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WO1997007129A1 - Synthese en solution de tetrapeptides opioides analgesiques a action peripherique - Google Patents

Synthese en solution de tetrapeptides opioides analgesiques a action peripherique Download PDF

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Publication number
WO1997007129A1
WO1997007129A1 PCT/CA1996/000552 CA9600552W WO9707129A1 WO 1997007129 A1 WO1997007129 A1 WO 1997007129A1 CA 9600552 W CA9600552 W CA 9600552W WO 9707129 A1 WO9707129 A1 WO 9707129A1
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WO
WIPO (PCT)
Prior art keywords
phe
process according
activating agent
tyr
group
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
Application number
PCT/CA1996/000552
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English (en)
Inventor
Nicholas Rinaldi
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
IAF BioChem International Inc
Biochem Pharma Inc
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 IAF BioChem International Inc, Biochem Pharma Inc filed Critical IAF BioChem International Inc
Priority to AU66539/96A priority Critical patent/AU6653996A/en
Publication of WO1997007129A1 publication Critical patent/WO1997007129A1/fr
Anticipated expiration legal-status Critical
Ceased 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
    • C07K5/1002—Tetrapeptides with the first amino acid being neutral
    • C07K5/1016—Tetrapeptides with the first amino acid being neutral and aromatic or cycloaliphatic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the objective compound is a family of peripherally acting opioid tetrapeptides of the formula (I) Tyr-(D)R ⁇ -R 2 - R 3 -NH 2 , where R- is Ala or Arg ; R 2 is Phe or Phe(p-F); and ;R 3 is Phe or Phe(p-F) (TAPP-like peptides) having valuable pharmacological properties which enable them to be used therapeutically, in particular in me therapy and management of pain.
  • the analgesic properties of the TAPP-like peptides are manifest through the ⁇ opioid receptor subtype. Moreover, the pharmacological profile of these tetrapeptides are unique and differ markedly from standard opiates because they activate peripheral nociceptors and do not affect central nervous system centers. Unlike conventional opiates, the compounds described herein exhibit markedly attenuated side effects.
  • peptides are synthesized on a solid support or beads, which are polystyrene based, through sequential incorporation of fully-protected amino acids via a dehydrating agent as described by Stewart and Young (J.M. Stewart and J.D. Young, Solid Phase Peptide Synthesis, Pierce Chemical Company, Rockford, Illinois, 1984).
  • This process is viable for research scale samples but not for pilot or commercial scale.
  • Such a process results in a yield that is relatively poor and is especially difficult to exploit industrially on account of the use of protecting agents (blocking/deblocking cycles) and of me requirement of many purification stages involving HPLC, stereochemical vulnerabiliy of the chiral centers during the synthesis and typical harsh conditions required to remove the peptide from the resin.
  • Conventional processes are expensive and require large excess of reagents and amino acids.
  • the use of a solid support (resin) limits the use of manual manufacturing equipment.
  • peripherally acting opioid tetrapeptides corresponding to formula (I): Tyr-(D)R--R 2 -R 3 -NH2 , where R- is Ala or Arg ; R 2 is Phe or Phe(p-F); and ;R 3 is Phe or Phe(p-F) and the lack of a commercial scale (i.e., yields on the order of kilogram quantities) process enabling it to be obtained with a satisfactory degree of purity, a good yield and, if possible, from fairly inexpensive commercially available starting materials and procedures, more detailed research has been carried out and has led to the discovery of a new process for their preparation.
  • a process for producing multikilo quantities of those TAPP-like peptides which overcomes the problems outlined above.
  • the process of the present invention provides a solution phase peptide synthesis process in which the yield of D-isomer of Rj is improved over the conventional processes using solid phase (eg. resin based oligopeptide building) and solution phase (employing costly blocking and deblocking agents) to increase efficiency and cost effectiveness for large scale production.
  • solid phase eg. resin based oligopeptide building
  • solution phase employing costly blocking and deblocking agents
  • the present invention provides for a synthesis of opioid analgesic tetrapeptides having the general structure represented by Formula I:
  • Ri is Ala, or Arg;
  • R 2 is Phe or Phe(p-F); and
  • R 3 is Phe or Phe(p-F); which comprises a coupling step comprising couphng (P-Tyr-(D)R ⁇ ), wherein P is an amino protecting group; with (R 2 -R3-NH 2 ) using 3-hy droxy- 1,2,3 benzotriazin- 4(3H)one (HODbht) as an activating agent, a neutralizing agent selected from the group consisting of diisopropylethylamine (DIEA) and n-ethylmorpholine (NEM); in a solvent suitable for a coupling reaction to yield to a protected intermediate of formula (II): P-Tyr-(D)R ⁇ -R 2 -R 3 -NH 2
  • DIEA diisopropylethylamine
  • NEM n-ethylmorpholine
  • the Applicant has succeeded, not without surprise, to perfect processes that minimize tlie investment costs and/or energy consumptions, and maximize the yields by adopting the most appropriate operating conditions for pre-pilot scale leading to commercial scale production.
  • the invention has also yielded an efficient process that is conserved from a microscale process to a pilot or commercial scale preparation of the desired tetrapeptide.
  • the process allows for almost racemization-free product (typically ⁇ 0.5%) on scales up to the multikilogram level.
  • the present process also removes the need for polystyrene resin as a solid phase support which is expensive on a manufacturing scale.
  • the process further circumvents the need for strong acids such as hydrofluoric acid to effect removal of side chain protecting groups.
  • the process of the present invention has important advantages, expecially as regards quality, commercial scale implementation and reproducibility.
  • the compounds of the present invention can be synthesized using conventional preparative steps and recovery methods known to those skilled in the art of organic and bio-organic synthesis, while providing new and unique combinations for the overall synthesis of each compound. Preferred synthetic routes for intermediates involved in the synthesis as well as the resulting compounds of the present invention follow.
  • the final product of this process is very similar to that obtained by costly procedures (ie. due to expensive purification steps), but it has two great advantages in that no costly protective blocking/deblocking steps are involved and only one or less purification steps are required entailing costly, time consuming chromatographic procedures.
  • the kilogram to pre-pilot scale application of this process is accordingly advantageous.
  • amino protecting group is well known in the art of peptide chemistry.
  • suitable amino protecting group can be found in Protective Groups In Organic Svnthesis. Greene T.W. and Wuts P.G., 1991, John Wiley & Sons, Inc.
  • Figure 1 shows the HPLC chromatogram of Tyr-(D)Arg-Phe-Phe-NH 2 • 2HC1 crystallized from methanol.
  • Figure 2 shows the HPLC chromatogram demonstrating separation of all the stereoisomers of the tetrapeptide Tyr-Arg-Phe-Phe.
  • Figure 3 shows chiral analysis by way of HPLC chromatography to separate the amino acids corresponding to formula (I): Tyr-(D)Arg-Phe-Phe-NH 2 following acid hydrolysis as described in Example 8. DETAILED DESCRIPTION OF THE INVENTION
  • Ri is preferably Ala, or Arg. Ri is more preferably Arg.
  • R 2 is preferably Phe or Phe(p-F).
  • R 2 is more preferably Phe.
  • R 2 is more preferably Phe(p-F).
  • R 3 is preferably Phe or Phe(p-F). R 3 is more preferably Phe. In an alternative embodiment, R 3 is more preferably Phe(p-F).
  • P is preferably selected from the group consisting of Boc (t-butyloxycarbonyl), Z (benzyloxycarbonyl), Fmoc (9-fluoromethyloxycarbonyl), Bz (benzoyl), and 3,5- dihydroxy benzoyl. P is more preferably Boc.
  • the neutrahzmg agent is preferably DIEA (diisopropylethylamine).
  • the solvent suitable for the coupling reaction is preferably dimethylformamide (DMF).
  • the process of this invention can be carried using a further activating agent selected from the group consisting of dicyclohexylcarbodiimide (DCC); dimethylaminopropylethylcarbodiimide (EDC); and benzotriazol-l-yloxy-tris(dimethylamino)-phosphonium hexafluorophosphate (BOP).
  • DCC dicyclohexylcarbodiimide
  • EDC dimethylaminopropylethylcarbodiimide
  • BOP benzotriazol-l-yloxy-tris(dimethylamino)-phosphonium hexafluorophosphate
  • Boc-Tyr-OH is activated by esterifying the carboxylate group of Boc-Tyr-OH in nonpolar solvent such as THF. Formation of the activated succinimate ester of Boc-Tyr-OH is accomplished by dissolving Boc-tyrosine in an appropriate solvent such as THF and adding n-hydroxysuccinimide, also dissolved in the same solvent. A solution containing a dehydrating agent solution such as dicyclohexylcarbodiimide is added to effect esterification.
  • a dehydrating agent solution such as dicyclohexylcarbodiimide
  • Coupling of the (D) amino acid by activated Boc-Tyrosine-succinimide ester is accomplished by dissolution of the respective components in specified solvents (THF or H 2 O) and mixing the two solutions at room temperature, wherein the dipeptide is formed.
  • Condensation of the two dipeptidyl units D and E in a specific manner that causes mimmal racemization ( ⁇ 4 %) at the ⁇ -stereogenic center corresponding to the (D)- R* residue is accomplished by following stringent conditions including, choice of solvent, pH, neutralizing agent, choice of activating agent and rate of addition of specific activating agent solution.
  • the activating agent(s) is HODbht
  • the neutralizing agent is DIEA
  • the solvent is DMF.
  • the first activating agent is HOBhbt
  • the second activating agent can be either DCC, EPC, BOP, or an equivalent activating agent
  • the neutralizing agent can be either DIEA, or NEM
  • the solvent is DMF.
  • N terminal t-butyl carbamate protecting group is removed by acid hydrolysis in a mixture of methylene chloride and trifluoroacetic acid, followed by evaporation of the solvents.
  • CrystalUzation of the pure (> 97%) product by preferred formation of the pharmaceutically acceptible salt, such as the hydrochloride salt, is accompUshed by stirring a specified concentration of compound G in a specified solvent, such as DMF.
  • the process consists of initially preparing independently two dipeptide fragments using minimal side chain protection. Subsequently, the two fragments are joined by reacting them in a suitable solvent. It is well known to those skilled in the art that amino acids are prone to racemization. It is also known that the potential for racemization is increased in the case where an amino acid is acylated as is the case where fragment D is joined to fragment E in Scheme I. In the case cited herein racemization was observed to be as high as 44% depending on reaction conditions.
  • a solution of n-hydroxysuccinimide (343.7 g, 2.986 moles) in THF (2L) is added to an amino acid solution comprising the blocked amino acid , Boc-Tyr-OH (700 g, 2.488 moles), dissolved in THF (4.7L).
  • a solution of dicyclohexylcarbodiimide (616.1 h, 2.986 moles) in THF is added at a rate of 200 mlJminute.
  • the resulting mixture is sti ⁇ ed at room temperature for 16 - 20 hours, after which precipitated DCU is filtered off and the solution evaporated to dryness.
  • the solid material is washed on a filter with isopropanol (3 x 1 L) and ethyl ether (3 x 1 L), and the product obtained and dried under high vacuum to yield 921 grams (97.8% yield).
  • the amino acid H-(D)Arg-OH (447.69 g, 2.57 moles) is dissolved in 6.7 L H 2 O and added while stirring at room temperature to a solution of Boc-Tyr-Osu (447.69 g, 2.57 moles), previously prepared by dissolution in 1.52 L THF. After stirring the reaction mixture for 16 - 20 hours, the THF is evaporated. The product is dissolved (1.98 moles, theoretical) in a total volume equaling approximately 10L H 2 O, filtered through two Whatman fibreglass filters and one Whatman #1 paper, after which the solution is injected onto an HPLC column at a rate of 300 ml/min. The product is purified following the gradient conditions described in Table I.
  • Analytical HPLC is used to monitor the eluant, which is collected in 3 - 4 L fractions. Fractions demonstrating an HPLC purity greater than 97% by this method are combined, the acetonitrile evaporated and product lyophilized or evaporated (yield: 668.57g, 77.18% ).
  • the dipeptide, Boc-Tyr-(D)Arg-OH (760 g, 1.737 moles) is added to 15 L of a solution of CHC1 3 , H O, Methanol 1:1:2 and dissolved by sonication and mixing at 30-37 °C in a waterbath. After dissolution, 3L of DMF is added and the solution concentration by evaporation to 2.5 L. , afterwhich 4 A molecular sieves (650 mL) are added, the solution gently swirled and allowed to stand 16 - 20 hours. The solution is decanted and sieves washed with 1.9 L DMF.
  • the second dipeptide, H-Phe-Phe-NH 2 • HCl (604.18 g, 1.737 moles) is dissolved in 4.8 L DMF and one equivalent of DIEA (1.737 moles) is added.
  • the two peptide solutions are combined and HODhbt (312 g, 1.911 moles) is added, afterwhich the pH is adjusted to 7.0 - 8.0 with 250 ml DIEA, and a solution of DCC (430 g, 1.084 moles) in IL DMF is added and the reaction allowed to stir 16 - 20 hours (Note: after 30minutes of mixing, the pH is adjusted to 7.0 - 8.0 with DIEA if necessary).
  • the mixture is filtered to remove DCU, which is washed on the filter 2 x 400 mL DMF, and evaporated at 40 °C under high vacuum.
  • the almost dry mixture is dissolved in 2 L acetone and the solution aUowed to stand for 1 hour at room temperature.
  • the precipitate is filtered and washed 3 x 500 mL acetone afterwhich the total volume of the solution is adjusted by adding or evaporating acetone to a total volume of 5.1 L.
  • the Boc- terminally protected peptide (1317 g) is dissolved in a solution consisting of 55% TFA, 45% CH 2 C1 2 in a ratio equivalent to 4 mL TFA solution/gram tetrapeptide, and the solution sti ⁇ ed at room temperature for 45 minutes.
  • the reaction mixture is evaporated on a rotary evaporator at room temperature. Following the evaporation of CH C1 2 with a water aspirator pump, the remaining TFA is evaporated under high vacuum.
  • a portion of the thick residue obtained is precipitated by pouring it into 4 L of ethyl ether with stirring until stirring becomes difficult.
  • the precipitate is filtered off and washed on the filter with 2 L ethyl ether.
  • the latter precipitation step is repeated until the total amount of thick residue is precipitated.
  • the precipitates are combined and dried overnight by connecting the dessicator to an aspirator pump, foUowed by drying under high vacuum for 4 hours. (Yield: 1322.7 g)
  • the peptide (831.1 g) is dissolved in 3324 mL MeOH (ratio 4 ml MeOH/g peptide) in a water bath at 50 °C and filtered over a fritted filter. After washing the filter with 100 mL MeOH the peptide solution is transferred to a 20 L evaporating round bottom flask and gently agitated (40 RPM) at 50 °C. Small increments of acetonitrile (ratio 4.8 mL AcN/g product) are added and agitation and heat are ceased once crystals begin to form. After allowing the mixture to reach room temperature (approximately 3 hr), the flask is cooled at 4 °C for 1 hour.
  • the crystalline material is filtered on a fritted funnel and washed twice with 1.5 L of a cold solution of MeOH/AcN (1:1.2), afterwhich the crystals are dried in a dessicator connected to an aspirator pump for 2 hours and the mother liquor is evaporated and recrystaUized by repeating this entire procedure from the point of dissolution in MeOH.
  • the drying process is completed under high vacuum for a minimum of 16 hours yielding combined product totalling 707.7 g.

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Abstract

Procédé permettant la synthèse en solution à grande échelle de tétrapeptides opioïdes analgésiques à action périphérique, énantiomériquement purs et de formule (I): Tyr-(D)R1-R2-R3-NH2, où R1 est Ala ou Arg; R2 est Phe ou Phe(p-F), et R3 est Phe ou Phe(p-F). Ce procédé en plusieurs étapes, nouveau et unique, consiste à joindre deux dipeptides par des techniques classiques de synthèse en phase de solution, et à modifier certains paramètres (par exemple solvants, agents d'activation, agents de neutralisation, etc.) de façon à réduire au minimum la racémisation du deuxième acide aminé. On obtient une efficacité par rapport au coût exceptionnelle, en raison de l'élimination des cycles séquentiels bloquage-débloquage classiques et des opérations de purification chromatographique multiples, ce qui permet également d'appliquer ces procédé simples, adaptés à des quantités de l'ordre du kilogramme, à une production commerciale à grande échelle.
PCT/CA1996/000552 1995-08-18 1996-08-15 Synthese en solution de tetrapeptides opioides analgesiques a action peripherique Ceased WO1997007129A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU66539/96A AU6653996A (en) 1995-08-18 1996-08-15 Solution synthesis of peripheral acting analgesic opioid tetrapeptides

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9516994.2 1995-08-18
GBGB9516994.2A GB9516994D0 (en) 1995-08-18 1995-08-18 Solution synthesis of peripheral acting analgestic opioid tetrapeptides

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WO1997007129A1 true WO1997007129A1 (fr) 1997-02-27

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999047548A1 (fr) * 1998-03-16 1999-09-23 Astrazeneca Ab Procede de preparation d'un tetrapeptide
WO2001019849A1 (fr) * 1999-09-15 2001-03-22 Astrazeneca Ab Procede de preparation de h-tyr-d-ala-phe(f)-phe-nh¿2?
EP1030831A4 (fr) * 1997-10-10 2003-01-02 Aventis Pharm Prod Inc Preparation des pseudotetrapeptides azacycloalkylalcanoyles
WO2017165676A1 (fr) * 2016-03-23 2017-09-28 Protagonist Therapeutics, Inc. Procédés de synthèse d'antagonistes de peptide α4β7
CN113624898A (zh) * 2021-08-23 2021-11-09 成都诺和晟泰生物科技有限公司 一种手性镇痛类多肽药物的纯化方法
US11472842B2 (en) 2015-12-30 2022-10-18 Protagonist Therapeutics, Inc. Analogues of hepcidin mimetics with improved in vivo half lives
US11753443B2 (en) 2018-02-08 2023-09-12 Protagonist Therapeutics, Inc. Conjugated hepcidin mimetics
US11807674B2 (en) 2013-03-15 2023-11-07 Protagonist Therapeutics, Inc. Hepcidin analogues and uses thereof
US11840581B2 (en) 2014-05-16 2023-12-12 Protagonist Therapeutics, Inc. α4β7 thioether peptide dimer antagonists
US11884748B2 (en) 2014-07-17 2024-01-30 Protagonist Therapeutics, Inc. Oral peptide inhibitors of interleukin-23 receptor and their use to treat inflammatory bowel diseases

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2359817A1 (fr) * 1976-07-27 1978-02-24 Reckitt & Colmann Prod Ltd Nouveaux peptides, leur procede de preparation et composition therapeutique les contenant
FR2465713A1 (fr) * 1979-09-20 1981-03-27 Erba Farmitalia Nouveaux peptides biologiquement actifs et leur emploi comme medicaments
WO1995022557A1 (fr) * 1994-02-21 1995-08-24 Astra Aktiebolag Nouveaux peptides opioides destines au traitement de douleurs et leur utilisation

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2359817A1 (fr) * 1976-07-27 1978-02-24 Reckitt & Colmann Prod Ltd Nouveaux peptides, leur procede de preparation et composition therapeutique les contenant
FR2465713A1 (fr) * 1979-09-20 1981-03-27 Erba Farmitalia Nouveaux peptides biologiquement actifs et leur emploi comme medicaments
WO1995022557A1 (fr) * 1994-02-21 1995-08-24 Astra Aktiebolag Nouveaux peptides opioides destines au traitement de douleurs et leur utilisation

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
MISICKA, ALEKSANDRA ET AL: "Structure-activity relationships of analogs of highly potent opioid peptide, biphalin", REGUL. PEPT. (1994), (SUPPL. 1), S131-S132 CODEN: REPPDY;ISSN: 0167-0115, XP000611981 *
P.W. SCHILLER ET AL.: "Dermorphin Analogues an Increased Positive Net Charge in Their Message Domain Display Extremely High mu Opioid Receptor Selectivity", JOURNAL OF MEDICINAL CHEMISTRY, vol. 32, no. 3, March 1989 (1989-03-01), WASHINGTON US, pages 698 - 703, XP002021558 *
SCHILLER, P. W. ET AL: "Two new families of opioid peptide analogs displaying extraordinary.mu.-receptor selectivity and preference for either peripheral or central sites", ADV. BIOSCI. (OXFORD) (1989), 75(PROG. OPIOID RES.), 85-8 CODEN: AVBIB9;ISSN: 0065-3446, XP000612379 *

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1030831A4 (fr) * 1997-10-10 2003-01-02 Aventis Pharm Prod Inc Preparation des pseudotetrapeptides azacycloalkylalcanoyles
WO1999047548A1 (fr) * 1998-03-16 1999-09-23 Astrazeneca Ab Procede de preparation d'un tetrapeptide
WO2001019849A1 (fr) * 1999-09-15 2001-03-22 Astrazeneca Ab Procede de preparation de h-tyr-d-ala-phe(f)-phe-nh¿2?
US11807674B2 (en) 2013-03-15 2023-11-07 Protagonist Therapeutics, Inc. Hepcidin analogues and uses thereof
US11840581B2 (en) 2014-05-16 2023-12-12 Protagonist Therapeutics, Inc. α4β7 thioether peptide dimer antagonists
US11884748B2 (en) 2014-07-17 2024-01-30 Protagonist Therapeutics, Inc. Oral peptide inhibitors of interleukin-23 receptor and their use to treat inflammatory bowel diseases
US11472842B2 (en) 2015-12-30 2022-10-18 Protagonist Therapeutics, Inc. Analogues of hepcidin mimetics with improved in vivo half lives
WO2017165676A1 (fr) * 2016-03-23 2017-09-28 Protagonist Therapeutics, Inc. Procédés de synthèse d'antagonistes de peptide α4β7
US10407468B2 (en) 2016-03-23 2019-09-10 Protagonist Therapeutics, Inc. Methods for synthesizing α4β7 peptide antagonists
US11753443B2 (en) 2018-02-08 2023-09-12 Protagonist Therapeutics, Inc. Conjugated hepcidin mimetics
CN113624898A (zh) * 2021-08-23 2021-11-09 成都诺和晟泰生物科技有限公司 一种手性镇痛类多肽药物的纯化方法
CN113624898B (zh) * 2021-08-23 2023-08-25 成都诺和晟泰生物科技有限公司 一种手性镇痛类多肽药物的纯化方法

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Publication number Publication date
GB9516994D0 (en) 1995-10-18
AU6653996A (en) 1997-03-12

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