Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-11-28
2002-07-02
Seaman, D. Margaret (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06413983
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to novel benzopyranyl heterocycle derivatives of the structural formula 1. It also relates to process for preparing the novel compounds and pharmaceutical compositions comprising the compounds as an active ingredient.
The present invention also relates to pharmaceutical use of the benzopyranyl heterocycle derivatives. In particular, the present invention is useful in the prevention, treatment of diseases related to “ischemia-reperfusion” injury such as ischemic heart, brain, neuronal cells and retina, and suppression of lipid peroxidation.
Wherein R
1
, R
2
, R
3
, R
4
, n and * are each defined in specification.
2. Description of the Prior Art
Ischemic heart diseases are usually caused by myocardial ischemia, when the oxygen supply is significantly decreased compared to the oxygen demand due to the imbalance between them [G. J. Grover,
Can. J. Physiol.
75, 309 (1997); G. D. Lopaschuk et al.
Science
&
Medicine
42 (1997)]. Myocardial ischemia triggers various pathophysiological changes progressively that will ultimately lead to irreversible myocardial injury, cell death and tissue necrosis. At a stage where the injury to the cells is reversible, this process can be prevented by early reperfusion of the myocardium. However, there is potential for “reperfusion-injury” to occur [D. J. Hearse,
Medicographia
18, 22 (1996)].
To delay the ischemic cascade and to minimize the reperfusion-injury, the use of adenosine agonists, inhibitors of Na
−
—K
−
antiport, oxygen free radical scavengers and K
ATP
(ATP sensitive potassium channel) openers are investigated as well as ACE (Angiotensin converting enzyme) inhibitors and calcium antagonists. In addition, global ischemia occurs during cardiac surgery or during heart storage prior to transplantation. Recent studies reported that the addition of K
ATP
openers to a hyperkalemic cardioplegic solution, improved the recovery of postischemic contractile function after normothermic or short periods of hypothermic ischemia [D. J. Chambers, D. J. Hearse,
Ann. Thoar. Surg.;
68, 1960 (1999)].
Both global and focal ischemia or hypoxia initiate progressive cellular changes by a reduction of oxygen, which lead to brain injury, cell death, and tissue necrosis [K. Nieber,
Pharmacol. Ther.
82, 71 (1999)]. Even after blood flow is restored, “reperfusion-injury” can be occurred same as in the heart. In order to prevent the brain injury and minimize the alteration of neuronal function, progressive pathophysiological changes arose from ischemia-reperfusion must be prevented. For that purpose, the development of several neuroprotectives such as excitatory amino acid antagonists, anti-oxidants, adenosine agonists and K
ATP
channel openers are being pursued. The use of those compounds as protectants or curatives for the organs related to “ischemia-reperfusion injury” such as retina and skeletal muscles besides heart and brain, is being investigated, too.
Damage or death of neuronal cells is known to be a main reason for various neurological disorders such as stroke, Alzheimer's disease, Parkinson's disease, etc. [G. J. Zoppo et al.,
Drugs
54, 9(1997); I. Sziraki et al.,
Neurosci.
85, 1101 (1998)]. Various factors including increases in iron concentration, reactive oxygen species, and oxidants within neurons are known to initiate neuronal cell damages [M. P. Mattson et al.,
Methods Cell Biol.
46, 187 (1995); Y. Goodman et al.,
Brain Res.
706, 328 (1996)].
An increase of oxygen radicals may induce a lipid peroxidation, and thus their formation results in the accumulation of oxidants in neuronal cell. The oxidants accumulated in cells are known to be responsible for cardiac infarction, dementia, and inflammatory diseases such as arthritis as well as acute and chronic injury of tissues and organs caused by ischemia-reperfusion.
Therefore, therapeutic approaches to minimize neuronal injury by oxidative stress and inhibit lipid peroxidation have been pursued, which may prevent or treat the deseases caused by the damage or death of neuronal cells. To date, anti-oxidants are reported to ameliorate the neuronal damage and death caused by an increase of iron concentration within neurons. Much effort has been continued to develop pharmaceutical drugs which are able to prevent neuronal damage by oxidative stress [Y. Zhang et al.,
J. Cereb. Blood Flow Metab.
13, 378 (1993)]. Diazoxide, a K
ATP
channel opener, has been reported to reversibly oxidize flavoproteins in mitochondria, resulting in inhibition of the formation of oxygen free radicals, which may protect cell injury by oxidative stress [A. A. Starkov,
Biosci, Rep.
17, 273 (1997); V. P. Skulachev,
Q. Rev. Biophus.
29, 169 (1996)]. In addition, there are reports that K
ATP
opening is related to the induction of anti-oxidant enzymes [S. Okubo et al.,
Mol. and cell Biochem,
196, 3 (1999)], and to decrease the release of excitatory amino acid [J-L Moreau, G. Huber,
Brain Res.,
31, 65 (1999)].
K
ATP
is found in a variety of tissues including cardiac muscle, skeletal muscle, pancreatic (&bgr;-cells, and the brain, which makes it attractive as a drug target. However, the same diversity poses a difficulty of finding tissue selective agents. Differently from conventional potassium channel openers, the benzopyranyl indole analogue represented by the following formula 2 and benzopyranyl cyanoguanidine compound (BMS-180448) represented by the following formula 3, have been reported to show modest antiischemic potency with excellent cardiac selectivity. Although the compound represented by formula 2 had all desirable features to serve as a lead compound, the synthesis of it presented a major challenge [K. S. Atwal et al.,
J. Med. Chem.
38, 3236 (1995); K. S. Atwal et al.,
J. Med. Chem.
40, 24 (1996); K. S. Atwal et al.,
Current Pharmaceutical Design,
2, 585 (1996)]. Also, the conventional compounds, which have cardioprotective potency without a significant lowering of blood pressure, still give the prospects for the development of a novel cardioprotectant.
Therefore, by the coupling of benzopyranyl epoxide and heterocyclic amine compounds which have increased nucleophilicity compared to indoleamines, the benzopyranyl heterocycle derivatives represented by the formula 1, having superior cardioprotective activity from ischemia-reperfusion damage, are synthesized in high yields. The compounds also exhibit various pharmaceutical efficacies, including protection of neuronal cells and prevention of lipid peroxidation and thus can be useful in the prevention and treatment of various diseases related to ischemia-reperfusion damage such as protection of heart, neuronal cells, retina, brain injury, and organ preservation for storage, or inhibition of lipid peroxidation.
SUMMARY OF THE INVENTION
One of the objectives of the present invention is to provide novel benzopyranyl heterocycle derivatives of formula 1.
Another objective of the present invention is to provide process for the preparation of the benzopyranyl heterocycle derivatives.
Further objective of the present invention is to provide pharmaceutical use of the benzopyranyl heterocycle derivatives. In particular, the present invention provides the use of the benzopyranyl heterocycle derivatives for the protection of heart, brain, retina from ischemic injury or protection of organ for storage, and suppression of lipid peroxidation.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides benzopyranyl heterocycle derivatives represented by the following formula 1 and their pharmaceutically acceptable salts.
Wherein
n is 0 or 1;
R
1
represents H, NO
2
, or NH
2
;
R
2
represents OH, or O(C═O)R
a
; and R
a
represents H; straight or branched alkyl group of C
1
-C
4
; or aryl group;
R
3
represents H, C(═O)OR
a
, CH
2
OR
a
, or C(═O)NR
a
2
; and R
a
is defined as above;
or R
2
and R
3
are connected to
Cho Insun
Jang Dongsoo
Kim Nak Jeong
Kim Sun-Ok
Lee Byung Ho
Bachman & LaPointe P.C.
Dongbu Hannong Chemical Co. Ltd.
Seaman D. Margaret
LandOfFree
Benzopyranyl heterocycle derivatives, process for... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Benzopyranyl heterocycle derivatives, process for..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Benzopyranyl heterocycle derivatives, process for... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2876699