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|Prucalopride succinate; 179474-85-2; Resolor; Prucalopride (succinate); UNII-4V2G75E1CK; R-108512;|
|Molecular Weight:||485.95838 g/mol|
Drug Name：Prucalopride Succinate
Trade Name：Resolor®, MOA：Serotonin (5-HT4) receptor agonist, Indication：Chronic constipation
Company：Shire (Originator) , Johnson & Johnson
APPROVED EU 2009-10-15
Prucalopride (brand name Resolor, developed by Johnson & Johnson and licensed to Movetis) is a drug acting as a selective, high affinity 5-HT4 receptor agonist which targets the impaired motility associated with chronic constipation, thus normalizing bowel movements. Prucalopride was approved for use in Europe in 2009, in Canada (named Resotran) on December 7, 2011 and in Israel in 2014 but it has not been approved by the Food and Drug Administration for use in the United States. The drug has also been tested for the treatment of chronic intestinal pseudo-obstruction.
Mechanism of action
Prucalopride, a first in class dihydro-benzofuran-carboxamide, is a selective, high affinity serotonin (5-HT4) receptor agonist with enterokinetic activities. Prucalopride alters colonic motility patterns via serotonin 5-HT4 receptor stimulation: it stimulates colonic mass movements, which provide the main propulsive force for defecation.
The observed effects are exerted via highly selective action on 5-HT4 receptors: prucalopride has >150-fold higher affinity for 5-HT4 receptors than for other receptors. Prucalopride differs from other 5-HT4 agonists such as tegaserod and cisapride, which at therapeutic concentrations also interact with other receptors (5-HT1B/D and the cardiac human ether-a-go-go K+ or hERG channelrespectively) and this may account for the adverse cardiovascular events that have resulted in the restricted availability of these drugs. Clinical trials evaluating the effect of prucalopride on QT interval and related adverse events have not demonstrated significant differences compared with placebo.
Prucalopride is rapidly absorbed (Cmax attained 2–3 hours after single 2 mg oral dose) and is extensively distributed. Metabolism is not the major route of elimination. In vitro, human liver metabolism is very slow and only minor amounts of metabolites are found. A large fraction of the active substance is excreted unchanged (about 60% of the administered dose in urine and at least 6% in feces).Renal excretion of unchanged prucalopride involves both passive filtration and active secretion. Plasma clearance averages 317 ml/min, terminal half-life is 24–30 hours, and steady-state is reached within 3–4 days. On once daily treatment with 2 mg prucalopride, steady-state plasma concentrations fluctuate between trough and peak values of 2.5 and 7 ng/ml, respectively.
In vitro data indicate that prucalopride has a low interaction potential, and therapeutic concentrations of prucalopride are not expected to affect the CYP-mediated metabolism of co-medicated medicinal products.
The primary measure of efficacy in the clinical trials is three or more spontaneous complete bowel movements per week; a secondary measure is an increase of at least one complete spontaneous bowel movement per week. Further measures are improvements in PAC-QOL (a quality of life measure) and PAC-SYM (a range of stool,abdominal, and rectal symptoms associated with chronic constipation). Infrequent bowel movements, bloating, straining, abdominal pain, and defecation urge with inability to evacuate can be severe symptoms, significantly affecting quality of life.
In three large clinical trials, 12 weeks of treatment with prucalopride 2 and 4 mg/day resulted in a significantly higher proportion of patients reaching the primary efficacy endpoint of an average of ≥3 spontaneous complete bowel movements than with placebo. There was also significantly improved bowel habit and associated symptoms, patient satisfaction with bowel habit and treatment, and HR-QOL in patients with severe chronic constipation, including those who did not experience adequate relief with prior therapies (>80% of the trial participants). The improvement in patient satisfaction with bowel habit and treatment was maintained during treatment for up to 24 months; prucalopride therapy was generally well tolerated.
Prucalopride has been given orally to ~2700 patients with chronic constipation in controlled clinical trials. The most frequently reported side effects are headache andgastrointestinal symptoms (abdominal pain, nausea or diarrhea). Such reactions occur predominantly at the start of therapy and usually disappear within a few days with continued treatment.
In the European Economic Area, prucalopride was originally approved for the symptomatic treatment of chronic constipation in women in whom laxatives fail to provide adequate relief. Subsequently, it has been approved by the European Commission for use in adults – that is, including male patients – for the same indication.
Prucalopride is contraindicated where there is hypersensitivity to the active substance or to any of the excipients, renal impairment requiring dialysis, intestinal perforation orobstruction due to structural or functional disorder of the gut wall, obstructive ileus, severe inflammatory conditions of the intestinal tract, such as Crohn’s disease, and ulcerative colitis and toxic megacolon/megarectum.
Prucalopride succinate, a first-in-class dihydrobenzofurancarboxamide, is a selective serotonin (5-HT4) receptor agonist.86–94 The drug, marketed under the brand name Resolor, possesses enterokinetic activity and was developed by the Belgian-based pharmaceutical firm Movetis. Prucalopride alters colonic motility patterns via serotonin 5-HT4 receptor stimulation, triggering the central propulsive force for defecation.95–97 The preparation of prucalopride succinate begins with the commercially available salicylic aniline 124 (Scheme 18). Acidic esterification, acetylation of the aniline nitrogen atom, and ambient-temperature chlorination via sulfuryl chloride (SO2Cl2) converted aminophenol 124 to acetamidoester 125 in 83% yield over the course of three steps.98–102 An unique set of conditions involving sodium tosylchloramide (chloramine T) trihydrate and sodium iodide were then employed to convert 125 to o-phenolic iodide 126, which then underwent sequential Sonogashira/cyclization reaction utilizing TMS-acetylene with tetramethylguanidine (TMG) in the presence of silica gel to furnish the benzofuran progenitor of 127.103 Hydrogenation of this intermediate benzofuranyl Sonagashira product saturated the 2,3-benzofuranyl bond while leaving the chlorine atom intact, ultimately delivering dihydrobenzofuran 127 in excellent yield for the two step sequence. Base-induced saponification and acetamide removal gave rise to acid 128. This acid was activated as the corresponding mixed anhydride and treated with commercial piperidine 129 to construct prucalopride which was stirred at room temperature for 24 h in ethanolic succinic acid to provide prucalopride succinate (XI). The yield for the formation of the salt was not provided.
86. Briejer, M. R.; Bosmans, J. P.; Van Daele, P.; Jurzak, M.; Heylen, L.; Leysen, J. E.;Prins, N. H.; Schuurkes, J. A. J. Eur. J. Pharmacol. 2001, 423, 71.
87. Briejer, M. R.; Prins, N. H.; Schuurkes, J. A. J. Neurogastroenterol. Motil. 2001, 13,465.
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Synlett 1993, 269
Chem. Pharm. Bull. 1998, 46,42.
In trichloromethane (135 ml) 4-amino-5-chloro-2,3-dihydro-7-benzofurancarboxylic acid (0.05 mol) (the preparation of which was described in EP-0,389,037-A) was suspended and cooled to ±5° C. N,N-diethylethanamine (0.05 mol) was added dropwise at a temperature below 10° C. Ethyl chloroformate (0.05 mol) was added dropwise and the reaction mixture was stirred for 40 min. while keeping the temperature below 10° C. The resulting mixture was added dropwise over a 20-min period to a solution of 1-(3-methoxypropyl)-4-piperidinamine (0.05 mol) in trichloromethane (35 ml). The cooling bath was removed and the reaction mixture was stirred for 150 min. Said mixture was washed with water (50 ml). The precipitate was filtered off over a glass filter and washed with water and CHCl3. The filtrate was separated in it’s layers. The separated organic layer was washed with water (50 ml)+a 50% NaOH solution (1 ml), dried, filtered and the solvent was evaporated. The residue was stirred in 2-propanol (100 ml). This mixture was acidified with HCl/2-propanol (7.2 ml; 5.29 N). The mixture was stirred for 16 hours at room temperature and the resulting precipitate was filtered off, washed with 2-propanol (15 ml) and dried (vacuum; 50° C.), yielding 12.6 g (62%) of 4-amino-5-chloro-2,3-dihydro-N- 1-(3-methoxypropyl)-4-piperidinyl!-7-benzofurancarboxamide monohydrochloride (comp. 1).
EXPERIMENTAL PART EXAMPLE 1
In trichloromethane (135 ml) 4-amino-5-chloro-2,3-dihydro-7-benzofurancarboxylic acid (0.05 mol) (the preparation of which was described in EP-0,389,037-A) was suspended and cooled to ±5° C. N,N-diethylethanamine (0.05 mol) was added dropwise at a temperature below 10° C. Ethyl chloroformate (0.05 mol) was added dropwise and the reaction mixture was stirred for 40 min. while keeping the temperature below 10° C. The resulting mixture was added dropwise over a 20-min period to a solution of 1-(3-methoxypropyl)-4-piperidinamine (0.05 mol) in trichloromethane (35 ml). The cooling bath was removed and the reaction mixture was stirred for 150 min. Said mixture was washed with water (50 ml). The precipitate was filtered off over a glass filter and washed with water and CHCl3. The filtrate was separated in it’s layers. The separated organic layer was washed with water (50 ml)+ a 50% NaOH solution (1 ml), dried, filtered and the solvent was evaporated. The residue was stirred in 2-propanol (100 ml). This mixture was acidified with HCl/2-propanol (7.2 ml; 5.29 N). The mixture was stirred for 16 hours at room temperature and the resulting precipitate was filtered off, washed with 2-propanol (15 ml) and dried (vacuum; 50° C.), yielding 12.6 g (62%) of 4-amino-5-chloro-2,3-dihydro-N- 1-(3-methoxypropyl)-4-piperidinyl!-7-benzofurancarboxamide monohydrochloride (comp. 1).
EP-0,389,037-A, published on September 26, 1990, N-(3-hydroxy-4-piperidin- yl) (dihydrobenzofuran or dihydro-2H-benzopyran)carboxamide derivatives are disclosed as having gastrointestinal motility stimulating properties. In our EP-0,445,862-A, published on September 11, 1991, N-(4-piperidinyl) (dihydrobenzo¬ furan or dihydro-2H-benzopyran)carboxamide derivatives are disclosed also having gastrointestinal motility stimulating properties.
The compound subject to the present application differs therefrom by showing superior enterokinetic properties.
The present invention concerns a compound of formula
and the pharmaceutically acceptable acid addition salts thereof.
The chemical name of the compound of formula (I) is 4-amino-5-chloro-2,3-dihydro-N- [l-(3-methoxypropyl)-4-piperidinyl]-7-benzofurancarboxamide.
In trichloromethane (135 ml) 4-amino-5-chloro-2,3-dihydro-7-benzofurancarboxylic acid (0.05 mol) (the preparation of which was described in EP-0,389,037-A) was suspended and cooled to ± 5 °C. H,N-diethylethanamine (0.05 mol) was added dropwise at a temperature below 10 °C. Ethyl chloroformate (0.05 mol) was added dropwise and the reaction mixture was stirred for 40 min. while keeping the temperature below 10°C. The resulting mixture was added dropwise over a 20-min period to a solution of l-(3-methoxypropyl)-4-piperidinamine (0.05 mol) in trichloromethane (35 ml). The cooling bath was removed and the reaction mixture was stirred for 150 min. Said mixture was washed with water (50 ml). The precipitate was filtered off over a glass filter and washed with water and CHCI3. The filtrate was separated in it’s layers. The separated organic layer was washed with water (50 ml) + a 50% NaOH solution (1 ml), dried, filtered and the solvent was evaporated. The residue was stirred in 2-propanol (100 ml). This mixture was acidified with HCl/2-propanol (7.2 ml; 5.29 N). The mixture was stirred for 16 hours at room temperature and the resulting precipitate was filtered off, washed with 2-propanol (15 ml) and dried (vacuum; 50 °C), yielding 12.6 g (62%) of 4-amino-5-chloro-2,3-dihydro-M-[ 1 -(3-methoxypropyl)-4-piperidinyl]-7- benzofurancarboxamide monohydrochloride (comp. 1).
A mixture of 4-amino-5-chloro-2,3-dihydro-N-(4-piperidinyl)-7-benzofuran- carboxamide(O.Olmol), l-chloro-3-methoxypropane (0.012mol), M,M-diethyl- ethanamine (2Jml) and KI (catalytic amount) in N,M-dimethylformamide (75ml) was stirred overnight at 50°C. The reaction mixture was cooled. The solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CHCl3/(CH3OH/NH3) 97/3). The pure fractions were collected and the solvent was evaporated. The residue was dissolved in 2-propanol and converted into the hydrochloric acid salt (1:1) with HCl/2-propanol. The precipitate was filtered off and dried (vacuum; 80°C), yielding 1.40g (35%) of 4-amino-5-chloro-2,3-dihydro-N-[l-(3-methoxypropyl)- 4-piperidinyl]-7-benzofurancarboxamide monohydrochloride (comp. 1).
Chinese Journal of Pharmaceuticals 2012, 43, 5-8.
Chinese Patent CN 103012337 A report is as follows:
Pharmaceutical & Clinical Research 2011, 19, 306-307.
US5374637 (CN1045781, EP389037) and J. Het Chem, 1980,17 (6): 1333-5 reported synthetic route, as follows:
Chinese Patent CN 104016949 A synthetic route reported as follows:
1. Preparation of Compound II
Compound I (167. lg, Imol), triethylamine (111. lg, I. Imol) and methylene chloride (KMOg) added to the reaction flask, nitrogen cooled to 5 ° C, was slowly added dropwise trifluoroacetic anhydride (220. 5g, 1.05mol) / methylene chloride (150g) solution, maintaining the temperature throughout 5~15 ° C, dropping was completed, the reaction after 3 hours at room temperature, TLC (DCM = MeOH = 25: 1) The reaction was monitored to complete the reaction; the reaction mixture was slowly poured into ice water (560g) and stirred for 20 minutes, standing layer, the aqueous phase was separated, the organic phase was washed with saturated aqueous sodium bicarbonate (IOOg) wash sash; IM hydrochloric acid (IlOg) wash sash, then with saturated brine (200g) washed sash, magnesium sulfate (40g) dried, filtered and concentrated to give compound II (250. Ig), yield: 952%.
 2. Preparation of Compound III
 Chloroacetyl chloride (101. 7g, 0. 9mol), nitrobenzene (20g) and dichloroethane (580 g) added to the reaction flask, nitrogen cooled to 5 ° C, was slowly added anhydrous trichloro aluminum powder (359. 2g, 2. 7mol), to keep the whole temperature 5~20 ° C, plus complete, insulation 15~25 ° C for 30 minutes to obtain a mixture A.
 Compound II (. 236. 7g, 0 9mol) and dichloroethane (500g) added to the reaction flask, nitrogen cooled to 15 ° C; the mixture was added Compound II A quick solution, plus complete, rapid heating 65~75 ° C, 1 hours later once every 15 minutes in the control, monitoring TLC (DCM = MeOH = 50: 1) to complete the reaction; the reaction mixture was immediately poured into ice water (800g) and stirred for 30 minutes, controlling the temperature between 15~25 ° C, the organic phase was separated, the organic phase washed with water (180g) was washed with saturated brine (240g), dried over magnesium sulfate (45g) was dried, filtered and concentrated to give crude compound III (303 . 2g).
 Take the crude compound III (291. 3g) / ethanol 1 dichloromethane: 1 solution (1500ml) was dissolved, and then adding activated carbon (14. 5g) was refluxed for one hour, cooled to room temperature filtered and the filtrate concentrated at room temperature to 600~ 650g, stop and concentrated down to 5~10 ° C, filtered to give a yellow solid (204. 7g); the resulting yellow solid (207. 6g) in tetrahydrofuran (510g) was purified, reduced to 10~15 ° C, filtered, The filter cake was washed with tetrahydrofuran (90g) dip, dried under vacuum to give compound III (181. 3g), yield: 61.7% billion
 3. Preparation of Compound IV
 Compound 111 (! 169.68,0.5 11〇1), methanol (5,801,111) and sodium acetate (123.38,1.5111〇1) was added to the reaction flask. After 6 hours of reaction, began TLC (DCM: MeOH = 30: 1 ) the reaction was monitored to completion of the reaction; the reaction mixture was cooled to room temperature, concentrated, and the residue with ethyl acetate (500g) and water (200g) was dissolved, the organic phase was separated, the organic phase was washed with 2M sodium hydrogen carbonate (120g) was washed, then with saturated brine (IOOg), dried over magnesium sulfate (50g) was dried, filtered and concentrated to 250~280g, cooled to room temperature with stirring was added cyclohexane (200 g of), after stirring for 1 hour and then filtered and dried to obtain compound IV (126. 7g), yield: 83.4% billion
 4. Preparation of Compound V
 Compound IV (12L 2g, 0. 4mol), methanol (380g) and Raney-Ni (12. 5g) added to the autoclave, purged with nitrogen, hydrogen is introduced (3. Ompa), the reaction was heated to 45 ° C after 8 hours, TLC (DCM = MeOH = 30: 1) to monitor the reaction, to complete the reaction, cooled to room temperature and pressure, and then purged with nitrogen, the reaction solution was filtered and concentrated to give crude compound V (103. 7g), taking compound V crude product (103g) was refluxed with ethyl acetate (420g) (1 hour) was purified, cooled to room temperature and stirred for 30 minutes and filtered to give a yellow solid was dried in vacuo to give compound V (76 8g.), yield: 663 %.
 5. Preparation of Compound VI
 Compound ¥ (57.88,0.2111〇1), 1 ^ dimethylformamide (4.58) and acetonitrile (30 (^) was added to the reaction flask and heated 74~76 ° C; solution of N- chlorosuccinimide imide (. 26. 7g, 0 2mol) and acetonitrile (45g) was added dropwise over 30 minutes and maintaining the temperature finished 76~82 ° C, dropping was completed, the reaction was kept, after one hour the reaction started TLC (DCM: MeOH = 30: 1) to monitor the reaction, the reaction is complete the reaction solution cooled to 5~8 ° C, the filter cake was washed with water (210g) washed stirred, filtered, and dried in vacuo to give compound VI (57. 6g), yield. rate of 89.1%.
6. Preparation of Compound VII
Compound VI (48. 5g, 0. 15mol) and methanol (80g) added to the reaction flask, stirring at room temperature was added dropwise 4M aqueous sodium hydroxide (HOg), dropwise complete, for the reaction, 25 ° C~35 after 4 hours of reaction ° C, samples of about 7:00 adjust PH TLC (DCM = MeOH = 30: 1) to monitor the reaction, until the reaction was complete, down to 5~10 ° C, with 6M hydrochloric acid solution PH ~ 7. 5, half the solution was concentrated, then 2M hydrochloric acid solution PH ~ 7, reduced to 15~20 ° C was stirred for 30 minutes, filtered, the filter cake with methyl tert-butyl ether (70g) beating, filtration, and dried in vacuo to give compound VII (28. 7g), yield: 903%.
Chem Pharm Bull 46 (1), 42-52 (1998) and Pharmaceutical and clinical study based on 2011 (4) 306-307 reported synthetic route is as follows:
|Description||Prucalopride is a selective, high affinity 5-HT4 receptor agonist, inhibiting human 5-HT(4a) and 5-HT(4b) receptor with Ki value of 2.5 nM and 8 nM, respectively.|
|Targets||5-HT4A ||5-HT4B |
|IC50||2.5 nM(Ki)||8 nM(Ki)|
|In vitro||Prucalopride induces contractions in a concentration-dependent manner with pEC50 of 7.5. Prucalopride (1 mM) significantly amplifies the rebound contraction of the guinea-pig proximal colon after electrical field stimulation. Prucalopride induces relaxation of the rat oesophagus preparation of rat oesophagus tunica muscularis mucosae with pEC50 of 7.8, yielding a monophasic concentration–response curve.  Prucalopride (0.1 μM) concentration-dependently increases the amplitude of submaximal cholinergic contractions and of acetylcholine release induced by electrical field stimulation in pig gastric circular muscle, and the effect is induced and enhanced IBMX (10 μM).  Prucalopride (1 μM) significantly enhances the electrically induced cholinergic contractions in pig descending colon, and the facilitating effect is significantly enhanced by Rolipram. |
|In vivo||Prucalopride alters colonic contractile motility patterns in a dose-dependent fashion by stimulating high-amplitude clustered contractions in the proximal colon and by inhibiting contractile activity in the distal colon of fasted dogs. Prucalopride also causes a dose-dependent decrease in the time to the first giant migrating contraction (GMC); at higher doses of prucalopride, the first GMC generally occurres within the first half-hour after treatment. |
Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
|Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×||mouse Km(3)||= 11.2 mg/kg|
Clinical Trial Information( data from http://clinicaltrials.gov, updated on 2016-07-23)
|NCT02806206||Not yet recruiting||Gastrointestinal Hemorrhage|Crohn Disease|Celiac Disease|Intestinal Diseases|Inflammatory Bowel Diseases||University of British Columbia||July 2016||Phase 4|
|NCT02781493||Not yet recruiting||Prucalopride Plus Polyethylene Glycol in Bowel Preparation for Colonoscopyp||Shandong University|Binzhou Peoples Hospital|Taian People …more||June 2016||Phase 4|
|NCT02538367||Recruiting||Functional Constipation||Yuhan Corporation||August 2015||Phase 1|Phase 2|
|NCT02228616||Recruiting||Constipation||Xian-Janssen Pharmaceutical Ltd.||October 2014||Phase 4|
|NCT02425774||Recruiting||Postoperative Ileus||Katholieke Universiteit Leuven|Universitaire Ziekenhuizen …more||July 2014||Phase 4|
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|Systematic (IUPAC) name|
|Trade names||Resolor, Resotran|
|AHFS/Drugs.com||International Drug Names|
|ATC code||A06AX05 (WHO)|
|Molar mass||367.870 g/mol|
//////////Prucalopride succinate, Resolor, R-093877, R-108512, Resolor®, Resolor, Resotran, UNII:0A09IUW5TP, 179474-81-8 , R-093877, R-108512, Shire , Johnson & Johnson, 179474-85-2, UNII-4V2G75E1CK, SHIRE, 2010, LAUNCHED, JANNSEN , PHASE 3, IRRITABLE BOWL SYNDROME