SE436569B - ANALOGY PROCEDURE FOR THE PREPARATION OF TIENAMYCIN DERIVATIVES - Google Patents

Description

'78044l fl-6 z 0:23 5' fe / ¶ \ S \ / \ NC = NR1RZ I 04 -N _- coog RÖ I Thienamycin, the parent compound, is described in U.S. Patent No. 3,950,357, which is incorporated herein by reference, since thienamycin can be used as starting materials for the preparation of the compounds of the present invention. Another suitable starting material for the preparation of the compounds of the present invention is N-alkylated thienamycin and O- and carboxylated derivatives thereof (III): thienamycin has the following structure 3- (1: SCHZCHZNHZ). Wherein X represents oxygen, sulfur or NR '(R' represents H or alkyl of 1 to 6 carbon atoms), R4 represents, inter alia, hydrogen, conventional blocking groups, such as trialkylsilyl , acyl and radicals (R4), giving rise to pharmaceutically acceptable salt, esters and amide moieties (COXR4), which are known in the β-lactamantibiotic cycle (β the definition of R4 is given below), R 5 represents hydrogen or 1) acyl (the group ORS is generally classified as an ester), or 2) R 5 represents alkyl, aryl, aralkyl or the like, so that the group OR 3 is generally classified as an ether; by "acyl" is meant nlcanoyl groups incl. derivatives and analogues thereof, such as thio analogues in which carbonyl oxygen is replaced by sulfur, and sulfur and phosphoracyl analogues, such as substituted sulfonyl, sulfinyl and sulphenyl radicals and substituents PIIII and V 7 substituents, 6 phosphoric acid, phosphonic acid and phosphonic acid radicals; such acyl radicals according to the present invention are referred to in more detail hereinafter as well as the radicals Z) (above), which constitute the ether embodiments of the present invention (R3 is defined in more detail below), and RS has the meaning given. The N- -alkylated thienamycins (III) are described in U.S. Patent Application 733611 of October 18, 1976. This application is incorporated herein by reference for the preparation of N-alkylthienamycins of formula III. Reference is also made to U.S. Patent Application 733654 of October 18, 1976, which discloses N-iminomethyl derivatives of thienamycin (IV): Rs / \ - II ~ S \ / \ N = c-NR'R2 J- coxR 4 1126/0 IV wherein R 3, X, R 4, R 1, R 2 and R 6 have the meaning given. Reference is made to this application, as it states the preparation of IV from thienamycin II (see above). It should be noted that the preparation of compound IV from II (II-> IV) is analogous to the preparation of the compounds of the present invention I from III (III- fl-I).

Finally, reference is made to Swedish patent application 7804446-8, which relates to N-alkyl-N-acyl derivatives of thienamycin: 0113 Ä / __S / \ / N = CRSRI O¿ .__ N ._coxn4 IVa wherein RS, X; R4 and R5 have the indicated meaning and R 'represents acyl. Reference is made to this application, since compound IVa is required in the preparation of embodiments of I, when RÖ represents OR or SR.

There is a continuous need for new antibiotics. Unfortunately, there is no static efficacy of a given antibiotic, since the widespread use of antibiotics selectively gives rise to resistant strains of pathogens. In addition, known antibiotics are associated with the disadvantage that they are effective only against certain types of microorganisms. Therefore, research into new antibiotics continues.

ITBOIIIIWY-G It has now unexpectedly been found that the compounds of the present invention are broad spectrum antibiotics which are valuable in animal and human therapy and in inanimate systems.

The present invention thus relates to the preparation of a new class of antibiotics which have the basic core structure of the antibiotic thienamycin, but which are characterized as N-alkyl-N-iminomethyl-derivatives thereof. These antibiotics are active against a large number of pathogens, which include gram-positive bacteria, such as S. aureus, Strep. pyogenesis and B. subtilis and gram-negative bacteria, such as E. Coli, Proteus morganii, Serratia and Klebsiella. The invention further relates to chemical processes for the preparation of such antibiotics and non-toxic pharmaceutically acceptable salts thereof; pharmaceutical compositions containing such antibiotics; and methods of treatment by administration of these antibiotics and compositions, when an antibiotic effect is indicated.

With reference to the general description of the present invention (formula I, above), the most suitable embodiments are those in which R 5 represents lower alkyl or alkenyl having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, allyl and the like or benzyl, and RÖ and R] have the specified meaning, which is further exemplified in the following.

The compounds of the present invention are most conveniently prepared by derivatizing an appropriately substitutable N-alkthienamycin: 3) "Rs / É /] __ s \ / \ NHRs / \ Sßn-çNr-.Énz '. 6, NI coon r * cooH R For embodiments according to the invention, wherein R 6 represents OR or SR, starting material IVa (see above) is used, wherein the acyl radical R 'represents thiocarbamyl or thiocarbamyl.

As previously stated, the reaction (III - I or IVa- »II is completely analogous to the reaction (II-rIV) described in U.S. Patent Application 733654 of October 18, 1976: 10113 0:13 R fi, -,» J, _ '\ | ::' í \ [* 5 \ / \ N "zf / w | / \ '- s \ / \ N = É * Nn1n ° f / N_LC ° XR4 i» N-Jß-coxl fl // 0 II 0 Iv 10 15 -l (l? 80lrl + ll7 * 6 except that the starting material II (or its O- and / or carboxyl derivatives) is replaced by an equivalent amount of starting material lll (or lVa).

Starting material II is described in U.S. Patent Application 733611 of October 18, 1970. This application is incorporated herein by reference for the preparation of N-monoalkylthienamycin derivatives (III). Such N-monoalkylthienamycin derivatives are prepared by reacting tlenamycin or a suitable derivative thereof or a suitably protected thienamycin compound with an N-alkylating agent. The process is not associated with any particular similarities and all well known N-alkylation processes can be used. The N-alkylating agent can be selected within the limits determined by the definition of R 1. The N-alkylation can be carried out in solvent systems which are inert or substantially inert at the desired course of the reaction. Suitable solvents are polar solvents such as water, lower alkanoyl compounds such as ethanol, dioxane, tetrahydrofuran (THF), acetonitrile, hexamethylphosphoramide (HMPA), dimethylformamide and the like and mixtures (especially aqueous mixtures); non-polar solvents such as benzene and halohydrocarbons such as methylene chloride, chloroform and the like. The reaction is conveniently carried out at a temperature of -40 ° C to 50 ° C for a few minutes to 5 hours. The reaction is usually carried out in the presence of an acid acceptor such as propylene oxide, magnesium oxide, potassium carbonate and the like. Suitable alkylating agents include active halides, sulfate esters and Michael addition reagents. The following reactants are representative of these alkylating agents: methyl iodide, allyl bromide, bromoacetone, phenacyl bromide, benzyl bromide, ethyl chloroacetate, propargyl bromide, 2-bromomethylethyl ether, dimethyl sulfate, methylfluorosulfonylfluorocetyl sulphonylcyculethomethylcuromethomethylcuromethylcuromethylcuromethylcuromethylcetomethylcarbonomethylcarbonomethylcarbonomethylcarbonomethane chloromethylpyridine, acrylonitrile, methyl methacrylate, nitroethylene and the like.

The starting material III can be prepared in different ways. A suitable starting material is tris-trimctylsilyl-thienamycin [Th (TMS) 3] (see below).

As previously indicated, the N-alkylation is carried out in any of the aforementioned solvents in the presence of the selected N-alkylating agent, such as R 5 X ', wherein X' represents a group which can be removed, e.g. halogen or a sulphate ester. For example, when Th (TMS) 3 is used, the desired product is obtained by aqueous hydrolysis after the N-alkylation step. The following reaction scheme illustrates the procedure: 7804447-6 o orns e orns Rsx 'rn Nnrns ------- s- Th Nnsrns coorns coorns on hydrolysis 5 _____-____> Th NHR coon wherein TMS represents trimethylsilyl and RS and X' have it specified meaning.

A second reaction scheme for the preparation of monoalkylthienamycins (III) consists in N-alkylation of an N-substituted thienamycin, wherein the substituent is a bulky group which can be easily removed (RO), such as an aralkyl group, t .ex. Substituted or unsubstituted benzyl, benzhydryl (-CH (C 6 H 5) 2) and trityl (-C (C 6 H 5} 3): wherein the ring substituent of the aralkyl group may be halogen, nitro, lower alkyl, lower alkoxyl or the like. This is illustrated in the following reaction scheme: -ï IORI * _ OR: 'fh NHR ° Rsx' Th nn ° n5 rfz / kaun. Th NRS, 4 -i -> '_-- à ___> coin LCOXR4 _coXR4 L Å. §, el1er IM vari symbolerna har den specified meaning.

Referring to this scheme, the starting material 1, prepared, for example, by reaction between thienamycin or a derivative thereof and an aralkyl halide, is reacted with the N-alkylating agent RIX 'in the manner indicated to give the N, N-dialkyl intermediate. The aralkyl-N substituent Ro can be easily removed by hydrogenolysis to give Ä. Suitable conditions for this final cleavage step consist in hydrogenating Å 1 a solvent such as ethanol under hydrogen (1 to 4 atm) in the presence of a catheter Lysator, such as platinum, palladium or oxides thereof. The final product of the reaction is primarily the Q, N-mono-lower alkyl compound. However, some N, N-dialkylalkylthienamycin is also present. Such contaminating by-products can be separated by chromatographic methods and the amount of contaminant can be reduced by using an equivalent or less of the alkylating agent RSX '. 7801M47 -6 A third method for preparing the N-monoalkyl compound III, especially the N-lower alkyl compound, is similar to the process previously described except that the starting material 1a is N, N-diaralkylthienamycin. Preparation of such starting materials is described in the following. This procedure is illustrated in the following reaction scheme: OR 3 5 oR ° OR 3 o o R X 'o o S 5 Th NR R --- Th NR R R H 2 / kacai. Th NR 4 4 "" "" "" 4 coxn la coxn coxR III wherein the symbols have the specified meaning.

It should be noted that this scheme for the preparation of N-lower alkylthienamycins is not complicated by the simultaneous preparation of N, N-lower alkylthienamycins.

A fourth method, which is particularly suitable for the preparation of N-lower alkyl-thienamycin compounds (III), is N-alkylation of a Schiff base of thienamycin. This is illustrated by the following scheme: oR3 OR3 r oR3 RSX, ¶ H 'hydrolysis or _ [5 Th N = g-0 -> Th N = CQ Hydrogenation' h NHR s ^ L coxR4 R 4 coxR4 COXR 4 5 Q or III n: rv wherein the symbols have the indicated meaning and 0 denotes phenyl, R 4 and R 5 may denote trimethylsilyl radicals (TMS) and X denotes oxygen. The appropriate Schiff base is obtained by reaction between thienamycin and benzaldehyde or nuclear substituted benzaldehyde.

There is no difficulty in preparing such Schiff bases and their preparation is described in U.S. Patent Application 733656 of October 18, 1976. Reference is made to this application because it describes the preparation of the starting material Q. The reaction between the alkylating agent and the RX 'gives the intermediate å, which in aqueous hydrolysis or catalytic hydrogenolysis gives the desired N-lower alkylthienamycin compound Q.

A fifth method for preparing N-lower alkylthienamycins (III) consists in desulfurizing an N-thioacyl-thienamycin in the presence of hydrogenation catalysts, such as Raney nickel: 3 OR; FOR Th_íNHGRs Raney nickel Th ~ §NncHZR8 IS _____ ~ _____ a_ LCOXR4 LCOXR4 vsouuáv-6 8 wherein X represents oxygen, Rs and R4 have the specified meaning but preferably denote hydrogen and R8 denotes hydrogen, aryl or a lower alkali - S carbon atoms. The N-thioacyl-thienamycin starting materials are described in U.S. Patent Application 7,336,53 of October 18, 1976, which is incorporated herein by reference for the preparation of such starting materials. The desulfurization is conveniently carried out in polar, protic solvents such as water, lower alkanols such as ethanol, and water mixtures thereof at a temperature of 0-50 ° C for 2 minutes to 5 hours.

In the general representation of the compounds of the present invention (I, above) the radical designated -COXR4 is i.a.

-COOH (X represents oxygen and R4 represents hydrogen) and all radicals known to be effective as pharmaceutically acceptable salt ester, anhydride (R4 represents acyl) and amide radicals in the icyclic β-lactam antibiotic technique , such as cephalosporins and penicillins and core analogues thereof.

Suitable radicals (R4) are conventional protecting or carboxyl blocking groups. By "blocking groups" is meant herein the same as in U.S. Patent No. 36,97515, which is incorporated herein by reference. Pharmaceutically acceptable thienamycin derivatives of the present invention, which fall into this class, are described below. Suitable blocking esters are thus those selected from the following list, which are representative and not intended to be exhaustive of possible ester groups, wherein X = O and R 4 are: (i) R 4 = CRaRbRc, wherein at least one of the symbols Ra, Rb and RC is a ZS electron donor, e.g. p-methoxyphenyl, 2,4,6-trimethylphenyl, 9-anthryl, methoxy, CH 2 SCHS, tetrahydrofur-2-yl, tetrahydropyran-2-yl or fur-Z-yl. The remaining Ra, Rb and Rc groups may be: ether or organic substituent groups. Suitable ester groups of this type include p-methoxybenzyloxycarbonyl and 2,4,6-trimethylbenzyloxycarbonyl. (ii) R4 = CRaRbRc, wherein at least one of the symbols Ra, R and RC is an electron-attracting group, e.g. benzoyl, p-nitrophenyl, 4-pyridyl, trichloromethyl, tribromomethyl, iodomethyl, cyanomethyl, ethylenecarbonylmethyl, arylsulfonylmethyl, 2-dimethylsulfoniummethyl, o-nitrophenyl or cyano. Suitable esters of this type include benzoylmethoxycarbonyl, p-nitrobenzyloxycarbonyl, 4-pyridylmethoxycarbonyl, 2,2, 2-trichloroethoxycarbonyl and 2,2,2-tribromethoxycarbonyl. b b (iii) R 4 = CR a R b R c, wherein at least two of the symbols Ra, R are hydrocarbon groups such as alkyl, e.g. methyl or ethyl, or aryl. and RC denotes 10 IU 7804447-6 9 e.g. phenyl and the remaining Ra-, R is present, is hydrogen. Suitable esters of this type include t-butyloxycarbonyl, t-amyloxycarbonyl, diphenylmethoxycarbonyl and the triphenylb- and Rc group, if such a methoxycarbonyl. (iv) R 4 = Rd, wherein Rd represents adamantyl, 2-benzyloxyphenyl, 4-methylthiophenyl or tetrahydropyran-2-yl.

Silyl esters of this category or blocking groups may conveniently be prepared from a halosilane or silazane having the formulas: 4! _ 4! _ 4! _ 4! 4! _ 41 R S1X '; R 2S1X'2; R 3S1.NR 2; R 3.S1.NH.COR; 4 '. . . 4 '4'. 4 '4'. 4 'R 3.S1.NH.CO.hH.S1R 3; R NH.CO.NH.S1R 3; or R C (OS1R 3); -c HN (SiR 4 3) 2, wherein X 'represents halogen, such as chlorine or bromine, and in the different groups R 4, which may be the same or different, represents hydrogen atoms or alkyl, e.g. methyl, ethyl, n-propyl, isopropyl; aryl, e.g. phenyl; or aralkyl, e.g. benzyl groups.

In general, pharmaceutically acceptable carboxyl derivatives of the present invention are those obtained by thienamycin | or an N-protected thienamycin such as III or an N-acylated thienamycin or a compound of the present invention I, is reacted with alcohols, phenols, mercaptans, thiophenols, acylating reagents and the like. These starting materials or embodiments of the present invention may be derivatized to form the R 3 group of the compounds of the invention (I, above). Esters and amides of interest are, for example, the compounds of formula I having the following group in the Z position: -COXR 4, wherein X represents oxygen, sulfur or NR '(R' represents hydrogen or R 4) and R 4 represents alkyl having 1 - Carbon atoms, which may be straight or branched, such as methyl, ethyl, t-butyl, pentyl, decyl and the like; carbonylmethyl, incl. phenacyl, p-bromophenacyl, p-t-butylphenacyl, acetoxyacetylmethyl, pivaloxyacetylmethyl, carboxymethyl and its alkyl and aryl esters, carboxy-isopropyl; ammonoalkyl incl. 2-methylaminoethyl, Z-dimethylaminoethyl, 2-acetamidoethyl, phthalimidomethyl, succinimidomethyl, alkoxyalkyl, wherein the alkoxy moiety contains 1 to 10 and preferably 1 to 6 carbon atoms; but which may be branched, straight or cyclic and the alkyl moiety contains 1 to 6 carbon atoms such as methoxymethyl, ethoxymethyl, isopropoxymethyl, decyloxymethyl, ethoxypropyl, decyloxypentyl, cyclohexyloxymethyl and the like; alkanoyloxyalkyl, wherein the alkanoyloxy moiety is straight or branched and contains 1 to 6 carbon atoms and the alkyl moiety has 1 to 6 carbon atoms, such as acetoxymethyl, pivalovyloxymethyl, acetoxyethyl, propionyloxyethyl, acetoxypropyl and the like; haloalkyl, wherein halogen represents chlorine, bromine, fluorine or iodine and the alkyl moiety is straight or branched with 1 P 6 carbon atoms, e.g. 2, Z, 2-trichloroethyl, trifluoroethyl, Z-bromopropyl, diiodomethyl, 2-chloroethyl, 2-bromomethyl and the like; alkenyl having 1 to 10 carbon atoms and straight or branched, e.g. allyl, 2-propenyl, 3-butenyl, 4-butenyl, 4-pentenyl, Z-butenyl, 3-pyrenyl, 3-methyl-3-butenyl, metalallyl, 1,4-cyclohexadien-1-yl-methyl and similar; alkynyl having 1 to 10 carbon atoms, and straight or branched, e.g. 3-pentenyl, prepargyl, ethynyl, 3-butyn-1-yl and the like; alkanoyl, and straight or branched, having 1 to 10 carbon atoms, such as pivaloyl, acetyl, propionyl and the like; aralkyl or heteroaralkyl, wherein alkyl contains 1 to 3 carbon atoms and is named: denotes 1 to 4 heteroatoms in the form of O, S or N, such as benzyl, benzhydryl and substituted benzyl, benzhydryl or e.g. benzyl or substituted with 1 to 3 substituents, such as benzyl, phenoxy, halogen, lower alkyl, lower alkanoyloxy having 1 to 5 carbon atoms, lower alkoxy, hydroxy, nitro, blocked carboxy or combinations thereof, e.g. p-chlorobenzyl, O-nitrobenzyl, 3,5-dinitrobenzyl, p-methoxybenzyl, m-benzoylbenzyl, pt-butylbenzyl, m-phenoxybenzyl, p-benzoylbenzyl, 3-nitrobenzyl, 3,5-dichloro-4-hydroxybenzyl, p- methoxycarbonylbenzyl, p-methoxybenzhydryl, p-carboxybenzyl, the latter being the free acid, ester or sodium salt, 2,4,6-trimethylbenzyl, p-pivaloyloxybenzyl, pt-butoxycarbenylbenzyl, p-methylbenzyl, p-benzoyl soyloxyl p-acetoxybenzyl, pZ-ethylhexanoylbenzoyl, p-ethoxycarbonylbenzyl, p-benzoylthiobenzyl, p-benzamidobenzyl, o-pivaloyloxybenzyl, m-pivaloyloxybenzyl, p-isopropoxybenzyl, p-butyloxybenzyl, pt-butyloxybenzyl 5-coumaranmethyl, S-indinylmethyl, p-trimethylsilylbenzyl, 3,5-bis-t-butoxy-4-hydroxybenzyl, 2-thienylmethyl, Z-furylmethyl, 3-t-butyl-5-isothiazolmethyl, 6-pivalo; oxy-3-pyridazinylethyl, 5-phenylthio-1-tetrazolylmethyl or the like fi lower alkyl or lower alkoxy in this context means 1 - 4 carbon atons in the chain); or phthalidyl; or phenylethyl, 2- (p-methylphenyl) -ethyl and aryltioalkyl analogs, aryloxyalkyl, wherein aryl is suitably a phenyl ring having 0 to 3 substituents, preferably 0 or 1 substituent in the ortho or para position and alkyl contains 1 to 6 carbon atoms, t .ex. (4-methoxy) -phenoxymethyl, phenoxymethyl, (4-chloro) phenoxymethyl, (4-nitro) -phenoxymethyl, (4-benzyloxy) phenoxymethyl, (4-methyl) phenoxymethyl, (4-benzyloxy) phenoxymethyl, (4-methyl ) phenoxymethyl, (2-methoxy) phenoxymethyl, (1-phenoxy) ethyl, (4-aminolphenoxymethyl, (4-methoxy) phenylthiomethyl, (4-chloro) phenylthiomethyl, phenylthioethyl; aryl, wherein aryl represents phenyl, 5-indanyl; phenyl having 0 to 3 substituents, suitably 0 or 1 substituent in the ortho or para position, eg (4-methyl) (phenyl), phenyl, (4-hydroxy] phenyl, ( 4-t-butyl) phenyl, p-nitrophenyl, 3,5-di-nitrophenyl, or p-carboxyphenyl, the latter being in the form of free acid or sodium salt form, aralkenyl, wherein aryl represents phenyl and alkenyl has 1 - 6 carbon atoms, such as 3-phenyl-Z-propenyl; aralkoxyalkyl, wherein aralkoxy represents benzyloxy and alkyl has 1-3 carbon atoms, such as benzyloxymethyl, (4-nitro) benzyloxymethyl, (4-chloro) -benzoxymethyl; alkylthioalkyl, wherein alkylthioalkyl has 1 - 10 and preferably 1 - 6 carbon atoms, but may be branched, straight or cyclic, and the alkyl moiety has 1 to 6 carbon atoms, such as methylthioethyl, ethylthioethyl, cyclohexylthiomethyl, decylthiobutyl, methylthiopropyl, isopropylthioethyl, methylthiobutyl and the like.

In addition to esters (and thioesters) mentioned above, amides are also encompassed by the present invention, i.e. in which X represents a -hi group. Representative of such amides are those in which R 'belongs to a group consisting of hydrogen, methyl, ethyl, phenyl, p-methoxyphenyl, benzyl, carboxymethyl, methylthioethyl and heteroaryl; -COXR4 also includes anhydrides, in which R4 represents benzyloxycarboxyl, ethoxycarbonyl, benzoyl and pivaloyl.

The most suitable radicals -coxR4 radical are those in which (in structure I above) X represents oxygen, sulfur or NR '(R' represents hydrogen or lower alkyl); and R 4 is selected from the group of lower alkyl, lower alkenyl, such as methallyl, 3-methylbutenyl, 3-butenyl and the like; methylthioethyl; benzyl and substituted benzyl, such as p-t-butylbenzyl, m-phenoxybenzyl, p-pivaloyloxybenzyl, p-nitrobenzyl and the like; pivaloyloxymethyl, 3-phthalidyl and acetoxymethyl, propionyloxymethyl, acetylthiomethyl, pivaloylthiomethyl, allyl, 4-butenyl, Z-butynyl, 3-methyl-Z-butenyl, phenacyl, acetoxyacetylmethyl, methoxymethyl, p-acetoxymethyl, p-acetoxymethyl isopropoxybenzyl, 5-indanylmethyl, S-indanyl, benzyloximotyl, ethylthioethyl, methylthiopropyl, methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl, dimethylaminoacactoxymethyl, crotonolacton-3-yl and acctamidomethyl.

In the general representation of the present invention (Figure I above), the radical R 3 denotes in addition to hydrogen, 1) acyl (the group -OR 3 is generally classified as an ester) or 2) R 5 denotes alkyl, aryl, aralkyl and the like so that the group - OR3 classification according to the present is defined as a cter. In the ester forms (1), R 3 is selected from the following definitions of acyl radicals (p = 1). In the s.k. the ether embodiments (Z) of the present invention, R 3 is selected from the same carbon acyl radicals, where the carbonyl moiety, -C-, or more generally, -C-, is II n O X removed (p = O); RJ is thus selected from the following radicals, the symbols being defined below. 1 il) (i) fl c p -n- c p- (cH2) nzR "íc / p-cnn" RH! x / x n 3 4 11 _ .- __ r * _ _ _ c p cnR R c p (.H2) m A (cH2) n Y With regard to the definition of R3 and R2, the acyl radical can e.g. Be a substituted or unsubstituted aliphatic, aromatic or heterocyclic, araliphatic or heterocyclic-aliphatic carboxylic acid radical, a substituted or unsubstituted carbamyl radical or a carbothioic acid radical. A group of acyl radicals may be represented by the general formula X n -c-R "g wherein X represents O or S and R" represents hydrogen; amino; substituted amino, such as alkyl and dialkylamino, wherein the alkyl radical contains 1 to about 6 carbon atoms; substituted or unsubstituted: straight or branched alkyl, wherein the alkyl radical contains 1 to about 6 carbon atoms; mercapto, aryloxy, suitably having 6 to 10 carbon atoms; alkylene or alkynyl groups suitably having 2 to 6 carbon atoms; aryl, the sauce phenyl; aralkyl such as benzyl; cycloalkyl, suitably having 3 to 6 carbon * atoms; or a heteroaryl or heteroaralkyl group (mono- or bicyclic], wherein the alkyl moiety suitably contains 1-3 carbon atoms and the heterocyclic ring contains 4-10 atoms and the heteroatom or the atoms are O, N or S; The compounds may be unsubstituted or substituted by radicals such as OH, SH, SR (R represents lower alkyl or aryl, such as phenyl), alkyl or alkoxy groups having 1 to about 6 carbon atoms, halogen, such as Cl, Br, R and J cyano, carboxy, sulfamino, carbamoyl, sulfonyl, azido, amino, substituted amino, such as alkylamino and quaternary ammonium, wherein the alkyl group contains 1 to 6 carbon atoms, haloalkyl, such as trifluoromethyl, carboxyalkyl, carbamoylalkyl, N-substituted carbamoylalkyl, carbamoylalkyl wherein the alkylene in the four preceding radicals contains 1 to about 6 carbon atoms, amidino, guanidino, N-substituted guanidino, guanidinol alkyl and the like. Representative examples of such acyl groups which may be mentioned are those in which R "represents benzyl, p-hydroxybenzyl, 4-amino-4-carboxybutyl, methyl, cyanomethyl, 2-pentenyl, n-amyl, n-heptyl, ethyl-3- or -4- nitrobenzyl, β, β-diphenylethyl, methyldiphenylmethyl, triphenylmethyl, Z-methoxyphenyl, 2,6-dimethoxyphenyl, 2,4,6-trimethoxyphenyl, 3,5-dimethyl-4-isoxazolyl, 3-butyl-S-methyl- 4-isoxazolyl, S-methyl-3-phenyl-4-isoxazolyl, 3- (2-chlorophenyl) -5-methyl-4-isoxazolyl, 3- (2,6-dichlorophenyl) -5-methyl-4-isoxazolyl oxazolyl, D-4-amino-4-carboxybutyl, D-4N-benzoylamino-4-carboxy-n-butyl, p-aminobenzyl, o-aminobenzyl, m-aminobenzyl, p-dimethylaminobenzyl, (3-pyridyl) methyl , 2-ethoxy-1-naphthyl, 3-carboxy-2-quinoxalinyl, 3- (2,6-dichlorophenyl) -5- (2-furyl) -4-isoxazolyl, 3-phenyl-4-isoxazolyl, 5-methyl -3- (4-guanidinophenyl) -4-isoxazolyl, 4-guanidinomethylphenyl, 4-guanidinomethylbenzyl, 4-guanidinobenzyl, 4-guanidinophenyl, 2,6-dimethoxy-4-guanidino, o-sulfobenzyl, p-carboxymethylbenzyl, p -carbamoylmethylbenzyl, m-fluorobenzyl, m-bromobenzyl, p-chlorobenzyl, p-methoxybenzyl, 1-naphthylmethyl, 3-isothia zolylmethyl, 4-isothiazolylmethyl, 5-isothiazolylmethyl, guanylthiomethyl, 4-pyridylmethyl, S-isoxazolylmethyl, 4-methoxy-S-isoxazolylmethyl, 4-methyl-S-isoxazolylmethyl, 1-imidazolylmethyl, 2-imanolylmethyl, 2 2-phenylvinyl, 2-phenylethynyl, 1-aminocyclohexyl, 2- and 3-thienylaminomethyl, 2- (5-nitrofuranyl) -vinyl, phenyl, o-methoxyphenyl, o-chlorophenyl, o-phenylphenyl, p-amino methylbenzyl, 1- (S-cyanotriazolyl) -methyl, difluoromethyl, dichloromethyl, dibromomethyl, 1- (3-methylimidazolyl) methyl, Z- or 3- (5-carboxymethylthienyl) methyl, 2- or 3- (4- carbamoylthienyl) methyl, 2- or 3- (S-methylthienyl) methyl, 2- or 3- (methoxythienyl) methyl, 2- or 3- (4-chlorothienyl) methyl, 2- or 3- (5-sulfothinyl) -methyl , 2- or 3- (5-carboxytienyl) methyl, 3- (1, Z, 5-thiadiazolyl) methyl, 3- (4-methoxy-1,Z, 5-thiadiazolyl) methyl, 3- (4-methoxy- 1,2, S-thiadiazolyl) methyl, 2-furylmethyl, 2- (S-nitrofuryl) methyl, 3-furylmethyl, 2-thienylmethyl, 3-thienylmethyl, tetrazolylmethyl, benzamidinomethyl and cyclohexylamidinomethyl.

The acyl group may also be a radical of the formula ä -C (CH2) nZR "wherein X represents O or S and n represents 0 - 4, Z represents oxygen, sulfur, carbonyl or nitrogen and R" has the meaning given. Representative examples of the substituent - (CH 2) n ZR "are allylthiomethyl, phenylthiomethyl, butylmercaptomethyl, α-chlorocrotyl-mercaptomethyl, phenoxymethyl, phenoxyethyl, phenoxybutyl, phenoxyxymethyl, diphoxymethyl, diphenoxymethyl, diphenoxymethyl guanidinophenoxymctyl, 4-pyridylthiomethyl, p- (carboxymethyl) phenoxymethyl, p- (carboxymethyl) phenylthiomethyl, 2-thiazolylthiomethyl, p- (sulfO) phenoxymethyl, p- (carboxymethyl) phenylmethyl] thiomethylmethyl] thiomethyl] - (5,6,7,8-Tetrahydronaphthyl) oxomethyl, N-methyl-4-pyridylthio, benzyloxy, methoxy, ethoxy, phenoxy, phenylthio, amino, methylamino, dimethylamino, pyridiniummethyl, trimethylammonizylmethyl, cyanomethylmethylmethyl, pyranomethylmethylmethyl, pyranethylmethylmethyl , 4-pyridylpropyl, 4-pyridylbutyl, 3-imidazolylethyl, 3-imidazolylpropyl, 3-imidazolylbutyl, 1-pyrroloethyl, 1-pyrrolopropyl and 1-pyrrolobutyl.

Alternatively, the acyl group may be a radical of the formula X -É -ene "Ru" wherein R "has the meaning given and R" 'represents a radical ac: amino, hydroxy, azido, carbamoyl, guanidino, amidino, acyloxy, kgiagen , such as Cl, F, Br, J, sulfamino, tetrazolyl, sulfo, carboxy, carbalkoxy, phosphono and the like.

Representative examples of the substituent -CHR "α 1 are (1-aminobenzyl, glamino- (2-thienyl) methyl, β- (methylamino) benzyl, 1-amino-methylmercuptopropyl, α-amino-5- or -4-chlorobenzyl, β-amino-3 or -4-hydroxybenzyl, amino-2,4-dichlorobenzyl, amino-3,4-dichlorobenzyl, D (-) - d-hydroxybenzyl, acarboxybenzyl, n = amino- (3-thienyl) methyl, ) -d-amino-3-chloro-4-hydroxybenzyl, αPamino (cyclohexyl] methyl, αβ (5-tetrazolyl) benzyl, 2-thienyl-carboxymethyl, 3-thienyl-carboxymethyl, 2-furylcarboxymethyl, 3-furylcarboxymethyl, cl- sulfaminzene benzyl, 3-thienylsulfonaminomethyl, d- (N-methylsulfamino) -benzyl, D (-) - thienyl-guanidinomethyl, D (-) - nsguanidinobenzyl, azguanylurcidobenzyl, Ofhydroxybenzyl, d-azidobenzyl (d. methoxy-1,3-ox -, diazolyl) -aminomethyl, 4- (5-methoxy-1,3-oxadiazolyl) -hydroxymethyl, 4- (5-methoxy-1,5-sulfadiazolyl) -hydroxymethyl, 4- (5 -chlorothienyl) -amine: -methyl, 2- (S-chlorothinyl) -hydroxymethyl, 4- (5-chlorothienyl) -carboxymethyl-3- (1,2-thiazolyl) -aminomethyl, 3- (1,2-thiazolyl) - hydroxymethyl, 3- (1, Z ~ thiazolyl) -carboxymethyl, 2- (1,4-thiazolyl) -aminomethyl, 2- (1,4-thiazolyl); Hydroxymethyl, 2- (1,4-thiazolyl) carboxymethyl, Z-benzynylaminomethyl, 2-henstinylhydroxymctyl, 2-henstinylcnroxymethyl, (1-sulfohenzyl, G-phosphonophosphonylphosphonyl) -phenyl Other carbon radicals of interest in this class, when X represents oxygen, are 83.

, -CCHR R wherein RS 'and RA' have the meaning given below. R 5 'represents hydrogen, halogen such as chlorine, Iluoro, bromine, iodine, amino, gunnidino, phosphono, hydroxy, tetrazolyl, carboxy, sulfo or sulfamine and R 4' represents phenyl, substituted phenyl, a mono- or bicyclic hydrocyclic group, which contains one or more oxygen, sulfur- 4! or nitrogen atoms in the ring, such as furyl, quinoxalyl, thienyl, quinolyl, quinazolyl, thiazolyl, siotiazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl and similarly substituted heterocyclic groups, phenylthio, phenylocetylalkyl ten groups; or cyano. The substituents for R 5 'and R 4' may be halogen, carboxymethyl, guanidino, guanidinomethyl, carboxamidomethyl, aminomethyl, nitro, methoxy or methyl. When R 5 'represents hydrogen, hydroxy, amino or carboxy and R 4' represents phenyl or a 5- or 6-membered heterocyclic ring having one or two sulfur, oxygen or nitrogen heteroatoms, such as tetrazolyl, thienyl, furyl and phenyl, is the following acyl radicals are representative: phenylacetyl, 3-bromophenylacetyl, p-aminomethylphenylacetyl, 4-carboxymethylphenylacetyl, 4-carboxyamidomethylphenylacetyl, 2-furylacetyl, 5-nitro-2-furylacetyl, 3-furylacetylcetyl 2-thienylacetyl, S-methoxy-2-thienylacetyl, e-guanidino-2-thienylacetyl, 3-thienylactyl, 2- (4-methylthienyl) acetyl, 3-isothiazolylacetyl, 4-methoxy-3-isothiazolylacetyl, 4-iscotyl -methyl-4-isothiazolylacetyl, 5-isothiazolacetyl, 3-chloro-5-isothiazolylacetyl, 3-methyl-1,2,5-oxadiazolylacetyl, 1,2,5-thiadiazolyl-4-octyl, 3-methyl-1H , 2, S-thiadiazolylacetyl, 3-chloro-1, Z, 5-thiadiazolylacetyl, 3-methoxy-1,2, S-thiadinzolylcetyl, phenylthionecyl, 4-pyridylthioacotyl, cyanoacetyl, 1-tetrazolylacetyl, α-flucyl , 4-hydrox 1-D-phenylglycyl, Z-thienylglycyl, 3-thienylglycyl, phenylmalonyl, 3-chlorophenylmalonyl, 2-thienylmalonyl, 3-thienylmalonyl, α-phosphonophenylacetyl, α-aminocyclohexadienylacetyl, α-sulfamycetyl, d-sulfamycyl tetrazolylphenylacetyl and Q-sulfophenylacetyl. 10 15 if! SD Tß fl lilill? The acyl radical can also consist of sulfur (1) or phosphorus (gl) radicals.

(O) (x) 11 "'| f * o -SY -p_y ~ H | (O) n Yu 1 2 wherein in the group 1 m and n is 0 or 1 and Y represents OQM @, -N (R") , and R ", wherein MQ represents hydrogen, alkali metal cations or organic bases; and R" has the indicated meaning, e.g. alkyl, alkenyl, aryl or heteroaryl. In the group Å, X represents 0 or S; n is zero or 1; and Y 'and Y "represent O6M®, -N (R") 2, R "or ZR" having the meaning given above, R "and ZR" represent, for example, alkyl, alkenyl, aryl, heteroaryloxy, Y' and Y "including R "moieties can together form cyclic ester, ester and amide and amide functions. Examples of radicals 1 are methylsulfonyl, p-nitrophenylsulfonyl, p-chlorophenylsulfinyl, o-nitrophenylsulphenyl, sulfamoyl, dimethylsulfamoyl and sulfo; examples of radicals are dimethoxyphosphino, dibenzyloxyphosphino, dihydroxyphosphino, dimethoxyphosphinyl, dimethoxyphosphinothioyl, dibenzyloxyphosphinyl and dihydroxyphosphinyl.

A class of acyl groups of particular interest are those constituted by conventionally known N-nylcyl blocking or protecting groups, such as carbobenzyloxy, ring-substituting cranobenzyloxy, such as o- and p-nitrocarbonsyloxy, p-methoxycarbonobencycloxy, -butoxycarbonyl, trifluoroacctyl: bromoxoxycarbonyl, 9-fluorenylmethoxycarbonyl, dichloromethyl, o-niLr® - phenylsulfonyl, 2,2,2-trichloroethoxycarbonyl, bromo-t-butoxycarbonyl, phnoxyncyl; non-acyl protecting groups, such as triglycylsilyl, e.g. trimethylsilyl and t-butyldimctyl are also of interest.

The following radicals according to the preceding definition of: cyl are suitable: formyl, propionyl, butyryl, chloroacyl, methoxyacyl, n-minoncetyl, methoxycarbonyl, ethoxycarbonyl, methylcuronmyl, ethylcrunmoyl, phenylthiocurhonyl, 3-ominopropylmethyl, methylphenylmethyl N-dimethylaminoactyl, N, N, N-trimethylaminooctyl, 3- (N, N-dimethyl) -uminoproplonyl, 3- (N, N, N-trimctyl) aminopropionyl, N, N, N-trictylaminoncactyl, pyridiniumnctyl, guunidinoacetyl, guunidinoacetyl, -guanidinopropionyl, N3-methylguunidinopropionyl, hydroxyacetyl, 3-hydroxypropionyl, acryloyl, propynoyl, imnonyl, phenoxycarbonyl, amidinuacactyl, octamidinoucotyl, amidinopropionyl, acylamino-14-acylamino carboxymethylaminoacetyl, sulfoacetylaminooacetyl, phosphononecetylaminoacetyl, N3-dimethylaminoacetamidinopropionyl, ureidocarbonyl, dimethylaminoguanylthioacetyl, 3- (1-methyl-4- (4-pyridinium) -propinyl, 3- imidazolium acetyl, 3-sydn onylacetyl, o-aminomethylhensoyl, o-nminohensoyl, u (J || (C) É / OCH3 -P ocu -P o H -P s 2 3 2 \ 0Na soou 1 nn -P [N (cH3) 2,2 - n¿N (cH3) 2 -P [N (cH3) 2] z 0Na f? A particularly suitable class of acyl radicals are terminally substituted acyl groups, wherein the substituent is a basic group, such as substituted and unsubstituted amino, amidino, guanidino, guanyl and nitrogen-containing mono- and bicyclic heterocyclic groups (aromatic, non-aromatic or hot aromatic). the atoms in addition to nitrogen may be oxygen or sulfur. Such suitably substituted acyl groups may be represented by the following formula -è (CH2) mA- (CH2) nY wherein m and n are integers of 0 - S, A represents 0, NR 'CR' represents hydrogen or lower alkyl having 1 to 6 carbon atoms) , S or A represents a single bond and Y is selected from any of the following groups: 1) Amino or substituted amino: -N (R) or -š (R) 3 wherein R represents any of the following groups: hydrogen; N (R ') 2 (R' is hydrogen or lower alkyl having 1 to 6 carbon atoms), lower alkyl and lower alkoxy having 1 to 6 carbon atoms; lower alkoxy lower alkyl, the varizoo oxide moiety contains 1 to 6 carbon atoms and the alkyl moiety 2 to 6 carbon atoms; cycloalkylC 3 cycloalkylalkyl, wherein the cycloalkyl moiety contains 3 to 6 carbon atoms and the alkylcene denotes 1 '3 k ° 1 fi t ° m0T, Vürvíd two R groups may be attached together with the N atom, to which they are attached to a ring of 3 - 6 carbon atoms. ll) IS 780l + lr47 ~ 6 2) Amidino and substituted amidino: -N = C-N (R) Z á wherein R represents any of the following groups: hydrogen; N (R ') 2 (R' represents hydrogen or lower alkyl having 1-6 carbon atoms); lower alkyl and lower alkoxyl having 1 to 6 carbon atoms, lower alkoxy lower alkyl, wherein the alkoxy moiety contains 1 to 6 carbon atoms and the alkyl moiety 2 to 6 carbon atoms (when the lower alkoxy lower alkyl radical is attached to carbon the alkyl moiety contains 1 to 6 carbon atoms; cycloalkyl and cycloalkylalkyl, wherein containing 1 to 3 carbon atoms two R groups may be bonded together with the atoms to which they are attached to form a ring of 5 to 6 carbon atoms; 3) Guanidino and substituted guanidino: -N} _ _ I g N ( R) z NR varí R has the meaning given under 2). 4) Guanyl and substituted guanyl: -ç = NR r N (R2) In which R has the meaning given under 2). 5) Nitro-containing mono- and bicyclic heterocyclic groups (aromatic and non-aromatic) having 4 to 10 core atoms, wherein the heteroatom or atoms in addition to nitrogen are oxygen or sulfur. Such; heterocyclic groups are illustrated in the following list of radicals (R 'represents H or lower alkyl having 1 to 6 carbon atoms): f) 7804læ47 ~ 6 7804447-6 The following specific acyl radicals falling into this class are representative and suitable: 9 W' | 1 -CCHZCHZNHC-CH3 g fifl -CCUZCHZNHC-H 3 ¶ “-CCH2CHáNHC-NH2 O n -CCH2CHZN (CH3) 2 o -Écu cn (šucn 1 2 z 3 3 3 ¶“ -CCH CHZC-NH 2 2 NH ge. .

- CHZCHZCHZNHC-CH3 O I -¿CH CH z zCHzN (CHs) sne -CCH2CH2CH2N (CH3) 2 R áu fl -ccuzs-c \ NH2 H; NH -CCH S-CH -C It is obvious, however, that any acyl radical can be used according to the invention and thus falls within the same. It may be noted that suitable "blocking groups" R 4 are those subgroups previously designated as aralkyl, haloalkyl, alkanoyloxyalkyl, alkoxynalkyl, alkenyl, substituted alkyl, or aralkoxyalkyl and further the alkylsilyl, wherein the alkyl group contains 1 - 10 carbon atoms. Suitable "blocking groups" R are, for example, benzyl, phenacyl, p-nitrobenzyl, methoxymethyl, trichlorethyl, trimethylsilyl, tributyltin, p-methoxybenzyl, benzhydryl. These blocking groups are preferred because they generally constitute blocking groups which can be easily removed by cefniosporin and penicillin techniques.

Suitable carboxyl blocking groups are benzyl and substituted (\) '(R n 0, R' = H) and R 'represents lower alkoxybenzyl: wherein n is 0 - 2 (n = or nitro.

Preparation of the compounds of the present invention I is conveniently carried out according to the definition of R 6. There are three possibilities: 1) Amidines (R6 = H or R); 2) Guanidines (R6 = NR1R2); and 3) Substituted pseudocarbamides (R6 = OR or SR). The symbols have the specified meaning. 1) Amidines. In general, the amidines of class 1) can be conveniently prepared by reacting the desired N-alkylthienamycin (III) with an imidoester (a) or a substituted imidohalide (b): oRS in 135 / \ __ S / VNH f I 4 In 4. w 'COXR o 1 e NR1 R'R2N = ex' x '@ Rc-on "R (a) (b) wherein R 1, R 2 and R have the indicated meaning; X' represents halogen, such as chlorine and -OR "represent a group which can be removed, wherein R" represents lower alkyl, such as methyl, ethyl and the like.

Suitable solvents for the preparation of the class 1 compounds according to the preceding purification scheme are, depending on the identity of 7804h # 7-6, the thienamycin substrate and the reactant, water, dioxane, tetrahydrofuran (THF), dimethylformamide (DMF), chloroform, acetone , acerenitrile or mixtures thereof. The reaction is carried out at a temperature of 0 to about 25 ° C for 1 to about 6 hours. The exact identity of the reaction solvent is not decisive, nor are the variables of the reaction within the limits described, provided that the reaction solvent is inert or substantially inert during the reaction. of ~ seen the course of the reaction. Suitable reactants include: a) Imido esters: 1 1 2 ß 'Mil "REx ° R" R-Ö-x ° R "x ° = o or s Methyl formimidate, ethyl formimidate, methyl acetimidate, ethyl acetimidate, methylbenzimidate, ethyl 4-pyridyl carboximidate , methylphenylacetimidate, methylsethienylcarboximidate, methyllazidoacetimidate, methylchloroacetimidate, methylcyclohexylcarboximidate, methyl-2-furylcarboximidate, methyl-p-nitrobenzimidate, methyl-2,4-dimethoxybenzimidate, methyl-N-imimimethyl-N-imim-N-imim , methyl-N-isopropyl-formimidate and the like.

Such imidoester reagents (a) are conveniently prepared by various known methods, e.g. 1) Reaction between a nitrile, RCN, and a lower alkanol in the presence of HCl according to the well known Pinner synthesis. _ 2) Reaction between a nitrile, RCN, and a lower alkanol in the presence is a base. The reaction is conveniently carried out at 0 DEG-40 DEG C. in the presence of an excess of the alcohol with a catalytic amount of an alkali metal alkoxide for 15 minutes to 4 hours. 3) Reaction between an amide, RENHRI, and an alkyl chloroformate, such as methyl chloroformate at 4) Reaction between an N-substituted amia, RÉNHR1 or RENn'R2, one equivalent of an alkylating agent such as triethyloxonium fluoroborate in an inert solvent such as ether, chloroform or the like at 0 - 4s ° c. z 3 ° c for 10 minutes to 2 hours. R "5) Conversion of an readily available imidoester, R NR '(R' may be hydrogen) to a desired imidoester, RNR4 by reaction between the former Ru and an alkylamine, R ' NH2, in a mixture of water and an immiscible solvent such as ether or chloroform at 0-3305 for 5 minutes to 1 hour: eg H) Substituted imidohalides Chloropiperidinomethylium chloride, chlorodimethylforminium chloride, chlorodiethylformine and the like .

Such a halide nitroaction component (h) is conveniently prepared according to known methods, such as: Ü 1) Reaction between an N, N-disubstituted amide, RENR logenating agent, such as thionyl chloride, phosgene, phosphorus pentachloride or the like in an inert chloroform, solvent The reaction comprising the reactants (a) can be represented by the following scheme: 3 OR OR I RS I If SCHZCHZN-ç = NR s / W- »Tf-] ~ -scH2cH2r'1H 151 Am IH i 4 Rc-OR ", -N - coxr <404 N mcoxR __________ 0 5 1 wherein OR" denotes the group removed from the imidoester reagent, and R, R 1, R 3, R 4 and X have the indicated meaning. This reaction is particularly suitable for embodiments where R 3 and R 4 represent hydrogen and X represents oxygen.

The reaction comprising the reactants (b) can be illustrated by the following scheme: R _ '1 2 Rhzzwäxxfå xß oR3 RS "'" - A l Q 1 2 G II H-scn2cH2N = cl-NR R x 'R off- N -LcoxR4 mild hydrolysis Å 1555) ------ 1 z PH 3_6 SCHZCHZN fl E-NR R Ae __. N_-L coon R 04 å, wherein the symbols have the specified meaning. When the product Å is desired, R 3 and R 4 suitably represent trimethylsilyl and X represents oxygen. 2) Guanidines. The class Z compounds can be conveniently prepared by reacting III with: fa) an -OR "- (eg O-alkyl-, O-aryl-Jpseudocarbamide or an S-alkyl- or S-aryl-pseudothiourea, or (b) by reacting a class 3 compound (above) with ammonia or an amino compound such as an alkyl, aralkyl or hydroalkylamine.

Suitable solvents for such reactions are water and buffered aqueous pillar organic solvent mixtures at pH 7-9 or anhydrous polar organic solvents such as dimethylformamide or hexamethylphosphoramide at a temperature of 0-40 ° C for 11-24 hours.

Suitable reactants (a) and (b) are: (a) -OR-pseudocarbamides and -SR-pseudothioureas O-methylpseudocarbamide, S-methylpseudothiourea, S-methylpseudothio-nitrourea, 0-2,4-dichlorocarbamyl-p nitrophenyl pseudothiourea, ON, N-trimethyl pseudocarbamide and the like. (b) Amino-reaction components Methylamine, ethylamine, 2-aminopyrimidine, dimethylamine, methylbenzylamine, 3-aminomethylpyridine, 2-aminomethylthiophene, ethanolamine, dimethylamine «ethylamine, N-2- (aminoethyl) pyrrolidine, cyclohexylamine, cyclohexylamine 2-methylallylamine, 3-phenyl-1-propylamine, 2-amino-4-picoline, 2-aminopyridine, 3-amino-4-carbethoxypyrazole, 2-aminopyridine, gg 3-amino-4-carbethoxypyrazole, 2-aminothiazole, 5 -amino-3-methylisothiazyl and 3-amino-1,2,4-thiazole.

Reactions incl. the reactants (a) can be illustrated by the following scheme: P13 / \ I? - ~ scH CH NH fi i 24 2 IURZN-æN-R 'O // - N_- coxR;' <--- R-- W RS 1 z // \\ | , NR R -Éq-sc fl zcnzw-Q 1 NR 4-11-1- coxR 4 0 111 3 wherein R 3, X, R 4, R 1 and R 2 have the meaning given; X "represents H or S and R" has the meaning given and suitably denotes lower alkyl or aryl. 78011447-6 Reactions incl. the reactants (b) can be illustrated by the following scheme: 8:13 lll Q,, I * _ scazcn N = ç-NR1RZ | | l 2 4 '>' <° R ___-__, 04, * ... ~ ___ coxR ß ï / Association in class 3 OH 5 | R - I / ... xl / Tscazcnzrwclz-Nnïnz 1 2 NR 4_N ___ coo @ R where X ° denotes 0 or S and other symbols have the specified meaning. 3) Substituted pseudocarbamides The compounds of class 3 can generally be conveniently prepared by substituting a carbamyl or thiocarbamyl-N-substituted thienamycin compound IVa (see above), e.g. [en Rs X I ”\, / \, _.- JscH2cH2N -% - Nr1crx3 I I _ ,, - l-N 'coon 0 O Iva e'. or PH Rs »1 f scnzcnzn-clzl-NHCHS-. IVa is reacted with an alkylating agent (b), such as an active alkyl or aralkyl halide or sulfate ester.

Suitable solvents in this reaction are lower alkanols, dioxane and acetonitrile at a temperature of 20 to 60 ° C for 1 to 4 hours. Suitable reactants IVa in this reaction are N-alkyl-X-acyl-thienamycins: 3 or R 4, wherein R 3, R 5, X and R 4 are as used herein and R 1 'represents acyl as above and preferably - * NR 1 R 2 or - NR 1 R 2 (R 1 and R 2 have the indicated meaning), such as carbamyl, methylcarbamyl, ethylcarbamyl, phenylcarbamyl, p-bromophenylcarbamyl, phenylthiocarbamyl, methylthiocarbamyl or dimethyl.

Suitable reactants (b), alkylating agents, are methyl iodide, benzyl bromide, dimethyl sulfate, diethyl sulfate, allyl bromide, 2-thienyl bromide, metal allyl bromide, p-nitrobenzyl bromide, methyl chloromethyl ether or the like. The reaction with reactants IVa and (b) can be illustrated by the following scheme: OR3 R5 I _- / -scu en Nc-Nuïaz 'I, - N - 1-coxn4 X' O, oR3 5 k »--K \ Ií -sCH 2 CH 2 N = Q-NR 1 R 2 0-4 N coxlr 'VR wherein X "represents O or S; X ° represents halogen, such as bromine, iodine or alkyl sulphate; RX ° represents the alkylating agent; and R 1, R 5, ii, R 3, X, R4 and R have the meanings given.

The products of the present invention (I) form a wide variety of pharmacologically acceptable salts, such as acid addition salts, e.g. with hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, toluene-p-sulfonic acid and methanesulfonic acid. The salts of the invention are pharmacologically acceptable, non-toxic derivatives which can be used as active ingredient in suitable unit dosage forms. They can also be combined with other drugs to form compositions with a wide range of activities. I 10 15 20 25 30 35 d7aoßn¿v-6 27 The new compounds are valuable antibiotics, which are active against various gram-positive and gram-negative bacteria and can thus be used in human and veterinary medicine. The compounds of the present invention can therefore be used as antibacterial drugs for the treatment of infections caused by gram-positive and gram-negative bacteria, e.g. against Staphylocuccus aureus, Escherichia coli, Klebsiella pneumoniae, Bacillus subtilis, Salmonella typhosa, Pseudomonas and Bacterium proteus. The antibacterial agents according to the invention can furthermore be used as additives to animal feedstuffs, for food preservation and as disinfectants. They can be used, for example, in aqueous compositions in concentrations of 0.1 - 100 parts of antibiotic per million parts of solution to destroy and inhibit the growth of harmful bacteria on medical and dental equipment and as bactericides in industry, e.g. as water-based paints and in backwater from paper mills to inhibit the growth of harmful bacteria.

The products of the present invention may be used alone or in combination as an active ingredient in a variety of pharmaceutical preparations. These antibiotics and their corresponding salts can be used in capsule form or as tablets, powders or liquid solutions or as suspensions or elixirs. They can be administered orally, intravenously or intramuscularly.

The compositions are conveniently presented in a form suitable for absorption in the gastrointestinal tract. Tablets and capsules for oral administration may be in unit dosage form and may contain conventional excipients, such as binders, e.g. syrup, acacia, gelatin, sorbitol, tragacanth or polyvinylpyrrolidone; fillers, e.g. lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine; lubricants, e.g. magnesium stearate, talc, polyethylene glycol, silica; explosives, e.g. potato starch or acceptable wetting agents, such as sodium lauryl sulfate. The tablets may be coated according to known methods. Oral liquid preparations may be in the form of aqueous or oleaginous suspensions, solutions, emulsions, syrups, elixirs, etc. or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.

Such liquid preparations may contain conventional additives, e.g. sorbitol, syrup, methylcellulose, glucose / sugar syrup, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel or hydrogenated edible oils, e.g. almond oil, fractionated coconut oil, oily esters, propylene glycol or ethyl alkanol; preservatives, e.g. methyl or propyl p-hydroxybenzoate or sorbic acid. Suppositories contain conventional suppository bases, e.g. cocoa butter or other glycerides.

Compositions for injection may be presented in unit dosage form in ampoules or in multi-dose containers containing preservatives. The compositions may be in the form of suspensions, solutions or emulsions in oily or aqueous vehicles and may contain formulatory agents such as suspending, stabilizing and / or dispersing agents. Alternatively, the active ingredient may be in powder form for reconstitution with a suitable vehicle, e.g., X-Steriite, pyrogen-free water before use.

The compositions may also be formulated in suitable forms for absorption through the mucous membranes of the nose and throat or bronchial tissues and may conveniently be in the form of powders or liquid sprays or inhalants, lozenges, brushings, etc .; For the treatment of eyes or ears, the preparations can be prepared as individual capsules, in liquid or semi-solid form, or can be used as drops, etc. Local application agents can be prepared in hydrophobic or hydrophilic bases, such as ointments, creams, lotions, make-up , powder etc.

In addition to carriers, the compositions of the invention may contain other ingredients, such as stabilizers, binders, antioxidants, preservative lubricants, suspending agents, viscosity control agents or flavoring agents and the like. In addition, the composites may contain other active ingredients to obtain a third spectrum of antibiotic activity.

For veterinary purposes, the compositions may, for example, be formulated as intramammary formulations in long-acting or rapid-release bases.

The dose to be administered is highly dependent on the condition of the individual to be treated and the weight of the individual, the route of administration and the frequency with which the parenteral route is to be preferred in the case of general infectious and oral in the case of intestinal infections. Generally, an oral daily dose consists of about 1 to about 600 mg of active ingredient per kg of body weight in one or more applications per day. A suitable daily dose for adults is in the range of 15 to 150 mg of active ingredient per kg of body weight. The present compositions may be administered in several unit dosage forms, e.g. in solid or liquid ingestion form. The compositions may contain per unit dose in solid or liquid form from 0.1 to 99% of active material, preferably from about 10 "to 60%. The compositions generally contain from about 15 mg to about 1500 mg of active ingredient; it is advisable to use a dose of about 100 mg to 1000 mg. For parenteral administration, the unit dose is usually the pure compound in weakly acidified, sterile aqueous solution or in the form of a soluble powder, intended for solution.

The invention is illustrated by the following examples. Example 1. Preparation of N-methyl-N-formimidoyl-thienamycin OH In NH H 4 -cyclic CH 3 O CO 2 N-methyl-thienamycin (14 mg) is dissolved in 0.1 N phosphate buffer (2, 5 ml, pH 7) and the solution is adjusted to pH 6.5 using an automatic burette which adds 1N NaOH. While maintaining a pH of 8.5, methyl formimidate hydrochloride (25 mg) is added to the magnetically stirred solution. After 20 minutes, additional methyl formimidate (25 mg) is added. The reaction is allowed to proceed for an additional 25 minutes and the pH is adjusted to 7.0 with 2.5N HCl. The whole solution is then chromatographed on Dowex 50-X4 resin (26 ml, Na + form, 200-400 mesh) and eluted with water. The N-methyl-N-formimidoyl derivative is eluted in 3-4 column volumes and lyophilized to a white solid (3 mg). uv (pH 7, 0.1N phosphate buffer) λ max 298 mn IR (nujol mull) 1760, 1710 cm NMR (100 MHz, D 2 O) 51.32 (d, J = 6Hz, C fl s -CH), 3.12 (s, NCH3), 7.86 (s, Ng = N) Example 2. N-formimidoyl-N-ethylthienamycin A solution of N-ethylthienamycin (5.6 mg) in 2.8 ml of 0.2N phosphate buffer (pH 7) is adjusted to pH 8.5 and ethylformimidate hydrochloride (SO mg) is added. The pH is maintained at 8.5 by the addition of 1N sodium hydroxide solution under the control of a pH state. The mixture is stirred at ZSOC for ZS min and an additional amount (50 mg) of formimidate is added.

After 25 minutes, the reaction mixture is neutralized with dilute hydrochloric acid and chromatographed on a 1.5x1.5 cm column of Dowex SO-X4 resin (Na + form, 200-400 mesh). The column is eluted with water at a fl? 0.5 ml / min and the effluent is monitored by HPLC (6x25 ml C18 Porasil; solvent 0.01N NaHPO 4 solution, flow rate - 2 ml / min, N-ethylthienamycin retention time = 5 min, N-formimidoyl, N- The combined product fractions (UV 42 ODU at 299 nm) are evaporated to 5 ml and lyophilized to a white powder. Example 3. Silylation of N-methylthienamycin To a suspension of N-methyl-thienamycin (8 mg) in 1 ml of tetrahydrofuran under a stream of nitrogen are added hexamethyldisilazane (0.1 ml) and trimethylchlorosilane (20 μl), the mixture is stirred vigorously at ZSOC for 20 minutes and then centrifuged to remove ammonium chloride. the supernatant liquid is evaporated to an oil under a stream of nitrogen and the remaining oil is used directly for further reactions.

Example 4, Cle CL \ @ \ I 3 H c = N \ Th Ncëc a "\ _ / ïcooe \ N> N-methyl-thienamycin _ Preparation of thienamycin-N-methyl-N-piperidin-1-yl-methylene derivative N -methyl-ticnamycin (57 mg) silylcras as previously indicated.

The silylated antibiotic is dissolved in methylene chloride (6 ml) in a sap-stoppered flask at positive nitrogen pressure and cooled in a dry ice-acetone bath. To the magnetically stirred solution is added a solution (180 μl) of triethylamine (644 pmol) in methylene chloride. This is followed by the addition of a solution of chloropiperidinomethylium chloride (67 mg, 453 pmol) in methylene chloride (465 μl). After 1 hour in a dry ice bath, the reaction solution is rapidly added to a tetrahydrofuran-1N phosphate buffer (pH 7.0) (1: 1) solution (50 ml). The mixture is then concentrated in vacuo to 10 ml to give a homogeneous solution. The solution is washed twice with ethyl acetate (Zx5 ml) and ether (ZXS ml) and then briefly placed under vacuum. This aqueous solution is then chromatographed on an XAD-2 resin column (60 ml bed). The product is eluted in 10% aqueous tetrahydrofuran (after water elution) to give the product, which is recovered by lyophilization. Éš2EBEl_É. gu @ ¿NH2 Th Nc fi ånš LCOZQ Û _ 10 15 20 25 780lr4le7-6 -31 Preparation of N-methyl-N-benzimidoyl-thienamycin N-methyl-thienamycin (59 mg) is dissolved in a 33% N, N- dimethylformamide phosphate buffer (0.05N, pH 7) solution (4.5 ml) and adjusted to pH 9.5 using 2.5N NaOH with an automatic burette. The solution is stirred magnetically at 25 ° C and methylbenzimidate-HCl (340 mg) is added all at once. After 30 minutes, the solution is extracted twice with equal volume of chloroform and adjusted to pH 7.0 with dilute aqueous phosphoric acid. The buffered solution is chromatographed on XAD-2 resin (65 ml). The column is eluted first with water and then with 10% aqueous tetrahydrofuran, which elutes the product.

This fraction is concentrated to half volume and lyophilized to give the product.

Example 6. (s: @, s NH Th-LNC \ @Z 1-co cn 2 z cu \ / c = c: 3 H CH3 Brc Preparation of N-methyl-N-benzimidoyl-thienamycin, 3-methyl- Z-butene-X1-ester N-methyl-N-benzimidoyl-thienamycin (5.9 g) is dissolved in hexamethylphosphoramide (100 μl), which contains 1-bromo-3-methyl-Z-butene (4.8 μl) and triethylamine (0.5 μl) and is stirred magnetically at 2 DEG C. After 1 hour, the crude reaction mixture is chromatographed on a 250 .mu.l thick silica gel plate eluting with 8: 2 chloroform / ethanol. The band with Rf 0.2 - Rf 0 3 is removed and eluted with ethanol Benzimidoyl-thienamycin, 3-methyl-2-buten-1-yl ester hydrobromide is isolated as a solid from an ethanol-chloroform solution with hexane.

Example 7.

OH ÉHS // Nxi Th NC; \ NH2 COZH Preparation of N-methyl-N-guanyl-thienamycin N-methyl-thienamycin (8.9 mg) is dissolved in phosphate buffer (0.1N, pH 7.0.7 ml) and N, N-dimethylformamide (0.3 ml) and the solution is adjusted to pH 9.5 by adding 2.5N sodium hydroxide solution. To the magnetically stirred solution is added O-methylisocarbamide hydrogen sulfate (43 ng), which causes a slight decrease in pH. Additional sodium hydroxy solution is added to restore the pH to 9.5 and the solution is stirred for 30 minutes at 23 ° C. The solution is then neutralized to pH 7.1.

The solution, which contains a mixture of N-methyl-thienamycin and 1-methyl-N-guanyl-thienamycin, is chromatographed on a 20 ml Dowex 50x4 resin column (Na + form, 200-400 mesh) and the product is recovered by lyophilization.

Exemgel 8.

G 'OH CH cl CH | Silylated N-methyl1- @ |. 3 /, N-CH 3 thienamycin (CH 3) 2N = CHCl 3%% Q \ H coase Preparation of N-methyl-N-dimethylaminomethylene-thienamycin N-methyl-thienamycin (16.5 mg] is silylated with hexamethyldisilazane (200 hl) and trimethylchlorosilane (60 .mu.l) in the usual manner The cibed X-methylthienamycin is suspended in (ethanol-free) chloroform (1 ml) with magnetic stirring under a nitrogen atmosphere, the mixture is cooled to -4506 and a solution of triethylamine (21 .mu.l) in chloroform (21 ul) is added and then a solution of (chloromethylene) -dimethylammonium chloride (11, š mg) in chloroform (SO p1). The mixture is heated to -25 ° C for 1 hour and phosphate buffer (0.1N, pH 7) (5 ml) is added. The mixture is stirred intensively for 15 minutes. The aqueous phase is separated and contains N-dimethylaminomethylene-thienamycin, which is recovered after chromatography on 1Dowex 50.4-Hurts.

Example 9. on -on | ¿NH2 R. f fl äánnzßäe Th- »mïc srcu occ (cn) Th Ncf | \ z s 3 \ CH; H P c-o-cH 2 O 6 (cH 1 ;: CO 2 Preparation of N-formimidoyl-N-methyl-thienamycin-pivaloxymethyl ester hydrobromide.

N-formimidoyl-N-methyl-thienamycin (10 mg) is dissolved in hexamethylphosphorane (200 μl), which contains bromomethyl pivalate (10 μl) and triethylamine (1 μl) and is stirred magnetically at ZZOC. After 2 hours, the hexamethyl-phosphoramide solution is dissolved in 2 ml of methylene chloride and the product is precipitated with a 50% hexane-ether solution. The precipitate is dissolved in aqueous 10% tetrahydrofuran solution and chromatographed on a column packed with XAD-2 resin. N-formimidoyl-N-methyl-thienamycin-pivaloxymethyl ester is isolated as a solid after elution with tetrahydrofuran of the column and after lyophilization.

Example 10. Preparation of N-ethyl-N-trifluoroacetimidoyl-thienamycin OH c H /, L \ 2 5 --r 'sc fl zcuzn-c = NH 10 / - N-coon CF 3 N-ethyl-thienamycin (199 mg) is dissolved in phosphate buffer (0.1N, pH 7) (7 ml) and adjusted to pH 8.5 with 1N sodium hydroxide solution. While maintaining the pH with an automatic burette, a solution of methyl trifluoroacetimidate (355 μl) in dioxane (2.5 ml) is added at once. After 30 minutes, the pH is restored to 7.0 by the addition of 1N hydrochloric acid.

The solution is then chromatographed on Dowex 50x4 resin (200 ml, Na + form, 200-400 mesh) and eluted with water. The N-ethyl-N-trifluoroacetimidoyl-thienamycin derivative elutes in the first half of the column volume. This eluate is similarly chromatographed on Dowex 50x4 (100 ml, Na + form, 200-400 mesh) and the first column volume is concentrated and chromatographed on XAD-2 resin (30 ml). The N-ethyl-N-trifluoroacetimidoyl-thienamycin derivative elutes in the 2.5 - 5.0 volume which is lyophilized to a white solid.

Example 11. Preparation of N-allyl-N-acetimidoyl-thienamycin one; cn2cH = cH2 // \\ - í / \\ r-scH2cH2N-c = NH 1 CH / - N --- coon 30 N-allyl-thienamycin (190 mg) is dissolved in phosphate buffer (0.1N, pH 7) (13 ml) and cooled in an ice bath with magnetic stirring. The solution is adjusted to pH 8.5 with 2.5N sodium hydroxide solution from an automatic burette. While maintaining pH 8.5, ethyl acetimidate hydrochloride (400 mg) is added portionwise over a few minutes. After a further 40 minutes, the solution is adjusted to pH 7.0 with 2.5N hydrochloric acid. The solution is then crematographed on Dowex 50-X8 resin (250 ml, Na + form, 100-200 mesh) and eluted with water. N-allyl-N-acetimidoyl derivative elutes in 1-2 column volumes (240-520 ml) and lyophilizes to a white solid. . Example 12. Preparation of N-ethyl-N -: (4-pyridyl) (imino) methyl-thienamycin OH CH 2, k 2, zs - (:: In [: scH2cn2N-c = NHz --N coon Kåï] 6 "\ ~ [4 N N-ethylthienamycin (80 mg) is dissolved in aqueous sodium carbonate (z4.1 mg, 0.294 mmol / l 2.0 ml) at zs Methyl isonicotinimidate mg, 0.588 mmol) is dissolved in the solution and the progress of the reaction is effected by set amounts using high performance cL:; - matography (HPLC): Waters instrument; 0.2x61 cm, C18 Bondapak inverted phase column; 1.5 ml / min aqueous THF; UV (254 nm) and R monitors. The reaction is essentially complete after 40 minutes and the reaction solution is chromatographed directly on an 18.4x270 mm XAD resin: column, eluting first with deionized distilled water and then with aqueous 10% THF. The eluate is monitored for red UV and HPLC is used to locate the pure product. The correct fractions are combined and lyophilized to give the product as a colorless, airy powder.

Example 13. Following the procedure of Example 12 but replacing the reagent with an equivalent amount of methyl 4-thiazolecarboximidate is also N-ethyl-N - (4-thiazolyl) (imino) methyl] thienamycin.

Example 14. Preparation of N-allylformamide A mixture of allylamine (5.00 g, 87.6 mmol) and methyl formate (1.3 g, 87.6 mmol) is stirred at 25 ° C for 2 hours. At the end of this time The reaction flask is equipped with a short path distillation head and your desired N-allylformamide is collected at 89-90 ° C / 0.7 mm Hg as a colorless oil. Yield 7.0 g (94%). IR (CHCl 3) 3380, 1680 cm -1; HKH (CHCl 3) 58.1 (1H, broad s), 56.4 - 7.9 (1H, very broad), 55.5 - 1.3 (1H, m), δ4.9 - 5.5 (ZH , m), §5.85 (ZH, m).

Example 15. Preparation of ethyl N-allylformimidate hydrochloride Ethyl chloroformate (Z, 66 g, 24.47 mmol) is added by injection spray 1 to N-allylformamide (2.68 g, 24.47 mmol) in a dry flask under nitrogen.

The resulting mixture is then stirred at 25 ° C for 2 hours, with CC developing rapidly. The reaction mixture is then heated to 45 ° C: until no further gas evolution takes place (2 hours). The viscous product is then cooled and kept in a vacuum of 0.1 nu Hg for 2 hours to remove all volatile material. Example 16. Preparation of methyl N-dimethylaminoformimidate To a stirred solution of N, N-dimethylformhydrazide (0.22 g) in 2.0 ml of chloroform is added under nitrogen methyl chloroformate (0.5 ml) . The mixture is heated at 40 ° C for 3 hours and then evaporated under nitrogen.

The mixture is triturated with anhydrous ether. The supernatant solution is decanted and the residue is dried in a stream of nitrogen.

Yield: 284 mg, NMR CDCl 5 69.13 (CH); 3.80 (OCH 3), 3.01 (N (CH 3) 2).

Example 17. Preparation of cyclopropylformamide A mixture of cyclopropylamine (5.00 g, 87.6 mmol) and methyl phonate (5.26 g, 87.6 mmol) is stirred for 2 hours at 25 ° C (initial exothermic reaction noted). The mixture is then placed in a rotary evaporator to remove MeOH formed during the reaction. The residual material is distilled through a short-wave head to give 6.92 g (93%) of the desired N-cyclopropylformamide as a colorless oil, NMR (CDCl 3) δ 8.1 (1H, broad S), δ Δ - 8.5 (1H, broad), 62.4-3.0 (1H, m), 50.4-1.0 (4H, m).

Example 18. Preparation of ethyl N-cyclopropylformimidate Ethyl chloroformate (4.078 g, 37.58 mmol) is syringed to N-cyclopropylformamide (3.194 g, 37.58 mmol) in a dry flask under N 2. After an induction period of 30 s, rapid gas evolution begins. The resulting reaction mixture is stirred at 25 ° C until no further evolution of gas can be detected (44 hours), after which the viscous product is subjected to a vacuum of 0.5 mm Hg for 1 hour to remove any unreacted ethyl chloroformate. NMR analysis of the product shows the formyl proton at 69.37 as a broad singlet (CDCl 3 solution).

Example 19. Preparation of N-ethyl-N'-dimethylamino-N-formimidoylthienamycin Th NC \ CZH COOH N-ethylthienamycin (115 mg) is dissolved in phosphate buffer (0.1N, pH 7) (7 ml) and the solution of The pH is adjusted to 8.5 with an automatic burette, which adds 1N NaOH. To this stirred solution is added methyl-N-dimethylaminoformimidate hydrochloride (284 mg) while maintaining the pH at 8.5. After 20 minutes, the pH of the solution is adjusted to 7.0 using Z, 5N HCl and the solution is chromatographed on Dowex SOXX4 resin (53 11).

Na + form, 200-400 mesh) and eluted with deionized water. The chromatography is performed in a water jacketed column at 3 ° C. The N-ethyl-H '-dimethylamino-N-formimidoyl derivative elutes in 2 column volumes c: L is lyophilized to a white solid.

Example 20. Preparation of N, N'-dimethyl-N-formimidoyl-thienamycin -OH - N-cH Tha 2 CH 3 COOH N-methyl-thienamycin (140 mg) is dissolved in phosphate buffer (0.1N, pH 7) (1 ml) and the pH of the solution is adjusted to 8.5 with an automatic burette, which adds 1N NaOH. To this solution is added methyl N-methyl-formimide: hydrochloride (200 nl) while maintaining the pH at 8.5. After 40 minutes, the pH is adjusted to 7.0 using 2.5N HCl and the solution is chromatographed on Dowex 50-X4 resin (72 ml, Na + form, 200-400 mesh) eluting with deionized water. The N, N'-dimethyl-N-formimidoyl derivative elutes in 2 column volumes and is lyophilized to a phase: white substance.

Example 21. Preparation of N-allyl-N'-benzyl-N-formimidoyl-tiexzone {nc-zoe ThfLNc mycin \ H CH2-CH = CH2 -COOH N-allyltienamycin (110 mg) is dissolved in phosphate buffer (0.1N, pH 7) (7 nl and the pH of the solution is adjusted to 8.5 using an automatic burette, which adds IN NaOH. A solution of ethyl N-benzylformimidate-Fluoroborate (572 mg) in p-dioxane (2 ml) is added to it. buffered the solution while maintaining the pH at 8.5 After 20 minutes, adjust the pH of the solution to 7.0 with 2.5N HCl and chromatograph on Dowex 50-Xl 2 Hurt (S3 ml, Na + form, 200-400 The chromatography is performed in a water jacketed column at the F * N-allyl-N'-benzyl-N-formimidoyl derivative elutes in 2 column volumes and lyophilizes to a white solid. substance.

Example 22. Preparation of N-ethyl-N'-isopropyl-N-formimidoylthienaminexcin -OH 2 CH (CH 3) 2 -COOH N-ethylthienamycin (110 mg) is dissolved in phosphate buffer (0.1N, pH 7) ( 7 ml) and the pH of the solution is adjusted to 8.5 with an automatic burette which adds 1N NaOH. A solution of methyl N-isopropyl-formimidate hydrochloride (300 mg) in p-dioxane (1 ml) is added to the magnetically stirred buffered solution while maintaining the pH at 8.5. After 25 min, the pH of the solution is adjusted to 7.0 using 2, SN NaOH and chromatographed on Dowex 50-X4 resin (53 ml, Na + form, 200-400 mesh) eluting with deionized water. The chromatography is performed in a water jacketed column at 3 ° C. The N-ethyl-N'-isopropyl-N-formimidoyl derivative elutes in 2 column volumes and lyophilizes to a white solid.

Example 23. Preparation of N-methyl-N) N'-allyl-formimidoyl) thienamycin OH - I 'N / CHZCH-claz J.

To a pre-cooled sample of thienamycin (123 mg), 0.452 mmol) was added 13 ml of cold 0.1N phosphate buffer. The solution is adjusted to pH 9 with 1N sodium hydroxide. To this basic solution is added at 2 ° C a batch of ethyl N-allyl-formimidate hydrochloride (0.5 g). The pH drops to 7.3 and is adjusted to 8.5 with additional sodium hydroxide. The reaction mixture is stirred at 2 ° C for an additional 30 minutes and the pH is adjusted to 7 with cold 0.1N sulfuric acid. The reaction mixture is chromatographed on a Dowex-50x4 column (60 ml, 200-400 mesh) eluting with water at a flow rate of 0.5 ml / cm 2 socket bed. After the first 400 ml of eluate is discarded, the next 150 ml is lyophilized, the desired the product is obtained. Example 24. Preparation of N-methyl-N (S-azidonropionimidoyl) thienamycin .OH §H NCCH Available; J LCOOH Till. To a solution of N-methyl-thienamycin (133 mg) in 10 ml of 0.1 M phosphate buffer flour 7 is added 1.2 g of O-ethyl-3-azidopropionimidate-HCl while maintaining the solution to pH 8.5 with 2.5 NaOH. The mixture is stirred at 0 ° C for 0.5 h, then neutralized to 1.5 N HCl to pH 7.0, concentrated to 5 mL and chromatographed on a Dowex F E53 ZCHZNS (Nu-form) column (4 x 34 cm), which is eluted with water, the desired product being cräw; 1es.

Example 25. Preparation of N-methyl-N (3-aminopropionimidoyl) thienemycin -OH OH NH NH. Ü H / pd H ® Th-TNCCHZCHZN3 2 Th §CCH2CHZNH3 ÉCH3 7 [CH3 L 6 GGI CO2 Na CO2 (I) (II) Example 26. Preparation of N-methyl-N-nitroguanyl-thienamycin N-methyl-thienamycin (T31 mg) is dissolved in a solution of dimethylsulfoxy (10 ml), tri-n-butylamine (0.30 ml) and Z-methyl-1 = nitro-2-thiopsuyl urea (0.3 g). The solution is heated in a water bath at 45 ° C while a stream of nitrogen is intensely bubbled through the solution. After 050 minutes, the solution is concentrated in high vacuum to 1.0 ml and dissolved in 0.05N phosphate buffer pH 7 (7 ml). Unreacted thiopseudocarbamide is precipitated and removed by filtration. The solution is chromatographed on Dowex 50-X4 resin (53 ml, 200-400 mesh, Na + form) and eluted with water. The N-nitroguanyl derivative is eluted in the first column volume and lyophilized to a solid.

Example 27. Preparation of ethyl N-benzylformimidate A solution of 690 mg (5.1 mmol) of N-benzylformamide in 5 ml of methylene chloride is cooled in an ice-water bath and kept under argon. The solution is stirred while adding 4.9 ml (4.9 mmol) of 1M triethyloxonium fluoroborate in ethylene chloride dropwise. After a reaction time of 45 minutes, the mixture is evaporated to dryness under reduced pressure and room temperature, and the residue is dried under reduced pressure over P 2 O 5. NMR spectra of the product in deuterochloroform are completely consistent in a fluoborate etherate complex of ethyl N-benzylformimidate. Example 28. Preparation of N-isopropylformamide Formamide (1.13 g, 0.98 ml) is dissolved in 10 ml of toluene containing toluenesulfonic acid (4.7 g) To this mixture is added isopropylamine (2.95 g, 4.25 ml) The mixture is heated under reflux overnight for a The nitrogen is filtered off and the toluene is evaporated off under reduced pressure, the residual oil is distilled off at 59-6206 / 0.07 mm Hg to give 1.0 g of the desired product.

Example 29. Preparation of methyl N-isopropylformimidate Isopropylformamide (535 mg) is treated with an equivalent amount of ethyl chloroformate (440 μl) for 2-3 hours under nitrogen at 40 ~ 45 ° C. The mixture is washed successively with petroleum ether, anhydrous ether and benzene to give the product as an oil.

Example 30. Preparation of N-ethyl-N-N '' -cyclopropylformimidoyl: thienamycin OH 2 H 5 Cl 2 N 3 * * -C 2 H LCOOH N-ethylthienamycin (100 mg) in 10 ml of 0.1M phosphate buffer with pH 7.0 is adjusted to and maintained at pH 8.5 - 9.0 while 300 mg of ethyl N-cyclopropylformimide hydrochloride are added dropwise to the solution. The mixture is stirred at 23 ° C for 40 minutes, then neutralized and chromatographed on a Dowex 50 X 8 (Na form) ion exchange column (4 x 25 cm). The column is eluted with water and 6.5 ml fractions are collected.

Fractions 43-95 are combined, concentrated and lyophilized to give a solid product.

Example 51. Preparation of 0, N-dimethyl-N- (p-nitrobenzyloxycarbonyl) -ticnamycin-p-nitrobenzyl ester AND CH 1 3 Th Nc-o-cnzf N-methyl-N- (p-nitrobenzyloxycarbonyl) -thienamycin, lithium salt To N-methylthienamycin (220 mg in 60 ml of water at 0 ° C) is added successively 679 mg of NaHCO 3, 60 ml of dioxane and then with stirring 1.1 equivalents of p-nitrobenzyl chloroformate under 1.5 min. The mixture is allowed to react for 10 minutes and then extracted J times with cold ethyl ether. Electrophoresis (0.05 M, pH 7, phosphate buffer, SO V / cn, 20 min) shows that no free N-methyl fi ienamycin is present. in The Aquatic Extrakw; instäiies at pH 2.2 with m H3Po4-1öe- ning and extrahorns 3 times with Et0Ac. The EtOAc extract is dried over MgSO 4, filtered and re-extracted with 0.1N LiOH to pH 5.2.

The final pH is adjusted to 7.0 with UM HSPO4 and the sample is lyophilized. Step B. N-Methyl-N- (p-nitrobenzyloxycarbonyl) thienamycin (p-nitrobexyl ester, A mixture of p-nitrobenzyloxycarbonyl-N-methyl-thienamycin lithium salt (295 mg) and 0.4 g of p- Nitrobenzyl bromide in 3 ml of hexamethyl phosphoramide is stirred for 3 hours at 2 DEG C. The solution is diluted with 50 ml of ethyl acetate and extracted successively with water (3 portions), phosphate buffer pH 7 and saturated sodium chloride solution. over magnesium sulphate and concentrated to 5 ml, whereby the product crystallizes in. The crystals are collected and washed with ethyl acetate.

Step C. 0, N-Dimethyl-N- (p-nitrobenzyloxycarbonyl) -thienamycin (p-nitrebenzyl ester To a solution of 135 mg of N-methyl-Np-nitrobenzyloxycarbonyl-thienomycin (p-nitrobenzyl) ester in 50 ml of methylene chloride at 0 ° C is added with vigorous stirring 0.5 ml of Û, 006M fluoroboric acid in ether-methylene chloride (3: 1) immediately followed by 10 ml of a cooled solution of 0.6M giazomethane in methylene chloride. The diazomethane is decolorized in 1 minute, the solution is extracted with 10 ml of 0,1N phosphate buffer, dried and evaporated to a small volume, the solution is applied to two 20x20 cm contains O, N-dimethyl-Np-nitrobenzyloxycarbonyl-thienamycin-p-nitrebenzylcystic acid eluted with ethyl acetate and the product is recovered by evaporation of cluat.

Example 32. 0, N-Dimethylthienamycin A solution of 20 mg of O, N-dimethyl-N- (p-nitrobenzyloxycarbonyl] thienamycin p-nitrobenzyl ester in 2 ml of tetrahydrofuran and 1 ml of ethanol is hydrogenated at 3.5 kp / cm2, 23 ° C in the presence of 20 mg of platinum oxide for 5 hours. The catalyst is filtered off and 1 ml of 0,1N phosphate buffer with pH 7 is taken to the filtrate, the solution is evaporated under reduced pressure to 1 ml and the mixture is taken up in 5 ml of water and 5 ml. The ethyl acetate layer is removed and the aqueous layer is re-extracted with ethyl acetate and ether and then filtered through Celite.

The aqueous solution is applied to a column (20 ml) of XAD-2 resin.

The column is eluted first with water and then with 10% tetrahydrofuran.

The tetrahydrofuran eluate is concentrated and lyophilized to give essentially pure O, N-dimethylthienamycin.

Example 33. Preparation of O, N-dimethyl-N-formimidoyl-thienamycin and fl, / Äc 3 §H} __S / ^ \ / »nen, N \\ f / en O 5 3 è02H O, N-dimethylthienamycin (14 mg ) is dissolved in 1N phosphate buffer (2.5 ml) at pH 7.0 and the solution is adjusted to pH 8.5 with an automatic burette which adds 1N NaOH. While maintaining a pH of 8.5, methylformimidate hydrochloride (25 mg) is added to the magnetically stirred solution. After 20 minutes, additional methylformimidate (25 mg) is added. The reaction is allowed to proceed for an additional 25 minutes and the pH is adjusted to 7.0 with 2.5N HCl. The whole solution is then chromatographed on Dowex 50-X4 resin (26 ml, Na + form, 200 -400 mesh) eluting with water. The O, N-dimethyl-N-formimidoyl derivative elutes in 3-4 column volumes and is recovered by lyophilization.

Example 34. | o-É-ens m, Th-mc-o-CH - / \ -No n 2 _. / 2 Û -coocH2- -NO2 Preparation of O-acetyl-N-methyl-N- (p-nitrobenzyloxycarbonyl) -tie - Nimycin (p-nitrohensyl) ester To a solution of 50 mg of N-methyl-N- (p-nitrobenzyloxycarbonyl-tin-mycin) -p-nitrobenzyl ester in 0.5 ml of pyridine is added 0.16 ml of acetic anhydride. The mixture is allowed to react at 25 ° C for 3 hours and then dried in a vacuum. The solid residue is dissolved in chloroform and chromatographed on a 20x20 cm -1000n silica gel plate in 3: 1 ethyl acetate-chloroform, in which 0-acetyl-N-methyl-N-p-nitrobenzyloxycarbonyl-thienamycin-p-nitrobenzyl ester is obtained. Example 35. O-acetyl-N-methyl-thienamycin A solution of 20 mg of O-acetyl-N-methyl-N- (p-nitrobenzyloxycarbonyl-cnamycin-p-nitrile begyl ester in 2 ml of tetrahydrofuran and 1 ml hydrogenated at 3.5 kp / cm 2 in the presence of 20 mg of platinum oxide for 2.5 years and 1 ml of 0.1 N phosphate buffer pH 7 to the filtrate. The solution is evaporated under reduced pressure to 2 ml and the mixture is taken up in 5 ml of water and 5 ml of ethyl acetate and centrifugation. The catalyst is filtered off, the ethyl acetate layer is removed and the aqueous layer is extracted with ethyl acetate and ether and filtered through Celite. The aqueous solution is applied to a column (20 ml) of a column (20 ml). The XAD-2 resin is first eluted with water and then with tetrahydrofuran.

The tetrahydrofuran eluate is concentrated and lyophilized to give essentially pure O-acetyl-N-methylthienamycin.

Example 36. Preparation of O-acetyl-N-methyl-N-formimidoyl-thienamine myCOCO3 1 x I O '/,' * "N // _ COF {O-acetyl-N-methylthienamycin (14 mg) is dissolved in O , 1N phosphate buffer at pH 7 (2.5: f¶ and the solution is adjusted to pH 8.5 with an automatic burette which adds 1N NaOH. While maintaining pH 8.5, methyl foil midate hydrochloride (25 ml) was added to the magnetically stirred 20 ml of additional formylimidimide (25 mg) are added, the reaction is allowed to proceed for a further 25 minutes and the pH is adjusted to 7.0 with 2.5N HCl, the whole solution is then chromatographed on Dowex 50-μl resin (26 ml, Na + form). , 200-400 mesh) eluting with water.

The fractions containing O-acetyl-N-methyl-N-formimidoyl-tic: mycine are combined and lyophilized.

Example 37.

Following the procedure set forth in the foregoing text and examples, the following compounds of the present invention are poured. The reagent components, imidoethers and imidohalides used in the reaction with thienamycin or derivatives thereof for the preparation of processes. v; : in the following compounds, are known or can be prepared from the foregoing Compound UW-bøilw-1 OH R CH3 CH3 CH3 CH3 Cïís C11 »J CH3 CH3 CH- J CH3 CH.

J CH- 3 CH3 CH3 CH3 CH CH CH CH- a CH CH 43 / Å _ 3 fifl ~ ._ ~ _scH2cH¿-Nc!: = N__ 1 LNB "Rs R 6” Üzooe ~ H6 JU CH.) H (H13 (IIIs LHS LHS N (CH3) 2 H cFs H JUN H '... ~ _ / -OH sN __ / ä ", H YN N 1," \ H ks / H -cmcnfs-cus H -cH (cH2) 3 H -cnccngs H -CHZCHB H -cH2-cH = cH2 H -c1-12-c = cH2 I CH H -f-ff '\ J cnzcll; -6 7801111117-6 44 Compound R RÖ R1 Rz zz C113 11 -Cnz-Q 1 11 _ \: s C115 11 ~ «<_ / 11 24 C113 11 H zs C113 11 m) 11 26 C113 11 11 27 C113 11 4 : 1 11 zs C113 11 CHZ-Q 11 29 C113 11 -Q-OCHB 11 so C113 11 -O-NHZ 11 31 C11 11 11 3 C119 C1: sz C113 11 G 11 ss C113 11 -C112C1121t o 11 34 C113 11 - C112C112 -Q 11 ss C11 .11 -C11 - (> -o11 11 o 2 36 C11. 11 -C11 Os-CH. 11 a 2 a 37 C113 11 -CHZ-O -N (C113) 2 11 ss C113 11 C113 C2115 39 C113 11 Cz115 C2115 40 C113 11 _ C113 1 C11 (C11313 41 C113 11 C113 ø 42 C113 11 C113 C112C11 = C11¿ 43 1 C113 -C = C112 11 11 44 4 C113 ÜOCH: 11 11 \ .S _, 45 C113 \ / 0 11 '11 45 ... 6 Forenlng RR 47 cn NaN * 3 ¿_ / N Nk 7 f * \ 48 cns CH3 1 N / M 49 CH3 H w N: CH- so nns | y NI 51 (113 (A13 S2 CH3 CH3 S3 CHS CHS 54 CH. CH3 S5 CH3 H S6 -CZHS CH3 57 -c, H5 H 58 -CZHS H 59 -c, H5 cm; oo -cn, ø u 61 -C fl zø H 62 -CH3 H 63 CH3 H 64 CH3 H es CHS NH, en cns Nu, 67 Cllš NH- (III3 68 CH3 NH-CH3 69 CH3 NH2 70 CH3 SCH3 71 CH3 SCH3 72 CH3 H 73 CH3 -CH2Br 74 CH3 -cH2N (cH5) 2 780h # h7-6 -CZHS -CH (CH3) 2 -CH3 -CH-cšcu _ H -CH3 -CH3 -ens u -cuš -cnzcuzou -cH2cH2N (cH5) Z -cH2cH2N (cn3) ¿cus ens H cuz NH 78011447-6 46 1 1 oR "ï '* fo I 1 / \ __ \ / \ = - SCHZCH -N = Cx I A9 1 | 1 I, / J-_. Nl- Coon' LO börvning RR ' IP 'X 75 C113 -C112C11 = C (C113) 2 11 11112 76 C115 -CHZ-Q-ocns 11 11112 71 C113 -Cnzool-MCHS) 3 _ 11 N11C113 o vs C113 -CHZoC-C (C113) 3 11 11112 O _ 79 C2115 -C112o-1š-C (C113) 3 11 11112 o so C115 -CHZCHZ-s-CHS 11 11112 81 C113 -C112-oC-C113 11 N11C113 os: C113 -Cuz-C-ø 11 11112 0. 83 CHS -S-indanyl H NHZ 114 C113 ful idy1 11 1111 ,, ss C113 Na S039 11112 se C113 N11 Posne 11112 9. Sv C113 -C11ZolC | -C (C113) 3 S03 11112 0 ss C113 -C112o-CC (C113) 3 103116 11112 HHHH Cl CHSCQ; Example 38. Preparation of Pharmaceutical Compositions A unit dosage form is prepared by mixing 120 mg of N-methyl-N-formimidoyl-thienamycin with 20 mg of lactose and 5 mg of magnesium stearate and introducing the mixture of 145 mg into a glatin capsule. No. 3. Similarly, by using more of the active ingredient lactose, other dosage forms are used in gelatin capsules No. 3, and in the same way and less it would the larvae, can also be prepared. The following examples illustrate the formulation of a pharmaceutical required to mix more than 145 mg of constituent larger capsules, such as compressed tablets and pill pharmaceutical formulations: Tablet Per tablet N-methyl-N-formimidoyl-thienmycin 125 mg Maize starch, USP 6 mg Dicalcate mg Lactose, USP 190 mg The active ingredient is mixed with the dicalcium phosphate, lactose and about half of the maize starch. The mixture is then granulated with 15% corn starch paste (6 mg) and sieved raw. It is dried at 45 DEG C. and sieved again through sieve No. 16. The rest of the corn starch and magnesium stearate are added and the mixture is beaten into tablets with a diameter of about 12 mm and a weight of 800 mg.

Barenteral solution Ampoule: N-methyl-N-formimidoyl-thienamycin 500 mg Ophthalmic solution N-methyl-N-formimidoyl-thienamycin 100 mg Hydroxypropyl methyl 5 mg Sterile water up to 1 ml Otic solution N-methyl-N-formimidoyl-thienamycin 100 mg Benzylconium chloride 0.1 mg Sterile water up to 1 ml Iopic Silva N-methyl-N-Eormimidoyl-thienamycin 100 may Polyethylene glycol 4000 usP 400 m: 1.0 g Polyethylene glycol 400 USP The active equine component of these preparations may be administered alone or in combination with other biologically active ingredients, e.g. lincomycin, a penicillin, streptomycin, novobiocin, gentamicin, neomycin, colistin and kanamycin, or with other therapeutic agents such as probenecid.

Claims (4)

'N fl lila-l fl- G H2 PATENT CLAIMS A process for the preparation of a compound of the formula f 'on 5 -li "" ieil // -scnzcnzn-c = NR1R2 l AC)' I: "m_n i-coon 6 ¿0 / f R. Wherein A represents a pharmaceutically acceptable counterion , R 5 represents lower alkyl, lower alkenyl or hensyl, RO represents hydrogen, lower alkyl, lower lower alkenyl, lower alkylthio, phenyl, pyridyl, thiazolyl or -NR 1 R ', R 1 and R independently represent hydrogen, lower alkyl, lower alkenyl, cyclo lower alkylamino, phenolamino, phenol or benzyl, characterized in that a compound of the formula 9 "RS //" «-scnzcaznn [::: 1í :: fl- COOH / 0 / I 'vnri R" has the indicated meaning, or a suitable U- and / or carhoxyl derivative thereof is treated with an imidoester NR1 II Rcx ° R "or an imidohalide {R'R2N * = c-xfl X . 'TBÛhlMÜ-G HQ A process for the preparation of a compound according to claim 1, characterized in that a compound of the formula 9 "Rs / \ _ '/ \, ___ f scnzcxlzml O¿L__N__l ~ COOH or a suitable O- and / or carboxyl derivative thereof is treated with x "R ° I R1RZN-C = NR] wherein X" represents O or S and -X "R ° is a group which can be removed. 3. .3. A process for the preparation of a compound according to claim 1, characterized in that a compound of the formula ou ': <5 "9 -scnzcnzfec-NR' RZ L_" 1 "__ L-C063 40 or a suitable O- and / or carboxyl derivative is treated with Nmduz, val-i x 'heweknuf -ou mer -sn. 4. A process for the preparation of a compound according to claim 1, characterized in that a compound of the formula ou 'u5 / _ I \, _...- f -s <: | 1, c || ¿ N <: - N | UR2 I 'M Ho -uoon xo or a suitable O- and / or carboxyl derivative thereof is treated with an alkylating agent to form a compound of the formula 780111447-6 RS * 9 oH II 1 2 w-scuzc fl zm- ( Iz-R R \ 0, / _í-coou x ° u wherein X0 represents O or S. ____l