomycoplanesin 1.4 f (
1,42 mmo/2) was added, left to stand for 2 hours, pressed seven times, and then left to stand at room temperature for 24 hours. Two drops of glacial acetic acid were added to the reaction mixture for 25 minutes (after stirring for 1 hour, the phase was removed by filtration, the filtrate was washed with J'dLj's water and saturated brine, and then with 4 te M sodium solution in still water). After drying, the bath agent was distilled off through a filter, and the resulting oil was subjected to flash chromatography using silica gel.The product was purified by adding 2 ethyl chlorides for 1 month to obtain N-benzyl- N-methyl-
L-valylneomycoplanesin 0.448P (27%
) Obtained as a white powder.

2) N-benzyl-N-methyl-L-valyl neomycoplanesin (14f (0-35 mmo/
) was dissolved in 30 methanol of methanol, and subjected to a debenzylation reaction by catalytic reduction using 10-thipalladium-carbon according to the method of Example 1-2) to give 1 and N-methyl-L-
Baryl bed mycoplanesin (0.29<57%) was obtained.

Melting point 149-155℃, [α] -6tt° (C1, Meth 1) Nor) Elemental analysis value C57H97NIII Otl・3H20
Theoretical value as C, 59, 39: H, 843; N, +
2.17 Actual measurement value C, 58, 98: H, 8, 14:
N, 11.893') t-butyloxycarbonyl L
-Glutamic acid γ-benzyl ester 0615-I2m
m0r) in 30 m# of ethyl acetate, and then diluted with 0.4 m of ethyl acetate while stirring in an ice-cooled oven.
13 f (2 mmol) N-methyl-L-valylneomycoplanesin obtained in O. Yohi if J 1.10
f (1 mmo/liter) was added, stirred for 2 hours, and left to stand overnight at room temperature. The precipitate was filtered off from the reaction solution, and the filtrate was washed with brine, and anhydrous sulfur 1) i/ ) The mixture was dried with IJum, and then the bath agent was removed from the box. The resulting oil was subjected to flash chromatography using silica gel and purified using ethyl acetate for 1+71 minutes.
&'J, 0.91 (69%) of t-butyloxycarbonyl-γ-benzyl-α-L-glutamyl-N-methyl-L-valylneomycoplanesin was obtained as a white powder.

Melting point 122-125°C, [α] -80.2° (C1
. After dissolving for 7 hours, let it cool at room temperature for 2 hours.
Time went back and forth. After removing the trifluoro-1 from the reaction mixture, add the residue to all ethyl acetate.
The solvent was distilled off and the resulting oil was washed with vinegar C1 ( ethyl-n
- Using hexane (recipitation rRj and γ-benzyruα
-L-glutamyl-N-methyl-L-valylneomycoplanesin 0.72f (78%) was mixed with a white powder.

5) Obtained frr-benzyl-α-L-glutamyl-N
-Methyl-L-valyl neomycoplanesin 0.729
(0.5 mmol) was dissolved in 15 ml of tetrahydrofuran, and the solution was exposed to light using 10% palladium on carbon according to the method of Example 1-2). After the reaction was completed, the solvent and bath agent were removed from the reaction mixture, and the resulting residual heat was reprecipitated using methanol-〇-hexane, resulting in compound 0.4F (59%) in Table 111. Obtained.

Melting point 191-193℃, [(χ) -9010(C1
, methanol) Elemental analysis value C62HIC6”+1014・1 (2U
and 14 theoretical values C, 57, 25: H, 8, 76: N,
11.81 Actual value C, 56,87; H, 8,29
: N, 11.8 Example 8 α-b-glutamyl-N-methyl-b-valyl, neomycoplanesin salt 2
+=α-L-glutamyl-N-methyl-L-valylneomycoplanesin obtained in Example 1 0.123 V
(0,1+n+ooolPrW4W to 5mg of methanol
#L, 50ml methanol was added under ice-cooling to adjust the pH to 20. Next, one mixture was distilled off using low l crystals,
+ I The separated I residue was reprecipitated with methanol-n-hexane once a month (jffQ L, and then vacuum-dried. Obtained.

2 Melting point 189-192°C, [α]D-91,2° (C1
, methanol) Original 1 minute 11 value C62H + p5 "11014・HCl"
2””Temporary value C, 5812: ) 1.7.81:
N, 12.03: C1,2,73 actual measurement (ll+ C, 57,92: H, 6,98: N,
11.95:C1,2,08 Example 9 α-L-glutamyl-N-methyl-L-valylneomycogranesin sodium salt α-L-glutamyl-N-methyl-L-valylneomycogranesin as prepared in Example 7 Planesin 0.1? (0,0
813mmo7? ) to 3 ml of metal/- ftJ
W (After that, diluted with water, then added sodium hydroxide under ice-cooling to adjust to I'H9, OK. Then, the reaction solution was subjected to column chromatography using IP-20 and washed with water. It was then eluted with methanol. The eluted bathing agent was distilled off, and the 14-ton residue was ladled with methanol-ether to give 7p+α (7), and then vacuum-dried to give the indicated compound 111.08M (83.3ch) as white. Obtained as a powder.

Melting point 1B (i ~ 19LI℃, (α) 22-93.4
"< ct, methanol) Elemental analysis value C62H,1 (14"HC14Na"20
Theoretical value C, 9867: H, 820: kJ,
12.14 Actual value C, 785: )l, 7.97
: li, 11.98 Example 10 α,ε-diaminobimelyl N-methyl-L-valyl neomycoplanesin sodium j 1) α,ε-di-t-butyloxycarbonylaminobimerin monomer -t-butyl ester 0.893F (0
, 2 mmol 11'iL'lt to 3 omg of ethyl acid in bath 1''
γ (k, dicyclohexylcarbodiimide 0.413P C2mm0IJ) while stirring under water cooling.
was added, and the N-methyl-L obtained in Example 1-2) was added to the mixture.
- Valylneomycoplanesin 1.1:l (0.1m
mol) was added and incubated for 2 hours, and further allowed to release at temperature for 24 hours. The precipitate was filtered off from the reaction mixture, and the filter was washed with ground water. The reaction solution was dried with sodium chloride to remove the solvent, and the resulting oil was subjected to flash chromatography using silica gel.

ε-di-t-butyloxycarbonylamino-1-t-
Petit Rubimelilu N-methyl-L-valylneomycoplanesin 1.13f (74%) Obtained as a pale white powder.

M':! Point 143~150°C9[α]-47.8°
(C1, MeJ Tanol) 2) l! The obtained α,S-di-t-butyloxycarbonylamino-ε-7-butylupimelyl-N-methyl-L-valylneomycogranesin was mixed with triflumerocholic acid according to the method VL of Example 1-4). When brought into contact with each other and subjected to depilation-butyloxycarbonyl reaction and det-butyl reaction, α,ε-diaminobimelylu N-medimethy L-
Valyl neomycoplanesin 0.8 & (85%) as white powder? ! J+:)ノ1k.

j,! , +l1 point 190-195℃, 1α] -79
, o' (C1, methanol) 6) The obtained α,ε-diaminobimelylu N-methyl-L-valyl neomycoplanesin 0.6F (0.5 mr
After diluting No. 6) in a small amount of methanol with 11 pJ and then adding water with ice-cooling, add 11 J of water and 1% aqueous sodium solution and adjust to 11%.

Next, this solution was subjected to t column chromatography using H'P-20 (1'CM=IL), washed with water, and then purified with methanol ((
I got 4. Agent 114 was distilled off from the acid extract, and the obtained oil was mixed with methanol-n-hexane.
When llWj, the indicated compound becomes a white powder and 0.4f
(6B Section) I was given a 4j.

Melting point 186-189℃, [α] -93.8° (C1
, Me1) Tanol element content inoj value C641 (112N12014N8.
51 (1 ri as 20 C, 55, 45: H, 8, 08:
N, 12.13: Actual value Co 5499: HH
s, is: N, 1187: Actual j11.1 Example 11 α,
ε-diaminobimelylu N-methyl-L-valylneomycoplanesin difun1'I・? α,ε-diaminobimelyl N-methyl-L-valylneomycoplanesin sodium 4Q2f ((J15mmO1kmethanol5
ml ni saki 1! +: The mixture was diluted by adding L, soap and water, and then 1μ of 1λA acid was added under water cooling to adjust the pH to 2.0. Next, the reaction solution was subjected to column chromatography using HP720, washed with water, and then washed with methanol.

By distilling off the liquid from the bath liquid and re-precipitating the oily substance using methanol-〇-hexane, the compound 9 shown below is obtained.
Of course, + 6 y (76,25b) was obtained as a white powder.

Melting point 183-188℃, [α'11 -105.1°
(cl.

Methanol) Elemental analysis value C64H113N, 2014-2Hc1.
Theory 11 as 5k120 C, 53, 52: I (, 8, 71: )
I, +1.71: C1,4,88 real ff1l[C,53,01: H,8,59; N,
11.5L: Implementation full 12 β-Benzyl-L-aspartyl-N-methyl-L-valylneomycoplanesin 1) N-Methyl-L-valylneomycoplanesin obtained in Example T-2) 1. 10f (1mmot)
and t-butylox7carpodiX-β-benzyl-L
'-Aspartic acid succinimide ester 0.646
When f (2mm04) was subjected to a condensation reaction according to the method of Example 1-1), t-butyloxycarbonyl-β-benzyl-L-aspartyl-N-methyl-I,-halylneomaikov"lanecine0. 90Of (64%) was obtained.

Melt, 153-155℃, [α)D-93,7°(C1
.
) was subjected to a monobutyloxycarbonyl reaction according to the method of Example 1-2), and the resulting residue was suspended in ethyl acetate and stirred with 5% aqueous sodium bicarbonate to give the indicated compound 0.
6G? (92%) was obtained.

Melting point 147-149°C, [α)D-82,7□(C1,
Methanol) Elemental analysis value 068H109"+1014 ・Theoretical value including H2O 0.61.r5: H, 8, 46: N,
N, 65 actual value 0.61.99; H, 8,53:
N, 11.63 examples Example 1a L-aspartyl-N
-Methyl-L-valylneomycoplanesin Example 12 β-benzyl-L-amehartyl-N-methyl-L-valylneomycoplanesin 0
1010t (0.05m mol) 'fr When subjected to a debenzylation reaction by catalytic reduction according to the method of Example 1-2 using 10% palladium-carbon, the indicated compound Q was obtained.
, 455F (91%) was obtained.

Melting point 184-186℃ Elemental analysis value C61H103N1+ 014 X H2
Theoretical value for O: c, ss:ss ;n, 8.5T
:N, 12.59 actual value (!, 59.81:
H,8,85:N, 12.25Example 14 t-butyloxycarbonyl-D-aipartyl-D-lysylneomycoplanesi 1,) N-t-butyloxycarbonyl/1-N-(2 -chlorobenzyloxycarbonyl)-
D-lysine/t-butylamine salt 2.95 El (6
,05mmat) suspended in vinegar rR ethyl 50+M,
After washing with 10% citric acid and water, it was dried over anhydrous sodium sulfate. This solution was filtered, and the solvent was removed from the filtrate under reduced pressure. Neomycoplanesin i in the resulting residue? (5,07 m mot) and dichloromethane 50 mt, then under stirring thick U hexylcarbodiimide 1.25 F (6,07 mm mot))J
The mixture was stirred for 30 minutes. After the reaction was completed, the reaction mixture was filtered, and the solvent was distilled off from the filtrate.

The obtained residue was subjected to column chromatography using silica gel and eluted with methanol-ethyl acetate (1:99). The solvent from the eluate was distilled off under reduced pressure 2, and the resulting residue was reprecipitated using ethyl acetate-α n-hexane to give N-t-butyloxycarbonyl-N'-(2-chlorobenzyloxy carbonyl)-D-lysyl neomycoplanesin 8.4 t
(91.5%) was obtained as a white powder.

Melting point 143-145°C, [α) -37.8° (C1,
2) Obtained N-t-butyloxycarbonyl-N-
, (2-chlorobenzyloxycarbonyl)-D-I
J Gilneomaikov' Laneshin 2.15F (1.55m
3 omzf of trifluoroacetic acid was added to the mixture under water cooling, and the mixture was stirred at room temperature for 5 hours. N-t-butyloxycarbonyl-N'-(2-chlorobenzyloxycarbonyl)
The reaction was continued until -D-lysyl neomycoplanesin disappeared. After the reaction was completed, trifluoroacetic acid # was distilled off from the reaction mixture under reduced pressure, and the resulting residue was neutralized with 10% M carbon dioxide solution [7] and then extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off from the filtrate under reduced pressure. When the obtained residue was reprecipitated using ethyl acetate-petroleum ether, N-(2-chlorobenzyloxycarbonyl)-D-lysyl neomycoplanesin 1.9F (95.0%) was obtained as a white powder. Obtained.

Melting point 140-141°C, [α) -52, ro (cl,
3) (J'=+il-N-(2-chlorobenzylox7carbonyl)-D-lysyl neomycoplanesin 1.
8 f (1,40 mmoz) and t-bufkoxycarbonyl-D-aspartic acid-β-benzyl ester 0.54 f (L67 mmot) in 50 ethyl acetate.
mtK? After the solution was dissolved, dicyclohexylcarbodiimide 0.35F (1, TOmmot) was added with stirring, and the mixture was stirred for 30 minutes. After the reaction was completed, the reaction mixture was filtered, and the filtrate was distilled off under reduced pressure. The obtained residue was subjected to preparative 4-layer chromatography (developing solvent: methanol: chloroform-1:9) with K.

Next, the object? Extraction was performed using methanol-chloroform (1:4). The solvent was distilled off from the extract under reduced pressure, and ethyl chloride was added to the distilled residue, which was then washed with water. After drying the organic layer with anhydrous sodium sulfate, ethyl acetate
Reprecipitation using n-hexane yields 7-butyloxycarbonyl-β-benzyl-D-aspartyl-N6-(
2-10 lobenzyloxycarbonyl)-D-lysylneomycoplanesin 1.83F (81.3%) was obtained as a white powder.

Melting point 122-124℃, [α), -33,5° (c
1.659 ( 1,03n+mo/=)'rTo a solution dissolved in 30mt of methanol, 10% palladium-carbon 1f was added to 100m/! of methanol, K was added, and hydrogen was bubbled through with stirring for 10 minutes.
Hydrogen was passed under stirring for an hour. After the reaction was completed, the catalyst was filtered off, and the solvent was removed from the filtrate under reduced pressure. The obtained residue was reprecipitated using chloroform-petroleum ether to obtain the title compound 1.31 (95.3%) as a white powder.

Melting point 183-1115°C, [α]D-3500 (cl,
methanol) elemental analysis direct C66H112N12016' 4H
Theoretical value c as 20, 56.55: H, 8, 82, N
, 1199 actual measurement value (!, 56.57:H, 8,4
0, N, 12.22 Example 15 D-Aspartyl-
D-lysylneomycoplanesin trifluoroacetate Example 14 t-\Butyloxycarbonyl 7D-7suno(rutile-D-lysylneomycoplanesin) obtained in Example 14
/70.2 f (1,50 m mot) was added with 20 mt of trifluoroacetic acid under water cooling, and the mixture was stirred at room temperature for 3 hours. After the reaction was completed, the solvent was distilled off from the reaction mixture, and the resulting residue was mixed with ether and then filtered. The filtrate was dissolved in methanol, and then Sephadex LH-2
The residue was subjected to column chromatography using 0 and eluted with methanol. Fractions of the target product were collected, the solvent was distilled off under reduced pressure, and the resulting residue was reprecipitated using ethyl acetate-ether to form the indicated compounds 0 and 1 f (
49.4%) was obtained as a white powder.

Melting point 193-195℃, [α)D-35.7° (C1゜methanol) Elemental analysis value 061H104N12014-OF500
Theoretical value as 0H・5 H2O 0.5248:H,j, 08:N, 11.73
;F.

3.1・8 Actual value 0.52.911;H,? , 85:N, 11
．． 50;F.

4.05 Practical Example ts t-Butyloxycarbonyl-D-phenylglyfur D-aspartyl-D-lysylneomycobranecne 1) t-Butyloxycarbonyl-β- obtained in Example 14-3) Benzyl-D-7 Subarthyl-N'-(2
-chlorobenzyloxycarbonyl)-D-lysylneomycobranecne2. Add 30 mt of trifluoroacetic acid to ysr (1,71 m mot) under ice-cooling, and add 1 mt of trifluoroacetic acid at room temperature.
Stir for hours. After the reaction was completed, citrifluoroacetic acid was distilled off from the reaction mixture under reduced pressure, and the resulting residue was dissolved in ethyl acetate, and then neutralized with 10% aqueous sodium bicarbonate. The reaction solution was washed with water, dried over anhydrous sulfuric acid, and then the solvent was distilled off from the reaction solution under reduced pressure. The obtained residue was subjected to preparative thin-layer chromatography (developing solvent: methanol:chloroform=1:9), and then the fraction was extracted using methanol-chloroform (1:4). The solvent was distilled off from the extract under reduced pressure, and ethyl acetate was added to the resulting residue.
After washing with water and drying the toM layer with anhydrous sodium sulfate, the toM layer was precipitated with ethyl acetate-n-hexane to give β-benzyl-D-asuno(rutile-N'(2-chlorobenzyloxycarbonyl)-D- Lysyl neomycoplanesin 2.35f (91,2%) was obtained as a white powder with an O melting point of 129-132°C, [α)D-41,0°
(C1゜methanol) 2) Obtained β-benzyl-D-asunorutile N' (
2-Chlorobenzylox7carbonyl)-D-lysyl neomycoplanesin 1. Of(0,64m mot)
and t-butyloxycarbonyl-D-phenylglycine 0.183f (043m moj) were dissolved in chloromethane 50L11AK and 7. -H, knocklow\xylcarbodiimide 15 (19 (0,73 m mo
j, ) f were added and stirred for 1 hour. After the reaction was completed, the reaction mixture was filtered, and the solvent was distilled off using filtrate J: F+reduced pressure of 1; (2) Total preparative thin layer chromatography (developing solvent; methanol:chloroform = 1:19)
), then the target product chemethanol-chloroform (
1:4)? It was extracted using #1 agent completely depressurized F from the extract liquid
Ethyl acetate was added to the resulting residue, and the 6-layer layer, which had been washed with water, was dried with anhydrous sulfuric acid. -Butylox7carbonyl-D-phenylglycyl-
β-Benzyl-D-aspartyl-N5-(2-chlorobenzylox7carbonyl)-D-lysylneomycobranecun (1.08193° 4%) was obtained as a white powder.

Melting point 128-130°C, [α)D-40,4'(cl,
methanol) 6) Obtained t-butyloxycarbonyl-D-phenylglycyl-β-benzyl-D-'7 Spar f-N
-(2-chloropenzyloxycarbonyl)-D-lysylneomycoplanesin o, sq (0,46m
moz)ffNqExample 14-4) was followed by Q-%11 and subjected to debenzylation and de-2-chlorobenzyloxycarbonyl reaction by catalytic reduction, and the residue was treated with ethyl acetate-n- F'TiE' using hexane,
When mixed, the indicated compound 061g (97,1≠) was obtained as a white powder.

Melting point 181-189℃1. [αJD-43,2°(C1
, methanol) Elemental analysis value C74H12oN13017・4H20 as 1st shift 0. 5883:H, 8, 20:N,
11.511 Isei 1st shift 0. 5B, 63; H, 8, 1
7; N, 11.88 fruit 1 FIlty 7-n ethyloxycarbonyl-bivaloyloxymethyl-β-D-asuno (rutile-D-lysyl neomycotranecne ε-1) obtained in Example 14-2) N-(2-chlorobenzylox7carbonyl)-D-lysylneomycotranecne1. 1 0 f ( 0.,, 8 7 Ill
moj) and t-butyloxycarbonyl-D-asparagine-α-pivaloyloxymethyl ester 0.
After dissolving 3f (0,97m mot) in 50ml of ethyl acetate, 0.18? (0.@Trn m
o/-) k) Pour the mixture and stir at room temperature for 2 hours. After the reaction, the anti-15 mixture was treated according to the method of Example 14-3) to obtain t-butyloxycarbonyl-α-pivaloyloxymethyl-D-aspartyl-N-(2-chlorobenzyloxycarbonyl)- D-lysyl neomycotranesin 0. 9F (64.1%) was obtained as a white powder.

Melting point 125-121°C, [α) -28.4° (C1,
methanol) 2) Obtained t-phthyloxycarbonyl-alpha-pivaloyloxymethyl-])-aspartic N-2-chlorobenzylox7carbonyl)-D-1) Silneomycotranesin 0. 7 f (0.

43 mmot) was subjected to a 2-chlorobenzyloxycarbonyl removal reaction by catalytic reduction according to the method of Example 16-5) to obtain the title compound 0.58f (93.2%) as a white powder.

Melting point 172-115°C, [α) -23.3° (C1,
Meta ■) Nor) Elemental analysis value Theoretical value as C72H122N12o18・3H2o 0, 58.12:H, 8.67:N,
11.30 Actual value C! , 58.13 :H, 8
．． 78:N, 1'1.11 Example 18 β-D-aspartyl-D-lysyl neomycon ranesine ditrifluoroacetate t-butyloxycarbonyl-α-pivaloyloxymethyl-β obtained in Example 11 -D-aspartyl-D-lysyl neomycoplanesin 0. 2
f (0.13 m mot) To the mixture was added ploverfluoroacetic acid (gl 2 Omz) under ice-cooling, and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, trifluoroacetic acid was distilled off from the reaction mixture under reduced pressure to obtain the The residue was washed with ether. The resulting solid was dissolved in water and lyophilized to yield 0.06 f (29.7%) of the title compound as a white powder.

Melting point 198-201°C+ () -as. aO(cl,
Methanol) Elemental analysis value C61HIMN12014 ・2 0F3
000H-' Theory as 8H20! 0. 5Q. 111:H, ? ．． 64:N,
10.80: F, 7.33 Actual value 0, 50.32; H, 7.60; N, 1
0.96:F, 7.01 Actual example 1sp-Aspartyl-D-) Liftfil neomycoplanesin 1) Neomyco7' lanesin 2r (2.03m
mot) Oyobi t-butyloxycarbonyl-D-
)−! 7 Buttofa y 0.74 f (1.2mm
After dissolving Ot) in ethyl acetate, 0.0% dicyclohexylcarbodiimide was added while stirring under water cooling. 50 2 f
(1.2 m mot) was added and stirred at room temperature. After the reaction is completed, the reaction mixture is treated according to the method of Example 14-3> to obtain t-butyloxycarbonyl-D-tryptophyl neomycoplanesin2. 2 f (84
．． 5%) was obtained as a white powder.

Melting point: 228-230°C, [α)-65.9° (C1, methanol) 2) Obtained t-butyloxycarbonyl-D-tritophilneomycoplanesin 1.3f (1,02m
mol) was added to 15 m7 of 99 tikiic acid and stirred for 24 hours. After the reaction, the solvent was distilled off from the reaction mixture, the resulting residue was suspended in ethyl acetate, and 5% M carbon dioxide solution was added.
94%) was obtained.

Melting point 175-11r℃, (α)-SS, ao(C1,
methanol) 6) Obtained D-tritophil neomycoplanesin 0.8? (0.68 m mot) and 0.242 t (0.75 m mot) of t-butyloxycarbonyl-β-benzyl-D-aspartic acid were dissolved in ethyl acetate, and dicyclohexylcarbodiimide 0.0 was added with stirring under water cooling. .154t (0.75m mot
) and stirred at room temperature for 3 hours. After completion of the reaction, the reaction mixture was treated in the same manner as in 1) to obtain t-butyloxy7carbonyl-β-benzyl-D-7subarthyl-D-)liftfil neomycoplanesin 0.9 F (82,
5%) was obtained.

Melting point 160-163°C, [α) -53.2° (C1° methanol) 4) Obtained t-butyloxycarbonyl-β-benzyl-D--aspartyl-D-triftonyl neomycoplanesin 0-59 (0,338 mmot) was subjected to debenzation by catalytic reduction according to the method of Example 1-2). ．．
3F (64%) was obtained.

Melting point 190-193℃, [α) -65,0'('01
．． methanol) 5) Obtained t-butyloxycarbonyl-D-72haltyl-D-) liftfil neomycoplanesin 0
．． When 2f (0,144 mmo7) was treated in the same manner as in 2), the indicated compound g, 17f (91.6%) was obtained.

Melting point 1g'6~tea℃+ (lD-66,1°(cl
, methanol) Elemental analysis value C6dH103N12014 ・Theoretical value as 4"2o C+ 58.2'3:H28,22;N,
12.35 actual measurement (IM G, 5g, 02; H, r,
84;N, 12.18 embroidery E>1120 β-L-asbarnal-D-enylglycylneomyconranesin 1) In Example 1t-1), instead of 1-butyloxycarbonyl-D-)linton ni-t-chill Dimensions 7-force Ruponyl ~ D-phenylglycine 0.3 f'
Example 19 using (1,2nn +n0t)'fr
-1) When subjected to a reduction reaction method according to method t, 1-Putinoginxycarbonyl-D-phenylglycylneomyconranenone 1.5 F (89.0%) was obtained, melting point 232-234. ℃I (ID-88,4°(01,
methanol) 2) imprinted t-butyloxycarbonyl-1)-
Phenylglycyl neomycon lanesin 1,4? (1
D-phenylglycylneomycobranesin 0.62F (48% )was gotten.

Melting point IT2-173℃, (cl:]Ij-101,
8° (cl.

methanol) 3) The obtained D-phenylglycide, λ mycoplanesin, s·t (0,446 m moz) and benzyloxycarbonyl-α-t-futi), -L, -
AsparakyyfR0,45f (0,895m mat)
According to the method of Example 1-1), the degree of condensation was 1 to 1.
Then, 0.4 f (74.0%) of pencyloxycarbonyl-α-t-phyl-β-L-aspartyl-D-phenylglycylneomyconranesin was obtained.

2 Melting point 157-159℃, (a) D-78,5'' (01
, methanol) 4) Letapendyloxycarbo;nyl-α-t-
Butyl-β-L-Anuvarchilu]-phenylglycylneomyconranesin□3F (0,21mrl'lO
/-) was brought into contact with trifluoroacetic acid to remove t-butylation according to the method of Example 1-2), resulting in benzyloxycarbonyl-β-L-asharthyl-D-phenylcrysyl neomycogranesin 0. .21f (71%)
was gotten.

Melting point 199-201°C, [α) -, 76,6° (C1
, methanol) 5) Obtained benzyloxycarbonyl-L-aspartyl-D-phenylglycyl 1. , i-myconolanesin 0. 1? (0.073 m mot)
is subjected to a debenzyloxy and J sulfonyl reaction using a catalytic violet reactant according to the method of Example 1-2) to obtain the indicated compound 0.
06f (66%) was obtained.

Melting point 203-205'C, (α) -91.4° (C1
, methanol) Element system analysis 11 mild C63H991J1 +0+4・H2O
Theoretical value as 0, 60.43:H, 8.13;N
, 12.30 6111 value 0, 60.12;H,
B, 13; N, 11.64V'416flH1 ρ
- Penjiro D - 7' Sunokunoshi Chirneomycofuranesone 1) A, Omycofuranesin 4. Of (4.0
5m mot) and t-braloxycarrJξyl-β-pencyl-D-'j'
After dissolving 1.56 S' (4.84 m mol) in dichloromethane somt, λk? ? -Dicyclohexylcarbodiimide 1 while stirring with F? (
4.85m mol. ) and then stirred at room temperature for 2 hours. After the reaction was completed, the reaction mixture was filtered and the solvent was distilled off from the filtrate. The obtained residue was subjected to column chromatography using silica gel, purified with dichloroform-methanol (20:1), and reprecipitated using ethyl acetate-n-hexane to obtain t-butynodoxycarbonyl-β. -Benzyl-D-asuno-rutileneomycoturanesin4. 8 F (91.71) was obtained as a white powder.

Melting point 130-135°C, [α]. -35.9° (C1,
methanol) 2) Obtained t-butyloki7carbonyl-β-benzy-D-aspartylneomycofuranesi: /4.7
? (3.63 mmot) fExample 1-2) +7
4.) When the compound is contacted with trifluoroacetic acid and subjected to a det-butyloxycarbonyl reaction according to method 4. O
f (92chi) was obtained.

Melting point 143-148°C, [α) -58.3° (C1,
Methanol) Elemental analysis 1st shift C62H981hO013' /2H
Theoretical value as 2° is 0, 62.03; H, 8.31;
N, 11. Rumor fruitful 4 ri 1 c, 62.01; H,
8.45:N, 1141Example 2 2 v-Arginyl-D-asunobutylneomycotranesin/hydrofluoride 1) β-benzyl-D-asbarthylneomycos obtained in Example 21 Furanesin 1.19f (1.0m mo
t) and N-t-butyloxycarbonyl-No-tosyl-D-arginine 0.4 rl (1.1 mmol)
When condensed according to the method of Example 21-1), N-t-
Butyloxycarbonyl-N-)sil-D-arginyl-β-benzyl-D-7 subartylneomycobranesin 1.31f<85, 5%) was obtained.

Melting point 150-154°C, [α]D-22.6° (C1,
methanol) 2) Obtained Nt-butyloxycarbonyl-N-
) Sollu D-Argini Lu β-benzyl-D-7 Subarthyl neomycoplanesin 0.2f.

(0.13 m mob) was added with anhydrous hydrogen fluoride in the presence of anisole and stirred for 30 minutes. After the reaction was completed, anhydrous hydrogen fluoride was distilled off from the reaction mixture, and ether was added to the resulting residue to solidify it, filter it, and dry it to obtain the title compound 0.15f (94%).

Melting point 192-194°C, [α) -43.5° (C1,
Methanol) Elemental analysis value C6+H104"+4"+4' HF
・Theoretical value as 10 H2O C, 50.26; l
(, 8.63; N, 13.45; F, 1.30 Actual value 0, 50.67; H, 8.67; N, 1
3.08; F, 0.95 Actual tm Example 2s D-Phenylglycyl-D-7 Subanototylneomycofuranesin trifluoroacetate 1) β-Benzyl-D-A obtained in Example 21 Subarthil Neomycofuranen L Of (0.84m
mot) and t-butyloxycarbonyl-D-phenylglycine 0.233 f (0.93 m m
at) according to the method of Example 2l-1), t
-butyloxycarbonyl-D-phenylglycyl-β
-Benzyl-D-aspartyl neomyconolanesin 1
．． 1 (1 (91,8%) was obtained, 7 h.

Melting point 147-149°C, [α)D-43,9°(C1,
methanol) 2) t-butyloxycarbonyl-D-quenylglycyl-β-benzyl-D-aspartylneomyconolanesin o, 5f ((1,35 mmot) by the method of Example 1-2) When subjected to debenzylation reaction by catalytic reduction according to the method, t-butynodoxycarbonyl-D-
0.45f (96%) of phenylglycyl-D-aspartyl neomycon lanesin was obtained.

Melting point tro~IT4℃, [α]ゎ-41.4° (C1,
methanol) 6) 0.4 t (0.15 mmol) of the obtained t-butyloxycarbonyl-D-phenylglycyl-D-asunorutile neomycotranesin was added to Example 2 Example 1-
Detation by contacting with etrifluoroacetic acid according to method 2).
- When subjected to butyloxycarbonyl reaction, the indicated compound 0
．． 17 f (04%) was obtained.

Melting point 118-182°C, [α) -43.9° (C1,
Methanol) Elemental analysis value C63”100N11014 = 0F3C
Theoretical value as OOH = 41120 (:!, 54.92; H, 7, 72: IJ,
10.84; F, 4.01 Actual measurement II c, 54.88; l(,?, 72; N,
10.71 ; F, 3.36 Example 24 N-α-trifluoroacetyl-D-arginyl-D-aspartyl neomyconranesine hydrofluoride 1) β-benzyl- obtained in Example 21 D-Aspartylneomycobrane 7n 1.19f (1,0mm
ob ) and NIIIE-trifluoroacetyl-N
o-tosyl-D-arginine 0.4(ill?(1)
, 2m mot) in accordance with the method of Example 22-1), N-trifluoroacetyl-N-)fluid D
-Arginyl-β-'\Njiru-D-Aspartylneo 1 myco7 caries 1.04F (65.0%) was obtained.

2 Melting point 165-168°c, (α), -25,6'(01
.
) was brought into contact with anhydrous hydrogen fluoride and subjected to detosylation and debenzylation reactions according to the procedure of Example 22-2) to obtain the title compound 0.11 (section 84).

Melting point 198-200°c, (α) -38,2° (C1
, methanol) Elemental analysis "C63H106"140+5F5 ・HF
・4 H2O and theoretical value C, 52,03: H, 8,00; N, 13.5
4;F, 5.25 Actual value 0.52.28:H, 7,69:N, 13.
40:F, 5.01 Fruit b% 91i 25 11-Phenylno'Raniru L
- Phenylalaniluk IJ, Nru D - Arginyl D
-Asbarthylneomycofuranesin hydrosifluoride 1) Real, male side 22-1) N-t-butyoxycarbonyl-N-tosyl-D-arginyl-β-benzyl- D-Aspartylneomycosus y 0.
8? (:0.50 mrnol-) in Example 1-2
) to remove t-t-
Butyloxycarbonyl reaction was applied, and then the mixture was combined with a conventional method to seal the tosyl-D-7rukynyl-β.
-Benzylu D-Aspartyl neomycocranesin 0
．． 75r (113%) was obtained.

Melting point 171-174°C, [α)-26,6° (C1, methanol) 2) 4% G) fc N-) Cyl-cyarginyl-β-benzyl-D-aspartyl neomyconolanesin 0.30B? (0,205 m moz) and benzyloxycarbonyl-D-phenylalanyl-L
-Phenylalanylglycine 0102F (0,205m
mot) is condensed according to the method of Example 2l-1) to give benzyloxycarbonyl-D-phenyla ranyl-L-phenylalanylglycyl-N-tosyl-D-arginyl-β-benzyl-D-asbarthylneo. Mycofuranesi y 0.3011 (75,0) was obtained. Melting point 150-153°C, [α) -12,9° (C1,
methanol) 3) Obtained benzyloxycarbonyl-D-phenylalanyl-b-phenylalanylcrisyl-No-tosyl-D-arginyl-β-benzyl-D-aspartylneomyconranesin 0.290 ? (0,146
m mot ) was contacted with anhydrous hydrogen chloride and subjected to a debenzyloxycarbonyl reaction, a detosylation reaction, and a debenzylation reaction according to the method of Example 22-2), yielding the indicated compound 0.18f (78, )was gotten.

Melting point 186-1951c, (α)D-43,3°(C1
, methanol) Elemental analysis value 01NH127N17017・2H'F・
Theoretical value 0.55.05 as 1lV2H20; H, 8,04:N, 13.4
8;p;2. ts Actual value 0.55.03; H, 7,66; N, 13.
Nl:F, 1.85 Example 26 α,ε-diaminobimelylneomycofuranesin 1) α,ε-di-t-butyl ox 7carponylaminobimelic acid monobenzyl ester 0.9 It f(2m
mot) 1 to ethyl acetate 30 ml to HFJ%t
After that, 0.413 F (2 m mat ) of synchronohexylcarbodiimide was added without stirring under water cooling.
Furthermore, neomycotranesin 0.985 W (1 m m
OA) f)) Stirred for 2 hours and then left at room temperature overnight. After the reaction was completed, the reaction mixture was converted into Example 1o-1.
), 0.8 g of α,ε-di-t-butyloki7carbonylamino-ε-(ndyloxycarbonyl bimeryl neomycon lanesin (SS, O
%) was obtained as a white powder.

Melting point: 189-193°C, [α) D-72,501. methanol) 2) Obtained α,ε-di-t-butyloxycarbonylamino-ε-penzylmexycarbonylhimerylneomycobranesin 0.8 F (0,526 m mol,
) is brought into contact with trinororoacetic acid and subjected to the det-butyloxocarbonyl reaction according to the method of Example T-4), resulting in ε-benzylox7carbonyl-α,ε-cyaminobimelyl neomycon lanenone 0. 6 f (86,9
%) was obtained as a white powder.

Melting point 185-189"C, (α) -68,5° (C1
, methanol) 6) Obtained ε-benzyloxy7carbonyl-α, ε-
Diaminobimelyl neomycon lanesin 0.6 t (
0,481m mot) was subjected to a debenzylation reaction by catalytic reduction using 10% palladium-carbon according to the method of Example 1-2), and the indicated compound 11.1179 (
21.0%) was obtained as a white powder.

Melting point 190-195°C, [α) -79,0° (C1,
Methanol) Elemental analysis 1st shift 058H29N110,3 Theoretical value as H2O C, 59, 23: H, 8, 43; N, 13
．． 11 fruit fall 1st shift o, se, se; H, 8, 08; N
, t3.42 Measurement of the antibacterial spectrum and urinary excretion rate of the myconolanesin derivative of the present invention by intravenous administration,
It was carried out by the following method.

1 Experimental method 1) Antibacterial spectrum Mycobacterium numegmatis AT (IC1ilN as the test bacterium, 10% albumin addition 11-F-Corbos Yutai Chochi (Eiken)'?: diluted twice as usual using The minimum inhibitory concentration (MIO) was determined by the method.The judgment was 31
The test was carried out after culturing at 1 to 10 days at °C.

2) Measurement of urinary excretion rate by intimal force in static 1j1 1n10
One mouse was given 10% of the sample dissolved in ethanol water.
0 to /' body weight - Administer into the tail vein 1. Ta. Collect urine within 24 hours after administration, use Micrococcus noshideus as a bacterial infection, and use the bio-attract method to collect urine, or
Alternatively, the urine was first subjected to column chromatography using Dia'ion Ml'-20 (Mitsubishi Kasei Corporation Momo), thoroughly washed with water, eluted with 80% aqueous acetone, and the eluate was concentrated. The residue obtained by drying was hydrolyzed in a sealed tube with concentrated hydrochloric acid-glacial acetic acid (1:1) at 105°C for 18 hours, and the amount of methylfuro-11 contained in the molecule was determined by amino acid analysis. I was able to claim by quantifying the amount.

Table 1 2 Results As is clear from Table 1, the in vivo utilization was very good.

Special Feature '1 Applicant Sankyo Co., Ltd. Agent, J1 Physician Shoji Zato Continued from page 1 0 Inventor Hidetsugu Takahashi Hiromachi 1, Tokyo Parts Center 0 Inventor Minoru Kitami Hirocho Tokyo Parts Office Sankyo Co., Ltd. Fermentation Research 2-58 Chome 2-58 Sankyo Co., Ltd. Fermentation Research Procedures Amendment (Shirakori 1981 (Spring Condolences 30th) Manabu Shiga, Commissioner of the Patent Office 1, Display of the incident 1982) Special revision application No. M151030 No. 2, name of the invention Mycoplanesin derivative 3, relationship with the case of the person making the amendment Patent applicant address 103!
6 name of the address (185) Tamakyo Co., Ltd. Later representative President and CEO Yoshitomo Kawamura 4 Agent residence 1-2-58 Hiromachi, Honbunagawa-ku, Tokyo 140 Sankyo Co., Ltd. Telephone number 492-3131 Name Patent attorney Shi (6007), 4'l! Osamu Isho (
゛) 5. Number of inventions increased by amendment None 6. Amendment number 1 Detailed explanation of the invention in Meisho M 1. Meisho, page 18, line 8, “Parenteral administration "Administration" is corrected.

2. Line 10 of the same page Delete "especially".

that's all

Claims (1)

[Scope of Claims] Formula (% Formula % Total cure mycoplanesin unit or its mulberry cape r
r Hitoshi Tani. However, in the formula, R represents an amino acid residue or a peptide residue containing at least one basic group and at least one carboxyl group or a mirrored carphogyl group.