Tivozanib, ティボザニブ塩酸塩水和物

EMA, orphan status Comments Off

Mar 142018

ChemSpider 2D Image | Tivozanib | C22H19ClN4O5

Tivozanib

Molecular FormulaC₂₂H₁₉ClN₄O₅
Average mass454.863 Da

AV951

AV951 (KRN951, Tivozanib)

AV-951; AV951;AV 951

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

KRN 951

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

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

475108-18-0 [RN] FREE FORM

AV 951

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

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

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

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

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

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

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

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

Image result for tivozanib

Image result for TIVOZANIB EMA

CAS HCL HYDRATE 682745-41-1

ティボザニブ塩酸塩水和物;

Pharmacotherapeutic group

Antineoplastic agents

Therapeutic indication

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

Treatment of advanced renal cell carcinoma

Fotivda : EPAR -Product Information

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

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

str6

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

Product details

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

Publication details

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

Contact address:

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

Mechanism

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

Results

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

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

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

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

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

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

SYNTHESIS

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

CLIP

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

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

PAPER

J MED CHEM 2005 48 1359

PATENT

WO 2002088110

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

Scheme 1 and Scheme 2

Skiing

PATENT

WO 2004035572

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

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

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

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

(2) Reduction process:

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

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

(3) Cyclization step:

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

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

(4) Clovalization process

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

(5) Phenol site introduction step:

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

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

(6) Ureaization process:

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

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

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

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

PATENT

WO 2011060162

WO 2017037220

CN 106967058

CN 104072492

CN 102532116

CN 102408418

PAPER

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

Synthesis of the compounds

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

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

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

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

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

PATENT

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

Example

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

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

[0037] CN 102532116 B specification 4/6

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

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

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

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

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

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

[0047] CN 102532116 B specification 5/6

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

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

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

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

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

Claims (3)

translated from Chinese

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

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

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

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

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

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

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

References

Tivozanib is currently being evaluated in the pivotal Phase 3 TIVO-3 trial, a randomized, controlled, multi-center, open-label study to compare tivozanib to sorafenib in subjects with refractory advanced RCC. FDA approval is expected in 2018. A Study of Tivozanib (AV-951), an Oral VEGF Receptor Tyrosine Kinase Inhibitor, in the Treatment of Renal Cell Carcinoma, clinicaltrials.gov
http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/004131/human_med_002146.jsp&mid=WC0b01ac058001d124.
Campas, C., Bolos, J., Castaner, R (2009). “Tivozanib”. Drugs Fut. 34 (10): 793.
Aveo Kidney Cancer Drug Shows Success; Shares Up, By John Kell, Dow Jones Newswires^{[dead link]}
“Phase III Results Lead Aveo and Astellas to Plan Regulatory Submissions for Tivozanib”. 3 Jan 2012.
“FDA Rejects Renal Cancer Drug Tivozanib”. MedPage Today. June 30, 2013.
http://meetinglibrary.asco.org/content/165081-176
http://investor.aveooncology.com/phoenix.zhtml?c=219651&p=irol-newsArticle&ID=2172669
http://www.eusapharma.com/files/EUSA-Pharma-file-tivozanib-in-EU-March-2016.pdf
“AVEO Pharma surges 48% on recommendation for European approval of its cancer drug”. Market Watch. June 28, 2017. Retrieved June 28, 2017.
“AVEO Oncology Announces FOTIVDA® (tivozanib) Approved in the European Union for the Treatment of Advanced Renal Cell Carcinoma” (PDF). AVEO Oncology. August 28, 2017. Retrieved February 9, 2018.

Patent ID	Patent Title	Submitted Date	Granted Date
US2017112821	Multi-Tyrosine Kinase Inhibitors Derivatives and Methods of Use	2017-01-09
US2014275183	AGENT FOR REDUCING SIDE EFFECTS OF KINASE INHIBITOR	2014-05-29	2014-09-18
US8969344	Method for assay on the effect of vascularization inhibitor	2012-09-21	2015-03-03
US2012252829	TIVOZANIB AND CAPECITABINE COMBINATION THERAPY	2012-03-30	2012-10-04
US8815241	Use of Combination of Anti-Angiogenic Substance and c-kit Kinase Inhibitor	2011-12-01

Patent ID	Patent Title	Submitted Date	Granted Date
US2011262525	METHODS OF TREATMENT	2011-10-27
US2013197016	DOSING REGIMES FOR THE TREATMENT OF OCULAR VASCULAR DISEASE	2011-10-25	2013-08-01
US2011091524	BIOMARKERS FOR SENSITIVITY TO ANTI-IGF1R THERAPY	2011-04-21
US2011009387	HISTONE H2AX (HH2AX) BIOMARKER FOR FTI SENSITIVITY	2011-01-13
US8470297	FDG-pet evaluation of Ewing’s sarcoma sensitivity	2010-09-10	2013-06-25

Patent ID	Patent Title	Submitted Date	Granted Date
US2006233810	Methods and compositions for treating or preventing cancer	2006-10-19
US2006205810	Platinum therapeutic combinations	2006-09-14
US8772269	Use of sulfonamide-including compounds in combination with angiogenesis inhibitors	2006-06-22
US2016376239	N-Acylalkyl Prodrugs of Multi-Tyrosine Kinase Inhibitors and Methods of Use	2016-06-28
US2016009785	NOVEL FUSION MOLECULES AND USES THEREOF	2013-11-05	2016-01-14

Patent ID	Patent Title	Submitted Date
US2017268065	ERK1 and ERK2 Mutations That Confer Resistance to MAPK Pathway Inhibitors	2015-06-11
US2010105031	METHOD FOR PREDICTION OF THE EFFICACY OF VASCULARIZATION INHIBITOR	2010-04-29
US2008090242	PANEL OF BIOMARKERS FOR PREDICTION OF FTI EFFICACY	2008-04-17
US2017143688	Multi-Tyrosine Kinase Inhibitors Derivatives and Methods of Use	2017-01-10
US2017020856	N-Acylalkyl Prodrugs of Multi-Tyrosine Kinase Inhibitors and Methods of Use	2016-10-07

Patent ID	Patent Title	Submitted Date	Granted Date
US2014148483	Method For Predicting Effectiveness Of Angiogenesis Inhibitor	2012-05-16	2014-05-29
US8962655	COMPOSITION FOR TREATMENT OF UNDIFFERENTIATED GASTRIC CANCER	2010-02-25
US8865737	ANTITUMOR AGENT FOR UNDIFFERENTIATED GASTRIC CANCER	2009-10-22
US2009209580	ANTITUMOR AGENT FOR THYROID CANCER	2009-08-20
US7615353	Tivozanib response prediction		2009-11-10

Patent ID	Patent Title	Submitted Date	Granted Date
US2014045715	TIVOZANIB RESPONSE PREDICTION	2013-08-05	2014-02-13
US7736861	Tivozanib response prediction		2010-06-15
US2012231478	TIVOZANIB RESPONSE PREDICTION	2010-06-03	2012-09-13

Patent ID	Patent Title	Submitted Date	Granted Date
US2010143340	METHODS AND COMPOSITIONS FOR TREATING CANCER	2010-06-10
US9006240	METHOD FOR ASSAY ON THE EFFECT OF VASCULARIZATION INHIBITOR	2010-04-15
US2012058112	ANTIBODIES	2010-04-06	2012-03-08
US2008112888	IGFBP2 BIOMARKER	2008-05-15
US2006286103	Stable antibody formulation	2006-12-21

Patent ID	Patent Title	Submitted Date	Granted Date
US2009053236	USE OF COMBINATION OF ANTI-ANGIOGENIC SUBSTANCE AND c-kit KINASE INHIBITOR	2009-02-26
US7166722	N-{2-chloro-4-[(6, 7-dimethoxy-4-quinolyl)oxy]phenyl}-n’-(5-methyl-3-isoxazolyl)urea salt in crystalline form	2006-03-09	2007-01-23
US7211587	Quinoline derivatives and quinazoline derivatives having azolyl group	2004-11-18	2007-05-01
US6821987	Quinoline derivatives and quinazoline derivatives having azolyl group	2003-05-08	2004-11-23
US2017191137	Method For Predicting Effectiveness Of Angiogenesis Inhibitor	2017-03-16

Patent ID	Patent Title	Submitted Date	Granted Date
US9006256	ANTITUMOR AGENT FOR THYROID CANCER	2011-08-25
US2015168424	IGFBP2 Biomarker	2014-12-01	2015-06-18
US7998973	Tivozanib and Temsirolimus in Combination	2011-05-19	2011-08-16
US8216571	FULLY HUMAN ANTI-VEGF ANTIBODIES AND METHODS OF USING	2011-04-28	2012-07-10
US2011014117	ANTI-IGF1R	2011-01-20

ivozanib
Names

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

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

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

Biafungin, CD 101, a Novel Echinocandin for Vulvovaginal candidiasis

orphan status Comments Off

Aug 012016

as CH3COOH salt

CD 101

Several structural representations above

Biafungin™; CD 101 IV; CD 101 Topical; CD101; SP 3025, Biafungin acetate, Echinocandin B

UNII-G013B5478J FRE FORM,

CAS 1396640-59-7 FREE FORM

MF, C63-H85-N8-O17, MW, 1226.4035

Echinocandin B,

1-((4R,5R)-4-hydroxy-N2-((4”-(pentyloxy)(1,1′:4′,1”-terphenyl)-4-yl)carbonyl)-5-(2-(trimethylammonio)ethoxy)-L-ornithine)-4-((4S)-4-hydroxy-4-(4-hydroxyphenyl)-L-allothreonine)-

Treat and prevent invasive fungal infections; Treat and prevent systemic Candida infections; Treat candidemia

2D chemical structure of 1631754-41-0

Biafungin acetate

CAS 1631754-41-0 ACETATE, Molecular Formula, C63-H85-N8-O17.C2-H3-O2, Molecular Weight, 1285.4472,

C₆₃ H₈₅ N₈ O₁₇ . C₂ H₃ O₂

1-[(4R,5R)-4-hydroxy-N²-[[4”-(pentyloxy)[1,1′:4′,1”-terphenyl]-4-yl]carbonyl]-5-[2-(trimethylammonio)ethoxy]-L-ornithine]-4-[(4S)-4-hydroxy-4-(4-hydroxyphenyl)-L-allothreonine]-, acetate (1:1)

UNII: W1U1TMN677

CD101 – A novel echinocandin antifungal C. albicans (n=351) MIC90 = 0.06 µg/mL C. glabrata (n=200) MIC90 = 0.06 µg/mL  Echinocandins have potent fungicidal activity against Candida species

Originator Seachaid Pharmaceuticals
Developer Cidara Therapeutics
Class Antifungals; Echinocandins; Small molecules
Mechanism of Action Glucan synthase inhibitors

Orphan Drug Status Yes – Candidiasis
On Fast track Candidiasis; Vulvovaginal candidiasis
Phase II Candidiasis; Vulvovaginal candidiasis
Most Recent Events
- 01 Jun 2016 Phase-II clinical trials in Vulvovaginal candidiasis in USA (Topical) (9197627; NCT02733432)
- 31 May 2016 CD 101 receives Qualified Infectious Disease Product status for Vulvovaginal candidiasis in USA
- 31 May 2016 CD 101 receives Fast Track designation for Vulvovaginal candidiasis [Topical] in USA
Restricted Access

POSTER……

https://www.jmilabs.com/data/posters/ICAAC2014/M-1082.PDF

http://www.cidara.com/wp-content/uploads/2014/12/A-694.-Biafungin-CD101-a-Novel-Echinocandin-Displays-a-Long-Half-life-in-the-Chimpanzee-Suggesting-a-Once-Weekly-IV-Dosing-Option.pdf

CLIPPED IMAGE FROM FILE ABOVE

BIAFUNGIN, CD 101

Watch this space as I add more info…………….

U.S. – Fast Track (Treat candidemia);
U.S. – Fast Track (Treat and prevent invasive fungal infections);
U.S. – Orphan Drug (Treat and prevent invasive fungal infections);
U.S. – Orphan Drug (Treat candidemia);
U.S. – Qualified Infectious Disease Program (Treat candidemia);
U.S. – Qualified Infectious Disease Program (Treat and prevent invasive fungal infections)

Fungal infections have emerged as major causes of human disease, especially among the immunocompromised patients and those hospitalized with serious underlying disease. As a consequence, the frequency of use of systemic antifungal agents has increased significantly and there is a growing concern about a shortage of effective antifungal agents. Although resistance rates to the clinically available antifungal agents remains low, reports of breakthrough infections and the increasing prevalence of uncommon fungal species that display elevated MIC values for existing agents is worrisome. Biafungin (CD101, previously SP 3025) is a novel echinocandin that displays chemical stability and long-acting pharmacokinetics that is being developed for once-weekly or other intermittent administration (see posters #A-693 and A- 694 for further information). In this study, we test biafungin and comparator agents against a collection of common Candida and Aspergillus species, including isolates resistant to azoles and echinocandins.

The echinocandins are an important class of antifungal agents, but are administered once daily by intravenous (IV) infusion. An echinocandin that could be administered once weekly could facilitate earlier hospital discharges and could expand usage to indications where daily infusions are impractical. Biafungin is a highly stable echinocandin for once-weekly IV administration. The compound was found to have a spectrum of activity and potency comparable to other echinocandins. In chimpanzees single dose pharmacokinetics of IV and orally administered biafungin were compared to IV anidulafungin, which has the longest half-life (T1/2 ) of the approved echinocandins.

Background  Vulvovaginal candidiasis (VVC) is a highly prevalent mucosal infection  VVC is caused by Candida albicans (~85%) and non-albicans (~15%)  5-8% of women have recurrent VVC (RVVC) which is associated with a negative impact on work/social life  Oral fluconazole prescribed despite relapse, potential DDIs and increased risk to pregnant women  No FDA-approved therapy for RVVC and no novel agent in >20 years

Cidara Therapeutics 6310 Nancy Ridge Drive, Suite 101 San Diego, CA 92121

The incidence of invasive fungal infections, especially those due to Aspergillus spp. and Candida spp., continues to increase. Despite advances in medical practice, the associated mortality from these infections continues to be substantial. The echinocandin antifungals provide clinicians with another treatment option for serious fungal infections. These agents possess a completely novel mechanism of action, are relatively well-tolerated, and have a low potential for serious drug–drug interactions. At the present time, the echinocandins are an option for the treatment of infections due Candida spp (such as esophageal candidiasis, invasive candidiasis, and candidemia). In addition, caspofungin is a viable option for the treatment of refractory aspergillosis. Although micafungin is not Food and Drug Administration-approved for this indication, recent data suggests that it may also be effective. Finally, caspofungin- or micafungin-containing combination therapy should be a consideration for the treatment of severe infections due to Aspergillus spp. Although the echinocandins share many common properties, data regarding their differences are emerging at a rapid pace. Anidulafungin exhibits a unique pharmacokinetic profile, and limited cases have shown a potential far activity in isolates with increased minimum inhibitory concentrations to caspofungin and micafungin. Caspofungin appears to have a slightly higher incidence of side effects and potential for drug–drug interactions. This, combined with some evidence of decreasing susceptibility among some strains ofCandida, may lessen its future utility. However, one must take these findings in the context of substantially more data and use with caspofungin compared with the other agents. Micafungin appears to be very similar to caspofungin, with very few obvious differences between the two agents.

Echinocandins are a new class of antifungal drugs^[1] that inhibit the synthesis of glucan in the cell wall, via noncompetitive inhibition of the enzyme 1,3-β glucan synthase^[2]^[3] and are thus called “penicillin of antifungals”^[4] (a property shared with papulacandins) as penicillin has a similar mechanism against bacteria but not fungi. Beta glucans are carbohydrate polymers that are cross-linked with other fungal cell wall components (The bacterial equivalent is peptidoglycan). Caspofungin, micafungin, and anidulafungin are semisynthetic echinocandin derivatives with clinical use due to their solubility, antifungal spectrum, and pharmacokinetic properties.^[5]

Echinocandin B

Caspofungin

List of echinocandins:^[17]

Pneumocandins (cyclic hexapeptides linked to a long-chain fatty acid)
Echinocandin B not clinically used, risk of hemolysis
Cilofungin withdrawn from trials due to solvent toxicity
Caspofungin (trade name Cancidas, by Merck)
Micafungin (FK463) (trade name Mycamine, by Astellas Pharma.)
Anidulafungin (VER-002, V-echinocandin, LY303366) (trade name Eraxis, by Pfizer)

History

Anidulafungin

Discovery of echinocandins stemmed from studies on papulacandins isolated from a strain of Papularia sphaerosperma (Pers.), which were liposaccharide – i.e., fatty acid derivatives of a disaccharide that also blocked the same target, 1,3-β glucan synthase – and had action only on Candida spp. (narrow spectrum). Screening of natural products of fungal fermentation in the 1970s led to the discovery of echinocandins, a new group of antifungals with broad-range activity against Candida spp. One of the first echinocandins of the pneumocandin type, discovered in 1974, echinocandin B, could not be used clinically due to risk of high degree of hemolysis. Screening semisynthetic analogs of the echinocandins gave rise to cilofungin, the first echinofungin analog to enter clinical trials, in 1980, which, it is presumed, was later withdrawn for a toxicity due to the solvent system needed for systemic administration. The semisynthetic pneumocandin analogs of echinocandins were later found to have the same kind of antifungal activity, but low toxicity. The first approved of these newer echinocandins was caspofungin, and later micafungin and anidulafungin were also approved. All these preparations so far have low oral bioavailability, so must be given intravenously only. Echinocandins have now become one of the first-line treatments for Candida before the species are identified, and even as antifungal prophylaxis in hematopoietic stem cell transplant patients.

CIDARA THERAPEUTICS DOSES FIRST PATIENT IN PHASE 2 TRIAL OF CD101 TOPICAL TO TREAT VULVOVAGINAL CANDIDIASIS

SAN DIEGO–(BUSINESS WIRE)–Jun. 9, 2016– Cidara Therapeutics, Inc. (Nasdaq:CDTX), a biotechnology company developing novel anti-infectives and immunotherapies to treat fungal and other infections, today announced that the first patient has been dosed in RADIANT, a Phase 2 clinical trial comparing the safety and tolerability of the novel echinocandin, CD101, to standard-of-care fluconazole for the treatment of acute vulvovaginal candidiasis (VVC). RADIANT will evaluate two topical formulations of CD101, which is Cidara’s lead antifungal drug candidate.

“There have been no novel VVC therapies introduced for more than two decades, so advancing CD101 topical into Phase 2 is a critical step for women with VVC and for Cidara,” said Jeffrey Stein, Ph.D., president and chief executive officer of Cidara. “Because of their excellent safety record and potency against Candida, echinocandin antifungals are recommended as first line therapy to fight systemic Candida infections. CD101 topical will be the first echinocandin tested clinically in VVC and we expect to demonstrate safe and improved eradication of Candida with rapid symptom relief for women seeking a better option over the existing azole class of antifungals.”

RADIANT is a Phase 2, multicenter, randomized, open-label, active-controlled, dose-ranging trial designed to evaluate the safety and tolerability of CD101 in women with moderate to severe episodes of VVC. The study will enroll up to 125 patients who will be randomized into three treatment cohorts. The first cohort will involve the treatment of 50 patients with CD101 Ointment while a second cohort of 50 patients will receive CD101 Gel. The third cohort will include 25 patients who will be treated with oral fluconazole.

The primary endpoints of RADIANT will be the safety and tolerability of a single dose of CD101 Ointment and multiple doses of CD101 Gel in patients with acute VVC. Secondary endpoints include therapeutic efficacy in acute VVC patients treated with CD101. Treatment evaluations and assessments will occur on trial days 7, 14 and 28.

The RADIANT trial will be conducted at clinical trial centers across the United States. More information about the trial is available at www.clinicaltrials.gov, identifier NCT02733432.

About VVC and RVVC

Seventy-five percent of women worldwide suffer from VVC in their lifetime, and four to five million women in the United Statesalone have the recurrent form of the infection, which is caused by Candida. Many women will experience recurrence after the completion of treatment with existing therapies. Most VVC occurs in women of childbearing potential (the infection is common in pregnant women), but it affects women of all ages. In a recent safety communication, the U.S. Food and Drug Administration(FDA) advised caution in the prescribing of oral fluconazole for yeast infections during pregnancy based on a published study concluding there is an increased risk of miscarriage. The Centers for Disease Control and Prevention (CDC) guidelines recommend using only topical antifungal products to treat pregnant women with vulvovaginal yeast infections. Vaginal infections are associated with a substantial negative impact on day-to-day functioning and adverse pregnancy outcomes including preterm delivery, low birth weight, and increased infant mortality in addition to predisposition to HIV/AIDS. According to the CDC, certain species of Candida are becoming increasingly resistant to existing antifungal medications. This emerging resistance intensifies the need for new antifungal agents.

About CD101 Topical

CD101 topical is the first topical agent in the echinocandin class of antifungals and exhibits a broad spectrum of fungicidal activity against Candida species. In May 2016, the FDA granted Qualified Infectious Disease Product (QIDP) and Fast Track Designation to CD101 topical for the treatment of VVC and the prevention of RVVC.

About Cidara Therapeutics

Cidara is a clinical-stage biotechnology company focused on the discovery, development and commercialization of novel anti-infectives for the treatment of diseases that are inadequately addressed by current standard-of-care therapies. Cidara’s initial product portfolio comprises two formulations of the company’s novel echinocandin, CD101. CD101 IV is being developed as a once-weekly, high-exposure therapy for the treatment and prevention of serious, invasive fungal infections. CD101 topical is being developed for the treatment of vulvovaginal candidiasis (VVC) and the prevention of recurrent VVC (RVVC), a prevalent mucosal infection. In addition, Cidara has developed a proprietary immunotherapy platform, Cloudbreak™, designed to create compounds that direct a patient’s immune cells to attack and eliminate pathogens that cause infectious disease. Cidara is headquartered inSan Diego, California. For more information, please visit www.cidara.com.

REF http://ir.cidara.com/phoenix.zhtml?c=253962&p=irol-newsArticle&ID=2176474

CLIP

Cidara Therapeutics raises $42 million to develop once-weekly anti-fungal therapy

Cidara Therapeutics (formerly K2 Therapeutics) grabbed $42 million in a private Series B funding round Wednesday to continue developing its once-weekly anti-fungal therapy. Just in June 2014, the company completed a $32 million Series A financing led by 5AM Ventures, Aisling Capital, Frazier Healthcare and InterWest Partners, which was the fourth largest A round in 2014 for innovative startups[1]. FierceBiotech named the company as one of 2014 Fierce 15 biotech startups.

Cidara has an impressive executive team. The company was co-founded by Kevin Forrest, former CEO of Achaogen (NASDAQ: AKAO), and Shaw Warren. Jeffrey Stein, former CEO of Trius Therapeutics (NASDAQ: TSRX) and Dirk Thye, former president of Cerexa, have joined Cidara as CEO and CMO, respectively. Trius successfully developed antibiotic tedizolid and was acquired in 2013 by Cubist Pharmaceuticals (NASDAQ: CBST) for $818 million.

Cidara’s lead candidate, biafungin (SP3025), was acquired from Seachaid Pharmaceuticals for $6 million. Biafungin’s half-life is much longer than that of similar drugs known as echinocandins (e.g., caspofungin, micafungin, anidulafungin), which may allow it to be developed as a once-weekly therapy, instead of once daily. The company is also developing a topical formulation of biafungin, namely topifungin. Cidara intends to file an IND and initiate a Phase I clinical trial in the second half of 2015.

Merck’s Cancidas (caspofungin), launched in 2001, was the first of approved enchinocandins. The drug generated annual sales of $596 million in 2008. The approved echinocandins must be administered daily by intravenous infusion. Biafungin with improved pharmacokinetic characteristics has the potential to bring in hundreds of millions of dollars per year.

[1] Nat Biotechnol. 2015, 33(1), 18.

CLIP

Biafungin is a potent and broad-spectrum antifungal agent with excellent activity against wild-type and troublesome azole- and echinocandin-resistant strains of Candida spp. The activity of biafungin is comparable to anidulafungin. • Biafungin was active against both wild-type and itraconazole-resistant strains of Aspergillus spp. from four different species. • In vitro susceptibility testing of biafungin against isolates of Candida and Aspergillus may be accomplished by either CLSI or EUCAST broth microdilution methods each providing comparable results. • The use of long-acting intravenous antifungal agents that could safely be given once a week to select patients is desirable and might decrease costs with long-term hospitalizations. Background: A novel echinocandin, biafungin, displaying long-acting pharmacokinetics and chemical stability is being developed for once-weekly administration. The activities of biafungin and comparator agents were tested against 173 fungal isolates of the most clinically common species. Methods: 106 CAN and 67 ASP were tested using CLSI and EUCAST reference broth microdilution methods against biafungin (50% inhibition) and comparators. Isolates included 27 echinocandin-resistant CAN (4 species) with identified fks hotspot (HS) mutations and 20 azole nonsusceptible ASP (4 species). Results: Against C. albicans, C. glabrata and C. tropicalis, the activity of biafungin (MIC50, 0.06, 0.12 and 0.03 μg/ml, respectively by CLSI method) was comparable to anidulafungin (AND; MIC50, 0.03, 0.12 and 0.03 μg/ml, respectively) and caspofungin (CSP; MIC50, 0.12, 0.25 and 0.12 μg/ml, respectively; Table). C. krusei strains were very susceptible to biafungin, showing MIC90 values of 0.06 μg/ml by both methods. Biafungin (MIC50/90, 1/2 μg/ml) was comparable to AND and less potent than CSP against C. parapsilosis using CLSI methodology. CLSI and EUCAST methods displayed similar results for most species, but biafungin (MIC50, 0.06 μg/ml) was eight-fold more active than CSP (MIC50, 0.5 μg/ml) against C. glabrata using the EUCAST method. Overall, biafungin was two- to four-fold more active against fks HS mutants than CSP and results were comparable to AND. Biafungin was active against A. fumigatus (MEC50/90, ≤0.008/0.015 μg/ml), A. terreus (MEC50/90, 0.015/0.015 μg/ml), A. niger (MEC50/90, ≤0.008/0.03 μg/ml) and A. flavus (MEC50/90, ≤0.008/≤0.008 μg/ml) using CLSI method. EUCAST results for ASP were also low for all echinocandins and comparable to CLSI results. Conclusions: Biafungin displayed comparable in vitro activity with other echinocandins against common wild-type CAN and ASP and resistant subsets that in combination with the long-acting profile warrants further development of this compound. 1. Arendrup MC, Cuenca-Estrella M, Lass-Florl C, Hope WW (2013). Breakpoints for antifungal agents: An update from EUCAST focussing on echinocandins against Candida spp. and triazoles against Aspergillus spp. Drug Resist Updat 16: 81-95. 2. Castanheira M, Woosley LN, Messer SA, Diekema DJ, Jones RN, Pfaller MA (2014). Frequency of fks mutations among Candida glabrata isolates from a 10-year global collection of bloodstream infection isolates. Antimicrob Agents Chemother 58: 577-580. 3. Clinical and Laboratory Standards Institute (2008). M27-A3. Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts: third edition. Wayne, PA: CLSI. 4. Clinical and Laboratory Standards Institute (2008). M38-A2. Reference Method for Broth Dilution Antifungal Susceptibility Testing of Filamentous Fungi: Second Edition. Wayne, PA: CLSI. 5. Clinical and Laboratory Standards Institute (2012). M27-S4. Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts: 4th Informational Supplement. Wayne, PA: CLSI. 6. European Committee on Antimicrobial Susceptibility Testing (2014). Breakpoint tables for interpretation of MICs and zone diameters. Version 4.0, January 2014. Available at: http://www.eucast.org/clinical_breakpoints/. Accessed January 1, 2014. 7. Pfaller MA, Diekema DJ (2010). Epidemiology of invasive mycoses in North America. Crit Rev Microbiol 36: 1-53. 8. Pfaller MA, Diekema DJ, Andes D, Arendrup MC, Brown SD, Lockhart SR, Motyl M, Perlin DS (2011). Clinical breakpoints for the echinocandins and Candida revisited: Integration of molecular, clinical, and microbiological data to arrive at species-specific interpretive criteria. Drug Resist Updat 14: 164-176. ABSTRACT Activity of a Novel Echinocandin Biafungin (CD101) Tested against Most Common Candida and Aspergillus Species, Including Echinocandin- and Azole-resistant Strains M CASTANHEIRA, SA MESSER, PR RHOMBERG, RN JONES, MA PFALLER JMI Laboratories, North Liberty, Iowa, USA C

PATENT

https://www.google.com/patents/WO2015035102A2?cl=en

BIAFUNGIN ACETATE IS USED AS STARTING MATERIAL

Example 30b: Synthesis of Compound 31

Step a. Nitration of Biafungin Acetate

To a stirring solution of biafungin (1 00 mg, 0.078 mmol) in glacial acetic acid(1 .5 ml_) was added sodium nitrite (1 1 mg, 0.159 mmol) and the reaction was stirred at ambient temperature for 20 hours. The mixture was applied directly to reversed phase H PLC (Isco CombiFlash Rf; 50g RediSep C1 8 column, 5 to 95% acetonitrile in Dl water containing 0.1 % formic acid: 15 minute gradient). The pure fractions were pooled and lyophilized to yield 85 mg of the desired product as a light yellow solid, formate salt. ¹ H-NMR (300 M Hz, Methanol-d4) δ 8.58 (d, 1 H, J = 1 1 .7 Hz), 8.47 (t, 2H, J = 8.7Hz), 8.05 (d, 1 H, J = 2.1 Hz), 7.99 (d, 2H, J = 9.3 Hz), 7.82 (d, 2H, J = 8.7 Hz), 7.79-7.60 (m, 12H), 7.1 7 (d, 1 H, J = 8.7 Hz), 7.03 (d, 2H, J = 9 Hz), 5.48 (d, 1 H, J = 6 Hz), 5.08 (dd, 1 H, J = 1 .2, 5.7 Hz), 4.95-4.73 (m, 5H), 4.68-4.56 (m, 2H), 4.53 (d, 1 H, J = 5.7 Hz), 4.48-4.39 (m, 2H), 4.31 -3.79 (m, 6H), 4.04 (t, 2H, J = 5.7 Hz), 3.72-3.44 (m,3H), 3.1 8 (s, 9H), 2.60-1 .99 (m, 5H), 1 .83 (m, 2H, J = 8.7 Hz), 1 .56-1 .35 (m, 5H), 1 .28 (d, 6H, J = 4.2 Hz), 1 .09 (d, 3H, J = 1 0.2 Hz), 0.99 (t, 3H, J = 8.7 Hz) ; LC/MS, [M/2+H]+: 635.79, 635.80 calculated.

Step b. Reduction of Nitro-Biafungin To Amino-Biafungin

To a stirring solution of Nitro-Biafungin (1 00 mg, 0.075 mmol) in glacial acetic acid(1 .5 ml_) was added zinc powder (50 mg, 0.77 mmol) and the reaction was stirred at ambient temperature for 1 hour. The mixture was filtered and applied directly to reversed phase HPLC (Isco CombiFlash Rf, 50g Redisep C18 column; 5 to 95% acetonitrile in Dl water containing 0.1 % formic acid: 15 minute gradient). The pure fractions were pooled and lyophilized to yield 55 mg of the desired product as a white solid, formate salt. ¹ H-NMR (300 MHz, Methanol-d4) 5 8.47 (bs, 1 H), 7.99 (d, 2H, J = 1 0.8Hz), 7.82 (d, 2H, J = 7.5 Hz), 7.80-7.67 (m, 6H), 7.62 (d, 2H, J = 8.7 Hz), 7.03 (d, 2H, J = 7.5 Hz), 6.77 (d, 1 H, J = 1 .9 Hz), 6.68 (d, 1 H, J = 8.2 Hz), 6.55 (dd, 2H, J = 8.2, 1 .9 Hz), 5.43 (d, 1 H, J = 2.5 Hz), 5.05 (d, 1 H, J = 3 Hz), 4.83-4.73 (m, 2H), 4.64- 4.56 (m, 2H), 4.43-4.34 (m, 2H), 4.31 -4.15 (m, 4H), 4.03-4.08 (m, 1 H), 4.1 1 -3.89 (m, 8H), 3.83 (d, 1 H, J = 1 0.8 Hz), 3.68-3.47 (m, 3H), 3.1 7 (s, 9H), 2.57-2.42 (m, 2H), 2.35-2.27 (m, 1 H), 2.14-1 .98 (m, 2H), 1 .83 (m, 2H, J = 6 Hz), 1 .56-1 .38 (m, 4H), 1 .28 (dd, 6H, J = 6.5, 2 Hz), 1 .09 (d, 3H, J = 7 Hz), 0.986 (t, 3H, J = 7 Hz); High Res LC/MS: [M+H]+ 1241 .61 63; 1241 .6136 calculated.

Step c. Reaction of Amino-Biafungin with lnt-2 to Produce Compound 31

To a stirring solution of Amino-Biafungin (50 mg, 0.04 mmol) in DM F (1 ml_) was added formyl-Met-Leu-Phe- -Ala-OSu (lnt-2) (36 mg, 0.06 mmol) and DI PEA (7 uL, 0.04 mmol). The reaction was stirred at ambient temperature for 1 8 hours. The mixture was applied directly to reversed phase HPLC (Isco CombiFlash Rf; 50g Redisep C1 8 column; 5 to 95% acetonitrile in Dl water containing 0.1 % formic acid: 15 minute gradient). The pure fractions were pooled and lyophilized to yield 26 mg of a white solid as a formate salt. ¹ H-NMR (300 M Hz, Methanol-d4) 5 8.55 (bs, 1 H), 8.44 (t, 1 H, J = 10 Hz), 8.1 8 (d, 1 H, J = 6 Hz), 8.1 1 (s, 1 H), 7.99 (d, 2H, J = 1 0 Hz), 7.84-7.70 (m, 6H), 7.63 (d, 2H, J = 7.8 Hz), 7.32-7.1 9 (m, 6H), 7.03 (d, 4H, J = 9 Hz), 6.87 (d, 1 H, J = 8.1 Hz), 5.44 (d, 1 H, J = 1 0.5 Hz), 5.05 (d, 1 H, J = 4.5 Hz), 4.83-4.74 (m, 2H), 4.66-4.50 (m, 6H), 4.45-4.29 (m, 10H), 4.1 9-3.82 (m, 1 0H), 3.67-3.57 (m, 6H), 3.1 7 (s, 9H), 2.64-2.46 (m, 6 H), 2.14-1 .92 (m, 6H), 1 .84 (m, 4H, J = 6 Hz), 1 .62-1 .40 (m, 8H), 1 .32-1 .22 (m, 6H), 1 .09 (d, 3H, J = 9 Hz), 0.99 (t, 3H, J = 7.5 Hz), 0.88 (m, 6H, J = 6.8 Hz) ; High Res LC/MS, [M/2+H]+ 865.4143, 865.4147 calculated.

REFERENCES

Denning, DW (June 2002). “Echinocandins: a new class of antifungal.”. The Journal of antimicrobial chemotherapy 49 (6): 889–91. doi:10.1093/jac/dkf045. PMID 12039879.
Morris MI, Villmann M (September 2006). “Echinocandins in the management of invasive fungal infections, part 1”. Am J Health Syst Pharm 63 (18): 1693–703.doi:10.2146/ajhp050464.p1. PMID 16960253.
Morris MI, Villmann M (October 2006). “Echinocandins in the management of invasive fungal infections, Part 2”. Am J Health Syst Pharm 63 (19): 1813–20.doi:10.2146/ajhp050464.p2. PMID 16990627.
^ Jump up to:^a ^b “Pharmacotherapy Update – New Antifungal Agents: Additions to the Existing Armamentarium (Part 1)”.
Debono, M; Gordee, RS (1994). “Antibiotics that inhibit fungal cell wall development”.Annu Rev Microbiol 48: 471–497. doi:10.1146/annurev.mi.48.100194.002351.

17 Eschenauer, G; Depestel, DD; Carver, PL (March 2007). “Comparison of echinocandin antifungals.”. Therapeutics and clinical risk management 3 (1): 71–97. PMC 1936290.PMID 18360617.

///////////Biafungin™, CD 101 IV, CD 101 Topical, CD101, SP 3025, PHASE 2, CIDARA, Orphan Drug, Fast Track Designation, Seachaid Pharmaceuticals, Qualified Infectious Disease Product, QIDP, UNII-G013B5478J, 1396640-59-7, 1631754-41-0, Vulvovaginal candidiasis, Echinocandin B, FUNGIN

FREE FORM

CCCCCOc1ccc(cc1)c2ccc(cc2)c3ccc(cc3)C(=O)N[C@H]4C[C@@H](O)[C@H](NC(=O)[C@@H]5[C@@H](O)[C@@H](C)CN5C(=O)[C@@H](NC(=O)C(NC(=O)[C@@H]6C[C@@H](O)CN6C(=O)C(NC4=O)[C@@H](C)O)[C@H](O)[C@@H](O)c7ccc(O)cc7)[C@@H](C)O)OCC[N+](C)(C)C

AND OF ACETATE

CCCCCOc1ccc(cc1)c2ccc(cc2)c3ccc(cc3)C(=O)N[C@H]4C[C@@H](O)[C@H](NC(=O)[C@@H]5[C@@H](O)[C@@H](C)CN5C(=O)[C@@H](NC(=O)C(NC(=O)[C@@H]6C[C@@H](O)CN6C(=O)[C@@H](NC4=O)[C@@H](C)O)[C@H](O)[C@@H](O)c7ccc(O)cc7)[C@@H](C)O)OCC[N+](C)(C)C.CC(=O)[O-]

Three antifungal drugs approved by the United States Food and Drug Administration, caspofungin, anidulafungin, and micafungin, are known to inhibit β-1 ,3-glucan synthase which have the structures shown below.

caspofungin

Anidulafungin

Other exemplary p-1 ,3-glucan synthase inhibitors include,

echinocandin B

cilofungin

pneumocandin A₀

pneumocandin B₀

L-705589

L-733560

A-174591

or a salt thereof,

Biafungin

or a salt thereof,

Amino-biafungin

or a salt thereof,

Amino-AF-053

ASP9726

Yet other exemplary p-1 ,3-glucan synthase inhibitors include, without limitation:

Papulacandin B

Ergokonin

//////////////

Pexidartinib

orphan status, Phase 3 drug, Uncategorized Comments Off

Jun 102016

Pexidartinib

PLX-3397

5-((5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl)-N-((6-(trifluoromethyl)pyridin-3-yl)methyl)pyridin-2-amine

N-[5-[(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]-2-pyridinyl]-6-(trifluoromethyl)-3-pyridinemethanamine

A Multi-targeted tyrosine kinase inhibitor potentially for the treatment of tenosynovial giant cell tumor (TGCT).


CAS No.:	1029044-16-3
Mol. Formula:	C20H15ClF3N5
Mol. Weight:	417.81

Pexidartinib; 1029044-16-3; PLX-3397; 5-((5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl)-N-((6-(trifluoromethyl)pyridin-3-yl)methyl)pyridin-2-amine; 5-[(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]-N-[[6-(trifluoromethyl)pyridin-3-yl]methyl]pyridin-2-amine; 5-[(5-Chloro-1h-Pyrrolo[2,3-B]pyridin-3-Yl)methyl]-N-{[6-(Trifluoromethyl)pyridin-3-Yl]methyl}pyridin-2-Amine;
Originator Plexxikon
Developer Barbara Ann Karmanos Cancer Institute; Columbia University; Merck & Co; National Cancer Institute (USA); Plexxikon; University of California at San Francisco
Class 2 ring heterocyclic compounds; Antineoplastics; Fluorine compounds; Pyridines; Pyrroles; Small molecules
Mechanism of Action Fms-like tyrosine kinase 3 inhibitors; Immunomodulators; Macrophage colony stimulating factor receptor antagonists; Proto oncogene protein c-akt inhibitors; Proto oncogene protein c-kit inhibitors

Orphan Drug Status Yes – Giant cell tumour of tendon sheath; Pigmented villonodular synovitis

Phase III Pigmented villonodular synovitis
Phase II Glioblastoma; Malignant melanoma; Prostate cancer
Phase I/II Breast cancer; Leukaemia; Peripheral nervous system diseases; Sarcoma; Solid tumours
Phase I Gastrointestinal stromal tumours
No development reported Neurological disorders; Rheumatoid arthritis
Discontinued Acute myeloid leukaemia; Hodgkin’s disease

Most Recent Events

25 May 2016 Plexxikon and AstraZeneca plan the MEDIPLEX phase I trial for Solid tumours (Combination therapy, Metastatic disease) in France (NCT02777710)
05 Apr 2016 Daiichi Sankyo plans a phase I trial for Solid tumours (Late-stage disease, Second-line therapy or greater) in Taiwan (PO) (NCT02734433)
11 Mar 2016 Plexxikon re-initiates enrolment in a phase Ib trial in Solid tumours and Gastrointestinal stromal tumours in USA (NCT02401815)

Multi-targeted receptor tyrosine kinase inhibitor of CSF1R, c-Kit, and FLT3 (IC50 values 13 nM, 27 nM, and 11 nM, respectively) Administration of PLX3397 reduced CIBP, induced substantial intratumoral fibrosis, and was also highly efficacious in reducing tumor cell growth, formation of new tumor colonies in bone, and pathological tumor-induced bone remodeling. PLX3397 is superior to imatinib in the treatment of malignant peripheral nerve sheath tumor (MPNST), and the combination of PLX3397 with a TORC1 inhibitor could provide a new therapeutic approach for the treatment of this disease.

Plexxikon is conducting phase III clinical studies with PLX-3397 for the treatment of pigmented villonodular synovitis. Phase II clinical studies are ongoing for the oral treatment of melanoma and glioblastoma multiforme. Additional early clinical trials are underway for the treatment of metastatic breast cancer, for the treatment of prostate cancer (adenocarcinoma), and for the treatment of malignant peripheral nerve sheath tumor. No recent development has been reported from preclinical studies for the treatment of systemic lupus erythematosus and for the treatment of multiple sclerosis. Prior to patient enrollment, a phase I clinical trial by Plexxikon for the treatment of rheumatoid arthritis was withdrawn. Daiichi Sankyo (parent of Plexxikon) decided to discontinue phase II trials of the product for the treatment of castration-resistant prostate cancer and for the treatment of Hodgkin’s lymphoma after reviewing its clinical study results and also have discontinued phase II studies for the treatment of acute myeloid leukemia due to strategic reasons.

In 2014, orphan drug designation was assigned to the compound in the US for the treatment of pigmented villonodular synovitis andf giant cell tumor of the tendon sheath. In 2015, the compound was granted orphan designation in the E.U. for the treatment of tenosynovial giant cell tumor, localised and diffuse type. In the same year, the product was granted breakthrough therapy designation for the treatment of tenosynovial giant cell tumor (TGCT) where surgical removal of the tumor would be associated with potentially worsening functional limitation or severe morbidity.

C-fms and c-kit arc both type III transmembrane receptor protein tyrosine kinases (RPTKs) that regulate key signal transduction cascades that control cellular growth and proliferation. Both receptors have similar structural features comprising five extracellular immunoglobulin (IG) domains, a single transmembrane domain, and a split cytoplasmic kinase domain separated by a kinase insert segment.

c-Fms
C-fms is a member of the family of genes originally isolated from the Susan McDonough strain ot teline sarcoma viruses, The cellular proto-oncogene FMS (c-fms, cellular feline McDonough sarcoma) codes for the receptor for the macrophage colony-stimuktmg tactor (M- CSF) C-fms is crucial for the growth and differentiation of the monocyte-macrophage lineage, and upon binding of Vf-CSF to the extracellular domain of c-fms, the receptor dimeπzes and trans- autophosphorylates cytoplasmic tyrosine residues

M-CSF, first described by Robinson and co-workers (Blood 1969, 33 396-9), is a cytokine that controls the production, differentiation, and function of macrophages M-CSF stimulates differentiation of progenitor cells to mature monocytes, and prolongs the survival of monocytes Furthermore, M-CSF enhances cytotoxicity, superoxide production, phagocytosis, chemota\is, and secondary cytokine production of additional factors in monocytes and macrophages Examples of such additional factors include granulocyte colony stimulating lactor (G-CSF) interleukin-6 (IL-6), and mterleukm-8 (IL-8) M-CSF stimulates hematopoiesis, promotes differentiation and proliferation of osteoclast progenitor cells, and has profound effects on lipid metabolism Furthermore, M-CSF is important in pregnancy Physiologically, large amounts of M-CSF are produced in the placenta, and M-CSF is believed to play an essential role in trophoblast differentiation (Motoyoshi, lnt J Hematol 1998, 67 109-22) l hc elevated semm levels of M-CSF m early pregnancy may participate in the immunologic mechanisms responsible for the maintenance of the pregnancy (Flanagan & Lader, Curr Opm Hematol 1998, 5 181-5)

Related to c-fms and c-kit are two p_latelet -derived growth factor receptors, alpha (i e , pdgfra) and beta (pdgfrb) (PDGF) 1 he gene coding for pdgfra is located on chromosome 4ql 1 -q!2 in the same region of chromosome 4 as the oncogene coding for c-kit The genes coding for pdgfra and c-fms appear to have evolved from a common ancestral gene by gene duplication, inasmuch as these two genes are tandemly linked on chromosome 5 They are oriented head to tail with the 5-pnme exon of the c-fms gene located only 500 bp from the last 3-pπme exon of the gene coding for pdgfra Most gastrointestinal stromal tumors (GIST) have activating mutations in c-kit and most patients with GISTs respond well to Gleevec, which inhibits c-kit Hemπch et al (Science 2003, 299 “OS-IO) have shown that approximately 35% of GISTs lacking c-krt mutations, have intragenic activation mutations m tht gene encoding pdgfra, and that tumors expressing c-kit or pdgfrd are indistinguishable with respect to activation of downstream signaling intermediates and cytogenetic changes associated with tumor progression Thus, c kit and pdgfra mutations appear to be alternative and mutually exclusive oncogenic mechanisms m GISTs [0007} Similarly, the observation that production of M-CSF, the major macrophage growth factor, is increased in tissues during inflammation points out a role for c-frns in diseases, such as for example inflammatory diseases. More particularly, because elevated levels of M-CSF are found in the disease state, modulation of the activity of c-fms can ameliorate disease associated with increased levels of M-CSF.

c-Kit
The Stem Cell Factor (SCF) receptor c-kit plays an important role in the development of melanocytes and mast, germ and hematopoietic cells. Stem Cell Factor (SCF) is a protein encoded by the Sl locus, and has also been called “kit ligand” (KL) and mast cell growth factor (MGF), based on the biological properties used to identify it (reviewed in Tsujimura, Pathol Int 1996, 46:933-938; Loveland, et al., J. Endocrinol 1997, 153:337-344; Vliagoftis, et al,, Clin Immunol 1997, 100:435-440; Broudy, Blood 1997, 90: 1345-1364; Pignon, Hermatol Cell Ther 1997, 39: 1 14-1 16; and Lyman, et al., Blood 1998, 91 : 1 101 -1 134.). Herein the abbreviation SCF refers to the physiological ligand for c-kit.

SCF is synthesized as a transmembrane protein with a molecular weight of 220 or 248 Dalton, depending on alternative splicing of the mRNA to encode exon 6. The larger protein can be proteolytically cleaved to form, a soluble, glycosylated protein which noncovalently dimerizcs. Both the soluble and membrane-bound forms of SCF can bind to and activate c-kit. For example, in the skin, SCF is predominantly expressed by fibroblasts, keratinocytes, and endothelial cells, which modulate the activity of melanocytes and mast cells expressing c-kit. In bone, marrow stromal cells express SCF and regulate hematopoiesis of c-kit expressing stem cells. In the gastrointestinal tract, intestinal epithelial cells express SCF and affect the interstitial cells of Cajal and intraepithelial lymphocytes. In the testis, Sertoli cells and granulosa cells express SCF which regulates spermatogenesis by interaction with c-kit on germ cells.

PATENT

WO 2008063888

PATENT

WO 2008064265

PATENT

WO 2008064255

PATENT

WO 2012158957

Fragments in the clinic: PLX3397

Practical Fragments covers a wide variety of journals. J. Med. Chem., Bioorg. Med. Chem. Lett., Drug Disc. Today, and ACS Med. Chem. Lett. are all well-represented, but we also range further afield, from biggies such asNature and Science to more niche titles such as ChemMedChem, Acta. Cryst. D., and Anal. Chim. Acta. The increasingly clinical relevance of fragment-based approaches is highlighted by a recent paper by William Tap and a large group of collaborators appearing in the New England Journal of Medicine. This reports on the results of the Daiichi Sankyo (née Plexxikon) drug PLX3397 in a phase I trial for tenosynovial giant-cell tumor, a rare but aggressive cancer of the tendon sheath.

The story actually starts with a 2013 paper by Chao Zhang and his Plexxikon colleagues in Proc. Nat. Acad. Sci. USA. The researchers were interested in inhibiting the enzymes CSF1R (or FMS) and KIT; both kinases are implicated in cancer as well as inflammatory diseases. The team started with 7-azaindole, the same fragment they used to discover vemurafenib. Structural studies of an early derivative, PLX070, revealed a hydrogen bond between the ligand oxygen and a conserved backbone amide. Further building led to PLX647, with good activity against both CSF1R and KIT. Selectivity profiling against a panel of 400 kinases revealed only two others with IC₅₀values < 0.3 µM. The molecule was active in cell-based assays, had good pharmacokinetics in mice and rats, and was active in rodent models of inflammatory disease.

The new paper focuses on the results of a clinical trial with PLX3397, a derivative of PLX647. Despite its close structural similarity to PLX647, it binds to CSF1R in a slightly different manner. Both inhibitors bind to the inactive form of the kinase, but PLX3397 also recruits the so-called juxtamembrane domain of the kinase to stabilize this autoinhibited conformation. Pharmacokinetic and pharmacodynamics studies in animals were also positive.

http://practicalfragments.blogspot.in/2015/10/fragments-in-clinic-plx3397.html

Tenosynovial giant-cell tumor seems to be dependent on CSF1R, so the researchers performed a phase 1 dose-escalation study with an extension in which patients treated with the chosen phase 2 dose were treated longer. Of the 23 patients in this extension, 12 had a partial response and 7 had stable disease. A quick search ofclinicaltrials.gov reveals that PLX3397 is currently in multiple trials for several indications, including a phase 3 trial for giant cell tumor of the tendon sheath.

Several lessons can be drawn from these studies. First, as the authors note, one fragment can give rise to multiple different clinical candidates. Indeed, in addition to vemurafenib, 7-azaindole was also the starting point forAZD5363. This is a good counterargument to those who believe that novelty is essential in fragments.

A second, related point is that selectivity is also not necessary for a fragment. The fact that 7-azaindole comes up so frequently as a kinase-binding fragment has not prevented researchers from growing it into remarkably selective inhibitors. An obvious corollary is that even subtle changes to a molecule can have dramatic effects: the added pyridyl nitrogen in PLX3397 is essential for stabilizing a unique conformation of the enzyme.

Patent ID	Date	Patent Title
US2015265586	2015-09-24	COMPOUNDS MODULATING C-FMS AND/OR C-KIT ACTIVITY AND USES THEREFOR
US2014243365	2014-08-28	COMPOUNDS MODULATING C-FMS AND/OR C-KIT ACTIVITY AND USES THEREFOR
US8722702	2014-05-13	Compounds modulating c-fms and/or c-kit activity and uses therefor
US2014045840	2014-02-13	COMPOUNDS AND METHODS FOR KINASE MODULATION, AND INDICATIONS THEREFOR
US2013274259	2013-10-17	KINASE MODULATION AND INDICATIONS THEREFOR
US8404700	2013-03-26	Compounds modulating c-fms and/or c-kit activity and uses therefor
US2011230482	2011-09-22	COMPOUNDS MODULATING C-FMS AND/OR C-KIT ACTIVITY
US7893075	2011-02-22	Compounds modulating c-fms and/or c-kit activity and uses therefor

//////1029044-16-3, Pexidartinib , PLX-3397, PHASE3

FC(F)(F)c1ccc(cn1)CNc2ccc(cn2)Cc4cnc3ncc(Cl)cc34

Start of the Euro 2016

Karyopharm Announces Initiation of Phase 2 Study of Selinexor (KPT-330) an orphan drug

orphan status, phase 2 1 Response »

Jun 102014

2D chemical structure of 1393477-72-9

Selinexor (KPT-330)

1393477-72-9

Karyopharm Therapeutics, Inc.

WO2011109799A1

WO2013019548A1

C17-H11-F6-N7-O

443.3099

Synonyms

(Z)-3-(3-(3,5-Bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-N’-(pyrazin-2-yl)acrylohydrazide
2-Propenoic acid, 3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-, 2-(2-pyrazinyl)hydrazide, (2Z)-
3-[3-[3,5-Bis(trifluoromethyl)phenyl]-1H-1,2,4-triazol-1-yl]-N’-(pyrazin-2-yl)acrylohydrazide

KPT-330
Selinexor

Karyopharm Announces Initiation of Phase 2 Study of Selinexor (KPT-330) in Patients with …

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“These patients were treated in our Phase 1 clinical trial of Selinexor in … Additional Phase 1 and Phase 2 studies are ongoing or currently planned and … the discovery and development of novel first-in-class drugs directed against …

Selinexor, a Exportin-1 (CRM1/XPO1) agonist, is in phase II clinical trials at Karyopharm for the treatment of advanced or metastatic gynecological malignancies (cervical, ovarian and uterine carcinomas) and recurrent glioblastomas. The company is also evaluating the compound in early clinical trials for the treatment of advanced solid tumors, hematological cancer (non-Hodgkin’s lymphoma, multiple myeloma and Waldenstrom’s macroglobulinemia), soft tissue or bone sarcoma, relapsed or refractory acute myeloid leukemia (AML) and relapsed or refractory acute lymphoblastic leukemia (ALL).

In 2014, orphan drug designation was assigned in U.S. for the treatment of acute myeloid leukemia and diffuse large B-cell lymphoma

Cells from most major human solid and hematologic malignancies exhibit abnormal cellular localization of a variety of oncogenic proteins, tumor suppressor proteins, and cell cycle regulators (Cronshaw et al. 2004, Falini et al 2006). For example, certain p53 mutations lead to localization in the cytoplasm rather than in the nucleus. This results in the loss of normal growth regulation, despite intact tumor suppressor function. In other tumors, wild-type p53 is sequestered in the cytoplasm or rapidly degraded, again leading to loss of its suppressor function. Restoration of appropriate nuclear localization of functional p53 protein can normalize some properties of neoplastic cells (Cai et al. 2008; Hoshino et al. 2008; Lain et al. 1999a; Lain et al. 1999b; Smart et al. 1999), can restore sensitivity of cancer cells to DNA damaging agents (Cai et al. 2008), and can lead to regression of established tumors (Sharpless & DePinho 2007, Xue et al. 2007). Similar data have been obtained for other tumor suppressor proteins such as forkhead (Turner and Sullivan 2008) and c-Abl (Vignari and Wang 2001). In addition, abnormal localization of several tumor suppressor and growth regulatory proteins may be involved in the pathogenesis of autoimmune diseases (Davis 2007, Nakahara 2009). CRMl inhibition may provide particularly interesting utility in familial cancer syndromes (e.g. , Li-Fraumeni Syndrome due to loss of one p53 allele,

BRCA1 or 2 cancer syndromes), where specific tumor suppressor proteins (TSP) are deleted or dysfunctional and where increasing TSP levels by systemic (or local) administration of CRMl inhibitors could help restore normal tumor suppressor function. Specific proteins and R As are carried into and out of the nucleus by specialized transport molecules, which are classified as importins if they transport molecules into the nucleus, and exportins if they transport molecules out of the nucleus (Terry et al. 2007;

Sorokin et al. 2007). Proteins that are transported into or out of the nucleus contain nuclear import/localization (NLS) or export (NES) sequences that allow them to interact with the relevant transporters. Chromosomal Region Maintenance 1 (Crml or CRM1), which is also called exportin-1 or Xpol, is a major exportin.

Overexpression of Crml has been reported in several tumors, including human ovarian cancer (Noske et al. 2008), cervical cancer (van der Watt et al. 2009), pancreatic cancer (Huang et al. 2009), hepatocellular carcinoma (Pascale et al. 2005) and osteosarcoma (Yao et al. 2009) and is independently correlated with poor clinical outcomes in these tumor types.

Inhibition of Crml blocks the exodus of tumor suppressor proteins and/or growth regulators such as p53, c-Abl, p21, p27, pRB, BRCA1, IkB, ICp27, E2F4, KLF5, YAP1, ZAP, KLF5, HDAC4, HDAC5 or forkhead proteins (e.g., FOX03a) from the nucleus that are associated with gene expression, cell proliferation, angiogenesis and epigenetics. Crml inhibitors have been shown to induce apoptosis in cancer cells even in the presence of activating oncogenic or growth stimulating signals, while sparing normal (untransformed) cells. Most studies of Crml inhibition have utilized the natural product Crml inhibitor Leptomycin B (LMB). LMB itself is highly toxic to neoplastic cells, but poorly tolerated with marked gastrointestinal toxicity in animals (Roberts et al. 1986) and humans (Newlands et al. 1996). Derivatization of LMB to improve drug-like properties leads to compounds that retain antitumor activity and are better tolerated in animal tumor models (Yang et al. 2007, Yang et al. 2008, Mutka et al. 2009). Therefore, nuclear export inhibitors could have beneficial effects in neoplastic and other proliferative disorders.

In addition to tumor suppressor proteins, Crml also exports several key proteins that are involved in many inflammatory processes. These include IkB, NF-kB, Cox-2, RXRa, Commdl, HIFl, HMGBl, FOXO, FOXP and others. The nuclear factor kappa B (NF-kB/rel) family of transcriptional activators, named for the discovery that it drives immunoglobulin kappa gene expression, regulate the mRNA expression of variety of genes involved in inflammation, proliferation, immunity and cell survival. Under basal conditions, a protein inhibitor of NF-kB, called IkB, binds to NF-kB in the nucleus and the complex IkB-NF-kB renders the NF-kB transcriptional function inactive. In response to inflammatory stimuli, IkB dissociates from the IkB-NF-kB complex, which releases NF-kB and unmasks its potent transcriptional activity. Many signals that activate NF-kB do so by targeting IkB for proteolysis (phosphorylation of IkB renders it “marked” for ubiquitination and then proteolysis). The nuclear IkBa-NF-kB complex can be exported to the cytoplasm by Crml where it dissociates and NF-kB can be reactivated. Ubiquitinated IkB may also dissociate from the NF-kB complex, restoring NF-kB transcriptional activity. Inhibition of Crml induced export in human neutrophils and macrophage like cells (U937) by LMB not only results in accumulation of transcriptionally inactive, nuclear IkBa-NF-kB complex but also prevents the initial activation of NF-kB even upon cell stimulation (Ghosh 2008, Huang 2000). In a different study, treatment with LMB inhibited IL-Ιβ induced NF-kB DNA binding (the first step in NF-kB transcriptional activation), IL-8 expression and intercellular adhesion molecule expression in pulmonary microvascular endothelial cells (Walsh 2008). COMMDl is another nuclear inhibitor of both NF-kB and hypoxia-inducible factor 1 (HIFl) transcriptional activity. Blocking the nuclear export of COMMDl by inhibiting Crml results in increased inhibition of NF-kB and HIFl transcriptional activity (Muller 2009).

Crml also mediates retinoid X receptor a (RXRa) transport. RXRa is highly expressed in the liver and plays a central role in regulating bile acid, cholesterol, fatty acid, steroid and xenobiotic metabolism and homeostasis. During liver inflammation, nuclear RXRa levels are significantly reduced, mainly due to inflammation-mediated nuclear export of RXRa by Crml . LMB is able to prevent IL-Ιβ induced cytoplasmic increase in RXRa levels in human liver derived cells (Zimmerman 2006).

The role of Crml -mediated nuclear export in NF-kB, HIF-1 and RXRa signalling suggests that blocking nuclear export can be potentially beneficial in many inflammatory processes across multiple tissues and organs including the vasculature (vasculitis, arteritis, polymyalgia rheumatic, atherosclerosis), dermatologic (see below), rheumatologic

(rheumatoid and related arthritis, psoriatic arthritis, spondyloarthropathies, crystal arthropathies, systemic lupus erythematosus, mixed connective tissue disease, myositis syndromes, dermatomyositis, inclusion body myositis, undifferentiated connective tissue disease, Sjogren’s syndrome, scleroderma and overlap syndromes, etc.).

CRM1 inhibition affects gene expression by inhibiting/activating a series of transcription factors like ICp27, E2F4, KLF5, YAP1, and ZAP.

Crml inhibition has potential therapeutic effects across many dermatologic syndromes including inflammatory dermatoses (atopy, allergic dermatitis, chemical dermatitis, psoriasis), sun-damage (ultraviolet (UV) damage), and infections. CRMl inhibition, best studied with LMB, showed minimal effects on normal keratinocytes, and exerted anti-inflammatory activity on keratinocytes subjected to UV, TNFa, or other inflammatory stimuli (Kobayashi & Shinkai 2005, Kannan & Jaiswal 2006). Crml inhibition also upregulates NRF2 (nuclear factor erythroid-related factor 2) activity, which protects keratinocytes (Schafer et al. 2010, Kannan & Jaiswal 2006) and other cell types (Wang et al. 2009) from oxidative damage. LMB induces apoptosis in keratinocytes infected with oncogenic human papillomavirus (HPV) strains such as HPV 16, but not in uninfected keratinocytes (Jolly et al. 2009).

Crml also mediates the transport of key neuroprotectant proteins that may be useful in neurodegenerative diseases including Parkinson’s disease (PD), Alzheimer’s disease, and amyotrophic lateral sclerosis (ALS). For example, by (1) forcing nuclear retention of key neuroprotective regulators such as NRF2 (Wang 2009), FOXA2 (Kittappa et al. 2007), parking in neuronal cells, and/or (2) inhibiting NFKB transcriptional activity by sequestering IKB to the nucleus in glial cells, Crml inhibition could slow or prevent neuronal cell death found in these disorders. There is also evidence linking abnormal glial cell proliferation to abnormalities in CRMl levels or CRMl function (Shen 2008).

Intact nuclear export, primarily mediated through CRMl, is also required for the intact maturation of many viruses. Viruses where nuclear export, and/or CRMl itself, has been implicated in their lifecycle include human immunodeficiency virus (HIV), adenovirus, simian retrovirus type 1, Borna disease virus, influenza (usual strains as well as H1N1 and avian H5N1 strains), hepatitis B (HBV) and C (HCV) viruses, human papillomavirus (HPV), respiratory syncytial virus (RSV), Dungee, Severe Acute Respiratory Syndrome coronavirus, yellow fever virus, West Nile virus, herpes simplex virus (HSV), cytomegalovirus (CMV), and Merkel cell polyomavirus (MCV). (Bhuvanakantham 2010, Cohen 2010, Whittaker 1998). It is anticipated that additional viral infections reliant on intact nuclear export will be uncovered in the future.

The HIV-1 Rev protein, which traffics through nucleolus and shuttles between the nucleus and cytoplasm, facilitates export of unspliced and singly spliced HIV transcripts containing Rev Response Elements (RRE) RNA by the CRMl export pathway. Inhibition of Rev-mediated RNA transport using CRMl inhibitors such as LMBor PKF050-638 can arrest the HIV-1 transcriptional process, inhibit the production of new HIV-1 virions, and thereby reduce HIV-1 levels (Pollard 1998, Daelemans 2002). Dengue virus (DENV) is the causative agent of the common arthropod-borne viral disease, Dengue fever (DF), and its more severe and potentially deadly Dengue hemorrhagic fever (DHF). DHF appears to be the result of an over exuberant inflammatory response to DENV. NS5 is the largest and most conserved protein of DENV. CRMl regulates the transport of NS5 from the nucleus to the cytoplasm, where most of the NS5 functions are mediated. Inhibition of CRMl -mediated export of NS5 results in altered kinetics of virus production and reduces induction of the inflammatory chemokine interleukin-8 (IL-8), presenting a new avenue for the treatment of diseases caused by DENV and other medically important flaviviruses including hepatitis C virus (Rawlinson 2009).

Other virus-encoded RNA-binding proteins that use CRMl to exit the nucleus include the HSV type 1 tegument protein (VP 13/14, or hUL47), human CMV protein pp65, the SARS Coronavirus ORF 3b Protein, and the RSV matrix (M) protein (Williams 2008, Sanchez 2007, Freundt 2009, Ghildyal 2009).

Interestingly, many of these viruses are associated with specific types of human cancer including hepatocellular carcinoma (HCC) due to chronic HBV or HCV infection, cervical cancer due to HPV, and Merkel cell carcinoma associated with MCV. CRMl inhibitors could therefore have beneficial effects on both the viral infectious process as well as on the process of neoplastic transformation due to these viruses.

CRMl controls the nuclear localization and therefore activity of multiple DNA metabolizing enzymes including histone deacetylases (HDAC), histone acetyltransferases (HAT), and histone methyltransferases (HMT). Suppression of cardiomyocyte hypertrophy with irreversible CRMl inhibitors has been demonstrated and is believed to be linked to nuclear retention (and activation) of HDAC 5, an enzyme known to suppress a hypertrophic genetic program (Monovich et al. 2009). Thus, CRMl inhibition may have beneficial effects in hypertrophic syndromes, including certain forms of congestive heart failure and hypertrophic cardiomyopathies.

CRMl has also been linked to other disorders. Leber’s disorder, a hereditary disorder characterized by degeneration of retinal ganglion cells and visual loss, is associated with inaction of the CRMl switch (Gupta N 2008). There is also evidence linking

neurodegenerative disorders to abnormalities in nuclear transport.

…………………………………………

PATENT

http://www.google.com/patents/WO2013019548A1?cl=en

To date, however, small-molecule, drug-like Crml inhibitors for use in vitro and in vivo are uncommon. SUMMARY OF THE INVENTION

The present invention relates to compounds, or pharmaceutically acceptable salts thereof, useful as nuclear transport modulators. The invention also provides

pharmaceutically acceptable compositions comprising compounds of the present invention and methods of using said compounds and compositions in the treatment of various disorders, such as those associated with abnormal cellular responses triggered by improper nuclear transport..

In one embodiment of the invention, the compounds are represented by formula I:

Figure imgf000013_0001

http://www.google.com/patents/WO2013019548A1?cl=en

HERE IT REFERS AS 1-16 READER PLEASE CHECKABOVE AND BELOW FOR ERROR

Figure imgf000101_0001

HERE IT REFERS AS 1-18 READER PLEASE CHECK

http://www.google.com/patents/WO2013019548A1?cl=en

Example 1 : Synthesis of Intermediate (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-lH-l,2,4- triazol-l-yl)acrylic acid.

Synthesis of 3,5-bis(trifluoromethyl)benzothioamid

A 2-L, 3-necked, round-bottomed flask was charged with a solution of 3,5- bis(trifluoromethyl)benzonitrile (200 g) in DMF (1 L). The solution was then treated with NaSH (123.7 g, 2.0 eq.) and MgCl₂ (186.7 g, 1.0 eq.) and the reaction mixture was stirred at RT for 3 hours. The mixture was poured into an ice-water slurry (10 L) and the compound was extracted with EtOAc (3 x 1 L). The combined organic layers were washed with aqueous saturated brine (3 x 100 mL), dried over anhydrous Na₂S0₄, filtered, and concentrated under reduced pressure to afford 205 g of desired crude 3,5- bis(trifluoromethyl)benzothioamide (yield: 90 %), which wasused without purification in the following step.

Synthesi -(3,5-bis(trifluoromethyl)phenyl)-lH-l 2,4-triazole:

A 5-L, 3-necked, round-bottomed flask was charged with a solution of 3,5- bis(trifluoromethyl)benzothioamide (205.65 g) in DMF (1.03 L). Hydrazine hydrate (73.2 mL, 2.0 eq.) was added dropwise and the reaction mixture was stirred at RT for 1 h. HCOOH (1.03 L) was added dropwise and the reaction mixture was refluxed at 90 °C for 3 hours. After being allowed to cool to RT, the reaction mixture was poured into saturated aqueous sodium bicarbonate solution (7 L) and extracted with EtOAc (3 x 1 L). The combined organic layers were washed with aqueous saturated brine (3 x 500 mL), dried over anhydrous Na₂S0₄, filtered, and concentrated under reduced pressure (35 °C, 20 mmHg) to afford 180 g of crude compound. This crude material was stirred with petroleum ether (3 x 500 mL) , filtered and dried to obtain 160 g. of 3-(3,5-bis(trifluoromethyl)phenyl)-lH- 1,2,4-triazole obtained as a pale yellow solid (yield: 75%).

Synthesis of (Z)-isopropyl 3-(3-(3,5-bis(trifluoromethyl)phenyl)-lH-l,2,4-triazol-l- yl)acrylate:

A 2-L, 3-necked, round-bottomed flask was charged with a solution of 3-(3,5- bis(trifluoromethyl)phenyl)-lH-l ,2,4-triazole (160 g) in DMF (960 mL). The solution was treated with DABCO (127.74 g, 2 eq.) and stirred for 30 min before adding (Z)-isopropyl 3- iodoacrylate (150.32 g, 1.1 eq.) dropwise. After ca. 1 hour, the reaction mixture was poured into an ice-water slurry (5 L) and extracted with EtOAc (3 x 1 L). The combined organic layers were washed with aqueous saturated brine (3 x 100 mL), dried over anhydrous Na₂S0₄, filtered, and concentrated under reduced pressure (35 °C, 20 mmHg) to afford 250 g of crude compound that was purified by column chromatography (60/120 silica gel) using a ethyl acetate/n-hexane gradient (the column was packed in hexane and the desired compound started eluting from 2% EtOAC/n-hexane). Fractions containing the desired compounds were combined to afford 138 g the pure desired compound (yield: 61%).

Synthesis of (Z)-3 -(3 -(3 ,5-bis(trifluoromethyl)phenyl)- 1 H- 1 ,2,4-triazol- 1 -yl)acrylic acid:

In a 5-L, 3-necked, round-bottomed flask, (Z)-isopropyl 3-(3-(3,5- bis(trifluoromethyl)phenyl)-lH-l,2,4-triazol-l-yl)acrylate (130 g, 1.0 eq.) was dissolved in THF (1.3 L). A solution of LiOH (69.3 g, 5.0 eq.) in water (1.3 L) was added dropwise to the solution and the reaction mixture was stirred at room temperature for 4 h before being quenched with 400 mL ice-water slurry and made acidic (pH = 2-3) with dilute aqueous HC1. The mixture was extracted with EtOAc (3 x 1 L) and the combined organic layers were washed with brine, dried over anhydrous Na₂S0₄ and concentrated under reduced pressure to afford 110 g of desired carboxylic acid (yield: 94 %) (cis content = 90.0%, trans content = 8.2% by LCMS).

Example 17: Synthesis of (E)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-lH-l,2,4-triazol-l-yl)- ‘-(pyrazin-2-yl)acrylohydrazide

Synthesis of 3,5-bis(trifluoromethyl)benzothioamide:

A 2-L, 3 -necked, round-bottomed flask, charged with a solution of 3,5- bis(trifluoromethyl)benzonitrile (200 g) in DMF (1 L), was treated with NaSH (123.7 g, 2.0 eq.) and MgCl₂ (186.7 g, 1 eq.). The reaction mixture was stirred at RT for 3 h before being poured into an ice-water slurry (10 L) and was extracted with EtOAc (3 x 1 L). The combined organic extracts were washed with brine (3 x 100 niL), dried over anhydrous Na₂S0₄, filtered, and concentrated under reduced pressure (25 °C, 20 mmHg) to afford 205 g of crude compound (yield: 90 %), which was used in the following step without further purification.

Synthesis of 3-(3,5-bis(trifluoromethyl)phenyl)-lH-l,2,4-triazole:

A 5-L, 3-necked, round-bottomed flask, charged with a solution of 3,5- bis(trifluoromethyl)benzothioamide (205.65 g) in DMF (1.03 L) was treated with hydrazine hydrate (73.16 mL, 2.0 eq.) added dropwise. The reaction mixture was stirred at room temperature for 1 h before being treated with HCOOH (1.028 L) added dropwise. The reaction mixture was refluxed at 90°C for 3 h then cooled to room temperature and poured into saturated aqueous NaHC0₃ solution (7 L) and extracted with EtOAc (3 x 1L). The combined organic layers were washed with brine (3 x 500 mL), dried over anhydrous Na₂S0₄, filtered, and concentrated under reduced pressure (35°C, 20 mmHg) to afford 180 g of a solid. The solid was suspended in petroleum ether and the suspension was stirred, filtered and dried to afford the desired triazole as a pale yellow solid (160 g, yield: 75%).

Synthesis of (Z)-isopropyl 3-(3-(3,5-bis(trifluoromethyl)phenyl)-lH-l,2,4-triazol-l- yl)acrylate and (E)-isopropyl 3-(3-(3,5-bis(trifluoromethyl)phenyl)-lH-l,2,4-triazol-l- yl)acrylate:

A 2-L, 3-necked, round-bottomed flask, charged with a solution of 3-(3,5- bis(trifluoromethyl)phenyl)-lH-l,2,4-triazole (160 g,) in DMF (0.96 L, 6V), was treated with DAB CO (127.74 g, 2 eq.) and stirred for 30 min. (Z)-isopropyl 3-iodoacrylate (150.32 g, 1.1 eq.) was added dropwise to the above reaction mixture and stirred for 1 h before being poured into an ice-water slurry (5 L) and extracted with EtOAc (3 x 1 L). The combined organic extracts were washed with brine (3 x 100 mL), dried over anhydrous Na₂S0₄, filtered, and concentrated under reduced pressure (35°C, 20 mmHg) to afford 250 g of crude compound. Purification by column chromatography (Si02, 60/120 mesh, elution with EtOAc:hexanes gradient; the desired compounds started eluting in 2-2.5 % EtOAc in hexanes) afforded pure cis ester (138 g, yield: 61.6%) and pure trans ester (11.6 g, yield: 5.2%). Synthesis of (E)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-lH-l ,2,4-triazol-l-yl);

acid:

A 500-mL, 3 -necked, round-bottomed flask was charged with a solution of (E)- isopropyl 3-(3-(3,5-bis(trifluoromethyl)phenyl)-lH-l ,2,4-triazol-l-yl)acrylate (5.0 g) in THF (50 mL). The solution was treated with a solution of LiOH (2.66 g, 5.0 eq.) in water (50 mL) and the reaction mixture was stirred at room temperature for 4 h. before being diluted with 40 mL water, acidified (pH = 2-3) with dilute aqueous HC1 and extracted with EtOAc (3 x 100 mL). The organic extract was washed with brine, dried over anhydrous Na₂S0₄, filtered and concentrated under reduced pressure to afford 2.75 g of the desired unsaturated carboxylic acid (yield: 61.6 %, purity: 99.0 % by LCMS).

Synthesis of (E)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-lH-l,2,4-triazol-l-yl)-N’- (pyrazin-2-yl)acrylohydrazide :

To a solution of (E)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-lH-l,2,4-triazol-l- yl)acrylic acid (0.75 g,) in EtOAc (25 mL) and THF (12.5 mL) was added a solution of 2- hydrazinopyrazine (0.23 g) in 12 mL THF at room temperature. T3P (50% in ethyl acetate, 1.52 mL) and DIPEA (1.46 mL) were added dropwise and simultaneously and the reaction mixture was stirred for 30 min at room temperature before being quenched with ice-cold water and extracted with EtOAc (3 x 25 mL). The combined organic layers were washed with brine, dried over anhydrous Na₂S0₄ and concentrated under reduced pressure (35°C, 20 mmHg), affording 0.698 g of a crude solid. Trituration first with petroleum ether then with Et₂0 afforded 275 mg (yield: 29%) (E)-3-(3-(3,5-bis(trifiuoromethyl) phenyl)- 1H- 1,2,4- triazol-l-yl)-N’-(pyrazin-2-yl)acrylohydrazide. 1H NMR (400 MHz, DMSO-d6) δ ,10.3 (s, 1H), 9.15 (s, 2H), 8.59 (s, 2H), 8.30-8.26 (d, J= 14.8 Hz, 1H), 8.13 (s, 1H), 8.06-8.07 (m, 1H), 6.98-6.95 (d, J= 13.4 Hz, 1H); LCMS for Ci₇H₁₂F₆N₇0 [M+H]⁺ 443.31 ; found 444.19 (RT 2.625 min, purity: 99.06%).

MY SUGESTION TO U

http://www.google.com/patents/WO2013019548A1?cl=en

(Z)-isopropyl 3-(3-(3,5-bis(trifluoromethyl)phenyl)-lH-l,2,4-triazol-l- yl)acrylate IS THE INTERMEDIATE

any discussion mail amcrasto@gmail.com

NOTE IF U USE Z OR CIS STARTING INTERMEDIATE U WILL GET Z ISOMER

…………………………………………………………

int 75 in

http://www.google.com/patents/WO2011109799A1?cl=en

Figure imgf000307_0001

Exam le 75

Molecular Weight: 239.12 Molecular Weight: 273.2 Molecular Weight: 281 .2

Molecular Weight: 393.3

[00715] Synthesis of Intermediate 1)

Molecular Weight: 239.12 Molecular Weight: 273.2

[00716] In a 100-mL, 3N round-bottomed flask equipped with nitrogen inlet, and a rubber septum, 3,5-bis(trifluoromethyl)benzonitrile (5.0 g,1.0 eq) dissolved in DMF (50 mL,10V),Added NaSH(3.09 g,2.0eq) and MgC12 (4.24 g,l eq).Reaction mixture was stirred at RT for 2-3h. The progress of reaction was followed by TLC analysis on silica gel with 40%EtOAc- hexane as mobile phase. SM Rf=0.5 and Product Rf=0.3. Reaction mixture was poured in to ice water (250mL) and extracted with EtOAc ( 3x 100 mL). The combined organic layers were washed with brine solution (3xl00mL), dried over MgS0₄, filtered, and concentrated by rotary evaporation (25°C, 20mmHg) to afford 5.0g of Crude compound which was used for next step without any purification, Yield (87.5%). Mass [M+l]⁺: 273.8

[00717] Synthesis of Intermediate-2

Molecular Weight: 273.20 Molecular Weight: 281 .16

[00718] In a 250-mL, 3N round-bottomed flask equipped with nitrogen inlet, and a rubber septum, Intermediate- 1(5.0 g, 1.0 eq.) was dissolved in DMF (50 mL,10V),added NH₂NH₂.H₂0 (25.0 mL,5V). The reaction mixture was stirred at RT for 1 h. To this reaction mixture HCOOH (25.0 mL, 5V) was added and reaction mixture was refluxed at 90 ⁰ for 2-3 h. The progress of reaction was followed by TLC analysis on silica gel with 50% Ethyl acetate-n-Hexane as mobile phase. SM Rf=0.50 and Product Rf=0.3. Reaction mixture was poured into ice water (500 mL) and neutralized with saturated sodium bicarbonate solution. The reaction mixture was extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine solution,(3xl00mL), dried over MgS0₄, filtered, and concentrated by rotary evaporation (25°C, 20mmHg) to afford 4.6g of crude compound, yield (89.49%). Mass: 279.6(-ve mode).

Molecular Weight: 281.2 Molecular Weight: 393.3

[00719] In a 100-mL, 3N round-bottomed flask equipped with nitrogen inlet, and a rubber septum, Intermediate-2(4.5 g, 1.0 eq.) was dissolved in DCM(45 mL,10V),added TEA (2.10 g, 1.3 eq) and isopropyl propiolate (2.33 g, 1.3 eq). The Reaction mixture was stirred at RT for 30 min. The progress of reaction was followed by TLC analysis on silica gel with 50% Ethyl acetate-Hexane as mobile phase, SM f=0.30 and Product Rf=0.5. Reaction mixture was concentrated by rotary evaporation (25°C, 20mmHg) to afford 5.8 g of Crude compound. The crude reaction mixture was purified by column chromatography using silica 60/120 using Ethyl acetate: Hexane as mobile phase. The column (5x10cm) was packed in Hexane and started eluting in Ethyl acetate in gradient manner starting with fraction collection(50-mL fractions) from 5 % to 20 % Ethyl acetate in hexane. Compound started eluting with 20% Ethyl acetate in Hexane. Fraction containing such TLC profile was collected together to obtain pure compound (1.4 g), Yield (22.26%).1H NMR: CDC1₃, 400 MHz) δ 9.74(s,lH),5 8.63(s,2H),5 7.95(s,lH),5 7.28-7.3 l(d,J: 12.0 Hz,lH),55.75-5.78(d,J: 11.2 Ηζ,ΙΗ) δ 5.14-5.17 (m,lH),5 1.27-1.35(m,6H). LCMS of Ci₆Hi₃F₆N₃0₂(M+l)⁺:393.28 found 393.77 at 4.707 min (LCMS 99.25%).

[00720] General method for Example 76, Example 77, Example 78, Example 79, Example 83: A mixture of 5-(3-Chlorophenyl)-l,2,4-triazole (0.50 g, 3.4 mmol), respective propiolate (0.52 ml, 5.1 mmol) and some drops of triethylamine in acetonitrile under nitrogen was stirred at room temperature for 12-16 h. Acetonitrile was removed under reduced pressure to give a residual oil, which was purified by flash chromatography (3-5%> EtOAc/hexanes) to afford the both cis and trans isomers. Cis isomer was isolated 10-30%) and trans was isolated in 30-50%) with overall yield of 50-80%.

WO2011109799A1 *	Mar 5, 2011	Sep 9, 2011	Karyopharm Therapeutics, Inc.	Nuclear transport modulatiors and uses thereof
US20110275607	Mar 5, 2011	Nov 10, 2011	Karyopharm Therapeutics, Inc.	Nuclear transport modulators and uses thereof

Panobinostat

orphan status, Phase 3 drug, Uncategorized Comments Off

Jan 232014

Panobinostat

HDAC inhibitors, orphan drug

cas 404950-80-7

2E)-N-hydroxy-3-[4-({[2-(2-methyl-1H-indol-3-yl)ethyl]amino}methyl)phenyl]acrylamide

N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide (alternatively, N-hydroxy-3-(4-{[2-(2-methyl-1H-indol-3-yl)-ethylamino]-methyl}-phenyl)-acrylamide)

Molecular Formula: C₂₁H₂₃N₃O₂ Molecular Weight: 349.42622

Faridak
LBH 589
LBH589
Panobinostat
UNII-9647FM7Y3Z

A hydroxamic acid analog histone deacetylase inhibitor from Novartis.

NOVARTIS, innovator

Histone deacetylase inhibitors

Is currently being examined in cutaneous T-cell lymphoma, CML and breast cancer.

clinical trials click here phase 3

DRUG SUBSTANCE–LACTATE AS IN http://www.google.com/patents/US7989639 SEE EG 31

Panobinostat (LBH-589) is an experimental drug developed by Novartis for the treatment of various cancers. It is a hydroxamic acid^[1] and acts as a non-selective histone deacetylase inhibitor (HDAC inhibitor).^[2]

panobinostat

Panobinostat is a cinnamic hydroxamic acid analogue with potential antineoplastic activity. Panobinostat selectively inhibits histone deacetylase (HDAC), inducing hyperacetylation of core histone proteins, which may result in modulation of cell cycle protein expression, cell cycle arrest in the G2/M phase and apoptosis. In addition, this agent appears to modulate the expression of angiogenesis-related genes, such as hypoxia-inducible factor-1alpha (HIF-1a) and vascular endothelial growth factor (VEGF), thus impairing endothelial cell chemotaxis and invasion. HDAC is an enzyme that deacetylates chromatin histone proteins. Check for

As of August 2012, it is being tested against Hodgkin’s Lymphoma, cutaneous T cell lymphoma (CTCL)^[3] and other types of malignant disease in Phase III clinical trials, against myelodysplastic syndromes, breast cancer and prostate cancer in Phase II trials, and against chronic myelomonocytic leukemia (CMML) in a Phase I trial.^[4]^[5]

Panobinostat is a histone deacetylase (HDAC) inhibitor which was filed for approval in the U.S. in 2010 for the oral treatment of relapsed/refractory classical Hodgkin’s lymphoma in adult patients. The company is conducting phase II/III clinical trials for the oral treatment of multiple myeloma, chronic myeloid leukemia and myelodysplasia. Phase II trials are also in progress for the treatment of primary myelofibrosis, post-polycythemia Vera, post-essential thrombocytopenia, Waldenstrom’s macroglobulinemia, recurrent glioblastoma (GBM) and for the treatment of pancreatic cancer progressing on gemcitabine therapy. Additional trials are under way for the treatment of hematological neoplasms, prostate cancer, colorectal cancer, renal cell carcinoma, non-small cell lung cancer (NSCLC), malignant mesothelioma, acute lymphoblastic leukemia, acute myeloid leukemia, head and neck cancer and gastrointestinal neuroendocrine tumors. Early clinical studies are also ongoing for the treatment of HER2 positive metastatic breast cancer. Additionally, phase II clinical trials are ongoing at Novartis as well as Neurological Surgery for the treatment of recurrent malignant gliomas as are phase I/II initiated for the treatment of acute graft versus host disease. The National Cancer Institute had been conducting early clinical trials for the treatment of metastatic hepatocellular carcinoma; however, these trials were terminated due to observed dose-limiting toxicity. In 2009, Novartis terminated its program to develop panobinostat for the treatment of cutaneous T-cell lymphoma. A program for the treatment of small cell lung cancer was terminated in 2012. Phase I clinical trials are ongoing for the treatment of metastatic and/or malignant melanoma and for the treatment of sickle cell anemia. The University of Virginia is conducting phase I clinical trials for the treatment of newly diagnosed and recurrent chordoma in combination with imatinib. Novartis is evaluating panobinostat for its potential to re-activate HIV transcription in latently infected CD4+ T-cells among HIV-infected patients on stable antiretroviral therapy.

Mechanistic evaluations revealed that panobinostat-mediated tumor suppression involved blocking cell-cycle progression and gene transcription induced by the interleukin IL-2 promoter, accompanied by an upregulation of p21, p53 and p57, and subsequent cell death resulted from the stimulation of caspase-dependent and -independent apoptotic pathways and an increase in the mitochondrial outer membrane permeability. In 2007, the compound received orphan drug designation in the U.S. for the treatment of cutaneous T-cell lymphoma and in 2009 and 2010, orphan drug designation was received in the U.S. and the E.U., respectively, for the treatment of Hodgkin’s lymphoma. This designation was also assigned in 2012 in the U.S. and the E.U. for the treatment of multiple myeloma.

Cardiovascular disease is the leading cause of morbidity and mortality in the western world and during the last decades it has also become a rapidly increasing problem in developing countries. An estimated 80 million American adults (one in three) have one or more expressions of cardiovascular disease (CVD) such as hypertension, coronary heart disease, heart failure, or stroke. Mortality data show that CVD was the underlying cause of death in 35% of all deaths in 2005 in the United States, with the majority related to myocardial infarction, stroke, or complications thereof. The vast majority of patients suffering acute cardiovascular events have prior exposure to at least one major risk factor such as cigarette smoking, abnormal blood lipid levels, hypertension, diabetes, abdominal obesity, and low-grade inflammation.

Pathophysiologically, the major events of myocardial infarction and ischemic stroke are caused by a sudden arrest of nutritive blood supply due to a blood clot formation within the lumen of the arterial blood vessel. In most cases, formation of the thrombus is precipitated by rupture of a vulnerable atherosclerotic plaque, which exposes chemical agents that activate platelets and the plasma coagulation system. The activated platelets form a platelet plug that is armed by coagulation-generated fibrin to form a biood clot that expands within the vessel lumen until it obstructs or blocks blood flow, which results in hypoxic tissue damage (so-called infarction). Thus, thrombotic cardiovascular events occur as a result of two distinct processes, i.e. a slowly progressing long-term vascular atherosclerosis of the vessel wall, on the one hand, and a sudden acute clot formation that rapidly causes flow arrest, on the other. This invention solely relates to the latter process.

Recently, inflammation has been recognized as an important risk factor for thrombotic events. Vascular inflammation is a characteristic feature of the atherosclerotic vessel wall, and inflammatory activity is a strong determinant of the susceptibility of the atherosclerotic plaque to rupture and initiate intravascular clotting. Also, autoimmune conditions with systemic inflammation, such as rheumatoid arthritis, systemic lupus erythematosus and different forms of vasculitides, markedly increase the risk of myocardial infarction and stroke.

Traditional approaches to prevent and treat cardiovascular events are either targeted 1) to slow down the progression of the underlying atherosclerotic process, 2) to prevent clot formation in case of a plaque rupture, or 3) to direct removal of an acute thrombotic flow obstruction. In brief, antiatherosclerotic treatment aims at modulating the impact of general risk factors and includes dietary recommendations, weight loss, physical exercise, smoking cessation, cholesterol- and blood pressure treatment etc. Prevention of clot formation mainly relies on the use of antiplatelet drugs that inhibit platelet activation and/or aggregation, but also in some cases includes thromboembolic prevention with oral anticoagulants such as warfarin. Post-hoc treatment of acute atherothrombotic events requires either direct pharmacological lysis of the clot by thrombolytic agents such as recombinant tissue-type plasminogen activator or percutaneous mechanical dilation of the obstructed vessel.

Despite the fact that multiple-target antiatherosclerotic therapy and clot prevention by antiplatelet agents have lowered the incidence of myocardial infarction and ischemic stroke, such events still remain a major population health problem. This shows that in patients with cardiovascular risk factors these prophylactic measures are insufficient to completely prevent the occurrence of atherothrombotic events.

Likewise, thrombotic conditions on the venous side of the circulation, as well as embolic complications thereof such as pulmonary embolism, still cause substantial morbidity and mortality. Venous thrombosis has a different clinical presentation and the relative importance of platelet activation versus plasma coagulation are somewhat different with an preponderance for the latter in venous thrombosis, However, despite these differences, the major underlying mechanisms that cause thrombotic vessel occlusions are similar to those operating on the arterial circulation. Although unrelated to atherosclerosis as such, the risk of venous thrombosis is related to general cardiovascular risk factors such as inflammation and metabolic aberrations.

Panobinostat can be synthesized as follows: Reduction of 2-methylindole-3-glyoxylamide (I) with LiAlH4 affords 2-methyltryptamine (II). 4-Formylcinnamic acid (III) is esterified with methanolic HCl, and the resulting aldehyde ester (IV) is reductively aminated with 2-methyltryptamine (II) in the presence of NaBH3CN (1) or NaBH4 (2) to give (V). The title hydroxamic acid is then obtained by treatment of ester (V) with aqueous hydroxylamine under basic conditions.

Panobinostat is currently being used in a Phase I/II clinical trial that aims at curing AIDS in patients on highly active antiretroviral therapy (HAART). In this technique panobinostat is used to drive the HI virus’s DNA out of the patient’s DNA, in the expectation that the patient’s immune system in combination with HAART will destroy it.^[6]^[7]

panobinostat

Panobinostat has been found to synergistically act with sirolimus to kill pancreatic cancer cells in the laboratory in a Mayo Clinic study. In the study, investigators found that this combination destroyed up to 65 percent of cultured pancreatic tumor cells. The finding is significant because the three cell lines studied were all resistant to the effects of chemotherapy – as are many pancreatic tumors.^[8]

Panobinostat has also been found to significantly increase in vitro the survival of motor neuron (SMN) protein levels in cells of patients suffering fromspinal muscular atrophy.^[9]

Panobinostat was able to selectively target triple negative breast cancer (TNBC) cells by inducing hyperacetylation and cell cycle arrest at the G2-M DNA damage checkpoint; partially reversing the morphological changes characteristic of breast cancer cells.^[10]

Panobinostat, along with other HDAC inhibitors, is also being studied for potential to induce virus HIV-1 expression in latently infected cells and disrupt latency. These resting cells are not recognized by the immune system as harboring the virus and do not respond to antiretroviral drugs.^[11]

Panobinostat inhibits multiple histone deacetylase enzymes, a mechanism leading to apoptosis of malignant cells via multiple pathways.^[1]

The compound N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide (alternatively, N-hydroxy-3-(4-{[2-(2-methyl-1H-indol-3-yl)-ethylamino]-methyl}-phenyl)-acrylamide) has the formula

as described in WO 02/22577. Valuable pharmacological properties are attributed to this compound; thus, it can be used, for example, as a histone deacetylase inhibitor useful in therapy for diseases which respond to inhibition of histone deacetylase activity. WO 02/22577 does not disclose any specific salts or salt hydrates or solvates of N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide.

The compounds described above are often used in the form of a pharmaceutically acceptable salt. Pharmaceutically acceptable salts include, when appropriate, pharmaceutically acceptable base addition salts and acid addition salts, for example, metal salts, such as alkali and alkaline earth metal salts, ammonium salts, organic amine addition salts, and amino acid addition salts, and sulfonate salts. Acid addition salts include inorganic acid addition salts such as hydrochloride, sulfate and phosphate, and organic acid addition salts such as alkyl sulfonate, arylsulfonate, acetate, maleate, fumarate, tartrate, citrate and lactate. Examples of metal salts are alkali metal salts, such as lithium salt, sodium salt and potassium salt, alkaline earth metal salts such as magnesium salt and calcium salt, aluminum salt, and zinc salt. Examples of ammonium salts are ammonium salt and tetramethylammonium salt. Examples of organic amine addition salts are salts with morpholine and piperidine. Examples of amino acid addition salts are salts with glycine, phenylalanine, glutamic acid and lysine. Sulfonate salts include mesylate, tosylate and benzene sulfonic acid salts.

……………………………..

GENERAL METHOD OF SYNTHESIS

ADD YOUR METHYL AT RIGHT PLACE

WO2002022577A2

As is evident to those skilled in the art, the many of the deacetylase inhibitor compounds of the present invention contain asymmetric carbon atoms. It should be understood, therefore, that the individual stereoisomers are contemplated as being included within the scope of this invention.

The hydroxamate compounds of the present invention can be produced by known organic synthesis methods. For example, the hydroxamate compounds can be produced by reacting methyl 4-formyl cinnamate with tryptamine and then converting the reactant to the hydroxamate compounds. As an example, methyl 4-formyl cinnamate 2, is prepared by acid catalyzed esterification of 4-formylcinnamic acid 3 (Bull. Chem. Soc. Jpn. 1995; 68:2355-2362). An alternate preparation of methyl 4-formyl cinnamate 2 is by a Pd- catalyzed coupling of methyl acrylate 4 with 4-bromobenzaldehyde 5.

CHO

Additional starting materials can be prepared from 4-carboxybenzaldehyde 6, and an exemplary method is illustrated for the preparation of aldehyde 9, shown below. The carboxylic acid in 4-carboxybenzaldehyde 6 can be protected as a silyl ester (e.g., the t- butyldimethylsilyl ester) by treatment with a silyl chloride (e.g., f-butyldimethylsilyl chloride) and a base (e.g. triethylamine) in an appropriate solvent (e.g., dichloromethane). The resulting silyl ester 7 can undergo an olefination reaction (e.g., a Horner-Emmons olefination) with a phosphonate ester (e.g., triethyl 2-phosphonopropionate) in the presence of a base (e.g., sodium hydride) in an appropriate solvent (e.g., tetrahydrofuran (THF)). Treatment of the resulting diester with acid (e.g., aqueous hydrochloric acid) results in the hydrolysis of the silyl ester providing acid 8. Selective reduction of the carboxylic acid of 8 using, for example, borane-dimethylsuflide complex in a solvent (e.g., THF) provides an intermediate alcohol. This intermediate alcohol could be oxidized to aldehyde 9 by a number of known methods, including, but not limited to, Swern oxidation, Dess-Martin periodinane oxidation, Moffatt oxidation and the like.

The aldehyde starting materials 2 or 9 can be reductively aminated to provide secondary or tertiary amines. This is illustrated by the reaction of methyl 4-formyl cinnamate 2 with tryptamine 10 using sodium triacetoxyborohydride (NaBH(OAc)₃) as the reducing agent in dichloroethane (DCE) as solvent to provide amine 11. Other reducing agents can be used, e.g., sodium borohydride (NaBH ) and sodium cyanoborohydride (NaBH₃CN), in other solvents or solvent mixtures in the presence or absence of acid catalysts (e.g., acetic acid and trifluoroacetic acid). Amine 11 can be converted directly to hydroxamic acid 12 by treatment with 50% aqueous hydroxylamine in a suitable solvent (e.g., THF in the presence of a base, e.g., NaOH). Other methods of hydroxamate formation are known and include reaction of an ester with hydroxylamine hydrochloride and a base (e.g., sodium hydroxide or sodium methoxide) in a suitable solvent or solvent mixture (e.g., methanol, ethanol or methanol/THF).

NOTE ….METHYL SUBSTITUENT ON 10 WILL GIVE YOU PANOBINOSTAT

……………………………….

Journal of Medicinal Chemistry, 2011 , vol. 54, 13 pg. 4694 – 4720

(E)-N-Hydroxy-3-(4-{[2-(2-methyl-1H-indol-3-yl)-ethylamino]-methyl}-phenyl)-acrylamide
lactate

(34, panobinostat, LBH589)

http://pubs.acs.org/doi/full/10.1021/jm2003552

http://pubs.acs.org/doi/suppl/10.1021/jm2003552/suppl_file/jm2003552_si_001.pdf

for str see above link

α-methyl-β-(β-bromoethyl)indole (29) was made according to method reported by Grandberg et al.(2. Grandberg, I. I.; Kost, A. N.; Terent’ev, A. P. Reactions of hydrazine derivatives. XVII. New synthesis of α-methyltryptophol. Zhurnal Obshchei Khimii 1957, 27, 3342–3345. )

The bromide 29 was converted to amine 30 by using similar method used by Sletzinger et al.(3. Sletzinger, M.; Ruyle, W. V.; Waiter, A. G. (Merck & Co., Inc.). Preparation of tryptamine
derivatives. U.S. Patent US 2,995,566, Aug 8, 1961.)

To a 500 mL flask, crude 2-methyltryptamine 30 (HPLC purity 75%, 1.74 g, 7.29 mmol) and 3-(4-
formyl-phenyl)-acrylic acid methyl ester 31 (HPLC purity 84%, 1.65 g, 7.28 mmol) were added,
followed by DCM (100 mL) and MeOH (30 mL). The clear solution was stirred at room temp for 30
min, then NaBH3CN (0.439 g, 6.99 mmol) was added in small portions. The reaction mixture was
stirred at room temp overnight. After removal of the solvents, the residue was diluted with DCM and
added saturated NaHCO3 aqueous solution, extracted with DCM twice. The DCM layer was dried
and concentrated, and the resulting residue was purified by flash chromatography (silica, 0–10%
MeOH in DCM) to afford 33 as orange solid (1.52 g, 60%). LC–MS m/z 349.2 ([M + H]+). 33 was
converted to hydroxamic acid 34 according to procedure D (Experimental Section), and the freebase
34 was treated with 1 equiv of lactic acid in MeOH–water (7:3) to form lactic acid salt which was
further recrystallized in MeOH–EtOAc to afford the lactic acid salt of 34as pale yellow solid. LC–MS m/z 350.2 ([M + H − lactate]+).

= DELTA

1H NMR (DMSO-d6)  10.72 (s, 1H, NH), 7.54 (d, J = 8.0 Hz, 2H), 7.44 (d, J = 16 Hz, 1H), 7.43 (d, J = 7.8 Hz, 2H), 7.38 (d, J = 7.6 Hz, 1H), 7.22 (d, J = 7.8 Hz, 1H), 6.97 (td, J = 7.8 Hz, 1H), 7.44 (d, J = 15.8 Hz, 1H), 7.22 (t, J = 7.8 Hz, 2H), 7.08 (d, J = 7.8Hz, 2H), 7.01 (t, J = 7.4, 0.9 Hz, 1H), 6.91 (td, J = 7.4, 0.9 Hz, 1H), 6.47 (d, J = 15.2 Hz, 1H), 3.94(q, J = 6.8 Hz, 1H, lactate CH), 3.92 (s, 2H), 2.88 and 2.81 (m, each, 4H, AB system, CH2CH2),2.31 (s, 3H), 1.21 (d, J = 6.8 Hz, 3H).;

13C NMR (DMSO-d6)  176.7 (lactate C=O), 162.7, 139.0,
137.9, 135.2, 134.0, 132.1, 129.1, 128.1, 127.4, 119.9, 119.0, 118.1, 117.2, 110.4, 107.0, 66.0, 51.3,
48.5, 22.9, 20.7, 11.2.

…………………………………………..

PANOBINOSTAT DRUG SUBSTANCE SYNTHESIS AND DATA

http://www.google.com/patents/US7989639

Figure US07989639-20110802-C00002

A flow diagram for the synthesis of LBH589 lactate is provided in FIG. A. A nomenclature reference index of the intermediates is provided below in the Nomenclature Reference Index:


Nomenclature reference index
Compound	Chemical name

1	4-Bromo-benzaldehyde
2	Methyl acrylate
3	(2E)-3-(formylphenyl)-2-propenoic acid, methyl ester
4	3-[4-[[[2-(2-Methyl-1H-indol-3-
	yl)ethyl]amino]methyl]phenyl]-2-
	propenoic acid, methyl ester, monohydrochloride
5	(2E)-N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-
	yl)ethyl]amino]methyl]phenyl]-2-propenamide
6	2-hydroxypropanoic acid, compd. with 2(E)-N-
	hydroxy-3-[4-[[[2-(2-methyl-1H-
	indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide
Z3a	2-Methyl-1H-indole-3-ethanamine
Z3b	5-Chloro-2-pentanone
Z3c	Phenylhydrazine

The manufacture of LBH589 lactate (6) drug substance is via a convergent synthesis; the point of convergence is the condensation of indole-amine Z3a with aldehyde 3.

The synthesis of indole-amine Z3a involves reaction of 5-chloro-2 pentanone (Z3b) with phenylhydrazine (Z3c) in ethanol at reflux (variation of Fischer indole synthesis).

Product isolation is by an extractive work-up followed by crystallization. Preparation of aldehyde 3 is by palladium catalyzed vinylation (Heck-type reaction; Pd(OAc)2/P(o-Tol)3/Bu3N in refluxing CH3CN) of 4-bromo-benzyladehyde (1) with methyl acrylate (2) with product isolation via precipitation from dilute HCl solution. Intermediates Z3a and 3 are then condensed to an imine intermediate, which is reduced using sodium borohydride in methanol below 0° C. (reductive amination). The product indole-ester 4, isolated by precipitation from dilute HCl, is recrystallized from methanol/water, if necessary. The indole ester 4 is converted to crude LBH589 free base 5 via reaction with hydroxylamine and sodium hydroxide in water/methanol below 0° C. The crude LBH589 free base 5 is then purified by recrystallization from hot ethanol/water, if necessary. LBH589 free base 5 is treated with 85% aqueous racemic lactic acid and water at ambient temperature. After seeding, the mixture is heated to approximately 65° C., stirred at this temperature and slowly cooled to 45-50° C. The resulting slurry is filtered and washed with water and dried to afford LBH589 lactate (6).

If necessary the LBH589 lactate 6 may be recrystallised once again from water in the presence of 30 mol % racemic lactic acid. Finally the LBH589 lactate is delumped to give the drug substance. If a rework of the LBH589 lactate drug substance 6 is required, the LBH589 lactate salt is treated with sodium hydroxide in ethanol/water to liberate the LBH589 free base 5 followed by lactate salt formation and delumping as described above.

All starting materials, reagents and solvents used in the synthesis of LBH589 lactate are tested according to internal specifications or are purchased from established suppliers against a certificate of analysis.

EXAMPLE 7 Formation of Monohydrate Lactate Salt

About 40 to 50 mg of N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide free base was suspended in 1 ml of a solvent as listed in Table 7. A stoichiometric amount of lactic acid was subsequently added to the suspension. The mixture was stirred at ambient temperature and when a clear solution formed, stirring continued at 4° C. Solids were collected by filtration and analyzed by XRPD, TGA and ¹H-NMR.

TABLE 7

				LOD, %
		Physical	Crystallinity	(T_desolvation)
Solvent	T, ° C.	Appear.	and Form	T_decomposit.	¹H-NMR

IPA	4	FFP	excellent	4.3 (79.3)	—
			H_A	156.3
Acetone	4	FFP	excellent	4.5 (77.8)	4.18 (H_bz)
			H_A	149.5

The salt forming reaction in isopropyl alcohol and acetone at 4° C. produced a stoichiometric (1:1) lactate salt, a monohydrate. The salt is crystalline, begins to dehydrate above 77° C., and decomposes above 150° C.

EXAMPLE 18 Formation of Anhydrous Lactate Salt

DL-lactic acid (4.0 g, 85% solution in water, corresponding to 3.4 g pure DL-lactic acid) is diluted with water (27.2 g), and the solution is heated to 90° C. (inner temperature) for 15 hours. The solution is allowed to cool down to room temperature and is used as lactic acid solution for the following salt formation step.

N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide free base (10.0 g) is placed in a 4-necked reaction flask with mechanical stirrer. Demineralized water (110.5 g) is added, and the suspension is heated to 65° C. (inner temperature) within 30 minutes. The DL-lactic acid solution is added to this suspension during 30 min at 65° C. During the addition of the lactate salt solution, the suspension converted into a solution. The addition funnel is rinsed with demineralized water (9.1 g), and the solution is stirred at 65° C. for an additional 30 minutes. The solution is cooled down to 45° C. (inner temperature) and seed crystals (10 mg N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide lactate monohydrate) are added at this temperature. The suspension is cooled down to 33° C. and is stirred for additional 20 hours at this temperature. The suspension is re-heated to 65° C., stirred for 1 hour at this temperature and is cooled to 33° C. within 1 hour. After additional stirring for 3 hours at 33° C., the product is isolated by filtration, and the filter cake is washed with demineralized water (2×20 g). The wet filter-cake is dried in vacuo at 50° C. to obtain the anhydrous N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide lactate salt as a crystalline product. The product is identical to the monohydrate salt (form H_A) in HPLC and in 1H-NMR, with the exception of the integrals of water signals in the 1H-NMR spectra.

In additional salt formation experiments carried out according to the procedure described above, the product solution was filtered at 65° C. before cooling to 45° C., seeding and crystallization. In all cases, form A (anhydrate form) was obtained as product.

EXAMPLE 19 Formation of Anhydrous Lactate Salt

DL-lactic acid (2.0 g, 85% solution in water, corresponding to 1.7 g pure DL-lactic acid) is diluted with water (13.6 g), and the solution is heated to 90° C. (inner temperature) for 15 hours. The solution was allowed to cool down to room temperature and is used as lactic acid solution for the following salt formation step.

N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide free base (5.0 g) is placed in a 4-necked reaction flask with mechanical stirrer. Demineralized water (54.85 g) is added, and the suspension is heated to 48° C. (inner temperature) within 30 minutes. The DL-lactic acid solution is added to this suspension during 30 minutes at 48° C. A solution is formed. Seed crystals are added (as a suspension of 5 mg N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide lactate salt, anhydrate form A, in 0.25 g of water) and stirring is continued for 2 additional hours at 48° C. The temperature is raised to 65° C. (inner temperature) within 30 minutes, and the suspension is stirred for additional 2.5 hours at this temperature. Then the temperature is cooled down to 48° C. within 2 hours, and stirring is continued at this temperature for additional 22 hours. The product is isolated by filtration and the filter cake is washed with demineralized water (2×10 g). The wet filter-cake is dried in vacuo at 50° C. to obtain anhydrous N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide lactate salt (form A) as a crystalline product.

EXAMPLE 20 Conversion of Monohydrate Lactate Salt to Anhydrous Lactate Salt

DL-lactic acid (0.59 g, 85% solution in water, corresponding to 0.5 g pure DL-lactic acid) is diluted with water (4.1 g), and the solution is heated to 90° C. (inner temperature) for 15 hours. The solution is allowed to cool down to room temperature and is used as lactic acid solution for the following salt formation step.

10 g of N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide lactate salt monohydrate is placed in a 4-necked reaction flask. Water (110.9 g) is added, followed by the addition of the lactic acid solution. The addition funnel of the lactic acid is rinsed with water (15.65 g). The suspension is heated to 82° C. (inner temperature) to obtain a solution. The solution is stirred for 15 minutes at 82° C. and is hot filtered into another reaction flask to obtain a clear solution. The temperature is cooled down to 50° C., and seed crystals are added (as a suspension of 10 mg N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide lactate salt, anhydrate form, in 0.5 g of water). The temperature is cooled down to 33° C. and stirring is continued for additional 19 hours at this temperature. The formed suspension is heated again to 65° C. (inner temperature) within 45 minutes, stirred at 65° C. for 1 hour and cooled down to 33° C. within 1 hour. After stirring at 33° C. for additional 3 hours, the product is isolated by filtration and the wet filter cake is washed with water (50 g). The product is dried in vacuo at 50° C. to obtain crystalline anhydrous N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl) ethyl]amino]methyl]phenyl]-2E-2-propenamide lactate salt (form A).

EXAMPLE 21 Formation of Anhydrous Lactate Salt

DL-lactic acid (8.0 g, 85% solution in water, corresponding to 6.8 g pure DL-lactic acid) was diluted with water (54.4 g), and the solution was heated to 90° C. (inner temperature) for 15 hours. The solution was allowed to cool down to room temperature and was used as lactic acid solution for the following salt formation step.

N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide (20 g) is placed in a 1 L glass reactor, and ethanol/water (209.4 g of a 1:1 w/w mixture) is added. The light yellow suspension is heated to 60° C. (inner temperature) within 30 minutes, and the lactic acid solution is added during 30 minutes at this temperature. The addition funnel is rinsed with water (10 g). The solution is cooled to 38° C. within 2 hours, and seed crystals (20 mg of N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide lactate salt, anhydrate form) are added at 38° C. After stirring at 38° C. for additional 2 hours, the mixture is cooled down to 25° C. within 6 hours. Cooling is continued from 25° C. to 10° C. within 5 hours, from 10° C. to 5° C. within 4 hours and from 5° C. to 2° C. within 1 hour. The suspension is stirred for additional 2 hours at 2° C., and the product is isolated by filtration. The wet filter cake is washed with water (2×30 g), and the product is dried in vacuo at 45° C. to obtain crystalline anhydrous N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide lactate salt (form A).

EXAMPLE 28 Formation of Lactate Monohydrate Salt

3.67 g (10 mmol) of the free base monohydrate (N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl) ethyl]amino]methyl]phenyl]-2E-2-propenamide) and 75 ml of acetone were charged in a 250 ml 3-neck flask equipped with a magnetic stirrer and an addition funnel. To the stirred suspension were added dropwise 10 ml of 1 M lactic acid in water (10 mmol) dissolved in 20 ml acetone, affording a clear solution. Stirring continued at ambient and a white solid precipitated out after approximately 1 hour. The mixture was cooled in an ice bath and stirred for an additional hour. The white solid was recovered by filtration and washed once with cold acetone (15 ml). It was subsequently dried under vacuum to yield 3.94 g of the lactate monohydrate salt of N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide (86.2%).

References

Revill, P; Mealy, N; Serradell, N; Bolos, J; Rosa, E (2007). “Panobinostat”. Drugs of the Future 32 (4): 315. doi:10.1358/dof.2007.032.04.1094476. ISSN 0377-8282.
Table 3: Select epigenetic inhibitors in various stages of development from Mack, G. S. (2010). “To selectivity and beyond”. Nature Biotechnology 28 (12): 1259–1266.doi:10.1038/nbt.1724. PMID 21139608. edit
ClinicalTrials.gov NCT00425555 Study of Oral LBH589 in Adult Patients With Refractory Cutaneous T-Cell Lymphoma
ClinicalTrials.gov: LBH-589
Prince, HM; M Bishton (2009). “Panobinostat (LBH589): a novel pan-deacetylase inhibitor with activity in T cell lymphoma”. Hematology Meeting Reports (Parkville, Australia: Peter MacCallum Cancer Centre and University of Melbourne) 3 (1): 33–38.
Simons, J (27 April 2013). “Scientists on brink of HIV cure”. The Telegraph.
ClinicalTrials.gov NCT01680094 Safety and Effect of The HDAC Inhibitor Panobinostat on HIV-1 Expression in Patients on Suppressive HAART (CLEAR)
Mayo Clinic Researchers Formulate Treatment Combination Lethal To Pancreatic Cancer Cells
Garbes, L; Riessland, M; Hölker, I; Heller, R; Hauke, J; Tränkle, Ch; Coras, R; Blümcke, I; Hahnen, E; Wirth, B (2009). “LBH589 induces up to 10-fold SMN protein levels by several independent mechanisms and is effective even in cells from SMA patients non-responsive to valproate”. Human Molecular Genetics 18 (19): 3645–3658. doi:10.1093/hmg/ddp313.PMID 19584083.
Tate, CR; Rhodes, LV; Segar, HC; Driver, JL; Pounder, FN; Burow, ME; and Collins-Burow, BM (2012). “Targeting triple-negative breast cancer cells with the histone deacetylase inhibitor panobinostat”. Breast Cancer Research 14 (3).
TA Rasmussen, et al. Comparison of HDAC inhibitors in clinical development: Effect on HIV production in latently infected cells and T-cell activation. Human Vaccines & Immunotherapeutics 9:5, 1-9, May 2013.
Drugs of the Future 32(4): 315-322 (2007)
WO 2002022577…
WO 2007146718
WO 2013110280
WO 2010009285
WO 2010009280
WO 2005013958
WO 2004103358
WO 2003048774…
Journal of Medicinal Chemistry, 2011 , vol. 54, 13 pg. 4694 – 4720
23009203

11-26-2012

Selective histone deacetylase 6 inhibitors bearing substituted urea linkers inhibit melanoma cell growth.

Journal of medicinal chemistry

21634430

7-14-2011

Discovery of (2E)-3-{2-butyl-1-[2-(diethylamino)ethyl]-1H-benzimidazol-5-yl}-N-hydroxyacrylamide (SB939), an orally active histone deacetylase inhibitor with a superior preclinical profile.

Journal of medicinal chemistry

21417419

4-28-2011

Discovery, synthesis, and pharmacological evaluation of spiropiperidine hydroxamic acid based derivatives as structurally novel histone deacetylase (HDAC) inhibitors.

Journal of medicinal chemistry

19317450

4-23-2009

Identification and characterization of small molecule inhibitors of a class I histone deacetylase from Plasmodium falciparum.

Journal of medicinal chemistry
15650931

1-1-2005

The American Society of Hematology–46th Annual Meeting and Exposition. HDAC, Flt and farnesyl transferase inhibitors.

IDrugs : the investigational drugs journal

US7989639	8-3-2011	PROCESS FOR MAKING SALTS OF N-HYDROXY-3-[4-[[[2-(2-METHYL-1H-INDOL-3-YL)ETHYL]AMINO]METHYL]PHENYL]-2E-2-PROPENAMIDE
US2010286409	11-12-2010	SALTS OF N-HYDROXY-3-[4-[[[2-(2-METHYL-1H-INDOL-3-YL)ETHYL]AMINO]METHYL]PHENYL]-2E-2-PROPENAMIDE
US2010179208	7-16-2010	Use of HDAC Inhibitors for the Treatment of Bone Destruction
US2010160257	6-25-2010	USE OF HDAC INHIBITORS FOR THE TREATMENT OF MYELOMA
US2010137398	6-4-2010	USE OF HDAC INHIBITORS FOR THE TREATMENT OF GASTROINTESTINAL CANCERS
US2009306405	12-11-2009	PROCESS FOR MAKING N-HYDROXY-3-[4-[[[2-(2-METHYL-1H-INDOL-3-YL)ETHYL]AMINO]METHYL]PHENYL]-2E-2-PROPENAMIDE AND STARTING MATERIALS THEREFOR
US2009281159	11-13-2009	USE OF HDAC INHIBITORS FOR THE TREATMENT OF LYMPHOMAS
US2009264439	10-23-2009	Combination of a) N–4-(3-pyridyl)-2-pyrimidine-amine and b) a histone deacetylase inhibitor for the treatment of leukemia
US2009197936	8-7-2009	SALTS OF N-HYDROXY-3-[4-[[[2-(2-METHYL-1H-INDOL-3-YL)ETHYL]AMINO]METHYL]PHENYL]-2E-2-PROPENAMIDE
US2009012066	1-9-2009	Method of Use of Deacetylase Inhibitors


US2008319045	12-26-2008	Combination of Histone Deacetylase Inhibitors and Radiation
US2008221126	9-12-2008	Use of Hdac Inhibitors for the Treatment of Myeloma
US2008176849	7-25-2008	DEACETYLASE INHIBITORS
US2006189674	8-25-2006	Deacetylase inhibitors
US7067551	6-28-2006	Deacetylase inhibitors
US2006100140	5-12-2006	Combination of a) n-{5-[4-(4-methyl-piperazino-methyl)-benzoylamido]2-methylphenyl}-4- (3-pyridyl)-2-pyrimidine-amine and b) a histone deacetylase inhibitor for the treatment of leukemia
US6833384	12-22-2004	Deacetylase inhibitors
US6552065	4-23-2003	Deacetylase inhibitors

GB776693A				Title not available
GB891413A				Title not available
GB2185020A				Title not available
WO2002022577A2	Aug 30, 2001	Mar 21, 2002	Kenneth Walter Bair	Hydroxamate derivatives useful as deacetylase inhibitors
WO2003016307A1	Aug 6, 2002	Aug 19, 1993	Jolie Anne Bastian	β3 ADRENERGIC AGONISTS
WO2003039599A1	Nov 5, 2002	May 15, 2003	Ying-Nan Pan Chen	Cyclooxygenase-2 inhibitor/histone deacetylase inhibitor combination
WO2005105740A2	Apr 26, 2005	Nov 10, 2005	Serguei Fine	Preparation of tegaserod and tegaserod maleate
WO2006021397A1	Aug 22, 2005	Mar 2, 2006	Recordati Ireland Ltd	Lercanidipine salts

…………………………………..

extras

5. Mocetinostat (MGCD0103), including pharmaceutically acceptable salts thereof. Balasubramanian et al., Cancer Letters 280: 211-221 (2009).
Mocetinostat, has the following chemical structure and name:

,………………………………

Vorinostat, including pharmaceutically acceptable salts thereof. Marks et al., Nature Biotechnology 25, 84 to 90 (2007); Stenger, Community Oncology 4, 384-386 (2007).
Vorinostat has the following chemical structure and name:

………………………

Belinostat (PXD-101 , PX-105684)

(2E)-3-[3-(anilinosulfonyl)phenyl]-N-hydroxyacrylamide

……………………………………………….

Dacinostat (LAQ-824, NVP-LAQ824,)

((E)-N-hydroxy-3-[4-[[2-hydroxyethyl-[2-(1 H-indol-3-yl)ethyl]amino]methyl]phenyl]prop-2-enamide

…………………………………………

Entinostat (MS-275, SNDX-275, MS-27-275)

4-(2-aminophenylcarbamoyl)benzylcarbamate

………………….

(a) The HDAC inhibitor Vorinostat™ or a salt, hydrate, or solvate thereof.

Vorinostat………………..

(b) The HDAC inhibitor Givinostat or a salt, hydrate, or solvate thereof.

Givinostat or a salt, hydrate, or solvate thereof.

……………………………………………

…………………………..

MIDOSTAURIN …with potential antiangiogenic and antineoplastic activities …

orphan status, Phase 3 drug, Uncategorized 1 Response »

Jan 142014

MIDOSTAURIN

(9S,10R,11R,13R)-2,3,10,11,12,13-Hexahydro-10-methoxy-9-methyl-11-(methylamino)-9,13-epoxy-1H,9H-diindolo[1,2,3-gh:3′,2′,1′-lm]pyrrolo[3,4-j][1,7]benzodiamzonine-1-one

N-[(9S,10R,11R,13R)-2,3,10,11,12,13-Hexahydro-10-methoxy-9-methyl-1-oxo-9,13-epoxy-1H,9H-diindolo[1,2,3-gh:3′,2′,1′-lm]pyrrolo[3,4-j][1,7]benzodiazonin-11-yl]-N-methylbenzamide

N-((9S,10R,11R,13R)-2,3,9,10,11,12-hexahydro-10-methoxy-9-methyl-1-oxo-9,13-epoxy-1H,9H-diindolo(1,2,3-gh:3′,2′,1′-lm)pyrrolo(3,4-j)(1,7)benzodiazonin-11-yl)-N-methyl-,

N-[(2R,4R,5R,6S)-5-methoxy-6-methyl-18-oxo-29-oxa-1,7,17-triazaoctacyclo[12.12.2.1²,⁶.0⁷,²⁸.0⁸,¹³.0¹⁵,¹⁹.0²⁰,²⁷.0²¹,²⁶]nonacosa-8,10,12,14(28),15(19),20(27),21(26),22,24-nonaen-4-yl]-N-methylbenzamide hydrate

N-benzoyl staurosporine

NOVARTIS ONCOLOGY ORIGINATOR

Chemical Formula: C35H30N4O4

Exact Mass: 570.22671

Molecular Weight: 570.63710

Elemental Analysis: C, 73.67; H, 5.30; N, 9.82; O, 11.22

Tyrosine kinase inhibitors

PKC 412。PKC412A。CGP 41251。Benzoylstaurosporine；4′-N-Benzoylstaurosporine；Cgp 41251；Cgp 41 251.

120685-11-2 CAS

PHASE 3

4′-N-Benzoylstaurosporine
Benzoylstaurosporine
Cgp 41 251
CGP 41251
CGP-41251
Midostaurin
PKC 412
PKC412
UNII-ID912S5VON

Midostaurin is an inhibitor of tyrosine kinase, protein kinase C, and VEGF. Midostaurin inhibits cell growth and phosphorylation of FLT3, STAT5, and ERK. It is a potent inhibitor of a spectrum of FLT3 activation loop mutations.

it is prepared by acylation of the alkaloid staurosporine (I) with benzoyl chloride (II) in the presence of diisopropylethylamine in chloroform. Production Route of Midostaurin

Midostaurin is a synthetic indolocarbazole multikinase inhibitor with potential antiangiogenic and antineoplastic activities. Midostaurin inhibits protein kinase C alpha (PKCalpha), vascular endothelial growth factor receptor 2 (VEGFR2), c-kit, platelet-derived growth factor receptor (PDGFR) and FMS-like tyrosine kinase 3 (FLT3) tyrosine kinases, which may result in disruption of the cell cycle, inhibition of proliferation, apoptosis, and inhibition of angiogenesis in susceptible tumors.

MIDOSTAURIN

Derivative of staurosporin, orally active, potent inhibitor of FLT3 tyrosine kinase (fetal liver tyrosine kinase 3). In addition Midostaurin inhibits further molecular targets such as VEGFR-1 (Vascular Endothelial Growth Factor Receptor 1), c-kit (stem cell factor receptor), H-and K-RAS (Rat Sarcoma Viral homologue) and MDR (multidrug resistance protein).

Midostaurin inhibits both wild-type FLT3 and FLT3 mutant, wherein the internal tandem duplication mutations (FLT3-ITD), and the point mutation to be inhibited in the tyrosine kinase domain of the molecule at positions 835 and 836.Midostaurin is tested in patients with AML.

Midostaurin, a protein kinase C (PKC) and Flt3 (FLK2/STK1) inhibitor, is in phase III clinical development at originator Novartis for the oral treatment of acute myeloid leukemia (AML).

Novartis is conducting phase III clinical trials for the treatment of aggressive systemic mastocytosis or mast cell leukemia. The National Cancer Institute (NCI) is conducting phase I/II trials with the drug for the treatment of chronic myelomonocytic leukemia (CMML) and myelodysplastic syndrome (MDS).

Massachusetts General Hospital is conducting phase I clinical trials for the treatment of adenocarcinoma of the rectum in combination with radiation and standard chemotherapy.

MIDOSTAURIN

Midostaurin (PKC412) is a multi-target protein kinase inhibitor being investigated for the treatment of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). It is a semi-synthetic derivative of staurosporine, an alkaloid from the bacterium Streptomyces staurosporeus, and is active in patients with mutations of CD135 (FMS-like tyrosine kinase 3 receptor).^[1]

After successful Phase II clinical trials, a Phase III trial for AML has started in 2008. It is testing midostaurin in combination with daunorubicin and cytarabine.^[2] In another trial, the substance has proven ineffective in metastatic melanoma.^[3]

Midostaurin has also been studied at Johns Hopkins University for the treatment of age-related macular degeneration (AMD), but no recent progress reports for this indication have been made available. Trials in macular edema of diabetic origin were discontinued at Novartis.

In 2004, orphan drug designation was received in the E.U. for the treatment of AML. In 2009 and 2010, orphan drug designation was assigned for the treatment of acute myeloid leukemia and for the treatment of mastocytosis, respectively, in the U.S. In 2010, orphan drug designation was assigned in the E.U. for the latter indication.

MIDOSTAURIN

References

Fischer, T.; Stone, R. M.; Deangelo, D. J.; Galinsky, I.; Estey, E.; Lanza, C.; Fox, E.; Ehninger, G.; Feldman, E. J.; Schiller, G. J.; Klimek, V. M.; Nimer, S. D.; Gilliland, D. G.; Dutreix, C.; Huntsman-Labed, A.; Virkus, J.; Giles, F. J. (2010). “Phase IIB Trial of Oral Midostaurin (PKC412), the FMS-Like Tyrosine Kinase 3 Receptor (FLT3) and Multi-Targeted Kinase Inhibitor, in Patients with Acute Myeloid Leukemia and High-Risk Myelodysplastic Syndrome with Either Wild-Type or Mutated FLT3”. Journal of Clinical Oncology 28 (28): 4339–4345. doi:10.1200/JCO.2010.28.9678. PMID 20733134. edit
ClinicalTrials.gov NCT00651261 Daunorubicin, Cytarabine, and Midostaurin in Treating Patients With Newly Diagnosed Acute Myeloid Leukemia
Millward, M. J.; House, C.; Bowtell, D.; Webster, L.; Olver, I. N.; Gore, M.; Copeman, M.; Lynch, K.; Yap, A.; Wang, Y.; Cohen, P. S.; Zalcberg, J. (2006). “The multikinase inhibitor midostaurin (PKC412A) lacks activity in metastatic melanoma: a phase IIA clinical and biologic study”. British Journal of Cancer 95 (7): 829–834. doi:10.1038/sj.bjc.6603331. PMC 2360547. PMID 16969355.
1. Midostaurin product page, Fermentek
2. Wang, Y; Yin, OQ; Graf, P; Kisicki, JC; Schran, H (2008). “Dose- and Time-Dependent Pharmacokinetics of Midostaurin in Patients With Diabetes Mellitus”. J Clin Pharmacol 48 (6): 763–775. doi:10.1177/0091270008318006. PMID 18508951.
3. Ryan KS (2008). “Structural studies of rebeccamycin, staurosporine, and violacein biosynthetic enzymes”. Ph.D. Thesis. Massachusetts Institute of Technology.

Bioorg Med Chem Lett 1994, 4(3): 399

US 5093330

EP 0657164

EP 0711556

EP 0733358

WO 1998007415

WO 2002076432

WO 2003024420

WO 2003037347

WO 2004112794

WO 2005027910

WO 2005040415

WO 2006024494

WO 2006048296

WO 2006061199

WO 2007017497

WO 2013086133

WO 2012016050

WO 2011000811

23787099	8-1-2013	Identification of potent Yes1 kinase inhibitors using a library screening approach.	Bioorganic & medicinal chemistry letters

22770610	3-1-2013	Evaluation of potential Myt1 kinase inhibitors by TR-FRET based binding assay.	European journal of medicinal chemistry

22257127	2-23-2012	Testing the promiscuity of commercial kinase inhibitors against the AGC kinase group using a split-luciferase screen.	Journal of medicinal chemistry

22221201	1-26-2012	VX-322: a novel dual receptor tyrosine kinase inhibitor for the treatment of acute myelogenous leukemia.	Journal of medicinal chemistry
22807997	1-1-2012	H2O2 production downstream of FLT3 is mediated by p22phox in the endoplasmic reticulum and is required for STAT5 signalling.	PloS one

21936542	10-27-2011	Discovery of 3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea (NVP-BGJ398), a potent and selective inhibitor of the fibroblast growth factor receptor family of receptor tyrosine kinase.	Journal of medicinal chemistry

21429632	6-1-2011	Discovery, synthesis, and investigation of the antitumor activity of novel piperazinylpyrimidine derivatives.	European journal of medicinal chemistry

20156689

3-1-2010

Colony stimulating factor-1 receptor as a target for small molecule inhibitors.

Bioorganic & medicinal chemistry

US8222244	7-18-2012	Staurosporine Derivatives as Inhibitors of FLT3 Receptor Tyrosine Kinase Activity
US8198435	6-13-2012	Crystal form of N-benzoyl-staurosporine
US8076321	12-14-2011	COMPOSITIONS FOR TREATMENT OF SYSTEMIC MASTOCYTOSIS
US7973031	7-6-2011	Staurosporine derivatives as inhibitors of flt3 receptor tyrosine kinase activity
US7973032	7-6-2011	Staurosporine Derivatives for Use in Alveolar Rhabdomyosarcoma
US2010310542	12-10-2010	Pharmaceutical Compositions for treating wouds and related methods
US2010280003	11-5-2010	COMBINATIONS OF JAK INHIBITORS
US2010184820	7-23-2010	COMBINATIONS COMPRISING STAUROSPORINES
US2010056467	3-5-2010	COMBINATION OF IAP INHIBITORS AND FLT3 INHIBITORS
US2010022467	1-29-2010	ANTI-CANCER PHOSPHONATE ANALOGS

US7645747	1-13-2010	Therapeutic phosphonate compounds
US2009286770	11-20-2009	Use of Staurosporine Derivatives for the Treatment of Multiple Myeloma
US2009181930	7-17-2009	KINASE INHIBITORY PHOSPHONATE ANALOGS
US2009156602	6-19-2009	Organic Compounds
US2009075972	3-20-2009	Use of Midostaurin for Treating Gastrointestinal Stromal Tumors
US2008287417	11-21-2008	PHARMACEUTICAL COMPOSITIONS COMPRISING A POORLY WATER-SOLUBLE ACTIVE INGREDIENT, A SURFACTANT AND A WATER-SOLUBLE POLYMER
US7452901	11-19-2008	Anti-cancer phosphonate analogs
US2008221132	9-12-2008	Multi-Functional Small Molecules as Anti-Proliferative Agents
US2008214521	9-5-2008	Sensitization of Drug-Resistant Lung Caners to Protein Kinase Inhibitors
US2008207591	8-29-2008	Organic Compounds

US7417055	8-27-2008	Kinase inhibitory phosphonate analogs
US2008096864	4-25-2008	Treatment Of Gastrointestinal Stromal Tumors With Imatinib And Midostaurin
US2007299049	12-28-2007	Pharmaceutical Uses of Staurosporine Derivatives
US2007281907	12-7-2007	Kinase Inhibitor Phosphonate Conjugates
US2007191338	8-17-2007	Combinations comprising staurosporines
US2006229290	10-13-2006	Staurosporine derivatives for hypereosinophilic syndrome
US2005153990	7-15-2005	Phosphonate substituted kinase inhibitors
US6806266	10-20-2004	Staurosporin derivatives

MIDOSTAURIN HYDRATE

Midostaurin according to the invention is N-[(9S,10R,11R,13R)-2,3,10,11,12,13-hexahydro-10-methoxy-9-methyl-1-oxo-9,13-epoxy-1H,9H-diindolo[1,2,3-gh:3′,2′,1′-lm]pyrrolo[3,4-j][1,7]benzodiazonin-11-yl]-N-methylbenzamide of the formula (II):

or a salt thereof, hereinafter: “Compound of formula II or midostaurin”.

Compound of formula II or midostaurin [International Nonproprietary Name] is also known as PKC412.

Midostaurin is a derivative of the naturally occurring alkaloid staurosporine, and has been specifically described in the European patent No. 0 296 110 published on Dec. 21, 1988, as well as in U.S. Pat. No. 5093330 published on Mar. 3, 1992, and Japanese Patent No. 2 708 047.

………………….

https://www.google.co.in/patents/EP0296110B1

The nomenclature of the products is, on the complete structure of staurosporine ([storage]-NH-CH ₃derived, and which is designated by N-substituent on the nitrogen of the methylamino group

Figure imgb0028

Example 18:

A solution of 116.5 mg (0.25 mmol) of staurosporine and 0.065 ml (0.38 mmol) of N, N-diisopropylethylamine in 2 ml of chloroform is added at room temperature with 0.035 ml (0.3 mmol) of benzoyl chloride and 10 stirred minutes.The reaction mixture is diluted with chloroform, washed with sodium bicarbonate, dried over magnesium sulfate and evaporated. The crude product is chromatographed on silica gel (eluent methylene chloride / ethanol 30:1), mp 235-247 ° with brown coloration.
cut paste may not be ok below

Staurosporine the formula [storage]-NH-CH ₃ (II) (for the meaning of the rest of [storage] see above) as the basic material of the novel compounds was already in 1977, from the cultures of Streptomyces staurosporeus AWAYA, and TAKAHASHI

O ¯

MURA, sp. nov. AM 2282, see Omura, S., Iwai, Y., Hirano, A., Nakagawa, A.; awayâ, J., Tsuchiya, H., Takahashi, Y., and Masuma, R. J. Antibiot. 30, 275-281 (1977) isolated and tested for antimicrobial activity. It was also found here that the compound against yeast-like fungi and microorganisms is effective (MIC of about 3-25 mcg / ml), taking as the hydrochloride = having a LD ₅ ₀ 6.6 mg / kg (mouse, intraperitoneal). Stagnated recently it has been shown in extensive screening, see Tamaoki, T., Nomoto, H., Takahashi, I., Kato, Y, Morimoto, M. and Tomita, F.: Biochem. and Biophys. Research Commun. 135 (No. 2), 397-402 (1986) that the compound exerts a potent inhibitory effect on protein kinase C (rat brain)

…………………

https://www.google.co.in/patents/US5093330

EXAMPLE 18 N-benzoyl-staurosporine

0.035 ml (0.3 mmol) of benzoyl chloride is added at room temperature to a solution of 116.5 mg (0.25 mmol) of staurosporine and 0.065 ml (0.38 mmol) of N,N-diisopropylethylamine in 2 ml of chloroform and the whole is stirred for 10 minutes. The reaction mixture is diluted with chloroform, washed with sodium bicarbonate solution, dried over magnesium sulphate and concentrated by evaporation. The crude product is chromatographed on silica gel (eluant:methylene chloride/ethanol 30:1); m.p. 235

…………………….

Bioorg Med Chem Lett 1994, 4(3): 399

http://www.sciencedirect.com/science/article/pii/0960894X94800049

……………………

http://www.google.com/patents/WO1998007415A2

A variety of PKC inhibitors are available in the art for use in the invention. These include bryostatin (U.S. Patent 4,560,774), safinogel (WO 9617603), fasudil (EP 187371), 7- hydoxystaurosporin (EP 137632B), various diones described in EP 657458, EP 657411 and WO9535294, phenylmethyl hexanamides as described in WO9517888, various indane containing benzamides as described in WO9530640, various pyrrolo [3,4-c]carbazoles as described in EP 695755, LY 333531 (IMSworld R & D Focus 960722, July 22, 1996 and Pharmaprojects Accession No. 24174), SPC-104065 (Pharmaprojects Accession No. 22568), P-10050 (Pharmaprojects Accession No. 22643), No. 4432 (Pharmaprojects Accession No. 23031), No. 4503 (Pharmaprojects Accession No. 23252), No. 4721 (Pharmaprojects Accession No. 23890), No. 4755 (Pharmaprojects Accession No. 24035), balanol (Pharmaprojects Accession No. 20376), K-7259 (Pharmaprojects Accession No. 16649), Protein kinase C inhib, Lilly (Pharmaprojects Accession No. 18006), and UCN-01 (Pharmaprojects Accession No. 11915). Also see, for example, Tamaoki and Nakano (1990) Biotechnology 8:732-735; Posada et al. (1989) Cancer Commun. 1:285-292; Sato et al. (1990) Biochem Biophys. Res. Commun. 173:1252-1257; Utz et al. (1994) Int. J. Cancer 57:104-110; Schwartz et al. (1993) J. Na . Cancer lnst. 85:402-407; Meyer et al. (1989) Int. J. Cancer 43:851-856; Akinaga et al. (1991) Cancer Res. 51:4888-4892, which disclosures are herein incorporated by reference. Additionally, antisense molecules can be used as PKC inhibitors. Although such antisense molecules inhibit mRNA translation into the PKC protein, such antisense molecules are considered PKC inhibitors for purposes of this invention. Such antisense molecules against PKC inhibitors include those described in published PCT patent applications WO 93/19203, WO 95/03833 and WO 95/02069, herein incorporated by reference. Such inhibitors can be used in formulations for local delivery to prevent cellular proliferation. Such inhibitors find particular use in local delivery for preventing rumor growth and restenosis.

N-benzoyl staurosporine is a benzoyl derivative of the naturally occurring alkaloid staurosporine. It is chiral compound ([a]_D=+148.0+-2.0°) with the formula C35H30R1O4 (molecular weight 570.65). It is a pale yellow amorphous powder which remains unchanged up to 220°C. The compound is very lipophilic (log P>5.48) and almost insoluble in water (0.068 mg/1) but dissolves readily in DMSO.

……………………….

staurosporine

Staurosporine (antibiotic AM-2282 or STS) is a natural product originally isolated in 1977 from the bacterium Streptomyces staurosporeus. It was the first of over 50 alkaloids to be isolated with this type of bis-indole chemical structure. The chemical structure of staurosporine was elucidated by X-ray analysis of a single crystal and the absolute stereochemical configuration by the same method in 1994.

Staurosporine was discovered to have biological activities ranging from anti-fungal to anti-hypertensive. The interest in these activities resulted in a large investigative effort in chemistry and biology and the discovery of the potential for anti-cancer treatment

Staurosporine is the precursor of the novel protein kinase inhibitor midostaurin(PKC412). Besides midostaurin, staurosporine is also used as a starting material in the commercial synthesis of K252c (also called staurosporine aglycone). In the natural biosynthetic pathway, K252c is a precursor of staurosporine.

Indolocarbazoles belong to the alkaloid sub-class of bisindoles. Of these carbazoles the Indolo(2,3-a)carbazoles are the most frequently isolated; the most common subgroup of the Indolo(2,3-a)carbazoles are the Indolo(2,3-a)pyrrole(3,4-c)carbazoles which can be divided into two major classes – halogenated (chlorinated) with a fully oxidized C-7 carbon with only one indole nitrogen containing a β-glycosidic bond and the second class consists of both indole nitrogen glycosilated, non-halogenated, and a fully reduced C-7 carbon. Staurosporine is part of the second non-halogenated class.

The biosynthesis of staurosporine starts with the amino acid L-tryptophan in its zwitterionic form. Tryptophan is converted to an imineby enzyme StaO which is an L-amino acid oxidase (that may be FAD dependent). The imine is acted upon by StaD to form an uncharacterized intermediate proposed to be the dimerization product between 2 imine molecules. Chromopyrrolic acid is the molecule formed from this intermediate after the loss of VioE (used in the biosynthesis of violacein – a natural product formed from a branch point in this pathway that also diverges to form rebeccamycin. An aryl aryl coupling thought to be catalyzed by a cytochrome P₄₅₀enzyme to form an aromatic ring system occurs

This is followed by a nucleophilic attack between the indole nitrogens resulting in cyclization and then decarboxylation assisted by StaC exclusively forming staurosporine aglycone or K252c. Glucose is transformed to NTP-L-ristoamine by StaA/B/E/J/I/K which is then added on to the staurosporine aglycone at 1 indole N by StaG. The StaN enzyme reorients the sugar by attaching it to the 2nd indole nitrogen into an unfavored conformation to form intermediated O-demethyl-N-demethyl-staurosporine. Lastly, O-methylation of the 4’amine by StaMA and N-methylation of the 3′-hydroxy by StaMB leads to the formation of staurosporine

US4107297 *	28 Nov 1977	15 Aug 1978	The Kitasato Institute	Antibiotic compound
US4735939 *	27 Feb 1987	5 Apr 1988	The Dow Chemical Company	Insecticidal activity of staurosporine
ZA884238A *				Title not available

Iloprost (ciloprost) used to treat a serious heart and lung disorder called pulmonary arterial hypertension

orphan status Comments Off

Jan 132014

Iloprost (ciloprost)

MF	C22H32O4
Formula Wgt	360.5

6,9ALPHA-METHYLENE-11ALPHA,15S-DIHYDROXY-16-METHYL-PROSTA-5E,13E-DIEN-18-YN-1-OIC ACID

6,9α-methylene-11α,15S-dihydroxy-16-methyl-prosta-5E,13E-dien-18-yn-1-oic acid

Iloprost Molecule

ILOPROST (Ventavis®) is used to treat a serious heart and lung disorder called pulmonary arterial hypertension. While iloprost inhalation solution will not cure this disorder, it is designed to improve symptoms and the quality of life. Generic iloprost inhalation solution is not yet available.

Iloprost is a second generation structural analog of prostacyclin (PGI) with about ten-fold greater potency than the first generation stable analogs, typified by carbaprostacyclin.1 Iloprost binds with equal affinity to the human recombinant IP and EP1 receptors with a Ki of 11 nM.2Iloprost constricts the isolated guinea pig ilium and fundus circular smooth muscle (an EP1 receptor preparation) as strongly as prostaglandin E2 (PGE2) itself.3 Iloprost inhibits the ADP, thrombin, and collagen-induced aggregation of human platelets with an ED50 of about 13 nM.1 In whole animals, iloprost acts as a vasodilator, hypotensive, antidiuretic, and prolongs bleeding time.4 It has been evaluated in several human clinical studies as a treatment for idiopathic pulmonary hypertension.5,6 In these studies, an aerosolized dose of 30 µg/day was effective, and doses as high as 150 µg/day for up to a year were well tolerated.

73873-87-7 CAS NO

78919-13-8 PHENACYL ESTER

Launched – 1992 bayer

Ilomedin®, Ventavis™

iloprost

An eicosanoid, derived from the cyclooxygenase pathway of arachidonic acid metabolism. It is a stable and synthetic analog of EPOPROSTENOL, but with a longer half-life than the parent compound. Its actions are similar to prostacyclin. Iloprost produces vasodilation and inhibits platelet aggregation.

BAY-q-6256 E-1030 SH-401 ZK-36374

BAY Q6256
Ciloprost
Iloprost
Iloprostum
Iloprostum [Latin]
UNII-AHG2128QW6
UNII-JED5K35YGL
Ventavis
ZK 00036374
ZK 36374

Endoprost Ilomedin Ilomédine Ventavis Iloprost is a synthetic prostacyclin analog discovered and developed by Schering AG and Berlex which has been available for more than ten years as therapy for peripheral arterial occlusive disease (PAOD), including Raynaud’s phenomenon and Buerger’s disease.

Iloprost improves blood flow, relieves the pain associated with circulatory disturbances and improves the healing of ulcers, which can develop as a result of poor arterial blood flow. Iloprost also produces vasodilatation of the pulmonary arterial bed, with subsequent significant improvement in pulmonary artery pressure, pulmonary vascular resistance and cardiac output, as well as mixed venous oxygen saturation. In 2003, Schering AG received approval in the E.U. for an inhaled formulation of iloprost (Ventavis[R]) for the treatment of primary pulmonary hypertension and the following year, the product was launched in Germany and the U.K.

Introduction on the U.S. market took place in March 2005 by CoTherix for the same indication in patients with NYHA Class III or IV symptoms. Iloprost is also available for the treatment of pulmonary hypertension and peripheral vascular disease. CoTherix had been developing a dry powder for potential use in the treatment of pulmonary hypertension; however, no recent development has been reported for this research. In Japan, phase III clinical trials are ongoing for the treatment of pulmonary arterial hypertension. In 2003, CoTherix licensed exclusive rights from Schering AG to market iloprost in the U.S. for primary pulmonary hypertension while Schering AG retained rights to the product outside the U.S. In April 2005, CoTherix established a collaborative research and development agreement with Quadrant to develop an extended-release formulation of iloprost inhalation solution. Iloprost was designated as an orphan medicinal product for the treatment of pulmonary hypertension in December 2000 by the EMEA and will fall under orphan drug protection until 2013.

The FDA has assigned to iloprost several orphan drug designations. In 1989, iloprost solution for infusion was granted orphan drug designation for the treatment of Raynaud’s phenomenon secondary to systemic sclerosis followed by another orphan drug designation in 1990 for iloprost solution for injection for the treatment of heparin-associated thrombocytopenia. In 2004, an additional orphan drug designation for iloprost inhalation solution for the treatment of pulmonary arterial hypertension was assigned.

The status has also been assigned in the E.U. for this indication. In 2012, orphan drug designation was assigned in the U.S. for the treatment of purpura fulminans in combination with eptifibatide and for the treatment of pulmonary arterial hypertension. In 2007, Cotherix was acquired by Actelion.

ILOPROST

iloprost phenacyl ester

Ventavis (TN), Iloprost phenacyl ester, Iloprost-PE, Iloprost (INN), CHEMBL138694, CHEMBL236025, AC1O6009, DAP000273, CID5311181

Molecular Formula: C₃₀H₃₈O₅ Molecular Weight: 478.61972

2-oxo-2-phenylethyl 5-[(2Z)-5-hydroxy-4-[(1E)-3-hydroxy-4-methyloct-1-en-6-yn-1-yl]-octahydropentalen-2-ylidene]pentanoate

IMPORTANT PUBLICATIONS

Ciloprost Drugs Fut 1981, 6(11): 676

A carbohydrate approach for the formal total synthesis of the prostacyclin analogue (16S)-iloprost Tetrahedron Asymmetry 2012, 23(5): 388

Angewandte Chemie, 1981 , vol. 93, 12 pg. 1080 – 1081

Tetrahedron Letters, 1992 , vol. 33, 52 pg. 8055 – 8056

Helvetica Chimica Acta, 1986 , vol. 69, 7 pg. 1718 – 1727

Journal of Medicinal Chemistry, 1986 , vol. 29, 3 pg. 313 – 315

US5286494 A1

US 4474802

US 2013253049

uS 2013184295

WO 1992014438

WO 1993007876

WO 1993015739

WO 1994008584

WO 2013040068

WO 2012174407

WO 2011047048

EP0011591A1 *	Oct 18, 1979	May 28, 1980	Schering Aktiengesellschaft	Prostane derivatives, their production and pharmaceutical compositions containing them
EP0084856A1 *	Jan 19, 1983	Aug 3, 1983	Toray Industries, Inc.	5,6,7-Trinor-4, 8-inter-m-phenylene prostaglandin I2 derivatives
EP0099538A1 *	Jul 11, 1983	Feb 1, 1984	Schering Aktiengesellschaft	Carbacyclines, process for their preparation and their use as medicines

……………………………………

5,6,7-trinor-4,8-inter-m-phenylene prostaglandin 1₂derivatives.
Prostaglandin I₂, hereinafter referred to as PGI₂, of

was first found by J.R. Vane et.al. in 1976 and is biosynthe- sized from arachidonic acid via endoperoxide(PGH₂ or PGG₂) in the vascular wall. PGI₂ is well known to show potent activity to inhibit platelet aggregation and to dilate peripheral blood vessels(C & EN, Dec. 20, 1976, page 17 and S. Moncade et al., Nature, 263,633(1976)).
[0003]

Because of the unstable exo-enolether structure thereof, PGI₂ is extremely unstable even in a neutral aqueous solution and is readily converted to 6-oxo-PGF_1α which is almost physiologically inactive. Such instability of PGI₂ is a big obstacle to its use as a drug. Furthermore, PGI₂ is unstable in vivo as well and shows only short duration of action.
The compounds of the present invention are novel PGI₂ derivatives in which the exo-enolether moiety characteristic of PGI₂ is transformed into “inter-m-phenylene” moiety. In this sense the compounds may be regarded as analogs of PGI₂.
The compounds of the present invention feature much improved stability in vitro as well as in vivo in comparison with PGI₂. The compounds are highly stable even in an aqueous solution and show long duration of action in vivo. Further, the compounds have advantages over PGI₂ for pharmaceutical application because they exhibit more selective physiological actions than PGI₂, which has multifarious, inseperable biological activities.
Some prostaglandin I₂ derivatives which have 5,6,7-tri- nor-4,8-inter-m-phenylene structure have already been described in publication by some of the present authors. (Kiyotaka Ohno, Hisao Nishiyama and Shintaro Nishio, U.S.P. 4,301,164 (1981)). But, the compounds of the present invention, which feature the presence of alkynyl side chain, have more potent physiological activities as well as decreased side effects than the already disclosed compounds analogous to those of the present invention.
It is an object of this invention to provide novel prostaglandin I₂derivatives which are stable and possess platelet aggregation-inhibiting, hypotensive, anti-ulcer and other activities.

is named as 16-methyl-18,19-tetradehydro-5,6,7-trinor-4,8-inter-m-phenylene PGI₂.
Alternatively, the compound of the formula (II) may be named as a derivative of butyric acid by the more formal nomenclature. In such a case, the condensed ring moiety is named after the basical structure of 1H-cyclopenta[b]benzofuran of the following formula:

The term “synthetic prostacyclins” as used herein can refer to any prostacyclin that can be prepared via synthetic organic chemistry, including those prostacyclins that are also naturally occurring, such as Prostacyclin (PGI₂):

which is also known as Epopreostenol.

Thus, examples of synthetic prostacyclins include, but are not limited to: Prosta

lloprost, which has the structure:

Trepro inil (also known as Rumodolin), which has the structure:

Beraprost, which has the structure:

as well as the esters, stereoisomers, and salts thereof, or other analogues or derivatives of the recited synthetic prostacyclins, such as compounds comprising other aliphatic linker groups linking the carboxylic acid group to the cyclic components of the synthetic prostacyclins, compounds containing additional alkene and/or alkyne bonds, and/or compounds containing additional substituents on the cyclic components of the synthetic prostacyclins.

iloprost, in contrast to PGI.sub.2 a stable prostacyclin derivative, has been known since 1980 by European patent application EP 11591, no other prostacyclin derivative has previously been tested in this indication. It is therefore reasonable to assume that a spontaneous healing is involved in the published case.

It has now been found, surprisingly, that iloprost is effective in the case of cerebral malaria.

For salt formation of iloprost, inorganic and organic bases are suitable, as they are known to one skilled in the art for the formation of physiologically compatible salts. For example, there can be mentioned: alkali hydroxides, such as sodium and potassium hydroxide, alkaline-earth hydroxides, such as calcium hydroxide, ammonia, amines, such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, morpholine, tris-(hydroxymethyl)-methylamine, etc.

The β-cyclodextrin clathrate formation takes place according to EP 259468.

The production of iloprost is described in detail in EP 11591.
- Nileprost iloprost, and a process for preparing these compositions.
- From EP 11 591 already carbacyclin derivatives of the cytoprotective effect on the gastric and intestinal mucosa, and the myocardial cytoprotection using carbacyclin derivatives is known.
- It has now been found that iloprost (I) and Nileprost (II)
  
  and their salts with physiologically acceptable bases and cytoprotective effect in the kidney.
- Forming salts of iloprost and Nileprost inorganic and organic bases are suitable, as are known to those skilled in the formation of physiologically compatible salts known. Examples which may be mentioned are: alkali metal hydroxides, such as sodium and potassium hydroxide, alkaline earth metal hydroxides such as calcium hydroxide, ammonia, amines, such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, morpholine, tris (hydroxymethyl) methylamine, etc.
- The production of iloprost and is described in detail in EP Nileprost 2234 and EP 11591.
………………..

J. Med. Chem., 1986, 29 (3), pp 313–315

DOI: 10.1021/jm00153a001

http://pubs.acs.org/doi/pdf/10.1021/jm00153a001

see paper

………………………………..

A carbohydrate approach for the formal total synthesis of the prostacyclin analogue (16S)-iloprost Tetrahedron Asymmetry 2012, 23(5): 388

The formal total synthesis of the synthetic and stable analogue of prostacyclin, (16S)– iloprost is described via a convergent synthesis starting from readily available d-glucose. Julia olefination and the aldol reaction are the key steps involved in the synthesis.

……………………………………

https://www.google.co.in/patents/EP0011591A1

Used as the starting material for the method described above ketone of general formula II can be prepared by reacting an alcohol of the formula IV

(EJCorey et al., J. Amer. Chem. 93, 1490 (1971)) transformed with dihydropyran in the presence of catalytic amounts of p-toluenesulfonic acid in the tetrahydropyranyl ether V.
[0026]

Lactone V with Diisobatylauminiumnydrid reduced at -70 ° C to the lactol VI, which is converted by Wittiereaktion Triphenylphosphoniummethylen with the olefin VII. After conversion to the tosylate with p-toluenesulfonyl chloride in the presence of pyridine is obtained by reaction with potassium nitrite in the dimethylsulfoxide 9SS-configured alcohol IX, which is converted with p-toluenesulfonyl chloride in the presence of pyridine in the tosylate X. Reaction with Malonsäurediäthylester in presence of potassium tert-butoxide gives the diester XI, which is converted by decarbalkoxylation with sodium cyanide in dimethyl sulfoxide in the ester XII.
[0027]

Oxidative cleavage of the double bond in the compound XII with Hatrium p j _o dat _it out in the presence of catalytic amounts of osmium tetroxide to give the aldehyde XIII, which is oxidized with Jones reagent to the acid XIV which is then esterified with diazomethane to the compound XV. By Dieckmann condensation of XV with potassium tert-butoxide in tetrahydrofuran is obtained a mixture of isomers of the ketocarboxylic acid ester XVI and XVII, which by means of a decarbalkoxylation with 1,4-diazabicyclo [2,2,2] octane in xylene converted into ketone XVIII as the only reaction product is.
[0028]

The removal of the Tetrahydropyranylätherschutzgruppe delivers the alcohol XIX, which is esterified with benzoyl chloride in the presence of pyridine to give the ester XX.
[0029]

Benzyläthers hydrogenolytic cleavage of a catalytic amount of acid gives the alcohol XXI, which is according to ketalization compound XXII oxidized with Collins reagent to aldehyde XXIII.
[0030]

This aldehyde XXIV with a phosphonate of the general formula

wherein D, E and R ₂ have the meanings given above is reacted in a Olefinicrungsreaktion to a ketone of the formula XXV.
[0031]

After reduction of the 15-keto group with zinc borohydride or sodium borohydride or reaction with alkylmagnesium bromide or alkyllithium and. Epimerentrennung obtain the 15α-alcohols XXVI (PG numbering).
[0032]

After hydrolysis of the ester group, for example with potassium carbonate in methanol and ketal cleavage with aqueous acetic acid yields the ketone of the formula XXVII,

……………………………………

THANKS AND REGARD’S

DR ANTHONY MELVIN CRASTO Ph.D GLENMARK SCIENTIST , NAVIMUMBAI, INDIA

did you feel happy, a head to toe paralysed man’s soul in action for you round the clock need help, email or call me

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I was paralysed in dec2007, Posts dedicated to my family, my organisation Glenmark, Your readership keeps me going and brings smiles to my family

Glybera – The Most Expensive Drug in the world & First Approved Gene Therapy in the West

orphan status, Uncategorized 2 Responses »

Jul 162013

Glybera® (alipogene tiparvovec), the first gene therapy approved in the Western world, is used to treat lipoprotein lipase deficiency (LPLD or familial hyperchylomicronemia), a very rare inherited condition that is associated with increased levels of fat in the blood.

One in a million people have damaged copies of a gene which is essential for breaking down fats. Without lipoprotein lipase (LPL), these patients have significantly increased levels of chylomicrons that carry fat throughout the body. Accumulation of these chylomicrons in the pancreas can lead the the often painful and potentially fatal condition pancreatitis.

Gene therapy using an AAV vector. A new gene is inserted into a cell using the AAV protein shell. The new gene often integrates in a precise location and then makes functional protein to treat a disease.

Alipogene tiparvovec (marketed under the trade name Glybera) is a gene therapytreatment that compensates for lipoprotein lipase deficiency (LPLD), which can cause severe pancreatitis. In July 2012, the European Medicines Agency recommended it for approval, the first recommendation for a gene therapy treatment in either Europe or the United States. The recommendation was endorsed by the European Commission in November 2012 and commercial rollout is expected in late 2013.

http://en.wikipedia.org/wiki/Alipogene_tiparvovec

Glybera, developed by Amsterdam-based UniQure and approved in the European Union in November 2012, is administered only once to be effective but will cost around $1.6 million per patient, a new record for pricey modern medicines. Up to this point in time, Alexion Pharmaceuticals’ orphan drug Soliris, which costs about $410,000/patient/year, has been the most expensive orphan drug in the world. The commerical rollout of Glybera is expected in late 2013.

When an important enzyme is missing, one option is to periodically deliver an exogenously produced replacement, which is what millions of people with diabetes do each day. The other, more permanent option, is to induce one’s own cells to produce the enzyme. Glybera is capable of doing this by encasing the correct LPL gene in an adeno-associated virus (AAV) which hones in on muscle cells. When the AAVs reach their target, they deliver the gene and within a few weeks functional protein is being produced.

The Dutch firm uniQure plans on making Glybera available at specialized medical centers throughout the European Union in summer 2013 and is currently seeking regulatory approval in the US, Canada, and other markets. The company is also developing a raft of other gene therapies to treat diseases including blood clotting disorder haemophilia B, metabolic disorder acute intermittent porphyria, central nervous system disorder Parkinson’s and enzyme disorder Sanfilippo B.

Use of gene therapy has been controversial, and not always successful.

Jesse Gelsinger, an 18-year-old student from Arizona with a mild genetic disorder, had volunteered to participate in a gene therapy trial for the rare genetic disease ornithine transcarbamylase deficiency (OTC) at the University of Pennsylvania in Philadelphia in 1999. He died four days later due to a massive immune response. That failure was followed in 2003 by the development of a leukemia-like disease among two French children treated for ‘bubble baby’ syndrome (X-SCID, severe combined immunodeficiency syndrome) and in 2007 by the death of a woman who received a modified gene in an arthritis trial and

Only two other gene therapies (Gendicine and H101) have previously been approved for sale, both in China. Both have so far shown limited success.

Gendicine (今又生), the first commercialized gene therapy in the world from Shenzhen-based SiBiono in China — Gendicine , the first commercialized gene therapy in the world from Shenzhen-based SiBiono in China

In October 2003, China’s State Food and Drug Administration (SFDA) approved Gendicine , the first commercialized gene therapy in the world from Shenzhen-based SiBion, after the medicine showed some promising results in tumor regression among 99 head and neck squamous cell carcinoma patients. Yet after desperate struggles to expand its market, SiBiono was acquired by NASDAQ-listed Chinese pharmaceutical firm Benda for only US$15 million (£7.6 million).

In November 2005, SFDA approved H101, the world’s first commercialized tumor-killing virus, produced by Shanghai Sunway Biotech . A subtype of gene therapy, H101 (commercially sold as Oncorineis a genetically-modified type-five adenovirus which can selectively replicate inside tumour cells with dysfunctional p53 genes, killing them and stopping the cancer’s spread. Oncorine, which hit the market in November 2006, has also reported a minimal market share.

Basilea reports isavuconazole orphan drug designation by US FDA

orphan status Comments Off

May 282013

isavuconazonium as sulfate

Isavuconazole (BAL4815) is a triazole antifungal. Its prodrug, Isavuconazonium sulfate (BAL8557) is currently in Phase III clinical trials.

Basilea reports isavuconazole orphan drug designation by US FDA
ITNews
Pharmaceutica AG / Basilea reports isavuconazole orphan drug designation by U.S. FDA .

Basel, Switzerland, May 28, 2013 – Basilea Pharmaceutica Ltd. (SIX: BSLN) reported today that the U.S. Food and Drug Administration (FDA) has granted orphan drug designation to isavuconazole for the treatment of invasive aspergillosis. An FDA orphan drug designation provides several benefits to the sponsor including a seven-year market exclusivity from product approval in the U.S. Isavuconazole was previously granted FDA fast track status that is designed to facilitate development and expedite the review of drugs to treat serious diseases

Isavuconazole (drug substance: isavuconazonium sulfate) is an investigational intravenous and oral broad-spectrum antifungal.

In collaboration with Astellas Pharma Inc., isavuconazole is being investigated in phase 3 clinical … read all at

http://www.itnews.it/news/2013/0528071501820/basilea-reports-isavuconazole-orphan-drug-designation-by-u-s-fda.html