Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-03-29
2003-05-13
Fay, Zohreh (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06562837
ABSTRACT:
TECHNICAL FIELD
The present invention relates, in general, to novel pharmaceutical uses of tetrahydroisoquinoline compounds represented by the following chemical formula 1 and 2. More particularly, the compounds of the present invention can be used to therapeutically effective ingredients in pharmaceutical compositions for treating heart failure, thrombosis, septicemia, disseminated intravascular coagulation (hereinafter referred to as “DIC”) and/or tissue injuries mediated by nitric oxide (NO), which is clearly driven from enhancement of inducible NO synthase (hereinafter referred to as “iNOS”) induction:
Tetrahydroisoqunoline (hereinafter referred to as “THI”) compounds are in the ring closing state of N-alkylphenylethylamines. Particularly, the chemical structures of 6,7-dihydroxytetrahydroisoquinolines possess a common backbone of catecholamine. That is, they contain, in their structures, 3,4-dihydroxyphenylethylamine, which is the backbone of catecholamine of which epinephrine, norepinephrine and dopamine are representative. Thus, many THI compounds show affinity for adrenergic receptors. In addition, it is reported that, depending on substituents' kinds and their binding positions, THI compounds act on &agr;- and/or &bgr;-receptors and exert agonistic and/or antagonistic effects, thereby exhibiting various pharmacological activities.
Particularly, THI compounds which have an hydroxy(OH—), methoxy(OCH
3
—), or halogen-substituted benzyl group on the carbon at the 1-position, are reported to show potent activities, such as bronchodilation, inhibitory activity against platelet aggregation, calcium channel blocking action, etc (King, V. F. et al.,
J. Biol. Chem
., 263, 2238-2244, 1988; Triggle, D. J. et al.,
Med. Res. Rev
., 9, 123-180, 1989; Lacorix, P. et al., Eur.
J. Pharmacol
., 192, 317-327, 1991; Chang, K. C. et al.,
Life. Sci
., 51, 64-74, 1992; Chang, K. C. et al., Eur.
J. Pharmacol
., 238, 51-60, 1993).
Recently, bisbenzyl-tetrahydroisoquionoline compounds, such as tetrandrine, isotetrandrine and chondrocurine, have been disclosed to have a potent inhibitory activity against the mass production of NO induced by the endotoxin lipopolysaccharide (hereinafter referred to as “LPS”) (Kondo, Y. et al.,
Biochem. Pharmacol
., 46, 1861-1863, 1993).
Higenamine, a THI compound containing a 4-hydroxybenzyl group at the position-1 and a hydroxy group at each of the positions-6 and -7, is very similar in structure to dobutamine which is clinically used as a cardiotonic agent. Higenamine is found to increase myocardial contractile force and heart rate and inhibit platelet aggregation in vitro experiments using isolated hearts and to show the increasing of cardiac output, hypotensive action, and anti-platelet aggregation in vivo experiments using rats or rabbits. In experiments using peritoneal macrophages of mice and thoracic aorta preparations from rats, higenamine was also reported to inhibit expression of iNOS and NO production by LPS, which accounted for restoration of the depressed vascular reactivity and lower the mortality due to endotoxin (Y. J. Kang et al.,
J.Pharmacol. Exp. Ther
. 291, 314-320, 1999). Further, in an arthritis model, anti-inflammatory and analgesic activity were observed from higenamine (Park, C. W. et al.,
Arch. Int. Pharmacodyn
., 267, 279-288, 1984; Chang, K. C. et al.,
Can. J. Physiol. Pharmacol
., 72, 327-334, 1994; Yun-Choi, H. S. et al.,
Yakhak Hoeju
, 38, 191-196, 1994; Kang, Y. J. et al.,
Kor. J. Physiol. Phamacol
., 1, 297-302, 1997; Shin, K. H. et al.,
Natural Products Sciences
, 2, 24-28, 1996) However, higenamine is disadvantageous in that it shows a drug effect only for a short period of time and the aforementioned pharmacological actions are insufficient.
As a result of the research on the development of higenamine derivatives having superior pharmacological effects, the present inventors succeeded in synthesizing novel compounds of Chemical Formulas 1 and 2, which have a long drug action period of time and show cardiotonic and hypotensive action, as disclosed in Korean Pat. No.148,755. In addition, these novel compounds were also found to have potent action for increasing myocardial contractile force and heart rate in an experiment using isolated rat heart preparations, for dilating the isolated blood vessels which are contracted with phenylephrine, and for increasing heart rate and decreasing blood pressure in an experiment using rabbits, as reported by the present inventors (Lee, Y. S. et al.).
In current use as therapeutics for congestive heart failure are digitalis cardiac glycosides and dopamines. Digitalis cardiac glycosides have an advantage of being suitable for oral administration, but are disadvantageous in that they have so a narrow safety margin that they are dangerous to use and cause arrhythmia. Sympathomimetic drugs, such as dopamine and dobutamine, are effective as therapeutic agents for congestive heart failure, but there are some shorcomings that they must be intravenously infused and their use causes the down regulation of the &bgr;-adrenoceptor.
A good therapeutic effect may be attained in patients suffering from heart failure by co-administration of cardiotonic drugs capable of increasing the lowered myocardial contractile force, and the drugs which can reduce the burden overloaded to the heart through vasodilation or by prevention of thrombogenesis for smooth blood circulation. Thus, because digitalis cardiac glycosides or dopamine have only cardiotonic activity, they can show a good therapeutic effect when being administered along with a vasodilator (hypotensive agent) and a platelet aggregation inhibitor. Such co-administration of various drugs, however, has a problem in that the drugs administered are interacted to affect the adsorption and drug metabolism of each drug in the body, so as to increase the frequency of side effect occurrence.
From various evidences, it has been disclosed that oxygen free radicals excessively generated, including NO, act as one of the major factors causing acute and chronic tissue/organ injury. The above tissue/organ injuries can be exemplified by the tissue injury upon re-perfusion for inflammatory diseases such as arthritis, myocardial infarction, cerebral apoplexy, or ischemic diseases or by the complex organ injury due to endotoxins derived from bacterial infection. Accordingly, much attention has been paid to developing the materials, suppressive of the expression of iNOS or inhibitory of mass production of NO, which can be used for treating various diseases caused by a large quantity of NO. These materials, also are expected to protect the myocardial injury due to, for example, acute cardiac infarction or ischemic cardiac diseases, thereby suppressing the aggravation of heart failure or curing it.
DISCLOSURE OF THE INVENTION
With the above problems in mind, the present inventors found, as, a result of active research, that the compounds of Chemical Formulas 1 and 2 are useful as therapeutic agents for heart failure by virtue of their expressing heart stimulating action, vasodilation (hypotensive action), anti-platelet aggregation and iNOS inhibition at once and in combination as well as a therapeutic agent for the treatment of thrombosis by taking advantage of their inhibitory activity against platelet aggregation and as a therapeutic agent for NO-mediated tissue injury, septicemia, and DIC by virtue of their suppressive activity against iNOS expression and NO synthesis.
Therefore, it is an object of the present invention to provide a therapeutic composition for the prophylaxis and treatment of heart failure, thrombosis, iNOS-induced tissue injury, septicemia, and DIC.
Based on the present invention, the above object could be accomplished by a provision of a pharmaceutical composition comprising, as a pharmacologically effective ingredient, 1-&agr;-naphthylmethyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline and/or 1-&bgr;-naphthylmethyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline, each of them showing heart stimulating activity, hypotensive activity, inhibitor
Chang Ki-Churl
Lee Duck-Hyung
Ryu Jae-Chun
Yun-Choi Hye Sook
Bachman & LaPointe P.C.
Fay Zohreh
Korea Institute of Science & Technology
Kwon Brian
LandOfFree
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