EP1569946A1 - Colchicin-derivate, verfahren zur ihrer herstellung, sowie deren verwendung - Google Patents

Colchicin-derivate, verfahren zur ihrer herstellung, sowie deren verwendung

Info

Publication number
EP1569946A1
EP1569946A1 EP03796156A EP03796156A EP1569946A1 EP 1569946 A1 EP1569946 A1 EP 1569946A1 EP 03796156 A EP03796156 A EP 03796156A EP 03796156 A EP03796156 A EP 03796156A EP 1569946 A1 EP1569946 A1 EP 1569946A1
Authority
EP
European Patent Office
Prior art keywords
compound
general formula
product
halogenated aliphatic
group
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP03796156A
Other languages
English (en)
French (fr)
Inventor
Christian Wehrey
Serge Droux
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Aventis Pharma SA
Original Assignee
Rhone Poulenc Rorer SA
Aventis Pharma SA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Rhone Poulenc Rorer SA, Aventis Pharma SA filed Critical Rhone Poulenc Rorer SA
Publication of EP1569946A1 publication Critical patent/EP1569946A1/de
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/08—Esters of oxyacids of phosphorus
    • C07F9/09—Esters of phosphoric acids
    • C07F9/12—Esters of phosphoric acids with hydroxyaryl compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates, in general and according to a first of its aspects, a new process for the preparation of colchicine derivatives.
  • the present invention relates to a process for the preparation of products of general formula 1:
  • the products of general formula 1 are derivatives of colchicine and colchicein.
  • Colchicine and colchicein are natural alkaloids extracted from Colchicum autumnale, a plant in the Liliaceae family.
  • Colchicine is known for its antimitotic properties and its ability to bind to tubulin (J.M. Andreu, S.N. Timasheff, Proc. Nat. Acad. Sci. USA 79, 6753, (1982).
  • the protected phosphate group is condensed on the phenol of combretastatin by reaction in pyridine at 25 ° C for 15 h then at 90 ° C for 2.5 hours in the case of the first method, and at 60 ° C for 10 hours then at temperature room for 56 hours, in the case of the second method.
  • trialkylamines are preferred.
  • a more preferred trialkylamine is triethylamine.
  • One of the advantages of the invention is also that it makes it possible to carry out the entire coupling reaction at room temperature, without having to heat, as is the case in the process described by George R. Pettit et al.
  • Another advantage of the invention is that it makes it possible to easily isolate the product obtained by extraction using conventional techniques, easily adaptable to the production of large quantities of product.
  • the invention relates to a process for the preparation of a product of general formula 1: comprising a coupling step between a compound of general formula
  • R1, R2 are independently selected from the group consisting of alkyl, cycloalkyl, substituted alkyl, substituted cycloalkyl,
  • R1 and R2 together form a single substituent chosen from alkyl, cycloalkyl, substituted alkyl, substituted cycloalkyl,
  • R3, R4 are labile substituents, in the presence of a compound comprising a non-aromatic amino function.
  • a compound comprising a preferred non-aromatic amino function is a trialkylamine, preferably triethylamine.
  • reaction advantageously carried out in the presence of a halogenated solvent.
  • a preferred halogenated solvent is dichloromethane.
  • R1 and R2 are advantageously halogenated aliphatic groups or together form a single halogenated aliphatic group.
  • An acceptable halogenated aliphatic group can be chosen from carbon chains substituted by at least one halogen selected from the group consisting of chlorine, bromine, iodine.
  • the carbon chain will advantageously comprise a perhalogenated free end portion, preferably having a pattern of the type -CH 2 -Rc ⁇ > Rci being a perchlorinated residue.
  • R1, R2 may each be a 2,2,2-trichloroethyl substituent.
  • R3 is advantageously chosen from H, Li, Na, K. A more preferred substituent R3 is H.
  • R4 is advantageously chosen from Cl, Br, I. A more preferred substituent R4 is Cl.
  • a process in accordance with the invention can be implemented in a particularly advantageous manner when the compound of general formula 1 is (5S) -5-Acetylamino-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo [a, c] bis- (2,2,2-trichloroethyl) cyclohepten-3-yl-phosphate.
  • a process in accordance with the invention can be implemented in a particularly advantageous manner when the compound of general formula 3 is N - [(5S) -3-Hydroxy-9,10,11-trimethoxy-6,7-dihydro- 5 / - / - dibenzo [a, c] cyclohepten-5-yl] -acetamide, and the compound of general formula 4 is bis- (2,2,2-trichloroethyl) phosphochloride.
  • the coupling reaction between the compound of general formula 3 and the compound of general formula 4 is preferably carried out between 0 and 100 ° C, more preferably between 20 and 100 ° C, very preferably between 20 and 50 ° C.
  • the invention relates to the products obtained according to its first aspect.
  • the invention relates to a process for the preparation of a compound of formula 4: comprising a step in which a product according to its second aspect undergoes cleavage of the substituents R1 and R2 in the presence of at least one transition metal, preferably zinc.
  • the substituents R1 and R2 are more advantageously cleaved in the presence of two different transition metals, preferably zinc and copper.
  • the compound of formula 4 can also be purified by passage over an ion exchange resin.
  • the invention relates to the products obtained by a process in accordance with its fourth aspect.
  • the invention relates to a process for the preparation of a compound of general formula 5:
  • each of R5, R6 is independently selected from the group consisting of H, Li, Na, K, provided that at least one of R5, R6 is Li, Na or K, said method comprising a step in which a product according to its fifth aspect is salified with an alkaline compound of a metal cation, said metal cation being chosen from Li, Na, K.
  • An alkali compound of a preferred metal cation can be chosen from LiOH, NaOH, and KOH. NaOH will be preferred.
  • the invention relates to the products obtained by a process according to its sixth aspect.
  • the invention relates to pharmaceutical compositions comprising a product according to its fifth or seventh aspect, in combination with a pharmaceutically acceptable excipient.
  • the invention relates to the use of a product according to its fifth or seventh aspect, for the manufacture of a medicament useful for treating a pathological condition, preferably cancer.
  • the invention relates to a product of general formula 1
  • R1 and R2 are independently distinct or identical substituents or R1 and R2 together form a single substituent; (ii) R1 and R2 can be cleaved in the presence of at least one transition metal to lead to the formation of a phosphate or phosphoric acid group; and
  • R1 and R2 are halogenated aliphatic groups, or (ii) R1 and R2 together form a single halogenated aliphatic group.
  • a preferred halogenated aliphatic group is a hydrocarbon chain, for example alkyl, cycloalkyl, comprising at least one halogen selected from the group consisting of chlorine, bromine, iodine.
  • the hydrocarbon chain will advantageously be chosen from those in which the free terminal part is perhalogenated, preferably from -CH 2 -Rc ⁇ , Rci being a linear or cyclic aliphatic perchlorinated residue.
  • R1 and R2 are each a 2,2,2-trichloroethyl substituent. Description of Figure 1
  • FIG. 1 represents a route for the synthesis of the sodium salt of colchinol phosphate (VI) starting from colchicein (I), implementing a process in accordance with the invention.
  • colchicein (I) is reacted with sodium hydroxide in the presence of iodine in order to lead to the flavored iodized derivative (II) with a yield of 70%.
  • the latter is then reduced by reaction with a zinc-acetic acid mixture to produce N-acetylcolchinol (III) with a yield of 82.9%.
  • the phenol function of N-acetylcolchinol (III) is esterified with a phosphoric acid derivative to yield the compound (IV) with a yield of 80%.
  • phosphoric ester on the compound (IV) is deprotected by a Zn-Cu amalgam to provide phosphoric acid (V) with a yield of 77%, then the latter is salified to result in colchinol phosphate ( VI), obtained with a yield of 98.3%.
  • a solution containing 2.6 L of acetic acid and 131 g of product (II) is introduced into a 6 L three-necked flask fitted with mechanical stirring, a nitrogen inlet and a refrigerant. 393 g of powdered Zinc are quickly added to the solution at room temperature (18 ° C). The resulting gray suspension is brought to the boil for 1 hour and then is cooled to room temperature. The solid residue is filtered, washed with twice 175 ml of acetic acid and the filtrates are collected in a 50 L decanter containing 17 L of ice water. The acidic aqueous phase is extracted with 1.5 L then 3 times 1 L of chloroform.
  • the solution is stirred for 2 hours then is decomposed by the addition of 750 ml of water.
  • the organic phase is separated, washed successively with (i) a solution containing 375 ml of water and 375 ml of a saturated NaHCO 3 solution , then with (ii) 750 ml of water.
  • the organic phase is dried over Na 2 S ⁇ 4 , and the solvent is evaporated under reduced pressure to obtain a green resin.
  • the precipitate is filtered, washed with twice 170 ml of diethyl ether, dried under reduced pressure at 40 ° C in the presence of CaCl 2 to obtain 63.39 g (98.3%) of the product (VI) expected under form of a white powder.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
EP03796156A 2002-12-06 2003-12-04 Colchicin-derivate, verfahren zur ihrer herstellung, sowie deren verwendung Withdrawn EP1569946A1 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
FR0215418A FR2848212B1 (fr) 2002-12-06 2002-12-06 Derives de la colchicine, procede de preparation, produits obtenus par ce procede et utilisation
FR0215418 2002-12-06
PCT/FR2003/003585 WO2004052895A1 (fr) 2002-12-06 2003-12-04 Derives de la colchicine, leur procede de preparation et utilisation

Publications (1)

Publication Number Publication Date
EP1569946A1 true EP1569946A1 (de) 2005-09-07

Family

ID=32320041

Family Applications (1)

Application Number Title Priority Date Filing Date
EP03796156A Withdrawn EP1569946A1 (de) 2002-12-06 2003-12-04 Colchicin-derivate, verfahren zur ihrer herstellung, sowie deren verwendung

Country Status (6)

Country Link
US (1) US20040138182A1 (de)
EP (1) EP1569946A1 (de)
JP (1) JP2006509023A (de)
AU (1) AU2003298409A1 (de)
FR (1) FR2848212B1 (de)
WO (1) WO2004052895A1 (de)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB0428103D0 (en) * 2004-12-23 2005-01-26 Angiogene Pharm Ltd Chemical Process
GB0428101D0 (en) * 2004-12-23 2005-01-26 Astrazeneca Ab Chemical Processes & Intermediates

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9714249D0 (en) * 1997-07-08 1997-09-10 Angiogene Pharm Ltd Vascular damaging agents
DE60111622T2 (de) * 2000-03-31 2006-05-18 Angiogene Pharmaceuticals Ltd. Getrennte dosis therapien mit gefässschädigender aktivität
EE200200565A (et) * 2000-03-31 2004-06-15 Angiogene Pharmaceuticals Ltd. Vaskulaarse kahjustava toimega kombinatsioonravi

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2004052895A1 *

Also Published As

Publication number Publication date
WO2004052895A1 (fr) 2004-06-24
FR2848212B1 (fr) 2006-10-27
AU2003298409A1 (en) 2004-06-30
FR2848212A1 (fr) 2004-06-11
JP2006509023A (ja) 2006-03-16
US20040138182A1 (en) 2004-07-15

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