Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-04-20
2002-11-05
Kifle, Bruck (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S211110, C540S546000, C540S547000
Reexamination Certificate
active
06476017
ABSTRACT:
TECHNICAL FIELD
The present invention relates to novel compounds, and it relates to novel compounds which enhance the physiological activity of the ligands to intranuclear receptors whose typical examples include retinoic acid and compounds having retinoic acid-like actions (retinoids).
BACKGROUND ART
Retinoic acid (vitamin A acid), an active metabolite of vitamin A, has extremely important physiological functions, e.g., differentiation of immature cells under development processes toward mature cells having specific functions, enhancement of cell proliferation, and life support action. It has been revealed that various vitamin A derivatives synthesized so far also have similar physiological functions, for example, the benzoic acid derivatives disclosed in Japanese Patent Unexamined Publication (KOKAI) Nos. (Sho)61-22047/1986 and (Sho)61-76440/1986 and the compounds described in Journal of Medicinal Chemistry, 1988, Vol. 31, No. 11, p.2182. “Retinoids” is a general term for retinoic acid and the aforementioned compounds having retinoic acid-like biological activities.
For example, it was proved that all-trans retinoic acid binds as a ligand to the retinoic acid receptor (RAR) present in cell nuclei, which belongs to the intranuclear receptor super family (Evans, R. M., Science, 240, p.889, 1988), and regulates proliferation and differentiation of animal cells or cellular mortalities (Petkovich, M., et al., Nature, 330, pp.444-450, 1987). It has also been suggested that the aforementioned compounds having the retinoic acid-like biological activities, e.g., 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carbamoyl]benzoic acid: Am80, also bind to RAR in similar manners to retinoic acid to exhibit their physiological actions (see, Hashimoto, Y., Cell Struct. Funct., 16, pp.113-123, 1991; Hashimoto, Y., et al., Biochem. Biophys. Res. Commun., 166, pp.1300-1307, 1990). Clinically, these compounds were found as useful for the therapeutic and preventive treatment of vitamin A deficiency disease, hyperkeratosis of epithelial tissue, rheumatism, delayed allergy, bone disease, leukemia and certain types of cancer.
Compounds are known which antagonize against these retinoids and reduce the primary actions of the retinoid (Eyrolles, L., et al., Journal of Medicinal Chemistry, 37(10), pp.1508-1517, 1994). However, a compound has not been known, other than those disclosed in EP 694,301 A1, which enhances the actions of the retinoids such as retinoic acid, while the compound, per se, has no retinoid action or its retinoid actions are negligible. In this publication, it is suggested that a ligand compound specific to RXR receptor has an enhancing activity on Am80, i.e., a ligand specific to RAR-&agr;-receptor.
SUMMARY OF THE INVENTION
An object of the present invention is to provide compounds having enhancing activities on the actions of the retinoids such as retinoic acid. More specifically, the object of the present invention is to provide compounds which can remarkably enhance the action of retinoids such as retinoic acid, while the compounds, per se, have no retinoid action or their retinoid actions are very weak.
The inventor of the present invention conducted various studies to achieve the foregoing object, and as a result, found that the compounds represented by the general formulas set out below enhance the action of retinoids such as retinoic acid. The present invention was achieved on the basis of the findings.
The present invention thus provides the compounds or the salts thereof represented by the following formula (I):
or the following formula (II):
wherein, R
1
represents hydrogen atom or a C
1-6
alkyl group; R
2
and R
3
independently represent a hydrogen atom or a C
1-6
alkyl group, or R
2
and R
3
may combine together with the carbon atoms of the phenyl ring to which R
2
and R
3
bind to represent a 5- or 6-membered cycloalkyl group which may optionally be substituted with one or more C
1-4
alkyl groups; R
4
represents a hydrogen atom, a C
1-6
alkyl group, a C
1-6
alkoxy group, hydroxyl group, nitro group, or a halogen atom; R
5
represents a hydrogen atom, a C
1-6
alkyl group, or an aryl-substituted C
1-6
alkyl group; R
6
represents a hydrogen atom or a C
1-6
alkyl group; X represents —NR
7
—, —O—, —CHR
7
— or —S— in which R
7
represents a hydrogen atom, a C
1-6
alkyl group, or an aryl-substituted C
1-6
alkyl group; and Y represents a phenylene group or a pyridinediyl group. In addition, according to further embodiments of the present invention, there are provided a medicament comprising the aforementioned compounds; an agent enhancing the actions of the retinoid which comprises the aforementioned compounds; and an agent enhancing the actions of the ligands to the intranuclear receptors which comprises the aforementioned compounds.
THE MOST PREFERRED EMBODIMENTS TO CARRY OUT THE INVENTION
In the above general formula (I), R
1
represents a hydrogen atom or a linear or branched C
1-6
(i.e., having 1 to 6 carbon atoms) alkyl group. Examples of the alkyl group include, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, sec-butyl group, and tert-butyl group, and methyl group is preferably used.
R
2
and R
3
independently represents a hydrogen atom or a linear or branched C
1-6
alkyl group. As for the alkyl group, those mentioned above may be used, and ethyl group, isopropyl group, tert-butyl group or the like may preferably be used. Each of R
2
and R
3
may independently substitute at any position and their substituting positions are not particularly limited. However, it is preferable that R
2
and R
3
are at para-position and meta-position with reference to X, respectively, R
2
and R
3
are at meta-position and ortho-position with reference to X. It is particularly preferable that R
2
and R
3
are at para-position and meta-position with reference to X, respectively.
R
2
and R
3
may combine to form a 5- or 6-membered cycloalkyl ring together with two carbon atoms on the phenyl ring to which R
2
and R
3
respectively bind. The cycloalkyl ring may have one or more C
1-4
alkyl groups. For example, the ring may have from two to four methyl groups, preferably four methyl groups. For example, it is preferable that R
2
and R
3
together with the phenyl ring substituted with R
2
and R
3
may form 5,6,7,8-tetrahydronaphthalene ring or 5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene ring.
R
4
represents a hydrogen atom, a C
1-6
alkyl group, a C
1-6
alkoxy group, hydroxyl group, nitro group, or a halogen atom. As the C
1-6
alkyl group, these exemplified above may be used. As the C
1-6
alkoxy group, for example, methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, sec-butoxy group, or tert-butoxy group, preferably methoxy group, may be used. As the halogen atom, any of fluorine atom, chlorine atom, bromine atom, or iodine atom may be used. R
4
may substitute at any position on the phenyl ring and its position is not particularly limited.
R
5
represents a hydrogen atom, a C
1-6
alkyl group, or an aryl-substituted C
1-6
alkyl group. The C
1-6
alkyl group may be either linear or branched and those mentioned above may preferably be used. Examples of the aryl moiety of the aryl-substituted C
1-6
alkyl group include, for example, phenyl, naphthyl, or pyridyl group, and the C
1-6
alkyl moiety may be either linear or branched. For example, a phenyl-substituted C
1-6
alkyl group such as benzyl group or phenethyl group, a naphthyl-substituted C
1-6
alkyl group such as naphthylmethyl group, or a pyridyl-substituted C
1-6
alkyl group such as pyridylmethyl group can be used.
The aryl group constituting these aryl-substituted C
1-6
alkyl group may have one or more substituents. For example, a halogen atom such as fluorine atom or chlorine atom; a C
1-6
alkyl group such as methyl group or ethyl group; a linear or branched C
1-6
alkoxy group such as methoxy group or ethoxy group; nitro group; a linear or branched halogenated C
1-6
alkyl group such as trifluoromethyl grou
Griffin & Szipl, P.C.
Institute of Medicinal Molecular Design Inc.
Kifle Bruck
LandOfFree
Compounds activating pharmacological effect of retinoids does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Compounds activating pharmacological effect of retinoids, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Compounds activating pharmacological effect of retinoids will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2946818