# US 5,708,169 A · 5-amidomethyl .alpha.,.beta.-saturated and -unsaturated 3-aryl butyrolactone antibacterial agents

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- Number: US 5,708,169 A
- Document ID: US5708169A
- Status: Granted
- Kind: A
- Application number: 08/708,765
- Filed: 1996-09-05
- Granted: 1998-01-13
- Earliest claimed: 1996-09-05
- Assignees: Pharmacia & Upjohn Company
- Inventors: Jackson B. Hester, Jr.; Steven Joseph Brickner; Michael Robert Barbachyn; Douglas K. Hutchinson; Dana Scott Toops
- Web page: https://patentgrep.com/patent/US5708169A

## CPC

- C07D 307/58: One oxygen atom, e.g. butenolide
- A61P 31/00: Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P 31/04: Antibacterial agents
- C07D 307/28: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D 307/52: Radicals substituted by nitrogen atoms not forming part of a nitro radical
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention provides for new 5-amidomethyl, .alpha.,.beta.-saturated and--unsaturated butyrolactone antibacterial agents of formula I ##STR1## characterized by 3-aryl substituents that include, for example, indolinyl and phenyl substituted with zero (0) to two(2) halogen atoms and substituted in the para position with, e.g., piperazinyl, thiomorpholinyl (and corresponding sulfoxide and sulfone), thiazolidinyl (and sulfoxide and sulfone), morpholinyl, azetidinyl, pyrrolidinyl, piperidinyl, pyrrolyl, azepinyl, troponyl, 3,7-diazabicyclo›3.3.0!octan-3-yl, bridged thiazinyl or bridged oxazinyl moieties. In those cases where a ring nitrogen is present, then this is substituted to form an amide, formamide, sulfonamide, urethane, or alkylated with a wide variety of moieties. These compounds are effective against a number of human and veterinary pathogens, including gram-positive aerobic bacteria such as multiply-resistant staphylococci, streptococci and enterococci, as well as anaerobic organisms such as Bacteroides spp. and Clostridia spp. species, and acid-fast organisms such as Mycobacterium tuberculosis, Mycobacterium avium and Mycobacterium spp., and in organisms such as Mycoplasma spp.

## Claims

### Claim 1

A compound of the formula I
wherein --- is a single or double bond;
wherein X.sup.1 and X.sup.2 are independently
--H,
--F, or
--Cl;
wherein Q.sup.1 is: ##STR36## Q.sup.1 and X.sup.2 taken together are ##STR37## wherein Z.sup.1 is a) --CH.sub.2 --,
b) --CH(R.sup.4)--CH.sub.2 --,
c) --C(O)--, or
d) --CH.sub.2 CH.sub.2 CH.sub.2 --;
wherein Z.sup.2 is
a) --O.sub.2 S--,
b) --O--,
c) --N(R.sup.7)--,
d) --OS--, or
e) --S--;
wherein Z.sup.3 is
a) --O.sub.2 S--,
b) --O--,
c) --OS--, or
d) --S--;
wherein A.sup.1 is
a) H--, or
b) CH.sub.3 ;
wherein A.sup.2 is
a) H--,
b) HO--,
c) CH.sub.3 --,
d) CH.sub.3 O--,
e) R.sup.2 O--CH.sub.2 --C(O)--NH--
f) R.sup.3 O--C(O)--NH--,
g) (C.sub.1 -C.sub.2)alkyl-O--C(O)--,
h) HO--CH.sub.2 --,
i) CH.sub.3 O--NH--,
j) (C.sub.1 -C.sub.3)alkyl-O.sub.2 C--
k) CH.sub.3 --C(O)--,
l) CH.sub.3 --C(O)--CH.sub.2 --, ##STR38## A.sup.1 and A.sup.2 taken together are: ##STR39## wherein R.sup.1 is a) --CHO,
b) --COCH.sub.3,
c) --COCHCl.sub.2,
d) --COCHF.sub.2,
e) --CO.sub.2 CH.sub.3,
f) --SO.sub.2 CH.sub.3, or
g) --COCH.sub.2 OH;
wherein R.sup.2 is
a) H--,
b) CH.sub.3 --,
c) phenyl-CH.sub.2 --, or
d) CH.sub.3 C(O)--;
wherein R.sup.3 is
a) (C.sub.1 -C.sub.3)alkyl-, or
b) phenyl-;
wherein R.sup.4 is
a) H--, or
b) HO--;
wherein R.sup.5 is
a) H--,
b) (C.sub.1 -C.sub.3)alkyl-,
c) CH.sub.2 .dbd.CH--CH.sub.2 --, or
d) CH.sub.3 --O--(CH.sub.2).sub.2 --;
wherein R.sup.6 is
a) CH.sub.3 --C(O)--,
b) H--C(O)--,
c) Cl.sub.2 CH--C(O)--,
d) HOCH.sub.2 --C(O)--,
e) CH.sub.3 SO.sub.2 --, ##STR40## g) F.sub.2 CHC(O)--, ##STR41## i) H.sub.3 C--C(O)--O--CH.sub.2 --C(O)--, j) H--C(O)--O--CH.sub.2 --C(O)--, ##STR42## l) HC.tbd.C--CH.sub.2 O--CH.sub.2 --C(O)--, or m) phenyl-CH.sub.2 --O--CH.sub.2 --C(O)--;
wherein R.sup.7 is
a) R.sup.2 O--C(R.sub.10)(R.sub.11)--C(O)--,
b) R.sup.3 O--C(O)--,
c) R.sup.8 --C(O)--, ##STR43## f) H.sub.3 C--C(O)--(CH.sub.2).sub.2 --C(O)--, g) R.sup.9 --SO.sub.2 --, ##STR44## i) HO--CH.sub.2 --C(O)--, j) R.sup.16 --(CH.sub.2).sub.2 --,
k) R.sup.13 --C(O)--O--CH.sub.2 --C(O)--,
l) (CH.sub.3).sub.2 N--CH.sub.2 --C(O)--NH--,
m) NC--CH.sub.2 --, or
n) F.sub.2 --CH--CH.sub.2 --;
wherein R.sup.8 is
a) H--,
b) (C.sub.1 -C.sub.4)alkyl,
c) aryl --(CH.sub.2).sub.p,
d) ClH.sub.2 C--,
e) Cl.sub.2 HC--,
f) FH.sub.2 C--,
g) F.sub.2 HC--, or
h) (C.sub.3 -C.sub.6)cycloalkyl;
wherein R.sup.9 is
a) --CH.sub.3,
b) --CH.sub.2 Cl
c) --CH.sub.2 CH.dbd.CH.sub.2,
d) aryl, or
e) --CH.sub.2 CN;
wherein R.sup.10 and R.sup.11 are independently
a) H--,
b) CH.sub.3 --; or
wherein R.sup.12 is
a) H--,
b) CH.sub.3 O--CH.sub.2 O--CH.sub.2 --, or
c) HOCH.sub.2 --;
wherein R.sup.13 is
a) CH.sub.3 --,
b) HOCH.sub.2 --,
c) (CH.sub.3).sub.2 N-phenyl, or
d) (CH.sub.3).sub.2 N--CH.sub.2 --;
wherein R.sup.14 is
a) HO--,
b) CH.sub.3 O--,
c) H.sub.2 N--,
d) CH.sub.3 O--C(O)--O--,
e) CH.sub.3 --C(O)--O--CH.sub.2 --C(O)--O--,
f) phenyl-CH.sub.2 --O--CH.sub.2 --C(O)--O--,
g) HO--(CH.sub.2).sub.2 --O--,
h) CH.sub.3 O--CH.sub.2 --O--(CH.sub.2).sub.2 --O--, or
i) CH.sub.3 O--CH.sub.2 --O--;
wherein R.sup.15 is
a) H--, or
b) Cl--;
wherein R.sup.16 is
a) HO--
b) CH.sub.3 O--, or
c) F;
wherein m is zero (0) or one (1);
wherein n is one (1) to three (3), inclusive;
wherein p is zero (0) or one (1);
wherein aryl is phenyl substituted with zero (0) or one (1) of the following:
a) --F,
b) --Cl,
c) --OCH.sub.3,
d) --OH,
e) --NH.sub.2,
f) --(C.sub.1 -C.sub.4)alkyl,
g) --O--C(O)--OCH.sub.3, or
h) --NO.sub.2 ;
or pharmaceutically acceptable salts thereof.

### Claim 2 (depends on 1)

The compound of claim 1 with the following provisos:
1) in the moiety of formula II, when Z.sup.1 is --CH.sub.2 -- or --C(O)--, n is one (1);
2) in the moiety of formula II, when Z.sup.1 is --CH.sub.2 --CH.sub.2 --CH.sub.2 --, n is not three (3).

### Claim 3 (depends on 1)

The compound of claim 1 wherein Q.sup.1 is the moiety of formula II.

### Claim 4 (depends on 1)

The compound of claim 1 wherein Q.sup.1 is the moiety of formula III.

### Claim 5 (depends on 1)

The compound of claim 1 wherein Q.sup.1 is the moiety of formula IV.

### Claim 6 (depends on 1)

The compound of claim 1 wherein Q.sup.1 is the moiety of formula V.

### Claim 7 (depends on 1)

The compound of claim 1 wherein Q.sup.1 is the moiety of formula VI.

### Claim 8 (depends on 1)

The compound of claim 1 wherein Q.sup.1 is the moiety of formula VII, VIII, IX, X, XI, XII, XIII, or XIV.

### Claim 9 (depends on 1)

The compound of claim 1 selected from the group consisting of:
Acetamide, N-››4-›3-fluoro-4-(4-morpholinyl)phenyl!-2,5-dihydro-5-oxo-2-furanyl}methy l!-, (R)-; and
Acetamide, N-››4-›4-›4-(2-methoxy)-5-oxo-1,3,6-cycloheptatrien-1-yl!phenyl!-2,5-dihyd ro-5-oxo-2-furanyl!methyl!-.