Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-07-30
2001-01-09
McKane, Joseph K. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S518000
Reexamination Certificate
active
06172102
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a pyrrole derivative, a pharmaceutically acceptable salt thereof, and a solvate of either of them, all of which are useful as medicines.
The compound of the invention has urinary bladder capacity increasing activity and is useful for the treatment of pollakiuria and urinary incontinence.
BACKGROUND ART
The frequency of urination of healthy humans is generally 4-6 times a day and usually no urine is voided during sleep at night. The condition of an abnormally increased frequency of urination is called pollakiuria and the condition of involuntary emptying of the urinary bladder is known as urinary incontinence. Both morbidities are bothersome to the affected person because sleep is disturbed and going out is restricted. The frequency of occuring pollakiuria or urinary incontinence is particularly high in the bedridden aged persons and patients with dementia and there is a pressing need for development of useful therapeutic drug in this field, not only for patients and clinical doctors but also for the people taking charge of nursing care.
As therapeutic drugs designed to ameliorate pollakiuria and urinary incontinence through increase in bladder capacity, flavoxate, oxybutynin, propiverine and so on are used today.
Meanwhile, as pyrrole derivatives apparently resembling the compound of the present invention, the compounds listed below in Table 1 are known. However, none of them are known to have the first medicinal use, namely, to be useful for the treatment of disease such as pollakiuria or urinary incontinence.
TABLE 1
Compound
No.
Structural formula
Literature
R1
J. Prakt. Chem., 318, 663 (1976).
R2
J. Heterocyclic Chem., 14, 383 (1977). Z. Chem., 1, 349 (1961).
R3
J. Heterocyclic Chem., 14, 383 (1977).
R4
J. Heterocyclic Chem., 14, 383 (1977).
R5
Khim. Geterotsiki. Soedim., (9), 1217, (1975) (Chem. Abstr., 84,59299 (1976))
R6
J. Heterocyclic Chem., 14, 383 (1977).
R7
Khim. Geterotsiki. Soedim., (9), 1217, (1975) (Chem. Abstr., 84,59299 (1976))
R8
J. Pharm. Sci., 68, 317 (1979).
R9
Synthesis, 217 (1979).
R10
Synthesis, 55 (1974).
R11
J. Pharm. Sci., 65, 908 (1976). J. Heterocyclic Chem., 23, 397 (1986).
R12
Farmaco, Ed. Sc., 43, 103 (1988).
R13
Khim. Geterotsiki. Soedim., (9), 1217, (1975) (Chem. Abstr., 84, 59299 (1976))
R14
J. Heterocyclic Chem., 14, 383 (1977).
R15
Khim. Geterotsiki. Soedim., (9), 1217, (1975) (Chem. Abstr., 84, 59299 (1976))
R16
Farmaco, Ed. Sc., 43, 103 (1988).
R17
Farmaco, Ed. Sc., 43, 103 (1988).
R18
Farmaco, Ed. Sc., 43, 103 (1988).
R19
Farmaco, Ed. Sc., 43, 103 (1988).
R20
Farmaco, Ed. Sc., 43, 103 (1988).
R21
Farmaco, Ed. Sc., 43, 103 (1988).
R22
Farmaco, Ed. Sc., 43, 103 (1988).
R23
Farmaco, Ed. Sc., 43, 103 (1988).
R24
Farmaco, Ed. Sc., 43, 103 (1988).
R25
Farmaco, Ed. Sc., 43, 103 (1988).
R26
Farmaco, Ed. Sc., 43, 103 (1988).
R27
Farmaco, Ed. Sc., 43, 103 (1988).
R28
Farmaco, Ed. Sc., 43, 103 (1988).
R29
J. Chem. Res., Synop. (8), 266 (1992). J. Chem. Res., Miniprint, 2049 (1992).
R30
Heterocycles, 10, 261 (1978).
R31
Heterocycles, 10, 261 (1978).
R32
J. Org. Chem., 43, 4273 (1978). J. Chem. Soc., B, (1), 79 (1970).
R33
J. Org. Chem., 43, 4273 (1978).
R34
J. Org. Chem., 43, 4273 (1978). EP 358047 A2.
R35
J. Org. Chem., 43, 4273 (1978).
R36
J. Org. Chem., 43, 4273 (1978).
R37
J. Org. Chem., 43, 4273 (1978). Heterocycles, 20, 829 (1983).
R38
J. Chem. Soc., B, (1), 79 (1970).
R39
Gazz. Chim. Ital., 71, 375 (1941).
R40
Justus Liebigs Ann. Chem., 447, 43 (1926).
R41
WO 93/19067.
R42
EP 480204 A1.
R43
EP 314009 A2. EP 389904 A2.
R44
Chem. Ber., 105, 1258 (1972).
R45
J. Org. Chem., 31, 4110 (1996).
R46
J. Org. Chem., 31, 4110 (1996).
R47
EP 389904 A2.
R48
EP 389904 A2.
R49
EP 389904 A2.
DISCLOSURE OF INVENTION
The inventors of the present invention did much research for developing a drug which is structurally different from the hitherto-known therapeutic drugs for pollakiuria or urinary incontinence and is more useful than those drugs.
As a result, the inventors found that the pyrrole derivative of the following formula [1] or a pharmaceutically acceptable salt thereof, or a solvate of either of them, has excellent bladder capacity increasing activity and is useful as a therapeutic drug for pollakiuria or urinary incontinence. The present invention has been completed on the basis of the above finding.
wherein R
1
represents hydrogen or alkoxycarbonylamino;
R
2
represents (1) alkyl, (2) aryl which may be substituted, (3) aromatic heterocyclyl which may be substituted,
R
6
and R
7
may be the same or different and each represents (1) hydrogen or (2) alkyl (which alkyl may be substituted by (1) hydroxy, (2) aryl which may be substituted by alkoxy, or (3) aromatic heterocyclyl);
Z
1
and Z
2
may be the same or different and each represents —CH
2
— or >C═O; provided that Z
1
and Z
2
do not concurrently represent >C═O;
Y represents —CH
2
—, —O—, —S—, or >NR
9
;
R
9
represents hydrogen, alkyl, acyl, aryl, or aromatic heterocyclyl;
m represents an integer of 1-3; n represents an integer of 0-2; p represents 0 or 1;
in case R
2
represents aryl which may be substituted or aromatic heterocyclyl which may be substituted, the aryl or aromatic heterocyclyl may be substituted by 1 member or 2-3 different members selected from the group consisting of (1) halogen, (2) alkyl which may be substituted by halogen, (3) cyano, (4) nitro, (5) alkoxycarbonyl, (6) hydroxy, (7) alkoxy (which alkoxy may be substituted by halogen, aryl which may be substituted by alkoxy, or alkoxy), (8) —NHSO
2
R
82
, and (9) —NR
83
R
84
; or two adjacent substituent groups may jointly represent —O—(CH
2
)
t
—O—;
R
82
represents (1) alkyl or (2) aryl which may be substituted by alkyl;
t represents 1 or 2;
R
83
or R
84
may be the same or different and each represents (1) hydrogen, (2) alkyl, or (3) acyl; or R
83
and R
84
jointly and taken together with the adjacent N atom are present 5- through 7-membered cyclic amino;
R
3
represents cyano or carbamoyl;
R
4
represents hydrogen or alkyl;
E represents alkylene; q represents 0 or 1;
A represents (1) methyl, (2) aryl which may be substituted, or (3) aromatic heterocyclyl which may be substituted;
in case A represents aryl which may be substituted or aromatic heterocyclyl which may be substituted, the aryl or aromatic heterocyclyl may be substituted by 1 member or 2-3 different members selected from the group consisting of (1) halogen, (2) alkyl which may be substituted by halogen, (3) cyano, (4) nitro, (5) alkoxycarbonyl, (6) hydroxy, (7) alkoxy (which alkoxy may be substituted by a halogen, aryl which may be substituted by alkoxy, or alkoxy), (8) —NHSO
2
R
92
, and (9) —NR
93
R
94
; or two adjacent substituent groups may jointly represent —O—(CH
2
)
u
—O—;
R
92
represents (1) alkyl or (2) aryl which may be substituted by alkyl;
u represents 1 or 2;
R
93
and R
94
may be the same or different and each represents (1) hydrogen, (2) alkyl, or (3) acyl; or R
93
and R
94
jointly and taken together with the adjacent N atom represent 5- through 7-membered cyclic amino;
A—(E)
q
, R
4
, and the double bond of the pyrrole ring may jointly, i.e.
X represents —O—, —S—, or >NR
90
where R
90
represents alkyl;
R
95
, R
96
and R
97
may be the same or different and each is selected from the group consisting of (1) hydrogen, (2) halogen, (3) alkyl which may be substituted by halogen, (4) cyano, (5) nitro, (6) alkoxycarbonyl, (7) hydroxy, (8) alkoxy (which alkoxy may be substituted by halogen or alkoxy), (9) —NHSO
2
R
92
(R
92
is as defined above), and (10) —NR
93
R
94
(R
93
and R
94
are as defined above); any two adjacent substituent groups among R
95
, R
96
, and R
97
may jointly represent —O—(CH
2
)
u
—O— (u is as defined above).
The present invention relates to a pharmaceutical composition comprising the compound of formula [1] as an active ingredient. The present invention further relates to the compound of formula [1].
Depending on the comb
Nakamura Ayatsugu
Tanaka Mitsushi
Tsuda Masami
McKane Joseph K.
Nippon Shinyaku Co. Ltd.
Wright Sonya
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