Organic compounds -- part of the class 532-570 series – Organic compounds – Unsubstituted hydrocarbyl chain between the ring and the -c-...
Reexamination Certificate
1999-09-20
2004-04-06
Raymond, Richard L. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Unsubstituted hydrocarbyl chain between the ring and the -c-...
C544S251000, C544S363000, C544S371000, C548S361100, C548S362500
Reexamination Certificate
active
06716978
ABSTRACT:
FIELD OF THE INVENTION
The present invention is in the field of compositions of matter, and pharmaceutical compositions and methods of treatment utilizing one or more of said compositions of matter as the active ingredient and the active agent with respect thereto, wherein said composition of matter comprises an indazole as an essential feature of its overall chemical structure, said indazole constituting a bioisosteric replacement of a catechol or functional derivative thereof.
The catechol-containing as well as the indazole-based compositions of matter have biological activity as selective inhibitors of phosphodiesterase (PDE) type IV and the production of tumor necrosis factor (TNF), and as such are useful in the treatment of asthma, chronic obstructive pulmonary disease (COPD), psoriasis, allergic rhinitis, dermatitis, Crohn's disease, arthritis, and other inflammatory diseases, AIDS, septic shock and other diseases involving the production of TNF. This invention also relates to a method of using such compounds in the treatment of the foregoing diseases in mammals, especially humans, and to pharmaceutical compositions containing such compounds.
BACKGROUND OF THE INVENTION
Since the recognition that cyclic adenosine phosphate (AMP) is an intracellular second messenger, E. W. Sutherland, and T. W. Rall, Pharmacol. Rev., 12, 265, (1960), inhibition of the phosphodiesterases has been a target for modulation and, accordingly, therapeutic intervention in a range of disease processes. More recently, distinct classes of PDE have been recognized, J. A. Beavo et al., TiPS, 11, 150, (1990), and their selective inhibition has led to improved drug therapy, C. D. Nicholson, M. S. Hahid, TiPS, 12, 19, (1991). More particularly, it has been recognized that inhibition of PDE type IV can lead to inhibition of inflammatory mediator release, M. W. Verghese et al., J. Mol. Cell Cardiol., 12 (Suppl. II), S 61, (1989) and airway smooth muscle relaxation (T. J. Torphy in “Directions for New Anti-Asthma Drugs,” eds S. R. O'Donnell and C. G. A. Persson, 1988, 37 Birkhauser-Verlag). Thus, compounds that inhibit PDE type IV, but which have poor activity against other PDE types, would inhibit the release of inflammatory mediators and relax airway smooth muscle without causing cardiovascular effects or antiplatelet effects.
TNF is recognized to be involved in many infectious and auto-immune diseases, W. Friers, FEBS Letters, 285, 199, (1991). Furthermore, it has been shown that TNF is the prime mediator of the inflammatory response seen in sepsis and septic shock, C. E. Spooner et al., Clinical Immunology and Immunopathology, 62, S11, (1992). The role of these mediators in the pathogenesis of Crohn's disease is discussed in Van Hogezand, R. A. and Verspaget, H. W., Drugs, 56(3), 299-305 (1998).
The present invention is concerned with the discovery that the indazole nucleus is a moiety which is capable of being a bioisostere replacement for the catechol moiety which is an essential part of endogenous ligands acting on phosphodiesterase-4 receptors and thereby carrying out essential metabolic functions in the body. The indazole nucleus is also a bioisostere replacement for the catechol moiety which is an essential part of numerous drugs which have been and in the future will be created and developed for therapeutic treatments as detailed further herein. This bioisostere replacement will be better understood from the following structural representation of the catechol moiety and the indazole moiety which replaces it:
The terms “bioisostere”, “bioisosteric replacement”, “bioisosterism” and closely related terms as used herein have the same meanings as those generally recognized in the art. Bioisosteres are atoms, ions, or molecules in which the peripheral layers of electrons can be considered identical. The term bioisostere is usually used to mean a portion of an overall molecule, as opposed to the entire molecule itself. Bioisosteric replacement involves using one bioisostere to replace another with the expectation of maintaining or slightly modifying the biological activity of the first bioisostere. The bioisosteres in this case are thus atoms or groups of atoms having similar size, shape and electron density. Bioisosterism arises from a reasonable expectation that a proposed bioisosteric replacement will result in maintenance of similar biological properties. Such a reasonable expectation may be based on structural similarity alone. This is especially true in those cases where a number of particulars are known regarding the characteristic domains of the receptor, etc. involved, to which the bioisosteres are bound or which works upon said bioisosteres in some manner.
Phosphodiesterase-4 is a cAMP-specific phosphodiesterase which plays an important role in the regulation of inflammatory and immune cell activation. A significant variety of different structural types of compounds active as PDE-4 inhibitors has been reported, and PDE isozymes have been characterized in cardiac muscle, and airway and arterial smooth muscles. Attention has also been focused on a high-affinity allosteric binding site which is abundant in brain PDE4 isozyme, whose differential modulation relative to the cAMP catalytic site has yielded drugs with greater therapeutic utility. Rolipram, which contains catechol as a key part of its overall chemical structure, is representative of this type of PDE4 inhibitor and may be depicted as follows:
Accordingly, there is disclosed herein a substantial number of indazole-containing compositions of matter which are PDE4 inhibitors and which are the result of a bioisostere replacement of catechol from a compound which originally contained said catechol moiety and which also had PDE4 inhibitor activity. However, there is also disclosed herein a number of catechol-containing compounds which are PDE4 inhibitors and which are also suitable to be subjected to indazole bioisostere replacement in accordance with the present invention. These latter compounds are claimed both as novel indazole compositions of matter and as the products of indazole bioisostere replacement in accordance with the present invention.
SUMMARY OF THE INVENTION
The present invention relates to compounds having therapeutic usefulness based on their activity as phosphodiesterase-4 inhibitors, comprising an indazole as one essential component of their overall chemical structure, wherein said indazole constitutes a bioisosteric replacement of a catechol component or functional derivative thereof in a known compound or compounds having the same said therapeutic usefulness based on possession of phosphodiesterase-4 inhibitor activity, as well as having the same remaining said components which make up the overall chemical structure of the compound(s) involved.
In particular, the present invention relates to the above-described compounds which are therapeutically useful in treating or preventing asthma.
The present invention thus also relates to an improved method of treating asthma using a known compound having a catechol moiety or functional derivative thereof as one essential component of its overall chemical structure; wherein the improvement consists of using a compound having an indazole moiety as one essential component of its overall chemical structure and having the same remaining said components of its overall chemical structure, wherein said indazole moiety constitutes a bioisosteric replacement for said catechol moiety.
The present invention further relates to a compound (a) useful as a therapeutically active agent in a therapeutically effective amount for a method of treating or preventing; and (b) useful as an active ingredient in a pharmaceutical composition for treating or preventing: one or members selected from the groups of diseases and conditions consisting essentially of (1) inflammatory comprising: joint inflammation, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, inflammatory bowel disease, ulcerative colitis, chronic glomerulonephritis, dermatitis, and Crohn's disease; (2) res
Benson Gregg C.
Pfizer Inc
Raymond Richard L.
Richardson Peter C.
Ronau Robert T.
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