Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-10-15
2002-06-11
Owens, Amelia (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06403814
ABSTRACT:
TECHNICAL FIELD
The present invention relates generally to the field of synthetic organic chemistry, and more particularly relates to a novel method for synthesizing diaryl-substituted heterocyclic compounds useful for treating inflammatory and immune disorders. The invention also pertains to novel chemical compounds useful as intermediates in the presently disclosed synthetic methods.
BACKGROUND
Allergy, asthma, autoimmune disorders and tissue injury are known to induce the release of lipid mediators, leukotrienes generated by the 5-lipoxygenase (“5-LO”) pathway, and platelet activating factor (“PAF”; 1-O-alkyl-2-acetyl-sn-glycerol-3-phosphoryl choline) from leukocytes. Leukotrienes and PAF trigger the major symptoms of inflammatory diseases: bronchoconstriction, cellular infiltration, swelling, congestion and pain. Recent efforts in identifying and developing effective agents to treat inflammatory and immune disorders have led to the synthesis of a family of important compounds, described in detail in U.S. Pat. No. 5,434,151 to Cai et al. Those compounds reduce damage arising from an inflammatory or immune response by acting as receptor antagonists of platelet activating factor by inhibiting the activity of 5-lipoxygenase, or both. As described in detail in the aforementioned patent, the compounds are 2,5-diaryl tetrahydrothiophenes, tetrahydrofurans, and pyrrolidines, 1,3-diaryl cyclopentanes, and 2,4-diaryl tetrahydrothiophenes, tetrahydrofurans and pyrrolidines. An exemplary compound is (±)trans-2-[5-(N′-methyl-N′-hydroxyureidylmethyl)-3-methoxy-4-p-chlorophenylthioethoxy-phenyl]-5-(3,4,5-trimethoxyphenyl)tetrahydrofuran, sometimes referred to herein as “CMI-392” and shown in the following formula:
CMI-392, a compound that, uniquely, is both a 5-LO inhibitor and a PAF receptor antagonist, has proved to be an extremely effective agent for treating inflammatory and immune disorders, as have the other compounds set forth in the Cai et al. patent. The compounds have been found to be particularly useful in treating psoriasis and atopic dermatitis, both chronic inflammatory skin disorders affecting millions of people. A number of pharmaceutical compositions containing these drugs have been proposed and prepared. However, there remains a need for an improved synthetic route to prepare these valuable agents.
Previously, the only known process for synthesizing and purifying CMI-392—as disclosed in U.S. Pat. No. 5,434,151 to Cai et al.—resulted in a waxy, low melting point solid that proved to be difficult to work with and sensitive to heat, light and moisture. In co-pending provisional patent application Ser. No. 09/173903, entitled “Topical Pharmaceutical Formulations Useful to Treat Inflammatory and Immune Disorders,” filed on even date herewith, a method is disclosed for preparing CMI-392 and analogs thereof in a crystalline form that is stable to heat, light and moisture. That method, which involves recrystallization in isopropyl alcohol, optionally combined with n-hexane, is extraordinarily valuable insofar as a variety of different types of pharmaceutical formulations may now be prepared, aqueous vehicles may be used, and far fewer precautions need to be taken with respect to possible exposure to slightly elevated temperatures and light. Nevertheless, there remains a need for an improved synthetic route to CMI-392 and analogs thereof, preferably in crystalline form, which avoids harsh reagents and extreme reaction conditions, and provides the desired product in high yield. The present invention is directed to such a synthesis.
SUMMARY OF THE INVENTION
Accordingly, it is a primary object of the invention to address the above-mentioned need in the art by providing a new method for synthesizing CMI-392 and other diaryl-substituted heterocycles, particularly 2,5-diaryl-substituted tetrahydrofurans and 2,5-diaryl-substituted tetrahydrothiophenes.
It is another object of the invention to provide methods for synthesizing starting materials and intermediates useful for preparing diaryl-substituted heterocycles such as 2,5-diaryl-substituted tetrahydrofurans and tetrahydrothiophenes.
It is still another object of the invention to provide novel compounds useful as starting materials and/or intermediates in the synthesis of diaryl-substituted heterocycles such as 2,5-diaryl-substituted tetrahydrofurans and 2,5-diaryl-substituted tetrahydrothiophenes.
The invention also provides additional methods of synthesis that are useful for preparing diaryl-substituted heterocycles such as 2,5-diaryl-substituted tetrahydrofurans, particularly optically active substituted tetrahydrofurans, such as optically active trans-2-[3-(3-N
1
-butyl-N
1
-hydroxyureidyl)propoxy)-4-propoxy-5-propylsulfonyl phenyl]-5-(3,4,5-trimethoxy phenyl) tetrahydrofuran (sometimes referred to herein as CMI-546), and optically active trans-2-[3-(3-(N
1
-butyl-N
1
-hydroxyureidyl)propoxy)-4-propoxy-5-methylsulfonyl phenyl]-5-(3,4,5-trimethoxy phenyl) tetrahydrofuran (sometimes referred to herein as CMI-568).
Additional objects, advantages and novel features of the invention will be set forth in part in the description which follows, and in part will become apparent to hose skilled in the art upon examination of the following, or may be learned by practice of the invention.
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Chorghade Mukund S.
Gurjar Mukund Keshao
Islam Amin ul
Mhaskar Sunil Vyankatesh
Prasad Anegondi Sreenivasa
Corless Peter F.
Edwards & Angell LLP
Millennium Pharmaceuticals Inc.
Owens Amelia
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