DD246546A5 - ACYLATED HEXOSEDERIVATES AND METHOD FOR THE PRODUCTION THEREOF - Google Patents

Abstract

The invention relates to a process for the preparation of acylated Hexosederivaten for use as a medicament. The aim of the invention is the provision of structurally relatively simple and relatively easy to prepare muramyl peptide derivatives which are applicable for the prophylaxis and therapy of viral infections in Warmbluetern. According to the invention, compounds of the formula I are prepared in which the hexose part is derived from D-glucose, D-mannose or D-galactose and is, for example: n is 0 or 1, R 1, R 4 and R 6 independently of one another are lower alkanoyl or benzoyl, R 2 is lower alkyl or phenyl, R3, R5 and R7 are each independently hydrogen or lower alkyl, or R5 with R8 together trimethylene and R7 is hydrogen, R8 is hydrogen and. a, R9 and R12 independently of one another hydroxy, amino, C1-10-alkoxy, aryl-lower alkoxy and. a., R10 is hydrogen, carboxy, lower alkoxycarbonyl or aryl-lower alkoxycarbonyl and R11 is hydrogen or unsubstituted or substituted by amino. a. substituted lower alkyl. Formula I

Description

Field of application of the invention

The invention relates to a process for the preparation of acylated hexose derivatives, in particular of 1,4,6-tri ^: O-acylated muramylpeptide and analogous D-mannose or D-galactose derivatives, pharmaceutical preparations containing these derivatives, and their use as medicaments.

Characteristic of the known technical solutions

Muramyl peptides of the type of the '- compound N-acetyl-muramyl-L-alanyl-D-isoglutamine ("MDP") are known from French patent application No. 7422 909 with publication number 2 292 486. These compounds are described as immunological adjuvants, that is, they can be used in admixture with vaccines to improve vaccination success, and our own studies, for example, on influenza virus-infected mice have shown that N-acetyl-muramyl-L-alanyl-D-isoglutamine per se without the addition of vaccines, in which prophylaxis and therapy of viral infections is ineffective.The applicability of structurally simple muramyl peptides and their analogues against viral infections has not been described so far.

Object of the invention

The aim of the invention is to provide structurally relatively simple and therefore relatively easy to prepare muramyl peptide derivatives, which are highly effective after administration to warm-blooded animals with regard to the prophylaxis and therapy of viral infections.

Explanation of the essence of the invention

The invention has for its object to find new muramyl peptide derivatives and processes for their preparation. According to the invention, compounds of the formula I,

OR

·, O

\ ^"L 2

NH-C-R

| R ³ -CH (D). - _R 9

7 \ - ^ IO

R ⁷ OCR ^X

IH I 1

C-N-C-C - NH-CH-CH - CH-C-

OR ^D R ° (D) OL O

NH-CH-C

produced, wherein the. Hexose portion of D-glucose, D-mannose or D-galactose, η is O or 1, and R ¹ , R ⁴ and R ^{6 are} independently lower alkanoyl or benzoyl, R ^{2 is} lower alkyl or phenyl, R ³ , R ⁵ and R ⁷ independently of one another are hydrogen or lower alkyl, or R with R ⁸ together are trimethylene and R ^{7 is} hydrogen, R ^{8 is} hydrogen or lower alkyl which is unsubstituted or substituted by phenyl, hydroxy, mercapto or lower alkylthio, R ⁹ and R ¹² are each independently hydroxyl, amino, C 1 -C 4 -io-alkoxy, Arylniederalkoxy, Alkanoyloxyniederalkoxy with up to 16C-ethers, Aroyloxyniederalkoxy, 3-cholesteryloxy or 2-trimethylammonio-ethyloxy, R ^{10 is} hydrogen, carboxy, lower alkoxycarbonyl or.

Aryl-lower alkoxycarbonyl and R ^{11 is} hydrogen or unsubstituted or by amino, hydroxy, lower alkanoylamino,

Lower alkanoyloxy, 2-benzyloxycarbonylaminoethylsulfinyl, 2-benzyloxycarbonylaminoethylsulfonyl, 2- _v

Lower alkoxycarbonylamino-ethyl-sulfinyl, 2-lower alkoxycarbonyiamino-ethyl-sulfonyl or guanidino substituted lower alkyl, with the proviso that at least one of R ⁹ and R ¹² of hydroxy, amino and C ^ ₇ alkoxy or R ¹⁰ of hydrogen, carboxy and alkoxycarbonyl having up to 7 carbon atoms in the alkoxy moiety, and salts of such compounds having at least one salt-forming group.

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

In the case of asymmetric substitution, the configuration at the atoms is CR ³ , CR ⁸ or C-CO-R ⁹ (D), (L) and (D), respectively, as indicated in formula I. The configuration at CR ¹¹ is in the case of asymmetric substitution (L) or (D), preferably

Lower alkanoyl R ¹ , R ⁴ and R ⁶ is especially C ₂ _6 alkanoyl, z. B. n-hexanoyl, preferably C ^ alkanoyl, z. Butyryl, propionyl or, preferably, acetyl,

Lower alkyl R ² is preferably C 1-4 -alkyl, especially C 1-4 -alkyl.

Lower alkyl R ³ , R ⁵ and R ⁷ is preferably C _1-3 -alkyl, in particular methyl.

Unsubstituted lower alkyl R ⁸ or R ¹¹ is preferably C 1-4 alkyl, e.g. Ethyl, isopropyl, 2-methylpropyl, sec. Butyl or especially methyl.

Substituted by phenyl, hydroxy, mercapto or lower alkylthio, in particular methylthio, lower alkyl R ⁸ is preferably correspondingly substituted Ci_ ₂ alkyl, z. B. benzyl, hydroxymethyl, 1-hydroxy-ethyl, mercaptomethyl or 2-methylthio-ethyl.

Alkoxy R ⁹ or R ¹² is preferably C 1-4 -alkoxy, e.g. As methoxy, n-butyloxy or tert. Butyloxy.

Aryl as part of Arylniederalkoxy, Aryiniederalkoxycarbonyl or Aroyloxyniederalkoxy is especially unsubstituted or by one or more, for. 1-3, the below-mentioned aryl substituent substituted phenyl or naphthyl, preferably unsubstituted phenyl.

Aryl substituents are in particular lower alkyl, for. Methyl, phenyl, halo, hydroxy, lower alkoxy, e.g. Methoxy, lower alkanoyloxy, e.g. For example, acetoxy, amino, mono- or di-lower alkylamino, z. For example, mono- or dimethylamines or Niederalkänoylamino, z. B. acetylamino.

Arylniederalkoxy R ⁹ and / or R ¹² is replaced by one or more, for. B. 1-3, preferably 1 or 2, aryl radicals substituted lower alkoxy, z. B. arylmethoxy, in particular ßenzyloxy or benzhydryloxy.

Aryl lower alkoxycarbonyl R ¹⁰ is substituted by one or more, for example 1-3, preferably 1 or 2, aryl substituted lower alkoxycarbonyl, z. B. arylmethoxycarbonyl, in particular benzyloxycarbonyl or benzhydryloxycarbonyl.

Lower alkoxycarbonyl R ^1C is preferably alkoxycarbonyl having up to 5C atoms, -z. B. Methoxycarb.onyl, n-butyloxycarbonyl or tert. Butyloxycarbonyl.

Lower alkyl R ¹¹ substituted by amino or lower alkanoylamino is preferably 4-amino-n-butyl or 4-lower alkanoylamino-n-butyl. By 2-benzyloxycarbonylamino-ethyl-sulfinyl or -sulfonyl or by 2-lower alkoxycarbonylamino-ethyl-sulfinyl or sulfonyl-substituted lower alkyl R ¹¹ is preferably correspondingly substituted methyl, z. C ₆ H ₅ -CH ₂ -O-Cl = O) -NH-CH ₂ -CH ₂ -Sf = O) -CH ₂ or C ₆ Hs-CH ₂ -OC (=) - NH-CH ₂ - CH ₂ -SO ₂ -CH ₂ - Guanidino-substituted lower alkyl R ¹¹ is preferably 3-guanidino-n-propyl.

Alkanoyloxy lower alkoxy R ⁹ I or R ¹² is especially lower alkanoyloxymethoxy, e.g. B. pivaloyloxymethoxy.

Aroyloxyniederalkoxy R ⁹ or R ¹² is in particular aroyloxymethoxy, z. B. benzoyloxymethoxy.

By hydroxy or lower alkanoyloxy substituted lower alkyl R ¹¹ is in particular correspondingly substituted Ci_ ₂ alkyl, for example hydroxymethyl, 1-hydroxy-ethyl, Niederalkanoyloxymethyl or 1-lower alkanoyloxy-ethyl.

3-Cholesteryloxy is the radical formed by abstraction of hydrogen from the hydroxy group of cholesterol.

The general terms used above and below preferably have the following meanings:

The prefix "lower" denotes radicals up to and including 7, in particular up to and including 4, carbon atoms.

Halogen is especially chlorine or bromine, far-fluorine or iodine.

Salifying groups in a compound of formula I are acidic groups, e.g. Free carboxyl groups, or basic groups,

'Such as in particular free amino or guanidino. Compounds of the formula I which have a trimethylammonium group are in salt form. Depending on the nature of the salt-forming group, the compounds of the formula I form metal or ammonium salts or acid addition salts. Salts of a compound of formula I are preferably pharmaceutically acceptable and non-toxic, e.g. B. alkali metal or alkaline earth metal salts, for. As sodium, potassium, magnesium or calcium salts, or salts with ammonia or suitable organic amines, wherein primarily aliphatic, cycloaliphatic, cycloaliphatic-aliphatic or araliphatic primary, secondary or tertiary mono-, di- or polyamines, and heterocyclic bases for the salt formation come into question, such as lower alkylamines, z. Triethylamine, hydroxy-lower alkylamines, e.g. 2-hydroxyethylamine, bis (2-hydroxyethyl) amine, 2-hydroxyethyl-diethyl-amine or tri- (2-hydroxyethyl) -amine, basic aliphatic esters of carboxylic acids, e.g. For example, -l-aminobenzoic acid ^ -diethylaminoethyl ester, lower alkylene amines, e.g. 1-ethylpiperidine, cycloalkylamines, e.g. B. dicyclohex'ylamine, or benzylamines, eg. B. Ν, Ν'-dibenzylethylenediamine, also bases of the pyridine type, z. As pyridine, collidine or chinoiin. Compounds of formula I having at least one basic group can acid addition salts, for. With inorganic acids such as hydrochloric acid, sulfuric acid or phosphoric acid, or with suitable organic carboxylic or sulfonic acids, e.g. Trifluoroacetic acid, as well as with amino acids such as arginine and lysine. In the presence of several acidic or basic groups, mono- or polysalts can be formed. Compounds of formula I with an acidic, z. Free carboxyl group, and a free basic, e.g. an amino group, may also be in the form of internal salts, i. H. in zwitterionic form, or it may be a part of the molecule as an inner salt, and another part as a normal salt.

For isolation or purification it is also possible to use pharmaceutically unsuitable salts. However, only the pharmaceutically acceptable, non-toxic salts, which are therefore preferred, are used for zosterapeutischen application. According to the invention, it has surprisingly been found that the abovementioned compounds of the formula I and their

'pharmaceutically acceptable salt are well suited both for the prophylaxis and for the treatment of viral infections, such as. B. from animal experiments, as exemplified in the example results. In these animal studies, animals, such as mice or guinea pigs, are infected with a variety of virus species in a dose that is lethal to all or the vast majority of untreated (control) animals, e.g. As LD _3o _ ₉ o, infected and observed the course of infection in the untreated control animals compared to animals that are treated before, simultaneously or after infection with one of the above compounds or a salt thereof.

It shows that a prophylactic effect in administration of the compounds of formula! already several days to some, z. B. four weeks before infection, and a therapeutic effect even when administered several days, z. B. 1 week after the infection occurs.

The compounds of the formula I are effective in the abovementioned test on the mouse already in the dose range between 0.0001 mg / kg and 0.1 mg / kg.

Also noteworthy is the broad viral spectrum against which the above compounds are effective. The compounds of the formula I can be used, in particular, for the prophylaxis and treatment of diseases which are caused by the virus which is described in more detail below (for a nomenclature, see JL Melnick, Prog. Med. Virol., 26, 214-232 [1980] and 28 , 208-221 [1982]):

Cubic symmetry and naked nucleocapsid DNA viruses, enveloped virion DNA viruses, and cubic and capsid helical symmetry viruses.

The compounds of the formula I are preferably used in the case of DNA viruses with enveloped virion and cubic symmetry of the capsid, in the case of RNA viruses with cubic symmetry of the capsid and naked virion and in the case of RNA viruses with a helical symmetry of the capsid, in which the nucleocapsid sheath is located at the surface membrane, but also in the case of Adenoviridae, Poxviridae and Coronaviridae, in particular human coronaviruses. In the first place, the compounds of the formula I are used in the case of Herpesviridae, Picornaviridae and Myxoviruses, but also in the case of mastadenoviruses, in particular human adenoviruses, in the case of Chordopoxvirinae, such as orthopoxviruses in particular z. As vaccinia viruses, in the case of Reoviridae, especially (especially human) rotavirus, as well as in the case of Caliciviridae and Rhabdoviridae, such as primarily vesiculoviruses in humans and horses, cattle and pigs.

Mainly used the compounds of formula I in the case of Alphaherpesvirinae, such as varicella viruses, z. Human varicella-zoster viruses, rhinoviruses, cardioviruses and orthomyxoviridae, but also in the case of betaherpesvirinae, in particular human cytomegaloviruses, in the case of aphthoviruses, primarily aupiviruses of ungulates, mainly of cattle, and in the case of paramyxoviridae, as primarily pneumoviruses, e.g. Human respiratory syncytial viruses, and, in addition, morbilliviruses or paramyxoviruses, such as parainfluenza viruses, e.g. Human parainfluenza viruses, including the Sendai viruses as well as in the case of arboviruses or vesiculoviruses, e.g. B. Vesicular stomatitis viruses.

First and foremost, the compounds of formula I are used in the case of simplex viruses, e.g. Human herpes simplex viruses of types 1 and 2, in the case of human encephalomyocarditis viruses, in the case of influenza viruses such as mainly influenza A and influenza B viruses, in the case of vaccinia and parainfluenza viruses, and more particularly in the case of the viruses mentioned in the examples ,

The compounds of the formula I can be used for the prophylaxis and therapy of viral infections, in particular in warm-blooded animals, including humans, by administering them enterally or parenterally, primarily together with suitable carriers or excipients. Preferably, they are applied to the mucosa, e.g. intranasally, rectally, vaginally or on the conjunctiva of the eye, or orally. However, the antiviral effect also occurs when applied by other routes, e.g. subcutaneously, intravenously, intramuscularly or when applied to normal skin.

The dosage of the active ingredient depends i.a. from the warm-blooded species, the defensive state of the organism, the mode of administration and the type of virus. The dose-response relationship is relatively weak.

For prevention, a single dose of about 0.01 mg to about 10 mg, preferably 0.05 to 1 mg, e.g. 0.2 mg, active ingredient to a warm-blooded animal of about 70 kg body weight, z. For example, humans. The prophylactic effect of this dose extends over several weeks. If necessary, z. As in times of increased risk of infection, one can repeat the administration of this dose.

The therapeutic dose for warm-blooded animals of about 70 kg body weight is between 0.1 mg and 25 mg, preferably between 0.1 and 1 mg, ζ. B. at 0.5 mg, especially for oral administration. The dosage in topical, especially intranasal administration is lower by a factor of 10. If necessary, the administration of the compounds of formula I may be repeated until the onset of disease recovery. Often, however, a single application is sufficient.

The compounds of formula I also have anti-tumor properties. These are based on their ability to As incorporated in multilamellar liposomes or in phosphate-buffered saline (PBS) to activate macrophages such that these body's defense cells are able to kill tumor cells (cytotoxicity) or to prevent their growth (cytostasis). The induction of tumoricidal and tumoristic alveolar macrophages of the rat in vitro and in situ can be determined e.g. show with the following experiment:

Alveolar macrophages are obtained by lung lavage with culture medium. These macrophages are activated either by injection of the test substances into the rats (intravenous or intranasal, in situ activation) or by preincubation for 24 hours with a compound of the formula I in the CGylncubator (in vitro activation). The thus activated macrophages are now incubated with tumor cells for a further 72 hours.

To measure tumoricidal activities of the macrophages, the tumor cells are labeled with ¹²⁵ I-iododeoxyuridine before the 72 hour incubation. The non-killed tumor cells, after washing away the radioactivity released by lysed tumor cells, can be measured by residual radioactivity.

In order to detect tumoristatic activities of the macrophages, ³ H-thymidine is added to the cultures 8 hours before the end of the 72-hour incubation and thereafter the ³ H-thymidine incorporation into the tumor cells is measured. In vitro, the substances, both dissolved in PBS and incorporated into liposomes, can already induce tumoricidal rat alveolar macrophages at doses of 20 nanograms / 0.2 ml of culture. In rats, a single intravenous administration of the compounds incorporated into liposomes at a dose of 160 μl / animal causes induction of tumoricidal and tumoristatic alveolar macrophages. In addition, a single intranasal administration of the substances in PBS at a dose of 25 μg / rat causes the induction of tumoricidal alveolar macrophages. ; ι "

The compounds of the formula I can thus also be used in the treatment of tumor diseases in warm-blooded animals, including humans, in particular e.g. to prevent the formation of metastases, e.g. at surgical removal of the primary tumor. ''

The invention relates in particular to those compounds of the formula I in which the hexose part is derived from D-glucose, D-mannose or D-galactose, η is 0 or 1 and R ¹ , R ⁴ and R ^{5 are} independently lower alkanoyl or benzoyl, R ^{2 is} lower alkyl or phenyl, R ³ , R ⁵ and R ^{7 are,} independently of one another, hydrogen or lower alkyl, or R ^{5 is} R ⁸ together with trimethylene and R ^{7 is} hydrogen, R ^{8 is} hydrogen or lower-alkyl which is unsubstituted or substituted by phenyl, hydroxyl, mercapto or lower alkylthio, R ⁹ and R ^{12 are} independently hydroxy, amino, Ci_io-alkoxy, Arylniederalkoxy, Alkanoyloxyniederalkoxy with up to 16C atoms, Aroyloxyniederalkoxy or 3-CholesterylOxy, R ^{10 is} hydrogen, carboxy, lower alkoxycarbonyl or Arylniederalkoxycarbonyl and R ^{11 is} hydrogen or unsubstituted or by amino or Hydroxy-substituted lower alkyl, with the proviso that at least one of R ⁹ and R ¹² of hydroxy, amino and Ci_ ₇ alkoxy or R ¹⁰ is different from hydrogen, carboxy and alkoxycarbonyl having up to 7 C atoms in the alkoxy part, and salts of such compounds having at least one salt-forming group.

The above-mentioned compounds of formula I, wherein R ⁹ and R ¹² are independently hydroxy, amino, CI_ ₁₀ alkoxy, Alkanoyloxyniederalkoxy having up to 16 carbon atoms, 3-cholesteryloxy or in each case unsubstituted or in the phenyl moiety by lower alkyl, such being preferred. Methyl, phenyl, halo, hydroxy, lower alkoxy, e.g. Methoxy, lower alkanoyloxy, e.g. For example, acetoxy, amino, mono- or di-lower alkylamino, for example mono- or dimethylamino, or lower alkanoylamino, for example acetylamino, substituted phenyl or benzoyloxy-lower alkoxy, and R ^{10 is} hydrogen, carboxy, lower alkoxycarbonyl or unsubstituted in the phenyl or by lower alkyl, z. Methyl, phenyl, halo, hydroxy, lower alkoxy, e.g. Methoxy, lower alkanoyloxy, e.g. For example, acetoxy, amino, mono- or di-lower alkylamino, z. For example, mono- or dimethylamino, or lower alkanoylamino, e.g. Acetylamino, substituted phenyl-lower alkoxycarbonyl, and the remaining substituents have the abovementioned meanings, with the proviso that at least one of R ⁹ and R ¹² of hydroxy, amino and NiederalkoxY or R ¹⁰ is different from hydrogen, carboxy and lower alkoxycarbonyl, and Salts of such compounds having at least one salt-forming group.

Particular preference is given to compounds of the formula I in which the hexose part is derived from D-glucose or D-mannose, η is 0 or 1, R ¹ , R ⁴ and R ⁶ independently of one another are C ₂ -alkanoyl or benzoyl, R ² C ^ -Alky! or phenyl, R ³ , R ⁵ and R ⁷ independently of one another are hydrogen or methyl, or R ^s with R ⁸ together are trimethylene and R ^{7 is} hydrogen, R ^{8 is} hydrogen, C 1-4 -alkyl or C 1 -C 4 -substituted by phenyl, hydroxyl, mercapto or methylthio Alkyl, R ^s and R ¹² are each independently of one another hydroxy, amino, lower alkoxy, phenyl-lower alkoxy, lower alkanoyloxy-lower alkoxy, benzyloxy-lower alkoxy or 3-cholesteryloxy, R ^{10 is} hydrogen, carboxy, lower alkoxycarbonyl or phenyl-lower alkoxycarbonyl and R ^{11 is} hydrogen or unsubstituted or amino- or hydroxy-substituted C 1 - Alkyl, with the proviso that at least one of R ⁹ and R ¹² of hydroxy, amino and lower alkoxy or R ¹⁰ of hydrogen, carboxy and lower alkoxycarbonyl. is different, and salts of such compounds having at least one salt-forming group.

Very particular preference is given to compounds of the formula I in which the hexose part is derived from D-glucose or D-mannose, η is 0 or 1, R ¹ , R ⁴ and R ⁶ independently of one another are C ₂ -4-alkanoyl or benzoyl, R ² Ci_2-alkyl or phenyl, R ³ , R ⁵ and R ^{7 are} independently hydrogen or methyl, R ⁸ C - ^ - alkyl, R ⁹ and R ^{12 are} independently hydroxy, amino, C ₁ ^ -alkoxy, phenylmethoxy, lower alkanoyloxymethoxy, benzoyloxymethoxy or 3-cholesteryloxy, R ^{10 is} hydrogen, carboxy, alkoxycarbonyl having up to 5C atoms or phenylmethoxycarbonyl and R ^{11 is} Ci-4-alkyl, with the proviso that at least one of R ⁹ and R ¹² of hydroxy, amino and C 4-alkoxy or R ¹⁰ is different from hydrogen, carboxy and alkoxycarbonyl having up to 5C atoms, and salts of such compounds having at least one salt-forming group. Very particular preference is given to compounds of the formula I in which the hexose part is derived from D-glucose, η is 0 or 1, R ¹ , R ⁴ and R ^{6 are} acetyl or butyryl, R ^{2 is} d_ ₂ -alkyl or phenyl, R ^{3 is} hydrogen or methyl, R ⁵ and R ⁷ is hydrogen, R ⁸ is C ^ alkyl, R ^{9 is} amino, C ₁ ^ -alkoxy, Pivaloyloxymethoxy or mono or diphenylmethoxy, R ¹⁰ is hydrogen, R ¹¹ is methyl and R ¹² mono- or diphenylmethoxy or 3 -Cholesteryloxy mean.

Very particular preference is also given to compounds of the formula I in which the hexose moiety is derived from D-glucose, η is 0 or 1, R ¹ , R ⁴ and R ^{6 are} C ₂ -6-alkanoyl, R ^{2 is} C _M -alkyl or phenyl, R ³ , R ⁵ and R ^{7 are} independently hydrogen or methyl, R ^{8 is} C 1-4 alkyl, R ^{9 is} amino, lower alkoxy, pivaloyloxymethoxy, diphenylmethoxy, benzyloxy or 2-trimethylammonioethoxy, R ¹⁰

R ^{12 is} C 1-8 alkyl, lower alkanoyloxymethyl or (2-benzyloxycarbonylaminoethyl) sulfonylmethyl and R ^{12 is} amino, lower alkoxy, pivaloyloxymethoxy, diphenylmethoxy, benzyloxy, 2-trimethylammonioethoxy, 3-cholesteryloxy or benzoylbxymethoxy, with the proviso that at least one of R ⁹ and R ¹² is other than amino and lower alkoxy, and salts of such salt-forming compounds.

Very particular preference is given in particular to compounds of the formula I in which at least one of the radicals R ⁹ and R ^{12 is} pivaloyloxymethoxy, diphenylmethoxy, benzyloxy, 2-trimethylammonioethoxy, 3-cholesteryloxy or benzoyloxymethoxy and the other of the radicals R ⁹ and R ¹² has the abovementioned meaning, and salts of such salt-forming compounds.

Most preferred are the compounds of formula I described in the Examples.

The compounds of the formula I are prepared in a manner known per se:

They are z. B. prepared by

A) a compound of formula II,

CH ₂ OR ^{6 a}

n / vw \ ^ * QP_

• χί /

" ¹ NH-R ²³

R ³ -CH (D)

⁷ 8 T Γ

-C-NH-CH-CH ₂ -CH- Q- ⁵ R ⁸ (D)

(L)

NH Cf

[-C-NH-CEi-C-

R ¹² η

wherein at least one of the radicals R ¹ ', R ² ', R ⁴ 'and R ^{6a is} hydrogen and the remaining of these radicals are the meanings of R ¹ , the group R ² -C (= O) -, R ⁴ and R, respectively ⁶ , and the remaining substituents have the abovementioned meanings, wherein in a compound of formula II existing free functional groups, with the exception of the groups to participate in the reaction, if necessary protected by easily cleavable protecting groups, with a R ^{1 to be introduced} , R ² -C (= O) -, R ⁴ or R ⁶ reacting transferring acylating agent and eliminates any necessary protective groups, or, b) a compound of formula III,

CH ₂ OR ⁶

\ Γ

wherein the substituents have the abovementioned meanings, or a reactive derivative thereof with a compound of the formula IV,

R9 .0

f? S

X-CH-C-N-C- € -NH-CH- R ³ δ

Et ⁵ R ⁸ (L)

R ₁ O

CH ₂ -CH-C- (D) ö

NH-CH-C

R ¹

wherein X is a reactive esterified hydroxy group, and the remaining substituents have the abovementioned meanings, which are protected in a compound of formula IV free functional groups with the exception of X if necessary protected by readily cleavable protecting groups, reacting and releasing existing protecting groups if necessary, or c) a compound of the formula V,

OH

wherein q, r, s and t are independently 0 or 1 and wherein the substituents have the abovementioned meanings, wherein in a compound of formula V existing free functional groups with the exception of the group to participate in the reaction, if necessary by light cleavable protecting groups are protected, or a reactive carboxylic acid derivative thereof with a compound of formula Vl,

H-CH ₂ -

NH-

¹ JH-C

R ¹²

fv

where u, ν and. χ independently of one another represent 0 or 1 and the other symbols and substituents have the abovementioned meanings, wherein, if necessary, free functional groups present in a compound of formula VI are protected by easily removable protective groups, with the exception of the group which is to take part in the reaction; where u, ν and χ are 1, if in the reactant of formula Vq and t are O, or u is 0 and ν and χ is 1, if q is 1 and t is O, or u and v are O and χ is 1, when q, round t is 1 and s is 0 or (for the preparation of compounds of formula I wherein η is 1) u and χ are 0 when q, r, s and t are 1, or with a reactive one Or d) for the preparation of a compound of formula! Wherein R ^{9 has} one of the above meanings except hydroxy and amino and / or R ¹⁰ for lower alcohol xycarbonyl or aryl-lower alkoxycarbonyl and the remaining substituents have the abovementioned meanings, a compound of the formula VII,

CH ₂ OR ⁶ .

xl /

R ³ -

¹ NH-CR ²

ί-CH-CH ₂ - (D)

NH-

_ »N γ / -

R ¹² η

wherein at least one of R ^10a ) and R ^{13 is} carboxy and the other of R ^10a and R ^{13 has} the abovementioned meaning of R ¹⁰ or of the group R ⁹ -C (= O) -hat, and in which the other substituents have the abovementioned meanings, free functional groups present in a compound of the formula VII, with the exception of the groups which are to participate in the reaction, being protected by readily cleavable protective groups if necessary, or esterifying a reactive carboxylic acid derivative thereof and eliminating protective groups present if necessary, or

e) in a compound of formula I wherein at least one of R ⁸ , C (= O) -R ⁹ , R ¹⁰ , R ¹¹ and C f = O) -R ^{12 is} in a protected form other than that defined corresponds to the desired end product, the corresponding protective group (s) splits off, or

f) for preparing a compound of the formula I in which R ^{9 is} amino and the other substituents have the abovementioned meanings, a compound of the formula VIII

- Ν- C-C-NH-CH-CH _z

R ³ - ^ (D)

R ¹¹

H-C

NH-CH-C

(D

wherein the radical R ^{14 is} carboxy and the remaining substituents have the abovementioned meanings, wherein in a compound of the formula VIII existing free functional groups, except for the groups to participate in the reaction, if necessary, are protected by readily cleavable protecting groups, or reactive carboxylic acid derivative thereof and eliminating protective groups present if necessary, and, if desired, after carrying out one of the processes af) converting a compound of formula I obtained with at least one salt-forming group into its salt or converting a salt of a compound of formula I obtained into the free compound , and / or a mixture of isomers obtained separates.

Preference is given to the processes a, c, d and e, furthermore process f.

The implementation of the abovementioned process variants is explained in more detail below: Process:

Preferably, method a) is used to introduce an acyl radical R ¹ , R ⁴ and / or R ⁶ . In this case, preference is given to compounds of the formula II, in which the radical R ^{2a is} the group R ² -C (= O). In a compound of the formula II optionally present free functional groups, which are preferably protected by readily removable protective groups, are in particular free hydroxy or mercapto in the radical R ⁸ , free carboxy R ⁹ -C (= O) -, R ¹⁰ or R ¹² - C (= O) - and free amino, hydroxy or guanidino in the radical R ¹¹ . Optional is the protection of free carbamoyl R ⁹ -C (= O) - or R ¹² -C (= O) -.

Protecting groups, their introduction and cleavage are described for example in "Protective Groups in Organic Chemistry", Plenum Press, London, New York 1973, and in "Methods of Organic Chemistry", Houben-Weyl, 4th Edition, Vol. 15/1, Georg-Thieme-Verlag, Stuttgart 1974 and in Theodora W. Greene, "Protective Groups in Organic Synthesis, John Wiley & Sons, New York 1981. It is characteristic of protecting groups that they are easily, i. H. without unwanted side reactions take place, for. B. solvolytic, reductive, photolytic or cleavable under physiological conditions.

Hydroxy protecting groups are e.g. Acyl radicals, as appropriate, e.g. by halogen, substituted lower alkanoyl, such as 2,2-dichloroacetyl, or acyl radicals of carbonic monoesters, especially tert-butyloxycarbonyl, optionally substituted benzyloxycarbonyl, e.g. 4-nitrobenzyloxycarbonyl, or diphenylmethoxycarbonyl, or 2-halo-lower alkoxycarbonyl, such as 2,2,2-trichloroethoxycarbonyl, also trityl or formyl, or organic silyl or stannyl radicals, and also readily cleavable etherifying groups, such as tert-lower alkyl , z. For example, tert-butyl, 2-oxa or 2-thia-aliphatic or cycloaliphatic hydrocarbon radicals, primarily 1-Niederalkoxyniederalkyl or 1-lower alkylthio-lower alkyl, z. Methoxymethyl, 1-methoxyethyl, 1-ethoxyethyl, methylthiomethyl, 1-methylthioethyl or 1-ethylthioethyl, or 2-oxa or 2-thiacycloalkyl having 5-6 ring atoms, e.g. As tetrahydrofuryl or 2-tetrahydropyranyl or corresponding thia analogues, and optionally substituted 1-phenyl-lower alkyl, such as optionally substituted benzyl or diphenylmethyl, wherein as substituents of the phenyl radicals z. As halogen, such as chlorine, lower alkoxy, such as methoxy and / or nitro come into question. Carboxyl groups are usually protected in esterified form, such ester groups being readily cleavable under mild conditions. Carboxyl groups protected in this way contain, as esterifying groups, lower alkyl groups branched in the first position or suitably substituted in the 1 or 2 position. Preferred esterified carboxylic groups include i.a. tert-lower alkoxycarbonyl, e.g. B. tert-butyloxycarbonyl, arylmethoxycarbonyl with one or two aryl radicals, these optionally being, for. B. by lower alkyl, such as tert-lower alkyl, z. Tert-butyl, lower alkoxy such as methoxy, hydroxy, halogen, e.g. As chlorine, and / or nitro, mono- or polysubstituted phenyl radicals, as appropriate, for. As mentioned above, substituted benzyloxycarbonyl, z. B. 4-Methoxybenzyloxycarbony.l, or 4-Nitrobenzyloxycarbonyl, or optionally, for. As mentioned above, substituted diphenylmethoxycarbonyl, z. Diphenylmethoxycarbonyl or di- (4-methoxyphenyl) -methoxycarbonyl, 1-lower alkoxy-lower alkoxycarbonyl such as methoxymethoxycarbonyl, 1-methoxyethoxycarbonyl or 1-ethoxymethoxycarbonyl, 1-lower alkylthio-lower alkoxycarbonyl such as 1-methylthiomethoxycarbonyl or 1-ethylthioethoxycarbonyl, aroylmethoxycarbonyl wherein the aroyl group is optionally substituted, e.g. , As halogen, such as bromine, substituted benzoyl represents, for. Phenacyloxycarbonyl, 2-halo-lower alkoxycarbonyl, e.g. 2,2,2-trichloroethoxycarbonyl, 2-bromoethoxycarbonyl or 2-iodoethoxycarbonyl, or 2- (trisubstituted silyl) -ethoxycarbonyl, wherein each of the substituents independently represents an optionally substituted, e.g. B. substituted by lower alkyl, lower alkoxy, aryl, halogen, and / or nitro, aliphatic, araliphatic, cycloaliphatic or aromatic hydrocarbon radical, such as corresponding, optionally substituted lower alkyl, phenyl, alkylene, cycloalkyl or phenyl, z. 2-tri-lower alkylsilylethoxycarbonyl, 2-trimethylsilylethoxycarbonyl or 2- (di-n-butyl-methyl-silyl) -ethoxycarbonyl, or 2-triarylsilylethoxycarbonyl such as 2-triphenylsilylethoxycarbonyl. The organic silyl or stannyl radicals mentioned above and below preferably contain lower alkyl, in particular methyl, as substituents of the silicon or tin atoms. Corresponding SiIyI or stannyl groups are primarily tri-lower alkylsilyl, in particular trimethylsilyl, furthermore dimethyl-tert-butyl-silyl, or correspondingly substituted stannyl, ζ. Β. Tri-n-butylstannyl.

Preferred protected carboxyl groups are tertiary lower alkoxycarbonyl, such as tert-butoxycarbonyl, and especially optionally, e.g. As mentioned above, substituted benzyloxycarbonyl, such as 4-nitrobenzyloxycarbonyl, or diphenylmethoxycarbonyl, especially 2- (trimethylsilyl) -ethoxycarbonyl.

A protected amino group may, for. Example in the form of an easily cleavable acylamino, Arylmethylamino-, etherified Mercaptoamiho-, 2-acyl-lower alk-i-en-yl-amino, SiIyI or Stannylaminogruppe or present as an azido group. For example, in a corresponding acylamino group, acyl is the acyl radical of an organic carboxylic acid with e.g. up to 18 carbon atoms, in particular an optionally, for. B. by halogen or aryl, substituted alkanecarboxylic acid or optionally, for. Example by halogen, 'lower alkoxy or nitro, substituted benzoic acid, or a carbonic acid. Such acyl groups are, for example, lower alkanoyl, such as formyl, acetyl or propionyl, halo-lower alkanoyl, such as 2-haloacetyl, especially 2-chloro, 2-bromo, 2-iodo; 2,2,2-Trifiuor- or 2,2,2-Trichlöracetyl, optionally, for. B. substituted by halogen, lower alkoxy or nitro substituted benzoyl, z. B. benzoyl, 4-chlorobenzoyl, 4-methoxybenzoyl or 4-nitrobenzoyl, or in the 1-position of the lower alkyl or branched in the 1- or 2-position suitably substituted lower alkoxycarbonyl, especially tert-Niederalkoxycarbonyl, z. B. tert-butyloxycarbonyl, arylmethoxycarbonyl with one or two aryl radicals, which are preferably optionally, for. B. by lower alkyl, irisbesondere tert-Niederaikyl, such as tert-butyl, lower alkoxy, such as methoxy, hydroxy, halogen, z. As chlorine, and / or nitro, mono- or polysubstituted phenyl, such as optionally substituted benzyloxycarbonyl, z. 4-nitro-benzyloxycarbonyl, or substituted diphenylmethoxycarbonyl, e.g. B. Benzhydryloxycarbonyl or di- (4-methoxyphenyl) -rnethoxycarbonyl, Aroylmethoxycarbonyl, wherein the aroyl group is preferably optionally, for. B. represented by halogen, such as bromine, substituted benzoyl, z. Phenacyloxycarbonyl, 2-halo-lower alkoxycarbonyl, e.g. 2,2,2-trichloroethoxycarbonyl, 2-bromoethoxycarbonyl or 2-iodoethoxycarbonyl, or 2- (trisubstituted silyl) -ethoxycarbonyl, wherein each of the substituents independently represents an optionally substituted, e.g. B. substituted by lower alkyl, lower alkoxy, aryl, halogen or nitro, aliphatic, araliphatic, cycloaliphatic or aromatic hydrocarbon radical having up to 15C atoms, such as corresponding, optionally substituted lower alkyl, phenyl, alkylene, cycloalkyl or phenyl, z. 2-tri-lower alkylsilylethoxycarbonyl such as 2-trimethylsilylethoxycarbonyl or 2- (di-n-butyl-methyl-silyl) -ethoxycarbonyl, or 2-triarylsilylethoxycarbonyl such as 2-triphenylsilylethoxycarbonyl.

Further acyl radicals which are suitable as amino-protecting groups are also corresponding radicals of organic phosphoric, phosphonic or phosphinic acids, such as dilower alkylphosphoryl, eg. Dimethylphosphoryl, diethylphosphoryl, di-n-propylphosphoryl or diisopropylphosphoryl, dicycloalkylphosphoryl, e.g. Dicyclohexylphosphoryl, optionally substituted diphenylphosphoryl, e.g. B. diphenylphosphoryl, optionally, for. As substituted by nitro di-. , (phenyl-lower alkyl) phosphoryi, e.g. B. dibenzylphosphoryl or di- (4-nitrobenzyl) -phosphoryl, optionally substituted phenyloxy-phenyl-phosphonyl, z. Phenyloxyphenyl phosphonyl, dilower alkyl phosphinyl, e.g. B. diethylphosphinyl, or optionally substituted diphenylphosphinyl, z. B. diphenylphosphinyl.

In an arylmethylammonium group which represents a mono-, di- or in particular triarylmethylamino group, the aryl radicals are in particular optionally substituted phenyl radicals. Such groups are for example benzyl, diphenylmethyl and especially tritylamino.

An etherified mercapto group in an amino group protected with such a radical is primarily arylthio or aryl-lower alkylthio, wherein aryl is especially optionally, e.g. is phenyl substituted by lower alkyl, such as methyl or tert-butyl, lower alkoxy, such as methoxy, halogen, such as chlorine, and / or nitro. A corresponding amino protecting group is z. B. 4-Nitrophenylthio.

In a usable as amino protecting group 2-γογΙ-ηίβαβΓ3 ^ -1-βηΙ-γΙ ^ · ίβ3ί is acyl ζ. Β, the corresponding radical of a lower alkanecarboxylic acid, an optionally, z. B. by lower alkyl, such as methyl or tert-butyl, lower alkoxy, such as methoxy, halogen, such as chlorine, and / or nitro substituted benzoic acid, or in particular a Kohlensäurehaibesters, such as a carbonic acid lower alkyl. Corresponding protecting groups are primarily 1-lower alkanoyl-prop-1-en-2-yl, e.g. 1-acetyl-prop-1-en-2-yl, or 1-lower alkoxycarbonyl-prop-1-en-2-yl, e.g. For example, 1-ethoxycarbonyl-prop-1-en-2-yl. An amino group can also be protected in protonated form; as corresponding anions are primarily those of strong inorganic acids, such as hydrogen halides, z. As the chlorine or Bromanion, or of organic sulfonic acids, such as p-toluenesulfonic acid in question.

Preferred amino-protecting groups are acyl radicals of carbonic monoesters, in particular tert-butyloxycarbonyl, if appropriate, for. B. as indicated, substituted benzyloxycarbonyl, z. 4-nitro-benzyloxycarbonyl, or diphenylmethoxycarbonyl, or 2-halo-lower alkoxycarbonyl such as 2,2,2-trichloroethoxycarbonyl, further trityl or formyl.

A mercapto group, such as. As in cysteine, in particular by S-alkylation with optionally substituted alkyl radicals, thioacetal, S-acylation or by creating asymmetric disulfide groups are protected. Preferred mercapto protecting groups are, for. B. optionally in the phenyl radical, for. Substituted by methoxy or nitro, substituted benzyl, such as 4-methoxybenzyl, optionally in the phenyl moiety, e.g. by methoxy, substituted diphenylmethyl, such as 4,4'-dimethoxydiphenylmethyl, triphenylmethyl, trimethylsilyl, benzylthiomethyl, tetrahydropyranyl, acylaminomethyl, benzoyl, benzyloxycarbonyl or aminocarbonyi, such as ethylaminocarbonyl.

Primary carboxylic acid amide groups (carbamoyl groups, -CONH ₂ ) are z. B. in the form of N- (9-xanthenyl) derivatives or in the form of N- (mono-, di- or TriarylmethyD derivatives protected, wherein aryl in particular unsubstituted or substituted with up to 5 identical or different substituents phenyl Phenyl substituents are preferably lower alkyl, such as methyl, or lower alkoxy, such as methoxy Examples of such arylmethyl protecting groups include: 4-methoxybenzyl, 2,4,6-trimethoxy-benzyl, diphenyl-methyl, di (4'-methoxy) The protection of carbamoyl groups is optional, ie not absolutely necessary under suitable reaction conditions, for example when using suitable condensing agents.

Guanidino groups are z. B. in the form of the acid addition salt, in particular protected as hydrochloride or as toluenesulfonate.

An acylating agent which transfers the radical R ¹ , R ² -C (= O) -, R ⁴ or R ⁶ is, in particular, the corresponding carboxylic acid, ie R'-OH, R ² -COOH, R ^d -OH or R ⁶ ~OH, or, preferably, a reactive acid derivative thereof, wherein the activation of the carboxylic acid used as an additional agent can also be effected in situ in the presence of the compound of formula II.

The invention particularly relates to those embodiments of process a), wherein an acyl radical R ¹ , R ⁴ and / or R ^{6 is} introduced.

Activated carboxylic acid derivatives useful as acylating agents are primarily reactive activated esters or reactive anhydrides, and also reactive cyclic amides.

Activated esters of acids are especially at the linking carbon atom of the esterifying radical unsaturated esters, eg. Vinyl ester type, such as actual vinyl esters (which can be obtained, for example, by transesterification of a corresponding ester with vinyl acetate; activated vinyl ester method), carbamoylvinyl esters (obtained, for example, by treating the corresponding acid with an isoxazolium reagent 1,2-oxazolium or Woodward method), or 1-lower alkoxyvinyl ester (which can be obtained, for example, by treating the corresponding acid with a lower alkoxyacetylene, ethoxyacetylene method), or amidino-type esters such as Ν, Ν'-disubstituted ones Amidinoester (which can be obtained, for example, by treating the corresponding acid with a suitable Ν, Ν'-disubstituted carbodiimide, eg., ^, N'-dicyclohexylcarbodiimide, carbodiimide method), or N, N-disubstituted Amidinoester (the can be obtained, for example, by treating the corresponding acid with a Ν, Ν-disubstituted cyanamide, cyanamide method), suitable aryl esters, in particular by electron-attracting substituents suitable et substituted phenyl esters (which z. B. by treating the corresponding acid with a suitably substituted phenol, for. 4-nitrophenol, 4-methylsulfonylphenol, 2,4,5-trichlorophenol, 2,3,4,5,6-pentachlorophenol or 4-phenyldiazophenol, in the presence of a condensing agent such as (n ', n'). Dicyclohexylcarbodiimide), cyanomethyl esters (which can be obtained, for example, by treating the corresponding acid with chloroacetonitrile in the presence of a base, cyanomethyl ester method), thioesters, especially if appropriate, e.g. B. by nitro, substituted phenyl thioester (which can be obtained, for example, by treating the corresponding acid with optionally, for example by nitro, substituted thiophenols, inter alia by means of the anhydride or carbodiimide method; activated thiolesters), amino or amido esters (which are obtained, for example, by treating the corresponding acid with an N-hydroxy-amino or N-hydroxy-amido compound, for example N-hydroxy-succinimide, N _r hydroxy-piperidine , N-hydroxyphthalimide or 1-hydroxybenzotriazole, for example by the anhydride or carbodiimide method; activated N-hydroxy ester method) or silyl ester (obtained, for example, by treating the corresponding acid with a silylating agent, e.g. B. hexamethyldisilazane, and which react easily with hydroxy, but not with amino groups).

Anhydrides of acids may be symmetrical or preferably mixed anhydrides of these acids, such. Example, anhydrides with inorganic acids, such as acid halides, in particular acid chlorides (which can be obtained, for example, by treating the corresponding acid with thionyl chloride, phosphorus pentachloride or oxalyl chloride, acid chloride method), azides (eg, from a corresponding acid ester over the corresponding hydrazide and its treatment can be obtained with nitrous acid, azide method), anhydrides with carbonic acid derivatives, as with corresponding esters, eg. B. Kohlensiederiederalkylhalbestern (which is obtained, for example, by treating the corresponding acid with halogen, such as lower alkyl chloroformate or with an i-Niederalkoxycarbonyl ^ -niederalkoxy-i ^ -dihydro-quinoliniZ, B. 1-Niederalkoxycarbonyl ^ -ethoxy-i method of mixed O-alkylcarbonic anhydrides), or anhydrides with dihalogenated, in particular dichlorinated phosphoric acid (which can be obtained, for example, by treating the corresponding acid with phosphorus oxychloride, phosphorus oxychloride method), or anhydrides with organic acids, such as mixed anhydrides with organic carboxylic acids (which can be obtained, for example, by treating the corresponding acid with an optionally substituted lower alkane or phenylalkanecarboxylic acid halide, eg phenylacetic acid, pivalic acid or trifluoroacetic acid chloride, mixed carboxylic acid anhydride method) or with organic sulfonic acids (which are ζ B. by treating a salt it, such as an alkali metal salt, of the corresponding acid, with a suitable organic sulfonic acid halide, such as lower alkane or aryl, ζ. For example, methane or p-toluenesulfonyl chloride, can be obtained; Mixed sulfonic acid anhydride method), as well as symmetrical anhydrides (obtained, for example, by condensation of the corresponding acid in the presence of a carbodiimide or of 1-diethylaminopropyne

can receive; Method of symmetrical anhydrides). .. ...

Suitable cyclic amides are, in particular, amides having five-membered diazacycles of aromatic character, such as amides with imidazoles, e.g. Imidazole (which can be obtained, for example, by treating the corresponding acid with Ν, Ν'-carbonyldiimidazole, imidazolide method), or pyrazoles, e.g. B. 3,5-dimethyl-pyrazole (which can be obtained, for example, via the acid hydrazide by treatment with acetylacetone, pyrazolide method).

As mentioned, derivatives of acids used as acylating agents can also be formed in situ. So you can z. B. Ν, Ν'-disubstituted amidinoester form in situ by reacting the mixture of the starting material of the formula II and the acid used as the acylating agent in the presence of a suitable Ν, Ν-disubstituted carbodiimide, z. As N-N'-dicyclohexylcarbodiimide, brings to reaction. Furthermore, one can form amino or amido esters of acids used as acylating in the presence of the starting material of the formula II to be acylated by reacting the mixture of the corresponding acid and amino starting materials in the presence of a Ν, Ν'-disubstituted carbodiimide, z. N, N'-dicyclohexyl-carbodiimide, and N-hydroxy-amine or N-hydroxy-amide, e.g. B. N-hydroxysuccinimide, optionally in the presence of a suitable base, for. For example, 4-dimethylamino-pyridine.

The reaction may be carried out in a manner known per se, the reaction conditions depending primarily on whether and how the carboxyl group of the acylating agent is activated, usually in the presence of a suitable solvent or diluent or a mixture of such and, if necessary, in the presence of a condensing agent, the z. For example, when the carboxyl group participating in the reaction is present as an anhydride, it may also be an acid-binding agent, with cooling or heating, e.g. B. in a temperature range of about -30 ° C to about + 150 ° C, in particular from about O ⁰ C to + 100 ° C, preferably from room temperature (about +20 ⁰ C) to + 7O ⁰ C, in a closed Reaction vessel and / or in the atmosphere of an inert gas, for example nitrogen. Usual Kondensationsmittei are z. Carbodiimides, for example Ν, Ν'-diethyl, N, N'-dipropyl, Ν, Ν'-dicyclohexyl or N-ethyl-N '- (3-dimethylaminopropyl) carbodiimide, suitable carbonyl compounds, for example carbonyldiimidazole, or 1,2-oxazolium compounds, e.g. 2-ethyl-5-phenyl-1,2-oxazolium-3'-sulfonate and 2-tert-butyl-5-methyl-isoxazolium perchlorate, or a suitable acylamino compound, e.g. B. 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline. Common acid-binding condylents are e.g. B. alkali metal carbonates or bicarbonates, z. Sodium or potassium carbonate or bicarbonate (usually together with a sulfate), or organic bases such as sterically hindered tri-lower alkylamines, e.g. B. Ν, Ν-diisopropyl-N-ethyl-amine.

The cleavage of the protecting groups, ζ. As the carboxyl, amino, hydroxy or mercapto protecting groups, which are not part of the desired end product of formula I, is carried out in a conventional manner, for. B. by Solvoiyse, in particular hydrolysis, alcoholysis or acidolysis, or by reduction, in particular hydrogenolysis or chemical reduction, optionally in stages or simultaneously, whereby enzymatic methods can be used. For example, lower alkoxycarbonyl or lower alkoxycarbonyl or optionally substituted diphenylmethoxycarbonyl substituted in the 2-position by an organic silyl group or in the 1-position by lower alkoxy or lower alkylthio may be prepared by treatment with a suitable acid such as formic acid or trifluoroacetic acid optionally with the addition of a nucleophilic compound such as Convert phenol or anisole into free carboxyl. Optionally substituted benzyloxycarbonyl may e.g. B. by hydrogenolysis, ie by treatment with hydrogen in the presence of a metallic hydrogenation catalyst, such as a palladium catalyst, are released. Furthermore, suitably substituted benzyloxycarbonyl, such as 4-nitrobenzyloxycarbonyl, also by means of chemical reduction, for. B. by treatment with an alkali metal, ζ. As sodium dithionite, or with a reducing metal, for. As zinc, or metal salt, such as a chromium-ll-salt, z. Chromium-II-chloride, usually in the presence of a hydrogen donating agent which is capable of producing nascent hydrogen together with the metal, such as an acid _r primarily a suitable carboxylic acid such as an optional, e.g. B. substituted by hydroxy, lower alkanecarboxylic, z. As acetic acid, formic acid, glycolic acid, diphenyl glycolic acid, lactic acid, mandelic acid, 4-chloro-mandelic acid or tartaric acid, or an alcohol or thiol, preferably adding water, convert into free carboxyl. By treating with a reducing metal or metal salt as described above, one can also convert 2-halo-lower alkoxycarbonyl (optionally after conversion of a 2-bromo-lower alkoxycarbonyl group to a corresponding 2-iodo-lower alkoxycarbonyl group) or aroylmethoxycarbonyl into free carboxyl, with aroylmethoxycarbonyl also can be cleaved by treatment with a nucleophilic, preferably salt-forming, reagent, such as sodium thiophenolate or sodium iodide. Substituted 2-silylethoxycarbonyl may also be prepared by treatment with a hydrofluoric acid hydrofluoric acid salt such as an alkali metal fluoride, e.g. Sodium or potassium fluoride, in the presence of a macrocyclic polyether ("crown ether"), or with a fluoride of an organic quaternary base such as tetra-lower alkylammonium fluoride or tri-lower alkyl-aryl-ammonium fluoride ^, eg tetraethylammonium fluoride or tetrabutylammonium fluoride, in the presence of an aprotic polar solvent such as Dimethylsulfoxide or N, N-dimethylacetamide are converted into free carboxyl.

Esterified carboxyl can also be cleaved enzymatically, e.g. B. esterified lysine, ζ. Β. Lysine methyl ester, by trypsin. A protected amino group is set in a manner known per se and depending on the nature of the protecting groups in various ways, preferably by means of Solvoiyse or reduction, free. 2-halo-lower alkoxycarbonylamino (optionally after conversion of a 2-bromo-lower alkoxycarbonylamino group to a 2-iodo-lower alkoxycarbonylamino group), aroylmethoxycarbonyiamino or 4-nitrobenzyloxycarbonylamino may be e.g. By cleavage with a suitable chemical reducing agent such as zinc in the presence of a suitable carboxylic acid such as aqueous acetic acid. Aroylmethoxycarbonyiamino may also be prepared by treatment with a nucleophilic, preferably salt-forming, reagent, such as sodium thiophenolate, and 4-nitrobenzyloxycarbonylamino also by treatment with an alkali metal, ζ. Β. Sodium dithionite, are split. Optionally substituted diphenylmethoxycarbonylamino, tertiary-lower alkoxycarbonylamino or 2-trisubstituted silylethoxycarbonylamino may be prepared by treatment with a suitable acid, e.g. B. formic or trifluoroacetic acid, optionally substituted Benzyloxycarbonylamino z. B. by hydrogenolysis, ie by treatment with hydrogen in the presence of a suitable hydrogenation catalyst, such as a palladium catalyst, optionally substituted triarylmethylamino or formylamino, for example by treatment with an acid such as mineral acid, ζ. Hydrochloric acid, or an organic acid, e.g. For example, formic, acetic or trifluoroacetic acid, optionally in the presence of water, are cleaved, and a protected with an organic silyl group amino group can be released for example by hydrolysis or alcoholysis. A by 2-haloacetyl, z. For example, 2-chloroacetyl, protected amino group may be released by treatment with thiourea in the presence of a base, or with a thiolate salt such as an alkali metal thiolate, of the thiourea and subsequent solvation such as alcoholysis or hydrolysis of the resulting condensation product. A 2-substituted silylethoxycarbonyl-protected amino group may also be converted to the free amino group by treatment with a fluoride anion-providing salt of hydrofluoric acid as described above in connection with the release of a suitably protected carboxyl group.

Amino protected in the form of an azido group is converted for example by reduction into free amino, for example by catalytic hydrogenation with hydrogen in the presence of a hydrogenation catalyst, such as platinum oxide, palladium or Raney nickel, or by treatment with zinc in the presence of a. Acid, such as acetic acid. The catalytic hydrogenation is preferably carried out in an inert solvent such as a halogenated hydrocarbon, e.g. As methylene chloride, or even in water or a mixture of water and an organic solvent such as an alcohol or dioxane, at about 20 ⁰ C to 25 ° C, or under cooling or heating performed.

A hydroxy or mercapto group protected by a suitable acyl group, an organic silyl group or by optionally substituted 1-phenyl-lower alkyl is liberated analogously to a correspondingly protected amino group. By optionally substituted 1-phenyl-lower alkyl, for. B. Benzyl, protected hydroxy is preferably by catalytic hydrogenation, for. B. released in the presence of a palladium-on-carbon catalyst. A protected by 2,2-dichloroacetyl hydroxy or mercapto group is z. Example, by basic hydrolysis, a by tert-lower alkyl or by a 2-oxa or 2-thia-aliphatic or -cycloaliphatic hydrocarbon rest etherified hydroxy or mercapto group by acidolysis, for. B. by treatment with a mineral acid or a strong carboxylic acid, ζ. Β. Trifluoroacetic acid, released. Two hydroxy groups which together through a preferably substituted methylene group, such as by lower alkylidene, z. B. isopropylidene, cycloalkylidene, z. As cyclohexylidene, or benzylidene, can be released by acidic · Solvoiyse, especially in the presence of a mineral acid or a strong organic acid. With an organic silyl, z. For example, trimethylsilyl, etherified hydroxy may also be reacted with a fluoride anion supplying salt of hydrofluoric acid, e.g. As tetrabutylammonium fluoride, are released.

Preferably, in the presence of multiple protected functional groups, the protecting groups are selected to simultaneously cleave more than one such group, for example acidolytically, such as by treatment with trifluoroacetic acid or formic acid, or reductive, such as by treatment with zinc and acetic acid, or with hydrogen and a hydrogenation catalyst such as a palladium-carbon catalyst. If the desired end-products contain protective groups,

z. B. when R ¹² aryimethoxy, such as benzyloxy, those protecting groups which are to be cleaved after the reaction is chosen so that they can be cleaved regioselectively again, z. For example, hydroxyl etherified with an organic silyl radical can be released in the radical R ⁸ or R ¹¹ with fluoride, an arylmethoxy protective group being retained in the radical R ⁹ or R ¹² .

The starting materials of formula II, wherein R ^{2a is} hydrogen, z. B. from corresponding compounds, wherein R ^{2a is} an amino protecting group, for example benzyloxycarbonyl.

Method b :.

A reactive derivative of a compound of formula III is z. For example, a metal oxy compound as z. By reaction of a compound of formula III with a suitable base such as an alkali metal hydride or amide.

Reactive esterified hydroxy X is z. B. with a strong inorganic or organic acid esterified hydroxy, such as with a mineral acid, eg. As hydrohalic acid, such as hydrochloric, hydrobromic or hydroiodic acid, further sulfuric acid, or halogenated sulfuric acid, eg. B. Fl.uorschwefelsäure, or with a strong organic sulfonic acid, such as an optionally, for. Example by halogen, such as fluorine, substituted lower alkanesulfonic acid or an aromatic sulfonic acid, eg. Example, an optionally substituted by lower alkyl, such as methyl, halogen, such as bromine, and / or nitro substituted benzenesulfonic acid, eg. B-. a methanesulfonic, trifluoromethanesulfonic or p-toluenesulfonic acid, esterified hydroxy, preferably a chloride, bromide or iodide.

Free functional groups in a compound of the formula IV, which are advantageously protected by easily removable protective groups, are in particular hydroxyl, mercapto or carboxy groups.

The reaction is carried out, if necessary C in the presence of an acid-binding agent, preferably in an inert organic solvent at a temperature between -30 ° C and + 150 ° C, in particular 0 ⁰ C to +100 ⁰ C, for example + 20 ° C and +70 ^0th

The removal of protective groups which are not part of the desired end product of the formula I is carried out as in the process

a) described.

Method c:

A reactive carboxylic acid derivative of a compound of formula V is primarily a reactive ester, a reactive anhydride or a reactive cyclic amide in which the carboxyl group is activated in a manner analogous to the reactive acylating agents described in method a) and wherein the activation also done in situ

Functional groups optionally present in compounds of the formulas V or VI are preferably protected by easily removable protecting groups. Amino and guanidino in the radical R ¹¹ , carboxy as the radical R ¹⁰ and hydroxy as the radical R ⁹ or R ¹² , but also hydroxy or mercapto fm radical R ⁸ or hydroxy in the radical R ¹¹ .

In a reactive derivative of a compound of formula VI, the amino group z. B. by reaction with a phosphite, eg. B. diethylchlorophosphite, 1,1-phenylene-chlorophosphite, ethyl-dichlorophosphite, ethylene-chloro-phosphite or tetraethylpyrophosphite, or by bonding to halocarbonyl, z. As chlorocarbonyl, or activated in the form of an isocyanate group. Preferably, the reaction is carried out by reacting a reactive carboxylic acid derivative of a compound of formula V with a compound of formula VI, wherein the participating in the reaction Ami no- or Hy droxygruppe is present in free form.

The reaction and the subsequent removal of the protective groups, which are not part of the desired end product, are carried out analogously as described in process a).

The esterification of a compound of the formula V in which q is approximately t for 1 can also be carried out with the aid of the esterification agents described in process d).

Method d:

In a compound of formula VII optionally present free functional groups which are protected by readily cleavable protecting groups, in particular carboxyl groups which are not to be esterified, and further hydroxy, mercapto, guanidino and amino groups.

Suitable protecting groups and their cleavage are described in process a).

In particular, a reactive carboxylic acid derivative of a compound of formula VII is a reactive ester, a reactive anhydride or a reactive cyclic amide in which the carboxyl group is activated in a manner analogous to the reactive acylating agents described in method a) and wherein the activation is also in situ can. Preferably, the reaction is carried out by reacting a reactive carboxylic acid derivative of a compound of

Formula VII for the esterification of carboxy R ¹³ with a compound HR ⁹ ', wherein R ⁹ ' has the abovementioned meanings of R ⁹ with the exception of hydroxy and amino, or, for the esterification of carboxy R ¹⁰ *, with a lower alkanol or aryl-lower alkanol.

Alternatively, a compound of the formula VII having a free carboxyl group can be esterified by reaction with a reactive derivative of the alcohol desired as the esterification component.

Suitable agents for esterification are, for example, corresponding diazo compounds, such as optionally substituted diazonium haloalkanes, eg. As diazomethane, diazoethane, diazo-n-butane or diphenyldiazomethane. These reagents are reacted in the presence of a suitable inert solvent such as an aliphatic, cycloaliphatic or aromatic hydrocarbon such as hexane, cyclohexane, benzene or toluene, a halogenated aliphatic hydrocarbon, e.g. B.

Methylene chloride, or an ether such as a di-lower alkyl ether, e.g. As diethyl ether, or a cyclic ether, ζ. Β.

Tetrahydrofuran or dioxane, or a solvent mixture, and, depending on the diazo reagent, with cooling, at room temperature or with gentle heating, further, if necessary, in a closed vessel and / or under one

Inertgas-, eg nitrogen atmosphere, brought to application. f>

Further suitable means for improving are esters of corresponding alcohols, primarily those with strong inorganic or organic acids, such as mineral acids, eg. For example, hydrohalic acids, such as hydrochloric, hydrobromic, or trifluoric acid, for example, orrn-a-rxA / ofolcal I TO nHor W alnnonerhuiofulcal irO-J R CIllfM-C ^ hvA / Qfoleotiro n ^ orp ^ ri / an Arn ^ nm ^ A «

Sulfonic acids, as appropriate, e.g. Example, by halogen, such as fluorine, substituted lower alkanesulfonic acids, or aromatic sulfonic acids, such as. B. optionally substituted by lower alkyl, such as methyl, halogen, such as bromine, and / or nitro substituted benzenesulfonic acids, eg. As methanesulfonic, trifluoromethanesulfonic or p-toluenesulfonic acid. Such esters include lower alkyl halides, di-lower alkyl sulfates such as dimethyl sulfate, and fluorosulfonic acid esters such as lower alkyl esters, e.g. As fluorosulfonate, or optionally Halqgen-substituted methanesulfonic acid lower alkyl, z. B. Trifluoromethanesulfonsäuremethylester. They are usually in the presence of an inert solvent, such as an optionally halogenated, such as chlorinated, aliphatic, cycloaliphatic or aromatic hydrocarbon, for. Methylene chloride, an ether such as dioxane or tetrahydrofuran, or a pure mixture thereof. In this case, it is preferable to use suitable condensing agents, such as alkali metal carbonates or bicarbonates, z. For example, sodium or potassium carbonate or bicarbonate (usually together with a sulfate), or organic bases, such as usually hindered Triniederalkylamine, z. N, N-diisopropyl.-N-ethyl-amine (preferably together with halosulfonic acid lower alkyl esters or optionally halogen-substituted methanesulfonic acid lower alkyl esters), with cooling, at room temperature or with heating, e.g. B. at temperatures of about -20 ° C to about 50 ⁰ C, and, if necessary, in a closed vessel and / or in an inert gas, such. As nitrogen atmosphere is worked. Further agents for esterification are corresponding trisubstituted oxonium salts (so-called seaweed salts), or disubstituted carbenium or halonium salts in which the substituents are the etherifying radicals, for example tri-lower alkyloxonium salts, and di-lower alkoxycarbenium or di-lower alkyl halonium salts, in particular the corresponding salts with complex, fluorine-containing acids, such as corresponding tetrafluoroborates, hexafluorophosphates, hexafluoroantimonates, or hexachloroantimonates. Such reagents are for. Trimethyloxonium or triethyloxonium hexafluoroantimonate, hexachloroantimonate, hexafluorophosphate or tetrafluoroborate, dimethoxycarbenium hexafluorophosphate or dimethylbromonium hexafluoroantimonate. It is preferable to use these agents in an inert solvent such as an ether or a halogenated hydrocarbon, e.g. Example, diethyl ether, tetrahydrofuran or methylene chloride, or in a mixture thereof, if necessary, in the presence of a base such as an organic base, for. B. one, preferably sterically hindered, Triniederalkylamins, z. B. Ν, Ν-diisopropyl-N-ethyl-amine, and with cooling, at room temperature or with gentle heating, for. At about -20 ° C to about 50 ° G, if necessary, in a closed vessel and / or in an inert gas, e.g. B. nitrogen atmosphere.

A preferred embodiment of process d) is the reaction of a cesium salt of a compound of formula VI with the alcohol desired as the esterification component wherein the hydroxyl group is in a reactive esterified form

 Method e:

A compound of the formula I in which at least one of the radicals R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ^{12 is present} in a protected form which does not correspond to the definition of the desired end product is in particular a compound of the formula I in which a Hydroxy or mercapto group in the radical R ⁸ , an amino or hydroxy group in the radical R ¹¹ , free hydroxy R ⁹ or R ¹² , and / or carboxy R ^{10 is} protected by a readily cleavable protecting group, which is not included in the desired end product. Easily removable protective groups are in particular those mentioned in process a). The cleavage of the protective groups is carried out analogously, as described in process a)

 Method f: '-.

In a compound of formula VIII optionally present free functional groups which are protected by readily cleavable protecting groups, in particular carboxyl groups which are not to be amidated, and further hydroxy,. Mercapto, guanidino and amino groups.

Suitable protecting groups and their cleavage are described in process a). -. '

In particular, a reactive carboxylic acid derivative of a compound of formula VIII is a reactive ester, a reactive anhydride or a reactive cyclic amide in which the carboxyl group is activated in a manner analogous to the reactive acylating agents described in method a) and wherein the activation is also in situ can. Preferably, the reaction is carried out by reacting a reactive carboxylic acid derivative of a compound of formula VIII with ammonia. Alternatively, it is also possible to react a compound of formula VIII with a free carboxyl group with a reactive ammonia derivative, wherein the activation of the amino group z. B. analogously as described in method c).

The reaction and the subsequent cleavage of the protective group, which are not part of the desired end product, are carried out analogously as described in process a).

Additional operations: Salts of compounds of the formula I with salt-forming groups can be prepared in a manner known per se. Thus, salts of compounds of formula I with acidic groups by reaction with a suitable base, for. By treating with suitable metal compounds, such as alkali metal salts of suitable organic carboxylic acids, e.g. As the sodium salt of a-ethyl-carboxylic acid, or with suitable inorganic alkali or alkaline earth metal salts, especially those derived from a weak and preferably volatile acid, z. As sodium bicarbonate, or form with ammonia or a suitable organic amine, preferably using stoichiometric amounts or only a small excess of the salt-forming agent. Acid addition salts of compounds of the formula I are obtained in a customary manner, for. By treatment with an acid or a suitable anion exchange reagent. Internal salts of compounds of the formula I, which z. B. contain a free carboxyl group and a free amino group, z. By neutralizing salts, such as acid addition salts, to the isoelectric point, e.g. with weak bases, or by treatment with liquid ion exchangers. Salts can usually be converted to the free compounds, metal and ammonium salts e.g. by treatment with suitable acids, and acid addition salts e.g. By treating with a suitable basic agent. Mixtures of isomers may be prepared in a manner known per se, e.g. fractionated crystallization, chromatography etc. are separated into the individual isomers.

The methods described above, including the methods for deprotection and the additional process measures are, unless otherwise stated, in a conventional manner, for. B. in the presence or absence of preferably inert solvents and diluents, if necessary, in the presence of condensing agents or catalysts, at reduced or elevated temperature, for example in a temperature range from about -20 ⁰ C to about + 15O ⁰ C, in particular of about ⁰ ° C to about + 7O ⁰ C, preferably from about + 1O ⁰ C to about +40 ⁰ C, principally at room temperature,

Taking into account all substituents in the molecule, if necessary, z. B. in the presence of easily hydrolyzable radicals, particularly gentle reaction conditions, such as short reaction times, use of mild acidic or basic agents in low concentration, stoichiometric proportions, choice of suitable catalysts, solvents, temperature and / or pressure conditions apply.

The invention also relates to those embodiments of the process starting from a compound obtainable as intermediate at any stage of the process and carrying out the missing process steps or breaking off the process at any stage or forming a starting material under the reaction conditions or in the form of a reactive derivative or Salt used. In this case, it is preferable to start from such starting materials, which according to the method lead to the compounds described above as being particularly valuable.

Novel starting materials and / or intermediates and processes for their preparation are also the subject of the present invention. Preferably, such starting materials are used and the reaction conditions are chosen so as to arrive at the compounds listed in this application as being particularly preferred. The invention also relates to pharmaceutical preparations which contain an effective amount, in particular an effective amount for the prophylaxis or therapy of viral infections or for the treatment of tumorous diseases, the active substance together with pharmaceutically acceptable excipients, the zurtropischen, z. B. intranasal, enteral, z. As oral or rectal, or parenteral administration, and may be inorganic or organic, solid or liquid. Thus, one uses tablets or gelatin capsules containing the active ingredient together with diluents, for. Lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycerol, and / or lubricants, e.g. For example, silica, talc, stearic acid or salts thereof, such as magnesium or Caleiumstearat, and / or polyethylene glycol. Tablets may also bind, e.g. Magnesium aluminum silicate, starches such as corn, wheat or rice starch, gelatin, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone, and, if desired, disintegrants, e.g. For example, starches, agar, alginic acid or a salt thereof, such as sodium alginate, and / or effervescent mixtures, or adsorbents, dyes, flavorings and sweeteners. Further, the pharmacologically active compounds of the present invention may be used in the form of parenterally administrable preparations or infusion solutions. Such solutions are preferably isotonic aqueous solutions or suspensions, these z. As in lyophilized preparations containing the active substance alone or together with a carrier material, for. As mannitol, can be prepared before use. The pharmaceutical preparations may be sterilized and / or adjuvants, eg. As preservatives, stabilizers, wetting agents and / or emulsifiers, solubilizers, salts for regulating the osmotic pressure and / or buffers. The present pharmaceutical preparations which, if desired, may contain other pharmacologically active substances, such as antibiotics, are prepared in a manner known per se, for. Example by means of conventional mixing, granulation, coating, solution or lyophilization process, prepared and contain from about 0.001% to 20%, in particular from about 0.01% to about 10%, primarily between 0.1% and 5%, of the active substance (s), where an active ingredient concentration below 1% is suitable in particular for preparations to be applied topically.

As topically applied dosage forms, the following are preferred: creams, ointments or pastes with an active ingredient content of 0.001% to 1%, in particular from 0.01% to 0.1%, z. B. 0.05%, z. As ointments for intranasal administration or lipsticks, or aqueous solutions with an active ingredient content of 0.001% to 1%, in particular 0.05% to 0.5%, z. B. 0.1%, preferably isotonic, sterile and physiologically acceptable solutions, eg. As eye drops, preferably in micro-containers for single use, or sprays for use in the oropharynx. Particularly suitable are the pharmaceutical preparations described in the examples.

Creams are oil-in-water emulsions that contain more than 50% water. As an oily basis are used primarily fatty alcohols, eg. For example, lauryl, cetyl or Stearylalkohole, fatty acids, eg. As palmitic or stearic, liquid to solid waxes, z. Isopropyl myristate, wool wax or beeswax, and / or hydrocarbons, e.g. Vaseline (petrolatum) or paraffin oil. Suitable emulsifiers are surface-active substances with predominantly hydrophilic properties, such as corresponding nonionic emulsifiers, e.g. Fatty acid esters of polyhydric alcohols or ethylene oxide adducts thereof, such as polyglycerol fatty acid esters or polyoxyethylene sorbitan fatty acid esters (Tweens), also polyoxyethylene fatty alcohol ethers or fatty acid esters, or corresponding ionic emulsifiers, such as alkali metal salts of fatty alcohol sulfates, e.g. For example, sodium lauryl sulfate, sodium cetyl sulfate or sodium stearyl sulfate, which is usually in the presence of fatty alcohols, eg. As cetyl alcohol or stearyl alcohol used. Additives to the water phase are u.a. Agents that reduce the drying of the creams, z. As polyhydric alcohol, such as glycerol, sorbitol, propylene glycol and / or polyethylene glycols, preservatives, fragrances, etc.

Ointments are water-in-oil emulsions containing up to 70%, but preferably from about 20% to about 50% water or aqueous phase. As the fatty phase come primarily hydrocarbons, eg. As petroleum jelly, paraffin oil and / or hard paraffins in question, which are preferably suitable for improving the water binding capacity hydroxy compounds, such as fatty alcohols or esters thereof, for. As cetyl alcohol or wool wax alcohols, or wool wax included. Emulsifiers are corresponding lipophilic substances, such as sorbitan fatty acid esters (Spans), z. B. sorbitan oleate and / or sorbitan isostearate. Additions of water phase are e.g. Humectants, such as polyalcohols, e.g. Glycerol, propylene glycol, sorbitol and / or polyethylene glycol, such as preservatives, fragrances, etc.

Fatty ointments are anhydrous and contain as a basis in particular hydrocarbons, eg. As paraffin, vaseline and / or liquid paraffins, also natural or partially synthetic fats, eg. Coconut fatty acid triglyceride, or preferably hardened oils, e.g. B. hydrogenated peanut or castor oil, also fatty acid partial esters of glycerol, ζ. B. glycerol mono- and distearate, and z. As mentioned in connection with the ointments, the hydrogen absorbing capacity-increasing fatty alcohols, emulsifiers and / or additives.

Pastes are creams and ointments with secretion-absorbing powder constituents, such as metal oxides, eg. As titanium oxide or zinc oxide, further talc and / or aluminum silicates, which have the task of binding existing moisture or secretions. Foams are administered from pressure vessels and are aerosolized liquid oil-in-water emulsions wherein halogenated hydrocarbons such as chlorofluoro-lower alkanes, e.g. As dichlorodifluoromethane and dichlorotetrafluoroethane, can be used as a blowing agent. As the oil phase u.a. Hydrocarbons, eg. As paraffin oil, fatty alcohols, eg. For example, cetyl alcohol, fatty acid esters, e.g. As isopropyl myristate, and / or other waxes. As emulsifiers u u. a. mixtures

those having predominantly hydrophilic properties, such as polyoxyethylene sorbitan fatty acid esters (Tweens), and those having predominantly lipophilic properties, such as sorbitan fatty acid esters (Spans). There are also the usual additives, such as preservatives, etc.

Tinctures and solutions usually have an aqueous-ethanolic basis, the u. a. Polyalcohols, for. As glycerol, glycols, and / or polyethylene glycol, as humectants to reduce evaporation, and refatting substances such as fatty acid esters with low polyethylene glycols, d. H. soluble in aqueous mixture, lipophilic substances as a substitute for the skin with the ethanol extracted fatty substances, and, if necessary, other auxiliaries and additives are added. The preparation of the topically usable pharmaceutical preparations is carried out in a conventional manner, for. By dissolving or suspending the active ingredient in the base or in a part thereof, if necessary. When processing the active ingredient as a solution this is usually dissolved before emulsification in one of the two phases; when processed as a suspension, it is mixed after emulsification with part of the base and then added to the remainder of the formulation.

embodiment

The following examples illustrate the invention without limiting it in any way. The Rf values are determined on silica gel thin-layer plates (Merck, Darmstadt, Germany). The ratio of the running agent in the solvent mixtures used is in volume fractions (V / V), temperatures are given in degrees Celsius. The concentration, c, of the substance in the solvent (mixture) is given in% (weight / volume) in the case of optical rotation.

Abbreviations: absolute Section. = tert. butyloxycarbonyl Boc = high vacuum HV vacuo vacuo. = methyl me methanol MeOH = Polytetrafluoroethylene, Teflon® PTFE room temperature RT melting point M = decomposition Dec. =

Example 1:

11.4 g (16.77 mmol) of N-propionyl-demethylmuramyl-L-alanyl-D-isoglutamine-benzhydryl ester (α, / 3 mixture) containing 1.17 mol of water are dissolved in 120 ml of absolute pyridine. The solution thus obtained is treated with 7.6 ml (80.3 mmol) of acetic anhydride and stirred for 92 hours at room temperature. Thereafter, the yellowish solution is evaporated in a high vacuum at 40 °. The crude product thus obtained is triturated with 100 ml of diethyl ether and the resulting suspension is stirred for 2 hours at room temperature. Then, the crystals formed are filtered off with suction and washed with diethyl ether.

After two recrystallizations from ethyl acetate-isopropanol-diethyl ether (100: 5: 40), one obtains an I.Fraction of chromatographically pure 1 ^, ö-tri-O-acetyl-N-propioriyl-desmethylmuramyl-L-alanyl-D-isoglutamine-benzhydryl ester ( a, ^ mixture) in the form of colorless crystals of mp. 165-166 ⁰ C.

The mother liquors of the recrystallizations are combined and evaporated in vacuo. The residue thus obtained is purified by column chromatography on 600 g of silica gel (type 60, very pure, Merck, 0.063-0.2 mm) in the system chloroform-ethanol (9: 1) (10 ml fractions).

Fractions 217-310 are combined and evaporated in vacuo. This gives a second fraction of pure lAe-tri-O-acetyl-N-propionyl-desmethylmuramyl-L-alanyl-D-isoglutamine-benzhydryl ester (α, ^ mixture), which together with the 1st fraction in 200 ml of absolute Methanol is dissolved. The solution thus obtained, lightly cloudy is then filtered through a Millipore filter (Fluoropore PTFE, 0.2 / xm) and evaporated the clear filtrate in vacuo at 4O ⁰ C. The residue is then dissolved in 50 ml of absolute ethyl acetate, which has been previously filtered through a Millipore filter (Fluoropore, PTFE, 0.2μηι), and by addition of 20ml of absolute diethyl ether, which has also been filtered through a Millipore filter, crystallized and filtered with, rinsed with absolute diethyl ether. This gives 1,4,6-tri-O-acetyl-N-propionyl-desmethylmu ramyl-L-alanyl-D-isoglutamine-benzhydryl ester (<*, / 3 mixture) in the form of colorless crystals of mp. 165-166 ° C, which still contain 0.27MoI of water.

C ₃₈ H ₄₈ N ₄ Oi ₄ -0,27H ₂ O (789.68) '

Ber. C57,80 H6,22 N7,10 028,91 H ₂ O0,62

Found. C57,91 H6,20 N7,11 028.77 H ₂ O0,62

[a] l ° = +32.7 ± 2.1 ° (c = 0.486, methanol) R, = 0.28 (chloroform: methanol = 9: 1), R _f = 0.70 (chloroform: methanol = 4 :1).

Another product is obtained from fractions 105-140 of the above-described column chromatography.

The yellow residue obtained after evaporation in vacuo (0.55 g, foam) is dissolved in cyclohexane-diethyl ether-methylene chloride (10: 30: 5) hot and the resulting solution cooled to room temperature. This separates out a yellow oil, which is stirred after decanting the solvent for 2 hours with 50 ml of absolute diethyl ether. The resulting crystals are filtered off with suction and washed with absolute diethyl ether.

The crystals are then dissolved in 100 ml of tert-butanol-water (1: 1). The solution thus obtained is filtered through a Millipore filter (Fluoropore, PTFE, 0.2μηι) and lyophilized.

There is obtained laAe-tri-O-acetyl ^ -deoxy ^ -propionylamino-D-mannos-S-O-yl-acetyl-L-alanyl-D-isoglutamine-benzhydryl ester as a colorless powder containing 1.11 moles of water.

C ₃₈ H ₄₈ NiO ₁₄ 1.11 H ₂ O (804.81)

Ber. C 56.71 H 6.31 N 6.96 030.03 H ₂ O 2.48

C, 56.94, H, 6.36, N, 7.22, 030, 15, H, _2, O 2.48

Ho ⁰ = + 5.5 + 2.7 ° (c = 0.365, methanol), R _f = 0.49 (chloroform: methanol = 9: 1), R _f = 0.79 (chloroform: methanol = 4: 1 ).

The starting material is obtained as follows:

Step 1.1: 16.0 g (31.63 mmol) of N-propionyl-demethylmuramyl-L-alanyl-D-isoglutamine containing 0.74 mol of water are dissolved in 300 ml of methanol-dimethoxyethane (1: 1) and then washed with 9.2 g (47.4 mmol) of diphenyldiazomethane are added. The whole is stirred for 20 hours at room temperature. After 20, 44 and 68 hours, 4.6 g (23.7 mmol) of diphenyldiazomethane are added in each case. After completion of the reaction (90 hours), the red solution is evaporated to dryness in vacuo at 40 ⁰ C, added to the resulting red resin with 300ml of absolute diethyl ether and V2 hour at room temperature

touched.

This gives colorless crystals, which are suction filtered and washed with diethyl ether.

Recrystallization from 400 ml of acetone gives N-propionyl-desmethylmuramyl-L-alanine-D-isoglutamine-benzhydryl ester in the form of colorless crystals of mp. 188-190 ° C (dec.), Which contain 1.17 mol of water.

C ₃₂ H ₄₂ N ₄ O ₁₁ -1.17 H ₂ O (679.78). ·.

Ber. · C56,55 H6,60 N8,24 028.63 _H2 O3,09

Gef. C 56.67 H 6.67 N 8.43 028.65 H ₂ O 3.09

[a] § ° = + 7.5 ± 0.1 ° (c = 0.898, methanol), R, = 0.62 (chloroform: methanol: water = 70: 30: 5), R, = 0.62 ( Chloroform: methanol = 7: 3).

Example 2: 2.33 g (3.8 mmol) of N-propionyl-demethylmuramyl-L-alanyl-D-isoglutamine-benzyl ester, which still contains 1.59 mol of water, are dissolved in 24 ml of absolute pyridine, then 1.4 ml (14.8 mmol) acetic anhydride, and the resulting solution is stirred at room temperature for 16 hours. Subsequently, the colorless solution is evaporated in a high vacuum at 30 ⁰ C. A slightly yellow foam is obtained, which is purified by column chromatography on 400 g of silica gel (type 60, very pure, Merck, 0.063-0.2 mm) in the system chloroform-ethanol (9: 1) (10 ml fractions) / 3-anomers, the α, / 3 anomeric mixture and the α-anomer of 1,4,6-tri-O-acetyl-N-propionyl-demethylmuramyl-L-alanyl-D-isoglutamine-benzyl ester.

The fractions 112-126 (/ 3-anomeres), 127-190 (α, / 3 mixture) and 191-260 (α-anomeres) are each combined and evaporated under high vacuum at 30 ° C. ·

The residue of fractions 112-126 is crystallized from 60 ml of chloroform: diethyl ether (1: 5). This gives 1 / 3,4,6-tri-O-acetyl-N-propionyl-desmethylmuramyl-L-alanyl-D-isoglutamine-benzyl ester in the form of colorless crystals, mp. 189-190 ⁰ C. The crystals are'anschließend in Dissolved 100 ml of double-distilled water-tert-butanol (1: 1). The resulting solution is filtered through a Millipore filter (Fluoropore, PTFE, 0.2M) and lyophilized under high vacuum. This gives 1 / 3,4,6-tri-O-acetyl-N-propionyl-desmethylmuramyl-L-alanyl-D-isoglutamine-benzyl ester as a colorless powder containing 1.21 mol of water. C ₃₂ H ₄₄ N ₄ O ₁₄ '1.21 H ₂ O (730.52)

Ber. C, 52.62, H, 6.43, N, 7.67, 033.30, H ₂ O, 2.98

Found C 52.97 H 6.27 N 7.86 033.24 H ₂ O 2.98

[a] g ° = + 14.3 ± 4.2 ° (c = 0.237, dimethylformamide), R, = 0.25 (chlorofromethanol = 9: 1), R _f = 0.67 (chlorofornrethanol = 4: 1) , R _f = 0.45 (chloroform: methanol = 9: 1).

The residue of fractions 127-190 crystallized from 120 ml of chloroform-diethyl ether (1: 5). This gives 1,4,6-tri-O-acetyl-N-propionyl-desmethylmuramyl-L-alanyl-D-isoglutamine-benzyl ester (α, / 3 mixture, according to ¹ H-NMR a: ß ~ 6: 1 ) as colorless' crystals of mp. 156-157 ⁰ C.

The crystals are then dissolved in 150 ml of double-distilled water-tert-butanol (1: 1), the resulting solution is filtered through a Millipore filter (Fluoropore, PTFE, 0.2 / 1) and lyophilized in a high vacuum. This gives 1,4,6-tri-O-acetyl-N-propionyl-desmethylmuramyl-L-alanyl-D-isoglutamine-benzyl ester (α, / 3 mixture) as a colorless powder containing 1.00 mol of water.

C ₃₂ H ₄₄ N ₄ O ₁₄ · 1.00 H ₂ O (726.73)

Ber. C52,89 H6,41 N7 / 71 033,02 H ₂ O2,48

Found C 53.18 H 6.42 N 7.49 032.81 H ₂ O 2.48

[a] g ° = + 56.0 ± 1.1 ° (c = 0.948, dimethylformamide), R _f = 0.17 + 0.24 (chloroform: ethanol = 9: 1, double spot), R _f = 0, 45 (chloroform: methanol = 9: 1), R _f = 0.67 (chloroform: methanol = 4: 1).

The residue of fractions 191-260 crystallizes from 90 ml of chloroform-diethyl ether (1: 5). 1a, 4,6-tri-O-acetyl-N-propionyl-desmethylmuramyl-L-alanyl-D-isoglutamine-benzyl ester is obtained in the form of colorless crystals of mp. 147-149 ° C. The crystals are then dissolved in 100 ml of double distilled water-tert-butanol (1: 1). The resulting solution is filtered through a Millipore filter (Fluoropore, PTFE, 0.2 / xm) and lyophilized under high vacuum. This gives 1 a, 4,6-tri-O-acetyldesmethylmuramyl-N-propionyl-L-alanyl-D-isoglutamine-benzyl ester as a colorless powder which still contains 1.12 mol of water. C ₃₂ H ₄₄ N ₄ O ₁₄ - 1.12 H ₂ O (728.89) ''

Ber. C52,74 H6,43 N7,69 033.18 H ₂ O2,76

Found. C52,96 H6,54 N7,62 033.15 H ₂ O2,76

[a] = +36.9 r3 ° ± 1.7 ° (c = 0.593; methylene chloride: methanol = 1: 1), R _f = 0.17 (chloroform: ethanol = 9: 1), Rf = 0.45 (Chloroform: methanol = 9: 1), R _f = 0.67 (chloroform: methanol = 4: 1).

Example 3 Analogously to Example 1, 1.19 g (1.54 mmol) of N-propionyl-desmethylmuramyl-L-alanyl-D-isoglutaminyl-L-alanine-benzhydryl ester (α, / 6 mixture) of the 2.24 mol of water are obtained containing 0.7 ml (7.4 mmol) of acetic anhydride in 12 ml of pyridine (20 hours, room temperature) - tri-O-acetyl-N-propionyl-desmethylmuramyl-L-alanyl-D-isoglutaminyl-L- alanine benzhydryl ester (a, yS mixture) as a colorless powder containing 1.33 moles of water.

C ₄ H H ₆₃ N ₅ O ₁₅ -1.33 H ₂ O (879.85)

Ber. C 55.97 H 6.40 N 7.96 029.69 H ₂ O 2.72

Found. C56,14 K6,36 N7,98 029.56 H ₂ O2,72

[a] g ° = +23.8 + 2.1 "C (c = 0.478, dimethylformamide), R _f = 0.36 (chloroform: methanol = 9: 1), R _f = 0.69 (chloroform: methanol = 4: 1), R _f = 0.87 (chloroform: methanol = 7: 3).

The starting material is obtained as follows:

Step 3.1: Analogously to Example 1, 2.11 g (4.07 mmol) of N-propionyl-dem-methylmuramyl-L-alanyl-D-isoglutaminyl-L-alanine containing 1.56 mol of water are obtained, in total 2.14 g (11.06 mmol) diphenyldiazomethane in 42 ml methanol-dimethoxyethane (1: 1) (18 hours, room temperature) N-propionyl-desmethylmuramyl-L-alanyl-D-isoglutaminyl-L-alanine-benzhydryl ester as a colorless powder containing 2, Contains 24MoI of water.

C ₃₅ H ₄₇ N ₅ O ₁₂ -2.24H ₂ O (770.14) '

Ber. C54.58 H6.76 N9.09 029.59 · H ₂ O 5.25

Found. C54,85 H6,86 N 9,11 029,21 H ₂ O5,25

[ _a ] § ° = + 2.9 + 2 ° C (c = 0.478, dimethylformamide), R _f = 0.57 (chloroform: methanol = 7: 3), R _f = 0.65 (chloroform: methanol: water = 70: 30: 5).

EXAMPLE 4 Analogous to Example 1, from 0.767 g (1.09 mmol) of N-propionyl-dem-methylmuramyl-L-alanyl-D-glutamic acid, C 1-methyl ester (C ₇ ) -benzhydryl ester, which still contains 1.42 mol of water, is obtained 0.49 ml (5.2 mmol) of acetic anhydride in 8.7 ml of pyridine (44 hours, room temperature). 1A-Tri-O-acetyl-N-propionyl-desmethylmuramyl-L-alanyl-D-glutamic acid iCJ-methyl ester- ( CyJ-benzhydryl ester (α, / 3 mixture) as a colorless powder containing 0.71 mol of water.

C ₃₉ H ₄₉ N ₃ O ₁₅ -0.71 H ₂ O (812.62) '. ·

Ber. C57.65 H6.28 N 5.17 030.92 H ₂ 01.57

Found C58.09 * H6.23 N5.28 030.71 H ₂ 01.57

[a] = +53.9 ± 1.9 ° § ⁰ C (c = 0.519; dimethylformamide), R _f = 0.55 (chloroform: methanol = 9: 1), R _f = 0.87 (chloroform: methanol = 4: 1), R _f = 0.95 (chloroform: methanol = 7: 3). The starting material is obtained as follows:

Stage 4.1: Analogously to Example 1, from 1.32 g (2, SmMoI) N-propionyl-desmethylm'uramyl-L-alanyl-D-glutamic acid (C _a) methyl ester, which still contains 0,68MoI water with a total 1.4 g (7.2 mmol) of diphenyldiazomethane in 27 ml of methanol-dimethoxyethane (1: 1) (18 hours, room temperature) of N-propionyl-demethylmuramyl-L-alanyl-D-glutamic acid iCJ methyl ester (C ₇ ) benzhydryl ester colorless powder containing 1.42 moles of water. C ₃₃ H ₄₃ N ₃ O ₁₂ 1.42H ₂ O (699.30)

Ber. C 56.69 H 6.63 N 6.01 030.70 H ₂ O 3.65

Found. C 56.75 H 6.73 N 6.21 3.65 H ₂ O 030,74

[ _a ] g ° = +10.3 ± 2.3 ⁰ C (c = 0.435, water), R, = 0.73 (chloroform: methanol: water = 70: 30: 5), R _f = 0.91 (Chloroform: methanol = 7: 3).

Example 5 Analogously to Example 1, 1.15 g (1.57 mmol) of N-propionyl-dem-methylmuramyl-L-alanyl-D-glutamic acid iCJ-n-butyl ester (C ₇ ) -benzhydryl ester, which still contains 0.99 mol of water containing 0.70 ml (7.4 mmol) acetic anhydride in 12 ml pyridine (16 hours, room temperature). 1A-Tri-O-acetyl-N-propionyl-desmethylmuramyl-L-alanyl-D-glutamic acid iCJ-n-butyl ester - (C _y ) -benzhydryl ester (a, / 3 mixture) as a colorless powder containing 0.73 mol of water. C ₄₂ Hg ₅ N ₃ O ₁₅ -0.73H ₂ O (855.08)

Ber. C58.99 H6.60 N 4.91 029.50 H ₂ 01.54

C 58.96 H 6.72 N 4.76 029.49 H ₂ 01.54

[a] g> = +12.6 + 2.3 ° C (c = 0.443, chloroform), R, = 0.72 (chloroform: methanol = 9: 1), R, = 0.96 (chloroform: methanol = 4: 1)

 The starting material is obtained as follows:

Stage 5.1: Analogously to Example 1, from 1.9 g (3.3 mmol) of N-propionyl-dem-methylmuramyl-L-alanyl-D-glutamic acid-iCJ-n-butyl ester, which contains 1.03 mol of water, with a total of 2.5 g ( 12.85 mmol) diphenyldiazomethane in 40 ml methanol-dimethoxyethane (1: 1.70 hours, room temperature) N-propionyl-desmethylmuramyl-L-alanyl-D-glutamic acid FcJ-n-butyl ester (C _y ) -benzhydryl ester as a colorless powder containing 0 Contains 99 mol of water. C ₃₆ H ₄₉ N ₃ O ₁₂ · 0.99 H ₂ O (733.62)

Ber. C 58.94 H7.03 N5 / 73 028.32 H ₂ O 2.43

Found C 59.24 H 7.06 N 5.59 028.08 H ₂ O 2.43

[a] § ° = 12.5 ± 1.9 ° C (c = 0.522, methanol), R _f = 0.46 (chloroform: methanol = 9: 1), R _f = 0.63 (chloroform: methanol = 4: 1), R _f = 0.88 (chloroform: methanol = 7: 3).

Example 6: Analogously to Example 1, 1.0 g (1.43 mmol) of crude N-acetyl-muramyl-L-alanyl-D-glutamic acid-fCJ-pivaloyloxymethyl ester (C _r ) benzyl ester and 0.57 ml (6, OmMoI ) Acetic anhydride in 10 ml of absolute pyridine (20 hours, room temperature) N-acetyl-1,4,6-tri-O-acetyl-muramyl-L-alanyl-D-glutamic acid (C _a ) -pivaloyloxy-methyl ester (C _r ) benzyl ester (α, / 3 mixture) as a colorless powder containing 0.79 mole of water.

C ₃₈ H ₅₃ N ₃ O ₁₇ 0.79 H ₂ O (838.08)

Ber. C 54.47 H 6.60 N 5.02 033.96 H ₂ 01.69

Found. C54,52 H6,36 N5,12 033.71 H ₂ O1,69

Md ⁰ = 68.5 ± 4.1 ° C (c = 0.241, dimethylformamide), R, = 0.52 (chloroform: methanol = 9: 1), R, = 0.55 (chloroform: ethanol = 9: 1 ).

The starting material is obtained as follows:

Step 6.1: 20.2 g (60 μmol) of N-tert-butyloxycarbonyl-D-glutamic acid iGjJ-benzyl ester are dissolved in a mixture of 300 ml of tetrahydrofuran and 50 ml of water. 19.55 g (60 mmol) of cesium carbonate (PuYum, Fluka), dissolved in 100 ml of water, are added to this solution and the whole is allowed to stand at room temperature for 2 hours. The mixture is then evaporated at 30 ⁰ C under high vacuum and the residue thus obtained successively with 200 ml of methanol and twice with 200 ml of dimethylformamide

The thus-obtained cesium salt of N-tert-butyloxycarbonyl-D-glutamic acid-1C-benzyl ester (28.1 g, 60 mol%) is suspended in 500 ml of dimethylformamide. At room temperature, 18.0 g (17.4 ml, 12 μmol) of pivaloyl chloromethyl ester (purum, FlUka) and 18.0 g (12 μmol) of sodium iodide are added to this suspension. The resulting mixture is stirred for 17 hours at room temperature. It is then filtered and the filtrate evaporated under high vacuum at 4O ⁰ C. The residue thus obtained is taken up in 500 ml of ethyl acetate and washed successively three times with 150 ml of 0.1 N sodium thiosulfate solution and water. After drying the ethyl acetate phase over sodium sulfate is evaporated again in vacuo. The still slightly yellow residue is recrystallized from 450 ml of methanol: water (1: 2). N-tert-butyloxycarbonyl-D-glutamic acid-tCJ-pivaloyloxymethyl ester-tC -benzyl ester is obtained in the form of colorless crystals of mp.

C ₂₃ H ₃₃ NO ₈ (451.52)

Ber. C 61.18 H 7.37 N 3.10. 028.35

C, C, 61.08, H, 7.25, N, 3.33, 028, 58

[α] g ° = + 18.4 ± 0.1 ° C (c = 1.034, ethyl acetate), R _f = 0.85 (methylene chloride: methanol = 9: 1); Stage 6.2: 20.0 g (44.3 mmol) of N-tert-butyloxycarbonyl-D-glutamic acid-fCJ-pivaloyloxymethyl ester-1C-benzyl ester are dissolved at ⁰ ° C. in a mixture of 400 ml of trifluoroacetic acid, methylene chloride (1: 1) 1, Stirred for 5 hours. Then the reaction solution in high vacuum at 3O ⁰ C is evaporated and the resulting residue repeatedly taken up in methylene chloride and again evaporated. A yellow oil is obtained, which is taken up in a mixture of 100 ml of water and 300 ml of diethyl ether and cooled to ⁰ ° C. With vigorous stirring, 80 ml of 1 N sodium hydroxide solution (pH 7.5) are added to the solution, and the ether phase is separated off. The ethereal solution is extracted once with 100 ml of water, the water phase once with 200 ml of diethyl ether. The ether phases are combined, dried over sodium sulfate and filtered. The reddish filtrate is then washed with 8.43 g (44.3 mmol) of p-toluenesulfonic acid monohydrate (puriss., Fluka) dissolved in 100 ml of diethyl ether; and 'for 1 hour at room temperature, then stirred for V2 h at ^{0 0} C. The crystals thus obtained are filtered off with suction and washed with diethyl ether. The crude product obtained is recrystallized from 400 ml of ethyl acetate. This gives D-glutamic acid-fCJ-pivaloyloxymethyl ester-Fc ^ -benzylestertosylatin in the form of colorless crystals, mp 135-137 ⁰ C.

C ₂₅ H ₃₃ NO ₉ S (523.60)

Ber. C57.35 H 6,35 N 2,68 027,50 S 6,12

C57.39 H 6.52 N 2.72 027.53 S 6.12

[a] & ° = + 8.8 + 0.1 ° C (c = 0.924, methylene chloride), R _f = 0.78 (methylene chloride: methanol = 9: 1, double spot), R _f = 0.84 (methylene chloride : Methanol = 5: 1; double spot).

Step 6.3: 2.6g (6.5moles) of N-acetyl-muramyl-L-alanine-sodium salt containing 0.63 moles of water is dissolved in 50ml of dimethylformamide. To this solution is added at room temperature 1.47 g (7.14 mmol) of N, N-dicyclohexylcarbodiimide, 0.74 g (7.14 mmol) of N-hydroxy succinimide and 3.41 g (6.5 mmol) of D-glutamic acid iCI-pivaloyloxymethyl ester -iCyl-benzyl ester tosylate and the resulting clear, colorless solution is stirred for 14 hours at room temperature.

The precipitated during the reaction crystals (Ν, Ν-dicyclohexylurea) are then filtered off with suction and the filtrate is evaporated under high vacuum at 4O ⁰ C. The residue is taken up in 300 ml of ethyl acetate, filtered, and the solution thus obtained successively washed once each with 100 ml of water, three times with 100 ml of saturated aqueous sodium sulfate solution and twice with 100 ml of water.

The ethyl acetate phases are combined, dried over sodium sulfate, filtered and evaporated again.

A slightly yellow foam is obtained, which is purified by column chromatography on 440 g silica gel (type 60, very pure, Merck, 0.063-0.200 mm) in the system acetone-ethyl acetate (7: 3) (10 ml fractions). Fractions 21-70 are combined and evaporated in vacuo at 40 ⁰ C. Low-contaminated N-acetyl-muramyl-L-alanyl-D-glutamic acid-fCJ-pivaloyloxymethyl ester (C _r ) -benzyl ester is obtained as a colorless foam, which is processed without further purification.

Rf = 0.74 (chloroform: methanol: water = 70: 30: 5), R _f = 0.85 (chloroform: methanol = 7: 3).

Example 7: 10 g (15.86 mmol) of N-benzoyl-demethylmuramyl-L-alanyl-D-isoglutamine-benzyl ester are dissolved in 100 ml of pyridine and mixed with 9 ml of acetic anhydride. After 24 hours at room temperature, the mixture is evaporated under high vacuum, the residue is taken up in methylene chloride and the organic phase is shaken successively with 300 ml of 1 N hydrochloric acid, water, 5% NaHCO ₃ solution and water. The aqueous phases are extracted twice with 150 ml of methylene chloride. The combined organic phases are dried with sodium sulfate and evaporated.

For crystallization, dissolve in 20 ml of ethanol and add 30 ml of ethyl acetate and then diethyl ether until cloudy (-60 ml). This gives colorless crystals of a ^ -IAe-tri-O-acetyl-N-benzoyl-desmethylmuramyl-L-alanyl-D-isoglutaminbenzylesters with mp. 168-169 ⁰ C. From the mother liquor, more crystals can be obtained. _[A] 2 ° = + 44.9 ⁰ C ± 1.2 ° C (c = 0.813, CHCl ₃₎ R _f = 0.54 (CHCI _3: methanol = 9: 1).

Example 8 4.5 g (6.4 mmol) of 1,4,6-tri-O-acetyl-N-benzoyl-demethylmuramyl-L-alanyl-D-isoglutamine, dissolved in 60 ml of acetonitrile, are added at 3.7 g (19.1 mmol) of diphenyldiazomethane in 30 ml of acetonitrile. After 5 hours at room temperature, the reaction is complete; it is evaporated to dryness in vacuo, the residue is extracted four times with 20 ml of diethyl ether each time and purified by chromatography over 250 g of silica gel (Merck, 0.04-0.6 mm). The column is eluted sequentially with 1 liter Methyienchlorid-acetone (9: 1, fraction 1), per fraction 500 ml of CH ₂ Cl ₂ -acetone (7: 3, fractions 2 and 3) and per fraction per 1 liter CH ₂ CI ₂ - Acetone (1: 1, fractions 4, 5 and 6). Thus, from fraction 1 impure α-anomeres, from fraction 3 of pure α-anomeres and from fractions 4 and 5 α, / 3-anomeric mixture of the lAe-tri-O-acetyl-N-benzoyl-desmethylmuramyl-L-alanyl- D-isoglutaminbenzhydrylesters.

a-anomer: m.p. 108-110 ° C, [α] £ ° = + 36.3 ± 1 ° C (c = 1.01, CHCl ₃ ), R _f = 0.27 (CHCl ₃ : acetone = 1 :1).

The starting material, lAe-tri-O-acetyl-N-benzoyl-desmethylmuramyl-L-alanyl-D-isoglutamine, is obtained by catalytic hydrogenation of the corresponding benzyl ester (Example 7) with 5% palladium-carbon in dimethoxyethane as Anomerengemisch. Mp 114-12O ⁰ C,

[a] ° l = + 51.9 ° C ± 1 ⁰ C (C = 0.963, H ₂ O), Rf = 0.16 (CHCl _3: methanol: H ₂ O = 85: 15: 2).

Example 9: 1.5 g (2 mmol) of N-benzoyl- (1a, / 3), 4,6-tri-O-butyryl-demethylmuramyl-L-alanyl-D-isoglutamine are reacted analogously to Example 8 with diphenyldiazomethane. After analogous work-up, a crude product is obtained which is chromatographed on 50 g of silica gel (Merck, 0.04-0.6 mm). Sequentially eluting with 1 liter of CH ₂ Cl ₂ -acetone (9: 1, fraction 1), per fraction per 1 liter of CH ₂ Cl ₂ -acetone (8: 2, fractions 2 and 3) and per fraction each 500ml CH ₂ CI _2- acetone (7: 3, fractions 4 and 5). From fraction 2 there is obtained a-anomeres, from fraction 4 impure / 3-anomeres of N-benzoyl-1,4,6-tri-O-butyryldesmethylmuramyl-L-alanyl-D-isoglutamine-benzhydryl ester. The α-anomer is obtained by crystallization by dissolving in acetone (0.7 ml / g) and adding diethyl ether (22 ml / g). . Mp 109-113 ⁰ C, [a] = + 45.1 g ° C ± 1.1 ^{0 0} C (c = 0.92, CHCI _3), R, = 0.62 (CHCl _3: acetone = 1 :1).

The / 3-anomer is obtained by crystallization by dissolving in 8 ml of acetone at 50 ^° C. and adding 20 ml of diethyl ether at room temperature.

'Mp 169-171 ° C, [a] = + 13.8 ° § ° C + 1.3 ⁰ C (c = 0.741, CHCI _3: methanol = 1: 1)., R _f = 0.52 (CHCI ₃ : acetone = 1: 1). The starting material is obtained as follows:

Step 9.1: N-Benzoyl- (1a, / 3), 4,6-tri-O-butyryl-desmethylmuramyl-L-alanyl-D-isoglutamine-benzyl ester is obtained in a known manner from N-benzoyl-desmethylmuramyl-L- alanyl-D-isoglutamine-benzyl ester in pyridine with 6 equivalents of butyric anhydride with the addition of catalytic amounts of 4-dimethylaminopyridine. . After customary working up, on trituration with diethyl ether, crystals of mp 166-171 ⁰ C, [a] o ° = + 43.2 ⁰ C ± 1 ° C (c = 0.954, CHCI ₃₎ a-anomer: R _f = 0.42 (CHCl ₃ : acetone = 1: 1), 0-anomeres: R _f = 0.28 (CHCl ₃ : acetone = 1: 1).

Step 9.2: By catalytic hydrogenation of N-benzoyl-fia-JAe-tri-O-butyryl-demethylmuramyl-L-alanyl-D-isoglutaminobenzyl ester with 5% palladium-carbon in tetrahydrofuran, N-benzoyl- (1a, / 3 , 4,6-tri-O-butyryl-desmethylmuramyl-L-alanyl-D-isoglutamine as hemihydrate with mp 100-105 ⁰ C, [a] § ° = + 54.2 ° C ± 1 ° C (c = 0.96, methanol), R _f = 0.45 (CHCl ₃ : methanol = 8: 2).

Example 10: Analogously to Example 1, 3.69 g (5.6 mmol) of N-acetyldimethylmuramyl-L-alanyl-D-isoglutaminebenzhydryl ester, dissolved in 40 ml of abs. Pyridine, with 2.04g (20mMo) acetic anhydride (1h, room temperature). The clear solution is highly concentrated at 30 ⁰ C, the residue taken up in 150 ml ethyl acetate and the solution was extracted twice with 50 ml of water. After drying and evaporation of the solvent remains N-acetyl-da ^ J ^^ - tri-O-acetyl-desmethylmuramyl-L-alanyl-D-isoglutamine-benzhydrylester.

Hg ⁰ + 33 = ⁰ C ± 1 ° C (c = 1.159, methanol), R, = 0.70 (chloroform: methanol: water = 70: 30: 5), R, = 0.48 (n-butanol: Acetic acid: water = 75: 7.5: 21) and R _f = 0.81 (ethyl acetate-butanol: pyridine: acetic acid: water = 42: 21: 21: 6: 10).

The N-acetyl-demmethylmuramyl-L-alanyl-D-isoglutamine-benzhydryl ester can be prepared as follows: Step 10.1: A solution of 22.8 g (40 mmol) of N-acetyl-demethylmuramyl-L-alanyl-D-isoglutamine in 500 ml of a A 1: 1 mixture of 1,2-dimethoxy-ethane and methanol is treated with 11.6 g (6OmMoI) diphenyl-diazomethan, and the solution stirred for 16 hours at room temperature. The red suspension is evaporated at 2O ⁰ C and under reduced pressure, and the residue mehrfach'mit diethyl ether until a nearly colorless product is obtained. This is dissolved in 100 ml of methanol and brought by the portionwise addition of a 2: 1 mixture of diethyl ether: petroleum ether to crystallize. After several hours of stirring, first at room temperature, then in an ice bath, the crystal mass is filtered off and dried under reduced pressure. This gives the N-acetyl-desmethylmurarnyl-L-alanyl-D-isoglutamine-benzhydryl ester in the form of cubic crystals. Mp 17O ⁰ C (with decomposition), [a] o ° = + 14 + 1 ⁰ C (c = 1.5, methanol), R _f = 0.40 (chloroform:. Methanol: water = 70: 30: 5 ) and R _f = 0.66 (ethyl acetate-butanol: pyridine: glacial acetic acid: water = 42: 21: 21: 6: 10). ,

Example 11: Analogously to Example 10 is obtained from 0.55 g (0.85 mmol) of N-acetyl-desmethylmuramyl-L-'a-aminobutyryl-D-isoglutarninbenzhydrylester, dissolved in 5ml abs. Pyridine, and 0.281 g (2.76 mmol) of acetic anhydride (30 minutes, room temperature) of N-acetyl-1α-Al-tri-O-acetyl-demethylmuramyl-la-aminobutyryl-D-isoglutamine-benzhydryl ester; R _f = 0.63 (chloroform: methanol: water = 70: 30: 5) and R _f = 0.82 (ethyl acetate-butanol: pyridine: acetic acid: water = 42: 21: 21: 6: 10).

Example 12: From 2.10 g (2.54 mmol) of N-acetyl-desmethylmuramyl-La-aminobutyryl-D-glutamic acid dibenzhydryl ester and 1.053 ml (11.43 mmol) of acetic anhydride in 6 ml of absolute pyridine are obtained analogously to Example 1 after standing for 12 hours at room temperature the peracetyl compound. Purification is carried out on 450 g of silica gel (type 60, Merck, particle size 0.063-0.200 mm;

5 ml fractions) first with chloroform, then from fraction 20 with chloroform: isopropanol (3: 1). The material contained in fractions 43-106 is collected, dissolved in 5 ml of chloroform, after addition of 40 ml of abs. Dioxan filtered through a Millipore filter (Fluoropore, PTFE, 0.2 ^ m) and then lyophilized. This gives N-acetyl-da ^ Aö-tri-O-acetyl-desmethylmuramyl-L-aaminobutyryl-D-glutamic acid dibenzhydrylester as a colorless, loose powder, containing 0.37 mol of water.

C ₆₁ H ₅₇ N ₃ O ₁₅ · 0.37 H ₂ O (958.69)

Ber. C63.90 H 6.09 N 4.38 H ₂ O 0.69

Gef. C 63.6 H 6.1 N 4.6 H ₂ O 0.70

[α] g ⁰ = + 29.6 ± 1.7 ° C (c = 0.577, methanol), R _f = 0.69 (n-butanol: acetic acid: water = 75: 7.5: 21) and R, = 0.93 (ethyl acetate: n-butanol: pyridine: acetic acid: water = 42: 21: 21: 6: 10).

The starting material is obtained analogously to Example 1 as follows:

3.00 g (6.1 mmol) of N-acetyl-demmethylmuramyl-L-α-aminobutyryl-D-glutamic acid, dissolved in 30 ml of a 1: 1 mixture of dimethylformamide and methanol, are treated at room temperature with stirring and excess diphenyldiazomethane.

After 3 days, the red suspension is evaporated under high vacuum at 30 ⁰ C, the red residue triturated several times with diethyl ether-petroleum ether (1: 3) and the supernatant decanted off. The solid residue is first by chromatography on 600 g of silica gel (type 60, Merck) in the system chloroform: methanol: water (70: 30: 5, inter alia, to remove half ester), then on a second column (100 g) first with ethyl acetate, then Ethyl acetate: methanol (3: 1, 5 ml fractions).

The collected material is dissolved in 4.5 ml of methanol and after addition of 70 ml of abs. Dioxane and conventional filtration through a Millipore filter lyophilized. N-acetyl-desmethylmuramyl-L-α-aminobutyryl-D-glutamic acid-dibenzhydryl ester is obtained as a colorless powder containing 0.93 mol of water.

Ber. C 64.14 H 6.34 N 4.99 H ₂ 01.99

Gef. C 64.1 H 6.5 N 4.9 H ₂ O 2.0

[a] o ° = + 11.6 ± 2.9 ° C (c = 0.344, methanol), R _f = 0.55 (ethyl acetate: methanol = 4: 1) and R _f = 0.77 (chloroform: isopropanol = 1: 1).

Example 13 Analogously to Example 1, 0.67 g (1 mmol) of Ν-

Benzhydrylester and 0,367g (3,6mMol) acetic anhydride in 5ml abs. Pyridine (30 minutes, room temperature) N-acetyl- (1a.βlAe-tri-O-acetyl-desmethylmuramyl-L-valyl-D-isoglutamine-benzhydryl ester.

[a] g ° = + 35 ° C ± 1 ⁰ C (c = 0.594; methanol), R _f = 0.92 (chloroform: methanol: water = 70: 30: 5) and R _f = 0.80 (ethyl acetate : n-butanol: pyridine: acetic acid: water = 42: 21: 21: 6: 10).

The starting material is obtained analogously to Example 1 as follows:

Step 13.1: 1.60 g (3.15 mmol) of N-acetyl-demethylmuramyl-L-valyl-D-isoglutamine dissolved in 30 ml of methanol are esterified with excess diphenyldiazomethane (2 hours, room temperature). The product is purified by repeated reprecipitation from MethanokDiethylether (1: 8). N-acetyl-desmethylmuramyl-L-valyl-D-isoglutamine-benzhydryl ester is obtained.

[a] g ⁰ = + 13 ⁰ C ± 1 ⁰ C (C = 1.067, methanol), R _f = 0.56 (chloroform: methanol: water = 70: 30: 5), R _f = 0.42 (n Butanol: acetic acid: water = 75: 7.5: 21) and R _f = 0.72 (ethyl acetate-butanol: pyridine: acetic acid: water = 42: 21: 21: 6: 10).

EXAMPLE 14 A solution of 1.2 g of N-acetyl-muramyl-L-diaryl-D-isoglutamine-benzhydryl ester in 12 ml of absolute pyridine is treated with 0.75 ml of acetic anhydride with stirring and allowed to stand at room temperature for 24 hours. The reaction mixture is then poured into 40 ml of ice-water, whereupon the product crystallizes out, the crystals are filtered off with suction, washed with water and dried. Recrystallization from ethyl acetate and diethyl ether gives N-acetyl-1,4,6-tri-O-acetyl-muramyl-L-valyl-D-isoglutamine-benzhydryl ester, R f = 0.3 (methylene chloride: methanol = 5: 1). , The starting material used is prepared as follows:

Stage 14.1: A solution of 2.0 g of N-acetyl-muramyl-L-valyl-D-isoglutamine in 25 ml of methanol and 25 ml of 1,2-dimethoxyethane is treated with 1.1 g of diphenyldiazomethane and stirred for 20 hours at room temperature. The reaction mixture is evaporated to dryness and extracted with diethyl ether. The residue is suspended in water, stirred, filtered off and dried over NaOH pills. The resulting N-acetyl-muramyl-L-valyl-D-isoglutamine benzhydryl ester melting at 185 ⁰ C (dec.), R _f = 0.5 (chloroform: methanol: water = 14: 6: 1), [a] § ° = + 38 ° C (c = 0.912, methanol).

Example 15: A solution of 2.0 g of N-acetyl-muramyl-L-alanyl-D-isoglutamine benzhydryiester in 20 ml of absolute pyridine is added under stirring with 1.7 ml of acetic anhydride and allowed to stand for 24 hours at room temperature. 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 semisaturated sodium chloride solution and dried over magnesium sulfate. Evaporation of the solvent gives N-acetyl-IAe-tri-O-acetyl-muramyl-L-alanyl-D-isoglutaminbenzhydrylester. Rf = 0.7 (methylene chloride: methanol = 5: 1)

 The starting material used is prepared as follows:

Step 15.1: To a solution of 1.1 g of N-acetyl-.muramyl-L-alanyl-D-isoglutamine in 12.5 ml of methanol and 12.5 ml of 1,2-dimethoxyethane is added 0.42 g of diphenyldiazomethane and allowed to stand at 40 for 20 hours ° C stirred. After evaporation of the solvent, the residue is extracted thoroughly with diethyl ether and water and dried over NaOH pills. N-acetyl-muramyl-L-alanyl-D-isoglutamine-benzhydryl ester is obtained in the form of white crystals. Rf = 0.6 (methylene chloride, ethane water = 14: 6: 1).

Example 16: 1.45 g (1.99 mmol) of N-acetyl-muramyl-L-alanyl-D-isoglutaminyl-L-alanine-benzhydryl ester, dissolved in 10 ml of abs.

Pyridine, 0.73 g (7.15 mmol) of acetic anhydride are added and allowed to stand at room temperature for 35 hours. The yellowish solution is evaporated under high vacuum at 30 ° C to dryness, the residue with abs. Dioxane added and lyophilized. The freeze-dried material is taken up in 10 ml of chloroform: methanol (1: 1) and extracted with 100 ml of abs.

Diethyl ether precipitated (3 times). The resulting powder is abs. In 100ml. Dioxane: Water (1: 1) dissolved, filtered as usual through a Millipore filter (PTFE, 0,2μηι) and lyophilized. This gives N-acetyl-iia ^ J ^^ - tri-O-acetyl-muramyl-L-alanyl-D-isoglutaminyl-L-alanine benzhydryl ester as a colorless powder, containing 1.42 moles of water and 0.7 moles of dioxane.

C ₄ iH ₅ iN ₅ O ₁₅ · 0.7 C ₄ H ₈ O ₂ · 1.42 H ₂ O

Ber. C 55.90 H 6.37 N 7.44 H ₂ O 2.72

Found C 55.98 H 6.42 N 7.76 H ₂ O 2.71

[a] § ° = + 25.5 ± 2.1 ° C (c = 0.475, dimethyl sulfoxide), R _f = 0.39

(n-butanol: acetic acid: water = 75: 7.5: 21), R _f = 0.83

(ChloroforiTKMethanokWater = 70: 30: 5) and R _f = 0.85

(Chloroform: methanol: water: acetic acid = 70: 40: 9: 1).

The starting material is obtained as follows:

Stage 16.1: 3.25 g (5.6 mmol) of N-acetyl-muramyl-L-alanyl-D-isoglutamine-L-alanine are dissolved in 50 ml of methanol and esterified with excess diphenyldiazomethane with stirring. After 6 hours, the violet solution is evaporated and the yellowish residue is purified by chromatography on 400 g of silica gel (type 60, Merck) in the system chloroform: methanol: water (70: 30: 5) (13 ml fractions). The material contained in a fraction of 600 ml in the fractions 42 to 60 is collected, taken up in 100 ml of chloroform, filtered through a Millipore filter (PTFE, 0.2μ, ιη) and evaporated. The residue is dissolved in 150 ml of abs. Dioxane taken and lyophilized. N-acetylmuramyl-L-alanyl-D-isoglutaminyl-L-alanine-benzhydryl ester is obtained as a colorless, loose powder.

C ₃₅ H ₄₇ N ₆ O ₁₂ · 1.51 H ₂ O (756.99)

Ber. C55.54 H 6.69 N 9.25 H ₂ O3.59

Found C 55.68 H 6.39 N 9.04 H ₂ O 3.59

[a] = + 16.3 ° § ± 1 ⁰ C (c = 0.979; dimethyl sulfoxide),

Rf = 0.31 (n-butanol: acetic acid: waters = 70: 7.5: 21),

Rf = 0.57 (chloroform: methanol: water = 70: 30: 5) and

Rf = 0.33 (chloroform: methanol: water: acetic acid = 75: 27: 5: 0.5).

Example 17 Analogously to Example 16, 1.00 g (1.53 mmol) of N-acetyl-muramyl-L-alanyl-D-isoglutaminyl-L-alanine benzyl ester, dissolved in 18 ml of abs. Pyridine, and 0.66 g (5.97 mmol) acetic anhydride, the peracetyl compound (6 hours, room temperature). It is purified by chromatography on 150 g of silica gel in the system chloroform: methanol: water (70: 30: 5, 5 ml fractions). N-acetyl-tia-JAe-tri-O-acetyl-muramyl-L-alanyl-D-isoglutaminyl-L-alanine-benzyl ester is obtained as colorless lyophilisate, containing 1.84 mol of water.

C ₃₅ H ₄₉ N ₅ O ₁₅ · 1.84 H ₂ O (812.94)

Ber. C 51.72 H 6.56 N 8.62 H ₂ O 4.07

Gef. C 51.5 H6.9 N8.3 H ₂ O 4.1

[a] o ° = + 38.5 ± 3.5 ° C (c = 0.282, dimethylformamide), R _f = 0.63 (acetonitrile: water = 3: 1), R _f = 0.39 (n-butanol : Acetic acid: water = 75: 7.5: 21), R _f = 0.83 (ethyl acetate-butanol: pyridine: acetic acid: water = 42: 21: 21: 6: 10).

Example 18: 1.45 g (1.5 mmol) of N-acetyl-muramyl-L-alanyl-D-isoglutaminyl-L-alanine-cholesteryl-S-ester and 0.72 g (7.1 mmol) of acetic anhydride are dissolved in 16 ml of a Mixture of abs. Pyridine and dimethylformamide (6: 1) "and allowed to stand for 22 hours at room temperature.The clear solution is concentrated under high vacuum at 30 ⁰ C to about 4ml, the resulting gelatinous residue triturated with 50 ml of ethyl acetate and the supernatant decanted (4 times). The solid residue is taken up in 5 ml of dimethylformamide, 50 ml of absolute dioxane are added, the whole is filtered through a Millipore filter (PTFE, 0.2 μm) and lyophilized to give N-acetyl-tia-1-ac-tri-O-acetyl -muramyl-L-aianyl-D-isoglutaminyl-L-alanine-cholesteryl-3-ester as a colorless powder containing 0.62 mol of water.

C ₅₅ H ₈₇ N ₅ O ₁₅ -0.62 H ₂ O (1069.49) ·

Ber. C61.77 H8.33 N6.55 H ₂ 01.04

Gef. C 61.8 H 8.4 N 6.8 H ₂ 01.0

[a] ⁰ = + 7.7 ± 1 § ⁰ C (c = 0.977; dimethyl sulfoxide), R, = 0.41 (n-butanol: acetic acid: water = 75: 7.5: 21) R _f = 0 , 87 (ethyl acetate: n-butanol: pyridine: acetic acid: water = 42: 21: 21: 6: 10).

EXAMPLE 19 Analogously to Example 1, N-acetyl-IAe-tri-O-acetyl-muramyl-L-alanyl-D-glutamine is obtained from N-acetyl-muramyl-L-alanyl-D-glutamine-pivaloyloxymethyl ester and acetic anhydride in absolute pyridine -pivaloyloxymethylester.

The starting material is obtained as follows:

Step 19.1: 3.0 g (8.54 mmol) of N-benzyloxycarbonyl-L-alanyl-D-glutamine are dissolved in a mixture of 300 ml of tetrahydrofuran and 20 ml of water. To this solution is added 1.39g (4.27mMo) of cesium carbonate (purum, Fluka) dissolved in 7ml of water, and allowed to stand at room temperature for 2h. It is then evaporated in a high vacuum at 30 ° C and the residue thus obtained, successively with 250ml of methanol and twice 250ml each dimethylformamide in a high vacuum at 4O ⁰ C evaporated.

The cesium salt of N-benzyloxycarbonyl-L-alanyl-D-glutamine thus obtained is suspended in 300 ml of dimethylformamide. To this suspension are added at room temperature 2.57 g (2.48 ml, 17.08 mmol) of pivaloyl chloroformate (purum, Fluka) and 2.56 g (17.08 mmol) of sodium iodide. The resulting mixture is stirred for 42 hours at room temperature.

C is then evaporated under high vacuum at 4O ^0th The yellow, crystalline residue thus obtained is taken up in 500 ml of ethyl acetate (suspension) and washed three times with 150 ml of water each time. The clear ethyl acetate phases are combined, dried over sodium sulfate and evaporated in vacuo at 30 ° C. The residue crystallizes from ethyl acetate: n-pentane = 1:15 (20: 300 ml). After two recrystallizations is obtained N-benzyloxycarbonyl-L-alanyl-D-glutamine-pivaloyloxymethyl ester in the form of colorless crystals of mp. 109-110 ⁰ C.

C ₂₂ H ₃₁ N ₃ O ₈ (465.50)

Ber. C56 / 76 H 6.71 N9.03 027.49

Gef. C 56.42 H 6.69 N 8.82 027.73

Md ⁰ = + 5.5 + 0.1 ° C (c = 0.973, methanol), R _f = 0.62 (methylene chloride: methanol = 5: 1), R _f = 0.86 (methylene chloride / methanol water = 70: 30: 5 ).

Step 19.2: A solution of 6.7 g (14.4 mmol) of N-benzyloxycarbonyl-L-alanyl-D-glutamine-pivaloyloxymethyl ester in 200 ml of dimethoxyethane is added at a constant pH of 5.5 (titration with 1 N hydrochloric acid) at 1.0 g 10% palladium carbon catalyst as hydrogenated for 40 minutes at room temperature and atmospheric pressure.

Then, the catalyst is filtered off and the filtrate is evaporated at 30 ⁰ C under high vacuum. The residue thus obtained is suspended in 30 ml of diethyl ether. The colorless crystals thus obtained are filtered off with suction and washed with diethyl ether.

This gives L-Alanyl'-D-glutamine pivaloyloxymethyl ester hydrochloride in the form of colorless crystals, mp. 110-111 ° C (dec.).

C ₁₄ H ₂₆ CIN ₃ O ₆ (367.83) ·

Ber. C45 / 72 H 7,13 Cl 9,64 N 11,42 026,10

C 45.51 H 7.36 Cl 9.34 N 11.47 026.40

[α] g ⁰ = + 25.5 + 0.1 ⁰ C (C = 1.128, methanol), R _f = 0.07 (methylene chloride: methanol = 5: 1), R _f = 0.37 (methylene chloride: methanol: Water = 70: 30: 5), R _f = 0.59 (methylene chloride: methanol: water = 5: 5: 1).

Step 19.3: 5.18 g (13, OmMoI; 2.52 mmol / g) of N-acetyl-O-O-isopropylidene-muramic acid sodium salt are suspended in 150 ml of dimethylformamide. Then, at room temperature, 4.8 g of (13, OmMoI) L-alanyl-D-glutamine pivaloyloxymethyl ester hydrochloride, 2.95 g (14.3 mmol) of dicyclohexylcarbodiimide and 1.64 g (14.3 mmol) of N-hydroxy-succinimide are added. The resulting slightly yellow suspension is stirred for 22 hours at room temperature. It is then filtered off with suction from the main amount of the resulting Dicyclohexylharnstoffes and the filtrate thus obtained under high vacuum at 4O ⁰ C evaporated. The residual yellow oil is taken up in 20 ml of methanol, a further fraction of dicyclohexylurea is filtered off with suction and re-evaporated under high vacuum.

The crude product thus obtained, which also contains little dicyclohexylurea, is purified by column chromatography on 1000 g of silica gel (type 60, very pure, Merck, 0.063-0.2 mm) in the system methylene chloride: methanol = 9: 1 (10 ml fractions).

The fractions 380-1 21.0 are combined, starting from fraction 850 with the system MethylenchloridiMethanokWasser = 70: 30: 5

is eluted. , ·

After evaporation of the eluates in a high vacuum at 30 ° to obtain a mixture consisting mainly of N-acetyl-4-0,6-0-isopropylidene-muramyl-L-alanyl-D-glutamine pivaloyloxymethylester and some N-acetyl-muramyl-L alanyl-D-glutamine-pivaloyloxymethyl ester, in the form of a pale yellow foam, which is processed without further purification.

Rf = 0.33 [N-acetyl-muramyl-L-alanyl-D-glutamine-pivaloyloxymethyl ester] and 0.66 [N-acetyl] -O-O-isopropylidene-muramyl-L-alanyl-D-glutamine-pivaloyloxymethyl ester ] (Methylene chloride: methanol: water = 70: 30: 5).

Step 19.4: A solution of 5.5 g (ca. 8.5 mmol) crude N-acetyl-O-O-isopropylidene-muramyl-L-alanyl-D-glutamine pivaloyloxymethyl ester in 100 ml glacial acetic acid (3: 2) becomes 4 , Stirred for 5 hours at room temperature. Thereafter batten view · yellow solution under high vacuum at 4O ⁰ C evaporated and residue der.so obtained by column chromatography on 500g silica gel (Type 60, reinst, Merck; 0,063-0,2mm) in the system methylene chloride: methanol: water (70:30: 5) cleaned (10ml fractions). Fractions 52-65 are combined and evaporated at 30 ° C under high vacuum. This gives N-acetyl-muramyl-L-alanyl-D-glutamine-pivaloyloxymethylester, which is dissolved in 60 ml bidistilled-water. The solution is filtered through a Millipore filter (Nalgene® S, 0.2 μιη) and then lyophilized in a high vacuum. N-acetyl-muramyl-L-alanyl-D-glutamine-pivaloyloxymethyl ester is obtained as a colorless powder which still contains 1.21 mol of water.

C ₂₅ H ₄₂ N ₄ O ₁₃ -1.21 H ₂ O (628.50)

Ber. C, 47.78 H, 7.16 N, 8.91, 036, 18, H ₂ O, 3.48

C48.09 H7.15 N9.02 036.01 H ₂ O3.48

(a) l ° = + 39.5 ± 0.1 ⁰ C (c = 0.443, water),

Rf = 0.61 (methylene chloride-methanol water = 70: 30: 5).

Example 20: Following the procedures described in this application, the following compounds are obtained:

a) N-acetyl-1,2,3-tri-O-acetyl-muramyl-L-N-methyl-alanyl-D-isoglutamine-benzhydryl ester,

b) N-acetyl-IAe-tri-O-acetyl-muramyl-a-amino-isobutyryl-D-isoglutamine-benzhydryl ester and

c) N-acetyl-IAe-tri-O-acetyl-desmethylmuramyl-L-alanyl-D-y-methoxycarbonyl-isoglutamine-benzhydryl ester.

Step Example! 21: Female MF-2f SPF mice weighing 14-16 g are under light anesthesia with a mixture of equal parts of diethyl ether, ethanol and chloroform, with lethal doses (about one LD _S o_9o; 1-4 plaqueforming units [PFU]) in the form of 0.05 ml each of a suspension of influenza A / Texas / 1/77 (virus A) or of influenza B / Hong Kong 15/72 (virus B) viruses (mouse-adapted strains) intranasally infected.

Each mouse from groups of 10 of each of these mice is given at the time indicated below [days] relative to the day of infection once (single dose) the amount of the respective active substance in 0.05 or in 0.2 ml of a 0.005 wt. % solution of carboxymethylcellulose sodium salt in double distilled, pyrogen-free water in the case of intranasal or oral administration in the manner mentioned in Table 1.

In each case 20 of the above-mentioned infected mice are used for control, d. H. they receive a placebo (0.005 wt% solution of carboxymethylcellulose sodium salt).

The intranasal administration of the active substance is carried out under light anesthesia with a mixture of equal parts of diethyl ether, ethanol and chloroform.

Compound I = lAe-tri-O-acetyl-N-propionyl-desmethylmuramyl-L-aianyl-D-isoglutamine-benzhydryl ester.

Table 1:

virus more Applika Applika Percentage of mice still living 23 days after infection , 005, ** P <0.01 (four-field test), n.t. = 0.0001 not tested substance tionsart tion time Dependence on the amount of active substance [mg / kg], statistical 0.1 0.01 0.001 n.t. 0 = control [Days] Significance * P <0, 70 (*) 100 ** n.t. n.t. 30 10 1 90 ** n.t. n.t. n.t. 20 A I orally +7 n.t. 100 ** 100 ** 80 ** n.t. 10 20 orally +7 80 ** 70 ** n.t. 50 ** 0 90 * 0 intranasally 7 n.t. 77 * n.t. 100 ** 100 ** 40 B I orally +7 n.t. n.t. intranasally n.t. n.t.

Example 22: Non-aqueous single dose for nasal application Composition:

LAE-tri-O-acetyl-N-propionyl-desmethylmuramyl-

L-alanyl-D-isoglutamine-benzhydryl ester 0.03 mg

Miglyol812 - 30.00 mg

production:

0.03 mg of the active ingredient is dissolved under aseptic conditions in 29.97 mg Miglyol.

This solution is filled in a commercial disposable nose applicator, which is placed on a fuel can before use.

0.02 mg - 0.30 mg 0.30 mg 10,10mg 10,10mg - 0.10 mg 0.50 mg 0.50 mg 3.70 mg 4.50 mg 988.30 mg 987.60 mg

Step Example! 23: nose drops composition:

10A-Tri-O-acetyl-N-propionyl-des-0.15 mg 0.10 mg

methylmuramyl-L-analyl-D-isoglutamin-

benzhydryl

thimerosal

Sodium monohydrogenphosphate 2H ₂ O

Sodium dihydrogen phosphate · 12H ₂ O

benzalkonium chloride

Ethylenediaminetetraacetic acid disodium salt (EDTA)

sodium chloride

Demineralized water

production:

In a part of the above-mentioned amount of demineralized water, without stirring, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium chloride, thiomersal and EDTA disodium salt are dissolved at room temperature.

In this solution, the drug is then dissolved and supplemented with the remaining demineralized water.

The solution or a part or multiple thereof is filtered through a membrane filter and filled into cleaned containers.

Suitable containers are z. B.

a) glass or plastic containers (a 5ml or 10ml) containing a glass or plastic pipette with an elastomeric pipettor,

b) plastic crumpled bottles with a riser and a plastic spraying head,

c) single dose plastic container (content 2-3 drops) or

d) Glass or plastic bottles provided with a normalized pumped dosing spray of plastic (without propellant gas).

Example 24: Nose Ointment Composition:

i ^^ - Tri-O-acetyl-N-propionyl-des-methylmuramyl-L-alanyl-D-isoglutamine 0.03 g

benzhydryl

Paraffin oil viscous. 20.00 g

white Vaseline 30.00 g

Wool fat, anhydrous, 40.00 g

demineralised water 19.97 g

production:

The fat phase, consisting of paraffin oil, petrolatum and wool fat, is melted together. The aqueous solution of the active ingredient is incorporated at about 50 ° C in the fatty phase.

Example 25 Preparation of 1000 Tablets Containing 0.5% Active Ingredient Composition per 1000 Tablets

LAE-tri-O-acetyl-Nr-propionyl-des-methylmuramyl-L-alanyl-D-

isoglutamine-benzhydryl ester 0.5 g

Lactose ground 43.0 g

Corn starch 52.0 g

Pharmacoat 603® (hydroxypropylmethylcellulose containing 28-30% methoxyl groups, supplied by Shinetsu Chemical Company,

Toio, Japan) 3.0 g

Aerosil® (colloidal silica, supplied by Degussa, Frankfurt,

Federal Republic of Germany) 1.0 g

Magnesium stearate 0.5 g

production:

The active ingredient and 15g lactose are premixed. The premix thus obtained is mixed together with 28 g of lactose and 47 g of corn starch. With the mixture thus obtained and an aqueous solution of the Pharmacoat a granulate-ready mass is prepared, which is granulated, dried and ground. For this purpose, 5 g of corn starch, Aerosil and magnesium magnesium stearate are mixed and compressed to give 1,000 tablets weighing 100 mg each. The compacts can be coated gastroresistant in a known per se.

Example 26: Following the procedures described in this application, the following compounds are obtained:

N-acetyl-1,4,6-tri-0-acetyl-muramyl-L-alanyl-D-isoglutaminyl-L-a - ([2-benzyloxy-carbonylamino-ethyl] sulfonyl-methyl) -glycine, benzyl ester,

N-acetyl-i ^^ - tri-O-acetyl-muramyl-L-analyl-D-isoglutaminyl-LO-acetyl-serine-benzyl ester, TAe-tri-O-acetyl-N-benzoyl-desmethylmuramyl-L-alanyl- D-glutamic acid dicholinester, N-propionyl-IAB-tri-O-propionyl-desmethylmuramyl-L-alanyl-D-isoglutamine-benzhydryl ester, IA-tri-O-acetyl-N-propionyl-desmethylmuramyl-L-alanyl-D glutamic acid-an-butyl ester-y-benzyl ester, lAe-tri-O-acetyl-N-propionyl-desmethylmuramyl-L-alanyl-D-glutamic acid dibenzyl ester, N-acetyl-IAe-tri-O-propionyl-muramyl-La aminobutyryl-D-isoglutamine-benzhydryl ester, 1,4,6-tri-O-acetyl-N-benzoyl-desmethylmuramyl-L-alanyl-D-isoglutamine-benzyl ester, and lAe-tri-acetyl-N-propionyl-desmethylmuramyl-L- alanyl-D-glutamic acid dipivaloyloxymethylester.

Example 27: Analogously to Example 1, from 250 mg (about 0.098 mmol) of crude 4,6-di-O-acetyl-N-propionyl-desmethylmuramyl-L-alanyl-D-glutamic acid dipivaloyloxymethylester (α, / 3 mixture) and 2.0 ml (21, OmMoI) acetic anhydride in 10 ml of absolute pyridine (18 hours, room temperature). 1A-Tri-O-acetyl-N-propionyl-des-methylmuramyl-L-alanyl-D-glutamic acid dipivaloyloxymethyl ester (α, / 3- Mixture); Rf = 0.43 (chloroform: ethanol = 95: 5), Rf = 0.56 (chloroform: methanol = 9: 1), Rf = 0.72 (chloroform: methanol = 4: 1)

 The starting material is obtained as follows:

Step 27.1: To a solution of 9.78 g (34.1 mmol) of N-tert.-butyloxycarbonyl-L-alanine-N-hydroxy-succinimide ester in 200 ml of absolute Ν, Ν-dimethylformamide is added at room temperature with stirring 15, 9g (34.1 mmol) of D-glutamic acid (C _a ) -pivaloyloxymethyl ester (C ,,) benzyl ester tosylate and 3.75 ml (34.1 mmol of 1N-methylmorpholine.) After stirring for 18 hours at room temperature in vacuo at 40 ° . evaporated ⁰ C. The crude product (yellow oil) so obtained is purified by column chromatography on 800g silica gel (type 60, reinst, Merck; 0,063-0,2mm) in the system methylene chloride-ethyl acetate (85:15) (10 ml fractions) fractions. 126-230 were combined and concentrated in vacuo at 3O evaporated ^0C to give N-tert-butyl-oxycarbonyl-L-alanyl-D-glutamic acid pivaloyloxymethyl ester ICJ-iCyJ-benzyl ester as a yellowish oil;. '

[ α ] l ° = -10.6 ± 0.1 ° C (c = 1.035, methylene chloride), Rf = 0.29 (methylene chloride / ethyl acetate = 85:15), Rf = 0.73 (methylene chloride: methanol = 9: 1 ), R _f = 0.78 (methylene chloride: methanol = 5: 1).

Stufe27.2: To a solution of 4.0 g (7,65mMol) N-tert.-butyloxycarbonyl-L-alanyl-D-glutamic acid-fCj-pivaloyloxymethylester- _(C?) -Benzyl ester in 50 ml of absolute Essigsäureethylestergibt one at 0 ⁰ C 100 ml approx. 5 N hydrochloric acid in. Ethyl acetate and stirred for 1 hour at 0 ° C. Thereafter, in a high vacuum at 3O ⁰ C evaporated and the resulting residue taken up several times in ethyl acetate and again evaporated. A colorless foam is obtained which is dissolved in 50 ml of ethyl acetate. After addition of 250 ml of pentane and cooling to -10 ° C is obtained L-alanyl-D-glutamic acid iCJ-pivaloyl-oxymethyl ester-iC ^ benzyl ester hydrochloride as colorless crystals of mp. 73-74 ⁰ C, which is still 0 , 63 moles of water; .. ·

Mg ⁰ = + 23.5 ± 0.1 ° C (c = 1.150, methanol), R f = 0.20 (methylene chloride: methanol = '9: 1), R f = 0.49 (methylene chloride: methanol = 5: 1 ), R _f = 0.87 (methylene chloride-methanol water = 70: 30: 5).

Step 27.3: To a suspension of 2.99 g (~ 5.0 mmol, still contains sodium chloride, 1.673 mmol / g) of 1-α-O-benzyl-4,6-0,0-isopropylidene-N-propionyl-desmethylmuramic acid sodium salt in 50 ml of absolute Ν, Ν-dimethylformamide, 1.34 g (6.5 mmol) of N, -dicyclohexylcarbodiimide, 1.03 g (6.5 mmol) of 1-hydroxybenzotriazole and 2.35 g (5, OmMoI L-alanyl -D-glutamic acid-ICJ-pivaloyloxymethyl-lCyJ-benzyl ester hydrochloride was added and then stirred for a further 22 hours at room temperature. the suspension is evaporated filtered (N, N-dicyclohexylurea) and the filtrate under high vacuum at 4O ⁰ C. the residue, A yellowish foam, taken up in 100 ml of ethyl acetate and the resulting solution is washed successively with 50 ml of 2N citric acid, 10% sodium bicarbonate solution and water The ethyl acetate phases are combined, dried over sodium sulfate and evaporated in vacuo is through columns chromatography on 400g silica gel (type 60, purest, Merck; 0.063-0.2 mm) first with chloroform (flow 2 liters), then in the system chloroform-ethanol (95: 5) cleaned (10ml fractions). Fractions 93-122 are combined and evaporated in vacuo. Is still slightly poorly contaminated iaO-benzyl ^ e-OiO-isopropylidene-N-propionyl-desmethylmuramyl-L-alanyl-D-glutamic acid iC;,) - pivaloyloxymethylester-fCyl-benzyl ester as a colorless foam, which is processed without further purification; Rf = 0.55 (chloroform: ethanol = 9: 1), Rf = 0.63 (chloroform: methanol = 9: 1).

Step 27.4: To a solution of 830mg (1, OmMoI) of 1o-Benzyl ^ eO ^ -isopropylidene-N-propionyl-desmethylmuramyl-L-alanyl-D-glutamic acid iCJ-pivaloyloxymethyl ester iCyJ-benzyl ester in 28.5ml of absolute methylene chloride 1.5 ml of trifluoroacetic acid at 0 ° C and stirred at 0 ° C for 1.5 hours. Thereafter, the colorless solution thus obtained is evaporated under high vacuum at 40 ⁰ C to dryness. The residue crystallizes from chloroform-methanol-diethyl ether (5: 1: 70). Ia O-Benzyl-N-propionyl-desmethylmuramyl-L-alanyl-D-glutamic acid iCJ-pivaloyloxymethyl ester-Fc ^ -benzyl ester is obtained as colorless crystals; M.p. 148-149 ⁰ C; Rf = 0.33 (chloroform: methanol = 9: 1), "Rf = 0.67 (chloroform: methanol = 4: 1), Rf = 0.90 (chloroform: methanol: water = 70: 30: 5) ,

Step 27.5: 400 mg (0.5 mmol) of iaO-benzyl-N-propionyl-demethylmuramyl-L-alanyl-D-glutamic acid-fCa) -pivaloyloxymethyl ester (C _r -benzyl ester in 80 ml of tetrahydrofuran-methanol (4: 1) with 200 mg of 10% palladium carbon After completion of the hydrogenation (1 hour), the catalyst is filtered off and the filtrate is evaporated under high vacuum The residue, a colorless foam, is dissolved in a mixture of 30 ml of tetrahydrofuran and 1 ml of water and the resulting solution A solution of 96 mg (0.25 mmol) of cesium carbonate in 0.38 ml of water is added at room temperature, after half an hour at room temperature, the colorless solution is evaporated in vacuo and the residue is washed twice with 100 ml of methanol and once with 100 ml Ν, Ν-dimethylformamide is added and evaporated again to give still heavily contaminated 1-aO-benzyl-N-propionyl-desmethylmuramyl-L-alanyl-D-glutamic acid-tCJ-pivaloyloxymethylester- cesium salt as a colorless foam, which is processed without further purification; R _f = 0.15 (chloroform: methanol = 4: 1), R _f = 0.35 (chloroform: methanol = 7: 3), R _f = 0.45 (chloroform: methanol: water = 70: 30: 5).

Step 27.6: To a solution of 420mg (0.5 mmol) of iaO-benzyl-N-propionyl-desmethylmuramyl-L-alanyl-D-glutamic acid (CJ-pivaloyloxymethyl ester cesium salt in 15 mL of Ν, Ν-dimethylformamide is added 150mg at room temperature with stirring (145μΙ, 1, OmMoI) pivaloyl chloromethyl ester and 150mg (1, OmMoI) sodium iodide The resulting mixture is stirred at room temperature for 18 hours then 145μΙ (1, OmMoI) pivaloyl chloroate and 150 mg (1, OmMoI) sodium iodide are added The mixture is then evaporated under high vacuum at 30 ^° C. The crude product is purified by double column chromatography on 200 or 250 g of silica gel (type 60, very pure, Merck, 0.063-0.2 mm) in the chloroform-methanol system (9: 1) or chloroform: methanol (95: 5) The fractions containing the desired product are each combined and evaporated in vacuo to give 1-a-benzyl-N-propionyl-desmethylmuramyl-L-alanyl-D-glutamic acid. dipivaloyloxymethy lester;

Rf = 0.25 (chloroform: methanol = 9: 1),

Rf = ~0.35 (chloroform: ethanol = 9: 1). "

Rf = 0.70 (chloroform: methanol = 4: 1).

Stage 27.7: Analogously to Example 1, from 80 mg (0.098 mmol) of 1-α-O-benzyl-N-propionyl-desmethylmuramyl-L-alanyl-D-glutamic acid dipivaloyloxymethyl ester and 0.8 ml (8.4 mmol) of acetic anhydride in 8 ml of absolute pyridine (18 hours Room temperature) 4,6-di-O-acetyl-ia-benzyl-N-propionyl-desmethylmuramyl-L-alanyl-D-glutamic acid

dipivaloyloxymethylester; '

Rf = 0.50 (chloroform: ethanol = 95: 5),

Rf = 0.65 (chloroform: ethanol = 9: 1),

Rf = 0.77 (chloroform: methanol = 9: 1).

Step 27.8: 140mg (0.098 mmol) of 4,6-di-O-acetyl-1-a-O-benzyl-N-propionyl-desmethylmuramyl-L-alanyl-D-giutamic acid dibivaloyloxymethyl ester are dissolved in 80 ml of dimethoxyethane-water (9: 1). with palladium carbon (Degussa, E101N) as the catalyst for 20 hours at room temperature under atmospheric pressure, followed by filtering off the catalyst and evaporating the filtrate in a high vacuum at 30 ° C. This gives crude 4,6-di-O-acetyl-N-propionyl -desmethylmurarnyl-L-alanyl-D-glutamic acid dipivaloyloxymethyl ester (α, / 3 mixture), which is processed without further purification, R f = 0.38 (chloroform: methanol = 9: 1),

Rf = 0.64 (chloroform: methanol: water = 70: 30: 5),

Rf = 0.68 (chloroform: methanol = 4: 1). .. ·

EXAMPLE 28 Analogous to Example 1, 174.0 mg (0.25 mmol) of N-pentoxodyl-dem-methylmuramyl-L-alanyl-D-isoglutaminyl-L-alanine-benzoyloxymethyl ester, which still contains traces of N-methylmorpholine hydrochloride, are obtained. in 1.7 ml of absolute pyridine with 0.1 ml (1.04 mmol) of acetic anhydride with the addition of a little 4-dimethylaminopyridine 1,4,6-tri-O-acetyl-N-propionyl-desmethylmuramyl-L-alanyl-D -isoglutaminyl-L-alanine-benzoyloxymethyl ester (α, / 3 mixture) as colorless crystals; Mp 177-178 ° C (from 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:

Step 28.1: A solution of 18.9 g (0.1 mol) of N-tert-butyloxycarbolyl-L-alanine in 50 ml of Ν, Ν-dimethylacetamide is mixed with 14.9 ml (0.1 mol) of 1,8-diazabicyclo [5.4 .O] undec-7-ene and 36.2 ml (0.45 mol) of diiodomethane and stirred at 22 ° C for 7 hours. The solution is evaporated under high vacuum and the residue is a suspension of 36.6 g (0.3 mol) of benzoic acid, 6.1 g (0.05 mol) of 4-dimethylaminopyridine and 37.3 ml!, S-DiazabicycloIöAOlundec-J- in 75ml Ν, Ν-dimethylacetamide. The resulting after 40 minutes clear solution is allowed to stand for 16 hours at 22 ⁰ C. The mixture is shaken with a mixture of 0.3 molar dipotassium hydrogen phosphate solution and ethyl acetate, the organic layer is separated, washed with further phosphate solution, dried over sodium sulfate and evaporated. Trituration of the residue with pentane, then pentane-diethyl ether (3: 1) gives N-tert-butyloxycarbonyl-L-alanine-benzoyloxymethyl ester; Rf = 0.68 (chloroformate = 9: 1).

Stufe28.2: 3,72g (11.5 mmol) of N-tert-butyloxycarbonyl-L-alanine benzoyloxymethylesterwerden clear solution at ^{0 °} C in 100 ml of a 5molaren hydrogen chloride solution in ethyl acetate and allowed to stand at 0 ° C for 2 hours. At ⁰ ° C., the solution is added to 200 ml of diethyl ether-pentane (1: 1) and, after stirring for 20 minutes at 0 ^° C., the precipitated gel-like crude product is filtered off. It is stirred for 2 hours at 22 ⁰ C in 360 ml of ethyl acetate-diethyl ether-pentane (1: 1: 1), then filtered off. L-alanine-benzoyloxymethyl ester hydrochloride is obtained; Mp. 99-100 ⁰ C.

Step 28.3: To a solution of 506 mg (1, OmMoI) of N-propionyl-desmethylmuramyl-L-alanyl-D-isoglutamine containing 0.77 mol of water in 10 ml of absolute Ν, Ν-dimethylformamide is added 268 mg at room temperature with stirring. 1.3 mmol) N, N-dicyclohexylcarbodiimide and 207 mg (1.3 mmol) of 1-hydroxybenzotriazole. After 2 hours, the thus obtained colorless suspension is added successively with 269 mg of (1, OmMoI) L-alanine-benzoyioxymethyl ester hydrochloride and 110 .mu.l (1, OmMoI) N-methylmorpholine and then stirred further at room temperature. After 22 hours, is filtered off from the precipitated N, N-dicyclohexylurea and the filtrate was evaporated under high vacuum at 3O ⁰ C. The thus obtained, slightly yellow-colored residue (foam) is suspended in 25 ml of ethyl acetate and this suspension is stirred for 1 hour at room temperature. The crude product obtained as colorless crystals is further purified by column chromatography on 150 g of silica gel (type 60, very pure, Merck, 0.063-0.2 mm) in the system chloroform-methanol-water (70: 30: 5) (5 ml fractions). Fractions 25-35 are combined and evaporated under high vacuum. Almost pure N-propionyl-desmethylmuramyl-L-alanyl-D-isoglutaminyl-L-alanine-benzoyioxymethylester (α, / 3 mixture) is obtained as a colorless foam, which still contains traces of N-methylmorpholine hydrochloride and processed without further purification becomes; 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: 1.95 g (2.18 mmol) of N-acetyl-muramyl-L-aylyl-D-isoglutaminyl-L-1-C 1 H 4 -benzyloxycarbonylamino-ethyl] -sulfonylmethyl) -glycine-benzyl ester are dissolved in 40 ml of abs. Pyridine and peracetylated with 30 times the molar amount of acetic anhydride (30 hours, RT). The gelatinous mass is brought into solution with a little water, the whole on a rotary evaporator in a high vacuum at 30 ^c C concentrated to a small volume and after addition of abs. Dioxane lyophilized. The crude product is chromatographed on silica gel (particle size 0.04-0.063 mm) first with chloroform, then with chloroform-methanol, mixtures (98: 2 to 1: 1 ') of a flash chromatography (145: 1; 25 ml fractions; 5 bar). The fractions containing the product are collected, dissolved in 90% dioxane (80 ml) and lyophilized after sterile filtration (0.2 / xm; PTFE). N-acetyl-1,4,6-tri-O-acetyl-muramyl-L-alanyl-D-isoglutaminyl-L- (C ") - ([2-benzyloxycarbonylaminoethyl-sulfonyl-methyl-glycine-benzyl ester (α , / 3 mixture) containing as a pale yellowish powder, 1.27 mole of water: [a] = +36.6 ± 1 ° § ⁰ C (c = 1.030; dimethylformamide), - r

Rf = 0.15 (chloroform: methanol: water = 70: 30: 5), Rf = 0.53 (n-butanol: acetic acid: water = 75: 7.5: 21),

R _f = 0.61 (acetonitrile: water = 3: 1). · ',

The starting material is obtained as follows:

Step 29.1: To a solution of 8.50 g (2OmMoI) N ^ benzyloxycarbonyl-L-thialysine benzyl ester hydrochloride are added dropwise within 30 minutes at RT with stirring 21.5 g (10QmMoI) of a 31.4% hydrogen peroxide solution. To . 30 hours of stirring to decompose excess peroxide 1.5 g of palladium (5%) are entered, with a strong gas evolution occurs. After stirring for 3 hours the catalyst is removed and the reaction solution is evaporated on a rotary evaporator at 30 ^c C to dryness. The oily residue is dissolved in 11 ml of acetone and brought to crystallization by addition of 20mi diethyl ether. Recrystallization from the same mixture gives Ν ^ε- benzyloxycarbonyl-L-thialysine-S-dioxide benzyl ester hydrochloride in the form of colorless needles; Mp 141-142 ^C C (Zers.); . Mp of the p-toluenesulfonate 130-134 ⁰ C (dec.); R _f = 0.50 (chloroform: methanol: water = 70: 30: 5), R _f = 0.89 (methyl ethyl ketone: pyridine: water = 65: 5: 20), R _f = 0.71 (n-butanol: glacial acetic acid : Water = 3: 1: 1). ,

Step 29.2: 2.95 g (6 mmol) of N-acetyl-murarnyl-L-alanyl-D-isoglutamine and 2.74 g (6 mmol) of N ^E -benzyloxycarbonyl-L-thialysine S, S-dioxide benzyl ester hydrochloride are as described customary (see step 30.1) by the Dicyclohexylcarbodiimid-i-hydroxy-benzotriazole method linked together. After a total of 51 hours of stirring at RT, the reddish suspension is mixed with 200 ml of ethyl acetate, after 1 hour of stirring, the insoluble matter is filtered off and the filtrate is evaporated to dryness in a high vacuum at 30 ° C. The residue is treated with 100 ml of ethyl acetate and water and stirred for one hour. The gelatinous material is filtered off, dried and then distributed between each 80 ml upper and lower phase of mutually saturated n-butanol-water (1: 1). After stirring for one hour, the insoluble material is filtered off with suction, washed and dried. This gives N-acetyl-muramyl-L-alanyl-D-isoglutaminyl-L (C ^oi ) - ([2-benzytoxycarbonylamino-ethyl] -sulfonylmethyl) -glycine-benzyl ester (α, / 3 mixture) in the form of a white Powder, containing 1.63 moles of water;

Rf = 0.60 (chloroform: methanol: water = 70: 30: 5),

R _f = 0.83 (acetonitrile: water = 3: 1). '. "_

Example 30: 1.50 g (2.24 mmol) of N-acetyl-muramyl-L-alanyl-D-isoglutaminyl-L-serine-benzyl ester are dissolved in 40 ml abs. Pyridine and peracetylated with 40 times the molar amount of acetic anhydride. The gelatinous material obtained after stirring for 24 hours at RT is brought into solution by addition of 5 ml of water, the whole on a rotary evaporator under high vacuum (30 ⁰ C) concentrated to about 5 ml, treated with double-distilled water and lyophilized. The crude product is taken up in 50 ml of warm ethyl acetate and precipitated by the addition of five volumes of diethyl ether (2X). The precipitate is dissolved in chloroform-methanol (1: 1), sterile filtered {0.2 ^ m, PTFE), after evaporation of the solvent in abs. Dioxane taken up and freeze-dried. N-acetyl-1 Ae-O-triacetyl-muramyl-L-alanyl-D-isoglutaminyl-L-O-acetyl-serine-benzyl ester hydrate is obtained as a colorless powder; [a] § ° = +26.5 ± 0.9 ° C (c = 1.096, 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 = 75: 7, 5:21)

 The starting material is obtained as follows:

Step 30.1: 5.00 g (10.15 mmol) of N-acetyl-muramyl-L-alanyl-D-isoglutamine, 2.00 g (13.2 mmol) of 1-hydroxybenzotriazole (containing 12% water) 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 RT, the reddish suspension is mixed with 100 ml of ethyl acetate and stirred for one hour. The insoluble dicyclohexylurea is filtered off and the filtrate is evaporated in a high vacuum on a rotary evaporator at 30 ° C. The resulting yellow oil is purified on silica gel (60: 1, 15 ml fractions) in the system chloroform: methanol: water = 70: 30: 5. The pure fractions containing the product are collected and, after evaporation of the solvent from tert-butanol-water (9: 1), lyophilized. This gives N-acetyl-muramyl-L-alanyl-D-isoglutaminyl-L-serine-benzyl ester (α, / 3 mixture) as a colorless powder, containing 1.87 moles of water; W§46nm = +12.4 ± 1 ⁰ C (c = 0.978; water), Rf = 0.41 (chloroform: methanol: water = 70: 30: 5),

Rf = 0.59 (ethyl acetate: n-butanol: pyridine: acetic acid: water = 42: 21: 21: 6: 10).

Example 31: 0.36 g (0.535 mmol) of N-acetyl-muramyl-LN-methyl-alanyl-D-isoglutamine-benzhydryl ester (α, / 3 mixture) are dissolved in 4 ml of abs. Pyridine dissolved and after addition of 0.15 ml (16 mmol) of acetic anhydride for three hours at RT allowed to stand. The yellowish solution is evaporated at 30 ⁰ C under high vacuum, taken up in 10 ml of water and lyophilized. The crude product is purified by chromatography on silica gel (1: 180) in the system chloroform-isopropanol (9: 1) (0.8 ml fractions). The uniform fractions are collected and from abs. Dioxane lyophilized. This gives N-acetyl-i ^^ - tri-O-acetyl-muramyl-LN-methyl-alanyl-D-isoglutamine-benzhydryl ester (α, / 3 mixture) as a colorless powder; Rf = 0.61 (n-butanol: acetic acid: water = 75: 7.5: 21), Rf = 0.20 (chloroforil-1-chloro-acetic acid = 70: 8: 2).

The starting material is obtained as follows:

Step 31.1: 0.50 g (0.99 mmol) of N-acetyl-muramyl-L-N-methyl-alanyl-D-isoglutamine (α, / 3 mixture) dissolved in methanol are esterified with excess diphenyldiazomethane. After standing for two hours, it is evaporated to dryness and the residue triturated several times with petroleum ether. It is suctioned off, the residue is taken up in a little methanol and the material precipitates with ten times the amount of diethyl ether: petroleum ether (1: 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: 0.50 g (0.99 mmol) of N-acetyl-muramyl-α-aminoisobutyryl-D-isoglutamine (α, / 3 mixture) are esterified analogously to step 31.1 with diphenyldiazomethane. The crude product (R _f = 0.48 [chloroform: methanol: water = 70: 30: 5]) is peracetylated analogously to Example 31. The reaction solution is evaporated to dryness in vacuo, taken up in water and lyophilized. Purification on silica gel (1: 100) in chloroform-methanol (9: 1.1 ml fractions). The pure fractions are combined, taken up in 5 ml of chloroform, filtered (PTFE, 0,2μηι) and then evaporated to dryness. The residue is in abs. Dioxane taken and lyophilized. This gives N-acetyl-i ^^ - tri-O-acetyl-muramyl-a-aminoisobutyryl-D-isoglutaminbenzhydrylester (α, / 3 mixture) as a colorless powder, containing 0.73 mol of water; [a] g ° = + 45.7 ± 1 ° C (c = 0.993, methanol),

Rf = 0.80 (chloroform: methanol: water = 70: 30: 5),

Rf = 0.32 (chloroform: methanol = 9: 1),

Rf = 0.50 (n-butanol: acetic acid: water = 75: 7, 5:21).

Example 33: 33 mg of N-acetyl-desmethylmuramyl-L-alanyi-Dy-methoxycarbonyl-isoglutamine-benzhydryl ester (α, / 3 mixture) are peracetylated analogously to Example 31. After lyophilization from abs. Dioxane remains N-acetyl-i ^^ - tri-O-acetyldesmethylmuramyl-L-alanyl-Dy-methoxycarbonyl-isoglutamin-benzhydryl ester (α, / 3 mixture) as a colorless powder; R _f = 0.67 (chloroform: methanol: water = 70: 30: 5),

Rf = 0.35 (n-butanol: acetic acid: water = 75: 7, 5:21).

The starting material is obtained as follows:

Step 33.1: 0.216 g (0.40 mmol) of N-acetyl-demethylmuramyl-L-alanyl-D-y-carboxy-isoglutamine (α, / 3 mixture) are esterified analogously to step 31.1 with diphenyldiazomethane (3 equivalents). The light reddish suspension is filtered after three hours of stirring and the filtrate evaporated to dryness. The mixture, consisting of educt, mono- and Dibenzhydrylester and decomposition products derived from the diphenyldiazomethane is separated by chromatography on silica gel (1: 100) in the system chloroform-methanol-water (70: 30: 5). After two chromatographs obtained N-Acetyldesmethylmuramyl-L-alanyl-D-y-benzhydryloxycarbonyl-isoglutamin-benzydryl ester (α, / 3 mixture) as a colorless resin with the

RF values. '

Rf = 0.67 (chloroform: methanol: water = 70: 30: 5) and

Rf = 0.46 (n-butanol: acetic acid: water = 75; 7.5: 21)

and N-acetyl-demethylmuramyl-L-alanyl-D-isoglutamine-benzhydryl ester of Rr value Rf = 0.13 (chloroform: methanol: water = 70: 30: 5).

Step 33.2: N-acetyl-demethylmuramyl-L-alanyl-D-isoglutamine-benzhydryl ester is esterified in methanolic solution as usual with a solution of diazomethane in diethyl ether. After evaporation, N-acetyl-desmethylmuramyl-L-alanyl-D-y-methoxycarbonyl-isoglutamine-benzhydryl ester (α, / 3 mixture) remains as a colorless resin; Rf = 0.56 (chloroform: methanol: water = 70: 30: 5).

Example 34: 1.70 g (2.53 mmol) of N-acetyl-muramyl-La-aminobutyryl-D-isoglutamine-benzhydryl ester (α, / 3 mixture), dissolved in 25 ml of abs. Pyridine are perpropionylated analogously to Example 31 (90 equivalents of anhydride). After three hours of standing at RT, 30 ml of water are added and the whole evaporated in the HV at 30 ⁰ C to dryness. The resinous residue is abs. In 80 ml. Dioxane taken, filtered (PTFE, 0.2 μίτι) and lyophilized. This gives N-acetyl-IAe-tri-O-propionyl-muramyl-La-aminobutyryl-D-isogiutamine-benzydryl ester (α, / 3 mixture) as a colorless powder, containing 0.79 mol of water; [a] § ° = + 52.2 ± .3.7 ⁰ C (c = 0.270, methanol),

Rf = 0.67 (acetonitrile: water = 3: 1),

Rf = 0.32 (chloroform-m propanoacetic acid = 70: 8: 2),

Rf = 0.87 (ethyl acetate: n-butanol: pyridine: acetic acid: water = 42: 21: 21: 6: 10).

The starting material is contained as follows:

Stage 34.1: 2.03 g (4 mmol) of N-acetyl-muramyl-L-α-aminobutyryl-D-isoglutamine (α, / 3 mixture) are converted into the benzhydryl ester analogously to stage 31.1. After the usual workup remains N-acetyl-muramyl-L-a-aminobutyryl-D-isoglutaminbenzhydrylester (α, / 3 mixture) as a colorless powder;

[a] g ⁰ = +41.8 ± 1.8 ⁰ C (c = 0.548, methanol), "

Rf = 0.73 (chloroform: methanol: water = 70: 30: 5),

Rf = 0.78 (acetonitrile: water = 3: 1).

EXAMPLE 35 Analogously to Example 1, 2.0 g (2.94 mmol) of N-propionyl-dem-methylmuramyl-L-alanyl-D-isoglutamine-benzhydryl ester (α, / 3 mixture) containing 1.17 mol of water are dissolved in 20 ml absolute pyridine with 1.68 ml (13.06 mmol) propionic anhydride (purissimum; d = 1.012) 1,4,6-tri-O-propionyl-N-propionyl-desmethylmuramyl-L-alanyl-D-isoglutamine-benzhydryl ester (α, / 3-mixture) as a colorless lyophilisate, which still contains 0.68 mol of water; Mp 156-157 ° C,

[a] § ° = +39.0 ± 2.1 ⁰ C (c = 0.467, methanol),

R, = 0.40 (chloroform: ethanol = 9: 1),

Rf = 0.48 (chloroform: methanol = 9: 1),

Rf = 0.88 (chloroform: methanol = 4: 1).

Example 36: Analogously to Example 1, from 2.0 g (3.1 mmol) of N-propionyl-desmethylmuramyl-L-alanyl-D-glutamic acid (C _a) -nbutylester- (C ,,) - benzyl ester (principally a- Anomeres), which still contains 0.41 mol of water, in 20 ml of absolute pyridine with 1.14 ml (12, OmMoI) acetic anhydride, 1-tri-O-acetyl-N-propionyl-desmethylmuramyl-L-alanyl-D-glutamic acid -tCo.l-n-butyl ester (C _y ) benzyl ester as a colorless Lyophiiisat, which still contains 0.73 mol of water. According to the ^ -NMR spectrum (360 MHz), the compound is present almost exclusively in the form of the α-anomer;

"Mp" 62-64 ° C,

[a] g ° = + 36.4 ± 3.6 ° C (c = 0.280, methanol),

Rf = 0.43 (chloroform: methanol = 9: 1),

Rf = 0.55 (chloroform: ethanol = 9: 1),

Rf = 0.85 (chloroform! Methanol = 4: 1). '·

EXAMPLE 37 Analogously to Example 1, 0.57 g (0.83 mmol) of N-propionyl-demethylmuramyl-L-alanyl-D-glutamic acid dibenzyl ester (α, / 3 mixture) containing 0.89 mol of water are obtained in 8 ml of absolute Pyridine with 0.36 ml (3.807 mmol) acetic anhydride 1,4,6-tri-O-acetyl-N-propionyl-demethylmuramyl-L-alanyl-D-glutamic acid dibenzyl ester {α, / 3 mixture) in the form of colorless crystals ;

Mp 141-142 ⁰ C (from chloroform: diethyl ether = 1:10).,

[a] § ° = + 22,7 ± 2,2 ° C (c = 0,454, methylene chloride),

Rf = 0.42 (chloroform: methanol = 9: 1),

Rf = 0.46 (chloroform: ethanol - 9: 1),

Rf = 0.70 (chloroform: methanol = 4: 1).

The starting material is obtained as follows:

Step 37.1: 0.74 g (1.95 mmol) of 4,6-0,0-isopropylidene-N-propionyl-desmethylmuramic acid, sodium salt are suspended in 20 ml of N, N-dimethylformamide, followed by 0.342 g (2.145 mmol) of 1-hydroxybenzotriazole , 0.42 g (2.14 SmMoI) of N, N-dicyclohexylcarbodiimide and 0.85 g (1.95 mmol) of L-alanyl-D-glutamic acid dibenzyl ester hydrochloride were added and the whole was stirred at room temperature overnight. The mixture is then filtered off from precipitated Ν, Ν-dicyclohexylurea and the resulting filtrate is evaporated to dryness under high vacuum at 30 ° C. The residue is taken up in 150 ml of ethyl acetate and washed successively with 50 ml each of saturated sodium bicarbonate solution, 2N citric acid, saturated sodium bicarbonate solution and water. The organic phases are combined, dried over sodium sulphate and evaporated at 30 ^° C. in a high vacuum. There is obtained 4,6-0,0-isopropylidene-N-propionyl-demethylmuramyl-L-alanyl-D-glutamic acid dibenzyl ester (α, / 3 mixture) containing some N-propionyl-desmethylmuramyl-L-alanyl-D- glutamic acid dibenzyl ester (α, / 3 mixture) and Ν, Ν-dicyclohexylurea and is processed without further purification.

Step 37.2: 3.3 g of crude 4,6-0,0-isopropylidene-N-propionyl-demethylmuramyl-L-alanyl-D-glutamic acid dibenzyl ester ( α, β mixture) are left in 30 ml of 50% acetic acid overnight , The solution thus obtained Wirde then filtered and the filtrate evaporated under high vacuum at 3O ⁰ C. The residue is purified by column chromatography on 150 g silica gel (type 60, very pure, Merck, 0.063-0.2 mm) in the system chloroform-ethanol (9: 1, 10 ml fractions). Fractions 56-95 are combined and evaporated under high vacuum. The residue is then dissolved in 80 ml of methanol and the resulting, slightly cloudy solution through a Millipore filter (Fluoropore, PTFE, 0.2 ^ m) filtered. The clear filtrate is evaporated in vacuo at 40 ° C. The residue is then dissolved in 10 ml of absolute methanol, previously filtered through Millipore filter (Fluoropore, PTFE, 0.2 ^ m) and crystallized by addition of 100 ml of absolute diethyl ether which has also been filtered through a Millipore filter and washed with filtered, absolute diethyl ether. This gives N-propionyl-desmethylmuramyl-L-alanyl-D-glutamic acid dibenzyl ester (α, / 3 mixture) in the form of colorless crystals containing 0.89 mol of water; M.p. 146-147 ⁰ C,

[ _a ] 2 ° = 14.6 + 2.1 ° C (c = 0.478, methanol),

Rf = 0.20 (chloroform: methanol = 9: 1),

Rf = 0.65 (chloroform: Me. "1: 1),

Rf = 0.81 (ChlorofomrMethano, - /: 3).

Example 38 Analogously to Example 1, pyridine and acetic anhydride are prepared from N-benzoyl-dem-methylmuramyl-L-alanyl-D-glutamic acid dicholinester dichloride, lAe-tri-O-acetyl-N-benzoyl-desmethylmuramyl-L-alanyl-D glutaminsäuredicholinester dichloride.

The starting material is obtained as follows:

Stage 38.1: Analogously to Synthesis 1982,138, D-glutamic acid dimethyl ester hydrochloride and oversaturated choline chloride are obtained with titanium tetraethyl ester as catalyst in acetonitrile at 80 ° C. D-glutamic acid-dicholinester-

dichloride hydrochloride. '·

Step 38.2: Analogously to Step 6.3, N-benzoyl-dem-methylmuramyl-L-alanyl-D-glutamic acid dichloro-dichloride dichloride is obtained from N-benzoyl-demethylmuramyl-L-alanine and D-glutamic acid-dichloroyl chloride dichloride with dicyclohexylcarbodiimide.

Example 39 Analogously to Example 1, N-benzoyl-dem-methylmuramyl-L-alanyl-D-isoglutamine-benzhydryl ester is obtained with n-hexanoyl chloride, pyridine and 4-dimethylaminopyridine-N-benzoyl-1,4,6-tri-O n-hexanoyl-L-alanyl-D-isoglutaminbenzhydrylester.

Claims (26)

Invention claim: wherein the hexose part is derived from D-glucose, D-mannose, or D-galactose, η is O or 1, and R ¹ , R ⁴ and R ^{6 are} independently lower alkanoyl or benzoyl, R ^{2 is} lower alkyl or phenyl, R ³ , R ⁵ and R ⁷ independently of one another are hydrogen or lower alkyl, or R ⁵ with R ⁸ together are trimethylene and R ^{7 is} hydrogen, R ^{8 is} hydrogen or lower-alkyl which is unsubstituted or substituted by phenyl, hydroxyl, mercapto or lower alkylthio, R ⁹ and R ¹² independently of one another, amino, C ₁ -I ₀ -alkoxy, aryl-lower alkoxy, Alkanoyloxyniederalkoxy with up to 16 C atoms, Aroyloxyniederalkoxy, 3-cholesteryloxy or 2-trimethylammonio-ethyloxy, R ¹⁰ is hydrogen; Carboxy, lower alkoxycarbonyl or aryl-lower alkoxycarbonyl, and R ^{11 is} hydrogen or unsubstituted or substituted by amino, hydroxy, lower alkanoylamino, lower alkanoyloxy, 2-benzyloxycarbonylaminoethylsulfinyl, 2-lower alkoxycarbonylaminoethylsulfinyl, 2-loweralkoxycarbonylaminoethylsulfonyl, 2-loweralkoxycarbonylaminoethyl -sulfonyl or guanidino substituted lower alkyl, with the proviso that at least one of R ⁹ and R ¹² of hydroxy, amino and Ci_ ₇ alkoxy or R ¹⁰ of hydrogen, carboxy and alkoxycarbonyl having up to 7 carbon atoms in the alkoxy different and salts of such compounds having at least one salt-forming group, characterized in that
a) a compound of formula II (ID 12 wherein at least one of R ^1a , R ^2a , R ^4a and R ^{6a is} hydrogen and the remaining of these radicals have the meanings of R ¹ , the group R ² -C (= O) -, R ⁴ and R ⁶ , and the remaining substituents have the meanings given above, wherein in a compound of formula II existing free functional groups, except for the groups which are to participate in the reaction, if necessary, are protected by readily cleavable protecting groups, with a R ^{1 to be introduced} , R ² -C (= O) -, R ^{Reacting 4} or R ⁶ transferring acylating agents and cleaves existing protecting groups if necessary, or
b) a compound of the formula III, • CH ₂ OR ⁶ (HD ί 11 '2 NH-C-R wherein the substituents have the abovementioned meanings, or a reactive derivative thereof with a compound of the formula IV, O
-CH- C-Ν-C-C-NH- Ri o H-CH ζ -CH-C (D) ö (L) NH- CH-C R ¹²
η wherein X is a reactive esterified hydroxy group, and the remaining substituents have the abovementioned meanings, which are protected in a compound of formula IV free functional groups except for X if necessary protected by readily cleavable protecting groups, reacting and deprotecting existing protecting groups, or ". c) a compound of the formula V, CH ₂ OR ⁶
-O. 'NH-CR? I ⁵ A ⁸ (L) R? , 0 γ a » NH-CH-CH ₂ -CH-g- (D) R ¹¹ NH-CH-C-O OH wherein q, r, s and t are independently O or 1 and wherein the substituents have the abovementioned meanings, wherein in a compound of the formula V existing free functional groups except the group to participate in the reaction, if necessary, by light cleavable protecting groups are protected, or a reactive carboxylic acid derivative thereof with a compound of formula Vl, V ^ pie T T NH-CH-CH ₂ -CH-g-}. (D) NH-CH-C _R 12 wherein u, ν and χ are each independentlyO or 1 and the remaining symbols and substituents have the abovementioned meanings, wherein in a compound of formula Vl existing free functional groups except the group to participate in the reaction, if necessary protected by readily cleavable protecting groups where u, ν and χ are 1 when in the reactant of the formula Vq and t are O, or u are O and ν andfused with each other when andf andO and x are 1, when q is 1 and iso or iso or (for the preparation of compounds of formula I, wherein η is 1) u and χ are O when q, r, s and t are 1, or reacting with a reactive derivative thereof and releasing protective groups present if necessary, or d) for the preparation of a compound of the formula I in which R ^{9 has} one of the abovementioned meanings other than hydroxy and amino and / or R ^{10 is} lower alkoxycarbonyl or aryl-lower alkoxycarbonyl and the other substituents have the abovementioned meanings, a compound of the formula VII CH ₂ OR ⁶ (VII) 13 10 f-C-C-NH-CH-T-CH ₂ -CH-C- (D) 1 1 NH-CH-C R ¹² η wherein at least one of R ^10a and R ^{13 is} carboxy and the other of R ^10a and R ^{13 has} the abovementioned meaning of R ¹⁰ or of the group R ⁹ -C (= O) -hat, and in which the other substituents have the abovementioned meanings, wherein free functional groups present in a compound of the formula VII, except the groups which are to participate in the reaction, are protected, if necessary, by readily cleavable protective groups, or esterifying a reactive carboxylic acid derivative thereof and eliminating protective groups present if necessary, or e) in a compound of formula I wherein at least one of R ⁸ , C f = O) -R ⁹ , R ¹⁰ , R ¹¹ and C f = O) -R ^{12 is} in a protected form other than the definition of the desired Endstoffes corresponding, the corresponding (n) protective group (s) splits off, or f) for preparing a compound of the formula I in which R ^{9 is} amino and the other substituents have the abovementioned meanings, a compound of the formula VIII (VIII) f S Γ : Ij-C-C-NH-CH- ϊ ¹⁰ CH ₂ -CH (D) -C- R ¹¹ NH-CH-C- ö R ^lz wherein the radical R ^{14 is} carboxy and the other substituents have the abovementioned meanings, wherein in a compound of formula VIII existing free functional groups, except for the groups which are to participate in the reaction, if necessary protected by readily cleavable protecting groups, or reactive carboxylic acid derivative thereof and eliminating protective groups present if necessary, and, if desired, after carrying out one of the processes af) converting a compound of formula I obtained having at least one salt-containing group into its salt or a salt of a compound of formula I obtained in the free compound converts, and / or a mixture of isomers obtained separates. , Process according to item 1, characterized in that the starting materials are chosen such that a compound of the formula I in which the hexose part is derived from D-glucose, D-mannose or D-galactose, η is O or 1, and R ¹ , R ⁴ and R ^{6 are} independently lower alkanoyl or benzoyl, R ^{2 is} lower alkyl or phenyl, R ³ , R ⁵ and R ^{7 are} independently hydrogen or lower alkyl, or R ⁵ with R ⁸ together trimethylene and R ^{7 is} hydrogen, R ^{8 is} hydrogen or unsubstituted or substituted by phenyl, hydroxy, mercapto, or lower alkylthio lower alkyl, R ⁹ and R ¹² independently of one another hydroxy, amino, C ₁ -I ₀ -alkoxy, aryl-lower alkoxy, alkanoyl-lower alkoxy having up to 16 C-atoms, Aroyloxyniederalkoxy or 3-cholesteryloxy, R R ^{10 is} hydrogen, carboxy, lower alkoxycarbonyl or aryl-lower alkoxycarbonyl, and R ^{11 is} hydrogen or lower alkyl unsubstituted or substituted by amino or hydroxy, with the proviso that at least one of the radicals e R ⁹ and R ^{12 are} different from hydroxy, amino and lower alkoxy or R ^{10 is} hydrogen, carboxy or lower alkoxycarbonyl, or a salt of such a compound is prepared with at least one salt-forming group. 3. The method according to item 1 or 2, characterized in that the starting materials are selected so that a compound of formula I, wherein R ⁹ and R ^{12 are} independently hydroxy, amino, Ci_i ₀ -alkoxy, Alkanoyioxyniederalkoxy with up to 16 C -Atomen, 3-cholesteryloxy or in the phenyl moiety each unsubstituted or by lower alkyl, phenyl, halogen, hydroxy, lower alkoxy, lower alkanoyloxy, amino, mono- or di-lower alkylamino or lower alkanoylamino substituted phenyl or benzoyloxy-lower alkoxy, and R ^{10 is} hydrogen, carboxy, lower alkoxycarbonyl or phenyl-lower alkoxycarbonyl unsubstituted or substituted by lower alkyl, phenyl, halogen, hydroxy, lower alkoxy, lower alkanoyloxy, amino, mono- or di-lower alkylamino or lower alkanoylamino, and the other substituents have the abovementioned meanings, with the proviso that at least one of the radicals R ⁹ and R ^{12 is} hydroxy, amino, and lower alkoxy or R ^{10 is} hydrogen, Ca Rboxy and Niederalkoxycarbonyl is different, or produces a salt of such a compound having at least one salt-forming group. 4. The method according to item!, Characterized in that one selects the starting materials so that a compound of formula I, wherein the hexose part of D-glucose or D-mannose derived, η is 0 or 1, R ¹ , R ⁴ and R ⁶ independently of one another are C ₂ -4-alkanoyl or benzoyl, R ^{2 is} C 1-4 -alkyl or phenyl, R ³ , R ⁵ and R ⁷ are each independently of the other hydrogen or methyl or R ^{5 is taken} together with trimethylene and R ⁸ R ^{7 is} hydrogen, R ^{8 is} hydrogen, C ^ -alky! or Ci_ ₂ alkyl substituted by phenyl, hydroxy, mercapto or methylthio, R ⁹ and R ^{12 are} independently hydroxy, amino, lower alkoxy, phenyl-lower alkoxy, lower alkanoyloxy-lower alkoxy, benzyloxy-lower alkoxy or 3-cholesteryloxy, R ^{10 is} hydrogen, carboxy, lower alkoxycarbonyl or phenyl-lower alkoxycarbonyl and R ¹¹ Is hydrogen or unsubstituted or substituted by amino or hydroxy C _M alkyl, with the proviso that at least one of R ⁹ and R ¹² of hydroxy, amino and lower alkoxy or R ¹⁰ is different from hydrogen, carboxy and lower alkoxycarbonyl, or a salt such a compound with at least one salt-forming group produces. 5. The method according to item 1, characterized in that one selects the starting materials so that a compound of formula I, wherein the hexose part of D-glucose or D-mannose derived, η is 0 or 1, R ¹ , R ⁴ and R ⁶ independently of one another are C 2-4 -alkanoyl or benzoyl, R ^{2 is} C 1-4 -alkyl or phenyl, R ³ , R ⁵ and R ⁷ are each independently hydrogen or methyl, R ^{8 is} C 1-4 -alkyl, R ⁹ and R ^{12 are} independently of one another Hydroxy, amino, Ci_4-alkoxy, phenylmethoxy, lower alkanoyloxymethoxy, benzoyloxymethoxy or 3-cholesteryloxy, R ^{10 is} hydrogen, carboxy, alkoxycarbonyl having up to 5 carbon atoms or phenylmethoxycarbonyl and R ^{11 is} C ^ -alkyl, with the proviso that at least one R ⁹ and R ¹² of hydroxy, amino and C 1-4 alkoxy or R ^{10 is} other than hydrogen, carboxy and alkoxycarbonyl, or a salt of such a compound having at least one salt-forming group. 6. The method according to item!, Characterized in that one selects the starting materials so that a compound of formula I, wherein the hexose part of D-glucose is derived, η is 0 or 1, R ¹ , R ⁴ and R ⁶ Acetyl or butyryl, R ^{2 is} C ¹ -, C ₂ -alkyl or phenyl, R ^{3 is} hydrogen or methyl, R ⁵ and R ^{7 are} hydrogen, R ^{8 is} C 1 -4 -alkyl, R ^{9 is} amino, C ₁ -alkoxy-pivaloyloxymethoxy or mono- or diphenylmethoxy, R ^{10 is} hydrogen, R ^{11 is} methyl and R ^{12 is} mono- or diphenylmethoxy or 3-cholesteryloxy. 7. The method according to item 1, characterized in that one selects the Ausgangsstofeseso that one obtains a compound of formula I, wherein the hexose part of D-glucose is derived, η is O or 1, R ¹ , R ⁴ and R ⁶ C ₂ -e-alkanoyl, R ² C ^ -alkyl or phenyl, R ³ , R ^s and R ^{7 are} independently hydrogen or methyl, R ⁸ Ci_4-alkyl, R ^{9 is} amino, lower alkoxy, pivaloyloxymethoxy, diphenylmethoxy, benzyloxy or 2-trimethylammonio -ethoxy, R ^{10 is} hydrogen or lower alkoxycarbonyl, R ^{11 is} C 1-4 -alkyl, lower alkanoyloxymethyl, or (2-benzyloxy-carbonylamino-ethyl) -sulfonyl-methyl and R ^{12 is} amino, lower alkoxy, pivaloyloxymethoxy, diphenylmethoxy, benzyloxy, 2-trimethylammonio-ethoxy, 3-cholesteryloxy or benzoyloxymethoxy, with the proviso that at least one of R ⁹ and R ^{12 is} other than amino or lower alkoxy, or a salt of such a salt-forming compound. 8. The method according to item 1 or 7, characterized in that one selects the Ausgangsstofeseso that a compound of formula I, wherein at least one of R ⁹ and R ^{12 is} pivaloyloxymethoxy, diphenylmethoxy, benzyloxy, 2-trimethylammonio-ethoxy, 3rd -Cholesteryloxy or Benzoyloxymethoxy and the other of the radicals R ⁹ and R ^{12 has} the meaning mentioned, or produces a salt of such a salt-capable compound. 9. The method according to item!, Characterized in that one selects the starting materials so that one produces 1,4,6-tri-O-acetyl-N-propionyl-desmethylmuramyl-L-alanyl-D-isoglutamine-benzhydryl ester. 10. The method according to item 1, characterized in that one selects the Ausgangsstofeseso that one prepares 1,4,6-tri-O-acetyl-N-propionyl-desmethylmuramyl-L-alanyl-D-isoglutamine-benzyl ester. 11. The method according to item 1, characterized in that one selects the starting materials so that 1,4,6-tri-O-acetyl-N-propionyl-desmethylmuramyl-L-alanyl-D-glutamic acid iCJ-n-butyl ester -fC ^ -benzhydrylester manufactures. 12. The method according to item 1, characterized in that one selects the starting materials, so that N-acetyl-1,4,6-tri-O-acetylmuramyl-L-alanyl-D-glutamic acid ICJ pivaloyloxymethylester IC. produces yi-benzyl ester. 13. The method according to item 1, characterized in that one selects the Ausgangsstofeseso that one prepares 1,4,6-tri-O-acetyl-N-benzoyl-desmethylmuramyl-L-alanyl-D-isoglutamine-benzyl ester. 14. The method according to item 1, characterized in that the starting materials.so selected that one prepares 1,4,6-tri-O-acetyl-N-benzoyl-desmethylmuramyl-L-alanyl-D-isoglutamine-benzhydryl ester. 15. The method according to item 1, characterized in that one selects the Ausgangsstoffeso that one prepares N-benzoyl-1,4,6-tri-O-butyryl-desmethylmuramyl-L-alanyl-D-isoglutamine-benzhydryl ester. 16. The method according to item!, Characterized in that the starting materials are selected such that N-acetyl (1a, / 3), 4,6-tri-O-acetyl-desmethylmuramyl-L-aamJnobutyryl-D-isoglutamin- Benzhydrylester manufactures. Method according to item 10, characterized in that the starting materials are chosen such that N-acetyl- (1a, / 3), 4,6-tri-O-acetyl-demethylmuramyl-La-aminobutyryl-D-glutamic acid dibenzhydryl ester manufactures. 18. The method according to item 1, characterized in that one selects the starting materials so that N-acetyl (1 a, / 3), 4,6-tri-O-acetyl-desmethylmuramyl-L-valyl-D-isoglutamine Benzhydrylester manufactures. 19. The method according to item 1, characterized in that one selects the starting materials so that N-acetyl (1 a, / 3), 4,6-tri-O-acetyl-muramyl-L-analyl-D-isoglutaminyl -L-analine-cholesteryl-S-ester. 20. The method according to item 1, characterized in that one selects the starting materials so that one produces N-acetyl-1,4,6-tri-O-acetyl-muramyl-a-amino-isobutyryl-D-isoglutaminbenzhydrylester. 21. Procedure according to item 1; characterized in that the starting material is selected to produce N-acetyl-1,4,6-tri-O-acetyl-demethylmuramyl-L-analyl-D-y-methoxycarbonyl-isoglutamine-benzhydryl ester. 22. The method according to item 1, characterized in that the starting materials are selected so that N-acetyl-1,4,6-tri-O-acetyl-muramyl-L-analyl-D-isoglutaminyl-La - ([2 -benzyloxy-carbonylaminoethyl] sulfonylmethyl) glycine benzyl ester. 23. The method according to item 1, characterized in that one selects the Ausgangsstofeseso that one produces 1,4,6-tri-O-acetyl-N-benzoyl-desmethylmuramyl-L-analyl-D-glutamic acid Dicholinester. 24. The method according to item!, Characterized in that one selects the starting material so that N-propionyl-1,4,6-tri-O-propionyl-demmethylmuramyl-L-analyl-D-isoglutamine-benzhydryl ester is prepared. 25. A process according to item 1, characterized in that the starting material is selected such that 1,4,6-tri-O-acetyl-N-propionyl-demethylmuramyl-L-alanyl-D-glutamic acid-an-butyl ester-y- Benzylester manufactures. 26. The method according to item 1, characterized in that one selects the starting materials so that one produces 1,4,6-tri-O-acetyl-N-propionyl-desmethylmuramyl-L-alanyl-D-glutamic acid dibenzylester. 27. The method according to item 1, characterized in that the starting materials are selected so that one produces 1,4,6-tri-O-acetyl-N-benzoyl-desmethylmuramyl-L-alanyl-D-isoglutamine-benzyl ester. 28. The method according to item 1, characterized in that the starting material is selected so that one prepares 1,4,6-tri-O-acetyl-N-propionyl-desmethylmuramyl-L-alanyl-D-glutamic acid dipivaloyloxymethylester. 29. The method according to item 1, characterized in that one selects the starting materials so that 1,4,6-tri-O-acetyl-N-propionyl-desmethylmuramyl-L-alanyl-D-isoglutaminyl-L-alanine benzoyloxymethylester manufactures.