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ICH gets new Members and informs about the ICH Q3D Implementation
ICH gets new Members and informs about the ICH Q3D Implementation
The International Conference on Harmonisation (ICH) is the most significant organisation for the harmonisation of requirements with regard to the authorisation and the manufacture of medicinal products. Read more about the current decisions of the ICH Steering Committees.
ICH gets new Members and informs about the ICH Q3D Implementation\
The International Conference on Harmonisation (ICH) is the most significant organisation for the harmonisation of requirements with regard to the authorisation and the manufacture of medicinal products. The ICH wants this function to be extended. For that reason – during the last meeting in Minneapolis, USA – the Steering Committee decided to welcome two new members. Beside the American FDA, the EMA/EU Commission and the Japanese Authority belong to the founding members. Now, the Swiss Authority Swissmedic and the Canadian one (Health Canada) have joined the ICH Board.
Another important notice has been announced after the meeting in Minneapolis. In September 2014, the harmonised Guideline ICH Q3D Elemental Impurities will reach the Step 4 status. The FDA as well as the EMA/EU Commission and the Japanese MHLW will take over the whole document into their respective national regulations. This last – and formal – procedure will be defined as Step 5. No changes will be made in the guidance document when the authorities will make the transfer to the regulatory framework.
The new ICH Q3D and the recently adopted ICH M7 (Genotoxic Impurities) will therefore be addressed at the international Impurities Forum in Berlin.
Source: Press Release of the ICH Meeting in Minneapolis
Avoiding a reactive starting material: The Synthesis of BA-824 (old)
I need to update my collection of journal articles to talk about. I will try and go next week. While you are waiting for a new blog post, I figured I would post another article from PHARMNBIOFUEL.COM. This was posted 2011-01-22
I am running a little behind my postings. Although I am now employed on a temporary assignment and figure I can commit that same amount of time on my website as before, however, I am having to re-organize my daily activities. The postings on this website may grind to a slow dribble. I will still forge ahead to provide you with what I find interesting in current chemical literature. I am dipping into some of the choices I picked from last year, but promise to update my collection soon as to what is happening currently in the chemosphere, particularly in process research.
I think that more than some of us, the “us” being…
View original post 503 more words
NICE Endorses Lundbeck’s Alcohol Dependency Drug For Use In UK
Nalmefene
17- (cyclopropylmethyl)-4,5-alpha-epoxy-6-methylenemorphinan-3,14-diol
(5α)-17-(Cyclopropylmethyl)-4,5-epoxy-6-methylenemorphinan-3,14-diol;
(-)-Nalmefene;
6-Deoxo-6-methylenenaltrexone; 6-Desoxy-6-methylenenaltrexone;
JF 1; Nalmetrene; ORF 11676;
Lundbeck’s novel alcohol dependency drug has been endorsed by the National Institute for Health and Care Excellence (NICE) for use in Britain’s state health service.
read at
A structural analog of Naltrexone (N285780) with opiate antagonist activity used in pharmaceutical treatment of alcoholism. Other pharmacological applications of this compound aim to reduce food cravings, drug abuse and pulmonary disease in affected individuals. Used as an opioid-induced tranquilizer on large animals in the veterinary industry. Narcotic antagonist.
 |
|
| Systematic (IUPAC) name | |
|---|---|
| 17-cyclopropylmethyl-4,5α-epoxy-6-methylenemorphinan-3,14-diol | |
| Clinical data | |
| Trade names | Selincro |
| AHFS/Drugs.com | monograph |
| MedlinePlus | a605043 |
| Legal status | POM (UK) |
| Routes | Oral, Intravenous |
| Pharmacokinetic data | |
| Protein binding | 45% |
| Metabolism | hepatic |
| Half-life | 10.8 ± 5.2 hours |
| Excretion | renal |
| Identifiers | |
| CAS number | 55096-26-9 58895-64-0 (HCl) |
| ATC code | N07BB05 |
| PubChem | CID 5284594 |
| ChemSpider | 4447642  |
| UNII | TOV02TDP9I |
| ChEMBL | CHEMBL982 |
| Chemical data | |
| Formula | C21H25NO3 |
| Mol. mass | 375.9 g/mol (hydrochloride) |
| Mol. Formula: C21H25NO3 |
| Appearance: Off-White to Pale Yellow Solid |
| Melting Point: 182-185˚C |
| Mol. Weight: 339.43 |
Nalmefene (trade name Selincro), originally known as nalmetrene, is an opioid receptor antagonist developed in the early 1970s,[1] and used primarily in the management of alcohol dependence, and also has been investigated for the treatment of other addictions such as pathological gambling and addiction to shopping.
Nalmefene is an opiate derivative similar in both structure and activity to the opiate antagonist naltrexone. Advantages of nalmefene relative to naltrexone include longer half-life, greater oral bioavailability and no observed dose-dependent liver toxicity. As with other drugs of this type, nalmefene can precipitate acute withdrawal symptoms in patients who are dependent on opioid drugs, or more rarely when used post-operatively to counteract the effects of strong opioids used in surgery.
Nalmefene differs from naltrexone by substitution of the ketone group at the 6-position of naltrexone with a methylene group (CH2), which considerably increases binding affinity to the μ-opioid receptor. Nalmefene also has high affinity for the other opioid receptors, and is known as a “universal antagonist” for its ability to block all three.
In clinical trials using this drug, doses used for treating alcoholism were in the range of 20–80 mg per day, orally.[2] The doses tested for treating pathological gambling were between 25–100 mg per day.[3] In both trials, there was little difference in efficacy between the lower and higher dosage regimes, and the lower dose (20 and 25 mg, respectively) was the best tolerated, with similar therapeutic efficacy to the higher doses and less side effects. Nalmefene is thus around twice as potent as naltrexone when used for the treatment of addictions.
Intravenous doses of nalmefene at between 0.5 to 1 milligram have been shown effective at counteracting the respiratory depression produced by opiate overdose,[4] although this is not the usual application for this drug as naloxone is less expensive.
Doses of nalmefene greater than 1.5 mg do not appear to give any greater benefit in this application. Nalmefene’s longer half-life might however make it useful for treating overdose involving longer acting opioids such as methadone, as it would require less frequent dosing and hence reduce the likelihood of renarcotization as the antagonist wears off.
Nalmefene is extensively metabolised in the liver, mainly by conjugation with glucuronic acid and also by N-dealkylation. Less than 5% of the dose is excreted unchanged. The glucuronide metabolite is entirely inactive, while the N-dealkylated metabolite has minimal pharmacological activity.
Lundbeck has licensed the drug from Biotie Therapies and performed clinical trials with nalmefene for treatment of alcohol dependence.[5] In 2011 they submitted an application for their drug termed Selincro to the European Medicines Agency.[6] It has not been available on the US market since at least August 2008.[citation needed]
Side effects
- Common: drowsiness, hypertension, tachycardia, dizziness, nausea, vomiting
- Occasional: fever, hypotension, vasodilatation, chills, headache
- Rare: agitation, arrhythmia, bradycardia, confusion, hallucinations, myoclonus, itching[7]
Properties
- Soluble in water up to 130 mg/mL, soluble in chloroform up to 0.13 mg/mL
- pKa 7.6
- Distribution half-life: 41 minutes
Nalmefene is a known opioid receptor antagonist which can inhibit pharmacological effects of both administered opioid agonists and endogenous agonists deriving from the opioid system. The clinical usefulness of nalmefene as antagonist comes from its ability to promptly (and selectively) reverse the effects of these opioid agonists, including the frequently observed depressions in the central nervous system and the respiratory system.
Nalmefene has primarily been developed as the hydrochloride salt for use in the management of alcohol dependency, where it has shown good effect in doses of 10 to 40 mg taken when the patient experiences a craving for alcohol (Karhuvaara et al, Alcohol. Clin. Exp. Res., (2007), Vol. 31 No. 7. pp 1179-1187). Additionally, nalmefene has also been investigated for the treatment of other addictions such as pathological gambling and addiction to shopping. In testing the drug in these developmental programs, nalmefene has been used, for example, in the form of parental solution (Revex™).
Nalmefene is an opiate derivative quite similar in structure to the opiate antagonist naltrexone. Advantages of nalmefene compared to naltrexone include longer half- life, greater oral bioavailability and no observed dose-dependent liver toxicity. Nalmefene differs structurally from naltrexone in that the ketone group at the 6- position of naltrexone is replaced by a methylene (CH2) group, which considerably increases binding affinity to the μ-opioid receptor. Nalmefene also has high affinity for the other opioid receptors (K and δ receptors) and is known as a “universal antagonist” as a result of its ability to block all three receptor types.
Nalmefene can be produced from naltrexone by the Wittig reaction. The Wittig reaction is a well known method within the art for the synthetic preparation of olefins (Georg Wittig, Ulrich Schόllkopf (1954). “Uber Triphenyl-phosphin- methylene ah olefinbildende Reagenzien I”. Chemische Berichte 87: 1318), and has been widely used in organic synthesis.
The procedure in the Wittig reaction can be divided into two steps. In the first step, a phosphorus ylide is prepared by treating a suitable phosphonium salt with a base. In the second step the ylide is reacted with a substrate containing a carbonyl group to give the desired alkene.
The preparation of nalmefene by the Wittig reaction has previously been disclosed by Hahn and Fishman (J. Med. Chem. 1975, 18, 259-262). In their method, naltrexone is reacted with the ylide methylene triphenylphosphorane, which is prepared by treating methyl triphenylphosphonium bromide with sodium hydride (NaH) in DMSO. An excess of about 60 equivalents of the ylide is employed in the preparation of nalmefene by this procedure.
For industrial application purposes, the method disclosed by Hahn and Fishman has the disadvantage of using a large excess of ylide, such that very large amounts phosphorus by-products have to be removed before nalmefene can be obtained in pure form. Furthermore, the NaH used to prepare the ylide is difficult to handle on an industrial scale as it is highly flammable. The use of NaH in DMSO is also well known by the skilled person to give rise to unwanted runaway reactions. The Wittig reaction procedure described by Hahn and Fishman gives nalmefene in the form of the free base. The free base is finally isolated by chromatography, which may be not ideal for industrial applications.
US 4,535,157 also describes the preparation of nalmefene by use of the Wittig reaction. In the method disclosed therein the preparation of the ylide methylene triphenylphosphorane is carried out by using tetrahydrofuran (THF) as solvent and potassium tert-butoxidc (KO-t-Bu) as base. About 3 equivalents of the ylide are employed in the described procedure.
Although the procedure disclosed in US 4,535,157 avoids the use of NaH and a large amount of ylide, the method still has some drawbacks which limit its applicability on an industrial scale. In particular, the use of THF as solvent in a Wittig reaction is disadvantageous because of the water miscibility of THF. During the aqueous work-up much of the end product (nalmefene) may be lost in the aqueous phases unless multiple re-extractions are performed with a solvent which is not miscible with water.
Furthermore, in the method described in US 4,535,157, multiple purification steps are carried out in order to remove phosphine oxide by-products of the Wittig reaction. These purification steps require huge amounts of solvents, which is both uneconomical and labor extensive requiring when running the reaction on an industrial scale. As in the case of the Wittig reaction procedure described by Hahn and Fishman (see above) the Wittig reaction procedure disclosed in US 4,535,157 also yields nalmefene as the free base, such that an additional step is required to prepare the final pharmaceutical salt form, i.e. the hydrochloride, from the isolated nalmefene base.
US 4,751,307 also describes the preparation of nalmefene by use of the Wittig reaction. Disclosed is a method wherein the synthesis is performed using anisole (methoxybenzene) as solvent and KO-t-Bu as base. About 4 equivalents of the ylide methylene triphenylphosphorane were employed in this reaction. The product was isolated by extraction in water at acidic pHs and then precipitating at basic pHs giving nalmefene as base.
Even though the isolation procedure for nalmefene as free base is simplified, it still has some disadvantages. The inventors of the present invention repeated the method disclosed in US 4,751,307 and found that the removal of phosphine oxide by-products was not efficient. These impurities co-precipitate with the nalmefene during basifϊcation, yielding a product still contaminated with phosphorus byproducts and having, as a consequence, a low chemical purity, as illustrated in example 2 herein.
There is therefore a need within the field to improve the method of producing nalmefene by the Wittig reaction. In particular, there is a need for a method that is readily applicable on a large industrial scale and which avoids the use of water- miscible solvents, such as THF, in the Wittig reaction, and permits easy isolation of nalmefene in a pure form suitable for its transformation to the final pharmaceutical salt form.
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http://www.google.com/patents/EP2435439A1?cl=en
present invention the Wittig reaction may be performed by mixing a methyltriphenylphosphonium salt with 2- methyltetrahydrofuran (MTHF) and a suitable base to afford the ylide methylene triphenylphosphorane :
Methyltriphenylphosphonium salt Methylene triphenylphosphorane Yhde
The preformed ylide is subsequently reacted ‘in situ’ with naltrexone to give nalmefene and triphenylphosphine oxide (TPPO):
Naltrexone Yhde Nalmefene TPPO
Example 1 Methyltriphenylphosphonium bromide (MTPPB, 25.8 Kg) was suspended in 2- methyltetrahydrofuran (MTHF, 56 litres). Keeping the temperature in the range 20-250C, KO-t-Bu (8.8 kg) was charged in portions under inert atmosphere in one hour. The suspension turned yellow and was stirred further for two hours. An anhydrous solution of naltrexone (8.0 Kg) in MTHF (32 litres) was then added over a period of one hour at 20-250C. The suspension was maintained under stirring for a few hours to complete the reaction. The mixture was then treated with a solution of ammonium chloride (4.2 Kg) in water (30.4 litres) and then further diluted with water (30.4 litres). The phases were separated, the lower aqueous phase was discarded and the organic phase was washed twice with water (16 litres). The organic phase was concentrated to residue under vacuum and then diluted with dichloromethane (40 litres) to give a clear solution. Concentrated aqueous hydrochloric acid (HCl 37%, 2 litres) was added over one hour at 20- 250C. The suspension was stirred for at least three hours at the same temperature, and then filtered and washed with dichloromethane (8 litres) and then with acetone (16 litres). The solid was then re-suspended in dichloromethane (32 litres) at 20-250C for a few hours and then filtered and washed with dichloromethane (16 litres), affording 9.20 Kg of nalmefene hydrochloride, corresponding to 7.76 kg of nalmefene hydrochloride (99.7% pure by HPLC). Molar yield 89%.
HPLC Chromatographic conditions
Column: Zorbax Eclipse XDB C-18, 5 μm, 150 x 4.6 mm or equivalent Mobile Phase A: Acetonitrile / Buffer pH = 2.3 10 / 90
Mobile Phase B: Acetonitrile / Buffer pH = 2.3 45 / 55
Buffer: Dissolve 1.1 g of Sodium Octansulfonate in 1 L of water. Adjust the pH to 2.3 with diluted
H3PO4. Column Temperature: 35°C
Detector: UV at 230 nm
Flow: 1.2 ml/min
Injection volume: 10 μl
Time of Analysis: 55 minutes
Example 2
The procedure described in US 4,751,307 was repeated, starting from 1Og of naltrexone and yielding 8.5g of nalmefene. The isolated product showed the presence of phosphine oxides by-products above 15% molar as judged by 1HNMR.
Example 3.
Methyltriphenylphosphonium bromide (MTPPB, 112.9g) was suspended in 2- methyltetrahydrofuran (MTHF, 245 ml). Keeping the temperature in the range 20- 25°C, KO-t-Bu (38.7 g) was charged in portions under inert atmosphere in one hour. The suspension was stirred for two hours. An anhydrous solution of naltrexone (35 g) in MTHF (144 ml) was then added over a period of one hour at 20-250C. The suspension was maintained under stirring overnight. The mixture was then treated with a solution of glacial acetic acid (17.7 g) in MTHF. Water was then added and the pH was adjusted to 9-10. The phases were separated, the lower aqueous phase was discarded and the organic phase was washed twice with water. The organic phase was concentrated to residue under vacuum and then diluted with dichloromethane (175 ml) to give a clear solution. Concentrated aqueous hydrochloric acid (HCl 37%, 10. Ig) was added over one hour at 20- 25°C. The suspension was stirred and then filtered and washed with dichloromethane and acetone. The product was dried affording 38.1g of Nalmefene HCl. Example 4
Example 3 was repeated but the Wittig reaction mixture after olefmation completeness was treated with acetone and then with an aqueous solution of ammonium chloride. After phase separation, washings, distillation and dilution with dichloromethane, the product was precipitated as hydrochloride salt using HCl 37%. The solid was filtered and dried affording 37.6 g of Nalmefene HCl.
Example 5 Preparation of Nalmefene HCl dihydrate from Nalmefene HCl Nalmefene HCl (7.67 Kg, purity 99.37%, assay 93.9%) and water (8.6 litres) were charged into a suitable reactor. The suspension was heated up to 800C until the substrate completely dissolved. Vacuum was then applied to remove organic solvents. The resulting solution was filtered through a 0.65 μm cartridge and then diluted with water (2.1 litres) that has been used to rinse the reactor and pipelines. The solution was cooled down to 500C and 7 g of Nalmefene HCl dihydrate seeding material was added. The mixture was cooled to 0-50C over one hour with vigorous stirring and then maintained under stirring for one additional hour. The solid was filtered of and washed with acetone. The wet product was dried at 25°C under vacuum to provide 5.4 Kg of Nalmefene HCl dihydrate (purity 99.89%, KF 8.3% , yield 69%).
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http://www.google.com/patents/EP2316456A1?cl=en
……………………
http://www.google.com/patents/US8598352
References
- US patent 3814768, Jack Fishman et al, “6-METHYLENE-6-DESOXY DIHYDRO MORPHINE AND CODEINE DERIVATIVES AND PHARMACEUTICALLY ACCEPTABLE SALTS”, published 1971-11-26, issued 1974-06-04
- Barbara J. Mason, Fernando R. Salvato, Lauren D. Williams, Eva C. Ritvo, Robert B. Cutler (August 1999). “A Double-blind, Placebo-Controlled Study of Oral Nalmefene for Alcohol Dependence”. Arch Gen Psychiatry 56 (8): 719. doi:10.1001/archpsyc.56.8.719.
- Clinical Trial Of Nalmefene In The Treatment Of Pathological Gambling
- http://www.fda.gov/cder/foi/label/2000/20459S2lbl.pdf
- “Efficacy of Nalmefene in Patients With Alcohol Dependence (ESENSE1)”.
- “Lundbeck submits Selincro in EU; Novo Nordisk files Degludec in Japan”. thepharmaletter. 22 December 2011.
- Nalmefene Hydrochloride Drug Information, Professional
- Brittain, H.G., et al.: Anal. Profiles Drug Subs. Excip., 24, 351 (1996), Anton, R., et al.: J. Clin. Psychopharmacol., 24, 421 (2004), Bart, G., et al.: Neuropsychopharmacol., 30, 2254 (2005), Wu, X., et al.: Chem. Pharmacol. Bull., 54, 977 (2006),
| US4535157 | Nov 1, 1983 | Aug 13, 1985 | Key Pharmaceuticals, Inc. | Reacting naloxone and naltrexone with potassium e-butoxide |
| US4751307 | Feb 27, 1987 | Jun 14, 1988 | Mallinckrodt, Inc. | Wittig-reaction processes |
| EP0035202A2 | Feb 23, 1981 | Sep 9, 1981 | Miles Laboratories, Inc. | Method of blood plasma fractionation |
| EP0039066A2 | Apr 25, 1981 | Nov 4, 1981 | E.I. Du Pont De Nemours And Company | 17-Substituted 6-desoxy-7,8-dihydro-6-alpha-methylnoroxymorphone narcotic antagonists |
| WO2007110761A2 | Mar 23, 2007 | Oct 4, 2007 | Azad Pharmaceutical Ingredient | Polymorphic forms of olopatadine hydrochloride and methods for producing olopatadine and salts thereof |
| Reference | ||
|---|---|---|
| 1 | Aycock, D.F., 2007, Solvent Applications of 2 Methyitetrahydrofuran in Organometallc and Biphasic Reactions, Organic Process Research & Development, 11:156-159. | |
| 2 | Dr. Rainer Aul et al., May 2007, A Green Alternative to THF, Manufacturing Chemist, pp. 33-34. | |
| 3 | Hahn F. and Fishman J., 1975, Narcotic Antagonists. 4. Carbon-6 Derivatives of N-Substituted Noroxymorphones as Narcotic Antagonists, Journal of Medicinal Chemistry 18(3):259-262. | |
| 4 | Hinkley et al., Feb. 10, 2005, Synthesis of a Caryophyllene Isoprenologue, a potential Diterpene Natural Product, Tetrahedron 61, pp. 3671-3680. | |
| 5 | J.M Aizapurua, Science of Synthesis, 4 (2001), p. 595. | |
| 6 | Search Report issued May 5, 2013 in Gulf Cooperation Council Application No. GC 2010-15942 filed May 25, 2010. | |
| 7 | Wittig et al., Jul. 10, 1954, “Über Triphenyl-phosphin-methylene als olefinbildende Reagenzien I“, Chemische Berichte 87: 1318. | |
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Protein heals wounds, boosts immunity and protects from cancer – Lactoferrin
04 May 2012
University of Calgary researcher edits special issue on disease fighting properties of lactoferrin
Hans Vogel, a professor in the biological sciences department, is the guest editor of a special issue of the journal Biochemistry and Cell Biology that focuses on lactoferrin, an important iron-binding protein with many health benefits.
“Some people describe this protein as the ‘Swiss army knife’ of the human host defense system,” says Vogel. “We now know that lactoferrin has many functions in innate immunity and that it plays a role in protecting us from bacterial, viral, fungal, and protozoal infections. It can even protect us from some forms of cancer.”
View original post 269 more words
Garlic compound fights source of food-borne illness better than antibiotics (100 times more effective than two popular antibiotics )
04 May 2012
Discovery could play role in treatments for food and prep areas
PULLMAN, Wash.—Researchers at Washington State University have found that a compound in garlic is 100 times more effective than two popular antibiotics at fighting the Campylobacter bacterium, one of the most common causes of intestinal illness. Their work was recently published in the Journal of Antimicrobial Chemotherapy.
The discovery opens the door to new treatments for raw and processed meats and food preparation surfaces.
View original post 546 more words
Beloranib, 성분명 벨로라닙 ZGN-433….Zafgen’s Prader-Willi syndrome therapy receives orphan drug designation in Europe
Beloranib
CAS 251111-30-5 (beloranib),529511-79-3 (beloranib hemioxalate)
(E)-(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl 3-(4-(2-(dimethylamino)ethoxy)phenyl)acrylate
6-O-(4-dimethylaminoethoxy)cinnamoyl fumagillol
Mechanism of Action:methionine aminopeptidase 2 (MetAP2) inhibitor
Indication:Obesity US Patent : US6063812 Patent Exp Date: May 13, 2019
Originator: Chong Kun Dang (CKD) Pharma (종근당) Chong Kun Dang Pharm Corp
Developer: Zafgen Inc. (자프젠)Zafgen Corporation
Zafgen’s Prader-Willi syndrome therapy receives orphan drug designation in Europe The European Commission (EC) has granted orphan drug designation to US-based Zafgen for its beloranib for treating Prader-Willi syndrome. Beloranib is a potent inhibitor of Methionine aminopeptidase-2 that reduces hunger while stimulating the use of stored fat as an energy source (MetAP2). MetAP2 is an enzyme that modulates the activity of key cellular processes that control metabolism. http://www.pharmaceutical-technology.com/news/newszafgens-prader-willi-syndrome-therapy-receives-orphan-drug-designation-in-europe-4316842?WT.mc_id=DN_News
INTRODUCTION Beloranib is an experimental drug candidate for the treatment of obesity. It was discovered by CKD Pharmaceuticals and is currently being developed by Zafgen. Beloranib, an analog of the natural chemical compound fumagillin, is an inhibitor of the enzyme METAP2. It was originally designed as angiogenesis inhibitor for the treatment of cancer. However, once the potential anti-obesity effects of METAP2 inhibition became apparent, the clinical development began to focus on these effects and beloranib has shown positive results in preliminary clinical trials for this indication. At such low doses, says Thomas E. Hughes, president and chief executive officer of Zafgen, toxicity concerns tend to evaporate, in part because so little opportunity exists to inhibit off-target proteins.
Zafgen, a small pharmaceutical company in Cambridge, Mass., sees high selectivity and low toxicity with its covalent molecule for treating obesity, beloranib hemioxalate, also known as ZGN-433. “You’re passing a wave of the molecule through the body,” he says. “It hits the different tissues, silences the target enzyme where it finds it, and then it goes away.” Zafgen’s drug candidate inhibits an enzyme called methionine aminopeptidase 2 (MetAP2), which had been of interest in oncology circles until it turned out to be a poor target for treating cancer in mice. However, animals treated with a MetAP2 inhibitor lost weight. Zafgen pursued the enzyme as a target for obesity. Its drug candidate contains a spiroepoxide that bonds with a histidine in the protein’s active site.
ZGN-433 has undergone a Phase I clinical trial, in which obese volunteers lost up to 2 lb per week. It will enter Phase II trials within a year, Hughes says, funded by $33 million the company raised from investors. With dosing of up to 2 mg twice per week, ZGN-433 reaches a maximum concentration in the body of just a few nanomolar for several hours before the body quickly eliminates it, Hughes says. During that time, the drug is much more likely to interact with MetAP2 than with anything else. “You’re flying under the radar of a lot of concerns,” he says. “Drug-drug interactions are not an issue. There’s just not enough inhibitor to go around.
The same is true for off-target inhibition: The chance of off-target toxicity is largely gone.” Proponents of covalent inhibitors are quick to point out that dozens of such drugs are already on the market. They include aspirin, the world’s most widely used medicine; penicillin and related antibiotics; and recently developed blockbusters such as Plavix, Prevacid, and Nexium. The drugs treat a broad range of conditions, and many have minimal side effects, even when taken for years. By one count, of the marketed drugs that inhibit enzymes, more than one-third work by covalent modification (Biochemistry, DOI: 10.1021/bi050247e).
6-O-(4-dimethylaminoethoxy) cinnamoyl fumagillol hemioxalate
| Beloranib, ZGN-433, CKD-732 | |
|---|---|
 |
|
| Identifiers | |
| CAS number | 251111-30-5 , 529511-79-3 (hemioxalate) |
| PubChem | 6918502 |
| ChemSpider | 26286923 |
| UNII | FI471K8BU6 |
| Jmol-3D images | Image 1 |
| Properties | |
| Molecular formula | C29H41NO6 |
| Molar mass | 499.64 g mol−1 |
| Except where noted otherwise, data are given for materials in their standard state (at 25 °C (77 °F), 100 kPa) | |
Beloranib (previously known as CKD-732; ZGN-433), a methionine aminopeptidase 2 (MetAP2) inhibitor originally designed as an anticancer agent, is being developed by Zafgen as a first-in-class obesity therapy. Beloranib, a twice-daily injection, is discovered by korean company Chong Kun Dang (CKD) Pharmaceuticals and was licensed to Cambridge, MA-based startup Zafgen, Inc. Zafgen holds exclusive worldwide rights (exclusive of Korea) for development and commercialization of beloranib. Beloranib, an analog of the antimicrobial agent fumagillin, is an inhibitor of the enzyme METAP2 involved in fatty acid production. It was originally designed as angiogenesis inhibitor for the treatment of cancer. However, once the potential anti-obesity effects of METAP2 inhibition became apparent, the clinical development began to focus on these effects.
Zafgen has chosen to develop beloranib not for the folks that need to shed a few pounds, but for severely obese people, and smaller groups of patients with rare and dangerous conditions. In January 2013, beloranib was granted orphan drug designation by the U.S. Food and Drug Administration to treat a rare genetic condition known as Prader-Willi Syndrome (PWS) that causes obesity through compulsive eating. Zafgen plans to seek the same designation for beloranib in craniopharyngioma (a rare benign brain tumor) related obesity as well. By going after these orphan indications, Zafgen can get onto the market quicker and cheaper than if it went straight for the larger obesity market. Zafgen recently completed two Phase 2a clinical trials evaluating beloranib’s ability to reduce body weight and to improve hyperphagia, one in PWS patients and one in severely obese patients. In its Phase 2a clinical trials, Zafgen observed reductions in body weight, body mass and body fat content in both patient populations and reductions in hyperphagia-related behaviors in PWS patients.
On June 19, 2014, Zafgen Inc. raised $96 million in its initial public offering (IPO) on the Nasdaq under the symbol “ZFGN” amid strong demand from investors. With its IPO cash, Zafgen plans to initiate its Phase 3 clinical program, consisting of two Phase 3 clinical trials, of beloranib in PWS patients, with the first Phase 3 trial to start in the second half of 2014, after finalizing the program design based on ongoing conversations with the FDA and certain European regulatory authorities. Zafgen is also planning a phase 2a trial in craniopharyngioma, and a Phase 2b trila in patients with severe obesity, all this year. The composition of matter patent (US6063812) on beloranib will each expire in May 2019. Zafgen owns two issued U.S. patents relating to beloranib polymorph compositions of matter that will expire in 2031 and two issued U.S. patents to methods of treating obesity that will expire in 2029. 
Beloranib is an experimental drug candidate for the treatment of obesity. It was discovered by CKD Pharmaceuticals and is currently being developed by Zafgen.[1] Beloranib, an analog of the natural chemical compound fumagillin, is an inhibitor of the enzyme METAP2.[2] It was originally designed as angiogenesis inhibitor for the treatment of cancer.[3] However, once the potential anti-obesity effects of METAP2 inhibition became apparent, the clinical development began to focus on these effects and beloranib has shown positive results in preliminary clinical trials for this indication.[4][5]
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http://www.google.com/patents/WO2005082349A1?cl=en
compound O-(4- dimethylaminoethoxycinnamoyl)fumagillol can be used in the form of a salt, e.g., acetate, lactate, benzoate, salicylate, mandelate, oxalate, methanesulfonate, or p- toluenesulfonate. Korean Patent No. 0357542 and its corresponding patents (U.S. Patent No. 6,063,812, Japanese Patent No. 3370985, and European Patent No. 1077964), filed by the present applicant, disclose fumagiUol derivatives, including the compounds used in the present invention. The composition of the present invention can be prepared in combination with pharmaceutically acceptable carriers commonly used in pharmaceutical formulations.
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http://www.google.com/patents/WO2012064838A1?cl=en
MetAP2 encodes a protein that functions at least in part by enzymatically removing the amino terminal methionine residue from certain newly translated proteins, such as, glyceraldehyde-3- phosphate dehydrogenase (Warder et al. (2008) J Proteome Res 7:4807). Increased expression of the MetAP2 gene has been historically associated with various forms of cancer. Molecules inhibiting the enzymatic activity of MetAP2 have been identified and have been explored for their utility in the treatment of various tumor types (Wang et al. (2003) Cancer Res 63:7861) and infectious diseases, such as, microsporidiosis, leishmaniasis, and malaria (Zhang et al. (2002) J. Biomed Sci. 9:34). Notably, inhibition of MetAP2 activity in obese and obese-diabetic animals leads to a reduction in body weight in part by increasing the oxidation of fat and in part by reducing the consumption of food (Rupnick et al. (2002) Proc Natl Acad Sci USA 99: 10730). [0003] 6-O-(4-Dimethylaminoethoxy)cinnamoyl fumagillol is a METAP2 inhibitor and is useful in the treatment of, e.g., obesity. 6-O-(4-Dimethylaminoethoxy)cinnamoyl fumagillol is characterized by formula I:
Example 1 [0060] Crystalline, Form A material of 6-O-(4-dimethylaminoethoxy)cinnamoyl fumagillol was prepared as follows: [0061] Approximately 423 mg of amorphous gum/oil-like 6-O-(4- dimethylaminoethoxy)cinnamoyl fumagillol free base compound was dissolved in ca. 6 mL of diisopropylether (IPE). The solution was allowed to stir for ca. 24 hours at ambient temperature (18-22°C) during which time solid precipitated. The resulting solid was isolated by filtration and dried under vacuum at ambient for ca. 4 hours (yield 35.8 %).
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http://www.google.com/patents/WO1999059986A1?cl=en
Example 14 : 0-(4-dimethylaminocinnamoyl)fumagillol 1) To a solution of 4-dimethylaminocinnamic acid (950 mg) in toluene (20 ml), dipyridyl disulfide (1.64 g) and triphenyl phosphine (1.97 g) were added, and the mixture was stirred for 12 hours. 2) The resultant solution of 1) was added to fumagillol (500 mg) at room temperature. Sodium hydride (142 mg) was added thereto, and the reaction mixture was stirred for 30 minutes. After adding saturated ammonium chloride solution (20 ml), the reaction mixture was extracted with ethyl acetate (100 ml). The organic layer was washed with brine and dried over anhydrous magnesium sulfate. After filtering, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (eluent: ethyl acetate/ n-hexane = 1/2) to obtain yellow solid (470 mg). ‘H-NMR (CDCI3) δ : 7.60 (d, IH, J=15.8Hz), 7.41 (d, 2H, J=8.9Hz), 6.67 (d, 2H, J=8.9Hz), 6.27 (d, IH, J=15.8Hz), 5.71 (m, IH), 5.22 (bit, IH), 3.70 (dd, IH, J=2.8, 11.0Hz), 3.45 (s, 3H), 3.02 (s, 6H), 3.01 (d, IH, J=4.3Hz), 2.63 (t, IH, J=6.3Hz), 2.56 (d, IH, J=4.3Hz), 2.41 – 1.81 (m, 6H), 1.75 (s, 3H), 1.67 (s, 3H), 1.22 (s, 3H), 1.15 – 1.06 (m, IH)
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Organic Letters, 16(3), 792-795; 2014
An efficient, two-step construction of highly complex alkaloid-like compounds from the natural product fumagillol is described. This approach, which mimics a biosynthetic cyclase/oxidase sequence, allows for rapid and efficient structure elaboration of the basic fumagillol scaffold with a variety of readily available coupling partners. Mechanistic experiments leading to the discovery of an oxygen-directed oxidative Mannich reaction are also described.
References
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- Chun, E; Han, CK; Yoon, JH; Sim, TB; Kim, YK; Lee, KY (2005). “Novel inhibitors targeted to methionine aminopeptidase 2 (MetAP2) strongly inhibit the growth of cancers in xenografted nude model”. International Journal of Cancer. Journal International Du Cancer 114 (1): 124–30. doi:10.1002/ijc.20687. PMID 15523682.
- Kim, EJ; Shin, WH (2005). “General pharmacology of CKD-732, a new anticancer agent: effects on central nervous, cardiovascular, and respiratory system”. Biological & Pharmaceutical Bulletin 28 (2): 217–23. doi:10.1248/bpb.28.217. PMID 15684472.
- “Zafgen Announces Positive Topline Phase 1b Data for ZGN-433 in Obesity”. MedNews. Drugs.com. 5 January 2011.
- “Fat-busting pill helps obese to shed two pounds a week – without changing their diets”. UK Daily Mail. 11 January 2011.
MORE REF Grenning, Alexander J. et al.Remodeling of Fumagillol: Discovery of an Oxygen-Directed Oxidative Mannich Reaction.Organic Letters, 16(3), 792-795; 2014
Hughes, T. E.; Kim, D. D.; Marjason, J.; Proietto, J.; Whitehead, J. P.; Vath, J. E. Ascending dose-controlled trial of beloranib, a novel obesity treatment for safety, tolerability, and weight loss in obese women. Obesity (2013), 21(9), 1782-1788.
Chung Il Hong, Jung Woo Kim, Sang Joon Lee, Soon Kil Ahn, Nam Song Choi, Ryung Kee Hong, Hyoung Sik Chun, Seung Kee Moon, Cheol Kyu Han. Angiogenesis inhibitors, antiarthritic agents and anticarcinogenic agents plus synthesis. US patent Number US6063812 A, Also published as CA2331873A1, CA2331873C, CN1301260A, CN100352810C, DE69903279D1, DE69903279T2, EP1077964A1,EP1077964B1,WO1999059986A1, Filing date: May 13, 1999.Original Assignee:Chong Kun Dang Corporation Crawford, Thomas; Reece, Hayley A.Preparation of crystalline forms of 6-O-(4-dimethylaminoethoxy)cinnamoylfumagillol.PCT Int. Appl. (2012), WO2012064838 A1, 20120518
Egorov, Maxim et al. Preparation of fumagillol derivatives useful for the treatment or prevention of bone tumors. PCT Int. Appl., WO2012130906, 04 Oct 2012
Stevenson, Cheri A.; Akullian, Laura C.; Petter, Russell C.; Kane, John J.; Hammond, Charles E.; Yin, Mao; Yurkovetskiy, Aleksandr.Preparation of biocompatible biodegradable fumagillin analog conjugates for the treatment of cancer. PCT Int. Appl. (2009), WO2009073445 A2, 20090611
Lee, Hong Woo et al.Design, synthesis, and antiangiogenic effects of a series of potent novel fumagillin analogues.Chemical & Pharmaceutical Bulletin, 55(7), 1024-1029; 2007
Lee, Hong Woo et al.Selective N-demethylation of tertiary aminofumagillols with selenium dioxide via a non-classical Polonovski type reaction.Heterocycles, 68(5), 915-932; 2006
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2: Shin SJ, Ahn JB, Park KS, Lee YJ, Hong YS, Kim TW, Kim HR, Rha SY, Roh JK, Kim DH, Kim C, Chung HC. A Phase Ib pharmacokinetic study of the anti-angiogenic agent CKD-732 used in combination with capecitabine and oxaliplatin (XELOX) in metastatic colorectal cancer patients who progressed on irinotecan-based chemotherapy. Invest New Drugs. 2012 Apr;30(2):672-80. doi: 10.1007/s10637-010-9625-x. Epub 2010 Dec 29. PubMed PMID: 21188464.
3: Shin SJ, Jeung HC, Ahn JB, Rha SY, Roh JK, Park KS, Kim DH, Kim C, Chung HC. A phase I pharmacokinetic and pharmacodynamic study of CKD-732, an antiangiogenic agent, in patients with refractory solid cancer. Invest New Drugs. 2010 Oct;28(5):650-8. doi: 10.1007/s10637-009-9287-8. Epub 2009 Jul 8. PubMed PMID: 19585083.
4: Rhee Y, Park SY, Kim YM, Lee S, Lim SK. Angiogenesis inhibitor attenuates parathyroid hormone-induced anabolic effect. Biomed Pharmacother. 2009 Jan;63(1):63-8. doi: 10.1016/j.biopha.2007.10.013. Epub 2007 Nov 20. PubMed PMID: 18457934.
5: Kim YM, An JJ, Jin YJ, Rhee Y, Cha BS, Lee HC, Lim SK. Assessment of the anti-obesity effects of the TNP-470 analog, CKD-732. J Mol Endocrinol. 2007 Apr;38(4):455-65. PubMed PMID: 17446235.
6: Kim EJ, Shin WH. General pharmacology of CKD-732, a new anticancer agent: effects on central nervous, cardiovascular, and respiratory system. Biol Pharm Bull. 2005 Feb;28(2):217-23. PubMed PMID: 15684472.
7: Chun E, Han CK, Yoon JH, Sim TB, Kim YK, Lee KY. Novel inhibitors targeted to methionine aminopeptidase 2 (MetAP2) strongly inhibit the growth of cancers in xenografted nude model. Int J Cancer. 2005 Mar 10;114(1):124-30. PubMed PMID: 15523682.
8: Lee HS, Choi WK, Son HJ, Lee SS, Kim JK, Ahn SK, Hong CI, Min HK, Kim M, Myung SW. Absorption, distribution, metabolism, and excretion of CKD-732, a novel antiangiogenic fumagillin derivative, in rats, mice, and dogs. Arch Pharm Res. 2004 Feb;27(2):265-72. PubMed PMID: 15029870.
9: Kim JH, Lee SK, Ki MH, Choi WK, Ahn SK, Shin HJ, Hong CI. Development of parenteral formulation for a novel angiogenesis inhibitor, CKD-732 through complexation with hydroxypropyl-beta-cyclodextrin. Int J Pharm. 2004 Mar 19;272(1-2):79-89. PubMed PMID: 15019071.
10: Myung SW, Kim HY, Min HK, Kim DH, Kim M, Cho HW, Lee HS, Kim JK, Hong CI. The identification of in vitro metabolites of CKD-732 by liquid chromatography/tandem mass spectrometry. Rapid Commun Mass Spectrom. 2002;16(21):2048-53. PubMed PMID: 12391579.
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Beehive extract shows potential as prostate cancer treatment
” “If you feed CAPE to mice daily, their tumors will stop growing. After several weeks, if you stop the treatment, the tumors will begin to grow again at their original pace,”
04 May 2012
Proteomics reveals how ancient remedy slows prostate tumor cell proliferation
An over-the-counter natural remedy derived from honeybee hives arrests the growth of prostate cancer cells and tumors in mice, according to a new paper from researchers at the University of Chicago Medicine.
Caffeic acid phenethyl ester, or CAPE, is a compound isolated from honeybee hive propolis, the resin used by bees to patch up holes in hives. Propolis has been used for centuries as a natural remedy for conditions ranging from sore throats and allergies to burns and cancer. But the compound has not gained acceptance in the clinic due to scientific questions about its effect on cells.
In a paper published in Cancer Prevention Research…
View original post 822 more words
Application of Process Modelling Tools in the Scale-Up of Pharmaceutical Crystallisation Processes
Crystallisations are frequent process steps in the manufacture of active pharmaceutical ingredients (APIs). They are the primary means of intermediate or product formation and separation to achieve the desired purity and form. These unit operations are complex processes which are difficult to control due to the interlinked chemical and physical effects. For example, chemical aspects such as salt and polymorph concerns are in the forefront of process research, but physical effects manifesting themselves on scale-up, due to equipment influences, can be equally important for the successful outcome of a campaign. Several operational parameters, such as temperature or impeller speed, need to be understood and controlled to achieve constant desupersaturation, consistent narrow particle size distribution around the desired mean, minimal attrition, and homogeneous growth conditions. This paper focuses on the equipment influence on crystallisations, relating it to first principles with respect to heat and momentum transfer, analysing it with computational fluid dynamics (CFD), and demonstrating its process impact using examples from recent development work. Dynamic process modelling and CFD are state-of-the-art engineering tools to identify process requirements and match them with equipment capabilities. The work reported here demonstrates how a semiquantitative application of these tools can lead to a controllable, robust process in an existing plant despite the time and resource limitations usually encountered in the industry.
http://pubs.acs.org/doi/full/10.1021/op040013n
Application of Process Modelling Tools in the Scale-Up of Pharmaceutical Crystallisation Processes
European Medicines Agency recommends 39 medicines for human use for marketing authorisation in first half of 2014
10/07/2014
European Medicines Agency recommends 39 medicines for human use for marketing authorisation in first half of 2014
Thirty-nine medicines for human use were recommended for marketing authorisationby the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) in the first half of 2014, compared with 44 in first half of 2013 and 33 in first half of 2012.
This figure includes a number of new innovative medicines with the potential to meet unmet medical needs, treat diseases for which no treatments were previously available or bring significant added benefit to patients over existing therapies. Among these medicines are the anticancer medicines Mekinist (trametinib) and Gazyvaro (obinutuzumab), the anti-inflammatory* Entyvio (vedolizumab), the anti-infective Daklinza (daclatasvir), as well as Translarna (ataluren) and Sylvant (siltuximab), which are both intended for the treatment of rare conditions.
In parallel, the number of medicines recommended for approval via the European Union centralised procedure based on generic or informed consent applications has decreased compared with the first half of 2013 (6 versus 13).
More than two in three applicants received scientific advice from the CHMP during the development phase of their medicine, and for innovative medicines four in five applicants received such advice. This is a significant increase compared with the first half of 2013 (when one in two applicants received scientific advice), and mirrors the growing number of requests for scientific advice received by the Agency.
Confirming the trend observed in the past few years, the number of new medicines intended for the treatment of rare diseases is steadily increasing, providing treatments for patients who often have only few or no options. In the first half of 2014, eight medicines were recommended for the treatment of rare diseases. This number includes three medicines for which the CHMP recommended conditional approval but whose applications were withdrawn by the sponsor prior to a final decision by the European Commission
**.
Conditional approval is one of the Agency’s mechanisms to provide early patient access to medicines that fulfill unmet medical needs or address life-threatening diseases. The CHMP also used this mechanism for the recommendation of the first treatment for Duchenne muscular dystrophy (Translarna), a life-threatening condition.
The CHMP granted two positive opinions after an accelerated assessment for the medicines Sylvant and Daklinza; this mechanism aims to speed up the assessment of medicines that are expected to be of major public health interest particularly from the point of view of therapeutic innovation.
The CHMP also gave an opinion on the use of a new combination product in the treatment of hepatitis C virus (HCV) infection in a compassionate use programme (ledipasvir and sofosbuvir). These programmes are intended to give patients with a life-threatening, long-lasting or seriously disabling disease access to treatments that are still under development. The treatment paradigm of hepatitis C is currently shifting rapidly, with the development of several new classes of direct-acting antivirals. By recommending the conduct of three compassionate use programmes and the marketing authorisation of three new medicines for HCV infection over the past eight months, the Agency is actively supporting this shift which is expected to bring significant added benefit to patients.
Notes
* On Friday 11 July 2014 at 11:00 the statement, ‘the anti-infectives Entyvio (vedolizumab) and Daklinza (daclatasvir)’ was corrected to ‘the anti-inflammatory Entyvio (vedolizumab), the anti-infective Daklinza (daclatasvir)’.
** The CHMP had recommended a conditional approval for Vynfinit (vintafolide) and its companion diagnostics Folcepri (etarfolatide) and Neocepri (folic acid). After authorisation, the company was to provide confirmatory data from an ongoing study with Vynfinit. However, before the authorisation process could be completed by the European Commission, preliminary data from this study became available which showed that the study could not confirm the benefit of Vynfinit in ovarian cancer patients. Therefore, the company terminated the study and decided to withdraw the applications.
DR ANTHONY MELVIN CRASTO
ORGANIC SPECTROSCOPY
New Drug Approvals 