Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1997-11-19
2003-02-04
Qazi, Sabiha (Department: 1616)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S337000, C514S465000, C514S231200, C514S231500, C514S232200, C514S232500, C514S252120, C514S252130, C514S449000, C514S461000, C514S462000, C514S464000, C514S278000, C514S277000, C514S320000, C514S319000, C546S271400, C546S271700, C546S281700, C546S283400, C546S268100, C546S284100, C546S282100, C546S184000, C546S190000, C549S345000, C549S462000, C549S466000, C549S467000, C549S429000, C549S456000, C548S517000, C548S525000, C544S106000, C544S162000, C544S358000, C544S359000, C544S374000, C544S375000, C544S
Reexamination Certificate
active
06514996
ABSTRACT:
TECHNICAL FIELD
The present invention relates to oxygen-containing heterocyclic compounds which exhibit phosphodiesterase (PDE) IV inhibitory activity and which are useful as therapeutic agents for inflammatory allergic diseases such as bronchial asthma, allergic rhinitis, and nephritis; autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, Crohn's disease, psoriasis, and systemic lupus erythematosus; diseases of the central nervous system such as depression, amnesia, and dementia; organopathy associated with ischemic reflux caused by cardiac failure, shock, and cerebrovascular diseases, and the like; insulin-resistant diabetes; wounds; AIDS, and the like.
BACKGROUND ART
Heretofore, it is known that the functions of numerous hormones and neurotransmitters are expressed by an increase in the concentration of adenosine 3′,5′-cyclic monophosphate (cAMP) or guanosine 3′,5′-cyclic monophosphate (cGMP), both of which are the secondary messengers in cells. The cellular concentrations of cAMP and cGMP are controlled by the generation and decomposition thereof, and their decomposition is carried out by PDE. Therefore, when PDE is inhibited, the concentrations of these secondary cellular messengers increase. Up to the present, 7 kinds of PDE isozymes have been found, and the isozyme-selective PDE inhibitors are expected to exhibit pharmacological effect based on their physiological significance and distribution in vivo (TiPS, 1990, 11, 150, TIPS, 1991, 12, 19).
It is known that the activation of inflammatory leukocytes can be suppressed by increasing the concentration of the cellular cAMP. The activation of leukocytes causes secretion of inflammatory cytokines such as tumor necrosis factor (TNF), and expression of the cellular adhesion molecules such as intercellular adhesion molecules (ICAM), followed by cellular infiltration [J. Mol. Cell. Cardiol., 1989, 12, (Suppl. II), S61].
It is known that the contraction of a respiratory smooth muscle can be suppressed by increasing the concentration of the cellular cAMP (T. J. Torphy in Directions for New Anti-Asthma Drugs, eds S. R. O'Donelland C. G. A. Persson, 1988, 37, Birkhauser-Verlag) . The contraction of a respiratory smooth muscle is a main symptom of bronchial asthma. Inflammatory-leukocyte infiltration of neutrophils and the like is observed in lesions of organopathy associated with ischemic reflux such as myocardial ischemia. It has been found that the IV type PDE (PDE IV) mainly participates in the decomposition of cAMP in these inflammatory cells and tracheal smooth muscle cells. Therefore, the inhibitors selective for PDE IV are expected to have therapeutic and/or preventive effect on inflammatory diseases, respiratory obstructive diseases, and ischemic diseases.
Further, the PDE IV inhibitors are expected to prevent the progress and spread of the inflammatory reaction transmitted by inflammatory cytokines such as TNF&agr; and interleukin (IL)-8&agr;, because the PDE IV inhibitors suppress the secretion of these cytokines by increasing the concentration of cAMP. For example, TNF&agr; is reported to be a factor of insulin-resistant diabetes because it declines the phosphorylating mechanism of insulin receptors of muscle and fat cells (J. Clin. Invest., 1994, 94, 1543-1549). Similarly, it is suggested that TNF&agr; participates in the onset and progress of autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, and Crohn's disease, and that the PDE IV inhibitors are useful for these diseases (Nature Medicine, 1995, 1, 211-214 and 244-248).
Drugs which increase cAMP are reported to enhance the healing of wounds [Nippon Yakuri-gakkai, the 68th annual meeting (Nagoya), P3-116, 1995].
PDE IV-selective inhibitors having catechol structures are disclosed in WO96-00218, WO96-00215, WO95-35285, WO95-35284, WO95-35283, WO95-35281, WO95-28926, WO95-27692, WO95-24381, WO95-22520, WO95-20578, WO95-17399, WO95-17392, WO95-14681, WO95-14680, WO95-14667, WO95-09837, WO95-09836, WO95-09627, WO95-09624, WO95-09623, WO95-08534, WO95-04046, WO95-04045, WO95-03794, WO95-01338, WO95-00516, WO95-00139, U.S. Pat. No. 5,461,056, EP0685479, EP0685475, EP0685474, EP0671389, WO93-25517, WO94-25437, EP623607, WO94-20446, WO94-20455, WO94-14800, WO94-14742, WO94-12461, WO94-10118, WO94-02465, WO93-19751, WO93-19750, WO93-19749, WO93-19748, WO93-19747, WO93-18024, WO93-15048, WO93-07141, Japanese Published Unexamined Patent Application No. 117239/93, WO92-19594, and EP497564.
Further compounds which have a benzofuran structure and PDE IV-inhibitory activity are reported (Bioorganic Med. Chem. Lett., 1994, 14, 1855-1860, EP685479, WO96-03399).
Heretofore, benzofuran derivatives are industrially useful and are disclosed in patents of intermediates of product materials, light emitting elements, agricultural chemicals, anthelminthics, drugs, and the like.
Benzofuran, benzopyran, and benzodioxole derivatives which have a carboxyl group or a tetrazolyl group are disclosed in J. Med. Chem., 1988, 31, 84-91, and Japanese Published Unexamined Patent Application Nos. 50977/86, 126061/86, 143371/86, and 230760/87, and are described to exhibit leukotriene antagonism, phospholipase inhibitory activity, 5&agr; reductase inhibitory activity, aldose-reductase inhibitory activity, and the like.
WO92-01681 and WO92-12144 disclose benzofuran and benzopyran derivatives which exhibit acyl-CoA acetyltransferase (ACAT) inhibitory activity.
WO93-01169 discloses benzofuran derivatives which exhibit tachykinin antagonism.
EP307172 and U.S. Pat. No. 4,910,193 disclose benzofuran derivatives which exhibit antagonistic activity against serotonin (5HT)
3
receptors.
DISCLOSURE OF THE INVENTION
The present invention relates to oxygen-containing heterocyclic compounds represented by following Formula (I):
wherein R
1
and R
2
independently represent hydrogen, substituted or unsubstituted lower alkyl, cycloalkyl, polycycloalkyl, lower alkenyl, cycloalkenyl, substituted or unsubstituted aryl, a substituted or unsubstituted aromatic heterocyclic group, aralkyl, cyano, or —(CH
2
)
n
—E
1
—CO—G
1
[wherein E
1
represents a bond, O, or NH; and G
1
represents hydrogen, substituted or unsubstituted lower alkyl, cycloalkyl, polycycloalkyl, substituted or unsubstituted aryl, a substituted or unsubstituted aromatic heterocyclic group, aralkyl, OR
6
(wherein R
6
represents hydrogen, lower alkyl, cycloalkyl, polycycloalkyl, substituted or unsubstituted aryl, a substituted or unsubstituted aromatic heterocyclic group, or aralkyl), or NR
7
R
8
(wherein R
7
represents hydrogen, substituted or unsubstituted lower alkyl, cycloalkyl, polycycloalkyl, substituted or unsubstituted aryl, a substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted aralkyl, or substituted or unsubstituted heteroarylalkyl; and R
8
represents substituted or unsubstituted lower alkyl, cycloalkyl, polycycloalkyl, substituted or unsubstituted aryl, a substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted aralkyl, or substituted or unsubstituted heteroarylalkyl; or R
7
and R
8
are combined to represent a substituted or unsubstituted heterocyclic group containing at least one nitrogen atom); and n represents an integer of 0 to 4]; R
1
and R
2
are combined to represent a saturated carbon ring together with a carbon atomadjacent thereto; or R
2
, and R
11
or R
13
described below are combined to form a single bond; R
3
represents hydrogen, phenyl, or halogen; R
4
represents hydroxy or substituted or unsubstituted lower alkoxy; A represents —C(R
9
)(R
10
)— (wherein R
9
and R
10
independently represent hydrogen, substituted or unsubstituted lower alkyl, cycloalkyl, or polycycloalkyl) or O; B represents O, NR
11
[wherein R
11
represents hydrogen, lower alkyl, cycloalkyl, polycycloalkyl, lower alkenyl, cycloalkenyl, substituted or unsubstituted aryl, a substituted or unsubstituted aromatic heterocyclic group, aralkyl, or —(CH
2
)
m
—E
2
—CO—G
2
(wherein E
2
, G
Ichimura Michio
Iida Kyoichiro
Ishii Hidee
Kawakita Takashi
Koike Rie
Fitzpatrick ,Cella, Harper & Scinto
Kyowa Hakko Kogyo Co. Ltd.
Phoenix B.
Qazi Sabiha
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