LUCITANIB

6-[7-[(1-aminocyclopropyl)methoxy]-6-methoxyquinolin-4-yl]oxy-N-methylnaphthalene-1-carboxamide

6-(7-((l-aminocyclopropyl)methoxy)-6-methoxyquinolin-4-yloxy)- N-methyl- 1 -naphthamide

1058137-23-7 (E-3810 free base); 1058137-84-0  (E-3810 HCl salt)

A 4-(3-methoxypropoxy)-3-methylpyridinyl derivative of timoprazole that is used in the therapy of STOMACH ULCERS and ZOLLINGER-ELLISON SYNDROME. The drug inhibits H(+)-K(+)-EXCHANGING ATPASE which is found in GASTRIC PARIETAL CELLS.
For in advanced solid tumors.

Lucitanib (E-3810): Lucitanib, also known as E-3810,  is a novel dual inhibitor targeting human vascular endothelial growth factor receptors (VEGFRs) and fibroblast growth factor receptors (FGFRs) with antiangiogenic activity. VEGFR/FGFR dual kinase inhibitor E-3810 inhibits VEGFR-1, -2, -3 and FGFR-1, -2 kinases in the nM range, which may result in the inhibition of tumor angiogenesis and tumor cell proliferation, and the induction of tumor cell death. Both VEGFRs and FGFRs belong to the family of receptor tyrosine kinases that may be upregulated in various tumor cell type

Overview

http://www.clovisoncology.com/products-companion-diagnostics/lucitanib/

Lucitanib is an oral, potent inhibitor of the tyrosine kinase activity of fibroblast growth factor receptors 1 through 3 (FGFR1-3), vascular endothelial growth factor receptors 1 through 3 (VEGFR1-3) and platelet-derived growth factor receptors alpha and beta (PDGFR α-ß). We own exclusive development and commercial rights to lucitanib on a global basis, excluding China. Lucitanib rights to markets outside of the U.S. and Japan have been sublicensed to Les Laboratoires Servier (Servier). We are collaborating with Servier on the global clinical development of lucitanib.

A Phase I/IIa clinical trial of lucitanib was initiated in 2010 and has demonstrated multiple objective responses in FGFR1 gene-amplified breast cancer patients, and objective responses were also observed in patients with tumors often sensitive to VEGFR inhibitors, such as renal cell and thyroid cancer. FGFR amplification is common in a number of tumor types, including breast cancer and squamous non-small cell lung cancer, and we intend to study lucitanib in these cancers as well as other solid tumors exhibiting FGFR pathway activation. A broad Phase II development program has been initiated by us and Servier in multiple indications, including advanced breast cancer and squamous NSCLC. For more information or to participate in the trials, contact the Clovis Oncology Clinical Trial Navigation Service at 1-855-262-3040, or 303-625-5010, or clovistrials@emergingmed.com.

http://www.asianscientist.com/2013/09/pharma/servier-license-lucitanib-simm-china-2013/

WO 2008/112408 Al and US 2008/0227812 Al disclose angiogenesis inhibitors with quinoline structure, useful for the treatment of neoplasias. One of the disclosed products is 6-(7-((l-aminocyclopropyl)methoxy)-6- methoxyquinolin-4-yloxy)-N-methyl-l-naphthamide of formula (I), described in example 3 of the above mentioned patent applications.

According to said documents, compound (I) is prepared by removing the benzyloxycarbonyl protective group from the compound benzyl l-((6- methoxy-4-(5-(methylcarbamoyl)-naphthalen-2-yloxy)quinolin-7- yloxy)methyl)cyclopropyl carbamate (II):

in acid medium or by hydrogenolysis, to give compound (I).

Compound (II) is obtained in a number of steps with different processes in which the benzyloxycarbonyl protected 1 -amino- 1-cyclopropylmethyl moiety is introduced by subjecting the acyl azide obtained from l-((6- methoxy-4-(5-(methylcarbamoyl)naphthalen-2-yloxy)quinolin-7- yloxy)methyl)cyclopropanecarboxylic acid of formula (III):

to Curtius rearrangement, in the presence of benzyl alcohol, or by alkylation of 6-(7-hydroxy-6-methoxyquinolin-4-yloxy)-N- methyl-1-naphthamide of formula (IV):

with 1 -benzyloxy carbony lamino- 1 -methylsolfonyloxymethyl- cyclopropane of formula (V):

The above mentioned applications do not provide yields concerning both the preparation of compound (II) by the two above mentioned reactions, and the conversion of compound (II) to (I).

Compound (III) is prepared by a process in which the 1-carboxy-l- cyclopropylmethyl moiety is introduced in 4-hydroxy-3-methoxyacetophenone as in the form of the ethyl ester, followed by formation of the 4- hydroxyquinoline ring and, finally, by the introduction of the 1- naphthylcarboxyamido fragment.

It is well known that the reactions requiring the use of azides, such as the formation of acyl azides, or Curtius rearrangement of the latter, are potentially hazardous as they involve risk of explosions, therefore they are not suitable for use in preparations on large scale. The synthetic methods reported in WO 2008/1 12408 and US

2008/0227812 include, inter alia, a general synthetic scheme in which the cycloalkyl-alkyl portion of the products is introduced by reaction between a cycloalkyl-alkyl mesylate and an hydroxy or amino acetophenone, followed by nitration to give a nitroacetofenone, reduction of the nitro group to amino group, formation of the 4-hydroxyquinoline ring and further work up of the latter to the final products. The above mentioned applications do not provide examples of the use of this process for compound (I) or the other described products.

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http://www.google.com/patents/WO2010105761A1?cl=en

LUCITANIB

Example 1: Preparation of l-[(4-acetyl-2-methoxyphenoxy)methyl]- N-benzyloxycarbonyl-1-aminocyclopropane

A 10 L reactor equipped with mechanical stirrer was loaded with triphenylphosphine (340.0 g, 1.296 mol) and THF (2 L) and the suspension was cooled with an ice bath. The stirred suspension was then slowly added with DIAD (264 g, 1.296 mol) over 30 minutes. After stirring for 30 min at 0⁰C, the stirred suspension was added dropwise with a solution of 4-hydroxy- 3-methoxyacetofenone (180 g, 1.08 mol) and DIPEA (210 g, 1.62 mol) in THF (1500 mL). The suspension was left under stirring for 45 min at 0⁰C, then added dropwise with a solution of 1-benzyloxycarbonylamino-l- hydroxymethylcyclopropane (China Gateway) (240 g, 1.08 mol) in THF (1500 mL). After Ih, LC-MS analysis of a sample from the reaction mixture showed the complete disappearance of 1-benzyloxycarbonylamino-l- hydroxymethylcyclopropane. The reaction mixture was evaporated and the crude product was recrystallized with EtOH 95% (4000 mL) to give l-[(4- acetyl-2-methoxyphenoxy)methyl]-N-benzyloxycarbonyl- 1 – aminocyclopropane (214 g, yield: 53.5%) as a white solid.

¹H-NMR (300 MHz, CDCl₃): δ: 7.41-7.45 (m, 2 H), 7.26 (s, 5 H), 6.77 (d, 1 H), 5.43 (s, 1 H), 5.00 (s, 2 H), 4.04 (s, 2 H), 3.82 (s, 3 H), 2.49 (s, 3H), 0.92 (m, 4 H).

LC-MS: M+H⁺: 370.4

Example 2: Preparation of l-[(4-acetyl-2-methoxy-5- nitrophenoxy)methyl]-N-benzyloxycarbonyl-l-aminocycIopropane

A solution of HNO₃ (65%, 3 mL) in Ac₂O (2 mL) at 0°C was slowly added with a suspension of the compound of Example 1 (1.1 g, 2.9 mmol) in

Ac₂O (3 mL). After stirring at 0⁰C for 2 h, the reaction mixture was poured into 50 mL of ice/water and the precipitate was recovered by filtration. The resulting yellow solid was recrystallized with 95% EtOH (5 mL) to give l-[(4- acetyl-2-methoxy-5-nitrophenoxy)methyl]-N-benzyloxycarbonyl-l- aminocyclopropane (0.69 g, yield: 56%) as a yellow solid.

¹H-NMR (300 MHz, CDCl₃): δ: 7.52 (s, 1 H), 7.26 (s, 5 H), 6.67 (s, 1 H), 5.36 (s, IH), 5.02 (s, 2 H), 4.05 (s, 2 H), 3.86 (s, 3 H), 2.42 (s, 3 H), 0.94 (m, 4 H).

LC-MS: M+H⁺: 414.41

Example 3: Preparation of l-[(4-(3-dimethylaminopropenoyl)-2- methoxy-5-nitrophenoxy)methyl]-N-benzyloxycarbonyl-l- aminocyclopropane

A mixture of the compound of Example 2 (1.7 g, 4.1 mmol) and N₅N- dimethylformamide dimethylacetal (0.9 g, 8.2 mmol) in DMF (6 mL) was stirred at 100⁰C for 2 h. After cooling at room temperature, the reaction mixture was diluted with water (30 mL) and extracted with AcOEt (3 x 50 mL). The combined organic phases were washed with brine (2 x 50 mL), dried and evaporated to give l-[(4-(3-dimethylaminopropenoyl)-2-methoxy-5- nitrophenoxy)methyl]-N-benzyloxycarbonyl-l -aminocyclopropane (1.9 g, yield: 95%) as a yellow solid. 1H-NMR (300 MHz, CDCl₃): δ: 7.50 (s, 1 H), 7.27 (s, 5 H), 6.75 (s, 1

H), 5.44 (s, 1 H), 5.23 (s, 1 H), 5.1 1 (br, 1 H), 5.01 (s, 2 H), 4.04 (s, 2 H), 3.83 (s, 3 H), 2.78-3.00 (m, 6 H), 0.94 (m, 4 H) LC-MS: M+H⁺: 470.49

Example 4: Preparation of l-[(4-hydroxy-6-methoxyquinolin-7- yloxy)methyl]-N-benzyloxycarbonyl-l-aminocyclopropane

A mixture of the compound of Example 3 (1.5 g, 3.2 mmol) and powder iron (1.8 g, 32 mmol) in AcOH (15 mL) was stirred a 80⁰C for 2 h. The reaction mixture was cooled at room temperature, diluted with AcOEt (150 mL), filtered and washed with 50 ml of AcOEt. The filtration liquors were combined, washed with water (2 x 100 mL) and an NaHCO₃ saturated solution (2 x 100 mL), dried and evaporated to give l-[(4-hydroxy-6-methoxyquinolin-7-yloxy)methyl]-N- benzyloxycarbonyl-1 -aminocyclopropane (1.2 g, yield: 95%) as a yellow solid.

¹H-NMR (300 MHz, MeOD): δ: 7.75 (d, 1 H), 7.51 (s, 1 H), 7.15 (m, 5 H), 6.80 (br, 1 H), 6.20 (d, 1 H), 4.97 (s,2 H), 4.05 (s, 2 H), 3.84 (s, 3 H), 0.87 (m, 4 H).

LC-MS: M+H⁺: 395.2

Example 5: Preparation of l-[(4-chloro-6-methoxyquinolin-7- yloxy)methyl]-N-benzyIoxycarbonyl-l-aminocyclopropane

a) By chlorination of the compound of Example 4

A 50 ml round-bottom flask fitted with magnetic stirrer, thermometer, condenser and kept under nitrogen atmosphere, was loaded at 20°/25°C with 3.90 g (9.89 mmol) of the compound of Example 4 and 25 ml of POCl₃. The resulting suspension became a solution after stirring for a few minutes. The solution was heated at 85°C inner T and after 30 minutes the reaction was monitored by TLC, showing the disappearance of the starting product. The solution was cooled and dropwise added, over about 30 minutes and keeping the temperature below 10⁰C, to a mixture of 250 ml of DCM and 250 ml of water, cooled at 0⁰C. After completion of the addition, stirring was maintained for 30 minutes at 0°-10°C. The phases were separated and the aqueous phase was washed with 150 ml of DCM; the phases were separated and the organic phases combined. The combined organic phase was added with 150 ml of water, stirred at 20°/25°C for 15 minutes and pH was adjusted to 7-8 with a sodium bicarbonate saturated solution. The phases were separated and the organic phase was washed with 150 ml of water; the phases were separated, the organic phase was dried with sodium sulfate, filtered and the solvent evaporated off by distillation under vacuum. Stripping with ethyl ether afforded 3.8 g of a brownish solid. The solid residue was dissolved in 20 ml of tert-butyl methyl ether, stirring at 20°/25°C for an hour; filtered and washed with ter /-butyl methyl ether, then dried to obtain l-[(4-chloro-6- methoxyquinolin-7-yloxy)methyl]-N-benzyloxycarbonyl- l- aminocyclopropane (3.4 g; yield: 87%) having (¹H-NMR) titre of 95%.

¹H-NMR (500 MHz, DMSO-d₆) δ ppm: 8.61 (d, 1 H), 7.91 (s, 1 H), 7.56 (s, 1 H), 7.44 (s, 1 H), 7.38 (s, 1 H), 7.29 (m, 5 H), 4.99 (s, 2 H), 4.23 (s, 2 H), 3.97 (s, 3 H), 0.87 (m, 4 H). b) by Mitsunobu reaction between 4-chloro-7-hydroxy-6- methoxyquinoline and 1 -benzyloxycarbonylamino- 1 – hydroxymethylcyclopropane 20 ml of DCM were added with 4-chloro-7-hydroxy-6- methoxyquinoline (300 mg, 1.43 mmol; from China Gateway),

1 -benzyloxycarbonylamino- 1 -hydroxymethylcyclopropane (412 mg,

1.87 mmol, 1.3 eq; from China Gateway) and triphenylphosphine (490 mg,

1.87 mmol, 1.3 eq). The resulting solution was dropwise added with a solution of DEAD (378 mg, 1.87 mmol, 1.3 eq) in 3 ml of DCM, keeping the temperature at 0⁰C for 2 hours. The mixture was then left at 10⁰C for 20 hours, then filtered to recover the unreacted 4-chloro-7-hydroxy-6- methoxyquinoline. The filtrate was evaporated under vacuum and the resulting residue was added with 20 ml of 95% EtOH and left under stirring for 30 min. The solid was collected by filtration, washed with 5 ml of 95% EtOH and dried under vacuum to give l-[(4-chloro-6-methoxyquinolin-7-yloxy)methyl]-

N-benzyloxycarbonyl-1-aminocyclopropane (273 mg; yield: 46%).

LC-MS: M+H⁺: 413.1

Example 6: Preparation of benzyl l-[(6-methoxy-4-(5- (methylcarbamoyl)naphthalen-2-yloxy)quinolin-7-yloxy)methyl)]cyclopropyl carbamate (II)

A solution of 0.51 g (2.53 mmol) of 6-hydroxy-N-methyl- 1 – naphthamide prepared according to WO2008/112408, 2, 7 ml of 2,6-lutidine and 0.3 g (2.42 mmol) of DMAP, kept at 20°/25°C and under nitrogen atmosphere, was added with the compound of Example 5 (1.0 g, NMR titre 95%, 2.30 mmol). The suspension was heated to 140⁰C inner temperature for

6 hours; then cooled to 20°/25°C and added with 80 ml of water and kept under stirring a 20°/25°C for 1 hour; the suspension was filtered and washed with water, to afford 0.88 g (yield: 66%) of benzyl l-[(6-methoxy-4-(5-

(methylcarbamoyl)naphthalen-2-yloxy)quinolin-7-yloxy)methyl)]cyclopropyl carbamate (II).

¹H-NMR (500 MHz, DMSO-d₆) δ ppm: δ: 8.56 (d, 1 H), 8.50 (d, 1 H), 8.39 (d, 1 H), 8.04 (d, 1 H), 7.94 (s, 1 H), 7.87 (s, 1 H), 7.59 (m, 4 H), 7.41 (s, 1 H), 7.44 (s, 1 H), 7.30 (m, 5 H), 6.56 (d, 1 H), 5.01 (s, 2 H), 4.48 (s, 2 H), 4.23 (s, 2 H), 3.95 (s, 3 H), 0.87 (m, 4 H). LC-MS: M+H⁺: 578.3

Example 7: Preparation of 6-(7-((l-aminocyclopropyl)methoxy)-6- methoxyquinolin-4-yloxy)-N-methyl-l-naphthamide (I)

A mixture of the compound of Example 6 (0.24 g, 0.42 mmol) in 2 ml of a solution of 40% HBr in acetic acid was stirred at 30⁰C for 3h, then added with 10 ml of water and the reaction mixture was extracted with AcOEt (2 x 10 mL). The organic phases were removed. The aqueous solution was dropwise added with a solution of 50% NaOH to reach pH 10. The mixture was extracted with DCM (3 x 20 mL) and the combined organic phases were dried and evaporated to give a crude containing 6-(7-((l-aminocyclopropyl)methoxy)-6-methoxyquinolin-4- yloxy)-N-methyl-l-naphthamide (I) with purity higher than >94% by LC-MS analysis. This crude was further purified by chromatography on a silica gel column eluting with DCM/MeOH 10: 1), to afford 6-(7-((l- aminocyclopropyl)methoxy)-6-methoxyquinolin-4-yloxy)-N-methyl-l- naphthamide (I) having purity higher than 98% by LC-MS analysis (140 mg, yield: 76%).

¹H-NMR (500 MHz, DMSO-d₆) δ ppm: 8.47 (d, 2 H), 7.87 (d, 1 H), 7.53 (m, 3 H), 7.51 (m, 1 H), 7.44 (d, 1 H), 7.38 (s, 1 H), 6.50 (d, 1 H), 6.16 (d, 1 H), 5.01 (s, 2 H), 4.05 (s, 2 H), 4.03 (s, 3 H), 3.12 (d, 3 H), 2.09 (m, 2 H), 0.80 (m, 4 H).

LC-MS: M+H⁺: 444.0

synthesis…….will be updated

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Patent Reference:

EOS ETHICAL ONCOLOGY SCIENCE S.p.A. in abbreviated form EOS S.p.A.; SPINELLI, Silvano; LIVI, Valeria Patent: WO2010/105761 A1, 2010 ; Location in patent: Page/Page column 21 ;

CAS NO. 1058137-23-7, 6-[7-[(1-aminocyclopropyl)methoxy]-6-methoxyquinolin-4-yl]oxy-N-methylnaphthalene-1-carboxamide H-NMR spectral analysis

CAS NO. 1058137-23-7, 6-[7-[(1-aminocyclopropyl)methoxy]-6-methoxyquinolin-4-yl]oxy-N-methylnaphthalene-1-carboxamide C-NMR spectral analysis