WO1988001614A1 - RESOLUTION OF dl-METHYL 3-[4-(2-HYDROXY-3-ISOPROPYLAMINO)PROPOXY]PHENYLPROPIONATE [(dl-ESMOLOL)] - Google Patents
RESOLUTION OF dl-METHYL 3-[4-(2-HYDROXY-3-ISOPROPYLAMINO)PROPOXY]PHENYLPROPIONATE [(dl-ESMOLOL)] Download PDFInfo
- Publication number
- WO1988001614A1 WO1988001614A1 PCT/US1987/002068 US8702068W WO8801614A1 WO 1988001614 A1 WO1988001614 A1 WO 1988001614A1 US 8702068 W US8702068 W US 8702068W WO 8801614 A1 WO8801614 A1 WO 8801614A1
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- WO
- WIPO (PCT)
- Prior art keywords
- hydroxy
- methyl
- isopropylamino
- esmolol
- phenylpropionate
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Ceased
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
Definitions
- Isomeric compounds are generally obtained as racemates. Oftentimes, it is desirable to obtain one of the isomers, usually the l-isomer. Consequently, various methods have been devised for resolving racemic mixtures. Two methods are asymmetric synthesis or optical resolution. A representative process for optical resolution is described in U.S. Patent 3,649,691.
- the above compound is an important beta-adrenergicblocking agent, its preparation and use is more fully described in the U. S. Patent Number 4,387,103.
- dl-Esmolol as a free base, is treated with (-)-2,3:4,6-di- O-isopropylidene-2-keto-L-gulonic acid [(-)-(DAG)], employing aqueous acetone and water as a solvent, preferably in a ratio of 1:1 to 1:10 of acetone to water.
- (-)-DAG-salt has the following optical rotations:
- the free base is recovered by treating the above (+)-esmolol . (-)-DAG-salt with an inorganic base, e.g., sodium hydroxide, the (+)-esmolol . hydrochloride salt of this base has the following optical rotation in metnanol:
- the free base is recovered by treating the above (-)-esmolol . (-)-DTT-(-) salt with an inorganic base, e.g., sodium hydroxide, the (-)esmolol-hydrochloride salt of this base has the following optical rotations:
- the compounds of the invention may be converted into their pharmaceutically acceptable non-toxic acid addition salts by conventional procedures.
- the acid addition salts may be prepared in the conventional manner by treating a solution or suspension of the free base in an organic solvent with the desired acid and then recovering the salts which form by crystallization techniques.
- the desired non-toxic acids are the following: acetic, maleic, fumaric, succinic, tartaric, citric, malic, cinnamic, sulfonic, hydrochloric, hydrobr ⁇ mic, sulfuric, and phosphoric acid.
- the compounds of the invention can be used in the treatment or prophylaxis of cardiac disorders.
- M. Schwartz et al. report on Efficacy and Safety of Esmolol for Postoperative Atrial Fibrillation/Flutter.
- esmolol racemic mixture
- a therapeutic response was obtained in 9/15 patients, the median effective dose being 100 mcg/kg/ minute with a mean time to response of 22 minutes.
- J. Askenazi et al. report on The Effect of Esmolol on Cardiac Hemodynamic Function.
- the relative potency of levo-esmolol and esmolol was determined utilizing ten-minute intravenous infusions of each compound at increasing doses. Each animal received both levo- esmolol and esmolol but the order of administration was randomized and a period of time for complete recovery from the effects of the first compound was allowed before initiating infusion of the other compound. Beta-blockade was assessed at the end of each ten-minute infusion period using bolus isoproterenol injections (0.5 ug/kg, i.v. bolus).
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
A process for the resolution of dl-methyl 3-[4-(2-hydroxy-3-isopropylamino)propoxy]phenylpropionate [(dl-esmolol)] into a dextro (+) and a levo (-) isomer.
Description
RESOLUTION OF dl -METHYL 3-[4-(2-HYDROXY-3-IS0PROPYLAMINO) PROPOXY] PHENYLPROPIONATE [ (dl-ESMOLOL) ]
BACKGROUND OF THE INVENTION
Isomeric compounds are generally obtained as racemates. Oftentimes, it is desirable to obtain one of the isomers, usually the l-isomer. Consequently, various methods have been devised for resolving racemic mixtures. Two methods are asymmetric synthesis or optical resolution. A representative process for optical resolution is described in U.S. Patent 3,649,691.
The preparation and use of methyl 3-[4-(2-hydroxy-3- isopropylamino)propoxy]phenylpropionate (dl-esmolol) is described in U.S. Patent 4,3.87,103, issued June7, 1983. This compound is a short-acting beta-adrenergic-blocking agent used in the treatment or prophylaxis of cardiac disorders. Since the l-isomer is more active than the dl-mixture, an effective method for resolving the racemic mixture is desirable. The present invention relates to a novel process for the optical resolution of dl-methyl 3-[4-(2-hydroxy-3-isopropyl- amino)propoxy]phenylpropionate (dl-esmolol) having the following structural formula
into its (-) and (+) isomers. The (-) isomer is about twice as potent as a beta-adrenergic-blocking agent than the racemate
(+). The above compound is an important beta-adrenergicblocking agent, its preparation and use is more fully described in the U. S. Patent Number 4,387,103.
According to the present invention, a novel process whereby this therapeutically important agent is further resolved into its optically active components is illustrated in the following schematic diagram.
l
-
l l l l
= + .
(c 1.0, MeOH) (c 1.0, MeOH)
dl-Esmolol, as a free base, is treated with (-)-2,3:4,6-di- O-isopropylidene-2-keto-L-gulonic acid [(-)-(DAG)], employing
aqueous acetone and water as a solvent, preferably in a ratio of 1:1 to 1:10 of acetone to water. The resulting (+)-esmolol . (-)-DAG-salt has the following optical rotations:
= -3.0 (c 10.0, MeOH)
The free base is recovered by treating the above (+)-esmolol . (-)-DAG-salt with an inorganic base, e.g., sodium hydroxide, the (+)-esmolol . hydrochloride salt of this base has the following optical rotation in metnanol:
= +19.1 (c 1.0, MeOH)
Similarly, the (-) isomer of esmolol is resolved as follows: dl-esmolol, as a free base, is treated with (-)-O,O'-di-p- toluoyl-L-tartaric acid [(-)-(DTT)], employing acetone as solvent. The resulting (-)-esmolol . (-)- DTT-(-)salt has the following optical rotation:
= -90.4 (c 1.0, MeOH)
The free base is recovered by treating the above (-)-esmolol . (-)-DTT-(-) salt with an inorganic base, e.g., sodium hydroxide, the (-)esmolol-hydrochloride salt of this base has the following optical rotations:
= -19.6 (c 1.0, MeOH)
The compounds of the invention may be converted into their pharmaceutically acceptable non-toxic acid addition salts by conventional procedures. The acid addition salts may be prepared in the conventional manner by treating a solution or suspension of the free base in an organic solvent with the
desired acid and then recovering the salts which form by crystallization techniques. The desired non-toxic acids are the following: acetic, maleic, fumaric, succinic, tartaric, citric, malic, cinnamic, sulfonic, hydrochloric, hydrobrαmic, sulfuric, and phosphoric acid.
The compounds of the invention, and particularly the l- isomer, can be used in the treatment or prophylaxis of cardiac disorders. In Clinical Research, Vol. 33, No. 3, 1985, p. 748A, M. Schwartz et al. report on Efficacy and Safety of Esmolol for Postoperative Atrial Fibrillation/Flutter. As reported, for the racemic mixture (esmolol), a therapeutic response was obtained in 9/15 patients, the median effective dose being 100 mcg/kg/ minute with a mean time to response of 22 minutes. In Clinical Research, Vol. 33, No. 2, 1985, p. 167A, J. Askenazi et al. report on The Effect of Esmolol on Cardiac Hemodynamic Function. A 4 minute loading dose of 500 ug/kg/minute was given followed by a 16-24 minute infusion at 300 ug/kg/minute. In Drug Intelligence and Clinical Pharmacy, Vol. 19, June 1984, p. 446, P. E. MacCosbe et al. report on Antiarrhythmic Efficacy and Safety of Esmolol in Supraventricular Tachycardia and a mean effective dose of 97.2 + 5.5 ug/kg/minute. J. Kirshenbaum et al. in Circulation, Vol. 72, No. 4, October 1985, pps. 873-880, report on the use of esmolol in patients with acute myocardial ischemia wherein esmolol was titrated to a maximum dose of 300 ug/kg/minute, infused for up to 420 minutes.
For the l-isomer, dosage ranges of one-half those reported in the above publications can be used for the same indications.
EXAMPLE 1
Preparation of (+)-esmolol . (-)-DAG
dl-Esmolol + (-)-DAG -------> (+)-Esmolol . (-)-DAG
A mixture of (+)-esmolol free base (15 g, 50 mmole) and (-)-DAG (13.7 g, 50 mmole) in acetone (10 mL) and water (30 mL) was warmed to give clear yellow solution and allowed to stand at 22°C for 7 days. The crystalline mass was filtered and washed with cold acetone (30 mL), acetone: ether (1:1, 20 mL) followed by ether and air dried to give 2.66 g (18.73.) white crystalline solid, m.p. 124°C,
= -3.0 (c 10.0, MeOH) . NMR indicated 1:1 complex.
Analysis calculated for: C28H43NO11.0.50H2O, C, 58.11,: H, 7.66,: N, 2.42 Found: C, 58.22,: H, 7.49,: N, 2.36
EXAMPLE 2
Preparation of (+)-esmolol
(+)-Esmolol . (-)-DAG Salt (+)-Esmolol . HCl
A mixture of (+)-esmolol . (-)-DAG (2 g, 3.51 mmole), in 0.1N NaOH (50 mL, 1.4 equivalence NaOH) and 50 mL of ether was stirred for 2 minutes. The ethereal layer was separated, dried (MgSO4), filtered and evaporated to give an oil. This was dissolved in 10 mL methyl ethyl ketone and acidified with hydrogen chloride, treated with ether until cloudy (3 mL) and allowed to stand at 22°C for 24 hours. The white crystalline solid was collected by filtration, washed with methyl ethyl ketone: ether (1:1, 20 mL), ether (20 mL) and air dried (0.48 g, 41.2%),
= +19.1 (c 1.0, MeOH), m.p. 93-94°C.
IR and NMR are consistent with the assigned structure.
Analysis calculated for C16H26CINO4, C, 57.91, H, 7.90, N, 4.22 Found: C, 57.89, H, 7.93, N, 4.26
EXAMPLE 3
Preparation of (-)-esmolol . (-)-DTT salt
dl-Esmolol + (-)-DTT --------> (-)-Esmolol . (-)-DTT Salt
A mixture of esmolol freebase (3.0 g, 10.16 mmole) and (-)- Di-p-toluoyl-L-tartaric acid monohydrate (4.10 g, 10.16 mmole) in acetone (20 mL) was warmed to dissolve and allowed to cool to 22°C. This clear solution was allowed to stand at 22°C for 16 hours, the crystalline product formed was diluted with acetone (30 mL) and filtered, washed with acetone (20 mL), then acetone:ether (1:1, 30 mL) followed by ether and air dried to give the white crystalline salt (1.9 g, 56.6%), m.p. 158-159°C,
25 [α] = -90.4 (c 1.0, MeOH).
589 Analysis calculated for C36H43NO12, C, 63.42, H, 6.36, N, 12.05 Found: C, 63.60, H, 6.36, N, 12.05
EXAMPLE 4
Preparation of (-)-esmolol . HCT
(-)-Esmolol . (-)-DTT Salt (-)-Esmolol . HCl
(-)-Esmolol(-)-DTT (2 g, 2.86 mmole) was suspended in water (100 mL) and to this, IN NaOH (15 mL) and ethyl acetate (100 mL) were added with vigorous stirring. The ethyl acetate layer was separated and washed with brine (2 X 100 mL), dried (MgSO4), filtered and evaporated to an oil. This was dissolved in methyl ethyl ketone (12 mL), acidified with hydrogen chloride, treated with ether (10 mL). and allowed to stand at 22°C for 16 hours. The crystalline solid was filtered, washed with methyl ethyl ketone: ether (1:1, 50 lm), followed by ether and air dried togive 300 mg (31.6%), of the title compound, m.p. 93-94°C,
= -19.6 (c 1.0, MeOH)
.
The relative potency of l-esmolol and dl-esmolol was determined in the following manner. Mongrel dogs of either sex were anesthetized with a combination of nembutal and sodium barbital (15.0 and 300 mg/kg, respectively). A femoral artery and both femoral veins were cannulated for measurement of diastolic blood pressure and administration of drugs, respectively. Rectal temperature was monitored and maintained at 36-38°C. The vagus nerves were cut. Heart rate was measured from the arterial blood pressure signal with a Beckman cardiotachometer. Following surgical preparation, one hour was allowed for equilibration prior to initiating the experiment.
The relative potency of levo-esmolol and esmolol was determined utilizing ten-minute intravenous infusions of each compound at increasing doses. Each animal received both levo- esmolol and esmolol but the order of administration was randomized and a period of time for complete recovery from the effects of the first compound was allowed before initiating infusion of the other compound. Beta-blockade was assessed at the end of each ten-minute infusion period using bolus isoproterenol injections (0.5 ug/kg, i.v. bolus). The reduction in control hypotension and tachycardia responses to isoproterenol by each compound was expressed as percent inhibition, calculated as (Control-Treated)/Control X 100. Percent inhibition values between 15 and 85 inclusive were related to the log of infusion rate, via least square regression and the LD50 was determined (infusion rate producing 50% reduction of isoproterenol response).
The levo-isomer of esmolol (LD50 = 29.3 + 1.7 ug/kg/minute) was approximately two-fold more potent than the racemic mixture (LD50 = 56.1 + 2 ug/kg/minute) in blocking isoproterenol tachycardia. Neither esmolol nor levo-esmolol modified baseline diastolic arterial blood pressure or diastolic arterial blood pressure responses to isoproterenol at any dose. 50
Claims
1. A method for resolving dl-methyl 3-[4-(2-hydroxy-3- isopropylamino)propoxy]phenylpropionate which method comprises: reacting dl-methyl 3-[4-(2-hydroxy-3-isopropyl- amino)propoxy]phenylpropionate, as the free base, with (-)- 0,0'-di-p-toluoyl-L-tartaric acid in acetone as a solvent to obtain the (-)-methyl 3-[4-(2-hydroxy-3-isopropylamino)- propoxy]phenylpropionate . (-)-0,0'-di-p-toluoyl-L-tartaric acid salt; and treating said salt with an inorganic base to obtain the (-)-isomer of methyl 3-[4-(2-hydroxy-3-isopropylamino)propoxy]phenylpropionate, or alternately, reacting dimethyl 3-[4-(2-hydroxy-3-isopropylamino)propoxyphenylpropionate, as the free base, with (-)-2,3:4,6-di-0- isopropylidene-2-keto-L-gulonic acid in a mixture of acetone and water in a ratio of 1:1 to 1:10 to obtain the (+)- esmolol . (-)-2,3:4,6-di-0-isopropylidene-2-keto-L-gulonic acid salt; and treating said salt with an inorganic base to obtain the (+) isomer of methyl-3-[4-(2-hydroxy-3-isopropylamino)propoxy]- phenylpropionate as a free base.
2. A method for resolving dl-methyl 3-[4-(2-hydroxy-3- isopropylamino)propoxy]phenylpropionate which method comprises: reacting dl-methyl 3-[4-(2-hydroxy-3-isopropylamino)propoxy]- phenylpropionate, as the free base, with (-)-0,0'-di-p-toluoyl- L-tartaric acid in acetone as a solvent to obtain the (-)-methyl 3-[4-(2-hydroxy-3-isopropylamino)propoxyphenylpropionate . (-)-0,0'-di-p-toluoyl-L-tartaric acid salt; and treating said salt with an inorganic base to obtain the (-)-isomer of methyl 3-[4-(2-hydroxy-3-isopropylamino)propoxy]- phenylpropionate as the free base.
3. The method of Claim 2 wherein the inorganic base is sodium hydroxide.
4. The method of Claim 3 wherein the methyl 3-[4-(2- hydroxy-3-isopropylamino)propoxy]phenylpropionate free base is treated with an appropriate acid to obtain a pharmaceutically acceptable salt.
5. The method of Claim 4 wherein the acid is hydrochloric acid.
6. A method for resolving dl-methyl 3-[4-(2-hydroxy-3- isopropylamino)propoxylphenylpropionate which method comprises: reacting dl-methyl 3-[4-(2-hydroxy-3-isopropylamino)propoxy] phenylpropionate, as the free base, with (-)-2,3:4,6-di-0- isopropylidene-2-keto-L-gulonic acid in aqueous acetone to obtain the (+)- methyl 3-[4-(2-hydroxy-3-isopropylamino- propoxylphenylpropionate . (-)-2,3:4,6-di-0-isopropylidene-2- keto-L-gulonic acid salt; and treating said salt with an inorganic base to obtain the (+) isomer of methyl 3-[4-(2- hydroxy-3-isopropylamino)propoxy]phenylpropionate as a free base.
7. The method of Claim 6 wherein the ratio of acetone to water is 1:1 to 1:10.
8. The method of Claim 6 wherein the inorganic base is sodium hydroxide.
9. The method of Claim 8 wherein the (esmolol) free base is treated with an appropriate acid to obtain a pharmaceutically acceptable salt.
10. The method of Claim 9 wherein the acid is hydrochloric acid.
11. (-)-Esmolol or a non-toxic pharmaceutically acceptable acid addition salt thereof.
12. The compound according to Claim 11 wherein said salt is hydrochloride salt.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US90280686A | 1986-09-02 | 1986-09-02 | |
| US902,806 | 1986-09-02 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1988001614A1 true WO1988001614A1 (en) | 1988-03-10 |
Family
ID=25416420
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/US1987/002068 Ceased WO1988001614A1 (en) | 1986-09-02 | 1987-08-25 | RESOLUTION OF dl-METHYL 3-[4-(2-HYDROXY-3-ISOPROPYLAMINO)PROPOXY]PHENYLPROPIONATE [(dl-ESMOLOL)] |
Country Status (4)
| Country | Link |
|---|---|
| EP (1) | EP0279844A4 (en) |
| JP (1) | JP2521317B2 (en) |
| AU (1) | AU607437B2 (en) |
| WO (1) | WO1988001614A1 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012103305A1 (en) | 2011-01-27 | 2012-08-02 | Baxter International Inc. | Use of (s) - esmolol for controlling venous irritation associated with the treatment of a cardiac disorder |
| WO2012103314A1 (en) | 2011-01-27 | 2012-08-02 | Baxter International Inc. | Methods of treating tachycardia and/or controlling heart rate while minimizing and/or controlling hypotension |
| CN113651706A (en) * | 2021-07-16 | 2021-11-16 | 湖州展望药业有限公司 | Preparation process of high-purity esmolol hydrochloride |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SE8801518D0 (en) * | 1988-04-22 | 1988-04-22 | Astra Pharma Prod | A NOVEL PROCESS |
| NZ589486A (en) | 2008-06-02 | 2012-08-31 | Generics Uk Ltd | A process for the preparation of enantiomerically pure 1-(R)-(2-propynylamino)indan |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0041491A1 (en) * | 1980-06-02 | 1981-12-09 | Aktiebolaget Hässle | New para-substituted 3-phenoxy-1-alkylamino-propanol-2-s having beta receptor blocking properties |
| US4387103A (en) * | 1980-11-28 | 1983-06-07 | American Hospital Supply Corporation | Method for treatment or prophylaxis of cardiac disorders |
| WO1985004168A1 (en) * | 1984-03-14 | 1985-09-26 | Bodor Nicholas S | SOFT beta-ADRENERGIC BLOCKING AGENTS |
| US4593119A (en) * | 1980-11-28 | 1986-06-03 | American Hospital Supply Corporation | Method for treatment or prophylaxis of cardiac disorders |
-
1987
- 1987-08-25 EP EP19870905856 patent/EP0279844A4/en not_active Withdrawn
- 1987-08-25 WO PCT/US1987/002068 patent/WO1988001614A1/en not_active Ceased
- 1987-08-25 AU AU79114/87A patent/AU607437B2/en not_active Ceased
- 1987-08-25 JP JP62505278A patent/JP2521317B2/en not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0041491A1 (en) * | 1980-06-02 | 1981-12-09 | Aktiebolaget Hässle | New para-substituted 3-phenoxy-1-alkylamino-propanol-2-s having beta receptor blocking properties |
| US4387103A (en) * | 1980-11-28 | 1983-06-07 | American Hospital Supply Corporation | Method for treatment or prophylaxis of cardiac disorders |
| US4593119A (en) * | 1980-11-28 | 1986-06-03 | American Hospital Supply Corporation | Method for treatment or prophylaxis of cardiac disorders |
| WO1985004168A1 (en) * | 1984-03-14 | 1985-09-26 | Bodor Nicholas S | SOFT beta-ADRENERGIC BLOCKING AGENTS |
Non-Patent Citations (2)
| Title |
|---|
| Journal of Pharmaceutical Sciences, Volume 68, No. 9, September 1979, Washington, D.C., YOST et al, "Resolution of (+/-)-Propanolol", pp 1181-1182, see the Entire Atricle. * |
| See also references of EP0279844A4 * |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012103305A1 (en) | 2011-01-27 | 2012-08-02 | Baxter International Inc. | Use of (s) - esmolol for controlling venous irritation associated with the treatment of a cardiac disorder |
| WO2012103314A1 (en) | 2011-01-27 | 2012-08-02 | Baxter International Inc. | Methods of treating tachycardia and/or controlling heart rate while minimizing and/or controlling hypotension |
| CN103338763A (en) * | 2011-01-27 | 2013-10-02 | 巴克斯特国际公司 | Methods of treating tachycardia and/or controlling heart rate while minimizing and/or controlling hypotension |
| US8686036B2 (en) | 2011-01-27 | 2014-04-01 | Baxter International Inc. | Methods of controlling heart rate while minimizing and/or controlling hypotension |
| US8829047B2 (en) | 2011-01-27 | 2014-09-09 | Baxter International Inc. | Methods of controlling venous irritation associated with the treatment of a cardiac disorder |
| US9084763B2 (en) | 2011-01-27 | 2015-07-21 | Baxter International Inc. | Methods for treating tachycardia and/or controlling heart rate while minimizing and/or controlling hypotension |
| AU2012211318B2 (en) * | 2011-01-27 | 2016-01-28 | Baxter Healthcare S.A. | Methods of treating tachycardia and/or controlling heart rate while minimizing and/or controlling hypotension |
| AU2012211318C1 (en) * | 2011-01-27 | 2016-08-04 | Baxter Healthcare S.A. | Methods of treating tachycardia and/or controlling heart rate while minimizing and/or controlling hypotension |
| CN113651706A (en) * | 2021-07-16 | 2021-11-16 | 湖州展望药业有限公司 | Preparation process of high-purity esmolol hydrochloride |
Also Published As
| Publication number | Publication date |
|---|---|
| EP0279844A4 (en) | 1990-06-05 |
| JP2521317B2 (en) | 1996-08-07 |
| AU607437B2 (en) | 1991-03-07 |
| JPH01500665A (en) | 1989-03-09 |
| AU7911487A (en) | 1988-03-24 |
| EP0279844A1 (en) | 1988-08-31 |
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