Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-03-17
2001-05-15
Morris, Patricia L. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S266200
Reexamination Certificate
active
06232335
ABSTRACT:
DESCRIPTION
1. Technical Field
The present invention relates to a novel 2,4-dioxopyrrolidine derivative and a novel 2,4-dioxotetrahydrofuran derivative having excellent pharmacological effects, and their salts, and medicines containing these compounds as active ingredients.
More particularly, the present invention relates to novel 1-(biphenyl-4-yl)methyl-1H-1,2,4-triazoles and 1-(biphenyl-4-yl)methy-4H-1,2,4-triazoles having a (2,4-dioxopyrrolidine-5-ylidene)methyl group or (2,4-dioxotetrahydrofuran-5-ylidene) methyl group at the 2′-position as a substituent, and their salts, which are useful as therapeutic agent for circulatory system disease, e.g. hypertension and/or diseases such as heart and renal diseases that are caused by the action of angiotensin II, due to their strong angiotensin II receptor antagonism and antihypertensive effect, and to medicines containing these compounds as active ingredient.
2. Background Art
The renin-angiotensin system plays an important role in vivo, in maintaining homeostasis for systemic blood, humoral amount and electrolyte balance.
The results of research on angiotensin II receptor antagonists, angiotensin II converting enzyme inhibitors, and renin inhibitors suggest strongly that the renin-angiotensin system is involved in the mechanism for the manifestation of hypertension. Angiotensin II converting enzyme inhibitors (ACE inhibitors) such as captopril and enalapril are effective in the treatment of hypertension or heart failure and already widely used.
An ACE inhibitor, however, affects the metabolic pathway of bradykinin or substance P, thereby inducing side effects such as dry cough or vascular edema being aesociated with the accumulation of these peptides. On the other hand, an angiotensin II receptor antagonist can restrain only the effects of angiotensin II, so it is expected to minimize the side effects. Peptidic antagonist suck as saralisin in the angiotensin II receptor antagonists is firmly bounded with the receptor, but due to its short half-life in the human body, it is inappropriate for oral administration [M. A. Ondatti and D. W. Cushman, Annual Reports in Medical Chemistry 13, 82-91 (1978)].
Under these circumstances, a non-peptidic angiotensin II receptor antagonist has been developed, though its activity is not so strong (U.S. Pat. No. 4,340,599, U.S. Pat. No. 4,355,040). A series of biphenylimidazole compounds have been reported to be as angiotensin II receptor antagonists which are non-peptidic, very effective and selective and as what exhibit antihypertensive effect in oral administration [D. J. Carini et al., J. Med. Chem. 34, 2525-2547 (1991)]. It has also been suggested that the presence of an acidic group at the 2′-position of a biphenyl group is important for binding with the angiotensin II receptor. A hydrophobic tetrazole group has been selected as an acidic group that is appropriate for oral administration and has a high bioavailability, and DUP-753 is known as a biphenylimidazole compound having a tetrazole group at the 2′-position.
Imidazolepyridine [N. B. Mantlo et al., J. Med. Chem. 37, 1632 to 1645 (1994)], benzimidazole [K. Kubo et al., J. Med. Chem. 35, 1772 to 1784 (1993)], quinoline (R. H. Bradbury et al., J. Med. Chem. 35, 4027 to 4038 (1992)), pyrazole [W. T. Ashton et al., J. Med. Chem. 36, 3595 to 3650 (1993)], triazole [W. T. Ashton et al., J. Med. Chem. 36, 591 to 609 (1993), PCT/US91/02926], pyrimidine [K. S. Atwal et al., J. Med. Chem. 35, 4751 to 4763 (1993)], and pyridine [R. H. Bradbury et al., J. Med. Chem. 36, 1245 to 1254 (1993)] have been disclosed as the alternative to an imidazole ring constituting the imidazole compound. Of these compounds, 1,2, 4-triazole is preferable, because it is a heterocyclic ring geometrically similar to the imidazole ring, and the G.D. Searle & Co. has disclosed SC-50560 with 1H-1,2,4-triazole as a superior compound having a strong angiotensin II receptor antagonism (PCT/US91/02926).
2,4-dioxopyrrolidine (called as tetramic acid, too) and 2,4-dioxotetrahydrofuran (called as tetronic acid, too) are known as components of the chemical structure of a certain physiologically active substance of natural origin [H. G. Henning and A. Gelbin, Advances in Heterocyclic Chemistry vol. 157, pp. 139 (1993), Academic Press. Inc., G. Pattenden, Progress in the Chemistry of Organic Natural Products Vol. 35, pp. 133 (1978)]. Such a heterocyclic group is easily presumed to fit with a hydrophobic pocket in a binding site of an organism that is required for the manifestation of physiological activity of a substance having the heterocyclic group as a component, and to play an important role as an acid component and expected to have, in the angiotensin II receptor antagonist too, that is a sufficient possibility as a bio-isostere for the tetrazole ring of the DUP-763.
Thus, the present inventors have synthesized a 2,4-dioxopyrrolidine derivative and a 2,4-dioxohydrofuran derivative and researched the angiotensin II receptor antagonism to find compounds having significant effects as new non-peptidic angiotensin II receptor antagonists as described hereinafter.
DISCLOSURE OF THE INVENTION
The present invention relates to a compound of the following formula (I) or its salt:
wherein X is a group of the following formula (II) or (III):
Y is a group of the following formula (IV) or (V):
R
1
and R
2
independently represent a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a haloalkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, an aryl group, a haloganated aryl group, an aralkyl group, or a heterocyclic group containing at least one ring atom selected from an oxygen atom, a sulfur atom and a nitrogen atom.
The compound of the formula (I) is:
(1) a compound of the following formula (I-a) or its salt:
wherein X is a group of the formula (II) and Y is a group of the formula (IV);
(2) a compound of the following formula (I-b) or its salt:
wherein X is a group of the formula (II) and Y is a groulp of the formula (V);
(3) a compound of the following formula (I-c) or its salt:
wherein X is a group of the formula (III) and Y is a group of the formula (IV), or
(4) a compound of the following formula (I-d) or its salt:
wherein X is a group of the formula (III) and Y is a group of the formula (V).
The alkyl group having 1 to 6 carbon atoms that is included in the definition of the substituent may be a straight chain or branched one, and for exanple, a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a tert-butyl group, a pentyl group, or a hexyl group may be mentioned as preferable one. In particular, an alkyl group such as a n-propyl group, an isopropyl group or a n-butyl group man be mentioned preferably.
The haloalkyl group having 1 to 6 carbon atoms is an alkyl group mono- or poly-substituted by halogen atoms, and is, for example, a fluoromothyl group, difluoromethyl group, trifluoromethyl group, chloromethyl group, dichloromethyl group, trichloromethyl group, 2,2,2-trifluoroethyl group, 2-fluoroethyl group, 2-chloroethyl group, 2,2,2-trichloroethyl group, 1,1-difluoroethyl group, 1,1-difluoropropyl group, 1,1-difluorobutyl group or 1,1-difluoropentyl group, or the like.
The cycloalkyl group is, for example, a cyclopropyl group, cyclobutyl group, cyclopentyl group or cyclohexyl group, or the like and a cyclopropyl group is preferable one.
As the aryl and halogenated aryl groups, a phenyl group, 2-fluorophenyl group or 4-fluorophenyl group, or the like is preferable one and, as the aralkyl group a phenylmethyl group or 2-phenylethyl group, or the like is preferable one.
The heterocyclic group containing at least one ring atom selected from an oxygen atom, a sulfur atom or a nitrogen atom is a furyl group, thienyl group or pyridyl group, or the like, and the preferable heterocyclic group is a furan-2-yl group, thiophene-2-yl group and pyridine-4-yl group.
As
Mori Masao
Yoshii Eiichi
Lead Chemical Co., Ltd.
Morris Patricia L.
Oliff & Berridg,e PLC
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