Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-03-01
2002-04-23
Owens, Amelia (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S414000, C514S450000, C514S464000, C514S465000, C514S466000, C549S305000, C549S362000, C549S366000, C548S454000
Reexamination Certificate
active
06376535
ABSTRACT:
BACKGROUND OF THE INVENTION
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 phosphodiesterase (PDE). Therefore, when PDE is inhibited, the concentrations of these secondary cellular messengers increase. Up to the present, 8 kinds of PDE isozymes have been found, and the isozyme-selective PDE inhibitors are expected to exhibit pharmaceutical effect based on their physiological significance and distribution in vivo [TiPS, 11, 150 (1990), ibid., 12, 19 (1991), and Biochemical & Biophysical Research Communications, 250, 751 (1998)].
It is known that the activation of inflammatory leukocytes can be suppressed by increasing the concentration of the cellular CAMP. The extraordinary 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., 12 (Suppl. II), S61 (1989)].
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'Donell and C. G. A. Persson, 1988, 37, Birkhauser-Verlag). The extraordinary contraction of a respiratory smooth muscle is a main symptom of bronchial asthma. Infiltration of inflammatory-leukocytes such as neutrophils is observed in lesions of organopathy associated with ischemia-reperfusion such as myocardial ischemia. It has been found that the type IV 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.
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, 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 in muscle and fat cells [J. Clin. Invest., 94, 1543 (1994)]. Similarly, it is suggested that the PDE IV inhibitors may be useful for autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, and Crohn's disease because TNF&agr; participates in the onset and progress of these diseases [Nature Medicine, 1, 211 (1995) and ibid., 1, 244 (1995)].
Further, participation of TNF&agr; in the fatigued feeling after dialysis and that of patients suffering from cancer has been also reported [International Journal of Artificial Organs, 21, 83 (1998) and Oncology Nursing Forum, 19, 419 (1992)]. Accordingly, a PDE IV inhibitor can be expected to be effective for improvement in fatigue, malaise, and the like.
It has been reported that a drug which increases cAMP promotes the healing of wounds [The 68th Annual Meeting of Japan Pharmacological Society (in Nagoya), Presentation P3-116 (1995)].
PDE-IV inhibitors exhibit a therapeutic effect to carcinomatous osteopenia model, sciatic nerve excision model and ovariectomic model which are animal models for osteoporosis and their possibility as a therapeutic agent for osteoporosis is suggested [Jpn. J. Pharmacol., 79, 477 (1999)].
Relaxation of ureter has been known to promote the excretion of calculus while a PDE IV inhibitor suppresses the vermicular movement of ureter, and therefore, there is a suggestion for the probability that it is effective for the therapy and/or prevention of urinary calculus [J. Urol., 160, 920 (1998)].
Japanese Published Unexamined Patent Application Nos. 95/242543 and 95/242655 disclose 1,4-benzodioxane derivatives as a therapeutic agent for hepatic diseases. WO 92/10494 discloses 1,4-benzodioxane derivatives having an antagonistic action to serotonin (5HT)
3
receptors.
In U.S. Pat. No. 5,166,367, 1,4-benzodioxane derivatives having an anti-hallucination action are disclosed.
In Japanese Published Unexamined Patent Application No. 88/179868, 1,4-benzodioxane derivatives having a vasodilating action are disclosed.
AU 521225 discloses 1,4-benzodioxane derivatives as intermediates for the synthesis of cinnamoylpiperazine.
WO 98/22455 discloses 1,4-benzodioxane derivatives having PDE IV inhibitory activity.
SUMMARY OF THE INVENTION
The present invention relates to oxygen-containing heterocyclic compounds which have phosphodiesterase (PDE) IV inhibitory activity and which are useful as a therapeutic agent for inflammatory allergic diseases such as bronchial asthma, allergic rhinitis, atopic dermatitis and nephritis; autoimmune diseases such as chronic obstructive pulmonary disease, rheumatism, 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 ischemia-reperfusion caused by cardiac failure, shock and cerebrovascular disease, and the like; insulin-resistant diabetes; wounds; AIDS; osteoporosis; urinary calculus; urinary incontinence and the like; and as a recuperative agent for fatigue, malaise and the like.
DETAILED DESCRIPTION OF THE INVENTION
Novel and useful PDE IV inhibitors are expected to have a preventive or therapeutic effect to diseases of a broad range. An object of the present invention is to provide novel oxygen-containing heterocyclic compounds having a bronchodilating or an anti-inflammatory action due to the presence of a PDE IV-selective inhibiting action so that CAMP concentrations in cells are increased.
The present invention relates to oxygen-containing heterocyclic compounds represented by the following formula (I):
wherein m represents an integer of 0 to 4;
R
1
, R
2
, R
3
and R
4
independently represent a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, polycycloalkyl, substituted or unsubstituted lower alkoxycarbonyl, substituted or unsubstituted lower alkanoyl, substituted or unsubstituted lower alkanoyloxy, cyano, hydroxy, substituted or unsubstituted lower alkoxy, substituted or unsubstituted lower alkenyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, a substituted or unsubstituted aromatic hetecyclic group, substituted or unsubstituted aralkyl, or —CONR
7
R
8
(wherein R
7
and R
8
independently represent a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkanoyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, a substituted or unsubstituted aromatic heterocyclic group or substituted or unsubstituted aralkyl, or R
7
and R
8
are combined to represent a substituted or unsubstituted heterocyclic group together with the adjacent nitrogen atom); two groups present on the same carbon atom among R
1
, R
2
, R
3
and R
4
are combined to represent a saturated Spiro carbon ring together with the said carbon atom; two groups present on the adjacent carbon atoms among R
1
, R
2
, R
3
and R
4
are combined to represent a saturated carbon ring together with the said adjacent two carbon atoms; two groups present on the adjacent carbon atoms among R
1
, R
2
, R
3
and R
4
are combined to represent a single bond (forming a double bond together with the already-existing bond)
R
5
represents hydroxy, or substituted or unsubstituted lower alkoxy;
R
6
represents a hydrogen a
Manabe Haruhiko
Masuda Yoshiaki
Miki Ichiro
Ohshima Etsuo
Yanagawa Koji
Fitzpatrick ,Cella, Harper & Scinto
Kyowa Hakko Kogyo Co. Ltd.
Owens Amelia
LandOfFree
Oxygen-containing heterocyclic compounds does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Oxygen-containing heterocyclic compounds, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Oxygen-containing heterocyclic compounds will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2888210