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Phase I
| C16H12ClNaO4S | |
| Molecular Weight: | 358.771849 g/mol |
|---|
A protein kinase inhibitor potentially for the treatment of acute radiation syndrome.
sodium;4-[(E)-2-[(4-chlorophenyl)methylsulfonyl]ethenyl]benzoate
Onc-01210; ON-01210.Na, Ex-RAD; ON 01210.Na; ON-01210; ON-01210-Na; Recilisib
CAS No. 334969-03-8(free)
CAS 922139-31-9(Recilisib sodium)
Benzoic acid, 4-[(1E)-2-[[(4-chlorophenyl)methyl]sulfonyl]ethenyl]-, sodium salt (1:1)
Onconova Therapeutics Inc, Univ Temple INNOVATOR
Stephen C Cosenza, Lawrence Helson,Premkumar E Reddy, Ramana M V Reddy INVENTORS
| Latest Stage of Development | Phase I |
| Standard Indication | Poisoning |
| Indication Details | Prevent radiation poisoning; Provide radation protection; Treat and prevent acute radiation syndrome (ARS) |
Ex-Rad (or Ex-RAD), also known by the code name ON 01210.Na, or recilisib sodium (INN, USAN) is a drug developed by Onconova Therapeutics and the U.S. Department of Defense.[1][2] This newly developed compound is said to be a potent radiation protection agent. Chemically, it is the sodium salt of 4-carboxystyryl-4-chlorobenzylsulfone.[3]
The results of two Phase I clinical studies in healthy human volunteers indicate that subcutaneously injected Ex-Rad is safe and well tolerated, with “no evidence of systemic side effects”.[4] A study in mice demonstrated the efficacy of Ex-Rad by increasing the survival rate of mice exposed to typically lethal whole-body irradiation. The study tested oral and parenteral administration of Ex-Rad for both pre- and post-exposure radiomitigation.[1]
Research on Ex-Rad has involved collaboration with the Armed Forces Radiobiology Research Institute (AFRRI), the Department of Biochemistry and Molecular & Cellular Biology at Georgetown University, Long Island University‘s Arnold & Marie Schwartz College of Pharmacy, and the Department of Oncological Sciences at the Mt. Sinai School of Medicine.[1]
Onconova suggests that Ex-Rad protects cells exposed to radiation against DNA damage, and that the drug’s mechanism of action does not involve scavenging free radicals or arresting the cell cycle. Instead, they claim it employs a “novel mechanism” involving “intracellular signaling, damage sensing, and DNA repair pathways”.[4] Ex-RAD is a chlorobenzylsulfone derivative that works after free radicals have damaged DNA. Onconova CEO Ramesh Kumar believes this is a better approach than trying to scavenge free radicals. “Free radicals are very short-lived, and so the window of opportunity to give a drug is very narrow,” he says. In cell and animal models, Ex-RAD protects hematopoieticand gastrointestinal tissues from radiation injury when given either before or after exposure.[5]
While anti-radiation suits or other protective gear may be effective at reducing radiation exposure, such gear is expensive, unwieldy, and generally not available to public. Moreover, radioprotective gear will not protect normal tissue adjacent to a tumor from stray radiation exposure during radiotherapy. Pharmaceutical radioprotectants offer a cost-efficient, effective and easily available alternative to radioprotective gear. However, previous attempts at radioprotection of normal cells with pharmaceutical compositions have not been entirely successful. For example, cytokines directed at mobilizing the peripheral blood progenitor cells confer a myeloprotective effect when given prior to radiation (Neta et al., Semin. Radiat. Oncol. 6:306-320, 1996), but do not confer systemic protection. Other chemical radioprotectors administered alone or in combination with biologic response modifiers have shown minor protective effects in mice, but application of these compounds to large mammals was less successful, and it was questioned whether chemical radioprotection was of any value (Maisin, J. R., Bacq and Alexander Award Lecture. “Chemical radioprotection: past, present, and future prospects”, Int J. Radiat Biol. 73:443-50, 1998). Pharmaceutical radiation sensitizers, which are known to preferentially enhance the effects of radiation in cancerous tissues, are clearly unsuited for the general systemic protection of normal tissues from exposure to ionizing radiation.
The major biological effects of radiation exposure are the destruction of bone marrow cells, gastrointestinal (GI) damage, lung pneumonitis, and central nervous system (CNS) damage. The long-term effects of radiation exposure include an increase in cancer rates. It has been estimated that the exposure of 100 rems (roentgen equivalent man: a measurement used to quantify the amount of radiation that would produce harmful biological effects) would produce ARS symptoms. Exposure levels above 300 rems would result in the death of approximately 50% of the exposed population.
The α,β-unsaturated aryl sulfones, in particular benzyl styryl sulfones, provide significant and selective systemic protection of normal cells from radiation-induced damage in animals. When used in radiotherapy techniques, these compounds also exhibit independent toxicity to cancer cells. These α,β-unsaturated aryl sulfones, in particular benzyl styryl sulfones, are described in U.S. Pat. Nos. 6,656,973 and 6,667,346, which are particularly incorporated herein by reference in their entirety. Although these compounds are stable in solid state their aqueous formulations for parenteral administration are pH sensitive and pose challenging hurdles to overcome physical stability. The most likely causative factor may be attributed to the reactive styryl sulfone conjugated double bond, which is prone to Michael addition by nucleophiles and eventual fallout of the conjugated addition product.
U.S. Patent No. 6,656,973, describes in vitro pharmacological effects of DMSO solubilization of a benzyl styryl sulfone (e.g. ON 01210.NA) but fails to disclose a composition comprising ON 01210. NA formulation and specifically, a shelf stable formulation which is suitable for administration to humans.
PCT Application WO 2007/016201 describes pharmaceutical solution compositions for parenteral administration for reducing toxic effects of ionizing radiation in a subject, comprising an effective amount of at least one radioprotective α,β-Unsaturated aryl sulfone, and at least one component selected from the group consisting of a) a water soluble polymer in an amount between about 0.5% and about 90% w/v, b) at least one chemically modified cyclodextrin in an amount between about 20% and about 60% w/v, and c) DMA in an amount between 10% and about 50% w/v.
U.S. Patent Application 20090247624, and corresponding PCT Application WO 2008/105808, are directed to aqueous solutions, which comprise between about 20 mg/ml to about 100 mg/ml of at least one α,β-unsaturated aryl sulfone (e.g., the compound ON 01210. Na ((E)-4-Carboxystyryl-4-chlorobenzylsulfone sodium salt, a cosolvent in an amount between about 25% and about 90% w/v (e.g., about 50% PEG 400), wherein the composition is buffered and exists within the range of about pH 7.0 to about pHIO (e.g., 0.2M Tris-EDTA, pH about 8.5). The aforementioned solution formulations have exhibited a sub-optimal shelf life and lack a preferred degree of solubility and/or stability. These formulations evolved progressively as a result of addressing the most challenging aspects in the formulation and drug development field, namely, solubility and stability parameters that defined the long term viability of these formulations. There seems to be a delicate balance between pH, solubility and stability of the active moiety in aqueous milieu, wherein achieving such balance and development of a shelf stable aqueous formulation has presented a formidable challenge. Therefore, a shelf stable effective solution formulation that prevents the breakdown of the therapeutically active entity and keeps the drug in the solution at the desired pH was most desired and significant effort was directed towards this goal.
What is needed therefore, is a shelf stable effective solution formulation of radioprotective α,β-unsaturated aryl sulfones that prevents the breakdown of the therapeutically active entity and keeps the drug in the solution at the desired pH. This invention solves these and other long felt needs by providing improved solution formulation of radioprotective α,β- unsaturated aryl sulfones having improved physical and chemical stability and enhanced shelf life.
WO 2011119863
An exemplary species of a radioprotective α,β-unsaturated aryl sulfone is ON 01210.Na. ON 01210.Na is a derivative of chlorobenzylsulfone. This compound is described in U.S. Pat. Nos. 6,656,973 and 6,667,346 as exhibiting valuable prophylactic properties which mitigate the effects of accidental and intentional exposure to life-threatening levels of irradiation. Hence, a systematic development of this compound is described with the objective of developing a shelf stable formulation.
Table 1 describes the general physical properties of ON. 1210. Na. The exemplary compound is a sodium salt of (E)-4-Carboxystyryl-4-chlorobenzylsulfone.
TABLE 1
Physical Properties of ON.1210.Na
Chemical Structure
Chemical Name (E)-4-Carboxystyryl-4-chlorobenzylsulfone,
Sodium Salt
Empirical Formula C16H12ClNa04S
Molecular Weight 358.79
Physical Nature White crystalline flakes
Melting Point 354-356° C.
Solubility Soluble in water at 8-10 mg/ml
The compound ON 01210. Na appears to form at least one polymorph. X-ray diffraction pattern, for example, of precipitated ON 01210. Na is different from that of the originally synthesized compound. Polymorphs of ON 01210.Na are intended to be within the scope of the claims appended hereto.
EXAMPLE 1
Preparation of ON 01210. Na
4-Chlorobenzyl-4-carboxystyryl sulfone (ON 01210) (49 g; 0.145 mol) was taken in a one-liter conical flask and 500 ml of distilled water was added. Sodium hydroxide solution (16 ml: 10 M stock) (0.150 mol.) was added to the conical flask. The contents of the flask were then boiled with stirring till ON 01210 was completely dissolved. The solution was then cooled to room temperature and shining crystals separated were filtered through a fluted filter paper. The crystalline material was dried under vacuum to yield (48 g) (92% yield) of pure ON 1210. Na.
EXAMPLE II
Preparation of ON 01210. Na Formulation A (Without Vitamin E TPGS)
TRIS (968.0 mg), EDTA (233.8 mg), and deionized (DI) water (24 ml) were combined in a beaker equipped with a Teflon coated stirring bar. The mixture was stirred until complete dissolution occurred, and the resulting solution was covered with aluminum foil and allowed to stir gently overnight at room temperature. The following morning, PEG 400 NF (40.0 ml) was added to the TRIS/EDTA aqueous solution with continued stirring. The vessel containing PEG 400 NF was rinsed with DI water (2 x 3.2 ml), and the rinsate added to the formulation mixture. After stirring the mixture to homogeneity (approx. 10 minutes), the pH was measured to be 9.46 using a calibrated electronic pH meter. The pH was adjusted to 8.37 (target pH = 8.40) by the careful addition of 98 pipet drops of 1.0 M HCl (aq) with stirring and allowed to fully equilibrate over a 10-15 minute period. Once the pH steadied at 8.37, ON 01210. Na (4.0 g) was added to the stirring formulation mixture. Complete dissolution required vigorous stirring and brief periodic sonication to break up ON 01210.Na clumps over a two hour period. After complete dissolution of ON 01210. Na, DI water (approx. 5 ml) was added to bring the final volume to approximately 80 milliliters. The pH of the resulting solution was determined to be 8.31, and thus 20 pipet drops of 1.0N NaOH(aq) were added to adjust the final formulation batch (defined as ON 01210.Na Formulation A) pH to 8.41-8.42. Formulation A was 0.22 micron filtered using a 100 ml Gastight Syringe equipped with a Millex®GP filter unit (Millipore Express® PES Membrane; Lot No R8KN13888).
PATENT
PATENT
The α,β unsaturated aryl sulfones are characterized by cis-trans isomerism resulting from the presence of one or more double bonds. The compounds are named according to the Cahn-Ingold-Prelog system, the IUPAC 1974 Recommendations, Section E: Stereochemistry, in Nomenclature of Organic Chemistry, John Wiley & Sons, Inc., New York, NY, 4th ed., 1992, p.
127-138. Stearic relations around a double bond are designated as “Z” or “E”.
(E)-α,β unsaturated aryl sulfones may be prepared by Knoevenagel condensation of aromatic aldehydes with benzylsulfonyl acetic acids or arylsulfonyl acetic acids. The procedure is described by Reddy et al, Ada. Chim. Hung. 115:269-71 (1984); Reddy et al, Sulfur Letters 13:83-90 (1991); Reddy et al, Synthesis No. 4, 322-23 (1984); and Reddy et al, Sulfur Letters 7:43-48 (1987), the entire disclosures of which are incorporated herein by reference.
According to the Scheme 1 below, Ra and Rb each represent from zero to five substituents on the depicted aromatic nucleus. For purposes of illustration, and not limitation, the aryl groups are represented as phenyl groups, that is, the synthesis is exemplified by the preparation of styryl benzylsulfones. Accordingly, the benzyl thioacetic acid B is formed by the reaction of sodium thioglycollate and a benzyl chloride A. The benzyl thioacetic acid B is then oxidized with 30% hydrogen peroxide to give a corresponding benzylsulfonyl acetic acid C. Condensation of the benzylsulfonyl acetic acid C with an aromatic aldehyde D via a Knoevenagel reaction in the presence of benzylamine and glacial acetic acid yields the desired (E)-styryl benzylsulfone E.
Scheme 1
The following is a more detailed two-part synthesis procedure for preparing (E)-styryl benzylsulfones according to the above scheme.
General Procedure 1: Synthesis (E)-Styryl Benzylsulfones
Part A. To a solution of (8g, 0.2 mol) sodium hydroxide in methanol (200 ml), thioglycollic acid (0.1 mol) is added slowly and the precipitate formed is dissolved by stirring the contents of the flask. Then an appropriately substituted benzyl chloride (0.1 mol) is added stepwise and the reaction mixture is refluxed for 2-3 hours. The cooled contents are poured onto crushed ice and neutralized with dilute hydrochloric acid (200 ml). The resulting corresponding benzylthioacetic acid (0.1 mol) is subjected to oxidation with 30% hydrogen peroxide (0.12 mol) in glacial acetic acid (125 ml) by refluxing for 1 hour. The contents are cooled and poured onto crushed ice. The separated solid is recrystalized from hot water to give the corresponding pure benzylsulfonylacetic acid.
Part B. A mixture of the benzylsulfonyl acetic acid (10 mmol), an appropriately substituted aromatic aldehyde (10 mmol), and benzylamine (0.2 ml) in glacial acetic acid (12 ml) is refluxed for 2-3 hours. The contents are cooled and treated with cold ether (50 ml). Any product precipitated out is separated by filtration. The filtrate is diluted with more ether and washed successively with a saturated solution of sodium bicarbonate (20 ml), sodium bisulfite (20 ml), dilute hydrochloric acid (20 ml) and finally with water (35 ml). Evaporation of the dried ethereal layer yields styryl benzylsulfones as a solid material.
According to an alternative to Part A, the appropriate benzylsulfonylacetic acids may be generated by substituting a thioglycollate
HSCH2COOR for thioglycollic acid, where R is an alkyl group, typically C1-C6 alkyl. This leads to the formation of the alkylbenzylthioacetate intermediate (F),
which is then converted to the corresponding benzyl thioacetic acid B by alkaline or acid hydrolysis.
(E)-styryl phenyl sulfones (formula I: n=zero; Qls Q2 = substituted or unsubstituted phenyl) are prepared according to the method of General Procedure 1, replacing the benzylsulfonyl acetic acid in Part B with the appropriate substituted or unsubstituted phenylsulfonyl acetic acid.
(Z)-Styryl benzylsulfones are prepared by the nucleophilic addition of the appropriate thiols to substituted phenylacetylene with subsequent oxidation of the resulting sulfide by hydrogen peroxide to yield the (Z)-styryl benzylsulfone. The procedure is generally described by Reddy et al., Sulfur Letters 13:83-90 (1991), the entire disclosure of which is incorporated herein as a reference.
In the first step of the (Z)-styryl benzylsulfones synthesis, the sodium salt of benzyl mercaptan or the appropriate substituted benzyl mercaptan is allowed to react with phenylacetylene or the appropriate substituted phenylacetylene forming the pure (Z)-isomer of the corresponding styryl benzylsulfide in good yield.
In the second step of the synthesis, the (Z)-styryl benzylsulfide intermediate is oxidized to the corresponding sulfone in the pure (Z)-isomeric form by treatment with hydrogen peroxide.
The following is a more detailed two-part synthesis procedure for preparing (Z)-styryl benzylsulfones:
Procedure 2: Synthesis of (Z)-Styryl Benzylsulfones
Part A. To a refluxing methanolic solution of substituted or unsubstituted sodium benzylthiolate prepared from 460 mg (0.02g atom) of (i) sodium, (ii) substituted or unsubstituted benzyl mercaptan (0.02 mol) and (iii) 80 ml of absolute methanol, is added freshly distilled substituted or unsubstituted phenylacetylene. The mixture is refluxed for 20 hours, cooled and then poured on crushed ice. The crude product is filtered, dried and recrystalized from methanol or aqueous methanol to yield a pure (Z)- styryl benzylsulfide.
Part B. An ice cold solution of the (Z)- styryl benzylsulfide (3.0g) in 30 ml of glacial acetic acid is treated with 7.5 ml of 30% hydrogen peroxide. The reaction mixture is refluxed for 1 hour and then poured on crushed ice. The separated solid is filtered, dried, and recrystalized from 2-propanol to yield the pure (Z)-styryl benzylsulfone. The purity of the compounds is ascertained by thin layer chromatography and geometrical configuration is assigned by analysis of infrared and nuclear magnetic resonance spectral data.
The bis(styryl) sulfones of formula IN are prepared according to Procedure 3:
Procedure 3
Synthesis of (E)(E)- and (E)(Z)-bis(Styryl) Sulfones
To freshly distilled phenyl acetylene (51.07 g, 0.5 mol) is added sodium thioglycollate prepared from thioglycollic acid (46 g, 0.5 mol) and sodium hydroxide (40 g, 1 mol) in methanol (250 ml). The mixture is refluxed for 24 hours and poured onto crushed ice (500 ml) after cooling. The styrylthioacetic acid, formed after neutralization with dilute hydrochloric acid (250 ml), is filtered and dried; yield 88 g (90%); m.p. 84-86°C.
The styrylthioacetic acid is then oxidized to styrylsulfonylacetic acid as follows. A mixture of styrylthioacetic acid (5 g, 25 mmol) in glacial acetic acid (35 ml) and 30% hydrogen peroxide (15 ml) is heated under reflux for 60 minutes and the mixture is poured onto crushed ice (200 ml) after cooling. The compound separated is filtered and recrystalized from hot water to give white crystalline flakes of (Z)-styrylsulfonylacetic acid; yield 2.4 g (41%); m.p. 150-51°C.
A solution of (Z)-styrylsulfonylacetic acid (2.263 g, 10 m mol) in glacial acetic acid (6 ml) is mixed with an aromatic aldehyde (10 mmol) and benzylamine (0.2 ml) and refluxed for 3 hours. The reaction mixture is cooled, treated with dry ether (50 ml), and any product separated is collected by filtration. The filtrate is diluted with more ether and washed successively with a saturated solution of sodium hydrogen carbonate (15 ml), sodium bisulfite (15 ml), dilute hydrochloric acid (20 ml) and finally with water (30 ml). Evaporation of the dried ethereal layer yields (E)(Z)-bis(styryl)sulfones.
(E),(E)-bis(styryl)sulfones are prepared following the same procedure as described above with exception that sulfonyldiacetic acid is used in place of (Z)-styrylsulfonylacetic acid, and twice the amount of aromatic aldehyde (20 mmol) is used.
The styryl sulfones of formula N, which are systematically identified as 2-(phenylsulfonyl)-l-phenyl-3-phenyl-2-propen-l-ones, may be prepared according to either Method A or Method B of Procedure 4:
Procedure 4
Synthesis of 2-(Phenylsulfonyl)-l-phenyl-3-phenyl-2-propen-l-ones
These compounds are synthesized by two methods which employ different reaction conditions, solvents and catalysts.
Method A: Phenacyl aryl sulfones are made by refluxing α-bromoacetophenones (0.05 mol) and sodium arylsulfinates (0.05 mol) in absolute ethanol (200 ml) for 6-8 hours. The product which separates on cooling is filtered and washed several times with water to remove sodium bromide. The product is then recrystalized from ethanol: phenacyl-phenyl sulfone, m.p. 90-91°C; phenacyl-p-fluorophenyl sulfone, m.p. 148-149°C; phenacyl-p-bromophenyl sulfone, m.p. 121-122°C; phenacyl-p-methoxyphenyl sulfone, m.p. 104-105°C; p-nitrophenacyl-phenyl sulfone, m.p. 136-137°C.
A solution of phenacyl aryl sulfone (0.01 mol) in acetic acid (10 ml) is mixed with an araldehyde (0.01 mol) and benzylamine (0.02 ml) and refluxed for 3 hours. The solution is cooled and dry ether (50 ml) is added. The ethereal solution is washed successively with dilute hydrochloric acid, aqueous 10% NaOH, saturated NaHSO3 solution and water. Evaporation of the dried ethereal layer gives a solid product which is purified by recrystallization.
Method B: Dry tetrahydrofuran (200 ml) is taken in a 500 ml conical flask flushed with nitrogen. To this, a solution of titanium (IN) chloride (11 ml, 0.01 mol) in absolute carbon tetrachloride is added dropwise with continuous stirring. The contents of the flask are maintained at -20°C throughout the course of the addition. A mixture of phenacyl aryl sulfone (0.01 mol) and aromatic aldehyde (0.01 mol) is added to the reaction mixture and pyridine (4 ml, 0.04 mol) in tetrahydrofuran (8 ml) is added slowly over a period of 1 hour. The contents are stirred for 10-12 hours, treated with water (50 ml) and then ether (50 ml) is added. The ethereal layer is separated and washed with 15 ml of saturated solutions of 10% sodium hydroxide, sodium bisulfite and brine. The evaporation of the dried ethereal layer yields 2-(phenylsulfonyl)-l-phenyl-3-phenyl-2 propen-l-ones.
PATENT
https://www.google.com/patents/CN104817488A?cl=en
The structure of this medicine formula (I) shown below,
Wherein, R1 is absent or is halogen, C1-3 alkyl, alkoxy and -CF3; R2 is absent or is halogen, C1-3 alkyl, alkoxy and -cf3; structural formula (I) The method for the preparation of compounds as follows:
| WO2007016201A2 | Jul 28, 2006 | Feb 8, 2007 | Onconova Therapeutics, Inc. | FORMULATION OF RADIOPROTECTIVE α, β UNSATURATED ARYL SULFONES |
| WO2008105808A2 | Jul 27, 2007 | Sep 4, 2008 | Onconova Therapeutics, Inc. | FORMULATIONS OF RADIOPROTECTIVE α, β UNSATURATED ARYL SULFONES |
| US6656973 | Nov 27, 2002 | Dec 2, 2003 | Temple University – Of The Commonwealth System Of Higher Education | (E)-4-carboxystyrl-4-chlorobenzyl sulfone and pharmaceutical compositions thereof |
| US6667346 | Feb 28, 2002 | Dec 23, 2003 | Temple University – Of The Commonwealth System Of Higher Education | Method for protecting cells and tissues from ionizing radiation toxicity with α, β unsaturated aryl sulfones |
| US6982282 * | May 17, 2002 | Jan 3, 2006 | Sonus Pharmaceuticals, Inc. | Emulsion vehicle for poorly soluble drugs |
| US20090247624 | Jul 27, 2007 | Oct 1, 2009 | Onconova Therapeutics Inc. | Formulations of radioprotective alpha beta unsaturated aryl sulfones |
| Patent ID | Date | Patent Title |
|---|---|---|
| US2015265549 | 2015-09-24 | STABLE AQUEOUS FORMULATION OF (E)-4-CARBOXYSTYRYL-4-CHLOROBENZYL SULFONE |
| US2015238448 | 2015-08-27 | FORMULATION OF RADIOPROTECTIVE ALPHA, BETA UNSATURATED ARYL SULFONES |
| US2013012588 | 2013-01-10 | COMPOSITIONS AND METHODS FOR PREVENTION AND TREATEMENT OF WOUNDS |
| US2013012589 | 2013-01-10 | STABLE AQUEOUS FORMULATION OF (E)-4-CARBOXYSTYRYL-4-CHLOROBENZYL SULFONE |
| US2011250184 | 2011-10-13 | METHODS FOR DETERMINING EFFICACY OF A THERAPEUTIC REGIMEN AGAINST DELETERIOUS EFFECTS OF CYTOTOXIC AGENTS IN HUMAN |
| US2011028504 | 2011-02-03 | Formulation of radioprotective alpha beta unsaturated aryl sulfones |
| US2009247624 | 2009-10-01 | FORMULATIONS OF RADIOPROTECTIVE ALPHA BETA UNSATURATED ARYL SULFONES |
 |
|
| Identifiers | |
|---|---|
922139-31-9  |
|
| PubChem | 23668369 |
| Properties | |
| C16H12ClNaO4S | |
| Molar mass | 358.77 g·mol−1 |
//////////Onc-01210, ON-01210.Na, 334969-03-8, 922139-31-9, Recilisib Sodium, Phase I , A protein kinase inhibitor, treatment of acute radiation syndrome, Orphan Drug Status, Ex-RAD
C1=CC(=CC=C1CS(=O)(=O)C=CC2=CC=C(C=C2)C(=O)[O-])Cl.[Na+]
Letermovir, MK 8828, AIC 246
2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazolin-4-yl]acetic acid
| CAS | 917389-32-3 |
|---|
Letermovir; UNII-1H09Y5WO1F; AIC-246; 2-((4S)-8-Fluoro-2-(4-(3-methoxyphenyl)piperazin-1-yl)-3-(2-methoxy-5-(trifluoromethyl)phenyl)-4H-quinazolin-4-yl)acetic acid; 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazolin-4-yl]acetic acid; Letermovir [INN]
| Molecular Formula: | C29H28F4N4O4 |
|---|---|
| Molecular Weight: | 572.550633 g/mol |
Letermovir (INN) is an antiviral drug that is being developed for the treatment of cytomegalovirus (CVM) infections. It has been tested in CMV infected patients with allogeneic stem cell transplants and may also be useful for other patients with a compromised immune system such as those with organ transplants or HIV infections.[1]
The drug has been granted fast track status by the US Food and Drug Administration (FDA) and orphan drug status by the European Medicines Agency.[1]
The drug candidate is under development by Merck & Co., Inc as investigative compound MK-8828.[2]
AIC246, also known as letermovir, is a novel anti-CMV compound with IC50 value of 5.1 ± 1.2 nM. It targets the pUL56 (amino acid 230-370) subunit of the viral terminase complex [1].
The subunit pUL56 is a component of the terminase complex which is responsible for packaging unit length DNA into assembling virions.
AIC246 has a novel mode of action targets the enzyme UL56 terminase and keep active to other drug-resistant virus. The anti-HCMV activity of AIC246 was evaluated in vitro by using different HCMV laboratory strains, GCV-resistant viruses. The result showed that the inhibitory potentcy of AIC246 surpasses the current gold standard GCV by more than 400-fold with respect to EC50s (mean, ∼4.5 nM versus ∼2 μM) and by more than 2,000-fold with respect to EC90 values (mean, ∼6.1 nM versus ∼14.5 μM). In the CPE-RA strains, the EC50 values of AIC 246 ranged from 1.8 nM to 6.1 nM [2].
In mouse model with HCMV subcutaneous xenograft, oral administration of AIC246 caused significant a dose-dependent reduction of the HCMV titer. 30 mg/kg/d AIC246 for 9 days induced PFU reduction with maximum efficiency, compared with the gold standard GCV at the ED50 and ED90 level [2].
References:
[1].Verghese PS, Schleiss MR. Letermovir Treatment of Human Cytomegalovirus Infection Anti-infective Agent. Drugs Future. 2013, 38(5):291-298.
[2]. Lischka P1, Hewlett G, Wunberg T, et al.In vitro and in vivo activities of the novel anticytomegalovirus compound AIC246.Antimicrob Agents Chemother. 2010, 54(3):1290-1297.
NMR
Human cytomegalovirus (HCMV) remains the leading viral cause of birth defects and life-threatening disease in transplant recipients. All approved antiviral drugs target the viral DNA polymerase and are associated with severe toxicity issues and the emergence of drug resistance. Attempts to discover improved anti-HCMV drugs led to the identification of the small-molecular-weight compound AIC246 (Letermovir). AIC246 exhibits outstanding anti-HCMV activity in vitro and in vivo and currently is undergoing a clinical phase IIb trial. The initial mode-of-action studies suggested that the drug acts late in the HCMV replication cycle via a mechanism distinct from that of polymerase inhibitors. Here, we extend our mode-of-action analyses and report that AIC246 blocks viral replication without inhibiting the synthesis of progeny HCMV DNA or viral proteins. The genotyping of mutant viruses that escaped AIC246 inhibition uncovered distinct point mutations in the UL56 subunit of the viral terminase complex. Marker transfer analyses confirmed that these mutations were sufficient to mediate AIC246 resistance. The mapping of drug resistance to open reading frame UL56 suggests that viral DNA processing and/or packaging is targeted by AIC246. In line with this, we demonstrate that AIC246 affects the formation of proper unit-length genomes from viral DNA concatemers and interferes with virion maturation. However, since AIC246-resistant viruses do not exhibit cross-resistance to previously published terminase inhibitors, our data suggest that AIC246 interferes with HCMV DNA cleavage/packaging via a molecular mechanism that is distinct from that of other compound classes known to target the viral terminase.
PATENT
Scheme 2:
Chromatography
on a chiral phase
Scheme 4:
Scheme 5:
Synthesis of {8-fluoro-2- [4- (3-methoxyphenyl) piperazin-l -yl] -3- [2-methoxy-5- (trifluoromethyl) phenyl] -3,4-dihydroquinazolin-4-yl }acetic acid
xample 1
N- (2-bromo-6-fluoφhenyl) -N ‘- [2-methoxy-5- (trifluoromethyl) phenyl] urea
2-methoxy-5-trifluoromethylphenyl isocyanate (274.3 g) are dissolved in acetonitrile (1 L), then 2-bromo-6-fluoroaniline (200 g) was added with acetonitrile (50 mL) flushed. The resulting clear solution is at 38 h reflux (ca. 85 0 stirred C), then under vacuum at 40 0 concentrated C a dogged mush. This is filtered off, with acetonitrile (260 mL, to 0-5 0 C cooled) washed and incubated overnight at 45 0 dried C in the VDO using entraining nitrogen. Thus, a total of 424.3 g of N- (2-bromo-6-fluorophenyl) -N ‘- get [2-methoxy-5- (trifluoromethyl) phenylJ-urea as a solid, corresponding to 99.2% of theory.
1 H NMR (300 MHz, d 6 -DMSO): δ = 8.93 (s, IH), 8.84 (s, IH), 8.52 (d, V = 2.3, 2H), 7, 55 (d, 2 = Vr = 7.7, IH), 7.38 to 7.26 (m, 3H), 7.22 (d, 2 J = 8.5, IH), 4.00 (s, 3H) ppm;
– – MS (API-ES-pos.): M / z = 409 [(M + H) + , 100%];
HPLC (Method 1): R τ = 22.4 and 30.6 min.
example 2
N- (2-bromo-6-fluorophenyl) -N ‘- [2-methoxy-5- (trifluoromethyl) phenyl] urea (Alterhativsynthese)
2-methoxy-5-trifluoromethylphenyl isocyanate (1.19 kg) are at about 35 0 dissolved melted and C in acetonitrile (4.2 L), then 2-bromo-6-fluoroaniline (870 g) was added and with acetonitrile ( 380 mL) rinsed. The resulting clear solution is at 74-88 45 h 0 stirred C, then under vacuum (200 mbar) at 50 0 C to a dogged mush concentrated (amount of distillate 4.4 L). This is at room temperature with diisopropylether (1.5 L), washed aspirated, with diisopropylether (1.15 L) washed and at 45 0 C in the VDO using entraining nitrogen to constant weight (24 h) dried. Thus, a total of 1, 63 kg Η- (2-bromo-6-fluoro-phenyl) -W- – obtained [2-methoxy-5 (trifluoromethyl) phenyl] urea as a solid, corresponding to 87.5% of theory.
HPLC (Method 1): R τ = 22.6 and 30.8 min.
example 3
{8-Fluor-3-[2-methoxy-5-(trifluormethyl)phenyl]-2-oxo-l,2,3,4-tetrahydrochinazolin-4-yl}essigsäuremethylester
N- (2-bromo-6-fluorophenyl) -N- [2-methoxy-5- (trifluoromethyl) phenyl] urea (300 g) under a nitrogen atmosphere in isobutyronitrile (1.2 L) was suspended, then triethylamine
(21O mL), bis (acetonitrile) dichloropalladium (7.5 g), tris- (o-tolyl) phosphine (18.0 g) and
Methyl acrylate (210 mL) were added in this order. The resulting suspension is for 16 hours at reflux (ca. 102 0 stirred C) and then cooled to room temperature. Water (1.2 L) is added and the mixture 1 at room temperature stirred, then aspirated and washed with water / methanol h: washed and acetonitrile (10O mL) (1 1 30O mL). The residue is treated overnight at 45 0 dried C in the VDO using entraining nitrogen. Thus, a total of 208 g as a solid, corresponding to 68.5% of theory.
1 H NMR (300 MHz, d 6 -DMSO): δ = 9.73 (s, IH), 7.72 (d, 2 J = 7.3, IH), 7.71 (s, IH), 7 , 33 (d, 2 J = 9.3, IH), 7.15 (dd, 2 J = 9.6, 2 J = 8.6, IH), 7.01 (d, 2 J = 7.3 , IH), 6.99 to 6.94 (m, IH), 5.16 (t, 2 , J = 5.9, IH), 3.84 (s, 3H), 3.41 (s, 3H) , 2.81 (dd, 2 J = 15.4, 2 J = 5.8, IH), 2.62 (dd, 2 J = 15.4, 2 J = 6.3, IH) ppm;
MS (API-ES-pos.): M / z = 413 [(M + H) + , 100%], 825 [(2M + H) + , 14%];
HPLC (Method 1): R τ = 19.3 min; Pd (ICP): 16,000 ppm.
example 4
{8-Fluor-3-[2-methoxy-5-(trifluormethyl)phenyl]-2-oxo-l,2,3,4-tetrahydrochinazolin-4-yl}essigsäuremethylester (Alternative synthesis)
N- (2-bromo-6-fluorophenyl) -N ‘- [2-methoxy-5- (trifluoromethyl) phenyl] urea (2.5 kg) is suspended under a nitrogen atmosphere in isobutyronitrile (9 L), then triethylamine (1.31 kg), bis (acetonitrile) dichloropalladium (64.9 g), tris (o-tolyl) phosphine (149 g) and methyl acrylate (1.59 kg) were added in this order. The resulting suspension is 22 hours at 90-100 0 stirred C, then cooled to room temperature. Water (9 L) is added and stirred, then aspirated and washed with water / methanol (1: 1, 2.5 L) at room temperature, the mixture for 1 hour and acetonitrile (850 mL). The residue is treated overnight at 45 0 dried C in the VDO using entraining nitrogen to constant weight (21 h). Thus, a total of 1.90 kg as a solid, corresponding to 74.9% of theory.
HPLC (Method 1): R τ = 19.4 min.
example 5
{2-Chlor-8-fluor-3-[2-methoxy-5-(trifluormethyl)phenyl]-3,4-dihydrochinazolin-4-yl}essigsäure-methylester / chlorination
A solution of 2.84 kg {8-fluoro-3- [2-methoxy-5- (trifluoromethyl) phenyl] -2-oxo-l, 2,3,4-tetrahydroquinazolin-4-yl} acetic acid methyl ester in 14.8 l of chlorobenzene is heated to reflux and the solvent is distilled off until water no longer separates. It is to 12O 0 cooled C. Within 10 min phosphorus oxychloride are metered in 3.17 kg, and then is added within a further 10 min 2.10 kg DBU. It is heated to reflux for 9 hours.
For working up the mixture is cooled to 40 0 C., stirred overnight and dosed the reactor contents to 11.4 L of water, previously estimated at 40 0 was tempered C. For dosing an internal temperature of 40-45 to 0 C, are satisfied. The mixture is allowed to cool to room temperature, 11.4 L of dichloromethane, filtered through a Seitz filter plate and the phases are separated. The organic phase is washed with 11.4 L of water, 11.4 L of an aqueous saturated sodium bicarbonate solution and again with 11.4 L of water. The organic phase is concentrated on a rotary evaporator in vacuo and the remaining residue (2.90 kg) is used without further treatment in the next step.
1 H NMR (300 MHz, d 6 -DMSO): δ = 7.93 to 7.82 (m, 2H), 7.38 (d, 2 J = 8.9, IH), 7.17 (m, 2H), 6.97 to 6.91 (m, IH), 5.45 and 5.29 (m and t, 2 , J = 5.4, IH), 3.91 and 3.84 (2s, 3H) , 3.48 (s, 3H), 3.0 to 2.6 (m, 2H) ppm;
MS (CI, NH 3 ): m / z = 431 [(M + H) + , 100%];
HPLC (Method 1): R τ = 23.5 min; typical Pd value (ICP): 170 ppm.
example 6
{8-Fluor-2-[4-(3-methoxyphenyl)piperazin-l-yl]-3-[2-methoxy-5-(trifluormethyl)phenyl]-3,4-dihydrochinazolin-4-yl}essigsäuremethylester / Amination – –
(52.5 g) is dissolved in 1,4-dioxane (10O mL), then (25.8 g) and DBU (20.4 g) was added at room temperature 3-methoxyphenylpiperazine, whereupon the temperature rises. The mixture is stirred at reflux for 22 h, then cooled to room temperature, with ethyl acetate (500 mL) and water (200 mL) and the phases separated. The organic phase (200 mL) washed with 0.2N hydrochloric acid (three times 100 mL) and water, dried over sodium sulfate and evaporated. Thus, a total of 62.5 g obtained as a solidified foam, which is reacted as the crude product without further purification.
HPLC (Method 1): R τ = 16.6 min.
example 7
{8-Fluor-2-[4-(3-methoxyphenyl)piperazin-l-yl]-3-[2-methoxy-5-(trifluormethyl)phenyl]-3,4-dihydrochinazolin-4-yl}essigsäuremethylester / Pot chlorination + amination
(50.0 g) is introduced in chlorobenzene (300 mL), then chlorobenzene is partially distilled (5O mL). The mixture is heated to 120 0 cooled C., DBU (36.9 g) is added, then at 120-128 is 0 C phosphorous oxychloride (33.4 mL) over 10 min. metered. The mixture (approximately 130 at reflux for 9 hours 0 C) stirred. Subsequently, at 40 0cooled C, slowly at 40-45 0 C with water (200 mL), cooled to room temperature and diluted with dichloromethane (200 mL), stirred and then the phases separated. The organic phase is washed with water (200 mL), saturated aqueous sodium bicarbonate solution (200 mL) and again water (200 mL), dried over sodium sulfate, concentrated by rotary evaporation and then under high vacuum at 50 0 dried C. The residue (48.1 g) is dissolved in chlorobenzene (20 mL), then with 1,4-dioxane (80 mL) at room temperature and 3-methoxyphenylpiperazine (23.6 g) and DBU (18.7 g) was added, whereupon the temperature rises. The mixture is stirred at reflux for 22 h, then cooled to room temperature, with ethyl acetate (500 mL) and water (200 mL) and the phases separated. The organic phase (200 mL) washed with 0.2N hydrochloric acid (three times 100 mL) and water, dried over sodium sulfate and evaporated. Thus, a total of 55.6 g obtained as a solidified foam, which is reacted as the crude product without further purification.
HPLC (Method 1): R τ = 16.2 min.
example 8
(^)-{8-Fluor-2-[4-(3-methoxyphenyl)piperazin-l-yl]-3-(2-methoxy-5-trifluormethylphenyl)-3,4-dihydrochinazolin-4-yl} acetate / saponification racemate
(64 g) is dissolved in 1,4-dioxane (45O mL) and IN sodium hydroxide solution (325 mL) and stirred for 2 h at room temperature, then dried in vacuo at 30 0 , a part of the solvent C is distilled off (400 mL). Toluene is added (300 mL) and the phases separated. The aqueous phase is washed with toluene (15O mL twice), then the combined organic phases again with IN sodium hydroxide solution (50 mL) are extracted. The pH of the combined aqueous phases with 2N hydrochloric acid (about 150 mL) to 7.5, then MIBK (15O mL) is added. The phases are separated, the aqueous phase extracted again with MIBK (15O mL), then dried the combined MIBK phases over sodium sulfate and at 45 0 concentrated C. Thus, a total of 64 g as an amorphous solid in quantitative yield.
HPLC (Method 1): R τ = 14.9 min.
Scheme 6:
Separation of enantiomers of {8-fluoro-2- [4- (3-methoxyphenyl) piperazin-l -yl] -3- [2-methoxy-5- (tri-fluoromethyl) phenyl] -3,4-dihydroquinazolin-4-yl } acetate
x (2S, 3S) -2,3-bis [(4-methylbenzoyl) – oxyjbemsteinsäure
x EtOAc
example 9
(2S, 3 £) -2,3-bis [(4-methylbenzoyl) oxy] succinic acid (1: 1 salt) / crystallization
(62.5 g, crude product) is dissolved and filtered in ethyl acetate (495 mL). To the filtrate is (35 25 ‘,) added 2,3-bis [(4-methylbenzoyl) oxy] succinic acid (42.0 g), the mixture for 30 minutes. stirred at room temperature, then with (35 25 “) -2,3-bis [(4-methylbenzoyl) oxy] -succinic acid – (l: l salt) (165 mg) was inoculated and stirred for 3 days at room temperature, then to 0-3 0 cooled C and stirred for a further 3 h, the suspension is suction filtered and washed with cold ethyl acetate (0-10. 0 C, 35 mL ) washed. the crystals are at 40 h 18 0 C in the VDO using entraining nitrogen dried. Thus 37.1 g of the salt are obtained as a solid, corresponding to 30.4% of theory over three stages (chlorination, amination and crystallization) on the racemate, or 60.8% based on the resulting S enantiomer.
– – 1 H NMR (300 MHz, d 6 -DMSO): δ = 7.90 (d, 2 J = 7.8, 4H), 7.56 (d, 2 J = 8.3, IH), 7 , 40 (d, 2 J = 7.8, 4H), 7.28 to 7.05 (m, 4H), 6.91 to 6.86 (m, 2H), 6.45 (d, 2 J = 8.3, IH), 6.39 to 6.36 (m, 2H), 5.82 (s, 2H), 4.94 (m, IH), 4.03 (q, 2 J = 7.1 , 2H), 3.83 (brs, 3H), 3.69 (s, 3H), 3.64 (s, 3H), 3.47 to 3.36 (m, 8H and water, 2H), 2, 98 to 2.81 (m, 5H), 2.58 to 2.52 (m, IH), 2.41 (s, 6H), 1.99 (s, 3H), 1.18 (t, 2 J = 7.2, 3H) ppm;
HPLC (Method 1): R τ = 16.6 and 18.5 min.
example 10
(25,3iS) -2,3-bis [(4-methylbenzoyl) oxy] succinic acid (1: 1 salt) / recrystallization
(2S, 3S) -2,3-bis [(4-methy lbenzoyl) oxy] succinic acid – { (l: l salt) (36.8 g) is suspended in ethyl acetate (37o mL) and (77 by heating to reflux 0 C) dissolved. The mixture is slowly cooled to room temperature. Here there is a spontaneous crystallization. The suspension is stirred at RT for 16 h, then 0-5 0 cooled C and stirred for another 3 h. The suspension is suction filtered and washed with cold ethyl acetate (0-10 0 C, twice 15 ml). The crystals are at 45 h 18 0 C in the VDO using entraining nitrogen dried. Thus 33.6 g of the salt are obtained as a solid, corresponding to 91.3% of theory.
HPLC (Method 1): R τ = 16.9 and 18.8 min .;
HPLC (Method 3): 99.9% ee
example 11
(5)-{8-Fluor-2-[4-(3-methoxyphenyl)piperazin-l-yl]-3-(2-methoxy-5-trifluormethylphenyl)-3,4-dihydrochinazolin-4-yl}essigsäure
(2IS I , 3S) -2,3-bis [(4-methylbenzoyl) oxy] succinic acid (l: l salt) (10.1 g, containing 14 ppm of Pd) are suspended in ethyl acetate (100 mL) and shaken with saturated aqueous sodium bicarbonate solution (10O mL) shaken until both phases are clear. The phases are separated, the organic phase is evaporated. The residue is dissolved in 1,4-dioxane (100 mL) and IN sodium hydroxide solution (31.2 mL) and stirred for 3 h at room temperature. Subsequently, the pH is adjusted with IN hydrochloric acid (about 17 mL) is set to 7.5, MIBK (8O mL) was added, then the pH is adjusted with IN hydrochloric acid (about 2 mL) adjusted to 7.0. The phases are separated, the organic phase dried over sodium sulfate and concentrated. The residue is dissolved in ethanol and concentrated (40 mL), then again in ethanol (40 mL) and concentrated under high vacuum at 50 0 C dried. The solidified foam is at 45 h 18 0 C in the VDO using entraining nitrogen dried. Thus, a total of 5.05 g as an amorphous solid, corresponding to 85.0% of theory.
1 H NMR (300 MHz, d 6 -DMSO): δ = 7.53 (d, 2 J = 8.4, IH), 7.41 (brs, IH), 7.22 (d, 2 J = 8 , 5, IH), 7.09 to 7.01 (m, 2H), 6.86 (m, 2H), 6.45 (dd, V = 8.2, 3 J = 1.8, IH) 6.39 to 6.34 (m, 2H), 4.87 (t, 2 J = 7.3, IH), 3.79 (brs, 3H), 3.68 (s, 3H), 3.50 -3.38 (m, 4H), 2.96 to 2.75 (m, 5H), 2.45 to 2.40 (m, IH) ppm;
MS (API-ES-neg.): M / z = 571 [(MH), 100%];
HPLC (Method 1): R τ = 15.1 min;
HPLC (Method 2): 99.8% ee; Pd (ICP): <1 ppm.
example 12
(2 / ?, 3Λ) -2,3-bis [(4-methylbenzoyl) oxy] succinic acid (1: 1 salt) / crystallization R-isomer from the mother liquor
The mother liquor from a crystallization of (2IS ‘, 3S) -2,3-bis [(4-methylbenzoyl) oxy] -succinic acid – {8-fluoro-2- [4- (3-methoxyphenyl) piperazin-l -yl] -3- [2-methoxy-5- (trifluoromethyl) phenyl] -3,4-dihydroquinazolin-4-yl} acetic acid methyl ester (l: l-salt) in 279 g scale is washed with saturated aqueous sodium bicarbonate solution (1.5 L ) shaken, the phases are separated and the organic phase is shaken with semi-saturated aqueous sodium bicarbonate solution (1.5 L). The phases are separated, the organic phase dried over sodium sulfate and evaporated. The residue (188.4 g) is dissolved in ethyl acetate (1.57 L), then (2R, 3R) -2,3-bis [(4-methylbenzoyl) oxy] succinic acid (121.7 g) was added and the mixture 10 min. stirred at room temperature. Is then treated with (2R, 3R) -2,3-bis [(4-methyl-benzoyl) oxy] succinic acid – (l: l salt) (0.38 g) was inoculated and stirred for 18 h at room temperature, then to 0-3 0 cooled C and stirred for another 3 h. The suspension is suction filtered and washed with cold ethyl acetate (0-10 0 C, 50O ml). The crystals are at 40 h 18 0 C in the VDO using entraining nitrogen dried. So a total of 160 g of the salt are obtained as a solid.
HPLC (Method 1): R τ = 16.6 and 18.5 min .;
HPLC (Method 3): -99.0% ee
example 13
(i?)-{8-Fluor-2-[4-(3-methoxyphenyl)piperazin-l-yl]-3-(2-methoxy-5-trifluormethylphenyl)-3,4-dihydrochinazolin-4-yl} acetate / production R-isomer
(2Λ, 3 /?) – 2,3-bis [(4-methylbenzoyl) oxy] succinic acid – {8-fluoro-2- [4- (3-methoxy-phenyl) pipera-tine 1-yl] -3- [ 2-methoxy-5- (trifluormethy l) pheny l] -3, 4-dihydroquinazolin-4-y 1} -acetic acid methyl ester (1: 1 salt) (170 g) are suspended in ethyl acetate (85O mL) and as long as with saturated aqueous sodium bicarbonate (850 mL) shaken until both phases are clear (about 5 min.). The phases are separated, the solvent of the organic phase under normal pressure with 1, 4-dioxane to a final temperature of 99 0 exchanged C (portions distilled total 2.55 L solvent, and 2.55 L of 1,4-dioxane used). The mixture is cooled to room temperature and 18 at room temperature IN sodium hydroxide solution (525 mL) stirred. Subsequently, the pH value with concentrated hydrochloric acid (about 35 mL) is set to 7.5, MIBK (85O mL) was added, then the pH with concentrated hydrochloric acid (ca. 1O mL) adjusted to 7.0. The phases are separated, the organic phase dried over sodium sulfate and concentrated. The residue is dissolved in ethanol and concentrated (350 mL), then again in ethanol (350 mL) at 50 and 0 concentrated C. Thus, a total of 91.6 g as an amorphous solid, corresponding to 91.6% of theory.
HPLC (method 1): R 7 = 14.8 min.
– – Example 14
{8-Fluor-2-[4-(3-methoxyphenyl)piperazin-l-yl]-3-(2-methoxy-5-trifluormethylphenyl)-3,4-dihydrochinazolin-4-yl} acetate / racemization R-enantiomer
acetic acid (50 g) is dissolved in acetonitrile (500 mL) and treated with sodium methoxide (30% in methanol, 32.4 mL) and then stirred at reflux for 60 h. After cooling to room temperature the mixture is concentrated in vacuo to half, then with hydrochloric acid (20% strength, ca. 20 ml) adjusted to pH 7.5, MIBK (200 mL) was added and hydrochloric acid (20%) on pH 7 adjusted. The phases are separated, the organic phase dried over sodium sulfate and evaporated to the hard foam. The residue is dissolved in ethanol and concentrated (15O mL), then again in ethanol (15O mL) and concentrated. Thus, 54.2 g as an amorphous solid in quantitative yield.
HPLC (Method 1): R τ = 14.9 min .;
HPLC (method 4): 80.8 wt.%.
example 15
{8-Fluor-2-[4-(3-methoxyphenyl)piperazin-l-yl]-3-[2-methoxy-5-(trifluormethyl)phenyl]-3,4-dihydrochinazolin-4-yl}essigsäuremethylester / Esterification racemate
acetic acid (54 g) (540 g) was dissolved in methanol, then concentrated sulfuric acid (7.85 mL) is added. The mixture is stirred at reflux for 26 h, then cooled and concentrated in vacuo to about one third of the original volume. Water (15O mL) and dichloromethane (15O mL) are added, then the phases are separated. The organic phase is washed with saturated sodium bicarbonate solution (two times 140 mL), dried over sodium sulfate and concentrated to a foamy residue. This is twice in succession in ethanol (150 mL) and concentrated, dried in vacuo using entraining nitrogen then 18 h. Thus, a total of 41.6 g as an amorphous solid, corresponding to 75.2% of theory.
HPLC (Method 1): R τ = 16.8 min .;
HPLC (method 4): 85.3 wt.%;
HPLC (Method 3): -8.5% ee
example 16
(25 1 , 3S) -2,3-bis [(4-methylbenzoyl) oxy] succinic acid – { (1: 1 salt) / crystallization of esterified racemate
(41.0 g) is suspended in ethyl acetate (287 mL), then (2S, 3IS) -2,3-bis [(4-methylbenzoyl) oxy] succinic acid (27.5 g) was added. The mixture is 30 minutes. stirred at room temperature, then with (2 <S ‘, 3S) -2,3-bis [(4-methylbenzoyl) oxy] succinic acid – (1: 1 salt) (0.08 g) was inoculated. The suspension is stirred at RT for 16 h, then 0-5 0 cooled C and stirred for another 3 h, then filtered off with suction and washed with cold ethyl acetate (0-10 0 C, four times 16 ml). The crystals are at 45 h 18 0 C in the VDO using entraining nitrogen dried. So a total of 25.4 g of the salt are obtained as a solid, corresponding to 37.4% of theory.
HPLC (Method 1): R τ = 16.9 and 18.8 min .;
HPLC (method 4): 99.5 wt.%;
HPLC (Method 3): 99.3% ee
example 17
(iS)-{8-Fluor-2-[4-(3-methoxyphenyl)piperazin-l-yl]-3-(2-methoxy-5-trifluormethylphenyl)-3,4-dihydrochinazolin-4-yl} acetate / saponification crystals
(25,3S) -2,3-bis [(4-methylbenzoyl) oxy] succinic acid – (l rl salt) (25.1 g) is suspended in ethyl acetate (25O mL) and shaken with saturated aqueous sodium bicarbonate solution (250 mL) shaken until both phases are clear. The phases are separated, the organic phase is evaporated. Dissolve the residue in 1, 4-dioxane (25O mL) and IN sodium hydroxide solution (77.4 mL) and stirred for 18 h at room temperature. Subsequently, the pH is adjusted with IN hydrochloric acid (about 50 mL) is set to 7.5, was added MIBK (240 mL), then the pH is adjusted with IN hydrochloric acid (about 15 mL) adjusted to 7.0. The phases are separated, the organic phase dried over sodium sulfate and concentrated. The residue is dissolved in ethanol and concentrated (90 mL), then again in ethanol (90 mL) and concentrated. The solidified foam is at 45 h 180 C in the VDO using entraining nitrogen dried. Thus, a total of 12 g as an amorphous solid, corresponding to 81.2% “ of the theory.
HPLC (Method 1): R τ = 15.1 min;
HPLC (Method 2): 97.5% ee; Pd (ICP): <20 ppm.
Alternative method for the racemization:
example 18
(i)-{8-Fluor-2-[4-(3-methoxyphenyl)piperazin-l-yl]-3-(2-methoxy-5-trifluormethylphenyl)-3,4-dihydrochinazolin-4-yl} acetic acid / saponification enriched R isomer from the mother liquor after crystallization
The mother liquor from a crystallization of (2 J S ‘, 35) -2,3-bis [(4-methylbenzoyl) oxy] -succinic acid – (l: l-salt) in 207 g scale is shaken with saturated aqueous sodium bicarbonate (500 mL), the phases are separated and the organic phase is shaken with semi-saturated aqueous sodium bicarbonate solution (500 mL). The phases are separated, the organic phase dried over sodium sulfate and evaporated. The residue is dissolved in ethanol (500 mL) and rotary evaporated to a hard foam. This is in 1,4-dioxane (1.6 L) and IN sodium hydroxide solution (1.04 L) and stirred at room temperature for 18 h, then toluene is added (1.5 L) and the phases separated. The aqueous phase is adjusted with hydrochloric acid (20% strength, ca. 155 ml) of pH 14 to pH 8, then is added MIBK (1.25 L) and hydrochloric acid (20% strength, ca. 25 mL) to pH 7 readjusted. The phases are separated, the organic phase dried over sodium sulfate and evaporated to the hard foam. This is at 45 h 18 0 C in the VDO using entraining nitrogen dried. Thus, a total of 150 g obtained as (R / S) mixture as an amorphous solid.
HPLC (Method 2): 14.6% ee
– – Example 19
(i)-{8-Fluor-2-[4-(3-methoxyphenyl)piperazin-l-yl]-3-(2-methoxy-5-trifluormethylphenyl)-3,4-dihydrochinazolin-4-yl} acetate / racemization
(150 g, R / S mixture with -14.6% ee) is dissolved in acetonitrile (1.5 L) and treated with sodium methoxide (30% in methanol, 97.2 mL) was added, then stirred at reflux for 77 h , After cooling to room temperature the mixture is concentrated in vacuo to half, then with hydrochloric acid (20% strength, ca. 80 mL) made of pH 13 to pH 7.5, was added MIBK (0.6 L) and treated with hydrochloric acid ( 20% strength, ca. 3 mL) adjusted to pH. 7 The phases are separated, the organic phase dried over sodium sulfate and evaporated to the hard foam. The residue is dissolved in ethanol and concentrated (500 mL), then again in ethanol (500 mL) and concentrated, then 18 h at 450 dried C in the VDO using entraining nitrogen. Thus, a total of 148 g as an amorphous solid, corresponding to 98.7% of theory.
HPLC (Method 2): 1.5% ee
example 20
{8-Fluor-2-[4-(3-methoxyphenyl)piperazin-l-yl]-3-[2-methoxy-5-(trifluormethyl)phenyl]-3,4-dihydrochinazolin-4-yl}essigsäuremethylester (Esterification)
(±) – {8-fluoro-2- [4- (3-methoxyphenyl l) piperazin-1 -yl] -3- (2-methoxy-5-trifluormethy lphenyl) -3, 4-dihydroquinazolin-4-yl} acetic acid (148 g) (1480 g) was dissolved in methanol, then concentrated sulfuric acid (21.5 mL) is added. The mixture is stirred at reflux for 6 h, then cooled and concentrated in vacuo to about one third of the original volume. Water (400 mL) and dichloromethane (400 mL) are added, then the phases are separated. The organic phase (diluted twice 375 mL, 300 mL water) with saturated sodium bicarbonate solution, dried over sodium sulfate and concentrated to a foamy residue. This is twice in succession in ethanol (each 400 mL) and concentrated, dried in vacuo using entraining nitrogen then 18 h. Thus, a total of 124 g as an amorphous solid, corresponding to 81.9% of theory.
HPLC (Method 1): R τ = 16.9 min .;
example 21
(25.35) -2,3-bis [(4-methylbenzoyl) oxy] succinic acid – (1: 1 salt) / crystallization of esterified racemate
(2S, 3S) -2,3-bis [(4-methylbenzoyl) oxy] succinic acid – (1: 1 salt) (123 g, 14.4% ee) is suspended in ethyl acetate (861 mL) and filtered, then (2IS ‘, 3IS) -2,3-bis [(4-methylbenzoyl) oxy ] succinic acid (82.5 g). The mixture 30 min. stirred at room temperature, then with (2 £, 3 <S) -2,3-bis [(4-methylbenzoyl) oxy] succinic acid – (1: 1 salt) (0.24 g) was inoculated. The suspension is stirred for 4 days at RT, then concentrated to approximately 600 mL and again with (25 ‘, 3 1 -2,3-bis [(4-methylbenzoyl) oxy] succinic acid S) – (l: l salt) (0.24 g) was inoculated. The suspension is stirred for 1 week at RT, to 0-5 0 cooled C and further stirred for 3 hours, then filtered off with suction and washed with cold ethyl acetate (0-10 0 C, 4 x 40 ml). The crystals are at 45 h 18 0 C in the VDO using entraining nitrogen dried. So a total of 1 1.8 g of salt are obtained as a solid, corresponding to 5.8% of theory.
Scheme 7:
example 22
N- (2-Fluoφhenyl) -N ‘- [2-methoxy-5- (trifluoromethyl) phenyl] urea
2-methoxy-5-trifluoromethylphenyl isocyanate (1057.8 g) is dissolved in acetonitrile (4240 mL), then 2-fluoro aniline (540.8 g) was added with acetonitrile (50 mL) flushed.The resulting clear solution is stirred for 4 h at reflux (about 82 ° C), then seeded at about 78 ° C and about 15 min. touched. The suspension is on 0 0 cooled C, aspirated and the product with acetonitrile (950 mL, to 0-5 0 cooled C) washed. The product is dried overnight at 45 ° C in a vacuum drying oven using entraining nitrogen. Thus, a total of 1380.8 g of N- (2-fluorophenyl) -N ‘- [2-methoxy-5- (trifluoromethyl) phenyl] -harnstqff ‘ obtained as a solid, corresponding to 86.4% of theory.
1 H NMR (500 MHz, d 6 -DMSO): δ = 9.36 (s, IH), 9.04 (s, IH), 8.55 (d, 1.7 Hz, IH), 8.17 ( t, 8.2 Hz, IH), 7.33 (d, 8.5 Hz, IH), 7.20 to 7.26 (m, 2H), 7.14 (t, 7.6 Hz, IH), 7, 02 (m, IH), 3.97 (s, 3H) ppm;
MS (API-ES-pos.): M / z = 329 [(M + H) + , 100%];
HPLC: R τ = 48.7 min.
Instrument: HP 1100 Multiple Wavelength detection; Column: Phenomenex-Prodigy ODS (3) 100A, 150 mm x 3 mm, 3 microns; Eluent A: (1.36 g KH 2 PO 4 +0.7 mL H 3PO 4 ) / L water, eluent B:
acetonitrile; Gradient: 0 min 20% B, 40 min 45% B, 50 min 80% B, 65 min 80% B; Flow: 0.5 mL / min; Temp .: 55 0 C; UV detection: 210 nm.
example 23
Methyl (2E) -3- {3-fluoro-2 – [({[2-methoxy-5 – (trifluormethy l) pheny 1] amino} carbonylation l) amino] pheny 1} acrylate
N- (2-fluorophenyl) -N ‘- [2-methoxy-5- (trifluoromethyl) phenyl] urea (0.225 kg) is dissolved in acetic acid (6.75 L) and (30.3 g) was added with palladium acetate. Then 65% oleum is (247.5 g) is added and then methyl acrylate (90 g). The solution is stirred overnight at room temperature. Then, at about 30 0 C and about 30 mbar acetic acid (3740 g) were distilled off. The suspension is treated with water (2.25 L) and stirred for about 1 hour. The product is drained, washed twice with water (0.5 L) and incubated overnight at 50 0 dried C in a vacuum drying oven using entraining nitrogen. Thus, a total of 210.3 g of methyl (2E) -3- {3-fluoro-be 2 – [({[2-methoxy-5- (trifluoromethyl) phenyl] amino} carbonyl) amino] phenyl} acrylate obtained as a solid, corresponding to 72.2% of theory.
1 H NMR (300 MHz, d 6 -DMSO): δ = 9.16 (s, IH), 8.84 (s, IH), 8.45 (d, 1.7 Hz, IH), 7.73 ( m, 2H), 7.33 (m, 3H), 7.22 (d, 8.6 Hz, IH), 6.70 (d, 16Hz, IH), 3.99 (s, 3H), 3.71 (s, 3H) ppm;
MS (API-ES-pos.): M / z = 429.9 [(M + NH,) + ]; 412.9 [(M + H) + ]
HPLC: R τ = 46.4 min.
Instrument: HP 1100 Multiple Wavelength detection; Column: Phenomenex-Prodigy ODS (3) 100A, 150 mm x 3 mm, 3 microns; Eluent A: (1.36 g KH 2 PO 4 +0.7 mL H 3PO 4 ) / L water, eluent B: acetonitrile; Gradient: 0 min 20% B, 40 min 45% B, 50 min 80% B, 65 min 80% B; Flow: 0.5 mL / min; Temp .: 55 0 C; UV detection: 210 nm.
example 24
{8-FluorO-[2-methoxy-5-(trifluormethyl)phenyl]-2-oxo-l,2,3,4-tetrahydrochinazolin-4-yl}essigsäuremethylester
Methyl (2E) -3- {3-fluoro-2 – [({[2-methoxy-5- (trifluoromethyl) phenyl] amino} carbonyl) amino] phenyl} acrylate (50 g) is dissolved in acetone (1.2 L) was suspended and 3.7 g) was added l, 8-diazabicyclo [5.4.0] undec-7-ene (. The suspension is heated to reflux (ca..56 ° C) and stirred for 4 h. The resulting clear solution is hot through diatomaceous earth (5 g) was filtered. The diatomaceous earth is rinsed with warm acetone (100 ml). Subsequently, acetone (550 g) was distilled off. The resulting suspension is in 3 h at O 0 cooled and stirred C. The product is drained, washed twice with cold acetone (50 ml) and incubated overnight at 45 0 dried C in a vacuum drying oven using entraining nitrogen. Thus, a total of 44.5 g of {8-fluoro-3- [2-methoxy-5- (trifluoromethyl) phenyl] -2-oxo-1, 2, 3, 4-tetrahydrochinazo-lin-4-yl} acetic acid methyl ester as a solid, corresponding to 89% of theory.
1 H NMR (300 MHz, d 6 -DMSO): δ = 9.73 (s, IH), 7.72 (d, 2 J = 7.3, IH), 7.71 (s, IH), 7 , 33 (d, 2 J = 9.3, IH), 7.15 (dd, 2 J = 9.6, 2 J = 8.6, IH), 7.01 (d, 2 J = 7.3 , IH), 6.99 to 6.94 (m, IH), 5.16 (t, 2 J =
5.9, IH), 3.84 (s, 3H), 3.41 (s, 3H), 2.81 (dd, 1 J = 15.4, V = 5.8, IH), 2.62 (dd, 2 Vr = = 15.4, V = 6.3, IH) ppm;
MS (API-ES-pos.): M / z = 413 [(M + H) + , 100%], 825 [(2M + H) + , 14%];
HPLC: R τ = 37.1 min.
Instrument: HP 1100 Multiple Wavelength detection; Column: Phenomenex-Prodigy ODS (3) 100A, 150 mm x 3 mm, 3 microns; Eluent A: (1.36 g KH 2 PO 4 +0.7 mL H 3PO 4 ) / L water, eluent B: acetonitrile; Gradient: 0 min 20% B, 40 min 45% B, 50 min 80% B, 65 min 80% B; Flow: 0.5 mL / min; Temp .: 55 0 C; UV detection: 210 nm.
PATENT
Human cytomegalovirus (HCMV) is ubiquitously distributed in the human population. In immunocompetent adults infections are mainly asymptomatic, but in
immunocompromised patients, such as transplant recipients or AIDS patients, life threatening infections occur at a high rate. HCMV is also the leading cause of birth defects among congenitally transmitted viral infections.
Various substituted heterocyclic compounds are inhibitors of the HCMV terminase enzyme. Included in these heterocycles are quinazolines related to Compound A, as defined and described below. These compounds and pharmaceutically acceptable salts thereof are useful in the treatment or prophylaxis of infection by HCMV and in the treatment, prophylaxis, or delay in the onset or progression of HCMV infection. Representative quinazoline compounds that are useful for treating HCMV infection are described, for example, in US Patent Patent No. 7, 196,086. Among the compounds disclosed in US7, 196,086, is (S)-2-(8-fluoro-3-(2-methoxy-5-(trifluoromethyl)phenyl)-2-(4-(3-methoxyphenyl)piperazin-l-yl)-3,4-dihydroquinazolin-4-yl)acetic acid, hereinafter referred to as Compound A. Compound A is a known inhibitor of HCMV terminase. The structure of Compound A is as follows:
Compound A
US Patent Nos. 7,196,086 and 8,084,604 disclose methodology that can be employed to prepare Compound A and related quinazoline-based HCMV terminase inhibitors. These methods are practical routes for the preparation of Compound A and related heterocyclic compounds.
EXAMPLE 6
Preparation of Compound A
To a slurry of compound 7 (20g, 18.9 mmol) in MTBE (40.0 mL) at room temperature was added a solution of sodium phosphate dibasic dihydrate (8.42 g, 47.3 mmol) in water (80 mL) and the resulting slurry was allowed to stir at room temperature for 40 minutes. The reaction mixture was transferred to a separatory funnel and the organic phase was collected and washed with a solution of sodium phosphate dibasic dihydrate (3.37 g, 18.91 mmol) in water (40.0 mL). A solution of KOH (4.99 g, 76 mmol) in water (80 mL) and methanol (10.00 mL) was then added to the organic phase and the resulting mixture was heated to 50 °C and allowed to stir at this temperature for 6 hours. MTBE (20 mL) and water (40 mL) were then added to the
reaction mixture and the resulting solution was transferred to a separatory funnel and the aqueous layer was collected and washed with MTBE (20 mL). Additional MTBE (40 mL) was added to the aqueous layer and the resulting solution was adjusted to pH 4-5 via slow addition of concentrated HCl. The resulting acidified solution was transferred to a separatory funnel and the organic phase was collected, concentrated in vacuo and solvent switched with acetone, maintaining a 30 mL volume. The resulting acetone solution was added dropwise to water and the precipitate formed was filtered to provide compound A as a white solid (10 g, 92%). XH NMR (500 MHz, d6-DMSO): δΗ 12.6 (1H, s), 7.52 (1H, dd, J= 8.6, 1.3 Hz), 7.41 (1H, brs), 7.22 (1H, d, J= 7.2 Hz), 7.08-7.02 (2H, m), 6.87-6.84 (2H, m), 6.44 (1H, dd, J= 8.3, 1.8 Hz), 6.39 (1H, t, J= 2.1 Hz), 6.35 (1H, dd, J= 8.1, 2.0 Hz), 4.89 (1H, t, J= 7.3 Hz), 3.79 (3H, br s), 3.68 (3H, s), 3.47 (2H, br s), 3.39 (2H, br s), 2.96-2.93 (2H, m), 2.82-2.77 (3H, m), 2.44 (1H, dd, J = 14.8, 7.4 Hz).
XAMPLE 1
Preparation of Intermediate Compound 2
N,N-dicyclohexylmethylamine
IPAC, 80°C
To a degassed solution of 2-bromo-6-fluoroaniline (1, 99.5 g, 0.524 mol), methyl acrylate (95.0 mL, 1.05 mol), Chloro[(tri-tert-butylphosphine)-2-(2-aminobiphenyl)] palladium(II) (0.537 g, 1.05 mmol) in isopropyl acetate (796 mL), was added degassed N,N-dicyclohexylmethylamine (135 mL, 0.628 mol). The resulting reaction was heated to 80 °C and allowed to stir at this temperature for 5 hours. The resulting slurry was cooled to 20 °C and filtered. The filtrate was washed with 1 M citric acid to provide a solution that contained compound 2 (99.3 g, 97% assay yield) in isopropyl acrylate, which was used without further purification. ‘H NMR (500 MHz, d-CHCl3): δΗ 7.79 ppm (1H, d, J= 15.9 Hz), 7.17 ppm (1H, d, J= 8.2 Hz), 7.00 ppm (1H, ddd, J= 10.7, 8.2, 1.2 Hz), 6.69 ppm (1H, td, J = 8.2, 5.1 Hz), 6.38 ppm (1H, d, J= 15.9 Hz), 4.06 ppm (2H, br s), 3.81 ppm (3H, s).
EXAMPLE 2
Preparation of Intermediate Compound 3
To a solution of compound 2 (48.8 g, 0.250 mol) in 683 mL of isopropyl acetate was added 244 mL of water, followed by di-sodium hydrogen phosphate (53.2 g, 0.375 mol). To the resulting solution was added phenyl chloroformate (39.2 mL, 0.313 mol) dropwise over 30 minutes. The resulting reaction was heated to 30 °C and allowed to stir at this temperature for 5 hours for 4 hours and then was heated to 60 °C and allowed to stir at this temperature for 5 hours for an additional 2 hours to remove excess phenyl chloroformate. An additional 293 mL of isopropyl acetate was then added and the reaction mixture was allowed to stir at room temperature until the solids completely dissolved into solution. The resulting reaction mixture was transferred to a separatory funnel and the organic phase was washed with 98 mL of water and collected to provide a solution of compound 3 in isopropyl acetate, which was used without further purification. XH NMR (500 MHz, d-acetonitrile): δΗ 7.91 ppm (1H, d, J= 15.9 Hz), 7.85 ppm (1H, br s), 7.63 ppm (1H, d, J= 7.9 Hz), 7.45-7.39 ppm (3H, m), 7.33-7.27 ppm (2H, m), 7.21 ppm (2H, br), 6.60 ppm (1H, d, J= 16.0 Hz).
EXAMPLE 3
Preparation of Intermediate Compound 4
A solution of compound 3 (79.0 g, 0.250 mol), 2-methoxy-5-(trifluoromethyl)aniline (52.7 g, 0.276 mol), and 4-dimethylaminopyridine (0.92 g, 0.0075 mol) in isopropyl acetate (780 mL) was heated to reflux and allowed to stir at this temperature for 5 hours. The resulting slurry was cooled to 20 °C, then allowed to stir at this temperature for for two hours at this temperature, then filtered. The collected filter cake was dried in vacuo to provide compound 5 (95.0 g, 0.230 mol) as a white solid, which was used without further purification. ¾ NMR (500 MHz, d-TFA): δΗ 7.98 ppm (1H, d, J= 16.1 Hz), 7.87 ppm (1H, s), 7.47 ppm (1H, d, J = 7.9 Hz), 7.41 ppm (1H, d, J= 8.5 Hz), 7.35 ppm (1H, q, J= 8.5 Hz), 7.19 ppm (1H, t, J= 8.6 Hz), 6.98 ppm (1H, d, J= 8.6 Hz), 6.56 ppm (1H, d, J= 16.0 Hz), 3.85 ppm (6H, br s).
EXAMPLE 4
Preparation of Intermediate Compound 6
To a stirred suspension of compound 4 (14.0 g, 34.0 mmol) in toluene (140 mL) at room temperature was added 2-picoline (10.1 mL, 102 mmol) followed by PCI5 (8.19 g, 37.3 mmol). The resulting reaction was heated to 40 °C and allowed to stir at this temperature for 4 hours, then was cooled to 0 °C and cautiously (internal temperature kept <15 °C) quenched with KOH (2 M, 102 mL). The resulting solution was allowed to warm to room temperature, allowed to stir for 30 minutes, then was filtered and the filtrate transferred to a separatory funnel. The organic phase was washed sequentially with H3PO4 (1M, 50 mL) and H20 (50 mL) to provide a solution of compound 5 in toluene, which was used without further purification. XH NMR (500 MHz, d6-DMSO): δΗ 7.96 (1H, d, J= 16.2 Hz), 7.74 (1H, d, J= 7.9 Hz), 7.61 (1H, dd, J= 6.7, 1.6 Hz), 7.50 (1H, d, J= 1.9 Hz), 7.43 (1H, t, J= 9.2 Hz), 7.30 (1H, d, J= 8.4 Hz), 7.28 (1H, m), 6.79 (1H, d, J= 16.2 Hz), 3.91 (3H, s), 3.74 (3H, s).
To the solution of compound 5 at room temperature was added an aqueous solution of piperazine hydrochloride (0.40 M, 93.3 mL, 37.3 mmol) followed by Na2HP04 (14.5 g, 102 mmol). The resulting reaction was allowed to stir for 1 hour at room temperature, then transferred to a separatory funnel. The organic phase was washed sequentially with aH2P04 (50 mL) and H20 (50 mL). Salicylic acid (5.16 g, 37.3 mmol) was then added to the organic phase, and the resulting solution was cooled to 0 °C and allowed to stir at this temperature for 1 hour to provide a slurry which was filtered and washed with cold toluene (50 mL). The filter cake was dried under air to provide compound 6 (23.0 g, 31.7 mmol, 93 %) as a white crystalline solid: XH NMR (500 MHz, d6-DMSO): δΗ 12.9 (1H, br s), 7.75 (1H, dd, J= 7.8, 1.8 Hz), 7.72 (1H, d, J= 16.1 Hz), 7.40 (1H, td, J= 7.2, 1.7 Hz), 7.27 (1H, d, J= 7.8 Hz), 7.17 (1H, m), 7.16 (1H, t, J= 8.2 Hz), 7.02 (1H, br s), 6.95 (1H, t, J= 8.6 Hz), 6.88-6.81 (3H, m), 6.78 (1H, br s), 6.60 (1H, dd, J= 8.2, 2.0 Hz), 6.54 (1H, m), 6.48 (1H, d, J= 16.1 Hz), 6.43 (1H, dd, J= 8.0, 2.1 Hz), 3.73 (3H, s), 3.71 (3H, s), 3.69 (4H, br s), 3.68 (3H, s).
Free Base: XH NMR (500 MHz, CD3CN): δΗ 7.91 (1H, d, J= 16.1 Hz), 7.29 (1H, d, J= 8.0 Hz), 7.24 (1H, d, J= 1.4 Hz), 7.20 (1H, t, J= 8.1 Hz), 7.15 (1H, dd, J= 8.6, 1.4 Hz), 6.94 (1H, m), 6.92 (1H, t, J= 8.1 Hz), 6.80 (1H, td, J= 8.1, 5.4 Hz), 6.60 (1H, dd, J= 8.3, 2.2 Hz), 6.54 (1H, t, J= 2.2 Hz), 6.50 (1H, d, J= 16.1 Hz), 6.47 (2H, m), 3.80 (3H, s), 3.79 (3H, s), 3.72 (3H, s), 3.63 (4H, t, J= 5.1 Hz), 3.25 (4H, t, J= 5.0 Hz).
2: 1 NDSA Salt: ‘H NMR (500 MHz, d6-DMSO): δΗ 10.2 (2H, br s), 8.86 (1H, d, J= 8.6 Hz), 7.92 (1H, d, J= 7.0 Hz), 7.47-7.37 (4H, m), 7.27-7.14 (4H, m), 6.96 (1H, d, J= 8.6 Hz), 6.65 (1H, d, J= 8.3 Hz), 6.59 (1H, s), 6.54 (1H, d, J= 15.9 Hz), 6.47 (1H, d, J= 8.3 Hz), 3.91 (4H, m), 3.77 (3H, s), 3.76 (3H, s), 3.74 (3H, s), 3.43 (4H, m). 1,5 -naphthalene disulfonic acid
EXAMPLE 5
Preparation of Intermediate Compound 7
To a suspension of compound 6 (12.5 g, 16.6 mmol) in 125 mL of toluene was added 50 mL of 0.43M aqueous K3P04. The resulting reaction was allowed to stir for 1 hour at room temperature and the reaction mixture was transferred to a separatory funnel. The organic phase was collected, washed once with 30 mL 0.43M aqueous K3P04then cooled to 0 °C and aqueous K3P04 (60 mL, 0.43 M, 25.7 mmol) was added. To the resulting solution was added a room temperature solution of ((lS,2S,4S,5R)-l-(3,5-bis(trifluoromethyl)benzyl)-2-((R)-
hydroxy( 1 -(3 -(trifluoromethyl)benzyl)quinolin- 1 -ium-4-yl)methyl)-5-vinylquinuclidin- 1 -ium bromide) (0.704 g, 0.838 mmol) in 1.45 mL of DMF. The resulting reaction was allowed to stir at 0 °C until the reaction was complete (monitored by HPLC), then the reaction mixture was transferred to a separatory funnel and the organic phase was collected and washed sequentially with 1M glycolic acid (25 mL) and water (25 mL). The organic phase was filtered through solka flok and concentrated in vacuo to a total volume of 60 mL. Ethyl acetate (20 mL) was added to the resulting solution, followed by (S,S)-Di-P-Toluoyl-D-tartaric acid (5.61 g, 14.1 mmol). Penultimate seed (0.2 g) was added the resulting solution was allowed to stir at room
temperature for 12 hours. The solution was then filtered and the collected solid was washed twice with ethyl acetate, then dried in vacuo to provide compound 7 as its DTTA salt ethyl acetate solvate (13.8 g, 78%) . ‘H NMR (500 MHz, d6-DMSO): δΗ 13.95 (2H, br s), 7.90 (4H, d, J= 8.1 Hz), 7.55 (1H, dd, J= 8.6, 1.3 Hz), 7.38 (4H, d, J= 8.1 Hz), 7.26 (1H, d, J= 7.8 Hz), 7.09-7.05 (3H, m), 6.91-6.86 (2H, m), 6.44 (1H, dd, J= 8.2, 1.7 Hz), 6.39 (1H, t, J= 2.0 Hz), 6.36 (1H, dd, J= 8.2, 2.0 Hz), 5.82 (2H, s), 4.94 (1H, t, J= 7.1 Hz), 4.02 (2H, q, J= 7.1 Hz), 3.83 (3H, br s), 3.68 (3H, s), 3.64 (3H, s), 3.47 (2H, br s), 3.37 (2H, br s), 2.95 (2H, br s), 2.87- 2.80 (3H, m), 2.56 (1H, dd, J= 14.3, 7.0 Hz), 2.39 (6H, s), 1.98 (3H, s), 1.17 (3H, t, J= 7.1 Hz).
PAPER
ACS Editors’ Choice – This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes.
The development of a concise asymmetric synthesis of the antiviral development candidate letermovir is reported, proceeding in >60% yield over a total of seven steps from commercially available materials. Key to the effectiveness of this process is a novel cinchonidine-based PTC-catalyzed aza-Michael reaction to configure the single stereocenter.
http://pubs.acs.org/doi/full/10.1021/acs.oprd.6b00076
(S)-2-(8-Fluoro-3-(2-methoxy-5-(trifluoromethyl)phenyl)-2-(4-(3-methoxyphenyl)piperazin-1-yl)-3,4-dihydroquinazolin-4-yl)acetic Acid (Letermovir, 1)
Masangkay, Estel Grace (July 29, 2014). “Merck Kicks Off Phase 3 Study Of CMV Drug Letermovir”. Retrieved 8 Oct 2014.
| Patent ID | Date | Patent Title |
|---|---|---|
| US8084604 | 2011-12-27 | Process for the Preparation of Dihydroquinazolines |
| US2007191387 | 2007-08-16 | Substituted dihydroquinazolines |
| Patent ID | Date | Patent Title |
|---|---|---|
| US2015133461 | 2015-05-14 | PHARMACEUTICAL COMPOSITION CONTAINING AN ANTIVIRALLY ACTIVE DIHYDROQUINAZOLINE DERIVATIVE |
| US2015050241 | 2015-02-19 | METHOD OF TREATING VIRAL INFECTIONS |
| US2015045371 | 2015-02-12 | Salts of a dihydroquinazoline derivative |
| US2015038514 | 2015-02-05 | SODIUM AND CALCIUM SALTS OF DIHYDROQUINAZOLINE DERIVATIVE AND USE THEREOF AS ANTIVIRAL AGENTS |
| US2015038728 | 2015-02-05 | NOVEL ARYLATED CAMPHENES, PROCESSES FOR THEIR PREPARATION AND USES THEREOF |
| US8816075 | 2014-08-26 | Process for the preparation of dihydroquinazolines |
| US2014193802 | 2014-07-10 | IDENTIFICATION OF AN ALTERED THERAPEUTIC SUSCEPTIBILITY TO ANTI-HCMV COMPOUNDS AND OF A RESISTANCE AGAINST ANTI-HCMV COMPOUNDS |
| US2014178432 | 2014-06-26 | PRODUCTION OF DENSE BODIES (DB) FROM HCMV-INFECTED CELLS |
| US8372972 | 2013-02-12 | Process for the preparation of dihydroquinazolines |
| US8084604 | 2011-12-27 | Process for the Preparation of Dihydroquinazolines |
 |
|
| Systematic (IUPAC) name | |
|---|---|
|
{(4S)-8-Fluoro-2-[4-(3-methoxyphenyl)-1-piperazinyl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydro-4-quinazolinyl}acetic acid
|
|
| Clinical data | |
| Routes of administration |
Oral |
| Legal status | |
| Legal status |
|
| Identifiers | |
| ATC code | None |
| PubChem | CID 45138674 |
| ChemSpider | 26352849 |
| UNII | 1H09Y5WO1F |
| ChEMBL | CHEMBL1241951 |
| Synonyms | AIC246 |
| Chemical data | |
| Formula | C29H28F4N4O4 |
| Molar mass | 572.55 g/mol |
/////Letermovir, MK 8828, AIC 246, fast track status, US Food and Drug Administration, orphan drug status , European Medicines Agency
COC1=C(C=C(C=C1)C(F)(F)F)N2[C@H](C3=C(C(=CC=C3)F)N=C2N4CCN(CC4)C5=CC(=CC=C5)OC)CC(=O)O
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 |
Sequence Length: 1018modified (modifications unspecified)
| 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 |
Reslizumab
(Cinqair®) Approved Active, FDA 2016-03-23
An interleukin-5 (IL-5) antagonist used to treat severe asthma.
CAS 241473-69-8
Research Code CDP-835; CEP-38072; CTx-55700; SCH-5570; SCH-55700; TRFK-5,
Anti-interleukin-5 monoclonal antibody – Celltech/Schering-Plough
Reslizumab was approved by the U.S. Food and Drug Administration (FDA) on March 23, 2016. It was developed and marketed as Cinqair® by Teva.
Reslizumab is an interleukin-5 antagonist, which binds to human IL-5 and prevents it from binding to the IL-5 receptor, thereby reducing eosinophilic inflammation. It is indicated for the maintenance treatment of patients with severe asthma in patients aged 18 years and older.
Cinqair® is available as injection for intravenous infusion, containing 100 mg of reslizumab in 10 mL solution in single-use vials. The recommended dose is 3 mg/kg once every four weeks.
Reslizumab (trade name Cinqair) is a humanized monoclonal antibody intended for the treatment of eosinophil-meditated inflammations of the airways, skin and gastrointestinal tract.[1] The FDA approved reslizumab for use with other asthma medicines for the maintenance treatment of severe asthma in patients aged 18 years and older on March 23, 2016. Cinqair is approved for patients who have a history of severe asthma attacks (exacerbations) despite receiving their current asthma medicines.[2]
Investigational Biologic for the Treatment of Inadequately Controlled Asthma in Patients with Elevated Blood Eosinophils Accepted for Review
JERUSALEM–(BUSINESS WIRE)–Jun. 15, 2015– Teva Pharmaceutical Industries Ltd., (NYSE: TEVA) announced today that the U.S. Food and Drug Administration (FDA) has accepted for review the Biologics License Application (BLA) for reslizumab, the company’s investigational humanized monoclonal antibody (mAb) which targets interleukin-5 (IL-5), for the treatment of inadequately controlled asthma in adult and adolescent patients with elevated blood eosinophils, despite an inhaled corticosteroid (ICS)-based regimen.
“Despite currently available medicines, uncontrolled asthma remains a serious problem for patients, physicians and healthcare systems, highlighting the need for targeted new treatment options,” said Dr. Michael Hayden, President of Global R&D and Chief Scientific Officer at Teva Pharmaceutical Industries Ltd. “The reslizumab BLA filing acceptance represents a significant milestone for Teva as we work toward serving a specific asthma patient population that is defined by elevated blood eosinophil levels and inadequately controlled symptoms despite standard of care therapy. In clinical trials, patients treated with reslizumab showed significant reductions in the rate of asthma exacerbations and significant improvement in lung function. If approved, we believe reslizumab will serve as an important new targeted treatment option to achieve better asthma control for patients with eosinophil-mediated disease.”
The BLA for reslizumab includes data from Teva’s Phase III BREATH clinical trial program. The program consisted of four separate placebo-controlled Phase III trials involving more than 1,700 adult and adolescent asthma patients with elevated blood eosinophils, whose symptoms were inadequately controlled with inhaled corticosteroid-based therapies. Results from these studies demonstrated that reslizumab, in comparison to placebo, reduced asthma exacerbation rates by at least half and provided significant improvement in lung function and other secondary measures of asthma control when added to an existing ICS-based therapy. Common adverse events in the reslizumab treatment group were comparable to placebo and included worsening of asthma, nasopharyngitis, upper respiratory infections, sinusitis, influenza and headache. Two anaphylactic reactions were reported and resolved following medical treatment at the study site.
Results from the reslizumab BREATH program were recently presented at the American Thoracic Society 2015 Annual Meeting and the American Academy of Allergy, Asthma and Immunology 2015 Annual Meeting, in addition to being published in The Lancet Respiratory Medicine. The BLA for reslizumab has been accepted for filing by the FDA for standard review, with FDA Regulatory Action expected in March 2016.
About Reslizumab
Reslizumab is an investigational humanized monoclonal antibody which targets interleukin-5 (IL-5). IL-5 is a key cytokine involved in the maturation, recruitment, and activation of eosinophils, which are inflammatory white blood cells implicated in a number of diseases, such as asthma. Elevated levels of blood eosinophils are a risk factor for future asthma exacerbations. Reslizumab binds circulating IL-5 thereby preventing IL-5 from binding to its receptor.
About Asthma
Asthma is a chronic (long term) disease usually characterized by airway inflammation and narrowing of the airways, which can vary over time. Asthma may cause recurring periods of wheezing (a whistling sound when you breathe), chest tightness, shortness of breath and coughing that often occurs at night or early in the morning. Without appropriate treatment, asthma symptoms may become more severe and result in an asthma attack, which can lead to hospitalization and even death.
About Eosinophils
Eosinophils are a type of white blood cell that are present at elevated levels in the lungs and blood of many asthmatics. Evidence shows that eosinophils play an active role in the pathogenesis of the disease. IL-5 has been shown to play a crucial role in maturation, growth and activation of eosinophils. Increased levels of eosinophils in the sputum and blood have been shown to correlate with severity and frequency of asthma exacerbations.
About Teva
Teva Pharmaceutical Industries Ltd. (NYSE and TASE: TEVA) is a leading global pharmaceutical company that delivers high-quality, patient-centric healthcare solutions to millions of patients every day. Headquartered in Israel, Teva is the world’s largest generic medicines producer, leveraging its portfolio of more than 1,000 molecules to produce a wide range of generic products in nearly every therapeutic area. In specialty medicines, Teva has a world-leading position in innovative treatments for disorders of the central nervous system, including pain, as well as a strong portfolio of respiratory products. Teva integrates its generics and specialty capabilities in its global research and development division to create new ways of addressing unmet patient needs by combining drug development capabilities with devices, services and technologies. Teva’s net revenues in 2014 amounted to $20.3 billion. For more information, visit www.tevapharm.com.
The U.S. Food and Drug Administration today approved Cinqair (reslizumab) for use with other asthma medicines for the maintenance treatment of severe asthma in patients aged 18 years and older. Cinqair is approved for patients who have a history of severe asthma attacks (exacerbations) despite receiving their current asthma medicines.
Asthma is a chronic disease that causes inflammation in the airways of the lungs. During an asthma attack, airways become narrow making it hard to breathe. Severe asthma attacks can lead to asthma-related hospitalizations because these attacks can be serious and even life-threatening. According to the Centers for Disease Control and Prevention, as of 2013, more than 22 million people in the U.S. have asthma, and there are more than 400,000 asthma-related hospitalizations each year.
“Health care providers and their patients with severe asthma now have another treatment option to consider when the disease is not well controlled by their current asthma therapies,” said Badrul Chowdhury, M.D., Ph.D., director of the Division of Pulmonary, Allergy, and Rheumatology Products in the FDA’s Center for Drug Evaluation and Research.
Cinqair is administered once every four weeks via intravenous infusion by a health care professional in a clinical setting prepared to manage anaphylaxis. Cinqair is a humanized interleukin-5 antagonist monoclonal antibody produced by recombinant DNA technology in murine myeloma non-secreting 0 (NS0) cells. Cinqair reduces severe asthma attacks by reducing the levels of blood eosinophils, a type of white blood cell that contributes to the development of asthma.
The safety and efficacy of Cinqair were established in four double-blind, randomized, placebo‑controlled trials in patients with severe asthma on currently available therapies. Cinqair or a placebo was administered to patients every four weeks as an add-on asthma treatment. Compared with placebo, patients with severe asthma receiving Cinqair had fewer asthma attacks, and a longer time to the first attack. In addition, treatment with Cinqair resulted in a significant improvement in lung function, as measured by the volume of air exhaled by patients in one second.
Cinqair can cause serious side effects including allergic (hypersensitivity) reactions. These reactions can be life-threatening. The most common side effects in clinical trials for Cinqair included anaphylaxis, cancer, and muscle pain.
Cinqair is made by Teva Pharmaceuticals in Frazer, Pennsylvania.
| Monoclonal antibody | |
|---|---|
| Type | Whole antibody |
| Source | Humanized (from rat) |
| Target | IL-5 |
| Clinical data | |
| Trade names | Cinquil |
| Identifiers | |
| ATC code | R03DX08 (WHO) |
| ChemSpider | none |
/////////CDP-835, CEP-38072, CTx-55700, SCH-5570, SCH-55700, TRFK-5, Reslizumab, Cinqair®, teva, interleukin-5 (IL-5) antagonist, severe asthma, FDA 2016, Orphan Drug StatuS
| C29H34Cl2N6O3S2 | |
| Molecular Weight: | 649.65466 g/mol |
|---|
Elemental Analysis: C, 53.61; H, 5.28; Cl, 10.91; N, 12.94; O, 7.39; S, 9.87
1-[3-chloro-5-[[4-(4-chlorothiophen-2-yl)-5-(4-cyclohexylpiperazin-1-yl)-1,3-thiazol-2-yl]carbamoyl]pyridin-2-yl]piperidine-4-carboxylic acid,
1-(3-Chloro-5-[[4-(4-chlorothiophen-2-yl)-5-(4-cyclohexylpiperazin-1-yl)thiazol-2-yl]carbamoyl]pyridin-2-yl)piperidine-4-carboxylic acid,
1-[3-Chloro-5-[[4-(4-chlorothiophen-2-yl)-5-(4-cyclohexylpiperazin-1-yl)thiazol-2-yl]carbamoyl]-2-pyridyl]piperidine-4-carboxylic acid
4-Piperidinecarboxylic acid, 1-[3-chloro-5-[[[4-(4-chloro-2-thienyl)-5-(4-cyclohexyl-1-piperazinyl)-2-thiazolyl]amino]carbonyl]-2-pyridinyl]-
Phase III Clinical Trials
Drugs used in platelet disorders
Idiopathic thrombocytopenic purpura (ITP)
small-molecule thrombopoietin receptor (c-Mpl) agonist that stimulates platelet production
INNOVATOR: YAMANOUCHI PHARMACEUTICAL
DEVELOPER: Eisai
| C33H38Cl2N6O7S2 | |
| Molecular Weight: | 765.72682 g/mol |
|---|
(Z)-but-2-enedioic acid;1-[3-chloro-5-[[4-(4-chlorothiophen-2-yl)-5-(4-cyclohexylpiperazin-1-yl)-1,3-thiazol-2-yl]carbamoyl]pyridin-2-yl]piperidine-4-carboxylic acid
INTRODUCTION
Avatrombopag, also known as AKR-501, YM477, AS 1670542 or E5501, is a novel orally-active thrombopoietin (TPO) receptor agonist. AKR-501 specifically targeted the TPO receptor and stimulated megakaryocytopoiesis throughout the development and maturation of megakaryocytes just as rhTPO did. Daily oral administration of AKR-501 dose-dependently increased the number of human platelets in these mice, with significance achieved at doses of 1 mg/kg and above. The peak unbound plasma concentrations of AKR-501 after administration at 1 mg/kg in NOD/SCID mice were similar to those observed following administration of an active oral dose in human subjects. AKR-501 may be useful in the treatment of patients with thrombocytopenia. (source: Eur J Haematol. 2009 Apr;82(4):247-54).
Avatrombopag is a thrombopoietin receptor (c-Mpl) agonist in phase III clinical evaluation at Eisai for the oral treatment of chronic immune thrombocytopenia (idiopathic thrombocytopenia purpura) and for the treatment of thrombocytopenia associated with liver diseases. Phase II studies are ongoing for the treatment of thrombocytopenia during antiviral therapy (inhibition and maintenance) with Interferon for hepatitis C.
The drug candidate may hold potential in treating thrombocytopenia of diverse etiologies, including idiopathic thrombocytopenic purpura (ITP) and thrombocytopenia of myelodysplastic syndromes (MDS), in combination with or as a substitute for platelet transfusion.
AKR-501, a novel, small-molecule thrombopoietin mimetic being investigated for the treatment of thrombocytopenia. AkaRx is now a wholly-owned subsidiary of Eisai Inc. and Eisai has the exclusive worldwide rights to develop, market and manufacture AKR-501. AKR-501 is an investigational thrombopoietin receptor agonist that, based on preclinical studies, increases platelet production by stimulating megakaryocytic proliferation and differentiation. Eisai is currently conducting Phase II clinical trials of AKR-501 in the United States as a potential treatment for idiopathic thrombocytopenic purpura (ITP) and thrombocytopenia associated with liver diseases (TLD), and has confirmed proof of concept in the clinical studies for ITP. In addition, Eisai will explore the compound’s potential as a treatment for chemotherapy-induced thrombocytopenia (CIT).
E-5501 stimulates the production of thrombopoietin (TPO), a glycoprotein hormone that stimulates the production and differentiation of megakaryocytes, the bone marrow cells that fragment into large numbers of platelets. The drug candidate was originally developed at Yamanouchi, and development responsibilities were passed to AkaRx when it was formed in 2005 as a spin-off following the creation of Astellas Pharma subsequent to the merger of Yamanouchi Pharmaceutical and Fujisawa Healthcare.
In 2007, MGI Pharma was granted a license to E-5501 for the treatment of thrombocytopenia. Eisai eventually gained the rights to the product as results of its acquisition of MGI Pharma. In 2010, Eisai acquired AkaRx. AkaRx is now a wholly-owned subsidiary of Eisai Inc. and Eisai has the exclusive worldwide rights to develop, market and manufacture E-5501. In 2011, orphan drug designation was assigned by the FDA for the treatment of idiopathic thrombocytopenic purpura.
E5501 (or AKR-501 or YM477) is a small molecule agonist c-Mpl, orally available. It is in clinical trials for the treatment of chronic idiopathic thrombocytopenic purpura (ITP). It acts as an agonist of the thrombopoietin receptor active orally, mimicking its biological effect. Thrombocytopenic purpura The is the idiopathic consequence of a low number of platelets (thrombocytopenia) of unknown cause. A very low platelets can even lead to purpura (bruises), or bleeding diathesis.
February 2012: A Phase III, multicenter, randomized, double-blind, controlled against placebo, parallel group, with an open-label extension phase to assess the efficacy and safety of combined oral E5501 to standard treatment for the treatment of thrombocytopenia in adults with chronic immune thrombocytopenia, is underway.
January 2010: Eisai Inc. announced its successful acquisition of the biopharmaceutical company, AkaRx Inc. Following this acquisition, AkaRx became a wholly owned subsidiary of Eisai Inc. Eisai now owns the worldwide exclusive rights to develop , marketing and manufacture AKR-501.
October 2009: Eisai Research Institute of Boston, Inc. (established in 1987) and Eisai Medical Research Inc. (established in 2002) were merged into Eisai Inc. 2005: AkaRx was founded as a spin-out of the merger of Yamanouchi Pharmaceutical Company Ltd. and Fujisawa Pharmaceutical Company Ltd. to form Astellas Pharma Inc. AKR-501 was discovered by Yamanouchi and was licensed to AkaRx as part of the foundation of the company in 2005.
In a Phase I trial in healthy volunteers, 10 mg of AKR-501 for 14 days, increased platelet count by 50%.AKR-501 was well tolerated in both studies, mono- and multi-dose. No adverse effects were reported, even at the highest doses.
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Patent
Compound A is a compound of the present invention has the following chemical structure.
That is, compounds useful as a platelet 增多 agent according to the present invention A, as well as medicaments for the Compound A as an active ingredient, in particular increasing platelets agents and Z or thrombocytopenia treating agent.
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PATENT
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JP 2014144916/WO 2013018362
https://www.google.co.in/patents/WO2013018362A1?cl=en
1-(3-chloro-5-{[4-(4-chlorothiophen-2-yl)-5-(4-cyclohexylpiperazin-1-yl)thiazol-2-yl]carbamoyl}pyridin-2-yl)piperidine-4-carboxylic acid as expressed by the following chemical formula (hereinafter referred to as “Compound X”) and pharmaceutically acceptable salts are known to have excellent thrombocytosis effects (patent literature 1, patent literature 2).
[Formula 1]
Patent literature 1 discloses a hydrochloride of compound X as example 16 (hereinafter referred to as “compound X hydrochloride”).
Furthermore, patent literature 2 discloses a maleic acid salt of compound X that has endothermic peaks near 198 degree C and 271 degree C in thermo gravimetric analysis (hereinafter referred to as “maleic acid salt of compound X”). However, patent literature 2 neither discloses nor suggests that the maleic acid salt of compound X exhibits crystal polymorphism.
On the other hand, compounds exhibiting crystal polymorphism demonstrate entirely different effects regardless of being the same compound, because various physical properties including physicochemical properties differ depending on the crystalline form. In pharmaceutical products in particular, if compounds that have different functional effects are expected to have the same effect, a different functional effect than expected will occur, which is thought to induce unexpected circumstances, and therefore there is demand for supply of a drug substance with constant quality. Therefore, when a compound which has crystal polymorphism is used as a medicine, one type of crystal of that compound must always be constantly provided in order to ensure constant quality and constant effects that are required of the medicine.
Under the aforementioned conditions, from the perspective of supplying a drug substance for medicines, there is a need for compound X or crystals of pharmaceutically acceptable salts thereof, which can ensure constant quality and constant effects and which can be stably supplied in mass production such as industrial production or the like, as well as for establishment of a manufacturing method thereof.
International patent publication WO 03/062233 International patent publication WO 2004/029049
The crystals of compound X maleic acid salt disclosed in patent literature 2 (hereinafter referred to as “compound X maleic acid salt A type crystals”) cannot be isolated as compound X maleic acid salt A type crystals when scaled up for mass production using the method disclosed in example 1 of patent literature 2, and therefore must be isolated in a different crystal form. (This other crystal form is referred to as “compound X maleic acid salt B type crystals”). Therefore, the compound X maleic acid salt A type crystals have a possibility that the crystal form will morph depending on the scale of production, and is clearly inappropriate as a drug substance for medicines which require constant quality and constant effects.
Preparation Example 1: Manufacture of Compound X Maleic Acid Salt B Type Crystal
310 mL of a 1 M aqueous solution of sodium hydroxide at room temperature was added to a mixture of 70.0 g of the ethyl ester of 1-(3-chloro-5-{[4-(4-chlorothiophen-2-yl)-5-(4-cyclohexyl piperazin-1-yl) thiazol-2-yl] carbamoyl} pyridin-2-yl) piperidine-4-carboxylic acid and 1.2 L of ethanol, the insoluble matter was filtered out, and then washed with 200 mL of ethanol. The reaction solution was stirred for 90 minutes at 60 degree C. After cooling to room temperature, 1.4 L of an aqueous solution containing 24.11 g of maleic acid was added to the solution obtained, and then the precipitate was collected by filtering.
The same operation was repeated and when combined with the previously obtained precipitate, 136.05 g of 1-(3-chloro-5-{[4-(4-chlorothiophen-2-yl)-5-(4-cyclohexyl piperazin-1-yl) thiazol-2-yl] carbamoyl} pyridin-2-yl) piperidine-4-carboxylic acid was obtained.
18.9 g of maleic acid and 2.1 L of 80% ethanol water were added to 88.90 g of the carboxylic acid obtained, and the solution was stirred for one hour at room temperature and for another hour at 100 degree C. After cooling to room temperature and further cooling with ice, the precipitated solid was filtered out to obtain 87.79 g of 1-(3-chloro-5-{[4-(4-chlorothiophen-2-yl)-5-(4-cyclohexyl piperazin-1-yl) thiazol-2-yl] carbamoyl} pyridin-2-yl) piperidine-4-carboxylic acid maleic acid salt as a crude product.
6.84 g of maleic acid was added to 231 g of the crude product containing the crude product obtained above and those manufactured in a similar manner, dissolved in 5.5 L of 80% ethanol water, and then the precipitated solid was collected by filtering to obtain 203 g of 1-(3-chloro-5-{[4-(4-chlorothiophen-2-yl)-5-(4-cyclohexyl piperazin-1-yl) thiazol-2-yl] carbamoyl} pyridin-2-yl) piperidine-4-carboxylic acid maleic acid salt.
Example 1: Manufacture of Compound X Maleic Acid Salt C Type Crystals (1)
1.52 L of ethanol, 0.38 L of water, and 15.7 g of maleic acid were added to 78.59 g of 1-(3-chloro-5-{[4-(4-chlorothiophen-2-yl)-5-(4-cyclohexyl piperazin-1-yl) thiazol-2-yl] carbamoyl} pyridin-2-yl) piperidine-4-carboxylic acid, and heated while stirring. After cooling to room temperature and further cooling with ice, the precipitated solid was collected by filtering to obtain 71.60 g of 1-(3-chloro-5-{[4-(4-chlorothiophen-2-yl)-5-(4-cyclohexyl piperazin-1-yl) thiazol-2-yl] carbamoyl} pyridin-2-yl) piperidine-4-carboxylic acid maleic acid salt as a crude product.
296 mg of maleic acid was added to 10.0 g of the crude product obtained, dissolved in 60 mL of acetone, 60 mL of DMSO, and 30 mL of water, and then the precipitated solids were collected to obtain 8.41 g of 1-(3-chloro-5-{[4-(4-chlorothiophen-2-yl)-5-(4-cyclohexyl piperazin-1-yl) thiazol-2-yl] carbamoyl} pyridin-2-yl) piperidine-4-carboxylic acid maleic acid salt.
Example 2: Manufacture of Compound X Maleic Acid Salt C Type Crystals (2)
A mixture containing 80.1 g of 1-(3-chloro-5-{[4-(4-chlorothiophen-2-yl)-5-(4-cyclohexyl piperazin-1-yl) thiazol-2-yl] carbamoyl} pyridin-2-yl) piperidine-4-carboxylic acid, 580 mL of DMSO, 580 mL of acetone, 17.2 g of maleic acid, and 290 mL of water was stirred at 69 degree C. The insoluble matter was filtered out, washed with a mixture of 32 mL of DMSO, 32 mL of acetone, and 16 mL of water, and then the filtrate was cooled and the precipitate was collected by filtering. Washing was successively performed using 150 mL of water, 80 mL of acetone, 650 mL of water, and 80 mL of acetone, followed by drying, to obtain 70.66 g of 1-(3-chloro-5-{[4-(4-chlorothiophen-2-yl)-5-(4-cyclohexyl piperazin-1-yl) thiazol-2-yl] carbamoyl} pyridin-2-yl) piperidine-4-carboxylic acid maleic acid salt.
Example 3: Manufacture of Compound X Maleic Acid Salt C Type Crystals (3)
A mixture containing 20 kg of 1-(3-chloro-5-{[4-(4-chlorothiophen-2-yl)-5-(4-cyclohexyl piperazin-1-yl) thiazol-2-yl] carbamoyl} pyridin-2-yl) piperidine-4-carboxylic acid, 100 L of DMSO, 100 L of acetone, 4.29 kg of maleic acid, and 50 L of water is stirred at 65 degree C, and then the insoluble matter is filtered out and washed with a mixture of 8 L of DMSO, 8 L of acetone, and 4 L of water, and then the filtrate is cooled, the precipitate is collected by filtering, successively washed using 40 L of acetone, 100 L of water, and 40 L of acetone, and then dried to obtain approximately 20 kg of 1-(3-chloro-5-{[4-(4-chlorothiophen-2-yl)-5-(4-cyclohexyl piperazin-1-yl) thiazol-2-yl] carbamoyl} pyridin-2-yl) piperidine-4-carboxylic acid maleic acid salt.
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REFERENCES
Garabet, L.; Ghanima, W.; Lee, S.; Mowinckel, M.C.; Liebman, H.; Jonassen, C.M.; Bussel, J.; Sandset, P.M.
Thrombopoietin receptor agonists do no not cause coagulation activation: In patients with immune thrombocytopenia
25th Congr Int Soc Thromb Haemost (ISTH) (June 20-25, Toronto) 2015, Abst PO311-MON
Terrault, N.; Hassanein, T.; Joshi, S.; Lake, J.R.; Sher, L.S.; Vargas, H.E.; McIntosh, J.W.; Tang, S.; Jenkins, T.
Once-daily oral avatrombopag (E5501) prior to elective surgical or diagnostic procedures in patients with chronic liver disease and thrombocytopenia: Results from a phase 2, randomized, double-blind, placebo-controlled study (study 202)
63rd Annu Meet Am Assoc Study Liver Dis (November 9-13, Boston) 2012, Abst
Thiophenyl Triazol-3-one Derivatives As Smooth Muscle relaxers: US6613786 (2003) Priority: US20010336865P, Nov. 2, 2001 (Bristol-Myers Squibb CO, US)
Preparation Of Avatrombopag: 2-Acylaminothiazole derivative or salt thereof: EP1466912 (2004) Priority: JP20020010413, 18 Jan. 2002 (Yamanouchi Pharma Co Ltd, Japan)
Synthesis And Use Of MSE Framework-Type Molecular Sieves: US2009318696 (2009) Priority: US20080214631 20 Jun. 2008 (Exxon Mobil, US).
5,6-Dichloro-Nicotinic Acid Production By Reacting 6-Hydroxy-Nicotinic Acid With Acid Chloride Reacting With Chlorine Products, Then With Acid Chloride And Hydrolysing Products: CH664754 (1988) Priority: CH19850002692, 25 Jun. 1985 (Lonza AG, Switzerland).
David J. Kuter, New Thrombopoietic Growth Factors, Lymphoma and Myeloma Clinical Journal Volume 9, Supplement 3, S347-S356
| WO2003062233A1 | 15 Jan 2003 | 31 Jul 2003 | Yamanouchi Pharma Co Ltd | 2-acylaminothiazole derivative or salt thereof |
| WO2004029049A1 | 29 Sep 2003 | 8 Apr 2004 | Yuuji Awamura | Novel salt of 2-acylaminothiazole derivative |
| Citing Patent | Filing date | Publication date | Applicant | Title |
|---|---|---|---|---|
| EP2764866A1 | 4 Feb 2014 | 13 Aug 2014 | IP Gesellschaft für Management mbH | Inhibitors of nedd8-activating enzyme |
| Patent | Submitted | Granted |
|---|---|---|
| CANCER TREATMENT METHOD [US2011160130] | 2011-06-30 | |
| METHOD FOR STIMULATING PLATELET PRODUCTION [US2011166112] | 2011-07-07 | |
| COMPOSITIONS AND METHODS FOR INCREASING BLOOD PLATELET LEVELS IN HUMANS [US2011224226] | 2011-09-15 | |
| Method of treating viral diseases with combinations of TPO receptor agonist and anti-viral agents [US2012020923] | 2012-01-26 |
| Patent | Submitted | Granted |
|---|---|---|
| 2-Acylaminothiazole derivative or salt thereof [US7638536] | 2005-07-14 | 2009-12-29 |
| Compositions and methods for treating thrombocytopenia [US2007203153] | 2007-08-30 | |
| Novel Combinations [US2009304634] | 2009-12-10 | |
| 2-ACYLAMINOTHIAZOLE DERIVATIVE OR SALT THEREOF [US2010222329] | 2010-09-02 | |
| 2-ACYLAMINOTHIAZOLE DERIVATIVE OR SALT THEREOF [US2010222361] | 2010-09-02 | |
| Compositions and methods for increasing blood platelet levels in humans [US2008039475] | 2008-02-14 | |
| CANCER TREATMENT METHOD [US2009022814] | 2009-01-22 | |
| Compositions and methods for treating thrombocytopenia [US2010041668] | 2010-02-18 | |
| CANCER TREATMENT METHOD [US2010075928] | 2010-03-25 |
///////E 5501, AKR 501, Phase III, eisai, Avatrombopag, y 477, orphan drug, ym 477, AS 1670542, Yamanouchi Pharma Co Ltd, Japan
UPDATE MAY 2018
Avatrombopag
https://newdrugapprovals.org/2015/08/24/avatrombopag/
The U.S. Food and Drug Administration today approved Doptelet (avatrombopag) tablets to treat low blood platelet count (thrombocytopenia) in adults with chronic liver disease who are scheduled to undergo a medical or dental procedure. This is the first drug approved by the FDA for this use.Continue reading.
May 21, 2018
The U.S. Food and Drug Administration today approved Doptelet (avatrombopag) tablets to treat low blood platelet count (thrombocytopenia) in adults with chronic liver disease who are scheduled to undergo a medical or dental procedure. This is the first drug approved by the FDA for this use.
“Patients with chronic liver disease who have low platelet counts and require a procedure are at increased risk of bleeding,” said Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “Doptelet was demonstrated to safely increase the platelet count. This drug may decrease or eliminate the need for platelet transfusions, which are associated with risk of infection and other adverse reactions.”
Platelets (thrombocytes) are colorless cells produced in the bone marrow that help form blood clots in the vascular system and prevent bleeding. Thrombocytopenia is a condition in which there is a lower-than-normal number of circulating platelets in the blood. When patients have moderately to severely reduced platelet counts, serious or life-threatening bleeding can occur, especially during invasive procedures. Patients with significant thrombocytopenia typically receive platelet transfusions immediately prior to a procedure to increase the platelet count.
The safety and efficacy of Doptelet was studied in two trials (ADAPT-1 and ADAPT-2) involving 435 patients with chronic liver disease and severe thrombocytopenia who were scheduled to undergo a procedure that would typically require platelet transfusion. The trials investigated two dose levels of Doptelet administered orally over five days as compared to placebo (no treatment). The trial results showed that for both dose levels of Doptelet, a higher proportion of patients had increased platelet counts and did not require platelet transfusion or any rescue therapy on the day of the procedure and up to seven days following the procedure as compared to those treated with placebo.
The most common side effects reported by clinical trial participants who received Doptelet were fever, stomach (abdominal) pain, nausea, headache, fatigue and swelling in the hands or feet (edema). People with chronic liver disease and people with certain blood clotting conditions may have an increased risk of developing blood clots when taking Doptelet.
This product was granted Priority Review, under which the FDA’s goal is to take action on an application within six months where the agency determines that the drug, if approved, would significantly improve the safety or effectiveness of treating, diagnosing or preventing a serious condition.
The FDA granted this approval to AkaRx Inc.
//////////////Doptelet, avatrombopag, fda 2018, akarx, priority review,
ET-743, Yondelis (trabectedin)
Trabectedin, Ecteinascidin 743, NSC-684766, ET-743, Yondelis, ID0YZQ2TCP
cas 114899-77-3
(-)-(1’R,6R,6aR,7R,13S,14S,16R)-5-Acetoxy-6′,8,14-trihydroxy-7′,9-dimethoxy-4,10,23-trimethyl-1′,2′,3′,4′,6a,7,12,13,14,16-decahydro-6H-spiro[6,16-(epithiopropanoxymethano)-7,13-epimino-1,3-dioxolo[7,8]isoquino[3,2-b][3]benzazocine-20,1′-isoquinolin]-19-one
Janssen seeks FDA approval for Yondelis drug to treat advanced STS
Janssen Research & Development is seeking approval from US Food and Drug Administration (FDA) for its Yondelis (trabectedin) to treat patients with advanced soft tissue sarcoma (STS).
http://www.pharmaceutical-technology.com/news/newsjanssen-yondelis-sts-4451060?WT.mc_id=DN_News
Trabectedin, also referred as ET-743 during its development, is a marine derived antitumoral agent discovered in the Carribean tunicate _Ecteinascidia turbinata_ and now produced synthetically. Trabectedin has a unique mechanism of action. It binds to the minor groove of DNA interfering with cell division and genetic transcription processes and DNA repair machinery.It is approved for use in Europe, Russia and South Korea for the treatment of advanced soft tissue sarcoma. It is also undergoing clinical trials for the treatment of breast, prostate, and paediatric sarcomas. The European Commission and the U.S. Food and Drug Administration (FDA) have granted orphan drug status to trabectedin for soft tissue sarcomas and ovarian cancer.
Trabectedin (also known as ecteinascidin 743 or ET-743) is an anti-tumor drug. It is sold by Zeltia and Johnson and Johnson under the brand name Yondelis. It is approved for use in Europe, Russia and South Korea for the treatment of advanced soft tissue sarcoma. It is also undergoing clinical trials for the treatment of breast, prostate, and paediatric sarcomas. The European Commission and the U.S. Food and Drug Administration (FDA) have granted orphan drug status to trabectedin for soft tissue sarcomas and ovarian cancer.
The ecteinascidins (herein abbreviated ETs) are exceedingly potent antitumor agents isolated from the marine tunicate Ecteinascidia turbinata. Several ecteinascidins have been reported previously in the patent and scientific literature. See, for example U.S. Pat. No. 5,089,273, which describes novel compounds of matter extracted from the tropical marine invertebrate Ecteinascidia turbinata, and designated therein as ecteinascidins 729, 743, 745, 759A, 759B and 770. These compounds are useful as antibacterial and/or antitumor agents in mammals. U.S. Pat. No. 5,478,932 describes other novel ecteinascidins isolated from the Caribbean tunicate Ecteinascidia turbinata, which provide in vivo antitumor activity against P388 lymphoma, B16 melanoma, M5076 ovarian sarcoma, Lewis lung carcinoma, and the LX- I human lung and MX- 1 human mammary carcinoma xenografts.
One of the ETs, ecteinascidin 743 (ET-743), is a tetrahydroisoquinoline alkaloid with considerable in vitro and in vivo antitumor activity in murine and human tumors, and potent antineoplastic activity against a variety of human tumor xenografts grown in athymic mice, including melanoma, ovarian and breast carcinoma.
ET-743 is a natural compound with the following structure:
ET-743 is also known with the generic name trabectedin and the trademark Yondelis®, and it is currently approved in Europe for the treatment of soft tissue sarcoma. The clinical development of trabectedin continues in phase 11/ III clinical trials in breast, ovarian and prostate cancer. A clinical development program of ET-743 in cancer patients was started with phase I studies investigating 1- hour, 3-hour, 24-hour, and 72-hour intravenous infusion schedules and a 1 hour daily x 5 (dx5) schedule. Promising responses were observed in patients with sarcoma, breast and ovarian carcinoma.
Therefore this new drug is currently under intense investigation in several phase 11/ III clinical trials in cancer patients with a variety of neoplastic diseases. Further information regarding the dosage, schedules, and administration of ET-743 for the treatment of cancer in the human body, either given alone or in combination is provided in WO 00/69441 , WO 02/36135, WO 03/39571 , WO 2004/ 105761 , WO 2005/039584, WO 2005/049031 , WO 2005/049030, WO 2005/049029, WO 2006/046080, WO 2006/005602, and PCT/US07/98727, which are incorporated by reference herein in their entirety.
A review of ET-743, its chemistry, mechanism of action and preclinical and clinical development can be found in Kesteren, Ch.
Van et al., Anti-Cancer Drugs, 2003, 14 (7), 487-502: “ET-743 (trabectedin, ET-743): the development of an anticancer agent of marine origin”, and references therein.
During the past 30 years medical oncologists have focused to optimise the outcome of cancer patients and it is just now that the new technologies available are allowing to investigate polymorphisms, gene expression levels and gene mutations aimed to predict the impact of a given therapy in different groups of cancer patients to tailor chemotherapy. Representative examples include the relationship between the Thymidylate Synthase (TS) mRNA expression and the response and the survival with antifolates, beta tubulin III mRNA levels and response to tubulin interacting agents, PTEN gene methylation and resistance to CPT- I l and, STAT3 over expression and resistance to Epidermal Growth Factor (EGF) interacting agents.
A molecular observation of potential clinical impact relates to the paradoxical relation between the efficiency of the Nucleotide Excision Repair (NER) pathway and the cytotoxicity of ET-743. In fact, tumour cells that are efficient in this DNA repair pathway appear to be more sensitive to ET-743. This evidence is in contrast with the pattern noted with platin based therapeutic regimens which are highly dependent on the lack of activity of this repair pathway (ie. an increase in ERCCl expression has been associated to clinical resistance to platinum-based anti-cancer therapy).
There are evidences on the key role of NER pathways on the cytotoxicity of ET-743 in cell lines. ET-743 binds to G residues in the minor groove of DNA forming adducts that distort the DNA helix structure and they are recognised by NER mechanisms (Pourquier, P. et al., 2001 , Proceedings of the American Association for Cancer Research Annual Meeting, Vol. 42, pp. 556. 92nd Annual Meeting of the American Association for Cancer Research. New Orleans, LA, USA. March 24-28, 2001. ISSN: 0197-016X). Takebayasi et al. (Nature Medicine, 2001 , 7(8), 961-966) have proposed that the presence of these DNA adducts in transcribed genes, blocks the Transcription Coupled NER (TC-NER) system by stalling the cleavage intermediates and producing lethal Single Strand Breaks (SSBs). It is known from Grazziotin et al (Proc.Natl.Acad.Sic.USA, 104: 13062- 13067) that the DNA adducts formed by exposure to ET-743 are transformed into double strand DNA breaks.
The fact that NER mediates ET-743 ‘s cytotoxicity has also been found in the yeast Saccharomyces cerevisae by Grazziotin et al. (Biochemical Pharmacology, 2005, 70, 59-69) and in the yeast Schizosaccharomyces pombe by Herrero et al. (Cancer Res. 2006, 66(16), 8155-8162).
In addition, Bueren et al. (Proceedings AACR Annual Meeting 2007, Abstract no. 1965) have been shown that ET-743 induces double-strand breaks in the DNA in early S phase that are detected and repaired by the Homologous Recombination Repair (HRR) pathway. In addition, Erba et al (Eur. J. Cancer, 2001 , 37(1), 97- 105) and Bueren et al (Proceedings AACR Annual Meeting 2007, Abstract no. 1965) have shown that inactivation/ mutations of genes related to the Double Strand Break detection such as DNA-PK, ATM and ATR and of genes related to Homologous Recombination Repair pathway, such as Fanconi Anemia genes, BRCAl , BRCA2 and RAD51 make cells more sensitive to trabectedin. Such unique finding is the opposite to the pattern with conventional DNA interacting agents, like in the case of microtubule poisons such as taxanes and vinorelbine.
Finally, pharmacogenomic studies prior have demonstrated that increased expression of the NER genes ERCCl and XPD in the tumor tissue does not impact the outcome of patients treated with
ET-743. However, the low expression of BRCAl in the tumor tissue is correlated with a better outcome in cancer patents treated with
ET-743. Further information can be found in WO 2006/005602, which is incorporated by reference herein in its entirety.
Three rare, autosomal recessive inherited human disorders are associated with impaired NER activity: xeroderma pigmentosum (XP), Cockayne Syndrome (CS), and trichothiodystrophy (Bootsma et al. The Genetic Basis of Human Cancer. McGraw-Hill, 1998, 245- 274). XP patients exhibit extreme sensitivity to sunlight, resulting in a high incidence of skin cancers (Kraemer et al. Arch. Dermatol. 123, 241-250, and Arch. Dermatol. 130, 1018- 1021). About 20% of XP patients also develop neurologic abnormalities in addition to their skin problems. These clinical findings are associated with cellular defects, including hypersensitivity to killing and mutagenic effects of UV, and inability of XP cells to repair UV-induced DNA damage (van Steeg et al. MoI. Med. Today, 1999, 5, 86-94).
Seven different NER genes, which correct seven distinct genetic XP complementation groups (XPA-XPG), have been identified (Bootsma et al. The Genetic Basis of Human Cancer. McGraw-Hill, 1998, 245-274). The human gene responsible for XP group G was identified as ERCC5 (Mudgett et al. Genomics, 1990, 8, 623-633; O’Donovan et al. Nature, 1993, 363, 185- 188; and Nouspikel et al. Hum. MoI. Genet. 1994, 3, 963-967). The XPG gene codes for a structure-specific endonuclease that cleaves damaged DNA ~5 nt 3′ to the site of the lesion and is also required non-enzymatically for subsequent 5’ incision by the XPF/ ERCCl heterodimer during the NER process (Aboussekhra et al. Cell, 1995, 80, 859-868; Mu et al. J. Biol. Chem. 1996, 271 , 8285-8294; and Wakasugi et al. J. Biol. Chem. 1997, 272, 16030- 16034). There is also evidence suggesting that XPG is also involved in transcription-coupled repair of oxidative DNA lesions (Le Page et al. Cell, 101 , 159- 171).
Takebayashi et al. (Cancer Lett., 2001 , 174: 1 15- 125) have observed an increase in heterozygosity loss and microsatellite instability in a substantial percentage of samples of ovarian, lung and colon carcinoma. Le Moirvan et al, (Int.J. Cancer, 2006,1 19: 1732- 1735) have described the presence of polymorphisms in the XPG gene in sarcoma patients. It is also known from Takebayashi et al. (Proceedings of the American Association forCancer Research Annual Meeting, March, 2001 , Vol. 42, pp. 813.92nd Annual Meeting of the American Association for Cancer
Research. New Orleans, LA, USA. March 24-28, 2001) that cells deficient in the NER system are resistant to treatment with ET-743 (Zewail-Foote, M. et al., 2001 , Chemistry and Biology, 8: 1033- 1049 and Damia, G. et al., 2001 , Symposium AACR NCI EORTC) and that the antiproliferative effects of ET-743 require a functional XPG gene.
Since cancer is a leading cause of death in animals and humans, several efforts have been and are still being undertaken in order to obtain an antitumor therapy active and safe to be administered to patients suffering from a cancer. Accordingly, there is a need for providing additional antitumor therapies that are useful in the treatment of cancer.
Trabectedin is a tetrahydroisoquinoline, a novel marine-derived antitumor agent isolated from the colonial tunicate Ecteinascidia turbinate. The drug binds to the minor groove of the DNA, bending the DNA towards the major groove, blocking the activation of genes in a unique way via several pathways, including selective inhibition of the expression of key genes (including oncogenes) involved in cell growth and drug resistance, inhibition of genetic repair pathways and inhibition of cell cycle progression leading to p53-independent programmed cell death.
In July 2003, the European Committee of Proprietary Medicinal Products (CPMP) recommended against granting marketing authorization to trabectedin for soft tissue sarcoma. PharmaMar appealed the decision in September 2003. Later that year, the CPMP rejected the company’s appeal. In 2006, the company filed another regulatory application for this indication and, finally, in 2007, a positive opinion was received in the E.U. for the treatment of metastatic soft tissue sarcoma. First commercialization of the product in the E.U. took place in October 2007 in the U.K. and Germany.
The compound is also available in several other countries. In 2008, the compound was filed for approval in the U.S. and the E.U. for the treatment of relapsed advanced ovarian cancer in combination with liposomal doxorubicin, and in 2009 approval was received in both countries. Trabectedin is available in several European countries, including the U.K. and Germany. Also in 2009 the drug candidate was approved in Philippines for the ovarian cancer indication.
The compound had been in phase II development by Johnson & Johnson for the treatment of prostate cancer; however, no recent development has been reported for this research. PharmaMar is evaluating the compound in phase II trials for the treatment of breast cancer. Additional early clinical trials are ongoing at the National Cancer Institute (NCI) to evaluate trabectedin for potential use in the treatment of advanced, persistent or recurrent uterine leiomyosarcomas and solid tumors.
In 2011, a regulatory application that had been filed in the U.S. seeking approval for the treatment of relapsed advanced disease in combination with liposomal doxorubicin was withdrawn by the company based on the FDA’s recommendation that an additional phase III study be conducted to obtain approval. In 2014, Janssen Research & Development, LLC submitted an NDA for trabectedin to the FDA for the treatment of patients with advanced soft tissue sarcoma (STS), including liposarcoma and leiomyosarcoma subtypes, who have received prior chemotherapy including an anthracycline.
Trabectedin was developed by PharmaMar, a subsidiary of Zeltia. The drug was being codeveloped and comarketed in partnership with Ortho Biotech, a subsidiary of Johnson & Johnson pursuant to an agreement signed in 2001. However, in 2008 the license agreement between the two companies was terminated.
The compound was granted orphan drug designation for the treatment of soft tissue sarcoma and for the treatment of ovarian cancer by the FDA and the EMEA. In 2011, orphan drug designation was granted in Japan for the treatment of malignant soft tissue tumor accompanied with chromosomal translocation. In 2009, the product was licensed to Taiho by PharmaMar in Japan for the treatment of cancer.
During the 1950s and 1960s, the National Cancer Institute carried out a wide ranging program of screening plant and marine organism material. As part of that program extract from the sea squirt Ecteinascidia turbinata was found to have anticancer activity in 1969.[1] Separation and characterisation of the active molecules had to wait many years for the development of sufficiently sensitive techniques, and the structure of one of them, Ecteinascidin 743, was determined by KL Rinehart at the University of Illinois in 1984.[2] Rinehart had collected his sea squirts by scuba diving in the reefs of the West Indies.[3]
Recently, the biosynthetic pathway responsible for producing the drug, has been determined to come from Candidatus Endoecteinascidia frumentensis, a microbial symbiont of the tunicate.[4] The Spanish company PharmaMar licensed the compound from the University of Illinois before 1994 and attempted to farm the sea squirt with limited success.[3]
Yields from the sea squirt are extremely low – it takes 1 tonne of animals to isolate 1 gram of trabectedin – and about 5 grams were believed to be needed for a clinical trial[5] so Rinehart asked the Harvard chemist E. J. Corey to search for a synthetic method of preparation. His group developed such a method and published it in 1996.[6] This was later followed by a simpler and more tractable method which was patented by Harvard and subsequently licensed to PharmaMar.[3] The current supply is based on a semisynthetic process developed by PharmaMar starting from Safracin B, an antibiotic obtained by fermentation of the bacterium Pseudomonas fluorescens.[7] PharmaMar have entered into an agreement with Johnson and Johnson to market the compound outside Europe.
Trabectedin was first dosed in humans in 1996.In 2007, the EMEA gave authorisation for the marketing of trabectedin, under the trade name Yondelis, for the treatment of patients with advanced soft tissue sarcoma, after failure of anthracyclines and ifosfamide, or who are unsuited to receive these agents. The agency’s evaluating committee, the CHMP observed that trabectedin had not been evaluated in an adequately designed and analyzed randomized trial against current best care, and that the clinical efficacy data was mainly based on patients with liposarcoma and leiomyosarcoma. However the pivotal study did show a significant difference between two different trabectedin treatment regimens, and due to the rarity of the disease the CHMP considered that marketing authorisation could be granted under exceptional circumstances.[8] As part of the approval PharmaMar agreed to conduct a further trial to identify whether any specific chromosomal translocations could be used to predict responsiveness to trabectedin.[9] Trabectedin is also approved in South Korea[10] and Russia.
In 2008 the submission was announced of a registration dossier to the European Medicines Agency (EMEA) and the FDA for Yondelis when administered in combination with pegylated liposomal doxorubicin (Doxil, Caelyx) for the treatment of women with relapsed ovarian cancer. In 2011, Johnson&Johnson voluntarily withdrew the submission in the United States following a request by the FDA for an additional Phase III study to be done in support of the submission.[11]
Trabectedin is also in phase II trials for prostate, breast and paediatric cancers.[12]
Trabectedin is composed of 3 tetrahydroisoquinoline moieties, 8 rings including one 10-membered heteocyclic ring containing a cysteine residue, and 7 chiral centers.
The biosynthesis of Trabectedin in Candidatus Endoecteinascidia frumentensis starts with a fatty acid loading onto the acyl-ligase domain of the EtuA3 module. A cysteine and glycine are then loaded as canonical NRPS amino acids. A tyrosine residue is modified by the enzymes EtuH, EtuM1, and EtuM2 to add a hydroxyl at the meta position of the phenol, and adding two methyl groups at the para-hydroxyl and the meta carbon position. This modified tyrosine reacts with the original substrate via a Pictet-Spangler reaction, where the amine group is converted to an imine by deprotonation, then attacks the free aldehyde to form a carbocation that is quenched by electrons from the methyl-phenol ring. This is done in the EtuA2 T-domain. This reaction is done a second time to yeid a dimer of modified tyrosine residues that have been further cyclized via Pictet-spangler reaction, yielding a bicyclic ring moiety. The EtuO and EtuF3 enzymes continue to post-translationally modify the molecule, adding several functional groups and making a sulfide bridge between the original cysteine residue and the beta-carbon of the first tyrosine to form ET-583, ET-597, ET-596, and ET-594 which have been previously isolated.[4] A third o-methylated tyrosine is added and cyclized via Pictet-Spangler to yield the final product.[4]
Proposed biosynthetic scheme for the biosynthesis of Trabecteden (ET-743)
The total synthesis by E.J. Corey used this proposed biosynthesis to guide their synthetic strategy. The synthesis uses such reactions as the Mannich reaction, Pictet-Spengler reaction, the Curtius rearrangement, and chiral rhodium-based diphosphine–catalyzed enantioselective hydrogenation. A separate synthetic process also involved the Ugi reaction to assist in the formation of the pentacyclic core. This reaction was unprecedented for using such a one pot multi-component reaction in the synthesis of such a complex molecule.
Org Lett 2000,2(7),993
The previously reported synthesis of 139221 (scheme 13922101a) has been investigated in order to find a more efficient, reproducible and economical route to work in the mutikilogram scale. Herein it is reported a new process which is simpler and proceeds with an overall yield of 54% (the original process, 35%). The condensation of intermediate aminolactone (I) (scheme 13922101a, intermediate (VII)) with acid (XLII) (the acid derived from scheme 13922101a, intermediate ester (IX)) by means of 2-chloro-1,3-dimethylimidazolidinium hexafluorophosphate (CIP), and 1-hydroxy-7-azabenzotriazole (HOAt) in THF/dichloromethane gives the coupling product (XLIII), which is allylated with allyl bromide (XLIV) and Cs2CO3 in DMF yielding the allyl ether (XLV). The reduction of the lactone group of (XLV) with LiAlH2(OEt)2 in ethyl ether affords the lactol (XLVI), which is desilylated with KF in methanol to provide the phenolic compound (XLVII). The opening of the lactol ring of (XLVII) with simultaneous cyclization by means of Tf-OH in water/trifluoroethanol gives the hexacyclic intermediate (XLVIII), which is finally reductocondensed with KCN by means of LiAlH2(OEt)2 in THF to furnish the previously reported pentacyclic intermediate (XI) (scheme 13922101a, intermediate (XI)).
……………………………………………
Reaction of cyanosafracin B (I) with Boc2O in ethanol gives the amino-protected compound (II), which is treated with methoxymethyl bromide (MOM-Br), DIEA and DMAP in acetonitrile yielding the O-protected compound (III). The demethylation of (III) with NaOH in methanol affords the hydroxyquinone (IV), which is reduced with H2 over Pd/C and cyclized with bromochloromethane and Cs2CO3 in hot DMF to provide compound (V). Reaction of (V) with allyl bromide (VI) and Cs2CO3 in DMF gives the allyl ether (VII), which first is treated with TFA, phenyl isothiocyanate and HCl to yield the primary amine (VIII) and then protected at the free NH2 group with Troc-Cl and pyridine, to afford the amino protected compound (IX).Org Lett 2000,2(16),2545
……………………………….
Reaction of (IX) with MOM-Br and DIEA as before affords the ether (X), which is treated with Zn/HOAc in order to regenerate the primary amino group giving (XI). The reaction of (XI) with NaNO2 and HOAc eliminates the NH2 group, affording the primary alcohol (XII), which is esterified with the protected (S)-cysteine (XIII) by means of EDC and DMAP in dichloromethane furnishing the cysteine ester (XIV). Reaction of (XIV) with Bu3SnH and PdCl2(PPh3)2, followed by oxidation with (PhSeO)2O in dichloromethane gives the hydroxyketone (XV), which is cyclized with Tf2O and Ac2O yielding the heptacyclic compound (XVI). Elimination of the MOM protecting group with TMSCl and NaI in CH3CN/CH2Cl2 affords the phenolic compound (XVII).
…………………….
Intermediate (XVII) by a treatment with Zn and HOAc eliminates the Troc protecting group, giving the primary amine (XVIII). This compound by treatment with 4-formyl-1-methylpyridinium iodide (NMPC), DBU and oxalic acid in order to convert the nitrile group into an alcohol, provides compund (XIX), which is finally cyclized with 2-(3-hydroxy-4-methoxyphenyl)ethylamine (XX) by means of SiO2 / EtOH, followed treatment with and AgNO3 in acetonitrile/water.
……………………….
The reaction of cyanosafracin B (I) with Boc2O in ethanol gives the amino protected compound (II), which is treated with Mom-Br, DIEA and DMAP in acetonitrile yielding the O-protected compound (III). The demethylation of (III) with NaOH in methanol affords the hydroxyquinone (IV), which is reduced with H2 over Pd/C and cyclized with bromochloromethane and Cs2CO3 in hot DMF providing the methylenedioxy compound (V). The reaction of (V) with acetyl chloride and pyridine in dichloromethane gives the acetate (VI), which is treated with TFA, phenyl isothiocyanate and HCl yielding the primary amine (VII). Finally, this compound is treated with phthalic anhydride (VIII) and CDI in dichloromethane to afford the target phthalimide (phthalascidin Pt-650)
………………………………
http://pubs.acs.org/doi/abs/10.1021/ol0056729
Ecteinascidins are a group of marine alkaloid having antineoplasticity which is isolated from the extracted products from the marine tunicate habitat of the Caribbean sea by a very small amount. Arming the ecteinascidins, Et 743 has a very strong antineoplastic activity, studies to put it into practical use as a carcinostatic agent are limited, and the phase II clinical tests are now being carried out in ten countries in Europe and America. It is known that Et 743 has an effect of depressing the proliferation of cancer cells by 10 to 100 times more potent than (IC50=0.1-1 nM) Toxol, Camptotesin, Adriamycin or Mitomycin which are currently used carcinostatic agents.
From the background mentioned above, various studies for synthesis were carried out; however, the complete synthesis was only reported by Prof. E. J. Corey of Harvard University in the U.S.A. (J. Am. Chem. Soc. 1996, 118, 9202-9203, reference document A).
In the process of the total synthesis disclosed in Document A (refer to page 9202), the main feature of the process is that Et 743 is synthesized from the analogous compound to the compound represented by general formula 1 of the present invention via intermediates 4 and 8. That is, according to said process, the C4 site of ring B (regarding the location of rings, and the sites of atoms comprising the 6 membered ring, refer to general formula 1), which composes a 6 membered ring, is formed from the intermediate 4 at the first step. Since the atom C4 composing the ring B of the 6-membered ring H, which lacks reactivity, is bonded, it becomes necessary to perform an oxidation reaction at the C4 site on the B ring. This oxidation reaction is not effective and is carried out under harsh conditions; therefore production on an industrial scale is difficult, and also the yield is not good. Further, since the atom N12 site of the synthesized intermediate is substituted by an alkyl group which lacks reactivity, in this case substituted by a methyl group, it is not suited to the synthesis of various compounds. Although total synthesis was reported, the supplying source of Et 743 still depends on the natural sample whose supply is very scarce. Therefore, the establishment of the method for a large scale production of Et 743 is desired and requires accomplishing an effective synthesizing process.
Since ET 743 is known as a medicine having high antineoplasticity, and phthalascidin induced from the intermediate product at the synthesis of Et 743 displays the same activity to ET 743, the establishment of an effective and mild method for synthesis of ET 743 and analogous compounds thereof is strongly desired.
Therefore, the subject of the present invention is to accomplish the effective method for total synthesis of Et 743, and further, to provide not only Et 743 but also analogous compounds.
To dissolve the subject, the present invention uses retrosynthetic analysis for easy synthesis. It will be possible to form a B ring by a ring forming reaction at the ortho position of phenol, which binds an A ring to inner molecular aldehyde in a compound generated by the 4-8 reaction. Further, the present invention contemplates that the generated compound by the 4-8 reaction can be synthesized based on the polycondensation reaction of general formula 4, and general formula 5 via a compound of general formula 3. Then the total synthesis of Et 743, which is the aimed compound, can be accomplished by way of the compounds represented by general formulae 5, 4, 3, 2 and 1 and the specific structure of general formulae 1 and 2. This synthetic route provides for the analogous compounds of Et 743.
The biological mechanism of action is believed to involve the production of superoxide near the DNA strand, resulting in DNA backbone cleavage and cell apoptosis. The actual mechanism is not yet known, but is believed to proceed from reduction of molecular oxygen into superoxide via an unusual auto-redox reaction on a hydroxyquinone moiety of the compound following. There is also some speculation the compound becomes ‘activated’ into its reactive oxazolidine form.
Schematic of the unique and complex mode of action of trabectedin. The antitumor effects of trabectedin are due to multiple mechanisms involving DNA binding in the minor groove, interactions with DNA repair mechanisms, modulation of transcription regulation, and induction of microenvironment changes.
 |
|
| Systematic (IUPAC) name | |
|---|---|
| (1′R,6R,6aR,7R,13S,14S,16R)-6′,8,14-trihydroxy-7′,9-dimethoxy-4,10,23-trimethyl-19-oxo-3′,4′,6,7,12,13,14,16-octahydrospiro[6,16-(epithiopropano-oxymethano)-7,13-imino-6aH-1,3-dioxolo[7,8]isoquino[3,2-b][3]benzazocine-20,1′(2′H)-isoquinolin]-5-yl acetate | |
| Clinical data | |
| AHFS/Drugs.com | International Drug Names |
| Licence data | EMA:Link |
| Legal status | |
| Routes | Intravenous |
| Pharmacokinetic data | |
| Bioavailability | Not applicable (IV only) |
| Protein binding | 94 to 98% |
| Metabolism | Hepatic (mostly CYP3A4-mediated) |
| Half-life | 180 hours (mean) |
| Excretion | Mostly fecal |
| Identifiers | |
| CAS number | 114899-77-3 |
| ATC code | L01CX01 |
| PubChem | CID 108150 |
| IUPHAR ligand | 2774 |
| DrugBank | DB05109 |
| ChemSpider | 16736970  |
| UNII | ID0YZQ2TCP |
| Chemical data | |
| Formula | C39H43N3O11S |
| Mol. mass | 761.84 g/mol |
……..
1 Corey, “Enantioselective Total Synthesis of Ecteinascidin 743“, J. Am. Chem. Soc. 1996, vol. 118, 9202-9203.
| 2 | * | Endo, “Synthetic Study on Ecteinascidin 743 Starting From D-Glucose“, Synlett 1999, No. 7, 1103-1105. |
| 3 | * | Endo, “Total Synthesis of Ecteinascidin 743“, J. Am. Chem. Soc. 2002, vol. 124, 6552-6554. |
| 4 | * | Hinterding, “Synthesis and In Vitro Evaluation of the Ras Farnesyltransferase Inhibitor Pepticinnamin E“, Angew. Chem. Int. Ed. 1998, 37, No. 9 1236-1239. |
| 5 | * | Tohma, “Synthesis of Optically Active alpha-Arylglycines: Stereoselective Mannich-Type Reaction with a New Chiral Template“, Synlett 2001, No. 7, 1179-1181.Hamprecht, D.W.; Berge, J.M.; Copley, R.C.B.; Eggleston, D.S.; Houge-Frydrych, C.S.V.; Jarvest, R.L.; Mensah, L.M.; O’Hanlon, P.J.; Pope, A.J.; Rittenhouse, S. Derivatives of the natural product SB-219383 and synthetic analogues: Potent inhibitors of bacterial tyrosyl tRNA synthetase 16th Int Symp Med Chem (September 18-22, Bologna) 2000, Abst PA-155Cuevas, C.; Perez, M.; Martin, M.J.; et al. Synthesis of ecteinascidin ET-743 and phathalascidin Pt-650 from cyanosafracin B Org Lett 2000, 2(16): 2545
|
| Patent | Submitted | Granted |
|---|---|---|
| Assay for identifying biological targets of polynucleotide-binding compounds [US2008096201] | 2008-04-24 | |
| Compounds of the saframycin-ecteinascidin series, uses, and synthesis thereof [US6936714] | 2004-07-01 | 2005-08-30 |
| Method For Total Synthesis Of Ecteinascidins And Intermediate Compounds Thereof [US7807833] | 2009-08-06 | 2010-10-05 |
| Method For Total Synthesis Of Ecteinascidins And Intermediate Compounds Thereof [US7820838] | 2009-02-05 | 2010-10-26 |
| Assay for identifying biological targets of polynucleotide-binding compounds [US7183054] | 2004-12-09 | 2007-02-27 |
3”-Tert-butyl-4′-(2-hydroxyethoxy)-4”-(pyrrolidin-1-yl)(1,1′:3′,1”)terphenyl-4-carboxylic acid
3′-[3-tert-butyl-4-(pyrrolidin-1-yl)phenyl]-4′-(2-hydroxyethoxy)-[1,1′-biphenyl]-4-carboxylic acid
UNII-0J8RN2W0HK,
Galderma Research & Development
459.5766
C29 H33 N O4
Trifarotene, sold under the brand name Aklief, is a medication for the topical treatment of acne vulgaris in those nine years of age and older.[1] It is a retinoid;[2] more specifically, it is a fourth generation selective retinoic acid receptor (RAR)-γ agonist.[3]
It was approved for medical use in the United States in 2019,[1][4][5] but is not approved in the European Union as of January 2021.[6] Trifarotene was granted orphan drug designation for the treatment of congenital ichthyosis by both the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA).[7][8]
State Solid
Experimental Properties
| PROPERTY | VALUE | SOURCE |
|---|---|---|
| melting point (°C) | 245C | FDA Label |
| pKa | 5.69 (pKa1) | FDA Label |
USFDA
The drug substance, trifarotene, a terphenyl acid derivative, is a retinoic
acid receptor (RAR) aQonist and is classified as a rotenoid. Trifarotene
intended as a drug for the treatment of acne vulgaris. Since trifarotene
has not been previously approved as an active ingredient in any drug
product in the United States, it is classified as a new molecular entity
(NME).
Trifarotene is produced as a white to off-white to slightly yellow crystalline
powder. It is slightly soluble in acetone, ethanol, and toluene, very slight
soluble in isopropanol, and practically insoluble in water (tiJT4
1
Cb><“JTrifarotene is nonhygroscopic and has pKa1 of 5.69 and pKa2 of 4.55. The chemical name
for trifarotene is 4-{3-[3-tert-butyl-4-(pyrrolidin-1-yl) phenyl]-4-(2-
hydroxyethoxy) phenyl} benzoic acid. It has the chemical formula of
C29H33NQ4, the molecular weiQht of 459.59, …………https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211527Orig1s000ChemR.pdf
Prescription Products
| NAME | DOSAGE | STRENGTH | ROUTE | LABELLER | MARKETING START | MARKETING END | ||
|---|---|---|---|---|---|---|---|---|
| Aklief | Cream | 50 mcg | Topical | Galderma | 2019-11-28 | Not applicable |  |
|
| Aklief | Cream | 50 ug/1g | Topical | Galderma Laboratories, L.P. | 2019-10-04 | Not applicable |  |
Galderma announced that the U.S. Food and Drug Administration (FDA) granted Orphan Drug Designation status for the company’s trifarotene molecule for the treatment of congenital ichthyosis. Based on this decision, Galderma plans to implement a clinical development plan, reinforcing its commitment to exploring new treatment options for rare diseases, as well as meeting the needs of all patients with skin diseases over the course of their lives.
Galderma治療先天性魚鱗癬的Trifarotene分子取得FDA的孤兒藥資格認定
http://news.msn.com.tw/market3773054.aspx
The company’s molecule trifarotene is a selective agonist of the gamma retinoic acid receptor (RAR-gamma), which is currently in clinical development for use in other more common dermatological conditions. It is the drug’s retinoid functionality and potent keratolytic properties that make it a potentially viable treatment of the lamellar ichthyosis pathology. Galderma has already initiated the program for investigating the treatment of lamellar ichthyosis with trifarotene and is currently working in collaboration with regulatory authorities to implement an innovative and expedient clinical development plan.
Ichthyoses comprise a large group of skin scaling disorders with diverse etiologies. The stereotypic pathophysiology is epidermal hyperplasia and abnormal desquamation, leading to visible accumulation of squames (scales) on the skin’s surface. Congenital ichthyosis is a term used to refer to a specific group of rare inherited forms of ichthyoses that are generally more severe than non-inherited forms of the disease. Lamellar ichthyosis is one such disorder that falls within the congenital ichthyosis category. Lamellar ichthyosis is recognized as a severe disease which persists throughout life. After birth, during the first post-natal weeks, the hyperkeratotic (colloidion) membrane patients are typically born with, is gradually shed and is replaced by scaling and lichenification that involves the entire body, including face, scalp, palms and soles. While usually not life threatening, lamellar ichthyosis can result in disability, partial deafness, poor adaptation to environmental conditions (due to hypohydrosis), severe discomfort (pruritus, fissuring of the skin), and significant psycho-social impact. The estimated prevalence of LI in the US is in the range of 1 per 100,000 to 1 per 200,000 persons.
Synthesis Reference
Thoreau, E. et. al. Structure-based design of Trifarotene (CD5789), a potent and selective RARγ agonist for the treatment of acne. Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 10. 2018. Pages 1736-1741
https://www.sciencedirect.com/science/article/abs/pii/S0960894X18303482
Reference: Biadatti, Thibaud; Dumais, Laurence; Soulet, Catherine; Talano, Sandrine; Daver, Sebastien. Preparation of [1,1′:3′,1”]terphenyl-4-carboxylic acid and esters a novel ligands modulating retinoic acid receptors (RAR), and use thereof in human medicine and in cosmetics. Assignee Galderma Research & Development, S.N.C., Fr. WO 2006066978. (2016).
PATENT
WO 2006066978
http://www.google.com/patents/WO2006066978A1?cl=en
Example 25 – 3″-ter.-Butyl-4′-(2-hvdroxyethoxy)-4″-pyrrolidin-1-ylM,1′:3′,1″1- terphenyl-4-carboxylic acid
In a manner similar to that of Example 6b, by reacting 500 mg (0.9 mmol) of ethyl 4′-(2- acetoxyethoxy)-3″-terf-butyl-4″-pyrrolidin-1 -yl[1 , 1 ‘;3’, 1 “]terphenyl-4-carboxylate with
300 mg (8 mmol) of sodium hydroxide, 242 mg of 3″-tert-butyl-4′-(2-hydroxyethoxy)-4″- pyrrolidin-1-yl[1l1′;3′,1″]terphenyl-4-carboxylic acid are obtained (yield = 55 %) in the form of a white solid (m.p. = 2230C).
1H NMR (DMSO. 400 MHz): 1.43 (s, 9H); 1.90 (m, 4H); 3.0 (m, 4H); 3.73 (d, J=4.7Hz, 2H); 4.1 (m, 2H); 4.7 (s, 1H); 7.2 (d, 1H, J=8.6Hz); 7.48 (m, 2H); 7.59 (d, J=1.6Hz, 1H); 7.64 (d, J=UHz, 1H); 7.68 (dd, J=2Hz, 7.8Hz, 1H); 7.82 (d, J=8.3Hz, 2H); 7.99 (d, J=8.4Hz, 2H).
PATENT
WO 2013178759
http://www.google.com/patents/WO2013178759A1?cl=en
PATENT
WO 2013178758
http://www.google.com/patents/WO2013178758A1?cl=en
PATENT
WO 2013178760
http://www.google.com/patents/WO2013178760A1?cl=en
The details of skin application are given in the table below.
SYN
New Drug Approvals for 2019: Synthesis and Clinical Applications
New Drug Approvals for 2019: Synthesis and Clinical Applications
Shuo Yuan, Bin Yu, Hong-Min Liu
PII: S0223-5234(20)30639-5
DOI: https://doi.org/10.1016/j.ejmech.2020.112667
Reference: EJMECH 112667
To appear in: European Journal of Medicinal Chemistry
Trifarotene (Aklief). In October 2019, trifarotene, a topical retinoid that
selectively targets retinoic acid receptor gamma (RAR-γ), was approved by the FDA
for the treatment of acne vulgaris [142]. The drug was developed and marketed by
Galderma Pharmaceutical in Switzerland. Trifarotene is considered as the first of the
‘fourth-generation’ retinoids due to its uniquely selective agonism at RAR-γ. The
selective agonism leads to downstream alterations, confering improved efficacy and
reduced side effects [143]. In two phase 3 clinical trials of 2420 patients with
moderate acne on the face and trunk, trifarotene was well tolerated and significantly
reduced inflammatory lesions as early as two weeks on the face and four weeks on the
back, shoulders and chest compared to vehicle (p＜0.05) [144].
The synthetic approach of this drug was disclosed by Galderma Research &
Development (Scheme 25) [145]. Bromination of commercially available
2-(tert-butyl)aniline 171 gave 4-bromo-2-(tert-butyl)aniline 172 in quantitative yield,
which then reacted with 1-dibromobutane 173 to give phenylpyrrolidine 174 in 52%
yield. Miyaura reaction of 174 was realized by employing n-BuLi and triisopropyl
borate (TIPB) followed by washed with aqueous HCl, resulting in arylboronic acid
adduct 175 in 66% yield. Treatment of 175 with aromatic bromide 176 in the presence
of Pd(PPh3)4 gave the coupling product 177 in 47% yield, which then underwent
hydrolysis delivering trifarotene (XIX) in 55% yield.
The preparation of coupling partner 176 is depicted in Scheme 26. Esterification of
4-hydroxy-4-biphenylcarboxylic acid 178 gave ethyl benzoate derivative 179 upon
treatment with catalytic H2SO4 in the refluxing EtOH [145]. The resulting ester was
subjected to treatment with tetrabutylammonium bromide (TBAB) in THF, resulting
in bromide 180 in good yields, further NaH-mediated Williamson ether synthesis with
2-bromoethyl acetate 181 gave 176 in 95% yield.
[142] L.J. Scott, Trifarotene: first approval, Drugs 79 (2019) 1905-1909.
[143] E. Thoreau, J.M. Arlabosse, C. Bouix-Peter, S. Chambon, L. Chantalat, S.
Daver, L. Dumais, G. Duvert, A. Feret, G. Ouvry, J. Pascau, C. Raffin, N.
Rodeville, C. Soulet, S. Tabet, S. Talano, T. Portal, Structure-based design of
trifarotene (CD5789), a potent and selective RARγ agonist for the treatment of
acne, Bioorg. Med. Chem. Lett. 28 (2018) 1736-1741.
[144] J. Tan, D. Thiboutot, G. Popp, M. Gooderham, C. Lynde, J.D. Rosso, J. Weiss,
U. Blume-Peytavi, J. Weglovska, S. Johnson, L. Parish, D. Witkowska, N.S.
Colon, A.A. Saenz, F. Ahmad, M. Graeber, L.S. Gold, Randomized phase 3
evaluation of trifarotene 50 µg/g cream treatment of moderate facial and truncal
acne, J. Am. Acad. Dermatol. 80 (2019) 1691-1699.
[145] T. Biadatti, L. Dumais, C. Soulet, S. Talano, S. Daver, Novel ligands that
modulate rar receptors, and use thereof in human medicine and in cosmetics,
2006. WO2006066978.
| WO2006066978A1 * | Dec 21, 2005 | Jun 29, 2006 | Galderma Res & Dev | Novel ligands that modulate rar receptors, and use thereof in human medicine and in cosmetics |
| EP0826366A2 | Aug 1, 1997 | Mar 4, 1998 | Unilever N.V. | Cosmetic compositions containing hydroxy acid or retinoid |
| EP0989846A2 | Sep 22, 1998 | Apr 5, 2000 | E-L Management Corp. | Non-irritating cosmetic and pharmaceutical compositions |
| EP1831149A1 | Dec 21, 2005 | Sep 12, 2007 | Galderma Research & Development | Novel ligands that modulate rar receptors and use thereof in human medicine and in cosmetics |
| FR2915682A1 * | Title not available | |||
| US5851538 | Dec 29, 1995 | Dec 22, 1998 | Advanced Polymer Systems, Inc. | Retinoid formulations in porous microspheres for reduced irritation and enhanced stability |
| WO1999010308A1 * | Aug 21, 1998 | Mar 4, 1999 | Bernardon Jean Michel | Biphenyl derivatives substituted by an aromatic or heteroaromatic radical and pharmaceutical and cosmetic compositions containing same |
| US6150413 * | May 26, 1998 | Nov 21, 2000 | Centre International De Recherches Dermatologiques | Treatment of dermatological, rheumatic, respiratory, cardiovascular, bone and ophthalmological disorders, as well as mammalian skin and hair conditions; 4-(4-(biphenyl-2-yl)but-3-en-1-ynyl)benzoic acid, for example |
 |
|
| Clinical data | |
|---|---|
| Trade names | Aklief |
| Other names | CD5789 |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a620004 |
| License data |
|
| Pregnancy category |
|
| Routes of administration |
Topical |
| Drug class | Skin and mucous membrane agents |
| ATC code | |
| Legal status | |
| Legal status | |
| Identifiers | |
| CAS Number | |
| PubChem CID | |
| DrugBank | |
| ChemSpider | |
| UNII | |
| KEGG | |
| ChEMBL | |
| CompTox Dashboard (EPA) | |
| ECHA InfoCard | 100.278.901  |
| Chemical and physical data | |
| Formula | C29H33NO4 |
| Molar mass | 459.586 g·mol−1 |
| 3D model (JSmol) | |
This article incorporates text from this source, which is in the public domain.| FORM | ROUTE | STRENGTH |
|---|---|---|
| Cream | Topical | 50 mcg |
| Cream | Topical | 50 ug/1g |
| Cream | Topical | 50 MICROGRAMMI/G |
| PHASE | STATUS | PURPOSE | CONDITIONS | COUNT |
|---|---|---|---|---|
| 4 | Enrolling by Invitation | Treatment | Acne Vulgaris | 1 |
| 3 | Completed | Treatment | Acne Vulgaris | 4 |
| 2 | Completed | Treatment | Acne Vulgaris | 1 |
| 2 | Recruiting | Treatment | Lamellar Ichthyosis | 1 |
| 1 | Completed | Treatment | Malignant Lymphomas | 1 |
(RTTNews) – Immunomedics, Inc. (IMMU), a biopharmaceutical company focusing mainly on the development of monoclonal antibody-based products for the targeted treatment of cancer, autoimmune and other serious diseases, said its antibody-drug conjugate for solid cancer therapy, IMMU-132, has received orphan drug status from the Office of Orphan Products Development of the U.S. Food and Drug Administration or FDA for small cell lung cancer or SCLC treatment.
Immunomedics has received orphan drug designation from the US Food and Drug Administration’s (FDA) Office of Orphan Products Development for its IMMU-132 for pancreatic cancer therapy.
IMMU-132 is Immunomedics’ antibody-drug conjugate in clinical development for treatment of patients with solid cancer.
Immunomedics president and CEO Cynthia Sullivan said that this is the second orphan designation from FDA for IMMU-132, which has demonstrated activity in patients with advanced pancreatic cancer, as well as partial responses in five other types of solid cancer.
“The humanised antibody internalises into cancer cells following binding to TROP-2, making it a suitable candidate for the delivery of cytotoxic drugs.”
The FDA previously granted orphan drug designation to IMMU-132 for treatment of small-cell lung cancer patients.
In an ongoing Phase I/II clinical study, IMMU-132 has resulted in partial responses in patients with colorectal cancer, esophageal cancer, triple negative breast cancer, and small-cell and non-small-cell lung cancers.
IMMU-132 is composed of a humanised antibody, hRS7, that binds to the trophoblast cell-surface antigen (TROP-2), also known as the epithelial glycoprotein-1 antigen (EGP-1).
The humanised antibody internalises into cancer cells following binding to TROP-2, making it a suitable candidate for the delivery of cytotoxic drugs.
In preclinical studies, IMMU-132 has demonstrated that it delivers 120-times the amount of SN-38, the active metabolite of irinotecan, to a human pancreatic tumor xenograft than when irinotecan is given.
IMMU-132 significantly improves survival and tumour regression in various animal models of human cancers.
Vatiquinone
バチキノン
Vatiquinone; Alpha-Tocotrienol quinone; EPI-743; UNII-6O85FK9I0X; 1213269-98-7; Vincerenone
| Molecular Formula: | C29H44O3 |
|---|---|
| Molecular Weight: | 440.668 g/mol |
2-[(3R,6E,10E)-3-hydroxy-3,7,11,15-tetramethylhexadeca-6,10,14-trienyl]-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione
2-((R,6E,10E)-3-hydroxy-3,7,11,15-tetramethylhexadeca-6,10,14-trien-1-yl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione
Vatiquinone is in phase II/III clinical trials for the treatment of leigh syndrome in JP. Phase II clinical trials is also ongoing for Friedreich’s ataxia, Parkinson’s disease, Pearson syndrome, cobalamin C deficiency syndrome, hearing loss and Rett’s syndrome.
Vatiquinone was originally developed by Edison Pharmaceuticals, then licensed to Sumitomo Dainippon Pharma in Japan in 2013.
Orphan drug designations for the treatment of Friedreich’s, Leigh syndrome and Rett’s syndrome were granted to the compound by FDA in 2014.
In 2013, the compound was licensed to Sumitomo Dainippon Pharma by Edison Pharmaceuticals in Japan for development and commercialization for the treatment of pediatric orphan inherited mitochondrial and adult central nervous system diseases.
EU
On 17 January 2018, orphan designation (EU/3/17/1971) was granted by the European Commission to Edison Orphan Pharma BV, The Netherlands, for vatiquinone (also known as alpha-tocotrienol quinone) for the treatment of RARS2 syndrome.
Vatiquinone, also known as EPI 743, is an orally bioavailable para-benzoquinone being developed for inherited mitochondrial diseases. The mechanism of action of EPI-743 involves augmenting the synthesis of glutathione, optimizing metabolic control, enhancing the expression of genetic elements critical for cellular management of oxidative stress, and acting at the mitochondria to regulate electron transport.
Vatiquinone has been investigated for the treatment and prevention of Retinopathy, Rett Syndrome, Genetic Disease, Noise-induced Hearing Loss, and Methylmalonic Aciduria and Homocystinuria,Cblc Type.
EPI-743 (vatiquinone) is a compound being developed by BioElectron (previously known as Edison Pharmaceuticals) to treat Friedreich’s ataxia (FA), a rare, autosomal recessive genetic disorder. The disorder is caused by mutations in the FXN gene, which encodes for a protein called frataxin. Frataxin is required for the normal functioning of mitochondria, or the energy factories of the cells. Decreased levels of frataxin, as observed in patients with FA, disrupts the normal function of mitochondria and leads to the gradual development of symptoms associated with the disease: impairment of muscle coordination, loss of muscle strength and sensation, and impaired speech, vision, and hearing.
Currently, there are no drugs available that could cure or help to effectively manage the condition, although a large number of potential treatments are in the pipeline.
EPI-743 is a drug belonging to the class of para-benzoquinones, a group of potent antioxidants. The regulation of oxidative stress is disturbed in people with FA. EPI-743 targets an enzyme called NADPH quinone oxidoreductase 1 (NQO1), helping to increase the biosynthesis of glutathione, a compound essential for the control of oxidative stress. The drug does not target any FA-specific biochemical pathways directly, but helps to improve the regulation of cellular energy metabolism in general. Due to its non-specific mechanism, the drug can be used in a variety of disorders where mitochondrial function is affected.
In December 2012, Edison Pharmaceuticals started a placebo-controlled Phase 2 study (NCT01728064) to examine the safety and efficacy of EPI-743 on visual and neurological function in FA patients. The study was completed in February 2016. The results indicated no significant differences in visual function at six months between patients treated with EPI-743 and those who received a placebo. However, researchers reported a trend toward improvement in neurological function.
In October 2013, the University of South Florida started a small Phase 2 study (NCT01962363) to evaluate the effects of EPI-743 in patients with rare point mutations leading to FA. The study investigated whether treatment with EPI-743 has a discernible impact on neurological function. The results announced in April 2016 demonstrated significant improvements in neurological functions over 18 months. However, the trial only included three participants.
Currently, no further trials testing EPI-743 in FA patients is taking place. However, the drug is in clinical trials for several other disorders that affect the functions of mitochondria, including Leigh syndrome, mitochondrial respiratory chain disease, Pearson syndrome, and others.
In February 2014, the U.S. Food and Drug Administration (FDA) granted orphan drug status to EPI-743, which allows a more expedited drug approval process. The FDA also granted fast track status to EPI-743 for the treatment of FA in March 2014.
Edison Pharmaceuticals is developing vatiquinone, which was awarded Fast Track status for Friedreich’s ataxia in March 2014.
Reference
Bioorg. Med. Chem. Lett. 2011, 21, 3693-3698.
https://www.sciencedirect.com/science/article/pii/S0960894X11005440
Reference
WO2013041676A1 / US9045402B2.
It is known that a-tocotrienol quinones are pharmaceutically active.
US 201 1 /0172312 A1 discloses that tocotrienol quinones are used in treating Leight Syndrome. WO 2010/126909 A1 and US 2006/0281809 A1 disclose that tocotrienol quinones can be used for treating ophthalmic diseases and mitochondrial diseases. US 5,318,993 discloses the activity of tocotrienol quinones as cholesterol suppression. W.D. Shrader et al., Bioorganic & Medical Chemistry Letters 21 (201 1 ), 3693-3698 disclose that the R-isomer of a-tocotrienol quinone is a metabolite of α-tocotrienol and is a potent cellular protectant against oxidative stress and ageing. The R-isomer of α-tocotrienol used for this study has been extracted from Elaeis guineensis. All these documents either use tocotrienol from natural sources or do not disclose the source of tocotrienol respectively tocotrienol quinones or disclose very specific complex synthesis thereof. These methods are very expensive and limited in producing industrial amounts of the desired products.
It is well known that from vitamin E the tocopherols and tocotrienols having the R-configuration have a significantly higher bioactivity (biopotency) than the corresponding S-isomer. This is also the case for the corresponding R-isomers of tocotrienol quinones.
Synthetic pathways to produce the R-isomer of tocotrienol quinones in a stereospecific way are very expensive and therefore only of limited interest.
The synthesis of a-tocotrienol is known from Kabbe and Heitzer, Synthesis 1978, 888-889, however, no indication of chirality whatsoever is indicated.
The synthesis of tocotrienol from the corresponding 4-oxo-chromanol-derivative is known from US 6,096,907, however, no indication of chirality is indicated.
J. Org. Chem. 1981 , 46, 2445-2450 and CH 356754 disclose the chemical transformation of a-tocopherol to a-tocopheryl quinone and to a-tocopherylhydro-quinone, however, neither tocotrienols nor tocotrienol quinones are mentioned.
Separation of chiral compounds by chromatography is principally known. However, it is also known that the quantitative separation is very often very difficult to achieve.
Due to the importance of these substances, there exists a high interest in a process which would produce R-tocotrienol quinones in a large scale in an easy and economic way.
Examples
The present invention is further illustrated by the following experiments.
1 . Chromatographic separation
Starting materials:
Solvents and reagents used as received were heptane (Fluka, 51750), ethanol (Merck, 1 .00983), isopropanol (Sigma-Aldrich, 59300) and acetic acid (Fluka, 45730).
Chromatography:
Preparative separations were performed on an Agilent 1 100 series hplc system consisting of an Agilent 1 100 degasser, Agilent 1 100 preparative pump, Agilent 1 100 diode array detector, Agilent 1 100 MPS G2250A autosampler/fraction collector controlled by chemstation/CC-mode software package.
HPLC conditions for preparative separation:
Column: Daicel Chiracel® OD-H, 250 mm x 20 mm; eluent 0.5% isopropanol, 0.2 % acetic acid in n-heptane; flow 13 ml/min; detection 220 nm, 400 μΙ injection.
Separation of (R)-6-hydroxy-2,5,7,8-tetramethyl-2-((3E,7E)-4,8, 12-trimethyl-trideca-3,7, 11-trienyl) chroman-4-one and (S)-6-hydroxy-2,5,7,8-tetramethyl-2-((3E, 7E)-4,8, 12-trimethyltrideca-3, 7, 11-trienyl) chroman-4-one
Example 1 :
6-Hydroxy-2,5,7,8-tetramethyl-2-((3E,7E)-4,8,12-trimethyltrideca-3,7,1 1 -trienyl) chroman-4-one was prepared according to the example 6a in Kabbe and Heitzer, Synthesis 1978, 888-889.
The product was analyzed by HPLC (Column: Daicel Chiracel® OD-H, 250 mm x 4.6 mm; eluent 1 % ethanol in n-hexane; flow 1 ml/min; detection 220 nm, 2 μΙ injection). Figure 9 b) shows this chromatogram. It shows that the product is a 49.5 : 50.5 mixture (Retention time 13.2 and 14.2 min.)
87.5 mg of this product in heptane was injected and the two peaks with retention time at maximum 35.4 min. (1 ) (50.9%) resp. 43.5 min. (2) (49.1 %) were se-parated by the preparative HPLC separation. Figure 9 a) shows the chromatogram of the preparative HPLC separation.
After evaporation to dryness and dissolution the two collected fractions have been reanalysis on an analytical column (Daicel Chiracel® OD-H, 250 mm x 4.6 mm; eluent 1 % ethanol in n-hexane; flow 1 ml/min; detection 220 nm, 2 μΙ injection). Figure 9 c), respectively Figure 9 d), show the chromatogram of the first fraction, respectively the second fraction. The separation of the two isomers (Retention time 13.2 min, resp. 14.2 min) in the two fraction shows to be 94.9 : 5.1 (Figure 9 c)) resp. 7.1 : 92.9 (Figure 9 d)). Hence, the two isomers have been separation by preparative chromatography almost completely.
Patent
The active component of the formulation of the present invention is selected from alpha- tocotrienol quinone, beta-tocotrienol quinone, gamma-tocotrienol quinone, delta-tocotrienol quinone, and mixtures thereof. In one embodiment, the formulation of the present invention comprises alpha-tocotrienol quinone as the active component. In other embodiments, the formulations of the present invention comprise one or more tocotrienol quinones of Formula I or mixtures thereof, in a pharmaceutically acceptable vehicle, and in other embodiments, the formulations of the present invention comprise alpha-tocotrienol quinone in a pharmaceutically acceptable vehicle. In other particular embodiments, the formulations are administered orally. In other embodiments, the formulations of the present invention comprise one or more tocotrienol quinones of Formula I or mixtures thereof, in an ophthalmically acceptable vehicle for topical, periocular, or intraocular administration, and in other embodiments, the formulations of the present invention comprise alpha-tocotrienol quinone in an ophthalmically acceptable vehicle.
[0120] The formulations of the present invention comprise tocotrienol quinones which can be produced synthetically from the respective tocotrienol by oxidation with suitable oxidizing agents, as for example eerie ammonium nitrate (CAN). Particularly, the formulations of the present invention comprise alpha-tocotrienol quinone (CAS Reg. No. 1401-66-7) produced by oxidation of alpha-tocotrienol. A preferred process for the production of alpha-tocotrienol has been described in co-owned US provisional application USAN 61/197,585 titled “Process for Enrichment and Isolation of alpha-Tocotrienol from Natural Extracts”.
[0121] Syntheses of various members of the tocotrienol family in the d,l- or (RS)-form have been published, see for example Schudel et al, HeIv. Chim. Acta (1963) 46, 2517-2526; H. Mayer et al, HeIv. Chim. Acta (1967) 50, 1376-11393; H.-J. Kabbe et al, Synthesis (1978), 888-889; M. Kajiwara et al, Heterocycles (1980) 14, 1995-1998; S. Urano et al, Chem. Pharm. Bull. (1983) 31, 4341-4345, Pearce et al, J. Med Chem. (1992), 35, 3595-3606 and Pearce et al, J. Med. Chem. (1994). 37, 526-541. None of these reported processes lead to the natural form of the tocotrienols, but rather produces racemic mixtures. Syntheses of natural form d-tocotrienols have been published. See for example. J. Scott et al, HeIv. CMm. Acta (1976) 59, 290-306, Sato et al. (Japanese Patent 63063674); Sato et al. (Japanese Patent NoJP 01233278) and Couladouros et al. (US Patent No. 7,038,067).
[0122] While synthetic and natural tocopherols are readily available in the market, the natural tocotrienol supply is limited, and generally comprises a mixture of tocotrienols. Crude palm oil which is rich in tocotrienols (800-1500 ppm) offers a potential source of natural tocotrienols. Carotech, Malaysia is able to extract and concentrate tocotrienols from crude palm oil, by a process patented in U.S. Pat. No. 5,157,132. Tocomin®-50 typically comprises about 25.32% mixed tocotrienols (7.00% alpha-tocotrienol, 14.42% gamma-tocotrienol, 3.30% delta-tocotrienol and 0.6% beta-tocotrienol ), 6.90% alpha-tocopherol and other phytonutrients such as plant squalene, phytosterols, co-enzyme QlO and mixed carotenoids.
[0123] Other methods for isolation or enrichment of tocotrienol from certain plant oils and plant oil by-products have been described in the literature. For some examples of such isolation and purification processes, see for instance Top A. G. et al, U.S. Pat. No. 5,190,618; Lane R et al, U.S. Pat No. 6,239,171; Bellafiore, L. et al. U.S. Pat. No.6,395,915; May, CY et al, U.S. Pat. No.6,656,358; Jacobs, L et al, U.S. Pat. No. 6,838,104; Sumner, C et al. Int. Pat. Pub. WO 99/38860, or Jacobs, L, Int. Pat. Pub. WO 02/500054. The compounds for use in the present invention and the other therapeutically active agents can be administered at the recommended maximum clinical dosage or at lower doses. Dosage levels of the active compounds in the compositions for use in the present invention may be varied so as to obtain a desired therapeutic response depending on the route of administration, severity of the disease and the response of the patient. When administered in combination with other therapeutic agents, the therapeutic agents can be formulated as separate compositions that are given at the same time or different times, or the therapeutic agents can be given as a single composition.
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////////////orphan drug status, EPI-743, fast track, EPI743, EPI-743, EPI 743, Vatiquinone; alpha-Tocotrienol quinone, Vincerenone, バチキノン , BioE-743
CC1=C(C(=O)C(=C(C1=O)C)CCC(C)(CCC=C(C)CCC=C(C)CCC=C(C)C)O)C
19 February 2013 EPI-743 Vatiquinone is a new drug that is based on vitamin E. Tests have shown that it can help improve the function of cells with mitochondrial problems. It may be able to treat people with genetic disorders that affect metabolism and mitochondria Edison Pharmaceuticals and Bambino Gesu Children’s Hospital have announced the commencement of EPI-743 Phase 2 cobalamin C deficiency syndrome trial. EPI-743 is an orally bioavailable small molecule and a member of the para-benzoquinone class of drugs. The trial’s principal investigator, Bambino Gesu Children’s Hospital, division of metabolism Professor Carlo Dionisi-Vici said, “Given the central role of glutathione in cellular redox balance and antioxidant defense systems, we are eager to explore whether a therapeutic that increases glutathione such as EPI-743 will provide clinical benefit.” Improvement in visual function is the primary endpoint of the placebo-controlled study while secondary outcome measurements assess neurologic and neuromuscular function, glutathione biomarkers, quality of life, in addition to safety parameters. The investigation is aimed at assessing the efficacy of EPI-743 in disorders of intermediary metabolism that also result in redox disturbances. EPI-743 is an orally absorbed small molecule that readily crosses into the central nervous system. It works by targeting the enzyme NADPH quinone oxidoreductase 1 (NQO1). Its mode of action is to synchronize energy generation in mitochondria with the need to counter cellular redox stress Friedreich’s ataxia (FRDA) is an autosomal recessive neurodegenerative and cardiodegenerative disorder caused by decreased levels of the protein frataxin. The disease causes the progressive loss of voluntary motor coordination (ataxia) and cardiac complications. Symptoms typically begin in childhood, and the disease progressively worsens as the patient grows older; patients eventually become wheelchair-bound due to motor disabilities. Patients with Friedreich’s ataxia develop loss of visual acuity or changes in color vision. Most have jerky eye movements (nystagmus), but these movements by themselves do not necessarily interfere with vision. ……………… Bioorg Med Chem Lett 2011, 21(12): 3693 http://www.sciencedirect.com/science/article/pii/S0960894X11005440We report that α-tocotrienol quinone (ATQ3) is a metabolite of α-tocotrienol, and that ATQ3 is a potent cellular protectant against oxidative stress and aging. ATQ3 is orally bioavailable, crosses the blood–brain barrier, and has demonstrated clinical response in inherited mitochondrial disease in open label studies. ATQ3 activity is dependent upon reversible 2e-redox-cycling. ATQ3 may represent a broader class of unappreciated dietary-derived phytomolecular redox motifs that digitally encode biochemical data using redox state as a means to sense and transfer information essential for cellular function. 
Figure 1.
The conversion of α-tocotrienol to α-tocotrienol quinone.
Figure 1.
The conversion of α-tocotrienol to α-tocotrienol quinone.
New Drug Approvals 
