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Agents and crystals for improving excretory potency of urinary bladder

a technology of urinary bladder and agents, which is applied in the field of drugs, can solve the problems of insufficient clinical efficacy of distiginine, inability to completely satisfy the needs of pregnant women, and inability to use bethanechol, etc., and achieves the effects of improving the excretion of the urinary bladder, high efficacy, and high efficacy

Inactive Publication Date: 2006-12-14
ISIHARA YUJI +3
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0053] (12) Agent for improving excretory potency of the urinary bladder which comprises a combination of an α-blocker and an amine compound of non-carbamate-type having an acetylcholin-esterase-inhibiting action, and
[0055] As a result of intensive investigations, the present inventors have succeeded in obtaining crystals of 8-[3-[1-[(3-fluorophenyl)methyl)-4-piperidinyl]-1-oxopropyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one, which are high in purity, high in quality, low in hygroscopic property, and extremely excellent in stability without deteriorating upon long-term storage under usual conditions, thereby providing the second aspect of the present invention.

Problems solved by technology

Inferior uropathy in the aged, particularly dysuria, especially dysuria caused by prostatomegaly, becomes a great problem of public concern with the advance of a recent aging society, though inferior uropathy may also be found in the youth.
Bethanechol however is incompatible with pregnant women, peptic ulcers, organic ileus, asthma, hyperthyroidism, etc., because it has adverse effects such as epiphora, sweating, gastro-intestinal disorders, stomachache, etc.
No entirely satisfactory drugs have yet been found.
However, it is known that, for example, distiginine is insufficient in its clinical efficacy since it contracts the muscle of the urinary bladder with constriction of the muscle of the urethra to increase urethral resistance and consequently make the voiding flow rate worse.
In addition, neostigmine has not been used in therapy because of the short duration of its action (Takamichi Hattori and Kosaku Yasuda, “Sinkeiinseiboukou-No-Sindan-To-Chiryou (Diagnosis and Therapy of Neurogenic Bladder)”, 2nd Ed., p.
In these compounds, however, there is neither report, suggestion nor disclosure on their effect as prophylactics or therapeutic agents for dysuria (difficulty of urination) or on their effect as excretion improving agents for urinary bladder.

Method used

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  • Agents and crystals for improving excretory potency of urinary bladder
  • Agents and crystals for improving excretory potency of urinary bladder
  • Agents and crystals for improving excretory potency of urinary bladder

Examples

Experimental program
Comparison scheme
Effect test

reference examples 1-30

[0481] According to per se known methods, compounds of Reference Examples 1-30 were obtained as depicted in the following Table, wherein R′═H.

TABLE 1Reference Example No.ArRnY1H22H23H24H25H26H27H28H29H210H2

[0482]

TABLE 2Reference Example No.ArRnY11H212H213H214H215H216H217H218H219H220H2

[0483]

TABLE 3Reference Example No.ArRnY21H222H223H224H225H226H227H228H2

[0484]

TABLE 4ReferenceExampleNo.2930

reference example 15-1

8-[3-[1-[(3-fluorophenyl)methyl]-4-piperidinyl]-1-oxopropyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one (Compound of Reference Example 15)

[0485]

[0486] 1) To thionyl chloride (300 mL) was added 3-(1-acetyl-4-piperidinyl)propionic acid (88.2 g, 0.443 mol) in small portions under ice cooling. The mixture was stirred at room temperature for 10 minutes, and then thionyl chloride was distilled off at 25° C. under reduced pressure. Diethyl ether was added to the residue and then evaporated in vacuo to give a yellow solid. Again, diethyl ether was added, and the solid was crushed with a spatula, and ether was evaporated in vacuo to give 3-(1-acetyl-4-piperidinyl)propionic acid chloride as crude light yellow powder. This light yellow powder and 1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one (64.0 g, 0.369 mol) were suspended into 1,2-dichloroethane (200 mL), into which aluminum chloride (162 g, 1.21 mol) was added in small portions at room temperature. The mixture was stir...

reference example 15-2

8-[3-[1-(phenyl methyl)-4-piperidinyl]-1-oxopropyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one (Compound of Reference Example 17)

[0499]

[0500] 8-[3-[(4-Piperidinyl)-1-oxopropyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one [obtained in section 2) of Reference Example 15-1 and benzyl bromide were treated in the same manner as in section 3) of Reference Example 15-1 to give colorless powder, which was crystallized from ether-isopropyl ether to give the title compound as colorless crystals having mp. 103-104° C.

[0501]1H-NMR (CDCl3) δ 1.20-1.75 (8H, m), 1.85-2.05 (2H, m), 2.71 (2H, t, J=7.6 Hz), 2.80-2.95 (3H, m), 3.02 (2H, t, J=7.6 Hz), 3.22 (2H, t, J=8.6 Hz), 3.49 (2H, s), 4.13 (2H, t, J=8.6 Hz), 7.20-7.35 (5H, m), 7.67 (1H, s), 7.71 (1H, s).

[0502] Elemental analysis for C26H30N2O2:

[0503] Calcd: C, 77.58; H, 7.51; N. 6.96

[0504] Found: C, 77.30; H, 7.49; N, 7.20

[0505] The above-mentioned title compound was dissolved in ethanol, to which was added 1.5 equivalent...

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Abstract

Agents for improving potentcy of the urinary bladder which comprise an amine compound of non-carbamate-type having an acetylcholinesterase-inhibiting action. Particularly, crystals of a tricyclic, condensed, heterocyclic derivative are provided, which possess an excellent action to inhibit acetylcholinesterase and an action to improve the excretory potency of the urinary bladder. As an example, crystals of of 8-[3-[1-[(3-fluorophenyl)-methyl]-4-piperidinyl]-1-oxopropyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one or a salt thereof and pharmaceutical compositions containing them are disclosed.

Description

[0001] This is a continuation-in-part of U.S. Serial No. 09 / 787,288, filed March 15, 2001.BACKGROUND OF THE INVENTION [0002] 1. Field of the Invention [0003] The present invention relates to drugs, particularly agents for further improving excretory potency of the urinary bladder. The present invention further relates to crystals and pharmaceutical compositions comprising the crystals of a tricyclic, condensed, heterocyclic compound which inhibit acetylcholinesterase and improve excretory potency of the urinary bladder. [0004] 2. Description of Related Art [0005] Inferior uropathy is a general term for subjective or objective disorders in a process through accumulation of urine (urinary storage) till excretion (urination), which may be classified into urinary cumulative disorders (incontinence of urine, pollakiuria, etc.), dysuria (difficulty of urination, scalding, obstruction of urinary tract, etc.), and the like. Inferior uropathy in the aged, particularly dysuria, especially dys...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/553A61K31/55A61K31/4745A61K31/454A61K31/453A61K31/452A61K31/473A61K31/00A61K31/343A61K31/382A61K31/395A61K31/404A61K31/435A61K31/445A61K31/4545A61K31/4709A61K45/06C07D211/26C07D211/32C07D273/06C07D401/06C07D471/06C07D487/04
CPCA61K31/00C07D487/04C07D471/06C07D401/06C07D273/06C07D211/32C07D211/26A61K45/06A61K31/553A61K31/55A61K31/4745A61K31/473A61K31/4709A61K31/4545A61K31/343A61K31/382A61K31/395A61K31/404A61K31/435A61K31/445A61K31/452A61K31/453A61K31/454A61K2300/00
Inventor ISIHARA, YUJIDOI, TAKAYUKINAGABUKURO, HIROSHIISHICHI, YUJI
Owner ISIHARA YUJI
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