Carbapenems having the formula: ##STR1## wherein ##STR2## is mono- or bicyclic quaternary heteroaryl, their preparation and antibiotic use are disclosed.

BACKGROUND OF THE INVENTION 
The present invention is concerned with carbapenem and 1-methylcarbapenem 
antibiotics having a quaternary mono- or bicyclic heteroaryl alkyl group 
in the 2-position. 
Thienamycin is a known carbapenem, broad spectrum antibiotic of the 
formula: 
##STR3## 
Other derivatives of A are also known. 
The present externally alkylated mono- or bicyclic 2-quaternary 
heteroarylalkyl substituted carbapenems are believed to have an antibiotic 
spectrum comparable to A. 
BRIEF DESCRIPTION OF DISCLOSURES IN THE ART 
Sankyo U.S. Pat. No. 4,377,591 and Japanese patent publications Nos. 
56-199682 and 56-60852 Shionogi Japanese patent publications Nos. 
57-145086 and 57-145087; and Roche U.K. patent publication No. 2 092 147A, 
all describe azabicycloheptene antibiotics having a 2-position substituent 
joined through a thioalkylene bridge. U.S. Pat. No. 4,189,493 to 
Bristol-Myers discloses externally alkylated heteroarylium 
alkylthioazabicycloheptene antibiotics. U.S. Pat. No. 4,465,672, U.S. Pat. 
No. 4,260,627 and U.S. Pat. No. 4,267,188, all assigned to Merck & Co., 
Inc., disclose 2,6-substituted-1-carba-2-penem-3-carboxylic acids wherein 
the 2-substituent can be substituted or unsubstituted alkyl or aryl. 
However, none of the above references specifically describe the carbapenem 
compounds of the present invention. 
SUMMARY OF THE INVENTION 
Carbapenems having the formula: 
##STR4## 
wherein R.sup.1 is hydrogen or methyl; R.sup.2 is a quaternizing 
substituent; L is an alkylene bridging group; 
##STR5## 
is mono- or bicyclic heteroarylium; and Y is a carboxy-containing 
substituent. 
DETAILED DESCRIPTION OF THE INVENTION 
The invention is embodied in a compound having the formula: 
##STR6## 
wherein: R.sup.1 is hydrogen or methyl; 
R.sup.4 and R.sup.5 are independently H, CH.sub.3 --, CH.sub.3 CH.sub.2 --, 
(CH.sub.3).sub.2 CH--,HOCH.sub.2 --, CH.sub.3 CH(OH)--, (CH.sub.3).sub.2 
C(OH)--, FCH.sub.2 --, F.sub.2 CH--, F.sub.3 C--, CH.sub.3 CH(F)--, 
(CH.sub.3).sub.2 C(F)--; CH.sub.3 CF.sub.2 --, or 
L is a bridging group comprising substituted or unsubstituted C.sub.1 
-C.sub.4 straight, C.sub.2 -C.sub.6 branched or C.sub.3 -C.sub.7 
cycloalkyl groups wherein the substituents are selected from C.sub.1 
-C.sub.6 alkyl, O--C.sub.1 -C.sub.6 alkyl, S-C.sub.1 -C.sub.6 alkyl, 
CF.sub.3, N(C.sub.1 -C.sub.6 alkyl).sub.2 ; 
##STR7## 
is a mono- or bicyclic heteroarylium group containing from 5-11 ring 
atoms of which up to 5 are heteroatoms in addition to the quaternary 
nitrogen; 
wherein R.sup.2 is 
(1) an unsubstituted or substituted C.sub.1 -C.sub.6 alkyl radical; 
(2) an unsubstituted or substituted C.sub.2 -C.sub.6 alkenyl radical; 
(3) an unsubstituted or substituted C.sub.2 -C.sub.6 alkynyl radical; 
(4) a C.sub.3 -C.sub.7 cycloalkyl radical in which the ring is substituted 
or unsubstituted and one or more atoms may be replaced by a heteroatom; 
(5) a C.sub.3 -C.sub.7 cycloalkyl methyl radical in which the ring may be 
substituted and one or more atoms may be replaced by a heteroatom; 
(6) an unsubstituted or substituted C.sub.5 -C.sub.7 cycloalkenyl radical; 
(7) an unsubstituted or substituted bivalent C.sub.2 -C.sub.6 alkylidene 
radical, optionally interrupted by a heteroatom, and joined to the 
heteroarylium group to form a ring which is carbocyclic or in which one or 
more atoms is replaced by a heteroatom and wherein the new ring may 
contain one or more double bonds; 
(8) an unsubstituted or substituted phenyl or heteroaryl radical; 
(9) an unsubstituted or substituted phenyl (C.sub.1 -C.sub.4 alkyl) or 
heteroaryl (C.sub.1 -C.sub.4 alkyl) radical; 
(10) a cyano (C.sub.1 -C.sub.4 alkyl) radical; 
(11) a carboxy (C.sub.1 -C.sub.4 alkyl) radical; 
(12) a sulfo (C.sub.1 -C.sub.4 alkyl) radical; 
(13) a carbamoyl (C.sub.1 -C.sub.4 alkyl) radical; 
(14) a phosphonyl (C.sub.1 -C.sub.4 alkyl) radical; 
(15) a hydroxy (C.sub.1 -C.sub.4 alkyl) radical; or 
(16) an amino (C.sub.1 -C.sub.4 alkyl) radical in which the nitrogen atom 
is unsubstituted or substituted with one to three C.sub.1 -C.sub.4 alkyl 
groups; 
wherein the substituents in the above definitions of R.sup.2 are 
independently selected from the group consisting of: 
(a) a trifluoromethyl group; 
(b) a halogen atom; 
(c) an unsubstituted or substituted C.sub.1 -C.sub.4 alkoxy radical; 
(d) a hydroxy group; 
(e) an unsubstituted or substituted (C.sub.1 -C.sub.6 alkyl)carbonyloxy 
radical; 
(f) a carbamoyloxy radical which is unsubstituted or substituted on 
nitrogen with one or two C.sub.1 -C.sub.4 alkyl groups; 
(g) a C.sub.1 -C.sub.6 alkylthio radical, C.sub.1 -C.sub.6 alkylsulfinyl 
radical or C.sub.1 -C.sub.6 alkylsulfonyl radical, each of which is 
unsubstituted or substituted on the alkyl group; 
(h) a sulfo group; 
(i) a sulfamoyl group which is unsubstituted or substituted on nitrogen by 
one or two C.sub.1 -C.sub.4 alkyl groups; 
(j) a formylamino group; 
(k) an unsubstituted or substituted (C.sub.1 -C.sub.6 alkyl)carbonylamino 
radical; 
(l) a (C.sub.1 -C.sub.4 alkoxyl)carbonylamino radical; 
(m) a ureido group in which the terminal nitrogen is unsubstituted or 
substituted with one or two C.sub.1 -C.sub.4 alkyl groups; 
(n) an arylsulfonamido or a (C.sub.1 -C.sub.6 alkyl)sulfonamido group; 
(o) a cyano group; 
(p) a formyl or acetalized formyl radical; 
(q) an unsubstituted or substituted (C.sub.1 -C.sub.6 alkyl)carbonyl 
radical wherein the carbonyl is free or acetalized; 
(r) an unsubstituted or substituted phenylcarbonyl or heteroarylcarbonyl 
radical; 
(s) a carboxyl group; 
(t) a (C.sub.1 -C.sub.6 alkoxy)carbonyl radical; 
(u) a carbamoyl radical which is unsubstituted or substituted on nitrogen 
by one or two C.sub.1 -alkyl groups; 
(v) an N-hydroxycarbamoyl or N(C.sub.1 -C.sub.4 alkoxy)carbamoyl radical in 
which the nitrogen atom may be additionally substituted by a C.sub.1 
-C.sub.4 alkyl group; 
(w) a thiocarbamoyl group; 
(x) a 5-(1H)-tetrazolyl group; 
(y) a phosphonate group --P(O) (O.sup.-)OR' where R' is C.sub.1 -C.sub.3 
alkyl; 
(z) an alkyl phosphonate group --(CH.sub.2).sub.n P(O) (O.sup.-)(OR') where 
n=1 to 3 and R' is C.sub.1 -C.sub.3 alkyl; 
(aa) hydrogen; 
(ab) an unsubstituted or substituted C.sub.1 -C.sub.6 alkyl radical; 
(ac) an unsubstituted or substituted C.sub.2 -C.sub.6 alkenyl radical; 
(ad) an unsubstituted or substituted C.sub.2 -C.sub.6 alkynyl radical; 
(ae) a C.sub.3 -C.sub.7 cycloalkyl radical in which the ring is substituted 
or unsubstituted and one or more atoms may be replaced by a heteroatom; 
(af) a C.sub.3 -C.sub.7 cycloalkyl methyl radical in which the ring may be 
substituted and one or more atoms may be replaced by a heteroatom; 
(ag) an unsubstituted or substituted C.sub.5 -C.sub.7 cycloalkenyl radical; 
(ah) an unsubstituted or substituted phenyl or heteroaryl radical; and 
(ai) an unsubstituted or substituted phenyl (C.sub.1 -C.sub.4 alkyl) or 
heteroaryl (C.sub.1 -C.sub.4 alkyl) radical; and 
R.sup.3 is 
(a) hydrogen, 
(b) an unsubstituted or substituted C.sub.1 -C.sub.6 alkyl radical; 
(c) an unsubstituted or substituted C.sub.2 -C.sub.6 alkenyl radical; 
(d) an unsubstituted or substituted C.sub.2 -C.sub.6 alkynyl radical; 
(e) a C.sub.3 -C.sub.7 cycloalkyl radical in which the ring is substituted 
or unsubstituted and one or more atoms may be replaced by a heteroatom; 
(f) a C.sub.3 -C.sub.7 cycloalkyl methyl radical in which the ring may be 
substituted and one or more atoms may be replaced by a heteroatom; 
(g) an unsubstituted or substituted C.sub.5 -C.sub.7 cycloalkenyl radical; 
(h) an unsubstituted or substituted phenyl or heteroaryl radical; 
(i) an unsubstituted or substituted phenyl (C.sub.1 -C.sub.4 alkyl) or 
heteroaryl (C.sub.1 -C.sub.4 alkyl) radical; and 
(j) a trifluoromethyl group; 
(k) a halogen atom; 
(l) an unsubstituted or substituted C.sub.1 -C.sub.4 alkoxy radical; 
(m) a C.sub.1 -C.sub.6 alkylthio radical, C.sub.1 -C.sub.6 alkylsulfinyl 
radical or C.sub.1 -C.sub.6 alkylsulfonyl radical, each of which is 
unsubstituted or substituted on the alkyl group; 
(n) a mono (C.sub.1 -C.sub.4 alkyl) amino or di(C.sub.1 -C.sub.4 alkyl) 
amino group, each of which is unsubstituted or substituted on the alkyl 
group; or 
(o) a cyano group; and 
Y is 
(i) COOH or a pharmaceutically acceptable ester or salt thereof, 
(ii) COOR wherein R is a removable carboxy protecting group, such as 
p-nitrobenzyl, benzyl or allyl, 
(iii) COOM wheren M is an alkali metal, or 
(iv) COO.sup.- ; provided that when Y is other than (iv) a counterion 
Z.sup.- is provided. 
As used herein, the term "heteroatom" means nitrogen, oxygen, or sulfur, 
independently selected where more than one heteroatom is involved. 
Representative L groups are substituted or unsubstituted branched or linear 
C.sub.1 -C.sub.4 alkyl and include --CH.sub.2 --, --CH(CH.sub.3)--, 
--CH(C.sub.2 H.sub.5)--, --(CH.sub.2).sub.2-4, --CH(CH.sub.3)--CH.sub.2 
--, CH.sub.2 --CH(OCH.sub.3)--, --CH(CH.sub.3)--(CH.sub.2).sub.2 --, 
--CH(CH.sub.2 OH)--CH.sub.2 --, --CH(CF.sub.3)--CH.sub.2 --, and the like. 
Preferred L groups are --CH.sub.2 --, --CH(CH.sub.3)--, --(CH.sub.2).sub.2 
--, and --CH(CH.sub.3)CH.sub.2 --. 
Examples of useful R.sup.2 groups are --CH.sub.3, --(CH.sub.2).sub.1-3 
--CH.sub.3, 
##STR8## 
--(CH.sub.2).sub.1-3 --O--CH.sub.3, --CH.sub.2 --CN, CH.sub.2 --COOC.sub.1 
--C.sub.3 alkyl, --(CH.sub.2).sub.2 --N(C.sub.1 -C.sub.3 alkyl).sub.2, 
--CH.sub.2 --COOH(Na), --(CH.sub.2).sub.2 --SO.sub.3 H(Na), 
##STR9## 
CH.sub.2 CONH.sub.2, --(CH.sub.2).sub.2 --N.sup.+ (CH.sub.3).sub.3 and the 
like. 
Preferred R.sup.2 groups are the C.sub.1 -C.sub.6 alkyls, both substituted 
and unsubstituted, carboxy (C.sub.1 -C.sub.4 alkyl), carbamoyl (C.sub.1 
-C.sub.4 alkyl), sulfo (C.sub.1 -C.sub.4 alkyl), heteroaryl (C.sub.1 
-C.sub.4 alkyl) or cyano (C.sub.1 -C.sub.4 alkyl). 
Preferred substituents are CN, CON(CH.sub.3).sub.2, CONH.sub.2, SOCH.sub.3, 
SO.sub.2 CH.sub.3, CO.sub.2 H, SO.sub.3 H, SO.sub.2 NH.sub.2 and 
##STR10## 
Examples of useful R.sup.3 groups are hydrogen, N(C.sub.1 -C.sub.3 alkyl), 
OC.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkyl, CN, CF.sub.3, CH.sub.2 OH 
and the like. 
Preferred R.sup.3 groups are H, --CH.sub.3, --OCH.sub.3, CN, --SO.sub.2 
CH.sub.3, CH.sub.2 CN, and the like. 
Preferred R.sup.4 and R.sup.5 groups are where R.sup.4 is hydrogen and 
R.sup.5 is 
##STR11## 
The 
##STR12## 
moiety is mono- or bicyclic quaternary heteroarylium group having 5-11 
ring atoms of which, in addition to the quaternary N.sup.+, up to four can 
be heteroatoms. 
Representative 
##STR13## 
groups are: 
##STR14## 
group is monocyclic heteroarylium having 5-6 ring atoms and optionally one 
heteroatom additional to the N atom already present, e.g., 
##STR15## 
where R.sup.2 and R.sup.3 are as defined in the preferred list above and L 
is --CH.sub.2 -- or --CH.sub.2 CH.sub.2 --. 
An especially preferred subclass includes the nuclei shown above where 
R.sup.3 (where present) is --CH.sub.3, L is --CH.sub.2 -- or --CH.sub.2 
CH.sub.2 -- and R.sup.2 is C.sub.1 -C.sub.6 alkyl, unsubstituted or 
substituted by --CN, --CON(CH.sub.3).sub.2, --CONH.sub.2, --SOCH.sub.3, 
--SO.sub.2 CH.sub.3, --CO.sub.2 H, --SO.sub.3 H, --SO.sub.2 NH.sub.2 and 
##STR16## 
Further preferred compounds of Formula I include those where R.sup.1 is H 
or CH.sub.3 and 
##STR17## 
is 
##STR18## 
The compounds of Formula I include inner (Zwitterion) salts when Y is 
COO.sup.- e.g. 
##STR19## 
or, when Y is other than COO.sup.-, salts with an external, 
physiologically acceptable counterion Z.sup.- such as Cl.sup.-, Br.sup.-, 
I.sup.-, OCH.sub.3.sup.-, OSO.sub.2 CF.sub.3.sup.-, OP(O) (O 
phenyl).sub.2.sup.- and the like. 
The inner salts are preferred. 
Again, the compounds of Formula I include the stereoisomers as mixtures and 
as separate isomers. 
A preferred isomer configuration is: 
##STR20## 
and where R.sup.1 is CH.sub.3, the preferred configuration is 
beta-CH.sub.3. 
The compounds of the present invention (I) are valuable antibiotics active 
against various Gram-positive and Gram-negative bacteria and accordingly 
find utility in human and veterinary medicine. Representative pathogens 
which are sensitive to antibiotics I include: Staphylococcus aureus, 
Escherichia coli, Klebsiella pneumoniae, Bacillus subtilis, Salmonella 
typhosa, Pseudomonas and Bacterium proteus. The antibacterials of the 
invention are not limited to utility as medicaments; they may be used in 
all manner of industry, for example: additives to animal feed, 
preservation of food, disinfectants, and in other industrial systems where 
control of bacterial growth is desired. For example, they may be employed 
in aqueous compositions in concentrations ranging from 0.1 to 100 parts of 
antibiotic per million parts of solution in order to destroy or inhibit 
the growth of harmful bacteria on medical and dental equipment and as 
bactericides in industrial applications, for example in waterbased paints 
and in the white water of paper mills to inhibit the growth of harmful 
bacteria. 
The compounds of this invention may be used in any of a variety of 
pharmaceutical preparations. They may be employed in capsule, powder form, 
in liquid solution, or in suspension. They may be administered by a 
variety of means; those of principal interest include: topically or 
parenterally by injection (intravenously or intramuscularly). 
Compositions for injection, a preferred route of delivery, may be prepared 
in unit dosage form in ampules, or in multidose containers. The 
compositions may take such forms as suspensions, solutions, or emulsions 
in oily or aqueous vehicles, and may contain formulatory agents. 
Alternatively, the active ingredient may be in powder form for 
reconstitution, at the time of delivery, with a suitable vehicle, such as 
sterile water. Topical applications may be formulated in hydrophobic or 
hydrophilic bases as ointments, creams, lotions, paints, or powders. 
The dosage to be administered depends to a large extent upon the condition 
and size of the subject being treated as well as the route and frequency 
of administration--the parenteral route by injection being preferred for 
generalized infections. Such matters, however, are left to the routine 
discretion of the therapist according to principles of treatment well 
known in the antibiotic art. In general, a daily dosage consists of from 
about 5 to about 600 mg of active ingredient per kg of body weight of the 
subject in one or more treatments per day. A preferred daily dosage for 
adult humans lies in the range of from about 10 to 240 mg of active 
ingredient per kg of body weight. Another factor influencing the precise 
dosage regimen, apart from the nature of the infection and peculiar 
identity of the individual being treated, is the molecular weight of the 
chosen species of this invention (I). 
The compositions for human delivery per unit dosage, whether liquid or 
solid, may contain from 0.1% to 99% of active material, the preferred 
range being from about 10-60%. The composition will generally contain from 
about 15 mg to about 1500 mg of the active ingredient; however, in 
general, it is preferable to employ a dosage amount in the range of from 
about 250 mg to 1000 mg. In parenteral administration, the unit dosage is 
usually the pure compound I in sterile water solution or in the form of a 
soluble powder intended for solution. 
The preferred method of administration of the formula I antibiotic is 
parenteral by i.v. infusion, i.v. bolus, or i.m. injection. 
For adults, 5-50 mg of Formula I antibiotic per kg of body weight given 2, 
3, or 4 times per day is preferred. Preferred dosage is 250 mg to 1000 mg 
of the Formula I antibiotic given two (b.i.d.) three (t.i.d.) or four 
(q.i.d.) times per day. More specifically, for mild infections, and 
particularly unitary tract infections, a dose of 250 mg t.i.d. or q.i.d. 
is recommended. For moderate infections against highly susceptible gram 
positive and gram negative organisms, a dose of 500 mg t.i.d. or q.i.d. is 
recommended. For severe, life-threatening infections against organisms at 
the upper limits of sensitivity to the antibiotic, a dose of 1000 t.i.d. 
or q.i.d. is recommended. 
For children, a dose of 5-25 mg/kg of body weight given 2, 3, or 4 times 
per day is preferred; a dose of 10 mg/kg t.i.d. or q.i.d. is usually 
recommended. 
Antibiotic compounds of Formula I are of the broad class known as 
carbapenems or 1-carbadethiapenems. Certain of these carbapenems are 
susceptible to attack by a renal enzyme known as dehydropeptidase (DHP). 
This attack or degradation may reduce the efficacy of the carbapenem 
antibiotic. Inhibitors of DHP and their use with carbapenem antibiotics 
are disclosed in the prior art [see published European Patent Applications 
No. 79102616.4 filed July 24, 1979 (Patent Number 10573); 79102615.6, 
filed July 24, 1979 (application no. 15573); and No. 82107174.3, filed 
Aug. 9, 1980 (application no. 72014)]. 
The present I compounds may, where DHP inhibition is desired or necessary, 
be combined or used with the appropriate DHP inhibitor as described in the 
aforesaid published applications. Thus, to the extent that the cited 
European patent applications 1.) define the procedure for determining DHP 
susceptibility of the present carbapenems and 2.) disclose suitable 
inhibitors, combination compositions and methods of treatment, they are 
incorporated herein by reference. A preferred weight ratio of I 
compound:DHP inhibitor in the combination compositions is about 1:1. A 
preferred DHP inhibitor is 
7-(L-2-amino-2-carboxyethylthio)-2-(2,2-dimethylcyclopropanecarboxamide)-2 
-heptenoic acid or a useful salt thereof. 
These combination compositions and their use is another embodiment of the 
present invention. 
The compounds of Formula I may be prepared by any convenient process. 
A key intermediate in the synthesis of compounds of Formula I, where the 
6-position is substituted by 1-hydroxyethyl, is represented by general 
structures A and A' 
##STR21## 
where R.sub.o is a hydroxyl protecting group such as t-butyldimethylsilyl, 
p-nitrobenzyloxycarbonyl, allyloxycarbonyl or the like, and R.sup.1, L and 
##STR22## 
are as defined above. The synthesis of A and A' may be achieved by any 
convenient method, representative examples of which follow. 
##STR23## 
or the like; M=Li, MgHalo, Cu or the like; 
R.sub.n =H or (R).sub.3 Si, where R is C.sub.1-4 alkyl, such as SiMe.sub.3 
or --Si(Me).sub.2 t--Bu; and 
R.sub.o, R.sup.1, and 
##STR24## 
are as above. 
##STR25## 
where R.sub.t =t--Bu, benzyl, allyl, p-nitrobenzyl, (R).sub.3 Si, such as 
Si(Me).sub.3 or SiMe.sub.2 --t--Bu or the like; 
R.sub.a =H or C.sub.1 -C.sub.3 alkyl; and 
X, R.sub.o, R.sub.n, R.sup.1, and 
##STR26## 
are as defined above. 
##STR27## 
where Z=X defined above, OSO.sub.2 CH.sub.3, OSO.sub.2 --(p--C.sub.6 
H.sub.4)CH.sub.3, OSO.sub.2 CF.sub.3 or the like; and 
R.sup.1, R.sub.o, R.sub.n, L, and 
##STR28## 
are as defined above. 
##STR29## 
where Lewis acid is BF.sub.3 O(CH.sub.2 CH.sub.3).sub.2, AgBF.sub.4, 
TMSOSO.sub.2 CF.sub.3, ZnI.sub.2 or the like; 
W=X is defined above, --OCOCH.sub.3, --OCO.phi., SO.sub.2 .phi. or the 
like; and 
R.sup.1, R.sub.o, R.sub.n, L and 
##STR30## 
are as defined above. 
##STR31## 
where R.sup.1, R.sub.o, R.sub.n, L, M and 
##STR32## 
are as defined above. 
##STR33## 
where L is --CHR.sub.a ; 
R.sub.a is hydrogen or C.sub.1 -C.sub.3 alkyl; and 
R.sup.1, R.sub.o, R.sub.n, R.sub.t and 
##STR34## 
are as defined above. 
Intermediates A and A' may be transformed to compounds of Formula I by any 
convenient process. Representative methods follow: 
##STR35## 
where R.sub.c is p-nitrobenzyl, allyl or the like; and 
R.sup.1, R.sub.o, R.sub.2, Z, L and 
##STR36## 
are as defined above. 
##STR37## 
where R.sub.p is --CH.sub.3, --CH.sub.2 CH.sub.3, --CH(CH.sub.3).sub.2 or 
the like; and 
R.sup.1, R.sub.2, R.sub.c, R.sub.o, Z, L and 
##STR38## 
are as defined above. 
In addition to the methods described above, many variations are possible 
involving permutation of the individual steps, for example: 
##STR39## 
where R.sup.1, R.sub.2, R.sub.o, R.sub.c, M, Z, L and 
##STR40## 
are as defined above.