Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-09-30
2001-05-01
Kifle, Bruck (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S220000, C514S234800, C514S250000, C514S411000, C540S460000, C540S469000, C540S479000, C540S496000, C540S545000, C540S561000
Reexamination Certificate
active
06225306
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a biphenyl derivative and pharmaceutically acceptable salts thereof as well as a drug composition comprising the same. More particularly, the present invention relates to a biphenyl derivative comprising a biphenyl group that carries a carbonylphenyl-carbamoyl group, which is further bonded to a tricyclic hetero ring and pharmaceutically acceptable salts thereof as well as a drug composition containing the same, in particular, a drug composition serving as a vasopressin receptor antagonist.
BACKGROUND ART
Vasopressin is a neuroendocrine hormone secreted from the posthypophysis and, in the periphery, plays a role of maintaining the circulatory kinetics and the body fluid homeostasis mainly by the strong vasoconstricting effect through the V1 receptor and the water resorption-promoting effect in the renal collecting tubule through the V2 receptor. In addition, vasopressin possesses various physiological effects such as an effect of promoting glycogenolysis in liver, an effect of promoting the adrenocoiticotropic hormone (ACTH)-secretion from the prehypophysis or an effect of promoting the platelet agglutination.
The excess secretion of vasopressin having such effects causes various pathemas such as conjestive heart failure Pharmacological Reviews, 1991, 43:73-108), brain edema (Stroke, 1992, 23:1767-1773), arginine-vasopressin polyrrhea syndrome (Journal of Cardiovascular Pharmacology, 1986, 8:S36-S43), hepatociurhosis (Ann. Intermn Med., 1982, 96:413-417) and hypertension. Therefore, if an excellent vasopressin antagonist is developed, such antagonist may be useful as a remedy and/or a prophylactic for these diseases caused due to the excess secretion of vasopressin, for instance, heart failure, edema such as brain edema, hydroperitoneum, pneumochysis, arginine-vasopressin polyrrhea syndrome, renal failure, pancreatitis, hypertension, hepatocirrhosis, hyponatremia, hypokalemia, diabetes, circulatory disorders, Meniere's syndrome and oxytocin-related diseases; and diuretics (IGAKU NO AYUMI, 1991, 157:166). Up to now, there have been developed a variety of vasopressin-receptor antagonists for the purpose of preventing or treating vasopressin-related diseases.
In particular, the non-peptide type compound can orally be administered unlike the peptide type one. Therefore, the former would be expected to have clinical usefulness and there have been proposed various such compounds in, for instance, Japanese Un-examined Patent Publication (hereunder referred to as “J.P. KOKAI”) Nos. Hei 7-2800, Hei 4-321669, Hei 4-154765, Hei 6-172317, Hei 5-132466, Hei 5-320135, Hei 6-157480, Hei 6-211800, Hei 6-16643, Hei 7-157486 and Hei 7-179430; and Published International Patent Application (hereunder referred to as “P.I.A.”) Nos. WO95/03305, WO94/12476, WO94/14796 and WO94/20473. Such technical background has been disclosed in P.I.A. No. WO97/17349.
Moreover, edema is a pathema in which the extracellular fluid is excessively accumulated in external parts of blood vessels. The causes for the crisis thereof can roughly be divided into two groups, i.e., the insufficient excretion of the extracellular fluid in the exterior of the blood vessel and the excess exudation of the extracellular fluid from blood vessels. Large amounts of the fluid in the thoracic cavity or ascites would impair systemic hemodynamics (circulatory kinetics), for instance, decreases in cardiac output, the flow rate of blood in liver, and the flow rate of blood in kidney. In addition, the disease often makes it difficult for the patients suffering from the same, to take a diet due to respiratory difficulty and/or abdominal inflation. There have thus been used diuretics for relieving and treating edema.
The so-called loop diuretics presently widely used such as Furosemide (Lasix (registered trademark)) are electrolyte-discharge type diuretics which can inhibit the resorption of water and electrolytes in the renal tubules. However, such electrolyte-discharge type diuretics suffer from a problem in that they would essentially break the electrolyte balance in the living body (Aifred Goodman Gilman et al., Goodman and Gilman's The Pharmacological Basis of Therapeutics, 8
th
edition, pp.721-731, 1990) and therefore, there has recently been tried to develop so-called aquaresis which permit the selective excretion of only water.
The drugs possessing vasopressin receptor antagonism have attracted special interest recently, as drugs having aquaresis (Yamamura Yoshitaka et al., Br. J. Pharmacol., 1992, 105:787). In particular, there have been conducted various studies to develop vasopressin V2 receptor antagonists.
J.P. KOKAI No. Hei 7-2800 discloses certain benzamide derivatives, which possess vasopressin-receptor antagonism and are thus useful as medicines, in particular, vasodilators, aquaresis or the like. In these compounds, however, the hetero ring bonded to the carbonylphenyl carbamoyl group is not a tricyclic hetero ring.
P.I.A- No. WO95/03305 discloses that a fused benzazepine derivative characterized in that it has a chemical structure carrying a tricyclic heterocyclic benzazepine has vasopressin receptor antagonism and is effective as a medicine. This compound is recognized to have stronger and longer-lasting vasopressin V2 receptor antagonism as compared with OPC-31260 (P.I.A. No. WO91/05549) which is a vasopressin receptor antagonist presently in course of development. The compound has a chemical structure carrying a carbonylphenyl carbamoyl group, but the tricyclic hetero ring linked thereto is a benzazepine.
J.P. KOKAI No. 7-157486 discloses that a compound having a tricyclic diazepin ring possesses vasopressin receptor antagonism. However, this compound never has a biphenyl group.
Thus, the development of medicines possessing aquaresis has been made progress. Edema does not appear until pathema such as cancers from which many patients suffer, congestive heart failure, nephrotic syndromes and hepatocirrhosis are advanced to some extent. Since the patients suffering therefrom feel severe pains, there have intensively been desired for the development of novel compounds which have almost no side effect, highly efficient aquaresis, in particular, vasopressin receptor antagonism and are very useful, among clinicians.
SUMMARY OF THE INVENTION
Under such circumstances, it is an object of the present invention to provide a drug composition, in particular, compounds useful as vasopressin receptor antagonists, which are completely different in the structure and effects from the diuretics presently employed, which have structure quite different from those of the compounds recently discovered and having vasopressin receptor antagonism, and which are highly efficient and have very high safety and efficiency.
The inventors of this invention have conducted various studies, have found that the compounds represented by the following general formula (1) permit the achievement of the foregoing object of the present invention and thus have completed the present invention. More specifically, the compounds of the present invention are biphenyl derivatives represented by the following general formula (1) and pharmaceutically acceptable salts thereof:
[in the formula, A represents a single bond, —CH
2
—,—CO—, —CS— or —SO
2
—; B represents a single bond or a group —CH
2
—; R
1
represents a hydrogen atom, —OH, —NR
11
R
12
(wherein R
11
and R
12
each independently represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms), —OCOCH
3
, or a halogen atom; R
2
represents a hydrogen atom or R
1
and R
2
represent ═O, in combination; R
3
represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms; provided that the absolute configuration at the position a may be either S or R.]
REFERENCES:
patent: 5521173 (1996-05-01), Venkatesan et al.
patent: 5536718 (1996-07-01), Albright et al.
patent: 5700796 (1997-12-01), Albright et al.
patent: WO 97/49707 (1997-12-01), None
Patent Abstracts of Japan, vol. 1996, No. 07, Jul. 31, 1996, JP 08 081460, Mar. 26,
Matsukawa Hidehiko
Naito Akira
Naito Kenji
Ohtake Yasuhiro
Saito Yoshiaki
Kifle Bruck
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
Wakamoto Pharmaceutical Co., Ltd.
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