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Nitisinone, ニチシノン

June 4, 2018 9:29 am / Leave a comment

ChemSpider 2D Image | Nitisinone | C14H10F3NO5

Nitisinone

ニチシノン

Orfadin

Launched – 2002, NTBC
SC-0735
SYN-118

2-(alpha,alpha,alpha-Trifluoro-2-nitro-p-tuluoyl)-1,3-cyclohexanedione

2-(2-Nitro-4-trifluoromethylbenzoyl)cyclohexane-1,3-dione

Priority, Orphan

Formula	C14H10F3NO5
CAS	104206-65-7
Mol weight	329.2281

1,3-Cyclohexanedione, 2-[2-nitro-4-(trifluoromethyl)benzoyl]-

104206-65-7 [RN]

2-(2-Nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione

Orfadin®|SC-0735

QB-0882

SC0735

UNII:K5BN214699

UNII-K5BN214699

Research Code：SC-0735

Trade Name：Orfadin^®

MOA：4-hydroxyphenylpyruvate dioxygenase inhibitor

Indication：Hereditary tyrosinemia

Company：Swedish Orphan Biovitrum AB (SOBI) (Originator)

Nitisinone is a synthetic reversible inhibitor of 4-hydroxyphenylpyruvate dioxygenase. It is used in the treatment of hereditary tyrosinemia type 1. It is sold under the brand name Orfadin.

Nitisinone was first approved by the U.S. Food and Drug Administration (FDA) on January 18, 2002, then approved by the European Medicines Agency (EMA) on February 21, 2005. It was developed and marketed as Orfadin^®bySwedish Orphan Biovitrum AB (SOBI) in the US .

The mechanism of action of nitisinone involves reversibile inhibition of 4-Hydroxyphenylpyruvate dioxygenase(HPPD). It is indicated for use as an adjunct to dietary restriction of tyrosine and phenylalanine in the treatment of hereditary tyrosinemia type 1 (HT-1).

Orfadin^® is available as capsule for oral use, containing 2, 5 or 10 mg of free Nitisinone. The recommended initial dose is 1 mg/kg/day divided into two daily doses. Maximum dose is 2 mg/kg/day.

Nitisinone was launched in 2002 by Swedish Orphan (now Swedish Orphan Biovitrum) in a capsule formulation as an adjunct to dietary restriction of tyrosine and phenylalanine in the treatment of hereditary tyrosinemia type I. In 2015, this product was launched in Japan for the same indication. The same year, an oral suspension formulation for pediatric patients was registered in the E.U., and launch took place in the United Kingdom shortly after. This formulation was approved in 2016 in the U.S. for the same indication. In 2016, nitisinone tablet formulation developed by Cycle Pharmaceuticals was approved in Canada (this formulation is also available also in the U.S.).

Indication

Used as an adjunct to dietary restriction of tyrosine and phenylalanine in the treatment of hereditary tyrosinemia type 1.

Associated Conditions

Hereditary tyrosinemia type-1

Image result for EU

http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/004281/WC500236080.pdf

Nitisinone MendeliKABS

22 June 2017 EMA/CHMP/502860/2017

Product name, strength, pharmaceutical form: Orfadin • Marketing authorisation holder: Swedish Orphan Biovitrum International AB • Date of authorisation: 21/02/2005

Procedure No. EMEA/H/C/004281/0000

During the meeting on 22 June 2017, the CHMP, in the light of the overall data submitted and the scientific discussion within the Committee, issued a positive opinion for granting a Marketing authorisation to Nitisinone MendeliKABS.

The chemical name of nitisinone is 2-[2-Nitro-4-(trifluoromethyl)benzoyl]-1,3-cyclohexanedione corresponding to the molecular formula C14H10F3NO5. It has a relative molecular mass of 329.23 g/mol and the following structure: Figure 1. Structure of nitisinone.

Nitisinone appears as off-white to yellowish non-hygroscopic fine crystalline powder. It is practically insoluble in unbuffered water. It is freely soluble in dichloromethane, sparingly soluble in ethyl alcohol, slightly soluble in isopropyl alcohol and 70% aqueous isopropyl alcohol and in pH 6.8 phosphate buffer, very slightly soluble in pH 4.5 acetate buffer and practically insoluble at pH 1.1. Solubility in acidified aqueous media depends on the acid counter ion. Solubility increases with increasing pH. Its pKa was found to be around 10. Nitisinone is achiral and does not show polymorphism.

ALSO

2005

http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Scientific_Discussion/human/000555/WC500049192.pdf

Nitisinone is a white to yellowish-white crystalline powder poorly soluble in water. The active substance is a weak acid and it is highly soluble in the pH range 4.5-7.2 in phosphate buffer solutions. Nitisinone has the chemical name 2-(2-nitro-4-trifluoromethylbenzoyl)-cyclohexane-1,3-dione. It does not show polymorphism.

US FDA

https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/206356Orig1s000ChemR.pdf

Company: Swedish Orphan Biovitrum AB
Application No.: 206356Orig1
Approval Date: April 22, 2016

Approval Letter(s) (PDF)
Printed Labeling (PDF)
Summary Review (PDF)
Officer/Employee List (PDF)
Cross Discipline Team Leader Review (PDF)
Chemistry Review(s) (PDF)
Pharmacology Review(s) (PDF)
Clinical Pharmacology Biopharmaceutics Review(s) (PDF)
Proprietary Name Review(s) (PDF)
Other Review(s) (PDF)
Administrative Document(s) & Correspondence (PDF)

Nitisinone (INN), also known as NTBC (an abbreviation of its full chemical name) is a medication used to slow the effects of hereditary tyrosinemia type 1. Since its first use for this indication in 1991, it has replaced liver transplantation as the first-line treatment for this rare condition. It is also being studied in the related condition alkaptonuria. It is marketed under the brand name Orfadin by the company Swedish Orphan Biovitrum (Sobi); it was first brought to market by Swedish Orphan International. It was originally developed as a candidate herbicide.

Uses

Nitisinone is used to treat hereditary tyrosinemia type 1, in combination with restriction of tyrosine in the diet.^[1]^[2]^[3]

Since its first use for this indication in 1991, it has replaced liver transplantation as the first-line treatment for this rare condition.^[4] I It is marketed under the brand name Orfadin.

It has been demonstrated that treatment with nitisinone can reduce urinary levels of homogentisic acid in alkaptonuria patients by 95%.^[5] A series of clinical trials run by DevelopAKUre to determine whether nitisinone is effective at treating the ochronosis suffered by patients with alkaptonuria are ongoing.^[6] If the trials are successful, DevelopAKUre will try to get nitisinone licensed for use by alkaptonuria patients.^[7]

Mechanism of action

The mechanism of action of nitisinone involves reversibile inhibition of 4-Hydroxyphenylpyruvate dioxygenase (HPPD).^[8]^[9] This is a treatment for patients with Tyrosinemia type 1 as it prevents the formation of maleylacetoacetic acid and fumarylacetoacetic acid, which have the potential to be converted to succinyl acetone, a toxin that damages the liver and kidneys.^[4] This causes the symptoms of Tyrosinemia type 1 experienced by untreated patients.^[10]

Alkaptonuria is caused when an enzyme called homogentisic dioxygenase (HGD) is faulty, leading to a buildup of homogenisate.^[11]Alkaptonuria patients treated with nitisinone produce far less HGA than those not treated (95% less in the urine),^[5] because nitisinone inhibits HPPD, resulting in less homogenisate accumulation. Clinical trials are ongoing to test whether nitisinone can prevent ochronosisexperienced by older alkaptonuria patients.^[6]

Adverse effects

Nitisinone has several negative side effects; these include but are not limited to: bloated abdomen, dark urine, abdominal pain, feeling of tiredness or weakness, headache, light-colored stools, loss of appetite, weight loss, vomiting, and yellow-colored eyes or skin.^[12]

Research

Nitisinone is being studied as a treatment for alkaptonuria.^[13]

Research at the National Institutes of Health (NIH) has demonstrated that nitisinone can reduce urinary levels of HGA by up to 95% in patients with alkaptonuria. The primary parameter of the NIH trial was range of hip motion, for which the results were inconclusive.^{[citation needed]}

Research done using alkaptonuric mice has shown that mice treated with nitisinone experience no ochronosis in knee joint cartilage. In contrast, all of the mice in the untreated control group developed ochronotic knee joints.^[14]

The efficacy of Nitisinone is now being studied in a series international clinical trials called DevelopAKUre.^[15] The studies will recruit alkaptonuria patients in Europe.^[16] A larger number of patients will be recruited in these trials than in the previous NIH trial.^[17] The trials are funded by the European Commission.^[18]

Nitisinone has been shown to increase skin and eye pigmentation in mice, and has been suggested as a possible treatment for oculocutaneous albinism.^[19]^[20]

History

Nitisinone was discovered as part of a program to develop a class of herbicides called HPPD inhibitors. It is a member of the benzoylcyclohexane-1,3-dione family of herbicides, which are chemically derived from a natural phytotoxin, leptospermone, obtained from the Australian bottlebrush plant (Callistemon citrinus).^[21] HPPD is essential in plants and animals for catabolism, or breaking apart, of tyrosine.^[22] In plants, preventing this process leads to destruction of chlorophyll and the death of the plant.^[22] In toxicology studies of the herbicide, it was discovered that it had activity against HPPD in rats^[23] and humans.^[24]

In Type I tyrosinemia, a different enzyme involved in the breakdown of tyrosine, fumarylacetoacetate hydrolase is mutated and doesn’t work, leading to very harmful products building up in the body.^[1] Fumarylacetoacetate hydrolase acts on tyrosine after HPPD does, so scientists working on making herbicides in the class of HPPD inhibitors hypothesized that inhibiting HPPD and controlling tyrosine in the diet could treat this disease. A series of small clinical trials attempted with one of their compounds, nitisinone, were conducted and were successful, leading to nitisinone being brought to market as an orphan drug Swedish Orphan International,^[8] which was later acquired by Swedish Orphan Biovitrum (Sobi).

Sobi is now a part of the DevelopAKUre consortium. They are responsible for drug supply and regulatory support in the ongoing clinical trials that will test the efficiacy of nitisinone as a treatment for alkaptonuria.^[25] It is hoped that if the trials are successful, nitisinone could also be licensed for treatment of alkaptonuria.^[7]

Generic versions

There is no generic version of Orfadin in G7 countries. Prior to the market authorization of MDK-Nitisinone in Canada, the only Nitisinone product available globally was Orfadin.^[26]Until recently, Nitisinone was not approved in Canada where it was distributed for over 20 years via a Health Canada Special Access Program. In September 2016, MendeliKABS was granted approval of a Priority New Drug Submission (PNDS) by Health Canada for a bioequivalent generic version of Orfadin capsules (MDK-Nitisinone). In November 2016 Cycle Pharma was also granted approval of a PNDS by Health Canada for Nitisinone tablets that are bioequivalent to Orfadin capsules.^[27] SOBI was granted approval of a PNDS in December 2016.^[28]

PAPER

¹H NMR, ¹³C NMR, and Computational DFT Studies of the Structure of 2-Acylcyclohexane-1,3-diones and Their Alkali Metal Salts in Solution

Przemysław Szczeciński *, Adam Gryff-Keller, and Sergey Molchanov

Faculty of Chemistry, Warsaw University of Technology, Noakowskiego 3, 00-664 Warszawa, Poland

J. Org. Chem., 2006, 71 (12), pp 4636–4641

DOI: 10.1021/jo060583g

¹H and ¹³C NMR spectra of 2-acyl-substituted cyclohexane-1,3-diones (acyl = formyl, 1; 2-nitrobenzoyl, 2; 2-nitro-4-trifluoromethylbenzoyl, 3) and lithium sodium and potassium salts of 1have been measured. The compound 3, known as NTBC, is a life-saving medicine applied in tyrosinemia type I. The optimum molecular structures of the investigated objects in solutions have been found using the DFT method with B3LYP functional and 6-31G** and/or 6-311G(2d,p) basis set. The theoretical values of the NMR parameters of the investigated compounds have been calculated using GIAO DFT B3LYP/6-311G(2d,p) method. The theoretical data obtained for compounds 1−3 have been exploited to interpret their experimental NMR spectra in terms of the equilibrium between different tautomers. It has been found that for these triketones an endo-tautomer prevails. The differences in NMR spectra of the salts of 1 can be rationalized taking into account the size of the cation and the degree of salt dissociation. It seems that in DMSO solution the lithium salt exists mainly as an ion pair stabilized by the chelation of a lithium cation with two oxygen atoms. The activation free energy the of formyl group rotation for this salt has been estimated to be 51.5 kJ/mol. The obtained results suggest that in all the investigated objects, including the free enolate ions, all atoms directly bonded to the carbonyl carbons lie near the same plane. Some observations concerning the chemical shift changes could indicate strong solvation of the anion of 1 by water molecules. Implications of the results obtained in this work for the inhibition mechanism of (4-hydroxyphenyl) pyruvate dioxygenase by NTBC are commented upon.

2-(2-Nitro-4-trifluoromethylbenzoyl)cyclohexane-1,3-dione (NTBC; 3). The compound was prepared in the same manner as 2. The synthesis of an appropriate benzoic acid derivative was started from the transformation of commercially available 2-nitro-4-trifluoromethylaniline into benzonitrile by the classical Sandmeyer method. Then the nitrile was hydrolyzed in 65% sulfuric acid to give 2-nitro-4-trifluoromethylbenzoic acid.¹³ The obtained triketone 3 had a mp of 140−142 °C (lit.¹⁴ 141−143 °C). For NMR data, see Supporting Information….. https://pubs.acs.org/doi/suppl/10.1021/jo060583g/suppl_file/jo060583gsi20060420_080852.pdf

NMR data for 2-(2-nitro-4-trifluoromethylbenzoyl)cyclohexane-1,3-dione, 3, in CDCl3

1 H NMR: 16.25 (s, 1H, OH), 8.47 (ddq, 1H, H10, J10,12=1.7 Hz, J10,13=0.4 Hz, J10,F=0.7 Hz), 7.94 (ddq, 1H, H12, J12,13=8.0 Hz, J12,F=0.7 Hz), 7.39 (ddq, 1H, H13, J13,F=0.8 Hz), 2.81 (t-like m, 2H, H4, H4’, JH4,H4’= -18.8 Hz, JH4,H5=5.4 Hz, JH4,H5’=7.3 Hz, JH4,H6=0.7 Hz, JH4,H6’= -0.8 Hz), 2.37 (tlike m, 2H, H6, H6’, JH6,H6’= -16.5 Hz, JH6,H5=4.6 Hz, JH6,H5’=8. 5 Hz), 2.04 (pentet-like m, 2H, H5, H5’, JH5,H5’= -13.6 Hz.

13C NMR: 196.3 (s, C(O)Ph), 195.8 (s, C3), 194.1 (s, C1), 145.5 (s, C9), 139.7 (s, C8), 132.0 (q, C11, J11,F=34.3 Hz), 130.8 (q, C12 J12,F=3.5 Hz), 127.7 (s, C13), 122.6 (q, CF3, JC,F=272.9 Hz), 121.1 (q, C10, J10,F=3.9 Hz), 112.7 (s, C2), 37.3 (s, C6) 31.6 (s, C4), 19.1 (s, C5).

PATENT

EP 186118

US 4780127

Nitisinone pk_prod_list.xml_prod_list_card_pr?p_tsearch=A&p_id=228471

The condensation of cyclohexane-1,3-dione (I) with 2-nitro-4-(trifluoromethyl)benzoyl chloride by means of TEA in dichloromethane gives the target Nitisinone.EP 0186118
JP 1986152642, US 4774360, US 4780127

Image result for nitisinone synthesis

Nitisinone

- Synonyms:NTBC, SC 0735
- ATC:A16AX04
Use:treatment of inherited tyrosinemia type I
Chemical name:2-[2-nitro-4-(trifluoromethyl)benzoyl]-1,3-cyclohexanedione
Formula:C₁₄H₁₀F₃NO₅

MW:329.23 g/mol
CAS-RN:104206-65-7

Synthesis Path

Substances Referenced in Synthesis Path

CAS-RN	Formula	Chemical Name	CAS Index Name
504-02-9	C₆H₈O₂	cyclohexane-1,3-dione	1,3-Cyclohexanedione
81108-81-8	C₈H₃ClF₃NO₃	2-nitro-4-trifluoromethylbenzoyl chloride

Trade Names

Country	Trade Name	Vendor	Annotation
D	Orfadin	Orphan Europe
USA	Orfadin	Swedish Orphan ,2002

Formulations

cps. 2 mg

References

- WO 9 300 080 (ICI; 7.1.1993; appl. 18.6.1992; GB-prior. 24.6.1991).
- US 4 774 360 (Stauffer Chemical; 27.9.1988; appl. 29.6.1987).

synergistic herbicidal combination:
- WO 9 105 469 (Hoechst AG; 2.5.1991; appl. 12.10.1990; D-prior. 18.10.1989).

preparation of benzoylcyclohexanedione herbicides:
- US 4 780 127 (Stauffer Chemical; 25.10.1988; appl. 30.6.1986; USA-prior. 25.3.1982).

certain 2-(2-nitrobenzoyl)-1,3-cyclohexanediones:
- EP 186 118 (Stauffer Chemical; 2.7.1986; appl. 18.12.1985; USA-prior. 20.12.1984).

stable herbicidal compositions:
- WO 9 727 748 (Zeneca; 7.8.1997; appl. 3.2.1997; USA-prior. 2.2.1996).

PATENT

US9783485B1

https://patents.google.com/patent/US9783485B1/en

NTBC is a drug marketed by Swedish Orphan Biovitrum International AB under the brand name Orfadin® and it is used to slow the effects of hereditary tyrosinemia type 1 (HT-1) in adult and pediatric patients. It has been approved by FDA and EMA in January 2002 and February 2005 respectively.

HT-1 disease is due to a deficiency of the final enzyme of the tyrosine catabolic pathway fumarylacetoacetate hydrolase. NTBC is a competitive inhibitor of 4-hydroxyphenylpyruvate dioxygenase (HPPD), an enzyme which precedes fumarylacetoacetate hydrolase. By inhibiting the normal catabolism of tyrosine in patients with HT-1, NTBC prevents the accumulation of the toxic intermediates maleylacetoacetate and fumarylacetoacetate, that in patients with HT-1 are converted to the toxic metabolites succinylacetone and succinylacetoacetate, the former inhibiting the porphyrin synthesis pathway leading to the accumulation of 5-aminolevulinate.

Usefulness of NTBC in the treatment of further diseases has also been documented. A non-comprehensive list is reported hereinafter.

Effectiveness of Orfadin® in the treatment of diseases where the products of the action of HPPD are involved (e.g., HT-1) has been described notably in EP0591275B1 corresponding to U.S. Pat. No. 5,550,165B1. Synthesis of NTBC is also described in this patent.

WO2011106655 reports a method for increasing tyrosine plasma concentrations in a subject suffering from oculocutaneous/ocular albinism, the method comprising administering to the subject a pharmaceutically acceptable composition comprising NTBC in the range of between about 0.1 mg/kg/day to about 10 mg/kg/day.

U.S. Pat. No. 8,354,451B2 reports new methods of combating microbial infections due to fungi or bacteria by means of administration to a subject of a therapeutically active amount of NTBC.

WO2010054273 discloses NTBC-containing compositions and methods for the treatment and/or prevention of restless leg syndrome (RLS).

EP1853241B1 claims the use of NTBC in the treatment of a neurodegenerative disease, notably Parkinson disease.

Introne W. J., et al., disclosed usefulness of nitisinone in the treatment of alkaptonuria (Introne W. J., et al., Molec. Genet. Metab., 2011, 103, 4, 307). The key step of the synthesis reported in EP0591275B1 (now propriety of Swedish Orphan Biovitrum International AB, SE), involves the reaction of 2-nitro-4-trifluromethylbenzoyl chloride and cyclohexane-1,3-dione in the presence of triethylamine and then use of acetone cyanohydrin in order to promote the rearrangement of the key intermediate enol ester. After washing and extraction from CH₂Cl₂, the crude product is recrystallized from ethyl acetate to get the desired 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione as a solid having a melting point of 88-94° C.

Another patent (U.S. Pat. No. 4,695,673) filed in name of Stauffer Chemical Company disclosed a process of synthesis of acylated 1,3-dicarbonyl compounds in which the intermediate enol ester is isolated prior to its rearrangement into the final product, said rearrangement making use of a cyanohydrin compound derived from alkali metal, methyl alkyl ketone, benzaldehyde, cyclohexanone, C₂-C₅aliphatic aldehyde, lower alkyl silyl or directly by using hydrogen cyanide.

Yet another patent (U.S. Pat. No. 5,006,158) filed in name of ICI Americas Inc. disclosed a process similar to the one disclosed in U.S. Pat. No. 4,695,673 wherein the intermediate enol ester was isolated prior to its rearrangement into the final product by use of potassium cyanide. Said reaction can optionally be done by concomitant use of a phase transfer catalyst such as Crown ethers. The preferred solvent for conducting such a reaction is 1,2-dichloroethane.

Still a further patent (EP0805791) filed in name of Zeneca Ltd disclosed an alternative synthesis of nitisinone involving the reaction of 1,3-cyclohexanedione and variously substituted benzoyl chloride in the presence of sodium or potassium carbonate in CH₃CN or DMF. Best yields were obtained using CH₃CN as solvent and sodium carbonate as the base. Reaction was performed at 55-57° C. in 17 hours.

It is well known that one of the problems of the actual drug formulation (i.e., Orfadin® capsules) is its chemical instability. Indeed, even if Orfadin® has to be stored in a refrigerator at a temperature ranging from 2° C. to 8° C., its shelf life is of only 18 months. After first opening, the in-use stability is a single period of 2 months at a temperature not above 25° C., after which it must be discarded. It will be evident that such storage conditions have an impact in the distribution chain of the medicine, in terms of costs and also in terms of logistics for the patient. Therefore, there is an urgent need of more stable formulations, both from a logistic supply chain point of view, and from the patient compliance point of view. Since the formulation of Orfadin® contains only the active ingredient and starch as excipient, relative instability may be attributed to the active pharmaceutical ingredient itself; in other words it can derive from the way it is synthesized and/or the way it is extracted from the reaction mixture, and/or the way it is finally crystallized. Furthermore, some impurities may contribute to render the final product less stable overtime. Consequently, it is of major importance to identify a process of synthesis and/or a crystallization method that enable the reliable production of a highly pure and stable product.

Impurities as herein-above mentioned can derive either from the final product itself (through chemical degradation) or directly from the starting materials/solvents used in the process of synthesis. Regarding the latter option, it is therefore primordial to ascertain that at each step, impurities are completely removed in order not to get them at the final stage, also considering that some of them could potentially be cyto/genotoxic.

The impurities correlated to nitisinone can be either derived from the starting materials themselves (i.e., impurities 1 and 2) or obtained as side products during the process of synthesis and/or under storage conditions (i.e., impurities 3 to 5) and are the following:

- 2-nitro-4-(trifluoromethyl) benzoic acid (Impurity no 1),
- 1,3-cyclohexanedione (CHD) (Impurity no 2),
- 4-(trifluoromethyl)salicylic acid (Impurity no 3),
- 2-[3-nitro-4-(trifluoromethyl)benzoyl]-1,3-cyclohexanedione (Impurity no 4), and
- 6-trifluoromethyl-3,4-dihydro-2H-xanthene-1,9-dione (Impurity no 5).

Impurity-2, impurity-3, and impurity-5 have been previously reported in WO2015101794. Strangely, impurity-4 has never been reported, even if it is an obvious side-product which can easily be formed during the coupling reaction between 1,3-cyclohexanedione and 2-nitro-4-(trifluoromethyl) benzoic acid, the latter being not 100% pure but containing some amount of regioisomer 3-nitro-4-(trifluoromethyl) benzoic acid.

Potential genotoxicity of impurity no 4 which possesses an aromatic nitro moiety was assessed using in-silico techniques and resulted to be a potential genotoxic impurity. According to the FDA ICH M7 guidelines, daily intake of a mutagenic impurity (Threshold of Toxicological Concern, TTC) in an amount not greater than 1.5 μg per person is considered to be associated with a negligible risk to develop cancer over a lifetime of exposure. Consequently, assuming a daily dose of 2 mg/kg, for a person weighing 70 kg, the maximum tolerated impurity content of such a compound would be of about 11 ppm, as calculated according to the equation underneath.

concentration ⁢ ⁢ limit ⁢ ⁢ ( ppm ) = T ⁢ ⁢ T ⁢ ⁢ C ⁡ ( µg / day ) Dose ⁡ ( g / day )

It is therefore of paramount importance to ensure that the process of synthesis of nitisinone and the purification steps of the same give rise to an API devoid of such impurity no 4, or at least far below the threshold of 11 ppm as indicated above. The skilled person will understand that total absence of said impurity is highly desirable.

It is well known in the pharmaceutical field that investigation of potential polymorphism of a solid API is of crucial importance and is also recommended by major regulatory authorities such as FDA.

Notwithstanding the fact that nitisinone has been used for years to treat HT-1 patients, it appears that no NTBC formulation fully satisfies the requisites of stability and/or compliance standard for the patients. Therefore, there is an unmet medical need of long-term pure and stable formulations.

Example 1

Thionyl chloride (162 g, 1.36 mol) was added dropwise into a suspension of 2-nitro-4-trifluoromethylbenzoic acid (228 g, 0.97 mol) in toluene (630 g) at 80° C. The thus obtained solution was kept under stirring at 80° C. for 20 hours, and then cooled to 50° C. The volatiles were removed under reduced pressure in order to get the expected 2-nitro-4-trifluoromethylbenzoyl chloride as an oil. The latter, cooled to 25° C. was added dropwise to a suspension of 1,3-cyclohexanedione (109 g, 0.97 mol) and potassium carbonate (323 g, 2.33 mol) in CH₃CN (607 g). After 18 h the mixture was diluted with water (500 ml) and slowly acidified to about pH=1 with HCl 37%. The mixture was then warmed to about 55° C. and the phases were separated. The organic layer was washed with a 10% aqueous solution of sodium chloride and then, concentrated under reduced pressure at a temperature below 55° C. to reach a volume of 380 ml. The thus obtained mixture was stirred at 55° C. for 1 h and then cooled to 0° C. in 16 to 18 h. The resulting solid was filtered and rinsed several times with pre-cooled (0° C.) toluene. The wet solid was dried at 60° C. under vacuum for 6 h to provide nitisinone (164 g) as a white to yellowish solid with a purity of 98.4% as measured by HPLC and a content of potentially genotoxic impurity no 4 of 6.1 ppm measured by HPLC/MS.

Example 2

Nitisinone as obtained from example 1 (164 g) was added to a 3/1 (w/w) mixture of CH₃CN/toluene (volume of solvent: 638 ml). The mixture was warmed gently to about 55° C. under stirring until solids were completely dissolved. The solution was then concentrated under reduced pressure maintaining the internal temperature below 50° C. to reach a volume of 290 ml. Then, more toluene (255 g) was added and the solution was concentrated again under reduced pressure until the residual volume reached 290 ml. The solution was heated to about 55° C. for 1 h and successively cooled slowly in 10 to 12 h to 10° C. The resulting solid was filtered and rinsed several times with pre-cooled (0° C.) toluene. The wet solid was dried at about 60° C. under vacuum for 4 h to provide nitisinone (136 g) as a white to yellowish solid, with a purity of 99.94% and a 99.8% assay measured by HPLC and a d(90) particle size between 310 and 350 μm. The content of potential genotoxic impurity no 4 resulted below 1 ppm.

CLIP

Nitisinone – WikiVisually

WikiVisually

4-Hydroxyphenylpyruvate dioxygenase – Proposed Reaction Mechanism of HPPD

References

^ Jump up to:^a ^b National Organization for Rare Disorders. Physician’s Guide to Tyrosinemia Type 1 Archived 2014-02-11 at the Wayback Machine.
Jump up^ “Nitisinone (Oral Route) Description and Brand Names”. Mayoclinic.com. 2015-04-01. Retrieved 2015-06-04.
Jump up^ Sobi Orfadin® (nitisinone)
^ Jump up to:^a ^b McKiernan, Patrick J (2006). “Nitisinone in the Treatment of Hereditary Tyrosinaemia Type 1”. Drugs. 66 (6): 743–50. doi:10.2165/00003495-200666060-00002. PMID 16706549.
^ Jump up to:^a ^b Introne, Wendy J.; Perry, Monique B.; Troendle, James; Tsilou, Ekaterini; Kayser, Michael A.; Suwannarat, Pim; O’Brien, Kevin E.; Bryant, Joy; Sachdev, Vandana; Reynolds, James C.; Moylan, Elizabeth; Bernardini, Isa; Gahl, William A. (2011). “A 3-year randomized therapeutic trial of nitisinone in alkaptonuria”. Molecular Genetics and Metabolism. 103(4): 307–14. doi:10.1016/j.ymgme.2011.04.016. PMC 3148330 . PMID 21620748.
^ Jump up to:^a ^b “About DevelopAKUre | DevelopAKUre”. Developakure.eu. 2014-06-20. Archived from the original on 2015-05-12. Retrieved 2015-06-04.
^ Jump up to:^a ^b “A Potential Drug – Nitisinone”. Akusociety.org. Archived from the original on 2015-05-05. Retrieved 2015-06-04.
^ Jump up to:^a ^b Lock, E. A.; Ellis, M. K.; Gaskin, P.; Robinson, M.; Auton, T. R.; Provan, W. M.; Smith, L. L.; Prisbylla, M. P.; Mutter, L. C.; Lee, D. L. (1998). “From toxicological problem to therapeutic use: The discovery of the mode of action of 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC), its toxicology and development as a drug”. Journal of Inherited Metabolic Disease. 21 (5): 498–506. doi:10.1023/A:1005458703363. PMID 9728330.
Jump up^ Kavana, Michael; Moran, Graham R. (2003). “Interaction of (4-Hydroxyphenyl)pyruvate Dioxygenase with the Specific Inhibitor 2-[2-Nitro-4-(trifluoromethyl)benzoyl]-1,3-cyclohexanedione†”. Biochemistry. 42 (34): 10238–45. doi:10.1021/bi034658b. PMID 12939152.
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Jump up^ “Nitisinone (Oral Route) Side Effects”. Mayoclinic.com. 2015-04-01. Retrieved 2015-06-04.
Jump up^ Phornphutkul, Chanika; Introne, Wendy J.; Perry, Monique B.; Bernardini, Isa; Murphey, Mark D.; Fitzpatrick, Diana L.; Anderson, Paul D.; Huizing, Marjan; Anikster, Yair; Gerber, Lynn H.; Gahl, William A. (2002). “Natural History of Alkaptonuria”. New England Journal of Medicine. 347 (26): 2111–21. doi:10.1056/NEJMoa021736. PMID 12501223.
Jump up^ Preston, A. J.; Keenan, C. M.; Sutherland, H.; Wilson, P. J.; Wlodarski, B.; Taylor, A. M.; Williams, D. P.; Ranganath, L. R.; Gallagher, J. A.; Jarvis, J. C. (2013). “Ochronotic osteoarthropathy in a mouse model of alkaptonuria, and its inhibition by nitisinone”. Annals of the Rheumatic Diseases. 73 (1): 284–9. doi:10.1136/annrheumdis-2012-202878. PMID 23511227.
Jump up^ “DevelopAKUre”. Developakure.eu. 2014-06-20. Retrieved 2015-06-04.
Jump up^ “2012-005340-24”. Clinicaltrialsregister.eu. Retrieved 2015-06-04.
Jump up^ “The Programme | DevelopAKUre”. Developakure.eu. 2014-06-20. Archived from the original on 2015-05-12. Retrieved 2015-06-04.
Jump up^ “European Commission : CORDIS : Search : Simple”. Cordis.europa.eu. 2012-05-30. Retrieved 2015-06-04.
Jump up^ Onojafe, Ighovie F.; Adams, David R.; Simeonov, Dimitre R.; Zhang, Jun; Chan, Chi-Chao; Bernardini, Isa M.; Sergeev, Yuri V.; Dolinska, Monika B.; Alur, Ramakrishna P.; Brilliant, Murray H.; Gahl, William A.; Brooks, Brian P. (2011). “Nitisinone improves eye and skin pigmentation defects in a mouse model of oculocutaneous albinism”. Journal of Clinical Investigation. 121 (10): 3914–23. doi:10.1172/JCI59372. PMC 3223618 . PMID 21968110. Lay summary – ScienceDaily (September 26, 2011).
Jump up^ “Nitisinone for Type 1B Oculocutaneous Albinism – Full Text View”. ClinicalTrials.gov. Retrieved 2015-06-04.
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^ Jump up to:^a ^b Moran, Graham R. (2005). “4-Hydroxyphenylpyruvate dioxygenase”. Archives of Biochemistry and Biophysics. 433 (1): 117–28. doi:10.1016/j.abb.2004.08.015. PMID 15581571.
Jump up^ Ellis, M.K.; Whitfield, A.C.; Gowans, L.A.; Auton, T.R.; Provan, W.M.; Lock, E.A.; Smith, L.L. (1995). “Inhibition of 4-Hydroxyphenylpyruvate Dioxygenase by 2-(2-Nitro-4-trifluoromethylbenzoyl)-cyclohexane-1,3-dione and 2-(2-Chloro-4-methanesulfonylbenzoyl)-cyclohexane-1,3-dione”. Toxicology and Applied Pharmacology. 133 (1): 12–9. doi:10.1006/taap.1995.1121. PMID 7597701.
Jump up^ Lindstedt, Sven; Odelhög, Birgit (1987). “4-Hydroxyphenylpyruvate dioxygenase from human liver”. In Kaufman, Seymour. Metabolism of Aromatic Amino Acids and Amines. Methods in Enzymology. 142. pp. 139–42. doi:10.1016/S0076-6879(87)42021-1. ISBN 978-0-12-182042-8. PMID 3037254.
Jump up^ “Others | DevelopAKUre”. Developakure.eu. 2014-06-20. Retrieved 2015-06-04.
Jump up^ Pr MDK-Nitisinone Summary Basis of Decisions, Health Canada 2016. http://www.hc-sc.gc.ca/dhp-mps/prodpharma/sbd-smd/drug-med/sbd-smd-2016-mdk-nitisinone-190564-eng.php
Jump up^ Pr Nitisinone Tablets Regulatory Decision Summary Health Canada, 2016. http://www.hc-sc.gc.ca/dhp-mps/prodpharma/rds-sdr/drug-med/rds-sdr-nitisinone-tab-193770-eng.php
Jump up^ PrOrfadin Regulatory Decision Summary Health Canada, 2016. http://www.hc-sc.gc.ca/dhp-mps/prodpharma/rds-sdr/drug-med/rds-sdr-orfadin-193226-eng.php

External links

DevelopAKUre

Nitisinone
Clinical data

AHFS/Drugs.com	Consumer Drug Information
License data	EU EMA: by INN US FDA: Nitisinone
Routes of administration	Oral
ATC code	A16AX04 (WHO)
Legal status
Legal status	US: ℞-only
Pharmacokinetic data
Elimination half-life	Approximately 54 h
Identifiers
IUPAC name [show]
CAS Number	104206-65-7
PubChem CID	115355
IUPHAR/BPS	6834
DrugBank	DB00348
ChemSpider	103195
UNII	K5BN214699
KEGG	D05177
ChEBI	CHEBI:50378
ChEMBL	CHEMBL1337
ECHA InfoCard	100.218.521
Chemical and physical data
Formula	C₁₄H₁₀F₃NO₅
Molar mass	329.228 g/mol
3D model (JSmol)	Interactive image

Title: Nitisinone

CAS Registry Number: 104206-65-7

CAS Name: 2-[2-Nitro-4-(trifluoromethyl)benzoyl]-1,3-cyclohexanedione

Additional Names: NTBC

Trademarks: Orfadin (Swedish Orphan )

Molecular Formula: C14H10F3NO5

Molecular Weight: 329.23

Percent Composition: C 51.07%, H 3.06%, F 17.31%, N 4.25%, O 24.30%

Literature References: Herbicidal triketone that inhibits 4-hydroxyphenylpyruvate dioxygenase (HPPD), an enzyme involved in plastoquinone biosynthesis in plants and in tyrosine catabolism in mammals. Prepn: C. G. Carter, EP 186118 (1986 to Stauffer); idem, US 5006158 (1991 to ICI). Inhibition of HPPD in plants: M. P. Prisbylla et al., Brighton Crop Prot. Conf. – Weeds 1993, 731; in rats: M. K. Ellis et al., Toxicol. Appl. Pharmacol. 133, 12 (1995). LC determn in plasma: M. Bielenstein et al., J. Chromatogr. B 730,177 (1999). Clinical evaluation in hereditary tyrosinemia type I: S. Lindstedt et al., Lancet 340, 813 (1992). Review of toxicology and therapeutic development: E. A. Lock et al, J. Inherited Metab. Dis. 21, 498-506 (1998); of clinical experience: E. Holme, S. Lindstedt, ibid. 507-517.

Properties: Solid, mp 88-94°.

Melting point: mp 88-94°

Therap-Cat: In treatment of inherited tyrosinemia type I.

////////////////Nitisinone, ニチシノン , Orfadin, FDA 2002, NTBC , SC-0735 , SYN-118 , JAPAN 2015, JAP 2015, EU 2005, Priority, Orphan

[O-][N+](=O)C1=C(C=CC(=C1)C(F)(F)F)C(=O)C1C(=O)CCCC1=O

FDA approves new uses for two drugs Tafinlar (dabrafenib) and Mekinist (trametinib) administered together for the treatment of BRAF-positive anaplastic thyroid cancer

May 6, 2018 10:24 am / Leave a comment

Image result for Novartis Pharmaceuticals Corporation.

FDA approves new uses for two drugs Tafinlar (dabrafenib) and Mekinist (trametinib) administered together for the treatment of BRAF-positive anaplastic thyroid cancer

The U.S. Food and Drug Administration approved Tafinlar (dabrafenib) and Mekinist (trametinib), administered together, for the treatment of anaplastic thyroid cancer (ATC) that cannot be removed by surgery or has spread to other parts of the body (metastatic), and has a type of abnormal gene, BRAF V600E (BRAF V600E mutation-positive). Continue reading.

May 4, 2018

Release

“This is the first FDA-approved treatment for patients with this aggressive form of thyroid cancer, and the third cancer with this specific gene mutation that this drug combination has been approved to treat,” said Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “This approval demonstrates that targeting the same molecular pathway in diverse diseases is an effective way to expedite the development of treatments that may help more patients.”

Thyroid cancer is a disease in which cancer cells form in the tissues of the thyroid gland. Anaplastic thyroid cancer is a rare, aggressive type of thyroid cancer. The National Institutes of Health estimates there will be 53,990 new cases of thyroid cancer and an estimated 2,060 deaths from the disease in the United States in 2018. Anaplastic thyroid cancer accounts for about 1 to 2 percent of all thyroid cancers.

Both Tafinlar and Mekinist are also approved for use, alone or in combination, to treat BRAF V600 mutation-positive metastatic melanoma. Additionally, Tafinlar and Mekinist are approved for use, in combination, to treat BRAF V600E mutation-positive, metastatic non-small cell lung cancer.

The efficacy of Tafinlar and Mekinist in treating ATC was shown in an open-label clinical trial of patients with rare cancers with the BRAF V600E mutation. Data from trials in BRAF V600E mutation-positive, metastatic melanoma or lung cancer and results in other BRAF V600E mutation-positive rare cancers provided confidence in the results seen in patients with ATC. The trial measured the percent of patients with a complete or partial reduction in tumor size (overall response rate). Of 23 evaluable patients, 57 percent experienced a partial response and 4 percent experienced a complete response; in nine (64 percent) of the 14 patients with responses, there were no significant tumor growths for six months or longer.

The side effects of Tafinlar and Mekinist in patients with ATC are consistent with those seen in other cancers when the two drugs are used together. Common side effects include fever (pyrexia), rash, chills, headache, joint pain (arthralgia), cough, fatigue, nausea, vomiting, diarrhea, myalgia (muscle pain), dry skin, decreased appetite, edema, hemorrhage, high blood pressure (hypertension) and difficulty breathing (dyspnea).

Severe side effects of Tafinlar include the development of new cancers, growth of tumors in patients with BRAF wild-type tumors, serious bleeding problems, heart problems, severe eye problems, fever that may be severe, serious skin reactions, high blood sugar or worsening diabetes, and serious anemia.

Severe side effects of Mekinist include the development of new cancers; serious bleeding problems; inflammation of intestines and perforation of the intestines; blood clots in the arms, legs or lungs; heart problems; severe eye problems; lung or breathing problems; fever that may be severe; serious skin reactions; and high blood sugar or worsening diabetes.

Both Tafinlar and Mekinist can cause harm to a developing fetus; women should be advised of the potential risk to the fetus and to use effective contraception.

The FDA granted Priority Review and Breakthrough Therapy designation for this indication. Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases, was also granted for this indication.

The FDA granted this approval to Novartis Pharmaceuticals Corporation.

///////////////Tafinlar, dabrafenib, Mekinist, trametinib, fda 2018, Priority Review, Breakthrough Therapy designation, Orphan Drug designation, Novartis Pharmaceuticals Corporation,

ビガバトリン , Vigabatrin

April 25, 2018 1:15 pm / Leave a comment

Vigabatrin

CAS: 60643-86-9

Molecular FormulaC₆H₁₁NO₂
Average mass129.157 Da

Infantile spasms, Anticonvulsant, Antiepileptic

orphan drug designation

γ Vinyl GABA

γ Vinyl γ Aminobutyric Acid, 4-Amino-5-hexenoic acid; γ vinyl GABA; γ-Vinyl GABA; γ-Vinyl-γ-aminobutyric acid; Vigabatrin; Vigabatrina; Vigabatrine; Vigabatrinum; Vinyl γ-aminobutyric acid, (±)-g-Vinyl GABA

CPP-109
GVG
M071754
MDL-71754
ORP-001
RMI-71754
RMI-71890 ((+)-enantiomer)

An analogue of gamma-aminobutyric acid, vigabatrin is an irreversible inhibitor of 4-aminobutyrate transaminase, the enzyme responsible for the catabolism of gamma-aminobutyric acid. (From Martindale The Extra Pharmacopoeia, 31st ed). Off-label uses include treatment of cocaine dependence.

Vigabatrin is an anticonvulsant that was originally launched by Sanofi (formerly known as sanofi-aventis) in 1989 in for the oral treatment of epilepsy not satisfactorily controlled by another anti-epileptic drug, and as monotherapy for infantile spasms (West Syndrome). In 2009, the product was launched in the U.S. for these indications. In 2016, the product was approved and launched for the treatment of infantile spasms in Japan. Orphelia Pharma has submitted a marketing Authorization Application (MAA) for a pediatric formulation of the product in the E.U.

Vigabatrin, brand name Sabril, is an antiepileptic drug that inhibits the breakdown of γ-aminobutyric acid (GABA) by acting as a suicide inhibitor of the enzyme GABA transaminase (GABA-T). It is also known as γ-vinyl-GABA, and is a structural analogue of GABA, but does not bind to GABA receptors.^[1]

Medical uses

Epilepsy

In Canada, vigabatrin is approved for use as an adjunctive treatment (with other drugs) in treatment resistant epilepsy, complex partial seizures, secondary generalized seizures, and for monotherapy use in infantile spasms in West syndrome.^[1]

As of 2003, vigabatrin is approved in Mexico for the treatment of epilepsy that is not satisfactorily controlled by conventional therapy (adjunctive or monotherapy) or in recently diagnosed patients who have not tried other agents (monotherapy).^[2]

Vigabatrin is also indicated for monotherapy use in secondarily generalized tonic-clonic seizures, partial seizures, and in infantile spasms due to West syndrome.^[2]

On August 21, 2009, Lundbeck announced that the U.S. Food and Drug Administration had granted two New Drug Application approvals for vigabatrin. The drug is indicated as monotherapy for pediatric patients one month to two years of age with infantile spasms for whom the potential benefits outweigh the potential risk of vision loss, and as adjunctive (add-on) therapy for adult patients with refractory complex partial seizures (CPS) who have inadequately responded to several alternative treatments and for whom the potential benefits outweigh the risk of vision loss.

In 1994, Feucht and Brantner-Inthaler reported that vigabatrin reduced seizures by 50-100% in 85% of children with Lennox-Gastaut syndrome who had poor results with sodium valproate.^[3]

Others

Vigabatrin reduced cholecystokinin tetrapeptide-induced symptoms of panic disorder, in addition to elevated cortisol and ACTH levels, in healthy volunteers.^[4]

Vigabatrin is also used to treat seizures in succinic semialdehyde dehydrogenase deficiency (SSADHD), which is an inborn GABA metabolism defect that causes intellectual disability, hypotonia, seizures, speech disturbance, and ataxia through the accumulation of γ-Hydroxybutyric acid (GHB). Vigabatrin helps lower GHB levels through GABA transaminase inhibition. However, this is in the brain only; it has no effect on peripheral GABA transaminase, so the GHB keeps building up and eventually reaches the brain.^[5]

Adverse effects

Central nervous system

Sleepiness (12.5%), headache (3.8%), dizziness (3.8%), nervousness (2.7%), depression (2.5%), memory disturbances (2.3%), diplopia (2.2%), aggression (2.0%), ataxia (1.9%), vertigo (1.9%), hyperactivity (1.8%), vision loss (1.6%) (See below), confusion(1.4%), insomnia (1.3%), impaired concentration (1.2%), personality issues (1.1%).^[1] Out of 299 children, 33 (11%) became hyperactive.^[1]

Some patients develop psychosis during the course of vigabatrin therapy,^[6] which is more common in adults than in children.^[7] This can happen even in patients with no prior history of psychosis.^[8] Other rare CNS side effects include anxiety, emotional lability, irritability, tremor, abnormal gait, and speech disorder.^[1]

Gastrointestinal

Abdominal pain (1.6%), constipation (1.4%), vomiting (1.4%), and nausea (1.4%). Dyspepsia and increased appetite occurred in less than 1% of subjects in clinical trials.^[1]

Body as a whole

Fatigue (9.2%), weight gain (5.0%), asthenia (1.1%).^[1]

Teratogenicity

A teratology study conducted in rabbits found that a dose of 150 mg/kg/day caused cleft palate in 2% of pups and a dose of 200 mg/kg/day caused it in 9%.^[1] This may be due to a decrease in methionine levels, according to a study published in March 2001.^[9] In 2005, a study conducted at the University of Catania was published stating that rats whose mothers had consumed 250–1000 mg/kg/day had poorer performance in the water maze and open-field tasks, rats in the 750-mg group were underweight at birth and did not catch up to the control group, and rats in the 1000 mg group did not survive pregnancy.^[10]

There is no controlled teratology data in humans to date.

Sensory

In 2003, vigabatrin was shown by Frisén and Malmgren to cause irreversible diffuse atrophy of the retinal nerve fiber layer in a retrospective study of 25 patients.^[11] This has the most effect on the outer area (as opposed to the macular, or central area) of the retina.^[12] Visual field defects had been reported as early as 1997 by Tom Eke and others, in the UK. Some authors, including Comaish et al. believe that visual field loss and electrophysiological changes may be demonstrable in up to 50% of Vigabatrin users.

The retinal toxicity of vigabatrin can be attributed to a taurine depletion.^[13]

Interactions

A study published in 2002 found that vigabatrin causes a statistically significant increase in plasma clearance of carbamazepine.^[14]

In 1984, Drs Rimmer and Richens at the University of Wales reported that administering vigabatrin with phenytoin lowered the serum phenytoin concentration in patients with treatment-resistant epilepsy.^[15] Five years later, the same two scientists reported a fall in concentration of phenytoin of 23% within five weeks in a paper describing their failed attempt at elucidating the mechanism behind this interaction.^[16]

Pharmacology

Vigabatrin is an irreversible mechanism-based inhibitor of gamma-aminobutyric acid aminotransferase (GABA-AT), the enzyme responsible for the catabolism of GABA, which increases the level of GABA in the brain.^[1]^[17] Vigabatrin is a racemic compound, and its [S]-enantiomer is pharmacologically active.^[18]^,^[19]

Crystal Structure (pdb:1OHW) showing vigabatrin binding to specific residues in the active site of GABA-AT, based off experiments by Storici et al.^[20]

Pharmacokinetics

With most drugs, elimination half-life is a useful predictor of dosing schedules and the time needed to reach steady state concentrations. In the case of vigabatrin, however, it has been found that the half-life of biologic activity is far longer than the elimination half-life.^[21]

For vigabatrin, there is no range of target concentrations because researchers found no difference between the serum concentration levels of responders and those of non-responders.^[22] Instead, the duration of action is believed to be more a function of the GABA-T resynthesis rate; levels of GABA-T do not usually return to their normal state until six days after stopping the medication.^[19]

History

Vigabatrin was developed in the 1980s with the specific goal of increasing GABA concentrations in the brain in order to stop an epileptic seizure. To do this, the drug was designed to irreversibly inhibit the GABA transaminase, which degrades the GABA substrate. Although the drug was approved for treatment in the United Kingdom in 1989, the authorized use of Vigabatrin by US Food and Drug Administration was delayed twice in the United States before 2009. It was delayed in 1983 because animal trials produced intramyelinic edema, however, the effects were not apparent in human trials so the drug design continued. In 1997, the trials were temporarily suspended because it was linked to peripheral visual field defects in humans.^[23]

Society and culture

Brand Names

Vigabatrin is sold as Sabril in Canada,^[24] Mexico,^[2] and the United Kingdom.^[25] The brand name in Denmark is Sabrilex. Sabril was approved in the United States on August 21, 2009 and is currently marketed in the U.S. by Lundbeck Inc., which acquired Ovation Pharmaceuticals, the U.S. sponsor in March 2009.

Synthesis

http://www.drugfuture.com/synth/syndata.aspx?ID=90252

This compound can be prepared in two different ways: 1) The reaction of 1,4-dichloro-2-butene (I) with diethyl malonate (II) by means of sodium ethoxide in refluxing ethanol gives 1,1-bis(ethoxycarbonyl)-2-vinylcyclopropane (III), which by reaction with ammonia gas in DMF at 120 C is converted into 3-carboxamido-5-vinyl-2-pyrrolidone (IV). Finally, this compound is treated with concentrated HCl in refluxing acetic acid. 2) The treatment of (IV) with sodium ethoxide in refluxing ethanol gives 3-carboxy-5-vinyl-2-pyrrolidone (V), which is decarboxylated by treatment with refluxing acetic acid to afford 5-vinyl-2-pyrrolidone (VI). The bromination of (VI) with Br2 in CCl4 yields 5-(1,2-dibromoethyl)-2-pyrrolidone (VII), which by treatment with Na in liquid NH3 in a pressure vessel at 25 C is converted into 4-aminohex-5-inoic acid (VIII). Finally, this compound is partially reduced with H2 over a suitable catalyst.

The synthesis of [14C]-labeled vigabatrin has been described: The reduction by known methods of pyroglutamic acid (I) to the alcohol (II) and its acylation with p-toluenesulfonyl chloride gives 5-(tosyloxymethyl)pyrrolidin-2-one (III), which by reaction with [14C]-labeled sodium cyanide in hot DMF yields 5-([14C]-cyanomethyl)pyrrolidin-2-one (IV). The reduction of (VI) with H2 over Pd/Al2O3 and treatment with dimethylamine affords 5-[2-(dimethylamino)ethyl]pyrrolidin-2-one (VI), which is oxidized with H2O2 in water to the N-oxide (VI). The treatment of (VI) with K2CO3 in refluxing xylene affords 5-([14C]-vinyl)pyrrolidin-2-one (VII), which is finally submitted to ring opening with hot 5 M aqueous HCl, followed by neutralization with triethylamine.

An efficient new synthesis for [14C]-labeled vigabatrin has been described: The reaction of triphenylphosphine (I) with [14C]-labeled methyl iodide (II) in benzene gives the corresponding phosphonium salt (III), which is submitted to a Wittig condensation with 1-(1-butenyl)-5-oxopiperidin-2-carbaldehyde (IV) to afford the vinylpyrrolidone (V). Finally, this compound is hydrolyzed with 6N HCl at 95 C.

The enantiocontrolled addition of phthalimide (I) to 1,3-butadiene monoepoxide (II) with a chiral palladium catalyst and Na2CO3 in dichloromethane gives N-(2-hydroxy-1(S)-vinylethyl)phthalimide (III), which is treated with triflic anhydride and TEA in dichloromethane to yield the triflate (IV). The condensation of (IV) with dimethyl malonate (V) by means of NaH in THF affords the alkylated malonate (VI), which is finally decarboxylated and deprotected by a treatment with aqueous refluxing HCl. Note that the synthesis of the biologically active (S)-enantiomer simply requires a change in the chirality of the Pd catalyst used in the first step of the synthesis.

The reaction of 3-aminotetrahydrofuran-2-one (I) with benzyloxycarbonyl chloride (II) and TEA in chloroform gives the carbamate (III), which is reduced to the lactol (IV) by means of DIBAL in toluene. It has been observed that lactol (IV) is in equilibrium with its tautomeric open chain aldehydic form.(V). The reaction of (IV)??(V) with phosphonium bromide (VI) by means of Bu-Li in THF yields 3-amino-4-penten-1-ol (VII), which is reprotected with benzyloxycarbonyl chloride (II) and TEA to afford the carbamate (VIII). The reaction of (VIII) with CBr4 and PPh3 in dichloromethane provides the pentenyl bromide (IX), which is treated with LiCN in THF to give 4-(benzyloxycarbonylamino)-5-hexenenitrile (X). Finally this compound is hydrolyzed with conc. HCl to yield the target 4-amino-5-hexenoic acid.

Title: Vigabatrin

CAS Registry Number: 60643-86-9

CAS Name: 4-Amino-5-hexenoic acid

Additional Names: g-vinyl-g-aminobutyric acid; gamma-vinyl GABA; g-vinyl GABA; GVG

Manufacturers’ Codes: MDL-71754; RMI-71754

Trademarks: Sabril (HMR)

Molecular Formula: C6H11NO2

Molecular Weight: 129.16

Percent Composition: C 55.79%, H 8.58%, N 10.84%, O 24.77%

Literature References: Irreversible inhibitor of g-aminobutyric acid transaminase, the enzyme responsible for the degradation of the neurotransmitter g-aminobutyric acid (GABA). Prepn: B. W. Metcalf, M. Jung, US 3960927 (1976 to Richardson-Merrell); and in vitro enzyme inactivation: B. Lippert et al., Eur. J. Biochem. 74, 441 (1977). Mechanism of action study: P. J. Schechter et al., Eur. J. Pharmacol. 45, 319 (1977). Anticonvulsant activity and toxicity studies: W. Löscher, Neuropharmacology 21, 803 (1982). HPLC determn in plasma and urine: J. A. Smithers et al., J. Chromatogr. 341, 232 (1985). The S(+)-enantiomer is the pharmacologically active form. Pharmacokinetics of enantiomers in humans: K. D. Haegele, P. J. Schechter, Clin. Pharmacol. Ther. 40, 581 (1986). Clinical studies in treatment resistant epilepsy: C. A. Tassinari et al., Arch. Neurol. 44, 907 (1987); T. R. Browne et al., Neurology37, 184 (1987). Series of articles on clinical use in adult and childhood epilepsy: J. Child Neurol. 6, Suppl. 2, S3-S69 (1991). Reviews of early literature and mechanism of action: M. J. Iadarola, K. Gale, Mol. Cell. Biochem. 39, 305-330 (1981); of pharmacology and toxicology: E. J. Hammond, B. J. Wilder, Clin. Neuropharmacol. 8, 1-12 (1985). Review: S. M. Grant, R. C. Heel, Drugs 41, 889-926 (1991).

Properties: Crystals from acetone/water, mp 209°. Freely sol in water. LD50 i.p. in mice: >2500 mg/kg (Löscher).

Melting point: mp 209°

Toxicity data: LD50 i.p. in mice: >2500 mg/kg (Löscher)

Therap-Cat: Anticonvulsant.

Keywords: Anticonvulsant.

References

^ Jump up to:^a ^b ^c ^d ^e ^f ^g ^h ⁱ Long, Phillip W. “Vigabatrin.” Archived April 23, 2006, at the Wayback Machine. Internet Mental Health. 1995–2003.
^ Jump up to:^a ^b ^c DEF Mexico: Sabril Archived September 14, 2005, at the Wayback Machine. Diccionario de Especialdades Farmaceuticas. Edicion 49, 2003.
Jump up^ Feucht M, Brantner-Inthaler S (1994). “Gamma-vinyl-GABA (vigabatrin) in the therapy of Lennox-Gastaut syndrome: an open study” (PDF). Epilepsia. 35 (5): 993–8. doi:10.1111/j.1528-1157.1994.tb02544.x. PMID 7925171. Retrieved 2006-05-25.
Jump up^ Zwanzger P, Baghai TC, Schuele C, Strohle A, Padberg F, Kathmann N, Schwarz M, Moller HJ, Rupprecht R (2001). “Vigabatrin decreases cholecystokinin-tetrapeptide (CCK-4) induced panic in healthy volunteers”. Neuropsychopharmacology. 25 (5): 699–703. doi:10.1016/S0893-133X(01)00266-4. PMID 11682253.
Jump up^ Pearl, Phillip L; Robbins, Emily; Capp, Philip K; Gasior, Maciej; Gibson, K Michael (May 5, 2004). “Succinic Semialdehyde Dehydrogenase Deficiency”. GeneReviews. Seattle, Washington: University of Washington. Retrieved September 6, 2010.
Jump up^ Sander JW, Hart YM (1990). “Vigabatrin and behaviour disturbance”. Lancet. 335 (8680): 57. doi:10.1016/0140-6736(90)90190-G. PMID 1967367.
Jump up^ Chiaretti A, Castorina M, Tortorolo L, Piastra M, Polidori G (1994). “[Acute psychosis and vigabatrin in childhood]”. La Pediatria Medica e Chirurgica : Medical and surgical pediatrics. 16 (5): 489–90. [Article in Italian] PMID 7885961
Jump up^ Sander JW, Hart YM, Trimble MR, Shorvon SD (1991). “Vigabatrin and psychosis”. Journal of Neurology, Neurosurgery, and Psychiatry. 54 (5): 435–9. doi:10.1136/jnnp.54.5.435. PMC 488544 . PMID 1865207.
Jump up^ Abdulrazzaq YM, Padmanabhan R, Bastaki SM, Ibrahim A, Bener A (2001). “Placental transfer of vigabatrin (gamma-vinyl GABA) and its effect on concentration of amino acids in the embryo of TO mice”. Teratology. 63 (3): 127–33. doi:10.1002/tera.1023. PMID 11283969.
Jump up^ Lombardo SA, Leanza G, Meli C, Lombardo ME, Mazzone L, Vincenti I, Cioni M (2005). “Maternal exposure to the antiepileptic drug vigabatrin affects postnatal development in the rat”. Neurological Sciences. 26 (2): 89–94. doi:10.1007/s10072-005-0441-6. PMID 15995825.
Jump up^ Frisén L, Malmgren K (2003). “Characterization of vigabatrin-associated optic atrophy”. Acta Ophthalmologica Scandinavica. 81 (5): 466–73. doi:10.1034/j.1600-0420.2003.00125.x. PMID 14510793.
Jump up^ Buncic JR, Westall CA, Panton CM, Munn JR, MacKeen LD, Logan WJ (2004). “Characteristic retinal atrophy with secondary “inverse” optic atrophy identifies vigabatrin toxicity in children”. Ophthalmology. 111 (10): 1935–42. doi:10.1016/j.ophtha.2004.03.036. PMC 3880364 . PMID 15465561.
Jump up^ Gaucher D; Arnault E; Husson Z; et al. (November 2012). “Taurine deficiency damages retinal neurones: cone photoreceptors and retinal ganglion cells”. Amino Acids. 43 (5): 1979–1993. doi:10.1007/s00726-012-1273-3. PMC 3472058 . PMID 22476345.
Jump up^ Sanchez-Alcaraz, Agustín; Quintana MB; Lopez E; Rodriguez I; Llopis P (2002). “Effect of vigabatrin on the pharmacokinetics of carbamazepine”. Journal of Clinical Pharmacology and Therapeutics. 27 (6): 427–30. doi:10.1046/j.1365-2710.2002.00441.x. PMID 12472982.
Jump up^ Rimmer EM, Richens A (1984). “Double-blind study of gamma-vinyl GABA in patients with refractory epilepsy”. Lancet. 1 (8370): 189–90. doi:10.1016/S0140-6736(84)92112-3. PMID 6141335.
Jump up^ Rimmer EM, Richens A (1989). “Interaction between vigabatrin and phenytoin”. British Journal of Clinical Pharmacology. 27 (Suppl 1): 27S–33S. doi:10.1111/j.1365-2125.1989.tb03458.x. PMC 1379676 . PMID 2757906.
Jump up^ Rogawski MA, Löscher W (2004). “The neurobiology of antiepileptic drugs”. Nat Rev Neurosci. 5 (7): 553–564. doi:10.1038/nrn1430. PMID 15208697.
Jump up^ Sheean, G.; Schramm T; Anderson DS; Eadie MJ. (1992). “Vigabatrin–plasma enantiomer concentrations and clinical effects”. Clinical and Experimental Neurology. 29: 107–16. PMID 1343855.
^ Jump up to:^a ^b Gram L, Larsson OM, Johnsen A, Schousboe A (1989). “Experimental studies of the influence of vigabatrin on the GABA system”. British Journal of Clinical Pharmacology. 27(Suppl 1): 13S–17S. doi:10.1111/j.1365-2125.1989.tb03455.x. PMC 1379673 . PMID 2757904.
Jump up^ Storici Paola; De Biase D; Bossa F; Bruno S; Mozzarelli A; Peneff C; Silverman R; Schirmer T. (2003). “Structures of γ-Aminobutyric Acid (GABA) Aminotransferase, a Pyridoxal 5′-Phosphate, and [2Fe-2S] Cluster-containing Enzyme, Complexed with γ-Ethynyl-GABA and with the Antiepilepsy Drug Vigabatrin”. The Journal of Biochemistry. 279(1): 363–73. doi:10.1074/jbc.M305884200. PMID 14534310.
Jump up^ Browne TR (1998). “Pharmacokinetics of antiepileptic drugs”. Neurology. 51 (5 suppl 4): S2–7. doi:10.1212/wnl.51.5_suppl_4.s2. PMID 9818917.
Jump up^ Lindberger M, Luhr O, Johannessen SI, Larsson S, Tomson T (2003). “Serum concentrations and effects of gabapentin and vigabatrin: observations from a dose titration study”. Therapeutic Drug Monitoring. 25 (4): 457–62. doi:10.1097/00007691-200308000-00007. PMID 12883229.
Jump up^ Ben-Menachem E. (2011). “Mechanism of Action of vigabatrin: correcting misperceptions”. Acta Neurologica Scandinavica. 124: 5. doi:10.1111/j.1600-0404.2011.01596.x.
Jump up^ drugs.com Vigabatrin Drug Information
Jump up^ Treatments for Epilepsy – Vigabatrin Norfolk and Waveney Mental Health Partnership NHS Trust

///////////Vigabatrin, ビガバトリン , MDL-71754; RMI-71754, orphan drug designation

Vigabatrin
Clinical data


Trade names	Sabril
Synonyms	γ-Vinyl-GABA
AHFS/Drugs.com	Consumer Drug Information
MedlinePlus	a610016
Pregnancy category	AU: D US: D (Evidence of risk)
Routes of administration	Oral
ATC code	N03AG04 (WHO)
Legal status
Legal status	AU: S4 (Prescription only) CA: ℞-only UK: POM (Prescription only) US: ℞-only
Pharmacokinetic data
Bioavailability	80–90%
Protein binding	0%
Metabolism	not metabolized
Biological half-life	5–8 hours in young adults, 12–13 hours in the elderly.
Excretion	Renal
Identifiers
IUPAC name [show]
CAS Number	60643-86-9
PubChem CID	5665
IUPHAR/BPS	4821
DrugBank	DB01080
ChemSpider	5463
UNII	GR120KRT6K
KEGG	D00535
ChEMBL	CHEMBL89598
ECHA InfoCard	100.165.122
Chemical and physical data
Formula	C₆H₁₁NO₂
Molar mass	129.157 g/mol
3D model (JSmol)	Interactive image
Melting point	171 to 177 °C (340 to 351 °F)
SMILES [hide] O=C(O)CCC(\C=C)N

Anagrelide アナグレリド ,

April 11, 2018 12:54 am / Leave a comment

Anagrelide アナグレリド;

QA-0023

BL 4162A

Imidazo[2,1-b]quinazolin-2(3H)-one, 6,7-dichloro-5,10-dihydro-

BL-4162A
BMY-26538-01
GALE-401
KRN-654
SPD-422

6,7-Dichloro-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-2-one

CAS: 68475-42-3

C10H7Cl2N3O, 256.0881

INGREDIENT	UNII	CAS
Anagrelide Hydrochloride	VNS4435G39	58579-51-4

Image result for Anagrelide

EMA

2018/2/15

EMA

APPROVED

Anagrelide

Anagrelide Mylan

Mylan S.A.S.

Cardiovascular agent

Anagrelide hydrochloride is a cyclic phosphodiesterase III inhibitor that was launched in 1997 in the U.S. by Shire Pharmaceuticals for the treatment of essential thrombocythemia and other myeloproliferative disorders

Anagrelide was assigned orphan drug status by the FDA in 1986, by the Japanese Ministry of Health in 2004 and by the European Commission in January 2001 for the treatment of essential thrombocythemia.

Anagrelide (Agrylin/Xagrid, Shire and Thromboreductin, AOP Orphan Pharmaceuticals AG) is a drug used for the treatment of essential thrombocytosis (ET; essential thrombocythemia), or overproduction of blood platelets. It also has been used in the treatment of chronic myeloid leukemia.^[1]

Anagrelide controlled release (GALE-401) is in phase III clinical trials by Galena Biopharma for the treatment of ET.^[2]

Medical uses

Anagrelide is used to treat essential thrombocytosis, especially when the current treatment of the patient is insufficient.^[3] Essential thrombocytosis patients who are suitable for anagrelide often meet one or more of the following factors:^[4]^[5]

age over 60 years
platelet count over 1000×10⁹/L
a history of thrombosis

According to a 2005 Medical Research Council randomized trial, the combination of hydroxyurea with aspirin is superior to the combination of anagrelide and aspirin for the initial management of ET. The hydroxyurea arm had a lower likelihood of myelofibrosis, arterial thrombosis, and bleeding, but it had a slightly higher rate of venous thrombosis.^[3] Anagrelide can be useful in times when hydroxyurea proves ineffective.

Side-effects

Common side effects are headache, diarrhea, unusual weakness/fatigue, hair loss, nausea and dizziness.

The same MRC trial mentioned above also analyzed the effects of anagrelide on bone marrow fibrosis, a common feature in patients with myelofibrosis. The use of anagrelide was associated with a rapid increase in the degree of reticulin deposition (the mechanism by which fibrosis occurs), when compared to those in whom hydroxyurea was used. Patients with myeloproliferative conditions are known to have a very slow and somewhat variable course of marrow fibrosis increase. This trend may be accelerated by anagrelide. Interestingly, this increase in fibrosis appeared to be linked to a drop in hemoglobin as it progressed. Fortunately, stopping the drug (and switching patients to hydroxyurea) appeared to reverse the degree of marrow fibrosis. Thus, patients on anagrelide may need to be monitored on a periodic basis for marrow reticulin scores, especially if anemia develops, or becomes more pronounced if present initially.^[6]

Less common side effects include: congestive heart failure, myocardial infarction, cardiomyopathy, cardiomegaly, complete heart block, atrial fibrillation, cerebrovascular accident, pericarditis, pulmonary infiltrates, pulmonary fibrosis, pulmonary hypertension, pancreatitis, gastric/duodenal ulceration, renal impairment/failure and seizure.

Due to these issues, anagrelide should not generally be considered for first line therapy in ET.

Mechanism of action

Anagrelide works by inhibiting the maturation of platelets from megakaryocytes.^[7] The exact mechanism of action is unclear, although it is known to be a phosphodiesterase inhibitor.^[8] It is a potent (IC₅₀ = 36nM) inhibitor of phosphodiesterase-II.^{[citation needed]} It inhibits PDE-3 and phospholipase A2.^[9]

Synthesis

Phosphodiesterase inhibitor with antiplatelet activity.

Synthesis 1^[10]^[11]	Synthesis 2

Condensation of benzyl chloride 1 with ethyl ester of glycine gives alkylated product 2. Reduction of the nitro group leads to the aniline and reaction of this with cyanogen bromidepossibly gives cyanamide 3 as the initial intermediate. Addition of the aliphatic would then lead to formation of the quinazoline ring (4). Amide formation between the newly formed imide and the ester would then serve to form the imidazolone ring, whatever the details of the sequence, there is obtained anagrelide (5).

PATENT

https://patents.google.com/patent/WO2010005480A2/en

Image result for Anagrelide

PATENT

US20130211083A1

Image result

PATENTS

https://patents.google.com/patent/EP2373654A1/en

Image result for Anagrelide SYNTHESIS

SYN

CA 1137474, WO 0208228

The nitration of 1,2,3-trichlorobenzene (I) with concentrated HNO3 gives 2,3,4-trichloronitrobenzene (II), which by reaction with cuprous cyanide in hot pyridine is converted to 2,3-dichloro-6-nitrobenzonitrile (III). The reduction of (III) with borane in THF yields 2,3-dichloro-6-nitrobenzylamine (IV), which by reaction with ethyl bromoacetate (V) by means of triethylamine in refluxing dioxane affords ethyl N-(2,3-dichloro-6-nitrobenzyl)glycinate (VI). The reduction of (VI) with SnCl2 in concentrated HCl gives ethyl N-(6-amino-2,3-dichlorobenzyl)glycinate (VII), which is cyclized with cyanogen bromide (VIII) in toluene affording ethyl 5,6-dichloro-3,4-dihydro-2-(1H)-iminoquinazoline-3-acetate (IX). Finally, this compound is submitted to a new cyclization by means of triethylamine in refluxing ethanol.

The reaction of 3-chloroaniline (X) with choral hydrate (XI) and hydroxylamine gives isonitroso-3-chloroacetanilide (XII), which is cyclized by means of H2SO4 to 4-chloroisatin (XIII). Chlorination of (XIII) with SO2Cl2 affords 4,5-dichloroisatin (XIV), which is oxidized with H2O2 yielding 5,6-dichloroanthranilic acid (XV). The reduction of (XV) with borane in THF gives 6-amino-2,3-dichlorobenzyl alcohol (XVI), which by reaction with SOCl2 in benzene is converted to 6-amino-2,3-dichlorobenzyl chloride (XVII). This compound is condensed with ethyl glycinate (XVIII) by means of triethylamine in refluxing methylene chloride to give ethyl N-(6-amino-2,3-dichlorobenzyl)glycinate (VII), which is cyclized with cyanogen bromide (VIII) in toluene affording ethyl 5,6-dichloro-3,4-dihydro-2-(1H)-iminoquinazoline-3-acetate (IX). Finally, this compound is submitted to a new cyclization by means of triethylamine in refluxing ethanol.

SYN

WO 0208228

The nitration of 2,3-dichlorobenzaldehyde (I) with HNO3/H2SO4 gives 2,3-dichloro-6-nitrobenzaldehyde (II), which is reduced with NaBH4 in methanol, yielding 2,3-dichloro-6-nitrobenzyl alcohol (III). The reaction of (III) with SOCl2 and TEA affords the benzyl chloride (IV), which is condensed with glycine ethyl ester (V) by means of TEA to provide the adduct (VI). The reduction of the nitro group of (VI) with SnCl2 in aq. HCl or H2 over PtO2/C in ethanol gives the expected amino derivative (VII), which is cyclized with CN-Br in toluene to yield the iminoquinazoline (VIII). Finally, this compound is further cyclized by means of TEA in water to afford the target imidazoquinazolinone.

US 3932407

The condensation of 2-nitro-6-chlorobenzyl chloride (I) with ethyl glycinate (II) by means of triethylamine in refluxing ethanol gives ethyl N-(2-nitro-6-chlorobenzyl)glycinate (III), which is reduced with H2 over Pd/C in ethanol yielding ethyl N-(2-amino-6-chlorobenzyl)glycinate (IV). The cyclization of (IV) with cyanogen bromide (A) in refluxing ethanol affords 6-chloro-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-2-one (V), which is finally chlorinated with Cl2 and FeCl3 in hot nitromethane.

PATENTS

CN 103254197

US 3932407

WO 2002008228

CN 102757434

WO 2012052781

WO 2005080398

PATENT

WO 2008096145

Applicants:	CIPLA LIMITED [IN/IN]; 289 Bellasis Road, Mumbai Central, Mumbai 400 008 (IN) (For All Designated States Except US). PATHI, Srinivas, Laxminarayan [IN/IN]; (IN) (For US Only). KANKAN, Rajendra, Narayanrao [IN/IN]; (IN) (For US Only). RAO, Dharmaraj, Ramachandra [IN/IN]; (IN) (For US Only). CURTIS, Philip, Anthony [GB/GB]; (GB) (MW only)
Inventors:	PATHI, Srinivas, Laxminarayan; (IN). KANKAN, Rajendra, Narayanrao; (IN). RAO, Dharmaraj, Ramachandra; (IN)

Yusuf Hamied

Anagrelide, is a potent reducer of platelet count induced by a variety of aggregating agents and has the following structure

( Formula II)

^TJS 4146718 disckre? the process for the preparation ->f ethyl-N-(2,3-dich’oro-6 n^:tr^benzyl) glycine hydrochloride from 1,2,3-trichlorobenzene as depicted in Scheme I via 2,3-dichloro-6-nitrobenzonitrile, which involves the use of poisonous reagents, such as cuprous cyanide. Cyanation is carried out at a temperature of 165⁰C which is highly exothermic, uncontrollable and not scalable. 2, 3-dichloro-6-nitrobenzonitri]e has extreme toxic and skin-irritant properties. Diborane is a flammable gas, used for the reduction of 2, 3-dichloro-6-nitrobenzonitrile. The reduction reaction is exothermic, uncontrollable and not feasible industrially.

Scheme I :

1 ,2,3-Tπchlorobenzene 2,3 ,4-Trichloronitro 2,3-Dichloro-6-nitro
benzene benzonitπle

Ethyl-N-(2,3-dichloro-6-mtrobenzyl) 2,3-Dichloro-6-nitro
glycine hydrochloride benzylamme

US 5801245 discloses process for the preparation of ethyl-N-(2,3-dichloro-6-nitrobenzyl)glycine hydrochloride from 2,3-dichloro toluene as depicted in Scheme II.

2,3-dichloro-toluene 2,3-dichloro-6-nιtrotoluene

+ H₂NCH₂COOEt HCI HCI

2,3-dιchloro-6-nitro Glycine ethyl ester ethyl-N-(2,3-dιchloro-6-nιtro benzyl bromide hydrochloride benzyl)glycιne HCI

The reaction involves a radical halogenation of the toluene group. The material is purified by column chromatography at each stage which makes the process more tedious and it is not viable industrially. The use of a chromatographic solvent, such as chloroform (which is a known carcinogen), is disadvantageous with respect to industrial application.

US 2003/0060630 discloses a method for making ethyl-N-(2, 3-dichloro-6-nitro benzyl)glycine hydrochloride form 2,3-dichloro benzaldehyde as depicted in Scheme III.

Scheme III :

2,3-Dichloro benzaldehyde 2,3-Dichloro-6-mtro 2,3-Dichloro-6-nitro
benzaldehyde benzylalcohol

Step c Thionyl chloride

Ethyl-N-(2,3-dichloro-6-nitrobenzyl) 2,3 -Dichloro-6-nitro
glycine hydrochloride benzyl chloride

In step (b), the reduction reaction is earned out in high boiling solvents like toluene. The reduction in step (b) and the chlorination in step (c) are sluggish. Also, the chlorination reaction is exothermic and uncontrollable, which leads to formation of more impurities and thereby resulting in low yield (page 4, column 2, and page 5, column 1 : 65 %) . Hence, this prior art process is not viable for industrial scale up.

Because of the difficulties encountered in the processes disclosed in the prior art, there is a need to develop more efficient and economical synthetic route for the preparation of ethyl-N- (2,3-dichloro-6-nitrobenzyl)glycine hydrochloride, which is suitable for industrial scale up. The present invention relates to a new process for the synthesis of Ethyl-N-(2, 3-dichloro-6-nitrobenzyl)glycine hydrochloride.

Scheme IV :

2,3-Dichloro-6-nitro 2, 3-Dichloro-6-nitro
benzaldehyde benzylalcohol
( III ) ( IV ) ( V )
Acetonitπle
H₂NCH₉COOEt
HCl(g) in DPA / Ethyl acetate

Ethyl-N-(2,3-dichloro-6-nitroberizyl)
glycine hydrochloride ( I )

EXAMPLES

Example 1
Preparation of 2, 3-dichloro-6-nitro benzyl methane sulphonate, a compound of formula

(V):
Methylene chloride (2000 ml) and sodium borohydride (120 g) were charged to a clean and dry flask and chilled to 0-5⁰C. Methanol (100 ml) was added slowly over a period of 20 minutes followed by 2,3-dichloro-6-nitro benzaldehyde solution (500 g in 2000 ml of methylene chloride) over a period of 2 hours maintaining the temperature at 0-5⁰C and the contents were stirred at 0-5⁰C for 1 hour. After completion of reaction, water (3000 ml) was added and stirred for 10 minutes. The organic layer was separated, dried over sodium sulphate and was filtered to get a clear filtrate.

To the clear filtrate triethylamine (460 ml), was slowly added over a period of 1 hour at 10- 5 15⁰C, then methane sulphonyl chloride (325 ml) was added drop wise over a period of 2 hours maintaining temperature of 10-15⁰C and the reaction mass was allowed to attain room temperature. Further the reaction mass was stirred at room temperature for 5 hours and after completion of reaction, the organic layer was washed with water (1000 ml) twice, followed by IN HCl solution (1000 ml) twice, 5% Sodium bicarbonate solution (1000 ml) twice, water 0 (1000 ml) twice and was dried over sodium sulfate. The clear organic layer was concentrated under vacuum below 4O⁰C to give the title compound which was used in the next step.

Example 2
Preparation of ethyl N-(2,3-dichIoro-6-nitrobenzyl)gIycine hydrochloride, a compound of formula (I) :
2,3-dichloro-6-nitro benzyl methane sulphonate ( Examplel ) was dissolved in acetonitrile (2400 ml). To this reaction mass were charged anhydrous Potassium carbonate (480 g), dimethyl amino pyridine (480 mg) and glycine ethyl ester (240 g) at room temperature. The contents were stirred at 37-4O⁰C for 24 hours. After completion of reaction, the insolubles were filtered, washed with acetonitrile (120 ml). The clear filtrate was concentrated and stripped off usin” ethyl acetate (240 ml).

Further ethyl acetate (1200 ml) was added, chilled the contents to 5-10⁰C, adjusted the pH to 2.0 using IP A-HCl at 5-1O⁰C. The contents were stirred at 5-10⁰C for 1 hour. The solids were filtered, washed with chilled ethyl acetate (120 ml) and dried under vacuum at room temperature for 4 hours to give the title compound (595 g, 76 % yield, 98.5% HPLC purity).

Example 3
Preparation of Anagrelide , a compound of formula (II)

a) Preparation of Ethyl-5,6-dichloro-3,4-dihydro-2[lH]-imino quinazolin-3-acetate hydrobromide A solution of stannous chloride dihydrate (1850 gms) in concentrated HCl (6.7 liters ) was added slowly to a cooled solution of ethyl-N-(2,3-dichloro-6-nitrobenzyl)glycine hydrochloride (595gms) in concentrated HCl (5.15 liters) maintaining temperature 15-20⁰C over a period of 2 hours. The contents were heated slowly to 40-45⁰C and stirred for 1 hour at 40-45⁰C. After completion of reaction, the contents were cooled to 15-2O⁰C, maintained for 15 minutes and filtered.

The solids thus obtained were suspended in water (2.9 liters), adjusted the pH of the reaction mass to 8.0-9.0 using potassium carbonate solution (prepared by dissolving 376 gms of potassium carbonate in 4.25 liters of water) at 0-5⁰C, extracted into toluene (3.0 liters><3), dried over sodium sulphate and clarified.

To the clear toluene layer, added Cyanogen bromide solution (prepared by dissolving 222 gms of cyanogen bromide in 655 ml of toluene) in 30 minutes maintaining temperature 15-20⁰C and stirred at 25-30⁰C for 2 hours. The contents were heated slowly to 105-110⁰C and maintained for 16 hours at 105-110⁰C. After completion of reaction, the mass was cooled to 15-2O⁰C and stirred for 45 minutes. Filtered the material, washed with chilled toluene (1.3 liters). The material was slurried in toluene (470 ml) at 15-20⁰C for 1 hour, filtered, washed with cold toluene (160 ml) and dried under vacuum at 50-60⁰C for 8 hours to give the title compound (445 gms ).

b) Preparation of 6,7-Dichloro-l,5-dihydroimidazo[2,l-b]quinazolin-2(3H)-one [Anagrelide]
A mixture of ethyl-5,6-dichloro-3,4-dihydro-2(lH)-iminoquinazolin-3-acetate hydrobromide (445 gms), isopropyl alcohol (4.45 liters) and triethylamine (246 ml) was refluxed for 2 hours. After completion of reaction, the mixture was cooled to 20-25⁰C, filtered, washed with chilled isopropyl alcohol (1.0 liters) and dried under vacuum at 50-55⁰C for 6 hours to give the title compound (285 gms).

Publication numberPriority datePublication dateAssigneeTitle

WO2010070318A1 *2008-12-172010-06-24Shire LlcProcess for the preparation of anagrelide and analogues

US8133996B22007-02-062012-03-13Cipla LimitedProcess for the preparation of ethyl-N-(2,3-dichloro-6-nitrobenzyl)glycine hydrochloride

KR20170102484A *2015-01-132017-09-11닛산 가가쿠 고교 가부시키 가이샤방향족 아민 화합물의 제조 방법

WO2016114312A1 *2015-01-132016-07-21日産化学工業株式会社反応混合物中のスズ化合物の処理方法

Publication numberPriority datePublication dateAssigneeTitle

US4208521A *1978-07-311980-06-17Bristol-Myers CompanyProcess for the preparation of imidazo[2,1-b]quinazolinones

EP0514917A1 *1991-05-221992-11-25Egis GyogyszergyarProcess for and 2-(cyanoimino)-quinazoline derivatives useful as intermediates in the preparation of 6,7-di-(chloro)-1,5-di(hydro)-imidazo-[2,1-b]quinazolin-2[3H]-one and process for preparing the 2-(cyanoimino)-quinazoline derivatives

US20030060630A1 *2000-07-262003-03-27Shire Us Inc.Method for the manufacture of Anagrelide

Family To Family Citations

US4146718A *1978-04-101979-03-27Bristol-Myers CompanyAlkyl 5,6-dichloro-3,4-dihydro-2(1h)-iminoquinazoline-3-acetate hydrohalides

JPH051255B2 *1984-05-231993-01-07Sumitomo Chemical Co

CA2171073A1 *1995-12-041997-06-05Philip C. LangProcess for the preparation of ethyl-n-(2,3 dichloro-6- nitrobenzyl) glycine

CN1335847A *1998-12-042002-02-13藤泽药品工业株式会社磺酰胺化合物及其药物用途

WO2008096145A12007-02-062008-08-14Cipla LimitedProcess for the preparation of ethyl-n-(2, 3-dichloro-6-nitrobenzyl) glycine hydrochloride

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Jump up^ Petrides PE (2006). “Anagrelide: what was new in 2004 and 2005?”. Semin. Thromb. Hemost. 32 (4 Pt 2): 399–408. doi:10.1055/s-2006-942760. PMID 16810615.
Jump up^ Jones GH, Venuti MC, Alvarez R, Bruno JJ, Berks AH, Prince A (February 1987). “Inhibitors of cyclic AMP phosphodiesterase. 1. Analogues of cilostamide and anagrelide”. J. Med. Chem. 30 (2): 295–303. doi:10.1021/jm00385a011. PMID 3027338.
Jump up^ Harrison CN, Bareford D, Butt N, et al. (May 2010). “Guideline for investigation and management of adults and children presenting with a thrombocytosis”. Br. J. Haematol. 149(3): 352–75. doi:10.1111/j.1365-2141.2010.08122.x. PMID 20331456.
Jump up^ W. N. Beverung, A. Partyka, U.S. Patent 3,932,407; USRE 31617; T. A. Jenks et al., U.S. Patent 4,146,718 (1976, 1984, 1979 all to Bristol-Myers).
Jump up^ Yamaguchi, Hitoshi; Ishikawa, Fumiyoshi (1981). “Synthesis and reactions of 2-chloro-3,4-dihydrothienopyrimidines and -quinazolines”. Journal of Heterocyclic Chemistry. 18: 67. doi:10.1002/jhet.5570180114.

External links

Title: Anagrelide

CAS Registry Number: 68475-42-3

CAS Name: 6,7-Dichloro-1,5-dihydroimidazo[2,1-b]quinazolin-2(3H)-one

Additional Names: 6,7-dichloro-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-2-one

Molecular Formula: C10H7Cl2N3O

Molecular Weight: 256.09

Percent Composition: C 46.90%, H 2.76%, Cl 27.69%, N 16.41%, O 6.25%

Literature References: Phosphodiesterase inhibitor with antiplatelet activity. Prepn: W. N. Beverung, A. Partyka, US 3932407; USRE 31617; T. A. Jenks et al., US 4146718 (1976, 1984, 1979 all to Bristol-Myers); H. Yamaguchi, F. Ishikawa, J. Heterocycl. Chem.18, 67 (1981). Antithrombotic and platelet aggregation inhibiting properties: J. S. Fleming, J. P. Buyniski, Thromb. Res. 15, 373 (1979). Mode of action studies: S. S. Tang, M. M. Frojmovic, J. Lab. Clin. Med. 95, 241 (1980); S. Seiler et al., J. Pharmacol. Exp. Ther. 243, 767 (1987). GC-MS determn in human plasma: E. H. Kerns et al., J. Chromatogr. 416, 357 (1987). Clinical reduction of platelet counts: W. A. Andes et al., Thromb. Haemostasis 52, 325 (1984). Clinical trials to control thrombocytosis in chronic myeloproliferative diseases: M. N. Silverstein et al., N. Engl. J. Med. 318, 1292 (1988); Anagrelide Study Group, Am. J. Med. 92,69 (1992). Review of pharmacology and clinical experience: P. E. Petrides, Expert Opin. Pharmacother. 5, 1781-1798 (2004).

Derivative Type: Hydrochloride monohydrate

CAS Registry Number: 58579-51-4

Manufacturers’ Codes: BL-4162A; BMY-26538-01

Trademarks: Agrylin (Shire); Thromboreductin (AOP Orphan Pharm.); Xagrid (Shire)

Molecular Formula: C10H7Cl2N3O.HCl.H2O

Molecular Weight: 310.56

Percent Composition: C 38.67%, H 3.25%, Cl 34.25%, N 13.53%, O 10.30%

Properties: Off-white powder. Very slightly sol in water; sparingly sol in DMSO, DMF. Also prepd as the hemihydrate; crystals from ethanolic HCl, mp >280°.

Melting point: mp >280°

Therap-Cat: Antithrombocythemic.

Keywords: Antithrombocythemic.

Anagrelide
Clinical data

Trade names	Agrylin
AHFS/Drugs.com	Monograph
MedlinePlus	a601020
License data	EU EMA: by INN
Pregnancy category	AU: B3 US: C (Risk not ruled out)
Routes of administration	Oral
ATC code	L01XX35 (WHO)
Legal status
Legal status	AU: S4 (Prescription only) CA: ℞-only UK: POM (Prescription only) US: ℞-only
Pharmacokinetic data
Metabolism	Hepatic, partially through CYP1A2
Biological half-life	1.3 hours
Excretion	Urine (<1%)
Identifiers
IUPAC name [show]
CAS Number	68475-42-3
PubChem CID	2182
IUPHAR/BPS	7114
DrugBank	DB00261
ChemSpider	2097
UNII	K9X45X0051
KEGG	D07455
ChEBI	CHEBI:142290
ChEMBL	CHEMBL760
Chemical and physical data
Formula	C₁₀H₇Cl₂N₃O
Molar mass	256.088 g/mol
3D model (JSmol)	Interactive image

/////////Anagrelide, アナグレリド , EU 2018, EMA 2018, SHIRE, FDA 1997. orphan drug status

FDA expands approval of Blincyto (blinatumomab) for treatment of a type of leukemia in patients who have a certain risk factor for relapse

March 30, 2018 2:26 am / Leave a comment

FDA expands approval of Blincyto for treatment of a type of leukemia in patients who have a certain risk factor for relapse

Blincyto (blinatumomab)

The U.S. Food and Drug Administration granted accelerated approval to Blincyto (blinatumomab) to treat adults and children with B-cell precursor acute lymphoblastic leukemia (ALL) who are in remission but still have minimal residual disease (MRD). MRD refers to the presence of cancer cells below a level that can be seen under the microscope. In patients who have achieved remission after initial treatment for this type of ALL, the presence of MRD means they have an increased risk of relapse.Continue reading.

March 29, 2018

Release

“This is the first FDA-approved treatment for patients with MRD-positive ALL,” said Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “Because patients who have MRD are more likely to relapse, having a treatment option that eliminates even very low amounts of residual leukemia cells may help keep the cancer in remission longer. We look forward to furthering our understanding about the reduction in MRD after treatment with Blincyto. Studies are being conducted to assess how Blincyto affects long-term survival outcomes in patients with MRD.”

B-cell precursor ALL is a rapidly progressing type of cancer in which the bone marrow makes too many B-cell lymphocytes, an immature type of white blood cell. The National Cancer Institute estimates that approximately 5,960 people in the United States will be diagnosed with ALL this year and approximately 1,470 will die from the disease.

Blincyto works by attaching to CD19 protein on the leukemia cells and CD3 protein found on certain immune system cells. Bringing the immune cell close to the leukemia cell allows the immune cells to attack the leukemia cells better. The FDA first approved Blincyto under accelerated approval in December 2014 for the treatment of Philadelphia chromosome (Ph)-negative relapsed or refractory positive B-cell precursor ALL. Full approval for this indication was granted in July 2017, and at that time, the indication was also expanded to include patients with Philadelphia chromosome-positive ALL.

The efficacy of Blincyto in MRD-positive ALL was shown in a single-arm clinical trial that included 86 patients in first or second complete remission who had detectable MRD in at least 1 out of 1,000 cells in their bone marrow. Efficacy was based on achievement of undetectable MRD in an assay that could detect at least one cancer cell in 10,000 cells after one cycle of Blincyto treatment, in addition to the length of time that the patients remained alive and in remission (hematological relapse-free survival). Overall, undetectable MRD was achieved by 70 patients. Over half of the patients remained alive and in remission for at least 22.3 months.

The side effects of Blincyto when used to treat MRD-positive B-cell precursor ALL are consistent with those seen in other uses of the drug. Common side effects include infections (bacterial and pathogen unspecified), fever (pyrexia), headache, infusion related reactions, low levels of certain blood cells (neutropenia, anemia), febrile neutropenia (neutropenia and fever) and low levels of platelets in the blood (thrombocytopenia).

Blincyto carries a boxed warning alerting patients and health care professionals that some clinical trial participants had problems with low blood pressure and difficulty breathing (cytokine release syndrome) at the start of the first treatment, experienced a short period of difficulty with thinking (encephalopathy) or other side effects in the nervous system. Serious risks of Blincyto include infections, effects on the ability to drive and use machines, inflammation in the pancreas (pancreatitis), and preparation and administration errors—instructions for preparation and administration should closely be followed. There is a risk of serious adverse reactions in pediatric patients due to benzyl alcohol preservative; therefore, the drug prepared with preservative free saline should be used for patients weighing less than 22 kilograms.

This new indication for Blincyto was approved under the accelerated approval pathway, under which the FDA may approve drugs for serious conditions where there is unmet medical need and a drug is shown to have certain effects that are reasonably likely to predict a clinical benefit to patients. Further study in randomized controlled trials is required to verify that achieving undetectable MRD with Blincyto improves survival or disease-free survival in patients with ALL.

The FDA granted this application Priority Review and it received Orphan Drugdesignation, which provides incentives to assist and encourage the development of drugs for rare diseases.

The FDA granted the approval of Blincyto to Amgen Inc.

//////amgen, fda 2018, Priority Review m Orphan Drug designation, Blincyto, blinatumomab,

ELECLAZINE, элеклазин , إيليكلازين , 依来克秦 , REVISITED

March 20, 2018 10:13 am / 1 Comment on ELECLAZINE, элеклазин , إيليكلازين , 依来克秦 , REVISITED

ChemSpider 2D Image | eleclazine | C21H16F3N3O3

ELECLAZINE

GS-6615

Molecular Formula:	C₂₁H₁₆F₃N₃O₃
Molecular Weight:	415.372 g/mol

1443211-72-0

4-(pyrimidin-2-ylmethyl)-7-[4-(trifluoromethoxy)phenyl]-2,3-dihydro-1,4-benzoxazepin-5-one

4-(pyrimidin-2-ylmethyl)-7-[4-(trifluoromethoxy)phenyl]-2,3,4,5- tetrahydro-1,4- benzoxazepin-5-one

7-(4-(Trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one

1,4-Benzoxazepin-5(2H)-one, 3,4-dihydro-4-(2-pyrimidinylmethyl)-7-[4-(trifluoromethoxy)phenyl]-

Eleclazine; UNII-PUY08529FK; 1443211-72-0; GS-6615; PUY08529FK; 4-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-on

элеклазин [Russian] [INN]

إيليكلازين [Arabic] [INN]

依来克秦 [Chinese] [INN]

Phase III Long QT syndrome

INGREDIENT	UNII	CAS
Eleclazine Hydrochloride	4R1JP3Q4HI	1448754-43-5

Eleclazine has been used in trials studying the treatment of LQT2 Syndrome, Long QT Syndrome, Ischemic Heart Disease, Ventricular Arrhythmia, and Long QT Syndrome Type 3, among others.

In 2015, orphan drug designation was assigned to the product by the FDA for the treatment of congenital long QT syndrome.

Originator Gilead Sciences
Class Antiarrhythmics; Ischaemic heart disorder therapies; Pyrimidines; Small molecules; Vasodilators
Mechanism of Action Sodium channel antagonists

Highest Development Phases

Phase III Long QT syndrome
Phase II/III Hypertrophic cardiomyopathy
Phase II Ventricular arrhythmias
No development reported Ischaemic heart disorders

Most Recent Events

15 Nov 2017 Gilead Sciences presents safety and adverse events data from a phase III trial in Long QT syndrome type 3 at the 90^th Annual Scientific Sessions of the American Heart Association (AHA-2017)
11 Nov 2017 Efficacy data from the phase II TEMPO trial in Ventricular arrthymmia presented at the 90th Annual Scientific Sessions of the American Heart Association
17 Feb 2017 Gilead Sciences terminates a phase II/III trial in Hypertrophic cardiomyopathy in Australia, France, Germany, Israel, Italy, Netherlands, USA and United Kingdom (NCT02291237)
Gilead Sciences was developing eleclazine (GS-6615), a late sodium current inhibitor, for the potential oral (tablet) treatment of hypertrophic cardiomyopathy and arrhythmias including long QT-3 (LQT3) syndrome.

Image result

Image result for Long QT syndrome

Long QT syndrome

The late sodium current (INaL) is a component of the fast Na⁺ current of cardiac myocytes and neurons. Late sodium current in cardiac cells is small compared with the fast component, but it may make a large contribution to sodium loading during each cardiac cycle. Impaired sodium channel function contributes to pathologic increase of the late sodium current, sodium overload, and sodium-induced calcium overload by way of the sodium-calcium exchanger. Calcium overload causes impaired diastolic relaxation, which increases diastolic wall tension, increases myocardial oxygen demand, reduces myocardial blood flow and oxygen supply, microvascular perfusion, and worsens ischemia and angina. Many common neurological and cardiac conditions are associated with abnormal (INaL) augmentation, which contributes to the pathogenesis of both electrical and contractile dysfunction in mammals. Inhibiting the late sodium current can lead to reductions in elevated intracellular calcium levels, which, in turn, may lead to reduced tension in the heart wall and reduced oxygen requirements for the heart muscle. Inhibition of cardiac late sodium current is a strategy used to suppress arrhythmias and sodium -dependent calcium overload associated with myocardial i schemia and heart failures. Thus, compounds that selectively inhibit the iate sodium current (INaL) in mammals may be useful in treating such disease states.

Eleclazine (4-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethoxy)pheny l)-3,4-dihydrobenzo[b]oxepin-5(2H)-one]; CAS # 144321 1-72-0) is an inhibitor of the late sodium current, Eleclazine is being investigated for the treatment of cardiomyopathy, specifically hypertrophic cardiomyopathy, as well as additional cardiovascular indications, including angina, heart failure, atrial fibrillation (AF), ischemic heart disorders, atrial premature beats (APBs), myocardial isch mia, and arrhythmias.

Eleclazine

Eleclazine shows a shortening of the QTc interval (the time interval between the start of the Q-wave and the end of T-wave in the electrical cycle of the heart) in patients with QT-3 (LQT3) sydrome. LQTS is a genetic disorder that prolongs the heart’s QTc interval and can cause life-threatening cardiac arrhythmias. Therefore, eleclazine is also being investigated for treatment of long QT syndrome.

Eleclazine may be metabolized in the liver and may be subject to extensive cytochrome P450-mediated oxidative metabolism. Eleclazine is metabolized predominantly by N-dealkylation, and elimination is principally in the bile and gastrointestinal tract. The primary metabolite of eleclazine is GS-623134

Adverse effects associated with eleclazine may include dizziness, dry mouth, nausea, weakness, ringing in ears, tremors, and the like. Additionally, some metabolites of eleclazine, particularly the metabolite GS 623134, may have undesirable side effects.

PATENT

PRODUCT, WO 2013112932, WO 2013006485

WO 2013006463

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2013006463&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

WO 2013006463 , ( US8962610 ) hold protection in the EU states until 2032 and in US until 2033 with US154 extension.

PATENT

WO 2015017661

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015017661

Provided herein is a method for reducing the prolongation of the QT interval in a human patient, said method comprising administering to the patient an effective amount of Compound 1:

Example 1: 4-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4- dihydrobenzo[f][1,4]oxazepin-5(2H)-one (Compound 1)

To a solution of Compound 1-A (20 g, 0.083 mol, 1 eq.) and Compound 1-B (25 g, 0.15 mol, 1.8 eq.) in DMF (150 mL), NaOH solution (20 mL, 10 M, 5 eq.) was slowly added at room temperature (slightly exothermic) and stirred at r.t. for 10 min, followed by heating at 95 °C for 2 h. After cooling the reaction mixture, ethyl acetate (200 mL) was added and the organic layer was separated. The organics was washed with water (20 mL), brine, dried over sodium sulphate and concentrated.

The residue was dissolved in 1,4-dioxane (50 mL) and to this 4 N HCl in dioxane (50 mL) and cone. HCl ( 2 mL) was added and stirred at room temperature for 4 h, filtered the precipitate, washed with ethyl acetate and dried. Compound 1-C was obtained (30 g) as a light yellow solid.

To the bromide (15 g, 0.04 mol, 1 eq), boronic acid (12.5 g, 0.06 mol, 1.5 eq) and potassium carbonate (22 g, 0.16 mol, 4 eq) in a round bottom flask, solvent (150 mL, toluene/isopropanol/water : 2/1/1) was added and stirred under nitrogen for 10 min. To the above solution the palladium catalyst (1 g, 0.012 mol, 0.02 eq) was added and heated at 85 °C for 2h. The reaction mixture was diluted with ethyl acetate, separated the organic layer and filtered the organic layer through a plug of celite and silica gel and concentrated. Column purification on silica gel using ethyl acetate/hexane as eluent provided Compound 1 (13 g).

To a solution of Compound 1 (26 g) in 1,4-dioxane (25 mL), 4N HCl/dioxane (25 mL) was added followed by cone. HCl (2 mL) and stirred at room temperature for 4h. Solvent was distilled off, dichlorom ethane was added and distilled off and to the residue, ethyl acetate (150 mL) was added and stirred at room temperature overnight and filtered the precipitate, washed with ethyl acetate, hexane and dried under vacuum. Compound 1-HCl obtained (24.8 g) was a white solid.

¹H-NMR (CDCl₃) 5 8.72 (d, 2H, J= 5.2 Hz), 8.17 (d, 1H, J= 2.4 Hz), 7.59-7.63 (m, 3H), 7.26 (d, 2H, J= 3.2 Hz), 7.22 (t, 1H, J= 4.8 Hz), 7.10 (d, 1H, J= 8.4 Hz), 5.10 (s, 2H), 4.56 (t, 2H, J = 5.0 Hz), 3.77 (t, 2H, J= 5.0 Hz); MS m/z 416.1 (M+H).

PATENT

WO-2018048977

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2018048977&redirectedID=true

Novel deuterated analogs of a substituted oxazepin compounds, particularly eleclazine and their salts, esters, prodrugs and solvates and compositions and combinations comprising them are claimed. Also claim is their use for treating a late sodium current-mediated disorder, such as acute coronary syndrome, angina, congestive heart disease, myocardial infraction, diabetes, ischemic heart disorders, inflammatory diseases and cancers.

EXAMPLE 1- COMPARATIVE

[00297] 4-(pyrimidin-2-ylmethyl)-7-[4-(trifluorome4hoxy)phenyl]-2,3,4,5-tetrahydro-l,4- benzoxazepin-5-one [Eleclazine]

[00299] To a solution of 5-bromo-2-hydroxybenzoate (10 g, 43.28 mmol, 1.00 equiv) in DMA (100 ml.) was added potassium carbonate (9 g, 65, 12 mmol, 1.50 equiv) and 2-chloroacetonitrile (3.4 mL, 1.25 equiv). The resulting suspension was stirred overnight. The solids were filtered out. The filtrate was washed with water. The resulting solution was extracted with ethyl acetate (3 x 50 mL). The organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum to afford 1 1 g (94%) of methyl 5-bromo-2-(cyanomethoxy)benzoate as a white solid, LC-MS: m/z = 270 [M+H]⁺.

[00300] Step 2: 7-bromo-2,3,4,5-tetrahydro-l,4-benzoxazepin-5-one

[00301] To a solution of 5-bromo-2-(cyanomethoxy)benzoate [Example 1 , Step 1 ] (4 g, 14.81 mmol, 1.00 equiv) in methanol (50 mL) was added saturated aq. NIL (4 mL) and Raney-Ni (2 mL) under a H2 atmosphere. The resulting solution was stirred overnight at room temperature. The catalyst was filtered out. The filtrate was concentrated under vacuum. The residue was purifsed by SiCte chromatography eluted with ethyl acetate/petroleum ether (1 : 1 ) to afford 530 mg (15%) of 7-bromo-2,3,4,5-tetrahydro-l,4-benzoxazepin-5-one as a yellow solid. LC-MS: m/z = 242 [M+H]⁺.

[00302] Step 3 : 7-bromo-4-(pyrimidin-2-ylmethyl)-2,3,4,5-tetrahydro-l,4-benzoxazepin-5- one

[00303] To a solution of 7-bromo-2,3,4,5-tetrahydro- l ,4-benzoxazepin-5-one [Example 1, Step 2] (530 mg, 2.19 mmol, 1.00 equiv) and 2-(chloromethyl)pyrimidine hydrochloride (650 mg, 3.96 mmol, 1.80 equiv) in DMF (10 mL), was slowly added a NaOH solution (0.55 mL, 10 M, 2.50 equiv), which was stirred at room temperature for 10 min. Then the mixture was stirred at 95°C for 2 h. After cooling the reaction mixture, ethyl acetate (30 mL) was added and the organic layer was separated. The organic layers were washed with water, brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to afford 600 mg (82%) of 7-bromo- 4-(pyrimidin-2-ylmethyl)-2,3,4,5-tetrahydro-l,4-benzoxazepin-5-one as light yellow oil . LC-MS: m/z = 334 [M+H]⁺.

[00304] Step 4: 4-(pyrimidin-2-ylmethyl)-7-[4-(trifluoromethoxy)phenyl]-2,3,4,5-tetrahydro- 1 ,4-benzoxazepin-5-one

[00305] To a solution of 7-bromo-4-(pyriraidin-2-ylmethyl)-2,3,4,5-tetrahydro-l,4- benzoxaze- pin-5-one [Example 1, Step 3] (277 mg, 0.83 mmol, 1.00 equiv) in Toluene/iPrOH/thO (2: 1 : 1, 4 mL) was added potassium carbonate (459 mg, 3.32 mmol, 4.00 equiv) and [4-(trifluoromethoxy)phenyl]boronic acid (257 mg, 1.25 mmol, 1.50 equiv). The mixture was stirred for 10 min at room temperature. Then Pd(dppf)Ch (12 mg, 0.02 equiv) was added to the solution. The mixture was stirred at 85°C for 2 h. After cooling the reaction mixture, ethyl acetate (30 mL) was added, and the organic layer was separated. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions: Column, XBridge Prep C18 OBD Column, Sum, 19*150mm; mobile phase, Water (10 mmol/L NH4HCO3) and CH₃CN (50,0% CH₃CN up to 52.0% in 7 min); Detector, UV 254, 220nra to afford 190 mg (55%) of 4-(pyrimidin-2-ylmethyl)-7-[4-(trifluoromethoxy)phenyl]-2,3,4,5- tetrahydro-1,4- benzoxazepin-5-one as a white solid. LC-MS: m/z = 416 [M+H]⁺

[00306] ¹H NMR (400 MHz, Chloroform-t/) δ 8.75-8.74 (m, 2H), 8.20-8. 19 (m, IH), 7.66- 7,61 (m, 3H), 7,29-7,28 (m, IH), 7.27-7.26 (m, IH), 7.24-7.23 (m, I H), 7.13-7.1 1 (m, IH), 5.12 (s, 2H), 4.60-4.57 (m, 2H), 3.81 -3.78 (m, 2H).

PAPER

Journal of Medicinal Chemistry (2016), 59(19), 9005-9017

Late sodium current (late I_Na) is enhanced during ischemia by reactive oxygen species (ROS) modifying the Na_v 1.5 channel, resulting in incomplete inactivation. Compound 4 (GS-6615, eleclazine) a novel, potent, and selective inhibitor of late I_Na, is currently in clinical development for treatment of long QT-3 syndrome (LQT-3), hypertrophic cardiomyopathy (HCM), and ventricular tachycardia–ventricular fibrillation (VT–VF). We will describe structure–activity relationship (SAR) leading to the discovery of 4 that is vastly improved from the first generation late I_Na inhibitor 1(ranolazine). Compound 4 was 42 times more potent than 1 in reducing ischemic burden in vivo (S–T segment elevation, 15 min left anteriorior descending, LAD, occlusion in rabbits) with EC₅₀values of 190 and 8000 nM, respectively. Compound 4 represents a new class of potent late I_Nainhibitors that will be useful in delineating the role of inhibitors of this current in the treatment of patients.

Discovery of Dihydrobenzoxazepinone (GS-6615) Late Sodium Current Inhibitor (Late I_Nai), a Phase II Agent with Demonstrated Preclinical Anti-Ischemic and Antiarrhythmic Properties

^†Medicinal Chemistry, ^‡Drug Metabolism, ^§Drug Safety Evaluation, ^∥Formulation and Process Development, and ^⊥Structural Chemistry, Gilead Sciences Inc., 333 Lakeside Drive, Foster City, California 94404, United States

^# Biology, Gilead Sciences Inc., 7601 Dumbarton Circle, Fremont, California 94555, United States

J. Med. Chem., 2016, 59 (19), pp 9005

7-(4-(Trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one 4

Compound 4 HCl obtained (24.8 g) was obtained as a white solid. Anal. HPLC 100% (6.78 min).

¹H NMR (CDCl₃) δ 8.72 (d, 2H, J = 5.2 Hz), 8.17 (d, 1H, J = 2.4 Hz), 7.59–7.63 (m, 3H), 7.26 (d, 2H, J = 3.2 Hz), 7.22 (t, 1H, J = 4.8 Hz), 7.10 (d, 1H, J = 8.4 Hz), 5.10 (s, 2H), 4.56 (t, 2H, J = 5.0 Hz), 3.77 (t, 2H, J = 5.0 Hz). LCMS m/z 416.1 (M + H).

HRMS-ESI+: [M + H]⁺ calcd for C₂₁H₁₆F₃N₃O₃, 416.1217; found, 416.1215.

PAPER

Inhibition of late sodium current suppresses calcium-related ventricular arrhythmias by reducing the phosphorylation of CaMK-II and sodium channel expressions
Scientific Reports (2017), 7, (1), 1-11.

https://www.nature.com/articles/s41598-017-01056-0

PATENT

US 20180064726

PATENTS

Patent ID	Patent Title	Submitted Date	Granted Date
US9126989	COMPOUND AND METHODS FOR TREATING LONG QT SYNDROME	2014-07-31	2015-02-05
US9193694	FUSED HETEROCYCLIC COMPOUNDS AS ION CHANNEL MODULATORS	2013-09-26	2014-05-15
US9125916	METHODS OF TREATING HYPERTROPHIC CARDIOMYOPATHY	2014-07-28	2015-02-05
US2016332976	PROCESSES FOR PREPARING FUSED HETEROCYCLIC ION CHANNEL MODULATORS	2016-05-02
US2015283149	METHODS OF TREATING PATIENTS HAVING IMPLANTABLE CARDIAC DEVICES	2015-03-20	2015-10-08

Patent ID	Patent Title	Submitted Date	Granted Date
US2015045305	COMBINATION THERAPIES USING LATE SODIUM ION CHANNEL BLOCKERS AND POTASSIUM ION CHANNEL BLOCKERS	2013-01-25	2015-02-12
US2016332977	PROCESSES FOR PREPARING FUSED HETEROCYCLIC ION CHANNEL MODULATORS	2016-05-02
US9598435	FUSED HETEROCYCLIC COMPOUNDS AS ION CHANNEL MODULATORS	2015-10-01	2016-04-07
US2015225384	PROCESSES FOR PREPARING FUSED HETEROCYCLIC ION CHANNEL MODULATORS	2015-02-13	2015-08-13
US9273038	SOLID FORMS OF AN ION CHANNEL MODULATOR	2015-02-12	2015-08-13

Patent ID	Patent Title	Submitted Date	Granted Date
US9676760	FUSED HETEROCYCLIC COMPOUNDS AS ION CHANNEL MODULATORS	2016-05-11
US8697863	Fused heterocyclic compounds as ion channel modulators	2013-03-07	2014-04-15
US8586732	Fused heterocyclic compounds as ion channel modulators	2012-06-29	2013-11-19
US2017007617	INTRAVENOUS FORMULATIONS OF A LATE SODIUM CURRENT INHIBITOR	2016-07-06
US2014329755	COMBINATION THERAPY FOR THE TREATMENT OF ARRHYTHMIAS OR HEART FAILURE	2014-04-30	2014-11-06

/////////////////ELECLAZINE, GS-6615, GS 6615, элеклазин , إيليكلازين , 依来克秦 , Phase III, Long QT syndrome, orphan drug designation, Long QT syndrome

C1COC2=C(C=C(C=C2)C3=CC=C(C=C3)OC(F)(F)F)C(=O)N1CC4=NC=CC=N4

FDA approves new HIV treatment Trogarzo (ibalizumab-uiyk) for patients who have limited treatment options

March 7, 2018 1:15 am / 1 Comment on FDA approves new HIV treatment Trogarzo (ibalizumab-uiyk) for patients who have limited treatment options

FDA approves new HIV treatment Trogarzo (ibalizumab-uiyk),for patients who have limited treatment options

Today, the U.S. Food and Drug Administration approved Trogarzo (ibalizumab-uiyk), a new type of antiretroviral medication for adult patients living with HIV who have tried multiple HIV medications in the past (heavily treatment-experienced) and whose HIV infections cannot be successfully treated with other currently available therapies (multidrug resistant HIV, or MDR HIV).Trogarzo is administered intravenously once every 14 days by a trained medical professional and used in combination with other antiretroviral medications. Continue reading.

March 6, 2018

Release

“While most patients living with HIV can be successfully treated using a combination of two or more antiretroviral drugs, a small percentage of patients who have taken many HIV drugs in the past have multidrug resistant HIV, limiting their treatment options and putting them at a high risk of HIV-related complications and progression to death,” said Jeff Murray, M.D., deputy director of the Division of Antiviral Products in the FDA’s Center for Drug Evaluation and Research. “Trogarzo is the first drug in a new class of antiretroviral medications that can provide significant benefit to patients who have run out of HIV treatment options. New treatment options may be able to improve their outcomes.”

The safety and efficacy of Trogarzo were evaluated in a clinical trial of 40 heavily treatment-experienced patients with MDR HIV-1 who continued to have high levels of virus (HIV-RNA) in their blood despite being on antiretroviral drugs. Many of the participants had previously been treated with 10 or more antiretroviral drugs. The majority of participants experienced a significant decrease in their HIV-RNA levels one week after Trogarzo was added to their failing antiretroviral regimens. After 24 weeks of Trogarzo plus other antiretroviral drugs, 43 percent of the trial’s participants achieved HIV RNA suppression.

The clinical trial focused on the small patient population with limited treatment options and demonstrated the benefit of Trogarzo in achieving reduction of HIV RNA. The seriousness of the disease, the need to individualize other drugs in the treatment regimen, and safety data from other trials were considered in evaluating the Trogarzo development program.

A total of 292 patients with HIV-1 infection have been exposed to Trogarzo IV infusion. The most common adverse reactions to Trogarzo were diarrhea, dizziness, nausea and rash. Severe side effects included rash and changes in the immune system (immune reconstitution syndrome).
The FDA granted this application Fast Track, Priority Review and Breakthrough Therapy designations. Trogarzo also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.

The FDA granted approval of Trogarzo to TaiMed Biologics USA Corp.

Theratechnologies Announces FDA Approval of Breakthrough Therapy, Trogarzo™ (ibalizumab-uiyk) Injection, the First HIV-1 Inhibitor and Long-Acting Monoclonal Antibody for Multidrug Resistant HIV-1

NEWS PROVIDED BY

Theratechnologies Inc.

First HIV treatment approved with a new mechanism of action in more than 10 years
Infused every two weeks, only antiretroviral treatment (ART) that does not require daily dosing
Trogarzo™ has no drug-drug interactions and no cross-resistance with other ARTs

MONTREAL, March 6, 2018 /PRNewswire/ – Theratechnologies Inc. (Theratechnologies) (TSX: TH) and its partner TaiMed Biologics, Inc. (TaiMed) today announced that the U.S. Food and Drug Administration (FDA) has granted approval of Trogarzo™ (ibalizumab-uiyk) Injection. In combination with other ARTs, Trogarzo™ is indicated for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in heavily treatment-experienced adults with multidrug resistant HIV-1 infection failing their current antiretroviral regimen.¹

Logo: Theratechnologies (CNW Group/Theratechnologies Inc.)

Trogarzo™ represents a critical new treatment advance as the first HIV therapy with a new mechanism of action approved in 10 years and proven effectiveness in difficult-to-treat patients with limited options. Unlike all other classes of ARTs, Trogarzo™ is a CD4-directed post-attachment HIV-1 inhibitor that binds to CD4+ receptors on host cells and blocks the HIV virus from infecting the cells.¹

“Today’s approval of Trogarzo™ by the FDA is great news for people infected with difficult-to-treat multidrug resistant HIV. We look forward to bringing this much-needed therapy to patients in the U.S within six weeks,” said Luc Tanguay, President and Chief Executive Officer, Theratechnologies Inc. “We are grateful to the patients, investigators, as well as the FDA who supported the clinical development of Trogarzo™, and are helping address this critical unmet medical need.”

Trogarzo™ previously received Breakthrough Therapy and Orphan Drug designations as well as Priority Review status from the FDA, underscoring the significance of the treatment for this patient population.

“I witnessed some of the earliest cases of HIV and AIDS, at a time when the diagnosis was terrifying to patients because in many cases it was a death sentence,” said David Ho, M.D., chief scientific advisor of TaiMed and scientific director and CEO of the Aaron Diamond AIDS Research Center. “Since then, treatment advances and the discovery that combinations of ARTs was the best way to bring viral load below the level of detection have allowed most people to manage HIV like a chronic condition and live long, healthy lives. However, this is not the reality for people whose HIV is resistant to multiple drugs and whose viral load is not controlled, which is why TaiMed dedicated the past decade to advancing ibalizumab in the clinic. For these patients, it represents the next breakthrough.”

Up to 25,000 Americans with HIV are currently multidrug resistant, of which 12,000 are in urgent need of a new treatment option because their current treatment regimen is failing them and their viral load has risen to detectable levels, jeopardizing their health and making HIV transmittable.^2-13 The best way to prevent the transmission of multidrug resistant HIV is to control the virus in those living with it. According to new guidance from the Centers for Disease Control and Prevention (CDC), the HIV virus cannot be transmitted if it is being fully suppressed.¹³

“I’ve struggled with multidrug resistant HIV for almost 30 years and it was completely debilitating to feel like I had run out of options – I made no long-term plans,” said Nelson Vergel, founder of the Program for Wellness Restoration (PoWeR) and Trogarzo™ patient. “Since starting treatment with Trogarzo™ six years ago and getting my viral load to an undetectable level, I have been my happiest, most productive self. Trogarzo™ is a new source of hope and peace of mind for people whose treatments have failed them, and I feel incredibly lucky to have been able to participate in the clinical trial program.”

TaiMed and Theratechnologies partnered on the development of Trogarzo™ so patients who can benefit from the treatment have access to it. For patients who need assistance accessing Trogarzo™ or who face challenges affording medicines, Theratechnologies has a team of patient care coordinators available to help. Patients can get assistance and expert support by contacting THERA patient support™ at 1-833-23-THERA (84372).

“In Phase 3 ibalizumab trials, we saw marked improvements in patients’ health who not only were heavily treatment-experienced and had limited remaining treatment options, but in cases they also had extremely high viral loads and significantly impaired immune systems,” said Edwin DeJesus, M.D., Medical Director for the Orlando Immunology Center. “As an investigator for ibalizumab clinical trials over nearly 10 years, it was remarkable and inspiring to see the dramatic effect ibalizumab had on such vulnerable patients. As a clinician, I am excited that we will now have another option with a different mechanism of action for our heavily pretreated patients who are struggling to keep their viral load below detection because their HIV is resistant to multiple drugs.”

Clinical Trial Findings

Clinical studies show that Trogarzo™, in combination with other ARTs, significantly reduces viral load and increases CD4+ (T-cell) count among patients with multidrug resistant HIV-1.

The Phase 3 trial showed:¹

Trogarzo™ significantly reduced viral load within seven days after the first dose of functional monotherapy and maintained the treatment response when combined with an optimized background regimen that included at least one other active ART for up to 24 weeks of treatment, while being safe and well tolerated.
More than 80% of patients achieved the study’s primary endpoint – at least a 0.5 log₁₀ (or 70%) viral load reduction from baseline seven days after receiving a 2,000 mg loading dose of Trogarzo™ and no adjustment to the failing background regimen.
The average viral load reduction after 24 weeks was 1.6 log₁₀ with 43% of patients achieving undetectable viral loads.

Patients experienced a clinically-significant mean increase in CD4+ T-cells of 44 cells/mm³, and increases varied based on T-cell count at baseline. Rebuilding the immune system by increasing T-cell count is particularly important as people with multidrug resistant HIV-1 often have the most advanced form of HIV.¹

The most common drug-related adverse reactions (incidence ≥ 5%) were diarrhea (8%), dizziness (8%), nausea (5%) and rash (5%). No drug-drug interactions were reported with other ARTs or medications, and no cross-resistance with other ARTs were observed.¹

About Trogarzo™ (ibalizumab-uiyk) Injection

Trogarzo™ is a humanized monoclonal antibody for the treatment of multidrug resistant HIV-1 infection. Trogarzo™ binds primarily to the second extracellular domain of the CD4+ T receptor, away from major histocompatibility complex II molecule binding sites. It prevents HIV from infecting CD4+ immune cells while preserving normal immunological function.

IMPORTANT SAFETY INFORMATION

Trogarzo™ is a prescription HIV medicine that is used with other antiretroviral medicines to treat human immunodeficiency virus-1 (HIV-1) infections in adults.

Trogarzo™ blocks HIV from infecting certain cells of the immune system. This prevents HIV from multiplying and can reduce the amount of HIV in the body.

Before you receive Trogarzo™, tell your healthcare provider if you:

are pregnant or plan to become pregnant. It is not known if Trogarzo™ may harm your unborn baby.
are breastfeeding or plan to breastfeed. It is not known if Trogarzo™ passes into breast milk.

Tell your healthcare provider about all the medicines you take, including all prescription and over-the-counter medicines, vitamins, and herbal supplements.

Trogarzo™ can cause serious side effects, including:

Changes in your immune system (Immune Reconstitution Inflammatory Syndrome) can happen when you start taking HIV-1 medicines. Your immune system might get stronger and begin to fight infections that have been hidden in your body for a long time. Tell your health care provider right away if you start having new symptoms after starting your HIV-1 medicine.

The most common side effects of Trogarzo™ include:

Diarrhea
Dizziness
Nausea
Rash

Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of Trogarzo™. For more information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. You may also report side effects to at 1-833-23THERA (1-833-238-4372).

About Theratechnologies

Theratechnologies (TSX: TH) is a specialty pharmaceutical company addressing unmet medical needs to promote healthy living and an improved quality of life among HIV patients. Further information about Theratechnologies is available on the Company’s website at www.theratech.com and on SEDAR at www.sedar.com.

/////Trogarzo, ibalizumab-uiyk, fda 2018, Fast Track, Priority Review, Breakthrough Therapy designations, Orphan Drug designation

Tivozanib, ティボザニブ塩酸塩水和物

February 26, 2018 10:18 am / Leave a comment

ChemSpider 2D Image | Tivozanib | C22H19ClN4O5

Tivozanib

Molecular FormulaC₂₂H₁₉ClN₄O₅
Average mass454.863 Da

AV951

AV951 (KRN951, Tivozanib)

AV-951; AV951;AV 951

AV-951|KRN-951|VEGFR tyrosine kinase inhibitor IV

KRN 951

1-{2-Chloro-4-[(6,7-diméthoxy-4-quinoléinyl)oxy]phényl}-3-(5-méthyl-1,2-oxazol-3-yl)urée

1-{2-Chloro-4-[(6,7-dimethoxy-4-quinolinyl)oxy]phenyl}-3-(5-methyl-1,2-oxazol-3-yl)urea

475108-18-0 [RN] FREE FORM

AV 951

N-(2-chloro-4-((6,7-dimethoxy-4-quinolyl)oxy)phenyl)-N’-(5-methyl-3-isoxazolyl)urea

N-[2-Chloro-4-[(6,7-dimethoxy-4-quinolinyl)oxy]phenyl]-N’-(5-methyl-3-isoxazolyl)urea
AV 951
KRN 951
Kil 8951
N-[2-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl]-N’-(5-methyl-3-isoxazolyl)urea
CAS HCL HYDRATE 682745-41-1
682745-43-3 HCL

Tivozanib (AV-951) is an oral VEGF receptor tyrosine kinase inhibitor. It has completed a pivotal Phase 3 investigation for the treatment of first line (treatment naive) patients with renal cell carcinoma.^[1] The results from this first line study did not lead to FDA approval, but Tivozanib was approved by the EMA in August 2017^[2]

Originally developed at Kirin Brewery, in January 2007 AVEO Pharmaceuticals acquired an exclusive license to develop and commercialize tivozanib in all territories outside of Asia.

In 2010, orphan drug designation was assigned in the E.U. for the treatment of renal cell carcinoma. In 2011, the compound was licensed to Astellas Pharma and AVEO Pharmaceuticals on a worldwide basis for the treatment of cancer

Tivozanib is an orally bioavailable inhibitor of vascular endothelial growth factor receptors (VEGFRs) 1, 2 and 3 with potential antiangiogenic and antineoplastic activities. Tivozanib binds to and inhibits VEGFRs 1, 2 and 3, which may result in the inhibition of endothelial cell migration and proliferation, inhibition of tumor angiogenesis and tumor cell death. VEGFR tyrosine kinases, frequently overexpressed by a variety of tumor cell types, play a key role in angiogenesis.

Tivozanib was originally developed by Kyowa Hakko Kirin and in 2007 AVEO Pharmaceutical acquired all the rights of the compound outside Asia. In December 2015, AVEO reached an agreement with EUSA Pharma, which acquired exclusive rights to tivozanib for advanced renal cell carcinoma in Europe, South America, Asia, parts of the Middle East and South Africa.

Tivozanib is an inhibitor of vascular endothelial growth factor (VEGF) receptors 1, 2, and 3 for first-line treatment of patients with advanced renal cell carcinoma in advanced disease or without VEGFR and mTOR inhibitors and progression after cytokine therapy Advanced renal cell carcinoma patients. Fotivda® is an oral capsule containing 890 μg and 1340 μg of Tivozanib per tablet. The recommended dose is 1 day, each 1340μg, taking three weeks, withdrawal for a week.

Image result for tivozanib

Image result for TIVOZANIB EMA

CAS HCL HYDRATE 682745-41-1

ティボザニブ塩酸塩水和物;

Pharmacotherapeutic group

Antineoplastic agents

Therapeutic indication

Fotivda is indicated for the first line treatment of adult patients with advanced renal cell carcinoma (RCC) and for adult patients who are VEGFR and mTOR pathway inhibitor-naïve following disease progression after one prior treatment with cytokine therapy for advanced RCC.

Treatment of advanced renal cell carcinoma

Fotivda : EPAR -Product Information

http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/004131/human_med_002146.jsp&mid=WC0b01ac058001d124

http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/004131/WC500239035.pdf

str6

Tivozanib is synthesized in three main steps using well defined starting materials with acceptable specifications.
Adequate in-process controls are applied during the synthesis. The specifications and control methods for intermediate products, starting materials and reagents have been presented. The critical process parameters are duly justified, methodology is presented and control is adequate.
The characterisation of the active substance and its impurities are in accordance with the EU guideline on chemistry of new active substances. Potential and actual impurities were well discussed with regards to their origin and characterised.
The active substance is packaged in a low-density polyethylene (LDPE) bag which complies with the EC
directive 2002/72/EC and EC 10/2011 as amended.

Product details

NAME	Fotivda
AGENCY PRODUCT NUMBER	EMEA/H/C/004131
ACTIVE SUBSTANCE	tivozanib
INTERNATIONAL NON-PROPRIETARY NAME(INN) OR COMMON NAME	tivozanib hydrochloride monohydrate
THERAPEUTIC AREA	Carcinoma, Renal Cell
ANATOMICAL THERAPEUTIC CHEMICAL (ATC) CODE	L01XE

Publication details

MARKETING-AUTHORISATION HOLDER	EUSA Pharma (UK) Limited
REVISION	0
DATE OF ISSUE OF MARKETING AUTHORISATION VALID THROUGHOUT THE EUROPEAN UNION	24/08/2017

Contact address:

EUSA Pharma (UK) Limited
Breakspear Park, Breakspear Way
Hemel Hempstead, HP2 4TZ
United Kingdom

Mechanism

An oral quinoline urea derivative, tivozanib suppresses angiogenesis by being selectively inhibitory against vascular endothelial growth factor.^[3] It was developed by AVEO Pharmaceuticals.^[4] It is designed to inhibit all three VEGF receptors.^[5]

Results

Phase III results on advanced renal cell carcinoma suggested a 30% or 3 months improvement in median PFS compared to sorafenibbut showed an inferior overall survival rate of the experimental arm versus the control arm.^[5]^[6] The Food and Drug Administration‘s Oncologic Drugs Advisory Committee voted in May 2013 13 to 1 against recommending approval of tivozanib for renal cell carcinoma. The committee felt the drug failed to show a favorable risk-benefit ratio and questioned the equipose of the trial design, which allowed control arm patients who used sorafenib to transition to tivozanib following progression disease but not those on the experimental arm using tivozanib to transition to sorafenib. The application was formally rejected by the FDA in June 2013, saying that approval would require additional clinical studies.^[6]

In 2016 AVEO Oncology published data in conjunction with the ASCO meeting showing a geographical location effect on Overall Survival in the Pivotal PhIII trial^[7]

In 2016 AVEO Oncology announced the start of a second Pivotal PhIII clinical study in Third Line advanced RCC patients. ^[8]

In 2016 EUSA Pharma and AVEO Oncology announced that Tivozanib had been submitted to the European Medicines Agency for review under the Centralised Procedure. ^[9]

In June 2017 the EMA Scientific Committee recommended Tivozanib for approval in Europe, with approval expected in September.^[10]

In August 2017 the European Commission (EC) formally approved Tivozanib in Europe.^[11]

SYNTHESIS

Heterocycles, 92(10), 1882-1887; 2016

CLIP

Paper

Heterocycles (2016), 92(10), 1882-1887

Short Paper | Regular issue | Vol 92, No. 10, 2016, pp. 1882 – 1887
Published online: 5th September, 2016

DOI: 10.3987/COM-16-13555

■ A New and Practical Synthesis of Tivozanib

Chunping Zhu, Yongjun Mao,* Han Wang, and Jingli Xu

*College of Chemistry and Chemical Engineering, Shanghai University of Engineering Science, 333 Longteng Rd., Songjiang, Shanghai, 201620, China

Abstract

New and improved synthetic route of tivozanib is described on a hectogram scale. An reduction cyclization process to prepare the key intermediate 6,7-dimethoxyquinolin-4-ol from the 3-(dimethylamino)-1-(2-nitrophenyl)prop-2- en-1-one compound at H2/Ni condition is adopted in good result. Commercial available materials, simple reaction and operation are used, including nitration, condensation, hydrogenation, chlorination and so on, to give the final product in 28.7% yield over six steps and 98.9% purity (HPLC).

Image result for tivozanib

PAPER

https://www.sciencedirect.com/science/article/pii/S0960894X15003054

Bioorganic & Medicinal Chemistry Letters

Volume 25, Issue 11, 1 June 2015, Pages 2425-2428

HC-1144 (yield: 69.0% ) as a white solid. ¹H NMR (400 MHz, CD₃OD): δ 8.33 (d, J=5.2 Hz, 1H,), 8.17(d, J=9.2 Hz, 1H), 7.47 (s, 1H), 7.29 (d, J=2.4 Hz, 1H), 7.23 (s, 1H), 7.10(m, 1H), 6.47(d, J=5.2 Hz, 1H), 6.28 (brs, 1H), 2.30 (s, 3H). MS (ESI, m/z): 461 [M+H]⁺.

PAPER

J MED CHEM 2005 48 1359

PATENT

WO 2002088110

KUBO, Kazuo; (JP).
SAKAI, Teruyuki; (JP).
NAGAO, Rika; (JP).
FUJIWARA, Yasunari; (JP).
ISOE, Toshiyuki; (JP).
HASEGAWA, Kazumasa; (JP)

Scheme 1 and Scheme 2

Skiing

PATENT

WO 2004035572

MATSUNAGA, Naoki; (JP).
YOSHIDA, Satoshi; (JP).
YOSHINO, Ayako; (JP).
NAKAJIMA, Tatsuo; (JP)

Preparation example: Preparation of N- {2-chloro-1- [(6,7-dimethoxy- 14 1 quinolyl) oxyl] phenyI} – N, – (5-methyl- 3 -isoxazolyl) urea ) Nitration process:

3, 4-Dimethoxyacetophenone (1 500 g) was dissolved in 5:: L 0 ° C of 17% nitric acid (1400 g), and 67% nitric acid (843 0 g) and sodium nitrite g) at a temperature of 5 to 10 ° C. over a period of 2 to 3 hours. After completion of dropping, the mixture was stirred at 5 to 10 ° C. for 1 to 2 hours. Cold water (7. 5 L) was added and after stirring for 30 minutes, filtration and washing with water (30 L). The filtrate was added to water (7. 5 L), neutralized with sodium bicarbonate water, filtered, and washed with water (7 L). The filtrate was dried under reduced pressure to obtain 3, 4-dimethoxy-6-nitroacetophenone (2164 g) (yield = 87.9%).

‘H-NMR (400 MHz, CD C 1 ₃ / p pm); 62. 5 0 (s, 3 H), 3. 9 7 (s, 3H), 3. 9 9 (s, 3 H), 6. 76 (s, 1 H), 7.6 2 (s, 1 H)

(2) Reduction process:

Methanol (5. 4 L), acetic acid (433 g:), 5% palladium / power monobonn (162 g) was added to 3, 4-dimethoxy-6-nitroacetophenone (1082 g) and hydrogen gas The mixture was stirred for 8 hours under pressure (2 Kg / cm 2, 40 ° C. The reaction solution was filtered, washed with methanol (1 L), and the filtrate was neutralized with aqueous sodium hydroxide solution and concentrated under reduced pressure Water (10 L) was added to the concentrate, stirred overnight, filtered and washed with water (7 L) Toluene (4 L) was added to the filtrate, heated to 80 ° C., 1 After stirring for a while, the residue was concentrated under reduced pressure and the residue was filtered, washed with toluene (300 mL), dried under reduced pressure to give 2-amino-4,5-dimethoxa Cetophenone (576 g) was obtained (yield = 6.1%).

‘H-NM (400 MHz, CD C 1 ₃ / p pm); 62. 5 6 (s, 3 H), 3. 84 (s, 3H), 3. 88 (s, 3 H), 6. 10 ( s, 1 H), 7.11 (s, 1 H)

(3) Cyclization step:

Tetrahydrofuran (THF) (5. 3 L) and sodium methoxide (3 1 3 g) were added to 2-amino-4, 5-dimethoxyacetophenone (33 7 g) and the mixture was stirred at 20 ° C for 30 minutes. At 0 ° C, ethyl formate (858 g) was added and stirred at 20 ° C for 1 hour. Water (480 mL) was added at 0 ° C. and neutralized with 1 N hydrochloric acid. After filtering the precipitate, the filtrate was washed with slurry with water (2 L). After filtration, the filtrate was dried under reduced pressure to obtain 6, 7-dimethoxy-141 quinolone (3 52 g) (yield = 8.15%).

‘H-NMR (400 MHz, DMS 0 – d ₆ / ppm); 63. 8 1 (s, 3 H), 3. 84 (s, 3 H), 5. 94 (d, 1 H), 7. 0 1 (s, 1 H), 7. 43 (s, 1 H), 7. 76 (d, 1 H)

(4) Clovalization process

Toluene (3 L) and phosphorus oxychloride (1300 g) were added to 6, 7-dimethoxy-1-quinolone (105 g), and the mixture was stirred under heating reflux for 1 hour. It was neutralized with aqueous sodium hydroxide solution at 0 ° C. The precipitate was filtered, and then the filtrate was washed with water (10 L) for slurry. After filtering, the filtrate was dried under reduced pressure to obtain 4 1 -chloro- 16, 7-dimethoxyquinoline (928 g) (yield – 87.6 %) _c ‘H-NMR (400 MHz, DMS 0 – d ₆ / ppm); 63. 9 5 (s, 3 H), 3. 9 6 (s, 3 H), 7. 3 5 (s, 1 H), 7. 43 (s, 1 H) , 7. 54 (d, 1 H), 8. 59 (d, 1 H)

(5) Phenol site introduction step:

4-Amino-3-chlorophenol · HC 1 (990 g) was added to N, N-dimethylacetamide (6. 6 L). Potassium t-butoxide (145 2 g) was added at 0 ° C. and the mixture was stirred at 20 ° C. for 30 minutes. 4-Chloro-6, 7-dimethoxyquinoline (82 5 g) was added thereto, followed by stirring at 115 ° C for 5 hours. After cooling the reaction solution to room temperature, water (8. 3 L) and methanol (8.3 L) were added and the mixture was stirred for 2 hours. After filtration of the precipitate, the filtrate was washed with slurry with water (8. 3 L), filtered, and the filtrate was dried under reduced pressure to give 4- [(4-amino-3-chlorophenol) 6, 7-Dimethoxyquinoline (8 52 g) was obtained (yield = 6 9. 9%).

‘H-NMR (400MH z, DMS 0 – d ₆ / ppm); 63. 9 2 (s, 3 H), 3. 93 (s, 3 H), 5. 4 1 (s, 2 H), 6 (D, 1 H), 6. 89 (d, 1 H), 6. 98 (dd, 1 H), 7. 19 (d, 1 H), 7. 36 (s, 1 H) , 7. 48 (s, 1 H), 8. 43 (d, 1 H)

(6) Ureaization process:

To 3 – amino – 5 – methylisoxazole (377 g), pyridine (1 2 1 5:), N, N – dimethylacetamide (4 L) at 0 ° C was added chlorobutyl carbonate phenyl

(60 1 g) was added dropwise and the mixture was stirred at 20 ° C. for 2 hours. 4- [(4-amino-1-chlorophenol) oxy] -6, 7-dimethoxyquinoline (84 7 g) was added to the reaction solution, and the mixture was stirred at 80 ° C. for 5 hours. The reaction solution was cooled to 5 ° C, then added with MeOH (8. 5 L) and water (8. 5 L) and neutralized with aqueous sodium hydroxide solution. After filtering the precipitate, the filtrate was washed with water (8. 5 L) for slurry. After filtration, the filtrate was dried under reduced pressure to give N- {2-chloro-4- [(6,7-dimethoxy-4-quinolyl) oxy] phenyl] – N, 1- -isoxazolyl) urea (1002 g) was obtained (yield = 86.1%).

‘H-NMR (400 MHz, DMS 0 – d ₆ / ppm); 62.37 (s, 3 H), 3. 92 (s, 3 H), 3. 94 (s, 3 H), 6. 7 (s, 1 H), 7. 48 (s, 1 H), 7 (s, 1 H), 6. 54 (d, . 5 1 (d, 1 H), 8. 2 3 (d, 1 H), 8. 49

(d, 1 H), 8. 77 (s, 1 H), 1 0.16 (s, 1 H)

PATENT

WO 2011060162

WO 2017037220

CN 106967058

CN 104072492

CN 102532116

CN 102408418

PAPER

Advanced Materials Research Vols. 396-398 (2012) pp 1490-1492

Synthesis of the compounds

The synthesis of 6,7-Dimethoxy-4-quinolinone (2a) The 33.7g (0.173mol) of 2-amino-4,5-dimethoxy acetophenone, 150 ml of methanol and 95.5g (0.69mol) of anhydrous potassium carbonate were added to the 500 ml flask and stirred about 1 h at room temperature. Then, the ethyl formate (75.8g, 0.861mol) was dropped the admixture and reactioned about 2 h in the same temperature. The admixture was filtrated and the 35.2 g white powder compound 2a (C11H11NO3) was obtained with the yield of 81.5% and m.p. 124-125. 1H-NMR (DMSO-d6/ppm): δ 3.81 (s, 3H), 3.84 (s,3H), 5.94 (d,1H), 7.01 (s,1H), 7.43 (s,1H), 7.76 (d,1H). ESI-MS: 206 (M+ +1).

The synthesis of 4-chloro-6,7-dimethoxy-quinoline (2b)The 100 ml of toluene, 15 g (0.103 mol) of phosphorus trichloride and 10.6 g (0.52 mol) compound 2a were added to the 250 ml of three bottles, the obtained mixture was refluxed about 2 h. Then, the reaction mixture was cooled to the room temperature, filtrated and the solid was dried. The 9.3 g similar white powder compound 2b (C11H10ClNO2 ) was obtained with the yield of 96.9% and m.p.138-140 ℃ . 1H-NMR (DMSO-d6/ppm): δ 3.95 (s,3H) , 3.96 (s,3H), 7.35 (s,1H), 7.43 (s,1H), 7.54 (d,1H), 8.59(d,1H). ESI-MS: 225 (M+ +1).

The synthesis of 4-[(4-Amino-3-phenol) oxy]-6,7-dimethoxy-quinoline (2c) The 60 ml of N, N-dimethylformamide, 8.9g (0.05 mol) of 4-amino-3-chlorophenol hydrochloride, 14.5g (0.105 mol) of potassium carbonate and 8.3 g (0.037 mol) compounds 2b were added to the 250 ml of three bottles, the obtained mixture was refluxed about 2 h. Then, the reaction mixture was cooled to the room temperature and the 100 ml of anhydrous ethanol was added. The obtained mixture was stirred about 1 h and filtrated. The filtered product was then dried under the reduced pressure to give the 8.5 g similar white powder compound 2c (C17H15ClN2O3) with the yield of 69.9%. 1H-NMR (DMSO-d6/ppm): δ 3.92 (s,3H), 3.93 (s,3H), 5.41 (s,2H), 6.41 (d,1H), 6.89 (d,1H), 6.98 (dd,1H), 7.19 (d,1H), 7.36 (s,1H), 7.48 (s,1H), 8.43(d,1H). ESI-MS: 331 (M+ +1).

The synthesis of N-{2-chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl} -N’- (5-methyl-3- isoxazole-yl) urea (2d) The 100 ml of N,N-dimethylformamide, 5.0g (0.051mol) of 3-amino-5- methylisoxa -zole, 7.98 g (0.051mol) of phenyl chloroformate and 17g (0.051mol) compound 2c were added to the 250 ml of three bottles. The mixture was refluxed about 5 h, cooled to room temperature, added the 100 ml of anhydrous ethanol. The obtained mixture was stirred 1 h and filtrated. The filtered product was slurried in water for washing. The slurry was filtered, and the filtered product was then dried under the reduced pressure to give the 20.0g white crystal compound 2d (C22H19ClN4O5) with the yield of 86.1% and the purity of more than 98.5 %. 1H-NMR (DMSO-d6/ppm): δ 2.37 (s,3H), 3.92 (s,3H), 3.94 (s,3H), 6.50 (s,1H), 6.54 (d,1H), 7.26 (dd,1H), 7.39 (s,1H), 7.48 (s,1H), 7.51 (d,1H), 8.23 (d,1H), 8.49 (d,1H), 8.77 (s,1H), 10.16(s,1H). ESI-MS: 456 (M+ +1).

Conclusions Tivozanib was synthesized through the cyclization, chlorinated, condensation reaction with 2-amino-4,5-dimethoxy acetophenone as the starting material. The total yield was 47.5% and the product purity of more than 98.5 %. The synthetic routs and methods of tivozanib are feasible to industrial production owing to the cheap raw materials, mild reaction conditions, stable technology and high yield.

PATENT

https://patents.google.com/patent/CN102532116B/en

Example

[0035] In 250ml three-neck flask, 80ml of chloroform and 22. 0g (0. 16mol) of anhydrous aluminum chloride at room temperature were successively added dropwise l〇.2g (0. 13mol) acetyl chloride, 13.8g (0. i mole) phthalic dimethyl ether, dropwise, stirred at room temperature until the reaction end point (GLC trace). The reaction solution was poured into 500ml diluted hydrochloric acid, with stirring, the organic phase was separated, the aqueous phase was extracted with chloroform and the combined organic phases were dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 15. Og of white powder Compound Ia (CltlH12O3), mp 48-52 ° C, 83% yield. HKcnT1): 1673,1585,1515,1418 1H-NMR (CDCl3 / ppm):! S 2. 55 (s, 3H), 3.73 (s, 3H), 3.73 (s, 3H), 6.77 (s, lH) , 7.26 (s, lH), 7.31 (s, lH).

[0036] The two 3 Synthesis of 4-dimethoxy-6-nitroacetophenone (Compound lb) Example

[0037] CN 102532116 B specification 4/6

[0038] In 500ml three-neck flask, was added IOOml formic acid and 18g (0 • lmol) compound la, KTC hereinafter 60ml of concentrated nitric acid was added dropwise, dropwise, warmed to 60-70 ° C, stirred for 30min. The reaction mixture was poured into 500ml ice water bath and stirred, suction filtered to give a pale yellow powder 36.9g Compound lb (CltlH11NO5), mp 135-137 ° C, in 82% yield. 1H-NMR (CDCl3 / ppm): S 2. 50 (s, 3H), 3 97 (s, 3H), 3 99 (s, 3H), 6 76 (s, 1H), 7. 62 (… s, 1H).

Example tri-2-amino-4, Synthesis of 5-dimethoxy acetophenone (Compound Ic), [0039] Embodiment

[0041] In 250ml three-neck flask, 36ml of water was added and 7g (0. 125mol) of reduced iron powder was heated and refluxed for LH, was slowly added 5. 6g (0. 025mol) LB compound, stirred for 3h, filtered off with suction, the filtrate is cooled, to give a yellow powder 7g compound Ic (C10H13NO3), mp 106-108 ° C, in 96% yield.1H-NMR (CDCl3Zppm): S 2. 56 (s, 3H), 3.84 (s, 3H), 3.88 (s, 3H), 6.10 (s, lH), 7.11 (s, lH).

Synthesis of four 6, 7-dimethoxy-4-quinolinone (Compound Id), [0042] Example

[0045] A 33. 7g (0 • 173mol) Compound lc, 150ml methanol and 95. 5g (0 • 69mol) of anhydrous potassium carbonate were added to a 500ml three-necked flask, LH stirred at room temperature, was added dropwise 75. 8g (0. 861mol) ethyl, the reaction incubated 2h. Suction filtration and dried, to give 35. 2g of a white powder compound Id (C11H11NO3), mp 124-125 ° C, yield 81.5%. 1H-NMR (DMSO-Cl6Zppm): 8 3.81 (s, 3H), 3.84 (s, 3H), 5.94 (d, 1H), 7.01 (s, 1H), 7.43 (s, lH), 7.76 (d, lH ).

[0046] Example 4- five-chloro-6, 7-dimethoxy-quinoline (compound Ie) Synthesis of

[0047] CN 102532116 B specification 5/6

[0049] The IOOml toluene, 10. 6g (0 • 52mol) Compound Id and 15g (0 • 103mol) phosphorus trichloride force the opening into a 250ml three-necked flask and heated at reflux for 2h, cooled suction filtration and dried to give 9 . 3g white powder compound Ie (C11H10ClNO2), mp 138-14 (TC, yield 87. 6% .1H-NMR (DMS〇-d6 / ppm): 8 3. 95 (s, 3H), 3.96 ( s, 3H), 7.35 (s, lH), 7.43 (s, lH), 7.54 (d, lH), 8.59 (d, lH).

Six 4 [0050] Example – [(4-amino-phenol) oxy] -6, 7-dimethoxy-quinoline (compound If) Synthesis of

[0053] In 250ml three-neck flask, was added 60ml of N, N- dimethylformamide, 8. 9g (0 • 05mol) 4- amino-3-chlorophenol hydrochloride, 14.5g (0.105mol) of potassium carbonate and (0.037 mol) compound le 8.3g, was heated refluxed for 2h. Cooled to room temperature, IOOml ethanol, stirred, filtered off with suction, and dried to give compound 8. 5g If (C17H15ClN2O3), a yield of 69. gQ / jH-NMlUDMSO-dyppm): S 3.92 (s, 3H), 3.93 ( s, 3H), 5.41 (s, 2H), 6.41 (d, 1H), 6.89 (d, 1H), 6.98 (dd, 1H), 7.19 (d, 1H), 7.36 (s, 1H), 7.48 (s , 1H), 8.43 (d, 1H).

-N’- (5- methyl-3-isobutyl – [0054] Example seven N- {[(6,7- dimethoxy-4-quinolyl) oxy] phenyl} -42- chloro oxazolyl) urea (compound Ig) synthesis of

[0056] The IOOml of N, N- dimethylformamide, 5. Og (0.051mol) of 3-amino-5-methylisoxazole, 7. 98g (0 • 051mol) and phenyl chloroformate 17g (0 • 051mol) If a compound was added to 250ml three-necked flask, the reaction was heated at reflux for 5h, cooled to room temperature, ethanol was added IOOml, stirring, filtration, and dried to give 20. Og compound Ig (C22H19ClN4O5), yield 86 . 1%. 1H-NMR (DMS0-d6 / ppm): S 2.37 (s, 3H), 3.92 (s, 3H), 3.94 (s, 3H), 6.50 (s, lH), 6.54 (d, lH), 7.26 (dd , lH), 7.39 (s, lH), 7.48 (s, lH), 7.51 (d, lH), 8.23 (d, lH), 8.49 (d, lH), 8.77 (s, lH), 10.16 (s, lH).

Claims (3)

translated from Chinese

1. An antitumor drugs Si tivozanib to synthesis, the method as follows: The lOOmL of N, N- dimethylformamide, 5 Og of 3-amino-5-methylisoxazole, 7 . 98g phenyl chloroformate and 17g 4- [(4- amino-3-chlorophenol) oxy] -6, 7-dimethoxy-quinoline was added to 250mL three-necked flask, the reaction was heated at reflux for 5h, cooled to rt, lOOmL ethanol was added, stirred, filtered off with suction, and dried to give 20. Og tivozanib, yield 86.1%, the reaction is:

Wherein the 4- [(4-amino-3-chlorophenol) oxy] -6, 7-dimethoxy-quinoline is obtained by the following synthesis method: in 250mL three-neck flask, was added 60mL of N, N- dimethylformamide, 8. 9g 4- amino-3-chloro-phenol hydrochloride, 14. 5g of potassium carbonate and 8. 3g 4- chloro-6, 7-dimethoxy quinoline, was heated at reflux for 2h cooled to room temperature, 100mL of absolute ethanol was added, stirred, filtered off with suction, and dried to obtain 8. 5g 4 – [(4_-amino-3-chlorophenol) oxy] -6, 7-dimethoxy quinoline, close was 69.9%, the reaction is:

Said 4-chloro-6, 7-dimethoxy-quinoline is obtained by the following synthesis method: A mixture of 100mL of toluene, 10 6g 6, 7- dimethoxy-4-quinolone and 15g trichloride phosphorus is added to 250mL three-necked flask and heated at reflux for 2h, cooled suction filtration, and dried to give an off-white powder 9. 3g 4- chloro-6, 7-dimethoxy quinoline, a yield of 87.6%, the reaction formula:

6, 7-dimethoxy-4-quinolone was synthesized by the following method: 33. 7g 2- amino-4, 5-dimethoxy acetophenone, 150 mL of methanol, and 95. 5g anhydrous potassium carbonate was added to the 500mL three-necked flask, stirred at room temperature LH, 75. 8g of ethyl dropwise, the reaction incubated 2h, filtered off with suction, and dried to give 35. 2g of white powder 6, 7-dimethoxy-4 – quinolinone, a yield of 81.5%, the reaction is:

The 2-amino-4,5-dimethoxy acetophenone is synthesized by the following method: In the 250mL three-neck flask, was added 36mL of water and 7g reduced iron powder was heated and refluxed for LH, was slowly added 5. 6g 3, 4-dimethoxy-6-nitroacetophenone, stirred for 3h, filtered off with suction, the filtrate was cooled to give a yellow powder 7g of 2-amino-4,5-dimethoxy acetophenone, yield 96 %, the reaction is:

2. The synthesis method according to claim 1, wherein: said 3,4-dimethoxy-6-nitroacetophenone is 3, 4-dimethoxy acetophenone nitration obtained by a reaction of reaction formula:

3. The method of synthesis according to claim 2, wherein: said 3,4-dimethoxy acetophenone in the catalyst, to give the phthalimido ether is reacted with acetyl chloride by Friedel The reaction is:

References

Tivozanib is currently being evaluated in the pivotal Phase 3 TIVO-3 trial, a randomized, controlled, multi-center, open-label study to compare tivozanib to sorafenib in subjects with refractory advanced RCC. FDA approval is expected in 2018. A Study of Tivozanib (AV-951), an Oral VEGF Receptor Tyrosine Kinase Inhibitor, in the Treatment of Renal Cell Carcinoma, clinicaltrials.gov
http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/004131/human_med_002146.jsp&mid=WC0b01ac058001d124.
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“Phase III Results Lead Aveo and Astellas to Plan Regulatory Submissions for Tivozanib”. 3 Jan 2012.
“FDA Rejects Renal Cancer Drug Tivozanib”. MedPage Today. June 30, 2013.
http://meetinglibrary.asco.org/content/165081-176
http://investor.aveooncology.com/phoenix.zhtml?c=219651&p=irol-newsArticle&ID=2172669
http://www.eusapharma.com/files/EUSA-Pharma-file-tivozanib-in-EU-March-2016.pdf
“AVEO Pharma surges 48% on recommendation for European approval of its cancer drug”. Market Watch. June 28, 2017. Retrieved June 28, 2017.
“AVEO Oncology Announces FOTIVDA® (tivozanib) Approved in the European Union for the Treatment of Advanced Renal Cell Carcinoma” (PDF). AVEO Oncology. August 28, 2017. Retrieved February 9, 2018.

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ivozanib
Names

IUPAC name 1-{2-Chloro-4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-3-(5-methylisoxazol-3-yl)urea
Other names AV-951
Identifiers
3D model (JSmol)	Interactive image
ChEMBL	ChEMBL1289494
ChemSpider	8087481
IUPHAR/BPS	6058
KEGG	D09683
PubChem CID	9911830
UNII	172030934T
InChI [show]
SMILES [show]
Properties
Chemical formula	C₂₂H₁₉ClN₄O₅
Molar mass	454.87 g·mol⁻¹
Pharmacology
ATC code	L01XE34 (WHO)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

////////Tivozanib, ema 2017, ASP-4130, AV-951, KRN-951, Kil-8951, Fotivda, Tivopath, orphan drug, ティボザニブ塩酸塩水和物,

CC1=CC(=NO1)NC(=O)NC2=C(C=C(C=C2)OC3=C4C=C(C(=CC4=NC=C3)OC)OC)Cl

FDA approves new treatment for certain digestive tract cancers Lutathera (lutetium Lu 177 dotatate)

January 27, 2018 6:42 am / Leave a comment

Image result for lutetium Lu 177 dotatate

lutetium Lu 177 dotatate

FDA approves new treatment for certain digestive tract cancers

The U.S. Food and Drug Administration today approved Lutathera (lutetium Lu 177 dotatate) for the treatment of a type of cancer that affects the pancreas or gastrointestinal tract called gastroenteropancreatic neuroendocrine tumors (GEP-NETs). This is the first time a radioactive drug, or radiopharmaceutical, has been approved for the treatment of GEP-NETs. Lutathera is indicated for adult patients with somatostatin receptor-positive GEP-NETs. Continue reading.\

https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm594043.htm?utm_campaign=01262018_PR_FDA%20approves%20new%20treatment%20for%20digestive%20cancers&utm_medium=email&utm_source=Eloqua

January 26, 2018

Release

“GEP-NETs are a rare group of cancers with limited treatment options after initial therapy fails to keep the cancer from growing,” said Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “This approval provides another treatment choice for patients with these rare cancers. It also demonstrates how the FDA may consider data from therapies that are used in an expanded access program to support approval for a new treatment.”

GEP-NETs can be present in the pancreas and in different parts of the gastrointestinal tract such as the stomach, intestines, colon and rectum. It is estimated that approximately one out of 27,000 people are diagnosed with GEP-NETs per year.

Lutathera is a radioactive drug that works by binding to a part of a cell called a somatostatin receptor, which may be present on certain tumors. After binding to the receptor, the drug enters the cell allowing radiation to cause damage to the tumor cells.

The approval of Lutathera was supported by two studies. The first was a randomized clinical trial in 229 patients with a certain type of advanced somatostatin receptor-positive GEP-NET. Patients in the trial either received Lutathera in combination with the drug octreotide or octreotide alone. The study measured the length of time the tumors did not grow after treatment (progression-free survival). Progression-free survival was longer for patients taking Lutathera with octreotide compared to patients who received octreotide alone. This means the risk of tumor growth or patient death was lower for patients who received Lutathera with octreotide compared to that of patients who received only octreotide.

The second study was based on data from 1,214 patients with somatostatin receptor-positive tumors, including GEP-NETS, who received Lutathera at a single site in the Netherlands. Complete or partial tumor shrinkage was reported in 16 percent of a subset of 360 patients with GEP-NETs who were evaluated for response by the FDA. Patients initially enrolled in the study received Lutathera as part of an expanded access program. Expanded access is a way for patients with serious or immediately life-threatening diseases or conditions who lack therapeutic alternatives to gain access to investigational drugs for treatment use.

Common side effects of Lutathera include low levels of white blood cells (lymphopenia), high levels of enzymes in certain organs (increased GGT, AST and/or ALT), vomiting, nausea, high levels of blood sugar (hyperglycemia) and low levels of potassium in the blood (hypokalemia).

Serious side effects of Lutathera include low levels of blood cells (myelosuppression), development of certain blood or bone marrow cancers (secondary myelodysplastic syndrome and leukemia), kidney damage (renal toxicity), liver damage (hepatotoxicity), abnormal levels of hormones in the body (neuroendocrine hormonal crises) and infertility. Lutathera can cause harm to a developing fetus; women should be advised of the potential risk to the fetus and to use effective contraception. Patients taking Lutathera are exposed to radiation. Exposure of other patients, medical personnel, and household members should be limited in accordance with radiation safety practices.

Lutathera was granted Priority Review, under which the FDA’s goal is to take action on an application within six months where the agency determines that the drug, if approved, would significantly improve the safety or effectiveness of treating, diagnosing or preventing a serious condition. Lutathera also received Orphan Drugdesignation, which provides incentives to assist and encourage the development of drugs for rare diseases.

The FDA granted the approval of Lutathera to Advanced Accelerator Applications.

MORE FROM PUBLIC DOMAIN……………..

WATCH THIS SPACE FOR SYNTHESIS COMING

Dotatate lutenium Lu-177.png

Dotatate lutenium Lu-177; 437608-50-9; DTXSID20195927

2-[4-[2-[[(2R)-1-[[(4R,7S,10S,13R,16S,19R)-10-(4-aminobutyl)-4-[[(1S,2R)-1-carboxy-2-hydroxypropyl]carbamoyl]-7-[(1R)-1-hydroxyethyl]-16-[(4-hydroxyphenyl)methyl]-13-(1H-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentazacycloicos-19-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-2-oxoethyl]-7,10-bis(carboxylatomethyl)-1,4,7,10-tetrazacyclododec-1-yl]acetate;lutetium(3+)

Image result for lutetium Lu 177 dotatate

Lutetium-177

Lutetium-177 has been quite a late addition as an isotope of significance to the nuclear medicine yet it is making big strides especially as a therapeutic radiopharmaceutical for neuroendocrine tumours in the form of ¹⁷⁷Lu-DOTA-TATE on regular basis as described by Das & Pillai (2013).

Lutetium-177 a lanthanide is an f block element that has a half-life of 6.7 days and decays mainly by beta emission to Hf-177, is accompanied by two gamma ray emissions. These radionuclide properties are very similar to those of I-131 which has long served as a therapeutic radionuclide, it was therefore not surprising that Lu-177 also emerged as a highly valuable radionuclide for similar applications,

There are several other upcoming applications especially for bone pain palliatiion. As a result of its convenient production logistics Lu-177 as discussed by Pillai et al (2003) is fast emerging a radionuclide of choice in radionuclide therapy (RNT).

Lu-177 can be prepared in a nuclear reactor by one of the two reactions given below :

¹⁷⁶Lu(n,gamma)¹⁷⁷Lu or

¹⁷⁶Yb(n,gamma)¹⁷⁷Yb –beta–> ¹⁷⁷Lu

The former reaction has a high thermal neutron capture cross section and is presently the method adopted at our reactors in spite of the formation of long lived Lu-177m whose yield is very much low and is considered insignificant to cause any great concern.

Lutetium-177 Impact

Recently there has been a rush of several research reviews and articles where Lu-177 holds the centre stage, for example, Banerjee et al (2015) have reviewed the chemistry and applications of Lu-177; Dash et al (2015) reviewed its production and available options; Knapp & Pillai (2015) highlighted its usefulness in cancer treatment and chronic diseases and Pillai and Knapp (2015) have discussed the evolving role of Lu-177 in nuclear medicine with this ready availability of Lu-177. Peptide receptor radionuclide therapy is one of the upcoming field of investigation where Lu-177 holds much promise among few other radionuclides. Indeed Lutetium-177 has covered a good distance especially for Therapeutic and as a palliative radiopharmaceutical.

Chemistry

Das et al (2014) have described the preparation of Lu-177 EDTMP kit.

Parus et al (2015) have discussed chemistry of bifunctional chelating agents for binding Lu-177.

Gupta et al (2014) have compiled methods of labelleing antibdoies with radioiodine and radiometals.

Applications

Limouris (2012) has reviewed applications in neuroendocrine tumors with focus on Liver metastasis. Das and Banerjee (2015) described the potential theranostic applications with Lu-177.

Anderson et al (1960) were among the first to use Lutetium (as chloride and citrate) in a clinical trial which were not so successful and did not encourage much promise. Keeling et al (1988) published their results with in vitro uptake of Lutetium hydroxylapatite particles. Lu-EDTMP as bone palliating agent by Ando et al (1998) soon followed, However the greatest impact was seen with the advent of a somatostatin analogue Lu-DOTATATE for targetting neuroendocrine tumors reported by Kwekkeboom et al (2001) and reviewed recently by Bodei et al (2013).

PRRNT – IAEA (2013) has brought out a human health series booklet on the subject with emphasis on neuroendocrine tumors.

¹⁷⁷Lu Labelled Peptides in NET Kam et al (2012).

¹⁷⁷Lu- DOTATATE – PRRNT – Bakker et al (2006)

¹⁷⁷Lu-EDTMP – Bone Pain Palliation – Bahrami-Samani et al (2012)

¹⁷⁷Lu-EDTMP – Pharmacokinetics, dosimetry and Therapeutic efficacy – Chakraborty S et al (2015)

¹⁷⁷Lu-Hydroxylapatite – Radiosynovectomy – Kamalleshwaran et al. (2014) Shinto et al. (2015)

117Lu- Radioimmunotherapy – Kameshwaran et al (2015)

177Lu – Pretargeted Radioimmunotherapy (PRIT) Frost et al (2015).

More specific applications and additional information about the highly valuable therapeutic isotope would soon be added.

References and Notes

Anderson J, Farmer FT, Haggith JW, Hill M. (1960). The treatment of myelomatosis with Lutetium. Br J Radiol. 33:374-378.

Ando A, Ando L, Tonami N, Kinuya S, Kazuma K, Kataiwa A, Nakagawa M, Fujita N. (1998). 177Lu-EDTMP: a potential therapeutic bone agent. Nucl Med Commun. 19: 587-591.

Bahrami-Samani A, Anvari A, Jalilian AR, Shirvani-Arani S, Yousefnia H, Aghamiri MR, Ghannadi-Maragheh M. (2012). Production, Quality Control and Pharmacokinetic Studies of 177Lu-EDTMP for Human Bone Pain Palliation Therapy Trials. Iran J Pharm Res. 11:137-44.

Bakker WH, Breeman WAP, Kwekkeboom DJ, De Jong LC, Krenning EP. ((2006) Practical aspects of peptide receptor radionuclide therapy with [177Lu][DOTA0, Tyr3]octreotate. Q J Nucl Med Mol Imaging 50: 265-271.

Banerjee S, Pillai MR, Knapp FF (2015). Lutetium-177 Therapeutic Radiopharmaceuticals: Linking Chemistry, Radiochemistry, and Practical Applications. Chem Rev. 115: 2934-2974.

Bodei L, Mueller-Brand J, Baum RP, Pavel ME, Hörsch D, O’Dorisio MS, O’Dorisio TM, Howe JR, Cremonesi M, Kwekkeboom DJ, Zaknun JJ. (2013).The joint IAEA, EANM, and SNMMI practical guidance on peptide receptor radionuclide therapy (PRRNT) in neuroendocrine tumours. Eur J Nucl Med Mol Imaging. 2013 40:800-16.

Chakraborty S, Balogh L, Das T, Polyák A, Andócs G, Máthé D, Király R, Thuróczy J, Chaudhari PR, Jánoki GA, Jánoki G, Banerjee S, Pillai MR (2015). Evaluation of 177Lu-EDTMP in dogs with spontaneous tumor involving bone: Pharmacokinetics, dosimetry and therapeutic efficacy. Curr Radiopharm (ahead of Pub)

Das T, Banerjee S. (2015). Theranostic Applications of Lutetium-177 in Radionuclide Therapy. Curr Radiopharm. (ahead of print).

Das T , Sarma HD, Shinto A, Kamaleshwaran KK, Banerjee S. (2014). Formulation, Preclinical Evaluation, and Preliminary Clinical Investigation of an In-House Freeze-Dried EDTMP Kit Suitable for the Preparation of Lu-177-EDTMP. Cancer Biotherap Radiopharm. 29: (ahead of publication).

Das T, Pillai M.R.A. (2013).Options to meet the future global demand of radionuclides for radionuclide therapy. Nucl Med Biol. 40: 23-32.

Dash A, Pillai MR, Knapp FF Jr. (2015). Production of 177Lu for targeted radionuclide therapy : Available options. Nucl Med Mol Imaging. 49: 85-107.

Frost SH, Frayo SL, Miller BW, Orozco JJ, Booth GC, Hylarides MD, Lin Y, Green DJ, Gopal AK, Pagel JM, Bäck TA, Fisher DR, Press OW. (2015) Comparative efficacy of 177Lu and 90Y for anti-CD20 pretargeted radioimmunotherapy in murine lymphoma xenograft models. PLoS One. 2015 Mar 18;10(3):e0120561.

Gupta S, Batra S, Jain M (2014) Antibody labeling with radioiodine and radiometals. Methods Mol Biol. 2014;1141:147-57.

IAEA (2013). Peptide receptor radionuclide therapy (PRRNT) for neuroendocrine tumors. IAEA Human Health Series No. 20., IAEA, Vienna.

Kam BLR, Teunissen JJM, Krenning EP, de Herder WW, Khan S, van Vliet EI, Kwekkeboom DJ. (2012). Lutetium-labelled peptides for therapy of neuroendocrine tumours. Eur J Nucl Med Mol Imaging 39 (Suppl 1):S103–S112.

Kamaleshwaran KK, Rajamani V, Thirumalaisamy SG, Chakraborty S, Kalarikal R, Mohanan V, Shinto AS.(2014).

Radiosynovectomy of the elbow joint synovitis in rheumatoid arthritis treated with Lutetium – 177 labeled hydroxylapatite (Lu-177HA) particulates; first case report and image of Lu -177 HA in the elbow joint. Indian J Nucl Med. 29:270-2.

Kameshwaran M, Pandey U, Dhakan C, Pathak K, Gota V, Vimalnath KV, Dash A, Samuel G. (2015) .Synthesis and Preclinical Evaluation of (177)Lu-CHX-A”-DTPA-Rituximab as a Radioimmunotherapeutic Agent for Non-Hodgkin’s Lymphoma. Cancer Biother Radiopharm. 2015 Aug;30(6):240-6

Kwekkeboom DJ, Bakker WH, Kooij PP, Konijnenberg MW, Srinivasan A, Erion JL, Schmidt MA, Bugaj JL, de Jong M, Krenning EP.. (2001). [177Lu-DOTAOTyr3]octreotate: comparison with [111In-DTPAo]octreotide in patients.Eur J Nucl Med. 28: 1319-1325.

(Russ) Knapp FF, Pillai MR.(2015). Lutetium-177 Labeled Therapeutics: Emerging Importance for Cancer Treatment and Therapy of Chronic Disease. Curr Radiopharm. (ahead of Pub)

Parus JL, Pawlak D, Mikolajczak R, Duatti A. (2015) Chemistry and bifunctional chelating agents for binding 177Lu Curr Radiopharm (Ahead of Pub)

Limouris G. (2012) Neuroendocrine tumors: a focus on liver metastatic lesions. Front Oncol. 2:20 (Ahead of Pub) PMC article

Pillai MR, (Russ) Knapp FF. (2015). Evolving Important Role of Lutetium-177 for Therapeutic Nuclear Medicine Curr Radiopharm (ahead of print).

Pillai MR, Chakraborty S, Das T, Venkatesh M, Ramamoorthy N. (2003). Production logistics of 177Lu for radionuclide therapy. Appl Radiat Isot. 59: 109-118.

Shinto AS, Kamaleshwaran KK, Vyshakh K, Thirumalaisamy SG, Karthik S, Nagaprabhu VN, Vimalnath KV, Das T, Chakraborty S, Banerjee S. (2015) Radiosynovectomy of Painful Synovitis of Knee Joints Due to Rheumatoid Arthritis by Intra‑Articular Administration of 177Lu‑Labeled Hydroxyapatite Particulates: First Human Study and Initial Indian Experience. World J Nucl Med. 14: (ahead of print).

Videos

Lutetium – Periodic Table of Videos

Lutetium — a new ally in the fight against cancer

Lutetium-177 octreotate (LuTate) Radionuclide therapy ( 3 videos)

DOTA-TATE
Names

Other names DOTA-(Tyr³)-octreotate
Identifiers
CAS Number	177943-89-4
3D model (JSmol)	Interactive image
ChemSpider	9345959
PubChem CID	11170867
InChI [show]
SMILES [show]
Properties
Chemical formula	C₆₅H₉₀N₁₄O₁₉S₂
Molar mass	1,435.63 g·mol⁻¹
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

DOTA-TATE, DOTATATE or DOTA-octreotate is a substance which, when bound to various radionuclides, has been tested for the treatment and diagnosis of certain types of cancer, mainly neuroendocrine tumours.

Chemistry and mechanism of action

DOTA-TATE is an amide of the acid DOTA (top left in the image), which acts as a chelator for a radionuclide, and (Tyr³)-octreotate, a derivative of octreotide. The latter binds to somatostatin receptors, which are found on the cell surfaces of a number of neuroendocrine tumours, and thus directs the radioactivity into the tumour.

Usage examples

Gallium (⁶⁸Ga) DOTA-TATE (GaTate^[1]) is used for tumour diagnosis in positron emission tomography (PET).^[2] DOTA-TATE PET/CT has a much higher sensitivitycompared to In-111 octreotide imaging.^[1]

Lutetium (¹⁷⁷Lu) DOTA-TATE^[3] has been tested for the treatment of tumors such as carcinoid and endocrine pancreatic tumor. It is also known as Lutathera.^[4]

Patients are typically treated with an intravenous infusion of 7.5 GBq of lutetium-177 octreotate. After about four to six hours, the exposure rate of the patient has fallen to less than 25 microsieverts per hour at one metre and the patients can be discharged from hospital.

A course of therapy consists of four infusions at three monthly intervals.^[5]

Availability

Lu177 octreotate therapy is currently available under research protocols in five different medical centers in North America: Los Angeles (CA), Quebec City, (Qc), Birmingham, AL, Edmonton, (Ab), London, (On) as Houston (Tx) on clinical trial.^[6] Medical centers in Europe also offer this treatment. For instance: Cerrahpasa Hospital in Turkey, Uppsala Centre of Excellence in Neuroendocrine Tumors in Sweden and Erasmus University in the Netherlands.^[7] In Israel, treatment is available at Hadassah Ein Kerem Medical Center. In Australia, treatment is available at St George Hospital and Royal North Shore Hospital, Sydney;^[8] the Royal Brisbane and Women’s Hospital in Brisbane ^[9], the Peter MacCallum Cancer Centre ^[1] and at the Department of Nuclear Medicine at Fremantle Hospital in Western Australia.^[10] In Aarhus universitet hospital in Denmark. In the coming years such therapy will also become commercially available in Latvia, Riga – “Clinic of nuclear medicine”.

References

^ Jump up to:^a ^b ^c Hofman, M. S.; Kong, G.; Neels, O. C.; Eu, P.; Hong, E.; Hicks, R. J. (2012). “High management impact of Ga-68 DOTATATE (GaTate) PET/CT for imaging neuroendocrine and other somatostatin expressing tumours”. Journal of Medical Imaging and Radiation Oncology. 56 (1): 40–47. doi:10.1111/j.1754-9485.2011.02327.x. PMID 22339744.
Jump up^ Breeman, W. A. P.; De Blois, E.; Sze Chan, H.; Konijnenberg, M.; Kwekkeboom, D. J.; Krenning, E. P. (2011). “68Ga-labeled DOTA-Peptides and 68Ga-labeled Radiopharmaceuticals for Positron Emission Tomography: Current Status of Research, Clinical Applications, and Future Perspectives”. Seminars in Nuclear Medicine. 41 (4): 314–321. doi:10.1053/j.semnuclmed.2011.02.001. PMID 21624565.
Jump up^ Bodei, L.; Cremonesi, M.; Grana, C. M.; Fazio, N.; Iodice, S.; Baio, S. M.; Bartolomei, M.; Lombardo, D.; Ferrari, M. E.; Sansovini, M.; Chinol, M.; Paganelli, G. (2011). “Peptide receptor radionuclide therapy with 177Lu-DOTATATE: The IEO phase I-II study”. European Journal of Nuclear Medicine and Molecular Imaging. 38(12): 2125–2135. doi:10.1007/s00259-011-1902-1. PMID 21892623.
Jump up^ Radiolabeled Peptide Offers PFS Benefit in Midgut NET
Jump up^ Claringbold, P. G.; Brayshaw, P. A.; Price, R. A.; Turner, J. H. (2010). “Phase II study of radiopeptide 177Lu-octreotate and capecitabine therapy of progressive disseminated neuroendocrine tumours”. European Journal of Nuclear Medicine and Molecular Imaging. 38 (2): 302–311. doi:10.1007/s00259-010-1631-x. PMID 21052661.
Jump up^ Clinical trial number NCT01237457 for “177Lutetium-DOTA-Octreotate Therapy in Somatostatin Receptor-Expressing Neuroendocrine Neoplasms” at ClinicalTrials.gov
Jump up^ “PRRT Behandelcentrum Rotterdam”. PRRT Behandelcentrum Rotterdam. Erasmus Universiteit.
Jump up^ http://www.swslhd.nsw.gov.au/liverpool/pet/PET.html
Jump up^ https://agitg.org.au/control-nets-study-set-to-commence
Jump up^ Turner, J. H. (2012). “Outpatient therapeutic nuclear oncology”. Annals of Nuclear Medicine. 26 (4): 289–97. doi:10.1007/s12149-011-0566-z. PMID 22222779.

Freedman, N; Klein, M; Gross, D; Glasberg, S; Meirovitz, A; Maimon, O; Krausz, Y; Bar-Shalom, R (2014). “Lu177-DOTATATE therapy for NET: Does tumor dose predict response?”. J Nucl Med. 55 (Supplement 1).

//////////////Lutathera, lutetium Lu 177 dotatate, fda 2018, PRIORITY REVIEW, ORPHAN DRUG

CC(C1C(=O)NC(CSSCC(C(=O)NC(C(=O)NC(C(=O)NC(C(=O)N1)CCCCN)CC2=CNC3=CC=CC=C32)CC4=CC=C(C=C4)O)NC(=O)C(CC5=CC=CC=C5)NC(=O)CN6CCN(CCN(CCN(CC6)CC(=O)[O-])CC(=O)[O-])CC(=O)[O-])C(=O)NC(C(C)O)C(=O)O)O.[Lu+3]

FDA approves first drug for Eosinophilic Granulomatosis with Polyangiitis, a rare disease formerly known as the Churg-Strauss Syndrome

December 13, 2017 1:00 am / Leave a comment

FDA approves first drug for Eosinophilic Granulomatosis with Polyangiitis, a rare disease formerly known as the Churg-Strauss Syndrome

The U.S. Food and Drug Administration today expanded the approved use of Nucala (mepolizumab) to treat adult patients with eosinophilic granulomatosis with polyangiitis (EGPA), a rare autoimmune disease that causes vasculitis, an inflammation in the wall of blood vessels of the body. This new indication provides the first FDA-approved therapy specifically to treat EGPA. Continue reading.

December 12, 2017

Release

According to the National Institutes of Health, EGPA (formerly known as Churg-Strauss syndrome) is a condition characterized by asthma, high levels of eosinophils (a type of white blood cell that helps fight infection), and inflammation of small- to medium-sized blood vessels. The inflamed vessels can affect various organ systems including the lungs, gastrointestinal tract, skin, heart and nervous system. It is estimated that approximately 0.11 to 2.66 new cases per 1 million people are diagnosed each year, with an overall prevalence of 10.7 to 14 per 1,000,000 adults.

“Prior to today’s action, patients with this challenging, rare disease did not have an FDA-approved treatment option,” said Badrul Chowdhury, M.D., Ph.D., director of the Division of Pulmonary, Allergy, and Rheumatology Products in the FDA’s Center for Drug Evaluation and Research. “The expanded indication of Nucala meets a critical, unmet need for EGPA patients. It’s notable that patients taking Nucala in clinical trials reported a significant improvement in their symptoms.”

The FDA granted this application Priority Review and Orphan Drug designations. Orphan Drug designation provides incentives to assist and encourage the development of drugs for rare diseases.

Nucala was previously approved in 2015 to treat patients age 12 years and older with a specific subgroup of asthma (severe asthma with an eosinophilic phenotype) despite receiving their current asthma medicines. Nucala is an interleukin-5 antagonist monoclonal antibody (IgG1 kappa) produced by recombinant DNA technology in Chinese hamster ovary cells.

Nucala is administered once every four weeks by subcutaneous injection by a health care professional into the upper arm, thigh, or abdomen.

The safety and efficacy of Nucala was based on data from a 52-week treatment clinical trial that compared Nucala to placebo. Patients received 300 milligrams (mg) of Nucala or placebo administered subcutaneously once every four weeks while continuing their stable daily oral corticosteroids (OCS) therapy. Starting at week four, OCS was tapered during the treatment period. The primary efficacy assessment in the trial measured Nucala’s treatment impact on disease remission (i.e., becoming symptom free) while on an OCS dose less than or equal to 4 mg of prednisone. Patients receiving 300 mg of Nucala achieved a significantly greater accrued time in remission compared with placebo. A significantly higher proportion of patients receiving 300 mg of Nucala achieved remission at both week 36 and week 48 compared with placebo. In addition, significantly more patients who received 300 mg of Nucala achieved remission within the first 24 weeks and remained in remission for the remainder of the 52-week study treatment period compared with patients who received the placebo.

The most common adverse reactions associated with Nucala in clinical trials included headache, injection site reaction, back pain, and fatigue.

Nucala should not be administered to patients with a history of hypersensitivity to mepolizumab or one of its ingredients. It should not be used to treat acute bronchospasm or status asthmaticus. Hypersensitivity reactions, including anaphylaxis, angioedema, bronchospasm, hypotension, urticaria, rash, have occurred. Patients should discontinue treatment in the event of a hypersensitivity reaction. Patients should not discontinue systemic or inhaled corticosteroids abruptly upon beginning treatment with Nucala. Instead, patients should decrease corticosteroids gradually, if appropriate.

Health care providers should treat patients with pre-existing helminth infections before treating with Nucala because it is unknown if Nucala would affect patients’ responses against parasitic infections. In addition, herpes zoster infections have occurred in patients receiving Nucala. Health care providers should consider vaccination if medically appropriate.

The FDA granted approval of Nucala to GlaxoSmithKline.

//////////////Nucala, mepolizumab, fda 2017, gsk, Eosinophilic Granulomatosis, Polyangiitis, Churg-Strauss Syndrome, Priority Review, Orphan Drug

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Company: Swedish Orphan Biovitrum AB Application No.: 206356Orig1 Approval Date: April 22, 2016

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Company: Swedish Orphan Biovitrum AB
Application No.: 206356Orig1
Approval Date: April 22, 2016

¹H NMR, ¹³C NMR, and Computational DFT Studies of the Structure of 2-Acylcyclohexane-1,3-diones and Their Alkali Metal Salts in Solution

Discovery of Dihydrobenzoxazepinone (GS-6615) Late Sodium Current Inhibitor (Late I_Nai), a Phase II Agent with Demonstrated Preclinical Anti-Ischemic and Antiarrhythmic Properties