Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
1997-05-28
2001-05-22
Nazario-Gonzalez, Porfirio (Department: 1621)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C514S595000, C514S617000, C514S624000, C514S628000, C514S629000, C560S024000, C560S037000, C564S056000, C564S183000, C564S189000, C564S204000, C564S219000, C564S138000
Reexamination Certificate
active
06235789
ABSTRACT:
TECHNICAL FIELD
This invention relates to a novel benzocycloalkene derivative having an excellent binding affinity for melatonin receptor, a process for producing it and use.
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. Further, melatonin exerts suppressively on pigment cells or female gonad and acts as a synchronous factor of biological clock while taking part in transmittance of photoperiodic code. Therefore, melatonin is considered to be possibly used for the therapy of diseases related with melatonin activity, such as reproduction and endocrinic disorders, sleep-awake rythm disorders, jet lag syndrome and various disorders related to ageing. Recently it was reported in Ann. N.Y. Acad. Sci., Vol. 719, PP.456-460 (1994) that the production of melatonin decline steadily into old age and the supplementing melatonin could reset the body's aging clock; However, in “Bioorganic & Medicinal Chemistry Letters, Vol.4, p.1485 (1994)”, there is described that, when the action on central nervous system is expected, melatonin is shown to be inactive by a peripheral administration.
As a compound having a melatonin receptor affinity,
1) a compound having acylamino group at the 2-position of tetrahydronaphthalene and of the formula
wherein R
1
and R
2
are independently, H, alkoxy etc., R
3
and R
5
are H etc., R
4
is aryl, C
1-4
alkyl etc., is described in EP-A-420064,
2) a compound having acylaminoethyl group at the 1-position of naphthalene and of the formula
wherein R is propyl, butyl, cyclopropyl etc., is described in “Journal of Medicinal Chemistry, No.35, pp.1484-1486, (1992)” and
3) (naphthylethyl)ureas are described in EP-A-530087.
And, as compounds having a benzocycloalkene structure
1) a compound of the formula
wherein R, R
1
and R
2
are independently H, lower alkoxy etc., R
3
and R
4
are independently H, lower acyl (—CO—R
5
) etc., R
5
is lower alkyl, n is 1 to 4, and having adrenaline activity and being useful as therapeutic agents in the treatment of hypertension is described in GB 2093837,
2) a compound of the formula
wherein R
1
, R
2
R
3
and R
4
are independently H, lower alkyl, and having &agr;
2
-adrenergic receptor agonist activity and being useful for hypertension is described in CA 1221639,
3) a compound of the formula
which is used as an intermediate of eptazocin hydrobromide being useful as a narcotic-antagonizing analgesic for relieving post-operative pains is described in EP-A-384917,
4) a compound of the formula
which is used as a starting material of tetralin having dopamine activity is described in “Journal of Medicinal chemistry, No. 26, p. 813, (1983)”.
None of them refers to the melatonin receptors affinities.
A melatonin agonist, which is different from melatonin in the structure, has stronger activities than those of melatonin, is metabolicaly stable and is excellent in the transferability into brain, can be expected to show superior therapeutic effects to those of melatonin. And, when the antagonistic activities of melatonin are desired, creation of a new melatonin antagonist is necessary.
At the present circumstances, no compounds which are fully satisfactory in the activities of melatonin receptors, in metabolical stability and in transferability into brain have been found. So, development of compounds, which are different from the above-mentioned known compounds in chemical structure, have excellent melatonin receptor affinities and are fully satisfactory as medicines, is ardently desired.
DISCLOSURE OF INVENTION
The present inventors diligently conducted extensive study and succeeded in creation of the novel compound which is characterized in having a R
3
CO-amino-C
2-5
alkyl group or a R
3
CO-amino-C
2-5
alkylidene group (R
3
is of the same meanings as defined hereinafter) at the 1-position of benzocycloalkenes of the formula:
wherein all symbols are of the same meaning as defined hereinafter and represented by the formula:
wherein R
1
and R
2
independently represent a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, or R
1
and R
2
, taken together with the adjacent carbon atom, may form an optionally substituted spiro ring;
R
3
represents an optionally substituted hydrocarbon group, an optionally substituted amino group, a substituted hydroxyl group or an optionally substituted heterocyclic group;
R
4
represents a hydrogen atom or an optionally substituted lower alkyl group; ring A represents a substituted benzene ring; m and n independently represent an integer of 1 to 4; and {overscore (.........)} represents a single bond or a double bond, or a salt thereof, and found that the compound (I) or a salt thereof and compound (Ia) containing the compound (I) and represented by the formula:
wherein ring A
1
represents an optionally substituted benzene ring and other symbols are of the same meaning as defined above, or salt thereof are excellent in affinity for melatonin receptors as melatonin agonists or antagonists and are satisfactory as medicines. Based on these findings, the present inventors have completed the invention.
More specifically, this invention relates to
(1) the compound (I) or salts thereof,
(2) the compound described in the above (1), in which R
1
and R
2
are independently a hydrogen atom or an optionally substituted hydrocarbon group, or R
1
and R
2
, taken together with the adjacent carbon atom, may form a spiro ring, R
3
represents an optionally substituted hydrocarbon group, an optionally substituted amino group or a substituted hydroxyl group,
(3) the compound described in the above (1), in which the hydrocarbon group is a C
1-6
aliphatic hydrocarbon group, a C
3-6
monocyclic saturated hydrocarbon group or a C
6-10
aromatic hydrocarbon group,
(4) the compound described in the above (1), in which the heterocyclic group is a 5- to 7-membered heterocyclic group having 1 to 3 hetero-atoms selected from nitrogen, oxygen and sulfur,
(5) the compound described in the above (1), in which the spiro ring is a 3 to 8-membered ring,
(6) the compound described in the above (1), in which the substituent of the amino group is an optionally substituted lower alkyl group or an optionally substituted aryl group,
(7) the compound described in the above (1), in which the substituted hydroxyl group is an optionally substituted lower alkoxy group,
(8) the compound described in the above (1), in which R
1
and R
2
are independently a hydrogen atom, a lower alkyl group or an aryl group,
(9) the compound described in the above (1), in which R
1
and R
2
are independently a hydrogen atom or a lower alkyl group,
(10) the compound described in the above (1), in which R
3
is (i) an optionally substituted lower alkyl group, (ii) an optionally substituted lower cycloalkyl group, (iii) an optionally substituted lower alkenyl group, (iv) an optionally substituted aryl group, (v) an optionally substituted lower alkylamino group, (vi) an optionally substituted arylamino group, (vii) an optionally substituted 5- or 6-membered nitrogen-containing heterocyclic group or (viii) an optionally substituted lower alkoxy group,
(11) the compound described in the above (1), in which R
3
is an optionally halogenated C
1-3
alkyl group,
(12) the compound described in the above (1), in which R
4
is a hydrogen atom,
(13) the compound described in the above (1), in which {overscore (.........)} is a single bond,
(14) the compound described in the above (1), in which n is an integer of 1 to 3,
(15) the compound described in the above (1), in which n is 1,
(16) the compound described in the above (1), in which m is 1 or 2,
(17) the compound described in the above (1), in which the ring A is a benzene ring having 1 to 3 substituents selected from the group consisting of (i) a halogen atom, (ii) a lower alkyl group, (iii) a lower alkoxy group optionally substituted with an aryl group, (iv) hydroxyl group and (v) a mono-lower
Miyamoto Masaomi
Ohkawa Shigenori
Uchikawa Osamu
Nazario-Gonzalez Porfirio
Takeda Chemical Industries Ltd.
Wenderoth , Lind & Ponack, L.L.P.
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