Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-07-23
2003-10-07
Powers, Fiona T. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S311000, C514S414000, C540S593000, C546S165000, C548S466000
Reexamination Certificate
active
06630463
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a heterocycle-containing carboxylic acid derivative and a drug containing said derivative.
BACKGROUND ART
Retinoic acid is an essential substance for the growth or life support of mammals including humans. It is known to have various effects, for example, upon ontogenesis, it serves as a morphogenetic factor, while in the adult body, it has effects on the differentiation and proliferation of cells. Described specifically, it is known to take part in the keratinization reaction, hair formation, sebaceous gland function or the like in the epidermis; the metabolism of bone or cartilage in the connective tissue; immunnomodulatory in the immune system; differentiation of neurocytes in the nerve system; differentiation and proliferation of hemocytes in the blood system; and lipid metabolism, mineral metabolism and basal metabolism. A wide variety of physiological effects of retinoic acid as exemplified above are exhibited by its various control mechanisms such as expression regulation of a transcription activator through an intranuclear retinoid receptor (RARs, RXRs) family, regulation of the hormone secretion or function at the target organ, regulation of growth factors such as EGF receptor or TGFA, expression regulation of enzymes such as collagenase, tissue plasminogen activator or tyrosine kinase, and production regulation of cytokine such as IL-6.
In recent years, the relationship between these physiological effects of retinoic acid and various morbid conditions has come to be apparent. Particularly in some cancers typified by acute myelocytic leukemia, differentiation and induction treatment by using all trans retinoic acid has drawn attentions as a novel therapeutic method of these cancers.
Retinoic acid, however, is found to involve various problems such as appearance of resistance caused by induction of P450 and expression of side effects due to its accumulation. Under such situations, there is accordingly a strong demand for the development of a novel retinoid-related compound, instead of retinoic acid, as a preventive and/or therapeutic for various diseases.
SUMMARY OF THE INVENTION
The present invention provides a heterocycle-containing derivative represented by the following formula (I):
wherein:
A is a group represented by the following formula (i), (ii), (iii) or (iv):
in which E
1
, F
1
, G
1
, H
1
, I
1
, E
2
, F
2
, G
2
, E
3
, F
3
and G
3
are the same or different and each independently represents an oxygen atom or a nitrogen, carbon or sulfur atom which may have a substituent; J represents a nitrogen atom which may have a substituent, with the proviso that the cases where in the ring (i), E
1
, F
1
, G
1
, H
1
and I
1
each represents a carbon group which may have a substituent, where in the ring (ii), E
2
, F
2
and G
2
each represents a carbon group which may have a substituent, and where in the ring (iii), E
3
, F
3
and G
2
each represents a carbon group which may have a substituent are excluded; R
1
, R
2
and R
3
are the same or different and each independently represents a hydrogen atom, a halogen atom, a lower alkyl group which may have a substituent, a cycloalkyl group which may have a substituent, a lower alkoxy group which may have a substituent, a cycloalkyloxy group which may have a substituent, an aryl group which may have a substituent, a heteroaryl group which may have a substituent, an aryloxy group which may have a substituent, a heteroaryloxy group which may have a substituent, a cycloalkylalkyl group which may have a substituent, an arylalkyl group which may have a substituent, a heteroarylalkyl group which may have a substituent, a cycloalkylalkyloxy group which may have a substituent, an arylalkyloxy group which may have a substituent, a heteroarylalkyloxy group which may have a substituent, an alkenyl group which may have a substituent or an alkynyl group which may have a substituent, or R
1
and R
2
are coupled together to form a cycloalkylene group which may have a substituent, a carbon group forming said cycloalkylene group may be substituted by a sulfur atom, an oxygen atom, a sulfinyl group, a sulfonyl group or >NR
4
, R
4
representing a hydrogen atom or a lower alkyl group, and n
2
stands for 1 to 3;
B is a heteroarylene group which may have a substituent, an arylene group which may have a substituent, or a group represented by the following formula:
wherein R
5
represents a hydrogen atom or a lower alkyl group; R
6
and R
7
are the same or different and each independently represents a hydrogen atom, a lower alkyl group or a halogen atom and m
1
stands for 1 to 3, m
2
stands for 0 to 2; R
8
to R
15
are the same or different and each independently represents a hydrogen atom or a lower alkyl group; X represents an oxygen atom, a sulfur atom or >NR
4
, R
4
having the same meaning as defined above;
D is an arylene group which may have a substituent, a heteroarylene group which may have a substituent, or a group represented by the formula: —CR
6
═CR
7
—, R
6
and R
7
having the same meanings as defined above;
n
1
stands for 0 or 1;
M is a hydroxyl group, a lower alkoxy group or a group represented by the following formula: —NR
16
R
17
in which R
16
and R
17
are the same or different and each independently represents a hydrogen atom, a hydroxyl group, a lower alkyl group, a lower alkoxy group, a hydroxyalkyl group, an aryl group or a heteroaryl group or R
16
and R
17
are coupled together with the adjacent nitrogen atom to form an oxygen- or sulfur-containing ring; and
{overscore (_ _ _ _)} represents a single bond or double bond; or a physiologically acceptable salt thereof.
In the definition of the formula (I), examples of the group represented by A include:
wherein R
1
and R
2
have the same meanings as defined above; R
18
to R
36
are the same or different and each independently represents a hydrogen atom, a lower alkyl group or a phenyl group. Among them, preferred are the groups represented-by the following formulae:
wherein R
1
and R
2
and R
18
to R
28
have the same meanings as defined above.
Preferred examples of the group represented by B include heteroarylene groups each of which may have a substituent, groups represented by the formula: —CONH— or groups represented by the formula: —CR
6
═CR
7
— in which R
6
and R
7
have the same meanings as defined above.
In the above definition, B embraces the group represented by the following formula:
D embraces the group represented by the formula —(CR
6
═CR
7
)m
1
— in which R
6
, R
7
and m
1
have the same meanings as defined above; and A embraces the groups represented by the following formulae:
wherein R
1
and R
2
have the same meanings as defined above, and E, F, G, H and I are the same or different and each independently represents a nitrogen or carbon atom which may have a substituent and at least one of E, F, G, H and I represents a nitrogen atom.
The halogen atom represented by R
1
, R
2
, R
3
, R
6
or R
7
in the definition of the formula (I) means a fluorine, chlorine, bromine or iodine atom. Examples of the lower alkyl group which is represented by R
1
to R
3
and may have a substituent include linear or branched C
1-6
alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, amyl, isopentyl and neopentyl groups. Examples of the substituent which the lower alkyl group may have include a halogen atom, a lower alkoxy group, a cycloalkyl group, an alkenyl group, an alkynyl group, an aryl group, a heteroaryl group, an arylalkyl group, a heteroarylalkyl group and —NR
40
R
41
in which R
40
and R
41
are the same or different and each independently represents a hydrogen atom, a lower alkyl group or a lower alkoxy group. Among them, methyl, ethyl, propyl and isopropyl groups are preferred. The lower alkyl group represented by R
4
to R
36
means any one of the above-exemplified lower alkyl groups.
Examples of the cycloalkyl group which is represented by R
1
to R
3
and may have a substituent include cyclopropyl, cyclobutyl, cyclopentyl,
Abe Shinya
Hibi Shigeki
Hida Takayuki
Higashi Seiko
Kikuchi Kouichi
Eisai Co. Ltd.
Powers Fiona T.
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