NL8303310A - CARBAPENEM ANTIBIOTICS. - Google Patents

Description

f VO 5102

Carbapenem antibiotics «fc -

The invention is directed to new carbapenem antibiotics in which * - the 2-substituent has the formula 10 of the formula sheet, wherein A represents a C 1 -C 8 straight or branched chain alkylene group; R 1 represents an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic, aliphatic, aryl, aliphatic, heteroaryl, heteroaliphatic, heterocyclyl, or heterocyclylaliphatic group; and the group of formula 11 of the formula sheet represents a nitrogen-containing aromatic heterocyclic group at a ring carbon atom bonded to the alkylene group A and quateraized by substituent R'5.

10 2. Description of the Prior Art

A number of β-lactam derivatives containing the carbapenem core according to formula 12 of the formula sheet have been described in the literature. These carbapenem derivatives are reported to be useful as antibacterial agents and / or g-lactamase inhibitors; The original carbapenem compounds were natural products such as thienamycin of the formula 13 of the formula sheet obtained by fermentation of Streotomyces catteleya (U.S. Patent 3,950.35T). Thienamycin is a particularly potent broad spectrum antibiotic which has remarkable activity in respect of differ-20 the Pseudomonas species, organisms notorious for their resistance to S-lactam antibiotics.

Other natural products containing the carbapenem core include olivanoic acid derivatives, such as the antibiotic Mi 13902 of the formula III of the formula sheet described in U.S. Pat. 113,856, the antibiotic MM U88O of the formula 15 of the formula sheet described in U.S. Patent 1,162,301, the antibiotic MM U55O A of the formula 16 of the formula sheet described in U.S. Patent 1,172,129 and the antibiotic 890A ^ with the formula 17 of the formula sheet disclosed in U.S. Patent 1,261,735 · 30 Besides the natural products, the desacetyl 890AQ compound of the formula 18 of the formula sheet is disclosed in U.S. Patent 1,261,731. it is prepared by enzymatic deacylation of the corresponding N-acetyl compound. Also fs "7 Λ * * Λ V / WV" jf - - * -2- $ ¥ various derivatives of the naturally occurring olivanic acids have been synthesized, for example, compounds of the formula 19 of the formula sheet in which COgR 1 carboxyl group or salt thereof ", n is 0 or 1 and Rg is H, an acyl group or a group of the formula R ^ O ^ S ^ -s" wherein R ^ is a salt-forming ion or a methyl or ethyl group, described " in European patent application 8885.

In U.S. Pat. No. 2,359,922 (see also European Patent Application 2058), the carbapenem derivative is described by formula 20 of the formula sheet, while British Patent Application 1,598,062 describes the isolation of the compound of formula 21 from the formula sheet from a Streptomyces fermentation broth mentions.

Carbapenem compounds which are unsubstituted at the 6 position have also been synthesized. Thus, U.S. Patent 1) - 210,661 discloses compounds of the formula (22) where Rg is phenyl or substituted phenyl; U.S. Pat. 267,177 compounds of formula 23 of the formula sheet wherein R ^ is an optionally substituted pyridyl group, U.S. Patent k, 255.kkl discloses compounds of formula 2k of the formula sheet, wherein R8 and R ^ are H or alkyl, R ^ is equal to NH-CO ^ Rg, wherein Rg is alkyl, phenyl, or substituted phenyl, and n is 1 or 2, and describes U.S. Patent No. 2,882,236 compounds of the formula sheet wherein R 1 H or alkyl and Rg is CN or COgR ^, wherein R ^ is H, alkyl, aryl or aralkyl.

Carbapenem compounds of the general formula 26 of the formula sheet, wherein RH is acyl and R ° H is substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, alkylcycloalkyl, aryl, aralkyl, ar alkenyl, ar alkynyl heteroaryl Heteroalkyl is heterocyclyl or heterocyclylalkyl are described in U.S. Pat. No. 2,118,663. No mention is made and optionally heteroalkyl-R substituents of the type according to formula 27 of the formula sheet, wherein A is alkylene and the group of formula 11 is a quaternized nitrogen-containing aromatic heterocyclic group, which is attached to a ring carbon atom is attached to the alkylene group A.

The natural product thienamycin has the absolute configuration 35 5R, 6S, 8R. This isomer, as well as the remaining 7 thienamycin isomers, can be obtained via a total synthesis as described in U.S. Pat. No. 233,596. Total synthesis procedures p4-3 for thienamycin are also described, for example, in U.S. Patents 4,287,123, 4,269,772, 4,282,148, 4,273-709, 4,290,947 and European Patent Application 7973. A key intermediate in the Synthesis methods described is the formula 28 of the formula sheet wherein pHB represents p-ni-5 trobenzyl.

- Due to the exceptional biological activity of thienamycin, a large number of derivatives have been prepared and described in the literature. These include (1) N-formimidoylthienamycin of formula 29 of the formula sheet described in European patent application 6639; (2) N-heterocyclic derivative thienamycin vessels of formulas 30 and 31 (I and II) of the formula sheet, wherein: the bifunctional ring may contain additional ring unsaturation; and wherein n is an integer selected from 1-6; p is o, 1 or 2; B1% is alkyl or aryl; and Z imino, oxo, H, amino, or alkyl is described in U.S. Patent 4,189,493; (3) substituted H-methylene-

Derivatives of thienamycin of formula 32 of the formula sheet, wherein X

12 ...

and YH, R, OR, SR or HR are R, wherein R is substituted or unsubstituted: alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, 1 heteroaryl, heteroaralkyl, heterocyclyl, or heterocyelylalkyl and R and RH or R disclosed in U.S. Patent 4,194,047; (4) compounds of formula 33 of the formula sheet, wherein R is aryl, alkyl, acyl 1 2 or aralkyl and R and R are independently selected from H and acyl (including type 0 I 11 * acyl ii -CR wherein R inter alia alkyl may be substituted by a quatera ammonium group, for example of formula 34 of the formula sheet described in U.S. Patent 4,226,870 (5) compounds of formula 35 of the formula sheet wherein RH , acyl or a monovalent, optionally substituted hydrocarbon group; R is optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl and R is acyl including type 0 II acyl.

-C-R wherein R alkyl is substituted with a quatera ammonium group, for example, a group of formula 34 described in U.S. Patent 1,604,276 (see also U.S. Patent 4,235,917); (6) compounds of formula 36 of the formula sheet, wherein R, R and R are independently selected from H and substituted - mr? "4" or unsubstituted: alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkylalkyl, aryl aralkyl, heteroaryl or heteroaralkyl described in U.S. Patent 4,235-920; (7) compounds of formula 37 of the formula sheet, wherein R and R each independently, a group as defined for R, a hydrogen atom or - a nitro, hydroxyl, C 1 -C 8 alkoxy, amino, alkylamino, di (C 1 -C 8 alkyl) -amino or tri (C 1 -C 6 alkylamino) group, wherein in the latter case an additional anion is present; or R and R are bonded, together with the nitrogen atom to which they are attached form a substituted or unsubstituted monocyclic or bicyclic heteroaryl or heterocyclyl radical having 4-10 ring atoms, one or more of which may be an additional heteroatom selected from oxygen, sulfur and nitrogen; R is a cyano group or a substituted or unsubstituted carbamoyl, carboxyl (C 1 -C 20 alkoxy) carbonyl, C 1 -C 8 alkyl, C 2 -C 10 alkenyl, C 1 -C 10 alkynyl, C 15 -C 20 cycloalkyl, C ^ -C ^ cycloalkylalkyl, C ^ -C12 cycloalkylaLtenyl, C ^ -C ^ cycloalkenyl, C ^ -C ^ 2 cycloalkenylalkenyl, C ^ -C ^ 2 cycloalkenylalkyl, Cg-C ^ Q aryl, C ^ -C ^ g aralkyl, C8 -C18 g aralkenyl, C8-C18 g aralkynyl or monocyclic or bicyclic heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl having 4-10 ring atoms, one or more of which is a heteroatom selected from oxygen, sulfur and nitrogen and in which the alkyl radical of the hetaralkylic heterocyclylalkyl group contains 1-6 carbon atoms; the substituent or sub-. 12. 12 stituents on R, R, R or on the ring formed by R and R chlorine; bromine; iodine; fluorine; azido; alkyl; mercapto; sulfo; phosphono; cyananthio (-SCR); nitro; cyano; amino; hydrazino; amino or hydrazino with up to 25 g of alkyl substituents; hydroxy; C 1 -C 6 alkoxy; C 1-8 alkylthio; carboxyl; oxo; (C 1-8 alkoxy) carbonyl; acyloxy; carbamoyl; (C 1 -alkyl) carbamoyl or di (C 1 -alkyl) carbamoyl; R-3 a hydrogen atom, an acyl group or. . 4.4 is a group of the type defined for R; Alkyl? substituted carbonylmethyl; (C 1 -6 alkoxy) - 1-g alkyl), (C 1 -cycloalkoxy) -30 (C 1-8 alkyl); C2 12 alkanoyloxyalkyl; partially or fully halogenated alkyl, wherein the halogen (s) is (are) chlorine, bromine or fluorine; aminoalkyl, C 1-4 alkenyl; alkynyl; acyl; alkoxycarbonylalkyl; ^ -iikylaminoacetoxyalkyl; C2-4 alkanoylaminoalkyl; ar- (C 1-4 alkyl), wherein the alkyl radical contains 6-10 carbon atoms, monocyclic or bicyclic heteroaralkyl or heterocyclyl alkyl of 4-10 ring atoms, 1-3 carbon atoms. in the alkyl radical, and 1-4 heteroatoms selected from oxygen, sulfur and / or nitrogen; core-substituted aralkyl or heteroaralkyl in which the substituent

W ': J i V

J

-5- '. ^ Ψ chlorine, fluorine, bromine, iodine or C1 -C8 alkyl; aryl or core-substituted aryl of 6-10 ring carbon atoms and wherein each core substituent is hydroxy, alkyl, chlorine, fluorine, or bromine, ar alkoxy alkyl; alkylthioalkyl; cycloalkylthioalkyl; (C21-4 acylthioMC1-2 alkyl); or phenylalkenyl which contains 2-6 carbon atoms; R 1 substituted or unsubstituted alkyl; ίο aikenyl, or alkynyl; ring-substituted and unsubstituted cycloalkyl, cycloalkenyl, cycloalkenylalkyl and cycloalkylalkyl having 3-6 ring carbon atoms and up to 6 carbon atoms in each chain; aryl; 10 aralkyl with 6-10 ring carbon atoms and 1-6 carbon atoms in the alkyl chain; monocyelic or bicicylic heteroaryl or heteroaralkyl having U-10 atoms, after which one or more is (are) oxygen, nitrogen or sulfur having 1-6 carbon atoms in the alkyl chain; and the ring or chain substituent (s) is / are chlorine, bromine, iodine, fluorine, azido, cyano, amino alkylamino; A di (C1 g alkyl) amino or tri (C1 g) alkylamino group, in which case an additional anion is present, hydroxy, alkoxy, alkyl thioalkyl; carboxyl, oxo, (C 1-6 alkoxy) carbonyl, 2-10 carbamoyl; (C. alkyl) carbamoyl; di (C1, alkyl) carbamoyl; cyanothio (-SCH) or nitro; 1 - 4 1 - 4 ^ 2 1 R 6 is hydrogen, hydroxy, mercapto, R, -OR, -SR or HR R, wherein R, R and 2 R have the aforementioned meanings; k 4

X hydrogen, mercapto, amino, acyloxy, -OR, -SR

4. 4 is -HER, -N-R, R * -OM, OQ or when the compound is in zwitterion form, -0, in which case JT is absent; A, when the compound is not in zwitterion form, is a counter ion, M is a pharmaceutically acceptable cation; and Q is a blocking group as defined herein are described in the 3-way patent 1,604,275; and (8) compounds of formula 38 of the formula sheet, wherein the group of formula 39 of the formula sheet attached to the amino nitrogen group of thiena mycine represents a mono- or polycyclic H-containing heterocyclic group and RH, substituted or unsubstituted: alkyl, aryl, alkenyl, 2 heterocyclylaikenyl, aralkenyl, heterocyclylalkyl, aralkyl, -HR, C00R, 35 COUR, -OR or CN are described in European patent application 21082. The compounds described in U.S. Pat. No. 4,235,920 include those according to formula 4θ of the formula sheet, where A is a pharmaceutical

'N

-6- * is acceptable anion. The above-mentioned quaternary amine derivative is also described in Recent Advances in the Chemistry of β-Lactam Antibiotics, Royal Society of Chemistry, London 1981, biz. 2 ^ 0-25 ^ in which its average antibacterial activity is reported to be about 5 1/2 to 2/3 that of thienamycin.

In addition to the aforementioned, carbapenem derivatives with various 6-substituents have also been synthesized. Thus, for example, in (1) European patent application 1 * 4θ8 discloses compounds of formula II of the formula sheet, wherein R 1 H is methyl or hydroxyl and R 1 is a monovalent organic group including heterocyclic alkyl; (2) disclose in European Patent Application 851 ^ compounds of formula k2 of the formula sheet, wherein R is an optionally substituted pyrimidinyl group and Rg represents hydrogen or a group CR ^ R ^ R ^, wherein R ^ is hydrogen or hydroxy R 1 is hydrogen or alkyl and R 1 is hydrogen, alkyl, benzyl or phenyl, or R 1 and R 1 together form a carbocyclic ring; (3) European Patent Application 38869 discloses compounds having the formula 6 T 3 le Ij-3 of the formula sheet wherein R, R and R are independently selected from hydrogen, substituted and unsubstituted: alkyl, alkenyl and alkylene with 1-10 carbon atoms, 20 cycloalkyl, cycloalkylalkyl and alkylcycloalkyl with 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl units; aryl such as phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl moiety is phenyl and the aliphatic portion contains 1-6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and the erocyclylalkyl; wherein the substituent or substituent and in connection with said radicals are selected from the group consisting of:

a

-7- r * -Xe halogen (chlorine, arofluorine) -0Ξ hydroxy -OR1 alkoxy, aryloxy 0 U 12 -OCNR R carbamcyloxy * 0 II 1 2. -CNR "R carbamoyl -NR1R2 amino / NR1 amidino

\ rV

R1 eNO ^ nitro Θ —NfR1) 2 tri-substituted amiiio (S ^ handle ^. Independently selected) * r I 2 ...

-C-NOR oxiaino -SR1 alkyl- and arylthio / -S02NR1R2 snlfonamido 0 ll 2 -NHCNR-R urea do 0. -R1CNR2- ami do -CO, S carboxy ^ 1. -CO2R carboxylate - 0 -CR1 acyl 0 ll -OCR * "acylcxy -SH mercapo -8- 0 • -SR1 alkyl ^ en aryl sulxinyl O '-SR1 alkyl and aryl sulfonyl

II

o -CN cyan o -1? 2 azido ^ rr g wherein, in connection with the aforementioned substituents on R, R and R, 12 the groups R and R are independently selected from: hydrogen, alkyl, alkenyl and alkynyl with 1- 10 carbon atoms; cycloalkyl, cycloalkylalkyl and 5 alkylcycloalkyl with 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl units; aryl, such as phenyl; aralkyl, ar alkenyl, and ar alkynyl, wherein the aryl moiety is phenyl and the aliphatic moiety contains 1-6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocycloalkyl wherein the heteroatom or heteroatoms in the aforementioned heterocyclic units are selected from the group consisting of 1-4 oxygen, nitrogen or sulfur atoms and the alkyl units associated with said heterocyclic units 1-6 carbon which contain omen. (See also European patent applications 1627, 1628, 10317, 17992, 37080, 37081 and 37082); (4) European Patent Application No. 24832 discloses compounds of the formula 44 of the formula sheet wherein R 1 is H or a group selected 2 3 2 from OH, OSO-H or a salt or C1. alkyl esters thereof, OR, SR, OCOR, 3 ^ 3 .2 Ί OCOgR or OCOUI, where R is a g alkyl group or an optionally substituted benzyl group and R ^ is a C 8 alkyl group or an optionally sub-. 12 is a benzyl or phenyl group, and RC ^. g alkyl, g alkenyl, C 1 -C 8 alkynyl, in which the triple bond is not present on the carbon adjacent to the sulfur atom, is aralkyl, O-0-alkanoyl, aralkanoyl, 12'-aryloxyalkanoyl or arylcarbonyl, which R groups are optionally substituted as antibacterial agents.

European patent application 44170 describes carbapenem derivatives of formula 45 of the formula sheet, wherein R is hydrogen or an organic group bonded to the carbapenem ring via a carbon atom, n 0 or 1; V '-9-, v ~, 4Γ * ;.

X is a saturated or unsaturated hydrocarbon group optionally substituted by bromine or chlorine and R is a C 1 -C 8 alkyl, a 1 and 3 R 3 aralkyl or aryl group, all R 1 groups of which are optionally substituted Sr does not mention any compound in which the tetrazole ring 5 is bonded to X via a quaternized nitrogen atom, ie a positively charged nitrogen atom which is not bonded to a hydrogen atom.

European patent application 38 869 as mentioned above describes the synthesis of the carbapenem derivatives via intermediates with the general

6 T

formula 46 of the formula sheet, wherein R and R have the above meanings and is an easily removable carbozyl protecting group. Further described as intermediates are compounds of the formula k-J of the formula sheet, wherein X is mentioned as a cleavable group.

During the Gordon Research Conference on Medicinal Chemistry held at Hew London, Hew Hampshire, August 2-6, 1982, a leaflet describing a series of carbapenem antibiotics was distributed. One of the compounds described on page 9 is the carbapenem compound of formula 48 of the formula sheet, which differs from the compounds of the subject group in that the quateraized heteroaromatic ring in the 20 2 substituent ate directly on the sulfur atom instead of the carbon uncle of an alkylene group is bonded.

European patent application 50334 describes carbapenem derivatives & 7 of the general formula 49 of the formula sheet, in which R and R are, among others, independently selected from hydrogen, alkyl, alkenyl, aryl and aralkyl; A is a direct, single bond linking indicated S and C atoms, or A is a cyclic or acyclic linking group selected, inter alia, from alkyl, cycloalkyl, aryl, heteroaryl or heteroalkyl; R and R, which define the carbamimidoyl function, are independently selected from among others hydrogen, alkyl and aryl; wherein said carbamimidoyl is further characterized by cyclic structures achieved by joining the two nitrogen atoms through their substituents and by joining the coupling group A; further describing "carbamimidium compounds" by quaternization of one of the nitrogen atoms of said carbamimidoyl.

On page 12 of said application, as a possible 2-substituent, the group 35® with the formula 50 of the formula sheet is described, wherein R is defined as hydrogen, substituted and unsubstituted: alkyl, cycloalkyl.

cyeloalkyialkyl, alkylcycloalkyl, aryl, aralkyl, heterocyclyl or hetero- Λ - - - - Λ \ \ -10-cyclylalkyl and the two nitrogen atoms "are part of cyclic structures indicated by dotted lines". No specific description is given of cyclized carbamimidoyl groups containing a quaternized nitrogen atom; however, on page 22, a cyclized carbamimidoyl group of formula 51 of the formula sheet is described.

.... 1

Starting from the stated definitions of substituent R, it is believed that in European Patent Application 50,333 none of the present compounds is described in general. However, since the language in said application is rather vague with respect to the intended cyclic structures, this reference is nevertheless mentioned in the present description.

Although, as noted above, carbapenem derivatives have been described in the prior art with a 2-substituent of the general formula: -SA-Het wherein A represents an alkylene group and Het represents a heterocyclic or heteroaramatic group, the applicant is known to is no description disclosing carbapenem compounds wherein Het is a group of formula 52 of the formula sheet wherein R ^ is an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aryl, araliphatic, heteroaryl, heteroaraliphatic, heterocyclyl or heterocyclylaliphatic group, and the group of formula 11 represents a quaternized nitrogen-containing aromatic heterocyclic group bonded to the alkylene carbon atom via a ring carbon atom.

As mentioned above, the carbapenem compound of formula 53 of the formula sheet has been mentioned as the 2 substituent as well as the carbapenem compound having a quateraized heteroaromatic ring bonded directly to the sulfur 2 substituent.

Despite the very large number of carbapenem-30 derivatives described in the literature, there is still a need for new carbapenem compounds since the spectrum of activity, potency, stability and / or toxic side effects of the known derivatives can be improved.

Summary of the invention

The present invention provides a new series of carbapenem fifty

"V

-11- derivatives characterized by a 2-substituent of formula 10 5

_S_A-i-N -R

* wherein A represents a C 1 -C 8 straight or branched chain alkylene group; an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aryl, araliphatic, heteroaryl, heteroaraliphatic, heterocyclyl or heterocyclyl aliphatic group; and the group of formula 11 represents a quaternized nitrogen-containing aromatic heterocyclic group bonded to the alkylene group A via a ring carbon atom. More specifically, the present invention provides

Q

Thing in earringsapenem derivatives of formula 1 of the formula sheet, wherein R is hydrogen and R1 is selected from the group consisting of hydrogen; substituted and unsubstituted: alkyl, alkenyl and alkynyl with 1-10 carbon atoms; cycloalkyl and cycloalkylalkyl with 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl units; phenyl; aralkyl, aralkenyl and aralkynyl, wherein the aryl moiety is phenyl and the aliphatic moiety contains 1-6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl. wherein the heteroatom or heteroatoms in said heterocyclic units are selected from 1-O oxygen, nitrogen or sulfur atoms and the alkyl units attached to said heterocyclic units contain 1-6 carbon atoms; wherein the substituent or substituents in connection with the aforementioned groups are independently selected from: C 1 -C 8 alkyl optionally substituted by amino, halo hydroxy or carboxyl halo -os 3 -oq? s3s ** -cns3s4 -ns3s4 Ά

V

-12- / NR3 - / ^ nr3r4 * »-S02NR3R4 0

I 3 4 -NHCNR R

0 3II 4 R CNR - <3

C02R

-OP (0) (OR3) (OR4) -0 0 -OCR3 -SR3 0 4r * 0 fl 9 -SR *

II

0

-CN

-N3 3

-0S03R

0 n §

-OS-R

0 0 3 * 1 9 -NR S-R II 0 3 4

-NR C = NO

-NR3CO2R4 -no2. -. . :: -13- Λ, 3 wherein with respect to the "above substituents, the groups R and k R are independently selected from hydrogen; alkyl, alkenyl and alkynyl of 1-10 carbon atoms; cycloalkyl, cyeloalkylalkyl and alkylcycloalkyl of 3-6 carbon atoms in the cyeloalkyl ring and 1-6 carbon atoms in the alkyl units; phenyl; ar alkyl, ar alkenyl and ar alkynyl, wherein the aryl unit is phenyl and the aliphatic moiety contains 1-6 carbon atoms; and heteroaryl, heteroaralkyl, heteroeyelyl and heterocyclylalkyl, wherein the heteroatom or heteroatoms in said heterocyclic units is selected from 1-4 oxygen, nitrogen or sulfur, and the alkyl units 10 attached to said heterocyclic units contain 1-6 carbon atoms, or R and R together taken with the nitrogen to which at least one is bonded a nitrogen-containing 5- or 6-membered heterocyclic ring, R 3 may have the meanings of R except that it does not contain hydrogen. be; or wherein R and R taken together represent C 8 -C 18 alkylidene or C 8 -C 18 alkylidene substituted by hydroxy; R1 is selected from the group consisting of substituted and unsubstituted: alkyl, alkenyl and alkynyl of 1-10 carbon atoms; cycloalkyl and cyeloalkylalkyl with 3-6 carbon atoms in the cyeloalkyl ring and 1-6 carbon atoms in the alkyl units; phenyl; ar alkyl, ar alkenyl or ar alkynyl, wherein the arylene moiety is phenyl and the aliphatic moiety contains 1-6 carbon atoms; heteroaryl, heteroaralkyl, heteroeyelyl and heterocyclylalkyl, wherein the heteroatom or heteroatoms in the aforementioned heterocyclic units are selected from the group consisting of 1-4 oxygen, nitrogen or sulfur, and the alkyl units associated with said heterocyclic units 1-6 carbon-25 contain substance atoms; wherein said radicals are optionally substituted by 1-3 substituents independently selected from: C 1 -C 8 alkyl, optionally substituted by amino, fluoro, chloro, carboxyl, hydroxy or carbamoyl; fluorine, chlorine or bromine; -OR3 -OCOgR3 -OCOR3 -OCONR3R4; 0 H 9 -OS-R? 10 O -oxo; v -14->

3 4 -NRJR

3 4 RJCONR - 7 3 4

-NR CO-R

3 1 3 4 -NO CONR R?

O

3II 9 -NR S-R7 7 o -SR3

O

Q

-S-R?

O O f \ J Q -S-R

-SO, R3

-3 3 -CO, R

z 3 4 -CONR R

-CN 7 o phenyl optionally substituted by 1-3 fluoro, chloro, bromo, C 1 -C 4 alkyl, -OR ^, -HR ^ R ^, -SO_r \ -C0oR ^ or 3 k 1 3 ° h 9 5 2 -COUR R m-wherein R, R and R are defined in such R-substituents as above or R 4 may be attached to the group of formula 11 at another point of the ring such that a condensed heterocyclic or heteroarea - a ring is formed, which ring may contain further, preferably up to 2, heteroatams selected from 0, N and S; R 10 is selected from the group consisting of hydrogen; substituted and unsubstituted: alkyl, alkenyl and alkynyl of 1-10 carbon atoms; cycloalkyl, cycloalkylalkyl and alkylcycloalkyl with 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl units; spirocycloalkyl of 3-6 carbon atoms; phenyl; aralkyl, aralkenyl and aralkynyl 15 wherein the aryl moiety is phenyl and the aliphatic moiety contains 1-6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl, wherein the heteroatom or heteroatom in said heterocyclic units are selected from 1-U oxygen, nitrogen and sulfur atoms and the alkyl units attached to said heterocyclic units contain 1-6 carbon-20 atoms; wherein the substituent or substituents are selected in conjunction with -15- ir> the aforementioned groups nit amino, mono-, di- and trialkylamino, hydroxyl, alkoxyl, mercapto, alkylthio, phenylthio, sulfamoyl, amidino, guanidino, nitro, chlorine , bromine, fluorine, cyano and carboxy; and wherein the alkyl units of the aforementioned substituents contain 1-6 carbon atoms; 2 A is a C 1 -C 6 straight or branched chain alkylene; R is hydrogen, an anxious charge or a conventional easily removable carboxyl-protecting group xs, provided that when R is hydrogen or a protecting group, a counterion is also present; and the group of formula 11 represents a substituted or unsubstituted mono-, bi- or polycyclic aromatic heterocyclic group having at least one ring nitrogen atom bonded to A via a ring carbon atom and with a ring nitrogen atom quaternized by the group R 1; and the pharmaceutically acceptable salt thereof.

The compounds of formula I are powerful antibacterial agents or intermediates suitable for the preparation of such agents.

Also within the scope of the invention are methods of preparing the new carbapenem derivatives as described above and pharmaceutical compositions containing the biologically active carbapenem derivatives in combination with pharmaceutically acceptable carriers or diluents.

Detailed description

New compounds of the general formula 1 contain the carbapenem core of formula 12a T,

1-K-L

0-425 and can thus be called 1-carba-2-penem-3-carboxylic acid derivatives.

Optionally, the compounds can be considered the basic structure of formula 12b cr i Λ 4

V

-16-

V

and they are referred to as 7-oxo-1-azabi cyclo (3,2,0) hept-2-en-2-carboxylic acid derivatives. Although the present invention contains compounds "wherein the" concerning stereochemistry of the 5, 6 protons is both cis and trans, the preferred compounds have the 5R, 6s (trans) stereochemistry, as in the case of thienamycin.

The compounds of formula 1 may be unsubstituted or substituted in the 6-position by substituent groups as previously for an-

O

other carbapenem derivatives have been described. More specifically, R ° may be hydrogen 1 and R ° may be hydrogen or a hydrogen substituent, as described, for example, in European Application 38869 (see definition of R 1).

8 1 ®

Optionally, R and R taken together may be C 1 -C 2 alkylidene or, for example, hydroxy-substituted C 1 -C 2 alkylidene.

The compounds of formula 1 may also be in the 1-position 15 (R-H) unsubstituted or substituted by substituent groups as previously described for other carbapenem derivatives. More particularly, R 1 ^ may be hydrogen or any of the non-hydrogen 1 substituents as described, for example, in European Patent Application 5 * + 917 (see definition of R or R there) or in U.S. Patent 1 *. 350,631.

. 15. *

Preferred hydrogen-R substituents include C 1 -C 6 alkyl, preferably methyl, phenyl; and phenyl (C 1 -C 6) alkyl. The non-hydrogen R substituent can be in the α or 3 configuration; The present invention is intended to include the individual α and 3 isomers as well as mixtures thereof. Most preferred 1-substituted compounds are those having the 3-configuration, especially those containing the B-methyl substituent. Further explanation of the definitions of R and R ° and (a) the aliphatic "alkyl", "alkenyl" and "alkynyl" groups may be straight or branched with 1-10 carbon atoms, preferably 1-6, in particular 1-1 * carbon groups; when part of another substituent, for example as in cycloalkylalkyl, or heteroaralkyl or aralkenyl, the alkyl, alkenyl and alkynyl groups preferably contain 1-6, most preferably 1-1 * carbon atoms.

(b) "Heteroaryl" includes mono-, di- and polycyclic aromatic heterocyclic groups having 1-1 + 0, N or S atoms; preferably 5- or 35-membered heterocycles, such as thienyl, furyl, thiadiazolyl, oxadiazolyl, triazolyl, iso-thiazolyl, thiazolyl, imidazolyl, isoxazolyl, tetrazolyl, oxazolyl, pyridyl pyradinyl, pyridinyl, pyridazinyl, pyrrolyl, pyrrolyl

(Het-life) "Heterocyclyl" includes mono-, bi- and polycyclic saturated or unsaturated non-aramatic heterocyclic groups with 1-¼ O, N or S atoms; preferably 5- or 6-membered heterocycles, such as morpholinyl, piperazyl, piperidyl, pyrazolinyl, pyrazolidinyl, imidazol vinyl, imidazol vinyl, pyrrolinyl, pyrrolidinyl etc.

(d) "halogen" includes chlorine, bromine, fluorine and iodine and is preferably chlorine, fluorine or bromine.

The term "conventional easily removable carboxyl protecting group" refers to a known ester group as used to block a carboxyl group during the chemical reaction steps described below and which can be optionally removed by methods which do not give rise to any appreciable destruction of the residual part of the molecule, for example by chemical or enzymatic hydrolysis, treatment with chemical reducing agents under mild conditions, irradiation with ultraviolet light or catalytic hydrogenation. Examples of such ester protecting groups include benzhydryl, allyl, p-nitrobenzyl, 2-naphthylmethyl, benzyl, trichloroethyl silyl, such as trimethylsilyl, phenacyl, p-methoxybenzyl, acetonyl, O-nitrobenzyl, h-pyridylmethyl, and C 1 -C 6 alkyl, such as methyl, ethyl or t-butyl. Such protecting groups include those that are hydrolyzed under physiological conditions, such as pivaloyloxymethyl, acetoxymethyl, phthalyl, indanyl, and methoxymethyl. A particularly favorable carboxyl protecting group is p-nitrobenzyl, which can be easily removed by catalytic hydrogenolysis.

The above pharmaceutically acceptable salts include the non-toxic acid addition salts, for example, salts with inorganic acids such as hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid, etc., and salts with organic acids, such as maleic acid, acetic acid, citric acid, succinic acid, tartaric acid, fumaric, mandelic, ascorbic acid, lactic, gluconic and malic. Compounds of formula 1 in the form of acid addition salts can be represented by formula 1 'of the formula sheet, (with R 2 = H or protecting group), wherein X® represents the acid anion. The counterion X® can be chosen to give pharmaceutically acceptable salts for therapeutic administration, but in the case of intermediate compounds of formula I, X® can also be a toxic anion. In such a case, the ion can subsequently be removed or substituted by a pharmaceutically acceptable anion. ✓ a '* »\ -18- to form an active end product for therapeutic use. When acidic or basic groups are present in the R1 or R1 group or on the group of formula II, the invention may also include suitable basic or acidic salts of. these functional groups include; for example acid-5 addition salts in the case of a basic group and metal salts (for example sodium, potassium, calcium and aluminum), the ammonium salt and salts with non-toxic amines (for example trialkylamines, procaine, dibenzyl-amine, 1-ephenamine benzyl β-phenylamine, N, R'-dibenzylethylenediamine etc.) in the case of an acidic group.

Compounds of formula I wherein R is hydrogen, an amonic charge or a physiologically hydrolyzable ester group together with pharmaceutically acceptable salts thereof are suitable antibacterial agents. The residual compounds of formula 1 are valuable intermediates which can be converted into the above biologically active compounds.

A preferred embodiment of the present invention includes 8 l of compounds of formula I, wherein R is hydrogen and R is hydrogen, CH 2 CH 1 - 2 CH 2 O 2 O 3 CS- / C- or CH.CH-

of this subgroup, preferred compounds are those wherein R

CE ^ CH-20 is preferably compounds with the absolute configuration 5R, 6S, 8R.

Another preferred embodiment includes compounds of the formula 1, wherein R and R taken together form an alkylidene group of the formula: H ° C22 ^ c = »^ 3 -19-yi> - /

The alkylene (i.e., substituent "A") group in the compounds of formula 1 can be straight or branched and contain 1-6 carbon atoms.

A preferred embodiment includes those compounds wherein A = - (CH ^) - ^. wherein n is 1 or 2 and a particularly preferred embodiment comprises those compounds wherein A is -CH 2 -.

The alkylene unit "A" is attached via a ring carbon atom to an unsubstituted quatemized aromatic heterocyclic group of the general formula 52 'of the formula sheet, wherein the R 1 substituent preferably refers to an optionally substituted C 1 -C 6 alkyl C 2 -C 10 alkenyl, C 8 -C 20 alkynyl, C 1 -C 8 cycloalkyl, C 1 -C 8 cycloalkyl-C 1 -C 8 alkyl, phenyl, phenyl-C 1 -C 8 alkyl, phenyl-C 1 -C 8 alkenyl, phenyl -C 1 -C 8 alkynyl, heteroaryl, heteroaralkyl in which the alkyl moiety contains 1-6 carbon atoms, heterocyclyl or heterocyclylalkyl in which the alkyl moiety contains 1-6 carbon atoms. The heteroaryl (or heteroaryl portion of heteroaralkyl) R 1 sub-15 stituent may be a mono-, bi- or polycyclic aromatic heterocyclic group having 1-U 0, IT or S atoms; preferably 5- or 6-membered heterocycles, such as thienyl, furyl, thiadiazolyl, oxadiazolyl, triazolyl, iso-thiazolyl, thiazolyl, imidazolyl, isoxazolyl, tetrazolyl, oxazolyl, pyridyl, pyrazinylpyrimidinyl, pyradolyl, pyrazolyl. The heterocyclyl 20 (or the heterocyclyl portion of heterocyclylalkyl) R 1 substituent may be a mono-, bi-, or polycyclic saturated or unsaturated non-aramatic heterocyclic group having 1-O, R, or S atoms; preferred are 5- or 6-membered heterocycles, such as morpholinyl, piperazinyl, piperidyl, pyrazolinyl, pyrazolidinyl, imdazolidinyl imidazodinyl, pyrrolinyl and pyrrolidinyl.

The R 1 substituent may be optionally substituted by 1-3 substituents independently selected from: (a) C 1 -C 8 alkyl optionally substituted by, preferably 1-3 amino, fluorine, chlorine, carboxyl, hydroxy or carbamyl groups; 30 (b) fluorine, chlorine or bromine (C) -OR3? (d) -0CO2R3; (e) -OCOR3; (f) -OCONR3R4;

(g) O

9ί 9 -OS-R? ; I!

O

* i4 *

S I

C * -20- (h) -oxo; (i) -NR3R4? (j) R3CONR4-; Ü0 -nr3co2r4 7 (l) -NR3CONR3R4 7

(m) O

3II o -NRJS-R *? ll

O

(n) -SR3 7 (o) -SOR9? (p) o / 1 9 -S-R; ll

O

(q) -S03R3? , (r) -CO 2 R 3 7 (s) -CONR 3 R 4; (t) -CN 7 £ * * ^ (u) phenyl optionally substituted by 1-3 substituents independently.

3 3 U 3 3

selected from fluoro, chloro, bromo, O, -C ^ alkyl, -OR, -UR R, -SO..R, -C0oR

3 U. . 15 5. 3 2 or -COUR R, wherein in conjunction with the above R substituents,

3 U

The groups R and R are independently selected from hydrogen; alkyl, alkenyl and alkynyl with 1-10 carbon atoms; cycloalkyl, cycloalkylalkyl and alkylcycloalkyl with 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkylene units; phenyl; aralkyl; aralkenyl and ar alkynyl, wherein the aryl moiety is phenyl and the aliphatic moiety contains 1-6 carbon atoms; and heteroaryl, heteroalkyl, heterocyclyl and heterocyclylalkyl wherein the heteroaryl group and the heterocyclyl group or part of the group have the meanings of R 1 and the alkyl units attached to said hetero- / 3 k cyclic units have 1-6 carbon atoms; or R and R taken together with the nitrogen atom to which they are attached may form a nitrogen-containing 5- or 6-membered heterocyclic ring (as defined for RO) and r has the meanings of R except that it must not be hydrogen. Most preferred R 3 substituent is C 1 -C 8 alkyl, especially methyl.

5

In addition, the R substituent, together with another ring atom of the group of formula 11, may form a fused heterocyclic or hetero-t -21-y aromatic ring, which ring may additionally contain, for example, 1 or 2 heteroatams selected from 0, 1 and S. For example, the group of formula 52 'may be a group of formula 5, 55 or $ 6 of the formula sheet.

The group of formula III preferably represents a substituted or unsubstituted mono-, bi- or polycyclic aromatic heterocyclic group containing at least one nitrogen atom in the ring and 0-5 additional ring heteroatams selected from 0, S and H, which heterocyclic ring is attached to A by a ring carbon atom and has a ring nitrogen-10 atom quateroized by the group.

The heteroaramatic ring of formula 11 * may be optionally substituted at available ring carbon atoms with preferably 1-5, especially 1-3 substituents independently selected from C 1 -C 6 alkyl; C 1 -C 4 alkyl substituted by preferably 1 - 3 hydroxy, amino, C 1 -C 6 alkylamino, di (C 1 -C 6) alkylamino, C 1 -C 6 alkoxy, carbonyl, halogen (hereinafter referred to as chlorine, bromine, fluorine or iodine, preferably chlorine, bromine or fluorine) or sulfo; C 1 -C 8 cycloalkyl; C 1 -C 8 cycloalkyl C 1 -C 1 alkyl optionally substituted by 1-3 substituents as mentioned above in connection with C 1 -C 12 alkyl; C 1 -C 2 alkoxy; C 1 -C 2 alkylthio; amino; C 1 -C 20 al-20 kylamino; diiC ^ -C ^) alkylamino; halogen; C 1 -C 2 alkanoylamino; C 1 -C 2 alkanoyloxy; carboxy; sulfo; O-C-O-C 1 -C 2 alkyl; hydroxy; amidino; guanidino; phenyl; phenyl substituted by 1-3 substituents independently selected from amino, halogen, hydroxy, trifluoromethyl, alkyl, alkoxy, C 1 -C 6 alkylamino, diiC 2 -C 6 alkylamino, carboxy and sulfo; phenyl (C 1 -C 1) alkyl, wherein the phenyl moiety may be optionally substituted with 1-3 substituents as mentioned above in conjunction with phenyl and the alkyl moiety may be optionally substituted with 13 substituents as mentioned above in conjunction with C 1 - 3 C 1 -alkyl? and heteroaryl or hetero-30 aralkyl, wherein the heteroatom or atoms are selected from the group consisting of 1-U 0, S or N atoms and the alkyl moiety linked to heteroaralkyl may contain 1-6 carbon atoms heteroaryl and heteroalkyl groups in the heterocyclic ring unit are optionally substituted by 1-3 substituents independently selected from: hydroxy, amino, halogen, trifluoromethyl C 1 -C 2 alkyl, C 1 -C 1 alkoxy, C 2 -C ^ alkylamino, diiC ^ -C ^) alkylamino carboxy and sulfo and in the alkyl unit by 1-3 substituents selected from hydroxy, amino, C ^ -C ^ alkylamino, iKc ^ -C ^) alkylamino, C ^ -C ^ alkoxy, ^ % - - K. · '*. V -22- s *%

V

carboxy, halogen and sulfo. In addition, available ring nitrogen atoms (other than the quaternized nitrogen) may be substituted by 1-3 substituents independently selected from C 1 -C 1 alkyl; C 1 -C 21 alkyl optionally substituted by 1-3 hydroxy, amino, C 1 -C 21 alkylamino, dKc -C 21 alkyl-amino, C 1 -C 20 alkoxy, carboxy, halogen or sulfo groups; C 1 -C 8 cycloalkyl, (C 1 -C 12) alkyl optionally substituted by 1-3 substituents as mentioned above in connection with C 1 -C 12 alkyl; phenyl; phenyl substituted by 1-3 substituents independently selected from amino, halogen, hydroxy, trifluoromethyl, C 1 -C 1 alkyl, C 1 -C 1 alkoxy, C 1 -C 1 alkylamino, di (C 1 -C 1) alkyΙ-ΙΟ amino, carboxy and sulfo; phenyl (C 1 -C 6) alkyl-wherein the phenyl moiety may optionally * be substituted by 1-3 substituents as mentioned above in connection with phenyl, and the alkyl moiety may optionally be substituted by 1-3 substituents as mentioned above in conjunction with C 1 -C 4 alkyl; and heteroaryl or heteroaralkyl, wherein the heteroatoam or atoms are selected from 1-4 O, S or N atoms and the alkyl moiety associated with heteroaralkyl contains 1-6 carbon atoms optionally containing heteroaryl and heteroaralkyl groups in the heterocyclic ring units are substituted by 1-3 substituents independently selected from amino, halogen, trifluoromethyl, C 1 -C 1 alkyl, C 1 -C 1 alkoxyi C 1 -C 1 alkylamino, diiC 2 -C 1) alkylamino, carboxy and sul -20 fo and in the alkyl unit by 1-3 substituents selected from hydroxy, amino, C 1-6 alkylamino, di (C 1 -C 6) alkylamino, C 1 -C 12 alkoxy, carboxy, halogen and sulfo. The most preferred ring carbon and nitrogen substituents are C 1 -C 6 alkyl, especially methyl.

In the preferred embodiment described above, the preferred compounds are those wherein A is - (CH_) -, with n 1 or 2, preferably those where

ι «δ Q

in A is -C1 -g and wherein (a) R and R taken together represent HOCH, ^ c * ch3 or (b) 8 1 R ° is hydrogen and R is hydrogen, CH ^ CHg-,

CS, CH, OH OH

^ CH-. I

^ C-, or CH.CH-.

* -23- y g

proposes. Particularly preferred compounds are those wherein R is hydrogen and R

OH

CS ^ CS-, especially those compounds which have the absolute configuration 5RS 6S, 8R.

In a preferred embodiment, the group of formula 11 * represents an aromatic N-containing heterocyclic 5- or 6-ring with 0-3 3x-tra heteroatoms selected from 0, S or N. Such an aromatic heterocyclic group may, if possible, be with another ring are condensed, for example a saturated or unsaturated carbocyclic ring, preferably a C 1 -C 2 carboxycyclic ring, an aromatic carbocyclic ring, preferably a phenyl ring, a heterocyclic ring (saturated or unsaturated) with 1-3 heteroatoms selected from 0, S, N or NR, wherein R is hydrogen, C 1 -C 4 alkyl optionally substituted with 1-2 substituents independently selected from -R 1, -NR R -COgR , oxo, phenyl, fluoro, chloro, bromo, -SO ^ R ^ and -COMR ^ R ^, or phenyl optionally substituted with 1-3 substituents independently selected from: s 3 k 3 3 3 k C, - Cr alkyl, -OR, -NR R, fluoro, bromine, -S0_R, -C0oR and -CONR R, where I k 11 5 d R and R in such R substituents are the v have meanings - | 20 in connection with substituent R, or a heteroatamatic 5- or 6-ring with 11. 11 1-3 heteroatoms selected from 0, S, N or NR wherein R has the aforementioned meanings. The aromatic quaternized 5- or 6-ring, or optionally, the carbocyclic, heterocyclic or heteroatamatic ring condensed therewith, or both such rings, may be optionally substituted in available ring atoms, preferably up to a total of 5 substituents for the total ring system, said substituents in connection with the group of formula 11. In the preferred embodiment described above, the preferred compounds are those wherein A is - (CH_) - with n 1 or 2, preferably

1 ^ n Q

those in which A is -CH 2 - and in which (a) R and R taken together represent HOCH, 2N = cm 8 1 or (b) R 0 is hydrogen and -R is hydrogen,

α3χ = H3n? H PB

c-, or CHlCS-.

CH3 CS,% -2k-.

8 i

Especially preferred are the compounds wherein R is hydrogen and R

OH

CH ^ CH, in particular, compounds with the absolute configuration are 5R, 6S, 8R.

Rog a further preferred embodiment of the present invention comprises compounds of formula 1, wherein the group of formula 52 represents a group selected from: 6 T 10

(a) a group of formula 5T of the formula sheet, wherein R, R and R

10 are independently selected from hydrogen, C 1 -C 12 alkyl; C 1 -C 1 alkyl substituted preferably by 1-3 hydroxy, C 1 -C 1 alkylamino, dKC 1 -C 1 alkyl) amino, C 1 -C 1 alkoxy, amino, sulfo, carboxy or halogen (chlorine, bromine, fluorine or iodine, preferably chlorine, fluorine or bromine), C 1 -C 8 cycloalkyl, C 1 -C 12 alkoxy; alkylthio; amino; C 1 -C 2 alkylamino; diiC ^ C ^ ialkylamino, halogen (chlorine, bromine, fluorine or iodine; preferably fluorine, chlorine or bromine); C 1 -C 2 alkanoylamino; C 1 -C 2 alkanoyloxy; carboxy; 0

II

-C-OC-C-alkyl; hydroxy; amidino; guanidino; phenyl; phenyl substituted by one, three or three amino, halogen (chlorine, bromine, fluoro or iodine; preferably chlorine, fluorine or bromine), hydroxyl, trifluoromethyl, C 1 -C 6 alkyl or C 1 -C 6 alkoxy groups; phenyl C 1 -C 6 alkyl, wherein the phenyl moiety may be optionally substituted by 1 to 3 substituents as mentioned above in conjunction with phenyl, and the alkyl moiety may be optionally substituted by 1 to 3 substituents as mentioned above in conjunction with phenyl -C 1-4 alkyl; and heteroaryl and heteroaralkyl, wherein the heteroatom or atoms in said heterocyclic units are selected from 1-U oxygen, nitrogen or sulfur atoms and contain the alkyl 6 T 10 unit 1-6 carbon atoms connected to said heteroalkyl unit; or wherein two of the R, R or R taken together may form a condensed saturated carbocyclic ring, a condensed aromatic carbocyclic ring, a condensed non-aromatic heterocyclic ring or a condensed heteroaromatic ring, which condensed rings may be optionally substituted are through one or two of the above substituents R 1, R 1 and R 10; (b) groups of formulas 58, 59 or 60 of the formula sheet, optionally 35 on a carbon atom substituted by 1-3 substituents independently selected from C 1 -C 6 alkyl; C 1 -C 2 alkyl substituted by 1-3 hydroxy, C 1 -C 4 alkylamino, sulfo, diiC 2 -C 1 alkyl) amino, C 1 -C 2 alkoxy, amino, carboxy * r - - - vy _ / y * -25-

jJ

at or halogen (chlorine, "bromine, fluoro or iodine," preferably chloro, fluoro or bromo); C 1 -C 8 cycloalkyl; C 1 -C 12 alkoxy; C 1 -C 2 alkylthio; amino; C 1 -C 2 alkylamino; di (C 1 -C 2 alkyl) amino; halogen (chlorine, bromine, fluorine or iodine), preferably chlorine, fluorine or bromine), C 1 -C 6 alkanoylamino, C 1 -C 6 alka-5 noyloxy; carboxy 0 II ....

-C-OC-C-alkyl; hydroxy; amidino; guamdino; phenyl; phenyl substituted by one or two or three amino, halogen (chlorine, bromine, fluorine or iodine, preferably chlorine, fluorine or bromine) hydroxyl, trifluoromethyl, C 1 -C 20 alkyl or C 1 -C 20 alkoxy groups; phenyl (C 1 -C 1 -alkyl) in which the phenyl moiety may be optionally substituted by 1 to 3 substituents as mentioned above in conjunction with phenyl and the alkyl moiety may be optionally substituted by 1 to 3 substituents as mentioned above in conjunction with C 1 -C alkyl, and hydroaryl or heteroaralkyl wherein the heteroatom or atoms in the aforementioned heterocyclic units are selected from 1-¼ oxygen, nitrogen or sulfur atoms and the alkyl unit attached to said heteroaralkylene units contains from 1 to 6 carbon atoms or optionally substituted, heterocyclic or heteroaramatic ring optionally substituted by one or two of the above substituents; (c) groups of formulas 61-66 of the formula sheet optionally substituted by a carbon atom with one or two substituents independently selected from: C ^ - C 1 -C 4 alkyl; C 1 -C 2 alkyl substituted with preferably 1-3, hydroxy, C 1 -C 1 alkylamino, sulfo, di (C 1 -C 1 alkyl) amino, C 1 -C 4 alkoxy, amino, carboxy or halogen (ch loor, bromine, fluorine or iodine, preferably chlorine, fluorine or bromine); C 1 -C 8 cycloalkyl; C 1 -C 2 alkoxy; C 1 -C 2 alkylthio; amino; C 1 -C 2 alkylamino; di (C 1 -Chalkyl) amino; halogen (chlorine, bromine, fluorine or iodine), preferably chlorine, fluorine or bromine); C 1 -C 2 alkanoylamino; C 1 -C 8 alkanoyloxy; carboxy O 30 -C-OC ^ -C ^ alkyl? hydroxy; amidino; guanidino; phenyl; phenyl substituted by one, two or three amino, halogen (chlorine, bromine, fluorine or iodine, preferably chlorine, fluorine or bromine) hydroxyl, trifluoromethyl, C 1 -C 2 alkyl or C 1 -C 20 alkoxy groups; phenyl (C 1 -C 6) alkyl in which the phenyl moiety may be optionally substituted with 1-3 substituents as noted above with respect to phenyl and the alkyl moiety may be optionally substituted with 1-3 substituents as listed above in conjunction with phenyl with C 1 -C 2 alkyl; and heteroaryl or heteroaralkyl, wherein the heteroatom or atoms in the aforementioned; -; "J" * J "^ ^ -26-

V

heterocyclic units are selected from 1-U oxygen, nitrogen or sulfur atoms and the alkyl unit associated with said heteroalkylity contains 1-6 carbon atoms, or optionally substituted to form a condensed carboxycyclic, heterocyclic or heteroaromatic ring is formed, optionally substituted by one or two substituent and as mentioned above; (d) groups of formulas 67-72 of the formula sheet, optionally substituted on a carbon atom by a substituent independently selected from C 1 -C 6 alkyl; C 1 -C 1 alkyl substituted preferably by 1-3 hydroxy, 10 C 1 -C 1 alkylamino, di (C 1 -C 1 alkyl) amino, sulfo, C 1 -C 1 alkoxy, amino, carboxy, or halogen (chlorine, bromine, fluorine or iodine, preferably chlorine, fluorine or bromine), C 1 -C 8 cycloalkyl; C 1 -C 2 alkoxy; C 1 -C 2 alkylthio; amino; C 1 -C 2 alkylamino; di (C 1 -C 6 alkyl) amino, halogen, (chlorine, bromine, fluorine or iodine preferably chlorine, fluorine or bromine) C 1 -C 6 alkanoylamino, C 1 -C 6 alkanoyloxy, 15 carboxy -C-OSC ^ -C ^ alkyl? hydroxy; amidino; guanidino; phenyl; phenyl substituted by one, two or three amino; halogen (chlorine, bromine, fluorine or iodine; preferably chlorine, fluorine or bromine), hydroxyl; trifluoromethyl; C 1 -C 2 alkyli or C 1 -C 2 alkoxy groups; phenyl (C 1 -C 6) alkyl, wherein the phenyl moiety may be optionally substituted by 1-3 substituents as mentioned above in conjunction with phenyl and the alkyl moiety may be optionally substituted with 1-3 substituents as noted above in conjunction with C ^ -C ^ alkyl; and heteroaryl or the eraralkyl; wherein the heteroatom or atoms in said heterocyclic units are selected, from the group consisting of 1-U oxygen, nitrogen or sulfur atoms and the alkyl unit attached to said heterocar alkyl unit having 1-6 carbon omen; (e) groups of formula 73 or 73 'of the formula sheet wherein X is O, S or ILR, wherein R is C 1 -C 12 alkyl; C 1 -C 18 alkyl substituted by 1-3 hydroxy, 30 amino, C 1 -C 20 alkylamino, diiC 1 -C 20 alkylamino, C 1 -C 20 alkoxy, carboxy, halogen or sulfo groups; C 1 -C 8 cycloalkyl; C 1 -C 8 cycloalkyl (C 1 -C 12) alkyl optionally substituted by 1-3 substituents as mentioned above in connection with C 1 -C 12 alkyl; phenyl; phenyl substituted by 1-3 substituents independently selected from amino, halogen, hydroxy, trifluoromethyl, C 1 -C 2 -alkyl, alkoxy, C 1 -C 1 -alkylamino, diiC 2 -C 1 -alkylamino, carboxy and sul fo; phenyl (C 1 -C 12) alkyl, wherein the phenyl moiety may be optionally substituted by 1-3 substituents as mentioned above in conjunction with phenyl and the v 1 J 4 4 -27 alkyl moiety may be optionally substituted by 1 -3 substituent and as mentioned above in connection with C 1 -C 12 alkyl; and heteroaryl and heteroalkyl, wherein the heteroatom or atoms are selected from the group consisting of 1-4, S or IT atoms and the heteroalkyl-linked alkyl moiety contains 1-6 carbon atoms, which heteroaryl and heteroaralkyl groups optionally in the heterocyclic ring are substituted by 1-3 substituents independently selected from amino, halogen, trifluoromethyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylamino, diiC 2 -C 3) alkylamino, carboxy and sulfo and in the alkyl unit by 1-3 substituents selected from hydroxy, amino, 10 G-C 1 -alkylamino, dKC 2 -C 6) alkylamino, C 1 -C 2 alkoxy, carboxy, halogen and sulfo; which heteroaromatic group on a carbon atom is optionally substituted by one or more substituents independently selected from C 1 -C 6 alkyl; C 1 -C 1 alkyl substituted by preferably 1-3, hydroxy, amino, C 1 -C 1 alkylamino, diiC 1 -C 1 alkyl) amino, C 1 -C 1 alkoxy, sulfo, carboxy, or halogen (chlorine, bromine, fluorine or iodine, preferably chlorine, fluorine or bromine); C 1 -C 8 cycloalkyl; C 1 -C 2 alkoxy; C 1 -C 2 alkylthio; amino; C 1 -C 2 alkylamino; diC 1 -C 2 alkyl) amino; halogen (chlorine, bromine, fluorine or iodine, preferably chlorine, fluorine or bromine); . C 1 -C 2 alkanoylamino, C 1 -C 2 alkanoyl oxy, carboxy; O-C 1 -C 20 -C 12 alkyl; hydroxy; amidino; guanidino; phenyl; phenyl substituted by 1, 2 or 3 amino; halogen (chlorine, bromine, fluorine or iodine, preferably chlorine, fluorine or bromine), hydroxyl, trifluoromethyl, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy groups; phenyl (C 1 -C 4) alkyl, wherein the phenyl moiety may be optionally substituted by 1-3 substituents as mentioned above in conjunction with phenyl and the alkyl moiety may be optionally substituted by 1-3 substituents as noted above in coherence with C 1 -C 2 alkyl; and heteroaryl or het eraralkyl, wherein the heteroatom or atoms in the aforementioned heterocyclic units are selected from 1-4 oxygen, nitrogen or sulfur atoms, and the alkyl unit connected to said er oar alkyl unit contains from 1 to 6 carbon atoms, or to is optionally substituted to form a fused carboxycyclic, heterocyclic or heteroaromatic ring, optionally substituted by one or two of the above substituents; (f) groups of formulas 74-79 of the formula sheet, wherein X is O, S or 35 UB, wherein R is C 1 -C 6 alkyl; C 1 -C 20 substituted by 1-3 hydroxy, amino, C 1 -C 20 alkylamino, di (C 1 -C 20) alkylamino, C 1 -C 20 alkoxy, carboxy, halo or sulfo groups; C 1 -C 8 cycloalkyl; C 1 -C 8 cycloalkyl (C 1 -C 1) alkyl optionally V-28 -Sr substituted by 1-3 substituents as mentioned above in connection with C 1 -C 12 alkyl; phenyl; phenyl substituted by 1-3 substituents independently selected from amino, halogen, hydroxy, trifluoromethyl, C 1 -C 2 alkyl, C 1 -C 1 alkoxy, C 1 -C 1 alkylamino, cu (C 1 -C 3) alkylamjno, carboxy and sulfo; phenyl (C 1 -C 4) alkyl, wherein the phenyl moiety may be optionally substituted by 1-3 substituents as mentioned above in conjunction with phenyl and the alkyl moiety may be optionally substituted with 1-3 substituents as mentioned above in conjunction with phenyl with C 1 -C 4 alkyl; and heteroaryl and the er alkyl, wherein the heteroatoam or atoms are selected from 1-4, S or N atoms 10 and the heteroar alkyl-linked alkyl moiety contains 1-6 carbon atoms, containing heteroaryl and heteroaralkyl groups optionally substituted in the heterocyclic ring by 1-3 substituents independently selected from hydroxy, amino, halogen, trifluoromethyl, C 1 -C 6 alkyl, C 1 -C 1 alkoxy, C 1 -C 1 alkylamino, diiC 1 -C ^ ) alkylamino, carboxy and sulfo and in the alkyl unit 15 by 1-3 substituents selected from hydroxy, amino, C 1 -C 1 alkylamino, di- (C 1 -C 1) alkylamino, C 1 -C 1 alkoxy, carboxy, halogen and sulfo; which heteroaromatic group on a carbon atom is optionally substituted by a substituent selected from C 1 -C 12 alkyl; C 1 -C 1 alkyl substituted by, preferably 1, 3, ydroxy, amino, C 1 -C 1 alkylamino, di 1 -C 1 alkyl) amino, C 1 -C 20 alkoxy, sulfo, carboxy or halogen (chlorine , bromine, fluorine or iodine, preferably chlorine, fluorine or bromine); C 1 -C 8 cycloalkyl; C 1 -C 2 alkoxy; C 1 -C 2 alkylthio; amino; C 1 -C 2 alkylamino; di- (C 1 -C 1 alkyl) amino; halogen (chlorine, bromine, fluorine or iodine, preferably chlorine, fluorine or bromine); C 1 -C 2 alkanoyl amino; C 1 -C 2 alkanoyloxy; carboxy 25 0 l * ....

-S-OC 2 -C 1 alkyl; hydroxy; amidino; guanidmo; phenyl; phenyl substituted by 1, 2 or 3 amino, halogen (chlorine, bromine, fluorine, or iodine; preferably chlorine, fluorine or bromine), hydroxy, trifluoromethyl, C 1 -C 6 alkyl or C 1 -C 12 alkyloxy groups; phenyl (C 1 -C 6) alkyl, in which the phenyl moiety may be optionally substituted by 1-3 substituents as mentioned above in conjunction with phenyl and the alkyl moiety may be optionally substituted by 1-3 substituents as mentioned above in conjunction with phenyl -C 1-4 alkyl; and heteroaryl or heteroaralkyl, wherein the heteroatom or atoms in said heterocyclic units are selected from 1-4 oxygen, nitrogen or sulfur atoms and the alkyl unit attached to said heteroaralkyl unit contains 1-6 carbon atoms; and (g) groups of formulas 80-85 of the formula sheet, wherein RC 1 -C 1 alkyl, C 1 -C 1 alkyl substituted by 1-3 hydroxy, amino, C 1 -C 1 alkylamino, --- --- 1 C 1 -C 1-6 di (C 1 -C 6) alkylarmino, C 1 -C 6 alkoxy, carboxy, halogen, or sulfo groups; C 1 -C 8 cycloalkyl; C 1 -C 8 cyeloalkyl (C 1-8 C 1 -alkyl optionally substituted by 1-3 substituents mentioned as courts in conjunction with C 1 -C 4 -alkyl; phenyl; phenyl substituted by 1-3 substituents independently selected from: amino, halogen, hydroxy, trifluoromethyl, C 1 -6 C 1 -alkyl, C 1 -C 1 -alkoxy, C 1 -C 5 alkylamino, di (C 1 -C 2) alkylamino, carboxy and sulfo; phenyl (C 1 -C 1) alkyl in which the phenyl moiety may be optionally substituted by 1-3 substituents as mentioned above in connection with phenyl, and the alkyl moiety may optionally be substituted with 1-3 substituents as mentioned above in connection with C 1 -C 6 alkyl, and heteroaryl and heteroaralkyl, wherein the heteroatoam or atoms are selected from 1-U 0, S or Il atoms and the one with heteroaralk yl linked alkyl moiety contains 1-6 carbon atoms, which heteroaryl and heteroaralkyl groups in the heterocyclic ring moiety are optionally substituted by 1-3 substituents independently selected from hydroxy, amino, halogen, trifluoromethyl, C 1 -C 6 alkyl, C ^ -C ^ alkoxy, C ^ -C ^ alkylamino, difC ^ -C ^) alkylamino, carboxy and sulfo and in the alkyl unit by 1-3 substituents selected from hydroxy, amino, C ^ -C ^ alkylamino, di (C 1-4) C 1 -alkylamino, C 1 -C 2 alkoxy, carboxy, halogen and sulfo. The R and R groups can also be taken together and form a condensed hetero-cylic or heteroaromatic ring.

In the preferred embodiment described above, the preferred compounds are those wherein A is - (0Ho) - with n 1 or 2, preferably where A is -CHg- and wherein (a) R 1 and R 0 taken together represent HOCH 2 3 S 1 25 or (b) R is hydrogen and R is hydrogen, CH 2 CH 2 -, - f, or CH.CH -.

proposes.

-Λ -30- 8 1

Particular preference is given to compounds in which R is hydrogen and R OH

CH ^ CH, in particular, compounds with the absolute configuration is 5R, 6s, 8r.

A particularly preferred embodiment of the present invention. thing includes compounds of formula 1 wherein the group of formula

6 T

le 52 represents a group of formula 57 of the formula sheet, wherein R, R and R 4 are independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, carboxyl and carbamoyl and R 5 has the aforementioned meanings, and preferably is C 1 -C 8 alkyl, most preferably -CH 2.

In the preferred embodiment described above, the preferred compounds are those wherein A is - (CH 2) - with n 1 or 2, and most preferably those wherein A is -CH 2 - and wherein (a) R and R taken together HOCH, βί "3 Q 1 15 represent whether (b) R hydrogen and R hydrogen,

CH

^ CH3 OH OH

/ CH "yc ~" CH 3 CH-.

• propose ch3 · ce3.

.8 .1

Especially preferred are the compounds wherein R is hydrogen and R

OH

J

CH3CH, especially compounds with the absolute configuration is 5R, 6S, 8R.

Another preferred embodiment includes compounds of formula 1 wherein the group of formula 52 (a) represents a group of formula 86 of the formula sheet, wherein R 1, g C 1 -C 2 alkyl, preferably methyl, and R 1 is hydrogen or C 2 - C1-alkyl represents -25; (b) a group of formula 87 of the formula sheet, wherein R 1, C 1 -C 12 alkyl,

. ·. ..... H

5 * -31-y & 7 "is preferably methyl, and B and R are hydrogen or C 1 -C 2 alkyl; (c) a group of formula 88 of the formula sheet wherein B 1 -C 1 -C 2 alkyl, preferably is methyl, and R 1 -C 1 -C 6 alkyl or phenyl C 1 -C 1 -alkyl; (d) is a group of formula 89 of the formula sheet, wherein R 1 -C 2> 6 I * + 5 alkyl, preferably methyl and RC is -C, alkyl, preferably methyl,

* ^ C

(e) a group of formula 90 of the formula sheet, wherein R is C 1 -C 6 alkyl, preferably methyl and R G 1 -C 1 alkyl, preferably methyl; or (f) a group of formula 91 of the formula sheet, wherein R 1, C 1 -C 12 alkyl, preferably methyl.

In the above-described embodiment, the preferred compounds are those wherein A-1C 1) is -, with n 1 or 2, preferably where A is -CHg and wherein 1 (8) a and R 8 taken together are 2 • 8 1 15 suggest whether (b) R is hydrogen and R is hydrogen, CH ^ CH, ^ -,

CH-. CH3 OE OH

/ o represents CH 2 CH-CH 3 CH 3.

g

Especially preferred are the compounds wherein R is hydrogen and r "*

20 OH

CH ^ CH- is, in particular, compounds with the absolute configuration 5R, 6S, 8R.

A particularly preferred embodiment of the present invention includes compounds of formula I wherein a group of formula 52 represents a group of formulas 92-105 [(a) - (n)] of the formula sheet,

In the above-described embodiment, the preferred compounds are those wherein A is - (CH 2) -, with n 1 or 2, preferably where A (CH 2) - is 2 ^ 8 2 and wherein (a) R and R taken together - 32-

V

τ HOCH.

C = s' -3 o 1 represent whether (b) R is hydrogen and R is hydrogen,

CH3 CH3 OH <pH

Xcs-. , ^ C-. oi <= 3 ° * · · cs3 ch3.

Particular preference is given to compounds in which R ° is hydrogen and E1

OH

In particular, compounds with the absolute configuration are 5R, 6s, 8R.

Specific compounds of the present inventions are those 2 »of formula 106 of the formula sheet, wherein R is hydrogen, an anionic charge or a conventional easily removable carboxy 1 protecting 2 group, provided that when R is hydrogen or a protecting group, there is a counterion is also present and in which the group of formula 10 is a group of formulas 107-122 '[- (a) - (p)] of the formula sheet, wherein the HNMRtD ^ O) spectrum shows characteristic peaks at δ : 1.23 (3H, d, J = 6.4 Hz), 3.12 (22, q, J = 1.4, 8.9 Hz), 3T39 (1H, q, J = 2.7, 6 .0 Hz), 4.07-4.68 (10H, m), 8.19 (1H, s); (q.) a group of formula 123 of the formula sheet, in which the KNMR (DgO) spectrum shows characteristic peaks at δ: 1.23 (3H, d, J = 6 * 4 Hz), 3.15 (2H, q, J = 3.7, 9.0 Hz), 3.37 (1H, q, J = 2.6, 6.0 Hz), 3.95-4.65 (10H, m), 8.62 (1H, s); 20 groups according to formula 12 ^ -128 of the formula sheet [(r) - (v)].

A particularly preferred embodiment of the present invention includes compounds of formula 1 wherein the group of formula 52 represents a group of formula 129 of the formula sheet.

'H V ** * -33-

In the above described embodiment. the preferred compounds are those wherein A is - (CH0) - with η 1 or 2, most preferably wherein A .2 * 1 8 -CHg- xs and wherein (A) R and R together represent HOCS-,> 8 1 5 , or (b) H is hydrogen and R represents hydrogen, CH ^ CH ^ -, “Sh- p / '/ ° *' ° £ β3®- · CH ^ ..

8

Especially preferred are the compounds wherein R is hydrogen and E1

10 OH

CH ^ CH-, in particular, compounds with the absolute configuration are 5H, 6S, SR.

The carbapenem derivatives of the general formula 1 are prepared from 1 8

starting materials of formula 3 of the formula sheet, wherein R, R

15. .2 ...

15 and R have the aforementioned meanings and wherein R represents a conventional easily removable carboxyl-protecting group. Compounds of formula III are described, for example, in European patent application 38 869 (compound £) and in European patent application 5 917, and can be prepared according to the general methods described therein.

The process for preparing compounds of formula 1 from starting materials of formula 3 can be summarized by the reaction scheme A of the formula sheet.

A variation on the method depicted above is indicated in reaction scheme B of the formula sheet.

In the above process, the starting material 3 is dissolved in an inert organic solvent, such as methylene chloride, acetonitrile or dimethylformamide, with an approximately equimolar amount of a compound R 1 -L. such as p-toluenesulfonic acid anhydride, p-nitrobenzeensulfonzuuranhydride, "" "- -3V- \ ·" £ 2, k, 6-triisopropylbenzeensulfonzuuranhydride, methanesulfonic anhydride, trifluormethaansulf onzuuranhydride, diphenyl chlorophosphate-toluenesulfonyl chloride, p-bromobenzenesulfonyl chloride, and the like are reacted, in which L the corresponding cleavable group is, such as toluene sulfonylozy, 5 p-nitrobenzenesulfonyloxy, diphenoxyphosphinyloxy, and other cleavable groups applied by conventional procedures and known in the art The reaction to place the cleavable group in the 2-position of intermediate III is conveniently performed in the presence of a base such as diisopropylethylamine, triethylamine, U-dimethylamino-pyridine and the like at a temperature of about -20 to + 40 ° C, preferably at about 0 ° C. intermediate can also be halogen, in which case such a group is applied by h reacting intermediate 3 with a halogenating agent such as 0 ^ 01 ^, 0 ^ Bt ^ 9 (00) oxalyl chloride and the like in a solvent such as CH 2 Cl 2, CH 2 CN, THF or the like, in the presence of a base, such as diisopropylethylamine, trimethylamine, k-dimethylamino-pyridine and the like. Intermediate U can be isolated if desired, but is generally used in the next step without isolation or purification.

Intermediate product is then converted to intermediate product 2 by a conventional shift reaction. Thus, intermediate U can be reacted with about an equimolar amount of a heteroaralkylmer captane reactant of the formula 130 of the formula sheet wherein A represents a C 1 -C 8 straight or branched alkylene group and the group of formula 11 "is a mono-, di- or polycyclic aromatic heterocyclic group containing a quaternizable nitrogen in the ring * which ring is attached to A via a ring carbon atom, in an inert organic solvent such as dioxane, dimethylformamide, dimethyl sulfoxide or acetonitrile and in the presence of a base, such as diisopropylethylamine, triethylamine, sodium bicarbonate, potassium carbonate or U-dimethylaminopyridine. The temperature for the shift is not critical, but an advantageous temperature range is from about -U0 to 25 ° C. Preferably the reaction is carried out under cooling, for example at about 0 to -10 ° C,

The quateraseization of the ring nitrogen in the heteroaralkyl group of intermediate 2 is performed by reacting the intermediate 2 in an inert organic solvent with at least an equivalent (up to about a molar excess of 50%) of an alkylating agent with the -35- ... V -r> formula R5 - X * where Έ? has the aforementioned meanings and X is a conventional cleavable group, such as halogen (chlorine, bromine or iodine) (preferably 5 iodine), or a sulfonate ester unit, such as a mesylate, tosylate or tri-flaat. Examples of suitable non-critical reactive organic solvents are chloroform, methylene chloride, tetrahydrofuran, dioxane, acetone, dimethyl sulfoxide and dimethyl formamide. The temperature of the alkylation reaction is not critical, and temperatures in the range of about 0 ° to 0 ° C are preferred. Preferably, the reaction step is performed at room temperature.

The intermediate 1 'has an associated counterion X' (for example from the alkylating agent used) which can be replaced in this step or a later step, ie after the deblocking step, by conventional procedures 15 by another counterion, for example a counterion which is more is pharmaceutically acceptable. Strange choice, the counterion can be removed during the release stage.

The deblocking step to remove the carboxyl-protecting group 2, of the intermediate 1 ', is carried out by customary procedures such as solvolysis, chemical reduction or hydrogenation. When a protecting group such as p-nitrobenzyl, benzyl, benzhydryl, or p-naphbyl-methyl is used that can be removed by catalytic hydrogenation, the intermediate 1T in a suitable solvent such as dioxane-water-ethanol, tetrahydrofuran aqueous dipotassium hydrogen phosphate isopropanol 25 and the like under a hydrogen pressure 1-1 atmosphere in the presence of a hydrogenation catalyst, such as palladium on carbon, palladium hydroxide, platinum oxide and the like are treated at a temperature of 0-50 ° C for about 0.2 ^ + - ¾ hours. When R is a group, such as 0-nitrobenzyl, photolysis can also be used for deblocking. Protective groups such as 2,2,2-trichloroethyl can be removed by mild zinc reduction. The allyl protecting group can be removed with a catalyst comprising a mixture of a palladium compound and triphenylphosphine in an aprotic solvent, such as tetrahydrofuran, diethyl ether or ethylene chloride. Similarly, other conventional carboxyl-35 protecting groups can be removed by methods known in the art lü -r «(T_ 5. ƒ _ · -Φ *. Finally, as mentioned above, compounds of formu 2 '-36-

V

T

V.

v 1, wherein R is a physiologically hydrolyzable ester such as acetoxy-methyl, phthalidyl, indanyl, pivaloyloxymethyl, methoxymethyl, etc. are administered directly to the host without deblocking as such esters are hydrolyzed in vivo under physiological conditions.

* Obviously, when the R **, R ^, R'5, or R ^ '' substituent or the heteroatomatic ring bonded to substituent A contains a functional group capable of interfering with the intended course of the reaction, a such group may be protected by a conventional blocking group then unblocked to form the desired functional group. Suitable blocking groups and procedures for entering and removing such groups are known to those skilled in the art,

In a variant of the method described above, the carboxyl protecting group of intermediate 2 can be removed before the quaternization reaction step 15. Thus, the carboxyl protecting group as described above is removed, whereby the corresponding free carboxylic acid is obtained and the free acid is then quaternized with alkylating agent R-X 'to form the desired quaternized product of formula 1'. When the deprotected intermediate 2a is quaternized, the solvent may be water or a non-reactive organic solvent or a mixture thereof. Examples of suitable solvents include water, organic solvents, such as chloroform, methylene chloride, tetrahydrofuran, dioxane, acetone, dimethyl sulfoxide and dimethyl formamide, and water organic solvents or mixtures, such as water acetone or water dimethyl formamide. The temperature for quaertizing intermediate 2a is not critical and temperatures in the range of from about 0 ° C to about room temperature can be used.

The reaction is most advantageously carried out at about 0 ° C.

When the deprotected intermediate 2a is obtained as a carboxylate salt, it is desirable to add a strong acid such as toluene sulfonic acid to form the free carboxylic acid before quaternization. It has been found that this considerably facilitates the preferential quaternization of the ring nitrogen atom.

The variant procedure described above is particularly suitable when the carboxyl protecting group can be more easily removed from the non-quaternized intermediate 2 than from the quaternized intermediate 1 '. In the preparation of the product of formula 131 of the -37 formula sheet from the intermediate of formula 132 of the formula sheet, removal of the allyl protecting group prior to quatemization leads to significantly improved yields of the desired end product.

Although the above-described process is suitable for preparing the compounds of the present invention, Pierre Dexfcraze * has found a new process which can be used to prepare compounds of the formula I. This alternative method, described in a U.S. patent application of the same date, is illustrated below and in the examples.

According to the alternative method of preparing compounds of formula 1, an intermediate of formula k of the formula sheet wherein R, E ° and H 7 have the aforementioned meanings, E is a conventional easily removable carboxyl protecting group and L is a conventional cleavable group, such as toluenesulfonyloxy, p-nitrobenzenesulfonyloxy, diphenoxyphosphinyloxy or halogen, is reacted with a thiol compound of formula 7 of the formula sheet, wherein A and the group of formula 52 have the aforementioned meanings and X® has a counter ion in an inert solvent and in the presence of a base to form a carbapenem product of the formula 1 'of the formula sheet, wherein R, R, E, A, E, is the group of formula 52, and the aforementioned 2 have meanings and, if desired, the carboxyl-protecting group E is removed, the corresponding deblocked compound of formula 1 or a pharmaceutically acceptable salt there of is obtained.

The alternative process in which the intermediate of formula k 25 is used is as previously mentioned, for example, described in European patent applications 38 869 and 5k 917 j and can be prepared according to the general methods described therein. L represents a conventional cleavable group (defined as "X" in European patent application 38869) such as chlorine, bromine, iodine, benzenesulfonyloxy, p-toluenesulfonyloxy, p-30 nitrobenzenesulfonyloxy, methanesulfonyloxy, trifluoromethanesulfonyloxy, diphenyloxyphosphine ethoxy) fo finyloxy. The preferred cleavable group is diphenoxyphosphinyloxy.

Intermediate and of formula k are generally formed in situ by an intermediate of formula 3, wherein E, E, E 7 and E have the aforementioned meanings, with a suitable acylating agent E 1 -L in response. The preferred intermediate, wherein L diphenoxyphosphinyloxy is, can be prepared by the keto ester 3 in an inert organic solvent, such as methylene chloride, acetonitrile, or dimethylformamide, at a temperature of about -20 to + 1t. -0 ° C, "preferably about 0 ° C, to react with an approximately equimolar amount of diphenylchlorophosphoric acid in the presence of a base such as diisopropylethylamine, triethylamine, U-dimethylm-aminopyridine and the like. The intermediate U can be isolated if desired, but is suitable as a starting material for the alternative process without isolation or purification.

The carbapenem intermediate k is reacted with a quateraic aminethiol compound of formula 7S wherein the group of formula 27 has the pre-10 meanings and X® is a counterion.

The reaction is carried out in an inert solvent such as acetonitrile, acetonitrile-dimethylformamide, tetrahydrofuran, tetrahydrofuran-HgO, acetonitrile-HgO or acetone in the presence of base. The base type is not critical. Suitable bases include sodium hydroxide, isopropylethylamine, 1,8-diazabicyclo [5, 3.0] undecene-7-ene, 1,5-diazabicyclo [li, 3.0] non-5-ene and tri ( C 1 -C 4) alkylamine, such as triethylamine, tributylamine or tripropylamine. The reaction of intermediate and thiol J can be carried out over a wide temperature range, for example -15 ° C to room temperature, but is preferably carried out at a temperature in the range of about -15 to + 15 ° C, in especially around 0 ° C.

The carbapenem product formed by reaction of the quateraic amine-thiol 7 with intermediate U, has a related counterion [for example (CgHj-OjgPOg®, Cl® or the anion linked to the quateraary thiol] which is at this stage by conventional procedures can be replaced by another counterion, for example, a type that is more pharmaceutically acceptable, its choice may be to remove the counterion during the subsequent deblocking step If the quaternized carbamebem compound and the counterion form an insoluble product, the product as the is formed, crystallized, and collected by filtration in a pure state.

After the formation of the desired carbapenem product, the carboxyl-2 '.

protecting group E of compound 1 'may be optionally removed by conventional procedures such as solvolysis, chemical reduction or hydrogenation. When a protecting group such as p-nitrobenzyl, benzyl, benzhydryl or 2-naffcylmethyl is used that can be removed by catalytic hydrogenation, the intermediate 11 can be in a suitable solvent, such as dioxane-water-ethanol, tetrahydrofuran diethyl ether buffer, * '* - · "r - J' \ 4 -39- h.

τ tetrahydrofuran-water-dipotassium hydrogen phosphate-isopropanol and the like under a hydrogen pressure of 1-atmosphere in the presence of a hydrogenation catalyst such as palladium on carbon, palladium hydroxide, platinum oxide and the like at a temperature of 0-50 ° C for 0 , 2i ~ l + hours are treated * 2 '5 άεη. When R is a group such as 0-nitrobenzyl, ti photolysis by deblocking can also be used. Protective groups, such as 2,2,2-trichloroethyl, can be removed by mild zinc reduction.

The ailyl protecting group can be removed using a catalyst comprising a mixture of a palladium compound and tritylphosphine 10 in a suitable aprotic solvent of tetrahydrofuran, methylene chloride or diethyl ether. Similarly, other conventional carboxyl protecting groups can be removed by methods known to those skilled in the art. Finally, as noted above, compounds of formula 11, wherein R is a physiologically hydrolyzable ester, such as acetoxymethylphthalidyl, indanyl, pivaloyloxymethyl, methoxymethyl, etc., can still be administered to the host without deblocking, as indicated. such esters are hydrolyzed in vivo under physiological conditions.

The thiol intermediates of formula 7 can be prepared, for example, from the corresponding thiol acetate compound of formula 133 of the formula sheet wherein A has the aforementioned meanings and the group of formula 11 M represents a mono-, bi- or polycyclic aromatic heterocyclic group which contains a quaternisible nitrogen atom in the ring, which ring is attached to A via a ring carbon atom. The thiol acetate compound is quaternized by reacting it in an inert organic solvent such as diethyl ether, dichloromethane, methylene chloride, dioxane, benzene, xylene, toluene or mixtures thereof with a suitable alkylating agent of the formula: R5-Xt 30 wherein R has the aforementioned meanings and X 'is a conventional cleavable group, such as halogen (chlorine, bromine or iodine preferably iodine), or a sulfonate ester unit, such as mesylate, tosylate, triflate. The temperature for the alkylation reaction is not critical, and temperatures in the range of about 0 ° C to 0 ° C are preferred.

For the reaction with the carbapenem intermediate h, the quatern ff * ~ -

VI

ionized thi olate et al compound subjected to acid or basic hydrolysis to form the quaternary thiol intermediate 7. This hydrolysis is preferably carried out immediately before coupling with i, in order to minimize decomposition of the relatively unstable quaternary thiol 7.

By proper selection of the solvents, the reaction of intermediates 3 to final 1 can be carried out without isolation of the various intermediates, i.e. in a "one-kettle" process. An example of such a method is illustrated in Example XXII below.

As is the case with other β-lactam antibiotics, compounds of the general formula 1 can be converted into pharmaceutically acceptable salts by known procedures which are practically equivalent to the non-salts for the purposes of the present invention. Thus, for example, a compound of formula 1, wherein R is an anionic charge, may be dissolved in a suitable inert solvent and then an equivalent of a pharmaceutically acceptable acid added. The desired acid addition salt can be recovered by known procedures, for example precipitation, from solvent, freeze-drying, etc. When other basic or acidic functional groups are present in the compound of formula 1, pharmaceutically acceptable basic addition salts and acidic addition salts are prepared by known methods.

It is clear that some products of the formula I can be formed as optical isomers and as epimeric mixtures thereof. The present invention is intended to encompass all such optical isomers and epimeric mixtures. For example, when the 6-substituent is hydroxyethyl, such a substituent may be in the R or S configuration and the resulting isomers as well as the epimeric mixtures thereof are within the scope of the present invention.

A compound of formula 1 wherein R is hydrogen or an anionic charge or its pharmaceutically acceptable salt can also be converted to the corresponding compound 2 by conventional procedures. .

wherein R is a physiologically hydrolyzable ester group or a compound 2 ...

according to formula 1, wherein R is a conventional carboxyl protecting group. . . 2, the corresponding compound can be converted, wherein R is hydrogen, an anionic charge or a physiologically hydrolyzable ester group, or a pharmaceutically acceptable salt thereof.

* · ’“ *** ”v 2 i é -4i-

The new carbapenem derivatives of the general formula 1, wherein R is hydrogen, an anionic charge or a physiologically hydrolyzable carboxyl protecting group or the pharmaceutically acceptable salts thereof, are potent antibiotics active against various gram-5 positive and gram- negative bacteria and which can be used, for example, as an animal feed supplement to promote growth, as food preservatives, as bactericides for industrial applications, for example in water-based dyes and in wastewater from paper mills to inhibit the growth of harmful bacteria and 10 as infectious agents to destroy or inhibit the growth of harmful bacteria or medical and dental equipment. However, they are particularly suitable for treating infectious diseases in humans and animals caused by gram positive or gram negative bacteria.

The pharmaceutically active compounds of this invention can be used individually or formulated as pharmaceutical compositions which contain, in addition to the active carbapenem component, a pharmaceutically acceptable carrier or diluent. The compounds can be administered in various ways; the main ones are: oral, topical or parenteral (for example intravenous or intramus-20 injections). The pharmaceutical preparations can be in solid form such as capsules, tablets, powders etc. or in liquid form such as solutions, suspensions or emulsions. Injection formulations, the preferred route of administration, may be administered in unit dosage form in ampoules or in multidose containers and may contain constituents or suspending agents, stabilizers and dispersants. The compositions may be ready for use or in the form of a powder which is prepared at the time of administration with a suitable carrier such as sterile water.

The dose to be administered depends to a great extent on the specific compound used, the specific composition, the route of administration and the type and condition of the host and the particular site and organism being treated. The choice of the specific preferred dose and route of administration is thus left to the discretion of the therapist. In general, however, the compounds can be administered parenterally or orally to warm-blooded animals in an amount of about 5-200 mg / kg / day. Administration is generally in divided doses, eg 3-4 times a day.

4 λ -U2-

Illustrating the potent antibacterial activity of the broad-spectrum carbapenem compounds of the present invention, both in vitro and in vivo, and the low toxicity of the compounds according to biological data hereinafter with respect to the present preferred carbapenem compounds of the present invention .

»In Vitro activity

Samples of the carbapenem compounds prepared in Examples 1-2 were found to show the following minimum inhibitory concentration (MRC) in mcg / ml after being dissolved in water and diluted with nutrient solution versus the indicated microorganisms, as determined by incubation at 3T ° C overnight by tube dilution. N-formimidoylthienamycin is included as a comparative compound in the following tables.

_ ______ - --------------- - · «? * v. · *.

- ^ 3-

In vitro

Antibacterial activity of carbapenem derivatives of Example 1 * r - mc (mcgr / ml) "Organism. Meuve compound N ~ Fo ^ iTii.iaidoy 1 th.ienajnyci.Ile S. pneumoniae A-9 5 85 0.25". 004 S. pyogenes A-9604 0.06 0.001 S. aureus A-9537 0.13 0.004 5 aureus t 50% serum A-9537 0.03 0.016 S. aureus r (? Ea-res.) A-9606 0 .06 0.008 5. aureus (Meth-res.) A15097 4 0.5 "S. faecalis A20S88 0 * 5 0j5 2. coli" (10-4 oil;) Ai5US tl, OS "0.015 2 - coli (ΙΟ- 3) A15113 - 0.03 2 «coli CIO" 2) "AIS119 - 0.06 2.- coli CIO" 4) A20341-1 0.03 0.03 2. coli (ΙΟ'3) A2Q341-1 - Q > 03 2. coli CIO "2) A20341-1 - Qfl3

V

λ —J + i | -

In vitro antibacterial activity of ranbapenem derivatives according to example I - continued - 4> * MRO (meq / ml)

Organism (Mi, ewe compound N- FoJiaimi doy 1 thlenaitryciae K. pneumoniae A-9SS4 0.25 0.13

pneumoniae A2Q4S8 0.25 0.0'S

P> mirahilis A-9900 0.13S 0.0S

g. vulgaris A21559 0.13-0.03? ► morganii A15153 0.13 0.13! ?. re-ttcreri A22424 0.25 0.25 j

S. marcescens A20Q19 Ό, 13 · 0.03 I

Cloacae A-95S9 0.13 0.06 5. Cloacae A-965S 0.13 0.06 P. aeruginosa A-9843A 4. aaraginosa A21213 1 0.25 5. influenzae A-9833 16 1 $ 3- influenzae A20178 32 22 g «influenza A21518 IS» 32 3 «influenza A21522 8 32 3. fraqilis A22862 .03 0.016 3« fraqills A22053-0; 03 0.06 3, fracrilis A22696 0.25 0.13 3, fracrilis A22863 0.03 ^.> ** ·

In vitro antibacterial activity of carbapenem derivatives according to example II-k5-4 i.

r MRC. (mcq / ml)

Organism Ifletcwe compound N-FoEiaimidoyl t hianaroycirsg S. pneurooniae A-9585 0.001 0.002 S. pyocrenes A-9604 0.001 0.002 S. aureus A-9537 0.004 0.004 5 aureus A-9537 0.016 0.016 + 50% serum S. aureus A-9606 0.008 0.008 (Pen-res.} 'S. aureus A 15097 8 4 (Metii.-res.) • S. faecalls A 20688 0.25 0.5. S. coli A 15119 0.016 0.016 2. coll A 20341- 1 0.016 0.03 K. pneumoniae Α9664 0.06 0.06 pneum. Pneumoniae A2Q468 0.13 0.13 at. Atirafcills Λ9900 0.03 0.06 Ρ. Vulcaris Α21559 0.016 0.03?. Morcanii Α15153 0/06 0.13 ret-tgeri A22424 0.13 0.13 S. marcesceas A2Q019 0.03 0.03 5. cloacae A9659 0.13 0.06 S. cloacae A9656 0.25 0.06 P. aerucinosa A9843A 8 1 p aeruginosa A21213 2 0.25 -H6- y

In vivo activity

The in vivo therapeutic efficacy of the compound of Example I and H-formimidoyIthienamycin after intramuscular administration to mice experimentally infected with different organisms is shown in the following table. The PD ^ q (dose in mg / kg required to give a protection of up to 50% of the infected mice) is as stated:

Protective effect in intramuscular treatment of infected mice PDjq / 'treatment (mg / kg)

Contamination Compound N-Foraimidoyl (number of

Organism) Image I "thienamycire _ P. mirabilis A-9900 3.6 X 106 3.3 '3 * / 15 * P. aeruginosa A-9843ay 5.5 X 10 ^ 0.3 0.5 * P. aeruginosa A-20481 5.4 X 10 ^ 0.63 0.4 * P. aeruginosa A-20599 1.4 X 108 0.7 0.18 * S. aureus A-9606 β, β X IQ8 0.09 0, 07 * S. faecalis A-20688 2.3 X IQ8 3.3 2.8 * 2. coli A-15119 6.2 X 106 0.6 2.5 * K. pneumoniae A-9964 5.1 X 108 2 , 5 2.2 * 3E Historical data

Treatment schedule: With the exception of E. coli A 15119 and K. pneumonia A 99èb, mice were treated intramuscularly 0 and 2 hours after infection. For E. coli and K. pneumoniae, the treatment regimen was 1 and 3.5 hours after infection.

5 mice per dose were used for each experiment.

ί -UT-

Toxicity

The toxicity of the compound of Example I was determined after intracranial administration to mice and is indicated in the following table.

5 Toxicity after intracranile administration to mice

Highest dose (mg / kg) * LD „without clinical signs

Compound (mg / kg) of toxicity 10 Compound of Example 1 1¼ 5 H-formimidoyl-thienamycin 32 5 ^ average of 25 / mice / compound 15 Blood levels in mice after intramuscular administration

The table below lists the blood levels and half-life of the compound of Example I after intramuscular administration of 20 mg / kg. mice.

20 Connection 10 20 30 k5 60 “t1 / 2 s AüC

. (min) (^ ug / h / ml)

Compound minutes after administration of Example 1U 10.8 6.8 2.6 0.8 0.6 10 6.3 25 N-formimido-yl-thienamycin 12.6 9.9 7.3 2.6 0, 7 0.3 9 6

The compounds were solubilized in 0.1 M phosphate buffer pH 7.

The values were obtained from a single run; h mice used per compound.

Ht1 / 2 refers to half-life in minutes AÜC refers to the area under the curve.

-1 + 8-

V

Amount of compound recovered in urine

The table below shows the amount of the compound of Example 1 recovered in urine after intramuscular administration (20 mg / kg) to mice.

5 Amount of compound recovered in the urine

Intramuscular administration of 20 mg / kg to mice_

Percentage of recovered dose 10 0-3 3-6 6-21 + o-2l +

Connection Hour after administration

Compound according to example I 26.1 0.5 0.1 26.7 +, 6.7 H- ormimi doyl-thienamycin 12.1 0.1 0.1 12.2 + 3.6

The compounds were solubilized in 0.1 M phosphate buffer pH J.

The values are from a single test, k mice per compound.

Further biological data ·

In vitro activity Samples of the carbapenem compounds as indicated below (identified by number example) after dissolving in water and diluting with nutrient broth were found to show the following minimum inhibitory concentrations (MRC) in mcg / ml versus the indicated microorganisms as determined by incubation at 37 ° C overnight via tube dilution.

Π-formimidoyl-thienamycin is included as a comparative compound in the following tables.

- ^ 9- f _MRC (/ Ug / ml) _______, _

Organism Ex III Ex IV Ex. IT-. _ ° ϧÏg— 5. oaeurreniae A-9585 0.002 0.002 0.004 0.004 0.004 0.002 Γ 22225225 A-9604 0.002 0.001 0.004 0.004 0.004 0.002 s. Saecalls A20638 OS 0.5 0.25 0.5 0.12 * s7 aurau * A-9537 0.01S 0.008- 0.004 0.03 0.008 0.004 A-9537 0.016 0.03 0.01 * 0.06 0.03 0.016 'L «giant A-9606 0.016 0.016 0.008 0.03 0.016 0.008 iPen-raa) L ·. A15097 4 4 8 4 2 (M «ch-r« s) _ ...

ï. call AIS 119 O.03 0.016 0.016 0.06 0.004 0.016

S. call A20341-1 O.016 0.016 0.016 0.06 0.004 ° * ÖJ

A-9664 0.06 0.03 0.03 0.13 0.016 0.06 X. CBeusaaiae 'A20468 0.06 0.03 0.06 0.25 0.016 0.13 £. cloacae A-9639 0.13 0.03 0.06 0.25 0.016. ^ ΓΞΞ A-9656 0.13 0.06 0.13 0.25 0.016 »·«?. alribllla A-9900 0.13 0.06 0.03 0.025 0.016 p. vulcaris A21559 0.016 0.016 0.016 0.06 0.008 0.03

7 aagcanii A15153 0.13 0.016 0.06 0.13 0.016 0.J

P. A22424 0.25 0.13 0.13 0.25 0.06 S ^ marcasceas A20019 0.016 0-03 0.06 0.13 0.008 p. aeraetnasa A-9843 * 2 2 4 8 ^.

?. aeruciaos * A21213 0.5 0.13 2 1 ° 25 g. influence A-9833 224> 32> 32 g. influenza »A21518 2 2 4> 32

Tiracilla A22862 0.25 0.06 0.03 0.03 0-016 0-06 ΖΈΞ1 A22696 0.5 0-5 0.25 0.25 0.25 0.13 '' IT-Formimidoylthienaraycine MRC (uc / al) _.

Orgtwfawft Ex. VIII Vb.IX Vb.X _ SL22S11- S. aaeuaoaiaa A-953S 0.002 0.001 0.001 0.002 0.002 S. svqcenes A-9604 0.002 0.001 0.001 0.002 0.002 S. faecalia A20638 0.5 0.13 0.25 0.5 0.25 S. aur-us A-9537 0.008 0.004 0.008 0.004 0.002 S. aareua A-9537 0.03 0.008 0.06 0.016 0.016 + 50% s «x« a ___ S. aaraua A-96Q6 0.03 O.QOa "0.008 0.016 0.00 (?« N-M5) S. aurcca A15097 * "* (Η · ώ-Γ83) _ 2. call AIS 113 0.016 0.008 0.016 0.016 0.016 2. call A20341-1 0.03 0.004 0.008 0.03 X. cneusiaaiae A-9664. 0.03 0.016 0-06 0-03 0.03 7 oneunaalae A20463 0.13 0.03 0.13 0.13 -13 7 cloacae ~~ A-96S9 0.13 0.03 0.13 0.06 0.13

2. cloacae A-9656 ° 06 3 * 03 ° '1 ** a * 0J

Γ ^ ΞΓΙΐ5 A-9900 3 · “° 'U °”; -: - r- 0.03 O.aoa o.ois 0.03 0.016 ^ rclcar ^ A2.559 ^ a.13 0.06 0.06 33δ 0.13 0.13 0.13 - rataceri A22424 - · «0> 36 Q, 06 0.a3 S. aarcsscens A20013 0.06 3-0-6 - -,, .32 0.5 1?. Aeryci .-. Esa A-9 843A - ..."., ΓΠΞΞ «« «« - «« · "! ^ -13 J · * 3 * ίΤ-Formimi doylthi enamy cine $ -50- c MRP (Hg / Wl) organism. Vb, XII Vb, XIII Vb'.XIV nx 0797 ·" S. sneus »niae A-9585 '3.002 0.0005 0.0005 0.002 S. ovoeanes A-9604 0.004 0.0005 0.0005 0.002

Si iaac13is A20639 0.5 0.13 0.13 0.25 .. S. aureus A-9537 0.003 0.003 0.003 0.002 S. aureus A-9537 0.01S 0.016 0.03 0.003 + 504 sarua - £ i A-9606 0.03 0.003 '0.016 0.003 (Pen, -ras) S. aureus A15097 ** --- (Has-breed) S. cali AIS 119 0.015 0.004 0.008 0.016 S. coli A20341-1 0.008 0.003 0.003 0.016 'X.' pneumoniae A-9664 0.03 '0.03 0.03 X. pneumoniae A20468 ° -13 0.03 0.06 S. cloacae A-96S9 0.06 0.06 0.03 0.06 Γ. cloaca1 A-9655 0.03 0.03 0.03 0.06?. mlraftills Λ-9,900 0.03 0.016 0.016 0.016?. vulgaris A21559 0.016 0.008 0.016 0.016 H. woraanii A15153 0.06 0.016 0.03 0.06?. raeegaJl A22424 0.13 0.25 0.06 0.13 5. aiarcescens A20013 0.03 Q.Q16 0.016 0.03?. aeruginosa A-9843A 1 $ 32 8 1 ii aaruginoaa A21213 2 2 0.5 0.13 IT-Formimdoylt hi enamycin MRC (ug / ai) 2ΞΒί5ΞΞ_ · Ib.XW Vb.XV'B "Vb" .XV''C "Ϊ717Γ fcawe? 1- a-9535 o-.eoos “o.0005- T77- -.

S. pyogenes A-9604 „000« „° 1Q0, -„, a.0005 0.001 0.0003 a an- S. Saecalrs A20633, ,, _ ° 00- o.i.3 0.5 S_. aureus A-9537 a a3. ..., ° 125 g1a3 0.004 0.016 a an.

S. aureus a-9537 "03. "... β · 00 'ΓΗΤ ^» "° · 01 <" · «« · «« * - »« 1 ... om 0.M <(Pan variety)

Si «^ aua λ1509 7 (Haeft-raa)

Xi £ 2ii A15119 a.004 0.008 0.06 0.008 eeli A20341-1 0.004 0.008 0.03. 0 016 X. SMUBWftiaa A-9664 Q.008 0.03 0.0S 0'03 X. pneumoniae A2Q463 0.008 0.016 0. "l3 0 06

Si cloacae A-9659 0.016 0.016 θ! Ϊ́3 0'l3 £ i cloacae a-9656 0.016 0.03 0.13 0 "l3 L · 99-9900 0.008 0.03 0.06 0'θ6

P ^ vulearis 1521559 0.008 0.003 0.06 O.'fllS

M._ aqgganii A15153 0.03 0.06 0.25 0. "l3 L2« 2SÉ A22424 0.03 0.13 0.25 θ! Ϊ́3 S. aareascans A20013 0.008 0.016 0.13 0 015 aeruginosa A-9843A 0.5 2 3 -05 P_, aeruginosa A21213 0.03 0.13 0.5 0> L3 H-Formimidoy-lthi enamycin -51- ί ϊ β. = 32? Ϊ »£, Ex.XVI Ex.XVII« MK 0797 S. nnaulBania »A-9S85 0.002 a.016 g.001 ii £ ïa.? An13. A-9604 0.002 o.016 0.001

S. faeealis A20688 1 1 Q_2S

S. «r« us A-9537 0.008 0.25 0.001 5. amrata A-9537 0.03 1 0.008 * 50% sansa 2i.iH £ 2S1 A-9808 0.015 0.5 0.002 agraua A15097 - (Ketft-ce1)

SiMU, A15119 0.015 0.6 0.008 S ^ eli A2Q341-1 0.016 0.S 0.008. X. Bneu.noni.aa A-9664 0.05 0.13 0.03

h. P «« m »WBiaa A20 46 8 0.0S 0.5 0.0S

. SS.5i2 £ «a A-9S59 0.05 2 0.05 Claacaa A-9555 0.06 2 0.06

Is. alrabiU ^ A-9900 0.06 0.13 o! oiS

^ 2 ± 25i A21559 0.03 0.13 0..008 ^ aog? AnU A15153 0.13 0.5 0.06?. A22424 0.25 2 0.06 S. aajgaacana A20013 0.06 0.13 a.01fi?. ΜΓ «ίΓ, ο» ί A-9843A 0.23> 63 0.5 li 25222 = 2221 A21213 0.13 15 0.13 * S-FoCTimidoyltiiieriamycin organism Ex.XVIII Ex.XIX Ex.XX »· .ΜΚ 0787 S. snaumoniae A-9535 1 0.002 0.06 0.001 S. avoaenaa A-9604 2 0.002 0.13 0.002 S. faeealis A20688 S3 0.5 16 0.25 S. auraus A-9537 32 0.004 0.5 0.002 5. aureus A-9537> 63 0.008 2 0.004 + 50% sera »S. aureua A- 9506> 125 0.016 '> 125 0.004 (P1a-r1s) S. aureus A15097 - - - (Hath-raai Z. cali A15119 IS 0.003 1 0.016 Z. tali A2Q341-1 IS 0.008' 2 0.016 X. aneumaniae A-9664 32 0.03 4 0.03 X. anaur.oniae A20 463 S3 0.06 4 0.06 Z. cloacae A-9659 S3 0.03 3 0.06 S. cloacae A-9656 125 0.03 16 0.06?. Airaailis A-9900 32 0.03 4 0.016?. Valcaris A21559 32 0.016 4 0.016 H. aorganii A15153 32 0.06 3 0.06?. Rattcari A22424 32 0.13 S 0.13 S. martsscans A20019 32 0.03 4 0.03?. Aerucinosa A-9843A 63 0.5 32 0.5?. Aerucincsa A212I3 53 0.06 16 0.13 11-Forniiaidoylth.i enamycin ΐ 5 -52-

In vivo activity

The in vivo therapeutic activity of some compounds of the present invention and N-formimidoylthienamycin (MK 0787) after intramuscular administration to mice experimentally infected with different organisms is indicated below. Also included is the PD ^ (dose in mg / kg) required to give infected mice up to 50% protection.

Protective effect in the intramuscular treatment of infected mice________ 'poso / treatment (mg / kg)

Ex. . Ex. Ex. Ex. Ex. yb. " Ex.

VI VIII IX-XII; XIV XV XV (Tl MC-0717.

. . a 21 0.39 0.07 '- - 0.07 S. auraus A9S0S o.iJi S. call AIS 119 - 0.36 1.2 *.

", pneumoniae A9664 - 1.8 1 * 8 -" 9. miraüilii A9900 - 1 · * 7,1 “Γ ae '» gl ^ la A9843A 0.4 0.19 0.13 1.3 0.4S 0.39 0.39 1 ^?. aeruginosa A24081 - 0.33 0.13

Ex. Ex. Ex.

. UI IV VTI_mx 0787 S. auraus A960S 0.07 0.1 0.2 0.07 Ê. call AIS 119 1 ° - ° 2 3 pneumoniae A9664 3 3 ^?. mirabilis A9900 3 4 2 · 4 9

?. aeruginosa A9843A 0.5 0.2 0.2 0.S

P. aeruginosa A24081 0.8 0.2 0.1 0.4

E.g. V_MX 0737 S. aureus 0.2 0.07 s. gr- 4 2 · 2 K. pneumoniae 0 2 · ί 31113 i. * 0.5

LA9843A

** "· - i -53- ί

Blood levels in mice after intramuscular administration

The table below lists blood levels and half-life of some compounds of the present invention after intramuscular administration of 20 mg / kg to mice.

5 C / 0 3ΞΕ.ΤΤΛ

max 1/2 AIC

VerbTwfKncr (min) (min) (/ug.h/ml) "Example I 1¾. 6.3 'Example II 13.9 9 5.3

Example III 11.5 10.9.9 Example IV 15.5 11 7.7

Example V - - -

Example VI 17.7 9 8.5

Example VII 19.2 11 11.8

Example VIII 18.8 11 10.5 15 Example IX 16.7 12 8.5

Example X 20.1 11 9.5

Example XI 1U, 9 11 7, ^

Example XIII 1, 8 11 6, U

Example XIV 15.8 13 7.6 Example XV "A" 16.7 12 9.5

Example 15 "B" 15.9 10 T9h

Example XV; "C" 15.1 10 7.3 MK 0787 1U, 6 10 6

Example XVII 11 8 3, ^ 25 Example XVIII 14.9 6 3.9

Example XIX 27 16.7 15.1

Example XX 28, U 1U 15.6

The compounds were solubilized in 0.1M phosphate buffer PI 7 values based on a single test, b mice per compound.

30 3eT ^ 2 Remove <3 to half-life in minutes ^ AUC refers to the area below the blood concentration / time graph.

The following examples illustrate the present invention without limiting it.

• Λ ^ Λ -5b-

V

i

Example I

Preparation of 1-methyl-U- [2-carboxy-6a- [1 (R) -hydroxyethyl] -7-oxo-1-azabicyclo [3.2.0] he-pt-2-en-3-thiomethyl] oyridinium hydroxide internal salt See formula 13¼ and reactions scheme C of the formula sheet.

5 A solution of 673 mg (1.86 mmol) p-nitrobenzyl 6a- [1- (R) -hydroxyethyl] -3,7-dioxo-1-azabicyclo [3,2,0] -hept-2- 1-2-carboxylate (1) in 10 ml of acetonitrile was cooled to -1 ° C under nitrogen atmosphere. After this, a solution of 2.5 mg (1.90 mmol) of diisopropylethylamine in 1 ml of acetonitrile was added, followed by dropwise addition of 510 mg of 10 (1.90 mmol) of diphenyl chlorophosphate in 1 ml of acetonitrile over a period of 2 minutes. The resulting solution was stirred at -10 ° C for 15 minutes, whereby p-nitrobenzyl-3- (diphenylphosphoryloxy) -6a- [1- (R) -hydroxyethyl] -7-oxo-1-azabicyclo [3.2 .0] -hept-2-en-2-carboxylate was obtained.

To this solution was added a solution of 2 ^ 5 mg (1.90 mmol) diisopropyl-15 ethylamine in 0.5 ml acetonitrile followed by a solution of 270 mg (2.16 mmol) ^ mercaptomethylpyridine in 0.5 ml acetonitrile. The reaction mixture was stirred at -10 ° C for 60 minutes and the white precipitate formed was collected by filtration and washed with 5 ml of ice cold acetonitrile to give 660 mg (76% yield) of compound 2 as white crystals, melting point 1 ^ 5 ° C.

NMR (DMSO-dS) δ: 1.20 (3H, d, J * 6.0 Hz), 3.2-3.4 (3H, m). 3.7-4.1 (2H, a), 4.23 (2H, s), 5.05 (LH, d, J = 4.0 Hz), 5.25: (1H, .d, J- 14.0 Hz), 5.48 (LH, d, J-14.0 Hz), 7.40 (2Ξ, d,: J * 5.5 Hz), 7.70 (2H, d, J * 8 .5 Hz), 8.23 (2H, d, J = 8.5 Hz) and 8.58 (2Ξ, d, J * 5.5 Hz).

IR (KBr) r max: 3 ^ 00, 1790, 1695 and 1600 cm -1.

Analysis calculated for C 14 H 14 O 2 S: C 58.01; H ^ 56; B 9.23 S 7.0¼

Found: C 57.7 ^ 5 H h, 56; Έ 9.58; S 7.21 To a solution of 660 mg (1.11 mmol) of intermediate 2 in 10 ml of acetone was added 5 ml of methyl iodide. The reaction solution was stirred at 75 ° C for 8 hours. The solvent was evaporated in vacuo to give a light yellow solid which was triturated with diethyl ether to form 779 mg (yield 90% of the title compound 3 as a white amorphous solid, mp 130 ° C (decomposition) ).

r * * "" * · '"-55- ï f 1.U (3H, d, J-β, Ο HZ), 3.2-3.4 (3H, m), 3.7-4.1 C2H, m), 4.25 (3H, s), 4.30 (2H, s), 5.25 (1a, d, J. 14.0 H2 ', 5.5s0 (1H, d, J «14 , o Hz), 7.70 (2H, d, J = 9.0 Hz), 8.10 (2H, d, J = 7.0 Hz), 8.25 (2H, d, J »9.0 Hz) and 8.90 (23, d, J * 7.0 Hz).

IE (KBr) V max: 3 ^ 00, 1770, 1690 and iSkO cm ”1.

Analysis calculated for C 14 Hg OGSI.HgO: C IA 39; H U, 22; Έ 6.82; S 5.20. Found: C IA, 66; , U, 01; N 6.8U; S 5.6¾ B. See reaction scheme D of the formula sheet.

To a solution of 779 mg (1.2 mmol) of compound 3, in tetrahydrofuran-water diethyl ether (80 ml-80 ml-100 ml), 1 ^ 0 mg (1.1 mmol) of potassium bicarbonate and 125 mg (0.7 mmol) dibasic potassium phosphate added.

Then, 700 mg of 10 # rs palladium on charcoal was added and the mixture was hydrogenated 2 at 2.8 kg / cm for 5 minutes on a Parr shaker. The mixture was then filtered and the catalyst washed with water (2 x 10 ml). The combined filtrate and washings were extracted with diethyl ether (A5 ml) and then lyophilized to yield a brown powder. This crude material was purified on a C.gBondapak reverse phase kolam (30 g) (Waters Associates), and eluted with water at a pressure of 0.56 kg / cm. Each fraction (20 ml) was examined by high pressure liquid chromatography and fractions with an ultraviolet absorption at "λ__" = 300 nm were collected and lyophilized,

ITlcLX

Yielding 135 mg (32 # fs yield) of the title compound h as a pale yellow solid.

NIS (D20) 6: 1.25 (3H, d, J * St0 Hz), 2.7-3.2 (2E, a), 3.40 (1Ξ, q, J = 9.0. And 2, 5 Hz), 3.9-4.2 (2H, m), 4.40 (3H, s), 4.72 (23, s), 8.10 (2H, d, J * €, 0 Hz) , 8.72 (2H, d, J * 0 · 0 Hz).

IX (NBr) yaax: 3400, 1755, 1640 and. 1590 ca ”1.

ÜV Xaax (H20): 295 na (ε = 7782), 258 na (ε = 6913).

4

V

-56-.

Example II

See formula 135 and reaction scheme E of the formula sheet.

(PUB = p-nitrobenzyl)

A suspension of 1.1 g (2.93 mmol) of diazo compound -1 was rinsed in 30 ml of dry benzene with nitrogen at room temperature for 5 minutes. This was treated with 25 mg of rhodium acetate dimer and the mixture heated to reflux for minutes. The warm solution was diluted with ethyl acetate (25ml), filtered to remove the catalyst and evaporated to dryness to give the title compound 2 as a white solid. This was dissolved in dry acetonitrile (20 ml) and cooled to -10 ° C. To this solution was added diisopropylethylamine (* H7mg, 3.2mmol) under nitrogen, followed by 810mg (3.0mmol) diphenylchlorophosphate and the reaction stirred at -10 ° C for 20 minutes. The reaction mixture was then treated with diisopropylethylamine (20mg, 3.2mmol) and 2- (U-pyridyl) ethanethiol (560mg, 03mmol) in 2ml acetonitrile [J. Org. Chem. 26: 82 (1961)

Ludwig Bauer and Libero A. Cardella Jr.]. The reaction mixture was stirred at -50 ° C to -10 ° C for 1 hour, then diluted with methylene chloride (100 ml) and successively with brine-H 2 O (1: 1), k% H 2 PO 2 .5, 20 aTaHCO 2, H 2 O and brine. The organic phase was dried (MgSO4) and evaporated to give a white solid. This solid was washed with diethyl ether: hexane (1: 1) and dried under high vacuum to give 901 mg (63.9 µ) of compound 3.

JS (KBr) 1790, 1690 ^ -1 NMR (CDCl3 / DMS0) <5 1.20 (3H, d, J = 3.0 Hz, CH3), 2.8 to 3.2 (7Ξ, m), 3 , 9 to 4.4 (2H, m), 5.1 (1H, d), 5.4 (2Ξ, q), 7.3 (2Ξ, 'd), 8.5 (2H, q), 7 .76 (2H, d), 8.3 (2Ξ, q).

25 B. See reaction scheme F of the formula sheet.

A suspension of carbapenem 3 (890 mg, 1.85 mmol) and 7 ml of iodomethane in 200 ml of dry acetone and 12 ml of methylene chloride was stirred at 25 ° C for 2 h. The reaction mixture became a clear solution after 18 hours. The solvent was removed under reduced pressure, the residue was washed with diethyl ether and 920 mg (1.18 mmol) (79.8¾) of h was obtained as a foamy solid.

- J

-57- f IR (K3r) 1765, 1690 cm -1 N.MR (DMSO) 6 1.3 (3E, d, J = 3.0 Hz), 3.1 tcÊ3.7 (73.a), 4.1 (3H, a), 4.3 (3H, s), 5.38 (23, q, J * 7.0 Hz), 8.1 (23, d, J «3.0 Hz) , 8.9 (2H; d, J = 3 ',' 0 - Hz), 7> 6 (2Ξ, d, J = 4.0 Hz), 8.2 (2H, d, J = 4.0 Hz).

C. See reactions scheme G of the formula sheet.

The carbapenem b (920 mg, 1, k7 mmol), dissolved in 90 ml tetrahydrofuran, 90 ml diethyl ether and 90 ml water, was treated with 265 mg 5 (1.51 mmol) dibasic potassium phosphate, 190 mg (1.9 mmol) potassium bicarbonate and 2800 mg of 10 #'s palladium on charcoal. It was hydrogenated at 5 25 kg / cm for 1 hour. The catalyst was filtered through Celite and the filtrate was washed with diethyl ether (3 x 25 ml). The water layer was freeze-dried to give a brownish material, which was purified twice by chromatography on a 12 g ^ C ^ Q column (H ^ O) to give 55 mg of J3.

• IH (X3r) 1750, 1640 cm ”1.

NMR (D20) 6 1.30 (33, d, J-3.0 Hz), 3.0 to 3.5 (7H, m), 4.3 (3H, s), 4.0 to 4.5 (3H , a), 7.90 (2H, d), 8.70 (2Ξ, d). 1 C ^ g B0NDAPAK inverted phase column (Waters Associates).

See formula 136 of the formula sheet.

Example III

Preparation of 3- (N-methylwridin-3-yl-methananthio) -6a- [1- (R) -hydroxyethyl] -7-oxo-1-azabicyclo (.3,2,0) hent-2-ene -2-carboxylate_

See reactions scheme H of the formula sheet.

-p-Hitrobenzyl-3- (Oyridine-3-vl-methananthio) -6α-f 1- (R) -hydroxyethyl] -7-oxo-20 -1-azabicyclo (3.2,0) hent-2-en- 2-carboxylate

To a cooled (0 °) solution of 925 mg (2.66 mmol) of the keto intermediate in 1 ml of acetonitrile, a solution of 377 mg (2.9 mmol) of diisopropylethylamine in 1 ml of acetonitrile was added, followed by 786 mg (2.9 mmol) diphenyl chlorophosphonate in 1 ml acetonitrile under a nitrogen atmosphere. The resulting solution was stirred at 0 C for 15 minutes and then a solution of 377 mg (2.9 mmol) 3-mer-Λ -58-

V

captomethylpyridine [prepared by the procedure described in Can. J. Chem.

56, 3068 (1978)) in 2 ml of acetonitrile. The reaction solution was stirred at 0 ° for 90 minutes. The precipitate was collected by filtration and washed with 20 ml of ethyl acetate to give 950 mg (60% yield) of the title product as white crystals.

NMR (DMS0-d6) 6: 1.30 (32, d, J-6.0Hz), 3.4-4.2 (52, m) 4.25 (2H, s), 5.1 (1H, d, J [4.5 Hz], 5.40 (2H, ABq, J »14.4 Hz), 7.2-8.5 (82, m).

IR (KSr) ymax 3500, 1775 and 1580 cm 1. Analysis Calculated for C22H21J3 ° 611: C 58.01; H 4.65; 2 9.23; S 7.04. Found C 57.19; H 5.19; 2 8.76; S 7.08. See reaction scheme I of the formula sheet.

10 3- (2-methylnyridin-3-yl-methananthio) -6a- C1 - (R) -hydroxyethyl] -7-oxo-1-aza-bicyclo (3,2,0) the ~ pt-2-en- 2-carboxylate

To a solution of 730 mg (1.56 mmol) of compound -1 in 9 ml of acetone, 5 ml of methyl iodide was added and the reaction stirred at room temperature for 18 hours. The precipitate was collected by filtration and washed with acetone (10ml) to give 940mg (100% yield) of the quaternized pyridine 20 as a pale yellow powder.

NMR (DMS0-d6) 5: 1.25 (32, d, J-5.82z), 3.6-4.3 (5H, o), 4.20 (3H, s), 4.25 ( 22, s) 5.25 (12, d, J »7.2Hz), 5.40 (2H, ASq, J-12.16Hz), «Λ.

7.6-9.2 (92, m). IR (K3r) X max: .300, 1765 and 1690 cm ”1. Analysis Calculated for CggHg ^ OgS ^ C 46.24; H 4.05; 2 7.03; S 5.37. Found C 45.82; H 4.11; 2 6.87; S.6.10.

To a solution of 933 mg (1.6 mmol) of compound 20 in 90 ml of tetrahydrofuran in 90 ml of ether was added 200 mg of KHCO 2 and 349 mg of K 2 HPO 2 in 90 ml of water, followed by 1.0 g of palladium-op cabbage. The mixture was hydrogenated on the Parr shaker for 45 minutes at 3.2 kg / cm. The mixture was filtered through a Celite plug and the catalyst washed with water (2 x 10 ml). The combined filtrate and washings were extracted with ether (2 x 100 ml) and lyophilized to give a yellow solution which was purified on a C 2 g B02 DAPAK (Waters Associates) inverted phase column (8 g) and Elute 5% acetonitrile in 2 water under a pressure of 0.56 kg / cm. Each 5 ml fraction was analyzed by high performance liquid chromatography and fractions with an ultraviolet absorbance at = 300 nm were collected and lyophilized to yield 230 mg (b3% yield) of the title compound as light-yellow crystals. Melting point 130 ° C (decomposition) -59- k / NKR. (D20) 6: 1.25 (311, d, J »7.0Ez), 3.12 (22, dd, J« 7.9Ez, 1.6Hz), 3.42 (12, q,> 7, 2 Hz, 1.6Ez), 3.9-4.6 (3H, m), 4.25 (22, s), 4.42 (32, s), and 8.0-9.0 (42, n). IR (K3r) ymax: 3400, 1750 and 1580 ca OVX max (ï20): 298 na (ε-8058).

Analysis Calculated for C ^ H.2 ^ 0: C 51, δ7; H 5.44; 2 7.56.

Found C 51.95; H 5.66; 2 7.56.

See formula 137 of the formula sheet.

Example IV

Preparation of 3- (2-methylnyridin-2-ylmethaanthio) -6a- [1 (R) -hydroxyethyl] - 7-oxo-1-azabicyclo (3,2,0) het) t-2-ene-2-carboxylate See reaction scheme J of the formula sheet.

P -phitrobenzyl-3- (wrridin-2-yl-methananthio) -6q- [1 (B) -hydroxyethyl] -7-oxo-1-10 azabicyclo (3.2,0) he-pt-2-en-2- carboxylate

To a cooled (0 °) solution of 925 ag (2.65 mmol) of the keto intermediate 5.ia 14 ml of acetonitrile, a solution of 377 mg (2.92 mmol) of diisopropylethylamine in 1 ml of acetonitrile was added, followed by 786 mg (2.90 mmol) diphenyl chlorophosphate in 1 ml acetonitrile under a nitrogen atmosphere. The resulting solution was stirred at 0 ° for 15 minutes and then added a solution of 377 mg (2.92 mmol) diisopropylethylamine in 1 ml acetonitrile followed by 350 mg (3.0 mmol) 2-mercaptomethylpyridine [prepared via the procedure described in Can.

J. Chem; 56, 3068 (1978)] in 1 ml of acetonitrile. The reaction solution was stirred at -10 ° C for 2 hours. The precipitate was collected by filtration and washed with 20 ml of methylene chloride to yield 650 mg (54 # yield) of the title product as a yellow powder.

2KR (DMS0-d6) 6: 1.26 (32, d, J = 7.0Hz), 2.7-3.5 (4H, m), 3.9-4.3 (2H, m), 4 .2 (22, s), 5.42 (22, ABq, J «14.4Hz) and. 7.2-8.8 (SH, a).

IR (13r) ymax: 3400, 1775 and 1690 cm 1.

Analysis Calculated for ^ 2 ^ 21 ^ 3 ^ 6 ^ 1C H 4.65; $ 9.23; S 7.04.

Found: C 57.56; 4.92; E 8.94; S 7.03.

See reaction scheme K of the formula sheet.

3- (N-methylpyridin-2-yl-m ethananthio) -6a- f ~ 1 (R) -hydroxyethyl] -7-oxo-1-azabicyclo (3.2,0) hent-2-en-2-carboxylate

To a solution of 650 mg (1.39 mmol) of compound 22 in 100 ml of acetone, 4 ml of methyl iodide was added. The reaction mixture was kept on for

V

V

-6.0- Stirred at room temperature for 3 days. The precipitate was collected by filtration and washed with acetone (10ml) to give 500mg (60% yield) of the quaternized pyridine 23 as a pale yellow solid.

NHH. (DUS0-d6) <$: 1.26 (3H, d, J * 7.0Hz) 3.9-4.2 (2H, m), 4.4 (3H, s), 4.78 (2H, s), 5.2'CIH, d, J-3.9Hs), 5.50 (2H, ASq, J-14Hz) and '7.8-9.4 (8H, m). IR (KBr) γ max: 3400.1765, and 1690 cm 5 Analysis Calculated for ^ 23 ^ 2 ^ 3 ^ 6 ^ 1 ^ 1: ^ ^ ^, 05; N 7.03; S 5.37.

Found: C 45.62; H 4.27; Ή 6.8θ; S 5.30.

To a solution of 1.0 g (1.167 nmol) of compound 23 in 90 ml of tetrahydrofuran and 90 ml of ether, 215 mg (2.15 mmol) of KHCO2 and 374 mg (2.1 mmol) of KgHPO2 in 90 ml of water were added followed by 1.0 g of 10 # 's palla-10 dium on carbon. The mixture was hydrogenated on the Parr shaker at 3.28 kg / cm 2 for 45 minutes. The mixture was filtered through a Celite plug and the catalyst washed with water (2x10ml). The combined filtrate and washings were extracted with ether (2 x 200 mL) and lyophilized to give a yellow solid, which was purified on a Cq BOWDAPAK (Waters Associates) reverse phase column (10 g), and eluted with 5l's acetonitrile in water at a pressure of 0.56 kg / cm. Each 15 ml fraction was analyzed by high pressure liquid chromatography and fractions with ultraviolet absorption at λ * 300 nm were collected and lyophilized to yield 390 mg (44% yield) of the title product. Recrystallization of this material from water-acetone-ethanol yielded fine needles. Melting point 194-196 ° C (dec.). NMR (D20) 6: 1.30 (3H, d, J »6.2Hz), 3.2 (2H, q, J- 9.0Hz, 3.6Hz) -3.46 (12, q, J- 6.0Ez, 2.7 Hz), 4.1-4.6 (3H, a), 4.60 (3H, s) and 7.9-8.9 (4H, m). IR (KBr) γ max: 3400, 1755 and; 1590 ca ”1. ÜV Amax (H 2 O): 292 nm (e-8092).

Analysis Calculated for C 4 H 15 gH 2 O 3 3 2 2 ° 1 C H 5.44; N 7.56.

Found: C 51.37; H 5.69; 5 7.37.

See formula 138 of the formula sheet.

-61- * 7 *

Example V

Preparation of 3- (N-methylnyridine-1-yl-ethananthio) -6α-1 (R) -hydroxyethyl] -7-oxo-1-azabicyclo (3,2,0) herit-2-en-2-carboxylate. See reaction scheme L of the formula sheet.

5 n-Nitrcbenzyl-3- (pyridin-2-yl) -ethaanthio) -6a- [1 (R) -hydroxyethyl-7-oxo-1-azabicyclo (3,2.0) hent-2-en-2-carboxylate

To a cooled solution of 1.78 g (5SO mmol) of the keto intermediate 5 in 25 ml of acetonitrile, 710 mg (5.5 mmol) of diisopropylethylamine in 1 ml of acetonitrile was added, followed by 1.4 g (5.0 mmol) diphenyl-10 chlorophosphate in 1 ml acetonitrile under a nitrogen atmosphere. The resulting solution was stirred at 0 ° C for 20 minutes and then added a solution of 710 mg (5.5 mmol) diisopropylethylamine in 1 ml acetonitrile followed by a solution of 850 mg (6.1 mmol) of the thiol. ? 4 [prepared according to the procedure described in J. Org. Chem; 26, 82 (1961)] in 2 ml of acetonitrile. The reaction mixture was stirred at 0 ° C for 60 minutes. The precipitate was collected by filtration and washed with methylene chloride (20 ml) to give 1.3 g (51%) of the title compound as a yellow solid.

N! S (CDC13) 5: 1.25 (3E, d, J «6.5Hz), 2.6-3.4 (7H, a), 4.2-4.6 (2H, m), 5 , 30 and. 5.65 (1H each ASq, J <14Hz) and. 7.2-8.5 (SH, n). IR (KBr) yax: 3400, 1780s. 1680ca 20 See reaction scheme M of the formula sheet.

3- (H-methylpyridin-2-yl-ethanethiol) -6a- [1- (R) -hydroxyethyl] -7-oxo-1-aza-bi-cydo (3-, 2.0) hent- 2-one-2-carboxylate

To a suspended solution of 800 mg (1.7 mmol) of compound 53 in 50 ml of acetone was added 5 ml of methyl iodide. The reaction mixture was stirred at room temperature for 48 hours. The precipitate was collected by filtration and washed with acetonitrile (15 ml) to give 810 mg (6% yield) of the quaternized pyridine as a pale yellow powder.

HKR (DMSO-dö) 6: 1.20 (3H, d, J = 5.6 Hz), 3.2-4.3 (9H, a), 4.20 (3H, s), 5.26 and 5.55 (1H, I, A3q, J-15 En) and 7.8-9.2 (8H, a). E6t (J3r) ymax: 3400, 1770 and 1690 cm ”1.

-62-

J

To a solution of 790 mg (1.27 mmol) of compound 55 in 100 ml of tetrahydrofuran and 100 ml of ether was added 100 ml of pH = 7.0 buffer solution, followed by 1.0 µg of 10% palladium on cabbage. The mixture was hydrogenated on the Parr shaker for 10 minutes at a pressure of 2.8 kg / cm 5. The mixture was filtered through a Celite plug and the catalyst washed with water (2 x 10 ml).

The combined filtrate and washings were extracted with ether (3x100ml) and freeze-dried to yield a yellow powder which was purified on a C12g BWDWDAK (Waters Associates) column (30g), and eluted with 10% acetonitrile in water at a pressure of 0.56 kg / cm 2.

Each 15 ml fraction was analyzed by high performance liquid chromatography and the ultraviolet absorbance fractions at 30 nm were collected and lyophilized to yield 65 mg (15 yield) of the title product as a yellow powder.

NKR (D20) δ: 1.25 (3H, d, J <6.2 Hz), 3.1-3.6 (7H, a), 4.0-4.3 (2H, m), 4, 32 (3H, s) and 7.8-8.9 (4H, a). I (ï3r) γτπηχ: 3400, 1750 and. 1590 ca -1. UV Xmax (HjO): 300 na (c-8108).

See formula 139 of the formula sheet.

Example VI

Preparation of 3- (1-propylpyridin-U-yl-methananthio) -6a- [1 (R) -hydroxyethyl] -20 7-oxo-1-azabicyclo (3,2,0) heut-2-en-2- carboxylate See reaction scheme H of the formula sheet.

p-nitrobenzyl-3- (pyridin-1-yl-methananthio) -6a- [1 - (R) -hydroxyethyl-7-oxo-1-azabicyclo (3,2,0) hept-2-en-2-carboxylate

A solution of 673 mg (1.86 mmol) p-nitrobenzyl 6a - [- (R) -hydroxy-25 ethyl] -357-dioxo-1-azabicyclo (3,2,0), hept-2-ene-2 carboxylate (5) in 10 ml of acetonitrile was cooled to -10 ° C under a nitrogen atmosphere. A solution of 2h-5mg (1.90mmol) diisopropylethylamine in 1ml acetonitrile was added, followed by dropwise addition of 510mg (1.90mmol) diphenylchlorophosphate in 1ml acetonitrile over a period of 2 minutes. The resulting solution was stirred at -10 ° C for 15 minutes with p-nitrobenzyl 3- (diphenylphosphoryloxy) -6a- [1- (R) -hydroxyethyl] -7-oxo-1-azabicyclo (3,2,0) - hept-2-an-2-carboxylate was formed. To this solution, a solution of 2U5 mg (1.90 mmol) of diisopropylethylamine in -63-, 0.5 ml of acetonitrile was added, followed by a solution of 270 mg (2.16 mmol) of 4-mercaptamethylpyridine in 0.5 ml of acetonitrile. The reaction mixture was stirred at -10 ° C for 60 minutes and the formed precipitate formed was collected by filtration and washed with 5 ml of ice-cold acetonitrile, 5 to give 660 mg {J6% yield) of compound 21 as wit crisp. numbers, melting point 145 ° C.

KHR

(DMSO ~ d6) 6: i, 20 (3H, d, J * 6.0Hz), 3.2-3.4 (32, a), 3.7-4.1 (2H, s), 4, 25 (2H, s), 5.05 (1H, d, J * 4.0Hz), 5.35 (1H, d, J-14.0Hz), 5.4S (1H, d,, J «14, 0Hz), 7.40 (2H, d, J »5.5Hz), 7.70 (22, d, J-8.5Hz), $ .23 (2H, d, J» 8.5Hz) and 8, 58 (2H, d,> 5.5 kHz). IB (i3r) Y = ax: 3400, 1790 and 1695 approx.

Analysis: Calculated for C22H21ff306S: C 58.01; H 4.5 $; N 9.23; S 7.0½.

Found: C 57.7 ^; Η k, 56; H 9.58; S 7.21.

10 See reaction scheme 0 of the formula sheet.

3- (1-allyl Pyridine-Ij-yl-methanethiol) -6a- [1 - (R) -hydroxyethyl] -7-oxo-1-aza-bicyclo (3,2,0) -hent-2-en- 2-carboxylate

To a solution of 900 mg (2.13 mmol) of compound -1 in 150 ml acetone, 2 ml allyl bromide and 380 mg sodium iodide are added. The mixture was stirred at room temperature for 8 hours and the solvent evaporated in vacuo to give a yellow solid. This material was suspended in 120 ml of acetonitrile, filtered and evaporated in vacuo to give 1.0 g (87% yield) of the title product as a yellow solid.

NMR

(CD3CN) 5: 1.20 (3H, d, J-6.2Hz), 3.0-3.4 (4H, m), 4.0-4.4 (42, m), 5.1- 5.6 (4H, m) and 7.4-7.9 (8H, m). IR (KBr) yam: 3400, 1770 and - 1690 cm -1.

Analysis: Calculated for ^ 5 ^ 26 ^ 3 ^ 6 ^ 1 ^ 1 ** C W3.16; H U »21; H 6, jk; S 5.15. Found: C U8.55; H4, U6; N 6.69; S 5.15.

See reaction scheme P of the formula sheet.

3- (1-Euro-ovluyridin-1-ylmethananthi o) -6a- [1- (R) -hydroxyetbyll-7-oxo-1-aza-bi cyclo (3,2,0) -ut-2-en-2 -carboxylate 25 To a solution of 1.27 g (2.15 mmol.) of compound J52 in 100 ml of tetrahydrofuran and 100 ml of ether, add 100 ml of pH = 7.0 buffer solution followed by 1.0 g of 10 $ palladium on charcoal. The mixture was hydrogenated on the Parr shaker for 10 minutes at a pressure of 2.8 kg / cm. The mixture is filtered through a Celite plug filtered a -

V

-64-

and the catalyst washed with water (2 x 10 ml). The combined filtrate and washings were extracted with ether (3 x 100 ml) and lyophilized to give a yellow powder which was mixed with C ^g BONDAPAK

(Waters Associates) column (40 g) was purified, eluting with 10% 1 s acetonitrile in 2 water under a pressure of 0.56 kg / cm. Each 15 ml fraction was analyzed by high pressure liquid chromatography and fractions with an ultraviolet absorption at 300 nm were collected and lyophilized to give if-8 mg (6% yield) of the title product as a yellow powder.

NMR (D20) <5: 0.95 (3H, t, J »7.5Hz), 1.25 (3H, d, 7.0Hz), 2.05 (2H, sextet, J = 7.5Ez) 3 , 10 (2H, dd, J-10 Hz, 2.5Hz) 3.35 (1H, dd, J «6.5Hz, 2.5Hz), 4.0-4.8 (6H, m), 7, 1 (2H, d, J = 6.0Hz) and 7.80 (2H, d, J> 6.0Hz). IR (K3r) ymax: 3400, 1750, and 1590cm -1.

Analysis: Calculated for C 4 HggEgO 2 S 2 gO: C 54.52; H 6.10; H 7.07.

Found: C 54.32; H 6.03; H 6.99.

See formula 140 of the formula sheet.

Example VII ^

Preparation of 3- (H-methyl-3-methylpyridine-2-methananthio) -6a- [1- (R) -hydroxy-15 ethyl] -7-oxo-1-azabicyclo (3.2,0) -hept-2- 1-2-carboxylate See reaction scheme Q of the formula sheet.

3-Me thy 1-2 mer mer apt omethylpyridine

A solution of 2.45 g (17.0 mmol) of the chlorine compound 36 and 1.37 g (18.0 mmol) of thiourea in 60 ml of absolute ethanol was stirred at the reflux temperature for 20 hours. Evaporation of ethanol, followed by addition of ether, yielded 3.08 g (72% yield) of the iso-thiourea salt, which was dissolved in 10 ml of water containing 1.44 g (26 mmol) of sodium hydroxide. The solution was then heated at 100 ° C under a nitrogen atmosphere for 5 minutes. The reaction mixture was cooled to 5 ° 0, adjusted to pH 6.4 by adding acetic acid and extracted with ether (4 x 50 ml). The combined ether extracts were washed with brine with 5% aqueous sodium bicarbonate. Evaporation of dried (MgSO4) solvent gave 1.4 g (83% yield) of the thiol 37 as a yellow oil, which was used in the next step without further purification. .....

NMR (CDCl3) δ: 2.20 (3H, s), 2.5-2.7 (1H, broad s), 3.8 (2H, t, J = 6.5Hz) and 6.9-8 2 (3S, m).

t -65- yr 7 x r

See reaction scheme R of the formula sheet.

P-Nitrobenzyl-3-r3 -methyl-lynridin-2-yl-methananthio) -6α- [1 - (R) -hydroxy-ethyi] -7-OXO-1 -azabieyclo (3,2,0) -he ~ pt-2-an-2-carboxylate

To a cooled (0 ° C) solution of 1.74 g (5.0 mmol) of the ke-5 intermediate 5 in 25 ml of acetonitrile, 960 mg (5.6 mmol) of diisopropylethylamine in 2 ml of acetonitrile were added, followed by 1.4 g (5.8 mmol) of diphenyl chlorophosphate in 2 ml of acetonitrile under a nitrogen atmosphere. The

♦ -. O

The resulting solution was stirred at 0 ° C for 20 minutes and then a solution of T60 mg (5.8 mmol) of diisopropylethylamine in 10 ml of acetonitrile was added, followed by 810 mg of the mercaptamethyl-pyridine 37 in 3 ml of acetonitrile. The reaction mixture was stirred at 0 ° C for 2 hours. The precipitate was collected by filtration and washed with acetonitrile to obtain 1.56 g (66% yield) of the title product as a white solid. Melting point 145 ° C.

HMR (DMS0-d6) 6: 1.23 (3E, d, J »6.5Hz), 2.30 (31.5), 3.1-4.3 (6H, a), 4.35 (2ï , s), 5.20 and 4.45 (13-each, ABq, J-15.0Hz). and. 7.3-8.4 (7H, m). IR (KBr) γτπηχ: 3400, 1767 and - 1695 cm "1.

Analysis: Calculated for C 47.91; H 4.69; N 6.98; S 10.66.

Found: C4-7.72; H 4m34; H 6.72; S 11.22.

See reaction scheme S of the formula sheet.

3- (N-methyl-3-methylpyridin-2-yl-methanethiol) -6a- [1 - (R) -hydroxyethyl-7-oxo-1-azabicyclo (3,2,0) -hept-2- 1-2-carboxylate 20 To a solution of 680 mg (1.45 mmol) of compound 38 and 120 ml of methylene chloride was added 270 mg (2.33 mmol) of methyl fluorosulfonate.

The reaction mixture was stirred at room temperature for 3 hours. The precipitate was collected by filtration and the methylene chloride (5ml) washed to give 840mg (99% yield) of the quattrified pyridine 39 as white crystals.

v

NMR

(DMS0-d6) $ 1.15 (3H, d, J »5.8Hz) 2.62 (3S, s), 3.2-4.4 (5H, m),

4.45 (3H, s), 4.60 and 4.82 (1H each:, A3q, J <9.2Hz), 5.30 µm; 5.46 (1H

eJUt ', ABq, J * 12.8Hz), and 7.6-8.9 (73, m). IR (K3r) ymax: 3400, 1750 and 1590 ca "1.

-66-

V

·}

Analysis: Calculated for C 1 H N N O S S F: C 49.14; H 4.47; N 7.13; S 11.43.

Found: C 49.56; H 4.16; N 7.26; S 11.03.

To a solution of 8TO mg (1.39 mmol) of compound 3 in 100 ml tetrahydrofuran and 100 ml ether was added 100 ml. pH * 7.0 buffer solution added, followed by 750 mg of 10 # 's palladium on charcoal. The mixture was hydrogenated on the Parr shaker for 60 minutes at a pressure of 31.5 kg / cm in a freezer (4-6 ° C). The mixture was filtered through a Celite plug and the catalyst washed with ether (2 x 10 ml). The combined filtrate and washings were extracted with ether (2 x 40 ml) and lyophilized to give a yellow solid which was purified over the C18 g BOHDAPAK (Waters Associates) column (20 g) and eluted with 5% acetonitrile in water at a pressure of 0.56 kg / cm 2.

Each 15 ml fraction was analyzed by high pressure liquid chromatography and fractions with an ultraviolet absorption at = 300 nm were collected and lyophilized to give 141 mg (30 # yield) of the title product as a yellow solid.

. NWR (D20) $. 1.24 (3H, d, J * 7.0Hz), 2.62 (3H, s), 3.2-3.5 (3H, a), 4.2-4, 4 (2H, a), 4.45 (3H, s), 4.50 and 4.59 (1H each, ABq, J «12.6Hz), 7.82 (1H, q, J» 7.0Hz, 6.5 Hz), 8.35 (1H, d, J * 7.0 Hz) and 8.65 (1H, d, J-6.5 Hz). IR (KBr) γ max: 3400, 1750 and 1580 ca UV laax (H 2 O): 296 na (e »8014).

Analysis: Calculated for. 1/4 HgO: C 57.85; H 5.85; W 7.94.

Found: C 58.60; H 5.86; H 7.87.

20 See formula 141 of the formula sheet.

Example VIII

Preparation of 3- (2-methyl-H-methylthiazol-4-yl-methananthio) -6a-Cl— (H) -hydroxyethyl-7-oxo-1-azabieyclo (3,2,0) -hept-en-2 -earboxylate See reaction scheme T of the formula sheet.

P-Hitrobenzyl-3- [2-methylthiazol-4-yl-methananthio] -6a- [1- (R) -hydroxyethyl] - 7-oxo-1-azabicyclo (3,2,0) -hept-2- 1-2-carboxylate

To a cooled (0 ° C) solution of 1.4 g (4.0 mmol) of the keto intermediate 5 in 12 ml of acetonitrile, 0.83 ml (4.6 mmol) of diisopropylethylamine was added, followed by 1 , 16 g (4.3 mmol) of diphenyl chlorophosphate in 2 ml of acetonitrile under a nitrogen atmosphere. The resulting solution was stirred at 0 ° for 30 minutes to give p-nitrobenzyl 3- (di-phenylphosphoryloxy) -6a- [1- (R) -hydroxyethyl] -7-oxo-azabicyclo (3,2,0) -hept-2- -67-rf one-2-carboxylate. To this solution, a solution of 0.83 mg (4.6 mmol) of diisopropylethylamine in 2 ml of acetonitrile was added, followed by a solution of 0.62 g (4.2 mmol) of 2-methyl-4-mercaptomethylthiazole [prepared according to the procedure described in J. Amer. Chem. Soc; 7J_, 3750 (1949)] in 3 ml of acetonitrile. The reaction solution was stirred at 0 ° for 40 minutes. The precipitate was collected and washed with ether (30 ml) to give 943 mg of the title product as a white solid.

HKR (CDC13) 5: 1.32 (3H, d, J »7Hz), 2.68 (3H, S), 3.20 (2H, m) 3.76 (iH, d, J * 5.5Hz) , 4.16 (2H, S), 4.20 (1H, n), 5.40 (22, q, J-142z), 1f06 (1H, S), 7.68 (2H, d, J «8Hz ) and 8.24 (2H, d, J8Ez). IR (KBr) ymax: 3500, 1770, and 1700 cm -1.

See reaction scheme U of the formula sheet.

10 3- (2-Methyl-H-methyl-thiazol-4-yl-methananthio) -6q- [1- (R) -hydroxyethyl] -7-oxo-1-azabicyclo (3% 2.0) -hept- 2-one-2-carboxylate

0.27 ml (3.3 mmol) of methyl fluorosulfonate was added to a solution of 525 mg (1.1 mmol) of compound 9, 20 ml of methylene chloride.

The reaction mixture was stirred at room temperature for 90 minutes. .

The precipitate was collected by filtration and washed with methylene chloride (50ml) to give 650mg (100% yield) of the quaternized thiazole 10 which was used in the next step without further purification.

Thus, to a solution of compound J0_ in 100 ml of tetrahydrofuran and 100 ml of ether, 100 ml of pH = 7.0 buffer solution was added, followed by 500 mg of 10% palladium on carbon. The mixture was hydrogenated on the Parr-seuder at a pressure of 2.45 kg / cm 2 for 45 minutes.

The mixture was filtered through a Celite plug and the catalyst washed with water (2 x 10 ml). The combined filtrate and wash liquor were extracted with ether (2 x 100ml) and freeze dried to yield a yellow powder which was purified on a C ^g BUDAPAK reverse phase column (8g) (Waters Associates) and eluted with 5 #'s acetonitrile in water at a pressure of 0.56 kg / cm 2. Each 15 ml fraction was analyzed by high pressure liquid chromatography and fractions with an ultraviolet absorption at X = 300 nm were collected and lyophilized,

H1QX

whereby 145 mg (48 # yield) of the title compound was obtained as a pale yellow powder.

V

-68- * * 'NMR (CDCl3) d: 1.20 (3H, d, J-7Hz), 2.92 (3H, S), 3.08 (1H, d, J-3.5Hz), 3 , 20 (IK, d, H = 3Hz), 3 ^ 44 (1H, dd, J = 1Hz, J «3.5Hz), 4.00 <3H, 5), 4.20 (3H, -m), 4.36 (2H, m) and 7.88 (1H, s). nt (KBr). ymax: 3400, 1750 and 1585 cm1.

07 Xmax (H 2 O): 296 nm (e * 7500).

Analysis: Calculated for C 25 Hggl 2 O 2 .2 O: C 46.15; H 5.64; N 7.17; S 16.41. Found: C 46.50; H 5.26; H 7.13; S 16.20.

See formula 142 of the formula sheet.

Example IX

Preparation of 3- (N, N1-dimethylimidazol-2-yl-methananthio) -6a- [1- (R) -hydroxyethyl] -7-oxo-1-azabi cyclo (3,2,0) - Hert-2-en-2-carboxy late See reaction scheme V of the formula sheet.

2-Mer cant omethyl-N-methylimidazole 10 To a solution of 10.4 g (58 mmol) of 2-chloonaethyl-U-methylimidazole 3J. [prepared according to the procedure described in J. Amer. Chem. Soc; 7J., 383 (1949)] in 200 ml of acetonitrile, 7.1 g (60 mmol) of N-acetylthiourea were added, and the reaction mixture was refluxed for 90 minutes. The precipitate was filtered and washed with acetonitrile (20 ml) to give the isothiourea salt, which was then dissolved in 120 ml of ethanol and heated under reflux for 18 hours under nitrogen atmosphere. The reaction mixture was cooled to room temperature, condensed in vacuo to about 60 ml volume and the precipitate removed by filtration. After evaporation of the filtrate in vacuo, 2-mercaptomethyl-H-methylimidazole 32 was obtained as a yellow oil, which was used in the next step without further purification. HMR (D 2 O) S: 3.90 (3H, s), 4.10 (2H, s) and 7.25 (2H, s).

See reactions scheme W of the formula sheet.

p-Nitrobenzyl-3- [N-methylimidazol-2-yl-methananthio] -6q- [1 - (R) -hydroxy-25 ethyl] -7-oxo-1-azabicyclo (3.2.0) -hept-2- 1-2-carboxylate

To a cooled (0 ° C) solution of 7.24 g (20.3 mmol) of the ke-to-intermediate J5 in 35 ml of acetonitrile, 2.8 g (21.3 mmol) of diisopropyl-ethylamine in 2 ml of acetonitrile added, followed by 5.5 g (20.4 mmol) of diphenyl chlorophosphate in 2 ml of acetonitrile under a nitrogen atmosphere.

The resulting solution was stirred at 0 ° C for 15 minutes and then a solution of 4.1 g (3.0 mmol) of diisopropylethylamine in 2 ml of acetonitrile was added, followed by 4.6 g (31, Q mmol) of the thiol 32.

f -69-

The reaction mixture was stirred at 0 ° C for 60 minutes. The white precipitate was collected by filtration and washed with methylene chloride * (20 ml), yielding 6.6 g (71 # yield) of the title product as a white solid. Melting point 142 ° C.

NMR

(DMS0-d6) 5: 1.32 (3H, d, J «7.0Hz), 3.2-4.5 (5H, m), 3.2 (22, s), 3.9 (32, s), 5.50 (22, ABq, J «14.0Ez), 7.65 (2E, d, J = 6.5 Hz), 7.70 (2H, s) and 8.24 (22, d, J = 6.6Hz). IR (KBr> Y max: 3450, 1770 - and 1690 cm -1. * 5. Analysis: Calculated for c21H20N406Si. 1 1/2 HgO: C 52.18; H 4.79; 2 11.59. Found C 52 22, H 4.91, 2 12, 16.

See reaction scheme X of the formula sheet.

3- (2,21-dimethylimidazol-2-yl-methanethiol) -6a- [1 - (R) -hydroxyethyl] -7-oxo-1-azabicyclo (3,2,0) -hept-2-en- 2-carboxylate 10 · To a suspended solution of 1.34 g (3.0 mmol) of compound 33 in 270 ml of acetone was added 20 ml of methyl iodide. The reaction mixture was stirred at room temperature for 4 days. The precipitate was collected by filtration and washed with acetone (20 ml) to obtain 1.70 g (95 # yield) of the quaternized imidazole 34 as yellow crystals. Melting point 175-177 ° C.

2MR (DMS0-d6) 6: 1.10 (32, d, H = 6.22z), 3.30 (22, s), 3.2-4.3 (62, m), 3.95 (62 , s), 5.45 (2H, ABq, J-14Hz), 7.65 (2H, d, J * 6.0Hz). IR (KBr) v max: 3400, 1750 and 1600 cm @ -1.

Analysis: Calculated for: C 21 H 22 Cl 4 S 6: C 1.08; H 9.60; 2 5.48.

Found: C 43.02; H, 9.02; 2 5.44.

To a solution of 1.30 g (1.86 mmol) of compound 34 in 120 ml of tetrahydrofuran and 120 ml of ether, 120 ml of pH = 7.0 buffer solution was added, followed by 900 mg of 30 # palladium-on-Celite . The mixture became 2

Hydrogenated on the Parr shaker at a pressure of 2.8 kg / cm for 40 minutes. The mixture was filtered through a Celite plug and the catalyst washed with water (2 x 15 ml). The combined filtrate and washings were extracted with ether (3x100ml) and lyophilized to yield a yellow amorphous powder which was over a B02DAPAK

(Waters Associates) column (30 g) was purified and eluted with 10 # acetonitrile in water under a pressure of 0.56 kg / cm. Each 20 ml fraction was added. _. . X Λ -70- analyzed by high pressure liquid chromatography and the fractions with an ultraviolet absorption at λ = 300 nm were collected and lyophilized to give 220 mg (35% yield) of the title product as a yellow powder.

NMR (D20) δ: 1.12 (3H; d, J-7.0Hz), 3.08 (1H, dd, J = 13.0Hz, 6.4Hz), 3 ^ 15 (1H, dd, J = 13.0Hz, 6.4Hz), 3.45 (1H, dd, J = 3.2Hz, 4.5Hz) 3.85 (6H, s,) 4.1-4.3 (2H, a), 4.40 (1H, d, J-13.5 Hz), 4.52 (1H, d,> 13.5 Hz) and -7.40 (2H, s). IH (KBr) pnax: 3500, 1750 and 1590 cm ”1. ÜV Amax (E20): 296 ca (ε * 8411).

5 Analysis: Calculated for CHNO S. HO: C 51.68; H 5.67; N 12.06; S 9.50.

19 5 4 *

Found: C 49.93; H 5.94; F 11.46; S 9.03.

See formula 143 of the formula sheet.

Example X.

Preparation of 3- (2,3,4-trimethylthiazol-5-yl-methananthio) -6a- [1 (R) -hydro-10-xyethyl] -7-oxo-1-azabicyclo (3,2,0) -hept -2-en-2-carboxylate See reaction scema Y of the formula sheet.

2,4-Dimethyl-5-mercaptomethyltbiazole

To a solution of 4.8 g (26.0 mmol) of chlorine compound J + 6 [prepared according to the procedure described in J. Amer. Chem. Soc; J04, 4461 (1982)} in 50 ml of absolute ethanol, 2.4 g (30 mmol) of thiourea were added. The reaction mixture was refluxed for 18 hours. The precipitate was collected by filtration and washed with ether (20 ml) to give the isothiourea salt, which was dissolved in 22 ml of 1N sodium hydroxide and heated at 100 ° C under a nitrogen atmosphere for 4 minutes. The reaction mixture was then cooled to room temperature, adjusted to pH 7.0 with 1N hydrochloric acid and extracted with ether (3 x 50ml). The combined ether phases were washed with water and brine and dried with MgSO4.

After evaporation of solvent, 780 mg (49% yield) of the thiol 47 was obtained as a colorless oil, which was used in the next step without further purification.

HMR (DC13) &: 2.05 (3H, s), 2.35 (3H, s) and 3.60 (2H, d, J = 6.5 Hz).

See reaction scema Z of the formula sheet.

p-Hitrobenzyl-3- Γ 2,4-dimethylthiazole-5-vl-methanethhi o -l -6α- Γ1 - (R) -hydroxy-30 ethyl] -7-oxo-1-azabicyclo (3,2, 0) -hept-2-an-2-earboxylate 71- ♦;

X

* To a cooled (0 ° C) solution of 1, bg (k, 0 wol) of the keto intermediate 5 in 25 ml of acetonitrile, 610 mg (1 +, 7 mmol) of diisopropyl ethylamine in 1 ml of acetonitrile was added, followed by 1.15 g (^3.3 mmol) diphenyl chlorophosphate in 1 ml acetonitrile under a nitrogen atmosphere.

The resulting solution was stirred at 0 ° C for 20 minutes and then a solution of 610 mg (b, J mmol) of diisopropylethylamine in 1 ml of acetonitrile was added, followed by 750 mg (h, 7 mmol) of the thiol ^ 7 in 2 ml of acetonitrile. The reaction mixture was stirred at 0 ° C for 3 hours. The precipitate was collected by filtration and washed with methylene chloride (20 ml) to yield 1.1 g g (61% yield) of the title product as a white solid.

NUR (DMSO-co) o: 1.25 (3H, d, J * 6.4Hz), 2.30 (3H, s), 2.65 (3H, s), 3.1-3.4 (3H , m), 4.10 (IH, broad s), 4.0-4.5 (3H, a), 5.25 and 5.50ζ1Η each, AB ^, J * 4Hz), 7.68 (2H, d> 1 * 8.5 Hz) and 8.25 (2H, d, J * 8.5 Hz). IR (KBr) 3500, 1770 and 1690 ca "1.

Analysis: Calculated for C 21 H 21 O 2 Og: C 53.73; H U, 71; H 8.58; S 13,

Found: C 53.97; H b, 7fc; ff 8.58; S 13.10.

15 See reaction scheme AA of the formula sheet. * 3- (2,3, Trimethylthi azol-5-yl-methanethiol) -6a- [1- (R) -hydroxyethyl] -7-oxo-1-azabicyclo (3,2,0) -hept-2- 1-2-carboxylate

To a solution of 1.97 g (4.0 mmol) of compound 48 in 180 ml of methylene chloride was added a solution of 0.98 ml (13 mmol) of methyl fluorosulfonate in 2 ml of methylene chloride. The reaction mixture was stirred at room temperature for 70 minutes. The reaction mixture was then poured into a solution of ether (400 ml) and n-pentane (100 ml). The precipitate was collected by filtration and washed with ether (20 ml) to give 1.6 g (65.5% yield) of the quaternized thiazole 49 as a white amorphous powder.

NMR (DtiSO-d6) d. 1.25 (3H, s, J-6 ^ 5Hz) f 2.45 (3H, s), 2.30 (3H, s), 3.2-4.5 (6H, m), 3.90 ( 3H, s), 5.30 (2H, broad s), 7.60 and 8.2 (1H each d, J * 8.5Hz).

IR (KBr) ymzxz 3400, 1770 "and 1690 ca" 1.

Analysis: Calculated for C23226N309S3F. 1/2 E 2 O: C 1 + 5.09; H 4.44; N 6.86.

Found: C 44.50; Η 4.38; H 6.58.

; ·% - * - «- ^. i r __ __

V

v -72-

To a. solution of 1.0 g (1.72 mmol) of compound 4 lb in 100 ml of tetrahydrofuran and 100 ml of ether, 100 ml of pH = 7.0 buffer solution was added, followed by 1.0 g of 10% palladium on cabbage. The mixture was left on. the hydrogenated on Parr shaker at a pressure of 2.8 kg / cm for 40 minutes. The mixture was filtered through a Celite plug and the catalyst washed with water (2 x 10 ml). The combined filtrate and washings were extracted with ether (3 x 100 ml) and lyophilized to yield a yellow powder which was passed over a C 1 g BONDAPAK (Waters

Associates column (40 g) was purified and eluted with 10% acetonitrile in water 2 at a pressure of 0.56 kg / cm.

Each 15 ml fraction was analyzed by high pressure liquid chromatography and the ultraviolet absorption fractions at Xmax = 300 nm were collected and lyophilized to yield 315 mg (50% yield) of the title product as a yellow solid. NMR (D20) 6: 1.25 (3E, d, J = 7.0H2), 2.25 (3H, s), 2.90 (3H, s), 3.0-3.30 (3H, n ), 3.90 (3H, s) and 4.1-4.4 (4H, a). IR (KBr) ynax 3400.1750 and 1580 cm -1. ÜV Xmax: (H20): 297na (ε * 8994).

Analysis: Calculated for 0 ^ ^ 0 ^ 8.2 ^ 0: C 48.25; H 6.09; N 7.79

Found: C 47.96; H 5.83; H 7.89-See formula 144 of the formula sheet.

Example XI

Preparation of 3- [2- (N-methylthiazolium) ethylthio] -6a-ri (R) -hydroxyethyl] -20 7-oxo-1-azabicyclo (3,2,0) -he-pt-2-ene -2-earboxylate See reaction scheme BB of the formula sheet.

2-Merca-ptomethylthiazole

To a chloroform solution (30ml) of thionyl chloride (3.81ml, 0.052M) at room temperature was added 3.60g (0.026m) of the hydroxymethyl-25 thiazole -1 followed by heating at 50 ° for 2 hours. Chloroform was evaporated in vacuo to leave a rubble solid which was dissolved in 30 ml of absolute ethanol. 2.04 g (0.026m) of thiourea was then added. The mixture was then refluxed for 18 hours. The precipitate was collected by filtration, washed with ethanol and ether and 3.4 g (55% yield) of it were obtained. isothiourea salt J3. The isothiourea salt _3 was dissolved in 30 ml of water and i? -73- - <

V

rinsed for 20 minutes. Then 1.10 g (0.027M) sodium hydroxide was added and the mixture heated at 100 ° for 2 minutes. The cooled (0 °) solution was adjusted to pH 6.0 with acetic acid, followed by extraction with ethyl acetate (35 ml x 2). The organic layer was dried (MgSO4) and evaporated in vacuo to give 0.75 (42% yield) of. the thiol-4 was obtained as a yellow oil, which was used without further purification; NME. (CDCl3) 6; 2.1 (1H, t), 4.0 (2H, d, J = 10Hz)> 7.27 (1K, d, J = * 3.0Hz) and 8.85 (1H, d, J »3, 0Hz).

See reaction scheme CC of the formula sheet.

10 n-Mt robenzyl-3 - [(2-thiazole) methylthio-6α-Γ1- (R) -hydroxyethyl] -7-oxo-1-azabicyclo (3,2,0) -hept-2-en- 2-carboxylate

To a cooled (^) solution of 1.4 g (4.0 mmol) of the keto intermediate JJ in 8 ml of acetonitrile, 0.79 ml (4.4 mmol) of diisopropylethylamine was added, followed by 1.17 g (4.4 mmol) diphenyl chlorophosphate under a nitrogen atmosphere. The resulting solution was stirred at 0 ° for 30 minutes to give p-nitrobenzyl-3- (diphenylphosphoryloxy) -6a- [-1- (R) -hydroxyethyl] -7-oxo-1-azabicyclo (3.2 0) hept-2-an-2-carboxylate. To this solution, a solution of 0.79 ml (4.4 mmol) of diisopropylethyl amine in 2 ml of acetonitrile was added, followed by a solution of 0.72 g of the thiol. 4 in 2 ml of acetonitrile. The reaction solution was stirred at 0 ° for 60 minutes and then diluted with 50 ml of ethyl acetate and washed with 30 ml of water, 20 ml of 10% aqueous H 2 PO 2 and 30 ml of brine. After evaporation of dried (MgSO4) solvent, a crystalline solid was triturated with ether to yield 782 mg (42% yield) of the title product 6 in the form of a white crystalline material.

Melting point 158-160 ° C.

KKS. (CDC13) δ: 1.32 (311, d, J * 7.0Ez), 3.28 (3H, a), 4.20 (2H, a), 4.36 (2H, s), 5.40 (2H, q), 7.40 (1H, d, J-4.0Hz), 7.64 (2H, d, J »8Hz), 7.76 (1H, d, J» 4.0Hz) and 8 } 24 (2H, d, J-8Hz) IR (KSr) yaax; 3500, 1770 and 1700 cm "1.

-τ * -> η

Analysis: Calculated for ^ 20 ^ 19 ^ 3 ° 6 ^ 2: ^ ^ 2 * 05; 2 4.15; N 9.10; S 13.89. Found: C 52.35; H 4.40; H 8.72; S 13.90.

See reaction scheme DD of the formula sheet.

3— Γ 2— (N-methylthiazolium) methylthio] -6α- [1 - (R) -hydroxyethyl] -7-oxo-1-aza-5 bi cyclo (3,2,0) -hept-2-en- 2-carboxylate

To a solution of 782 mg (1.36 mmol) of compound 6 in 55 ml of methylene chloride, 0.5 ml of methyl fluorosulfonate was added and the mixture stirred at room temperature for 90 minutes. The precipitate was collected by filtration and washed with methylene chloride (30 ml) and ether (20 ml) to give 630 mg of a crude quizinated thiazole 7, which was used in the next step without further purification.

Thus, to a solution of compound X in 140 ml of tetrahydrofuran and 120 ml of ether, 140 ml of a buffer solution of pH 7.0 was added, followed by 650 mg of 10% palladium-on-carbon. The mixture was hydrogenated on the Parr shaker at 2.1 kg / cm for 2 minutes. Then the mixture was filtered and the catalyst washed with water (2 x 10 ml). The combined filtrate and washings were extracted with ether (2 x 150 ml) and lyophilized to yield a yellow powder. The crude yellow powder was purified on a C18 20 BOWDAPAK inverse phase column (7 g) (Waters Associates) and eluted with 5% acetonitrile in water at a pressure of 0.56 kg / cm. Each 15 ml fraction was analyzed by high pressure liquid chromatography and fractions with an ultraviolet absorption at 300 nm were collected and lyophilized to yield> 23 mg (5% yield) of the title compound as a yellow amorphous solid .

NKR (D20) 5: 1.28 (32, d, J = 7.0Hz), 3.12 (2H, d, J = 7.0 Hz), 3.44 (1H, dd, J = 1.0Hz) and ^ 3.0Hz), 4.20 (32, s), 4.24 (2H, m), 4.76 (3H, a), 8; 12 (1H, d, J = 4Hz) and 8.24 (1H, d, J * Hz): IR (KBr) ymax: 3400, 1740 - # B - 1580 cm ~ *. uv Xmax (H ^ O) 292 nm (ε * 7285).

See formula 1U5 of the formula sheet.

Example XII

Preparation of 3- Π- (RS) -methyl-N-methyl-pyridin-3-yl-methananthio] -6α- [1- (R) -hydroxyethyl] -7-oxo-1-azabicyclo (3.2, 0) -hent-2-an-2-carboxylate See reaction scheme EE of the formula sheet.

-75- f-e p-Hitrobenzyl-3--1- (R.5) methyl-pyridine-3-yl-methanethiol-6α-Γ1- (5) -hydro-xyethyl] -T-oxo-1-azabicyclo ( 3,2,0) -he-pt-2-en-2-carbozylate

To a concentrated (0 °) solution of 1.85 g (5.3 mmol) of the keto-5 intermediate 5 in 20 ml of acetonitrile, 75¼ mg (5.8 mmol) of diisopropyl ethylamine in 1 ml of acetonitrile was added, followed by dissolving 1.57 g (5.8¼ mmol) of diphenyl chlorophosphate in 2 ml of acetonitrile under a nitrogen atmosphere. The resulting solution was stirred at 0 ° C for 15 minutes and then a solution of 75¼ mg (5.8 mmol) of diiso-10 propylethylamine in 1 ml of acetonitrile was added thereto, followed by 81¼ mg (5.8 mmol) of the thiol 27 in 2 ml of acetonitrile. The mixture was stirred at 0 ° for 3 hours and the reaction mixture then diluted with 200 ml ethyl acetate and washed with ice cold brine (200 ml), water (200 ml), aqueous sodium bicarbonate (100 ml) and brine (100 ml). Evaporation of dried (MgSO4) solvent gave a yellow oil, which was purified by silica gel column chromatography eluting with 50% acetone-50 methylene chloride to give 1.65 g of the title product as a yellow solid.

NKR (CDCl ^) <5: 1.22 and 1.25 (3H each.d, J * 7.0Hz), 1.46 * n 1.50 (3H each ^ d, J * 7t2Hz), 2.4 -3.3 (3H, m), 3.8-4r2 (3H, m), 5.35 (20, ABq, J »14.5Hz) and 7.2-8f6 (8H, a). IR (KBr) vnax: 3400, 1765 and 1690 cm -1.

Analysis: Calculated for ¢ 23 ^ 23 ^ 3 ^ 3 ^ 1: C 58.83; H k} 9ki H 8.95; S 6.83. Found: C 57.15; H 5.0¼; H 8.28; S 6.78.

See reactions scheme FF of the formula sheet.

Ij— (1 * -mer cant ethyl) -pyridine

To a solution of 25 g of 1 - (4-pyridyl) -ethanol 2 ounces according to the procedure described in J. Chem. Soc; Perkin II, lk62 (197¼)] in 100 ml of chloroform, 50 g of thionyl chloride was added. The mixture was refluxed for 2 hours. After evaporation of the solvents in vacuo, the chlorine compound 26 was obtained as a semi-solid, which was used in the next step without further purification. Thus, to a solution of 26 in 160 ml of ethanol, a warm solution of 1, k g of thiourea in 75 ml of ethanol was added. The reaction mixture was refluxed for 18 hours. Methanol was evaporated and the residue dissolved in 100 ml water and adjusted to pH 10 by addition of 2H HaOH. The mixture was stirred at room temperature for 90 minutes, -76- »Ί.

adjusted to pH 6.0 by addition of 6 HHCl and extracted with ether (2 x 200 ml). After evaporation of dried (MgSO4) solvent, a yellow oil was obtained, which was distilled 5 mmHg and whose boiling range of 60-65 ° C was collected in an amount of 11.0 g (38% yield) of the pure thiol 27 as a colorless oil.

NKR (CDCl 3) 6: 1.70 (3H, d, J * 6, QH2), 2.05 (1H, d, J * 5r8Hz), 4.20 (1H, c, J-6.0Hz, 5, 8Hz), 1f20 (2H, d, J »6.2Hz) and 8.5 (2H, d, J« 6.2Hz).

See reaction scheme GG of the formula sheet.

3- [1 - (RS) -methyl-pyridin-3-yl-methananthio] -6a- [1 - (R) -hydroxyethyl] -7-oxo-1-azabicyclo (3,2,0) -hept-2 -a-2-carboxylate 10 To a solution of 1.1 g (2.34 mmol) of compound 28 in 100 ml of acetone was added 10 ml of methyl iodide. The reaction mixture was stirred at room temperature for 18 hours. The precipitate was collected by filtration and washed with methylene chloride (10 ml) to give 1.4 g (100% yield) of the quaternized pyridine 29 as a yellow powder.

NMR (DMS0-d6) 5: 1.10 (3H, d, J <6.5 Hz), 1.62 (3H, d, J * 7.5 Hz), 2.6-4.2 (6H, m), 4.39 (3H, s), 5.42 (2H, ABq, J-13.6 Hz) and 7.9-9.2 (8H, m). IR (KBr) vmax: 3400, 1770 and -1190 cm -1.

Analysis: Calculated for: C 47.14; H 4.29; N 6.87; S 5 »24.

Found: C 47.18; H 4.78; N 6.11; S 5.41.

To a solution of 1.45 g (2.37 mmol) of compound 29 in 120 ml of tetrahydrofuran and 120 ml of ether, 120 ml of buffer solution with a pH of 7.0 was added, followed by 1.5 g of 10% palladium -on-cabbage. The mixture was hydrogenated on the Parr shaker at a pressure of 31.5 kg / cm for 60 minutes. The mixture was filtered through a Celite plug and the catalyst washed with water (2 x 15 ml). The combined filtrate and washings were extracted with ether (2 x 200 ml) and freeze-dried to give a yellow solid which was purified on a Cg BIOIDAPAK ("Waters Associates) reverse phase column (50 g) 2 eluting with 5% aqueous acetonitrile under a pressure of 0.56 kg / cm.

Each 20 ml fraction was analyzed by high pressure liquid chromatography and the fractions with an ultraviolet absorption at = 300 nm max were collected and lyophilized to yield 200 mg (24% yield). > ·.

-77-> * of the title product as a yellow amorphous solid.

KMR (D20) 6: 1Γ32 (3H, d, J »7.0 Hz), 1.63 (3Ξ, d, J» 7.2 Hz), 2.5-4.6 (6H, m), 4 .32 (3H, s) and 8.2-8.9 (4H, m). IR (KBr) vmax: 3400, 1750 and 1590cm -1. UV Xmax (JLO): 296 na (ε = 7573).

Analysis: Preparing: c - ^ 20 ^ 2 ° ^ ^ 1 1 ^ 2 H2 O: C ^ 4.38; 2 5.77; N 7.46. Found: C 54.39; H 5.98; N 7.68.

5 See formula 146 of the formula sheet.

Example XIII

Preparation of 3- (N-methyl-N * -benzylimidazol-2-yl-methananthio) -6a- [1 - (R) -hydroxyethyl] -7-oxo-1-azabicyelo (3,2,0) -hept -2-en-2-carboxylate See reaction scheme HH of the formula sheet.

N-benzyl-2-mereaptomethylimldazole

To a solution of 3.23 g (13.0 mmol) of the chlorine compound 4L [prepared according to the procedure described in J. Amer. Chem. Soc; 71, 383 (1949)] in 80 ml of acetonitrile, 1.72 g (14.5 mmol) of N-acetylthiourea were added. The reaction mixture was refluxed for 3 hours. The precipitate was collected by filtration and washed with acetonitrile (10 ml) to form the isothiourea salt, which was then dissolved in 80 ml of absolute ethanol and refluxed for 18 hours under nitrogen atmosphere. The reaction mixture was cooled to room temperature, condensed in vacuo to about 30 ml volume and the precipitate removed by filtration. Evaporation of the filtrate in vacuo gave 3.5 g (91%) of the thiol 42 as a yellow thick syrup.

NMR (CDCl3) 5: 2.1 (1H, t, J »4.5Hz), 3.80 (2H, s), 5.20 (2H, s), and 6.8-7.5 (7H, m ).

See reaction scheme II of the formula sheet.

25 u-Nitroben2yl-3- [N-benzylimidazol-2-yl-methananthio] -6a- [1- (R) -hydroxyethyl] - 7-oxo-1-azabicyclo (3,2,0) -Hut-2- 1-2-carboxylate

To a cooled (0 °) solution of 3.03g (8.5mmol) of the keto intermediate in 70ml acetonitrile, 1.17g (9.0mmol) diisopropyl ethylamine in 2ml acetonitrile was added, followed by 2.4 g (9.0 mmol) of 30 diphenyl chlorine phosphate in 2 ml of acetonitrile, under a nitrogen atmosphere.

> -78-

The resulting solution was stirred at 0 ° C for 20 minutes and then a solution of 1.17 g (9.0 mmol) of diisopropylethylamine in 2 ml of acetonitrile was added, followed by 4.8 g (15 mmol) of the thiol 42 A further 1.93 g (15 mmol) of diisopropylethylamine was added and the reaction mixture was stirred at 0 ° C for 2 hours. The precipitate was collected by filtration and washed with cold methylene chloride (20 ml) to give 2.5 g (55% yield) of the title product as a white solid.

HUR (DMS0-d6) δ: 1.23 (3H, d, J «7.2Hz), 2f5-4, l (6H, m), 4.25 (2H, s), 5.20 (2H, s ), 5.20 and 5.45 (1H each, d, J14.5Hz) and 6.9-8.3 (UH, m). IR (K5r) ymax: 3400, 1775 and 1690cm ”1.

10 See reaction scheme JJ of the formula sheet.

3- (N-methyl-N * -benzylimidazol-2-yl-methananthio) -6a- [1 - (R) -hydroxyethyl] -7-. oxo-1-azabicyclo (3,2,0) -hept-2-en-2-carboxylate

To a solution of 1.76 g (3.3 mmol) of compound 43 in 1.1 L of methylene chloride, added 1.15 ml (13.4 mmol) of methyl fluorosulfonate.

The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture is concentrated in vacuo to about 15 ml volume concentrated. The precipitate was collected by filtration and washed with methylene chloride (10 ml) to yield 1.58 g (74% yield) of the vatemized imidazole 44 as a white solid.

NMR (DMS0-d6) δ: 1.15 (3H, d,> 7.0Hz), 3.2-4.4 (6H, m), 4.70 and 5.0 (1H each, ABq, J- 10.8Hz), 5.24f / 5.46 (1H e-1k, ABq, J-14Hz), 5.50 (2H 2 s) 'and 7.4-8.4 (11H, m). IR (KBr) γτηβχ: 3500, '1770 e »1700 cm" 1. <20 Analysis: Calculated for CggH ^ H ^ O ^ SgF: C 51.48; H 4.47; N 8.67; S 10.20 Found: C 51.84, H 4.52, H 8.65, S 9.87.

To a solution of 1.11 g (1.71 mmol) of compound 44 in 100 ml of tetrahydrofuran and 100 ml of ether, add 100 ml of buffer solution with a pH of 7.0, followed by 1.0 g of 10% palladium -on-cabbage. The mixture was hydrogenated on the Parr shaker for 45 minutes at a pressure of 31.5 kg / cm. The mixture is filtered through a Celite plug and the catalyst is washed with water (2 x 10 ml). The combined τ -79- Λ r filtrate and washings were extracted with ether (2 x JO ml) and lyophilized to give a yellow powder which was passed over a C Cg BQHDAPAK (Waters Associates) column (4θg) was purified, eluting

O

with 10je's acetonitrile in water under pressure of 0.56 kg / cm.

Each 15 ml fraction was analyzed by high pressure liquid chromatography and fractions with an ultraviolet absorption at λ = 200 nm were collected and freeze dried to give 305 mg (43%) of the title compound as a pale yellow amorphous solid.

SMS (DMSO) S: 1.40 (3H, d, J «7.0Hz), 2.9-3.4 (3H, m), 3.98 (3H, s), 4.0-4.2 (2H, m), 4.23 (2H, broad s), 5.57 (2H, s) and 7.2-7.65 (7H, m). IS (KBr) γ max: 3400, 1760 and 1590 cm "1.

UV Xaax (H20): 299 nm (ε-8807).

Analysis: Calculated for 1 1 / ¾ ° 1 C 57.25; H 5.9b; N 9.5b; S 7.28. Found: C 56.55; H 5.70; N 9, b9; S 8.30.

See formula 1 ^ 7 of the formula sheet.

Example XIV

Preparation of 3- (2-methyl) -S-methylnyridin-3-yl-methananthio) -6a- [1- (R) -15 hydroxyethyl] -7-oxo-1-azabicyclo (3.2.0) -hent-2 -a-2-carboxylate.

See reaction scheme KEC of the formula sheet.

2-Methyl-3-mercaptomethylpyridine

The ester 1-2 was prepared according to the procedure described in J. Org. Chem; 21,800 (1956). To a cooled (0 °) suspended solution of 2.86 g of lithium aluminum hydride in 50 ml of dry tetrahydrofuran, a solution of 6.23 g (0.038 M) of ester Jj2 in 15 ml of tetrahydrofuran was added dropwise over a period of 15 minutes. The mixture was stirred at 0 ° for 60 minutes and then 50 ml of ethyl acetate was added thereto. The precipitate was filtered and washed with saturated aqueous ammonium chloride. The organic layer was dried with MgSQ 4, filtered and evaporated in vacuo to give 3.2 g (70% yield) of the hydroxymethylpyridine J3 as a yellow oil.

HMB (CDCl3) of compound ^ yy g: 2.46 (3H, S), 4.73 (2H, S), 5.1 (1H, wide), 7.2 (1H, dd, J * 8Hz), 7.8 <1H, dd, J = 8Hz, J * 1Hz) and 8.3 (1H, dd, J = 7Kz, J = 1Hz) and 8.3 (1H, dd J * 7Ez, J * 1Hz).

-80- *>

To a cooled (0 °) solution of U xnl thionyl chloride in 10 ml methylene chloride was added dropwise a solution of 3.2 g (0.026 M) of alcohol J3 in 10 ml methylene chloride over a period of 15 minutes under a nitrogen atmosphere. The cooling bath was removed and the reaction mixture stirred at room temperature for 3 hours. All soluble. agents were evaporated in vacuo to leave a compound -1U as a brown solid which was used in the next step without further purification. The crude brown solid was dissolved in 30 ml of absolute ethanol. Then 2.5 g (0.032 M) of thiourea was added and the mixture heated at 65-70 ° C for 18 hours. The mixture was cooled to room temperature. The precipitate was collected by filtration and washed with ethanol (20 ml) and ether (50 ml) to give 30 g of the isothiourea salt. This salt was dissolved in 10 ml of water and a solution of 60 mg (0.016 M) of sodium hydroxide in 10 ml of water was added under nitrogen. The reaction mixture was heated at 100 ° C for 2 minutes and then cooled to 0 °, adjusted to pH 6.0 with acetic acid and extracted with chloroform (2 x 35 ml). Evaporation of dried (MgSQ 2) chloroform gave 9 1 -1 mg {b6% yield) of the thiol -1-5 as a yellow oil.

NMB. (C0C13) of the thiol 15 / δ: 1.8 (1H, c), 2.60 (3H, S), 3.73 (2H, d, J-10 Hz), 7.13 (1H, dd, J 8 Hz) 7.57 (1H, dd, J * 8 Hz). -δη 8.43 (1H, dd, J-8Hz, 3Hz).

- 20 See reaction scheme LL of the formula sheet.

p-Hitrobenzyl-3- (2-methyl-1-pyridine- 3-v 1-methane hi o) -6ot- [1 - (R) -hydroxyethyl] - 7-oxo-1-azabicyclo (3,2,0 ) -hent-2-an-2-carboxylate

To a cooled (0 °) solution of 1.52 g (U, 37 mmol) of the keto intermediate in 5 ml of acetonitrile, 0.86 ml (U, 8Q mmol) of diisopropyl-25 ethylamine was added, followed by a solution 1.17 g (0.37 mmol) of diphenylchlorophosphate in 3 ml of acetonitrile under a nitrogen atmosphere.

The resulting solution was stirred at 0 ° C for 30 minutes to give p-nitrobenzyl-3- (diphenylphosphoryloxy) -6a- [1 - (R) -hydroxyethyl] -7-èxo-1-azabicyclo (3 2.0) hept-2-an-2-carboxylate. To this solution, a solution of 0.86 ml (U, 80 mmol) of diisopropylethylamine in 2 ml of acetonitrile was added, followed by a solution of 9 ^ 0 mg (6.76 mmol) of the thiol J5 in 2 ml acetonitrile. The reaction mixture was stirred at 0 ° C for 60 minutes. The precipitate was collected by filtration and washed with ether (30 ml) 1-81- to yield 1.12 g (55% yield) of the title compound as a pale yellow solid. Melting point 186-188 ° C (decomposition).

2MR (DMS0-d6) 5: 1.20 (3H, d, J «7Hz), 2.60 (32, S), 3.40 (m, 2H), 4.16 (m, 2H), 4, 32 (2H, S), 5.16 (1H, d, J = 5Hz), 5.44 (2H, q, J = 14Hz), 7.32 (2H, a), 7.8 (22, d, J = 8Hz) 8.36 (2H, d, J «82s) and 8.48 (1H, dd, J» 5.5Hz, 1.5Hz). IR (ΚΒΓ) γιηax: 3500, 1770 and 1750 cm "1.

Analysis: Calculated for ^ 23 ^ 24 ^ 3 ^ 6 ^: ^ 58.83; H 4.94; 2 8.94; S 6.83.

5 Found: C 58.63; H 4.99; 2 9.06; S 6.58.

See reaction scheme MM of the formula sheet.

3- (2-methyl-2-methylpyridin-3-yl-methananthio) -6a- [1 - (R) -hydroxyethyl] -7-oxo-1-azabioyclo (3,2,0) -he ~ pt -2-an-2-carboxylate

To a solution of 697 mg (1.19 mmol) of compound 16 in 100 ml of methylene chloride was added dropwise at 10 ° C 0.5 ml (6.18 mmol) of methyl fluorosulfonate over a period of 10 minutes.

The mixture was stirred at room temperature for 2.5 hours. The precipitate was collected by filtration and washed with 30 ml of methylene chloride to give 777 mg (90%) of the quaternized pyridine J7. as a yellow solid.

NMR (CDCl 3) of Compound 3: $ 1.20 (3H, J 7Hz), 2.82 (3H, s), 4.36 (32, s), 4 ?16 (2H, m), 4, 60 (22, s), 5.2Q (1H, m), 5.42 (2H, q, J-14Hz), 7.80 (22, d, J = 8Hz), 8.04 (12, dd, J »7Hz, 6.5Ez), 8.32 (22, d, J« 8Hz) 8.64 (1H, d, J-7.5 Hz) and 9.08 (1H, d, J = 7.5 Hz). IR (KEr) vmax: 3500 and 1765 ca "1.

Analysis: calculated for C 48.91; H 4.55; 2 7.23; S 11.04.

Found: C 49.39; H 3.97; 2 7.20; S 10.98.

To a solution of 1.10 g (1.88 mmol) of compound _17 in 80 ml of tetrahydrofuran and 80 ml of ether was added 80 ml of an intermediate solution with a pH of 7.0, followed by 800 mg of 10 # palladium-on-carbon . The mixture was hydrogenated on the Parr shaker at a pressure of 2.1 kg / cm for 40 minutes. The mixture was filtered through a Celite plug 25 and the catalyst washed with water (2 x 10 ml). The combined filtrate and washings were extracted with ether (2 x 100 ml) and freeze-dried to give a yellow powder, which was purified by 82 -82 HP-20 column chromatography, eluting with water, followed by 5 µl. aceto-nitrile in water. Each 15 ml fraction was analyzed by high pressure liquid chromatography and the fractions with an ultraviolet absorbance at = 300 nm were collected and lyophilized to yield 614 mg • may 5 (42% yield) of the title product as a pale yellow powder.

NMR (D20) δ: 1.28 (d, 3H, J «7Hz), 2.86 (3H, s), 3f20 (2H, dd, J = 10Hz, 3.5Hz), 3.42 (1H, dd , J »5.4Hz, 3.5Hz), 4.20 (3H, a), 4.32 (3H, s), 4.35 (2H, S), 9.88. (1H, dd, J = 7.2 Hz, 6.5 µl), 8 ^ 5ClH, d, J * 8 Hz) and ~. 8.70 (1H, d, J = 8Hz). 1H (KBr) ymax: 3400, 1760, et al. 1590 csf. UV Xmax (H20): 298 nm (ε-8391).

Analysis: Calculated for C 16 H 15 Hg O: C 55.73; Η 5.46; E 7.65; S 8.74. Found: C 55.50; H 6.05; N 7.74; S 8.68.

Example XV

Preparation of 3- [4- (N, 1-dimethyl-1,2,3-triazolium) methylthio-6α-ri- (R) -hydroxyethyl] -7-oxo-1-azabi cyclo (3,2,0 hept-2-en-2-carboxylate See formula 148 of the formula sheet.

A. Preparation of Isomer A. See reaction scheme M of the formula sheet.

Methyl trifluoromethanesulfonate (0.58 nl, 5.16 mmol) was added dropwise to an ice-cooled, stirred solution of 4- (methanethiol acetate) -1-methyl-1,2,3-triazole (590 mg, 3.52 mmol) ) in dry methylene chloride (2 ml) under nitrogen. After half an hour the bath was removed and after 1 hour the solvent was removed with an aspirator. The residual oil was dissolved in a few millimeters of water and this solution was cooled in an ice-bath. A cold solution of sodium hydroxide (305 mg, 7.59 mmol) in a few millimeters of water was then added and the reaction stirred for 3/4 hours. The solution of solid sodium dihydrogen phosphate monohydrate. Then, 14 ml of this solution (about 1.9 mmol of the triazonium thiol) was added to an ice-cooled, stirred solution of the enol phosphate (1.0 g, 1.72 mmol) in tetrahydrofuran (THE) (10 ml). It was stirred for 3/4 hours (with some crystalline material, presumably HagHPO4, precipitated over the course of this reaction). The suspension was transferred to a pressure flask with the addition of some THF (20 ml) and water (20 ml). Ether (30 ml) and 10% palladium-on-30 charcoal (1.0 g) were added and the mixture was hydrogenated (40 psi) for 1 µl. The organic phase was separated and washed with water -83 'C' * (2x5 ml). The combined aqueous phases were filtered and the filtrate was concentrated under high vacuum (ca 0.5 nm, 1.5 hours). The yellow solution was then chromatographed (medium pressure reverse phase colam, 35 x 90 mm, HgO as eluent) and, after lyophilization, 5 395 mg of the carbapenem was obtained, which was slightly contaminated with some inorganic material. It was purified by HPLC (10 x 300 mm Waters Micro bondapak C-18 column, multiple injections, 100 as eluent) to give 310 mg (51%) of isomer A as a tan powder: HNMR (D20) <5: 1.23 (3H, d, J * 6.4 Hz), 3.10 (2H, d, J = 9.1 Hz), 3.24 (1H, q, J = 2.7, 6 .1Hz), 4 * 03r 4.71 (10H, m), 8.46 (1H, s); IR (nujol) 1760 cm S uv (phosphate buffer, pH 7.4, M = 0, Q5) ^ mav: 296 (ε = * 7,500).

10 B. Preparation of isomer B and isomer C.

See reaction scheme 00 of the formula sheet.

Methyl trifluoromethanesulfonate (1.60 mL, 14.0 mmol) was added dropwise under nitrogen to an ice-cooled solution of 4- (methanethiol acetate) -2-methyl-1,2,3-triazole (1.20 g, 7.02 mmol ) in dry methylene-15 chloride (6 ml). The mixture was allowed to warm to room temperature and then stirred for 16 hours. Then additional methyl trifluoromethanesulfonate (0.40 ml, 3.56 mmol) was added and after 3 hours at room temperature, the solvent was removed with an aspirator.

The residue oil was triturated with ether and the resulting gum dissolved in water (5 ml). This was cooled in an ice bath and a solution of sodium hydroxide (844mg, 21.1mmol) in water (5ml) was added. After stirring for 3/4 hours, this solution was diluted with water to 60 ml and the pi was adjusted by adding solid potassium dihydrogen phosphate. Then, 40 ml of this solution (approx. 4.7 mmol of a mixture of isomeric tri-azolium thiols) was added to an ice-cooled, stirred solution of the enol phosphate (2.00 g, 3.45 mmol) in THF (60 ml) . This mixture was stirred in the ice bath for half an hour, after which it was transferred to a pressure flask containing a suspension of 100% palladium on charcoal (2.00 g) and ether (60 ml). The mixture was hydrogenated (2.8 kg / cm) for one hour. The organic phase was separated and washed with water (2 x 10 ml). The combined aqueous phases were filtered and the filtrate was concentrated under high vacuum (ca 0.5 nm, 1.5 hours). The remaining solution was then chromatographed (medium pressure inverted Λ -Qk phase column, x 130 mm, H 2 O as eluent) and, after lyophilization, 595 mg of a mixture of isomeric carbapenem compounds contaminated with a little inorganic material was obtained . These were separated and purified by HPLC (10 x 300 mm Waters Microbondapack C-18, column, multiple 5-fold injections, HgO as eluent) to give in order of elution: isomer B; 153 mg (13/0; ^ INMR (d20) δ: 1.23 (3H, d, J = 6.4 Hz), 3.12 (2H, q, Jl. 4, 8.9 Hz), '3.39 (1H, q, J-2.7 , 6.0 Hz), 4.07-4.68 (10H, m), 8.19 (1H, s); IR (nujol) 1755 cm-1; UV (-phosphate buffer, pH = 7.4, M = 0.05) λ: 296 nm ( £ = 6,700) and isomer C; '284 mg (24%)? 1HNMR (D20) 6: 1.23 (3H, d, H = 6.4 Hz), 3.15 (2H, q, J-3.7, 9.0 Hz), 3.37 (1H, q, J = 2.6, 6.0 Hz), 3.95-4.65 (10H, m), 8.62 (1H, s); IR (nujol) 1750 cm -1, uv Γ '' phosphate buffer, pH 7.4, M = 0.05) 298 nm (ε = 7,600).

Example XVI

(5R.6S) 6- (1R-hydroxyethyl) -3- (2-methyl-1,2,3-thiadiazolium-1-ylmethylthio) -10 7-oxo-1-azabicyclo (3,2,0) -hept -2-an-2-carboxylate - *

See formula 1 ^ + 9 of the formula sheet.

A. Ethyl 1,2,3-thiadiazol-1-ylcarboxylate See reaction scheme PP of the formula sheet.

A solution of ethyl α-N-carbethoxyhydrazone propionate (31.2 g, 0.15 µmmol) in thionyl chloride (80 ml) was stirred at 23 ° C for 3 hours and then heated at 70 ° C for 20 minutes. Thionyl chloride was evaporated and the residue triturated in hexane (1 x 30 ml). The red solid was dissolved in dichloromethane (150ml) and the solution washed with saturated sodium bicarbonate solution and water. After drying on 20 Na 2 SO 2, the solution was concentrated until the compound crystallized. After standing at 23 ° C for some time, the crystals were filtered; 16.8 g, melting point 86 ° C, 69%. The filtrate was concentrated and purified by chromatography on a silica gel column eluting with dichloromethane to give 3.17 g> mp 86 ° C.

r ·; "" 25 -85-

a

/, 13%, ir (KBr) v: 1720 (ester) cm -1: 1Hmr (CDCl,) max - 5: 1.52 (3H, t, J = 7.1 Hz, CE ^ CE20), 4, 57 (2H, g, J = 7.1 Hz, CH 3 CH 2 O), 9.47 (IE, s, H of thiadiazole).

- ^ .D. Hurd e «. R.I. Mori, J. Am. Chem. 5oc., 77, 5359 (1955).

B. 1,2,3-thiadiazole-1-ylmethanol

See reaction scheme QQ of the formula sheet.

To a suspension of ethyl 1,2,3-thiadiazole-1-ylcarboxylate 5 (18.35, 0.116 mol) in ether (1 * 00 ml) was aliquoted lithium aluminum hydride (2, 1, 00 ml) in portions over a period of 1 hour. 1 * 7 g, 0.065 mol) was added.

The reaction mixture was stirred at 23 ° C for 7 hours and treated with lithium aluminum hydride (2.1 * 7 g, 0.065 ml). Stirring was continued for 2 hours * before water (7 ml), 15% sodium 10 hydroxide solution (7 ml) and water (21 ml) were added successively. After stirring for 15 minutes, the ether solution was decanted and the gum extracted with ether (5 X 100 ml). The ether extracts were combined, dried (MgSQ4) and concentrated (5 µg). The crude material was purified on a silica gel column (120 g, 1 * x 16 cm), with ether as eluent, and 1.3 g (7%) of ethyl 1,2,3-thiadiazole-1 was obtained. * -ylcarboxylate and 2.1 * 5 g (18 lb) of 1,2,3-thiadiazole-1 * -ylmethanol; . ir (film) v: 3380 (OH) cm "1? ^ nr (CDC1,) 6: 2.31 max o (1H, s, OH), 5.22 (2H, s, CH2O), 8.50 ( 1H, s, H of thiadiazole J.

AS.I. Ramsby, S.O. Ogren, S.B. Ross and N.E. Stjernstrom,

Acta Pharm. Succica., 10, 285-96 (1973)? C.A., 79, 137052W (1973).

C. 1,2,3-thiadiazol-1-yl-ethanol mpf / h sulfonate See reaction scheme HE of the formula sheet.

A solution of 1,2,3-thiadiazole-1 * -ylmethanol (0.75 g, 6.5 mmol) in dichloromethane (20 ml) was cooled to 5 ° C under a nitrogen atmosphere and with triethylamine (1.018 ml, 7 > 3 mmol) and methanesulfonyl chloride (0.565 ml, 7.3 mmol). After 15 minutes, the ice bath was removed and the reaction mixture was stirred for 2 hours. The solution was washed with 1N saline-25 acid solution (2x2ml) and water, dried (MgSO4 + MgO) and L-1.

V

a

-86- concentrated. The residue was purified by chromatography (silica gel 1.5 x 21 cm) with ether as eluent to give 0.90 S (71 $) 1,2,3-thia-diazol-1 + -yl with methanol methanesulfate;

ir (film) v: 1350 (SO.) cm "1, 1172 (SO.) cm" 1; 1Hmr (CDC1,) 6: max 2 - J

3/09 (3Ξ, s, CH 3), 5.75 (2H, s, CH 2), 8.72 (1H, s, H of thiadiazole); uv (CH.C1.) λ ^: 251 (ε1990).

2 2 max 5 Analysis: Calculated for C 8 H 15 N 3 S: C 2, 73; H 3.11; N 1U, U2; S 33.02.

Found: C 21+, 78; H 3.09; N 1U, 65; S 31.9 µ and 0.13 g, (19%) of di- (1,2,3-thiadiazol-4-ylmethyl) ether; ir (film) v: 1272, 1242, 1200, 986, 805, max 728 cm ”; Tlnr (CDCl3) <5: 5.16 (s, 4H, CH2), 8.42 (s, 2H, H's of thiadiazole) D. U-aetylthiomethyl-1,2,3-thi adiazole See reaction scheme SS of the formula sheet.

10 To a solution of 1,2,3-thiadiazole-U-ylmethanolmethanesulfonate (0.90 g, ht6 mmol) in tetrahydrofuran (9 a1), an aqueous solution (2 ml) of sodium thiol acetate [prepared from thiol acetic acid (0.38 ml 5.3 mmol) and sodium bicarbonate (0.5 g, 5.3 mmol)]. The resulting mixture was stirred at 23 ° C for 1 hour and diluted with ether (75 nil).

The organic solution was washed with water (3x3 ml), dried (MgSO4) and concentrated. The crude mixture was purified by chromatography (silica gel column: 1.1 + x 19 cm) with 50% ether in hexane as eluent to give 0.60 g (75 $); . ir (film) v: 1675 (C = 0) cm -1; ^ Tmr (CDCl 3) 6: 2.37 (3H, s, CH-),

HlcLX J j 4.58 (2H, s, CH2) / 8.44 (1H, s, H of 'thiadiazole';

Analysis: Calculated for C 3 ^ 7 ^; H 3, 7; N 16.08; S 36.80.

Found: C 3M8; Ξ 3.83; II 16.28; S 36.80.

E. b-acetylthi omethyl-2-methyl-1,2,3-thiadiazolium trifluoromethanesulfonate and U-acetylthiomethyl-3-methyl 1-1,2,3-thiadiazolium trifluoromethanesulfonate 25 See reaction scheme TT of the formula sheet + - 87- 4 /

To a solution of 4-acetylthiomethyl-1,2,3-thiadiazooi (0.60g, 3.5mmol) in a mixture of ether (4ml) and dichloromethane (0.5ml) were added some crystals of the title compounds and trifluoromethane sulfonate (0.407 ml, 3.6 mmol) was added over a 5 minute period.

The reaction mixture was stirred at 23 ° C under a nitrogen atmosphere for 6 hours. The white solid consisting of a mixture of the two title compounds was filtered and washed with ether, 1/05 g, 90%; ir (KBr) v:: 1675 (C = 0) cm ½Inr (DMSO, d-6) δ: 2.43 (3H, s, CH3COS) / 3.33, CH3 on N-3), 4.57 (s, C 1 to N-2), 4.66 (2H, s, CH 2), 9.55 (H to thiadiazolium N-2), 9.66 (Rooster thiadiazolium N-3).

Analysis: Calculated for C 20.27; H 2.38; N 9.45; S 32.46.

Found: C, 24.6L; H 2.57; N 8.47; S 28.21.

F. 4-mer cant omethyl-2-methyl-1,2,3-thi adiazolium trifluoromethanesulfonate and 4-mercaptamethyl-3-methyl-1,2,3-thiadiazolium trifluoromethanesulfonate

See reaction scheme üü of the formula sheet.

A solution of a mixture of 4-acetylthiomethyl-2-methyl-1,2,3-thiadiazolium trifluoromethanesulfonate and 4-acetylthiomethyl-3-methyl-1,2,3-thiadiazolium trifluoromethanesulfonate (1.05 g, 3.1 mmol) and 6N hydrochloric acid (10ml) was heated under a nitrogen atmosphere at 65 ° C for 1.75 hours. The solvent was evaporated under reduced pressure to give 0.91 g of a yellow syrup. This compound was used in the next step without purification.

G. (5R, 6s) 6- (1R-hydroxyethyl) -3- (2-methyl-1,2,3-thi-azolium-4-ylmethyl-thio) -7-oxo-1-azabi cyclo (3, 2.0) he-pt-2-an-2-carboxylate

See reaction scheme W of the formula sheet.

A cold (5 ° C) solution of (5E, 6S.) Paranitrobenzyl 6- (1R-hydroxy- - ethyl) -3- (diphenylphosphono) -7-oxo-1-azabicyclo (3,2,0) - hept-2-en-2-carboxylate (1.7 g, 2.92 mmol) in tetrahydrofuran (10 ml) was treated with a solution of a crude mixture of 4-mercaptomethyl-2-methyl-1,2,3- thiadiazolium trifluoromethanesulfonate and 4-mercaptomethyl-3-methyl-1,2,3-thiadiazolium-30 trifluoromethanesulfonate (0.9 g) in a mixture of phosphate buffer (pH 7.2, 0.3 M, 15 ml) and tetrahydrofuran ( 5 ml). The reaction mixture was stirred for 1 hour and the pH kept at 7.2 with 2S sodium hydroxide solution.

> -88- u

V

Stirring was continued for an additional hour before adding ether (50 ml) and 10% palladium on charcoal (1 g). The resulting mixture was hydrogenated for 2 hours under pressure of 3.15 kg / cm @ 2 at 23 ° C and filtered through a Celite plug. The organic phase was separated, 5 with ether (50 ml) and phosphate buffer (pH 7). .2, 0.3M, 20 ml) and hydrogenated under pressure of 3.5 kg / cm for 2 hours (2 g of 10 $ palladium on charcoal) for 2 hours. (from the first and second hydrogenolysis), washed with ether and purified by chromatography on PrekPak 500-C / 18 with water as an eluent to obtain 0.22 g of crude material.

This was purified again by HPLC with water as the eluent to yield 0.0 ^ 0 g (k%) of the title compound after lyophilization. ir '(KBr) v: 3400 (br, OH), 1745 (C = 0 or max ^.

6-lactam), 1580 (carboxylate.) Cm -1; * Έιπγ (D20) $: 1/22 (3H, d, J J 6.3 Hz, CT [3CHOH), 3.04, 3.05, 3, 16 (2H, m, H-4), 3.38 (1H, dd, J = 2.8 Hz, J = 6.0 Hz, H-6), 3.9-4.6 (2H, m, H-5, CH 3 CHOH), 4.51, 4.53 (2Ms ", SCH 2), 4.61 (s, N + CH 3); uv (H, 0): 224 (ε4345), 262 (ε4980), 296 (ε6885), [α] 33 18β (c 0.18, Η20), * Τ1 / 2 = 9.8 h

(measured at a concentration of 10 µM in phosphate buffer pH 7, U at 36.8 ° C). Example XVII

Potassium 3- [5- (1-carboxylate-methyl-3-methyl-1,2,3-triazolium) -methananthio] -6a- [1- (R) -hydroxyethyl] -7-oxo-1-azabicyclo (3, 2.0) The> t-2-en-2-carboxylate See formula 150 of the formula sheet.

See reaction scheme W of the formula sheet.

Lithium aluminum hydride (2.83 g, 70 mmol) was added in small amounts to a stirred suspension of 1-methyl-1,2,3-triazole-k-carboxylic acid (9.00 g, 70.9 mmol) in dry THF (200 ml). The mixture was stirred at room temperature for 15 hours, after which a 20% aqueous solution of sodium hydroxide (20ml) was carefully added in portions of about 1ml. The resulting granular suspension was filtered and the solid washed with additional THF (5 x 75 ml). The combined THF solutions were dried (MgSO4) and the solvent removed. The yellow oil residue was flash chromatographed on a silica gel column (90 x 35 mm) (100 ml parts hexane, mixtures of ethyl acetate-hexane (1: 1) and (1: 3) and finally ethyl acetate-methanol (9: 1) as eluent). This gave U-hydroxymethyl-1-me-30-methyl-1,2,3-triazole (3.18 g, U0 $) as a colorless oil 4 -89-t, * HNMR (CDC1-) 5 4.07 (3H, s), 4.73 (2H, d), 7.52 (1H, s); IR (net 3320 cm "".

Methanesulfonyl chloride (3.82ml, 49.6mmol) was added dropwise to an ice-cooled, stirred solution of the alcohol (4.67ml, 4l, 3mmol) and triethylamine (7.47ml, 53.7mmol) in methylene chloride 5 (20 ml). After half an hour, the solvent was removed and the residual solid was taken up in acetonitrile (30 ml). Potassium thiol acetate (7.06 g, 62.0 mmol) was added and the suspension stirred at room temperature for 3 hours. A further amount of potassium thiol acetate (3.0 g, 26.3 mmol) was added and the suspension stirred for an additional 16 hours. The dark-10 colored suspension was then concentrated and water (10 ml) was added. This mixture was extracted with methylene chloride (5 x 1 / ml).

The combined extracts were dried (MgSO4) and the solvent removed. The residue oil was flash chromatographed on a silica gel column (90 x 36 mm) [hexane followed by a mixture of hexane-ethyl acetate (1: 1) as eluent]. This gave 4- (methanethiol acetate) -1-methyl-1,2,3-triazole (5.95 g, 84 $) as a light pink colored solid. (CDCl 3) δ 2 * 40 (3H, s), 4.10 (3H, s), 4.20 (2H, s), 7.53 (1H, s); IR (nujol mouth) 1675 cm- *.

C. Pederson, Acta Chem. Scand., 1959, J3., 888.

A solution of the triazole (1.00g, 5.85mmol) and ethyl bromoacetate (1.48ml, 13.3mmol) in dry acetonitrile (10ml) was heated at 6 ° under nitrogen for 90 hours. The solvent was removed and the residue oil triturated with ether (4 x 25 mL), whereby 1-methyl-3- (ethyl-carboxymethyl) -4-methanethiol acetate-1,2,3-triazolium bromide as a brown-like gum was obtained which was used directly.

A cold solution of KOH (0.66 g, 12 mmol) in water (5 ml) was added to an ice-cooled, stirred solution of the triazolium bromide in water (20 ml). After 20 minutes, it was diluted to 35 ml and enough solid potassium dihydrogen phosphate added to adjust the pH of this solution to 8.0. The mixture was then added to a stirred, ice-cooled solution of the final phosphate in THF (35 ml). After half an hour

a

V.

90 -90- + this mixture was transferred to a pressure flask containing ether (35 ml) and 10% palladium on charcoal (1.5 g). The mixture was hydrogenated at 2.8 kg / cm for 55 minutes. The organic phase was separated and washed with water (2x5 ml). The combined aqueous phases were filtered and the filtrate concentrated under high vacuum. The residue material was chromatographed. over an inverted phase column (35 x 120 mm) with water as the eluent. Freeze drying of the carbapenem compound containing fractions gave 1.20 g of a green colored solid.

This was re-chromatographed on a Waters Prep. 500 HPLC 10 (PrepPak-500 / Cg column) with 2% acetonitrile water as eluent. The fractions containing the carbapenem were combined and lyophilized. This material was again chromatographed by HPLC (10 x 300 nm Waters MicroBONDAPAK C-18 column) with water as an eluent to give, after lyophilization, the pure title compound (190 mg, 17%) as a pale yellow solid:

. NMR

(D20) δ 1.24 (3H, d, J = 6.4 Hz), 3.07 (2H, d, J = 9 Hz), 3.38 (1H, q, J = 2.7, 6, 0 Hz), 4.02-4.30 (3H, m), 4.29 (3H, s), 5.23 (2H, s), 8.52 (1H, s); IR (nujol mull) 1750 cm -1, UV-phosphophosphate buffer, pH 7.4) 296 nm (ε = 7.520).

Example XVIII

Potassium- 3- [fr- (1-carboxylatomethyl-3-methyl-1,2,3-triazolium) -methanethiol] -6α- Γ 1- (R) -hydroxyethyl] -7-oxo-1-azabicyclo (3,2,0) hept-2-en-2-carboxylate 20 See formula 151 of the formula sheet.

See reactions scheme XX of the formula sheet.

A mixture of ethyl azido acetate (30.0 g, 0.23 mol) and propiol acid (14.3 ml, "0.23 mol) in toluene (75 ml) was stirred at room temperature. The reaction continued for 1.5 hours moderately exothermic, after which it rapidly became vigorously exothermic and cooling with an ice bath was necessary. After this exothermic phase had passed, the reaction was heated to reflux temperature for 0.5 hours. After being cooled in an ice bath, the crystal -talline material collected by filtration and washed with a little toluene The crude material obtained (33.3 g, 72%) consisted of a single 30 isomer 1

. [“TINMR

(DMSO-dg) δ 1.20 (3H, t, J = 7 Hz), 4.15 (2H, q, J = 7 Hz), 5.42 (2H, s), 8.67 (1H, 3 )],. '

H

-91- presumably 1- (ethylcarboxymethyl) -1,2,3-triazole-1i-carboxylic acid by analogy with earlier work1.

A solution of the carboxylic acid (5.00g, 25.1mmol) and triethylamine (3.68ml, 26ummol) in dry methylene chloride (50ml) was added to an ice-cooled, stirred solution of ethyl chloroformate ( 2.252 ml, .26, k mmol) in dry methylene chloride (50 ml). The purple colored solution was stirred for half an hour, after which it was washed with water (10 ml), dried {MjgSO2) and the solvent removed. The crude mixed anhydride was dissolved in YHF (50ml) and slowly added to an ice-cooled suspension of sodium borohydride (0.72g, 18.9mmol) in THF (50ml). After stirring for half an hour, additional sodium borohydride (0.30 g, 7.9 mmol) was added and the reaction mixture was left in an ice bath for 1 hour. Water (5 ml) was then added and after 10 minutes this was followed by 10 # aqueous HCl (3 ml). After the gas evolution had stopped, solid potassium carbonate (2 g) was added with stirring.

The organic phase was then removed and the remaining white paste was extracted with additional THF. The combined organic phases were dried (MgSO4) and the solvent was removed. Flash column chromatography over silica gel, eluting with hexane, mixtures of ethyl acetate-hexane and finally ethyl acetate, gave 1- (ethylcarboxymetyhyl) -if-hydroxymethyl-1,2,3-triazole (2, Qk g, hk %) as a crystalline solid: ^ NMR (CDCl3) δ 1.28 (3H, t, J = 7 Hz), 4.23 (2H, q, J »7 Hz), 4.75 (2Ξ, s) , 4.85 (2H, s), 7.73 (1H, s).

Diisopropylazodicarboxylate (h, 11ml, 20.8mmol) was added dropwise under nitrogen to an ice-cooled solution of triphenylphosphine (5Λ7g, 20.8mmol) in dry THF (100ml). After half an hour, an ice-cooled solution of the alcohol (1.93 g, 10 mmol) and thiol acetic acid (1SJ + 9 mL, 20.8 mmol) in dr-og THF (50 mL) was added to this mixture under nitrogen. It was left in the ice bath for 2 hours and then at room temperature for another 12 hours, after which the solvent was removed.

The reaction mixture was flash chromatographed on silica gel (U0g; eluting with 100ml parts hexane, 5 #, 10%, 15 #, 50 # ethyl acetate-1C. Pederson, Acta. Chem. Scand; 1959, 13, 888.

. - ^

F

-92-% Ψ

YOU

hexane). Fractions containing the thiol acetate were combined and re-chromatographed on silica gel (60 g) [eluting with 200 ml parts: hexane, 5%, 10%, 15%, 20% ethyl acetate-hexane and 22.5, 25, 27, 5 ··· 35% ethyl acetate-hexane). This gave 1.24 g (49%) 1- (ethylcarboxymethyl) -5-4-methanethiol acetate-1,2,3-triazole as a crystalline solid [^ iNMR δ 1.28 (3H, t, J * 7 Hz) , 2.37 (3H, s), 3.87 (2H, s), 3.90 (2H, q, J = 7 Hz), 5.12 (2H, s), 7.63 (1H, s) ; IR (nujol muil), 1735, 1780 απ * * 1] and a further t, 40 g of material contaminated with triphenylphosphine oxide.

Methyl trifluoromethanesulfonate (0.51ml, 4.53mmol) was added dropwise to an ice-cooled stirred solution of the triazole (1.00g, 4.12mmol) in dry methylene chloride (5ml). The bath was removed after half an hour and after a further 0.5 hours, the solvent was removed with an aspirator vacuum. This gave a white solid, which was suspended in water (15 ml) and the stirred mixture was cooled in an ice bath. A solution of Ξ0Ξ (0.16g, 12.4mmol) in water (5ml) was added and the reaction stirred for 1 hour.

It was then diluted to 30 ml with water and solid potassium dihydrogen phosphate added to adjust the pH to 8.0. Part of this solution (22 ml, ca 3.0 mmol) of the thiol carboxylate) was added to an ice-cooled, stirred solution of the enol phosphate (1.60 g, 2.76 mmol) in THF (30 ml). After half an hour, the reaction was carried out under high vacuum to remove the THF. The yellow solution was then chromatographed on an inverted phase column (35 x 120 ml) eluting with water (300 ml), followed by 100 ml aliquots of 5, 10, 15 ... 30% acetonitrile water. Freeze-drying of the desired fraction gave the p-nitrobenzyl-25 ester as a yellow solid (39 mg). This was transferred to a pressure flask containing ether (25 ml), THF (25 ml) and phosphate buffer (25 ml, prepared by dissolving potassium dihydrogen phosphate (1.36 g, 0.01 mol) in water (100 ml) and adjusting the pH to 7.4 by adding 45 # of aqueous KOH] and 10% palladium on charcoal (900 mg). The hydrogenation was carried out at 2.8 kg / h for 30 hours. cm after which the organic phase was separated and washed with water (2x5 ml) The combined aqueous phases were filtered and concentrated under high vacuum The residue solution was chromatographed on an inverted phase column (35 x 120 mm) under elue -93- 4 ring with water The fractions containing the carbapenem were combined and lyophilized to obtain 1.21 g of a slightly greenish solid, which was purified by HPLC (10 x 300 mm Waters Micro-bondapack C-19- holom, H 2 O as eluent and the pure title product was obtained, 10 mg (^ 1 / *): (D20) δ λ> 23 (3H 'd' J = S, 4 Hz), 3.11 ( 2H, d, Js9 Hz) 3.37 (IE, q, J = 3.0, 6.1 Hz), 4.02 (7H, m),

5.18 (2H, s), 8.53 (1H, s): IR (nujol muil) 1750 cm OV

(phosphate buffer, oK 7.4) λ 205 nm (ε = 7.810).

* * max

Example XIX

3- Γ5- (1% U-dimethyl-1,2, U-triazolium) methaahthio1 -6a- [1 - (R) -hydroxyethyl] -7-οχο — 1-azabieyclo (3,2,0] hent-2 -a-2-carboxylate 10 See formula 152 of the formula sheet.

A. 1-methyl-5-methanethiol acetate-1,2 Λ-triazole

See reaction scheme Yï of the formula sheet.

Methanesulfonyl chloride (0.06ml, 6.0mmol) was added dropwise to an ice-cooled, stirred solution of 1-methyl-5-hydroxymethyl-1,2, U-15 triazole * 5 & 5mg, 5.0mmol) and triethylamine (0 , 91 ml, 6.5 mmol) in methylene chloride (5 ml).

* R.G. Jones and C. Ainsworth, J. Amer. Chem. Soc., 1955, 77-1938.

After 20 minutes, additional triethylamine (1.05ml, 7.5mmol) followed by thiolacetic acid (0.53ml, 7.5mmol) was added and stirring continued for mi 5mins. The reaction mixture was then diluted with methylene chloride and washed with water. The water phase was extracted with methylene chloride (3x5 ml) and the combined organic phases were dried (MgSO4), after which the solvent was removed. Column chromatography on silica gel provided pure 1-methyl-5-methanethiol acetate-1,2, Utiazoo 25 (570 mg) as a yellow oil [additionally re-chromatographing an impure fraction (200 mg) (preparative TLC, silica gel) of a further 100 mg of pure material (total yield: 85%)]

... .... . ^ JNMR

i (CDCl 3) <5 2.38 (3H, s), 3.90 (3H, s), 4.25 (3h7 s), 7.80 (1H, s).

-9b-. Λ> Β. 3- [5- (11'-dimethyl-1,2, U-triazolium) -methananthio] -6α-Γ1 - (R) -hydroxy-ethyl] -7-0X0-1 -azabicyclo (3,2,0) The ~ pt-2-en-2-carboxylate See reaction scheme XX of the formula sheet.

Methyl trifluoromethanesulfonate (1.20ml, 10.7mmol) was added dropwise to an ice-cooled solution of 1-methyl-5-methanethiplacetate - 1,2,6-triazole (730mg, b2r [mmol) in methylene chloride (7 ml) added.

The reaction mixture was allowed to warm slowly to room temperature for 3 hours, after which it was concentrated. The residue oil was triturated with ether to yield crude 1,1-dimethyl-5-methanethiol olacetate-1,2, U-10 triazolium trifluomethanesulfonate (1.1 * 6 g) which was used directly.

A solution of sodium hydroxide (512mg, 12.8mmol) in water (5ml) was added to an ice-cooled solution of the triazolium salt (1.1 * 5g, 1 *, 35mmol) in water (5ml). After h-5 minutes this was diluted 15 to 25 ml with water and the pH adjusted to 7.6 with solid potassium dihydrogen phosphate. This solution was then added to an ice-cooled, stirred solution of the enol phosphate (2.00 g, 3.1 * 5 mmol) in THF (25 ml).

After 30 minutes, the reaction mixture was transferred to a pressure flask containing ether (1 * 0 ml) and 10% palladium on charcoal (2.0 g). This was hydrogenated (3.15 kg / cm) for 1.25 hours. The reaction mixture was then diluted with ether (25 ml) and filtered. The organic phase was separated and washed with water (2 x 5 ml). The combined water phases were washed with ether (3 x 25 ml) and concentrated under high vacuum. Column chromatography (reverse phase, 1 + 5 x 130 mm, water as eluent) followed by lyophilization of the carbapenem-containing fractions gave 650 mg of crude material. This was chromatographed again to yield the pure title product (1 * 50 mg, 39%) · "(D 2 O) δ 1.24 (3H, d, J = 6.4 Hz), 3.19 (2H, q, J = 2.6, 9.2 Hz), 3.45 (1H, q, J = 2.8, 6.0 Hz), 3.91 (3H, s), 4.06 (3H, s), 4 .08-4.36 (2H, m), 4.54 (2H, d, J = 2.8 Hz), 8.71 (1H, s); IR (nujol mouth) 1755 cm; UV '(phosphate buffer, pH 7.4) 294 nm (ε = 8.202); T ^ y2 '. (phosphate buffer, pH 7.4, M = 0.067, T = 37 ° C) 9.1 h.

i '-95- <- /

Example XX

(11, R.5R, 6s) 3 - ΓC1,3-dimethyl-5-tetrazolium) -methylthiol-6- (1-hydroxy-ethyl) -T-oxo-1-azabicyclo (3,2,0) pt-2-en-2-carboxylate See formula 153 of the formula sheet.

5 A. 5-carbethoxy-2-methyltetrazole and 5-carbethoxy-1-methyltetrazole

See reaction scheme A of the formula sheet.

1a. Methylation of diazamethane

A solution of 5-carbethoxytetrazole (19 7 g, 0.064 mmol) in 2 ethyl ether 1D. Moderhack, Chem. Ber, 108, 887 (1975)% using a mixture of ethanol and ether gave the same ratio of isamers.

(80 ml) was cooled to 0 ° C and treated dropwise (15 minutes) with a solution of diazamethane. (3 g, 0.71 mmol) in ether (200 ml). The light-yellow solution was stirred for 30 minutes and the excess diazamethane destroyed by addition of acetic acid (1 ml). After evaporation of. the solvent and distillation of the residue, a clear oil was obtained: boiling point 95-100 ° C / 0.5 torr; »6 g g, (9 * 6 #) ^ -NMR indicated a mixture of 1-methyl and 2-methyl isamers in a ratio of 6: k. Separation of the two isamers could be performed neither by distillation nor by EPLC: ir (film): 1740 cm 1 - max (C = 0 of ester) 7 nmr (CDCl 3) <5: 1.53 (3Ξ, two overlapping J = 7.0, CH_CH2), 4.46 and 4.53 (3H, 2S, CH, of 1-methyl en- 2- \ 2 - - * - - - - - - methyl-tetrazoles, ratio 6: You.

The methyl of the 2-isamer is in a lower field and is the minor product), k.5 ppm (2H, 2 overlapping α, CEJY ^).

25 1b. 5-Carbethoxy-2-methyltetrazole See reaction scheme B 'of the formula sheet.

A mixture of 5-carbethoxy-2-methyltetrazole and 5-carbethoxy-1-methyltetrazole (0.252 g, 1.61 mmol, ratio of the two isamers 1: 1) in iodomethane (0.5 ml) was closed in a glass tube and heated at 100 ° C for 30 hours and at 130 ° C for 6 hours. After distilling the reaction mixture, the title compound was obtained as a pale yellow oil: Λ -96-

a

0.139 g ($ 55); boiling point 95-100 ° C / 0.5 torr (air bath temperature): ir (film): mo cm-1 (C = 0 of ester); limr (CDC1_) t: 1,1) 6 (3H, t, J = 7,0, max ^ CH3CH2), 1) -, 53 (3Ξ, s, CH3-2), 1), 5 (2H , ς, J = 7.0, C 1 C 2 C).

, 2 2. Methylation of dimethyl sulfate

A solution of 5-carbethoxytetrazole (1.1) 2 g, 0.01 mol) in dry acetone (20 ml) was mixed with anhydrous potassium carbonate (1.38 g, 0.01 mol) and dimethyl sulfate (1.26 g, 0 0.01 mol). The mixture was refluxed for 12 hours. The carbonate was filtered and the solvent evaporated under reduced pressure. The residue was diluted with dichloromethane (30ml), washed with saturated sodium bicarbonate (10ml), brine (10ml) and dried over anhydrous sodium sulfate. After evaporation of the solvent and distillation under vacuum, a clear oil was obtained: 1.1) 5 g (83%); boiling point 85-100 ° C / 0.5 torr. 1HMR indicated the presence of two isamers in a 1: 1 ratio.

E. 5-hydr oxymethyl-2-methylt et r azo

See reaction scheme C of the formula sheet.

1 · By reducing the mixture of esters

A mixture of 5-carbethoxy-1-methyltetrazole and 5-carbethoxy-2-20 methyltetrazole (ratio 60.1)) (7 ^ 60 g, 0.01) 9 mol) in dry tetrahydrofuran (50 ml) was added to Cooled to 0 ° C and treated with lithium borohydride (1.06 g, 0.01 (9 mmol)) which was added in small portions over 15 minutes. The mixture was kept at 10 ° C for a further 30 minutes and stirred at 20 ° C for k hours. The mixture was cooled to 0 ° C and the excess hydride carefully destroyed by addition of 6N HCl (pH 7 after no gas evolved). The solvent was concentrated in vacuo and the residual oil diluted with dichloromethane (200ml), washed with brine (10ml) and finally dried over NagSO 2. Concentration of the solvent and distillation of the residue under vacuum gave 1.83 g (33%) of.

1.

30 a clear oil. HMR of this material indicated that the product was 5-hydroxy-methyl-2-methyltetrazole.

2. By reduction of 5-carbethoxy-2-methyltetrazole

To a solution of 5-carbethoxy-2-methyltetrazole (0.139 g, 0.89 mmol), obtained by isomerization of the mixture of esters with methyl iodide) in dry tetrahydrofuran (1 ml), solid lithium borohydride (10 ° C) was 0.019 g, 0.87 mmol). The mixture was slowly warmed to room temperature and stirred for 1 hour. The excess borohydride -97- was destroyed by careful addition of 6N HCl at 0 ° C (pH 7).

The solvent was evaporated and the residue was dissolved in dichloromethane (25ml) and dried with anhydrous sodium sulfate. After evaporation of the solvent, the title compound was obtained as a clear oil: 0.092 g (91%); boiling point 90-120 ° C / 0.5 torr with decomposition; ir (film) 0 · ay: 3350 cm -1 (broad, OH); 1HMR (GDC1) S: 4.4 (2H, s, CH3-2), 4.93 (2H, s, CH2-5).

C. 5-Acetyl mercaptomethyl-2-methyltetrazole See reaction scale D 'of the formula sheet, 10 To a solution of 5-hydroxyethyl-2-methyltetrazole (1.83 g,

11.7mmol) in dry dichloromethane (25ml) was added at 0 ° C with lanesulfonyl-chloride (1.47g, 12.9mmol) followed by triethylamine (1.30g, 12.9mmol) which was added dropwise 5 minutes was added. The mixture was stirred at 0 ° C for 1 hour and then treated with a solution of potassium thioaetate (1.60 g, 14.0 mmol) in dry N, N-dimethylformamide (10 ml). The resulting gel was stirred at 0 ° C for 3 hours. The reaction mixture was diluted with dichloromethane (200ml), washed with brine (20ml) and dried with anhydrous sodium sulfate. Evaporation of the solvent under vacuum and chromatography of the verier e-20 gene oil on silica gel (2x15 cm, eluting with dichloromethane and dichloromethane-acetone 5%) gave the title compound as a clear oil: 1.31 g (65 # ); ir (film) 1: 1696 cm-1 (C = 0 of thioester); ^ HMR

2Q3JC

(CDCl3) S: 2.43 (3H, s, SAc), 4.36 (3H, s, 2-¾), 4.38 ppm (2Ξ, s, 5-¾).

D. 5-mercaptomethyl-1,3-dimethyltetrazolium trifluoromethanesulfonate. See reaction scheme E * of the formula sheet.

A solution of 5-acetyl mercaptamethyl-2-methyltetrazole (0.400g, 2.32mmol) in dry dichloromethane (3ml) was treated with methyl trifluorate (0.76g, 4.64mmol) and stirred at 22 ° C for 16 hours. After evaporation of the solvent under vacuum, a red oil was obtained. This salt was dissolved in cold oxygen-free water (5ml) and treated with 4N sodium hydroxide (0.8ml, 3.2mmol). The mixture was stirred at 0 ° C for 40 minutes, diluted with water (7 ml) and adjusted to pH 7 with saturated KHgPO 2. The resulting clear solution was stored under nitrogen and used immediately for the next step.

. *** V- -98- E. (1 ^, 5 ^, 65) -3- [1,3-dimethyl-5-tetrazolium) -methylthio] -6- (1-hydro-xyethyl) -7-oxo -1-azabicyelo (3,2,0) hent-2-e en-2-c arb oxylate See reaction scheme F 'of the formula sheet.

A solution of enol phosphate (0.915g, 1.53mmol) in tetrahydrofuran (8ml) was cooled to 0 ° C and treated dropwise with a solution of 5-mercaptomethyl-1,3-dimethyltetrazolium trifluoromethanesulfonate (2.32mmol) prepared as courts) for a period of 20 minutes. The pH of the reaction mixture was stable at 6.5 throughout the addition. After 20 additional minutes, the pH of the solution was adjusted to 7.0 with saturated sodium bicarbonate. The mixture was transferred to a hydrogenation flask, diluted with THF (10 ml) ether (20 ml) and ice (20 g). The carbapenem compound was hydrogenated over a 10% palladium-on-activated carbon under 3.15 kg / cm 2, the temperature being maintained for 90 minutes

O

Was slowly increased to 22 ° C. The catalyst was filtered and washed with cold water (5ml) and ether (20ml). The water phase was washed with ether (20 ml) and kept under vacuum for 20 minutes to remove traces of organic solvent. After chromatography on Prepak 500-C / 18 and elution with water, after freeze-drying, the title compound was obtained as a white powder, 0.266 g (b9%); [a] J23 + 13 ° (c 1.0U, HgO); UV (H 0, pH 7, U) V: 29b nm (S 7,500); ir (KBr) n): 1755 (C = 0 or

^ IJjLEÜC 4 TflStX

3-lactam), 1600 cm (broad, C = O of carboxylate); HMR (D ^ O) 6: 1.2U

(3H, d, J = 6.4 Hz), C 1 -CHOH), 3.0-3.3 (2H, m, H-1t); 3, te (1H, dd, J = 5.8 J = 2.9, H-6), bb, 2 (2H, m, H-5 and CH ^ OH), b, 3b and U, 57 (2 x 3H, 2S, 25 CH - 1 and 3 of tetrazole ), te and U, 51 (2H, 2s, 0HoS). The product has 0 ° -1 * half-life 10.5 hours at 37 ° C (c of 10 ** M in pH 7Λ phosphate buffer.

Example XXI

Other procedure for the preparation of 3- (N-methylpyridin-2-yl-methane-thio) -6a- [1 - (R) -hydroxyethyl] -7-oxo-1-azabi cyclo (3.2.0) hept- 2-en-2-carbo-30 xylate

See reaction scheme G 'of the formula sheet.

Into a 2 L flask equipped with a magnetic stirrer, equipped with a Vigreaux column for distillation, a heating mantle, and N 3, 1.0 mol (U32 ml) of methyl acetyl acetate and 8.0 mole (46.6 g) of allyl alcohol were added -35 lined. The reaction mixture was distilled at 92 ° C for 12 hours. Then 136 mg (2.0 mol) of allyl alcohol was added and the mixture distilled for 23 hours. After this, 136 ml (2.0 mol) of allyl alcohol was added and the mixture distilled for 16 hours. The reaction mixture was then distilled under vacuum and the product collected at 105-110 ° C / 35 mmHg. MU g of allylacetoacetate (73 # yield) was obtained.

See reaction scheme H 'of the formula sheet.

To a solution of allylacetoacetate (226.5 g, 1.59½ moles) in 3 1 5 acetonitrile and triethylamine (2 ^ 3 ^ ml »1.753 mol) evaporate p-toluenesulfonyl azide (3 ^ 5.3 ml, 1.753 mol) ) added for a period of 1 hour,. -the temperature being kept at about 20 ° C with a cooling bath.

The reaction mixture turned yellow. Then the reaction mixture was stirred at room temperature under a nitrogen atmosphere for 18 hours. The mixture was concentrated to a rotary evaporator. The residue was dissolved in ethyl ether (2.6 L) and 1M aqueous KOH (800 ml). The organic phase was washed five times with 1N KOH (500 ml) and once with brine (k00 ml).

After drying over MgSO4 and concentration on a rotary evaporator (temperature below 30 ° C), 260.2 g (97 #) of the title product were obtained.

15 See Reaction Scheme I of the formula sheet.

To a stirred suspension of allyldiazoacetoacetate (203 g, 1.195 mol) in 2 l of methylene chloride and 199 ml (1 ^ 3½ mol) of triethylamine was added 302 ml (1.315 mol) of t-butyldimethylsilyl trifluorate at 5 ° C for 45 minutes. . The mixture was stirred at 5 ° C for 1 hour and then stirred for an additional hour without cooling. The reaction mixture was washed 4 x with 500 ml H 2 O and then 1 x with 500 ml brine. After this it was dried over Na 2 SO 4 and concentrated to 3 g of an orange oil. This oil was used directly in the next step.

D. See reaction scheme J 'of the formula sheet.

25 To a mixture of (1 rR, 3R, ^ R) -3- (1 f-tert-butyldimethylsilyloxyethyl) -1- acetoxy-azetidin-2-one (28.7 g, 0.1 mol) and fresh molten ZnCl 2 (6.8 g, 0.05 mol) in dry CH 2 Cl 2 (700 ml) was added dropwise a solution of allyl-2-diazo-3-tert-butyldimethylsilyloxy-3-butenoate (33.8½ g, 0.12 mol) in CH 2 Cl 2 (50 ml) over a period of 5 hours.

The mixture was stirred at room temperature for 2 hours, at which time TLC (thin layer chromatography) detected a small amount of residual starting material. A further amount of allyl-2-diazo-3-tert-butyldimethylsilyloxy-3-butenoate (U, 23 g, 0.015 mol) in 10 ml CH 2 Clg was added over a period of 1 hour and stirring at room temperature for Continued for 10 hours. The reaction mixture was then diluted with ethyl acetate (750 ml), washed (2 x 300 ml saturated HCO 3, 300 ml brine), dried (MgSO 4) and evaporated to yield 62.5 g dark orange *.

-100- oil was obtained, which was dissolved in methanol (500 ml) and treated with 1N aqueous (100 ml). The resulting mixture was stirred at room temperature for 2 hours, after which 10 ml of 1N HCl was added, followed by an additional 2 hours of stirring. The reaction mixture was concentrated to half volume-5 'volume and poured into a mixture of ethyl acetate (800ml) and water (800ml). The organic phase was separated, washed with water (800ml) and the combined aqueous extracts washed with ethyl acetate (> 00ml). The combined organic extracts were washed with brine (2 x 1 + 00 ml), dried (MgSO 4) and concentrated to 32 g of a dark orange-red oil. Flash chromatography gave 9.33 g (33% yield) of the title product as a golden yellow oil, which solidified to a pale yellow solid. 1 H-nmr (CDCl 3): 6.20-5.72 (m, 2H), 5.1 + 8-5.21 (m, 2H), 1 +, 7¼ (dt, J = 5.8, <Γ = 1.2Ηζ, 2Ξ), 1 +, 30-3.88 (m, 2H), 3.30-3.20 (m, 2H), 2.89 (dd, J = 7.3, J -2.1, 1H), 2.18 (s, 1H), 1.32 (d, J = 6.2, 3H).

15 See reaction scheme K 'of the formula sheet.

A mixture of diazo ester prepared in step D as mentioned above (9.2 g, 32.7 ml) and rhodium acetate [RH 2 COAC] in benzene (1 L) was refluxed for 1 hour. The solution was treated with activated charcoal and filtered through a Celite plug. The plug was washed with 100 ml of aqueous benzene. The concentration of the filtrate was obtained 8.08 g (97% yield) of the title product as a light brown crystalline solid. "* H-nmr (CDCl 3) <$: 6.15-5.68 (m, 1H), 5.1 + 5-5.18 (m, 2H), 1 +, 71-1 +, 60 ( m, 2H), 1 +, 1 + 0-1 +, 05 (m, 2H), 3.17 (dd, J = 7.1, J '= 2.0, 1H), 2.95 (dd, J = 6.9, J '= 18.9, 1i), 2.1 + 2 (dd, J = 7.6, J' = 18.8, 1H), 1.88 (s, 1H), 25 1.39 (d, J = 6.3, 3H9.

See reaction scheme L 'of the formula sheet.

To a solution of ketoester prepared in step E (7.5 g, 0.03 mol) was added diisopropylamine (6.08 ml, 0.035 mol) at 0 ° C under atmosphere, followed by diphenylphosphoryl chloride. After 15 minutes, TLC showed no residual starting material. Diisopropylamine (6.26 ml, 0.036 mol) and a solution of freshly distilled 2-mercaptomethylpyridine (1.5 g, 0.036 mol) in 5 ml of acetonitrile were added to the reaction mixture.

After stirring at 0 ° C for 2 hours, the mixture was poured into ethyl acetate (1 L), washed with water (2 x 150 ml), saturated NaHCO 3 (150 ml), 35 HgO (150 ml) and brine (200 ml) . The organic phase was dried (MgSO4) and concentrated to a dark-colored orange-yellow gum. Flash chromatography. delivered the product as a golden yellow oil. The product was dissolved in -101-y-diethyl ether and cooled to 0 ° C. Filtration gave 4.8 g (44% yield) of the purified title product as cream-colored crystals.

1H-HMR CDCl3) d: 8.6-8.¾ (m, 1H), 7.85-7.15 (m, 3H), 6.20-5.7¾ (m, 1H), 5.54- 5.15 (m, 2H), 4.80-4.66 (m, 2H), 4.29-4.03 (a, 1H), 4.19 (s, 2H), 55 3.69- 2.85 (m, 1H), 2.97 (s, 1Ξ), 1.32 (d, J-6.2, 3H).

G. See reaction scheme M "of the formula sheet.

To a solution of the allyl ester prepared under step P (1.79 g, 4.97 mmol), tetrakistriphenylphosphine palladium (175 ag, 0.15 mmol) and triphenylphosphine (175 mg, 0.67 mmol) in CH 2 Clg (25 ml), a solution of 10 potassium 2-ethylhexanoate (1.085 g, 5.96 mmol) in ethyl acetate (12 ml) was added. Stirring for 1 hour at room temperature, TLC showed only a trace of starting material. The reaction mixture was diluted with anhydrous diethyl ether (150ml) and the precipitate collected by filtration, washed with ethyl acetate and then ether to give a light brown solid. This solid was dissolved in H 2 O (10 ml) and purified by reverse phase chromatography to obtain 1.85 g of the title product as a tan solid. This material was further purified by slurrying in acetone to yield 1.47 g (83%) of the title product. ^ -HMR (Dg0) 6: 8.45-8.36 (m, 1H), 7.92-7.22 (m, 3H), 4.78-3.91 (m, 2H), 4, 69 (β, 2H), 3.34-2.71 (a, 3H), 1.19 (d, J = 6.4, 3H).

H. See reaction scheme Hf of the formula sheet.

Toluene sulfonic acid (27.6 mg, 0.16 mmol) was added to a cooled (0 ° C) suspension of potassium 6-hydroxyethyl 2- (2-pyridylmethylthio) carbapenem-3-carboxylate (53.8 mg 0.15 mmol) in acetone (2 ml). The mixture was stirred at 0 ° C for 20 minutes and treated with methyl trifluorate (0.02 ml). Stirring at 0 ° C for 60 minutes, LA-1 resin was added, followed by hexane (6ml). The mixture was extracted with water (4 x 0.5 ml) and the combined water phases were purified by reverse phase HPLC to give 10 mg of the title product.

30 Example XXII

Preparation of 3- (H-methyluyridin-2-yl-methananthio) -6a-ri- (R) -hydroxyethyl1-7-oxo-1-azabicyclo (3-, 2.0) -tt-2-en-2 -carboxylate by "one barrel" method See formula 15¾ of the formula sheet.

See reaction scheme 0 * of the formula sheet.

35 A. Preparation of enol phosphate (2)

See reaction scheme P 'of the formula sheet.

An ice-cooled solution of ketone (3 g, 8.62 mmol) in acetone

V

c -102-vibration (30 ml) - was treated with ethyl diisopropyl (9 mmol, 1.0U eq, 1.57 ml) (addition period ca 2 minutes) and chlorodiphenyl phosphate (9 mmol, 1.0 ^ eq, 1.87 ml ) addition period approx. 2 minutes). The reaction mixture was stirred for 11 * 5 minutes and TLC (ethyl acetate, silica gel) showed disappearance of the on. The solution was diluted with ethyl acetate (60ml), washed with cold water (2 x 50ml) and brine, dried over sodium sulfate and concentrated (bath temperature 120 ° C) to give a foam which was used as such.

B. Preparation of thiol (J +) T0.

See reaction scheme Q 'of the formula sheet.

An ice-cooled solution of thioacetate 3 (3.31 g, 10 mmol) in water, purged with nitrogen for 5 minutes, was treated dropwise (about 5 minutes) with a cooled solution of sodium hydroxide (1.75 eq, 17.5 mmol, 0.7 g), in water (8 ml). The mixture turned yellow. After 15 minutes under nitrogen, the pH was adjusted to 7.0 with a saturated aqueous solution of KHgPO2. The reaction mixture was diluted with water (15 ml). This aqueous solution of thiol k (50 ml, 0.2 mmol / ml) was used as such.

C. Koupeling 20 See reaction scheme R 'of the formula sheet.

An ice-cooled solution of 2 (crude, prepared in A, 8.62 mmol) in tetrahydrofuran (50 ml) was treated dropwise with an aqueous solution of thiol J + as prepared in B (5 min each 5 ml solution). During the course of the reaction, the pH of the reaction mixture was kept at 6.7-7.5 (preferably 7) by adding a cooled 2N sodium hydroxide solution. The reaction was followed by TLC (a) silica gel, ethyl acetate; (b) reverse phase Amaltech RPSF, CH 2 CH-pH 7 buffer (L-; 6).

At the end, 1.15 eq thiol was used (50 ml solution).

The reaction was completed after 1 hour at 0 ° C and the mixture was used as such for hydrogenation after the pH was adjusted to 7.

D. Hydrogenation

See reaction scheme S 'of the formula sheet.

The reaction mixture containing 5. (prepared as under C) was transferred to a Parr flask with THF (10ml), phosphate buffer (OH 7.0, 1M) (10ml), ether (75ml) and palladium-op -coal 10% (5 g) and for 2 hours at 2 o

3.15 kg / cm and hydrogenated at 3-10 C. The catalyst was then filtered, washed with water (3 x 10 ml) and the pH carefully with cold 2H

<-103-

NaOH set at 6.2. Ether was added and the water phase separated and washed again with ether. The water phase was freed from organic solvent under vacuum and then purified on a BONDAPACK C-18 column 5 (100 g, h, 5 x 13 cm) with cold distilled water. The pale yellow fraction containing the product (checked by UV and TLC) was lyophilized to obtain 1.5 g (50%) S of 6 as a yellow powder.

> 293, € = 9,000, X2T1, € = 11061).

Example XXIII

10 Following the general procedures of Examples I-XX

The following carbapenem products are obtained by using the intermediate of formulas 155 and 156 of the formula sheet

Pre- / '' N © c heal ïfo. ^ / ΓΛ © XXXIIa "CH2 * \ / N" CH3 xxiiib -ch2ch2-xxiiic -ch2- _ // Λ CH3 @ CH3 M? -V xxxiid -ch2-y ^ Yield calculated from bicyclic ketone.

V

N- -10k- C \ @ ^ N— \ mile -CH2CH2- - '(/ y »“ Ïllf - <= 2- - / ^ ®h2ch2ch3 CH3 ^ ^ ing -ch2- V / "Λ CH © • T 3 XXIIIh.-CH2- -jpNN ^ CH3 ίΗ3

XXIIIi "CH2" I

- CH3 CH ® XXXII j -ch2- 3> -n-ch3 -ks> “cH3 XXIIIk -CH2- - ^

© H

ch3 ππη ch3 -r ^ -ch3 -CH- / CH2 ~ 0

N

XXIIIm -CH2- v.

© 7 — I

• CH3 XXIIIn -CH2- | ^ 7: 3ö io ch3 l® * -105- λ / ¾ (mixture of —N 3 possible XXIIIo “CH2” iscmers) a 3 ch3 ™ -r Ü7j®H3 cocr ΰ #

XXXIIq. CH2 -N

éH3? H3® XXIIIr “CH2 ~" If 'ΐβ CRy-COtfi CH, 1 3 Θ xxuis -ch2-

N- N

Ck N — N-CH, spleen “ca2 *. > ~ ^ - * * >> -106- i *

Example XXIV

Following the general procedures of Examples I-XX, the following carbapenem products are prepared using the * intermediate of formulas 157 and 158 of the formula sheet *

Example

den No, A

jrλ © • mva -ch2- mvb -ch2ch2- XXIVc “^ 2” - ^ ^ 'c \ ® ^ CH3 XXIVd "CH2" \ / ° \ θ

Njj-- XXIYe -CH2CH2- Λ mvf -ch, - f / K ^ yN “CH2CH2C53 c \ 0 \ 'XXIYg -CHj- h \\ CI ^ ï -r; -107- <

V

Λ CH ® I 3 • BCCVh -CH2- * -s 9¾ ÏJ® xxrvi -cs2- __ <v | \ —- * CH3 CH © XXIVj -CH, - -N-CH, 2 J (I 3 ~ ^ S ^ a3 jotm ~ CS2 ~ '®y— CH3 ΧΧΓ71 * CH, Z' \ ©

- = L

/ CH2- ^ XXI7m -CE ^ - ®p CH ^ XXTVh -CH2- cv ^ Ss'N> / \ -.

CE3 I Θ is3> -108- * λ. 0 (mixture of -CH - P 3 possible \] QCIVo 2 L's4 ^ vf * ^ isomers) * ° Ρ ^ = Η3 «3 -CH, - -N ^ mTp 2 I μ ©

^ cocP

-CH2-? H2

Tlj # <^ η3

pQ

XXIVr J “CH2“ ~ xf ^ τβ> L-γ CH.-COO ^ CH- A * Θ xxiys -ch2- —t <^ * s

N- N

CH3 ran -CH, - y? tj_CH3 • y Λ; "]; i y -109- Λ

J

Example XXV

See reaction scheme Tf of the formula sheet.

If, in the procedure of Example XXII, the keto intermediate is replaced by an equimolar amount of the corresponding 5 1 S-methyl intermediate, the carbapenem end product is shown above.

Example XXVI

See formula 1Ö0 of the formula sheet.

In the procedure of Example XXII, if the keto intermediate J10 is replaced by an equimolar amount of the corresponding 1a-methyl intermediate, the end carbapenem product is obtained as indicated above.

Claims (189)

1. A compound of formula 1, wherein R is hydrogen and R is selected from hydrogen, substituted or unsubstituted: alkyl, alkenyl, and alkynyl with 1-10 carbon atoms, cycloalkyl and cycloalkylalkyl with 3-6 carbon *. atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl units; phenyl; aralkyl, ar alkenyl and aralkynyl wherein the aryl moiety is phenyl and the aliphatic moiety contains 1-6 carbon atoms; heteroaryl; het er alkyl, heterocyclyl and heterocyclylalkyl wherein the heteroatom or the atoms in the aforementioned heterocyclic units are selected from 1 to 2 oxygen, nitrogen or sulfur atoms and the alkyl units associated with said heterocyclic units contain 1 to 6 carbon atoms, the substituent or substituents being associated with the above groups are independently selected from C 1 -C 8 alkyl optionally substituted with amino, halogen, hydroxy or carboxyl 20 halogen -OR 3 \ O II 3 4 -OCNR R 0 -cnr3r4 -nr3r4 3, NR ^ niR3R4 II 3 4 -S-NR R II 0 o II 3 4 -NHCNR R 0 3II 4 RJCNR - -co2R3 * 0 1 ··· -1 () · - - - .. iy ______ «r 'o -OCR3 -SR3 O II 9 -SR O ll 9 -SR1 II o -CN -n3 -oso3r3 o il 9 -OS-R lt oo 3ti g -NR S-R1 II o -OP (O) (OR3) (OR4). »3 4 -NR C-NR 1“ -NR 3 CO 2 R 4 -no 2 3 h wherein, in connection with the above substituents, the R and R groups are independently selected from hydrogen; alkyl, alkenyl and alkynyl of 1-10 carbon atoms, cycloalkyl, cycloalkylalkyl and alkylcycloalkyl of 5-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl units; phenyl; aralkyl, ar alkenyl and aralkynyl wherein the aryl moiety is phenyl and the aliphatic moiety contains 1-6 carbon atoms; and heteroaryl, heteroaralkyl, heterocyolyl and heterocyclylalkyl in which it is determined whether the atoms in the aforementioned heterocyclic units are selected from 1-h oxygen, nitrogen or sulfur and the heterocyclic units. 3 I; the linked alkyl units comprise 1-o carbon atoms, or R and R taken together with the nitrogen to which at least one of them is bonded a -112% * / / -. 9 can form nitrogen-containing 5- or 6-membered heterocyclic ring; R de • 3. -. . Has signs of R with the exception that it may be hydrogen; or 1 where R and R taken together represent C 1 -C 12 alkylidene or C 2 "C 10 alkyl" 1 substituted by hydroxy; R1 is selected from substituted or unsubstituted: alkyl, alkenyl and alkynyl with 1-10 carbon atoms; cycloalkyl and cycloalkylalkyl with 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl units; phenyl, aralkyl, aralkenyl and aralkynyl wherein the alkyl moiety is phenyl and the aliphatic moiety contains 1-6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and hetero-10 cyclylalkyl wherein the heteroatom or atoms in the aforementioned heterocyclic units are selected from 1-4 oxygen, nitrogen or sulfur atoms and the alkyl units attached to said heterocyclic units contain 1-6 carbon atoms , Wherein the above R '' groups are optionally substituted with 1-3 substituents independently selected from: C 1 -C 6 alkyl optionally substituted by amino, fluoro, chloro, carboxyl, hydroxy or carbamoyl; fluorine, chlorine or bromine; 3 -OR-CO 2 R 3; -0C0R3; -OCONR3R4; 0 "9 -S-R 3 t 10 -oxo; -NR 3 R 4; R 3 CONR4-; -NR 3 CO 2 R 4; 3 3 4 -NRJCONR R; O 3" 9 -NRJS-R3; II O -SR3; O -S-R3? i ν '· -113- 0 o K 7 o -S-ST? -SojR3; CO2R3; 3 4 -COUR R; -CN; phenyl optionally substituted with 1-3 fluoro, chloro, bromo, C 1 -C 6 alkyl -OR 3, -NR 3r -SO R 3, - (XLR3 or -CNR3R1 <'where R3, R ^ and R9 are similar). 5 R 3 substituents have the aforementioned meanings, or R 5 may be attached to the group of formula 11 at another point on the ring and form a fused heterocyclic or heteroaramatic ring, which ring may contain additional heteroatams selected from 0, S and N; A is C 1 -C 8 straight or branched chain alkylene; R 0 is hydrogen, an anionic charge or a conventional easily removable carboxyl protecting group, provided that when R is hydrogen or a protecting group, a counterion is also present; and the group of formula 11 / represents a substituted or unsubstituted mono-, bis- or polycyclic aromatic heterocyclic group containing at least one nitrogen in the ring, which ring is attached to A via a ring carbon atom and which contains a ring nitrogen contains quatemized by the group R ^; or a pharmaceutically acceptable salt thereof. 2. A compound according to claim 1, wherein R is hydrogen, CH 2 Cl 3> OH OH 'Π3ν ^ 3- | I CS-, c- or CS, CS-. // 3 csf CHj is 20. 1 8 A compound according to claim 1, characterized in that R and R taken together are -11 µ-4 V \ HOCH. CH3 ^. i +. Compound according to claim 1, characterized in that R 1 is OH CH 3 CO 5. Compound according to claim 1, characterized in that R OH is CH 3 CH- and the absolute configuration is 5RS 6s, 8R. Compound according to claim 1, 2, 3, b or 5S, characterized in that A is -CH0- or -CH0CH0-. d d d Q ^ T. Compound of formula 1, wherein R is hydrogen and R is selected from hydrogen; substituted and unsubstituted: alkyl, alkenyl and alkynyl with 1-10 carbon atoms, cycloalkyl, and cycloalkylalkyl with 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkylene units; phenyl; aralkyl, aralkenyl and ar alkynyl wherein the aryl moiety is phenyl and the aliphatic moiety contains 1-6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl in which the heteroatom or atoms in the aforementioned heterocyclic units are selected from 1 to 2 acid, nitrogen or sulfur atoms and 1 to 6 carbon units attached to said heterocyclic units contain; wherein the substituent or substituents in connection with the above groups are independently selected from C 1 -C 6 alkyl optionally substituted with amino, halogen, hydroxy or carboxyl halogen - - - - V 1 * / - V -115-f -OR 3 0 l * 3 4 -OCNR R. 0 -CNR3R4 -nrV / NR3 'NR3R4 0 11 3 4 -S-NRJR * 12 0 0 12 3 4 -NECNR R * 0 3 21 4 R CNR - -co2r3 sO »*' 0 -OCR3 -SR3 0/1 g -SR3 0 ft 9 -SR3 tl 0 -CN - «3 3 -0S03Rj 0 it 9 -0S-R3 noo 3 // g -NR S-R3 it 0 -OP (O) (OR3) (OR4)« dB * ® # ............ _ _ -116- t • * -nr3c = nr4 -NR3C02R4 -N02. 3 ij. in connection with the above substituents the groups R and R are independently selected from hydrogen; alkyl, alkenyl of 1-10 carbon atoms; cycloalkyl, cycloalkylalkyl and alkylcycloalkyl with 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl unit; phenyl, aralkyl, aralkenyl and aralkynyl wherein the aryl moiety is phenyl and the aliphatic moiety contains 1-6 carbon atoms; and heteroaryl, the alkyl, heterocyclyl and heterocyclylalkyl wherein the heteroatom or atoms in the above heterocyclic units are selected from 1-4 oxygen-10 nitrogen or sulfur atoms. and the alkyl units linked to said heterocyclic units contain 1-6 carbon atoms or R and R taken together with the nitrogen to which at least one of them is attached can form a nitrogen-containing 5- or 6-membered heterocyclic ring, R the R meanings mean that it is not hydrogen; or where C 8 -C 8 alkylidene or R 3 R 3 (3-en-substituted with hydroxy), and R 2 is selected from substituted and unsubstituted: alkyl, taken together at R and R alkenyl and alkynyl of 1-10 carbon atoms; cycloalkyl and cycloalkylalkyl of 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl units; phenyl; aralkyl, aralkenyl and aralkynyl where the aryl moiety is phenyl and having the aliphatic part 1-6 heteroaryl, heteroaralkyl, heterocyclyl, and heterocyclylalkyl wherein the heteroatom or atoms in said heterocyclic units are selected from 1-4 oxygen, nitrogen, or sulfur atoms and the alkyl units attached to said heterocyclic units contain 1-6 carbon atoms; the above-mentioned R 1 groups are optionally substituted from 1 to 3 substituents independently selected from: C 1 -alkyl, optionally substituted with amino, fluoro, chloro, carboxyl, 10 hydroxy or carbamoyl; fluoro, chlorine or bromine; —I IT— J? φ -OR3 -0C02R3; -OCOR3; -OCONR3R4; 0 It Q -OS-R5 II 0 -oxo; NR3R4; R3CONR4-; 3 4 -NR ^ CC ^ R? -NR3CONR3R4; 0 3 "* Q -NR S-R 7 i (0 -SR3; 0 T * Q -S-R5; 0. K 7 g -S-R5; -SO3R3; -co2r3? -CONR3R4; -CN; or phenyl optionally substituted by 1-3 fluir, chlorine, bromine, C1 -C6 alkyl. 3. U 3 3 3 U .3 ^ Q 'O -OR, -NRR, -SO_RJ, -CO fl or -COUR R wherein R, R and R m such 5 R substituents have the aforementioned meanings; 3 3 3 k -5it 9. ..5 5 -SO-5, -CO R or -COffl R, wherein R, R and R m such R substitu- 5 grafts have the aforementioned meanings, or R may be attached to the group of formula 11 at another point of the ring to form a condensed heterocyclic or heteroaromatic ring, which ring may contain additional heteroatoms selected from O, S and N; A is C 1 -C 8 straight or branched chain alkylene; R is hydrogen, an anionic charge or a conventional easily removable carboxy 1 protecting group, provided that when R is hydrogen or a protecting group there is also a counterion; and the group of formula 11 represents an aromatic mono-, bi- or polycyclic heter -containing heterocyclic ring containing 0-5 additional 5 heteroatoms selected from 0, S or I, said heterocyclic ring attached to A and a ring nitrogen quaternized by the group R * 'wherein said heterocyclic ring is optionally substituted at available ring carbon atoms by 1-5 substituents independently selected from alkyl, alkyl substituted with 1-3 hydroxy, amino-C 1 -C 6 alkylamino , alkylamino, alkoxy, carboxy, halogen or sulfo; C 1 -C 8 cycloalkyl; C 1 -C 6 cycloalkyl (0-¾) alkyl optionally substituted with 1-3 substituents as mentioned above in connection with 0 2 -¾ alkyl, 0 ^-^ alkoxy; (^ -¾ alkylthio; amino; alkylamino; di (C ^ -C ^) alkylamino; halogen; 0 ^ -¾ alkanqylamino; 0 ^ -¾ 15 alkanoyloxy; carboxy; sulfo; 0 | 1 .... -C — 0 - C 1 -C 12 alkyl; hydroxy; amidino; guanidino; phenyl; phenyl substituted with 1-3 substituents independently selected from amino, halogen, hydroxy, trifluoromethyl, 0 ^ -¾ alkyl, 0 ^ -¾ alkoxy, alkylamino, di (C ^ -C ^) alkyl-amino, carboxy and sulfo; phenyl (C-¾) alkyl wherein the phenyl moiety is optionally substituted by 1-3 substituents as mentioned above in connection with phenyl and the alkyl moiety is optionally substituted by 1- 3 substituents as mentioned above in connection with C 1 -C 4 alkyl, as well as heteroaryl or the alkyl in which the heteroatom or atoms are selected from 25 1-¾ 0, S or N atoms and the heteroalkyl-linked alkyl moiety Has 1-6 carbon atoms, which heteroaryl and heteroaralkyl groups are optionally substituted in the heterocyclic ring unit by 1-3 substituents independently selected from hydroxy, amino, halo none, trifluoromethyl, alkyl, alkoxy, alkylamino, di (C 1 -C 2) alkylamino, carboxy 30 and sulfo and in the alkyl unit by 1-3 substituents selected from hydroxy, amino, t alkylamino, di (C 1 -C ^) alkylamino, C 1 -C 6 alkoxy, carboxy, haloin and sulfo, said heterocyclic ring being optionally substituted with available ring nitrogen atoms having 1 to 3 substituents independently selected from C 1 -C 2 alkyl; C 1 -C 18 alkyl substituted with 1-3 hydroxy, 35 amino, C 1 -C 20 alkylamino (C 1 -C 20) alkylamino, C 1 -C 20 alkoxy, carboxy, halogen or sulfo groups C 1 -C 8 cycloalkyl; C 1 -C 8 cycloalkyl (C 1 -C 1) alkyl optionally substituted with 1-3 substituents as mentioned above in connection with Γ * "* ·, - -7 i 'Λ *" · * · J 1 -ï' ·· - - / - - - - - - - - - - - C - - alkyl; phenyl; phenyl substituted with 1-3 substituents independently selected amino, halogen, hydroxy, trifluoromethyl-C 1 -C 2 -alkyl, C 1 -C 2 -alkoxy, C ^ -C ^ alkylamino, diCc ^ -C ^ Jalkylamino, and carboxy and sulfo; phenyl (0, -¾) alkyl wherein the phenyl moiety may optionally be substituted with 5 1-3 substituents as mentioned above in conjunction with phenyl and the alkyl moiety may optionally be substituted with 1-3 substituents as mentioned above in connection with C 1 -C 6 alkyl, and heteroaryl or heteroaralkyl wherein the heteroatom or atoms are selected from 1-k O, S or if atoms and the heteroaryl-linked alkyl moiety contains 1-6 carbon atoms, which hetero-10 aryl and heteroaralkyl group are optionally substituted in the heterocyclic ring unit with 1-3 substituents independently selected from hydroxy, ami no, halogen, trifluoromethyl, C 1 -C 2 alkyl, C 1 -C 2 alkoxy, C 1 -C 2 alkylamino, diCc 2 -C 2) alkylamino, carboxy and sulfo and in the alkyl moiety with 1-3 substituents selected from hydroxy , amino, C 1 -C 1 -alkylamino, diiC 1 -C 1 -alkyl alkyl 15 amino C 1 -C 1 -alkoxy, carboxy, halogen and sulfo; or a pharmaceutically acceptable salt thereof. 8. A compound according to claim 7, characterized in that R1 is hydrogen, ch3ch2-, -¾ * es ca3 pa pa • ^ 3 20. 1 8 9. A compound according to claim 7, characterized in that R and R taken together represent HOCH-3. 10. A compound according to claim 7, characterized in that R 1 is V-120-OH-ch 3 -C-. 11. A compound according to claim 7, characterized in that R 5 OH is CH3CH- and the absolute configuration is 5R »6s, 8R. 12. A compound according to claim 7, 8, 9, 10 or 11, characterized in that A is -CH_- or -CH0CH0-. d d d 8 1 A compound of formula 1, wherein R is hydrogen and R is selected from hydrogen; substituted and unsubstituted: alkyl, alkenyl and alkynyl of 1-10 carbon atoms, cycloalkyl and cycloalkylalkyl of 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkylene units; phenyl; aralkyl, ar alkenyl and aralkynyl wherein the aryl moiety is phenyl 15 and the aliphatic moiety contains 1-6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the heteroatoam or atoms in the aforementioned Heterocyclic unit are selected from 1-4 oxygen, nitrogen or sulfur atoms and the alkyl units attached to said heterocyclic units contain 1-6 carbon atoms; wherein the substituents are independently selected in conjunction with the above radicals consisting of C 1 -C 8 alkyl optionally substituted with amino, halogen, hydroxy or carboxyl halogen -OR 3 O tl 34 -OCNR-RO / I 3 4 -CNR R 3 4 -NRJR -121- • i A *, nr3 - / \ 3 4 Wr o If 3 4 -S-NR R ll O o ll 3 4 -NBCNR RO 3 ll 4 3TCNR - -COjR3 = 0 O -OCR3 - SR3 O ll 9 -SR * O fi 9 -SR * II o -CN -n3 J 3 -OS03R o / 1 9 -OS-R * / ί O o 3ff 9 -NR SR ff O -O? (O) ( OR3) (OR4) 3 -NR C = NR -NR3CO2R4 -NO2 %% -122- \ * wherein in connection with the above substituents, the groups B3 and R1 are independently selected from hydrogen; alkyl, alkenyl and alkynyl of 1-10 carbon atoms, cycloalkyl, cycloalkylalkyl and alkylcycloalkyl of 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl units; phenyl; aralkyl, ar alkenyl and ar alkynyl wherein the aryl moiety is phenyl and the aliphatic moiety contains 1-6 carbon atoms; as well as heteroaryl, heteroalkyl, heterocyclyl and heterocyclylalkyl in which the heteroatom or atoms in the aforementioned heterocyclic units are selected from 1-4 oxygen, nitrogen or sulfur atoms and the alkyl units linked to named heterocyclic units 1-6 carbon atoms, or RR taken together with the nitrogen to which at least one of them is attached can form a nitrogen * containing 5- or 6-membered heterocyclic ring; R has the meanings of R except that it must not be hydrogen; or wherein R and R 0 taken together represent C 8 -C 12 alkylidene or C 8 -C 10 alkylidene substituted with hydroxy; R1 is selected from substituted and unsubstituted: alkyl, alkenyl and alkynyl of 1-10 carbon atoms; cycloalkyl and cycloalkylalkyl with 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkylene units; aralkyl, aralkenyl and aralkynyl wherein the aryl moiety is phenyl and the aliphatic portion has 1-6 carbon atoms; heteroaryl, the er alkyl, heterocyclyl and heterocyclylalkyl in which the heteroatom or atoms in the aforementioned N heterocyclic units are selected from the group consisting of 1-4 oxygen, nitrogen or sulfur atoms and the alkyl unit 1-6 associated with said heterocyclic units carbon atoms, wherein the above-mentioned R 2 groups are optionally substituted by 1-3 substituents independently selected from: C 1 -C 6 alkyl optionally substituted with amino, fluoro, chloro, carboxyl, hydroxyl or carbamoyl, fluoro, chlorine or bromine .times. * -123- * -OR3 -0CO2R3; -OCOR3? -OCONR 3 R 4 7 0 n Q -OS-Rs 10 O -oxo; -nr3r4? R3CONR4- 7 -NR3C02R4 7 3 3 4 -NR CONR R? 0 3 «o -NITS-ir 7 If 0 -SR3? 0 * * -S-R? 70 -S-R * 7 -SO3R3; -C02R3? -CONR3R4 7 -CN? or phenyl optionally substituted with 1-3 fluoro, "bromo, chloro C 1 -C 3 -alkyl, 3 3¾ 3 3 -3b 9. 1 0 OR, -ffiY, -SO.R, -COpR or -COHRn where R , R and R ^ in such R substituents have the aforementioned meanings, or R 5 may be attached to the group of formula 11 at another point on the ring to form a fused heterocyclic or heteroaromatic ring, which ring may contain additional heteroatoms selected from O, N and S, A straight or branched alkylene of 1-6 carbon atoms, 2. . ... 10. hydrogen, an anxonic charge or a conventional easily removable carboxyl protecting group is provided that when R is hydrogen or a protecting group, a counterion is also present; and the group of formula 52 represents an aromatic 5- or 6-N-containing heterocyclic ring with 0-3 additionally the omen selected from H, S or 0, which heterocyclic ring may optionally be substituted with available ring carbon sites with 1 -5 substituents independently selected from C 1 -C 12 alkyl; alkyl substituted with 1-3 hydroxy, amino, C 1 -C 6 alkyl-amino. di (C 1 -C 6) alkylamino, C 1 -C 6 alkoxy, carboxy, halogen or sulfo, C 1 -C 8 cycloalkyl; C 1 -C 8 cycloalkyl (C 1 -C 12) alkyl optionally substituted with 1-3 substituents as noted above in conjunction with C 1 -C 12 alkyl; C 1 -C 2 alkoxy; C 1 -C 2 alkylthio; amino; C 1 -C 2 alkylamino; di (C 1 -C 2) alkylamine; halogen; C 1 -C 2 alkanoylamino, C 1 -C 2 alkanoyloxy; carboxy; sulfo; 0 11. -C-O-C 1 -C 1 -alkyl; hydroxy; amidino; guanidino; phenyl; phenyl substituted 15 with 1-3 substituents independently selected from amino, halogen, hydroxy, trifluoromethyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylamino, di (C 1 -C 6) alkylamino, carboxy or sulfo, phenyl (C 1 -C 12) alkyl wherein the phenyl moiety is optionally substituted with 1-3 substituents as mentioned above in connection with phenyl and the alkyl moiety is optionally substituted with 1-3 sub-20 stituents as mentioned above in connection with C 1 -C 12 alkyl; as well as heteroaryl or heteroaralkyl in which the atom or atoms are selected from the group consisting of 1-1 + 0, S or N atoms, and the heteroaralkyl-linked alkyl moiety contains 1-6 carbon atoms heteroaryl and aralkyl groups of choice in the heterocyclic ring unit are substituted by 1-3 substituents independently selected from hydroxy, amino, halogen, trifluoromethyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -alkylamino, diiC ^ -C ^ Jal-kylamino, carboxy and sulfo and in the alkyl unit by 1-3 substituents selected from hydroxy, amino, C ^ -C ^ alkylamino, di (C ^ -C ^) alkylamino, C ^ -C ^ alkoxy carboxy, halogen and sulfo, said heterocyclic ring 30 being optionally substituted in the available ring nitrogen atoms with 1-3 substituents independently selected from C 1 -C 6 alkyl; -Chalkyl substituted with 1-3 hydroxy, amino, alkylamino, diCC ^ -C ^ alkylamino, C1 -C12 alkoxy, carboxy, halogen or sulfo groups; C 1 -C 8 cycloalkyl; C 1 -C 8 cycloalkyl (C 1 -C 1) alkyl optionally substituted with 1-3 substituents as mentioned above in connection with C 1 -C 12 alkyl; phenyl .; phenyl substituted with 1-3 substituents independently selected from amino, halogen, hydroxy, trifluoromethyl, alkoxy, C 1 -C 2 alkylamino, di (C 1 -C 2) alkylamino, carboxy. J * -125- egg and sulfo; phenyl (C 1 -C 6) alkyl in which the phenyl moiety may be optionally substituted with 1-3 substituents as mentioned above in conjunction with phenyl and the alkyl moiety may be optionally substituted with 1-3 substituents as listed above in conjunction with phenyl with C 1 -C 2 alkyl; and heteroaryl or heteroaralkyl and the heteroatom or atoms are selected from 1-4, 0, S or at atoms and the heteroaralkyl-linked alkyl moiety contains 1-6 carbon atoms, which heteroaryl and heteroaralkyl groups are optionally in the heterocyclic ring unit are substituted by 1-3 substituents on-10 dependent selected from hydroxy, amino, halogen, trifluoro, C 1 -C 1 alkyl, C 1 -C 1 alkoxy, C 1 -C 1 alkylamino, di (C 1 -C ^ alkylamino, carboxy or sulfo and in the alkyl moiety by 1-3 substituents selected from hydroxy, amino, C 1 -C 6 alkylamino, diiC 2 -C 6) alkylamino, C 1 -C 6 alkoxy, carboxy, halogen or sulfo; or a pharmaceutically acceptable salt thereof. A compound according to claim 13, characterized in that the heterocyclic ring of formula 52 is optionally substituted with available ring carbon or nitrogen atoms with up to 5 substituents independently selected from (lower) alkyl. Compound according to claim 14, characterized in that A -CH 2 -, 20 is -CH 2 CH 2 - or C 1 -C 3 -CI- -. Compound according to claim 13, 14 or 15, characterized in that E1 25 is OH \ C & SCE and the absolute configuration is 5H, 6s, 8R. 8 1 1T. Compound of formula 1 wherein R is hydrogen and R is selected from hydrogen; substituted and unsubstituted: alkyl, alkenyl and alkynyl of 1-10 carbon atoms, cycloalkyl and cycloalkylalkyl of 1-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl units; phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl moiety is phenyl and the aliphatic moiety contains 1-6 carbon atoms; heteroaryl, heteroaralkyl heterocyclyl and heteroeyclylalkyl wherein the heteroatom or atoms in the aforementioned heterocyclic units are selected from 1-4 oxygen, nitrogen or sulfur atoms and the alkyl units associated with said heterocyclic units contain 1-6 carbon atoms; wherein the substituent -126- or substituents in connection with the above groups are independently selected from alkyl optionally substituted with amino, halogen, hydroxy or carboxyl. halogen -OR3 O (I 34 -OCNRk OI! 34 -CNR R 3 4 -NRJR., NR3 'nr3r4 o II 34 -S-NR'V il O o II 3 4 -NHCNRR * O 3II 4 R CNR - -co2r3 = 0 O -OCR3 -SR3 O II 9 -SR * OH 9 -SR * II o -CN - «3 3 -0S03R * -127- £ 0 il ο -OS-ÏT nooa 3fi 9 3 -NR SR It 0 -0? (0) (OR3) (OR4) 3 4 -NRC = NR 1 * 3 4 -NR C02R -no2 3 h delusions in connection with the "substituents mentioned above, the groups R and R become independent selected from hydrogen; alkyl, alkenyl and alkynyl of 1-10 carbon atoms, cycloalkyl, cyeloalkylalkyl and alkylcycloalkyl of 5-3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl units; phenyl; aralkyl, aralkenyl and ar alkynyl wherein the aryl moiety is phenyl and the aliphatic moiety contains 1-6 carbon atoms and heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the heteroatom or atoms in the aforementioned heterocyclic moiety are selected from 10 1 -t oxygen, nitrogen or sulfur atoms and the alkyl units attached to said heterocyclic 3 k units contain 1-6 carbon atoms, or R and R taken together with the nitrogen to which at least one of them is attached: xs attached to a nitrogen-containing 5- or 6-ring heterocycle can form, R the 3 b has characteristics of R with the exception that it must not be hydrogen 1 8 15; or wherein R and R taken together are alkylidene or C 1 -C 18 kylidene substituted by hydroxy, R 1 is selected from substituted or unsubstituted: alkyl, alkenyl and alkynyl of 1-10 carbon atoms; cycloalkyl and cyeloalkylalkyl with 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl units; phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl moiety is phenyl and the aliphatic moiety contains 1-6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclylalkyl wherein the oxygen atom or atoms in the aforementioned heterocyclic units are selected from 1-U oxygen, nitrogen or sulfur atoms -128- s and the alkyl units of 1-6 carbon atoms associated with said heterocyclic units; wherein the above groups are optionally substituted with 1-3 substituents independently selected from: C 1 -C 6 alkyl optionally substituted with amino, fluoro, chloro, carboxy, hydroxy or carbamoyl; fluorine, chlorine or bromine. -OR3 -CO2R3; ! ~ OCOR3; -OCONR3R4; 0 H 9 -OS-R * 1/0-oxo; -NR3R4; 3 4 R CONR -; 3 4 4HR CO2R; 3 3 4 -NR CONR R; O 3 "9 -NR SR 7 II O -SR3 7 O Ί- Q -SR 7 ALSO 7 Q -SR 7 -so3r3 7 -co2r3, -conr3r4 7 -CN? Or J -129- Γ * phenyl optionally substituted with 1-3 fluoro, chloro, bromo, C 1 -C 8 alkyl, OR 3, -BrV *, -SO R 3, CH R 3 or -COlffiV 1, where R 3, R 1 and R 9 in such c 3 d 5 R substituents have the aforementioned meanings or R may be attached to the group of formula 11 at another point on the ring and form a condensed heterocyclic or heteroaromatic ring, which ring may contain additional heteroatoms selected from 0, N and S; 2 ... AC -Cg is straight or branched alkylene; R is hydrogen, an anxious charge or a conventional easily removable carboxyl protecting group 2, provided that when R is hydrogen or a protecting group, there is also a counterion; and 52 represents a group selected from & T 10 (a) the group of formula 57 wherein R, R and R are independently selected from hydrogen; C 1 -C 2 alkyl; C 2 - C 1 -alkyl substituted with hydroxy, C 1 -C 1 -alkylamino, diCC-C 1 -alkylamino, C 1 -C 1 -alkoxy, amino, sulfo carboxy, or halogen; C 1 -C 8 cycloalkyl; C 1 -C 2 alkoxy, C 1 -C 2 alkylthio; amino, C 1 -C 2 alkylamino, diCC 1 -C 2) alkylamino; halogen, C 1 -C 6 alkanoylamino; C 1 -C 4 alkanoyloxy, carboxy; 0 μ · -C-OC ^ -C ^ hydroxy; amidino; guanidino; phenyl; phenyl substituted with 1, 20. or 3 amino, halogen, hydroxy, trifluoromethyl, C 1 -C 2 alkyl or C 1 -C 20 alkoxy groups; phenyl (C 1 -C 4) alkyl and the phenyl moiety therein may optionally be substituted with 1-3 substituents as noted above in conjunction with phenyl and the alkyl moiety optionally may be substituted with 1-3 substituents as noted above in conjunction with phenyl C 1 -C 12 alkyl '; and heteroaryl and heteroaralkyl wherein the heteroatoam or atoms are selected from 1-1 * oxygen, nitrogen or sulfur, and the alkyl moiety associated with said heteroalkyl moiety contains 1-6 carbon atoms; or wherein two of 6 7 10 R, R and R taken together are a fused saturated carbocyclic ring, fused aromatic carbocyclic ring, a fused non-aromatic heterocyclic ring or a fused heteroatom ring which may be condensed rings optionally substituted 6 Tests with 1 or 2 of the substituents as mentioned above for R, R and b10; (b) the groups of formulas 58, 59 or 60, optionally substituted on a carbon atom by 1-3 substituents independently selected from alkyl; C 1 -C 18 alkyl substituted by hydroxy, C 1 -C 18 alkylamino, di (C 1 -C 18 alkyl) amino, sulfo C 1 -C 18 alkoxy, amino, carboxy or halogen; C 1 -C 8 cyclo-V -130-V ** alkyl; alkoxy; C 1 -C 2 alkylthio; amino, C 1 -C 2 alkylamino; dKC 1 -C 2 alkyl) amino, halogen, C 1 -G 2 alkanoylamino; C 1 -C 4 alkanoyloxy, carboxy; O # -C-OC ^ -C ^ alkyl; hydroxy; amidino; guanidino; phenyl; phenyl substituted 5 with 1, 2 or 3-amino, halogen, hydroxyl, trifluoromethyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy groups; phenyl (C 1 -C 1) alkyl-wherein the phenyl moiety may optionally be substituted with 1-3 substituents as mentioned above in conjunction with phenyl and the alkyl moiety may optionally be substituted with 1-3 substituents as noted above in conjunction with C ^ -C ^ alkyl; and hetero-10 aryl and heteroaralkyl wherein the atoms in the aforementioned heterocyclic units are selected from 1-U oxygen, nitrogen or sulfur atoms and the alkyl moiety linked to said heteroaralkyl unit contains 1-6 carbon atoms, or is optionally substituted to form of a fused carbocyclic, heterocyclic or heteroaromatic ring optionally substituted with one or two of the substituents as defined above; (c) the groups of formulas 61-66 optionally substituted on a carbon atom by one or two substituents independently selected from C 1 -C 6 alkyl; alkyl substituted by hydros, C ^ -C ^ alkylamino, 20 (ϋ (θ ^ -θ ^) alkylamino, alkoxy, sulfo, amino, alkoxy or halogen; C ^ -Cg cycloalkyl; C ^ -C ^ alkoxy; C ^ - C ^ alkylthio; amino; C ^ -C ^ alkylamino; di (C1-Chalkyl) amino; halogen; C1 -C6 alkanoylamino; C1-alkanoyloxy; carboxy; 0 H -C-OC-C-alkyl; hydroxy, amidino, guanidino, phenyl; phenyl substituted with 1, 2 or 3-amino, halogen, hydroxyl, trifluoromethyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy groups; phenyl (C 1 -C 6) alkyl in which the phenyl moiety may be optionally substituted with 1-3 substituents as mentioned above in conjunction with phenyl and the alkyl moiety may be optionally substituted with 1-3 sub-30 stituents as listed in conjunction with phenyl C 1 -C 2 alkyl; and heteroaryl or heteroaralkyl wherein the heteroatom or atoms in said heterocyclic units are selected from 1-U oxygen, nitrogen or sulfur atoms and the alkyl unit attached to said heteroaralkyl unit contains 1-6 oxygen atoms or is optionally substituted to form a . fused carbocyclic, heterocyclic or heteroaromatic ring substituted with one or two of the above defined substituents; (d) the groups of formulas 67-72, optionally substituted on a -131-4 carbon atom by a substituent independently selected from C 1 -C 6 alkyl; C 1 -C 2 alkyl substituted by hydroxy, amino, C 1 -C 8 alkylamino, diC 1 -C 8 alkyl alkylamino, C 1 -C 20 alkoxy, sulfo, carboxy, or halogen; C 1 -C 8 cycloalkyl; CrCu alkoxy; C 1 -C 2 alkylthio; amino, C 1 -C 2 alkyalmino; di (C 1 -C 2) alkylamino; Halogen; C 1 -C 2 alkanoylamino; C 1 -C 2 alkanoyloxy; carboxy; O 2 -C-OC-C 1 -C 6 alkyl, hydroxy, amidino; guanidino, phenyl; phenyl substituted with 1, 2 or 3 amino, halogen, hydroxyl, trifluoromethyl, C 1 -C 2 alkyl or alkoxy groups; phenyl (C 1 -C 6) alkyl wherein the phenyl moiety may optionally be substituted with 1-3 substituents as mentioned above in conjunction with phenyl and the alkylene optionally may be substituted with 1-3 substituents as mentioned above in conjunction with C ^ -C ^ alkyl; as well as heteroaryl or heteroaralkyl wherein the heteroatoam or atoms in said heterocyclic unit are selected from 1-h oxygen, nitrogen 15 or zvavata and the alkyl moiety associated with said heteroaralkyl unit contains 1-6 carbon atoms; (e) the groups of formulas 73 and 73 ', wherein X is O, S or HE wherein R is 0,1-alkyl; C 1 -C 18 alkyl substituted with 1-3 hydroxy; amino; C ^ -C ^. alkylamino; dilC 2 C 1) alkylamino, C 1 -C 2 alkoxy, carboxy, halogen or sulfo groups; C 1 -C 8 cycloalkyl; C 1 -C 8 cycloalkyl (C 1 -C 12) alkyl optionally substituted with 1-3 substituents as mentioned above in connection with C 1 -C 12 alkyl; phenyl; phenyl substituted with 1-3 substituents independently selected from amino, halogen, hydroxy, trifluoromethyl, C 1 -C 2 alkyl, C 1 -C 1 alkoxy, C 1 -C 1 alkylamino, dj (C 1 -C 1) alkylamino, carboxy and sulfo; Phenyl (C 1 -C 4) alkyl, wherein the phenyl moiety may be optionally substituted with 1-3 substituents as noted above in conjunction with phenyl and the alkyl moiety may be optionally substituted with 1-3 substituents as listed above in conjunction with phenyl with C 1 -C 2 alkyl; and heteroaryl and heteroaralkyl wherein the heteroatom or atoms are selected from 1-k, S or H atoms and the heteroaralkyl-linked alkyl moiety contains 1-6 carbon atoms, which are heteroaryl and heteroaralkyl groups optionally in the heterocyclic ring moiety substituted with 1-3 substituents independently selected from hydroxy, amino, halogen, trifluoromethyl, C 1 -C 1 alkyl, C 1 -C 1 alkoxy, C 1 -C 1 alkylamino, di (C 1 -C 1) alkylamino, carboxy and sulfo and in the alkylene-35 by 1-3 substituents selected from hydroxy, amino, C 1 -C 2 alkylamino, di (C 1 -C 2) alkylamino, C 1 -C 2 alkoxy, carboxy, halogen and sulfo, which group may optionally be substituted on a carbon atom by one or more substituents independently selected from C 1 -C 6 alkyl; C 1 -C 2 alkyl substituted. Λ -132- tuated with hydroxy, C 1 -C 6 alkylamino, di (C 1 -C 6) alkylamino, C 1 -C 6 alkoxy, amino, sulfo, carhoxy or halogen; C 1 -C 8 cycloalkyl, C 1 -C 1 alkoxy, C 1 -C 1 alkylthio, amino, C 1 -C 1 alkylkyino, di (C 1 -C 1 alkyl) amino; halogen; C 1 -C 2 alkanoylamino; C 1 -C 2 alkanoyloxy; carhoxy; 5? .... -C-OC ^ -C ^ alkyl; hydroxy; amidino; guanidino; phenyl; phenyl substituted with 1, 2 or 3 amino, halogen, hydroxyl, trifluoromethyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy groups; phenyl (C 1 -C 6) alkyl in which the phenyl moiety may be optionally substituted with 1-3 substituents as mentioned above in conjunction with phenyl and the alkyl moiety may optionally be substituted with 1-3 substituents as mentioned above in conjunction with phenyl with C 1 -C 2 alkyl; and heteroaryl or heteroaralkyl wherein the heteroatom or atoms in said heterocyclic units are selected from 1 to 1 oxygen, nitrogen or sulfur atoms and the alkyl unit connected to said heteroaralkyl unit comprises 1 to 6 carbon atoms, or optionally substituted to form a condensed carbocyclic, heterocyclic or heteroaromatic ring optionally substituted with one or two of the above defined substituents; * (f) the groups of formulas 71-79, wherein X is 0, S or NR, wherein R 20 C 1 -C 12 alkyl; C 1 -C 2 alkyl substituted by 1-3 hydroxy, amino, C 1 -C 2 alkylamino, diCC 2 -C 2) alkylamino, alkoxy, carboxy or halogen or sulfo groups; cycloalkyl; C 1 -C 8 cycloalkyl (C 1 -C 1) alkyl optionally substituted by 1-3 substituents as mentioned above in connection with C 1 -C 12 alkyl; phenyl; phenyl substituted with 1-3 substituents independently selected from amino, halogen, hydroxy, trifluoromethyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, alkylamino, ditC 1 -C 6 alkylkyino, carboxy and sulfo; phenyl (C 1 -C 6) alkyl in which the phenyl moiety may be optionally substituted with 1-3 substituents as noted above in conjunction with phenyl and the alkyl moiety may be optionally substituted with 1-3 substituents as listed above in conjunction with C ^ -C ^ alkyl? and heteroaryl and heteroaralkyl wherein the heteroatom or atoms are selected from 1 to 10, S or N atoms and the heteroaralkyl-linked alkyl moiety contains 1-6 carbon atoms which heteroaryl and heteroaralkyl groups may optionally be in the heterocyclic ring moiety are substituted with 1-3 substituents on-35 dependent selected from hydroxy, amino halogen, trifluoromethyl, alkyl, alkoxy, C 1 -C 6 alkylamino, dKC 2 -C 6) alkylamino, carboxy and sulfo, and in the alkyl unit by 1- 3 substituents selected from hydroxy, amino, -133-.rr * C ^ -C ^ alkylamino, di (C ^ -C ^) alkylamino, C ^ -C ^ alkoxy, carboxy, halogen and sulfo, which heteroaramatic group of choice on a carbon atom may be substituted by a substituent selected from C 1 -C 1 alkyl, C 1 -C 1 alkyl substituted by hydroxy, C 1 -C 1 alkylamino, di (C 1 -C 1) alkylamino, C 1 -C 12 alkoxy, amino, sulfo, carboxy or halogen; C 1 -C 8 cycloalkyl; C 1 -C 2 alkoxy; C 1 -C 2 alkylthio; amino; C 1 -C 2 alkylamino; diiC ^ -C ^) alkylamino; halogen; C 1 -C 2 alkanoylamino; C 1 -C 2 alkanoyloxy; carboxy; O-Fe-OC-C 1-6 alkyl; hydroxy; amidino; guanidino; phenyl; phenyl substituted 10 by 1, 2 or 3 amino, halo, hydroxyl, trifluoromethyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy groups; phenyl (C 1 -C 6) alkyl in which the phenyl moiety may be optionally substituted with 1-3 substituents as mentioned above in conjunction with phenyl and the alkyl moiety may be optionally substituted with 1-3 substituents as mentioned above in conjunction with phenyl -C 1-4 alkyl; and hetero-aryl or heteroaralkyl wherein the heteroatom or atoms in the aforementioned heterocyclic units are selected from 1-4 oxygen, nitrogen or sulfur atoms and the alkyl moiety linked to said heteroaralkyl unit has 1-6 carbon atoms; and (g) the groups of formulas 80-85 wherein B is C 1 -C 12 alkyl; C 1 -C 12 alkyl substituted with 1-3 hydroxy, amino, C 1 -C 20 alkylamino, diC 1 -C 20 alkyl amino, C 1 -C 20 alkoxy, carboxy, halogen or sulfo groups; C 1 -C 8 cycloalkyl; C 1 -C 8 cycloalkyl (C 1 -C 1) alkyl optionally substituted with 1-3 substituents as mentioned above in connection with C 1 -C 12 alkyl; phenyl; phenyl substituted with 1-3 substituents independently selected from amino, halogen, hydroxy, trifluoromethyl C 1 -C 1 alkyl, C 1 -C 1 alkoxy, C 1 -C 1 alkylamino, di- (C 1 -C 1) alkyl amino , carboxy and sulfo, phenyl (C 1 -C 6) alkyl wherein the phenyl moiety may be optionally substituted with 1-3 substituents as mentioned above in conjunction with phenyl and the alkylene may be optionally substituted with 1-3 substituents as noted above in conjunction with C 1 -C 2 30 alkyl; and heteroaryl and heteroaralkyl, wherein the heteroatom or atoms are selected from 1-40, S- or N-atoms and the heteroaralkyl-linked alkyl moiety comprises 1-6 carbon atoms, optionally heteroaryl and heteroaralkyl groups in the heterocyclic ring unit can be substituted with 1-3 substituents independently selected from hydroxy, amino, halogen, trifluoromethyl, C 1 -C 6 alkyl, C 1 -C 1 alkoxy, C 1 -C 1 alkylamino, di (C 1 -C 1 ^ ) alkylamino, carboxy and sulfo and in the alkyl unit with 1-3 substituents selected from hydroxy, amino, C ^ -C ^ alkylamino, diCC ^ -C ^) alkylamino, • · - '' '-' --- aA V Λ -13-C-C-G-alkoxy, carboxy, halogen, and sniff; or a pharmaceutically acceptable salt thereof. 18. A compound according to claim 17, characterized in that the group 'according to formula 52 represents a group selected from C1-5 (a) groups according to formula 57, wherein R 1? C 1 -C 8 alkyl, and R, R and 10 R are each independently hydrogen or C 1 -C 20 alkyl; (b) groups of formulas 58, 59 and 60, wherein R 5 is C 1 -C 8 alkyl and wherein available ring carbon or atoms are optionally substituted by 1-3 substituents independently selected from alkyl; (C) groups of formulas 61-66, wherein R 1 is C 1 -C 12 alkyl and wherein available ring carbon atoms are optionally substituted by one or two substituents independently selected from C 1 -C 12 alkyl; (d) groups of formulas 67-72, wherein R 1 is C 1 -C alkyl wherein an available ring carbon or atom is optionally substituted with C 1 -C. alkyl; 5 1 ^ 15 (e) groups of formulas 73 and 73 ', wherein R is C 1 -C 8 alkyl, X is 0, S or KR wherein R 1 is -C 1 alkyl and wherein one or more available carbon atoms may be substituted by C 1 -C 2 alkyl; (f) groups of formulas 7 ^ 79, wherein R 1 is C 1 -C 8 alkyl.-, X is 0, S or NR wherein C 1 -C 12 is alkyl and wherein one or more available ring carbon atoms are optional substituted with C 1 -C 12 alkyl; and (g) groups of formulas 80-85, wherein R '' is C 1 -C 6 alkyl and R is C 1 -C 1 alkyl. 19. A compound according to claim 18, characterized in that R1 hydrogen, ch3ch2-, 25 '3V CH3 \? H? H CH-, f af · _ / ot ™ 3a "" 3 CH ^. 1 8 A compound according to claim 18, characterized in that R and R taken together BOCH 'C =. "·» * W 3 i -135- proposals. 21. A compound according to claim 18, characterized in that R 1 OH is ch 3 C 5. A compound according to claim 18, characterized in that R OH is CH 3 CH- and the absolute configuration is 5R »6S, ÖR. Compound according to claims 17, 18, 19, 20, 21 or 22, characterized in that A is -CH0 or -CH_0HO. 2h. Compound of formula 1, wherein R 0 is hydrogen and R is selected from hydrogen; substituted or unsubstituted: alkyl, alkenyl and alkynyl with 1-10 carbon atoms, cycloalkyl and cycloalkylalkyl with 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl units; phenyl; aralkyl, ar alkenyl and ar alkynyl, wherein the aryl moiety is phenyl and the aliphatic moiety contains 1-6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the heteroatom or atoms in the aforementioned heterocyclic units are selected from 1 to 1; oxygen, nitrogen or sulfur atoms wherein the alkyl units attached to said heterocyclic units contain 1-6 carbon atoms; wherein the substituent or substituents in connection with the above groups are independently selected from C 1 -C 6 alkyl optionally substituted with amino, halogen, hydroxy or carboxyl halogen ψ -OR 3 -136- k> O 11 3 4 -OCNR RO -cnr3r4 -nr3r4, NR3 'nr3r4 O II 34 -S-NRJR il OO II 34 -NHCNR RO 3II 4 R CNR - -co2r3 = 0 O -OCR3 -SR3 O II 9 -SR OU 9 -SR5 II o - - CN 'K3 3 -0S03R o il- 9 -OS-R / 1 oo 3/1 9 -NR SR II O -OP (O) (OR3) (OR4) "f' ./ t Jr -137- ί> 3 4 -KR C = NR 1 * -NR 3 CO 2 R 4 -KO 2 3 wherein in connection with the above substituents the groups R and R are independently selected from hydrogen; alkyl, alkenyl and alkynyl with 1-10 carbon atoms; cycloalkyl, cycloalkylalkyl and alkylcycloalkyl with 5 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl units; phenyl; aralkyl, ar alkenyl and ar alkynyl wherein the aryl unit is phenyl and the aliphatic moiety contains 1-6 carbon atoms t; and heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the heteroatoam or atoms in said heterocyclic unit are selected from 10 1-U oxygen, nitrogen or sulfur atoms and the alkyl units 1-6 carbon atoms linked to said heterocyclic-3 h units. to have; or R and R taken together with the nitrogen to which at least one of them is attached can form a nitrogen-containing 5- or 6-membered heterocyclic ring; R ^ has the 3 meanings of R except that it must not be hydrogen; Or where R 1 and R 8 taken together represent C 1 -C 2 alkylidene or C 1 -C 2 alkylidene substituted by hydroxy, R 1 is selected from the group consisting of substituted and unsubstituted: alkyl, alkenyl and alkynyl having 1 -10 carbon atoms, cycloalkyl and cycloalkylalkyl with 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl units; Phenyl, aralkyl, aralkenyl and aralkynyl wherein the aryl moiety is phenyl and the aliphatic moiety contains 1-6 carbon atoms; heteroaryl, the eroaralkyl, heterocyclyl and heterocyclylalkyl wherein the heteroatom or atoms in the aforementioned heterocyclic units are selected from 1-¼ oxygen, nitrogen or sulfur atoms and the alkyl units associated with said heterocyclic units contain 1-6 carbon atoms; wherein said backgroups are optionally substituted with 1-3 substituents independently selected from: C 1 -C 8 alkyl optionally substituted by amino, fluoro, chloro, carboxy, hydroxy or carbamoyl; Fluorine, chlorine or bromine; λ -138- \ -0R3 -oco2r3? -OCOR3? -OCONR3R4; * Ο ft ο -OS-R * I! . Ox -oxo; -NR3R4; R3CONR4-; -NR3CO2R4; 3 3 4 -NRCONRR; 0 3 "9 -NR s-R *; II 0 -SR 3; 0 -S-R *; 0. K Z a -S-R? ? -SO3R3 y -CO2R3; 3 4 -CONK R; -CN? phenyl optionally substituted with 1-3 fluoro, chloro, bromo, C 1 -C 8 alkyl, -OR 3, -NR 3r -SO..R3, -CO ^ R3 or -CMR3r wherein R3, R ^ and R ^ in such 5 · d 5 R substituents have the aforementioned meanings; or R may be bonded to the group of formula 11 at another point on the ring to form a fused heterocyclic or heteroaromatic ring, which ring may contain additional heteroatoms selected from O, N and S; or 2 A is a C 1 -C 8 straight or branched chain alkylene; R is hydrogen, an amine charge or a conventional easily removable carboxyl protecting group, provided that when R is hydrogen or a protecting group, there is also a counterion; and the group of formula 52 represents a group selected from that of formula 57 wherein R, R, R and R are independently selected from hydrogen; C 1 -C 1 alkyl, C 1 -C 1 alkyl substituted with hydroxy, C 1 -C 1 alkylamino, di (C 1 -C 1) alkylamino, 5C 1 -C 2 alkoxy, amino, sulfo, carhoxy or halogen; C 1 -C 2 cyeloalkyl; C 1 -C 2 alkoxy; C 1 -C 2 alkylthio; amino; C 1 -C 2 alkylamino; di (C 1 -C 1) alkylamino, halogen, C 1 -C 1 alkanoyl and C 1 -C 1 alkanoyloxy; carhoxy; 0 t. . . -C-OC-C-alkyl; hydroxy, amidino; guanidino; phenyl; phenyl substituted 10 with 1, 2 or 3 amino, halogen, hydroxyl, trifluoromethyl, C 1 -C 2 alkyl or -C 1 -C 2 alkoxy groups; phenyl (C 1 -C 6) alkyl in which the phenyl moiety may be optionally substituted with 1-3 substituents as mentioned above in conjunction with phenyl and the alkyl may be optionally substituted with 1-3 substituents as mentioned above in conjunction with C 1 -C 1-4 alkyl; and heteroaryl 15 and heteroaralkyl wherein the heteroatom or atoms are selected from 1-4 oxygen, nitrogen or sulfur atoms and the alkyl moiety connected to said heteroalkyl unit contains 1-6 carbon atoms; or wherein two 6 7 10 of R, R, R taken together may form a condensed saturated carbocyclic ring, a condensed aromatic carbocyclic ring, a condensed non-aromatic heterocyclic ring, or a condensed heteroaromatic ring which fused rings of choice, 6710 are substituted with 1-2 of substituents defined for R, R and R above; or a pharmaceutically acceptable salt thereof. 25. A compound according to claim 24, characterized in that R1 is hydrogen, -CH2CH2-OH OH CH-, t- or ΟΗ- ^ ^- / / CH3 ch3. 1 8 A compound according to claim 24, characterized in that R and R together form HOCH2 -1U0 -1. % \ Ύ \ =. introduce ra3. A compound according to claim 2ks, characterized in that R 1 is OH 5 ch 3 ch-. A compound according to claim 2k, characterized in that R 1 OH is CH 3 CH-1 and the absolute configuration is 5R, 6S, 8R. 29. A compound according to claim 2b, 25, 26, 27 or 28, characterized in that A is -CEL or -CH0CH0-. d d d g .j 30. A compound of formula 1, wherein R 0 is hydrogen and R is selected from hydrogen; substituted and unsubstituted: alkyl; alkenyl 15 and alkynyl with 1-10 carbon atoms; cycloalkyl and cycloalkylalkyl with 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl ring units; phenyl, aralkyl, ar alkenyl and aralkynyl wherein the aryl moiety is phenyl and the aliphatic moiety contains 1-6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the heteroatom or 20 atoms in the aforementioned heterocyclic units are selected from 1-U oxygen, nitrogen or sulfur atoms, and the 1 alkyl units 1-6 carbon attached to said heterocyclic units omen, wherein the substituent or substituents in conjunction with the above. groups are independently selected from C 1 -C 8 alkyl optionally substituted, with amino, halogen, hydroxy or carboxyl, -1U-1-halogen -OR 3 O -ocnr3r4 -cnr3r4 -nr3r4. / NR3 ^ nr3r4 o II 3_4 -S-NR R il O O tl 3 4 -KHCNR R O 3 H 4 R ^ CNR - -co2a3 = 0 o -OCR3 -SR3 O n 9 -SR3 O U 9 -SR3 II O -CN -n3 -0S03R3 o ff 9 -0S-R3 ff O 9 -1U2- V V% Λ. N -NR S-R it 0 -OP (0) (OR3) (OR4) -nr3c = nr4 '-NR3C02 ?. -ho2 3 k wherein in connection with the aforementioned substituents, the groups R and R are independently selected from hydrogen; alkyl, alkenyl and alkynyl of 1-10 carbon atoms; cycloalkyl, cycloalkylalkyl and alkylcycloalkyl of 5 3-6 carbon atoms. in the cycloalkyl ring and 1-6 carbon atoms in the alkyl units; phenyl; aralkyl, ar alkenyl and ar alkynyl wherein the aryl moiety is phenyl and the aliphatic moiety contains 1-6 carbon atoms "; and heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the heteroatom or atoms in said heterocyclic units are selected from 1-h 10 oxygen, nitrogen or sulfur atoms and the alkyl units connected to said heterocyclic 3 1+ units contain 1-6 carbon atoms, or R and R taken together with the nitrogen to which at least one of them is attached / - 9 a nitrogen-containing heterocyclic 5- or 6-nng; R has the 3 meanings for R with the exception that it must not be hydrogen; 1 8 15 or in which R and R ° taken together are C 1 -C 6 alkylidene or 0 C-C 1 alkylidene substituted by 1U ^ d IQ by hydroxy represent; R is selected from substituted and unsubstituted: alkyl, alkenyl and alkynyl of 1-10 carbon atoms: cycloalkyl and cycloalkylalkyl of 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon dust atoms in the alkyl units; phenyl, aralkyl, aralkenyl 20 and aralkynyl wherein the aryl moiety is phenyl and the aliphatic moiety has 1-6 carbon atoms, heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the heteroatom or atoms in the aforementioned heterocyclic units are selected from 1-U oxygen units, nitrogen or sulfur atoms, and the alkyl units attached to said heterocyclic units contain 1-6 carbon atoms, wherein the above R '' groups are optionally substituted by 1-3 substituents independently selected from: C 1 -C 8 alkyl optionally substituted by amino, fluorine, chlorine, carboxyl, hydroxy or carbamoyl; fluorine, chlorine or bromine; -O * -0C02R3; -tOCOR3? -OCONR3R4; O t10 -OS-R * I) O -oxo; -NR3R4; 3 4 R COUR -; -NR3CO2R4; -NR3CONR3R4 '? - O 3> 9 -NRJS-R; n O -SR3? O -r * e -S-R *; O O R 7 q -S-R *; -SO3R3; CO2R3; -CONR3R4; -CN? phenyl optionally substituted with 1-3 fluoro, chloro, bromo, C 1 -C 6 alkyl, -OR 3, -HR 1, r -SO or CO_R ^ or -COIRE ^ R ^, where R ^, R ^ and R ^ in such substituents have the aforementioned meanings; or R may be attached to the group of formula 11 at another point on the ring to form * Λ - λ -1W- of a condensed heterocyclic or heteroaromatic ring, which ring may contain additional heteroatoms selected from 0, II and S; A is a straight ... or branched alkylene; R hydrogen, an anomalous charge or a conventional easily removable carboxyl protecting group is 2 provided that when R is hydrogen or a protecting group there is / is also a counterion, and the group of formula 52 is a group of the formula. 58, 59 or 60, optionally on a carbon atom substituted with 1-3 substituents independently selected from C 1 -C 6 alkyl; C 1 -alkyl substituted by hydroxy, C 1 -C 6 alkylamino, 10 diC 1 -C 6 alkyl) amino, sulfo, C 1 -C 6 alkoxy, amino, carboxy or halogen; C 1 -C 8 cycloalkyl; C 1 -C 2 alkoxy; C 1-6 alkylthio; amino, C 1 -C 2 alkylamino, di (C 1 -C 2) alkylamino; halogen; C 1 -C 2 alkanoylamino; C ^ -C ^ alkanoyloxy, carboxy 0 I '.... -C-OC-C-alkyl, hydroxy; amidino; guanidino; phenyl; phenyl substituted with 1, 2 or 3 amino, halogen, hydroxy, trifluoromethyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy groups; phenyl (C 1 -C 6) alkyl in which the phenyl moiety may be optionally substituted with 1-3 substituent and as mentioned above in conjunction with phenyl and the alkyl moiety may optionally be substituted with 1-3 substituents as mentioned above in conjunction with phenyl C 1 -C 2 alkyl; and heteroaryl or heteroaralkyl in which the heteroatom or atoms in the aforementioned heterocyclic units are selected from 1-oxygen, nitrogen or sulfur atoms, and the alkyl moiety linked to said heteroaralkyl unit has 1-6 carbon atoms, or choice is substituted to form a fused carbocyclic, heterocyclic or heteroaromatic ring, optionally substituted with one or two of the above defined substituents; or a pharmaceutically acceptable salt thereof. The compound of claim 30 wherein the group of formula 52 is a group of formula 58. The compound of claim 30, wherein the group of formula 52 is a group of formula 59. The compound of claim 30, wherein the group of formula 52 is a group of formula 60. 3 ^. Compound according to claims 30, 31, 32, 33, characterized in that 35 R hydrogen, CH 1 CH 2 -> **. - / -1 ^ 5- / 3 \ uHHCH "/ C-OCH, CH-. CSf CH3. Compound according to claim 30, 31, 32 or 33, characterized in that 1 „8. R and R taken together HOCH-2 \ 0. ai 5 introduce. 36. A compound according to claim 30, 31, 32 or 33, characterized in that R 1 is OH CH 3 CH-10. Compound according to claim 30, 31, 32 or 33, characterized in that B1 is OH CH3CH-15 and the absolute configuration is 5B, 6S, 8R. 38. A compound according to claim 30, 31, 32 or 33, characterized in that A is -CH 2 or -CH 2 CH 2 -, R 1 is 0Ξ ch 3 ch-20 and the absolute configuration is 5R, 6S, 8R. 8 1 39. A compound of formula 1, wherein R is hydrogen and R is substituted. -1U6- V 'V selected from hydrogen; substituted and unsubstituted: alkyl, alkenyl and alkynyl with 1-10 carbon atoms; cycloalkyl and cycloalkylalkyl with 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkylenes, phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl moiety is phenyl 5 and the aliphatic moiety contains 1-6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the heteroatom or atoms in the aforementioned heterocyclic units are selected from 1-¼ oxygen, nitrogen or sulfur atoms and the alkyl units attached to said heterocyclic units contain 1-6 carbon atoms; wherein the substituent or substituents in connection with the above groups are independently selected from the group consisting of C 1 -C 8 alkyl optionally substituted with amino, halogen, hydroxy, or carboxyl halogen -OR 3 O 11 34 -OCNRJR 0 -cnr3r4 - nrV 5 // ^ \ rV o II 3 4 -S-NRJR * il 0 o ti 3 4 -KBCNR RO 3 ll 4 3TCNR - -co2r3 —OO -OCR3 -SR3 OU 9 -SR9 ........ - - -...................... »-> T» * -T ** * '&' {. ! - .................... 4 * * τ / -1 ^ 7- 0 '(ί 9 -SR * It * Ο -CN - «3 3 -0S03R ο II ο -Ο SR * H Ο. Ο 3, {9 -NR ^ SR * η ο -0? {0) (OR3) (OR4) -nr3c = nr4 i3 -NR3cÓ2R4 -ηο2 In connection with the above substituents, the groups E and E are independently selected from hydrogen; alkyl, alkenyl and alkynyl with 1-10 carbon atoms; cycloalkyl, eyeliaalkylalkyl and alkylcycloalkyl having 5 3-6 carbon atoms in the cycloalkyl unit and 1-6 carbon atoms in the alkyl unit; phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl moiety is phenyl and the aliphatic moiety contains 1-6 carbon atoms; and heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the heteroatom or atoms in said heterocyclic unit are selected from 10 1-U oxygen, nitrogen or sulfur atoms and the alkyl units attached to said heterocyclic 3 4 units have carbon atoms whether E and E taken together with the nitrogen to which at least one of them is attached can form a nitrogen-containing 5- or 6-membered heterocyclic ring, E ^ has the 3 meanings of E except that it must not be hydrogen; 1 δ 15 cf in which E and E taken together represent C 1 -C 8 alkylidene or C 1 -C alkylidene w Iuq ^ 10 substituted with hydroxy; κ is selected from substituted V 1 to 1 unsubstituted: alkyl, alkenyl and alkynyl of 1-10 carbon atoms; cycloalkyl and cycloalkylalkyl with 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl units; phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl moiety is phenyl and the aliphatic moiety contains 1-6 carbon atoms "; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclyl alkyl wherein the heteroatom or atoms in said heterocyclic units are selected from 1-4 oxygen, nitrogen or sulfur atoms and the alkyl units attached to said heterocyclic units contain 1-6 carbon atoms, wherein the above R 1 groups are optionally substituted with 1-3 substituents independently selected from: C 1 -C 8 alkyl to optionally substituted by amino, fluoro, chloro, carboxyl, hydroxy or carbamoyl; fluoro, chloro or bromo; -OR3 -0CO2R3 yr ^ OCOR3; -oconr3r4? 0 nq -os-sr II o -oxo; -h'R R; 3 4 R CONR -; -NR3C02R4; -nr3conr3r4; 0 311 0 -NRJS-R *; u 0 -SR3; Λ 0 9 -SR; 0. n 7 0 -SR *; -S03R3; -C02R3; -CONR3R4;? -149-> <C * phenyl optionally substituted with 1-3 fluorine, chlorine, bromine, C 1 -C 8 alkyl, -OR 3, -Μ 3ε \ -SO-r \ -CO_ R3 or -COBE3h, where R3, R19 and R9 in such 5d. 5 R. substituent and have the meanings mentioned; or R may be attached to the group of formula 11 at another point on the ring such that a fused heterocyclic or heteroatamatic ring is formed which ring may additionally contain the group selected from 0, N and S; A a C.-C. straight or branched chain alkylene; R is hydrogen, an anionic charge, or a conventional easily removable carboxyl-protecting group 2 provided that when R is hydrogen or a protecting group there is also a counterion present; and the group of formula 52 represents a group of formulas 61-66, optionally on a carbon atom substituted by 1-3 substituents independently selected from C 1 -C 6 alkyl; C 1 -G 2 alkyl substituted by hydroxy, C 1 -C 2 alkylamino, diCC 1 -C 2 alkylamino, sulfo, C 1 -C 20 alkoxy, amino, carboxy or halogen; C 1 -C 8 cycloalkyl; C 1 -C 2 alkoxy, C 1 -C 2 alkylthio; amino; C 1 -C 2 alkylamino; di (C 1 -C 2) alkylamino; halogen; C 1 -C 12 alkanoylamino, C 1 -C 20 alkanoyloxy; carboxy: -C-OC-C 1-6 alkyl; hydros; amidino; guarddino; phenyl; phenyl substituted with 1, 2 or 3 amino, halogen, hydroxyl, trifluoromethyl, C 1 -C 6 alkyl or C 1 -C 6 alkoxy groups; phenyl (C 1 -C 2) alkyl, phenyl (C 1 -C 1 -C) alkyl in which the phenyl moiety may be optionally substituted by 1-3 substituents as noted above in conjunction with phenyl and the alkyl moiety may be optionally substituted with 1-3 substituents as mentioned above in connection with C 1 -C 12 alkyl; and heteroaryl or heteroaralkyl in which the heteroatom or atoms in the aforementioned heterocyclic units are selected from 1-4 oxygen, nitrogen or sulfur atoms, and the alkyl unit linked to said heteroalkylene moiety contains 1-6 carbon atoms, or is optionally substituted that a condensed carbocyclic, heterocyclic or heteroaromatic ring is formed, optionally substituted with one or two of said defined substituents; or a pharmaceutically acceptable salt thereof. 40. A compound according to claim 39, characterized in that R 1 is hydrogen, CH 3 CH 2 -, 35 V -150-CH, OH-1, 'C-C or C 5 -CH-3 CH 2. 1 8 hi. A compound according to claim 39, characterized in that R and R taken together represent HOCH, C-ch 3. k2. A compound according to claim 39, characterized in that R ** OH is CH3CH-. 10 i + 3. Compound according to claim 39, characterized in that R OH is CH 3 CH-, and the absolute configuration is 5R, 6S, 8R. kk. A compound according to claim 39, 0, h1, k2 or 13 wherein A is -CH ^ -15 or -CH0CH0-. £ d 8 1 Compound of formula 1, wherein R is hydrogen and R is selected from hydrogen, substituted and unsubstituted: alkyl, alkenyl and alkynyl with 1-10 carbon atoms, cycloalkyl and cycloalkylalkyl with 3-6 carbon atoms in the cycloalkyl ring and 1 -6 carbon atoms in the alkylene-20 present; phenyl, aralkyl, aralkenyl and aralkynyl wherein the aryl moiety is phenyl * -151-% and the aliphatic moiety contains 1-6 carbon atoms, heteroacyl, heteroaralkyl, heterocyclyl and heterocyelylalkyl, wherein the heteroatom or atoms in the aforementioned heterocyclic units selected from 1-4 oxygen, nitrogen or sulfur atoms and the alkyl units attached to said heterocyclic units contain 1-6 carbon atoms; wherein the substituent or substituents in connection with the above groups are independently selected from: C 1 -C 8 alkyl optionally substituted by amino, halogen, hydroxy or carboxyl, 10 halogen -OR 3 O 3 3 -OCNR RO -CNR3R4-nr3r4 / NR3 . • “Cv O II 34 -S-NR R il 0 0 M 34 -NHCNR R * 0 3II 4 R CNR - -co2r3 = 0 0 -OCR3 -SR3 0/1 9 -SR * 0 II g -Sk ll o. * V -152- -CN ”N3 -oso3r3 o tl q -OS-K / (O o 3 tl g -NR sr I! O -OP (O) (OR3) (OR4) 3 4 -NR C = NR i 3 -4 -NR CO 2 R -NO 2 3 wherein, in connection with the above substituent and, the groups R and r 4 are independently selected from hydrogen, alkyl, alkenyl and alkynyl with 1-10 carbon atoms: cyeloalkyl, cycloalkylalkyl and alkylcycloalkyl 5 with 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl units; phenyl, aralkyl, ar alkenyl and ar alkynyl wherein the arylene moiety is phenyl and the aliphatic moiety has 1-6 carbon atoms; and heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl in which the heteroatom or atoms in the aforementioned heterocyclic units are selected from 1-4 oxygen, nitrogen or sulfur, and the alkyl units 1-6 associated with said heterocyclic units carbon atoms contain 3 lv. or R and R taken together with the nitrogen to which at least one of them is bound a nitrogen 5- or 6-membered heterocyclic ring, 9.3. R has the meanings of R except that it has no hydrogen -. . .18 may be 15; or where R and R taken together represent C 1 -C 20 alkylidene or O 2 -alkylidene substituted by hydroxy; R1 is selected from substituted and unsubstituted alkyl, alkenyl and alkynyl with 1-10 carbon atoms; cyeloalkyl and cycloalkylalkyl with 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl units; phenyl, aralkyl, ar alkenyl and ar alkynyl wherein the aryl moiety is phenyl and the aliphatic moiety contains 1-6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl in which the heteroatom or atoms in the aforementioned heterocyclic units are selected from 1-5 oxygen, nitrogen or sulfur atoms and the alkyl units related to said heterocyclic units 1-6 carbon atoms; wherein the above groups 5 are optionally substituted with 1-3 substituents independently selected from: C 1 -C 6 alkyl optionally substituted with amino, fluoro, chloro, carboxyl, hydroxyl, carbamoyl; fluorine, chlorine or bromine; -OR3 -CO2R3; -OCQR3; -OCONR3R4; 0 n g -OS-R3 U. o -oxo; 3 4 -NITR? 3 4 RJCONR -; -NR3CO2R4; -NR3CONR3R4; O 3 9 9 -NR--R 3; O -SR3; . O * 9 -S-R; O O K 7 o -S-R3; -so3r3? CO2R3; -CONR3R4; -CNj o £ λ - * -151 * - * V 3 phenyl optionally substituted with 1-3 fluoro, chloro, ci-cg alkyl, OR - -NR3r \ -SO R3, -CO R3 or -COHrV * where R3 , R ^ and R9 in such R5-. 3 ά. 5 .. substituents have the aforementioned meanings; or R may be attached to the group of formula 11 at another point of the ring such that a fused heterocyclic or heteroaromatic ring is formed which ring may contain additional heteroatoms selected from 0, I and S, A straight or branched alkylene with 1-6 carbon is omen; 2. . ... R is hydrogen, an amonic charged or a conventional, easily removable carboxyl protecting group provided that when R 10 is hydrogen or a protecting group, a counterion is also present; and the group of formula 52 represents a group of formulas 67-72, optionally substituted on a carbon atom with a substituent independently selected from C 1 -C 6 alkyl; C 1 -C 2 alkyl substituted by hydroxy, amino, C 1 -C 20 alkylamino, di (C 1 -C 20) alkylamino, sulfo, C 1 -C 20 alkoxy, carboxy, or halogen; C 1 -C 8 cyeloalkyl; alkoxy; alkylthio; amino, C 1 -C 2 alkylamino, di (C 1 -C 2) alkylamino, halogen, C 1 -C 2 alkanoylamino; C 1 -C 2 alkanoyloxy; carboxy; 0'-C-OC-C 1-6 alkyl; hydroxy; amidino; guamdino; phenyl; phenyl substituted with 1, 2 and 3 amino, halogen, hydroxyl, trifluoromethyl, C 1 -C 6 alkyl or C 1 -C 6 alkoxy groups; phenyl (C 1 -C 6) alkyl, wherein the phenyl moiety may be optionally substituted with 1-3 substituents as mentioned above in conjunction with phenyl and the alkyl moiety may be optionally substituted with 1-3 substituents as noted above in conjunction with C ^ -C ^ alkyl? and hetero-aryl or heteroaralkyl wherein the heteroatom or atoms in the above heterocyclic units are selected from 1-U oxygen, nitrogen or sulfur atoms and the alkyl unit attached to said heteroaralkyl unit has 1-6 carbon atoms, or a pharmaceutically acceptable salt thereof. k6. Compound according to claim U5, characterized in that R ** is hydrogen, 30 represents -C12CH2-, a3 \ ra CH-, C- or CH.CH- / / 3 ra3-ra3 -155- ƒ. 1 8 Vf. Compound according to claim 45, characterized in that R and K taken together hoch2. “3 5 proposals. 48. A compound according to claim 45, characterized in that R 1 is OH 1 CH 3 CLI-. A compound according to claim 45, characterized in that R * '<* OH is CH 3 CH- and the absolute configuration is 5R, 6S, 8R. 50. A compound according to claim 45, 46, 47, 48 or 49, characterized in that A is -CH - or -CH - CH -. d d d g ^ 51. A compound of formula 1, wherein R 0 is hydrogen and R is selected from hydrogen, substituted and unsubstituted; alkyl, alkenyl and alkynyl with 1-10 carbon atoms, cycloalkyl, and cyeloalkylalkyl. with 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl units; Phenyl, aralkyl, ar alkenyl and ar alkynyl wherein the aryl moiety is phenyl and the aliphatic moiety contains 1-6 carbon atoms, heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the heteroatom or atoms in the aforementioned heterocyclic units are selected from 1-4 oxygen, nitrogen or sulfur atoms and the alkyl units linked to said heterocyclic units contain 1-6 carbon atoms; wherein the substituent or substituents in connection with the above groups are independently selected from the group consisting of: - -156- C 1 -C 8 alkyl optionally substituted, by amino, halogen, hydroxy or carboxyl, halogen -OR 3 O 11 3 4 -OCNR R .0 tl 34 -cnrjr '3 4 -NR R, NR3 ^ NR3R4 O II 3 4 -S-NRk' II oo II 3 4 -rNHCNR'R * O 4 R CNR - -co2r3 = 0 O -OCR3 -SR3 O II 9 -SR * OU 9 -SR * II o -CN • -N3 3 -0S03R o H 9 -OS-R * noo 3> l 9 -NRJS-R * II O · -OP (O) ( OR3) (OR4) * -157- -NR3C * NR4 -NR3CO2R4 -NO2 3 wherein, in connection with the above substituents, the groups R and R are independently selected from hydrogen, alkyl, alkenyl and alkynyl. . having 1 to 10 carbon atoms; cycloalkyl, cycloalkylalkyl and alkylcycloalkyl having 5 to 6 carbon atoms in the cyeloalkyl ring and 1 to 6 carbon atoms in the alkyl units; phenyl, aralkyl; ar alkenyl and ar alkynyl wherein the aryl moiety is phenyl and the aliphatic moiety has 1-6 carbon atoms, and heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the heteroatoam or atoms in the aforementioned heterocyclic units are selected from 10 1 4 oxygen, nitrogen or sulfur atoms, and the alkyl units attached to said heterocyclic units contain 1-6 carbon atoms, or R and R 2 taken together with the nitrogen to which at least one of them is bonded a nitrogen-containing 5- or 6-ring heterocycle can form, 9 .3. R has the meanings of R except that it cannot be hydrogen 1 8 15; or wherein R and R taken together represent C8 -C18 alkylidene or C8 -C18 alkylidene substituted by hydroxy; R ^ is selected from substituted and unsubstituted: alkyl, alkenyl, alkynyl of 1-10 carbon atoms, cycloalkyl and cycloalkylalkyl of 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl units: phenyl, aralkyl, ar arkenyl and ar alkynyl wherein the aryl moiety is phenyl and the aliphatic moiety contains 1-6 carbon atoms; heteroaryl, the eraralkyl, heterocyclyl and heterocyclylalkyl wherein the heteroatoam or atoms in the aforementioned heterocyclic units are selected from 1-5 oxygen, nitrogen or sulfur atoms and the alkylene units associated with said heterocyclic units 1-6 carbon atoms contain; wherein the above R groups are optionally substituted with 1-3 substituents independently selected from: C 1 -C 8 alkyl optionally substituted with amino, fluoro, chloro, carboxy, hydroxyl, carbamoyl, fluoro, chloro or bromo; '_ * -158- V% -OR3 -oco2r3? -OCOR3; -OCONR3R4; O II 9 -OS-R * II • o -oxo; 3 4 -NRR; R3CONR4-; -no3co2r4; -nr3conr3r4? O 3 "9 -NR SR *; II O -SR3; O -SR *; OO n 7> o -SR *; -S03R3; -CO2R3; -CONR3R4; -CN; or 3 phenyl optionally substituted with 1-3 fluorine, chlorine, C 1 -C 8 alkyl, OR - ,ffiV *, -SO R3, -CO R3 or -COER3R ^ in which R3, R ^ and R9 in such R5-5 d substituents have the aforementioned meanings or R may be attached to the group of formula 11 at another point of the ring such that a condensed heterocyclic or heteroaromatic ring is formed which ring may contain additional heteroatoms selected from O, ET or S; A a straight or branched alkylene with 1-6 carbon atoms are 2 ... R hydrogen, an aniomally charged or a conventional, easily removable carboxy 1 protecting group, provided that when R is -159% hydrogen or a protecting group there is also a counterion present, and the group of formula 52 represents a group of formula 73 or 73 'wherein X is O, S or KR, wherein R is C 1 -C 2 alkyl; C 1 -C 2 alkyl substituted with 1-3 hydroxy, amino, C 1 -C 20 alkylamino, di (C 1 -C 20) alkylamino, C 1 -C 20 alkoxy, carboxy, halogen or sulfo groups; C 1 -C 8 cyeloalkyl, C 1 -C 8 (C 1 -C 12) alkyl optionally substituted with 1-3 substituents as mentioned above in connection with C 1 -C 12 alkyl; phenyl, phenyl substituted with 1-3 substituents independently selected from amino, halogen, hydroxy, trifluoromethyl, C 1 -C 2 alkyl, C 1 -C 2 alkoxy, alkylamino., di (C 1 -C 2) alkylamino, 10 carboxy and sulfo; phenyl (C 1 -C 6) alkyl in which the phenyl moiety may be optionally substituted with 1-3 substituents as mentioned above in conjunction with phenyl and the alkyl moiety may be optionally substituted with 1-3 substituents as mentioned above in conjunction with phenyl -C 1-4 alkyl; and heteroaryl and heteroaralkyl wherein the heteroatoam or atoms are selected from 15-1 * 0, S or N atoms and the heteroaralkyl-linked alkyl moiety contains 1-6 carbon atoms, which heteroaryl and heteroaralkyl groups are optionally substituted in the heterocyclic ring moiety with 1-3 substituents independently selected from hydros, amino, halogen, trifluoromethyl, C 1 -C 1 alkyl, C 1 -C 1 alkoxy, C 1 -C 1 alkylamino, diCC ^ -C ^} alkylamino, carboxy 20 and sulfo and in the alkyl moiety by 1-3 substituents selected from hydroxy, amino, C 1 -C 6 alkylamino, diiC 2 C 6) alkylamino, C 1 -C 6 alkoxy, carboxy, halogen which is heteroaramatic group optionally substituted by a carbon atom or more substituents independently selected from C 1 -C 1 alkyl, C 1 -C 1 alkyl substituted with hydroxy, C 1 -C 1 alkylamino, di (C 1 -C 1) - alkylamino, C 1 -C 1 alkoxy, amino sulfo, carboxy or halogen, C 1 -C 8 cycloalkyl, C 1 -C 1 alkoxy, C 1 -C 1 alkylthio, amino, alkylamino, diiC 1 -C 2) - alkylamino, halogen, C 1 -C 1 -alkanoylamino, C 1 -C 1 -alkanoyloxy; carboxy O] {... -C-OC-C 1 -C 2 alkyl; hydroxy; amidino; guamdino; phenyl; phenyl substituted with 1, 2 or 3 amino, halogen, hydroxy, trifluoromethyl, C 1 -C 6 alkyl or C 1 -C 6 alkoxy groups; phenyl (C 1 -C 6) alkyl, wherein the phenyl moiety may be optionally substituted with 1-3 substituents as mentioned above in conjunction with phenyl and the alkyl moiety may be optionally substituted with 1-3 substituents as noted above in conjunction with C ^ -C ^ alkyl; and hetero-aryl or heteroaralkyl wherein the heteroatoam or atoms in the above cyclic units are selected from 1-1 oxygen, nitrogen or sulfur atoms and the alkylene-> v -160-A unit 1-6 associated with said heteroaralkyl unit carbon atoms "or is optionally substituted to form a condensed carbocyclic, heterocyclic or heteroatomization optionally substituted with one or two of the above-defined substituents or a pharmaceutically acceptable salt thereof. 52. A compound according to claim 51, characterized in that R 1 is hydrogen, -ch 3 ch 2 -, <= 3 CH \ OH OH. r- * * 10 CHCH-. 0H3 CH ^ 3 is 10. 1 8 A compound according to claim 51, characterized in that R and R taken together represent hoch 2> CH 3. Compound according to claim 51, characterized in that R 1 is OH CH 3 CH-. 55. A compound according to claim 51, characterized in that r "'* 20 OH is ch3ch- and the absolute configuration is 5R» 6S, 8R. 56. A compound according to claims 51, 52, 53, 5, 55> characterized in, j i tj -161-f J which is -CH0- or -CH CH -, ώ 2 g * j 57. A compound of formula 1, wherein R is hydrogen and R is selected from hydrogen, substituted or unsubstituted: alkyl, alkenyl or alkynyl of 1-10 carbon atoms, cycloalkyl and cycloalkylalkyl of 5-6 carbon atoms in a cycloalkyl ring and 1-6 carbon atoms in the alkyl units; phenyl, aralkyl, ar alkenyl, and aralkynyl wherein the aryl moiety is phenyl and the aliphatic moiety contains 1-6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the heteroatom or atoms in the aforementioned heterocyclic units are selected from 10 1-k oxygen, nitrogen or sulfur atoms, the alkyl units attached to said heterocyclic units containing 1-6 carbon atoms; wherein the substituent or substituents in connection with the above groups are independently selected from C 1 -C 8 alkyl, optionally substituted with amino, halogen, hydroxy or carboxyl, halogen -OR 3 O 11 3 4 -OCNRJR O II 34 -CNR R 3 4 -NRJR. / NS3 r4 'nr3r4 o li 34 -S-NR R It O o M 34 -KHCNR RO 3 Η 4 R CNR - -co2r3 = 0 -162- V fc 0 -OCR3 -SR3 O n 9 - -SR5 O // 9 -SR5 II o -CN - »3 3 -OSOsR o H 9 -OS-R5 II o. o -nr3s-r9 ci -OP (O) (OR3) (OR4) -NR3C = NR4 -NR3C02R4 -no2 3 U • wherein in connection with the above-mentioned substituent and the groups R and R are independently selected from hydrogen, alkyl, alkenyl and alkynyl of 1-10 carbon atoms. Cycloalkyl, cycloalkylalkyl and alkylcycloalkyl of 5-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl units; phenyl; aralkyl; aralkenyl and aralkynyl wherein the aryl moiety is phenyl and the aliphatic moiety contains 1-6 carbon atoms; and heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the heteroatoms or atoms in said heterocyclic unit are selected from 10 1-1) oxygen, nitrogen or sulfur atoms and the alkyl units attached to said heterocyclic units have 1-6 carbon atoms or R3 and R1 taken together with the nitrogen to which at least one of them is attached, ». ·; 'i' '"J i -163- / £% 9 can form a nitrogen-containing 5- or 6-membered heterocyclic ring; a O has the meanings of R except that it must not be hydrogen or where R and R taken together, C 1 -C 2 alkylidene or C 1 -C 1 alkylidene substituted by hydroxy, R 1 is selected from substituted and unsubstituted: alkyl, alkenyl and alkynyl of 1-10 carbon atoms, cycloalkyl and cycloalkylalkyl with 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl units, phenyl, aralkyl, ar alkenyl and aralkynyl wherein the aryl moiety is phenyl and the aliphatic moiety contains 1-6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and the heterocyclylalkyl wherein the heteroatom or atoms in the aforementioned heterocyclic units are selected from 1-1 h oxygen, nitrogen or sulfur and the alkyl units attached to said heterocyclic units contain 1-6 carbon atoms; wherein the aforementioned R ^ groups optionally substituted with 1-3 substituents independently selected from: C 1 -C 8 alkyl optionally substituted by amino, fluoro, chloro, carboxy, hydroxy, or carbamoyl; fluorine, chlorine or bromine, -OR 3 -O 2 CO 2 R 3; r-OCOR3? -OCONR3R4; 0/1 Q —OS-λ? II • O -OXO? -NR3R4; R3CONR4-; -NR3CO2R4 7 3 3 4 -NR CONR R; 0 311 o -ms-zc 7 if 0 -SR3 7 ^% - ·· -161 * -0 -r 9 -S-λ * 0 o K 7 9 -S-R 7 -so3r3; -co2R3; -CONR3R4 7 -CN; phenyl optionally substituted with 1-3 fluoro, chloro, bromo C. -C5 alkyl, OR3 -mVm -SO_R3, CO ^ R3 6f -CONrV * where R3, R ^ and R9 • 5 · 5. 3 ^ 5 m such R substituents have the aforementioned meanings; or R 5 may be attached to the group of formula 11 at another point on the ring to form a fused heterocyclic or heteroaromatic ring, which ring may contain additional heteroatoms selected from 0, 1 and S; or 2 A is C 1 -C 8 straight or branched alkylene; R hydrogen or an anionic charge 10 or a conventional easily removable carboxyl group is provided that when R is hydrogen or a protecting group there is also a counterion and the group of formula 52 represents a group of formulas 7 ^ 79 » where X is 0, S or NR wherein R 1 is -C 1 -alkyl; C 1 -alkyl substituted with 1-3 hydroxy, amino, C 1 -C 2 alkylamino, di-15 (C 1 -C 2) alkylamino, C 1 -C 2 alkoxy, carboxy or halogen or sulfo groups ; C 1 -C 8 cycloalkyl, C 1 -C 8 cycloalkyl (C 1 -C 1) alkyl optionally substituted with 1-3 substituents as mentioned above in connection with C 1 -C 1 alkyl; phenyl; phenyl substituted by 1-3 substituents independently selected from amino, halogen, hydroxy, trifluoromethyl, C ^ C ^ alkyl, C ^ -C ^ alkoxy, C ^ -C ^ alkylami-20 no, di (C ^ -C ^) alkylamino ,. carboxy and sulfo; phenyl (C 1 -C 6) alkyl, wherein the phenyl moiety may be optionally substituted with 1-3 substituents as mentioned above in conjunction with phenyl and the alkyl moiety may be optionally substituted with 1-3 substituents as noted above in conjunction with C ^ -C ^ alkyl; and heteroaryl and heteroaralkyl wherein the heteroatom or atoms are selected from the group consisting of 1-1 * 0; S- or N-atoms the heteroaralkyl-linked alkyl moiety contains 1-6 carbon atoms which heteroaryl and heteroaralkyl groups are substituted in the heterocyclic moiety with 1-3 substituents independently selected from hydroxy, amino, -165-halogen, trifluoromethyl , C 1 -C 1 alkyl, C 1 -C 1 alkoxy, alkylamino, di (C 1 -C 1) alkylamino, carboxy and sulfo and in the alkyl unit by 1-3 substituents selected from hydroxy, amino, C 1 -C ^ alkylamino, diCC ^ -C ^) alkylamino, alkoxy. carboxy, halogen and sulfo, which heteroaromatic group is optionally substituted on a carbon atom with one or more substituents independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted with hydroxy; C 1 -C 20 alkylamino, di (C 1 -C 20) alkylamino, C 1 -C 20 alkoxy, amino, sulfo, carboxy or halogen; C 1 -C 8 cycloalkyl; C 1 -C 2 alkoxy, C 1 -C 2 alkylthio; amino; C 1 -C 2 alkylamino; diiC ^ -C ^) alkylamino; halogen; C 1 -C 4 alkanoylami-10 no; C 1 -C 2 alkanoyloxy; carboxy-C-OC-C 1 -C 2 alkyl; hydroxy; amidino; guanidino; phenyl; phenyl substituted with 1, 2 or 3 amino, halogen, hydroxyl, trifluoromethyl, C 1 -C 6 alkyl or alkoxy groups; phenyl (C 1 -C 6) alkyl, wherein the phenyl moiety may optionally be substituted with 1-3 substituents as mentioned above in conjunction with phenyl and the alkyl moiety may be optionally substituted with 1-3 substituents as noted above in coherence with C 1 -C 2 alkyl; and heteroaryl or heteroaralkyl wherein the heteroatom or atoms in the above cyclic units are selected from 1-4 oxygen, nitrogen or sulfur atoms and the alkyl moiety associated with said heteroaralkyl contains 1-6 carbon atoms, or a pharmaceutical acceptable salt thereof. 58. A compound according to claim 57, characterized in that R is hydrogen, -ch 3 ch 2 -, 25 ct 3 ra, oh Nl Λ I - 'C- or CH.CH-. CBj 'is 3. 1 ft Compound according to claim 57, characterized in that R and R ° taken together are hoch2. = 3 ^ -166->> N suggest. 60. A compound according to claim 57, characterized in that R is OH, J f CH 3 CH-X 5. A compound according to claim 57, characterized in that r "'OH is ch 3 ch - and that the absolute configuration is 5R, 6S, 8R. A compound according to claim 57, 58, 59, 60 or 61, characterized in that A is -CHO- or -CH.CH-. d d 2 Q -y 63. A compound of formula 1, wherein R is hydrogen and R is selected from hydrogen, substituted and unsubstituted: alkyl, alkenyl and alkynyl of 14-10 carbon atoms, cycloalkyl and cycloalkylalkyl of 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkylene present, phenyl, aralkyl, ar alkenyl and ar alkynyl wherein the aryl moiety is phenyl and the aliphatic moiety contains 1-6 carbon atoms, heteroaryl, heteroarylaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the heteroatom or atoms in the said heterocyclic units are selected from 1-U oxygen, nitrogen or sulfur atoms and the alkyl units attached to said heterocyclic units have 1-6 carbon atoms; wherein the substituent or substituents in connection with the above groups are independently selected from the group consisting of: C 1 -C 8 alkyl optionally substituted by amino, halogen, hydroxy or carboxyl, halogen -OR 3 O 11 3 4 -OCNR RO -ctr3r4 -nr3r4 _ », * * - * -> \ £ 4. -167- // ^ \ nr3r4 o II 34 -s-nr r II 0 0 M 3 4 -nhcnr r 0 _3« 4 a CNR - - CO2R3 = 0 0 -OCR3 -SR3 0 II g -SR3 0 // g -SR3 ii 0 -CH * 3 3 -0S03R 0 il g -0S-R no. o 3 // 9 -NR S-R // 0 -0? (0) (OR3) (OR4) \ • x -168- 3 4 -NR C = NR 1 '-NR 3 CO 2 R 4 -no 2 3' U • in which, in connection with the above-mentioned substituents, the groups R and R are independently selected from hydrogen, alkyl, alkenyl and alkynyl with 1-10 carbon atoms, cycloalkyl, cycloalkylalkyl and alkylcycloalkyl with 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl units; phenyl; aralkyl, ar alkenyl and ar alkynyl wherein the aryl moiety is phenyl and the aliphatic moiety has 1-6 carbon atoms; and heteroaryl, the alkyl, heterocyclyl and heterocyclyl and heterocyclylalkyl wherein the heteroatom or atoms in the aforementioned heterocyclic units are selected from 1-¾ oxygen, nitrogen or sulfur, and the alkyl units 1-6 associated with said heterocyclic units carbon atoms include, x or R and R taken together with the nitrogen to which at least one of them is bonded can form a nitrogen-containing 5- or 6-membered heterocyclic ring; R has the meanings of R except that it must not be 1 8 15 hydrogen; or wherein R and R taken together represent 0 ^ -O ^ alkylidene or C8 -C18 alkylidene substituted by hydroxy; R ^ is selected from substituted and unsubstituted: alkyl, alkenyl, alkynyl of 1-10 carbon atoms, cycloalkyl and cycloalkylalkyl of 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl units; phenyl; ar-20 alkyl, aralkenyl and ar alkynyl wherein the aryl moiety is phenyl and the aliphatic moiety contains 1-6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the heteroatom or atoms in the aforementioned heterocyclic units are selected from 1-h oxygen, nitrogen or sulfur atoms and the alkyl-25 units attached to said heterocyclic units contain 1-6 carbon atoms; wherein the above R 1 groups are optionally substituted with 1-3 substituents independently selected from: C 1 -C 8 alkyl optionally substituted with amino, fluoro, chloro, carboxyl, hydroxyl, carbamoyl; fluorine, chlorine or bromine, F. i 4T * -169- t -OR3 -oco2r3? f r-OCOR3; -OCONR3R4; o n Q -OS-R * i; . O -OXO; -NR3R4; R3CONR4-? -NR3CO2R4; -nr3conr3r4? O 3 »* 9 -NR S-R *? HO - SR3? O -S-R * 7 O O K * g -S-R5 7 -SO3S3 -CO2X3; -CONR3R4; -CN? or 3 phenyl optionally substituted with 1-3 fluoro, chloro, C 1 -C 8 alkyl-. OR, 3 1). 1l 3 3 k 3 kg '° e -KR R, -SO ^ R 3 -CO ^ R or COKR R wherein R, R and ΈΓ in such R substituents have the aforementioned meanings or R ^ may be attached to the group of formula 11 at another point on the ring such that a fused heterocyclic or heteroaromatic ring is formed which ring may contain additional heteroatoms selected from O, N or S; A is a straight or branched chain alkylene of 1-6 carbon atoms; 2 ..... R hydrogen, an anionically-charged or a conventional, easily-lit ·? * * · 'Ij · 2 -170- Λ * »carboxy1 protecting group can be protected provided that when R is hydrogen or a protecting group there is also a counterion and the group of formula 52 represents a group of formulas 80- 85, wherein R is C 1 -C 12 alkyl; C 1 -C 2 alkyl substituted with 1-3 hydroxy, amino, C 1 -C 1 alkylamino, di (C 1 -C 1) alkylamino, C 1 -C 1 alkoxy, carboxy, halogen or sulfo groups; C 1 -C 8 cycloalkyl, C 1 -C 8 cycloalkyl (C 1 -C 1) alkyl optionally substituted with 1-3 substituents as mentioned above in connection with C 1 -C 1 alkyl; phenyl; phenyl substituted with 1-3 substituents independently selected from amino, halogen, hydro, trifluoromethyl, C 1 -C 2 alkyl, C 1 -C 2 alkoxy, C 1 -C 1 alkylamino, diiC 2 -C 1) alkylamino, carboxy or sulfo ; phenyl (C 1 -C 6) alkyl in which the phenyl moiety may be optionally substituted with 1-3 substituents as mentioned above in conjunction with phenyl and the alkyl moiety may be optionally substituted with 1-3 substituents as mentioned above in conjunction with phenyl -C 1-4 alkyl; and heteroaryl and heteroaralkyl wherein the heteroatom or atoms are selected from the group consisting of 1-K, S or U atoms and the heteroaralkyl-linked alkyl moiety contains 1-6 carbon atoms, which heteroaryl and heteroaralkyl groups are optionally in the heterocyclic ring unit are substituted with 1-3 substituents independently selected from hydroxy, amino, halogen, trifluoromethyl, C 1 -C 2 alkyl, C 1 -C alkoxy, C 1 -C 2 alkylamino, diC 1 C 1) alkylamino, carboxy and sulfo and in the alkyl moiety by 1-3 substituents selected from hydroxy, amino, C 1 -C 2 alkylamino, di (C 1 -C 2) alkylamino, C 1 -C 2 alkoxy, carboxy, halogen and sulfo; or a pharmaceutically acceptable salt thereof. 6k. A compound according to claim 63, characterized in that R is hydrogen, ch3ch2-, CH- pti 3V '3 OH OH · I r »' C- or c ch3ch-. cb3 is CH2. 1 8 65. A compound according to claim 63, characterized in that R and R ° taken together represent -171 * r * HOCH- \ C = CH 2. Ί 66. A compound according to claim 63, characterized in that R is OH 1.5 ch3ch-. -J 67. A compound according to claim 63S, characterized in that R OH is 1 CH 3 CH-10 and the absolute configuration. 5RS is 6s, 8R. 68. A compound according to claim 63, 64, 65, 66 or 67, characterized in that A is -H0, -C1-CH -. d d d g - | 69. A compound of formula 1, wherein R is hydrogen and R is selected from hydrogen, substituted or unsubstituted; alkyl, alkenyl 15 alkynyl of 1-10 carbon atoms, cycloalkyl and cycloalkylalkyl of 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl units; phenyl, aralkyl ar alkenyl and ar alkynyl, wherein the aryl moiety is phenyl and the aliphatic moiety contains 1-6 carbon atoms; heteroaryl, the er alkyl, heterocyclyl and heterocyclylalkyl wherein the heteroatom or atoms in the aforementioned heterocyclic units are selected from 1-4 oxygen, nitrogen or sulfur atoms, the alkyl units linked to said heterocyclic units containing 1-6 carbon atoms ; wherein the substituent or substituents in connection with the above groups are independently selected from C 1 -C 8 alkyl optionally substituted with amino, halo-25, hydroxy or carboxyl halogen v 3 -172 -OR OU 34 -OCNR ROU 34 -CNR R 3 4 -NR R, NR 3 'NR 3 R 4 O II 34 -S-NRJR II O. o M 34 -NHCNRJR * O 3II 4 R CNR - -co2r3 -OO -OCR3 -SR3 O II 9 -SR5 O // 9 -SR5 ii o -CN - «3 3 -0S03R o il 9 -0S-R5 / ( O o 3 tl 9 -NR SR // O -OP (O) (OR3) (OR4) ^ ..... --- ^ \ V »vi * -173- - r * $ 3 4 -NR C = NR -no3co2r4 -no2 3 U in which in connection with the above substituents the groups R and R are independently selected from hydrogen, alkyl, alkenyl and alkynyl with 1-10 carbon atoms, cycloalkyl, cycloalkylalkyl and alkycycloalkyl with 5 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl units; phenyl; aralkyl and ar alkenyl and ar alkynyl wherein the aryl moiety is phenyl and the aliphatic moiety contains 1-6 carbon atoms; and heteroaryl, heteroalkyl, heterocyclyl and heterocyclylalkyl wherein the heteroatams or atoms in said heterocyclic unit are selected from 1-h 10 oxygen, nitrogen or sulfur atoms and the alkyl units 1-6 carbon associated with said heterocyclic-3 1 * units omen whether R and R taken together with the nitrogen to which at least one of them is attached can form a nitrogen-containing 5- or 6-membered heterocyclic ring; R 3 has the 3 meanings of R except that it may not be hydrogen or where R and R taken together represent C 1 -C 6 alkylidene or C 2 -C 10 alpha substituted by hydroxy; R'5 is selected from substituted and unsubstituted: alkyl, alkenyl and alkynyl having 1-10 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl units; phenyl, aralkyl, aralkenyl and ar alkynyl wherein the aryl moiety is phenyl and the aliphatic part contains 1-6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the heteroatom or atoms in the aforementioned heterocyclic units are selected from 1-¾ oxygen, nitrogen or sulfur atoms and the alkyl units attached to said heterocyclic units contain 1-6 carbon atoms; wherein the aforementioned R 1 groups are optionally substituted with 1-3 substituents independently selected from: C 1 -C 8 alkyl optionally substituted by amino, fluoro, chloro, carboxyl, hydroxy or carbamoyl, fluoro, chloro or bromo,. χ - * - - * - · M Λ Μ V -17 ^ - -OR3 -0C02R3 7 -OCOR3? -OCONR3R4; O n g -OS-R3 II. o -oxo; -NR3R4; 3 4 R CONR-7 -NR 3 CO 2 R 4; -NR3CONR3R4; O 3 "9 -HR SR; II O -SR3 7 O -S-R3 7 ALSO 7 Q -S-R3 7 -S03R3 y -CO2R3? -CONR3R4 7 -CN7 or phenyl optionally substituted with 1-3 fluoro, chlorine, bromine, C 1 -C 8 alkyl, -OR 3, -NR 3 R 1, -SO R 3, -COpR 3, or -CONR 3 R 1 wherein R 3, R 1, and R 9 in such R substituents have the aforementioned meanings; · Straight or branched chain alkylene, 2 1 × ... R ... hydrogen or an anomic charge or a conventional easily removable carboxyl protecting group provided that when R is hydrogen or a protecting group there is also a counterion is present and the group of formula 52 represents a group of formula 57 »where j Λ« .. - \ {'·. t -175-' fi ζ j ΊΟ in R, R and R are independently selected from hydrogen C 1 -C 6 alkyl, C 1 -C 6 alkoxy, carboxy and carbamoyl, or a pharmaceutically acceptable salt thereof. 70. A compound according to claim 69, characterized in that R ** is hydrogen, CH3CE2- CH3 CH3 OH -OH- · J3- 'C- or CH3CH-. = * 3 is CH3- ^. 1 8 71. A compound according to claim 69, characterized in that R and R taken together are HOCH-2 \ C = CH, /. 3 10 proposals. A compound according to claim 69, characterized in that R 1 is OH ch 3 ch-. 73. A compound according to claim 69, characterized in that R is OH C 1 -CH- and the absolute configuration is 5R, 6S, 8R. jh. Compound according to claim 69, 70, 71, 12 and 73, characterized in that A is -CH_- or -OHnCHo. 2 2 2 75 A compound of formula 106, wherein A is straight or branched chain alkylene of 1-6 carbon atoms; -176- v s 2. ... R is hydrogen, an anion sage charge or a conventional easily removable carboxyl protecting group provided that R is hydrogen or a protecting group and a counterion is also present; and the group of formula 52 represents a group 5 * (a) of the formula 86, r g wherein R 1 is -Chalkyl, and R represents hydrogen or C 1 -C 1 alkyl, (b) of the formula 87, wherein R 1 is? C 1 -C 12 alkyl and R and R are hydrogen or C 1 -C 12 alkyl; (c) of the formula 88, wherein R 1 is C 1 -C 1 alkyl and R C 1 -C 1 alkyl or phenyl (C 1 -C 1) alkyl-1 -is; (d) of the formula 89 ', wherein R 1 is C 1 -C 1 -alkyl and R 1 is C 1 -C 1 -alkyl; (e) of the formula 9G wherein R 1 is C 1 -C 1 -alkyl and R is C 1 -C 1 -alkyl; Or (f) of the formula 91, wherein R 1 is C 1 -C 12 alkyl; or a pharmaceutically acceptable salt thereof. 76. A compound of formula 106, 2 wherein A is straight or branched chain alkylene of 1-6 carbon atoms, R 20 is hydrogen, an anionic charge or a conventional removable carbonyl protecting group provided that when R is hydrogen or a protecting group there is also a counterion present, and the group of formula 52 represents a group of formulas 92-105 [(a) - (n)], or a pharmaceutically acceptable salt thereof. 2 · 77 · Compound of formula 106, wherein R is hydrogen, an anionic charge or a conventional easily removable carboxyl-protecting 2 group provided that when R is hydrogen or a protecting group there is also a counterion and what is the group of formula 10 represents a group selected from those of formulas 107-122 [[a) - (p)], wherein the ^ HKMR (D ^ O) spectrum exhibits characteristic peaks at £: 1.23 (3H, d, J = 6, k Hz), 3.12 (2Ξ, q J = * 1, U, 8.9 Hz), 3.39 (1H, q, J = 2.7, 6.0 Hz), M7-M8 (10H, m), 8.19 (1Ξ, s) (q) a group of formula 123 • j in which the HIJMR (D ^ o) spectrum shows characteristic peaks at £>: 1.23 (3H, d, J = 6, U Hz), 3.15 (2H, q, J = 3.7, 9.0 Hz), 3.37 (1H, q, J = 2.6, 6.0 Hz), 3.95-M5 d ° H, m), 8.62 (1H, s,); (r) - (v) groups of formulas 12U-128, l. * ·. . XJ 2 -177- or a pharmaceutically acceptable salt thereof. 78. A compound of formula 161, wherein R is hydrogen, an anionic charge, or a conventional easily removable carboxyl protecting ". 2 group is provided that R hydrogen or a protecting group xs and 5 is also a counterion; or a pharmaceutically acceptable salt thereof. 79 * A compound according to claim 78, characterized in that R is p-nitrobenzyl. 80. A compound according to claim 78, characterized in that R is an anionic charge. 81. A compound of formula 1β2, wherein R 2 is hydrogen, an anionic charge or a conventional easily removable earboxyl-protecting group 2 provided that when R is hydrogen or a protecting group, a counterion is also present; or a pharmaceutically acceptable salt thereof. 82. A compound according to claim 81, characterized in that R is p-nitro-benzyl. 2 83. A compound according to claim 8l, characterized in that R is an anionic charge. 2 84. A compound of formula 163, wherein R is hydrogen, an anionic charge or a conventional easily removable carboxyl protecting 2 group provided that when R is hydrogen or a hydroxyl protecting group, there is also a counterion; or a pharmaceutically acceptable salt thereof. A compound according to claim 84, characterized in that R is p-nitrol benzyl. 2 A compound according to claim 84, characterized in that R is an anionic charge. 2 87. A compound of formula 164, wherein R is hydrogen, an anionic charge, or a conventional easily removable carboxyl-protecting group 2 provided that when R is hydrogen or a protecting group, there is also a counterion, or a pharmaceutically acceptable salt thereof. 2 88. A compound according to claim 87, characterized in that R is p-nitro-35 benzyl. 2 A compound according to claim 87, characterized in that R is an anionic charge. - ».. * 2 -178- 90. A compound of formula 165 »wherein R is hydrogen, an anionic charge or a conventional easily removable carboxyl-protecting 2 group, provided that when R is hydrogen or a protecting group there is also a counterion or a pharmaceutically acceptable salt thereof. . 2 91. A compound according to claim 90, characterized in that R is p-nitro-benzyl. 2 92. A compound according to claim 90, characterized in that R is an anionic charge. 2 1Ό; 93. A compound of formula 166, wherein R hydrogen is an anionic charge or a conventional easily removable carboxyl-protecting 2 group, provided that when: R hydrogen or a protecting group, there is also a counterion or a pharmaceutically acceptable salt thereof . 15 9k. A compound according to claim 93, characterized in that R is p-nitrobenzyl. 2. . A compound according to claim 93, characterized in that R is an anionic charge. 96. A compound of formula 167, wherein R is hydrogen, an anionic charge or a conventional easily removable carboxyl-protecting 2 group provided that when R is hydrogen or a protecting group, there is also a counterion or a pharmaceutically acceptable salt thereof. A compound according to claim 96, characterized in that R is p-nitro-benzyl. 2 98. A compound according to claim 93, characterized in that R is an anionic charge. 2 99 · A compound of formula 168, wherein R is hydrogen, an anionic charge, or a conventional easily removable carboxyl-protecting group provided that when R is hydrogen or a protecting group, there is also a counterion or a pharmaceutically acceptable salt thereof. 100. A compound according to claim 99, characterized in that R is p-nitro-benzyl. Compound according to claim 99, characterized in that R is an anionic charge. 2 102. A compound of formula 169, wherein R is hydrogen, an anionic charge or a conventional easily removable carboxyl-protecting-y y 2 * -179- group, provided that when E is hydrogen or a protecting group there is also a counterion is present or a pharmaceutically acceptable salt thereof. 2 A compound according to claim 102, characterized in that R is p-mtro-5 benzyl. 2 10¾. A compound according to claim 102, characterized in that R is an anionic charge. 2. . 105 · A compound of formula 170, wherein R is hydrogen, an anomic charge or a conventional easily removable earboxyl group provided that when R is hydrogen or a protecting group, there is also a counterion or a pharmaceutically acceptable salt thereof. 2 106. A compound according to claim 105, characterized in that R is p-nitro-benzyl. 2 107. A compound according to claim 105, characterized in that R is an anionic charge. 2 108. A compound of formula 171, wherein R is hydrogen, an anionic charge or a conventional easily removable carboxyl-protecting 2 group, provided that when R is hydrogen or a protecting group, there is also a counterion or a pharmaceutically acceptable salt thereof . 109. A compound according to claim 108, characterized in that R is p-nitro-benzyl. 2 110. A compound according to claim 108, characterized in that R is an anionic charge. 2 111. A compound of formula 172, wherein R is hydrogen, an anionic charge or a conventional easily removable carboxyl group protecting group provided that when R is hydrogen or a protecting group, a counterion is also present; or a pharmaceutically acceptable salt thereof. 2 112. A compound according to claim 111, characterized in that R is p-nitro-benzyl. 2 113. A compound according to claim 111, characterized in that R is an anionic charge. 2 35 11¾. Compound of formula 173, wherein R hydrogen is an anionic charge or a conventional easily removable carboxyl-protecting group 2 provided that when R is hydrogen or a -T-7 protecting group "V" *% · '-180- \ Λ group there is also a counterion present; ' or a pharmaceutically acceptable salt thereof. 115. A compound according to claim 11 b, characterized in that R is p-nitro-benzyl. 2 A compound according to claim 11U, characterized in that R is an anionic charge. 2 117. A compound of formula 17 ^ wherein R is hydrogen, an anionic charge or a conventional easily removable carboxyl-protecting 2 group, provided that when R is hydrogen or a protecting group there is also a counterion or a pharmaceutically acceptable salt thereof. 2 118. A compound according to claim 11T9, characterized in that R is p-nitro-benzyl. . . 2 119. A compound according to claim 117, characterized in that R is an anionic charge. 2 120. Compound of formula 175 »wherein R is hydrogen, an anionic charge or a conventional easily removable carboxyl protective. 2 group is provided that when R is hydrogen or a protecting group, a counterion is also present; or a pharmaceutically acceptable salt thereof. 2 121. A compound according to claim 120, characterized in that R is p-nitro-benzyl. 2 122. A compound according to claim 120, characterized in that R is an anionic charge. 2 123. A compound of formula 176, wherein R is hydrogen, an anionic charge or a conventional easily removable carboxyl-protecting group 2 provided that when R is hydrogen or a protecting group, a counterion is also present; or the pharmaceutically acceptable salt thereof. 2 30 12b. A compound according to claim 123, characterized in that R is p-nitrol benzyl. . . 2 125. A compound according to claim 123, characterized in that R is an anionic charge. 2 126. A compound of formula 177 wherein R is hydrogen, an anionic charge or a conventional easily removable carboxyl-protecting 2 'group provided that when R is hydrogen or a protecting group there is also a counterion; or a pharmaceutically acceptable salt thereof. V -181- ** 2 127. A compound according to claim 126, characterized in that R is p-nitro-benzyl. O 128. A compound according to claim 126, characterized in that R is an anionic charge. 2 129. A compound of formula 178, wherein R is hydrogen, an anionic charge or a conventional easily removable carboxyl-protecting group 2 provided that when R hydrogen or a protecting group there is also a counterion; or a pharmaceutically acceptable salt thereof. 2 130. A compound according to claim 129, characterized in that R is p-mtrol benzyl. 2 131. A compound according to claim 129, characterized in that R is an anionic charge. 2 132. A compound of formula 179 wherein R is hydrogen, an anionic charge or a conventional easily removable carboxyl protecting group 2 provided that when R is hydrogen or a protecting group there is also a counterion or a pharmaceutically acceptable salt thereof. 2 133. A compound according to claim 132, characterized in that R is p-mtro-20 benzyl. 2 13k. A compound according to claim 132, characterized in that R is an anionic charge. 2 135 · A compound of formula 180, wherein R is hydrogen, an anionic charge or a conventional easily removable carboxyl-protecting group provided that when R is hydrogen or a protecting group, a counterion is also present; or a pharmaceutically acceptable salt thereof. 136. A compound according to claim 135, characterized in that R p-nitrile; benzyl. A compound according to claim 135, characterized in that R is an anionic charge. j 138. A compound of the formula: '. 181, in which the HNMR (D ^ O) spectrum shows characteristic peaks at £: 1.23 (3H, d, J = 6, U Hz), 3.12 (2H, 1, J 1, k, 8.9 Hz), 3.39 (1H, q., J = 2.7, 6.0 Hz), 4.07-M8 (10H, m), 8.19 35 (1H, s) or a pharmaceutically acceptable salt or an acceptable ester thereof. A compound according to claim 138, characterized in that the carboxyl * -182- Ar group is protected as a p-nitrobenzyl ester. 11 * 0. Compound of formula 182, wherein the HIMR (D ^ O) spectrum shows characteristic peaks at S: 1.23 (3H, d, J »6.1 * Hz), 3.15 (2Ξ, a, J = 3.7 , 9.0 Hz), 3.37 (1H, 4, J-2.6, 6.0 Hz), 3.95-1 *, 65 (10H, m), 8.62 5 (1H, s) or a pharmaceutically acceptable salt or an acceptable ester thereof. 1U1. A compound according to claim 11 * 0, characterized in that the carboxyl group is protected as a p-nitrobenzyl ester. 1U2. Process for the preparation of a compound of formula 183, wherein 8 l R 0 is hydrogen and R is selected from hydrogen, whether or not substituted: alkyl, alkenyl, alkynyl with 1110 carbon atoms; cycloalkyl and cycloalkylalkyl with 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl units; phenyl ,. aralkyl, ar alkenyl and ar alkynyl wherein the aryl moiety is phenyl and the aliphatic moiety contains 1-6 carbon atoms; Heteroaryl; heteroaralkyl; heterocyclyl and heterocyclylalkyl wherein the heteroatom or atoms in the aforementioned heterocyclic units are selected from 1-1 * oxygen, nitrogen or sulfur atoms and the alkyl units attached to said heterocyclic units contain 1-6 carbon atoms; wherein the substituent or substituents in connection with the above-mentioned groups are independently selected from: C 1 -C 8 alkyl optionally substituted with amino, halogen, hydroxy or carboxyl halogen-3 -OR O 11 3 4 -OCNR R 0 -CNR3R4 -nr3r4 / NR3 -4 'nr3r4 M 34 -S-NR R II o -183- - O II 3 4 -NHCNR RO 3JI 4 R CNR - -co2r3 = 0 O -OCR3 -SR3 O II 9 -SR1 O II g -SR1 ll O -CN -n3 -cso3r3 o ll g -OS-R1 l {O o 311 9 -NR SR ff O -OP (O) (OR3) (OR4) 3 4 -NR C = NR -NR3C02R4 -no2 - '7 Λ 4 Λ -181 * - N Λ .... 3 k is ij coexistence with the above substituent and the R and R groups are independently selected from hydrogen, alkyl, alkenyl and alkynyl with 1-10 carbon atoms, cycloalkyl, cyeloalkylalkyl and alkycycloalkyl with 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in 5 the alkyl units; phenyl; aralkyl, ar alkenyl and ar alkynyl wherein the aryl moiety is phenyl and the aliphatic moiety contains 1-6 carbon atoms; and heteroaryl, heteroalkyl, heterocyclyl and heterocyclylalkyl wherein the heteroatams or heteroatoam in said heterocyclic units are selected from 1-1 * oxygen, nitrogen or sulfur, and the alkyl units linked to said 10 heterocyclic units include 1-6 carbon atoms ; or R3 and R1 taken together with the nitrogen to which at least one of them is bound a nitrogen-containing heterocyclic 5- or 6-ring 9. 3 can form; R has the meanings of R except that it may be 1 8 hydrogen; or wherein R and R ° taken together represent C 1 -C 8 alkylidene or C 8 -C 20 alkylidene substituted by hydroxy; R 1 is selected from substituted or unsubstituted alkyl, alkenyl, alkynyl of 1-10 carbon atoms cycloaikyl, and cyeloalkyl alkyl of 3-6 carbon atoms in the cycloalkyl ring of 3-6 carbon atoms in the alkyl units; phenyl, aralkyl, aralkenyl and aralkynyl wherein the alkyl moiety is phenyl and the aliphatic part contains 1-6 carbon atoms; heteroaryl, heteroalkyl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the heteroatom or atoms in the aforementioned heterocyclic units are selected from 1-b oxygen, nitrogen or sulfur atoms and the alkyl units attached to said heterocyclic units contain 1-6 carbon atoms; wherein the above R 1 groups are optionally substituted with 1-3 substituents independently selected from; C 1 -C 8 alkyl, optionally substituted by amino, fluoro, chloro, carboxyl, hydroxy or carbamoyl, fluoro, chloro or bromo -OR 3 -O 2 CO 2 R 3; -OCOR3; -OCONR3R4? 0 Η 9 -OS-R * 1/0 - * ^ '1 τ * Λ. .. '> »/ J * *' Z '*' -185-i * -oxo; -nr3r4? R3CONR4-; -NR3C02R4, * 2 3 4 -HR COHR R? O 3 »9 -HR S-R; II O -SR3; O -S-R *; O O K Z o -S-R *; -SO3R3; CO2R3. ; 3 4 -COHR R? -CN; or phenyl optionally substituted by 1-3 fluoro, chloro, bromo, C 1 -C 8 alkyl, -OR 3, -HR 3r -SO-R 3, -CCLR 3, or-1 where R 3, R 1, and R 9 in such 5. d R substituents have the aforementioned meanings; or R9 may be attached to the group of formula 11 at another point on the ring and thus form a fused heterocyclic or heteroaromatic ring which ring may contain additional heteroatoam selected from O, S, N; R1 is selected from hydrogen, substituted and unsubstituted; alkyl, alkenyl and alkynyl with 1-10 carbon atoms; cycloalkyl, cyeloalkylalkyl and alkylcycloalkyl with 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl units; spirocycloalkyl with 3-6 carbon atoms; phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl moiety is phenyl and the aliphatic moiety contains 1-6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heteroeyclylalkyl wherein the heteroatom or atoms in the above heterocyclic units are selected from 1-¼ oxygen, nitrogen or sulfur atoms and the alkyl units to which they are attached contain 1-6 carbon atoms; wherein the substituent or substituents in connection with the above radicals are selected from amino, mono-,> - - - «,> -186-di- and trialkylamino, hydroxyl, alkoxyl, mercapto, alkylthio, phenylthio, sulfamoyl, amidino, guanidino, nitro, chlorine, chromium, fluorine, cyano and carbonyl and wherein the alkyl units of the above substituents contain 1-6 carbon atoms; A is a C 1 -C 6 straight or branched chain alkylene; 2. 1. ... 5. hydrogen, an amine charge or a conventional easily removable carboxyl protecting group is provided that when E is hydrogen or a protecting group there is also a counterion present, and the group of formula 11 'is a substituted or unsubstituted mono-, bi- or polycyclic aromatic heterocyclic group which contains at least one nitrogen in the ring, which ring is attached to A via a ring carbon atom and which contains a ring nitrogen substituted by the group R ''; or a pharmaceutically acceptable salt thereof which process comprises the following steps: (1) reacting an intermediate of formula 3 wherein R 8. 2, 15. and R have the aforementioned meanings and R is a conventional easily removable carboxyl-protecting group in an inert organic solvent with a reactant capable of a conventional cleavable group L on the 2-plate of intermediate 3 in to give an intermediate of the formula k wherein R, R, R, L and Rde have the above meanings and L is a conventional cleavable group; (2) reacting intermediate 1 * in an inert organic solvent and in the presence of a base with a mercaptan reactant of the formula 130, wherein A has the above meanings and the group of formula 11'1 is a mono, bi - or represents polycyclic aromatic heterocyclic group 25 with a quaternizable nitrogen in the ring, which ring is attached to A by a ring carbon atom to yield an intermediate of formula 1, wherein R, R, R, A, R and the group of formula 11 "have the aforementioned meanings; (3) reacting intermediate 2 in an inert organic solvent with an alkylating agent of the formula R-X", wherein R has the aforementioned meanings and X 'is a conventional cleavable group whereby, with the R' group, a ring nitrogen of substituent of formula 11 "is quaternized on intermediate 2 and a compound is formed of formula 1", in which R, R , R, R, A, the group of formulas 52 and 35 X 'have the aforementioned meanings, optionally replacing the counter ion X "with another counterion and, if desired, the carboxyl protection 2". . The group R is removed to give the desired unblocked compound ".sub. -18" -—- of formula 1, or a pharmaceutically acceptable salt thereof. 1 ^ 3. Process according to claim 1, characterized in that the quaternized ionized step is carried out after removal of the carboxyl-protecting 2 'group R 5 11. Process for preparing a compound of formula 183, wherein "Q-1 R" is hydrogen and R is selected from hydrogen, substituted or unsubstituted alkyl , alkenyl, alkynyl of 1-10 carbon atoms, cycloalkyl, and cycloalkylalkyl of 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl units, phenyl; aralkyl, ar alkenyl and aral-10 kynyl in which the aryl unit is phenyl and the aliphatic moiety contains 1-6 carbon atoms; heteroaryl, heteroarallyl, heterocyclyl and heterocyclylalkyl wherein the heteroatom or atoms in the aforementioned heterocyclic units are selected from 1-k oxygen, nitrogen or sulfur atoms one, wherein the alkyl units attached to said heterocyclic units contain 1-6 carbon or atoms; wherein the substituent or substituents in connection with the above groups are independently selected from C 1 -G 8 alkyl optionally substituted with amino, halogen, hydros or carboxyl, halogen -OR 3 O 3 3 -OCNR RO -CNR3R4-nr3r4, NR3 - 4 \ ir3r4 o II 3_ 4 -S-NR R II OO II 34 -NHCNR RO 3II 4 RJCNR - '-188- c -co2r1 * 0 0 -OCR1 -SR1 O II Q -SR * OH q -SR * II o -CN -N3 -oso3r1 o it a -OS-R * noo 3tl g -NRö-R * II o -OP (O). (OR1) (OR2 3) 3 4 -NRC = NR 3 4 -NR C02R -no2 In the context of the above substituents the groups E and R are independently selected from hydrogen, alkyl, alkenyl, alkynyl of 1-10 carbon atoms, cycloalkyl, cycloalkyalkyl and alkylcycloalkyl of 3 -3 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl units phenyl, aralkyl, aralkenyl and aralkynyl wherein the aryl unit is phenyl and the aliphatic moiety contains 1-6 carbon atoms; heteroaryl, heteroarallyl, heterocyclyl and heterocyclylalkyl, wherein the heteroatoms or atoms in the aforementioned heterocyclic unit are selected from -189-? * 1-1 + oxygen, nitrogen or sulfur atoms and the alkyl units attached to said heterocyclic 3 1+ units contain 1-6 carbon atoms "or E and R taken together with the nitrogen to which at least one of them" is attached is a nitrogen-containing heterocyclic - or 6-ring, R ^ the 3 5 meanings of R except that it cannot be hydrogen 1 8. or wherein R and R taken together represent C 1 -C 20 alkylidene or substituted hydroxy; R1 is selected from substituted and unsubstituted: alkyl, alkenyl and alkynyl of 1-10 carbon atoms, cycloalkyl and cycloalkylalkyl of 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl units; phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl moiety is phenyl and the aliphatic moiety contains 1-6 carbon atoms; heteroaiyl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the heteroatom or atoms in the aforementioned heterocyclic units are selected from 1-1 + oxygen, nitrogen or sulfur atoms and the alkyl units attached to said heterocyclic units contain 1-6 carbon atoms; wherein said R 1 groups are optionally substituted with 1-3 substituents independently selected from: C 1 -C 8 alkyl optionally substituted with arnino, fluoro, chloro, bromo, carboxyl, hydroxy or carbamoyl; 20 fluorine, chlorine or bromine -OR3 -oco2r3? -OCOR3? -OCONR3R4; O n q -OS-R * u o -0X0? 3 -HR R; r3conr4-? -NR3CO2R4; 3 3 4 -NO CONR R? 0 3 “9 -NS S-R? II 0 i Λ -190 -SR3; O "T * Q -S-R *; ALSO ? Q -S-R *; -SO3R3; CO2R3; 3 4 -CONR R; -CN? or phenyl optionally substituted with 1-3 fluoro, chloro, "bromo, C 1 -C 8 alkyl, -OR 3, -ΚΕ 3ΒΒ, -SO_R3, -CChR3 or -C0HR3r, wherein R3, R19 and R9 are the above. ά 5 mentioned meanings; or R may be attached to the group of formula 11 at another point on the ring to form a fused heterocyclic or heteroaromatic ring which ring may contain additional heteroatoms selected from 0, S, N, R ^ is selected from hydrogen, substituted ♦ * substituted or unsubstituted: alkyl, alkenyl and alkyne / l having 1-10 carbon atoms; cycloalkyl, cycloalkylalkyl and alkylcycloalkyl, having 3-6 carbon-10 atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl units, spirocycloalkyl of 3-6 carbon atoms; phenyl; aralkyl; aralkenyl and aralkynyl where the aryl unit is -phenyl and the aliphatic moiety contains 1-6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl, where the heteroatoms in the the above heterocyclic units are selected and from 1-4 oxygen, nitrogen and sulfur atoms and the alkyl units associated with said heterocycles have 1-6 carbon atoms; wherein the substituent or substituent and in connection with the aforementioned groups are selected from: amino, mono-di- and trialkylamino, hydroxyl, alkoxyl, mercapto, alkylthio, phenylthio, sulfamoyl, amidino, guanidino, nitro, chlorine, bromine, fluorine, cyano and carboxy; wherein the alkyl units of the above substituents contain 1-6 carbon atoms; or A C-C ^ 2 ".. 16 is straight or branched alkylene; R hydrogen is an amonic charge or a conventional easily removable carboxyl group provided that 2 when R is hydrogen or a protecting group there is also a counter ion is present and the group of formula 11 'represents a substituted or -191- * unsubstituted mono-, bi- or polycyclic aromatic heterocyclic group with at least one nitrogen in the ring, which ring is attached to A by a ring carbon atom and a ring nitrogen which is quaternized by the group R 1 or a pharmaceutically acceptable salt thereof, the process comprising reacting an intermediate of formula 2 wherein R, R, R, A and R have the aforementioned meanings and the group of formula 11 '' represents a mono-, bi- or polycyclic aromatic heterocyclic group with a quateraized nitrogen in the ring, which ring is attached to A via a ring carbon fatoma, 10 in an inert organic solvent with an alkylating agent of the formula R5-X 'where R' has the above meanings and X 'is a conventional cleavable group, so that with the R *' group a ring carbon of the substituent of formula 11 '1 is quatemized on intermediate 2 and a compound is formed of formula 1' wherein R, R, R, R2 ', A, the group of formula 52 and X' have the aforementioned meanings; and optionally replacing the counter ion X 'with another counterion and optionally removing the carbon-2T xyl protecting group R to yield the desired deblocked compound of formula 1 or a pharmaceutically acceptable salt thereof. 1 ^ 5- Process according to claim 1hU, characterized in that the quateriization step is performed after removal of the carboxyl group R. 8 1 1 k6. Compound of formula 183, wherein R is hydrogen and R is selected from hydrogen, substituted or unsubstituted: alkyl, alkenyl, alkynyl of 1-10 carbon atoms, cycloalkyl, and cycloalkylalkyl of 3-6 carbon atoms in an eyeloalkyl ring and 1-6 carbon atoms in the alkyl units; phenyl; aralkyl, ar alkenyl and ar alkynyl, wherein the aryl moiety is phenyl and the aliphatic moiety contains 1-6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyelylaliyl wherein the heteroatom or the atoms in the aforementioned heterocyclic units are selected from 1-U oxygen, nitrogen or sulfur atoms wherein the alkyl units attached to said heterocyclic units contain 1-6 carbon atoms; wherein the substituent or substituents in connection with the above groups are independently selected from 35 C 1 -C 8 alkyl optionally substituted with amino, halogen, hydroxyl or »-192-carboxyl, halogen, -OR 3 0 H 3 4 -OCNR R 0 -cnr3r4 -n * V / NR3 \ r3r4 o II 34 - S-NR R tl 0 o II 34 -NECNR RO 3II 4 rcnr- -C02R3 = 0 o -OCR3 -SR3 0 II 3 -SR3 O 11 9 -SR3 II o -CN -u3 * 3 -0S03R o H 9 -OS -R · II 0 o 3 // 9 -NR SR II o _ ............. -O? (O) (OR2) (0R4) '^ ƒ / ί Cu ν -192- 3 4 -NR C = NR i »-NR3C02R4 -no2 • 3 t in which the groups R and R are independently selected in connection with the above substxtuents from hydrogen, alkyl, alkenyl and alkynyl of 1-10 carbon atoms; cycloalkyl, cycloalkylalkyl and alkylcycloalkyl having 5-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl units; phenyl; aralkyl, aralkenyl and ar alkynyl wherein the aryl moiety is phenyl and the aliphatic moiety contains 1-6 carbon atoms; and heteroaryl, heteroaralkyl, heterocyclyl and heterocycloalkyl, wherein the heteroatoms or atoms in said heterocyclic unit are selected from 10 1-oxygen, nitrogen or sulfur, and the alkyl units associated with said heteroeylic units having 1 to 1 6 are carbon atoms; or R and R1 taken together with the nitrogen to which at least one of them is attached can form a nitrogen-containing 5- or 6-membered heterocyclic ring; o 3 R has the meanings of R except that it must not be hydrogen Ί 8 15; or wherein R and R taken together represent C 1 -C 20 alkylidene or O 2 -alkylidene substituted with hydroxy; R ^ is selected from substituted and unsubstituted: alkyl, alkenyl and alkynyl with 1-10 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl units; phenyl; aralkyl, aralkenyl and ar alkynyl wherein the aryl moiety is phenyl and the aliphatic moiety contains 1-6 carbon atoms; heteroaryl, heteroaralkyl heterocyclyl and heterocyclylalkyl in which the heteroatom or atoms in the aforementioned heterocyclic units are selected from 1-k oxygen, nitrogen or sulfur atoms and the alkyl units attached to said heterocyclic units contain 1-6 carbon atoms, wherein said R ^ 25 groups of choice are substituted with 1-3 substuents independently selected from: C 1 -C 8 alkyl optionally substituted by amino, fluoro, chloro, carboxyl, hydroxy or carbamoyl; fluorine, chlorine or bromine; -193- ί V Ά -0R3 -0C02R3; -OCOR3; -OCONR3R4; O II g -OS-R *; If 0 -OXO; -NR3R4; R3CONR4- y -nr3co2r4 j -nr3conr3r4? 0 3 »(g -NRJS-Rs; it 0 -SR3; 0. Το, -S-R * y 0. K P a -S-R 9 y -SO 3 R 3; CO2R3; -CONR3R4? -CN; or phenyl optionally substituted with 1-3 fluoro, chloro, bromo, C 1 -C 4 alkyl, o 3 it 3 li o li. -0RJ, -HR R, -SO_R, -C0.R3 or -COHRJR where R, R "3 and R * in such 5. ^ Ά. 5 .. R substituents have the aforementioned meanings; or R may be attached to the group of formula 11 at another point on the ring to form a condensed heterocyclic or heteroaromatic ring, which ring may contain additional heteroatoms selected from O, N and S; or R is selected from hydrogen; substituted and unsubstituted: alkyl , alkenyl and alkynyl with 1-10 carbon atoms; cycloalkyl, cycloalkylalkyl and alkylcycloalkyl with 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl units; spirocycloalkyl with 3-6 carbon atoms; phenyl; aralkyl, ar alkenyl and aralkynyl wherein the aryl moiety is phenyl and the aliphatic moiety contains 1-6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the heteroatom or atoms in 5 the aforementioned heterocyclic units are selected ¾ oxygen, sti nitrogen or sulfur atoms and the alkyl unit linked to said heterocyclic units contains 1-6 carbon atoms; wherein the substituent or substituents in connection with the above groups "are selected from: amino, mono-, di- and trialkylamino, hydroxyl, alkoxyl, mercapto, alkylthio, phenyl, phenylthio, sulfomoyl, amidino, guanidino, nitro, chlorine, bromine , fluoro, cyano and carboxy: and wherein the alkyl units of the above substituents contain 1-6 carbon atoms; A is a straight or branched chain alkylene of 1-6 carbon atoms; 2 R hydrogen, an ionic charge or a conventional easily removable carboxy 1 protecting group is provided that when R is hydrogen or a protecting group there is also a counterion present, and the group of formula 11 'represents a substituted or unsubstituted mono-, bi- or polycyclic aromatic heterocyclic group containing at least one nitrogen atom in the ring, which ring is attached to A 20 via a ring carbon atom and contains a ring nitrogen atom which has been quaternized by the group R ^ or a pharmaceutical pharmaceutically acceptable salt thereof. 8 1 1 cy. Compound of formula 18U, wherein R is hydrogen and R is selected from hydrogen, substituted or unsubstituted; alkyl, alkenyl, alkynyl of 1-10 carbon atoms; cyeloalkyl and cycloalkylalkyl with 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl units; phenyl; aralkyl, ar alkenyl and aralkynyl, wherein the aryl moiety is phenyl and the aliphatic contains 1-6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the heteroatom or atoms in the aforementioned heterocyclic units are selected from 1-¾ oxygen, nitrogen or sulfur atoms, the alkyl units attached to said heterocyclic units containing 1-6 carbon atoms; wherein the substituent or substituents in connection with the above groups are independently selected from C 1 -C 6 alkyl optionally substituted with amino, halogen, hydroxy or carboxyl, halogen, -OR 3, -195-O 3, 3 4 -ocnr * r * o «34 -CNR R • -nr3r4, NR3 \ ®V 0 II 34 -S-NRJR4 tl O o '« 34 -NHCNR * R4 O r3cnr4- -co2r3 = 0 O -OCR3 -SR3 O n 9 -SR * O // g -SR * U o -CN 3 -0S03Rj o «g · -OS-R * noo 3 // g -NR SR // O -O? (0) (OR3) (OR4) -196- **> -nr3c = ns4i -NS3CO2a4 -ho2. 3 wherein, in connection with the above substituent and the groups R and B are independently selected from hydrogen; alkyl, alkenyl and alkynyl with 1-10 carbon atoms; cycloalkyl, cyeloalkylalkyl and alkylcycloalkyl with 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl units; phenyl; aralkyl, ar alkenyl and ar alkynyl wherein the arylene moiety is phenyl and the aliphatic moiety contains 1-6 carbon atoms; and heteroaryl, heteroaralkyl, heterocyclyl and heterocycloalkyl wherein the hetero atoms or atoms in the aforementioned heterocyclic units are selected from 1-¼ oxygen, nitrogen or sulfur atoms and the alkyl units 1-6 associated with said heterocyclic units carbon atoms, or S3 and R1 taken together with the nitrogen to which at least one of them is attached can form a nitrogen-containing 5- or 6-membered heterocyclic ring. one; B has the meanings of B except that it must not be hydrogen, or where B and B taken together represent C 1 -C 20 alkylidene or C 2 -C 18 alkyliden substituted by hydroxy; B ^ is selected from substituted and unsubstituted: alkyl, alkenyl and alkynyl of 1-10 carbon atoms, cycloalkyl, and cyeloalkylalkyl of 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl units; phenyl; Aralkyl, ar alkenyl and ar alkynyl wherein the aryl moiety is phenyl and the aliphatic moiety contains 1-6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the heteroatom or atoms in the aforementioned heterocyclic units are selected from 1-¼ oxygen, nitrogen or sulfur atoms and the alkyl units attached to said heterocyclic units contain 1-6 carbon atoms, wherein said B groups of choice are substituted with 1-3 substituents independently selected from: C 1 -C 8 alkyl optionally substituted by amino, fluoro, chloro, carboxyl, hydroxy or carbamoyl, fluoro, chloro or bromo, -7; S X -197 -OR 3 -CO 2 R 3; -OCOR3; -OCONR3R4; t * ’O tl 9 -os-R3; II o -0X0? -NR3R4 7 R3CONR4- 7 -NR3C02R4 7 -NR3CONR3R4 7 o 3 "9 -NRJS-R? 7 II O -SR3 7 O. * ^ -R 9, -SR 7 OO IK P e -SR 7 -S03R3; -C02R3 7-COKR3R4 7 -CM; or phenyl optionally substituted with 1-3 fluoro, chloro, bromo, C 1 -C 4 alkyl, 3 3 -U 3 3 3 b 3 col. 1 0 .. OR, -ERn, -SO R, -CO R or -COUR R, wherein R, R and R m the like 5. J ά. 5 .. R substituents have the aforementioned meanings; or R may be bonded to the group of formula 11 at another point on the ring to form a fused heterocyclic or heteroaromatic ring, which ring may contain additional heteroatoms selected from O, N and S; or R 4 is selected from hydrogen, substituted and unsubstituted: alkyl, alkenyl and alkynyl with 1-10 carbon atoms, cycloalkyl, cycloalkylalkyl, 10 and alkylcycloalkyl with 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon -198- * / atoms in the alkylene units; spirocycloalkyl with 3-6 carbon atoms; phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl unit is phenyl and the aliphatic moiety contains 1-6 carbon atoms "; heteroaryl, heteroalkyl, heterocyclyl and heteroeyelylalkyl wherein the heteroatom or atoms in the aforementioned heterocyclic units are selected from 1-4 oxygen units, nitrogen and sulfur atoms and the alkyl unit linked to said heterocyclic units contains 1-6 carbon atoms, the substituent or substituents being selected in connection with the above groups from amino, mono, di and trialkylamino, hydroxyl, alkoxy, mercapto, alkylthio, phenyl, phenylthio, sulfamoyl, amidino., guanidino, nitro, chlorine, bromine, fluorine, cyano and carboxy; the alkyl units of the above substituents containing 1-6 carbon atoms; A straight or branched chain alkylene having 1- 6 carbon atom is, 2. R hydrogen, an amine charge or a conventional easily removable carboxyl protecting group is provided that t when R is hydrogen or a protecting group there is also a counterion present; and the group of formula 11 represents a substituted or unsubstituted mono-, bi- or polycyclic aromatic heterocyclic group containing at least one nitrogen atom in the ring which ring is attached to 20 A via a ring carbon atom and with a ring nitrogen atom which is through the group R ^ quaternized or a pharmaceutically acceptable salt thereof. 148. A compound according to claims 14-7, characterized in that R 1 OH is CH 1 Cl 2 - and R is methyl. 25 "149. A compound according to claim 147, characterized in that R 1 OH 1 16 CH 3 CH-, R methyl and the absolute configuration is 5R, 6s, 8R. 150. A compound according to claim 147, 148, 149 wherein A is -CH 2 - or 30 -CH 2 -CH_-. & d 8 1 151. A compound of formula 184, wherein R is hydrogen and R is selected from hydrogen, substituted or unsubstituted: alkyl, alkenyl, alkynyl of 1-10 carbon atoms, cycloalkyl, and cycloalkylalkyl of 3-6 * * "* ^ ^". -199- carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkylenes: phenyl, aralkyl, aralkenyl and aralkynyl wherein the aryl moiety is phenyl and contains the aliphatic moiety 1-6 carbon atoms "; heteroaryl, hetero-. aralkyl, heterocyclyl and heterocyclylalkyl wherein the heteroatom or 5 atoms in the aforementioned heterocyclic units are selected from 1-U * oxygen, nitrogen or sulfur, the alkyl units linked to said heterocyclic units containing 1-6 carbon atoms, wherein the substituent or substituents in connection with the above groups are independently selected from C 1 -C 8 alkyl, optionally substituted with amino, halogen, hydroxy or carboxyl, halogen, -OR 3 O 3 3 4 -OCNR R. O II 34 -CNR R -nr3r4, NR3 'NR3R4 0 II 3 4 -S-NR R ll O 0 II 34 -NHCNRJR ^ O 3 U 4 R CNR -CO2 R3 -O O -OCR3 -SR3 O11 9 -SR5; · '· .. *. '/ -200- *> * b O' tl o -SR5 tt O -CN - »3 3 -0S03Rj o tl Q -OS - T K oo 3f / 9 -ia s-r u o -O? (0) (OR3) (OR4) 3 4 -NR C = NR 1 »3 4 -NR C02R -NO 2. . . 3 in which, in connection with the "above substituents, the groups R and k S are independently selected from hydrogen, alkyl, alkenyl and alkynyl of 1-10 carbon atoms, cycloalkyl, cycloalkylalkyl and alkylcycloalkyl of 5-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl units; phenyl aralkyl, ar alkenyl and ar alkynyl wherein the aryl moiety is phenyl and the aliphatic moiety contains 1-6 carbon atoms; and heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl, wherein the heteroatom or atoms in the said heterocyclic units are selected from: 1-k 10 oxygen, nitrogen or sulfur atoms and the alkyl units associated with said heterocyclic monocarbons have 1-6 carbon atoms, or R and R taken together with the nitrogen to which at least one is confirmed to form a Q nitrogen-containing heterocyclic 5- or 6-ring, R has the meanings of R except that it must not be hydrogen, Or wherein R and R taken together represent C 1 -C 12 alkylidene or C 2 10 substituted by hydroxy; R ^ is selected from substituted and unsubstituted: alkyl, alkenyl and alkynyl of 1-10 carbon atoms, 4-20 cycloalkyl, and cyeloalkyl alkyl of 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon to fat. omen in the alkyl units; phenyl; aralkyl, aralkenyl and araliynyl wherein the aryl moiety is phenyl and the aliphatic moiety contains 1-6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and hetero-5-cyclylalkyl-wherein the heteroatom or atoms in the aforementioned heterocyclic units are selected from 1-4 oxygen, nitrogen or sulfur atoms and the alkyl units attached to said heterocyclic units contain 1-6 carbon atoms wherein the aforementioned R 2 groups are optionally substituted with 1-3 substituents independently selected from: C 1 -C 8 alkyl optionally substituted by amino, fluoro, chloro, carboxyl, hydroxy or carbamoyl, fluoro, chloro or bromo -OR 3 -OCO 2 R 3; -OCOR3; -OCONR3R4; 0 t 10 -OS-Ry M + * 0 -OXO; -NR3R4; R3CONR4-; -NR3CO2R4; -NR3CONR3R4; 0 3 »1 q -NR S-λ; II 0 '-sa3; o * 9 -S-R *; 0. K q -S-R ·; -SO3R3; C02R3; -CONR3R4; -CN; -202-f * phenyl optionally substituted with 1-3 fluoro, chloro, bromo, C ^ -C8 alkyl, -OR ^, -HR ^ R ^, -S0oR ^, -CO R ^ or -CONR ^ R ^ where R ^, R ^ and R ^ in such 5 ^ ^. 5 R - substituent and the aforementioned meanings; or R may be attached to the group of formula 11 at another point on the ring to form a condensed heterocyclic or heteroatamatic ring, which may contain 16 ring additional heteroatoms selected from 0, S and N: R selected from hydrogen, substituted and unsubstituted: alkyl, alkenyl and alkynyl with 1-10 carbon atoms; cycloalkyl, cycloalkylalkyl and alkylcycloalkyl with 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl units; spirocycloalkyl with 3-6 carbon atoms; phenyl; aralkyl, aralkenyl and ar alkynyl wherein the aryl moiety is phenyl and the aliphatic moiety contains 1-6 carbon atoms; heteroaryl, heteroalkyl, heterocyclyl and heterocyclylalkyl wherein the heteroatom or atoms in the aforementioned heterocyclic units are selected from 1-4 oxygen, nitrogen or sulfur atoms and the alkyl unit linked to said heterocyclic units contains 1-6 carbon atoms, substituent or the substituents in connection with the above groups are selected from amino, mono, di and trialkylamino, hydroxyl, alkoxy, mercapto, alkylthio, phenylthio, sulfamoyl, amidino, guanidino, nitro, chlorine, bromine , fluorine, cyano and carboxy; and wherein the alkyl units of the above substituents contain 1-6 carbon atoms; A is a straight or branched chain alkylene of 1-6 carbon atoms, or R hydrogen is an anionic charge or a conventional readily. 2 removable carboxyl protecting group is provided that when R 25 is hydrogen or a protecting group there is also a counterion present, and the group of formula 11 represents a substituted or unsubstituted mono-, bi- or polycyclic aromatic heterocyclic group, which contains at least one nitrogen atom in the ring, which ring is attached to A via a ring carbon atom and with a ring nitrogen atom quaternized by the group R 4, or wherein said heterocyclic ring is substituted with a choice of available ring carbon atoms with 1 to 5 substituents independently are selected from C 1 -C 2 alkyl; C 1 -C 8 alkyl substituted by 1-4 hydroxy, amino, C 1 -C 8 alkylamino, di-C 1 -alkyl amino, C 1 -C 8 alkoxy, carboxy, halogen or sulfo; C 1 -C 8 cycloalkyl; C 1 -C 8 cycloalkyl alkyl optionally substituted with 1-3 substituents as mentioned above in connection with C 1 -C 12 alkyl; C 1 -C 2 alkoxy; C 1 -C 2 alkyl-thio; amino; C 1 -C 2 alkylamino, di (C 1 -C 2) alkylamino; halogen; C 1 -C 2 alkancylamino; C 1 -C 2 alkanoyloxy; carboxy; sulfo; -203-0 w -C-OC 1 -C 1 alkyl; hydroxy; amidino; guanxdino; phenyl; phenyl substituted with 1-3 substituents independently selected from amino, halogen, hydroxy, trifluoromethyl, C 1 -C 2 alkyl, C 1 -C 1 alkoxy, C 1 -C 1 alkylamino, di (C 1 -C 1) - 5 alkylaoino , carboxy and sulfo; phenyl (C 1 -C 1) alkyl in which the phenyl moiety is optionally substituted with 1-3 substituents as mentioned above in conjunction with phenyl and the alkyl moiety is optionally substituted with 1-3 substituents as mentioned above in conjunction with C 1 -C alkyl; one heteroaryl or heteroaralkyl in which the heteroatom or atoms are selected from 10 1-H O, S or N atoms and the heteroar alkyl linked alkyl moiety has 1-6 carbon atoms, which heteroaryl and heteroaralkyl groups are optionally in the heterocyclic ring units are substituted with 1 to 3 substituents independently selected from hydroxy, amino, halogen, trifluoromethyl, C 1 -alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylamino, diiC 2 -C 7 jalkylamino, carboxy and sulfo and in the alkyl moiety by 1-3 substituents selected from hydroxy, amino, C 1 -C 2 alkylamino, di (C 1 -C 2) alkylamino, C 1 -C 1 alkoxy, carboxy, halogen and sulfo, said heterocyclic ring being optionally for available ring nitrogen atoms is substituted with 1-3 substituents independently selected from C 1 -C 2 alkyl, C 1 -C 2 alkyl substituted with 1-3 hydroxy; amino, C 1 -C 6 alkylamino, di (C 1 -C 6) alkylamino, alkoxy, carboxy, halogen or sulfo groups, C 1 -C 8 cyeloalkyl; C 1 -C 8 cycloalkyl (C 1 -C 1) alkyl optionally substituted with 1-3 substituents as mentioned above in connection with C 1 -C alkyl; phenyl; phenyl substituted with 1-3 substituents independently selected from amino, halogen, hydroxy, trifluoro-methyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylamino, di ^ -C ^) alkylamino, carboxy and sulfo; phenyl (C 1 -C 6) alkyl in which the phenyl moiety may be optionally substituted with 1-3 substituents as mentioned above in conjunction with phenyl and the alkyl moiety may be optionally substituted with 1-3 substituents as noted above in conjunction with phenyl C 1 -alkyl; and heteroaryl 30 and heteroaralkyl wherein the heteroatom or atoms are selected from 1-4, S or f atoms and the heteroaralkyl-linked alkyl moiety has 1-6 carbon atoms which are heteroaryl and heteroaralkyl groups optionally in the heterocyclic ring moiety substituted by 1-3 substituents independently selected from hydroxy, amino, halogen, trifluoroethyl, C 1 -C 1 -alkyl, C 1 -C 1 -alkoxy, C 1 -C 1 -alkylamino, di (C 1 -C 2) alkylamino, carboxy and sulfo and in the alkyl unit by 1-3 substituents selected from hydroxy, amino, C 1 -C 2 alkylamino, diCC 2 -C 2) alkylamino, C 1 -C 2 alkoxy, carboxy, halo-20 kph, none and sulfo; or a pharmaceutically acceptable salt thereof. 152. A compound according to claim 151, characterized in that R OH 1 is 16 CH 2 CH- and E methyl. 153. A compound according to claim 151, characterized in that R OH is "16 CH 2 CH- and R methyl and the absolute configuration is 5R, 6S, 8R. 15 ^. Compound according to claim 151, 152, 153, characterized in that 10 A is -CH- or -CH-CHO-. d d d g 1 155. A compound of formula 184, wherein R is hydrogen and R is selected from hydrogen, substituted or unsubstituted: alkyl, alkenyl, alkynyl of 1-10 carbon atoms, cyeloalkyl, and eyeloalkylalkyl of 3-6 carbon atoms in a cycloalkyl ring and 1- 6 carbon atoms in the alkyl-15 units; phenyl; aralkyl ar alkenyl and ar alkynyl, wherein the aryl moiety is phenyl and the aliphatic moiety contains 1-6 carbon atoms; heteroaiyl,. heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the heteroatom or atoms in the aforementioned heterocyclic units are selected from 1-1; oxygen, nitrogen or sulfur, in which the alkyl units attached to said hetero-20 cyclic units contain 1-6 carbon atoms, and the substituent or substituents in connection with the above groups are independently selected from C 1 -C 6 alkyl optionally substituted with amino, halogen, hydroxy or carboxyl, halogen, -OR 3 O fJ 3 4 -oarer R. o -cnr3r4 -nr3r4 -205-) \ 'Λ®3' NR3R4 Ο II 3 4 -S-NR ^ R4 ii ο ο It 3 4 -NHCNRJR4 Ο 3 «4 R CNR - -co2r3 = 0 0 II 3 -OCR 3 -SR3 »0 // q -SR3 0 It Q -SR3 It 0 -CN -N3 3 -OSO ^ R * 3 0/1 q -0S-R3 / (0 -nr3s-r9 It 0 -OP (0 ) (OR3) (OR4) .- 'S'. ** »·. ^ -206 · ί t -nr3c = nr4 i '-NR3C02R4 -N02 3 in which, in connection with the" substituents mentioned above, the groups R and 4 S independently selected from hydrogen, alkyl, alkenyl and alkynyl with 1-10 carbon atoms; cycloalkyl, cycloalkylalkyl and alkyloycloalkyl with 3-6 carbon atoms in the cyeloalkyl ring and 1-6 carbon atoms in the alkyl units; phenyl; aralkyl, ar alkenyl and ar alkynyl wherein the arylene moiety is phenyl and the aliphatic moiety contains 1-6 carbon atoms "; and heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the hetero atoms or atoms are selected in the aforementioned heterocyclic unit from 1-4 oxygen, nitrogen or sulfur atoms, and the ones mentioned heterocyclic units joined alkyl units have 1-6 carbon atoms; 3 4. . or R and R taken together with the nitrogen to which at least one of them is attached a nitrogen-containing 5- or 6-ring heterocyclic o. 3. to shape; R has the meanings of R except that it must not be hydrogen or wherein R and R taken together represent alkylidene substituted or unsubstituted by hydroxy; R1 is selected from substituted and unsubstituted: alkyl, alkenyl and alkynyl of 1-10 carbon atoms, cycloalkyl and cycloalkylalkyl of 3-6 carbon atoms in the cyeloalkyl ring and 1-6 carbon atoms in the alkyl units; phenyl; aralkyl, ar alkenyl and ar alkynyl wherein the aryl moiety is phenyl and the aliphatic moiety contains 1-6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the heteroatom or atoms in the aforementioned heterocyclic units are selected from 1-4 oxygen, nitrogen or sulfur atoms and the alkyl-25 units attached to said heterocyclic units contain 1-6 carbon atoms, wherein the the aforementioned R 2 groups are optionally substituted with 1 to 3 substituents independently selected from: C 1 -C 8 alkyl optionally substituted by aino, fluoro, chloro, carboxy, hydroxy or carbamoyl, fluoro, chloro or bromo, * -207- -OR3 -OCO2R3; -OCOR3; -OCONR3R4; O II Q -OS-R *; 1 / O -oxo; -NR3R4; R3CONR4-; -no3co2r4; 3 3 4 -NR CONR R; O 3 »a -NRJS-R * 7 II O -SR3; O + Q -S-IT; O O K Z q -S-R *; -SO3R3; CO2R3; "~ CONR3R4; -CN; or phenyl optionally substituted with 1-3 fluoro, chloro," bromo. C 1 -C 4 alkyl 3 -3 k 33 3 3 k 3 U 9 ° s -OR, -EETR, -SOJR, -CO Ir or -COBR ^ R, wherein R, R and R are as such 5. * 5. . ke R substituents have the aforementioned meanings; or R may be bonded to the group of formula 11 at another point on the ring to form a fused heterocyclic or heteroaramatic ring, which ring may contain additional heteroatoms selected from O, S and N; R is selected from hydrogen, substituted and unsubstituted: alkyl, alkenyl, and alkynyl of 1-10 carbon atoms, cycloalkyl, cycloalkylalkyl, and alkyl Ι-ΙΟ cycloalkyl of 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms .1 Ex -208- * * in the alkyl units, spirocyeloalkyl of 3-6 carbon atoms; phenyl; aralkyl, ar alkenyl and aralkynyl wherein the aryl moiety is phenyl and the aliphatic portion contains 1-6 carbon atoms; heteroaryl, heteroalkyl, heterocyclyl and heterocyelylalkyl wherein the heteroatoam or atoms in the aforementioned heterocyclic units are selected from 1-4 oxygen, nitrogen or sulfur atoms and the alkyl unit linked to said heterocyclic units contains 1-6 carbon atoms, the substituent or the substituents in connection with the above groups are selected from amino, di and trialkylamino, hydroxyl, alkoxy, mercapto, alkylthio, phenylthio, sul-10 famoyl, amidino, guanidino, nitro, chlorine, bromine, fluorine, cyano and carboxy; wherein the alkyl units of the above substituents contain 1-6 carbon atoms; A is a straight or branched chain alkylene of 1-6 carbon atoms, o R hydrogen, an anionic charge or a conventional easily removable carboxy 1 protecting group provided that when R is hydrogen or a protecting group there is also a counterion is present and the group of formula 52 represents an anionic li-containing deflaeterocyclic 5- or 6-ring containing 0-3 additional heteroatams selected from S, S and 0, said heterocyclic ring being substituted with 1 available ring carbon atoms with 1 -5 substituents independently selected from C 1 -C 1 -alkyl, C 1 -C 1 -alkyl substituted by 1-3 hydroxy, amino, C 1 -C 1 alkylamino, di (C 1 -C 1) alkylamino, C 1 -C alkoxy, carboxy, halogen, or sulfo; C 1 -C 8 cycloalkyl; C 1 -C 8 cycloalkyl (C 1 -C 1 -alkyl) optionally substituted with 1-3 substituents as mentioned above in connection with C 1 -C 6 alkyl; C 1 -C 2 alkoxy; amino, C 1 -C 6 alkylamino, a (C 1 -C 6) alkylamino, halogen, C 1 -C 6 alkanoylamino, C 1 -C 6 alkanoyloxy, carboxy, sulfo, -O-0-C-alkyl; hydroxy, amidino; guanidino, phenyl; phenyl substituted with 1-3 substituents independently selected from amino, halogen, hydroxy, trifluoromethyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, alkylamino, dKC ^ -C ^) alkylamino , carboxy and sulfo; phenyl (C 1 -C 6) alkyl in which the phenyl moiety is optionally substituted with 1-3 substituents as mentioned above in connection with phenyl, the alkyl moiety is optionally substituted with 1-3 substituents as mentioned above in conjunction with phenyl C 1-6 alkyl, and heteroaryl or heteroaralkyl wherein the heteroatom or atoms are selected from the group consisting of 1-4, 0, S, or N atoms and the heteroaralkyl-linked alkyl-m *. The unit has 1-6 carbon atoms, which heteroaryl and heteroaralkyl groups are optionally substituted in the heterocyclic ring unit with 1-3 substituents independently selected from hydroxy, amino, halogen, trifluoromethyl , C 1 -alkyl, C 1 -C 2 alkoxy, C 1 -C 2 alkylamino, <ϋ (01-0 ^) η] ^ ΐ3αιχηο, 5 carboxy, and sulfo and in dealkyl moiety selected from 1-3 substituents hydroxy, amino, alkylamino, di (C 1 -C 6) alkylamino, C 1 -C 6 alkoxy, carbonyl, halogen and sulfo, said heterocyclic ring being optionally substituted with available ring nitrogen atoms with 1-3 substituents independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted with 1-3 hydroxy, amino, alkylamino, ditC 1 -C 6 alkylkyino, C 1 -C 6 alkoxy, carbonyl, halogen or sulfo groups; C 1 -C 8 cycloalkyl, C 1 -C 1 cycloalkyl (C 1 -C 1) alkyl optionally substituted with 1-3 substituents as mentioned above in connection with C 1 -C 12 alkyl; phenyl; phenyl substituted with 1-3 substituents independently selected from amino, halogen, hydroxy, trifluoromethyl, C 1 -C 12 alkyl, alkoxy, C 1 -C 20 alkylamino, di (C 1 -C 20) alkylamino, carboxy, and sulfo; phenyl (C 1 -C 6) alkyl in which the phenyl moiety may be optionally substituted with 1-3 substituents as mentioned above in conjunction with phenyl and the alkyl moiety may be optionally substituted with 1-3 substituents as mentioned above in conjunction with phenyl -C 1-4 alkyl; and heteroaryl and hot-roaralkyl in which the heteroatoam or atoms are selected from the group consisting of 1-O 0, S- or II-atoms and the alkyl moiety bonded with hot-roaralkyl has 1-6 carbon atoms, which heteroaryl and heteroaralkyl groups of choice in the heterocyclic ring unit are substituted by 1-3 substituents independently selected from hydroxy, amino, halogen, trifluoroethyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 1 ^ alkylamino, di (C1 -C 1 -alkyl-amino, carboxy and sulfo and in the alkyl unit by 1-3 substituents selected from hydroxy, amino, C 1 -C 2 -alkylamino, diC 1 -C 2 -alkylamino, alkoxy, carboxy, halogen and sulfo; or a pharmaceutically acceptable salt thereof. 156. A compound according to claim 155, characterized in that the heterocyclic ring of formula 52 is optionally substituted with available ring carbon or nitrogen atoms with up to 5 substituents independently selected from (lower) alkyl. 157 · A compound according to claim 156, characterized in that A -CHg-, 35 is -CH 2 CH 2 - or CH 1 3 -CH-. »V Λ '' * *** 1 -210-? ' t r 158. A compound according to claims 155 * 156, 157 »characterized in that R 1 OH is yr ig CH-CE- and R is methyl and the absolute configuration is 5R, 6S, 8R. J 8l 159. A compound of formula 18k, wherein R is hydrogen and R is selected from hydrogen, substituted or unsubstituted: alkyl, alkenyl, alkynyl of 1-10 carbon atoms; cycloalkyl and cycloalkylalkyl with 3-6 carbon atoms in a cycloalkyl ring and 1-6 carbon atoms in the alkyl units; phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl moiety is fe-10 nyl and the aliphatic moiety contains 1-6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocycloalkyl wherein the heteroatom. or the atoms in the aforementioned heterocyclic ring are selected from 1-oxygen, nitrogen or sulfur atoms wherein the alkyl units attached to said heterocyclic units contain 1-6 carbon atoms and the substituent or substituents in connection with the above groups are independently selected from C 1 -C 8 alkyl, optionally substituted with amino, halo hydroxy or carboxyl, halogen -OR 3 O -ocnr3r4 -cnr3r4 -nr3r4 / * 3 - 'nr3r4 o II 34 -S-NR Roo « 34 -NHOSTR O 3II 4 R CNR- V -211- -C02R3 * 0 o -OCR3 -SR3 O «9 -SR3 O // g -SR3 · KO -CN -¾ 3 -oso3rj O / 1 Q -0S- R3 no -NR0 -R3 // O -OP- (O) (OR3) (OR4) 3 4 '-NR C-NR -NR3CO2R4 -no2. 3 in which, m in conjunction with the "above substituent and the groups R and h R are independently selected from hydrogen, alkyl, alkenyl and aynyyl with 1-10 carbon atoms, cycloalkyl, cycloalkylalkyl and alkylcycloalkyl having 5-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl units; phenyl; aralkyl, aralkenyl and araikynyl wherein the aryl unit is phenyl and the aliphatic moiety contains 1-6 carbon atoms; and heteroaryl, heteroaralkyl, heterocyclyl and heterocylalkyl wherein the heteroatoms or the atoms in the aforementioned heterocyclic unit are selected from 10 1-1 * oxygen, nitrogen or sulfur atoms, and those with said heterocyclic -212-ƒ r 3 U units of linked alkyl units contain 1-6 carbon atoms; or R and R taken together with the nitrogen to which at least one of them is attached can form a nitrogen-containing 5- or 6-membered heterocyclic ring; R 3 has the meanings of R except that it must not be hydrogen Ί 3 5, or where R and R taken together represent C 1 -C 6 q alkylidene or alkylidene substituted by hydroxy; R 1 is selected from substituted and unsubstituted: alkyl, alkenyl and alkynyl with 1-10 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl units; phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl moiety is phenyl and the aliphatic moiety contains 1-6 carbon atoms; heteroaryl, the alkyl, heterocyclyl and heterocyclylalkyl in which the heteroatom or atoms in the aforementioned heterocyclic units are selected from 1-1 + oxygen, nitrogen or sulfur atoms and the alkyl units linked to said heterocyclic units contain 1-6 carbon atoms, wherein the aforementioned R 15 groups are optionally substituted with 1-3 substituents independently selected from: -OS 3 -O 2 CO 2 S3; ^ OCOK2; -OCONS3S4; O n o -OS-S *; w • o -oxo; -NS3S4; S3CONS4-; -NS3CO2S4; 3 3 4 -NO CONS S 7 0 3 «o S-r; II 0 -SS3? o * 5 -S-R * 7> ·· · - · »*. * * »> -213- Y Λ 0 Ο a -sR"; -SO.R3; j -co2r3; 3 4 -con-γη; -CN? Or phenyl optionally substituted with 1-3 fluoro, chloro, bromo, C 1 -C 8 alkyl, -OR 3, -I-R 1 R, -SO-R 3, -CO R 3, or -CONR 3 R 1-where R 3, R 2, and R 2 in such 5.3 R substituents have the aforementioned meanings, or 5 R1 can be attached to the group of formula II at another point on the ring to form a fused heterocyclic and heteroaromatic ring, which ring may contain additional heteroatoms selected from 0.16S and N; or R is selected from substituted and unsubstituted: alkyl, alkenyl and alkynyl with 1-10 carbon atoms; cycloalkyl, cycloalkylalkyl and 10 alkylcycloalkyl. with 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl units; spirocycloalkyl with 3- 6 carbon atoms; phenyl; aralkyl, ar alkenyl and aralkynyl wherein the aryl moiety is "phenyl" and the aliphatic moiety contains 1-6 carbon atoms; heteroaryl, the alkyl alkyl, heter o-cyclyl and heterocyclylalkyl wherein the heteroatom or atoms in the aforementioned heterocyclic units are selected from 1-¼ oxygen, nitrogen and sulfur atoms and the alkyl unit attached to said heterocyclic units contains 1-6 carbon atoms, the substituent or substituents in connection with the above groups are selected from amino, mono-, di- or trialkylamino, hydroxyl, alkoxy, mercapto, alkylthio, phenyl, phenylthio, sulfamoyl, amidino, guanidino, nitro, chlorine, bromine, fluorine , cyano and carboxy, and wherein the alkyl units of the above substituents contain 1-6 carbon atoms, A is a straight or branched alkylene of 1-6 carbon atoms, R is hydrogen, an anionic charge or a conventional easily removable carboxyl. protecting group is provided that when R is hydrogen or a protecting group, a counterion is also present; and the group of formula 52 represents a group selected from 0 7 "10 (a) groups of formula 57, wherein R, R and R are independently selected from hydrogen; alkyl; alkyl substituted with hydroxy;" "J" 4 " J Jr "-211 + - alkylamino, di-C 1 -alkylamino, C 1 -C 2 alkoxy, amino, sulfo carboxy or halogen; C 1 -C 8 cycloalkyl, C 1 -C 2 alkoxy, C 1 -C 2 alkylthio, amino; C 1 -C 2 alkylamino; diiC ^ -C ^) alkylamino; halogen; C 1 -C 6 alkanoylamino, 0-¾ alkanoyloxy; carboxy; 5 * a -0-O-O-O-alkyl; hydroxy; amidino, guanidino, phenyl; phenyl substituted by 1, 2 or 3 amino, halogen, hydroxyl, trifluoromethyl -. C 1 -C 2 -alkyl-, C 1 -C 2 -alkoxy groups; phenyl (C 1 -C 6) alkyl wherein the phenyl moiety may optionally be substituted with 1-3 substituents as mentioned above in conjunction with phenyl and the alkyl moiety may optionally be substituted with 1-3 substituents as noted above in in connection with C 1 -C 6 alkyl, and the er o-aryl and heteroaralkyl, wherein the heteroatoam or atoms in the group consist of 1-1 + oxygen, nitrogen or sulfur atoms and the alkyl unit 1 connected to said eraralkyl unit -6 contains carbon atoms; or 6 T 10 15 wherein two of R, R and R taken together may form a condensed saturated carbocyclic ring, a condensed aromatic carbocyclic ring, a condensed nonaramatic heterocyclic ring or a condensed heteroaromatic ring, which condensed rings are optionally substituted with one or two from the top for 6 7 10 R, R and R defined substituents; (b) groups of formulas 58, 59 and 60, optionally substituted on a carbon atom by 1-3 substituents independently selected from O 2 -alkyl; C 1 -C 6 alkyl substituted by hydroxy, 0 ^ -¾ alkylamino, diiC ^ -C ^) alkylamino, sulfo (C ^ -C ^ alkoxy, amino, carboxy or halogen; C ^ -C8 cyclo-25 alkyl; (^ - ¾ alkoxy; Cj-C ^ alkylthio; amino; (^ -¾ alkylamino; diiC ^ C ^) - alkylamino; halogen; 0 ^ -¾ alkanoylamino; ¢ ^ -¾ alkanoyloxy; carboxy; 0 -C-0-C ^ - C 1 -alkyl; hydroxy; amidino, guanidino; phenyl; phenyl substituted with 1, 2 or 3 amino, halogen, hydroxyl, difluoromethyl, (^ -¾alkyl-30 or C 1 -C 4 alkoxy groups; phenyl (C 1) ^ -C ^) alkyl wherein the phenyl moiety may be optionally substituted with 1-3 substituents as mentioned above in conjunction with phenyl and the alkyl moiety may be optionally substituted with 1-3 substituents as noted above in conjunction with C C-C alkyl, and heteroaryl or heteroaralkyl, wherein the heteroatom or atom is selected in the aforementioned heterocyclic units from 1-1 + oxygen, nitrogen or sulfur atoms and the alkyl unit 1 linked to said heteroaromatic alkyl unit -6 contains carbon atoms, or is optionally substituted to form a condensed carbocyclic, heterocyclic or heteroaromatic ring optionally substituted with 1-2 of the substituents as defined above; * (c) groups of formulas 61-66, optionally substituted on a carbon atom with 1 or 2 substituents independently selected from C 1 -C 6 alkyl; C 1 -C 18 alkyl substituted by hydroxy, C 1 -C 18 alkylamino, diC 1 -C 20 alkyl, C 1 -C 20 alkoxy, sulfo, amino, carboxy, or halogen; C 1 -C 8 cycloalkyl; C 1 -C 18 alkoxy, C 1 -C 20 alkylthio; amino; C.j-C ^ alkylamino; diCC ^ -C ^) alkylamino; halogen, C 1 -C 2 alkanoylamino, C 1 -C 2 alkanoyloxy; carboxy; 10 -C-O-C 1 -C 12 alkyl, hydroxy; amidino; guanidino; phenyl; phenyl substituted with 1, 2 or 3 amino, halogen, hydroxyl, trifluoromethyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy groups; phenyl (C 1 -C 6) alkyl in which the phenyl moiety may be optionally substituted with 1-3 substituents as mentioned above in connection with phenyl, the alkyl moiety may optionally be substituted with 1-3 substituents as mentioned above in conjunction with phenyl with C 1 -C 2 alkyl; and heteroaryl or heteroaralkyl in which the heteroatom or atoms in said heterocyclic units are selected from 1-U oxygen, nitrogen or sulfur atoms and the alkyl unit linked to said heteroaralkyl unit contains 20 to 6 carbon atoms or is optionally substituted to form a condensed carbocyclic, heterocyclic or heteroaromatic ring optionally substituted by one or two of the above-defined substituents; (d) groups of formulas 67-72, optionally substituted on a carbon atom by a substituent independently selected from C 1 -C 6 alkyl; C 1 -C 2 alkyl substituted by hydroxy; amino C 1 -C 2 alkylamino, di (-C 2) alkylamino; C 1 -C 2 alkoxy; sulfo; carboxy or halogen; C 1 -C 8 cycloalkyl; C 1 -C 2 alkoxy; C 1 -C 2 alkylthio; amino; C 1 -C 2 alkylamino; diiC 2 -C 2) alkylamino, halogen, C 1 -C 2 alkanoylamino, C 1 -C 2 alkanoyloxy, carboxy; 30 0 ll ..... -C-O-C 1 -C 1 -alkyl; hydroxy, anadxno; guanidino; phenyl; phenyl substituted with 1, 2 or 3 amino, halogen, hydroxyl, trifluoromethyl, C 1 -C 6 alkyl C 1 -C 6 alkoxy groups; phenyl (C 1 -C 6) alkyl in which the phenyl moiety may be optionally substituted with 1-3 substituents as mentioned above in connection with phenyl and the alkyl moiety may optionally be substituted with 1-3 substituents as mentioned above in conjunction with phenyl with C 1 -C 2 alkyl; and heteroaryl or heteroaralkyl wherein the heteroatom or atoms are in the aforementioned het - T - Λ. '· ....... ........... * ··' * -, Λ * Λ F »V * · Χ 'J £ V ** t -216- * it terocyclic units are selected from 1-¾ oxygen, nitrogen or zva vessel atoms and the alkyl unit linked to said heteroaralkyl unit contains 1-6 carbon atoms; (e) groups of formulas 73 or 73 ', where X 5, S or HE is where R 5 is O-1-alkyl; C 1 -C 2 alkyl substituted with 1-3 hydroxy, amino, (^ -¾ "alkylamino, alkylamino, C 1 -C 2 alkoxy, carboxy, halo, or sulfo groups; C 1 -C 8 cycloalkyl C 1 -C 8 cycloalkyl (C 1 -C 1 alkyl) optionally substituted with substituents as mentioned above in connection with C 1 -C 8 alkyl; phenyl; phenyl substituted with 1-3 substituents independently selected from amino. halogen, hydroxy, trifluoromethyl, alkyl, C 1 -C 2 alkoxy, C 1 -C 2 amino, dKC 2 c ^) 8 ^^ 182 ^ 110 ”carboxy and sulfo groups; phenyl (0 ^ -¾) alkyl, wherein the phenyl moiety may optionally be substituted with 1-3 substituents as mentioned above in connection with phenyl and the alkyl moiety may optionally be substituted with 1-3 substituents as mentioned above in conjunction with C 1 -C alkyl, and heteroaryl and heteroaralkyl, the heteroatom or atoms of which are selected from 1-O-, S- or N-atoms and the alkyl moiety linked to heteroaralkyl contains 1-6 carbon atoms, many heteroaryl and heteroaralkyl groups of choice e in the heterocyclic ring unit are substituted with 1-3 substituents 20 independently selected from hydroxy, amino, halogen, trifluoromethyl, C 1 -C 6 alkyl, 0-¾ alkoxy, 0 ^ -¾ alkylamino, diiC, C 1) alkylamino, carboxy and sulfo and in the alkyl moiety by 1-3 substituents selected from hydroxy, amino, 0 ^ -¾ alkylamino, 11 (0 ^ -¾) alkylamino, 0 ^ -¾ alkoxy, carboxy, halogen, and sulfo, any group of choice at a carbon atom may be substituted with one or more substituents independently selected from 0 ^ -¾ alkyl, 0 ^ -¾ alkyl substituted by hydroxy, ¢ ^ -¾ alkylamino, di (C 1 -C ^ alkyl) amino, ¢ ^ Alkoxy, amino, sulfo, carboxy or halogen; C 1 -C 8 cycloalkyl; 0 ^ -¾ alkoxy; 0 ^ -¾ alkylthio, amino, 0 ^ -¾ alkylamino, di (C 1 -C 6) alkylamino; halogen; 0 ^ -¾ alkanoylamino; 0 ^ -¾alkanqyloxy, 30 carboxy, 0 II. -O-O-O-alkyl; hydroxy; amicb.no; guanidmo; phenyl; phenyl substituted with 1, 2 or 3 amino, halogen, hydroxyl, trifluoromethyl, ,¢ ^¾ alkyl, 0. ^ --¾alkoxy groups; phenyl "(C 1 -C 6) alkyl where the phenyl moiety is optionally substituted by 1-3 substituents as listed above in conjunction with phenyl and the alkyl moiety may optionally be substituted by 1-3 substituents as listed above in conjunction with phenyl Alkyl, and hetero- "*" * "*. V 4 -217-aryl or heteroaralkyl in which the heteroatom or atoms in the aforementioned heterocyclic units are selected from 1-4 oxygen, nitrogen or sulfur atoms and the alkyl unit connected to said heteroaralkyl unit 5 1-6 carbon atoms or is optionally substituted to form a fused carbocyclic, heterocyclic or heteroaromatic O ring optionally substituted by one or two of the substituents as defined above; (f) groups of formulas 74-79, wherein X is O, S or NE, wherein R 1 -C 1 -C 10 alkyl, C 1 -C 1 alkyl substituted with 1-3 hydroxy, amino, C 1 -C 10 alkyl-amino, di (C 1 -C 6) alkylamino, C 1 -C 6 alkoxy, carboxy, halogen or sulfo groups; C 1 -C 8 cycloalkyl; C 1 -C 8 cycloalkyl, (C 1 -C 12) alkyl optionally substituted with 1-3 substituents as mentioned above in connection with C 1 -C 12 alkyl; phenyl; phenyl substituted with 1-3 substituents independently selected from amino, halogen, hydroxy, trifluoromethyl, C 1 -C 2 alkyl, C 1 -C 1 alkoxy, C 1 -C 1 alkylamino, di (C 1 -C 1) alkylamino, carboxy and sulfo; phenyl (C 1 -C 6) alkyl in which the phenyl moiety may be substituted with 1-3 substituents as mentioned above in conjunction with phenyl and the alkyl moiety may optionally be substituted with 1-3 substituents as noted above in conjunction with C 1 - 3 C1-4 alkyl, and heteroaryl ^ and heteroaralkyl, wherein the heteroatom or atoms are selected from 1-4, S or H atoms and the heteroaralkyl-linked alkyl moiety contains 1-6 carbon atoms, which are heteroaryl and heteroaralkyl groups optionally in the heterocyclic ring unit are substituted with 1-3 substituents independently selected from hydroxy, amino, halogen, trifluoromethyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 2 alkylamino, di ( C ^ -C ^) alkylamino, carboxy and sulfo and in the alkyl unit by 1-3 substituents selected from hydroxy, amino, C ^ -C ^ alkylamino, di- (C ^ -C ^) alkylamino, C ^ -C ^ alkoxy ., carboxy, halogen and sulfo, which heteroaromatic group is optionally substituted on the carbon atom with a substituent selected from C 1 -C 6 alkyl; alkyl substituted by hydroxy, C 1 -C 8 alkylamino, di (C 1 -C 8 alkyl) amino, C 1 -C 8 alkoxy, amino, sulfo, carboxy or halogen; C 1 -C 8 cycloalkyl, C 1 -C 2 alkoxy, C 1 -C 2 alkylthio; amino, C 1 -C 2 alkylamino; di (C 1 -C 2) alkylamino, halogen, C 1 -C 2 alkanoylamino, C 1 -C 2 alkanoyloxy, carboxy, 35 ° C-alkyl; hydroxy, amidino, guanidino; phenyl; phenyl substituted with 1, 2 or .3 amino, halogen, hydroxyl, trifluoromethyl, C 1 -C 2 alkyl, C 1 -C 2 alkoxy groups, phenyl (C 1 -C 2) alkyl in which the phenyl moiety of choice -218- * / kau are substituted by 1-3 substituents as mentioned above in conjunction with phenyl and the alkyl moiety may optionally be substituted with 1-3 substituents as mentioned above in conjunction with C 1 -C 4 alkyl; and heteroaryl "* or heteroaralkyl wherein the heteroatoam or atoms in said 5 heterocyclic units are selected from 1-h oxygen, nitrogen or n sulfur atoms and the alkyl moiety linked to said heteroaralkyl unit contains 1-6 carbon atoms, and (g) groups of formulas 80-85, wherein R 2 -C 1 -alkyl, C 1 -C 1 -alkyl substituted with 1-3 hydroxy, amino, C 1 -C 1 alkylamino, di (C 1 -C ^) alkylamino, C 1 -C 6 alkoxy, carboxy, halogen, or sulfo groups; C 1 -C 8 cycloalkyl, C 1 -C 8 ^ 1 ° ^ 1 (C 1 -C 6) alkyl optionally substituted with 1-6 substituents as above reported in conjunction with C 1 -C 4 alkyl; phenyl; phenyl substituted with 1 to 3 substituents independently selected from amino, halogen, hydroxy, trifluoromethyl, C 1 -C 4 alkyl, C 1 -C 2 alkoxy, C 1 -C 2 alkylamino, di- (C 1 -C 2) alkylamino, carboxy and sulfo; phenyl (C 1 -C 1) alkyl in which the phenyl moiety may be optionally substituted with 1-3 substituents as mentioned above in conjunction with phenyl and the alkyl moiety of choice are substituted with 1-3 substituents as mentioned above in connection with C 1 -C 20 alkyl; and heteroaryl and heteroaralkyl wherein the heteroatom or atoms are selected from 1-k, S or N atoms and the heteroaralkyl-linked alkyl moiety contains 1-6 carbon atoms, which heteroaryl and eroaralkyl groups are optionally in the heterocyclic ring moiety substituted with 1-3 substituents independently selected from hydroxy, amino, halogen, trifluoromethyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylamino, dKC 2 -C 1 -alkylamino, carboxy and sulfo and in the alkyl unit by 1-3 substituents selected from hydroxy, amino, C 1 -C 6 alkylamino, diiC 2 -C 6 alkylamino, C 1 -C 6 alkoxy, carboxy, halogen and sulfo; or a pharmaceutically acceptable salt thereof. 160. A compound according to claim 159, characterized in that the group of formula 52 represents a group selected from 5 6 7 10 (a) groups of formula 5T, wherein R 7 is C 1 -C 8 alkyl and E, B and R are independently selected from hydrogen, C 1 -C 12 alkyl; (b) groups of formulas 58-60, wherein R 1 is C 1 -C 20 alkyl and wherein available ring carbon atoms are. choice are substituted by 1-3 substituents independently selected from CL-C. alkyl; * 5 ^ (c) groups of formulas 61-66, wherein R 1 is -C alkyl and in which available 6 - - - - - '' ..... -219-A> optionally substituted ring carbon atoms are substituted by a or two substituents independently selected from C.-C. alkyl; C * 4 (d) groups of formulas 67-72 wherein Pr is C 1 -C 8 alkyl and wherein an available ring carbon atom is optionally substituted by C 1 -C 4 alkyl; 5 (e) groups of formulas 73 and 73 ', wherein R is C 1 -C 8 alkyl and X is 0, S or HR 9, wherein R 1 is C 1 -C 6 alkyl and wherein one or more available ring carbon atoms are of choice are substituted by C 1 -C 4 alkyl; (f) groups of formulas 7 ^ -79 »in which R 1 is C 1 -C 8 alkyl, X is 0, S or HR 10 wherein R 1 is -C 1 -C 6 alkyl and wherein one or more available ring carbon atoms are optionally substituted by C 1 -C 2 alkyl; and (g) groups of formulas 80-85, wherein R 1 is C 1 -C 1 alkyl and R is C 1 -C 1 alkyl. 161. A compound according to claim 160, characterized in that R1 15 OH i. 16 is CH 2 CH- and R is methyl. 162. A compound according to claim 160, characterized in that R 1 is OH ch 3 ha- and methyl, 20 and the absolute configuration is 5R, 6S, 8R. 163. A compound according to claims 159, 160, 161 and 162, characterized in that A is -CH- or -CHgCHg-. 16¾. A compound of formula 185, wherein A is a C 1 -C 8 straight or branched alkylene; R is hydrogen, an anomic charge, or a conventional easily removable carboxyl protecting group provided that 2 when R is hydrogen or a protecting group, there is always a counter ion present; and the group of formula 52 represents a group 5 6 (a) of formula 86, wherein R? C 1 -C 8 alkyl, and R represents hydrogen or C 1 -C 2 alkyl, 5. T 30 (b) of the formula 87, wherein R 1 C 1 -C 12 alkyl and R 8 and R are hydrogen or C 1 -C 12 alkyl; (c) of the formula 88, wherein R 1 is C 1 -C 1 alkyl and R is C 1 -C 1 alkyl or phenyl (C 1 -C 6) alkyl; (d) of the formula 89, wherein R 1 is C 1 -C 1 alkyl and R is C 1 -C 1 alkyl; -220-rc (e) of the formula 90, wherein Ir is C1 -C1 alkyl and R is C1 -C1 alkyl; or (f) of the formula 91 'wherein R 1 is C 1 -C 1 -C 4 alkyl; or a pharmaceutically acceptable salt thereof. 165. A compound of the formula 185, characterized in that A is a straight 2 ... 5 or branched C 1 -C 6 alkylene; R is hydrogen, an amonic charge or a conventional, easily removable carboxyl protecting group 2, provided that when R is hydrogen or a protecting group, there is also a counterion and the group of formula 52 represents a group of formulas 92-105 [(a) - (n)], or a pharmaceutically acceptable salt thereof. 166. A compound of formula 186, wherein R is hydrogen, an anionic charge, or a conventional easily removable carboxyl-protecting group 2 provided that when R is hydrogen or a protecting group, a counterion is always present; or a pharmaceutically acceptable salt thereof. 2 167. A compound of formula 187, wherein R is hydrogen, an anionic charge or a conventional easily removable carboxyl protecting group, provided that when R is hydrogen or a protecting group, there is always a counterion present; or a pharmaceutically acceptable salt thereof. 168. A compound of formula 188, wherein R is hydrogen, an anionic charge, or a conventional easily removable carboxyl protecting group, provided that when R is hydrogen or a protecting group, there is always a counterion or a pharmaceutically accepted. barable salt thereof. 169. Compound of formula 189 wherein R is hydrogen, an anionic charge or a conventional easily removable carboxyl protecting group, provided that when R is hydrogen or a protecting group, there is also a counterion or a pharmaceutically acceptable agent. 30 bar salt thereof. . 2 ITO. A compound of formula 190, wherein R is hydrogen, an anionic charge or a conventional easily removable carboxyl protecting group, provided that when R is hydrogen or a protecting group, there is also a counterion present as a pharmaceutically acceptable salt thereof. 2 171. A compound of formula 191, wherein R is hydrogen, an anionic charge, or a conventional easily removable carboxyl-protecting group, provided that when R is hydrogen or a protecting '- - »· * * - _, a -221 -> group there is also a counterion; or a pharmaceutically acceptable salt thereof. . . 2 172. A compound of formula 192, wherein R is hydrogen, an anionic Q charge, or a conventional easily removable carboxyl-protecting group, provided that when E is hydrogen or a protecting V group, there is also a counterion; or a pharmaceutically acceptable salt thereof. 2 173. A compound of formula 193, wherein R is hydrogen or an anionic charge or a conventional easily removable carboxyl protecting group, provided that when R hydrogen or a protecting group also contains a counterion; or a pharmaceutically acceptable salt thereof. 2 17 ^ Compound of formula 19 ^, wherein R represents hydrogen or an anionic charge or a conventional easily removable carboxyl protecting group provided that when R is hydrogen or a protecting group there is also a counterion present; or a pharmaceutically acceptable salt thereof. . . 2. 175. A compound of formula 195, wherein R is hydrogen, an anionic charge, or a conventional easily removable, carboxyl-protecting group, provided that when R 1 represents hydrogen or a protecting group, there is also a counterion; or a pharmaceutically acceptable salt thereof. 176. A compound of formula 196, wherein R is hydrogen, an anionic charge, or a conventional easily removable carboxyl-protecting group, provided that when R represents hydrogen or a protecting group, a counterion is also present; or a pharmaceutically acceptable salt thereof. 2 '. 177. A compound of formula 197, wherein R is hydrogen or an anionic charge or a conventional easily removable carboxyl protecting group provided that when R represents hydrogen or a protecting group, a counterion is also present; or a pharmaceutically acceptable salt thereof. 2 178. A compound of formula 198, wherein R is hydrogen, an anionic charge or a conventional easily removable carboxyl protecting group, provided that when R represents hydrogen or a protecting group, a counterion is also present; or a pharmaceutically acceptable salt thereof. £ -222- * 2 179. A compound of formula 199, wherein R is hydrogen, an anionic charge or a conventional easily removable carboxy-1 bonding moiety 2, provided that when R represents hydrogen or a protecting group there is also a counterion present; or a pharmaceutically acceptable salt thereof. v / 2 180. A compound of formula 200, wherein R is hydrogen, an anomic charge or a conventional easily removable protecting group 2, provided that when R represents hydrogen or a protecting group, there is also a counterion; or a pharmaceutical. T0 acceptable salt thereof. 2 181. A compound of formula 201, wherein R is hydrogen, an anionic charge or a conventional easily removable carboxyl protecting group, provided that when R represents hydrogen or a protecting group, a counterion is also present; or a pharmaceutically acceptable salt thereof. 2 182. A compound of formula 202, wherein R is hydrogen, an anomic charge, or a conventional easily removable carboxyl-protecting 2 group, provided that when R represents hydrogen or a protecting group, a counterion is also present; or a pharmaceutically acceptable salt thereof. 2 183. A compound of formula 203, wherein R is hydrogen or an anionic charge or a conventional easily removable carboxyl protecting group, provided that when R represents hydrogen or a protecting group there is also a counterion or a pharmaceutical. acceptable salt thereof. 2 18¼. A compound of formula 20h, wherein R is hydrogen, an anionic charge or a conventional easily removable carboxy 1 protecting 2 group, provided that when R represents hydrogen or a protecting group, a counterion is also present; or a pharmaceutically acceptable salt thereof. 2 185. A compound of formula 205, wherein R hydrogen is an anomic charge or a conventional easily removable carboxyl protecting group, provided that when R represents hydrogen or a protecting group, there is also a counterion; or a pharmaceutically acceptable salt thereof. 2 186. A compound of formula 206, wherein R is hydrogen, an anionic charge or a conventional easily removable carboxyl protecting