NZ535318A - Processes for the preparation of combretastatins - Google Patents
Processes for the preparation of combretastatinsInfo
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- NZ535318A NZ535318A NZ535318A NZ53531803A NZ535318A NZ 535318 A NZ535318 A NZ 535318A NZ 535318 A NZ535318 A NZ 535318A NZ 53531803 A NZ53531803 A NZ 53531803A NZ 535318 A NZ535318 A NZ 535318A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/04—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/78—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
- C07C217/80—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings
- C07C217/82—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings of the same non-condensed six-membered aromatic ring
- C07C217/84—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings of the same non-condensed six-membered aromatic ring the oxygen atom of at least one of the etherified hydroxy groups being further bound to an acyclic carbon atom
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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- Transition And Organic Metals Composition Catalysts For Addition Polymerization (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
- Solid-Sorbent Or Filter-Aiding Compositions (AREA)
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Abstract
Disclosed are processes for the preparation of combretastatins of general formula (I) in which A represents an amino group, comprising condensing a (3,4,5-trimethoxybenzyl)triphenylphosphonium salt with a 3-amino-4-methoxy benzaldehyde or condensing a (3-amino-4-methoxybenzyl)triphenylphosphonium salt with 3,4,5-trimethoxybenzaldehyde and reducing the nitro group in the presence of iron. Also disclosed is a process and intermediates for producing serine salts of formula (I) by way of reaction with a cyclic protected serine derivative of formula (IIb) to form an intermediate of formula (III) which is subsequently deprotected.
Description
New Zealand Paient Spedficaiion for Paient Number 535318
53531
PROCESSES FOR THE PREPARATION OF COMBRETASTATINS The present invention relates to a novel process for the preparation of combretastatins and of their derivatives.
The term "combretastatins" or "stilbene derivatives" is understood to mean the derivatives of following general formula:
in which A represents a hydroxyl group or an amino 10 group, and its pharmaceutically acceptable salts.
Mention may be made, among the salts, of the hydrochloride, acetate, phosphate or methanesulphonate. When A in the compound is an amino group, it can also be coupled to amino acids to result in amides, and 15 their pharmaceutically acceptable salts.
The synthesis of stilbene derivatives or combretastatins, which can be in the form of a pharmaceutical acceptable salt, and the pharmaceutical compositions which comprise them are disclosed in 20 Patents US 4 996 237, US 5 525 632, US 5 731 353 and US 5 674 906. These patents disclose combretastatins and their metabolites and disclose their in vitro oncologic activity.
According to these patents, combretastatins 25 are prepared from (3,4 , 5-trimethoxybenzyl)triphenyl-phosphonium salts, which are condensed with a 3-nitro-
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or 3-hydroxy-4-methoxybenzaldehyde (the hydroxyl group of which is protected) in the presence of sodium hydride or of lithium derivatives, and then the derivative obtained, when it is nitrated, is reduced in 5 the presence of zinc.
The isomer with the cis configuration is subsequently prepared by the action of light or by chromatographic separation of the mixture.
The present invention relates to novel 10 processes for the preparation of combretastatins or of their derivatives and to improvements to the existing processes.
A first process route VO 1 for the preparation of derivatives of formula (I) for which A 15 represents an amino group has first been discovered, which process is an improvement to the process disclosed in the abovementioned patents, which consists, after the Wittig condensation in the presence of (3,4,5-trimethoxybenzyl)triphenylphosphonium bromide 20 or chloride and of 3-nitro-4-methoxybenzaldehyde, in carrying out the reduction in the presence of iron, instead of the zinc used in the prior publications, which makes it possible to achieve an overall reaction yield, with respect to the aldehyde charged, of 60% 25 (the yield with respect to the aldehyde charged in Patent US 5 525 632 is between 21% and 33%).
The first process route VO 2 consists in condensing 3,4,5-trimethoxybenzaldehyde with (4-methoxy-3-nitrobenzyl)triphenylphosphonium bromide intellectual property office of n.z.
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or chloride. For both these first two processes routes VO 1 and VO 2, the reaction is carried out in the presence of a base chosen in particular from potassium tert-butoxide, sodium tert-pentoxide, sodium 5 hydride, butyllithium, LDA (lithium diisopropylamide), sodium methoxide, potassium carbonate or alkaline derivatives of hexamethyldisilazanes.
This reaction is carried out in various solvents, such as ethers (THF), polar aprotic solvents 10 (acetonitrile, NMP, DMF, DMSO, and the like), alcohols, aromatic solvents or water, at a temperature which will be adjusted by a person skilled in the art to the base used and to the solvent used.
This reaction, as regards the first process 15 route VO 2, is described in particular in the publication by K.G. Piney which appeared in Bioorg. Med. Chem., 8(2000), 2417-2425.
2-Methoxy-5-[2-(3,4,5-trimethoxyphenyl)-vinyl]nitrobenzene is reduced according to the improved 20 process of the invention by the action of iron. It is advantageous to use an amount of iron in excess if complete conversion of the starting material is desired. This excess is advantageously greater than 2 equivalents per one mol of starting nitro derivative. 25 It has been shown that the same stage,
carried out in the presence of zinc in acetic acid, a conventional solvent for reductions with zinc, does not make it possible to obtain complete reaction (in Patent
US 5 525 632, the yield of the reduction carried out on intellectual property office" of n.z.
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the pure Z isomer varies between 46 and 66%) and, moreover, the amounts of zinc used are large and consequently result in considerable industrial waste. Furthermore, the process generates a large amount of 5 "azo" compound resulting from coupling between the amino formed and the nitroso intermediate in the reduction.
Reduction with nascent hydrogen, generated by ammonium formate in the presence of a conventional 10 catalyst, such as palladium or platinum, leads to high isomerization of the double bond to the undesirable E isomer and to partial saturation of the double bond.
The abovementioned Piney publication describes the reduction by sodium hydrosulphite of a 15 pure nitro Z isomer, obtained after chromatography and recrystallization, leading to an amino Z isomer with a yield of only 37%.
Hydrogenations with molecular hydrogen, catalysed by platinum or palladium, are rarely complete 20 and result in particular in the saturation of the ethylenic double bond.
A second process has also been found which avoids the intermediate reduction stage necessary when starting from a nitro derivative. This is because it is 25 much more economical to condense, according to a first method of carrying out this second process, a (3,4,5-trimethoxybenzyl)triphenylphosphonium bromide or chloride with a 3-amino-4-methoxybenzaldehyde or, according to a second method of carrying out this
second process, 3,4,5-trimethoxybenzaldehyde with a (3-amino-4-methoxybenzyl)triphenylphosphonium salt.
This second process according to its two alternative forms requires a stage in which less in the 5 way of CMR (Cancerogenic, Mutagenic or Reproductive toxic) products are given off in comparison with the first processes routes VO 1 and VO 2, which is a considerable advantage at the industrial level from the viewpoint of safety and production cost. 10 According to the second process route VO 3
for implementing the invention, the
(3,4,5-trimethoxybenzyl)triphenylphosphonium salt and 3-amino-4-methoxybenzaldehyde are brought together and the reaction is carried out, preferably, in the 15 presence of a base chosen in particular from potassium tert-butoxide, sodium tert-pentoxide, sodium hydride, butyllithium, LDA, sodium methoxide, potassium carbonate or alkaline derivatives of hexamethyldisilanes. Use is preferably made of sodium 2 0 methoxide.
This reaction is carried out in various solvents, such as ethers (THF), polar aprotic solvents (acetonitrile, NMP, DMF, DMSO, and the like), alcohols, aromatic solvents or water, at a temperature which will 25 be adjusted by a person skilled in the art to the base used and to the solvent used.
The reaction temperature will be adjusted by a person skilled in the art to the base used. When methoxide is used, it is preferably between 0 and 10°C.
6
After reaction, the base used is neutralized with an acid in aqueous solution, the organic phase is washed and concentrated, and the expected product is obtained after chromatographing the crude concentrate.
According to the second process route VO 4
for implementing the invention, in which the (3-amino-4-methoxybenzyl)triphenylphosphonium salt and 3,4,5-trimethoxybenzaldehyde are brought together, the reaction is preferably carried out in the presence of 10 an inorganic base chosen in particular from potassium tert-butoxide, sodium tert-pentoxide, sodium hydride, butyllithium, LDA, sodium methoxide, potassium carbonate or alkaline derivatives of hexamethyldisilanes. Use is preferably made of sodium 15 methoxide.
This reaction is carried out in various solvents, such as ethers (THF), polar aprotic solvents (acetonitrile, NMP, DMF, DMSO, and the like), alcohols, aromatic solvents or water, at a temperature which will 20 be adjusted by a person skilled in the art to the base used and to the solvent used.
The reaction temperature will be adjusted by a person skilled in the art to the base used. When methoxide is used, it is preferably between 0 and 10°C. 25 After reaction, the base used is neutralized with an acid in aqueous solution, the organic phase is washed and concentrated, and the expected product is obtained after chromatographing the crude concentrate.
The derivative obtained according to the intellectual property office of n.z.
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second process route VO 3 or VO 4 or during the second stage of the first process route VO 1 or VO 2 has the following formula:
formula (Ila)
It is advantageous, when it is desired to couple serine with the compound of formula (Ila), to use L-serine doubly protected on the nitrogen of the serine and on the hydroxyl functional group of general formula (lib)
O
HO
(Mb)
O
.N-
PG \
where PG represents a protecting group for the amine functional group known to any person skilled in the art, to give a novel intermediate of following general formula:
(IN)
which is subsequently cleaved, preferably simultaneously with the opening of the ring, by acid hydrolysis according to a deprotection reaction known to any person skilled in the art. Preferably, the PG
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group of the formulae (lib) or (III) represents a protecting group chosen from the following groups: tert-butoxycarbonyl, benzyloxycarbonyl (CBZ) or 9-fluorenylmethyloxycarbonyl (FMOC).
The compound of formula (III) above is novel and is claimed as such.
The condensation is advantageously carried out in the presence of EDC1 (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide chloride) or in the presence of DCC 10 (dicyclohexylcarbodiimide) and of HOBT
(hydroxybenzotriazole) or in the presence of DCC (dicyclohexylcarbodiimide) and of HOSU
(N-hydroxysuccinimide) or, finally, in the presence of TOTU (0-[(ethoxycarbonyl)cyanomethyleneamino]-15 N,N,N',N'-tetramethyluronium tetrafluoroborate) or of HBTU (O-benzotriazol-l-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate) or of N,N-carbonyldiimidazole. The reaction is preferably carried out in a solvent which is inert with respect to the reaction, which solvent is 20 chosen in particular from polar aprotic solvents, such as acetonitrile, dimethylformamide, tetrahydrofuran or chlorinated aliphatic solvents, such as dichloromethane, or, finally, esters.
The coupling to the derivative of 25 formula (Ila) can also certainly be carried out by the action of a mixed anhydride, synthesized in situ between a chloroformate or a carboxylic acid chloride, for example pivaloyl chloride, and doubly protected L-serine of formula (lib), in the tfWBiSSiLttte PEERS' OFFICE OF N.Z.
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tertiary base of the NMM (N-methylmorpholine) type in various solvents which are inert with respect to the reaction, esters, ethers, chlorinated solvents, acetonitrile, and the like. The mixed anhydride is 5 preferably prepared at a temperature of between 0 and 10°C and then the reaction is carried out at ambient temperature. After reaction, the reaction mixture is hydrolysed with an aqueous solution, then the mixture is separated by settling and the organic phase obtained 10 is washed with a hydroxylated base.
The double deprotection of the compound of formula (III) is carried out by the action of an organic or inorganic acid. Use is preferably made of concentrated aqueous hydrochloric acid in an alcoholic 15 medium. The reaction temperature is, according to a better means of implementation of the invention,
between 50 and 70°C.
The invention will be more fully described with the help of the following examples, which must not 20 be regarded as limiting the invention.
The composition of the mixtures, the monitoring and the progression of the reactions, and the yield of the unisolated products/intermediates and their assays are determined by HPLC (High Performance 25 Liquid Chromatography) analysis.
The term "comprising" as used in this specification and claims means "consisting at least in part of"; that is to say when interpreting statements in this specification and claims which include 30 "comprising", the features prefaced by this term in each statement all need to be present but other features can also be present. Related terms such as "comprise" and "comprised" are to be interpreted in similar manner.
Example 1 - First process route VO 2 according to the invention
(Z)-N-[2-Methoxy-5-[2-(3,4,5-trimethoxyphenyl)vinyl]
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DCOCI\/cn
phenyl]-L-serinamide hydrochloride
General scheme of the synthesis
The novel "inverse Wittig" process, starting from (4-methoxy-3-nitrobenzyl)triphenylphosphonium 5 bromide and 3,4,5-trimethoxybenzaldehyde, makes it possible to obtain the mixture of Z and E isomers of 2-methoxy-5-[2-(3,4,5-trimethoxyphenyl)vinyl]-nitrobenzene with a Z/E ratio of 75/25.
OMe
MeO^J^^OMe
V •
Witlig reaction
PPh,8r ?Mfi
J ' MeO^J^^OMe
MeONa / toluene T|
NO,
Phosphontum salt
S^S-Trimethoxybenzaldehyde .
K.G. Piney et al.. Commercial Bioorg. Med. Chem.,
8 (2000),241 7-2425
CiB isomer
OMe Me O
1) Reduction Fe/HCl M
2) HCI purification
MeOH-HCI Acetonitrile
OMe
MeO A. ,OMS
DCC
8oC'L'Ser-PG
EDC! / Dichioromethane
OMe vOMe
Deprotsctton MeOH / HCI
OMe
MeO^ -L .OMe
N-"—r^*^0 H A
o=< •
HCI Crystallization AcOfPr
This ratio is sufficiently high in the
Z nitro isomer to be able to use the Z/E mixture directly in the reduction and to obtain, by crystallization of the hydrochloride, the Z amino isomer with an HPLC assay of 97% IS (internal 15 standardization).
(4-Methoxy-3-nitrobenzyl)triphenylphosphonium bromide (4) is prepared according t dAlTfiJtiKTUto MOPBRtngpFICE of |\|.z
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ch2ci2
o ^Br ^PPh3Br
(1) (2)
3-Nitro-4-methoxybenzyl alcohol (2):
90.5 g of 3-nitro-4-methoxybenzaldehyde (1) 5 are charged, followed by 450 ml of THF and 90 ml of ethanol, to a 2-litre three-necked flask equipped with a mechanical stirrer, a thermometer, a T piece, a funnel for the addition of solid and a reflux condenser surmounted by a bubble counter. The pale-yellow 10 solution obtained is cooled to 10°C and then 10 g of sodium borohydride are charged over 40 minutes at 10/15°C (the reaction is very exothermic and the temperature has to be maintained with an ice/acetone bath); at the end of the addition, the brown solution 15 turns navy blue. The solution is stirred for 30 minutes at 10°C, the end of the reaction is monitored by TLC (thin layer chromatography), the solution is stirred for a further 1 hour at 10°C and then the temperature is allowed to return to ambient temperature. 20 The addition funnel is replaced by a 500 ml pressure-equalizing dropping funnel, via which 300 ml of distilled water are run in dropwise over 30 minutes while maintaining the mixture at 20°C. Gas evolution is observed when the water begins to be run in. 25 The mixture is concentrated to 2/3 on a
12
rotary evaporator (50°C/20 mmHg) and a white product crystallizes in the aqueous concentrate in the form of lumps.
The cooled aqueous phase is extracted with 5 250 ml and then 150 ml of dichloromethane, and the combined organic phases are washed with 250 ml of distilled water and then dried over magnesium sulphate.
After filtration, the dichloromethylene solution is used as is in the following bromination 10 reaction.
The yield of this stage is regarded as being
100%.
N.B.: The alcohol (2) is commercially available but very difficult to get hold of. 15 3-Nitro-4-methoxybenzyl bromine (3):
The dichloromethylene solution of 3-nitro-4-methoxybenzyl alcohol (2) is charged to a 1 litre three-necked flask equipped with a mechanical stirrer, a thermometer, a T piece, a dropping funnel and a 20 reflux condenser surmounted by a bubble counter, and 100 ml of dichloromethane are added. The stirred solution is cooled to 5°C and then 135.4 g of phosphorus tribromide are run in dropwise while maintaining the temperature at 5°C. 25 The solution is stirred at 5°C for 1 hour
minutes, the end of the reaction is monitored by TLC and then 250 ml of saturated sodium hydrogencarbonate solution are run in dropwise while maintaining the temperature at 15°C. Very strong evolution of gas takes intellectual property office of n.z.
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place with a slight delay as the phosphorus tribromide is run in.
The organic phase is separated by settling in a separating funnel, is washed successively with 250 ml 5 of distilled water and 200 ml of saturated sodium hydrogencarbonate solution. The organic phase is dried over magnesium sulphate, filtered and concentrated on a rotary evaporator (50°C/20 mmHg).
119 g of solid in the form of green-yellow 10 felt-like needles are obtained with a chemical yield over two stages of 97%.
N.B.: This product (3) can also be prepared according to the following scheme, described in the publication: K.G. Piney et al., Bioorg. Med. Chem., 8 (2000), 2417-15 2425.
rVW°' NBS
cci4
(3-Nitro-4-methoxybenzyl)triphenylphosphonium bromide (4) :
119 g of 3-nitro-4-methoxybenzyl bromine (3) 20 are charged to a stirred heel of 1 000 ml of toluene in a 2 litre three-necked flask equipped with a mechanical stirrer, a thermometer, a T piece, a funnel for the addition of solid and a reflux condenser surmounted by a bubble counter, and the mixture, warmed to 25°C, 25 passes into solution. 126.5 g of triphenylphosphine are then added and the solution obtained is gradually intellectual property office of n.2
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heated to 60°C; a precipitate is formed from 30°C. The mixture is maintained at 60/65°C for 4 hours, is then cooled to 30°C and is filtered through a sintered glass filter. The filter residue is washed on the filter with 5 2 times 300 ml of toluene, pulled dry and dried in an oven (35°C/20 mmHg/20 hours).
phosphonium bromide are obtained with a chemical yield of 88%.
(solvent used: dichloromethane)
K.G. Piney et al., Bioorg. Med. Chem., 8(2000), 2417-2425.
Spectrum No. = 4 865-V 15 *H N.M.R. spectrum (300 MHz, d6-(CD3)2SO, 8 in ppm) : 3.90 (s, 3H), 5.26 (d, J = 15 Hz, 2H), 7.33 (mt, 2H), 7.41 (mt, 1H), from 7.65 to 8.05 (mt, 15H).
Mass spectrum No. 212217, m = 428 EI m/z = 262 [PPh3]+ base peak 20 DC I m/z = 445 MNH3+
m/z = 428 M+
m/z = 263 [PPh3H]+ base peak IR spectrum 426469 KBr
2869, 2843, 2776, 1619, 1527, 1438, 1362, 1287, 1270, 25 1111, 752, 692 and 502 cm-1
Z and E mixture of 2-methoxy-5-[2-(3,4,5-trimethoxy-phenyl)vinyl]nitrobenzene (6) and (7):
217 g of (4-methoxy-3-nitrobenzyl)triphenyl-
Synthesis described in the publication:
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(4) (5)
(7)
54.7 g of 3,4,5-trimethoxybenzaldehyde (5), 148.6 g of (4-methoxy-3-nitrobenzyl)triphenylphosphonium bromide (4) and 1 3 00 ml of toluene are 5 charged, at 2 0°C and under nitrogen, to a 2 litre three-necked flask equipped with a mechanical stirrer, a thermometer, a T piece, a dropping funnel and a reflux condenser surmounted by a bubble counter. The stirred suspension is cooled to 5°C using an ice bath 10 and then 63.2 g of a 25% w/w solution of sodium methoxide in methanol are run in at 5°C over 40 minutes.
As the addition progresses, the suspension changes from off-white to yellow and then to brown. 15 The mixture is stirred for 1 hour at 5°C and the end of the reaction is monitored by HPLC (complete consumption of the aldehyde). 3 g (0.05 mol) of acetic acid are then added.
The suspension is heated to 40°C and is 20 maintained at 40°C for 30 minutes. At this temperature, only the salts remain insoluble. The mixture is filtered at 40°C through a sintered glass filter No. 3 and the salts are washed on the filter with 3 times 100 ml of toluene.
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The filtrate is returned to a round-bottomed flask with 250 ml of distilled water, and the two-phase mixture is stirred for 20 minutes at 40°C and then separated by settling in a separating funnel. The 5 toluene phase is washed again with 2 times 250 ml of distilled water and then concentrated to dryness on a rotary evaporator.
The residue is taken up in 600 ml of isopropanol and 12 ml of toluene at 40°C, the expected 10 product begins to crystallize and the temperature is allowed to return to ambient temperature overnight with slow stirring.
The stirred suspension is cooled to and maintained for 1 hour at 5°C and then filtered through 15 a sintered glass filter, and the cake is washed with 2 times 125 ml of isopropanol, pulled dry and dried in an oven under vacuum (35°C/3 0 mmHg/18 hours).
91.7 g of a mixture of Z and E isomers (6) and (7) are obtained with a Z/E ratio of 75/25 20 (IS HPLC) and a yield of 95%.
Synthesis described in publication: (solvent used: dichloromethane: base used: NaH)
K.G. Piney et al., Bioorg. Med. Chem., 8(2000), 2417-2425 .
N.B.: Numerous operating conditions were experimented with, such as:
Solvents: THF, acetonitrile, methanol and other alcohols, dichloromethane, NMP, DMF, DMSO, and the like.
17
Bases: potassium t-butoxide, sodium t-pentoxide, sodium hydroxide, NaH, BuLi/LDA, potassium carbonate and the like.
Temperatures: from -10°C to the reflux temperatures of 5 some solvents
Z-2-Methoxy-5-[2-(3,4,5-trimethoxyphenyl)vinyl]-phenylamine hydrochloride (8):
80 g of 75/25 Z and E mixture of 10 2-methoxy-[2-(3,4,5-trimethoxyphenyl)vinyl]nitrobenzene (6) and (7), 640 ml of absolute ethanol and 160 ml of distilled water are charged, at 20°C and under nitrogen, to a 2 litre three-necked flask equipped with a mechanical stirrer, a thermometer, a T piece, a 15 funnel for the addition of solid, a reflux condenser surmounted by a bubble counter, and a heating bath.
The mixture is rapidly stirred and heated on an oil bath, 7.8 ml of 6N hydrochloric acid are added to the suspension at 50°C and then the temperature of 20 the mixture is raised to 77 + 2°C. The mixture is virtually soluble.
52 g of iron powder are added portionwise over 5 minutes. With the first addition, the mixture passes into solution and then a blackish deposit is pntellecmtproperty office
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formed on the walls of the round-bottomed flask.
The mixture is maintained at 77 ± 2°C for 2 hours and the disappearance of the starting nitro compounds (6) and (7) is monitored by HPLC.
The mixture is allowed to cool to 40°C and is filtered through a sintered glass filter covered with clarcel and the cake is rinsed with 2 times 160 ml of 80/20 ethanol/water mixture.
The filtrate, aqueous mother liquors and 10 aqueous wash liquors, is concentrated on a rotary evaporator. As soon as the azeotrope has been driven off, an oil begins to precipitate in the residual aqueous phase.
This aqueous phase is extracted in a 15 separating funnel with 2 times 3 00 ml of dichloromethane and then the organic phase is washed with 2 times 300 ml of half-saturated aqueous sodium chloride solution and with 300 ml of distilled water.
The organic phase is concentrated to dryness 2 0 on a rotary evaporator and 7 6 g of an oil are obtained, which oil exhibits a Z/E ratio of 80/20 by HPLC. This oil is dissolved in 591 ml of methanol and transferred into a stirred 1 litre round-bottomed flask, 100 ml of 2.32N methanolic hydrochloric acid are then added, 25 precipitation is initiated and the mixture is allowed to precipitate overnight with stirring.
The amount of methanol + methanolic hydrochloric acid is such that the final concentration of Z isomer (determined by HPLC) is equal to 8.8% w/v.
19
In the morning, the mixture is filtered through a sintered glass filter. The dried cake weighs 8.2 g and is composed only of E isomer (HPLC).
The filtrate (693 g), ratio Z/E = 86/14 5 (IS HPLC), is concentrated to half on a rotary evaporator, 400 ml of acetonitrile are added to the 347 g of concentrate and the mixture is reconcentrated until a concentrate of 347 g is again obtained.
1 000 ml of acetonitrile are then added and the mixture 10 is concentrated until crystallization begins. The concentrate is then transferred into a stirred 4 litre round-bottomed flask containing 1 500 ml of acetonitrile at 60°C. The mixture copiously precipitates.
The mixture is kept stirred at 60°C for
2.5 hours and is allowed to cool to 30°C over approximately 1 hour. The slurry is filtered through a sintered glass filter (the E isomer (9) is soluble in the filtrate). The cake is washed with 2 times 200 ml 20 of acetonitrile and dried in an oven (35°C/30 mmHg/ 18 hours).
45.7 g of Z-2-methoxy-5-[2-(3,4,5-trimethoxy-phenyl ) vinyl ] phenylamine (8) are obtained with an IS HPLC assay of 97% and a yield as such of 56%, i.e. a 25 yield of Z isomer obtained with respect to Z isomer charged of 72%.
EXAMPLE 2 - Synthesis according to the second process route V0 3 according to the invention
The advantage of the second process route
VO 3 with respect to the first "inverse Wittig" process route VO 2 is that of carrying out the Wittig reaction between a product which has already been reduced, the aminoaldehyde (la), and the phosphonium (2a) and thus 5 of eliminating a chemical stage which gives off CMR products.
(Z)-N-[2-Methoxy-5-[2-(3,4,5-trimethoxypheny1)vinyl]-phenyl]-L-serinamide hydrochloride
General scheme of the synthesis
Wittig reaction
OMe
V *
PPH3Br Phosphonium salt
MeO
OMe
MeO.. A. .OMe
MeONa / toluene
NH,
3-Amino-4-methoxybenzaldehyde
Cis isomer
OMe
MeO. v-OMe
0 0 I
o^C
Boc-L-Sar-PG
EDCII Dichloromethane
Deprotection MeOH/HCl
HCI Crystallization AcOiPr
OMe
MeO. ✓OMe
N-S^OH
H NH,*HCl
3-Amino-4-methoxybenzaldehyde (la):
21
2 0 g of 3-nitro-4-methoxybenzaldehyde (1) and 350 ml of absolute ethanol are charged to a 2 litre three-necked flask rendered inert with argon and 5 equipped with a mechanical stirrer, a thermometer, a T piece, a funnel for the addition of solid, a reflux condenser surmounted by a bubble counter, and a heating bath, and the mixture is stirred and heated to 60°C. The mixture passes into solution. 10 The dropwise addition is carried out at 60°C
of 115 ml of distilled water, followed by 14 ml of 2N hydrochloric acid. 24.7 g of iron powder are then introduced portionwise.
The temperature of the mixture is allowed to 15 return to ambient temperature over 2 hours. The reaction is complete (TLC).
The mixture is filtered through celite and concentrated under vacuum, the residue is taken up in dichloromethane and the organic solution is washed 20 twice with distilled water and then dried over magnesium sulphate, filtered and concentrated to dryness under vacuum.
16 g of crude (la) are obtained and are chromatographed on a silica column eluted with 2 5 dichloromethane.
22
2 fractions comprising the clean expected product are obtained, which fractions, after concentrating, give 11.5 g of pure (la), i.e. a yield of 69%.
*H N.M.R. spectrum No. 2810-V (300 MHz, d6-(CD3)2SO, 8 in ppm): 3.88 (s, 3H), 5.11 (unresolved peak, 2H), 7.01 (d, J = 8 Hz, 1H), 7.14 (d, J = 2 Hz, 1H), 7.18 (d, J = 8 Hz, 1H) , 9.53 (s, 1H) .
Mass spectrum No. 210112, m = 151 10 EI m/z = 151 M+- base peak m/z = 136 [M-CH3] +
m/z = 108 [136-CO]+
m/z = 80 [I08-C0]+
IR spectrum: 425135 KBr 15 3464, 3437, 3367, 3349, 1675, 1655, 1582, 1513, 1293, 1241, 1139, 1023, 803 and 640 cm-1
Z- and E-2-Methoxy-5-[2-(3,4,5-trimethoxyphenyl)vinyl]-phenylamine (8') and (9'):
N.B.: The phosphonium salt (2a) is a starting material already disclosed in the original patent Ajinomoto Co. Ltd, US 5 525 632 and WO 01/12579 A2.
2.20 g of aminobenzaldehyde (la) and 100 ml of toluene,
\
■o
-O
8.0 g of phosphonium salt (2a), followed by
INTELLECTUAL property'office OF N.2.
05 DEC 2006
23
are charged to a 250 ml three-necked flask rendered inert with nitrogen and equipped with a magnetic stirrer, a thermometer, a T piece, a dropping funnel, a reflux condenser surmounted by a bubble counter, and a 5 cooling bath. The stirred suspension is cooled to 5°C and 3.51 ml of a 25% w/w methanolic sodium methoxide solution are run in over 15 minutes. After 2.5 hours at 5°C, the reaction remains incomplete (DC: 45%) but does not change further (HPLC) and the Z/E ratio is 61/39. 10 0.2 ml of acetic acid diluted in 50 ml of water is then run in, the temperature rises to 13°C, the mixture is stirred for 30 minutes and then it is separated by settling in a separating funnel. The organic phase is concentrated under vacuum on a rotary evaporator and 15 8 g of yellow oil are obtained.
By HPLC, this oil comprises starting aldehyde, phosphine oxide and the expected Z/E mixture with a ratio of 61/39.
The oil is chromatographed on a silica column 20 (40 parts w/w) eluted with a eyelohexane/ethyl acetate/ triethylamine (50/50/2) mixture.
2 series of combined fractions are concentrated to dryness: the first dry extract of 360 mg comprises 93% of the Z isomer + unidentified 25 impurities; the second, of 2.09 g, comprises starting aldehyde and a Z/E mixture representing 39 and 37.5% by IS HPLC.
The balance by weight of Z isomer (8'), determined by IS HPLC, is 1.15 g with respect to 2.2 0 g
24
of aldehyde charge, i.e. a yield of 24%.
EXAMPLE 3 - Synthesis according to the second process route VO 3 according to the invention
VO 3 with respect to the first "inverse Wittig" process route VO 2 is that of carrying out the Wittig reaction between a product which has already been reduced, (3-amino-4-methoxybenzyl)triphenylphosphonium bromide (lb), and 3,4,5-trimethoxybenzaldehyde (5) and thus of 10 eliminating a chemical stage which gives off CMR products.
(Z)-N-[2-Methoxy-5-[2-(3,4,5-trimethoxyphenyl)vinyl]-phenyl]-L-serinamide hydrochloride
General scheme of the synthesis
As for route VO 2, the advantage of route
Wittig reaction
OMe
1
.OMe
Trans isomer
Deprotection
MeOH / HCi
OMe
HCI Crystallization AcOiPr
H NH,-HCI
(4-Methoxy-3-aminobenzyl)triphenylphosphonium bromide (lb)
o
Fe / HCI ^ _.NH2 HCI
EtOH-HzO
PPh,Br
3 PPh3Br
(4) (1b)
g of (4), 240 ml of ethanol and 60 ml of 5 distilled water are charged to a 1 litre three-necked flask equipped with a mechanical stirrer, a thermometer, a T piece, a funnel for the addition of solid, a reflux condenser surmounted by a bubble counter, and a heating bath.
1.76 ml of 6N hydrochloric acid are added to the stirred suspension, which is heated to 7 0°C.
9.9 g of iron powder are then added portionwise over 15 minutes; the mixture remains insoluble. The mixture is maintained at 75°C for 15 2 hours; the organic materials slowly pass into solution while a brownish deposit of iron and of iron oxide is formed.
After monitoring by HPLC, 5% of starting material still remains; 2 g of iron are again added and 20 heating is continued for 1 hour; the DC is complete.
The mixture is cooled to 40°C and filtered through clarcel, the filter residue is rinsed with 100 ml of ethanol comprising 2 0% water, and the filtrate is concentrated to dryness under vacuum on a 2 5 rotary evaporator.
26
The residue is taken up in 3 00 ml of isopropanol and crystallizes from the mixture, which is stirred and heated to 50°C and passes back into solution. 14 ml of a 5N solution of hydrochloric acid 5 in isopropanol are then run in, the mixture precipitates, it is held at 50°C for 1 hour and then it is allowed to return to ambient temperature.
The slurry is filtered through a sintered glass filter and the cake is washed with 50 ml of 10 isopropanol, pulled dry thoroughly and dried in an oven under vacuum.
27.3 g of (lb) are obtained with a yield as such of 89.9%.
N.M.R. spectrum No. 4584-V (300 MHz, d6-(CD3)2SO, 8 in 15 ppm): 3.78 (s, 3H), 5.03 (broad d, J = 15 Hz, 2H), 6.43 (unresolved peak, 1H), 6.62 (broad s, 1H), 6.82 (broad d, J = 8 Hz, 1H), from 7.60 to 8.00 (mt, 15H).
Mass spectrum No. 211915, m = 397 EI m/z = 397 M+'
m/z = 382 [M-CH3] +
m/z = 2 62 [PPh3]+ base peak DC I m/z = 398 MNH4+
M/z = 263 [PPh3H]+ base peak IR spectrum 42 6386 KBr 25 3254, 2474, 1920, 1628, 1520, 1439, 1433, 1279, 1110, 736, 690, 527 and 511 cm"1
Z- and E-2-Methoxy-5-[2-(3,4,5-trimethoxyphenyl)vinyl]-phenylamine (8') and (97):
27
<ib)
PPh3Br
NHj-HCI —O
+
(5)
O
0'
CHjONa / CH3OH
Toluene
■0
.O
11.02 g of (lb), 4 g of (5) and 70 ml of toluene are charged to a 250 ml three-necked flask rendered inert with nitrogen and equipped with a 5 magnetic stirrer, a thermometer, a T piece, a dropping funnel, a reflux condenser surmounted by a bubble counter, and a cooling bath.
4.92 ml of a 25% w/w solution of sodium methoxide in 10 methanol are run in over 15 minutes. The suspension is stirred at 5°C for 2.5 hours, then 0.2 ml of acetic acid diluted in 50 ml of water is then run in, the temperature rises to 14°C and the mixture becomes very thick. It is diluted with 10 ml of toluene and 10 ml of 15 water. A brown insoluble material remains.
cake is washed with 3 times 50 ml of toluene (the wash liquors comprise virtually only the starting aldehyde and are not added to the two-phase filtrate), the clear 20 filtrate (pH 12) is separated by settling in a separating funnel, and the organic phase is concentrated to dryness under vacuum at 40°C. The Z/E ratio, determined by IS HPLC, is 43/57.
The stirred suspension is cooled to 5°C and
The mixture is filtered through clarcel, the
The brown oil obtained (4 g) is
28
chromatographed on a silica column (100 parts w/w) eluted with a cyclohexane/ethyl acetate/triethylamine (50/50/2) mixture.
Two series of combined fractions are 5 concentrated to dryness: the first dry extract of 1.1 g comprises 14% of E isomer and 59% of Z isomer; the second weighs 1.08 g and comprises 86% of E isomer and 7% of Z isomer.
The balance by weight of Z isomer (8'), 10 determined by IS HPLC, is 0.725 g with respect to 4 g of aldehyde charged, i.e. a yield as such of 11.3%. Z-4-{2-Methoxy-5-[2-(3,4,5-trimethoxyphenyl)vinyl]-phenylcarbamoyl}-2,2-dimethyloxazolidine-3-carboxylic
(11)
Release of the base (8') from the hydrochloride (8):
44 g of (8), 16 g of sodium hydrogencarbonate and then 2 00 ml of distilled water and 37 5 ml of dichloromethane are charged to a 1 litre Erlenmeyer 20 flask. The mixture is stirred for 20 minutes at ambient temperature and two clear phases are obtained.
The organic phase is separated by settling, dried over sodium sulphate and then filtered.
Approximately 400 ml of a dichloromethane
29
solution comprising (8#) are obtained.
Preparation of 2,2-dimethyloxazolidine-3,4-dicarboxylic acid 3-tert-butyl ester (10)
Although commercially available, this product 5 is very difficult to get hold of. It has therefore been prepared by saponification with lithium hydroxide of its methyl ester according to: J. Org. Chem., 63(12), p. 3983 (1998).
XH N.M.R. spectrum (300 MHz, d6-(CD3)2SO, 8 in ppm) : 1.38 10 (s, 3H), 1.45 (s, 9H), 1.55 (s, 3H), 3.95 (mt, 1H), 4.16 (mt, 1H), 4.31 (mt, 1H), from 12.50 to 13.10 (broad unresolved peak, 1H).
Mass spectrum: No. 213135, m = 245 DC I m/z = 263 MNH4+
m/z = 246 MH+
m/z = 207 [MNH4-t-Bu]+ base peak m/z = 146 [MH-BOC]+
IR spectrum: 426759 KBr
1744, 1704, 1638, 1407, 1368, 1164, 1104, 856, 836 and 20 62 3 cm"1 Coupling:
The solution of (87) is charged to a 2 litre three-necked flask equipped with a mechanical stirrer, a thermometer, a T piece, a funnel for the addition of 2 5 solid, a reflux condenser surmounted by a bubble counter, and an ice bath, 600 ml of dichloromethane are added and the mixture is cooled with stirring.
42.9 g of 2,2-dimethyloxazolidine-3,4-dicarboxylic acid 3-tert-butyl ester (10) are added
at 5°C and pass into solution, and then 48 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC1) are added portionwise between 5 and 10°C.
The mixture is slowly allowed to return to ambient temperature by allowing the ice in the bath to melt overnight.
In the morning, 330 ml of distilled water are added and the mixture is vigorously stirred. The 10 mixture turns cloudy over 3 0 minutes (hydrolysis of the EDCl). Stirring is maintained for a further 30 minutes.
The mixture is separated by settling in a separating funnel and the organic phase is washed successively with 2 times 280 ml of 0.55N sodium 15 hydroxide solution and then with 3 00 ml of distilled water.
The organic phase is concentrated to dryness on a rotary evaporator (50°C/50 mmHg).
79.4 g of a sticky oil (11) are obtained, 20 which oil hardens at 20°C, with a yield by weight with respect to (8) charged of 117%.
Spectrum No. =5 578-V
1H N.M.R. spectrum (400 MHz, d6-(CD3)2SO, at a temperature of 373 K, 5 in ppm): 1.41 (s, 9H), 1.53 (s, 25 3H), 1.64 (s, 3H), 3.64 (s, 6H), 3.71 (s, 3H), 3.86 (s, 3H), 3.99 (dd, J = 9 and 3 Hz, 1H), 4.19 (dd, J = 9 and 7 Hz, 1H), 4.52 (dd, J = 7 and 3 Hz, 1H), 6.48 (d, J = 12.5 Hz, 1H), 6.55 (d, J = 12.5 Hz, 1H), 6.58 (s, 2H) , 7.02 (mt, 2H), 8.13 (broad s, 1H), 8.82 (broad s, 1H).
31
Mass spectrum No. 213565, m = 542 DC I m/z = 560 MNH4"" base peak m/z = 543 MH+
m/z = 504 [MNH4-t-Bu]+
m/z = 443 [MH-BOC] +
IR spectrum: 425857 CCI4
3409, 2982, 2938, 2837, 1712, 1698, 1534, 1363, 1249, 1133, 1092 and 851 cm"1
Other coupling conditions were employed, such
as:
- Mixed anhydride (pivaloyl chloride/(10)).
- DCC/HOBT, DCC/HOSU, TOTU, N,N-carbonyldiimidazole, and the like.
- In acetonitrile, DMF, THF, dichloromethane, ester, 15 and the like.
EDC1-HC1 in dichloromethane gave the best result.
(Z)-N-[2-Methoxy-5-[2-(3,4,5-trimethoxyphenyl)vinyl]-phenyl]-L-serinamide hydrochloride
(11) (12)
61.8 g of (11), in solution in 54 ml of methanol, are charged at 2 0°C to a 1 litre three-necked flask equipped with a mechanical stirrer, a
Claims (14)
1. Process for the preparation of combretastatins of following general formula (I): ch3°^C^v3k"a (o CH3° ochg och3 in which A represents an amino group, wherein after the Wittig condensation in the presence of (3,4,5-trimethoxybenzyl)triphenylphosphonium bromide or chloride and of 3-nitro-4-methoxybenzaldehyde or of 3,4,5-trimethoxybenzaldehyde with a (4-methoxy-3-nitrobenzyl)triphenylphosphonium salt, the nitro group is reduced in the presence of iron.
2. Process according to Claim 1, wherein the amount of iron used is in excess.
3. Process according to Claim 2, wherein this excess is greater than 2 equivalents per one mol of starting nitro derivative.
4. Process for the preparation of combretastatins of following general formula (I): CH3O-~/J> (I) CH3° OCH, och in which A represents an amino group, wherein according to the second implementational process, 327T45 1.DOC n c intellectual property office i OF N.Z. 34 a (3,4,5-trimethoxybenzyl)triphenylphosphonium salt is condensed with 3-amino-4-methoxybenzaldehyde or a (3-amino-4-methoxybenzyl)triphenylphosphonium salt is condensed with 3,4,5-trimethoxybenzaldehyde.
5. Process according to Claim 4, wherein a (3,4,5-trimethoxybenzyl)triphenylphosphonium salt is condensed with 3-amino-4-methoxybenzaldehyde.
6. Process according to Claim 4 or Claim 5, wherein the reaction is preferably carried out in the presence of a base chosen from potassium tert-butoxide, sodium tert-pentoxide, sodium hydride, butyllithium, LDA (lithium diisopropylamide), sodium methoxide, potassium carbonate or alkaline derivatives of hexamethyldisilanes.
7. Process according to Claim 4 or Claim 5, wherein sodium methoxide is used.
8. Process according to Claim 4 or Claim 5, wherein the reaction solvent which is inert with respect to the reaction is chosen from ethers (THF), polar aprotic solvents (acetonitrile, NMP, DMF, DMSO, and the like), alcohols, aromatic solvents or water.
9. Process according to Claim 7, wherein the reaction temperature is preferably between 0 and 10°C.
10. Process for the preparation of compounds of formula (I) in the serine salt form by coupling of INTELLECTUAL property office Or l\j,Z. 0 5 DEC 2006 RECEIVED 35 the derivatives of formula (Ila] (Ha) O with the cyclic protected serine derivative of formula (lib) "w .i-Jr- PG \ where PG represents a protecting group for the amine functional group, to give an intermediate of following general formula: ' 0" o o o. o (III) o N- PG which is subsequently deprotected.
11. Intermediate for the coupling between aminocombretastatin and the cyclic protected serine derivative, wherein it corresponds to the following formula: o-" (III) in which PG is a protecting group. INTELLECTUAL PROPERTY OFRC'f OF H.I 0 5 DEC 2006 RECEIVED 36
12. Intermediate according to Claim 11, wherein PG represents a protecting group chosen from the following groups: tert-butoxycarbonyl, benzyloxycarbonyl (CBZ) or 9-fluorenylmethyloxycarbonyl (FMOC)
13. A process as defined in any one of claims 1, 4 or 10 substantially as herein described with reference to any example thereof.
14. An intermediate as defined in claim 11 substantially as herein described with reference to any example thereof. 827745 l.TJOC Intellectual property of H.Z office 0 5 DEC 2006 RECEIVED
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| Application Number | Priority Date | Filing Date | Title |
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| FR0204499A FR2838437B1 (en) | 2002-04-11 | 2002-04-11 | PROCESSES FOR THE PREPARATION OF COMBRETASTATINS |
| PCT/FR2003/001117 WO2003084919A2 (en) | 2002-04-11 | 2003-04-09 | Method for preparing combretastatins |
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| US7235688B1 (en) | 2004-11-04 | 2007-06-26 | University Of Notre Dame Du Lac | Process for preparing histone deacetylase inhibitors and intermediates thereof |
| FR2928148B1 (en) * | 2008-02-28 | 2013-01-18 | Sanofi Aventis | PROCESS FOR PREPARING COMBRETASTATIN |
| FR2939665B1 (en) | 2008-12-12 | 2011-10-07 | Sanofi Aventis | ANTITUMOR COMBINATION ASSOCIATING WITH AVE8062A AND DOCETAXEL |
| FR2945210B1 (en) | 2009-05-07 | 2011-07-01 | Sanofi Aventis | ANTITUMOR COMBINATION COMPRISING AVE8062 AND SORAFENIB |
| FR2953518B1 (en) | 2009-12-03 | 2012-01-20 | Sanofi Aventis | PROCESS FOR PREPARING A COMBRETASTATIN DERIVATIVE |
| EP2397135A1 (en) | 2010-06-18 | 2011-12-21 | Sanofi | An antitumoral combination comprising ombrabulin, a taxane derivative and a platinum derivative |
| PH12012502483A1 (en) | 2010-06-18 | 2013-03-25 | Sanofi Sa | An antitumoral combination comprising ombrabulin, a taxane derivative and a platinum derivative |
| EP2481404A1 (en) | 2010-11-15 | 2012-08-01 | Sanofi | An antitumoral combination comprising ombrabulin, a taxane derivative and a platinum derivative |
| EP2407161A1 (en) | 2010-07-13 | 2012-01-18 | Sanofi | An antitumoral combination comprising ombrabulin and bevacizumab |
| FR2968557A1 (en) | 2010-12-09 | 2012-06-15 | Sanofi Aventis | ANTITUMOR COMBINATION COMPRISING A DRIFT OF THE COMBRETASTATIN FAMILY AND THE CETUXIMAB |
| FR2978662A1 (en) | 2011-08-01 | 2013-02-08 | Sanofi Sa | ANTITUMOR COMBINATION COMPRISING OMBRABULIN AND CISPLATIN ASSOCIATED WITH RADIOTHERAPY |
| FR2978663A1 (en) | 2011-08-01 | 2013-02-08 | Sanofi Sa | ANTITUMOR COMBINATION COMPRISING OMBRABULIN AND CETUXIMAB ASSOCIATED WITH RADIOTHERAPY |
| CN103012248B (en) * | 2013-01-11 | 2014-11-05 | 浙江大德药业集团有限公司 | Synthesis of amino combretastatin derivative and application of amino combretastatin derivative as oral antitumour drug |
| EP2805705B1 (en) | 2013-05-23 | 2016-11-09 | IP Gesellschaft für Management mbH | Packaging with one or more administration units comprising a sodium salt of (R)-3-[6-amino-pyridin-3-yl]-2-(1-cyclohexyl-1 H-imidazol-4-yl)-propionic acid |
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| US4996237A (en) | 1987-01-06 | 1991-02-26 | Arizona Board Of Regents | Combretastatin A-4 |
| SU1766257A3 (en) * | 1988-02-24 | 1992-09-30 | Ф.Хоффманн-Ля Рош Аг (Фирма) | Method of obtaining stilbene derivatives |
| NZ232897A (en) * | 1989-04-03 | 1992-12-23 | Squibb & Sons Inc | Interphenylene 7-oxabicycloheptyl substituted heterocyclic amide prostaglandin analogues, preparation and pharmaceutical compositions thereof |
| TW325458B (en) | 1993-09-08 | 1998-01-21 | Ajinomoto Kk | Stilbene derivatives and pharmaceutical compositions comprising the same for anti-cancer |
| US5731353A (en) * | 1993-09-08 | 1998-03-24 | Ajinomoto Co., Inc. | Stilbene derivatives and pharmaceutical compositions containing them |
| RU2138482C1 (en) * | 1994-04-06 | 1999-09-27 | Ниппон Синяку Ко., Лтд. | Derivatives of aminostilbazole or their hydrates, or their salts and pharmaceutical composition based on said |
| TW334418B (en) * | 1995-03-07 | 1998-06-21 | Ajinomoto Kk | Stilbene derivatives and pharmaceutical compositions |
| JP4551514B2 (en) * | 1999-07-23 | 2010-09-29 | 住友化学株式会社 | Process for producing unsaturated hydrocarbon residue-substituted anilines |
| GB9918912D0 (en) | 1999-08-12 | 1999-10-13 | Angiogene Pharm Ltd | New stilbenes with vascular damaging activity |
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2010
- 2010-09-01 NO NO20101215A patent/NO331372B1/en not_active IP Right Cessation
-
2011
- 2011-08-05 AR ARP110102854A patent/AR082581A2/en unknown
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