CS225819B2 - The production of new 6-aminepenam derivates - Google Patents

Description

The present invention relates to a process for the preparation of novel therapeutically valuable 6-aminopenamide derivatives.

The novel δ-aminopenamide derivatives correspond to the general formula I

M fji

R 1 = CH = N-i-J- ^S o> _N- CH ₃ CH ³

Rj (I) wherein

R 1 is a C 8 -C 11 azatricycloalkenyl group and A 2 is a C 3 -C 16 alkanoyloxyalkoxycarbonyl or C 4 -C 16 alkoxycarbonyloxyalkoxycarbonyl group, and also include salts of the compounds of formula I.

The C 8 -C 11 azatricycloalkenyl is, for example, an azatricyclodecenyl group, in particular a 4-azatrioyklo [5,2,1,0 ² '] dec-8-en-4-yl group, and an azatricycloundecanyl group, in particular a 4- azatricyclo [5,3,2,0 ² ®] undec-8-en-4-yl or 8-azatricyclo [4,3,2,0 ¹ '^] undec-3-en-8-yl group.

The naming of the above compounds is carried out according to the IUPAC (International Union of Pure and Applied Chemistry) rules currently in force, and the nomenclature is commented on, for example, in D. Hellwinkel The systematic nomenclature of organ chemistry, Springer-Verlang, Berlin, 1974, p. to 28.

Particularly preferred R ₁ radicals are those linked via the ring nitrogen atom which are derived from azatricycloalkene, such as 7-azatricyclo- (5,2,2,2,26) undee-8-ene.

The physiologically cleavable C 3 -C 16 alkanoyloxyalkoxycarbonyl radical is, for example, pivaloyloxyraethoxycarbonyl or pivaloyloxyethoxycarbonyl.

The physiologically cleavable alkoxycarbonyloxy alkoxycarbonyl radical Rg having 4 to 16 carbon atoms is, for example, methoxycarbonyloxymethoxycarbonyl or ethoxycarbonyloxyethoxycarbonyl.

The compounds of formula I have a basic amidino group R 1, -CH = N- and can form salts with acids, for example with inorganic acids such as hydrochloric acid, sulfuric acid or phosphoric acid, or with suitable organic carboxylic or sulfonic acids such as aliphatic mono-, di- or tricarboxylic acids such as acetic acid, malonic acid, tartaric acid, emonic acid, citric acid, 4- (N, N-dipropylsulfemoyl) benzoic acid (Probenecid), p-toluenesulfonic acid, alpha- or beta- naphthalenesulfonic acid or naphthalenedisulfonic acid, in particular naphthalene-1,5-disulfonic acid or with cation exchangers.

The novel compounds may exist in the form of a mixture of isomers, for example as racemates, or as pure isomers, for example as optically active antipodes or as syn- or anti-derivatives.

The novel compounds of the formula I and their salts have valuable pharmacological, in particular particularly pronounced antimicrobial, in particular antibacterial, effects. Thus, for example, they are active against microorganisms, such as gram-positive bacteria, such as Staphylococcus aureus, at minimum inhibitory concentrations (MHK) in vitro of from about 0.0101 mg / ml, in particular against grsm-negative, in particular entero-bacteria. as set forth below at a dosage range of from about 0.0002 to about 0.5 mg / ml.

Thus, the compounds are active in vitro against the following gram-negative microorganisms from about the following MHK values: Klebsiella pneumonieae ¢ 0.0008 mg / ml), Salmonella typhimurium (0.004 mg / ml), Neisseria species, for example Neisseria gonorrhoeae ( 0.0002 mg / ml), Neisseria menigitidis (0.0004 mg / ml), Aerobacter species, for example Aerobacter cloacae (0.0008 mg / ml) and in particular against pathogenic strains of Escherichia coli ¢ 0.0004 mg / ml). The compounds are effective in vivo, for example, in E. coli infected mice, at a dosage range of from about 10 to about 70 mg / kg (subcutaneously), and from about 20 to about 150 mg / kg (orally).

Another excellent property of the novel compounds is the excellent effect against Influenza viruses, demonstrated in vivo in mice in particular against Influenza type A viruses, for example against the Victoria 3/75 strain and Hong Kong 1/68, at a dosage range of about 1 mg / kg especially 10 mg / kg to 250 mg / kg (orally) or a 30-minute inhalation of 1% aerosol, corresponding to 0.5 mg / mouse (perinhalation).

The compounds according to the invention are further characterized in that, in mixtures with known antimicrobials, such as antibiotic, antifungal and antiviral agents, for example with known antibiotics, in particular with beta-lactam type antibiotics such as penam or esphetine-type antibiotics, or with aminoglycoids, or other antibacterial active agents, for example, the following, at a dosage range of from about 0.1 to 500 mg / kg orally or 0.1 to 500 mg / kg parenterally, for example iv, ip, sc or i.m., the compounds of formula I and in a mixed ratio of 1:29 to 29: 1, preferably in a mixed ratio of 1: 5 to 5: 1, exhibit efficacy by complementing the antimicrobial spectrum of action or optionally exhibit synergistic efficacy.

however, for example, the compounds of formula I, in particular pivaloyloxymethyl 6beta 3, γ 26 may be used

- [4- (4-azatricyclo- [5,2,2,0 '] undec-8-enyl) methylenamino] penicillanic acid, mixed and coadministered with beta-lactam type antibiotics such as any of the penicillins, from the group consisting of · Amoxycillin, ampicillin, azlocilin, bacampillin, meslocillin, penicillin G, penicillin V, piperacillin, pivampicillin, some of the cefalosporin antibiotics from the group consisting of cefacetril, cefalexin, cefamandole, cefaeulbamide, cefuritin-7, cefazoline-cefazoline (hexadienglycylamido) -3-methoxy-3-cephen-4-carboxylic acid or 7beta- [4- (2-iminothiazolidinyl) acetamido] -3- [1- (2-dimethylaminoethyl) tetrazolylthiomethyl] -3-oephem-4-carboxylic acid 7beta- [3- (methylsulfonylaminophenyl) glycylamido] -3-methoxy-3-cephem-4-carboxylic acid or an aminoglycoside type antibiotic such as amikacin, gentamycin, sisomyoin, netilmycin or tobramycin, or a macrolide type antibiotic such as erythromycin sulfonamide as j e sulfamethoxazole, sulfametrol, sulfamethizole, or with a mixture of sulfonamide with trimethoprim, for example with a mixture of sulfamethoxazole and trimethoprim (5: 1) or sulfametrol and trimethoprim (5: 1), as well as with another synthetic antimicrobial agent such as trimethoprine or antiviral agents an adsmantic type such as 1-aminoadamantane hydrochloride.

Especially for the treatment of colds, in particular influenza and infections which prevent, accompany or follow it, and which are of the bacterial type, the compounds of the formula I according to the invention may be used, in particular pivaloyloxymethyl ester 6beta-1- (4-endo-azatrioyl). 5,2,2, ² '6] undex-8-enyl) methyleneamino] penicillanic acid in admixture with one or more in such infections of the usual and effective antimicrobial effects of substances such as those mentioned above and / or additionally ameliorating the symptoms of these diseases or mixtures of active ingredients, in particular in a mixed ratio of 1:10 to 10: 1. Particularly suitable antimicrobial agents for this purpose are, for example, other antiviral active compounds, such as adamantane type compounds, for example 1-aminoadamantane, 1- (1-aminoethyl) adamantane, 1-methylspiro [adamantane-2,3-pyrrolidine], 1- ( ethoxymethylcarbonylamino> adamantane or 1- (2'-dimethylaminoethoxymethylcarbonylamino) adamantane or non-toxic salts, for example hydrochlorides, of these compounds, as well as antimicrobial active agents such as ampicillin, bacampicillin, dihydroampicillin, amoxicillin, penicillin G, penicamillin V 7beta-Q4- (2-iminothiazolidinyl) acetamido] -3- [1- (2-dimethylaminoethyl) tetrazol-5-ylthiomethyl] -3-cephem-4-carboxylic acid, erythromycin, netilmycin, tobramycin, sulfamethoxazole, trimethoprim or a mixture of sulfamethoxazole trimethoprim (5: 1) or their physiologically acceptable salts. used in respiratory tract infections that facilitate respiration or mixtures thereof.

The antiviral active compound of the formula I is optionally mixed with other antimicrobial active ingredients or with a compound for alleviating disease symptoms and / or with suitable pharmaceutical excipients to form a combination preparation which can be applied in respiratory tract infections in the usual manner, for example as nasal drops, inhalation sprays, syrup or lozenges.

Substances which are known to alleviate the symptoms of the disease include respiratory aids, in particular methanol, such as 1-memthol, which are particularly suitable for application in the form of sprays (inhalation).

The present invention preferably relates to those compounds of formula I wherein R 1 is azatricyclodecenyl, for example 4-azatricyclo [5.2.1.0 ² '] dec-8-en-4-yl or azatricycloundecenyl, for example 4-azatricyclo [ 5,2,2,0 ² ', ⁴ ' - undec-8-en-4-yl or 8 azatrioyklo [4,3,2 '(4')] unde-3-en-8-yl and Rg stands for pivloyloyloxymethoxycarbonyl or ethoxycarbonylethoxycarbonyl.

The novel compounds of the formula I are obtained by reacting in a compound of the formula Ia

wherein the functional groups present in the radical R are optionally protected,

Rg represents a carboxyl group or a protected carboxyl group of up to 18 carbon atoms, esterifies the group Rg by treatment with an alkanoyloxyalkanol or alkoxycarbonyloxyalkanol corresponding to Rg or a derivative thereof, optionally in the presence of a condensing agent or a base; optionally converted to the free compound of formula 1 and / or the mixture of isomers obtained is separated into the individual isomers.

In a particularly simple manner, the physiologically tolerable esterified carboxyl groups R8 can be obtained from the corresponding carboxylic compounds and the corresponding alcohol by condensation in the presence of a conventional condensing agent such as a carbodiimide such as dicyclohexylcarbodiimide or reactive Ν, Ν'-bis-heterooyclylureas such as carbonyldiimidazole. a polar solvent.

Furthermore, such esters are obtained, for example, by reaction with a Ν, Ν'-disubstituted O- or S-substituted isourea or isothiourea wherein the substituent of the oxygen and sulfur atom is, for example, a lower alkyl radical, especially a tert-butyl radical or phenyl (lower) alkyl radical and substituents. N or N 'are, for example, a lower alkyl radical, in particular an isopropyl radical, a cycloalkyl radical, or a phenyl radical, or by any other known and suitable esterification procedures, such as by reacting an acid salt with a reactive alcohol ester and a strong inorganic acid or a strong organic sulfonic acid.

The starting materials of the formula Ia are obtained by reacting an optionally activated formamide or thioformamide of the formula II

II, -ΟΗ = Χ (II) y which

X is oxygen or sulfur; and

R ₁ has the meaning given under formula I, and wherein functional groups present in R are optionally protected, or a reactive derivative of such a formamide and thioformamide, and 6-aminopenamderivátém formula III

wherein the amino group at the 6-position is optionally present in a protected form and Rg is a free or protected carboxyl group or a compound with an inorganic or organic salt, whereupon the existing functional group is optionally cleaved in one or more protected functional groups or / and, if desired, the compound of formula (Ia) obtained is converted into another compound of formula (Ia) within the meaning of the general symbols of the fines, and / or the compound of formula (1a) obtained is optionally converted into a halide or or into another salt, and / or the mixture of isomers obtained is optionally separated into individual isomers.

Preferred compounds used to react with the 6-aminopenamide derivatives of Formula III are the below defined reactive derivatives of formamide or thioformamide of Formula II.

2Ž5819

Reactive derivatives of compounds of formula (II) are, for example, formiminium salts of formula IIa [R _] = CH.X] ® Z (IIa) in which:

R | is as defined above, wherein the free functional groups that are optionally present in R ₁ are preferably temporarily protected,

Ϊ represents halogen, in particular chlorine, or optionally phenyl, lower alkoxy or halogen, such as chlorine, substituted lower alkoxy, in particular methoxy, ethoxy or benzyloxy, and

Z represents a halogen such as chlorine, bromine or iodine, or an anionic radical of an alkylating agent, in particular a monoalkylsulfate, such as monomethylsulfate, or monoethylsulfate, dialkylphosphate, such as dimethylphosphate, or tetrafluoroborate.

In the compound of formula IIa, Y represents in particular halogen, in particular chlorine, as well as lower alkoxy, in particular methoxy or ethoxy, and Z represents in particular halogen, in particular chlorine, furthermore a metho- or ethosulphate radical.

Preferred examples of starting materials of formula IIIa are formiminium halides of formula [R 1 = CH-Hal] ® Hal ® which can also be regarded as formamide dihalides of formula R 1 -CH (Hal) ₂ , as well as adducts with an alkylating agent of formula [R 1 = CH- O-Alk] ® Z in which

R1 is as defined above, especially as defined above for the radicals R1,

Hal is halogen, especially chlorine,

Alk is methoxy or ethoxy and

Z represents a halogen such as chlorine, bromine or iodine as well as a monomethyl or monoethyl sulfate radical.

Reactive derivatives of formamide or thioformamide of formula II are, for example, also formamide acetals or formamide thioacetals of formula IIb.

R, -CH (lib) \ -X-Alk wherein

R ₁ and X have the abovementioned meaning and

Alk is an optionally halogen, phenyl or lower alkoxy substituted lower alkyl radical, especially methyl or ethyl.

In the compounds of formula IX or IIb, the free functional groups optionally present in the Rp moiety may be temporarily protected if necessary or desired.

The starting materials of the formula III in which Rg represents a free or protected carboxyl group are known and are described, for example, in DOS Nos. 2 055 531, 2 132 111, 2 404 587 and 2 530 299, as well as Japanese publication 039958/1976 (Derwent - No. 89 393 X / 48).

The carboxyl or amino protecting groups optionally used in the starting materials, for example starting materials of formula III, are known and are described in many patents, for example those mentioned above or in J. W. F. McOmie,

Thus, there are examples of the amino protecting groups in this publication in Chapter 2, the hydroxyl protecting groups in Chapter 3, and the carboxyl protecting groups in Chapter 2.

5.

Free protecting groups of this type are also disclosed in E. Schroder and Lubke, The Peptides, Vol. I, Academic Press, 1965, for example p. 72-75.

In particular, the protected carboxyl group Rg in the starting material of formula III is an easily cleavable, esterified carboxyl group or a carboxyl group present in the anhydride form.

The readily cleavable esterified carboxyl group is, for example, preferably, especially in the alpha, further also in the beta-position substituted and / or in the alpha-position branched lower alkoxycarbonyl group. The substituents of such a group are, for example, a carbocyclic aryl radical, such as, for example, lower alkyl such as tert-butyl, phenyl, hydroxy, lower alkoxy such as methoxy, and / or nitro substituted phenyl, aryloxy, such as optionally, for example lower alkoxy such as methoxy, substituted phenyloxy, arylcarbonyl such as, for example, halogen, such as bromine, substituted benzoyl, cyano or acylamino, such as diacylamino, such as phthalimino, or succinylimino; such substituents are preferably present at the alpha position of the lower alkoxycarbonyl group, which group may contain one, two or more such residues, depending on the type of substituents. Other substituents which are preferably located in the beta-position of the lower alkoxycarbonyl group are halogen, for example chlorine, bromine or iodine, and in such residues a single chlorine or bromine atom can be easily converted to iodine before the liberation of the carboxyl group thus protected.

Examples of such suitable lower alkyl radicals as substituents in the abovementioned optionally substituted lower alkoxycarbonyl groups are a tertiary lower alkyl radical, for example a tert-butyl radical, optionally in a phenyl radical, for example as above, a substituted alpha-phenyl (lower) alkyl radical such as benzyl, 4-methoxybenzyl or 4-nitrobenzyl, optionally in phenyl radicals, for example as mentioned, in particular lower alkoxy, for example methoxy, substituted diphenylmethyl, such as benzhydryl, or 4,4'-dimethoxydiphenylmethyl, trityl, and tris- a (p-methoxyphenyl) methyl radical, optionally in phenyl radicals, for example as mentioned, in particular by a lower alkoxy group, a substituted bis-phenyloxymethyl radical, such as a bis- (4-methoxyphenyloxy) methyl radical, optionally, in particular a halogen substituted phenacyl radical, such as phenecylo or 4-bromophenacyl, longer cyanomethyl, diacyliminomethyl, such as phthalyliminomethyl or succinyliminomethyl, or 2-halo (lower) alkyl, such as 2,2,2-trichloroethyl, 2-bromoethyl or 2-iodoethyl.

Furthermore, an easily cleavable esterified carboxyl group may also be a cycloalkoxycarbonyl group, the alpha position of which preferably represents the carbon atom forming the bridgehead. A corresponding cycloalkyl radical is, for example, a 1-adamantyl radical.

Further protected carboxyl groups R 8 are organic silyloxy- or stannyloxycarbonyl groups containing 1 to 3 organic, especially aliphatic hydrocarbon radicals, such as a lower alkyl radical, for example methyl, ethyl, propyl or butyl or tert-butyl, or a halogen (lower) alkyl radical , for example, chloromethyl or 2-chloroethyl, as well as optionally substituted cycloaliphatic, aromatic or araliphatic hydrocarbon radicals such as cycloalkyl, phenyl or phenyl (lower) alkyl radicals, further etherified hydroxyl groups such as lower alkoxy such as methoxy and which may optionally as other halogen-containing substituents such as chlorine.

Preferred examples of such carboxyl-protecting groups are a tri (lower) alkyl7 silyl group, for example a triaethylsilyl or tert-butyldimethylsilyl group, a phenyl-substituted tri (lower) alkylsilyl group, for example a triethyldimethylsilyl group, a lower alkoxy (lower) alkylhalogensilyl group such as a chloromethoxymethylsilyl group, or a tri (lower) alkylethannyl group, for example a tri-n-butylstannyl group.

The protected carboxyl group R8 can also be a carboxyl group esterified with a negatively substituted phenyl moiety. Negative radicals are halogen, especially chlorine, as well as nitro. A suitable residue of this type is the pentachlorophenyl protecting group described in British Patent Specification No. 1,442,435.

Another suitable protected carboxyl group is described in Belgian Patent No. 851,576, the substituted beta-silylethoxycarbonyl group, in particular the beta-trimethylsilylethoaycarbonyl group, organic, for example the silyl protecting groups mentioned above.

The protected carboxyl group Rg present in the anhydride form is preferably an optionally esterified phosphoryloxycarbonyl group, for example an OO-diphenylphosphoryloxycarbonyl group or a diphenylphosphinyloxycarbonyl group.

Preferred ester protecting groups are those which can be cleaved already in a weakly acidic to slightly basic range under particularly gentle conditions for the panama ring skeleton, such as solvolytically readily cleavable ester protecting groups that are derived from tris-organosilyl alcohols, such as trimethylsilyl alcohol, or beta-trimethylsilylethanol. Such groups are described, for example, in British Patent Specification No. 1,073,530, in DOS 1,800,698 and in the above-mentioned Belgian Patent Specification.

Also, the primary amino group of a compound of formula III may be temporarily protected, preferably by easily cleavable amino protecting groups known from the chemistry of peptides or pancillins. Such protecting groups may be, for example, acyl, arylmethyl, 2-carbonyl-1-vinyl, arylthio or aryl (lower) alkylthio-, further arylsulfonyl, as well as the above-mentioned organic silyl or stannyl groups.

In a particularly readily cleavable form, protected amino groups are amino acylated with a carbonic acid or thiocarbonic acid semi-ester moiety such as a 2-iodoethoxycarbonyl moiety (DOS 2 126 277), a 6-nitrovaratryloxycarbonyl moiety and a 2-nitrobenzyloxycarbonyl moiety (J. Amer. Chem. 333 (1970)), a 2-methylthioethoxycarbonyl radical (Chem. Ber. 109, 3 693 (1976)) or a tert-butyloxycarbonyl radical, a 2-acyloxymethylbenzoyl radical, for example a 2-benzoyloxymethylbenzoyl radical (J. Org.

Chem. 4J 2029 (1976)) or an aromatic phosphinic acid residue such as a diphenylphosphinyl residue (Tetrahedron Letters 1976, 3,623).

The process used for the preparation of the compounds of formula Ia is known per se and is carried out in an analogous manner to that described in DOS 2,055,531, 2,123,111, 2,440,587 and 2,530,299.

The optionally activated formamides or thioformamides of the formula II or reactive derivatives thereof and the compound of the formula III are preferably reacted with one another, preferably in the presence of an inert diluent, for example an inert, preferably polar solvent and, if necessary, in the presence of other reaction promoting additives such as strong organic bases, condensation agents and / or catalysts, at reaction temperatures between -80 and +80 ° C, preferably in the temperature range below +30 ° C, especially under initial strong cooling to temperatures below 0 ° C, if necessary, in an inert gas atmosphere, as well as generally excluding moisture.

In carrying out this process, reactive derivatives of formamide or thioformamide of formula II may be reacted with a penamerivative of formula III as before.

AND

22581 9

Thus, they are recovered in situ from their starting materials without prior purification or isolation. Thus, for example, the formamide or thioformamide of the formula II can be reacted first with a halogenating agent, as described below, for the production of haloformimine halides of the formula IIa with a useful halogenating agent, in particular phosgene or oxalyl chloride, optionally in the presence of a strong base; for example, with a reactive orthoester, such as the following orthoester, formic acid, a suitable pentavalent phosphorus ester, or a reactive amide acetal, preferably 8 dimethylformamide dimethylacetal, and then allowing the crude reaction mixture which contains the aeziproducts of formula IIa or IIb to be reacted for longer thereafter or for an extended period of 1n suture with an optionally protected amine of formula HI in a manner analogous to the use of previously isolated compounds to produce compounds of formula Ia.

Finally, it is also possible to react advantageously with an equimolar mixture of amines of the formula R1-H and HI, whereby the amino and / or carboxyl group present in the formula HI as well as the free functional groups present in the compound R, -H may be temporarily hindered. , with a condensing agent providing an amidino carbon atom. The condensing agents that provide the amidine carbon atom are primarily reactive orthoformic acid derivatives, for example orthoformic acid esters, particularly aliphatic, such as tri (lower) orthoformic acid esters, the corresponding thioorthoformic acid esters, the diacetals of dl (lower) alkylformamide, and 1,1 - halomethyl (lower) alkyl ether. Preferred derivatives of this type are trimethyl ester or triethyl orthoformate, trimethyl ester or triethyl thio-formate, dimethylformamide dimethylformamide and 1,1-dichlorodimethyl ether.

The reaction variant via the starting materials of formula IIa using 1,1-dichlorodimethyl ether as condensing agent is conveniently carried out in the presence of a strong organic base and in an inert organic solvent, a Barienta process running through the starting compounds of formula IIb using an orthoformic acid ester or thioorthoformic acid ester The condensation agent is preferably carried out in the presence of an alkylation catalyst such as a Lewis acid, for example zinc chloride or boron trifluoride ether.

The reaction of the isolated or in situ prepared starting material of formula (IIa) with a penamdivative of formula (HI) is preferably carried out with temporary protection of the free functional groups and in the presence of a strong organic base. For example, at least about an equimolar amount of the imide halide of Formula IIa and a base are used, but the base may also be used in excess, for example, about 2 to 3 times the equivalent amount. An additional base equivalent must be used for each free carboxyl group that is optionally present in the intermediate. Suitable strong organic bases are, in particular, customary, acid-binding, salt-forming, tertiary amines, for example tertiary aliphatic mono- or diamines, such as tri (lower) alkylamines, for example trimethylamine, triethylamine, tripropylsmin or diisopropylamine, longer N, Ν, Ν ,, Ν'-tetra (lower) alkyl (lower) alkylenediamines, for example Ν, Ν, Ν ', Ν'-tetraethylethylenediamine, cyclic mono- or diamines, such as N-substituted, for example N- (lower) alkylated alkylene-, azaalkylene- or oxaalkylehamines, for example N-methylpiperidine or N-methylmorpholine; preferably suitable salt-forming tertiary amines are in particular tri (lower) alkyl amines, for example triethylamine or disopropylethylamine, furthermore N-methylmorpholine.

Suitable inert solvents or diluents are all absolute, preferably polar, solvents which do not contain any functional groups. Suitable reaction media are, in particular, halogenated hydrocarbons, in particular methylene chloride or chloroform, in some cases also ketones such as acetone, ethers such as diethyl ether, anisole or tetrahydrofuran, as well as aromatic hydrocarbons such as benzene or toluene or hydrolyzed esters such as ethyl acetate.

In general, starting from the previously isolated starting materials of formula (IIa) or (Hb), starting with the above reaction, they are dissolved or suspended in one of the above-mentioned inert solvents or diluents and added to the solution - if starting materials of the formula

First of all, on the carboxyl group Rg, for example, the protected compound of formula III, for example, the protected compound is cooled, and the mixture is cooled to said reaction temperature and the reaction is activated or accelerated by the addition of a strong organic base.

In order to prepare the compounds of formula (Ia), the starting materials of formula (IIa) can also be prepared in situ and used directly for longer, without prior purification or isolation. The same reaction conditions as mentioned above are observed, except that the reaction temperature is preferably chosen somewhat lower. Thus, the reaction can be carried out, for example, at temperatures from -30 to 70 ° C and the temperature is allowed to rise slowly.

The reaction of the starting materials of the formula IIb with the compounds of the formula HI is characterized by the particular advantage that, in a process which in itself corresponds to that described above, the free carboxyl group in the compound of the formula III need not generally be protected, that the reaction is optimally carried out at somewhat higher temperatures, starting at about 0 ° C and rising to about +20 to +40 ° C.

The compound of formula (Ia) obtained in the manner described above can optionally be liberated by the carboxyl group R2, if desired or necessary, in a manner known per se, for example by solvolytic, reducing or photolytic methods, but also enzymatically.

Thus, a silyl capping group, such as a trimethylsilyl capping group, can be removed solvolytically, for example, hydrolytically or alcoholytically, to protect the carboxyl, hydroxyl and / or amino groups, unless such cleavage has already occurred completely during the reaction mixture. A carboxyl group protected by a halogen (lower) alkyl group, in particular a 2,2,2-trichloroethyl group, can be converted, for example, by treatment with a chemical reducing agent such as a metal such as chromium chloride or acetate, usually in the presence of an acid such as aqueous acetic acid or formic acid; or preferably a suitable alcohol, to a caoxylate, and a carboxyl group esterified with an arylcarbonylmethyl group can be converted to a carboxylate by treatment with a nucleophilic cleaving agent, such as sodium thiophenoxide or sodium iodide. The carboxyl group esterified with a suitable arylmethyl group may be cleaved, for example, by irradiation, preferably with ultraviolet light, for example below 290 nm, if the arylmethyl group is represented, for example, optionally in the 3,5 and / or 5 position, for example lower alkoxy and / or nitro substituted with benzyl, or long-wave ultraviolet light, for example above 290 nm, (If the arylmethyl group is represented, for example, in the 2-position by a nitro group substituted by a benzyl group.

A carboxyl group which is esterified with a suitably substituted methyl group, such as a tert-butyl group or a diphenylmethyl group, is liberated from particularly gentle conditions, for example by treatment with a suitable acidic agent such as trifluoroacetic acid, optionally with addition of a nucleophilic compound such as phenol or anisole. The activated esterified carboxylic acid or carboxylic acid group present in the form of the anhydride can be cleaved by hydrolysis in a neutral to slightly acidic or weakly basic or water-containing medium such as acetic acid, aqueous sodium bicarbonate or aqueous potassium phosphate buffer at pH 7 to 9 and hydrogenolytically cleavable esterified, for example benzyl, p-nitrobenzyl or p-methoxybenzyl esterified carboxyl, can be cleaved preferably by hydrogenolysis, for example by treatment with hydrogen in the presence of a palladium catalyst.

A carboxyl or hydroxyl group protected by an optionally substituted, such as phanyl, methoxy or nitro group, one or more times substituted by a benzyl protecting group, can be cleaved more or less easily by the action of active hydrogen or, alternatively, by a weakly acidic cleavage agent. Thus, the benzyl ester or p-methoxybenzyl ester group is cleaved by treatment with active hydrogen in an inert, preferably alcoholic solvent such as a lower alkanol such as ethanol at normal or slightly elevated temperature and the trityl- or tris- (p-methoxyphenyl) methyl22581. optionally by treatment with water containing formic acid, for example at room temperature.

A carboxyl group protected by a lower alkoxycarbonyl group branched at the alpha position, such as a tert-butyloxycarbonyl group or an adamantyloxycarbonyl group, can also be released ecidolytically, for example by treatment with lower alkanecarboxylic acids, for example acetic acid or formic acid.

In addition to the weakly acidic cleavers mentioned above, other weak inorganic or organic acids or other weakly acidic organic or inorganic compounds are suitable as cleavers.

Thus, polymers or adsorbents having acidic groups, as well as acids adsorbed on polymers, for example acidic ion exchangers, acid adsorbents such as silica gel or acidic alumina, for example metaphosphoric acids or acid salts of phosphorous acids, as well as acidic phosphorous acid salts, Lewis acids in inert solvents. AND

A carboxyl group protected with a negatively substituted aryl moiety, such as a penteehlorophenyl moiety, may deprotect the moieties by mild treatment with an alkali or organic base, such as the above.

The beta-silylethyl, for example the beta-trlmethylailylethyl protecting group, is cleaved in a mild, specific manner by fluoride dissolved in an organic medium, for example potassium fluoride in the presence of erown ether, e.g. 18-crown-6-ether, tetraethylmonium fluoride or pyrldinhydrofluoride. dimethylformamide.

Salts of the compounds of formula I can be prepared in a manner known per se.

The acid addition salts of the compound of formula 1 with a basic amidine moiety are obtained in a conventional manner, for example by treatment with an acid or a suitable anion exchange resin.

Salts can be converted to the free compounds in a conventional manner. Thus, metal salts and ammonium salts can be converted by treatment with suitable acids or cation exchangers, for example, and acid addition salts can be converted by treatment with suitable basic agents or anion exchangers.

The mixtures of the isomers obtained can be separated by known methods into individual isons, mixtures of diastereomers or stereolsomers, for example syn- and antl-isomers, for example by fractional crystallization, thin layer adsorption chromatography or other known separation procedures. The racemates obtained can be separated into the antipodes in the customary manner, if appropriate after the introduction of suitable salt-forming groups, for example by formation of a mixture of diastereoisomeric salts, treatment with Aptically active salt forming agents, separation of the mixture into diastereoisomeric salts and conversion of the separated salts into free compounds. .

The process also includes those embodiments in which the compounds obtained as intermediates are used as starting materials, and the remaining reaction steps are carried out with the compounds or those in which the process is interrupted at any stage. Furthermore, the starting materials may be used in the form of derivatives or formed during the reaction.

Preferably, such starting materials are used, and the reaction conditions are selected so as to obtain the compounds mentioned above as being particularly preferred.

The starting materials of formula Π in which the amino group is optionally substituted by an acylating group are known or can be obtained by known methods.

22581 9

Thus, compounds of formula IIIa in which Y and Z are halogen, especially chlorine, can be obtained by reacting an amine of formula R1-QH with a reactive formic acid derivative such as 1,1-dihalomethyl alkyl ether, for example 1,1-dichlorodimethyl ether or by using formamide or thioformamide of the formula II as starting material and reacting it in a known manner with a halogenating agent and the haloformimide halide of the formula IIa obtained in both the first and second cases is isolated or used further in situ.

Suitable halogenating agents are customary halogenating agents, such as inorganic or organic acid halides, preferably those which decompose into volatile or readily separable reaction products, in particular the corresponding chlorides, such as oxalyl chloride, phosgene, diphosgene (trichloromethyl chloroformate), phosphorus oxychloride, phosphorus pentachloride or thionyl chloride.

The reaction is generally carried out in an inert diluent or solvent, such as, in particular, methylene chloride, chloroform, diethyl ether or toluene, at temperatures between -10 and +30 ° C. Compounds of formula IIIa in which Y is lower alkoxy, in particular methoxy BUY or ethoxy, and Z is an alkylating agent residue, in particular a halogen, mono (lower alkyl sulfate or tetrafluoroborate residue) are obtained by treating the formamide or thioformamide of formula II with an alkylating agent. alkylating agents are suitable customary alkylating agents, for example lower alkyl halides, especially methyl iodide, di (lower) alkyl sulfates, for example dimethylsulfate, and diethyl sulfate, as well as onium salts, for example fluoroboric acid or fluorosilicic acid, for example triethyloxoniurotetrafluoroborate. in any of the inert solvents mentioned at room temperature or at temperatures up to the boiling point of the solvent.

The obtained iminium ether or iminium thloether salts of formula IIIa may be isolated and purified or may be prepared in situ as described above and further used.

Acetals or thioacetals of formamide Hb can be obtained by reacting the above-described iminium ether or iminium thioether salts of alcohols such as lower alkanols, e.g. methanol or ethanol, preferably in the presence of basic agents such as the aforementioned tertiary amines or alkoxides, e.g. sodium methoxide, or by treating the amine of formula R 1 -H with an activated reactive derivative of orthoformate or thioorthoformate, such as an ester or amide acetal thereof, e.g. orthothioformic acid and zinc chloride or boron trifluoride etherate, or dimethylformamide diacetal, for example dimethylformamide dimethyl acetal, or by leaving formamide or thioformamide of formula II reacted in a manner known per se with an acetalizing agent, such as a trialkyloxonium tetrafluoroborate, for example triethyloxonium tetrafluoroborate, and optionally thereafter with an alkaline agent, for example sodium methoxide.

The reaction conditions are known and depend primarily on the severity of the expected reaction. Thus, the reaction of the iminium ether salt with sodium methoxide or an alcohol is carried out in the presence of a tertiary base preferably under cooling, for example at temperatures from about -70 ° C to about +10 ° C, but may also be operated at higher temperatures, e.g. temperatures up to about 75 ° C if the stability of the starting materials and reaction products is elevated.

Other reactions, for example the reaction of dimethylformamide dimethyl acetal with an amine of formula R, -H, are preferably carried out in an inert solvent or in an excess of the orthoformic acid derivative as diluent, and optionally to accelerate the reaction at its boiling point.

Formamides or thioformamides of formula (H) optionally used as starting materials may also be obtained from amines of formula R, -H, by treatment with customary formulating agents, for example chloral, for example by heating in an inert solvent such as chloroform for several hours.

22581 9

The amines of formula B, -H are known or can be prepared from known starting materials in a known or analogous manner.

The pharmacologically usable compounds of the present invention can be used, for example, for the manufacture of pharmaceutical preparations containing effective amounts of the substance or active substance or mixture, such as any of the aforementioned active compound mixtures, together or in admixture with customary inorganic or organic, solid or liquid. pharmaceutically acceptable carriers or excipients which are suitable for enteral or preferably perenteral administration, optionally in the treatment of respiratory tract infections, in particular also for topical administration (e.g. in the form of nasal drops), for inhalation (e.g. as an aerosol spray) or buccal administration (e.g., in the form of lozenges). Thus, tablets or gelatin capsules are used which contain the active ingredient together with excipients such as carriers and fillers or diluents, for example sucrose, lactose, dextrose, mannitol, sorbitol, cellulose, or cellulose derivatives such as methylcellulose, calcium phosphate such as is, for example, calcium phosphate or secondary calcium phosphate and / or glycine, and lubricants such as silicic acid, talc, stearic acid or its salts such as magnesium or calcium stearic acid, and / or polyethylene glycol.

The tablets also contain binders such as magnesium aluminum silicate, starches such as corn starch, wheat starch, rice starch, or marzipan starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone, and optionally disintegrating agents such as starches, starches, alginic acid or a salt thereof, for example sodium alginate, and / or mixtures thereof, or adsorbents, colorants, flavoring agents and sweeteners.

Furthermore, the novel pharmacologically active compounds can be used in the form of injectable, for example intravenously administrable, or in the form of solutions suitable for infusion, for administration in the form of drops or for inhalation. Such solutions are preferably isotonic aqueous solutions or suspensions, which preparations may be prepared prior to use, optionally from lyophilized preparations which contain the active ingredient alone or a mixture thereof and a carrier material, for example mannitol.

The pharmaceutical preparations may be sterilized and / or contain adjuvants, for example preservatives, stabilizers, wetting agents and / or emulsifiers, co-solvents, salts for regulating the osmotic pressure and / or buffers. The present pharmaceutical compositions, which, if desired, may contain other pharmacologically valuable substances, are prepared in a manner known per se, for example by means of conventional mixing, granulating, coating, dissolving or lyophilizing processes, and contain about 0.1 to 100%, in particular about 1 to 100%. up to 50% of the active ingredient, and up to about 100% of the active ingredient in the case of a lyophilisate.

The following examples serve to illustrate the invention. Temperatures are given in degrees Celsius. As a solvent system for thin-layer chromatography:

System A = mixture of isopropanol, formic acid and water (77: 4: 19); silica gel is used as the carrier medium and empicillin is the reference substance.

Example 1

Pivaloyloxymethyl 6-beta-FU-endo-azatrlcyklo, 2,2,0 ^{2'®Jundec-8-enyl)} methylenaminoj Penic liánová acid obtained by AE (5.0 g, 0.013 mol) 6bete- [(4-endo-azatricykloj5 2,2,0 ® (Jundec-8-enyl) methylamino] penicillanic acid and 2 ml (0.015 mol) of triethylamine are stirred in 40 ml of dlmethylformamide until an almost clear solution is formed, then 1.95 g (0.013 mol) is added in one portion. of pivaloyloxymethyl chloride and the reaction mixture is stirred overnight under nitrogen as protective gas at room temperature, the solvent is evaporated off under vacuum, the residue is taken up in ethyl acetate, the suspension is filtered, the filtrate is filtered twice

22581 9 was extracted with ice-cooled saturated sodium bicarbonate solution and once with ice-water, dried over magnesium sulfate, evaporated and the foam solidified as recrystallized from 20 ml of diethyl ether. Mp 115-118 ° C; [α] D P = 210-1 ° (1.0% in chloroform).

To convert to the hydrochloride, the above compound is dissolved in methylene chloride, a calculated amount of ethereal hydrogen chloride is added, and the hydrochloride is crystallized by addition of additional ether and then dried. White crystals of melting point 127 DEG-129 DEG C. (decomposition), [.alpha.] = 173 DEG and 1 DEG (1% in chloroform), were obtained.

IR (in methylene chloride): bands at 5.60, 5.80 and 5.90 .mu.m.

Example 2

To a suspension of 9.85 g (25 Maol) 6-beta-hemihydrate C (4-endoezatricyklo [5.2,2.0 ² ^ Jundec) _8-phenyl) -methyleneamino] penicillanic acid in 100 ml dlmethylformamidu was added 4 mL (29 mmol of triethylamine and the reaction mixture was stirred at 22 ° C for 15 minutes. A solution of 25 mmol of 1-ethyloxycarbonyloxy-1-ethyl iodiflu in 25 ml of methylene chloride was added dropwise at -10 ° C, and then the reaction mixture was stirred at -10 ° C for 30 minutes and at 0 ° C for 45 minutes. For working-up, the reaction mixture was poured into 1 liter of water (ice), adjusted to pH 7.5 by addition of 2N sodium hydroxide solution, and then extracted twice with 1 liter of a 9: 1 mixture of toluene and ethyl acetate. To the extracts washed with 1M phosphate buffer, pH 7.5, 1 liter of water was added and the stirred mixture with concentrated phosphoric acid was added. The aqueous phase was separated, neutralized with 2N sodium carbonate solution to pH 7.5 and extracted with 0.5 L of ethyl acetate. Drying of the extract with sodium sulfate and evaporation in vacuo gave the crude ester. Digestion with ether and then with heptane gave 6-beta-C (4-ando-azatricyclo-1-5,2,2,0 ^-2 '] undex-8-enyl) methyleneamino-penicillanic acid 1-ethoxycarbonyloxy-1-ethyl ester in the form of a light beige powder. Since the 1-ethoxycarbonyloxy-1-ethyl iodide used is a racemic substance, the product is a mixture of diastereomers about

Claims (7)

A process for the preparation of the novel 6-eminopenemerivatives of the general formula I-1 CH = N · O 'CH,' CH, r ₂ (I) wherein R ¹ represents an azatricycloalkenyl group having 8 to 11 ring atoms and R 2 represents a C 3 -C 16 alkanoyloxyalkoxycarbonyl or C 4 -C 16 alkoxycarbonyloxyalkoxycarbonyl group and a salt of the compounds of formula I, characterized in that in a compound of formula Ia (Ia): R1 is as defined above, R1 represents a carboxyl group or a protected carboxyl group of up to 18 carbon atoms, esterifies the group H6 by the action of an alkanoyloxyalkanol or alkoxycarbonyloxyalkanol corresponding to the symbol Rj or a derivative thereof, optionally in the presence of a condensing agent or 22581 9, whereupon the obtained compound of formula 1 is optionally converted into a salt or e and the obtained salt is optionally converted into a free compound of formula 1 and / or the resulting mixture of isomers is separated into individual isoners. 2. A process according to claim 1 for the preparation of compounds of the formula I in which R @ 1 represents an azatricycloundecenyl group and represents a C3 -C16 alkanoyloxyalkoxycarbonyl group or C4 -C16 alkoxycarbonyloxyalkoxycarbonyl group and salts thereof, characterized in that of formula (Ia) wherein R1 is as defined above and R1 is a carboxyl group, esterifies R1 with an alkanoyloxyalkanol or alkoxycarbonyloxyalkanol corresponding to the residue mentioned above or a derivative thereof in the presence of a base, whereupon the optionally obtained compound of formula 1 is converted to a salt. 3. A process according to claim 2 wherein the alkanoyloxyalkanol derivative is a chloride of the alcohol in the presence of a base. 4. A process according to claim 2 wherein the alkoxycarbonyloxyalkanol derivative is an iodide of the alcohol in the presence of a base. Method according to one of Claims 1 to 4, characterized in that triethy laminate is used as the base. 6. A process according to any one of claims 1 to 5 for the preparation of 6beta-η 4-endo-azatricyclo [5.2.2.0 < 2,7 > (4-en-4-yl) methyleneamine] peniolanic acid pivaloyloxymethyl ester, characterized in that 6beta-C (4-endo-azatricyclo [5.2.2.0 < 2,7 > -undec-8-ei-4-yl) methyleneamino] penicillanic acid and pivaloyloxymethyl chloride are used as starting materials. 7. The process of any one of items 1 to 5 for the preparation of 6-beta-Q (4-endo-azatricyclo [5.2.2.0 < 2,7 > -undec-8-en-4-yl) methyleneamino] penicillanic acid 1-ethoxycarbonyloxy-1-ethyl ester characterized in that 6beta-Γ (4-epdo-aaatricyclo [5.2.2.0.0] undec-8-en-yl) methylamino] -caproic acid and 1-ethoxycarbonyloxy-1-ethyl iodide are used as starting materials. .