Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving oxidoreductase
Reexamination Certificate
1999-11-05
2001-07-24
Naff, David M. (Department: 1651)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving oxidoreductase
C435S189000
Reexamination Certificate
active
06265178
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to sulfur oxidized tetrahydrothiopyran N-phenyloxazolidinone compounds in which the phenyloxazolidinone moiety is linked with a thiopyran ring through a carbon—carbon bond. The invention also relates to a novel assay for determining the inhibitory activity of oxazolidinones to human monamine oxidase.
BACKGROUND OF THE INVENTION
The oxazolidinone antibacterial agents are a novel synthetic class of antimicrobials with potent activity against a number of human and veterinary pathogens, including gram-positive aerobic bacteria such as multiply-resistant staphylococci and streptococci, gram-negative aerobic bacteria such as
H. influenzae
and
M. catarrahlis
, as well as anaerobic organisms such as bacteroides and clostridia species, acid-fast organisms such as
Mycobacterium tuberculosis
and
Mycobacterium avium
. It is also known that as a chemical compound class, oxazolidinones inhabit monoamine oxidase (MAO), the enzyme responsible for preventing acute blood pressure elevation by the endogenuous and dietary amine, tyramine. Accordingly, there is a demand to discover oxazolidinone antibiotics which possess minimum MAO inhibitory activity to eliminate the related side effects from potential drug—drug interactions. There is also currently an interest in developing a high throughput screening assay to determine the MAO inhibitory activity of oxazolidinone antibiotics.
INFORMATION DISCLOSURE
International Publication WO 97/09328, pending U.S. application Ser. No. 08/693,313 now U.S. Pat. No. 5,968,962, discloses phenyloxazolidinones having a C—C bond to 4-8 membered heterocyclic rings, which generically covers the compounds of the present application.
International Publication No. WO 97130995 discloses antibiotic oxazolidinone derivatives.
Other references that disclose aromatic heterocycles attached to a phenyloxazolidinone include European Patent Publication No. 0352 781 A2, International Publication No. WO 9309103-A1 and U.S. Pat. Nos. 5,130,316, 5,254,577 and 4,948,801.
Additional references of general interest include: Flaherty et al., Synthesis and Elective Monoamine Oxidase B-Inhibiting Properties of 1-Methyl-1,2,3,6-Tetrahydropyrid-4-yl Carbamate Derivatives: Potential Prodrugs of (R)- and (S)-Nordeprenyl,
J. Med Chem.
, Vol. 39, pp. 4756-4761 (1996); Walter Weyler and J. I. Salach, “Purification and Properties of Mitochondrial Monoamine Oxidase Type A from Human Placenta”,
J. of Bio. Chem.
, Vol. 260, No. 24, pp. 13199-13207 (1985) (Oct. 25, 1985). J. I. Salach and Walter Weyler, Preparation of the Flavin-Containing Aromatic Amine Oxidases of Human Placenta and Beef Liver,
Methods Enzymol.
, Vol. 142, pp 627-623 (1987); Joseph J. P. Zbou, et al., “Direct Continuous Fluorometric Assay for Monoamine Oxidase B”,
Analytical Biochemistry
, Vol. 234, pp. 9-12 (1996); Matthew J. Krueger, et al., “An Examination of the Reliability of the Radiochemical Assay for Monoamine Oxidases A and B”,
Analytical Biochemistry
, Vol. 214, pp. 116-123 (1993); Keith F. Tipton, et al., “Commentary—The Radiochemical Assay for Monoamine Oxidase Activity—Problems and Pitfalls”,
Biochemical Pharmacology
, Vol. 46, No.
8
, pp. 1311-1316 (1993).
SUMMARY OF THE INVENTION
In one aspect, the present invention is a compound of formula I
or pharmaceutically acceptable salts thereof wherein R
1
is methyl, ethyl, cyclopropyl, or dichloromethyl; R
2
and It
3
are the same or different and are hydrogen or fluoro. The formula I of the invention embraces both tran- and cis-isomers.
In another aspect, the present invention is a compound of formula II
or pharmaceutically acceptable salts thereof wherein R
2
and R
3
are the same as defined above; R
4
is ethyl or dichloromethyl.
Preferably, in the above formula I, R
1
is methyl or ethyl.
Preferably, in the above formula II, R
4
is ethyl.
Also preferably, compounds of formulas I and II are mono- fluoro compounds.
Preferred compounds of the present invention are:
a. [4(S)-cis]-(−)-N-[[3-[3-Fluoro-4-(tetrahydro-1-oxido-2H-thiopyran-4-yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide,
b. [4(S)-cis]-(−)-N-[[3-[3-Fluoro-4-(tetrahydro-1-oxido-2H-thiopyran-4-yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]propionamide,
c. [4(S)-cis]-(−)-N-[[3-[3-Fluoro-4-(tetrahydro-1-oxido-2H-thiopyran-4-yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]cyclopropanecarboxamide,
d. [4(S)-cis]-2,2-Dichloro-N-[[3-[3-fluoro-4-(tetrahydro-1-oxido-2H-thiopyran-4-yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide,
e. (S)-(−)-N-[[3-[3-Fluoro-4-(tetrahydro-1,1-dioxido-2H-thiopyran-4-yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]propionamide,
f. (S)-(−)-2,2-Dichloro-N-[[3-[3-Fluoro-4-(tetrahydro-1,1-dioxido-2H-thiopyran-4-yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide,
g. [4(S)-trans]-(−)-N-[[3-[3-Fluoro-4-(tetrahydro-1-oxido-2H-thiopyran-4-yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]propionamide,
h. [4(S)-trans]-(−)-N-[[3-[3-Fluoro-4-(tetrahydro-1-oxido-2H-thiopyran-4-yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]cyclopropanecarboxamide, or
i. [4(S)-trans]-2,2-Dichloro-N-[[3-[3-fluoro-4-(tetrahydro-1-oxido-2H-thiopyran-4-yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide.
More preferred is compound [4(S)-cis]-(−)-N-[[3-[3-Fluoro-4-(tetrahydro-1-oxido-2H-thiopyran-4-yl)phenyl]-2-oxo-5-oxazolidinyl]methyl acetamide.
In still another aspect, the present invention provides a method of assaying an oxazolidinone antibiotic's MAO inhibitory activity, which comprises the steps of
a) incubating an oxazolidinone with a monoamine oxidase in a buffer solution having pH value from about 7.0 to about 7.5;
b) adding 1-methyl-4-(1-methyl-2-pyrryl)-1,2,3,6-tetrahydropyridine into said incubating solution; and
c) determining the monoamine oxidase inhibitory activity of said oxazolidinone.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides sulfur oxidized tetrahydrothiopyran phenyloxazolidinone of formula I and formula II as defined above. The compounds are useful antimicrobial agents, effective against a number of human and veterinary pathogens as disclosed above. In particular, it has been discovered that, while oxazolidinones as a chemical compound class are inhibitors of human monoamine oxidase A (MAO A) and monoamine oxidase B (MAO B), the compounds of the present invention have unexceptedly weak MAO inhibitory activity, which indicates that these compounds possess the capacity to minimize or eliminate potential drug-drug interactions since strong inhibition of monoamine oxidase can result in altered clearance rates for other compounds normally metabolized by it, including several pharmaceuticals.
The present invention also provides a novel spectrophotometric assay for determining the ability of an oxazolidinone to inhibit human monoamine oxidases. MAO A and MAO B are membrane bound flavoproteins localized in the outer mitochondrial membrane. The two enzymes prefer different substrate in catalyzing the oxidative deamination of biogenic and xenobiotic amines. Historically, MAO enzymes have been assayed by radioactive end point (discontinuous) methods using two different substrates. These methods have been criticized because as commonly practiced, they lack the proof of linearity of the reaction time course under prevailing assay conditions. The use of these methods are also inadequate due to their cumbrous nature when screening a large number of compounds in a short period of time. The methods involve multiple processing steps including solvent extraction of reaction products. These steps lead to inaccuracies in the resulting data. See: Matthew J. Krueger, et al., “An Examination of the Reliability of the Radiochemical Assay for Monoamine Oxidases A
Meller Mike
Naff David M.
Pharmacia & Upjohn Company
Yang Lucy X.
LandOfFree
Assay for determining oxazolidinone antibiotics having... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Assay for determining oxazolidinone antibiotics having..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Assay for determining oxazolidinone antibiotics having... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2496746