Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-04-03
2003-10-07
Stockton, Laura L. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S392000, C548S252000, C548S325500
Reexamination Certificate
active
06630497
ABSTRACT:
FIELD OF THE INVENTION
Non-peptidic 1-phenyl imidazol-2-one biphenylmethyl compounds are described for use in treatment of circulatory disorders such as hypertension and congestive heart failure. Of particular interest are angiotensin II antagonist compounds provided by imidazol-2-one compounds having a mono- or poly-substituted phenyl moiety attached to a nitrogen atom of the imidazole-2-one nucleus and having a biphenylmethyl moiety attached to other nitrogen atom of the imidazol-2-one nucleus.
BACKGROUND OF THE INVENTION
The renin-angiotensin system is one of the hormonal mechanisms involved in regulation of pressure/volume homeostasis and in expression of hypertension. Activation of the renin-angiotensin cascade begins with renin secretion from the juxtaglomerular apparatus of the kidney and culminates in the formation of angiotensin II, the primary active species of this system. This octapeptide, angiotensin II, is a potent vasoconstrictor agent and also produces other physiological effects such as promoting aldosterone secretion, promoting sodium and fluid retention, inhibiting renin secretion, increasing sympathetic nervous system activity, increasing vasopressin secretion, causing positive cardiac inotropic effect and modulating other hormonal systems.
Previous studies have shown that antagonizing angiotensin II at its receptors is a viable approach to inhibit the renin-angiotensin system, given the pivotal role of this octapeptide which mediates the actions of the renin-angiotensin system through interaction with various tissue receptors. There are several known angiotensin II antagonists, most of which are peptidic in nature. Such peptidic compounds are of limited use due to their lack of oral bioavailability or their short duration of action. Also, commercially-available peptidic angiotensin II antagonists (e.g., Saralasin) have a significant residual agonist activity which further limit their therapeutic application.
Non-peptidic compounds with angiotensin II antagonist properties are known. For example, the sodium salt of 2-n-butyl-4-chloro-1-(2-chlorobenzyl)imidazole-5-acetic acid has specific competitive angiotensin II antagonist activity as shown in a series of binding experiments, functional assays and in vivo tests [P. C. Wong et al,
J. Pharmacol. Exp. Ther.,
247(1), 1-7 (1988)]. Also, the sodium salt of 2-butyl-4-chloro-1-(2-nitrobenzyl) imidazole-5-acetic acid has specific competitive angiotensin II antagonist activity as shown in a series of binding experiments, functional assays and in vivo tests [A. T. Chiu et al,
European J. Pharmacol.,
157, 31-21 (1988)]. A family of 1-benzylimidazole-5-acetate derivatives has been shown to have competitive angiotensin II antagonist properties [A. T. Chiu et al,
J. Pharmacol. Exp. Ther.,
250(3), 867-874 (1989)]. U.S. Pat. No. 4,816,463 to Blankey et al describes a family of 4,5,6,7-tetrahydro-1H-imidazo(4,5-c)-tetrahydro-pyridine derivatives useful as antihypertensives, some of which are reported to antagonize the binding of labelled angiotensin II to rat adrenal receptor preparation and thus cause a significant decrease in mean arterial blood pressure in conscious hypertensive rats. EP No. 253,310, published Jan. 20, 1988, describes a series of aralkyl imidazole compounds, including in particular a family of biphenylmethyl substituted imidazoles, as antagonists to the angiotensin II receptor. EP No. 323,841 published Jul. 12, 1989 describes four classes of angiotensin II antagonists, namely, biphenylmethylpyrroles, biphenylmethylpyrazoles, biphenylmethyl-1,2,3-triazoles and biphenylmethyl 4-substituted-4H-1,2,4-triazoles, including the compound 3,5-dibutyl-4-[(21-carboxybiphenyl-4-yl)methyl]-4H-l,2,4-triazole. U.S. Pat. No. 4,880,804 to Carini et al describes a family of biphenylmethylbenzimidazole compounds as angiotensin II receptor blockers for use in treatment of hypertension and congestive heart failure.
There are several families of known compounds having one or two oxo substituents on a triazole ring. For example, East German Patent No. 160,447 published Aug. 3, 1983 describes a family of 1,2,4-triazolin-5-one compounds, specifically 2,4-dihydro-4,5-bis (phenylmethyl)-3H-1,2,4-triazol-3-one, for use as herbicides. Belgian Patent No. 806,146 published Oct. 16, 1972 describes a family of triazolinone compounds, including the compound (3-(4-m-chlorophenyl-1-piperazinyl) -propyl)-3,4-diethyl-1,2,4-triazolin-5-one, having tranquilizer, hypotensive and analgesic activities. Belgian Patent No. 631,842 published Feb. 28, 1963 describes a family of 1,2,4-triazolones having hypnotic, tranquilizer, narcotic, sedative and analgetic activities, which includes a class of 4-N-aralkyl -1,2,4-triazol-5-one compounds. EP #7,180 published Jun. 15, 1978 describes a family of 1,2-disubstituted -4-alkyl-1,2,4-triazolidine-3,5-dione compounds having a wide variety of activities, such as antiulcer, bronchodilator, antifertility and cardiovascular-related activities which include antihypertensive, antiarrhythmic, platelet aggregation inhibition and smooth muscle activities. EP #283,310 published Mar. 18, 1987 describes a family of N
1
-diarylmethyl-N
2
-aminoalkyl-diaza-heterocyclic derivatives for treating cerebral vascular and ischemic diseases and for protecting against anoxia.
There are several families of known compounds having an oxo group attached to a imidazole biphenylmethyl nucleus. For example, U.S. Pat. No. 5,177,097 to Poss describes acyl amidine and acyl guanidine biphenylmethyl compounds as angiotensin II antagonists, including imidazole-4-one-type biphenylmethyl compounds such as 4′-[[4.5-Dihydro-5-methyl-4-oxo-2-(propylamino)-1H-imidazol -1-yl]methyl]-[1,1′-biphenyl]-2-carboxylic acid, trifluoroacetate (1:1) salt. U.S. Pat. No. 5,087,634 to Reitz et al describes a class of N-substituted imidazole-2-one biphenylmethyl compounds as angiotensin II antagonists, including the compound 1-phenyl-4-butyl-1,3-dihydro-3-[2′-(1H-tetrazol-5-yl)[1,1′-biphenyl]-4-ylmethyl]-2H-imidazol-2-one. In PCT Application WO 91/14679 published Oct. 3, 1991, there is described a family of imidazol-4-one biphenylmethyl compounds as angiotensin II antagonists, including compounds having the 5-position of the imidazol-4-one moiety substituted with spirocyclopentyl, or diethyl, or other alkyl groups. EP #475,898 published Mar. 18, 1992 describes a class of imidazol-4-one and triazol-3-one biphenylmethyl compounds as angiotensin II antagonists, including the compound 2-(n-Butyl)-4-ethyl-5-oxo-1-[2′-(1H-tetrazol-5-yl) biphenyl-4-ylmethyl]-4,5-dihydro-1H-imidazole. In PCT Application WO 92/07834 published May 14, 1992, there is described a family of N-substituted imidazol-2-one biphenylmethyl compounds as angiotensin II antagonists, including the compound 4-butyl-1-(2-chlorophenyl)-3-[2′-(1H-tetrazol -5-yl)[1,1′-biphenyl]-4-yl]methyl-2H-imidazole-2-one.
DESCRIPTION OF THE INVENTION
A class of mono- or polysubstituted 1-phenyl-imidazol -2-one biphenylmethyl compounds useful in treating circulatory disorders, particularly cardiovascular disorders, is defined by Formula I:
wherein each of R
1
, R
2
and R
3
is independently selected from hydrido, alkyl, alkoxy, cyano, halo, hydroxy, nitro, amino, alkylamino, carboxyl, alkoxycarbonyl, formyl, alkylcarbonyl and haloalkylcarbonyl; with the proviso that at least one of R
1
, R
2
and R
3
must be a substituent other than hydrido, and with the further proviso that when each of R
1
and R
3
is hydrido, then R
2
cannot be chloro; wherein R
4
is selected from hydrido, alkyl, halo, haloalkyl, formyl, carboxyl and alkoxyalkyl; wherein R
5
is selected from alkyl, phenyl, phenylalkyl, cycloalkyl and cycloalkylalkyl; and wherein R
6
is an acidic group selected from COOH and
or a stereoisomer or a tautomer thereof or a pharmaceutically-acceptable salt thereof.
Regioisomers of compounds of Formula I are also embraced as part of the in
Manning Robert E.
Reitz David B.
G.D. Searle & Co
Keane J. Timothy
Stockton Laura L.
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