Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-10-15
2004-03-23
Stockton, Laura L. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S118000, C546S273400, C548S302100, C548S304400, C548S309700, C548S306100, C514S338000, C514S394000, C514S393000
Reexamination Certificate
active
06710054
ABSTRACT:
TECHNICAL FIELD
This invention relates to aryl or heteroaryl fused imidazole compounds, or their pharmaceutically acceptable salts, pharmaceutical compositions containing them, and their medical uses. The compounds of this invention have activity as prostaglandin E
2
receptor antagonists, and these are useful in the treatment or alleviation of pain and inflammation and other inflammation-associated disorders, such as arthritis. treating or preventing disorders or medical conditions selected from pain, inflammatory diseases and the like.
BACKGROUND ART
Prostaglandins are mediators of pain, fever and other symptoms associated with inflammation. Especially prostaglandin E
2
(PGE
2
) is the predominant elcosanoid detected in inflammation conditions. In addition, it is also involved in various physiological and/or pathological conditions and such as hyperalgesia, uterine contraction, digestive peristalsis, awakeness, suppression of gastric acidsecretion, blood pressure, platelet function, bone metabolism, angiogenesis or the like.
Four PGE
2
receptor subtypes (EP
1
, EP
2
, EP
3
and EP
4
) displaying different pharmacological properties have been cloned. EP
4
subtype, a Gs-coupled receptor stimulates cAMP production, and is distributed in a wide variety of tissue suggesting major role in PGE
2
-mediated biological events.
WO99/47497 discloses carboxylic acids and acylsulfonamides compounds as prostaglandin-receptor antagonists.
BRIEF DISCLOSURE OF THE INVENTION
The present invention provides a compound of the following formula:
or the pharmaceutically acceptable salts thereof, wherein
Y
1
, Y
2
, Y
3
and Y
4
are independently selected from N, CH or C(L);
R
1
is H, C
1-8
alkyl, C
2-8
alkenyl, C
2-8
alkynyl, C
3-7
cycloalkyl, C
1-8
alkoxy, halo-substituted C
1-8
alkoxy, C
1-8
alkyl-S(O)m-, Q
1
—, pyrrolidinyl, piperidyl, oxopyrrolidinyl, oxopiperidyl, amino, mono- or di-(C
1-8
alkyl)amino, C
1-4
alkyl-C(═O)—N(R
3
)— or C
1-4
alkyl-S(O)m-N(R
3
)—, wherein said C
1-8
alkyl, C
2-8
alkenyl and C
2-8
alkynyl are optionally substituted with halo, C
1-3
alkyl, hydroxy, oxo, C
1-4
alkoxy-, C
1-4
alkyl-S(O)m-, C
3-7
cycloalkyl-, cyano, indanyl, 1,2,3,4-tetrahydronaphtyl, 1,2-dihydronaphtyl, pyrrolidinyl, piperidyl, oxopyrrolidinyl, oxopiperidyl, Q
1
—, Q
1
—C(═O)—, Q
1
—O—, Q
1
—S(O)m-, Q
1
—C
1-4
alkyl-O—, Q
1
—C
1-4
alkyl-S(O)m-, Q
1
—C
1-4
alkyl-C(O)—N(R
3
)—, Q
1
—C
1-4
alkyl-N(R
3
)— or C
1-4
alkyl-C(O)—N(R
3
)—;
Q
1
is a 5-12 membered monocyclic or bicyclic aromatic ring optionally containing up to 4 heteroatoms selected from O, N and S, and is optionally substituted with halo, C
1-4
alkyl, halo-substituted C
1-4
alkyl, hydroxy, C
1-4
alkoxy, halo-substituted C
1-4
alkoxy, C
1-4
alkylthio, nitro, amino, mono- or di-(C
1-4
alkyl)amino, cyano, HO—C
1-4
alkyl, C
1-4
alkoxy-C
1-4
alkyl, C
1-4
alkylsulfonyl, aminosulfonyl, C
1-4
alkyl(═O)—, HO(O═)C—, C
1-4
alkyl-O(O═)C—, R
3
N(R
4
)C(═O)—, C
1-4
alkylsulfonylamino, C
3-7
cycloalkyl, R
3
C(═O)N(R
4
)— or NH
2
(HN═)C—;
A is a 5-6 membered monocyclic aromatic ring optionally containing up to 3 heteroatoms selected from O, N and S, wherein said 5-6 membered monocyclic aromatic ring is optionally substituted with up to 3 substituents selected from halo, C
1-4
alkyl, halo-substituted C
1-4
alkyl, hydroxy, C
1-4
alkoxy, halo-substituted C
1-4
alkoxy, C
1-4
alkylthio, nitro, amino, mono- or di-(C
1-4
alkyl)amino, cyano, HO—C
1-4
alkyl, C
1-4
alkoxy-C
1-4
alkyl, C-
1-4
alkylsulfonyl, aminosulfonyl, acetyl, R
3
N(R
4
)C(═O)—, HO(O═)C—, C
1-4
alkyl-O(O═)C—, C
1-4
alkylsulfonylamino, C
3-7
cycloalkyl, R
3
C(═O)N(R
4
)— and NH
2
(HN═)C—;
B is halo-substituted C
1-6
alkylene, C
3-7
cycloalkylene, C
2-6
alkenylene, C
2-6
alkynylene, —O—C
1-5
alkylene, C
1-2
alkylene-O—C
1-2
alkylene or C
16
alkylene optionally substituted with an oxo group or C
1-3
alkyl;
W is NH, N—C
1-4
alkyl, O, S, N—OR
5
or a covalent bond;
R
2
is H, C
1-4
alkyl, OH or C
1-4
alkoxy;
Z is a 5-12 membered monocyclic or bicyclic aromatic ring optionally containing up to 3 heteroatoms selected from O, N and S, wherein said 5-12 membered monocyclic or bicyclic aromatic ring is optionally substituted with halo, C
1-4
alkyl, halo-substituted C
1-4
alkyl, C
1-4
alkenyl, C
1-4
alkynyl, hydroxy, C
1-4
alkoxy, halo-substituted C
1-4
alkoxy, C
1-4
alkylthio, nitro, amino, mono- or di-(C
1-4
alkyl)amino, cyano, HO—C
1-4
alkyl, C
1-4
alkoxy-C
1-4
alkyl, C
1-4
alkylsulfonyl, aminosulfonyl, C
1-4
alkyl(═O)—, R
3
C(═O)N(R
4
)—, HO(O═)C—, C
1-4
alkyl-O(O═)C—, C
1-4
alkylsulfonylamino, C
3-7
cycloalkyl, NH
2
(HN═)C—, Q
2
—S(O)m-, Q
2
—O—, Q
2
—N(R
3
)— or Q
2
—;
L is halo, C
1-4
alkyl, halo-substituted C
1-4
alkyl, hydroxy, C
1-4
alkoxy, halo-substituted C
1-4
alkoxy, C
1-4
alkylthio, nitro, amino, mono- or di-(C
1-4
alkyl)amino, cyano, HO—C
1-4
alkyl, C
1-4
alkoxy-C
1-4
alkyl, C
1-4
alkylsulfonyl, aminosulfonyl, C
1-4
alkyl(═O)—, HO(O═)C—, C
1-4
alkyl-O(O═)C—, C
1-4
alkylsulfonylamino, C
3-7
cycloalkyl, R
3
C(═O)N(R
4
)—, NH
2
(HN═)C—, R
3
N(R
4
)C(═O)—, R
3
N(R
4
)S(O)m-, Q
2
—, Q
2
—C(═O)—, Q
2
—O—, Q
2
—C
1-4
alkyl-O—, or two adjacent L groups are optionally joined together to form an alkylene chain having 3 or 4 members in which one or two (non-adjacent) carbon atoms are optionally replaced by oxygen atoms;
m is 0, 1 or 2;
R
3
and R
4
are independently selected from H and C
1-4
alkyl
R
5
is H, C
1-4
alkyl, C
1-4
alkyl-(O═)C— or C
1-4
alkyl-O—(O═)C—; and
Q
2
is a 5-12 membered monocyclic or bicyclic aromatic ring, or a 5-12 membered tricyclic ring optionally containing up to 3 heteroatoms selected from O, N and S, wherein said 5-12 membered monocyclic or bicyclic aromatic ring is optionally substituted with halo, C
1-4
alkyl, halo-substituted C
1-4
alkyl, C
1-4
alkenyl, C
1-4
alkynyl, hydroxy, C
1-4
alkoxy, halo-substituted C1
1-4
alkoxy, C
1-4
alkylthio, nitro, amino, mono- or di-(C-
1-4
alkyl)amino, cyano, HO—C
1-4
alkyl, C
1-4
alkoxy-C
1-4
alkyl, C
1-4
alkylsulfonyl, aminosulfonyl, C
1-4
alkyl-(O═)C—, R
3
(R
4
)C(═O)N—, HO(O═)C—, C
1-4
alkyl-O(O═)C—, C
1-4
alkylsulfonylamino, C
3-7
cycloalkyl, C
1-4
alkyl-C(═O)NH— or NH
2
(HN═)C—.
The aryl or heteroaryl fused imidazole compounds of this invention have an antagonistic action towards prostaglandin and are thus useful in therapeutics, particularly for the treatment of a disorder or condition selected from the group consisting of pain, fever or inflammation associated with rheumatic fever, influenza or other viral infections, common cold, low back and neck pain, skeletal pain, post-partum pain, dysmenorrhea, headache, migraine, toothache, sprains and strains, myositis, neuralgia, fibromyalgia, synovitis, arthritis, including rheumatoid arthritis, degenerative joint diseases (osteoarthritis), gout and ankylosing sspondylitis, bursitits, burns including radiation and corrosive chemical injuries, sunburns, pain following surgical and dental procedures or bone fracture, immune and autoimmune diseases such as systemic lupus erythematosus; AIDS(acquired immuno deficiency syndrome), gastrointestinal cancers such as colon cancer ; cellular neoplastic transformations or metastic tumor growth; Diabetic retinopathy, tumor angiogenesis; prostanoid-induced smooth muscle contraction associated with dysmenorrhea, premature labor, allergic rhinitis, atopic dermatitis, asthma or eosinophil related disorders, Hyperimmunoglobulinaemia, Castleman's disease, myeloma; Alzheimer's disease, sleep disorders, endocrine disturbance; glaucoma; bone loss; osteoporosis; promotion of bone formation; Paget's disease: cytoprotection in peptic ulcers, gastritis, regional enteritis, ulcerative colitis, diverticulitis or other gastrointestinal lesions; GI bleeding and patients undergoing chemotherapy; coagulation disorders selected from hypoprothrombinemia, haemophilia and other bleeding problems; kidney
Hashizume Yoshinobu
Kato Tomoki
Kawai Akiyoshi
Matsumizu Miyako
Miyake Yoriko
Pfizer Inc
Stockton Laura L.
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