Home » 2018 » June (Page 4)

Monthly Archives: June 2018

FDA approves first biosimilar to Neulasta, Fulphila (pegfilgrastim) to help reduce the risk of infection during cancer treatment

June 5, 2018 10:50 am / Leave a comment

Image result for pegfilgrastim-jmdb

FDA approves first biosimilar to Neulasta to help reduce the risk of infection during cancer treatment

The U.S. Food and Drug Administration today approved Fulphila (pegfilgrastim-jmdb) as the first biosimilar to Neulasta (pegfilgrastim) to decrease the chance of infection as suggested by febrile neutropenia (fever, often with other signs of infection, associated with an abnormally low number of infection-fighting white blood cells), in patients with non-myeloid (non-bone marrow) cancer who are receiving myelosuppressive chemotherapy that has a clinically significant incidence of febrile neutropenia.

June 4, 2018

Release

“Bringing new biosimilars to patients is a top priority for the FDA, and a key part of our efforts to help promote competition that can reduce drug costs and promote access,” said FDA Commissioner Scott Gottlieb, M.D. “We’ll continue to prioritize reviews of these products to help ensure that biosimilar medications are brought to the market efficiently and through a process that makes certain that these new medicines meet the FDA’s rigorous standard for approval. This summer, we’ll release a comprehensive new plan to advance new policy efforts that promote biosimilar product development. Biologics represent some of the most clinically important, but also costliest products that patients use to promote their health. We want to make sure that the pathway for developing biosimilar versions of approved biologics is efficient and effective, so that patients benefit from competition to existing biologics once lawful intellectual property has lapsed on these products.”

Biological products are generally derived from a living organism and can come from many sources, such as humans, animals, microorganisms or yeast. A biosimilar is a biological product that is approved based on data showing that it is highly similar to a biological product already approved by the FDA (reference product) and has no clinically meaningful differences in terms of safety, purity and potency (i.e., safety and effectiveness) from the reference product, in addition to meeting other criteria specified by law.

The FDA’s approval of Fulphila is based on review of evidence that included extensive structural and functional characterization, animal study data, human pharmacokinetic and pharmacodynamic data, clinical immunogenicity data, and other clinical safety and effectiveness data that demonstrates Fulphila is biosimilar to Neulasta. Fulphila has been approved as a biosimilar, not as an interchangeable product.

The most common side effects of Fulphila are bone pain and pain in extremities. Patients with a history of serious allergic reactions to human granulocyte colony-stimulating factors such as pegfilgrastim or filgrastim products should not take Fulphila.

Serious side effects from treatment with Fulphila include rupture of the spleen, acute respiratory distress syndrome, serious allergic reactions including anaphylaxis, acute inflammation of the kidney (glomerulonephritis), an abnormally high level of white blood cells (leukocytosis), capillary leak syndrome and the potential for tumor growth. Fatal sickle cell crises have occurred.

The FDA granted approval of Fulphila to Mylan GmbH.

Image result for Neulasta

//////////// pegfilgrastim, fda 2018, Fulphila, Neulasta, Mylan GmbH, biosimilars, MONOCLONAL ANTIBODY,

YINLITINIB

June 5, 2018 10:43 am / Leave a comment

YINLITINIB

error EMAIL ME amcrasto@gmail.com

(E)-4-[(4aR,7aS)-2,3,4a,5,7,7a-hexahydro-[1,4]dioxino[2,3-c]pyrrol-6-yl]-N-[4-(3-chloro-4-fluoroanilino)-7-methoxyquinazolin-6-yl]but-2-enamide

(E)-N-(4-((3-Chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-((4aR,7aS)-tetrahydro-2H-[1,4]dioxin[2,3-c]pyrrol-6(3H)-yl)but-2-enamide

CAS 1637253-79-2

2-Butenamide, N-[4-[(3-chloro-4-fluorophenyl)amino]-7-methoxy-6-quinazolinyl]-4-[(4aR,7aS)-hexahydro-6H-1,4-dioxino[2,3-c]pyrrol-6-yl]-, (2E)-rel–

C₂₅ H₂₅ Cl F N₅ O₄, 513.95

DNT-04110 ; yinlitinib maleate , Guangdong Hec Pharmaceutical

Use for treating proliferative diseases, atherosclerosis and pulmonary fibrosis

Phase I CHINA

NOTE AND USE YOUR JUDGMENT ON DRUG SUBSTANCE, EMAIL ME amcrasto@gmail.com

Molecular Formula:	C₂₅H₂₅ClFN₅O₄
Molecular Weight:	516.973 g/mol

Yinlitinib methoxy-d₃

CAS 1637254-71-7

C₂₅ H₂₂ Cl D₃ F N₅ O₄

2-Butenamide, N-[4-[(3-chloro-4-fluorophenyl)amino]-7-(methoxy-d₃)-6-quinazolinyl]-4-[(4aR,7aS)-hexahydro-6H-1,4-dioxino[2,3-c]pyrrol-6-yl]-, (2E)-rel–

CN 104119350

YINLITINIB MALEATE methoxy-d₃

CAS ?

EMAIL ME amcrasto@gmail.com

MAY BE DRUG COMD

Patent ID	Patent Title	Submitted Date	Granted Date
US9556191	AMINOQUINAZOLINE DERIVATIVES AND THEIR SALTS AND METHODS OF USE THEREOF	2014-04-28	2016-02-11

In March 2015, an IND was filed in China ; in February 2016, approval to conduct a clinical trial was obtained

Guangdong Hec Pharmaceutical is investigating an oral capsule formulation of yinlitinib maleate (DNT-04110), an irreversible pan-ErbB inhibitor, for the potential treatment of solid tumors . In March 2015, an IND was filed in China ; in February 2016, approval to conduct a clinical trial was obtained . In December 2016, a phase I trial was planned in China

Protein kinases (PKs) represent a large family of proteins, which play an important role in the regulation of a wide variety of cellular processes and maintaining control over cellular functions. There are two classes of protein kinases (PKs): the protein tyrosine kinases (PTKs) and the serine-threonine kinases (STKs). The protein tyrosine kinase is an enzyme that catalytically transfers the phosphate group from ATP to the tyrosine residue located at the protein substrate, and has a play in the normal cell growth. Many growth factor receptor proteins operate via the tyrosine kinase, and influence the conduction of signal passage and further regulate the cell growth by this process. However, in some circumstances, these receptors become abnormal due to either mutation or overexpression, which cause the uncontrolled cell multiplication, cause the tumor growth, and finally initiate the well-known disease, i.e., cancer. The growth factor receptor protein tyrosine kinase inhibitor, via the inhibition of the above phosphorylation process, may treat cancers and other diseases characterized by the uncontrolled or abnormal cell growth.

Epidermal growth factor receptor (EGFR), a kind of receptor tyrosine kinases, is a multifunction glycoprotein that is widely distributed on the cell membranes of the tissues of the human body, and is an oncogene analog of avian erythroblastic leukemia viral (v-erb-b). Human EGFR/HER1/ErbB-1 and HER2 (human epidermal growth factor receptor-2)/ErbB-2/Teu/p185, HER3/ErbB-3, HER4/ErbB-4 and the like are grouped into the HER/ErbB family, and belong to protein tyrosine kinases (PTKs). They are single polypeptide chains, and each is encoded respectively by genes located on different chromosomes. EGFR and the like are expressed in the epithelia-derived tumors such as squamous cell carcinoma of head and neck, mammary cancer, rectal cancer, ovarian cancer, prostate carcinoma, non-small cell lung cancer, and the like, which are associated with cell proliferation, metastasis, and the like. Pan-HER tyrosine kinase inhibitor, via the competitive binding to the kinase catalytic sites in the intracellular region against ATP, blocks the autophosphorylation of intramolecular tyrosine, blocks the tyrosine kinase activation, inhibits HER-2 family activation, and therefore inhibits cell cycle progression, accelerates cell apoptosis, and exerts the therapeutic action.

EGFR, after binding to the ligand, forms a dimer with a subgroup of HER family, and then combines with ATP to activate the tyrosine kinase activity of the EGFR itself. Therefore, the autophosphorylation occurs in several tyrosine sites of the intracellular kinase region. Pan-HER tyrosine kinase inhibitor, via simultaneity acting on EGFR and HER2/4, inhibits the activation of HER family, and plays a good role in the tumor growth inhibition.

It is indicated in the study that Pan-HER tyrosine kinase irreversible inhibitor has an inhibition effect on HER2/4, besides it effectively inhibits EGFR. The pharmaceutical drugs of this kind, having an irreversible inhibition to both of HER/ErbB families, not only increase the drug activity, but also reduce the drug resistance, and have a substantial inhibition effect on H1975 cell lines which are resistant to erlotinib.

The pharmaceutical drugs that are now commercially available include selective EGFR tyrosine kinase inhibitor gefitinb (IRESSA®, ZD1839), erlotinib (TARCEVA®, OSI-774), double EGFR/HER2 inhibitor Lapatinib (TYKERB®, GW572016), and the like. These three drugs are all reversible EGF receptor tyrosine phosphorylation kinase inhibitor. It has been found in the study that they have good therapeutic response to some tumors initially. However, several months after the treatment, the disease progression appears again and therefore a natural or secondary drug resistance forms. For example, about half of the patients administered with gefitinib or erlotinib develop resistance to gefitinib or erlotinib, which can not lead to the desired therapeutic effect. And it has been indicated by study that the development of drug resistance to selective EGFR tyrosine kinase inhibitor relates to mutations in EGFR.

The mutations of EGFR gene mostly located in the tyrosing kinase coding domain (TK, exons 18-21) are mainly deletion mutation in exon 19 and point mutation in exon 21, both of which are drug-sensitive, and few are point mutation in exon 18 and insertion mutation in exon 20. T790M mutation recognized as one of the mechanism of drug resistance is a point mutation in exon 20 of EGFR. The presence of a second-site EGFR mutation leads to the substitution of methionine for threonine at position 790 (T790M) and changes in the structure of EGFR, which hinder the binding of EGFR inhibitors to EGFR or greatly increase the affinity between EGFR and ATP, so that ATP affinity back to the level of wild-type EGFR, thus resulting in drug resistance. Further studies shows that the pre-treatment tumor samples with mutations of EGFR contain T790M mutation, which indicates that T790M mutation is not just associated with drug resistance and it may have the carcinogenic potential itself.

Irreversible inhibitor can bind to EGFR tyrosine kinase by covalent bond. Thus, the drugs can act on the entire link of epidermal growth factor signal transduction pathway, and improve efficiency of drug blocking. Many clinical studies show that some irreversible inhibitors in current development can against T790M mutation, and overcome the drug resistance caused by T790M. Meanwhile, listed drug Afatinib (BIBW 2992) and some irreversible inhibitors in clinical development (e.g., Dacomitinib, PF00299804, etc.), can inhibit multiple members of EGFR receptor family, especially to the role of EGFR and HER-2, possibly by blocking collaborative signal pathway activated by homodimer and heterodimer to enhance inhibitory effect (Oncologist, 2009, 14 (11): 1116-1130).

Upon developing the drug having an excellent antineoplastic effect, being able to reduce the drug resistance and having a good tolerance, the present inventors discover a quinazoline derivatives as tyrosine kinase inhibitors having a Pan-HER irreversible inhibition function.

PATENT

https://patents.google.com/patent/US9556191

EXAMPLES Example 1 (E)-N-(4-((3-Chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-((4aR,7aS)-tetrahydro-2H-[1,4]dioxin[2,3-c]pyrrol-6(3H)-yl)but-2-enamide

Step 1) N-(3-chloro-4-fluorophenyl)-7-methoxy-6-nitroquinazolin-4-amine

A solution of N-(3-chloro-4-fluorophenyl)-7-fluoro-6-nitroquinazolin-4-amine (10.00 g, 29.8 mmol) and sodium methanolate (2.80 g, 51.8 mmol) in methanol (150 mL) was heated to 70° C. and stirred for 4.0 hours. The reaction mixture was then cooled to 25° C. The resulting mixture was poured into ice water (500 mL), and a yellow solid precipitated out. The mixture was filtered and the filter cake was dried under vacuum to give the title compound as a yellow solid (9.00 g, 86.9%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) m/z: 349.1 [M+1]⁺; and ¹H NMR (400 MHz, DMSO-d₆) δ: 11.60 (s, 1H), 9.55 (s, 1H), 8.08 (dd, J₁=6.6 Hz, J₂=2.4 Hz, 1H), 7.90 (s, 1H), 7.76-7.71 (m, 1H), 7.58 (s, 1H), 7.55 (t, J=9.4 Hz, 1H), 4.10 (s, 3H).

Step 2) N⁴-(3-chloro-4-fluorophenyl)-7-methoxyquinazoline-4,6-diamine

To a solution of N-(3-chloro-4-fluorophenyl)-7-methoxy-6-nitroquinazolin-4-amine (9.00 g, 25.9 mmol) in ethanol (100 mL) were added iron powder (14.50 g, 259.0 mmol) and concentrated hydrochloric acid (3.0 mL) at 25° C. The reaction mixture was heated to 90° C. and stirred for 3.0 hours. Then heating was stopped, and the resulting mixture was adjusted to pH 11 with aqueous sodium hydroxide solution (1 M) while the mixture was still at a temperature of about 60±10° C. The pH-adjusted resulting mixture was then immediately filtered hot to remove iron mud. The filtrate was concentrated in vacuo. The residue was triturated with ethanol (50 mL) and filtered. The filter cake was dried under vacuum to give the title compound as a yellow solid (6.00 g, 73.0%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) m/z: 319.1 [M+1]⁺.

Step 3) (E)-4-bromobut-2-enoyl chloride

To a solution of 4-bromocrotonic acid (2.47 g, 15.0 mmol) and DMF (0.05 mL) in DCM (60 mL) was added oxalyl chloride (4.19 g, 33.0 mmol) dropwise at 0° C. The reaction mixture was stirred at 0° C. for 3.0 hours, and then concentrated in vacuo. The residue was stored in a refrigerator for the next step.

Step 4) (E)-4-bromo-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)but-2-enamide

To a solution of N⁴-(3-chloro-4-fluorophenyl)-7-methoxyquinazoline-4,6-diamine (4.00 g, 12.6 mmol) and TEA (6.0 mL, 37.8 mmol) in anhydrous tetrahydrofuran (80 mL) was added (E)-4-bromobut-2-enoyl chloride (2.74 g, 15.1 mmol) slowly at 0° C. The reaction mixture was then heated to 25° C. and stirred for 2.0 hours. The resulting mixture was poured into water (100 mL) and extracted with DCM (50 mL×3). The combined organic phases were dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. The residue was triturated with DCM (30 mL) and filtered. The filter cake was dried under vacuum to give the title compound as a brownish yellow solid (2.00 g, 34.5%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) m/z: 465.1 [M+1]⁺.

Step 5) (E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-((4aR,7aS)-tetrahydro-2H-[1,4]dioxin[2,3-c]pyrrol-6(3H)-yl)but-2-enamide

To a solution of (E)-4-bromo-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)but-2-enamide (0.50 g, 1.1 mmol) and diisopropylethylamine (0.6 mL, 3.2 mmol) in N,N-dimethylacetamide (10 mL) was added (4aR,7aS)-hexahydro-2H-[1,4]dioxino[2,3-c]pyrrole (0.42 g, 3.2 mmol) at 25° C., and the reaction mixture was then stirred at 25° C. for 5.0 hours. The resulting mixture was poured into water (70 mL) and extracted with DCM (40 mL×3). The combined organic phases were dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (CH₂Cl₂/MeOH (v/v)=20/1) to give the title compound as a brownish yellow solid (0.30 g, 54.5%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) m/z: 514.1 [M+1]⁺; and ¹H NMR (400 MHz, DMSO-d₆) δ: 10.60 (s, 1H), 9.35 (s, 1H), 8.90 (s, 1H), 8.08 (dd, J₁=6.6 Hz, J₂=2.4 Hz, 1H), 7.76-7.70 (m, 1H), 7.58 (s, 1H), 7.55 (t, J=8.4 Hz, 1H), 6.75-6.65 (m, 1H), 6.63 (d, J=16.2 Hz, 1H), 4.10 (s, 3H), 3.78 (t, J=6.2 Hz, 4H), 3.26 (t, J=4.4 Hz, 2H), 3.20 (dd, J₁=7.8 Hz, J₂=2.6 Hz, 2H), 2.20 (d, J=4.6 Hz, 4H).

PATENT

WO2017067447

DIFFERENT COMPD

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2017067447

claiming novel crystalline polymorphic forms of a similar EGFR, useful for treating cancer. One of these two compounds is probably yinlitinib maleate , an irreversible pan-ErbB inhibitor, being developed by Guangdong Hec Pharmaceutical , another subsidiary of HEC Pharm , for treating solid tumors; in April 2017, yinlitinib maleate was reported to be in preclinical development

Chinese patent CN 103102344 A (publication number) have disclosed the structure of 4- [ (3-chloro-4-fluorophenyl) amino] -7-methoxy-6- [3- [ (1R, 6S) -2, 5-dioxa-8-azabicyclo [4.3.0] nonan-8-yl] propoxy] quinazoline in example 6 of specification, page 57, and the structure is shown as Formula (II) . The compound of Formula (II) has a high inhibition activity against EGFR, and can be used for treating proliferative disorders.

PATENT

https://patents.google.com/patent/WO2014177038A1/en

InventorYingjun Zhang Bing Liu Jinlei Liu Jiancun Zhang Changchun Zheng

Original AssigneeSunshine Lake Pharma Co., Ltd.

PATENT

CN104119350B

Inventor张英俊刘兵刘金雷张健存郑常春 Original Assignee广东东阳光药业有限公司

https://patents.google.com/patent/CN104119350B/en

Figure CN104119350BD00731

Figure CN104119350BD00741

Figure CN104119350BD00742

Figure CN104119350BD00751

Example 1

[0442] (E) -N- (4- ((3- chloro-4-fluorophenyl) amino) -7-methoxy-quinazolin-6-yl) -4- ((4aR, 7aS) – tetrahydro _2H_ [1,4] dioxin burning and [2,3_c] R ratio slightly -6 (3H) – yl) butyric acid amide dilute _2_

[0443]

[0444] Synthesis Step Shu: N- (3- chloro-4-fluorophenyl) -7-methoxy-6-nitro quinazolin-4-amine

[0445] The N- (3- chloro-4-fluorophenyl) -7-fluoro-6-nitro-quinazolin-4-amine (10 • 0g, 29 • 8mmol) and sodium methoxide (2.80g, 51.8 mmol) was dissolved in methanol (150 mL), the reaction was warmed to 70 ° C 4. Oh. Was cooled to 25 ° C, the reaction mixture was poured into ice-water (500 mL), the precipitated yellow solid was filtered, the filter cake was dried in vacuo to give a yellow solid 9.00g, yield 86.9%.

[0446] MS (. ESI, pos ion) m / z: 349.1 [M + l] +;

[0447] bandit R (400MHz, DMS〇-d6) S: 11 • 60 (s, 1H), 9 • 55 (s, 1H), 8 • 08 (dd, Ji = 6 • 6Hz, J2 = 2.4Hz, lH), 7.90 (s, lH), 7.76-7.71 (m, lH), 7.58 (s, lH), 7.55 (t, J = 9.4Hz, 1H), 4.10 (s, 3H) square

[0448] Synthesis Step 2: n4- (3- chloro-4-fluorophenyl) -7-methoxy-quinazolin-4,6-diamine

[0449] The N- (3- chloro-4-fluorophenyl) -7-methoxy-6-nitro quinazolin-4-amine (9.00g, 25.9mmol) was dissolved in ethanol (100 mL), the was added reduced iron powder (14.5g, 259. Ommol) and concentrated hydrochloric acid (3mL) at 25 ° C, the reaction was warmed to 90 ° C 3.Oh. With 1M aqueous sodium hydroxide solution adjusted to pH 11, filtered hot to remove iron sludge, the mother liquor was concentrated and the residue was purified slurried with ethanol (50 mL), filtered, and the filter cake was dried in vacuo to a yellow solid 6.00g, yield 73.0%.

[0450] MS (ESI, pos ion.) M / z: 319.1 [M + l] + square

[0451] Synthesis Step 3: (E) -4- bromo-but-2-enoyl chloride

The [0452] square ° C Oxalyl chloride (4.19g, 33. Ommol) was slowly added dropwise to a solution containing 4-bromo crotonic acid (2.47g, 15. Ommol) and DMF (0.05mL) in dichloromethane (60 mL) solution of in 3. Oh reaction was stirred at 0 ° C. The reaction solution was concentrated, the residue was stored in a refrigerator until use.

[0453] Synthesis Step 4: (E) -4- bromo–N- (4- ((3- chloro-4-fluorophenyl) amino) -7-methoxy-quinazolin-6-yl) butan – 2_ dilute amide

[0454] The N4- (3- chloro-4-fluorophenyl) -7-methoxy-quinazolin-4,6-diamine (4.00g, 12.6mmol) and triethylamine (6.0mL, 37.8mmol ) was dissolved in anhydrous tetrahydro-furan in Misaki (80 mL), cooled to 0 ° C, was slowly added (E) -4- bromo-2-dilute acid chloride (2.748,15.12 dirty 〇1), warmed to 25 ° ( : 2.011 reaction the reaction mixture was poured into water (1001 ^) and extracted with methylene chloride (50mL X 3), the organic phases were combined, dried over anhydrous sodium sulfate filtered, concentrated and the residue with dichloromethane (30 mL). beating purified filtered, the filter cake was dried in vacuo 2.00g tan solid, yield 34.5%.

[0455] MS (ESI, pos ion.) M / z: 465.1 [M + l] + square

[0456] Synthesis Step 5: (E) -N- (4 _ ((3- chloro-4-fluorophenyl) amino) -7_ methoxy-quinazolin-6-yl) _4_ ((4aR, 7aS) – tetrahydro -2H- [1,4] dioxin burning and [2,3_c] P ratio slightly -6 (3H) – yl) butyric acid amide dilute _2_

[0457] The (E) -4- bromo–N- (4- ((3- chloro-4-fluorophenyl) amino) -7-methoxy-quinazolin-6-yl) but-2-ene amide (0.50g, 1.08mmol) and diisopropylethylamine (0.6mL, 3.24mmol) was dissolved in dimethylacetamide (10 mL) was added at 25 ° C (4aR, 7aS) – hexahydro–2H- [1,4] dioxane, and [2,3-c] pyrrole (0 • 42g, 3 • 24mmol) 5. Oh reaction was continued under stirring, 25 ° C. The reaction mixture was poured into water (70 mL) and extracted with methylene chloride (40mL X 3), the organic phases were combined, dried over anhydrous sodium sulfate. Filtered, concentrated and the residue purified by column chromatography (CH2Cl2 / MeOH (V / v) = 20/1), to give 0.30g tan solid, yield 54.5%.

[0458] MS (. ESI, pos ion) m / z: 514.1 [M + l] +;

[0459] XH NMR (400MHz, DMS0-d6) 8: 10.60 (s, lH), 9.35 (s, lH), 8.90 (s, lH), 8.08 (dd, Ji = 6.6Hz, J2 = 2.4Hz, 1H ), 7.76-7.70 (m, 1H), 7.58 (s, 1H), 7.55 (t, J = 8.4Hz, 1H), 6.75-6.65 (m, lH), 6.63 (d, J = 16.2Hz, lH) , 4.10 (s, 3H), 3.78 (t, J = 6.2Hz, 4H), 3.26 (t, J = 4.4Hz, 2H), 3.20 (dd, Ji = 7.8Hz, J2 = 2.6Hz, 2H), 2.20 (d, J = 4.6Hz, 4H)

PATENT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2018095353&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=FullText

Patent applications WO 2014/177038 and CN 104119350 discloses aminoquinazoline tyrosine kinase inhibitors with irreversible inhibition effect on Pan-HER, wherein the compound (E) -N- (4- (3-chloro-4-fluorophenyl) amino) -7- (methyloxy-D₃) -quinazolin-6-yl) -4- ( (4aR, 7aS) -tetra hydro-2H- [l, 4] dioxino [2, 3-c] pyrrole-6 (3H) -yl) butyl-2-enamide (i.e. compound (I) ) has an excellent antitumor effect. It can reduce the generation of drug resistance and also have good tolerance.

[0011]

EXPERIMENTAL PART

[0184]

The specific synthetic method for compound (I) (E) -N- (4- (3-chloro-4-fluorophenyl) amino) -7- (methyloxy-D₃) -quinazolin-6-yl) -4- ( (4aR, 7aS) -tetra hydro-2H- [l, 4] dioxino [2, 3-c] pyrrole-6 (3H) -yl) butyl-2-enamide refers to Example 20 of Patent CN 104119350 A (Application Publication No. ) .

[0185]

EXAMPLES

[0186]

Example 1

[0187]

(E) -N- (4- (3-chloro-4-fluorophenyl) amino) -7- (methyloxy-D₃) -quinazolin-6-yl) -4- ( (4aR, 7aS) -t etrahydro-2H- [l, 4] dioxino [2, 3-c] pyrrole-6 (3H) -yl) butyl-2-enamide dimesylate having crystalline form A

[0188]

1. Preparation of dimesylatesulfonate having crystalline form A

[0189]

(E) -N- (4- (3-Chloro-4-fluorophenyl) amino) -7- (methyloxy-D₃) -quinazolin-6-yl) -4- ( (4a R, 7aS) -tetrahydro-2H- [l, 4] dioxino [2, 3-c] pyrrole-6 (3H) -yl) butyl-2-enamide (1.032 g, 2.0 mmol) was added to acetone (80 mL) , the mixture was heated to reflux for 30 minutes and filtered. The filtrate was refluxed, and mesylate (0.481 g, 5.0 mmol) was added. The resulting mixture was refluxed overnight. A part of solvent was evaporated under reduced pressure, then the temperature of the residue was gradually cooled to room temperature and maintained at this temperature overnight. The resulting mixture was filtered with suction. The filter cake was washed with acetone and dried at 50 ℃ for 8 hours in vacuo to give a white solid (1.15 g, 81.3%) .

PATENT

https://encrypted.google.com/patents/CN103102344B?cl=en

https://encrypted.google.com/patents/WO2013071697A1?cl=en

Example 6

[00221] N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-(tetrahvdro-2H-n,41dioxinor2,3-clpyrrol-6(3H -vn propoxy quinazolin-4-amine

[00222] Step Ubenzyl 3,4-dihvdroxypyrrolidine-l -carboxylate

To a solution of N- carbobenzoxy-3-pyrroline ( 1.00 g, 4.92 mmol, 1.0 eq) in acetone (20 mL) was added NMO ( 1.0 g, 7.38 mmol, 1.5 eq) followed by Os0₄ (cat. 10 mg in 1 mL ‘PrOH). The mixture was stirred for 3 h. To this, saturated NaHS0₃aqueous solution (5 mL) was added, and the mixture was stirred for another 0.5 h. The organic phase was separated from the mixture, and the water phase was extracted with EtOAc (20 mL x 3). The combined organic phases were dried over anhydrous Na₂S0₄ and filtered. The filtrate was concentrated in vacuo and the residue was purified by a silica gel column chromatography (EtOAc) to give the compound as colorless oil (1.16 g, 100 %).

[00223] Step 2) benzyl tetrahvdro-2H-n.41dioxino[2.3-c1pyrrole-6(3H)- carboxylate

A mixture of NaOH aqueous solution (35 w/w %, 21 mL, aq.), C1CH₂CH₂C1 (21 mL), benzyl 3,4-dihydroxypyrrolidine-l -carboxylate (1.16 g, 4.9 mmol, 1.0 eq) and TBAB (0.31 g, 0.98 mmol, 0.2 eq) was heated at 55 °C for 48h in a round-bottom flask. The reaction mixture was cooled to room temperature and poured into water (50 mL), extracted with EtOAc (50 mL). The organic phase was separated from the mixture, and the water phase was extracted with EtOAc (20 mLx3). The combined organic phases were dried over anhydrous Na₂S0₄ and filtered. The filtrate was concentrated in vacuo and the residue was purified with a silica gel column chromatography ( 1 : 1 (v/v) PE/EtOAc) to give the product as colorless oil (0.50 g, 39 %).

[00224] Step 3) hexahvdro-2H-n.41dioxinor2.3-clpyrrole

To a solution of benzyl tetrahydro-2H-[l ,4]dioxino[2,3-c] pyrrole-6(3H)-carboxylate (0.46 g, 1 .94 mmol) in MeOH (20 mL) was added two drops of HC0₂H followed by 20 % Pd(OH)₂ (50mg). The reaction mixture was stirred under H₂ for 4h at rt and was filtered. The filtrate was concentrated in vacuo to give the crude product, which was used for the next step without further purification.

[00225] Step 4) N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-(tetrahvdro-2H-n,41 dioxinor2,3-clpyrrol-6(3H) -yl)propoxy)quinazolin-4-amine

A mixture of hexahydro-2H-[ l ,4]dioxino[2,3-c]pyrrole (1.0 eq), N-(3-chloro-4-fluorophenyI)-6- (3-chloropropoxy)-7-methoxyquinazolin-4-amine (710 mg, 1.8 mmol, 0.95 eq), ₂C0₃ (524 mg, 3.8 mmol, 2.0 eq) and KI (16 mg, 0.095 mmol, 0.05 eq) in DMF (12 mL) was heated at 60 °C for 3 h and cooled to room temperature. The reaction mixture was quenched with water (10 mL) and diluted with EtOAc (20 mL). The organic phase was separated from the mixture, and the water phase was extracted with EtOAc (20 mLx3). The combined organic phases were dried over anhydrous Na₂S0₄ and concentrated in vacuo. The residue was purified by a silica gel column chromatography (20: 1 (v/v) CH₂Cl₂/CH₃OH) to give the crude product, which was recrystallized from CH₂C1₂/PE to afford the title compound as a grayish-white solid (230 mg, 25.00 %), HPLC:99.1 1 % . The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 489.9 (M+1 );’H NMR (400 MHz, CDC1₃) δ: 2.09 (2H, m), 2.74 (4H, m), 2.99 (2H, dd, = 3.3, 10.4 Hz), 3.56 (2H, m), 3.80 (2H, m), 3.99 (3H, s), 4.12 (2H, t, J = 3.5 Hz), 4.22 (2H, t, J = 6.8 Hz), 7.14 (1 H, t, J = 8.8 Hz), 7.23 (1 H, s), 7.29 ( 1 H, d, J = 15.8 Hz), 7.60 (1 H, m), 7.89 (1 H, dd, J = 2.5, 6.5 Hz), 8.63 (1 H, s) ppm.

PATENT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2014177038&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

Example 1

[00192] (^-N 4 (3-Chloro -fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4 (4aR,7a5)-tetrahydro-2H-[ l,4]dioxino[2,3-c]pyrrol-6(3H)

[00193] Step 1) N-(3-chloro-4-fluorophenyl)-7-methoxy-6-nitroquinazolin-4-amine

A solution of N-(3-chloro-4-fluorophenyl)-7-fluoro-6-nitroquinazolin-4-amine (10.00 g, 29.8 mmol) and sodium methanolate (2.80 g, 51.8 mmol) in methanol (150 mL) was heated to 70 °C and stirred for 4.0 hours. The reaction mixture was then cooled to 25 °C. The resulting mixture was poured into ice water (500 mL), and a yellow solid precipitated out. The mixture was filtered and the filter cake was dried under vacuum to give the title compound as a yellow solid (9.00 g, 86.9%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) m/z : 349.1 [M+l]⁺; and ‘H NMR (400 MHz, DMSO-<&) δ: 11.60 (s, 1H), 9.55 (s, 1H), 8.08 (dd, J_x = 6.6 Hz, J₂ = 2.4 Hz, 1H), 7.90 (s, 1H), 7.76-7.71 (m, 1H), 7.58 (s, 1H), 7.55 (t, J = 9.4 Hz, lH ), 4.10 (s, 3H).

[00194] Step 2) N⁴-(3-chloro-4-fluorophenyl)-7-methoxyquinazoline-4,6-diamine

To a solution of N-(3-chloro-4-fluorophenyl)-7-methoxy-6-nitroquinazolin-4-amine (9.00 g, 25.9 mmol) in ethanol (100 mL) were added iron powder (14.50 g, 259.0 mmol) and concentrated hydrochloric acid (3.0 mL) at 25 °C. The reaction mixture was heated to 90 °C and stirred for 3.0 hours. Then heating was stopped, and the resulting mixture was adjusted to pH 11 with aqueous sodium hydroxide solution (1 M) while the mixture was still at a temperature of about 60 ± 10 °C. The pH-adjusted resulting mixture was then immediately filtered hot to remove iron mud. The filtrate was concentrated in vacuo. The residue was triturated with ethanol (50 mL) and filtered. The filter cake was dried under vacuum to give the title compound as a yellow solid (6.00 g, 73.0%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) m/z : 319.1 [M+l]⁺.

[00195] Step 3) (£)-4-bromobut-2-enoyl chloride

To a solution of 4-bromocrotonic acid (2.47 g, 15.0 mmol) and DMF (0.05 mL) in DCM (60 mL) was added oxalyl chloride (4.19 g, 33.0 mmol) dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 3.0 hours, and then concentrated in vacuo. The residue was stored in a refrigerator for the next step.

[00196] Step 4) (ii)-4-bromo-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)but-2-enamide

To a solution of N⁴-(3-chloro-4-fluorophenyl)-7-methoxyquinazoline-4,6-diamine (4.00 g, 12.6 mmol) and TEA (6.0 mL, 37.8 mmol) in anhydrous tetrahydrofuran (80 mL) was added (E)-4-bromobut-2-enoyl chloride (2.74 g, 15.1 mmol) slowly at 0 °C. The reaction mixture was then heated to 25 °C and stirred for 2.0 hours. The resulting mixture was poured into water (100 mL) and extracted with DCM (50 mL x 3). The combined organic phases were dried over anhydrous NaaSOzi, filtered and concentrated in vacuo. The residue was triturated with DCM (30 mL) and filtered. The filter cake was dried under vacuum to give the title compound as a brownish yellow solid (2.00 g, 34.5%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) m/z : 465.1 [M+l]⁺.

[00197] Step 5) (^-N 4 (3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl) (4aR,7aS)-tetrahydro-2H-[l,4]dioxino[2,3-c]pyrrol-6(3H)-yl)but-2-enamide

To a solution of (iT)-4-bromo-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)but-2-enamide (0.50 g, 1.1 mmol) and diisopropylethylamine (0.6 mL, 3.2 mmol) in N^V-dimethylacetamide (10 mL) was added (4aR,7aS)-hexahydro-2H-[l,4]dioxino[2,3-c]pyrrole (0.42 g, 3.2 mmol) at 25 °C, and the reaction mixture was then stirred at 25 °C for 5.0 hours. The resulting mixture was poured into water (70 mL) and extracted with DCM (40 mL x 3). The combined organic phases were dried over anhydrous Na₂S0₄, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (CH₂Cl₂ MeOH (v/v) = 20/1) to give the title compound as a brownish yellow solid (0.30 g, 54.5%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) m/z : 514.1 [M+l]⁺; and ^lH NMR (400 MHz, DMSO-t/_tf) δ: 10.60 (s, 1H), 9.35 (s, 1H) , 8.90 (s, 1H), 8.08 (dd, J_x = 6.6 Hz, J₂ = 2.4 Hz, 1H), 7.76-7.70 (m, 1H), 7.58 (s, 1H), 7.55 (t, J = 8.4 Hz, 1H ), 6.75-6.65 (m, 1H), 6.63(d, J = 16.2 Hz, 1H), 4.10 (s, 3H), 3.78 (t, J= 6.2 Hz, 4H), 3.26 (t, J = 4.4 Hz, 2H), 3.20 (dd, J_x = 7.8 Hz, J₂ = 2.6 Hz, 2H), 2.20 (d, J= 4.6 Hz, 4H).

////////////DNT-04110, yinlitinib maleate , Guangdong Hec Pharmaceutical, PHASE 1, CHINA, yinlitinib

Fc1ccc(cc1Cl)Nc2ncnc3cc(OC)c(cc23)NC(=O)/C=C/CN4C[C@H]5OCCO[C@H]5C4

Fc1ccc(cc1Cl)Nc2ncnc3cc(OC([2H])([2H])[2H])c(cc23)NC(=O)/C=C/CN4C[C@H]5OCCO[C@H]5C4

SIMILAR COMPDS

Canertinib [INN:BAN]
267243-28-7

MW: 485.9445 –

Canertinib dihydrochloride [USAN]
289499-45-2

MW: 558.8663

Dacomitinib [USAN:INN]
1110813-31-4

MW: 469.9455

439081-18-2

MW: 485.9445

Afatinib [USAN:INN]
850140-72-6

MW: 485.9445

Doxepin, ドキセピン

June 5, 2018 10:40 am / Leave a comment

Doxepin

1668-19-5
1229-29-4 (hydrochloride), 4698-39-9 ((E)-isomer); 25127-31-5 ((Z)-isomer)

Launched – 1964

1-Propanamine, 3-dibenz(b,e)oxepin-11(6H)-ylidene-N,N-dimethyl-

1-Propanamine, 3-dibenz[b,e]oxepin-11(6H)-ylidene-N,N-dimethyl-, (3Z)-

3-(Dibenzo[b,e]oxepin-11(6H)-ylidene)-N,N-dimethylpropan-1-amine

N,N-Dimethyldibenz[b,e]oxepin-D11(6H),g-propylamine

(3Z)-3-(Dibenzo[b,e]oxepin-11(6H)-ylidene)-N,N-dimethylpropan-1-amine

Doxepin Hydrochloride

3U9A0FE9N5

1229-29-4

NSC-108160
P-3693A
SO-101

Aponal
Quitaxon
Silenor
Sinequan
Sinquan
Xepin
Zonalon

USP

USP32/pub/data/v32270/usp32nf27s0_m28110

N,N-Dimethyldibenz[b,e]oxepin-D11(6H),-propylamine hydrochloride [1229-29-4; 4698-39-9 ((E)-isomer); 25127-31-5 ((Z)-isomer)].

» Doxepin Hydrochloride, an (E) and (Z) geometric isomer mixture, contains the equivalent of not less than 98.0 percent and not more than 102.0 percent of doxepin (C19H21NO·HCl), calculated on the dried basis. It contains not less than 13.6 percent and not more than 18.1 percent of the (Z)-isomer, and not less than 81.4 percent and not more than 88.2 percent of the (E)-isomer.

Title: Doxepin

CAS Registry Number: 1668-19-5

CAS Name: 3-Dibenz[b,e]oxepin-11(6H)-ylidene-N,N-dimethyl-1-propanamine

Additional Names:N,N-dimethyldibenz[b,e]oxepin-D11(6H),g-propylamine; 11-(3-dimethylaminopropylidene)-6,11-dihydrodibenz[b,e]oxepin

Manufacturers’ Codes: P-3693A

Molecular Formula: C19H21NO

Molecular Weight: 279.38

Percent Composition: C 81.68%, H 7.58%, N 5.01%, O 5.73%

Literature References: Prepn of mixture of cis- and trans-isomers: K. Stach, F. Bickelhaupt, Monatsh. Chem.93, 896 (1962); F. Bickelhaupt et al.,ibid.95, 485 (1964); NL6407758; K. Stach, US3438981 (1965, 1969 both to Boehringer Mann.); and separation and activity of isomers: B. M. Bloom, J. R. Tretter, BE641498; eidem,US3420851 (1964, 1969 both to Pfizer). Pharmacology: A. Ribbentrop, W. Schaumann, Arzneim.-Forsch.15, 863 (1965). Metabolism in animals: D. C. Hobbs, Biochem. Pharmacol.18, 1941 (1969). Determn in plasma by GC/MS: T. P. Davis et al.,J. Chromatogr.273, 436 (1983); by HPLC: T. Emm, L. J. Lesko, ibid.419,445 (1987). Clinical study in depression: K. Rickels et al.,Arch. Gen. Psychiatry42, 134 (1985). Comparative clinical trial with cimetidine, q.v., in treatment of ulcer: R. K. Shrivastava et al.,Clin. Ther.7, 181 (1985). Review of pharmacology and therapeutic efficacy: R. M. Pinder et al.,Drugs13, 161 (1977).

Properties: Oily liq consisting of a mixture of cis- and trans-isomers. bp0.03 154-157°, bp0.2 260-270°. LD50 in mice, rats (mg/kg): 26, 16 i.v.; 79, 182 i.p.; 135, 147 orally (Ribbentrop, Schaumann).

Boiling point: bp0.03 154-157°; bp0.2 260-270°

Toxicity data: LD50 in mice, rats (mg/kg): 26, 16 i.v.; 79, 182 i.p.; 135, 147 orally (Ribbentrop, Schaumann)

Derivative Type: Hydrochloride

CAS Registry Number: 1229-29-4

Trademarks: Adapin (Lotus); Aponal (Boehringer, Mann.); Curatin (Pfizer); Quitaxon (Boehringer, Mann.); Sinequan (Pfizer)

Molecular Formula: C19H21NO.HCl

Molecular Weight: 315.84

Percent Composition: C 72.25%, H 7.02%, N 4.43%, O 5.07%, Cl 11.22%

Properties: Crystals, mp 184-186°, 188-189°.

Melting point: mp 184-186°, 188-189°

Derivative Type: Maleate

Properties: Crystals, mp 161-164°, 168-169°.

Melting point: mp 161-164°, 168-169°

Derivative Type:trans-Form hydrochloride

CAS Registry Number: 3607-18-9

Properties: mp 192-193°.

Melting point: mp 192-193°

Derivative Type:cis-Form hydrochloride

CAS Registry Number: 25127-31-5

Additional Names: Cidoxepin hydrochloride

Manufacturers’ Codes: P-4599

Properties: Crystals, mp 209-210.5°.

Melting point: mp 209-210.5°

Therap-Cat: Antidepressant.

Therap-Cat-Vet: Antipruritic.

Keywords: Antidepressant; Tricyclics.

US FDA

https://www.accessdata.fda.gov/drugsatfda_docs/nda/2010/022036Orig1s000ChemR.pdf

NDA 22-036 Silenor (doxepin HCl) Tablets Somaxon Pharmaceuticals, Inc

Introduction: Doxepin Hydrochloride has been marketed by Pfizer since 1969 for the treatment of depression, anxiety, and psychotic depressive disorders. It is available, under the tradename Sinequan®, as 10-, 25-, 50-, 75-, 100-, and 150 mg capsules and 10 mg/mL oral concentrate. In the current NDA, Somaxon proposes to market doxepin, under the tradename Silenor™, for treatment of insomnia. The product will be available as 1-, 3-, and 6 mg tablets. Silenor Tablets will be packaged in 30-, 100- and 500-count HDPE bottles, 4-count blister packs (physician sample), and 30-count blister packs.

Drug Substance: The active ingredient, Doxepin Hydrochloride, USP, [chemical name: 3- dibenz[b,e]oxepin- 11(6H)ylidene-N,N-dimethyl-1-propanamine hydrochloride] is a member of the tricyclic class of antidepressants. It is a well characterized small molecule with molecular formula C19H21O•HCl and molecular weight 315.84. Doxepin hydrochloride is readily soluble in water. The active moiety, doxepin, exists as an approximately mixture of E- and Zisomers. The relative amounts of the two geometric isomers are controlled through drug substance specification. The drug substance CMC information is referenced to DMF . The DMF was reviewed and found to be inadequate to support this NDA. Subsequently, the DMF holder provided adequate responses to the c

DESCRIPTION

SINEQUAN® (doxepin hydrochloride) is one of a class of psychotherapeutic agents known as dibenzoxepin tricyclic compounds. The molecular formula of the compound is C19H21NO•HCl having a molecular weight of 316. It is a white crystalline solid readily soluble in water, lower alcohols and chloroform.

Inert ingredients for the capsule formulations are: hard gelatin capsules (which may contain Blue 1, Red 3, Red 40, Yellow 10, and other inert ingredients); magnesium stearate; sodium lauryl sulfate; starch.

Inert ingredients for the oral concentrate formulation are: glycerin; methylparaben; peppermint oil; propylparaben; water.

Chemistry

SINEQUAN (doxepin HCl) is a dibenzoxepin derivative and is the first of a family of tricyclic psychotherapeutic agents. Specifically, it is an isomeric mixture of: 1-Propanamine, 3-dibenz[b,e]oxepin-11(6H)ylidene-N,N-dimethyl-, hydrochloride.

SINEQUAN® (doxepin HCl) Structural Formula Illustration

For Consumers

WHAT ARE THE POSSIBLE SIDE EFFECTS OF DOXEPIN (SINEQUAN) (SINEQUAN)?

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Report any new or worsening symptoms to your doctor, such as: mood or behavior changes, anxiety, panic attacks, trouble sleeping, or if you feel impulsive, irritable, agitated, hostile, aggressive, restless, hyperactive (mentally or physically), more depressed, or have thoughts about suicide or hurting yourself.

Synthesis Reference

Luigi Schioppi, Brian Talmadge Dorsey, Michael Skinner, John Carter, Robert Mansbach, Philip Jochelson, Roberta L. Rogowski, Cara Casseday, Meredith Perry, Bryan Knox, “LOW-DOSE DOXEPIN FORMULATIONS AND METHODS OF MAKING AND USING THE SAME.” U.S. Patent US20090074862, issued March 19, 2009.

US20090074862

DOI: 10.1007/BF00904459

DOI: 10.1007/BF00901313 US 3420851

DE 1232161

SYN 2

Synth Commun 1989, 19(19): 3349, US 3438981

Doxepin hydrochloride pk_prod_list.xml_prod_list_card_pr?p_tsearch=A&p_id=91437

Condensation of dibenzo-oxepinone (I) with 3-(dimethylamino)propylmagnesium chloride (II), followed by a dehydration of the resultant tertiary alcohol with hot HCl gives the target 3-(dimethylamino)propylidene derivative.

SYN 3

Doxepin hydrochloride pk_prod_list.xml_prod_list_card_pr?p_tsearch=A&p_id=91437

Chlorination of 2-(phenoxymethyl)benzoic acid (I) with SOCl2 at 50 °C gives 2-(phenoxymethyl)benzoyl chloride (II), which undergoes cyclization in the presence of FeCl3 in toluene to furnish dibenzo[b,e]oxepin-11-one (III)

Grignard reaction of intermediate (III) with tert-butyl 3-chloropropyl ether (IV) using Mg in refluxing THF or Et2O provides 11-(3-tert-butoxypropyl)-6,11-dihydrodibenzo[b,e]oxepin-11-ol (V), which upon elimination by means of HCl in refluxing EtOH affords alkene (VI).

Treatment of tert-butyl ether (VI) with SOCl2 in refluxing toluene gives 11-(3-chloropropylidene)-6,11-dihydrodibenzo[b,e]oxepine (VII), which is then coupled with dimethylamine (VIII) in the presence of Ni(OAc)2, PPh3 and K2CO3 in DMF or in EtOH at 100 °C to furnish doxepin (VII) .

Finally, treatment of tertiary amine (VII) with HCl at 140 °C yields the target doxepin hydrochloride .

US 2014309437, CN 102924424

Doxepin is a dibenzoxepin-derivative tricyclic antidepressant (TCA). Structurally similar to phenothiazines, TCAs contain a tricyclic ring system with an alkyl amine substituent on the central ring. In non-depressed individuals, doxepin does not affect mood or arousal, but may cause sedation. In depressed individuals, doxepin exerts a positive effect on mood. TCAs are potent inhibitors of serotonin and norepinephrine reuptake. Tertiary amine TCAs, such as doxepin and amitriptyline, are more potent inhibitors of serotonin reuptake than secondary amine TCAs, such as nortriptyline and desipramine. TCAs also down-regulate cerebral cortical β-adrenergic receptors and sensitize post-synaptic serotonergic receptors with chronic use. The antidepressant effects of TCAs are thought to be due to an overall increase in serotonergic neurotransmission. TCAs also block histamine H₁ receptors, α₁-adrenergic receptors and muscarinic receptors, which accounts for their sedative, hypotensive and anticholinergic effects (e.g. blurred vision, dry mouth, constipation, urinary retention), respectively. Doxepin has less sedative and anticholinergic effects than amitriptyline. See toxicity section below for a complete listing of side effects. When orally administered, doxepin may be used to treat depression and insomnia. Unlabeled indications of oral doxepin also include chronic and neuropathic pain, and anxiety. Doxepin may also be used as a second line agent to treat idiopathic urticaria. As a topical agent, doxepin may be used relieve itching in patients with certain types of eczema. It may be used for the management of moderate pruritus in adult patients with atopic dermatitis or lichen simplex chronicus

Doxepin is a tricyclic antidepressant (TCA) used as a pill to treat major depressive disorder, anxiety disorders, chronic hives, and for short-term help with trouble remaining asleep after going to bed (a form of insomnia).^[8]^[7]^[9] As a cream it is used for short term treatment of itchiness due to atopic dermatitis or lichen simplex chronicus.^[10]

At doses used to treat depression, doxepin appears to inhibit the reuptake of serotonin and norepinephrine and to have antihistamine, adrenergic and serotonin receptor antagonistic, and anticholinergic activities; at low doses used to treat insomnia it appears to be selective for the histamine H₁ receptor.^[11]

It was introduced under the brand names Quitaxon and Aponal by Boehringer, which discovered it, and as Sinequan by Pfizer,^[12] and has subsequently been marketed under many other names worldwide.^[2]

Medical uses

Doxepin is used as a pill to treat major depressive disorder, anxiety disorders, chronic hives, and for short-term help with trouble remaining asleep after going to bed (a form of insomnia).^[8]^[7]^[9] As a cream it is used for short term treatment of itchiness to due atopic dermatitis or lichen simplex chronicus.^[10]

In 2016 the American College of Physicians advised that insomnia be treated first by treating comorbid conditions, then with cognitive behavioral therapy and behavioral changes, and then with drugs; doxepin was among those recommended for short term help maintaining sleep, on the basis of weak evidence.^[13]^[14] The 2017 American Academy of Sleep Medicine recommendations focused on treatment with drugs were similar.^[13] A 2015 AHRQ review of treatments for insomnia had similar findings.^[15]

A 2010 review found that topical doxepin is useful to treat itchiness.^[16]

A 2010 review of treatments for chronic hives found that doxepin had been superseded by better drugs but was still sometimes useful as a second line treatment.^[17]

Chemistry

Doxepin is a tricyclic compound, specifically a dibenzoxepin, and possesses three rings fused together with a side chain attached in its chemical structure.^[38] It is the only TCA with a dibenzoxepin ring system to have been marketed.^[64] Doxepin is a tertiary amine TCA, with its side chain–demethylated metabolite nordoxepin being a secondary amine.^[40]^[41] Other tertiary amine TCAs include amitriptyline, imipramine, clomipramine, dosulepin (dothiepin), and trimipramine.^[65]^[66] Doxepin is a mixture of (E) and (Z) stereoisomers (the latter being known as cidoxepin or cis-doxepin) and is used commercially in a ratio of approximately 85:15.^[3]^[67] The chemical name of doxepin is (E/Z)-3-(dibenzo[b,e]oxepin-11(6H)-ylidene)-N,N-dimethylpropan-1-amine^[38]^[68] and its free base form has a chemical formula of C₁₉H₂₁NO with a molecular weight of 279.376 g/mol.^[68] The drug is used commercially almost exclusively as the hydrochloride salt; the free base has been used rarely.^[3]^[69] The CAS Registry Number of the free base is 1668-19-5 and of the hydrochloride is 1229-29-4.^[3]^[69]

Image result for synthesis doxepin

clip

https://www.sciencedirect.com/science/article/pii/S0040402007016079

Image result for synthesis doxepin

History

Doxepin was discovered in Germany in 1963 and was introduced in the United States as an antidepressant in 1969.^[38] It was subsequently approved at very low doses in the United States for the treatment of insomnia in 2010.^[44]^[69]

Society and culture

Generic names

Doxepin is the generic name of the drug in English and German and its INN and BAN, while doxepin hydrochloride is its USAN, USP, BANM, and JAN.^[3]^[69]^[70]^[2] Its generic name in Spanish and Italian and its DCIT are doxepina, in French and its DCF are doxépine, and in Latin is doxepinum.^[2]

The cis or (Z) stereoisomer of doxepin is known as cidoxepin, and this is its INN while cidoxepin hydrochloride is its USAN.^[3]

Brand names

It was introduced under the brand names Quitaxon and Aponal by Boehringer and as Sinequan by Pfizer.^[12]

As of October 2017, doxepin is marketed under many brand names worldwide: Adnor, Anten, Antidoxe, Colian, Dofu, Doneurin, Dospin, Doxal, Doxepini, Doxesom, Doxiderm, Flake, Gilex, Ichderm, Li Ke Ning, Mareen, Noctaderm, Oxpin, Patoderm, Prudoxin, Qualiquan, Quitaxon, Sagalon, Silenor, Sinepin, Sinequan, Sinequan, Sinquan, and Zonalon.^[2] It is also marketed as a combination drug with levomenthol under the brand name Doxure.^[2]

Approvals

The oral formulations of doxepin are FDA-approved for the treatment of depression and sleep-maintenance insomnia and its topical formulations are FDA-approved the short-term management for some itchy skin conditions.^[71] Whereas in Australia and the United Kingdom, the only licensed indication(s) is/are in the treatment of major depression and pruritus in eczema, respectively.^[20]^[72]

Research

Antihistamine

As of 2017 there was no good evidence that topical doxepin was useful to treat localized neuropathic pain.^[73] Cidoxepin is under development by Elorac, Inc. for the treatment of chronic urticaria (hives).^[74] As of 2017, it is in phase II clinical trials for this indication.^[74] The drug was also under investigation for the treatment of allergic rhinitis, atopic dermatitis, and contact dermatitis, but development for these indications was discontinued.^[74]

Headache

Doxepin was under development by Winston Pharmaceuticals in an intranasal formulation for the treatment of headache.^[75] As of August 2015, it was in phase II clinical trials for this indication.^[75]

PATENT

https://patents.google.com/patent/US9486437B2/en

Doxepin:

Doxepin HCl is a tricyclic compound currently approved and available for treatment of depression and anxiety. Doxepin has the following structure:

For all compounds disclosed herein, unless otherwise indicated, where a carbon-carbon double bond is depicted, both the cis and trans stereoisomers, as well as mixtures thereof are encompassed.

Doxepin belongs to a class of psychotherapeutic agents known as dibenzoxepin tricyclic compounds, and is currently approved and prescribed for use as an antidepressant to treat depression and anxiety. Doxepin has a well-established safety profile, having been prescribed for over 35 years.

Doxepin, unlike most FDA approved products for the treatment of insomnia, is not a Schedule IV controlled substance. U.S. Pat. Nos. 5,502,047 and 6,211,229, the entire contents of which are incorporated herein by reference, describe the use of doxepin for the treatment chronic and non-chronic (e.g., transient/short term) insomnias at dosages far below those used to treat depression.

It is contemplated that doxepin for use in the methods described herein can be obtained from any suitable source or made by any suitable method. As mentioned, doxepin is approved and available in higher doses (75-300 milligrams) for the treatment of depression and anxiety. Doxepin HCl is available commercially and may be obtained in capsule form from a number of sources. Doxepin is marketed under the commercial name SINEQUAN® and in generic form, and can be obtained in the United States generally from pharmacies in capsule form in amounts of 10, 25, 50, 75, 100 and 150 mg dosage, and in liquid concentrate form at 10 mg/mL. Doxepin HCl can be obtained from Plantex Ltd. Chemical Industries (Hakadar Street, Industrial Zone, P.O. Box 160, Netanya 42101, Israel), Sifavitor S.p.A. (Via Livelli 1—Frazione, Mairano, Italy), or from Dipharma S.p.A. (20021 Baranzate di Bollate, Milano, Italy). Also, doxepin is commercially available from PharmacyRx (NZ) (2820 1^stAvenue, Castlegar, B.C., Canada) in capsule form in amounts of 10, 25, 50, 75, 100 and 150 mg. Furthermore, Doxepin HCl is available in capsule form in amounts of 10, 25, 50, 75, 100 and 150 mg and in a 10 mg/ml liquid concentrate from CVS Online Pharmacy Store (CVS.com).

Also, doxepin can be prepared according to the method described in U.S. Pat. No. 3,438,981, which is incorporated herein by reference in its entirety. It should be noted and understood that although many of the embodiments described herein specifically refer to “doxepin,” other doxepin-related compounds can also be used, including, for example, pharmaceutically acceptable salts, prodrugs, metabolites, in-situ salts of doxepin formed after administration, and solid state forms, including polymorphs and hydrates.

Metabolites:

In addition, doxepin metabolites can be prepared and used. By way of illustration, some examples of metabolites of doxepin can include, but are not limited to, desmethyldoxepin, hydroxydoxepin, hydroxyl-N-desmethyldoxepin, doxepin N-oxide, N-acetyl-N-desmethyldoxepin, N-desmethyl-N-formyldoxepin, quaternary ammonium-linked glucuronide, 2-O-glucuronyldoxepin, didesmethyldoxepin, 3-O-glucuronyldoxepin, or N-acetyldidesmethyldoxepin. The metabolites of doxepin can be obtained or made by any suitable method, including the methods described above for doxepin.

Desmethyldoxepin has the following structure:

Desmethyldoxepin is commercially available as a forensic standard. For example, it can be obtained from Cambridge Isotope Laboratories, Inc. (50 Frontage Road, Andover, Mass.). Desmethyldoxepin for use in the methods discussed herein can be prepared by any suitable procedure. For example, desmethyldoxepin can be prepared from 3-methylaminopropyl triphenylphosphonium bromide hydrobromide and 6,11-dihydrodibenz(b,e)oxepin-11-one according to the method taught in U.S. Pat. No. 3,509,175, which is incorporated herein by reference in its entirety.

Hydroxydoxepin has the following structure:

2-Hydroxydoxepin can be prepared by any suitable method, including as taught by Shu et al. (Drug Metabolism and Disposition (1990) 18:735-741), which is incorporated herein by reference in its entirety.

Hydroxyl-N-desmethyldoxepin has the following structure:

2-Hydroxy-N-desmethyldoxepin can be prepared any suitable method.

Doxepin N-oxide has the following structure:

Doxepin N-oxide can be prepared by any suitable method. For example, doxepin N-oxide can be prepared as taught by Hobbs (Biochem Pharmacol (1969) 18:1941-1954), which is hereby incorporated by reference in its entirety.

N-acetyl-N-desmethyldoxepin has the following structure:

N-acetyl-N-desmethyldoxepin can be prepared by any suitable means. For example, (E)-N-acetyl-N-desmethyldoxepin has been produced in filamentous fungus incubated with doxepin as taught by Moody et al. (Drug Metabolism and Disposition (1999) 27:1157-1164), hereby incorporated by reference in its entirety.

N-desmethyl-N-formyldoxepin has the following structure:

N-desmethyl-N-formyldoxepin can be prepared by any suitable means. For example, (E)-N-desmethyl-N-formyldoxepin has been produced in filamentous fungus incubated with doxepin as taught by Moody et al. (Drug Metabolism and Disposition (1999) 27:1157-1164), hereby incorporated by reference in its entirety.

N-acetyldidesmethyldoxepin has the following structure:

N-acetyldidesmethyldoxepin can be prepared by any suitable means. For example, (E)-N-acetyldidesmethyldoxepin has been produced in filamentous fungus incubated with doxepin as taught by Moody et al. (Drug Metabolism and Disposition (1999) 27:1157-1164), hereby incorporated by reference in its entirety.

Didesmethyldoxepin has the following structure:

Didesmethyldoxepin can be prepared by any suitable means. For example, (Z)- and (E)-didesmethyldoxepin have been isolated from plasma and cerebrospinal fluid of depressed patients taking doxepin, as taught by Deuschle et al. (Psychopharmacology (1997) 131:19-22), hereby incorporated by reference in its entirety.

3-O-glucuronyldoxepin has the following structure:

3-O-glucuronyldoxepin can be prepared by any suitable means. For example, (E)-3-O-glucuronyldoxepin has been isolated from the bile of rats given doxepin, as described by Shu et al. (Drug Metabolism and Disposition (1990) 18:1096-1099), hereby incorporated by reference in its entirety.

2-O-glucuronyldoxepin has the following structure:

2-O-glucuronyldoxepin can be prepared by any suitable means. For example, (E)-2-O-glucuronyldoxepin has been isolated from the bile of rats given doxepin, and also in the urine of humans given doxepin, as described by Shu et al. (Drug Metabolism and Disposition (1990) 18:1096-1099), hereby incorporated by reference in its entirety.

Quaternary ammonium-linked glucuronide of doxepin (doxepin N⁺-glucuronide) has the following structure:

N⁺-glucuronide can be obtained by any suitable means. For example, doxepin N⁺-glucuronide can be prepared as taught by Luo et al. (Drug Metabolism and Disposition, (1991) 19:722-724), hereby incorporated by reference in its entirety.

PATENT

https://patents.google.com/patent/CN105330638A/en

doxepin hydrochloride, the chemical name is N, N- dimethyl-3-dibenzo (b, e) _ oxepin -11 (6H) -1-propanamine salt subunit cistron iso the mixture body configuration. CAS Number 1229-29-4 thereof, of the formula

[0003]

[0004] Doxepin hydrochloride is a drug for the treatment of depression and anxiety neurosis that act to inhibit the central nervous system serotonin and norepinephrine reuptake, such that these two synaptic cleft neurotransmitter concentration increased and antidepressant effect, but also has anti-anxiety and sedative effects. Doxepin hydrochloride oral absorption, bioavailability of 13-45%, half-life (Shu 1/2) is 8-12 hours, to apparent volume of distribution (1) ^ 9-33171.Primarily metabolized in the liver to active metabolites thereof demethylation.Metabolite excretion from the kidney, elderly patients decline of metabolism and excretion ability of this product

[0005] Chinese Patent CN102924486A discloses a method for preparing a hydrochloride of doxepin. The method comprises the coupling reaction CN, i.e., the use of Ni (0Α〇) 2 / ΡΡ1 ^ φ to the amine-based compound. Although Ni catalyst the reaction step (OAc) 2 is more readily available and inexpensive, but the low yield of this step, and low product purity.

SUMMARY

[0006] Accordingly, the present invention provides a method of o-toluic acid synthesized multi doxepin hydrochloride, the higher the yield and purity of the obtained product was purified by this method.

[0007] – o-methylbenzoate method for the synthesis of doxepin hydrochloride, comprising the steps of:

[0008] (1) o-methylbenzoic acid with N- halosuccinimide benzylation halogenation reaction occurs in an acetonitrile solvent in the light conditions, to give o-halo-methylbenzoic acid (Compound J), the following reaction formula,

[0009]

[0010] (2) Compound J celite load cesium fluoride intramolecular substitution reaction, to give phthalide (Compound H) in an acetonitrile solvent and as a catalyst, the following reaction formula,

[0011]

[0012] (3) The phenol compound J with sodium methoxide in an alcohol solvent substitution reaction, to give a compound I, the following reaction formula,

[0013]

[0014] (4) The cyclization reaction of Compound I in a solvent in the catalytic DMS0 anhydrous aluminum chloride to give 6, 11-dihydro-dibenzo [b, e] oxepin -11- one (compound A), the following reaction formula,

[0015]

[0016] (5) 6, 11-dihydro-dibenzo [b, e] oxepin-11-one (Compound A) and 3-chloropropyl alkyl tert-butyl ether (compound B) is added magnesium powder and with THF and / or a nucleophilic addition of anhydrous diethyl ether under the conditions of the reaction solvent to give the hydroxy compound (compound C), the following reaction formula,

[0017]

[0018] (6) heating elimination reaction to give an olefin compound (Compound D) in a strong base in an alcoholic solvent to the hydroxy compound, the following reaction formula,

[0019]

[0020] (7) to the olefinic compound in the nucleophilic substitution reaction of a hydrogen halide acid, to give halide (Compound E), the following reaction formula,

[0022] wherein the compound E X is a C1, Br, or a a I;

[0023] (8) the halide with dimethylamine in a solvent under an organic lithium compound is added in ether to nucleophilic substitution reaction to yield doxepin (Compound F.), The following reaction formula,

[0024]

[0025] (9) the doxepin neutralization reaction with hydrochloric acid to give sulfasalazine (Compound G), the following reaction formula,

Example 1

[0043] placed in a 20L reaction vessel acetonitrile, o-methylbenzoic acid, N- bromosuccinimide, using a water bath temperature controlled at 10 ° C, under stirring for 4h. A known separation method, separation of o-bromomethyl-benzoic acid. This compound is named J.

[0044] placed in a 20L reaction container, Compound J, diatomaceous earth in an amount of 0.05 to load cesium fluoride (compound J as a mass basis), acetonitrile in an amount of 2.5 (in Compound J 1 is a mass basis), and the temperature was adjusted to 30 ° C, with stirring under reflux for 20h adjustment. Then, a known means for separating the reaction phthalide.

After [0045] placed in a 20L reaction vessel phthalide, 3 an amount of sodium methoxide in ethanol solvent (total mass of phenol phthalide and 1 meter), the reaction solution temperature adjusted to 50 ° C, was added dropwise start phenol was 1.05 mass (in mass was 1 meter phthalide), dropwise over lh. After the dropwise addition, the reaction temperature after 5h using known separation methods, to give o-methyl benzyl phenyl ether, this compound is named I.

[0046] The above compound I, in an amount of 10% anhydrous aluminum chloride (mass of Compound I was 100% basis), the amount of DMS0 3 (mass basis Compound I 1) into a reaction vessel , the temperature was adjusted to 95 ° C. The reaction time is to be 12h. Using known separation means for separating the 6, 11-dihydro-dibenzo [b, e] oxepin-11-one.

[0047] placement 6, 11-dihydro-dibenzo in a reaction vessel and 20L [b, e] oxepin-11-one, 1.1-dihydro-fold of the mole of diphenyl at 6, 11 and [ b, e] oxepin-11-one 3-chloropropyl alkyl tert-butyl ether, 2 times the mass 6, 11-dihydro-dibenzo [b, e] oxepin-11-one magnesium in , taking all of fifths THF (5 to 6 times by mass, 11-dihydro-dibenzo [b, e] THF oxepin-11-one) and heated to 35 ° C and allowed to react. After the reaction started, the remaining 3/5 of THF was added dropwise.Was added dropwise to the system to be completed into hydrogen, reflux. After a total reaction 5h, the reaction was stopped. After the system was cooled and then poured into saturated ammonium chloride solution, extracted twice with ethyl acetate was added, dried over anhydrous sodium sulfate 5h, the resulting crude product was recrystallized from acetonitrile to give hydroxy compound.

[0048] placed in a 20L reaction vessel above hydroxy compound, an ethanol solution of 1.5 times the mass of hydroxy compound class of sodium hydroxide (concentration l〇wt mass%), was heated to 65 ° C, 2h elimination reaction after the reaction was stopped, cooled, the solvent was distilled off more of the obtained crude product was crystallized from acetonitrile to give the olefinic compounds.

[0049] placed in a 20L reaction vessel of the olefin compound, in an aqueous solution plus 1 times the mass of the olefinic compound hydrochloride (concentration of 5wt%), and heated to 50 ° C, so that a nucleophilic substitution reaction . The reaction time is to be after 4h, the reaction was stopped, cooled, the solvent was distilled off more of the obtained crude product was crystallized from acetonitrile to give the halides.

[0050] placed in a 20L reaction vessel above halide, 0.1 times the mass of methyl lithium halides to 2 times the mass of the halide in diethyl ether, heated to 40 ° C, so that the nucleophilic substitution reaction. The reaction time is to be after 5h, the reaction was stopped, reaction was complete and extracted with ethylacetate three times, dried over anhydrous sodium sulfate 5h, the resulting crude product was recrystallized from acetonitrile to obtain doxepin.

[0051] 20L is placed in a pressure reactor above doxepin, 1.05 times the mass of material in the doxepin hydrochloride (concentration of 30wt%), the control pressure to 3 ~ 4MPa, and heated to 130 ° C , and among the responses. Time after to be reacted for 20 h, cooled to room temperature and should be finished by filtration, and dried to give doxepin hydrochloride. In this embodiment overall yield 37.9%, measured by HPLC obtaining 99.2% purity.

[0052] Example 2

[0053] placed in a 20L reaction vessel acetonitrile, o-methylbenzoic acid, N- bromosuccinimide, using a water bath temperature controlled at 20 ° C, under stirring for 2h. A known separation method, separation of o-toluic acid halide.

[0054] placed in a 20L reaction container, Compound J, an amount of load of cesium fluoride Celite ~ 0.05 0.15 (in mass Compound J is 1 meter), in an amount of 2.5 to 8 acetonitrile (compound J as a mass basis), and the temperature was adjusted to 30 ~ 50 ° C, 12 ~ 20h at reflux with stirring under regulation. Then, a known means for separating the reaction phthalide.

After [0055] phthalide placed in 20L reaction vessel, an amount of sodium methoxide in 10 ethanol solvent (total mass of phenol phthalide and 1 meter), adjusting the temperature of the reaction solution was 60 ° C, was added dropwise start phenol was 1.15 mass (in mass was 1 meter phthalide), dropwise over lh.After the dropwise addition, the reaction temperature after 5h using known separation methods, to give o-methyl benzyl phenyl ether, this compound is named I.

[0056] The above compound I, in an amount of 40% anhydrous aluminum chloride (mass of Compound I was 100% basis), in an amount of DMS0 8 (in compound I is a mass basis) into a reaction vessel , the temperature was adjusted to 105 ° C. The reaction time is to be for 6h. Using known separation means for separating the 6, 11-dihydro-dibenzo [b, e] oxepin-11-one.

[0057] placement 6, 11-dihydro-dibenzo in a reaction vessel and 20L [b, e] oxepin-11-one, 1.5-dihydro-fold of the mole of diphenyl at 6, 11 and [ b, e] oxepin-11-one 3-chloropropyl alkyl tert-butyl ether, 2.4 times the mass in 6, 11-dihydro-dibenzo [b, e] oxepin-11-one of magnesium, taking all fifths THF (5 to 7 times the mass in 6, 11-dihydro-dibenzo [b, e] THF oxepin-11-one) is to make, and heated to 40 ° C reaction.After the reaction started, the remaining 3/5 of THF was added dropwise. Was added dropwise to the system to be completed into hydrogen, reflux. When the total reaction 2h, the reaction was stopped. After the system was cooled and then poured into saturated ammonium chloride solution, extracted twice with ethyl acetate was added, dried over anhydrous sodium sulfate 5h, the resulting crude product was recrystallized from acetonitrile to give hydroxy compound.

[0058] placed in a 20L reaction vessel above hydroxy compound, an ethanol solution of 5 times the mass of hydroxy compound class of sodium hydroxide (concentration of 70wt%), was heated to 80 ° C, the reaction was stopped after the elimination reaction LH, cooling, the solvent was distilled off more of the obtained crude product was crystallized from acetonitrile to give the olefinic compounds.

[0059] placed in a 20L reaction vessel of the olefin compound, in an aqueous solution of 2 times the mass of the olefinic compound added hydrobromic acid (concentration of 30wt%), and heated to 60 ° C, so that nucleophilic Substitution reaction. The reaction time is to be after the 1. 5h, the reaction was stopped, cooled, the solvent was distilled off more of the obtained crude product was crystallized from acetonitrile to give the halides.

[0060] placed in a 20L reaction vessel above halide, 0.8 times the mass of phenyl lithium halide to 8 times the mass of the halide in diethyl ether, heated to 50 ° C, so that the nucleophilic substitution reaction. The reaction time is to be after 2h, the reaction was stopped, reaction was complete and extracted with ethylacetate three times, dried over anhydrous sodium sulfate 5h, the resulting crude product was recrystallized from acetonitrile to obtain doxepin.

[0061] 20L is placed in a pressure reactor above doxepin, 1.2 times the mass of material in the doxepin hydrochloride (concentration of 38wt%), the control pressure to 3 ~ 4MPa, and heated to 150 ° C , and among the responses. Time after to be reacted for 16 h, cooled to room temperature and should be finished by filtration, and dried to give doxepin hydrochloride. In this embodiment overall yield 39.7%, measured by HPLC obtaining 99.4% purity.

[0062] Example 3

[0063] placed in a 20L reaction vessel acetonitrile, o-methylbenzoic acid, N- bromosuccinimide, using a water bath temperature controlled at 15 ° C, under stirring for 3h. A known separation method, separation of o-bromomethyl-benzoic acid.

[0064] placed in a 20L reaction container, Compound J, an amount of load of cesium fluoride Celite ~ 0.05 0.15 (in mass Compound J is 1 meter), in an amount of 2.5 to 8 acetonitrile (compound J as a mass basis), and the temperature was adjusted to 30 ~ 50 ° C, 12 ~ 20h at reflux with stirring under regulation. Then, a known means for separating the reaction phthalide.

After [0065] phthalide placed in 20L reaction vessel, an amount of sodium methoxide in ethanol solvent 6 (total mass of phenol phthalide and 1 meter), adjusting the temperature of the reaction solution was 55 ° C, was added dropwise start phenol was 1.10 mass (in mass was 1 meter phthalide), dropwise over lh.After the dropwise addition, the reaction temperature after 3. 5h using known separation methods, to give o-methyl benzyl phenyl ether, this compound is named I.

[0066] Anhydrous aluminum above compound I, in an amount of 25% of the chloride (compound I mass is 100% basis), in an amount of DMS0 6. 5 (in compound I is a mass basis) into the reaction vessel temperature is adjusted to 100 ° C. The reaction time is to be 9h. Using known separation means for separating the 6, 11-dihydro-dibenzo [b, e] oxepin-11-one.

[0067] placement 6, 11-dihydro-dibenzo in a reaction vessel and 20L [b, e] oxepin-11-one, 1.3-dihydro-fold of the mole of diphenyl at 6, 11 and [ b, e] oxepin-11-one 3-chloropropyl alkyl tert-butyl ether, 2.2 times the mass in 6, 11-dihydro-dibenzo [b, e] oxepin-11-one of magnesium, taking all fifths THF (5 to 7 times the mass in 6, 11-dihydro-dibenzo [b, e] THF oxepin-11-one) is to make, and heated to 38 ° C reaction.After the reaction started, the remaining 3/5 of THF was added dropwise. Was added dropwise to the system to be completed into hydrogen, refluxed for 2h. After a total reaction 3. 5h, the reaction was stopped. After the system was cooled and then poured into saturated ammonium chloride solution, extracted twice with ethyl acetate was added, dried over anhydrous sodium sulfate 5h, the resulting crude product was recrystallized from acetonitrile to give hydroxy compound.

[0068] placed in a 20L reaction vessel above hydroxy compound, an ethanol solution of 3-hydroxysteroid times the mass of the compound of sodium hydroxide (concentration of 40wt%), and heated to 75 ° C, 1. 5h the reaction stopped after elimination the reaction was cooled, the solvent was distilled off more of the obtained crude product was crystallized from acetonitrile to give the olefinic compounds.

[0069] placed in a 20L reaction vessel of the olefin compound, an aqueous solution of 1.5-fold increase in the mass of hydroiodic olefinic compounds (concentration of 18wt%), was heated to 55 ° C, so nucleophilic substitution reaction. The reaction time is to be after 2h, the reaction was stopped, cooled, the solvent was distilled off more of the obtained crude product was crystallized from acetonitrile to give the halides.

[0070] placed in a 20L reaction vessel above halide, 0.4 times the mass of the halide in n-butyllithium, in diethyl ether five times the mass of halide and heated to 45 ° C, so that a nucleophilic substitution reaction . The reaction time is to be 3. After 5h, the reaction was stopped, reaction was complete and extracted with ethylacetate three times, dried over anhydrous sodium sulfate 5h, the resulting crude product was recrystallized from acetonitrile to obtain doxepin.

[0071] 20L is placed in a pressure reactor above doxepin, 1.12 times the mass of material in the doxepin hydrochloride (concentration of 34wt%), the control pressure to 3 ~ 4MPa, and heated to 140 ° C , and among the responses. Time after to be reacted for 18 h, cooled to room temperature and should be finished by filtration, and dried to give doxepin hydrochloride. In this embodiment overall yield 40.2%, measured by HPLC obtaining 99.5% purity.

[0072] Example 4

[0073] placed in a 20L reaction vessel acetonitrile, o-methylbenzoic acid, N- bromosuccinimide, using a water bath temperature controlled at 15 ° C, under stirring for 4h. A known separation method, separation of o-toluic acid halide.

[0074] placed in a 20L reaction container, Compound J, an amount of load of cesium fluoride Celite ~ 0.05 0.15 (in mass Compound J is 1 meter), in an amount of 2.5 to 8 acetonitrile (compound J as a mass basis), and the temperature was adjusted to 30 ~ 50 ° C, 12 ~ 20h at reflux with stirring under regulation. Then, a known means for separating the reaction phthalide.

After [0075] phthalide placed in 20L reaction vessel, 5 an amount of sodium methoxide in ethanol solvent (total mass of phenol phthalide and 1 meter), adjusting the temperature of the reaction solution was 55 ° C, was added dropwise start phenol was 1.15 mass (in mass was 1 meter phthalide), dropwise over lh.After the dropwise addition, the reaction temperature after 5h using known separation methods, to give o-methyl benzyl phenyl ether, this compound is named I.

[0076] The above compound I, in an amount of 25% anhydrous aluminum chloride (mass of Compound I was 100% basis), in an amount of DMS0 8 (in compound I is a mass basis) into a reaction vessel , the temperature was adjusted to 100 ° C. The reaction time is to be 12h. Using known separation means for separating the 6, 11-dihydro-dibenzo [b, e] oxepin-11-one.

[0077] placement 6, 11-dihydro-dibenzo in a reaction vessel and 20L [b, e] oxepin-11-one, 1.3-dihydro-fold of the mole of diphenyl at 6, 11 and [ b, e] oxepin-11-one 3-chloropropyl alkyl tert-butyl ether, 2.4 times the mass in 6, 11-dihydro-dibenzo [b, e] oxepin-11-one of magnesium, taking all fifths THF (5 to 7 times the mass in 6, 11-dihydro-dibenzo [b, e] THF oxepin-11-one) is to make, and heated to 40 ° C reaction.After the reaction started, the remaining 3/5 of THF was added dropwise. Was added dropwise to the system to be completed into hydrogen, reflux. When the total reaction 2h, the reaction was stopped. After the system was cooled and then poured into saturated ammonium chloride solution, extracted twice with ethyl acetate was added, dried over anhydrous sodium sulfate 5h, the resulting crude product was recrystallized from acetonitrile to give hydroxy compound.

[0078] placed in a 20L reaction vessel above hydroxy compound, an ethanol solution of 5 times the mass of hydroxy compound class of sodium hydroxide (concentration of 70wt%), was heated to 80 ° C, the reaction was stopped after the elimination reaction LH, cooling, the solvent was distilled off more of the obtained crude product was crystallized from acetonitrile to give the olefinic compounds.

[0079] placed in a 20L reaction vessel of the olefin compound, an aqueous solution of 1.5-fold increase in the mass of hydroiodic olefinic compounds (concentration of 30wt%), and heated to 60 ° C, so nucleophilic substitution reaction. The reaction time is to be after the 1. 5h, the reaction was stopped, cooled, the solvent was distilled off more of the obtained crude product was crystallized from acetonitrile to give the halides.

[0080] placed in a 20L reaction vessel above halide, 0.8 times in mass n-butyl lithium halide, eight times the mass of the halide in diethyl ether, heated to 50 ° C, so that a nucleophilic substitution reaction . The reaction time is to be after 2h, the reaction was stopped, reaction was complete and extracted with ethylacetate three times, dried over anhydrous sodium sulfate 5h, the resulting crude product was recrystallized from acetonitrile to obtain doxepin.

[0081] 20L is placed in a pressure reactor above doxepin, 1.2 times the mass of material in the doxepin hydrochloride (concentration of 38wt%), the control pressure to 3 ~ 4MPa, and heated to 150 ° C , and among the responses. Time after to be reacted for 16 h, cooled to room temperature and should be finished by filtration, and dried to give doxepin hydrochloride. In this embodiment overall yield 41.6%, measured by HPLC obtaining 99.7% purity.

[0082] Example 5

[0083] placed in a 20L reaction vessel acetonitrile, o-methylbenzoic acid, N- bromosuccinimide, using a water bath temperature controlled at 15 ° C, the reaction 2. 5h under stirring. A known separation method, separation of o-bromomethyl-benzoic acid.

[0084] placed in a 20L reaction vessel o-bromomethyl benzoic acid, diatomaceous earth in an amount of load of cesium fluoride 0.05 ~ 0.15 (in mass Compound J is 1 meter), in an amount of 2. 5-8 acetonitrile (compound J as a mass basis), and the temperature was adjusted to 30 ~ 50 ° C, 12 ~ 20h at reflux with stirring under regulation. Then, a known means for separating the reaction phthalide.

After [0085] phthalide placed in 20L reaction vessel, 5 an amount of sodium methoxide in ethanol solvent (total mass of phenol phthalide and 1 meter), adjusting the temperature of the reaction solution was 55 ° C, was added dropwise start was 1.08 mass of phenol (mass was phthalide 1 meter), dropwise over lh.After the dropwise addition, the reaction temperature after 3h using known separation methods, to give o-methyl benzyl phenyl ether, this compound is named I.

[0086] Anhydrous aluminum above compound I, in an amount of 25% of the chloride (compound I mass is 100% basis), in an amount of DMS0 5 (in compound I is a mass basis) into a reaction vessel , the temperature was adjusted to 100 ° C.The reaction time is to be 8h. Using known separation means for separating the 6, 11-dihydro-dibenzo [b, e] oxepin-11-one.

[0087] placement 6, 11-dihydro-dibenzo in a reaction vessel and 20L [b, e] oxepin-11-one, 1.2-dihydro-fold of the mole of diphenyl at 6, 11 and [ b, e] oxepin-11-one 3-chloropropyl alkyl tert-butyl ether, 2.2 times the mass in 6, 11-dihydro-dibenzo [b, e] oxepin-11-one of magnesium, taking all fifths THF (5 to 7 times the mass in 6, 11-dihydro-dibenzo [b, e] THF oxepin-11-one) is to make, and heated to 38 ° C reaction.After the reaction started, the remaining 3/5 of THF was added dropwise. Was added dropwise to the system to be completed into hydrogen, reflux. When the total reaction 2h, the reaction was stopped. After the system was cooled and then poured into saturated ammonium chloride solution, extracted twice with ethyl acetate was added, dried over anhydrous sodium sulfate 5h, the resulting crude product was recrystallized from acetonitrile to give hydroxy compound.

[0088] placed in a 20L reaction vessel above hydroxy compound, an ethanol solution of 2 times the mass of hydroxy compound class of sodium hydroxide (concentration of 40wt%), was heated to 70 ° C, the reaction was stopped after the elimination reaction 2h, cooling, the solvent was distilled off more of the obtained crude product was crystallized from acetonitrile to give the olefinic compounds.

[0089] placed in a 20L reaction vessel of the olefin compound, an aqueous solution of 1.5-fold increase in the mass of hydroiodic olefinic compounds (concentration of 15wt%), and heated to 50 ° C, so nucleophilic substitution reaction. The reaction time is to be after 4h, the reaction was stopped, cooled, the solvent was distilled off more of the obtained crude product was crystallized from acetonitrile to give the halides.

[0090] placed in a 20L reaction vessel above halide, 0.4 times the mass of the halide in n-butyl lithium, 2 to 8 times the mass of the halide in diethyl ether, heated to 45 ° C, so that nucleophilic Substitution reaction. The reaction time is to be after 3h, the reaction was stopped, reaction was complete and extracted with ethylacetate three times, dried over anhydrous sodium sulfate 5h, the resulting crude product was recrystallized from acetonitrile to obtain doxepin.

[0091] 20L is placed in a pressure reactor above doxepin, 1.12 times the mass of material in the doxepin hydrochloride (mass concentration 37. 6wt%), the control pressure to 3 ~ 4MPa, heated to 140 ° C, allowing the reaction among. Time after to be reacted for 20 h, cooled to room temperature and should be finished by filtration, and dried to give doxepin hydrochloride. In this embodiment overall yield 43.9%, measured by HPLC obtaining 99.9% purity.

PATENTS

CN102924424A *2012-09-042013-02-13苏州弘森药业有限公司Method for synthesizing doxepin hydrochloride

CN105061386A *2015-08-172015-11-18苏州黄河制药有限公司Method for synthesizing doxepin hydrochloride by utilizing phthalic anhydride as raw material

Doxepin
Clinical data


Trade names	Sinequan, many others^[2]
Synonyms	NSC-108160^[3]
AHFS/Drugs.com	Monograph
MedlinePlus	a682390
License data	US FDA: Doxepin
Pregnancy category	AU: C US: B (No risk in non-human studies)
Routes of administration	By mouth, topical, intravenous, intramuscular injection^[1]
ATC code	N06AA12 (WHO)
Legal status
Legal status	AU: S4 (Prescription only) CA: ℞-only UK: POM (Prescription only) US: ℞-only
Pharmacokinetic data
Bioavailability	13–45% (mean 29%)^[5]^[6]
Protein binding	76%^[7]
Metabolism	Hepatic (CYP2D6, CYP2C19)^[4]^[5]
Metabolites	Nordoxepin, glucuronide conjugates^[4]
Elimination half-life	Doxepin: 8–24 hours (mean 17 hours)^[7] Nordoxepin: 31 hours^[7]
Excretion	Urine: ~50%^[4]^[5] Feces: minor^[5]
Identifiers
IUPAC name [show]
CAS Number	1668-19-5 1229-29-4 (hydrochloride) 3607-18-9 (cidoxepin)
PubChem CID	3158
IUPHAR/BPS	1225
DrugBank	DB01142
ChemSpider	3046
UNII	5ASJ6HUZ7D
KEGG	D07875
ChEBI	CHEBI:4710
ChEMBL	CHEMBL1628227
Chemical and physical data
Formula	C₁₉H₂₁NO
Molar mass	279.376 g/mol
3D model (JSmol)	Interactive image

Virtanen R, Iisalo E, Irjala K: Protein binding of doxepin and desmethyldoxepin. Acta Pharmacol Toxicol (Copenh). 1982 Aug;51(2):159-64. [PubMed:7113722]
Virtanen R, Scheinin M, Iisalo E: Single dose pharmacokinetics of doxepin in healthy volunteers. Acta Pharmacol Toxicol (Copenh). 1980 Nov;47(5):371-6. [PubMed:7293791]
Negro-Alvarez JM, Carreno-Rojo A, Funes-Vera E, Garcia-Canovas A, Abellan-Aleman AF, Rubio del Barrio R: Pharmacologic therapy for urticaria. Allergol Immunopathol (Madr). 1997 Jan-Feb;25(1):36-51. [PubMed:9111875]
Sansone RA, Sansone LA: Pain, pain, go away: antidepressants and pain management. Psychiatry (Edgmont). 2008 Dec;5(12):16-9. [PubMed:19724772]
Kirchheiner J, Meineke I, Muller G, Roots I, Brockmoller J: Contributions of CYP2D6, CYP2C9 and CYP2C19 to the biotransformation of E- and Z-doxepin in healthy volunteers. Pharmacogenetics. 2002 Oct;12(7):571-80. [PubMed:12360109]
ZONALON® (doxepin hydrochloride) CREAM, 5% [Link]
FDA Label: SilenorTM (doxepin) tablets for oral administration [Link]

//////////////Doxepin, ドキセピン , NSC-108160 , P-3693A , SO-101

[H]C(CCN(C)C)=C1C2=CC=CC=C2COC2=CC=CC=C12

Doxepin Hydrochloride

usp32nf27s0_m28120

http://www.drugfuture.com/Pharmacopoeia/USP32/pub/data/v32270/usp32nf27s0_m28110.html

C19H21NO·HCl 315.84

1-Propanamine, 3-dibenz[b,e]oxepin-11(6H)ylidene-N,N-dimethyl-, hydrochloride.
N,N-Dimethyldibenz[b,e]oxepin-D11(6H),

-propylamine hydrochloride

[1229-29-4; 4698-39-9 ((E)-isomer); 25127-31-5 ((Z)-isomer)].

Packaging and storage— Preserve in well-closed containers.

USP Reference standards

—
USP Doxepin Hydrochloride RS.
USP Doxepin Related Compound A RS

.
USP Doxepin Related Compound B RS

.
USP Doxepin Related Compound C RS.

Identification—

A: Infrared Absorption

197K

B: The retention time of the major peak in the chromatogram of the Assay preparation corresponds that in the chromatogram of the Standard preparation, as obtained in the Assay.

C: A solution (1 in 100) in a mixture of water and alcohol (1:1) meets the requirements of the test for Chloride

191

in amine hydrochlorides.

Loss on drying

731

— Dry it in vacuum at 60

for 3 hours: it loses not more than 0.5% of its weight.

Residue on ignition

281

: not more than 0.2%.

Heavy metals, Method II

231

: 0.002%.

Related compounds—

Diluted phosphoric acid— Prepare a mixture of water and phosphoric acid (10:1), and mix well.

Buffer— Dissolve 1.42 g of dibasic sodium phosphate in 1 L of water, adjust with Diluted phosphoric acid to a pH of 7.7, and mix.

Mobile phase— Prepare a filtered and degassed mixture of methanol, Buffer, and acetonitrile (50:30:20). Make adjustments if necessary (see System Suitabilityunder Chromatography

621

Diluent— Prepare a mixture of Mobile phase and 2 N sodium hydroxide (1000:2).

Standard solution— Dissolve accurately weighed quantities of USP Doxepin Hydrochloride RS, USP Doxepin Related Compound A RS, USP Doxepin Related Compound B RS, and USP Doxepin Related Compound C RS in Diluent to obtain a solution having a known concentration of about 0.001 mg of doxepin hydrochloride, doxepin related compound A, and doxepin related compound B each per mL, and 0.002 mg per mL of doxepin related compound C. [NOTE—Sonication for about 1 minute may be used to aid the initial dissolution of the compounds.]

Test solution— Dissolve an accurately weighed quantity of Doxepin Hydrochloride in Diluent to obtain a final solution having a known concentration of about 1 mg per mL.

Chromatographic system (see Chromatography 621)— The liquid chromatograph is equipped with a 215-nm detector and a 4.6-mm × 25-cm column that contains 5-µm packing L1. The flow rate is about 1 mL per minute. The column temperature is maintained at 30. Chromatograph about 20 µL of the Standard solution, and record the peak areas as directed for Procedure: the resolution, R, between doxepin related compound A and doxepin related compound C is not less than 1.5; the resolution between doxepin related compound C and doxepin related compound B is not less than 1.5; and the signal-to-noise ratio for all the peaks is not less than 10. [NOTE—Use the approximate relative retention times given in Table 1 for the purpose of peak identification. The doxepin related compound C peak will be the largest peak in the Standard solution chromatogram.]

Table 1

Name	Relative Retention Time (RRT)	Limit (%)
Doxepin related compound A	0.48	0.10
Doxepin related compound C	0.55	0.20
Doxepin related compound B	0.63	0.10
Doxepin hydrochloride	1.0	—
Unknown impurity	—	0.10 each

Procedure— Inject a volume (about 20 µL) of the Test solution into the chromatograph, record the chromatogram for up to 2.2 times the retention time of doxepin, and measure the peak responses. Calculate the percentage of each individual doxepin related compound in the portion of Doxepin Hydrochloride taken by the formula:

100(rU / rS)(CS / CT)

in which rU is the individual peak response for each doxepin related compound obtained from the Test solution; rS is the response of the corresponding peak in theStandard solution; CS is the concentration, in mg per mL, of each doxepin related compound in the Standard solution; and CT is the concentration, in mg per mL, of Doxepin Hydrochloride in the Test solution. The related substance limits are listed in Table 1. [NOTE—Discard any peak with a relative retention time less than 0.25. This method is not intended to resolve the E- and Z-isomers of doxepin hydrochloride. Minor variations in the mobile phase composition could result in a shoulder in the trailing edge of doxepin. In cases where there may be separation, both the E- and Z-isomers should be used in the appropriate calculations.] Use the response of the doxepin peak obtained from the Standard solution and the concentration of doxepin hydrochloride in the Standard solution to calculate the percentage of unknown individual impurities.

Assay—

Mobile phase— Prepare a mixture of 0.2 M monobasic sodium phosphate buffer and methanol (7:3), adjust with 2 N phosphoric acid to a pH of 2.5, filter, and degas. Make adjustments if necessary (see System Suitability under Chromatography

621

Standard preparation— Dissolve an accurately weighed quantity of USP Doxepin Hydrochloride RS in Mobile phase, and dilute quantitatively and stepwise with Mobile phase to obtain a solution having a known concentration of about 100 µg per mL.

Assay preparation— Transfer about 50 mg of Doxepin Hydrochloride, accurately weighed, to a 100-mL volumetric flask. Add about 70 mL of Mobile phase, and sonicate to dissolve. Dilute with Mobile phase to volume, and mix. Pipet 10.0 mL of this solution into a 50-mL volumetric flask, and dilute with Mobile phase to volume.

Chromatographic system— The liquid chromatograph is equipped with a 254-nm detector and a 4-mm × 12.5-cm column, heated to 50

, that contains packing L7. The flow rate is about 1 mL per minute. Chromatograph the Standard preparation, and record the peak responses as directed under Procedure: the resolution between the (E)- and (Z)-isomers is not less than 1.5, the tailing factor for each analyte peak is not more than 2.0, and the relative standard deviation for replicate injections is not more than 2.0%.

Procedure— Separately inject equal volumes (about 20 µL) of the Standard preparation and the Assay preparation into the chromatograph, record the chromatograms, and measure the responses for the major peaks. Calculate the quantity, in mg, of C19H21NO·HCl in the portion of Doxepin Hydrochloride taken by the formula:

0.5C[(rU(Z) + rU(E)) / (rS(Z) + rS(E))]

in which C is the concentration, in µg per mL, of USP Doxepin Hydrochloride RS in the Standard preparation, and rU(Z) and rU(E) are the respective peak responses of the (Z)- and (E)-isomers obtained from the Assay preparation, and rS(Z) and rS(E) are the respective peak responses of the (Z)- and (E)-isomers obtained from the Standard preparation. Calculate the percentage of the (Z)-isomer in the Assay preparation taken by the formula:

(rU(Z) / rS(Z))(WS / WT)(PZ)

in which WS is the weight, in mg, of USP Doxepin Hydrochloride RS in the Standard preparation, WT is the weight, in mg, in the portion of Doxepin Hydrochloride taken, and PZ is the labeled percentage of (Z)-isomer in USP Doxepin Hydrochloride RS. Similarly calculate the percentage of (E)-isomer in the Assay preparationtaken by the formula:

(rU(E) / rS(E))(WS / WT)(PE)

in which PE is the labeled percentage of (E)-isomer in USP Doxepin Hydrochloride RS.

Auxiliary Information— Please check for your question in the FAQs before contacting USP.

Topic/Question	Contact	Expert Committee
Monograph	Ravi Ravichandran, Ph.D. Senior Scientist 1-301-816-8330	(MDPP05) Monograph Development-Psychiatrics and Psychoactives
Reference Standards	Lili Wang, Technical Services Scientist 1-301-816-8129 RSTech@usp.org

USP32–NF27 Page 2206

Pharmacopeial Forum: Volume No. 32(2) Page 330

Chromatographic Column—

DOXEPIN HYDROCHLORIDE

Chromatographic columns text is not derived from, and not part of, USP 32 or NF 27.

PF-06409577

June 4, 2018 9:35 am / Leave a comment

PF-06409577

6-Chloro-5-[4-(1-hydroxycyclobutyl)phenyl]-1H-indole-3-carboxylic acid

CAS Number 1467057-23-3, C₁₉H₁₆ClNO_3,341.79

Biochem/physiol Actions

PF-06409577 is a potent and selective activator of 5′ adenosine monophosphate-activated protein kinase (AMPK).

PF-06409577 potently activates a1β1γ1 AMPK (5′ adenosine monophosphate-activated protein kinase) isoform, and prevents its dephosphorylation. It is similarly potent for β1 containing isoforms, but shows significantly lower potency for β2-containing isoforms of AMPK. Patch-clamp assays show that this compound does not inhibit hERG (human ether-a-go-go gene). It interacts with the allosteric drug and metabolite site (ADaM) of AMPK.

General description

PF-06409577 is a 6-chloro-indole derivative obtained from 5-bromo-6-chloro-indole.

PF-06409577 is a potent and selective activator of 5′ adenosine monophosphate-activated protein kinase (AMPK) for the Potential Treatment of diabetic nephropathy. PF-06409577 has AMPK α1β1γ1 Kd=9.0 nM. AMPK α1β1γ1 EC50 = 7.0 nM; AMPK α1β2γ1 EC50 > 40000 nM. PF-06409577 showed efficacy in a preclinical model of diabetic nephropathy. Upon the basis of its potent and selective AMPK activation, low metabolic turnover in human hepatocytes, clean off-target profile, and favorable preclinical in vivo efficacy results, PF-06409577 was profiled in regulatory toxicology studies and was subsequently advanced to clinical trials to assess human pharmacokinetics and safety/ tolerability.

Diabetes is a major public health concern because of its increasing prevalence and associated health risks. The disease is characterized by high levels of blood glucose resulting from defects in insulin production, insulin action, or both. Two major forms of diabetes are recognized, type I and type II. Type I diabetes develops when the body’s immune system destroys pancreatic beta cells, the only cells in the body that make the hormone insulin that regulates blood glucose. To survive, people with type 1 diabetes must have insulin delivered by injection or a pump. Type II diabetes accounts for about 90 to 95 percent of all diagnosed cases of diabetes. Type II diabetes usually begins as insulin resistance, a disorder in which the cells do not use insulin properly. Key target tissues, including liver, muscle, and adipose tissue, are resistant to the effects of insulin in stimulating glucose and lipid metabolism. As the need for insulin rises, the pancreas gradually loses its ability to produce insulin. Controlling type II diabetes with medication is essential; otherwise it can progress into pancreatic beta-cell failure requiring complete dependence on insulin.

Obesity increases the risk of type II diabetes as well as many other health conditions including coronary heart disease, stroke, and high blood pressure. More than one-third of U.S. adults (over 72 million people) and 17% of U.S. children are obese. During 1980-2008, obesity rates doubled for adults and tripled for children. During the past several decades, obesity rates for all population groups— regardless of age, sex, race, ethnicity, socioeconomic status, education level, or geographic region— have increased markedly.

Research has identified the enzyme 5′ adenosine monophosphate-activated protein kinase (AMPK) as a regulator of cellular and whole-body energy homeostasis. AMPK is activated by cellular stress resulting in downstream events that serve to conserve or generate ATP. AMPK is composed of three distinct subunits, each with multiple isoforms: the alpha subunit (alpha 1 or 2); the beta subunit (beta 1 or 2); and the gamma subunit (gamma 1, 2, or 3); for a total of twelve possible heterotrimeric isoforms.

In the liver, activated AMPK phosphorylates a variety of substrates including 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (Clarke, P.R. & Hardie, D.G., EMBO J 9, 2439-2446 (1990)) and acetyl-CoA carboxylase (Carling, D. et al. FEBS Letters 223, 217-222 (1987)) which inhibits cholesterol biosynthesis and decreases fatty acid synthesis, respectively. Therefore, activation of AMPK should lead to decreases in the levels of triglycerides and cholesterol. AMPK is also thought to regulate plasma glucose levels by decreasing hepatic gluconeogenesis through downregulation of key gene products following phosphorylation of CRTC2 (Koo S.H. et. AL, Nature 437, 1109-1111 (2005)). In muscle and myocardial tissues, AMPK activates the transport activity of glucose transporter 4 (GLUT4) increasing glucose uptake into cells thereby producing an additional avenue for decreasing plasma glucose (Kurth-Kraczek, E.J. et. al., Diabetes 48, 1667-1671 (1999)). AMPK activation has also been shown to enhance mitochondrial biogenesis improving fatty acid oxidation and decreasing circulating lipids (Merrill, G.M. et. al., Am. J. Physiol. 273, E1107-E1112 (1997)). Direct activation of AMPK using AICAR (5-aminoimidazole-4-carboxamide riboside) has been shown to lead to beneficial effects on several metabolic endpoints including improved glucose disposal, decreased hepatic glucose output and decreases in plasma triglycerides and free fatty acids (Song, X.M. et. al., Diabetologia 45, 56-65 (2002); Bergeron, R. et. al., Diabetes 50, 1076-1082 (2001); Buhl, E.S.et. al., Diabetes 50, 12-17 (2001); Iglesias, M.A. et. al., Diabetes 51, 2886-2894 (2002), Fogarty, S. & Hardie, D.G., Biochim et Biophys Acta 1804, 581-591 (2010)). Because of AMPK’s pluripotent effects on carbohydrate, lipid, and cholesterol metabolism and biosynthesis, agents that activate AMPK are attractive therapeutic targets for treating metabolic syndrome disorders such as diabetes, obesity, and dyslipidemia.

Decreases in renal AMPK activation have been implicated in the etiology of diseases of the kidney, including diabetic nephropathy, acute kidney injury (AKI), and polycystic kidney disease (PKD); activation of AMPK through hormonal (adiponectin) or pharmacological (AICAR) mechanisms has been shown to be protective in rodent models of these diseases. In diabetic nephropathy decreased AMPK activation in podocytes occurs early in the disease and is associated with increased expression of the NADPH-Oxidase protein Nox4 and increased proteinuria. These effects were reduced following administration of the AMPK activators AICAR, metformin, and Adiponectin (Lee, MJ. et.al. American Journal of Physiology – Renal Physiology. 292.

F617-F627 (2007); Sharma, K. et.al. Journal of Clinical Investigation.118. 1645-1656. (2008)). In ischemia/reperfusion models of AKI the AMPK activators metformin and AICAR were shown to dose-dependently reduce subsequent proteinuria, oxidative tissue damage, and kidney macrophage infiltration (Lempiainen, J. et.al. British Journal of Pharmacology 166. 1905-1915 (2012); Seo-Mayer, P.W. et.al. American Journal of Physiology – Renal Physiology, 301, F1346-F1357 (2011)). In two rodent models of PKD the AMPK activator metformin was shown to reduce renal cyst expansion (Takiar, V. et. al. PNAS 108, 2462-2467 (2011)). These studies suggest a broad benefit of AMPK activators in multiple renal diseases.

The compounds of the present invention activate AMPK and are, therefore, useful in treating metabolic disorders such as diabetes, obesity, and dyslipidemia as well as the renal diseases chronic kidney disease, diabetic nephropathy, acute kidney injury and polycystic kidney disease.

PATENT

US 20130267493

WO 2014140704

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2014140704&recNum=232&docAn=IB2013058819&queryString=EN_ALL:nmr%20AND%20PA:pfizer&maxRec=8241

Example 5

6-Chloro-5-(4-(3-hydroxyoxetan-3-yl)phenyl)-1H-indole-3-carboxylic acid

Step 1

6-chloro-5-(4-(3-hydroxyoxetan-3-yl)phenyl)-1H-indole-3-carbaldehyde

A mixture of 5,5,5′,5′-tetramethyl-[2,2′]bi[[1,3,2]dioxaborinanyl] (149.0 mg, 0.44 mmol), oven dried potassium acetate (173.0 mg, 1.75 mmol) and 3-(4-bromo-phenyl)-oxetan-3-ol (100.0 mg, 0.44 mmol) in 1,4-dioxane (2 mL) was degassed with N₂ for 5 minutes, treated with [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (33.0 mg, 0.044 mmol) and subjected to microwave irradiation at 110 °C for 1 hour. The cooled reaction mixture was filtered through celite and concentrated in vacuo to give a black oil. To the dark oil was added 5-bromo-6-chloro-1H-indole-3-carbaldehyde (112.0 mg, 0.43 mmol), 2 N aqueous potassium carbonate (0.4 mL, 0.80 mmol), toluene (1.5 mL) and EtOH (0.5 mL). The reaction mixture was degassed with N₂ for 10 minutes, treated with [1, 1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II) (25.0 mg, 0.034 mmol), and heated in a pressure tube to 110 °C for 2 hours. The cooled reaction mixture was purified by flash chromatography (33-100% EtOAc/ heptanes) to give a solid. The solid was triturated in MeOH and filtered to afford the title compound (50 mg, 35%) as a yellow solid. MS (ES+) 328.0 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 12.23 (s, 1 H), 9.92 (s, 1 H), 8.35 (s, 1 H), 8.02 (s, 1 H), 7.66 (d, J = 9.4 Hz, 2 H), 7.44 (d, J = 8.2 Hz, 2 H), 6.36 (s, 1 H), 4.80 – 4.76 (m, 2 H), 4.75 – 4.71 (m, 2 H).

Step 2

6-Chloro-5-(4-(3-hydroxyoxetan-3-yl)phenyl)-1 H-indole-3-carboxylic acid To the mixture of 6-chloro-5-[4-(3-hydroxy-oxetan-3-yl)-phenyl]-1H-indole-3-carbaldehyde (50.0 mg, 0.15 mmol) in MeCN (2 mL) was added 2-methyl-2-butene (2.0 mL, 13.7 mmol), followed by sodium chlorite (138 mg, 1.53 mmol) and sodium phosphate monobasic hydrate (211.0 mg, 1.53 mmol) in water (1 mL). The reaction mixture was stirred at room temperature for 20 hours, and concentrated in vacuo. The residue was acidified with 1 N aqueous citric acid (1 mL) and extracted with EtOAc. The organic layer was dried over MgSO₄ and concentrated in vacuo. The crude material was purified by flash chromatography (34-80% EtOAc/heptanes, with 0.2% formic acid modifier) to afford the title compound (18 mg, 34%) as a brown solid. MS (ES-) 342.3 (M-H)-. ¹H NMR (400 MHz, CD₃OD) δ 8.02 (s, 1 H), 7.98 (s, 1 H), 7.66 (d, J = 8.20 Hz, 2 H), 7.56 (s, 1 H), 7.47 (d, J = 8.20 Hz, 2 H), 4.87 – 4.80 (m, 4 H).

Paper

Discovery and Preclinical Characterization of 6-Chloro-5-[4-(1-hydroxycyclobutyl)phenyl]-1H-indole-3-carboxylic Acid (PF-06409577), a Direct Activator of Adenosine Monophosphate-activated Protein Kinase (AMPK), for the Potential Treatment of Diabetic Nephropathy. Cameron KO et al Journal of Medicinal Chemistry 59(17), 8068-8081, (2016)

https://pubs.acs.org/doi/10.1021/acs.jmedchem.6b00866

Adenosine monophosphate-activated protein kinase (AMPK) is a protein kinase involved in maintaining energy homeostasis within cells. On the basis of human genetic association data, AMPK activators were pursued for the treatment of diabetic nephropathy. Identification of an indazole amide high throughput screening (HTS) hit followed by truncation to its minimal pharmacophore provided an indazole acid lead compound. Optimization of the core and aryl appendage improved oral absorption and culminated in the identification of indole acid, PF-06409577 (7). Compound 7 was advanced to first-in-human trials for the treatment of diabetic nephropathy.

Discovery and Preclinical Characterization of 6-Chloro-5-[4-(1-hydroxycyclobutyl)phenyl]-1H-indole-3-carboxylic Acid (PF-06409577), a Direct Activator of Adenosine Monophosphate-activated Protein Kinase (AMPK), for the Potential Treatment of Diabetic Nephropathy

^†Cardiovascular, Metabolic and Endocrine Diseases Medicinal Chemistry, ^‡Cardiovascular, Metabolic and Endocrine Diseases Research Unit, and ^§Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development, 610 Main Street, Cambridge, Massachusetts 02139, United States

^∥Cardiovascular, Metabolic and Endocrine Diseases Medicinal Chemistry, ^⊥Cardiovascular, Metabolic and Endocrine Diseases Research Unit, ^#Worldwide Medicinal Chemistry, ^∇Pharmacokinetics, Dynamics and Metabolism, ^○Pharmaceutical Sciences, Pfizer Worldwide Research & Development, Groton, Connecticut 06340, United States

J. Med. Chem., 2016, 59 (17), pp 8068–8081

DOI: 10.1021/acs.jmedchem.6b00866

*For K.O.C.: phone, 617-551-3234; E-mail, Kimberly.O.Cameron@pfizer.com., *For D.W.K.: E-mail, Daniel.W.Kung@pfizer.com.

ACS Editors’ Choice – This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes.

6-Chloro-5-[4-(1-hydroxycyclobutyl)phenyl]-1H-indole-3-carboxylic Acid (7)

7 as a crystalline off-white solid (72.4 g, 58%). The mother liquor was concentrated to ∼30% of the initial volume, and a precipitate formed. The solids were collected by filtration and were dried under vacuum to obtain an additional batch of off-white solid (14.5 g, 12%). MS (ES−) 340.3 (M – H)⁻. ¹H NMR (400 MHz, DMSO-d₆) δ 12.12 (s, 1H), 11.95 (br s, 1H), 8.09 (d, J = 2.3 Hz, 1H), 7.96 (s, 1H), 7.65 (s, 1H), 7.58 (d, J = 7.8 Hz, 2H), 7.42 (d, J = 8.2 Hz, 2H), 5.53 (s, 1H), 2.42–2.48 (m, 2H), 2.28–2.35 (m, 2H), 1.91–2.01 (m, 1H), 1.62–1.79 (m, 1H). Analytical % Calcd: C, 66.77; H, 4.72; N, 4.10. Found: C, 66.59; H, 4.56; N, 3.96. mp 220–222 °C.

PAPER

Evolution of the Synthesis of AMPK Activators for the Treatment of Diabetic Nephropathy: From Three Preclinical Candidates to the Investigational New Drug PF-06409577

Aaron C. Smith *^†

, Daniel W. Kung *^†

, Andre Shavnya^†, Thomas A. Brandt^†, Philip D. Dent^†, Nathan E. Genung^†, Shawn Cabral^†, Jane Panteleev^†, Michael Herr^†, Ka Ning Yip^‡, Gary E. Aspnes^‡, Edward L. Conn^†, Matthew S. Dowling^†

, David J. Edmonds^‡

, Ian D. Edmonds^§, Dilinie P. Fernando^†, Paul M. Herrinton^∥, Nandell F. Keene^†, Sophie Y. Lavergne^†, Qifang Li^†, Jana Polivkova^†, Colin R. Rose^†, Benjamin A. Thuma^†, Michael G. Vetelino^†, Guoqiang Wang^†, John D. Weaver, III^†, Daniel W. Widlicka^†, Kristin E. Price Wiglesworth^†, Jun Xiao^†, Todd Zahn^∥, and Yingxin Zhang^†

^† Pfizer Worldwide Research & Development, Eastern Point Road, Groton, Connecticut 06340, United States

^‡ Pfizer Worldwide Research & Development, 610 Main Street, Cambridge, Massachusetts 02139, United States

^§ Bridge Organics, 311 West Washington Street, Vicksburg, Michigan 49097, United States

^∥ BoroPharm, Inc., 39555 Orchard Hill Place, Suite 600, Novi, Michigan 48375, United States

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.8b00059

*E-mail for Aaron C. Smith: Aaron.Smith2@pfizer.com., *E-mail for Daniel W. Kung: Daniel.W.Kung@pfizer.com.

https://pubs.acs.org/doi/10.1021/acs.oprd.8b00059

Indole acids 1, 2, and 3 are potent 5′-adenosine monophosphate-activated protein kinase (AMPK) activators for the potential treatment of diabetic nephropathy. Compounds 1–3 were scaled to supply material for preclinical studies, and indole 3 was selected for advancement to first-in-human clinical trials and scaled to kilogram quantities. The progression of the synthesis strategy for these AMPK activators is described, as routes were selected for efficient structure–activity relationship generation and then improved for larger scales. The developed sequences employed practical isolations of intermediates and APIs, reproducible cross-coupling, hydrolysis, and other transformations, and enhanced safety and purity profiles and led to the production of 40–50 g of 1and 2 and 2.4 kg of 3. Multiple polymorphs of 3 were observed, and conditions for the reproducible formation of crystalline material suitable for clinical development were identified.

Mp: 192–194 °C. ¹H NMR (400 MHz, DMSO-d₆): δ 12.12 (s, 1H), 11.94 (br d, J = 2.2 Hz, 1H), 8.08 (d, J = 2.9 Hz, 1H), 7.95 (s, 1H), 7.64 (s, 1H), 7.57 (d, J = 8.3 Hz, 2H), 7.40 (d, J = 8.1 Hz, 2H), 5.52 (s, 1H), 2.48–2.40 (m, 2H), 2.35–2.26 (m, 2H), 2.00–1.89 (m, 1H), 1.74–1.63 (m, 1H). ¹³C NMR (101 MHz, DMSO-d₆): δ 165.6, 146.6, 138.1, 136.0, 133.8, 133.0, 129.2, 125.6, 125.3, 124.6, 122.8, 112.9, 107.6, 75.1, 37.3, 12.8. MS (ES): calcd for C₁₉H₁₇ClNO₃ ([M – H]⁻) 340.1; found 340.3. Anal. Calcd (%): C, 66.77; H, 4.72; N, 4.10. Found: C, 66.59; H, 4.71; N, 3.96.

///////////////////PF-06409577, PHASE 1

O=C(C1=CNC2=C1C=C(C3=CC=C(C4(O)CCC4)C=C3)C(Cl)=C2)O

Burosumab-twza, ブロスマブ

June 4, 2018 9:32 am / Leave a comment

> Burosumab Heavy Chain Sequence
QVQLVQSGAEVKKPGASVKVSCKASGYTFTNHYMHWVRQAPGQGLEWMGIINPISGSTSN
AQKFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARDIVDAFDFWGQGTMVTVSSAST
KGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY
SLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSV
FLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY
RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTK
NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG
NVFSCSVMHEALHNHYTQKSLSLSPGK

> Burosumab Light Chain Sequence
AIQLTQSPSSLSASVGDRVTITCRASQGISSALVWYQQKPGKAPKLLIYDASSLESGVPS
RFSGSGSGTDFTLTISSLQPEDFATYYCQQFNDYFTFGPGTKVDIKRTVAAPSVFIFPPS
DEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTL
SKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

ALSO

(Heavy chain)
QVQLVQSGAE VKKPGASVKV SCKASGYTFT NHYMHWVRQA PGQGLEWMGI INPISGSTSN
AQKFQGRVTM TRDTSTSTVY MELSSLRSED TAVYYCARDI VDAFDFWGQG TMVTVSSAST
KGPSVFPLAP SSKSTSGGTA ALGCLVKDYF PEPVTVSWNS GALTSGVHTF PAVLQSSGLY
SLSSVVTVPS SSLGTQTYIC NVNHKPSNTK VDKKVEPKSC DKTHTCPPCP APELLGGPSV
FLFPPKPKDT LMISRTPEVT CVVVDVSHED PEVKFNWYVD GVEVHNAKTK PREEQYNSTY
RVVSVLTVLH QDWLNGKEYK CKVSNKALPA PIEKTISKAK GQPREPQVYT LPPSRDELTK
NQVSLTCLVK GFYPSDIAVE WESNGQPENN YKTTPPVLDS DGSFFLYSKL TVDKSRWQQG
NVFSCSVMHE ALHNHYTQKS LSLSPGK
(Light chain)
AIQLTQSPSS LSASVGDRVT ITCRASQGIS SALVWYQQKP GKAPKLLIYD ASSLESGVPS
RFSGSGSGTD FTLTISSLQP EDFATYYCQQ FNDYFTFGPG TKVDIKRTVA APSVFIFPPS
DEQLKSGTAS VVCLLNNFYP REAKVQWKVD NALQSGNSQE SVTEQDSKDS TYSLSSTLTL
SKADYEKHKV YACEVTHQGL SSPVTKSFNR GEC
(dimer; disulfide bridge:H22-H96, H144-H200, H220-L213, H220-H’226, H229-H’229, H261-H321, H367-H425, H’22-H’96, H’144-H’200, H’220-L’213, H’261-H’321, H’367-H’425, L23-L88, L133-L193, L’23-L’88, L’133-L’193)

Burosumab-twza, KRN 23

ブロスマブ

CAS1610833-03-8

UNII G9WJT6RD29

Protein chemical formulaC₆₃₈₈H₉₉₀₄N₁₇₀₀O₂₀₀₆S₄₆

Protein average weight144100.0 Da

Protein Based Therapies
Monoclonal antibody (mAb)

breakthrough therapy and orphan drug designations

Company:Ultragenyx

Approval Status:Approved April 2018

Specific Treatments:X-linked hypophosphatemia

Crysvita (burosumab-twza) is a fibroblast growth factor 23 (FGF23) blocking antibody.

This drug is indicated for the treatment of X-linked hypophosphatemia with radiological evidence of bone disease in children of 1 year of age and older and adolescents with growing skeletons ^[4].

Burosumab (INN, trade name Crysvita) known as KRN23 is a human monoclonal antibody designed for the treatment of X-linked hypophosphatemia.^[1]^[2]^[3] Burosumab was approved by the FDA for its intended purpose, in patients aged 1 year and older, on 17 April 2018.^[4] The FDA approval fell under both the breakthrough therapy and orphan drug designations.^[4]

This drug was developed by Ultragenyx and is in a collaborative license agreement with Kyowa Hakko Kirin.^[5]

Burosumab (KRN23) is an entirely human monoclonal IgG1 antibody that binds excess fibroblast growth factor 23 (FGF23) and has been successfully tested in clinical trials in children with X-linked hypophosphatemic rickets ^[1].

The U.S. Food and Drug Administration approved Crysvita (burosumab) in April 2018. This is the first drug approved to treat adults and children ages 1 year and older with X-linked hypophosphatemia (XLH), which is a rare, inherited form of rickets. X-linked hypophosphatemia causes low circulating levels of phosphorus in the blood. It causes impaired bone growth and development in children and adolescents and issues with bone mineralization throughout a patient’s life ^[3].

XLH is a serious disease which affects about 3,000 children and 12,000 adults in the United States. Most children with XLH suffer from bowed or bent legs, short stature, bone pain and severe dental pain. Some adults with this condition suffer from persistent, unrelenting discomfort and complications, such as joint pain, impaired mobility, tooth abscesses and hearing loss ^[3]

Crysvita is specifically indicated for the treatment of X-linked hypophosphatemia (XLH) in adult and pediatric patients 1 year of age and older.

Crysvita is supplied as a subcutaneous injection. The recommended starting dose for pediatrics is 0.8 mg/kg of body weight, rounded to the nearest 10 mg, administered every two weeks. The minimum starting dose is 10 mg up to a maximum dose of 90 mg. After initiation of treatment with Crysvita, measure fasting serum phosphorus every 4 weeks for the first 3 months of treatment, and thereafter as appropriate. If serum phosphorus is above the lower limit of the reference range for age and below 5 mg/dL, continue treatment with the same dose. Follow dose adjustment schedule per the drug label. The recommended dose regimen in adults is 1 mg/kg body weight, rounded to the nearest 10 mg up to a maximum dose of 90 mg, administered every four weeks. After initiation of treatment with Crysvita, assess fasting serum phosphorus on a monthly basis, measured 2 weeks post-dose, for the first 3 months of treatment, and thereafter as appropriate. If serum phosphorus is within the normal range, continue with the same dose. See drug label for specific dose adjustments.

Mechanism of Action

Crysvita (burosumab-twza) is a fibroblast growth factor 23 (FGF23) blocking antibody. X-linked hypophosphatemia is caused by excess fibroblast growth factor 23 (FGF23) which suppresses renal tubular phosphate reabsorption and the renal production of 1,25 dihydroxy vitamin D. Burosumab-twza binds to and inhibits the biological activity of FGF23 restoring renal phosphate reabsorption and increasing the serum concentration of 1,25 dihydroxy vitamin D.

REFERENCES

1 file:///H:/761068Orig1s000ChemR.pdf

REF

Kutilek S: Burosumab: A new drug to treat hypophosphatemic rickets. Sudan J Paediatr. 2017;17(2):71-73. doi: 10.24911/SJP.2017.2.11. [PubMed:29545670]
Kinoshita Y, Fukumoto S: X-linked hypophosphatemia and FGF23-related hypophosphatemic diseases -Prospect for new treatment. Endocr Rev. 2018 Jan 26. pii: 4825438. doi: 10.1210/er.2017-00220. [PubMed:29381780]
FDA approves first therapy for rare inherited form of rickets, x-linked hypophosphatemia [Link]
Crysvita Drug Label [Link]
Burosumab for a rare bone disease [Link]
DRUG: Burosumab [Link]
NHS document [Link]
Burosumab for XLH [Link]

Burosumab
Monoclonal antibody
Type	Whole antibody
Source	Human
Target	FGF 23
Clinical data
Trade names	Crysvita
Synonyms	KRN23
ATC code	M05BX05 (WHO)
Identifiers
CAS Number	1610833-03-8
ChemSpider	none
UNII	G9WJT6RD29
KEGG	D10913
Chemical and physical data
Formula	C₆₃₈₈H₉₉₀₄N₁₇₀₀O₂₀₀₆S₄₆
Molar mass	144.1 kDa

References

Jump up^ Statement On A Nonproprietary Name Adopted By The USAN Council – Burosumab, American Medical Association.^{[permanent dead link]}
Jump up^ World Health Organization (2016). “International Nonproprietary Names for Pharmaceutical Substances (INN). Proposed INN: List 115”(PDF). WHO Drug Information. 30 (2): 255.
Jump up^ “Burosumab (KRN23) for X-Linked Hypophosphatemia (XLH)” (PDF). n.d. Retrieved 2018-04-18.
^ Jump up to:^a ^b “FDA approves first therapy for rare inherited form of rickets, x-linked hypophosphatemia” (Press release). FDA. 17 April 2018.
Jump up^ “Collaboration with Ultragenyx to Develop and Commercialize KRN23 for X-linked Hypophosphatemia” (Press release). Kyowa Kirin. 4 September 2013. Retrieved 2018-04-17.

//////////////Burosumab-twza, Crysvita FDA 2018, BLA 761068, Protein Based Therapies, Monoclonal antibody, mAb, KRN 23, breakthrough therapy, orphan drug designations, Peptide, ブロスマブ

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.
Jump up^ “Newborn Screening”. Newbornscreening.info. 2013-05-14. Retrieved 2015-06-04.
Jump up^ “What is Alkaptonuria?”. Akusociety.org. Archived from the original on 2015-04-05. Retrieved 2015-06-04.
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.
Jump up^ G. Mitchell, D.W. Bartlett, T.E. Fraser, T.R. Hawkes, D.C. Holt, J.K. Townson, R.A. Wichert Mesotrione: a new selective herbicide for use in maize Pest Management Science, 57 (2) (2001), pp. 120–128
^ 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

ONC201 disrupts mitochondrial function and kills breast cancer cells, reveals study — Med-Chemist

June 2, 2018 4:16 am / 1 Comment on ONC201 disrupts mitochondrial function and kills breast cancer cells, reveals study — Med-Chemist

TRAIL, a member of the TNF family of ligands, causes caspase-dependent apoptosis through activation of its receptors, death receptor 4 and DR5.ONC201 was originally identified as a small molecule that inhibits both Akt and ERK, resulting in dephosphorylation of Foxo3a and thereby induces TRAIL transcription.Recently, two independent groups, Wafik El Deiry at Fox Chase and…

via ONC201 disrupts mitochondrial function and kills breast cancer cells, reveals study — Med-Chemist

Tildrakizumab-asmn

June 1, 2018 8:14 am / Leave a comment

Heavy chain:
	QVQLVQSGAEVKKPGASVKVSCKASGYIFITYWMTWVRQAPGQGL
	EWMGQIFPASGSADYNEKFEGRVTMTTDTSTSTAYMELRSLRSDD
	TAVYYCARGGGGFAYWGQGTLVTVSSASTKGPSVFPLAPSSKSTS
	GGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS
	LSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTC
	PPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDP
	EVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNG
	KEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKN
	QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFL
	YSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
	Light chain:
	DIQMTQSPSSLSASVGDRVTITCRTSENIYSYLAWYQQKPGKAPK
	LLIYNAKTLAEGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQH
	HYGIPFTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCL
	LNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT
	LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

Tildrakizumab-asmn

Immunoglobulin G1, anti-(human interleukin 23) (human-Mus musculus monoclonal heavy chain), disulfide with human-Mus musculus monoclonal light chain, dimer

CAS 1326244-10-3, BLA 761067

Tildrakizumab (SCH 900222/MK-3222)

ILUMYA; MK-3222; SCH-900222; SUNPG 1622; SUNPG 1622 I; SUNPG 1623 I; SUNPG 1623 II; SUNPG 1623 III; SUNPG 1623 IV; SUNPG1623; Tildrakizumab-asmn

DRUG BANK https://www.drugbank.ca/drugs/DB14004

Company Sun Pharmaceuticals

Approval Status FDA Approved March 2018 FOR Psoriasis, plaque

Treatments plaque psoriasis

Protein chemical formulaC₆₄₂₆H₉₉₁₈N₁₆₉₈O₂₀₀₀S₄₆

Protein average weight144400.0 DaSequences

>Tildrakizumab Sequence
MLGSRAVMLLLLLPWTAQGRAVPGGSSPAWTQCQQLSQKLCTLAWSAHPLVGHMDLREEG
DEETTNDVPHIQCGDGCDPQGLRDNSQFCLQRIHQGLIFYEKLLGSDIFTGEPSLLPDSP
VGQLHASLLGLSQLLQPEGHHWETQQIPSLSPSQPWQRLLLRFKILRSLQAFVAVAARVF
AHGAATLSP

Tildrakizumab
Monoclonal antibody
Type	?
Source	Humanized (from mouse)
Target	IL23
Clinical data
Trade names	Ilumya
Synonyms	Tildrakizumab-asmn
Routes of administration	Subcutaneous injection
ATC code	none
Identifiers
CAS Number	1326244-10-3
ChemSpider	none
KEGG	D10400
Chemical and physical data
Formula	C₆₄₂₆H₉₉₁₈N₁₆₉₈O₂₀₀₀S₄₆
Molar mass	144.4 kg/mol

Originator Schering-Plough
Developer Almirall S.A.; Merck & Co; Schering-Plough; Sun Pharmaceutical Industries
Class Antipsoriatics; Monoclonal antibodies
Mechanism of Action Interleukin 23 inhibitors

Orphan Drug StatusNo
New Molecular EntityYes

Highest Development Phases

Registered Plaque psoriasis
Phase II Ankylosing spondylitis; Psoriatic arthritis
Discontinued Autoimmune disorders

Most Recent Events

21 Mar 2018 Registered for Plaque psoriasis in USA (SC) – First global approval
16 Feb 2018 Adverse events data from two phase III trials (reSURFACE 1 and 2) in chronic Plaque psoriasis presented at the 76^th Annual Meeting of the American Academy of Dermatology (AAD-2018)
16 Feb 2018 Pharmacokinetics data from population PK model in healthy volunteers and patients with psoriasis presented at the 76^th Annual Meeting of the American Academy of Dermatology (AAD-2018)

Ilumya (tildrakizumab-asmn) is an interleukin-23 antagonist.

Humanized monoclonal IgG1-kappa antibody against IL-23p19; produced in CHO cells
Immunoglobulin G1, anti-(human interleukin 23) (human-Mus musculus monoclonal heavy chain), disulfide with human-Mus musculus monoclonal light chain, dimer

Ilumya is specifically indicated for the treatment of adults with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy.

Ilumya is supplied as a solution for subcutaneous injection. The recommended dose is 100 mg at Weeks 0, 4, and every twelve weeks thereafter.

Image result for tildrakizumab-asmn

Tildrakizumab (Ilumya) is a monoclonal antibody designed for the treatment of immunologically mediated inflammatory disorders.^[1] In the United States, it is approved for the treatment of moderate-to-severe plaque psoriasis.^[2]

Tildrakizumab was designed to block interleukin-23, a cytokine that plays an important role in managing the immune system and autoimmune disease. Originally developed by Schering-Plough, this drug is now part of Merck‘s clinical program, following that company’s acquisition of Schering-Plough.

Sun Pharmaceutical acquired worldwide rights to tildrakizumab for use in all human indications from Merck in exchange for an upfront payment of U.S. $80 million. Upon product approval, Sun Pharmaceutical will be responsible for regulatory activities, including subsequent submissions, pharmacovigilance, post approval studies, manufacturing and commercialization of the approved product. ^[3]

Image result for tildrakizumab-asmn

As of March 2014, the drug was in phase III clinical trials for plaque psoriasis. The two trials enrolled nearly 2000 patients. ^[4]^[5]

In 2016, tildrakizumab became the first IL-23p19 inhibitor to demonstrate positive results in Phase-3 clinical trials for the treatment of moderate-to-severe plaque psoriasis, further validating the importance of the role of IL-23 in psoriasis. Sun Pharma signed a licensing pact with Spain’s Almirall for marketing tildrakizumab in Europe ^[6]

In March 2018, it was approved by the Food and Drug Administration for the treatment of moderate-to-severe plaque psoriasis as an injection for subcutaneous use in the United States.^[2]

In 2014, Sun Pharma acquired worldwide rights to tildrakizumab from Merck; upon product approval, Sun Pharma is responsible for regulatory activities, including subsequent submissions, pharmacovigilance, post approval studies, manufacturing and commercialization of the product. In 2016, Almirall sublicensed the product for the development and marketing in Europe for the treatment of psoriasis.

References

Mechanism of Action

Tildrakizumab is a humanized IgG1/k monoclonal antibody that selectively binds to the p19 subunit of IL-23 and inhibits its interaction with the IL-23 receptor. IL-23 is a naturally occurring cytokine that is involved in inflammatory and immune responses. Tildrakizumab inhibits the release of proinflammatory cytokines and chemokines.

FDA APPROVAL DATA

BLA 761067

https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2018/761067Orig1s000REPLACEMENT_ltr.pdf

Please refer to your Biologics License Application (BLA) dated and received March 23, 2017 and your amendments, submitted under section 351(a) of the Public Health Service Act for ILUMYA (tildrakizumab-asmn) injection. We also refer to our approval letter dated March 20, 2018 which contained the following error: the Final Report Submission date was incorrectly listed for postmarketing requirement 3357-3. This replacement approval letter incorporates the correction of the error. The effective approval date will remain March 20, 2018, the date of the original approval letter.

LICENSING We have approved your BLA for ILUMYA (tildrakizumab-asmn) effective this date. You are hereby authorized to introduce or deliver for introduction into interstate commerce, ILUMYA under your existing Department of Health and Human Services U.S. License No. 0002. ILUMYA is indicated for the treatment of adults with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy.

MANUFACTURING LOCATIONS Under this license, you are approved to manufacture ILUMYA drug substance at . The final formulated drug product will be manufactured, filled, labeled, and packaged at MSD Ireland, Carlow, Ireland. You may label your product with the proprietary name, ILUMYA, and market it in 100 mg/1 mL single-dose prefilled syringe

DATING PERIOD The dating period for ILUMYA drug product shall be 36 months from the date of manufacture when stored at 2-8°C. The date of manufacture shall be defined as the date of final sterile filtration of the formulated drug product. The dating period for your drug substance shall be months from the date of manufacture when stored at We have approved the stability protocols in your license application for the purpose of extending the expiration dating period of your drug substance and drug product under 21 CFR 601.12.

PATENTS

WO 2014109927

PAPER

https://www.tandfonline.com/doi/full/10.4161/19420862.2015.988944

Tildrakizumab (SCH 900222/MK-3222) targets the p19 subunit of IL-23. The mAb was developed by Schering-Plough, which was acquired by Merck & Co. in 2009, and it was then licensed by Merck to Sun Pharmaceutical Industries Ltd in September 2014. Clinical development and regulatory activities will be conducted by Merck, but funded by Sun Pharma. As of October 2014, the safety and efficacy of tildrakizumab are being evaluated in 2 Phase 3 studies that are ongoing but not recruiting patients. Both studies include patients with moderate-to-severe chronic plaque psoriasis and subcutaneously administered drug. The 52-week Phase 3 NCT01729754 study has 4 arms (200 mg tildrakizumab; 100 mg tildrakizumab; 50 mg etanercept; and placebo only), and includes an optional long-term safety extension study. The estimated enrollment is 1050, and the estimated primary completion date is October 2019. The 64-week Phase 3 NCT01722331 study is evaluating the effects of either 200 mg or 100 mg tildrakizumab to placebo; it includes an optional long-term safety extension study. The estimated enrollment is 885, and the estimated primary completion date is June 2015.

Image result for tildrakizumab-asmn

Sun Pharma Announces U.S. FDA Approval of ILUMYA™ (tildrakizumab-asmn) for the Treatment of Moderate-to-Severe Plaque Psoriasis

NEWS PROVIDED BY

Sun Pharma

Mar 21, 2018, 09:04 ET

MUMBAI, India and PRINCETON, N.J., March 21, 2018 /PRNewswire/ — Sun Pharmaceutical Industries Ltd. (Reuters: SUN.BO, Bloomberg: SUNP IN, NSE: SUNPHARMA, BSE: 524715, “Sun Pharma” and includes its subsidiaries and/or associate companies) today announced that the U.S. Food and Drug Administration (FDA) has approved ILUMYA™ (tildrakizumab-asmn) for the treatment of adults with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy. ILUMYA selectively binds to the p19 subunit of IL-23 and inhibits its interaction with the IL-23 receptor leading to inhibition of the release of pro-inflammatory cytokines and chemokines. ILUMYA is administered at a dose of 100 mg by subcutaneous injection every 12 weeks, after the completion of initial doses at weeks 0 and 4. ILUMYA is contraindicated in patients with a previous serious hypersensitivity reaction to tildrakizumab or to any of the excipients.

“With the approval of ILUMYA and our long-standing commitment in dermatology, we are focused on making a difference for people living with moderate-to-severe plaque psoriasis,” said Abhay Gandhi, President and Chief Executive Officer, North America, Sun Pharma. “We are committed to working with all relevant stakeholders to make ILUMYA available to appropriate people with plaque psoriasis.”

The FDA approval of ILUMYA for the treatment of adults with moderate-to-severe plaque psoriasis was supported by data from the pivotal Phase-3 reSURFACE clinical development program. In the two multicenter, randomized, double-blind, placebo-controlled trials (reSURFACE 1 and reSURFACE 2), 926 adult patients were treated with ILUMYA (N=616) or placebo (N=310). Results from these studies were published in The Lancet in July 2017, with primary endpoints presented at the 25th European Academy of Dermatology and Venereology (EADV) Congress.

Both Phase-3 studies met the primary efficacy endpoints, demonstrating significant clinical improvement with ILUMYA 100 mg compared to placebo when measured by at least 75 percent of skin clearance (Psoriasis Area Sensitivity Index or PASI 75) and Physician’s Global Assessment (PGA) score of “clear” or “minimal” at week 12 after two doses.

*Efficacy Primary Endpoint at Week 12 in Adults with Plaque Psoriasis (NRI)**
	reSURFACE 1 Study (NCT01722331)		reSURFACE 2 Study (NCT01729754)
	ILUMYA 100 mg n=309	Placebo n=154	ILUMYA 100 mg n=307	Placebo n=156
PGA of “clear” (0) or “minimal” (1)†	179 (58%)	11 (7%)	168 (55%)	7 (4%)
PASI 75†	197 (64%)	9 (6%)	188 (61%)	9 (6%)
PASI 90	107 (35%)	4 (3%)	119 (39%)	2 (1%)
PASI 100	43 (14%)	2 (1%)	38 (12%)	0 (0%)

* NRI = Non-Responder Imputation † Co-Primary Endpoints

Of the patients in the reSURFACE 1 study 74 percent (229 patients) achieved 75 percent skin clearance at week 28 after three doses, and 84 percent of patients who continued receiving ILUMYA 100 mg maintained PASI 75 at week 64 compared to 22 percent of patients who were re-randomized to placebo. In addition, 69 percent of the patients receiving ILUMYA 100 mg who had a PGA score of “clear” or “minimal” at week 28 maintained this response at week 64 compared to 14 percent of patients who were re-randomized to placebo.

Full Prescribing Information and Medication Guide for ILUMYA are attached:
PDF: https://mma.prnewswire.com/media/656994/Sun_Pharma_ILUMYA_US_Prescribing_Information.pdf
PDF: https://mma.prnewswire.com/media/656995/Sun_Pharma_ILUMYA_US_Medication_Guide.pdf

IMPORTANT SAFETY INFORMATION (continued)

Cases of angioedema and urticaria occurred in ILUMYA treated subjects in clinical trial. If a serious hypersensitivity reaction occurs, discontinue ILUMYA immediately and initiate appropriate therapy.

ILUMYA may increase the risk of infection. Treatment with ILUMYA should not be initiated in patients with a clinically important active infection until the infection resolves or is adequately treated. Consider the risks and benefits of treatment prior to prescribing ILUMYA in patients with a chronic infection or a history of recurrent infection. Instruct patients receiving ILUMYA to seek medical help if signs or symptoms of clinically important chronic or acute infection occur. If a patient develops a clinically important or serious infection, or is not responding to standard therapy, closely monitor and discontinue ILUMYA until the infection resolves.

Evaluate patients for TB infection prior to initiating treatment with ILUMYA. Initiate treatment of latent TB prior to administering ILUMYA. Monitor patients for signs and symptoms of active TB during and after ILUMYA treatment. Do not administer ILUMYA to patients with active TB infection.

Prior to initiating ILUMYA, consider completion of all age-appropriate immunizations according to current immunization guidelines. Avoid use of live vaccines in patients treated with ILUMYA.

The most common (≥1%) adverse reactions associated with ILUMYA include upper respiratory infections, injection site reactions, and diarrhea. Adverse reactions that occurred at rates less than 1% but greater than 0.1% in the ILUMYA group and at a higher rate than in the placebo group included dizziness and pain in extremity.

About the Phase-3 reSURFACE Trials
The Phase-3 studies (reSURFACE 1 and reSURFACE 2) were randomized, placebo-controlled, multicenter, three-part studies designed to demonstrate efficacy of ILUMYA in moderate-to-severe plaque psoriasis compared to placebo and comparative drug and to assess safety and tolerability. Part one of the studies randomized patients into three or four treatment arms, including ILUMYA 100 mg, ILUMYA 200 mg, placebo and etanercept (reSURFACE 2 only). After Week 12, patients on placebo were then re-randomized into ILUMYA 100 mg and 200 mg treatment arms to proceed into part two of the studies. Finally, in part three of the reSURFACE 1 study, responders (PASI ≥75) and partial responders (PASI ≥50 and PASI <75) to ILUMYA were re-randomized after Week 28 to continue the same treatment, a different dose of ILUMYA or placebo. Partial and non-responders to etanercept were treated with ILUMYA 200 mg in part three of the reSURFACE 2 study. Patients with guttate, erythrodermic, or pustular psoriasis were excluded.

About Psoriasis
Psoriasis is a chronic immune disease that appears on the skin. It is a non-contagious disorder that speeds the growth cycle of skin cells¹ and results in thick scaly areas of skin². The most common form, affecting about 80 to 90 percent of people living with psoriasis, is called plaque psoriasis³. It appears as red, raised areas of skin covered with flaky white scales, which may be itchy and painful and can crack and bleed². Many people with plaque psoriasis continue to struggle with the ongoing, persistent nature of this chronic disease.

About Sun Dermatology
Sun Dermatology (the branded dermatology division of a wholly owned subsidiary of Sun Pharma) is committed to expanding its dermatology portfolio to bring healthcare providers and patients around the world more treatment options and ongoing support for conditions like moderate-to-severe plaque psoriasis. Sun Pharma, along with its subsidiaries, is ranked fourth in dermatology prescription volume within the U.S. per IMS and is fifth largest specialty generic pharmaceutical company globally. In addition to ILUMYA, Sun Dermatology is comprised of several branded products indicated for the treatment of acne and actinic keratosis with a focus on other dermatologic conditions.

About Sun Pharma, Merck & Co., Inc., Kenilworth, NJ, USA, Agreement
Sun Pharmaceutical Industries Ltd.’s wholly owned subsidiary licensed worldwide rights to ILUMYA from a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, in 2014. Funded by a Sun Pharma subsidiary, Merck & Co., Inc., Kenilworth, NJ, USA was responsible for the completion of Phase-3 trials and submission of a Biologics License Application to the United States Food and Drug Administration (FDA), as well as manufacturing finished goods to support Sun Pharma’s initial product launch. Sun Pharma will be responsible for all post-approval regulatory activities, including subsequent submissions, pharmacovigilance, post approval studies, manufacturing and commercialization of the approved product. Sun Pharma will also be responsible for all regulatory, pharmacovigilance, post approval studies, manufacturing and commercialization of approved products for all non-U.S. markets. Merck & Co., Inc., Kenilworth, NJ, USA is eligible to receive milestone payments and royalties on sales of ILUMYA.

About Sun Pharma, Almirall S.A, Europe, Agreement
Sun Pharma and its wholly owned subsidiary and Almirall (Spanish Stock Exchange ticker: ALM) closed on July 2016 a licensing agreement on the development and commercialization of tildrakizumab-asmn for psoriasis in Europe. Under the terms of the licensing agreement, Almirall is able to lead European studies, and participate in larger Global clinical studies for plaque psoriasis indication subject to the terms of the Sun Pharma – Merck & Co., Inc., Kenilworth, NJ, USA agreements, as well as certain cost sharing agreements. Sun Pharma will be eligible to receive development and regulatory milestone payments and, additionally, sales milestone payments and royalties on net sales. Sun Pharma will continue to lead development of tildrakizumab-asmn for other indications, where Almirall will have right of first negotiation for certain indications in Europe. The agreement between Sun Pharma and Almirall remains subject to the exclusive licensing agreement between Sun Pharma and Merck & Co., Inc., Kenilworth, NJ, USA.

About Sun Pharmaceutical Industries Ltd. (CIN – L24230GJ1993PLC019050)
Sun Pharma is the world’s fifth largest specialty generic pharmaceutical company and India’s top pharmaceutical company. A vertically integrated business, economies of scale and an extremely skilled team enable us to deliver quality products in a timely manner at affordable prices. It provides high-quality, affordable medicines trusted by customers and patients in over 150 countries across the world. Sun Pharma’s global presence is supported by 41 manufacturing facilities spread across 6 continents, R&D centres across the globe and a multi-cultural workforce comprising over 50 nationalities. In India, the company enjoys leadership across 11 different classes of doctors with 30 brands featuring amongst top 300 pharmaceutical brands in India. Its footprint across emerging markets covers over 100 markets and 6 markets in Western Europe. Its Global Consumer Healthcare business is ranked amongst Top 10 across 3 global markets. Its API business footprint is strengthened through 14 world class API manufacturing facilities across the globe. Sun Pharma fosters excellence through innovation supported by strong R&D capabilities comprising about 2,000 scientists and R&D investments of approximately 8% of annual revenues. For further information, please visit www.sunpharma.com & follow us on Twitter @SunPharma_Live.

References
1. National Psoriasis Foundation. Facts about psoriasis. www.psoriasis.org/sites/default/files/for-media/MediaKit.pdf. Accessed on February 22, 2018.
2. National Psoriasis Foundation. About Psoriasis. www.psoriasis.org/about-psoriasis. Accessed on February 22, 2018.
3. Menter A, Gottlieb A, Feldman SR, Van Voorhees AS et al. Guidelines of care for the management of psoriasis and psoriatic arthritis: Section 1. Overview of psoriasis and guidelines of care for the treatment of psoriasis with biologics. J Am Acad Dermatol 2008 May; 58(5):826-50.

////////////////tildrakizumab-asmn, FDA 2018, MERCK, Schering-Plough, MONOCLONAL ANTIBODY, SCH 900222, MK-3222, Psoriasis, plaque, BLA 761067, SCH-900222, SUNPG 1622, SUNPG 1622 I, SUNPG 1623 I, SUNPG 1623 II, SUNPG 1623 III, SUNPG 1623 IV, SUNPG1623,

	shivkr2 on SPSR Excellence Award 2025 – S…
	Bonkasaurus on Infigratinib phosphate
	PALOVAROTENE \| ORGAN… on Palovarotene
	Pfizer just purchase… on Temanogrel
	Pfizer To Cash In On… on Temanogrel

Monthly Archives: June 2018

SEARCH THIS BLOG

Blog Stats

Flag and hits

Follow Blog via Email

Pages

Archives

Categories

Recent Posts

ORGANIC SPECTROSCOPY

SUBSCRIBE

Follow Blog via Email

Verified Services

Pages

Archives

Categories

Recent Comments

SEARCH THIS BLOG

Release

Share this:

MAY BE DRUG COMD

Share this:

USP

DESCRIPTION

Chemistry

For Consumers

WHAT ARE THE POSSIBLE SIDE EFFECTS OF DOXEPIN (SINEQUAN) (SINEQUAN)?

Medical uses

Chemistry

History

Society and culture

Generic names

Brand names

Approvals

Research

Antihistamine

Headache

Share this:

PF-06409577

Biochem/physiol Actions

Discovery and Preclinical Characterization of 6-Chloro-5-[4-(1-hydroxycyclobutyl)phenyl]-1H-indole-3-carboxylic Acid (PF-06409577), a Direct Activator of Adenosine Monophosphate-activated Protein Kinase (AMPK), for the Potential Treatment of Diabetic Nephropathy

Share this:

Mechanism of Action

References

Share this:

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

Uses

Mechanism of action

Adverse effects

Research

History

Generic versions

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

Nitisinone

Substance Classes

Synthesis Path

Substances Referenced in Synthesis Path

Trade Names

Formulations

References

synergistic herbicidal combination:

preparation of benzoylcyclohexanedione herbicides:

certain 2-(2-nitrobenzoyl)-1,3-cyclohexanediones:

stable herbicidal compositions:

References

External links

Share this:

Share this:

Tildrakizumab-asmn

Highest Development Phases

Most Recent Events

See also

References

Mechanism of Action

Antibodies to watch in 2015

Share this:

Post navigation

SEARCH THIS BLOG

FLAGS AND HITS

Follow Blog via Email

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