Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1997-08-28
1999-07-27
Spivack, Phyllis G.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514343, 514350, 514354, 514357, 514358, A61K 3144
Patent
active
059290960
DESCRIPTION:
BRIEF SUMMARY
SCOPE OF THE INVENTION
This invention relates to a method for treating atopic dermatitis or contact dermatitis comprising using certain compounds containing a substituted pyridyl group linked to a substituted phenyl group of an alkyl or heteroatom-containing tether.
BACKGROUND OF THE INVENTION
The family of bioactive lipids known as the eicosanoids exert pharmacological effects on cutaneous, respiratory, cardiovascular, and gastrointestinal systems. The leukotrienes are generally divided into two sub-classes, the peptidoleukotrienes (leukotrienes C.sub.4, D.sub.4 and E.sub.4) and the dihydroxyleukotrienes (leukotriene B.sub.4). This invention is primarily concerned with the hydroxyleukotrienes (LTB.sub.4) but is not limited to this specific group of leukotrienes. In fact, the receptor with which LTB.sub.4 interacts appears to also be utilized by a variety of other eicosanoids, including 12-HETE and dihydro 12-HETE. These receptors are either the same or closely-related so that compounds of this invention inhibit the action of several eicosanoids by antagonising this receptor.
These eicosanoids are derived from arachidonic acid and are critically involved in mediating many types of cardiovascular, pulmonary, dermatological, renal, allergic, and inflammatory diseases including asthma, adult respiratory distress syndrome, cystic fibrosis, psoriasis, and inflammatory bowel disease.
By antagonizing the effects of eicosanoids that interact at the LTB.sub.4 receptor, or other pharmacologically active mediators at the end organ, for example airway smooth muscle, the compounds and pharmaceutical compositions of the present invention are valuable in the treatment of diseases in subjects, including human or animals, in which these eicosanoids are a factor.
SUMMARY OF THE INVENTION
This invention relates to a process for treating atopic dermatitis or contact dermatitis in a mammal which process comprises administering to a mammal suffering from either disease a therapeutically effective amount of at least one compound of formula I. ##STR2## or an N-oxide, or a pharmaceutically acceptable salt thereof, where
A is Ch.sub.2 and Z is S(O).sub.q where q is 0, 1 or 2; CHOH; C.dbd.O; or NR.sub.x ; or O; or
A is C.dbd.O and Z is NR.sub.x ;
m is 0-5;
R is C.sub.1 to C.sub.20 -aliphatic, unsubstituted or substituted phenyl C.sub.1 to C.sub.10 -aliphatic where substituted phenyl has one or more radicals selected from the group consisting of lower alkoxy, lower alkyl, trihalomethyl, and halo, or R is C.sub.1 to C.sub.20 -aliphatic-O-, or R is unsubstituted or substituted phenyl C.sub.1 to C.sub.10 -aliphatic-O- where substituted phenyl has one or more radicals selected from the group consisting of lower alkoxy, lower alkyl, trihalomethyl, and halo;
R.sub.1 is --(C.sub.1 to C.sub.5 aliphatic)R.sub.4, --(C.sub.1 to C.sub.5 aliphatic)CHO, --(C.sub.1 to C.sub.5 aliphatic)CH.sub.2 OR.sub.8, --R.sub.4, --CH.sub.2 OH, or CHO;
R.sub.2 is H, halo, lower alkyl, lower alkoxy, --CN, --(CH.sub.2).sub.n R.sub.4, --CH(NH.sub.2)(R.sub.4), or --(CH.sub.2).sub.n R.sub.9 where n is 0-5 and where R.sub.9 is --N(R.sub.7).sub.2 where each R.sub.7 is independently H, or an aliphatic group of 1 to 10 carbon atoms, or acyl of 1-6 carbon atoms, or a cycloalkyl--(CH.sub.2).sub.n -- group of 4 to 10 carbons where n is 0-3, or both R.sub.7 groups from a ring which includes the nitrogen and having 4 to 6 carbons; or
R.sub.3 is hydrogen, lower alkyl, lower alkoxy, halo, --CN, R.sub.4, NHCONH.sub.2, or OH;
each R.sub.4 group is independently --COR.sub.5 where R.sub.5 is --OH, a pharmaceutically acceptable ester-forming group --OR.sub.6, or --OX where X is a pharmaceutically acceptable cation, or R.sub.5 is --N(R.sub.7).sub.2 where each R.sub.7 is independently H, or an aliphatic group of 1 to 10 carbon atoms, or a cycloalkyl--(CH.sub.2).sub.n -- group of 4 to 10 carbons where n is 0-3, or both R.sub.7 groups form a ring having 4 to 6 carbons, or R.sub.4 is a sulfonamide, or an amide, or tetrazol-5-yl; and
R.sub.8 is hydrogen, C.sub.1 to C.sub.6 alkyl, or
REFERENCES:
Journal of Investigative Dermatology, Ruzicka T. et al., Leukotrienes in skin of atopic dermatitis, vol. 82, No. 5 p. 563 dated May 5, 1994 (Abstract).
Allergy, 1900, vol. 45 pp. 457-463, S. Thorsen et al., Leukotriene B.sub.4 in atopic dermatitis: increased skin levels and altered sensitivity of peripheral blood T-cells.
Yamashita et al., "Skin-Lightening Preparations Containing Fusaric Acid And/Or Picolinic Acids", Chemical Abstracts, 113:217815 (1990).
Kanagy James M
Kinzig Charles M.
SmithKline Beecham Corporation
Spivack Phyllis G.
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