CS226166B2 - Method of preparing thienamycine derivatives - Google Patents

Description

The present invention relates to certain substituted N-methylene derivatives of the novel antibiotic thienamycin. These compounds and their pharmaceutically acceptable salts, ethers, esters and amides are useful as antibiotics. It is an object of the present invention to provide a process for the preparation of these compounds.

Thienamycin is claimed in U.S. Patent No. 3,950,057 of April 13, 1976 and is used as a starting material in the present invention in the preparation of the compounds of the present invention.

Thienamycin is a compound of structural formula I

OH (I) sch ₂ ch ₂ n ₂

COOH

The substituted N-methylene thienamycin derivatives of the present invention can be represented by the following structural formulas II

OH sch ₂ ch ₂ n = cx

COOH I

2261 66

2261 66 which, depending on the basicity of the amine nitrogen atom (function of the methylene substituents X and X), may correspond to the internal salts of formula II

OH

SCH, CH, N — Ccoo® · (II) which is a canonical form of a single resonant structure which, for example, for the meaning X is -Hr 'Sp and X is R, has the formula II

OH ©

SCH ₂ CH ₂ NH ⁴ -C -u 2 NR ¹ R ² COO ® (II)

For the simplicity of the compounds of the present invention, the formula ThN = C-X may be represented

I * - COOH (II) wherein Th is the bicyclic core of thienamycin and its hydroxyl, amino and carboxyl functional groups are listed and wherein X and X are as defined below.

The compounds of the present invention also include compounds of formula IIa

OR ³ (Ha) sch ₂ ch ₂ n = c — X COX'r 3 'I which may also exist in the form of a salt of formula IIIa

OR ³

LO ^: ©

sch ₂ ch ₂ nh = c - X COX'r 3 'I

A® or which, for simplicity, are illustrated using the above symbol as a compound of formula IIIa

Th ·

³ OR ³ ©

-NH = C-X

AND

Y

COX'fí ³

A (IIIa) wherein the non-critical anion A is selected to provide pharmaceutically acceptable salts such as halides (chlorides, bromides and the like), sulfates, phosphates, citrates, acetates, benzoates and wherein R ³ , X * and R ³ are independently selected from the groups listed below:

X * is oxygen, sulfur or NR ^# , where R * is hydrogen- or R ³ ,

R ³ is a hydrogen atom or is chosen to form pharmaceutically acceptable salts, esters, anhydrides (R ³ is acyl) and amides, these portions of the molecule being those known from the literature of bicyclic beta-lactam antibiotics and these portions of the molecule are listed below,

R ³ is first acyl ^(OR3 group generally is classified as an ester), or 2. R ³ is selected from the group consisting of alkyl, aryl, alkenyl, aralkyl and the like. (This group ^OR3 is generally classified as an ether) R ^j may be also a hydrogen atom.

The term acyl includes alkanoyls including derivatives and analogs thereof such as thio analogues wherein the carbonyl oxygen atom is replaced by a sulfur atom, as well as sulfur and phosphorus acyl analogs such as substituted sulfonyl, sulfinyl and sulfenyl and substituted pentavalent and trivalent phosphorus residues such as substituted phosphorous, phosphorous, phosphonous and phosphonous residues. These R ³ radicals according to the present invention are further calculated below.

New antibiotics are still needed. Due to the widespread use of antibiotics, these do not have constant efficacy, as resistant pathogen strains are produced. In addition, known antibiotics have the disadvantage that they are only effective against certain types of microorganisms. Therefore, research into new antibiotics is ongoing.

Unexpectedly, it has now been found that the compounds of the present invention have a broad spectrum of antibiotic activity and are useful for the treatment of animals and humans and for use in non-animal systems.

According to the present invention, novel antibiotics are prepared which have a core structure of the thienaaycin (I) core, but which are characterized as being substituted N-methylthienamycin derivatives. These antibiotics are active against a broad spectrum of pathogens, including both gram-positive bacteria such as S, aureus, Streptomyces pyogenss and B. subtilis, and gram-negative bacteria such as E. coli, Proteus morganii, Klebsiella, Sorratia and Pseu- »Domonas.

The present invention provides a process for the preparation of thienamycin derivatives of formula (IX)

OH

where

X is hydrogen or S,

Y is -N? R ² ,

2

R, R, and R are independently of one another and are hydrogen, alkyl of 1 to 6 carbon atoms, aminoalkyl of 1 to 6 carbon atoms, and alkenyl of 2 to 6 carbon atoms, characterized in that a compound of formula X is reacted

OH

-N-SCH ₂ CH ₂ NH ₂

COOH (I) or a suitable O- and / or carboxyl derivative with an imidoester of formula III

2η'η ²

RCX ° R ** (III) or with an imidohalide of the formula IV r'r ² n® = c-x '

AND

R

IV (IV) wherein R, R ¹ and R ² are as defined above, -X ° R is a leaving group wherein X ° is an oxygen or sulfur atom, R is an alkyl of 1 to 6 carbon atoms and X * is a halogen atom to form a compound of formula II.

The compounds of the present invention are preferably prepared from thlenamycin (I above). The compounds of the present invention of formula IIIa above, wherein the secondary alcohol and / or carboxyl group are varied, are preferably prepared from either the corresponding O-, carboxyl- or O- and carboxyl derivatives of thlenamycin or compounds of formula II or thienamycin followed by a further reaction of introducing the residues R ³ and R ³ (or -X * R ³ ) or a combination thereof. These starting materials are fully disclosed in the following U.S. patents, which are incorporated herein by reference: U.S. Patent No. 4,220,330, which claims O-derivatives of thlenamycin (esters and ethers of secondary alcohol groups of thlenamycin), compounds of structural formula Ia

OR ³

O'

Nsch ₂ ch ₂ nh ₂

COOH (Ia) also discloses the N-acyl derivatives of thlenamycin of structural formula Ib

OH

-N ._sch ₂ ch ₂ nr ¹ 'r ² ''COOH (lb)

Wherein S and R are selected from the group consisting of hydrogen and acyl is the term acyl as defined in reference to the application below.

U.S. Pat. No. 4,181,773 discloses thienamycin carboxy derivatives of Structural Formula 1c

OH

JO— ^ονΠ2 '·

^L- COX'r3 '(1c) also refers to N-aeyl and thienamycin carboxy derivatives of structural formula Id

OH

U.S. Patent No. 4,226,870 discloses N-acyl and O- and carboxy derivatives of thienamycin of structural formula Ie

OR ²

----__ sch ₂ ch ₂ to ¹ 'r ² '

--- N-U-COX'r3 '(le)

The compounds of the present invention of the formula IIa can be prepared from the corresponding derivatives Ia, 1b, 1c, 1d, 1e or the compounds of the formula IIa can be prepared directly from thien-mycine of the formula I. (I → II) followed by introduction of a substituent and / or X * R-® (II → Ha) as described in the above-mentioned US patents.

The radicals R i, R ^j, X 'and acyl (R and R in relation k.strukturám Ia, Ib, Ic, Id, Ie are defined as follows:

i *

-COX ^ R ² identification

In general, the compounds of the present invention (IIIa, supra), the radicals represented by -COX * r3 are, inter alia, -COOH (X * is an oxygen atom and P1 is a hydrogen atom) and any radicals known to be effective pharmaceutically acceptable esters, anhydrides ( E is acyl) amides in bicyclic beta-lactam antibiotics such as cephalosporins and penicillins and analogs thereof.

□ '

Suitable radicals (R) include conventional protecting or carboxyl-blocking groups. The term blocking group is used herein in the same sense as disclosed in U.S. Patent No. 3,697,515, which is incorporated herein by reference. The pharmaceutically acceptable thienamycin derivatives of the present invention belonging to this group are listed below. Suitable blocking esters include those selected from the following list, which is formulated by way of example, not as an exhaustive list of possible ester groups where X '= O and R 6 are:

I. R 6 = CR ^and R ^b R ^c , wherein at least one of the substituents R ^a R ^{b and} R ^c is an electron donor, for example p-methoxyphenyl, 2,4,6-trimethylphenyl, 9-anthryl, methoxy, CH 3 SCH 4, tetrahydrofur-2-yl, tetrahydropyran-2-yl, or fur-2-yl. The remaining substituents R ^a , R x ³ and R 0 may be hydrogen atoms or organic substituents. Suitable ester groups of this type include p-methoxybenzyloxycarbonyl and 2,4,6-trimethylbenzyloxycarbonyl.

II. R 6 = CR ^and R ^b R ^c , wherein at least one of R ^a , R ^b and R ^c is an electron withdrawing group, for example benzoyl, p-nitrophenyl, 4-pyridyl, tri-chloromethyl, tribromomethyl, iodomethyl, cyanomethyl, ethoxycarbonylmethyl, 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.

III. R 6 = CR ^and R ^b R ^c , wherein at least two of the substituents R ^a , R ^b and R ^c are hydrocarbon radicals such as alkyl, for example methyl or ethyl or aryl, for example phenyl and the remaining groups R ^a , R ^b and R °, if they are one, they are hydrogen atoms. Suitable esters of this type are tert-butoxycarbonyl, tert-aryloxycarbonyl, diphenylmethoxycarbonyl and triphenylmethoxycarbonyl.

IV. R 1 = R 1 wherein R 1 is adamantyl, 2-benzyloxyphenyl, 4-methylthiophenyl or tetrahydropyran-2-yl.

Silyl esters falling into this category of blocking groups are preferably prepared from halogensilanes or silazanes of the formula:

R ^{4 3} SiX '; R ^{4 2} SiX '₂; R ^{4 3} Si ¹ NR ⁴ 2; R ⁴ 3Si.NH.COR ⁴ ; R ⁴ 3Si.NH.CO.NH.SiR ⁴ 3; R ⁴ NH.CO.NH.SiR ⁴ 3 or R ⁴ C (OSiR ⁴ 3); HN (SiR ⁴ 3) ₂ , wherein X 'is a halogen atom such as a chlorine or bromine atom, and wherein the various R ⁴ groups which may be the same or different are hydrogen atoms or alkyls such as methyl, ethyl, n-propyl isopropyl, aryl, for example phenyl or arylalkyl, for example benzyl.

More generally, the pharmaceutically acceptable carboxyl derivatives of the present invention are those derived from the reaction of thienamycin or N -chromed thienamycin, such as N-acylated thienamycin, with alcohols, phenols, mercaptans, thiophenols, acylating reagents and the like. For example, esters and amides are the starting compounds mentioned above and the end products have the following group at the 2-thienamycin ring position: -COX'r 3, where X 'is an oxygen, sulfur or NR' atom (R 'is H or R') and R is alkyl having 1; up to 10 carbon atoms which is branched or unbranched such as methyl, ethyl, t-butyl, pentyl, decyl and the like; carbonylmethyl, including phenaeyl, p-bromophenacyl, p-t-butylphenaoyl, acetoxyacetylmethyl, pivaloxyacetylmethyl, carboxymethyl, and their alkyl and aryl esters, alpha-carboxy-alpha-isopropyl; aminoalkyl including 2-methylaminoethyl, 2-diethylaminoethyl, 2-acetamidoethyl, phthalimidomethyl, succinimidomethyl; alkoxyalkyl wherein the alkoxy moiety has 1 to 10, preferably 1 to 6 carbon atoms and which may be unbranched or branched or cyclic and the alkyl moiety has 1 to 6 carbon atoms such as methoxymethyl, ethoxymethyl, isopropoxymethyl, decyloxymethyl, ethoxypropyl, decyloxypentyl, cyclohexyloxymethyl and the like; alkanoyloxyalkyl wherein the alkanoyloxy moiety is unbranched or branched by 8 to 6 carbon atoms and the alkyl moiety has 1 to 6 carbon atoms such as acetoxymethyl, pivaloyloxymethyl, acetoxyethyl, propionyloxyethyl, acetoxypropyl and the like; haloalkyl wherein the halogen is a chlorine, bromine, fluorine or iodine atom and the alkyl moiety is unbranched or branched with 1 to 6 carbon atoms, for example 2,2,2-trichloroethyl, trifluoroethyl, 2-bromopropyl, dliodomethyl, 2-chloroethyl, 2- bromoethyl and the like; alkenyl of 1 to 10 carbon atoms, either straight or branched, for example allyl, 2-propenyl, 3-butenyl, 4-butenyl, 4-pentenyl, 2-butenyl, 3-pentenyl, 3-methyl-3-butenyl, metallyl, 1,4-cyclohexadien-1-ylmethyl and the like;

alkynyl of 1 to 10 carbon atoms, either linear or branched, for example 3-pentenyl, propargyl, ethinyl, 3-butin-1-yl and the like; alkanoyl, either straight or branched having 1 to 10 carbon atoms such as pivaloyl, acetyl, propionyl and the like; aralkyl or heteroaralkyl wherein alkyl has 1 to 3 carbon atoms and hetero is 1 to 4 heteroatoms selected from O, S or N, such as benzyl, benzhydryl, and substituted benzyl, benzhydryl or, for example, benzyl or benzhydryl substituted with 1 to 3 substituents such as benzyl, phenoxy, halogen, lower alkyl, lower alkanoyloxy of 1 to 5 carbon atoms, lower alkoxy, residroxyl, nitro, blocked carboxy or combinations thereof, for example p-chlorobenzyl, o-nitrobenzyl, 3,5-nitrobenzyl, p -methoxybenzyl, m-benzoylbenzyl, p-butylbenzyl, m-phenoxy benzyl, p-benzoylbenzyl, p-nitrobenzyl, 3,5-dichloro-4-hydroxybenzyl, p-methoxycarbonylbenzyl, p-methoxybenzhydryl, p-carboxybenzyl, the last one being free acid, ester or sodium salt, 2,4,6-trimethylbenzyl, p-piveloyloxybenzyl, p-butoxycarbonylbenzyl, p-methylbenzyl, p-benzoyloxybenzyl, p-acetoxybenzyl, p-2-ethylhexenoylbenzyl, p-ethoxycarbonylbenzyl, p-benzoylthi -benzamidobenzyl, o pivaloyloxybenzyl, m-pivaloyloxybenzyl, p-isopropoxybenzyl, p -butoxybenzyl, as well as their cyclic analogs, 2,2-dimethyl-5-cumaranmethyl, 5-indanylmethyl, p-trimethylsilylbenzyl, 3,5-bis-t-butoxy-4 -hydroxybenzyl; 2-thienylmethyl, 2-furylmethyl, 3- t -butyl-5-isothiazolmethyl, 6-pivaloyloxy-3-pyridazinylethyl, 5-phenylthio-1-tetrazolylmethyl and the like (using lower alkyl or lower alkoxy means a chain of 1 to 4 atoms) or phthalidyl or phenylethyl, 2- (p-methylphenyl) ethyl and arylthioalkyl analogs, aryloxyalkyl, wherein aryl is 3 preferably phenyl with 0 to 3 substituents, preferably 0 or 1 substituents in the ortho or para position, and alkyl has 1 to 3 carbon atoms. 6 carbon atoms, for example (4-methoxy) phenoxymethyl, phenoxymethyl, (4-chloro) phenoxymethyl, (4-nitro) phenoxymethyl, (4-benzyloxy) phenoxymethyl, (4-methylphenoxymethyl, (4-benzyloxy) phenoxy) ethyl, (4-methyl) phenoxymethyl, (2-methoxy) phenoxymethyl, (1-phenoxy) ethyl, (4-amino) phenoxymethyl, (4-methoxy) phenylthiomethyl, (4-chloro) phenylthiomethyl, phenylthioethyl, aryl, wherein aryl is phenyl , 5-indanyl or substituted phenyl with 0 to 3 substituents, preferably 0 or 1 substituents in the ortho or para position, for example (4-methyl) phenyl, (4-hydroxy) phenyl, (4-t-butyl) phenyl, p -nitrof enyl, 3,5-dinitrophenyl or p-carboxyphenyl, the latter being either free acid or sodium salt; aralkenyl wherein aryl is phenyl and alkenyl has 1 to 6 carbon atoms such as 3-phenyl-2-propenyl; aralkoxyalkyl wherein the aralkoxy group is benzyloxy and alkyl of 1 to 3 carbon atoms such as benzyloxymethyl, (4-nitro) benzyloxymethyl, (4-chloro) benzyloxymethyl, alkylthioalkyl wherein the alkylthio group has 1 to 10, preferably 1 to 6 carbon atoms, which may be unbranched or branched, the cyclic and alkyl moieties of 1 to 6 carbon atoms such as methylthioethyl, ethylthioethyl, cyclohexylthiomethyl, decylthiobutyl, methylthiopropyl, isopropylthioethyl, methylthiobutyl and the like.

In addition to the esters (and thioeaters) mentioned above, the present invention also includes amides, i.e. compounds wherein X 'is the -NS'-group. Examples of such amides are those wherein R * is selected from the group consisting of hydrogen, methyl, ethyl, phenyl, p-methoxyphenyl, benzyl, carboxymethyl, methylthioethyl and heteroaryl; also included in the substituent -COX'R 4 are anhydrides wherein r 3 is acyl, for example, benzyloxycarbonyl, ethoxycarbonyl, benzoyl and pivaloyl.

The most preferred -COX'S 4 groups of the present invention are those wherein (with respect to structure IIIa above) X 'is an oxygen, sulfur or NR' atom (R 'is selected from the group consisting of hydrogen and lower alkyl); and R is selected from the group consisting of lower alkyl, lower alkenyl such as metallyl, 3-methylbutenyl, 3-butenyl and the like; methylthioethyl; benzyl and substituted benzyl such as p-t-butylbenzyl, s-phenyloxybenzyl, p-pivaloyloxybenzyl, p-nitrobenzyl and the like; pivaloyloxymethyl, 3-phthalidyl and acetoxymethyl, propionyloxymethyl, acetylthiomethyl, pivoylthiomethyl, allyl, 4-butenyl, 2-butenyl, 3-methyl-2-butenyl, phenacyl, acetoxyacetylmethyl, aetoxymethyl, p-acetoxybenzyl, p-pivaloyloxybenzyl, p-pivaloyloxybenzyl, p-pivaloyloxymethyl 5-indanylaethyl, 5-indanyl, benzyloxymethyl, ethylthioethyl, methylthiopropyl, methoxycarbonyloxymethyl, ethoxycarbonyloxyaethyl, diaethylaminoacetoxymethyl, crotonolacton-3-yl and acstamidomethyl.

In a general sense, the present invention is the structure IIa (above), the radical R ^J is hydrogen except for the first acyloxy (-OlP group generally is classified as an ester), or 2. R is selected from the group consisting of alkyl, aryl, arylalkyl etc., So that -OR ³ is classifiable as ether. For ester compounds (1), R 1 is selected from the group consisting of the following definitions of acyl groups (p = 1). In the so-called ether compounds (2) of the present invention, R 1 is selected from the same acyl radicals,

II wherein the carbonyl moiety -C- or more generally -ΟΧ is omitted (p = 0); thus R ³ is selected from the group consisting of the following radicals, wherein all symbols have the meaning given below:

'2'

H and R 1 are selected from the above moieties where p = 1. Thus, with respect to the definition of R ¹ , R ¹ and R ² , the acyl residue may be, inter alia, a substituted or unsubstituted aliphatic, aromatic or heterocyclic, arylaliphatic or heterocyclylaliphatic carboxylic acid residue. , substituted or unsubstituted carbamyl or carbothioic acid. One group of acyl residues can be represented by the general formula:

X

Wherein X is an oxygen or sulfur atom and R is a hydrogen atom, an amino group, a substituted amino group such as alkyl and a dialkylamino group wherein the alkyl moiety contains from 1 to 6 carbon atoms, substituted or unsubstituted, branched or unbranched alkyl wherein an alkyl radical containing from 1 to 6 carbon atoms, a mercapto group, an aryloxy group containing from 6 to 10 carbon atoms, an alkenyl or alkynyl group containing from 2 to 6 carbon atoms, an aryl such as phenyl, an arylalkyl such as benzyl, a cycloalkyl containing from 3 to 6 carbon atoms or heteroaryl or heteroaralkyl (mono- and bicyclic) wherein the alkyl moiety contains 1 to 3 carbon atoms and the heterocyclic ring contains from 4 to 10 atoms and the heteroatom or heteroatoms are selected from the group consisting of O, K and S. These above groups they may be unsubstituted or substituted radicals such as OH, SH, SR (R is lower alkyl or aryl such as phenyl) alkyl or alkoxy of 1 to 6 carbon atoms, such as m halogen such as Cl, Br, F and J, cyano, carboxy, sulfamino, carbamoyl, sulfonyl, azido, amino, substituted amino such as alkylamino including quaternary ammonium, wherein the alkyl group contains from 1 to 6 carbon atoms, haloalkyl such as trifluoromethyl, carboxyalkyl, carbamoylalkyl, N-substituted carbamoylalkyl, wherein the alkyl portion of the foregoing four radicals contains 1 to about 6 carbon atoms, amidino, guanidino, N-substituted guanidino, guanidino lower alkyl and the like.

Examples of such acyl groups are those wherein R is benzyl, p-hydroxybenzyl, 4-amino-4-carboxybutyl, methyl, cyanomethyl, 2-pentenyl, n-amyl, n-heptyl, ethyl 3- or 4-nitrobenzyl, phenethyl, beta, beta-diphenylethyl, methyldiphenylmethyl, triphenylmethyl, 2-methoxyphenyl, 2,6-dimethoxyphenyl ,. 2,4,6-trimethoxyphenyl, 3,5-dimethyl-4-isoxazolyl, 3-butyl-5-methyl-4-isoxazolazol, 5-methyl-3-phenyl-4-isoxazolyl, 3- (2-chlorophenyl) -5 -methyl-4-isoxazolyl, 3- (2,6-dichlorophenyl) -5-methyl-4-isoxazolyl, D-4-amino-4-carboxybutyl, D-4N-benzoylamino-4-carboxy-n-butyl, p-aminobenzyl, o-arainobenzyl, 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-isothiazolylmethyl, 4-isothiazol 5-isothiazolylmethyl, guanylthiomethyl, 4-pyridylmethyl, 5-isoxazolylmethyl, 4-methoxy-5-isoxazolylmethyl, 4-methyl-5-isoxazolylmethyl, 1-imidazolylmethyl, 2-benzofuranylmethyl, 2-indolylmethyl, 2-phenylvinyl, -phenyletinyl, 1-aminocyclohexyl, 2- and 3-thienylaminomethyl, 2- (5-nitrofuranyl) -vinyl, phenyl, o-methoxyphenyl, o-chlorophenyl, o-phenylphenyl, p-aminomethylbenzyl, 1- (5-cyanotriazolyl) methyl, difluoromethyl, dichloromethyl, dibromomethyl, 1- (3-methylimidazolyl) methyl, 2- or 3- (5-carboxymethylthienyl) methyl, 2- or 3- (4-carbamoylthienyl) methyl, 2- or 3- (5-methylthienyl) methyl , 2- or 3- (methoxythienyl) methyl, 2- or 3- (4-chlorothienylmethyl), 2- or 3- (5-sulfothienyl) methyl, 2- or 3- (5-carboxythienyl) methyl, 3- (1, 2,5-thiadiazolyl) methyl, 3- (4-methoxy-1,2,5-thiadiazolyl) methyl, 2-furylmethyl, 2- (5-nitrofuryl) methyl, 3-furylmethyl, 2-thienylmethyl, 3-thienylmethyl, tetrazolylmethyl, benzamidinomethyl and cyclohexylamidinomethyl.

The acyl groups may also be radicals of the formula

X

Π

-C (CH8) ZR wherein X is O or S and n is 0 to 4, Z is oxygen, sulfur, carbonyl or nitrogen and R6 is as defined above.

Examples of substituents

- (CH ₂ ) _n ZR · are allylthiomethyl, phenylthiomethyl, butylmercaptomethyl, alpha-chlorocrotylmercaptomethyl, phenoxymethyl, phenoxyethyl, phenoxybutyl, phenoxybenzyl, diphenoxymethyl, dimethylmethoxyethyl, p-methylbutoxymethyl, 4-methoxyphenoxymethyl, 4-methoxyphenoxymethyl; phenoxymethyl, p- (carboxymethyl) phenylthiomethyl, 2-thiazolylthiomethyl, p- (sulfo) phenoxymethyl, p- (carboxymethyl) phenylthiomethyl, 2-pyrimidinylthiomethyl, phenethylthiomethyl, 1- (5,6, 7,8-tetrahydronaphthyl) oxomethyl, N -methyl-4-pyridylthio, benzyloxy, methoxy, ethoxy, phenoxy, phenylthio, amino, methylamino, dimethylamino, pyridiniummethyl, trimethylammonium-methyl, cyanomethylthiomethyl, trifluoromethylthiomethyl, 4-pyridylethyl, 4-pyridylpropyl, 4-pyridylbutyl, 3-imidazolylethyl -imidazolyipropyl, 3-imidazolylbutyl, 1-pyrroloethyl,

1-pyrrolopropyl and 1-pyrrolobutyl.

Alternatively, the acyl group may be a radical of formula

X

- $ - CHR k

wherein R is as defined above and R 'is a residue such as amino, hydroxyl, azido, carbamoylguanidino, amidino, acyloxy, halogen, such as Cl,

F, Br, J, sulfamino, tetrazolyl, sulfo, carboxyl, carbalkoxy, phosphono and the like.

Examples of substituents of formula

2261Ó6

-CH-R

are alpha-aminobenzyl, alpha-amino- (2-thienyl) methyl, alpha- (methylamino) benzyl, alpha-aminomethylmercaptopropyl, alpha-amino-3- or 4-chlorobenzyl, alpha-amino-3- or 4-hydroxybenzyl, alpha -amino-2,4-dichlorobenzyl, alpha-amino-3,4-dichlorobenzyl, D (-) - alpha-hydroxybenzyl, alpha-carboxybenzyl, alpha-amino (3-thienyl) methyl D (-) - alpha-amino- 3-chloro-4-hydroxybenzyl, alpha-amino (cyclohexyl) methyl, alpha- (5-tetrazolyl) benzyl, 2-thienylcarboxymethyl, 3-thienylcarboxymethyl, 2-furylcarboxymethyl, 3-furylcarboxymethyl, alpha-sulfaminobenzyl, 3-thienylsulfaminomethyl, alpha - (N-methylsulfamino) -benzyl, D (-) - 2-thienylguanidinomethyl, D (-) - alpha-guanidinobenzyl, alpha-guanylureidobenzyl, alpha-hydroxybenzyl, alpha-azidobenzyl, alpha-fluorobenzyl, 4- (5-methoxy- 1,3-oxadiazolyl) aminomethyl, 4- (5-methoxy-1,3-oxadiazolyl) hydroxymethyl, 4- (5-methoxy-1,3-sulfadiazolyl) hydroxymethyl, 4-C5-chlorothienyl) eminomethyl, 2- (5-chlorothienyl) hydroxymethyl, 2- (5-chlorothienyl) carboxymethyl, 3- (1,2-thiazol-4-aminomethyl, 3- (1,2-thiazolyl) -hydroxymethyl, 3 - (1,2-thiazolyl) carboxymethyl, 2-0,4-thiazolyl) aminomethyl, 2- (1,4-thiazolyl) hydroxymethyl, 2- (1,4-thiazolyl) carboxymethyl, 2-benzothienylaminomethyl, 2- benzothienylhydroxymethyl, 2-benzothienylcarboxymethyl, alpha-sulfobenzyl, alpha-phosphonobenzyl, alpha-diethylphosphono and alpha-monoethylphosphono.

Other acyl radicals of this group, wherein X = oxygen, are radicals of the formula

Ϊ 45

-cchr ^{4 r->} wherein R ^ and R ^ are as defined below. R 6 is hydrogen, halogen, such as chlorine, bromine, fluorine, iodine, amino, guanidino, phosphonosubstituted, hydroxyl, tetrazolyl, carboxyl, sulfo or sulfamino; is phenyl, substituted phenyl, a monobicyclic heterocyclic radical containing one or more oxygen, sulfur, or ring nitrogen atoms such as furyl, quinoxalyl, thienyl, quinolyl, quinazolyl, thiazolyl, isothiazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl and similar substituted heterocycles, phenylthio phenyloxy, lower alkyl of 1 to 6 carbon atoms, heterocyclic or substituted heterocyclic thio or cyano.

5

The substituents on the R and R moieties may be halogen, carboxymethyl, guanidino, guanidinomethyl, carboxamidomethyl, aminomethyl, nitro, methoxy or methyl. When R 6 is selected from the group consisting of hydrogen, hydroxy, amino or carboxy, and R 6 is selected from the group consisting of a phenyl or a 5- or 6-membered heterocyclic ring having one or two sulfur, oxygen or nitrogen atoms as heteroatoms such as tetrazolyl, thienyl , furyl and thienyl, examples include the following acyl radicals: phenylacetyl 3-bromophenylacetyl, p-aminomethylphenylacetyl, 4-carboxymethylphenylacetyl, 4-carboxyamidomethylphenylacetyl, 2-furylaethyl, 5-nitro-2-furylacetyl, 3-furylacetyl, 2-furylacetyl, 2-furylacetyl, , 5-chloro-2-thienylacetyl, 5-methoxy-2-thienylacetyl, alpha-guenidino-2-thienylacetyl, 3-thienylacetyl, 2- (4-methylthienyl) acetyl, 3-isothiazolylacetyl, 4-methoxy-3-isothiazolylacetyl, 4-isothiazolylacetyl, 3-methyl-4-isothiazolylacetyl, 5-isothiazolylacetyl, 3-chloro-5-isothiazolylacetyl, 3-methyl-1,2,5-oxadiazolylacetyl, 1,2,5-thiadiazolyl-4-acetyl, 3- methyl-1,2,5-thiadiazolylacetyl, 3-chloro-1,2,5-thiadiazoles lacetyl, 3-methoxy-1,2,5-thiadiazolylacetyl, phenylthioacetyl, 4-pyridylthioacetyl, cyanoacetyl, 1-tetrazolylacetyl, alpha-fluorophenylacetyl, D-phenylglycyl, 4-hydroxy-D-phenylglycyl, 2-thienylglycyl, 3-thienylglycyl, phenylmalonyl, 3-chlorophenylmalonyl, 2-thienylmalonyl, 3-thienylmalonyl, alpha-phosphonophenylacetyl, alpha-aminocyclohexadienylacetyl, alpha-sulfaminophenylacetyl, alpha-hydroxyphenylacetyl, alpha-tetrazolylphenylacetyl and alpha-sulfophenylacetyl.

The acyl radical may also be selected from the group consisting of sulfur atom (1) and phosphorus atom (2) / V

1

(0) m (1 (X) n 1 -S-Y ° and -P-Y * II l ,. {0) n Y 1 zV £

wherein for formula 1 pan are integers 0 or 1 and Y ° = O ® M ®, -R (R) ,, ah ", wherein M ® is a hydrogen atom, an alkali metal cation or an organic base, and B ** has the meaning given above, for example alkyl, alkenyl, aryl and heteroaryl, U of formula 2 X is O or S; n = 0 or 1 and X * and Y ** are selected from the group consisting of OOiv, -Κ (Κ) ₂ , Η and ZR ¹ , wherein all symbols have the meaning given above, for example R 1 and ZR are alkyl, alkenyl, aryl, heteroaryloxy, Y * and Y including B. parts of the molecule may be joined together to form a cyclic ester, esteramide and amide.

Examples of compounds are O- (methylsulfonyl) thienamycin, O- (p-nitrophenylsulfonyl) thienamycin, O- (p-chlorophenylsulfinyl) thienamycin, O- (o-nitrophenylsulfenyl) thienamycin, O-sulfamoylthienamycin, O-dimethylsulfamoylthienamine thienamycin. -sulfonic acids.

Examples of compounds of formula (6) are O- (dimethoxyphosphino) thienamycin, O- (dibenzyloxyphosphino) thienamycin, O- (dihydroxyphosphino) thienamycin disodium salt, O- (dimethoxyphosphinyl) thienamycin, O-diraethoxyphosphinothioyl) thienamycin, thienamycin, thienamycin, thienamycin, thienamycin, thienamycin, thienamycin. , and O- (dihydroxyphosphinyl) thienamycin disodium salt. The definitions of R ¹ and R ² radicals, and does not include the second

Particularly preferred acyl residues are those selected from the group consisting of commonly known N-acyl-blocking or protecting groups such as carbobenzyloxy, book-substituted carbobenzyloxy, such as o- and p-nitrocarbobenzyloxy, p-methoxycarbobenzyloxy, bromoacetyl, chloroacetyl, chloroacetyl t-butoxycarbonyl, trifluoroacetyl, bromoethoxycarbonyl, 9-fluorophenylmethoxycarbonyl, dichloroacetyl, o-nitrophenylsulfenyl, 2,2,2-trichloroethoxycarbonyl, bromo-t-butoxycarbonyl, phenoxyacetyl; non-acyl protecting groups such as trisyl alkylsilyl, for example trisyl silos 1 and tert-butyldiraethyl,

The following radicals according to the foregoing acyl definition are particularly preferred for the R 1 structures of Formula IIa: formyl, acetyl, propionyl, butyryl, chloroacetyl, methoxyacetyl, aminoacetyl, methoxycarbonyl, ethoxycarbonyl, methylcarbamoyl, ethylcarbamoyl, phenylthiocarbonyl, 3-aminopropionyl, 4-aminobutyryl , Ν, Ν-dimethylaminoacetyl, Ν, Ν, Ν-trimethylaminoacetyl, 3- (N, N-dimethyl) aminopropionyl, 3- (N, N, N-trimethyl) aminopropionyl, Ν, Ν, Ν-triethylaminoacetyl, pyridiniumacetyl, guanidinoacetyl 3-guanidinopropionyl N ^ -metylguanidinopropionyl, hydroxyacetyl, 3-hydroxypropionyl, acryloyl, propionyl, malonyl, phenoxycarbonyl, amidinoacetyl, acetamidinoacetyl, amidinopropionyl, acetamidinopropionyl, guanylureidoacetyl, guanylkarbamoyl, karboxymetylaminoacetyl, sulfoacetylaminoacetyl, fosfonoacetylaminoacetyl N ^ -dimetylaminoacetamidinopropíonyl, -ureidocarbonyl, dimetylaminoguanylthioacetyl 3- (1-methyl-4-pyridinium) propionyl, 3- (5-aminoimidazol-1-yl) propiononyl, 3-methyl-1-imidazolium-

acetyl, 3-sydonylacetyl, o-aminomethylbenzoyl, o-aminobenzoyl, sulfo, phenoquinone, 0 with with S 0 J (OCl ₃ ) ₂ , and -P (OCH ₃ ) ₂ , !! , .OCH, -p <» -••About me 11, ii jNÍCH -P _{3) 2,} J _2, -P-.N _{(CH3) 2} 'axis 0 with

-I [N _{(CH3) 2] 2,} John _{<CH3) 2}

ONa r?

Another group of acyl radicals are at the end of the substituted aryl group, wherein the substituent is a basic group such as substituted or unsubstituted amino, amidino, guanidino, guanyl and nitrogen containing monocyclic and bicyclic heterocycles (aromatic and non-aromatic) wherein the heteroatom or heteroatoms other than nitrogen are selected from. oxygen and sulfur. These substituted acyls may be represented by the following formula

- (CH 2 -A-CH 2 -Y ⁰ where m and n are integers selected from 0 to 5; A is O, N 1T (R * is hydrogen or lower alkyl of 1 to 6 carbon atoms), S or A is single bond and Y ° is selected from the following groups:

An amino group or a substituted amino group

-N (R °) ₂ and -N (R °).

wherein the values of R 0 are independently selected from the group consisting of N (R *) ₂ (R * is hydrogen or lower alkyl of 1 to 6 carbon atoms) lower alkyl and lower alkoxy of 1 to 6 carbon atoms, lower alkoxy-lower alkyl wherein the alkoxy part of the molecule contains 1 to 6 carbon atoms and the alkyl part contains 2 to 6 carbon atoms, cycloalkyl and cycloalkylalkyl, wherein the cycloalkyl portion contains 3 to 6 carbon atoms and the alkyl portion contains 1 to 3 carbon atoms, be linked together with the nitrogen atom to which they are attached to form a ring of 3 to 6 atoms.

2. Amidino or substituted amidinosulfone wherein R c is independently selected from the group consisting of hydrogen, N (R ') ₂ (r' is hydrogen or lower alkyl of 1 to 6 carbon atoms), lower alkyl, lower alkoxy 1 to 6 carbon atoms, lower alkoxy lower alkyl, wherein the alkyl portion of the molecule contains 2 to 6 carbon atoms (if the lower alkoxy lower alkyl is attached to the alkyl portion of the molecule containing 1 to 6 carbon atoms); cycloalkyl or cycloalkylalkyl, wherein the alkyl moiety contains from 1 to 3 carbon atoms; the two R 0 groups may be joined together with the atoms to which they are attached to form a ring of 3 to 6 carbon atoms;

3. JüanWiasjampa A-aMžžfi & .toaY.Hfla stopina

-NCN (R °) - ² NR ° wherein R ° is as defined above under 2.

4. Guanv1 and substituted guanv1

-C = NR ° ¹ o N (R °) ₂ wherein R ° is as defined above under 2.

5. Nitrogenous monocyclic and bicyclic heterocycles (aromatic and non-aromatic) having 4 to 10 ring atoms, wherein the heteroatom or heteroatoms are, in addition to nitrogen, selected from oxygen and sulfur. These heterocycles are exemplified in the following residue list (R * is hydrogen or lower alkyl of 1 to 6 carbon atoms):

Other examples of acyl radicals belonging to this group include:

About NH

H 11

-CCH ₂ CH ₃ NHC-CH ₃ a

-cch. _? ch ₂ n (ch ₃ ) ₂

HH

-CCH ₂ CH ₂ HHC-H

K ©

-CCH ₂ CH ₂ N (CH ₃ ) ₃

NH

NH

-CCH ₂ CH ₂ NHC-NH ₂

-CGagCB2C-HH, (4

About NH

-ch ₂ ch ₂ ch ₂ nhc-ch ₃

NH nh ₂

AT

-CCH ₂ CH ₂ CH ₂ § (° ^h 3) ₃

NH o

II

-CCH ₂ CH ₂ CH ₂ N (CH ₃ ) ₂

-CCH ₂ -O-CH ₂ C

NH ^{2 O 4 NH} II

-CCH SC nh ₂

The compounds of the present invention can be prepared by reacting a thienamycin of formula

1 * 9 * or a derivative thereof (Ia, Ic, or Ie if R ¹ = R = H) or a suitably protected form of thienamycin, such as a silylated derivative (E), with an imidoester of formula III or substituted imidohalide of formula IV

OTMS sch ₂ ch ₂ nhtms

COOTMS (X) TMS = trimethylsilyl

NR ¹ .

R-C-OR

² r'r ² n = cx 'χ'Θ

I p

(IV) wherein r 1, R ² and R are as defined above, X * is a halogen atom such as chlorine and -OR 2 is a leaving group wherein R is lower alkyl such as methyl, ethyl and the like.

Suitable solvents for the preparation of the compounds of the invention are dependent on the type of thienamycin substrate and reagent and include water, dioxane, tetrahydrofuran, dimethyl formamide, chloroform, acetone, acetonitrile, or mixtures thereof. The reaction is carried out at a temperature of from 0 ° C to about 25 ° C for 1 to 6 hours. The type of reaction solvent is not critical nor variation within the limits set forth above, only the reaction solvent must be inert or sufficiently inert or sufficiently inert to the expected course of the reaction.

Suitable reagents include:

(a) Imidocstery:

r 'r' r ²

NN b _o ,, © «o ..

R-C-X ° R, R-C-X ° R

X ° = O or S methyl formimidate, ethyl formimidate, methyl acetimidate, ethyl acetimidate, methylbenzimidate, ethyl 4-pyridyl carboximidate, methylphenylacetiraidate, methyl-3-thienylcarboximidate, methyl azidoacetimidate, methylchloroacetimidate, methylcyclohexylcarboximidate methyl-2-furyl, methyl-2-furyl, -2,4-dimethoxybenzimidate, ethyl N-methylformimidate, methyl N-methylformimidate, methyl N-isopropylformimidate and the like.

These imidoester reagents of formula XII are preferably prepared by known methods such as:

1. Reaction of nitriles with a lower alkanol in the presence of HCl according to the known Pinner synthesis.

2. Reaction of RNC nitriles with a lower alkanol in the presence of a base. The reaction is carried out at a temperature of from 0 ° C to 40 ° C in the presence of an excess of alcohol with a catalytic amount of an alkali metal alkoxide for 15 minutes to 4 hours.

O a,

3. Reaction of the amide R-C-NHR with an alkyl chloroformate such as methyl chloroformate at 25 ° C to 45 ° C for 1 to 4 hours.

0 II i II i o

4. Reaction of an N-substituted amide RC-NHR or RC-NR R with an equivalent of an alkylating agent such as triethyloxonium fluoroborate in an inert solvent such as ether, chloroform and the like at 0 ° C to 23 ° C for 10 minutes to two hours.

5. Conversion of the readily available imidoester RCNR * (R * may be hydrogen) to the desired imido ester R-CNR ¹ by reaction of the former with an alkylamine R'NH ₃ in a mixture of water and not mixed.

OR a soluble solvent such as ether or chloroform at a temperature of from 0 ° C to 23 ° C for 5 minutes for 1 hour.

Chlorpiperidinomethyl chloride, chlordimethylforminium chloride, chlordiethylforminium chloride and the like

These imidohalides as reagents of formula (III) are conveniently prepared by any of the commonly known methods, such as:

·

H i 2

1. Reaction of Ν, Ν-disubstituted RCNR R amide with a halogenating agent such as thionyl chloride, phosgene, phosphorus pentachloride and the like in an inert solvent such as chloroform, methylene chloride and the like at 0 ° C to 40 ° C for 1 to 5 hours.

The reaction comprising the reagents of formula III can be illustrated by the following scheme:

on ² sch ₂ ch ₂ nh ₂

COX'a3 '

NR ¹

II ..

RC-OR on ³ SCH ₂ CH ₂ N = C-NHR '• COX'R ^3' wherein OR ' is a leaving group reagent imidoesterového and R H *, R ^ and R ^ and X 'are as defined supra. The reaction is particularly suitable for the preparation of compounds wherein R 1 and R 2 are hydrogen and X 1 is an oxygen atom.

and

The reaction comprising reagents of formula IV may be illustrated by the following scheme:

OR ³ s-ch ₂ ch ₂ nh ₂

COX'R ³ '

0} ¼¾ ⁺ = cx '] x' R

OR ³

H ⁺ sch ₂ ch ₂ n = c-nr'r 2

COX ^Z R3 '/,

OH mild hydrolysis jL

-> J <] t - sch ₂ ch ₂ n = c - nr1r2 pH 3-6 - U - _COOH &

wherein all symbols have the meaning given above. If the two desired products, suitable values for R ^ and R * _SO u j trimethylsilyl, and X is oxygen.

The compounds of the present invention (IX and IIa) form a wide variety of pharmacologically acceptable salts, such as salts with hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, p-toluenesulfonic acid and methanesulfonic acid. The salts of the present invention are pharmacologically acceptable non-toxic derivatives which can be used as active ingredients in suitable unit doses of pharmaceutical forms. They can also be combined with other active ingredients to produce mixtures with a broad spectrum of activity.

The novel compounds of the present invention are valuable antibiotics effective against various gram-positive and gram-negative bacteria and can therefore be used in human and veterinary medicine. Thus, the compounds of the present invention can be used as antibiotics for the treatment of infections caused by gram-positive or graia-negative bacteria, for example Staphylococcus aureus, E. coli, Klebsiella pneumoniae, Serratia, Salmonella typhosa, Pseudomonas and Bacteria proteus. The antibacterial compounds of the present invention can further be used as additives for feed, for food preservation and for disinfection. For example, they can be used in the form of aqueous mixtures at a concentration of 0.1 to 100 parts antibiotic per million parts solution to kill and inhibit the growth of harmful bacteria in medical and dental equipment, or they can be used as bactericidal compounds in industrial applications such as dyes water-based and for inhibiting the growth of roasting bacteria in papermaking circuit waters.

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

The compositions are preferably formulated to be suitable for absorption by the gastro-intestinal tract. Tablets and capsules for oral administration may be in unit dosage form and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth or polyvinylpyrrolidone, fillers such as lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine, lubricants such as magnesium stearate, talc, polyethylene glycol, silica, disintegrants such as potato starch or suitable wetting agents such as sodium lauryl sulfate. The tablets may be coated by known methods. Oral liquid preparations may be in the form of aqueous oily suspensions, solutions, emulsions, syrups, infusions, and the like. or may be in the form of dry products which are treated with water or other suitable carrier before use. Such liquid preparations may contain conventional additives such as suspending agents, for example, sorbitol syrup, methylcellulose, glucose and sugar syrup, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminum stearate gel or hydrogenated edible oils such as almond oil, fractionated coconut oil, oily esters, propylene glycol or ethyl alcohol; preservatives such as methyl or propyl p-hydroxybenzoates or sorbic acid. Darts contain conventional suppository compositions, such as coconut butter or other glyeerides.

Compositions for injection may be presented in unit dosage form in ampoules or in multi-container containers with added preservatives. The compositions may also be in the form of suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain substances such as suspending, stabilizing and / or dispersing agents. Alternatively, the active ingredients may be in the form of powders suitable for preparation of the preparations by reconstitution with a suitable carrier before use, for example with sterile pyrogen-free water.

The compositions may also be formulated in a form suitable for absorption through the mucous membranes of the nose and throat, and may preferably be in the form of powder or liquid sprays or as inhalation solutions, enemas, lipsticks and the like. or can be used in the form of drops. Topical applications may be formulated in hydrophobic or hydrophilic bases such as ointments, creams, enemas, lipsticks, powders and the like.

Likewise, the compositions of the present invention may contain, in addition to the carrier, other ingredients such as stabilizers, binders, antioxidants, preservatives, lubricants, suspending agents, viscosity adjusters or flavoring agents and the like. A wide range of antibiotic activity was obtained.

For veterinary use, the compositions of the present invention may be formulated as either long- or fast-release nitrosoval preparations.

The dosages that can be administered depend to a large extent on the condition of the subject being treated and the weight of the host, on the mode and frequency of administration, the parenteral route being preferred for general infections and the oral route being suitable for intestinal infections. Generally, a daily dose consists of 2 to 600 mg of active ingredient per kg body weight of the subject in one or more doses per day. A preferred daily dose for an adult is in the range of 15 to 150 mg of active ingredient per kg body weight.

The compositions of the present invention may be administered in several unit doses, for example in the form of solid or liquid orally digestible dosage forms. The compositions may contain 0.1 na per unit dose. up to 99% of active ingredient, preferably from 10 to 60% of active ingredient. The compositions generally contain from about 15 mg to about 1500 mg of active ingredient, but generally a dosage amount in the range of about 100 mg to 1000 milligrams is generally used. For parenteral administration, the unit dosage form of the pure compound is in a slightly acidified sterile aqueous solution or in the form of a soluble powder for solution preparation.

The following examples illustrate; but in no way limit the products, process, compositions or treatment method of the present invention. In the examples, the thienamycin core (I, supra) is represented by the following symbol:

corner

Th _-NH2 -COOH L where a secondary alcoholic group, amino group and carboxyl group is depicted. Thus, the compounds of the present invention can be represented as follows by formulas II and IIIa.

pOH pOR ³ Th - —N = C-X and and Th NH = C-X t 1 Y 1 Y '-COOH —Cox'r ³ _

and (II) (IIa) wherein X, Y, R ³ , X 1, R ³ and A are as defined above

The present invention is described in more detail in the following examples.

Example 1

Preparation of N-formimidoyl thienamycin

OH

O ^! sch ₂ ch ₂ n = c-imh ₂

COOH J,

Thienamycin (517 mg) was dissolved in 0.1 N phosphate buffer pH 7 (25 mL) and cooled in an ice bath with magnetic stirrer. The solution was adjusted to pH 8.5 using a 2.5 N sodium hydroxide solution supplied from an automatic burette. While maintaining the pH of 8.5, methylformimidate hydrochloride (711 mg) was added in portions over 2-3 minutes. After a further 10 minutes, the pH was adjusted to 7.0 using 2.5 N hydrochloric acid. The solution was chromatographed on a XAD-2 resin column (150 mL), eluting with water. The N-formimidoyl thienamycin derivative was eluted in 1.5-2.0 column volumes (200-300 mL) and lyophilized to give a white solid (217 mg).

UV (pH 7 0.1N phosphate buffer) λ _πθχ 297 nm (8.590).

IR (Nujol) 1,767 cm ¹ (beta-lactam)

NMR (D ₂ O) 51.37 (d, J = 6Hz, CH 3 CH), 3.0 to 3.75 (m, -CH 2), 4.2 to 4.8 (m, C _{9 H} , C _{5 H} ,

NH n

C _{7 H} ), 7.86 (s, -CH).

Example

2.

Cl © ©

(CH3) N = CHCl Th (TMS) 1-OH

H ·>

Th N = C +

CO ₂ ©? ^Η 3

_N-CH3

H

a) Preparation of sillated thienamycin i-OTMS

Th

NHTMS or ThiMSMS-COOTMS

TMS = trimethylsily1

Thienamycin (80.0 mg) was suspended in 40 mL tetrahydrofuran (THF) under nitrogen and concentrated to 10 mL, then hexamethyldisilazane (1.0 mL) and trimethylchlorosilane (300 µL) were added. The mixture was allowed to react for 20 minutes at 25 ° C with vigorous stirring. The suspension is then centrifuged to remove ammonium chloride. In a stream of nitrogen, the supernatant was evaporated to an oil, which was used for the next reaction.

b) Preparation of N-dimethylmethylene methylene thienamines

Thienamycin (1.6.5 mg) was silylated as above by reaction with hexamethyldisilazane (200 µl) and trimethylchlorosilane (60 µl) .Silylated thienamycin was suspended in ethanol-free chloroform (1 mL) with magnetic stirring under nitrogen atmosphere. at -45 degrees Celsius and a solution of triethylamine (21 µl) in chloroform (21 µl) was added followed by a solution of (chloromethylene) -dimethylammonium chloride (11.5 mg) in chloroform (50 µl) and warmed to -25 ° The mixture was stirred vigorously for 15 minutes and the aqueous phase separated and contains N-dimethylaminomethylene thienamycin having electrophoretic mobility (50 V / cm, 1 hour, buffer). pH 7) 3.6 towards the cathode.

Example 3

Preparation of N-acetimidoylthienamycin

OH

O ^; sch ₂ ch ₂ n = c-nh ₂ ^COOH L

Thienamycin (190 mg) was dissolved in 0.1 N phosphate buffer pH 7 (13 mL) and cooled in an ice bath with magnetic stirring. The solution was adjusted to pH 8.5 by the addition of a 2.5N aqueous sodium hydroxide solution supplied from an automatic burette. Ethyl acetimidate hydrochloride (400 mg) was added portionwise over a few minutes while maintaining the pH at 8.5. After a further 40 minutes, the solution was adjusted to pH 7.0 by addition of 2.5 N hydrochloric acid. The solution is then chromatographed on DOWEX 50-X8 resin (250 mL Na ⁺ cycle passing through sieves of 0.150-0.075 mm) and eluted with water. The N-acetimidoyl derivative was eluted with 1 to 2 column volumes (24Q to 520 mL) and then lyophilized to a white solid (88 mg).

UV (pH 7 0.1N phosphate buffer) _{λ] ηβχ} 297 nm (r 7.620).

.mu.l (nujol) 1774 cm @ -1, .beta.-lactam.

NH

NMR (D ₂ O) δ 1.27 (d, d = 6Hz, CH-j-CH), 2.24 (S, -S-CH-j), 3.2 to 3.5 (m, -CH ₂ ), 3.5 to 3.9 (m, -CH ₂ -), 4.2 to 4.6 (m, C 1 H 3, C 8 H 3, C 1 H 3).

Example 4

Preparation of N'-tert-butyl-N-formimidoylthienamycin r-OH

N-C (CH3)

Th · n

-NHC

3'3

-COOH

Thienamycin (105 mg) was dissolved in 0.1 N phosphate buffer (5 mL) and to this was added a solution of ethyl N-tert-butylformimidate (290 mg) in tetrahydrofuran (1 mL). Value

The pH of the solution was adjusted and maintained at 8.5 by adding 1N NaOH solution from an automatic burette.

After 30 minutes, the pH is adjusted to 7.0 by the addition of 2.5 N hydrochloric acid. The solution is chromatographed on a column equipped with an ice-water condenser on a Dowex-X4 resin column (53 ml Na ⁺ cycle, passing through sieves with an aperture size of 0.075-0.030 mm). and deionized water is used as eluent. Fractions containing the title compound were combined and lyophilized.

Example 5

Preparation of N '- (1-methyl-2-propenyl) -N-i ^- ormimidoylthienamycinu

Th ~ OH

NCH (CH3) CH = CH-

I ³ 2

--NHCH

L.COOH

Thienamycin (126 mg) was dissolved in 0.1 N phosphate buffer, pH 7 (6 mL). The pH of this solution was adjusted to 8.5 by adding 1 N NaOH solution from an automatic burette. To this stirred solution was added ethyl N1-methyl-2-propenylformimidate hydrochloride (300 µL) and the pH was maintained at 8.5. After 30 minutes, the pH of the solution was adjusted to 7.0 by the addition of 2.5N hydrochloric acid, and the solution was chromatographed on a column equipped with an ice-water condenser and filled with Domex 50-X4 resin (49 ml Na ⁺ cycle, passing through sieves of 0.075 to 0.030 mm), and elution is performed with deionized water. N ^? The (1-methyl-2-propenyl) -N-formimidoyl derivative was eluted in 2-4 column volumes and lyophilized to give a white solid (59 mg).

UV (0.1N phosphate buffer), λ 299 nm, £ 7,820,

IR (nujol) 1760 cm -1 (beta-lactam).

Fig. 1 a d 6

Preparation of N-propionimidoyl thienamycin r OH

NH

Th-NHC 'ch ₂ ch ₃

OOH

Thienamycin (114 mg) was dissolved in 0.1 N phosphate buffer pH 7 (10 mL) and the pH of the solution was adjusted to 8.5 using an automatic burette with 1 N sodium hydroxide solution. Ethyl propionimidate hydrochloride solid (231 mg) was added in portions as quickly as possible so that the pH remained close to 8.5. After 30 minutes, the pH was adjusted to 7.0 using 2.5N hydrochloric acid and the solution was chromatographed on a Dowex 50-X4 resin column (72 ml per cycle, passing through sieves with an aperture size of 0.075-0.030 mm) and eluted with deionized water. The N-propionimidoyl derivative was eluted in 2 column volumes and lyophilized to give a white solid (76 mg).

UV (pH 0.1N phosphate buffer), λ _max 298 nm (ε 7.830),

NMR (D 6 O) δ 1.28 (d, J = 6 Hz, CH 3 CH (OH)), 1.23 (t, J = 8 Hz, -CH 3 -CH 3), 2.50 (q, J = 8 Hz, Si) ₂ ch ₃ ).

Example?

Preparation of N'-methyl-N-formimidoylthienamycin

Th ~ OH

N-CH, II ^{3 -} NHC -

H

- COOH

Thienamycin (140 mg) was dissolved in 0.1 N phosphate buffer pH 7 (10 mL) and the pH of the solution was adjusted to 8.5 using an automated burette with 1N NaOH. To this solution was added methyl N-methylformimidate hydrochloride (200 µl), maintaining the pH at 8.5. After 40 minutes, the pH was adjusted to pH 7.0 with 2.5N hydrochloric acid and the solution was chromatographed on Dowex 50-X4 resin (72 mL, Na ⁺ cycle, passing through sieves of 0.075-0.030 mm) through elution with deionized water. The N'-methyl-N-formimidoyl derivative was eluted in 2 column volumes and lyophilized to give a white solid (43 mg).

VV (pH 7 0.1N phosphate buffer), λ _max 298 nm (r. 7.250).

IR (nujol) 1765 cm ^- '(beta-lactam).

NMR ( »0 ₂₎ '1.29 (d, J" 6 Hz, CH-CH), 2.92 (s, N-CH₃), 7.80 (s, N-CH₃), 7.80 ( s, N-CH 2).

Example 1 and d 8

Preparation of N, N -isopropyl-N-formimidoylthienamycin r-OH

NCH (CH), II 3 ‘

Th ·

-NHC • COOH

Thienamycin (110 mg) was dissolved in 0.1 N phosphate buffer pH 7 (7 mL) and the pH of the solution was maintained at 8.5 using an automatic burette with 1 N sodium hydroxide solution. To the magnetically stirred buffer solution was added a solution of methyl N-isopropylformimidate hydrochloride (300 mg) in p-dioxane (1 mL), maintaining the pH at 8.5. After 25 minutes, the pH of the solution was adjusted to 7.0 using 2.5N sodium hydroxide solution and chromatographed on Dowex 50-X4 resin (53 mL Na ⁺ cycle passing through 0.075-0.030 mm sieves) eluting with deionized water. The chromatography is carried out in a column equipped with a cooling sheet at 3 ° C. The N * -isopropyl-N-formimidoyl derivative was eluted in 2 column volumes and lyophilized to give a white solid of 12 mg.

UV (0.1N phosphate buffer pH 7) λ _θθ 299 nm (8 8.130).

[mu] nujol 1,760 cm ^& lt ^; -1 &gt; (beta-lactam).

Example 9

Preparation of N (N * -allylformimidoyl) thienamycin pOH

Th

Lcooh .ch ₂ ch-ch ₂ • H

To a precooled sample of thienamycin (123 mg, 0.452 mmol) was added 13 mL of cold 0.1 N phosphate buffer. The solution is adjusted to pH 9 by addition of 1N sodium hydroxide solution.

To this alkaline solution at 2 ° C was added ethyl N-allylformimidate hydrochloride (0.3 g) all at once. The pH drops to 7.3 and is brought back to 8.5 by addition of additional sodium hydroxide solution. The reaction mixture was stirred for an additional 30 minutes at 2 ° C and the pH was adjusted to 7 by addition of cold 0.1N sulfuric acid. The reaction mixture was analyzed by high pressure liquid chromatography on a _C18- Porosil column eluting with 10% aqueous tetrahydrofuran and was found to show only trace amounts of thienamycin (retention time 5 minutes) and almost pure product (retention time 70.5 minutes). The reaction mixture is chromatographed on a Dowex 50 x 4 column (60 ml,

Na ⁺ cycle, passing through sieves with an aperture size of 0.075 to 0.030 mm) eluting with water at a p

0.5 ml / min / cm. After pouring out the first 400 ml of eluate, an additional 150 ml is lyophilized to give the product. Yield 96 mg (63%).

UV 301 nm 24.60 optical density / mg (NH ₂ OH quench) 90% purity.

IR (nujol) shows C = O at 5.67 (U and 5.90 μl).

NMR 100 MHz, DgO shows a 1: 1 mixture of syn- and anti-N- (N'-ellylformimidoyl) thienamycin.

Example 10

Preparation of N-isobutylimidoylthienamycin

Following the procedure of Example 3 but substituting ethyl acetateimidate hydrochloride for hydrochloride. isobutylimidate and carrying out the reaction at 20 ° C and pH 8.2 gave N-isobutylimidoylthienamycin (14%).

UV (pH 7 _{0.1 H} phosphate buffer) _{λ was} 298 nm (c 8.290).

NMR (D ₂ O) δ 1.27 (d, J = 7 Hz, CH (Cl ₃ ) ₂ ), 1.29 (d, J = 6 Hz, CH ₃ CH (OH)), 2.79 ept,

J = 7Hz, £ H (CH _{3) 2)}

They did

Preparation of N'-methyl-N-acetimidoyl thienamycin

Following the procedure of Example 3, but substituting ethyl acetimidate hydrochloride for methyl N-methylacetimidate to give N-methyl-N * -acetimidoylthienamycin (10%) _.

226166 24

UV (pH 7 0.1N phosphate buffer) λ _ωθχ 298 nm (f 6.700).

IR (nujol) 1750 cm ^- '(beta-lactam), 1660 cm ^"1 (C = NCH).

^J N

NMR (D ₂ O) δ 1.27 (d, J = 6 Hz, CH-JCH 3 OH)), 2.22 and 2.25 (-S, Ν- &lt; ₃ &gt; _-3 ), 2.97 (S, NCH3).

Example 2

Preparation of N'-methyl-N-formimidoyl thienamycin

Following the procedure of Example 3, but substituting ethyl acetimidate hydrochloride for ethyl N-methylformimidethane hydrochloride, N-methyl-N-formimidoyl thienamycin (10%) was obtained »

UV (pH 7 0.1N phosphate buffer) to 298 nm.

max U

II

NMR (D 6 O) δ 1.30 (d, J = 6 Hz, CH-CH (OH)), 2.92 (S, N-CH 3), 7.78 (S, -CH).

Example 13 *

Following the procedure of Example 3, but substituting the reagent for an equivalent amount of methyl methoxyacetimidate to give N (methoxyacetimidoyl) thienamycin (34%).

UV .lambda.max, 301 nm (t 16.180, 8.700).

iC (nujol) 1,760 om- ¹ (beta-lactam),

NMR (60 MHz, D 6 O) 1,2 1.28, 3H, (d, J = 6Hz, 22 ₃ · 0Η (0Η)>, δ 3.50 3H (S, C CJyO.CHg), β 4.35,

2H (S, CH3 O.CHg), HPLC, 1.50 x retention time of thienamycin.

Example 1 a d 14

Preparation of N- (s'-ethylformimidoyl) thienamycin r-OH

Th

NEt

II

NHC-H

I - CO ₂ H

Thienamycin (100 mg) in 10 ml of 0.1 M phosphate buffer pH 7.0 was adjusted and maintained at pH 8.5-9.0 by the addition of 2.5N sodium hydroxide solution. 300 mg of N-ethylformimidate hydrochloride are added to the solution. The mixture was stirred at 23 ° C for 20 minutes and then neutralized with 2.5N hydrochloric acid to pH 7.0 and chromatographed on a Dowex 50 x 8 (Na form) ion exchange column (4 cm x 25 cm). The column is eluted with water and 6.7 ml fractions are collected. Fractions 40 to 90 are combined, concentrated and freeze-dried to give 15 mg of a solid. Electrophoresis of the product at 50 V / cm for 20 minutes in 0.1 M phosphate buffer pH 7.0 shows the presence of one bioactive zone moving 2 mm to the cathode UV λ ^ 2θ 301

NMR (100 MHz, _D? 0), 7.77 (s) and 7.82 (s) formimidoyl CH.

They did

By carrying out the above procedures and examples, the following compounds of the present invention are prepared. The reagents, imidoethers and imidohalides used in the reaction with thienamycin or derivatives thereof provide the following compounds which are either known or can be prepared as described above.

OH sch ₂ ch ₂ n = cn

COOH i

R ¹

R ²

Slou- chinese R R ¹ R ² 1 H -ch ₂ ch ₂ ch ₂ ch ₃ H 2 H -ch ₂ -ch-ch, k, 3 ^ch 3 H 3 H -CHCH ₂ CH ₃ CH ₃ ’H 4 H -CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ H 5 H -CH-CH ₂ CH ₂ CH ₃ CH ₃ H ' 6 H -CH-CH-CH-CH, 2,2,3 ch ₃ H 7 'H -CH-CH-CH, 1 I ³ CH ₃ CH ₃ CH | ^J H · 8 H -C-CH-CH, 1 ^{2 3} ch ₃ H 9 H --ch _{2 -} c (ch ₃ ) ₃ H 10 H -CH ₂ CH ₂ CH ₂ CH ₂ CH (CH ₃ ) ₂ H 11 H -CH-CH ₂ CH (CH ₃ ) ₂ ch ₃ H

continued table

Compound

-CH - CH 2 CH 2 ₍ 2

CH

-CH ₂ -CH = CH-CH ₃

-CH-CH = CH

CH,

-CH ₂ CH ₂ CH = CH ₂

-CH ₂ CH ₂ -CH = CH-CH ₃

-ch ₂ -ch ₂ -ch = ch ₂

Uh,

-CH ₂ -CH-CH = CH ₂

CH,

-CH-C = CH

CH ₃ CH ₃

-CH-CH = CH, ^G 2 ^H 5

-gh ₂ -ch = ch-ch ₂ ch ₂ ch ₃

-ch ₂ -ch ₂ -ch = ch-ch ₂ ch ₃

-ch-ch = ch-ch ₅ ch

I ^{£ J}

CH,

-CH ₂ -CH ₂ -CH = CH ₂ -CH ₃

CH,

-CHCH ₂ -CH ₂ CH ₂ = CH ₂

CH,

-c ₂ H ₅

-c ₂ H ₅

-CH (CH _{3) 2}

-CH _{(CH3) 2}

-ch ₂ ch ₂ ch ₃ .

-CH ₂ CH ₂ CH ₃ continued table

Slou- chenina R R ¹ R ² 29 'H -ch ₃ -c ₂ h ₅ 30 H -CH ₃ -CH (CH _{3) 2} 31 H . -ch ₃ -ch ₂ ch = ch ₂ 32 H -ch ₂ ch = ch ₂ -ch ₂ ch = ch ₂ 33 H -C (CH3) ₃ -ch ₃ 34 H -ch ₃ -CH-CH _{2 R} ²⁵ CH ₃ 35 H -c ₂ h ₅ . -CH (CH _{3) 2} 36 H - ^CH 3 -CHCH = CH-. 1 ² CH ₃ 37 H -ch ₃ -CH ₂ -CH (CH ₃ ) 38 H -ch ₃ -CH ₂ CH ₂ CK ₃ 39 H -ch ₃ -CH ₂ -CH = CH ₂ CH ₃ 40 -ch ₃ - ^C 2 ^H 5 H Ί 41 ^ 42 -CH ₃ -ch ₃ -CH ₂ CH = CH ₂ -CH (CH ₃ ) ₂ H H 43 -ch = ch ₂ -ch ₃ H 44 -ch = ch ₂ -c ₂ h ₅ ^s H 45 -ch = ch ₂ -CH (CH _{3) 2} H 46 -ch ₃ -CH (CH _{3) 2} H 47 -ch ₃ -CHCH = CH 1 CH ₃ H 48 -ch ₃ -CH ₀ -C-CH ^{11 12} CH ₃ H

continued table

Slou- chenina R r ’ R ² 49 -ch ₃ -CH, -CH, CH, 1 ^{2 2 3} CH ₃ H 50 -ch = ch ₂ H • H 51 , ch ₃ CH ₃ CH ₃ 52 ch ₃ ch ₃ c ₂ n _p 53 ch ₃ ch ₃ -CH (CH _{3) 2} 54 CH ₃ CH ₃ -ch ₂ ch = ch ₂ 55 CH ₃ ^C 2 «5 ^C 2 ^H 5 56 ' ^CH 3 - ch ₃ 1 -CH, -CH = CH, 1 and ₃ 57 H -CH ₂ CH ₂ -N (CH ₃ ) ₂ Η 5Θ H -CH ₂ GH ₂ CH-N (CH ₃ ) ₂ H 59 H -CH ₂ CH ₂ -N (CH ₃ ) ₃ H 60 -GHGH, 1 ^J ch ₃ ch ₃ -CHCH, i ³ ch ₃ 6, -CHCIL · -GHGH, -CHCH, CH ₃ gh ₃ 'ch ₃ 62 -C _{(CH3) 3} -C _{(CH3) 3} -C (CH ₃ ) ₃

Η + s — ch ₂ ch _{2 —} n = c — χ

Υ

Slou- chenina R R ' X Y AND 63 H -CH ₂ CH = C (CH ₂ ) ₂ NH ₂ H Cl 64 H —Ch ₂ - <ζ ~ ^ - och ₃ nh ₂ H Cl 65 H _A -CH -0-CC (CH) ² H ³³ 0 NHCH ₃ H HSO ₄ 66 H -CH 2 -O-CC (CH ² ) ² II J ³ 0 nh ₂ CH ₃ CHjCOO 67 H -CH ₂ CH ₂ -CH = CH ₂ NHCH _{(CH3) 2} H Cl 68 H -CH ₂ CH ₂ -S-eH ₃ NHCH ₃ CH ₃ 69 H -CHg-O-J-CH3 0 NHCHj ch ₃ Cl 70 H -CH-C-O ² II 0 nh ₂ H Cl 71 H -5 indanyl N _{(CH3) 2} H Cl 72 H -phthalidyl -6H ₂ CH = CH ₂ H Cl 73 Sat ₃ - On nh ₂ H - 74 after ₄ h ₂ -CH-OCCH (CH3) ² II ^J 0 nh ₂ CHj - 75 S0 ₃ - -CH ₂ -CH = C (CH ₃ ) ₂ NHCH ₃ H - 76 ^MO 4 ^H 2 On NHCH _{(CH3) 2} H -

Example 16

Preparation of pharmaceutical mixtures

One unit dose consists of mixing) 20 mg of N-acetimidoylthienamycin (product of Example 3) with 20 mg of lactose and 5 mg of magnesium stearate and 145 mg of this mixture are placed in gelatin capsule 3. Similarly, using more active ingredient and less lactose another dosage form can be prepared which can be placed in gelatin capsule # 3 and larger capsules as well as compressed tablets and pills can also be prepared if more than 145 mg of ingredients have to be mixed. The following examples illustrate the preparation of pharmaceutical preparations.

Tabletvi For one tablet N-acetimidoylthienamycin 125 mg corn starch U.S.P. 6 mg calcium phosphate 192 mg lactose 190 mg

The active ingredient is mixed with calcium phosphate, lactose and one-half of the corn starch. The mixture is then granulated with 15% starch paste (6 mg) and screened. It is dried at 45 ° C and screened again through No. 16 sieves. The remainder of the corn starch and the magnesium stearate are added and the mixture is compressed into tablets of a diameter of 1.25 cm and a weight of 800 mg.

P.ar.sntgr.élnÁ xa & tok,

Ampoule

N-acetimidoylthienamycin sterile water

500 mg 2 ml

N-acetimidoylthienamycin hydroxypropylmethylcellulose sterile water

100 mg 5 mg to 1 ml

Ear solution

N-acetimidoylthienamycin benzalkonium chloride sterile water

100 mg

0.1 mg to 1 ml

N-acetimidoylthienamycin polyethylene glycol 4000 U.S.P, polyethylene glycol 400 U.S.P.

100 mg 400 mg

1.0 g

The active ingredients in the above preparations may be administered alone or in admixture with other biologically active ingredients, such as other antibacterial agents such as lincomycin, penicillin, streptomycin, novobiocin, gentamicin, neomycin, colistin and kanamycin, or other therapeutic agents, like probenecid.

Claims (1)

SUBJECT OF THE INVENTION A process for the preparation of thienamycin derivatives of the general formula II X is hydrogen or R, Y is -NR ¹ R ² , 1 2 R and R and R are independently of one another and are hydrogen, alkyl of 1 to 6 carbon atoms, aminoalkyl of 1 to 6 carbon atoms and alkenyl of 2 to 6 carbon atoms, characterized in that a compound of formula I or a suitable compound is reacted 0-sch ₂ ch ₂ nh ₂ COOH and / or a carboxyl derivative with an imidoester of formula III NR ¹ R ² RCX ° R or with an imidohalide of the formula IV r ¹ r ² n = cx 'I R Θ (I) (III) (IV) wherein R, R 'and R ² are as defined above, R ° -X is a leaving group, where X c is O or S, R is alkyl of 1 to 6 carbon atoms and X 'is a halogen atom to form a compound of formula II.