Fingolimod hydrochloride CAS 162359-56-0

Introduction：Basic information about Fingolimod hydrochloride CAS 162359-56-0, including its chemical name, molecular formula, synonyms, physicochemical properties, and safety information, etc.

Fingolimod hydrochloride Basic information

• Product Name: Fingolimod hydrochloride
• Synonyms: Fingolimod (FTY720) hydrochloride;Fin;limod hydrochloride;fingolimod hydrochloride;FTY720;2-AMINO-2-[2-(4-OCTYLPHENYL)ETHYL]-1,3-PROPANEDIOL, HYDROCHLORIDE;2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol hydrochloride;Fingolimod HCl
• CAS: 162359-56-0
• MF: C19H34ClNO2
• MW: 343.93
• EINECS: 680-631-1
• Product Categories: Pharmaceuticals;Aromatics;Intermediates & Fine Chemicals;Metabolites & Impurities;API;Other APIs;All Inhibitors;Inhibitors;Metabolites;Pharmaceutical intermediate
• Mol File: 162359-56-0.mol

Fingolimod hydrochloride Chemical Properties

• Melting point: 102-107°C
• storage temp.: -20°C
• solubility: water: soluble10mg/mL, clear
• form: powder
• color: white to beige
• biological source: synthetic
• Water Solubility: water: 10mg/mL, clear
• Merck: 14,4083
• Stability: Stable for 1 year from date of purchase as supplied. Solutions in DMSO or ethanol may be stored at -20° for up to 3 months.
• InChI: InChI=1S/C19H33NO2.ClH/c1-2-3-4-5-6-7-8-17-9-11-18(12-10-17)13-14-19(20,15-21)16-22;/h9-12,21-22H,2-8,13-16,20H2,1H3;1H
• InChIKey: SWZTYAVBMYWFGS-UHFFFAOYSA-N
• SMILES: C1(C=CC(CCCCCCCC)=CC=1)CCC(N)(CO)CO.Cl
• CAS DataBase Reference: 162359-56-0(CAS DataBase Reference)

Safety Information

• Hazard Codes: Xi
• Risk Statements: 36/37/38-52/53
• Safety Statements: 26-61
• WGK Germany: 3
• RTECS: TY3130000
• HS Code: 29221990
• Storage Class: 11 - Combustible Solids
• Hazard Classifications: STOT RE 2
• Toxicity: LD50 orally in rats: 300-600 mg/kg (Troncoso)

Fingolimod hydrochloride Usage And Synthesis

Oral drug for the treatment of multiple sclerosis

Fingolimod hydrochloride is the first oral drug for the treatment of multiple sclerosis. It is successfully developed by the pharmaceutical company Novartis, and it has been approved for marketing by the US Food and Drug Administration (FDA). The recommended dose is 0.5mg once a day for oral administration.
Multiple sclerosis is a debilitating neurological disease that can cause the patient to lose a sense of balance, appear muscle spasms and other movement disorders. The disease has been treated with injectable drugs. This kind of medication brought great inconvenience to patients.
Fingolimod is a sphingosine-l-phosphate (S1PR) receptor modulator. After phosphorylation, It is bound to s1P receptor that is on the surface of lymphocyte, which will change lymphocyte migration, and promote cells into the lymphatic tissue, and prevent lymphocytes from leaving the lymphoid tissue and get into the graft. Thereby, it will prevent these cells from infiltrating the central nervous system (CNS), which achieves the effect of immunosuppression. According to the drug's introduction, drugmaker Novartis said that this process of pharmacological effects is reversible. If medication is stopped, the level of lymphocytes in circulating system will return to normal.
The above information is edited by the chemicalbook of Kui Ming.

Description

Approved by the U.S. FDA in September 2010, fingolimod (also referredto as FTY720) is the first approved oral therapy for the relapsing-remittingform ofmultiple sclerosis (RRMS). Because of fingolimod’s structuralresemblance to sphingosine, a metabolite of sphingolipids that constitutesthe cell membrane of all eukaryotic cells, it was hypothesized thatfingolimod may be affecting sphingolipid metabolism in cells. A series ofelegant in vitro and in vivo studies confirmed that fingolimod isconverted to (S)-fingolimod phosphate primarily by sphingosine kinase-2 and that (S)-fingolimod phosphate mediates multiple biological processesby binding to novel GPCR’s referred to as sphingosine-1-phosphate (S1P)receptors. S1P receptors are divided into five subtypes, S1P_1–5, which havevarying tissue and cellular distribution. S1P_1–3 receptors are ubiquitouslyexpressed in the immune, cardiovascular, and central nervous systems, S1P4is restricted to the hematopoietic system, and S1P₅ is mostly localized in thewhite matter of CNS. S1P_1–3 receptors play important roles in endothelialbarrier function, maintaining vascular tone, regulating heart rate and allowingfor lymphocyte egress fromsecondary lymphoid organs. The functionalrole of S1P₄ is unknown,while the S1P5 receptor is thought to be involved innatural killer cell trafficking and oligodendrocyte function.

Chemical Properties

White Solid

Originator

Yoshitomi Pharmaceutical Industries(now Mitsubishi Tanabe Pharma) (United States)

Uses

A derivative of ISP-1 (myriocin), a fungal metabolite of the Chinese herb Iscaria sinclarii as well as a structural analogue of Sphingosine. It is a novel immune modulator that prolongs allograft transplant survival in numberour models by inhibitin

Uses

Oral medicine for the treatment of multiple sclerosis

Uses

FTY720 is a derivative of ISP-1 (myriocin), a fungal metabolite of the Chinese herb Iscaria sinclarii as well as a structural analogue of Sphingosine. FTY720 is a novel immune modulator that prolongs allograft transplant survival in numberour models by inhibiting lymphocyte emigration from lymphoid organs. FTY720 us reported to be phosphorylated by sphingosine kinase to FTY720-P, which has been shown to potently stimulate GTPgS binding activity in S1P-transfected CHO cells (EC50 = 210 pM, 4.9 nM, 4.3 nM, and 1 nM for S1P1, S1P3, S1P4 and S1P5, respectively).

Uses

A cell-permeable aminopropanediol immunosuppressive agent that displays lymphocyte sequestration properties.

Uses

Fingolimod Hydrochloride is a derivative of ISP-1 (myriocin), a fungal metabolite of the Chinese herb Iscaria sinclarii as well as a structural analogue of Sphingosine. Fingolimod is a novel immune modulator that prolongs allograft transplant survival in numerous models by inhibiting lymphocyte emigration from lymphoid organs. Fingolimod is reported to be phosphorylated by sphingosine kinase to FTY720-P, which has been shown to potently stimulate GTPgS binding activity in S1P-transfected CHO cells (EC50 = 210 pM, 4.9 nM, 4.3 nM, and 1 nM for S1P1, S1P3, S1P4 and S1P5, respectively).

Definition

ChEBI: The hydrochloride salt of 2-amino-2-[2-(4-octylphenyl) ethyl]-1,3-propanediol (fingolimod).

Brand name

Gilenya

Biochem/physiol Actions

FTY720 is an immunomodulating drug and sphingosine 1-phosphate (S1P) receptor modulator. Phosphorylation of FTY270 by sphingosine kinase causes S1P1R internalization, which sequesters lymphocytes in lymph nodes, preventing them from taking part in an autoimmune response. Clinically, it has been approved for the treatment of multiple sclerosis (MS). It has also been shown to block and reverse paclitaxel-induced chemotherapy induced peripheral neuropathy (CIPN) through S1PR inhibition as well as inhibit the activity of histone deacetylases in the hippocampus of mouse brains, thereby modulating memory.

Clinical Use

Fingolimod hydrochloride is an immunosuppressive drug developed by Novartis and approved in theU.S., Europe, and Australia in 2010 for the treatment of multiple sclerosis. The structure offingolimod derives from the naturally-occurring myriocin (ISP-1) metabolite of the fungus I. sinclairiiand the aminoalcohol functionality within the drug possesses structural similarity to the sphingosinefamily of natural products.

Synthesis

Although several convenient preparations of fingolimod (FTY720)have been reported in the literature, the route most closely resembling the process-scaleapproach is described in the scheme. Friedel-Crafts acylation of commercial toluene derivative 89with bromoacetyl chloride followed by ethoxide-mediated N-acylated aminomalonate (91) attack ontothe resulting -bromoketone 90 gave rise to ketoamide 92 in good overall yield. Next, separate hydridereduction protocols were employed to furnish diol 93. Presumably, triethylsilyl hydride reduced theketone and both ethyl esters within 92 to the corresponding diacid, which then underwent lithiumaluminum hydride treatment to arrive at diol 93. Careful attention to stoichiometry was required toavoid over reduction of amide 93, which was critical to achieve high-yielding (76%) salt formation offingolimod HCl (VI) through the use of 6 N ethanolic hydrochloric acid.

target

COX | PGE | Histamine Receptor | PAK | p21 | S1P

storage

+4°C

References

[1] V. BRINKMANN. The Immune Modulator FTY720 Targets Sphingosine 1-Phosphate Receptors*[J]. The Journal of Biological Chemistry, 2002, 10 1: 21453-21457. DOI:10.1074/jbc.c200176200
[2] ANNA MARIA WOLF. The sphingosine 1-phosphate receptor agonist FTY720 potently inhibits regulatory T cell proliferation in vitro and in vivo.[J]. Journal of immunology, 2009, 183 6: 3751-3760. DOI:10.4049/jimmunol.0901011
[3] ANTHONY O AWOJOODU. Sphingosine 1-phosphate receptor 3 regulates recruitment of anti-inflammatory monocytes to microvessels during implant arteriogenesis.[J]. Proceedings of the National Academy of Sciences of the United States of America, 2013, 110 34: 13785-13790. DOI:10.1073/pnas.1221309110
[4] CHIBA K. FTY720, a new class of immunomodulator, inhibits lymphocyte egress from secondary lymphoid tissues and thymus by agonistic activity at sphingosine 1-phosphate receptors[J]. Pharmacology & Therapeutics, 2005, 108 3: Pages 308-319. DOI:10.1016/j.pharmthera.2005.05.002