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WO2010149688A2 - Composés anticancéreux - Google Patents

Composés anticancéreux Download PDF

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Publication number
WO2010149688A2
WO2010149688A2 PCT/EP2010/058879 EP2010058879W WO2010149688A2 WO 2010149688 A2 WO2010149688 A2 WO 2010149688A2 EP 2010058879 W EP2010058879 W EP 2010058879W WO 2010149688 A2 WO2010149688 A2 WO 2010149688A2
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Prior art keywords
substituted
unsubstituted
hydrogen
alkyl
compound according
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WO2010149688A3 (fr
Inventor
María GARRANZO GARCÍA-IBARROLA
Carmen MURCIA PÉREZ
Alberto RODRÍGUEZ VICENTE
María Cristina MATEO URBANO
Francisco SÁNCHEZ SANCHO
Andrés FRANCESCH SOLLOSO
María del Carmen CUEVAS MARCHANTE
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Pharmamar SA
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Pharmamar SA
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Publication of WO2010149688A3 publication Critical patent/WO2010149688A3/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/12—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/22—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
    • 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
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages

Definitions

  • the present invention relates to new antitumoral compounds, pharmaceutical compositions containing them and their use as antitumoral agents.
  • Phoon et al. reported the isolation of Gymnastatin N and its 12'-hydroxy analogue from the fungus Arachniotus punctatus (Phoon et al. Tetrahedron 2004, 60, 11619- 11628) .
  • Cancer is a leading cause of death in animals and humans. Huge efforts have been and are still being undertaken in order to obtain an antitumor agent active and safe to be administered to patients suffering from a cancer.
  • the problem to be solved by the present invention is to provide compounds that are useful in the treatment of cancer.
  • the present invention is directed to compounds of general formula I or pharmaceutically acceptable salts, prodrugs or stereoisomers thereof
  • each Ray, Rby, and R cy is independently selected from hydrogen, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C2-C12 alkenyl, and substituted or unsubstituted C2-C12 alkynyl;
  • each Re, R7, Rs, R ⁇ >, and Rio is independently selected from hydrogen, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C2-C12 alkenyl, and substituted or unsubstituted C2-C12 alkynyl;
  • Rn is selected from NRi3Ri 4 and OR15;
  • W is selected from O and NRi 2 ;
  • R12 is selected from hydrogen, COR e , COORd, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C2-C12 alkenyl, and substituted or unsubstituted C2-C12 alkynyl, or R12 and Rio together with the corresponding N atom and C atom to which they are attached may form a substituted or unsubstituted heterocyclic group;
  • each Ri3 and Ri 4 is independently selected from hydrogen, COR e , COORd, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C2-C12 alkenyl, substituted or unsubstituted C2-C12 alkynyl, and substituted or unsubstituted C 4 -Ci2 alkenynyl;
  • Ri5 is selected from substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C2-C12 alkenyl, and substituted or unsubstituted C2-C12 alkynyl;
  • each dashed line represents an optional additional bond with the proviso that at least one additional bond exits either between the C atoms to which Re and R7 are attached or between the C atoms to which Rs and Rg are attached, and with the further proviso that when a triple bond exists between the C atoms to which Ri and R3 are attached then Ri and R3 are absent, when a triple bond exists between the C atoms to which R 4 and R5 are attached then R 4 and R5 are absent, when a triple bond exists between the C atoms to which Re and R7 are attached then Re and R7 are absent, and when a triple bond exists between the C atoms to which Rs and Rg are attached then Rs and Rg are absent;
  • each Ra and Rb is independently selected from hydrogen, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C2-C12 alkenyl, substituted or unsubstituted C2-C12 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic group, and amino protecting group;
  • R c is independently selected from hydrogen, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C2-C12 alkenyl, substituted or unsubstituted C2-C12 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic group, and SH protecting group;
  • Rd is independently selected from hydrogen, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C2-C12 alkenyl, substituted or unsubstituted C2-C12 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic group, and OH protecting group; and
  • e ach Re is independently selected from hydrogen, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C2-C12 alkenyl, substituted or unsubstituted C2-C12 alkynyl, substituted or unsubstituted aryl, and substituted or unsubstituted heterocyclic group;
  • the present invention is also directed to a compound of formula I including compounds A and B, or a pharmaceutically acceptable salt, prodrug or stereoisomer thereof, for use as medicament.
  • the present invention is also directed to a compound of formula I including compounds A and B, or a pharmaceutically acceptable salt, prodrug or stereoisomer thereof, for use as medicament for treating cancer.
  • the present invention is also directed to the use of compounds of formula I including compounds A and B, or pharmaceutically acceptable salts, prodrugs or stereoisomers thereof, in the treatment of cancer, or in the preparation of a medicament for the treatment of cancer.
  • Other aspects of the invention are methods of treatment, and compounds for use in these methods. Therefore, the present invention further provides a method of treating any mammal, notably a human, affected by cancer which comprises administering to the affected individual a therapeutically effective amount of a compound of formula I including compounds A and B, or a pharmaceutically acceptable salt, prodrug or stereoisomer thereof.
  • the present invention is also directed to a compound of formula I including compounds A and B, or a pharmaceutically acceptable salt, prodrug or stereoisomer thereof, for use as anticancer agent.
  • the p re s e nt inve ntion is dire c te d to pharmaceutical compositions comprising a compound of formula I including compounds A and B, or a pharmaceutically acceptable salt, prodrug or stereoisomer thereof, together with a pharmaceutically acceptable carrier or diluent.
  • the present invention relates to compounds of general formula I as defined above.
  • Alkyl groups may be branched or unbranched, and preferably have from 1 to about 12 carbon atoms.
  • One more preferred class of alkyl groups has from 1 to about 6 carbon atoms. Even more preferred are alkyl groups having 1, 2, 3 or 4 carbon atoms.
  • Methyl, ethyl, n-propyl, isopropyl and butyl, including n-butyl, tert-butyl, sec-butyl and isobutyl are particularly preferred alkyl groups in the compounds of the present invention.
  • Another preferred class of alkyl groups has from 6 to about 10 carbon atoms; and even more preferably 7, 8 or 9 carbon atoms.
  • Heptyl, octyl and nonyl are the most preferred alkyl groups of this class.
  • Preferred alkenyl and alkynyl groups in the compounds of the present invention may be branched or unbranched, have one or more unsaturated linkages and from 2 to about 12 carbon atoms.
  • One more preferred class of alkenyl and alkynyl groups has from 2 to about 6 carbon atoms. Even more preferred are alkenyl and alkynyl groups having 2, 3 or 4 carbon atoms.
  • Another preferred class of alkenyl and alkynyl groups has from 4 to about 10 carbon atoms, still more preferably 6 to about 10 carbon atoms; and even more preferably 7, 8 or 9 carbon atoms.
  • alkenynyl group as an alkyl group containing one or more double bonds and one or more triple bonds
  • preferred alkenynyl groups are those having from 4 to about 12 carbon atoms.
  • One more preferred class of alkenynyl groups has from 6 to about 10 carbon atoms; and even more preferably 7, 8 or 9 carbon atoms.
  • Suitable aryl groups in the compounds of the present invention include single and multiple ring compounds, including multiple ring compounds that contain separate and/or fused aryl groups.
  • Typical aryl groups contain from 1 to 3 separated or fused rings and from 6 to about 18 carbon ring atoms.
  • Preferably aryl groups contain from 6 to about 10 carbon ring atoms.
  • Specially preferred aryl groups include substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted biphenyl, substituted or unsubstituted phenanthryl and substituted or unsubstituted anthryl.
  • Suitable heterocyclic groups include heteroaromatic and heteroalicyclic groups containing from 1 to 3 separated or fused rings and from 5 to about 18 ring atoms.
  • Preferably heteroaromatic and heteroalicyclic groups contain from 5 to about 10 ring atoms, most preferably 5, 6 or 7 ring atoms.
  • Suitable heteroaromatic groups in the compounds of the present invention contain one, two or three heteroatoms selected from N, O or S atoms and include, e.g., coumarinyl including 8- coumarinyl, quinolyl including 8-quinolyl, isoquinolyl, pyridyl, pyrazinyl, pyrazolyl, pyrimidinyl, furyl, pyrrolyl, thienyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl, isoxazolyl, oxazolyl, imidazolyl, indolyl, isoindolyl, indazolyl, indolizinyl, phthalazinyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, pyridazinyl, triazinyl, cinnolinyl, benz
  • Suitable heteroalicyclic groups in the compounds of the present invention contain one, two or three heteroatoms selected from N, O or S atoms and include, e.g., pyrrolidinyl, tetrahydrofuryl, dihydrofuryl, tetrahydrothienyl, tetrahydrothiopyranyl, piperidyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridyl, 2- pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3- dioxolan
  • Suitable halogen substituents in the compounds of the present invention include F, Cl, Br and I.
  • Suitable protecting groups are well known for the skilled person in the art.
  • a general review of protecting groups in organic chemistry is provided by Wuts, P. G. M. and Greene T.W. in Protecting groups in Organic Synthesis, 4 th Ed. Wiley-Interscience, and by Kocienski P.J. in Protecting Groups, 3 rd Ed. Georg Thieme Verlag.
  • These references provide sections on protecting groups for OH, amino, and SH groups. All these references are incorporated by reference in their entirety.
  • Examples of such protected OH include ethers, silyl ethers, esters, sulfonates, sulfenates and sulfinates, carbonates, and carbamates.
  • the protecting group for the OH can be selected from methyl, methoxymethyl, methylthiomethyl, (phenyldimethylsilyl)methoxymethyl, benzyloxymethyl, p-methoxybenzyl-oxymethyl, [(3,4- dimethoxybenzyl)oxy]methyl, p-nitrobenzyl-oxymethyl, o- nitrobenzyloxymethyl, [[R)- l-(2-nitrophenyl)ethoxy]methyl, (4-methoxy- phenoxy)methyl, guaiacolmethyl, [(p-phenylphenyl)oxy] methyl, t-butoxy- methyl, 4-pentenyloxymethyl, siloxymethyl, 2-methoxyethoxymethyl, 2- cyanoethoxymethyl, bis
  • the protecting group for the OH can be selected from trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, dimethylhexylsilyl, 2- norbornyldimethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl, di-t- butylmethylsilyl, bis(t-butyl)- 1-pyrenylmethoxysilyl, tris (trimethylsilyl) silyl, (2-hydroxystyryl)dimethylsilyl, (2-hydroxystyryl)diisopropylsilyl, t- butylmethoxyphenylsilyl, t-
  • the protecting group for the OH can be selected from formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trichloroacetamidate, trifluoroacetate, methoxyacetate, triphenylmethoxy- acetate, phenoxyacetate, p-chlorophenoxyacetate, phenylacetate, diphenylacetate, 3-phenylpropionate, bisfluorous chain type propanoyl, 4- pentenoate, 4-oxopentanoate, 4,4-(ethylenedithio)pentanoate, 5[3-bis(4- methoxyphenyl)hydroxymethylphenoxy]levulinate, pivaloate, 1- adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6-trimethylbenzoate, 4-bromobenzoate, 2,5-difluorate, a
  • the protecting group for the OH can be selected from sulfate, allylsulfonate, methanesulfonate, benzylsulfonate, tosylate, 2-[(4-nitrophenyl)ethyl]- sulfonate, 2-trifluoromethylbenzenesulfonate, 4-monomethoxytrityl- sulfenate, alkyl 2,4-dinitrophenylsulfenate, 2,2,5,5-tetramethylpyrrolidin- 3-one- l-sulfinate, borate, and dimethylphosphinothiolyl.
  • the protecting group for the OH can be selected from methyl carbonate, methoxymethyl carbonate, 9-fluorenylmethyl carbonate, ethyl carbonate, bromoethyl carbonate, 2-(methylthiomethoxy)ethyl carbonate, 2,2,2-trichloroethyl carbonate, 1, l-dimethyl-2,2,2-trichloroethyl carbonate, 2-(trimethylsilyl)ethyl carbonate, 2-[dimethyl(2- naphthylmethyl)silyl]ethyl carbonate, 2-(phenylsulfonyl) ethyl carbonate, 2-(triphenylphosphonio)ethyl carbonate, cis-[4-
  • Examples of protected amino groups include carbamates, ureas, amides, heterocyclic systems, iV-alkyl amines, iV-alkenyl amines, iV-alkynyl amines, iV-aryl amines, imines, enamines, N-metal derivatives, N-N derivatives, N-P derivatives, N-Si derivatives, and N-S derivatives.
  • the protecting group for the amino group can be selected from methylcarbamate, ethylcarbamate, 9-fluorenylmethyl- carbamate, 2,6-di-t-butyl-9-fluorenylmethylcarbamate, 2,7- bis(trimethylsilyl)fluorenylmethylcarbamate, 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluorenylmethylcarbamate, 17- tetrabenzo[ ⁇ ,c,g, ⁇ ]fluorenylmethylcarbamate, 2-chloro-3-indenylmethyl- carbamate, benz[/]inden-3-ylmethylcarbamate, 1, 1- dioxobenzo[b]thiophene-2-ylmethylcarbamate, 2-methylsulfonyl-3-phenyl- l-prop-2-enyloxycarbamate, 2,7-di-t-butyl-[9
  • the protecting groups for the amino group can be selected from phenothiazinyl-(10)-carbonyl, N'-p- toluenesulfonylaminocarbonyl, iV'-phenylaminothio-carbonyl, 4- hydroxyphenylaminocarbonyl, 3-hydroxytryptaminocarbonyl, and N- phenyl-aminothiocarbonyl.
  • the protecting group for the amino group can be selected from formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, pent-4-enamide, picolinamide, 3-pyridyl- carboxamide, iV-benzoylphenylalanyl, benzamide, p-phenylbenzamide, o- nitrophenylacetamide, 2,2-dimethyl-2-(o-nitrophenyl)acetamide, o- nitrophenoxyacetamide, 3-(o-nitrophenyl)propanamide, 2-methyl-2-(o- nitrophenoxy)propanamide, 3-methyl-3-nitrobutanamide, o- nitrocinnamide , o-nitrobenzamide , 3- (4- t-butyl-2 , 6-dinitrophenyl) -2 ,2- dimethylpropanamide, o-benzoyloxymethyl)benzamide
  • the protecting group for the amino group can be selected from 4,5-diphenyl-3-oxazolin-2-one, N- phthalimide, iV-dichlorophthalimide, iV-tetrachlorophthalimide, iV-4- nitrophthalimide, iV-thiodiglycoloyl, iV-dithiasuccinimide, N-2,3- diphenylmaleimide, iV-2,3-dimethylmaleimide, iV-2,5-dimethylpy ⁇ role, N- 2,5-bis(triisopropylsiloxy)pyrrole, iV-1 , 1 ,4,4-tetramethyldisilylazacyclo- pentane adduct, iV- l, l,3,3-tetramethyl- l,3-disilaisoindoline, N- diphenylsilyldiethylene, iV-5
  • the protecting group for the amino group can be selected from JV- methyl, N- 1- butyl, iV-allyl, JV-prenyl, iV-cinnamyl, iV-phenylallyl, iV-propargyl, JV- methoxymethyl, iV-[2-(trimethylsilyl)ethoxy]methyl, iV-3-acetoxypropyl, JV- cyanomethyl, iV-2-azanorbornenes, iV-benzyl, iV-4-methoxybenzyl, JV-2,4- dimethoxybenzyl, iV-2-hydroxybenzyl, iV-ferrocenylmethyl, JV-2,4- dinitrophenyl, o-methoxyphenyl, p-methoxyphenyl,
  • the protecting group for the amino group can be selected from JV- l, l-dimethylthiomethylene, JV- benzylidene, JV-p-methoxybenzylidene, JV-diphenylmethylene, JV- [2- pyridyl)mesityl] methylene, JV-(JV, JV-dimethylaminomethylene), N-[N, JV- dibenzylaminomethylene), JV- (JV- t-butylaminomethylene), N, N- isopropylidene, JV-p-nitrobenzylidene, JV-salicylidene, JV-5- chlorosalicylidene, JV-(5-chloro-2-hydroxyphenyl)phenylmethylene, JV- cyclohexylidene, and JV-t-butylidene.
  • the protecting group for the amino group can be selected from JV-(5,5-dimethyl-3-oxo- l- cyclohexenyl), JV-2,7-dichloro-9-fluorenylmethylene, JV- l-(4,4-dimethyl-2,6- dioxocyclohexylidene)ethyl, JV-(1 , 3-dimethyl-2,4,6-(lH,3H,5 ⁇ )- trioxopyrimidine-5-ylidene)methyl, JV-4,4,4-trifluoro-3-oxo- l-butenyl, and JV-(l-isopropyl-4-nitro-2-oxo-3-pyrrolin-3-yl).
  • the protecting group for the amino group can be selected from N-borane, JV-diphenylborinic acid, JV-diethylborinic acid, JV-9- borabicyclononane, JV-difluoroborinic acid, and 3,5- bis(trifluoromethyl)phenylboronic acid; and also including JV- [phenyl(pentacarbonylchromium)]carbenyl, JV-[phenyl(pentacarbonyl- tungsten)]carbenyl, JV-[methyl(pentacarbonylchromium)]carbenyl, JV- [methyl(pentacarbonyltungsten)]-carbenyl, JV-copper chelate, JV-zinc chelate, and a 18-crown-6-derivative.
  • the protecting group for the amino group can be selected from JV-nitro, JV- nitroso, JV-oxide, azide, triazene, and JV-trimethylsilylmethyl-JV- benzylhydrazine.
  • the protecting group for the amino group can be selected from diphenylphosphinamide, dimethylthiophosphinamide, diphenylthiophosphinamide, dialkyl phosphoramidate, dibenzyl phosphoramidate, diphenyl phosphoramidate, and iminotriphenylphosphorane.
  • the protecting group for the NH2 can be selected from t-butyldiphenylsilyl and triphenylsilyl.
  • the protecting group for the amino group can be selected from N-sulfenyl or N-sulfonyl derivatives.
  • the N-sulfenyl derivatives can be selected from benzenesulfenamide, 2- nitrobenzenesulfenamide, 2,4-dinitrobenzenesulfenamide, pentachloro- benzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide, triphenyl- methylsulfenamide, l-(2,2,2)-trifluoro- l ,l-diphenyl)ethylsulfenamide, and JV-3-nitro-2-pyridinesulfenamide.
  • the N-sulfonyl derivatives can be selected from methanesulfonamide, trifluoromethanesulfonamide, t- butylsulfonamide, benzylsulfonamide, 2-(trimethylsilyl)ethanesulfonamide, p-toluenesulfonamide, benzenesulfonamide, o-anisylsulfonamide, 2- nitrobenzenesulfonamide, 4-nitrobenzenesulfonamide, 2,4- dinitrobenzene sulfonamide, 2-naphthalenesulfonamide, 4-(4',8'- dimethoxynaphthylmethyl)benzenesulfonamide, 2-(4-methylphenyl)-6- methoxy-4-methylsulfonamide, 9-anthracenesulfonamide, pyridine-2- sulfonamide, benzothiazole-2-sulfonamide, phenacy
  • SH examples include thioethers, disulfides, silyl thioethers, thioesters, thiocarbonates, and thiocarbamates.
  • the protecting group for the SH can be selected from S-alkyl, S- benzyl, S-p-methoxybenzyl, S-o- hydroxybenzyl, S-p-hydroxybenzyl, S-o- acetoxybenzyl, S-p-acetoxybenzyl, S-p-nitrobenzyl, S-o-nitrobenzyl, S- 2,4,6-trimethylbenzyl, S-2,4,6,-trimethoxybenzyl, S-4-picolyl, S-2-picolyl- N-oxide, S-2-quinolinylmethyl, S-9-anthrylmethyl, S-9-fluorenylmethyl, S- xanthenyl, S-ferrocenylmethyl, S-diphenylmethyl, S-bis(4
  • the protecting group for the SH can be selected from S-acetyl, S-benzoyl, S-2-methoxyisobutyryl, S-trifluoroacetyl, S-iV-[[p-biphenylyl)- isopropoxy]carbonyl]-iV-methyl- ⁇ -aminothiobutyrate , and S-N-(t- butoxycarbonyl)-iV- methyl- ⁇ -amino thiobu tyrate .
  • the c as e of thiocarbonate protecting group for the SH can be selected from S-2,2,2- trichloroethoxycarbonyl, S-t-butoxycarbonyl, S-benzyloxycarbonyl, S- p- methoxybenzyloxycarbonyl, and S-fluorenylmethylcarbonyl.
  • the protecting group for the SH can be selected from S-[N- ethylcarbamate) and S-(iV-Methoxymethylcarbamate).
  • salts refers to any salt which, upon administration to the patient is capable of providing (directly or indirectly) a compound as described herein. It will be appreciated that non-pharmaceutically acceptable salts also fall within the scope of the invention since those may be useful in the preparation of pharmaceutically acceptable salts.
  • the preparation of salts can be carried out by methods known in the art. For instance, pharmaceutically acceptable salts of compounds provided herein are synthesized from the parent compound, which contains a basic or acidic moiety, by conventional chemical methods. Generally, such salts are, for example, prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent or in a mixture of the two.
  • nonaqueous media like ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred.
  • acid addition salts include mineral acid addition salts such as, for example, hydrochloride, hydrobromide, hydroiodide, sulphate, nitrate, phosphate, and organic acid addition salts such as, for example, acetate, trifluoroacetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate and p-toluenesulfonate.
  • alkali addition salts include inorganic salts such as, for example, sodium, potassium, calcium and ammonium salts, and organic alkali salts such as, for example, ethylenediamine, ethanolamine, N,N- dialkylenethanolamine, triethanolamine and basic aminoacids salts.
  • the compounds of the invention may be in crystalline form either as free compounds or as solvates (e.g. hydrates, alcoholates, particularly methanolates) and it is intended that both forms are within the scope of the present invention. Methods of solvation are generally known within the art.
  • the compounds of the invention may present different polymorphic forms, and it is intended that the invention encompasses all such forms.
  • prodrug any compound that is a prodrug of a compound of formula I is within the scope and spirit of the invention.
  • the term "prodrug” is used in its broadest sense and encompasses those derivatives that are converted in vivo to the compounds of the invention.
  • Examples of prodrugs include, but are not limited to, derivatives and metabolites of the compounds of formula I that include biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogues.
  • prodrugs of compounds with carboxyl functional groups are the lower alkyl esters of the carboxylic acid.
  • the carboxylate esters are conveniently formed by esterifying any of the carboxylic acid moieties present on the molecule.
  • Prodrugs can typically be prepared using well-known methods, such as those described by Burger “Medicinal Chemistry and Drug Discovery 6 th ed. (Donald J. Abraham ed. , 2001 , Wiley) and “Design and Applications of Prodrugs” (H. Bundgaard ed., 1985, Harwood Academic Publishers).
  • any compound referred to herein is intended to represent such specific compound as well as certain variations or forms.
  • compounds referred to herein may have asymmetric centres and therefore exist in different enantiomeric or diastereomeric forms.
  • any given compound referred to herein is intended to represent any one of a racemate, one or more enantiomeric forms, one or more diastereomeric forms, and mixtures thereof.
  • stereoisomerism or geometric isomerism about the double bond is also possible, therefore in some cases the molecule could exist as (£)-isomer or (Z)-isomer (trans and cis isomers).
  • each double bond will have its own stereoisomerism, that could be the same or different than the stereoisomerism of the other double bonds of the molecule.
  • compounds referred to herein may exist as atropisomers. All the stereoisomers including enantiomers, diastereoisomers, geometric isomers and atropisomers of the compounds referred to herein, and mixtures thereof, are considered within the scope of the present invention. Unless otherwise stated, the compounds of the invention are also meant to include isotopically- labelled forms i.e. compounds which differ only in the presence of one or more isotopically-enriched atoms.
  • compounds having the present structures except for the replacement of at least one hydrogen atom by deuterium or tritium, or the replacement of at least one carbon by 13 C- or 14 C-enriched carbon, or the replacement of at least one nitrogen atom by 15 N-enriched nitrogen are within the scope of this invention.
  • preferred compounds of general formula I are those also having general formula II or pharmaceutically acceptable salts, prodrugs or stereoisomers thereof
  • each dashed line represents an optional additional bond with the proviso that at least one additional bond exits either between the C atoms 5 and 6 or between the C atoms 7 and 8, and with the further proviso that when a triple bond exists between the C atoms 1 and 2 then Ri is absent;
  • R ay , Rby, and R cy are independently selected from hydrogen and substituted or unsubstituted C1-C12 alkyl. More preferred R ay , Rby, and R cy are independently selected from hydrogen and substituted or unsubstituted Ci-C ⁇ alkyl, and even more preferred are independently selected from hydrogen, substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, and substituted or unsubstituted butyl, including substituted or unsubstituted n-butyl, substituted or unsubstituted tert-butyl, substituted or unsubstituted isobutyl, and substituted or unsubstituted sec-butyl.
  • Ri and R5 are independently selected from hydrogen and ORd, wherein Rd is selected from hydrogen, substituted or unsubstituted Ci-Ci 2 alkyl, and an OH protecting group. More preferred Rd is hydrogen, a substituted or unsubstituted Ci-C ⁇ alkyl, and an OH protecting group selected from trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, dimethylhexylsilyl, 2-norbornyldimethylsilyl, t- butyldimethylsilyl (TBS), t-butyldiphenylsilyl, tribe nzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl, di-t-butylmethylsilyl, bis(t-butyl)- l
  • Ri is hydrogen and ORd where Rd is selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl and substituted or unsubstituted butyl, including substituted or unsubstituted n-butyl, substituted or unsubstituted tert-butyl, substituted or unsubstituted isobutyl and substituted or unsubstituted sec-butyl.
  • Rd is selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl and substituted or unsubstituted butyl, including substituted or unsubstituted n-butyl, substituted or unsubstituted tert
  • R a and Rb are independently selected from hydrogen and substituted or unsubstituted Ci-C ⁇ alkyl, and more preferred Rd is selected from hydrogen, substituted or unsubstituted Ci-C ⁇ alkyl, and an OH protecting group selected from trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, dimethylhexylsilyl, 2- norbornyldimethylsilyl, t-butyldimethylsilyl (TBS), t-butyldiphenylsilyl, tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl, di-t- butylmethylsilyl, bis(t-butyl)- l-pyrenylmethoxysilyl, tris (trimethylsilyl) silyl, (2-hydroxy
  • particularly preferred R3 and R 4 are independently selected from hydrogen and substituted or unsubstituted C1-C12 alkyl. More preferred R3 and R 4 are independently selected from hydrogen and substituted or unsubstituted Ci-C ⁇ alkyl, and even more preferred are hydrogen.
  • Re, R7, Rs, Rg, and Rio are independently selected from hydrogen and substituted or unsubstituted C1-C12 alkyl. More preferred Re, R7, Rs, R ⁇ >, and Rio are independently selected from hydrogen and substituted or unsubstituted Ci-C ⁇ alkyl, and even more preferred from hydrogen, substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl and substituted or unsubstituted butyl, including substituted or unsubstituted n-butyl, substituted or unsubstituted tert-butyl, substituted or unsubstituted isobutyl and substituted or unsubstituted sec-butyl.
  • Hydrogen, methyl, isopropyl, isobutyl, tert-butyl, and benzyl are the most preferred Re, R7, Rs, R ⁇ >, and Rio groups.
  • particularly preferred Re, R7, Re, and Rg are hydrogen, and particularly preferred Rio is selected from hydrogen, methyl, isopropyl, isobutyl, tert-butyl, and benzyl.
  • Most preferred Rio is isopropyl, isobutyl, or tert-butyl.
  • particularly preferred Rio is hydrogen and substituted or unsubstituted C1-C12 alkyl. More preferred Rio is hydrogen and substituted or unsubstituted Ci-C ⁇ alkyl, and even more preferred is hydrogen, substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl and substituted or unsubstituted butyl, including substituted or unsubstituted n-butyl, substituted or unsubstituted tert-butyl, substituted or unsubstituted isobutyl and substituted or unsubstituted sec-butyl.
  • the substituents may be chosen from the foregoing list. Even more preferred Rio is hydrogen, methyl, isopropyl, isobutyl, tert-butyl and benzyl. Most preferred Rio is isopropyl, isobutyl, or tert-butyl.
  • W is NRi2 wherein R12 is as defined before.
  • R12 is hydrogen and substituted or unsubstituted C1-C12 alkyl. More preferred R12 is hydrogen and substituted or unsubstituted Ci-C ⁇ alkyl; and even more preferred is hydrogen, methyl, ethyl, n- propyl, isopropyl and butyl, including tert- butyl. Hydrogen is the most preferred.
  • R12 and Rio together with the corresponding N atom and C atom to which they are attached form a substituted or unsubstituted heterocyclic group.
  • preferred heterocyclic group is a heteroalicyclic group containing one, two or three heteroatoms selected from N, O or S atoms, most preferably one N atom, and having from 5 to about 10 ring atoms, most preferably 5, 6 or 7 ring atoms.
  • a pyrrolidine group is the most preferred.
  • Rn is NRi3Ri 4 , wherein R13 and Ri 4 are as defined before.
  • R13 is hydrogen and substituted or unsubstituted C1-C12 alkyl . More preferred R13 is hydrogen and substituted or unsubstituted Ci-C ⁇ alkyl; and even more preferred are hydrogen, methyl, ethyl, n-propyl, isopropyl and butyl, including tert- butyl. Hydrogen is the most preferred.
  • Particularly preferred Ri 4 is hydrogen, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C2-C12 alkenyl, substituted or unsubstituted C2-C12 alkynyl, and substituted or unsubstituted C 4 -Ci2 alkenynyl, and more preferably is hydrogen, substituted or unsubstituted C2-C12 alkenyl, substituted or unsubstituted C2-C12 alkynyl, and substituted or unsubstituted C 4 -Ci2 alkenynyl.
  • the preferred substituted alkyl, substituted alkenyl, substituted alkynyl and substituted alkenynyl may present not only one but two or more substituents. More preferred alkyl groups are those having from 6 to about 10 carbon atoms; and even more preferably 7, 8 or 9 carbon atoms. Heptyl, octyl and nonyl are the most preferred alkyl groups. On the other hand, more preferred alkenyl groups are those having from 6 to about 10 carbon atoms; and even more preferably 7, 8 or 9 carbon atoms.
  • more preferred alkynyl groups are those having from 6 to about 10 carbon atoms; and even more preferably 7, 8 or 9 carbon atoms.
  • Oct-7-ynyl, oct-6-ynyl, oct-5-ynyl, oct-4-ynyl, oct-3-ynyl, oct-2-ynyl, oct- 1- ynyl, non-8-ynyl, non-7-ynyl, non-6-ynyl, non-5-ynyl, non-4-ynyl, non-3- ynyl, non-2-ynyl, non- 1-ynyl, hept-6-ynyl, hept-5-ynyl, hept-4-ynyl, hept- 3-ynyl, hept-2-ynyl, and hept- 1-ynyl are the most preferred alkynyl groups.
  • more preferred alkenynyl groups are those having from 6 to about 10 carbon atoms; and even more preferably 7, 8 or 9 carbon atoms.
  • Rn is OR15, wherein R15 is as defined before.
  • Particularly preferred R15 is a substituted or unsubstituted C1-C12 alkyl. More preferred R15 is a substituted or unsubstituted Ci-C ⁇ alkyl, and even more preferred is substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl and substituted or unsubstituted butyl, including substituted or unsubstituted n-butyl, substituted or unsubstituted tert- butyl, substituted or unsubstituted isobutyl and substituted or unsubstituted sec-butyl.
  • Most preferred R15 is methyl.
  • the bond between the C atoms to which Ri and R3 are attached is a double bond
  • the bond between the C atoms to which R 4 and R5 are attached is a single bond
  • the bond between the C atoms to which Re and R7 are attached is a double bond
  • the bond between the C atoms to which Rs and Rg are attached is a double bond.
  • the bond between the C atoms to which Ri and R3 are attached is a double bond
  • the bond between the C atoms to which R 4 and R5 are attached is a double bond
  • the bond between the C atoms to which Re and R7 are attached is a double bond
  • the bond between the C atoms to which Rs and Rg are attached is a double bond.
  • the bond between the C atoms 1 and 2 is a double bond
  • the bond between the C atoms 3 and 4 is a single bond
  • the bond between the C atoms 5 and 6 is a double bond
  • the bond between the C atoms 7 and 8 is a double bond.
  • the bond between the C atoms 1 and 2 is a double bond
  • the bond between the C atoms 3 and 4 is a double bond
  • the bond between the C atoms 5 and 6 is a double bond
  • the bond between the C atoms 7 and 8 is a double bond.
  • each double bond may exist as (E) or (Z).
  • the single isomers and mixtures of the isomers fall within the scope of the present invention.
  • Ra, Rb, Rc, Rd, and R e present in the compounds of the invention, and unless it is stated explicitly so, it should be understood that they can be each independently different within the given definition, i.e. Ra does not represent necessarily the same group simultaneously in a given compound of the invention.
  • the compounds of the invention can be obtained synthetically by joining different fragments or, when the bonds between the C atoms 1 and 2 and between the C atoms 3 and 4 are independently single or double, by opening the lactone ring of fragment E.
  • Ri, R2, R3, R4, Rs, Re, R7, Rs, R9, Rio, Rn, Y and W are the desired groups or a suitable protected group thereof as needed, and J, K, L, and M are appropriate reacting or leaving groups.
  • Examples of leaving groups are iodine, bromine, chlorine, tosylate, mesylate, nosylate, betylate, alkyl fluorosulfonate, triflate, and nonaflate.
  • the compounds of the invention can be obtained by either of the following strategies:
  • Fragments A and C can be coupled following standard procedures in organic chemistry for the synthesis of esters and amides [i.e. Bodanszky M and Bodanszky A, The Practice of Peptide Synthesis, Springer- Ve rlag, 1993).
  • Fragments B and D can be coupled following standard procedures of organometallic chemistry [Le. R. B. Crabtree, "The Organometallic Chemistry of the Transition Metals", 2 nd Ed., Wiley, Nueva York, 1994) . Coupling reactions catalysed by palladium such as Suzuki, Stille, Sonogashira, Hiyama, and Negishi reactions, and their analogues catalysed by other transition metals, are useful for the stereospecific coupling of Fragments B and D.
  • the lactone in Fragment E can be transformed in the compounds of formula I or II where the bonds between the pairs of C atoms 1 and 2 and between the pairs of C atoms 3 and 4 are independently single or double following standard procedures in organic chemistry (i.e. Michael B. Smith, Jerry March, "March' s Advanced Organic Chemistry: Reactions , Mechanisms and Structure, 6 th Ed., Wiley, New Jersey, 2007).
  • Michael B. Smith Jerry March
  • March' s Advanced Organic Chemistry Reactions , Mechanisms and Structure, 6 th Ed., Wiley, New Jersey, 2007.
  • Fragment E can be selectively hydrolysed under acid conditions to provide carboxylic acids that can be optionally derivatised to compounds of formula IA (Scheme II):
  • R 1 , R3, R 4 , Re, R7, Rs, R ⁇ >, Rio, Rn, W, Y, and the dashed lines are as defined in formula I or II or a suitable protected group thereof as needed;
  • Fragment E can be selectively hydrolysed under basic conditions to provide hydroxy carboxylic acids that can be optionally derivatised to provide a compound of formula IB (Scheme III):
  • Fragment E can be reduced to provide a dihydroxylated compound that can be optionally derivatised to provide a compound of formula IC (Scheme IV):
  • Fragment E can be opened with a nucleophilic amine to provide hydroxyl amides that can be optionally derivatised to provide a compound of formula ID (Scheme V)
  • Fragments A, B, C, D, and E can be independently prepared following standard procedures in organic synthesis.
  • standard procedures in organic synthesis By way of example:
  • Fragment A 1 Fragment A Compounds included in the definition of Fragment A can be obtained from a compound of formula AA
  • P is selected from OProt OH and N(Prot NH )(Ri 2 ); J is an appropriate reacting or leaving group such as halogen, NHR13, OH, or an activated OH; Prot OH is a protecting group for OH; Prot NH is a protecting group for amino; and Rio, R12, and R13 are as defined in formula I or II or
  • R12 is an appropriate protecting group as needed; by reaction with:
  • Fragment D can be obtained by coupling of fragment A with a compound of formula DD or a stereoisomer thereof according to Scheme VI:
  • each dashed line represents an optional additional bond
  • J is selected from halogen, OH and an activated OH
  • K is OH or NHR12
  • Rs, R9, Rio, Rn, R12, and W are as defined in formula I or II or a suitable protected group thereof as needed
  • M is an appropriate reacting or leaving group for a transition metal catalyzed coupling reaction such as halogen, triflate, organotin, organoboron, and organosilane.
  • M can also be hydrogen and Rs and Rg are absent.
  • fragment D when fragment D has one additional bond or two additional bonds between the C atoms to which Rs and Rg are attached, it can be obtained by: (a) coupling of Fragment A with a compound of formula EE or a stereoisomer thereof according to Scheme VII:
  • J is selected from halogen, OH and an activated OH
  • K is OH or NHR12
  • Rs, R9, Rio, Rn, R12, and W are as defined in formula I or II or a suitable protected group thereof as needed; followed by
  • hydrometalation reactions examples include hydrostannylation, hydrob oration, and hydrozirconation; or
  • fragment D when fragment D has two additional bonds between the carbon atoms to which Rs and Rg are attached, fragment D can be metallated by deprotonation of the terminal alkyne and reaction with a suitable metallic salt such as a cuprous halide .
  • Organometallic compounds included in the definition of Fragment D can be transformed into the corresponding halides by halogenolysis.
  • suitable reagents for such reaction are h, Br2, N- iodosuccinimide, and iV-bromosuccinimide.
  • each dashed line represents an optional additional bond
  • Ri, R2, R3, R 4 , R5, Re, R7, and Y are as defined in formula I or II or a suitable protected group thereof as needed
  • L is a suitable reacting or leaving group for a transition-metal catalyzed coupling reaction or a CHO group
  • Prot OH is a protecting group for OH.
  • an aldehyde of formula Bl reacts with an Evans -oxazolidinone, where BG is a bulky group, to provide a startery alcohol that is protected or derivatised to give a group R5, followed by reduction of the acyl oxazolidinone and optional oxidation to yield the aldehyde of fragment B2 (Phukan et al. Eur. J. Org. Chem. 2003, 9, 1733- 1740).
  • the aldehyde of formula Bl can be treated according to Scheme XI with an allylboron compound to provide a secondary alcohol that is protected or derivatised to give a group R5, followed by ozonolysis of the double bond to yield the aldehyde of fragment B2 (Nicolaou and Sorensen, Classics in Total Synthesis, Chapter 31, Wiley- VCH, 4 th Ed. 2003).
  • an aldehyde of formula Bl is treated with a metalated propyonaldehyde acetal to provide a secondary alcohol that is protected or derivatised to give a Rs group, followed by deprotection of the acetal group to yield fragment B2.
  • fragment B2 can be obtained according to Scheme XIII:
  • fragment B2 can be alternatively obtained according to Scheme XV by stereospecific cis- 1,4-cuprate addition followed by electrophilic capture and acetal deprotection (Alexakis et. al, Tetrahedron, 1984, 40, 715-731).
  • fragment B2 can be stereospecifically obtained from a compound of formula
  • fragment B2 can be obtained by hydrogenation of their unsaturated analogues.
  • Appropriate selection of starting materials and chiral hydrogenation catalysts provide specific stereoisomers.
  • fragment B2 can be obtained from a fragment B2 wherein Y is -CHR ay - and L is CHO by the Corey-Fuchs reaction (Corey and Fuchs, Tetrahedron Lett. 1972, 36, 3769-3772), with optional capture of the alkynyl lithium intermediate with a suitable electrophile (Scheme XVII).
  • fragment B2 can be stereoselectively obtained from a fragment B2 wherein Y is -CHR ay - and L is CHO using olefination reactions such as Wittig and Horner-Wadsworth- Emmons (Kishi et al. J. Am. Chem. Soc. 1979, 101, 259-260), followed by reduction and optional oxidation (Scheme XVIII).
  • olefination reactions such as Wittig and Horner-Wadsworth- Emmons (Kishi et al. J. Am. Chem. Soc. 1979, 101, 259-260), followed by reduction and optional oxidation (Scheme XVIII).
  • fragment B2 can be stereoselective ⁇ obtained from a fragment B2 wherein Y is -CHRay-C ⁇ CRcy by hydrozirconation with Schwartz reagent and optional halogenolysis or transmetalation (Scheme XIX).
  • fragment B2 can be stereoselectively obtained from a fragment B2 wherein Y is -CHRay- and L is CHO by Wittig or Takai's olefinations according to Scheme XX (Stork and Zhao, Tetrahedron Lett. 1989, 30, (17), 2173-2174 and F ⁇ rstner Chem. Rev. 1999, 99, 991- 1045).
  • the Wittig olefination can be extended to the synthesis of fragments B2 wherein R cy is different from hydrogen (Shair, et. al. J. Am. Chem. Soc. 2002, 124, 773-775).
  • fragment B2 can be obtained from a compound of formula
  • fragment B2 can be stereospecifically obtained from a fragment B2 wherein Y is -CHRay-C ⁇ C- and L is C ⁇ 2Me by trans- iodochlorination of the triple bond (Ogilvie et. al., J. Org. Chem.
  • fragment B2 can be obtained by hydrogenation of their unsaturated analogues.
  • Appropriate selection of starting materials and chiral hydrogenation catalysts provide specific stereoisomers.
  • Fragment B3 wherein Re is hydrogen or is absent can be obtained from a fragment B2 wherein L is CHO by a suitable carbonyl olefination reaction.
  • Specially preferred carbonyl olefination methods are those mentioned above for the synthesis of fragments B2.
  • Fragment B3 can also be obtained from a fragment B2 wherein L is halogen, hydrogen, or organometallic by a suitable palladium or copper catalysed coupling.
  • suitable palladium or copper catalysed couplings are Stille coupling, Sonogashira coupling, Hiyama coupling, Negishi coupling, and Suzuki coupling with suitable alkyl, alkenyl, and alkynyl organometallic compounds.
  • Examples of useful bifunctionalized C3 synthons for such couplings with a fragment B2 are compounds of formula: ⁇ ⁇ OH ⁇ OProt OH
  • Prot OH is a protecting group for OH
  • L is selected from H, halogen, organotin, organocopper, organozinc, organoboron, and organomagnesium; or
  • Re is as defined in formula I or II, and L is selected from halogen, organotin, and organocopper, obtainable by hydroxy-guided anti- hydrometalation of a propargylic alcohol, followed by optional transmetallation or halogenolysis (Corey et. al. J. Am. Chem. Soc. 1967, 89, 4245-4247); or
  • Re and R7 are as defined in formula I or II and L is selected from halogen, organotin, and organocopper, obtainable by hydroxy-guided anti metalation of a propargylic alcohol, followed by optional transmetallation or halogenolysis (Duboidin, et al. J. Organomet. Chem. 1979, 168, 1- 1 1); or L H
  • R ⁇ OProt OH wherein Re is as defined in formula I or II, L is halogen, organozirconium, organotin, and organozinc, and Prot OH is a protecting group for OH; that is obtainable by hydrozyrconation of a protected 2-alkynyl- l -alcohol, followed by optional transmetallation or halogenolysis (Schwartz et. al. J. Am. Chem. Soc.
  • Re is as defined in formula I or II
  • L is halogen or an organoalu- minium
  • Prot OH is a protecting group for OH; that is obtainable by reaction of a 2-alkynyl- l -ol with LiAlH 4 and MeONa, followed by optional halogenolysis (Corey et. al. J. Am. Chem. Soc. 1967, 89, 4245-4247); or R 6
  • Re and R7 are as defined in formula I or II, but are not hydrogen, that is obtainable by stereoselective iodo-chlorination of 2-alkynylesters, followed by one regioselective palladium catalysed coupling with an orgametallic of formula R7M wherein M is an organotin, an organoboron, or an organozinc (Ogilvie et. al. J. Org. Chem. 2007, 72, 977); or
  • R 6 wherein Re and R7 are as defined in formula I or II, R is an alkyl group, and L is an appropriate reacting or leaving group, that is obtainable by stereoselective carbometallation or hydrometallation of a 1- trialkylsilylalkyne, followed by optional trans me tallation or halogenolysis (Nicolaou and Sorensen, Classics in Organic Synthesis, Cap 31, Wiley- VCH, 4th Ed); or
  • Re and R7 are as defined in formula I or II, R is an alkyl group, and L is an appropriate reacting or leaving group, that is obtainable by stereoselective bis-metallation with a silyl organometallic such as Me3SiSnBu3, followed by optional transmetallation or halogenolysis of the organometallic group.
  • fragment B3 can be obtained from a fragment B2 wherein L is a suitable organometallic such as organomagnesium, organocopper, organozinc, or organoboron by regioselective 1 ,4-addition to ⁇ , ⁇ -unsaturated carbonyl compounds, followed by an optional reaction with an electrophile of formula R7L wherein R7 is as defined in formula I or II and L is a leaving group.
  • organometallic such as organomagnesium, organocopper, organozinc, or organoboron
  • organometallic reagents such as organozincs, organomagnesiums, and organoaluminiums
  • organosilicon organozincs, organoborons, and stannanes
  • R 6 ⁇ C0R ⁇ COR " ⁇ COR where Re is as defined in formula I or II, and R is alkoxy, amine, alkylamine, or dialkylamine group.
  • Fragment B3 can be transformed to fragment B4 according to Scheme XXIII:
  • fragment B can be stereoselective ⁇ obtained from a suitable fragment B4 by addition of a suitable electrophilic reagent wherein Ri and R2 are as defined in formula I or II, or a suitable protected group thereof as needed, to provide a leadery alcohol that is optionally protected or derivatised to give a group R 3 (Scheme XXIV):
  • the secondary alcohol can also be oxidized to a ketone that can be derivatizated through its enolate to provide a compound where the bond between the C atoms 1 and 2 is double.
  • fragment B can be stereoselective ⁇ obtained from a suitable fragment B4
  • fragment B can be obtained from a suitable fragment B4 by Corey-Fuchs alkynylation, followed by capture of the intermediate alkynyllithium with a suitable electrophile of formula R 2 L wherein L is a leaving group and R2 is as defined in formula I or II or a suitable protected group thereof as needed.
  • fragment B can be obtained from another fragment B wherein R 5 is OH and the bond between the C atoms 3 and 4 is a single bond, according to a suitable procedure selected from:
  • each dashed line represents an optional additional bond
  • R 1 , R2, R3, Re, R7, and Y are as defined in formula I or II or a suitable protected group thereof as needed
  • L is a suitable reacting or leaving group for a transition-metal catalyzed coupling reaction or a CHO group
  • Prot OH is a protecting group for OH.
  • Fragment B2' can be obtained by addition of the acetylide of fragment Bl' to a suitable electrophile reagent or by a transition metal- catalyzed coupling with a suitable organometallic reagent. Fragments B3' and B4' can be obtained using the procedures disclosed for the synthesis of fragments B3 and B4, respectively.
  • Fragment C can be obtained by a suitable palladium or copper catalysed coupling of fragment B with a compound of formula CC, followed by deprotection and optional activation of the carboxylic acid according to Scheme XXIX:
  • Fragment B CC Fragment C
  • each dashed line represents an optional additional bond
  • R 1 , R2, R3, R 4 , R5, Re, R7, Re, R9, and Y are as defined in formula I or II or an appropriately protected group as needed
  • Q is selected from OH and OProt OH
  • L and M are apropriate reacting or leaving groups for a transition- metal catalyzed coupling reaction
  • J is halogen, OH or an activated OH
  • Prot OH is a protecting group for OH.
  • Examples of useful reacting or leaving groups for said coupling reactions are halogen, an organomagnesium, an organocopper, an organozinc, an organoboron, an organotin, an organozirconium, and an organosilane; or hydrogen if compound of formula CC is a 2-alkynylester.
  • fragment C when the C atoms to which Rs and Rg are attached are linked through a single or double bond, fragment C can be obtained from a fragment B wherein L is a suitable organometallic such as an organomagnesium, an organocopper, an organozinc, or an organoboron by regioselective 1 ,4-addition to ⁇ , ⁇ -unsaturated esters of formula EE or an stereoisomer thereof (Scheme XXX):
  • Ri, R2, R3, R 4 , Rs, Re, R7, Rs, Rg, Y, and the dashed lines are as defined in formula I or II;
  • Prot OH is a protecting group for OH; and J is halogen, OH or an activated OH.
  • fragment C can be stereoselectively obtained from a fragment B wherein L is CHO using Wittig or Horner-Wadsworth-Emmons reactions or using Corey- Fuchs olefination followed by capture of the intermediate alkynyllithium with a suitable electrophile (Scheme XXXI).
  • Suitable protecting groups can be used on the substituents to ensure that reactive groups are not affected.
  • the synthesis can be designed to employ precursor substituents which can be converted at the appropriate stage to a desired substituent. Saturation or unsaturation can be introduced or removed as part of the synthesis.
  • the stereochemistry of the double bonds can be selectively controlled by the use of stereospecific methods known by an expert in the art. Starting materials and reagents can be modified as desired to ensure synthesis of the intended compound.
  • analogues can also be synthesized from the obtained compounds by usual procedures in synthetic organic chemistry which are known by a person skilled in the art.
  • the synthetic routes above mentioned can be modified as desired to give stereospecific compounds as well as mixtures of stereoisomers. It is possible to synthesize specific stereoisomers or specific mixtures by various methods including the use of stereospecific reagents or by introducing chiral centers into the compounds during the synthesis. It is possible to introduce one or more stereocenters during synthesis and also invert existing stereocenters. In addition, it is possible to separate stereoisomers once the compound has been synthesized by standard resolution techniques known to the skilled reader.
  • compositions of compounds of general formula I and II including compounds A and B that possess cytotoxic activity and their use as antitumor agents.
  • present invention further provides pharmaceutical compositions comprising a compound of this invention, a pharmaceutically acceptable salt, prodrug or stereoisomer thereof with a pharmaceutically acceptable carrier.
  • carrier refers to a diluent, adjuvant, excipient or vehicle with which the active ingredient is administered. Suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences” by E. W. Martin, 1995.
  • compositions include any solid (tablets, pills, capsules, granules, etc.) or liquid (solutions, suspensions or emulsions) compositions for oral, topical or parenteral administration.
  • Administration of the compounds or compositions of the present invention may be by any suitable method, such as intravenous infusion, oral preparations, and intraperitoneal and intravenous administration.
  • infusion times of up to 24 hours are used, more preferably 1- 12 hours, with 1-6 hours most preferred. Short infusion times which allow treatment to be carried out without an overnight stay in hospital are especially desirable. However, infusion may be 12 to 24 hours or even longer if required. Infusion may be carried out at suitable intervals of say 1 to 4 weeks.
  • Pharmaceutical compositions containing compounds of the invention may be delivered by liposome or nanosphere encapsulation, in sustained release formulations or by other standard delivery means.
  • the correct dosage of the compounds will vary according to the particular formulation, the mode of application, and the particular situs, host and tumour being treated. Other factors like age, body weight, sex, diet, time of administration, rate of excretion, condition of the host, drug combinations, reaction sensitivities and severity of the disease shall be taken into account. Administration can be carried out continuously or periodically within the maximum tolerated dose.
  • the terms “treat”, “treating”, and “treatment” include the eradication, removal, modification, or control of a tumor or primary, regional, or metastatic cancer cells or tissue and the minimization or delay of the spread of cancer.
  • the compounds of the invention have activity against cancers including, but not limited, lung cancer, colon cancer, and breast cancer.
  • the pharmaceutical composition comprising the compounds of formula I or II including compounds A and B as defined above is for the treatment of lung cancer, colon cancer, or breast cancer.
  • Scheme 1 provides an example of the synthesis of fragment 7.
  • Silyl ether 1 was obtained following the procedure disclosed in WO 2007/ 144423. PPTS (837.7 mg, 3.33 mmol) was added in one portion to a solution of 1 (4 g, 8.33 mmol) in ethanol (80 mL). The reaction mixture was stirred at room temperature for 7 h and then was concentrated. The residue was diluted in DCM and washed with a saturated aqueous solution of NaHCO 3 . The organic layer was extracted, dried over anhydrous Na2SO 4 , filtered and concentrated. Flash chromatography (Hex/EtOAc, 95: 1) gave the silyl eter 2 (2.12 g, 69% yield) as a colourless oil.
  • a resealable Schlenk tube was charged with copper (I) iodide (85.1 mg, 0.447 mmol), potassium carbonate (0.618 g, 4.47 mmol) and Boc-tert-L- LeuCONH2 (prepared following the procedure described in Pozdnev, V. F., Tetrahedron Letters 1995, 36, 7115-71 18) (0.514 g, 2.23 mmol), evacuated and filled with argon.
  • iV,iV-Dimethylethylenediamine (DMEDA) 0.095 mL, 0.89 mmol
  • vinyl iodide 4 0.727g, 1.49 mmol
  • anhydrous DMF 11 mL
  • aldehyde 8 (150 mg, 0.37 mmol), which was obtained following the procedure disclosed in WO 2007/ 144423, in MeOH (3 mL) under N2 atmosphere at 0 °C, was added (methoxycarbonylmethylene) triphenylphosphorane (388 mg, 1.01 mmol) in one portion. After 3 hours at 0°C, volatiles were removed under reduced pressure and hexane was added to the mixture . Filtration over Celite ® and evaporation under reduced pressure gave an oil that was purified by column chromatography (hexane/EtOAc 20: 1) affording pure 9 (75 mg, 44% yield) as a colourless oil.
  • Scheme 3 depicts a synthetic process for several compounds of the invention.
  • Scheme 4 provides an example of synthesis of several intermediates.
  • Scheme 5 provides an example of the synthesis of several compounds of the invention.
  • the aim of this assay is to evaluate the in vitro cytostatic (ability to delay or arrest tumor cell growth) or cytotoxic (ability to kill tumor cells) activity of the samples being tested.
  • SRB sulforhodamine B
  • This form of assay employs SBS-standard 96-well cell culture microplates (Faircloth et al. Methods in Cell Science, 1988, 11(4), 201-205;
  • DMEM Dulbecco's Modified Eagle Medium
  • FBS Fetal Bovine Serum
  • 2mM L-glutamine 100 U/mL penicillin and 100 U/mL streptomycin at 37°C, 5% CO 2 and 98% humidity.
  • cells were harvested from subconfluent cultures using trypsinization and resuspended in fresh medium before counting and plating.
  • the antitumor effect was estimated by the SRB method: Briefly, cells were washed twice with PBS, fixed for 15 min in 1% glutaraldehyde solution, rinsed twice in PBS, and stained in 0.4% SRB solution for 30 min at room temperature. Cells were then rinsed several times with 1% acetic acid solution and air-dried. SRB was then extracted in 1OmM trizma base solution and the absorbance measured in an automated spectrophotometric plate reader at 490 nm. Cell survival was expressed as percentage of control cell growth. The final effect of the sample being tested was estimated by applying the NCI algorithm (Boyd MR and Paull KD. Drug Dev. Res. 1995, 34, 91- 104).
  • GI50 concentration that produces 50% growth inhibition
  • TGI concentration that produces total growth inhibition (cytostatic effect)
  • LC50 concentration that produces 50% net cell killing (cytotoxic effect).
  • Table 1 illustrates data on the biological activity of compounds of the present invention.

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Abstract

La présente invention concerne un composé de formule générale (I), dans laquelle Y, W, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, et les traits tiretés ont différentes significations, destiné à être utilisé dans le traitement du cancer.
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JP2016526042A (ja) * 2013-05-31 2016-09-01 ファルマ、マール、ソシエダード、アノニマＰｈａｒｍａ Ｍｒｓ，Ｓ．Ａ． 抗体薬物コンジュゲート
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CN108467378A (zh) * 2017-02-23 2018-08-31 复旦大学 一种二氢吡喃酮类化合物及其制备方法和用途
US10538535B2 (en) 2017-04-27 2020-01-21 Pharma Mar, S.A. Antitumoral compounds
US11332480B2 (en) 2017-04-27 2022-05-17 Pharma Mar, S.A. Antitumoral compounds
US11339180B2 (en) 2017-04-27 2022-05-24 Pharma Mar, S.A. Antitumoral compounds
US11713325B2 (en) 2017-04-27 2023-08-01 Pharma Mar, S.A. Antitumoral compounds
US12384800B2 (en) 2017-04-27 2025-08-12 Pharma Mar, S.A. Antitumoral compounds

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