DE3641872A1 - Pyrazinylthiocarbapenems, processes for their preparation, and their use - Google Patents

Abstract

The invention relates to pyrazinylthiocarbapenems of the general formula (I) <IMAGE> in which R<1>, R<2>, R<3> and R<4> have the meaning indicated in the description, processes for their preparation, and their use as medicaments.

Description

The invention relates to pyrazinylthio-carbapenems, processes for their manufacture and their use as Drug.

It is known that thienamycin-type carbapenems [T. Kametani, Heterocycles 17, 463 (1982)] are notable for their good antibacterial activity, which for the most part also affects methicillin and oxacillin-resistant staphylococci [BG Christensen et al. in AG Brown & SM Roberts (eds), Recent Advances in the Chemistry of β- Lactem- Antibiotics, Royal Society of Chemistry, Special Publication No. 52, 86 (1985)]. However, compounds such as thienamycin and imipenem have antibacterial weaknesses against certain staphylococci and enterococci. In addition, many derivatives of these compounds as monosubstance are unstable to degradation by the peptidases of the kidney, especially dehydropeptidase (I) (DHP-I) [H. Krobb et al., Antimicrob. Agents., Chemother. 22, 62 (1982)]. This enzyme is responsible for the metabolic inactivation of carbapenems and for the formation of toxic metabolites.

Pzyrazinylthio-carbapenem antibiotics have been general Formula (I)

in which

R¹- for hydrogen or
- stands for a hydroxy protecting group, R²- for hydrogen or
- for a carboxy protecting group or
- represents an ester residue which can be split off in vivo, R³- represents hydrogen or
- stands for C₁-C₆-alkyl

and

R⁴- represents a group of the formula -OR⁵, -SO _m R⁵ or -NR⁶R⁷,

wherein

R⁵- C₃-C₈-cycloalkyl or trifluoromethyl means, or
- Straight-chain or branched C₁-C₁₀-alkyl means that by hydroxy, C₁-C Alk-alkoxy, C₁-C₄-alkylthio, carboxy, C₁-C₆-alkoxycarbonyl, cyano, halogen, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, amino, C₁-C₅ Alkylamino, di-C₁-C₅-alkylamino, C₁-C₆-alkylsulfonyl, C₆-C₁₂-arylsulfonyl, sulfamoyl, di-C₁-C₃-alkylaminosulfonyl, pyridyl, thienyl, furyl, pyrimidyl, pyrazinyl, pyridazinyl, quinolyl, quinolyl, isoquinolyl , Quinoxalyl, Benzthiazolyl, Benzoxazolyl or Benzimidazolyl may be substituted, or
- C₆-C₁₂-aryl, C₇-C₁₄-aralkyl or a heteroaryl radical from the series pyridyl, thienyl, furyl, pyrimidyl, pyridazinyl, pyrazinyl, quinolyl, isoquinolyl, quinazolyl, quinoxalyl, benzothiazolyl, benzoxazolyl or benzimidazolyl bis, where means the 4 times the same or different by halogen, cyano, nitro, C₁-C₆-alkyl, C₁-C₆-alkoxy, C₁-C₄-alkylthio, trifluoromethyl, trifluoromethoxy, -S (O) _m CF₃, amino, C₁-C₅-alkylamino, Di-C₁-C₅-alkylamino, C₁-C₆-alkylsulfonyl, C₆-C₁₂-arylsulfonyl, sulfamoyl or di-C₁-C₃-alkylaminosulfonyl may be substituted, m - represents a number 0, 1 or 2,

and

R⁶ and R⁷ are the same or different and

      - Hydrogen, optionally by trifluoromethyl are substituted C₁-C₁₂ alkyl, or C₆- C₁₂ aryl, C₇-C₁₄ aralkyl, C₁-C₇ acyl, C₁-C₄ alkylsulfonyl or C₆-C₁₂ arylsulfonyl,     

or in what

R⁶ and R⁷ together with the nitrogen atom form a ring of the formula

in which

m - stands for a number 0, 1 or 2, n - stands for a number 1 to 8,

R⁸ and R⁹ are the same or different and

      - for C₁-C₈-alkyl, C₁-C₄-hydroxyalkyl, carboxy, Carbamoyl or C₁-C₆ alkoxycarbonyl     

and

X- for hydrogen or
- represents C₁-C₆-alkyl, which may be substituted by phenyl, halogen or hydroxy, or
- represents C₆-C₁₂-aryl, which can be substituted up to 3 times the same or different by halogen, cyano, trifluoromethyl, trifluoromethoxy, C₁-C₆-alkyl, C₁-C₆-alkoxy, or
- represents C₁-C₆-alkylsulfonyl, C₆-C ₁₂ -aryl-sulfonyl, sulfamoyl or di-C₁-C₆-alkylaminosulfonyl, or
- for a group of the formula

wherein

R ¹⁰ , R ¹¹ , R ¹² and R ^{13 are the} same or different and are hydrogen, C₁-C₆-alkyl, C₆-C ₁₂ - aryl or C₇-C ₁₄ -aralkyl and their salts found.

Amino protective group in the context of the definition given above generally represents an amino protective group which is customary in β- lactam chemistry. Examples include: vinyl, allyl, tert. Butoxycarbonyl, benzyl, benzyloxycarbonyl, 2-nitrobenzyl, 4-nitrobenzyl, 2-nitrobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, formyl, benzoyl, acetyl, ethylcarbonyl, chloroacetyl, trichloroacetyl, trifluorocylylilylylylylylylylylethyllylylilylylilylyltrilyloxyylyltrylethyllylylilylyltryloxytrylyltrylyltrylyltrylylyltrylyltrylyltryloxytrylyltryloxytrylyltrylloxytryloxytryllyltrylloxylyltrylethyltryloxytryllyltrylloxylyltrylethyltryloxytrylyltrylethyltryloxytrylyltrylethyltrylethyltryloxytryloxytryloxytrylethyltryloxyethyl tert. Butyldimethylsilyl, methyldiphenylsilyl, 2,4-dimethoxybenzyl, 2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyl, phenyloxymethyl, 4- (methoxymethyloxy) phenyl, bis (4-methoxyphenyl) methyl, tert. Butoxycarbonylmethyl, allyloxycarbonylmethyl, methoxymethyl, methylthiomethyl, methoxyethoxymethyl, [2- (trimethylsilyl) ethoxy] methyl or 2- (methylthiomethoxy) ethoxycarbonyl.

Hydroxy protective group in the context of the definition given above generally represents a hydroxy protective group which is customary in β- lactam chemistry. Examples to be mentioned are: trimethylsilyl, triethylsilyl, triisopropylsilyl, tert. Butyldimethylsilyl, triphenylsilyl, trimethylsilylethoxycarbonyl, benzyl, benzyloxycarbonyl, 2-nitrobenzyl, 4-nitrobenzyl, 2-nitrobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, tert. Butyloxycarbonyl, allyloxycarbonyl, 4-methoxybenzyl, 4-methoxybenzyloxycarbonyl, formyl, acetyl, trichloroacetyl, 2,2,2-trichloroethoxycarbonyl, 2,4-dimethoxybenzyl, 2,4-dimethoxybenzyloxycarbonyl, methoxymethyl, methylthiomethyl, methoxymethyl, [2- (trimoxymethyl) ethoxy] methyl, 2- (methylthiomethoxy) ethoxycarbonyl, tetrahydrophenyl or benzoyl.

Carboxy protecting group in the context of the definition given above stands for the carboxy protecting group customary in β- lactam chemistry. Easily cleavable groups are preferred, for example: methyl, ethyl, tert. Butyl, decyl, 2-chloroethyl, 2,2,2-trichloroethyl, cyanoethyl, diphenylmethyl, triphenylmethyl, acetomethyl, allyl, benzyl, 4-methoxyphenyl, 4-nitrobenzyl, 2-nitrobenzyl, 4-methoxybenzyl, 2,4-dimethoxybenzyl, Trimethylsilylethyl, tert. Butyl-dimethyl-silylethyl, trimethylsilyl, acetonyl, 1-phenoxyethyl or 2-methyl-2-propenyl.

R² stands for an easily removable ester residue in vivo, thus are pharmaceutically acceptable ester residues  meant that the carbonyl groups easily free in vivo (R² = H) be hydrolyzed.

Such ester residues are well known in the β- lactam field. In most cases, they improve the absorption properties of the β- lactam compounds. In addition, the R² group should be of a type that imparts pharmaceutically acceptable properties to a compound of formula (I) and releases pharmaceutically acceptable fragments upon cleavage in vivo.

Examples of such groups can be found in DE-OS 25 17 316. Preferred ester groups which can be split off in vivo are those of the following formulas:

wherein

R ¹⁴ and R ^{15 are the} same or different and

- for hydrogen, phenyl or
- represent C₁-C₄-alkyl, preferably methyl,

R ¹⁶ and R ^{17 are the} same or different and

- for hydrogen or
- C₁-C₄-alkyl, preferably methyl

and

R ¹⁸ - stands for C₁-C₆-alkyl, preferably for C₁-C₄-alkyl.

Compounds of the general formula (I) are preferred

in which

R₁- represents hydrogen, or
- For a hydroxyl protective group from the series trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, triphenylsilyl, trimethylsilylethoxycarbonyl, benzyl, benzyloxycarbonyl, 2-nitrobenzyl, 4-nitrobenzyl, 2-nitrobenzyloxycarbonyl, 4- nitrobenzyloxycarbonyl. Butoxycarbonyl, allyloxycarbonyl, 4-methoxybenzyl, 4-methoxybenzyloxycarbonyl, formyl, acetyl, trichloroacetyl, 2,2,2-trichloroethoxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, methoxymethyl or methoxyethoxymethyl, R²- is hydrogen, or
- for methyl, ethyl, tert. Butyl, 2-chloroethyl, 2,2,2-trichloroethyl, cyanoethyl, diphenylmethyl, triphenylmethyl, acetoxymethyl, allyl, benzyl, 4-methoxybenzyl, 2,4-dimethoxybenzyl, 1-phenoxyethyl, 2-methyl-2-propenyl, 4- Nitrobenzyl, 2-nitrobenzyl, trimethylsilylethyl or tert. Butyl-dimethylsilylethyl stands, or
- for a remainder of the formula

R³- for hydrogen or
- represents C₁-C₃-alkyl,

and

R⁴- represents a group of the formula -OR⁵, -SO _m R⁵ or -NR⁶R⁷,

wherein

R⁵- C₃-C₇-cycloalkyl or trifluoromethyl means or
- Straight-chain or branched C₁-C₈-alkyl means that by hydroxy, C₁-C₄-alkoxy, trifluoromethyl, carboxy, C₁-C₄-alkoxycarbonyl, cyano, fluorine, chlorine, bromine, trifluromethyl, trifluoromethoxy, C₁-C₃-alkylamino, di -C₁-C₃-alkylamino, C₁-C₄-alkylsulfonyl, phenylsulfonyl, dimethylaminosulfonyl, pyridyl, thienyl, pyrimidyl, pyrazinyl, pyridazinyl, quinolyl or isoquinolyl, or may be substituted
- for phenyl, benzyl, phenethyl, pyridyl, thienyl, furyl, pyrimidyl, pyrazinyl, pyridazinyl, quinolyl or isoquinolyl, the radicals mentioned being up to 3 times the same or different by fluorine, chlorine, bromine, cyano, nitro, C₁-C₅- Alkyl, C₁-C₅-alkoxy, methylthio, trifluoromethyl, trifluoromethoxy, -S (O) _m CF₃, C₁-C₃-alkylamino, di-C₁-C₃-alkylamino, C₁-C₄-alkylsulfonyl, phenylsulfonyl or dimethylaminosulfonyl may be substituted, m - means a number 0, 1 or 2

and

R⁶ and R⁷ are the same or different and

- hydrogen or
- C₁-C ₁₂ alkyl optionally substituted by trifluoromethyl, or phenyl, benzyl, acetyl, methylsulfonyl or phenylsulfonyl

or in what

R⁶ and R⁷ together with the nitrogen atom Ring of the formula  

in which

m - stands for a number 0, 1 or 2, n - stands for a number 0 to 3,

R⁸ and R⁹ are the same or different and

      - for hydrogen, C₁-C₆ alkyl, hydroxymethyl, Hydroxyethyl, carboxy or C₁-C₄ alkoxycarbonyl are     

and

X- for hydrogen or
- C₁-C₅-alkyl, which may be substituted by phenyl, fluorine, chlorine, bromine or hydroxy or
- represents phenyl, which can be substituted up to 2 times the same or different by fluorine, chlorine, bromine, trifluoromethyl, C₁-C₄-alkyl or C₁-C₄-alkoxy, or
- represents C₁-C₄-alkylsulfonyl, phenylsulfonyl, sulfamoyl or di-C₁-C₄-alkylaminosulfonyl, or
- for a group of the formula

wherein

R ¹⁰ , R ¹¹ , R ¹² and R ^{13 are the} same or different and are hydrogen, C₁-C₄-alkyl, phenyl or benzyl

and their salts.

Such compounds are particularly preferred general formula (I)

in which

R¹- represents hydrogen, or
- For trimethylsilyl, triphenylsilyl, trimethylsilylethoxycarbonyl, tert. Butyl-dimethylsilyl, 2-nitrobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, allyloxycarbonyl or formyl, R²- is hydrogen, or
- for methyl, ethyl, tert. Butyl, 2,2,2-trichloroethyl, allyl, acetoxymethyl, 4-nitrobenzyl, 2-nitrobenzyl, 4-methoxybenzyl, benzyl or trimethylsilylethyl, or
- for a remainder of the formula

or -CH₂-OCO-C (CH₃) ₃,

R³- represents hydrogen or methyl

and

R⁴- represents a group of the formula -OR⁵, -SO _m R⁵ or -NR⁶R⁷,

wherein

R⁵- cyclopropyl, cyclopentyl, cyclohexyl or trifluoromethyl means, or
- Straight-chain or branched C₁-C₆ alkyl means, which can be substituted by methoxy, carboxy, methoxycarbonyl, ethoxycarbonyl, trifluoromethyl, dimethylamino, pyridyl or pyrimidyl, or
- Phenyl, benzyl, pyridyl, pyrimidyl or pyridazinyl means, where the radicals mentioned can be substituted up to 3 times the same or different by fluorine, chlorine, bromine, nitro, methyl, methoxy, trifluoromethyl, or -S (O) _m CF₃, m - means a number 0, 1 or 2

and

R⁶ and R⁷ are the same or different and

- hydrogen or
- C₁-C ₁₂ alkyl optionally substituted by trifluoromethyl,

or

R⁶ and R⁷ together with the nitrogen atom Ring of the formula

in which

m - stands for a number 0, 1 or 2, n - stands for a number 0 or 1, R⁵- stands for hydrogen or methyl, R⁶- stands for hydrogen, methyl, carboxy or ethoxycarboxyl,

and

X- represents hydrogen, C₁-C₄ alkyl or benzyl, or
represents phenyl which is optionally substituted by fluorine, or
- stands for sulfamoyl or dimethylaminosulfonyl, or
- for a group of the formula

wherein

R ¹⁰ , R ¹¹ , R ¹² and R ^{13 are the} same or different and are hydrogen or methyl

and their salts.

In addition to those according to the invention listed in the examples Connections are the following general connections Formula (I) and its salts are particularly preferred:

The compounds of the general formula according to the invention (I) can be used as free acids, as esters, as internal salts

or as non-toxic physiologically acceptable salts with a counter cation

are available.

Preferred counter cations are alkali or alkaline earth cations such as sodium, potassium, magnesium or calcium ions, or aluminum or ammonium ions, and non-toxic substituted ammonium ions from amines such as di-lower alkyl amines, tri-lower alkyl amines, procaine, dibenzylamine, N, N '-Dibenzylethylenediamine, N-benzyl- β- phenyl-ethylamine, N-methylmorpholine, 1-ephenamine, dihydrobiethylamine, N, N'-bis-dihydroabiethylenediamine, N-lower alkylpiperidine and other amines which are used to form salts of β - Lactam compounds can be used.

The compounds of the invention have several asymmetric carbon atoms and can thus in several stereochemical forms exist. The invention includes the mixtures of isomers as well as the individual Stereoisomers. Preferred compounds of formula (I) are those with 5R, 6S, 8S configuration:  

In addition, a method for producing the invention Pyrazinylthio carbaphenems of the general Found formula (I) and its salts, which is characterized in that one Keto esters of the general formula (II)

in which

R¹- has the meaning given

and

R ¹⁹ - for a carboxy protecting group or
- stands for an ester residue which can be split off in vivo

and

Thiols of the general formula (III)

in which

R³ and R⁴ have the meaning given above,
reacted with auxiliaries in inert solvents in the presence of bases,
splitting off protective groups if necessary
and optionally produces the desired salts or converts the salts into the free compounds.

If you use as starting materials (2R, 5R, 6S) -3,7-dioxo-6- [(1R) -1-hydroxyethyl] -1-azabicyclo [3,2,0] heptane-2-carboxylic acid - p-nitrobenzyl ester and 2-amino-5- (4-morpholinyl) -3- pyrazinthiol, the method can be described by the following Clarify scheme:

All organic solvents are suitable as solvents, that do not change under the reaction conditions. These preferably include ethers such as diethyl ether, Dioxane, tetrahydrofuran, glycol dimethyl ether or butyl methyl ether, or hydrocarbons such as benzene, toluene, Xylene, hexane or petroleum fractions, or halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, 1,1,2-trichloroethane, dichlorethylene or trichlorethylene, Chlorobenzene or dichlorobenzene, or amides such as dimethylformamide, Dimethylacetamide, hexamethylphosphoric triamide, 1,3-dimethyl-2-imidazolidinone (DMI), N, N'-dimethyl- propylene urea (DMPU), or acetone, ethyl acetate, Sulfolane, dimethyl sulfoxide or acetonitrile. Likewise it is possible to use mixtures of the solvents mentioned.

The usual organic bases are suitable as bases. These preferably include trialkylamines such as Trimethylamine, triethylamine, tripropylamine, tributylamine or ethyldiisopropylamine, or tertiary organic bases such as pyridine, dimethylaminopyridine, picoline, lutidine, N-methylmorpholine, N-methylpiperidine, 1,5-diazabicyclo [5,4,0] - undec-5-ene (DBU) or 1,5-diazabicyclo [4,3,0] non-3-ene [DBN).  

Substances are generally used as auxiliary substances, which the keto esters of general formula (II) in compounds of the general formula (IV)

in which

R¹ and R¹⁹ have the meaning given above

and

Y- for a leaving group from the series

prefers

stands, convict.

These preferably include acid halides or acid anhydrides of 4-toluenesulfonic acid, 4-bromophenylsulfonic acid, Trifluoromethanesulfonic acid, or diphenylchlorophosphate. Especially Diphenyl chlorophosphate is preferably used.  

The reaction can be carried out in one step without isolating the Intermediates are carried out. However, it has proved to be favorable, the intermediates of the general Isolate formula (IV).

The method is preferably carried out by the Intermediates in a suitable solvent with the corresponding thiol, optionally in the presence of Bases.

It is also possible to use the thiol (III) in the form of its salts use or the corresponding thiolate by adding of base in the reaction mixture.

The base is generally used in an amount of 1 to 3 mol, preferably from 1 to 1.5 mol based on 1 mol of Ketoester used. The thiol is generally in an amount of 1 to 4 mol, preferably of 1 to 2 mol based on 1 mol of the keto ester used. One creates the thiolate in the reaction solution becomes the thiolate further base in amounts of 1 to 5 mol, preferably of 1 up to 2 mol based on 1 mol of thiol.

The reaction is generally in a temperature range from -80 ° C to + 60 ° C, preferably from -50 ° C to + 40 ° C carried out. The reaction is generally carried out Normal pressure through. But it is also possible with negative pressure or to work at overpressure.

The keto esters used as starting materials of the general Formula (II) are known or can be according to known Methods are made [T. N. Salzmann et al., J. Am. Chem. Soc. 102: 6163 (1980)].  

The following aminopyrazinthiols are known:
2-amino-3-pyrazinthiol, 2-amino-5-bromo-3-pyrazinthiol, 2-amino-5-methyl-3-pyrazinthiol, 2-amino-5,6-dimethyl-3-pyrazinthiol, 2-amino- 5,6-diphenyl-3-pyrazinthiol and 2-amino-5-methoxy-3-pyrazinthiol [F. Chillemi et al., Pharmacol. Et. SCI, 18, 566 (1963); TS Safonora et al., Chem. Heterocycl. Compds, 6, 1019 (1970); G. Palamidessi et al., Gazz. Chem. Ital., 91, 1438 (1961); M. Hatori et al., Bull. Chem. Soc. Jpn. 46, 1890 (1973); LA Myschkina et al., Chem. Heterocycl. Compds. 6: 1028 (1970); TS Safonora et al., CA 78, 43417 (1973); Brit. Patent specification 958 626].

The 2-amino-3-pyrazinthiols used as starting materials of the general formula (IIIa)

in which

R⁴- represents a group of the formula -S (O) _m R⁵, -OR⁵ ′ or -NR⁶R⁷,

wherein

R⁵- C₃-C₈-cycloalkyl or trifluoromethyl means, or
- Straight-chain or branched C₁-C₁₀-alkyl means that by hydroxy, C₁-C Alk-alkoxy, C₁-C₄-alkylthio, carboxy, C₁-C₆-alkoxycarbonyl, cyano, halogen, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, amino, C₁-C₅ Alkylamino, di-C₁-C₅-alkylamino, C₁-C₆-alkylsulfonyl, C₆- C₁₂-arylsulfonyl, sulfamoyl, di-C₁-C₃-alkylaminosulfonyl, pyridyl, thienyl, furyl, pyrimidyl, pyrazinyl, pyridazinyl, quinolyl, quinolyl, isoquinolyl , Quinoxalyl, Benzthiazolyl, Benzoxazolyl or Benzimidazolyl may be substituted, or
- C₆-C₁₂-aryl, C₇-C₁₄-aralkyl, pyridyl, thienyl, furyl, pyrimidyl, pyridazinyl, pyrazinyl, quinolyl, isoquinolyl, quinazolyl, quinoxalyl, benzothiazolyl, benzoxazolyl or benzimidazolyl, the radicals mentioned being the same or up to 4 times the same different from halogen, cyano, nitro, C₁-C₆-alkyl, C₁-C₆-alkoxy, C₁-C₄-alkylthio, trifluoromethyl, trifluoromethoxy, -S (O) _m CF₃, amino, C₁-C₅-alkylamino, di-C₁- C₅- alkylamino, C₁-C₆-alkylsulfonyl, C₆-C₁₂-arylsulfonyl, sulfamonyl or di-C₁-C₃-alkylaminosulfonyl may be substituted, R⁵- has the same meaning as R⁵ but does not represent methyl, m - a number 0, 1 or 2 means

and

R⁶ and R⁷ are the same or different and

- Hydrogen or optionally substituted by halogen C₁-C₁₂ alkyl, or
- C₆-C₁₂-aryl, C₇-C₁₄-aralkyl, C₁-C₇-acyl, C₁-C₄-alkylsulfonyl, C₆-C₁₂-arylsulfonyl,

or

R⁶ and R⁷ together with the nitrogen atom form a ring the series

in which

m - stands for a number 0, 1 or 2, n - stands for a number 0 to 4,

R⁸ and R⁹ are the same or different and

      - for hydrogen, C₁-C₈-alkyl, C₁-C₄-hydroxyalkyl, Carboxy, carbamoyl or C₁-C₆- Alkoxycarbonyl stand     

and

X- for hydrogen or
- represents C₁-C₆-alkyl, which may be substituted by phenyl, halogen or hydroxy, or
- is C₆-C₁₂-aryl, which can be substituted up to 3 times the same or different by halogen, cyano, trifluoromethyl, trifluoromethoxy, C₁-C₆-alkyl or C₁-C₆-alkoxy, or
- stands for C₁-C₆-alkylsulfonyl, C₆-C₁₂-arylsulfonyl, sulfamoyl, di-C₁-C₆-alkylaminosulfonyl, or
- for a group of the formula

in which

R¹⁰, R¹¹, R¹² and R¹³ are the same or different are and

      - Hydrogen, C₁-C₆ alkyl, C₆-C₁₂ aryl or C₇-C₁₄ aralkyl,     

are new.

They can be made by one Thiazolopyrazines of the general formula (V)

in which  

R⁴- has the meaning given above

and

R²⁰- for C₆-C₁₀ aryl or
- represents C₁-C₄-alkyl, preferably methyl,

reacted with bases in inert solvents and then in the case of the production of the salts with the corresponding acids.

If 6- (morpholin-4-yl) -2- is used as the starting material methyl-thiazolo [4,5-b] pyrazine, so the reaction clarify with the following formula:

Water or inert solvents are suitable as solvents organic solvents, which are under the reaction conditions Don `t change. These preferably include alcohols such as methanol, ethanol, propanol, isopropanol or butanol, or ethers such as diethyl ether, tetrahydrofuran, dioxane, glycol dimethyl ether or butyl methyl ether, or amides such as bimethylformamide, Dimethylacetamide or hexamethylphosphoric triamide, or acetonitrile, pyridine, picoline or dimethylaminopyridine. It is also possible to mix the use mentioned solvents.  

The usual basic compounds are suitable as bases. These include preferred inorganic bases such as alkali or alkaline earth metal hydroxides such as sodium hydroxide, Potassium hydroxide or barium hydroxide, or alkali or Alkaline earth carbonates such as sodium carbonate or Potassium carbonate, or alkali alcoholates such as sodium methoxide, Sodium ethanolate, potassium methoxide, potassium ethanolate or potassium tert-butoxide. It is also possible to be strong to use basic ion exchangers.

The reaction is generally in a temperature range from 0 ° C to + 200 ° C, preferably from + 50 ° C to + 130 ° C carried out.

The reaction can be normal, increased or reduced Pressure (e.g. from 0.5 to 5 bar). Generally one works at normal pressure.

In some cases the reaction may be required to carry out under an inert protective gas. These include preferably protective gases such as nitrogen, carbon dioxide or Noble gases, preferably argon.

When carrying out the reaction, the base is generally in an amount of 1 to 50, preferably 1 to 20, particularly preferably from 1 to 10 mol based on 1 mol of thiazolopyrazine used.

The reaction has proven to be particularly favorable in alcohol or alcohol-water mixtures with alkali hydroxides carry out and possibly for the purpose of better Solubility of the educt as a further diluent Add ethers such as tetrahydrofuran or dioxane.  

The implementation can be carried out, for example, by the thiazologpyrazine in a suitable solvent mixes with the base and heated if necessary. The Working up the reaction mixture and the isolation and purification of the reaction products takes place in itself known manner by extraction, chromatography and / or Crystallization.

The thiazolopyrazines used as starting materials general formula (V) are partially known [G. B. Barlin et al., Aust. J. Chem. 36 (5), 983; 37 (8), 1729].

The new thiazolopyrazines of the general formula (Va)

in which

R⁴ and R²⁰ have the meaning given above

being however

R²⁰- is not methyl or phenyl if R⁴- methylthio, 2- (dimethylamino) ethylthio or 3- (Di methylamino) propylthio means

can be made by Halothenthiazolopyrazine of the general formula (VI)  

in which

R²⁰ has the meaning given above

and

Z is halogen, preferably chlorine or bromine,

in inert solvents, if appropriate in the presence of bases
with acidic compounds of the general formula (VII)

R⁴′-H (VII)

in which

R⁴′- for a group of the formula -SR⁵, -OR⁵ ′ or NR⁶R⁷ stands,

in which

R⁵, R⁵ ′, R⁶ and R⁷ have the meaning given above to have

implements  and then in the case of the production of the sulfoxides or sulfones in inert solvents, reacted with oxidizing agents.

If 6-bromo-2-methyl-thiazolo is used as starting material [4,5-b] pyrazine and thioglycolic acid methyl ester the preparation of the thiazolopyrazine by the following Clarify scheme:

The usual inert solvents are suitable as solvents Solvents that are not under the reaction conditions change. These preferably include alcohols such as methanol, Ethanol, propanol, isopropanol or butanol, or ether such as diethyl ether, butyl methyl ether, tetrahydrofuran, dioxane or glycol dimethyl ether, or amides such as dimethylacetamide, Dimethylformamide or hexamethylphosphoric triamide, or hydrocarbons such as benzene, toluene, xylene, Hexane, cyclohexane, or petroleum fractions, or halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, Dichloroethane or dichlorethylene, or Dimethyl sulfoxide, acetonitrile, ethyl acetate or sulfolane,  Pyridine, piperidine, morpholine, thiomorpholine, or picoline Dimethylaminopyridine.

The usual inorganic or organic bases are suitable Bases that are released during the reaction Can bind hydrogen halide. These preferably include Alkali carbonates such as sodium carbonate, sodium hydrogen carbonate or potassium carbonate, or alkali or alkaline earth hydroxide such as sodium hydroxide, potassium hydroxide or barium hydroxide or organic amines such as Triethylamine, ethyldiisopropylamine, pyridine, piperidine Quinoline, morpholine, thiomorpholine, 1,4-diazabicyclo [2.2.2] octane (DABCO), 1,5-diazabicyclo [4.3.0] non-5- en (DBN) or 1,5-diazabicyclo [5.4.0] undec-5-en (DBU). It is also possible to use strongly basic ion exchangers use.

The reaction is generally in a temperature range from -50 ° C to + 300 ° C, preferably from + 20 ° C to + 200 ° C carried out.

The reaction is generally carried out at normal pressure. It is also possible with increased or decreased Pressure to work.

When carrying out the reaction, the acidic compound (VII) generally in an amount of 1 to 6 mol, preferably from 1 to 2 moles, based on 1 mole of the halogenothiazolopyrazine used. Works very particularly preferably one with molar amounts of the reactants.  

In a special embodiment, it has proven to be cheap proven the acidic compound (VII) in a large Use excess as a solvent at the same time.

It is also possible to form the acidic compound (VII) their salts, preferably their alkali or alkaline earth salts to use. These preferably include lithium, sodium or potassium salts of the acidic compounds, d. H. depending on the meaning of R ′ alkali or alkaline earth alcoholates, phenates, thiolates or amides. Here it is possible to Prepare salts beforehand in a separate reaction and in a second reaction step with the halothiazolopyrazines to implement, or in a reaction solution in a first step with the help of another Manufacture base and then implement directly.

In some cases, it did when the reaction was carried out proven to be favorable under a protective gas atmosphere work. Nitrogen is the preferred protective gas, Carbon dioxide or noble gas, in particular argon applied.

The production of the sulfones or sulfoxides (R⁴ = SOR⁵ or SO₂R⁵ takes place just like the production of connections with a sulfone or sulfoxide group in the side chain (e.g. thiomorpholine S-oxide or thiomorpholine S, S-dioxide) is generally carried out by oxidation of the corresponding Thio compound in inert solvents.

The usual oxidizing agents come as oxidizing agents for the production of sulfoxides and sulfones in question. These preferably include periodates such as alkali periodiodates,  preferably sodium metaperiodate, peroxo compounds such as Hydrogen peroxide, optionally in a mixture with organic Carboxylic acids such as acetic acid, tert. Butyl hydroperoxide or organic peracids such as chloroperbenzoic acids, preferably metachloroperbenzoic acid.

Suitable solvents for this are depending on the type of used oxidizing agent water or usual organic Solvents that are under the reaction conditions Don `t change. These preferably include halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, Dichloroethane or dichlorethylene, or ether such as diethyl ether, tetrahydrofuran, dioxane, glycol dimethyl ether or butyl methyl ether, or alcohols such as methanol, Ethanol, propanol, isopropanol or butanol, or amides such as dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide, or dimethyl sulfoxide or carboxylic acids or their anhydrides such as acetic acid, Propionic acid or acetic anhydride. Mixtures are also possible to use the solvents mentioned.

The oxidation is generally in a temperature range from -80 ° C to + 150 ° C, preferably from -20 ° C to + 60 ° C carried out.

The oxidation is generally carried out under normal pressure. But it can also be the same with increased or decreased Pressure to be worked.  

In some cases, it may be necessary Carry out reaction under protective gas. As protective gases preferably nitrogen, carbon dioxide or noble gas, preferably called argon.

The oxidation is carried out, for example, by the corresponding thio compound in an inert solvent, selected depending on the oxidizing agent used is reacted with a suitable oxidizing agent. Working up is carried out in the usual manner Extraction, chromatography and / or crystallization.

The halothiazolopyrazines used as starting materials of the general formula (VI) are known or can be produced by known methods [G. Palamidessi et al., Gazz. Chim. Italian 91: 1438 (1961); Brit. Patent 958,626].

The acidic compounds of the general formula (VII) are known or can be prepared by known methods [Houben-Weyl's "Methods of Organic Chemistry" IX, 42; Partai, The Chemistry of the Thiol Group Interscience Publishers, London 1974, 455; Houben-Weyl's "Methods of Organic Chemistry" XI / 2, 1; S. Patai, The Chemistry of the Amino-Group Interscience Publishers, New York 1968].  

The MIC values in the table below are some of the compounds according to the invention compared to imipenem specified.

Antibacterial effect

The agar solution method was used to determine the antibacterial Effect used, an iso-sensitivity test Agar was used and the minimum inhibitory concentration (MIC) of the sample was expressed by µg / ml of the culture medium (Table).

Table: Comparison of antibacterial activity with imipenem

The compounds of the invention surprisingly have compared to conventional carbapenem antibiotics such as thienamycin or imipenem, particularly against numerous staphylococci and enterococci improved antibacterial activity. Furthermore show  the carbapenems of formula (I) according to the invention are metabolic Stability towards the enzyme dehydropeptidase (I) (DHP I) and are therefore other compounds of this Compatibility superior to substance class.

These valuable properties enable their use as chemotherapeutic agents in medicine as well as substances for the preservation of inorganic and organic Materials, especially organic materials of all kinds, e.g. B. polymers, lubricants, paints, Fibers, leather, paper and wood, of food and of Water.

The compounds of the invention are against a very wide range of microorganisms effective. With their Gram-negative and gram-positive bacteria and can help fights bacteria-like microorganisms and by prevents these pathogens caused diseases, improved and / or be cured.

The compounds according to the invention are particularly effective against bacteria and bacteria-like microorganisms. they are therefore particularly good for prophylaxis and chemotherapy of local and systemic infections in human and Suitable veterinary medicine caused by these pathogens will.

For example, local and / or systemic diseases that are caused by the following pathogens or by mixtures of the following pathogens can be treated and / or prevented:
Gram-positive cocci, e.g. B. Staphylococci (Staph. Aureus, Staph. Epidermidis) and Streptococci (Strept. Agalactiae, Strept. Faecalis, Strept. Pneumoniae, Strept. Pyogenes); gram-negative cocci (Neisseria gonorrhoeae) and gram-negative rods such as enterobacteriaceae, e.g. B. Escherichia coli, Haemophilus influenzae, Citrobacter (Citrob. Freundii, Citrob. Divernis), Salmonella and Shigella; also Klebsielles (Klebs, pneumoniae, Klebs, oxytoca), Enterobacter (Ent. aerogenes. Ent. agglomerans), Hafnia, Serratia (Serr. marcescens), Proteus (Pr. mirabilis, Pr. rettgeri, Pr. vulgaris), Providencia, Yersinia , as well as the genus Acinetobacter. In addition, the antibacterial spectrum includes strictly anaerobic bacteria such as. B. Bacteroides fragilis, representatives of the genus Peptococcus, Peptostreptococcus and the genus Clostridium; also mycoplasma (M. pneumoniae, M. hominis, M. urealyticum) and mycobacteria, e.g. B. Mycobacterium tuberculosis.

The above list of pathogens is only an example and is in no way to be interpreted as limiting. Examples of diseases which can be caused by the pathogens mentioned or mixed infections and which can be prevented, improved or cured by the compounds according to the invention are:
Infectious diseases in humans such as otitis, pharyngitis, pneumonia, peritonitis, pyelonephritis, cystitis, endocarditis, systemic infections, bronchitis (acute, chronic), septic infections, diseases of the upper airways, diffuse panbronchiolitis, pulmonary emphysema, dysentery, enteritis, liver abscess , Prostatitis, epididymitis, gastrointestinal infections, bone and joint infections, cystic fibrosis, skin infections, postoperative wound infections, abscesses, phlegmon, wound infections, infected burns, burns, infections in the mouth area, infections after dental surgery, osteomyelitis, septic arthritis, cholecystitis, periton , Cholangitis, intra-abdominal abscess, pancreatitis, sinusitis, mastoiditis, mastitis, tonsillitis, typhoid, meningitis and infections of the nervous system, salpingitis, endometritis, genital infections, peloperoperitis and eye infections.

In addition to humans, bacterial infections can also be treated in other species. Examples include:
Pig: coli-diarrhea, enterotoxemia, sepsis, dysentery, salmonellosis, metritis-mastitis-agalaktiae syndrome, mastitis;
Ruminants (cattle, sheep, goats): diarrhea, sepsis, bronchopneumonia, salmonellosis, pasteurellosis, mycoplasmosis, genital infections;
Horse: bronchopneumonia, foal paralysis, puerperal and postpuerperal infections, salmonellosis;
Dog and cat: bronchopneumonia, diarrhea, dermatitis, otitis, urinary tract infections, prostatitis;
Poultry (chicken, turkey, quail, pigeon, ornamental birds and others): mycoplasmosis, E. coli infections, chronic respiratory diseases, salmonellosis, pasteurellosis, psittacosis.

Bacterial diseases during rearing can also occur and keeping of farmed and ornamental fish are treated, the antibacterial spectrum over the previous mentioned pathogens to other pathogens such as Pasteurella, Brucella, Campylobacter, Listeria, Erysipelothrix, Corynebacteria, Borellia, Treponema, Nocardia, Rikettsia, Yersinia, expanded  

The present invention includes pharmaceutical preparations which in addition to non-toxic, inert pharmaceutical suitable carriers one or more of the invention Contain connections or which consist of one or several active ingredients according to the invention, and Process for the preparation of these preparations.

Pharmaceuticals also belong to the present invention Preparations in dosage units. This means that the preparation in the form of individual parts, e.g. B. tablets, Dragees, capsules, pills, suppositories and ampoules are available, whose active ingredient content is a fraction or a Correspond to multiples of a single dose. The dosage units can e.g. B. 1, 2, 3 or 4 single doses or ½, ¹ / ₃ or ¼ of a single dose included. A single dose preferably contains the amount of active ingredient in a Application is administered and usually an entire, a half or a third or a quarter corresponds to a daily dose.

Among non-toxic, inert pharmaceutically suitable Carriers are solid, semi-solid or liquid diluents, Fillers and formulation aids to understand every kind.

The preferred pharmaceutical preparations are tablets, Coated tablets, capsules, pills, granules, suppositories, Solutions, suspensions and emulsions, pastes, Called ointments, gels, creams, lotions, powders and sprays.  

Tablets, coated tablets, capsules, pills and granules can the active ingredient or ingredients in addition to the usual carriers contain, such as (a) fillers and extenders, e.g. B. strengths, Milk sugar, cane sugar, glucose, mannitol and silica, (b) binders, e.g. B. carboxylmethyl cellulose, alginates, Gelatin, polyvinylpyrrolidone, (c) humectant, e.g. B. Glycerin, (d) disintegrant, e.g. B. agar-agar, calcium carbonate and sodium carbonate, (e) solution retarders, e.g. B. Paraffin and (f) absorption accelerators, e.g. B. quaternary Ammonium compounds, (g) wetting agents, e.g. B. cetyl alcohol, Glycerol monostearate, (h) adsorbent, e.g. B. Kaolin and bentonite and (i) lubricants, e.g. B. talc, calcium and magnesium stearate and solid polyethylene glycols or mixtures of the substances listed under (a) to (i).

The tablets, dragees, capsules, pills and granules can with the usual, optionally opacifying agents containing, coatings and sleeves provided and also be composed so that it the active ingredient (s) only or preferably in a certain part of the intestinal tract if necessary delayed delivery, whereby as Embedding compounds e.g. B. polymer substances and waxes are used can be.

The active ingredient (s) can optionally be combined with a or more of the above-mentioned carriers also in microencapsulated form.

Suppositories can contain the usual water-soluble or water-insoluble excipients in addition to the active ingredient or ingredients, e.g. B. polyethylene glycols, fats, e.g. B. cocoa fat and higher esters (z. B. C ₁₄ alcohol with C ₁₆ fatty acid) or mixtures of these substances.

Ointments, pastes, creams and gels can next to the or Active substances containing the usual carriers, e.g. B. animal and vegetable fats, waxes, paraffins, starch, Tragacanth, cellulose derivatives, polyethylene glycols, silicones, Bentonites, silica, talc and zinc oxide or mixtures of these substances.

Powders and sprays can in addition to the active ingredient (s) contain usual carriers, e.g. B. milk sugar, talc, Silicic acid, aluminum hydroxide, calcium silicate and polyamide powder or mixtures of these substances. Sprays can be added the usual blowing agents, e.g. B. chlorofluorocarbons, contain.

Solutions and emulsions can be in addition to the active ingredient (s) the usual carriers such as solvents, solubilizers and emulsifiers, e.g. B. water, ethyl alcohol, Isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, Benzyl benzoate, propylene glycol, 1,3-butylene glycol, Dimethylformamide, oils, especially cottonseed oil, Peanut oil, corn oil, olive oil, castor oil and sesame oil, Glycerin, glycerin formal, tetrahydrofuryl alcohol, polyethylene glycols and sorbitan fatty acid esters or mixtures contain these substances.

The solutions and emulsions can be used for parental application also available in sterile and blood isotonic form.

In addition to the active ingredient (s), suspensions can be the usual ones Carriers such as liquid diluents, e.g. B. Water, ethylene alcohol, propylene glycol, suspending agent,  e.g. B. ethoxylated isostearyl alcohols, polyoxyethylene sensor bit and sorbitan esters, microcrystalline cellulose, aluminum minium metahydroxide, bentonite, agar and tragacanth or Mixtures of these substances contain.

The formulation forms mentioned can also contain colorants, Preservatives as well as smell and taste better additives, e.g. B. peppermint oil and eucalyptus oil and Sweeteners, e.g. B. saccharin.

The therapeutically active compounds should be in the preferred pharmaceutical preparations listed above in a concentration of about 0.1 to 99.5 preferably from about 0.5 to 95% by weight of the total mixture to be available.

The pharmaceutical preparations listed above in addition to the compounds of the invention can also contain active pharmaceutical ingredients.

The manufacture of the pharmaceutical listed above Preparations are carried out in the usual way according to known Methods, e.g. B. by mixing the active ingredient (s) with the or the carriers.

The preparations mentioned can be used in humans and animals either oral, rectal, parenteral (intravenous, intramuscular, subcutaneous), intracisternal, intravaginal, intraperi toneal, local (powder, ointment, drops) and for the therapy of Infections in cavities, body cavities can be applied. Injection solutions are suitable preparations, Solutions and suspensions for oral therapy, gels,  Infusion formulations, emulsions, ointments or drops in Question. For local therapy, ophthalmic and dermatological formulations, silver and other salts, Ear drops, eye ointments, powder or solutions are used will. In animals, the intake can also be via the feed or drinking water in suitable formulations. Gels, powders, powders, tablets, slow-release Tablets, premixes, concentrates, granules, pellets, tablets, Boli, capsules, aerosols, sprays, inhalants in humans and animal can be applied. Furthermore, the fiction appropriate connections in other carrier materials such as Example plastic, (plastic chains for local Therapy), collagen or bone cement.

In general, it has been in both human and proven to be beneficial in veterinary medicine, the or the active compounds according to the invention in total amounts of about 0.5 to about 500, preferably 5 to 100 mg / kg body weight each 24 hours, possibly in the form of several units to achieve the desired results submit. A single dose contains the inventor Active ingredients according to the invention preferably in amounts of about 1 to about 80, especially 3 to 30 mg / kg body weight. However, it may be necessary from the dosie mentioned deviations, depending on the type and the body weight of the object to be treated, Art and the severity of the disease, the type of preparation and the application of the drug and the period or interval within which the administration follows.  

So in some cases it may be enough with less than the above amount of active ingredient, while in other cases the amount of active ingredient mentioned above must be taken. The determination of each required optimal dosage and type of application of the drug fabrics can be purchased by any professional based on their subject knowingly done easily.

The new compounds can be found in the usual concentra tions and preparations together with the feed or with Feed preparations or with drinking water. This can cause an infection through gram-negative or Gram-positive bacteria prevented, improved and / or be cured and thereby promote growth and an improvement in the utilization of the feed can be achieved.

Manufacturing examples Example 1 2-methyl-6- (piperidin-1-yl) thiazolo [4,5-b] pyrazine

A mixture of 6.50 g (22.5 mmol) of 6-bromo-2-methylthia zolo [4,5-b] pyrazine, 10.00 g (17.4 mmol) of piperidine and 40 ml of dioxane were added to the complete reaction heated at reflux. The mixture was allowed to cool, the mixture was concentrated, water was added and the mixture was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, concentrated and the residue was purified by column chromatography on silica gel.
Quantitative yield: (5.27 g)
Mp .: 111-112 ° C

The following were prepared as in Example 1:

Example 2 2-methyl-6- (4-methyl-piperazin-1-yl) thiazolo [4,5-b] pyrazine

Yield: 97% of theory
Mp .: 113-115 ° C

Example 3 2-methyl-6- (morpholin-4-yl) thiazolo [4,5-b] pyrazine

Yield: 86% of theory
Mp .: 170-172 ° C

Example 4 2-methyl-6- (thiomorpholin-4-yl) thiazolo [4,5-b] pyrazine

Yield: 92% of theory
Mp: 208 ° C

Example 5 2-methyl-6- (pyrrolidin-1-yl) thiazolo [4,5-b] pyrazine

Yield: 76% of theory
Mp: 128-129 ° C

Example 6 2-methyl-6-n-docecylamino-thiazolo [4,5-b] pyrazine

Yield: 20% of theory
Mp: 169-171 ° C

Example 7 2-methyl-6- (3-trifluoromethyl-phenyl) thio-thiazolo [4,5-b] pyrazine

3.00 g (13.0 mmol) of 5-bromo-2-methylthiazolo [4,5-b] pyrazine, 2.00 g of potassium carbonate and 3.33 g (18.7 mmol) of 3-trifluoromethylthiophenol were added to 20 ml of dioxane with stirring and exclusion of atmospheric oxygen (nitrogen transfer) heated to reflux until the reaction is complete. The reaction mixture was concentrated, the residue was chromatographed on silica gel.
Yield: 94% of theory

NMR (CDCl₃): w = 2.96 (s, 3H, CH₃ at C-2), 7.55-8.15 (m, 4H, aryl-H, 3-CF₃-Ph), 8.58 (s , 1H, H-5) ppm.

The following were prepared as in Example 7:

Example 8 2-methyl-6-ethoxycarbonylmethylthio-thiozolo [4,5-b] pyrazine

Yield: 93% of theory
Mp .: 82-84 ° C

Example 9 2-methyl-6- (1-oxo-thiomorpholin-4-yl) thiazolo [4,5-b] pyrazine

To a solution of 2.52 g (10.0 mmol) of 2-methyl-6- (thio morpholin-4-yl) thiazolo [4,5-b] pyrazine (Example 4) in 50 ml of dry dichloromethane was added in portions at -15 ° C 1.58 g (corresponding to 8.0 mmol) m-chloroperoxybenzoic acid. The mixture was stirred for 3 h at 0 ° C and 20 h at room temperature, suction filtered and the solid was washed with diethyl ether.
Yield: 77% of theory (based on Example 4 used).
Mp: 284-286 ° C

The following were prepared as in Example 9:  

Example 10 2-methyl-6- (1,1-dioxothiomorpholin-4-yl) thiazolo [4,5-b] pyrazine

Yield: 94% of theory
Mp: 261 ° C

Example 11 2-amino-5- (morpholin-4-yl) -3-pyrazinthiol

4.30 g (18.20 mmol) of 6- (morpholin-4-yl) -2-methyl-thiazolo [4,5-b] pyrazine (Example 3) were in a mixture of 35 ml of 2N sodium hydroxide solution with 18 ml of methanol heated under reflux until complete conversion. The mixture was allowed to cool, concentrated in vacuo, the residue was taken up in as little water as possible and the reaction product was precipitated by adding glacial acetic acid. It was washed with ice water and dried in a high vacuum.
Yield: 96% of theory
Mp: 181-184 ° C

The following were prepared as in Example 11:

Example 12 2-amino-5- (pyrrolidin-1-yl) -3-pyrazinthiol

Yield: 88% of theory
Mp: 188-190 ° C

Example 13 2-amino-5- (4-methyl-piperazin-1-yl) -3-pyrazinthiol

Yield: 21% of theory
Mp: <280 ° C

Example 14 2-amino-5- (piperidin-1-yl) -3-pyrazinthiol

Yield: 93% of theory
Mp .: 179-181 ° C

Example 15 2-amino-5- (thiomorpholin-4-yl) -3-pyrazinthiol

Yield: 91% of theory
Mp: <280 ° C

Example 16 2-amino-5- (1-oxo-thiomorpholin-4-yl) -3-pyrazinthiol

Yield: 85% of theory
Mp: 189-190 ° C

Example 17 2-amino-5- (1,1-dioxothiomorpholin-4-yl) -3-pyrazinthiol

Yield: 99% of theory
Mp: <280 ° C

Example 18 2-amino-5- (3-trifluoromethylphenyl) -3-pyrazinthiol

Yield: 66% of theory
Mp: 195-196 ° C

Example 19 2-amino-4-carboxymethylthio-3-pyrazinthiol

Yield: 90% of theory
Mp: 215-217 ° C

Example 20 (5R, 6S) -3-diphenylphosphonyloxy-6 - [(1R) -1-hydroxyethyl] - 7-oxo-1-azabicyclo [3,2,0] hept-2-en-2-carboxylic acid p-nitrobenzyl ester

To a solution of 3.48 g (10.0 mmol) of (2R, 5R, 6S) -3,7-dioxo-6 - [(1R) -1-hydroxyethyl] -1-azabicyclo [3 , 2,0] heptane-2-carboxylic acid p-nitrobenzyl ester [TN Salzmann et al., J. Am. Chem. Soc. 102, 6163 (1980)] in 40 ml of anhydrous acetonitrile, 1.82 ml (10.5 mmol) of N, N-diisopropylethylamine and 2.18 ml (10.5 mmol) of phosphoric acid diphenyl ester chloride were simultaneously added dropwise within 5 min. The mixture was stirred at 0 ° C for 30 min and then poured into a mixture of cold NaHCO₃ solution and ethyl acetate. It was extracted with ethyl acetate, the organic extracts were washed with NaHCO₃ solution and dried over MgSO₄. After evaporation of the solvent in vacuo and drying of the residue in a high vacuum, the title compound was obtained as a light foam, which was directly reacted further.
R _f : 0.45 (toluene: ethyl acetate 3: 7)
IR (KBr): 3450, 1782, 1729, 1643, 1590, 1526, 1490, 1350 cm ^-1

1 H-NMR (200 MHz, CDCl₃): w = 1.34 (d, J = 6.5 Hz, 3 H, CH₃CHOH), 3.25 (m, 3 H, H-4, H-4 ′, H -6), 4.25 (m, 2 H, H-5, CH₃CHOH), 5.25 and 5.41 (AB, J = 13 Hz, 2 H, COOH₂), 7.2-7.5 (m , 10 H, Ph), 7.59 and 8.17 (AB, J = 8.5 Hz, 4 H, p-NO₂-C₆H₄).

Example 21 (5R, 6S) -3- (2-amino-5-methoxy-3-pyrazinylthio) -6 - [(1R) -1- hydroxyethyl] -7-oxo-1-azabicyclo [3,2,0] hept-2-ene-2-carboxylic acid - p-nitrobenzyl ester Process method A

To a solution of 1.22 g (2.1 mmol) (5R, 6S) -3-diphenylphosphonyloxy-6 - [(1R) -1-hydroxyethyl] -7-oxo-1-azabicyclo [cooled to -40 ° C. 3.2.0] hept-2-en-2-carboxylic acid p-nitrobenzyl ester in 4 ml of anhydrous dimethylformamide (DMF), 0.38 ml (2.21 mmol) of N, N-diisopropylethylamine were added dropwise and then 348 mg 2.21 mmol) 2-amino-5-methoxy-3-pyrazinthiol [G. Palamidesi et al., Gazz. Chim. Italian 91, 1438 (1961)]. The suspension obtained was allowed to warm to 0 ° C within 2 h and was poured into a mixture of ice, NaHCO₃ solution and ethyl acetate for working up. It was extracted with ethyl acetate, the organic extracts were washed with NaHCO₃ solution (twice) and dried over MgSO₄. After evaporation of the solvent in vacuo and chromatography of the residue on 98 g of silica gel (toluene: ethyl acetate 3: 7), 74 g (7% of theory) of the title compound are obtained as an amorphous solid.
R _f = 0.25 (toluene: ethyl acetate 3: 7)
IR (KBr): 3449, 1772, 1704, 1607, 1525, 1470, 1349 cm ^-1

1 H-NMR (200 MHz, DMSO): δ = 1.09 (d, J = 6.5 Hz, 3 H, CH₃CHOH), 2.78 (dd, J = 18 Hz, 10 Hz, 1 H, H- 4), 2.98 (dd, J = 18 Hz, 8 Hz, 1 H, H-4 '), 3.33 (m, H-6, under H₂O), 3.79 (s, 3 H, OCH₃ ), 3.93 (m, 1 H, CH₃CHOH), 4.11 (m, 1 H, H-5), 5.03 (d, J = 5 Hz, 1 H, OH), 5.34 and 5 , 50 (AB, J = 14 Hz, 2 H, COOCH₂), 6.11 (bs, 2 H, NH₂), 7.75 and 8.25 (AB, J = 9.5 Hz, 4 H, p- NO-CH₆H₄), 7.87 (s, 1H, pyrazine-H).

Method B:

A 285 mg (0.82 mmol) solution cooled to 0 ° C (2R, 5R, 6S) -3,7-dioxo-6 - [(1R) -1-hydroxyethyl] -1-azabicyclo [3,2,0] heptane-2-carboxylic acid p-nitrobenzyl ester [T. N. Salzmann et al., J. Am. Chem. Soc. 102, 6163 (1980)] in 4 ml anhydrous acetonitrile was added within 15 min simultaneously with 150 µl (0.87 mmol) of N, N-diisopropylethylamine and 180 ul (0.87 mmol) of diphenyl chlorophosphate were added. The mixture was then stirred at 0 ° C. for 15 minutes and cooled to -40 ° C. and gave 150 µl (0.87 mmol) of N, N-diisopropylethylamine successively and 135 mg (0.87 mmol) of 2-amino-5-methoxy-3-pyrazinthiol  to. The reaction mixture was allowed to warm to 0 ° C and was finished in a mixture of cold NaHCO₃ solution and ethyl acetate stirred. The mixture was extracted with ethyl acetate, with NaCl solution and water washed and dried over MgSO₄. After evaporation of the solvent and chromatography of the residue on 60 g Silica gel gave 26 g (6% of theory) of the title compound. The physical data were identical to the substance obtained by method A.

Example 22 (5R, 6S) -3- [2-amino-5- (morpholin-4-yl) -3-pyrazinylthio] -6- [(1R) -1-hydroxyethyl] -7-oxo-1-azabicyclo [3,2,0] hept-2-en- 2-carboxylic acid p-nitrobenzyl ester

As described for Example 21A, 4.48 g (7.72 mmol) of (5R, 6S) -3-diphenylphosphonyloxy-6 - [(1R) -1-hydroxyethyl] - 7-oxo-1-azabicyclo [3 , 2,0] hept-2-en-2-carboxylic acid p-nitrobenzyl ester and 1.72 g (8.10 mmol) of 2-amino-5- (morpholin-4-yl) -3-pyrazinthiol after 1.75 h at 0 ° C and chromatography of the crude product on 90 g of silica gel (ethyl acetate: actetonitrile 9: 1) 1.93 g (46% of theory) of the title compound as orange crystals.
Mp: 164 ° C
R _f = 0.32 (ethyl acetate: acetonitrile 9: 1)
IR (KBr): 3454, 1776, 1710, 1606, 1521, 1470, 1449, 1346, 1331 cm ^-1

1 H-NMR (250 MHz, DMSO): δ = 1.09 (d, J = 6.5 Hz, 3 H, CH₃CHOH), 2.77 (dd, J = 18 Hz, 9 Hz, 1 H, H- 4), 2.92 (dd, J = 18 Hz, 8 Hz, 1 H, H-4 ′), 3.20 (m, 4 H, CH₂N), 3.32 (m, H-6 under H₂O) , 3.70 (m, 4 H, CH₂O), 3.91 (dd, J = 6.5 Hz, 6 Hz, 1 H, CH₃CHOH), 4.09 (dt, J = 10 Hz, 3 Hz, 1 H, H-5), 5.00 (d, J = 5 Hz, 1 H, OH), 5.32 and 5.48 (AB, J = 15.5 Hz, 2 H, COOCH₂), 5.85 (bs, 2 H, NH₂), 7.72 and 8.24 (AB, J = 9 Hz, 4 H, p-NO₂-C₆H₄), 7.90 (s, 1 H, pyrazine-H).

Example 23 (5R, 6S) -3- (2-Amino-5,6-dimethyl-3-pyrazinylthio) -6 - [(1R) - 1-hydroxyethyl] -7-oxo-1-azabicyclo [3,2,0] hept-2-en-2- carboxylic acid p-nitrobenzyl ester

As described for Example 21A, 5.80 g (10.0 mmol) of (5R, 6S) -3-diphenylphosphonyloxy-6 - [(1R) -1-hydroxyethyl] -7-oxo-1-azabicyclo [3 , 2,0] hept-2-en-2-carboxylic acid p-nitrobenzyl ester and 1.63 g (10.5 mmol) 2-amino-5,6-dimethyl-3-pyrazinthiol according to [M. Hattari et al., Bull Chem. Soc. Jpn 46, 1890 (1973); TS Safonova et al., Chem. Heterocycl. Compds 6, 1019 (1970)] after 42 h at 0 ° C. and chromatography of the crude product on 600 g of silica gel (ethyl acetate) 534 mg (11%) of the title compound as crystals.
Mp: 156 ° C.
R _f = 0.25 (ethyl acetate).
IR (KBr): 3452, 1771, 1703, 1635, 1608, 1558, 1526, 1350, 1331 cm ^-1

1 H-NMR (250 MHz, DMSO): δ = 1.10 (d, J = 6.5 Hz, 3 H, CH₃CHOH), 2.19, 2.20 (s, 6 H, CH₃), 2.68 (dd, J = 14 Hz, 7.5 Hz, 1 H, H-4), 2.90 (dd, 14 Hz, 6 Hz, 1 H, H-4 ′), 3.32 (m, H- 6, under H₂O), 3.93 (dq, J = 6.5 Hz, 6 Hz, 1 H, CH₃CHOH), 4.09 (dt, J = 7.5 Hz, 3 Hz, 1 H, H-5 ), 4.98 (d, J = 5 Hz, 1 H, OH), 5.36 and 5.50 (AB, J = 13 Hz, 2 H, COOCH₂), 6.33 (bs, 2 H, NH₂ ), 7.77 and 8.26 (AB, J = 9 Hz, 4 H, p-NO₂-C₆H₄).

Example 24 (5R, 6S) -3- (2-amino-5- (4-methyl-piperazin-1-yl) -3-pyrazinylthio] - 6 - [(1R) -1-hydroxyethyl] -7-oxo-1-azabicyclo [3,2,0] hept- 2-en-2-carboxylic acid p-nitrobenzyl ester

As described for Example 21A, 1.88 g (3.24 mmol) of (5R, 6S) -3-diphenylphosphonyloxy-6 - [(1R) -1-hydroxyethyl] -7-oxo-1-azabicyclo [3, 2,0] hept-2-en-2-carboxylic acid p-nitrobenzyl ester and 767 mg (3.4 mmol) 2-amino-5- (4-methyl-piperazin-1-yl) -3-pyrazinthiol after 20 h at 0 ° C and trituration of the crude product with ether 1.76 g (97% of theory) of the title compound as an amorphous solid, which was used for the next step without purification.
R _f = 0.36 (CH₃CN: H₂O 7: 3)
IR (KBr): 1780, 1674, 1606, 1568, 1525, 1470, 1350 cm ^-1

1 H-NMR (250 MHz, DMSO): δ = 1.10 (d, J = 6.5 Hz, 3 H, CH₃CHOH), 2.40 (s, 3 H, NCH₃), 2.78 (dd, J = 18 Hz, 10 Hz, 1 H, H-4), 2.95 (dd, J = 18 Hz, 9 Hz, 1 H, H-4 ′), 3.2-3.5 (m, 9 H , CH₂N, H-6), 3.92 (m, 1 H, CH₃CHOH), 4.10 (dt, J = 9 Hz, 2.5 Hz, 1 Hz, 1 H, H-5), 5.03 (d, J = 5 Hz, 1 H, OH), 5.35 and 5.50 (AB, J = 14 Hz, 2 H, COOCH₂), 5.90 (bs, 2 H, NH₂), 7.75 and 8.27 (AB, J = 9 Hz, 4 H, p-NO₂-C₆H₄), 7.94 (s, 1 H, pyrazine-H).

Example 25 (5R, 6S) -3- [2-amino-5- (piperidin-1-yl) -3-pyrazinylthio] -6- [(1R) -1-hydroxyethyl] -7-oxo-1-azabicyclo [3,2,0] hept-2-en- 2-carboxylic acid p-nitrobenzyl ester

As described for Example 21A, 3.54 g (6.1 mmol) of (5R, 6S) -3-diphenylphosphonyloxy-6 - [(1R) -1-hydroxyethyl] - 7-oxo-1-azabicyclo [3, 2.0] hept-2-en-2-carboxylic acid p-nitrobenzyl ester and 1.35 g (6.4 mmol) of 2-amino-5- (piperidin-1-yl) -3-pyrazinthiol after 3.5 h at 0 ° C and chromatography of the crude product on 280 g of silica gel (toluene: ethyl acetate 1: 4) 0.84 g (25% of theory) of the title compound as yellow crystals.
Mp: 170 ° C
R _f = 0.24 (toluene: ethyl acetate 1: 4)
IR (KBr): 3460, 1771, 1708, 1607, 1525, 1478, 1348 cm ^-1

1 H-NMR (250 MHz, DMSO): δ = 1.10 (d, J = 6.5 Hz, 3 H, CH₃CHOH), 1.56 (m, 6 H, CH₂), 2.78 (dd, J = 18 Hz, 9 Hz, 1 H, H-4), 2.95 (dd, 18 Hz, 8 Hz, 1 H, H-4 ′), 3.30 (m, CH₂N), approx.3.32 (m, H-6 under H₂O), 3.93 (dd, J = 6.5 Hz, 6.5 Hz, 1 H, CH₃CHOH), 4.10 (dt, J = 9 Hz, 2.5 Hz, 1 H, H-5), 5.03 (d, J = 5.5 Hz, 1 H, OH), 5.35 and 5.49 (AB, J = 16 Hz, 2 H, COOCH₂), 5, 77 (bs, 2 H, NH₂), 7.75 and 8.26 (AB, J = 10 Hz, 4 H, p-NO₂-C₆H₄), 7.90 (s, 1 H, pyrazine-H).

Example 26 (5R, 6S) -3- [2-amino-5- (pyrrolidin-1-yl) -3-pyrazinylthio] - 6 - [(1R) -1-hydroxyethyl] -7-oxo-1-azabicyclo [3,2,0] hept-2- en-2-carboxylic acid p-nitrobenzyl ester

As described for Example 21A, 3.80 g (6.55 mmol) of (5R, 6S) -3-diphenylphosphonyloxy-6 - [(1R) -1-hydroxyethyl] - 7-oxo-1-azabicyclo [3, 2.0] hept-2-en-2-carboxylic acid p-nitrobenzyl ester and 1.35 g (6.88 mmol) of 2-amino-5- (pyrrolidin-1-yl) -3-pyrazinthiol after 2.5 h at 0 ° C and chromatography of the crude product on 294 g of silica gel (toluene: ethyl acetate 1: 9) 0.84 g (24% of theory) of the title compound as an orange solid.
Mp: 140 ° C (dec.)
R _f = 0.28 (toluene: ethyl acetate 1: 9)
IR (KBr): 3429, 1778, 1699, 1580, 1518, 1475, 1348, 1332 cm ^-1
1 H-NMR (250 MHz, DMSO): δ = 1.09 (d, J = 6.5 Hz, 3 H, CH₃CHOH), 1.92 (m, 4 H, CH₂), 2.83 (dd, J = 18 Hz, 10 Hz, 1 H, H-4), 2.96 (dd, J = 18 Hz, 8.5 Hz, 1 H, H-4 ′), 3.32 (m, 5 H CH₂N, H-6), 3.93 (dd, J = 6.5 Hz, 6 Hz, 1 H, CH₃CHOH), 4.10 (dt, J = 9 Hz, 3 Hz, 1 H, H-5), 5 , 01 (d, J = 6 Hz, 1 H, OH), 5.36 and 5.50 (AB, J = 15.5 Hz, 2 H, COOCH₂), 5.53 (bs, 2 H, NH₂) , 7.59 (s, 1 H, pyrazine-H), 7.75 and 8.25 (AB, J = 9.5 Hz, 4 H, p-NO₂-C₆H₄).

Example 27 (5R, 6S) -3- [2-amino-5- (thiomorpholin-4-yl) -3-pyrazinylthio] -6- [(1R) -1-hydroxyethyl] -7-oxo-1-azabicyclo [3,2,0] hept-2-en-2- carboxylic acid p-nitrobenzyl ester

As described for Example 21A, 4.23 g (7.29 mmol) of (5R, 6S) -3-diphenylphosphonyloxy-6 - [(1R) -1-hydroxyethyl] - 7-oxo-1-azabicyclo [3 , 2,0] hept-2-en-2-carboxylic acid p-nitrobenzyl ester and 1.75 g (7.66 mmol) of 2-amino-5- (thiomorpholin-4-yl-3-pyrazinthiol after 2.5 h at 0 ° C and trituration of the crude product with ether 3.80 g (87% of theory) of the title compound as a yellow solid.
Mp: 172 ° C (dec.)
R _f = 0.26 (toluene: ethyl acetate 1: 4)
IR (KBr): 3450, 1772, 1711, 1666, 1605, 1524, 1470, 1347 cm ^-1

1 H-NMR (300 MHz, DMSO): δ = 1.13 (d, J = 6.5 Hz, 3 H, CH₃CHOH), 2.60 (m, 4 H, CH₂S), 2.30 (dd, J = 18 Hz, 9 Hz, H-4), 2.95 (dd, J = 18 Hz, 8.5 Hz, 1 H, H-4 ′), approx.3.3 (m, H-6 under H₂O ), 3.70 (m, 4 H, CH₂N), 3.94 (m, 1 H, CH₃CHOH), 4.10 (dt, J = 9 Hz, 2.5 Hz, 1 H, H-5), 5.02 (d, J = 4.5 Hz, 1 H, OH), 5.35 and 5.48 (AB, J = 16 Hz, 2 H, COOCH₂), 5.80 (bs, 2 H, NH₂ ), 7.75 and 8.23 (AB, J = 9 Hz, 4 H, p-NO₂-C₆H₄), 7.92 (s, 1 H, pyrazine-H).

Example 28 Sodium (5R, 6S) -3- (2-amino-5-methoxy-3-pyrazinylthio) -6- [(1R) -1-hydroxyethyl] -7-oxo-1-azabicyclo [3,2,0] hept-2-en- 2-carboxylate

A solution of 62 mg (0.12 mmol) (5R, 6S) -3- (2-amino-5-methoxy-3-pyrazinylthio) -6 - [(1R) -1-hydroxyethyl] -7-oxo-azabicyclo [3,2,0] hept-2-en-2-carboxylic acid p-nitrobenzyl ester in 4 ml of a mixture consisting of tetrahydrofuran and 0.1 M phosphate buffer pH 7 (1: 1) was added in the presence of 62 mg palladium Charcoal (10%) hydrogenolyzed for 2 h. The catalyst was then separated off by filtration through kieselguhr, the tetrahydrofuran was removed in vacuo and the remaining solution was adjusted to pH 7. The aqueous solution was extracted twice with ethyl acetate, concentrated in vacuo to about 10 ml and loaded onto a column with 120 Diaion HP 20. It was eluted with water, which contained an increasing proportion of acetonitrile. The fractions containing the product were collected, filtered through a 0.2 µ filter and freeze-dried. 34 mg (76% of theory) of the title compound were obtained as a colorless lypophilisate, in a purity of 92% (HPLC).
R _f = 0.24 (acetonitrile: water 9: 1)
IR (KBr): 3985, 1755, 1601, 1468, 1397, 1287, 1101 cm ^-1

1 H-NMR (300 MHz, D₂O): δ = 1.26 (d, J = 6 Hz, 3 H, CH₃CHOH), 2.74 (dd, J = 17 Hz, 9 Hz, 1 H, H-4) , 2.89 (dd, J = 17 Hz, 8 Hz, 1 H, H-4 ′), 3.39 (dd, J = 6 Hz, 2.5 Hz, 1 H, H-6), 3, 94 (s, 3 H, OCH₃), 4.20 (m, 2 H, CH₃CHOH, H-5), 7.87 (s, 1 H, pyrazine-H).

MS (FAB) m / e = 375 (M + Na), 397 (M + 2 Na-H).

Example 29 Sodium (5R, 6S) -3- (2-amino-5,6-dimethyl-3-pyrazinylthio] - 6 - [(1R) -1-hydroxyethyl] -7-oxo-1-azabicyclo [3,2,0] hept-2-en-2- 2-carboxylate

As described for Example 28, 534 mg (1.1 mmol) of (5R, 6S) -3- (2-amino-5,6-dimethyl-3-pyrazinylthio) - 6 - [(1R) -1-hydroxyethyl were obtained ] -7-oxo-1-azabicyclo [3,2,0] - hept-2-en-2-carboxylic acid p-nitrobenzyl ester 81 mg (20% of theory) of the title compound as a colorless lyophilisate in a purity of 90% ( HPLC).
R _f = 0.46 (acetonitrile: water 4: 1)
IR (KBr): 3410, 1762, 1609, 1378, 1185 cm ^-1

1 H-NMR (300 MHz, D₂O): δ = 1.22 (d, J = 6.5 Hz, 3 H, CH₃CHOH), 2.33, 2.37 (s, 6 H, CH₃), 2.55 (dd, J = 14 Hz, 9 Hz, 1 H, H-4), 2.76 (dd, J = 14 Hz, 7.5 Hz, 1 H, H-4 ′), 3.32 (dd, J = 6 Hz, 2.5 Hz, 1 H, H-6), 4.05-4.20 (m, 2 H, CH₃CHOH, H-5).

Example 30 Sodium (5R, 6S) -3- (2-amino-5- (morpholin-4-yl) -3-pyrazinylthio] - 6 - [(1R) -1-hydroxyethyl] -7-oxo-1-azabicyclo [3,2,0] - hept-2-en-2-carboxylate

As described for Example 28, 1.98 g (3.6 mmol) of (5R, 6S) -3- [2-amino-5- (morpholin-4-yl) -3-pyrazinylthio] - 6- [ (1R) -1-hydroxyethyl] -7-oxo-1-azabicyclo- [3,2,0] hept-2-en-2-carboxylic acid p-nitrobenzyl ester 1.27 g (82% of theory) of the title compound as bright lyophilisate in a purity of 88% (HPLC).
R _f = 0.26 (acetonitrile: water 9: 1)
IR (KBr): 3432, 1756, 1601, 1468, 1450, 1384, 1250 cm ^-1

1 H-NMR (300 MHz, D₂O): δ = 1.23 (d, J = 6 Hz, 3 H, CH₃CHOH), 2.75 (dd, J = 16 Hz, 8 Hz, 1 H, H-4) , 2.96 (dd, J = 16 Hz, 8 Hz, 1 H, H-4 '), 3.35 (m, 5 H, CH₂N, H-6), 3.88 (m, 4 H, CH₂O ), 4.14 (dt, J = 6 Hz, 2 Hz, H-5), 4.16 (dq, J = 6 Hz, 6 Hz, CH₃CHOH) together 2 H, 7.80 (s, 1 H, Pyrazine-H).

Example 31 Sodium (5R, 6S) -3- [2-amino-5- (4-methyl-piperazin-1-yl) -3- pyrazinylthio] -6 - [(1R) -1-hydroxyethyl] -7-oxo-1-azabicyclo [3,2,0] hept-- 2-en-2-carboxylate

As described for Example 28, 1.81 g (3.26 mmol) of (5R, 6S) -3- [2-amino-5- (4-methyl-piperazin-1-nyl) -3-pyrazinylthio] -6 - [(1R) -1-hydroxyethyl] -p-nitrobenzyl ester 285 mg (20% of theory) of the title compound as a bright lyophilisate, in a purity of 91% (HPLC).
R _f = 0.17 (acetonitrile: water 7: 3)
IR (KBr): 3444, 1764, 1594, 1453, 1386, 1258 cm ^-1

1 H-NMR 08357 00070 552 001000280000000200012000285910824600040 0002003641872 00004 08238 (250 MHz, D₂O): δ = 1.10 (d, J = 6.5 Hz, 3 H, CH₃CHOH), 2.49 (s, 3 H, CH₃), 2.5-2.8 (m, 2 H, H-4), 2.90 (m, 4 H, CH₂N), 3.23 (dd, J = 6 Hz, 2.5 Hz, 1 H, H -6), 3.85 (m, 4 H, CH₂N), 4.00 (dt, J = 8 Hz, 2.5 Hz, H-5), 4.03 (dq, J = 6.5 Hz, 6 Hz, CH₃CHOH) together 2 H, 7.68 (s, 1 H, pyrazine-H).

Example 32 Sodium (5R, 6S) -3- [2-amino-5- (piperidin-1-yl-3-pyrazinylthio] - 6 - [(1R) -1-hydroxyethyl] -7-oxo-1-azabicyclo [3,2,0] hept- 2-en-carboxylate

As described for Example 28, 840 mg (1.55 mmol) of (5R, 6S) -3- [2-amino-5- (piperidin-1-yl-3-pyrazinylthio] -6 - [(1R) -1-hydroxyethyl] -7-oxo-1-azabicyclo [3,2,0] hept-- 2-en-2-carboxylic acid p-nitrobenzyl ester 227 mg (34% of theory) of the title compound as a colorless lyophilisate.
R _f = 0.24 (acetonitrile: water 9: 1) in a purity of 98% (HPLC).
IR (KBr): 3439, 1761, 1593, 1462, 1386, 1251, 1105 cm ^-1

1 H-NMR (300 MHz, D₂O): δ = 1.21 (d, J = 6.5 Hz, 3 H, CH₃CH), 1.65 (m, 6 H, CH₂), 2.72 (dd, J = 16 Hz, 8 Hz, 1 H, H-4), 2.86 (dd, J = 16 Hz, 7 Hz, 1 H, H-4), 3.29 (m, 4 H, NCH₂), 3 , 36 (dd, J = 6 Hz, 2.5 Hz, 1 H, H-6), 4.15 (dt, J = 7 Hz, H-5), 4.20 (m, CH₃CHOH) together 2 H , 7.81 (s, 1H, pyrazine-H).

Example 33 Sodium (5R, 6S) -3- [2-amino-5- (pyrrolidin-1-yl-3-pyrazinylthio] - 6 - [(1R) -1-hydroxyethyl] -7-oxo-1-azabicyclo [3,2,0] hept- 2-en-2-carboxylate

As described for Example 28, 840 mg (1.59 mmol) of (5R, 6S) -3- [2-amino-5- (pyrrolidin-1-yl-3-pyrazinylthio] -6 - [(1R) -1-hydroxyethyl] -7-oxo-1-azabicyclo [3,2,0] hept-2-en-2-carboxylic acid p-nitrobenzyl ester 255 mg (39% of theory) of the title compound as a bright lyophilizate.
R _f = 0.21 (acetonitrile: water 9: 1) in a purity of 96% (HPLC).
IR (KBr): 3426, 1756, 1588, 1474, 1397, 1104 cm ^-1

1 H-NMR (300 MHz, D₂O): δ = 1.22 (d, J = 6.5 Hz, 3 H, CH₃CH), 1.99 (m, 4 H, CH₂), 2.69 (dd, J = 16 Hz, 8 Hz, 1 H, H-4), 2.82 (dd, J = 16 Hz, 7.5 Hz, 1 H, H-4), 3.30 (m, 5 H, CH₂N, H-6), 4.10 (dt, J = 6.5 Hz, 2 Hz, H-5), 4.18 (m, CH₃CHOH) together 2 H, 7.54 (s, 1 H, pyrazine-H ).

Example 34 (5R, 6S) -3- [2-amino-5- (1-oxo-thiomorpholin-4-yl) -3-pyrazinylthio] - 6 - [(1R) -1-hydroxyethyl] -7-oxo-1-azabicyclo [3,2,0] hept- 2-en-2-carboxylic acid p-nitrobenzyl ester

As described for Example 21A, 3.80 g (6.55 mmol) of (5R, 6S) -3-diphenylphosphonyloxy-6 - [(1R) -1-hydroxyethyl] -7-oxo-1-azabicyclo [3 , 2,0] hept-2-en-2-carboxylic acid p-nitrobenzyl ester and 1.68 g (6.67 mmol) 2-amino-5- (1-oxo-thiomorpholin-4-yl) -3-pyrazinthiol after 2.5 h at 0 ° C. and treating the crude product with ether, 2.17 g (58%) of the title compound as yellow crystals.
Mp: 198 ° C (dec.)
IR (KBr): 3439, 1779, 1710, 1608, 1520, 1479, 1348 cm ^-1

1 H-NMR (300 MHz, D₂O): δ = 1.12 (d, J = 6.5 Hz, 3 H, CH₃CHOH); 2.6-3.0 (m, 6H, H-4, H-4 ', CH₂SO); 3.85 (m, CH₂N); 3.92 (m, CH₃CHOH); together 5 H; 4.11 (dt, J = 9 Hz, 2.5 Hz, 1H, H-5); 5.02 (d, J = 5 Hz, 1H, OH); 5.35 and 5.50 (AB, J = 15.5 Hz, 2 H, COOCH₂); 5.85 (s, 2H, NH₂); 7.75 and 8.24 (AB, J = 9.5 Hz, 4 H, p-NO₂-C₆H₄); 8.02 (s, 1H, pyrazine-H).

Example 35 (5R, 6S) -3- [2-amino-5- (1,1-dioxo-1-thiomorpholin-4-yl) -3- pyrazinylthio] -6 - [(1R) -1-hydroxyethyl] -7-oxo-1-azabicyclo [3,2,0] hept-- 2-en-2-carboxylic acid p-nitrobenzyl ester

As described for Example 21A, 3.97 g (6.84 mmol) of (5R, 6S) -3-diphenylphosphonyloxy-6 - [(1R) -1-hydroxyethyl] -7-oxo-1-azabicyclo [3 , 2,0] hept-2-en-2-carboxylic acid p-nitrobenzyl ester and 1.87 g (7.18 mmol) 2-amino-5- (1,1-dioxothiomorpholin-4-yl) -3 -pyrazinthiol after 3 h at 0 ° C and treating the crude product with ether 3.35 g (78%) of the title compound as yellow crystals.
Mp: 172 ° C (dec.)
R _f = 0.12 (ethyl acetate)
IR (KBr): 3455, 1774, 1710, 1661, 1607, 1520, 1471, 1350, 1283, 1189 cm ^-1

1 H-NMR (200 MHz, DMSO): δ = 1.10 (d, J = 6 Hz, 3 H, CH₃CH); 2.72 (s, 1H, H-4); 2.88 (s, 1H, H-4 ′); 3.10 (m, 4H, CH₂SO₂); 3.37 (H-6 under H₂O); 3.88 (m, 5H, CH₂N, CH₃CHOH); 4.08 (dt, J = 10 Hz, 1.5 Hz, 1H, H-5); 5.02 (d, J = 5 Hz, 1H, OH); 5.32 and 5.46 (AB, J = 14.5 Hz, 2 H, COOCH₂); 5.42 (bs, 2H, NH₂); 7.72 and 8.23 (AB, J = 9.5 Hz, 4 H, p-NO₂-C₆H₄); 8.03 (s, 1H, pyrazine-H).

Example 36 Sodium (5R, 6S) -3- [2-Amino-5- (thiomorpholin-4-yl) -3-pyrazinylthio] - 6 - [(1R) -1-hydroxyethyl] -7-oxo-1-azabicyclo [3,2,0] hept- 2-en-2-carboxylate

As described for Example 28, 3.80 g (6.80 mmol) of (5R, 6S) -3- [2-amino-5- (thiomorpholin-4-yl-3-pyrazinylthio] -6 - [(1R ) -1-hydroxyethyl] -7-oxo-1-azabicyclo [3,2,0] hept-- 2-en-2-carboxylic acid p-nitrobenzyl ester 455 mg (15%) of the title compound as a bright lyophilisate; R _f = 0.34 (acetonitrile: water 9: 1); in a purity of 91% (HPLC)
IR (KBr) 3434, 1754, 1595, 1469, 1394, 1242, 1003 cm ^-1

1 H-NMR (300 MHz, D₂O): δ = 1.22 (d, J = 6.5 Hz, 3 H, CH₃CH); 2.73 (m, CH₂S, H-4); 2.85 (dd, J = 16 Hz, 8 Hz, H-4 ′) together 6 H; 3.35 (dd, J = 6 Hz, 2 Hz, 1H, H-6); 3.71 (m, 4H, CH₂N); 4.12 (dt, J = 8 Hz, 2 Hz, H-5); 4.18 (m, CH₃CHOH) together 2 H; 7.78 (s, 1H, pyrazine-H).

Example 37 Sodium (5R, 6S) -3- [2-amino-5- (1-oxo-thiomorpholin-4-yl) - 3-pyrazinylthio] -6 - [(1R) -1-hydroxyethyl] -7-oxo-1-azabicyclo [3,2,0] he-pt- 2-en-2-carboxylate

As described for Example 28, 2.28 g (3.96 mmol) of (5R, 6S) gave -3- [2-amino-5- (1-oxo-thiomorpholin-4-yl-3-pyrazinylthio] -6 - [(1R) -1-hydroxyethyl] -7-oxo-1-azabicyclo [3,2,0-] hept-2-en-2-carboxylic acid p-nitrobenzyl ester 523 mg (29%) of the title compound as a bright lyophilizate ;
R _f = 0.13 (acetonitrile: water 9: 1) in a purity of 89% (HPLC)
IR (KBr): 3420, 1761, 1592, 1488, 1388, 1252, 1209, 1096 cm ^-1

1 H-NMR (300 MHz, D₂O): δ = 1.23 (d, J = 6.5 Hz, 3 H, CH₃CH); 2.76 (dd, J = 15.5 Hz, 8 Hz, H-4); 2.86 (dd, J = 15.5 Hz, 7.5 Hz, H-4 ′); 2.9-3.1 (m, CH₂SO) together 6 H; 3.35 (dd, J = 6 Hz, 2 Hz, 1H, H-6); 3.90 (m, 4H, CH₂N); 4.10-2.25 (m, 2H, H-5, CH₃CHOH); 7.85 (s, 1H, pyrazine-H).

Example 38 Sodium (5R, 6S) -3- [2-amino-5- [1,1-dioxothiomorpholine-4- yl) -3-pyrazinylthio] -6 - [(1R) -1-hydroxyethyl] -7-oxo-1- azabicyclo [3,2,0] hept-2-ene-2-carboxylate

As described for Example 28, 3.33 g (5.64 mmol) of (5R, 6S) -3- [2-amino-5- (1,1-dioxothiomorpholin-4-yl) -3-pyrazinylthio were obtained ] -6 - [(1R) -1-hydroxyethyl] -7-oxo-1-azabicyclo [3,2,0] hept-2-en-2-carboxylic acid p-nitrobenzyl ester 464 mg (17%) of the title compound as light lyophilisate; R _f = 0.24 (acetonitrile: water 9: 1) in a purity of 94% (HPLC).
IR (KBr): 3426, 1753, 1592, 1469, 1390, 1281, 1207, 1207, 1125, 1100 cm ^-1

1 H-NMR (250 MHz, D₂O): δ = 1.25 (d, J = 6.5 Hz, 3 H, CH₃CH); 2.78 (dd, J = 18.5 Hz, 9 Hz, H-4); 2.89 (dd, J = 18.5 Hz, 7.5 Hz, H-4 ′) together 2 H; 3.29 (m, 4H, CH₂SO₂); 3.38 (dd, J = 7.5 Hz, 2.5 Hz, 1H, H-6); 4.04 (m, 4H, CH₂N); 4.15 (dt, J = 7.5 Hz, 2.5 Hz, H-5); 4.21 (m, CH₃CHOH) together 2 H; 7.99 (s, 1H, pyrazine-H).

Claims (7)

1. Pyrazinylthio-carbapenems of the general formula (I) in which R¹- for hydrogen or
- stands for a hydroxy protecting group, R²- for hydrogen or
- for a carboxy protecting group or
- represents an ester residue which can be split off in vivo, R³- represents hydrogen or
- stands for C₁-C₆-alkyl and R⁴- stands for a group of the formula -OR⁵, -SO _m R⁵ or - NR⁶R⁷, whereR⁵- means C₃-C₈-cycloalkyl or trifluoromethyl, or
- Straight-chain or branched C₁-C₁₀-alkyl means that by hydroxy, C₁-C Alk-alkoxy, C₁-C₄-alkylthio, carboxy, C₁-C₆- alkoxycarbonyl, cyano, halogen, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, amino, C₁-C₅ Alkylamino, di-C₁-C₅-alkylamino, C₁-C₆-alkylsulfonyl, C₆-C₁₂-arylsulfonyl, sulfamoyl, di-C₁-C₃-alkylaminosulfonyl, pyridyl, thienyl, furyl, pyrimidyl, pyrazinyl, pyridazinyl, quinolyl, quinolyl, isoquinolyl , Quinoxalyl, Benzthiazolyl, Benzoxazolyl or Benzimidazolyl may be substituted, or
- C₆-C₁₂-aryl, C₇-C₁₄-aralkyl or a heteroaryl radical from the series pyridyl, thienyl, furyl, pyrimidyl, pyridazinyl, pyrazinyl, quinolyl, isoquinolyl, quinazolyl, quinoxalyl, benzothiazolyl, benzoxazolyl or benzimidazolyl bis, where means the 4 times the same or different by halogen, cyano, nitro, C₁-C₆-alkyl, C₁-C₆-alkoxy, C₁-C₄-alkylthio, trifluoromethyl, trifluoromethoxy, -S (O) _m CF₃, amino, C₁-C₅-alkylamino, Di-C₁-C₅-alkylamino, C₁-C₆-alkylsulfonyl, C₆-C₁₂-arylsulfonyl, sulfamoyl or di-C₁-C₃-alkylaminosulfonyl may be substituted, m - represents a number 0, 1 or 2, andR⁶ and R⁷ are identical or different are and- are hydrogen, optionally substituted by trifluoromethyl C₁-C₁₂-alkyl, or C₆- C₁₂-aryl, C₇-C₁₄-aralkyl, C₁-C₇-acyl, C₁-C₄-alkylsulfonyl or C₆-C₁₂-arylsulfonyl, or in whichR⁶ and R⁷ together with the nitrogen atom form a ring of the formula where m - represents a number 0, 1 or 2, n - represents a number 1 to 8, R⁸ and R⁹ are the same or different and - for C₁-C₈-alkyl, C₁-C₄-hydroxyalkyl, carboxy, carbamoyl or C₁ -C₆-Alkoxycarbonyl standundX- for hydrogen or
- C₁-C₆-alkyl, which may be substituted by phenyl, halogen or hydroxy, or
- represents C₆-C₁₂-aryl, which can be substituted up to 3 times the same or different by halogen, cyano, trifluoromethyl, trifluoromethoxy, C₁-C₆-alkyl, C₁-C₆-alkoxy, or
- stands for C₁-C₆-alkylsulfonyl, C₆-C₁₂-arylsulfonyl, sulfamoyl or di-C₁-C₆-alkylaminosulfonyl, or
- for a group of the formula wherein R¹⁰, R¹¹, R¹² and R¹³ are the same or different and are hydrogen, C₁-C₆-alkyl, C₆-C₁₂-aryl or C₇-C₁₄-aralkyl and their salts. 2. Compounds of general formula (I) according to claim 1, in which R¹- is hydrogen, or
- For a hydroxy protecting group from the series trimethylsilyl, triethylsilyl, triisopropylsilyl, tert. Butyldimethylsilyl, triphenylsilyl, trimethylsilylethoxycarbonyl, benzyl, benzyloxycarbonyl, 2-nitrobenzyl, 4-nitrobenzyl, 2-nitrobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, tert. Butoxycarbonyl, allyloxycarbonyl, 4-methoxybenzyl, 4-methoxybenzyloxycarbonyl, formyl, acetyl, trichloroacetyl, 2,2,2, - trichloroethoxycarbonyl, 2,4-dimethoxybenzyl oxycarbonyl, methoxymethyl or methoxyethoxymethyl, R²- represents hydrogen, or
- for methyl, ethyl, tert. Butyl, 2-chloroethyl, 2,2,2-trichloroethyl, cyanoethyl, diphenylmethyl, triphenylmethyl, acetoxymethyl, allyl, benzyl, 4-methoxybenzyl, 2,4-dimethoxybenzyl, 1-phenoxyethyl, 2-methyl-2-propenyl, 4- Nitrobenzyl, 2-nitrobenzyl, trimethylsilylethyl or tert. Butyl-dimethylsilylethyl stands, or
- for the rest of the formula R³- for hydrogen or
- represents C₁-C₃-alkyl, andR⁴- represents a group of the formula -OR⁵, -SO _m R⁵ or - NR⁶R⁷, whereR⁵- means C₃-C₇-cycloalkyl or trifluoromethyl or
- Straight-chain or branched C₁-C₈-alkyl means that by hydroxy, C₁-C₄-alkoxy, trifluoromethyl, carboxy, C₁-C₄-alkoxycarbonyl, cyano, fluorine, chlorine, bromine, trifluoromethyl, trifluoromethoxy, C₁-C₃-alkylamino, di -C₁-C₃-alkylamino, C₁-C₄-alkylsulfonyl, phenylsulfonyl, dimethylaminosulfonyl, pyridyl, thienyl, pyrimidyl, pyrazinyl, pyridazinyl, quinolyl or isoquinolyl, or may be substituted
- for phenyl, benzyl, phenethyl, pyridyl, thienyl, furyl, pyrimidyl, pyrazinyl, pyridazinyl, quinolyl or isoquinolyl, the radicals mentioned being up to 3 times the same or different by fluorine, chlorine, bromine, cyano, nitro, C₁-C₅- Alkyl, C₁-C₅-alkoxy, methylthio, trifluoromethyl, trifluoromethoxy, -S (O) _m CF₃, C₁-C₃- alkylamino, di-C₁-C₃-alkylamino, C₁-C₄- alkylsulfonyl, phenylsulfonyl or dimethylaminosulfonyl may be substituted, m - represents a number 0, 1 or 2 and R⁶ and R⁷ are the same or different and - hydrogen or
- C₁-C₁₂-alkyl optionally substituted by trifluoromethyl, or phenyl, benzyl, acetyl, methylsulfonyl or phenylsulfonyl, or wherein R⁶ and R⁷ together with the nitrogen atom form a ring of the formula where m - stands for a number 0, 1 or 2, n - stands for a number 0 to 3, R⁸ and R⁹ are the same or different and - for hydrogen, C₁-C₆-alkyl, hydroxymethyl, hydroxyethyl, carboxy or C₁-C₄ -Alkoxycarbonyl and X- represent hydrogen or
- C₁-C₅-alkyl, which may be substituted by phenyl, fluorine, chlorine, bromine or hydroxy or
- represents phenyl, which can be substituted up to 2 times the same or different by fluorine, chlorine, bromine, trifluoromethyl, C1-C₄-alkyl or C₁-C₄-alkoxy, or
- stands for C₁-C₄-alkylsulfonyl, phenylsulfonyl, sulfamoyl or di-C₁-C₄-alkylaminosulfonyl, or
- for a group of the formula wherein R¹⁰, R¹¹, R¹² and R¹³ are the same or different and are hydrogen, C₁-C₄-alkyl, phenyl or benzyl and their salts. 3. Compounds of general formula (I) according to claim 1 in which R¹- is hydrogen, or
- For trimethylsilyl, triphenylsilyl, trimethylsilylethoxycarbonyl, tert. Butyl-di methylsilyl, 2-nitrobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, allyloxycarbonyl or formyl, R²- is hydrogen, or
- for methyl, ethyl, tert. Butyl, 2,2,2-trichloroethyl, allyl, acetoxymethyl, 4-nitrobenzyl, 2-nitrobenzyl, 4-methoxybenzyl, benzyl or trimethylsilylethyl, or
- for a remainder of the formula or -CH₂-OCO-C (CH₃) ₃, R³- represents hydrogen or methyl andR⁴- represents a group of the formula -OR⁵, -SO _m R⁵ or -NR⁶R⁷, whereinR⁵- denotes cyclopropyl, cyclopentyl, cyclohexyl or trifluoromethyl, or
- Straight-chain or branched C₁-C₆ alkyl means, which can be substituted by methoxy, carboxy, methoxycarbonyl, ethoxycarbonyl, trifluoromethyl, dimethylamino, pyridyl or pyrimidyl, or
- Phenyl, benzyl, pyridyl, pyrimidyl or pyridazinyl means, where the radicals mentioned can be substituted up to 3 times identically or differently by fluorine, chlorine, bromine, nitro, methyl, methoxy, trifluoromethyl or -S (O) _m CF₃, m - is 0, 1 or 2 and R⁶ and R⁷ are the same or different and are hydrogen or
- C₁-C₁₂-alkyl optionally substituted by trifluoromethyl, orR⁶ and R⁷ together with the nitrogen atom form a ring of the formula where m - is a number 0, 1 or 2, n - is a number 0 or 1, R⁵- is hydrogen or methyl, R⁶- is hydrogen, methyl, carboxy or ethoxycarbonyl, andX- is hydrogen, C₁- C₄-alkyl or benzyl, or
represents phenyl which is optionally substituted by fluorine, or
- stands for sulfamoyl or dimethylaminosulfonyl, or
- for a group of the formula wherein R¹⁰, R¹¹, R¹² and R¹³ are the same or different and are hydrogen or methyl and their salts. 4. A process for the preparation of pyrazinylthio-carbapenems of the general formula (I) in Claim 1 and their salts, characterized in that keto esters of the general formula (II) in whichR¹- has the meaning given andR¹⁹- for a carboxy protecting group or
represents an ester residue which can be split off in vivo and thiols of the general formula (III) in which
R³ and R⁴ have the meaning given above,
reacted with auxiliaries in inert solvents in the presence of bases,
splitting off protective groups if necessary
and optionally produces the desired salts or converts the salts into the free compounds. 5. Pyrazinylthio-carbapenems of the general formula (I) in which R¹- for hydrogen or
- stands for a hydroxy protecting group, R²- for hydrogen or
- for a carboxy protecting group or
- represents an ester residue which can be split off in vivo, R³- represents hydrogen or
- stands for C₁-C₆-alkyl and R⁴- stands for a group of the formula -OR⁵, -SO _m R⁵ or - NR⁶R⁷, whereR⁵- means C₃-C₈-cycloalkyl or trifluoromethyl, or
- Straight-chain or branched C₁-C₁₀-alkyl means that by hydroxy, C₁-C Alk-alkoxy, C₁-C₄-alkylthio, carboxy, C₁-C₆- alkoxycarbonyl, cyano, halogen, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, amino, C₁-C₅ Alkylamino, di-C₁-C₅-alkylamino, C₁-C₆-alkylsulfonyl, C₆-C₁₂-arylsulfonyl, sulfamoyl, di-C₁-C₃-alkylaminosulfonyl, pyridyl, thienyl, furyl, pyrimidyl, pyrazinyl, pyridazinyl, quinolyl, quinolyl, isoquinolyl , Quinoxalyl, Benzthiazolyl, Benzoxazolyl or Benzimidazolyl may be substituted, or
- C₆-C₁₂-aryl, C₇-C₁₄-aralkyl or a heteroaryl radical from the series pyridyl, thienyl, furyl, pyrimidyl, pyridazinyl, pyrazinyl, quinolyl, isoquinolyl, quinazolyl, quinoxalyl, benzothiazolyl, benzoxazolyl or benzimidazolyl bis, where means the bisimidazolyl bis, where die means 4 times the same or different by halogen, cyano, nitro, C₁-C₆-alkyl, C₁-C₆-alkoxy, C₁-C₄-alkylthio, trifluoromethyl, trifluoromethoxy, -S (O) _m CF₃, amino, C₁-C₅-alkylamino, Di-C₁-C₅-alkylamino, C₁-C₆-alkylsulfonyl, C₆-C₁₂-arylsulfonyl, sulfamoyl or di-C₁-C₃-alkylaminosulfonyl may be substituted, m - represents a number 0, 1 or 2, andR⁶ and R⁷ are identical or different are and are hydrogen, optionally substituted by trifluoromethyl C₁-C₁₂-alkyl, or C₆- C₁₂-aryl, C₇-C₁₄-aralkyl, C₁-C₇-acyl, C₁-C₄-alkylsulfonyl or C₆-C₁₂-arylsulfonyl, or in whichR⁶ and R⁷ together with the nitrogen atom form a ring of the formula where m - represents a number 0, 1 or 2, n - represents a number 1 to 8, R⁸ and R⁹ are identical or different and - for C₁-C₈-alkyl, C₁-C₄-hydroxyalkyl, carboxy, carbamoyl or C₁ -C₆-Alkoxycarbonyl standundX- for hydrogen or
- represents C₁-C₆-alkyl, which may be substituted by phenyl, halogen or hydroxy, or
- represents C₆-C₁₂-aryl, which can be substituted up to 3 times identically or differently by halogen, cyano, trifluoromethyl, trifluoromethoxy, C₁-C₆-alkyl, C₁-C₆-alkoxy, or
- represents C₁-C₆-alkylsulfonyl, C₆-C₁₂-arylsulfonyl, sulfamoyl or di-C₁-C₆-alkylaminosulfonyl, or
- for a group of the formula wherein R¹⁰, R¹¹, R¹² and R¹³ are the same or different and are hydrogen, C₁-C₆-alkyl, C₆-C₁₂-aryl or C₇-C₁₄-aralkyl and their salts for use in a method for the therapeutic treatment of the human or animal body. 6. Medicament containing pyrazinylthio-carbapenems of the general formula (I) in which
R¹- for hydrogen or
- stands for a hydroxy protecting group, R²- for hydrogen or
- for a carboxy protecting group or
- represents an ester residue which can be split off in vivo, R³- represents hydrogen or
- stands for C₁-C₆-alkyl and R⁴- stands for a group of the formula -OR⁵, -SO _m R⁵ or - NR⁶R⁷, whereR⁵- means C₃-C₈-cycloalkyl or trifluoromethyl, or
- Straight-chain or branched C₁-C₁₀-alkyl means that by hydroxy, C₁-C Alk-alkoxy, C₁-C₄-alkylthio, carboxy, C₁-C₆- alkoxycarbonyl, cyano, halogen, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, amino, C₁-C₅ Alkylamino, di-C₁-C₅-alkylamino, C₁-C₆-alkylsulfonyl, C₆-C₁₂-arylsulfonyl, sulfamoyl, di-C₁-C₃-alkylaminosulfonyl, pyridyl, thienyl, furyl, pyrimidyl, pyrazinyl, pyridazinyl, quinolyl, quinolyl, isoquinolyl , Quinoxalyl, Benzthiazolyl, Benzoxazolyl or Benzimidazolyl may be substituted, or
- C₆-C₁₂-aryl, C₇-C₁₄-aralkyl or a heteroaryl radical from the series pyridyl, thienyl, furyl, pyrimidyl, pyridazinyl, pyrazinyl, quinolyl, isoquinolyl, quinazolyl, quinoxalyl, benzothiazolyl, benzoxazolyl or benzimidazolyl bis, where means the bisimidazolyl bis, where die means 4 times the same or different by halogen, cyano, nitro, C₁-C₆-alkyl, C₁-C₆-alkoxy, C₁-C₄-alkylthio, trifluoromethyl, trifluoromethoxy, -S (O) _m CF₃, amino, C₁-C₅-alkylamino, Di-C₁-C₅-alkylamino, C₁-C₆-alkylsulfonyl, C₆-C₁₂-arylsulfonyl, sulfamoyl or di-C₁-C₃-alkylaminosulfonyl may be substituted, m - represents a number 0, 1 or 2, andR⁶ and R⁷ are identical or different are and are hydrogen, optionally substituted by trifluoromethyl C₁-C₁₂-alkyl, or C₆- C₁₂-aryl, C₇-C₁₄-aralkyl, C₁-C₇-acyl, C₁-C₄-alkylsulfonyl or C₆-C₁₂-arylsulfonyl, or in whichR⁶ and R⁷ together with the nitrogen atom form a ring of the formula where m - represents a number 0, 1 or 2, n - represents a number 1 to 8, R⁸ and R⁹ are identical or different and - for C₁-C₈-alkyl, C₁-C₄-hydroxyalkyl, carboxy, carbamoyl or C₁ -C₆-Alkoxycarbonyl standundX- for hydrogen or
- represents C₁-C₆-alkyl, which may be substituted by phenyl, halogen or hydroxy, or
- represents C₆-C₁₂-aryl, which can be substituted up to 3 times identically or differently by halogen, cyano, trifluoromethyl, trifluoromethoxy, C₁-C₆-alkyl, C₁-C₆-alkoxy, or
- stands for C₁-C₆-alkylsulfonyl, C₆-C₁₂-arylsulfonyl, sulfamoyl or di-C₁-C ¶-alkylaminosulfonyl, or - for a group of the formula wherein R¹⁰, R¹¹, R¹² and R¹³ are the same or different and are hydrogen; Are C₁-C₆-alkyl, C₆-C₁₂-aryl or C₇-C₁₄-aralkyl and their salts. 7. Use of pyrazinylthio-carbapenems of the general formula (I) in which R¹- for hydrogen or
- stands for a hydroxy protecting group, R²- for hydrogen or
- for a carboxy protecting group or
- represents an ester residue which can be split off in vivo, R³- represents hydrogen or
- stands for C₁-C₆-alkyl and R⁴- stands for a group of the formula -OR⁵, -SO _m R⁵ or - NR⁶R⁷, whereR⁵- means C₃-C₈-cycloalkyl or trifluoromethyl, or
- Straight-chain or branched C₁-C₁₀-alkyl means that by hydroxy, C₁-C Alk-alkoxy, C₁-C₄-alkylthio, carboxy, C₁-C₆- alkoxycarbonyl, cyano, halogen, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, amino, C₁-C₅ Alkylamino, di-C₁-C₅-alkylamino, C₁-C₆-alkylsulfonyl, C₆-C₁₂-arylsulfonyl, sulfamoyl, di-C₁-C₃-alkylaminosulfonyl, pyridyl, thienyl, furyl, pyrimidyl, pyrazinyl, pyridazinyl, quinolyl, quinolyl, isoquinolyl , Quinoxalyl, Benzthiazolyl, Benzoxazolyl or Benzimidazolyl may be substituted, or
- C₆-C₁₂-aryl, C₇-C₁₄-aralkyl or a heteroaryl radical from the series pyridyl, thienyl, furyl, pyrimidyl, pyridazinyl, pyrazinyl, quinolyl, isoquinolyl, quinazolyl, quinoxalyl, benzothiazolyl, benzoxazolyl or benzimidazolyl bis, where means the bisimidazolyl bis, where die means 4 times the same or different by halogen, cyano, nitro, C₁-C₆-alkyl, C₁-C₆-alkoxy, C₁-C₄-alkylthio, trifluoromethyl, trifluoromethoxy, -S (O) _m CF₃, amino, C₁-C₅-alkylamino, Di-C₁-C₅-alkylamino, C₁-C₆-alkylsulfonyl, C₆-C₁₂-arylsulfonyl, sulfamoyl or di-C₁-C₃-alkylaminosulfonyl may be substituted, m - represents a number 0, 1 or 2, andR⁶ and R⁷ are identical or different are and are hydrogen, optionally substituted by trifluoromethyl C₁-C₁₂-alkyl, or C₆- C₁₂-aryl, C₇-C₁₄-aralkyl, C₁-C₇-acyl, C₁-C₄-alkylsulfonyl or C₆-C₁₂-arylsulfonyl, or in whichR⁶ and R⁷ together with the nitrogen atom form a ring of the formula where m - represents a number 0, 1 or 2, n - represents a number 1 to 8, R⁸ and R⁹ are identical or different and - for C₁-C₈-alkyl, C₁-C₄-hydroxyalkyl, carboxy, carbamoyl or C₁ -C₆-Alkoxycarbonyl standundX- for hydrogen or
- represents C₁-C₆-alkyl, which may be substituted by phenyl, halogen or hydroxy, or
- represents C₆-C₁₂-aryl, which can be substituted up to 3 times identically or differently by halogen, cyano, trifluoromethyl, trifluoromethoxy, C₁-C₆-alkyl, C₁-C₆-alkoxy, or
- represents C₁-C₆-alkylsulfonyl, C₆-C₁₂-arylsulfonyl, sulfamoyl or di-C₁-C₆-alkylaminosulfonyl, or
- for a group of the formula whereinR¹⁰, R¹¹, R¹² and R¹³ are the same or different and are hydrogen, C₁-C₆-alkyl, C₆-C₁₂-aryl or C₇-C₁₄-aralkyl and their salts for the manufacture of medicaments.