Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-10-16
2003-06-24
Dentz, Bernard (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S786000, C549S201000, C549S396000
Reexamination Certificate
active
06583174
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a novel composition comprising a novel bi-cyclic compound and a glyceride, and a method for stabilizing the bi-cyclic compound comprising the step admixing the same with a glyceride.
BACKGROUND ART
A glyceride has been applied widely in the medical field and is useful as an immediate alimentation or an entero-protecting agent (JP-A-4-210631). In addition, it is also useful as a solvent for various pharmaceutically active compounds such as active vitamin Ds, diazepam, thiazole derivatives, prostaglandins or flavonoids, as a diluent for a capsule preparation, as a vehicle of eye drop, and as a stabilizing agent (JP-A-53-50141, JP-A-53-75320, U.S. Pat. No. 4,248,867, JP-A-55-136219, U.S. Pat. No. 4,247,702, JP-A-59-137413, JP-A-02-204417, JP-A-04-46122, U.S. Pat. No. 5,411,952, U.S. Pat. No. 5,474,979 and U.S. Pat. No. 5,981,607).
However, the prior arts are silent on the effect of glycerides on the novel pharmaceutically active bi-cyclic compounds.
SUMMARY OF THE INVENTION
The object of the present invention is to provide a novel composition comprising a certain bi-cyclic compound having a pharmacological activity and a glyceride, and a method for stabilizing the bi-cyclic compound by admixing the same with a glyceride.
Another object of the present invention is to provide a novel compound having a pharmacological activity.
This inventor studied to improve the stability of a novel bi-cyclic compound and found that a composition comprising the bi-cyclic compound and a glyceride can attain the above object.
Accordingly, the present invention provides a novel composition comprising a bi-cyclic compound represented by the formula (I):
wherein,
A is —CH
2
OH, —COCH
2
OH, —COOH or a functional derivative thereof;
X
1
and X
2
are hydrogen atom, lower alkyl or halogen atom;
V
1
and V
2
are carbon or oxygen atoms;
W
1
and W
2
are
wherein R
4
and R
5
are hydrogen atom, hydroxy, halogen atom, lower alkyl, lower alkoxy or hydroxy (lower) alkyl with the proviso that R
4
and R
5
are not hydroxy or lower alkoxy at the same time;
Z is a carbon, oxygen, sulfur or nitrogen atom;
R
1
is a saturated or unsaturated bivalent lower-medium aliphatic hydrocarbon residue which is unsubstituted or substituted with halogen, an alkyl group, hydroxy, oxo, aryl or heterocyclic group;
R
2
is a saturated or unsaturated, lower or medium aliphatic hydrocarbon residue which is unsubstituted or substituted with halogen atom, oxo, hydroxy, lower alkyl, lower alkoxy, lower alkanoyloxy, lower cycloalkyl, lower cycloalkyloxy, aryl, aryloxy, heterocyclic group or heterocyclic-oxy group; lower cycloalkyl; lower cycloalkyloxy; aryl, aryloxy, heterocyclic group or heterocyclic-oxy group;
R
3
is a hydrogen atom, a lower alkyl, lower cycloalkyl, aryl or heterocyclic group; and a glyceride, and a method for stabilizing the above-specified bi-cyclic compound by means of dissolving said compound in a glyceride.
The present invention also provides a novel bi-cyclic compound represented by the above formula (I).
In the above formula (I), the term “unsaturated” in the definitions for R
1
and R
2
is intended to include at least one or more double bonds and/or triple bonds that are isolatedly, separately or serially present between carbon atoms of the main and/or side chains. According to the usual nomenclature, an unsaturated bond between two serial positions is represented by denoting the lower number of the two positions, and an unsaturated bond between two distal positions is represented by denoting both of the positions.
The term “lower or medium aliphatic hydrocarbon” refers to a straight or branched chain hydrocarbon group having 1 to 14 carbon atoms (for a side chain, 1 to 3 carbon atoms are preferable) and preferably 1 to 10, especially 2 to 8 carbon atoms for R
1
and 1 to 10, especially 1 to 8 carbon atoms for R
2
.
The term “halogens atom” covers fluorine, chlorine, bromine and iodine. Particularly preferable is a fluorine atom.
The term “lower” throughout the specification is intended to include a group having 1 to 6 carbon atoms unless otherwise specified.
The term “lower alkyl” refers to a straight or branched chain saturated hydrocarbon group containing 1 to 6 carbon atoms and includes, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl and hexyl.
The term “lower alkoxy” refers to a group of lower alkyl-O—, wherein lower alkyl is as defined above.
The term “hydroxy(lower)alkyl” refers to a lower alkyl as defined above which is substituted with at least one hydroxy group such as hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl and 1-methyl-1-hydroxyethyl.
The term “lower alkanoyloxy” refers to a group represented by the formula RCO—O—, wherein RCO— is an acyl group formed by oxidation of a lower alkyl group as defined above, such as acetyl.
The term “lower cycloalkyl” refers to a cyclic group formed by cyclization of a lower alkyl group as defined above but contains three or more carbon atoms, and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
The term “lower cycloalkyloxy” refers to the group of lower-cycloalkyl-O—, wherein lower cycloalkyl is as defined above.
The term “aryl” may include unsubstituted or substituted aromatic hydrocarbon rings (preferably monocyclic groups), for example, phenyl, naphthyl, tolyl, xylyl. Examples of the substituents are halogen atom and halo(lower)alkyl, wherein halogen atom and lower alkyl are as defined above.
The term “aryloxy” refers to a group represented by the formula ArO—, wherein Ar is aryl as defined above.
The term “heterocyclic group” may include mono-to tri-cyclic, preferably monocyclic heterocyclic group which is 5 to 14, preferably 5 to 10 membered ring having optionally substituted carbon atom and 1 to 4, preferably 1 to 3 of 1 or 2 type of hetero atoms selected from nitrogen atom, oxygen atom and sulfer atom. Examples of the heterocyclic group include furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, furazanyl, pyranyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, 2-pyrrolinyl, pyrrolidinyl, 2-imidazolinyl, imidazolidinyl, 2-pyrazolinyl, pyrazolidinyl, piperidino, piperazinyl, morpholino, indolyl, benzothienyl, quinolyl, isoquinolyl, purinyl, quinazolinyl, carbazolyl, acridinyl, phenanthridinyl, benzimidazolyl, benzimidazolonyl, benzothiazolyl, phenothiazinyl. Examples of the substituent in this case include halogen, and halogen substituted lower alkyl group, wherein halogen atom and lower alkyl group are as described above.
The term “heterocyclic-oxy group” means a group represented by the formula HcO—, wherein Hc is a heterocyclic group as described above.
The term “functional derivative” of A includes salts (preferably pharmaceutically acceptable salts), ethers, esters and amides.
Suitable “pharmaceutically acceptable salts” include conventionally used non-toxic salts, for example a salt with an inorganic base such as an alkali metal salt (such as sodium salt and potassium salt), an alkaline earth metal salt (such as calcium salt and magnesium salt), an ammonium salt; or a salt with an organic base, for example, an amine salt (such as methylamine salt, dimethylamine salt, cyclohexylamine salt, benzylamine salt, piperidine salt, ethylenediamine salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, tris(hydroxymethylamino)ethane salt, monomethyl-monoethanolamine salt, procaine salt and caffeine salt), a basic amino acid salt (such as arginine salt and lysine salt), tetraalkyl ammonium salt and the like. These salts may be prepared by a conventional process, for example from the corresponding acid and base or by salt interchange.
Examples of the ethers include alkyl ethers, for example, lower alkyl ethers such as methyl ether, ethyl ether, propyl ether, isopropyl ether, butyl ether, isobutyl ether, t-butyl ether, pentyl ether and 1-cyclopropyl ethyl ether; and medium or higher alkyl ethers such as octyl ether, diethylhexyl ether, lauryl ether and cetyl ether; unsaturated ethers such a
Habe Tsuyoshi
Ueno Ryuji
Dentz Bernard
Sucampo A.G.
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