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DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO
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Ponesimod
Ponesimod
Phase III
MW 460.97, C23 H25 Cl N2 O4 S
A sphingosine-1-phosphate receptor 1 (S1P1) agonist potentially for the treatment of multiple sclerosis.
(Z,Z)-5-[3-chloro-4-(2R)-2,3-dihydroxy-propoxy)-benzylidene]-2-propylimino-3-o-tolylthiazolidin-4-one
- (2Z,5Z)-5-[[3-Chloro-4-[(2R)-2,3-dihydroxypropoxy]phenyl]methylene]-3-(2-methylphenyl)-2-(propylimino)-4-thiazolidinone
- 5-[3-Chloro-4-[((2R)-2,3-dihydroxypropyl)oxy]benz-(Z)-ylidene]-2-((Z)-propylimino)-3-(o-tolyl)thiazolidin-4-one
- ACT 128800
ACT-128800; RG-3477; R-3477
CAS No. 854107-55-4
update 18/3/21 FDA APPROVEDAS PONVORY
SYNTHESIS
Ponesimod
NMR CDCL3 FROM NET
Ponesimod (INN, codenamed ACT-128800) is an experimental drug for the treatment of multiple sclerosis (MS) and psoriasis. It is being developed by Actelion.
The first oral treatment for relapsing multiple sclerosis, the nonselective sphingosine-1-phosphate receptor (S1PR) modulator fingolimod, led to identification of a pivotal role of sphingosine-1-phosphate and one of its five known receptors, S1P1R, in regulation of lymphocyte trafficking in multiple sclerosis. Modulation of S1P3R, initially thought to cause some of fingolimod’s side effects, prompted the search for novel compounds with high selectivity for S1P1R. Ponesimod is an orally active, selective S1P1R modulator that causes dose-dependent sequestration of lymphocytes in lymphoid organs. In contrast to the long half-life/slow elimination of fingolimod, ponesimod is eliminated within 1 week of discontinuation and its pharmacological effects are rapidly reversible. Clinical data in multiple sclerosis have shown a dose-dependent therapeutic effect of ponesimod and defined 20 mg as a daily dose with desired efficacy, and acceptable safety and tolerability. Phase II clinical data have also shown therapeutic efficacy of ponesimod in psoriasis. These findings have increased our understanding of psoriasis pathogenesis and suggest clinical utility of S1P1R modulation for treatment of various immune-mediated disorders. A gradual dose titration regimen was found to minimize the cardiac effects associated with initiation of ponesimod treatment. Selectivity for S1P1R, rapid onset and reversibility of pharmacological effects, and an optimized titration regimen differentiate ponesimod from fingolimod, and may lead to better safety and tolerability. Ponesimod is currently in phase III clinical development to assess efficacy and safety in relapsing multiple sclerosis. A phase II study is also ongoing to investigate the potential utility of ponesimod in chronic graft versus host disease.http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4707431/
Biology and pharmacology of sphingosine-1-phosphate receptor 1
The past decades have witnessed major advances in the treatment of autoimmune and chronic inflammatory diseases. A plethora of novel therapies targeting specific molecules involved in the inflammatory or immune system activation cascades have become available. These have significantly increased our understanding of disease pathogenesis and improved the management of immune-mediated disorders. However, most of the targeted therapies are biological drugs which need to be injected, are eliminated slowly (e.g. over several weeks) and can lose efficacy or tolerability due to their potential immunogenicity. In an attempt to overcome these hurdles, pharmaceutical research has made considerable efforts to develop novel oral targeted therapies for autoimmune and chronic inflammatory diseases.
Sphingosine-1-phosphate receptor 1 (S1P1R) is one of five known G protein-coupled receptors with nanomolar affinity for the lysophospholipid sphingosine-1-phosphate (S1P), which is generated through physiologic metabolism of the cell membrane constituent sphingomyelin by all cells [Brinkmann, 2007]. S1P receptors, including S1P1R, are widely expressed in many tissues [Chun et al. 2010]. S1P1R expression on lymphocytes controls their egress from thymus and secondary lymphoid organs [Cyster and Schwab, 2012]. Lymphocyte egress requires a gradient of S1P concentration, which is established by a high S1P concentration in blood and lymph compared with a low concentration in the interstitial fluid of lymphoid organs [Grigorova et al. 2009].
Synthetic S1P1 receptor modulators disrupt the interaction of the physiologic S1P ligand with S1P1R by promoting initial activation followed by sustained internalization and desensitization of S1P1R [Hla and Brinkmann, 2011; Pinschewer et al. 2011]. Experiments conducted in animal models of transplant rejection, multiple sclerosis, lupus erythematosus, arthritis and inflammatory bowel disease with the first-generation, nonselective S1P receptor modulator, fingolimod, have demonstrated the potential efficacy of this mode of action across several immune-mediated chronic inflammatory conditions [Brinkmann, 2007]. Fingolimod is a structural analog of sphingosine that is phosphorylated in the body by a sphingosine kinase to generate the bioactive form of the drug, fingolimod phosphate, which binds to multiple S1P receptors [Brinkmann, 2007]. Clinical trials in multiple sclerosis (MS) have confirmed the efficacy of fingolimod in relapsing MS, but not in primary progressive disease, and led to the approval of the first oral medication for the treatment of relapsing forms of MS in 2010 [Kappos et al. 2010].
The mechanism of action of fingolimod has increased our understanding of MS pathogenesis. T and B cells, but not natural killer (NK) cells, express functional S1P1R and are affected by fingolimod [Cyster and Schwab, 2012]. Furthermore, S1P1R is differentially expressed and regulated in functionally distinct subsets of lymphocytes and fingolimod has been shown to predominantly affect naïve T cells and central memory T cells (TCM) while sparing effector memory T cells (TEM), and terminally differentiated effector T cells (TE) in patients with relapsing MS [Mehling et al. 2008, 2011]. This has raised the possibility that, at least in MS, retention of TCM cells, which include pro-inflammatory T helper 17 (Th17) cells, by fingolimod may prevent their accumulation in the cerebrospinal fluid (CSF) and subsequent differentiation to TE cells in the central nervous system (CNS) [Hla and Brinkmann, 2011]. The effects of S1P1R modulation on B cells are less well defined. Recent data from patients with relapsing MS have shown predominant reduction of memory B cells and recently activated memory B cells (CD38int-high) in peripheral blood after treatment with fingolimod [Claes et al. 2014; Nakamura et al. 2014]. As memory B cells are implicated in the pathogenesis of MS and other autoimmune diseases, these observations suggest another potential mechanism underlying the therapeutic effects of S1P1R modulators.
Astrocytes, microglia, oligodendrocytes and neurons express various S1P receptors including S1P1R, S1P3R and S1P5R. Fingolimod has been shown to penetrate the CNS tissues and in vitro studies have shown activation of astrocytes and oligodendrocytes by fingolimod [Foster et al. 2007]. Conditional deletion of S1P1R on neural cells in mice reduced the severity of experimental autoimmune encephalomyelitis (EAE) and reductions in the clinical scores were paralleled by decreased demyelination, axonal loss and astrogliosis [Choi et al. 2011]. Unfortunately, there was no beneficial effect in a recently completed, large study of fingolimod in patients with primary progressive MS [Lublin et al. 2015], suggesting that the direct effect on CNS cells alone may not be sufficient. Taken together, these data suggest the possibility of a direct beneficial effect of S1P1R modulation in the brain of patients with relapsing MS [Dev et al. 2008]; however, its contribution to efficacy relative to the immunological effects remains unclear.
Initial studies in rodents suggested that modulation of S1P3R on cardiac myocytes by fingolimod was associated with a reduction of heart rate (HR) by activation of G-protein-coupled inwardly rectifying potassium channels (GIRK) that regulate pacemaker frequency, and the shape and duration of action potentials [Koyrakh et al. 2005; Camm et al. 2014]. Modulation of S1P2R and S1P3R on myofibroblasts by fingolimod was also shown to stimulate extracellular matrix synthesis [Sobel et al. 2013]. Modulation of these receptors on vascular smooth muscle cells appeared to be associated with vasoconstriction, leading to the slight increase in blood pressure observed with fingolimod treatment [Salomone et al. 2003; Watterson et al. 2005; Hu et al. 2006; Lorenz et al. 2007; Kappos et al. 2010]. These observations raised the possibility that some side effects associated with fingolimod treatment could be avoided by more selective S1P1R modulators, thus triggering the search for novel compounds.
Currently, there are several selective S1P1R modulators in clinical development [Gonzalez-Cabrera et al.2014; Subei and Cohen, 2015]. Here we review data and the development status of ponesimod, a selective S1P1R modulator developed by Actelion Pharmaceuticals Ltd.http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4707431/
Ponesimod, a selective, rapidly reversible, orally active, sphingosine-1-phosphate receptor modulator
Ponesimod (ACT-128800 (Z,Z)-5-[3-chloro-4-(2R)-2,3-dihydroxy-propoxy)-benzylidene]-2-propylimino-3-o-tolylthiazolidin-4-one) is a selective, rapidly reversible, orally active, S1P1R modulator. Ponesimod emerged from the discovery of a novel class of S1P1R agonists based on the 2-imino-thiazolidin-4-one scaffold (Figure 1) [Bolli et al. 2010]. Ponesimod activates S1P1R with high potency [half maximal effective concentration (EC50) of 5.7 nM] and selectivity. Relative to the potency of S1P, the potency of ponesimod is 4.4 higher for S1P1R and 150-fold lower for S1P3R, resulting in an approximately 650-fold higher S1P1R selectivity compared with the natural ligand.
Clinical trials
In a 2009–2011 Phase II clinical trial including 464 MS patients, ponesimod treatment resulted in fewer new active brain lesions thanplacebo, measured during the course of 24 weeks.[3][4]
In a 2010–2012 Phase II clinical trial including 326 patients with psoriasis, 46 or 48% of patients (depending on dosage) had a reduction of at least 75% Psoriasis Area and Severity Index (PASI) score compared to placebo in 16 weeks.[3][5]
SEE https://clinicaltrials.gov/ct2/show/NCT02425644
Adverse effects
Common adverse effects in studies were temporary bradycardia (slow heartbeat), usually at the beginning of the treatment,dyspnoea (breathing difficulties), and increased liver enzymes (without symptoms). No significant increase of infections was observed under ponesimod therapy.[3] QT prolongation is detectable but was considered to be too low to be of clinical importance in a study.[6]
Mechanism of action
Like fingolimod, which is already approved for the treatment of MS, ponesimod blocks the sphingosine-1-phosphate receptor. This mechanism prevents lymphocytes (a type of white blood cells) from leaving lymph nodes.[3] Ponesimod is selective for subtype 1 of this receptor, S1P1.[7]
PAPER
Bolli, Martin H.; Journal of Medicinal Chemistry 2010, V53(10), P4198-4211 CAPLUS
2-Imino-thiazolidin-4-one Derivatives as Potent, Orally Active S1P1Receptor Agonists
Sphingosine-1-phosphate (S1P) is a widespread lysophospholipid which displays a wealth of biological effects. Extracellular S1P conveys its activity through five specific G-protein coupled receptors numbered S1P1 through S1P5. Agonists of the S1P1 receptor block the egress of T-lymphocytes from thymus and lymphoid organs and hold promise for the oral treatment of autoimmune disorders. Here, we report on the discovery and detailed structure−activity relationships of a novel class of S1P1 receptor agonists based on the 2-imino-thiazolidin-4-one scaffold. Compound 8bo (ACT-128800) emerged from this series and is a potent, selective, and orally active S1P1 receptor agonist selected for clinical development. In the rat, maximal reduction of circulating lymphocytes was reached at a dose of 3 mg/kg. The duration of lymphocyte sequestration was dose dependent. At a dose of 100 mg/kg, the effect on lymphocyte counts was fully reversible within less than 36 h. Pharmacokinetic investigation of8bo in beagle dogs suggests that the compound is suitable for once daily dosing in humans.
(Z,Z)-5-[3-Chloro-4-((2R)-2,3-dihydroxy-propoxy)-benzylidene]-2-propylimino-3-o-tolyl-thiazolidin-4-one (8bo)
PATENT
WO 2014027330
https://www.google.com/patents/WO2014027330A1?cl=3Den
The present invention relates inter alia to a new process for the preparation of (2Z,5Z)-5-(3-chloro-4-((R)-2,3-dihydroxypropoxy)benzylidene)-2-(propylimino)-3-(o-tolyl)thiazolidin-4-one (hereinafter also referred to as the “COMPOUND” or “compound (2)”), especially in crystalline form C which form is described in WO 2010/046835. The preparation of COMPOUND and its activity as immunosuppressive agent is described in WO 2005/054215. Furthermore, WO 2008/062376 describes a new process for the preparation of (2Z,5Z)-5-(3-chloro-4-hydroxy-benzylidene)-2-propylimino-3-o-tolyl-thiazolidin-4-one which can be used as an intermediate in the preparation of COMPOUND.
Example 1 a) below describes such a process of preparing (2Z,5Z)-5-(3-chloro-4-hydroxy-benzylidene)-2-propylimino-3-o-tolyl-thiazolidin-4-one according to WO 2008/062376. According to WO 2008/062376 the obtained (2Z,5Z)-5-(3-chloro-4-hydroxy-benzylidene)-2-propylimino-3-o-tolyl-thiazolidin-4-one can then be transformed into COMPOUND by using standard methods for the alkylation of phenols. Such an alkylation is described in Example 1 b) below. Unfortunately, this process leads to the impurity (2Z,5Z)-5-(3-chloro-4-((1 ,3-dihydroxypropan-2-yl)oxy)benzylidene)-2-(propylimino)-3-(o-tolyl)thiazolidin-4-one which is present in about 2% w/w in the crude product (see Table 1 ) and up to 6 recrystallisations are necessary in order to get this impurity below 0.4% w/w (see Tables 1 and 2) which is the specified limit based on its toxicological qualification.
the obtained (R)-3-chloro-4-(2,3-dihydroxypropoxy)-benzaldehyde (1 ) with 2-[(Z)-propylimino]-3-o-tolyl-thiazolidin-4-one to form (2Z,5Z)-5-(3-chloro-4-((R)-2,3-dihydroxypropoxy)benzylidene)-2-(propylimino)-3-(o-tolyl)thiazolidin-4-one (2):
.
The reaction of (R)-3-chloro-4-(2,3-dihydroxypropoxy)-benzaldehyde (1 ) with 2-[(Z)-propylimino]-3-o-tolyl-thiazolidin-4-one can be performed under conditions which are typical for a Knoevenagel condensation. Such conditions are described in the literature for example in Jones, G., Knoevenagel Condensation in Organic Reaction, Wiley: New York, 1967, Vol. 15, p 204; or Prout, F. S., Abdel-Latif, A. A., Kamal, M. R., J. Chem. Eng. Data, 2012, 57, 1881-1886.
2-[(Z)-Propylimino]-3-o-tolyl-thiazolidin-4-one can be prepared as described in WO 2008/062376, preferably without the isolation and/or purification of intermediates such as the thiourea intermediate that occurs after reacting o-tolyl-iso-thiocyanate with n-propylamine. Preferably 2-[(Z)-propylimino]-3-o-tolyl-thiazolidin-4-one obtained according to WO 2008/062376 is also not isolated and/or purified before performing the Knoevenagel condensation, i.e. before reacting 2-[(Z)-propylimino]-3-o-tolyl-thiazolidin-4-one with (R)-3-chloro-4-(2,3-dihydroxypropoxy)-benzaldehyde (1 ), i.e. in a preferred embodiment compound (2) is prepared in a one-pot procedure analogous to that described in WO 2008/062376.
Example 1 : (2Z,5Z)-5-(3-Chloro-4-((R)-2,3-dihydroxypropoxy)benzylidene)-2-(propylimino)-3-(o-tolyl)thiazolidin-4-one
a) Preparation of (2Z,5Z)-5-(3-chloro-4-hydroxy-benzylidene)-2-propylimino-3-o-tolyl-thiazolidin-4-one:
Acetic acid solution: To acetic acid (149.2 mL) are added sodium acetate (1 1 .1 1 g, 2.00 eq.) and 3-chloro-4-hydroxybenzaldehyde (10.60 g, 1.00 eq.) at 20 °C. The mixture is stirred at 20 °C until complete dissolution (2 to 3 h).
n-Propylamine (4.04 g, 1.00 eq.) is added to a solution of o-tolyl-iso-thiocyanate (10 g, 1.00 eq.) in dichloromethane (100 mL) at 20 °C. The resulting pale yellow solution is agitated for 40 min at 20 °C before IPC (conversion specification≥ 99.0 %). The reaction is cooled to -2 °C. Bromoacetyl bromide (13.53 g, 1.00 eq.) is added and the resulting solution is stirred for 15 min at -2 °C. Pyridine (10.92 g, 2.05 eq.) is then added slowly at -2 °C. The intensive yellow reaction mixture is stirred for 15 min at -2 °C before IPC (conversion specification≥ 93.0 %). 70 mL of dichloromethane are distilled off under atmospheric pressure and jacket temperature of 60 °C. The temperature is adjusted to 42 °C and the acetic acid solution is added to the reaction mixture. The resulting solution is heated to 58 °C and stirred at this temperature for 15 h before IPC (conversion specification≥ 95 %). 25 mL of solvents are distilled off under vacuum 900 – 500 mbars and jacket temperature of 80 °C. The temperature is adjusted to 60 °C and water (80.1 mL) is added to the reaction mixture over 1 h. The resulting yellow suspension is stirred at 60 °C for 30 min. The suspension is cooled to 20 °C over 1 h and stirred at this temperature for 30 min.
The product is filtered and washed with a mixture of acetic acid (30 mL) and water (16 mL) and with water (50 mL) at 20 °C. The product is dried under vacuum at 50 °C for 40 h to afford a pale yellow solid; yield 25.93 g (78 %).
b) Preparation of crude (2Z,5Z)-5-(3-chloro-4-((R)-2,3-dihydroxypropoxy)benzylidene)-2-(propylimino)-3-(o-tolyl)thiazolidin-4-one:
To a suspension of (2Z,5Z)-5-(3-chloro-4-hydroxy-benzylidene)-2-propylimino-3-o-tolyl-thiazolidin-4-one (10.00 g, 1.00 eq.) in ethanol (47.2 mL) is added (R)-3-chloro-1 ,2-
propanediol (3.37 g, 1.18 eq.) at 20 °C. Potassium tert-butoxide (3.39 g, 1.13 eq.) is added in portions at 20 °C. The resulting fine suspension is stirred at 20 °C for 25 min before being heated to reflux (88 °C). The reaction mixture is stirred at this temperature for 24 h before IPC (conversion specification≥ 96.0 %). After cooling down to 60 °C, acetonitrile (28.6 mL) and water (74.9 mL) are added. The resulting clear solution is cooled from 60 °C to 0 °C over 2 h. During the cooling ramp, (2Z,5Z)-5-(3-chloro-4-((R)-2,3-dihydroxypropoxy)benzylidene)-2-(propylimino)-3-(o-tolyl)thiazolidin-4-one seeds of crystalline form C (0.010 g, 0.001 eq.; crystalline form C can be prepared as described in WO 2010/046835) are added at 50 °C. The suspension is heated from 0 °C to 50 °C, cooled to 0 °C over 6 h and stirred at this temperature for 12 h.
The product is filtered and washed with a mixture of acetonitrile (23.4 mL) and water (23.4 mL) at 0 °C. The product is dried under vacuum at 45 °C for 24 h to afford a pale yellow solid; yield 1 1.91 g (84 %).
c) Purification of (2Z,5Z)-5-(3-chloro-4-((R)-2,3-dihydroxypropoxy)benzylidene)-2-(propylimino)-3-(o-tolyl)thiazolidin-4-one:
Recrystallisation I: The crude (2Z,5Z)-5-(3-chloro-4-((R)-2,3-dihydroxypropoxy)benzylidene)-2-(propylimino)-3-(o-tolyl)thiazolidin-4-one (10 g) is dissolved in acetonitrile (30 mL) at 70 °C. The reaction mixture is cooled from 70 °C to 0 °C over 2 h. During the cooling ramp, (2Z,5Z)-5-(3-chloro-4-((R)-2,3-dihydroxypropoxy)benzylidene)-2-(propylimino)-3-(o-tolyl)thiazolidin-4-one seeds of crystalline form C (0.0075 g, 0.00075 eq.) are added at 50 °C. The suspension is heated up to 52 °C, cooled to 0 °C over 6 h and agitated at this temperature for 2 h. The product is filtered and washed with acetonitrile at -10 °C (2 x 12.8 mL).
Recrystallisation II: The wet product is dissolved in acetonitrile (27.0 mL) at 70 °C. The reaction mixture is cooled from 70 °C to 0 °C over 2 h. During the cooling ramp, (2Z,5Z)-5-(3-chloro-4-((R)-2,3-dihydroxypropoxy)benzylidene)-2-(propylimino)-3-(o-tolyl)thiazolidin-4-one seeds of crystalline form C (0.0075 g, 0.00075 eq.) are added at 50 °C. The suspension is heated up to 52 °C, cooled to 0 °C over 6 h and agitated at this temperature for 2 h. The product is filtered and washed with acetonitrile at -10 °C (2 x 1 1.3 mL).
Recrystallisation III: The wet product is dissolved in acetonitrile (24.3 mL) at 70 °C. The reaction mixture is cooled from 70 °C to 0 °C over 2 h. During the cooling ramp, (2Z,5Z)-5-(3-chloro-4-((R)-2,3-dihydroxypropoxy)benzylidene)-2-(propylimino)-3-(o-tolyl)thiazolidin-4- one seeds of crystalline form C (0.0075 g, 0.00075 eq.) are added at 50 °C. The suspension is heated up to 52 °C, cooled to 0 °C over 6 h and agitated at this temperature for 2 h. The product is filtered and washed with acetonitrile at -10 °C (2 x 10.1 mL).
Recrystallisation IV: The wet product is dissolved in acetonitrile (21.9 mL) at 70 °C. The reaction mixture is cooled from 70 °C to 0 °C over 2 h. During the cooling ramp, (2Z,5Z)-5-(3-chloro-4-((R)-2,3-dihydroxypropoxy)benzylidene)-2-(propylimino)-3-(o-tolyl)thiazolidin-4-one seeds of crystalline form C (0.0075 g, 0.00075 eq.) are added at 50 °C. The suspension is heated up to 52 °C, cooled to 0 °C over 6 h and agitated at this temperature for 2 h. The product is filtered and washed with acetonitrile at -10 °C (2 x 9.1 mL).
Recrystallisation V: The wet product is dissolved in acetonitrile (19.7 mL) at 70 °C. The reaction mixture is cooled from 70 °C to 0 °C over 2 h. During the cooling ramp, (2Z,5Z)-5-(3-chloro-4-((R)-2,3-dihydroxypropoxy)benzylidene)-2-(propylimino)-3-(o-tolyl)thiazolidin-4-one seeds of crystalline form C (0.0075 g, 0.00075 eq.) are added at 50 °C. The suspension is heated up to 52 °C, cooled to 0 °C over 6 h and agitated at this temperature for 2 h. The product is filtered and washed with acetonitrile at -10 °C (2 x 8.2 mL).
Recrystallisation VI: The wet product is dissolved in acetonitrile (23.9 mL) at 70 °C. Water (20 mL) is added at 70 °C. The reaction mixture is cooled from 70 °C to 0 °C over 2 h.
During the cooling ramp, (2Z,5Z)-5-(3-chloro-4-((R)-2,3-dihydroxypropoxy)benzylidene)-2- (propylimino)-3-(o-tolyl)thiazolidin-4-one seeds of crystalline form C (0.0075 g, 0.00075 eq.) are added at 50 °C. The suspension is heated up to 52 °C, cooled to 0 °C over 6 h and agitated at this temperature for 2 h. The product is filtered and washed twice with a mixture of acetonitrile (4.5 mL) and water (4.5 mL) at -10 °C.
The product is dried under vacuum at 45 °C for 24 h to afford a pale yellow solid; yield: 7.0 g (70 %).
Example 2: (R)-3-Chloro-4-(2,3-dihydroxypropoxy)-benzaldehyde
Potassium tert-butoxide (1 18 g, 1.20 eq.) is added to n-propanol (963 mL) followed by 3-chloro-4-hydroxybenzaldehyde (137 g, 1.00 eq.). To the mixture is added (R)-3-chloro-1 ,2-propanediol (126 g, 1.30 eq.). The suspension is heated to 90 °C and stirred at this temperature for 17 h. Solvent (500 mL) is distilled off at 120 °C external temperature and reduced pressure. Water is added (1.1 L) and solvent (500 mL) is removed by distillation. The turbid solution is cooled to 20 °C. After stirring for one hour a white suspension is obtained. Water (500 mL) is added and the suspension is cooled to 10 °C. The suspension is filtered and the resulting filter cake is washed with water (500 mL). The product is dried at 50 °C and reduced pressure to yield 149 g of a white solid (73%), which is (R)-3-chloro-4-(2,3-dihydroxypropoxy)-benzaldehyde in crystalline form A.
Example 3: (R)-3-Chloro-4-(2,3-dihydroxypropoxy)-benzaldehyde
Potassium tert-butoxide (8.60 g, 1.20 eq.) is added to n-propanol (70 mL) below 15 °C, the temperature is allowed to rise. After the addition the temperature is corrected again to below 15 °C before addition of 3-chloro-4-hydroxybenzaldehyde (10 g, 1 .00 eq.). The suspension is heated to 40 °C and stirred for 30 min. (R)-3-Chloro-1 ,2-propanediol (9.18 g, 1.30 eq.) is added at 40 °C. The resulting suspension is heated to 60 °C and stirred at this temperature for 15 h then heated to 94 °C till meeting the IPC-specification (specification conversion≥ 90.0 %). The mixture is cooled to 30 °C and n-propanol is partially distilled off (-50 mL are distilled off) under reduced pressure and a maximum temperature of 50 °C, the jacket temperature is not allowed to raise above 60 °C.
Water (81 mL) is added and a second distillation is performed under the same conditions (24 mL are distilled off). The mixture is heated till homogeneous (maximum 54 °C) and then cooled to 24 °C. At 24 °C the mixture is seeded with crystalline (R)-3-chloro-4-(2,3-dihydroxypropoxy)-benzaldehyde of form A (0.013 g, 0.00085 eq.). How to obtain the crystalline seeds is described in Examples 2 and 5. The reaction mixture is cooled to 0 °C over 7.5 h.
The product is filtered and washed with water (2 x 35 mL) and once with methyl tert-butyl ether (20 mL) at 5 °C. The product is dried under vacuum at 40 °C for 20 h to afford an off-white solid; yield: 10.6 g (72 %), which is (R)-3-chloro-4-(2,3-dihydroxypropoxy)-benzaldehyde in crystalline form A.
Example 4: (2Z,5Z)-5-(3-Chloro-4-((R)-2,3-dihydroxypropoxy)benzylidene)-2-(propylimino)- 3-(o-tolyl)thiazolidin-4-one
a) Preparation of crude (2Z,5Z)-5-(3-chloro-4-((R)-2,3-dihydroxypropoxy)benzylidene)-2-(propylimino)-3-(o-tolyl)thiazolidin-4-one:
n-Propylamine (5.23 g, 1.32 eq.) is added to a solution of o-tolyl-iso-thiocyanate (10 g, 1.00 eq.) in dichloromethane (100 mL) at 20 °C. The resulting pale yellow solution is agitated for 15 min at 20 °C before IPC (conversion specification≥ 99.0 %). The reaction is cooled to -2 °C. Bromoacetyl bromide (14.88 g, 1.10 eq.) is added and the resulting solution is stirred for 15 min at -2 °C. Pyridine (10.92 g, 2.05 eq.) is then added slowly at -2 °C. The intensive yellow reaction mixture is stirred for 15 min at -2 °C before IPC (conversion specification≥ 93.0 %). Dichloromethane is partially distilled off (66 mL are distilled off) under atmospheric pressure and jacket temperature of 60 °C. Ethanol (1 1 1.4 mL), sodium acetate (12.75 g, 2.30 eq.) and (R)-3-chloro-4-(2,3-dihydroxypropoxy)-benzaldehyde from Example 3 (14.38 g, 0.93 eq.) are added. The remaining dichloromethane and a part of ethanol are distilled off (49.50 mL are distilled off) under atmospheric pressure and jacket temperature up to 85 °C. The reaction mixture (orange suspension) is stirred for 3 – 5 h under reflux (78 °C) before IPC (conversion specification≥ 97.0 %).
Water (88.83 mL) is added and the temperature adjusted to 40 °C before seeding with micronized (2Z,5Z)-5-(3-chloro-4-((R)-2,3-dihydroxypropoxy)benzylidene)-2-(propylimino)-3-(o-tolyl)thiazolidin-4-one in crystalline form C (0.075 g, 0.0024 eq.). The reaction mixture is cooled to 0 °C over 5 h, heated up to 40 °C, cooled to 0 °C over 6 h and stirred at this temperature for 2 h.
The product is filtered and washed with a 1 :1 ethanohwater mixture (2 x 48 mL) at 0 °C. The product is dried under vacuum at 45 °C for 10 h to afford a pale yellow solid; yield: 24.71 g (86 %).
b) Purification of (2Z,5Z)-5-(3-chloro-4-((R)-2,3-dihydroxypropoxy)benzylidene)-2-(propylimino)-3-(o-tolyl)thiazolidin-4-one:
The crude (2Z,5Z)-5-(3-chloro-4-((R)-2,3-dihydroxypropoxy)benzylidene)-2-(propylimino)-3-(o-tolyl)thiazolidin-4-one (10 g) is dissolved in ethanol (40 mL) at 70 °C. The temperature is adjusted at 50 °C for seeding with micronised (2Z,5Z)-5-(3-chloro-4-((R)-2,3- dihydroxypropoxy)benzylidene)-2-(propylimino)-3-(o-tolyl)thiazolidin-4-one in crystalline form C (0.016 g, 0.0016 eq.). The reaction mixture is cooled from 50 °C to 0 °C over 4 h, heated up to 50 °C, cooled to 0 °C over 6 h and agitated at this temperature for 2 h.
The product is filtered and washed with ethanol at 0 °C (2 x 12.8 mL). The product is dried under vacuum at 45 °C for 10 h to afford a pale yellow solid; yield: 9.2 g (92 %).
Example 5: Preparation of crystalline seeds of (R)-3-chloro-4-(2,3-dihydroxypropoxy)- benzaldehyde
10 mg of (R)-3-chloro-4-(2,3-dihydroxypropoxy)-benzaldehyde of at least 99.5% purity by 1 H-NMR assay is dissolved in a 4 mL vial by adding 1 mL of pure ethanol (puriss p. a.). The solvent is allowed to evaporate through a small hole in the cap (approx. 2 mm of diameter) of the vial until complete dryness. The white solid residue is crystalline (R)-3-chloro-4-(2,3- dihydroxypropoxy)-benzaldehyde in crystalline form A. Alternatively, methanol or methylisobutylketone (both in puriss p. a. quality) is used. This procedure is repeated until sufficient seeds are made available.
PATENT
WO 2005054215
SEE https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2005054215
| WO2005054215A1 | Nov 16, 2004 | Jun 16, 2005 | Actelion Pharmaceuticals Ltd | 5-(benz- (z) -ylidene) -thiazolidin-4-one derivatives as immunosuppressant agents |
| WO2008062376A2 | Nov 22, 2007 | May 29, 2008 | Actelion Pharmaceuticals Ltd | New process for the preparation of 2-imino-thiazolidin-4-one derivatives |
| WO2010046835A1 | Oct 19, 2009 | Apr 29, 2010 | Actelion Pharmaceuticals Ltd | Crystalline forms of (r) -5- [3-chloro-4- ( 2, 3-dihydroxy-propoxy) -benz [z] ylidene] -2- ( [z] -propylimino) -3-0-tolyl-thiazolidin-4-one |
| Reference | ||
|---|---|---|
| 1 | * | BOLLI, M.H. ET AL.: “2-Imino-thiazolidin-4-one Derivatives as Potent, Orally Active S1P1 Receptor Agonists“, JOURNAL OF MEDICINAL CHEMISTRY, vol. 53, no. 10, 2010, pages 4198-4211, XP55090073, ISSN: 0022-2623, DOI: 10.1021/jm100181s |
References
- “Multiple-dose tolerability, pharmacokinetics, and pharmacodynamics of ponesimod, an S1P1 receptor modulator: Favorable impact of dose up-titration”. The Journal of Clinical Pharmacology 54: 179–88. Feb 2014. doi:10.1002/jcph.244. PMID 24408162.
- “Mass balance, pharmacokinetics and metabolism of the selective S1P1 receptor modulator ponesimod in humans”. Xenobiotica 45: 139–49. Feb 2015. doi:10.3109/00498254.2014.955832. PMID 25188442.
- H. Spreitzer (29 September 2014). “Neue Wirkstoffe – Ponesimod”. Österreichische Apothekerzeitung (in German) (20/2014): 42.
- “Oral ponesimod in relapsing-remitting multiple sclerosis: a randomised phase II trial”. Journal of Neurology, Neurosurgery 85: 1198–208. Nov 2014. doi:10.1136/jnnp-2013-307282. PMC 4215282. PMID 24659797.
- “Oral ponesimod in patients with chronic plaque psoriasis: a randomised, double-blind, placebo-controlled phase 2 trial”. The Lancet 384: 2036–45. Dec 2014. doi:10.1016/S0140-6736(14)60803-5. PMID 25127208.
- “Effect of Ponesimod, a selective S1P1 Receptor Modulator, on the QT Interval in Healthy Subjects”. Basic 116: 429–37. May 2015.doi:10.1111/bcpt.12336. PMID 25287214.
- “Ponesimod”. Actelion. Retrieved 31 October 2014.
ABOUT PONESIMOD
Ponesimod is a potent orally active, selective sphingosine-1-phosphate receptor 1 (S1P1) immunomodulator.
Ponesimod prevents lymphocytes from leaving lymph nodes, thereby reducing circulating blood lymphocyte counts and preventing infiltration of lymphocytes into target tissues. The lymphocyte count reduction is rapid, dose-dependent, sustained upon continued dosing, and quickly reversible upon discontinuation. Initial data suggest that ponesimod does not cause lymphotoxicity by destroying/depleting lymphocytes or interfering with their cellular function. Other blood cells e.g. cells of the innate immune system are largely unaffected. Ponesimod is therefore considered a promising new oral agent for the treatment of a variety of autoimmune disorders.
CURRENT STATUS
OPTIMUM (Oral Ponesimod versus Teriflunomide In relapsing MUltiple sclerosis) is a Phase III multi-center, randomized, double-blind, parallel-group, active-controlled superiority study to compare the efficacy and safety of ponesimod to teriflunomide in patients with relapsing multiple sclerosis (RMS). The study aims to determine whether ponesimod is more efficacious than teriflunomide in reducing relapses. The study is expected to enroll approximately 1’100 patients, randomized in 2 groups in a 1:1 ratio to receive ponesimod 20 mg/day or teriflunomide 14 mg/day, and is expected to last a little over 3 years. An additional study to further characterize the utility and differentiation of ponesimod in multiple sclerosis is being discussed with Health Authorities.
Ponesimod is also evaluated in a Phase II open-label, single-arm, intra-subject dose-escalation study to investigate the biological activity, safety, tolerability, and pharmacokinetics of ponesimod in patients suffering from moderate or severe chronic graft versus host disease (GvHD)inadequately responding to first- or second-line therapy. The study will also investigate the clinical response to ponesimod treatment in these patients. Approximately 30 patients will be enrolled to receive ponesimod in escalating doses of 5, 10, and 20 mg/day over the course of 24 weeks. The study is being conducted at approximately 10 sites in the US and is expected to last approximately 18 months.
AVAILABLE CLINICAL DATA
The decision to move into Phase III development was based on the Phase IIb dose-finding study with ponesimod in patients with relapsing-remitting multiple sclerosis. A total of 464 patients were randomized into this study and the efficacy, safety and tolerability of three ponesimod doses (10, 20, and 40 mg/day) versus placebo, administered once daily for 24 weeks.
The primary endpoint of this study was defined as the cumulative number of new gadolinium-enhancing lesions on T1-weighted magnetic resonance imaging (MRI) scans at weeks 12, 16, 20, and 24 after study drug initiation. A key secondary endpoint of this study was the annualized relapse rate over 24 weeks of treatment. Patients who completed 24 weeks of treatment were offered the opportunity to enter into an extension study. This ongoing trial is investigating the long-term safety, tolerability, and efficacy of 10 and 20 mg/day of ponesimod in patients with relapsing-remitting multiple sclerosis, in a double-blind fashion. The study continues to provide extensive safety and efficacy information for ponesimod in this indication, with some patients treated for more than 6 years.
The safety database from all studies with ponesimod now comprises more than 1,300 patients and healthy volunteers.
MILESTONES
2015 – Phase III program in multiple sclerosis initiated
2011 – Phase IIb dose-finding study in multiple sclerosis successfully completed
2006 – Entry-into-man
2004 – Preclinical development initiated
KEY SCIENTIFIC LITERATURE
Olsson T et al. J Neurol Neurosurg Psychiatr. 2014 Nov;85(11):1198-208. doi: 10.1136/jnnp-2013-307282. Epub 2014 Mar 21
Freedman M.S, et al. Multiple Sclerosis Journal, 2012; 18 (4 suppl): 420 (P923).
Fernández Ó, et al. Multiple Sclerosis Journal, 2012; 18 (4 suppl): 417 (P919).
Piali L, Froidevaux S, Hess P, et al. J Pharmacol Exp Ther 337(2):547-56, 2011
Bolli MH, Abele S, Binkert C, et al. J Med Chem. 53(10):4198-211, 2010
Kappos L et al. N Engl J Med. 362(5):387-401, 2010
 |
|
 |
|
| Systematic (IUPAC) name | |
|---|---|
|
(2Z,5Z)-5-{3-Chloro-4-[(2R)-2,3-dihydroxypropoxy]benzylidene}-3-(2-methylphenyl)-2-(propylimino)-1,3-thiazolidin-4-one
|
|
| Clinical data | |
| Routes of administration |
Oral |
| Legal status | |
| Legal status |
|
| Pharmacokinetic data | |
| Metabolism | 2 main metabolites |
| Biological half-life | 31–34 hrs[1] |
| Excretion | Feces (57–80%, 26% unchanged), urine (10–18%)[2] |
| Identifiers | |
| CAS Number | 854107-55-4 |
| ATC code | none |
| PubChem | CID 11363176 |
| ChemSpider | 9538103 |
| ChEMBL | CHEMBL1096146 |
| Synonyms | ACT-128800 |
| Chemical data | |
| Formula | C23H25ClN2O4S |
| Molar mass | 460.974 g/mol |
////Ponesimod, Phase III , A sphingosine-1-phosphate receptor 1, S1P1 agonist, multiple sclerosis. ACT-128800; RG-3477; R-3477, autoimmune disease, lymphocyte migration, multiple sclerosis, psoriasis, transplantation
CCC/N=C\1/N(C(=O)/C(=C/C2=CC(=C(C=C2)OC[C@@H](CO)O)Cl)/S1)C3=CC=CC=C3C
FDA approves new diagnostic imaging agent FLUCICLOVINE F-18 to detect recurrent prostate cancer
FLUCICLOVINE F-18
Cyclobutanecarboxylic acid, 1-amino-3-(fluoro-18F)-, trans- [
- Molecular FormulaC5H818FNO2
- Average mass132.124 Da
May 27, 2016
Release
The U.S. Food and Drug Administration today approved Axumin, a radioactive diagnostic agent for injection. Axumin is indicated for positron emission tomography (PET) imaging in men with suspected prostate cancer recurrence based on elevated prostate specific antigen (PSA) levels following prior treatment.
Prostate cancer is the second leading cause of death from cancer in U.S. men. In patients with suspected cancer recurrence after primary treatment, accurate staging is an important objective in improving management and outcomes.
“Imaging tests are not able to determine the location of the recurrent prostate cancer when the PSA is at very low levels,” said Libero Marzella, M.D., Ph.D., director of the Division of Medical Imaging Products in the FDA’s Center for Drug Evaluation and Research. “Axumin is shown to provide another accurate imaging approach for these patients.”
Two studies evaluated the safety and efficacy of Axumin for imaging prostate cancer in patients with recurrent disease. The first compared 105 Axumin scans in men with suspected recurrence of prostate cancer to the histopathology (the study of tissue changes caused by disease) obtained by prostate biopsy and by biopsies of suspicious imaged lesions. Radiologists onsite read the scans initially; subsequently, three independent radiologists read the same scans in a blinded study.
The second study evaluated the agreement between 96 Axumin and C11 choline (an approved PET scan imaging test) scans in patients with median PSA values of 1.44 ng/mL. Radiologists on-site read the scans, and the same three independent radiologists who read the scans in the first study read the Axumin scans in this second blinded study. The results of the independent scan readings were generally consistent with one another, and confirmed the results of the onsite scan readings. Both studies supported the safety and efficacy of Axumin for imaging prostate cancer in men with elevated PSA levels following prior treatment.
Axumin is a radioactive drug and should be handled with appropriate safety measures to minimize radiation exposure to patients and healthcare providers during administration. Image interpretation errors can occur with Axumin PET imaging. A negative image does not rule out the presence of recurrent prostate cancer and a positive image does not confirm the presence of recurrent prostate cancer. Clinical correlation, which may include histopathological evaluation of the suspected recurrence site, is recommended.
The most commonly reported adverse reactions in patients are injection site pain, redness, and a metallic taste in the mouth.
Axumin is marketed by Blue Earth Diagnostics, Ltd., Oxford, United Kingdom
Patent
http://www.google.com/patents/WO2014023775A1?cl=en
The non-natural amino acid [ F]-l-amino-3-fluorocyclobutane-l-carboxylic acid
([18F]-FACBC, also known as [18F]-Fluciclovine) is taken up specifically by amino acid transporters and has shown promise for tumour imaging with positron emission tomography (PET).
A known synthesis of [18F]-FACBC begins with the provision of the protected precursor compound 1 -(N-(t-butoxycarbonyl)amino)-3 –
[((trifluoromethyl)sulfonyl)oxy]-cyclobutane-l-carboxylic acid ethyl ester. This precursor compound is first labelled with [18F]-fluoride:
II before removal of the two protecting groups:
IT III
EP2017258 (Al) teaches removal of the ethyl protecting group by trapping the [18F]- labelled precursor compound (II) onto a solid phase extraction (SPE) cartridge and incubating with 0.8 mL of a 4 mol/L solution of sodium hydroxide (NaOH). After 3 minutes incubation the NaOH solution was collected in a vial and a further 0.8 mL 4 mol/L NaOH added to the SPE cartridge to repeat the procedure. Thereafter the SPE cartridge was washed with 3 mL water and the wash solution combined with the collected NaOH solution. Then 2.2 mL of 6 mol/L HCl was then added with heating to 60°C for 5 minutes to remove the Boc protecting group. The resulting solution was purified by passing through (i) an ion retardation column to remove Na+ from excess NaOH and Cl~ from extra HCl needed to neutralise excess of NaOH to get a highly acidic solution before the acidic hydrolysis step, (ii) an alumina column, and (iii) a reverse-phase column. There is scope for the deprotection step(s) and/or the
purification step in the production of [18F]-FACBC to be simplified.
Example 1: Synthesis of f FIFACBC
No-carrier- added [18F]fluoride was produced via the 180(p,n)18F nuclear reaction on a GE PETtrace 6 cyclotron (Norwegian Cyclotron Centre, Oslo). Irradiations were performed using a dual-beam, 30μΑ current on two equal Ag targets with HAVAR foils using 16.5 MeV protons. Each target contained 1.6 ml of > 96% [180]water (Marshall Isotopes). Subsequent to irradiation and delivery to a hotcell, each target was washed with 1.6 ml of [160]water (Merck, water for GR analysis), giving approximately 2-5 Gbq in 3.2 ml of [160]water. All radiochemistry was performed on a commercially available GE FASTlab™ with single-use cassettes. Each cassette is built around a one-piece-moulded manifold with 25 three-way stopcocks, all made of polypropylene. Briefly, the cassette includes a 5 ml reactor (cyclic olefin copolymer), one 1 ml syringe and two 5 ml syringes, spikes for connection with five prefilled vials, one water bag (100 ml) as well as various SPE cartridges and filters. Fluid paths are controlled with nitrogen purging, vacuum and the three syringes. The fully automated system is designed for single-step fluorinations with cyclotron-produced [18F]fluoride. The FASTlab was programmed by the software package in a step-by-step time-dependent sequence of events such as moving the syringes, nitrogen purging, vacuum, and temperature regulation. Synthesis of
[18F]FACBC followed the three general steps: (a) [18F]fluorination, (b) hydrolysis of protection groups and (c) SPE purification.
Vial A contained K222 (58.8 mg, 156 μπιοΐ), K2C03 (8.1 mg, 60.8 μπιοΐ) in 79.5% (v/v)
MeCN(aq) (1105 μΐ). Vial B contained 4M HC1 (2.0 ml). Vial C contained MeCN
(4.1ml). Vial D contained the precursor (48.4 mg, 123.5 μιηοΐ) in its dry form (stored at -20 °C until cassette assembly). Vial E contained 2 M NaOH (4.1 ml). The 30 ml product collection glass vial was filled with 200 mM trisodium citrate (10 ml). Aqueous
[18F]fluoride (1-1.5 ml, 100-200 Mbq) was passed through the QMA and into the 180-
H20 recovery vial. The QMA was then flushed with MeCN and sent to waste. The trapped [18F]fluoride was eluted into the reactor using eluent from vial A (730 μΐ) and then concentrated to dryness by azeotropic distillation with acetonitrile (80 μΐ, vial C). Approximately 1.7 ml of MeCN was mixed with precursor in vial D from which 1.0 ml of the dissolved precursor (corresponds to 28.5 mg, 72.7 mmol precursor) was added to the reactor and heated for 3 min at 85°C. The reaction mixture was diluted with water and sent through the tC18 cartridge. Reactor was washed with water and sent through the tC18 cartridge. The labelled intermediate, fixed on the tC18 cartridge was washed with water, and then incubated with 2M NaOH (2.0 ml) for 5 min after which the 2M NaOH was sent to waste. The labelled intermediate (without the ester group) was then eluted off the tC18 cartridge into the reactor using water. The BOC group was hydrolysed by adding 4M HC1 (1.4 ml) and heating the reactor for 5 min at 60 °C. The reactor content with the crude [18F]FACBC was sent through the HLB and Alumina cartridges and into the 30 ml product vial. The HLB and Alumina cartridges were washed with water (9.1 ml total) and collected in the product vial. Finally, 2M NaOH (0.9 ml) and water (2.1 ml) was added to the product vial, giving a purified formulation of [18F]FACBC with a total volume of 26 ml. Radiochemical purity was measured by radio-TLC using a mixture of MeCN:MeOH:H20:CH3COOH (20:5:5: 1) as the mobile phase. The radiochemical yield (RCY) was expressed as the amount of radioactivity in the [18F]FACBC fraction divided by the total used [18F]fluoride activity (decay corrected). Total synthesis time was 43 min.
The RCY of [18F]FACBC was 62.5% ± 1.93 (SD), n=4.
/////FDA, diagnostic imaging agent, recurrent prostate cancer, fda 2016, Axumin, marketed, Blue Earth Diagnostics, Ltd., Oxford, United Kingdom, fluciclovine F 18
C1[C@@](C[C@H]1[18F])(N)C(=O)O
UPDATE
SEE EMA
| Axumin : EPAR – Summary for the public | EN = English | 06/07/2017 |
The active substance fluciclovine (18F) is prepared from the precursor AH113487 by nucleophilic substitution
of a triflate group by 18F-fluoride, followed by two deprotection steps. Due to the short half-life of the 18Ffluorine
radioisotope, each batch is prepared on the day of clinical use.
The active substance is prepared in a proprietary automated synthesiser unit. The synthesiser module is
computer-controlled. A fluid path for synthesis is provided in the form of a single use cassette (FASTlab). The
cassette contains 3 reagent vials and 3 solid phase cartridges. Two other reagent vials are supplied
separately as they have a recommended storage temperature of 2-8°C. These 2 vials are inserted into the
cassette on the day of production.
Assessment report
EMA/237809/2017 Page 13/90
Fluciclovine (18F) is produced in a continuous operation from the precursor AH113487. Due to the radioactive
nature of the process, and the short half-life of [18F] fluorine, intermediates are not isolated and there is no
opportunity for operator intervention or in-process testing. Control of the synthesis of fluciclovine (18F) from
the precursor is achieved through the automated synthesis platform, which is pre-programmed with
synthesis parameters optimised for the process. On-board detectors record transfers of radioactivity through
the fluid path at critical points and monitor temperature and pressure as appropriate so that the operator
may track the progress of the synthesis.
The active substance fluciclovine (18F) progressses immediately to purification, formulation and dispensing as
the finished product within a single, continuous operation. Validation of the manufacturing process for
fluciclovine (18F) is therefore described as part of finished product validation.
The characterisation of the active substance is in accordance with the EU guideline on chemistry of new
active substances.
As mentioned, the manufacture of the active substance and finished product takes place in a single,
continuous process. The active substance is not isolated at any point. Therefore, relevant information about
impurities is given only for the finished product.
For the same reason, information for the container closure system is provided only for the finished product.http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/004197/WC500230836.pdf
Albutrepenonacog alfa
Albutrepenonacog alfa
recombinant factor IX
(Idelvion®)Approved, 2016-03-04 USFDA
A recombinant albumin-human coagulation factor IX (FIX) fusion protein indicated for the treatment and prevention of bleeding in patients with hemophilia B.
Research Code CSL-654
| Type | Recombinant coagulation factor |  |
| Source | Human | |
| Molecular Formula | C5077H7846N1367O1588S67 | |
| Molecular Weight | ~125000 |
Other Names
- Albutrepenonacog alfa
Protein Sequence
Sequence Length: 1018modified (modifications unspecified)
- Originator CSL Behring
- Class Albumins; Antihaemorrhagics; Blood coagulation factors; Recombinant fusion proteins
- Mechanism of Action Blood coagulation factor replacements; Factor X stimulants
- Orphan Drug Status Yes – Haemophilia B
- Marketed Haemophilia B
Most Recent Events
- 21 Mar 2016 Launched for Haemophilia B (In adolescents, In children, In adults) in USA (IV) – First global launch
- 07 Mar 2016 Preregistration for Haemophilia B in Australia (IV) before March 2016
- 04 Mar 2016 Registered for Haemophilia B (In children, In adolescents, In adults) in USA (IV)
| Latest Stage of Development | Approved |
| Standard Indication | Hemophilia |
| Indication Details | Treat and prevent bleeding episodes in hemophilia B patients; Treat hemophilia B |
| Regulatory Designation | U.S. – Orphan Drug (Treat and prevent bleeding episodes in hemophilia B patients); EU – Orphan Drug (Treat and prevent bleeding episodes in hemophilia B patients); Switzerland – Orphan Drug (Treat and prevent bleeding episodes in hemophilia B patients) |
-
BNF Category:Antifibrinolytic drugs and haemostatics (02.11)
Pharmacology: Albutrepenonacog alfa is a recombinant factor IX (rIX-FP) albumin fusion protein, designed to exhibit an extended half-life. Factor IX has a short half-life which necessitates multiple injections. Epidemiology: Haemophilia B is a genetic disorder caused by missing or defective factor IX, a clotting protein. It has a prevalence of around 1 in 50,000 live births in the UK and is more common in males. In 2012-13, there were 476 hospital admissions in England due to haemophilia B, accounting for 508 finished consultant episodes and 125 bed days. Indication: Haemophilia B
Albutrepenonacog alfa was approved by the U.S. Food and Drug Administration (FDA) on March 4, 2016. It was developed and marketed as Idelvion® by CSL Behring.
Albutrepenonacog alfa is a recombinant albumin-human coagulation factor IX (FIX) fusion protein, which replaces the missing FIX needed for effective hemostasis. It is indicated for the treatment and prevention of bleeding in children and adults with hemophilia B.
Idelvion® is available as injection (lyophilized powder) for intravenous use, containing 250 IU, 500 IU, 1000 IU or 2000 IU of albutrepenonacog alfa in single-use vials. In control and prevention of bleeding episodes and perioperative management, the required dosage is determined using the following formulas: Required Dose (IU) = Body Weight (kg) x Desired Factor IX rise (% of normal or IU/dL) x (reciprocal of recovery (IU/kg per IU/dL)). In routine prophylaxis, the recommended dose is 25-40 IU/kg (for patients ≥12 years of age) or 40-55 IU/kg (for patients <12 years of age) every 7 days.
On 25 February 2016, the Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion, recommending the granting of a marketing authorisation for the medicinal product IDELVION, intended for treatment and prophylaxis of bleeding in patients with Haemophilia B. IDELVION was designated as an orphan medicinal producton 04 February 2010. The applicant for this medicinal product is CSL Behring GmbH.
IDELVION will be available as 250 IU, 500 IU, 1000 IU and 2000 IU Powder and solvent for solution for injection. The active substance of IDELVION is albutrepenonacog alfa, an antihaemorrhagic, blood coagulation factor IX, (ATC code: B02BD04). It works as replacement therapy and temporarily increases plasma levels of factor IX, helping to prevent and control bleeding.
The benefits with IDELVION are its ability to stop the bleeding when given on demand and prevent bleeding when used as routine prophylaxis or for surgical procedures. The most common side effects are injection site reaction and headache.
The full indication is: “the treatment and prophylaxis of bleeding in patients with Haemophilia B (congenital factor IX deficiency)”. Idelvion can be used in all age groups. It is proposed that IDELVION be prescribed by physicians experienced in the treatment of haemophilia B.
Detailed recommendations for the use of this product will be described in the summary of product characteristics (SmPC), which will be published in the European public assessment report (EPAR) and made available in all official European Union languages after the marketing authorisation has been granted by the European Commission.
| Name | Idelvion |
|---|---|
| INN or common name | albutrepenonacog alfa |
| Therapeutic area | Hemophilia B |
| Active substance | albutrepenonacog alfa |
| Date opinion adopted | 25/02/2016 |
| Company name | CSL Behring GmbH |
| Status | Positive |
| Application type | Initial authorisation |
//////Albutrepenonacog alfa, CSL-654, Idelvion; Recombinant factor IX – CSL Behring, Recombinant factor IX fusion protein linked with human albumin, rFIX-FP – CSL Behring; rIX-FP, Orphan Drug Status, Haemophilia B, recombinant factor IX , FDA 2016
update
Human medicines European public assessment report (EPAR): Idelvion, albutrepenonacog alfa, Hemophilia B, 11/05/2016,  , 9, Authorised |
The US Food and Drug Administration (FDA) has approved Bayer HealthCare’s Gadavist (gadobutrol) injection as the first magnetic resonance contrast agent for evaluation of breast cancer in the US
GADOBUTROL
gadolinium(III) 2,2′,2”-(10-((2R,3S)-1,3,4-trihydroxybutan-2-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate
Gadobutrol, SH-L-562, Gadovist,138071-82-6
The US Food and Drug Administration (FDA) has approved Bayer HealthCare’s Gadavist (gadobutrol) injection as the first magnetic resonance contrast agent for evaluation of breast cancer in the US.
The agency has approved the new indication for Gadavist injection for intravenous use with magnetic resonance imaging of the breast to assess the presence and extent of malignant breast disease.
Approval is based on priority review of two Phase III studies with identical design (GEMMA-1 and GEMMA-2).
Bayer HealthCare’s Gadavist (gadobutrol)
Bayer’s Gadavist injection cleared for breast cancer evaluation
UPDATE……. Gadoteridol 279.3 mg/ml for injection , CDSCO INDIA 29.07.2021
For intravenous use in magnetic
reasonance imaging (MRI) in adults and
pediatric patients over 2 years of age for
whole body MRI including the head, neck,
liver, breast, musculoskeletal system and
soft tissue pathologies
The US Food and Drug Administration (FDA) has approved Bayer HealthCare’s Gadavist (gadobutrol) injection as the first magnetic resonance contrast agent for evaluation of breast cancer in the US.
GADOBUTROL
| Clinical data | |
|---|---|
| AHFS/Drugs.com | International Drug Names |
| Licence data | US FDA:link |
| Pregnancy cat. | C (US) |
| Legal status | POM (UK) ℞-only (US) |
| Routes | IV |
| Identifiers | |
| CAS number | 138071-82-6  |
| ATC code | V08CA09 |
| PubChem | CID 72057 |
| DrugBank | DB06703 |
| UNII | 1BJ477IO2L |
| KEGG | D07420 |
| Chemical data | |
| Formula | C18H31GdN4O9 |
| Mol. mass | 604.710 g/mol |
………………………..
Gadobutrol (INN) (Gd-DO3A-butrol) is a gadolinium-based MRI contrast agent (GBCA).
It received marketing approval in Canada[1] and in the United States.[2][3][4]
As of 2007, it was the only GBCA approved at 1.0 molar concentrations.[5]
Gadobutrol is marketed by Bayer Schering Pharma as Gadovist, and by Bayer HealthCare Pharmaceuticals as Gadavist.[6]
WORLDCUP FOOTBALL WEEK 2014 BRAZIL
……………………………………………….
http://www.google.com/patents/EP0988294B1?cl=en
-
This type of complexes with metal ions, in particular with paramagnetic metal ions; is used for the preparation of non-ionic contrast agents for the diagnostic technique known as magnetic resonance (MRI, Magnetic Resonance Imaging), among which are ProHance(R) (Gadoteridol, gadolinium complex of 10-(2-hydroxypropyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid), and Gadobutrol (gadolinium complex of [10-[2,3-dihydroxy-1-(hydroxymethyl)propyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid).
-
[0003]Two different synthetic approaches are described in literature for the preparation of this kind of complexes, said approaches differing in the strategy taken to discriminate one of the four nitrogen atoms: the first one (Dischino et al., Inorg. Chem., 1991, 30, 1265 or EP 448191, EP 292689, EP 255471) is based on the selective protection of one of the nitrogen atoms by formation of the compound of formula (III), 5H,9bH-2a,4a,7-tetraazacycloocta[cd]pentalene, and on the subsequent hydrolysis to compound of formula (IV), 1-formyl-1,4,7,10-tetraazacyclododecane, followed by the carboxymethylation of the still free nitrogen atoms and by the deprotection and alkylation of the fourth nitrogen atom, according to scheme 1.
-
[0004]The step from 1,4,7,10-tetraazacyclododecane disulfate (a commercially available product) to compound (III) is effected according to the conventional method disclosed in US 4,085,106, followed by formation of the compound of formula (IV) in water-alcohol medium.
-
[0005]This intermediate is subsequently tricarboxymethylated with tert-butyl bromoacetate (TBBA) in dimethylformamide at 2.5°C and then treated with a toluene-sodium hydroxide diphasic mixture to give the compound of formula (V), 10-formyl-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic, tris(1,1-dimethylethyl) ester, which is subsequently hydrolysed to compound of formula (II) in acidic solution.
-
[0006]In the process described in WO 93/24469 for the synthesis of Gadobutrol, at first one of the nitrogen atoms is alkylated in conditions such as to minimize the formation of polyalkylated derivatives, then the monoalkylderivative is purified and carboxymethylated, according to scheme 2.
-
[0007]The alkylation of 1,4,7,1,0-tetraazacyclododecane with the epoxide of formula (VI), 4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]octane, is carried out in anhydrous n-BuOH under reflux and the reaction mixture is extracted with water, evaporated to dryness and the residue is subsequently diluted with water and extracted with methylene chloride.
-
[0008]The aqueous phase containing the mono-alkylated product (65% yield in Example 7 which reports the procedure for the preparation of 5 kg of Gadobutrol) is directly carboxymethylated at 70°C with chloroacetic acid, keeping pH 9.5 by addition of NaOH. The reaction mixture is adjusted to pH 1, concentrated to dryness and dissolved in methanol to remove the undissolved salts. The filtrate is then concentrated under vacuum, dissolved in water, and loaded onto a cation exchanger in the H+ form to fix the product. The subsequent elution with ammonia displaces the desired product, which is concentrated to small volume and subsequently complexed with gadolinium oxide according to conventional methods, and the resulting complex is purified by means of ion exchange resins. The overall yield is 42%.
-
[0009]Although the first of these two processes could theoretically provide a higher yield, in that all the single steps (protection, carboxymethylation and deprotection) are highly selective, the complexity of the operations required to remove salts and solvents and to purify the reaction intermediates makes such theoretical advantage ineffective: the overall yield is in fact, in the case of Gadoteridol, slightly higher than 37%.
-
[0010]The preparation of Gadobutrol according to the alternative process (WO 93/24469) provides a markedly better yield (72%) only on laboratory scale (example 2): example 7 (represented in the above Scheme 2) actually evidences that, when scaling-up, the yield of this process also remarkably decreases (42%).
-
[0011]In addition to the drawback of an about 40% yield, both processes of the prior art are characterized by troublesome operations, which often involve the handling of solids, the use of remarkable amounts of a number of different solvents, some of them having undesirable toxicological or anyway hazardous characteristics.
-
[0012]Moreover, the synthesis described by Dischino makes use of reagents which are extremely toxic, such as tert-butyl bromoacetate, or harmful and dangerous from the reactivity point of view, such as dimethylformamide dimethylacetal.
-
[0013]An alternative to the use of dimethyl formamide dimethylacetal is suggested by J. Am. Chem. Soc. 102(20), 6365-6369 (1980), which discloses the preparation of orthoamides by means of triethyl orthoformate.
-
[0014]EP 0596 586 discloses a process for the preparation of substituted tetraazacyclododecanes, among them compounds of formula (XII), comprising:
- formation of the tricyclo[5.5.1.0] ring;
- alkylation with an epoxide;
- hydrolysis of the 10-formyl substituent;
- reaction with an acetoxy derivative bearing a leaving group at the alpha-position.
-
[0015]Nevertheless, this method requires quite a laborious procedure in order to isolate the product of step b).
-
[0016]It is the object of the present invention a process for the preparation of the complexes of general formula (XII)
wherein
- R1 and R2
- are independently a hydrogen atom, a (C1-C20) alkyl containing 1 to 10 oxygen atoms, or a phenyl, phenyloxy group, which can be unsubstituted or substituted with a (C1-C5) alkyl or hydroxy, (C1-C5) alkoxy, carbamoyl or carboxylic groups,
- Me3+
- is the trivalent ion of a paramagnetic metal;
comprising the steps represented in the following Scheme 3:
-
The process of the present invention keeps the high selectivity typical of the protection/deprotection strategy described by Dischino in the above mentioned paper, while removing all its drawbacks, thus providing for the first time a reproducible industrial process for the preparation of the concerned compounds in high yields and without use of hazardous substances.
-
[0019]The preparation of the gadolinium complex of 10-(2-hydroxypropyl)-1,4,7,10-tetraazacyclododecane-1,4,7-tri-acetic) acid (Gadoteridol), according to scheme 4, is particularly preferred:
in which the synthetic steps a), b), c), d), e), and f) have the meanings defined above and the epoxide of formula (XI) in step d) is propylene oxide.
-
[0020]The preparation of the gadolinium complex of [10-[2,3-dihydroxy-1-(hydroxymethyl)propyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic) acid (Gadobutrol), according to the scheme 5, is also preferred.
in which the synthetic steps a), b), c), d), e), and f) have the meanings defined above and the epoxide of formula (XI) in step d) corresponds to the one of formula (VI), defined above.
-
[0021]On the other hand, step a) of the process of the present invention involves the use of triethyl orthoformate in the presence of an acid catalyst, instead of dialkylformamide-dialkylacetal.
-
[0022]Triethyl orthoformate can be added in amounts ranging from 105% to 200% on the stoichiometric value.
-
[0023]The reaction temperature can range from 110 to 150°C and the reaction time from 5 to 24 h.
-
[0024]The catalyst is a carboxylic acid having at least 3 carbon atoms, C3-C18, preferably selected from the group consisting of propionic, butyric and pivalic acids.
-
[0025]Triethyl orthoformate is a less toxic and less expensive product than N,N-dimethylformamide-dimethylacetal and does not involve the formation of harmful, not-condensable gaseous by-products. Moreover, triethyl orthoformate is less reactive than N,N-dimethylformamide-dimethylacetal, which makes it possible to carry out the loading procedures of the reactives as well as the reaction itself in utterly safe conditions even on a large scale, allows to better monitor the progress of the reaction on the basis of such operative parameters as time and temperature, without checking the progress by gas chromatography, and makes dosing the reactive less critical, in that it can be added from the very beginning without causing the formation of undesired by-products: all that rendering the process suitable for the production of compound (III) on the industrial scale in easily reproducible conditions.
-
[0026]The subsequent step b) involves the carboxymethylation of compound (III) in aqueous solution, using a haloacetic acid, to give compound (IX), i.e. the 10-formyl-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid salt with an alkali or alkaline-earth metal, the salts of compound (IX) with sodium, potassium or calcium being most preferred.
Example 2
-
[0065]
-
[0066]The procedure of Example 1 is followed until step C included, to obtain a solution of DO3A trisodium salt.
-
[0067]pH is adjusted to 12.3 with conc. HCl and 57.7 kg (0.4 kmol) of 4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]-octane are added. After reaction for 4 h at 40°C and for 8 h at 80°C, the solution is cooled to 50°C, 120 kg of an aqueous solution containing 0.135 kmol of gadolinium trichloride are added. After 1 h the mixture is cooled at 17°C and acidified to pH 1.7 with conc. HCl, keeping this pH for 2 h. The solution is subsequently warmed to 50°C, pH is adjusted to 7 with sodium hydroxide, keeping these conditions for 1 h.
-
[0068]After that, the resulting crude Gadobutrol is purified repeating exactly the same process as in steps E and F of Example 1.
Recovery of the product (Gadobutrol)
-
[0069]The product-rich fraction is then thermally concentrated to a viscous residue and the residue is added with 350 kg of ethanol at 79°C.
-
[0070]The resulting suspension is refluxed for 1 h, then cooled, centrifuged and dried under reduced pressure to obtain 66.0 kg of Gadobutrol (0.109 kmol), HPLC assay 99.5% (A%).
Overall yield: 79.1% -
[0071]The IR and MS spectra are consistent with the indicated structure.
References
- Cheng, KT (2007). “Gadobutrol”. Molecular Imaging and Contrast Agent Database (MICAD) (Bethesda, MD: National Center for Biotechnology Information (NCBI)). PMID 20641787. NBK23589.
- http://bayerimaging.com/products/gadavist/index.php
- “FDA approves imaging agent for central nervous system scans” (Press release). U.S. Food and Drug Administration (FDA). March 15, 2011. Retrieved March 31, 2011.
- “U.S. FDA Approves Bayer’s Gadavist (Gadobutrol) Injection for MRI of the Central Nervous System” (Press release). Bayer HealthCare Pharmaceuticals. March 14, 2011. Retrieved March 31, 2011.
- “Gadobutrol 1.0-molar in Cardiac Magnetic Resonance Imaging (MRI) – Further Enhancing the Capabilities of Contrast-enhanced MRI in Ischaemic and Non-ischaemic Heart Disease?”
- “Gadavist full prescribing information”. Retrieved 2011-03-14.
Fexinidazole Hoe-239
Fexinidazole, Hoe-239
1-Methyl-2-{[4-(methylsulfanyl)phenoxy]methyl}-5-nitro-1H-imidazole
| cas59729-37-2 |
| Molecular formula | C12H13N3O3S |
| Molar mass | 279.31 g mol−1 |
Sanofi (Originator)
University of Dundee
Drugs for Neglected Diseases Initiative
Winkelmann, E.; Raether, W.
Chemotherapeutically active nitro compounds. 4,5-nitroimidazoles. Part III
Arzneim-Forsch Drug Res 1978, 28(5): 739
US 4042705, DE 2531303,
UPDATE 7/16/2021 FDA APPROVES
To treat human African trypanosomiasis caused by the parasite Trypanosoma brucei gambiense
600 MG TABLET ORAL, DRUGS FOR NEGLECTED DISEASES INITIATIVE
US FDA approves fexinidazole as the first all-oral treatment for sleeping sickness
POSTED ON JULY 19
The US Food and Drug Administration (FDA) has approved fexinidazole as the first all-oral treatment for both stages of the Trypanosoma brucei gambiense form of sleeping sickness (Human African trypanosomiasis) in patients 6 years of age and older and weighing at least 20 kg.
Fexinidazole was developed as part of an innovative partnership between the non-profit research and development organization Drugs for Neglected Diseases initiative (DNDi), which conducted the pivotal clinical trials for this treatment, in partnership with the National Sleeping Sickness Programs of the Democratic Republic of Congo (DRC) and Central African Republic (CAR), and Sanofi.
Sleeping sickness is a parasitic disease transmitted by the bite of an infected tse-tse fly. It affects mostly populations living in remote rural areas of sub-Saharan Africa, where about 65 million people are at risk of infection. Left untreated, sleeping sickness is almost always fatal. Through Sanofi’s collaboration the number of sleeping sickness cases reported to the WHO has been reduced by ~97% between 2001 and 2020. DNDi, Sanofi and partners are deeply committed to ensuring access to fexinidazole in all sleeping sickness-endemic countries.
Current treatment options for the disease are effective, but burdensome for patients and health workers due to the need for infusion or injection, requiring hospitalization, especially challenging for people living in remote areas.
“Having a simple, all-oral treatment for sleeping sickness is a dream come true for frontline clinicians,” said Dr Bernard Pécoul, DNDi Executive Director. “We are proud of this latest milestone in our long-term partnership with Sanofi, developed in close collaboration with researchers in countries hard-hit by sleeping sickness.”
Fexinidazole is indicated as a 10-day once-a-day treatment for Trypanosoma brucei gambiense sleeping sickness, the most common form of the disease found in West and Central Africa. Fexinidazole is the first all-oral treatment that works both for the first stage of the disease, as well as the second stage of the disease in which the parasites have crossed the blood-brain barrier, causing patients to suffer from neuropsychiatric symptoms.
“This FDA approval is a key milestone in Sanofi’s long-term commitment to fight sleeping sickness, started 20 years ago alongside the WHO through an ambitious partnership to combat Neglected Tropical Diseases” said Luc Kuykens, Senior Vice President, Sanofi Global Health unit. “Following the positive scientific opinion granted by the European Medicines Agency end 2018, the FDA approval is an important step to revitalize efforts to support the sustainable elimination of the disease”.
As a result of FDA approval, a Tropical Disease Priority Review Voucher (PRV) has been awarded to DNDi. The FDA Tropical Disease PRV Program was established in 2007 to incentivize development of new treatments for neglected tropical diseases, including sleeping sickness. Any benefits from the PRV will be shared between Sanofi and DNDi, which will enable continued investments in innovating for and ensuring access to new health tools for sleeping sickness and other neglected diseases. Sanofi commits to continue to provide the drug free-of-charge to the World Health Organization for distribution to affected countries, as part of a long-term collaboration with WHO.
About Sleeping sickness
Sleeping sickness, or human African trypanosomiasis (HAT), is usually fatal without treatment. Transmitted by the bite of an infected tse-tse fly, following a period with nonspecific symptoms, it evolves to cause neuropsychiatric symptoms, including abnormal behaviour, and a debilitating disruption of sleep patterns that have given this neglected disease its name. About 65 million people in sub-Saharan Africa are at moderate to very high risk of infection.
About DNDi
The Drugs for Neglected Diseases initiative (DNDi) is a collaborative, patient needs-driven, not-for-profit research and development (R&D) organization that develops safe, effective, and affordable treatments for sleeping sickness, leishmaniasis, Chagas disease, filarial infections, mycetoma, paediatric HIV, hepatitis C, and covid-19. Since its inception in 2003, DNDi has delivered eight new treatments, including nifurtimox-eflornithine combination therapy (NECT) for late-stage sleeping sickness, and fexinidazole, the first all-oral drug for sleeping sickness.
Fexinidazole is an antiparasitic agent.[1] It has activity against Trypanosoma cruzi, Tritrichomonas foetus, Trichomonas vaginalis,Entamoeba histolytica,[1] Trypanosoma brucei,[2] and Leishmania donovani.[3] The biologically relevant active metabolites in vivo are the sulfoxide and sulfone [3][4]
Fexinidazole was discovered by the German pharmaceutical company Hoechst AG, but its development as a pharmaceutical was halted in the 1980s.[5] Fexinidazole is now being studied through a collaboration between Sanofi and the Drugs for Neglected Diseases Initiative for the treatment of Chagas disease and human African trypanosomiasis (sleeping sickness).[6][7] Fexinidazole is the first drug candidate for the treatment of advanced-stage sleeping sickness in thirty years.[8]
Fexinidazole is currently in phase II/III clinical development at Drugs for Neglected Diseases Initiative for the oral treatment of African trypanosomiasis (sleeping sickness). In May 2009, Sanofi (formerly known as sanofi-aventis) licensed the drug candidate to Drugs for Neglected Diseases Initiative for the development, manufacturing and distribution as a treatment of human African trypanosomiasis. Once approved, the companies plan to make the drug available on a nonprofit basis.
Fexinidazole was originally developed by a German pharmaceutical company called Hoechst, now part of Sanofi; however, its development was abandoned in the 1980s when the company gave up its tropical disease programs. Fexinidazole is one of a class of drugs known as azoles, like fluconazole, that work against fungi and may work against cancer.
-
Onset of trypanosomiasis is caused by Trypanosoma protozoa and it is said that every year 200,000 to 300,000 of new patients of African sleeping sickness fall sick. At present the number of patients of African sleeping sickness cannot be confirmed due to the low reliability of the investigative data. According to the WHO, at least 150,000 people died of African sleeping sickness in 1996 and it is said that its aftereffect remains in not less than 100,000 people. Beyond that, enormous is the damage to domestic animals caused by a disease called as nagana, and several hundred thousands of cattle which are to be protein sources for people die every year. Further, in the area of about 10,000,000 km2of savanna equal to the United States of America, cattle-breeding is impossible due to Trypanosoma. Thus, African sleeping sickness remarkably damages the health and the economical development of African people, and this is the reason why the WHO adopts the trypanosomiasis as one of the infectious diseases that should be controlled.
-
African sleeping sickness is a protozoal infectious disease by Trypanosoma transmitted through tsetse flies and the protozoa appear in the blood stream in about 10 days after infection. In the initial period of infection the protozoa multiply in the blood stream and give fever, physical weakness, headache, a pain of muscles and joints and a feeling of itching to proceed. On entering the chromic period, the central nerve is affected to show symptoms such as mental confusion and systemic convulsion, and finally the patients lapse into lethargy and are led to death.
-
The trypanosomiasis of domestic animals has Trypanosoma brucei brucei, Trypanosoma evansi, Trypanosoma congolense and Trypanosoma vivax as pathogens and is a communicable disease which affects domestic animals such as horses, cattle, pigs and dogs and, in addition, mice, guinea pigs, rabbits and the like. Particularly, the loss of cattle and horses is greatest and almost fetal, and they are led to anemia, edema, weakening and the like and fall dead in one month after infection.
-
In treating trypanosomiasis, pentamidine, melarsoprol, eflornithine and the like are used and there was a feeling in the 1960s that its eradication might be possible. However, these drugs are old and are gradually losing their efficacy. Particularly, the resistance to melarsoprol of an arsenic agent causes a big problem and the situation is so dire that patients with no efficacy only await death and the development of novel antitrypanosoma agents are strongly desired.
-
Trypanosoma mainly lives in the blood stream of the human body. This bloodstream energy metabolism depends on the glycolytic pathway localized in the organelle characteristic of the protozoa which is called as glycosome and the so-called oxidative phosphorylation does not function. However, in order to efficiently drive this glycolytic pathway, the produced NADH has to be reoxidized, and the glycerol-3-phosphate oxidation system of mitochondria plays an important role in this reoxidation. The terminal oxidase of this oxidation system functions as a quinol oxidase having a reduced ubiquinone as an electron donor and has properties greatly different from those of cytochrome oxidase of an aerobic respiration system which the host has. Particularly, a remarkable point is that the terminal oxidase of the oxidation system is non-sensitive to the cyanide which quickly inhibits the cytochrome oxidase of the host. Then, many researchers centered around Western countries have tried to develop drugs targeting this cyanide resistant oxidase but effective drugs having a selective toxicity have not been obtained.
-
Under these circumstances the present inventors et al. found that isoprenoid based physiologically active substances of ascochlorin, ascofuranone and derivatives thereof, particularly ascofuranone specifically inhibits the glycerol-3-phosphate oxidation system of trypanosome at a very low concentration of the order of nM and filed a patent application (Japanese Patent Publication A No. : H09-165332). They also clarified that acofuranone exhibits a very strong multiplication inhibition effect in the copresence of glycerin (Molecular and Biochemical Parasitology, 81: 127-136, 1996).
In consideration of practical use of ascofuranone, it was found essential to discover agents which replace glycerin and exhibit an effect of the combined use in a small amount, and by using an alkaloid compound having an indole skeleton existing in a plant of the family Simaroubaceae together with ascofuranone, the prolongation of life and recovery effect in African seeping sickness was found and a patent application was filed (Japanese Patent Application No.: 2003-24643, Japanese Patent Publication A No.: 2004-23601).
Method for the preparation of fexinidazole, useful for the treatment of parasitic diseases, visceral leishmaniasis, chagas disease and human African trypanosomiasis. Family members of the product patent, WO2005037759, are expected to expire from October 2024. This to be the first application from Drugs for Neglected Diseases Initiative (DNDi) on this API. DNDi in collaboration with Sanofi, the Swiss Tropical & Public Health Institute and the University of Dundee, is developing fexinidazole, an antiparasitic agent, for treating human African trypanosomiasis (HAT) and visceral Leishmaniasis (VL). By June 2013, phase I clinical studies had been completed and at that time, DNDi was planning to initiate a phase II proof-of-concept study in VL patients in early 2013.
fexinidazole[inn], 59729-37-2, 1-Methyl-2-((4-(methylthio)phenoxy)methyl)-5-nitro-1H-imidazole, Fexinidazol, Fexinidazolum
………………..
http://www.google.com/patents/EP1681280A1?cl=en
…………..
US 4042705
http://www.google.co.in/patents/US4042705
…………
new patent june 2014
WO-2014079497
Process for preparing fexinidazole – comprising the reaction of 1-methyl-2-hydroxymethyl-5-nitro-imidazole with methanesulfonyl chloride, followed by reaction with 4-methylmercapto-phenol, and further manipulative steps.
1-Methyl-2-hydroxymethyl-5-nitro-imidazole is (I) and 1-methyl-2-(4-methylmercapto-phenyloxymethyl)-5-nitro-imidazole (fexinidazole) is (II) (claim 1, page 12).
The synthesis of (II) via intermediate (I) is described (example 1, pages 6-8).
A process for preparing fexinidazole comprising the reaction of 1-methyl-2-hydroxymethyl-5-nitro-imidazole with methanesulfonyl chloride in the presence of a suspension of powdered alkaline carbonate (eg potassium carbonate) in an anhydrous organic solvent (eg acetone), followed by reaction with 4-methylmercapto-phenol, removal of hydrochloride salt, and isolation and purification is claimed. Also claimed is their use for treating parasitic diseases, visceral leishmaniasis, chagas disease, and human African trypanosomiasis. Fexinidazole is known to be an antiparasitic agent.
|
2-1-1983
|
The activity of fexinidazole (HOE 239) against experimental infections with Trypanosoma cruzi, trichomonads and Entamoeba histolytica.
|
Annals of tropical medicine and parasitology
|
|
|
1-1-1983
|
The use of the 2 substituted 5-nitroimidazole, Fexinidazole (Hoe 239) in the treatment of chronic T. brucei infections in mice.
|
Zeitschrift für Parasitenkunde (Berlin, Germany)
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5-1-2011
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1-Aryl-4-nitro-1H-imidazoles, a new promising series for the treatment of human African trypanosomiasis.
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European journal of medicinal chemistry
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2-1-2011
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Compounds containing 2-substituted imidazole ring for treatment against human African trypanosomiasis.
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Bioorganic & medicinal chemistry letters
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1-1-2011
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Trypanocidal activity of nitroaromatic prodrugs: current treatments and future perspectives.
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Current topics in medicinal chemistry
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12-1-2010
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Potential new drugs for human African trypanosomiasis: some progress at last.
|
Current opinion in infectious diseases
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|
|
7-1-2010
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Cross-resistance to nitro drugs and implications for treatment of human African trypanosomiasis.
|
Antimicrobial agents and chemotherapy
|
|
|
1-1-2010
|
Fexinidazole–a new oral nitroimidazole drug candidate entering clinical development for the treatment of sleeping sickness.
|
PLoS neglected tropical diseases
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1-1-1999
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[Use of megazol for the treatment of trypanosomiasis].
|
Médecine tropicale : revue du Corps de santé colonial
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11-1-1998
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A method to assess invasion and intracellular replication of Trypanosoma cruzi based on differential uracil incorporation.
|
Journal of immunological methods
|
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|
10-1-1996
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Topical chemotherapy for experimental murine African CNS-trypanosomiasis: the successful use of the arsenical, melarsoprol, combined with the 5-nitroimidazoles, fexinidazole or MK-436.
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Tropical medicine & international health : TM & IH
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|
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6-1-1991
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Chemotherapy of CNS-trypanosomiasis: the combined use of the arsenicals and nitro-compounds.
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|
11-15-2013
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Targeting the human parasite Leishmania donovani: discovery of a new promising anti-infectious pharmacophore in 3-nitroimidazo[1,2-a]pyridine series.
|
Bioorganic & medicinal chemistry
|
|
|
10-1-2013
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The R enantiomer of the antitubercular drug PA-824 as a potential oral treatment for visceral Leishmaniasis.
|
Antimicrobial agents and chemotherapy
|
|
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2-1-2013
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Assessing the essentiality of Leishmania donovani nitroreductase and its role in nitro drug activation.
|
Antimicrobial agents and chemotherapy
|
|
|
9-1-2012
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Genotoxicity profile of fexinidazole–a drug candidate in clinical development for human African trypanomiasis (sleeping sickness).
|
Mutagenesis
|
|
|
7-15-2012
|
Discovery of nitroheterocycles active against African trypanosomes. In vitro screening and preliminary SAR studies.
|
Bioorganic & medicinal chemistry letters
|
|
|
2-1-2012
|
The anti-trypanosome drug fexinidazole shows potential for treating visceral leishmaniasis.
|
Science translational medicine
|
|
|
1-1-2012
|
Fexinidazole: a potential new drug candidate for Chagas disease.
|
PLoS neglected tropical diseases
|
|
|
1-1-2012
|
Management of trypanosomiasis and leishmaniasis.
|
British medical bulletin
|
|
|
12-1-2011
|
Antitrypanosomal activity of fexinidazole, a new oral nitroimidazole drug candidate for treatment of sleeping sickness.
|
Antimicrobial agents and chemotherapy
|
|
|
6-1-2011
|
Development of novel drugs for human African trypanosomiasis.
|
Future microbiology
|
| US3682951 * | 2 Nov 1970 | 8 Aug 1972 | Searle & Co | 1-{8 {62 -(1-adamantyloxy)halophenethyl{9 {0 imidazoles and congeners |
| US3714179 * | 8 Sep 1970 | 30 Jan 1973 | Searle & Co | 1-alkyl-2-furfurylthioimidazoles and congeners |
| US3796704 * | 16 Aug 1971 | 12 Mar 1974 | Bayer Ag | Phenyl-imidazolylalkanyl derivatives |
| US3828065 * | 11 Dec 1972 | 6 Aug 1974 | Searle & Co | 2-methyl-5-nitro-1-(2-phenylthioethyl)imidazoles |
| US3842097 * | 22 Jan 1973 | 15 Oct 1974 | Searle & Co | 2-(phenoxyalkylthio)imidazoles and congeners |
| US3910925 * | 24 May 1974 | 7 Oct 1975 | Searle & Co | {8 2-(2-Methyl-5-nitro-1-imidazolyl)ethyl{9 benzo(b)pyridyloxy ethers |
| US3922277 * | 14 Nov 1974 | 25 Nov 1975 | Hoechst Ag | (1-Alkyl-5-nitro-imidazolyl-2-alkyl)-pyridyl compounds |
| DE2124103A1 * | 14 May 1971 | 25 Nov 1971 | Title not available |
References
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- Jennings, FW; Urquhart, GM (1983). “The use of the 2 substituted 5-nitroimidazole, Fexinidazole (Hoe 239) in the treatment of chronic T. brucei infections in mice”. Zeitschrift für Parasitenkunde 69 (5): 577–581. doi:10.1007/bf00926669. PMID 6636983.
- Wyllie, S; Patterson, S; Stojanovski, FRC; Norval, S; Kime, R; Read, RD; Fairlamb, AH (2012). “The anti-trypanosome drug fexinidazole shows potential for treating visceral leishmaniasis”. Science Translational Medicine 4 (119): 119re1.doi:10.1126/scitranslmed.3003326. PMC 3457684. PMID 22301556.
- Sokolova, AY; Wyllie, S; Patterson, S; Oza, SL; Read, RD; Fairlamb, AH (2010). “Cross-resistance to nitro drugs and implications for treatment of human African trypanosomiasis”. Antimicrobial Agents and Chemotherapy 54 (7): 2893–900. doi:10.1128/AAC.00332-10.PMID 20439607.
- “Jump-Start on Slow Trek to Treatment for a Disease”. New York Times. January 8, 2008.
- “Fexinidazole Progresses into Clinical Development”. DNDi Newsletter. November 2009.
- “Sanofi-aventis and DNDi enter into a Collaboration Agreement on a New Drug for Sleeping Sickness, Fexinidazole”. DNDi. May 18, 2009.
- Torreele, E; Bourdin Trunz, B; Tweats, D; Kaiser, M; Brun, R; Mazué, G; Bray, MA; Pécoul, B (2010). “Fexinidazole–a new oral nitroimidazole drug candidate entering clinical development for the treatment of sleeping sickness”. In Boelaert, Marleen. PLOS Neglected Tropical Diseases 4 (12): e923. doi:10.1371/journal.pntd.0000923. PMC 3006138. PMID 21200426.
New Drug Approvals 