Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-01-12
2002-02-19
Lambkin, Deborah C. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S381000
Reexamination Certificate
active
06348481
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to a pharmaceutical composition for angiotensin II-mediated diseases, which comprises a compound having angiotensin II antagonistic activity or a salt thereof in combination with a compound having diuretic activity or a compound having calcium antagonistic activity, and to a method of its use.
BACKGROUND OF THE INVENTION
Diuretic drugs, due to their having mild hypotensive effects, have long been clinically used as antihypertensive agents. However, as undesirable side effects caused by the use for a long time, influences on metabolism, for example, hypokalemia, hyperuricemia, hyperlipemia and diabetes melitus, have been taken up. While calcium antagonists have been used as therapeutic agents of circulatory diseases such as hypertension, cardiac diseases, cerebral apoplexy, nephritis and arteriosclerosis, it has also been known that they tend to cause such undesirable side effects as tachycardia, hypotension, erythroprosopalgia and encephalagia, which are considered to be due to their abrupt vasodilative action.
On the other hand, it is disclosed in EP-0425921, EP-0459136 and EP-0520423 that benzimidazole derivatives have an angiotensin II antagonistic activities and are useful for the therapy of circulatory diseases including hypertension, cardiac diseases (cardiac insufficiency, myocardial infarction, etc.), cerebral apoplexy, nephritis and arteriosclerosis. The mechanism of the action is considered that the benzimidazole derivatives inhibit the binding of angiotensin II having a strong vasoconstrictive action to an angiotensin II acceptor. And, while, in JPA H3(1991)-27362 and JPA H5(1993)-132467, it is disclosed that an imidazole derivative having angiotensin II antagonistic action is administered together with a diuretic agent or a calcium antagonistic agent.
OBJECT OF THE INVENTION
The invention is intended, by combination of a compound having angiotensin II antagonistic action or a salt thereof with a compound having diuretic action or a compound having calcium antagonistic activity, to perform especially remarkable effects, to reduce undesirable side effects and to cover up defects observed in administration of a medicine consisting of a single component.
SUMMARY OF THE INVENTION
Circumstances being such as above, the present inventors have made extensive and intensive studies on the effects of co-use of a benzimidazole derivative having angiotensin antagonistic activity with a compound having diuretic activity or a compound having calcium antagonistic activity, and, as a result, they have found that the co-use performs especially remarkable effects which were not observed in the administration of the respective compounds singly, thus accomplishing the present invention.
More specifically, the present invention relates to
(1) a pharmaceutical composition for angiotensin II-mediated diseases, which comprises a compound having angiotensin II antagonistic activity of the formula (I):
wherein R
1
is H or an optionally substituted hydrocarbon residue; R
2
is an optionally esterified carboxyl group; R
3
is a group capable of forming an anion or a group convertible thereinto; X is a covalent bond between the 2 phenyl rings or a spacer having a chain length of 1 to 2 atoms as the linear moiety between the adjoining phenylene group and phenyl group; n is 1 or 2; the ring A is a benzene ring having 1 or 2 optional substituents in addition to R
2
; and Y is a bond, —O—, —S(O)m— (wherein m is 0, 1 or 2) or —N(R
4
)— (wherein R
4
is H or an optionally substituted alkyl group) or a pharmaceutically acceptable salt thereof in combination with a compound having diuretic activity or a compound having calcium antagonistic activity, and
(2) a method for the prophylaxis or treatment of angiotensin II-mediated diseases in a mammal which comprises administering an effective amount of a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof in combination with an effective amount of a compound having diuretic activity or a compound having calcium antagonistic activity.
DETAILED DESCRIPTION OF THE INVENTION
The compounds to be used for the pharmaceutical composition of this invention are those represented by the above-mentioned formula (I). One of the most remarkable structural characteristic of the compounds results when R
2
is an optionally esterified carboxyl group and R
3
is a group capable of forming anion or a group convertible thereinto. By having such a specific structure as above, the compounds (I) have a very strong angiotensin II antagonistic action.
In formula (I), R
1
stands for H or an optionally substituted hydrocarbon residue.
Examples of the hydrocarbon residue represented by R
1
include alkyl, alkenyl, alkynyl, cycloalkyl, aryl and aralkyl groups. Among them alkyl, alkenyl and cycloalkyl groups are preferable.
The alkyl group represented by R
1
is a straight chain or branched lower alkyl group having 1 to about 8 carbon atoms, as exemplified by methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, i-pentyl, hexyl, heptyl or octyl.
The alkenyl group represented by R
1
is a straight chain or branched lower alkenyl group having 2 to about 8 carbon atoms, as exemplified by vinyl, propenyl, 2-butenyl, 3-butenyl, isobutenyl or 2-octenyl.
The alkynyl group represented by R
1
is a straight chain or branched lower alkynyl group having 2 to about 8 carbon atoms, as exemplified by ethynyl, 2-propinyl, 2-butynyl, 2-pentynyl or 2-octynyl.
The cycloalkyl group represented by R
1
is a lower cycloalkyl group having 3 to about 6 carbon atoms, as exemplified by cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
The above mentioned alkyl, alkenyl, alkynyl or cycloalkyl group may optionally be substituted with hydroxyl group, an optionally substituted amino group (e.g. amino, N-lower (C
1-4
) alkylamino or N,N-dilower (C
1-4
) alkylamino), halogen, a lower (C
1-4
) alkoxy group, a lower (C
1-4
) alkylthio group.
The aralkyl group represented by R
1
is, for example, a phenyl-lower (C
1-4
) alkyl such as benzyl or phenethyl, and the aryl group represented by R
1
is, for example, phenyl.
The above mentioned aralkyl or aryl group may optionally have, on any position of its benzene ring, for example, halogen (e.g. F, Cl or Br), nitro, an optionally substituted amino group (e.g. amino, N-lower (C
1-4
) alkylamino or N,N-dilower (C
1-4
) alkylamino), lower (C
1-4
) alkoxy (e.g. methoxy or ethoxy), lower (C
1-4
) alkylthio (e.g. methylthio or ethylthio) or lower (C
1-4
) alkyl (e.g. methyl or ethyl).
Among the above mentioned groups represented by R
1
, optionally substituted alkyl, alkenyl or cycloalkyl groups (e.g. a lower (C
1-5
) alkyl, lower (C
2-5
) alkenyl or lower (C
3-6
) cycloalkyl group optionally substituted with hydroxyl group, amino group, halogen or a lower (C
1-4
) alkoxy group) are preferable.
Y stands for a bond, —O—, —S(O)m— (wherein m is 0, 1 or 2) or —N(R
4
)— (wherein R
4
is hydrogen or an optionally substituted lower alkyl group). Y is preferably a bond, —O—, —S— or —N(R
4
)— (wherein R
4
is hydrogen or a lower (C
1-4
) alkyl group (e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, t-butyl)).
With respect to formula (I) above, the group for R
3
, capable of forming an anion (a group having a hydrogen atom capable of leaving as a proton), or a group capable of changing thereto, is exemplified by 5- to 7- membered (preferably 5- or 6- membered) monocyclic heterocyclic ring residues which contain one or more of N, S and O and which may be substituted (preferably N-containing heterocyclic residues having a hydrogen atom capable of leaving as a proton), and groups capable of changing thereto in vivo. Such groups include the following:
The chemical bond between the group for R
3
and the partner phenyl group may be a carbon-carbon bond as shown above, or a nitrogen-carbon bond via one of the several nitrogen atoms when the symbol g stands for —NH— in the above formulas. For instance, when R
3
is represented by
embodiments are
Other R
3
examples binding thr
Inada Yoshiyuki
Kubo Keiji
Lambkin Deborah C.
Takeda Chemical Industries Ltd.
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