Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-08-30
2001-10-23
Oswecki, Jane C. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S235200, C514S252060, C514S339000, C514S363000, C514S365000, C514S374000, C514S378000, C514S406000, C514S415000, C514S422000, C544S143000, C544S238000, C546S279100, C548S136000, C548S201000, C548S236000, C548S248000, C548S374100, C548S491000, C548S494000, C548S495000
Reexamination Certificate
active
06306890
ABSTRACT:
TECHNICAL FIELD
The present invention, in general, relates to ester derivatives and amide derivatives of various indoles, more specifically, esters and amides derived from N-(4-substituted aroyl)- or N-(4-substituted aryl)-5-alkoxy-2-alkylindole-3-alkanols and N-(4-substituted aroyl)- or N-(4-substituted aryl)-5-alkoxy-2-alkylindole-3-alkyl amines, which resultant esters and amides exhibit inhibition of cyclooxygenase-2 (COX-2) far exceeding inhibition of cyclooxygenase-1 (COX-1), and also, which still exhibit an analgesic, antiinflammatory, and/or antipyretic effect like that of the indole known as indomethacin (an NSAID), in warm blooded vertebrate animals, including humans.
Table of Abbreviations
Abbreviations
Definitions
AcOH
acetic acid
CH
2
Ph
benzyl
C(O)Ph
benzoyl
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
COOH
carboxylic acid moiety
CID
collision-induced dissociation
IC
50
concentration in &mgr;M of indomethacin
(or indomethacin derivative) at which
there is 50% inhibition of COX
activity--the lower IC
50
is, then the
more potent the drug is
COX
cyclooxygenase
CDCl
3
deuteriated chloroform
DCC
dicyclohexylcarbodiimide
Et
2
O
diethyl ether
DIPEA
diisopropylethyl amine
DMF
dimethyl formamide
DMSO
dimethyl sulfoxide
DMEM
Dulbecco's modified essential medium
ESI
electrospray ionization
EtOAc
ethyl acetate
FBS
fetal bovine serum
4-BBBr
4-bromobenzyl bromide
4-CBC
4-chlorobenzoyl chloride
DMAP
4-dimethylamino pyridine
GI
gastrointestinal
HPLC
high performance liquid
chromatography
HOBt
hydroxybenzotriazole
IFN-g
interferon gamma
kg
kilogram
LPS
lipopolysaccharide
LiBH
4
lithium borohydride
mp
melting point
MeOH
methyl alcohol
&mgr;L
microliter
&mgr;M
micromole/liter
mg
milligram
mL
milliliter
NSAID
non-steroidal antiinflammatory drug
N
normal (when used in conjunction
with acid concentrations)
NMR
nuclear magnetic resonance
14
C-AA
[1-
4
C]-arachidonic acid
EDCl
1-(3-dimethylaminopropyl)-3-ethyl
carbodiimide.HCl
(COOH)
2
oxalic acid
PER
peroxidase
Ph
phenyl
PBS
phosphate-buffered saline
PGD
2
prostaglandin D
2
PGE
2
prostaglandin E
2
PGHS
prostaglandin endoperoxide synthase
PGH
2
prostaglandin H
2
rt
room temperature (about 72° F., 22° C.)
SDS PAGE
sodium dodecyl sulfate poly-
acrylamide gel electrophoresis
NaH
sodium hydride
SF-9
spodoptera frugiperda
SAR
structure-activity relationship
BOC
tert-butoxy carbonyl
THF
tetrahydrofuran
TLC
thin layer chromatography
Et
3
N
triethyl amine
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. See, 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. 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 exhibit essentially the same inhibitory activity against both COX-1 and COX-2. The fact that all of the currently marketed NSAIDs inhibit both isozymes to different extents is thought to account for their antiinflammatory activity as well as their GI liabilities. Thus, targeting the inhibition of COX-2 alone has been the goal of drug developers for several years in order to reduce or to eliminate the GI irritation caused by COX-1 inhibition.
More specifically, prostaglandins (particularly prostaglandin E
2
) are important mediators of inflammation and are also involved in a cytoprotective role in the gastric mucosa. These bioactive molecules are biosynthesized by conversion of arachidonic acid to prostaglandin H
2
, which is catalyzed by prostaglandin endoperoxide synthase (PGHS or COX). See, Marnett and Kalgutkar, “Design of Selective Inhibitors of Cyclooxygenase-2 as Nonulcerogenic Antiinflammatory Agents”, Vol. 2
, Curr. Op. Chem. Biol
., pp. 482-490 (1998).
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:
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. On the other hand, COX-2 is inducible and short-lived. Its expression is stimulated in response to endotoxins, cytokines, and mitogens. Importantly, COX-2 plays a major role in prostaglandin biosynthesis in inflammatory cells (monocytes/macrophages) and in the central nervous system.
Hence, the difference in the function of COX-1 and COX-2 provides a goal of separating toxicity from efficacy of NSAIDs by developing 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 DeWitt, “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 (certain acidic sulfonamides and certain diarylheterocyclics) of selective COX-2 inhibitors (specificity for COX-2 inhibition far exceeds COX-1 inhibition). The in vivo activities of these selective COX-2 inhibitors validate the concept that selective COX-2 inhibition is antiinflammatory and nonulcerogenic. Specifically, in vivo efficacy studies with the diarylheterocycle class of selective COX-2 inhibitors have not only validated the hypothesis, but have also resulted in the approval of the first selective COX-2 inhibitor, namely celecoxib (sold under the trade name CELEBREX by Monsanto/Searle) for marketing in the United States.
Although acidic sulfonamides and diarylheterocyclics have been extensively studied as selective COX-2 inhibitors, there are very few reports on converting NSAIDs that are selective COX-1 inhibitors into selective COX-2 inhibitors. However, U.S. Pat. No. 5,681,964 (issued in 1997) to Ashton et al., assignors to the University of Kentucky Research Foundation, shows conversion of indomethacin (an NSAID) into certain ester derivatives with concomitant reduction of GI irritation (see,
FIG. 1
of U.S. Pat. No. 5,681,964 for the structure of the ester derivatives); and U.S. Pat. Nos. 5,607,966 (Parent) (issued in 1997) and 5,811,438 (CIP) (issued in 1998), both to Hellberg et al., assignors to Alcon Laboratories, show conversion of various NSAIDs (such as indomethacin) into certain ester derivatives and amide derivatives (that are useful as antioxidants and inhibitors of 5-lipoxygenase), but do not address selective COX-2 inhibition. Moreover, U.S. Pat. Nos. 5,436,265 (issued in 1995) to Black et al. and 5,510,368 (issued in 1996) to Lau et al., both patents assigned to Merck Frosst Canada
Kalgutkar Amit S.
Marnett Lawrence J.
Jenkins & Wilson, P.A.
Oswecki Jane C.
Vanderbilt University
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