Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-07-13
2003-01-28
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S235500, C544S070000
Reexamination Certificate
active
06511975
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to novel spiropiperidine derivatives which exhibit antagonistic action against tachykinin receptors (NK
1
, NK
2
and NK
3
).
BACKGROUND OF THE INVENTION
It is already known that NK
1
receptors, NK
2
receptors and NK
3
receptors act as tachykinin receptors. A number of compounds are known to exhibit antagonistic action against one of these receptors. Recently, compounds which block as many subtypes as possible among these three subtypes have attracted a great deal of attention for use in methods of preventing or treating diseases induced by tachykinin. Compounds exhibiting antagonistic action against both NK
1
and NK
2
receptors are under investigation.
As a compound having antagonistic activities against both NK
1
and NK
2
receptors, for example, Compound A shown below is disclosed in EP-776893. However, it is not reported that this compound exhibits an antagonistic activity against NK
3
receptor.
DISCLOSURE OF THE INVENTION
The present invention relates to:
(1) a compound represented by the formula (I), or a pharmacologically acceptable salt, ester or other derivative thereof
{wherein,
R
1
and R
2
are the same or different and each represents an aryl group, a heteroaryl group, an aryl group substituted with 1 to 3 groups selected from Substituent Group A or a heteroaryl group substituted with 1 to 3 groups selected from Substituent Group A,
A represents a methylene group, a carbonyl group or a sulfonyl group,
B represents a single bond, a C
1-4
alkylene group or a C
2-4
alkenylene group,
D represents an oxygen atom or a sulfur atom,
E represents a C
1-4
alkyene or a C
2-4
alkenylene group,
[wherein,
G represents a C
5-8
cycloalkene ring, a C
5-9
cycloalkane ring substituted with 1 or 2 groups selected from Substituent Group B or a cycloalkene ring substituted with 1 or 2 groups selected from Substituent Group B,
Ar represents an aryl ring, a heteroaryl ring, an aryl ring substituted with 1 to 3 groups selected from Substituent Group A or a heteroaryl ring substituted with 1 to 3 groups selected from Substituent Group A],
R
3
represents a lower alkyl group, and
n represents an integer from 1 to 3;
with the proviso that G does not include a group substituted with only an oxo group or a group substituted with only a lower alkanesulfonyl group},
[Substituent Group A]
halogen atoms, lower alkyl groups, halogeno-lower alkyl groups, lower alkoxy groups, lower alkoxycarbonyl groups, carboxyl groups, hydroxyl groups, lower aliphatic acyl groups, lower aliphatic acylamino groups, amino groups and cyano groups;
[Substituent Group B]
oxo groups, hydroxyl groups, carboxyl groups and thiol groups.
Among these, preferred compounds are:
(2) compounds wherein R
1
represents an aryl group, a heteroaryl group or an aryl group substituted with 1 to 3 groups selected from Substituent Group A,
(3) compounds wherein R
1
represents an aryl group or an aryl group substituted with 1 to 3 groups selected from Substituent Group A
1
defined below,
(4) compounds wherein R
2
represents an aryl group or an aryl group substituted with 1 to 3 groups selected from Substituent Group A,
(5) compounds wherein R
2
represents an aryl group substituted with at least one group selected from Substituent Group A,
(6) compounds wherein A represents a carbonyl group,
(7) compounds wherein B represents a single bond,
(8) compounds wherein D represents an oxygen atom,
(9) compounds wherein E represents a C
1-4
alkylene group,
(10) compounds wherein E represents a C
2-3
alkylene group,
(11) compounds wherein
(12) compounds wherein G represents a cyclopentane or cyclopentene ring which is substituted with one or two groups selected from Substituent Group B,
(13) compounds wherein G represents a cyclopentane or cyclopentene ring which is substituted with a hydroxy group,
(14) compounds wherein n represents 1 or 2, and
(15) compounds wherein n represents 2;
and pharmacologically acceptable salts, esters or other derivatives thereof.
[Substituent Group A
1
]
lower alkyl groups, halogeno-lower alkyl groups and lower alkoxy groups.
Of the above-described compounds, compounds which comprise a combination of factors selected from eight groups consisting of (2) and (3); (4) and (5); (6); (7); (8); (9) and (10); (11) to (13); and (14) and (15) are also preferred.
(16) The more preferred compounds are:
1-{2-[(2R)-(3,4-dichlorophenyl)-4-(3,4,5-trimethoxybenzoyl)morpholin-2-yl]ethyl}spiro[(2-hydroxy)indane-1,4′-piperidine],
1-{2-[(2R)-(3,4-dichlorophenyl)-4-(3,4,5-trimethoxybenzoyl)morpholin-2-yl]ethyl}spiro[(3-hydroxy)indane-1,4′-piperidine],
1-{2-[(2R)-(3,4-dichlorophenyl)-4-(3,4,5-trimethoxybenzoyl)morpholin-2-yl]ethyl}spiro[1H-indene-1,4′-piperidine],
1-{2-[(2R)-(3,4-dichlorophenyl)-4-(3,5-dimethoxybenzoyl)morpholin-2-yl]ethyl}spiro[(2-hydroxy)indane-1,4′-piperidine],
1-{2-[(2R)-(3,4-dichlorophenyl)-4-(3,5-dimethoxybenzoyl)morpholin-2-yl]ethyl}spiro[(3-hydroxy)indane-1,4′-piperidine], and
1-{2-[(2R)-(3,4-dichlorophenyl)-4-(3,5-dimethoxybenzoyl)morpholin-2-yl]ethyl}spiro[(1H-indene-1,4′-piperidine],
and pharmacologically acceptable salts, esters and other derivatives thereof.
(17) The most preferred compounds are:
1-{2-[(2R)-(3,4-dichlorophenyl)-4-(3,4,5-trimethoxybenzoyl)morpholin-2-yl]ethyl}spiro[(2-hydroxy)indane-1,4′-piperidine] and
1-{2-[(2R)-(3,4-dichlorophenyl)-4-(3,4,5-trimethoxybenzoyl)morpholin-2-yl]ethyl}spiro[(3-hydroxy)indane-1,4′-piperidine],
and pharmacologically acceptable salts, esters and other derivatives thereof.
A novel medicine of the present invention comprises as an effective ingredient a compound selected from any one of the compounds described above in (1) to (17), or a pharmacologically acceptable salt, ester or other derivative thereof, and it can be used particularly as a preventive agent or remedy for asthma and/or bronchitis, rhinitis, allergy and urinary incontinence.
In the formula (I), examples of the “aryl group” in the definitions of R
1
and R
2
, the “aryl group” of the “aryl group substituted with 1 to 3 groups selected from Substituent Group A” in the definitions of R
1
and R
2
, and the “aryl group” of the “aryl group which may be substituted with a group selected from Substituent Group A” in the definition of “Substituent Group B”, include C
5-14
aromatic hydrocarbon groups such as phenyl, indenyl, naphthyl, phenanthrenyl and anthracenyl groups, of which phenyl groups are preferred.
Incidentally, the above-described “aryl group” may form a fused ring with a C
3-10
cycloalkyl group and examples of such a group include 5-indanyl groups.
The “heteroaryl group” in the definitions of R
1
and R
2
, and the “heteroaryl group” of the “heteroaryl group substituted with 1 to 3 groups selected from Substituent Group A” in the definitions of R
1
and R
2
, mean a 5- to 7-membered aromatic heterocyclic group containing 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms. Examples include furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl groups. Among these, 5- to 7-membered aromatic heterocyclic groups each of which contain at least one nitrogen atom and may further contain an oxygen atom or sulfur atom are preferred. Examples include pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl groups, of which pyridyl, imidazolyl, oxazolyl, pyrazinyl and thiazolyl groups are more preferred.
Incidentally, the above-described “heteroaryl group” may form a fused ring with another cyclic group. Examples of s
Iio Yukiko
Nakajima Katsuyoshi
Nishi Takahide
Takemoto Toshiyasu
Yamaguchi Takeshi
McKenzie Thomas C.
Sankyo Company Limited
Shah Mukund J.
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