Amide derivatives for antiangiogenic and/or antitumorigenic use

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...

Reexamination Certificate

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Reexamination Certificate

active

06399647

ABSTRACT:

TECHNICAL FIELD
The present invention, in general, relates to conversion of the carboxylic acid moiety of various compounds into amide derivatives of the compounds. More specifically, the present invention relates to secondary amide derivatives of non-steroidal antiinflammatory drugs (NSAIDs), particularly of indomethacin (an NSAID), that exhibit inhibition of cyclooxygenase-2 (COX-2) far exceeding inhibition of cyclooxygenase-1 (COX-1), and also, that still exhibit the analgesic, antiinflammatory, and/or antipyretic effect of the compound, i.e., of the NSAID, and moreover, also exhibit cancer inhibition, i.e., an antiangiogenic and/or antitumorigenic effect, in warm blooded vertebrate animals, including humans.
Table of Abbreviations
Abbreviations
Definitions
NSAID
non-steroidal antiinflammatory drug
COOH
carboxylic acid moiety
COX
cyclooxygenase
PGH
2
prostaglandin H
2
PGD
2
prostaglandin D
2
PGHS
prostaglandin endoperoxide synthase
PER
peroxidase
SAR
structure-activity relationship
GI
gastrointestinal
IC
50
concentration in micromoles of
indomethacin (or the indomethacin
derivative) at which there is 50%
inhibition of COX activity - the lower
the IC
50
is, then the more potent the
drug is
DMSO
dimethyl sulfoxide
14
C-AA
[1-
14
C]-arachidonic acid
HPLC
high performance liquid
chromatography
TLC
thin layer chromatography
mg
milligram
kg
kilogram
mL
milliliter
&mgr;M
micromole/liter
&mgr;L
microliter
N
normal (when used in conjunction
with acid concentrations)
NMR
nuclear magnetic resonance
Et
2
O
diethyl ether
EtOAc
ethyl acetate
Et
3
N
triethyl amine
AcOH
acetic acid
CDCl
3
deuteriated chloroform
rt
room temperature (about 72° F., 22° C.)
BOP-Cl
bis(2-oxo-3-oxazolidinyl)phosphonic
chloride (sold by Aldrich in
Wisconsin), and also see the journal
article, Diago-Meseguer, Palomo-
Coll, Fernandez-Lizarbe, and
Zugaza-Bilbao, “New Reagent for
Activating Carboxyl Groups;
Preparation and Reactions of N,N-
Bis[2-oxo-3-oxazolidinyl]
phosphorodiamidic Chloride”
Synthesis (1980) pp. 547-551
mp
melting point
FBS
fetal bovine serum
DMEM
Dulbecco's modified essential medium
LPS
lipopolysaccharide
PBS
phosphate-buffered saline
IFN-g
interferon gamma
BACKGROUND OF THE INVENTION
As discussed in more detail below, the COX enzyme is really two enzymes, COX-1 and COX-2, which serve different physiological and pathophysiological functions. As is well known, at antiinflammatory and/or analgesic doses, indomethacin, aspirin, and other NSAIDs effect great inhibition of COX-1, which protects the lining of the stomach from acid, along with relatively minimal inhibition of COX-2, which provokes inflammation in response to joint injury or a disease like arthritis. Also, certain NSAIDs possess essentially the same inhibitory activity against both COX-1 and COX-2. Thus, zeroing in on inhibition of COX-2 alone has been the goal of drug developers for several years in order to reduce or eliminate the GI. irritation caused by COX-1 inhibition.
More specifically, as discussed in Smith, Garavito, and DeWitt, “D. L. Prostaglandin Endoperoxide H Synthases (Cyclooxygenases) -1 and -2
”, J. Biol. Chem
., (1996) Vol. 271, pp. 33157-33160, the pertinent step in prostaglandin and thromboxane biosynthesis involves the conversion of arachidonic acid to PGH
2
, which is catalyzed by the sequential action of the COX and PER activities of PGHS, as set out in the following reaction scheme:
That COX activity originates from two distinct and independently regulated enzymes, termed COX-1 and COX-2, is described in DeWitt and Smith, “Primary Structure of Prostaglandin G/H Synthase from Sheep Vesicular Gland Determined from the Complementary DNA Sequence”,
Proc. Natl. Acad. Sci. U.S.A
. (1988) Vol. 85, pp. 1412-1416; Yokoyama and Tanabe, “Cloning of Human Gene Encoding Prostaglandin Endoperoxide Synthase and Primary Structure of the Enzyme”,
Biochem. Biophys. Res. Commun
. (1989) Vol. 165, pp. 888-894; and HIa and Neilson, “Human Cyclooxygenase-2-cDNA”,
Proc. Natl. Acad. Sci. U.S.A
. (1992) Vol. 89, pp. 7384-7388.
COX-1 is the constitutive isoform and is mainly responsible for the synthesis of cytoprotective prostaglandins in the GI tract and for the synthesis of thromboxane, which triggers platelet aggregation in blood platelets. See, Allison, Howatson, Torrence, Lee, and Russell, “Gastrointestinal Damage Associated with the Use of Nonsteroidal Antiinflammatory Drugs”,
N. Engl. J. Med
. (1992) Vol. 327, pp. 749-754.
On the other hand, COX-2 is inducible and short-lived. Its expression is stimulated in response to endotoxins, cytokines, and mitogens. See, Kujubu, Fletcher, Varnum, Lim, and Herschman, “TIS10, A Phorbol Ester Tumor Promoter Inducible mRNA from Swiss 3T3 Cells, Encodes a Novel Prostaglandin Synthase/Cyclooxygenase Homologue”,
J. Biol. Chem
. (1991) Vol. 266, pp. 12866-12872; Lee, Soyoola, Chanmugam, Hart, Sun, Zhong, Liou, Simmons, and Hwang, “Selective Expression of Mitogen-Inducible Cyclooxygenase in Macrophages Stimulated with Lipopolysaccharide”,
J. Biol Chem
. (1992) Vol. 267, pp. 25934-25938; and O'Sullivan, Huggins, Jr., and Mccall, “Lipopolysaccharide-Induced Expression of Prostaglandin H Synthase-2 in Aveolar Macrophages is Inhibited by Dexamethasone by not by Aspirin”,
Biochem. Biophys. Res. Commun
. (1993) Vol.191, pp.1294-1300.
Importantly, COX-2 plays a major role in prostaglandin biosynthesis in inflammatory cells (monocytes/macrophages) and in the central nervous system. See, Masferrer, Zweifel, Manning, Hauser, Leahy, Smith, Isakson, and Seibert, “Selective Inhibition of Inducible Cyclooxygenase-2 in vivo is Antiinflammatory and Nonulcerogenic”,
Proc. Natl. Acad. Sci. U.S.A
. (1994) Vol. 91, pp. 3228-3232; Vane, Mitchell, Appleton, Tomlinson, Bishop-Bailey, Croxtall, and Willoughby, “Inducible Isoforms of Cyclooxygenase and Nitric Oxide Synthase in Inflammation”,
Proc. Natl. Acad. Sci. U.S.A
. (1994) Vol.91, pp. 2046-2050; Harada, Hatanaka, Saito, Majima, Ogino, Kawamura, Ohno, Yang, Katori, and Yamamoto, “Detection of Inducible Prostaglandin H Synthase-2 in Cells in the Exudate of Rat Carrageenin-Induced Pleurisy”,
Biomed. Res
. (1994) Vol. 15, pp. 127-130; Katori, Harada, Hatanaka, Kawamura, Ohno, Aizawa, and Yamamoto, “Induction of Prostaglandin H Synthase-2 in Rat Carrageenin-Induced Pleurisy and Effect of a Selective COX-2 Inhibitor”,
Advances in Prostaglandin, Thromboxane
, and
Leukotriene Research
(1995) Vol. 23, pp. 345-347; and Kennedy, Chan, Culp, and Cromlish, “Cloning and Expression of Rat Prostaglandin Endoperoxide Synthase (Cyclooxygenase-2) cDNA”,
Biochem. Biophys. Res. Commun
. (1994) Vol. 197, pp. 494-500.
Hence, the differential tissue distribution of COX-1 and COX-2 provides a basis for the development of drugs that are selective COX-2 inhibitors (i.e., specificity for inhibition of COX-2 far exceeds inhibition of COX-1) as antiinflammatory, analgesic, and/or antipyretic agents with minimization of or without the GI and hematologic liabilities from COX-1 inhibition that plague most all currently marketed NSAIDs, most of which inhibit both COX-1 and COX-2, with specificity for COX-1 inhibition greatly exceeding that for COX-2 inhibition, although some have essentially similar inhibitory activity against both COX-1 and COX-2. See, for instance, Meade, Smith, and DeWift, “Differential Inhibition of Prostaglandin Indoperoxide Synthase (Cyclooxygenase) Isozymes by Aspirin and Other Non-Steroidal Antiinflammatory Drugs”,
J. Biol. Chem
., (1993) Vol. 268, pp. 6610-6614.
Detailed SAR studies have been reported for two general structural classes of selective COX-2 inhibitors (specificity for COX-2 inhibition far exceeds COX-1 inhibition) including certain acidic sulfonamides and diarylheterocyclics. The in vivo activities of these selective COX-2 inhibitors validate the concept that selective COX-2 inhibition is antiinflammatory and nonulcerogenic, as discussed in the following journal articles. Gans, Galbraith, Roman, Haber, Kerr, Schmidt, Smith, Hewes, and Ackerman, “Anti-Inflammatory and Safety Profile of DuP 697, a Novel Orally Effectiv

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