Antimicrobial activity of gemfibrozil

Details Antimicrobial activity of gemfibrozil Antimicrobial activity of gemfibrozil

1996-02-29

2004-03-30

Jones, Dameron L. (Department: 1616)

Drug, bio-affecting and body treating compositions

Radionuclide or intended radionuclide containing; adjuvant...

In an organic compound

C424S001110, C424S009100, C424S001650, C435S025000

Reexamination Certificate

active

06713043

ABSTRACT:

BACKGROUND OF THE INVENTION
Throughout this application, various publications are referenced by author and date. Full citations for these publications may be found listed alphabetically at the end of the specification immediately preceding Sequence Listing and the claims. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art as known to those skilled therein as of the date of the invention described and claimed herein.
Gemfibrozil (GFZ) is a compound that has been utilized as a drug for increasing intracellular accumulation of hydrophilic anionic agents (U.S. Pat. No. 5,422,372, issued Jun. 6, 1995) and as a lipid regulating composition (U.S. Pat. No. 4,859,703, issued Aug. 22, 1989). Gemfibrozil has been shown to be effective in increasing the amount of cholesterol excreted in to bile. (Ottmar Leiss et al., Metabolism, 34(1):74-82 (1985)). Gemfibrozil is described in U.S. Pat. No. 3,674,836 and in The Merck Index, 11 ed., Merck & Co., Inc. Rahway, N.J. 1989; #4280. Gemfibrozil, a drug which therapeutically lowers triglycerides and raises HDL-cholesterol levels, previously has not been reported to have antimicrobial activity. (Brown, 1987; Oliver et al., 1978 and Palmer et al., 1978).
SUMMARY OF THE INVENTION
The present invention provides for a method for inhibiting growth of a bacterium which consists essentially of contacting the bacterium with a compound having the structure
In the compound each of R
1
,, R
2
, R
3
, R
4
, R
5
and R
6
may be independently H, F, Cl, Br, I, —OH, —OR
7
, —CN, —COR
7
, —SR
7
, —N(R
7
)
2
, —NR
7
COR
8
, —NO
2
, —(CH
2
)
p
OR
7
, —(CH
2
)
p
X(R
7
)
2
, —(CH
2
)
p
XR
7
COR
8
, a straight chain or branched, substituted or unsubstituted C
1
-C
10
alkyl, C
2
-C
10
alkenyl, C
2
-C
10
alkynyl, C
3
-C
10
cycloalkyl, C
3
-C
10
cycloalkenyl, thioalkyl, methylene thioalkyl, acyl, phenyl, substituted phenyl, or heteroaryl; wherein R
7
or R
8
may be independently H, F, Cl, Br, I, —OH, —CN, —COH, —SH
2
, —NH
2
, —NHCOH, —(CH
2
)
p
OH, —(CH
2
)
p
X(CH
2
), —(CH
2
)
p
XCOH, a straight chain or branched, substituted or unsubstituted C
1
-C
10
alkyl, C
2
-C
10
alkenyl, C
2
-C
10
alkynyl, C
3
-C
10
cycloalkyl, C
3
-C
10
cycloalkenyl, thioalkyl, methylene thioalkyl, acyl, phenyl, substituted phenyl, or heteroaryl; wherein A may be —N
2
—, —NH—, —C═C═CH
2
—, —C≡C—C
2
HOH—, —C≡C—CH
2
—, —CH
2
—CH
2
O—, —CH
2
—CH
2
—CH
2
—O—, —S—, —S(═O)
2
—, —C═O—, —C═O—O—, —NH—C═O—, —C═O—NH—; and wherein Q, p, n and x may independently be an integer from 1 to 10, or if Q is 1 A may be a (C
1
-C
10
)-alkyl chain, (C
1
-C
10
)-alkenyl chain or (C
1
-C
10
)-alkynyl chain which is branched or unbranched, substituted or unsubstituted and can optionally be interrupted 1 to 3 times by —O— or —S— or —N—; or a pharmaceutically acceptable salt or ester thereof, which compound is present in a concentration effective to inhibit growth of the bacterium. In this method, A may be an (C
1
-C
10
)-alkylene chain, (C
1
-C
10
)-alkyl chain, (C
1
-C
10
)-alkenyl chain or (C
1
-C
10
)-alkynyl chain which is branched or unbranched, substituted or unsubstituted and can optionally be interrupted 1 to 3 times by —O— or —S— or —N—; and wherein the ether linkage to the benzene ring may be alternatively —S—, —N— or —C—.


REFERENCES:
patent: 3674836 (1972-07-01), Creger
patent: 4859703 (1989-08-01), Krause
patent: 4891220 (1990-01-01), Donzis
patent: 5422372 (1995-06-01), Silverstein et al.
patent: 5837480 (1998-11-01), Sacchettini et al.
patent: 6531291 (2003-03-01), Kabbash et al.
patent: WO9937800 (1999-07-01), None
Vernon et al, Biochimica et Biophysica Acta, 788, 124-131 ‘The Presence’ of Essential Arginine Residues at the NADPH Binding Sites of B-Ketoacyl Reductose and Enyl Reductose Domains of the Multi-functional Fatty Acid Synthetase of Chicken Liver, 1984.*
Hashimoto et al (Apr. 1997), Bid. Pharm. Bull., vol. 20, No. 4, pp. 315-321, Effect of Gemfibrozil on Centrifugal Behavior of Rat Peroxisomes and Activities of Perokisomal Enzymes Involved in Lipio Metabolism.*
Baldock et al (1996, Dec.) , Science, vol. 274, pp. 2107-2110, “A Mechanism of Drug, Action Revealed by Structural Studies of Enolyl Reductase”.*
The Merck Index, 10th ed., Merck & Co., Inc. Rahway, N.J., 1983, #4246.
C. Kabbash, H. Shuman, S. Silverstein, P. Della-Latta, J. Blanchard, U.S. Serial No. 09/438144, filed Nov. 10, 1999.
The Merck Index, 10thEd., Merck & Co., Inc., Rahway, New Jersey, 1983, No. 4246.
Vernon et al. (1984) The Presence of Essential Arginine Residues at the NADPH-Binding Sites of &bgr;-Ketoacyl Reductase, And Enoyl Reductase Domains of the Multifunctional Fatty Acid Synthetase of Chicken Liver,Biochim. et Biophys. Acta.vol. 788, pp. 124-131.
Clements, P.R. and Barden, R. E. (1982) Irreversible Inhibition of Fatty Acid Synthase From Rat Mammary Gland With S-(4-bromo-2,3-dioxobutyl) -CoA.Biochem. J.vol. 207, pp. 291-296.
Bergler, H. et al. (1996) The enoyl-[acyl-carrier-protein] reductase (FabI) ofEscherichia coli, which catalyzes a key regulatory step in fatty acid biosynthesis, accepts NADH and NADPH as cofactors and is inhibited by palmitoyl-CoA.Eur. J. Biochem.vol. 242, pp. 689-694.
Heath, R. J. and Rock, C. O. (1996) Regulation of Fatty Acid Elongation and Initiation by Acyl-Acyl Carrier Protein inEscherichia coli. J. Biol. Chem.vol 271, No. 4, pp. 1833-1836.
Cardon, J. W. and Hammes, G. G. (1983) Kinetic and Structural Investigation of Acyl-binding Sites on Avian Fatty Acid Synthase.J. Biol. Chem.vol. 258, No. 8, pp. 4802-4807.
Bronfman, M., et al. (1992) Hypolipidaemic drugs are activated to acyl-CoA esters in isolated rat hepatocytes.Biochem. J.vol. 284, pp. 289-295.
Amigo, L. et al. (1992) Subcellular distribution and characteristics of ciprofibroyl-CoA synthetase in rat liver.Biochem. J.vol. 284, pp. 283-287.
Urrea, R. and Bronfman, M. (1996) Species Differences in the Intracellular Distribution of Ciprofibroyl-CoA hydrolase. Implications for peroxisome proliferation. FEBS Letters vol. 389, pp. 219-223.

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