Aminoaryl oxazolidinone N-oxides

Details Aminoaryl oxazolidinone N-oxides Aminoaryl oxazolidinone N-oxides

2001-06-28

2002-08-27

Coleman, Brenda (Department: 1624)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C548S232000

Reexamination Certificate

active

06441188

ABSTRACT:

FIELD OF THE INVENTION
The present invention provides for aminoaryl oxazolidinone N-oxide compounds. These compounds are exceedingly water soluble which is useful in preparing pharmaceutical formulations of these compounds. They are also rapidly converted back to the parent amines in vivo, making them useful as prodrugs of the parent amines.
These compounds have antibiotic activity comparable to the parent amines. They 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.
BACKGROUND OF THE INVENTION
A variety of antibiotic oxazolidinone compounds are known in the art. For example, please see the following:
WO 95/07271, published Mar. 16, 1995, “Substituted Oxazine and Thiazine Oxazolidinones Antimicrobials”; WO96/15130, published May 23, 1996, “Bicyclic Oxazine and Thiazine Oxazolidinone Antibacterials”; WO96/13502, published May 9, 1996, “Phenyloxazolidinone Antimicrobials”; WO 93/23384, published Nov. 25, 1993, “Oxazolidinone Antimicrobials Containing Substituted Diazine Moieties”; WO 90/02744, published Mar. 22, 1990; U.S. Pat. No. 5,164,510; U.S. Pat. No. 5,225,565; U.S. Pat. No. 5,182,403; “5′-Indolinyl-5&bgr;-Amidomethyloxazolidin-2-ones”; WO 95/25106, published Sep. 21, 1995, “Oxazolidinone Derivatives and Pharmaceutical Compositions Containing Them”; WO 93/09103, published May 13, 1993, “Substituted Aryl and Heteroaryl-Phenyloxazolidinones”; WO 95/14684, published Jun. 1, 1995, “Esters of Substituted Hydroxyacetyl-Piperazine Phenyl Oxazolidinones”; PCT/US96/05202, filed Apr. 18, 1996, “Spirocyclic and Bicyclic Diazinyl and Carbazinyl Oxazolidinones”; U.S. Pat. Nos. 5,231,188 and 5,247,090, “Tricyclic [6,6,5]-Fused Oxazolidinone Antibacterial Agents;” WO 96/23788, published Aug. 8, 1996, “Hetero-Aromatic Ring Substituted Phenyloxazolidinone Antimicrobials;” and WO 94/13649, published Jun. 23, 1994, “Tropone-Substituted Phenyloxazolidinone Antibacterial Agents.”
Nowhere do these patents, applications or publications teach or suggest N-oxide oxazolidinone compounds.
INFORMATION DISCLOSURE
U.S. Pat. No. 4,722,928 discloses N-oxide prodrug derivatives of 3-hydroxy morphinans and partial morphinans analgesics, agonist-antagonists, and narcotic antagonists, which are useful therapeutic entities providing enhanced bioavailability of these compounds from orally administered dosage forms. In contrast, there is no change in the bioavailability of the N-oxide compounds of the present invention.
This patent further states that there is no way to accurately predict which prodrug structure will be suitable for a particular drug. A derivative which may work well for one drug may not do so for another. Differences in the absorption, metabolism, distribution, and excretion among drugs do not permit generalizations to be made about prodrug design.
Chemical Abstracts 118:147331y (1993) discloses anti-cancer anthracene amine N-oxide prodrugs with low cytotoxicity which are bioreduced within anaerobic neoplastic tissue to the cytotoxic amine anticancer agents. There is no suggestion that N-oxide prodrugs can be bioreduced in normal tissue. These compounds are also potentially useful against anaerobic bacterial and protozoal infections.
L. H. Patterson, “Rationale for the use of aliphatic N-oxides of cytotoxic anthraquinones as prodrug DNA binding agents: a new class of bioreductive agent,”
Cancer and Metastasis Review
12:119-134 (1993) discloses that such N-oxides are not intrinsically cytotoxic. It further states that investigations into the fate of N-oxide administration to animals show that, in general, aliphatic N-oxides are stable in vivo and are recovered quantitatively following intravenous dosing. Hence, the article concludes that it would appear that aliphatic N-oxides are not metabolised in oxygenated tissue to any significant extent. In contrast, the aliphatic N-oxide compounds of the present invention are surprisingly and unexpectedly reduced back to the parent amine very rapidly in vivo.
The problem in the art is difficulty in formulating the parent amine compounds for intravenous and injectable use. The N-oxide compounds of the present invention have high water solubility and are readily formulated in aqueous vehicles.
SUMMARY OF THE INVENTION
The present invention particularly provides:
A compound of the formula I
wherein X
1
and X
2
are independently
—H,
—F, or
—Cl;
wherein Q
1
is:
wherein Z
1
is
a) —CH
2
—, or
b) —CH(R
5
)—CH
2
—;
wherein Z
2
is
a) —O
2
S—,
b) —O—, or
c) —N(R
8
)—;
wherein Z
3
is
a) —O
2
S—, or
b) —O—;
wherein A
1
is
a) H—, or
b) CH
3
—;
wherein A
2
is
a) H—,
b) HO—,
c) CH
3
CO
2
—,
d) CH
3
—,
e) CH
3
O—,
f) R
2
O—CH
2
—C(O)—NH—,
g) R
3
O—C(O)—NH—,
h) R
4
—C(O)—NH—,
i) (C
1
-C
2
)alkyl—O—C(O)—, or
j) HO—CH
2
—; or
A
1
and A
2
taken together are:
or
b) O═
wherein R
1
is
a) —CHO,
b) —COCH
3
,
c) —COCHCl
2
,
d) —COCHF
2
,
e) —CO
2
CH
3
,
f) —SO
2
CH
3
, or
g) —COCH
2
OH;
wherein R
2
is
a) H—,
b) CH
3
—,
c) phenyl-CH
2
-, or
d) CH
3
C(O)—;
wherein R
3
is
a) (C
1
-C
3
)alkyl-, or
b) phenyl-;
wherein R
4
is
a) H—,
b) (C
1
-C
4
)alkyl,
c) aryl-(CH
2
)p,
d) ClH
2
C—,
e) Cl
2
HC—,
f) FH
2
C—,
g) F
2
HC—, or
h) (C
3
-C
6
)cycloalkyl;
wherein R
5
is
a) H—, or
b) (C
1
-C
3
)alkyl;
wherein R
6
is
a) H—, or
b) HOH
2
C—;
wherein R
7
is
a) H—, or
b) H
3
C—;
wherein R
8
is
a) R
2
O—C(R
10
)(R
11
)—C(O)—,
b) R
3
O—C(O)—,
c) R
4
—C(O)—,
f) H
3
C—C(O)—(CH
2
)
2
—C(O)—,
g) R
9
—SO
2
—,
i) R
12
—NH—C(O)—;
wherein R
9
is
a) —CH
3
,
b) —CH
2
Cl
c) —CH
2
CH═CH
2
,
d) aryl, or
e) —CH
2
CN;
wherein R
10
and R
11
are independently
a) H—,
b) CH
3
—; or
R
10
and R
11
taken together are —CH
2
—CH
2
—;
wherein R
12
is —(CH
2
)
p
-aryl;
wherein R
13
is
a) R
2
O—C(R
10
)(R
11
)—C(O)—,
b) R
3
O—C(O)—,
c) R
4
—C(O)—,
d) R
9
—SO
2
—, or
e) R
12
—NH—C(O)—;
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
3
,
d) —OH,
e) —NH
2
,
f) —(C
1
-C
4
)alkyl,
g) —O—C(O)—OCH
3
,
h) —NO
2
, or
i) —CN;
with the following provisos:
1) in the moiety of formula II, Z
1
is —CH(R
5
)—CH
2
—wherein R
5
is (C
1
-C
3
)alkyl, only when n is one (1), Al is H and A
2
is R
2
O—CH
2
—C(O)—NH—, R
3
O—C(O)—NH—, or R
4
—C(O)—NH—; and
2) in the moiety of formula II, when Z
1
is —CH
2
—, n is one (1).
The present invention more particularly provides:
The compound of claim
1
wherein Q
1
is the moiety of formula II;
The compound of claim
1
wherein Q
1
is the moiety of formula III;
The compound of claim
1
wherein Q
1
is the moiety of formula IV;
The compound of claim
1
wherein Q
1
is the moiety of formula V;
The compound of claim
1
wherein one of X
1
and X
2
is —H and the other is —F or wherein X
1
is —F and X
2
is —F; and
The compound of claim
1
wherein R
1
is acetyl.
The compounds of the present invention are named according to the IUPAC or CAS nomenclature system.
The carbon atom content of various hydrocarbon-containing moieties is indicated by a prefix designating the minimum and maximum number of carbon atoms in the moiety, i.e., the prefix C
i
-C
j
indicates a moiety of the integer “i” to the integer “j” carbon atoms, inclusive. Thus, for example, (C
1
-C
3
)alkyl refers to alkyl of one to three carbon atoms, inclusive, or methyl, ethyl, propyl and isopropyl, straight and branched forms thereof.
Throughout this application, abbreviations which are well known to one of ordinary skill in the art may be used, such as “Ph” for phenyl, “Me” for methyl, and “Et” for ethyl.
The following Charts I-IX describe the preparation of the parent amine compounds, which are the starting compounds from which the N-oxide compounds of the presen

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