Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-10-20
2001-11-27
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...
C514S449000, C514S450000, C514S452000, C514S463000, C514S475000, C549S347000, C549S370000, C549S399000, C549S404000, C549S448000, C549S510000, C549S511000
Reexamination Certificate
active
06323238
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to novel benzopyranyl guanidine derivatives of formula 1. IL also relates to process for preparing the novel compounds and pharmaceutical formulations comprising one or more of the compounds as an active ingredient.
The present invention also relates to pharmaceutical use of the benzopyranyl guanidine derivatives. In particular, the present invention is pharmacologically useful in the protection of heart, neurconsonal cell or brain injury, or preserving organs, and also pharmacologically useful for inhibition of NO generation, lipid peroxidation, angiogenesis or restenosis.
Wherein R
1
, R
2
, R
3
, R
4
, R
5
, R
6
, n and * are each defined in specification.
2. Description of the Prior Art
Ischemic heart diseases usually occur as a result of myocardial ischemia, when the oxygen supply is significantly decreased compared to the oxygen demand due to the imbalance between them. In most cases, a coronary artery disorder was found to be a main reason of the ischemic heart diseases. If the inner diameter of coronary artery becomes narrow, the blood supply, resulting in oxygen supply, becomes insufficient, which can cause angina pectoris, myocardial infarction, acute cardioplegia, arrhythmia, and so on (G. J. Grover,
Can. J. Physiol.
75, 309 (1997); G. D. Lopaschuk et al.,
Science
&
Medicine
42 (1997)). Because ischemic heart diseases are also caused by other complex factors besides coronary artery disorders, drug therapy as well as operational method such as perculaneous transluminal coronary angioplasty (PTCA) is required for its treatment. For that purpose, several drugs are being used, including anti-thrombotic agents, arteriosclerosis curatives, especially by beta blockers, nitrate, calcium antagonists such as nifedipin, thromobolytics, aspirin, and angiotensin converting enzyme (ACE) inhibitors.
Differently from conventional potassium channel openers, the pyranyl guanidine compound (BMS-180448) represented by the following formula 2, has been reported to act selectively on ATP-sensitive potassium channels (K
ATP
) located in the heart (K. S. Atwal et al. ,
J. Mde. Chem.
36, 3971 (1993); K. S. Atwal et al.,
J. Me. Chem.
38, 1966 (1995)). The BMS 180448 compound was found to protect ischemic hearts without a significant lowering of blood pressure, which gives the prospects for novel drug development as a cardionprotectant.
Both global and focal ischemia initiate progressive cellular changes, which lead to ischemic brain injury (M. D. Ginsburg,
Neuros Scientist
1, 95 (1995)). Even after blood flow is restored, oxygen can enhance the biochemical reactions that generate free radicals, which can lead to a potential for “reperconsfusion injury” to occur. In order to prevent the brain injury caused by ischemia-reperfusion, the brain must be protected during ischemic period to avoid additional injury and pathological progressive cellular to changes have to be minimized. For that purpose, neuroproteconstives such as excitatory amino acid antagonists and anti-oxidants are being used.
Damage or death of neurons is known to be a main cause for various neurological disorders such as stroke, head trauma, Alzheimer's disease, Parkinson's disease, infant asphyxia, glaucoma and daiabetic neuropathy, etc. (G. J. Zoppo et al.,
Drugs
54, 9(1997); I. Sziraki et al.,
Neurosci.
85, 110(1998)). Neurons are damaged by various consfactors and typically by increase in iron concentration, reactive oxygen species, and peroconsxidants within neurons (M. P. Mattson et al. ,
Methods Cell Biol.
46, 187 (1995); Y. Goodman et al.,
Brain Res.
706, 328 (1996)).
An increase of iron concentration in neuronal cells induces the formation of highly reactive hydroxyl radicals. An excess of oxygen free radicals facilitates lipid peroxidation, so that peroxidants are accumulated in neurons. The reactive free radicals accumulated in cells are known o be responsible for inflammatory diseases such as arthritis; atherosclerosis; cardiac infarction; and neurodegenerative disease such as dementia as well as acute and chronic injury of tissues and organs caused by ischemia-reperfusion or by endotoxins via bacterial infection.
Therefore, therapeutic approaches to minimize the damage or death of neurons have been pursued, including the inhibition of lipid peroxidation, NO formation, and reactive oxygen species induced by endotoxins. 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)).
Infant asphyxia (IA), triggered by transient deficiency of oxygen supply during delivery, was reported to be caused by the reduction of energy production, damage of cell membrane due to oxygen free radical, release of excitatory neurotransmitters, change of intracellular ion concentrations including calcium, zinc, etc. IA is a major worldwide problem, because if IA is severe, the chances of mortality are high (around ⅓ of the cases) [C. F. Loid et. al.
Physiology and Behavior
68; 263-269 (2000)]. In addition, it can produce long term sequela such as movement disorders, learning disabilities, epilepsy, dystonia, mental retardation, and spasticity.
Antioxidant enzymes, allopurinol, Vitamine C & E, free radical scavengers, inhibitors of excitatory neurotransmitters, calcium channel blockers such as nimodipinconsa and flunarizine, inhibitors of NO formation, hyperglycemic and hypothermic therapy may be beneficial for the protection of brain injury, but their clinical application is still limited. Thus more intensive research is required to treat infant asphyxia properly.
Glaucoma, one of the leading causes of blindness, is defined as an optic neuropathy associated with characteristic changes in optic nerve. In humans, the optic nerve consists of 1 million axons from neurons whose perikarya reside primarily in the ganglion cell layer and, to a less extent, in the inner part of the inner nuclear layer. The excavated appearance of the optic nerve head in glaucoma is thought to be caused by the death and subsequent loss of ganglion cells and their axons [N. N. Osborne, et.
Al. Survey of Ophthalmology,
43; suppl. S102-s128 (1999)]. Neuroprotective agents in glaucoma may protect death of retinal neurons, in particular the ganglion cells, either directly or indirectly. A variety agents such as NMDA receptor antagonist, &bgr;-blockers, calcium antagonists, and antioxidants can be used to protect the death of retinal neurons induced by ischemia.
Although the pathogenesis of diabetic neuropathy has not been clearly established, two main hypotheses have been proposed for it. One is metabolic abnormalities, and the other is blood flow deficits in peripheral nerve [K. Naka et.
Al. Diabetes Research and Clinical Practice,
30: 153-162 (1995)]. Acetyl-L-carnitine (ALC) by stimulating metabolism of lipid and improving impaired nociceptive responses of neurons, and Prosaptide by releasing neutrophic factors are in clinical trials. In addition, memantime showing good effects on vascular dementia through the regulation of NMDA receptor, is pursuing clinical trial. Then, neuroprotective agents having a variety of mechanisms of action may be developed to treat diabetic neuropathy.
The ratio of cancer in human diseases is being gradually increased. Angiogenesis, formation of new blood vessels, is recognized as the core process for growth and metastasis of solid tumors (Folkma, J. et al.,
J. Biol. Chem.
267: 10931-10934 (1992)). Angiogenesis is controlled by inducers and inhibitors of angiogenesis. When the balance between them is broken, that is, when angiogenesis inducers prevail over angiogenesis inhibitors, a large quantity of new blood vessels are formed. Angiogenesis is closely related to various physiological phenomena, such as embryonic de
Cho In Sun
Hwang Sun Kyung
Jang Dongsoo
Kim Nak-Jeong
Kim Sun-Ok
Bachman & LaPointe P.C.
Dongbu Hannong Chemical Co. Ltd.
Owens Amelia
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