EP1224316A2 - 13-alkyl epothilone derivatives - Google Patents
13-alkyl epothilone derivativesInfo
- Publication number
- EP1224316A2 EP1224316A2 EP00966129A EP00966129A EP1224316A2 EP 1224316 A2 EP1224316 A2 EP 1224316A2 EP 00966129 A EP00966129 A EP 00966129A EP 00966129 A EP00966129 A EP 00966129A EP 1224316 A2 EP1224316 A2 EP 1224316A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- formula
- compound
- methyl
- stage
- acid
- 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- Withdrawn
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- 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
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D277/24—Radicals substituted by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/34—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/36—Sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/0002—Antibodies with enzymatic activity, e.g. abzymes
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
- C12P17/16—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms containing two or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
- C12P17/18—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms containing at least two hetero rings condensed among themselves or condensed with a common carbocyclic ring system, e.g. rifamycin
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P41/00—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture
- C12P41/002—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by oxidation/reduction reactions
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Definitions
- the invention relates to 13-lower alkyl epothilones; intermediates and a process for the preparation of epothilones and 13-lower alkyl epothilones; a pharmaceutical composition comprising 13-lower alkyl epothilones; the use of such compounds for the treatment of tumor diseases; a method of treatment of warm-blooded animals; catalytic antibodies having aldolase activity; a process for enantioselectively resolving a racemic mixture of aldol synthons by means of antibody catalyzed retro-aldol reaction.
- Epothilones A and B represent a new class of microtubul e-stabilising cytotoxic agents (see Gerth, K. et al., J. Antibiot. 1996. 49, 560-3) of the formula:
- R x means hydrogen (epothilone A) or methyl (epothilone B).
- Taxol ® a branded product already introduced for the treatment of tumours, that has the same mechanism of action but has however a series of disadvantages, such as very poor water solubility, making the preparation of pharma - ceutical formulations very difficult (at present, such formulations are normally characterised by the toxic side effects of the carrier materials), and inefficacy on a series of tumours.
- the advantages are as follows:
- epothilones for example for tumour treatment
- Pharmaceutical application of the epothilones is possible in an analogous manner to that described for Taxol, see, for example, US 5.641.803; US 5.496.804; US 5.565.478.
- One disadvantage of the epothilones is the relatively low therapeutic index, i.e. the dosage range between the necessary dose and the maximum tolerable dose is very small.
- R 2 is hydrogen or methyl
- R 3 is hydrogen or lower alkyl
- Z is O or a bond; can be obtained from chemical intermediates II obtained by a process of enantioselectively resolving a racemic mixture of an aldol synthon ( ⁇ )-ll
- the invention relates to a process for enantioselectively resolving a racemic mixture of an aldol synthon, the racemic mixture including a first and a second enantiomer of the aldol synthon, said process comprising the following steps:
- Step A Catalyzing a retro-aldol reaction for enantioselectively converting the first enantiomer of the aldol synthon to form an aldehyde product while leaving the second enantiomer of the aldol synthon unmodified, said catalyst employing a catalytic antibody;
- Step B Separating the aldehyde product from the unmodified second aldol synthon.
- racemic mixture need not to be a 50/50 mixture of the two enantiomers.
- the invention relates to a process wherein the racemic mixture of the aldol synthon of formula ( ⁇ )-ll is resolved to provide an unmodified enantiomer of formula II* and an aldehyde of formula III
- a catalytic antibody selected from the group consisting of 84G3, 85H6 and 93F3 is employed.
- Ri represents methyl, hydroxymethyl, halomethyl, methylthio or methoxy
- R represents C 1-5 alkyl, n-but-1 -en-4-yl or halomethyl. More preferably, R , represents methyl, hydroxymethyl, fluoromethyl, methylthio or methoxy, and R represents methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-but-1 -en-4-yl or fluoromethyl.
- R ⁇ represents methyl, hydroxymethyl, methylthio or methoxy
- R represents methyl, ethyl, n-propyl, n-butyl, n-pentyl or n-but-1 -en-4-yl.
- Catalytic antibodies 84G3, 85H6 and 93F3 were generated through immunization of mice against the hapten of formula IV
- catalytic antibodies 84G3, 85H6 and 93F3 have antipodal reactivity with regard to catalytic antibody 38C2. These three antibodies are especially effective with regard to the catalytic resolution of compounds ( +)-ll. E.g., the antibodies 84G3 is used in such resolution in a multi-gram scale in a quantity of between 0.00001 and 0.5 mol%.especially 0.0004, 0.003 or 0.005 mol%.
- the present invention relates to a process for the preparation of a compound of formula I, in which
- Ri is methyl, hydroxymethyl, halomethyl, methylthio or methoxy
- R 2 is hydrogen, methyl
- R 3 is hydrogen or lower alkyl
- compound of formula V Mes represents mesityl and Ph phenyl, followed by the detaching of the protecting group by a suitable reagent, and in which process directly before or after detaching the protecting groups present a compound of formula I wherein Z represents a bond can optionally be transformed by epoxidation in analogy to the procedure described in Example 26 of W099/43653 into a compound of formula I wherein Z represents O, and, after carrying out the above process, if necessary for the preparation of a salt, converting a resulting free compound of the formula I into a salt or, if necessary for preparation of a free compound, converting a resulting salt of a compound of the formula I into the free compound.
- 13-lower alkyl epothilone are pharmacologically highly effective for the indications mentioned herein.
- the invention relates also to 13-lower alkyl epothilone of formula IA wherein
- R is methyl, hydroxymethyl, halomethyl, methylthio or methoxy
- R z is hydrogen, methyl, R 3 is lower alkyl, and Z is O or a bond;
- the compounds of formula IA and their pharmaceutically acceptable salts have advantageous pharmaceutical properties. For example, they are active against multidrug- resistant cell lines and tumours and/or they have an improved therapeutic index over natural epothilones.
- the prefix “lower” denotes a radical having up to and including a maximum of 7, especially up to and including a maximum of 5 carbon atoms, the radicals in question being either branched with single or multiple branching or unbranched.
- Asymmetric carbon atoms that are optionally present in the substituents may exist in the (R), (S) or (R,S) configuration, preferably in the (R) or (S) configuration.
- the present compounds may thus exist as mixtures of isomers or as pure isomers, preferably as pure diastereoisomers.
- Lower alkyl has mono- or multiple-branching or, preferably, is unbranched or and is in particular methyl, ethyl, propyl, especially n-propyl, or butyl, especially n-butyl. Very preferably lower alkyl is methyl or ethyl.
- Halogen is especially fluorine, chlorine, bromine, or iodine, in particular fluorine or chlorine.
- Halomethyl is fluoromethyl or chloromethyl, in particular fluoromethyl.
- R T is methyl, hydroxymethyl, halomethyl, methylthio or methoxy
- R 2 is hydrogen or methyl
- R 3 is lower alkyl
- Z is O or a bond.
- Ri is methylthio
- R 2 is hydrogen
- R 3 is lower alkyl, especially methyl or ethyl and
- Z is O or a bond, prefeably a bond.
- the present invention provides compounds of formula II * , which are useful intermediates for the preparation of epothilone derivatives of formula I.
- R 1 represents methyl, hydroxymethyl, halomethyl, lower alkoxy lower alkylenoxy methyl, preferably methoxy methylenoxy methyl, methylthio or methoxy, and R represents lower alkyl, n-but-1 -en-4-yl or halomethyl.
- Ri represents methylthio
- R represents methyl or ethyl.
- Salts of compounds of formula I with a salt-forming group may be prepared in a manner known perse. Acid addition salts of compounds of formula I may thus be obtained e.g. by treatment with an acid or with a suitable anion exchange reagent.
- Salts can usually be converted to free compounds, e.g. by treating with suitable basic agents, for example with alkali metal carbonates, -hydrogencarbonates, or -hydroxides, typically potassium carbonate or sodium hydroxide.
- suitable basic agents for example with alkali metal carbonates, -hydrogencarbonates, or -hydroxides, typically potassium carbonate or sodium hydroxide.
- the compound V is solved in a suitable, dry solvent or mixture of solvents with a boiling point between 30 and 60 °C, e.g., dichloro methane.
- the catalyst of formula VI is added, preferably, in an amount of 5 mol % to 30 mol %, very preferably between 15 and 25 mol %, e.g., 20 mol %, and the cyclisation is carried out, e.g., at the reflux temperature of the solvent for a duration of 12 to 120 h, preferably 20 to 96 h.
- the reaction can be controlled by NMR analysis of the reaction mixture.
- the starting materials are known, may be produced by known processes or are commer - aily available, or they may be produced as described in the following:
- protecting groups which are to be in protected form can be protected if necessary at suitable stages, whereby selective pro - tection or deprotection is also possible.
- the protecting groups and the methods of introdu - cing and/or removing them correspond to those named above under process a), especial ly those named in the above-mentioned standard reference works or, in particular, in the ex - amples.
- protecting groups are not mentioned in the following; the following ex - amples show where the usage of the protecting groups is appropriate or necessary and can therefore be regarded as a preferred instruction as to when protecting groups should be used and if compounds should be produced with other radicals.
- protecting groups are not mentioned at all the points where they are appropriately used. The person skilled in the art is clear as to where this usage ought to or must occur.
- radicals Rj and R 3 have the same meaning as in the compound of formula V, with an acid of formula VIII
- esterification can be carried out under conditions known perse, especially in the presence of a dehydrating agent like DCC (dicyclohexylcarbodiimide).
- a dehydrating agent like DCC (dicyclohexylcarbodiimide).
- the acid can be solved in a suitable, inert and dry solvent, e.g. tetrahydrofuran or, preferably, dichloromethane, together with the alcohol at a temperature between - 10 °C and room temperature, e.g., 0 C C.
- EDC and DMAP (4-(dimethylamino)-pyridine) can be added and the mixture is stirred for 12 to 24 h, e.g. 16 h, at the same temperature.
- radicals Ri and R 3 have the same meaning as in the compound of formula VII and P' is a protecting group, with a reagent suitable to detach the protecting group.
- P' is a protecting group
- a reagent suitable to detach the protecting group E.g., if P' is terf-butyl dimethylsilyl, treatment of IX with TBAF in a suitable solvent, like tetrahydro- furan, at a temperature between 0°C and room temperature, provides the unprotected alcohol VII.
- R ⁇ comprises a hydroxy group protected by the same protecting group P', the treatment mentioned before also detaches the protecting group in R 1.
- the protecting group /erf-butyl dimethylsilyl can be reintroduced by reacting VII with TBSCI (fetr-butyl dimethylsilyl chloride) in the presence of diisoproylethylamine in a suitable solvent, like, e.g., dichloromethane, at a temperature between 0 °C and room temperature for 6 to 12 h, e.g., 8 h.
- a suitable solvent like, e.g., dichloromethane
- a compound of formula IX is obtainable by a Wittig reaction of a compound of formula X
- the radicals Ri, R 3 and P' have the same meaning as in the compound of formula IX using, e.g., the Wittig reagent methyl-triphenylphosphonium iodide.
- the Wittig reaction is known as such.
- the reaction can be carried out in dry tetrahydrofuran or another suitable solvent at temperatures between -10 °C and + 30 °C, preferably between 10 °C and room temperature.
- the solution is stirred for about 30 minutes at room temperature.
- the compound of formula X is added and the solution is stirred for further 15 to 90 minutes at the same temperature.
- a compound of formula X can be prepared by reacting a compound of formula II wherein the radicals Ri and R 3 have the same meaning as in the compound of formula X, with a reagent suitable to introduce a protecting group P', e.g. with TBSCI, in a suitable solvent, especially dimethylformamide, preferably in the presence of imidazole, at room temperature
- radical R 3 has the same meaning as in the compound of formula ( ⁇ )-ll, in which reaction the compound of formula XII is first solved in dry tetrahydrofuran and a solution of LDA is added at -78 C C. After stirring for between 1 and 4 h, the solution is cooled further to a temperature of about -100 °C and the compound of formula XI is added at the same temperature. The reaction mixture is stirred for further 30 to 120 minutes and then quenched by the addition of a suitable acidic reagent, e.g. an aqueous solution of NH 4 CI.
- a suitable acidic reagent e.g. an aqueous solution of NH 4 CI.
- Stereoisomeric mixtures e.g. mixtures of diastereoisomers
- Diastereoisomeric mixtures may thus be separated into their individual diastereoisomers by means of fractionated crystallization, chromatography, solvent distribution, and similar pro - cedures, preferably according to the purification procedures described in the Examples. This separation may take place either at the stage of one of the starting com pounds.
- Enantiomers may be separated through the for mation of diastereoisomeric salts, for example by salt formation with an enantiomer-pure chiral acid, or by means of chromatography, for example by HPLC, using chromatographic substrates with chiral ligands. (Enantiomer separation is normally effected at the interme diate stage).
- All process steps described here can be carried out under known reaction conditions, pre - ferably under those specifically mentioned, in the absence of or usually in the presence of solvents or diluents, preferably those that are inert to the reagents used and able to dissol - ve them, in the absence or presence of catalysts, condensing agents or neutralisi ng agents, for example ion exchangers, typically cation exchangers, for example in the H + form, depending on the type of reaction and/or reactants at reduced, normal, or elevated temperature, for example in the range from -100°C to about 190°C, preferably from about - 80°C to about 150°C, for example at -80 to 60°C, at room temperature, at - 20 to 40°C or at the boiling point of the solvent used, under atmospheric pressure or in a closed vessel, if required under pressure, and/or in an inert, for example an argon or nitrogen, atmosphere.
- solvents or diluents preferably
- Salts may be present in all starting compounds and intermediates, if these contain salt- forming groups. Salts may also be present during the reaction of such compounds, provided that the reaction is not thereby disturbed.
- isomeric mixtures that occur can be separated into their individual isomers, e.g. diastereoisomers or enantiomers, or into any mixtures of isomers, e.g. racemates or diastereoisomeric mixtures, for example analogously to methods described under "Additional process steps".
- the solvents from which those can be selected which are suitable for the reaction in question include for example water, esters, such as lower alkyl-lower alkanoate, e.g ethyl acetate, ethers, such as aliphatic ethers, e.g. diethylether, or cyclic ethers, e.g.
- liquid aromatic hydrocarbons such as benzene or toluene
- alcohols such as methanol, ethanol or 1- or 2-propanol
- nitriles such as acetonitrile
- halogenated hydrocarbons such as methylene chloride
- acid amides such as dimethylformamide
- bases such as heterocyclic nitrogen bases, e.g. pyridine
- carboxylic acids such as lower alkanecarboxylic acids, e.g. acetic acid
- carboxylic acid anhydrides such as lower alkane acid anhydrides, e.g.
- acetic anhydride cyclic, linear, or branched hydrocarbons, such as cyclohexane, hexane, or isopentane, or mixtures of these solvents, e.g. aqueous solutions, unless otherwise stated in the description of the process.
- solvent mixtures may also be used in working up, for example by chromatography or partitioning.
- the invention relates also to those embodiments of the process in which one starts from a compound obtainable at any stage as an intermediate and carries out the missing steps, or breaks off the process at any stage, or forms a starting material under the reaction condi - tions, or uses said starting material in the form of a reactive derivative or salt, or produces a compound obtainable by means of the process according to the invention under the pro - cess conditions therein, and further processes the said compound in situ.
- the compounds of formula I are also obtainable in the form of hydrates, or their crystals may include for example the solvent used for crystallisation (present as solvates).
- the invention relates also to a compound of formula I obtained by the process of preparation disclosed herein.
- Salts are primarily the pharmaceutically acceptable salts of compounds of formula I.
- Such salts are formed, for example, as acid addition salts, preferably with organic or inor - ganic acids, from compounds of formula I with a basic nitrogen atom, especially the pharmaceutically acceptable salts.
- Suitable inorganic acids are, for example, hydrohalic acids, such as hydrochloric acid, sulphuric acid, or phosphoric acid.
- Suitable organic acids are, for example, carboxylic, phosphonic, sulphonic or sulphamic acids, for example acetic acid, propionic acid, octanoic acid, decanoic acid, dodecanoic acid, glycolic acid, lactic acid, 2-hydroxybutyric acid, gluconic acid, glucosemonocarboxylic acid, fumaric acid, succinic acid, adipic acid, pimelic acid, suberic acid, azelaic acid, malic acid, tartaric acid, citric acid, glucaric acid, galactaric acid, amino acids, such as glutamic acid, aspartic acid, N-methyl- glycine, acetylaminoacetic acid, N-acetylasparagine or N-acetylcysteine, pyruvic acid, acetoacetic acid, phosphoserine, 2- or 3-glycerophosphoric acid, maleic acid, hydroxy- maleic acid, methylmaleic acid
- the compounds of formula IA have valuable pharmacological properties, as described hereinbefore and hereinafter.
- test compounds (10 mM) are prepared in DMSO and stored at -20°C.
- Microtubule protein is extracted from pigs' brain by two cycles of temperature-dependent depolymerisation/polymerisation, as known (see Weingarten et al., Biochemistry 1974: 13, 5529-37).
- Working stock solutions of micro tubule protein i.e. tubulin plus micro tubule- associated proteins
- the degree of test-compound-induced poly - merisation of microtubule protein is determined basically as already known (see Lin et al., Cancer Chem. Pharm. 1996. 38, 136-140).
- Drug or vehicle (DMSO, final concentration 5%) are diluted in 1x MEM buffer (100 mM MES, 1 mM EGTA, 1 mM MgCI 2 , pH 6.7) and placed in an eppendorf tube on ice. Following additon of microtubule protein (final concentration 1 mg ml), the polymerization reaction is started by transferring the incubation mixtures to a room-temperature water bath for 5 min. Then, the reaction mixtures are placed in an Eppendorf microcentrifuge and incubated for a further 15 minutes at room temperature. The samples are then centrifuged for 15 minutes at 14,000 rpm at room temperature, in order to separate polymerised from unpolymerised microtubule protein.
- 1x MEM buffer 100 mM MES, 1 mM EGTA, 1 mM MgCI 2 , pH 6.7
- the protein concentration of the su pernatant (which contains the remaining non-polymerised, soluble microtubule protein) is determined by the Lowry method (DC Assay Kit, Bio-Rad Laboratories, Hercules, CA, USA), and the optical density (OD) of the colour reaction is measured at 750 nm using a spectrometer (Spectra Max 340, Molecular Devices, Sunnyvale, CA, USA).
- Spectra Max 340 Molecular Devices, Sunnyvale, CA, USA
- the difference in OD's between samples treated with a test compound and vehicle-treated controls is compared with that obtained with incubations containing 25 ⁇ M epothilon B (positive control).
- the degree of polymerisation induced by a test compound is expressed relatively to the positive control (100%).
- In this test compounds of formula I exhibit a degree of polymerisation of 2 to 78 %, in particular 39% to 78% for compounds of formula IA wherein R ⁇ is methylthio.
- tumour cells The efficacy against tumour cells may be demonstrated in the following way:
- the plates are than incubated for an additional 4 days, after which the cells are fixed with 3.3 % v/v glutaraldehyde, washed with water and stained with 0.05% w/v methylene blue. After washing, the dye is eluted with 3 % HCI and the optical density measured at 665 nm with a SpectraMax 340 (Molecular Devices, Sunnyvale, CA, USA). IC50 values are determined by mathematical curve-fitting using the Softmax program currently version 2.6 ( Molecular Devices, Sunnyvale, CA, USA) using the formula (OD treated - OD start) / (OD control - OD start) x 100.
- the IC50 is defined as the drug concentration which leads to 50 % of cells per well compared to control cultures at the end of the incubation period.
- Compounds of formula IA show for the KB-31 cell line an IC50 in the range of 0.05 and 250 nM, preferably between 1 and 50 nM.
- Tests on other tumour cell lines e.g., A549 (lung; ATCC CCL 185), NCIH460 (lung), HCT- 15 (colon; ATCC CCL 225), HCT-116 (colon), MCF-7 (breast; ATCC HTB 22), or Du-145 (prostate; ATCC No. HTB 81 ) can be carried out in a comparable manner.
- tumours such as KB-31 or KB-8511 epidermoid tumours
- the anti-tumour efficacy of the test compounds may be measured in female BLB/c nu nu mice for example against the corresponding subcutaneously transplanted cell line.
- tumour frag - ments of about 25 mg are implanted into the left side of each of the mice (for example 6 animals per dose).
- the test compound is administered for example on day 11 after trans - plantation in different dosages (for example 0.1 ; 0.5; 1 ; 5 and 10 mg/kg), if desired repeating the administration, if required several times, after between two days and two weeks.
- the volumes of the tumours are determined for example after about 2 to 4 weeks (e.g. two weeks after the start of treatment).
- the tumour volumes are calculated by measuring the tumour diameter along two vertically arranged axes and according to published methods (see Evans et al., Brit. J. Cancer 1982. 45, 466-8).
- the anti-tumour efficacy is determined as the mean increase in tumour volume of the treated animals divided by the mean increase in tumour volume of the untreated animals (controls) and, after multiplication by 100, is ex - pressed as T/C%.
- Tumour regression (given in %) is calculated as the smallest mean tu - mour volume (Vt) in relation to the mean tumour volume at the start of treatment (Vo) ac - cording to the formula
- the compounds of formula IA are suitable for the treatment of proliferative diseases, especially tumour diseases, including metastases; for example solid tumours such as lung tumours, breast tumours, colorectal tumours, prostate tumours, melanomas, brain tumours, pancreas tumours, neck tumours, bladder tumours, neuro- blastomas, throat tumours, but also proliferative diseases of blood cells, such as leukaemia; also for the treatment of other diseases which respond to treatment with micro tubule depolymerisation inhibitors, such as psoriasis.
- the compounds of formula IA are used for the treatment of prostate tumours.
- a compound of formula IA can be administered alone or in combination with one or more other therapeutic agents, possible combination therapy taking the form of fixed combina - tions or the administration of a compound of the invention and one or more other therapeu - tic agents being staggered or given independently of one another, or the combined admini - stration of fixed combinations and one or more other therapeutic agents.
- a compound of formula IA can besides or in addition be administered for tumour therapy in combination with chemotherapy, radiotherapy, immunotherapy, surgical intervention, or a combination of these. Long-term therapy is equally possible as is adjuvant therapy in the context of other treatment strategies, as described above. Other possible treatments are therapy to maintain the patient's status after tumour regression, or even chemopreventive therapy, for example in patients at risk.
- Therapeutic agents for possible combination are especially one or more antiproliferative, cytostatic or cytotoxic compounds, for example one or more chemotherapeutic agent (s) selected from the group comprising the classical chemotherapeutic agents, an inhibitor of polyamine biosynthesis, an inhibitor of protein kinase, especially of serine/threo nine protein kinase, such as protein kinase C, or of tyrosine protein kinase, such as epidermal growth factor receptor protein tyrosine kinase, a cytokine, a negative growth regulator, such as TGF- ⁇ or IFN- ⁇ , an aromatase inhibitor, and a classical cytostatic.
- chemotherapeutic agent selected from the group comprising the classical chemotherapeutic agents, an inhibitor of polyamine biosynthesis, an inhibitor of protein kinase, especially of serine/threo nine protein kinase, such as protein kinase C, or of tyrosine protein kinase,
- compositions that contain a compound of formula IA as active ingredient and that can be used especially in the treatment of the diseases mentioned above.
- Compositions for enteral administration such as nasal, buccal, rectal or, especially, oral administration, and for parenteral administration, such as intravenous, intramuscular or subcutaneous administration, to warm-blooded animals, especially humans, are especially preferred.
- the compositions contain the active ingredient alone or, preferably, together with a pharmaceutically acceptable carrier.
- the dosage of the active ingredient depends upon the disease to be treated and upon the species, its age, weight, and individual condition, the individual pharmacokinetic data, and the mode of administration.
- the invention relates also to pharmaceutical compositions for use in a method for the pro - phylactic or especially therapeutic treatment of warm-blooded animals, including human, especially suffering from a tumour disease, in particular breast cancer or prostate cancer, to a process for the preparation thereof (especially in the form of compositions for the treatment of tumours) and to a method of treating the above-mentioned diseases, primarily neoplastic diseases, especially those mentioned above.
- tumour disease that is treated is prostate cancer or breast cancer.
- the invention relates also to the use of compounds of formula IA for the preparation of pharmaceutical preparations which contain compounds of formula IA as active component. Furthermore, the invention relates to a compound of formula IA for use in a process for the diagnostic or therapeutic treatment of humans and to the use of a compound of formula IA for the treatment of a tumour disease.
- a pharmaceutical composition that is suitable for administration to a warm-blooded animal, especially a human or commercially useful mammal, suffering from a disease that is responsive to the enhancement of micro tubule polymerisation, for example psoriasis or especially a neoplastic disease, comprising a correspondingly effective amount of a compound of formula IA, or a pharmaceutically acceptable salt thereof when salt- forming groups are present, together with at least one pharmaceutically acceptable carrier.
- a pharmaceutical composition for the prophylactic or especially therapeutic treatment of neoplastic and other proliferative diseases of a warm-blooded animal, especially a human or a commercially useful mammal requiring such treatment, especially suffering from such a disease, comprising a new compound of formula IA, or a pharmaceutically acceptable salt thereof, as active ingredient in a quantity that is prophylactically or especially therapeutically active against said diseases, is likewise preferred.
- compositions contain from about 0.000001 % to 95 % of the active ingredi - ent, whereby single-dose forms of administration preferably have from approximately 0.00001 % to 90 % and multiple-dose forms of administration preferably have from approxi - mately 0.0001 to 0.5 % in the case of preparations for parenteral administration or 1 % to 20 % active ingredient in the case of preparations for enteral administration.
- Unit dosage forms are, for example, coated and uncoated tablets, ampoules, vials, suppositories or capsules. Further dosage forms are, for example, ointments, creams, pastes, foams, tine - tures, lipsticks, drops, sprays, dispersions, etc.
- Dosage unit forms, such as coated tablets, tablets or capsules contain about 0.01 g to about 2 g, preferably about 0.02 g to about 1.0 g, of the active ingredient, in particular 0.02 to 0.6 g.
- the pharmaceutical preparations of the present invention are prepared in a manner known perse, for example by means of conventional mixing, granulating, coating, dissolving or lyophilising processes. Preference is given to the use of solutions of the active ingredient, and also suspensions or dispersions, which, for example in the case of lyophilised preparations which contain the active ingredient on its own or together with a carrier, for example mannitol, can be made up before use.
- the pharmaceutical preparations may be sterilised and/or may contain excipients, for example preservatives, stabilisers, wetting agents and or emulsifiers, solubilisers, salts for regulating the osmotic pressure and/or buffers and are prepared in a manner known perse.
- Suspensions in oil contain as the oil component the vegetable, synthetic, or semi-synthetic oils customary for injection purposes.
- liquid fatty acid esters that contain as the acid component a long-chained fatty acid having from 8 to 22, carbon atoms, for example lauric acid, tridecylic acid, myristic acid, penta- decylic acid, palmitic acid, margaric acid, stearic acid, arachidic acid, be henic acid or corresponding unsaturated acids, for example oleic acid, elaidic acid, erucic acid, brassidic acid or linoleic acid, if desired with the addition of antioxidants, for example vitamin E, ⁇ - carotene or 3,5-di-tert-butyl-4-hydroxytoluene.
- the alcohol component of these fatty acid esters has a maximum of 6 carbon atoms and is a mono- or polyhydric, for exam pie a mono-, di- or trihydric, alcohol, or the isomers thereof, but especially glycol and glycerol.
- fatty acid esters As fatty acid esters, the refore, the following are mentioned: ethyl oleate, isopropyl myristate, isopropyl palmitate, "Labrafil M 2375” (polyoxyethylene glycerol trioleate from Gattefosse, Paris), “Labrafil M 1944 CS” (unsaturated polyglycolised glycerides prepared by alcoholysis of apricot seed oil and consisting of glycerides and polyethylene glycol ester; Gattefosse, France), “Labrasol” (saturated polyglycolised glycerides prepared by alcoholysis of TCM and consisting of glycerides and polyethylene glycol ester; Gattefosse, France), and/or "Miglyol 812” (triglyceride of saturated fatty acids of chain length C 8 to C 12 from H ⁇ ls AG, Germany), but especially vegetable oils such as olive oil, cottonseed oil, almond oil, castor oil
- injectable preparations are usually carried out under sterile conditions, as is the filling, for example, into ampoules or vials, and the sealing of the containers.
- compositions for oral administration can be obtained, for example, by com - bining the active ingredient with one or more solid carriers, if need be granulating a resulting mixture, and processing the mixture or granules, if desired, to form tablets or tablet cores, if need be by the inclusion of additional excipients.
- Suitable carriers are especially fillers, such as sugars, cellulose preparations, and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, and also binders, such as starches, for example corn, wheat, rice or potato starch, and/or polyvinylpyrrolidone, and/or, if desired, disintegra tors, such as the above-mentioned starches, also carboxymethyl starch, crosslinked polyvinylpyrrolidone, alginic acid or a salt thereof, such as sodium alginate.
- Additional excipients are especially flow conditioners and lubricants, for example silicic acid, talc, stearic acid or salts thereof, and/or polyethylene glycol, or derivatives thereof.
- Tablet cores may be provided with suitable, if need be enteric, coatings, using inter alia concentrated sugar solutions which may comprise gum arabic, talc, polyvinylpyrrolidone, poly - ethylene glycol and/or titanium dioxide, or coating solutions in suitable organic solvents or solvent mixtures, or, for the preparation of enteric coatings, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate. Dyes or pigments may be added to the tablets or tablet coatings.
- suitable, if need be enteric, coatings using inter alia concentrated sugar solutions which may comprise gum arabic, talc, polyvinylpyrrolidone, poly - ethylene glycol and/or titanium dioxide, or coating solutions in suitable organic solvents or solvent mixtures, or, for the preparation of enteric coatings, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate. Dyes or pigments may be added to the tablets or tablet coating
- Orally administrable pharmaceutical compositions also include hard capsules consisting of gelatin, and also soft, sealed capsules consisting of gelatin and a plasticiser, such as gly - cerol or sorbitol.
- the hard capsules may contain the active ingredient in the form of granu - les, for example in admixture with fillers, such as corn starch, binders, and/or glidants, such as talc or magnesium stearate, and if need be stabilisers.
- the active ingredient is preferably dissolved or suspended in suitable liquid excipients, such as fatty oils, paraffin oil or liquid polyethylene glycols or fatty acid esters of ethylene or propylene glycol, to which stabilisers and detergents, for example of the polyoxyethylene sorbitan fatty acid ester type, may also be added.
- suitable liquid excipients such as fatty oils, paraffin oil or liquid polyethylene glycols or fatty acid esters of ethylene or propylene glycol, to which stabilisers and detergents, for example of the polyoxyethylene sorbitan fatty acid ester type, may also be added.
- the formulations suitable for parenteral administration are primarily aqueous solutions of an active ingredient in water-soluble form, e.g. a water-soluble salt, or aqueous injectable suspensions containing viscosity-increasing agents, e.g. sodium carboxymethyl cellulose, sorbitol and/or dextran, and where appropriate stabilisers.
- the active ingredient if need be together with excipients, can also be in the form of a lyophilisate and can be made into a solution before parenteral administration by the ad dition of suitable solvents.
- Solutions such as those used, for example, for parenteral administration can also be emplo yed as infusion solutions.
- the invention similarly relates to a process or a method for the treatment of one of the abo - ve-mentioned pathological conditions, especially a disease which responds to an enhancement of microtubule polymerisation, especially a corresponding neoplastic disease.
- a compound of formula IA can be administered as such or in the form of pharmaceutical composi - tions, prophylactically or therapeutically, preferably in an amount effective against the said diseases, to a warm-blooded animal, for example a human, requiring such treatment, the compounds especially being used in the form of pharmaceutical compositions.
- the dose administered is from approxi - mately 0.1 mg to approximately 1 g, preferably from approximately 0.5 mg to approximately 200 mg, of a compound of the present invention.
- Administration is preferably effected e.g. every 1 to 4 weeks.
- the present invention also relates in particular to the use of a compound of formula IA, or a pharmaceutically acceptable salt thereof, especially a compound of formula IA named as a preferred compound, or a pharmaceutically acceptable salt thereof, as such or in the form of a pharmaceutical formulation containing at least one pharmaceutically employable car - rier, for the therapeutical and also prophylactic treatment of one or more of the above disea ⁇ ses.
- the present invention also relates in particular to the use of a compound of formula IA, or a pharmaceutically acceptable salt thereof, especially a compound of formula IA named as a preferred compound, or a pharmaceutically acceptable salt thereof, for the preparation of a pharmaceutical formulation for the therapeutical and also prophylactic treatment of one or more of the above diseases.
- Ketone (1.1 equiv; 2.2 equiv for compounds ( ⁇ )-11 of Example 5 and Example 4) is added to a solution of LDA (0.5 M, 1.2 equiv; 2,4 equiv for compounds ( ⁇ )-11 of Example 5 and Example 4), freshly prepared from BuLi and i-Pr 2 NH in THF) at -78 °C.
- LDA 0.5 M, 1.2 equiv; 2,4 equiv for compounds ( ⁇ )-11 of Example 5 and Example 4
- the solution is stirred for 2 h at the same temperature, and then cooled to -100 °C.
- the corresponding aldehyde (1.0 equiv) in THF is added.
- the mixture is stirred at - 100 - -80 °C for 0.5 to 1 h, and then quenched with a saturated solution of NH 4 CI and allowed to warm to rt.
- the mixture is diluted with water and extracted with EtOAc.
- the combined organic layers are washed with brine and dried over MgSO 4 . Solvents are removed under vacuum and the residue is purified over silica gel (hexane-EtOAc) to afford the pure racemic aldol product.
- Antibody 84G3 (65 mg, 0.000434 mmol) is added to a sterilized solution of 6.43 g (26.9 mmol) of the racemic thiazole aldol (+)-1 in degassed CH 3 CN (10 - 20 mlJg aldol) and a degassed buffer (PBS, pH 7.4, 200 mL/g aldol) in a plastic bottle. The mixture is incubated at 37 °C for 5 days.
- degassed CH 3 CN 10 - 20 mlJg aldol
- PBS pH 7.4, 200 mL/g aldol
- the mixture is filtered using Amicon to recover the antibody and the filtrate is passed through a reverse phase column (C-18) to elute first water and then the organic compounds using methanol as eluants. Solvents are removed under vacuum and the residue is purified by CC (silica gel, hexanes - EtOAc (3:1)) to afford the optically pure aldol compounds 1 (99% ee) and the corresponding aldehyde 1a.
- CC sica gel, hexanes - EtOAc (3:1)
- Solvent systems (A) acetonitrile-water (3:17) and 0.1 % TFA, (B) acetonitrile-water (1 :4) and 0.1% TFA, (C) acetonitrile-water (3:7) and 0.1% TFA, at a flow rate of 0.4 mL/min.
- Compound 11 Solvent system B, R t of 11 , 12.56 min and ent- ⁇ ⁇ 14.38 min.
- Compound 12 Solvent system C R t of 12, 17.10 min and e ⁇ f-12 18.42 min.
- Compound 13 Solvent system B, R, of 13, 44.27 min and ent- Z 48.72 min.
- TFAA (4 equiv.) is added dropwise to a solution of the 2.8:1 mixture (70 mg, 0.096 mmol) of stage 6.5 in dry CH 2 CI 2 (0.1 M solution) at 0 °C and the mixture is stirred at the same temperature for 4 h and then concentrated under vacuum. The residue is dissolved in EtOAc, washed with brine and dried over MgSO . Solvents are evaporated and the resulting residue is purified by preparative TLC (PTLC) (silica gel, hexane - EtOAc 2:1) to afford the compounds of the above formula (60 % A, 21 % B)
- PTLC preparative TLC
- TBSCI (1 .5 equiv) is added to a solution of the compound of Example 1 (3.0 g, 12.6 mmol) and imidazole (3.0 equiv) in DMF (2M solution).
- the reaction mixture is stirred at rt for 24 h and worked up with ether and water.
- the organic layer is separated and the water phase is extracted with ether.
- the combined organic layer is washed with brine, dried over MgSO 4 .
- BuLi (1.1 equiv) is added to a heterogeneous mixture of MePPh 3 l (1 .2 equiv) in dry THF (0.5 M solution) at 0 C C. After the mixture is stirred for 0.5 h at rt, a solution of the compound of stage 6.1 (570 mg, 1.61 mmol) in THF (2 M solution) is added. The reaction mixture is stirred for an additional 0.5 h, and then quenched with a saturated solution of NH 4 CI and extracted with ether. The combined organic layer is washed with brine and dried over MgSO 4 .
- stage 7.5 The 1.5:1 mixture (77 mg, 0.10 mmol) of stage 7.5 is deprotected according to the method described in the final stage of Example 6 to give pure compounds A (50%) and B (34%); PTLC conditions: silica gel, hexanes - EtOAc (2:1).
- stage 8.5 The 2.4:1 mixture (60 mg, 0.078 mmol) of stage 8.5 is deprotected according to the method described in the final stage of Example 6 to yield pure compounds A (59%) and B (24%); PTLC conditions: silica gel, hexanes - EtOAc (3:1).
- stage 6.5 the diene of stage 8.4 (110 mg, 0.14 mmol) is metathesized to afford a mixture of the metathesized products which is taken to the next step without separation; CC conditions: silica gel, hexanes - EtOAc (14:1 ).
- stage 9.6 The 2.3:1 mixture (70 mg, 0.08 mmol) of stage 9.6 is deprotected according to the method described in the final stage of Example 6 to yield pure compounds A (63%) and B (27%); PTLC conditions: silica gel, hexanes - EtOAc (1 :2).
- the compound of stage 9.2 (180 mg, 0.37 mmol) is deprotected; CC conditions: silica gel, hexanes - EtOAc (1 :2).
- Stage 9.6 According to the method described in stage 6.5, the diene of stage 9.5 (90 mg, 0.1 mmol) is metathesized to afford a mixture of the metathesized products which is taken to the next step without separation; CC conditions: silica gel, hexanes - EtOAc (20:1 ).
- HF-pyridine (0.5 mL) is added to a solution of the 1.2:1 mixture (70 mg, 0.097 mmol) of stage 10.5 in dry THF (0.05 M solution) at rt. The solution is stirred at the same temperature for 6 h. The completion of the reaction is judged by TLC. The reaction mixture is slowly poured into a cold aqueous solution of NaHC0 3 and extracted with EtOAc. The organic layer is washed with brine and dried over MgS0 4 . Solvents are evaporated under reduced pressure. The residue is purified by PTLC (silica gel, hexanes - EtOAC (2:1 )) to yield the pure epothilones A (54%) and B (45%).
- PTLC sica gel, hexanes - EtOAC (2:1 )
- stage 6.5 the diene of stage 10.4 (94 mg, 0.13 mmol) is metathesized to afford a mixture of the metathesized products which is taken to the next step without separation; CC conditions: silica gel, hexanes - EtOAc (12:1 ).
- stage 11.6 is deprotected according to the method described in the final stage of Example 10 to yield pure compounds A (55%) and B (36%); PTLC conditions: silica gel, hexanes - EtOAc (1 :2).
- stage 6.3 the compound of stage 11.2 (492 mg, 1.05 mmol) is deprotected; CC conditions: silica gel, hexanes - EtOAc (1 :2).
- TBSCI 140 mg, 0.93 mmol
- a solution of the compound of stage 1 1.3 180 mg, 0.75 mmol
- /-Pr 2 NEt 0.26 mL, 1.50 mmol
- CH 2 CI 2 5 mL
- the reaction mixture is worked up with water and CH 2 CI 2 .
- the combined organic layer is washed with water and dried over MgSO 4 .
- stage 6.5 the diene of stage 1 1 .5 (125 mg, 0.14 mmol) is metathesized to afford a mixture of the metathesized products which is taken to the next step without separation; CC conditions: silica gel, hexanes - EtOAc (20:1 ).
- 3000 capsules each of which contain 0.25 g of one of the compounds of the formula IA mentioned in the preceding Examples as active ingredient, are prepared as follows:
- Preparation process The active ingredient is passed through a No. 30 hand screen.
- the active ingredient, lactose, Avicel PH 102 and Polyplasdone XL are blended for 15 minutes in a mixer.
- the blend is granulated with sufficient water (about 500 mL), dried in an oven at 35°C overnight, and passed through a No. 20 screen.
- Magnesium stearate is passed through a No. 20 screen, added to the granulation mixture, and the mixture is blended for 5 minutes in a mixer.
- the blend is encapsulated in No. 0 hard gelatin capsules each containing an amount of the blend equivalent to 25 mg of the active ingredient.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Health & Medical Sciences (AREA)
- Zoology (AREA)
- Engineering & Computer Science (AREA)
- Wood Science & Technology (AREA)
- Genetics & Genomics (AREA)
- General Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biochemistry (AREA)
- General Engineering & Computer Science (AREA)
- Microbiology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Biotechnology (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Immunology (AREA)
- Biomedical Technology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Analytical Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
Description
Claims
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US09/415,453 US6294374B1 (en) | 1999-10-08 | 1999-10-08 | Use of catalytic antibodies for synthesizing epothilone |
US415453 | 1999-10-08 | ||
US21306400P | 2000-06-21 | 2000-06-21 | |
US213064P | 2000-06-21 | ||
PCT/EP2000/009817 WO2001027308A2 (en) | 1999-10-08 | 2000-10-06 | 13-alkyl epothilone derivatives |
Publications (1)
Publication Number | Publication Date |
---|---|
EP1224316A2 true EP1224316A2 (en) | 2002-07-24 |
Family
ID=26907736
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP00966129A Withdrawn EP1224316A2 (en) | 1999-10-08 | 2000-10-06 | 13-alkyl epothilone derivatives |
Country Status (4)
Country | Link |
---|---|
EP (1) | EP1224316A2 (en) |
AU (1) | AU7662600A (en) |
CA (1) | CA2425620A1 (en) |
WO (1) | WO2001027308A2 (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1228087A1 (en) * | 1999-10-08 | 2002-08-07 | The Scripps Research Institute | Antibody catalysis of enantio- and diastereo-selective aldol reactions |
Families Citing this family (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU756699B2 (en) | 1996-12-03 | 2003-01-23 | Sloan-Kettering Institute For Cancer Research | Synthesis of epothilones, intermediates thereto, analogues and uses thereof |
DE60330651D1 (en) | 2002-03-12 | 2010-02-04 | Bristol Myers Squibb Co | C3-cyanoepothilonderivate |
EP2065054A1 (en) | 2007-11-29 | 2009-06-03 | Bayer Schering Pharma Aktiengesellschaft | Combinations comprising a prostaglandin and uses thereof |
EP2070521A1 (en) | 2007-12-10 | 2009-06-17 | Bayer Schering Pharma Aktiengesellschaft | Surface-modified nanoparticles |
DE102007059752A1 (en) | 2007-12-10 | 2009-06-18 | Bayer Schering Pharma Aktiengesellschaft | Functionalized solid polymer nanoparticles containing epothilones |
EP2210584A1 (en) | 2009-01-27 | 2010-07-28 | Bayer Schering Pharma Aktiengesellschaft | Stable polymeric composition comprising an epothilone and an amphiphilic block copolymer |
AU2011255647A1 (en) | 2010-05-18 | 2012-11-15 | Cerulean Pharma Inc. | Compositions and methods for treatment of autoimmune and other diseases |
CA2858806A1 (en) | 2011-12-23 | 2013-06-27 | Innate Pharma | Enzymatic conjugation of polypeptides |
EP2872894B1 (en) | 2012-07-13 | 2019-04-17 | Innate Pharma | Screening of conjugated antibodies |
US10036010B2 (en) | 2012-11-09 | 2018-07-31 | Innate Pharma | Recognition tags for TGase-mediated conjugation |
WO2014140300A1 (en) | 2013-03-15 | 2014-09-18 | Innate Pharma | Solid phase tgase-mediated conjugation of antibodies |
WO2014202773A1 (en) | 2013-06-20 | 2014-12-24 | Innate Pharma | Enzymatic conjugation of polypeptides |
JP6744212B2 (en) | 2013-06-21 | 2020-08-19 | イナート・ファルマ・ソシエテ・アノニムInnate Pharma Pharma S.A. | Enzymatic binding of polypeptides |
WO2019092148A1 (en) | 2017-11-10 | 2019-05-16 | Innate Pharma | Antibodies with functionalized glutamine residues |
CN110065267B (en) | 2019-04-26 | 2021-03-26 | 京东方科技集团股份有限公司 | Deformable material, deformation structure, Micro-LED display device and strain sensor |
-
2000
- 2000-10-06 AU AU76626/00A patent/AU7662600A/en not_active Abandoned
- 2000-10-06 EP EP00966129A patent/EP1224316A2/en not_active Withdrawn
- 2000-10-06 WO PCT/EP2000/009817 patent/WO2001027308A2/en not_active Application Discontinuation
- 2000-10-06 CA CA002425620A patent/CA2425620A1/en not_active Abandoned
Non-Patent Citations (1)
Title |
---|
See references of WO0127308A2 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1228087A1 (en) * | 1999-10-08 | 2002-08-07 | The Scripps Research Institute | Antibody catalysis of enantio- and diastereo-selective aldol reactions |
EP1228087A4 (en) * | 1999-10-08 | 2004-11-03 | Scripps Research Inst | Antibody catalysis of enantio- and diastereo-selective aldol reactions |
Also Published As
Publication number | Publication date |
---|---|
AU7662600A (en) | 2001-04-23 |
WO2001027308A2 (en) | 2001-04-19 |
CA2425620A1 (en) | 2001-04-19 |
WO2001027308A3 (en) | 2001-12-13 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US9771386B2 (en) | Z-selective ring-closing metathesis reactions | |
EP1767535B1 (en) | Synthesis of epothilones, intermediates thereto, analogues and uses thereof | |
US7145018B2 (en) | Method for synthesizing epothilones and epothilone analogs | |
WO2001027308A2 (en) | 13-alkyl epothilone derivatives | |
US20030203938A1 (en) | Epothilone derivatives and their synthesis and use | |
US8513429B2 (en) | Synthesis of epothilones, intermediates thereto and analogues thereof | |
US20040127432A1 (en) | Epothilone analogs | |
US6294374B1 (en) | Use of catalytic antibodies for synthesizing epothilone | |
EP1722791A2 (en) | Synthesis of epothilones, intermediates thereto, analogues and uses thereof | |
US6921769B2 (en) | Synthesis of epothilones, intermediates thereto and analogues thereof | |
US20060014796A1 (en) | Epothilone derivatives | |
RU2462463C2 (en) | Synthesis of epothiliones, intermediate products thereof, analogues and use thereof | |
JP5839328B2 (en) | EPOSILON COMPOUND AND METHOD FOR PREPARING THE SAME | |
US20070203346A1 (en) | Method for synthesizing epothilones and epothilone analogs |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
17P | Request for examination filed |
Effective date: 20020508 |
|
AK | Designated contracting states |
Kind code of ref document: A2 Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE |
|
AX | Request for extension of the european patent |
Free format text: AL;LT;LV;MK;RO;SI |
|
17Q | First examination report despatched |
Effective date: 20030110 |
|
RTI1 | Title (correction) |
Free format text: SYNTHESIS OF PRECURSORS OF 13-ALKYL EPOTHILONE DERIVATIVES BY ANTIBODY-CATALYZED RETROALDOL REACTION |
|
GRAP | Despatch of communication of intention to grant a patent |
Free format text: ORIGINAL CODE: EPIDOSNIGR1 |
|
GRAP | Despatch of communication of intention to grant a patent |
Free format text: ORIGINAL CODE: EPIDOSNIGR1 |
|
GRAS | Grant fee paid |
Free format text: ORIGINAL CODE: EPIDOSNIGR3 |
|
RAP1 | Party data changed (applicant data changed or rights of an application transferred) |
Owner name: THE SCRIPPS RESEARCH INSTITUTE |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN |
|
18D | Application deemed to be withdrawn |
Effective date: 20060503 |