# US 5,350,746 A · Triazolyl and tetrazolyl phenyl substituted carbapenems, compositions containing such compounds and methods of use

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- Number: US 5,350,746 A
- Document ID: US5350746A
- Status: Granted
- Kind: A
- Application number: 08/048,534
- Filed: 1993-04-14
- Granted: 1994-09-27
- Earliest claimed: 1993-04-14
- Assignees: Merck & Co., Inc.
- Inventors: Alan D. Adams; James V. Heck
- Web page: https://patentgrep.com/patent/US5350746A

## CPC

- C07D 231/12: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D 233/56: with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
- C07D 249/08: 1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
- C07D 477/14: with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 3
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

Triazolyl and tetrazolyl phenyl substituted carbapenems of the formula I are disclosed. ##STR1## One or two of the variables X, Y and Z represent nitrogen atoms. The heteroaryl ting may be charged or uncharged. Pharmaceutical compositions and methods of treatment are also disclosed.

## Claims

### Claim 1

A triazolyl or tetrazolyl phenyl substituted carbapenem represented by formula I ##STR196## or a pharmaceutically acceptable salt thereof, wherein: R.sup.1 and R.sup.2 independently represent 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 CH(OH)--, F.sub.2 CHCH(OH)--, F.sub.3 CCH(OH)--, CH.sub.3 CH(F)--, CH.sub.3 CF.sub.2 -- or (CH.sub.3).sub.2 CF--;
R.sup.3 is H or methyl:
R.sup.a is H or is selected from the group consisting of
a) --CF.sub.3 ;
b) a halogen atom selected from the group consisting of: --Br, --Cl, --F and --I;
c) --OH;
d) --OC1-4 alkyl, wherein the alkyl is optionally mono-substituted by Rq, where Rq is selected from the group consisting of --OH, --OCH.sub.3, --COOM, with M representing H, a negative charge, a metal cation or an ester forming group;
e) --NR'R" wherein R' and R" independently represent H or C1-4 alkyl;
f) --S(O).sub.n --R.sup.s, where n=0-2, and R.sup.s is C1-4 alkyl or phenyl, each of which is optionally mono-substituted by R.sup.q as defined above;
g) --CN;
h) --C(O)H or --CH(OCH.sub.3).sub.2 ;
i) --C(O)R.sup.s, where R.sup.s is as defined above;
j) --C(O)OC1-4 alkyl, where the alkyl is optionally mono-substituted by R.sup.q as defined above;
k) --C(O)N(R.sup.y)R.sup.z, where R.sup.y and R.sup.z are independently H, C1-4 alkyl, (optionally mono-substituted by R.sup.q as defined above), or N(R.sup.y)R.sup.z are taken together to represent an amino acid residue, or are taken together to represent a 4- to 5-membered alkylidene radical which forms a ring (optionally substituted with R.sup.q as defined above), or a 3- to 4-membered alkylidene radical interrupted by --O--, --S--, --S(O)-- or --S(O).sub.2 --which forms a ring;
l) --C(S)N(R.sup.y)R.sup.z where R.sup.y and R.sup.z are as defined above:
m) --SCN;
n) --SCF.sub.3 ;
o) --OCF.sub.3 ;
p) tetrazolyl, where the point of attachment is the carbon atom of the tetrazole ring and one of the nitrogen atoms is mono-substituted by hydrogen, an alkali metal or a C1-C4 alkyl;
q) a C2-C.sub.4 alkenyl radical, optionally mono-substituted by one of the substituents a) to p) above and phenyl which is optionally substituted by R.sup.q as defined above:
r) a C2-C4 alkynyl radical, optionally mono-substituted by one of the substituents a) to q) above;
s) a C1-C4 alkyl radical;
t) a C1-C4 alkyl group substituted with 1-3 groups R.sup.q as defined above, or mono-substituted by one of the substituents a)-s) above;
R.sup.b is present or absent; when R.sup.b is absent, the nitrogen to which said group is shown optionally attached is uncharged; when R.sup.b is present, R.sup.b is selected from the group consisting of:
(a) --C.sub.1-4 alkyl; (b) --NR'R" with R' and R" equal to H or C.sub.1-4 alkyl and (c) C.sub.1-4 alkyl substituted with up to three groups selected from:
hydroxy;
C1-4 alkoxy;
phenyl, nitrophenyl, methoxyphenyl or dimethoxyphenyl;
heteroaryl;
heteroaryl substituted with R.sup.s, as defined above;
--NR'R", with R' and R" as defined above;
--OC(O)R.sup.s, where R.sup.s is C.sub.1-4 alkyl or phenyl, each of which is optionally mono-substituted by R.sup.q as defined above;
--C(O)--R.sup.s with R.sup.s as previously defined;
--C(O)N(R.sup.y)R.sup.z, where R.sup.y and R.sup.z are as defined above;
--C(O)OC.sub.1-4 alkyl, where the alkyl is optionally mono-substituted by R.sup.q as defined above; and
COOM, with M as defined above;
one or two of X, Y and Z represent a N atom and the other variables are carbon atoms;
each R.sup.c is independently selected from the group consisting of hydrogen, halo, C1-4 alkyl, --COOM with M as previously defined, and C1-4 alkyl substituted with from 1 to 3 groups selected from:
hydroxy;
--C(O)--Rs with Rs as previously defined;
COOM, with M as previously defined;
--O--(C1-4) alkyl, wherein the alkyl portion is optionally substituted with Rq, as defined above;
--NR'R", with R' and R" as defined above;
--C(O)O(C1-4) alkyl, where the alkyl portion is optionally mono-substituted with Rq as defined above;
--C(O)N(R.sup.y)R.sup.z, where R.sup.y and R.sup.z are independently H, C1-4 alkyl (optionally mono-substituted by R.sup.q as defined above), or N(R.sup.y)R.sup.z are taken together to represent an amino acid residue, or are taken together to represent a 4- to 5-membered alkylidene radical which forms a ring (optionally substituted with R.sup.q as defined above), or a 3- to 4-membered alkylidene radical interrupted by --O--, --S--, --S(O)-- or --S(O).sub.2 -- which forms a ring;
--OC(O)N(R.sup.y)R.sup.z, where R.sup.y and R.sup.z are as defined above:
alternatively, the two R.sup.c groups may be taken in combination to represent an aromatic ring fused to the ring to which they are attached, said aromatic 5-6 membered ring selected from the group consisting of phenyl, pyridine, pyrazine, pyrimidine, pyrrole, imidazole, thiophene, furan and thiazole;
W is selected from: --COOH, or a pharmaceutically acceptable salt or ester thereof; COORP where RP is a readily removable carboxyl covering group which is not a pharmaceutically acceptable ester; COOM.sup.a where M.sup.a is an alkali metal, or a negative charge.

### Claim 2 (depends on 1)

A compound in accordance with claim 1, wherein R.sup.1 is hydrogen and R.sup.2 is (R)CH.sub.3 CH(OH)-- or (R)CH.sub.3 CH(F)--.

### Claim 3 (depends on 1)

A compound in accordance with claim 1 wherein R.sup.3 represents a beta methyl substituent group.

### Claim 4 (depends on 1)

A compound in accordance with claim 1 wherein the triazole or tetrazole ting attached to the phenyl group at position 3' is uncharged.

### Claim 5 (depends on 1)

A compound in accordance with claim 1 wherein the triazole or tetrazole ting attached to the phenyl group at position 3' is positively charged.

### Claim 6 (depends on 1)

A compound in accordance with claim 1 wherein R.sup.a is selected from the group consisting of:
a) --CF.sub.3 ;
b) a halogen atom selected from the group consisting of: --Br, --Cl, --F and --I;
c) --OH;
d) --OC1-4 alkyl;
e) --NR'R" wherein R' and R" independently represent H or C1-4 alkyl;
f) --S(O).sub.n --R.sup.s, where n=0-2, and R.sup.s is C1-4 alkyl or phenyl, each of which is optionally mono-substituted by R.sup.q as defined above;
g) --CN;
h) --C(O)R.sup.s, where R.sup.s is selected from the group consisting of --OH, --OCH.sub.3, --COOM, with M representing H, a negative charge, a metal cation or an ester forming group;
i) --C(O)OC1-4 alkyl where the alkyl is optionally mono-substituted by R.sup.q as defined above;
j) --C(O)N(R.sup.y)R.sup.z, where R.sup.y and R.sup.z are independently H, C1-4 alkyl (optionally mono-substituted by R.sup.q as defined above), or are taken in combination with the N to which they are attached to represent an amino acid residue, or are taken together to represent a 4- to 5-membered alkylidene radical which forms a ring (optionally substituted with R.sup.q as defined above), or a 3- to 4-membered alkylidene radical interrupted by --O--, --S--, --S(O)-- or --S(O).sub.2 -- which forms a ring;
k) --C(S)N(R.sup.y)R.sup.z where R.sup.y and R.sup.z are as defined above independently or in combination with the nitrogen to which they are attached;
l) --SCF.sub.3 ;
m) --OCF.sub.3 ;
n) tetrazolyl, where the point of attachment is the carbon atom of the tetrazole ring and one of the nitrogen atoms is mono-substituted by hydrogen, an alkali metal or a C1-C4 alkyl;
o) a C1-C4 alkyl radical, and
p) a C1-C4 alkyl group substituted with 1-3 groups R.sup.q as defined above, or mono-substituted by one of the substituents a)-o) above.

### Claim 7 (depends on 6)

A compound in accordance with claim 6 wherein R.sup.1 represents hydrogen, R.sup.2 represents (R)CH.sub.3 CH(OH)-- or (R)CH.sub.3 CH(F)-- and R.sup.3 represents a beta methyl substituent group.

### Claim 8 (depends on 7)

A compound in accordance with claim 7 wherein W is selected from: --COOH or a pharmaceutically acceptable salt or ester thereof, COOM.sup.a where M.sup.a represents an alkali metal cation or a negative charge.

### Claim 9 (depends on 1)

A compound in accordance with claim 1 wherein the two R.sup.c groups are taken together to represent an aromatic ring fused to the triazole ring, said aromatic ring being a member of the group consisting of phenyl, pyridine, pyrazine, pyrimidine, pyrrole, imidazole, thiophene, furan or thiazole.

### Claim 10 (depends on 1)

A composition comprised of an antibacterial effective amount of a compound in accordance with claim 1 in combination with a pharmaceutically acceptable carder.

### Claim 11 (depends on 1)

A method of treating a bacterial infection in a mammalian patient in need of such treatment, comprising administering to said mammal a compound in accordance with claim 1 in an amount effective to treat said bacterial infection.