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Agents and crystals for improving excretory potency of urinary bladder

a technology of urinary bladder and agents, applied in the field of drugs, can solve the problems of insufficient clinical efficacy of distigmine, incompatibility of bethanechol with pregnant women, peptic ulcers,

Inactive Publication Date: 2002-11-28
TAKEDA PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

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, distigmine 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

[0632] According to per se known methods, compounds of Reference Examples 1-30 were obtained as depicted in the following Table, wherein R'.dbd.H.

1TABLE 1 159 Reference Example No. Ar R n Y 1 160 H 2 161 2 162 H 2 163 3 164 H 2 165 4 166 H 2 167 5 168 H 2 169 6 170 H 2 171 7 172 H 2 173 8 174 H 2 175 9 176 H 2 177 10 178 H 2 179

[0633]

2TABLE 2 180 Reference Example No. Ar R n Y 11 181 H 2 182 12 183 H 2 184 13 185 H 2 186 14 187 H 2 188 15 189 H 2 190 16 191 H 2 192 17 193 H 2 194 18 195 H 2 196 19 197 H 2 198 20 199 H 2 200

[0634]

3TABLE 3 201 Reference Example No. Ar R n Y 21 202 H 2 203 22 204 H 2 205 23 206 H 2 207 24 208 H 2 209 25 210 H 2 211 26 212 H 2 213 27 214 H 2 215 28 216 H 2 217

[0635]

4TABLE 4 Reference Example No. 29 218 30 219

reference example 15-1

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

[0636] 220

[0637] 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.degree. 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 mix...

reference example 15-2

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

[0650] 221

[0651] 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.degree. C.

[0652] .sup.1H-NMR (CDCl.sub.3) .delta.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).

[0653] Elemental analysis for C.sub.26H.sub.30N.sub.2O.sub.2:

[0654] Calcd: C, 77.58; H, 7.51; N, 6.96.

[0655] Found: C, 77.30; H, 7.49; N, 7.20.

[0656] The above-mentioned title compound was dissolved i...

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Abstract

Agents for improving potentcy of the urinary bladder which comprises 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 acetylcholine esterase and an action to improve the excretory potency of 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. Ser. No. 09 / 787,288, filed Mar. 15, 2001.[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 dysuria caused by prostatomegaly, bec...

Claims

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Application Information

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IPC IPC(8): A61K31/00A61K31/343A61K31/382A61K31/395A61K31/404A61K31/435A61K31/445A61K31/454A61K31/4545A61K31/4709A61K31/473A61K31/4745A61K31/55A61K31/553A61K45/06C07D211/26C07D211/32C07D273/06C07D401/06C07D471/06C07D487/04
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 ISHIHARA, YUJIDOI, TAKAYUKINAGABUKURO, HIROSHIISHICHI, YUJI
Owner TAKEDA PHARMA CO LTD
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