Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1993-08-25
1995-02-28
Ivy, C. Warren
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
540479, 540586, 544158, 544170, 544391, 546133, 546146, 546194, 546245, 546257, 546336, 549 65, 549 66, 549417, 549476, 558 32, 558250, 558252, 558257, 560 9, 560 11, 560 59, 560 61, 560174, 562431, 564162, 568 74, 568 75, 514183, 514217, 5142375, 514255, 514305, 514307, 514317, 514318, 514529, 514530, 514531, 514532, 514534, 514576, 514618, 514445, 514460, 514550, 514570, A61K 3134, C07D30720
Patent
active
053937643
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/US92/03569 filed May 5, 1992.
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to cyclic phenolic thioethers and more particularly relates to the novel compounds of Formula I which are 5-lipoxygenase inhibitors. The compounds of Formula I are useful, for example, as anti-inflammatory and anti-allergy agents and in the treatment of hypersensitivity reactions, psoriasis, asthma, and related disorders and conditions in which physiologically active agents formed in the 5-lipoxygenase metabolic pathway are involved. Compounds of the present invention may be useful in treating arthritis, asthma, and psoriasis. Some compounds of the present invention also stimulate superoxide generation and may be useful as adjunctive therapeutic agents in the treatment of infections. Other compounds of the present invention inhibit superoxide generation and may be useful in the therapeutic or prophylactic treatment of disease conditions which are mediated wholly or partly by superoxide generation such as adult respiratory distress syndrome, superoxide mediated inflammatory or allergic conditions, and other medical conditions which are caused by or aggravated by superoxide.
2. Background Information
It is well recognized that arachidonic acid, an essential unsaturated fatty acid, is enzymatically oxygenated to various products, including, prostaglandins, thromboxanes, the 5-, 11-, 12- and 15-hydroxyeicosatetraenoic acids (HETEs, DIHETEs) and hydroperoxyeicosatetraenoic acids (HPETEs) and the leukotrienes, all of which have potent physiological effects. The leukotrienes, which are produced via the 5-lipoxygenase pathway, are the major contributors to the onset of the symptoms of asthma, and mediators for immediate hypersensitivity reactions, inflammation and other allergic responses.
Leukotrienes are found in inflammatory exudates and are involved in the process of cellular invasion during inflammation. The term "leukotrienes" is used as a generic term to describe a class of substances, such as slow-reacting substance (SRS) which is an important mediator in asthma and other hypersensitivity reactions. Immunologically generated SRS is usually referred to as slow-reacting substance of anaphylaxis (SRS-A). SRS-A consists of leukotrienes (LT) known as A.sub.4, B.sub.4, C.sub.4, D.sub.4, and E.sub.4. LTC.sub.4 is at least 100 times more potent than histamine in causing long lasting bronchoconstricting effects. The leukotrienes also increase vascular permeability and cause decreased cardiac output and impaired ventricular contraction. LTB.sub.4 may be an important mediator of inflammation in, for example, inflammatory bowel disease.
Chemotaxis is a reaction by which the direction of migration of cells is determined by substances in their environment. It is one of the major processes bringing leukocytes from the blood to an inflammatory site, whether the inflammation is caused by an infectious agent, allergic challenge, or other pro-inflammatory stimuli. LTB.sub.4 is not only chemotactic for neutrophils and monocytes, but is also highly active in stimulating eosinophil locomotion. LTB.sub.4 also stimulates calcium influx and aggregation of polymorphonuclear leukocytes and LTB.sub.4 may, thus, play an important role in mediating both acute and chronic inflammation.
Rheumatoid spondylitis is characterized by an acute neutrophil flareup in the joint which is associated with elevated levels of LTB.sub.4. LTB.sub.4 is also present in gouty effusions; and exposure to urate crystals is known to stimulate LTB.sub.4 production by neutrophils. Accordingly, the 5-lipoxygenase inhibitors of the present invention through inhibition of neutrophil attraction and activation in arthritic joints should reduce the protease and oxidative burden believed responsible for joint destruction in arthritic diseases.
Aspirin and the other non-steroidal anti-inflammatory agents (NSAIDs) such as indomethacin, ibuprofen, fenoprofen, and the like, inhibit the synthesis of prostaglandins via the cycl
REFERENCES:
patent: 3574512 (1971-04-01), Weber et al.
patent: 4029812 (1977-06-01), Wagner et al.
patent: 4076841 (1978-02-01), Wagner et al.
patent: 4078084 (1978-03-01), Wagner et al.
patent: 4153803 (1979-05-01), Thiele et al.
patent: 4621098 (1986-11-01), Umminger et al.
patent: 4711903 (1987-12-01), Mueller et al.
patent: 4755524 (1988-07-01), Mueller et al.
patent: 4801611 (1989-01-01), Chinn et al.
patent: 4857558 (1989-08-01), Mueller
patent: 5002967 (1991-03-01), Mueller et al.
patent: 5036105 (1991-07-01), Chinn et al.
patent: 5047593 (1991-09-01), Mueller
patent: 5064860 (1991-11-01), Mueller et al.
patent: 5082854 (1992-01-01), Mueller et al.
patent: 5147893 (1992-09-01), Mueller et al.
patent: 5162365 (1992-11-01), Chinn et al.
patent: 5208262 (1993-05-01), Mueller
patent: 5229421 (1993-07-01), Mueller
Chemical Abstracts, vol. 82, No. 12, Abstract No. 86,190q, p. 506, Mar. 24, 1975.
Chemical Abstracts, vol. 83, No. 5, Abstract No. 43024s, p. 472, 1976.
D. E. Auer, et al. J. Vet. Pharmacol. Therap., 13(1):59-66 (1990).
P. Biermond, et al. Scand. J. Rheumatology, 19:151-156 (1990).
L. Caglioti, et al. "Acid Decomposition of Tosylazocyclohex-1-ene and 3-Tosylazocholesta-3,5-diene", J. Org. Chem., 38(5):920-932 (1973).
M. Cencetti, et al. Clinical Rheumatology, 9(1):51-55 (1990).
C. E. Cross, et al. "Oxygen Radicals and Human Disease", Ann. Int. Med., 107:526-545 (1987).
F. A. Davis, et al. "Chemistry of the Sulfur-Nitrogen Bond. VII..sup.1 Rearrangement of Sulfenimines (S-Aryl Thiooximes) to .beta.-Keto Sulfides. Attempted Synthesis of Benzo[b]thiophenes]", J. Org. Chem., 39(6):807-811 (1974).
Kal'Yan, et al. "Arylthiosulfonium Salts as Transfer Agents of an S-Aryl Group to a Double Bond", Izv. Akad. Mauk SSSR Ser Kim, 2:378-386 (1982).
J. R. Kanofsky Chem. Biol. Interactions, 70:1-28 (1989).
K. Katayama, et al. Agents and Actions, 21(3/4):269-271 (1987).
Ikuo Katsumi, et al. "Studies on Styrene Derivatives. II. Synthesis and Antiinflammatory Activity of 3,5-Di-tertbutyl-4-hydroxystyrenes", Chem. Pharm. Bull., 34(4):1619-1627 (1986).
Kenichi Kanai, et al. "Preparation of Dialkylphenol derivatives as modifiers for biosynthesis of prostaglandins and leukotrienes", Chem. Abs. 107:197783q, 1987.
G. Kocan, et al. Inflammation Research Association, Fifth International Conference Poster Session, Abstract 20, Sep. 23-27 (1990).
W. Kreutner, et al. J. Pharmacol. Exp. Ther., 247(3):997-1003 (1988).
R. Kukreja, et al. "PGH Synthase and Lipoxygenase Generate Superoxide in the Presence of NADH or NADPH", Circulation Research, 59(6):612-619 (1986).
N. E. MacKenzie, et al. "Ring Contractions of Thiochroman-4-ones and Thiochromen-4-ones", J. Chem. Soc. Perkin Trans. 1(2):396-402, 1977.
A. M. Magerramov, et al. "Reactions of Arenesulfenyl Chlorides with Methylenecycloalkanes and Vinylcyclopropane", Zhurnal Organischeskoi Khimii, 26(11): 2333-41 (1990).
A. Medvedev, et al. Khimiya i Khimicheskaya Tekhnologiya, 20:568-574 (1977).
T. Mukaiyama, et al. "Reactions of Mercuric Salts with Bis(diethylthiocarbamoyl) Disulfide and Benzenesfulenyl Chloride", The Journal of Organic Chemistry, 33(6):2242-5 (1968).
A. N. Pushin, et al. "Doping Effect and Acid Catalysis in the Addition of Sulfenyl Chlorides to Cyclohexene in Acetic Acid", Zhurnal Organicheskoi Khimii, 27(7):1473-8 (1991).
V. L. Shepherd "The role of the respiratory burst of phagotytes in host defense", Semin. Respir. Infect. (United States) Jun. 1986, 1(2):99-106.
P. A. Ward, et al. "Oxygen Radicals, Inflammation, and Tissue Injury", Free Radical Biology and Medicine, 5:403-408 (1988).
N. S. Zefirov, et al "A New Method of Increasing the Effective of Electrophilicity of Weak Electrophiles: 1,2-Thiomidation of Alkenes--A New Conjugated Addition Reaction" Zhurnal Organicheskai Khimi, 13(2):245-50 (Feb., 1977).
N. S. Zefirov, et al. "Stereochemiocal Studies-XX: Conformations of 1,2-Trans-Disubstituted Cyclohexanes", Tetrahedron, 32:1211-1219 (1976).
A. M. Tolkach, et al. "Nucleophilic reactions of substituted chl
Mueller Richard A.
Partis Richard A.
Davis Zinna N.
G. D. Searle & Co.
Hastreiter Roberta L.
Ivy C. Warren
Williams Roger A.
LandOfFree
Cyclic phenolic thioethers does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Cyclic phenolic thioethers, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Cyclic phenolic thioethers will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-848675