Tenapanor
Molecular FormulaC50H66Cl4N8O10S2
Average mass1145.049 Da
1234423-95-0 [RN]
1234423-95-0 (free base) 1234365-97-9 (2HCl)
9652
3-((S)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-N-(26-((3-((S)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl)sulfonamido)-10,17-dioxo-3,6,21,24-tetraoxa-9,11,16,18-tetraazahexacosyl)benzenesulfonamide
Benzenesulfonamide,
12,15-Dioxa-2,7,9-triazaheptadecanamide, 17-[[[3-[(4S)-6,8-dichloro-1,2,3,4-tetrahydro-2-methyl-4-isoquinolinyl]phenyl]sulfonyl]amino]-N-[2-[2-[2-[[[3-[(4S)-6,8-dichloro-1,2,3,4-tetrahydro-2-methyl-4-isoquinolinyl]phenyl]sulfonyl]amino]ethoxy]ethoxy]ethyl]-8-oxo-
1-[2-[2-[2-[[3-[(4S)-6,8-dichloro-2-methyl-3,4-dihydro-1H-isoquinolin-4-yl]phenyl]sulfonylamino]ethoxy]ethoxy]ethyl]-3-[4-[2-[2-[2-[[3-[(4S)-6,8-dichloro-2-methyl-3,4-dihydro-1H-isoquinolin-4-yl]phenyl]sulfonylamino]ethoxy]ethoxy]ethylcarbamoylamino]butyl]urea
17-[[[3-[(4S)-6,8-Dichloro-1,2,3,4-tetrahydro-2-methyl-4-isoquinolinyl]phenyl]sulfonyl]amino]-N-[2-[2-[2-[[[3-[(4S)-6,8-dichloro-1,2,3,4-tetrahydro-2-methyl-4-isoquinolinyl]phenyl]sulfonyl]amino]ethoxy]ethoxy]ethyl]-8-oxo-12,15-dioxa-2,7,9-triazaheptadecanamide
Tenapanor, also known as AZD-1722 and RDX 5791, is an inhibitor of the sodium-proton (Na(+)/H(+)) exchanger NHE3, which plays a prominent role in sodium handling in the gastrointestinal tract and kidney. Tenapanor possesses an excellent preclinical safety profile and, as of now, there are no serious concerns about its side effects.
Tenapanor is a drug developed by Ardelyx, which acts as an inhibitor of the sodium-proton exchanger NHE3. This antiporterprotein is found in the kidney and intestines, and normally acts to regulate the levels of sodium absorbed and secreted by the body. When administered orally, tenapanor selectively inhibits sodium uptake in the intestines, limiting the amount absorbed from food, and thereby reduces levels of sodium in the body.[1] This may make it useful in the treatment of chronic kidney disease and hypertension, both of which are exacerbated by excess sodium in the diet.[2]
Ardelyx and licensees Kyowa Hakko Kirin and Fosun Pharma are developing tenapanor, an NHE3 (Na+/H+ exchange-3) inhibitor that increases fluid content in the GI tract and which also reduces GI tract pain via an unknown TRPV-1-dependent pathway, for treating constipation-predominant irritable bowel syndrome (IBS-C) and hyperphosphatemia in patients with end stage renal disease (ESRD).
Syn
PATENT
WO2010078449
PATENT
WO-2019091503
A novel crystalline form of tenapanor free base, process for its preparation, composition comprising it and its use for the preparation of tenapanor with chemical purity >98.8% is claimed. Also claimed are salt forms of tenapanor, preferably tenapanor phosphate and their use for treating irritable bowel syndrome, constipation, hyperphosphatemia, final stage renal failure, chronic kidney disease and preventing excess sodium in patients with kidney and heart conditions. Further claimed are processes for the preparation of tenapanor comprising the steps of reaction of a diamine compound with 1,4-diisocyanatobutane, followed by deprotection and condensation to obtain tenapanor. Novel intermediates of tenapanor and their use for the preparation of tenapanor are claimed. Tenapanor is known to be a sodium hydrogen exchanger 3 inhibitor and analgesic.
enapanor, having the chemical name 17-[[[3-[(4S)-6,8-dichloro-l,2,3,4-tetrahydro-2-methyl-4-isoquinolinyl]phenyl]sulphonyl]amino]-N-[2-[2-[2-[[[3-[(4S)-6,8-dichloro-l,2,3,4-tetrahydro-2-methyl -4-isoquinolinyl] phenyl] sulphonyl] amino] ethoxy] ethoxy ] ethyl] – 8 -oxo- 12,15 -dioxa-2 ,7,9-triazaheptadecaneamide, is a selective inhibitor of the sodium protonic NHE3 antiporter. Orally administered tenapanor selectively inhibits the absorption of sodium in the intestine. This leads to an increase of water content in the digestive tract, improved bowel flow and normalization of the frequency of bowel movement and stool consistency. At the same time it exhibits antinociceptive activity and ability to lower serum phosphate levels. Because of these properties, it is clinically tested for the treatment of irritable bowel syndrome, especially when accompanied by constipation, treatment of hyperphosphatemia, especially in patients with dialysis with final stage renal failure, treatment of chronic kidney disease, and prevention of excess sodium in patients with kidney and heart conditions. The tenapanor molecule, which was first described in the international patent application WO 2010/078449, has the following structural formula:
In this document, tenapanor was prepared as bishydrochloride salt. The bishydrochloride salt was prepared only in the form of an amorphous foam, which, after solidification, required grinding for further processing. However, the thus obtained particles are of varying sizes, while a narrow particle size distribution is required for pharmaceutical use in order to ensure uniform behavior. The amorphous foam obtained in the said document is essentially a thickened reaction mixture or a slightly purified reaction mixture containing, in addition to tenapanor, various impurities. The possibilities to purify the reaction mixtures are limited. Moreover, amorphous foams tend to adsorb solvents, and it is usually difficult to remove (or dry out) the residual solvents from the amorphous foam. This is undesirable for pharmaceutical use. A typical feature of amorphous foams is a large specific surface, resulting in a greater interaction of the substance with the surrounding environment. This significantly increases the risk of decomposition of the substance, for example through air oxygen, moisture or light. The present invention aims at overcoming these problems.
It would be advantageous to provide tenapanor solid forms (tenapanor free base or tenapanor salts) which are precipitated in solid forms, thus allowing to filter off the liquid reaction mixture containing the impurities. This results in a significantly improved purity.
The process used in WO 2010/078449 for the preparation of bishydrochloride salt of tenapanor was based on the preparation of 3-(6,8-dichloro-2-methyl-l,2,3,4-tetrahydroisoquinolin-4-yl)benzene-l-sulfonyl chloride of formula III from 4-(3-bromophenyl)-6,8-dichloro-2-methyl-l, 2,3,4-te
Scheme 1
The said document also discloses resolution of the starting tetrahydroisoquinoline of formula II by L-or D-dibenzoylt
(II) (S-II) (R-II)
Scheme 2
WO 2010/078449 discloses further steps of preparation of tenapanor, as shown in Scheme 3.
(V) (I)
Scheme 3
Individual synthetic steps described in Scheme 3 result in low yields: 42% for the reaction of the chloride of formula III with 2-(2-(2-aminoethoxy)ethoxy)ethylamine of formula IV, and 59% for the subsequent reaction with 1,4-diisocyanatobutane of formula V. The products of both synthetic steps are isolated by preparative chromatography which is technologically an unsuitable isolation and purification technique. The low yields and the need to use preparative chromatography for the isolation are caused by an abundance of side products and impurities and by the inability of the intermediates as well as of the product to provide a crystalline form.
Thus present invention thus further aims at providing a method of preparation of tenapanor which would be economically effective, in particular in relation to the expensive starting compound 4-(3-bromophenyl)-6,8-dichloro-2-methyl-l,2,3,4-tetrahydroisoquinoline, and which would also enable industrial scale production, in particular by removing steps which cannot be scaled up effectively or which cannot be scaled up at all. Furthermore, the method of preparation of tenapanor should provide tenapanor in a form which is useful for use in pharmaceutical forms and does not have the disadvantages of an amorphous foam.
Tenapanor free base in the form of an amorphous solid foam was prepared by the procedure disclosed in patent application WO 2010/078449, Example 202. The chemical purity of the tenapanor prepared by this procedure was 96.5% (HPLC). The structure of tenapanor was verified by MS and H and 13C NMR spectra.
Step A
Preparation of (5)- -(3-(benzylthio)phenyl)-6,8-dichloro-2-methyl-l,2,3,4-tetrahydroisoquinoline
Potassium carbonate (9.30 g) and anhydrous xylene (500 ml) were added to the reaction vessel. Benzyl mercaptane (25 g) was added dropwise to the stirred mixture under ice -cooling. The resulting mixture was stirred at 25 °C for lh.
(S)-4-(3-bromophenyl)-6,8-dichloro-2-methyl-l,2,3,4-tetrahydroisoquinoline 50 g in anhydrous xylene (500 ml), Pd2(dba)3 (3 g) and Xantphos (3 g). The resulting solution was stirred at 25 °C for 30 minutes and then added to a solution of benzyl mercaptane. The resulting reaction mixture was maintained at 140 °C for 16 h. The mixture was then concentrated and the residue was subjected to preparative chromatography on silica gel with the mobile phase ethyl acetate / petroleum ether (1: 100-1 :50). 20 g of product are obtained as a yellow oil (36% yield).
Ste B
Preparation of (5) -3 -(6 , 8 -dichloro-2 -methyl- 1,2,3 ,4-tetr ahydroisoquinolin-4-yl)benzenesulf onyl chloride hydrochloride
(S)-4-(3-(benzylthio)phenyl)-6,8-dichloro-2-methyl-l,2,3,4-tetrahydroisoquinoline (16 g) was dissolved in the reaction vessel in acetic acid/water (160 mL: 16 mL) mixture. The mixture was cooled in an ice bath and then gaseous Cl2 was introduced into the well stirred mixture. After disappearance of the starting material, the reaction mixture was purged with nitrogen and concentrated in vacuo. A product (10 g, 66.6%) was obtained as a colorless substance.
Step C
Preparation of (S)-N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-3-(6,8-dichloro-2-methyl-l, 2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide
2-(2-(2-Aminoethoxy)ethoxy)ethylamine HC1 (30 g; 0.2 mol) and triethylamine (5.2 g; 52 mmol) were dissolved in dichloromethane (500 ml) and the mixture was chilled in an ice bath. (S)-3-(6,8-Dichloro-2-methyl-l,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonyl chloride hydrochloride (10 g; 26 mmol) was added in parts during 40 minutes to the chilled reaction mixture. The ice bath was removed and the reaction mixture was stirred at laboratory temperature for additional 30 minutes.
The dichloromethane solution was extracted three times by brine (2x 250 ml), dried over sodium sulphate, and concentrated in vacuo. The residue was purified using preparative chromatography on silica gel with dichloromethane-methanol mobile phase.
Yield 7.2 g. HRMS 502.1247 [M+H]+, C22H29CI2N3O4S.
Step D
Preparation of 17-[[[3-[(4S)-6,8-dichloro-l,2,3,4-tetrahydro-2-methyl-4-isoquinolinyl]phenyl]sulphonyl]amino]-N-[2-[2-[2-[[[3-[(4S)-6,8-dichloro-l,2,3,4-tetrahydro-2-methyl -4-isoquinolinyl] phenyl] sulphonyl] amino] ethoxy] ethoxy ] ethyl] – 8 -oxo- 12,15 -dioxa-2 ,7,9-triazah
(S)-N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-3-(6,8-dichloro-2-methyl-l,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide (5g; 10 mmol) prepared in step A was dissolved in dichloromethane (50 ml). Triethylamine (1.5 g; 14.9 mmol) and 1 ,4-diisocyanatobutane (0.48 g; 3.4 mmol) were added to the solution. The reaction mixture was cooled using ice and stirred overnight. The resulting fine suspension was filtered off, the filtrate was concentrated and the obtained product was purified by preparative chromatography on on silica gel with dichloromethane-methanol mixture as a mobile phase
Yield: 2 g of tenapanor in the form of amorphous solid foam. HPLC purity 96.5 %.
HRMS 1143.3186 [M+H]+, C5oH66Cl4N8010S2. *H NMR (500MHz, DMSO, ppm):7.69-7.66 (m, 6H), 7.54-7.50 (m, 6H), 6.89 (bs, 2H), 5.9 (t, 2H), 5.79 (t, 2H), 4.4 (dd, 2H), 3.7 (dd, 4H), 3.44-3.44 (m, 8H), 3.35 (dd, 8H), 3.12 (dd, 4H), 2.96-2.64 (m, 12H), 2.37 (s, 6H), 1.31 (bs, 4H).
Ste E
Preparation of bishydrochloride salt of tenapanor
Tenapanor free base (1 g; 0.85 mmol) prepared in step B was dissolved in a mixture of methanol (10 ml) and 4M aqueous HCl (0.5 ml; 2 mmol) under mild reflux. The solution was concentrated on rotary vacuum evaporator, and the title product was obtained in the yield of 1 g of amorphous solid foam.
Example 1
Preparation of tenapanor, crystalline form I
Tenapanor free base (200 mg, 0.17 mmol), prepared as in step D of the comparative example, was dissolved in 0.4 ml acetonitrile under mild reflux. The clear solution was cooled at the rate of 1 °C/min with stirring to laboratory temperature (i.e., range from 22 °C to 26 °C) and then stirred for additional 2 hours at this temperature. The resulting crystals were isolated by filtration on sintered glass filter and dried for 6 hours in a vacuum oven at 40 °C. Crystallization yield was 170 mg of crystalline form I of tenapanor. HPLC showed a purity of 99.5%.
Examples 4 to 9 illustrate the inventive method of preparation of crystalline tenapanor.
Example 4
Preparation of (5)- -(3-(benzylthio)phenyl)-6,8-dichloro-2-methyl-l ,2,3,4-tetrahydroisoquinoline
DIPEA (9.6 mL) and anhydrous dioxane (100 mL) were added to a reaction vessel. Benzyl mercaptan (8.1 ml) was added dropwise to the stirred mixture under ice -cooling. The resulting mixture was stirred at 25 °C for lh.
In a second reaction vessel, (S)-4-(3-bromophenyl)-6,8-dichloro-2-methyl-l,2,3,4-tetrahydroisoquinoline (21.2 g) in anhydrous dioxane (140 mL), Pd2(dba)3 (835 mg)and Xantphos (835 mg) were mixed. The resulting solution was stirred at 25 °C for 30 minutes and then added to the solution of benzyl mercaptan. The resulting reaction mixture was maintained at gentle reflux for 3 hours.
After cooling, the suspension obtained was filtered through a thin layer of celite. HC1 was added to the filtrate. The precipitated hydrochloride was isolated by filtration, washed well and dried. 21 g of pinkish product were obtained (81.6% yield).
Example 5
Preparation of (5) -3 -(6 , 8 -dichloro-2 -methyl- 1,2,3 ,4-tetr ahydroisoquinolin-4-yl)benzenesulf onyl chloride hydrochlorid
(S)-4-(3-(benzylthio)phenyl)-6,8-dichloro-2-methyl-l,2,3,4-tetrahydroisoquinoline hydrochloride (11.1 g) was stirred in DCM/2M HC1 (70 mL:6 mL) mixture in a reaction vessel. The mixture was cooled in an ice bath and then gaseous Cl2 was introduced into the vigorously stirred mixture. After disappearance of the starting material, the resulting suspension was bubbled through by nitrogen and the product was filtered off and washed with DCM. 9.2 g of white product was obtained (82.7% yield).
Example 6
In the reaction vessel, t-butyl 2-(2-(2-amionoethoxy)ethoxy)ethylcarbamate (21.8 g) was stirred in DCM. The mixture was cooled in an ice bath under an inert atmosphere. To the cooled solution was
added 1 ,4-diisocyanatobutane (6.14 g) and TEA (0.1 mL). The cooling bath was removed and the reaction mixture was further stirred for 2 h.
35% HCl was added to the reaction mixture and the mixture was stirred under gentle reflux overnight.
After cooling, the precipitated product was filtered off and washed with DCM.
The product was recrystallized from propan-2-ol. 22.3 g of white product was obtained (80% yield).
Example 7
Preparation of (5)-N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-3-(6,8-dichloro-2-methyl-l , 2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide
(S)-3-(6,8-dichloro-2-methyl-l ,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonyl chloride hydrochloride (11.7 g) prepared in Example 2 was stirred in dichloromethane (100 ml) and the suspension was cooled in an ice bath. To the cooled suspension was added a solution of t-butyl 2-(2-(2-amionoethoxy)ethoxy)ethylcarbamate (6.8 g) and DIPEA (14 ml) in DCM (50 ml). The resulting solution was stirred for 2 hours in an ice bath. The reaction mixture was extracted twice with water. Concentrated HCl (15 mL) was added to the dichloromethane solution and the mixture heated at gentle reflux for 2 h.
The precipitated product, after cooling, was extracted into water. The aqueous phase was separated and basified with Na2C03. The product as the free base was extracted into DCM and the dichloromethane solution was dried over sodium sulfate and concentrated in vacuo. 12.9 g of product were obtained.
Yield 93.4%. HRMS 502.1247 [M+H]+, C22H29CI2N3O4S.
Example 8
Preparation of 17-[[[3-[(45)-6,8-dichloro-l ,2,3,4-tetrahydro-2-methyl-4-isoquinolinyl]phenyl] sulfonyl]amino]-N-[2-[2-[2-[[[3-[(45)-6,8-dichloro-l ,2,3,4-tetrahydro-2-methyl-4-isoquinolinyl] phenyl] sulf onyl] amino] ethoxy ] ethoxy ] ethyl] – 8 -oxo- 12,15 -dioxa-2 ,7 ,9-triazaheptadecanamide (tenapanor free base)
(S)-N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-3-(6,8-dichloro-2-methyl-l,2,3,4- tetrahydroisoquinolin- 4-yl)benzenesulfonamide (12.9 g) prepared in Example 4 was dissolved in dichloromethane (150 ml). To the solution was added triethylamine (0.3 ml) and 1,4-diisocyanatobutane (1.7 g). The reaction mixture was stirred at 25 °C for 2 h. The resulting reaction mixture was extracted with water and aqueous Na2C03. The dichloromethane solution of the product was dried over sodium sulfate and concentrated to a solid foam. Yield 13.9 g. The crude product was taken up in acetone (100 ml) and then recrystallized from methanol (80 ml). 7.3 g of white crystalline product was obtained. Yield 49.8%.
HRMS 1143.3186 [M+H]+, C5oH66Cl4N8010S2. !H NMR (500MHz, DMSO, ppm):7.69-7.66 (m, 6H), 7.54-7.50 (m, 6H), 6.89 (bs, 2H), 5.9 (t, 2H), 5.79 (t, 2H), 4.4 (dd, 2H), 3.7 (dd, 4H), 3.44-3.44 (m, 8H), 3.35 (dd, 8H), 3.12 (dd, 4H), 2.96-2.64 (m, 12H), 2.37 (s, 6H), 1.31 (bs, 4H)
Example 9
Preparation of 17-[[[3-[(45)-6,8-dichloro-l,2,3,4-tetrahydro-2-methyl-4-isoquinolinyl]phenyl] sulfonyl]amino]-N-[2-[2-[2-[[[3-[(45)-6,8-dichloro-l,2,3,4-tetrahydro-2-methyl-4-isoquinolinyl] phenyl] sulf onyl] amino] ethoxy ] ethoxy ] ethyl] – 8 -oxo- 12,15 -dioxa-2 ,7 ,9-
(S)-3-(6,8-dichloro-2-methyl-l,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonyl chloride hydrochloride (0.81 g) prepared in Example 2 and l,l’-(butane-l,4-diyl)bis(3-(2-(2-(2-aminoethoxy)ethoxy)ethyl)urea) dihydrochloride prepared according to Example 3 (0.48 g) were stirred in anhydrous ΝΜΡ (10 ml). To the suspension was added DIPEA (2 mL) and the resulting solution was stirred at 60 °C for 1.5 h. Water (10 mL) was added dropwise to the reaction mixture and the mixture was cooled to 5 °C. The precipitated product was isolated and stirred in acetone at 5 °C overnight. The beige product was filtered off (0.67 g) and recrystallized from methanol (12 ml).
0.53 g of a colorless crystalline product was obtained.
Yield 78.7 %. HRMS 502.1247 [M+H]+, C22H29CI2N3O4S. DSC analysis showed the melting temperature of 130.5 °C.
Example 10
Tenapanor (1.48 g, 1.3 mmol) is dissolved in 10 ml of tetrahydrofurane (THF). From the thus prepared solution, 1 ml is taken and phosphoric acid (0.4 mmol) is added. The mixture is stirred at room temperature for 24 hours. Salt of tenapanor with phosphoric acid precipitated from the solution in solid stable form, the salt was filtered off, washed with THF and dried by stream of inert gas. XRPD confirmed amorphousness of the product.
Example 11
Tenapanor (1.48 g, 1.3 mmol) is dissolved in 10 ml of tetrahydrofurane (THF). From the thus prepared solution, 1 ml is taken and hydrobromic acid (0.4 mmol) is added. The mixture is stirred at room temperature for 24 hours. Salt of tenapanor with hydrobromic acid precipitated from the solution in solid stable form, the salt was filtered off, washed with THF and dried by stream of inert gas. XRPD confirmed amorphousness of the product.
Example 12
Tenapanor (1.48 g, 1.3 mmol) is dissolved in 10 ml of acetone. From the thus prepared solution, 1 ml is taken and phosphoric acid (0.4 mmol) is added. The mixture is stirred at room temperature for 24 hours. Salt of tenapanor with phosphoric acid precipitated from the solution in solid stable form, the salt was filtered off, washed with acetone and dried by stream of inert gas. XRPD confirmed amorphousness of the product.
Example 13
Tenapanor (1.48 g, 1.3 mmol) is dissolved in 10 ml of acetone. From the thus prepared solution, 1 ml is taken and citric acid (0.4 mmol) is added. The mixture is stirred at room temperature for 24 hours. Salt of tenapanor with citric acid precipitated from the solution in solid stable form, the salt was filtered off, washed with acetone and dried by stream of inert gas. XRPD confirmed amorphousness of the product.
Other pharmaceutically acceptable acids were tested by the procedures shown in Examples 10-13, but did not yield salts which would precipitate in amorphous stable solid form from the solution. The tested acids were: methanesulfonic acid, benzenesulfonic acid, oxalic acid, maleinic acid, tartaric acid, fumaric acid, trichloroacetic acid.
Example 14
Tenapanor (500 mg, 0.44 mmol) is dissolved in 20 ml of THF at 45 °C. To this clear solution, a solution of phosphoric acid in THF (50 μ1/5 ml) is added dropwise during 10 minutes. The resulting suspension is stirred at room temperature for 30 minutes. The precipitated salt of tenapanor with phosph (79 %) oric is filtered off, washed with 3 ml of THF and dried by stream of inert gas. Yield: 430 mg of colourless salt of tenapanor with phosphoric acid. XRPD showed amorphousness of the product.
Example 15
Tenapanor (500 mg, 0.44 mmol) is dissolved in 20 ml of THF at 45 °C. To this clear solution, hydrobromic acid (48%; 100 μΐ) is added dropwise during 10 minutes. A fine precipitate forms already during the dropwise addition of HBr, and the suspension is stirred at room temperature for 30 minutes. The precipitated salt of tenapanor with HBr is filtered off, washed with 3 ml of THF and dried by stream of inert gas. Yield: 397 mg (69 %) of colourless salt of tenapanor with HBr (1 :2). XRPD showed amorphousness of the product.
References
- ^ Spencer AG, Labonte ED, Rosenbaum DP, Plato CF, Carreras CW, Leadbetter MR, Kozuka K, Kohler J, Koo-McCoy S, He L, Bell N, Tabora J, Joly KM, Navre M, Jacobs JW, Charmot D (2014). “Intestinal inhibition of the na+/h+ exchanger 3 prevents cardiorenal damage in rats and inhibits na+ uptake in humans”. Sci Transl Med. 6 (227): 227ra36. doi:10.1126/scitranslmed.3007790. PMID 24622516.
- ^ Salt-buster drug cuts sodium absorbed from food. New Scientist, 14 March 2014
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20: Spencer AG, Labonte ED, Rosenbaum DP, Plato CF, Carreras CW, Leadbetter MR, Kozuka K, Kohler J, Koo-McCoy S, He L, Bell N, Tabora J, Joly KM, Navre M, Jacobs JW, Charmot D. Intestinal inhibition of the Na+/H+ exchanger 3 prevents cardiorenal damage in rats and inhibits Na+ uptake in humans. Sci Transl Med. 2014 Mar 12;6(227):227ra36. doi: 10.1126/scitranslmed.3007790. PubMed PMID: 24622516.
 |
|
| Clinical data | |
|---|---|
| Routes of administration |
Oral |
| Identifiers | |
| CAS Number | |
| PubChem CID | |
| ChemSpider | |
| CompTox Dashboard (EPA) | |
| ECHA InfoCard | 100.243.471  |
| Chemical and physical data | |
| Formula | C50H66Cl4N8O10S2 |
| Molar mass | 1145.046 g/mol g·mol−1 |
| 3D model (JSmol) | |
//////////////Tenapanor, AZD 1722, RDX 5791, chronic kidney disease, hypertension
CN1CC(C2=CC(=CC(=C2C1)Cl)Cl)C3=CC(=CC=C3)S(=O)(=O)NCCOCCOCCNC(=O)NCCCCNC(=O)NCCOCCOCCNS(=O)(=O)C4=CC=CC(=C4)C5CN(CC6=C(C=C(C=C56)Cl)Cl)C