Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-05-10
2001-04-17
Kight, John (Department: 1612)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C549S458000, C514S923000
Reexamination Certificate
active
06218429
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a tricyclic compound with excellent binding affinity for melatonin receptor, a process for producing and use thereof.
BACKGROUND ART
Melatonin (N-acetyl-5-methoxytryptamine), which is a hormone synthesized and secreted principally in the pineal gland, increases in dark circumstances and decreases in light circumstances. Melatonin exerts suppressively on pigment cells and the female gonads, and acts as a synchronous factor of biological clock while taking part in transmittance of photoperiodic code. Therefore, melatonin is expected to be used for the therapy of diseases related with melatonin activity, such as reproduction and endocrinic disorders, sleep-awake rhythm disorders, jet-lag syndrome and various disorders related to aging, etc.
Recently, it has been reported that the production of melatonin melatonin could reset the body's aging clock (see Ann. N. Y. Acad. Sci., Vol. 719, pp. 456-460 (1994)). As previously reported, however, melatonin is easily metabolized by metabolic enzymes in vivo (see Clinical Examinations, Vol. 38, No. 11, pp. 282-284 (1994)). Therefore, it cannot be said that melatonin is suitable as a pharmaceutical substance.
Various melatonin agonists and antagonists such as those mentioned below are known.
Tricyclic or more poly-cyclic compounds with a cyclic ether moiety, such as those mentioned below, are known.
are disclosed in Tetrahedron Lett., Vol. 36, p. 7019 (1995).
are disclosed in J. Med. Chem., Vol. 35, p. 3625 (1992).
are disclosed in Tetrahedron, Vol. 48, p. 1039 (1992).
are disclosed in Tetrahedron Lett., Vol. 32, p. 3345 (1991).
is disclosed in Bioorg. Chem., Vol. 18, p. 291 (1990).
is disclosed in J. Electroanal. Chem. Interfacial Electrochem., Vol. 278, p. 249 (1990).
However, there is no report referring to the relationship between these compounds and melatonin receptors.
As tricyclic compounds with an affinity for melatonin receptor, known are compounds of:
wherein R
1
represents a hydrogen atom, a halogen atom or a C
1-6
alkyl group; R
2
represents —CR
3
R
4
(CH
2
)
p
NR
5
COR
6
(in which R
3
, R
4
and R
5
are the same or different and each represents a hydrogen atom or a C
1-6
alkyl group, and R
6
represents a C
1-6
alkyl group or a C
3-7
cycloalkyl group); n represents an integer of 2 to 4; and p represents an integer of from 1 to 4 (WO-A-9517405), and compounds of:
wherein R
1
represents —CR
3
R
4
(CH
2
)
p
NR
5
COR
6
(in which R
3
, R
4
and R
5
are the same or different and each represents a hydrogen atom or a C
1-6
alkyl group, and R
6
represents a C
1-6
alkyl group or a C
3-7
cycloalkyl group; R
2
represents a hydrogen atom, a halogen atom, a C
1-6
alkyl group, OR
7
or CO
2
R (in which R
7
represents a hydrogen atom or a C
1-6
alkyl group), provided that when q is 2, each of R
2
are the same or different and each represents a hydrogen atom, a halogen atom, a C
1-6
alkyl group, OR
7
or CO
2
R
7
; n represents an integer of 0 to 2; p represents an integer of 1 to 4; and q represents 1 or 2 (WO-A-9529173).
Melatonin agonists having different structures from that of melatonin and having an excellent binding affinity for melatonin receptor, excellent intracerebral mobility and excellent metabolical stability are expected to be more effective as a pharmaceutical remedy than melatonin.
At present, no compounds are known which are fully satisfactory with respect to their activity on melatonin receptor, and to their metabolical stability and the intracerebral mobility. Therefore, it is earnestly desired to develop compounds which are different from the above-mentioned known compounds in terms of their chemical structure, which have excellent agonistic or antagonistic activity towards melatonin receptor and which are therefore fully satisfactory for use in medicines such as pharmaceutical preparations.
SUMMARY OF THE INVENTION
The present invention relates to a novel compound which is characterized in having a R
1
—CO—amino—C
1-4
alkylene group (in which R
1
is of the same meanings as defined hereinafter) at Y of the basic skeleton moiety of the formula:
wherein all symbols are of the same meanings as defined hereinafter and is represented by the formula:
wherein R
1
represents an optionally substituted hydrocarbon group, an optionally substituted amino group or an optionally substituted heterocyclic group;
R
2
represents a hydrogen atom or an optionally substituted hydrocarbon group;
R
3
represents a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group;
X represents CHR
4
, NR
4
, O or S in which R
4
represents a hydrogen atom or an optionally substituted hydrocarbon group;
Y represents C, CH or N, provided that when X is CH
2
, Y is C or CH;
represents a single bond or a double bond;
ring A represents an optionally substituted, 5- to 7-membered oxygen-containing heterocyclic ring;
ring B represents an optionally substituted benzene ring; and
m represents an integer of 1 to 4, or a salt thereof, or a salt thereof [hereinafter referred to as compound (I)], which has an unexpected good binding affinity for melatonin receptor as a melatonin agonist and is therefore sufficiently satisfactory for use in medicines such as pharmaceutical preparations.
DETAILED EXPLANATION OF THE INVENTION
The present invention provides;
(1) the compound (I),
(2) the compound of the above (1), wherein R
1
is
(i) a C
1-6
alkyl, C
2-6
alkenyl, C
2-6
alkynyl, C
3-6
cycloalkyl or C
6-14
aryl group which may be substituted by 1 to 5 substituents selected from the group consisting of a halogen, nitro, cyano, hydroxy, an optionally halogenated C
1-6
alkyl, C
1-6
alkoxy, amino, mono-C
1-6
alkylamino, di-C
1-6
alkylamino, carboxyl, C
1-6
alkyl-carbonyl, C
1-6
alkoxy-carbonyl, carbamoyl, mono-C
1-6
alkylcarbamoyl, di-C
1-6
alkylcarbamoyl, C
6-10
aryl-carbamoyl, C
6-10
aryl, C
6-10
aryloxy and an optionally halogenated C
1-6
alkyl-carbonylamino,
(ii) an amino group which may be substituted by 1 or 2 substituents selected from the group consisting of a C
1-6
alkyl, C
2-6
alkenyl, C
2-6
alkynyl, C
3-6
cycloalkyl and C
6-14
aryl group, each of which may be substituted by 1 to 5 substituents selected from the group consisting of a halogen, nitro, cyano, hydroxy, an optionally halogenated C
1-6
alkyl, C
1-6
alkoxy, amino, mono-C
1-6
alkylamino, di-C
1-6
alkylamino, carboxyl, C
1-6
alkyl-carbonyl, C
1-6
alkoxy-carbonyl, carbamoyl, mono-C
1-6
alkyl-carbamoyl, di-C
1-6
alkyl-carbamoyl, C
6-10
aryl-carbamoyl, C
6-10
aryl, C
6-10
aryloxy and an optionally halogenated C
1-6
alkyl-carbonylamino, or
(iii) a 5- to 14-membered heterocyclic group containing, besides carbon atoms, 1 to 3 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom, which group may be substituted by 1 to 5 substituents selected from the group consisting of a halogen, C
1-6
alkyl, C
3-6
cycloalkyl, C
2-6
alkynyl, C
2-6
alkenyl, C
7-11
aralkyl, C
6-10
aryl, C
1-6
alkoxy, C
6-10
aryloxy, formyl, C
1-6
alkyl-carbonyl, C
6-10
aryl-carbonyl, formyloxy, C
1-6
alkyl-carbonyloxy, C
6-10
aryl-carbonyloxy, carboxyl, C
1-6
alkoxy-carbonyl, C
7-11
aralkyloxy-carbonyl, carbamoyl, an optionally halogenated C
1-4
alkyl, oxo, amidino, imino, amino, mono-C
1-4
alkylamino, di-C
1-4
alkylamino, 3- to 6-membered cyclic amino, C
1-3
alkylenedioxy, hydroxy, nitro, cyano, mercapto, sulfo, sulfino, phosphono, sulfamoyl, mono-C
1-6
alkylsulfamoyl, di-C
1-6
alkylsulfamoyl, C
1-6
alkylthio, C
6-10
arylthio, C
1-6
alkylsulfinyl, C
6-10
arylsulfinyl, C
1-6
alkylsulfonyl and C
6-10
arylsulfonyl;
R
2
is (i) a hydrogen atom or (ii) a C
1-6
alkyl, C
2-6
alkenyl, C
2-6
alkynyl, C
3-6
cycloalkyl or C
6-14
aryl group which may be substituted by 1 to 5 substituents selected from the group consisting of a halogen, nitro, cyano, hydroxy, an optionally halogenated C
1-6
alkyl, C
1-6
alkoxy, amino, mono-C
1-6
alkylamino, di-C
1-6
alkylamino, carboxyl, C
1-6
alkyl-carbonyl, C
1-6
alkoxy-carbonyl, carbamoyl
Fukatsu Kohji
Miyamoto Masaomi
Ohkawa Shigenori
Uchikawa Osamu
Covington Raymond
Fitzpatrick ,Cella, Harper & Scinto
Kight John
Takeda Chemical Industries Ltd.
LandOfFree
Tricyclic compounds, their production and use does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Tricyclic compounds, their production and use, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Tricyclic compounds, their production and use will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2482019