Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-07-20
2001-12-11
Davis, Zinna Northington (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S329000, C564S305000, C514S646000
Reexamination Certificate
active
06329405
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to a series of novel cyclobutene derivatives having excellent inhibitory activity against an ileal bile acid transporter.
Hyperlipemia is one of three major risk factors in the causation of ischemic heart disease. It is widely accepted that reducing high blood cholesterol levels is particularly useful for the treatment or prevention of ischemic heart disease. Commercially available remedies for hyperlipemia at present include HMG-CoA reductase inhibitors and anion exchange resins, and these are used for treating or preventing hyperlipemia or arteriosclerosis [Am. J. Cardiol., 76, 899-905 (1995)].
HMG-CoA reductase inhibitors not only inhibit cholesterol synthesis but also increase LDL (low density lipoprotein) receptors in the liver, which increases the uptake of blood cholesterol and accelerates its excretion into bile [Science, 232, 34 (1986)]. Because these compounds are widely recognized to be both useful and safe, they have been used for a large number of patients.
Anion exchange resins, on the other hand, adsorb bile acid and disturb the re-absorption of bile acid in the intestines, thereby promoting the intrahepatic conversion of cholesterol to bile acid, which is a mechanism by which cholesterol may be removed from the blood. As a result, they are effective for reducing blood cholesterol levels [N. Engl. J. Med., 302, 1210-1222 (1980)]. Cholestyramine is such an anion exchange resin and has already been used in practice for this purpose. Because this compound is not readily absorbed by the body, it is the treatment of choice for infantile hyperlipemia where higher standards of safety are required. However, a large quantity of cholestyramine must be administered in one dose and moreover, being a resin, it has an unpleasant mouthfeel, which often discourages patients from using it regularly. Furthermore, it interferes with the absorption of fat from the gastro-intestinal tract and results in a reduced absorption of fat-soluble vitamins, and may inhibit or reduce the absorption of minerals. It may also delay or reduce the absorption of other drugs, particularly acidic ones, which are administered concurrently. Thus, although it is effective, a drug having a similar activity but without these disadvantages would be desirable.
In recent years, a protein which acts on the first step of the re-absorption of bile acid into the ileum, that is an ileal bile acid transporter, has been cloned [Wong M. H. et al., J. Biol. Chem., 269, 1340-1347 (1994)]. It has been suggested that similar pharmacological effects to those of cholestyramine could be achieved by the inhibition of this ileal bile acid transporter, and attempts have been made to find such an inhibitor [Wess G. et al, J. Med. Chem., 37, 873-875 (1994)].
The following prior art is thought relevant to the present invention:
(1) Japanese Laid-Open Publication No. Hei 6-509820 (WO93/25517)
This discloses compounds having the following formula (Z-1):
in which: Z represents a group of formula —N(R
3
)CO—, where R
3
represents an aryl group; X represents a group of formula —N(R
5
)—, where R
5
represents a hydrogen atom or an alkyl group; R
2
represents a cycloalkyl or cycloalkenyl group which may optionally be substituted, and R
4
represents an aryl or heteroaryl group.
Of the compounds of formula (I) according to the present invention, those in which D represents a nitrogen atom and in which E represents a —CO— group have a similar structure to the compounds of formula (Z-1), but they differ in that the cyclobutenyl portion of A in the compound of formula (I) has two oxo or thioxo groups as essential substituents, while the cycloalkenyl group defined in R
2
of the compound of formula (Z-1) contains neither an oxo nor a thioxo group.
Moreover, this prior art does not specifically disclose any compound having an analogous structure to the compounds of formula (I) of the present invention and, of the compounds disclosed, the closest to the compounds the present invention is only the following compound:
Finally, the compounds of formula (Z-1) are disclosed as selective phosphodiesterase IV inhibitors. There is no suggestion that they may have ileal bile acid transporter inhibitory action.
(2) Japanese Patent Application Kokai No. Hei 7-309837 (EP623597A) and Japanese Patent Application Kokai No. Hei 8-175994
These publications disclose compounds of formula (Z-2):
[in which, Ring A and Ring B each represents a benzene ring which may be substituted further, and Q represents a group of formula —OQ
1
(in which, Q
1
represents an aliphatic hydrocarbon group which may be substituted)].
Of the compounds of formula (I) of the present invention, the closest structurally to the compounds of formula (Z-2) are those wherein, in the compounds of the present invention, the broken line represents a double bond, D represents a carbon atom and E represents a group of formula ═N—O—. The compounds of the present invention and those of the prior art differ in that the former contains an oxo- or thioxo-substituted cyclobutenylamino group as a substituent A of the benzene ring, while there is no disclosure of a cyclobutenylamino group as a substituent of the benzene ring in the prior compounds.
Moreover, this prior art does not specifically disclose any compound having an analogous structure to the compounds of formula (I) of the present invention and, of the compounds disclosed, the closest to the compounds the present invention is only the following compound:
Finally, in these publications, the compounds of formula (Z-2) are disclosed as calcium channel opening agents and lipometabolism-improving agents, respectively. There is no suggestion that they may have ileal bile acid transporter inhibitory action.
(3) Japanese Laid-Open Publication No. Hei 11-60548 (WO98/56757)
This discloses compounds having the following formula (Z-3) as ileal bile acid transporter inhibitor:
in which: R
1
represents an C
6
-C
10
aryl group which be substituted by from one to three of substituents &agr; or a tetrazolyl group which may optionally be substituted by from one to three of substituents &bgr;; R
2
, R
3
and R
4
represents a hydrogen group; R
5
represents an C
6
-C
10
aryl group which may optionally be substituted by from one to three of substituents &bgr;; and R
6
represents C
7
-C
10
aralkyl group which may optionally be substituted by from one to three of substituents &ggr;.
Of the compounds of formula (I) according to the present invention, the closest structurally to the compounds of formula (Z-3) are those wherein, in the compounds of the present invention, D represents a carbon atom, in which in which E represents a —NH— group and the broken line represents a single bond have a similar structure to the compounds of formula (Z-3), but they differ in that the former contains an oxo- or thioxo-substituted cyclobutenylamino group as a substituent A of the benzene ring, while there is no disclosure of a cyclobutenylamino group as a substituent of the benzene ring in the prior compounds.
Moreover, this prior art does not specifically disclose any compound having an analogous structure to the compounds of formula (I) of the present invention and, of the compounds disclosed, the closest to the compounds the present invention is only the following compound:
(4) Japanese Patent Application Kokai No. Hei 11-199570
This publication discloses compounds of formula (Z-4):
[in which, Ar
1
and Ar
2
each represents an aromatic group which may optionally be substituted further, and Q represents a chain aliphatic hydrocarbon bivalent group which may be interposed with a bivalent group selected from O, S and a imino group; X represents a hydrogen group; and Ring A represents a nitrogenous 5 to 7-membered cyclic group which may optionally be substituted further.].
Of the compounds of formula (I) of the present invention, the closest structurally to the compounds of formula (Z-4) are those wherein, in the compounds of the pres
Kitayama Ken
Kohama Takafumi
Kono Keita
Kurata Hitoshi
Davis Zinna Northington
Frishauf, Holtz Goodman, Langer & Chick, P.C.
Sankyo Company Limited
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