Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1998-07-01
1999-10-12
Higel, Floyd D.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
5142352, 514253, 514323, 514339, 514414, 514415, 544153, 544373, 546208, 5462784, 548500, 548506, 548510, 548454, C07D20910, C07D40306, C07D40106, C07D41306, A61R 3140
Patent
active
059657456
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
The present invention relates to N-o-tolylsulfonylbenzamide compounds, pharmaceutical compositions comprising such compounds and the use of such compounds as antagonists of leukotriene D4. The compounds of this invention are useful in the treatment of inflammatory diseases.
It is known that arachidonic acid (AA) is metabolized in mammals by two distinct pathways. The metabolism of arachidonic acid by cyclooxygenase enzymes results in the production of prostaglandins and thromboxanes. The other pathway of AA metabolism involves lipoxygenase enzymes and results in the production of a number of oxidative products called leukotrienes. The latter are designated by the LT nomenclature system, and one of the most significant products of the lipoxygenase metabolic pathway is the leukotriene D4. Leukotrienes participate in inflammatory reactions, exhibit chemotactic activities, stimulate lysosomal enzyme release and act as important factors in the immediate hypersensitivity reaction. For example, LTD4 is a potent bronchoconstrictor of the human bronchi.
The biological activity of the leukotrienes indicates that a rational approach to drug therapy to prevent, remove or ameliorate the symptoms of asthma, rheumatoid arthritis, osteoarthritis, bronchitis, chronic obstructive airways disease, psoriasis, allergic rhinitis, atopic dermatitis, shock and other inflammatory diseases must focus on either blocking the release of mediators of these conditions or antagonizing their effects. Thus, compounds which inhibit the biological effects of the leukotrienes are considered to be of value in treating such conditions defined above.
SUMMARY OF THE INVENTION
The present invention relates to a compound of the formula ##STR2## or a pharmaceutically acceptable salt thereof, wherein
R.sup.1 is CHO, CH.sub.2 F, CHF.sub.2 or CONR.sup.3 R.sup.4 wherein R.sup.3 and R.sup.4 are each independently selected from the group consisting of hydrogen, (C.sub.1 -C.sub.6)alkyl, (C.sub.2 -C.sub.5)alkenyl, (C.sub.2 -C.sub.6)alkynyl, (C.sub.6 -C.sub.10)aryl, (C.sub.6 -C.sub.10)aryl(C.sub.1 -C.sub.6)alkyl, ((C.sub.1 -C.sub.6)alkyl).sub.2 amino(C.sub.1 -C.sub.5)alkyl, pyridinyl and CHR.sup.5 R.sup.6 wherein R.sup.5 and R.sup.6 are each independently (C.sub.1 -C.sub.6)alkyl or (C.sub.8 -C.sub.10)aryl;
or R.sup.3 or R.sup.4 may be taken together with the nitrogen to which they are attached to form morpholinyl, pyrrolidinyl or a group of the formula ##STR3## wherein the broken lines represent optional double bonds;
n is 0, 1 or 2;
X, Y and Z are each independently CH, O, S or N; and
R.sup.7 R.sup.8, R.sup.9, R.sup.10 and R.sup.11 are each independently selected from the group consisting or hydrogen, (C.sub.1 -C.sub.6)alkyl, (C.sub.2 -C.sub.6)alkenyl, (C.sub.2 -C.sub.6)alkynyl, (C.sub.8 -C.sub.10)aryl, (C.sub.6 -C.sub.10)aryl(C.sub.1 -C.sub.6)alkyl, ((C.sub.1 -C.sub.6)alkyl).sub.2 amino(C.sub.1 -C.sub.6)alkyl, pyridinyl, CHR.sup.5 R.sup.6 wherein R.sup.5 and R.sup.6 are each independently (C.sub.1 -C.sub.6)alkyl or (C.sub.6 -C.sub.10)aryl; or benzhydryl optionally substituted by one to five halo;
R.sup.2 is a group of the formula ##STR4##
or a group of the formula ##STR5## wherein X is O, NH or CH.sub.2 ; and
R.sup.12 is (C.sub.3 -C.sub.7)cycloalkyl or a group of the formula ##STR6## wherein the broken line represents an optional double bond; n is 0 or 1; m is 0, 1 or 2; p is 0, 1 or 2; Q and R.sup.3 are both CH or both CH.sub.2 ;
with the proviso that when Q and R.sup.3 are both CH, the broken line represents a double bond; and
with the proviso that when n is 1 or 2, only two of the three variables X, Y and Z can be O, S or N.
The term "alkyl", as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight, branched or cyclic moieties or combinations thereof, optionally substituted by 1 to 3 halo.
The term "aryl", as used herein, unless otherwise indicated, includes an organic radical derived from an aromatic hydrocarbon by removal of one hydrogen, such as phenyl or naphthyl,
REFERENCES:
patent: 5280039 (1994-01-01), Eggler
patent: 5399714 (1995-03-01), Gerspacher et al.
Brown et al, J. Med. Chem., vol. 35(13), pp. 2419 to 2439, 1992.
Jacobs et al, J. Med. Chem., vol. 37(9), pp. 1282 to 1297, 1994.
Brown Matthew F.
Marfat Anthony
Ginsburg Paul H.
Higel Floyd D.
Levine Jacob M.
Pfizer Inc
Richardson Peter C.
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