214766-78-6

Basic information

• Product Name: DEGARELIX
• Synonyms: DEGARELIX;Degarelix acetate;N-Acetyl-3-(2-naphthyl)-D-alanyl-4-chloro-D-phenylalanyl-3-(3-pyridyl)-D-alanyl-L-seryl-4-[2,6-dioxohexahydropyrimidin-4(S)-ylcarboxamido]-L-phenylalanyl-4-ureido-D-phenylalanyl-L-leucyl-N6-isopropyl-L-lysyl-L-prolyl-D-alaninamide acetate;D-Alaninamide, N-acetyl-3-(naphtalen-2-yl)-D-alanyl-4-chloro-D-phenylalanyl-3-(pyridin-3-yl)-D-alanyl-L-seryl-4-((((4S)-2,6-dioxohexahydropyrimidin-4-yl)carbonyl)amino)-L-phenylalanyl-4-(carbamoylamino)-D-phenylalanyl-L-leucyl-N6-(1-methylethyl)-L-lysyl-L-prolyl-;Degarelix acetate(FE-200486,Degarelix);FirMagon;Degarelix, Degarelix acetate
• CAS NO: 214766-78-6
• Molecular Formula: C₈₂H₁₀₃ClN₁₈O₁₆
• Molecular Weight: 1632.28
• EINECS: 1312995-182-4
• Product Categories: API
• Mol File: 214766-78-6.mol
• Article Data: 4

Chemical Properties

• Appearance: /
• Density: 1.325 g/cm³
• Storage Temp.: Keep in dark place,Inert atmosphere,Store in freezer, under -20°C
• PKA: 10.38±0.40(Predicted)
• CAS DataBase Reference: DEGARELIX(CAS DataBase Reference)
• NIST Chemistry Reference: DEGARELIX(214766-78-6)
• EPA Substance Registry System: DEGARELIX(214766-78-6)

Safety Data

• Hazardous Substances Data: 214766-78-6(Hazardous Substances Data)

Usage

Description

Antagonists of GnRH have proven to be an effective therapy for hormonally regulated cancers, such as prostate and some types of breast. As analogs of GnRH, they bind competitively and reversibly to GnRH receptors in the pituitary gland, thereby blocking the release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). In men, the reduction of LH triggers the ablation of testosterone secretion from the testes, and these castration-like levels have been essential in the effective management of advanced prostate cancer. In comparison to GnRH agonists, antagonists do not suffer from a potential flare of the disease as a result of an initial stimulation of the hypothalamic-pituitary-gonadal axis prior to down-regulation of the GnRH receptor. Moreover, GnRH antagonists provide beneficial effects more rapidly postdosing and result in a more efficient suppression of gonadotropin levels. With this in mind, degarelix acetate has been launched as a third-generation GnRH antagonist for the treatment of prostate cancer, and it joins other third-generation agents, ganirelix and cetronelix, on the market.

Originator

Ferring Pharmaceutical (Switzerland)

Uses

Different sources of media describe the Uses of 214766-78-6 differently. You can refer to the following data:
1. Degarelix, is a competitive and reversible gonadotropin-releasing hormone receptor (GnRHR) antagonist.
2. Advanced hormone-dependent prostate carcinoma

Brand name

Firmagon

Clinical Use

Ferring launched degarelix acetate, a gonadotrophin-releasing hormone (GnRH) antagonist, in 2009 in the U.S. for the treatment of prostate cancer. The compound has been approved by the E.U. for the same indication, and in the same year it was launched in the UK and Germany. Degarelix has been developed as a one-month or three-month sustained-release injectable formulation. Compared to other GnRH antagonists, degarelix displays improved aqueous solubility, longer acting effects and weaker histamine-releasing properties.

Side effects

The most common adverse events included injection site reactions (pain, erythema, swelling, or induration), hot flashes, increased weight, and increases in serum levels of transaminases and gamma-glutamyltransferase. In addition to being contraindicated in patients with a previous hypersensitivity to degarelix, it should not be administered to women who are or may become pregnant as fetal harm can occur. Since long-term androgen deprivation therapy prolongs the QT interval, physicians should consider whether the benefits of degarelix outweigh the potential risks in patients with congenital long QT syndrome, electrolyte abnormalities, or congestive heart failure or in patients taking antiarrhythmic medications.

Synthesis

The synthesis of degarelix acetate employed iterative peptide coupling and protection/de-protection sequences in high yields (85–99%), and this sequence is described in the scheme. Boc-D-alanine (21) was immobilized via MBHA resin (Bachem) by reaction with diisopropyl carbodiimide (DIC) and 1-hydroxybenzotriazole (HOBT). The resulting product was treated with trifluoroacetic acid (TFA) to remove the N-Boc protecting group to reveal amine 22. The N-terminus of 22 was then subjected to sequential coupling and de-protection cycles with the following protected amino acids: N-Boc-L-proline, N-a- Boc-N6-isopropyl-N6-carbobenzoxy-L-lysine and N-Boc-L-leucine to give 23 and 24, respectively. The N-terminus of 24 was coupled with N-a-Boc-D-4-(Fmoc-amino)phenylalanine, followed by removal of the Fmoc group with piperidine in DMF to give the corresponding free aniline. The free aniline resin was then reacted with t-butyl isocyanate to generate the corresponding t-butyl urea followed by reaction with TFA to remove the Boc group to give the t-butyl urea amine 25. The N-terminus of 25 was coupled with N-a-Boc-L-4-(Fmoc-amino)phenylalanine, followed by removal of the Fmoc group with piperidine in DMF to generate the corresponding free aniline. The free aniline was reacted with L-hydroorotic acid, followed by reaction with TFA to liberate amine 26. Amine 26 was then coupled with O-benzylated-N-Boc-serine, followed by removal of the Boc group with TFA and reacting the resulting amine with N-a-Boc-D-(3-pyridyl)alanine and subsequent removal of the Boc group with TFA gave amine 27. Amine 27 was coupled with N-Boc-D-(4-chlorophenyl)alanine, followed by removal of the Boc group with TFA, and the resulting amine was then coupled with N-Boc-D-(2-naphthyl)alanine, followed by removal of its Boc group with TFA to give 28. Acylation of 28 with acetic anhydride followed by sequential treatment with HF and TFA resulted in cleavage from the resin, removal of the O-benzyl group, and conversion of the t-butyl urea to the corresponding NH2-urea, resulting in free degarelix. Finally, treatment with acetic acid provided degarelix acetate (V).

Drug interactions

Potentially hazardous interactions with other drugsNone known

Metabolism

Undergoes peptide hydrolysis in the hepato-biliary system, and is mainly (70-80%) excreted as peptide fragments in the faeces.

Synthetic route

C148H217ClN18O20 → acetyl-3-(naphthalen-2-yl)-D-alanyl-4-chloro-D-phenylalanyl-3-(pyridin-3-yl)-D-alanyl-Ser-4-((((4S)-2,6-dioxohexahydropyrimidin-4-yl)carbonyl)amino)-L-phenylalanyl-4-(carbamoylamino)-D-phenylalanyl-Leu-N6-(1-methylethyl)-L-lysyl-Pro-D-Ala-NH2 (214766-78-6)

Conditions	Yield
With chlorotriisopropylsilane; trifluoroacetic acid In water at 20℃; for 2h; Cooling with ice;

Fmoc-Rink resin + Fmoc-Leu-OH (35661-60-0) + Fmoc-L-Lys(iPr,Boc)-OH + 9-fluorenylmethyloxycarbonyl-N(4)-(L-hydroorotyl)-4-aminophenylalanine + Fmoc-Pro-OH (71989-31-6) + Fmoc-Ser(tBu)-OH (71989-33-8) + acetic anhydride (108-24-7) + N-(9-fluorenylmethoxycarbonyl)-D-alanine (35661-38-2, 35661-39-3, 79990-15-1) + N-[(9-fluorenyl)methoxycarbonyl]-3-(2-naphthyl)-D-alanine + 9-fluorenylmethyloxycarbonyl-D-4-chlorophenylalanine + Nα-(fluorenylmethyloxycarbonyl)-p-ureido-D-phenylalanine + (R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(pyridin-3-yl)propanoic acid → acetyl-3-(naphthalen-2-yl)-D-alanyl-4-chloro-D-phenylalanyl-3-(pyridin-3-yl)-D-alanyl-Ser-4-((((4S)-2,6-dioxohexahydropyrimidin-4-yl)carbonyl)amino)-L-phenylalanyl-4-(carbamoylamino)-D-phenylalanyl-Leu-N6-(1-methylethyl)-L-lysyl-Pro-D-Ala-NH2 (214766-78-6)

Conditions

Yield

Stage #1: Fmoc-Rink resin With tert-butylamine In N,N-dimethyl-formamide Rink amide resin; Stage #2: N-(9-fluorenylmethoxycarbonyl)-D-alanine With diisopropyl-carbodiimide In N,N-dimethyl-formamide for 1h; Rink amide resin; Stage #3: Fmoc-Leu-OH; Fmoc-L-Lys(iPr,Boc)-OH; Fmoc-4-[2,6-dioxohexahydropyrimidine-4-carbonylamino]phenylalanine-OH; Fmoc-Pro-OH; Fmoc-Ser(tBu)-OH; acetic anhydride; N-[(9-fluorenyl)methoxycarbonyl]-3-(2-naphthyl)-D-alanine; N-Fmoc-D-(4-chlorophenyl)alanine; Nα-(fluorenylmethyloxycarbonyl)-p-ureido-D-phenylalanine; (R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(pyridin-3-yl)propanoic acid Further stages;

67%

...Expand

C97H114ClN18O18Pol → acetyl-3-(naphthalen-2-yl)-D-alanyl-4-chloro-D-phenylalanyl-3-(pyridin-3-yl)-D-alanyl-Ser-4-((((4S)-2,6-dioxohexahydropyrimidin-4-yl)carbonyl)amino)-L-phenylalanyl-4-(carbamoylamino)-D-phenylalanyl-Leu-N6-(1-methylethyl)-L-lysyl-Pro-D-Ala-NH2 (214766-78-6)

Conditions	Yield
With hydrogen fluoride; methoxybenzene MBHA resin;

C62H82N11O11Pol + Fmoc-Ser(tBu)-OH (71989-33-8) + acetic anhydride (108-24-7) + N-[(9-fluorenyl)methoxycarbonyl]-3-(2-naphthyl)-D-alanine + 9-fluorenylmethyloxycarbonyl-D-4-chlorophenylalanine + (R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(pyridin-3-yl)propanoic acid → acetyl-3-(naphthalen-2-yl)-D-alanyl-4-chloro-D-phenylalanyl-3-(pyridin-3-yl)-D-alanyl-Ser-4-((((4S)-2,6-dioxohexahydropyrimidin-4-yl)carbonyl)amino)-L-phenylalanyl-4-(carbamoylamino)-D-phenylalanyl-Leu-N6-(1-methylethyl)-L-lysyl-Pro-D-Ala-NH2 (214766-78-6)

Conditions

Yield

Stage #1: C62H82N11O11Pol With piperidine In N,N-dimethyl-formamide for 0.416667h; Rink amide resin; Stage #2: Fmoc-Ser(tBu)-OH With ethyl cyanoglyoxylate-2-oxime; diisopropyl-carbodiimide for 1h; Rink amide resin; Stage #3: acetic anhydride; N-[(9-fluorenyl)methoxycarbonyl]-3-(2-naphthyl)-D-alanine; N-Fmoc-D-(4-chlorophenyl)alanine; (R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(pyridin-3-yl)propanoic acid Further stages;

1.53 g

C91H118ClN18O18Pol → acetyl-3-(naphthalen-2-yl)-D-alanyl-4-chloro-D-phenylalanyl-3-(pyridin-3-yl)-D-alanyl-Ser-4-((((4S)-2,6-dioxohexahydropyrimidin-4-yl)carbonyl)amino)-L-phenylalanyl-4-(carbamoylamino)-D-phenylalanyl-Leu-N6-(1-methylethyl)-L-lysyl-Pro-D-Ala-NH2 (214766-78-6)

Conditions	Yield
With chlorotriisopropylsilane; water; trifluoroacetic acid	291 g

Upstream product

• 35661-60-0 Fmoc-Leu-OH 
• 201003-48-7 Fmoc-L-Lys(iPr,Boc)-OH 
• 71989-31-6 Fmoc-Pro-OH 
• 71989-33-8 Fmoc-Ser(tBu)-OH 
• 108-24-7 acetic anhydride 
• 35661-38-2 N-(9-fluorenylmethoxycarbonyl)-D-alanine 
• 138774-94-4 N-[(9-fluorenyl)methoxycarbonyl]-3-(2-naphthyl)-D-alanine 
• 175453-07-3 (R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(pyridin-3-yl)propanoic acid 

Relevant articles and documents

Overcoming Chemical Challenges in the Solid-Phase Synthesis of High-Purity GnRH Antagonist Degarelix. Part 2

The hydrolysis and rearrangement of the dihydroorotic (Hor) residue in the presence of bases, leading to the formation of the hydantoin (Hyd) impurity, represent one of the major problems in manufacturing of the gonadotropin-releasing hormone antagonist Degarelix. In an attempt to find efficient strategies to overcome this problem, we carried out a screening of organic bases in order to select those which afforded both the rapid Fmoc deprotection during the solid-phase synthesis and the absence of this peculiar rearrangement. Among the bases tested, only tert-butylamine did not affect the peptide molecule and was able to perform fast Fmoc removal. The use of tert-butylamine for the synthesis of Degarelix led to a product with excellent purity and yield without a detectable amount of the hydantoin impurity. Thus, we showed that tert-butylamine can be a suitable alternative to piperidine for industrial-scale production of Degarelix or other Hor-containing peptide pharmaceuticals.

Overcoming Chemical Challenges in the Solid-Phase Synthesis of High-Purity GnRH Antagonist Degarelix. Part 1.

The highly potent, long-acting, gonadotropin-releasing hormone antagonist Degarelix is known to be very efficient for prostate cancer treatment. The synthesis of decapeptide Degarelix is complicated because of the presence in its sequence of several unnatural α-amino acids, which are prone to rearrangements and side reactions. In particular, the rearrangement of the dihydroorotic (Hor) moiety with following hydantoin formation in the presence of bases represents one of the major problems. In this study, we describe a novel chemical strategy to overcome this obstacle by the use of the corresponding p-nitrophenylalanine derivative, which is reduced on the solid support to p-aminophenylalanine and acylated with dihydroorotic acid at the end of the solid-phase synthesis. Thus, the contact of Hor with the bases required for Fmoc deprotection is completely avoided. This approach provides a superior purity of Degarelix when the synthesis is carried out in the industrial scale as well.