PL95747B1 - METHOD OF MAKING NEW PENAM DERIVATIVES - Google Patents

Description

The subject of the invention is a method for the preparation of new penam derivatives, and in particular new compounds with antimicrobial action being penam derivatives, which are valuable additives to animal feed, medicaments used to combat infectious diseases caused by gram-positive or gram-negative bacteria. , sterilants used in hospitals and the like. Despite the existence of many penam derivatives which have been proposed for use as antimicrobials, there is still a need for compounds with improved antimicrobial properties. US Pat. No. 3,427,302. and 3,468,874 show penam derivatives containing a tetrazolyl group as part of the acylamino group on the 6-position. The compounds of the present invention are distinguished from other penam derivatives by the fact that the tetrazolyl group is attached directly to the penam ring. no groups that the carboxylic acid, optionally in the form of a salt, attached at the 3-position. There are also known derivatives of penam with other radicals derived from the carboxylic acid at the 3-position. These include esters of penam derivatives containing a carboxylic group at the 3-position, described by Kirchner et al., Journal of Organic Chemi-14, 388/1959 /, Carpentera, Journal of American Chemical Society, 70, 2964/1948 /, Johnson, Journal of American Chemical Society, 75, 3636/1953 /, Barnden et al., Journal of the Chemical Society (London), 3733 (1953) and Janson and Russell, Journal of the Chemical Society (London), 2127 (1965), and the carbonamides of these derivatives described, for example, by Holysz and Stevely, Journal of the American Chemical Society, 72, 4760 (1950t) and Huanga et al., Antimicrobial Agents and Chemotherapy, 493 (1963) Peron et al. (Journal of Medicinal Chemistry, 7, 483, (1964) 6-amino-2,2-dimethylpenamecarboxylic acid azides-3 with the group substituted amine, which was converted to the corresponding 3-isocyanates and 3-benzylcarbamates. Peron et al. In the cited work also described some 3- (hydroxymethyl) penam derivatives. Dehydration of the simple benzylpenicillin amide leads to the corresponding nitrile (Khoskhlov et al., Doklady Akad. Sci. Teachings SSSR, 135 (1960). According to the generally known opinion, modifications consisting in changes of the substituent in the 3-position would not lead to better results. The method of the invention provides new derivatives of 6-amino-2,2-dimethylpenam with a substituted group amine, containing an optionally substituted tetrazolyl-5 group in the 3-position. Thus, derivatives 14, 388 (I1949), Carpenter, Journal of 95 74 795 747 3 4 substituted with an activator substituent has antibacterial properties, and Rz represents a tetrazolyl group of formula 2 or formula 3 or a precursor of a tetrazolyl group of formula -C / CtyNHG 'or -OO-NH-G', and R2 and R8 in formulas 2 and 3 are hydrogen, trialkylsilyl group containing 1-4 carbon atoms in each alkyl group, alkanoyloxymethyl group containing 3-8 carbon atoms, 1- / a "icanoyloxy / ethyl group containing 4-9 carbon atoms, phthalidyl group or the same group the nitrogen atom in the system trazolylpenemic, easy to remove, and G 'stands for the protecting group of the nitrogen atom in the tetrazolylpenamic system, possibly in the form of a salt. According to the above description, the compound of formula 1 can be represented by the formulas 4 and 5, in which R1 represents the group acyl group of an organic carboxylic acid, and R2 and R8 are hydrogen, a trialkylsilyl radical of 1-4 carbon atoms in each alkyl group, an alkanoyloxymethyl radical of 3-8 carbon atoms, a 1- (alkanoyloxy) radical - ethyl with 4 to 9 carbon atoms or a phthalidyl radical, and R2 is moreover a protective group for the nitrogen atom in the tetrazolylpename system, which will be further defined. Particularly preferred penam derivatives according to the invention are due to their large number active against a large number of pathogenic bacteria, there are compounds of the formulas 4 and 5, where R2 and R8 are hydrogen, and R1 is an acetyl group substituted with one or two groups such as, for example, a 2-arylacetyl group, a 2-amino-2-arylacetyl group, and a 2-amino-2-aryl acetyl group with a substituted amino group. Particularly preferred intermediates are compounds of Formulas 6 and 7 in which R5 is A hydrogen atom, a trialkylsilyl radical containing 1-4 carbon atoms in each alkyl group or the protecting group of the amino group as defined hereinafter, and R2 and R8 have the above meanings, and their salts. 7, in which R2, R8 and R5 are hydrogen or trialkylsilyl radicals containing 1-4 carbon atoms in each alkyl group, are particularly useful in the preparation of new penam derivatives of formulas 4 and 5. amino group is to be understood as groups protecting the amino group at position 6 of the penam ring during the synthesis of the basic structure, especially during the formation of the theitrazolyl ring. Ease of removal of such groups before or after acylation of the nitrogen atom to which they are attached is required. In a particular application of the process according to the invention, the term encompasses all or one of the known protecting groups which make it possible to synthesize a compound of formula VI, wherein R5 is an amino protecting group and R2 is the protecting group of the nitrogen atom of the tetrazolyl ring substituted with to penam, and can easily be removed from a compound of formula VI in which R2 is a hydrogen atom or the protecting group of a tetrazolyl ring atom substituted for penam, under conditions in which the penam ring remains substantially intact. The amino protecting group of R5 represents a group that effectively protects the amino group of 6-aminopenicylic acid during the following in detail conversion of the 6-aminopenicylanic acid with a protected amino group to the compound of formula 6, which is easily removable under conditions where no there is a destruction of the penam ring; however, there are situations in which a group may be treated as a protecting group for an amino group, if it can be attached to the amino group at position 6 of the penam ring, it then allows the group to be hooped. the amine dust and it is easily split off from the nitrogen atom to which it is attached. A specific example of each type of amino protecting group is the triphenylmethyl radical and the trialkylsilyl radical, respectively. Of course, whole groups of both types of radicals can be considered in the process of the invention. The chemical structure of the amino protecting group is not the most important, as its importance lies only in its ability to act in the manner described above. The identification and selection of the group to be used can easily be made by one of ordinary skill in the art. The nature of the group chosen is in no way relevant to the novelty of the antimicrobial compound according to the invention. Further examples of radicals which may be used as amino protecting groups in the process of the present invention are given hereinafter. Similarly, the term "tetrazolylpenam nitrogen protecting group" should generally be understood to mean the tetrazole ring protecting group before or after. The term encompasses groups such as the trialkylsilyl or triphenylmethyl radical which may be attached to the tetrazolyl ring during, for example, the acylation of the amino group at position 6. In a particularly preferred embodiment of the present invention, the term stands for all or one of the known groups enabling the following synthesis of the compound of formula 6, in which R5 is an amino protecting group and R2 is the above-mentioned protecting group of the tetrazolylpenam nitrogen atom with a protected 6-amino-pendicillanic acid. amino group, and easily removable from a compound of formula IV in which R1 is an acyl group a, and R2 represents the above-mentioned protecting group of the nitrogen atom of tetrazolylpenam, or the compound of formula 6, in which R5 represents a hydrogen atom or an amino protecting group, and R2 represents the above-mentioned group protecting the nitrogen atom of the tetrazolyl ring, the penam ring system remains essentially intact upon removal of this group. The protective group of the nitrogen atom of tetrazolylpenam is needed to protect the nitrogen atom which will end up in position 1 of the tetrazolyl ring in the compound of formula IV or formula 6, 40 45 50 55 6095 74? 6 during the conversion of 6-aminopenicillanic acid with a protected amino group in the compound of the formula (5. Similarly, in this case, the ability of the protective group of the nitrogen atom of tetrazolylpenam to perform the specific function discussed hereinafter, not its chemical structure, is significant. The novelty of the antimicrobial compounds according to the invention does not depend on the chemical structure of the protecting group. The identification and selection of the appropriate protecting group can be easily done by a person skilled in the art. Examples of several groups used are given hereinafter. Carboxyl groups at position 3 are carried out. In a tetrazolyl ring, it is usually done before the active group is attached to the nitrogen atom that is substituted at 6, but the conversion can be done in reverse order. For example, a tetrazolyl group can be formed and then a free suppressing amino group can be quoted. to position 6. The choice of the order of the reaction depends, of course, on the type The method of producing compounds of the formulas 4 and 5 is therefore not a problem for an expert who knows the problem of the stability of groups and the specificity of the reaction. for each of the alkyl groups, and R2 and R8 have the meanings given above. A method for the preparation of intermediate products of Formula 6, wherein R5 is a protected amino group and R2 is a tetrazolylpenam nitrogen protecting group, comprises the conversion of 6-aminopenicillanic acid from protected amino group in an amide of formula VIII, in which (Rfy '' is the protecting group of the amino group, and G is the protecting group of the nitrogen atom of the tetrazole ring of penam, or a group that can be easily carried out during or after the reaction is completed) , reactions of this amide with an imidoyl halide forming agent in the presence of tertiary amine, and reactions of the resulting imidoyl halide with a source of jo The resulting intermediates are used in the preparation of penam derivatives of the formulas 4 and 5. It is easy to see alternative methods of converting the carboxyl group into a tetrazolyl group. Alternatively, a tetrazolyl derivative may be converted into an amine derivative at the 6-position. with an optionally protected amino group, and then convert the compound obtained into an acyl derivative. The protecting group of the nitrogen atom of tetrazolylpenam can be removed before or after acylation, as can be introduced before or after acylation alkanoyloxyalkyl radicals R2 or R1. Method of treatment and prevention of infectious diseases caused by gram-positive and gram-negative bacteria , a method of locally controlling bacteria on human tissue, in hospitals, etc., and supplementing the animal's diet, are important applications for the compounds of the invention. They consist in the use of an effective amount of a compound of formula IV or 5, in which R1 is an acyl group, and R2 and R1, which are identical or different, represent hydrogen atoms, alkanoyloxymethyl radicals containing 3-8 carbon atoms, 1-and / alkanoyloxy radicals (ethyl) containing 4-9 carbon atoms or phthalidyl radicals or its salts. For convenience, the compounds of the invention are called "penum" derivatives, as defined by Sheehan et al. in the Journal of the American Chemical Society, 75, 3293 (1953) as structure of formula 9. Although the pen system does not normally exhibit spatial isomerism, the stereochemistry of the penam derivatives of the present invention corresponds to that of natural penicillins. Using Sheehan and others terminology, the well-known antibiotics are well known. The tick, penicyline G, is called 6- (2-phenylacetamido) -2,2-dimethylpenamocarboxyl-3 acid. Many of the compounds of the invention are positively substituted tetrazoles. tion 5, appearing in two isomeric forms, formula 10 and LI. As can be readily seen, both forms exist in a tautomeric equilibrium mixture with dynamic equilibrium when R2 is hydrogen. If, on the other hand, RB is a substituent other than hydrogen alto, then both forms are different chemical entities, not subject to spontaneous interconversion. • ¦-¦; ¦ Preferred antimicrobial compounds according to the invention include those of Formulas 4 and 5, wherein R1 is an acyl group and R2 and R *, identical or different, represent hydrogen atoms, alkane radicals ¬yloxymethyl groups containing 3-8 carbon atoms, 1- (alkanoyloxy / ethyl radicals containing 4-9 carbon atoms) or phthalidyl radicals and their salts. The type of oxygen substituent does not determine the bacterial action of the above compounds of formulas 4 and 5. And indeed, Each of the acyl radicals can be used as R1, and all compounds of the formulas 4 and 5, in which R2 and R3, identical or different, represent hydrogen atoms, alkanoyloxymethyl radicals "containing 3-8 carbon atoms, Ethyl groups containing 4-9 carbon atoms or phthalidyl radicals and R1 being an acyl group exhibit significant antibacterial activity. The acyl group may be derived from a mono- or polycarboxylic acid. acyl group "town A network of acyl parts of carboxylic acids which cannot be isolated but which are in the form of esters, amides, acid chlorides etc. A particularly preferred form of the acyl part is the group of formula 12 where n is 0 or 1 and R7 is an atom hydrogen, alkyl radical containing 1-12 carbon atoms, alkenyl radical containing 2-12 carbon atoms, cycloalkyl radical containing 3-7 carbon atoms, cycloalkenyl radical containing 5-8 carbon atoms, cycloheptatrienyl radical, cycloheptatrienyl radical, cyclo-13 33 40 45 50 55 60 & 5T47 1 3 hexadien-1,4-yl, 1-aminacycloalkyl radical with 4-7 carbon atoms, cyanomethyl radical, 5-methylOH3-phenylisoxalolyl- -4 radical, 5-methyl-3- / o-radical hloKphenyl / isoxalolyl-4, 5-methyl-3-i (2,6-dichlorophenyl) isoxalolyl-4 radical, 5-methyl-3- (2-chloroH6-fluorb-phenyl) isoxalolyl-4 radical, 2- radical alkoxy-1-naphthyl having 1-4 carbon atoms in the alkoxy group, possibly a phenyl radical, optionally an optionally substituted phenylthio radical, an optionally substituted pyridylthio radical, an optionally substituted benzyl radical, a sydmonyl radical, an optionally substituted thienyl radical, an optionally substituted furyl radical, an optionally substituted pyridyl radical, an optionally substituted thiazole radical, and an optionally substituted thiazole radical an optionally substituted isothiazolyl radical, an optionally substituted pyrimidyl radical, an optionally substituted tetrazolyl radical, an optionally substituted triazolyl radical, an optionally substituted imidazolyl radical, or an optionally substituted pyrazolyl radical, such as each optionally substituted pyrazolyl radical, fluoTu, chlorine atom, bromine atom, hydroxyl group, hydroxymethyl radical, amino group, N, N-dialkylamino group containing 1-4 carbon atoms in each alkyl radical, alkyl radical containing 1-4 carbon atoms, aminomethyl radical, aminoethyl radical, alkoxy radical with 1-4 carbon atoms, alkylthio radical containing 1-4 carbon atoms, 2-aminoethoxy radical or N-alkylamino group containing 1-4 carbon atoms, and R is hydrogen, alkyl radical containing 1-6 carbon atoms, hydroxyl group, azido group, carboxyl group, aulfo group, carbamyl group, phenoxycarbonyl radical, indanyloxycarfoonyl radical, sulfoamino group, aminomethyl radical, amino group or NH - ^ / 00-CH2r ^ NH / m group -Cp-Z in which Z is an alkyl radical containing 1-6 carbon atoms, optionally substituted phenylic radical, furyl radical, thienyl radical, pyridyl radical, pyrrolyl radical, amino group, N-alkylamino group containing 1-6 carbon atoms, optionally substituted anilino group, guanidine group, acylamino group containing 2-7 carbon atoms, optionally substituted benzamide group, thiophenecarbamide group, furanocarfoamide group, pyridine carboxamide group, aminomethyl radical, guanidinomethyl radical, alkanecanonamidinomethyl radical with 3 to 8 carbon atoms, benzamidinomethyl radical optionally substituted on the benzamidine part, thiophenecarbonamidinomethyl radical, furancarbonamidinomethyl radical, pyridinecarbonamidinomethyl radical, pyridinecarbamide-pyrimethyl-benzamidinamide radical of the substituted radicals contain at most 2 groups, such as fluorine atom, chlorine atom, iodine atom, alkyl radical containing 1-4 carbon atoms, alkoxy radical containing 1-4 carbon atoms, sulfamyl radical, carfoamyl or cyano, m is 0 or 1, where if R 7 is 1-aminocycloalkyl then n = 0 and when R 7 is optionally substituted phenoxy, optionally substituted phenylthio or optionally substituted pyridylthio, n = 1 , then Q is a hydrogen atom, an alkyl radical of 1-6 carbon atoms, a carboxy group Alkyl, sulfo, caribamyl, optionally substituted phenoxycarbonyl, indanyloxycarbonyl, or aminomethyl. Particularly useful antioxidants according to the invention are compounds of Formulas 4 and 5, wherein Rf and R8 are hydrogen and R1 is the group of formula 12, where n is 1, and R7 is an optionally substituted phenyl or an optionally substituted phenoxy radical. Particularly valuable representatives of this type of compound are the derivatives of formulas 4 and 5 in which R2 and R8 are hydrogen, and R1 is the group of formula (12) in which n is equal to 1, R7 is optionally substituted phenyl or optionally substituted phenoxy and Q is hydrogen. Other particularly valuable compounds thereof. Pu are derivatives of the formulas 4 and 5, where Rl and R8 are hydrogen, and R1 is the group of formula 12, in which n is equal to 1, R7 is optionally substituted phenyl radical, and Q is amino. Still other valuable compounds of this type are the derivatives of formula 4 and 5 where R2 and R8 are hydrogen and R1 is the group of formula 12, where n is 1, R7 is an optionally substituted phenyl radical and Q is a group of the formula NH- / CO- ^ CH2-NH / m- -CO-Z. Especially preferred are compounds for which m is equal to 0, and Z is an optionally substituted benzamide group, a thiophenocarfoonamide group, a furanocarbonamide group, a pyridine carboxamide group, an amino methyl radical, a benzamidinomethyl radical or optionally substituted in the benzamidine part , thiophenecarbonamidinomethyl radical, radical. pyridinocarbonamidinomethyl or 2-foenzimidazolocanbonamidinomethyl radical. The second series of particularly useful antimicrobial compounds according to the invention include the compounds of the formulas 4,15 in which R2 and R8 are hydrogen; and R 1 is the group of formula 12, where n is 1, and R 7 is sydnonyl, thienyl radical, pyridyl radical, thiazolol radical, isothiazolyl radical, pyrimidyl radical, tetrazolyl radical, triazolyl radical, imidazyl radical or a pyrazolyl radical, each of them optionally substituted with the above-mentioned radicals. The preferred heterocyclic radicals include the thienyl radical, the furyl radical and the isothiazolyl radical. Among the compounds of this second series, the compounds of the formulas 4 and 5, in which Q is a hydrogen atom, an amino group or a 40 45 CO 55 609 group, are particularly valuable. of the formula NH— / CO — CH1 -HNH ^ —CO — Z. Preferred compounds where m is equal to 0 and Z has the meaning mentioned above. The most useful compounds of the invention are: oacetainido / -2 ^ -dimet3do ^ - / tetraTOli-5 / ipenam, 6t- / 2-fenokfeyacetamido / -i2,2H-dimethyl-3-A € t, razolyl-6 / penam, * ¦ 6- / D -2-amino-2-phenylacetamido / - (2'-dimethyl-3- (tettfazoli'l4 *) penam, 6- [D-) 2-amino-2 - '/ p-hydroxy (syfenyacVacetaniido] -2, 2-N-dimethyl J-Z-tetrazolyl-S (pentem, 6-tD-2-nmino-2 -. (3-chloro-4-hydroikphyiphenyl) acetamide] -2,2-dimethyl-3- (tet-Thiazolyl-5) / penam, 6- [D 2 -aminoH 2-thienyl- 2 -acetamido] -2,2-dimethyl-1 2 N - (tetrazolyl-5) / penam, 6- [D-2-amino-2- (thienyl-3) -acetamido] -2,2-dimethyl-3- (tetna) zolyl-5 / penam, 6- [D-2n / 2-aminoacetamido / -2-phenylacetamido] -2,2-dimteylOH3- / tetrazolyl-5 / penam, 6- (D-2- (2-aminoacetamido) - 2- (4-hydroxyphenyl) acetamido] 72,2-dimethyl-3H (tetrazolyl-5i) Denam, 6- [D-2- (2-aminoacetamido) -2- (thienyl-2) acetiamido] -2.2 -dimethyl-3- (tetrazolyl-5) penam, 6- [D-2n / 2-aminoacetamlido / -2- (thienyl-3) acetamido] -2,2-dimethyl-3- (tetrazolyl-5) penam, 6- {2- [o- (aminomethyl / phenyl]} - 2,2-dimethyl-3- - tetrazolyl-S / penam, <5- {D-2- (2- / 4-pyridinecaribonamidine / acetamido] -2-phenylacetamido} -2.2 ^ dimets (io-3- / tetrazolyl--5 / penam, and 6- {D-242 - (3-guenyJoureido / acetamido] -2-i [4-hydroxysiphenyl] iacetamido} -2,2-dimethylJ3- / tetrazolyl4 / penaim. It is easy to see that the acyl group R1 may contain one or more asymmetric centers, that is, it may take two forms, D and L. All these variations and combinations of all forms can be obtained by the process of the invention. Preferred antimicrobial compounds according to the invention of Formulas 4 and 5, wherein R 1 represents the group of acyl, and R2 and Ra are hydrogen, can be obtained from the well-known intermediate, 6-amino-penicillanic acid (6-APA), and a series of product reactions are shown in Scheme 1, in which R1 represents an acyl group, (R2) represents a tetrazolylpenam nitrogen protecting group, and (R5) represents an amino protective group. Formulas 4 and 5, where R1 is acyl, and R2 and R8, identical or different, represent alkanoyloxymethyl, 1- (alkanoyloxy) ethyl radicals or phthalidyl radicals, are shown in Scheme 2, where R1 is an acyl group, (R5) 'represents an amino protecting group, and -R28 represents an alkanoyloxymethyl radical, a 1- (alkanoyloxy) ethyl radical or a phthalidyl radical. For simplicity, Scheme 2 shows only R26 at the 1-position of the tetrazole ring. However, as explained later, alkylation of the 5-substituted tetrazoU leads to J747 yielding a mixture of mono-substituted products in which the newly introduced radical is in the 1 or 2 position in the tetrazole ring. From Scheme 1 it is clear how to use the compounds of the formulas 6 and 4 (analog of the compound of formula 16), in which R2 is the protecting group of the nitrogen atom of tetrazolylpenam, as intermediates in the preparation of compounds against - bacterial by the method according to the invention The protecting group of the nitrogen atom of tetrazolylpenam must fulfill two functions. First, it must enable the synthesis of a compound of formula 6, wherein R5 is an amino protecting group and R2 is the aforementioned tetrazolylpenam nitrogen protecting group. Second, it can be easily removed from a compound of formula IV, where R1 is acyl and R * is the protective nitrogen group of tetrazolylpenam, or from a compound of formula 6 where R8 is hydrogen and R2 is the nitrogen protecting group of tetrazolylpenam, or of the compound of formula 6, where R5 is the amino protecting group and R2 is the tetrazolylpenam protecting group, in each case without destroying the penam ring system. As is apparent from the discussion that follows, not all of the tetrazolyl ring protecting groups useful in the present invention need to be removed from each of the compounds of formulas 4 and 6. Useful are those tetrazolylpenam nitrogen protecting groups which are suitable for use in the present invention. remove from at least one of the following three types of compounds: (a) compounds of formula IV in which R1 is acyl and R2 is protecting the nitrogen atom of tetrazolylpenam, and b) compounds of formula VI in which R5 is a hydrogen atom and R2 is a tetrazolylpenam protecting group, and a compound of formula 6 wherein R5 is an amino protecting group and R2 is a tetrazolylpenam nitrogen protecting group. The conditions under which the nitrogen protecting group of tetrazolylpenam is removed are well known and obvious to those skilled in the art. Moreover, the conditions for carrying out reactions without decomposition of the penam ring, previously used for penam derivatives, are also well known. The groups of the formulas -CH2CH2Y, ^ C / = 0 / belong to the individual protecting groups of the tetrazolyl ring. R20-, R14, SOg-R14 or (R1) ', in which Y represents a cyano group, an alkoxycarbonyl radical containing 2--7 carbon atoms, a phenoxycarbonyl radical, an alkylsulfonyl radical containing 1--6 carbon atoms, a phe radical Nylsulfonyl or a group of the formula N -R15RW, in which R15 and R18, identical or different, represent hydrogen, alkyl radicals containing 1-4 carbon atoms, benzyl or phenyl radicals, R14 is an alkyl radical containing 1 - 6 carbon atoms, a benzyl radical, a phenyl radical, optionally substituted with up to two radicals, such as a nitro group, a fluorine atom, a chlorine atom, a bromine atom, an alkyl radical containing 1 to 4 carbon atoms, or 74X 11 12 radical adkoxy y containing 1-4 carbon atoms, while (R8) is a group of formula 23 or 24, in which R4 and R17, identical or different, represent hydrogen atoms, hydroxyl groups, nitro groups, fluorine atoms, chlorine atoms, bromine, iodine atoms, alkyl radicals containing 1-8 carbon atoms, alkoxy radicals containing 1-8 carbon atoms, alkanoyloxy radicals containing 2-7 carbon atoms, formyloxy radicals, alkoxymethoxyyl radicals containing 2-7 carbon atoms , phenyl radicals or benzyloxy radicals, R18 represents a hydrogen atom, an alkyl radical containing 1-4 carbon atoms, or a phenyl radical, R19 and R20, identical or different, represent hydrogen atoms or methyl radicals, and X represents an oxygen atom or sulfur. A typical example of a tetrazolyl ring nitrogen protecting group is that of the formula —CHjj- ^ CH / Y / Y1, where Y is an electron-capturing group and Y1 is hydrogen or an electron-capturing group, same or different from Y. Trapping group function an electron is the donation of a hydrogen atom to a carbon atom to which the radicals Y and Y1 are attached, sufficiently acidic that the group can be removed by the reverse Michael reaction. Such a reaction is well known, for example described by Mouse in " Modern Synthetic Reactions ", WA Benjamin, Inc., New York / Amsterdam, 1965, p. 207. A typical electron-capturing group is the cyano group, an alkoxycarbonyl radical containing 2-7 carbon atoms, phenoxycarbonyl radical, alkylsulfonyl radical containing 1-6 carbon atoms, the phenylsulfonyl radical and the group of the formula SO2-NR16R16, in which R15 and R18, identical or different, represent hydrogen atoms, alkyl radicals containing 1-4 carbon atoms, phenyl or benzyl radicals A protective group configuration in which Y1 is hydrogen and Y is preferably an alkoxycaribbnyl radical having 2 to 7 carbon atoms or a phenylsulfonyl radical is particularly preferred. Another applicable protecting group a is the tetrazolyl ring is a group of the formula -C / = O / -O-R14. Such a group can be removed by hydrolysis under mild conditions, such as hydrolysis in a slightly alkaline environment, or by treatment with a nucleophilic compound such as an amine, thiol or thiolate. Although many groups may be used as R14, it is preferably an alkyl radical of 1-6 carbon atoms, a benzyl radical or a phenyl radical, optionally substituted with up to two radicals, such as a nitro group, a fluorine atom, a chlorine atom, and bromine, an alkyl radical of 1-4 carbon atoms or an alkoxy radical of 1-4 carbon atoms. Another nitrogen protecting group in the parenchyma-substituted tetrazolyl ring is the group of formula —SO6 — R14. These groups can also be removed by hydrolysis or treatment with a nucleophilic agent as described for the group of the formula —C / = 0 / - O — R14, and R14 is preferably a radical containing 1-6 carbon atoms, a benzyl radical or a phenyl radical, optionally substituted with up to 2 radicals, such as a nitro group, a fluorine atom, a chlorine atom, a bromine atom, an alkyl radical containing 1-4 carbon atoms, and an alkoxy radical containing 1-4 carbon atoms. * Yet another protecting group a ^ nitrogen volume piettc-. The tetrazolyl group substituted for the penam is a group of the formula —CH / W / W1, where W is an optionally substituted phenyl radical, an optionally substituted furyl radical, or an optionally substituted thienyl radical, and W1 is a hydrogen moiety, an alkyl radical, an optionally substituted phenyl radical, or An optionally substituted iuryl radical or an optionally substituted thienyl radical. If W is an optionally substituted phenyl radical and W 1 is a hydrogen atom, an alkyl radical, or an optionally substituted phenyl radical, then such a group may be removed by hydrolysis. It can also be removed by solvolization in trifluoroacetic acid if the combined effect of the interaction of W and W1 is sufficient to achieve the desired degree of stability of the carboria ion formed + CH / W / W1. Particularly suitable configurations of such protecting groups are those of the formulas 23 and 24, in which R4 and R17, identical or different, represent hydrogen atoms, hydroxyl groups, nitro groups, fluorine atoms, chlorine atoms, bromine atoms, iodine atoms, and rhodium. Alkyl radicals containing 1-6 carbon atoms, alkoxy radicals containing 1-6 carbon atoms, alkanoyloxy radicals containing 2-7 carbon atoms, formyloxy radicals, alkoxomethoxy radicals containing 2-7 carbon atoms, phenyl or benzyloxy radicals, R18 represents a hydrogen atom, an alkyl radical containing 1-4 carbon atoms or a phenyl radical, R19 and RM, identical or different, mean hydrogen atoms or methyl radicals, and X represents an oxygen or sulfur atom. As one skilled in the art can easily ascertain, the substituents W cited above and W1 can be replaced by other groups, also stabilizing the carbonium ion / W—CH-^W1 ^. Yet another protecting group of the nitrogen atom in the tetrazolyl ring attached to the pen may be a optionally substituted phenicyl radical. The radical is removed by reaction with a nucleophilic reactant such as thiophene oxide. The phenacyl groups of formula 25 are typical where R 21 is hydrogen, nitro, fluorine, chlorine, bromine or phenyl. the method of preparing the antibacterial compounds of the invention is discussed and described in detail. Methods A, B and F are deprotecting the tetrazolyl ring substituted for penam, method C is acylating to R1, method D is alkylating the tetrazolyl ring, and process E, related to process C, consists in modifying the acylation product to give another acyl derivative. The same product can of course be obtained in two or more ways. For example, method A can be used to remove the protective group from an intermediate, acylated then with C and optionally modified with method E and, in turn, acylated with method D. Of course, the choice of method or The nature of the steps depends solely on the characteristics of the compounds and chemical reactions used. Method A is useful in the synthesis of compounds of formulas 4 and 5 where R1 is an acyl group and R £ and R8 are hydrogen. Hydrogenolift is performed on a compound of formula IV, in which R1 is an acyl group, and R2 is a group of formula 23, in which R4 and R17, identical or different, represent hydrogen atoms, hydroxyl groups, nitro groups, fluorine atoms, chlorine, bromine atoms, iodine atoms, alkyl radicals containing 1-6 carbon atoms, alkoxy radicals containing 1-6 carbon atoms, alkanoyloxy radicals containing 2-5 carbon atoms, formylbxyl radicals, alkoxymethophenyl radicals acylation of 2 to 7 carbon atoms, phenyl radicals and benzyloxy radicals. The substrate used in this process can be obtained by acylating a suitable compound of formula VI or its salt, in which R 5 is a hydrogen atom or a trialkylsyl radical containing 1 to 4 atoms carbon in the alkyl groups, and R6 has the meaning given above. The acylation can be carried out in an analogous manner to the method C described below. Reactions can be carried out in many ways known for this type of transformation, such as, for example, discussed by Augustine in "Catalytic Hydirbgenation", Marcel Dokker, Inc., New York, 1965, For example, one skilled in the art can readily appreciate the reaction conditions that do not damage the p-latam ring of the penam core. A particularly convenient method is to shake or stir the reagent solution in an inert solvent such as methanol, ethanol. , ethyl acetate or water, or in a mixture of such solvents in the presence of a catalyst such as palladium (10%) on carbon under a hydrogen atmosphere. The catalyst is used in an amount of about 10-100% by weight, based on To the substrate derivative of penam, and the hydrogen pressure can vary between 1 and 100 atm. At ambient temperature, the reaction is complete within a few hours. Method B is useful for for the preparation of compounds of formula 4 and 5 where R1 is acyl and R2 and R8 are hydrogen. The method consists in treating the base of the compound where R1 is acyl and R * is 23, wherein at least one of R4 and R17 is a hydroxyl group in the 2 or 4 position. The substrate can be obtained by hydrogenolysis of a suitable compound wherein the hydroxyl groups, R4 or R17, are protected with a benzyl radical. for this purpose, use the method discussed in the description of method A. Process B 747 14 can be carried out immediately after carrying out the reaction in method A without isolating an intermediate product, or if the hydrogenolization can be performed in an alkaline environment, the reactions with method B can be carried out simultaneously with the hydrogenolysis. Under certain conditions of hydrogenolysis, immediately after formation of the penam derivative, in which R 'is a hydroxybenzyl group, hydrogenolytic cleavage occurs not of the hydrofcsybenzyl group and the formation of a compound having a weight of 4 or 5, in which R * and R s are hydrogen. Reactions in method B are carried out by first dissolving the starting material in a suitable solvent and adding about 1 mole equivalent of base at or slightly below ambient temperature. Usually the reaction takes place in a few minutes. In this case, inert solvents used to dissolve the suffostrat are suitable. examples of solvents include nTC esters such as ethyl acetate and butyl acetate, lower aliphatic ketones such as acetone and methyl ethyl ketone, chlorinated hydrocarbons such as chloroform, methylene chloride and 1,2- dichloromethane, lower alkanols such as methanol and ethanol, and tetrahydrofuran. A great number of alkali compounds can be used because it appears that the function of the base is primarily to remove hydrogen from the hydroxyl group which is substituted for the phenolic ring and which is present as a hydroxyibenzyl protecting group. As alkaline reagents, alkali metal salts of acids can be used. alkanetarboxylic acids such as sodium acetate and sodium 1-ethylpentane carboxylate, organic amines such as triethylamine, triethylamine, N, N-dimethylamine, N-ethylpiperidine, pyridine or N-methyl morpholine, alkali metal hydroxides such as such as sodium hydroxide, potassium hydroxide, alkaline earth metal hydroxides such as barium hydroxide and calcium hydroxide, and alkali metal and alkaline earth metal hydrides such as sodium hydride, potassium hydride and calcium hydride. Usually about one mole equivalent of the base is used, although in some circumstances an excess of the base may also be used. In cases where the substrate has a different acid functionality, it is necessary to add two molar equivalents of the base. A skilled person can easily assess that the reaction conditions are limited by the sensitivity of the β-lactam ring of the penal core and the use of an excess of an alkaline compound in the reaction environment should be avoided, as otherwise it may react with the mentioned ring (3 A particularly preferred method of carrying out this reaction is the treatment of the suffostat with an aqueous solution having a pH of 7.5-9.6. Method C is useful for the preparation of compounds of the formulas 4 and 5 in which R 1 is acyl and R2 and Rs, the same or different forms, are hydrogen atoms, alkanoyloxymethyl radicals containing 3-8 carbon atoms, 1- (alkanoyloxy) ethyl radicals containing 4-9 carbon atoms, 74716 and phthalidyl radicals. on the acylation of a compound of formula 6 or 7 or a salt thereof, in which R2 is a hydrogen atom, an alkanoyloxymethyl radical, a 1- (alkanoyloxy / ethyl radical, a phthalidyl radical or a trialkylsilyl radical having 1-4 atoms) thats carbon in each alkyl group. The acylation product is treated, if necessary, with a protective solvent, which is necessary when R2, R * or RB is a thyalkylsilyl radical. The compound of formula 6 or 7, or a salt-acylation thereof, is treated by the action of a nanactivated derivative of the appropriate carboxylic acid in a suitable solvent system. The commonly used activated derivative is an acid halide such as an acid chloride. Following the usual acylation method around 1 molar equivalent of the acid chloride is added to a solution of said compound of formula VI or 7 or its salt in a solvent such as a chlorinated hydrocarbon such as chloroform or methylene chloride, an ether such as tetrahydrofuran or 1,2- dimethoxyethane, an ester such as, for example, ethyl acetate or butyl acetate, a lower aliphatic ketone, such as, for example, acetone or methyl ethyl ketone, or also a tertiary amide, such as, for example, N, N-dimethylformamide or N-methylpyrrolidone. The reactions are carried out at a temperature from -40 ° C to ° C, preferably from -10 ° C to 10 ° C, optionally in the presence of about 1 molar equivalent of an acid binding agent such as triethylamine, pyridine or sodium bicarbonate. The reaction ends fairly quickly, i.e. after 1 hour. If R2 and R8 are hydrogen, it is preferable to use as reactant a salt of a compound of formula 6 or 7 with a tertiary amine, such as, for example, triethylamine. An alternative method suitable for the acid halide acylation of a compound of Formula 6 or Formula 7 wherein R2, R8, and R5 are hydrogen is by carrying out the reaction in an aqueous environment. According to this method, similar to the Schotten-Baumann method, the acid halide is added to a solution of the substrate in water or a mixture of water with another inert solvent at or slightly below ambient temperature, keeping the pH of the solvent in the range of about 6 .0-9.0 before, during or after the addition of the halide. Other activated carboxylic acid derivatives useful in process C include mixed anhydrides. In this case, the salt of the corresponding carboxylic acid is treated with about 1 mole equivalent of the lower alkyl chloroformate in an inert aprotic solvent at a temperature of -20 ° C to 20 ° C, preferably 0 ° C. Suitable salts include alkali metal salts such as sodium and potassium salts, and salts with tertiary amines such as triethylamine, triethylamine, N-ethylpiperidine, N, N-dimethylaniline, N-methylmorpholine, and pyridine. Suitable solvents include, for example, chloroform, methylene chloride, acetonitrile, tetrahydrofuran, dioxane and N, N-dimethylformamide. The mixed carboncarboxylic anhydride thus formed is usually used in situ for the acylation of the compound of formula VI or 7. These reactions are usually carried out by mixing solutions of the just-formed mixed anhydride and the compound of formula VI or 7. If R2 and R8 are hydrogen, then it is preferable to use as reactant a salt of a compound of formula 6 or 7 with a tertiary amine, such as, for example, triethylamine. The acylation temperature is usually from -30 ° C to 20 ° C, preferably around ≤ 10 ° C. The reaction is usually complete after a few hours. In most cases, the molar ratio of mixed anhydride to the compound of Formula 6 or Formula 7 is substantially 1: 1. Another method of carrying out the process is that the carboxylic acid is first converted to an active ester, which is then treated with the compound of Formula 6 or 7 or its salt. Active esters include, for example, phenyl carboxylates such as p-nitrophenyl and 2,4,5-trichlorophenyl carboxylate, thioesters such as phenylthiol and methylthiol esters, and N-hydroxy esters, such as N-hydroxysuccinimide and N-hydroxyphthalimide. The esters are prepared in known manner, and the acylation is conveniently carried out by dissolving the active ester and said compound of formula 6 or 7 or its salt in a polar aprotic solvent such as N, N-dimethylformamide, N N-dimethylacetamide or N-methylpyrrolidone. The solution is stored at about room temperature for several hours for. for example overnight and the product is isolated by standard methods. In many cases, the active ester may be replaced with suitable acid azides. Yet another alternative for Process C, useful for the acylation of compounds of Formula 6 and Formula 7, is the action of carboxylic acid on Formula 6 or 7 in the presence of certain known agents that enable the formation of peptide bonds. Such agents include carfoondimides such as, for example, dicyclohexyiokairtoondimide and 1-ethyl-3- (3-dimethylaminopropyl) carbpndimide, alkoxyacetylene, such as, for example, methoxyacetylene and ethoxyacetylene and N-ethoxycarboxonyl-2-carbonyl. 1,2-dihydroquinoline. The reactions are carried out in a suitable solvent in which the reactants dissolve without affecting the product suffostrates, such as, for example, acetonitrile, N, N-dimethylformamide, and N-methylpyrrolidone. we can replace the hydrogen substituents R2, R8 and R5 in the aicylated compound of formula 6 or 7 with trialkyl silyl radicals. After acylation, the trialkylsilyl radicals are removed by replacing them with hydrogen atoms, a simple way of treating the product with a protic solvent system such as water or a lower alkanol such as, for example, methanol or ethanol. Derivatives containing trialkylsilyl radicals are preferred in view of the easier availability of starting materials. Such a radical can be introduced into the suffostratate compound of formula 6 and 7 40 45 50 55 6017 $ 5f47 and * 2 byilyl methods, for example using trimethylchlorosilane or N, methylsilylacetamide as described by Biifeofer and Ritter in Amgewandte Chemie / International Edftion in English /, 4, 417-418 and 4126/1965 /. The reaction conditions should be selected in order not to damage the P ^ lactam group of the penam core. In method C, it is also possible to use silyl derivatives formed by the reaction of the compounds of the formulas 6 and 7 with the lower dichlorodisilanes. The siliconization is carried out by known methods, such as, for example, described in German Patent Specification No. 1,933,187. After the compound has been quoted, the silicon groups are removed by treatment with a protic solvent such as water or a lower alkanol such as, for example, methanol or ethanol. If necessary, the tetrazole ring of a compound of formula 8 or 7, in which R2, R8 and R6 are hydrogen atoms, can be protected against the acylation by method C with various other groups. Then, after quoting, the protecting groups are removed to give the desired antimicrobial agent o ' Formula 4 or 5, wherein R 1 is acyl, and R 2 and R 8 are hydrogen. Many radicals may be used as protecting groups, such as, for example, an optionally substituted triphenylmethyl radical, an alkoxymethyl radical, an optionally substituted benzyloxymethyl radical, and a cyanomethyl radical. The use of the triphenylmethyl radical as a protecting group is particularly advantageous. Those skilled in the art can readily appreciate that all the discussed methods for carrying out Method C are equally effective and convenient for acylating a compound of the formula VI or 7. The relative effectiveness always depends on a number of factors, such as for example, the structure of the compound of formula 6 or 7, the availability of starting materials, the scale of the reaction, and in particular the structure and reactivity of the acyl group introduced. In practice, the specialist will select the most appropriate course of action in each case, considering all relevant factors. Moreover, in some instances, certain precautions or modifications are necessary or desirable, especially if R 1 is the group of formula 12 where n is equal to i. For example, if R 1 is the group of formula 12, n = l and Q is an optionally substituted phenoxycatlbonyl radical or an indanyloxycarbonyl radical, the acylation may be carried out as described in US Patent No. 3,879,801. For the preparation of compounds of Formula 4 and 5, wherein R 1 is a group of Formula 12 where n = 1, Q is a carboxylic acid and R7 is an optionally substituted phenylic radical or an optionally substituted hetetrocyclic radical, an effective and useful acylating agent in Process C is a 2-substituted malonic acid monochloride The preparation and use of the acid monohydrides is described in Belgian Patent Specification No. 788,928. If R 1 is the group of formula 12, in which n = 1 and Q is or includes basic amino group, primary or secondary, it is necessary to protect the amino group in the starting carboxylic acid before activating the carboxyl group of this acid. After protection of the amino group, the substrate is acylated by method C, followed by deprotection to give the antimicrobial derivative of penam of formula 4 or 5. As amino protecting groups for the formation of the peptide bond, many known The benzyloxycarbonyl group, as reported by Doyle et al. In the Journal of the Chemical Society (London), 1440 (1962), and the enamine formed by the reaction of the starting amino acid with the fl-is-dicarbonyl derivative, are particularly suitable for this purpose. reported by Dane and Dockner in Angewandte Chemie / International Edition in English /, 3, 439/1964 / and in Chemiische Berichte der Deutschen Chemischen Geselflschaft, 98, 789/1965 /. In the case of using other protection groups, the publication Green- Stein and Winitz, "Chemistry of the Amino Acidis", John Wiley and Sons, Inc., New York / London, 1961, pp. 882-922. In some cases where n = 1 and Q is or contains a basic amino group, a particularly valuable acylation method is the use of a hydrochloride of the acid precursor. First, the chloride of the acid hydrochloride is prepared, followed by acylation as described for 2-amino-2-phenylacetyl chloride hydrochloride, followed by the acylation of 6-aminopenicillate acid (US Pat. No. 3,140,282). Method D is useful in the preparation of compounds of formulas 4 and 5 wherein R1 is acyl and R2 and R * are alkanoyloxymethyl, 1- (aalkanoyloxy) ethylen or phthalidyl radicals. According to this method a suitable compound of formula IV or 5, wherein R1 is acyl and R2 and R8 are hydrogen, is alkylated with alkanoyloxymethyl, 1- (alkanoyloxy) or phthalide. The term halide here should be understood as meaning iodide, bromide and chloride. The reactions are conveniently carried out by dissolving the tetrazolate of said compound of Formula IV or wherein R2 and Rs are hydrogen in a suitable polar organic solvent such as N-dimethylformamide and about 1 molar equivalent of an alkanoyloxymethyl halide. As substrate salts, commonly used alkali metal salts such as sodium and potassium salts and salts with tertiary amines such as triethylamine, N-efcylopiperidine, N, N-diethylaniline and N-55-methylmorpholine are used. Reactions are usually carried out at about ambient temperature, and the time taken to complete the reaction depends on many factors such as the concentration of the reactants and their reactivity. In the case of halogen derivatives, iodides react faster than bromides, and these react faster than chlorides. Indeed, when using chlorinated derivatives, it is usual to add up to one molar equivalent of an alkali metal iodide. This speeds up the reactions, moreover, it is believed that the addition of iodide leads to an exchange of halogens and the formation, in situ, of certain amounts of a more reactive iodine derivative. Taking into account All factors, reactions are usually carried out within many hours for example overnight. As stated previously, for compounds of formulas 4 and 5, where R * and R * are hydrogen, for each. for R1, there is an equilibrium mixture. It has been found that the crude product obtained by alkylating such a mixture is also a mixture of this type. It contains products substituted with one alkyl radical in which the newly introduced alkanoyloxymethyl groups are in the 1 or 2 position of the tetrazole ring. The ratio of these products depends on many factors, such as the structure of the penam derivative, the structure of the alkylating agent, and the reaction conditions. In some cases, almost only one isomer can be held. Although the mixture of products can be separated by conventional methods, for example by chromatography, the mixture of isomers can be used directly for the further transformations described below, if desired, as both isomers have bactericidal properties. Alkanoyloxyallkyl halides are either known compounds, or may be obtained by known methods (Ulich and Adams, Journal of the American Chemical Society, 43, 862 (1921); Dachne et al., Joumal of Medicinal Chemisttry, 13, 607, (1970). Method E is a valuable method for the preparation of compounds of formula 4 and 5, where R * and R * are independently hydrogen, an alkanoyloxymethyl radical, 1- (alkanoyloxy) ethyl or phthalidyl, and R1 is a radical of formula L2, where R1 is as defined above, n is 1 and Q is a carboxyl, sulfoammonium, carbamyl, amino or NH group - / CO— —cA- ^ NH / m — CO — iZ. This method consists in carrying out a further transformation of some of the compounds of formula 4 and 5, which is prepared by method C. Thus compounds of formula 4 and 5 where n is 1 and Q is a carboxyl group can be prepared of the corresponding compounds of formula IV or V in which Q is phenoxycarbonyl, optionally substituted or indanyloxycarbonyl, by mild hydrolysis of the phenoxycarbonyl group, optionally substituted phenoxycarbonyl group, or indenyloxycarbonyl group to liberate the carboxyl group. The reactions are carried out by treating the starting material with a mildly alkaline aqueous solvent system until the hydrolysis is substantially complete, for example, according to the method described in US Patent No. 3,679,601. in which n is 1 and Q is sulfoamino, may be obtained from the corresponding compounds of formula IV or 5 in which Q is amino by direct sulfonation. The sulfonation is conveniently performed using the method described in U.S. Patent No. 3,381,091. Compounds where n is 1 and Q is a carbamyl group can be obtained by treatment with ammonia from suitable compounds in which Q is a phenoxycarbonyl group or more preferably a phenoxycarbonyl group substituted with one or more electron-attracting groups. Particularly suitable substituted groups are the nitro- and dinitrophenoxycarbonyl groups, and the reaction itself is carried out using known methods (see Johnson, Journal of the American Chemdcal Society, 75, 3636, (1953). Compounds in which n is 1, and Q is a group of the formula: NH— / CO — CH * —NH / m — CO — Z, where n is 0, and Z is an alkyl group of 1-6 carbon atoms, optionally substituted phenyl, the furyl, thienyl, pyridyl or pyrallyl groups are prepared from the corresponding compounds of formula IV or V, wherein Q is an amino group by reaction with an active derivative of the corresponding carboxyyl acid. The methods of activating the corresponding carboxylic acids and the acylation methods that may be used in this process are discussed above in the description of Method C. In many cases, the use of carboxylic acid chloride is a particularly convenient method. Compounds where n is 1 and Q is a group of formula NH— / CO — CH ^ —NH ^ m - CO — Z, in which m is 0 and Z is an amino ethyl group, is prepared from the corresponding compounds of formula 4 or 5, in which Q is a group ¬ new by coupling with glycine. This coupling is carried out in the following steps: protection of the amino functional group in glycine, activation of the carboxyl group in nitrogen-protected glycine, and reaction of the intermediate product thus obtained with the compound of formula IV or 5 or a salt thereof, (4) removing the nitrogen protecting group. Convenient methods for carrying out the individual steps are described in Belgian Patent Specification No. 681,660. Compounds in which n is 1 and Q is a group of the formula NH— / CO — CH — NH / m — CO — Z, where m is 0 and Z is optionally substituted anilino, and is prepared from the corresponding compounds of formula IV or 5, wherein Q is amino, by reaction with an isocyanate or optionally a substituted phenyl isocyanate. The reactions are carried out by contacting substantially equimolar amounts of isocyanate with a penam derivative or a salt thereof, for example a triephylamine salt, in an organic solvent inert to the reactants, for example N, N-dimethylformamide at a temperature around ambient temperature. . The complete reaction takes a few hours, for example the reaction takes about 3 hours, and the product can be isolated simply by evaporation of the solvent. Compounds where n is 1 and Q is NH NH / CO-. r-CHz- ^ NH / m — CO — Z, in which m is 0, and Z is a guanidine group, is prepared from the corresponding compounds of formula 4 or 5, in which Q is an amino group by reaction with the agent introduces 40 45 50 55 60 PLN with guanylcarfoamyl group. These agents are prepared by treating the 4-guanyflosemicarbamide aftbo with a nitrous acid-donating compound or some oxidizing agents; The guanylcarfoamyl introducing agents thus prepared are particularly valuable in the process in question. The preparation and use of such agents is discussed in US Pat. Nos. 3,570,501 and 3,570,514. A synonym for the guanyl group is the term "amidine". Compounds in which n is 1 and Q is a group of the formula NH— / CO — CHf — NH / m — CO — Z, in which m is 0 and Z is a guanidinomethyl group, is prepared from the corresponding compounds - formula IV or 5, in which Q is amine group by reaction with guanidinoacetic acid chloride hydrochloride. Reactions are usually carried out by treatment of the starting solution of the penam compound or its salt in a polar organic solvent such as N, N-dimethylformamide or N, N-dimethylacetamide at a temperature of about 0 ° C with guanidinoacetyl chloride hydrochloride. The reaction time is usually about 2 hours to complete the reaction. The salt of the starting material is used in those cases where R1 or R8 is hydrogen and the corresponding soda is at ¬ clade alkali metal salts and tertiary amine salts. Typically, at least one mole equivalent, and more preferably up to about 4 mole equivalents of the acylating agent, is necessary to obtain a high yield product. Compounds where n is 1 and Q is NH— / CO- ^ CH * - NH / m — CO — Z in which m is 0 and Z is an acylamino group, optionally substituted benzamide, thiophenecarboxamide, luranecarboxamide, and pyridine carboxamide groups are prepared from the corresponding compounds of formula 4 or 5, in which Where Q is amino, by reaction with the appropriate acylisocyanate. The latter is developed by the method and according to the teachings of U.S. Patent No. 3,470,330. Compounds in which n is 1 and Q is a group of the formula NH— / CO — ^ CH * —NH / m — CO — Z where m is 1 and Z is an alkyl radical of 1-6 carbon atoms, optionally substituted phenyl, fuiryl, thienyl, pyridyl, pyrrolyl, aminomethyl, optionally substituted aniline, guanidine, guanidinomethyl, acylamino radicals, The optionally substituted foenzamide, thiophenocarboxamide, furanokifoxamide, or pyridine-carboxamide radical is prepared in a manner analogous to that described for the corresponding compounds in which m is 0 *, except that the corresponding compound of formula 4 or 5 is related to Compound in which Q represents a group of formula NH— —CO — CHg — Compounds in which n is 1, and Q represents a group of formula NH - (CO - CH - NH) - CO - Z, in which m is 0, and Z is an alkane and carboxyainidine meftyt group, containing i - <2 carbon atoms in the molecule, optionally substituted foenzamidinomethyl, thiophenocarfoxamidinomethyl, furanocanboxamidinomethyl, pyridine carboxamidinomethyl, pyrrolokairboxamidinomethyl, or a 2-foenzimilazoyl azides of the corresponding 4-foenzimilazoyl azides of the formula Q is a group of formula NH — CO — CH — NH2 by reaction with a suitable imidate ester, for example ethyl benzimidate. The reactions are usually carried out by contacting substantially equal amounts of the ester and the penam compound or its salt, for example a triethylamine salt, in an organic solvent that is inert with respect to the reactants, for example chloroform, N, N-dimethylformamide or N, N-dimethylacetamide, - at a temperature close to the ambient temperature. The reaction takes several hours, for example about 6 hours, and then the product separates. The imidate esters used in the above process are either known compounds or are prepared by known methods. For example, they can be prepared by acid-catalyzed addition of an alkanol to the corresponding nitrile (Pinner reaction) by corresponding carboxamidides with a triethyloxonium fluorophoreate, for example, triethyloxonium iloroborate, or in some cases by alkane-catalyzed alkanoyl addition reaction. The base catalyzed addition reaction is particularly convenient when the cyano residue is attached to an electron attracting group, 33 for example 4-cyanopyridine. Further information can be found in the literature: Shriner and Neumann, Chemical Reviews, 35, 354-358 (1044); Meerwein, Organic Syntheses, Vol. V, 1080-1082 (1S73); Schaefer and Peters, Journal of Organic Chemistry, 4026, 412, (1061); Belgian Patent Specification No. 803 004 and references cited. Method F is a valuable method for the preparation of compounds of formulas 4 and 5 wherein R1 is acyl and R2 and R8 are hydrogen. The method is based on the hydrolysis of a suitable compound of formula IV, in which R1 is an acyl group, and R2 is a group of formula —C / = O / - -O — R14 or SO5 — R14, in which formulas R14 is an alkyl radical containing 1— 6 carbon atoms, a benzyl radical or a phenyl radical optionally substituted with one or two substituents such as nitro, fluorine, chlorine, phorom, an alkyl group containing 1-4 carbon atoms, or an "alkoxy group containing 1-4" Hydrolysis is carried out by contacting with an aqueous or partially aqueous solvent system in the temperature range (-5 / -30 ° C, most preferably 10-25 ° C), with a pH in the range of 7.5-0.5. usually around 8.5. Reactions are carried out until the hydrolysis is complete. This usually takes about 1 hour. Usually, although it is not essential, a co-solvent is used in this process. Suffostants are suitable for the use of co-solvents. mixing with water, which 23 9S747 24 sl a dent to dissolve the original penny compound. Typical examples of co-solvents that can be used are acetone, lower alkanols such as methanol and ethanol, ethylene glycol, lower mono- and di-ethylene glycol ethers such as 2-netoxyethanol and 1,2-dimethoxyethane. , tetrahydrofuran, dioxane and acetonitrile. The product is isolated by known methods. The starting penam compounds of the formulas 6 and 7, in which Rf, R8 and R5 are hydrogen, can be obtained by the C method from the corresponding compounds of the formula VI or their acid addition salts. wherein R 5 is hydrogen and R 2 is a group of formula 26 or 24 in which (R 4) and (R 17) are independently hydrogen, hydroxy, fluorine, chlorine, bromine or iodine, an alkyl radical, containing 1-6 carbon atoms, alkoxy, containing 1-6 carbon atoms, adkanoyloxy, containing 2-7 carbon atoms, phenyl or benzyloxy, R18 is hydrogen, alkyl containing 1-4 carbon atoms, or phenyl radical, R19 and Rf0 are independently of a hydrogen atom or a methyl radical, and X is a sulfur or oxygen atom, with the proviso that if R18 is a hydrogen atom then at least one of the substituents (R4) and (R17) is a 2- or 4-alkoxy group, containing 1-6 carbon atoms, 2 or 4 alkanoyloxy contains having 2-7 carbon atoms, 2- or 4-formyloxy, 2- or 4-alkoxy-methoxy having 2-7 carbon atoms, or 2- and 4-benzyloxy. These compounds are obtained by the action of trifluoroacetic acid. Although not essential, it is preferable to add an alkoxy benzene such as anisole, phenethol or veratrol to the reaction environment. The reaction is conveniently carried out by dissolving the starting material in a small volume of an anode-containing trifluoroacetic acid, keeping the solution at -70 ° C, most preferably at 30-40 ° C for a suitable period of time, and (then kneading the product for a period of time). the addition of a solubiliser. The product is then separated by filtration. Alternatively, especially when handling small amounts, it is sometimes advantageous to stop the reaction by rapidly evaporating the trifluoroacetic acid under reduced pressure at a temperature close to ambient temperature. The amount of trifluoroacetic acid used in the reaction is not critical, but must be sufficient to dissolve the starting material, and is usually 10-100 mole equivalents with respect to the penam compound. Usually one mole equivalent of anisole is used but for Reaction environments can be added in larger amounts up to 10 equivalents in molar. The starting material which reacts in a particularly effective manner is a sulfoman salt, for example the methanesulfonate salt or p-toluenesulfonate of the compound of formula 6. The time of the reaction depends on many factors, such as temperature, structure of the substance. starting point, the concentration of the solution. However, a convenient method of carrying out is to measure the progress of the reaction carried out using nuclear magnetic resonance spectroscopy so as to determine the reaction time leading to the optimal conversion of products for the given reaction conditions. When operating at a temperature of about 35 ° C, the usual time is 0.1-1.5 hours. The starting pamoate compound of formula 6 and 7 used in method C, where R, R8 and R5 are hydrogen, can also be to obtain by hydrogenolysis the corresponding compound of formula 6 or an acid addition salt thereof, in which R5 is hydrogen, and R2 is a radical of formula 23, in which R4 and R17 are hydrogen, hydroxyl, nitro, fluorine, chlorine, ibromine or iodine, alkyl group containing 1-6 carbon atoms, alkoxy group containing 1-6 carbon atoms, alkanoyloxy group containing 2-7 carbon atoms, phenyl group or benzyloxy group. In this process, the methods and conditions discussed earlier for method A can be successfully applied. The starting formulas 6 and 7, in which R2, R8 and R5 are hydrogen, are obtained by removing the triphenylmethyl protecting group from the compound Formula 6, wherein R5 is triphenylmethyl and Rf is hydrogen. The triphenylmethyl protecting group is removed from the compound by treatment with an acid, and this method may employ a variety of acid reagents under various conditions conventionally used to remove triphenylmethyl groups. For example, it is possible to use a sulfonic acid such as methanesulfonic acid, benzenesulfonic acid or p-toluenesulfonic acid, anhydrous hydrohalic acid such as hydrogen chloride or hydrogen phosphide, an alkanoic acid such as acetic, propionic, chloroacetic, trifluoroacetic and the like. is accomplished by dissolving the starting material in a suitable solvent and adding about two molar equivalents of the acid reagent at about ambient temperature. The reaction takes about 1 hour for a complete reaction and the product is present in the reaction environment in the form of an acid addition salt corresponding to the acid reagent used. The solvent should be chosen so that the starting penam compound dissolves in it; Examples of such solvents are ethers such as diethyl ether, tetrahydrofuran, dioxane and 1,2-dimethoxyethane, chlorinated hydrocarbons such as chloroform, methylene chloride and 1,2-dichloroethane, lower aliphatic ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone, esters such as ethyl acetate and butyl acetate, hydrocarbons such as hexane, cyclohexane and benzene, and lower alkanols such as methanol, ethanol and butanol. While usually about two molar equivalents of the acid are used in this process, only one molar equivalent is needed if the reactions are carried out in the presence of one equivalent of 40 45 50 55 6005 747 26 molar water or when the acid is introduced as monohydrate. However, the reaction product, as is obvious to one skilled in the art, should not be exposed to an excess of acid for an extended period, since in this case there is a risk of damaging the β-lactam system. A particularly convenient method of carrying out this process is this selecting an acid-solvent system in which the starting material is soluble but the acid addition salt formed in the reaction is precipitated out immediately after formation. It can then be separated by filtration after the reaction is complete. When p-toluenesulfonic acid is used in combination with acetone, the p-toluenesonate salt of the product is often precipitated out of the reaction medium. The starting materials of formula VI were prepared in a similar manner, wherein T15 is hydrogen and R8 is the group of formula —C (= O) —R14, —SOe-Ru and (R1) in which R14 is the radical an alkyl group containing 1-6 carbon atoms, a radical (benzyl or phenyl radical substituted with one or two residues, such as nitro, fluorine, bromine, chlorine or an alkyl group containing 1-4 carbon atoms, an alkoxy group having 1-4 carbon atoms, and (R) represents a group of formula 23 or a group of formula 24, in which R4 and R17 are independently hydrogen, hydroxyl, nitro, fluorine, chromium, bromine or iodine , an alkyl group containing 1-6 carbon atoms, an alkoxy group containing 1-6 carbon atoms, an alkanoyloxy group containing 2-7 carbon atoms, a formyloxy group, an alkoxymethoxy group containing 2-7 carbon atoms, a phenyl group or enzyloxy, R18 is a hydrogen atom or an alkyl group of 1-4 carbon atoms or a phenyl group, R " and R "are independently hydrogen or methyl, and X is oxygen or sulfur. These compounds are prepared from the corresponding compounds wherein R 1 is a triphenylmethyl group. These groups are removed by treatment with an acid exactly as described above. Starting materials of Formula 6, where R 5 is triphenylmethyl and R * is hydrogen, are prepared by a Michael reverse reaction from the corresponding compounds where R 2 represents a group of the formula —CH2CHfY, where Y is a cyano / alkoxycarbonyl group of 2-7 carbon atoms, phenoxycarbonyl, 1-4 carbon-alkoxy sulfonyl, phenylsulfonyl or SO * —NR15R18 group, in which R15 and R16 represents a downstream atom, an alkyl group containing 1-4 carbon atoms, a phenyl group or a benzyl group. The Michael reverse reaction consists in acting on the compound in question with approximately one molar equivalent of a base, under the conditions normally used in the Michael reaction, but not in violation of the parenchymal ring. Typically, the compound of Formula 7 is treated with one equivalent of a relatively non-nucleophilic base in a non-hydroxylic solvent at 0-25 ° C for a period of 23 minutes to 2 hours. More details are given in the Journal of the Chemical Society, / London /, Part B, 5867, /1970/ Preparation of the starting materials for method C, compounds of formulas 6 and 7 where R5 is hydrogen and Rs and R * denote independently the alkanoyloxymethyl group containing 3-8 carbon atoms, the 1- (alkanoyloxy) ethyl group containing 4-0 carbon atoms or the phthalidyl group by alkylation of tetrazolone salts, such as triethylamine salts, of the corresponding compound of formula 6 or 7, in which R * and R 'are hydrogen, using the appropriate alkanoyloxyalkyl or phthalide halide. Method D is used, except that usually at least two molar equivalents are used, and most preferably about 3 the molar equivalents of the alkylating agent. The starting materials for the preparation of the active antimicrobial compounds according to the invention are the novel penam derivatives of formula VI, in which R8 represents an amino protecting group, for example e is a triphenylmethyl group and Rf is a tetrazolylpope protecting group, for example a group of the formula CH2CH2Y, _C / = 0 / —O — R "or / Rf /, wherein Y, R" and / RY have the previously given meanings. These compounds can be prepared by a new method consisting of three successive reactions. Said new penam derivatives of formula 6 can be prepared starting from the well-known intermediate, O-triphenylmethylaminopeaafcylanic acid by certain transformations of the carboxylic group function in position 3. Production of acid 6 -triphenylmethylloaminopenicillate is described by Sheehan and Henery-Logan in the Journal of the American Chemical Society, 81, 5838 (1950). As shown previously, the preparation of the bactericidal compounds according to the invention involves the use of two kinds of protecting groups, and these groups have been described with respect to their ability to act in a specific manner. The nitrogen protecting group in the tetrazoyl penam system has been defined in relation to its ability to perform two functions. The first is the ability to remove this group under certain particular conditions previously discussed. The second is the ability to synthesize a compound of formula 6, where R * is the amino protecting group and Rf is the nitrogen protecting group in a tetrazolylpenam system. Similarly, the amino protecting group must also perform two functions. of them, after joining to the amino group at the 6-position in the 6-aminopenicillanic acid, it must allow for the performance of individual operations during the amide formation, the conversion of the amide to the imidoyl halide and the conversion of the latter to the 1-protected -tetrazoylpenam compound of formula 6. The second function of the amino protecting group in the process according to the invention is that it must be easily removable under conditions which do not decompose the penam ring system in: / a / 27 95 747 28 the compound of formula 6, wherein R5 is an amino protecting group, and R2 is a nitrogen protecting group in the tetrazolpenamine system, (b) a compound of formula 6, wherein R5 is g is a protecting amino group, and R2 is a hydrogen atom, or a compound of formula 6, in which R5 is one of the following groups: alkanoyloxymethyl, 1- (alkanoyl) oxy / ethyl or phthalidyl. The amino protecting group can be easily accomplished by one skilled in the art. All groups known for peptide synthesis are particularly useful. However, particularly suitable protecting groups are optionally substituted triphenylmethyl and P, β, β-trihaloethoxycarbonyl, such as β, β, β-tribromoethoxycarbonyl and P, O, β-trichloroethoxycarbonyl. Examples of substituted triphenylmethyl groups which are particularly useful are those of the general formula in which R22, R28 and R24 are independently hydrogen, fluorine, chlorine, bromine, and an alkyl radical of 1-4 carbon atoms. , an alkoxy radical having 1-4 carbon atoms or a phenyl radical. Due to easy availability, the triphenylmethyl group is the most preferred. The new 3-tetrazolyl-5 / -penam derivatives are subclassed with the compounds of the formulas 28 and 29, in which R8 is phenyl, cyclohexadiene-1,4-yl, sydnonyl. -3, thienyl, furyl, pyridyl, thiazolyl, isothiazolyl, tetrazolyl, triazolyl, imidazolyl, pyrazolyl, substituted phenyl, substituted thienyl, substituted furyl, substituted pyridyl, substituted thiazole, substituted thiazole an isothiazolyl radical, a substituted triazolyl radical, a substituted imidazolyl radical and a substituted pyrazolyl radical, the number of substituents of which may be one or two, such as fluorine, chlorine, bromine, hydroxyl, an alkyd group containing 1- 6 carbon atoms, an alkoxy group containing 1-6 carbon atoms and an alkylthio group containing 1-6 carbon atoms, R9 and R10 are substituents such as hydrogen, methyl or e and R11 represents a substituent such as a hydrogen atom, an alkanoyloxy methyl group containing 1-8 carbon atoms, a 1-, (alkanoyloxy) ethyl group containing 4-9 carbon atoms or a phthalidyl group. The compounds of formula 28 and 29 are prepared from the corresponding compounds of formula IV or 5, in which R 1 is a substituent of formula 12, where n is 1, Q is an amino group, and R 7 is the same as previously defined, and R2 and R8 represent the substituents previously described for R11. The synthesis is carried out by the condensation of the above-mentioned compound of formula IV or 5 with a suitable aldehyde or ketone of formula R9-OO-R10. The condensation reactions are usually carried out by contacting the starting penam derivative with a large excess of the aldehyde or ketone in the presence of at least one a molar equivalent of a tertiary amine at room temperature or slightly below. Typically such an amount of aldehyde or ketone is used that no additional solvent is needed * However, if desired, an additional thinner may be used that does not adversely affect the starting materials or the product. Examples suitable for the use of tertiary amines. Triethylamine, tributylamine, pyridine, N, N-dimethylaniline, N-methylmorpholine and quinoline are included in this process. Although it is necessary to use at least one equivalent of a tertiary amine, a much larger excess of up to about 10 equivalents is usually used. molar. The process in question usually requires a reaction time of several hours, for example overnight. In the event that the product falls out of the solution after the reaction, it is filtered off. Alternatively, if the product remains in solution after completion of the reaction, it is isolated by evaporation of the solvent under reduced pressure. Another subclass of new 3-tetrazolylpenam derivatives, which are valuable antimicrobial compounds, are compounds of general expression. 30 and 31, in which R12 and R18 independently represent alkyl groups having 1-6 carbon atoms, or together with the nitrogen atom to which they are bound, represent a pyrrolidine, morpholino, piperidine- or azacycloheptanyl-1 group. R11 has the meaning given above. Compounds of Formulas 30 and 31, produces pie from the corresponding compounds of Formulas 6 or 7, wherein R2 and R8 are as previously defined for R11 and R5 is hydrogen. The synthesis is the introduction of a foTmamidine residue using the methods given by Lund and Tybring (Nature, New Biology, 236, 135 (1972)). A characteristic feature of the compounds of the formulas 4, 5, 6, 7, 28, 29, 30 and 31, in which R2, R8 and R11 are hydrogen, is their salt formation ability. Due to the acidic nature of the 5-monosubstituted tetrazole, these compounds have the ability to form salts with basic agents, and these salts are generally referred to herein as "tetrazolates". These salts may be prepared by known methods such as contacting the acidic component with an alkali. These are separated, usually in a 1: 1 molar ratio in an aqueous, non-aqueous or wet-aqueous medium, and are then separated by filtration, by precipitation with solubilizers, followed by filtration, by evaporation of the solvent. or, in the case of aqueous solutions, by lyophilization. Basic agents which are suitable for the formation of such salts are both organic and inorganic bases. This group of basic compounds includes ammonia, organic amines, metal hydroxides. "alkali, carbonates, hydrogen carbonates, hydrides and alkanolates, as well as alkaline earth metal hydroxides and their carbonates, hydrides and lcanolates. Representative examples of such bases are primary amines such as n-propylamine, n-butylamine, aniline, cyclohephysylamine, benzylamine, p-toluidine and octylamine, secondary amines such as diethylamine, N-40 45 50 55 6095 747 29 30 -methylaniline, morpholine, pyrrolidine and piperidine, tertiary amines, as well as triethylamine, N, N-dimethylaniline, N-ethylpiperidine, N- (methylmorpholine and 1,5-diazabicyclo [4,3,0] monone - S, hydroxides such as sodium, potassium, ammonium and barium hydroxides, alkanolates such as sodium ethoxide and potassium ethoxide, hydrides such as potassium and sodium hydride, carbonates such as potassium carbonate and sodium carbonate, and bicarbonates, such as sodium bicarbonate and potassium bicarbonate. In addition, compounds of formula IV and V in which R1 contains one or more acid functional groups, for example carboxyl, sulfonate and the like, are capable of forming other salts, for example of the carboxylate type. and sulfonates. These salts can be prepared in exactly wt the same method and using the same basic agent as described above for the tetrazolate salts. Of course, some compounds of the formula 4 or 5 can form both mono- and poly-salts. In the case of a multi-salt, the different cationic residues may be the same or different. Compounds of formula 4, 5, 6 and 7 which contain basic groups have the ability to form acid addition salts. Examples of acid addition salts which are especially valuable are the following salts: hydrochlorides, hydrobromides, phosphates, perchlorates, citrates, tartrates, salts of pus and glutaric acid, benzoates, sulphates, (lactates and arylsulphonates). When using the salts of the compounds according to the invention with respect to mammals, it is certainly the use of pharmaceutically acceptable salts, but other salts are useful in a number of other applications, such as, for example, isolating and purifying individual compounds. of the compounds, the change of the solubility properties of the individual compounds and the conversion into pharmaceutically acceptable salts. The penam derivatives of the invention have bactericidal activity against a broad spectrum of gram-positive and gram-negative bacteria. In vitro activity can be demonstrated by conventional the method of two-fold serial dilution in cerebral-cheese broth brand / Difeo /. The broth is inoculated with a bacterial culture and the test antibiotic is added, then incubated overnight. The following day, the broth is subjected to visual observation. The minimum inhibitory concentration (MIC) is the lowest concentration of antibiotic which prevents choking, that is, which prevents the growth of microorganisms. The in vitro activities of a number of penam derivatives according to the invention are shown below. The in vitro activity of the antimicrobial compounds makes them particularly suitable for local application, for example in the semi-coating of creams or ointments and for the sterilization of hospital rooms and other hospital surfaces. The antibacterial penam derivatives according to the invention show (also in vivo activity. In order to determine this activity, the test antibiotic is administered to the infected mice using a multi-dose regimen. The severity of the infection was changed from about 1 to about 10 times as needed for 100% of mice were killed under the test conditions. At the end of the test, the activity of the compound was assessed by counting the number of survivors among the test animals. Both subcutaneous (PS) and oral (DU) administration were used. The results are given in Table 1 for the two compounds produced by the method. According to the invention, the ability of the compound to be secured is shown mice against infections caused by the lethal intraperitoneal inoculation of Staphylococcus aureus and Escherichia coli. The in vivo activity of the antibacterial compounds obtained according to the invention makes them suitable for combating bacterial infections in mammals, including humans. by both oral and parenteral administration. These compounds can be found in Table 11 Compound J. 6VD-amino-2- (thienyl-3- (acetamid) -2,2-dimethyl-3-tetrazolyl-6) -penam 6- (D-amino-2-thienyl) -3- / acetamido / -2y2-dimethyl-3-tetrazolyl-thie-penam 6- (D-amino-2- / thienyl-3- / acetamido / A2-dimethyl-3-tetrazolyl-5 / - (penam 6- (D-amino-2- (thienyl-3- (acetamid)) (2,2-dimethyl-3-tetrazolyl-5) -penam 6- (D-amino-2- (thienyl-3-) acetamido) -2y2-dimethyl-3-tetrazolyl-5- / penam 6n / D-2-amino-2- (p-hydroxyphenyl) -acetamide / - * 2,2-dimethyl-3- (tetrazolyl-5) -penam 6n (D-2-amino-2- (p-hydroxyphenyl) -acetamido) (2, 2-dimethyl-3- (tetrazolyl-5i) -penam 6- (D-2-amino-2-) p-hydrotosyphenyl / -aceitamido / -! 2,2- | -dimethyl-3- / tetrazolyl-5 / -penam Dose / mg / kg / 2 50 12 6 200 50 '12 Method of administration 3 PS PS PS PS DU PS PS PS Security% 1 S. aurens 4 40 60 50 50 80 70 '50 E. coli 0 100 80 »5 747 31 32 1 6- / D- <2-amino-2- / p-hydroxyphenyl / -acetaniido / -2,2-dimethyl-3- / tetrazolyl-5 / -penam 6-D-2-amino-2- / p-hydroxyphenyl / -acetamido / -2,2-dimethyl-3- / tetrazolyl-5 \ / - penam 2 6 200 3 PS DU 4 1 50 table I cd 1 100 is used to combat infections caused by possible gram-positive and gram-negative bacteria in relation to man. If you take into account the therapeutic use of the compounds according to the invention or their salts in relation to mammals, in particular to humans, then the compound may be administered as it is, or it may be mixed with other antibiotic substances and / or pharmaceutically acceptable carriers or diluents. Such carrier or diluent will be selected depending on the intended route of administration. For example, when administered orally, the antimicrobial penam derivative may be used in the form of tablets, capsules, lozenges, colic, powders, syrups, elixirs, aqueous solutions and suspensions, and the like in accordance with customary pharmaceutical practice. The quantitative ratio of active ingredient to carrier will naturally depend on the chemical properties, solubility and stability of the active ingredient, as well as the anticipated dosage amount. In the case of tablets for oral administration, usually lactose, sodium citrate and salts of phosphoric acid are used as carriers. Typically, tablets are also used with a variety of dispersing mediums, such as starch and lubricants, such as magnesium stearate, sodium lauryl sulfonate and talc. For oral administration in capsule form, diluents include lactose and high-density polyethylene glycols. molecular. If aqueous suspensions intended for oral administration are prepared, the active ingredient is combined with emulsifying and suspending agents. If desired, some sweetening and / or flavoring agents may also be added. For parenteral administration, which includes intramuscular, subcutaneous, intravenous and intraperitoneal administration, usually sterile solutions of the active ingredient are made, the pH of which is suitably adjusted. and buffers. For intravenous administration, the total concentration of the dissolved substances should be chosen so as to preserve the isotonic of the preparation. As mentioned above, the antibacterial penam derivatives of the invention are useful in the treatment of humans and the daily doses to be used do not differ significantly. way from other clinically used penam antibiotics. The provider of treatment must determine the appropriate dose for the individual patient. The dose will vary according to the age, weight, and sensitivity of the individual patient, as well as the severity of the patient's symptoms. The compounds according to the invention are generally to be administered orally in dosages of 10-290 mg per kg body weight per day and parenterally in doses of 100 mg per kg body weight per day. After- . the figures given are purely indicative and in some cases it may be necessary to use doses outside the range indicated. The following is an example of the preparation of pharmaceutical preparations containing as an active ingredient a compound obtained according to the invention. The following ingredients were carefully mixed in the indicated proportions. by weight: Sucrose / according to the Pharmacopoeia U1SA / 80.0 Tapioca starch 13.5 Magnesium stearate 6.5 6- / D-2-amino-2-phenylacetoamido / -2,2-dimethyl-3-tetrazolyl-5 / -penam 100, After thorough mixing of the ingredients of the formulation, tablets were prepared, the size of the tablet being chosen so as to contain 100 mg of pamoate. Tablets containing 50 and 250 mg of the active ingredient were also prepared by selecting the appropriate proportions of the penam compound and the other ingredients in the mixture. The following ingredients are carefully mixed in the given proportions by weight: Calcium carbonate tl7.6 Dicalcium phosphate 18.8 Tris Magnesiumate 5.2 40 Lactose / according to the US Pharmacopoeia / 5.2 Potato starch 0.8 6- (D-2-amino-2- / thienyl-3) -acetamido] -2,2-dimethyl-3- / tetrazolyl-5 / -penam 50.0 The components of the pharmaceutical preparation were carefully mixed and filled into soft gelatine capsules so that each of them contained 100 mg of active ingredient. Capsules were also prepared containing 50 and 250 mg of active ingredient, respectively, for 50 change of the proportions of the penam derivative and the remaining components of the mixture. 6- [D-2-amino-2- (p-hydroxyphenyl] and - -acetamido] -2,2-dimethyl-3- (tetrazo: 11-yl-5) sodium salt The penam was mixed thoroughly and ground with sodium citrate (4% by weight). The ground and dried mixture was sterilized and packaged in sterile ampoules which were closed under sterile conditions with a diaphragm stopper. Prior to the intended use of the preparation, sterile water was introduced into the ampoule to dissolve the ingredients to obtain a solution containing 25 mg / ml of the active ingredient. For parenteral administration, the solution was withdrawn from the ampoule using a hypodermic syringe. c5 Similarly, by changing the amounts, add ^ S574? 34 of water, solutions containing 10, 50, 100 and 200 mg / ml of active ingredient, respectively, were obtained. The examples given below are only given to further illustrate the invention. The infrared spectrum (IR) was measured with a potassium bromide pellet (KBr disc) or in nujol and the specific absorption bands are shown in their wavenumber (cm-1). Nuclear magnetic resonance spectrum / NMR / measured at a frequency of 00 MHz for solutions in deuterochloroform / CBC1 $ /, perdeuterodimethylsulfoxide / DMSO-d6 / or deuterium oxide / D20 /, and the position of the peak is expressed in parts of the million / ppm down from tetramethylsilane or sodium 2,2-dimethyl-2-si-K lapentanesilane. The following abbreviations were used to define the nature of the peaks: s-singlet, d-doublet, t-triplet, q-quadruplet, m-multiplet. Example I. Flask containing 965 mg p-tt-toluenesulfurate 6-ami * no-2,2-dimethyl-3- [1- (4-methoxybenzyl) tetrazol'-5] penam, 40 drops of anisole and 5 ml of trifluoroacetic acid are immersed in a water bath at 35-40 ° C. The course of the reaction is followed by taking samples from time to time and determining the nuclear magnetic resonance spectrum. After about 25 minutes it can be seen that the methoxybenzyl group at position 4 of the tetrazolyl ring is 90% removed. At this point the reaction mixture is added with vigorous stirring to an ice-cooled solution of ml of pyridine in 50 ml of chloroform. All mixed for 5 minutes, adding 0.24 ml of phenylacetide chloride, removing the cooling bath and the meat for another 20 minutes. Then 100 ml of water are added and the pH of the aqueous phase is adjusted to 2.5 by adding 0.5 N hydrochloric acid. The chloroform layer was separated, washed with saturated saline solution, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The crude product Toz is dissolved in Chloroform and the solution is divided into two equal parts. The same volume of water is added to one of the portions, stirred vigorously and adjusted (pH of the water phase to 6 °, by dropwise addition of 0.1N sodium hydroxide solution. The chloroform layer is separated and discarded until the An equal amount of chloroform is added to the water. The mixture is stirred vigorously and the pH is adjusted to 2.5 with dilute hydrochloric acid. The chloroform layer is separated, washed with saturated saline, dried with anhydrous magnesium sulphate and dry under vacuum. 197 mg of oily residue is obtained. The residue 55 is dissolved in 3 ml of chloroform and the whole is added dropwise to 30 ml of hexane. A fluffy white precipitate is collected which is filtered off to obtain 80 mg of 6- / 2- - phenylacetamido (-2,2-dimethyl-3- (tetrazolyl-5) penam. The infrared spectrum (KBr, pellet) shows the existence of absorption bands at 1795, 1660 and Li510 cm-1. NMR spectrum (CDCd8) shows absorption at 7.20 ppm / s, 5H, 5.55 ppm / m, 2H,, 15 ppm (s, 1H), 3.60 ppm / s, 2H), 1.40 ppm / s, 3H) and 1.05 / s, 3Ify. ^ The MIC of the obtained compound against the strain of Streptococcus pyogenes is <0.1 µg / ml. Example II. For a suspension of 460 mg of 6-amino--2,2-dimethyl-3- (tetrazolyl-5 / penam) in 10 ml of water cooled to 0 ° C, the pH of which was adjusted to 8.0 using a 1- n sodium hydroxide solution, 0.25 ml of phenoxyacetyl chloride is added in portions with stirring, while maintaining the pH of the solution at 7-8 by adding 0.1 N sodium hydroxide solution. The mixture is stirred for 30 minutes at 0 ° C, pH = 8, and extracted with chloroform. The extracts were discarded and the aqueous layer was acidified to pH = 2 with dilute hydrochloric acid solution and re-extracted with chloroform. The extracts obtained are dried with calcium sulphate and, under reduced pressure, the crude product is obtained in the form of a sticky solid. The product is purified by dissolving it in ml of chloroform and dropping the resulting solution into 250 ml of hexane. The formed precipitate was filtered off to give 385 mg of 6- (2-phenoxyacetamido) -2,2-dimethylH3- (tetrazolyl5) penam in the form of an amorphous white solid. The infrared spectrum (KBr, pellet) shows an absorption band at 1785, 1670 and 1540 cm-1. Nuclear magnetic resonance spectrum (DMSO-d8y shows absorptions at 7.50? 45.70 ppm / m, 5H),, 70 ppm / m, 2H), 5.35 ppm / s, 3H), 4.60 ppm / s , 2H), 1.60 ppm / s, 3H) and 1.05 ppm / s, 3H). The MIC of the compound obtained with respect to Streptococcus pyogenes is <04 \ xgfml. Example III. A solution of 1.61 g (9.1 mmol) of 2-azido-2-phenylacetic acid [Forster, Mueller, J. Chem. Soc., 97, 138 (1970)] in 5 ml of thienyl chloride is boiled for one hour, then evaporated under reduced pressure to give 2-azido-2-phenyl-acetyl chloride. The chloride was dissolved in 10 ml of dichloromethane and added, under stirring, to a solution of 2.4 g (10 mmol) 6-amino-2,2-dimethyl-3- (tetrazolyl-5) on an ice bath, over 5 minutes. of penam and 2.02 g (20 mmol) of triethylamine in 50 ml of dichloromethane. The total is left for 30 minutes in an ice bath and then allowed to warm to room temperature. After a further 3 hours, the solvent is removed to a reduced temperature. under high pressure, and the residue is mixed with 50 ml of water. The aqueous solution is washed twice with ethyl acetate and the pH is adjusted to 2.5 with 6N hydrochloric acid. The resulting mixture is extracted twice with ethyl acetate, the collected extracts are dried over anhydrous sodium sulfate. is filtered and the solvent is evaporated off under reduced pressure. The remainder is dissolved in 10 ml of dimoromethane, 1.0 ml of triethylamine is added and the whole is poured into 350 ml of vigorously stirred ethyl ether. The precipitate is filtered off to obtain 1.62 g of 6- / 2-azy c-2-phenylacetamido (-2,2-dimethyl-3- (tetrazolyl-5) penam in the form of the triethyl amine salt. The yield of the reaction is 38%. The infrared spectrum (KBr, pellet) shows an absorption band at 1792 cm-1 (β-lactates) and 1698 cm-1 (amide I). NMR spectrum / in Kfi / / NaHCO3 / vetch- & 5fr4 * 5 3 * results in the absorption and at 7.40 ppm / s, 5H, aromatic ring hydrogens /, 5.60 and 5.80 ppm / m and m, 2H, hydrogens at 5 and 6 carbon atoms /, 5.30 ppm / m , 2H, hydrogen at the 3rd carbon atom and hydrogen at the methine group of the side chain (5.20 ppm (q, 6H, 5NCHZCH8), 1.00 ppm / s, 3H, methyl hydrogens at the 2nd carbon atom), 1 30 ppm (t, 9H, NCHZCHS), 1.10 ppm / s, 3H, hydrogens of the methyl group at 2 carbon atom (MIC of the compound obtained in the ratio of Streptococcus pyogeneas) is <0.1 g / ml. Example IV. To a solution of 2.0 g of 2-cyanoacetic acid and 2.7 g of N-hydroxysuccinimide in 50 ml of tetrahydrofuran are added 4.85 g of dicyclohexylcarto-diimide, the whole is stirred at ambient temperature overnight, and the precipitate is filtered off and discarded. The solvent is evaporated from the filtrate to give N-hydroxysuccinimide cyanoacetate, which melts after recrystallization from chloroform at 123-30 ° C, and is further purified at 128-130 ° C. 177 mg of 6-amino into a suspension The -2,2-dimethyl-3- (teltrazoyl-5) penam in 10 ml of methyflene chloride is added with stirring, under nitrogen, 157 mg of triethylamine and the mixture is stirred until a clear solution is obtained (about 35 minutes). 135 mg of the N-hydroxysuccinimide cyanoacetate obtained as described above are added all at once to this solution, stirred for 2.5 hours. The reaction mixture is then poured into 15 ml of water and the pH of the aqueous layer is adjusted to the value. ¬ tness 8.0. The methylene chloride layer is separated and discarded, and the aqueous layer is acidified to pH = 2 and extracted with ethyl acetate. The acetate layer is dried with anhydrous sodium sulfate and a solution of 110 mg of sodium il-ethido pentane canbofosylate in a small amount of ethyl acetate is added thereto. The precipitate was filtered off to obtain 138 mg of 6- (2-cyanoacetamlido) -2,2-dimethyl-3- (tetrazolyl-5) penam sodium. The yield of the reaction was 57%. The infrared spectrum (KBr, pellet) shows absorption bands at 2200 cm-1 (cyano group), 1775 cm-1 / P-lactam carbonyl group / 1680 cm-1 / amide group, band I / and 1550 cm- 1 / amide group, 2nd band /. The 45 NMR spectrum (in DzO) shows the absorption at 5.90 and 5.40 ppm (2 doublets, hydrogen at carbon 5 and 6), *, 30 ppm (singlet, hydrogen at carbon 3), 1.65 ppm) singlet, 2-carbon methyl hydrogens) and 1.0 ppm (singlet, 2-carbon methyl hydrogens) The MIC of the resulting compound is 0.1 µg / ml against Streptococcus pyogenes. To a solution of 90 mg of (tetrazolyl-1) acetic acid 55 and 71 mg of triethylamine in 5 ml of chloroform, cooled to 0 ° C., 85 mg of trimethylacetyl chloride were added with stirring and the mixture was stirred at this temperature for 30 minutes. The solution obtained is added to an ice-cooled solution of 169 mg of 6-amino-2,2-dimethyl-3- (teitrazolyl-5) penam and 142 mg of triethylamine in 5 ml of chloroform and the mixture is stirred at the same temperature. in nature around 0 ° C for 2.5 hours. The mixture is then warmed to ambient temperature, poured into 20 miles of water, and the pH of the aqueous layer adjusted to 7.0. The formed layers are separated and the chloroform layer is discarded, and the aqueous layer is acidified to pH = 2 and extracted with ethyl acetate. The acetate layer is dried and a solution of 100 mg of sodium 1-ethylpentanecarboxylate in a small amount of ethyl acetate is added thereto. The precipitate was filtered off to obtain 80 mg of the sodium salt of 6- [2 N (tetrazolyl-1) acetamido] -2,2-dimethyl-3- (tetrazolyl-5) penam. The yield of the reaction is 31%. Infrared spectrum (KBr, pellet) shows an absorption band at 1785 cm-1 (β-lafctam carbonyl group), 1695 cm-1 (amide group, band I) and 1575 cm-1 (amide group, band II), NMR spectrum (in DgO) shows an absorption at 5.90- ^ 5.40 ppm (multiplet, hydrogens at the 5th and 6th carbon atoms), (broad duglet, hydrogen at the tetrazole ring), 5.20 ppm (sine, hydrogen at 3 carbon (1.70 ppm (singlet, methyl hydrogens on 2 carbon) and 1.00 ppm (singlet, methyl hydrogens on 2 carbon). Acetic acid (tetrazolyl-1) used in the present process is obtained by the method described in the US Patent No. 3,468,874. The MIC of the obtained compound in relation to Streptococcus pyogenes is <0.39pg / ml. Example VI To a suspension of 3.0 g (0.0125 mole) of 6-amino-2,2-dimethyl-3- (tetrazolyl-5) penam in 15 ml of water is added 1.74 g (0.0125 mole) with stirring. of bromoacetic acid dissolved in 5 ml of water and the pH of the mixture is adjusted to 6.0 with 20% sodium hydroxide solution. The resulting clear solution is cooled to 0 ° C, 2.4 g (0.0125 mol) is added to it. 1-Ethyl-3- (3-dimethylaminopropyl) carbondimide hydrochloride is stirred at 0 ° C. for 2.5 hours while maintaining the pH at 6-7 with 6N hydrochloric acid solution. Then the mixture with a pH of 7 is extracted with ethyl acetate, the extract is discarded, the pH of the mixture is adjusted to 2.0 with a 6 N solution of hydrochloric acid and extracted with ethyl acetate. The acetate film was washed with water, dried and concentrated to give 3.2 g of 6- (2-bromo-acetamido) -2-dimethyl-3- (tetrazolyl-5) () jpenam as a white foam. The yield of the reaction was 72 %. The infrared spectrum of yKBr, pellet (shows an absorption band at 1795 cm-1 (p4ak-tam), 1 © 70 cm-1 (amide group 1) and 1530 cm-1 (amide group II). NMR spectrum (CDC18) has an absorption at 10.6-9.6 ppm (broad singlet, tetrazole ring hydrogen), 8 µl ppm (doublet, amide group hydrogen), 5.8-5.4 pipm (multiplet, hydrogens at 5 and 6) carbon (5.35 ppm (sine, hydrogen at 3 carbon), 4.0 ppm (singlet, hydrogen, methyl), 1.90 ppm (singlet, methyl hydrogens at 2 carbon) - The product thus obtained is dissolved in 15 ml of water containing 1 equivalent of sodium bicarbonate. This solution is lyophilized to obtain 3.4 g of the sodium salt of the obtained compound. The yield of the reaction is 72%. The MIC of the obtained compound against Streptococcus pyogenes is <04 [ig / ml.d5? 4? Example VII. 0.28 is added to a suspension of 1.0 g (0.0026 mol) of 6- (2-bromoacetamido) -2,2-dimethyl-3- (tetrazolyl-5) in 25 ml of methylene chloride. g (0.0028 mol) of triethylamine and stirred at room temperature until a clear solution was obtained. Then 0.39 g of 4-raier capopyridine is added to the solution and the mixture is stirred at ambient temperature for 4 hours. The resulting precipitate is filtered off and washed with methylene chloride and then with ether to give 0.68 g of 6- [2-i (4-pyridylthio) acetamido] n2,2-dimethyl-α-Ztetra-11-S / penam. melting decomposed at 120 ° C. The reaction yield is 78%. The infrared spectrum (KRr, stick) shows absorption bands at 1790 cm -1 (fl-aafctam) and 1670 cm -1 (amide group II). NMR spectrum (DMSO-dc) shows an absorption at 9.0-7.0 ppm (multiplet, pyridine hydrogen), 5.9-5.5 ppm (multiplet, hydrogen at 5 and 6 carbon), 4.0 ppm (singlet, methylene group hydrogens), 1.7 ppm (singlet, methylene group hydrogens at the 2nd carbon atom) and 1.1 ppm (singlet hydrogens of the methylene group at the 2nd carbon atom) .MIC of the obtained compound in relation to Strep- tococcus pyogenes is <0.1 ng / ml. Example VIII. 6- (D-2-amino-2-phenylacetinido) -2,2-dimethyl-3- (tetrazolyl-5) penam. To a vigorously stirred solution of 23.8 ml of ethyl chloroformate in 600 ml of acetone was added ml of 3§ / o a solution of N-mephtylmorpholine in acetone. The resulting solution was cooled to 0 ° C., and then 75.2 g of sodium N- (2-methoxycarbonyl-1-methylvinylacetate) -D-2-amino-2-phenylacetate were added. The temperature was adjusted to -20 ° C and stirring was continued for 20 minutes. 35 The solution was cooled down to -40 ° C again and an ice-cooled solution resulting from the preparation of a suspension of 60.0 g of 6-amino-2,2-dimethyl-3- (tetrazolyl-5-yipenam) in 250 ml of water was added, - at the pH of the solution adjusted to the value of 7.0. The resulting solution was stirred for 30 minutes without further cooling, then acetone was evaporated under reduced pressure. An equal volume of tetrahydrofuran was added to the aqueous residue, and then, at 5 ° C., the pH was adjusted to 1.5 by adding dilute hydrochloric acid. The mixture was kept at this temperature and at this pH value for a period of 30 minutes, and then the tetrahydrofuran was removed by evaporation under reduced pressure. The aqueous residue was extracted with ethyl acetate, then with ether, and the extracts were discarded, the pH of the remaining aqueous phase was raised to 5.4 and the product began to crystallize. After one hour, the product was filtered off and dried. The crude product yield was 68.8 g. The product was suspended in water at 25 ° C and the pH of the suspension was adjusted to 1.5. After stirring for a short time, the insoluble matter was filtered off and the filtrate was extracted with ether. The aqueous solution was then cooled to 5 ° C and the pH was adjusted to 5.2. The precipitated solid was filtered to obtain 62.7 g (yield 38.7%) 65 38 60 of 6- (D-2-amino-2-phenylacet, mido) -2,2-dimethyl-3- (tetrazolyl) trihydrate. -5 (penam having a melting point of 201-202 ° C. [Α -H-228.2 (1 °) solution in CH CHOH). Infrared absorption bands (KBr, pellet). 1780 cm-1. NMR spectrum (in DMiSO-d6 (D20)): 7.60 ppm / s, 5H), 5.70 ppm / d, 1H), 5.56 ppm / d, 1H), 5.20 ppm / s, 1H) , 5115 ppm / d, 1H), 1.50 ppm / s, 3H4, 0.90 ppm / s, 3H). Elemental content analysis calculated for C16H1JA, N7S.3 H2Or C- 4.95%, H— 5.89%, N — 22.94%, S — 7.50%, analytically determined contents: C— - ^ 15.01%, H — 5.84%, N — 122.81%, S — 7, 34% sodium N- (2-methoxycarbonyl-1-methylvinyl) -D-2-amino-2-phenylacetate, sodium was prepared from methyl acetoacetate and p-2-amino-2-phenylacetic acid using the method used by Long and others / J. Chem. Soc, London, Part C, 1920, (1971) for the corresponding p-hydroxyl derivative. The MIC value (minimum inhibitory concentration) for the compound of the example against the strain Streptococcus pyogenes was <0 µl fig / ml. Example IX. 6- [D-2- (iguanidinobenzamido) -phenylacetamido] -2,2-dimethyl-3- (tetrazolyl-5) penam. A mixture of 2.15 g of p-guanidinobenzoic acid hydrochloride and 75 ml of thienyl chloride was heated to boil under reflux for 10 hours. The mixture was then cooled to 25 ° C. and concentrated to dryness under reduced pressure. The residue was washed thoroughly with ethylene chloride. 1.7 g of p-guanidinobenzoyl chloride hydrochloride was obtained. In a vigorously stirred solution (0.854 g of 6- (D-2-amino-2-phenylacetamido) -2,2-dimethyl-3- (tetrazolyl) trihydrate solution was obtained. 5 / pena! M and 0.54 ml of triethylamine in 10 ml of N, N-dimethylformamide were added 0.468 g of p-guanidinobenzoyl chloride hydrochloride at 0 ° C. Stirring was continued for 30 minutes and then a further 0.14 was added. ml of triethylamine and 0.124 g of p-guanidinobenzoyl chloride hydrochloride. After stirring for a further 30 minutes, the mixture was filtered and the filtrate was added dropwise to 300 ml of ether. The thus precipitated body was constantly filtered and washed gently with methylene chloride containing triethylamine. Yield 0.8 g (yield 75%) of a product with a melting point of 196 ° -200 ° C. Infrared absorption bands (KBr, pellet): 1770 cm-1 (3-lactam). NMR spectrum (in DMSO-de) (D20): 8.25-7.20 ppm / m, 9H), 6.00 ppm ((d, 1H), 50 ppm / m, 2H), 5.00 ppm / s, 1H), 1.1 50 ppm / s, 3H), 0.95 ppm / s, 3H). Produced and e p-guanidinobenzoic acid is described in Rec. Trav. Chim. Pay-Bas, 72, 643 / 1952/. The MIC value of the compound of the example against the Streptococcus pyogenes strain was 1.56 µg / ml. Example X 6- [D-2-amino-2/4-hydroxyphenyl / - acetamido] -2,2-dimethyl-3- (tetrazoyl-5) perm. To a vigorously stirred solution of 0.19 ml of ethyl chloroformate in 15 ml of dry aceto-9574739n, cooled to 0 ° C, added 1 drop N-methylmorpholine followed by 576 mg of N- (2-methoxycarbonyl-1-methylvinyl) -D-2-amino- -2 / 4-hydroxyphenyl / sodium oethane / Long et al., Journal of the Chemical Society / London / , part C, 1920/197 <1 //. The mixture was stirred for a further 30 minutes, then cooled to about -35 ° C. To the mixture was added an ice-cooled solution of 6-amino-2,2-dimethyl-3- (tetrazolyl-5) penam sodium salt, prepared by adding 10% sodium hydroxide solution to a suspension of 436 mg of 6-amino acid. 2,2-dimethyl-3- (tetrazolyl--5) penam in 5 ml of water (to give a pH of 7.8) and then completely diluted with 25 ml of acetone. The cooling bath was removed and the reaction mixture was stirred for a further 30 minutes. At this stage, the acetone was removed by evaporation under reduced pressure, and then 20 ml of methyl isobutyl ketone was added to the aqueous residue. The resulting two-phase system was cooled to 10 ° C., acidified to pH 0.9 with dilute hydrochloric acid, and stirred at 10 ° C. for 1 hour. The onethyl-butyl ketone layer was removed and discarded, the pH of the aqueous phase was raised to 6.6, and then kept in a freezer for 3 hours. The precipitate was filtered to yield 520 mg of i6- [D-2-amino-2- (4-hydroxyphenyl) -acetamido] -2,2-dimethyl-3- (tetrazolyl-5) penam. Infrared spectrum / KBr , the pellet of this product had an absorption band at 1775 cm -1 (carbonyl (3-lactam) and 1680 cm -1 (amide band). The spectrum (in DM'SO-de (D 2 Q) showed an absorption. - options at 7.35 ppm and 6.85 ppm (2d, aromatic hydrogens), 5.60 ppm / q, C-5 and C-6 hydrogens, 10 ppm / m, benzyl hydrogens and * C hydrogens -3 /, 1.45 ppm / ls, C-2 methyl hydrogens / and 0.95 ppm / s, C-2 methyl hydrogens /. The MIC value (minimum inhibitory concentration) for this compound against Streptococcus pyogenes was <0.1 (mg / ml. Example XI. 6- (1-aminocyclohexanecarboxamMo) -2; 2-dimethyl-3- (tetrazolyl-5) / penam pH of the mixed suspension 720 mg / 3.0 mmol / 6 - -amino-2,2-dimethyl-3- (tetrazolyl-5) penam in 50 ml of water at 0 ° C was adjusted to 7 with 1.0 N sodium hydroxide solution. After dissolving the whole solid, the pH was lowered to the value 6.0 (using 1.0 N hydrochloric acid) and then 750 mg (3.4 mmol) of 2,4-oxazaspiro [4.5 decanedione-1,3 (Album et al., Antimicrobial Agents and Chemotherapists, 586 (1967). The mixture was stirred at a temperature of about 0 ° C and a pH of 6 for 1 hour, then filtered: The pH of the mixture was adjusted to 4.2 and the mixture was freeze-dried. was dissolved in 5 ml of methylene chloride containing 606 mg of triethylamine. This new solution was added dropwise with stirring to 100 ml of ether and the separated body was continuously filtered off. There was thus obtained 1.3 g (93% yield) of a complex combination of the bee compound.giving the subject of the example with triethylamine in a ratio of 2: 1. Infrared absorption bands (KBr, pellet): 1786, 1680 and 1640 cm-1. 40 NMR spectrum (in D20): 5.90 ppm / d, 1H), 5.40 ppm / d, 1H), 30 ppm / s, "1H), 3.10 ppm / q, 3H), 1, 90-1.50 ppm / m, 10H /, 1.60 ppm / s, 3H /, 1.20 ppm / t, 4.5H /, 100 ppm / s, 3H / MIC value (minimum inhibitory concentration) for of this compound in relation to the strain Streptoepceus pyogenes was 25 µg / ml. Example XII. 6- [2-D- (2-ibenzamidoacetam- to / -2-phenylacetamido] -2.2- dimethyl-3- / tetrazol- and lo- 5 / pename. For a vigorously stirred solution of 1.29 g 6- [2- -D - (/ 2-aninoacetamido / -2-phenylacetamido] -2,2j-dimethyl-3- (tetrazolyl-5) penam and 1.3 ml of triethylamine in 15 ml of dimethylformamide was added 0.4 ml of benzoyl chloride. Stirring was continued for a further 30 minutes, then the reaction mixture was filtered. The filtrate was added dropwise to 300 ml of ether, which resulted in the precipitation of a resinous solid. The ether was removed by decantation, while The solid was partitioned between ethyl acetate and water. The pH of the aqueous phase was adjusted to 2.0 (dilute hydrochloric acid) and the ethyl acetate layer was removed. it was combined with the further ethyl acetate extract obtained from extraction of the acidified aqueous phase. The combined extracts were washed with water, then brine, and dried with anhydrous sodium sulfate. Evaporation of the solvent under reduced pressure gave a resinous solid which was dissolved in 30 ml of ethyl acetate, and the solution was then added dropwise to 200 ml of hexane. The precipitated white body was continuously drained to give 0.85 g of the exemplified compound having a melting point of 150 ° C (decomposition). Infrared absorption bands (KBr, pellet): 1780 cm-1 (L-lactam). NMR spectrum (in DMISO-dtf): 9.40-9.20 ppm / m, 1H), 8.90— —8.40 ppm / m, 2H), 8.00-7.10 ppm (il2H) , 5.90— —540 ppm / m, 3H), 5.25 ppm / s, 1H), 4.00 ppm / d, 2H), 1.60 ppm / s, 3H), and 1.00 ppm / s , 3H /. 40 The MIC value / minimum inhibitory concentration / for this compound against Streptpcoccus pyogenes was <0.1 ng / ml. Example XIII. 6- [2 -, (3-phenylureido) -2- (p- -hydroxyphenyl) -acetamido} -2,2-dimethyl-3- (tetrazolyl-5) penam, For a vigorously stirred solution 0.78 (0.002 mol) 6- [2-amino-2- (p-hydroxyphenyl) -acetatfrndo] -2,2-dimethyl-3- (tetrazolyl-5) penam in 40 ml of a 1: 1 mixture of acetone and water While the pH was adjusted to 6.0 by the addition of sodium bicarbonate solution, 0.238 g (0.002 mole) of phenyl isocyanate was added at ambient temperature. Stirring was continued at this temperature for a further 30 minutes and then 50 ml of ethyl acetate were added. The pH of the aqueous phase was lowered to 1.5 with 1N hydrochloric acid solution, and then the organic layer was removed, dried and evaporated to dryness under reduced pressure. The remainder was redissolved in a small amount of ethanol, to which 0.2 ml of triacinol was added. ethylamine. The resulting solution was added dropwise to 200 ml of ether with vigorous stirring, then the precipitated body was constantly filtered off. This gave 0.8 g (a yield of 06%) 6- [2- (3-phenylureido) -65 -2- (P-nyaroxyphenyl) -acertamido] -2,2-dimethyl-41 95 747 42 -3- (tetrazolyl-5) penam in the form of its triethylamine salt, m.p. 165-170 ° C (decomposed). The infrared spectrum of the product (KBr, pellet) showed absorption bands at 1790 cm -1 (0-lactam) and 1670 cm -1 (1 amide band). The NMR spectrum (in DMSO-d6) (D6O) showed an absorption at 7.60-6.70 ppm / m, 9H), aromatic hydrogens), 5.80-6.50 ppm / m, 3 N hydrocarbons. -5 and C-6 and side-chain aromatic hydrogens /, 5.80-5.430 ppm / m, 3H, C-5 and C-6 hydrogens and methylene group side-chain hydrogen / 5.05 ppm / s , 1H, C-3 hydrogens, 3.05 ppm / q, 6H, NH2CH2CH3), 1.55 ppm / s, 3H, C-2 methyl hydrogen, 1.10 ppm / t, 9H , N-CH2CH * / and 0.95 ppm / s, 3H, C-2 methyl hydrogens /. The MIC value (minimum inhibitory concentration) for this compound in relation to iStreptococcus pyogenes was <0.1 µg / ml. Example XIV. 6- {D-2 - [, 2- (benzoamidino) - -acetamido] -2-phenylacetamido} -2,2-dimethyl-3- - (tetrazolyl-5) pename. A mixture of 1.72 g 6- [D- 2- / 2-aminoacetamido / -2-phenylacetamido-2,2-dimethyl- <3- (tetrazolyl-5) -penam, 0.66 g. Ethyl benzimidene and 20 ml. N, N-, dimethylformamide were stirred for 1 hour at 25 ° C. The filtered reaction mixture was then added dropwise with stirring to a large excess of chloroform and the precipitated solid was filtered off. In this way, 0.93 g (43% yield) of the compound of the example having a melting point of 198 ° C (with decomposition) was obtained. Infrared absorption bands (KBr, pellet): 1770 cm -1 ((3-lactam / NMR spectrum) / in DMSO-d6 /: 9.35-9.00 ppm / m, 2H), 8.00 - 7.15 ppm / m, 12H), 5.95 ppm / d, 2H), 5.55—5.30 ppm, / s, 1H), 4.35 ppm / s, '2H, 1.50 ppm / s, 3H / and 0.90 ppm / s, 3H /. The MIC value / minimum inhibitory concentration / for this compound in relation to the Streptococcus pyogenes strain was <0.1 µg / ml. Example XV. 6- [D-2- / 3-phenylthioureido / -2-phenylacetamido] -2,2-dimethyl-3- (tetrazolyl-5) penam. For an energetically mixed solution 910 mg 6- / D-2-amino - 2-phenylacetamido (2,2-dimethyl-3- (tetrazolyl-5) penam and 0.61 ml of triethylamine in 20 ml of methylene chloride, 0.27 ml of phenyl isocyanate was added. Stirring was continued for 2 hours at ambient temperature and then the solvent was removed by evaporation under reduced pressure. The residue was dissolved in water at a pH value of 7.8 and the water was washed with ethyl acetate. The pH of the aqueous phase was lowered to 2.0 and the product was extracted with ethyl acetate. These ethyl acetate layers were washed with water, dried over anhydrous sodium sulfate and evaporated under reduced pressure. There was thus obtained 707 mg (64% yield) of the compound of the example having a melting point of 150 ° -167 ° C (decomposition). Infrared absorption bands (KBr, pellet): 1706, 1681 and 11515 cm -1. MRJ spectrum / in CDC13 / / DMSO-d6 /: 9.17 ppm / s, 1H /, 8.27 ppm / m,, 1H /, 7.97 ppm / d, J = 7Hz, 1H /, 7.4 ppm / m, 10H), 6.3 ppm / d, j = 7 Hz, 1H), 5.63 ppm / m, 2H), 5.27 ppm / s, 1H), 1.6 ppm / s, 3H) and 1.1 ppm / s, 3H). * "" The MIC value / minimum inhibitory concentration / for this compound relative to the Strpetocoocus pyogenes strain was <0.1 [xg / ml. Example XVI. 6- [D-2 - / - guanyloureido / -2-phenylacetam, ido] -) 2,2-dimethyl-3- (tetrazolyl-5) -penium. For a vigorously stirred solution of 0.5 g of bi- Guanyl-semicarbazide hydrochloride (US Pat. No. 3,579,514) in 5 ml of water was added dropwise 0.184 g of sodium nitrite in 2 ml of water at a temperature of about 0 ° C. On <a second solution was prepared stepwise from 1.14 g <6- (D- -2-amino-2-phenylacetamido) -2,2-dimethyl-3- (tetrazolyl-5 / lpenam, 20 ml of water, 6 ml of dioxane and the appropriate amount of triethylamine to adjust the pH to the value of 8.0. The pH of this second solution was then lowered to 7.5, and the first solution was added dropwise thereto at a temperature of about 0 ° C. The resulting reaction mixture was stirred for 45 minutes, and then a solution prepared from 0.95 g of sodium nitrite, 0.25 g of guanyl-semicarbazide dihydrochloride and 3 ml of water was added thereto. Stirring was continued for a further 45 minutes and the reaction mixture was then freeze-dried. The residue was extracted with chloroform. The undissolved material was then suspended in 20 ml of water, and the pH of the suspension was adjusted to 5.0. The body was continuously filtered off and dried to give 0.87 g (yield 71%) of the compound of the example having a melting point of 192 ° -194 ° C (with decomposition). Infrared absorption bands (KBr, pellet): 1785 cm. 1 / lactam /. NMR spectrum (in DMSO-de): 7.55 ppm / m, 5H), 5.85-5.55 ppm / m, 3H), 5.10 ppm, / s, 1H), 1.55 ppm / s , 3H /, 0.95 ppm / s, 3H /. The MIC value / minimum inhibitory concentration / 40 for this compound in relation to the Streptococcus pyogenes strain was <0.1 µg / ml. Example XVII. 6-D-2-ureido-2-phenylacetamide / -2,2-dimethyl-3-) tetr, azolyl-5 / penam. 0.5 g mixture of 2- (D-2-amino-2-phenylacetami-) 45 to (-2,: 2-dimethyl-3- (tetrazolyl-5) penam and 94 mg of potassium cyanate in 10 ml of water were heated rapidly to 80 ° C and then rapidly cooled to 25 ° C. The reaction mixture was stirred at room temperature for 18 hours and then filtered. The filtrate was acidified to a pH of 2.0 and the precipitated solid was filtered off. This precipitate was dissolved in a little ethanol to which was added 0.067 ml of triethylamine. The solution was then poured into 100 ml of ether and the precipitated solid was drained steadily to give 0.23 g (yield 33%) of the exemplified compound having a melting point of 138-150 ° C (decomposition). Infrared absorption bands (KBr, pellet): 1785 cm -1 (3-lactam), and 1670 cm -1 (amide band). NMR spectrum (in DMSO-de), D2C): 7, nc ppm / m, 5H), 5.80-5.40 ppm / m, 3H), 5.10 ppm / s, 1H), 3.10 ppm / q, 6H /, 1.60 ppm, / s, 3H /, 1.20 ppm / t, 9H /, 0.95 ppm / s, 3H / .M MIC value / minimum inhibitory concentration / 95 747 43 44 for of this compound for Streptococcus pyogenes strain was 0.1 (Ag / ml. Example XVIII. 6- [D-2- (2-guenylacetam- to / -2-phenylacetamido] -2,2-dimethyl-3-) tetrazolyl -5 / pename. To a vigorously stirred solution of 405 mg of p-nitrophenol in 10 ml of N, N-dimethylformamide was added 620 mg of dicyclohexylcarbodiimide followed by 410 mg of 2-guanylacetic acid hydrochloride. Stirring was continued for 4 hours. and then a solution of 948 mg of the triethylamine salt of 6- (D-2-amino-2-phenylacetamido) -12,2-dimethyl-3- (tetrazolyl-5) parenchyma in 10 ml of N -dimethyl ormamide. Stirring was continued overnight, then the filtered reaction mixture was poured into 300 ml. of ether. A gum-like precipitate formed and excess solvent was removed. by decantation. The gum material was taken up in 300 ml of methylene chloride containing 1 ml of triethylamine. Thus, after filtering 0.4 g (a yield of 44%) of the compound of the example having a melting point of 172-176 ° C (decomposed) was obtained. Infrared absorption bands (KBr, pellet): 1780 cm-1 (µMafctam) NMR spectrum (in DMSO-d6 (D20): 7.45 ppm / m, 5H), 85 ppm / d, 1H), 5.55 ppm / m, 2H), 5.05 ppm / s, 1H), 2.70 ppm / m, 4H), 1.55 ppm / s, 3H), 0.95 ppm / s, 3H). The 2-guanylacetic acid hydrochloride used in this example was prepared from ethyl 2-cyanoacetate in an analogous manner to that described for the preparation of 3-guanylpropionic acid hydrochloride. The MIC value (minimum inhibitory concentration) for this compound was 12 for Staphylococcus aureus. , 5 \ vg / ml. Example XIX. 6- [D-2- (4-aminobenzamido) - -2-phenylacetamido] -2,2-dimethyl-3- (tetrazolyl--5) penam. A solution was prepared by slurrying 1.05 g of 6- {D -2- (4-nitrobenzamido) -2-phenylacimido] - (2,2-dimethyl-3- (tetrazolyl-5) penam in 50 ml of water, and its pH was adjusted to 7.3 with a solution of Sodium hydrogen carbonate. 1.0 g of palladium 10% on carbon was added to this solution. The mixture was shaken under a hydrogen atmosphere at a pressure of about 2.8 atm, until the hydrogen was consumed. The spent catalyst was removed by filtration. and the aqueous solution was freeze-dried, thus obtaining 0.91 g of crude product. Part of the crude product was subjected to further purification in a chromatographic column filled with Sephadex LH-20, using water as eluent. The purified product had a melting point of 260 —272 ° C. Infrared absorption bands (KBr, pellet): 1770 and 1626 cm. * NMR spectrum (in D20): 7.6-7.0 ppm / m, 7H), 6.5 ppm (d, J = 9 Hz, 2H), 5.6-5.4 ppm / m, 3H), 5 , 2 ppm, (s, 1H), 1.4 ppm / s, 3H, and 0.88 ppm, (s, 3H). , The MIC value / minimum inhibitory concentration / for this compound against Streptococcus pyogenes was <0.1 µg / ml. 40 45 50 55 60 In a similar manner, hydrogenation of 6- {D-2- [2- (4- -iiitrophenyl) -acetamido] -2-phenyla | ce1; aimildo} -2,2-dimethyl] 3- (l-tetirazolyl-5) penam gives a 23% yield of 6- {D-2- {2i (4-aminophenyi) -acetamido] -2-phenylacetamido} -2,2-dimethyl-3- (tetrazolyl--5) penam with a melting point of 260- 270 ° C. Infrared absorption bands (KBr, pellet): 1770.1.653 cm -1. Example XX. 6- (D-2-sulfamino-2-phenylacimido) -2,2-dimethyl-3- (itetrazolium-5i) pename. For a vigorously stirred suspension 2.13 g / 0.005 mol / 6- / D- 2-amino-2-phenylacetamido (-2-dimethyl-3- (tetrazolyl-5) penam in 50 ml of methylene chloride was added 0.84 ml (0.006 mol) of triethylamine. The mixture was stirred until most of the solid was dissolved. Approximately 2 g of Linde 4A powdered molecular sieve was then added to the solution and stirring continued for a further hour. The molecular sieves were removed by filtration and the filtrate was cooled to 0 ° C. 0.84 g (0.06 mol) of a trimethylamine-sulfur trioxide complex was added in portions over 5 minutes to the cooled solution. The solution was stirred at 0 ° C. for a period of 5 minutes and then at room temperature for 2.5 hours. Then 2.5 g of sodium 2-ethyl hexane carboxylate in 10 ml of 1-butanol was added. The resulting precipitate was filtered off, dissolved in 20 ml and cooled to 0 ° C. The pH of the reaction mixture was adjusted to 5.0 with (glacial acetic acid), and the resulting methyl solution was stirred for 1 hour. After filtering through the diatomaceous earth, the filtrate was added dropwise with stirring to 700 ml of cold (0 ° C) acetone. The precipitate formed was collected and dried to give IL 80 g (65.3% yield) 6- (D-2-sulfoamino-2-phenylacetam! Ido) -2.2-dimethyl (tetrasolyl). -5 / penam in the form of its disodium salt. Infrared spectrum (KBr, pellet): showed absorption bands at 1770 cm-1 / L-lactam /, 1650 cm-1 / I amide band / and 1560 cm-1 / II band The amide spectrum (NMR spectrum in D20) showed an absorption at 7.46 ppm / s, aromatic hydrogens 5H), 5.64 ppm / q, 2H, C ^ 5 and C-6 hydrogens / 5.33 ppm / s, 1H, methyne hydrogen /, 5.10 ppm / s, 1H, C-3 hydrogen), 1.1, -58 ppm / s, 3H, C-a methyl hydrogens / 1.00 ppm / s, 3H, hydrogen Methyl C — 2 /. [a] D25 = 108 ° / H ^ O/. Elemental analysis: contents calculated for: C16HirN06S ^ Na2: C — 34.85%, H - ^, 20%, N-h17.78% , S — 0.1 ^ 63%; analytically determined contents: C— # 5.02%, H- ^ 1.311%, N — 117.82%, S — III, 9 µl%. MIC value / minimum inhibitory concentration / for of this compound for Streptococcus pyogenes strain was 12.5 µg / ml. Example XXI. 6- [D-2- (carboxymethoxy) - -acetamido-2-phenylacetamido] -2,2-dimethyl-3- (tetrazolyl-6) penam. To a vigorously stirred solution of 2.59 g (6.0 mmol) 6- (D-2-amino-2-phenylacetamino trihydrate) -2, 2-dimethyl-3- (tetrazolyl-5) penam and 1.70 ml (12.2 mmol) triethylamine in 70 ml methylene chloride at 0.5 ° C a solution of 1.40 g (12.0 mmol) anhydride was added glycolic acid (hydroxyacetic acid) in 30 ml of methylene chloride. 95 747 45 46 The solution was stirred at 0.1 ° C for 1 hour and then extracted with 200 ml of 10% sodium bicarbonate solution. The pH of the aqueous phase was adjusted to 2.0 and the product was extracted with ethyl acetate. The organic layer was dried (MgSO4) and then concentrated under reduced pressure to give 820 mg (yield 28%) of the exemplified compound. Infrared absorption bands (KBr, pellet): 1780 cm -1 (0-lactam) and 1650 cm -1 (amide band). NMR spectrum (in DMSO-de): 7.41 ppm / m, 5H), 5.85- < 5.90 ppm / m, 3H), 5.24 ppm / m, 1H), 447 ppm / s, 2H /, 4.10 ppm / s, 2H /, 1.57 ppm / s, 3H /, 0.09 ppm / s, 3H /. The MIC value / minimum inhibitory concentration / for this compound against Streptococcus pyogenes was 0.2 In a similar manner, starting from epoxy succinic anhydride, the yield was 73% 6- [D-2- (4-canboxy-2,3-epoxysuccinimido) -2-20-phenylacetamido] -2,2-dimethyl -3- (tetrazolyl-5 / penam. Infrared absorption bands / KBr,. pastille /: 1790 and 1665 cm-1. Example XXII. 6- / D-2-ureMocarboxamid--2-phenylacetamido / -2,2-dimethyl-3 - / tetrazolyl-M -5 / pename. For a vigorously stirred solution 1.12 g / 3 mmol / 6- / D- 2-amino-2-phenylacetamide (-2,2-dimethydo-3- (tetrazolyl-5) penam and 0.485 ml of triethylamine in 6 ml of water were added in portions over a period of minutes. 0.5112 g / 3.5 mMol / N-methyl-N-nitro-na-uureth. Stirring was continued for a further 2 hours and then the pH was adjusted to i2.0. The product was extracted with ethyl acetate and 0.42 ml (3.0 mmol) of triethylamine was added to the extract and then it was evaporated to dryness under reduced pressure. This gave 1.4 g (84% yield) of the exemplified compound in the form of its triethylamine salt. Infrared absorption bands (KBr, pellet): 1785, 1695 and 1540 cm-1. NMR spectrum (in CDCl3): 9.4-8.4 ppm / m, 8.3 ppm / s, 7.7-7.1 ppm, (m), 7.1-6.7 ppm / m /, 5.9-5.3 ppm / m /, 5.3-5.0 ppm / d /, 4.5 -M ppm / d /, 1.6 ppm, / s /, 1.0 ppm /s/ The MIC value / minimum inhibitory concentration / 45 for this compound relative to the strain Streptococcus pyogenes was <0.1 µg / ml Example XXIII. 6 -: [(hexahydroazepinyl--1] -J-methylamino] -2,2-dimethyl-3- (tetrazolyl-5) -penam. 50 To a vigorously stirred solution of 1.2 g / 5 mmol / 6-amino-2,2-dimethyl-3- (tetrazolyl-5) penta, 1.0 g / 10 mmol / triethylamine and 30 ml of cooled dichloromethane 0 ° C, 0.54 g (5 mmol) of chlorotrimethylsilane was added. After 15 minutes, 0.86 g (5 mmol) of 1- (diethoxymethyl) hexahydroreazepine (British Patent No. 1,293,590) was added and stirring was continued for 1 hour. The volatile constituents were removed by evaporation under reduced pressure of 60 and the residue was extracted with 25 ml of acetone. The insoluble matter was filtered off and the acetone was evaporated under reduced pressure to a yellowish foam which turned to a white powder on trituration with ether. There was thus obtained 1.44 g (yield 82% / 6 ° C). (hexahydroazepine-1) -methyleneamino] -2,2-dimethyl-3- (tetrazolyl-5) penam. The infrared spectrum of the product (KBr, pellet) showed absorption bands at: 1795 cm-1 (β-lactam), 1706 cm-1 and 1645 cm-1. The NMR spectrum (in CDC13) showed bands at 8.00 ppm / s, lH, N-CH = tN, 5.90 and 5.60 ppm, (2 d, J = 4 Hz, C-5 and C hydrogens 6), 5.40 ppm / s, 1H, C-3 hydrogen, 90-3.50 (m), 4H, CH 2 - -1.50 ppm, 1m, UH, C- methyl hydrogens 2 and [CH 2] and 1.20 ppm / s, 3 H, C-2 methyl hydrogens. Examination of the product by thin layer chromatography (0.2 m NaOAc + acetone; 1: 6 showed a single spot, (Rf 0.23). The MIC value (minimum inhibitory concentration) for this compound against the strain Streptococcus pyogenes was 50 µg / ml. Example XXIV. 6 - [(dimethylamino) -methyleneamino] -2,2-dimethyl-3- (tetrazolyl-5) penam. Reaction of N, N-dimethylformamide dimethylacetal from 6-amino-2,2-dimethyl-3-) tetrazolyl-5), in accordance with the method described in Example XXIII, in a yield of 89% complex compound (3: 1/6 - [(dimethylamino) -methyleneamino] -2,2-dimethyl-3-) tetrazolyl-5 / penam. Infrared absorption bands (KBr, pellet): 1780, 1710 and 1640 cm-1. NMR spectrum (in CDC1S): 8.0 ppm / s, 1H), 5.80 and 5.50 ppm (did, 2H, j = 4Hz), 30 (s, 1H), 3.40-3.00 ppm / m, 8H /, 1.70 ppm / s, 3H /, 1.30 ppm / t, 3H /, 1.70 ppm / s, 3H /. MIC value / minimum inhibitory concentration / for this compound relative to the Streptococcus strain pyogenes was 12.5 µg / ml. Example XXV. 6- (2,2-dimethyl-5-keto-4- phenyimidazolidinyl-1) -2,2-dimethyl-3- (tetrazolyl-5) (pename). Mixture 1.0 g (2.34 mmol) 6- (D-2-amino-2-phenylacetamido) -2,2-dimethyl-3- (tetrazolyl-5) -penam, 0.654 ml (4.86 mmol) triethylamine and 100 ml of anhydrous acetone were stirred for about 24 hours. days at a temperature of about 25 ° C. The solvent was then removed by evaporation under reduced pressure to give 1.10 g of 6- (2,2-dimethyl-5-keto-4-phenyimidazo'liidinyl-1-) -2,2-dimethyl-3. - (tetrazolyl-5) penam in the form of the triethylamine salt. Infrared absorption bands (KBr, pellet): 1786 cm-1 (flat) and 1709 cm-1. NMR spectrum (in DMSO-dj (D.jP): 7.76-7.15 ppm / m, 5H), 5.22 ppm / s, 1H), 5.7 <8 and 5.10 ppm (2Xd, 2H, J = 4 Hz), 4.69 ppm / s, 3H), 3.10 ppm / q, 6H, J = 8 Hz), 1.62 ppm i / s , 3H), 1.50 ppm / s, 3H), 1.40 ppm / s, 3H), 1.21 ppm / t, 9H, J = 8 Hz), and 0.98 ppm / s, 3H). The MIC / minimum inhibitory concentration / for this compound against the Staphylococcus aureus strain was 6.25 µg / ml. Example XXVI. 6- [2,2-dimethyl-5-keto (p-hydroxyenyl) -imidazolidinyl-1] -2,12-dimethyl-3- (tetrazolyl-5) penam. Reaction 6- [ D-2-amino-2- (p-hydroxyphenyl) -2-phenylacetamido] -2,2-dimethyl-3- (tetrazolyl-5) peptide with acetone and triethylamine according to the method described in the example XXV away 6- [2,2-dimethyl-5-keto-4- (p-hydroxyphenyl) -imidazolidinyl-1] -2,2-dimethyl-3- (tetrazolyl-5 / penam in the form of " 5747 47 48 Ci of the triethylamine salt. Infrared absorption bands (KBr, pellet): 1786 and 1686 cm "1. NMR spectrum / in DMSO-de (r 2 O): 6.82 and 7.35 ppm 7ft, 4H /, 5.16 ppm / s, 1H), 5.71 and 5.07 ppm (2Xd, 2H), J = 4 Hz), 4.52 ppm / s, 3H), 3.07 ppm / q, 6H, j = 8 Hz), 1. 60 ppm / s, 3H /, 1.43 ppm / s, 3H /, 1.36 ppm / s, 3H /, 1.16 ppm / t, 9H, J = 8 Hz / and 0.97 ppm / s, 3H /. The MIC value (minimum inhibitory concentration) for this compound against the Staphyilococcus aureus strain was 0.78 µg / ml. Example XXVII. 6- (5-keto-4-phenyimidazolidinyl) -2,2-dimethyl -3- (tetrazolyl-5) penham. For a stirred suspension of 1.0 g (2.26 mmol) N 6- (D- -2-amino-2-phenylacetamido) -2,2-dimethyl-3-) Tetrazolyl-5) penam trihydrate in 15 ml of water was added 151 µl (2.53 mmol) of 2-aminoethanol followed by 342 µl (4.6 mmol) 37% aqueous formaldehyde solution. period of 7 hours and then freeze-dried, obtaining 0.96 g (yield 92%) of the compound of the example in the form of its triethanolamine salt. infrared (KBr, pellet): 1773 cm 1 (β-lactam) and 1681 cm -1 (1 amide band). NMR spectrum (in DMSO-d6): 8.75 ppm / m, 2H), 7.30 ppm / s, 5H), 6.00-5.60 ppm and 4.90 ° C, 40 ppm / m, 4H) , 4.00-3.20 ppm / m, 4H /, 1.70 and 1.06 ppm / 2s, 6H). The MIC value (minimum inhibitory concentration) for this compound was 6.25 µg / for the Streptococcus pyogenes strain / ml. Example XXVIII. 6- [5'keto-4- (p-hydroxy-phenyl) -imidazolidinyl-1] -2,2-dimethyl) -l-3 - (! Tetrazolyl-5) pename. The operations described in Example XXVII were repeated, with that instead of trazolyl-5 / penam 6- (D- -2-amino-2-phenyl) trihydrate, an equal amount of the trihydrate was used. 6- [D-2-amino-2- (p-hydroxyphenyl) -acetamido] -2,2--dimethyldt-3- (tetrazolyl-5) penam. In this way, 0.96 g (92% yield) of the compound of interest in the form of its ethanolamine salt was obtained. Infrared absorption bands (KBr, pellet): 1776 µm -1 (0-latetam) and 1675 cm -1 (amide band). NMR spectrum (in I) MSO-d6): 8.52 ppm (m, 2H), 7.14 ppm (Im, 4H), 90-5.00 ppm and 4.80-4.40 ppm / m, 4H), 3.80-3.00 ppm (m, 4H), 1.67 ppm and 1.06. ppm / 2s, 6H /. The MIC value (minimum inhibitory concentration) for this compound for the strain Streptococcus pyogenes was 6.25 µg / ml. Example XXIX. The compounds shown in Tables II, III, IV and V were obtained by reacting the appropriate penam derivative with the appropriate reagent. The compounds listed in Table II were prepared from 6-amino-2,2-dimethyl-3- (tetrazolyl-5) penam. The compounds shown in Table III were obtained from 6- (D-2-amino-2-phenylacetamido) -2,2-dimethyl-3- (tetrazolyl-5) penam or from 6- [D-2-amino-3- (4-hydroxyphenyl) -acetamido] -2,2-dimethyl-3- (tetrazolyl-5) penam. The compounds shown in Table IV were prepared from 6- [D-2- (2-aminoacetamido) -2-phenylacetamido] -2.2H-dimethyl-3- (tetrazol-5) penam or from 6- [D-2 - (2-aminoacetamido) -2- (4-hydroxyphenyl) -acetamido] -2,2-dimethyl-3- (tetrazol-5) penam, and the compounds shown in Table V are obtained from 6- [D-2- (3-amino-propionamido) -2-phenylacetamido] -2,2-dimethyl-3- (tetirazolyl-5) penam. In each of the tables a method of synthesis is given in which the coupling reaction of a penam derivative takes place by referring to the examples given earlier. The minimum inhibitory concentration (MIC value) of the listed compounds against strains of Streptococcus pyogenes is also given. The structure of the discussed compounds was confirmed by nuclear magnetic resonance spectroscopy1 methods. Ri and Formula 32 Formula 33 C6HsO — CO— CgHgCHgO ^ CO— CH8CHiO — CO— CHj — CO— H2N — CO — CH = CH — CO— H— 2.6 - / CH80 / 2 — C6H5 — GO— formula 34. '. D 3 — HOC6H4 — CH — CO— and! 1 NH2 Table II Compounds of formula 4 Method of synthesis (Example No.) II II II II II II V "III III III VIII Yield% 3 89 26 43 32 48 33 40 59 54 Melting point ° C 4 192—194 102 — illlB 145—170 80-4115 215 IR, cm-1 ~~ 1770, 1650 1520 1808, 1718 1678 1795, 1740 1880, 1725 1800, 1725 1780, 1645 1918, 1692 1760, 1660 1808, 1643 1605 1780, 1715 1667 1776, 1686 MIC ng / ml X ~ 6 <0.1 <0.1 <0.1 <0.1 <0.1 0.2 <0.1 Comments 7 1, 2 3 4 2, 5, 6 7 2 4, 995 747 49 50 table II cont. 1 DL 3,4— / HO / gCeHg — CH — CO— ii NH2 D 4— / CHsO / C6H4 ^ CH ^ CO— il NH2 L 4 — HOC6H4 — CH — CO ii NH2 formula 35 DL 4— / CH3 / 2NC6H4 —CH — CO— ii NH2 D 3 — Cl ^ l — HOC6H3 — CH — CO— and 1 NH2 DL 4 — C1C6H4 — CH — CO and 1 NH2 DL 3 — C1C6H4 — CH — CO— and 1 NH2 DL 3 ^ / NO2 / C6H4 — CH — CO— and 1 NH2 DL 4 — NH2SO2C6H4 — CH — CO— and 1 NH2 D 4 — FC6H4 — CH — CO— and 1 NH2 formula 38 formula 37 formula 33 DL 2 — Br — 5 — HOC6H3 ^ CH — CO— il NH2 D 3 — FC6H4 — CH — CO— il NH2 NH2 — CH2 — CO D / CH3 / 2CH — CH ^ CO— ii NH2 D C6H5CH2 — CO— ii NH2 Formula 39 Formula 40 D 4 — NH2C6H4— CH — CO— ii NH2 D 3 — NH2C6H4 — CH — CO— ii NH2 4— / NH2CH2 / C6H4 — CH2 ^ CO— 2— / NH2CH2 / C6H4 — CH2 — CO 2— / NH2CH2 / C6H4- ^ S — CHa— CO— model 41 2 VIII VIII - VIII VIII VIII VIII VIII VIII VIII VIII 1 VIII VIII VIII VIII VIII VHI VIII VIII VIII VIII VIII VI VIII VIII IX VI 3 3 7 28 27 H 7 "14 22 18 50 28 17 41. 58 38 4 13 11 13 14 36 4 | 5 ^ 190—200 1 1770, 1684 1775 1770 1775, 1690 1783 1785, 1695 1780, 1700 1785, 1666 1775, 1650 1775, 1650 1780, 1695 1780, 1690 1775 1780, 1690 1780, 1670 1785 1775, 1680 1775, 1680 1775, 1680 1770, 1680 1770 1 775, 1650 1770, 1650 1515 1780, 1645 1780, 1665 1779, 1678 1 6 <0.1 <0.001 <0.1 0.1 0.39 0.1 <0, T 0.79 0.004 <0.1 3.12 0.39 <0.1 200 0.2 0.39 6.25 <0.1 0.039 <0.01 <0.1 1.56, <0.1 1 7 1 9 8, 9 9 9 4.9 4, 9, 10 4, 9, 10 4, 9, 10 9 9 9 9 9 9, 11 9 8, 9 9 9 8, 9 8, 9 4, 9 9, 12 13 1 14 14 1595 747 51 52 Table II cont .1 DL CeHg — CH — CO— and CH2NH2 2— / NHZCH ^ GH2 O / C6H4 — CHa-CO— 3— / NH2CH2CHzO / C6H4 ^ CH2 ^ CO— 4— / NH2CHaCH2O / C6H4 ^ CH2 — CO— 4— / N3CHzO / C6H4k-CH2- ^ CO— L 4 — HOC6H4 — CHj ^ CH — CO— and 1 NH2 CeHgS — CH2- ^ CO— CHSCH2S — CH2 — CO— CHpCO ^ CHzCH2CH2 — CO— CHjjCHjOCO — CH2 — CO— C6H5CH2 —S — CHa — CO— 3,5— / CH3 / 2C6H ^ -C — NH — CH2 — CO- ll NH formula 42 CH8 — C ^ NH ^ CH2 — CO— ii NH formula 43 CHs — CO — NH — CO - formula 44 4 — CHgCeH ^ COg — NH — CO— L C6H5 — CH — CO— ii OH D C6H5 — CH — CO— ii OH C6H5 ^ OH — CO— 1 CO2H formula 45 formula 46 C6H5 — CH — CO— 1 and SOsH formula 47 2— / HOCOOH2 / C6H4 — CH2 — CO— C6H5 — CH — CO— 1 1 CO — CHg C6H5 — CH2 — CO- ^ CO— CH3CHzO — CO — CO— C6H5 — CO — CO— C ^ - C — CO— HH — C — CH2NH2 4 — C1C6H4CH ^ - —C — NH — CO — NH — CH2 — CO— n 1 NH C6H5 — C — NH — CO ^ NH — CH2 ^ CO— NH 2 VIII VIII VIII VIII VI VIII XII XII XII XII XII XIV XIV XIV XIV XV XV XV IV IV VI VI VI V VI VI IV III III III XII XII 3 17 64 33 60 56 31 22 46 31 41 31 24 69 67 58 60 91 50 77 64 51 67 24 63 74 36 65 60 85 87 64 81 4 170—186 170—182 118—127 175 ^ 180 150 — il62 153—164 1792, 1681 1780, 1667 1780, 1660 1785, 1667 1770, 1660 1780, 1688 1780 1 785 1785 1785 1780 1775 1785, 1580 1770, 1680 1780 1790, 1695 1795, H695 1795, 1695 1705, 1670 11600 1780, 1670 16il5 1775, 1670 1620 1765, 1660 1780, 1705 1680 1770, 1667 1780 1700, 1670 1780, 1710 1785, 1670 1770 1780 1780 6 12.5 <0.1 <0.1 0.2 0.78 <0.1 6.25 0.39 0.2 0.39 <0.1 1.56 1.56 1.56 <0.1 <0.1 0.002 0.1 0.1 200 <0.1 0.2 0.004 <0.1 12.5 100 <0.1 7 9, 10, 16, 16, 16 2, 16 2 17 17 17 17, 18 2 2 1995 747 53 54 table II cont. II 4 — CH, OC “H4 ^ - —C ^ NH — CO — NH — CH2 — CO— NH C6H5 — NH — CO— CH8CHjHNH — CO— 2 XII XV XV 3 71 84 70 4 162—168 1-10— 120 80-90 1775 1700, 1600 1785, 1688 6 0.1 <0.1 7 Note: 1. Starting material as described in Journal of the Chemicak Society / London /, 5638/1963 /. 2. The product was isolated in the form of the sodium salt. 3. The starting reagent was acetic anhydride. 4. Isobutyl cMoformate was used to prepare the mixed anhydride. The product was isolated as the free acid. 6. The starting reagent was acetic formic anhydride. 7. Starting material as described in Journal of the American Chemical Society, 61, 1418 (1936). 8. The MIC value (minimum inhibitory concentration) for this compound was determined against the Staphylococcus aureus strain. 9. The starting enamines were obtained by condensation of the appropriate glycine with methyl acetoacetate according to the method described by Longin et al. (Journal of the Chemical Society (London), Part C, 1920 (1971). the α-amino acids which have been described in the literature were obtained according to published methods. New α-amino acids obtained from the corresponding aldehydes by the Strecker synthesis, described by Greenstein and Winitz in "Chemistry of the Amino Acids", John Wiley and Sons, Inc., New York / London, 1961, pp. 698-8. 700, and the references cited therein Strecker synthesis yields D, L amino acids which are separated into optical isomers by conventional methods (see Greenstein and Winitz, loc. Cii, pp. 715-755; Nishimura et al., Nippon). Kagaku Zasshi, 82, 1688 (1961), Chemical Abstracts, 58, 11464 (1963) and Belgian Patent Specification No. 795 874. See also British Patent Specification No. 40 45 50 No. 1221227. 5-pyridyl-3-hydantoine was obtained using the method given by Henzo and Knowles, J. Org. Chem., 19, 1127, (1054) and hydrolyzed to 2-amino-2- (pyridyl-3 - / - acetic acid, the method described by Davis et al. (Archives Biochem and Biophys., 87, (1960) for the corresponding 4-isomer. The compound was isolated in the form of the triethylamine salt. 11. For the preparation of mixed anhydride trimethylacetyl chloride was used. 12. The amino groups in the starting material were protected during coupling with benzyloxycarbonyl groups which were removed after coupling by hydrogenolysis. 13. Starting material as described in Journal of the American Chemical Society, 80, 4317 (1958). 14. Starting material according to US Pat. No. 3,766,175. Starting material as described in Journal on FiNiTedicinal Chemistry, 14, 117, (1971), Anti-microbial Agent's and Chemotherapy, 686 (1967). 16. Starting material according to US Pat. No. 3,759,905. 17. The compound was isolated in the form of the disodium salt. 18. Starting material as described in Annali di Chimica, 53, 14, (1963). 19. The starting material was 3-azidomethyl-2-phenylisocrotonyl chloride. After coupling, the final product was obtained by hydrogenation. The starting penam compound was 6- (2-aminoacetamido) -2,2-dimethyl-3- (teitrazolyl--5) penam. Table III Compounds of formula 4 Ri 1 QiH5 — CH — CO - 1 • NH — CO — CH2Br C6H5 — CH — CO— 1 NH — CO — CH2C1 C6H5 — CH — CO— 1 NH — SOjj — CH8 Synthesis method / example number / 2 VI II II Efficiency% 3 40 48 45 Temperature (mp. ° C 4 128-135 142-146 117-148 IR, cm -1 1800, 1653 1780, 1650 1785 MIC ng / ml 6, <0.1 <0.1 1.56 Notes 7/95 747 55 56 Table III continued 1 6 C6H5 — CH — CO— I NH ^ SOs — CH2CH2CH3 C6H5 — CH — CO— I NH- ^ SO2 — C6H4—4 — OCH3 C6H5 — CH — CO— I NH — CO — CH2—5 — CH2—5 — CH2C6H5 C6H5 — CH —CO— I NH — CO — NH — C6H4 — OCH3 C6H5 — CH — CO— I NH — CO — NH — C6H4 - i — Cl C6H5 — CH — CO— I NH — CO — NH — C6H4 — l — CH3 C6H5 — CH — CO— I NH — CO — NH — C6H5 C6H5 — CH — CO— I NH — CO — NH — CH3 4 — HOC6H4 — CH — CO— I NH — CO — NH — C6H4— —4 — OCH3 formula Formula 49 C6H5 — CH — CO— I NH — SO2 — CH2CH3 C6H5 — CH — CO— I NH ^ SO2 — C6H4—4 — Cl C6H5 — CH — CO— I NH — SO2 — C6H4- ^ 1 — NO2 C6H5— CH — CO— I NH- ^ SO2 — C6H5 C6H5 — CH — CO— I NH- ^ SO2 — CH2C6H5 4 — HOC6H4 — CH — CO— I NH — SO2 — CH2CH2CH3 4 — HOC6H4 — CH — CO— I NH — SO2 —CgHg CgHg — CH — CO— I NH — CO ^ -GHjf — S — C6H5 C6H5 — CH — CO— I NH — CO — CH2 ^ S — CH2CH3 C6H5 — CH — CO— I NH — CO — CH2CH2CH2CH3 II II II XIII XIII XIII XIII XIII XIII II II II II II II II II II II II II 63 39 39 64 75 79 79 45 63 50 52 62 68 74 50 38 53 22 59 68 100—130 130—155 1780 1790 1780 -148 ^ 152 148 ^ 155 1785, 1670 17 $ 5, 1680 152—155 1785, 1680 150—155 112 ^ 120 165—170 70—105 127—16 / 1 126—145 135—149 135—154 133—147 117—145, 115—157 152—165 1785, 1670 1785, 1655 1785, 1670 1780 1790 1785 17 80 1790 1790 1780 1780 1780 1785 1785 1790 0.78 0.2 0.78 <0.1 <0.1 <0.1 <0.1 50 0.1 0.2 0.39 0.39 1.56 1.56 <0.1 <0.1 0.1 <0.1 <0.1 6.2595 747 S7 58 Table III cdC6H5 — CH — CO— I NH — CO — CH2 — C02CH2CH3 4 — HOC6H4 — CH — CO— I NH — CO — NH ^ C6H4— —4 ^ C1 C6H5— CH — CO— I NH — CO — CH2 ^ NH2 4 — HOC6H4 - CH — CO— I NH — CO — CH2NH2 CCH5 — CH — CO— I NH — CO — CH2CH ^ NH2 4 — HOC6H4 — CH — CO— I NH —CO — CH2 — o — C6H5 4 — HOC6H4 — CH — CO— - I NH — CO — NH — C / = = NH / —NH2 C6H3 — CH — CO— I SO2 ^ NH2 C6H5 — CH — CO— I NH —CO — CH2 — NH — C — NH2 NH formula 50 C6H5 — CH — CO— I NH — CO — CH2—4 — C6H4NH— —C — NHa NH C6H5 — CH — CO— I NH — CO — CH2OH2 — C— NH2 II NH C6H5 — CH — CO— I NH — CO — CH2 — iNH— —C — NHCH3 II NH C6H5 — CH — CO— I NH — CO — CH2 — NH — CO— —NH — C — NH2 NH C6H5— CH — CO— IN —NH — C — NH2 NCH8 II XIII VIII VIII VIII III XVI II IX IX IX IX IX IX IX 3 * 39 37 45 94 58 77 37 53 79 54 85 170 211—230 173—188 53 1J0O 166 —A 76 170— ^ 177 106—200 1775 1785, 1680 1770 a 785 1763 180—192 186—19 <9 129—139 1786, 1783, 1667 1770 1667 1695 180—186 200—208 106—176 168—171 1780 1785 1780 1785 1172 1785 1786, 1667 <0.1 <0.1 <0.1 <0.1 <0.1 0.2 0.004 <0.1 <0.1 3.12 1.56 <0.1 <0.1 3.12 <0.195 747 59 60 Table III continued 1 1 C6H5 — CH — CO— and 1 NH — CO — CH2 — NH — CO— —NH — C — NH2 D NCH2CHS C6H5 — CH — CO— 1 NH — CO — CH2-hNH — CO— —NH — C— NH2 NCH2C6H5 4 — HOC6H4 — CH — CO— 1 NH — CO — CH2 — NH— CO — NH — C — NH2 NH formula 51 C8H5 — CH — CO— il NH — CO — NH — CO — CH8 C “H5 — CH —CO— 1 l NH — CO — NH — CO— —CH2CH2CH2CHg C6H5 — CH — CO— and 1 NH — CO ^ STH — CO — CH2C1 formula 52 C6H. ~ CH — CO— and 1 1 NH — CO — NH— CO — C6H5 1 C6H5 — CH — CO— and 1 NH — CO — NH — CO — C6H3— —3.5 — Br2 formula 53 C6H5 — CH — CO— and 1 NH — CO — NH — CO— —CH2CH2CH formula 54 C6H5 — CH — CO— and NH — CS — NH — CO — C6H5 CflH5 — CH — CO— and NH — CO — NH — SO2 — C6H4— - ^ - CH, C6H5 — CH — CO— 11 NH — CO— NH — CO — CH2C6H5 C "H5 — CH — CO— 1 1 NH — CO — CO — C6H5 C6H5 — CH — CO— and 1 NH — CO — CO — CH8 CflH5 — CH — CO— and 1 NH — CO — CO -hOCH2CHs 1 2 IX IX IX XV XV XV XV XV XV XV XV XV XV XV XV XV XV | XV III 1 III III | 3 | 4 60 165—175 58 59 76 98 84 '88 48 49 68 80 83 79 70 82 66 37 78 165—169 178—190 90—115 1783, 1667 1786, 1681 1626 1786, 1681 1626 1778 1785, 1680 1770, 1695 1770, 1695 1785, 1695 il785, 1670 1770, 1670 1785, 1670 1770, 1695 1770, 1695 1770, T680 I18OO, 1600 1700, 1685 1785, 1670 1785, 1680 1785, 1680 6 <0.1 0.1 0.004 <0.1 <0.1 0.2 <0.1 <0.1 0.2 1.56 6.25 <0.1 50 <0.1 1 7 3 3 3 3 3 1 3 3 3 3 3 3 1.3 4 ^ 31 3 195 * 4? 61 «2 Table III cont. 1. 1 C6H5 — CH — CO— 1 NH — CO — CO — OC6H5 C6H5 — CH — CO— l 1 NH — CO — O — OH2C6H5 formula 55 C6H5 — CH — CO— i 1 | NH — CO— 1 c — fH P-TT 4 PI 1 CO 2 H C6H5 — CH — CO— and 1 NH — CO — CH2— —NH — CO — NH — C = NH J 4 — C1C «H4 — CH2 C8H5 — CH —CO— ii NH — CO — CH2 — NH — CO— —NH — C — CflH5 NH C6H5 — CH — CO— ii NH — GO — CH2 — NH — CO— —NH — C — CaH4 — OCH, NH 1 C6H5 —CH — CO— iii NH — CO — CH2 — C6H5 C "H5 — CH — CO— I and NH — CO — C" H5 C "H5 — CH — CO— | NH — CO — CH, C "H5 — CH — CO— 1 NH — CO — CH2 / CH2 / 2CH, formula 56 formula 57 formula 58 formula 59 formula 60 C8H5 — CH — CO— ii NH — CO — CH2 — C8H4- ^ 4 — Br CflH5 — CH — CO— 1 and NH — CO — CH2 — C8H4— - ^ l — OCH, formula 61 * * 2 III III VI VI XII XII XII III III III III III III III III III III III 3 60 55 71 50 45 64 77 65 74 74 73 88 69 62 58 75 70 52 4 160—169 160—165 168—174 130—140 145—165 140—160 146 — L 60 143 ^ 165 a30 — '1 & 5 134 ^ 148 164 ^ 185 170—195 140—162 134 — T50 160—180 1785, 1725 1600 1785, 1680 1780, 1660 1600 1780, 1670 1780 1775 ^ 75 1800, 1655 1785, 1640 1790, 11655 1795, 1695 1660 1795, 1665 1800, 1695 1640 1795, 1655 1785, 1660 1600 1795, 1695 1640 1800, 1647 1798, 1652 1795, 1666 1 « <: o, i <0.1 <0.1 0.78 1.56 <0.1 0.78 0.39 0.1 <0.1 0.1 <0.1 0.2 0.1 3.12 1 7 1 3 3 3 3 <1 & 5T47 ** 64 Table III cont. 1 1 1 C6H5 — CH — CO— and 1 NH — CO — CH2 — C6H4 - ^ - NO2 formula 62 C6H5 — CH — CO— and 1 NH — CO — C6H4 - ^ - NO2 C6H5 — CH — CO— and 1 NH —CO — CH2 — OC6H5 C6H5 — CH — CO— 1 NH — CO — CH2 — CN C6H5 — CH — CO— 1 NH — CO — CH2 — Ns C6H5 — CH — CO— 1 N = CH = N / CH3 / 2 4 — HOC6H4 — CH — CO— 1 N = CH — iN / CH8 / 2 2 III III III III III III XXIII XXIII 1 1 3 49 73 81 77 41 90 17 1 4 145—170 165—184 160—178 120— 128 135—145 138—147 1 1795, 1653 1795, 1653 1795, 1653 1795, 1667 2250, 1790 1667 21110, 1795 1667 1T86, 1710 1652 1786, 1715 1652 6 <0, T <0.1 0.004 0.004 0.004 0.2 <0.1? <0.1 1 7 3 3 1. The MIC value / minimum concentration of inhiibi-Long et al., Journal of the Chemical Society, suppressing / for this compound was determined relative to 30 / London /, part C, 1920/1971 /. Staiphyllococcus aureus strain. m 3. The compound was isolated as the tri-2 salt. The starting enamines were obtained via the condensate. ? sations of the corresponding amino acids with methacetate 4. The compound was isolated in the form of a sodium or ethyl salt using the methods given in Table IV Compound of formula 4 1 R1 1 1 C6H5 — CH — CO— 1 NH — CO — CH2 — NH - ^ sb2 — ch3 C6H5 — CH — CO— 1 NH — CO — CH2 — NH— —SO2 — C6H5 C6H5 — CH — CO— 1 NH — CO — CH2 — NH— —SO2 — CH2C6H5 formula 63 ^ C6H5 — CH— CO— 1 NH — CO — CH2 — NH— —CO — CH8 1 CH * —CH — CO— 1 NH — CO — CH2 — NH— —CO — CHaCHg] j Synthesis method / example no. / ° / o 2 | 3 II II II II December December 37 56 29 42 59 58 Melting point ° C 4 93-125 120-144 130-12152 1128-150 135-442 (1148-153 IR, cm -1 1 5 1780 1790 1760 1780 1780 1790 • 1 MIC fig / md 6 <0.1 <0.1 <0.1Note 7 195 747 65 66 Table IV continued ; 1 | 1 1 NH — CO — CH * - ^ NH — CO— —c8h4 - ^ - a CfiH5 — CH — CO— 1 and NH — CO — CH2 — NH — CO— —C6H4 - ^ - NO2 C6H5 — CH — CO— ii NH — CO — CH2 — NH — CO— n TT 4 OPTT. 1 V ^ gXl4 "r ^ -A ^ J ^ -thij C6H5 — CH — CO— l 1 NH — CO — CH2- ^ NH— —C — CH2 — C6H4 ^^ - C1 II NH C6H5 — CH — CO— and 1 NH — CO — CH2— —NH — C — C6H4—4 — NO2 NHi C6H5 — CH — CO— and 1 | NH — CO — CH2 — NH— and _c — C6H4—3 ^ SONH2 NH C6H5 — CH — CO— 1 l | NH — CO — CH2 — NH— 1 —C — C6H4—3 — ON W NH formula 64 formula 65 C6H5 — CH — CO—! NH — CO — CH2 — NH— —C — C6H3—3 — CN— 5 — I NH formula 66 C6H5 — CH — CO— ii NH — CO — CH2 — NH— —C — C6H4—3 — CONH2 NH formula 67 C6H5 — CH — CO— and 1 NH — CO — CH2 — NH— —C —C6H3—3,5 - / $ 02NH2 / 2 NH C6H5 — CH — CO— 1 1 NH — CO — CH2 — NH— 2 1 XII 1 XII XII XIV XIV XIV XIV XIV XIV XIV XIV XIV XIV XIV XIV _? 1 67 1 67 54 45 82 51 75 59 49 58 53 81 83 31 71 4 I '. 180—185 155—! Lfe4 151 — il58 192 * ¦ 197 180—185 180—185 126—140 149—169 185-H192 197 —200 »| 1790 1 1780 1780 1770 1770 1780 1785 1785 1785 17180 1785 1785 1785 1770, 1667 1770, 1667 * 1 <0.1 0.1 0.2 <0.1 <0.1 6.25 <0.1 0.78 <0.1 0.1 <0.1 50 0.004 0.004 7 '1 195 747 ST 68 Table III continued' * —C — C6H, —3 — SOjNHa — 5 — Cl li NH CeHj — CH — CO— 1 NH — CO — CH * —NH— —C — C5H, —3 — Cl — 5 — CN 1 'NH formula 68 C8Hs — CH — CO— 1 and NH — CO — CH2 — NH— —C — C6H, —3- ^ SOiNH ^ —5 — Br 1 'NH formula 69 C6H5 — CH — CO— and NH — OO — CH ^ - ^ NH — CO— —NH — CH2CH8 CeHg — CH — CO-- 1 i NH — CO — CH * —NH — CO— —NHCbHb C ^ Hg — CH — CO— 1 i 'NH — CO — CHjj — NH— CO— —NHCE, C ^ Hg — CH — CO— 1 Nn — CO — CH2 — N = CH— -N / CH, / 2 1 formula 70.C6H5 — CH — CO— ii NH — CO — CH ^ NH— CO— -CH2CH, CH8 CJeHB — CH — CO— 1 ii NH — CO — CH2- ^ NH — CO— —OCH2CH8 C6H5 — CH — CO— and 1 ii NH — CO — CHj-hNH — CO— -OCH ^ CeHs formula 71 CeHg — CH ^ CO— iii NH — CO — CH ^ NH— - -C — CaH, —3.5 — Br2 1 NH * formula 72 C6H5 — CH — CO— and NH — CO — CH2 — NH— - C ^ CH, I1 NH formula 73 2 XIV and XIV • XIV «XIV XV XV XV XXIII XXIII XII XII XII XIV XIV XIV XIV XIV 3 73 73 78 80 49 38 33 29 43 60 40 65 60 32 69 22 4 203 199 196 —200 195 162 1'58 154 120—132 131 — H38 123—128 193 195 185 185 200 1786, 1681 1786, 1667 1786, H681% 1775 1785 1780 1785 1760, 1715 1667 1780, 1695 1785 1780 1760 1770 1775 1770 1775 1770 1 6 0.004 0.39 0.004 &Lt; 0yl 6.25 1.56 <0.1 0.39 <0.1 1.56 1.56 <0yl 1 7 1 ^ 2 9 1.3 1.3 1 195 747 69 70 1. The MIC value / minimum concentration of inhibitylformamide, and the product was isolated by adding a large volume of ether and saturating to the reaction mixture / for this compound it was determined in to a strain of Staphylococcus aureus. step by step filtering out the product. 3. The compound was isolated in the form of a triethyl-2 salt. N, N-dinnine-5amine was used as a solvent. Table V Compound of formula 4 R1 and C6H5 — CH — CO— 1 1 NH — CO — CH2CH2 — NH — CO — C6H5 C6H5 — CH — CO— 1 l MW PO CR PH NH PO P-TT 4 PI C6H5 — CH — CO— 1 1 NH — CO — CH2CH2 — NH — CO — C6H4—3 — Cl formula 74 C6H5 — CH — CO— and NH — CO — CH2CH2 — NH — CO — CH8 C6H5 — CH — CO— 1 1 NH — CO — CH2CH2 — NH — C — C6H5 II NH C6H5 — CH — CO— il NH — CO — CH2CH2 — NH — C— C6H, - E, 5 — Br2 NH C6H5 — CH — CO— 1 NH — CO — CH2CH2 — NH — C — CH8 II NH C6H5 — CH — CO— and 1 µl NH — CO — CHssCHj- ^ NH — C —CgHj — 3,5 — Cl2 II NH C6H5 — CH — CO— i 1 'tsjh after PH «PH NH P CR C ~ T1 4 PI ± y JTL — v • v • ^^^» xl2 ^ xl2 ^^ • '¦ ^ - ^ ^ v * ^ i £ - 6 "^^ 4» * i NH formula 75 formula 76 formula 77 (Synthesis method / example number / 2 XII XII XII XII XII XIV XIV XIV XIV XIV XIV XIV XIV Efficiency 3 43 63 57 34 33 74 82 70 81 86. 63 82 78 IR, cm "1 4 1780 1785 1785 il780 1780 1765 1770 1770 1770 1770 1765 1770 1775 MIC lig / nU« U <0.1 3.12 <0.1 0.78 1.56 <0 ', 1 3.12 <0.195 747 71 72 Table VI Compounds of formula 4 - BP 1 formula 78 formula 79 CjH5 — CH — CO— NHOH3 1. 1 NH — CO — CH2- ^ S — C = NOH8 formula 80 CjHg — CH - CO— NHCH2CH8 1 1 NH — CO — CHg — S — C — NCH ^ CH, C ^ Hg — CH — CO ^ NHCH ^ CH ^ CHs 1 • 1 NH — CO — CH2- ^ S — C = NCH2 / CH2 / 2CH8 formula 61 CeH5 — CH — CO— NH2 1 1 NH — CO — CHj- ^ S — C = NH formula 82 CaHj — CH — CO— NH 1 "D NH — CO — NH — CHj — CO- ^ S — C — NH2 C6H6 —CH — CO— NCH2CH8 1. II NH — CO — NH — CO — CHg — S — C— —NHCH2CH8 Yield f / o 2 33 73 37 62 88 41 50-61 92 32 Melting point ° C 3 182—198 166—175 240- ^ 250 150—-190 172—178 155—170 177—185 193—21.1 IR cm-1 4 1780, 1667 1785, 1667 1775, 1667 1770, 1667 1770, 1667 1775, 1667 1785, 1667 1780, 1670 1780, 1660 1780, 1670 MIC pgfttil 100 <0.1 0.004 <0.1 0.004 «0.004 0.1 0.004 0.2 0.004 0.004 Notes 6 1 2 3 3 3 3 3 3 Tylo-3- [2- / 2H-Trimethylacitoxymethyl / Htetrazolyl--5] penaim, For a stirred suspension 10.0 g (0.0264 mol) of sodium 6- (2-phenylacetamido) -2,2-dimethyl-3- (tetrazolyl-5) penam in 105 ml of acetone was added 2.6 ml of 25% aqueous sodium iodide solution, and then 4. 35 g (0.0290 mol) of chlorTomethyl trimethylacetate. The mixture was heated to reflux for 4.5 hours, then cooled to room temperature. 100 ml of water was added to the mixture and the resulting suspension was extracted with ethyl acetate. The extracts were dried and evaporated to give 6.3 g of a white foam. The MIC value / minimum inhibitory concentration / mixtures of the compounds of the example against Streptococcus pyogenes was 0.2 µg / wt. The white foam was re-dissolved in a small volume of a mixture of chloroform and ethyl acetate in the ratio 80:20 and absorbed in the chromatography column filled with 180 g of silica gel. The column was eluted with an 80:20 mixture of chloroform and ethyl acetate collecting the individual fractions. Each fraction consisted of 700 drops of solvent. Fractions 55-95 were combined and evaporated to dryness to give 2.03 g of (6- (2-phenylacetamido) -2,2,2-dimethyl-3- [2- (p-trimethylacetoxymethyl) -tetrazolyl-5] penam. Infrared absorption band / KBr, pellet /: 1785, 1760, 1670 and -1515 cm "1. MBJ spectrum / in DMSO-de / - Notes: 1. The MIC value / minimum inhibitory concentration / for this compound was determined relative to the jaws Staphylococcus aureus 2. The starting material was 6- (2-f2Hbromoace-40 toamido] -2-phenylacetamido / -2y2-dimethyl-3- / tetrazolyl-5 / pename. 3. The starting material was 6- / 2- [ 2-Chloroacetamido] -2-phenylacetamido (-2,2-dimethyl-3- (trazolyl-5) penam. 45 Example XXX The compounds listed in Table VI were prepared by either 6- [D-2-) 2-bromoacetamido (-2-phenylacetamido] -2,2-dimethyl-3- (tetrazolyl-5) penam, 6- [D-2- (2-chloroacetamido) -2-phenylacetamido] -2, 2-dimethyl-3- (tetrazolyl-5) penam or 6- {D-2- [3- (2-chloroacetyl) -ureido] -2-phenylacetamido} -2,2-dimethyl-3-) tetrazolyl-5 / penam with an appropriate thiamide or thiourea derivative according to the method described in example XVII 55 Table VI also shows the minimum inhibitory concentration / value and MIC / compounds given against strains of Streptococcus pyogenes. The structure of the compounds in question has been confirmed by nuclear magnetic resonance spectroscopy. Example XXXI. 6- (2H-phenylacetamido / -2,2-dimethyl-3-Hl- (trimethylacetoxymethyl) -tetrazolyl-5] penam and 6- (2-phenylacetamido) -2,2-dimethyl 65 • 5 747 nu / r20 (7.50 (s, 5H), 6.70 (s, 2H), 6.00-5.60 (m, 2H), 3.85 (s, 2H), 1.65 (s, 3H) , 1.36 (s, 9H) and 1.20 (s, 3H) ppm. Fractions 100 to 164 were combined and evaporated to dryness to give 0.80 g of 6- (2-phenyl-acetamido) -2,2-dimethyl-3- [1- (trimethylacetoxymethyl) -tetrazolyl-5. ] penamu. Infrared absorption bands (KBr, pellet): 1780, 1760, 1670 and 1515 cm-1. NMR spectrum / in DM1SO-d6 (D * 0): 7.50 (s, 5H), 6.80 (s, 2H), 6.50 (s, 2H), 5.60 (s, 1H), 3 , 85 (s, 2H), ii, 75 (s, 3H), 1.36 (s, 9H) and 1.34 (s, 3H), ppm. Example 1 Example XXXII, 6-amino-2, 2-dimethyl-3 - [2- (4-6 µMeAlyaceitoxyimethyl) -tetrazolyl-5) -penam. To vigorously stirred a solution of 0.932 g (7.21 mmol) quinoline in 0.840 g (4.05 mmol) phosphorus pentachloride. The suspension was cooled to 15 ° C and 1.81 g (3.84 mmol) 6- (2-phenylacetamido) -2,2-dimethyl-3- [2- (trimethylacetoxymethyl) was added. / -Jtetrazolyl-5 / pena'mu. Stirring was continued for a further 30 minutes at -5 ° C., and then 2.15 g (35.7 mmol) of n-propanol was added. Stirring was continued for a further minutes at about -5 ° C, then 25 ml of a 90:10 mixture of isopropyl ether / acetone was added, followed immediately by a solution of 1.35 g of sodium chloride 6.02 ml in water. The temperature was raised to 15 ° C and then lowered to -15 ° C again. The resulting precipitate was filtered off and dried to give 1.33 g (88% yield) of 6-amino-2,2-dimethyl-3- - {2- (trimethylacetoxymethyl) -tetrazolyl-5-penammonium hydrochloride. The infrared spectrum (KBr, pellet) showed absorption bands at 1785 cm -1 (β-lactam) and 1750 cm -1 (ester). NMR spectrum (in DMSO-d6) showed absorption at 6.70 ppm / s, 2H, trimethylacetoxymephthyl hydrogens /, 5.75 ppm / d, 1H, hydrogen C-5 /, 5.50 ppm / s, 1H, hydrogen C-3), 5.70 ppm / d, 1H, C-6 hydrogen, 1.75 ppm / s, 3H, C-2 methyl hydrogens, 1.20 ppm / s, 9H, tertiary hydrogens. - -butyl (1.10 ppm / s, 3H, C-2 methyl hydrogens). Example XXXIII. 6-amino-2,2-dimethyl-3- [1 (triethylacetoxyimethyl) -tetrazolyl-Slpenam. The example compound was obtained in the form of the hydrochloride in a yield of 90% of 6- (2-phenyloacetamido). 2,2H-Dimethyl-3- [1 (trimethylacetoxymethyl) -tetrazolyl-5] penam using the method described in Example XXXII. Infrared absorption bands (KBr, pellet): 1780 cm "1 (µl-lactam) and 1740 cm -1 (ester). NMR spectrum (MSG-d6): 6.71 ppm / s, EH /, 5.88 ppm / s, 1H /, 50, 83 ppm / d, IH /, 5 ^ 0 / d, 1H /, 1.80 ppm / s, 3H /, 1.26 ppm / s, OH / , and 1.16 ppm / s, 3H). Example XXXIV 6- [D-2-amino-2- (p-hydroxyphenyl) -acetamido] -2.2- dimethyl-8- [2- (triethyl) - tyloacetoxymethyl / -tetrazolyl-5] penamine. For a stirred suspension of 287 mg / 1.0 mmol / N- - (2-methoxycarbonyl-.1-methylvinyl) -D-2-amino- - E - / p-hydroxyphenyl) - of sodium acetate (Long et al. Journal of the Chemical Society (London), Part C, I "20/1071) and 1 drop of N-methylmorpholine in 6 ml of ethyl acetate were added 0.97 ml (1.03 mmol) of ethyl chloroformate in at -15 ° C. Stirring was continued for a further 30 minutes at this temperature. The mixture was then added 45 06 to the pre-cooled (to -15 ° C) suspension of 300.5 mg / 1.0 mmol / 6-amino-2,2-hydrochloride. dimethyl, lo-3- [2- (trimethylacetofcsylmethyl)] tetrazolyl-5] penam in 2 ml of ethyl acetate containing 101 mg (1.0 mmol) of triethylamine. The reaction mixture was vigorously stirred at -15 ° C for 1 hour, then at 5 ° C for 1 hour. The ethyl acetate was removed by evaporation under reduced pressure and the resulting white solid was suspended in 10 ml of a 1: 1 mixture of water and tetrahydrofuran. The slurry was cooled to 0 ° C and then adjusted to pH 2.1. The slurry was stirred at 0 ° C. for a period of 45 minutes, with the subsequent addition of acid to maintain the pH at 2.1. The p-tetrahydrofuran was then removed by evaporation under reduced pressure, the remaining aqueous phase was saturated with sodium chloride and the product was extracted with ethyl acetate. The ethyl acetate layer was dried and evaporated under reduced pressure to give, after trituration of the residue with ether, 425 mg (yield 8%) 6- (D--2-amino-2- (p-hydroxyphenyl) -acetamido] -2 hydrochloride. 2-dimethyl-3- [2- (trimethylacetoxymethyl) -tetrazolyl- -5] penam. Infrared absorption bands (KBr, pellet): 1780 cm-1/0-latetam /, 1755 cm-1 (ester), 1682 cm-1 / I amide band / The NMR spectrum / in DMSO-d6 / showed absorption at 7.09 ppm / q, 4H /, aromatic hydrogens /, 6.59 ppm / s, 2H, methylene in the trimethylacetoxy group / , 52 ppm / m, C-5 and C-6 hydrogens /, 5.22 ppm / s, 1H, side-chain methine hydrogens /, 5.00 ppm / s, IH, C-3 hydrotreater /, 1, 47 ppm / s, 3H, C-2 methyl hydrogen, 1.0 ppm / s, 9H, tertiary butyl hydrogens) and 0.96 ppm / s, 3H, C-2 methyl hydrogens. The MIC / minimum inhibitory concentration * for this compound against the strain Streptococcus pyogenes was 0.39 µg / ml. Example XXXV. 6- [D-2-amino-2- (p-hydroxyphenyl) -acetamido] -2.2 -dimethyl-3- [1- (trimethylol) cetoxy-methyl) -tetrazolyl-5] penamine. The compound of the example was obtained in the form of the hydrochloride in a yield of 50% of 6-amino-2 ^ 2-dimethyl-3- [1- (trimethylacetoxy-methyl) -tetrazolyl- 5] penam, using the method described in example XXXIV. Infrared absorption bands (KBr, pellet): 1780 cm -1 (0-lafctam) and 1680 cm -1 (amide band). NMR spectrum (in DMSO-d6): 7.09 ppm / q. 4H /, 6.55 ppm / s, 2H /, 5.61 ppm / m, 3H /, 5.06 ppm / s, IH /, 1.55 ppm / s, 3H /, 1 ^ 10 ppm / s, 3H /. 1.10 ppm / s, 9H) and 1.03 ppm / s, 3H). Example XXXVI. 6- (2-phenylacetamido) -2,2- -dijmethyl-3- [1- [2] - (1-acetoxyethyl) -tetrazolyl -5] penam. Reaction of the sodium salt of 6- (2-phenylacetamido) -2 2-Dimethyl-3- (tetrazolium-5) penaim with 1-acetoxyethyl chloride was obtained using the method described in Example XXXI in a yield of 28% of the compound (subject of the example) in the form of a mixture of isomers. The melting point of the mixture was 55-70 ° C. Infrared absorption bands (KBr, pellet): 1780, 1770, 1670 and 1515 * 5-47 75 76 µt-1. MftJ spectrum (in CDCW: 7.20 (s, 6H), 6.25 (m, 1H), 5.75 - 5.40 (m, 2H), 5.20 (s, 1H), 3.60 (s, 2H), 2.00 (m, 6H), 1.45 (s, 3H) and 0.95 (s, 3H) ppm. Example XXXVII. 6- (2H-phenylacetamido) - -2,2-dimethyl-3- [1- (2] - / phthalidyl-3) -tetrazolyl-, 5] penam. Reactions of 6- (2-phenylacetamido) sodium salt -2.2- -Dimethyl-3- (tetrazolyl-5) pearam with 3-bromophthalide was carried out as described in Example XXXI, obtaining the compound of the example in the form of a mixture of isomers with a melting point of 70 ° 85 ° C, with a yield of 9 -1 ° (o. Infrared absorption bands (KBr, palette): 1785, 1675 and 1500 cm-1. MRJ spectrum (in CDCl1,): 8.05-7.10 (m, 9H), 6 , 55-6.20 (m, 2H), 5.80 (m, 1H), 3.60 (s, 2H), 1.60 (s, 3H) and 1.00 (s, 3H) ppm. XXXVIII. 6- (2-phenylacetamido) - -2,2-dimethyl-3- [1- (4-benzyloxytenzyl) -tetrazolyl-5] pename. For a vigorously stirred solution of 180 g of 6-amino-2, 2-diinethyl-3- [1- (4-benzyloxybenzyl) -tetrazolyl-5] penam in 4 ml of chloroform was added at room temperature to 0.038 ml of pyridine, followed by 0.057 ml of phenylacetyl chloride. Stirring was continued for a further 25 minutes. and then dilute the reaction mixture It was mixed with 25 ml of chloroform, then washed with water. The organic layer was dried over anhydrous magnesium sulfate and evaporated in vacuo. The residual was 209 µg (yield: 86%). 6- (2-phenylacetamido) -2,2-dimethyl-3- [1- [4-4] benzene. zyloxybenzyl) -tetrazolyl-5] penam. The NMR spectrum (in CDCl *) showed absorption (m, aromatic hydrogens), 6.4 ppm / d, amide hydrogen, 5.80-5.20 ppm / m, benzyl hydrogens and C-6 and C-hydrogens 5), 5.10 ppm / s, C-3 hydrogen, 0.05 ppm / s, benzyl hydrogens (3.60 ppm / s, phenylacetylmethyl hydrogens), 1.30 ppm / s, C-methylene hydrogens 2) and 0.85 ppm / s, C-2 (R) methylene hydrogens, example XXXIX. 6- (2-phenylacetamido) - -2,2-dimethyl-3- (tetrazolyl-5) penaim. For a vigorously stirred suspension 2.4 g 6-amino-2,2-dimethyl-3- (tetrazolyl) - 5 / penam in 50 ml of chloroform was added to 4.2 ml of triethylamine. Stirring was continued for a further 15 minutes and then the solution thus obtained was cooled to 0 ° C. 2.16 g of trimethylsilyl chloride was then added to the solution. The cooling bath was removed and the reaction mixture was vigorously stirred at room temperature for 1 hour, then heated to reflux for a further hour. Cooled to room temperature to give a chloroform solution of the bis-trimethylsilyl derivative of 6-amino. - -2,2-dimethyl-3- (tetrazolyl-5) penam. This solution was cooled to 0 ° C and 1.72 g of phenoxyacetyl chloride was added dropwise with stirring. The cooling bath was removed and the mixture was stirred. The chloroform layer was washed with water, dried with anhydrous sodium sulfate and then evaporated to dryness under reduced pressure. The crude 6- (phenoxyacetainin) to (H 2, 2, dimethyl-3) was thus obtained. - (tetrazolyl-5) pename Example XL 8- [D-2-amino-2- - (4-hydroxyphenyl) -acetamido] -2,2-dimethyl-3- (tetrazolyl-5) penam potassium salt. To a vigorously stirred solution, 1.94 g of 6- [D- -2-amino-2- (4-hydroxyphenyl) -acetamido] -2.2- tetrol-3- (tetrazolyl-5) penam in 100 ml of methanol, cooled to -30 ° C, was added dropwise 5 ml of a 1.0 N solution of potassium hydroxide in methanol. The mixture was allowed to warm to 0 ° C and then added dropwise with stirring to 700 ml of ether. The precipitated body was permanently removed by filtration and dried under high vacuum. This resulted in 1.65 g (76% yield) of the potassium salt of the compound of the example having a melting point of 185 ° C. (decomposition). Using the above method, but replaced by PUJ3C. Potassium equimolar amount of sodium hydroxide was obtained as the product, sodium salt 6- [D-2-amino-2- (4-hydroxyphenyiZ-acetamino] -1,2,2-dimethyl-3n (tetrazolyl-5) penam. Example XLI. 6- (D-2-amino--2-phenylacetamido) -2,2-dimethyl-3- (Itetrazoli'l- -5) penam hydrochloride. Suspension 50 mg 6- (D-2-amino-2-phenylacetami-) The (-2.2-dimethyl-3- (tetrazolyl-penam) in 2 ml of ionized water was stirred vigorously for 5 minutes at room temperature, and the mixture was then adjusted to pH 2.45 with dilute hydrochloric acid. The solution thus obtained was immediately lyophilized, yielding 52 mg of 6- (D-2-amino--2-phenylacetamido) -2,2-dVumethyl-3- (tetrazolyl--5) penam hydrochloride in the form of a crayfish solid. . PL

Claims (6)

Claims 1. Process for the preparation of new peptide derivatives of formula 83, optionally in the form of a salt, wherein R1 is an acyl group of an organic carboxylic acid of formula 12, wherein n is 0 or 1, R7 is a hydrogen atom, an alkyl radical containing 1-4 carbon atoms, alkenyl radical containing 2-4 carbon atoms, cycloalkyl radical containing 3-7 carbon atoms, cyclohexenyl radical, cytolhexadiene-1,4-yl radical, 1-aminocycloalkyl radical containing 4-7 carbon atoms , cyanomethyl radical, 2,6-dVu (alkoxy) phenyl radical, containing 1-4 carbon atoms in the alkoxy group, 5H-methyl-3-phenylisoxalyl-4 radical, 5-methyl-3- (o-chlorophenyl) radical (isoxalyl-4, 5-methyl-3- (2,6-dichlorophenyl) isoxalyl-4 radical, 5-methyl-3- (2-chloro-6-fluorophenyl) isoxalyl-4 radical, 2-alkoxyl-1 radical -naphthyl having 1-4 carbon atoms in the alkoxy group, sidinonyl-3 radical, tetrazolyl radical, optionally substituted y a phenyl radical, an optionally substituted phenoxy radical, an optionally substituted phenylthio radical, an optionally substituted pyridylthio radical, an optionally substituted thienyl radical, an optionally substituted furyl radical, an optionally substituted pyridyl radical, an optionally substituted thiazolyl radical, or -MU1 Tl 7 * tuain an optionally substituted isothiazolyl radical, an optionally substituted triazolyl radical, an optionally substituted imidazolyl radical or an optionally substituted pyrazolyl radical, each of these radicals being substituted with up to 2 substituents, such as a fluorine atom, chlorine or bromine, hydroxyl, amino, alkyl, alkoxy or alkylthio containing 1-4 carbon atoms, and Q is hydrogen, alkyl containing 1-4 carbon atoms, amino group, aminomethyl group, hydroxyl group, carboxyl group, sulfo group, sulfoamino group, carboxamide group, 2-aminoacetamide group, 3- (2-formamidino) -1 -uredd, 2-guanidinoacetamide group, azide group, optionally substituted phenoxycarfoonyl radical, indanyloxyicarbonyl radical, 2- (2-phenyl-1-formamidine / acetamide group, 2 ^ group [2 - / substituted phenyl) -1-formamidine] -acetamide, 2- [2- (disubstituted phenyl) -1-formamidino] acetamide group, igrupe 2- (2-pyridyl--1-formamidine / aoethamide, 2- / group) 2-furyl-1- formamidine / acetamide or a 2- (2-thienyl-formamidine / acetamide group) with the substituents of each of the radicals being a fluorine, chlorine or bromine atom, a hydroxyl group, an alkyl group, an alkoxy group, or an alkylthio group containing 1-4 carbon atoms, where if R7 is a 1-aminocycloalkyl radical, when R7 is an optionally substituted phenoxy radical, an optionally substituted phenylthio radical or an optionally substituted pyridylthio radical, n = 1, then Q is a hydrogen atom , an aminomethyl group, a carboxyl group, a sulfo group, a carboxamide group, or the unically substituted phenoxycarfoonyl or indanyloxycarpoonyl radical, and Rz of formula 83 represents a tetrazoyl group of formula II or formula III, in which the formula R * represents a hydrogen atom, a trialkylsilyl group containing 1-4 carbon atoms in each of the alkyl groups, an alkanoyloxymethyl group containing 3 to 8 carbon atoms or a benzyl group, a substituted alkoxy or alkanoyloxy group containing 1 to 4 carbon atoms, a hydroxyl group, a trimethylsilyloxy group containing a hydrogen atom, and R e * trialkylsilyl in which each of the alkyl groups contains 1-4 carbon atoms or a 1-alkanoyloxymethyl group containing 1-4 carbon atoms in the alkyl group, characterized in that the compound of formula 84 or its silylated derivative salt is acylated organic acid. 2. The method according to claim A compound according to claim 1, characterized in that the acylation is carried out on the silylated derivative of penim of formula 84, wherein Rz is as defined in claim 1. Claim 1 having a trialkylsilylamino group in the 6-position, each of the alkyl groups having 1-4 carbon atoms. 3. Process for the preparation of the new peptide derivatives of formula 83, optionally in the form of a salt, in which R1 is an acyl group of an organic carboxylic acid of formula 12, in which n is 0 or 1, R7 is an alkyl or alkenyl radical containing 5-12 carbon atoms , a cycloalkenyl radical containing 5, 7 or 8 carbon atoms, a cycloheptatrienyl radical, a sydnonyl radical, an optionally substituted benzyl radical, or an optionally substituted pyrimidinyl radical, each of these radicals having up to 2 substituents such as a fluorine atom. chlorine or bromine, hydroxy, hydroxymethyl, amino, N, N-dialkylamino groups containing 1-4 to 4 carbon atoms in each alkyl group, amino methyl, aminoethyl, 2-aminoethoxy, alkyl, alkoxy , alkylthiolo N-αKkylamino containing 1-4 carbon atoms, and Q is hydrogen, alkyl radical containing 1-6 carbon atoms, hydroxyl, azide, carboxyl o, sulfo group, carfoamyl group, phenoxycarfoonyl group, indanyloxycarbonyl group, sulfamino group, aminomethyl group, amino group, or group of formula NH— / CO — CH * —NH / m — CO — Z, in which, Z is the group alkyl with% - ** & carbon atoms, optionally substituted phenyl group, furyl group, thienyl group, pyridyl group, pyrrolyl group, amino group, N-alkylamino group containing 1-6 carbon atoms, optionally substituted group anilino group, guanidine group, acylamino group containing 2 to 7 carbon atoms, optionally substituted benzamide group, thiophenoc tfoxyamide group, furanecarboxamide group, pyridine carboxamide group, aminomethyl group, guanidinomethyl-4-carboxamidomethyl group * carbon atoms, benzamide methyl group optionally substituted in the new foenzamide part, thiophenocarfoxyamidinomethyl group, furanecarboxamidinomethyl group, pyridine carboxamidinomethyl group This, a pyrrolecarboxamidinomethyl group or a benzimidazole carboxamidinomethyl group, each of the substituted groups having up to 2 substituents such as fluorine, chlorine, ¦ bromine or iodine, an alkyl or alkoxy group containing 1-4 carbon atoms, sulfamyl or carbamyl groups P-cyano, m is 0 or 1, and Rz is we. Formula 83 is a tetrazoyl group of Formula II or Formula III, in which formulas R1 and R1 are hydrogen, a trialkylsilyl group containing 1-4 carbon atoms in each alkyl group, an alkanoyloxymethyl group containing 3 to 8 carbon atoms, 1- (alkanoyloxy) ethyl rupee containing 4-9 carbon atoms, 'phthalidyl or nitrogen protecting group in the tetrazoylpenam system, easy to remove from the compound of formula 83, characterized in that the compound with Formula 84, or a salt of a silylated derivative thereof is acylated with an organic acid. 4. The method according to p. A process according to claim 3, characterized in that the acylation is carried out on the silylated peptide derivative of formula 84, in which Rz is as defined in Claim 3. 3, containing a trialkylsilylamino group in the 6-position, each alkyl group containing 1-4 carbon atoms. 5. Process for the preparation of new peptide derivatives of formula 83, optionally in the form of a salt in 10 15 20 25 30 35 and 40 45 50 55 6095 747 79 * # wherein R 1 is the acyl group of the organic cartoxylic acid of formula 12 in which n is 0 or 1, R7 represents a hydrogen atom, an alkyl radical of 1-4 carbon atoms, an alkenyl radical of 2-4 carbon atoms, a cycloalkyl radical of 3-7 carbon atoms, a cyclohexenyl radical, a cyclohexadiene--1,4-yl radical , 1-aminocycloalkyl radical containing 4-7 carbon atoms, cyanomethyl radical, 2,6-di (alkoxy) phenyl radical containing 1-4 carbon atoms in the alkoxy group, 5-methyl-3-phenylisoxalyl-4 radical, 5-radical -methyl-3- (o-chloro-phenyl / isoxalyl-4, 5-methyl-3- (2,6-dichlorophenyl) isoxalyl-4, 5--methyl-3- (2-chloro-6-fluoxQ-phenyl) radical (isoxyalkyl-4, 2-alkoxy-1-naphthyl radical with 1-4 carbon atoms in the alkoxy group, sydnonyl-3, tetrazolyl radical, optionally that a substituted phenyl radical, an optionally substituted phenoxy radical, an optionally substituted phenyl radical, an optionally substituted pyridyl radical, an optionally substituted thienyl radical, an optionally substituted fur Io radical, an optionally substituted pyridyl radical, an optionally substituted thiazolyl radical, an optionally substituted isothiazolyl radical, an optionally substituted triazolyl radical, an optionally substituted imidazolyl radical or an optionally substituted pyrazolyl radical, each of these radicals being substituted with up to 2 substituents such as fluorine, chlorine or bromine, hydroxyl, amino, alkyl, atf-hydroxy, butealkylthio containing 1-4 carbon atoms, and Q is an alkyl radical of 5 or 6 carbon atoms, carbamyl group, and a group of formula NH— / CO — CHg— —J * H / m —CO-2 Z, in which Z is an alkyl group containing 1-6 carbon atoms, optionally substituted phenyl group, furyl group a thienyl group, a pyridyl group, a pyrrolyl group, an amino group, an N-alkylamino group with 1 to 6 carbon atoms, an optionally substituted anilino group, a guanidino group, an acyl-amino group with 2 to 7 carbon atoms, possibly - optionally substituted benzamide group, thiophenecarboxamide group, furanecarboxamide group, pyridine carboxamide group, aminomethyl group, guanidinomethyl group, alkanoicartoxyamidinomethyl group, thiophenemethylmethyl thiophenemethyl thiophene methylsubstituted thiophene methyl atoms , a furanecarboxamidyinomethyl group, a pyridine-carboxyamidinomethyl group, a pyrrolocariboxamidinomethyl group, or a benzimidazole-carboxyamidinomethyl group, or a benzimidazole-carboxyamidinomethyl group, with each of the two substituted fluoro groups substituted for each of the chlorine at most 2 iodine, alkyl group solder 1-4 carbon alkoxy, sulfamyl, cartoamyl, or cyano, and n1 is 0 or 1, whereby if R7 is 1-aminocycloalkyl then n = 0 and R7 is optionally substituted phenoxy an optionally substituted phenylthio radical or an optionally substituted pyridylthio radical, an-1, then Q is an alkyl radical containing 5, 6, 6 carbon atoms, or a cartoamyl group, and Rz in formula 83 is a tetrazoyl giupe of formula II or Formula 3, in which the formulas R * and R * represent a hydrogen atom, a trialkylsilyl group containing 1-4 carbon aphoms in each alkyl group, an alkanoyloxymethyl group containing 4-9 carbon atoms, a phthalidyl group, the nitrogen protecting group in the tetrazoylpenam system, easy to remove from the compound of formula 83 or R2, is a phenyl group, a substituted alkoxy group, or an alkanoyloxy group, containing 1-4 carbon atoms or a benzyloxy group, characterized by The compound of formula 84, or its salt, a solderosilylated derivative, is acylated with an organic acid. 6. The method according to p. A process according to Claim 5, characterized in that the acylation is a syllated derivative of the perrrile of formula 84, wherein Rz is as defined in claim 5, 5 has a trialkylsffylamino group in the 6-position, each of the alkyl groups containing 1-4 carbon atoms. ERRATA Lam 2, verse 1 is: 14, 388 (1959), should be: stry 14, 388 (1949), Lam 2, verse 30 is: stry, 14, 388 (1949), Carpenter, J ° «^ ° * it should be: ne penam of formula 1, in which Rn is 95 747 Rn er M R2 n JVzd / - 2 f -N Wzdr / CH3 CH3 Rz - ^ 'healthy 3 R- R - NK O R-NH ON l ^ healthy 5 N CHa CH3 CHa CHa2R; Wzdr 6 R2 R1-NH O ', r -N- XH3' R2 Formula No. 4 (R5) -NH R5 "NH ON CHa CHa 'Hi. \ N / v, ^ r 7 ^ R3 Formula 8 7 ^ -N" ^ 3 IA'zdr 9 o95747 -o / .N .. l U 3. Formula 10 R 'I -C; N R7 ^ L Pattern UH fc I n Pattern 12, R2 NH2vvS ^ 3 0H ChU C02H Formula 13 U \ ^ N ^^ f CH' ^ N_N \ CH NH2 Sr3CH3- (RllHJsS * CH. O II -c- R-NH O Formula 16 CH3 N CH3 / SJ-CH3 NH; .s (R * ¦ / 7 CHs Moons 17 h ^ NN ^ W "° ^ '" ^ fl <^ H -PH . 0 ^ ouv% R-RH O CH3 / -SX-CH3 Wzdr4 Scheme 1 mN (r5) 'nh c PH »^ N NN o ^ c \ *; n * R Scheme 295 747 -CH- fr8, R4 R17 S19 Formula Z3 -CH2 C R21 Formula 25 Formula 24 -CH R 13 R4) '(R17)' R 23 R22 \ V n R 24 Wrfl / - i17 R8 ^ ^ 0 CH-cr Hl (k / N \ s Wzdr 28 R8 Hfl Rs CH-C -f 0 ^ R10 ^ N 0 Formula 29 .ChU -CH3 0 ^ R Rlf $ hT CHa CH3 R1 R12 Rv N-CH = N, N-tf tf Formula 30 R «RB / N-CH = N, 0 -N / 1'z ^ r 3 / CH3 CH3 N-NN \ R1195 747 o-CICehU C0- D n CH3 ^ CH2-CO- '^ LCfr 32 Formula 33 co- ^ -0CH2CH3 d DL - "ST "CH-CO- Wzdr 3+ NH2 Formula 35 D CH-CO- NH2 Formula 36 CH-CO- W2 \ Nucfr37 DL D CH-CO- NH2 Formula 38 -CH-CH-CO- NH2 H Formula 3395 747 D _CH- CO NH2 Formula 40 ^ CH-CO- NH2 Formula 41 CsHsrOfCO- NH-S02 Formula 46 CgHs-CH-CO n (^ c-nh-ch2-co NH Formula «CO-NH-CO- Nzdr 44" CH-CO- V co2h Formula 46 C-NH-CHfCa NH] Nz.dr 43 C H-CO- C02H Formula 45 C6M5-CH-C0 NH-S WzCfr 43 * t * H- NH-C0-CH2-NH ^ "] Wzd 50 H CeHs-CH-CO- co-o Wzcrr 47 C6Hs-CH- C0- NH-CO-NH-CO Wdr SI CeHs-CH-CO- _N NH-C0-NH-C0 ^ ("/ flzdr 5295 747 C6H5-CH-CO- NH-CO-NH-CO - A ^ I Formula 53 C6H5-CH-CO- NH-CO-NH-CO- Wzdr 54 CeHs-CH-CO- NH-CO-C = CH-U CbHs ^ CH-CO- C02H NH-CCk a Wzdr 56 C6H5-CH- C0- NH-CO CeHs-CH-CO- NH-C0-CH2 < n Formula 58 Formula 55 Wzdr 57 C6H5-CH-C0- NH-CO ^^ - N »*» U C6H5-CH-C0- H NH-CO ^ N Wzdr SO C6H5-CH-C0 NH-CO C6H5-CH- CO- Wals 61 NH-CO-ChW0 ^ Wals 62 N C6H5-CH-C0- NH-CO-CH2-NH-SO2 Wals 63 C6H5-CH-C0- NH-CO-CH2-NH-C- NH <N Wals 64 C6H5-CH-C0- NH-CO-CH2-NH-O - ^^ NH Wzdr 6595 747 CeHs-CH-CO- Ji NH-CO-CH2-NH-C NH Formula 68 C6H5-CH-CO- NH- CO-CH2-NH-C NH Wzctr 67 CbHs-CH-CO- N nh-co-ch2-nh-c- ^ o NH Formula 68 4-HOC6HrCH-CO- H NH-CO-CHz-NH-C- ^ N Formula 69 NH C6H5 CH-CO- NH-C0-CH2: N = CH-N: Formula 70 C6H5-CH-C0- _ NH-C0-CH2-NH-C- ^ T ^ J NH Wdr 71 C6H5-CH -C0- NH-CO-CH2-NH-C NH Formula 72 C6H5-CH-C0- _ NH-C0-CH2-NH- C - Qsl-0 NH Formula 73 C6Hs-CH-CO- NH-CO-CH2CH2 -NH-CO- Formula 74 CeHs-CH-CO- _N NH-CO-CH2CH2-NH-C - ^ / Wzd 75 NH C6H5-CH-Co-k, NH-CO-CH2CH2-NH-C — Q. 0 Formula 76 NH95 74? C6H5-CN-C0- NH-C0-CH2CH2-NH-C NH Wzdr 77 C6HrCH-CO- - _ nh-co-ch2-s ^ Qn mor 78 CeHg-CH-CO- n NH-C0-CH2-S— ^ ^ | Wzdr 79 N C6H5-CH-C0- N NH-C0-CH2-S- ^ f N mor 8o H C6H5-CH-C0- ^ NH-CO-CH2-S ^ (Wzdr 81 H C6H5-CH-C0- n NH-C0-CH2-S —- 4 N Model 62 H tf-NH Wzdr 8i Bltk 2930/77 r. 105 copies A4 Price PLN 45 PL