EP1212350A1 - Procede de preparation de h-tyr-d-ala-phe(f)-phe-nh 2? - Google Patents

Procede de preparation de h-tyr-d-ala-phe(f)-phe-nh 2?

Info

Publication number
EP1212350A1
EP1212350A1 EP00963222A EP00963222A EP1212350A1 EP 1212350 A1 EP1212350 A1 EP 1212350A1 EP 00963222 A EP00963222 A EP 00963222A EP 00963222 A EP00963222 A EP 00963222A EP 1212350 A1 EP1212350 A1 EP 1212350A1
Authority
EP
European Patent Office
Prior art keywords
group
derivative
ester
protecting group
benzyl
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.)
Withdrawn
Application number
EP00963222A
Other languages
German (de)
English (en)
Inventor
Marten Ellburg
Henry Franzen
Maths Nilsson
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shire Canada Inc
Original Assignee
AstraZeneca AB
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by AstraZeneca AB filed Critical AstraZeneca AB
Publication of EP1212350A1 publication Critical patent/EP1212350A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1027—Tetrapeptides containing heteroatoms different from O, S, or N
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention is directed to a new process for the preparation of a tetrapeptide, more specifically the tetrapeptide H-Tyr-D-Ala-Phe(pF)-Phe- NH2, or a pharmaceutically acceptable salt thereof.
  • the present invention also relates to new intermediates used in the process.
  • WO 97/07129 discloses a process for producing inter alia the peptide H-Tyr-D-Ala- Phe(pF)-Phe-NH 2 .
  • the peptide H-Tyr-D-Ala-Phe(pF)-Phe-NH 2 is also disclosed in WO 97/07130.
  • Said peptide exhibits peripheral analgesic activity and selectivity for the ⁇ - subtype of opioid receptors, and is particularly suitable in pain therapy.
  • it is prepared using solid phase synthesis according to procedures well established in the art. The drawback with solid phase synthesis is that it is difficult to use in large-scale production, in addition to being expensive.
  • WO99/47548 discloses a process for the preparation of the tetrapeptide H-Tyr-D-Ala- Phe(pF)-Phe- NHb using stepwise synthesis.
  • the process of the present invention provides the tetrapeptide H-Tyr-D-Ala-Phe(pF)-Phe- NH 2 in a simpler manufacturing process with, e.g. easier purification of the final product.
  • the object of the present invention is to provide a novel process suitable for use in large-scale synthesis.
  • a further object of the present invention is to provide a process containing as few reaction steps as possible.
  • the present invention provides a new process for large-scale preparation of the peptide H- Tyr-D-Ala-Phe(pF)-Phe-NH2, which is the peptide of formula (I)
  • the process according to the present invention for preparing the compound of formula (I) is a fragment synthesis (2+2).
  • a fragment synthesis a plurality of intermediate compounds, are prepared in parallel and then coupled together to give the key intermediate(s) or the final compound.
  • This strategy should be compared to a traditional stepwise synthesis wherein a number of synthetic steps are performed sequential.
  • the different approaches in a stepwise vs. fragment synthesis are schematically shown in Figure 1 below.
  • A is an amino protecting group
  • R is an activating agent residue group
  • 2 R is H or a benzyl-like group; previously prepared by a pre-activation step or generated in situ, is reacted with the amino group of D-alanine, wherein the carboxyl group is protected as an ester, i.e. a compound of tthhee ffoorrmmuullaa DD--AAllaa--RR wwhheerreeiinn RR iiss tthhee eesstteerr ggrrooiup, e.g. OMe, in the presence of a solvent, providing a protected dipeptide derivative (IV)
  • A is an amino protecting group
  • R is an ester residue group
  • Step 2 A deprotection step wherein a protected dipeptide derivative (IV) prepared in the previous step, is deprotected by treatment with aqueous base or acid to give the dipeptide derivative (V),
  • A is an amino protecting group
  • activated tyrosine derivative is an activated ester or urethane protected N- carboxyanhydride (UNCA) of the structure (II')
  • A is an amino protecting group
  • the carboxyl group of D-alanine needs no protection, i.e. can be a compound of the formula D-Ala-OH, and the coupling reaction thereby provides a protected dipeptide derivative V, which can be used directly in the step 3 without any further deprotection.
  • UNCA-derivatives The preparation and use of UNCA-derivatives is discussed by Fehrentz et al. (1995). "The use of N-urethane protected N-carboxyanhydrides (UNCAs) in amino acid and peptide synthesis.” J. Pept. Sci., 1(2), 124-131 ; and by Fuller et al, (1996). "Urethane-protected a- aminoacid N-carboxanhydrides and peptide synthesis.” Biopolymers (Peptide Science), 40(2), 183-205 which are incorporated herein by reference.
  • the activated tyrosine derivative (II) can be reacted with the amino group of non-protected D-Ala, i.e. H-D-Ala-OH, providing dipeptide derivative (V) directly.
  • Step 1' A coupling step wherein an activated /7-fluorophenylalanine derivative (VI),
  • A is an amino protecting group
  • R is an activating agent residue group
  • previously prepared by a pre-activation step or generated in situ is reacted with the amino group of phenylalanine, wherein the carboxyl group is protected as an ester or amide, i.e. a compound of the formula Phe-R (VII), wherein R is -NH2 or an ester residue group, e.g. OMe, in the presence of a solvent, providing a protected dipeptide derivative (VIII)
  • A is an amino protecting group, and R is -NH2 or an ester residue group;
  • Step 2' A deprotection step wherein a protected dipeptide derivative (VIII) prepared in the previous step, is deprotected by either catalytic hydrogenation, base or acid treatment, depending on the amino protecting group used, to give the dipeptide derivative (IX),
  • R is -NH2 or an ester residue group
  • A is an amino protecting group
  • R is an activating agent residue group
  • A is an amino protecting group
  • R is -NH2 or an ester residue group
  • A is an amino protecting group
  • R 1 is -NH 2 .
  • the additional step described above may be prepared on the protected dipeptide derivative (VIII), if R is an ester, whereby the ester compound (VIII) is reacted with an amine in an organic alcohol, preferably ammonia in methanol, providing the protected dipeptide derivative (VHP),
  • A is an amino protecting group, and R 1 is -NH 7
  • Step 4 A deprotection step wherein the protected tetrapeptide derivative (X) is deprotected either by catalytic hydrogenation, or treatment with acid or base, depending on the amino protecting group used, providing the final tetrapeptide (I), which optionally may be converted to a pharmaceutically acceptable salt thereof
  • N -amino protecting group may be selected from any protecting group suitable in peptide synthesis, such as tert- butoxycarbonyl (Boc), 9-fluorenylmetoxycarbonyl (Fmoc) or benzyloxycarbonyl, often abbreviated Z-, just to mention three possible amino protecting groups
  • benzyloxycarbonyl is particularly preferred to be used in the present invention since it is easily removed by catalytic hydrogenation, and contrary to the protecting group Boc, it does not require neutralization of the liberated amine C i-C ⁇ alkyl esters and alkylaryl ester, such as benzyl, are preferred carboxyl protecting groups
  • Methyl esters are particularly preferred carboxyl protecting groups
  • Benzyl-like protecting groups are suitable tyrosine side-chain protecting groups to be used in the present invention Preferably no tyrosine side
  • the pre-activation step preceding steps 1 , 1 ' and 3, or the in situ generation of the activated amino acid derivatives (II), (VI) and (V), is achieved by reacting an amino acid, wherein the amino function has been protected by a suitable protecting group, such as tert- butoxycarbonyl (Boc), 9-fluorenylmetoxycarbonyl (Fmoc) or benzyloxycarbonyl (Z), which are either commercially available or available by techniques known in the art, with an activating agent in the presence of a suitable amine and an organic solvent, to give the activated amino acid derivative.
  • a suitable protecting group such as tert- butoxycarbonyl (Boc), 9-fluorenylmetoxycarbonyl (Fmoc) or benzyloxycarbonyl (Z), which are either commercially available or available by techniques known in the art
  • A is an amino protecting group
  • R is an activating agent residue group
  • Steps 1, Land 3 a variety of powerful solvents may be used, as long as the amino component is essentially soluble and available for immediate reaction with the activated peptide derivative.
  • suitable solvents for the coupling step are acetone, acetonitrile, DMF, N-methyl pyrrolidone (NMP), EtOAc, and mixtures thereof.
  • benzyl-like group denotes any substituted or un-substituted benzyl group that is hydrogenolyzed under similar reaction conditions as the benzyloxycarbonyl group.
  • C 1-C alkyl ' denotes a cyclic or linear, straight or branched, substituted or unsubstituted alkyl group having from 1 to 6 carbon atoms
  • alkyl include but are not limited to methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert - butyl, cyclohexyl. and cyclopentyl
  • substituted denotes a group that is substituted by one or more C
  • Suitable activating agents may be selected from those that generates any of the commonly used activated ammo acid derivatives including, but not limited to, carbod ⁇ mides, activated esters, azide, or anhydrides
  • Isobutylchloroformiate (iBuOCOCl) and 2-( lH- Benzot ⁇ azole-l-yl)- l , l,3,3-tetramethyluron ⁇ um tetrafluoroborate (TBTU) are the preferred activating agents together with UNCA-de ⁇ vatives
  • the amount of activating agent is between 0 9- 1 2 molar equivalents, preferably 0 95- 1 05 equivalents From a practical point of view the amount of activating agent shall be as close to 1 0 as possible
  • isobutylchloroformiate (iBuOCOCl) is the activating agent
  • the activated peptide derivative will have the following structure, exemplified on D-alanine,
  • the suitable amine may be selected from any tertiary amine However, NMM (N-methylmorphohne), di-isopropylethylamine and t ⁇ ethylamine are preferred.
  • the amount of amine is between 0 9-2 0 molar equivalents, compared to the acid, and preferable between 0.95 to 1.5 molar equivalents. From a practical point of view the amount of suitable amine shall be at least equal to the molar amount of activating agent used.
  • the organic solvent may be any organic solvent known to a person skilled in the art to be suitable in peptide chemistry. However, ethyl acetate, acetonitrile, acetone, tetrahydrofurane, DMF as well as mixtures thereof are preferred solvents in the pre- activation step.
  • the solvent used for the coupling step may be selected from a variety of solvents, as long as the amino component is essentially soluble and available for immediate reaction with the activated amino acid residue.
  • suitable solvents for the coupling steps are acetone, acetonitrile, DMF, N-methyl pyrrolidone (NMP), EtOAc, and mixtures thereof, of which acetone, EtOAc, NMP and DMF are preferred.
  • any temperature where the activated amino acid derivative is not degraded or the reaction rate is too slow may be used.
  • the preferred range when isobutyl chloroformate is used as the activating agent is from 0°C to -20°C, and particularly preferred is from -5°C to -15°C.
  • the preferred range when TBTU is used as the activating agent is around room temperature. The rate of addition is in both cases adjusted so that the preferred temperature is maintained in the reaction mixture.
  • the catalyst used for hydrogenation may be selected from a great variety of catalysts as will be appreciated by a person skilled in the art. However 5% Pd on carbon is preferred. Any solvent that can dissolve at least some of the peptide is possible to use except ketones, such as acetone, or those solvents that poison the catalyst or react with the components of the reaction. A person skilled in the art will appreciate the choice of solvent. DMF and NMP are the preferred solvents.
  • Hydrolysis of the ester residue group in compound (IV) can be achieved by any method known to the skilled person, e.g. aqueous acid, base treatment or hydro genolyzis, depending on the carboxyl protecting group used.
  • Cj-C ⁇ alkyl esters are preferred esters and treatment with aqueous base under standard conditions is the preferred method for ester hydrolysis.
  • the protected amino acid preferably oc using benzyloxycarbonyl- as N -amino protecting group
  • the method employed is based on the general method reviewed by J. Meienhofer in The Peptides,
  • the activation time can be extended to at least 30 min at a temperature about 0 - -15°C, contrary to the recommended 1-2 min at -15°C.
  • strictly anhydrous conditions are not necessary as otherwise is recommended. This allows the present method to be used for large-scale production where the longer reaction times allow a safe and reproducible process to be carried out.
  • the stereochemical integrity has been completely maintained and the chemical purity as well as yields have been typically over 90%.
  • the generated mixed anhydride is coupled with the slow addition of the amino component (amino acid/ peptide amide or ester) at about 0 - -15°C and the reaction mixture is then allowed to reach 20-30°C in about 30-60 min. or longer before crystallization of the product is initiated directly from the reaction mixture.
  • isobutylchloroformiate can be used in the key step in the fragment synthesis of the present invention, i.e. coupling step 3, without any substantial racemization of the D-alanine aminoacid fragment.
  • Another object of the present invention is to provide new intermediates that can be used in the preparation of compound of formula I.
  • a further aspect of the present invention is a compound of the general formula X'
  • A is tert-butoxycarbonyl (Boc), 9-fluorenylmethoxycarbonyl (Fmoc), benzyloxycarbonyl
  • R 1 is -NH 2 ,C r C 6 alkyl ester, benzyl ester, OH, 9-fluorenylmetyl ester or a substituted benzyl ester derivative:
  • R 2 is H, a benzyl-like group, tert. butyl group, or 9-flourenylmefhyl group, as intermediates for use according to the present invention.
  • Z-Tyr-D-Ala-OMe ( l.Og, 2.46mmol, of purity 95%) was dissolved in dioxane (8mL). 1M NaOH (aq) (5.2mL) was then charged and the reaction left over night. The solvents were removed by vacuum distillation. The residue was dissolved in EtOAc (250mL) and extracted, first with brine (4x75mL) followed by 1M KHSO 4 (3x75mL). The organic layer was then dried over MgSO (anh d ) for several hours before filtration. The filtrate was evaporated to dryness by vacuum distillation.
  • Example 3 Z-Tyr-OH (63,1 g, 200 mmol) and H-(D)-Ala-OMe x HCl (31,0 g, 222 mmol) were charged to a one liter reactor under nitrogen. Acetone (400 ml) was added and the slurry cooled to -20°C. Isobutylchloroformiat (30, 1 g, 220 mmol) was then added, quickly followed by N-Methylmorpholine (47,9 g, 472 mmol) while maintaining the temp at about -10°C. Upon completion of the NMM-charge the temp was allowed to reach 20°C, the precipitate filtered off and washed with Acetone (100ml).
  • a 250 mL flask was charged with H-D-Alanine-OH (4,52 g; 50,2 mmol; 2 eq), potassium carbonate anhydrate (7,05 g; 50,2 mmol; 2 eq) and polyethylene glycol 200 (50 mL; 11,1 mL/g Alanine), which was stirred at ambient temperature.
  • Another 250 mL flask was charged with Z-Tyrosine (8,00 g; 25,1 mmol) and EtOAc (100 mL; 12,6 mL/g Z- Tyrosine).
  • Z-Phe(pF)-OH ( 1 eq.) is first dissolved in acetonitrile (MeCN)( 1.7L/mole) and cooled before addition of z ' -Butylchloroformiate ( 1.05 eq). The reaction is then controlled by the rate of addition, (about 20 minutes) 15 min actual, of N-Methylmorpholine ( 1.4eq). A reaction temperature between 0 and -15°C is recommended where the reaction occurs immediately upon addition of N-Methylmorphohne, yet prevents the mixed anhydride from decomposing to rapidly
  • H-Phe- ⁇ H 2 x HCl ( 1 04 eq) is meanwhile dissolved in DMF (4 OL/mole), neutralized with s N-Methylmorpholine (1 04eq) and cooled to about -10°C This slurry is upon completion of the activation added at a rate that maintains the temperature around -10°C for about 15 minutes
  • Z-Phe(pF)-Phe-NH prepared in the previous step is mixed with DMF (3 5L/mole) and a 0 Pd/C catalyst (5% Pd) is added 5%, by weight and the resulting mixture hydrogenated for more than 0 5 hours at 25-30°C and about 3bar H 2
  • the reaction mixture is then filtered and cooled to about -15°C before the next step 99 6% purity in solution and >99% conversion of starting material
  • Example 8 Z-Tyr-(D)-Ala-OH (15.0 g, 39 mmol) and H-Phe(pF)-Phe-NH2xHCl (12.8 g, 35 mmol) were mixed with aceton (450 ml) in a one liter reactor. The slurry temperature was reduced to -10°C prior to addition of isobutylchloroformate (4.55 ml, 35 mmol). NMM (8.45 ml, 77 mmol) was slowly charged to maintain the temp at about -10°C. Upon completed addition the temp was increased to room temperature and 2M HCl (40 ml, 80 mmol) added followed by water (365 ml).
  • the free base compound I is dissolved in a mixture of water and acetone with one equivalent HCl added and clear filtered (146g/mole 25% HCl/H 2 O, 2L Acetone/mole in actual run).
  • the salt has a limited solubility in acetone and therefore the filter is washed once with an additional amount of the acetone/water (95:5) mixture (0.5L/mole).
  • the crystallization is initiated by a slow addition of acetone (3.4L/mole) at high agitation rate and then 1% w/w of seeding crystals is optionally added. After 30 minutes the first amount of MIBK (3L/mole) is slowly charged and left with slow stirring until the batch clearly thickens.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Biochemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)

Abstract

La présente invention concerne un procédé nouveau et amélioré de préparation du tétrapeptide H-Tyr-D-Ala-Phe(F)-Phe-NH2 qui est un peptide de formule (I). On décrit ce tétrapeptide ou un sel pharmaceutiquement acceptable de ce dernier ainsi que de nouveaux intermédiaires utiles dans la préparation dudit tétrapeptide. Le nouveau procédé est une synthèse fragmentaire à étapes parallèles en nombre réduit qui est adaptée à la production de masse.
EP00963222A 1999-09-15 2000-09-07 Procede de preparation de h-tyr-d-ala-phe(f)-phe-nh 2? Withdrawn EP1212350A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
SE9903291 1999-09-15
SE9903291A SE9903291D0 (sv) 1999-09-15 1999-09-15 New process
PCT/SE2000/001747 WO2001019849A1 (fr) 1999-09-15 2000-09-07 Procede de preparation de h-tyr-d-ala-phe(f)-phe-nh¿2?

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EP1212350A1 true EP1212350A1 (fr) 2002-06-12

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EP (1) EP1212350A1 (fr)
JP (1) JP2003509437A (fr)
AU (1) AU7466900A (fr)
CA (1) CA2383184A1 (fr)
SE (1) SE9903291D0 (fr)
WO (1) WO2001019849A1 (fr)

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MX354786B (es) 2007-06-04 2018-03-21 Synergy Pharmaceuticals Inc Agonistas de guanilato ciclasa utiles para el tratamiento de trastornos gastrointestinales, inflamacion, cancer y otros trastornos.
US8969514B2 (en) 2007-06-04 2015-03-03 Synergy Pharmaceuticals, Inc. Agonists of guanylate cyclase useful for the treatment of hypercholesterolemia, atherosclerosis, coronary heart disease, gallstone, obesity and other cardiovascular diseases
FR2928372B1 (fr) * 2008-03-10 2010-12-31 Solvay Procede de synthese peptidique
ES2627848T3 (es) 2008-06-04 2017-07-31 Synergy Pharmaceuticals Inc. Agonistas de la guanilato ciclasa útiles para el tratamiento de trastornos gastrointestinales, inflamación, cáncer y otros trastornos
ES2624828T3 (es) 2008-07-16 2017-07-17 Synergy Pharmaceuticals Inc. Agonistas de la guanilato ciclasa útiles para el tratamiento de trastornos gastrointestinales, inflamación, cáncer y otros
ES2608050T3 (es) 2008-12-03 2017-04-05 Synergy Pharmaceuticals Inc. Formulaciones de agonistas de guanilato ciclasa C y métodos de uso
WO2018129556A1 (fr) 2017-01-09 2018-07-12 Ardelyx, Inc. Composés et procédés pour l'inhibition d'un antiport à médiation par échangeur sodium/proton (nhe) dans le traitement de troubles associés à une rétention d'eau ou à une surcharge en sel et de troubles du tractus gastro-intestinal
PL2384318T3 (pl) 2008-12-31 2018-04-30 Ardelyx, Inc. Związki i sposoby inhibicji mediowanego przez NHE antyportu w leczeniu zaburzeń związanych z retencją płynów lub nadmiarem soli i chorób przewodu pokarmowego
US9616097B2 (en) 2010-09-15 2017-04-11 Synergy Pharmaceuticals, Inc. Formulations of guanylate cyclase C agonists and methods of use
CN103764672A (zh) 2011-03-01 2014-04-30 辛纳吉制药公司 制备鸟苷酸环化酶c激动剂的方法
US10376481B2 (en) 2012-08-21 2019-08-13 Ardelyx, Inc. Compounds and methods for inhibiting NHE-mediated antiport in the treatment of disorders associated with fluid retention or salt overload and gastrointestinal tract disorders
CN104902930A (zh) 2012-08-21 2015-09-09 阿德利克斯公司 在治疗与液体潴留或盐分过载相关的疾病和胃肠道疾病中用于抑制nhe-介导的反向转运的化合物和方法
EP2970384A1 (fr) 2013-03-15 2016-01-20 Synergy Pharmaceuticals Inc. Agonistes de la guanylate cyclase et leurs utilisations
US9486494B2 (en) 2013-03-15 2016-11-08 Synergy Pharmaceuticals, Inc. Compositions useful for the treatment of gastrointestinal disorders
WO2014169094A2 (fr) 2013-04-12 2014-10-16 Ardelyx, Inc Composés de liaison à nhe3 et procédés d'inhibition du transport de phosphate
KR102272746B1 (ko) 2013-06-05 2021-07-08 보슈 헬스 아일랜드 리미티드 구아닐레이트 사이클라제 c의 초순수 작용제, 및 이의 제조 및 사용 방법
MX2019008170A (es) 2017-01-09 2020-02-07 Ardelyx Inc Compuestos útiles para tratar transtornos del tracto gastrointestinal.
AU2018206479B2 (en) 2017-01-09 2022-07-14 Ardelyx, Inc. Inhibitors of NHE-mediated antiport

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GB9516994D0 (en) * 1995-08-18 1995-10-18 Iaf Biochem Int Solution synthesis of peripheral acting analgestic opioid tetrapeptides
SE9800865D0 (sv) * 1998-03-16 1998-03-16 Astra Ab New Process

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AU7466900A (en) 2001-04-17
WO2001019849A1 (fr) 2001-03-22
CA2383184A1 (fr) 2001-03-22
JP2003509437A (ja) 2003-03-11
SE9903291D0 (sv) 1999-09-15

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