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New methods for making barusiban and its intermediates

An intermediate, homocysteine ​​technology, which is applied in the new field of manufacturing balusaban and its intermediates, and can solve the problems of cumbersome large-scale manufacturing

Inactive Publication Date: 2018-07-17
FERRING BV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Therefore, this method requires the synthesis of orthogonally protected homocysteine ​​derivatives (such as Fmoc-hCy((CH 2 ) 2 -COOBu)-OH)), which can be tedious for large-scale manufacturing

Method used

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  • New methods for making barusiban and its intermediates
  • New methods for making barusiban and its intermediates
  • New methods for making barusiban and its intermediates

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0256] Example 1 : Synthesis of Parucipan

[0257] 1.1. Synthesis flow chart

[0258]

[0259]

[0260] 1.2. Description of the manufacturing method

[0261] to assemble

[0262] Direct coupling of protected o-NBS-N-MeOrn(Boc)-alcohol to chloro-2-chlorotrityl resin (CTC resin) in DMF in the presence of pyridine at 60 °C within 17 hours . After capping the resin, the NBS group was deprotected by washing with a DBU / mercaptoethanol / NMP mixture. The second protected amino acid (Fmoc-hCy(Trt)-OH) was coupled with PyBOP / HOBt / DIEA in DMF after removal of the NBS protecting group. Reaction completion was checked by coupling test (Chloranil test). Four additional residues (Fmoc-Asn(Trt)-OH, Fmoc-AlloIle-OH, Fmoc-Ile-OH and Fmoc-D-Trp(Boc)-OH) were introduced by successive cycles of Fmoc deprotection and amino acid coupling ):

[0263] 1. Fmoc removal

[0264] 2. DMF washing

[0265] 3. Fmoc-AA-OH will be coupled with DIC / HOBt in DMF.

[0266] 4. Conjugation test (ninh...

Embodiment 2

[0273] 2. Example 2: Using 3-chloropropionic acid instead of 3-bromopropionic acid to synthesize crude balucipan

[0274] The experiment was carried out according to the method described above (see Example 1), wherein 3-chloropropionic acid was used instead of 3-bromopropionic acid.

[0275] 2.1. Assembly

[0276] resin loading

[0277] The assembly was performed on a 5 millimolar scale (7.14 g chloro-2-chlorotrityl resin (CTC resin) with a degree of substitution of 0.7 meq / g). After swelling the resin in DMF (7 mL) within 15 minutes, o-NBS-N-MeOrn(Boc)-alcohol (1 equiv, 2.92 g) was dissolved in 9 mL DMF and added onto the resin. Pyridine (2 equiv, 0.81 mL) was added and the reaction mixture was heated to 60 °C and stirred over 17 hours. After 1 hour, 6 mL of DMF was added to homogenize the reaction mixture. The concentration of o-NBS-N-MeOrn(Boc)-alcohol during the loading reaction was 0.22 mol / L. After 17 hours, 15 mL of DMF was added to the resin to homogenize the re...

Embodiment 3

[0311] 3. Example 3. According to different synthetic pathways for the synthesis of balucipan

[0312] 3.1. Synthesis flow chart

[0313] A flow chart of the production of balusiaban according to the method of Example 3 is shown below:

[0314]

[0315]

[0316] 3.2. Description of the manufacturing method

[0317] 3.2.1. Assembly

[0318] The protected Fmoc-N-MeOrn(Boc)-alcohol was directly coupled to the carboxyl resin in DMF in the presence of DMPA within 2 hours at room temperature. After capping the resin, the Fmoc group was deprotected by washing with piperidine solution (20% in DMF). Five additional residues (Fmoc-hCy(mmt)-OH, Fmoc-Asn(Trt)-OH, Fmoc-alloIle-OH, Fmoc-Ile-OH and Fmoc- D-Trp(Boc)-OH):

[0319] 1. Fmoc removal

[0320] 2. DMF washing

[0321] 3. Coupling of Fmoc-AA-OH with DIC / HOBt in DMF by Preactivating Amino Acids

[0322] 4. Coupling test (ninhydrin test or chloranil test)

[0323] 5. DMF washing

[0324] Reaction volumes were calculated...

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Abstract

The present invention relates to new solid phase peptide methods for synthesizing analogues that exhibit oxytocin antagonist activity, specifically Barusiban and its intermediates. Specifically, the present invention relates to a solid phase process for preparing a compound having the formula c[AA1-AA6]-AA7-ol, wherein AA1 is propionic acid, AA2 is preferably D-Trp, AA3 is Ile, AA4 is preferably AlloIle, AA5 is Asn, AA6 is hCy, and AA7 is preferably N-Me-Orn-ol, or a pharmaceutically acceptable salt or solvate thereof.

Description

[0001] The present invention relates to novel solid-phase polypeptide methods and intermediates for the synthesis of analogues exhibiting oxytocin antagonist activity, in particular balucaban, which are particularly useful for reducing or blocking uterine muscle contractions. Background technique [0002] Oxytocin, a peptide hormone that stimulates uterine muscle contractions, is thought to be involved in the etiology of premature labor and dysmenorrhea. Oxytocin antagonists have been shown to be useful in the management of these conditions and in WO 95 / 02609, published January 26, 1995, oxytocin antagonist peptides of good potency and selectivity are disclosed for therapeutic use. They are generally intended to be administered in aqueous solutions, and the manufacture of ready-to-use doses of such antagonists may require that such solutions be stable for extended periods of time; however, they may not always be so. The potential need to prepare such drugs immediately before u...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/16C07K1/00
CPCA61P15/06C07K7/06C07K7/16A61K38/00C07K1/04C07K1/042
Inventor L·马利克K·维希涅夫斯基C·德温
Owner FERRING BV
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