Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-08-02
2003-04-29
Reamer, James H. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06555543
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to methods of inhibiting the effects of platelet activating factor using certain diketopiperazines. The invention also relates to methods of inhibiting the production and/or release of interleukin 8 (IL-8) using these diketopiperazines. Finally, the invention relates to pharmaceutical compositions comprising the diketopiperazines.
BACKGROUND
Platelet activating factor (PAF; 1-O-alkyl-2-acetyl-sn-glycerol-3-phosphorylcholine) is a potent inflammatory phospholipid mediator with a wide variety of biological activities. It is generated and released by basophils, monocytes, macrophages, polymorphonuclear leukocytes, eosinophils, neutrophils, natural killer lymphocytes, platelets and endothelial cells, as well as by renal and cardiac tissues under appropriate immunological and non-immunological stimulation. See PCT application WO 94/04537. PAF mediates biological responses by binding to specific PAF receptors found in a wide variety of cells and tissues. Structure-activity studies on PAF and its analogs indicate that the ability of PAF to bind to these receptors is structure specific and stereospecific. See PCT WO 94/04537.
While PAF mediates essential biological responses, it also appears to play a role in pathological immune and inflammatory responses. Many published studies have provided evidence for the involvement of PAF in diseases, including arthritis, acute inflammation, asthma, allergic reactions, cardiovascular diseases, neoplastic diseases, endotoxic shock, pain, psoriasis, ophthalmic inflammation, ischemia, gastrointestinal ulceration, myocardial infarction, inflammatory bowel diseases, and acute respiratory distress syndrome. See PCT application WO 94/04537.
The involvement of PAF in pathological inflammatory and immune states has stimulated a substantial research effort to identify PAF receptor antagonists, and a number of compounds of diverse chemical structure have been identified as PAF antagonists. See, e.g., PCT applications WO 94/04537 and WO 96/00212 (and references cited in these two applications), PCT applications WO 95/18610 and WO 99/49865, U.S. Pat. Nos. 4,940,709, 5,358,938, 5,434,151, 5,463,083, 5,648,486, 5,741,809 5,792,776, 5,780,503, 5,856,323, Japanese application 63 290868, Shimazaki et al.,
Chem. Pharm. Bull.,
35(8), 3527-3530 (1987), Shimazaki et al.,
J. Med. Chem.,
30, 1709-1711 (1987), Yoshida et al.,
Prog. Biochem. Pharmacol.,
22, 68-80 (1988), Shimazaki et al.,
Lipids,
26(12), 1175-1178 (1991). Given the significant number of pathological immune and inflammatory responses that are mediated by PAF, there remains a need to identify new compounds and compositions that inhibit PAF activity.
Diketopiperazines have been reported to exhibit a variety of biological activities. See, e.g., U.S. Pat. Nos. 4,289,759 (immunoregulatory agents), 4,331,595 (immunoregulatory agents), 4,940,709 (PAF antagonists), 5,700,804 (inhibitors of plasminogen activator inhibitor), 5,750,530 (inhibitors of plasminogen activator inhibitor), 5,990,112 (inhibitors of metalloproteases), PCT applications WO 97/36888 (inhibitors of farnesyl-protein transferase) and WO 99/40931 (treatment of central nervous system injury), EP application 43219 (immunoregulatory agents), Japanese application 63 290868 (PAF antagonists), Japanese application 31 76478 (immunosuppressive agents), Shimazaki et al.,
Chem. Pharm. Bull.,
35(8), 3527-3530 (1987) (PAF antagonists), Shimazaki et al.,
J. Med. Chem.,
30,1709-1711 (1987) (PAF antagonists), Shimazaki et al.,
Lipids,
26(12), 1175-1178 (1991) (PAF antagonists), Yoshida et al.,
Prog. Biochem. Pharmacol.,
22, 68-80 (1988) (PAF antagonists), Alvarez et al.,
J. Antibiotics,
47(11), 1195-1201 (1994) (inhibitors of calpain)
The diketopiperazine composed of aspartic acid and alanine (3-methyl-2,5-diketopiperazine-6-acetic acid; DA-DKP) is known. It has been reported to be formed as a result of the degradation of human albumin stored above 30° C. Chan et al.,
Eur. J Biochem.,
227, 524-528 (1995). It is not known to have biological activity.
SUMMARY OF THE INVENTION
The invention provides a method of treating a disease or condition mediated by platelet activating factor. The method comprises administering to an animal in need thereof an effective amount of a diketopiperazine of the formula:
wherein:
R
1
is —CH
2
COR
3
, or —CH
2
CH
2
COR
3
;
R
2
is the side chain of an amino acid selected from the group consisting of glycine, alanine, valine, leucine, isoleucine, serine, threonine, aspartic acid, asparagine, glutamic acid, glutamine, lysine, hydroxylysine, histidine, arginine, phenylalanine, tyrosine, tryptophan, thyroxine, cysteine, methionine, norvaline and ornithine;
R
3
is —OH, —NH
2
, —OR
4
, —NHR
4
, or —NR
4
R
4
; and
each R
4
is independently an alkyl, aryl, alkylaryl, or arylalkyl; or
a physiologically-acceptable salt thereof.
The invention further provides a method of inhibiting inflammation. The method comprises administering to an animal in need thereof an effective amount of a compound of formula (1) or a physiologically-acceptable salt thereof.
The invention also provides a method of inhibiting aggregation of platelets. The method comprises contacting the platelets with an effective amount of a compound of formula (1) or a physiologically-acceptable salt thereof.
In addition, the invention provides a method of inhibiting the production, release or both of interleukin 8 by cells. The method comprises contacting the cells with an effective amount of a compound of formula (1) or a physiologically-acceptable salt thereof.
The invention further provides a method of inhibiting the effects of platelet activating factor (PAF). The method comprises contacting the PAF with an effective amount of a compound of formula (1) or a physiologically-acceptable salt thereof.
Finally, the invention provides a pharmaceutical composition. The composition comprises a pharmaceutically-acceptable carrier and a compound of formula (1) or a physiologically-acceptable salt thereof.
DETAILED DESCRIPTION OF THE PRESENTLY-PREFERRED EMBODIMENTS
By “side chain” of an amino acid is meant that portion of the amino acid attached to the common NH
2
—CH—COOH backbone of all of the amino acids listed above. For instance, the side chain of glycine is —H, the side chain of alanine is —CH
3
, and the side chain of serine is —CH
2
OH.
By “alkyl” is meant a straight-chain or branched-chain alkyl containing 1-30 carbon atoms, preferably 1-18 carbon atoms. “Lower alkyl” means a straight-chain or branched chain alkyl containing 1-6 carbon atoms.
By “aryl” is meant an aromatic group having at least one aromatic ring (e.g., phenyl).
By “alkylaryl” is meant a lower alkyl having an aryl having attached thereto (e.g., —CH
2
C
6
H
5
or —CH
3
CH(C
6
H
5
)CH
3
).
By “arylalkyl” is meant an aryl having a lower alkyl having attached thereto (e.g., —C
6
H
4
—CH
3
).
“Inhibit” is used herein to mean to reduce (wholly or partially) or to prevent.
“Mediated” is used herein to mean caused by, exacerbated by, or involving.
“Treat” is used herein to mean to reduce (wholly or partially) the symptoms of a disease or condition, including curing the disease or condition, or to prevent the disease or condition.
The present invention is based on the discovery that 3-methyl-2,5-diketopiperazine-6-acetic acid (DA-DKP) inhibits PAF activity. This inhibition appears to be due to the binding of DA-DKP to both PAF and PAF receptors. It is believed that the binding of DA-DKF to PAF is due to ion pairing of the carboxyl of DA-DKP with N
+
on the choline portion of PAF. Thus, other diketopiperazines comprising one or more carboxyls would be expected to be effective inhibitors of PAF. Indeed, it is possible that other non-diketopiperazine compounds comprising carboxyls, such as poly-aspartic acid or poly-glutamic acid, would also be effective inhibitors of PAF. The mechanism by which DA-DKP binds to PAF receptors is not known, but it is hypothesized to be due to the diketopiperazine ring structure of the DA-DKP and/or the hydrophobic R
2
si
Bar-Or David
Curtis C. Gerald
Rao Nagaraja K. R.
Thomas Greg
DMI BioSciences, Inc.
Reamer James H.
Sheridan & Ross P.C.
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