JPS61194099A - Acylated hexose derivative and medicine - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

Detailed Description of the Invention [Industrial Application Field] The present invention provides 1,4,6-tri-O-momyl peptide derivatives and related D-mannose- or D-
The present invention relates to galactose derivatives, methods for producing the same, pharmaceutical preparations containing the derivatives, and pharmaceutical uses thereof.

[Summary of the invention]

The present invention particularly relates to the general formula (I): Each independently represents a lower alkanoyl group or a benzoyl group, R2 represents a lower alkyl group or a phenyl group, R3, R5 and R7 each independently represent hydrogen or a lower alkyl group, or R5 together with R8 represents a trimethylene group. , R7 represents hydrogen, R8 represents hydrogen or an unsubstituted lower alkyl group, or a lower alkyl group substituted with a phenyl group, a hydroxy group, a mercapto group, or a lower alkylthio group, R9 and Rl
t is each independently a hydroxy group, an amino group, an alkoxy group having 1 to 10 carbon atoms, an alkyl lower alkoxy group, an alkanoyloxy lower alkoxy group having 16 or less carbon atoms, an aroyloxy lower alkoxy group, or 3-cholesteryloxy. group or a 2-trimethylammonio-ethyloxy group, R10 represents hydrogen, a carboxy group, a lower alkoxycarbonyl group, or an aryl lower alkoxycarbonyl group, and R is hydrogen or an unsubstituted or amino group,
Hydroxy group, lower alkanoylamino group, lower alkanoyloxy group, 2-benzyloxycarbonylamino-ethyl-sulfinyl group, 2-benzyloxycarbonylamino-ethyl-sulfonyl group, 2-lower alkoxycarbonylamino-ethyl-sulfinyl L2-lower It represents a lower alkyl group substituted with an alkoxycarbonylamino-ethylsulfonyl group or a guanidino group, but at least one of the groups R9 and Rlt is different from a hydroxy group, an amino group, and an alkoxy group having 1 to 7 carbon atoms. , or RIG represents hydrogen, a carboxy group, and an alkoxycarbonyl group in which the alkoxy moiety has up to 7 carbon atoms] and salts of the compounds having at least one salt-forming group.

[Specific explanation]

Preferably, the hexose moiety is derived from D-glucose.

In case of asymmetric substitution, dan-R3, dan-R8 or dan-CO-
The structure at the carbon atom of R9 is (D), (L) or (D), respectively, as described in general formula (I). C
In the case of asymmetric substitution, the structure at R11 is (L) or (D), preferably (D).

Lower alkanoyl radicals R1, R4 and R6 are in particular alkanoyl radicals having 2 to 6 carbon atoms, such as n-hexanoyl, preferably alkanoyl radicals having 2 to 4 carbon atoms, such as butyryl, propionyl or preferably acetyl. It is.

The lower alkyl group R2 preferably has 1 to 4 carbon atoms,
In particular, it is an alkyl group having 1 to 2 carbon atoms.

The lower alkyl group R3, R5 or R7 is preferably an alkyl group having 1 to 3 carbon atoms, especially a methyl group.

The unsubstituted lower alkyl group R11 or R'' is preferably an alkyl group having 1 to 4 carbon atoms, such as ethyl, isopropyl, 2-methylpropyl, 5ec-butyl or especially methyl.

A lower alkyl group R8 substituted with a phenyl, hydroxy, mercapto or lower alkylthio group, such as in particular a methylthio group, is preferably a correspondingly substituted C1-C2 alkyl group, such as a benzyl group, Hydroxymethyl group, 1-hydroxy-ethyl group, mercaptomethyl group or 2-methylthio-ethyl group.

The alkoxy group R9 or Rlt is preferably an alkoxy group having 1 to 4 carbon atoms, such as a methoxy group, n-butyloxy group or tert-butyloxy group.

An aryl group as part of an aryl lower alkoxy group, an aryl lower alkoxycarbonyl group or an aroyloxy lower alkoxy group is in particular a phenyl phenyl group or naphthyl group, preferably unsubstituted phenyl group.

Oryl substituents are particularly suitable for lower alkyl groups such as methyl, phenyl, halogen, hydroxy, lower alkoxy groups such as methoxy, lower alkanoyloxy groups such as acetoxy, amino, mono- or di-lower An alkylamino group, such as a heptano or dimethylamino group, or a lower alkanoylamino group, such as an acetylamino group.

Aryl lower alkoxy group R9 and/or R'' is 1
A lower alkoxy group substituted with one or more aryl groups, for example 1 to 3, preferably 1 or 2, aryl groups, such as an arylmethoxy group, such as especially a benzyloxy group or a benzhydryloxy group.

Aryl lower alkoxycarbonyl group R10 is a lower alkoxycarbonyl group substituted with one or more, for example 1 to 3, preferably 1 or 2, aryl groups, such as an arylmethoxycarbonyl group, such as especially a benzyloxycarbonyl group, or It is a benzhydryloxycarbonyl group.

The lower alkoxycarbonyl group RIG is preferably an alkoxycarbonyl group having 5 or less carbon atoms, such as a methoxycarbonyl group, n-butyloxycarbonyl group or t
It is an ert-butyloxycarbonyl group.

The lower alkyl group Rl substituted with an amino group or a lower alkanoylamino group is preferably 4-amino-n-
It is a butyl group or a 4-lower alkanoylamino-n-butyl group. A lower alkyl group R1 substituted with a 2-benzyloxycarbonylamino-ethyl-sulfinyl group or an -sulfonyl group or a 2-lower alkoxycarbonylamino-ethyl-sulfinyl group or a monosulfonyl group is preferably a correspondingly substituted methyl group. , for example, Cb Hs -CHz OC(=O) NH-
cHz -cHz -s (=O) -cHz- group or Cb Hs -CHt OC(=O) NHCHz
-CHt5Ch-CHz- group. The lower alkyl group R'' substituted with a guanidino group is 3-guanidino-
It is an n-propyl group.

An alkanoyloxy lower alkoxy group R9 or R12 is in particular a lower alkanoyloxymethoxy group, for example a pivaloyloxymethoxy group.

Aroyloxy lower alkoxy radical R9 or R11 is in particular an aroyloxymethoxy radical, for example a benzoyloxymethoxy radical.

A lower alkyl group R1 substituted by a hydroxy group or a lower alkanoyloxy group is in particular a correspondingly substituted C1-C2 alkyl group, such as a hydroxymethyl group, a 1-hydroxy-ethyl group, a lower alkanoyloxy group. It is a methyl group or a 1-lower alkanoyloxyethyl group.

A 3-cholesteryloxy group is a group formed by removing hydrogen from the hydroxy group of cholesterin.

The general concepts used above and below preferably have the following meanings.

The term "lower" refers to groups having up to 7 carbon atoms, especially up to 4 carbon atoms.

Halogen is especially chlorine or bromine, and also fluorine or iodine.

Salt-forming groups in the compounds of general formula (1) are acidic groups, such as free carboxy groups, or basic groups, such as in particular free amino groups or guanidino groups. Compounds of general formula (I) having a trimethylammonio group exist in salt form. Depending on the type of salt-forming group, the compounds of general formula (I) form metal salts, ammonium salts or acid addition salts.

The salts of the compound of general formula (I) are preferably those which can be used in medicine and have no toxicity, such as alkali metal salts or alkaline earth metal salts, such as sodium salts,
a potassium salt, a magnesium salt or a calcium salt, or a salt with ammonia or a suitable organic amine;
In particular, aliphatic, cycloaliphatic, cycloaliphatic-aliphatic or araliphatic primary, secondary or tertiary mono-, di- or polyamines, and heterocyclic bases such as lower alkyl amines, e.g. Triethylamine, hydroxy lower alkylamines such as 2-hydroxy-ethylamine, bis-(2-hydroxyethyl)-amine, 2-hydroxy-ethyl-diethyl-amine or tri(2
-hydroxyethyl)-amines, basic aliphatic esters of carboxylic acids, such as 4-amino-benzoic acid-2-diethylaminoethyl ester, lower alkylene amines, such as 1-ethylpiperidine, cycloalkylamines, dicyclohexylamine or benzylamine, For example, N,
N9-Dibenzylethylenediamine and also bases of the piperidine type, such as pyridine, collidine or quinoline, are used for salt formation. Compounds of general formula (1) having at least one basic group can be used, for example, inorganic acids, such as hydrochloric acid, sulfuric acid or phosphoric acid, or suitable organic carboxylic or sulfonic acids, such as trifluoroacetic acid, and amino acids, such as arginine and Acid addition salts can be formed with lysine. If several acidic or basic groups are present, mono- or polysalts can be formed. Compounds of general formula (,1) having an acidic group, such as a free carboxy group and a free basic group, such as an amino group, can be used as an inner salt,
That is, it can exist in the form of a zwitterion, or part of the molecule can be present as an internal salt and the other part can be present as a normal salt.

For isolation or purification purposes, pharmaceutically unsuitable salts can be used. However, for treatment only pharmaceutically acceptable non-toxic salts are used and are therefore preferred.

French patent application No. 7422909 (publication number 22
92486) from the specification, N-acetyl-muramyl-
Shi-alanyl-D-isoglutamine compound (“MDP”)
) type muramyl peptides are known. These compounds have been described as immunological adjuvants. That is, they can be used in combination with vaccines to improve the effectiveness of inoculation. When specific tests were conducted on mice infected with influenza virus, for example, N.
-Acetyl-muramyl-alanyl-D-isoglutamine itself was found to be ineffective in preventing and treating viral infections, ie, unless mixed with waratin. The utility of the structurally simple muramyl peptide and its analogs against viral infections has not been previously described.

The present invention aims to provide muramyl peptide derivatives that are relatively simple in structure and therefore relatively easy to produce, which are highly active in the prevention and treatment of viral infections when administered to warm-blooded animals. purpose.

According to the present invention, it has surprisingly been found that the compounds of general formula (1) and their pharmaceutically acceptable salts are eminently suitable for the prevention and treatment of viral infections. This becomes clear, for example, from animal experiments as exemplified in the Examples section. In these animal experiments, animals, such as mice or guinea pigs, are treated with a dose, such as LD, that is lethal to all or a majority of untreated (control) animals. The course of infection in untreated control animals infected with various viruses at -7° was observed in comparison with animals treated with the above compounds or salts thereof before, simultaneously or after infection.

In this case, the preventive effect occurs when the compound of general formula (I) is administered before infection, from several days to several weeks, for example 4 weeks,
It has been found that therapeutic effects occur even when administered several days, eg, one week, after infection.

The compound of general formula (1) was 0.0 in the above test on mice.
It is already effective in the dosage range from 0.001 ■/eyelid to 0.1 ■/kg.

It is also noteworthy that said compounds are effective against a broad spectrum of viruses.

The compounds of general formula (1) can be used in particular for the prophylaxis and treatment of diseases caused by the viruses detailed below [for nomenclature see J.

L, Melnick, Prog, med, Vi
rol, Vol. 26, pp. 214-232 (1980) and 2
8, pp. 208-221 (1982)]: that is, DNA with cubic symmetry and naked nucleocapsid.
Virus, ``DNA-'' with coated virus particles
Viruses and RNA-Viruses with cubic symmetry - Viruses and RNA-Viruses with helical symmetry of the capsid.

DNA with virus particles coated with compounds of general formula (I) and cubic symmetry of the capsid - RN with cubic symmetry of the capsid and naked virus particles
A-RN with helical symmetry of viruses and capsids
A-virus (having a nucleocapsid envelope on the surface membrane), and also Adenoviridae (Adenoviridae).
ae), Poxviridae (Poxv1ridae)
) and Coronaviridae
) viruses, such as especially human coronaviruses.

The compound of the general formula (1) is particularly used in the Herpesviridae family (I (
erpesviridae), viruses of the family Picornaviridae and myxoviruses, as well as mast adenoviruses, such as especially human adenoviruses, subfamily cordoboxvirinae (Ch
ordopoxvirinae, such as mainly orthopoxviruses, such as especially vaccinia virus, viruses of the family Reoviridae, especially (especially human) rotavirus, and viruses of the family Caliciviridae and Rhabdoviridae. , for example in particular in the case of human as well as equine, bovine and porcine vesiculoviruses.

The compound of general formula (1) is mainly used in the Alphaherpesvirinae subfamily (81phaherpesvirinae).
) viruses, such as varicella viruses, such as human varicella-herpes zoster virus, rhinoviruses, cardioviruses and Orthomyxoviridae (Orthon+y
xoviridae), as well as viruses of the subfamily Betaherpesvirinae.
) viruses, especially human cytomegalovirus,
Aphthoviruses, especially artiodactyls, such as mainly bovine aphthoviruses, as well as paramyxoviridae (Paramyxoviridae).
myxoviridae), such as in particular pneumoviruses, such as human respiratory syncytial virus, and also viruses of the genus measles or baramyxoviruses, such as parainfluenza viruses, such as human parainfluenza and Sendai virus, and arboviruses or varicella viruses, such as varicella Used in cases of genital stomatitis virus.

Compounds of general formula (1) can be used in particular to contain simple viruses such as human herpes simplex virus types 1 and 2, human encephalomyocarditis virus, influenza viruses, mainly influenza A and B viruses, vaccinia virus and Used in the case of influenza viruses and especially the viruses mentioned in the examples.

Use of compounds of general formula (I) for the prophylaxis and treatment of viral infections, especially in bleeding animals, including humans, by intraintestinal or parenteral administration, in particular with suitable auxiliaries or excipients. I can do it. Preferably, the compound is administered to the mucous membranes, for example intranasally, rectally, vaginally, or to the ocular mucous membranes or orally. However, antiviral effects also occur with other methods of administration, such as subcutaneous, intravenous, intramuscular administration or application on normal skin.

The dosage of the active ingredient depends, inter alia, on the type of warm-blooded animal, the state of the defenses of the organism, the method of administration and the type of virus. The relationship between dose and effect is less pronounced.

For prophylaxis, a single dose of the active ingredient should be administered to a bleeding animal weighing about 70 kg, such as a human, from about 0.01 mg to about 10 mg.
, preferably 0.05 to 1 μ, for example 0.2 μ. The prophylactic effect of this dose extends for several weeks. Administration of this dose can be repeated if necessary, for example during periods of high risk of infection.

The therapeutic dose for a warm-blooded animal weighing approximately 70 kg is:
In particular, oral administration: 0.1 to 25, preferably 0.1 to 25
1■, for example 0.5■. Dosages for topical, especially intranasal, administration are up to 10 times lower. If necessary, administration of the compound of general formula (I) can be repeated until amelioration of the disease occurs. However, often one administration is sufficient.

The compound of general formula (1) further has antitumor activity.

This effect is caused by the body's own defense cells killing tumor cells (cytotoxicity) when introduced into the body, for example in multilamellar liposomes or phosphate-buffered saline (PBS).
It is based on the ability to activate macrophages so that they can inhibit or inhibit their growth (cytoinhibition). Induction of antitumor and tumor suppressive alveolar macrophages in rats in vitro and in situ is demonstrated, for example, in the tests described below.

Alveolar macrophages are obtained by lavage of the lungs with culture medium. These macrophages were obtained by injecting the test substance into rats (intravenously or intranasally, in situ activation) or by pre-incubating them for 24 hours with a compound of general formula (I) in a CO,-warming lid (in vitro). activation). The macrophages thus activated are cultured with tumor cells for an additional 72 hours.

To measure the antitumor activity of macrophages, tumor cells were labeled with 1251-iododeoxyuridine before culturing for 72 hours. After washing away the radioactivity released by lysed tumor cells, unkilled tumor cells can be determined based on the remaining radioactivity.

To measure the tumor suppressive activity of macrophages, 3H-thymidine is added to the culture medium 8 hours before the end of the 72-hour culture, and then ``H-thymidine incorporated into tumor cells is measured. In vitro. In rats, a dose of 20 nanograms in 10.2 ml of culture medium can already induce antitumor rat-alveolar macrophages, whether the substance is dissolved in PBS or incorporated into liposomes. A single intravenous injection of the compound at a dose of 160 μg/animal can induce antitumor and tumor suppressive alveolar macrophages.
A single intranasal administration of the substance in BS at a dose of 25 μg/rat can induce anti-tumor alveolar macrophages.

The compounds of general formula (I) may therefore be used in the treatment of tumor diseases in warm-blooded animals, including humans, in particular to avoid the formation of metastases, e.g. during surgical removal of secondary tumors. I can do it.

In particular, the present invention provides that the hexose moiety is D-glucose, D-glucose,
- derived from mannose or D-galactose, n represents O or 1, R1, R4 and R6 each independently represent a lower alkanoyl group or benzoyl group, Rt represents a lower alkyl group or phenyl group, R3, R5 and R
7 each independently represents hydrogen or a lower alkyl group,
Or R5 represents a trimethylene group together with R8, and R? represents hydrogen, Ra is hydrogen or unsubstituted or represents a lower alkyl group substituted with a phenyl group, hydroxy group, mercapto group, or a lower alkylthio group, R9 and Rt2
each independently represents a hydroxy group, an amino group, an alkoxy group having 1 to 10 carbon atoms, a lower alkoxy group,
represents an alkanoyloxy lower alkoxy group, an aroyloxy lower alkoxy group or a 3-cholesteryloxy group having 16 or less carbon atoms, R10 is hydrogen, a carboxy group,
Represents a lower alkoxycarbonyl group or a lower alkoxycarbonyl group, in which RI 1 represents hydrogen or a lower alkyl group that is unsubstituted or substituted with an amino group or a hydroxy group, and at least one of the groups R9 and R'' The general formula ( 1) and a salt thereof having at least one salt-forming group.

R9 and RIM each independently represent a hydroxy group, an amino group, an alkoxy group having 1 to 10 carbon atoms, or a carbon atom number 1
6 or less alkanoyloxy lower alkoxy group, 3-cholesteryloxy group or phenyl moiety is unsubstituted or lower alkyl group, such as methyl group, phenyl group, halogen,
hydroxy group, lower alkoxy group, such as methoxy group,
phenyl- or benzoyloxy-lower substituted with a lower alkanoyloxy group, such as an acetoxy group, an amino group, a mono- or di-lower alkylamino group, such as a mono- or dimethylamino group, or a lower alkanoylamino group, such as an acetylamino group; represents an alkoxy group, R1 (1 is hydrogen, a carboxy group, a lower alkoxycarbonyl group, or a phenyl moiety is an unsubstituted or lower alkyl group, such as a methyl group, a phenyl group, a halogen, a hydroxy group, a lower alkoxy group, such as a methoxy group, a lower Alkanoyloxy groups, such as acetoxy groups, amino groups,
represents a phenyl lower alkoxycarbonyl group substituted by a mono- or di-lower alkylamino group, such as a heptano or dimethylamino group, or a lower alkanoylamino group, such as an acetylamino group, with the remaining substituents being as defined above; , at least one of the groups R9 and R12
a compound of the general formula (I) and at least one salt-forming compound in which RIG is different from a hydroxy group, an amino group and a lower alkoxy group, or RIG is different from a hydrogen, a carboxy group and a lower alkoxycarbonyl group; Salts of said compounds having groups are preferred.

the hexose moiety is derived from D-glucose or D-mannose, n represents O or 1, R1, R4 and R6
each independently represents an alkanoyl group or benzoyl group having 2 to 4 carbon atoms, RZ represents an alkyl group or phenyl group having 1 to 4 carbon atoms, and R3, R5 and R7 each independently represent hydrogen or a methyl group. or RS is R
together with 11 represents a trimethylene group, R7 represents hydrogen, and R8 has 1 to 2 carbon atoms substituted with hydrogen, an alkyl group having 1 to 4 carbon atoms, or a phenyl group, a hydroxy group, a mercapto group, or a methylthio group represents an alkyl group, R9 and RZ2 each independently represent a hydroxy group, an amino group, a lower alkoxy group, a phenyl lower alkoxy group,
lower alkanoyloxy lower alkoxy group, benzoyloxy lower alkoxy group or 3-cholesteryloxy group, RZ6 represents hydrogen, carboxy group, lower alkoxycarbonyl group or phenyl lower alkoxycarbonyl group, R1 is hydrogen or an unsubstituted or amino group or represents an alkyl group having 1 to 4 carbon atoms substituted with a hydroxy group, in which at least one of the groups R9 and Ra2 is different from a hydroxy group, an amino group, and a lower alkoxy group,
Particularly preferred are compounds of the general formula (I) in which R10 is different from hydrogen, a carboxy group and a lower alkoxycarbonyl group, and salts of these compounds having at least one salt-forming group.

Very preferred compounds are those in which the hexose moiety is derived from D-glucose or D-mannose, n represents 0 or 1, and R1, R4 and R6 each independently represent an alkanoyl group or a benzoyl group having 2 to 4 carbon atoms. , R2
represents an alkyl group having 1 to 2 carbon atoms or a phenyl group, R:I, R5 and R7 each independently represent hydrogen or a methyl group, R8 represents an alkyl group having 1 to 4 carbon atoms, R9 and R12 each independently represents a hydroxy group, an amino group, an alkoxy group having 1 to 4 carbon atoms, or a phenyl group.
Represents a methoxy group, a lower alkanoyloxymethoxy group, a benzoyloxymethoxy group, or a 3-cholesteryloxy group, R111 is hydrogen, a carboxy group, and has 5 carbon atoms.
It represents the following alkoxycarbonyl group or phenylmethoxycarbonyl group, R11 represents an alkyl group having 1 to 4 carbon atoms, and at least one of the groups R9 and RZ2 is a hydroxy group, an amino group, or a phenylmethoxycarbonyl group having 1 to 4 carbon atoms. Compounds of the general formula (I) in which R1 (l is different from hydrogen, a carboxy group, and an alkoxycarbonyl group having up to 5 carbon atoms) and at least one
is a salt of the compound having , salt-forming groups.

The hexose moiety is derived from D-glucose and n is 0
or 1, R1, R4 and R6 represent an acetyl group or a butyryl group, R2 represents an alkyl group having 1 to 2 carbon atoms or a phenyl group, R'' represents hydrogen or a methyl group, R5 and R? represents hydrogen, and R8 has 1 to 3 carbon atoms
represents an alkyl group, R9 is an amino group, and the number of carbon atoms is 1 to
4 represents an alkoxy group, a pivaloyloxymethoxy group, or a mono- or diphenylmethoxy group, RIG represents hydrogen, R'' represents a methyl group, and RIt represents a mono- or diphenylmethoxy group or a 3-cholesteryloxy group. Particularly preferred are compounds of general formula (1).

The hexose moiety is derived from D-glucose and n is 0
or 1, and R1, R4 and R6 have 2 to 6 carbon atoms
represents an alkanoyl group, R2 represents an alkyl group having 1 to 4 carbon atoms or a phenyl group, Rff, R5 and R''
each independently represents hydrogen or a methyl group, R8 represents an alkyl group having 1 to 4 carbon atoms, R9 represents an amino group,
Represents a lower alkoxy group, pivaloyloxymethoxy group, diphenylmethoxy group, benzyloxy group or 2-trimethylammonio-ethoxy group, R10 represents hydrogen or a lower alkoxycarbonyl group, and R11 has 1 to 4 carbon atoms. Alkyl group, lower alkanoyloxymethyl group or (2-benzyloxycarbonylamino-ethyl)
-sulfonyl-methyl group, and RI2 is an amino group, a lower alkoxy group, a pivaloyloxymethoxy group, a diphenylmethoxy group, a benzyloxy group, a 2-trimethylammonio-ethoxy group, a 3-cholesteryloxy group, or a benzoyloxymethoxy group. represents the groups R9 and RI
! Particularly preferred are compounds of general formula (1) in which one group is different from an amino group and a lower alkoxy group, and salts of these compounds capable of forming salts.

In particular, at least one of the groups R9 and RI2 is a pivaloyloxymethoxy group, a diphenylmethoxy group, a benzyloxy group, a 2-trimethylammonio-ethoxy group, a 3-
Particularly preferred are compounds of the general formula (1) which represent a cholesteryloxy group or a benzoyloxymethoxy group, in which the other groups R9 and RI2 represent the aforementioned groups, and salts of these compounds which can form salts.

The compounds described in the Examples of general formula (1) are most preferred.

The compound of general formula (1) is produced by a method known per se.

These compounds have, for example, a) general formula (■): (L) [wherein at least one of the groups R"% R"% R" and R"
represents hydrogen, and the rest of these groups are R', the group R” −
C(=O)-1R' or R' in Table L, the remaining substituents are as described above, and the free functional group present in the metal compound of general formula (n) is a group that should participate in the reaction. The compound is optionally protected with a protecting group that can be easily removed by removing the group R', R'' -C(=0)-1R
or b) a compound of the general formula (■): [wherein the substituents represent the above-mentioned]. or a reactive derivative thereof with the general formula (■): LL) [wherein X represents a reactive esterified hydroxy group, the remaining substituents represent the above, and in the compound of the general formula (I'/) Existing free functional groups are protected with a protecting group that can be easily removed as necessary except for X], and the existing protecting groups are removed as necessary, or ) General formula (V): (L) [In the formula, q, r, s and t each independently represent 0 or 1, the substituent represents the above-mentioned group, and is present in the compound of general formula (V) The free functional group is protected with a protecting group that can be easily removed except for the group that should participate in the reaction] or its reactive carboxylic acid derivative with the general formula (■): The following margin (L ) [In the formula, u, v and X each independently represent 0 or 1,
The remaining symbols and substituents represent those mentioned above, and the general formula (V
The free functional groups present in the compound of formula (1) are optionally protected with easily removable protecting groups, except for groups that should participate in the reaction, and in the reaction component of general formula (V), q and If t is 0, u, v and X represent 1; if q is 1 and t is O, then U represents 0 and V
and X represent 1; q, r and t represent 1, and S
is 0, U and V represent 0 and X represents 1; or when preparing a compound of general formula (I) where n represents 1, q% r, S and t are 1 , U and In order to produce a compound of general formula (1) representing a hydroxy group and an amino group, and/or R'' represents a lower alkoxycarbonyl group or an aryl lower alkoxycarbonyl group, and the remaining substituents are as described above, the general Formula (■): (L) [In the formula, at least one of the groups R10m and R11 represents a carboxy group, and the other of the groups R1111 and RI3 is R'6
or has the above definition of the group R9-C(=O)-, the remaining substituents are as defined above, and the free functional group present in the compound of general formula (■) is a group to participate in the reaction. or a reactive carboxylic acid derivative thereof, which is protected with a protecting group that can be easily removed if necessary, excluding the protective groups present, or e) at least one of the radicals R', C(=O)-R', R'', R'' and C(=O)-R'' is in a protected form, which does not correspond to the definition of the desired target substance; Existing general formula (
I) to remove the corresponding protecting group in the compound of general formula (1), or f) R9 represents an amino group and the remaining substituents are as described above, (
■): (L) [In the formula, R14 represents a carboxy group, the remaining substituents represent those mentioned above, and the free functional group present in the compound of general formula (■) is a group that should participate in the reaction. or a reactive carboxylic acid derivative thereof, which is optionally protected with a protecting group that can be easily removed, and optionally removes the existing protecting group, Method a) After carrying out one of -f), if necessary, the obtained compound of general formula (I) having at least one salt-forming group is converted into a salt or the obtained compound of general formula (1) is converted into a salt. It is produced by converting the salt of the compound into the free compound and/or separating the resulting isomeric mixture.

Methods a, c, d and e, and also method f, are preferred.

The implementation of the method is detailed below: Method To introduce the miniacyl groups R1, R4 and/or R6 it is preferred to use method a). In this case, preference is given to starting from compounds of the general formula (n) in which the radical R2m represents the radical R''-C(=O).

Free functional groups (preferably protected with easily removable groups) optionally present in the compounds of general formula (If) are in particular free hydroxy or mercapto groups in the radical R@, free carboxy Group R9-C(=O)
-1R1(l or R"-C(=O)- and a free amino group, hydroxy group or guanidino group in the group R. A free carbamoyl group R' -C(=O)-
or R''-C(=O)- is optionally protected.

Protecting groups, their introduction and removal can be described, for example, in "Prote
Active Groups in Organic C
he+m1stry” (Plenum Press London, New York (1973)) and “Met
der organischen Che
mie'' (Houben-Weyl, 4th edition, 15
Volume/l, Georg--Thieme-Verla
g, Stuttgart (1974)) and The
odora W, Greene, “Protec
tive Groupsin Organic 5y
nthesis' (John Wiley &
5ons, New York (1981)]. A characteristic feature of protecting groups is that they are easily eliminated, ie without undesired side reactions, for example by solvolysis, reduction, photolysis or under physiological conditions.

Hydroxy protecting groups include, for example, acyl groups, e.g. lower alkanoyl groups optionally substituted with e.g. halogen,
for example a 2,2-dichloroacetyl group, or an acyl group of a carbonic acid half ester, in particular a tert-butyloxycarbonyl group, an optionally substituted benzyloxycarbonyl group, such as a 4-nitro-benzyloxycarbonyl group or a diphenylmethoxycarbonyl group, or 2-halogen-lower alkoxycarbonyl group, e.g. 2,2.2
-trichloroethoxycarbonyl groups, furthermore trityl or formyl groups, or organosilyl- or stannyl groups, furthermore easily removable etherification groups, such as te
rt-lower alkyl group, e.g. tert-butyl group, 2
-oxy- or 2-thia-aliphatic or cycloaliphatic hydrocarbon radicals, especially 1-lower alkoxy-lower alkyl or 1-lower alkylthio-lower alkyl groups, such as methoxymethyl, -methoxyethyl, 1-ethoxyethyl a methylthiomethyl group, a -methylthioethyl group or a 1-ethylthioethyl group, or a 2-oxa- or 2-thiacycloalkyl group having 5 to 6 ring atoms, such as a tetrahydrofuryl group or a 2-tetrahydropyrani group. or the corresponding thia analogues, as well as optionally substituted 1-phenyl lower alkyl groups, such as optionally substituted benzyl or diphenylmethyl groups; substituents for the phenyl group include, for example, halogen, e.g. Suitable examples include chlorine, lower alkoxy groups, such as methoxy and/or nitro groups.

Carboxy groups are usually protected in an esterified form, and such ester groups can be easily removed under mild conditions. Carboxy groups thus protected include, as ester groups, in particular lower alkyl groups which are branched in the 1-position or suitably substituted in the 1- or 2-position. Preferred carboxy groups which are present in esterified form are in particular ter-lower alkoxycarbonyl groups, such as tert-butyloxycarbonyl groups, arylmethoxycarbonyl groups having one or two aryl groups. A group optionally includes, for example, a lower alkyl group, such as a tert-lower alkyl group, such as a tert-lower alkyl group, such as a tert-lower alkyl group, e.g.
- represents a phenyl group substituted with one or more substituents by a butyl group, a lower alkoxy group, such as a methoxy group, a hydroxy group, a halogen, such as chlorine, and/or a nitro group), e.g.
optionally a substituted benzyloxycarbonyl group, e.g. as described above, such as a 4-methoxybenzyloxycarbonyl group, or a 4-nitrobenzyloxycarbonyl group, or an optionally substituted diphenylmethoxy group, e.g. as described above carbonyl group, such as diphenylmethoxycarbonyl group or di(4-methoxyphenyl)-methoxycarbonyl group, ■-lower alkoxy-lower alkoxycarbonyl group, such as methoxymethoxycarbonyl group, 1-methoxyethoxycarbonyl group or 1-ethoxymethoxycarbonyl group, 1-lower alkylthio lower alkoxycarbonyl group, e.g. 1-
methylthiomethoxycarbonyl group or 1-ethylthioethoxycarbonyl group, aroylmethoxycarbonyl group (aroyl group optionally represents a benzoyl group substituted with halogen, e.g. bromine), e.g. phenacyloxycarbonyl group, 2-halogen A lower alkoxycarbonyl group, such as a 2,2.2-trichloroethoxycarbonyl group, a 2-bromoethoxycarbonyl group, or a 2-iodoethoxycarbonyl group, or a 2-(trisubstituted silyl)-ethoxycarbonyl group (substituents are each independently aliphatic, araliphatic, cycloaliphatic or aromatic hydrocarbon radicals optionally substituted, e.g. 2-tri-lower alkylsilylethoxycarbonyl group, 2-trimethylsilylethoxycarbonyl group or 2-(di-n-butyl- methyl-silyl)-ethoxycarbonyl group, or 2
-triarylsilylethoxycarbonyl group, e.g. 2
-triphenylsilylethoxycarbonyl group.

The organic silyl group or stannyl group described above and below preferably contains a lower alkyl group, particularly a methyl group, as a substituent for the silicon atom or tin atom. Corresponding silyl or stannyl groups are in particular trilower alkylsilyl groups, especially trimethylsilyl groups, and also dimethyl-tert-butyl-silyl groups, or correspondingly substituted stannyl groups, such as tri-n-butylstannyl groups. .

Preferred protected carboxy groups include ter -lower alkoxycarbonyl groups, such as tar t-butoxycarbonyl groups, particularly optionally, e.g. as described above.
Substituted benzyloxycarbonyl groups, such as 4-nitrobenzyloxycarbonyl groups, or diphenylmethoxycarbonyl groups, especially 2-(trimethylsilyl)-ethoxycarbonyl groups.

Protected amino groups include, for example, easily removable acylamino groups, arylmethylamino groups, etherified mercaptoamino groups, 2-acyl-lower alk-1-ene-
It can be present in the form of an yl-amino, silylamino or stannylamino group or as an azido group.

In the corresponding acylamino groups, the acyl group is, for example, an acyl group of an organic carboxylic acid having, for example, 18 carbon atoms or less, in particular an alkanecarboxylic acid optionally substituted, for example by a halogen or an aryl group, or optionally, for example by a halogen , an acyl group of benzoic acid or carbonic acid half ester substituted with a lower alkoxy group or a nitro group.

Such acyl groups include, for example, lower alkanoyl groups, such as formyl, acetyl or propionyl groups,
Halogen lower alkanoyl groups, such as 2-halogenacetyl groups, especially 2-chloro-12-bromo-12-iodo-12,2,2-trifluoro- or 2.2.2-
a 1-lichloroacetyl group, a benzoyl group optionally substituted, for example by a halogen, a lower alkoxy group or a nitro group, such as an evabenzoyl group, a 4-chlorobenzoyl group, a 4-methoxybenzoyl group or a 4-nitrobenzoyl group, or A lower alkoxycarbonyl group branched at the 1-position of the lower alkyl group or suitably substituted at the 1- or 2-position, in particular a tert-lower alkoxycarbonyl group, such as a tert-butyloxycarbonyl group, 1 An arylmethoxycarbonyl group having one or two ter-r groups (aryl groups preferably optionally contain, for example, lower alkyl groups, in particular ter-
lower alkyl groups, e.g. a benzyloxycarbonyl group, such as a 4-nitro-benzyloxycarbonyl group, or a substituted diphenylmethoxycarbonyl group, such as a benzhydryloxycarbonyl group or a di(4-methoxyphenyl)-methoxycarbonyl group, an aroylmethoxycarbonyl group (aroyl group) preferably represents a benzoyl group optionally substituted, for example by halogen, e.g. bromine), e.g. phenacyloxycarbonyl group, 2-halogen lower alkoxycarbonyl group, e.g. 2-bromoethoxycarbonyl group or 2
-iodoethoxycarbonyl group, or 2-(trisubstituted silyl)-ethoxycarbonyl group (each substituent is independently optionally substituted, e.g. carbon substituted with lower alkyl group, lower alkoxy group, aryl group, halogen or nitro group) aliphatic, araliphatic, cycloaliphatic or aromatic hydrocarbon group having up to 15 atoms, such as the corresponding optionally substituted lower alkyl group, phenyl lower alkyl group, cycloalkyl group or phenyl group), For example, 2-trimethylsilylethoxycarbonyl group or 2-(di-
n-butylmethyl-silyl)-ethoxycarbonyl group,
or a 2-triarylsilylethoxycarbonyl group, such as a 2-triphenylsilylethoxycarbonyl group.

Suitable acyl groups as amino-protecting groups are furthermore suitable groups of organophosphoric, phosphonic or phosphinic acids, such as di-lower alkylphosphoryl groups, such as dimethylphosphoryl, diethylphosphoryl, di-n-propylphosphoryl or diisopropylphosphoryl. a dicycloalkylphosphoryl group, such as a dicyclohexylphosphoryl group, an optionally substituted diphenylphosphoryl group, such as a diphenylphosphoryl group, a di(phenyllower alkyl)-phosphoryl group, optionally substituted with a nitro group, such as dibenzyl a phosphoryl or di(4-nitrobenzyl)-phosphoryl group, an optionally substituted phenyloxy-phenyl-phosphonyl group, such as a phenyloxyphenyl-phosphonyl group, a di-lower alkylphosphinyl group, such as a diethyl unsuphinyl group, or An optionally substituted diphenylphosphinyl group, such as a diphenylphosphinyl group.

In arylmethylamino groups (which are mono-, di- or especially triarylmethylamino groups), the aryl group is especially an optionally substituted phenyl group. Such groups are, for example, benzylamino, diphenylmethylamino and especially tritylamino.

Etherified mercapto groups in amino groups protected with such groups are in particular arylthio groups or lower alkylthio groups, the aryl group optionally being in particular a lower alkyl group, for example a methyl group. or a tert-butyl group, a lower alkoxy group such as a methoxy group, a phenyl group substituted with a halogen such as chlorine and/or a nitro group. A corresponding amino protecting group is, for example, the 4-nitrophenylthio group.

In the 2-acyl-lower alk-1-enylyl group which can be used as an amino protecting group, the acyl group is, for example, a lower alkanecarboxylic acid, optionally, for example, a lower alkyl group, such as a methyl group or a tert-butyl group, a lower alkoxy group. , for example benzoic acid substituted with a methoxy group, a halogen such as chlorine, and/or a nitro group, or in particular the corresponding group of a carbonic acid half-ester, such as a lower alkyl carbonic acid half-ester. Corresponding protecting groups are in particular the 1-lower alkanoyl-prop-1-en-2-yl group, such as the 1-acetyl-prop-1-en-2-yl group, or the 1-lower alkoxycarbonyl-prop-1-yl group. En-2
-yl group, e.g. 1-ethoxycarbonyl-prop-1
-en-2-yl group.

The amino group may be protected in protonated form; the corresponding anions are in particular the anions of strong inorganic acids, such as hydrohalides, such as chloride or bromide, or organic sulfonic acids, e.g. This is the anion of p-)luenesulfonic acid.

Preferred amino protecting groups are acyl groups of carbonic acid half esters,
In particular a tert-butyloxycarbonyl group, optionally substituted e.g. as mentioned above, such as a 4-nitro-benzyloxycarbonyl group or a diphenylmethoxycarbonyl group, or a 2-
Halogen-lower alkoxycarbonyl group, e.g. 2.2
．． 2-trichloroethoxycarbonyl group, further trityl group or formyl group.

Mercapto groups can be protected by S-alkylation, especially with optionally substituted alkyl groups, thioacetal formation, S-acylation or creation of asymmetric disulfide groups, as in cysteine, for example. Preferred mercapto protecting groups are, for example, benzyl groups optionally substituted on the phenyl group with e.g. methoxy or nitro groups, e.g. 4-methoxybenzyl groups, diphenylmethyl groups optionally substituted on the phenyl moiety e.g. with methoxy groups, e.g. .41-dimethoxydiphenyl-
A methyl group, a triphenylmethyl group, a trimethylsilyl group, a benzylthiomethyl group, a tetrahydropyranyl group, an acylaminomethyl group, a benzoyl group, a benzyloxycarbonyl group or an aminocarbonyl group, such as an ethylaminocarbonyl group.

Primary carboxylic acid amide group (carbamoyl group, CON
Hz) is, for example, a N-(9-xanthenyl)-derivative or N-(mono-, di- or triarylmethyl)
- protected in the form of derivatives (aryl represents in particular a phenyl group which is unsubstituted or substituted with up to 5 identical or different substituents). Such phenyl substituents are
Preference is given to lower alkyl groups, such as methyl, or lower alkoxy groups, such as methoxy. Examples of such arylmethyl protecting groups include 4-methoxy-benzyl, 2.4.6-)rimethoxybenzyl, diphenyl-methyl, di(4'-methoxy-phenyl)
-methyl group and di(4-methyl-phenyl)-methyl group.

Protection of the carbamoyl group is optional, ie can be carried out under suitable reaction conditions, for example using a suitable condensing agent, but is not necessary.

The guanidino group is protected, for example, in the form of an acid addition salt, especially the hydrochloride or toluenesulfonate.

The acylating agent carrying the group R', R''-C(=O)-1R4 or R6 is especially suitable for the corresponding carboxylic acid, i.e. R'-
0)1. R''-COOH, R'-OH or R'-0H
1 or preferably a reactive acid derivative thereof, which is used as acylating agent, can also be activated in situ in the presence of a compound of general formula (If).

The invention particularly relates to embodiments of process a) for introducing acyl groups R1, R4 and/or R6.

Activated carboxylic acid derivatives which can be used as acylating agents are in particular reactive activated esters or anhydrides, and also reactive cyclic amides.

Activated esters of acids are in particular esters which are unsaturated at the bonded carbon atom of the group to be esterified, such as esters of the vinyl ester type, such as the original vinyl ester (for example obtained by transesterification of the corresponding ester with vinyl acetate). 1,2-
oxacillium method or Woodward method), or 1-lower alkoxy vinyl esters (obtained, for example, by treating the corresponding acid with a lower alkoxy acetylene;
ethoxyacetylene method) or amidino-type ester,
For example, N,N'-disubstituted amidino esters (e.g., replacing the corresponding acid with the appropriate N).

N1-disubstituted carbodiimide, for example obtained by treatment with N,N''-dicyclohexylcarbodiimide (carbodiimide method), or N.

N-disubstituted amidino esters (e.g. when the corresponding acid is N,
obtained by treatment with an N-disubstituted cyanamide (cyanamide method), a suitable aryl ester, especially a phenyl ester sequentially substituted with electron-withdrawing substituents (e.g. the corresponding acid with a condensing agent, e.g. N, N" -dicyclohexyl-carbodiimide, suitably substituted phenols, such as 4-nitrophenol, 4-methylsulfonyl-phenol, 2.4.5-)lichlorophenol, 2.3.4.5.6 - obtained by treatment with pentachlorophenol or 4-phenyldiazophenol; activated ester method), cyan methyl ester (obtained, for example, by treatment of the corresponding acid with chloroacetonitrile in the presence of a base; cyan methyl ester method), thioester,
In particular phenyl-thioesters optionally substituted, for example with nitro groups, such as those obtained by treating the corresponding acids with thiophenols optionally substituted with e.g. nitro groups, in particular using the anhydride method or the carbodiimide method. activated thiol ester method), amino ester or amide ester (e.g. the corresponding acid is converted into an N-hydroxy-amino- or N-hydroxy-amide compound, e.g. N-hydroxysuccinimide, N-hydroxy-piperidine, N-hydroxy obtained by treatment with phthalimide or 1-hydroxy-benztriazole, e.g. by the anhydride method or the carbodiimide method; activated N-hydroxy ester method) or silyl ester (e.g. by treating the corresponding acid with a silylating agent, e.g. obtained by treatment with silazane,
It reacts easily with hydroxy groups, but not with amino groups).

Anhydrides of acids are symmetrical anhydrides or preferably mixed anhydrides of these acids, such as anhydrides with inorganic acids, such as acid halides, especially acid chlorides, such as thionyl chloride, phosphorus pentachloride or chloride of the corresponding acids. (obtained by treatment with oxalyl; acid chloride method), azides (e.g. obtained from the corresponding acid ester via the corresponding hydrazide, which is then treated with nitrous acid; azide method), carbonate derivatives, e.g. Anhydrides such as esters, such as carbonic acid lower alkyl half esters, such as halogen-1, e.g. -Lower alkoxycarbonyl-
Obtained by treatment with 2-ethoxy-1,2-dihydroquinoline; mixed O-alkyl carbonic anhydride method)
, or dihalogenated, especially anhydrides with dichlorinated phosphoric acids (obtained, for example, by treating the corresponding acid with phosphorus oxychloride; phosphorus oxychloride method), or anhydrides with organic acids,
For example, mixed anhydrides with organic carboxylic acids (e.g. obtained by treating the corresponding acids with optionally substituted lower alkane- or phenylalkane carboxylic acid halides, such as phenylacetic acid chloride, pivalic acid chloride or trifluoroacetic acid chloride) ; mixed carboxylic anhydride method) or a mixed anhydride with an organic sulfonic acid (e.g. a salt of the corresponding acid, e.g. an alkali metal salt) with a suitable organic sulfonic acid halide, e.g. a lower alkane- or aryl-sulfonic acid chloride, e.g. methane. obtained by treatment with sulfonic acid chloride or p-)luenesulfonic acid chloride; mixed sulfonic anhydride method), as well as symmetrical anhydrides (e.g. by condensing the corresponding acid in the presence of carbodiimide or 1-diethylaminopropyne). (symmetrical anhydride method).

Suitable cyclic amides are, in particular, amides with aromatic five-membered diazacyclenes, such as imidazoles, for example amides with imidazole (obtained, for example, by treatment of the corresponding acid with N,N'-carbonyldiimidazole; imidazolides). method), or pyrazole, e.g. 3,5-
amides with dimethyl-pyrazole (obtained, for example, by treatment of acid hydrazide with acetylacetone;
pyrazolid method).

As mentioned above, the derivatives of the acids used as acylating agents can also be formed in situ. For example, the general formula (I
The mixture of the starting material of I) and the acid used as acylating agent is mixed with a suitable N,N-disubstituted carbodiimide, e.g.
N,N'-disubstituted amidino esters can be formed in situ by reacting in the presence of N'-dicyclohexylcarbodiimide. Furthermore, a mixture of the corresponding acid- and amino-starting materials can be combined with an N,N'-disubstituted carbodiimide, e.g. N,N'-dicyclohexyl-carbodiimide and an N-hydroxy-amine or N-hydroxy-amide, e.g. The amino or amide ester of the acid used as acylating agent is to be acylated in the presence of hydroxysuccinimide, optionally in the presence of a suitable base, such as 4-dimethylamino-pyridine, of the general formula (n). Can be formed in the presence of starting materials.

The reaction can be carried out in a manner known per se, the reaction conditions depending, inter alia, on whether and how the carboxy group of the acylating agent is activated. Usually, in the presence of a suitable solvent or diluent or a mixture thereof, and if necessary, a condensing agent (which may be an acid binder, for example if the carboxy group involved in the reaction is present as an anhydride). for example from about -30°C to +150°C, especially from about 0°C to
Temperature range of +100°C, preferably room temperature (approximately +20°C)
It can be carried out in a temperature range of up to +70° C. in a closed reaction vessel and/or in an inert gas atmosphere, for example a nitrogen gas atmosphere. Common condensing agents are, for example, carbodiimides, such as N.

N'-diethyl-1N, N'-dipropyl-1N.

N'-dicyclohexyl- or N-ethyl-N'-
(3-dimethylaminopropyl)-carbodiimide, a suitable carbonyl compound such as carbonyldiimidazole, or a 1,2-oxacillium compound such as 2-ethyl-5-phenyl-1,2-oxacillium-3'-
sulfonate and '1-tert-butyl-5-methyl-isoxazolium perchlorate, or a suitable acylamino compound, such as 2-ethoxy-1-ethoxycarbonyl 1,2-dihydroquinoline. Common acid-binding condensing agents are, for example, alkali metal carbonates or hydrogen carbonates, such as sodium or potassium carbonates or hydrogen carbonates (usually together with sulfates), or organic bases, such as usually sterically hindered tri-lower alkyl amines, such as N,N-diisopropyl-N=ethyl-amine.

A protecting group that is not a component of the desired target substance of general formula (1),
For example, removal of carboxy-, amine-, hydroxy- or mercapto-protecting groups can be carried out in a manner known per se, for example by solvolysis, in particular hydrolysis, alcoholysis or acidolysis, or by reduction, in particular hydrogenolysis or It can be carried out optionally stepwise or simultaneously by chemical reduction; it is also possible to use enzymatic methods.

ter is a -lower alkoxycarbonyl group, a lower alkoxycarbonyl group substituted at the 2-position with an organic silyl group, or a lower alkoxycarbonyl group substituted at the 1-position with a lower alkoxy group or a lower alkylthio group, or an optionally substituted diphenylmethoxycarbonyl group can be converted into a free carbonyl group, for example, by treatment with a suitable acid, such as formic acid or trifluoroacetic acid, optionally with the addition of a nucleophilic compound, such as phenol or anisole. Optionally substituted benzyloxycarbonyl groups can be liberated, for example, by hydrogenolysis, for example by treatment with hydrogen in the presence of a metal hydrogenation catalyst, such as a palladium catalyst. Furthermore, a suitably substituted benzyloxycarbonyl group, for example a 4-nitrobenzyloxycarbonyl group, can be prepared by chemical reduction, for example an alkali metal dithionate, for example sodium dithionite, or a reducing metal, for example zinc or metal salt, For example, using chromium(n) salts, such as chromium(n) chloride, hydrogen releasing agents capable of producing nascent hydrogen together with the metal, such as acids, in particular suitable carboxylic acids, such as optionally the presence of lower alkane carboxylic acids substituted with hydroxy groups, such as acetic acid, formic acid, glycolic acid, diphenylglycolic acid, lactic acid, mandelic acid, 4-chloromandelic acid or tartaric acid, or alcohols or thiols (preferably with addition of water) can be converted to a free carboxy group by treatment with 2-halogen-lower alkoxycarbonyl group (optionally after converting the 2-bromo-lower alkoxycarbonyl group to the corresponding 2-iodo-lower alkoxycarbonyl group by treatment with a reducing metal or metal salt as described above) ) or the aroylmethoxycarbonyl group can also be converted into a free carboxy group, by likewise treating the aroylmethoxycarbonyl group with a nucleophilic, preferably salt-forming, reagent, such as sodium thioferlate or sodium iodide. It can be decomposed by A substituted 2-silylethoxycarbonyl group is substituted by the presence of a macrocyclic polyether (“crown ether”),
Treatment with fluoride ion-forming salts of hydrofluoric acid, such as alkali metal fluorides, such as sodium or potassium fluoride, or treatment with aprotic polar solvents, such as dimethyl sulfoxide or N,N-dimethylacetamide. in the presence of an organic quaternary base by treatment with a fluoride, such as a tetra-lower alkylammonium fluoride or a tri-lower alkylaryl ammonium fluoride, such as tetraethylammonium fluoride or tetrabutylammonium fluoride, to the free carboxy group. You can also do that.

Esterified carboxy groups can also be enzymatically degraded, for example esterified lysine, such as lysine methyl ester, can be degraded by trypsin.

The protected amino group is liberated in a manner known per se in various ways depending on the type of protecting group, preferably by solvolysis or reduction. 2-halogen-lower alkoxycarbonylamino group (in some cases, a 2-bromo-lower alkoxycarbonylamino group can be replaced with the corresponding 2-iodo-
(after conversion into a lower alkoxycarbonylamino group), the aroylmethoxycarbonylamino group or the 4-nitrobenzyloxycarbonylamino group is converted, for example, by zinc in the presence of a suitable chemical reducing agent, such as a suitable carboxylic acid, such as an aqueous solution of acetic acid. It can be decomposed by processing. The aroylmethoxycarbonylamino group can be cleaved by treatment with a nucleophilic, preferably salt-forming reagent, such as sodium thioferrate, and the 4-
The nitro-benzyloxycarbonylamino group can also be decomposed by treatment with an alkali metal, for example sodium dithionite. optionally substituted diphenylmethoxycarbonylamino group, tert-
A lower alkoxycarbonylamino group or a 2-trisubstituted silylethoxycarbonylamino group can be prepared by treatment with a suitable acid, such as formic acid or trifluoroacetic acid.
An optionally substituted benzyloxycarbonylamino group can also be prepared by, for example, hydrogenolysis, i.e. by treatment with hydrogen in the presence of a suitable hydrogenation catalyst, such as a palladium catalyst, and an optionally substituted triarylmethylamino group. The group or formylamino group can be decomposed, for example, by treatment with an acid, such as a mineral acid, such as hydrochloric acid, or an organic acid, such as formic acid, acetic acid or trifluoroacetic acid, optionally in the presence of water; Amino groups protected with silyl groups can be liberated, for example, by hydrolysis or alcoholysis. An amino group protected with a 2-halogen-acetyl group, e.g. a 2-chloroacetyl group, is treated with thiourea in the presence of a base or with a thiolate salt of thiourea, e.g. a submetallic thiolate, and then the condensation that occurs The product can be liberated by solvolysis, for example alcoholysis or hydrolysis.

Amino groups protected with 2-substituted silylethoxycarbonyl groups can be prepared by treatment with a fluoride ion-generating salt of hydrofluoric acid, as described in connection with the release of the correspondingly protected carboxy group. Can be converted into free amino acids.

Amino groups protected in the form of azido groups can be converted into free amino groups, for example by reduction, e.g. by catalytic hydrogenation with hydrogen in the presence of a hydrogenation catalyst, such as platinum, palladium or Raney nickel oxide, or by acid, For example, it is converted into free amino groups by treatment with zinc in the presence of acetic acid.

Catalytic hydrogenation is carried out in an inert solvent, such as a halogenated hydrocarbon, such as methylene chloride, or in water or a mixture of water and an organic solvent, such as alcohol or dioxane, at about 20-25°C, or with cooling or heating. It is preferable to carry out the

Hydroxy or mercapto groups protected with suitable acyl groups, organosilyl groups or optionally substituted 1-phenyl lower alkyl groups are liberated analogously to correspondingly protected amino groups.

The optionally substituted 1-phenyl lower alkyl group, for example a hydroxy group protected by a benzyl group, is preferably liberated by catalytic hydrogenation, for example hydrogenation in the presence of a palladium-coated activated carbon catalyst. 2. A hydroxy group or a mercapto group protected with a 2-dichloroacetyl group can be released, for example, by basic hydrolysis, and ter
Hydroxy or mercapto groups etherified with -lower alkyl groups or 2-oxa- or 2-thia-aliphatic or monocycloaliphatic hydrocarbon groups can be prepared by acidolysis, e.g. with mineral acids or strong carboxylic acids, e.g. trifluoro It is liberated by treatment with acetic acid. Preferably substituted methylene groups, such as lower alkylidene groups, such as isopropylidene groups, cycloalkylidene groups,
For example, two hydroxy groups protected together with a cyclohexylidene or benzylidene group can be liberated by acidic solvolysis, especially in the presence of mineral acids or strong organic acids. Hydroxy groups etherified with organic silyl groups, such as trimethylsilyl groups, can also be liberated with fluoride ion-forming salts of hydrofluoric acid, such as tetrabutylammonium fluoride.

If several protected functional groups are present, more than one protecting group can be treated simultaneously, e.g. by acidolysis, e.g. with trifluoroacetic acid or formic acid, or by reduction, e.g. with zinc and acetic acid or hydrogen and Preferably, the protecting group is selected such that it can be removed by treatment with a hydrogenation catalyst, such as palladium on activated carbon.

When the desired target substance contains a protecting group, for example, when R'2 represents a radical methoxy group, such as a benzyloxy group, the protecting group to be removed after the reaction is regioselectively removed. The protecting group is chosen in such a way that it can be removed, for example the hydroxy group etherified with an organosilyl group in the group R11 or R'' can be liberated with a fluoride,
In this case, the tert-methoxy protecting group in the group R9 or RI2 is retained.

Starting materials of general formula (n) in which R"" represents hydrogen are prepared, for example, from the corresponding compounds in which R2" represents an amino-protecting group, such as a benzyloxycarbonyl group.

Process b. Reactive derivatives of compounds of general formula (n[) are, for example, metal oxy compounds, which can be obtained, for example, by reacting compounds of general formula (III) with a suitable base, such as an alkali metal hydride or an amide. It will be done.

Reactive esterified hydroxy groups X are, for example, hydroxy groups esterified with strong inorganic or organic acids, such as mineral acids, such as hydrohalic acids, such as hydrochloric acid, hydrobromic acid or hydroiodic acid, and also sulfuric acid, or halogen sulfuric acids, such as fluorosulfuric acid, or strong organic sulfonic acids, such as lower alkanesulfonic acids or aromatic sulfonic acids, optionally substituted with, for example, halogens, such as fluorine, such as optionally lower alkyl groups, such as methyl groups, halogens, hydroxy groups, preferably chlorides, bromides or iodides, esterified with benzenesulfonic acids, e.g. methanesulfonic acid, trifluoromethanesulfonic acid or p-toluenesulfonic acid, substituted with e.g. bromine and/or nitro groups. .

Free functional groups in the compounds of general formula (IV), which are preferably protected with easily removable protecting groups, are in particular hydroxy, mercapto or carboxy groups.

The reaction is preferably carried out in an inert organic solvent at a temperature of -30 DEG C. to +150 DEG C., especially 0 DEG C. to +100 DEG C., for example +20 DEG C. to +70 DEG C., optionally in the presence of an acid binder.

Removal of protecting groups which are not components of the desired target substance of general formula (1) is carried out as described in method a).

Method C The reactive carboxylic acid derivative of the compound of general formula (V) is in particular a reactive ester, a reactive anhydride or a reactive cyclic amide, the carboxy group being reactively acylated as described in method a). It is activated in the same way as in agents, and activation can also be performed in situ.

-i Functional groups which are optionally present in the compounds of formula (V) or (VI) and which are preferably protected with easily removable protecting groups are in particular amino groups and guanidino groups in the group R, groups R1 carboxy group and group R9 or R as °
A hydroxy group as '2, further a hydroxy group or a mercapto group in the group R8, or a hydroxy group in the group R''.

In reactive derivatives of compounds of general formula (Vl), for example phosphites, such as diethylchlorophosphite,
1. Reacted with 1-phenylene-chlorophosphite, ethyl-dichlorophosphite, ethylene-chloro-phosphite or tetraethylpyrophosphite or bonded at the halogen carbonyl, e.g. chlorocarbonyl, or in the form of an isocyanate group Activate the amino group with A reactive carboxylic acid derivative of a compound of general formula (V) is a compound of general formula (Vf) (the amino group or hydroxyl group involved in the reaction exists in a free form)
Preferably, the reaction is carried out so as to react with.

The reaction and subsequent removal of protecting groups which are not constituents of the desired end product are carried out analogously to those described in process a).

The esterification of compounds of the general formula (V) in which q, r and t represent 1 can also be carried out using the esterification agents described in process d).

Method d Free functional groups which are optionally present in the compound of the general formula (■) and are protected with easily removable protecting groups are in particular carboxy groups (which should not be esterified) and also hydroxy groups. , mercapto group, guanidino group and amino group.

Suitable protecting groups and their removal are described in method a).

The reactive carboxylic acid derivative of the compound of general formula (■) is in particular a reactive ester, a reactive anhydride or a reactive cyclic amide, in which the carboxy group is the same as in the case of the reactive acylating agent described in method a). Similarly, activation may be performed in situ. A reactive carboxylic acid derivative of the compound of general formula (■) is reacted with a compound of the formula H-R" (wherein R" has the above definition of R9 excluding hydroxy and amino groups) to form a carboxy group R13. Preferably, the reaction is carried out such that the carboxy group R1 (Ill) is esterified or reacted with a lower alkanol or an aryl lower alkanol.

Compounds of general formula (■) having free carboxy groups can also be esterified by reacting them with reactive derivatives of the desired alcohols as esterification components.

Suitable esterifying agents are, for example, the corresponding diazo compounds,
For example, optionally substituted diazo lower alkanes such as diazomethane, diazoethane, diazo-n-butane or diphenyldiazomethane. These esterification agents can be used in suitable inert solvents, such as aliphatic, cycloaliphatic or aromatic hydrocarbons, such as hexane, cyclohexane,
Cooling depending on the diazo reagent in the presence of benzene or toluene, a halogenated aliphatic hydrocarbon, such as methylene chloride, or an ether, such as a di-lower alkyl ether, such as diethyl ether, or a cyclic ether, such as tetrahydrofuran or dioxane, or a solvent mixture. However, it is used at room temperature or with slight heating and, if necessary, in a closed container and/or under an inert gas atmosphere, for example a nitrogen atmosphere.

Suitable esterifying agents are furthermore esters of the corresponding alcohols, in particular strong inorganic or organic acids, such as mineral acids such as hydrohalic acid, hydrochloric acid, hydrobromic acid or hydriodic acid, furthermore sulfuric acid, or halogen acids. Sulfuric acid, such as fluorosulfuric acid, or strong organic sulfonic acids, such as lower alkanesulfonic acids optionally substituted with halogens, such as fluorine, or aromatic sulfonic acids, such as optionally lower alkyl groups, such as methyl groups, halogens, such as bromine. , and/or esters with benzenesulfonic acids substituted with nitro groups, such as methanesulfonic acid, trifluoromethanesulfonic acid or p-)luenesulfonic acid. Such esters are in particular lower alkyl halides, di-lower alkyl sulfates, such as dimethyl sulfate, and also fluorosulfonic esters, such as -lower alkyl esters, such as trifluorosulfonic acid methyl ester, or optionally substituted with halogen. Methanesulfonic acid lower alkyl esters, such as trifluoromethanesulfonic acid methyl ester.

These are usually in the presence of an inert solvent, such as an optionally halogenated, e.g. chlorinated, aliphatic, cycloaliphatic or aromatic hydrocarbon, e.g. methylene chloride, an ether, e.g. dioxane or tetrahydrofuran, or mixtures thereof. use. In this case, suitable condensing agents are used, such as alkali metal carbonates or hydrogencarbonates, such as sodium or potassium carbonates or hydrogencarbonates (usually together with sulfates), or organic bases, such as usually sterically hindered tricarbonates. Preference is given to using lower alkyl amines, such as N,N-diisopropyl-N-ethylamine (preferably together with halogen sulfonic acid lower alkyl esters or methanesulfonic acid lower alkyl esters optionally substituted with halogens), in which case While cooling, at room temperature or while heating, for example, from about -20°C to about 5°C.
It is operated at a temperature of 0° C., optionally in a closed container and/or in an inert gas atmosphere, for example a nitrogen gas atmosphere.

The esterifying agent may furthermore be the corresponding tri-substituted oxonium salts (so-called Meerwein salts) or di-substituted carbenium or halonium salts (where the substituents are groups to be etherified), such as tri-lower alkyl oxonium salts, and di-lower Alkylhalonium salts or di-lower alkylhalonium salts, especially salts with complex fluorine-containing acids, such as the corresponding tetrafluoroborates, hexafluorophosphates, hexafluorophosphates or hexachloroantimonates. Such reagents are, for example, trimethyloxonium- or triethyloxonium-hexafluoroantimonate, -hexachloroantimonate, -hexafluorophosphate or monotetrafluoroborate, dimethoxycarbenylam hexafluorophosphate or dimethylbromonium Hexafluoroantimonate. These reagents are treated in the presence of an inert solvent such as an ether or a halogenated hydrocarbon such as diethyl ether, tetrahydrofuran or methylene chloride, or a mixture thereof, optionally with a base,
For example, in the presence of an organic base, such as a preferably sterically hindered tri-lower alkylamine, such as N,N-diisopropyl-N-ethyl-amine, with cooling, at room temperature or with slight heating, e.g. ℃～about 50
C., optionally in a closed container and/or in an inert gas atmosphere, for example a nitrogen gas atmosphere.

A preferred embodiment of process d) is to react the cesium salt of the compound of general formula (■) with the desired alcohol as esterification component (the hydroxy group is present in reactive ester form).

Method e: Compounds of the general formula (1) in which at least one of the groups Ra, R9, RIG, R11 and RI2 (D) are present in protected form (does not correspond to the definition of the desired target substance), especially,
Hydroxy group or mercapto group in group R1, group R1
This is a compound in which an amino group or hydroxy group, a free hydroxy group R9 or RI2, and/or a carboxy group R'' is not contained in the desired target substance and is protected with an easily removable protecting group.

Easily removable protecting groups are in particular those mentioned under method a). Removal of the protecting group is carried out analogously to that described in method a).

Method f. Free functional groups which are optionally present in the compounds of the general formula (■) and are protected with easily removable protecting groups are in particular carboxy groups (which should not be amidated), and also hydroxy groups. group, mercapto group, guanidino group and amino group.

Suitable protecting groups and their removal are described in method a).

The reactive carboxylic acid derivative of the compound of general formula (■) is in particular a reactive ester, a reactive anhydride or a reactive cyclic amide, the carboxy group being as in the reactive acylating agent described in method a). Activation may be performed on the fly. Preferably, the reaction is carried out in such a way that the carboxylic acid derivative of the compound of general formula (■) is reacted with ammonia.

Alternatively, a compound of general formula (■) having a free carboxy group can be reacted with a reactive ammonia derivative,
Activation of the amino groups is then carried out, for example, as described in method C).

The reaction and subsequent removal of protecting groups which are not constituents of the desired end product are carried out analogously to those described in process a).

A salt of the compound of general formula (I) having a salt-forming group can be produced by a method known per se. Salts of compounds of general formula (1) having acidic groups can be prepared by reaction with a suitable base, for example with a suitable metal compound, such as an alkali metal salt of a suitable organic carboxylic acid, such as the sodium salt of α-ethyl-caproic acid, or a suitable inorganic alkali metal or alkaline earth metal salt, especially a salt derived from a weak acid, preferably a volatile acid, such as sodium bicarbonate, or formed by treatment with ammonia or a suitable organic amine; In this case, it is preferred to use a stoichiometric amount or a small excess of salt formers. Acid addition salts of compounds of general formula (I) are obtained in conventional manner, e.g. by treatment with acids or suitable anion exchange reagents. Molecules of compounds of general formula (I) containing, for example, free carboxy and free amino groups Inner salts can be formed, for example, by neutralizing a salt, such as an acid addition salt, to its isoelectric point using, for example, a weak base, or by treatment with a liquid ion exchanger.

Salts can be converted into free compounds in the usual manner, e.g. metal and ammonium salts can be converted into free compounds by treatment with a suitable acid, and acid addition salts can be converted into free compounds, e.g. by treatment with a suitable basic reagent. Can be converted into the free compound.

Isomer mixtures can be separated into the individual isomers in a manner known per se, for example by fractional crystallization, chromatography or the like.

The above methods, including the protecting group removal methods and additional operations, include:
in a manner known per se, for example in the presence or absence of preferably inert solvents and diluents, unless otherwise stated.
Optionally in the presence of a condensing agent or catalyst, the temperature may be lowered or increased, e.g.
C., primarily at room temperature, in a closed container and/or in an inert gas atmosphere, for example a nitrogen gas atmosphere.

At that time, considering all substituents present in the molecule,
If necessary, e.g. in the presence of readily hydrolyzable groups, particularly mild reaction conditions, e.g. short reaction times, use of mildly acidic or basic reagents at low concentrations, extenuating stoichiometric proportions, suitable Apply selection of catalyst, solvent, temperature conditions and/or pressure conditions.

The invention further provides that the compounds obtained as intermediates at any stage can be used as starting materials to carry out the remaining steps, or the operation can be interrupted at any stage, or the starting materials can be brought under reaction conditions. Embodiments of the process are produced or used in the form of reactive derivatives or salts. In this case, preference is given to starting from starting materials which, by manipulation, produce the compounds mentioned as being particularly preferred.

New starting materials and/or intermediate products and processes for their production are likewise the subject of the invention. It is preferred to use starting materials which give rise to the compounds listed as particularly preferred herein and to select reaction conditions accordingly.

The present invention further provides an effective amount of the active ingredient, particularly an amount effective for preventing or treating viral infections or treating tumor diseases.
Suitable for topical administration, e.g. intranasally, enteral administration, e.g. oral or rectal administration, or parenteral administration, together with inorganic or organic solid or liquid, pharmaceutically acceptable excipients. Relating to pharmaceutical formulations containing. Diluent for active ingredients,
For example, lactose, glucose, sucrose, mannitol or sorbitol, cellulose and/or glycerin, and/or lubricants such as diatomaceous earth, talc, stearic acid or its salts, such as magnesium or calcium stearate, and/or polyethylene glycol. Use accompanying tablets or gelatin capsules.

Tablets may likewise contain binders such as magnesium aluminum silicate, starches such as corn starch, wheat starch or rice starch, gelatin, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, and/or optionally disintegrants such as starch. ,
Parenteral administration of the pharmaceutically active compounds of the invention may further include agar, alginic acid or a salt thereof, such as sodium alginate, and/or a blowing agent, or an adsorbent, a coloring agent, a flavoring agent, and a sweetening agent. It can also be used in the form of possible formulations or injectable solutions. Such solutions are preferably isotonic aqueous solutions or suspensions, e.g. in the case of lyophilized preparations containing the active ingredient alone or together with excipients, e.g. mannitol, before use. can be manufactured. The pharmaceutical preparations may be sterile and/or contain auxiliary agents such as preservatives, stabilizers, wetting agents and/or emulsifying agents, solubilizing agents, osmotic salts and/or buffers.

The pharmaceutical preparations according to the invention may optionally contain further substances with pharmacological action, for example antibiotics, and can be prepared in a manner known per se, for example by conventional mixing, granulation, sugar coating, dissolution or freezing. It is produced by a drying method, and contains about 0.001% to 20% of the active ingredient, particularly about 0.01% to about 10%,
In particular, active ingredient concentrations of 0.1% to 5% and 1% or less,
It is particularly suitable for formulations to be applied topically.

For preparations to be applied topically, the active ingredient content is 0.0.
01% to 1%, especially 0.01% to 0.1%, e.g.
05% cream, ointment or paste, such as intranasal ointment or lipstick, or active ingredient content o;
oot%~1%, especially 0.05%~0.5%, e.g. 0
．． 1% aqueous solutions, preferably isotonic, sterile, physiologically acceptable solutions, such as eye drops, preferably microcontainers for single use, or sprays for oral and throat application. preferable.

The pharmaceutical formulations described in the Examples are particularly suitable.

Creams are oil-in-water emulsions containing more than 50% water. Oily bases include in particular fatty alcohols such as lauryl alcohol, cetyl alcohol or stearyl alcohol, fatty acids such as valmitic acid or stearic acid, liquid to solid waxes such as isopropyl myristate, wool wax or beeswax, and/or hydrocarbons, For example, Vaseline (Petrolatu)
m) or use paraffin oil. Emulsifiers include surface-active substances with markedly hydrophilic properties, such as corresponding nonionic emulsifiers, such as fatty acid esters of polyalcohols or their ethylene oxide adducts, such as polyglycerol fatty acid esters or polyoxyethylene sorbitan fatty acid esters (Tween). ), and also polyoxyethylene fatty alcohol ethers or fatty acid esters, or corresponding ionic emulsifiers, such as alkali metal salts of fatty alcohol sulfates, such as sodium lauryl sulfate, sodium cetyl sulfate or sodium stearyl sulfate; Metal salts are usually used in the presence of fatty alcohols, such as cetyl alcohol or stearyl alcohol. Additives to the aqueous phase are, in particular, agents which reduce the dryness of the cream, such as polyalcohols such as glycerin, sorbitan, propylene glycol and/or polyethylene glycol, as well as preservatives, perfumes and the like.

Ointments are water-in-oil emulsions containing up to 70% water or an aqueous phase, preferably from about 20% to about 50%. As fatty phase, hydroxy compounds suitable in particular for improving the water-binding power, such as fatty alcohols or their esters, such as cetyl alcohol or wool wax alcohol, or hydrocarbons containing wool wax, such as petrolatum, paraffin oil and/or solid paraffin, are suitable. is applicable. Emulsifiers are corresponding lipophilic substances, such as sorbitan fatty acid esters (spans), sorbitan oleate and/or sorbitan isostearate. Additives to the aqueous phase are, for example, water retention agents, such as polyalcohols such as glycerin, propylene glycol, sorbitol and/or polyethylene glycol, such as preservatives, perfumes, etc.

Fatty ointments are anhydrous and contain as bases in particular hydrocarbons, such as paraffin, petrolatum and/or liquid paraffin, and also natural or partially synthetic fats, such as coconut fatty acid triglycerides, or preferably hydrogenated oils, such as hydrogenated peanut oil or Castor oil also contains fatty acid partial esters of glycerin, such as glycerin mono- and distearate, as well as fatty alcohols, emulsifiers and/or additives which enhance water absorption, such as those mentioned in connection with ointments.

Pastes are creams and ointments that contain powder components that absorb secretions, such as water present or metal oxides that bind secretions, such as titanium oxide or zinc oxide, as well as talc and/or aluminum silicates.

Effervescent formulations are liquid oil-in-water emulsions administered from pressure containers and present in the form of an aerosol, in which halogenated hydrocarbons, such as chlorofluoro-lower alkanes, such as dichlorodifluoromethane and dichlorotetrafluoroethane, are used as foaming agents. be done. As oil phase, in particular hydrocarbons such as paraffin oil, fatty alcohols such as cetyl alcohol, fatty acid esters such as isopropyl myristate, and/or other waxes are used.

As emulsifiers, those having particularly remarkable hydrophilicity, such as polyoxyethylene-sorbitan-fatty acid ester (
(Tween) and those with significant lipophilic properties, such as sorbitan fatty acid esters (Span). Conventional additives, such as preservatives, are also used.

Tinctures and solutions often have a water-ethanolic base, in particular polyalcohols such as glycerin, glycols and/or polyethylene glycols as water retaining agents to reduce evaporation, and ethanol from the skin. fat-returning substances as substitutes for the fatty substances extracted with them, e.g. fatty acid esters with lower polyethylene glycols, i.e. lipophilic substances soluble in aqueous mixtures;
Other auxiliaries and additives may also be added as necessary.

Pharmaceutical preparations which can be used topically are produced in a manner known per se, for example by dissolving or suspending the active ingredient in the carrier or, if appropriate, in a part thereof. When preparing the active ingredient as a solution, the active ingredient is generally dissolved in one of the two phases before emulsification. When prepared as a suspension, it is mixed with a portion of the base after emulsification and then added to the remaining formulation ingredients.

The following examples illustrate the invention and do not limit it in any way. The Rf value was measured using a thin silica gel plate (Merck, Darmstad, West Germany).
Get it. The mutual proportions of the developing agents in the developing agent mixtures used are expressed in volume fractions (V/■) and the temperatures are given in degrees Celsius. solvent(
The concentration C of a substance in a mixture) is given in % (weight/volume) in case of optical rotation.

Eμ electron Boc = tert-butylated dicarbonyl Me
= Methyl MeOH = 11.4 g of N-propionyl-desmethylmuramyl-si-alanyl-D-isoglutamine-benzhydryl ester (α,β-mixture) containing 1.17 mol of methanol (1
6.77 mol) is dissolved in 120 ml of anhydrous pyridine. To the solution thus obtained was added 7.6 ml (80 ml) of acetic anhydride.
, 3 mmol) and stirred at room temperature for 92 hours. The yellowish solution is then concentrated by evaporation at 40° C. in a high vacuum. The crude product thus obtained is triturated with 100 ml of diethyl ether and the suspension thus obtained is stirred for 2 hours at room temperature. The formed crystals are then passed through a suction port and washed with diethyl ether.

After two recrystallizations from acetic acid ethyl ester/isopropanol/diethyl ether (100:5:40), pure 1,4
．． 6-Tri-O-acetyl-N-7'ropionyldesmethylmurami/L/-L-alanyl-D-isoglutamine-benzhydryl ester (α,β-mixture) is a colorless crystal with a melting point of 165-166°C obtained as.

The recrystallization mother liquors are combined and concentrated by evaporation in vacuo. The residue thus obtained was subjected to column chromatography using 600 g of silica gel (type 60, purest, Merck & Co., Ltd., 0.063-0.2 m) in a chloroform/ethanol (9:1) system (10 ml fractions). refine.

Fractions 217-310 are combined and concentrated by evaporation in vacuo. By chromatography of the second fraction pure 1. 4. 6-tri-O-acetyl-N
-propionyl-desmethylmuramyl-shi-alanyl-
D-isoglutamine-benzhydryl ester (α, β
- mixture) is obtained, which is dissolved together with the first fraction in anhydrous methanol 200a+1. The slightly cloudy solution thus obtained was then filtered through a Milliball filter (Fluoropore, PT).
FE, 0.2 μm) and the clear mouth liquid is concentrated by evaporation in vacuo at 40°C. Next, the residue was filtered in advance through a milliball filter [fluoropol, PTFE,
Acetic anhydride ethyl ester 50
ml, crystallized by adding 20 ml of anhydrous diethyl ether which had also been passed through a milliball filter, and washed with the passed anhydrous diethyl ether. ■.

4.6-Tri-O-acetyl-N-propionyl-desmethylmuramyl-shi-alanyl-D-isoglutamine-
Benzhydryl ester (α,β-mixture) has a melting point of 16
Obtained as colorless crystals at 5-166°C. This is still 0
．． Contains 27 moles of water.

Cs5HallNa O+a ・0.27 Hz O(
789,68) CHNOH,0 Calculated value 57.80 6.22 7.10 2B,9
1 0.62 Actual value 57.91 6.20 ?
, 11 28.77' 0.62(α) 80=
+32.7±2.1° (C=0.486.methanol), Rf=0.28 (chloroform:methanol=9
: 1), Rf = 0.70 (chloroform: methanol = 4: 1) Fraction 105 of the above column chromatography
Another product is obtained from ~140.

Yellow residue obtained by evaporation in vacuo (0,5
5g, foam) in cyclohexane/diethyl ether/
Dissolve statically in methylene chloride (10:30:5) and cool the solution thus obtained to room temperature. After decanting the solvent, the precipitated yellow oil is stirred with 50 ml of anhydrous diethyl ether for 1/2 hour. The crystals thus obtained are passed through a suction port and washed with anhydrous diethyl ether.

Next, the crystals were dissolved in tert-butanol/water (1:1).
Dissolve in 100ml. The solution thus obtained was filtered through a milliball filter [Fluoropol, PTFE, 0.2μ
M] and lyophilize.

1α,4,6-tri-〇-acetyl-2-desoxy-2-propionylamino-D-mannose-3-0-yl-acetyl-alanyl-D containing 1.11 moles of water
-isoglutamine-benzhydryl ester is obtained as a colorless powder.

Below margin C3a Ha s N a 014・ 1.11H2
0(804,81)CHNOH,0 Calculated value 56.71 6.31 6.96 30.0
3 2.48 Actual value 56.94 6.36 7.
22 30.15 2.48 [α] 6° = +5.5
±2.7° (c=o, 365; methanol), Rf
=0.49 (Chloroform:methanol=9:
1), Rf = 0.79 (chloroform: methanol = 4: 1) The starting material is obtained as follows: Step 1.1: N-propionyl-desmethylmuramyl-L containing 0.74 mol of water. -alanyl-D-isoglutamine 16.0
g (31.63 mmol) are dissolved in 300 ml of methanol/dimethoxyethane (1:1) and then 9.2 g (47.4 mmol) of diphenyldiazomethane are added. The whole is stirred at room temperature for 20 hours. After 20, 44 and 68 hours, a further 4.6 g (23.7 mmol) of diphenyldiazomethane are added in each case. After the reaction was completed (90 hours), the red solution was evaporated to dryness in vacuo at 40°C, and 300% of anhydrous diethyl ether was added to the resulting red resin.
Add m1 and stir at room temperature for 1/2 hour.

The colorless crystals obtained are filtered through a suction port and washed with diethyl ether.

After recrystallization from 400 ml of acetone, N-propionyl-desmethylmuramyl-shi-alanyl-D-isoglutamine-benzhydryl ester contains 1.17 mol of water and is colorless with a melting point of 188-190°C (decomposed). Obtained in crystalline form.

C32H4t N a Or +・1.17H,O(6
・79.78) CHN OHzO Calculated value 56.55 6.60 8.24 28.6
3 3.09 Actual value 56.67 6.67 8.4
3 2B, 65. 3.09((r)g0=+7.5±
O01° (c=0.898; methanol), Rf=0
．． 62 (chloroform: methanol: water = 70: 3
0:5), Rt =0.62 (chloroform:
Methanol + 7:3) 2.33 g (3.8 mmol) of N-propionyl-desmethylmuramyl-silicyl-alanyl-D-isoglutamine-benzyl ester containing 1.59 mol of water was added to 24 ml of anhydrous pyridine. and then 1.4 ml of acetic anhydride
(14.8 mmol) is added and the solution thus obtained is stirred for 16 hours at room temperature.

The colorless solution is then concentrated by evaporation at 30° C. in a high vacuum. The resulting pale yellow foam was fused with silica gel (type 60,
Most pure frame, Merck; 0.063-0.21m) 400g
It is purified by column chromatography in a chloroform/ethanol (9:1) system (fraction 10n+1). In this case, β- of 1.4.6-tri-O-acetyl-N-propionyl-desmethylmuramyl-L-alanyl-D-isoglutamine-benzyl ester
The anomer, α, β-anomer mixture and α-anomer are sequentially eluted.

Fractions 112-126 (β-anomer), 127
~190 (α,β-mixture) and 191–260 (α
-anomers) are combined and concentrated by evaporation at 30° C. in a high vacuum.

The residue of fractions 112-126 is crystallized from 60 ml of chloroform:diethyl ether (1:5). 1β,4.6-1-so-0-acetyl-N-propionyl-desmethylmuramyl-dis-alanyl-D-isoglutamine-benzyl ester is obtained in the form of colorless crystals with a melting point of 189-190°C. The crystals are then dissolved in 100+ wl of twice-distilled water/1 ert-butanol (1:1). The solution thus obtained is passed through a Millipol filter (Fluoroball, PTFE, 0.2 um) and lyophilized in a high vacuum. 1 containing 1.21 moles of water
β, 4゜6-tri0-acetyl-N-propionyl-
Desmethylmuramyl-L-alanyl-D-isoglutamine-benzyl ester is obtained as a colorless powder.

Csz H44N a Or a・1.21 H,O(
730,52) CHN OHzO Calculated value 52,62 6.43 7.67 33.3
0 2.98 Actual value 52.97 6.27 ? ,
86 33.24 2.98 [α] ε0=+14.3±
4.2° (c=o, 237; dimethylformamide)
, Rf =0.25 (chloroform:ethanol=
9:1), Rf = 0.67 (chloroform: ethanol = 4:1), Rf = 0.45 (chloroform: methanol = 9: 1) fractions 127-1
The residue of 90 was dissolved in chloroform:diethyl ether (1:5).
) Crystallize from 120 ml. 1.4.6-tri-O-
Acetyl-N-propionyl-desmethylmuramyl-shi-alanyl-D-isoglutamine-benzyl ester (
α,β-mixture, 'H-NMR shows α:β=about 6:
1) is obtained in the form of colorless crystals with a melting point of 156-157°C.

The crystals are then dissolved in 150+ nl of twice-distilled water/1 ert-butanol (1:1). The solution thus obtained was filtered through a milliball filter [Fluoropol, PT].
FE, 0.2 μm] and freeze-dried in a high vacuum. 1,4,6-tri-O-acetyl-N-propionyl-desmethylmuramyl-shi-alanyl-D-isoglutamine-benzyl ester (α,
β-mixture) is obtained as a colorless powder.

032H,4N4 014- 1.00 H20(72
6゜73) CHNOH,0 Calculated value 52.89 6.41 7.71 33.0
2 2.4B actual measurement value 53.18 6.42 7゜4
9 33.81 2.48 [α] 6° = + 56.0
±1.1° (c=o, 948; dimethylformamide), Rf =0.17 +0.24 (chloroform:
Ethanol = 9:1, Doubles Bot)), Rf = 0
．． 45 (Chloroform:methanol=9:1)
, Rf =0.67 (chloroform:methanol=
4:1) The residue of fractions 191-260 is crystallized from chloroform:diethyl ether (1:5) 90n+1. 1α, 4.6-1-ly O-acetyl-N-propionyl-desmethylmuramyl-L-alanyl-D-isoglutamine-benzyl ester has a melting point of 147-149°C
It is obtained in the form of colorless crystals.

The crystals are then dissolved in 100 m+1 double-distilled water/1 ert-butanol (1:1). The solution thus obtained was filtered through a Milliball filter [Fluoroball, PT].
FE, 0.2 μm] and freeze-dried in a high vacuum. In addition, 1α, 4゜6-tri- containing 1.12 mol of water
O-acetyl-N-propionyl-desmethylmuramyl-dis-alanyl-D-isoglutamine-benzyl ester is obtained as a colorless powder.

Cs z Ha N a OIa・1.12H,o
(728,89) CHNOH! 0 Calculated value 52.74 6,43 7.69 33.1
8 2.76 Actual value 52.96 6.54 7.6
2 33.15 2.76 [α) i5'=+36.9±
1.7" (c=o, 593; methylene chloride: methanol = 1:1), Rf = 0.17 (chloroform: ethanol = 9: 1), Rf value 0.45 (chloroform: methanol = 9 = 1) , Rf = 0.67 (chloroform:methanol = 4:1) N-propionyl-desmethylmuramyl-alanyl-D-isoglutaminyl root containing 2.24 moles of water
Alanine-benzhydryl ester (α, β-mixture)
1.19 g (1.54 mmol) to 12 m of pyridine
1,4.
6-tri-O-acetyl-N-propionyl-desmethylmuramyl-dis-alanyl-D-isoglutaminyl-mono-alanine-benzhydryl ester (α,β-mixture), containing 1.33 moles of water. Obtained as a colorless powder.

C4IHssNs O+s・1.33 Hz O(87
9,85) CHNOH! 0 Calculated value 55.97 6.40? , 96 29.
69 2.72 Actual value 56.14 6.36 7.
9B 29.56 2.72 (cr) 60= +
23.8±2.1'(c=0.478; dimethylformamide), Rf =0.36 (chloroform:methanol = 9:1), Rf =0.69 (
Chloroform:methanol=4:1), Rf=0.87
(Chloroform:methanol = 7:3) The starting material is obtained as follows: Step 1: N-propionyl-desmethylmuramyl-L-alanyl-〇-iso containing 1.56 mol of water. From 2.11 g (4.07 mmol) of glutaminyl monoalanine to a total of 2.14 g (11,
06 mmol) in the same manner as in Example 1 (18 hours,
room temperature), N-propionyl-desmethylmuramyl-
Alanyl-D-isoglutaminyl-monoalanine-benzhydryl ester is obtained as a colorless powder containing 2.24 mol of water.

Ca5HnyNs O+z・2.24Hz O(770
,14) CHN OHzO Calculated value 54,58 6.76 9.09 29.5
9 5.25 Actual value 54.85 6.86 9.1
1 29.21 5.25 (α)! '=+2.9±2°
(c=o, 478; dimethylformamide), Rf
=0.57 (chloroform:methanol=7:
3), Rf = 0.65 (chloroform: methanol: water = 70:30:5) ■ N-propionyl-desmethylmuramyl-L-alanyl-D-glutamic acid-( C
0.767 g (1.09 mmol) of acetic anhydride (0.49 ml) of acetic anhydride (5.2
(44 hours, room temperature) using 1. 4. 6-1-Li〇-acetyl-N-propionyl-desmethylmuramyl-shi-alanyl-D-glutamic acid = (C)-methyl ester-<c>-benzhydryl ester (α, β-mixture), water 0.7
It is obtained as a colorless powder containing 1 mol.

C3q Ha q N s O+ s・0.71 H,
O(812,62)CHNOH,0 Calculated value 57.65 6.28 5.1? 30,
92 1.57 actual value 5B, 09 6.23 5.
28 30.71 1.57[α]ε'=+53.9±
1.9° (C=0.519; dimethylformamide)
, Rf=0.55 (chloroform:methanol=9:
1), Rf = 0.87 (chloroform: methanol = 4:1), Rf = 0.95 (chloroform: methanol = 7:3) The starting materials are obtained as follows: In addition, 0868 mol N-propionyl-desmethylmuramyl-Ll11alanyl-D-glutamic acid- containing water
(C6)-methyl ester 1.32 g (2.5 mmol) to methanol/dimethoxyethane (1:1)
Total of 1.4 g diphenyldiazomethane in 27 ml
(18 mmol) in the same manner as in Example 1 using
time, room temperature), N-propionyl-desmethylmuramyl-shi-alanyl-D-glutamic acid-(C&)-methyl ester-(CT)-benzhydryl ester was dissolved in water 1
．． Obtained as a colorless powder containing 42 mol.

Cs s H4s N s O+ t・1.42 Hz
O(699,30)CHNOH,0 Calculated value 56.69 6.63 6.01 30.7
0 3.65 Actual value 56.75 6.73 6.2
1 30.74 3.65 [α) i30=+10.3±
2.3° (c=o, 435; water), Rf =0.73
(Chloroform:methanol:water=70:30
: 5), Rt = 0.9+ (Chloroform: methanol = 7: 3) Flame] N-bugopionyldesmethylmuramyl-L-alanyl-D-glutamic acid-(C
Iy) From 1.15 g (1.57 mmol) of n-phthyl ester--benzhydryl ester using 0.70 ml (7.4 mmol) of acetic anhydride in 12 ml of pyridine ( 16 hours at room temperature)
, 1.4.6-Tri-O-acetyl-N-propionyl-desmethylmuramyl-shi-alanyl-D-glutamic acid-(C&)-n-butyl ester-(CT)-benzhydryl ester (α,β - mixture) is water 0.73
Obtained as a colorless powder containing mol.

C 4 z H s s N s O Is・o. 't
s H, O (s s 5.0 8) CHNOH.
0 Calculated value 5B. 99 6.60 4.91 2
9.50 1.54 Actual value 58.96 6.7
2 4.76 29.49 1.54 [α] 3°
= + 1 2. 6±2.3° (C=0.443;
chloroform), Rf = 0.72 (chloroform:methanol = 9:1), Rf = 0.96 (chloroform:methanol = 4:1) The starting materials are obtained as follows: Step 1: 1 , N-propionyl-desmethylmuramyl-shi-alanyl-D-glutamic acid-(C&) containing 03 moles of water
1.9 g (3.3 mmol) of n-butyl ester to methanol/dimethoxyethane (1:1) 4
A total of 2.5 g (1
N-propionyl-desmethylmuramyl-thi-
Alanyl-D-glutamic acid-(C61) n-butyl ester-benzhydryl ester is
It is obtained as a colorless powder containing 9 mol.

C3hHaqNx Ot□・0.9 9 1(, O
(7 3 3.6 2) CHNOH20 Calculated value 5B. 94 7.03 5.73 2
8.32 2.43 Actual value 59.24 7.0
6 5.59 28.08 2.43 [α) i5
0 = +12.5 ± 1.9° (c = 0.522; methanol), Rf = 0.46 (chloroform: methanol = l 1), Rf = 0.63 (chloroform: methanol = 4: 1), Rf =0.88
(Chloroform:methanol = 7:3) Flame-coated crude N-acetyl-muramyl-shi-alanyl-D-glutamic acid-(C□)-pivaloyloxymethyl ester-1.0 g (1.43 mmol) and anhydrous pyridine 10m
Acetic anhydride in 0.1 5 7 ml (6.0 mmol) (20 hours, room temperature) as in Example 1.
Acetyl-1,4.6-1-lyO-acetylumramyl-L-alanyl-D-glutamic acid-(CIy)-pivaloyloxymethyl ester-(Ca)-benzyl ester (α,β-mixture) It is obtained as a colorless powder containing 0.79 mol of water.

CssHs+Ns O+,・0.7 9 H, O (
8 3 8.0 8) C H N O
HzO calculation value 54.47 6.60 5.
02 33.96 1.69 Actual value 54.52
6.36 5.12 33.71 1.69
[α]6°= +6 8. 5±4.1° (c=0.
241; dimethylformamide), Rf = 0.52
(Chloroform:methanol=9:l), Rf
=0.55 (chloroform:ethanol=9:1
) The starting material is obtained as follows: Step 6.1
: N tert-butyloxycarbonyl-D-glutamic acid-(0)-benzyl ester (60 mmol)
is dissolved in a mixture of 300 ml of tetrahydrofuran and 50 ml of water. To this solution, add cesium carbonate (purus+ rFluka) dissolved in water LOO+++I.
19.55 g (60 mmol) are added and the whole is left at room temperature for 1/2 hour. It is then concentrated by evaporation at 30° C. in a high vacuum and the residue thus obtained is in turn treated with 200+wl of methanol and 200s+1 each time.
of dimethylformamide in a high vacuum at 40°C.

The cesium salt of N-tert-butyloxycarbonyl-D-glutamic acid-(C,)-benzyl ester thus obtained (28.1 g; 60 mmol) is suspended in 500 ml of dimethylformamide.

Pivalic acid chloromethyl ester (
purum, Fluka) 1 8.0 g
(1 7.4n+1 ; 120 mmol) and sodium iodide 1 8. Add 0 g (120 mmol). The mixture thus obtained is stirred at room temperature for 17 hours.
Thereafter, it is passed through the mouth and the 0 liquid is concentrated by evaporation at 40°C in a high vacuum. The residue thus obtained is taken up in 500 ml of ethyl acetate and washed successively with 150 ml of 0.1N sodium thiosulfate solution and with water three times each.

After drying the acetate ester over sodium sulfate, it is again concentrated by evaporation in vacuo. The still slightly yellow residue is recrystallized from 450 ml of methanol/water (1:2). N-tert-butyloxycarbonyl-D
-Glutamic acid-(Ctl)-pivaloyloxymethyl ester-(CT)-benzyl ester has a melting point of 76-7
Obtained in the form of colorless crystals at 7°C.

Below margin C23H33NOl (451.52) CHN
O Calculated value 61.18 7.37 3.10 2
8.35 Actual value 61.08 7.25 3.3
3 28.58[α]ε'=+18.4±0.1°
(c=1.034; acetic acid ethyl ester), Rf =0
．． 85 (methylene chloride:methanol = 9:1) [: N-tert-butyloxycarbonyl-D-glutamic acid-(C&)-pivaloyloxymethyl ester-(0)-benzyl ester (44.3 mmol) 1,5 in 400 ml of a mixture of trifluoroacetic acid/methylene chloride (1:1) at 0°C.
Stir for an hour. The reaction solution is then concentrated by evaporation in a high vacuum at 30° C., and the residue thus obtained is taken up several times in methylene chloride and concentrated again by evaporation. The yellow oil obtained is taken up in a mixture of 100 ml of water and 300 ml of diethyl ether and cooled to 0°C. Add 80 ml of IN caustic soda (pH 7.5) to this solution while stirring vigorously.
is added and the ether phase is separated. Add ethereal solution to 1 part water
Extract once with 00ml of
Extract once with m1. The ethereal phases are combined, dried over sodium sulfate and filtered. 8.43 g of p-toluenesulfonic acid monohydrate (Puriss, Fluka) dissolved in 100 ml of diethyl ether in a reddish solution.
(44.3 mmol) and stirred for 1 hour at room temperature and then for 1/2 hour at 0°C. The crystals thus obtained are filtered through a suction port and washed with diethyl ether. The resulting crude product is recrystallized from 1 ml of ethyl acetate. Obtained in crystalline form.

C*5HssNOv S (523,60)CHN
O3 Calculated value 57.35 6.35 2.68 27.
50 6.12 Actual value 57.39 6.52 2.
72 27.53 6.12 [α] day + 8.8
±0.1″ (c=o, 924; methylene chloride), Rf
= 0.78 (methylene chloride: methanol = 9:1, double spot), Rf = 0.84 (methylene chloride: methanol ≠ 5:1, double spot) Yl+: N-acetyl- containing 0.63 mol of water 2.6 g (6.5 mmol) of the sodium salt of muramyl-shi-alanine are dissolved in 50 ml of dimethylformamide. Add 1.47 g of N,N-dicyclohexylcarbodiimide to this solution at room temperature.
(7.14 mmol), 0.74 g (7.14 mmol) of N-hydroxy-succinimide and 3.41 g (6.5 mmol) of D-glutamic acid-(C6)-pivaloyloxymethyl ester-steltosylate. The clear colorless solution thus obtained is stirred at room temperature for 14 hours.

Next, the crystals precipitated during the reaction (N.
Concentrate by evaporation at °C. The residue was converted into ethyl acetate 3
00 ml, sip, and wash the resulting solution successively 4 times with 100 n+1 water each time, 3 times with 100+*1 saturated aqueous sodium sulfate solution each time, and twice with 100 ml each time water.

The acetate ester phases are combined, dried over sodium sulfate, filtered and concentrated again by evaporation.

The pale yellow foam obtained was purified by column chromatography using 440 g of silica gel (type 60, Merck & Co., Ltd.; 0.063-0.200 Tsuru) in an acetone/acetic acid ethyl ester (7:3) system ( 10-1 fraction), fractions 21 to 70 were combined, and 4
Concentrate by evaporation at 0°C. N- containing slight impurities
Acetyl-muramyl-shi-alanyl-D-glutamic acid-(C&)-pivaloyloxymethyl ester-(C
a)-Benzyl ester is obtained as a colorless foam.

This is processed without further purification.

Rf=0.74 (chloroform:methanol:water=70
: 30: 5), Rf = 0.85 (Chloroform:methanol = 173) Flood N-benzoyl-desmethylmuramyl-shi-alanyl-
D-isoglutamine-benzyl ester 10g (15.
86 mmol) is dissolved in 100 ml of pyridine and acetic anhydride 91I11 is added. After 24 hours at room temperature, it is concentrated by evaporation in a high vacuum, the residue is taken up in methylene chloride and the organic phase is dissolved in each case in 300 ml of IN hydrochloric acid, water and 5% NaHC.
Shake out sequentially with O, I solution and water. Water phase 150m each time
Extract twice with l of methylene chloride. The combined organic phases are dried over sodium sulphate and concentrated by evaporation.

To crystallize, dissolve in 20.IIll of ethanol,
Add 30 ml of acetic acid ethyl ester and then diethyl ether until cloudy (approximately 60 ml). Melting point 168~1
α,β-1.4.6-tri-〇-acetyl-N at 69℃
-benzoyl-desmethylmuramyl-shi-alanyl-D
Colorless crystals of -isoglutamine-benzyl ester are obtained. Further crystals can be recovered from the mother liquor.

[α] de= +4 4. 9±1.2° (c=0.8
13; chloroform), Rf = 0.54 (chloroform:methanol = 9:1) dissolved in 60 ml of acetonitrile, 1°, 4.6-)
+J -0-acetyl-N-benzoyl-desmethylmuramyl-L-alanyl-D-isoglutamine 4.5 g (
3.7 g (19.1 mmol) of diphenyldiazomethane in 30 IIll of acetonitrile are added to the mixture (6.4 mmol). After 5 hours at room temperature, the reaction is complete. It was evaporated to dryness in vacuo and the residue was extracted four times with 20 ml of diethyl ether each time and extracted with silica gel (Merck, 0.04-0.
6) Purify by chromatography on 250 g. Sequentially 11 methylene chloride/acetone (9:1,
Fraction 1), 500 ml of CHz C1g/acetone (7:3, fractions 2 and 3) and IIt of C per fraction
1,c12/acetone (1:1, fraction 4.5
and 6). Thus fractions 1 to 1.
4. Impure α-anomer of 6-tri-O-acetyl-N-benzoyl-desmethylmuramyl-shi-alanyl-D-isoglutamine-benzhydryl ester, fraction 3 to pure α-anomer, fractions 4 and 5
A mixture of α,β-anomers is obtained.

α-anomer: melting point 108-110°C, [α]6°=
+ 36.3±1° (c=1.01; CHCl+
), Rf=0.27 (CHCl3:acetone=
1:, 1) The starting material 1,4.6-)g O-acetyl-N-benzoyl-desmethylmuramyl-shi-alanyl-D-isoglutamine was prepared by converting the corresponding benzyl ester (Example 7) with dimethoxy Obtained as an anomeric mixture by catalytic hydrogenation in ethane using activated carbon with 5% palladium.

Melting point 114-120°C, [α]8°=+51.9°±1° (c=0.963,
Hz O), Rf = 0.16 (CHCh:
Methanol:H,0=85:15:2) Salmon N-benzoyl-(1α,β), 4.6-)g O-butyryl-desmethylmuramyl-shi-alanyl-D-isoglutamine 1.5 g ( 2 mmol) are reacted analogously to Example 8 with diphenyldiazomethane. After a similar work-up, the resulting crude product was purified using silica gel (Merck & Co., Ltd., 0
．． 04-0.6fi) Chromatograph on 50g. Sequentially, 11 cttz ch/acetone (9:1
, fraction 1), IIl per fraction of Cb/acetone (8:2, fraction 2)
and 3) and 500 ml of c per fraction.
Elute with ut c12/acetone (7:3, fractions 4 and 5).

From fraction 2, N-benzoyl-1,4゜6-tri-O-butyrilludesmethylmurami, α- of L-alanyl-D-isoglutamine-benzhydryl ester
The impure β-anomer is obtained from the anomer fraction 4. α by dissolving in acetone (0,7 ml/g) and adding diethyl ether (22 ml/g)
- The anomer is obtained in crystalline form.

Melting point 109-113℃, [α)1m'=+45.1°±
1.1° (c-0,92, CHCl3), Rf
=0.62 (CIfCl, , acetone = 1:1)5
The β-anomer is obtained in crystalline form by dissolving in 8+1 acetone at 0° C. and adding 20 ml of diethyl ester at room temperature.

Melting point 169-171°C, [α)i! O=+13.8°±
1.3° (c=0.741, cHcls: meta/
-)Lt-1:1), Rf =0.52 (CH
CIs: 7set7=1:1) The starting material is obtained as follows.

Step 9.1: From N-benzoyl-desmethylmuramyl-shi-alanyl-D-isoglutamine-benzyl ester in pyridine with addition of a catalytic amount of 4-dimethylaminopyridine to 6
N-benzoyl-
(lα,β), 4°6-tri-O-butyryl-desmethylmuramyl-shi-alanyl-D-isoglutamine-benzyl ester is obtained. After post-treatment in a conventional manner, by rubbing with diethyl ether, crystals with a melting point of 166-171°C are obtained. [α] Furnace = + 43.2°±1°
(c=0.954, CHCl3), Cl7/
? -: Rf = 0.42 (CuCl2:acetone = 1:1), β-anomer: Rf = 0.28 (
CIC13: Acetone = 1 = 1) = JUL1: N-benzoyl-(1α, β), 4.6-1-LeeO-
Butyryl-desmethylmuramyl-shi-ara, Niru D-
N-benzoyl-(1α,β), 4. by catalytic hydrogenation of isoglutamine-benzyl ester using 5% palladium on activated carbon in tetrahydrofuran.
6-to-so-0-butyryl-desmethylmuramyl-L-
Alanyl-D-isoglutamine has a melting point of 100-105℃
Obtained as a hemihydrate.

[α) i50=+54.2°±1° (c=0.96,
methanol), Rf = 0.45 (CIC13:
Methanol - 8:2) ■ N-acetyl-desmethylmuramyl-L-alanyl-D-isoglutamine dissolved in 40n+1 of Emperor's anhydrous pyridine
3.69 g (5.6 mmol) of benzhydryl ester are reacted with 2.04 g (20 mmol) of acetic anhydride analogously to Example 1 (1 hour, room temperature). The clear solution was thoroughly concentrated at 30°C, and the residue was diluted with 150% ethyl acetate.
ml and extract the solution twice with 50 ml of water each time. After drying and evaporation of the solvent, N-acetyl-(1α
, β).

4.6-tri-O-acetylidesmethylmuramyl-L
-alanyl-D-isoglutamine-benzhydryl ester remains.

[α] 3° = +33° ± 1° (c = 1.159, methanol), Rf = 0.70 (chloroform: methanol: water -70: 30: 5), Rf = 0.4
8 (n-butanol:acetic acid:water=75nia, 5:21
) and Rf = 0.81 (ethyl acetate: n-butanol: pyridine: acetic acid: water = 42:21:21:6
: 10) N-acetyl-desmethylmuramyl-L-alanyl-D
-Isoglutamine-benzhydryl ester can be prepared as follows Step 10.1: 1. N-acetyl- in 500 ml of a 1=1 mixture of 2-dimethoxy-ethane and methanol Desmethylmuramyl-L-alanyl-D-isoglutamine 22.8g (40
11.6 g of diphenyldiazomethane in a solution of
(60 mmol) is added and the solution is stirred at room temperature for 16 hours. The red suspension was concentrated by evaporation under reduced pressure at 20°C,
The residue is triturated with diethyl ether several times until a mostly colorless product is obtained. Add this to 10 methanol
0+++1 and crystallized by adding portionwise a 2:1 mixture of diethyl ether dipetroleum ether. After stirring for several hours, first at room temperature and then in a water bath, the crystalline material is separated and dried under reduced pressure. N-acetyl-desmethylmuramyl-L-alanyl-D-isoglutamine-benzhydryl ester is thus obtained in the form of cubic crystals with a melting point of 170 DEG C. (decomposed).

[α]6°=+14−' ±1° (c=1.5, methanol), Rf=0.40 (chloroform:methanol:water=70:30:5) and Rf=0.
66 (ethyl acetate: n-butanol: pyridine: glacial acetic acid: water = 42:21:21:6:10) ■1 N-acetyl-desmethylmuramyl-L-α-aminobutyryl dissolved in anhydrous pyridine 5II11 -D-isoglutamine-benzhydryl ester 0.55 g (0
, 85 mmol) and acetic anhydride 0.281 g (2
, 76 mmol) as in Example 10 (30 min, room temperature) to N-acetyl-(1α).

β), 4,6-tri-O-acetyl-desmethylmuramyl-shi-α-aminobutyryl-D-isoglutamine-benzhydryl ester is obtained.

Rf=0.63 (chloroform:methanol:water=70
:30:5) and Rf=0.82 (ethyl acetate:n-butanol:pyridine:acetic acid:water=42:21:
2.10 g (2.54 mmol) of N-acetyl-desmethylmuramyl-L-α-aminobutyryl-D-glutamic acid-dibenzhydryl ester and acetic anhydride in 6 ml of anhydrous pyridine. From 1.053 ml (11.43 mmol), the peracetyl compound is obtained analogously to Example 1 after standing for 12 hours at room temperature. Silica gel (60 type,
Purification is carried out using 450 g of Merck; particle size 0.063-0.200 vs. fraction 5 ml), first with chloroform and then from fraction 20 with chloroform:isopropanol (3:1). Fraction 43~
Collect the substances contained in 106, °chloroform 5n+1
After adding 40 ml of anhydrous dioxane, millipore filter (Fluoropol, PTFE, 0.2
μm) and then lyophilized. N-acetyl-(1α,β), 4.6-tri-O-acetylidesmethylmuramyl-L-α-aminobutyryl-D-glutamic acid-dibenzhydryl ester is a colorless coarse ester containing 0.37 mol of water. Obtained as a powder.

Below margin C3lH57N3 013・0.37 H20 (958
,69) CHN H,0 Calculated value 63.90 6,09 4.38 0.6
9 Actual value 63.6 6.1 4.6 0.
70 [α) 30 = +29.6° Upper 1°7° (c = 0
．． 577, methanol), Rf ~0.69 (n-
butanol:acetic acid:water=75nia, 5:21) and Rf
= 0.93 (acetic acid ethyl ester: n-butanol: pyridine: acetic acid: water = 42:21:21:6:10) Starting materials are dimethylformamide and methanol obtained as follows in the same manner as in Example 1. 1:1 mixture with 3
N-acetyl-desmethylmuramyl-L-α-aminobutyryl-D-glutamic acid dissolved in Oal3. OO
An excess of diphenyldiazomethane is added to a solution of g (6.1 mmol) at room temperature with stirring. After 3 days, the red suspension is concentrated by evaporation at 30° C. in a high vacuum, the red residue is triturated several times with diethyl ether/petroleum ether (1:3) and the supernatant is decanted. The solid residue is first
Chromatography on 600 g of silica gel (type 60, Merck & Co., Ltd.) with a system of chloroform/methanol/water (70:'30:5; particularly for removal of half-esters) followed by a second column (100 g ) first using acetic acid ethyl ester, then acetic acid ethyl ester/methanol (3
: 1; Purify by chromatography using fraction 5ml).

The collected substance is dissolved in 4.5 ml of methanol, anhydrous dioxane 70II11 is added thereto, passed through a Millipol filter in the usual manner, and then freeze-dried. N-acetyl-desmethylmuramyl-L-α-aminobutyryl-D-glutamic acid-dibenzhydryl ester is obtained as a colorless powder containing 0.93 mol of water.

Ca s Hs + N 30□・0.93H,O(8
42,67)c HN H,0 Calculated value 64.14 6,34 4.99 1.9
9 Actual value 64.1 6.5 4. -! l
2.0 [α] 3° = +11.6° Upper 2°9° (C
20.344, methanol), Rf ~0.55 (
acetic acid ethyl ester:methanol=4:1) and Rt=
o, 77<chloroform:isopropanol=1:1)
Example 13 0.67 g (1 mmol) of N-acetyl-desmethylmuramyl-shi-valyl-D-isoglutamine-benzhydryl ester in 5 ml of anhydrous pyridine and 0 acetic anhydride.
．． From 367 g (3.6 mmol), N-acetyl-(1α,β), 4
．． 6-tri-O-acetyl-desmethylmuramyl-L-
Valyl-D-isoglutamine-benzhydryl ester is obtained.

[α] 6° = +35° ± 1° (C = 0.594, methanol), Rf ~ 0.92 (chloroform: methanol: water = 70: 30: 5) and Rf = 0.8
0 (ethyl acetate: n-butanol: pyridine:
(acetic acid:water = 42:21:21:6:10) starting materials are:
Analogously to Example 1, it is obtained as follows: The following margin step 13.1: 1.6 N-acetyl-desmethylmuramyl-L-valyl-D-isoglutamine dissolved in 30 ml of methanol.
0 g (3.15 mmol) are esterified with excess diphenyldiazomethane (2 hours, room temperature). The product is purified by reprecipitation several times from methanol/diethyl ether (1:8). N-acetyl-desmethylmuramyl-L-valyl-D-isoglutamine-benzhydryl ester is obtained.

[α] 6° = +13° ± 1° (c = 1.067, methanol), Rf = 0.56 (chloroform: methanol: water = 70:30:5), Rf = 0.42 (
n-butanol:acetic acid:water=75nia, 5:21) and Rf=0.72 (acetic acid ethyl ester:n-butanol:pyridine:acetic acid:water=42:21:21:6:10) Open earth↓ Anhydrous N-acetyl-muramyl- in pyridine 12orl
To a solution of 1.2 g of di-valyl-D-isoglutamine-benzhydryl ester was added 0.75 g of acetic anhydride with stirring.
Add m1 and leave at room temperature for 24 hours.

The reaction mixture was then poured onto 40 ml of ice water, whereupon
The product crystallizes out. The crystals are filtered through a suction port, washed with water, and dried. After recrystallization from acetic acid ethyl ester and diethyl ether, N-acetyl-1,4,6-t-so0
-Acetyl-muramyl-shi-valyl-D-isoglutamine-benzhydryl ester is obtained. Rf=0.3
(Methylene chloride:methanol=5:1) The starting materials used are produced as follows: Step 14.1: 25 ml of methanol and 25 ml of 1,2-dimethoxyethane
N-acetyl-muramyl-shi-valyl-D- in s+1
Add 1.1 g of diphenyldiazomethane to a solution of 2.0 g of isoglutamine and stir at room temperature for 20 hours. The reaction mixture is evaporated to dryness and extracted with diethyl ether. The residue is suspended in water, stirred, filtered and dried over NaOH-granules. The obtained N-acetyl-muramyl-L-valyl-
D-isoglutamine-benzhydryl ester is 18
Melts at 5°C (decomposition). Rf = 0.5 (chloroform: methanol: water = 14:6:1), [α] total = +38
° (c=0.912, methanol)j- N-acetyl-muramyl-shi- in anhydrous pyridine 201
To a solution of 2.0 g of alanyl-D-isoglutamine-benzhydryl ester was added 1.7 ml of acetic anhydride with stirring.
Add and leave at room temperature for 24 hours.

The reaction mixture is then poured onto 50 ml of ice water. The precipitated material is taken up in 100 ml of ethyl acetate, washed with dilute hydrochloric acid and half-saturated sodium chloride solution, and dried over magnesium sulfate. After evaporating the solvent, N-acetyl-1,4,6-
Tri-O-acetyl-muramyl-L-alanyl-D-isoglutamine-benzhydryl ester is obtained. R
f=0.7 (methylene chloride:methanol=5:1)
The starting materials used are prepared as follows: Step 15.1: N-acetyl-muramyl-shi-alanyl-D-isoglutamine in 12.5a+1 methanol and 12.5 ml 1,2-dimethoxyethane. Add 0.42 g of diphenyldiazomethane to 1.1 g of the solution and stir at 40° C. for 20 hours. After evaporating the solvent, the residue is extracted with diethyl ether and water and dried over NaOH. N-acetyl-muramyl-shi-alanyl-D-isoglutamine-
The benzhydryl ester is obtained in the form of white crystals. R
f=0.6 (methylene chloride:methanol:water=14:6
:1) - 1.45 g (1,9
9 mmol) was added with 0.73 g (7.15 mmol) of acetic anhydride and left at room temperature for 35 hours. The yellowish solution is evaporated to dryness in a high vacuum at 30° C., anhydrous dioxane is added to the residue and lyophilized. The lyophilized material is taken up in 10 ml of chloroform/methanol (1:1) and precipitated with 100 ml of anhydrous diethyl ether (3 times). The powder thus obtained was mixed with anhydrous dioxane/water (1:1).
Dissolve in 100ml and pass through millibore filter (P) in the usual manner.
Pass through TFE (0.2 μm) and freeze-dry.

N-acetyl-(1α,β), 4.6-tri-O-acetyl-muramyl-L-alanyl-D-isoglutaminyl-alanine-benzhydryl ester is water 1.42
It is obtained as a colorless powder containing 0.7 mol of dioxane and 0.7 mol of dioxane.

Ca+HsINs OSs ・0.7 Ca Ha O
z ・1.42Hz OCHN HtO Calculated value 55.90 6.37 7.44 2.7
2 Actual measurement value 55.98 6.42 7.76 2.
71[α]6°=+25°5°±2.1° (c=0.
475, dimethyl sulfoxide), Rf = 0.39
(fl-butanol:acetic acid:water=75nia, 5:21
), Rf=0.83 (chloroform:methanol:water=
70=30:5) and Rf=0.85 (chloroform:
The starting material (methanol:water:acetic acid = 70:40:9:1°) is obtained as follows: Step 16.1: N-acetyl-muramyl-L-alanyl-D-isoglutaminyl Alanine 3.25g (5.6 mmol)
is dissolved in 50 ml of methanol and esterified with excess diphenyldiazomethane while stirring. After 6 hours, the purple solution is concentrated by evaporation and the yellowish residue is purified by chromatography on 400 g of silica gel (type 60, Merck & Co.) in a system of chloroform:methanol:water (70:30:5) (fraction 13m1
).

After the initial distillation of 600 ml, the substances contained in fractions 42 to 60 were collected, taken up in 100 ml of chloroform, and filtered through a milliball filter (PTFE; 0.2, ! l m
) and concentrated by evaporation. The residue is taken up in anhydrous dioxane 150n+1 and lyophilized. N-acetyl-
Muramyl-alanyl-D-isoglutaminyl-alanine-benzhydryl ester is obtained as a colorless coarse powder.

Margin C3SH4 below? NS OSs・1.51 Hz O(
756,99) CHN HzO Calculated value 55.54 6.69 9.25 3.5
9 Actual value 55.68 6.39 9.04 3.
59[α]6°=+16.3°±1” (c=0.9
79, dimethyl sulfoxide), Rf = 0.31
(n-butanol:acetic acid:water=75 nia, 5:2
1), Rf = 0.57 (chloroform: methanol: water = 70:30:5) and Rf = 0.33 (chloroform: methanol: water: acetic acid = 75 = 27:5:0.5
) N-acetyl-muramyl-L-acyel-D-isoglutaminyl-L-alanine-benzyl ester dissolved in 18 ml of anhydrous pyridine. A peracetyl compound is obtained in the same manner as in Example 6 from OOg (1,53 mmol) and acetic anhydride 0.66 g (5,97 mmol) (6
time, room temperature). Purification was performed using 150 g of silica gel (type 60, Merck & Co., Ltd.) using chloroform/methanol/water (70:3).
0:5; fraction 5 ml) system. N-acetyl-(1α, β
).

4.6-Tri-O-acetyl-muramyl-L-alanyl-D-isoglutaminyl-L-alanine-benzyl ester is obtained as a colorless lyophilizate containing 1.84 mol of water.

C3sHaqNs OSs-1,84Hz O(812
,94) CHN H! 0 Calculated value 51.72 6.56 8.62 4.0
7 Actual measurement value 51.5 6.9 8.3 4.
1 [α] day + 38.5' ±3.5° (c,
=0.282, dimethylformamide), Rf =0.
63 (acetonitrile: water = 3: 1), Rf
= 0.39 (n-butanol: acetic acid: water = 75 nia, 5:21) and Rf = 0.83 (acetic acid ethyl ester: n-butanol: pyridine: acetic acid: water = 42:21:
21:6:10) Example 18 1.45 g (1.5 mmol) of N-acetyl-muramyl-shi-alanyl-D-isoglutaminilum-alanine-cholesteryl-3-ester and 0.72 g of acetic anhydride
g (7.1 mmol) is dissolved in 16 ml of a mixture of anhydrous pyridine and dimethylformamide (6:1) and left at room temperature for 22 hours. The clear solution was heated at 30°C in a high vacuum.
The resulting gel-like residue is triturated with 50 ml of acetic acid ethyl ester and the supernatant is decanted (4 times).

The solid residue was taken up in 5 ml of dimethylformamide, 50 ml of anhydrous dioxane was added, and the whole was filtered through a Millipore filter.
(PTPE: 0.2 μm) and freeze-dried. N-acetyl-(1α,β), -4,6-tri-O-
Acetyl-muramyl-L-alanyl-D-isoglutaminyl-L-alanine-cholesteryl-3-ester is
Obtained as a colorless powder containing 0.62 mol of water.

Cs5H selftNs OSs ・Q, 62 H! O(
1069,49) CHN H,0 Calculated value 61.77 8,33 6,55 1.0
4 Actual measurement value 61.8 8.4 6゜81゜0〔α
]6°= + 7.7° ±1° (c=0.977,
dimethyl sulfoxide”), Rf =0.41 (
n-butanol:acetic acid:water = 75 nia, 5:21) and Rf = 0.87 (acetic acid ethyl ester: n-butanol: pyridine: acetic acid: water = 42:21:21:6: in anhydrous pyridine) From N-acetyl-muramyl-shi-alanyl-D-glutamine-pivaloyloxymethyl ester and acetic anhydride in the same manner as in Example 1, N-acetyl-1
, 4,6-tri-O-acetylumamyl-L-furanyl-D-glutamine-pivaloyloxymethyl ester is obtained.

The starting material is obtained as follows: 1. 3.0 g (8.54 mmol) of N-benzyloxycarbonyl-cycloalanyl-D-glutamine in a mixture of 300 ml of tetrahydrofuran and 20 ml of water. Dissolve in

Add cesium carbonate (pu) dissolved in water 7a+1 to this solution.
rum, Fluka) 1.39'g (4,2
7 mmol) and the whole is left at room temperature for 1/2 hour.

It is then concentrated by evaporation at 30° C. in a high vacuum and the residue thus obtained is evaporated twice at 40° C. in a high vacuum, successively with 250+1 methanol and each time with 250 ml of dimethylformamide.

Thus obtained N-benzyloxycarbonyl-
The cesium salt of alanyl-D-glutamine is suspended in 300 ml of dimethylformamide.

Pivalic acid chloromethyl ester (
purum, Fluka) 2.57 g (2,4
8 ml; 17.08 mmol) and sodium iodide 2
．． Add 56 g (17.08 mmol). The mixture thus obtained is stirred at room temperature for 42 hours. Then,
Concentrate by evaporation at 40° C. in high vacuum. The yellow crystalline residue thus obtained was mixed with 500ml of ethyl acetate.
1 (suspended) and washed 3 times with 150 ml of water each time. The clear acetate ester phases are combined, dried over sodium sulfate and concentrated by evaporation at 30° C. in vacuo. The residue was converted into ethyl acetate: n-pentane = 1: 15 (
20: Crystallize from 300ml). After recrystallizing twice, N-benzyloxycarbonyl-shi-alanyl-
D-glutamine-pivaloyloxymethyl ester is obtained in the form of colorless crystals with a melting point of 109-110°C.

C! ZH31N30s (465,50)CHN
O Calculated value 56.76 6,71 9.03 27.4
9 Actual value 56.42 6.69 8.82 27.
73 [α] Otsu 0 = +5.5° ± 0.1° (c = 0.9
73, methanol), Rf=0.62 (methylene chloride:
Methanol = 5:1), Rf = 0.86 (methylene chloride: methanol: water = 70:30:5) Step 19.2 = N-benzyloxycarbonyl-alanyl-D-glutamine in 200 ml of dimethoxyethane A solution of 6.7 g (14.4 mmol) of pivaloyloxymethyl ester was prepared on activated carbon with 10% palladium as a catalyst while keeping the pH constant at 5.5 (titrated with IN hydrochloric acid).
．． Hydrogenation was carried out using 0 g at room temperature and normal pressure for 40 minutes.

The catalyst is then cracked and the mouth liquid is concentrated by evaporation at 30° C. in a high vacuum. The residue thus obtained is suspended in 30 ml of diethyl ether. The colorless crystals thus obtained are filtered through a suction port and washed with diethyl ether. L-Asiel-D-glutamine-pivaloyloxymethyl ester hydrochloride is obtained in the form of colorless crystals with a melting point of 110 DEG -111 DEG C. (decomposed).

C, HzbCIN306 (367,83)CHCI
N O Calculated value 45.72 7.13 9.64 11.
42 26.10 Actual value 45.51 7.36 9
．． 34 11.47 26.40 (α) g mouth = +
25.5° ±0.1° (c = 1.128, methanol), Rf = 0.07 (methylene chloride: methanol = 571), Rf = 0.37 (methylene chloride:
methanol:water=70:30:5), Rf=0.59(
Methylene chloride: methanol: water = 5: 5: soil
Uni-N-acetyl-4-mu,6-0-isopropylidene-muramic acid sodium salt 5.18 g (13.0 mmol,
2.52 mmol/g) in dimethylformamide 15
Suspend in 0ml. Then L-alanyl-D-
Glutamine-pivaloyloxymethyl ester hydrochloride 4
．． 8 g (13,0 mmol).

Dicyclohexylcarbodiimide 2.95 g (14
, 3 mmol) and N-hydroxy-succinimide 1
．． 64 g (14.3 mmol) are added. The pale yellow suspension thus obtained is stirred at room temperature for 22 hours. Then, most of the resulting dicyclohexyl urea was sucked out,
The oral fluid obtained is concentrated by evaporation at 40° C. in a high vacuum. The remaining yellow oil is taken up in 20 ml of methanol, further dicyclohexylurea is passed through the suction port and concentrated again by evaporation in a high vacuum.

The obtained crude product, which also contains a small amount of dicyclohexyl urea, was purified by silica gel (type 60, purest, Merck; 0
．． 063-0.2 m) 1000 g, purified by column chromatography in methylene chloride:methanol = 9:1 (fraction 10 ml)
.

Combine fractions 380 to 1'210, and combine fractions 850 and above with methylene chloride: methanol: water = 70:
Elute using a 30:5 system.

After concentrating the eluent by evaporation at 30° C. in a high vacuum,
Mainly N-acetyl-4-0,6-0-isopropylidene-muramyl-L-alanyl-D-7' rutamine-pivaloyloxymethyl ester and some N-acetyl-muramyl-shi-alanyl-D-glutamine A mixture consisting of -pivaloyloxymethyl ester is obtained in the form of a pale yellow foam, which is processed without further purification.

Rf = 0.33 (N-acetyl-muramyl-shi-alanyl-D-glutamine-pivaloyloxymethyl ester) and 0.66 (N-acetyl-4-0°6-0-
Isopropylidene-muramyl-L-alanyl-D-'1
7'Lutamine-pivaloyloxymethyl ester〕 (
Methylene chloride:methanol:water = 70:30:5) Crude N-acetyl-4-0,6-0-isopropylidene-muramyl-L in 100 ml of glacial acetic acid/water (3:2) −
A solution of 5.5 g (6,8,5 mmol) of alanyl-D-glutamine-pivaloyloxymethyl ester is stirred at room temperature for 4.5 hours. The pale yellow solution was then concentrated by evaporation at 40° C. in a high vacuum, and the resulting residue was dissolved in silica gel (type 60, purest, Merck & Co., Ltd., 0.063-0.2
Tsuru) 500g, methylene chloride:methanol:water (70g
:30:5) (fraction 10 ml). Fractions 52-65 are combined and concentrated by evaporation at 30° C. in a high vacuum. The resulting N-acetyl-muramyl-L-alanyl-D-glutamine-pivaloyloxymethyl ester is dissolved in 60 ml of twice-distilled water. Filter the solution through a Millipore filter (Na12ene (trademark) S: 0.2 μm
) and then lyophilized in a high vacuum. N-acetyl-muramyl-shi-alanyl-D-glutamine-pivaloyloxymethyl ester is obtained as a colorless powder, which still contains 1.21 mol of water.

Below margin CzsHa□N401:l・ 1.21 H,0(62
8,50) CHN OHzO Calculated value 47.78 7.16 8.91 36.1
8 3°48 Actual value 48.09 7.15 9.0
2 36.01 3.48 [α] day + 39.5°
±0.1° (C=0.443°water), Rf =0
．． 61 (methylene chloride:methanol:water=70:3
The following compounds were obtained by the method described herein: a) N-acetyl-1,4,6-tri-O-acetyl-
Muramyl-L-N-methyl-alanyl-D-isoglutamine-benzhydryl ester, b) N-acetyl-1
,4,6-)gu O-acetyl-muramyl-α-amino-isobutyryl-D-isoglutamine-benzhydryl ester and c) N-acetyl-1,4,6-tri-O
-acetyl-desmethylmuramyl-L-alanyl-D-
T-Methoxycarbonyl-isoglutamine-benzhydryl ester W Female MF-2f SPF mice weighing 14-16 g were lightly anesthetized with a mixture of diethyl ether, ethanol, and chloroform in equal parts and treated with influenza A/
Texas/1/77 (Virus A) or Influenza B/Hong Kong 15/72 (Virus B) Kill each 0.05ml suspension of virus (strain compatible with mice)! (Approximately L D go-qo: 1-4 plaque forming value (PFU)) Infection is administered intranasally.

These groups of 10 mice were each treated with carboxymethylcellulose sodium salt in double-distilled, pyrogen-free water for intranasal or oral administration at the following times (days) to the infected mortar: o, o o
Each active ingredient is administered once (one dose) in the manner listed in Table 1 in 0.05 ml or 0.2+sl of a %w solution.

Twenty of the infected mice described above are used as controls.

That is, a placebo (0.005% by weight solution of carboxymethyl cellulose sodium salt) is administered.

Intranasal administration of the active ingredient is carried out under light anesthesia with a mixture consisting of equal parts diethyl ether, ethanol and chloroform.

Compound I = 1.4.6-tri-O-acetyl-N-propionyl-desmethylmuramyl-shi-alanyl-D-isoglutamine-benzhydryl ester.

(Left below) Kanmatata: Non-water applied to the nose Unit r given -1'#@: 1, 4. 6-Tri-O-acetyl-N-propionyl-desmethylmuramyl-L-alanyl-D-isoglutamine-benzhydryl ester
0.03 ■ Miglyol 812
30. OOmg alliance: Active ingredient 0.03tw under sterile conditions Miglyol 29
．． Dissolve in 97mg.

This solution is filled into a commercially available disposable nasal applicator and the applicator is placed in the spray box drawer prior to use.

Example 23: T! 3. Nasal medicine dish bottom: 1.4.6-tree 0- 0.15w O,1
0eg acetyl-N-propionyl-desmethylmuramyl-alanyl-〇-isoglutamine-benzhydryl ester thiomersal 0.02■ -phosphoric acid-
Sodium hydrogen 2Hz OO, 30■ 0.30■ Sodium dihydrogen phosphate 12 H20 10, 10■ 10.10■ Benzalkonium chloride 0.10■ Ethylenediaminetetraacetic acid disodium salt (EDTA) 0.50■ 0
．． 50 ■ Sodium chloride 3.70 ■
4.50■ Deionized water 988.30■
987.60 x 11 M = Sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium chloride, thiomersal and EDTA-disodium salt are dissolved in a portion of the above amount of deionized water at room temperature with stirring.

This solution is then dissolved with the active ingredient and replenished with the remaining deionized water.

This solution, or a portion thereof, is passed through a membrane filter and filled into a clean container. Suitable containers are, for example: a) glass or plastic containers (5 ml or 10 ml) with a glass or plastic pipette fitted with an elastomeric pipette suction device; b) plastic containers with a riser tube and a plastic spray top. C) Plastic disposable containers (2-3 drops content) or d) Glass or plastic bottles with plastic standard pump metered spray.

■1↓: Nasal feces U: 1.4.6-tri-〇-acetyl-N-propionyl-
Desmethylmuramyl-L-alanyl-D-isoglutamine-benzhydryl ester 0.
03 g thick paraffin oil 20.
00 g white petrolatum 30.
OOg Anhydrous Lanolin 40.0
0 g deionized water 19.97
g1 pouring: The fatty phase consisting of paraffin oil, petrolatum and lanolin is melted together. The aqueous solution of the active ingredient is mixed into the fatty phase at about 50°C.

夛［1''-: T O, 5% tablet 1000
0 0 1.4.6-Tri-O-acetyl-N-propionyl-desmethylmuramyl-L-alanyl-D-isoglutamine-benzhydryl ester 0
．． 5g crushed lactose 43.0
g corn starch 52.0
g Pharmacoat 603 (trademark) (hydroxypropyl methylcellulose containing 28-30% methoxy groups, manufactured by Shin-Etsu Chemical Co., Ltd., Tokyo, Japan)
3.0g Aerosil (＾erosil trademark) (
Colloidal silicon dioxide (manufactured by Dagfusa, Frankfurt, Germany) 1.0 g Magnesium stearate 0.5 g 1 part: The active ingredient and 15 g of lactose are premixed. The premix thus obtained is mixed with 28 g of milk $Ji and 47 g of corn starch. The mixture thus obtained and the aqueous solution of Pharmacoat are granulated, dried, and ground to produce a granular material. Mix this with 5g of corn starch, Aerosil and magnesium stearate, and make 1000 tablets each weighing 100cm.
Compression mold into pieces.

The compression molded bodies can be coated in a gastric fluid-resistant manner in a manner known per se.

511 The following compound was obtained by the method described herein: N-acetyl-1,4,6-tri-O-acetyllamyl-L-alanyl-D-isoglutaminyl-L-α-
([2-benzyloxy-carbonylamino-ethyl]
-sulfonyl-methyl)-glycine-benzyl ester, N-acetyl-1,4,6-tri-O-acetyl-muramyl-L-alanyl-D-isoglutamini/L/-L-
0-acetyl-serine-benzyl ester, 1.4.6-tri-O-acetyl-N-benzoyl-desmethylmuramyl-shi-alanyl-D-glutamic acid-
Dicholine ester, N-propionyl-1,4,6-tri-O-propionyl-desmethylmuramyl-shi-alanyl-D-isoglutamine-benzhydryl ester, 1.4.6-1-di-0- Propionyl-desmethylmuramyl-shi-alanyl-D-glutamic acid-α-n-butyl ester-T-
Benzyl ester, 1.4.6-1-so-0-propionyl-desmethylmuramyl-shi-alanyl-D-glutamic acid-dibenzyl ester, N-acetyl-1,4,6-tri-O-propionyl-
muramyl-shi-α-aminobutyryl-D-isoglutamine-benzhydryl ester, 1.4.6-tri-O-
Acetyl-N-benzoyl-desmethylmuramyl-L-
Asiel-D-isoglutamine-benzyl ester, and 1.4.6-tri-O-acetyl-N-propionyl-desmethylmuramyl-L-alanyl-D-glutamic acid-dipivaloyloxymethyl ester.

, fLLL: 7L/-L of crude 4,6-di-acetyl-N-probionyludesmethylmurami in 10+ml of anhydrous pyridine
-alanyl-D-glutamic acid-dipivaloyloxymethyl ester (α,β-mixture) 250μ (approximately 0.09
8 mmol) and 2.0 ml (21.0 mmol) of acetic anhydride as in Example 1 (18 hours, room temperature), 1,
4.6-Tri-O-acetyl-N-propionyl-desmethylmuramyl-shi-alanyl-D-glutamic acid dipivaloyloxymethyl ester (α,β-mixture) is obtained.

Rf=0.43 (chloroform:ethanol=95:5
), Rf = 0.56 (Chloroform: methanol ■9: 1), Rf = 0.72 (Chloroform: methanol = 4:1) The starting materials are obtained as follows: Work ■1 Soil: Anhydrous N- in 200ml of N,N-dimethylformamide
tert-butyloxycarbonyl-alanyl-N
-Hydroxy-succinimide ester 9.78g (3
15.9 g of D-glutamic acid-(C&)-pivaloyloxymethyl ester-(C1)-benzyl ester tosylate was added to a solution of 4.1 mmol) with stirring at room temperature.
(34.1 mmol) and N-methylmorpholine 3.7
5 ml (34.1 mmol) are added. After stirring for 18 hours at room temperature, it is concentrated by evaporation at 40° C. in vacuo.

The crude product thus obtained (yellow oil) was mixed with silica gel (
60 type, purest, Merck &Co.; 0.063-0.2 Tsuru) 8
methylene chloride/acetic acid ethyl ester (85
:15) by column chromatography (fraction 10 ml). Fractions 126-230 are combined and concentrated by evaporation at 30° C. in vacuo. N-tert~butyloxycarbonyl-s-alanyl-D-glutamine ft1-(C&)-pivaloyloxymethyl ester-(0)-benzyl ester is obtained as a yellowish fade.

[α] Furnace=-10.6±0.1° (c=1.035:
methylene chloride), Rf = 0.29 (methylene chloride:
Ethyl acetate = 85:15), Rf = 0.
73 (methylene chloride: methanol = 9:1), Rf = 0
．． 78 (Methylene chloride:methanol=5:1) Step 21.2: N-tert-butyloxycarbonyl-alanyl-D-glutamic acid-(C&)-pivaloyloxymethyl ester- in 50 ml of acetic anhydride ethyl ester. (C
T)-benzyl ester 4.0 g (7.65 mmol)
50 m+1 of ethyl acetate at 0°C in a solution of
Add 100 ml of N-hydrochloric acid and stir at 0° C. for 1 hour. It is then concentrated by evaporation in a high vacuum at 30° C., the residue thus obtained is taken up several times in ethyl acetate and concentrated again by evaporation. The colorless foam obtained is dissolved in 50n+1 ethyl acetate. Pentane 250ml
was added and cooled to -10°C, L-alanyl-D-
Glutamic acid = (C)-pivaloyloxymethyl ester-hydrochloride is obtained as colorless crystals with a melting point of 73-74°C,
This still contains 0.63 mol of water.

[α] Day + 2 3. 5±0.1° (c=1.
150; methanol), Rf = 0.20 (methylene chloride:methanol = 9:1), Rf = 0.4
9 (methylene chloride:methanol=5:1), Rf=0
．． 87 (methylene chloride: methanol: water = 70:30
:5) Step 27.3: 1- in anhydrous N,N-dimethylformamide 50a+1
α-〇-Benzyl-4.6-0,O-isopropylidene-N-propionyl-desmethylmuramic acid sodium salt 2.99 g (approximately 5.0 mmol, including sodium chloride; 1.673 mmol/g) N was added sequentially to the suspension with stirring at room temperature.

1.34 g of N-dicyclohexylcarbodiimide (6.
5 mmol), 1-hydroxybenzotriazole 1.
03g (6.5 mmol) and L-alanyl-D-
Glutamic acid-(Cya)-pivaloyloxymethyl ester-(C1)-benzyl ester hydrochloride 2.35g (
5.0 mmol) and stirred for an additional 22 hours at room temperature. Then, sip the suspension into the mouth. N-dicyclohexylurea), the oral fluid is concentrated by evaporation at 40° C. in a high vacuum. The residue, a yellowish foam, was dissolved in ethyl acetate 10
The solution thus obtained is washed successively with 50 ml each of 2N citric acid, 10% sodium bicarbonate solution and water. The acetate ester phases are combined, dried over sodium sulphate and concentrated by evaporation in vacuo.

The crude product thus obtained was mixed with 400 g of silica gel (type 60, purest, Merck & Co., Ltd.; 0.063-0, 2 Tsuru), first with chloroform (first distillation 21), then with chloroform/
Purify using ethanol (95:5) system (
fraction 10ml).

Fractions 93-122 are combined and concentrated by evaporation in vacuo. 1-α-〇-benzyl-4.6-0.0-impropylidene-N-propionyl-desmethylmuramyl-shi-alanyl-D-glutamic acid-(C&)-pivaloyloxy containing a slight amount of impurities The methyl ester-dyle ester is obtained as a colorless foam and is processed without further purification.

Rf = 0.55 (chloroform: ethanol ÷ 9 = 1)
, Rf = 0.6 3 (chloroform:methanol 9:1) Soil: 1-α-O-benzyl-4.6-0.0-isopropylidene-N-propionyl-des in 28.5 ml of anhydrous methylene chloride 1.5 ml of trifluoroacetic acid was added to a solution of methylmuramyl-shi-alanyl-D-glutamic acid-(C61)-pivaloyloxymethyl ester 830 (1.0 mmol) at 0°C, and the total temperature was reduced to 0. Stir at ℃ for 1.5 hours. The residue thus obtained is then crystallized from chloroform/methanol/diethyl ether (5:1 near 0). 1-α-〇-benzyl-N-propionyl-desmethylmuramyl-shi-alanyl-〇-glutamic acid-(C3)-pivaloyloxymethyl ester-benzyl ester is obtained as colorless crystals.

Melting point 148-149°C; Rf = 0.33 (chloroform:methanol; 9:1)
, Rf -0.6 7 (chloroform: methanol = 4:1) Rf = 0.9 0 (chloroform: methanol: water = 70:30:5) [: 1-α-0-benzyl-N-propionyl- Desmethylmuramyl-shi-alanyl-D-glutamine filt
c&> -pivaloyloxymethyl ester- (0 units)
-mmol of benzyl ester) in tetrahydrofuran/methanol (4:
1) Hydrogenation is carried out in 80 ml at room temperature and normal pressure using 200 μl of activated carbon with 10% palladium as a catalyst. After hydrogenation (1 hour), the catalyst is split and the zero liquid is concentrated by evaporation in a high vacuum. The residue, which is a colorless foam, is dissolved in a mixture of 30+ wl of tetrahydrofuran and 1 ml of water, and the solution thus obtained is diluted with 0.0 ml of water at room temperature.
Cesium carbonate 96■ (0.25 mmol) in 38+1
Add the solution.

After standing for half an hour at room temperature, the colorless solution is concentrated by evaporation in vacuo. The residue is then heated twice with 100 ml of methanol each time and once with 100 ml of N,N-dimethylformamide and concentrated again by evaporation. 1-α-〇-benzyl-N-propionyl-desmethylmuramyl-L-alanyl-D-glutamine fi-(C*)-pivaloyloxymethyl ester-cesium salt containing a small amount of impurities is a colorless foam. obtained as, which is processed without further purification: Rf=0.15 (chloroform:methanol=4=1)
, Rf -0.35 (chloroform:methanol-7:3), Rf =0.45 (chloroform:methanol:water=70:30:5) Step 27.6: 1 in 15 ml of N,N-dimethylformamide −α−0
-benzyl-N-propionyl-desmethylmuramyl-
L-alanyl-D-glutamic acid-(C)-pivaloyloxymethyl ester-cesium salt 420■(0
．． 150 μm (145 μm, 1.0 mmol) of pivalic acid chloromethyl ester and 150 μm (1.0 mmol) of sodium iodide are added to a solution of 5 mmol) with stirring at room temperature.

The mixture thus obtained was stirred at room temperature for 18 hours and then again mixed with 145 μn of pivalic acid chloromethyl ester.
(1.0 mmol) and 15011 jg of sodium iodide
(1.0 mmol) and stirred for an additional 48 hours. The mixture is then concentrated by evaporation at 30° C. in a high vacuum. The crude product was mixed with 200 or 250 g of silica gel (type 60, purest, Merck: 0.063-0.2 Tsuru) in a system of chloroform/methanol (9:1) or chloroform/methanol (95:5). Purify by column chromatography twice. The fractions containing the desired product are combined and concentrated by evaporation in vacuo. 1-α-0-benzyl-N-propionyl-desmethylmuramyl-shi-alanyl-D-glutamic acid-dipivaloyloxymethyl ester is obtained.

Rf=0.25 (chloroform,:methanol-9=1
), Rf = 0.35 (chloroform: ethanol-9: 1), Rf = 0.70 (chloroform: methanol = 4:1) 1 hill 11 steps: 1-α-0-benzyl- in 8 ml of anhydrous pyridine N-propionyl-desmethylmuramyl-shi-alanyl-D-
Glutamic acid dipivaloyloxymethyl ester 80
■ (0.098 mmol) and acetic anhydride 0.8 ml (
8.4 mmol) as in Example 1 (18 hours, room temperature) to give 4,6-di-acetyl-1-α-0-benzyl-N-propionyl-desmethylmuramyl-s-alanyl-D. -Glutamic acid-dipivaloyloxymethyl ester is obtained.

Rf=0.50 (chloroform:ethanol=95:5
), Rf=0.65 (chloroform; ethanol=9
: 1), Rf = 0.77 (chloroform: methanol = 9: l) Step 27.8: 4.6-di-O-acetyl-1-α-0-benzyl-N
-Propionyl-desmethylmuramyl-shi-alanyl-
D-glutamic acid dipivaloyloxymethyl ester 140 μm (0,098 mmol) in dimethoxyethane/
Hydrogenation is carried out in 80 ml of water (9:1) at room temperature and normal pressure for 2 hours using activated carbon with palladium (Degussa, E10IN) as a catalyst. Then, separate the catalyst by day,
The 0 liquid is concentrated by evaporation at 30° C. in a high vacuum. Crude 4゜6-di-0-acetyl-N-propionyl-desmethylmuramyl-dis-alanyl-D-glutamic acid-dipivaloyloxymethyl ester (α,β-mixture) is obtained, which is further purified. Process without any problems.

Rf=0.38 (chloroform:methanol=9:1)
, Rf = 0.64 (chloroform:methanol:
Water=70:30:5), Rf=0.68
(Chloroform:methanol = 4:1) Suji L also contains traces of N-methyl- in 1.7 ml of anhydrous pyridine.
N-propionyl-desmethylmuramyl-dis-alanyl-D-isoglutaminyl-mono-alanine-benzoyloxymethyl ester containing morpholine hydrochloride 174.0
■ (0.25 mmol) to 0.1 ml (1,04 mmol) of acetic anhydride by adding a small amount of 4-dimethylamino-pyridine.
mmol) and 1.4.6-tri-O-acetyl-N-propionyl-desmethylmuramyl-shi-alanyl-D-isoglutaminyl-L-alanine-benzoyloxymethyl ester (α,β- mixture) is obtained as colorless crystals.

Melting point: 177-178°C (methylene chloride: diethyl ether = 1:1), Rf = 0.45 (chloroform: methanol = 4:1), Rf = 0.64
(Chloroform:methanol = 7:3) The starting material is obtained as follows: Main soil: N-ter in 50 ml of N,N-dimethylacetamide.
18.9g of t-7' methyloxycarbonyl monoalanine
(0,1 mol) of 1,8-diazabicyclo(5,
4,0) undec-7-ene14.9n+1 (0,1
mol) and 36.2 ml (0.45 mol) of short methane were added, and the mixture was stirred at 22°C for 2 hours. The solution is concentrated by evaporation in a high vacuum and the residue contains 36.6 g (0.3 mol) of benzoic acid, 6.1 g (0.05 mol) of 4-dimethylaminopyridine in 75 ml of N,N-dimethylacetamide and 1. Add a suspension of 37.3 ml of 8-diazabicyclo(5,4,0)undec-7-nin. The clear solution that forms after 40 minutes is left at 22° C. for 16 hours. shaking the batch with a mixture of 0.3 molar dipotassium hydrogen phosphate solution and ethyl acetate, separating the organic layer;
further washed with phosphate solution and dried over sodium sulfate;
Concentrate by evaporation. Trituring the residue with pentane and then pentane/diethyl ether (3:1) gives N
-tert-butyloxycarbonyl monoalanine-benzoyloxymethyl ester is obtained.

Rf-0,68 (chloroform:acetic acid ethyl ester=
9: 1) Main: N-tert-butyloxycarbonyl monoalanine-benzoyloxymethyl ester 3.72 g (11
, 5 mmol) in 100 ml of a 5 molar hydrogen chloride solution in ethyl acetate at 0 DEG C. and left at 0 DEG C. for 2 hours. This solution was diluted with diethyl ether/
After adding to 2001 ml of pentane (1:1) and stirring at 0° C. for 20 minutes, the precipitated gel-like crude product is separated. Acetate ethyl ester/diethyl ether/pentane (1:
1: 1) Stir in 360 ml at 22°C for 2 hours,
By day.

A monoalanine-benzoyloxymethyl ester hydrochloride having a melting point of 99-100°C is obtained.

Step 2B, 3: 0.0 ml of water in 10 ml of anhydrous N,N-dimethylformamide.
N-propionyl-desmuramyl containing 77 moles
To a solution of 506 μ (1.0 mmol) of alanyl-D-isoglutamine was added 268 μ (193 mmol) of N,N-dicyclohexylcarbodiimide and 1 with stirring at room temperature.
-Hydroxy-benzotriazole 207 mr (1,3
mmol).

After 2 hours, 269 μ (1
,0 mmol) and N-methylmorpholine 110μ/(
1.0 mmol) and further stirred at room temperature. After 22 hours, the precipitated N,N-dicyclohexylurea is split and the liquid solution is concentrated by evaporation at 30° C. in a high vacuum. The slightly yellow colored residue thus obtained (foam) is suspended in 25 ml of ethyl acetate and the suspension is stirred for 1 hour at room temperature. The crude product obtained in the form of colorless crystals was purified by silica gel (type 60, purest, Merck; 0.0
Further purification is carried out by column chromatography on 150 g of chloroform/methanol/water (70:30:5) (fraction 5a+
1). Fractions 25-35 are combined and concentrated by evaporation in a high vacuum.

Pure N-propionyl-desmethylmuramyl-L
-alanyl-D-isoglutaminyl-alanine-benzoyloxymethyl ester (α.

.beta.-mixture) is obtained as a colorless foam, which still contains traces of N-methyl-morpholine hydrochloride and is processed without further purification.

Rf=0.36 (chloroform:methanol=7=3)
, Rf = 0.41 (chloroform: methanol; water = 70: 30: 5), Rf = 0.74
(acetonitrile:water=3:1) Example 29 N-acetyl-muramyl-shi-alanyl-D-isoglutaminyl-L-(Cα)-((2-benzyloxycarbonylamino-ethyl]-sulfonyl-methyl)- 1.95 g (2.18 mmol) of glycine-benzyl ester are dissolved in 40 ml of anhydrous pyridine and peracetylated with 30 times the molar amount of acetic anhydride (30 hours, room temperature).The gel-like material is dissolved in a small amount of water. The whole is concentrated to a small volume in a rotary evaporator at 30° C. in a high vacuum and, after addition of anhydrous dioxane, lyophilized. The crude product is evaporated onto silica gel (
First, chloroform,
Next, a chloroform/methanol mixture (98: 2-1
:1) using flash chromatography (14
,5i1; fraction 25m1 B 0.5bar
). The fractions containing the product were collected, dissolved in 90% dioxane (80 ml) and filtered through a sterile mouth filter (0.2 u
m; PTFE) and then freeze-dried. N-acetyl-1,4,6-tri-〇-acetyllumamyl-L-acyel-D-isoglutaminyl-(Cα)-
((2-benzyloxycarbonylamino-ethyl)-
Sulfonyl-methyl)-glycine-benzyl ester (
α, β-mixture) is obtained as a pale yellowish powder containing 1.27 mol of water.

[α] 6°= + 36.6±1° (c=1.030
; dimethylformamide), Rf = 0.15 (chloroform; methanol: water = 70:30:5), Rf = 0
．． 53 (n-butanol:acetic acid:water=75:1.5:2
1), Rf = 0.61 (acetonitrile: water =
3 = The starting material is obtained as follows: Technique: Into a solution of 8.50 g (20 mmol) of Nε-benzyloxycarbonyl-thialidine-benzyl ester hydrochloride at room temperature with stirring within 30 minutes. 21.5 g (100 mmol) of a 31.4% hydrogen peroxide solution is added dropwise to the solution. 3
After stirring for 0 hours, 1.5 g of activated carbon with palladium (5%) is added to decompose excess peroxide. In this case, intense gas evolution occurs. After stirring for 3 hours, the catalyst is removed and the reaction solution is evaporated to dryness on a rotary evaporator at 30°C.

The oily residue is dissolved in 11 ml of acetone and crystallized by adding 20 ml of diethyl ether. After recrystallization from the same amount of mixture, Nε-benzyloxycarbonyl-
Thiarisine-8,S-dioxide-benzyl ester hydrochloride is obtained in the form of colorless needles. Melting point 141-142
°C (decomposition), p-) Melting point of luenesulfonate 130~
134°C (decomposed).

Rf=0.50 (chloroform:methanol:water=70
: 30: 5), Rf = 0.89 (methyl ethyl ketone: pyridine: water = 65: 5: 20), R
f=0.71 (n-butanol: glacial acetic acid: water = 3:
1: Step 29.2: 2.95 g (6 mmol) of N-acetyl-muramyl-shi-alanyl-D-isoglutamine and Nε-benzyloxycarbonyl-thialidine-8,S-dioxide-benzyl ester hydrochloride 2 .74 g (6 mmol) are combined with each other in the customary manner (see step 30.1) by the dicyclohexylcarbodiimide-1-hydroxy-benzotriazole method. After stirring at room temperature for a total of 51 hours, 200 ml of acetic acid ethyl ester was added to the reddish suspension, and 1
After stirring for an hour, the insoluble material is removed and the liquid is evaporated to dryness in a rotary evaporator at 30° C. in a high vacuum.

100 ml each of ethyl acetate and water are added to the residue and stirred for 1 hour. The gel-like material is filtered, dried and distributed between 80 ml each of upper and lower layers of mutually saturated n-butanol/water (1:1). After stirring for 1 hour, the insoluble material is filtered off with suction, washed and dried. N
-Acetyl-muramyl-L-acyl-D-isoglutaminyl-(C")-((2-benzyloxycarbonylamino-ethyl)-sulfonyl-methyl)-glycine-benzyl ester (α,β-mixture) Ka, 1.63
Obtained in the form of a white powder containing moles of water.

Rf=0.60 (chloroform:methanol:water=70
: 30: 5), Rr = 0.83 (acetonitrile:water = 371) ■ 1.50 g of 1 standing N-acetyl-muramyl-silanyl-D-isoglutaminroot-serine-benzyl ester (
2.24 mmol) is suspended in 40 s+l of anhydrous pyridine and peracetylated with 40 times the molar amount of acetic anhydride.

The gel-like material obtained after stirring at room temperature for 24 hours was mixed with 5 ml of water.
The whole is concentrated in a rotary evaporator under high vacuum (30° C.) to about 5 ml, added with double-distilled water and lyophilized. The crude product is taken up in 50 mJ of warm acetic acid ethyl ester and precipitated by addition of 5 parts by volume of diethyl ether (2x). Dissolve the precipitate in chloroform/methanol (1:1) and add 0.2μ
m, PTFE), after evaporation of the solvent, taken up in anhydrous dioxane and freeze-dried. N-acetyl-1,4,6
-Triacetyl-muramyl-L-alanyl-D-isoglutaminyl-L-0-acetyl-serine-benzyl ester hydrate (α,β-mixture) is obtained as a colorless powder.

[α]6°=+26.5±0.9° (c=1.0
96; Chloroform:methanol=1:1), Rf=0
．． 10 (chloroform: isopropanol = 7 = 2)
, Rf = 0.69 (chloroform:methanol:
Water=70:30:5), Rf=0.33
(n-butanol:acetic acid:water=75nia, 5:21) The starting material is obtained as follows: Step 30.1: N-acetyl-muramyl-shi-alanyl-D-isoglutamine 5.00 g (10,15 mmol), l-hydroxybenzotriazole (containing 12% water) 2
．． 00 g (13.2 mmol) and 2.35 g (10.15 mmol) of L-serine-benzyl ester hydrochloride are dissolved in 50 ml of dimethylformamide. To this are added 1.17 ml (10.66 mmol) of N-methylmorpholine and finally 2.72 g (13.2 mmol) of N,N'-dicyclohexylcarbodiimide. After stirring for 24 hours at room temperature, 100 ml of ethyl acetate is added to the reddish suspension and stirred for 1 hour. Insoluble dicyclohexyl urea is extracted and the 0 liquid is condensed by evaporation in a rotary evaporator at 30° C. in a high vacuum. The yellow oil obtained is purified on silica gel (60:1; fraction 15 ml) in a system of chloroform:methanol:water=70:30:5. The pure fractions containing the product were collected and, after evaporation of the solvent, tert-butanol/water (9:
Freeze-dry from 1). N-acetyl-muramyl-shi-alanyl-D-isoglutaminoroot-serine-benzyl ester is obtained as a colorless powder containing 1.87 mol of water.

(α) 54bnll = + 12.4±1' (
c=0.978B water), Rf=0.41 (chloroform:methanol:water=70730:5), Rf=
0.59° (ethyl acetate: n-butanol: pyridine: acetic acid: water = 42:21:21:6:10) N-acetyl-muramyl-L-N-methyl-alanyl-
D-isoglutamine-benzhydryl ester (α, β
- 0.36 g (0,535 mmol) of the mixture) was dissolved in 4 ml of anhydrous pyridine, and 0.15 ml (1
6 mmol) and then left at room temperature for 3 hours. The yellowish solution is concentrated by evaporation in a high vacuum at 30° C., taken up in 10+al of water and lyophilized. The crude product was chromatographed on silica gel (1:180) with a system of chloroform/isopropanol (9:1) (fraction 0).
．． 8ml). Homogeneous fractions are collected and lyophilized from anhydrous dioxane. N-acetyl-1,4,6-tri-O-acetyl-muramyl-
L-N-methyl-alanyl-D-isoglutamine-benzhydryl ester (α.

β-mixture) is obtained as a colorless powder.

Rf = 0.61 (n-butanol: acetic acid: water = 75
The starting material is obtained as follows.

Step 31.1: N-acetyl-muramyl-L-N dissolved in methanol
-Methyl-alanyl-D-isoglutamine (α,β-mixture) 0.50 g (0.99 mmol) is esterified with excess diphenyldiazomethane. After standing for 2 hours, it is evaporated to dryness and the residue is rubbed several times with petroleum ether. Using a suction port, take up the residue in a small amount of methanol.
Add the substance to 10 times the amount of diethyl ether: petroleum ether (1
: Precipitate in step 1). N-acetyl-muramyl-L-
N-methyl-alanyl-D-isoglutamine-benzhydryl ester is obtained as a colorless powder.

Rf=0.76 (acetonitrile:water=3:1),
Rf=0.63 (chloroform:methanol:water=70
:30:5), Example 32 N-acetyl-muramyl-α-aminoisobutyryl-D
-isoglutamine (α,β-mixture) 0,50 g (
0,9,9 mmol) with diphenyldiazomethane analogously to step 31.1.

The crude product (Rf = 0.48 (chloroform:methanol:water = 7010:5)) is peracetylated as in Example 31. The reaction solution is evaporated to dryness in vacuo, taken up in water and lyophilized. do. Purification was performed using silica gel (1:100
) in chloroform/methanol (9:1; fractions 1 ml). Combine the pure fractions,
Add 5 ml of chloroform and add PTFE; 0
．． 2 pm) and evaporate to dryness.

The residue is taken up in anhydrous dioxane and lyophilized.

N-acetyl-1,4,6-tri-O-acetyl-muramyl-α-aminoisobutyryl-D-isoglutamine-
Benzhydryl ester (α, β-mixture) is 0.7
Obtained as a colorless powder containing 3 mol of water.

[α] Pi= + 45.7±1° (C=0.993;
methanol"), Rf = 0.80 (chloroform: methanol: water = 70: 30: 5), Rf
=0.32 (chloroform:methanol=11),
Rf=0.50 (n-butanol:acetic acid:water=75nia, 5:■ main unit N-acetyl-desmethylmuramyl-L-alanyl-D
-γ-Methoxycarbonyl-isoglutamine-benzhydryl ester (α,β-mixture) 33■ is peracetylated analogously to Example 31.

After lyophilization from anhydrous dioxane, N-acetyl-1
,4,6-tri-O-acetyl-desmethylmuramyl-
L-alanyl-D-r-methoxycarbonyl-isoglutamine-benzhydryl ester (α,β-mixture) is obtained as a colorless powder.

Rf=0.67 (chloroform:methanol:water=70
: 30 : 5), Rf = 0.35 (n-
(butanol:acetic acid:water=75 nia, 5:21) The starting material is obtained as follows:
: N-acetyl-desmethylmuramyl-L-alanyl-D
-r-carboxy-isoglutamine (α.

β-mixture) 0.216 g' (0.4Q mmol) are esterified with diphenyldiazomethane (3 equivalents) analogously to step 31.1. After stirring the pale red suspension for 3 hours, it was filtered and the liquid was evaporated to dryness.

The mixture consisting of the adducts, mono- and dibenzhydryl esters and decomposition products caused by diphenyldiazomethane is separated by chromatography on silica gel (1:100) in a system of chloroform/methanol/water (TO:30:5). do. After chromatography twice, Rf=0.67 (chloroform:methanol:water=70:30:5) and Rf=O646 (n-
N-acetyl-desmethylmuramyl- as a colorless resin with butanol:acetic acid:water = 75 nia, 5:21)
L-alanyl-D-γ-benzhydryloxycarbonyl-isoglutamine-benzhydryl ester (α, β
- mixture), and Rr=0.13 (chloroform:methanol:water=70
:30:5) N-acetyl-desmethylmuramyl-L-alanyl-0-isoglutamine-benzhydryl ester is obtained.

Step 33.2: N-acetyl-desmethylmuramyl-L-alanyl-D
The isoglutamine-benzhydryl ester is esterified in methanolic solution in the usual manner with a solution of diazomethane in diethyl ether.

After concentration by evaporation, N-acetyl-desmethylmuramyl-L-alanyl-D-r-methoxycarbonyl-isoglutamine-benzhydryl ester (α,β-mixture) is obtained as a colorless resin.

Rf=0.56 (chloroform:methanol:water=70
:30:5) N-acetyl-muramyl-shi-α-aminobutyryl-D-isoglutamine-benzhydryl ester (α, β-mixture) dissolved in 25 ml of anhydrous pyridine 1.70
g (2.53 mmol) is perpropionylated analogously to Example 31 (90 equivalents of anhydride). After standing for 3 hours at room temperature, 30 ml of water was added and the whole was placed in a high vacuum for 3 hours.
Evaporate to dryness at 0°C.

The resinous residue is taken up in 80 ml of anhydrous dioxane, optionally PTFE; 0.2 #m) and freeze-dried. N
-Acetyl-1,4,6-tri-O-propionyl-muramyl-α-aminobutyryl-D-isoglutamine-benzhydryl ester (α,β-mixture) with 0.
Obtained as a colorless powder containing 79 mol of water.

[α] Day + 52.2±3.7° (c=0.27
0; methanol), Rf = 0.67 (acetonitrile: water = 3:1), Rf stomach 0.32 (chloroform: isopropanol: acetic acid = 70:8:2), Rf = 0
．． 87 (acetic acid ethyl ester: n-butanol: pyridine: acetic acid: water = 42:21:21:6: The starting materials are obtained as follows: The following margins are shown in step 1.''-: N-acetyl- muramyl-shi-α-aminobutyryl-D
- 2.03 g (4 mmol) of isoglutamine (α, β-mixture) are converted into benzhydryl ester analogously to step 31.1. After post-treatment in a conventional manner, N-acetyl-
Muramyl-L-α-aminobutyryl-D-isoglutamine-benzhydryl ester (α,β-mixture) is obtained as a colorless powder.

(α) 15o=+41.8 +1.8° (c=0
．． 548; methanol), Rf = 0.73 (chloroform: methanol: water = 10:30:5), Rf =
O,7B (acetonitrile:water=3:1) Example 35 Analogously to Example 1, N-propionyl-desmethylmuramyl-L-alanyl-D-isoglutamine-benzhydryl ester ( α, β-mixture)
2.0 g (2.94 mmol) of propionic anhydride (purissim) in 20 ml of anhydrous pyridine.
um; d = 1.012) 1.68ml (13
, 06 mmol), 1.4.6-tri-O-propionyl-N-propionyl-desmethylmuramyl-
Shi-alanyl-D-isoglutamine-benzhydryl ester (α,β-mixture) is obtained as a colorless lyophilizate which still contains 0.68 mol of water. Melting point 156-1
57℃, (α) 80= + 39.0±2.1° (c=0.
467; methanol), Rf = 0.40 (chloroform:ethanol = 9:1), Rf = 0.4
8 (chloroform: methanol = 9: 1),
Rf = 0.88 (chloroform: methanol = 4
: 1) Example 36 Analogously to Example 1, N-propionyl-desmethylmuramyl-shi-alanyl-D-glutamic acid-(C&) n-butyl ester-(CT)- with 0.41 mol of water.
2.0 g of benzyl ester (mainly α-anomer) (
3.1 mmol) to 1.14 ml (12.0 mmol) of acetic anhydride in 20 ml of anhydrous pyridine.
．． 4.6-Tri-〇-acetyl-N-propionyl-desmethylmuramyl-L-alanyl-D-glutamic acid-
(C&)-n-butyl ester-(C1)-benzyl ester is obtained as a colorless lyophilizate which still contains 0.73 mol of water. 'H-NMR-spectrum (360
MHz), this compound exists almost entirely in the form of the α-anomer. Melting point 62-64℃, [α]6°=+36.4±3.6° (c=0.2
80; methanol), Rf = 0.43 (chloroform:methanol = 9:1), Rf = 0.55
(chloroform:ethanol=9:1), Rf
=0.85 (chloroform:methanol=4:
1) Part 37 - N-prohionyldesmethylmuramyl-L-alanyl-D-glutamic acid dibenzyl ester (α) containing 0.89 mol of water in the same manner as in Example 1.

β-mixture) from 0.57 g (0.83 mmol) of acetic anhydride 0.36 ml (
1.4.6-tIJ
Q-acetyl-N-propionyl-desmethylmuramyl-shi-alanyl-D-glutamic acid dibenzyl ester (α,β-mixture) is obtained as colorless crystals.

Melting point 141-142°C (from chloroform:diethyl ether = 1:10), [α] 6° = + 22.7 ± 2
．． 2° (c=0.454; methylene chloride), Rf =
0.42 (Chloroform:methanol=9:1)
, Rr =0.46 (chloroform:ethanol=
971), Rf = 0.70 (Chloroform: Methanol = 4:1) The starting material is obtained as follows: 1 Ueuni 1: 4.6-0. O-isopropylidene-N-propionyl-desmethylmuramic acid sodium salt 0.74 g (1,
95 mmol) in N,N-dimethylformamide 20 m
1 and then 0.342 g (2,145 mmol) of 1-hydroxy-benzotriazole, 0.442 g (2,145 mmol) of N,N-dicyclohexylcarbodiimide
mmol) and L-alanyl-D-glutamic acid dibenzyl ester hydrochloride 0.85 g (1,95 mmol)
Then, the precipitated N was added and the whole was stirred at room temperature overnight.

The N-dicyclohexylurea is separated out and the tetracycle thus obtained is evaporated to dryness at 30 DEG C. in a high vacuum.

The residue is taken up in 150a+1 of acetic acid ethyl ester and washed successively with 50 ml each of saturated sodium hydrogen carbonate solution, 2N citric acid, saturated sodium hydrogen carbonate solution and water. The organic phases are combined, dried over sodium sulphate and concentrated by evaporation at 30° C. in a high vacuum. Some N-propionyl-desmethylmuramyl-shi-alanyl-D-glutamic acid dibenzyl ester (α,β-mixture) and N
, N-dicyclohexyl urea is obtained. This is processed without further purification.

Step 37.2: Crude 4.6-0.0-isopropylidene-N-propionyl-desmethylmuramyl-shi-alanyl-D-glutamic acid-dibenzyl ester (α.

3.3 g of β-mixture) are left overnight in 30 ml of 50% acetic acid. The solution thus obtained is then filtered and the tetracycle is concentrated by evaporation at 30° C. in a high vacuum. The residue is silica gel (60 type, purest; Merck & Co., Ltd.; 0.063~
Purify by column chromatography on 150 g of chloroform/ethanol (9:1; fraction 10 ml). Fractions 56-95 are combined and concentrated by evaporation in a high vacuum. The residue was dissolved in 80 ml of methanol and the slightly cloudy solution thus obtained was filtered through a Milliball filter (
Pass through the mouth with Fluoroball, PTFE, 0.2 μm).

The clear tetracycle is concentrated in vacuo at 40° C. in one shot. Next, the residue was mixed with 1 ml of anhydrous methanol that had been passed through a Millipore filter (Fluoropol, PTFE, 0.2 μm).
01, and 100 ml of anhydrous diethyl ether previously passed through a milliball filter (Fluoropol, PTFE, 0.2 μm) is added to crystallize it, and washed with the passed anhydrous diethyl ether. N-propionyl-
Desmethylmuramyl-L-alanyl-D-glutamic acid-dibenzyl ester (α.

.beta.-mixture) is obtained as colorless crystals containing 0.89 mol of water. Melting point 146-147°C, [α[0=+1.
4.6±2.1'(c=0.478; methanol)
, Rf = O020 (chloroform:methanol = 9
71), Rf = 0.65 (chloroform: methanol = 421), Rf = 0.81 (chloroform: methanol = 773)
Benzoyl-desmethylmuramyl-shi-alanyl-D-
From glutamic acid-dicoliline ester-dichloride, 1
, 4,6-tri-O-acetyl-N-benzoyl-desmethylmuramyl-shi-alanyl-D-glutamic acid dicholine ester dichloride is obtained.

The starting material is obtained as follows: in acetonitrile from D-glutamic acid dimethyl ester hydrochloride and excess choline chloride in a similar manner as described in Synthesis 1982.138. Using titanium tetraethyl ester as a catalyst, D-glutamic acid dicholine ester dichloride hydrochloride is obtained at 80°C.

Step 38.2: Similarly to Step 6.3, N-benzoyl esters are prepared using dicyclohexylcarbodiimide from N-penzoylutesmethylmurami-mono-alanine and D-glutamic acid-dicholine ester-dichloride hydrochloride. -desmethylmuramyl-dis-alanyl-D-glutamic acid-dicholine ester dichloride is obtained.

Example 39 Similarly to Example 1, N-benzoyl-desmethylmuramyl-shi-alanyl-D-isoglutamine-benzhydryl ester was prepared using n-hexanoyl chloride, pyridine and 4-dimethylamino-pyridine. Benzoyl-1,4,6-to'J-0-n-hexanoyl-alanyl-D-isoglutamine-benzhydryl ester is obtained. Melting point 95°C to 98°C.

(α),! 0=+40.9±1.8° (c=0.55
2; chloroform), Rf=0.38 (chloroform:
Acetone = 7 = 3)

Claims (1)

[Claims] 1. General formula (I): ▲Mathematical formula, chemical formula, table, etc.▼(I) [In the formula, the hexose moiety is derived from D-glucose, D-mannose or D-galactose, and n is 0 or 1, R^1, R^4 and R^6 each independently represent a lower alkanoyl group or benzoyl group, R^2 represents a lower alkyl group or phenyl group, R^3, R^5 and R^7 each independently represent hydrogen or a lower alkyl group, or R^5 together with R^8 represents a trimethylene group, R^7 represents hydrogen, and R^8 represents hydrogen or an unsubstituted lower Represents an alkyl group or a lower alkyl group substituted with a phenyl group, hydroxy group, mercapto group, or lower alkylthio group, and R^9 and R^1^0 each independently represent a hydroxy group, an amino group, or a carbon atom number of 1 to 10. alkoxy group, aryl lower alkoxy group, alkanoyloxy lower alkoxy group having up to 16 carbon atoms, aroyloxy lower alkoxy group, 3-cholesteryloxy group or 2-
Represents trimethylammonio-ethyloxy group, R^1
^0 represents hydrogen, a carboxy group, a lower alkoxycarbonyl group, or an aryl lower alkoxycarbonyl group, and R
^1^1 is hydrogen or unsubstituted or amino group, hydroxy group, lower alkanoylamino group, lower alkanoyloxy group, 2-benzyloxycarbonylamino-ethyl-sulfinyl group, 2-benzyloxycarbonylamino-
Represents a lower alkyl group substituted with an ethyl-sulfonyl group, a 2-lower alkoxycarbonylamino-ethyl-sulfinyl group, a 2-lower alkoxycarbonylamino-ethyl-sulfonyl group, or a guanidino group, but the group R^
At least one of 9 and R^1^2 is different from a hydroxy group, an amino group, and an alkoxy group having 1 to 7 carbon atoms, or R^1^0 is hydrogen, a carboxy group, and a carbon atom of an alkoxy moiety different from alkoxycarbonyl groups having a number of 7 or less] and salts of the compounds having at least one salt-forming group. 2. The hexose moiety is derived from D-glucose, D-mannose or D-galactose, n represents 0 or 1, and R^1, R^4 and R^6 each independently represent a lower alkanoyl group or benzoyl group. , R^2 represents a lower alkyl group or phenyl group, R^3, R^5 and R
^7 each independently represents hydrogen or a lower alkyl group, or R^5 together with R^8 represents a trimethylene group,
R^7 represents hydrogen, R^8 represents hydrogen or a lower alkyl group unsubstituted or substituted with a phenyl group, hydroxy group, mercapto group, or lower alkylthio group, and R^9
and R^1^2 are each independently a hydroxy group, an amino group, an alkoxy group having 1 to 10 carbon atoms, an aryl lower alkoxy group, an alkanoyloxy lower alkoxy group having 16 or less carbon atoms, an aroyloxy lower alkoxy group, or a 3- Represents a cholesteryloxy group, R^1^0 represents hydrogen, a carboxy group, a lower alkoxycarbonyl group, or an aryl lower alkoxycarbonyl group, and R^1^1
represents hydrogen or a lower alkyl group unsubstituted or substituted with an amino group or a hydroxy group, but the groups R^9 and R^
At least one of 1^2 is different from a hydroxy group, an amino group, and a lower alkoxy group, or R^1^0 is different from hydrogen, a carboxy group, and a lower alkoxycarbonyl group, Claim 1 The general formula (
Compounds of I) and salts thereof having at least one salt-forming group. 3, R^9 and R^1^2 are each independently a hydroxy group, an amino group, an alkoxy group having 1 to 10 carbon atoms, an alkanoyloxy lower alkoxy group having 16 or less carbon atoms, a 3-cholesteryloxy group, or phenyl partially unsubstituted or lower alkyl group, phenyl group, halogen, hydroxy group, lower alkoxy group, lower alkanoyloxy group, amino group, mono- or di-lower alkylamino group,
or represents a phenyl- or benzoyloxy-lower alkoxy group substituted with a lower alkanoylamino group,
R^1^0 is hydrogen, carboxy group, lower alkoxycarbonyl group, or phenyl moiety is unsubstituted or lower alkyl group, phenyl group, halogen, hydroxy group, lower alkoxy group, lower alkanoyloxy group, amino group, mono- or di- represents a phenyl lower alkoxycarbonyl group substituted with a lower alkylamino group or a lower alkanoylamino group, and the remaining substituents represent the above,
At least one of the groups R^9 and R^1^2 is different from a hydroxy group, an amino group and a lower alkoxy group, or R^1^0 is different from a hydrogen, carboxy and lower alkoxycarbonyl group A compound of the general formula (I) according to claim 1 or 2 and a salt of the compound having at least one salt-forming group. 4, the hexose moiety is derived from D-glucose or D-mannose, n represents 0 or 1, R^1, R^4
and R^6 each independently represent an alkanoyl group or benzoyl group having 2 to 4 carbon atoms, R^2 represents an alkyl group or phenyl group having 1 to 4 carbon atoms, R^3, R
^5 and R^7 each independently represent hydrogen or a methyl group, or R^5 and R^6 together represent a trimethylene group, R^7 represents hydrogen, and R^8 represents hydrogen or a carbon atom Number 1
~4 alkyl group, or an alkyl group having 1 to 2 carbon atoms substituted with a phenyl group, hydroxy group, mercapto group, or methylthio group, and R^9 and R^1^2 each independently represent a hydroxy group, an amino group, lower alkoxy group, phenyl lower alkoxy group, lower alkanoyloxy lower alkoxy group, benzoyloxy lower alkoxy group or 3-cholesteryloxy group, and R^1^0 is hydrogen, carboxy group, lower alkoxycarbonyl group or phenyl lower Represents an alkoxycarbonyl group, R^1^
1 represents hydrogen or an alkyl group having 1 to 4 carbon atoms that is unsubstituted or substituted with an amino group or a hydroxy group,
At least one of the groups R^9 and R^1^2 is different from a hydroxy group, an amino group, and a lower alkoxy group, or R^1^0 is different from a hydrogen, a carboxy group, and a lower alkoxycarbonyl group. A compound as claimed in claim 1 and a salt thereof having at least one salt-forming group. 5, the hexose moiety is derived from D-glucose or D-mannose, n represents 0 or 1, R^1, R^4
and R^6 each independently represent an alkanoyl group or benzoyl group having 2 to 4 carbon atoms, R^2 represents an alkyl group or phenyl group having 1 to 2 carbon atoms, R^3, R
^5 and R^7 each independently represent hydrogen or a methyl group, R^8 represents an alkyl group having 1 to 4 carbon atoms, and R
^9 and R^1^2 each independently represent a hydroxy group, an amino group, an alkoxy group having 1 to 4 carbon atoms, phenyl-
Represents a methoxy group, lower alkanoyloxymethoxy group, benzoyloxymethoxy group or 3-cholesteryloxy group, R^1^0 represents hydrogen, a carboxy group, an alkoxycarbonyl group having 5 or less carbon atoms, or a phenylmethoxycarbonyl group, R^1^1 represents an alkyl group having 1 to 4 carbon atoms, and at least one of the groups R^9 and R^1^2 is a hydroxy group, an amino group, or an alkyl group having 1 to 4 carbon atoms.
The compound according to claim 1, and at least one compound in which R^1^0 is different from the alkoxy group of 4 or different from hydrogen, a carboxy group, and an alkoxycarbonyl group having 5 or less carbon atoms. A salt of the compound having a salt-forming group of 6, the hexose moiety is derived from D-glucose, n
represents 0 or 1, R^1, R^4 and R^6 represent an acetyl group or a butyryl group, and R^2 has 1 to 2 carbon atoms.
represents an alkyl group or phenyl group, R^3 represents hydrogen or a methyl group, R^5 and R^7 represent hydrogen, R^
8 represents an alkyl group having 1 to 3 carbon atoms, R^9 represents an amino group, an alkoxy group having 1 to 4 carbon atoms, a pivaloyloxymethoxy group, or a mono- or diphenylmethoxy group, and R^1 The compound according to claim 1, wherein ^0 represents hydrogen, R^1^1 represents a methyl group, and R^1^2 represents a mono- or diphenylmethoxy group or a 3-cholesteryloxy group. 7, the hexose moiety is derived from D-glucose, n
represents 0 or 1, R^1, R^4 and R^6 represent an alkanoyl group having 2 to 6 carbon atoms, R^2 represents an alkyl group or phenyl group having 1 to 4 carbon atoms, R^3,
R^5 and R^7 each independently represent hydrogen or a methyl group, R^8 represents an alkyl group having 1 to 4 carbon atoms,
R^9 represents an amino group, a lower alkoxy group, a pivaloyloxymethoxy group, a diphenylmethoxy group, a benzyloxy group or a 2-trimethylammonio-ethoxy group,
R^1^0 represents hydrogen or a lower alkoxycarbonyl group, and R^1^1 is an alkyl group having 1 to 4 carbon atoms, a lower alkanoyloxymethyl group, or (2-benzyloxycarbonylamino-ethyl)-sulfonyl- Represents a methyl group, and R^1^2 is an amino group, a lower alkoxy group, a pivaloyloxymethoxy group, a diphenylmethoxy group, a benzyloxy group, a 2-trimethylammonio-ethoxy group, a 3-cholesteryloxy group, or a benzoyloxy group. The compound according to claim 1, which represents a methoxy group, but at least one of the groups R^9 and R^1^2 is different from an amino group and a lower alkoxy group, and the compound capable of forming a salt. Salts of compounds. 8. At least one of the groups R^9 and R^1^2 is a pivaloyloxymethoxy group, a diphenylmethoxy group, a benzyloxy group, a 2-trimethylammonio-ethoxy group,
3-Cholesteryloxy group or benzoyloxymethoxy group, and the other group R^9 and R^1^2 represent the above-mentioned compounds and salts are formed. A salt of the compound. The compound according to claim 1, which is 9,1,4,6-tri-O-acetyl-N-propionyl-desmethylmuramyl-L-alanyl-D-isoglutamine-benzhydryl ester. Claim 1 which is 10,1,4,6-tri-O-acetyl-N-propionyl-desmethylmuramyl-L-alanyl-D-isoglutamine-benzyl ester
Compounds described in Section. 11,1,4,6-tri-O-acetyl-N-propionyl-desmethylmuramyl-L-alanyl-D-glutamic acid-(C_α)-n-butyl ester-(C_γ)
- The compound according to claim 1, which is a benzhydryl ester. 12, N-acetyl-1,4,6-tri-O-acetyl-muramyl-L-alanyl-D-glutamic acid-(C_
α)-pivaloyloxymethyl ester-(C_γ)-
The compound according to claim 1, which is a benzyl ester. The compound according to claim 1, which is 13,1,4,6-tri-O-acetyl-N-benzoyl-desmethylmuramyl-L-alanyl-D-isoglutamine-benzyl ester. 14. The compound according to claim 1, which is 14,1,4,6-tri-O-acetyl-N-benzoyl-desmethylmuramyl-L-alanyl-D-isoglutamine-benzhydryl ester. 15. The compound according to claim 1, which is N-benzoyl-1,4,6-tri-O-butyryl-desmethylmuramyl-L-alanyl-D-isoglutamine-benzhydryl ester. 16, N-acetyl-(1α,β),4,6-tri-O
-acetyl-desmethylmuramyl-L-α-aminobutyryl-D-isoglutamine-benzhydryl ester. 17, N-acetyl-(1α,β),4,6-tri-O
The compound according to claim 1, which is -acetyl-desmethylmuramyl-L-α-aminobutyryl-D-glutamic acid-dibenzhydryl ester. 18, N-acetyl-(1α,β),4,6-tri-O
-acetyl-desmethylmuramyl-L-valyl-D-isoglutamine-benzhydryl ester. 19, N-acetyl-(1α,β),4,6-tri-O
-acetyl-muramyl-L-alanyl-D-isoglutaminyl-L-alanine-cholesteryl-3-ester. 20. The compound according to claim 1, which is N-acetyl-1,4,6-tri-O-acetyl-muramyl-α-amino-isobutyryl-D-isoglutamine-benzhydryl ester. 21, N-acetyl-1,4,6-tri-O-acetyl-desmethylmuramyl-L-alanyl-D-γ-methoxycarbonyl-isoglutamine-benzhydryl ester according to claim 1 compound. 22, N-acetyl-1,4,6-tri-O-acetyl-muramyl-L-alanyl-D-isoglutaminyl-L
The compound according to claim 1, which is -α-([2-benzyloxy-carbonylamino-ethyl]-sulfonyl-methyl)-glycine-benzyl ester. The compound according to claim 1, which is 23,1,4,6-tri-O-acetyl-N-benzoyl-desmethylmuramyl-L-alanyl-D-glutamic acid-dicoline ester. 24. The compound according to claim 1, which is N-propionyl-1,4,6-tri-O-propionyl-desmethylmuramyl-L-alanyl-D-isoglutamine-benzhydryl ester. Claim 1 which is 25,1,4,6-tri-O-acetyl-N-propionyl-desmethylmuramyl-L-alanyl-D-glutamic acid-α-n-butyl ester-γ-benzyl ester Compounds described in Section. Claim 1 which is 26,1,4,6-tri-O-acetyl-N-propionyl-desmethylmuramyl-L-alanyl-D-glutamic acid-dibenzyl ester
Compounds described in Section. The compound according to claim 1, which is 27,1,4,6-tri-O-acetyl-N-benzoyl-desmethylmuramyl-L-alanyl-D-isoglutamine-benzyl ester. 28, 1,4,6-Tri-O-acetyl-N-propionyl-desmethylmuramyl-L-alanyl-D-glutamic acid-dipivaloyloxymethyl ester, the compound according to claim 1 . 29, 1,4,6-tri-O-acetyl-N-propionyl-desmethylmuramyl-L-alanyl-D-isoglutaminyl-L-alanine-benzoyloxymethyl ester according to claim 1 Compound. 30. General formula (I): ▲Mathematical formula, chemical formula, table, etc.▼(I) [In the formula, the hexose moiety is derived from D-glucose, D-mannose or D-galactose, n represents 0 or 1, R^1, R^4 and R^6 each independently represent a lower alkanoyl group or a benzoyl group, R^2 represents a lower alkyl group or a phenyl group, and R^3, R^5 and R^7 respectively independently represents hydrogen or a lower alkyl group, or R^5 together with R^8 represents a trimethylene group, R^7 represents hydrogen, R^8 is hydrogen or an unsubstituted lower alkyl group or a phenyl group, Represents a lower alkyl group substituted with a hydroxy group, a mercapto group, or a lower alkylthio group, and R^9 and R^1^2 each independently represent a hydroxy group, an amino group, an alkoxy group having 1 to 10 carbon atoms, or a lower aryl group. Alkoxy group, alkanoyloxy lower alkoxy group having up to 16 carbon atoms, aroyloxy lower alkoxy group, 3-cholesteryloxy group or 2-
Represents trimethylammonio-ethyloxy group, R^1
^0 represents hydrogen, a carboxy group, a lower alkoxycarbonyl group, or an aryl lower alkoxycarbonyl group, and R
^1^1 is hydrogen or unsubstituted or amino group, hydroxy group, lower alkanoylamino group, lower alkanoyloxy group, 2-benzyloxycarbonylamino-ethyl-sulfinyl group, 2-benzyloxycarbonylamino-
Represents a lower alkyl group substituted with an ethyl-sulfonyl group, a 2-lower alkoxycarbonylamino-ethyl-sulfinyl group, a 2-lower alkoxycarbonylamino-ethyl-sulfonyl group, or a guanidino group, but the group R^
At least one of 9 and R^1^2 is different from a hydroxy group, an amino group, and an alkoxy group having 1 to 7 carbon atoms, or R^1^0 is hydrogen, a carboxy group, and a carbon atom of an alkoxy moiety alkoxycarbonyl group having a number of 7 or less] or a salt thereof together with a pharmaceutical excipient. 31. The pharmaceutical preparation according to claim 30 for use in the prevention and treatment of viral infections. 32. The pharmaceutical preparation according to claim 30, which is used for the prevention and treatment of viral infections caused by influenza virus, parainfluenza virus, herpes virus, encephalomyocarditis virus, or vaccinia virus.