NL8301193A - CARBAPENEM ANTIBIOTICS. - Google Patents

Description

IV

VO 4609

Carbapenem antibiotics.

The invention relates to new carbapenem antibiotics in which the 2-substituent has formula 1 of the formula sheet, wherein A represents a straight or branched chain alkylene group with 2 to 6 carbons and R 11 and 11 are each independently substituted optionally. aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aryl, heterocyclyl, heterocyclyl-aliphatic, heteroaryl or heteroariphatic groups, or R * 0 and R * ^ together with the S ® to which they are attached, optionally substituted sulfur-containing heterocyclic ring.

A number of β-lactam derivatives containing the carbapenem core of formula 2 have been described in the literature. These carbapenem derivatives have been reported to have utility as antibacterial agents and / or 3-lactamase inhibitors.

The first carbapenem compounds were natural products such as thienamycin of formula 3, obtained by fermentation of Strepto myces cattleya (US Patent 3,950,357). Thienamycin is an extremely powerful broad spectrum antibiotic, which has remarkable activity against several Pseudomonas species, organisms known for their resistance to β-lactam antibiotics.

Other natural products containing the carbapenem core include olivanoic acid derivatives such as the antibiotic MM 13902 of formula 4, which is described in US patent 4,113,856, the antibiotic MM 17880 of formula 5, which is described in US patent 4,162,304 the antibiotic MM 4550A of formula 26, which is described in U.S. Patent 4,172,129 and the antibiotic 890A of formula 7, which is described in U.S. Patent 4,264,735. In addition to the natural products, the compound desacetyl 890Aq of Formula 8 is described in U.S. Patent 4,264,734, which is prepared by an enzymatic deacylation of the corresponding N-acetyl compound. Several derivatives of the naturally occurring olivanic acids have also been synthesized, for example, the compounds of formula 9 wherein CQ ^ R ^ is a free salted or esterified carbozyl group, n 0 or 8301193 2 \ # 2 3 1 and R is hydrogen, an acyl group or a group of formula R 0, S 3 wherein R represents a salt-forming ion or a methyl or ethyl group, which are described in European patent application 8885.

U.S. Patent 4,235,922 (see also European Patent Application 2058) describes the carbapenem derivative of Formula 10, while British Patent Application 1,598,062 describes the isolation of the compound of Formula 11 from a Streptomyces fermentation broth.

Carbapenem compounds which are unsubstituted at the 6-10 position have also been prepared. US Pat. No. 4,210,661 discloses compounds of Formula 12 wherein R represents phenyl or substituted phenyl, U.S. Patent 4,267,177 discloses compounds of Formula 13 wherein R represents an optionally substituted pyridyl group, in U.S. Patent No. 4,255,441 disclose compounds of formula 14, 2 3 4 6

wherein R and R represent hydrogen or alkyl and R represents the group NH-CO R.

6 ** wherein R is alkyl, phenyl or substituted phenyl and n is 1 or 2, and U.S. Patent 4,282,236 discloses compounds of Formula 15 wherein R * represents hydrogen or alkyl 2 3 3 20 and R represents CN or C C 4 R wherein R represents hydrogen, alkyl, aryl or aralkyl.

Carbapenem compounds of formula 16, wherein R represents hydrogen or acyl and R represents hydrogen or substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, alkylcycloalkyl, aryl, aralkyl, aralkenyl, aralkynyl, heteroaryl, heteroaralkyl, hetero- cyclyl or heterocyclylalkyl are described in U.S. Patent 4,218,463. However, there is no mention of R substituents of the type of formula 17 wherein A is alkylene.

The natural product thienamycin has the absolute configuration 5R, 6S, 8R. This isomer as well as the other seven thienamycin isomers can be obtained via the total synthesis described in U.S. Patent 4,234,596. Total synthesis procedures 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 disclosed synthetic methods is the compound of formula 18 wherein 8301193 3 *>: * pNB represents the group p-nitrobenzyl.

Due to the extraordinary biological activity of thienamycin, a large number of derivatives have been prepared and described in the literature. These include 5 (1) N-formimidoyl-thienamycin of formula 19, which is described in European patent application 6639; (2) N-heterocyclic derivatives of thienamycin of formulas 20 and 21, wherein the ring bifunctional ring may have additional unsaturation; and wherein n is an integer from 1 to 6; p 10 is equal to 0, 1 or 2; R * represents hydrogen, alkyl or aryl; and Z represents imino, oxo, hydrogen, amino or alkyl, which compounds are described in U.S. Patent 4,189,493; (3) substituted N-methylene derivatives of thienamycin of formula 22, wherein X and Y represent hydrogen, R, OR, SR or NR R, wherein R is substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl , aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl, and R and R are hydrogen or R which are disclosed in U.S. Patent 4,194,047; 3 20 * (4) compounds of formula 23, wherein R represents aryl, alkyl, 1 2 acyl or aralkyl and R and R are independently selected from hydrogen and acyl (including type 11 11 -C (0-acyl) R wherein R may be substituted by a quaternary ammonia group, for example, the group of formula 24, which are described in U.S. Patent 4,226,870; 3 (5) compounds of formula 25, wherein R represents hydrogen, acyl or a monovalent, optionally substituted, hydrocarbon group; R * optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl and R is acyl (including -C (0) R acyl where R substituted by a quaternary ammonium group, for example, the group of formula 24, which are disclosed in British Patent 1,604: 276 (see also U.S. Patent 4,235,917); 5 6 7

(6) compounds of formula 26, wherein R, R and R

independently selected from hydrogen and substituted

830 1 1 9 J

* * 4 or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl, which compounds are described in U.S. Patent 4,235,920; 1 2 5 (7) compounds of formula 27, wherein R and R each independently are a group of the type defined for R, a hydrogen atom, or a nitro, hydroxyl, alkoxy of 1 to 6 carbon atoms, amino, alkylamino with 1 to 6 carbon atoms, dialkylamino in which each alkyl group has 1 to 6 carbon atoms, or trialkylamino in which each alkyl group has 1 to 6 carbon atoms, the group being 1, in the latter case an additional anion being present; or R and R together with the nitrogen atom to which they are attached form a substituted or unsubstituted monocyclic or bicyclic heteroaryl or heterocyclyl group containing from 4 to 10 atoms in the ring, 15 of which may be an additional heteroatom oxygen, sulfur and nitrogen; R a cyano group or a substituted or unsubstituted carbamoyl, carboxyl, alkoxycarbonyl wherein alkoxy has 1 to 10 carbon atoms, alkyl of 1 to 10 carbon atoms, alkenyl with 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, 20 cycloalkyl with 3 to 10 carbon atoms, cycloalkylalkyl with 4 to 12 carbon atoms, cycloalkylalkenyl with 5 to 12 carbon atoms, cycloalkenyl with 3 to 10 carbon atoms, cycloalkeny lalkenyl with 5 to 12 carbon atoms, cycloalkenylalkyl with 4 to 12 carbon atoms, aryl of 6 to 10 carbon atoms, aralkyl of 7 to 16 carbon atoms, aralkynyl of 8 to 16 carbon atoms, aralkynyl of 8 to 16 carbon atoms or monocyclic or bicyclic heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl group representing 4 to 10 has atoms in the ring, one or more of which is a heteroatom selected from oxygen, sulfur and nitrogen, and in which the alkyl group of the heteroaralkyl or heterocyclylalkyl growth p contains 1 to 6 carbon atoms; wherein the substituent or substituents on R, R, R or on the ring formed by combining 1 2 R and R, chlorine; bromine; Jew; fluorine; azido; alkyl of 1 to 4 carbon atoms; mercapto; sulfo; phosphono; cyanothio (-SCN); nitro; cyano; amino; hydrazine; amino or hydrazino with up to 3 alkyl substituents from 1 to 6 carbon atoms; hydroxy; alkoxy of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms; carboxyl; oxo; alkoxycarbonyl where 830 1 1 9 3 τ '5 in alkoxy has 1 to 6 carbon atoms; acyloxy with 2 to 10 carbon atoms; carbamoyl; alkylcarbamoyl wherein alkyl has 1 to 4 carbon atoms, or dialkylcarbamoyl wherein each alkyl group has 1 to 4 carbon atoms; to be; R 1 represents a hydrogen atom, an acyl group or a group of the type defined for R; R alkyl of 1 to 10 carbon atoms; substituted carbonyimethyl; alkoxyalkyl in which both the alkoxy and the alkyl groups have 1 to 6 carbon atoms, cycloalkoxyalkyl in which the cycloalkoxy group has 3 to 6 carbon atoms and the alkyl group has 1 to 6 carbon atoms; alkanoyloxyalkyl of 2 to 12 carbon atoms; partially or fully halogenated alkyl of 1 to 6 carbon atoms, wherein the halogen or halogen atoms are chlorine, bromine or fluorine; aminoalkyl; alkenyl of 2 to 10 carbon atoms; alkynyl of 2 to 10 carbon atoms; acyl; alkoxycarbonylalkyl of 3 to 14 carbon atoms; di-alkylaminoacetoxyalkyl of 4 to 21 carbon atoms; alkanoylamino-15 alkyl of 2 to 13 carbon atoms; aralkyl in which the alkyl group has 1 to 3 carbon atoms and in which the aryl group contains 6 to 10 carbon atoms; monocyclic or bicyclic heteroaralkyl or heterocyclylalkyl having 4 to 10 ring atoms, 1 to 3 carbon atoms in the alkyl group, and 1 to 4 hetero atoms selected from oxygen, sulfur and / or nitrogen; Nuclear-substituted aralkyl or heteroaralkyl wherein the substituent is chlorine, fluorine, bromine, iodine or alkyl of 1 to 6 carbon atoms; aryl or nuclear-substituted aryl of 6 to 10 carbon atoms in the ring and wherein the optional substituent in the core is hydroxy, alkyl of 1 to 6 carbon atoms, chlorine, fluorine, or bromine; aralkoxyalkyl; alkyl-25thioalkyl of 2 to 12 carbon atoms; cycloalkylthioalkyl of 4 to 12 carbon atoms; acylthioalkyl wherein the acylthio group has 2 to 10 carbon atoms and the alkyl group has 1 to 6 carbon atoms; or phenyl-alkenyl wherein alkenyl has 2 to 6 carbon atoms; R substituted or unsubstituted alkyl of 1 to 10 carbon atoms; Alkenyl or alkynyl with 2 to 10 carbon atoms; ring-substituted and unsubstituted cycloalkyl, cycloalkenyl, cycloalkenylalkyl, a cycloalkylalkyl having 3 to 6 carbon atoms in the ring and up to 6 carbon atoms in optional chains; aryl of 6 to 10 carbon atoms; aralkyl having 6 to 10 carbon atoms in the ring and 1 to 6 carbon atoms in the alkyl-35 chain; monocyclic or bicyclic heteroaryl or heteroaralkyl having 4 to 10 ring atoms, of which there are more or more oxygen, nitrogen or 8301193 * 6 sulfur, and 1 to 6 carbon atoms in the alkyl chain; proposes; and the substituent or substituents of the ring or chain are chlorine, bromine, iodine, fluorine, azido, cyano, amino, alkylamino of 1 to 6 carbon atoms, dialkylamino in which each alkyl group has 1 to 6 carbon atoms or trialkylamino in which each alkyl group 1 up to 6 carbon atoms, in the latter case an additional anion is present, hydroxy, alkoxy with 1 to 6 carbon atoms, alkyl thioalkyl with 1 to 6 carbon atoms; carboxyl; oxo; alkoxycarbonyl in which alkoxy has 1 to 6 carbon atoms; acyloxy of 2 to 10 carbon atoms; carbamoyl; alkyl-10 carbamoyl wherein the alkyl group has 1 to 4 carbon atoms; dialkyl carbamoyl wherein the alkyl groups have 1 to 4 carbon atoms; cyanoogothio- (- SCN) ·· or.nitro; R is hydrogen, hydroxy, mercapto, R, -OR, 12 12 -SR or NR R, wherein R, R and R are as defined above; 4 4 4 4 X hydroxy, mercapto, amino, acyloxy, -OR, -SR, -NHR, -N (R) “OM, 15 -OQ or, when the compound is in the form of a zwitterion, -O, in which case A is missing; A when the compound is not in the form of a zwitterion, it is a counterion; M is a pharmaceutically acceptable cation; and Q is a blocking group as defined herein, which compounds are described in British Patent 1,604,275; and (8) compounds of formula 28, wherein the group of formula 29 which is attached to the amino nitrogen group of thienamycin represents a mono- or polycyclic N-containing heterocyclic group and R represents hydrogen, substituted or unsubstituted alkyl, aryl, alkene Nyl, heterocyclylalkenyl, aralkenyl, heterocyclylalkyl, aralkyl, -NR2, COOR, CONR2, -OR, or CN, which compounds are described in European patent application 21082. Among the compounds described in U.S. Patent 4,235,920 are the compound of formula 30, wherein A is a pharmaceutically acceptable anion 4. The quaternary amine derivative noted above is also described in Recent Advances in the Chemistry of 2-Lactam Antibiotics,

Royal Society of Chemistry, London, 1981, biz. 240-254, where its antibacterial activity is said to be on average about half to 2/3 that of thienamycin. Applicant is not aware of any literature describing carbapenem derivatives of the present invention having a 2-substituent of the formulas of formula 8301193 tmule 31, although there are several recent patent publications where such compounds may be generic in their broadest scope. includes. For example, European patent application 40408 describes compounds of formula 32, wherein R * is hydrogen, methyl or hydroxyl and R 5 * represents a monovalent organic group, including under 7 7

other substituted alkyl or a group of the formula -Q ^ R wherein R

is an optionally substituted 5- or 6-membered heterocyclic ring. In the

European patent application 38869 discloses compounds of formula 33-6 7 8 wherein R, R and R are independently selected from hydrogen, substituted or unsubstituted alkyl, alkenyl, and alkynyl, with 1 to 10 carbon atoms; cycloalkyl, cycloalkylalkyl, and alkylcycloalkyl, with 3 to 6 carbon atoms in the cycloalkyl ring and 1 to 6 carbon atoms in the alkyl groups; aryl, for example phenyl; aralkyl, aralkenyl, and aralkynyl wherein the aryl group is phenyl and the aliphatic portion has 1 to 6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl; wherein the substituent or substituents for the above groups are selected from: -X ° halogen (chlorine, bromine, fluorine) -OH hydroxy 20 -OR * alkoxy, aryloxy 0 1 2 -OCNR R carbamoyloxy ί 1 2 -CNR R carbamoyl - NR * R ^ amino 25 HE1 / amidino \ 12

NR R

E1 30 · -NO ^ nitro Θ χ ^ -N (R} 2 trisubstituted amino (R group selected independently) E1 '2.

35 -C = NOR oximxno -SR * alkyl- and arylthio 8301193 f * 8 1 2 -SO2NR R sulfonamido 0 -NHCNR ^ R ^ ureldo 0 Γ '2 R CNR - amido -CO-H carboxy 1 1 5 “c02R carboxylate

O

"1 -CR acyl 0" 1

-OCR acyloxy -SH mercapto O

"1

-SR alkyl and aryl sulfinyl O

"1 10 -SR alkyl and aryl sulfonyl

II

O -CN cyano -N ^ azido; 6 wherein, with respect to the substituents listed on R, R 8 and R 8, 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 3 to 6 carbon atoms in the cycloalkyl ring and 1 to 6 carbon atoms in the alkyl groups; aryl such as phenyl; aralkyl, aralkenyl, and aralkynyl wherein the alkyl group is phenyl and the aliphatic portion has 1 to 6 carbon atoms; heteroaryl, hetero-20 aralkyl, heterocyclyl and heterocyclylalkyl and wherein the heteroatom or heteroatoms in the above-mentioned heterocyclic groups are selected from 1 to 4 oxygen, nitrogen or sulfur atoms, and wherein the alkyl groups associated with said heterocyclic groups are 1 to 6 carbon have dust atoms. (See also European patent applications 25 1627, 1628, 10317, 17992, 37080, 37081 and 37082); in the European patent

application 24832 discloses compounds of formula 34, wherein R

hydrogen or a group selected from OH, OSQ-H or a salt or alkyl ester J 2 3 thereof whose alkyl group has 1 to 4 carbon atoms, OR, SR, 1 8301193 3 3 2 OCOR, OCO2R or OCONHR, wherein R represents an alkyl group of 1 to 6 carbon atoms or an optionally substituted benzyl group and R3 represents an alkyl group of 1 to 6 carbon atoms or an optionally substituted benzyl or phenyl group, and R alkyl of 1 to 6 carbon atoms, alkenyl with 2 to 6 carbon atoms, alkynyl of 3 to 6 carbon atoms in which the triple bond is not on the carbon adjacent to the sulfur atom, aralkyl, alkanoyl of 1 to 6 carbon atoms, aralkanoyl, aryloxyalkanoyl, or arylcarbonyl, where 12 these R groups may be optionally substituted. The compounds are described as antibacterial agents.

The above-described European patent application 3S.869 discloses a synthesis of the carbapenem derivatives via intermediates of the general formula 35, in which R and R are as defined above 2 'and R an easily removable carboxyl protecting group is. As intermediates also compounds of formula 36 are described, wherein X is indicated as a leaving group.

Although as noted above, carbapenem derivatives have been described in the art with a 2-substituent of the type of formula 37 and derivatives with a 2-substituent of the type 1 -SASR wherein R is hydrogen, alkyl, alkenyl, alkynyl , cycloalkyl, cycloalkylalkyl, alkylcycloalkyl, phenyl, aralkyl, aralkenyl, aralkynyl, heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl, as far as the applicant is aware, no carbapenem compounds have been described in which the 2-substituent alkylene group A is directly linked to a sulfonium group, ie a group of the type of formula 31.

Despite the large number of carbapenem derivatives described in the literature, there is still a need for new carbapenem compounds because known derivatives can be surpassed in terms of spectrum of action, strength, stability and / or toxic side effects.

The present invention provides a new series of carbapenem derivatives, which are characterized by a 2-substituent of formula 1, wherein A is a straight or branched chain alkylene group having 2 to 6 carbon atoms and R 1 and R 2 each independently optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aryl, heterocyclyl, heterocyclyl-aliphatic, heteroaryl or heteroaraliphatic groups, or R ^ and R * ^ together with the S ^ to which they are attached, represent an optionally substituted sulfur-containing heterocyclic ring containing 0 contains up to 2 double bonds and may contain from 0 to 2 additional heteroatoms selected from, N and S, which ring is bonded to A by a sulfur atom to form a sulfonium group. More specifically, the present invention provides carbapenem derivatives of formula 38, wherein R is hydrogen and R is selected from the group of hydrogen; substituted and unsubstituted alkyl, alkenyl, and alkynyl of 1 to 10 carbon atoms; cycloalkyl and cycloalkylalkyl with 3 to 6 carbon atoms in the cycloalkyl ring and 1 to 10 carbon atoms in the alkyl groups; phenyl; aralkyl, aralkenyl and aralkynyl wherein the alkyl group is phenyl and the aliphatic moiety has 1 to 6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the heteroatom or heteroatoms in the above heterocycles are selected from 1 to 4 oxygen, nitrogen or sulfur atoms and the alkyl groups linked to said heterocycle have 1 to 6 carbon atoms; wherein the substituent or substituents for the above groups are independently selected from the group consisting of C 1 -C alkyl, optionally substituted by amino, halogen, hydroxy 1 O 20 or carboxyl halogen -OR 3 O

"34 -OCNR R

25 0

"34 -CNR R

3 4 -NR R

NR3 - <> 34

NR R

-so2nr3r4 30 0

"34 -NHCNR R

O

3 "4 R CNR - -co / = 0 8301 193 r 11 0, -OCR3 -SR3

O

.. g

-SR

O

"9

-SR

H

O

5 -CN

• “3 3

-OSO, R

* 3 -OSO „R

3 4

-NR SOgR

io -nr3c = nr4 R3 -NR3C02R4 -no9, Δ 3

wherein with respect to the above substituents, the groups R

4 and R are independently selected from hydrogen? alkyl, alkenyl and alkylnyl of 1 to 10 carbon atoms; cycloalkyl, cycloalkylalkyl and alkyl-cycloalkyl with 3 to 6 carbon atoms in the cycloalkyl ring and 1 to 6 carbon atoms in the alkyl groups? phenyl? aralkyl, aralkenyl and aralkynyl wherein the aryl group is phenyl and the aliphatic moiety has 1 to 6 carbon atoms; and heteroaryl, heteroaralkyl, heterocyclyl, and hot-rocyclylalkyl wherein the hetero atom or hetero atoms in the above heterocycles are selected from 1 to 4 oxygen, nitrogen or sulfur atoms and those with said heterocycles

groups of linked alkyl groups have 1 to 6 carbon atoms, or R and R.

semen with the nitrogen to which at least one is attached can form a nitrogen-containing heterocyclic 5- or 6-ring? R is like

defined for R3 except it cannot be hydrogen? or where 1 S

R and R together represent alkylidene of 2 to 10 carbon atoms or alkylidene of 2 to 10 carbon atoms substituted by hydroxy; A represents a straight or branched chain alkylene group having 2 to 6 carbon atoms; R represents hydrogen, an anionic charge or a conventional easily removable carboxyl protecting group, in the case where R is hydrogen or a protecting group also a counter-anion 10 11 is present, and R and R are each independently for (a) alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 5 6 carbon atoms or cycloalkylalkyl of 3 to 6 carbon atoms in the cycloalkyl ring and 1 to 6 carbon atoms in the alkyl group, wherein the alkyl, alkynl, alkynyl, cycloalkyl or cycloalkylalkyl group are optionally substituted by 1 to 3 substituents independently selected from hydroxy, alkoxy of 1 to 6 carbon atoms, alkanoyloxy with 1 to 6 carbon atoms, carboxy, alkoxycarbonyl with 1 to 6 carbon atoms, amino, alkylamino with 1 to 6 carbon atoms, dialkylamino in which each alkyl group has 1 to 6 carbon atoms, alkanoylamino with 1 to 6 carbon atoms, phenyl, phenyl substituted by 1 to 3 halogen, alkoxy with 1 to 6 carbon atoms, alkyl with 1 to 6 carbon-15 atoms, carboxy, carboxyalkyl wherein alkyl has 1 to 6 carbon atoms, amino, alkylamino with 1 to 6 carbon atoms, dialkylamino in which each alkyl group has 1 to 6 carbon atoms, or dialkylaminoalkyl in which each alkyl group has 1 to 6 carbon atoms, halogen or oxo; (b) phenyl, optionally substituted by 1 to 3 halo-20 none, alkoxy of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms, carboxy, amino, alkylamino of 1 to 6 carbon atoms or dialkylamino groups, where each alkyl group contains 1 to Has 6 carbon atoms; (c) heterocyclyl or heterocyclylalkyl, wherein the heterocyclic group is a 4 to 6 ring having 1 to 3 hetero atoms selected from O, N and S, and the alkyl group has 1 to 6 carbon atoms, the heterocyclyl or heterocyclylalkyl ring is optionally substituted by 1 to 3 alkyl groups of 1 to 6 carbon atoms or alkoxy groups of 1 to 6 carbon atoms; or (d) heteroaryl or heteroaralkyl wherein the heterocyclic group is a 5- or 6-membered aromatic ring having 1 to 3 heteroatoms selected from O, N and S and the alkyl group has 1 to 6 carbon atoms, which heteroaryl or heteroaralkyl ring optionally substituted by 1 to 3 alkyl groups of 1 to 6 carbon atoms, alkoxy groups of 1 to 6 carbon atoms, carboxy groups, carboxyalkyl groups, wherein the alkyl has 1 to 6 carbon atoms, amino groups, alkylaminc groups of 1 to 6 carbon atoms,, dialkylamino groups in which each alkyl group has 1 up to 6 830 1 19 3 13 carbon atoms, aminoalkyl of 1 to 6 carbon atoms or dialkyl aminoalkyl groups, wherein each alkyl group has 1 to 6 carbon atoms; or wherein R and R together with the SO to which they are attached form a sulfur-containing heterocyclic 4 to 6 ring containing 0-2 double bonds and 0-2 additional hetero atoms selected from 'O, N and S, which ring is bonded to A by a sulfur atom to form a sulfonium group, which heterocyclic ring is optionally substituted by 1 to 3 substituents independently selected from alkyl of 1 to 6 carbon atoms, optionally substituted by 1 to 3 hydroxy alkoxy with 1 to 6 carbon atoms, carboxy, halogen, amino, alkylamino with 1 to 6 carbon atoms or dialkylamino groups in which each alkyl group has 1 to 6 carbon atoms, hydroxy, alkoxy with 1 to 6 carbon atoms, alkanoyloxy with 1 to 6 carbon atoms, amino, alkylamino of 1 to 6 carbon atoms, dialkylamino in which each 15 alkyl group has 1 to 6 carbon atoms, alkanoylamino of 1 to 6 carbon atoms, carboxy, alkoxycarbonyl of 1 to 6 carbon atoms, halogen, oxo or phenyl; or wherein the heterocyclic ring of formula 39 is fused with a carocyclic 5- to 6-ring, a phenyl ring, a heterocyclic 5- to 6-ring or a heteroaryl 5- or 6-ring, which rings may optionally be substituted are 1 to 3 of the substituents listed above for the ring of formula 39? as well as pharmaceutically acceptable salts thereof.

The compounds of formula 38 are potent antibacterial agents or intermediates useful for the preparation of such agents.

The invention also encompasses methods of preparing the novel carbapenem derivatives described above as well as pharmaceutical compositions containing the biologically active carbapenem derivatives in combination with pharmaceutically acceptable carriers or diluents.

The new compounds of general formula 38 contain the carbapenem core of formula 2 and can therefore be referred to as 1-carba-2-penem-3-carboxylic acid derivatives. On the other hand, the compounds can be considered as having the basic structure of formulas 40 and 35 designated as 7-oxo-1-azabicyclo (3,2,0) hept-2-en-2-carboxylic acid derivatives. While the present invention includes compounds wherein the relative stereochemistry of the 5,6 protons is both cis and trans, the preferred compounds have 5R, 6S (trans) stereochemistry as in the case of thienamycin.

The compounds of formula 38 may be unsubstituted at the 6 position or substituted by substituent groups previously disclosed for other carbapenem derivatives. More in particular, R 1 may be hydrogen and R may be hydrogen or a non-hydrogen substituent as disclosed, for example, in the European

6 8 - patent application 38,869 (see the definition of R). on the other hand, R

and R * together are an alkylidene with 2 to 10 carbon atoms or alkylidene with 10 2 to 10 carbon atoms substituted by, for example, hydroxy.

The following is an elaboration of the definitions for R and R 8: (a) The aliphatic "alkyl", "alkenyl" and "alkynyl" groups may have a straight or branched chain of 1 to 10 carbon-15 atoms; preferably they have 1 to 6, most preferably 1 to 4, carbon atoms; when they are part of another substituent, for example as in cycloalkylalkyl, or heteroaralkyl or aralkenyl, the alkyl, alkenyl and alkynyl group preferably contain 1 to 6, most preferably 1 to 4 carbon atoms.

(B) "Heteroaryl" includes mono-, bi- and polycyclic aromatic heterocyclic groups having 1 to 4 O, N or S atoms; preference is given to 5- or 6-membered heterocycles such as thienyl, furyl, thiadiazolyl, oxadiazolyl, triazolyl, isothiazolyl, thiazolyl, imidazolyl, iso-xazolyl, tetrazolyl, oxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyrida-25yl, pyridrolyl pyrazolyl, etc.

(c) "Heterocyclyl" includes mono-, bi- and polycyclic saturated or unsaturated non-aromatic heterocyclic groups containing 1 to 4 O, N or S atoms; preferred are 5- or 6-membered heterocycles such as morpholinyl, piperazinyl, piperidyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, pyrrolinyl, pyrrolidinyl, etc.

(D) "Halogen" (also used to define R and R) includes chlorine, bromine, fluorine and iodine and is preferably chlorine or bromine.

The term "conventional easily removable carbo-35 xyl protecting group" refers to a known ester group which has been used to block a carboxyl group during the chemical reaction steps described below and which may be removed, if desired, by methods which do not result in a lead to noticeable destruction of the remaining 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, p-nitrobenzyl, 2-naphthylmethyl, benzyl, trichlorethyl, silyl such as trimethylsilyl, phenacyl, p-methoxybenzyl, acetonyl, o-nitraenzyl, 4-pyridylmethyl and alkyl of 1 to 6 carbon atoms such as 10 methyl , ethyl or t-butyl. Such protecting groups include those which are hydrolyzed under physiological conditions such as pivaloyloxymethyl, acetoxymethyl, phthalidyl, indanyl and methodemethyl.

A particularly advantageous carboxyl protecting group is p-nitrobenzyl, which can be easily removed by catalytic hydrogenolysis.

The pharmaceutically acceptable salts referred to above include the non-toxic acid addition salts, for example salts with inorganic acids such as hydrogen chloride, hydrogen bromide, hydrogen iodide, phosphoric acid, sulfuric acid, etc. and salts with organic acids such as maleic acid, acetic acid, citric acid, tartaric acid, benzoic-20 acid, tartaric acid, fumaric acid, α-hydroxybenzene acetic acid, ascorbic acid, lactic acid, gluconic acid and malic acid. Compounds of formula 38 in the form of acid addition salts can be written as compounds 2 of formula 41 wherein R is hydrogen or a protecting group, where X 1 represents the anion of the acid. The counter anion X4 can be selected to provide pharmaceutically acceptable salts for therapeutic administration, but in the case of intermediates of formula 38, can also be a toxic anion. In such a case, the ion can then be removed or replaced with a pharmaceutically acceptable anion to form an active end product for therapeutic use. When acidic or basic groups are present in the R * group or on the R 1 or R 2 substituents, the present invention may also include suitable base or acid salts of these functional groups, for example acid addition salts in the case of a basic group and metal salts (e.g., sodium, potassium, calcium, and aluminum, 35), the ammonium salt, and salts with non-toxic amines (e.g., trialkylamines, procaine, dibenzylamine, 1-ephenamine, N-benzyl-3301193 16 β-phenethylamine, N, N dibenzylethylenediamine, etc.) in the case of an acidic group.

2

Compounds of formula 38 wherein R is hydrogen, an anionic charge or a physiologically hydrolyzable ester group, together with pharmaceutically acceptable salts thereof, are useful as antibacterial agents. The other compounds of formula 38 are valuable intermediates which can be converted into the above biologically active compounds.

A preferred embodiment of the present invention comprises compounds of formula 38 wherein R is hydrogen and R represents hydrogen, CH3CH2-, (CH3) 2CH-, (CH3) 2C (OH) - or CH3CH (OH) -.

Of these subclasses, those compounds are preferred, wherein R * represents CH3CH (OH) -, most preferably compounds having the absolute configuration 5R, 6S, 8R.

Another preferred embodiment comprises compounds 18 of formula 38 wherein R and R together form an alkylidene group of the formula HOCH2 “G (CH3) =. The alkylene group (i.e., substituent A) in the compound of formula 38 may have a straight or branched chain and may contain from 2 to 6 carbon atoms. A preferred embodiment includes those compounds wherein A represents - (CH_) - wherein n equals 2, μ Π 3 or 4 and a particularly preferred embodiment comprises those compounds wherein A represents -CH2CH2-.

The 2 substituent of the present compounds is characterized by the presence of a sulfonium group attached to the alkylene group A. As noted above, R * 0 and R * 1 can each be independently selected from optionally substituted aliphatic, cycloaliphatic, cycloaliphatic aliphatic, aryl, heterocyclyl, heterocyclyl aliphatic, heteroaryl or heteroaraliphatic groups. On the other hand, the R and R substituents together with the to which they are attached may form an optionally substituted sulfur-containing heterocyclic 4 to 6 ring containing 0 to 2 double bonds and 0 to 2 additional heteroatoms selected from O, N and S which ring is bonded to A by a sulfur atom to form a sulfonium group. In the latter case where the group of formula 35 39 represents a heterocyclic ring, the ring may also be fused to a carbocyclic 5- or 6-ring, a phenyl ring or a hetero-3301193 17 aryl 5- or 6-ring (which 1 to 40, N or S) and each of these fused rings may also be optionally substituted.

The aliphatic R 10 and / or R 2 substituents are preferably alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms or alkynyl of 2 to 6 carbon atoms. Cycloaliphatic substituents are preferably cycloalkyl groups of 3 to 6 carbon atoms, while cycloaliphatic aliphatic groups are especially cycloalkylalkyl groups in which the cycloalkyl group has 3 to 6 carbon atoms and the alkyl group has 1 to 6 carbon atoms. Such aliphatic, cycloaliphatic and cycloaliphatic-aliphatic substituents may be unsubstituted or substituted (preferably by 1 to 3 substituents) by the following substituents: hydroxy, alkoxy of 1 to 6 carbon atoms, alkanoyloxy of 1 to 6 carbon atoms, carboxy, C 3 - C 6 -alkoxycarbony1 (e.g. -COOC ^ H ^ or -COOC ^ H ^), ami-15 no, alkylamino of 1 to 6 carbon atoms, dialky.laTnj.no where each alkyl group has 1 to 6 carbon atoms, alkancylamino of 1 to 6 carbon atoms , phenyl, phenyl substituted by preferably 1 to 3 and most preferably 1 to 2 halogens, alkoxy groups of 1 to 6 carbon atoms, alkyl groups of 1 to 6 carbon atoms, carboxy groups, carboxyl alkyl groups in which the alkyl group has 1 to 6 carbon atoms, amino groups, alkylamino groups having 1 to 6 carbon atoms, dialkylamino groups in which each alkyl group has 1 to 6 carbon atoms or dialkylaminoalkyl groups in which each alkyl group has 1 to 6 carbon atoms, halogen and or oxo.

The R 1 and / or substituents may also be aryl (aromatic hydrocarbon of 6 to 10 carbon atoms), which is in particular phenyl. The aryl group or groups may be unsubstituted or substituted by 1 to 3, preferably 1 to 2 substituents selected from halogen, alkoxy of 1 to 6 carbon atoms, alkyl of 1 to 30 carbon atoms, carboxy, amino, alkylamino of 1 to 6 carbon atoms and dialkylamino in which each alkyl group has 1 to 6 carbon atoms.

when R10 and / or R11 represent heterocyclyl or heterocyclyl aliphatic groups, the heterocyclyl moiety is a non-aromatic 4 to 6 ring containing 1 to 3 heteroatoms selected from 0, N and 35 S. The aliphatic group, in the case of heterocyclyl aliphatic groups, is preferably alkyl of 1 to 6 carbon atoms. The hetero-01193 18 cyclic ring of such groups may be unsubstituted or substituted by 1 to 3, preferably 1 to 2, alkyl substituents of 1 to 6 carbon atoms or alkoxy substituents of 1 to 6 carbon atoms.

When R * 0 and / or R * 1 represent heteroaryl or heteroaraliphatic 5 groups, the heterocyclic portion is a 6- or 6-membered aromatic ring containing 1 to 3 heteroatoms selected from O, N and S, and the aliphatic portion (at preferred alkyl) has 1 to 6 carbon atoms.

The heteroaryl ring of such substituents may be unsubstituted or substituted by 1 to 3, preferably 1 to 2, substituents selected from alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, carboxy, carboxyalkyl wherein the alkyl group is 1 to Has 6 carbon atoms, amino, alkylamino having 1 to 6 carbon atoms, dialkyl amino in which each alkyl group has 1 to 6 carbon atoms, aminoalkyl having 1 to 6 carbon atoms and dialkylaminoalkyl in which each alkyl group has 1 to 6 carbon atoms.

The R 1 and R 2 substituents, together with the S 1 to which they are attached, can also form a sulfur-containing 4- to 6-ring heterocyclic ring having 0-2 double bonds and 0-2 additional hetero atoms selected from 0, N and S which ring is attached to the alkylene-20 (A) group by a sulfur atom to form a sulfonium group. The heterocyclic ring formed by the group of formula 39 may be unsubstituted or substituted by 1 to 3, preferably 1 to 2, substituents selected from alkyl of 1 to 6 carbon atoms, optionally substituted by 1 to 3 hydroxy, alkoxy having 1 to 6, carboxy, halogen, amino, alkylamino having 1 to 6 carbon atoms or dialkylamino groups in which each alkyl group has 1 to 6 carbon atoms; hydroxy, alkoxy of 1 to 6 carbon atoms; alkanoyloxy with 1 to 6 carbon atoms; amino; alkylamino with 1 to 6 carbon atoms; dialkylamino in which each alkyl group has 1 to 6 carbon atoms; 30 alkanoylamino with 1 to 6 carbon atoms; carboxy; alkoxycarbonyl in which the alkoxy group has 1 to 6 carbon atoms; halogen; oxo; and phenyl.

The heterocyclic ring may also be fused to a carbocyclic 5- or 6-ring, a phenyl ring, a heterocyclic 5- or 6-ring (containing 1 to 4 heteroatoms selected from O, N and S) or a 35 heteroaryl 5- or 6-ring (containing 1 to 4 heteroatoms selected from O, N and S), which condensed rings may all be optionally substituted by 1 to 3 / preferably 1 to 2 of the above in connection with substituents described on the sulfur-containing heterocyclic ring.

A particularly preferred embodiment of the present invention includes compounds of formula 38 wherein either 5 (a) R * ^ and R1 * each independently represents alkyl of 1 to 6 carbon atoms or (b) R and R together with the S to which they are attached , represent a group of formula 42 or a group of formula 43; as well as the pharmaceutically acceptable salts thereof.

Examples of preferred 2 substituents wherein

R 1 and R ** are alkyl, the groups of formulas include 44 to 50. Within this subclass, the preferred compounds are those wherein A

stands for - (CH,) - where n equals 2, 3 or 4, preferably those where ^ n 18 A stands for -CH_CH - and where either (a) R and R together represent * * 8 1 15 HOCH ^ -C (CH 2) =, either (b) R is hydrogen and R represents hydrogen, CH 2 -CH 2 - (CH 3) 2 CH-, (CH 3) 2 C (OH) - or CH 3 CH (0H) -.

Particular preference is given to the compounds in which R 1 is hydrogen and R * represents CH 3 CH (OH) - most preferably compounds with the absolute configuration 5R, 6S, 8R.

A most preferred embodiment of the present invention includes compounds of formula 38 wherein the group of formula 39 represents the group of formula 42, and pharmaceutically acceptable salts thereof. Within this subclass, those compounds are preferred, wherein A stands for - (CH_) where n equals 2, 3 or 4, 1 n 18 25 most preferably that where A stands for -CH0CH 2 - and wherein either (a) R and R together represent HOCH2-C (CH3) = either (b) R is hydrogen and R is hydrogen, CH3CH2-, (CH3) 2CH-, (CH3) 2C (OH) - or CH3CH ( OS) - suggests. Particular preference is given to the compounds in which R is hydrogen and R * represents CH 3 CH (OH) - most preferably compounds with the absolute configuration 5R, 6S, 8R.

The most preferred embodiment of the present invention includes the compounds of formula 51, wherein R is hydrogen, an anionic charge or a conventional easily removable carboxyl protecting group, in which case R is hydrogen or a protecting group a counter anion is also present, as well as pharmaceutically acceptable acid addition salts thereof.

It will be appreciated that when R * ^ and R ^ in formula O 3 0 1 1 9 3 20 38 are different, both the R and S optical isomers of such compounds can be formed as well as epimeric mixtures thereof.

The present invention is contemplated to include all such optical isomers and epimeric mixtures. Also, in certain cases, the 5-6 substituent, for example, as in hydroxyethyl, may exist in either the R or S configuration, and the resulting isomers and epimeric mixtures thereof are therefore encompassed by the present invention.

The carbapenem derivatives of the general formula 38-18 are prepared from starting materials of formula 52 wherein R and R are as 2 '10 as defined above and wherein R represents a conventional easily removable carboxyl protecting group. Compounds of formula 52 are described, for example, in European patent application 38,869 (compound 7) and can be prepared according to the general methods described therein.

The method of preparing compounds of formula 38 from starting materials of formula 52 can be summarized by the reaction scheme shown on the formula sheet.

Elaborating on the method described above, starting material of formula 52 is reacted in an inert organic solvent such as methylene chloride, acetonitrile or dimethylformamide with about an equimolar amount of diphenylchlorophosphate in the presence of a base such as diisopropylethylamine, triethylamine, 4-dimethylaminopyridine and the like, where het intermediate of formula 53 was obtained. The acylation to form the diphenylphosphoryloxy leaving group at the 2-position of the intermediate of formula 52 is preferably performed at a temperature of about -20 to + 40 ° C, most preferably at about 0 ° C. The intermediate of formula 53 can be isolated if desired, but is suitably used for the next step without isolation or purification.

The intermediate of formula 53 is then converted into the intermediate of formula 54 by a conventional replacement reaction. The intermediate of formula 53 can be reacted with about an equimolar amount of a mercaptan reagent of the formula HS-A-OH wherein A represents a straight or branched chain alkylene group having from 2 to 6 carbon atoms, in an inert organic solvent such as dioxane, dimethylformamide , dimethyl sulfoxide or acetonitrile, and in the presence of a base such as diisopropylethylamine, triethyl amine, sodium hydrogen carbonate, potassium carbonate or 4-diaethylamino-pyridine. The temperature for the displacement is not critical, but a suitable temperature range is from about -40 ° C to + 25 ° C. Most preferably, the reaction is carried out while cooling, for example at about 0 ° C.

The intermediate of formula 54 is then acylated with methanesulfonyl chloride or a functional acylation equivalent thereof, such as methanesulfonic anhydride, in an inert organic solvent and in the presence of base to obtain the methanesulfonyloxy leaving group of the intermediate of formula 55. The acylation is performed in an inert organic solvent such as tetrahydrofuran, methylene chloride, acetonitrile or dimethylformamide, and in the presence of a suitable base such as diisopropylethylamine, triethylamine, 4-dimethylaminopyridine and the like.

The reaction can be carried out over a wide temperature range, for example from -40 to + 40 ° C, but is preferably carried out under cooling, for example at about -30 to -40 ° C.

The intermediate of formula 55 is then subjected to a replacement reaction to introduce the leaving iodine group into the intermediate of formula 56. This particular group has been found to greatly facilitate the preparation of the carbapenem end products of formula 38. The intermediates of general formula 56 therefore comprise a preferred embodiment of the present invention.

The replacement of the methanesulfonyloxy leaving group is carried out by reacting the intermediate of formula 55 with a source of iodide ions in an inert organic solvent such as acetone, dimethylformamide or dimethyl sulfoxide. Any compound that ionizes in the solvent used to form iodide-30 ions can be used, for example, an alkali metal iodide such as MAI or KI. The temperature for the replacement is not critical, but temperatures of room temperature or higher are very advantageous to allow completion of the reaction in a reasonable period of time. The iodide ion source is used in an amount such that about 35 equivalent or excess iodide ions are obtained relative to the intermediate of formula 55.

830 1 19 3 22

Preparation of the desired carbapenem derivatives of formula 38 is performed by nucleophilic replacement of the leaving iodine group of the intermediate of formula 56 with the desired sulfide of the general formula R 1 -S-R 2. The intermediate of formula 56 is reacted with at least an equivalent, preferably an excess of the desired sulfide in an inert organic solvent and in the presence of silver ions. Suitable inert organic solvents include, for example, tetrahydrofuran, dioxane, methylene chloride, diglyme, dimethoxyethane and the like. Any silver compound 10 which highly ionizes in the solvent and gives silver ions and an inert anion can be used as a source of silver ions, for example AgC104. In general, preferably about an equivalent amount (relative to the intermediate of formula 56) of silver ions is used to facilitate replacement. The reaction 15 can be conducted over a wide temperature range, for example from about -25 to about + 25 ° C, but is preferably conducted at about 0 ° C. The intermediate of formula 57 will have an associated counter anion (from the silver salt used) which can be replaced at this stage by another counter anion, for example an anion which is pharmaceutically acceptable, according to conventional procedures. On the other hand, the counterion can be removed later in the deblocking step.

The deblocking step for removing the car-2 'boxyl protecting group R from the intermediate of formula 57 is carried out according to conventional procedures such as solvolysis, chemical reduction or hydrogenation. In the case where a protecting group such as p-nitrobenzyl, benzyl, benzhydryl or 2-naphthylmethyl is used, which can be removed by catalytic hydrogenation, the intermediate of formula 57 in a suitable solvent such as dioxane-water-ethanol, tetrahydrofuran aqueous dipotassium hydrogen phosphate isopropanol and the like under a hydrogen pressure of 1 to 4 atmospheres; The hydrogenation catalyst such as palladium on charcoal, palladium hydroxide, platinum oxide and the like are treated at a temperature of 0 to 50 ° C for about 0.24 to 4 hours.

2 '35 In case R is a group such as o-nitrobenzyl, photolysis for deblocking can also be used. Protection groups such as 2,2,2-8301193 23 trichloroethyl can be removed by mild zinc reduction. Also can. other conventional carboxyl protecting groups are removed by methods known to those skilled in the art. Finally, compounds 2 * of formula 57 wherein R represents a physiologically hydrolyzable ester such as acetoxymethyl, phthalidyl, indanyl, pivaloyloxymethyl, methoxymethyl etc. as noted above can be administered directly to the host without deblocking because such esters are in vivo under physiological conditions be hydrolyzed.

1 8

It will be appreciated that when the R and / or R sub-10 stituent or the heteroaromatic nucleophilic group attached to substituent A contain a functional group that could interfere with the intended course of the reaction, this group can be protected by a conventional blocking group and then can be unlocked later to regain the desired functional group. Suitable blocking groups and procedures for introducing and removing such groups are well known to those skilled in the art.

As in the case of other β-lactam antibiotics, compounds of general formula 38 can be converted, according to known procedures, into pharmaceutically acceptable salts which are highly equivalent for the purposes of the present invention to the non-salt form compounds. Thus, for example, a 2 compound of formula 38 wherein R represents an anionic charge can be dissolved in a suitable inert solvent and then added an equivalent of a pharmaceutically acceptable acid. The desired acid addition salt can be recovered by conventional procedures, for example, solvent precipitation, lyophilization, etc. When other basic or acidic functional groups are present in the compound of formula 38, pharmaceutically acceptable base addition salts and acid addition salts according to known methods are prepared.

A compound of formula 38 wherein R is hydrogen or represents an anionic charge, or a pharmaceutically acceptable salt thereof, cain are also converted according to conventional procedures into a corresponding compound in which R is a physiological hydro- 2

lysable ester group, or may be a compound of formula 38 wherein R

35 is a conventional carboxyl protecting group, are converted to the 2 corresponding compound wherein R represents hydrogen, an anionic charge or 8301193 24 a physiologically hydrolyzable ester group, or a pharmaceutically acceptable salt thereof.

The new carbapenem derivatives of the general formula 23 wherein R represents hydrogen, an anionic charge or a physiologically hydrolyzable carboxyl protecting group, or the pharmaceutically acceptable salts thereof, are potent antibiotics effective against several gram positive and Gram-negative bacteria and which can be used, for example, as feed additives to promote growth, as food preservatives, as bacteria in industrial applications, for example, in water-based paints and in the white water of paper mills to promote the growth of inhibit harmful bacteria and as disinfectants to destroy or inhibit the growth of harmful bacteria on medical and dental equipment. However, they are particularly useful in the treatment of infectious diseases in humans and other animals caused by gram-positive or gram-negative bacteria.

The pharmaceutically active compounds of the invention can be used alone or formulated as pharmaceutical compositions comprising, in addition to the active carbapenem ingredient, a pharmaceutically acceptable carrier or diluent. The compounds can be administered in various ways; the most important of which are oral, topical or parenteral (intravenous or intramuscular injection) administration. The pharmaceutical compositions can be in solid form, such as capsules, tablets, powders, etc.

Or in liquid form such as solutions, suspensions or emulsions. Compositions for injection, the preferred route of administration, may be formulated in dosage units in ampoules or in multi-dose containers and may contain formulants such as suspending agents, stabilizers and dispersants. The compositions can be in ready-to-use form or in the form of a powder to be reconstituted with a suitable vehicle such as sterile water at the time of administration.

The dosage to be administered depends to a great extent on the particular compound used, the particular formulated composition, the route of administration, the nature and condition of the host and the particular site and organism under treatment 8301193. Selection of the particular preferred dosage and route of administration is then left to the discretion of the therapist. Generally, however, the compounds can be administered parenterally or orally to mammalian hosts in an amount of from about 5 to 200 mg / kg / day. Administration is usually performed in split doses, for example three to four times a day.

In order to illustrate the potent broad spectrum antibacterial activity of the carbapenem compounds of the present invention, both in vitro and in vivo, as well as the low toxicity of the compounds, the following biological data are provided for the preferred carbapenem compound of the present invention, ie 3- [2- {1-tetrahydrothiophenium) ethylthio] -6a- [1- (R) -hydraxyethyl] -7-oxo-1-azabicyclof 3.2.0] hept-2-en-2-carbacacylate the preparation of which is described in Example I.

In vitro efficacy

A sample of the above-identified carbapenem compound after aqueous solution and dilution with nutrient broth was found to exhibit the following minimum inhibitory concentrations (MIC) in micrograms / ml against the listed microorganisms as determined by overnight incubation at 37 ° C by tube dilution. N-formimidoyl-thienamycin was included for comparison.

In vitro

Antibacterial activity of the carbapenem _ Derivative of Example I_ MIC (mcg / ml) _

Organism New compound N-Formimidoyl-thienamycin S. pneumoniae A-9585 0.002 0.004 S. pyogenes A-9604 0.004 0.001 S. aureus A-9537 0 * 008 0.004 30 - 7 7 S. aureus + 50% serum A- 9537 0.03 0.016 S. aureus / (Pen-res.) A-9606 0 ^ 016 0.008 35 S. aureus (Meth-res.) A15097 2 0.5 8301193 26 (Table continued) ^ MIC (mcg / ml)

Organism New compound N-Formimidoyl-thienamycine S. faecalis A20688 0.5 0.5 5 S. coli (10 “4 dil.) A15119 - 0.03 0.016 E. coli C10'3) A15119 0.06 o. 03 E. coli 10 -2 (10 n A15119 0.06 0.06 E. coli CIO "4) A2Q341-1 0.03 0.03 E. coli (10 ~ 3) A20341-1 0.03 0.03 E. coli (1θ “2) A20341-1 0? 06 0.13 K. pneumoniae A-9664 0.06 0.13 K. pneumoniae A20468 0.13 0.06 20 P-mirabilis A-9900 0.13 0.06 P. vulgaris A21559 0.03 0.03 'P. morganii A15153 0.06 0.13 P. rettqeri A22424 0.25 0.25 S. marcescens A2QQ19 0.06 0.03 25 E. cloacae a-9659 0, 0.06 E. cloacae A-9656 0.13 0.06 P. aeruginosa A-9843A 2.1 P. aeruginosa A21213 0.25 0.25 H. influenzae A-9833 8 16 30 H. influenzae A20178 8 32 H. influenzae A21518 8 32 H. influenzae A21522 8 32 B. fraqilis A22862 0.06 0.016 B. fraqilis A22053 0.06 0.06 35 B. fraqilis A22696 0.25 0.13 B. fraqilis A22863 0.06 1 830 1 19 3 27 * In vivo efficacy

The in vivo therapeutic yield of the compound of Example I and N-formimidoyl-thienamycin after intramuscular administration to mice experimentally infected with various organisms is shown in the following table. The PD ^ q (dose in mg / kg needed to confer protection to 50% of the infected mice) is indicated.

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Toxicity.

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

5 Toxicity after intracranial administration to mice_

Compound x LD5Q (mg / kg) Highest dose (mg / kg) without clinical signs of toxicity _ Compound acc. e.g. I> 40 ^ 5 N-formimidoyl thienamycin 32 ^ 5 mean of 25 mice / compound 15 Blood levels in mice after intramuscular administration

Blood levels and the half-life of the compound of Example I after intramuscular administration of 20 mgAg in mice are shown in the table below.

Blood level (µg / ml)

20 Compound 10 20 30 45 60 90 xtl / 2 xx AUC

minutes after administration (min) (µg.h / ml) acc. e.g. I 14.7 13.5 8.7 3.2 0.9 <0.6 9 7.4 N-formimidoyl thienamycin 12.6 9.9 7.3 2.6 0.7 <0.3 9 The compounds were dissolved in a 0.1 M phosphate buffer with a pH of 7.

The values are from a single test; four mice were used per compound, x t1 / 2 indicates the half-life in minutes 30 xx AUC indicates the area under the curve.

Urinary recovery

The urinary recovery of the compound of Example I after intramuscular administration (20 ml / kg) to mice is shown in the following table.

830 1 1 9 3 30

Urinary recovery after intramuscular administration of 20 mg / kg to mice_ 5 Percentage of recovered dose 0-3 3-6 6-24 24-24

Connection hours after administration_

Compound according to example I 15/6 2.1 <0.2 17.7 ± 2.9 10 N-formimidoyl thienamycin 12.1 0.1 <0.1 12.2 ± 3.6

The compounds were dissolved in 0.1 M phosphate buffer with a pH of 7. The values are from a single test; 4 mice per compound.

The present invention is further illustrated by the following examples, which are not intended to be limiting. Example I

Preparation of 3- [2- (1-tetrahydrothiophenium) ethylthio] -6a- [1- (R) -hydroxy-ethyl3-7-oxo-1-azabicyclo [3.2.0] hept-2-en-2-carboxylate formula 58 A. p-Nitrobenzyl 3- (2-hydroxyethylthio) -6a- [1- (R) -hydroxyethyl] -7-oxo-20-1-azabicyclo [3.2.03hept-2-en-2-carboxylate of formula 60 (see reaction A, in which pNB = p-nitrcbenzyl).

A solution of 1.69 g (4.85 mmol) p-nitrobenzyl 6a- [1- (R) -hydroxyethyl] -3,7-dioxo-1-azabicyclo (3.2.0) hept-2-en-2- carbo-xylate of formula 59 in 20 ml of acetonitrile was cooled to 0 ° C under a nitrogen atmosphere. A solution of 726 mg (7.18 mmol) of dixsopropyl-ethylamine in 2 ml of acetonitrile was added, followed by dropwise addition of 1.51 g (5.60 mmol) of diphenyl chlorophosphate in 12 ml of acetonitrile over a period of 3 minutes. The resulting solution was stirred at 0 ° C for 20 minutes, p-nitrobenzyl 3- (diphenyl-3-phosphoryloxy) -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 726 mg (7.18 mmol) of dixsopropylethylamine in 2 ml of acetonitrile, followed by a solution of 439 mg (5.63 mmol) of 2- mercaptoethanol in 2 ml acetonitrile The reaction solution was stirred at 0 ° C for 3 hours, then diluted with 200 ml ethyl acetate and washed with 200 ml water, 100 ml 20% aqueous H 2 PO 4, and brine. the solution dried over MgSO 2 gave a semisolid which was triturated with methylene chloride and filtered to yield 1.2 g (61% yield) of the title product of formula 60 as a white amorphous solid.

NMR (DMS0-d6) $: 1.20 (3H, d, J = 6.0 Hz), 2.9-3.2 (9H, m), 5.22 (1H, 5 d, J = 8, 5 Hz) and 8.23 (2H, d, J = 8.5 Hz); ir (KBr) max: 3500, 1770 and 1700 cm -1; Anal, calcd for C 12 N 2 N 7 7 S 2 C: 52.93; H: 4.94; N: 6.86; S: 7.85. Found: C: 52.83; H: 4.90; N: 6.42; S: 8.31.

B. p-Nitrobenzyl 3- (2-methanesulfonyloxyethylthio) -6a-f 1- (R) -hydroxy-ethyl] -7-oxo-1-azabicyclo (3.2.0) hept-2-en-2-carboxylate with -10 mule 61 (see reaction B)

To a solution of 4.2 g (10.3 mmol) of the compound of formula 60 in 200 ml of tetrahydrofuran was added at -40 ° C 1.3 g (11.3 mmol) of methanesulfonyl chloride, followed by dropwise addition of 1, 26 g (12.4 mmol) of triSthylamine in 5 ml of tetrahydrofuran. The reaction mixture was stirred at -40 ° C for 5 hours, then stirred at -30 ° C for 2 hours under a nitrogen atmosphere and then poured into a mixture of 700 ml ethyl acetate and 1000 ml 5% aqueous phosphoric acid. The organic layer was washed with brine, dried over MgSO4, filtered and condensed into a syrup. This material was purified by silica gel column chromatography (elution with methylene chloride ethyl acetate (3: 1 v / v)) yielding 3.55 g (75% yield) of the title compound of formula 61 as a white amorphous solid was obtained.

NMR (CDCl3) $: 1.25 (3H, d, J = 6.0 Hz), 3.05 (3H, s), 3.06-3.40 (5Ξ, m), 4.05-4 .40 (4H, m), 5.25 (1H, d, J = 14.0 Hz), 5.50 (1H, d, J = 14.0 Hz), 7.70 (2H, d, J = 8.5 Hz) and 8.23 (2H, d, J * 8.5 Hz); ir (KBr) y max: 3400, 1770 and 1600 cm -1. Anal '. calculated for cigH22N2 ° 9S2: C: 46.90; H: 4.56; N: 5.76. Found: C: 46.52; H: 4.32; N: 5.91.

C. p-Nitrobenzyl 3- (2-iodoethylthio) -6α- [1- (R) -hydroxyethyl] -7-axo-1-30 azabicyclo (3.2.0) hept-2-en-2-carboxylate of formula 62 (see reaction C)

A solution of 350 mg (0.72 mmol) of the intermediate of formula 61 and 216 ml (1.4 mmol) of sodium iodide in 20 ml of acetone was refluxed for 4 hours. Evaporation of the acetone gave a white amorphous solid which was suspended in 10 ml ether - 10 ml water. Filtration of the white solid and vacuum drying gave 300 mg (80% yield) of the title compound of formula 62 as a white amorphous powder.

NMR (DMSO-d6) yy: 1.18 (3H, d, J = 6.0 Hz), 3.20-3.60 (7H, m), 3.80-4.25 (2H, m), 5.10 (1H, d, J = 5.5 Hz), 5.25 (1H, d, J = 12.0 Hz), 5.45 (1H, d, J = 12.0 Hz), 7 .70 (2H, d, J = 8.5 Hz) and 8.27 (2H, d, J = 8.5 Hz); ir (KBr) y max: 3500, 1768 and 1700 cm S Anal, calculated for C 18 H 19 N 2 O 6 I: C: 41.71; H: 3.70; N: 5.41; I: 24.48, found: C: 42.10; H: 3.75; N: 5.97; I: 23.20.

D. 3- [2- (1-Tetrahydrothiophenium) ethylthio] -6ot- [1- (R) -hydroxyethyl] -7-10 oxo-1-azabicyclo [3.2.0] hept-2-en-2-carboxylate of formula 58 (see reaction D)

To a solution of 104 mg. 0.2 mmol p-nitrobenzyl 3- (2-iodoethylthio) -6a- [1- (R) -hydroxyethyl] -7-oxo-1-azabicyclo [3.2.0] hept-2-en-2-carboxylate in 5 ml of tetrahydrofuran 0.3 ml, 0.35 mmole of tetrahydothiophene was added, followed by a solution of 60 ml, 0.3 mmole of silver perchlorate in 0.5 ml of tetrahydrofuran. The mixture was stirred at room temperature for 60 minutes. The solvent was evaporated under reduced pressure to give the compound of formula 63 as a yellow gum. This gum was digested with 100 ml of CELITE to yield an amorphous solid.

-1 IR (KBr) Y max: 3400, 1772, 1700 and 1100 cm. Without any further purification, the compound of formula 63 was hydrogenated in the following manner: To a suspended solution of the compound of formula 63 in 20 ml of ether and 20 ml of tetrahydrofuran was added a solution of 40 mg, 0.4 mmol of potassium bicarbonate and 35 mg, 0.2 mmol di-basic potassium phosphate in 20 ml of water. Then, 120 mg of 10% palladium on charcoal was added and the mixture was hydrogenated at 40 psi (2.8 x 105 Pa) on the Parr shaker for 60 minutes. The mixture was then filtered and the catalyst was washed with two 5 ml of water. The combined filtrate and washings were extracted with 50 ml of ether twice and then lyophilized to yield a yellow powder. This crude material was purified on a C, BONDAPAK inverted phase column (7 g) (Waters Associates) eluting with water under a pressure of 8 psi (0.55 x 10 Pa).

Each fraction (15 ml) was analyzed by high pressure liquid chromatography. and fractions with an ultraviolet absorbance of 300 nm were collected and lyophilized 830 1 19 3 33 to yield 12 mg (18% yield, based on the compound of formula 62) of the title product as a white solid obtained.

NMR (D »0) ΰ 1/23 (3H, d, J = 6.0 Hz), 2.25 - 2.45 (4H, m), 3.0 - 3.70 Z -1 5 (11H, m), 3.95-4.30 (2H, m); ir (KBr) fmax: 3400, 1760 and 1590 cm.

UV X (CE CE.QE) 289 nm (£ = 6200).

dSLX m »830 1 19 3

Claims (42)

8 A compound of formula 38, wherein R is hydrogen and R * is selected from the group of hydrogen; substituted and unsubstituted: alkyl, alkenyl and alkynyl of 1 to 10 carbon atoms; cycloalkyl and cycloalkylalkyl with 3 to 6 carbon atoms in the cycloalkyl ring and 1 to 5 carbon atoms in the alkyl groups; phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl group is phenyl and the aliphatic moiety has 1 to 6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the heteroatoam or heteroatoms in the above mentioned heterocyclic groups are selected from 1 to 4 oxygen, 10 nitrogen or sulfur atoms and the alkyl groups associated with said heterocyclic groups have 1 to 6 carbon atoms; wherein the substituent or substituents for the above-mentioned groups are independently selected from the group of alkyl of 1 to 6 carbon atoms, optionally substituted by amino, halogen, hydroxy or carboxyl; Halogen; -OR3 3 4 -OCONR R -conr3r4 -NR R 3 4 3 20 -C (NR R) = NR -so9nr3r4 ^ 3 4 -NHCONR R r3conr4- -CO2r3 25 = 0 -OCOR3 -SR3 -SOR9 9 -so2r 30 -CN -3 3 -0S03R -OSO.R3 3 ^ 4 -NR S02R 8301193 3 3 '4 -NR C (R) = NR -nr3co2r4 -no2 where with regard to the above-mentioned substituents, the 3 4 5 groups R and R are independently selected from hydrogen; alkyl, alkenyl and alkynyl of 1 to 10 carbon atoms; cycloalkyl, cycloalkylalkyl and alkylcycloalkyl having 3 to 6 carbon atoms in the cycloalkyl ring and 1 to 6 carbon atoms in the alkyl groups; phenyl; aralkyl, aralkenyl and aralkynyl where the aryl group is phenyl and the aliphatic portion has 1 to 6 carbon atoms? and heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the heteroatom or hetero atoms in the above heterocycles are selected from 1 to 4 oxygen, nitrogen or sulfur atoms and the alkyl groups 1 to 6 carbon atoms connected to said heterocycles 4 15, or R and R together with the nitrogen to which at least one of them is bound, can form a nitrogen-containing 5- or 6-ring heterocycle 9 3? R is as defined for R, except that it cannot be hydrogen 1 8? or wherein R and R together represent alkylidene of 2 to 10 carbon atoms or alkylidene of 2 to 10 carbon atoms substituted by hydroxy? A represents straight or branched chain alkyl one having 2 to 6 carbon atoms; R represents hydrogen, an anionic charge or a conventional easily removable carboxyl protection group, where 2 in the case where R is hydrogen or a protecting group also a counter anicm is present, and R 1 and R ** each independently represents 25 (a) alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or cycloalkylalkyl of 3 to 6 carbon atoms in the cycloalkyl ring and 1 to 6 carbon atoms in the alkyl group, which alkyl -, alkenyl, alkynyl, cycloalkyl or cycloalkylalkyl group is optionally substituted by 1 to 3 substituents independently selected from hydroxy, alkoxy of 1 to 6 carbon atoms, alkanoyloxy of 1 to 6 carbon atoms, peroxy, alkoxycarbonyl wherein the alkoxy group has 1 to 6 carbon atoms, amino, alkylamino with 1 to 6 carbon atoms, dialkylamino where each alkyl group has 1 to 6 carbon atoms, 35 alkanoylamino with 1 to 6 carbon atoms 6 carbon atoms, phenyl, phenyl substituted by 1 to 3 halogen, alkoxy with 1 to 6 carbon atoms, alkyl with 1 to 8301193 6 carbon atoms, carboxy, carboxyalkyl where the alkyl group has 1 to 6 carbon atoms, amino, alkylamino with 1 to 6 carbon atoms, dialkylamino where each alkyl group has 1 to 6 carbon atoms or di-alkylaminoalkyl wherein each alkyl group has 1 to 6 carbon atoms, ha-5-logene or oxo; (b) phenyl, optionally substituted by 1 to 3 halogen, alkoxy of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms, carboxy, amino, alkylamino of 1 to 6 carbon atoms or dialklamino groups, each alkyl group having 1 to 6 carbon atoms; (C) heterocyclyl or heterocyclylalkyl wherein the heterocyclic group is a 4 to 6 ring having 1 to 3 heteroatoms selected from O, N and S and the alkyl group has 1 to 6 carbon atoms, which hetocyclyl or heterocyclylalkyl ring is optionally is substituted by 1 to 3 alkyl groups of 1 to 6 carbon atoms or alkoxy groups of 1 15 to 6 carbon atoms; or (d) heteroaryl or heteroaralkyl wherein the heterocyclic group is an aromatic 5- or 6-ring with 1 to 3 heteroatoms selected from O, N and S and the alkyl group has 1 to 6 carbon atoms, which heteroaryl or heteroaralkyl ring is optionally substituted by 1 to 3 alkyl groups of 1 to 6 carbon atoms, alkoxy groups of 1 to 6 carbon atoms, carboxy groups, carboxyalkyl groups in which alkyl has 1 to 6 carbon atoms, amino groups, alkylamino groups., With t to 6 carbon atoms, dialkylamino groups in which each alkyl group has 1 to 6 carbon atoms has aminoalkyl groups of 1 to 6 carbon atoms or dialkylaminoalkyl groups in which each alkyl group has 1 to 6 carbon atoms; or wherein R ^ and R ^ together with the S ^ to which they are attached form a sulfur-containing heterocyclic 4- to 6-ring containing 0 to 2 double bonds and 0 to 2 additional heteroatoms selected from o, N and S which ring is bonded to A by a sulfur atom to form a sulfonium group, the heterocyclic ring being optionally substituted by 1 to 3 substituent and independently selected from alkyl of 1 to 6 carbon atoms, optionally substituted by 1 up to 3 hydroxy, alkoxy with 1 to 6 carbon atoms, carboxy, halogen, amino, alkylamino with 1 to 6 carbon atoms or dialkylamino-35 groups in which each alkyl group has 1 to 6 carbon atoms, hydroxy, alkoxy with 1 to 6 carbon atoms, alkanoyloxy with 1 to 6 6 carbon atoms 8301193, amino, alky lam ino with 1 to 6 carbon atoms, dialky lamino in which each alkyl group has 1 to 6 carbon atoms, alkanoy lamino with 1 to 6 carbon atoms, carbaxy, alkoxycarbonyl in which the alkoxygro ep has 1 to 6 carbon atoms, halogen, oxo or phenyl; or wherein the hetero-5 cyclic ring of formula 39 is fused to a carbocyclic 5- or 6-ring, a phenyl ring, a heterocyclic 5- or 6-ring or a heteroaryl 5- or 6-ring, wherein all these rings are optionally substituted can be by 1 to 3 of the substituent listed above for the ring of formula 39 and; or a pharmaceutically acceptable salt thereof. * 1 2. A compound according to claim 1, characterized in that R represents hydrogen, C 2 -C 4 -N- (CH 2 CH-, (CH 2 -CCOH) or CH 2 CHiOH). Compound according to claim 1, characterized in that R and R 1 together represent HCCH-C (CH 3) =. M J 1 15 4. A compound according to claim 1, characterized in that R represents CH * CS (OH) -. J 1 Compound according to claim 1, characterized in that R stands for CH (CHÉOH) - and the absolute configuration is 5R, & S, 8R. 6. A compound according to any one of claims 1 to 5, characterized in that A stands for -CH_CH 2 -. 4 4 · Q 7. A compound of formula 38, wherein R is hydrogen and R1 is selected from the group of hydrogen; substituted and unsubstituted: alkyl, alkenyl and alkynyl of 1 to 10 carbon atoms; cycloalkyl and cycloalkylalkyl with 3 to 6 carbon atoms in the cycloalkyl ring and 1 to 6 carbon atoms in the alkyl groups; phenyl; aralkyl, aralkenyl and aralkenyl wherein the aryl group is phenyl and the aliphatic portion has 1 to 6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the heteroatom or heteroatoms in the above heterocycles are selected from 1 to 4 oxygen, nitrogen or sulfur atoms and the alkyl groups linked to said heterocycles have 1 to 6 carbon atoms ; wherein the substituent or substituents for the above-mentioned groups are independently selected from the group of alkyl of 1 to 6 carbon atoms, optionally substituted by amino, halogen, hydroxy or carboxyl; Halogen; -OR3 8301193 4 3 4 -OCONR R -conr3r4 -nr3r4 3 4 3 -C (NR R) = NR 3 4 5 -SO, NR R * 3 4 -NHCONR R 3 4 R CONR - -co2®3 = 0 3 10 -OCOR -SR3 -SOR9 -so2r9 -ON 15 -N3 -OSO-R3 J 3 -OSO, R 1 4 -NR SO, R 3 ^ 3 4 -NR C (R) = NR -NR 3 CO 2 R 4 -N ° 2 wherein, with respect to the above-mentioned substituents, the 3 4 groups R and R are independently selected from hydrogen; alkyl, alkenyl. and alkynyl of 1 to 10 carbon atoms; cycloalkyl, cycloalkyl-25 alkyl and alkylcycloalkyl, with 3 to 3 carbon atoms in the cycloalkyl ring and 1 to 6 carbon atoms in the alkyl groups; phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl group is phenyl and the aliphatic moiety has 1 to 6 carbon atoms; and heteroaryl, heteroaralkyl, hetero-cyclyl and heterocyclylalkyl wherein the heteroatom or heteroatoms in the aforementioned heterocyclic groups are selected from 1 to 4 oxygen, nitrogen or sulfur atoms and the alkyl groups 1 to 6 carbon atoms associated with said heterocyclic groups have 3 4 or R and R together with the nitrogen to which at least one of them is bound can form a nitrogen-containing 5- or 6-membered heterocyclic ring; R is as defined for R except that it cannot be hydrogen 1 83 0 1 1 S 3 8; or wherein R and R together represent alkylidene of 2 to 10 carbon atoms or alkylidene of 2 to 10 carbon atoms substituted by hydroxy; A represents straight or branched chain alkylene of 2 to 6 carbon atoms; R represents hydrogen, an anionic charge or a conventional easily removable carboxyl protecting group, in the case where R is hydrogen or a protecting group also a counter anion is present, and R * ^ and R ^ each independently alkyl with 1 represents up to 6 carbon atoms; or wherein and R ^ * together with the S® to which they are attached represent a group of formula 42 or a group of formula 43; or a pharmaceutically acceptable salt thereof. A compound according to claim 7, characterized in that R 1 represents hydrogen, C 1 CH 3 -, (CH 1 CH -, (CH 1 CCOH) - or CH 3 CH (OH) -. 9. A compound according to 7, characterized in that R1 and R8 together represent HOCH ^ -CCCH ^) =. 10. A compound according to claim 7, characterized in that 15 R * represents CH 2 CHiOH) -. Compound according to claim 7, characterized in that R * represents CH 1 CH (OH) - and the absolute configuration is 5R, 6S, 8R. Compound according to any one of claims 7 to 11, characterized in that A represents -CH, CH 3 -. 8 A compound of formula 38, wherein R is hydrogen and R * is selected from the group of hydrogen; substituted and unsubstituted: alkyl, alkenyl and alkynyl of 1 to 10 carbon atoms; cycloalkyl and cycloalkylalkyl with 3 to 6 carbon atoms in the cycloalkyl ring and 1 to 6 carbon atoms in the alkyl groups; phenyl; aralkyl aralkenyl and ar-25 alkynyl wherein the aryl group is phenyl and the aliphatic moiety has 1 to 6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the heteroatom or heteroatoms in the above heterocycles are selected from 1 to 4 oxygen, nitrogen or sulfur atoms and the alkyl groups linked to said heterocycles have 1 to 6 carbon atoms; wherein the substituent or substituents for the above-mentioned groups are independently selected from the group of alkyl of 1 to 6 carbon atoms, optionally substituted by amino, halogen, hydroxy or carboxyl; halogen; 35 -OR3 -oconr3r4 8301193 -conr3r4 „3 4 -NR R 3 4 3 -C (MR R) = NR -so.nr3r4 e ^ 34 3 -NHCONR R r3conr4 -002r3 = 0 -OCOR3 10 -SR3 -SOR9 -so2r9 -CN 'N3 15 -0S03R3 -OSO-R3 i 4 -NR SO R 3 Z 3 4 -NR C (R) = NR-4 -NR CO-R 20 -no 2 where, with respect to the above substituents, the 3 4 groups R and R are independently selected from hydrogen; alkyl, alkenyl and alkynyl of 1 to 10 carbon atoms; cycloalkyl, cycloalkylalkyl and alkylcycloalkyl having 3 to 6 carbon atoms in the cycloalkyl ring and 1 to 6 carbon atoms in the alkyl groups; phenyl; aralkyl, ar-alkenyl and aralkynyl wherein the aryl group is phenyl and the aliphatic portion has 1 to 6 carbon atoms; and heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the heteroatom or heteroatoms in the above heterocycles are selected from 1 to 4 oxygen, nitrogen or sulfur atoms and the alkyl groups linked to said heterocycles 6 carbon atoms 3 4, or R and R together with the nitrogen to which at least one of them is bound can form a nitrogen-containing 5- or 6-membered heterocyclic ring 9 3; R is as defined for R except that it cannot be hydrogen; or wherein R and R together represent alkylidene of 2 to 10 carbon atoms or alkylidene of 2 to 10 carbon atoms substituted 83 0 1 1 9 3 by hydroxy; A represents straight or branched chain alkylene having 2 to 6 carbon atoms; R is hydrogen, an anionic charge or a conventional easily removable carboxyl protecting group, wherein in the case where R is hydrogen or a protecting group, a counter anion is also present; and R and R together with the S to which they are attached represent the group of formula 42; or a pharmaceutically acceptable salt thereof. A compound according to claim 13, characterized in that R 1 represents hydrogen, CH 3 CH 2 -, (CH 1 CH -, (CH 1 C 10 OH) - or CH 3 CH (OH) -. Compound according to claim 13, characterized in that R and R 8 together represent HOCH 2 -C (CH 3) =. Compound according to claim 13, characterized in that R * represents CH 3 CH (0H) -. Compound according to claim 13, characterized in that 15 R * represents CH 3 CH (OH) - and the absolute configuration is 5R, 6S, 8R. Compound according to any one of claims 13 to 17, characterized in that A represents -CH-CEL-. ^ ^ 2 19. A compound of formula 51, wherein R is hydrogen, an anionic charge or a conventional easily removable carbacacyl-protecting group, wherein in the case where R is hydrogen or a protecting group also a counteranion is present, or a pharmaceutically acceptable salt thereof . 2 The compound of claim 19, wherein R represents p-nitrob enzyme. Compound according to claim 19, characterized in that 2 R represents an anionic charge. 22. A method of preparing a compound of 8 L of formula 38, wherein R is hydrogen and R is selected from the group of hydrogen; substituted and unsubstituted; alkyl, alkenyl and alkynyl 30 of 1 to 10 carbon atoms; cycloalkyl and cycloalkylalkyl with 3 to 6 carbon atoms in the cycloalkyl ring and 1 to 6 carbon atoms in the alkyl groups; phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl group is phenyl and the aliphatic moiety has 1 to 6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the heteroatom or heteroatoms in the above heterocycles are selected from 1 to 4 oxygen, nitrogen or sulfur atoms 8301193 and the alkyl groups associated with said heterocycles have 1 to 6 carbon atoms ; wherein the substituent or substituents for the above groups are independently selected from the group of alkyl of 1 to 6 carbon atoms, optionally substituted by amino, halogen, hydroxy or carboxyl; halogen; -OR1 -oconr1r2 -conr1r3 4 5 6 10 -nr1r2 3 4 3 -C (NR R} = NR -so_nr3r2 3 4 -NHCONR R 3 4 R CONR - 15 ~ C ° 2r3 = 0 -OCOR1 -SR1 -S0R7 20 " S02r9 -ON -N 3 -OSO RJ 3 -OSO_R 3 ^ 4 25 -NR SO-R 830 1 1 9 3 ^ 3 4 2 -NR C (R) = NR 3 -nr1co2r2 4 -no2 5 whereby with regard to the above mentioned substituents, the 3 4 30 groups R and R are independently selected from hydrogen; alkyl, 6 alkenyl and alkynyl of 1 to 10 carbon atoms; cycloalkyl, cycloalkylalkyl and alkylcycloalkyl with 3 to 6 carbon atoms in the cycloalkyl ring and 1 to 6 carbon atoms in the alkyl groups; phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl group is phenyl and the aliphatic moiety has 1 to 35 carbon atoms; and heteroaryl, heteroaralkyl, heterocyclyl and 7 heterocyclylalkyl wherein the heteroatom or heteroatoms in the above-mentioned heterocyclic groups are selected from 1 to 4 oxygen, nitrogen or sulfur atoms and the alkyl groups 1 to 6 carbon atoms associated with said heterocyclic groups or R and 4 R together with the nitrogen to which at least one of them is bound may form a nitrogen-containing 5- or 6-membered heterocyclic ring; R is as defined for R ^ except it cannot be hydrogen; or 1 wherein R and R together represent alkylidene of 2 to 10 carbon atoms or alkylidene of 2 to 10 carbon atoms substituted by hydroxy; 2 A represents straight or branched chain alkylene of 2 to 6 carbon atoms; R 10 is hydrogen, an anionic charge or a conventional easily removable carboxyl protecting group, where in the case where R is hydrogen or a protecting group also a counter anion is present, and and R ** each independently represent ( a) alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 15 carbon atoms, alkynyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or cycloalkylalkyl of 3 to 6 carbon atoms in the cycloalkyl ring and 1 to 6 carbon atoms in the alkyl group wherein said alkyl? alkenyl? alkynyl? cycloalkyl or cycloalkylalkyl group is optionally substituted by 1 to 3 substituents independently selected from hydroxy, alkoxy of 1 to 6 carbon atoms, alkanoyloxy of 1 to 6 carbon atoms, carboxy, alkoxycarbonyl in which the alkoxy group contains 1 to 6 carbon atoms has, amino, alkylamino of 1 to 6 carbon atoms, dialkylamino in which each alkyl group has 1 to 6 carbon atoms, alkanoylamino of 1 to 6 carbon atoms, phenyl, phenyl 25 substituted by 1 to 3 halogen, alkoxy of 1 to 6 carbon atoms, alkyl of 1 up to 6 carbon atoms, carboxy, carboxyalkyl in which the alkyl group has 1 to 6 carbon atoms, amino, alkylamino of 1 to 6 carbon atoms, dialkylamino in which each alkyl group has 1 to 6 carbon atoms, or dialkylaminoalkyl in which each alkyl group has 1 to 6 carbon atoms, halogen or oxo; (b) phenyl, optionally substituted by 1 to 3 halogen, alkoxy of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms, carboxy, amino, alkylamino of 1 to 6 carbon atoms or di-alkylamino groups in which each alkyl group has 1 to 6 carbon atoms; (C) heterocyclyl or heterocyclylalkyl wherein the hot rocyclic group is a 4- to 6-ring having 1 to 3 heteroatoms selected from 8301193 from O, N and S and the alkyl group having 1 to 6 carbon atoms / wherein the heterocyclyl or heterocyclylalkyl ring is optionally substituted is by 1 to 3 alkyl groups with 1 to 6 carbon atoms or alkoxy groups with 1 to 6 carbon atoms? or 5 (d) heteroaryl or heteroaralkyl wherein the heterocyclic group is an aromatic 5- or 6-ring having 1 to 3 heteroatoms selected from 0, N and S and the alkyl group having 1 to 6 carbon atoms, the heteroaryl or heteroaralkyl ring is optionally substituted by 1 to 3 alkyl groups of 1 to 6 carbon atoms, alkoxy groups of 1 to 6 carbon atoms, carboxy groups, carboxyalkyl groups where the alkyl group has 1 to 6 carbon atoms, amino groups, alkylamino groups of 1 to 6 carbon atoms , dialkylamino groups in which each alkyl group has 1 to 6 carbon atoms, aminoalkyl groups of 1 to 6 carbon atoms or dialkylaminoalkyl groups in which each alkyl group has 1 to 6 carbon atoms? or wherein and together with the S® to which they are attached represent a sulfur-containing heterocyclic 4 to 6 ring containing 0 to 2 double bonds and 0 to 2 additional heteroatoms selected from O, N and S, which ring by a sulfur atom is bonded to A to form a sulfonium group, which heterocyclic ring is optionally substituted by 1 to 3 substituents independently selected from alkyl of 1 to 6 carbon atoms, optionally substituted by 1 to 3 hydroxy, alkoxy with 1 to 6 carbon atoms, carboxy ,. halogen, amino, alkylamino with 1 to 6 carbon atoms or di-alkylamino groups in which each alkyl group has 1 to 6 carbon atoms, hydroxy, alkoxy with 1 to 6 carbon atoms, alkanoyloxy with 1 to 6 carbon atoms, amino, alkylamino of 1 to 6 carbon atoms, dialkyl amino in which each alkyl group has 1 to 6 carbon atoms, alkanoylamino of 1 to 6 carbon atoms, carboxy, alkoxycarbonyl in which the alkoxy group has 1 to 6 carbon atoms, halogen, oxo or phenyl; or wherein the heterocyclic ring of formula 39 is fused to a carbocyclic 5- or 6-ring, a phenyl ring, a heterocyclic 5- or 6-ring or a heteroaryl 5- or 6-ring, all these rings may be optionally substituted by 1 to 3 of the substituents listed above for the ring of formula 39? or a pharmaceutically acceptable salt 35 thereof, wherein an intermediate of formula 56 wherein R, R. 8301193 2 'and & as defined above and R represents a conventional easily removable carboxyl protecting group, is subjected to a nucleophilic replacement in an inert organic solvent and in the presence of silver ions with a sulfide reagent containing the 10 11 10 11 5 formula R -SR wherein R and R are as defined above such that the iodo group of the intermediate of formula 56 is replaced by the group of formula 39, and a compound of formula 57 18 10 11 2 'is formed wherein X is a counteranian and R, R, A, R, R and R 2 'are as defined above, and the carboxyl protecting group R 10 is optionally removed to obtain the corresponding deblocked compound of formula 38, or a pharmaceutically acceptable salt thereof. 23. A method of preparing a compound of formula 38, wherein R is hydrogen and R is selected from the group of hydrogen; Substituted and unsubstituted: alkyl, alkenyl and alkynyl of 1 to 10 carbon atoms; cycloalkyl and cycloalkylalkyl with 3 to 6 carbon atoms in the cycloalkyl ring and 1 to 6 carbon atoms in the alkyl groups; phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl group is phenyl and the aliphatic moiety has 1 to 6 carbon atoms; heteroaryl, hetero-20alkyl, heterocyclyl and hetrocyclylalkyl wherein the heteroatom or heteroatoms in the above heterocycles are selected from 1 to 4 oxygen, nitrogen or sulfur atoms and the heterocycles linked to said heterocycles Have 6 carbon atoms; wherein the substituent or substituents for the above-mentioned groups are independently selected from the group of alkyl of 1 to 6 carbon atoms, optionally substituted by amino, halogen, hydroxy or carboxyl; halogen; -OR3 30 -OCGNR3R4 -conr3r4 3 4 -NR R 3 4 3 ~ C (NR R) = NR 3 4 -SO-NR R Z 3 4 35 -NHCONRR r3conr4- 8301193 J ί -002r1 2 3 = 0 -0C0R3. -SR3 9 5 -SOR -so / -CN -3 3 -0SO3R 10 -OSO.R3 3 * 4 -NR SO R 3 ^ 3 4 -NR C (R) = NR -nr3co2r4 -no2 where, with respect to the above substituent and, the 3 4 groups R and R are independently selected from hydrogen; alkyl, alkenyl and alkynyl of 1 to 10 carbon atoms; cycloalkyl, cycloalkylalkyl and alkylcycloalkyl having 3 to 6 carbon atoms in the cycloalkyl ring and 1 to 6 carbon atoms in the alkyl groups; phenyl; aralkyl, aralkenyl 20 and aralkynyl wherein the aryl group is phenyl and the aliphatic moiety has 1 to 6 carbon atoms; and heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the heteroatom or heteroatoms in the above mentioned heterocyclic groups are selected from 1 to 4 oxygen, nitrogen or sulfur atoms and the alkyl groups associated with said heterocyclic groups have 1 to 6 carbon atoms, or R and R together with the nitrogen to which at least one of them is bound may form a 9 nitrogen-containing 5- or 6-membered heterocyclic ring; R xs as 3 as defined for R except that it cannot be hydrogen; or 830 1 1 9 3 8 wherein R and R together represent alkylidene of 2 to 10 carbon atoms or alkylidene of 2 to 10 carbon atoms substituted by hydroxy; A represents straight or branched chain alkyl one having 2 to 6 carbon atoms; 2 3 R is hydrogen, an anionic charge or a conventional easily removable carboxyl protecting group, where appropriate. R is hydrogen or a protecting group, a counter anion is also present, 35 and and R 4 each independently represent (a) alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 6 6 carbon atoms or cycloalkylalkyl with 3 to 6 carbon atoms in the cycloalkyl ring and 1 to 6 carbon atoms in the alkyl group, the alkyl, alkenyl, alkynyl, cycloalkyl or cycloalkylalkyl group being optionally substituted by 1 to 3 substituent and, which independently selected from hydroxy, alkoxy of 1 to 6 carbon atoms, alkanoyloxy of X to 6 carbon atoms, carboxy, alkoxycarbonyl wherein the alkoxy group has 1 to 6 carbon atoms, amino, alkylamino of 1 to 6 carbon atoms, dialkylamino where each alkyl group 1 to 6 carbon atoms has 10, alkanoylamino of 1 to 6 carbon atoms, phenyl; phenyl substituted by 1 to 3 halogen, alkoxy of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms, carboxy, carboxyalkyl where the alkyl group has 1 to 6 carbon atoms, amino, alkylamino with 1 to 6 carbon atoms, dialkylamino where each alkyl group is X to 6 carbon atoms, or dialkylaminoalkyl wherein each alkyl group has 1 to 6 carbon atoms, halogen or oxo; (b) phenyl, optionally substituted by 1 to 3 halogen, alkoxy of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms, carboxy, amino, alkylamino of 1 to 6 carbon atoms or dialkyl amino groups, each alkyl group having 1 to 6 carbon atoms ; (c) heterocyclyl or heterocyclylalkyl wherein the heterocyclic group is a 4- to 6-ring having 1 to 3 heteroatoms selected from O, N and S and the alkyl group has X to 6 carbon atoms, the heterocyclyl or heterocyclylalkyl ring being optionally substituted by 25 up to 3 alkyl groups with 1 to 6 carbon atoms or alkoxy groups with X to 6 carbon atoms; or (d) heteroaryl or heteroaralkyl wherein the heterocyclic group is an aromatic 5- or 6-ring having X to 3 heteroatoms selected from O, N and S and the alkyl group having X to 6 carbon atoms, which heteroaryl or heteroaralkyl ring is optionally substituted by X to 3 alkyl groups of X to 6 carbon atoms, alkoxy groups of X to 6 carbon atoms, carboxy groups, carboxyalkyl groups where the alkyl group has X to 6 carbon atoms, amino groups, alkylamino groups of 1 to 6 carbon atoms, dialkylamino groups where each alkyl group has 1 to 6 carbon atoms, aminoalkyl groups having X to 6 carbon atoms or dialkylaminoalkyl groups, each alkyl group having 1 to 6 carbon atoms 8301193 ii; or wherein R ^ and together with the S ^ to which they are attached represent a sulfur-containing heterocyclic 4 to 6 ring containing 0 to 2 double bonds and 0 to 2 additional heteroatams selected from 0, N and S, which ring bonded to zw by a sulfur atom to form a sulfonium group, which heterocyclic ring is optionally substituted by 1 to 3 substituents independently selected from alkyl of 1 to 6 carbon atoms, optionally substituted by 1 to 3 hydroxy, alkoxy of 1 to 6 carbon atoms, carboxy, halogen, amino, alkylamino of 1 to 6 carbon atoms or dial-10 kylamino groups, each alkyl group having 1 to 6 carbon atoms, hydroxy, alkoxy of 1 to 6 carbon atoms, alkanoyloxy of 1 to 6 carbon atoms, amino , alkylamino of 1 to 6 carbon atoms, dialkyl amino where each alkyl group has 1 to 6 carbon atoms, alkanoylamino of 1 to 6 carbon atoms, carboxy, alkoxycarbonyl wherein the alkoxy group 1 to Has 6 carbon atoms, halogen, oxo or phenyl; or wherein the heterocyclic ring of formula 39 is fused to a carbocyclic 5- or 6-ring, a phenyl ring, a heterocyclic 5- or 6-ring or a heteroaryl 5- or 6-ring, all these rings being optionally substituted by 1 to 3 of the substituents listed above for the ring of formula 39; or a pharmaceutically acceptable salt thereof, wherein 1 8 (1) an intermediate of formula 52 wherein R and R 2 'are as defined above and R is a conventional easily removable carboxyl protecting group, in reaction with an inert organic solvent with diphenyl chlorophosphate charged in the presence of base to form an intermediate of formula 18 21 53, wherein R, R and R are as defined above; (2) the intermediate of formula 53 in an inert organic solvent and in the presence of base is reacted with a mercaptan reagent of the formula HS-A-OH wherein A is as defined above to form an intermediate of 18 2 * formula 54, wherein R, R, A and R are as defined above; (3) the intermediate of formula 54 in an inert organic solvent and in the presence of base is reacted with methanesulfonyl chloride or a functional acylation equivalent thereof to form an intermediate of formula 55 8301193 * 18 'wherein E, S r A ens as defined above; (4) the intermediate of formula 55 in an inert organic solvent is reacted with an iodide ion source to replace the methanesulfonyloxy group with an iodo group and the intermediate is formed of formula 56 wherein R, R, 2 'A and R are as defined above; and (5) the intermediate of formula 56 is subjected to a nucleophilic replacement in an inert organic solvent and in the presence of silver ions with a sulfide reagent of the formula R 1 -SR 2 * wherein R 2 and as defined above are to replace the iodo group of the intermediate of formula 56 with the group of formula 39 to form a compound of formula __. ". 8 „8,„ 10 11 2 ′ 57 wherein X is a counter anion and R, R, A, R, R and R are as defined above, and if desired the carboxyl protection-2 ′ 15 group R is removed to remove the corresponding deblocked compound of formula 38, or a pharmaceutically acceptable salt thereof. Pharmaceutical composition with antibacterial activity, characterized in that it comprises a compound according to one or more of claims 1 to 21. 8301193 f 1. 2 © R10 6 5 / ^ 2 “s ~ a- <r11 Γ * | 3 0H H --- sca, ca, NH- pi I— N -—- COOH ° k CH3 HO-SO ^^ N - SCS = CHNKCOCH- ir ó- -—COOH bo CH_ i ^ X ^^ SCH- CH ^ NHCOCH-H03S0 ^ j | -p J 22 JN -J COOH ° 5 CH_OL 3 I ^ / \ ^ _ S-CH®CHNHC0CH3 H03S0 f | qJ-N -COCH ^ 3 7 IJO 1 «^ 5CH = CHNHCCH3 H03S0 ^ IJ (ƒ N COOH CH3 8 H03SO ^ ^ -p | 2 2 ON COOH 8 3 0 1 19 3 wwwiivw Bristol-Myers Company ch3 9 0J _, - l02H, w (7 N COOH 11 ^ A ^ V ^^ SCH-CH-NHCOCH- II | T 2 2 3 12 ON COOH -J ~ I 13 /? - N COOH ^^ S-Rl <f ~ N- COOH Ir ^ 'V'3 "0 * 2 - ^ 3 R4 o N COOH 15 __ / A \ r ^ CH = CR1 R2 16' | r \ th —- S '^ v" 3r8 LN -J COOH. COOH 17. oh 18 - * - <TS ~ * L ~ C02PNB 19 OH ^ SCH „CH„ N = C-NK_ r 2 2/2 I 'IH CT H COOH 8301193 Bristol-Myers Company 20. ΟΗ' i2 '” - Y „«, s 's' ~ 1 TV "• JN --1 ^, 00Η 0 22 OH / x — ra 2 2 III * g N coch 23 OR3 24 ^ Js ^ ^ vs ^^ sch2ch2nr1r2? Θ ^ λ Tj, _l -C-CH2-2 (/ o * COOH or3 25 / V. Sch2ch2nrV ^ - \ if 26 j— »-L_cooh f ........ 0 5 S 7 / \ _ y ^ v ^ sch2ch2nr : 5r r J— H-coP 0, = Λ „r ® 1, XX / \ ^ SCH2CH2N-C = NR RA © I if * so ^ - N -L-cox 8301193 Bristol-Myers Company 28 yr θ? X ' ^ N - SCH, Gi2NH — 31 'I' () © VN COcP '' - S — A — S <^ 0 „29 30 ffif f © Θ ^ XXpSC3, CH, M (approx.), 1 a ^ - N- -i C00H 32 0 R1 vi 1 x-n ^ 51 7 CH CH ^ -X ^ Vs ^ -SR3 'R7. ^ 1 tivv - N -COOH II f— 11 - ^ - fcOOH 34 ° CH.-CH— | -jX ^ N-SR12 R7 ', 6 X \ .0 Jr-S - CO..H -Tl - 36 <T ~ S ^ 02κ2 'RR® - r ^ rx 37 i © 40 rN ^ ° 2 * 2' -sa-? Xe Lk, 38 ileJL R8 H © R10 ^ 0 1 R * t__iXX ~ Ss \ r — S —A—,, Θ 1 | R10— | —R11 CP ^ “OOOR2 a ^ R i Λ θ ^ * 10 ai__p '^ VsAs <" X1 xu R Γ J ^ R11 - N --COÖR2 _ O 8301193 Bristol-Myers Company h2 · 43 hh © / - © / - \ -s (-s> -S-CH2CH2-S ^ \ _ / ®3 45 46 © / “3 © / C2H5 -S-CH ^ jjCHj-S ^ -S-CH2CH2CH2Ca2-S ^ ^ C2Hs C2H5 W © · «· © .CSH11 i-propyl ~ S_Ca2CH2 ~ s ^ C5H11 49 -s-ch2ch2ce2ch2ch2ch2-s ^ * CS3 50 Q ^ C2H5 51 -S-CH2CH2C32 <32CS2-S ^ OH _ __ C2H5 II _ © O / ΓΤ i ^ JN ^ "COOR2" 52 0 '** H R1-- λ ----- 2 * COOR on h '58 _ © / "η L = X ^ Y-SCH2CH2- \] J— H ~ co © o * 8 3 0 119 3 Bristol-Myers Company i 3 REACT! ESCHEMA ψ · Η -1 — rv -) 2 »'£ - ϊϊ -----. COOR 52 s8 η B a8 η« 1 _ ^ Χ \ ^ 0Ρ {0α.Ης) 2 1 l / X SA-OH Γ Γ. —R LX - COOS2 v N ^ COOR2 0 0 53 _. . U RS H i ^ S-A-OS 0., 0 ^ χ r1 * f, -) L— N -1 - COOR2 0 55 8. a10 r8 a s ^ Xy * 1 N r11 a I ,, Ag + X '4? N-COOR 0 s © r10 φ R H xU R1__11 OPTIONAL 1. UNLOCKING v I ^ ^ j7 ~ yy COOR 0 57 R8 H - ©. * “„ 1 IX ^ -SA- / j> ή ^ 11 ^ 7— S '- -COOR2 38 oil) 1 19 3 UO w II w Bristol-Myers Company * r A OH I Η /. -> J-Ν-V, Ο 'CO ^ pNB 59' ΟΗ 1 η f / ^ v_SC2i, ΟΗ, ΟΗ □ [cf- C02pNB 60 OH 8 \ Γ -> a C02pNB 50 OH 'I l <. _ = / ^ \ ^ SCH2CH20S02CH3 o N C02pNB 61 8 3 0 1 1 9 3 Bristol-Myers Company OH C} H I I) -> * - COjPNB 61 yo co2pnb 62. D OH H ^ ^ γΗγ ^ 1 -> Γ * - ^ «2?» 62 OH / Λ I I © / \ 0 \ ^ - 30Η20Η2 — s? C104W Y — N !. __ \ 0 co2pnb “63 OH i § © / ^] - uX ° o cocP 58 8301193 Bristol-Myers Company