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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 29 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 29 year tenure till date Aug 2016, Around 30 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 25 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 13 lakh plus views on New Drug Approvals Blog in 212 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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The US Food and Drug Administration (FDA) has approved Bayer HealthCare’s Gadavist (gadobutrol) injection as the first magnetic resonance contrast agent for evaluation of breast cancer in the US


Gadobutrol skeletal.svgGADOBUTROL

gadolinium(III) 2,2′,2”-(10-((2R,3S)-1,3,4-trihydroxybutan-2-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate

Gadobutrol, SH-L-562, Gadovist,138071-82-6

The US Food and Drug Administration (FDA) has approved Bayer HealthCare’s Gadavist (gadobutrol) injection as the first magnetic resonance contrast agent for evaluation of breast cancer in the US.

The agency has approved the new indication for Gadavist injection for intravenous use with magnetic resonance imaging of the breast to assess the presence and extent of malignant breast disease.

Approval is based on priority review of two Phase III studies with identical design (GEMMA-1 and GEMMA-2).

Bayer HealthCare’s Gadavist (gadobutrol)

Bayer’s Gadavist injection cleared for breast cancer evaluation
The US Food and Drug Administration (FDA) has approved Bayer HealthCare’s Gadavist (gadobutrol) injection as the first magnetic resonance contrast agent for evaluation of breast cancer in the US.

http://www.pharmaceutical-technology.com/news/newsbayer-gadavist-injection-cleared-breast-cancer-evaluation-4293723?WT.mc_id=DN_News

GADOBUTROL

Clinical data
AHFS/Drugs.com International Drug Names
Licence data US FDA:link
Pregnancy cat. C (US)
Legal status POM (UK) -only (US)
Routes IV
Identifiers
CAS number 138071-82-6 Yes
ATC code V08CA09
PubChem CID 72057
DrugBank DB06703
UNII 1BJ477IO2L Yes
KEGG D07420 Yes
Chemical data
Formula C18H31GdN4O9 
Mol. mass 604.710 g/mol

………………………..

Gadobutrol (INN) (Gd-DO3A-butrol) is a gadolinium-based MRI contrast agent (GBCA).

It received marketing approval in Canada[1] and in the United States.[2][3][4]

As of 2007, it was the only GBCA approved at 1.0 molar concentrations.[5]

Gadobutrol is marketed by Bayer Schering Pharma as Gadovist, and by Bayer HealthCare Pharmaceuticals as Gadavist.[6]

 

 

 

Gadobutrol, SH-L-562, Gadovist
A different synthesis started from the previously reported tetraaza cyclopentaacenaphthylene (XV). Treatment of (XV) with a solution of piperazine at pH 6 gave rise to the bicyclic lactam (XVI). Alkylation of (XVI) with bromoacetic acid, followed by basic lactam hydrolysis furnished the tris(carboxymethyl) derivative (X), which was processed as in Scheme 3.
Argese, M.; Ripa, G. (Bracco SpA; Dibra SpA); 1,4,7,10-Tetraazabicyclo[8.2.2]tetradecan-2-one, a process for the preparation thereof and the use thereof for the preparation of tetraazamacrocycles. EP 0998476; JP 2002511884; WO 9905145
Gadobutrol, SH-L-562, Gadovist
In a related method for obtaining the precursor (V), epoxide (II) was condensed with the tosyl-protected tetraamine (XIII) in an autoclave at 170 C to give (XIV). The N-tosyl groups of (XIV) were then removed by treatment with lithium metal in liquid ammonia, yielding intermediate (III), which was then subjected to alkylation with bromoacetic acid, followed by acid hydrolysis
Platzek, J.; Gries, H.; Weinmann, H.-J.; Schuhmann-Giampieri, G.; Press, W.-R. (Schering AG); 1,4,7,10-Tetraazacyclododecane-butyl-triols, process for their preparation, and pharmaceutical agents containing these cpds.. DE 4009119; EP 0448191;
Gadobutrol, SH-L-562, Gadovist
The macrocyclic tetraamine (I) was protected as the triaminomethane derivative (VIII) by treatment with either triethyl orthoformate (4) or with dimethylformamide dimethylacetal (5). Alkylation of (VIII) with bromoacetic acid gave rise to the N-formyl N’,N”,N”’-tris(carboxymethyl) compound (IX). After basic hydrolysis of the formamide function of (IX), the resultant N-deprotected amine (X) was condensed with epoxide (II) to yield (XI). Further complexation with GdCl3 and ketal group hydrolysis led to the target compound
Murru, M.; Ripa, G.; Scala, A.; Viscardi, C.F.; Ausonio, M.; Scotti, C.; Cossuta, P. (Bracco SpA; Dibra SpA); A process for the preparation of macrocyclic chelants and the chelates thereof with paramagnetic metal ions. WO 9856775

 

 

WORLDCUP FOOTBALL WEEK 2014 BRAZIL

……………………………………………….

http://www.google.com/patents/EP0988294B1?cl=en

 

  • This type of complexes with metal ions, in particular with paramagnetic metal ions; is used for the preparation of non-ionic contrast agents for the diagnostic technique known as magnetic resonance (MRI, Magnetic Resonance Imaging), among which are ProHance(R) (Gadoteridol, gadolinium complex of 10-(2-hydroxypropyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid), and Gadobutrol (gadolinium complex of [10-[2,3-dihydroxy-1-(hydroxymethyl)propyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid).

  • [0003]
    Two different synthetic approaches are described in literature for the preparation of this kind of complexes, said approaches differing in the strategy taken to discriminate one of the four nitrogen atoms: the first one (Dischino et al., Inorg. Chem., 1991, 30, 1265 or EP 448191, EP 292689, EP 255471) is based on the selective protection of one of the nitrogen atoms by formation of the compound of formula (III), 5H,9bH-2a,4a,7-tetraazacycloocta[cd]pentalene, and on the subsequent hydrolysis to compound of formula (IV), 1-formyl-1,4,7,10-tetraazacyclododecane, followed by the carboxymethylation of the still free nitrogen atoms and by the deprotection and alkylation of the fourth nitrogen atom, according to scheme 1.

  • [0004]
    The step from 1,4,7,10-tetraazacyclododecane disulfate (a commercially available product) to compound (III) is effected according to the conventional method disclosed in US 4,085,106, followed by formation of the compound of formula (IV) in water-alcohol medium.
  • [0005]
    This intermediate is subsequently tricarboxymethylated with tert-butyl bromoacetate (TBBA) in dimethylformamide at 2.5°C and then treated with a toluene-sodium hydroxide diphasic mixture to give the compound of formula (V), 10-formyl-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic, tris(1,1-dimethylethyl) ester, which is subsequently hydrolysed to compound of formula (II) in acidic solution.
  • [0006]
    In the process described in WO 93/24469 for the synthesis of Gadobutrol, at first one of the nitrogen atoms is alkylated in conditions such as to minimize the formation of polyalkylated derivatives, then the monoalkylderivative is purified and carboxymethylated, according to scheme 2.

  • [0007]
    The alkylation of 1,4,7,1,0-tetraazacyclododecane with the epoxide of formula (VI), 4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]octane, is carried out in anhydrous n-BuOH under reflux and the reaction mixture is extracted with water, evaporated to dryness and the residue is subsequently diluted with water and extracted with methylene chloride.
  • [0008]
    The aqueous phase containing the mono-alkylated product (65% yield in Example 7 which reports the procedure for the preparation of 5 kg of Gadobutrol) is directly carboxymethylated at 70°C with chloroacetic acid, keeping pH 9.5 by addition of NaOH. The reaction mixture is adjusted to pH 1, concentrated to dryness and dissolved in methanol to remove the undissolved salts. The filtrate is then concentrated under vacuum, dissolved in water, and loaded onto a cation exchanger in the H+ form to fix the product. The subsequent elution with ammonia displaces the desired product, which is concentrated to small volume and subsequently complexed with gadolinium oxide according to conventional methods, and the resulting complex is purified by means of ion exchange resins. The overall yield is 42%.
  • [0009]
    Although the first of these two processes could theoretically provide a higher yield, in that all the single steps (protection, carboxymethylation and deprotection) are highly selective, the complexity of the operations required to remove salts and solvents and to purify the reaction intermediates makes such theoretical advantage ineffective: the overall yield is in fact, in the case of Gadoteridol, slightly higher than 37%.
  • [0010]
    The preparation of Gadobutrol according to the alternative process (WO 93/24469) provides a markedly better yield (72%) only on laboratory scale (example 2): example 7 (represented in the above Scheme 2) actually evidences that, when scaling-up, the yield of this process also remarkably decreases (42%).
  • [0011]
    In addition to the drawback of an about 40% yield, both processes of the prior art are characterized by troublesome operations, which often involve the handling of solids, the use of remarkable amounts of a number of different solvents, some of them having undesirable toxicological or anyway hazardous characteristics.
  • [0012]
    Moreover, the synthesis described by Dischino makes use of reagents which are extremely toxic, such as tert-butyl bromoacetate, or harmful and dangerous from the reactivity point of view, such as dimethylformamide dimethylacetal.
  • [0013]
    An alternative to the use of dimethyl formamide dimethylacetal is suggested by J. Am. Chem. Soc. 102(20), 6365-6369 (1980), which discloses the preparation of orthoamides by means of triethyl orthoformate.
  • [0014]
    EP 0596 586 discloses a process for the preparation of substituted tetraazacyclododecanes, among them compounds of formula (XII), comprising:

    • formation of the tricyclo[5.5.1.0] ring;
    • alkylation with an epoxide;
    • hydrolysis of the 10-formyl substituent;
    • reaction with an acetoxy derivative bearing a leaving group at the alpha-position.
  • [0015]
    Nevertheless, this method requires quite a laborious procedure in order to isolate the product of step b).
  • [0016]
    It is the object of the present invention a process for the preparation of the complexes of general formula (XII)

    wherein

    R1 and R2
    are independently a hydrogen atom, a (C1-C20) alkyl containing 1 to 10 oxygen atoms, or a phenyl, phenyloxy group, which can be unsubstituted or substituted with a (C1-C5) alkyl or hydroxy, (C1-C5) alkoxy, carbamoyl or carboxylic groups,
    Me3+
    is the trivalent ion of a paramagnetic metal;

    comprising the steps represented in the following Scheme 3:

 

  • The process of the present invention keeps the high selectivity typical of the protection/deprotection strategy described by Dischino in the above mentioned paper, while removing all its drawbacks, thus providing for the first time a reproducible industrial process for the preparation of the concerned compounds in high yields and without use of hazardous substances.
  • [0019]
    The preparation of the gadolinium complex of 10-(2-hydroxypropyl)-1,4,7,10-tetraazacyclododecane-1,4,7-tri-acetic) acid (Gadoteridol), according to scheme 4, is particularly preferred:

    in which the synthetic steps a), b), c), d), e), and f) have the meanings defined above and the epoxide of formula (XI) in step d) is propylene oxide.

  • [0020]
    The preparation of the gadolinium complex of [10-[2,3-dihydroxy-1-(hydroxymethyl)propyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic) acid (Gadobutrol), according to the scheme 5, is also preferred.

    in which the synthetic steps a), b), c), d), e), and f) have the meanings defined above and the epoxide of formula (XI) in step d) corresponds to the one of formula (VI), defined above.

  • [0021]
    On the other hand, step a) of the process of the present invention involves the use of triethyl orthoformate in the presence of an acid catalyst, instead of dialkylformamide-dialkylacetal.
  • [0022]
    Triethyl orthoformate can be added in amounts ranging from 105% to 200% on the stoichiometric value.
  • [0023]
    The reaction temperature can range from 110 to 150°C and the reaction time from 5 to 24 h.
  • [0024]
    The catalyst is a carboxylic acid having at least 3 carbon atoms, C3-C18, preferably selected from the group consisting of propionic, butyric and pivalic acids.
  • [0025]
    Triethyl orthoformate is a less toxic and less expensive product than N,N-dimethylformamide-dimethylacetal and does not involve the formation of harmful, not-condensable gaseous by-products. Moreover, triethyl orthoformate is less reactive than N,N-dimethylformamide-dimethylacetal, which makes it possible to carry out the loading procedures of the reactives as well as the reaction itself in utterly safe conditions even on a large scale, allows to better monitor the progress of the reaction on the basis of such operative parameters as time and temperature, without checking the progress by gas chromatography, and makes dosing the reactive less critical, in that it can be added from the very beginning without causing the formation of undesired by-products: all that rendering the process suitable for the production of compound (III) on the industrial scale in easily reproducible conditions.
  • [0026]
    The subsequent step b) involves the carboxymethylation of compound (III) in aqueous solution, using a haloacetic acid, to give compound (IX), i.e. the 10-formyl-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid salt with an alkali or alkaline-earth metal, the salts of compound (IX) with sodium, potassium or calcium being most preferred.

 

 

Example 2

  • [0065]
  • [0066]
    The procedure of Example 1 is followed until step C included, to obtain a solution of DO3A trisodium salt.
  • [0067]
    pH is adjusted to 12.3 with conc. HCl and 57.7 kg (0.4 kmol) of 4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]-octane are added. After reaction for 4 h at 40°C and for 8 h at 80°C, the solution is cooled to 50°C, 120 kg of an aqueous solution containing 0.135 kmol of gadolinium trichloride are added. After 1 h the mixture is cooled at 17°C and acidified to pH 1.7 with conc. HCl, keeping this pH for 2 h. The solution is subsequently warmed to 50°C, pH is adjusted to 7 with sodium hydroxide, keeping these conditions for 1 h.
  • [0068]
    After that, the resulting crude Gadobutrol is purified repeating exactly the same process as in steps E and F of Example 1.

Recovery of the product (Gadobutrol)

  • [0069]
    The product-rich fraction is then thermally concentrated to a viscous residue and the residue is added with 350 kg of ethanol at 79°C.
  • [0070]
    The resulting suspension is refluxed for 1 h, then cooled, centrifuged and dried under reduced pressure to obtain 66.0 kg of Gadobutrol (0.109 kmol), HPLC assay 99.5% (A%).
    Overall yield: 79.1%
  • [0071]
    The IR and MS spectra are consistent with the indicated structure.

 

 

 

 

References

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Ioforminol (GE-145; AN-113111) as an iv contrast agent (Phase 2)


ioforminol

Ioforminol [INN], UNII-95FNF21CDN, 1095110-48-7, FEK-256-062

5-[formyl-[3-[formyl-[3,5-bis(2,3-dihydroxypropylcarbamoyl)-2,4,6- triiodophenyl]amino]-2-hydroxypropyl]amino]-N,N’-bis(2,3-dihydroxypropyl)-2,4,6-triiodobenzene- 1 ,3-dicarboxamide
1,3-Benzenedicarboxamide, 5,5′-[(2-hydroxy-1,3-
propanediyl)bis(formylimino)]bis[N1,N3-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-

All-ambo-5,5′-[2-hydroxypropane-1,3-diylbis(formylazanediyl)]bis[N,N’-bis(2,3-
dihydroxypropyl)-2,4,6-triiodobenzene-1,3-dicarboxamide]

https://download.ama-assn.org/resources/doc/usan/x-pub/ioforminol.pdf

MOLECULAR FORMULA C33H40I6N6O15

MOLECULAR WEIGHT 1522.1

SPONSOR GE HealthCare Ltd

CODE DESIGNATION FEK-256-062

CAS REGISTRY NUMBER 1095110-48-7

WHO NUMBER 9245

Visualisation of anatomical structures of the body during computed tomography for diagnostic purposes

 

ChemSpider 2D Image | ioforminol | C33H40I6N6O15

All diagnostic imaging is based on the achievement of different signal levels from different structures within the body. Thus, in X-ray imaging for example, for a given body structure to be visible in the image, the X-ray attenuation by that structure must differ from that of the surrounding tissues. The difference in signal between the body structure and its surroundings is frequently termed contrast and much effort has been devoted to means of enhancing contrast in diagnostic imaging since the greater the contrast between a body structure and its surroundings the higher the quality of the images and the greater their value to the physician performing the diagnosis. Moreover, the greater the contrast the smaller the body structures that may be visualized in the imaging procedures, i.e. increased contrast can lead to increased spatial resolution. The diagnostic quality of images is strongly dependent on the inherent noise level in the imaging procedure, and the ratio of the contrast level to the noise level can thus be seen to represent an effective diagnostic quality factor for diagnostic images.

For the last 50 years the field of X-ray contrast agents has been dominated by soluble iodine containing compounds. Commercial available contrast media containing iodinated contrast agents are usually classified as ionic monomers such as diatrizoate (Gastrografen™), ionic dimers such as ioxaglate (Hexabrix™), nonionic monomers such as iohexol (Omnipaque™), iopamidol (Isovue™), iomeprol (lomeron™) and the non-ionic dimer iodixanol (Visipaque™). The most widely used commercial non-ionic X-ray contrast agents such as those mentioned above are considered safe. Contrast media containing iodinated contrast agents are used in more than 20 million of X-ray examinations annually in the USA and the number of adverse reactions is considered acceptable. However, since a contrast enhanced X- ray examination will require up to about 200 ml contrast media administered in a total dose, there is a continuous drive to provide improved contrast media.

Achieving improvement in such a diagnostic quality factor has long been and still remains an important goal.

In techniques such as X-ray, one approach to improve the diagnostic quality factor has been to introduce contrast enhancing materials formulated as contrast media into the body region being imaged. Thus for X-ray, early examples of contrast agents were insoluble inorganic barium salts which enhanced X-ray attenuation in the body zones into which they distributed. For the last 50 years the field of X-ray contrast agents has been dominated by soluble iodine containing compounds.

Commercial available contrast media containing iodinated contrast agents are usually classified as ionic monomers such as diatrizoate (marketed e.g. under the trade mark Gastrografen™), ionic dimers such as ioxaglate (marketed e.g. under the trade mark Hexabrix™), nonionic monomers such as iohexol (marketed e.g. under the trade mark Omnipaque™), iopamidol (marketed e.g. under the trade mark Isovue™), iomeprol (marketed e.g. under the trade mark Iomeron™) and the non-ionic dimer iodixanol (marketed under the trade mark Visipaque™). The clinical safety of iodinated X-ray contrast media has continuously been improved over the recent decades through development of new agents; from ionic monomers (Isopaque™) to non-ionic monomers (e.g. Omnipaque™) and non-ionic dimers (e.g. Visipaque™).

The utility of the contrast media is governed largely by its toxicity, by its diagnostic efficacy, by adverse effects it may have on the subject to which the contrast medium is administered, but also by the ease of production, storage and administration. The toxicity and adverse biological effects of a contrast medium are contributed to by the components of the formulation medium, i.e. of the diagnostic composition, e.g. the solvent or carrier as well as the contrast agent itself and its components such as ions for the ionic contrast agents and also by its metabolites.

The manufacture of non-ionic X-ray contrast media involves the production of the active

pharmaceutical ingredient (API), i.e. the contrast agent prepared in the primary production, followed by the formulation into the drug product, herein denoted the X-ray composition, prepared in the secondary production. In the preparation of an X-ray composition, the contrast agent is admixed with additives, such as salts, optionally after dispersion in a physiologically tolerable carrier. The contrast agent has to be completely solved in the carrier when additives are included and the composition is prepared. A well-known process for preparing X-ray compositions includes heating the contrast agent in the carrier, such as water for injection, to ensure complete dissolution. For instance, for the contrast media Visipaque™ the secondary production process includes dissolution of the contrast agent iodixanol in water for injection and heating to about 98 °C. Heating at this temperature for an adequate period of time ensures that the contrast agent is completely dissolved.

However, different X-ray contrast agents have different solubility. For instance WO 2009/008734 of GE Healthcare AS discloses a new class of compounds and their use as X-ray contrast agents. The compounds are dimers containing two linked iodinated phenyl groups. Compound I, now called

Ioforminol, falling within the formula I of WO2009/008734, has been found by the applicant to have particularly favourable properties. Ioforminol is supersaturated at the relevant storage conditions.

 

Figure imgf000003_0001

Compound I, Ioforminol:

5-[formyl-[3-[formyl-[3,5-bis(2,3-dihydroxypropylcarbamoyl)-2,4,6- triiodophenyl]amino]-2-hydroxypropyl]amino]-N,N’-bis(2,3-dihydroxypropyl)-2,4,6-triiodobenzene- 1 ,3-dicarboxamide.

A solution in which the concentration of the solute (API) exceeds the equilibrium solute concentration at a given temperature is said to be supersaturated. This is possible because the solute does not precipitate immediately when the solution is cooled below the saturation temperature. Such solutions are denoted supersaturated.

As the solubility of Ioforminol decreases with decreasing temperature, the supersaturation increases. At room temperature the solubility of Ioforminol is limited. To achieve solutions with a concentration higher than the thermodynamic equilibrium concentration, at room temperature, Ioforminol is dissolved at a temperature above room temperature. When a clear solution has been achieved the solution is cooled and enters a state defined as supersaturated.

Supersaturated solutions are thermodynamically unstable and prone to nucleate and therefore to precipitate on storage. Among several factors, the onset of the precipitation depends on the degree of supersaturation, presence of the crystals of the solute and foreign particles such as dust or other impurities, i.e. purity, and storage temperature of the solution.

The injection solution of Ioforminol, i.e. the administrable X-ray composition, is highly supersaturated. The nucleation (precipitation) in the injection solution at storage conditions is strongly undesirable. The physical stability of the solution, i.e. prevention of the nucleation for a certain time at storage conditions, may be improved substantially by heat treatment of the solution well above its saturation temperature for a sufficiently long period of time.

WO2011/117236 of the applicant is directed to a process involving hea treatment at low pH to avoid degradation and precipitation of an X-ray contrast agent composition. However, a high heat load is needed to obtain a seed- free solution. This heat load causes a greater degradation of the product and a lower pH in the final product resulting in liberation of iodine. This sets a restriction to the total heat load that may be given to the formulated solution.

 

………………..

WO2014052091A1

X-ray contrast media containing a chemical compound as the active pharmaceutical ingredient(s) having two triiodinated phenyl groups linked by a linking group are usually referred to as dimeric contrast agents or dimers. During the years a wide variety of iodinated dimers have been proposed. Currently, one contrast medium having an iodinated non-ionic dimer as the active pharmaceutical ingredient is on the market^ the product Visipaque™ containing the compound iodixanol. In WO2009/008734 of the applicant a novel dimeric contrast agent named loforminol is disclosed.

The properties of this is described in more detail in the publications Chai et al. “Predicting cardiotoxicity propensity of the novel iodinated contrast medium GE-145: ventricular fibrillation during left coronary arteriography in pigs”, Acta Radiol, 2010, and in Wistrand, L.G., et al “GE-145, a new low-osmolar dimeric radiographic contrast medium”, Acta Radiol, 2010. loforminol (GE-145) is named Compound 1 herein and has the following structure:

 

Figure imgf000003_0001

Compound 1 :

5,5′-(2-Hydroxypropane-1 ,3-diyl)bis(formylazanediyl)bis(N1 ,N3-bis(2,3- dihydroxypropyl)-2,4,6-triiodoisophthalamide)

The manufacture of non-ionic X-ray contrast media involves the production of the chemical drug, the active pharmaceutical ingredient (API), i.e. the contrast agent, followed by the formulation into the drug product, herein denoted the X-ray composition. WO2009/008734 of the applicant provides a synthetic route for preparing the API loforminol.

loforminol can e.g., as provided by the general preparation description and Example 1 of WO2009/008734, be synthesized from 5- amino-N,N’-bis-(2,3-dihydroxy-propyl)-2,4,6-triiodo-isophthalamide (compound (4)), which is commercially available. The preparation of this compound is known from the synthesis of both iohexol and iodixanol and can also be prepared from 5- nitroisophthalic acid for instance as described in WO2006/016815, including hydrogenation and subsequent iodination e.g. by iodine chloride, I CI. Alternatively,

5-amino-2,4,6-triiodoisophthalic acid may be used, which is commercially available precursor, e.g. from Sigma-Aldrich. The free amino group of the isophthalamide compound (compound (4)) is then acylated and the hydroxyl groups in the substituents may also be protected by acylation. The protecting groups may be removed for example by hydrolysis to give N1 ,N3-bis(2,3-dihydroxypropyl)-5- formylamino-2,4,6-triiodoisophthalamide.

In a dimerization step this is reacted e.g. with epichlorohydrin to provide the loforminol contrast agent compound. The state of the art synthesis of loforminol, as disclosed in examples 1 and 2 of WO2009/008734, is shown in Scheme 1 below.

 

Figure imgf000004_0001

Scheme 1 .

As described in WO2009/008734 compound 3 is a mixture comprising 1 – formylamino-3,5-bis(2,3-bis(formyloxy)propan-1 -ylcarbamoyl)-2,4,6-trioodobenzene, and X is then a formyl group. In each synthetic step it is important to optimize the yield and minimize the production of impurities. The problem to be solved by the present invention may be regarded as the provision of optimizing the process for preparation of compound mixture (3) of scheme 1 , i.e. a mixture comprising 1 -formylamino-3,5-bis(2,3- bis(formyloxy)propan-1 -ylcarbamoyl)-2,4,6-trioodobenzene.

The process is hence directed to the preparation of compound mixture (3) by the formylation of the amino function of 5-amino-N1 ,N3-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide (4), including a work-up procedure.

Examples

Example 1 : Preparation of compound mixture (3) comprising 1-formylamino- 3,5-bis(2,3-bis(formyloxy)propan-1-ylcarbamoyl)-2,4,6-trioodobenzene

5-amino-N1 ,N3-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide (compound (4)) (7.5 kg, 10.6 moles) was dissolved in formic acid (4.9 I) and heated to 45 until a clear solution was obtained (~4 hours), then the thick amber solution was cooled to 10 °C.

Formic acid (9.4 I) was charged into a different reactor and cooled to 10 <€, after reaching the target temperature acetic anhydride was added at such a rate that the temperature did not exceeded 15 <€.

After 2.5 hours all acetic anhydride was added to the formic acid and the mixed anhydride solution was added drop wise to the compound (4) solution. The rate of addition was adjusted so that the temperature never exceeded 20 °C. After 2 hours all mixed anhydride had been added and the reaction was left stirring at 15 °C for additional 1 hour. Isopropanol (4.9 I) was added carefully and the suspension became noticeable thicker and was left stirring at ambient temperature. After 16 hours the reaction slurry was filtered on a vacuum nutch and washed with isopropanol (3 * 1 .5 I) to give compound mixture (3) comprising 1 -formylamino-3,5- bis(2,3-bis(formyloxy)propan-1 -ylcarbamoyl)-2,4,6-trioodobenzene as a dense white powder (7.98kg). The quantitative yield with regards to N-formylation was > 99 %.

…………….

WO2009008734A2

Preparation of intermediates (when not commercially available)

The precursors to the compounds of formulas (IVa) and (IVb), the tri-iodinated phenyl groups having a free amino group are commercially available or can be produced following procedures described or referred to e.g. in WO95/35122 and WO98/52911. 5-amino-2,4,6-triiodo-isophtalic acid for example is available e.g. from Aldrich and 5-amino-2,4,6-triiodo-N,N’-bis(2,3-dihydroxypropyl)-isophtalamide is commercially available e.g. from Fuji Chemical Industries, Ltd.

Examples of commercial available precursors of the compounds of formulas (IVa) and (IVb), either commercially available or previously described in the literature include:

 

Figure imgf000019_0001

5-Amino-N,N’-bis-(2,3-dihydroxy-propyl)-2,4,6-triiodo-isophthalamide

 

Figure imgf000019_0002

5-Amino-N-(2,3-dihydroxy-propyl)-N’-(2-hydroxy-1-hydroxymethyl-ethyl)- 2,4,6-triiodo-isophthalamide (WO2002044125)

Figure imgf000020_0001

5-Amino-N,N’-bis-(2,3-dihydroxy-propyl)-2,4,6-triiodo-N,N’-dimethyl- isophthalamide

 

Figure imgf000020_0002

5-Amino-N-(2,3-dihydroxy-propyl)-N’-(2-hydroxy-ethyl)-2,4,6-triiodo-is ophthalamide (WO 8700757)

The compounds of formulas (IVa) and (IVb), may be prepared by acylation of the corresponding compounds having free amino groups. In this reaction, hydroxyl groups in the substituents R may also be protected by acylation.

Acylation may be effected by any convenient method, e.g. by use of activated formic acid such as mixed anhydrides which can prepared by a variety of methods described in the literature.

A convenient method of preparing mixed anhydrides is to add a carboxylic acid anhydride to an excess of formic acid under controlled temperature. It is also possible to make mixed anhydrides by addition of a carboxylic acid chloride to a solution of a formic acid salt. Formyl-mixed anhydrides may include acetyl, isobutyryl, pivaloyl, benzoyl etc.

In the present implementation acetic-formic mixed anhydride is employed. To an excess of cooled pre-prepared acetic-formic mixed anhydride is added a 5-amino- monomer and the mixture is stirred overnight. The mixture is concentrated in vacuo and may be used directly in the alkylation step as described in the experimental section (procedure B) or alternatively the O-acylated groups may be hydrolysed prior to alkylation as described in the experimental section (procedure A). Hydrolysis is conveniently performed in aqueous basic media as exemplified in the experimental section or may alternatively be effected by alcoholysis e.g. as described in WO1997000240.

It is also possible to dissolve the 5-aminomonomer in formic acid and subsequently add the carboxylic acid anhydride but in order to reduce unwanted acylation it is preferred to prepare the mixed anhydride separately and subsequently mix this with the 5-aminomonomer as described above.

Experimental

Example 1

5,5′-(2-hvdroxypropane-1 ,3-diyl)bis(formylazanediyl)bis(N1,N3-bis(2,3- dihvdroxypropyl)-2.4,6-triiodoisophthalamide)

 

Figure imgf000021_0001

Procedure A:

1 a) N,N’-Bis-(213-dihvdroxy-propyl)-5-formylamino-2,4,6-triiodo-isophthalamide Formic acid (300 ml) was charged in a dry 1000 ml flask fitted with a dropping funnel, stir bar, thermometer and a gas inlet. The acid was cooled on an ice bath under a nitrogen blanket and acetic anhydride (144.8 g, 1.418 mol) was added drop wise at a rate so that the temperature did not exceed 2.5 C. After complete addition, the ice bath was removed and the temperature was allowed to reach 10 °C. The mixture was again ice cooled and 5-amino-N,N’-bis(2,3-dihydroxypropyl)-2,4,6- triiodo-isophthalamide (100 g, 141.8 mmol) was added over 5 minutes and the mixture was left stirring over night while attaining ambient temperature. The mixture was evaporated to dryness and methanol (300 ml) and water (300 ml) was added. 2 M potassium hydroxide was added until all material was in solution and a stable pH 12.5 was attained. The methanol was removed in vacuo. The mixture was neutralized with 4 M HCI and a slow precipitation started. 300 ml water was added and the product was precipitated over night. The precipitate was collected and rinsed with a small amount of water and dried on filter to a moist cake and further dried in vacuo to yield 84.8 g ( 81.5 %) of N,N’-bis-

(2,3-dihydroxy-propyl)-5-formylamino-2,4,6-triiodo-isophthalamide.

1H-NMR 500 MHz (solvent: D2O, ref. H2O=4.8 ppm, 25 0C): 8.35 and 8.05 ppm (2s,

1 H), 3.94 ppm (m, 2H), 3.67 ppm (m, 2H), 3.55 ppm (m, 2H), 3.45 ppm (m, 2H),

3.34 ppm (m, 2H).

LC-MS (column Agilent Zorbax SB-Aq 3.5 μm 3.0 x 100 mm, solvents: A = water/ 0.1 % formic acid and B = acetonitrile/ 0.1% formic acid; gradient 0-30 % B over 20 min; flow 0.3 ml/ min, UV detection at 214 and 254 nm, ESI-MS) gave two peaks centred at 5.5 minutes with m/z (M + H+) 733.828, m/z (M + NH4+) 750.855, m/z (M + Na+) 755.817 corresponding to the structure.

1 b) 5,5′-(2-hvdroxypropane-1 ,3-diyl)bis(formylazanediyl)bis(N1,N3-bis(2,3- dihvdroxypropyl)-2,4,6-triiodoisophthalamide)

Potassium hydroxide (1.07 g) was dissolved in water (6.9 ml) and methanol (3.4 ml) in a 50 ml round bottomed flask fitted with a magnetic stir bar. Boric acid (0.41 g, 6.6 mmol) and N,N’-bis-(2,3-dihydroxy-propyl)-5-formylamino-2,4,6-triiodo- isophthalamide (7.0 g, 9.56 mmol) was added to the stirred solution.. Epichlorohydrin (260 ul, 3.32 mmol) was added to the solution and a pH electrode was fitted in the flask and the pH was maintained at pH 12.7 by drop wise addition of 4 M potassium hydroxide for 4 h. At this point, the mixture was left stirring over night. The pH was adjusted with 4 M hydrochloric acid to pH 4 and the methanol was removed in vacuo. The remaining aqueous solution was diluted with water (75 ml) and treated with ion exchangers (AMB200C and IRA67) to zero conductivity. The ion exchangers were removed by filtration and rinsed with water and the combined aqueous filtrates were freeze dried. The crude product was purified by preparative HPLC (column Phenomenex Luna C18 10 μm solvents: A = water and B = acetonitrile; gradient 05-20 % B over 60 min. After freeze drying 3.80 g of 5,5′- (2-hydroxypropane-1 ,3-diyl)bis(formylazanediyl)bis(N1,N3-bis(2,3-dihydroxypropyl)- 2,4,6-triiodoisophthalamide) (74.8 % yield) was obtained.

1H-NMR 500 MHz (solvent: D2O, ref. H2O=4.8 ppm, 25 0C): 8.34 and 8.08 ppm (m, 2 H), 2.80-4.80 ppm (m 26 H). LC-MS TOF; 1522.68 m/z (M + H+), 1544.66 m/z (M + Na+).

…………

 New patent

WO-2014052091

Process for the preparation of 1-formylamino-3,5-bis(2,3-bis(formyloxy)propan-1-ylcarbamoyl)-2,4,6-trioodobenzene, used as a key intermediate in the preparation of ioforminol. Also claims a process for the preparation of ioforminol, useful in X-ray imaging. GE Healthcare is developing ioforminol (GE-145; AN-113111) as an iv contrast agent (Phase 2). See WO2013104690 claiming X-ray imaging contrast media with low iodine concentration and X-ray imaging process. Also see concurrently published WO2014052092 claiming preparation of ioforminol. Appears to be the first filing from Medi-Physics on this compound.

 

 

……………

The most preferred iodinated agents are;

 

Figure imgf000010_0001

Diatrizoic acid

 

Figure imgf000010_0002

loxaglinic acid

 

Figure imgf000010_0003

 

Figure imgf000011_0001

loversol

 

Figure imgf000011_0002

lodixanol

 

Figure imgf000011_0003

lomeprol

 

Figure imgf000011_0004

lobitriol

 

The most preferred chelates are:

 

Figure imgf000012_0001

Gadopentetate

 

Figure imgf000013_0001

Ňadoversetamide

 

Figure imgf000014_0001

 

Figure imgf000014_0002

 

Figure imgf000014_0003

Gadoxetinic acid

GADODIAMIDE, OMNISCAN Drug Patent Expiration, 1 st oct 2013


GADODIAMIDE

GE HEALTHCARE, OMNISCAN

Drug Patent Expiration

1 st oct 2013, US5560903, CAS 122795-43-1

GADODIAMIDE INJECTABLE; INJECTION 287MG/ML RX  NDA 020123

Gadodiamide is a gadolinium-based MRI contrast agent, used in MR imaging procedures to assist in the visualization of blood vessels. It is commonly marketed under the trade name Omniscan.

For intravenous use in MRI to visualize lesions with abnormal vascularity (or those thought to cause abnormalities in the blood-brain barrier) in the brain (intracranial lesions), spine, and associated tissues.

Gadodiamide is a contrast medium for cranial and spinal magnetic resonance imaging (MRI) and for general MRI of the body after intravenous administration. The product provides contrast enhancement and facilitates visualisation of abnormal structures or lesions in various parts of the body including the central nervous system (CNS). It does not cross an intactblood brain barrier but might give enhancement in pathological conditions.

Based on the behavior of protons when placed in a strong magnetic field, which is interpreted and transformed into images by magnetic resonance (MR) instruments. Paramagnetic agents have unpaired electrons that generate a magnetic field about 700 times larger than the proton’s field, thus disturbing the proton’s local magnetic field. When the local magnetic field around a proton is disturbed, its relaxation process is altered. MR images are based on proton density and proton relaxation dynamics. MR instruments can record 2 different relaxation processes, the T1 (spin-lattice or longitudinal relaxation time) and the T2 (spin-spin or transverse relaxation time). In magnetic resonance imaging (MRI), visualization of normal and pathological brain tissue depends in part on variations in the radiofrequency signal intensity that occur with changes in proton density, alteration of the T1, and variation in the T2. When placed in a magnetic field, gadodiamide shortens both the T1 and the T2 relaxation times in tissues where it accumulates. At clinical doses, gadodiamide primarily affects the T1 relaxation time, thus producing an increase in signal intensity. Gadodiamide does not cross the intact blood-brain barrier; therefore, it does not accumulate in normal brain tissue or in central nervous system (CNS) lesions that have not caused an abnormal blood-brain barrier (e.g., cysts, mature post-operative scars). Abnormal vascularity or disruption of the blood-brain barrier allows accumulation of gadodiamide in lesions such as neoplasms, abscesses, and subacute infarcts.

1.Schenker MP, Solomon JA, Roberts DA. (2001). Gadolinium Arteriography Complicated by Acute Pancreatitis and Acute Renal Failure, Journal of vascular and interventional radiology 12(3):393.[1]
2 Unal O, Arslan H. (1999). Cardiac arrest caused by IV gadopentetate dimeglumine. AJR Am J Roentgenol 172:1141.[2]
3  Cacheris WP, Quay SC, Rocklage SM. (1990). The relationship between thermodynamics and the toxicity of gadolinium complexes, Magn Reson Imaging 8(6):467-81. doi:10.1016/0730-725X(90)90055-7
4  Canavese, C; Mereu, MC; Aime, S; Lazzarich, E; Fenoglio, R; Quaglia, M; Stratta, P (2008). “Gadolinium-associated nephrogenic systemic fibrosis: the need for nephrologists’ awareness”. Journal of nephrology 21 (3): 324–36. PMID 18587720.

COUNTRY       PATENT    APPROVED,     EXPIRY

United States 5560903 1993-10-01 2013-10-01
Canada 1335819 1995-06-06 2012-06-06
United States 5362475 1994-11-08 2011-11-08
Canada 1335819 1995-06-06 2012-06-06
United States 5560903 1993-10-01 2013-10-01

Gadolinium contrast agents are used as contrast media to enhance magnetic resonance imaging as they are paramagnetic. This compound has a low incidence of adverse side effects, although there is a rare association with nephrogenic systemic fibrosis (NSF) when given to people with severe renal impairment (ie, GFRglomerular filtration rate <30mL/min/1·73m2).It seems to be related to the liberation of free gadolinium ions, and UK CHM advice is against using the least stable of the agents – Omniscan (gadodiamide) – in patients with severe renal impairment, and carefully considering whether to use others where renal function is impaired.

OMNISCAN (gadodiamide) Injection is the formulation of the gadolinium complex of diethylenetriamine pentaacetic acid bismethylamide, and is an injectable, nonionic extracellular enhancing agent for magnetic resonance imaging. OMNISCAN is administered by intravenous injection. OMNISCAN is provided as a sterile, clear, colorless to slightly yellow, aqueous solution. Each 1 mL contains 287 mg gadodiamide and 12 mg caldiamide sodium in Water for Injection.

The pH is adjusted between 5.5 and 7.0 with hydrochloric acid and/or sodium hydroxide. OMNISCAN contains no antimicrobial preservative. OMNISCAN is a 0.5 mol/L solution of aqua[5,8-bis(carboxymethyl)11-[2-(methylamino)-2-oxoethyl]-3-oxo-2,5,8,11-tetraazatridecan-13-oato (3-)-N5, N8, N11, O3, O5, O8, O11, O13] gadolinium hydrate, with a molecular weight of 573.66 (anhydrous), an empirical formula of C16H28GdN5O9•xH2O, and the following structural formula:

OMNISCANTM (gadodiamide) Structural Formula Illustration

Pertinent physicochemical data for OMNISCAN are noted below:

PARAMETER

Osmolality (mOsmol/kg water) @ 37°C 789
Viscosity (cP) @ 20°C 2
@ 37°C 1.4
Density (g/mL) @ 25°C 1.14
Specific gravity @ 25°C 1.15

OMNISCAN has an osmolality approximately 2.8 times that of plasma at 37°C and is hypertonic under conditions of use.

gadodiamide, chemical name: [5,8 _ bis (carboxymethyl) -11 – [2_ (methylamino)-2_ ethyl] -3 – O 2 ,5,8, 11 – tetraazacyclododecane-decane -13 – oxo-(3 -)] gadolinium trihydrate. Its structure is shown in formula one.

[0003] Structural Formula:

[0004]

Figure CN102001964AD00031

[0005] Magnetic resonance contrast agent gadodiamide resonance than ionic contrast agents safer generation of products, it is non-ionic structure significantly reduces the number of particles in solution, osmotic balance of body fluids is very small.Meanwhile, gadodiamide relatively low viscosity to bring the convenience of nursing staff, making it easier to bolus. In addition, gadodiamide pioneered the use of amide-substituted carboxyl part, not only reduces the toxicity of carboxyl groups and ensure the non-ionic nature of the product solution.

[0006] reported in the literature and their intermediates gadodiamide synthetic route is as follows:

[0007] 1. Compound III synthetic routes for its preparation in U.S. Patent No. US5508388 described as: In the synthesis process, the inventors using acetonitrile as solvent, acetic anhydride as dehydrating agent, pyridine as acid-binding agent, at 55 ~ 60 ° C, the reaction 18h. Anti-

See the reaction should be a process. The disadvantage of this synthesis are acetonitrile toxicity, not widely used.

[0008]

Figure CN102001964AD00032

[0009] Reaction a

[0010] (2) Synthesis of Compound III in many articles are reported in the patent and its implementation method similar to the patent US5508388.

[0011] In US3660388, the diethylenetriamine pentaacetic acid (Compound II), pyridine, acetic anhydride, the mixture was reacted at 65 ° C or 20h at 125 ° C the reaction 5min, to give compound III.

[0012] In US4822594, the compounds II, pyridine, acetic anhydride mixture was reacted at 65 ° C 20h, to give compound III.

[0013] In US4698263, the compounds II, pyridine, acetic anhydride heated in a nitrogen or argon atmosphere under reflux for 18h, to give compound III. [0014] In the EPO183760B1, the compounds II, pyridine, acetic anhydride mixture was reacted at 55 ° C 24h, to give compound III.

[0015] In CN1894223A, the compounds II, pyridine, acetic anhydride, the mixture above 65 ° C the reaction mixture, and the pyridine of DTPA feed ratio is: 1: (0.5 to 3).

[0016] The above patents do not provide for the compound III is post-processing method.

[0017] 3 Synthesis of Compound IV.

[0018] In U.S. Patent US4859451, the diethylenetriamine pentaacetic acid dianhydride (compound III) and ammonia, methanol and the reaction of compounds IV, see Reaction Scheme II.

[0019]

Figure CN102001964AD00041

[0020] Reaction two

[0021] In the patent US5087439, the compound III with methylamine in aqueous solution for several hours, or overnight reactions, see reaction formula III.

[0022]

Figure CN102001964AD00042

[0023] Reactive three

[0024] These two patents using ammonia and methylamine, which can form explosive mixtures with air, in case of fire or high pressure can cause an explosion in the production process of great insecurity. Although raw material prices are lower, but higher production conditions (such as requiring sealed, low temperature, etc.). Compared to this synthesis process,

[0025] 4, gadodiamide (Compound I) synthesis.

[0026] In the patent US4859451, the use of gadolinium chloride with the compound IV is carried out under acidic conditions, complexing. Finally, tune

Section PH neutral, see reaction IV.

[0027]

Figure CN102001964AD00043

[0028] Reaction formula tetrakis [0029] in the patent US5087439, the chlorides are used as reactants, and details of the post-processing method of Compound I.

[0030] In the patent US5508388, the use of gadolinium oxide with compound IV in acetonitrile, water with stirring, the resulting compound I.

[0032] The synthetic route  is as follows:

[0033]

Figure CN102001964AD00051

[0034] 1) Compound II (diethylenetriamine pentaacetic acid) in pyridine, acetic anhydride in the presence of a dehydration reaction into the acid anhydride, and the product was stirred with cold DMF, leaving the solid filtered, washed with ether reagents, drying , to obtain a white powdery solid compound III (diethylenetriamine pentaacetic acid anhydride);

[0035] 2) Compound III in DMF with methylamine hydrochloride, the reaction of the compound IV (5,8 _ bis carboxymethyl methyl-11 – [2 – (dimethylamino) -2 – oxoethyl] – 3 – oxo -2,5,8,11 – tetraazacyclododecane _13_ tridecyl acid); and the control compound III: MeNH2 · HCl molar ratio = 1: (1 to 4), control the temperature between 20 ~ 80 ° C, the reaction time is 4 ~ 6h, after the treatment, the method of distillation under reduced pressure to remove DMF, the product is dissolved in a polar solvent, methanol, and then adding a solvent polarity modulation, so that the target Compound IV from system completely precipitated;

[0036] 3) Compound IV with gadolinium oxide formed in the presence of hydrochloric acid of the complex, after the reaction, filtration and drying, to obtain a white powdery compound I, i.e. gadodiamide.

[0037] Existing gadodiamide Synthesis basically from the synthesis of Compound IV as a starting material, the present invention is first introduced to the compound II as a starting material to synthesize gadodiamide. Synthesis of the conventional method of gadodiamide, the present invention has the advantage of inexpensive starting materials, convenient and easy to get. In addition, the synthetic pathway intermediates are involved in the post-processing is simple, enabling continuous reaction, saving time and cost savings, the reaction becomes controlled step by step, and try to avoid the use of toxic reagents, reducing the possibility of operator injury , while also greatly reducing damage to the environment.

Navidea starts clinical trial for Alzheimer’s diagnostic drug


Navidea Biopharmaceuticals hopes to bring an early diagnostic drug for Alzheimer’s disease to market.

 

Navidea Biopharmaceuticals hopes to bring an early diagnostic drug for Alzheimer’s disease to market.

AZD4694, NAV4694 STRUCTURE

Navidea starts clinical trial for Alzheimer’s diagnostic drug
Business First of Columbus
The Phase 3 trial for the Alzheimer’s agent, at the moment named NAV4694, will compare how well the drugdisplays the buildup of a damaging protein in the brain of patients believed to have Alzheimer’s compared with what’s found in the autopsy. There 

read all at

http://www.bizjournals.com/columbus/news/2013/06/27/navidea-starts-clinical-trial-for.html

http://jnm.snmjournals.org/content/54/6/880.abstract

Navidea Biopharmaceuticals, a Dublin, Ohio biopharmaceutical company focused on precision diagnostics, earlier this week announced the completion of a study of its novel radiopharmaceutical NAV4694 as a biomarker for Alzheimer’s disease (AD).

NAV4694 is designed to aid visual detection and quantification of cerebral beta amyloid in diagnosing Alzheimer’s disease (AD). One hallmark of AD is the accumulation of beta amyloid plaques between nerve cells in the brain.

The study was designed and conducted by Navidea’s partner, AstraZeneca, to assess the safety and of the biomarker during PET scanning in subjects with AD and in healthy volunteers. Efficacy measures included binding parameters and overall image quality.  The 16-patient trial was completed at Karolinska Institutet sites in Stockholm, Sweden.

Florbetaben (18F), FDA and EMA accept NDA and MAA for Piramal‘s Alzheimer’s imaging agent


Florbetaben (18F)

PHOTO CREDIT-KEGG

902143-01-5 cas no

(18F-AV-1/ZK; BAY-94-9172; 18F-BAY-94-9172; ZK-6013443)

Mr Ajay Piramal, Chairman, Piramal Healthcare

Imaging with amyloid-β PET can potentially aid the early and accurate diagnosis of Alzheimer’s disease. Florbetaben (¹⁸F) is a promising ¹⁸F-labelled amyloid-β-targeted PET tracer in clinical development. We aimed to assess the sensitivity and specificity of florbetaben (¹⁸F) PET in discriminating between patients with probable Alzheimer’s disease and elderly healthy controls.

METHODS:

We did a multicentre, open-label, non-randomised phase 2 study in 18 centres in Australia, Germany, Switzerland, and the USA. Imaging with florbetaben (¹⁸F) PET was done on patients with probable Alzheimer’s disease (age 55 years or older, mini-mental state examination [MMSE] score=18-26, clinical dementia rating [CDR]=0·5-2·0) and age-matched healthy controls (MMSE ≥ 28, CDR=0). Our primary objective was to establish the diagnostic efficacy of the scans in differentiating between patients with probable disease and age-matched healthy controls on the basis of neocortical tracer uptake pattern 90-110 min post-injection. PET images were assessed visually by three readers masked to the clinical diagnosis and all other clinical findings, and quantitatively by use of pre-established brain volumes of interest to obtain standard uptake value ratios (SUVRs), taking the cerebellar cortex as the reference region. This study is registered with ClinicalTrials.gov, number NCT00750282.

FINDINGS:

81 participants with probable Alzheimer’s disease and 69 healthy controls were assessed. Independent visual assessment of the PET scans showed a sensitivity of 80% (95% CI 71-89) and a specificity of 91% (84-98) for discriminating participants with Alzheimer’s disease from healthy controls. The SUVRs in all neocortical grey-matter regions in participants with Alzheimer’s disease were significantly higher (p < 0·0001) compared with the healthy controls, with the posterior cingulate being the best discriminator. Linear discriminant analysis of regional SUVRs yielded a sensitivity of 85% and a specificity of 91%. Regional SUVRs also correlated well with scores of cognitive impairment such as the MMSE and the word-list memory and word-list recall scores (r -0·27 to -0·33, p ≤ 0·021). APOE ɛ4 was more common in participants with positive PET images compared with those with negative scans (65%vs 22% [p=0·027

MAR 21 2013

Piramal Imaging SA, a division of Piramal Enterprises, today announced that the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have accepted its applications for review of the investigational PET amyloid imaging agent [18F] florbetaben. A New Drug Application (NDA) was submitted to the U.S. Food and Drug Administration (FDA) and a Marketing Authorization Application to the EMA for [18F] florbetabenuse in the visual detection of beta-amyloid in the brains of adultswith cognitive impairment who are being evaluated for Alzheimer’s disease and other causes of cognitive decline.[18F] florbetaben binds to beta-amyloid plaques in the human brain, a hallmark characteristic in Alzheimer’s disease.

Today, Alzheimer’s disease is usually diagnosed after a person with a cognitive impairment undergoes an extensive clinical examination which typically includes family and medical history, physical and neurological examinations, laboratory tests, and imaging procedures such as computed tomography (CT) and magnetic resonance imaging (MRI) scans. Still, a definitive diagnosis of Alzheimer’s disease can only be made after death where an autopsy can reveal the presence of beta-amyloid plaques and neurofibrillary tangles in the brain. However, post-mortem studies looking for accumulations of beta-amyloid in the brain have shown that 10 to 30 percent of diagnoses based on clinical examinations are incorrect. [18F] florbetaben is being studied to determine its potential ability to detect beta-amyloid plaquesin living subjects with cognitive impairment.

 


FLORBETABEN F18

Diagnostic radiopharmaceutical

1. Benzenamine, 4-[(1E)-2-[4-[2-[2-[2-(fluoro-18F)ethoxy]ethoxy]ethoxy]phenyl]
ethenyl]-N-methyl-

2. 4-{(1E)-2-(4-{2-[2-(2-[18F]fluoroethoxy)ethoxy]ethoxy}phenyl)eth- 1-en-1-yl}-N-methylaniline

C21H26[18F]NO3
358.5
Bayer Healthcare

UNII-TLA7312TOI
CAS REGISTRY NUMBER  902143-01-5
https://www.ama-assn.org/resources/doc/usan/florbetaben-f18.pdf

4-[(E)-2-(4-{2-[2-(2-fluoroethoxy)ethoxy]ethoxy}phenyl)vinyl]-N-methylaniline has been labeled with [F-18]fluoride and is claimed by patent application WO2006066104 and members of the corresponding patent family.

Figure imgf000002_0001

4-[(E)-2-(4-{2-[2-(2-[F-18]fluoroethoxy)ethoxy]- ethoxy}phenyl)vinyl]-N-methylaniline

The usefulness of this radiotracer for the detection of Αβ plaques have been reported in the literature (W. Zhang et al., Nuclear Medicine and Biology 32 (2005) 799-809; C. Rowe et al., Lancet Neurology 7 (2008) 1 -7).

The synthesis of 4-[(E)-2-(4-{2-[2-(2-[F-18]fluoroethoxy)ethoxy]ethoxy}phenyl)- vinyl]-N-methylaniline has been described before:

a) W. Zhang et al., Nuclear Medicine and Biology 32 (2005) 799-809.

Figure imgf000003_0001

4-[(E)-2-(4-{2-[2-(2-[F-18]fluoroethoxy)ethoxy]- ethoxy}phenyl)vinyl]-N-methylaniline

4 mg precursor 2a (2-[2-(2-{4-[(E)-2-{4-[(tert-butoxycarbonyl)(methyl)amino]- phenyl}vinyl]phenoxy}ethoxy)ethoxy]ethyl methanesulfonate) in 0.2 mL

DMSO were reacted with [F-18]fluoride/kryptofix/potassium carbonate complex. The intermediate was deprotected with HCI and neutralized with

NaOH. The mixture was extracted with ethyl acetate. The solvent was dried and evaporated, the residue was dissolved in acetonitrile and purified by semi-preparative HPLC. 20% (decay corrected), 1 1 % (not corrected for decay) 4-[(E)-2-(4-{2-[2-(2-[F-18]fluoroethoxy)ethoxy]ethoxy}phenyl)vinyl]-N- methylaniline were obtained in 90 min.

WO2006066104

4 mg precursor 2-[2-(2-{4-[(E)-2-{4-[(tert-butoxycarbonyl)(methyl)amino]- phenyl}vinyl]phenoxy}ethoxy)ethoxy]ethyl methanesulfonate in 0.2 mL DMSO were reacted with [F-18]fluoride/kryptofix/potassium carbonate complex. The intermediates was deprotected with HCI and neutralized with NaOH. The mixture was extracted with ethyl acetate. The solvent was dried and evaporated, the residue was dissolved in acetonitrile and purified by semi- preparative HPLC. 30% (decay corrected), 17% (not corrected for decay) 4- [(E)-2-(4-{2-[2-(2-[F-18]fluoroethoxy)ethoxy]ethoxy}phenyl)vinyl]-N- methylaniline were obtained in 90 min. to yield N-Boc protected 4-[(E)-2-(4-{2-[2-(2-[F- 18]fluoroethoxy)ethoxy]ethoxy}phenyl)vinyl]-N-methylaniline. The unreacted perfluorinated precursor was removed using a fluorous phase cartridge.

Deprotection, final purification and formulation to obtain a product, suitable for injection into human is not disclosed. Furthermore, the usefulness (e.g. regarding unwanted F-19/F-18 exchange) of this approach at a higher radioactivity level is not demonstrated. Finally, this method would demand a two-pot setup (first reaction vessel: fluorination, followed by solid-phase- extraction, and deprotection in the second reaction vessel).

However, the focus of the present invention are compounds and methods for an improved “one-pot process” for the manufacturing of 4-[(E)-2-(4-{2-[2-(2- [F-18]fluoroethoxy)ethoxy]ethoxy}phenyl)vinyl]-N-methylaniline.

Very recently, further methods have been described:

d) US201001 13763

The mesylate precursor 2a was reacted with [F-18]fluoride species in a solvent mixture consisting of 100 μΙ_ acetonitrile and 500 μΙ_ tertiary alcohol. After fluorination for 10 min at 100-150 °C, the solvent was evaporated. After deprotection (1 N HCI, 5 min, 100-120 °C), the crude product was purified by HPLC (C18 silica, acetonitrile / 0.1 M ammonium formate).

e) H. Wang et al., Nuclear Medicine and Biology 38 (201 1 ) 121 -127

5 mg precursor 2a (2-[2-(2-{4-[(E)-2-{4-[(tert-butoxycarbonyl)(methyl)amino]- phenyl}vinyl]phenoxy}ethoxy)ethoxy]ethyl methanesulfonate) in 0.5 ml_

DMSO were reacted with [F-18]fluoride/kryptofix/potassium carbonate complex. The intermediate was deprotected with HCI and neutralized with NaOH. The crude product was diluted with acetonitrile / 0.1 M ammonium dformate (6/4) and purified by semi-preparative HPLC. The product fraction was collected, diluted with water, passed through a C18 cartridge and eluted with ethanol, yielding 17% (not corrected for decay) 4-[(E)-2-(4-{2-[2-(2-[F- 18]fluoroethoxy)ethoxy]ethoxy}phenyl)vinyl]-N-methylaniline within 50 min. In the paper, the conversion of an unprotected mesylate precursor (is described:

5 mg unprotected mesylate precursor (2-{2-[2-(4-{(E)-2-[4- (methylamino)phenyl]vinyl}phenoxy)ethoxy]-ethoxy}ethyl 4- methanesulfonate) in 0.5 ml_ DMSO were reacted with [F- 18]fluoride/kryptofix/potassium carbonate complex. The crude product was diluted with acetonitrile / 0.1 M ammonium formate (6/4) and purified by semi- preparative HPLC. The product fraction was collected, diluted with water, passed through a C18 cartridge and eluted with ethanol, yielding 23% (not corrected for decay) 4-[(E)-2-(4-{2-[2-(2-[F-

18]fluoroethoxy)ethoxy]ethoxy}phenyl)vinyl]-N-methylaniline within 30 min. Beside the purification by HPLC, a process based on solid-phase-extraction was investigated, but the purity was inferior to that with HPLC purification. So far, one-pot radiolabelings have been performed using a mesylate precursor. It is know, that for F-18 labeling of stilbenes, mesylates have advantages over corresponding tosylates by providing more clean reactions with less amount of by-products (W. Zhang et al. Journal of Medicinal Chemistry 48 (2005) 5980- 5988), whereas the purification starting from the tosylate precursor was tedious and time consuming resulting in a low yield.

In contrast to this teaching of the prior art, we found advantages of tosylate and further arylsulfonate precursors for 4-[(E)-2-(4-{2-[2-(2-[F- 18]fluoroethoxy)ethoxy]ethoxy}phenyl)vinyl]-N-methylaniline compared to the corresponding mesylate. Less non-radioactive by-products that eluted close to the retention time of 4-[(E)-2-(4-{2-[2-(2-[F-

18]fluoroethoxy)ethoxy]ethoxy}phenyl)vinyl]-N-methylaniline were found in the crude products if arylsulfonate precursors were used (Example 2 – Example 6) compared to the crude mixture that was obtained after conversion of the mesylate precursor (Example 1 ).

The favorable by-product profile after radiolabeling of tosylate precursor 2b (Figure 10) compared to the radiolabeling of mesylate precursor 2a (Figure 7) supported an improved cartridge based purification (Example 8, Example 9).

…………………

WO2011151281A1

The term “F-18” means fluorine isotope 18F. The term”F-19″ means fluorine isotope 19F. EXAMPLES

Example 1 Radiolabeling of mesylate precursor 2a

Figure imgf000016_0001

4-[(E)-2-(4-{2-[2-(2-[F-18]fluoroethoxy)ethoxy]- ethoxy}phenyl)vinyl]-N-methylaniline

Radiolabeling was performed on a remote controlled synthesis module (Tracerlab FXN). Precursor 2a (2 mg) in 0.5 mL DMSO + 0.5 mL acetonitrile was treated with dried potassium carbonate/kryptofix/[F-18]fluoride complex for 6 min at 100 °C. 1 M HCI (1 mL) + 10 mg ascorbic acid was added and the mixture was heated for 4 min at 100 °C. 2M NaOH (0.5 mL), water (6 mL) and ethanol (1 mL) were added and the crude mixture was trapped on a C18 cartridge. The crude product mixture was eluted with acetonitrile and diluted with 0.1 M ammonium formiat buffer (1 mL) + 5 mg ascorbic acid. A sample of the crude product was taken and analyzed by analytical HPLC (Figure 1 ). After purification by semi- preparative HPLC, the product was diluted with water + 5 mg ascorbic acid, trapped on a C18 cartridge and eluted with 1 mL ethanol.

Yield of 4-[(E)-2-(4-{2-[2-(2-[F-18]fluoroethoxy)ethoxy]ethoxy}phenyl)-vinyl]-N- methylaniline: 21 % (corrected for decay).

Example 2 Synthesis and radiolabeling of tosylate precursor 2b

Figure imgf000017_0001
Figure imgf000017_0002

4-[(E)-2-(4-{2-[2-(2-[F-18]fluoroethoxy)ethoxy]- ethoxy}phenyl)vinyl]-N-methylaniline

4-Dimethylaminopyridine (26.7 mg) and triethylamine (225 μΙ_) were added to a solution of 1 .0 g terf-butyl {4-[(E)-2-(4-{2-[2-(2- hydroxyethoxy)ethoxy]ethoxy}phenyl)vinyl]phenyl}methylcarbamate (4) in dichloromethane (12 mL) at 0 °C. A solution of p- toluenesulfonyl chloride (417 mg) in dichloromethane (13.5 mL) was added at 0 °C. The resulting mixture was stirred at room temperature over night. The solvent was removed under reduced pressure and the crude product was purified by flash chromatography (silica, 0- 80% ethyl acetate in hexane). 850 mg 2b were obtained as colorless solid.

1 H NMR (300 MHz, CDCI3) δ ppm 1 .46 (s, 9 H), 2.43 (s, 3 H), 3.27 (s, 3 H), 3.59-3.73 (m, 6 H), 3.80- 3.86 (m, 2 H), 4.05-4.19 (m, 2 H), 6.88-7.05 (m, 4 H), 7.21 (d, J = 8.3 Hz, 2 H), 7.32 (d, J = 8.3 Hz, 2 H), 7.39-7-47 (m, 4 H), 7.80 (d, J = 8.3 Hz, 2 H). MS (ESIpos): m/z = 612 (M+H)+

Radiolabeling was performed on a remote controlled synthesis module (Tracerlab FXN). Precursor 2b (2 mg) in 0.5 mL DMSO + 0.5 mL acetonitrile was treated with dried potassium carbonate/kryptofix/[F-18]fluoride complex for 6 min at 100 °C. 1 M HCI (1 mL) + 10 mg ascorbic acid was added and the mixture was heated for 4 min at 100 °C. 2M NaOH (0.5 mL), water (6 mL) and ethanol (1 mL) were added and the crude mixture was trapped on a C18 cartridge. The crude product mixture was eluted with acetonitrile and diluted with 0.1 M ammonium formiat buffer (1 mL) + 5 mg ascorbic acid. A sample of the crude product was taken and analyzed by analytical HPLC (Figure 2). After purification by semi- preparative HPLC, the product was diluted with water + 5 mg ascorbic acid, trapped on a C18 cartridge and eluted with 1 mL ethanol.

Yield of 4-[(E)-2-(4-{2-[2-(2-[F-18]fluoroethoxy)ethoxy]ethoxy}phenyl)-vinyl]-N- methylaniline: 25% (corrected for decay).

Example 3 Synthesis and radiolabeling of 2c (2-[2-(2-{4-[(E)-2-{4-[(tert- butoxycarbonyl)(methyl)amino]phenyl}vinyl]phenoxy}ethoxy)ethoxy]ethyl

4-bromobenzenesulfonate)

Figure imgf000018_0001

4-[(E)-2-(4-{2-[2-(2-[F-18]fluoroethoxy)ethoxy]- ethoxy}phenyl)vinyl]-N-methylaniline To a stirred solution of 100 mg (0,219 mmol) tert-butyl-{4-[(E)-2-(4-{2-[2-(2- hydroxyethoxy)ethoxy]ethoxy}phenyl)vinyl]phenyl}methylcarbamate

(WO2006/066104) in 2 mL THF was added a solution of 140 mg (0.548 mmol) 4-brombenzene sulfonylchlorid in 3 mL THF drop by drop. The reaction mixture was cooled to 0°C. 156.8 mg (1 .1 mmol) potassium trimethylsilanolat was added. The milky suspension was stirred at 0°C for 2 hours and at 80°C for another 2 hours. The reaction mixture was poured onto ice-cooled water. The aqueous solution was extracted with dichloromethane several times. The combined organic phases were dried with sodium sulphate and concentrated in vacuum. The crude product was purified using silica gel with ethyl acetate/hexane-gradient as mobile phase. The desired product 2c was obtained with 77 mg (0.1 14 mmol, 52.0 % yield).

1 H NMR (300 MHz, CDCI3) δ ppm 1 .39 (s, 10 H) 3.20 (s, 3 H) 3.50 – 3.57 (m, 2 H) 3.57 – 3.61 (m, 2 H) 3.61 – 3.66 (m, 2 H) 3.72 – 3.80 (m, 2 H) 4.02 – 4.10 (m, 2 H) 4.10 – 4.17 (m, 2 H) 6.79 – 6.85 (m, 2 H) 6.91 (d, J=8.10 Hz, 2 H) 7.10 – 7.17 (m, 2 H) 7.32 – 7.41 (m, 5 H) 7.57 – 7.65 (m, 2 H) 7.67 – 7.74 (m, 2 H)

MS (ESIpos): m/z = 676/678 (M+H)+

Radiolabeling was performed on a remote controlled synthesis module (Tracerlab FXN). Precursor 2c (2 mg) in 0.5 mL DMSO + 0.5 mL acetonitrile was treated with dried potassium carbonate/kryptofix/[F-18]fluoride complex for 6 min at 100 °C. 1 M HCI (1 mL) + 10 mg ascorbic acid was added and the mixture was heated for 4 min at 100 °C. 2M NaOH (0.5 mL), water (6 mL) and ethanol (1 mL) were added and the crude mixture was trapped on a C18 cartridge. The crude product mixture was eluted with acetonitrile and diluted with 0.1 M ammonium formiat buffer (1 mL) + 5 mg ascorbic acid. A sample of the crude product was taken and analyzed by analytical HPLC (Figure 3). After purification by semi- preparative HPLC, the product was diluted with water + 5 mg ascorbic acid, trapped on a C18 cartridge and eluted with 1 mL ethanol.

Yield of 4-[(E)-2-(4-{2-[2-(2-[F-18]fluoroethoxy)ethoxy]ethoxy}phenyl)-vinyl]-N- methylaniline: 43% (corrected for decay). Example 4 Synthesis and radiolabeling of 2d (2-[2-(2-{4-[(E)-2-{4-[(tert- butoxycarbonyl)(methyl)amino]phenyl}vinyl]phenoxy}ethoxy)ethoxy]ethyl

4-(adamantan-1 -yl)benzenesulfonate)

Figure imgf000020_0001

4-[(E)-2-(4-{2-[2-(2-[F-18]fluoroethoxy)ethoxy]- ethoxy}phenyl)vinyl]-N-methylaniline

To a stirred solution of 151 mg (0,330 mmol) tert-butyl-{4-[(E)-2-(4-{2-[2-(2- hydroxyethoxy)ethoxy]ethoxy}phenyl)vinyl]phenyl}methylcarbamate

(WO2006/066104), 4.03 mg (0,033 mmol) DMAP und 36.7 mg (363 mmol) triethylamine in 4 mL dichlormethane was added a solution of 97,4 mg (0,313 mmol) 4-(adamantan-1 -yl)benzene sulfonylchloride in 1 mL dichlormethane at 0°C. The reaction mixture was stirred at 0°C for 1 hour and over night at room temperature. 7.3 mg (0,072 mmol) triethylamin und 19.5 mg (0.062 mmol) 4- (adamantan-l -yl)benzenesulfonyl chloride were added to the reaction mixture. The reaction mixture was stirred at room temperature for 3 days. It was concentrated in vacuum. The crude product was purified using silica gel with ethyl acetate/hexane-gradient as mobile phase. The desired product 2d was obtained with 104 mg (0.142 mmol, 43.4% yield).

1 H NMR (300 MHz, CDCI3) δ ppm 1 .51 (s, 9 H), 1 .62 (s, 1 H), 1 .74 – 1 .91 (m, 6 H), 1 .94 (d, J=3.20 Hz, 6 H), 2.16 (br. s., 3 H), 3.31 (s, 3 H), 3.63 – 3.69 (m, 2 H), 3.69 – 3.73 (m, 2 H), 3.76 (dd, J=5.27, 4.52 Hz, 2 H), 3.89 (d, J=4.90 Hz, 2 H), 4.13 – 4.26 (m, 4 H), 6.95 (d, J=8.85 Hz, 2 H), 7.02 (d, J=8.29 Hz, 2 H), 7.25 (d, J=8.48 Hz, 2 H), 7.40 – 7.52 (m, 4 H), 7.55 (m, J=8.67 Hz, 2 H), 7.89 (m, J=8.67 Hz, 2 H)

MS (ESIpos): m/z = 732 (M+H)+

Radiolabeling was performed on a remote controlled synthesis module (Tracerlab FXN). Precursor 2d (2 mg) in 0.5 mL DMSO + 0.5 mL acetonitrile was treated with dried potassium carbonate/kryptofix/[F-18]fluoride complex for 6 min at 100 °C. 1 M HCI (1 mL) + 10 mg ascorbic acid was added and the mixture was heated for 4 min at 100 °C. 2M NaOH (0.5 mL), water (6 mL) and ethanol (1 mL) were added and the crude mixture was trapped on a C18 cartridge. The crude product mixture was eluted with acetonitrile and diluted with 0.1 M ammonium formiat buffer (1 mL) + 5 mg ascorbic acid. A sample of the crude product was taken and analyzed by analytical HPLC (Figure 4). After purification by semi- preparative HPLC, the product was diluted with water + 5 mg ascorbic acid, trapped on a C18 cartridge and eluted with 1 mL ethanol.

Yield of 4-[(E)-2-(4-{2-[2-(2-[F-18]fluoroethoxy)ethoxy]ethoxy}phenyl)-vinyl]-N- methylaniline: 27% (corrected for decay).

Example 5 Synthesis and radiolabeling of 2e (2-[2-(2-{4-[(E)-2-{4-[(tert- butoxycarbonyl)(methyl)amino]phenyl}vinyl]phenoxy}ethoxy)ethoxy]ethyl

4-cyanobenzenesulfonate)

Figure imgf000022_0001
Figure imgf000022_0002

4-[(E)-2-(4-{2-[2-(2-[F-18]fluoroethoxy)ethoxy]- ethoxy}phenyl)vinyl]-N-methylaniline

To a stirred solution of 151 mg (0.330 mmol) tert-butyl-{4-[(E)-2-(4-{2-[2-(2- hydroxyethoxy)ethoxy]ethoxy}phenyl)vinyl]phenyl}methylcarbamate

(WO2006/066104), 4.03 mg (0.033 mmol) DMAP und 36.7 mg (0.363 mmol) triethylamine in 4 mL dichlormethane was added a solution of 63.2 mg (0.313 mmol) 4-cyanobenzenesulfonyl chloride in 1 mL dichlormethane at 0°C. The reaction mixture was stirred over night and concentrated in vacuum. The crude product was purified using silica gel with ethyl acetate/hexane-gradient as mobile phase. The desired product 2e was obtained with 118 mg (0.190 mmol, 57.6 % yield).

1 H NMR (400 MHz, CDCI3) δ ppm 1 .47 (s, 9 H) 3.28 (s, 3 H) 3.58 – 3.63 (m, 2 H) 3.63 – 3.68 (m, 2 H) 3.70 – 3.75 (m, 2 H) 3.81 – 3.87 (m, 2 H) 4.1 1 – 4.18 (m, 2 H) 4.24 – 4.30 (m, 2 H) 6.91 (d, J=8.59 Hz, 2 H) 6.99 (dt, 2 H) 7.22 (d, J=8.34 Hz, 2 H) 7.39 – 7.50 (m, 4 H) 7.83 (m, J=8.59 Hz, 2 H) 7.98 – 8.1 1 (m, 2 H)

MS (ESIpos): m/z = 623 (M+H)+

Radiolabeling was performed on a remote controlled synthesis module (Tracerlab FXN). Precursor 2e (2 mg) in 0.5 mL DMSO + 0.5 mL acetonitrile was treated with dried potassium carbonate/kryptofix/[F-18]fluoride complex for 6 min at 100 °C. 1 M HCI (1 mL) + 10 mg ascorbic acid was added and the mixture was heated for 4 min at 100 °C. 2M NaOH (0.5 mL), water (6 mL) and ethanol (1 mL) were added and the crude mixture was trapped on a C18 cartridge. The crude product mixture was eluted with acetonitrile and diluted with 0.1 M ammonium formiat buffer (1 mL) + 5 mg ascorbic acid. A sample of the crude product was taken and analyzed by analytical HPLC (Figure 5). After purification by semi- preparative HPLC, the product was diluted with water + 5 mg ascorbic acid, trapped on a C18 cartridge and eluted with 1 mL ethanol.

Yield of 4-[(E)-2-(4-{2-[2-(2-[F-18]fluoroethoxy)ethoxy]ethoxy}phenyl)-vinyl]-N- methylaniline: 31 % (corrected for decay).

Example 6 Synthesis and radiolabeling of 2f (2-[2-(2-{4-[(E)-2-{4-[(tert- butoxycarbonyl)(methyl)amino]phenyl}vinyl]phenoxy}ethoxy)ethoxy]ethyl

2-nitrobenzenesulfonate)

Figure imgf000023_0001
Figure imgf000023_0002

4-[(E)-2-(4-{2-[2-(2-[F-18]fluoroethoxy)ethoxy]- eth oxy} phe nyl )vi ny I] -N -methyla n i I i ne

To a stirred solution of 200 mg (0.437 mmol) tert-butyl-{4-[(E)-2-(4-{2-[2-(2- hydroxyethoxy)ethoxy]ethoxy}phenyl)vinyl]phenyl}methylcarbamate

(WO2006/066104), 5.34 mg (0.044 mmol) DMAP und 47.5 mg (0.470 mmol) triethylamine in 4 mL dichlormethane was added a solution of 92 mg (0,415 mmol) 2-nitrobenzenesulfonyl chloride in 1 mL dichlormethane at 0°C. The reaction mixture was stirred over night and concentrated in vacuum. The crude product was purified with ethyl acetate/hexane-gradient as mobile phase using silica gel. The desired product 2f was obtained with 77 mg (0.1 19 mmol, 59.5 % yield). 1 H NMR (400 MHz, CDCI3) δ ppm 1 .39 (s, 9 H) 3.20 (s, 3 H) 3.55 – 3.63 (m, 4 H) 3.59 (m, 4 H) 3.69 – 3.74 (m, 2 H) 3.75 – 3.80 (m, 2 H) 4.06 (dd, J=5.68, 3.92 Hz,

2 H) 4.32 – 4.37 (m, 2 H) 6.80 – 6.84 (m, 2 H) 6.84 – 6.98 (dt, 2 H) 7.14 (d, J=8.59 Hz, 2 H) 7.35 (d, J=3.03 Hz, 2 H) 7.37 (d, J=2.78 Hz, 2 H) 7.62 – 7.74 (m,

3 H) 8.06 – 8.1 1 (m, 1 H)

FDA Approves Dotarem, a New Magnetic Resonance Imaging Agent


Gadoterate meglumine     STR-  CREDIT PUBCHEM
Also known as: Magnescope, Magnescope (TN), AC1OCEY3, Meglumine gadoterate (JAN), EK-5504, D03355
Molecular Formula: C23H42GdN5O13
Molecular Weight: 753.85528
Cas No. 98059-18-8
 Name 2-[4,7-bis(carboxylatomethyl)-10-(carboxymethyl)-1,4,7, 10-tetrazacyclododec-1-yl]acetate; gadolinium(3+); (2R,3R,4R,5S)-6-(methylamino)hexane-1,2,3,4,5-pentol
MORE ABOUT STRUCTURE , CODE  CAS NO, ETC-  http://www.ama-assn.org/resources/doc/usan/gadoterate-meglumine.pdf
FDA Approves Dotarem, a New Magnetic Resonance Imaging Agent

March 20, 2013 — The U.S. Food and Drug Administration today approved Dotarem (gadoterate meglumine) for use in magnetic resonance imaging (MRI) of the brain, spine and associated tissues of patients ages 2 years and older.

Dotarem is a gadolinium-based contrast agent (GBCA) that helps radiologists see abnormalities on images of the central nervous system (CNS), the part of the body that contains the brain and spine, and surrounding tissues.

“Dotarem was shown to be a safe and effective magnetic resonance imaging agent in patients ages 2 years and older,” said Dwaine Rieves, M.D., director of the Division of Medical Imaging Products in the FDA’s Center for Drug Evaluation and Research. “Today’s approval provides doctors with another option to help evaluate anatomic abnormalities within the central nervous system.”

Dotarem (gadoterate meglumine)

Company: Guerbet
Treatment for: Diagnostic

Dotarem (gadoterate meglumine) is a gadolinium-based contrast agent under review for use in magnetic resonance imaging (MRI).

Dotarem is the only macrocyclic and ionic gadolinium-based contrast agent (GBCA) for the intravenous use with magnetic resonance imaging (MRI) in the brain (intracranial), spine and associated tissues in adults and pediatric patients to detect and visualize areas with disruption of the blood-brain barrier (BBB) and/or abnormal vascularity. The Guerbet NDA recommended dose is 0.1 mmol Gd/kg.

File:Gadoteric acid.png

Gadoteric acid

Gadoteric acid (trade names ArtiremDotarem) is a macrocycle-structured gadolinium-based MRI contrast agent. It consists of the organic acid DOTA as a chelating agent, and gadolinium (Gd3+), and is used in form of the meglumine salt.[1] The drug is approved and used in a number of countries worldwide.[2]

  1. Herborn, C. U.; Honold, E.; Wolf, M.; Kemper, J.; Kinner, S.; Adam, G.; Barkhausen, J. (2007). “Clinical Safety and Diagnostic Value of the Gadolinium Chelate Gadoterate Meglumine (Gd-DOTA)”. Investigative Radiology 42 (1): 58–62. doi:10.1097/01.rli.0000248893.01067.e5PMID 17213750edit
  2. Drugs.com: Gadoteric Acid

A gadolinium chelate paramagnetic contrast agent. When placed in a magnetic field, gadoterate meglumine produces a large magnetic moment and so a large local magnetic field, which can enhance the relaxation rate of nearby protons; as a result, the signal intensity of tissue images observed with magnetic resonance imaging (MRI) may be enhanced. Because this agent is preferentially taken up by normal functioning hepatocytes, normal hepatic tissue is enhanced with MRI while tumor tissue is unenhanced. In addition, because gadobenate dimeglumine is excreted in the bile, it may be used to visualize the biliary system using MRI.

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