Protected forms of a combination of pharmacologically active...

Details Protected forms of a combination of pharmacologically active... Protected forms of a combination of pharmacologically active...

2000-06-02

2001-10-23

Killos, Paul J. (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Ortho-hydroxybenzoic acid or derivative doai

C514S161000, C514S569000, C514S570000, C514S567000, C514S629000, C514S158000

Reexamination Certificate

active

06306842

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to novel conjugated forms of pharmacologically active agents, and methods for the preparation and use thereof In a particular aspect of the invention, methods are provided for treating pathological conditions with a protected form of a combination of pharmacologically active agents, thereby reducing the occurrence of side-effects caused thereby.
BACKGROUND OF THE INVENTION
Despite the advent of modem pharmaceutical technology, many drugs still possess untoward toxicities which often limit the therapeutic potential thereof For example, although non-steroid anti-inflammatory drugs (NSAIDs) are a class of compounds which are widely used for the treatment of inflammation, pain and fever, NSAIDs (e.g., naproxen, aspirin, ibuprofen and ketoprofen) can cause gastrointestinal ulcers, a side-effect that remains the major limitation to the use of NSAIDs (see, for example, J. L. Wallace, in Gastroenterol. 112:1000-1016 (1997); A. H. Soll et al., in Ann Intern Med. 114:307-319 (1991); and J. Bjarason et al., in Gastroenterol. 104:1832-1847 (1993)).
There are two major ulcerogenic effects of NSAIDs: (1) topical irritant effects on the epithelium of the gastrointestinal tract and (2) suppression of gastrointestinal prostaglandin synthesis. In recent years, numerous strategies have been attempted to design and develop new NSAIDs that reduce the damage to the gastrointestinal tract. These efforts, however, have largely been unsuccessful. For example, enteric coating or slow-release formulations designed to reduce the topical irritant properties of NSAIDs have been shown to be ineffective in terms of reducing the incidence of clinically significant side effects, including perforation and bleeding (see, for example, D. Y. Graham et al., in Clin. Pharmacol. Ther. 38:65-70 (1985); and J. L. Carson, et al., in Arch. Intern. Med., 147:1054-1059 (1987)).
It is well recognized that aspirin and other NSAIDs exert their pharmacological effects through the non-selective inhibition of cyclooxygenase (COX) enzymes, thereby blocking prostaglandin synthesis (see, for example, J. R. Van in Nature, 231:232-235 (1971)). There are two types of COX enzymes, namely COX-1 and COX-2. COX-1 is expressed constitutively in many tissues, including the stomach, kidney, and platelets, whereas COX-2 is expressed only at the site of inflammation (see, for example, S. Kargan et al. in Gastroenterol., 111:445-454 (1996)). The prostagladins derived from COX-1 are responsible for many of the physiological effects, including maintenance of gastric mucosal integrity.
Many attempts have been made to develop NSAIDs that only inhibit COX-2, without impacting the activity of COX-1 (see, for example, J. A. Mitchell et al., in Proc. Natl. Acad. Sci. USA 90:11693-11697 (1993); and E. A. Meade et al., in J. Biol. Chem., 268:6610-6614 (1993)). There are several NSAIDs presently on the market (e.g., rofecoxib and celecoxib) that show marked selectivity for COX-2 (see, for example, E. A. Meade, supra.; K. Glaser et al., in Eur. J. Pharmacol. 281:107-111 (1995) and Kaplan-Machlis, B., and Klostermeyer, BS in Ann Pharmacother. 33:979-88, (1999)). These drugs appear to have reduced gastrointestinal toxicity relative to other NSAIDs on the market.
On the basis of encouraging clinical as well as experimental data, the development of highly selective COX-2 inhibitors appears to be a sound strategy to develop a new generation of anti-inflammatory drugs. However, the physiological functions of COX-1 and COX-2 are not always well defined. Thus, there is a possibility that prostagladins produced as a result of COX-1 expression may also contribute to inflammation, pain and fever. On the other hand, prostagladins produced by COX-2 have been shown to play important physiological functions, including the initiation and maintenance of labor and in the regulation of bone resorption (see, for example, D. M. Slater et al., in Am J. Obstet Gynecol., 172:77-82 (1995); and Y. Onoe et al., in J. Immunol. 156:758-764 (1996)), thus inhibition of this pathway may not always be beneficial. Considering these points, highly selective COX-2 inhibitors may produce additional side effects above and beyond those observed with standard NSAIDs, therefore such inhibitors may not be highly desirable.
Indeed, recent studies with first generation COX-2 inhibitors reveal that arthritic patients treated with rofecoxib had a five-fold higher risk of heart attack,compared to patients treated with naproxen (Wale St. Jrnl, 5/1/10). Thus, like aspirin, naproxen appears to exert cardioprotecture effects, while selective COX-2 inhibitors do not.
Accordingly, there is still a need in the art for modified forms of NSAIDs, and other pharmacologically active agents, e.g., selective COX-2 inhibitors, which cause a reduced incidence of side-effects, relative to the incidence of side-effects caused by such pharmacologically active agents in unmodified form.
BRIEF DESCRIPTION OF THE INVENTION
In accordance with the present invention, there are provided conjugates of a combination of pharmacologically active agents (e.g., NSAIDs and selective COX-2 inhibitors). Invention conjugates (e.g., NSAID-COX-2) provide a new class of pharmacologically active agents (e.g., anti-inflammatory agents) which provide the therapeutic benefits of both NSAIDs and selective COX-2 inhibitors, while causing a much lower incidence of side-effects than are typically observed with such agents due to the protective effects imparted by modifying the pharmacologically active agents as described herein.
There are a number of advantages of conjugates according to the invention (e.g., NSAID-COX-2
i
), including:
(i) reduced topical irritant effects of NSAIDs and COX-2 inhibitors, and
(ii) enhanced tissue delivery of both drugs as a result of a decrease in net charges on the molecule, particularly for acidic NSAIDs such as naproxen, aspirin, diclofenac and ibuprofen, thereby reducing the quantity of material which must be delivered to.
In accordance with the present invention, cleavage of the novel bio-cleavable conjugates described herein releases both components thereof as active pharmaceutical agents.
DETAILED DESCRIPTION OF THE INVENTION
In accordance with the present invention, there are provided compounds comprising a conjugate wherein a NSAID is covalently attached to a selective COX-2 inhibitor. Invention compounds have the structure:
X-L-Y
wherein:
X=a non-steroidal anti-inflammatory drug (NSAID),
L=an optional linker/spacer, and
Y=a selective COX-2 inhibitor.
Invention compounds can be readily prepared in a variety of ways, e.g., by direct reaction of NSAIDs with COX-2 inhibitors, or by indirectly linking NSAIDs to COX-2 inhibitors employing a suitable linker/spacer.
The components of invention conjugates are directly or indirectly covalently attached employing a variety of linkages (including an optional linker), e.g., ester linkages, disulfide linkages, amide linkages, immine linkages, enamine linkages, ether linkages, thioether linkages, imide linkages, sulfate ester linkages, sulfonate ester linkages, sulfone linkages, sulfonamide linkages, phosphate ester linkages, carbonate linkages, O-glycosidic linkages, S-glycosidic linkages, and the like. Such linkages can be accomplished using standard synthetic techniques as are well known by those of skill in the art, either by direct reaction of the starting materials, or by incorporating a suitable functional group on the starting material, followed by coupling of the reactants.
When the phanrmacologically active agents contemplated for use herein contain suitable functionality thereon, e.g., hydroxy, amino, carboxy, and the like, invention conjugate can be prepared by direct linkage between the two agents. Alternatively, one or both of the pharmacologically active agents can be functionalized so as to facilitate linkage between the two agents. When present, linker/spacer L has one of the following structures:
-Z-W-,
-W-Z-, or
-W-Z-W-
wherein:
Z is alkylene, substituted alkylene, cycloalkylene,

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