WO2007026027A1 - Novel ansamycin derivatives - Google Patents
Novel ansamycin derivatives Download PDFInfo
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- WO2007026027A1 WO2007026027A1 PCT/EP2006/065941 EP2006065941W WO2007026027A1 WO 2007026027 A1 WO2007026027 A1 WO 2007026027A1 EP 2006065941 W EP2006065941 W EP 2006065941W WO 2007026027 A1 WO2007026027 A1 WO 2007026027A1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D225/00—Heterocyclic compounds containing rings of more than seven members having one nitrogen atom as the only ring hetero atom
- C07D225/04—Heterocyclic compounds containing rings of more than seven members having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D225/06—Heterocyclic compounds containing rings of more than seven members having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems condensed with one six-membered ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Definitions
- the present invention relates to derivatives of ansamycin compounds that are useful, e.g. in the treatment of cancer or B-cell malignancies, in particular the derivatives are pro-drugs of ansamycin compounds.
- the present invention also provides methods for the production of these compounds and their use in medicine, in particular in the treatment and / or prophylaxis of cancer or B-cell malignancies.
- Hsp90 The 90 kDa heat shock protein
- So far nearly 50 of these so-called client proteins have been identified and include steroid receptors, non-receptor tyrosine kinases e.g. src family, cyclin-dependent kinases e.g.
- Hsp90 plays a key role in stress response and protection of the cell against the effects of mutation (Bagatell and Whitesell, 2004; Chiosis et al., 2004).
- Hsp90 The function of Hsp90 is complicated and it involves the formation of dynamic multi-enzyme complexes (Bohen, 1998; Liu et al., 1999; Young et al., 2001 ; Takahashi et al., 2003; Sreedhar et al., 2004; Wegele et al., 2004).
- Hsp90 is a target for inhibitors (Fang et al., 1998; Liu et al., 1999; Blagosklonny, 2002; Neckers, 2003; Takahashi et al., 2003; Beliakoff and Whitesell, 2004; Wegele et al., 2004) resulting in degradation of client proteins, cell cycle dysregulation and apoptosis.
- Hsp90 has been identified as an important extracellular mediator for tumour invasion (Eustace et al., 2004). Hsp90 was identified as a new major therapeutic target for cancer therapy which is mirrored in the intense and detailed research about Hsp90 function (Blagosklonny et al., 1996; Neckers, 2002; Workman and Kaye, 2002; Beliakoff and Whitesell, 2004; Harris et al., 2004; ⁇ ez et al., 2003; Lee et al., 2004) and the development of high-throughput screening assays (Carreras et al., 2003; Rowlands et al., 2004).
- Hsp90 inhibitors include compound classes such as ansamycins, macrolides, purines, pyrazoles, coumarin antibiotics and others (for review see Bagatell and Whitesell, 2004; Chiosis et al., 2004 and references therein).
- the benzenoid ansamycins are a broad class of chemical structures characterised by an aliphatic ring of varying length joined either side of an aromatic ring structure.
- Naturally occurring ansamycins include: macbecin and 18,21-dihydromacbecin (also known as macbecin I and macbecin Il respectively) (1 & 2; Tanida et al., 1980), geldanamycin (3; DeBoer et al., 1970; DeBoer and Dietz, 1976; WO 03/106653 and references therein), and the herbimycin family (4; 5, 6, Omura et al., 1979, Iwai et al., 1980 and Shibata et al, 1986a, WO 03/106653 and references therein).
- Hsp90 inhibitors are currently being assessed in clinical trials (Csermely and Soti, 2003; Workman, 2003).
- geldanamycin has nanomolar potency and apparent specificity for aberrant protein kinase dependent tumour cells (Chiosis et a/., 2003; Workman, 2003). It has been shown that treatment with Hsp90 inhibitors enhances the induction of tumour cell death by radiation and increased cell killing abilities (e.g.
- Hsp90 client protein HIF-1 ⁇ plays a key role in the progression of solid tumours (Hur et al., 2002; Workman and Kaye, 2002; Kaur et a/., 2004).
- Hsp90 inhibitors also function as immunosuppressants and are involved in the complement-induced lysis of several types of tumour cells after Hsp90 inhibition (Sreedhar et a/., 2004). Treatment with Hsp90 inhibitors can also result in induced superoxide production (Sreedhar et al., 2004a) associated with immune cell-mediated lysis (Sreedhar et al., 2004).
- Hsp90 inhibitors as potential anti-malaria drugs has also been discussed (Kumar et al., 2003).
- geldanamycin interferes with the formation of complex glycosylated mammalian prion protein PrP c (Winklhofer et al., 2003).
- ansamycins are of interest as potential anticancer and anti-B-cell malignancy compounds, however the currently available ansamycins exhibit poor pharmacological or pharmaceutical properties, for example they show poor water solubility, poor metabolic stability, poor bioavailability or poor formulation ability (Goetz et al. , 2003; Workman 2003; Chiosis 2004). Both herbimycin A and geldanamycin were identified as poor candidates for clinical trials due to their strong hepatotoxicity (review Workman, 2003) and geldanamycin was withdrawn from Phase I clinical trials due to hepatotoxicity (Supko et al., 1995, WO 03/106653)
- Geldanamycin was isolated from culture filtrates of Streptomyces hygroscopicus and shows strong activity in vitro against protozoa and weak activity against bacteria and fungi. In 1994 the association of geldanamycin with Hsp90 was shown (Whitesell et al., 1994). The biosynthetic gene cluster for geldanamycin was cloned and sequenced (Allen and Ritchie, 1994; Rascher ef a/., 2003; WO 03/106653). The DNA sequence is available under the NCBI accession number AY179507. The isolation of genetically engineered geldanamycin producer strains derived from S. hygroscopicus subsp.
- duamyceticus JCM4427 and the isolation of 4,5- dihydro-7-O-descarbamoyl-7-hydroxygeldanamycin and 4,5-dihydro-7-O-descarbamoyl-7- hydroxy-17-O-demethylgeldanamycin were described recently (Hong et al., 2004).
- geldanamycin By feeding geldanamycin to the herbimycin producing strain Streptomyces hygroscopicus AM-3672 the compounds 15-hydroxygeldanamycin, the tricyclic geldanamycin analogue KOSN-1633 and methyl-geldanamycinate were isolated (Hu et al., 2004).
- the two compounds 17-formyl-17- demethoxy-18-0-21 -O-dihydrogeldanamycin and 17-hydroxymethyl-17- demethoxygeldanamycin were isolated from S. hygroscopicus NRRL 3602 containing plasmid pKOS279-78 with various genes from the herbimycin producing strain Streptomyces hygroscopicus AM-3672 (Hu et al., 2004).
- ansamycin antibiotic herbimycin A was isolated from the fermentation broth of Streptomyces hygroscopicus strain No. AM-3672 and named according to its potent herbicidal activity.
- the antitumour activity was established by using cells of a rat kidney line infected with a temperature sensitive mutant of Rous sarcoma virus (RSV) for screening for drugs that reverted the transformed morphology of the these cells (for review see Uehara, 2003).
- RSV Rous sarcoma virus
- Herbimycin A was postulated as acting primarily through the binding to Hsp90 chaperone proteins but the direct binding to the conserved cysteine residues and subsequent inactivation of kinases was also discussed (Uehara, 2003). Chemical derivatives have been isolated and compounds with altered substituents at
- 18,21- Dihydromacbecin is characterized by containing the hydroquinone form of the nucleus. Both macbecin and 18,21-dihydromacbecin were shown to possess similar antibacterial and antitumour activities against cancer cell lines such as the murine leukaemia P388 cell line (Ono et al., 1982).
- the antibiotics TAN-420A to E were identified from producer strains belonging to the genus Streptomyces (7-11 , EP 0 110 710).
- geldanamycin related, non-benzoquinone ansamycin metabolite reblastatin from cell cultures of Streptomyces sp. S6699 and its potential therapeutic value in the treatment of rheumatoid arthritis was described (Stead et al., 2000).
- a further Hsp90 inhibitor, distinct from the chemically unrelated benzoquinone ansamycins is Radicicol (monorden) which was originally discovered for its antifungal activity from the fungus Monosporium bonorden (for review see Uehara, 2003) and the structure was found to be identical to the 14-membered macrolide isolated from Nectria radicicola. In addition to its antifungal, antibacterial, anti-protozoan and cytotoxic activity it was subsequently identified as an inhibitor of Hsp90 chaperone proteins (for review see Uehara, 2003; Schulte et al., 1999). The anti-angiogenic activity of radicicol (Hur ef a/., 2002) and semi-synthetic derivates thereof (Kurebayashi et al., 2001 ) has also been described.
- geldanamycin was derivatised on the 17-position to create 17-geldanmycin amides, carbamates, ureas and 17-arylgeldanamycin (Le Brazidec et al., 2003).
- a library of over sixty 17-alkylamino-17-demethoxygeldanamycin analogues has been reported and tested for their affinity for Hsp90 and water solubility (Tian et al., 2004).
- a further approach to reduce the toxicity of geldanamycin is the selective targeting and delivering of an active geldanamycin compound into malignant cells by conjugation to a tumour-targeting monoclonal antibody (Mandler ef a/., 2000).
- novel ansamycin derivatives which are prodrugs and may be cleaved, chemically or enzymatically, to the parent molecule and which generally have improved pharmaceutical properties compared with the presently available ansamycins; in particular they show improvements in respect of one or more of the following properties: water solubility, bioavailability and formulation ability.
- the present invention provides derivatives of ansamycins, methods for the preparation of these compounds, intermediates thereto and methods for the use of these compounds in medicine.
- the derivatives of ansamycins are pro-drugs.
- the present invention provides derivatives of benzenoid ansamycins containing self-cleaving and water solubilizing derivatising group(s) at positions 18 and/or 21 of the parent molecule. These groups are designed to be chemically cleaved to produce the bioactive parent molecule, alternatively cleavage may occur via enzymatic means.
- the invention relates to derivatives of a benzenoid ansamycin which contain a 1 ,4- dihydroxyphenyl moiety bearing at position 6 an amino carboxy substituent, in which position 2 and the carboxy substituent at position 6 are connected by an aliphatic chain of varying length characterised in that one or both of the 1 -hydroxy and the 4-hydroxy position(s) of the phenyl ring are independently derivatised by an aminoalkyleneaminocarbonyl group, which alkylene group (which may optionally be substituted by alkyl eg methyl groups) has a chain length of 2 or 3 carbons and which derivatising group(s) increase the water solubility and/or the bioavailability of the parent molecule but which are capable of being removed in-vivo eg by self-cleavage.
- the "parent molecule” means the corresponding molecule bearing an underivatised hydroxyl group at positions 1 and 4 of the phenyl ring (i.e. hydroquinone)
- the present invention provides derivatives of ansamycins according to the formulas (IA-IC) below, or a pharmaceutically acceptable salt thereof:
- R 2 represents OH, or keto;
- R 3 represents OH or OMe;
- R 5 represents H or wherein: n represents 0 or 1 ; Re represents H, Me, Et or iso-propyl;
- R 7 , R 8 and R 9 each independently represent H or a C1 -C4 branched or linear chain alkyl group; or R 7 and R 8 , or R 8 and Rg, may be connected so as to form a 6-membered carbocyclic ring;
- R 10 represents H or a C1 -C4 branched or linear chain alkyl group; provided however that the R 5 moieties are not both H and that when neither R 5 moiety represents H then the two R 5 moieties are the same.
- the above structure shows a representative tautomer and the invention embraces all tautomers of the compounds of formula (IA), (IB) and (IC) for example keto compounds where enol compounds are illustrated and vice versa.
- the present invention provides ansamycin derivatives such as compounds of formula (I) or a pharmaceutically acceptable salt thereof, for use as a pharmaceutical.
- analogue means one analogue or more than one analogue.
- analogue(s) refers to chemical compounds that are structurally similar to another but which differ slightly in composition (as in the replacement of one atom by another or in the presence or absence of a particular functional group).
- cancer refers to a malignant new growth that arises from epithelium, found in skin or, more commonly, the lining of body organs, for example, breast, prostate, lung, kidney, pancreas, stomach or bowel.
- a cancer tends to infiltrate into adjacent tissue and spread (metastasise) to distant organs, for example to bone, liver, lung or the brain.
- cancer includes both metastatic tumour cell types, such as but not limited to, melanoma, lymphoma, leukaemia, fibrosarcoma, rhabdomyosarcoma, and mastocytoma and types of tissue carcinoma, such as but not limited to, colorectal cancer, prostate cancer, small cell lung cancer and non-small cell lung cancer, breast cancer, pancreatic cancer, bladder cancer, renal cancer, gastric cancer, gliobastoma, primary liver cancer and ovarian cancer.
- metastatic tumour cell types such as but not limited to, melanoma, lymphoma, leukaemia, fibrosarcoma, rhabdomyosarcoma, and mastocytoma
- types of tissue carcinoma such as but not limited to, colorectal cancer, prostate cancer, small cell lung cancer and non-small cell lung cancer, breast cancer, pancreatic cancer, bladder cancer, renal cancer, gastric cancer, gliobastoma, primary liver cancer and ovarian cancer.
- bioavailability refers to the degree to which or rate at which a drug or other substance is absorbed or becomes available at the site of biological activity after administration. This property is dependent upon a number of factors including the solubility of the compound, rate of absorption in the gut, the extent of protein binding and metabolism etc. Various tests for bioavailability that would be familiar to a person of skill in the art are described herein (see also Egorin et al. (2002).
- B-cell malignancies includes a group of disorders that include chronic lymphocytic leukaemia (CLL), multiple myeloma, and non-Hodgkin's lymphoma (NHL). They are neoplastic diseases of the blood and blood forming organs. They cause bone marrow and immune system dysfunction, which renders the host highly susceptible to infection and bleeding.
- CLL chronic lymphocytic leukaemia
- NHL non-Hodgkin's lymphoma
- pro-drug refers to a precursor or derivative form of a pharmaceutically active substance that has an improved formulation profile compared to the parent drug, e.g. it may be less cytotoxic or more soluble compared to the parent drug, and it is capable of being activated (e.g. cleaved chemically or enzymatically) or otherwise converted into the more active parent form (see, for example, Wilman D.E.V. (1986) "Pro-drugs in Cancer Chemotherapy” Biochemical Society Transactions 14, 375-382 (615th Meeting, Harbor) and Stella VJ. et al (1985) "Pro-drugs: A Chemical Approach to Targeted Drug Delivery” Directed Drug Delivery R. Borchardt et a/ (ed.) pages 247-267 (Humana Press).
- water solubility refers to solubility in aqueous media, e.g. phosphate buffered saline (PBS) at pH 7.4, or in 5% glucose solution. Tests for water solubility are given below in the Examples as “water solubility assay”.
- PBS phosphate buffered saline
- ansamycin derivative refers to a benzenoid ansamycin derivative referred to above as representing the invention in its broadest aspect, for example a compound according to formula (I) above, or a pharmaceutically acceptable salt thereof.
- compounds are also referred to as “compounds of the invention” or “derivatives of ansamycins and these terms are used interchangeably in the present application.
- the pharmaceutically acceptable salts of compounds of the invention include conventional salts formed from pharmaceutically acceptable inorganic or organic acids or bases as well as quaternary ammonium acid addition salts. More specific examples of suitable acid salts include hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, perchloric, fumaric, acetic, propionic, succinic, glycolic, formic, lactic, maleic, tartaric, citric, palmoic, malonic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, fumaric, toluenesulfonic, methanesulfonic, naphthalene-2-sulfonic, benzenesulfonic hydroxynaphthoic, hydroiodic, malic, steroic, tannic and the like.
- Hydrochloric acid salts are of particular interest.
- Other acids such as oxalic, while not in themselves pharmaceutically acceptable, may be useful in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable salts.
- suitable basic salts include sodium, lithium, potassium, magnesium, aluminium, calcium, zinc, N 1 N'- dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N- methylglucamine and procaine salts.
- References hereinafter to a compound according to the invention include both compounds of formula (I) and their pharmaceutically acceptable salts.
- Alkyl, alkenyl and alkynyl groups may be straight chain or branched. Examples of alkyl eg C1-C4 alkyl groups include methyl, ethyl, n-propyl, i-propyl and n- butyl.
- Figure Legend Figure 1 Graph showing the decay of the parent compound and the relative amounts of released compounds in a cleavage assay.
- the present invention provides derivatives of ansamycins with an alternative method of rate controlled active drug release.
- This approach utilises self-cleaving of an incorporated amino side chain triggered at physiological pH via an intramolecular cyclisation-elimination reaction.
- Such intramolecular attack by a terminal amino group upon a carbamate functionality generates a cyclic urea fragment and leads to parent drug release.
- the rate of drug release is governed by chemical cyclisation rate constants and associated substituents rather than by external influence.
- the compounds of the invention are capable of chemically mediated self-cleavage, it is also possible that they are substrates for enzymatic cleavage and this is also encompassed within the scope of the present invention.
- the present invention provides derivatives of ansamycins, as set out above, methods for the preparation of these compounds, intermediates thereto and methods for the use of these compounds in medicine.
- R 6 represents H, Me or Et
- R-io represents a C1 -4 branched or linear alkyl group
- R 6 represents H, Me or Et and R-io represents a C1-4 branched or linear alkyl group.
- Each of the R 5 groups will be the same or one will be H whilst the other is substituted as described herein.
- one of the R 5 groups is H; in an alternative example aspect neither R 5 group is H.
- the C21 R 5 group is H.
- R 6 represents Me.
- R 6 represents Et.
- Ri 0 represents Me.
- Ri 0 represents Et.
- R 7 represents H.
- Re represents H.
- Rg represents H.
- R 7 and Re or R 8 and Rg are connected to form a six-membered carbocyclic ring that ring may suitably be a cyclohexyl ring.
- n 0.
- the stereochemistry of side chains relative to the ansamycin ring preferably follows that of the corresponding parent compounds (i.e. macbecin, geldanamycin, herbimycin A, see eg structure shown above Table 4).
- the compound of formula (I) may, for example, represent a derivative of the following compounds: • macbecin (formula (IA));
- herbimycin B (formula (IB) in which R 1 represents H, particularly when R 2 represents OH);
- the compounds of the invention are prepared by semi-synthetic derivatisation of the ansamycin family of compounds.
- a process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises:
- P represents a protecting group
- P represents a protecting group
- exemplary leaving groups L include halogen (eg chlorine, bromine), alkoxy (eg C1-4alkoxy), aryl (eg phenoxy or substituted phenoxy such as 4- nitrophenoxy) or alkylaryl (eg C1-4alkylaryl eg benzyloxy).
- L represents 4- nitrophenoxy.
- exemplary protecting groups P include t-butyloxycarbonyl ("Boc") and the trityl group.
- reaction of compounds of formula (M) with compound of formula (H) may be performed under conventional conditions known per se for carbamate formation eg reflux of the ingredients in an inert solvent such as dichloromethane with water work-up.
- a preferred compound of formula J is 4- nitrophenylchloroformate.
- reaction of compounds of formula (III) with compound of formula (J) may be performed under conventional conditions known per se eg reflux of the ingredients in an inert solvent such as dichloromethane.
- compounds of formula (HD)-(IIF) may be obtained by reacting the corresponding compound of formula (MIA)- (MIC) with a slight excess of the compound of formula J.
- Compounds of formula (MA)-(MC) may be obtained by reacting the corresponding compound of formula (MIA)-(MIC) with a greater than two times excess of the compound of formula J.
- the naturally occurring ansamycins for use as templates may be obtained via direct fermentation of strains which produce the desired compound.
- a person of skill in the art will be able to culture a producer strain under suitable conditions for the production and isolation of the natural product template.
- the strains listed in Table 1 are examples of producer strains for the natural product templates, but a person of skill in the art will appreciate that there may be alternative strains available that will produce the same compound under appropriate conditions.
- the compounds may be commercially available; Table 2 lists the compounds that may be purchased together with their catalogue numbers:
- hydroquinone form may be isolated from the fermentation broth. If the benzoquinone form is isolated then it will need to be converted to the corresponding compound of formula (III) (hydroquinones). It is well-known in the art that benzoquinones can be chemically converted to hydroquinones (reduction) and vice versa
- this transformation is carried out by dissolving macbecin or geldanamycin in ethyl acetate and mixing this solution vigorously with an aqueous solution of sodium hydrosulfite (Muroi et al., 1980).
- the resultant organic solution can then be washed with water, dried and the solvent removed under reduced pressure to yield an almost quantitative amount of 18,21- dihydromacbecin or 18,21-dihydrogeldanamycin respectively.
- Compounds of formula (MB) and (NC) such as those derived from geldanamycin may or do contain a secondary hydroxyl group at the C-1 1 position. In order to derivatise these compounds at the C-18 hydroxyl exclusively it may be necessary to first modify the C-1 1 hydroxyl. Additionally, compounds derivatised at the C-11 position in combination with derivatisation at C-18 or C-21 are specifically contemplated as compounds of the invention in their own right. Described below are methods for accomplishing this for geldanamycin, but a person of skill in the art will appreciate that these can equally be applied to other compounds of formula (MB) and (NC), (ME) and (NF) for which the parent compound contains an OH group at C-1 1.
- the C-1 1 hydroxyl could be oxidised to a ketone, by one of many standard protocols for oxidising secondary alcohols to a ketone, such as but not limited to, Swern oxidation, Dess-Martin periodination, tetrapropylammonium peruruthenate (TPAP), Jones' reagent, pyridinium chlorochromate (Corey's reagent) or pyridinium dichromate.
- TPAP tetrapropylammonium peruruthenate
- Jones' reagent Jones' reagent
- pyridinium chlorochromate Corey's reagent
- pyridinium dichromate pyridinium dichromate
- Protecting groups may, if desired, be generally employed in the synthesis of compounds of the invention and intermediate compounds as would be understood by a person skilled in the art.
- Hydroquinone ansamycins as shown as Formula (III) converted if required from their benzoquinone forms, may be used as templates for further semi-synthesis (i.e. process (a)).
- Other compounds embraced by the invention may be prepared by methods described herein and/or by methods known to a skilled person.
- a variety of self-cleaving and water solubilizing side- chains can be introduced at the 18 and/or 21 -position of 18,21-dihydromacbecin. This may be achieved by treating a mono N-protected diamine of variable chain length and substitution pattern (H) with an intermediate 4-nitrophenyl carbonate analogue of macbecin (e.g. a compound of formula (II) above).
- the imine formed is treated with an alkylating agent e.g. a trialkyloxonium tetrafluoroborate to introduce R-io and thus generate an iminium salt (C).
- Hydride reduction to the benzylamine (D) and subsequent di- debenzylation via catalytic hydrogenolysis provides secondary amines of type (E).
- N-Boc protection to (F) is followed by hydroxyl activation to a suitable leaving group e.g. mesylate (G).
- the Boc group of compounds (F), (G) and (H) in the diagram may be replaced by a different protecting group if desired by treating compound (E) with an alternative protecting reagent.
- a preferred alternative protecting group is trityl.
- salt formation and exchange may be performed by conventional methods known to a person of skill in the art.
- Interconversions of compounds of formula (I) may be performed by known processes for example hydroxy and keto groups may be interconverted by oxidation/reduction as described elsewhere herein.
- Suitable hydroxyl protecting groups include alkyl (e.g. methyl), acetal (e.g. acetonide) and acyl (e.g. acetyl or benzoyl) which may be removed by hydrolysis, and arylalkyl (e.g. benzyl) which may be removed by catalytic hydrogenolysis, or silyl ether, which may be removed by acidic hydrolysis or fluoride ion assisted cleavage.
- Suitable amine protecting groups include sulphonyl (e.g. tosyl), acyl (e.g. benzyloxycarbonyl or t-butoxycarbonyl) and arylalkyl (e.g. benzyl) which may be removed by hydrolysis or hydrogenolysis as appropriate.
- Compound of formula (I) in which the C18 R 5 is H may be prepared by deprotecting compounds of formula (IVA)-(IVC) (collectively known as “compounds of formula (IV)"):
- R 1 , R 2 , R3 and R 5 are as defined above (save that R 5 does not represent H) and Pa represents a protecting group, or a further protected derivative thereof.
- exemplary hydroxyl protecting groups Pa include those mentioned above, especially silyl ethers. Deprotection by removal of the silyl group may be achieved by hydrolysis under conventional conditions.
- Compounds of formula (V) or a protected derivative thereof may be prepared by reacting a compound of formula (VIA)-(VIC) (collectively known as “compounds of formula (Vl)”): or a protected derivative thereof, with a compound of formula (J). Suitable conditions include those given above for the reaction of compounds of formula
- Compounds of formula (Vl) or a protected derivative thereof may be prepared by protecting compounds of formula (III).
- Pa represent a silyl ether
- protection may be achieved by treating the compound of formula (III) with trialkylsilyl chloride or trialkylsilyl triflate in the presence of base.
- the compounds of the invention are useful directly, and as templates for further semi- synthesis or biocon version, to produce compounds useful as anticancer agents.
- Methods for the semi-synthetic derivatisation of ansamycins such as geldanamycin and related compounds are well known in the art and include (but are not limited to) those modifications described in e.g. WO 03/013430, WO 02/079167, WO 03/066005.
- the compounds of the invention have utility as pro-drugs, they may be chemically cleaved to produce the active parent compound.
- Cleavage assays to assess the rate of cleavage are known in the art and are
- Novel compounds of formula (II), (III), (IV), (V) and (Vl) and protected derivatives thereof are also claimed as an aspect of the invention.
- the invention additionally provides for the use of a compound of the invention in the treatment of cancer or B-cell malignancies. It also provides a compound of the invention for use in the treatment of cancer or B-cell malignancies. It also provides a method of treatment of cancer or B-cell malignancies which comprises administering to a patient an effective amount of a compound of the invention. It also provides the use of a compound of the invention in the preparation of a medicament for the treatment of cancer or B-cell malignancies.
- Ansamycins are also known to have utilities in the treatment of other conditions, including, but not limited to, the treatment of cardiac arrest and stroke (US 6,174,875, WO 99/51223), the treatment of fibrogenic disorders (WO 02/02123), the treatment or prevention of restenosis (WO 03/079936), the treatment or prevention of diseases associated with protein aggregation and amyloid function (WO 02/094259), the treatment of peripheral nerve damage and the promotion of nerve regeneration (WO 01/03692, US 6,641 ,810, EP 1 024 806, US
- the present invention provides compounds with utility in the treatment of cancer.
- One skilled in the art would be able by routine experimentation to determine the ability of these compounds to inhibit tumour cell growth, (see Tian et al., 2004; Hu et al. 2004; Dengler ef a/, 1995).
- the present invention also provides a pharmaceutical composition
- a pharmaceutical composition comprising an ansamycin derivative, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier.
- the existing ansamycin HSP90 inhibitors that are or have been in clinical trials, such as geldanamycin, 17-AAG and 17-DMAG have poor pharmacological profiles, poor water solubility and poor bioavailability.
- the present invention provides ansamycin derivatives which have improved properties such as solubility and/or bioavailability.
- a person of skill in the art will be able to readily determine the solubility of a given compound of the invention using standard methods. A representative method is shown in the examples herein.
- bioavailability of a compound of the invention is determined by a number of factors, (e.g. water solubility, rate of absorption in the gut, the extent of protein binding and metabolism) each of which may be determined by in vitro tests as described below, it will be appreciated by a person of skill in the art that an improvement in one or more of these factors will lead to an improvement in the bioavailability of a compound.
- factors e.g. water solubility, rate of absorption in the gut, the extent of protein binding and metabolism
- the bioavailability of a compound may be measured using in vivo methods as described in more detail below.
- Confluent Caco-2 cells (Li, A.P., 1992; Grass, G. M., et al., 1992, Volpe, D.A., et al., 2001 ) in a 24 well Corning Costar Transwell format are used to establish the permeability and efflux rate of compounds using methods as described herein, suitable formats include those provided by In Vitro Technologies Inc. Baltimore, Maryland, USA.
- suitable formats include those provided by In Vitro Technologies Inc. Baltimore, Maryland, USA.
- the apical chamber contains 0.15 ml. HBBS pH 7.4, 1 % DMSO, 0.1 mM Lucifer Yellow and the basal chamber contains 0.6 mL HBBS pH 7.4, 1 % DMSO.
- Controls and test assays are incubated at 37 0 C in a humidified incubator, shaken at 130 rpm.
- Lucifer Yellow is able to permeate via the paracellular route only (i.e. between the tight junctions), a high Apparent Permeability (P app ) for Lucifer Yellow indicates cellular damage during assay and all such wells are rejected.
- Suitable reference controls in addition to the parent compound include propranolol, which has good passive permeation with no known transporter effects and acebutalol, which has poor passive permeation attenuated by active efflux by P-glycoprotein.
- Compounds are tested in a uni- and bi-directional format by applying compound to the apical or basal chamber (at 0.01 mM). Compounds in the apical or basal chambers are analysed by LC-MS. Results are expressed as Apparent Permeability, P app , (nm/s) and as the Flux Ratio (A to B versus B to
- volume Acceptor 0.6mL (A>B) and 0.15mL (B>A) Area of monolayer: 0.33cm 2 ⁇ time: 60min
- a positive value for the Flux Ratio indicates active efflux from the apical surface of the cells. Therefore, improved bioavailability is shown in the above assay by an increased P app and/or a decreased flux ratio for the compound of the invention relative to its parent molecule.
- Liver homogenates provide a measure of a compounds inherent vulnerability to Phase I (oxidative) enzymes, including CYP450S (e.g. CYP2C8, CYP2D6, CYP1A, CYP3A4, CYP2E1 ), esterases, amidases and flavin monooxygenases (FMOs).
- CYP450S e.g. CYP2C8, CYP2D6, CYP1A, CYP3A4, CYP2E1
- esterases e.g. CYP2C8
- amidases e.g. CYP1A, CYP3A4, CYP2E1
- FMOs flavin monooxygenases
- T1/2 half life of compounds can be determined, on exposure to Human Liver Microsomes, by monitoring their disappearance over time by LC-MS.
- Compounds at 0.001 imM are incubated at for 40 min at 37 0 C, 0.1 M Tris-HCI, pH 7.4 with a human microsomal subcellular fraction of liver at 0.25 img/mL protein and saturating levels of NADPH as co-factor.
- acetonitrile is added to test samples to precipitate protein and stop metabolism. Samples are centrifuged and analysed for parent compound. Improved bioavailability is shown in the above assay by an increased T1/2 relative to the parent compound.
- In vivo assays may also be used to measure the bioavailability of a compound.
- a compound is administered to a test animal (e.g. mouse or rat) both intraperitoneal ⁇ (i.p.) or intravenously (i.v.) and orally (p.o.) and blood samples are taken at regular intervals to examine how the plasma concentration of the drug varies over time.
- the time course of plasma concentration over time can be used to calculate the absolute bioavailability of the compound as a percentage using standard models.
- Mice are dosed with 1 , 10, or 75 mg/kg of the compound of the invention or the parent compound i.p. i.v. or p.o..
- Blood samples are taken at 5, 10, 15, 30, 45, 60, 90, 120, 180, 240, 360, 420 and 2880 minutes and the concentration of the compound of the invention or parent compound in the sample is determined via HPLC.
- the time-course of plasma concentrations can then be used to derive key parameters such as the area under the plasma concentration- time curve (AUC - which is directly proportional to the total amount of unchanged drug that reaches the systemic circulation), the maximum (peak) plasma drug concentration, the time at which maximum plasma drug concentration occurs (peak time), additional factors which are used in the accurate determination of bioavailability include: the compound's terminal half life, total body clearance, steady-state volume of distribution and F%.
- AUC - area under the plasma concentration- time curve
- additional factors which are used in the accurate determination of bioavailability include: the compound's terminal half life, total body clearance, steady-state volume of distribution and F%.
- the aforementioned compounds of the invention or a formulation thereof may be administered by any conventional method for example but without limitation they may be administered parenterally (including intravenous administration), orally, topically (including buccal, sublingual or transdermal), via a medical device (e.g. a stent), by inhalation, or via injection (subcutaneous or intramuscular).
- the treatment may consist of a single dose or a plurality of doses over a period of time.
- a compound of the invention Whilst it is possible for a compound of the invention to be administered alone, it is preferable to present it as a pharmaceutical formulation, together with one or more acceptable carriers.
- a pharmaceutical composition comprising a compound of the invention together with one or more pharmaceutically acceptable diluents or carriers.
- the diluents(s) or carrier(s) must be "acceptable” in the sense of being compatible with the compound of the invention and not deleterious to the recipients thereof. Examples of suitable carriers are described in more detail below.
- the compounds of the invention may be administered alone or in combination with other therapeutic agents. Co-administration of two (or more) agents may allow for significantly lower doses of each to be used, thereby reducing the side effects seen.
- composition comprising a compound of the invention and a further therapeutic agent together with one or more pharmaceutically acceptable diluents or carriers.
- present invention provides for the use of a compound of the invention in combination therapy with a second agent for the treatment of cancer or B-cell malignancies.
- a compound of the invention is co-administered with another therapeutic agent for the treatment of cancer or B-cell malignancies
- preferred agents include, but are not limited to, methotrexate, leukovorin, adriamycin, prenisone, bleomycin, cyclophosphamide, 5-fluorouracil, paclitaxel, docetaxel, vincristine, vinblastine, vinorelbine, doxorubicin, tamoxifen, toremifene, megestrol acetate, anastrozole, goserelin, anti-HER2 monoclonal antibody (e.g.
- a compound of the invention may be administered in combination with other therapies including, but not limited to, radiotherapy or surgery.
- the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Such methods include the step of bringing into association the active ingredient (compound of the invention) with the carrier which constitutes one or more accessory ingredients. In general the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.
- the compounds of the invention will normally be administered orally or by any parenteral route, in the form of a pharmaceutical formulation comprising the active ingredient, optionally in the form of a non-toxic organic, or inorganic, acid, or base, addition salt, in a pharmaceutically acceptable dosage form.
- the compositions may be administered at varying doses.
- the compounds of the invention can be administered orally, buccally or sublingually in the form of tablets, capsules, ovules, elixirs, solutions or suspensions, which may contain flavouring or colouring agents, for immediate-, delayed- or controlled-release applications.
- Such tablets may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate and glycine, disintegrants such as starch (preferably corn, potato or tapioca starch), sodium starch glycollate, croscarmellose sodium and certain complex silicates, and granulation binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxy-propylcellulose (HPC), sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, stearic acid, glyceryl behenate and talc may be included.
- Solid compositions of a similar type may also be employed as fillers in gelatin capsules.
- Preferred excipients in this regard include lactose, starch, a cellulose, milk sugar or high molecular weight polyethylene glycols.
- the compounds of the invention may be combined with various sweetening or flavouring agents, colouring matter or dyes, with emulsifying and/or suspending agents and with diluents such as water, ethanol, propylene glycol and glycerin, and combinations thereof.
- a tablet may be made by compression or moulding, optionally with one or more accessory ingredients.
- Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder (e.g. povidone, gelatin, hydroxy propyl methyl cellulose), lubricant, inert diluent, preservative, disintegrant (e.g. sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent.
- Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
- the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethylcellulose in varying proportions to provide desired release profile.
- Formulations in accordance with the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets, each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
- the active ingredient may also be presented as a bolus, electuary or paste.
- Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavoured basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouth-washes comprising the active ingredient in a suitable liquid carrier.
- the formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavouring agents.
- compositions adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, impregnated dressings, sprays, aerosols or oils, transdermal devices, dusting powders, and the like.
- These compositions may be prepared via conventional methods containing the active agent.
- they may also comprise compatible conventional carriers and additives, such as preservatives, solvents to assist drug penetration, emollient in creams or ointments and ethanol or oleyl alcohol for lotions.
- Such carriers may be present as from about 1 % up to about 98% of the composition. More usually they will form up to about 80% of the composition.
- a cream or ointment is prepared by mixing sufficient quantities of hydrophilic material and water, containing from about 5- 10% by weight of the compound, in sufficient quantities to produce a cream or ointment having the desired consistency.
- compositions adapted for transdermal administration may be presented as discrete patches intended to remain in intimate contact with the epidermis of the recipient for a prolonged period of time.
- the active agent may be delivered from the patch by iontophoresis.
- the compositions are preferably applied as a topical ointment or cream.
- the active agent may be employed with either a paraffinic or a water-miscible ointment base.
- the active agent may be formulated in a cream with an oil-in-water cream base or a water-in-oil base.
- fluid unit dosage forms are prepared utilizing the active ingredient and a sterile vehicle, for example but without limitation water, alcohols, polyols, glycerine and vegetable oils, water being preferred.
- the active ingredient depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle.
- the active ingredient can be dissolved in water for injection and filter sterilised before filling into a suitable vial or ampoule and sealing.
- agents such as local anaesthetics, preservatives and buffering agents can be dissolved in the vehicle.
- the composition can be frozen after filling into the vial and the water removed under vacuum.
- the dry lyophilized powder is then sealed in the vial and an accompanying vial of water for injection may be supplied to reconstitute the liquid prior to use.
- Parenteral suspensions are prepared in substantially the same manner as solutions, except that the active ingredient is suspended in the vehicle instead of being dissolved and sterilization cannot be accomplished by filtration.
- the active ingredient can be sterilised by exposure to ethylene oxide before suspending in the sterile vehicle.
- a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the active ingredient.
- the compounds of the invention may also be administered using medical devices known in the art.
- a pharmaceutical composition of the invention can be administered with a needleless hypodermic injection device, such as the devices disclosed in U.S. 5,399,163; U.S. 5,383,851 ; U.S. 5,312,335; U.S. 5,064,413; U.S.
- implants and modules useful in the present invention include : US 4,487,603, which discloses an implantable micro-infusion pump for dispensing medication at a controlled rate; US 4,486,194, which discloses a therapeutic device for administering medicaments through the skin; US 4,447,233, which discloses a medication infusion pump for delivering medication at a precise infusion rate; US 4,447,224, which discloses a variable flow implantable infusion apparatus for continuous drug delivery; US 4,439,196, which discloses an osmotic drug delivery system having multi-chamber compartments; and US 4,475,196, which discloses an osmotic drug delivery system. Many other such implants, delivery systems, and modules are known to those skilled in the art.
- the dosage to be administered of a compound of the invention will vary according to the particular compound, the disease involved, the subject, and the nature and severity of the disease and the physical condition of the subject, and the selected route of administration.
- the appropriate dosage can be readily determined by a person skilled in the art.
- compositions may contain from 0.1 % by weight, preferably from 5-60%, more preferably from 10-30% by weight, of a compound of invention, depending on the method of administration. It will be recognized by one of skill in the art that the optimal quantity and spacing of individual dosages of a compound of the invention will be determined by the nature and extent of the condition being treated, the form, route and site of administration, and the age and condition of the particular subject being treated, and that a physician will ultimately determine appropriate dosages to be used. This dosage may be repeated as often as appropriate. If side effects develop the amount and/or frequency of the dosage can be altered or reduced, in accordance with normal clinical practice.
- the fermentation medium (5% of glycerol, 2% of corn steep liquor, 2% of yeast extract, 2% of KH 2 PO 4 , 0.5% of MgCI 2 and 0.1 % of CaCO 3 , pH6.5, see US 4,315,989 and US 4,187,292) is initially incubated at 28 0 C for 24 h followed by an incubation period at 26 0 C for four to six days. The culture is then harvested for extraction.
- LCMS is performed on an integrated Agilent HP1100 HPLC system in combination with a Bruker Daltonics Esquire 3000+ electrospray mass spectrometer operating in positive ion mode. Chromatography was achieved over a Phenomenex Hyperclone column (Ci 8 BDS, 3u, 150 x 4.6 mm) eluting over 11 min at a flow rate of 1 mL/min with a linear gradient from acetonitrile / water (40/60) to acetonitrile / water (80/20).
- Assays to determine the rate of cleavage of the pro-drugs into their parent compounds were performed as described herein. These were carried out in plasma, blood or buffer. Mixed mouse, human or mixed rat plasma containing EDTA or heparin as an anti-coagulant was used or whole defibrinated rabbit blood (mouse and rat plasma and rabbit blood were obtained from Harlan-Sera Labs, human plasma was obtained from Biopredic International),
- Plasma was thawed at 37 0 C in a water bath. Plasma was dispensed into individual 20 mL tubes for each test compound allowing 0.5 mL plasma for each time point to be analysed. A tube containing plasma was also included as a control. These tubes were incubated for 15 minutes at 37 0 C. Each test compound was reconstituted in DMSO or other appropriate solvent. The plasma was removed from the water bath and the compound was added to the plasma to give a final concentration of 0.001-0.010 img/mL keeping the final concentration of solvent below 5%. In the case of the control, an equivalent volume of DMSO or other solvent was added. Immediately after the addition of compound a 0.4 ml.
- sample was taken from the tube, transferred to a 2 ml. microfuge tube. The plasma was promptly returned to the 37 0 C water bath. 0.4 ml. samples were taken at regular time points (e.g. after 30 min and then hourly) and were immediately frozen at -80 0 C.
- the stability of the test compounds in phosphate-buffered saline (PBS) of specific pH over the course of each experiment was also analysed using the same methodology. After the final time point was sampled, the samples were extracted as follows. For each time point sample an Oasis MCX (3cc/60mg) or Oasis HLB (333/60 mg) cartridge was conditioned and equilibrated with 2 mL methanol followed by 2 mL water. 1.5 mL water and an internal standard (IS) at 0.002 mg/mL were added to eacl ⁇ .4 mL plasma sample. This was loaded to the cartridge. The cartridge was washed with 2mL water and the analytes were eluted in 2 ml MeOH.
- PBS phosphate-buffered saline
- This extract was analysed without further treatment by LC/MS using the conditions described below. If using whole blood such as defibrinated whole rabbit blood the following protocol was used: The blood was thawed at 37 0 C in a water bath. Blood was dispensed into individual 20 mL tubes for each test compound allowing 0.5 mL for each time point to be analysed. A tube containing blood was also included as a control. These tubes were incubated for 15 minutes at 37 0 C. Each test compound was reconstituted in DMSO or other appropriate solvent. The blood was removed from the water bath and the compound was added to give a final concentration of 0.001-0.010 mg/mL keeping the final concentration of solvent below 5%.
- the HPLC conditions were: 30 % B for 2 min followed by a linear gradient to 100 %B over a period of 14 min and an isocratic period of 4 min at 100 % B.
- the analytes were detected by UV absorbance at 255 nm and mass spectrometry using a Bruker Daltonics Esquire 3000+ mass spectrometer coupled to the HPLC.
- the analytes were quantified based on the extracted ion chromatogram. To ensure a reliable quantification, the linear response of the mass spectrometer was checked for the concentration range of interest.
- the HPLC conditions were: 10 % B for 1 min followed by a linear gradient to 100 %B over a period of 7 min and an isocratic period of 2 min at 100 % B.
- the analytes were detected by UV absorbance at 255 nm and mass spectrometry using a Bruker Daltonics Esquire 3000+ mass spectrometer coupled to the HPLC.
- the analytes were quantified based on the extracted ion chromatogram. To ensure a reliable quantification, the linear response of the mass spectrometer was checked for the concentration range of interest.
- Mobile phase B 0.1 % Formic acid in acetonitrile Flow rate: 1 mL/minute.
- the HPLC conditions were: 10 % B for 1 min followed by a linear gradient to 100 %B over a period of 7 min and an isocratic period of 2 min at 100 % B.
- the analytes were detected by UV absorbance at 255 nm and mass spectrometry using a Bruker Daltonics Esquire 3000+ mass spectrometer coupled to the HPLC.
- the analytes were quantified based on the extracted ion chromatogram. To ensure a reliable quantification, the linear response of the mass spectrometer was checked for the concentration range of interest.
- Oncotest cell lines were established from human tumor xenografts as described by Roth et al., (1999). The origin of the donor xenografts is described by Fiebig et al., (1999). Other cell lines were either obtained from the NCI (H460, SF-268, OVCAR-3, DU145, MDA-MB- 231 , MDA-MB-468) or purchased from DSMZ, Braunschweig, Germany (LNCAP).
- a modified propidium iodide assay was used to assess the effects of the test compound(s) on the growth of twelve human tumour cell lines (Dengler et al., (1995)). Briefly, cells were harvested from exponential phase cultures by trypsinization, counted and plated in 96 well flat-bottomed microtitre plates at a cell density dependent on the cell line (5 - 10.000 viable cells/well). After 24 h recovery to allow the cells to resume exponential growth, 0.010 ml. of culture medium (6 control wells per plate) or culture medium containing macbecin was added to the wells. Each concentration was plated in triplicate. Compounds were applied in two concentrations (0.001 mM and 0.01 mM).
- cell culture medium with or without test compound is replaced by 0.2 ml. of an aqueous propidium iodide (Pl) solution (7 mg/L).
- Pl propidium iodide
- cells are permeabilized by freezing the plates. After thawing the plates, fluorescence was measured using the Cytofluor 4000 microplate reader (excitation 530 nm, emission 620 nm), giving a direct relationship to the total number of viable cells.
- PRXF DU-145 is a prostate cancer cell line initially isolated from a metastatic central nervous system lesion of a 69-year-old man with prostate carcinoma. PRXF DU-145 cell suspensions were injected subcutaneously into nude mice and the resulting xenografts were passaged in nude mice until establishment of a stable growth pattern.
- Tumour fragments were obtained from xenografts in serial passage in nude mice. After removal of tumours from donor mice, they were cut into fragments (1-2 mm diameter) and placed in RPMI 1640 culture medium (RPMI 1640 medium with 25 mM HEPES buffer with L- Glutamine, Gibco, catalogue # 52400-025) until subcutaneous implantation. Recipient mice were anaesthetized by inhalation of isoflurane. For bilateral implantation a small incision was made in the skin of the back. Tumour fragments were transplanted with tweezers.
- tumour bearing animals were stratified into treatment and control groups according to tumour volume, using "Lindner ' s Randomization Tables". Only animals carrying a tumour of appropriate size (mean tumor diameter: 6-8 mm, minimum acceptable tumor diameter: 5 mm) were considered for randomization. Mice were randomized when a maximum number of mice qualified for randomization. The day of randomization was designated as Day 0. Day 0 was also the first day of dosing. Tumour growth was then compared between mice given different dosing regimes. Mice were monitored daily, with the observation period lasting 42 Days. The tumour volume was determined by two-dimensional measurement with a caliper on the day of randomization (Day 0) and then twice weekly. Tumour volumes were calculated according to the formula: (a x b2) x 0.5 where a represents the largest and b the perpendicular tumor diameter.
- Antitumour activity was evaluated as maximum tumour volume inhibition versus the vehicle control group.
- ReI. volumes of individual tumors were calculated by dividing the individual tumor volume on Day X (Tx) by the individual tumor volume on Day 0 (TO) multiplied by 100%.
- Group tumor volumes were expressed as the median RTV of all tumours in a group (group median RTV).
- Group median RTV values were used for drawing growth curves and for treatment evaluation.
- tumour inhibition on a particular day was calculated from the ratio of the median RTV values of the respective test group and the vehicle control group, multiplied by 100%.
- the minimum (or optimum) T/C% value recorded for a particular test group during an experiment represents the maximum antitumour activity for the respective treatment.
- the baffles were tilted at 45 ° and impeller tip speed was adjusted according to oxygen demand (minimum dissolved oxygen was maintained at 30 %).
- Antifoam SAG471 was added at 0.2 % v/v prior to autoclaving and then as and when required during the fermentation run.
- the fermentation broth was centrifuged for 30 min at 3500 rpm to separate the cells from the supernatant.
- the supernatant was then partitioned three times with an equal volume of ethyl acetate.
- the cell pellet was extracted twice with an equal volume of acetone.
- the organic fractions were combined and the solvent removed in vacuo.
- the resulting aqueous slurry was extracted three times with an equal volume of ethyl acetate and the combined organic fractions concentrated to yield a crude extract.
- Flash Silica gel was added to the crude extract previously dissolved in acetone and the solvent then removed in vacuo.
- the impregnated silica was added onto an open column of flash silica pre-conditioned with hexane. This was eluted with a step gradient of hexane:ethyl acetate (100:0, 80:20, 75:25, 70:30, 50:50, 0:100) and finally ethyl acetate:methanol (50:50, 0:100).
- Each step fraction volume was about one litre of solvent mixture. The fractions containing macbecin were combined and evaporated to dryness.
- Macbecin (107.8 mg, 0.193 mmol) was dissolved in ethyl acetate (25 ml.) and treated with 96 imM sodium hydrosulfite solution (3 x 5 ml_). On each occasion the phases were vigorously mixed in a separating funnel and the aqueous drained off. The organic layer goes from an intense yellow colour to virtually colourless. This organic layer was then washed with water (3 x 10 ml_), before being dried with anhydrous sodium sulfate, filtered and the solvent removed under reduced pressure to yield 18,21 -dihydromacbecin as an off-white glassy solid (105.0 mg, 0.187 mmol, 97 % isolated yield). 18,21 -dihydromacbecin was used without any further purification
- 18,21 -dihydromacbecin (2.00 mg, 3.6 x 10 "3 mmol) was dissolved in anhydrous degassed dichloromethane (1 ml_).
- 4-Nitrophenylchloroformate (0.86 mg, 4.3 * 10 "3 mmol) was added followed by 2,6-lutidine (2.48 x 10 "3 ml_, 21.4 x 10 "3 mmol).
- the reaction mixture was heated to reflux for 4 hrs to form the intermediate carbonate.
- ⁇ /-terf-Butoxycarbonyl- ⁇ /,/V- dimethylethylenediamine (2.70 mg, 14.2 x 10 "3 mmol) was added and the reaction heated to reflux for a further 2 h.
- Macbecin Il (0.30 g, 0.54 mmol) was dissolved in anhydrous dichloromethane (72 ml). To this solution was added 4-nitrophenylchloroformate as a solid (0.183 g, 0.91 mmol) followed by 2,6-lutidine (0.217 ml, 1.87 mmol). The reaction mixture was heated at reflux under argon for 5 hours at 50°C (oil bath). The reaction was allowed to cool to ambient and washed successively with equal volumes of 1 N HCI and water, dried over NaaSCu and filtered, and the solvent removed under reduced pressure.
- N-trityl-N, N'-dimethylethylenediamine N, N'-dimethylethylenediamine (5.0 g, 56.7 mmol) was dissolved in dichloromethane (20 ml) under argon and then treated with trimethylamine (5.74 g, 56.7 mmol).
- the stirring mixture was cooled to 0°C prior to drop wise slow addition of a solution of tritylchloride (15.82 g, 56.7 mmol) in dichloromethane (20 ml_). Following complete addition of this solution the reaction mixture was stirred at 0 °C for a further 30 min, at which point the cooling bath was removed and the reaction allowed to warm up to room temperature.
- N-Methylethylenediamine (5.96 g, 80.41 mmol) was dissolved in dichloromethane (100 mL) under argon.
- the stirring mixture was cooled to 0°C prior to drop wise slow addition of a solution of tritylchloride (6.47 g, 23.21 mmol) in dichloromethane (40 ml).
- tritylchloride (6.47 g, 23.21 mmol) in dichloromethane (40 ml).
- the reaction mixture was stirred at 0°C for a further 30 min, at which point the cooling bath was removed and the reaction allowed to warm up to room temperature.
- the mixture was stirred under argon at room temperature overnight.
- N-trityl-N, N'-diethylethylenediamine N, N'-diethylethylenediamine (2.5 g, 21.5 mmol) was dissolved in dichloromethane (20 ml) under argon.
- the stirring mixture was cooled to 0 °C prior to drop wise slow addition of a solution of tritylchloride (2.4 g, 8.6 mmol) in dichloromethane (20 imL). Following complete addition of this solution the reaction mixture was stirred at 0 °C for a further 30 min, at which point the cooling bath was removed and the reaction allowed to warm up to room temperature.
- the mixture was stirred under argon at room temperature overnight.
- N,N'-Dimethyl-1 ,3-propanediamine (2.50 g, 24.5 mmol) was dissolved in dichloromethane (20 ml.) under argon.
- the stirring mixture was cooled to 0 °C prior to drop wise slow addition of a solution of tritylchloride (2.73 g, 9.80 mmol) in dichloromethane (20 ml_).
- tritylchloride 2.73 g, 9.80 mmol
- 18-O-(N-trityl-N,N'-diisopropylethylenediamine-N'-carbamoyl)-18,21 -dihydromacbecin (0.055 g, 0.06 mmol) was dissolved in anhydrous dichloromethane (10 imL) under argon and cooled to -5 °C using an ice/salt bath.
- a solution of 2M HCI in ether 0.055 mL, 0.11 mmol was dissolved in anhydrous dichloromethane (1 mL) and then added drop wise to the cooled substrate solution. The reaction was stirred for 5 min at -5 °C and then 90 min at room temperature.
- Compound 1 was incubated in human plasma as described in the General Methods - Cleavage Assay above. An aliquot was sampled every 15 min and acidified by the addition of 0.01 ml. phosphoric acid to stop the chemical triggered cleavage of the parent compound. The samples were subsequently extracted as described above and analysed immediately using Analysis Method B. The decay of the parent compound and the relative amounts of released compounds are shown in Figure 1 , where the open circles show the decay of 1 and the filled squares and filled triangles indicate the accumulation of macbecin and 18,21-dihydromacbecin respectively.
- Example 8 Comparison of cleavage rates for compounds 1 -5 in phosphate buffer and in whole blood Each compound was assessed for cleavage to 18,21-dihydromacbecin as follows.
- Example 10 Biological data - In vitro evaluation of anticancer activity of macbecin
- Example 11 Biological data - In vivo evaluation of 18-O-( ⁇ /, ⁇ /'-dimethylethylenediamine- ⁇ /'-carbamoyl)-18,21 -dihydromacbecin hydrochloride salt (compound 1)
- 18-O-( ⁇ /,/V- dimethylethylenediamine- ⁇ /-carbamoyl)-18,21 -dihydromacbecin hydrochloride 1 was administered intraperitoneal ⁇ at a dose level of 60 mg/kg/d on days 0-4, 7-1 1 , 14-18, 21 , 24, 25, 28 and 29, in a vehicle of 5% glucose, and compared to a control group dosed with the standard vehicle 10% DMSO, 0.05% Tween 80.
- Antitumour activity was determined as tumour volume inhibition relative to tumours in a control group receiving the standard vehicle 10% DMSO, 0.05% Tween ⁇ O in PBS i.p. at 10 mL/kg/d on Days 0-4, 7-11 , 14-18, 21 , 24, 25, 28 and 29.
- Group size was 6 mice for the vehicle control group and 6 mice in the therapy groups implanted with two tumour fragments. The experiment was terminated on Day 42.
- Hsp90 binds and regulates the ligand-inducible ⁇ subunit of eukaryotic translation initiation factor kinase Gcn2. MoI Cell Biol 19:8422-8432.
- SBA1 encodes a yeast Hsp90 cochaperone that is homologous to vertebrate p23 proteins. MoI Cell Biol 18:3727-3734.
- HSP90 interacts with RAR1 and SGT1 and is essential for RPS2-mediated disease resistance in Arabidopsis. Proc. Natl. Acad. Sci. USA 20:1 1777-1 1782.
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EP06793160A EP1937644A1 (en) | 2005-09-02 | 2006-09-01 | Novel ansamycin derivatives |
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CA002620023A CA2620023A1 (en) | 2005-09-02 | 2006-09-01 | Novel ansamycin derivatives |
US12/063,791 US20100279995A1 (en) | 2005-09-02 | 2006-09-01 | Novel Ansamycin Derivatives |
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CN109295125B (en) * | 2018-10-08 | 2020-12-18 | 中国科学院南海海洋研究所 | Ansamycin compound and preparation method and application thereof |
CN116768910B (en) * | 2023-08-18 | 2023-10-31 | 山东齐都药业有限公司 | Refining method of rifabutin |
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JPS5874651A (en) * | 1981-09-17 | 1983-05-06 | Takeda Chem Ind Ltd | Macbecin derivative and its preparation |
US4421687A (en) * | 1981-09-26 | 1983-12-20 | Takeda Chemical Industries, Limited | Macbecin derivatives |
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Title |
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SAARI W S ET AL: "CYCLIZATION-ACTIVATED PRODRUGS. BASIC CARBAMATES OF 4-HYDROXYANISOLE", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY. WASHINGTON, US, vol. 33, 1990, pages 97 - 101, XP001120293, ISSN: 0022-2623 * |
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