Details for Patent: 6,613,900

Title:	Cephalotaxane derivatives and process for their preparation
Abstract:	The present invention concerns a new general process for asymetric hemisynthesis of harringtonines and their analogs, that are alcaloids used in chimiotherapy. This process comprises direct esterification of a natural cephalotaxine with an acylating compound constituted of a side chain precursor which backbone and fonctionalization are entirely preformed.
Inventor(s):	Robin; Jean-Pierre (Le Mans, FR), Blanchard; Julie (Le Mans, FR), Cavoleau; Sylvie (Angers, FR), Chauviat; Ludovic (Le Mans, FR), Charbonnel; Sandra (Angers, FR), Dhal; Robert (Pruille le Chetif, FR), Dujardin; Gilles (Rouillon, FR), Fournier; Florence (Le Mans, FR), Gilet; Chrystelle (Le Mans, FR), Girodier; Laurent (Le Mans, FR), Mevelec; Laurence (Louvier, FR), Poutot; Sandrine (Le Mans, FR), Rouaud; Sylvie (Le Mans, FR)
Assignee:	Oncopharm Corporation (Houston, TX)
Filing Date:	Mar 27, 2001
Application Number:	09/817,176
Claims:	1. A process for the preparation of sidechain-bearing cephalotaxane of the following formula and/or a salt thereof: where .OMEGA. ("omega") is a representative radical of the chain terminal moiety and --CO-- is the carbonyl of the ester group bonded to cephalotaxane; the .OMEGA.-CO-- radical is corresponding: either to the following substituted heterocycloalkane formula: ##STR166## where n ranges from 0 to 8; Z is oxygen or sulfur heteroatom, or NH R.sup.5, R.sup.6 and R.sup.8 are independently hydrogen; hydrocarbon radical, saturated, unsaturated or aromatic, linear or branched and/or cyclic, --CH.sub.2 COOH, --CH.sub.2 CO.sub.2 Me,; or R.sup.6 and R.sup.8 may be present in a cycle; oxygen ether bearing one of the hydrocarbon radicals; or to the following linear alkene formula: ##STR167## where m ranges from 1 to 8; R.sup.5, R.sup.6 and R.sup.8 are as defined above; or to the following formula: ##STR168## where n, R.sup.5, R.sup.6 and R.sup.8 are as defined above; Z represents N or Z represents an oxygen atom, NH or sulfur heteroatom when R.sup.11 is null; Q.sup.2 is oxygen, NH or sulfur heteroatom; Q.sup.1 is carbon; R.sup.9 and R.sup.10 are independently hydrogen, alkoxy, hydrocarbon radical, saturated, unsaturated or aromatic, linear or branched and/or cyclic; wherein R.sup.9 may be absent and R.sup.10 may form a multiple bond with Q1 or wherein R.sup.10 may be absent and R.sup.9 may form a multiple bond with Q1, wherein R.sup.9 or R.sup.10 may be a heteroatom, wherein R.sup.9 and R.sup.11 may be absent and Q1forms a multiple bond with Z when Z represents NH; and R.sup.11 is hydrogen, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl or alkylcarbonyl; where --O--CTX is cephalotaxine moiety of the following formula or a salt thereof: ##STR169## where p is equal to 1 or 2; the two types of radicals --.OMEGA. and --CTX above-mentioned being bonded with an ester bond --CO--O-- the said process bringing together: either carboxylic acid with a formula .OMEGA.-CO--OH or a salt thereof; or an activated form of an acid with a formula .OMEGA.-CO--A or a salt thereof, with .OMEGA.-CO of the following formula: ##STR170## where n, Z, R.sup.5, R.sup.6 and R.sup.8 are as defined above; where .OMEGA.-CO having the following formula: ##STR171## m ranges from 1 to 8, Z, R.sup.5, R.sup.6 and R.sup.8 are as defined above; or .OMEGA.-CO having the following formula: ##STR172## where n, Z, Q.sup.1, Q.sup.2, R.sup.5, R.sup.6, R.sup.8, R.sup.9, R.sup.10 and R.sup.11 are as defined above A represents: either cyclic anhydride of the following formula: ##STR173## where n, R.sup.6 and R.sup.8 are as defined above; this reaction has been completed by methylation of the primary carboxyl thus formed with: either a hydroxyl group bearing cephalotaxane or a salt thereof of the formula H--O--CTX, where CTX are as defined above; or a metallic alkoxide of the formula M--O--CTX, where CTX are as defined above and M is a metal; or an activated form of its hydroxyl group of the formula Y--O--CTX, where --O-- CTX is as defined above and Y is, either a leaving group to allow a negative charge on oxygen atom by cleavage between Y-- and --O--CTX, or to allow a carbocation by cleavage between Y--O-- and --CTX; optionally in the presence of one or several reaction additives to form said sidechain-bearing cephalotaxane and/or a salt thereof. 2. The process of claim 1, wherein Z is an oxygen atom and the cephalotaxane is a cephalotaxine of the following formula, or a salt thereof: ##STR174## where R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are independently hydrogen, hydroxyl group or alkoxide. 3. The process of claim 2, wherein said cephalotaxane is a cephalotaxine of the following formula, or a salt thereof: ##STR175## 4. The process of claim 1 wherein R.sup.5 is hydrogen. 5. The process of claim 1, wherein R.sup.5 is --CH.sub.2 --CO--O--Me. 6. The process of claim 1, wherein n is 1 to 4, R.sup.6 and R.sup.8 are methyl. 7. The process of claim 1, wherein n is 1 or 2, R.sup.6 is phenyl and R.sup.8 is hydrogen. 8. The process of claim 1 wherein, R.sup.5 is --CH.sub.2 --CO--O--Me, n is 0, Z is a nitrogen atom and R.sup.8 is hydrogen and said cephalotaxane is a cephalotaxane of the following formula or a salt thereof: ##STR176## 9. The process of claim 1, wherein A is .OMEGA.--CO--O-- radical. 10. The process of claim 1, wherein A is halide. 11. The process of claim 1, wherein A is a radical selected from substituents: methoxyformyloxy of formula MeOCOO--, trifluoroacetyloxy of formula CF.sub.3 COO--, alkylsulfonoxy of formula RSO.sub.3 --, phosphoxy of formula (RO).sub.2 PO--, halophosphoxy of formula ROP(Cl)O--, trialkylsilyloxy of formula R.sub.3 SiO--, dimethyl-formamidinium chloride of formula: ##STR177## or acyloxy-pyridinium bromide of the formula: ##STR178## wherein R is alkyl. 12. The process of claim 1, wherein A is a 2,4,6-trichlorobenzoyloxy radical. 13. The process of claim 12, wherein the reagent of formula .OMEGA.--CO--A when A is 2,4,6-trichlorobenzoyloxy radical is obtained by contacting an acid .OMEGA.--CO--OH, as defined according to claim 1, with 2,4,6-trichlorobenzoyl chloride in presence of one or more O-acylation additives. 14. The process of claim 1, wherein radical A corresponds to the following formula: ##STR179## 15. The process of claim 14, wherein the reagent of formula .OMEGA.--CO--A is obtained by contacting an acid .OMEGA.--CO--OH, as defined according to claim 1, with carbonyl-diimidazole in presence of a strong base. 16. The process of claim 15, wherein the strong base is an alkoxide. 17. The process of claim 1, wherein a coupling additive is present, comprising a substituted carbodiimide and/or a basic additive such as tertiary amine. 18. The process of claim 17, wherein the substituted carbodiimide is selected from cyclohexylcarbodiimide (DCC), 1,3-diisopropylcarbodiimide (DIC) and chlorhydrate of 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide. 19. The process of claim 1, wherein the cephalotaxine alkoxide corresponds to the following formula: is obtained by contacting a cephalotaxine of the following formula: with metal, a metal amide, a metallic hydride or an alkyl-metal. 20. The process of claim 1, wherein M is an alkaline metal. 21. The process of claim 1, wherein when the cyclic side-chain of sidechain-bearing cephalotaxane, and/or a salt thereof, of the following formula: ##STR180## where n, R.sup.5, R.sup.6, R.sup.8, CTX and Z are as defined according to claim 1; the said chain is open with an agent and/or a protonic electrophilic radical E in aqueous or non-aqueous medium, to provide an intermediate compound of the following formula: ##STR181## where n, CTX, R.sup.5, R.sup.6 and R.sup.8 are as defined above, E is either hydrogen or an eletrophilic radical; the aforementioned intermediate compound may be attacked with an agent or a nucleophilic radical Z', and when the cyclic side-chain of sidechain-bearing cephalotaxane, and/or a salt thereof, of the following formula: ##STR182## where n, R.sup.5, R.sup.6, R.sup.8, R.sup.9, R.sup.10 and R.sup.11 are as defined according to claim 1, and Z' is an heteroatom; the said chain is open by hydrolysis or carefully solvolysis optionally in the presence of activation and/or opening additive; to provide an open sidechain-bearing cephalotaxane of the following formula: ##STR183## where n, CTX, R.sup.5, R.sup.6 and R.sup.8 are as defined according to claim 1; Z' is: either an halogen or an heteroatom bearing a hydrogen or a radical R.sup.11 such as defined accordint to claim 1; or an hydrogen, hydrocarbon radical, the said radical bearing or not heteroatom(s), saturated, unsaturated or aromatic, linear or branched and/or cyclic, especially alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocycloalkyl. 22. The process of claim 21, wherein the cyclic side-chain of sidechain-bearing cephalotaxane, and/or a salt thereof, of the following formula: ##STR184## where n, R.sup.8, R.sup.6, R.sup.5 CTX and Z are defined according to the claim 1, the said chain is open by treatment with a solution of hydrobromic acid in acetic acid, in an halogenated solvent, followed by in situ hydrolysis to provide, without isolation of the intermediate, a sidechain-bearing cephalotaxane of the following formula: ##STR185## 23. The process according to claim 1, wherein said acids correspond to the following formula: the said formula equivalent to racemic mixture containing compounds of the formulas (+)-.OMEGA.--CO--OH and (-)-.OMEGA.--CO--OH wherein (+)-.OMEGA.--CO--OH represents its dextrogyre enantiomer and (-)-.OMEGA.--CO--OH represent its levogyre enantiomer, were obtained a) by contacting said racemic mixture or one of the activated forms of the formula which is as defined according to claim 1; the said racemic mixture or said activated form generating respectively: either an anion corresponding to the formula (.OMEGA.--CO--O).sup.- ; or a cation corresponding to the formula (.OMEGA.--CO).sup.+ ; with a pure enantiomeric form of chiral entity, said "resolution agent" symbolized by .DELTA.* (delta stella), having the ability to form: either a stable combination, by covalent bonding; or an easily reversible labil combination, by hydrogen bonding or by hydrophobic interaction; or intermediate lability bonding by electrostatic interaction; to provide a diastereomeric mixture of .OMEGA.--CO--O--.DELTA.* and de .OMEGA.--CO--.DELTA.*; b) then by physical separation of the mixture of two diastereomers or two complex compounds or more generally of two new entities physically and/or chemically different then obtained; c) then by regeneration and finally separation of each one of enantiomers of the generic formula .OMEGA.*--CO--OH, where .OMEGA.* (<<omega stella<<) represents the generic symbol of the same chiral radical in the either one or the other pure enantiomeric forms corresponding to the following formulas (+)-.OMEGA.--CO--OH and (-)-.OMEGA.--CO--OH which are as defined above. 24. The process of claim 23, wherein .OMEGA.--CO-- is a radical corresponding to the following formula: ##STR186## 25. The process of claim 23, wherein the stable combination is represented by an ester of the following formula .OMEGA.--CO--O--.DELTA.*, said stable combination obtained by contacting acid with a chiral alcohol corresponding to the formula HO--.DELTA.*. 26. The process of claim 23, wherein the stable combination is represented by an amide corresponding to the either one or the other formulas .OMEGA.--CO--NH--.DELTA.* or .OMEGA.--CO--N--.DELTA.*, said stable combination obtained by contacting acid with primary or secondary chiral amine corresponding to formulas H.sub.2 N--.DELTA.* or NNis.DELTA.*. 27. The process of claim 23, wherein the stable combination is represented by an thioester of the following formula .OMEGA.--CO--S--.DELTA.*, said stable combination obtained by contacting acid with a chiral thiol corresponding to the formula HS--.DELTA.*. 28. The process of claim 23, wherein the ionic combination is represented by a salt prepared by contacting an acid with a chiral amine corresponding to one of the following formulas: 29. The process of claim 23, wherein the bringing into play of a labile bonding based combination is achieved in the form of chromatography with the help of a chiral stationary phase. 30. The process of claim 23, wherein the bringing into play of an interatomic or intermolecular labile bonding based combination, within crystalline latice, is achieved in the form of fractionated crystallization initiated by a chiral precursor. 31. The process of claim 25, wherein chiral alcohol HO--D* is (-)-quinine corresponding to the following formula: ##STR187## 32. The process of claim 25, wherein the chiral alcohol HO--.DELTA.* is (-) or (+)-methyl mandelate corresponding to the following formulas: ##STR188## 33. The process of claim 25, wherein the chiral alcohol HO--D* is (-)- or (+)-menthol corresponding to the following formulas: ##STR189## 34. The process of claim 28, wherein the chiral amine H.sub.2 N--.DELTA.* is (-)- or (+)-ephedrine corresponding to the following formulas: ##STR190## 35. The process of claim 1, wherein the carboxylic acid is: either the tertiary heterocycloalcane carboxylic acid corresponding to the following formula: ##STR191## where n, Z, R.sup.5, R.sup.6 and R.sup.8 are as defined according to claim 1; the said acid is obtained by treatment in aprotic or protic solvent, optionally in the presence of cyclization additive and/or dehydrating agent; or open tertiary ethylenic acid corresponding to the following formula: ##STR192## where m, Z, R.sup.5, R.sup.6 and R.sup.8 are as defined according to claim 1; or open tertiary ethylenic acid corresponding to-the following formula: ##STR193## where m ranges from t to 8, Z, R.sup.5, R.sup.6 and R.sup.8 are as defined according to claim 1, R.sup.12, is not a CTX radical according to claim 1, represents R.sup.5 and/or a protective group of acids and/or a chiral group; then R.sup.12 is removed later, either just by saponification, or by hydrogenolysis, or by a method to remove protective groups of acids. 36. The process of claim 35, wherein in the absence of a cyclization additive, the reaction of cyclization is conducted by heating. 37. The process of claim 35, wherein the cyclization additive is a protic acid or an aprotic acid, included in immobilized form. 38. The process of claim 35, wherein the acid is sulfonic acid or formic acid. 39. The process of claim 35, wherein Z is an oxygen atom. 40. The process of claim 1, wherein said cephalotaxane H--O--CTX is a cephalotaxine of the following formula, or a salt thereof, or a diastereoisomer thereof: ##STR194## where R.sup.13 and R.sup.14 are independently hydrogen, hydroxyl or alkoxide and R.sup.15 to R.sup.18 and R.sup.20 to R.sup.26 are independently hydrogen, hydroxyl, thiol, halogen, alcoxy, alkylthio group, or alkoxide, or R.sup.15, R.sup.17 and R.sup.18 independently represent OR.sup.19, R.sup.19 being hydrogen or an hydrocarbon radical. 41. The process of claim 40, wherein to R.sup.20 to R.sup.26 are hydrogen, R.sup.13 and R.sup.14 are independently hydroxyl or hydrogen, R.sup.15 to R.sup.18 are defined as in claim 40. 42. The process of claim 41, wherein R.sup.16 and R.sup.20 to R.sup.26 are hydrogen, R.sup.13 is hydroxyl, R.sup.14 is hydrogen, R.sup.15, R.sup.17 and R.sup.18 are independently OR.sup.19, R.sup.19 being alkyl, alkenyl, alkynyl, cycloalkyl, cycloaklenyl, aryl or heteroalkyl, said radicals including or not heteroatom(s). 43. The process of claim 42, wherein H--O--CTX is drupacine of formula: ##STR195## or a salt thereof. 44. The process of claim 2, where R.sup.1 and R.sup.4 are hydroxyl, R.sup.2 is hydrogen and R.sup.3 is methoxyl, wherein said cephalotaxane H--O--CTX is 11-hydroxy-cephalotaxine, or a salt thereof, of formula: ##STR196##