Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-12-20
2001-04-24
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S392000, C544S403000, C514S255030
Reexamination Certificate
active
06221868
ABSTRACT:
DESCRIPTION
1. Technical Field
The present invention relates to a pharmaceutical preparation comprising a compound having a tropone structure and in particular to remedies/preventives (therapeutic or preventive agents) against frequent urination (pollakiuria) or urinary incontinence.
2. Background Art
With the aging society, pollakiuria, urinary incontinence, and dementia become a social problem. There is a need for medical care with the aim of maintaining QOL (quality of life) in one's old age. In particular, pollakiuria and urinary incontinence limit the range of behavior for the aged and significantly lower their quality of life, thus bringing about a very heavy burden not only on a patient but also on a nurse or a care worker.
Tropone compounds including hinokitiol are marketed as a part of daily articles as a bathing agent and a humectant. Further, they are extensively studied as pharmaceutical preparations. For example, JP-A 6-509318 discloses such compounds as therapeutic and preventive agents against ischemic diseases such as cerebral vascular diseases and heart vascular diseases. However, the effect of the compounds having a tropone structure on pollakiuria and urinary incontinence is not known.
As chemicals for treatment of diseases such as pollakiuria and urinary incontinance, an anticholinergic agent, a smooth muscle direct relaxant, a, tricyclic antidepressant, etc. have been used, but the action of the smooth muscle direct relaxant on the bladder is lower as that of the anticholinergic agent, and the effect thereof on urinary incontinence is unsatisfactory. Further, the anticholinergic agent has the side effects of dry mouth, ischuria, etc. In the change of the human bladder smooth muscle along with aging, an increase in atropine resistance contraction is observed, and these chemicals are not necessarily adequate in respect of the effect and side effects. In particular, the chemicals alone having an anticholinergic action are considered unsatisfactory in their effect on urinary incontinence for the aged. In the clinical field of chemotherapy at present under these circumstances, development of a new therapeutic agent for pollakiuria and urinary incontinence is desired earnestly. Further, with the highly aging society near at hand, comprehensive therapy came to be conducted for nerve diseases such as cerebral apoplexy, spinal damage or nerve-degenerated disease, and further collective therapy for uterine cancer and rectal cancer and therapy for diabetes have been developed thereby enabling the prolonging of the life of a fatal patient in the past, and as a result and also for raising the QOL of the patient, there is an increasing need for treatment and prevention of pollakiuria and urinary incontinence.
DISCLOSURE OF THE INVENTION
As a result of eager study to solve the problem described above, the present inventors unexpectedly found that compounds having a tropone structure have the following effects: (1) they increase the bladder capacity by their inhibitory action on urination reflexes, thus prolonging urination intervals, (2) they do not cause dry mouth and ischuria as the side effects of the anticholinergic agent, and (3) they are also effective for patients observed to have an increase in atropine resistance contraction and the like, and the present inventors found that these compounds are effective as a therapeutic and preventive agent against pollakiuria and urinary incontinence, and the present invention was thereby completed. That is, the present invention relates to the following items 1 to 19.
1. A therapeutic or preventive agent against pollakiuria or urinary incontinence, comprising a compound having a tropone structure or a pharmaceutically acceptable salt thereof as an active ingredient.
2. The therapeutic or preventive agent against pollakiuria or urinary incontinence according to item 1 above, wherein the tropone compound or a pharmaceutically acceptable salt thereof used as an active ingredient has 1 to 3 substituent groups on the tropone structure, and at least one of the substituent groups is a lower alkyl group substituted with a 6- to 7-membered cyclic group having at least one nitrogen atom in the ring, and when there are 2 or more substituent groups, each of the substituent groups is independently a C
1
to C
20
hydrocarbon residue bound via or not via a hetero atom to the tropone structure.
3. The therapeutic or preventive agent against pollakiuria or urinary incontinence according to item 1 or 2 above, wherein the compound having a tropone structure is a compound represented by the general formula (1):
wherein R
1
and R
2
are the same or different and represent a hydrogen atom, a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted aryl group, R
3
represents —OR or —NR
7
—R
8
, R
6
represents a hydrogen atom, a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted aralkyl group or a substituted or unsubstituted C
1
to C
5
acyl group, R
7
and R
8
are the same or different and represent a hydrogen atom, a lower alkyl group which may be substituted with a hetero atom, or a substituted or unsubstituted aralkyl group, or R
7
and R
8
are combined to form a 5- to 10-membered ring which may contain 1 to 3 —O— or —NR
9
— residues, R
9
represents a hydrogen atom, a substituted or unsubstituted lower alkyl group or a substituted or unsubstituted aryl group; R
4
and R
5
are the same or different and represent a hydrogen atom or a lower alkyl group, R
12
represents a hydrogen atom and a lower alkyl group, X represents a nitrogen atom or CH, Z represents —CH(Ar
1
)(Ar
2
), an unsubstituted or substituted phenyl, benzyl, benzoyl, 2-pyridyl or 2-pyrimidyl group, Ar
1
and Ar
2
are substituted or unsubstituted aryl groups which may be the same or different, and m is 1 or 2.
4. The therapeutic or preventive agent against pollakiuria or urinary incontinence according to any one of items 1 to 3 above, wherein the compound having a tropone structure is a compound represented by the general formula (2):
wherein R
1
and R
2
are the same or different and represent a hydrogen atom, a lower alkyl group, a substituted or unsubstituted aryl group, R
3
′ represents —OR
6
′ or —NR
7
R
8
, R
6
′ represents a hydrogen atom, a lower alkyl group which may be substituted with a hetero atom, or a substituted or unsubstituted aralkyl group, R
7
and R
8
are the same or different and represent a hydrogen atom, a lower alkyl group which may be substituted with a hetero atom, or a substituted or unsubstituted aralkyl group, or R
7
and R
8
are combined to form a 5- to 10-membered ring which may contain 1 to 3 —O— or —NR
9
— residues, R
9
represents a hydrogen atom, a lower alkyl group or a substituted or unsubstituted aryl group; R
4
and R
5
are the same or different and represent a hydrogen atom or a lower alkyl group, Ar
1
and Ar
2
are the same or different and represent a substituted or unsubstituted aryl group, and n is 1 or 2.
5 The therapeutic or preventive agent against pollakiuria or urinary incontinence according to item 4 above, wherein R
1
represents an isopropyl group, R
2
, R
4
and R
5
represent a hydrogen atom, R
3
′ represents a 2-hydroxyethylamino group, Ar
1
and Ar
2
independently represent a phenyl group or a 4-fluorophenyl group, and n is 1.
6. A novel tropone derivative represented by the general formula (3):
wherein R
10
represents a hydrogen atom or a C
1
to C
5
alkyl group, R
11
represents a hydrogen atom atom, a C
1
to C
5
alkyl group, a C
1
to C
5
alkyl group having a hydroxyl group or an alkoxy group, an unsubstituted or substituted benzyl group, or a C
1
to C
5
acyl group, R
12
represents a hydrogen atom or a C
1
to C
3
alkyl group, Z′ represents an unsubstituted or substituted phenyl, benzyl, benzoyl, 2-pyridyl or 2-pyrimidyl group, X represents a nitrogen atom or CH, and m is an integer of 1 or 2, as well as pharmaceutically acceptable salts thereof.
7. The novel tropone derivative according to item 6 above, wherein
Koga Ichiro
Narita Kazuhisa
Okada Atsushi
Liu Hong
Nields & Lemack
Nippon Kayaku Kabushiki Kaisha
Shah Mukund J.
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