Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1998-10-06
2001-04-03
Ramsuer, Robert W. (Department: 1613)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S231800, C514S236200, C514S235500, C514S255030
Reexamination Certificate
active
06211175
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to cardiac diseases improving agents containing effective ingredients of aromatic compounds or pharmacologically acceptable salts thereof.
The cardiac diseases improving agents of the present invention exert sufficient improving effects against cardiac diseases despite of substantially null or very weak antagonistic action to type 1 angiotensin II receptor which participates to hypotensive action.
BACKGROUND OF THE INVENTION
Patients with cardiac diseases recently show a rapid increasing tendency. One major cause is a delay of development of definitive drug for the treatment of cardiac diseases in addition to the increasing population of aged persons and changes of living environments. Cardiac diseases such as cardiac failure, cardiac hypertrophy, abnormal heart rate and valvular diseases have been mainly managed with symptomatic treatment of lesions including prevention of cardiac hypertrophy with a hypotensive agent, diet or exercise therapy. Particularly, cardiac diseases often accompanies with hypertension which is suspected to be one of a cause of aggravation, thus, hypotensive agents have been generally used. Among them, inhibitors of production or action of angiotensin II have often been tried because angiotensin II elevates blood pressure and stimulates proliferation of interstitial cells of heart causing aggravation of cardiac diseases. Therefore, elimination of these factors as far as possible is expected to improve the symptoms of cardiac diseases and determinative therapeutic drugs for cardiac diseases have been eagerly awaited.
An agent for inhibiting the enzyme which converts angiotensin I to a pressor angiotensin II, that is angiotensin converting enzyme (ACE) inhibitor (ACEI) such as Enalapril or Captopril® has been used as a hypotensive. These hypotensives are reported to lower blood pressure and improve the progress of renal dysfunction (J. Clin. Pharmacol., 30:155-158, 1990). However, these drugs are pointed out to cause dry cough or adverse reaction of acute renal failure accompanied with hypotensive action and require careful administration [The Saishin-Igaku (Modern Therapy), 48: 1404-1409, 1993].
In addition, an angiotensin II receptor antagonist (AGIIRA) was developed as a hypotensive. Two type 1 and 2 receptors of angiotensin II have been known. The type 1 has been known to participate in blood pressure, however, the action of type 2 has not thoroughly been elucidated, thus, an antagonist of type 1 receptor became a target for the development of hypotensive agent. A hypotensive imidazole derivative having potent antagonistic action to angiotensin II receptor, 2-butyl-4-chloro-5-(hydroxymethyl)-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]imidazole (DuP 753 or MK 954) has been known. Its action on renal diseases has already been investigated.
Furthermore, compounds having similar chemical structure with that of above mentioned imidazole derivative have been disclosed in specifications, for example, Published Japanese Unexamined Patent Application No. 23,868 (1988), and U.S. Pat. Nos. 5,128,355, 5,153,197 and 5,155,118. These compounds are disclosed to be effective to hypertension and congestive heart failure in Published Japanese Unexamined Patent Application No. 23,868 (1988), effective to hypertension in U.S. Pat. No. 5,153,197, effective to cardiac failure in U.S. Pat. No. 5,128,355, and effective in renal failure caused by non-steroidal antiinflammatory drugs (NSAIDs) in U.S. Pat. No. 5,155,118, respectively. However, all these imidazole derivatives have characteristic potent angiotensin II receptor antagonistic action and exhibit hypotensive action.
In addition, compounds having benzene structure are disclosed in, for example, EP058829A2 and EP0475206A2 and their indication to renal diseases are also disclosed. However, these benzene compounds have characteristic features of potent angiotensin II receptor antagonistic action accompanying hypotensive action. Administration of a benzene analogue, 2-[N-propyl-N-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]amino]-pyridine-3-carboxylic acid (A-81988), to rats with renal diseases was reported to show improvement in proteinuria accompanied with hypotension (J. Pharmacol. Exp. Ther., 267: 657-663, 1993). That is, the above mentioned benzene analogues exhibit hypotensive action because of potent type 1 receptor antagonistic action and are likely to lead to acute renal failure by application to patients with renal diseases.
Cardiac failure is a final stage in cardiac diseases with progressive symptoms and very poor prognosis of 50% survival rate within five years. Their treatment is classified in acute and chronic phases.
Treatment in acute phase is mainly composed of countermeasures to sudden failure of cardiac pump function and administration of cardiotonics.
On the other hand, chronic phase treatment is focused to arrest the progress of diseases and improve the quality of life (QOL). Under these situation, administration of cardiotonics in a similar manner to that of acute phase often leads to insufficient therapeutic effect or aggravation of the prognosis. At present, it is clear that angiotensin converting enzyme inhibitors (ACEIs) solely improve the prognosis.
However, some administration of angiotensin converting enzyme inhibitors (ACEIs) caused hypotension as mentioned above and led to adverse reactions such as dry cough and acute renal failure.
Treatment of cardiac diseases with conventional hypotensives basically requires potent hypotensives as far as possible. Though hypertension is an important symptom to be treated in cardiac diseases, not only to lower blood pressure but also to maintain appropriate blood pressure is important. Control of blood pressure by various combination of hypotensives at suitable dosages according to the symptoms are necessary. While cardiac diseases per se is desirably treated continuously with sufficient dosage, blood pressure control and effective treatment of cardiac diseases are essentially incompatible in the treatment with a sole drug. The inventors of the present invention have been investigating to find novel unknown characteristic compounds which exhibit sufficient improvement in renal disturbances and devoid of action on blood pressure, and found novel benzene derivatives with antagonistic action to type 1 receptor of angiotensin II at ratios of 1/100 to 1/1,000 or less to those of typical hypotensives and with sufficient improvement in renal disturbances without substantial antagonistic action [Published Japanese Unexamined Patent Application No. 48,651 (1996) and Japanese Patent Application No. 148,382 (1996)].
The inventors of the present invention further investigated the pharmacological action of these benzene derivatives and found that these compounds not only improve renal failure, but also improve symptoms of cardiac diseases such as cardiac failure, while maintaining moderate blood pressure without lowering blood pressure. The present invention is accomplished on the bases of above mentioned characteristic results.
SUMMARY OF THE INVENTION
Thus, one object of the present invention is to provide novel cardiac disease improving agents which maintain moderate blood pressure without lowering blood pressure and improve cardiac diseases.
The present invention relates to cardiac disease improving agents containing effective ingredients of aromatic compounds shown by the following general formula (I) or pharmacologically acceptable salts thereof.
Chemical formula 3
[General formula (I)]
[wherein, R
1
represents hydrogen atom, an alkyl group having 1-8 carbon atoms, a haloalkyl group having 1-8 carbon atoms, —NH
2
or —NHR
21
; R
2
represents hydroxyl group, —OR
22
, a 3-7 membered saturated aliphatic cyclic amino group optionally interrupted with nitrogen atom, oxygen atom or sulfur atom, a 3-7 membered saturated aliphatic cyclic amino group containing at least one nitrogen atom substituted with an alkyl group havin
Enari Hiroyuki
Ise Michihito
Nishijima Fuyuhiko
Sugano Mikio
Suzuki Shigeru
Kureha Chemical Industry Co. Ltd.
Ramsuer Robert W.
Testa Hurwitz & Thibeault LLP
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