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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

June 17, 2014 3:59 am / Leave a comment

GADOBUTROL

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

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

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

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

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

Bayer HealthCare’s Gadavist (gadobutrol)

Bayer’s Gadavist injection cleared for breast cancer evaluation

UPDATE……. Gadoteridol 279.3 mg/ml for injection , CDSCO INDIA 29.07.2021

For intravenous use in magnetic
reasonance imaging (MRI) in adults and
pediatric patients over 2 years of age for
whole body MRI including the head, neck,
liver, breast, musculoskeletal system and
soft tissue pathologies
The US Food and Drug Administration (FDA) has approved Bayer HealthCare’s Gadavist (gadobutrol) injection as the first magnetic resonance contrast agent for evaluation of breast cancer in the US.

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
ATC code	V08CA09
PubChem	CID 72057
DrugBank	DB06703
UNII	1BJ477IO2L
KEGG	D07420


Chemical data
Formula	C₁₈H₃₁Gd N₄O₉
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

Cheng, KT (2007). “Gadobutrol”. Molecular Imaging and Contrast Agent Database (MICAD) (Bethesda, MD: National Center for Biotechnology Information (NCBI)). PMID 20641787. NBK23589.
http://bayerimaging.com/products/gadavist/index.php
“FDA approves imaging agent for central nervous system scans” (Press release). U.S. Food and Drug Administration (FDA). March 15, 2011. Retrieved March 31, 2011.
“U.S. FDA Approves Bayer’s Gadavist (Gadobutrol) Injection for MRI of the Central Nervous System” (Press release). Bayer HealthCare Pharmaceuticals. March 14, 2011. Retrieved March 31, 2011.
“Gadobutrol 1.0-molar in Cardiac Magnetic Resonance Imaging (MRI) – Further Enhancing the Capabilities of Contrast-enhanced MRI in Ischaemic and Non-ischaemic Heart Disease?”
“Gadavist full prescribing information”. Retrieved 2011-03-14.

Researchers discover new form of cancer

June 12, 2014 1:16 am / Leave a comment

Lyra Nara Blog

This is the story of two perfectly harmless genes. By themselves, PAX3 and MAML3 don’t cause any problems. However, when they combine during an abnormal but recurring chromosomal mismatch, they can be dangerous. The result is a chimera—a gene that is half of each—and that causes biphenotypic sinonasal sarcoma. The tumor usually begins in the nose and may infiltrate the rest of the face, requiring disfiguring surgery to save the individual. Because Mayo Clinic pathology researchers have now described the molecular makeup of the rare tumor, several existing cancer drugs may be targeted against it. The findings appear in the current issue of Nature Genetics.

In 2004, Mayo Clinic pathologists Andre Oliveira, M.D., Ph.D., and Jean Lewis, M.D., first noticed something unusual about a tumor sample they were analyzing under the microscope. By 2009, they had seen the same pathology several times and had begun collecting data. In 2012…

View original post 427 more words

Tie up with Emcure…..Roche to launch cheaper cancer drugs in India

June 6, 2014 10:41 am / 2 Comments on Tie up with Emcure…..Roche to launch cheaper cancer drugs in India

Reuters | Updated On: June 06, 2012 12:36 (IST)

Mumbai:

Swiss drugmaker Roche Holding AG plans to offer cut-price versions of two blockbuster cancer drugs for the Indian market soon, a company spokesman said on Friday, days after New Delhi moved to slash the price of a rival cancer treatment.

India stripped German’s Bayer AG of its exclusive rights to Nexavar earlier this month and licensed a local drugs company to produce a cheap, generic version, on the grounds that poor Indians could not otherwise afford the life-saving drug.

Roche, the world’s biggest maker of cancer drugs, said it would offer “significantly” cheaper, locally branded versions of its two cancer drugs, Herceptin and MabThera, by early next year, under an alliance with India’s Emcure Pharmaceuticals Ltd.

http://profit.ndtv.com/news/corporates/article-roche-to-launch-cheaper-cancer-drugs-in-india-300344

Taiho’s Colon Cancer Drug Ups OS in Phase 3

May 14, 2014 4:02 am / Leave a comment

TAS-102 (nonproprietary names: trifluridine and tipiracil hydrochloride)

Taiho’s Colon Cancer Drug Ups OS in Phase 3

Taiho Pharmaceutical Co. Ltd. announced results from its global Phase 3 RECOURSE trial on its oral combination anticancer drug TAS-102 in refractory metastatic colorectal cancer (mCRC). Read more…

FULL STORY

http://www.dddmag.com/news/2014/05/taihos-colon-cancer-drug-ups-os-phase-3?et_cid=3937577&et_rid=523035093&type=cta

TAS-102 is an anti-cancer drug under development for colorectal cancer.^[1]

Clinical trials

A phase II trial reported in 2011^[2] and a phase III trial is due to end in 2014.^[1]^[3]

Mechanism

TAS-102 consists of the cytotoxin trifluridine and the thymidine phosphorylase inhibitor (TPI) tipiracil.^[4] Trifluridine is incorporated into DNA during DNA synthesis and inhibits tumor cell growth. Tipiracil protects trifluridine from being broken down when taken orally.^[1]

References

Trifluridine

Trifluridine (also called trifluorothymidine or TFT) is an anti-herpesvirus antiviral drug, used primarily on the eye. It was sold under the trade name, Viroptic, by Glaxo Wellcome, now merged into GlaxoSmithKline. The brand is now owned by Monarch Pharmaceuticals, which is wholly owned by King Pharmaceuticals.

It is a nucleoside analogue, a modified form of deoxyuridine, similar enough to be incorporated into viral DNA replication, but the -CF₃ group added to the uracil component blocks base pairing.

It is a component of the experimental anti-cancer drug TAS-102.

A Cochrane Systematic Review showed that trifluridine was a more effective treatment than idoxuridine or vidarabine, significantly increasing the relative number of successfully healed eyes in 14 days.^[1]

References

Wilhelmus KR (2010). “Antiviral treatment and other therapeutic interventions for herpes simplex virus epithelial keratitis”. Cochrane Database Syst Rev 12: CD002898. doi:10.1002/14651858.CD002898.pub4. PMID 21154352.

External links

Costin D, Dogaru M, Popa A, Cijevschi I (2004). “Trifluridine therapy in herpetic in keratitis”. Rev Med Chir Soc Med Nat Iasi 108 (2): 409–12. PMID 15688823.
Kuster P, Taravella M, Gelinas M, Stepp P (1998). “Delivery of trifluridine to human cornea and aqueous using collagen shields.”. CLAO J 24 (2): 122–4. PMID 9571274.
O’Brien W, Taylor J (1991). “Therapeutic response of herpes simplex virus-induced corneal edema to trifluridine in combination with immunosuppressive agents.”. Invest Ophthalmol Vis Sci 32 (9): 2455–61. PMID 1907950.
“Trifluridine Ophthalmic Solution, 1%” (PDF). Retrieved 2007-03-24.

Fig 4. Open Babel bond-line chemical structure with annotated hydrogens. Click to toggle size.

Spectrum Plot

Fig 5. ¹H NMR spectrum of C₁₀H₁₁F₃N₂O₅ in CDCL3 at 400 MHz

Trifluridine

CAS Registry Number: 70-00-8

CAS Name: a,a,a-Trifluorothymidine

Additional Names: 2¢-deoxy-5-(trifluoromethyl)uridine; 5-(trifluoromethyl)-2¢-deoxyuridine; F3TDR

Manufacturers’ Codes: NSC-75520

Trademarks: TFT Thilo (Alcon-Thilo); Virophta (Dulcis); Viroptic (Burroughs Wellcome)

Molecular Formula: C10H11F3N2O5

Molecular Weight: 296.20

Percent Composition: C 40.55%, H 3.74%, F 19.24%, N 9.46%, O 27.01%

Literature References: Prepn: C. Heidelberger et al., J. Am. Chem. Soc. 84, 3597 (1962); eidem, J. Med. Chem. 7, 1 (1964); C. Heidelberger, US 3201387 (1965 to U.S. Dept. HEW). Crystal structure: A. H. Tench, Diss. Abstr. Int. B 33, 3587 (1973). NMR study: R. J. Cushley et al., J. Am. Chem. Soc. 90, 709 (1968). Metabolism: D. L. Dexter et al., Cancer Res. 32, 247 (1972); W. J. O’Brien, H. F. Edelhauser, Invest. Ophthalmol. Visual Sci. 16, 1093 (1977). Pharmacodynamics: B. L. Wigdahl, J. R. Parkhurst,Antimicrob. Agents Chemother. 14, 470 (1978); G. J. Smith et al., Biochem. Biophys. Res. Commun. 83, 1538 (1978). Teratogenicity study: M. Itoi et al., Arch. Ophthalmol. 93, 46 (1975). Cytotoxicity and mutagenicity study: E. Huberman, C. Heidelberger, Mutat. Res. 14, 130 (1972). Clinical studies: H. E. Kaufman, Invest. Ophthalmol. Visual Sci. 17, 941 (1978); R. A. Hyndiuk et al., Arch. Ophthalmol. 96, 1839 (1978). Review of mechanism of antiviral activity: C. Heidelberger, Ann. N.Y. Acad. Sci. 255, 317 (1975). Review of pharmacology and therapeutic use: A. A. Carmine et al., Drugs 23, 329-353 (1982).

Properties: Cryst from ethyl acetate, mp 186-189°. uv max (0.1N HCl): 260 nm (e 9960); (0.1N NaOH): 260 nm (e 6590).

Melting point: mp 186-189°

Absorption maximum: uv max (0.1N HCl): 260 nm (e 9960); (0.1N NaOH): 260 nm (e 6590)

Therap-Cat: Antiviral (ophthalmic).

Keywords: Antiviral; Purines/Pyrimidinones.

………………………………………………………….

Tipiralacil, also known as TPI, is a thymidine phosphorylase inhibitor (TPI). Tipiracil is one of the active components in TAS-102, which is an anticancer drug candidate currently in clinical trials. TAS-102 consists of the cytotoxin Trifluridine and the thymidine phosphorylase inhibitor (TPI) tipiracil. Trifluridine is incorporated into DNA during DNA synthesis and inhibits tumor cell growth. Tipiracil protects trifluridine from being broken down when taken orally.

183204-72-0 (Tipiracil -HCl); 183204-74-2(Tipiracil ).

References

1: Peters GJ, Bijnsdorp IV. TAS-102: more than an antimetabolite. Lancet Oncol. 2012 Dec;13(12):e518-9. doi: 10.1016/S1470-2045(12)70426-6. PubMed PMID: 23182191.

2: Yoshino T, Mizunuma N, Yamazaki K, Nishina T, Komatsu Y, Baba H, Tsuji A, Yamaguchi K, Muro K, Sugimoto N, Tsuji Y, Moriwaki T, Esaki T, Hamada C, Tanase T, Ohtsu A. TAS-102 monotherapy for pretreated metastatic colorectal cancer: a double-blind, randomised, placebo-controlled phase 2 trial. Lancet Oncol. 2012 Oct;13(10):993-1001. doi: 10.1016/S1470-2045(12)70345-5. Epub 2012 Aug 28. PubMed PMID: 22951287.

3: Sobrero A. TAS-102 in refractory colorectal cancer: caution is needed. Lancet Oncol. 2012 Oct;13(10):959-61. doi: 10.1016/S1470-2045(12)70376-5. Epub 2012 Aug 28. PubMed PMID: 22951286.

4: Doi T, Ohtsu A, Yoshino T, Boku N, Onozawa Y, Fukutomi A, Hironaka S, Koizumi W, Sasaki T. Phase I study of TAS-102 treatment in Japanese patients with advanced solid tumours. Br J Cancer. 2012 Jul 24;107(3):429-34. doi: 10.1038/bjc.2012.274. Epub 2012 Jun 26. PubMed PMID: 22735906; PubMed Central PMCID: PMC3405214.

5: Suzuki N, Nakagawa F, Nukatsuka M, Fukushima M. Trifluorothymidine exhibits potent antitumor activity via the induction of DNA double-strand breaks. Exp Ther Med. 2011 May;2(3):393-397. Epub 2011 Mar 21. PubMed PMID: 22977515; PubMed Central PMCID: PMC3440718.

6: Shintani M, Urano M, Takakuwa Y, Kuroda M, Kamoshida S. Immunohistochemical characterization of pyrimidine synthetic enzymes, thymidine kinase-1 and thymidylate synthase, in various types of cancer. Oncol Rep. 2010 May;23(5):1345-50. PubMed PMID: 20372850.

7: Temmink OH, Bijnsdorp IV, Prins HJ, Losekoot N, Adema AD, Smid K, Honeywell RJ, Ylstra B, Eijk PP, Fukushima M, Peters GJ. Trifluorothymidine resistance is associated with decreased thymidine kinase and equilibrative nucleoside transporter expression or increased secretory phospholipase A2. Mol Cancer Ther. 2010 Apr;9(4):1047-57. doi: 10.1158/1535-7163.MCT-09-0932. Epub 2010 Apr 6. PubMed PMID: 20371715.

8: Bijnsdorp IV, Kruyt FA, Fukushima M, Smid K, Gokoel S, Peters GJ. Molecular mechanism underlying the synergistic interaction between trifluorothymidine and the epidermal growth factor receptor inhibitor erlotinib in human colorectal cancer cell lines. Cancer Sci. 2010 Feb;101(2):440-7. doi: 10.1111/j.1349-7006.2009.01375.x. Epub 2009 Sep 29. PubMed PMID: 19886911.

9: Bijnsdorp IV, Peters GJ, Temmink OH, Fukushima M, Kruyt FA. Differential activation of cell death and autophagy results in an increased cytotoxic potential for trifluorothymidine compared to 5-fluorouracil in colon cancer cells. Int J Cancer. 2010 May 15;126(10):2457-68. doi: 10.1002/ijc.24943. PubMed PMID: 19816940.

10: Bijnsdorp IV, Kruyt FA, Gokoel S, Fukushima M, Peters GJ. Synergistic interaction between trifluorothymidine and docetaxel is sequence dependent. Cancer Sci. 2008 Nov;99(11):2302-8. doi: 10.1111/j.1349-7006.2008.00963.x. Epub 2008 Oct 18. PubMed PMID: 18957056.

11: Overman MJ, Kopetz S, Varadhachary G, Fukushima M, Kuwata K, Mita A, Wolff RA, Hoff P, Xiong H, Abbruzzese JL. Phase I clinical study of three times a day oral administration of TAS-102 in patients with solid tumors. Cancer Invest. 2008 Oct;26(8):794-9. doi: 10.1080/07357900802087242. PubMed PMID: 18798063.

12: Overman MJ, Varadhachary G, Kopetz S, Thomas MB, Fukushima M, Kuwata K, Mita A, Wolff RA, Hoff PM, Xiong H, Abbruzzese JL. Phase 1 study of TAS-102 administered once daily on a 5-day-per-week schedule in patients with solid tumors. Invest New Drugs. 2008 Oct;26(5):445-54. doi: 10.1007/s10637-008-9142-3. Epub 2008 Jun 5. PubMed PMID: 18528634.

13: Temmink OH, Emura T, de Bruin M, Fukushima M, Peters GJ. Therapeutic potential of the dual-targeted TAS-102 formulation in the treatment of gastrointestinal malignancies. Cancer Sci. 2007 Jun;98(6):779-89. Epub 2007 Apr 18. Review. PubMed PMID: 17441963.

14: Temmink OH, Hoebe EK, van der Born K, Ackland SP, Fukushima M, Peters GJ. Mechanism of trifluorothymidine potentiation of oxaliplatin-induced cytotoxicity to colorectal cancer cells. Br J Cancer. 2007 Jan 29;96(2):231-40. PubMed PMID: 17242697; PubMed Central PMCID: PMC2360012.

Dovitinib in phase 3 for Cancer, bladder (urothelial carcinoma)

May 13, 2014 6:51 am / Leave a comment

Dovitinib
(3E)-4-amino-5-fluoro-3-[5-(4-methylpiperazin-1-yl)-1,3-dihydrobenzimidazol-2-ylidene]quinolin-2-one, is one kind of white crystalline powder, odorless, little bitter taste.

4-Amino-5-fluoro-3-[6-(4-methyl-1-piperazinyl)-1H-benzimidazol-2-yl]-2(1H)-quinolinone 2-hydroxypropanoate

4-Amino-5-fluoro-3-[6-(4-methyl-1-piperazinyl)-1H-benzimidazol-2-yl]-2(1H)-quinolinone 2-hydroxypropanoate hydrate (1:1:1);

CAS No.	405169-16-6 (free base), 915769-50-5, 804551-71-1 of lactate
	TKI-258; CHIR-258.
Formula	C₂₁H₂₁FN₆O^.C₃H₆O₃^.H₂O
Molecular Weight	500.53

for treatment of cancer

Novartis Ag, innovator

Dovitinib lactate is the orally bioavailable lactate salt of a benzimidazole-quinolinone compound with potential antineoplastic activity. Dovitinib strongly binds to fibroblast growth factor receptor 3 (FGFR3) and inhibits its phosphorylation, which may result in the inhibition of tumor cell proliferation and the induction of tumor cell death. In addition, this agent may inhibit other members of the RTK superfamily, including the vascular endothelial growth factor receptor; fibroblast growth factor receptor 1; platelet-derived growth factor receptor type 3; FMS-like tyrosine kinase 3; stem cell factor receptor (c-KIT); and colony-stimulating factor receptor 1; this may result in an additional reduction in cellular proliferation and angiogenesis, and the induction of tumor cell apoptosis. The activation of FGFR3 is associated with cell proliferation and survival in certain cancer cell types

Dovitinib (TKI258) is a highly potent, novel multitargeted growth factor receptor kinase inhibitor with IC50 of 1, 2, 10, 8, 27, 36 nM for FLT3, c-KIT, VEGFR1/2/3, PDGFRß and CSF-1R, respectively. It shows both antitumor and antiangiogenic activities in vivo. ^[1] It potently inhibits FGFR3 with an inhibitory concentration of 50% (IC50) of 5 nM in in vitro kinase assays and selectively inhibited the growth of B9 cells and human myeloma cell lines expressing wild-type (WT) or activated mutant FGFR3. Antiproliferative activity of Dovitinib (TKI258) against MV4;11 was ~24-fold greater compared with RS4;11, indicating more potent inhibition against cells with constitutively activated FLT3 ITD. ^[2][3]

References on Dovitinib (TKI258)

[1] Clin Cancer Res 2005;11:3633-3641
[2] Blood 2005;105: 2941-2948
[3] Clin Cancer Res 2005;11:5281-5291

Dovitinib lactate is an angiogenesis inhibitor in phase III clinical trials at Novartis for the treatment of refractory advanced/metastatic renal cell cancer. Early clinical trials are also under way at the company for the oral treatment of several types of solid tumors, multiple myeloma and glioblastoma multiforme. Phase II trials are ongoing for the treatment of castration-resistant prostate cancer and for the treatment of Von-Hippel Lindau disease, for the treatment of non-small cell lung cancer (NSCLC) and for the treatment of colorectal cancer. Novartis and Seoul National University Hospital are conducting phase II clinical studies for the treatment of adenoid cystic carcinoma. Additional phase II clinical trials are ongoing at Asan Medical Center for the treatment of metastatic or advanced gastrointestinal stromal tumors (GIST). The University of Pennsylvania is conducting phase II clinical trials for the treatment of advanced malignant pheochromocytoma or paraganglioma. Phase II clinical studies are ongoing by Novartis for the treatment of advanced malignant pleural mesothelioma which has progressed following prior platinum-antifolate chemotherapy (DOVE-M) and for the oral treatment of hepatocellular carcinoma.

In 2009, Novartis discontinued development of dovitinib lactate for the treatment of acute myeloid leukemia (AML) based on the observation of time dependent drug accumulation. A phase I trial was also stopped for the same reason.

The drug candidate has been shown to inhibit multiple growth factor tyrosine kinases, including vascular endothelial growth factor receptor (VEGFR) tyrosine kinases VEGFR1 and VEGFR2, fibroblast growth factor receptor (FGFR) and platelet-derived growth factor receptor (PDGFR) tyrosine kinases. In previous studies, the benzimidazole-quinoline inhibited VEGF-mediated human microvascular endothelial cell (HMVEC) proliferation and demonstrated concentration-dependent antiangiogenic activity in in vitro assays, as well as potent antiproliferative activity against a subset of cancer cell lines.

In 2013, an orphan drug designation was assigned in the U.S. for the treatment of adenoid cystic carcinoma.

“Molecularly Targeted Agents for Renal Cell Carcinoma: The Next Generation”, C. Lance Cowey and Thomas E. Hutson -Clinical Advances in Hematology & Oncology, 2010, 8, 357.

Lee S. H.; Lopes de Menezes, D. Vora, J. Harris, A.; Ye, H. Nordahl, L.; Garrett, E.; Samara, E.; Aukerman, S. L.; Gelb, A. B. Heise, C. In Vivo Target Modulation and Biological Activity of CHIR-258, a Multitargeted Growth Factor Receptor Kinase Inhibitor, in Colon Cancer Models. Clin. Cancer Res. 2005, 11 (10), 3633–3641.
Lopes de Menezes, D. E.; Peng, J.; Garrett, E. N.; Louie, S. G.; Lee, S. H.; Wiesmann, M.; Tang, Y.; Shephard, L.; Goldbeck, C.; Oei, Y.; Ye, H.; Aukerman, S. L.; Heise, C. CHIR-258: A Potent Inhibitor of FLT3 Kinase in Experimental Tumor Xenograft Models of Human Acute Myelogenous Leukemia. Clin. Cancer Res. 2005, 11 (14), 5281–5291.
Trudel, S.; Li, Z. H.; Wei, E.; Wiesmann, M.; Chang, H.; Chen, C.; Reece, D.; Heise, C.; Stewart, A. K. CHIR-258, a novel, multitargeted tyrosine kinase inhibitor for the potential treatment of t(4;14) multiple myeloma. Blood 2005, 105 (7), 2941–2948.

Synthesis of Dovitinib

Tetrahedron Letters 47 (2006) 657–660
LHMDS mediated tandem acylation–cyclization of 2-aminobenzenecarbonitriles with 2-benzymidazol-2-yl acetates: a short and efficient route to the synthesis of 4-amino-3-benzimidazol-2-ylhydroquinolin-2-ones
William R. Antonios-McCrea, Kelly A. Frazier, Elisa M. Jazan, Timothy D. Machajewski, Christopher M. McBride, Sabina Pecchi, Paul A. Renhowe, Cynthia M. Shafer and Clarke Taylor

cas 852433-84-2

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852433-84-2

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WO 2002022598 or https://www.google.com/patents/EP1317442A1?cl=en

Figure imgf000090_0001

Figure imgf000090_0002

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WO 2003087095 or http://www.google.fm/patents/US20030028018?cl=un

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WO 2005046589 or http://www.google.com/patents/EP1692085A2?cl=en

lactate salt of the compound of

Structure I or the tautomer thereof is administered to the subject and/or is used to prepare the medicament. [0062] In some embodiments, the compound of Structure I has the following formula

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WO 2006125130

http://www.google.com/patents/WO2006125130A1?cl=en

formula IHB

HIB

Scheme 1

Example 4

Synthesis of 4-Amino-5-fluoro-3-[6-(4-rnethyl-piperazin-1 -yl)-1 H-benzimidazol- 2-yl]-1 H-quinolin-2-one Procedure A

[0149] [6-(4-Methyl-piperazin-1-yl)-1 H-benzimidazol-2-yl]-acetic acid ethyl ester (250 g, 820 mmol) (dried with ethanol as described above) was dissolved in THF (3800 ml_) in a 5000 ml_ flask fitted with a condenser, mechanical stirrer, temperature probe, and purged with argon. 2-Amino-6-fluoro-benzonitrile (95.3 g, 700 mmol) was added to the solution, and the internal temperature was raised to 40°C. When all the solids had dissolved and the solution temperature had reached 4O⁰C, solid KHMDS (376.2 g, 1890 mmol) was added over a period of 5 minutes. When addition of the potassium base was complete, a heterogeneous yellow solution was obtained, and the internal temperature had risen to 62°C. After a period of 60 minutes, the internal temperature decreased back to 40°C, and the reaction was determined to be complete by HPLC (no starting material or uncyclized intermediate was present). The thick reaction mixture was then quenched by pouring it into H₂O (6000 ml_) and stirring the resulting mixture until it had reached room temperature. The mixture was then filtered, and the filter pad was washed with water (1000 ml_ 2X). The bright yellow solid was placed in a drying tray and dried in a vacuum oven at 50°C overnight providing 155.3 g (47.9%) of the desired 4-amino-5-fluoro-3-[6-(4-methyl-piperazin-1-yl)-1 H-benzimidazol-2- yl]-1 H-quinolin-2-one.

Procedure B

[0150] A 5000 mL 4-neck jacketed flask was equipped with a distillation apparatus, a temperature probe, a N₂ gas inlet, an addition funnel, and a mechanical stirrer. [6-(4-Methyl-piperazin-1-yl)-1 H-benzimidazol-2-yl]-acetic acid ethyl ester (173.0 g, 570 mmol) was charged into the reactor, and the reactor was purged with N₂ for 15 minutes. Dry THF (2600 mL) was then charged into the flask with stirring. After all the solid had dissolved, solvent was removed by distillation (vacuum or atmospheric (the higher temperature helps to remove the water) using heat as necessary. After 1000 mL of solvent had been removed, distillation was stopped and the reaction was purged with N₂. 1000 mL of dry THF was then added to the reaction vessel, and when all solid was dissolved, distillation (vacuum or atmospheric) was again conducted until another 1000 mL of solvent had been removed. This process of adding dry THF and solvent removal was repeated at least 4 times (on the 4^thdistillation, 60% of the solvent is removed instead of just 40% as in the first 3 distillations) after which a 1 mL sample was removed for Karl Fischer analysis to determine water content. If the analysis showed that the sample contained less than 0.20% water, then reaction was continued as described in the next paragraph. However, if the analysis showed more than 0.20% water, then the drying process described above was continued until a water content of less than 0.20% was achieved.

[0151] After a water content of less than or about 0.20% was achieved using the procedure described in the previous paragraph, the distillation apparatus was replaced with a reflux condenser, and the reaction was charged with 2-amino-6- fluoro-benzonitrile (66.2 g, 470 mmol)( in some procedures 0.95 equivalents is used). The reaction was then heated to an internal temperature of 38-42⁰C. When the internal temperature had reached 38-42⁰C, KHMDS solution (1313 g, 1.32 mol, 20% KHMDS in THF) was added to the reaction via the addition funnel over a period of 5 minutes maintaining the internal temperature at about 38-50°C during the addition. When addition of the potassium base was complete, the reaction was stirred for 3.5 to 4.5 hours (in some examples it was stirred for 30 to 60 minutes and the reaction may be complete within that time) while maintaining the internal temperature at from 38-42⁰C. A sample of the reaction was then removed and analyzed by HPLC. If the reaction was not complete, additional KHMDS solution was added to the flask over a period of 5 minutes and the reaction was stirred at 38-42⁰C for 45-60 minutes (the amount of KHMDS solution added was determined by the following: If the IPC ratio is < 3.50, then 125 ml_ was added; if 10.0 >IPC ratio >3.50, then 56 mL was added; if 20.0 ≥IPC ratio >10, then 30 mL was added. The IPC ratio is equal to the area corresponding to 4-amino-5-fluoro-3-[6- (4-methyl-piperazin-1 -yl)-1 H-benzimidazol-2-yl]-1 H-quinolin-2-one) divided by the area corresponding to the uncyclized intermediate). Once the reaction was complete (IPC ratio > 20), the reactor was cooled to an internal temperature of 25- 30⁰C, and water (350 mL) was charged into the reactor over a period of 15 minutes while maintaining the internal temperature at 25-35°C (in one alternative, the reaction is conducted at 40⁰C and water is added within 5 minutes. The quicker quench reduces the amount of impurity that forms over time). The reflux condenser was then replaced with a distillation apparatus and solvent was removed by distillation (vacuum or atmospheric) using heat as required. After 1500 mL of solvent had been removed, distillation was discontinued and the reaction was purged with N₂. Water (1660 mL) was then added to the reaction flask while maintaining the internal temperature at 20-30⁰C. The reaction mixture was then stirred at 20-30⁰C for 30 minutes before cooling it to an internal temperature of 5- 10⁰C and then stirring for 1 hour. The resulting suspension was filtered, and the flask and filter cake were washed with water (3 x 650 mL). The solid thus obtained was dried to a constant weight under vacuum at 5O⁰C in a vacuum oven to provide 103.9 g (42.6% yield) of 4-amino-5-fluoro-3-[6-(4-methyl-piperazin-1-yl)-1H- benzimidazol-2-yl]-1H-quinolin-2-one as a yellow powder.

Procedure C

[0152] [6-(4-Methyl-piperazin-1-yl)-1 H-benzimidazol-2-yl]-acetic acid ethyl ester (608 g, 2.01 mol) (dried) and 2-amino-6-fluoro-benzonitrile (274 g, 2.01 mol) were charged into a 4-neck 12 L flask seated on a heating mantle and fitted with a condenser, mechanical stirrer, gas inlet, and temperature probe. The reaction vessel was purged with N₂, and toluene (7.7 L) was charged into the reaction mixture while it was stirred. The reaction vessel was again purged with N₂ and maintained under N₂. The internal temperature of the mixture was raised until a temperature of 63⁰C (+/- 3°C) was achieved. The internal temperature of the mixture was maintained at 63°C (+/- 3⁰C) while approximately 2.6 L of toluene was distilled from the flask under reduced pressure (380 +/- 10 torr, distilling head t = 40°C (+/- 1O⁰C) (Karl Fischer analysis was used to check the water content in the mixture. If the water content was greater than 0.03%, then another 2.6 L of toluene was added and distillation was repeated. This process was repeated until a water content of less than 0.03% was achieved). After a water content of less than 0.03% was reached, heating was discontinued, and the reaction was cooled under N₂ to an internal temperature of 17-19°C. Potassium t-butoxide in THF (20% in THF; 3.39 kg, 6.04 moles potassium t-butoxide) was then added to the reaction under N₂ at a rate such that the internal temperature of the reaction was kept below 20°C. After addition of the potassium t-butoxide was complete, the reaction was stirred at an internal temperature of less than 2O⁰C for 30 minutes. The temperature was then raised to 25°C, and the reaction was stirred for at least 1 hour. The temperature was then raised to 30°C, and the reaction was stirred for at least 30 minutes. The reaction was then monitored for completion using HPLC to check for consumption of the starting materials (typically in 2-3 hours, both starting materials were consumed (less than 0.5% by area % HPLC)). If the reaction was not complete after 2 hours, another 0.05 equivalents of potassium t-butoxide was added at a time, and the process was completed until HPLC showed that the reaction was complete. After the reaction was complete, 650 mL of water was added to the stirred reaction mixture. The reaction was then warmed to an internal temperature of 50°C and the THF was distilled away (about 3 L by volume) under reduced pressure from the reaction mixture. Water (2.6 L) was then added drop wise to the reaction mixture using an addition funnel. The mixture was then cooled to room temperature and stirred for at least 1 hour. The mixture was then filtered, and the filter cake was washed with water (1.2 L), with 70% ethanol (1.2 L), and with 95% ethanol (1.2 L). The bright yellow solid was placed in a drying tray and dried in a vacuum oven at 50°C until a constant weight was obtained providing 674 g (85.4%) of the desired 4-amino-5-fluoro-3-[6-(4-methyl-piperazin-1-yl)-1 H- benzimidazol-2-yl]-1 H-quinolin-2-one.

Preparation of Lactic Acid salt of 4-Amino-5-fluoro-3-[6-(4-methyl-piperazin-1- yl)-1 H-benzimidazol-2-yl]-1 H-quinolin-2-one

D,L-Lactic Acid

[0154] A 3000 ml_ 4-necked jacketed flask was fitted with a condenser, a temperature probe, a N₂ gas inlet, and a mechanical stirrer. The reaction vessel was purged with N₂ for at least 15 minutes and then charged with 4-amino-5-fluoro- 3-[6-(4-methyl-piperazin-1-yl)-1 H-benzimidazol-2-yl]-1 H-quinoiin-2-one (484 g, 1.23 mol). A solution of D,L-Lactic acid (243.3 g, 1.72 mol of monomer-see the following paragraph), water (339 mL), and ethanol (1211 mL) was prepared and then charged to the reaction flask. Stirring was initiated at a medium rate, and the reaction was heated to an internal temperature of 68-72⁰C. The internal temperature of the reaction was maintained at 68-72°C for 15-45 minutes and then heating was discontinued. The resulting mixture was filtered through a 10-20 micron frit collecting the filtrate in a 12 L flask. The 12 L flask was equipped with an internal temperature probe, a reflux condenser, an addition funnel, a gas inlet an outlet, and an overhead stirrer. The filtrate was then stirred at a medium rate and heated to reflux (internal temperature of about 78⁰C). While maintaining a gentle reflux, ethanol (3,596 mL) was charged to the flask over a period of about 20 minutes. The reaction flask was then cooled to an internal temperature ranging from about 64-70⁰C within 15-25 minutes and this temperature was maintained for a period of about 30 minutes. The reactor was inspected for crystals. If no crystals were present, then crystals of the lactic acid salt of 4-amino-5-fluoro-3-[6-(4-methyl- piperazin-1-yl)-1 H-benzimidazol-2-yl]-1 H-quinolin-2-one (484 mg, 0.1 mole %) were added to the flask, and the reaction was stirred at 64-7O⁰C for 30 minutes before again inspecting the flask for crystals.

[0155] Once crystals were present, stirring was reduced to a low rate and the reaction was stirred at 64-70⁰C for an additional 90 minutes. The reaction was then cooled to about 0⁰C over a period of about 2 hours, and the resulting mixture was filtered through a 25-50 micron fritted filter. The reactor was washed with ethanol (484 ml_) and stirred until the internal temperature was about 0⁰C. The cold ethanol was used to wash the filter cake, and this procedure was repeated 2 more times. The collected solid was dried to a constant weight at 50⁰C under vacuum in a vacuum oven yielding 510.7 g (85.7%) of the crystalline yellow lactic acid salt of 4-amino-5-fluoro-3-[6-(4-methyl-piperazin-1 -yl)-1 H-benzimidazol-2-yl]-1 H-quinolin- 2-one. A rubber dam or inert conditions were typically used during the filtration process. While the dry solid did not appear to be very hygroscopic, the wet filter cake tends to pick up water and become sticky. Precautions were taken to avoid prolonged exposure of the wet filter cake to the atmosphere.

[0156] Commercial lactic acid generally contains about 8-12% w/w water, and contains dimers and trimers in addition to the monomeric lactic acid. The mole ratio of lactic acid dimer to monomer is generally about 1.0:4.7. Commercial grade lactic acid may be used in the process described in the preceding paragraph as the monolactate salt preferentially precipitates from the reaction mixture.

[0157] It should be understood that the organic compounds according to the invention may exhibit the phenomenon of tautomerism. As the chemical structures within this specification can only represent one of the possible tautomeric forms at a time, it should be understood that the invention encompasses any tautomeric form of the drawn structure. For example, the compound having the formula NIB is shown below with one tautomer, Tautomer INBa:

HIB

Tautomer HIBa

Other tautomers of the compound having the formula NIB, Tautomer INlBb and Tautomer IHBc, are shown below:

Tautomer IIIBb

Tautomer IIIBc

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WO 2006127926

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Design, structure-activity relationships and in vivo characterization of 4-amino-3-benzimidazol-2-ylhydroquinolin-2-ones: A novel class of receptor tyrosine kinase inhibitors
J Med Chem 2009, 52(2): 278

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WO 2003087095

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WO 2005046589

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WO 2006125130

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WO 2006127926

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Qingqi Chen’s Book……”Anticancer Drug Research Guide.” New drugs in development for cancers

May 13, 2014 5:15 am / Leave a comment

Chen Qingqi,

http://chen.medkoo.com/Anticancer-NewDrug.htm

Qingqi Chen’s Book

“Anticancer Drug Research Guide.”
New drugs in development for cancers

Very First Human Trials Using Cannbis To Treat Brain Cancer Are Under Way

May 13, 2014 3:43 am / Leave a comment

hemp

The picture to your left is showing immunofluorescence of the human glioma cell line. (View more pictures here)

A European based pharmaceutical company called GW Pharmaceuticals is set to commence its first phase of clinical trials for the treatment of Glioblastoma Multiforme (GBM). It’s a bio-pharmaceutical company focused on discovering, developing and commercializing novel therapeutics from its proprietary cannabinoid product platform.

According to the New England Journal of Medicine, GBM accounts for approximately 50% of the 22,500 new cases of brain cancer diagnosed in the United States alone each year.(1) Treatment with regards to brain cancer are very limited which makes the study of cannabis and its effect on brain tumors crucial.

http://www.hempforfuture.com/2014/03/26/very-first-human-trials-using-cannbis-to-treat-brain-cancer-are-under-way/?utm_content=buffer8c9a9&utm_medium=social&utm_source=facebook.com&utm_campaign=buffer

Very First Human Trials Using Cannbis To Treat Brain Cancer Are Under Way

The picture to your left is showing immunofluorescence of the human glioma cell line. (View more pictures here) A European…

WWW.HEMPFORFUTURE.COM

Rucaparib, PF-01367338 for the treatment of patients with advanced ovarian cancer and in patients with locally advanced or metastatic breast cancer.

May 9, 2014 6:49 am / 1 Comment on Rucaparib, PF-01367338 for the treatment of patients with advanced ovarian cancer and in patients with locally advanced or metastatic breast cancer.

Rucaparib, PF-01367338

283173-50-2 cas

6H-Pyrrolo[4,3,2-ef][2]benzazepin-6-one, 8-fluoro-1,3,4,5-tetrahydro-2-[4-[(methylamino)methyl]phenyl]-

6H- Azepino[5,4,3-cd]indol-6-one, 8-fluoro-1,3,4,5-tetrahydro-2-[4-[(methylamino)methyl]phenyl] -

8-Fluoro-2-[4-[(methylamino)methyl]phenyl]-1,3,4,5- tetrahydro-6H-azepino[5,4,3-cd]indol-6-one;

8-Fluoro-2-(4-methylaminomethyl-phenyl)-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one

8-Fluoro-2-(4-methylaminomethyl-phenyI)-l,3,4,5-tetrahydro-azepino[5,4,3- cd]indol-6-one

MW..C₁₉ H₁₈ F N₃ O

cas of csa salt—–1327258-57-0

773059-19-1 (hydrochloride)
773059-22-6 (L-tartrate)
773059-23-7 (acetate)

459868-92-9 PHOSPHATE

AG-014699
AG-14699
CO-338
PF-01367338
AG-014447 (free base)
AG-14447 (free base)

Agouron (Originator)
Pfizer (Originator)

WO 2014052550, WO 2014037313, WO 2000042040WO 2004087713WO 2005012305

Inhibition of poly(ADP ribose) polymerase, or PARP, is an exciting new mechanism for the treatment of cancer.(1) The PARP enzyme is responsible for repair of damaged DNA in both normal and tumor cells, and inhibition of this repair mechanism is expected to make the cell more likely to undergo apoptosis. Preclinical work has shown that PARP inhibitors coadministered with a standard chemotherapuetic agent are more effective than the standard treatment alone

Rucaparib is a NAD+ ADP-ribosyltransferase inhibitor in phase II clinical development at Cancer Research UK for the treatment of patients with advanced ovarian cancer and in patients with locally advanced or metastatic breast cancer. Clovis Oncology is conducting early clinical evaluation of rucaparib for the treatment of triple negative breast cancer or ER/PR +, HER2 negative with known BRCA1/2 mutations p2 and for the treatment of gBRCA mutation breast cancer.. Pfizer discontinued development of rucaparibin 2011.In 2011, the compound was licensed to Clovis Oncology by Pfizer for the treatment of cancer. In 2012, orphan drug designation was assigned in the U.S. and the E.U. for the treatment of ovarian cancer.The compound 8-fluoro-2-{4-[(methylamino)methyl]phenyl}-1 ,3,4,5-tetrahydro-6H-azepino[5,4,3- cd]indol-6-one represented by formula is a small molecule inhibitor of poly(ADP-ribose) polymerase (PARP). 8-Fluoro-2-{4- [(methylamino)methyl]phenyl}-1,3,4,5-tetrahydro-6H-azepino[5,4,3-cd]indol-6-one and salts thereof, is disclosed in U.S. Patent No. 6,495,541 and PCT Application No. PCT/IB2004/000915, International Publication No. WO 2004/087713, the disclosures of which are incorporated herein by reference in their entireties. U.S. Provisional Patent Applications No. 60/612,459 and 60/679,296, entitled “Polymorphic Forms of the Phosphate Salt of 8-Fluoro-2-{4-[(methylamino)methyl]phenyl}-1 ,3,4,5-tetrahydro-6H- azepino[5,4,3-cd]indol-6-one,” the disclosures of which are incorporated herein by reference in their entireties, describe novel polymorphic forms of the phosphate salt of 8-fluoro-2-{4- [(methylamino)methyl]phenyl}-1 ,3,4,5-tetrahydro-6H-azepino[5,4,3-cd]indol-6-one, and methods for their preparation. U.S. Provisional Patent Applications No. 60/612,458; and 60/683,006, entitled “Therapeutic Combinations Comprising Poly(ADP-Ribose) Polymerases Inhibitor,” the disclosures of which are incorporated herein by reference in its entirety, describe pharmaceutical combinations of 8-fluoro-2-{4- [(methylamino)methyl]phenyl}-1 ,3,4,5-tetrahydro-6H-azepino[5,4,3-cd]indol-6-one.

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http://www.google.com/patents/WO2000042040A1?cl=en

Example IIII:8-Fluoro-2-(4-methylaminomethyl-phenyI)-l,3,4,5-tetrahydro-azepino[5,4,3- cd]indol-6-one 4-(8-fluoro-6-oxo-3,4,5,6-tetrahydro-lH-azepino[5,4,3-cd]indol-2-yl)- benzaldehyde (100 mg, 0.32 mmol; prepared in a manner similar to that described for compound 12 for 2-bromo-8-fluoro-l,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one and 4-formylphenylboronic acid) was reacted with methylamine (1.62 mmol) as described for Compound PPP to yield 8-fluoro-2-(4-methylaminomethyl-phenyl)- l,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one, 32 mg (31%) as a yellow solid: m.p. 1543-155 °C; Η NMR (300 MHz, d₆-DMSO) 2.28 (s, 3H), 3.04 (m, 2H), 3.40 (m, 2H), 3.69 (s, 2H), 7.32 (dd, 7= 9.0, 2.4 Hz, IH), 7.44 (m, 3H), 7.57 (d, 7= 8.1 Hz, 2H), 8.25 (br t, IH), 11.67 (br s, IH). HRMS (MALDI MH+) Calcd for C₁₉H₁₈N₃OF: 324,1512. Found: 325.1524. Anal. (C₁₉H₁₈N₃OF03 H₂O) C, H, N.

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Org. Process Res. Dev., 2012, 16 (12), pp 1897–1904

DOI: 10.1021/op200238p

http://pubs.acs.org/doi/full/10.1021/op200238p

Novel PARP inhibitor 1 is a promising new candidate for treatment of breast and ovarian cancer. A modified synthetic route to 1 has been developed and demonstrated on 7 kg scale. In order to scale up the synthesis to multikilogram scale, several synthetic challenges needed to be overcome. The key issues included significant thermal hazards present in a Leimgruber–Batcho indole synthesis, a low-yielding side-chain installation, a nonrobust Suzuki coupling and hydrogen cyanide generation during a reductive amination. In addition to these issues, changing from intravenous to oral delivery required a new salt form and therefore a new crystallization procedure. This contribution describes development work to solve these issues and scaling up of the new process in the pilot plant.

8-Fluoro-2-(4-methylaminomethyl-phenyl)-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one (1) To a solution of aqueous sodium hydroxide (40% w/w, 3.6 kg, 2.0 equiv) in water (88 L, 14 L/kg) and methanol (35 L, 5.5 L/kg) was added 12 ……………………………………………………deleted……………………..and dried at 45 °C under vacuum to give 1 as a 1:1 THF solvate (5.57 kg, 14.08 mol, 84% yield); mp (THF) dec at 220 °C; δ_H: (400 MHz, DMSO-d₆) 2.25 (s, 3H), 2.99–3.01 (m 2H), 3.65 (s, 2H), 7.27 (dd, 1H, J = 2.4, 9.3 Hz), 7.39 (dd, 1H, J = 2.4, 9.3 Hz), 7.42 (d, 2H, J = 8.5 Hz), 7.53 (d, 2H, J = 8.3 Hz), 8.18 (t, br, 1H, J = 5.7 Hz), 11.60 (s, 1H); δ_C: (100 MHz, DMSO-d₆) 28.74, 35.58, 41.84, 54.74, 100.47 (d, J = 25.8 Hz), 109.44 (d, J = 25.8 Hz), 111.47, 123.19, 125.72 (d, J = 8.8 Hz), 127.55, 128.20, 129.86, 135.38 (d, J = 3.7 Hz), 136.67 (d, J = 12.4 Hz), 140.52, 158.31 (d, J = 233), 168.39. 8-Fluoro-2-(4-methylaminomethyl-phenyl)-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one (S)-camphorsulfonate Salt (21) To a slurry of 1 (5.32 kg, 13.48 mol) in isopropanol (30 L, 5.5 L/kg) and water (39 L, 7.3 L/kg) was added a solution of (S)-camphorsulfonic acid (3.75 kg, 16.18 mol, 1.2 equiv) in water (10.6 L, 2 L/kg). The resultant slurry was then heated to 70 °C and held for 1 h to ensure dissolution. …………………………..deleted…………………..C to give 21 as a white crystalline solid (7.09 kg, 12.76 mol, 95% yield); mp (IPA/water) 303 °C; δ_H: (400 MHz, DMSO-d₆) 0.74 (s, 3H), 1.05 (s, 3H), 1.28 (m, 1H), 1.80 (d, 1H, J = 18.0 Hz), 1.81–1.88 (m, 1H), 1.93 (app t, 1H, J = 4.5 Hz), 2.24 (m, 1H), 2.41 (d, 1H, J = 14.6 Hz), 2.62 (s, 3H), 2.66–2.72 (m, 1H), 2.91 (d, 1H, J = 14.7 Hz), 3.04–3.07 (m, br, 2H), 3.36–3.45 (m, br, 2H), 4.20 (s, 2H), 7.37 (dd, 1H, J = 2.4, 9.3 Hz), 7.44 (dd, 1H, J = 2.4, 11.0 Hz), 7.63 (d, 2H, J = 8.3 Hz), 7.71 (d, 2H, J = 8.3 Hz), 8.26 (t, br, 1H, J = 5.5 Hz), 11.76 (s, 1H); δ_C: (100 MHz, DMSO-d₆) 19.51, 20.02, 24.14, 26.37, 28.74, 32.28, 41.77, 42.13, 42.22, 46.71, 47.00, 51.06, 58.21, 100.65 (d, J = 25.8 Hz), 109.72 (d, J = 25.8 Hz), 112.41, 123.03, 126.04 (d, J = 8.7 Hz), 127.98, 130.19, 131.22, 132.22, 134.50, 136.83 (d, J = 12.0 Hz), 158.52 (d, J = 235 Hz), 168.27, 216.24. …………………. WO 2006033003 http://www.google.com/patents/WO2006033003A1?cl=en The compound 8-fluoro-2-{4-[(methylamino)methyl]phenyl}-1 ,3,4,5-tetrahydro-6H-azepino[5,4,3- cd]indol-6-one represented by formula is a small molecule inhibitor of poly(ADP-ribose) polymerase (PARP). 8-Fluoro-2-{4- [(methylamino)methyl]phenyl}-1,3,4,5-tetrahydro-6H-azepino[5,4,3-cd]indol-6-one and salts thereof, is disclosed in U.S. Patent No. 6,495,541 and PCT Application No. PCT/IB2004/000915, International Publication No. WO 2004/087713, the disclosures of which are incorporated herein by reference in their entireties. U.S. Provisional Patent Applications No. 60/612,459 and 60/679,296, entitled “Polymorphic Forms of the Phosphate Salt of 8-Fluoro-2-{4-[(methylamino)methyl]phenyl}-1 ,3,4,5-tetrahydro-6H- azepino[5,4,3-cd]indol-6-one,” the disclosures of which are incorporated herein by reference in their entireties, describe novel polymorphic forms of the phosphate salt of 8-fluoro-2-{4- [(methylamino)methyl]phenyl}-1 ,3,4,5-tetrahydro-6H-azepino[5,4,3-cd]indol-6-one, and methods for their preparation. U.S. Provisional Patent Applications No. 60/612,458; and 60/683,006, entitled “Therapeutic Combinations Comprising Poly(ADP-Ribose) Polymerases Inhibitor,” the disclosures of which are incorporated herein by reference in its entirety, describe pharmaceutical combinations of 8-fluoro-2-{4- [(methylamino)methyl]phenyl}-1 ,3,4,5-tetrahydro-6H-azepino[5,4,3-cd]indol-6-one. Example 13. Synthesis of 8-Fluoro-2-(4-methylaminomethyl-phenyl)-1,3.4.5-tetrahvdro-azepinor5.4.3- ccflindol-6-one (15) i Lactam 14 (14.42 g, 0.038 mol) was dissolved in hydrobromic acid in acetic acid (30%-32%, 140 ml). The reaction solution was stirred for 46 hours at room temperature in a 500ml flask that was connected to an ethanolamine scrubber system. HPLC analysis indicated the completion of the reaction. Ice (30 g) was added to the reaction solution followed by addition of aqueous NaOH (327 ml, 10 M, 3.27 mol) while the temperature was maintained between 25 ⁰C and 35 ⁰C. When addition of NaOH was complete, the pH was 10. The resulting solid was collected by filtration, washed with water (2 x 50 ml). The filter cake was then suspended in water (125 ml) and stirred for 2 hours. The solid was collected by filtration, washed with water (2 x 25 ml) and dried to afford 10.76 g of product (88% yield). ¹H NMR (300 MHz, DMSO-d₆) δ 2.577(s, 3H), 3.053(m, 2H), 3.406(m, 2H), 4.159(s, 2H), 7.36(dd, 1 H, J= 2.4 Hz and J= 9.3 Hz), 7.44(dd, 1 H, J= 2.4 Hz and J= 11.1 Hz), 7.63(d, 2H, J=8.1 Hz), 7.70(d, 2H, J= 8.1 Hz), 8.265(t, 1H, J= 5.7 Hz), 11.77(s, 1 H). Exact mass calculated for C₁₉H₁₉FN₃O: 324.1512. Found: 324.1497.

Tomensides A–D, new antiproliferative phenylpropanoid sucrose esters from Prunus tomentosa leaves…..might be valuable source for new potent anticancer drug candidates.

May 6, 2014 4:07 am / 2 Comments on Tomensides A–D, new antiproliferative phenylpropanoid sucrose esters from Prunus tomentosa leaves…..might be valuable source for new potent anticancer drug candidates.

Full-size image (35 K)

http://www.sciencedirect.com/science/article/pii/S0960894X14003540

Bioorganic & Medicinal Chemistry Letters

Volume 24, Issue 11, 1 June 2014, Pages 2459–2462

Department of Natural Products Chemistry, Shenyang Pharmaceutical University, Shenyang 110016, PR China

To search for novel cytotoxic constituents against cancer cells as lead structures for drug development, four new 3-phenylpropanoid-triacetyl sucrose esters, named tomensides A–D (1–4), and three known analogs (5–7) were isolated from the leaves of Prunus tomentosa. Their structures were elucidated by spectroscopic analyses (1D, 2D NMR, CD and HRESIMS). The cytotoxic activities of all isolates against four human cancer cell lines (MCF-7, A549, HeLa and HT-29) were assayed, and the results showed that these isolates displayed stronger inhibitory activities compared with positive control 5-fluorouracil. Tomenside A (1) was the most active compound with IC₅₀ values of 0.11–0.62 μM against the four tested cell lines. The structure–activity relationship (SAR) of the isolates was also discussed. The primary screening results indicated that these 3-phenylpropanoid-triacetyl sucrose esters might be valuable source for new potent anticancer drug candidates.

Buparlisib in phase 3 for Breast tumor; Hematological neoplasm; Solid tumor

May 3, 2014 6:53 am / Leave a comment

Buparlisib

Novartis Ag

5-[2,6-Di(4-morpholinyl)-4-pyrimidinyl]-4-(trifluoromethyl)-2-pyridinamine.

5-[2,6-Di(morpholin-4-yl)pyrimidin-4-yl]-4-(trifluoromethyl)pyridin-2-amine

5-(2,6-Di-4-morpholinyl-4-pyrimidinyl)-4- trifluoromethylpyridin-2-amine

944396-07-0

Chemical Formula: C18H21F3N6O2

Mass: 410.16781

NVP-BKM-120, BKM-120;

Novartis AG phase 3 for breast cancer

Phosphoinositide 3-kinase inhibitor

Buparlisib, also known as BKM120, is an orally bioavailable specific oral inhibitor of the pan-class I phosphatidylinositol 3-kinase (PI3K) family of lipid kinases with potential antineoplastic activity. PI3K inhibitor BKM120 specifically inhibits class I PIK3 in the PI3K/AKT kinase (or protein kinase B) signaling pathway in an ATP-competitive manner, thereby inhibiting the production of the secondary messenger phosphatidylinositol-3,4,5-trisphosphate and activation of the PI3K signaling pathway. This may result in inhibition of tumor cell growth and survival in susceptible tumor cell populations. Activation of the PI3K signaling pathway is frequently associated with tumorigenesis. Dysregulated PI3K signaling may contribute to tumor resistance to a variety of antineoplastic agents.

NVP-BKM-120 is an oral selective phosphatidylinositol 3-kinase (PI3K) inhibitor in phase III clinical development at Novartis for the treatment of breast cancer in combination with fulvestrant in postmenopausal women with hormone receptor-positive HER2-negative locally advanced or metastatic breast cancer which progressed on or after aromatase inhibitor treatment.

Early clinical development at Novartis Oncology, a division of Novartis, is also ongoing for the treatment of solid tumors, advanced endometrial carcinoma, non-small cell lung cancer (NSCLC), bladder cancer, gastrointestinal stromal cancer and for the treatment of metastatic castration-resistant prostate cancer.

Novartis is conducting phase II clinical trials for the treatment of follicular lymphoma, diffuse large B-cell lymphoma, mantle cell lymphoma and squamous cell carcinoma of head and neck.

The University of Kansas is evaluating the compound in phase I clinical trials for the treatment of advanced colorectal cancer in combination with irinotecan, while additional phase I trials are ongoing at the Dana-Farber Cancer Institute for the treatment of renal cell carcinoma. The Dana-Farber Cancer Institute is also conducting phase II clinical trials for the oral treatment of recurrent glioblastoma and preclinical studies for the treatment of ovarian cancer. Novartis is also conducting early clinical studies for the treatment of metastatic melanoma

pyrimidine derivative 5-(2,6-Di- 4-morpholinyl-4-pyrimidinyl)-4-trifluoromethylpyridin-2-amine (Compound A, see below), its hydrates, its salts and hydrates and solvates of its salts, to said specific solid forms thereof, to pharmaceutical compositions containing said solid forms, to processes for the preparation of pharmaceutical compositions containing said solid forms, to methods of using said solid forms and to pharmaceutical compositions for the therapeutic treatment of warm-blooded animals, especially humans. Background of the invention

WO 2007/084786 (priority date: January 20, 2006) describes certain pyrimidine derivatives having PI3 inhibiting properties, their use as pharmaceuticals and manufacturing processes thereof. One pyrimidine derivative disclosed in WO 2007/084786 is the selective

phosphatidylinositol 3-kinase inhibitor compound 5-(2,6-Di-4-morpholinyl-4-pyrimidinyl)-4- trifluoromethylpyridin-2-amine, hereinafter referred to as “Compound A” or “the compound of formula A”.

Compound A is described in WO 2007/084786 in free form and as the hydrochloric acid salt. The manufacturing process for preparing Compound A is described in Example 10 of this document. The manufacturing processes described therein are, although suitable, regarded as disadvantageous for commercial production.

Due to the high potency of pyrimidine derivatives, in particular PI3K inhibitors, there is a need for improved manufacturing methods of such compounds. In particular there is a need to provide processes that fulfill one or more of the following criteria: scalable, safer; simpler; higher yielding and more economical when compared to known.

…………………………………….

WO 2007084786

http://www.google.com/patents/WO2007084786A1?cl=en

Example 10

Preparation of 4-(“trifluoromethyπ-5-(2,6-dimorpholmoρyrirnidin-4-yπpyridin-2- amine

[0388] To a slurry of 2-moφholino-4,6-dichloropyrimidine (prepared as in

Method 22, 2.0 g, 8.54 mmol) in NMP (14 mL), triethylamine (1.43 mL, 10.25 mmol) was added. The heterogeneous mixture was stirred for 15 minutes, then treated with morpholine (0.75 mL, 8.54 mmol). Upon refluxing at 85 ⁰C under argon for 2 hours, the solution was cooled, then added to EtOAc (160 mL). The organic solution was washed with 25 mL of NaHCO3(_sat.) (2 x), water (2 x) and brine, dried over Na₂SO₄, filtered and concentrated. The crude material was dissolved in 200 mL EtOAc and filtered through a SiO₂ pad, further eluting with EtOAc, yielding 2.2 g (93%) of 2,4-dimorpholino-6- chloropyrimidine as an off-white solid. LCMS (m/z): 285.0 (MH⁺), ¹H NMR (CDCl₃): δ 5.86 (s, IH), 3.71-3.76(m, 12H), 3.52-3.56(m, 4H).

[0389] 4-(trifluoromethyl)-5-(2,6-dimoφholmopyrimidin-4-yl)pyridin-2-amine 8

[0390] Argon gas was bubbled through a heterogeneous mixture of 2,4- dimoφholino-6-chloropyrimidine (4.1 g, 14.3 mmol) and 4-(trifluoromethyl)-5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyridm-2-amine (16.5 g, 57.3 mmol) in 1,2- dimethoxyethane and 2M Na₂Cθ₃ (3:1) for 20 minutes. 1,1′-

Bis(diphenylphosphino)ferrocene palladium (IT) chloride (292 mg, 0.36 mmol) was added and the high pressure glass vessel containing the mixture was sealed. The reaction mixture was then heated at 90⁰C for 15 hours, cooled and diluted with EtOAc (300 mL). The organic solution was washed with 300 mL of a mixture of water: Na2Cθ3(_sat.)^:NH4θH(conc.) ⁼ 5:4:1, then NH4Cl(_sat), and brine (2x), dried over Na₂SO₄, filtered and concentrated. The crude material was purified by SiO₂ chromatography (50- 90% EtOAc/hexanes with 0.1% TEA) resulting in 5.62 g (95%) of 4-(trifluoromethyl)-5- (2,6-dimorpholinopyrimidin-4-yl)pyridin-2-amine as an off-white solid.

LCMS (m/z): 411.3 (MH⁺);

¹H NMR (CDCl₃): δ 8.27 (s, IH), 6.78 (s, IH), 5.97 (s, IH), 4.77 (bs, 2H), 3.59-3.80(m, 12H), 3.58-3.61(m, 4H).

…………….

WO2012044727 or equi as below

http://www.google.com/patents/EP2621908A2?cl=en

Example 1: 4,4′-(6-Chloropyrimidine-2,4-diyl)di[morpholine] (3) U 2011/053808

Prepare a solution of 22 g (0.12 mol) of 2,4,6-trichloropyrimidine 1 , in 95.2 g (110 mL) of toluene and charge it to the 25 mL addition funnel. Charge a nitrogen-flushed 500 mL round bottom 4- neck flask that equipped with a condenser, heating mantle, thermocouple, 125 mL addition funnel, mechanical stirrer and nitrogen inlet / outlet with 62.7 g (63 mL, 0.72 mol) of morpholine 2, 95.2 g (110 mL) of toluene and 44 g (44 mL) of water. Add the toluene solution of 1 over 10 minutes. Heat the reaction mixture to 83 ± 3 °C. Stir at 83 ± 3 °C for 2 h. Check the progress of the reaction. Cool to 30 + 3 °C. Transfer the 2-phase mixture to a 1L separatory funnel.

Separate the phases. Wash the organic phase (top) twice with 200 mL (2 x 100 mL) of warm (30 °C) water. Separate the phases after each wash. Transfer the organic (top) phase back to the 500 mL reaction flask that equipped with a condenser, heating mantle, thermocouple, 125 mL addition funnel, mechanical stirrer and nitrogen inlet / outlet. Stir and add 50.0 mL of 10.0 N aqueous hydrochloric acid solution. Heat the solution to 53 ± 3 °C and stir for 12 – 18 h. Check the progress of the reaction. Cool to 22 + 3 °C. Transfer the 2-phase mixture to a 1 L separatory funnel. Separate the phases. Transfer the aqueous (bottom) phase to a 500 mL round bottom 4-neck flask equipped with a cooling bath, thermocouple, addition funnel, pH probe, mechanical stirrer and nitrogen inlet / outlet. Stir and cool to 0 ± 3 °C. Add 85.0 g of 25% aqueous sodium hydroxide solution by drops over 30 minutes, maintaining a batch temperature of 10 ± 10 °C throughout the addition. Warm to 20 ± 3 °C and stir for 30 minutes. Isolate the solids by vacuum filtration. Wash the cake with 3 x 100 mL of water. Dry the solids (55°C, 30 mbar) for 24 hours to afford 30.9 g (91.9% yield) of 3 as a white crystalline solid.

Example 2:

4,4′-[6-(4_>4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine-2,4-diyl]di[morpholine] (4)

Charge a nitrogen-flushed 2 L round bottom 4-neck flask that equipped with a condenser, heating mantle, thermocouple, rubber septum, mechanical stirrer and nitrogen inlet / outlet with 100.0 g (0.351 mol) of 4,4′-(6-chloropyrimidine -2,4-diyl)di[morpholine] 3 and 943 g (1200 mL) of acetonitrile. Stir and heat to 60 + 3 °C. Hold this solution at 60 + 3 °C for charge to batch. Charge a nitrogen-flushed 3 L reactor that equipped with an overhead stirrer, condenser, nitrogen inlet/outlet and rubber septum with 115.9 g (0.457 mol) of bis(pinacolato)- diboron, 51.7 g (0.527 mol) of potassium acetate, 12.9 g (0.014 mol) of tris(dibenzylideneacetone) – dipalladium(O), 7.9 g (0.029 mol) of tricyclohexylphosphine and 393 g (500 mL) of acetonitrile. Stir and heat the slurry to 84 ± 3 °C (reflux). Collect 00 mL of distillate. Transfer the warm 3 acetonitrile solution via peristaltic pump to the 3 L reactor containing the reaction mixture over 30 minutes and continue collecting distillate. Wash the 2 L flask and transfer lines with 79 g (100 mL) of acetonitrile and transfer the wash to the batch. Maintain distillation at 84 ± 3 °C and collect an additional 900 mL of distillate (batch volume ~ 1100 mL). Check the progress of the reaction 2 h from the start of the addition of 3. Cool the reaction mixture to 70 ± 3 °C and charge 693 g (800 mL) of toluene over 1-2 min. The batch will cool upon the addition of the toluene. Further cool the reaction mixture to 50 ± 3 °C. Charge to a clean 1 L flask, 347 g (400 mL) of toluene and warm it to 50 °C. This will be used as the cake wash. Filter the reaction mixture through a 15 g pad of Celite 545. Wash the filter cake with the warm (50 °C) toluene (400 mL) and collect this wash separately from the batch. This wash will be charged to the distillation residue later in the process. Transfer the filtrate back to the 3 L reactor. Concentrate the batch (25 °C to 40 °C internal temperature, 50 mbar) until a batch volume of 250 mL is reached.

Charge toluene cake wash held in reserve (~400 mL) and continue to concentrate the batch (37 °C to 43 °C internal temperature, 50 mbar) until a batch volume of 250 mL is reached. Check for complete removal of acetonitrile using the described Process Steering Control. Warm to 50 °C and stir for 15 min. Add 164 g (240 mL) of heptane over 30 minutes maintaining 50 °C throughout the addition. Stir the resulting suspension for 1 h. Cool the slurry to 23 ± 3 °C over 1 h and hold at this temperature for at least 1 h. Blanket the filtering funnel used for isolation of the product with nitrogen (to avoid moisture) and quickly filter the solids. Wash the filter cake twice with a mixture of 22 g (25 mL) of toluene and 51 g (75 mL) of heptane. Dry the solids at 50 °C, 35 mbar for 16 h to afford 4.4 g (72.7% corrected yield) of 4 as a sandy, beige solid. Example 3: 5-Bromo-4-(trifluoromethyl)pyridin-2-amine (4a)

4b 4a

Charge a nitrogen-flushed 3 L reactor that equipped with an overhead stirrer, condenser, nitrogen inlet/outlet and rubber septum with 112.14 g (0.63 mol) of N-bromosuccinimide (NBS) and 645 g (725 mL) of tetrahydrofuran. Stir and cool the slurry to -5 ± 3 °C. Charge a nitrogen- flushed 1 L round bottom 4-neck flask that equipped with a thermocouple, mechanical stirrer and nitrogen inlet / outlet with 97.26 g (0.6 mol) of 2-amino-4-(trifluoromethyl)pyridine, 4b and 511 g (575 mL) of tetrahydrofuran. Stir to dissolve the 4b. Transfer the 4b solution to the addition funnel on the reactor and add the solution to the NBS slurry over 2 h maintaining an internal temperature of 0 ± 3 °C throughout the addition. Rinse the 1 L flask and addition funnel with 44 g (50 mL) of tetrahydrofuran and add the wash to the reaction mixture. Warm the solution to 20 + 3 °C over 30 minutes. Check for completeness of the reaction. Quench by charging a solution of 24.6 g of sodium thiosulfate pentahydrate dissolved in 475 mL of water over 10 minutes, maintaining a batch temperature of 20 ± 3 °C throughout the addition. Stir for 1 h after the quench. Concentrate (internal temp = 25 °C, 50 mbar) to remove tetrahydrofuran. Add 379 g (500 mL) of fert-butyl methyl ether. Stir and warm the resulting solution/suspension to 30 ± 3 °C and stir for 15 minutes. Separate the phases. Wash the extract four times with a solution of 32 g of sodium chloride dissolved in 768 g (768 mL) of water (4 x 200 mL per wash), separating the phases after each wash. Finally, wash the extract with 150 g (150 mL) of water. Separate the phases. Charge 152 g (200 mL) of terf-butyl methyl ether. Partially concentrate (57 ± 3 °C) to a volume of 350 mL. Cool to 50 °C and add 265 g (350 mL) of ferf-butyl methyl ether. Resume the concentration (57 ± 3 °C) until a batch volume of 350 mL is reached. Cool to 50 °C and add 265 g (350 mL) of fe/f-butyl methyl ether. Again, resume the concentration (57 ± 3 °C) until a batch volume of 350 mL is reached. Cool to 50 °C and add 103 g (150 mL) of terf-butyl methyl ether to raise the batch volume to 500 mL. Charge 1026 g (1500 mL) of heptane over 15 minutes maintaining 45 ± 3 °C throughout the addition. Slowly increase the vacuum and concentrate (internal temp = 40 °C to 50 °C) to a batch volume of 1000 mL. Release the vacuum and seed the batch. Resume the distillation, further increase the vacuum (slowly) and concentrate (internal temp = 25 °C to 40 °C) to a batch volume of 500 mL. Stir the resulting suspension at 0 °C for 30 min. Filter the solids. Wash the filter cake with 68 g (100 mL) of cold (0 °C) heptane (containing 30 ppm Octastat). Dry the solids (40 °C, 50 mbar) for 16 h to afford 109.8 g (78.0% yield) 4a as an orange solid.

Example 4: 5-(2,6-Di-4-morpholinyl^^yrimidinyl)-^trifluoromethylpyridin-2-ami^ (5)

Charge a 500 mL round bottom 3-neck flask that equipped with a thermocouple, mechanical stirrer, nitrogen inlet/outlet and cooling bath with 202.8 g (0.622 mol) of cesium carbonate and 260 g (260 mL) of water. Stir and cool the resulting solution to 22 ± 3 °C. Transfer the solution to the addition funnel. Charge a nitrogen-flushed 3 L reactor that equipped with an overhead stirrer, condenser, pH probe, nitrogen inlet/outlet and 500 mL addition funnel with 50.0 g (0.207 mol) of 5-bromo-4-(trifluoromethyl) pyridin-2-amine 4a, 190.9 g (0.456 mol) of 4,4′-[6-(4,4,5,5- tetramethyl-1 ,3,2- dioxaborolan-2-yl)pyrimidine-2,4-diyl]di[morpholine] 4, 6.75 g (0.0103 mol) of 1,1′-bis(di-ferf-butylphosphino) ferrocene palladium dichloride and 556 g (625 mL) of thf. Stir the slurry at 22 ± 3 °C. Add the aqueous cesium carbonate solution via the addition funnel to the slurry over 1 – 2 min. Stir rapidly (to ensure good mixing), heat to 45 ± 3 °C over 15 min and hold at this temperature for at least 30 minutes. Check for completeness of the reaction. Cool to 22 ± 3 °C. Separate the phases. Partially concentrate the THF (25 °C, 90 mbar) to a volume of 400 mL. Add 654 g (750 mL) of isopropyl acetate, resume the vacuum distillation and concentrate to a volume of 400 mL. Add 610 g (700 mL) of isopropyl acetate, stir and filter the hazy solution through a 25 g pad of Celite. Wash the reactor and filter cake with 87 g (100 mL) of isopropyl acetate and add the wash to the batch. Add 1 L of 0. 25N aqueous N-acetyl-L- cysteine solution and stir at 60 ± 3 °C for 1 h. Cool to 22 ± 3 °C and drain the aqueous wash. Add 1 L of 0.25N aqueous N-acetyl-L-cysteine pH = 7 solution and stir at 60 ± 3 °C for 1 h. Cool to 22 ± 3 °C and drain the aqueous wash. Again, add 1 L of 0.25N aqueous N-acetyl-L-cysteine pH = 7 solution and stir at 60 ± 3 °C for 1 h. Cool to 22 ± 3 °C and drain the aqueous wash. Charge 34.5 g of Si-Thiol functionalized silica gel and stir the suspension at 60 ± 3 °C for 1 h. Cool to 22 ± 3 °C and filter to remove the silica gel. Add 1 L of 1 N aqueous hydrochloric acid solution and stir for 15 minutes. Separate the phases and retain the aqueous phase which now contains product. Extract the organic phase again by adding 500 mL of 1N aqueous HCI solution and stirring for 15 minutes. Separate the phases and combine the aqueous extracts. Adjust the pH to 2.3 ± 0.2 by the addition of ~280 mL of 4N aqueous sodium hydroxide solution. Charge 17.2 g of Si-Thiol functionalized silica gel and stir the suspension at 50 ± 3 °C for 1 h. Cool to 22 ± 3 °C and filter to remove the silica gel. Adjust the pH to 5.0 ± 0.2 by the slow addition of ~75 mL of 4N aqueous sodium hydroxide solution maintaining a batch temperature of 15 ± 3 °C. Stir the slurry for at least 16 h at 22 ± 3 °C to allow the product to completely solidify. Filter the solids and wash the filter cake once with 250 g (250 mL) of water. Dry the solids (50 °C, 35 mbar) for 16 h to obtain 75 g (89% yield) of 5 as a tan solid. Following this procedure, Compound 5 is the hemihydrate polymorph form H_A of the Compound of Formula A.

Alternative procedure:

4,4′[6(4,4,5,5tetramethyl1 ,3,2 dioxaborolan2yl)pyrimidine2,4diyl]di[morpholine] 4, 6.75 g (0.0103 mol) of 1 ,1′-bis(di-fert-butylphosphino) ferrocene palladium dichloride and 556 g (625 mL) of tetrahydrofuran. Stir the slurry at 22 ± 3 °C. Add the aqueous cesium carbonate solution via the addition funnel to the slurry over 1-2 min. Stir rapidly (to ensure good mixing), heat to 45 ± 3 °C over 15 min and hold at this temperature for at least 30 minutes. Check for completeness of the reaction . Cool to 22 + 3 °C. Separate the phases. Partially concentrate the THF (25 C, 90 mbar) to a volume of 400 mL. Add 654 g (750 mL) of isopropyl acetate, resume the vacuum distillation and concentrate to a volume of 400 mL. Add 610 g (700 mL) of isopropyl acetate, stir and filter the hazy solution through a 25 g pad of Celite. Wash the reactor and filter cake with 87 g (100 mL) of isopropyl acetate and add the wash to the batch. Add 1 L of 0.125N aqueous N- acetyl-L-cysteine solution and stir at 60 ± 3 °C for 1 h. Cool to 22 + 3 °C C and drain the aqueous wash. Add 1 L of 0.25N aqueous N-acetyl-L-cysteine pH = 7 solution and stir at 60 + 3 °C for 1 h. Cool to 22 + 3 °C and drain the aqueous wash. Again, add 1 L of 0.25N aqueous N- acetyl-L-cysteine pH = 7 solution and stir at 60 + 3 °C for 1 h. Cool to 22 ± 3 °C and drain the aqueous wash. Charge 34.5 g of Si-Thiol functionalized silica gel and stir the suspension at 60 + 3 °C for 1 h. Cool to 22 ± 3 °C and filter to remove the silica gel. Add 1 L of N aqueous hydrochloric acid solution and stir for 15 minutes. Separate the phases and retain the aqueous phase which now contains product. Extract the organic phase again by adding 500 mL of 1N aqueous hydrochloric acid solution and stirring for 15 minutes. Separate the phases and combine the aqueous extracts. Adjust the pH to 2.3 + 0.2 by the addition of ~280 mL of 4N aqueous sodium hydroxide solution. Charge 17.2 g of Si-Thiol functionalized silica gel and stir the suspension at 50 ± 3 °C for 1 h. Cool to 22 ± 3 °C and filter to remove the silica gel. Adjust the pH to 5.0 ± 0.2 by the slow addition of ~75 mL of 4N aqueous sodium hydroxide solution maintaining a batch temperature of 15 ± 3 °C. Stir the slurry for at least 16 h at 22 ± 3 °C to allow the product to completely solidify. Filter the solids and wash the filter cake once with 250 g (250 mL) of water. Dry the solids (50 °C, 35 mbar) for 16 h to obtain 75 g (89% yield) of 5 as a tan solid. Following this procedure, Compound 5 is the hemihydrate polymorph form H_A of the Compound of Formula A.

…………..

WO-2014064058

Improved process for manufacturing 5-(2,6-di-4-morpholinyl-4-pyrimidinyl)-4-trifluoromethylpyridin-2-amine

Improved process for the preparation of buparlisib, an oral PI3K inhibitor Novartis is developing for the treatment of solid tumors, including breast cancer and hematological tumors. In January 2014, a phase III development was ongoing and Novartis expected to file for regulatory approval for breast cancer in 2015. Buparlisib was originally claimed in WO2007084786, protection for which expires in both the US and Europe in January 2027. Also see WO2012044727 for a more recent process case.

Burger, M.T.; Pecchi, S.; Wagman, A.; et al.
Discovery of BKM120, a pan class I PI3 kinase inhibitor in phase I/II clinical trials
240th ACS Natl Meet (August 22-26, Boston) 2010, Abst MEDI 489

Vu, A.T.; Morris, J.; Malhotra, S.V.
Efficient and improved synthesis of a PI3K inhibitor anticancer agent
241st ACS Natl Meet (March 27-30, Anaheim) 2011, Abst ORGN 115

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