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DR ANTHONY MELVIN CRASTO, WORLDDRUGTRACKER

From lab to patient: journey of a medicine. EMA

 EMA, EU, regulatory, Uncategorized  Comments Off on From lab to patient: journey of a medicine. EMA
Sep 092021
 

From lab to patient: journey of a medicine. EMA

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Follow the journey of a medicine for human use assessed by EMA in this interactive timeline. It explains all stages from initial research to patient access, including how EMA supports medicine development, assesses the benefits and risks and monitors the safety of medicine

  • From laboratory to patient: the journey of a centrally authorised medicine (PDF/1.75 MB)

    First published: 04/03/2019
    Last updated: 10/02/2020

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Tivozanib, ティボザニブ塩酸塩水和物

 EMA, orphan status  Comments Off on Tivozanib, ティボザニブ塩酸塩水和物
Mar 142018
 

Tivozanib.svg

ChemSpider 2D Image | Tivozanib | C22H19ClN4O5

Tivozanib

  • Molecular FormulaC22H19ClN4O5
  • Average mass454.863 Da
AV951
AV951 (KRN951, Tivozanib)
AV-951; AV951;AV 951
AV-951|KRN-951|VEGFR tyrosine kinase inhibitor IV
KRN 951
1-{2-Chloro-4-[(6,7-diméthoxy-4-quinoléinyl)oxy]phényl}-3-(5-méthyl-1,2-oxazol-3-yl)urée
1-{2-Chloro-4-[(6,7-dimethoxy-4-quinolinyl)oxy]phenyl}-3-(5-methyl-1,2-oxazol-3-yl)urea
475108-18-0 [RN] FREE FORM
AV 951
N-(2-chloro-4-((6,7-dimethoxy-4-quinolyl)oxy)phenyl)-N’-(5-methyl-3-isoxazolyl)urea
  • N-[2-Chloro-4-[(6,7-dimethoxy-4-quinolinyl)oxy]phenyl]-N’-(5-methyl-3-isoxazolyl)urea
  • AV 951
  • KRN 951
  • Kil 8951
  • N-[2-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl]-N’-(5-methyl-3-isoxazolyl)urea
  • CAS HCL HYDRATE 682745-41-1
  • 682745-43-3  HCL

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

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

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

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

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

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

Image result for tivozanib

Image result for TIVOZANIB EMAImage result for TIVOZANIB EMA

  • CAS HCL HYDRATE 682745-41-1

ティボザニブ塩酸塩水和物;

Pharmacotherapeutic group

Antineoplastic agents

Therapeutic indication

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

Treatment of advanced renal cell carcinoma

Fotivda : EPAR -Product Information

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

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

str6

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

Product details

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

Publication details

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

Contact address:

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

Mechanism

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

Results

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

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

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

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

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

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

SYNTHESIS

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

STR1

 

 

CLIP

Image result for tivozanib synthesis

Paper

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

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

DOI: 10.3987/COM-16-13555
■ A New and Practical Synthesis of Tivozanib

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

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

Abstract

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

 

Image result for tivozanib

PAPER

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

Bioorganic & Medicinal Chemistry Letters

Volume 25, Issue 11, 1 June 2015, Pages 2425-2428
STR1
HC-1144 (yield: 69.0% ) as a white solid. 1H NMR (400 MHz, CD3OD): δ 8.33 (d, J=5.2 Hz, 1H,), 8.17(d, J=9.2 Hz, 1H), 7.47 (s, 1H), 7.29 (d, J=2.4 Hz, 1H), 7.23 (s, 1H), 7.10(m, 1H), 6.47(d, J=5.2 Hz, 1H), 6.28 (brs, 1H), 2.30 (s, 3H). MS (ESI, m/z): 461 [M+H]+.

PAPER

J MED CHEM 2005 48 1359

STR1 STR2 str3

PATENT

WO 2002088110

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

Scheme 1 and Scheme 2

Skiing

PATENT

WO 2004035572

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

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

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

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

(2) Reduction process:

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

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

(3) Cyclization step:

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

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

(4) Clovalization process

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

(5) Phenol site introduction step:

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

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

(6) Ureaization process:

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

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

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

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

 

PATENT

WO 2011060162

WO 2017037220

CN 106967058

CN 104072492

CN 102532116

CN 102408418

PAPER

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

STR1

 

Synthesis of the compounds

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

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

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

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

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

PATENT

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

Example

Figure CN102532116BD00063

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

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

[0037] CN 102532116 B specification 4/6

Figure CN102532116BD00071

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

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

Figure CN102532116BD00072

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

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

Figure CN102532116BD00073

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

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

[0047] CN 102532116 B specification 5/6

Figure CN102532116BD00081

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

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

Figure CN102532116BD00082

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

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

Figure CN102532116BD00083

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

Claims (3)
translated from Chinese
1. An antitumor drugs Si tivozanib to synthesis, the method as follows: The lOOmL of N, N- dimethylformamide, 5 Og of 3-amino-5-methylisoxazole, 7 . 98g phenyl chloroformate and 17g 4- [(4- amino-3-chlorophenol) oxy] -6, 7-dimethoxy-quinoline was added to 250mL three-necked flask, the reaction was heated at reflux for 5h, cooled to rt, lOOmL ethanol was added, stirred, filtered off with suction, and dried to give 20. Og tivozanib, yield 86.1%, the reaction is:
Figure CN102532116BC00021
Wherein the 4- [(4-amino-3-chlorophenol) oxy] -6, 7-dimethoxy-quinoline is obtained by the following synthesis method: in 250mL three-neck flask, was added 60mL of N, N- dimethylformamide, 8. 9g 4- amino-3-chloro-phenol hydrochloride, 14. 5g of potassium carbonate and 8. 3g 4- chloro-6, 7-dimethoxy quinoline, was heated at reflux for 2h cooled to room temperature, 100mL of absolute ethanol was added, stirred, filtered off with suction, and dried to obtain 8. 5g 4 – [(4_-amino-3-chlorophenol) oxy] -6, 7-dimethoxy quinoline, close was 69.9%, the reaction is:
Figure CN102532116BC00022
Said 4-chloro-6, 7-dimethoxy-quinoline is obtained by the following synthesis method: A mixture of 100mL of toluene, 10 6g 6, 7- dimethoxy-4-quinolone and 15g trichloride phosphorus is added to 250mL three-necked flask and heated at reflux for 2h, cooled suction filtration, and dried to give an off-white powder 9. 3g 4- chloro-6, 7-dimethoxy quinoline, a yield of 87.6%, the reaction formula:
Figure CN102532116BC00023
6, 7-dimethoxy-4-quinolone was synthesized by the following method: 33. 7g 2- amino-4, 5-dimethoxy acetophenone, 150 mL of methanol, and 95. 5g anhydrous potassium carbonate was added to the 500mL three-necked flask, stirred at room temperature LH, 75. 8g of ethyl dropwise, the reaction incubated 2h, filtered off with suction, and dried to give 35. 2g of white powder 6, 7-dimethoxy-4 – quinolinone, a yield of 81.5%, the reaction is:
Figure CN102532116BC00031
The 2-amino-4,5-dimethoxy acetophenone is synthesized by the following method: In the 250mL three-neck flask, was added 36mL of water and 7g reduced iron powder was heated and refluxed for LH, was slowly added 5. 6g 3, 4-dimethoxy-6-nitroacetophenone, stirred for 3h, filtered off with suction, the filtrate was cooled to give a yellow powder 7g of 2-amino-4,5-dimethoxy acetophenone, yield 96 %, the reaction is:
Figure CN102532116BC00032
2. The synthesis method according to claim 1, wherein: said 3,4-dimethoxy-6-nitroacetophenone is 3, 4-dimethoxy acetophenone nitration obtained by a reaction of reaction formula:
Figure CN102532116BC00033
3. The method of synthesis according to claim 2, wherein: said 3,4-dimethoxy acetophenone in the catalyst, to give the phthalimido ether is reacted with acetyl chloride by Friedel The reaction is:

References

  1.  Tivozanib is currently being evaluated in the pivotal Phase 3 TIVO-3 trial, a randomized, controlled, multi-center, open-label study to compare tivozanib to sorafenib in subjects with refractory advanced RCC. FDA approval is expected in 2018. A Study of Tivozanib (AV-951), an Oral VEGF Receptor Tyrosine Kinase Inhibitor, in the Treatment of Renal Cell Carcinoma, clinicaltrials.gov
  2.  http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/004131/human_med_002146.jsp&mid=WC0b01ac058001d124.
  3.  Campas, C., Bolos, J., Castaner, R (2009). “Tivozanib”Drugs Fut34 (10): 793.
  4.  Aveo Kidney Cancer Drug Shows Success; Shares Up, By John Kell, Dow Jones Newswires[dead link]
  5.  “Phase III Results Lead Aveo and Astellas to Plan Regulatory Submissions for Tivozanib”. 3 Jan 2012.
  6. “FDA Rejects Renal Cancer Drug Tivozanib”. MedPage Today. June 30, 2013.
  7.  http://meetinglibrary.asco.org/content/165081-176
  8.  http://investor.aveooncology.com/phoenix.zhtml?c=219651&p=irol-newsArticle&ID=2172669
  9.  http://www.eusapharma.com/files/EUSA-Pharma-file-tivozanib-in-EU-March-2016.pdf
  10.  “AVEO Pharma surges 48% on recommendation for European approval of its cancer drug”Market Watch. June 28, 2017. Retrieved June 28, 2017.
  11.  “AVEO Oncology Announces FOTIVDA® (tivozanib) Approved in the European Union for the Treatment of Advanced Renal Cell Carcinoma” (PDF). AVEO Oncology. August 28, 2017. Retrieved February 9, 2018.
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2011-12-01
Patent ID

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ivozanib
Tivozanib.svg
Names
IUPAC name

1-{2-Chloro-4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-3-(5-methylisoxazol-3-yl)urea
Other names

AV-951
Identifiers
3D model (JSmol)
ChEMBL
ChemSpider
KEGG
PubChem CID
UNII
Properties
C22H19ClN4O5
Molar mass 454.87 g·mol−1
Pharmacology
L01XE34 (WHO)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

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

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

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PADELIPORFIN

 EMA, Uncategorized  Comments Off on PADELIPORFIN
Mar 142018
 

 

Padeliporfin.png

2D chemical structure of 759457-82-4

PADELIPORFIN

759457-82-4; 457P824,

RN: 759457-82-4
UNII: EEO29FZT86

3-[(2S,3S,12R,13R)-8-acetyl-13-ethyl-20-(2-methoxy-2-oxoethyl)-3,7,12,17-tetramethyl-18-(2-sulfoethylcarbamoyl)-2,3,12,13-tetrahydroporphyrin-22,24-diid-2-yl]propanoic acid;palladium(2+)

 (SP-4-2)-[(7S,8S,17R,18R)-13-acetyl-18-ethyl-5-(2-methoxy-2-oxoethyl)-2,8,12,17-tetramethyl-3-[[(2-sulfoethyl)amino]carbonyl]-21H,23H-porphine-7-propanoato (4-)-kN21,kN22,kN23,kN24] palladate(2-)

Palladate(2-​)​, [(7S,​8S,​17R,​18R)​-​13-​acetyl-​18-​ethyl-​7,​8-​dihydro-​5-​(2-​methoxy-​2-​oxoethyl)​-​2,​8,​12,​17-​tetramethyl-​3-​[[(2-​sulfoethyl)​amino]​carbonyl]​-​21H,​23H-​porphine-​7-​propanoato(4-​)​-​κN21,​κN22,​κN23,​κN24]​-​, (SP-​4-​2)​-
Coordination Compound

Other Names

  • (SP-4-2)-[(7S,8S,17R,18R)-13-Acetyl-18-ethyl-7,8-dihydro-5-(2-methoxy-2-oxoethyl)-2,8,12,17-tetramethyl-3-[[(2-sulfoethyl)amino]carbonyl]-21H,23H-porphine-7-propanoato(4-)-κN21,κN22,κN23,κN24]palladate(2-)
Molecular Formula: C37H43N5O9PdS
Molecular Weight: 840.257 g/mol

img

Chemical Formula: C37H41K2N5O9PdS
Molecular Weight: 916.43

cas 698393-30-5

WST11; WST-11; WST 11; Stakel; padeliporfin; palladiumbacteriopheophorbide monolysine taurine.

Palladate(2-​)​, [(7S,​8S,​17R,​18R)​-​13-​acetyl-​18-​ethyl-​7,​8-​dihydro-​5-​(2-​methoxy-​2-​oxoethyl)​-​2,​8,​12,​17-​tetramethyl-​3-​[[(2-​sulfoethyl)​amino]​carbonyl]​-​21H,​23H-​porphine-​7-​propanoato(4-​)​-​κN21,​κN22,​κN23,​κN24]​-​, potassium (1:2)​, (SP-​4-​2)​-

Tookad : EPAR -Product Information

Tookad : EPAR – Summary for the public (English only) 29/11/2017

Product details

Pharmacotherapeutic group

Antineoplastic agents

Therapeutic indication

Tookad is indicated as monotherapy for adult patients with previously untreated, unilateral, low risk, adenocarcinoma of the prostate with a life expectancy ≥ 10 years and:

  • Clinical stage T1c or T2a;
  • Gleason Score ≤ 6, based on high-resolution biopsy strategies;
  • PSA ≤ 10 ng/mL;
  • 3 positive cancer cores with a maximum cancer core length of 5 mm in any one core or 1-2 positive cancer cores with ≥ 50 % cancer involvement in any one core or a PSA density ≥ 0.15 ng/mL/cm³.
Name Tookad
Agency product number EMEA/H/C/004182
Active substance padeliporfin di-potassium
International non-proprietary name(INN) or common name padeliporfin
Therapeutic area Prostatic Neoplasms
Anatomical therapeutic chemical (ATC) code L01XD07
Additional monitoring This medicine is under additional monitoring. This means that it is being monitored even more intensively than other medicines. For more information, see medicines under additional monitoring.
Marketing-authorisation holder STEBA Biotech S.A
Revision 0
Date of issue of marketing authorisation valid throughout the European Union 10/11/2017

Contact address:

STEBA Biotech S.A
7 place du theatre
L-2613 Luxembourg
Luxembourg

Padeliporfin is a vascular-acting photosensitizer consisting of a water-soluble, palladium-substituted bacteriochlorophyll derivative with potential antineoplastic activity. Upon administration, paldeliporfin is activated locally when the tumor bed is exposed to low-power laser light; reactive oxygen species (ROS) are formed upon activation and ROS-mediated necrosis may occur at the site of interaction between the photosensitizer, light and oxygen. Vascular-targeted photodynamic therapy (VTP) with padeliporfin may allow tumor-site specific cytotoxicity while sparing adjacent normal tissues.

WST-11 (Stakel) is a water-soluble bacteriochlorophyll (chemical structure shown below) derivative coordinated with palldium, which has maximum absorption wavelength in the near infrared (753 nm) and rapid clearance from the body ( t 1/2 = 0.37 hour for a 10-mg/kg drug dose in the rat and t 1/2 = 0.51 hour, 1 hour, and 2.65 hours for 1.25-, 2.5-, and 5-mg/kg drug doses, respectively. It binds to serum albumin and has potent antivascular activity through the generation of hydroxyl radicals when stimulated by the proper light wavelength.

Image result for PADELIPORFIN

Photodynamic therapy (PDT) is a non-surgical treatment of tumors in which non-toxic drugs and non-hazardous photosensitizing irradiation are combined to generate cytotoxic reactive oxygen species in situ. This technique is more selective than the commonly used tumor chemotherapy and radiotherapy. To date, porphyrins have been employed as the primary photosensitizing agents in clinics. However, current sensitizers suffer from several deficiencies that limit their application, including mainly: (1) relatively weak absorption in the visible spectral range which limits the treatment to shallow tumors; (2) accumulation and long retention of the sensitizer in the patient skin, leading to prolonged (days to months) skin phototoxicity; and (3) small or even no differentiation between the PDT effect on illuminated tumor and non-tumor tissues. The drawbacks of current drugs inspired an extensive search for long wavelength absorbing second-generation sensitizers that exhibit better differentiation between their retention in tumor cells and skin or other normal tissues.

In order to optimize the performance of the porphyrin drugs in therapeutics and diagnostics, several porphyrin derivatives have been proposed in which, for example, there is a central metal atom (other than Mg) complexed to the four pyrrole rings, and/or the peripheral substituents of the pyrrole rings are modified and/or the macrocycle is dihydrogenated to chlorophyll derivatives (chlorins) or tetrahydrogenated to bacteriochlorophyll derivatives (bacteriochlorins).

Due to their intense absorption in favorable spectral regions (650-850 nm) and their ready degradation after treatment, chlorophyll and bacteriochlorophyll derivatives have been identified as excellent sensitizers for PDT of tumors and to have superior properties in comparison to porphyrins, but they are less readily available and more difficult to handle.

Bacteriochlorophylls are of potential advantage compared to the chlorophylls because they show intense near-infrared bands, i.e. at considerably longer wavelengths than chlorophyll derivatives.

The spectra, photophysics, and photochemistry of native bacteriochlorophylls (Bchls) have made them optimal light-harvesting molecules with clear advantages over other sensitizers presently used in PDT. In particular, these molecules have a very high extinction coefficient at long wavelengths (λmax=760-780 nm, ε=(4-10)xl04 M-1cm-1), where light penetrates deeply into tissues. They also generate reactive oxygen species (ROS) at a high quantum yield (depending on the central metal).

Under normal delivery conditions, i.e. in the presence of oxygen at room temperature and under normal light conditions, the BChl moieties are labile and have somewhat lower quantum yields for triplet state formation, when compared with, e.g., hematoporphyrin derivative (HPD). However, their possible initiation of biological redox reactions, favorable spectral characteristics and their ready degradation in vivo result in the potential superiority of bacteriochlorophylls over other compounds, e.g. porphyrins and chlorophylls, for PDT therapy and diagnostics and for killing of cells, viruses and bacteria in samples and in living tissue. Chemical modification of bacteriochlorophylls is expected to further improve their properties, but this has been very limited due to lack of suitable methods for the preparation of such modified bacteriochlorophylls .

The biological uptake and PDT efficacy of metal-free derivatives of Bchl have been studied with the objective to manipulate the affinity of the sensitizers to the tumor cellular compartment. Cardinal to this approach is the use of highly lipophilic drugs that may increase the accumulation of the drug in the tumor cells, but also renders its delivery difficult. In addition, the reported biodistribution shows significant phototoxic drug levels in non-tumor tissues over prolonged periods (at least days) after administering the drug.

In applicant’s previous Israel Patent No. 102645 and corresponding EP 0584552, US 5,726,169, US 5,726,169, US 5,955,585 and US 6,147,195, a different approach was taken by the inventors. Highly efficient anti- vascular sensitizers that do not extravasate from the circulation after administration and have short lifetime in the blood were studied. It was expected that the inherent difference between vessels of normal and abnormal tissues such as tumors or other tissues that rely on neovessels, would enable relatively selective destruction of the abnormal tissue. Hence, it was aimed to synthesize Bchl derivatives that are more polar and, hence, have better chance to stay in the vascular compartment, where they convey the primary photodynamic effect. To this end, the geranylgeranyl residue at the C-17 position of Bchl a (Compound 1, depicted in Scheme 1 herein) has been replaced by various residues such as amino acids, peptides, or proteins, which enhance the sensitizer hydrophilicity. One particular derivative, Bchl-Ser (Scheme 1, Compound 1, wherein R is seryl), was found to be water-soluble and highly phototoxic in cell cultures. Following infraperitoneal injection, the Bchl-Ser cleared from the mouse blood and tissues bi-exponentially in a relatively short time (t1/2~2 and 16 h, respectively). Clearance from the circulation was even faster following intravenous injection. Under the selected treatment protocol (light application within minutes after drug injection), phototoxicity was predominantly conferred to the tumor vasculature (Rosenbach-

Belkin et al., 1996; Zilberstein et al., 2001 and 1997). However, unfortunately, like native Bchl, the Bchl-Ser derivative undergoes rapid photo-oxidation, forming the corresponding 2-desvinyl-2-acetyl-chlorophyllide ester and other products.

To increase the stability of the Bchl derivatives, the central Mg atom was replaced by Pd in the later applicant’s PCT Publication WO 00/33833 and US 6,569,846. This heavy atom was previously shown to markedly increase the oxidation potential of the Bchl macrocycle and, at the same time, to greatly enhance the intersystem-crossing (ISC) rate of the molecule to its triplet state. The metal replacement was performed by direct incorporation of Pd2+ ion into a Bpheid molecule, as described in WO 00/33833. Based on the pigment biodistribution and pharmacokinetics, it was assumed that the derivative Pd-Bpheid remained in the circulation for a very short time with practically no extravasation to other tissues, and is therefore a good candidate for vascular-targeting PDT that avoids skin phototoxicity. The treatment effect on the blood vessels was demonstrated by intravital microscopy of treated blood vessels and staining with Evans-Blue. Using a treatment protocol with a minimal drug-to-light interval, Pd-Bpheid (also designated Tookad) was found to be effective in the eradication of different tumors in mice, rats and other animal models and is presently entering Phase I/II clinical trials in patients with prostate cancer that failed radiation therapy (Chen et al, 2002; Schreiber et al., 2002; Koudinova et al., 2003).

Because of its low solubility in aqueous solutions, the clinical use of Pd-Bpheid requires the use of solubilizing agents such as Cremophor that may cause side effects at high doses. It would be highly desirable to render the Pd-Bpheid water-soluble while retaining its physico-chemical properties. Alternatively, it would be desirable to prepare Bchl derivatives that are cytophototoxic and, at the same time, more water-soluble than Pd-Bpheid itself. Such water solubility is expected to further enhance the drug retention in the circulation and, thereby, the aforementioned selectivity. In addition, having no need to use carriers such as detergents or lyposomes, may prevent side effects.

 

SYNTHESIS

START FROM CAS 17499-98-8, Phorbine, magnesium deriv., Bacteriochlorophyll aP

STR1

PADELIPORFIN

Paper

Novel water-soluble bacteriochlorophyll derivatives for vascular-targeted photodynamic therapy: Synthesis, solubility, phototoxicity and the effect of serum proteins
Photochemistry and Photobiology (2005), 81, (July/Aug.), 983-993

PAPER

Journal of Medicinal Chemistry (2014), 57(1), 223-237

Abstract Image

With the knowledge that the dominant photodynamic therapy (PDT) mechanism of 1a (WST09) switched from type 2 to type 1 for 1b (WST11) upon taurine-driven E-ring opening, we hypothesized that taurine-driven E-ring opening of bacteriochlorophyll derivatives and net-charge variations would modulate reactive oxygen species (ROS) photogeneration. Eight bacteriochlorophyll a derivatives were synthesized with varying charges that either contained the E ring (2a5a) or were synthesized by taurine-driven E-ring opening (2b5b). Time-dependent density functional theory (TDDFT) modeling showed that all derivatives would be type 2 PDT-active, and ROS-activated fluorescent probes were used to investigate the photogeneration of a combination of type 1 and type 2 PDT ROS in organic- and aqueous-based solutions. These investigations validated our predictive modeling calculations and showed that taurine-driven E-ring opening and increasing negative charge generally enhanced ROS photogeneration in aqueous solutions. We propose that these structure–activity relationships may provide simple strategies for designing bacteriochlorins that efficiently generate ROS upon photoirradiation.

Modulation of Reactive Oxygen Species Photogeneration of Bacteriopheophorbide a Derivatives by Exocyclic E-Ring Opening and Charge Modifications

 Department of Pharmaceutical Sciences, Leslie L. Dan Faculty of Pharmacy, University of Toronto, 144 College Street, Toronto, Ontario M5S 3M2, Canada
 Ontario Cancer Institute and Techna Institute, UHN, 101 College Street, Toronto, Ontario M5G 1L7, Canada
§ Department of Chemical Engineering and Applied Chemistry, University of Toronto, 200 College Street, Toronto, Ontario M5S 3E5, Canada
J. Med. Chem.201457 (1), pp 223–237
DOI: 10.1021/jm401538h
*Tel: 416-581-7666. Fax 416-581-7667. E-mail: gzheng@uhnresearch.ca.
Palladium 31-Oxo-15-methoxycarbonylmethyl-rhodobacteriochlorin 13′-(2-Sulfethyl)amide (1b)
……………… The dried crude product was dissolved in 200 μL of DMSO and purified by reverse-phase HPLC. The product was quantified spectrophotometrically, the identity was characterized using ESI+MS and UV–vis spectroscopy, and the purity was found to be >95% using HPLC–MS. This yielded 0.21 mg (250 nmol) of 1b(0.7% yield). ESI+MS: [M]+ = 840 m/z. UV–vis (MeOH, λmax): 748, 517, 385, 332 nm.
PATENT

 

CHEMICAL EXAMPLES

Example 1. Palladium 31-oxo-15-methoxycarbonylmethyl-Rhodobacteriochlorin 131-(2-sulfoethyl)amide dipotassium salt ( Compound 4)

Nine hundred and thirty five (935) mg of Pd-Bpheid (3) were dissolved in a 1 L round bottom flask with 120 ml of DMSO while stirring under Argon (bubbled in the solution). Taurine (1288 mg) was dissolved in 40 ml of 1M K2HPO4 buffer, and the pH of the solution was adjusted to 8.2 (with HCl ). This aqueous solution was added into the DMSO solution while stirring, and the Argon was bubbled in the solution for another 20 minutes. Then the reaction mixture was evaporated at 30°C for 3.5 hours under ~2 mbar and then for another 2 hours at 37°C to a complete dryness. The dry solids were dissolved in 300 ml of MeOH and the colored solution was filtered through cotton wool to get rid of buffer salts and taurine excess.

The progress of the reaction was determined by TLC (Rf of unreacted Pd- Bpheid is 0.8-0.85 and of the reaction (aminolysis) product is 0.08-0.1) and by following the optical absorption spectrum of the reaction mixture after liophylization and resolubihzation in MeOH. The absorption spectrum was characterized by a Qytransition shift from 756 nm (for Pd-Bpheid) to 747 nm (for the product 4) and by Qx shift from 534 nm of Pd-Bpheid to 519 nm (of the product 4). The MeOH was evaporated and the product 4 was purified by HPLC with ODS-A 250X20 S10P μm column (YMC, Japan). Solvent A: 95% 0.005 M phosphate buffer, pH 8.0 and 5% MeOH. Solvent B: 100% MeOH. The dry solid was dissolved in 42 ml of distilled water and injected in portions of 1.5 ml each .

The elution profile is described in Table 1. The product 4_(Scheme 1, see below) was eluted and collected at ~ 9-11 minutes. The main impurities, collected after at 4-7 min (ca 5-10%), corresponded to byproduct(s) with the proposed structure 7. Peaks at 22-25 min (ca 2-5%) possibly corresponded to the iso-form of the main product 4 and untreated Pd-Bpheid residues.

The solvent (aqueous methanol) was evaporated under reduced pressure. Then, the purified product 4 ]was re-dissolved in ~150 ml MeOH and filtered through cotton wool. The solvent was evaporated again and the solid pigment 4 was stored under Ar in the dark at -20°C. The reaction yield: ~90% (by weight, relative to 3).

The structure of product 4 was confirmed by electrospray mass spectroscopy. (ESI-MS, negative mode, Fig.2), (peaks at 875 (M–K-H), 859 (M–2K-H+Na), 837 (M–2K), 805 (M2K-H-OMe), 719) and 1H-NMR spectrum (Fig. 4 in MeOH-d4). Table 4 provides the shifts (in ppm units) of the major NMR peaks.

Optical absorption (UN-VIS) spectrum (MeOH): λ, 747 (1.00), 516 (0.13), 384 (0.41), 330 (0.50); ε747 (MeOH) is 1.2 x 105 mol-1 cm _1.

ΝMR (MeOH-d4): 9.38 (5-H, s), 8.78 (10-H, s), 8.59 (20-H, s), 5.31 and 4.95 (151-CH2, dd), 4.2-4.4 (7,8,17,18-H, m), 3.88 (153-Me, s), 3.52 (21-Me, s), 3.19 (121 -Me, s), 3.09 (32-Me, s), 1.92-2.41, 1.60-1.75 (171, 172-CH2, m), 2.19 (81-CH2, m), 1.93 (71-Me, d), 1.61 (181-Me, d), 1.09 (82-Me, t), 3.62, 3.05 (CH2‘s of taurine).

Octanol/water partition ratio is 40:60.

Example 2. Preparation of 31-oxo-15-methoxycarbonylmethyl- Rhodobacteriochlorin 131-(2-sulfoethyl)amide dipotassium salt (Compound 5) One hundred and sixty (160) mg of taurine were dissolved in 5 ml of 1M

K2HPO4 buffer, and the pH of the solution was adjusted to 8.2. This solution was added to 120 mg of compound 2 dissolved in 15 ml of DMSO, and the reaction and following purification were analogous to those described in previous Example.

Absorption spectrum (MeOH): λ, 750 (1.00), 519 (0.30), 354 (1.18) nm.

ESI-MS (-): 734 (M–2K).

ΝMR (MeOH-d4): 9.31 (5-H, s), 8.88 (10-H, s), 8.69 (20-H, s), 5.45 and 5.25 (151-CH2, dd), 4.35 (7,18-H, m), 4.06 (8,17-H, m), 4.20 and 3.61 (2-CH2, m of taurine), 3.83 (153-Me, s), 3.63 (21-Me, s), 3.52 (3-CH2, m oftaurine), 3.33 (121-Me, s), 3.23 (32-Me, s), 2.47 and 2.16 (171-CH2, m), 2.32 and 2.16 (81-CH2, m), 2.12 and 1.65 (172-CH2, m), 1.91 (71-Me, d), 1.66 (181– Me, d), 1.07 (82-Me, t).

Octanol/water partition ratio is 60:40.

Example 3. Preparation of copper(II) 31-oxo-15-methoxycarbonylmethyl- Rhodobacteriochlorin 131-(2-sulfoethyl)amide dipotassium salt (Compound 10)

Fifty (50) mg of compound 5 of Example 2 and 35 mg of copper (II) acetate were dissolved in 40 ml of methanol, and argon was bubbled into solution for 10 minutes. Then 500 mg of palmitoyl ascorbate was added, and the solution was stirred for 30 min. The absorption spectrum was characterized by a Qy transition shift from 750 nm (for 5) to 768 nm (for the product 10) and by Qx shift from 519 nm of 5 to 537 nm (of the product 10). Then the reaction mixture was evaporated, re-dissolved in acetone and filtered through cotton wool to get rid of acetate salt excess. The acetone was evaporated and the product was additionally purified by HPLC at the conditions mentioned above with the elution profile, described in Table 2.

The solvent (aqueous methanol) was evaporated under reduced pressure. Then, the purified pigment 10 was re-dissolved in methanol and filtered through cotton wool. The solvent was evaporated again and the solid pigment 10 was stored under Ar in the dark at -20°C. Reaction yield: -90%.

Absorption spectrum (MeOH): λ, 768 (1.00), 537 (0.22), 387 (0.71) and 342 (0.79) nm.

ESI-MS (-): 795 (M–2K).

Octanol/water partition ratio is 40:60.

Example 4. Preparation of zinc 31-oxo-15-methoxycarbonylmethyl-Rhodobacteriochlorin 131-(2-sulfoethyl)amide dipotassium salt (Compound 11)

Zn insertion into compound 5 was carried out with Zn acetate in acetic acid as previously described (US Patent No. 5,726,169). Final purification was carried out by HPLC in the same conditions as for compound 5 in Example 2 above.

Absorption spectrum (MeOH): λ, 762 (1.00), 558 (0.26), 390 (0.62) and 355 (0.84) nm.

Octanol/water partition ratio is 50:50.

Example 5. Preparation of manganese(III) 31-oxo-15-methoxycarbonylmethyl-Rhodobacteriochlorin 131-(2-sulfoethyl)amide dipotassium salt (Compound 12)

Mn insertion into compound 5 was carried out with Zn acetate in acetic acid as previously described (WO 97/19081; US 6,333,319) with some modifications. Thus, fifty (50) mg of compound 5 in 10 ml of DMF were stirred with 220 mg of cadmium acetate and heated under argon atmosphere at 110°C about 15 min (Cd-complex formation is monitored by shifting Qx transition absorption band from 519 to 585 nm in acetone). Then the reaction mixture was cooled and evaporated. The dry residue was re-dissolved in 15 ml of acetone and stirred with manganese (II) chloride to form the Mn(III)-product 12. The product formation is monitored by shifting Qx transition band from 585 to 600 nm and Qy transition band from 768 to 828 nm in acetone. The acetone was evaporated and the product 12 was additionally purified by HPLC in the conditions mentioned in Example 2 above with the elution profile described in Table 3 below where the] solvent system consists of: A – 5% aqueous methanol, B -methanol.

The solvent (aqueous methanol) was evaporated under reduced pressure and the solid pigment 12 was stored under Ar in the dark at -20°C.

Absorption spectrum (MeOH): λ, 828 (1.00), 588 (0.32) and 372 (0.80) nm. Octanol/water partition ratio is 5:95.

Example 6. Preparation of palladium bacteriopheophorbide a 17 -(3-sulfo-1-oxy- succinimide)ester sodium salt (Compound 6)

Fifty (50) mg of Pd-Bpheid (compound 2), 80 mg of N-hydroxy- sulfosuccinimide (sulfoNHS) and 65 mg of 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide (EDC) were mixed in 7 ml of dry DMSO for overnight at room temperature. Then the solvent was evacuated under reduced pressure. The dry residue was re-dissolved in chloroform (ca. 50 ml), filtered from insoluble material, and evaporated. The conversion was ab. 95%) (TLC). The product 6 was used later on without further chromatographic purification. ESI-MS (-): 890 (M–Na).

NMR (CDCl3): 9.19 (5-H, s), 8.49 (10-H, s), 8.46 (20-H, s), 5.82 (132-H, s), 4.04- 4.38 (7,8,17,18-H, m), 3.85 (134-Me, s), 3.47 (21-Me, s), 3.37 (^-Me, s), 3.09 (32– Me, s), 1.77 (71-Me, d), 1.70 (lδ’-Me, d), 1.10 (82-Me, t), 4.05 (CH2 of sNHS), 3.45 (CH ofs NHS).

Example 7. Preparation of palladium bacteriopheophorbide a 173-(3-sulfopropyl) amide potassium salt (Compound 7)

Ten (10) mg of compound 6 in 1 ml of DMSO was mixed with 20 mg of homotaurine (3-amino-1-propane-sulfonic acid) in 1 ml of 0.1 M K-phosphate buffer, pH 8.0 for overnight. Then the reaction mixture was partitioned in chloroform/water. The organic layer was dried over anhydrous sodium sulfate and evaporated. The dry residue was re-dissolved in chloroform-methanol (19:1) and applied to a chromatographic column with silica. The product 7 was obtained with chloroform-methanol (4:1) elution. The yield was about 80-90%.

ESI-MS (-): 834 (M-K) m/z.

NMR (MeOH-d4): 9.16 (5-H, s), 8.71 (10-H, s), 8.60 (20-H, s), 6.05 (132-H, s), 4.51, 4.39, 4.11, 3.98 (7,8,17,18-H, all m), 3.92 (134-Me, s), 3.48 (21-Me, s), 3.36 (121-Me, s), 3.09 (32-Me, s), 2.02-2.42 (171 arid 172-CH2, m), 2.15 ( 81-CH2, q), 1.81 (71-Me, d), 1.72 (181-Me, d), 1.05 (82-Me, t), 3.04, 2.68, and 2.32 (CH2‘s of homotaurine, m).

Example 8. Preparation of palladium 31-oxo-15-methoxycarbonylmethyl-Rhodo-bacteriochlorin 13 ,17 -di(3-sulfopropyl)amide dipotassium salt (Compound 8)

Ten (10) mg of compound 6 or 7 were dissolved in 3 ml of DMSO, mixed with 100 mg of homotaurine in 1 ml of 0.5 M K-phosphate buffer, pH 8.2, and incubated overnight at room temperature. The solvent was then evacuated under reduced pressure as described above, and the product 8 was purified on HPLC. Yield: 83%.

Absorption spectrum (MeOH): 747 (1.00), 516 (0.13), 384 (0.41), 330 (0.50), ε747 =1.3×105 modern-1.

ESI-MS(-):1011 (M–K), 994 (M–2K+Na),972 (M–2K), 775 (M–2K-CO2Me-homotaurineNHCH2CH2CH2SO3), 486 ([M-2K]/2)

NMR (MeOH-d4): 9.35 (5-H, s), 8.75 (10-H, s), 8.60 (20-H, s), 5.28 and 4.98 (15-1-CH2, dd), 4.38, 4.32, 4.22, 4.15 (7,8,17,18-H, all m), 3.85 (15~3-Me, s), 3.51 (21-Me, s), 3.18 (121-Me, s), 3.10 (32-Me, s 2.12-2.41 (171-CH2, m), 2.15-2.34 (81-CR2, m), 1.76-2.02 (172-CH2, m), 1.89 (71-Me, d), 1.61 (lδ^Me, d), 1.07 (82-Me, t). 3.82, 3.70,

3.20, 3.10, 2.78, 2.32, 1.90 (CH2‘s of homotaurine at C-131 and C-173)

Example 9. Palladium 31-(3-sulfopropylimino)-15-methoxycarbonylmethyl-Rhodo-bacteriochlorin 131,173-di(3-sulfopropyl)amide tripotassium salt (Compound 9)

Compound 9 was obtained from HPLC as a minor product during synthesis of 8.

Absorption spectrum (MeOH): 729 (1.00), 502 (0.10), 380 (0.69), 328 (0.57).

ESI-MS (30.4.2000): 1171 (M-K+H), 1153 (M–2K-H+Na), 1131 (M-2K), 566 ([M-K]/2), 364 ([M-3K]/3).

NMR (MeOH-d4): 8.71 (1H), 8.63 (1.5H), 8.23 (0.5H) (5-, 10- and 20-H, all-m), 5.30 and 4.88 (151-CH2, dd), 4.43 and 4.25 (7,8,17,18-H, m), 3.85 (15~3-Me, s), 3.31 (21-Me, s), 3.22 (121-Me, s), 3.17 (32-Me, m), 1.89-2.44 (171 and 172-CH2, m), 2.25 (81-CH2, m), 1.91 (71-Me, s), 1.64 (181– Me, s), 1.08 (82-Me, t), 4.12, 3.56, 3.22, 3.16, 2.80 and 2.68 (CH2‘s of homotaurine).

Example 10. Palladium 31-oxo-15-methoxycarbonylmethyl-Rhodobacteriochlorin 131-(2-sulfoethyl)amide, 173-(N-immunoglobulin G)amide potassium salt (Compound 13)

Ten (10) mg of compound 4 were reacted with 20 mg of sulfo-NHS and 15 mg of EDC in 1 ml of dry DMSO for 1 hour at room temperature, then rabbit IgG (0.6 mg) in PBS (2.5 ml) was added, and the mixture was further incubated overnight at room temperature. The mixture was evaporated to dryness, then re-dissolved in 1 ml of PBS and loaded on Sephadex G-25 column equilibrated with PBS. A colored band was eluted with 4-5 ml of PBS. The pigment/protein ratio in the obtained conjugate 13 was determined by optical density at 753 and 280 mn, respectively, and varied between 0.5/1 to 1/1 of pigment 13/protein.

Example 11. Preparation of palladium 31-oxo-15-methoxycarbonylmethyl-Rhodobacteriochlorin 131-(2-carboxyethyl)amide dipotassium salt (Compound

M)

The preparation and purification of the title compound 14 were carried out as described in Example 2, by reaction of compound 2 with 3-aminopropionic acid (β-alanine) (150 mg) instead of taurine. Yield: 85%.

Example 12. Preparation of palladium 31-oxo-15-methoxycarbonylmethyl-Rhodobacteriochlorin 131-(3-phosphopropyl)amide tripotassium salt (Compound

15)

The preparation and purification of the title compound 15 were carried out as described in Example 2, by reaction of compound 2 with 3 -amino- 1-propanephosphonic acid (180 mg) instead of taurine. Yield: 68%.

Example 13. Palladium 31-(3-sulfopropylamino)-15-methoxycarbonylmethyl-Rhodobacteriochlorin 131,173-di(3-sulfopropyl)amide tripotassium salt (Compound 16)

For reduction of the imine group in 31-(3-sulfopropylimino) to the correspondent 31-(3-sulfopropylamino) group, compound 9 (8 mg) was reacted by stirring with sodium cyanoborohydride (15 mg) in 5 ml of methanol overnight at room temperature. Then the reaction mixture was treated with 0.05 M HCl (5 ml), neutralized with 0.01 M KOH, and evaporated. The title product 16 was purified using HPLC conditions as described in Example 2. Yield: 80-90%).

PATENT
US 7947672

REFERENCES

1: Kessel D, Price M. Evaluation of DADB as a Probe for Singlet Oxygen Formation during Photodynamic Therapy. Photochem Photobiol. 2012 Feb 2. doi: 10.1111/j.1751-1097.2012.01106.x. [Epub ahead of print] PubMed PMID: 22296586.

2: Betrouni N, Lopes R, Puech P, Colin P, Mordon S. A model to estimate the outcome of prostate cancer photodynamic therapy with TOOKAD Soluble WST11. Phys Med Biol. 2011 Aug 7;56(15):4771-83. Epub 2011 Jul 13. PubMed PMID: 21753234.

3: Chevalier S, Anidjar M, Scarlata E, Hamel L, Scherz A, Ficheux H, Borenstein N, Fiette L, Elhilali M. Preclinical study of the novel vascular occluding agent, WST11, for photodynamic therapy of the canine prostate. J Urol. 2011 Jul;186(1):302-9. Epub 2011 May 20. PubMed PMID: 21600602.

4: Dandler J, Wilhelm B, Scheer H. Photochemistry of bacteriochlorophylls in human blood plasma: 1. Pigment stability and light-induced modifications of lipoproteins. Photochem Photobiol. 2010 Mar-Apr;86(2):331-41. Epub 2009 Nov 23. PubMed PMID: 19947966.

5: Dandler J, Scheer H. Inhibition of aggregation of [Pd]-bacteriochlorophyllides in mesoporous silica. Langmuir. 2009 Oct 20;25(20):11988-92. PubMed PMID: 19772311.

6: Ashur I, Goldschmidt R, Pinkas I, Salomon Y, Szewczyk G, Sarna T, Scherz A. Photocatalytic generation of oxygen radicals by the water-soluble bacteriochlorophyll derivative WST11, noncovalently bound to serum albumin. J Phys Chem A. 2009 Jul 16;113(28):8027-37. PubMed PMID: 19545111.

7: Moore CM, Pendse D, Emberton M. Photodynamic therapy for prostate cancer–a review of current status and future promise. Nat Clin Pract Urol. 2009 Jan;6(1):18-30. Review. PubMed PMID: 19132003.

8: Preise D, Oren R, Glinert I, Kalchenko V, Jung S, Scherz A, Salomon Y. Systemic antitumor protection by vascular-targeted photodynamic therapy involves cellular and humoral immunity. Cancer Immunol Immunother. 2009 Jan;58(1):71-84. Epub 2008 May 17. PubMed PMID: 18488222.

9: Fleshker S, Preise D, Kalchenko V, Scherz A, Salomon Y. Prompt assessment of WST11-VTP outcome using luciferase transfected tumors enables second treatment and increase in overall therapeutic rate. Photochem Photobiol. 2008 Sep-Oct;84(5):1231-7. Epub 2008 Apr 8. PubMed PMID: 18399928.

10: Berdugo M, Bejjani RA, Valamanesh F, Savoldelli M, Jeanny JC, Blanc D, Ficheux H, Scherz A, Salomon Y, BenEzra D, Behar-Cohen F. Evaluation of the new photosensitizer Stakel (WST-11) for photodynamic choroidal vessel occlusion in rabbit and rat eyes. Invest Ophthalmol Vis Sci. 2008 Apr;49(4):1633-44. PubMed PMID: 18385085.

11: Fabre MA, Fuseau E, Ficheux H. Selection of dosing regimen with WST11 by Monte Carlo simulations, using PK data collected after single IV administration in healthy subjects and population PK modeling. J Pharm Sci. 2007 Dec;96(12):3444-56. PubMed PMID: 17854075.

12: Brandis A, Mazor O, Neumark E, Rosenbach-Belkin V, Salomon Y, Scherz A. Novel water-soluble bacteriochlorophyll derivatives for vascular-targeted photodynamic therapy: synthesis, solubility, phototoxicity and the effect of serum proteins. Photochem Photobiol. 2005 Jul-Aug;81(4):983-93. PubMed PMID: 15839743.

13: Mazor O, Brandis A, Plaks V, Neumark E, Rosenbach-Belkin V, Salomon Y, Scherz A. WST11, a novel water-soluble bacteriochlorophyll derivative; cellular uptake, pharmacokinetics, biodistribution and vascular-targeted photodynamic activity using melanoma tumors as a model. Photochem Photobiol. 2005 Mar-Apr;81(2):342-51. PubMed PMID: 15623318.

14: Plaks V, Posen Y, Mazor O, Brandis A, Scherz A, Salomon Y. Homologous adaptation to oxidative stress induced by the photosensitized Pd-bacteriochlorophyll derivative (WST11) in cultured endothelial cells. J Biol Chem. 2004 Oct 29;279(44):45713-20. Epub 2004 Aug 31. PubMed PMID: 15339936.

////////PADELIPORFIN,  WST11, WST-11, WST 11, Stakel, padeliporfin, palladiumbacteriopheophorbide monolysine taurine, EU 2017, EMA 2017

CCC1C(C2=NC1=CC3=C(C(=C([N-]3)C(=C4C(C(C(=N4)C=C5C(=C(C(=C2)[N-]5)C(=O)C)C)C)CCC(=O)O)CC(=O)OC)C(=O)NCCS(=O)(=O)O)C)C.[Pd+2]

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EMA issues new Guideline on “Chemistry of Active Substances”

 EMA, regulatory  Comments Off on EMA issues new Guideline on “Chemistry of Active Substances”
Dec 222016
 

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The new EMA “Guideline on the chemistry of active substances” represents the current state of the art in regulatory practice and fits into the context of the ICH Guidelines Q8-11. Find out what information regarding active substances European authorities expect in an authorization application.

http://www.gmp-compliance.org/enews_05704_EMA-issues-new-Guideline-on-%22Chemistry-of-Active-Substances%22_15982,15721,S-WKS_n.html

A medicinal product authorization application requires comprehensive information on origin and quality of an active substance. What information is required was defined in two Guidelines so far: the Guideline “Chemistry of Active Substances” (3AQ5a) from 1987 and the “Guideline on the Chemistry of New Active Substances” from 2004. Because both Guidelines’ content do not take into account the ICH Guidelines Q8-11 issued in the meantime and do thus not meet the current state of the art in sciences and in regulatory practice, the EMA Quality Working Party (QWP) developed an updated document  entitled “Guideline on the chemistry of active substances” (EMA/454576/2016), which was issued on 21 November.

The new Guideline describes the information on new or already existing active substances required in an authorization dossier. In the context of this Guideline “already existing” ingredients are those that are used in a product already authorized in the EU.

In detail the information and data regarding the substance have to be included in the following chapters of the CTD:

3.2.S.1: Nomenclature, information on the structural formula, pharmacological relevant physicochemical properties.

3.2.S.2: Information on the manufacturer(s), contractor(s), testing facilities etc.; description of the manufacturing processes (schematic representation with flow diagram as well as narrative); where appropriate detailed information on alternative manufacturing processes, for recovering of solvents and for routine reprocessing. Information with regard to re-working should not be included in the authorization dossier.

3.2.S.2.3: Information for controlling the material used during the manufacture and for its specification (incl. identity test). This paragraph is more comprehensive in the new Guideline compared with its predecessor and takes into account the requirements of the ICH Guideline Q11. This Guideline comprises requirements for the following materials: materials from biological sources, those used for the chemical synthesis of starting materials, materials from herbal origin, excipients like solvents (incl. water), reagents, catalysts etc.

3.2.S.2.4: Information on critical process steps (the Guideline comprises examples for these critical steps) as well as on quality and control of isolated intermediates within the synthesis steps. All information has to be provided with the appropriate justifications.

3.2.S.2.5: Information on Process Validation

3.2.S.2.6: Information on the development of the manufacturing process. Here all changes have to be described that were performed during the various phases (pre-clinical, clinical, scale-up, pilot and possibly production phase) of the process for new active substances. For already existing active substances available in production scale no information on process development is needed.

3.2.S.3: Information on Characterisation. Comprehensive information on the elucidation of the structure of the active substance, its physico-chemical properties and its impurities profile have to be provided. Further, the mutagenic potential of degradation products has to be considered. The analytical methods have to be described and their suitability has to be justified.

3.2.S.4: Information on the control of active substances. The analytical procedures and their validation have to be described. Data for the analytical method development should be provided if critical aspects of the analysis regarding the active substance’s specification need to be clarified. Analytical data are necessary for batches for pre-clinical and clinical studies as well as for pilot batches which are not less than 10% of the maximum production scale. The substance’s specification and its control strategy have to be justified on the basis of data from the pre-clinical and clinical phase and, if available, from the production phase.

3.2.S.5: Information on reference materials. If no Chemical Reference Substances (CRS) of the European Pharmacopoeia – counting as completely qualified reference standards – are used, comprehensive information on the analytical and physico-chemical characterization are required even for established primary standards.

3.2.S.6: Information on Container Closure System. Here a brief description is sufficient. However, if a Container-/Closure System is critical for the substance’s quality, its suitability has to be proven and justified. A reference to stability data can be used as supporting information.

3.2.S.7: Information on Stability. A detailed description of the stability studies carried out and the protocol used as well as a summary of the results are expected. Information on stress studies and conclusions on storage conditions and re-test dates or expiry dates are also to be made. This does not apply to substances monographed in the European Pharmacopoeia. If no re-test period or expiry date of batches on the production scale is available at the time of submission of the application, a stability commitment has to be attached with a post-approval stability protocol. The analytical methods have to be described.

The Guideline’s provisions also apply to an Active Substance Master File (ASMF) or to a Certificate of Suitability (CEP). They apply to active substances that have undergone development in a “traditional” way or according to the “enhanced” approach. The provisions of the ICH Guidelines Q8-11 have to be taken into account.

The Guideline is not applicable to active substances of herbal, biological and biotechnological origin as well as to radiolabelled products and radiopharmaceuticals.

The Guideline “Guideline on the chemistry of active substances” (EMA/454576/2016) becomes effective six months after issuing, which means in May 2017.

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Compassionate use is a treatment option….allows the use of an unauthorised medicine.

 EMA, EU  Comments Off on Compassionate use is a treatment option….allows the use of an unauthorised medicine.
Aug 202014
 

 

 

 

Compassionate use is a treatment option that allows the use of an unauthorised medicine. Compassionate-use programmes are for patients in the European Union (EU) who have a disease with no satisfactory authorised therapies or cannot enter aclinical trial. They are intended to facilitate the availability to patients of new treatment options under development.

 

 

Compassionate-use programmes are often governed by legislation in individual EU Member States, to make medicines available on a named-patient basis or to cohorts of patients.

In addition to this, EU legislation provides an option for Member States to ask the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) to provide an opinion to all EU Member States on how to administer, distribute and use certain medicines for compassionate use. The CHMP also identifies which patients may benefit from compassionate-use programmes. This is described in Article 83 of Regulation (EC) No 726/2004External link icon and is complementary to national legislation.

 

 

The objectives of Article 83 are to:

  • facilitate and improve access to compassionate-use programmes by patients in the EU;
  • favour a common approach regarding the conditions of use, the conditions for distribution and the patients targeted for the compassionate use of unauthorised new medicines;
  • increase transparency between Member States in terms of treatment availability.

More information is available in:

 

 

Compassionate-use opinions from the CHMP

Name of medicine Ledipasvir/Sofosbuvir
Active substance ledipasvir, sofosbuvir
Dosage 90mg / 400 mg
Pharmaceutical form Film coated tablet
Member State notifying the Agency Ireland
CHMP opinion documents Conditions of use, conditions for distribution and patients targeted and conditions for safety monitoringSummary on compassionate use
Date of opinion 20/02/2014
Company contact information Gilead Sciences Limited
Granta Park
Abington
Cambridgeshire
CB21 6GT
United Kingdom
Tel. +44 (0)208 5872206
Fax +44 (0)1223 897233
E-mail: eamemed.info@gilead.com
Status Ongoing
Related documents  –

 

Name of medicine Daclatasvir
Active substance daclatasvir
Dosage 30 and 60 mg
Pharmaceutical form Film coated tablet
Member State notifying the Agency Sweden
CHMP opinion documents Conditions of use, conditions for distribution and patients targeted and conditions for safety monitoringSummary on compassionate use
Date of opinion 21/11/2013
Company contact information Bristol-Myers Squibb Pharma EEIG
Uxbridge Business Park
Sanderson Road
Uxbridge UB8 1DH
United Kingdom
Tel. +44 (0)1895 523 740
Fax +44 (0)1895 523 677
E-mail: medical.information@bms.com
Status Ongoing
Related documents  –

 

Name of medicine Sofosbuvir Gilead
Active substance Sofosbuvir
Dosage 400 mg
Pharmaceutical form Film-coated tablet
Member State notifying the Agency Sweden
CHMP opinion documents Conditions of use, conditions for distribution and patients targeted and conditions for safety monitoring
Summary on compassionate use
Date of opinion 24/10/2013
Company contact information Gilead Sciences International Ltd
Granta Park, Abington
Cambridgeshire CB21 6GT
United Kingdom
Tel. +44 (0)1223 897496
Fax +44 (0)1223 897233
E-mail: eamemed.info@gilead.com
Status Ongoing
Related documents  –

 

Name of medicine IV Zanamivir
Active substance Zanamivir
Dosage 10 mg/ml
Pharmaceutical form Solution for infusion
Member State notifying the Agency Sweden
CHMP opinion documents Conditions of use, conditions for distribution and patients targeted and conditions for safety monitoring
Summary on compassionate use
Date of opinion 18/02/2010
Company contact information GlaxoSmithKline Research & Development Limited
980 Great West Road, Brentford
Middlesex TW8 9GS
United Kingdom
Tel. +44 (0)20 8047 5000 or +44 (0)20 8990 3885
E-mail: julie.c.kerrison@gsk.com
Status Ongoing
Related documents  –

 

Name of product Tamiflu IV
Active substance Oseltamivir phosphate
Dosage 100 mg
Pharmaceutical form Powder for solution for infusion
Member State notifying the Agency Finland
CHMP opinion documents Conditions of use, conditions for distribution and patients targeted and conditions for safety monitoring
Summary on compassionate use
Date of opinion 20/01/2010
Company contact information F. Hoffmann-La Roche Ltd.
Pharmaceuticals Division
PBMV Bldg 74/3O 104
CH-4070, Basel
Switzerland
Tel. +41 61 688 5522
Fax +41 61 687 2239
E-mail: basel.tamifluquestions@roche.com
Status Closed
Related documents Public statement on Tamiflu IV: Closure of compassionate-use programme in the EU
Tamiflu IV compassionate-use programme EMEA/H/K/002287 – Closure of programme

 

 

Expanded access (also known as compassionate use) refers to the use of an investigational drug outside of a clinical trial by patients with serious or life-threatening conditions who do not meet the enrollment criteria for the clinical trial in progress. Outside the US, such access is allowed through Named patient programs. In the US this type of access may be available, in accordance with United States Food and Drug Administration (FDA) regulations, when it is clear that patients may benefit from the treatment, the therapy can be given safely outside the clinical trial setting, no other alternative therapy is available, and the drug developer agrees to provide access to the drug. The FDA refers to such a program as an expanded access program (EAP).[1] EAPs can be leveraged in a wide range of therapeutic areas including HIV/AIDS and other infectious diseases, cancer, rare diseases, and cardiovascular diseases, to name a few.

There are several types of EAPs allowed in the United States. Treatment protocols and treatment INDs provide large numbers of patients access to investigational drugs. A single-patient IND is a request from a physician to the FDA that an individual patient be allowed access to an investigational drug on an emergency or compassionate use basis.[2] When the FDA receives a significant number of requests (~10 to 100) for individual patient expanded access to an investigational drug for the same use, they may ask the trial sponsor to consolidate these requests, creating an intermediate-size group.[3] “Compassionate use” is a more colloquial term that is not generally used by the FDA.

FDA regulations

Since 1987, the FDA has had rules in place that have enabled patients, under specific circumstances, to access drugs or biologics that are still in development for treatment purposes. These expanded access program rules were amended in 2009 by the FDA to ensure “broad and equitable access to investigational drugs for treatment.”[4]

The regulations include the following:[4]

  • Criteria that must be met in order to authorize the expanded access use
  • Requirements for expanded access submissions
  • Safeguards to protect patients and the clinical trial process

The regulations also include general criteria for granting expanded access:[3]

  • The patient must have a serious condition or disease for which there is no comparable alternative therapy available
  • The patient must be unable to participate in a clinical trial
  • The potential benefit must outweigh the potential risk of using the treatment
  • There should be no impact on the completion of the clinical trial or the drug’s approval

Despite the updated regulations, debate remains over key elements of expanded access:

  • Deciding at what point in the clinical trial process access should be given. Some stakeholders support expanded access programs after phase I testing in clinical trials. The FDA has stated that most drugs should not be eligible until some point during phase III when efficacy data have been obtained, unless compelling phase II data on safety and efficacy are available.[3][5]
  • Weighing risks to the patient against the potential benefits. The FDA requires that a physician and an institutional review board (IRB) determine that a treatment will not pose undue risk to the patient, relative to the condition he or she is suffering from.[6] However, the FDA maintains the right to overrule the physician and IRB.[3]
  • Determining who should get access. The FDA states that expanded access should only be considered for patients with a serious disease or condition, but the FDA’s rules do not provide a definition of “serious”; instead it provides examples of diseases and conditions that fall into this category.[3] In the case of a cancer drug, the sponsor of an expanded access program must define exactly which patients will get access. Most often, access is limited to those patients with the same type of cancer the drug is being tested for.[7]

A number of challenges can exist when patients seek access to investigational drugs:

  • Obtaining an IRB review. Finding time on an IRB’s schedule can be difficult, particularly for doctors who are not based at research centers where IRBs are readily available. The fee for the review may pose a problem as well. It may be unclear who is responsible for the cost of the IRB review, which can be as much as $2,000. Many IRBs conduct reviews pro bono but others that charge will often only waive their fees for research done in their hospital.[6][8]
  • Protecting physicians against liability risk. Currently, physicians may be concerned that they could face a liability risk for investigational drugs that they recommend to patients or help them gain access to, potentially discouraging them from doing so. The FDA does not have jurisdiction over this issue but there is a bill in Congress, the Compassionate Access Act of 2010 (H.R. 4732), that would address the situation.[6][8][9]
  • Paying for the drug. While the FDA allows drug companies to recover the costs of providing a treatment through an EAP, many companies may hesitate to do so because it requires disclosing the cost of their drug, which is often a closely guarded secret. In addition, many insurance companies won’t cover the costs of experimental treatment so access could be limited to patients with the means to pay for it.[6][8]
  • Assessing the potential impact of adverse events on drug development. Adverse events (AEs) that result from expanded access programs must be reported to the FDA in the same way AEs are reported in the case of a clinical trial. The FDA states that, to their knowledge, no drug candidate has been turned down for approval because of an adverse event that appeared in an expanded access program.[3][6]

Outside the United States

Outside the U.S., programs that enable access to drugs in the pre-approval and pre-launch phase are referred to by a variety of names including “named patient programs,” “named patient supply” and “temporary authorization for use.”[10] In the EU, named patient programs also allow patients to access drugs in the time period between centralized European Medicines Agency (EMEA) approval and launch in their home countries which can range from one year to eighteen months.[11]

References

  1. Jump up^ US National Cancer Institute – Access to Investigational Drugs accessed April 22, 2007
  2. Jump up^ FDA Final Rules for Expanded Access to Investigational Drugs for Treatment Use and Charging for Investigational Drugs
  3. Jump up to:a b c d e f Final FDA Rules on Expanded Access to Investigational Drugs for Treatment Use
  4. Jump up to:a b FDA website
  5. Jump up^ Expanded Access to Investigational Drugs Genetic Engineering & Biotechnology News, January 15, 2010.
  6. Jump up to:a b c d e Access to Investigational Drugs Remains Challenge Despite New FDA Rules ‘’The Pink Sheet’’
  7. Jump up^ Managing Access to Drugs Prior to Approval and Launch ‘’Life Science Leader’’[dead link]
  8. Jump up to:a b c FDA webinar accessed May 5, 2010
  9. Jump up^ FDA Law Blog accessed May 5, 2010
  10. Jump up^ Helene S (2010). “EU Compassionate Use Programmes (CUPs): Regulatory Framework and Points to Consider before CUP Implementation”Pharm Med 24 (4): 223–229.
  11. Jump up^ [Ericson, M., Harrison, K., Laure, N. & De Crémiers, F., Compassionate Use Requirements in the Enlarged European Union. RAJ Pharma, May 2005: 83.

External links

 

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European Medicines Agency …Clinical trials in human medicines

 EMA, EU  Comments Off on European Medicines Agency …Clinical trials in human medicines
Aug 132014
 

 

The European Medicines Agency relies on the results of clinical trials carried out by pharmaceutical companies to reach its opinions on the authorisation of medicines. Although the authorisation of clinical trials occurs at Member State level, the Agency plays a key role in ensuring that the standards of good clinical practice (GCP) are applied across the European Economic Area in cooperation with the Member States. It also manages a database of clinical trials carried out in the European Union.

Clinical trials are studies that are intended to discover or verify the effects of one or more investigational medicines. The regulation of clinical trials aims to ensure that the rights, safety and well-being of trial subjects are protected and the results of clinical trials are credible.

Regardless of where they are conducted, all clinical trials included in applications for marketing authorisation for human medicines in the European Economic Area (EEA) must have been carried out in accordance with the requirements set out in Annex 1 ofDirective 2001/83/ECExternal link icon. This means that:

In the EEA, approximately 4,000 clinical trials are authorised each year. This equals approximately 8,000 clinical-trial applications, with each trial involving two Member States on average. Approximately 61% of clinical trials are sponsored by the pharmaceutical industry and 39% by non-commercial sponsors, mainly academia.

Role of the Agency

Clinical-trial data is included in clinical-study reports that form a large part of the application dossiers submitted by pharmaceutical companies applying for a marketing authorisation via the Agency.

The Agency’s Committee for Medicinal Products for Human Use (CHMP) is responsible for conducting the assessment of a human medicine for which an EU-wide marketing authorisation is sought. As part of its scientific evaluation work, the CHMP reviews the clinical-trial data included in the application.

Assessments are based on purely scientific criteria and determine whether or not the medicines concerned meet the necessary quality, safety and efficacy requirements in accordance with EU legislation, particularly Directive 2001/83/ECExternal link icon.

Good clinical practice

The Agency plays a central role in ensuring application of good clinical practice (GCP). GCP is the international ethical and scientific quality standard for designing, recording and reporting clinical trials that involve the participation of human subjects.

The Agency works in cooperation with GCP inspectors from medicines regulatory authorities (‘national competent authorities’) in EEA Member States on the harmonisation and coordination of GCP-related activity at an EEA level.

The Agency does not have a role in the approval of clinical-trial applications in the EEA. The approval of clinical-trial applications is the responsibility of the national competent authorities.

EudraCT database and the EU Clinical Trials Register

The Agency is responsible for the development, maintenance and coordination of the EudraCT database. This is a database used by national competent authorities to enter clinical-trial data from clinical trial sponsors and paediatric-investigation-plan (PIP) addressees.

A subset of this data is made available through the European Union Clinical Trials Register, which the Agency manages on behalf of EU Member States and forms part ofEudraPharmExternal link icon, the EU database of medicines.

Users are able to view:

  • the description of phase-II to phase-IV adult clinical trials where the investigator sites are in the EEA;
  • the description of any clinical trials in children with investigator sites in the EU and any trials that form part of a PIP including those where the investigator sites are outside the EU.

As of 21 July 2014, it will be mandatory for sponsors to post clinical trial results in the EudraCT database. A subset of the data included in EudraCT is made available to the public in the European Union Clinical Trials Register. The content and level of detail of these summary results is set out in a European Commission guideline and in its technical guidance. A typical set of summary results provides information on the objectives of a given study, explains how it was designed and gives its main results and conclusions.

The Agency is also working towards the proactive publication of data from clinical trials carried out on the medicines that it authorises. For more information, see release of data from clinical trials.

Clinical trials conducted in countries outside the EU

Clinical trials conducted outside the EU but submitted in an application for marketing authorisation in the EU have to follow the principles which are equivalent to the provisions of the Directive 2001/20/ECExternal link icon.

In April 2012, the Agency published the final version of this paper:

This paper aims to strengthen existing processes to provide assurance that clinical trials meet the required ethical and GCP standards, no matter where in the world they have been conducted.

The number of clinical trials and clinical-trial subjects outside Western Europe and North America has been increasing for a number of years. More information is available in this document:

Revision of EU clinical trial legislation

In July 2012, the European Commission published a proposal on a regulation to revise the EU clinical trial legislation.

More information is available at: Revision of the clinical trials directiveExternal link icon.

Clinical Trials Facilitation Group

The Clinical Trials Facilitation GroupExternal link icon (CTFG) is a working group of the Heads of Medicines Agencies that:

  • acts as forum for discussion to agree on common principles and processes to be applied throughout the European medicines regulatory network;
  • promotes harmonisation of clinical-trial-assessment decisions and administrative processes by national competent authorities;
  • operates the voluntary harmonisation procedure for assessment of clinical-trial applications involving several Member States.

The Group is composed of representatives from the clinical-trial departments of the national competent authorities.

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EMA clears Roche’s polyarticular juvenile idiopathic arthritis drug

 EMA  Comments Off on EMA clears Roche’s polyarticular juvenile idiopathic arthritis drug
Jun 212013
 
EMA clears Roche’s polyarticular juvenile idiopathic arthritis drug
The European Medicines Agency has cleared Roche’s RoACTEMRA for the treatment of a rare form of arthritis, polyarticular juvenile idiopathic arthritis (PJIA), in children aged two years and above…

read all at

http://regulatoryaffairs.pharmaceutical-business-review.com/news/ema-clears-roches-polyarticular-juvenile-idiopathic-arthritis-drug-120613

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