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WO2008034895A2 - dérivés d'ansamycine - Google Patents

dérivés d'ansamycine Download PDF

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Publication number
WO2008034895A2
WO2008034895A2 PCT/EP2007/060032 EP2007060032W WO2008034895A2 WO 2008034895 A2 WO2008034895 A2 WO 2008034895A2 EP 2007060032 W EP2007060032 W EP 2007060032W WO 2008034895 A2 WO2008034895 A2 WO 2008034895A2
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Prior art keywords
alkyl
aryl
heteroaryl
substituted
alkenyl
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PCT/EP2007/060032
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English (en)
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WO2008034895A3 (fr
Inventor
Friedrich Georg Hansske
Simon Werner
Peter Eckard
Rajendra-Prasad Maskey
Hans-Falk Rasser
Bernd Sontag
Iris Grun-Wollny
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Discovery Partners International Gmbh
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Publication of WO2008034895A2 publication Critical patent/WO2008034895A2/fr
Publication of WO2008034895A3 publication Critical patent/WO2008034895A3/fr

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    • 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

Definitions

  • the invention relates to novel ansamycin derivatives, pharmaceutical compositions and medicinal products containing them or salts thereof, and the use of ansamycin derivatives for the treatment of diseases, in particular neoplastic diseases.
  • Ansamycin derivatives such as derivatives of geldanamycin and related compounds, which act as strong inhibitors of the molecular chaperone Hsp90 (heat shock protein 90), are potential candidates for a new class of antitumour medications, either in monotherapy or in combination therapy with other cytostatics.
  • the first substances with this mechanism of action, 17-(allylamino)-17-desmethoxy geldanamycin (17-AAG) and 17-desmethoxy-17-N,N- dimethylaminoethylamino-geldanamycin (17-DMAG) are already in clinical phase I and II.
  • ansamycin derivatives are described, with high affinity for Hsp90, reduced hepatotoxicity and improved pharmacological properties, for example solubility in water. Furthermore, ansamycin derivatives are candidates for improved therapy of fungal infections and diseases caused by parasites.
  • 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 (macbecin I and macbecin Il respectively) (Tanida, et al., (1980) J Antibiotics 33:199- 204), geldanamycin (DeBoer, C, et al., (1970) J. Antibiot.
  • Geldanamycin is a natural product with an ansacyclic quinoid basic structure, which was described for the first time in 1970 (US patent 3,595,955) and can be produced by fermentation of the soil bacterium Streptomyces hygroscopicus.
  • Geldanamycin displays cytostatic activity in several tumour cell lines (Supko, J. G. et al., Cancer Chemother.
  • Hsp90 is a ubiquitous chaperone protein, which is required for the folding, activation and assembly of a large number of proteins, including key molecules for signal transduction, control of the cell cycle and control of transcription. Some of these proteins play an important role in oncogenesis, for example p53, Cdk4, RaM kinase and ErbB2.
  • 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, Y. (2003) Current Cancer Drug Targets 3:325-330).
  • Hsp90 plays an important role in the development of resistance, as its chaperone function facilitates the development of genetic diversity in reaction to stress factors (Heitman, 1, Science 2005, 309, 2175). Inhibition of Hsp90, e.g. by geldanamycin or radicicol, can prevent the development of resistance and increase the sensitivity of pathogenic fungi to antifungal agents (Cowen, L.E. and Lindquist, S., Science 2005, 309, 2185).
  • Geldanamycin derivatives can therefore also be used in combination with other fungicides as a fungicide in plant protection.
  • a related mechanism may play a role in the synergistic action of Hsp90-inhibitors (e.g. geldanamycin) with cyclosporin A against the malarial parasite Plasmodium falciparum (Kumar, R., et al., MoI Biochem Parasitol. 2005, 141, 29).
  • Hsp90-inhibitors e.g. geldanamycin
  • cyclosporin A against the malarial parasite Plasmodium falciparum Kermar, R., et al., MoI Biochem Parasitol. 2005, 141, 29.
  • neoplastic diseases e.g. Hodgkin's lymphomas, melanomas, multiple myelomas, solid tumours and other neoplastic diseases.
  • neoplastic diseases e.g. Hodgkin's lymphomas, melanomas, multiple myelomas, solid tumours and other neoplastic diseases.
  • These substances can be used either in monotherapy or in combination with other cytotoxic medicinal products, for example other Hsp90 inhibitors, microtubulin stabilizing substances, intercalating agents, DNA linking substances, alkylating substances, antimetabolites, angiogenesis inhibitors, topoisomerase inhibitors, nucleoside analogues and tyrosine kinase inhibitors.
  • the invention relates to novel ansamycin derivatives of general formula I or II as described below. Additionally, the present invention relates to processes for the preparation of the compounds of the invention. In a further aspect the present invention provides pharmaceutical compositions comprising compounds of the invention and their use in medicine, in particular in the treatment of tumours, fungal infections and malaria.
  • the invention relates to novel ansamycin derivatives of general formula (I) or (II):
  • ⁇ represents H; OH; OR 11 ; NH 2 , NHR 11 ; NR 11 R 12 ; SR 11 ; N 3 ; F; Cl; Br; I; NHCOOR 11 , NHCONR 11 R 12 , NHCONHOR 11 ; NHCH 2 CH 2 OPO(OH) 2 ; NHCH 2 CH 2 OSO 3 H; NHCH 2 CH 2 C NH(NH 2 ); NHpyranose; NHfuranose;
  • R 11 represents d-C 8 -alkyl; C 2 -C 8 -alkenyl; C 2 -C 8 -alkynyl; cycloalkyl, heterocycloalkyl, aryl; heteroaryl; d-C 4 -alkyl-aryl; d-C 4 -alkyl-heteroaryl; where each of these residues can optionally be substituted, independently of one another, once, twice or three times with RS 11 ; R 12 represents d-C 8 -alkyl; C 2 -C 8 -alkenyl; C 2 -C 8 -alkynyl; cycloalkyl, heterocycloalkyl, aryl; heteroaryl; where each of these residues can optionally be substituted, independently of one another, once, twice or three times with RS 12 ; or
  • R 1 and R 12 together form a 3, 4, 5, 6, 7-membered substituted or unsubstituted ring system, whose carbon atoms can be substituted with one, two, three or four O, S, N atoms;
  • R 2 represents H; OH; OR 21 ; OCOR 21 ; OCONH 2 , OCONR 21 R 22 , NH 2 ; NR 21 R 22 ; NHCONH 2 ; NHCSNH 2
  • R 21 represents Ci-Cs-alkyl; C 2 -C 8 -alkenyl; C 2 -C 8 -alkynyl; cycloalkyl, heterocycloalkyl, aryl; heteroaryl; d-C 4 -alkyl-aryl; d-C 4 -a I kyl -heteroaryl; where each of these residues can optionally be substituted, independently of one another, once, twice or three times with RS 21 ; R 22 represents d-C 8 -alkyl; C 2 -C 8 -alkenyl; C 2 -C 8 -alkynyl; cycloalkyl, heterocycloalkyl, aryl; heteroaryl; where each of these residues can optionally be substituted, independently of one another, once, twice or three times with RS 22 ; R 2a represents H; d-Cs-alkyl; COR2al; CONHOH; CONHOR2al; CONH 2 ;
  • R 2a2 represents d-C 8 -alkyl; C 2 -C 8 -alkenyl; C 2 -C 8 -alkynyl; cycloalkyl, heterocycloalkyl, aryl; heteroaryl; where each of these residues can optionally be substituted, independently of one another, once, twice or three times with RS 2a2 ; R 2b represents H, d-C 8 -alkyl; COR 2bl
  • R 2bl represent d-C 8 -alkyl; C 2 -C 8 -alkenyl; C 2 -C 8 -alkynyl; cycloalkyl, heterocycloalkyl, aryl; heteroaryl; d-C 4 -alkyl-aryl; Ci-C 4 -alkyl-heteroaryl; where each of these residues can optionally be substituted, independently of one another, once, twice or three times with RS 2bl ; R 3 represents H; F; Cl; Br; I; CN; N 3 ; SCN; -CH 2 -OH; -CH 2 NH 2 ; -CH 2 NHR 31 ; CH 2 NR 31 R 32 ; SR 31 ;
  • R 31 represents d-C 8 -alkyl; C 2 -C 8 -alkenyl; C 2 -C 8 -alkynyl; cycloalkyl, heterocycloalkyl, aryl; heteroaryl; d-C 4 -alkyl-aryl; Ci-C 4 -alkyl-heteroaryl; where each of these residues can optionally be substituted, independently of one another, once, twice or three times with RS 31 ; R 32 represents d-C 8 -alkyl; C 2 -C 8 -alkenyl; C 2 -C 8 -alkynyl; cycloalkyl, heterocycloalkyl, aryl; heteroaryl; where each of these residues can optionally be substituted, independently of one another, once, twice or three times with RS 32 ;
  • R 4 represents H; d-C 8 -alkyl; CO-d-C 8 -alkyl; R 5 represents OCONH 2 ; -0-CO-CO-NH 2 ; -O-CO-CO-NH-OH; OCS-NH 2 ; -OSO 2 -NH 2 ; OCONHOH R 6 represents H; OH; OCH 3 ; OCOR 61
  • R 61 represents d-C 8 -alkyl; C 2 -C 8 -alkenyl; C 2 -C 8 -alkynyl; cycloalkyl, heterocycloalkyl, aryl; heteroaryl; d-C 4 -alkyl-aryl; Ci-C 4 -alkyl-heteroaryl; where each of these residues can optionally be substituted, independently of one another, once, twice or three times with RS 61 ; R 7 represents H; -OH; OCH 3 ; OCOR 71
  • R 7I represents d-C 8 -alkyl; C 2 -C 8 -alkenyl; C 2 -C 8 -alkynyl; cycloalkyl, heterocycloalkyl, aryl; heteroaryl; d-C 4 -alkyl-aryl; d-C 4 -alkyl-heteroaryl; where each of these residues can optionally be substituted, independently of one another, once, twice or three times with RS 71 ; or
  • RS 11 , RS 12 , RS 21 , RS 22 , RS 2al , RS 2a2 , RS 2bl , RS 31 , RS 32 , RS 61 , RS 71 denote for each optional substitution, independently of one another, d-C 4 -alkyl, C 2 -C 4 -alkenyl, C 2 -C 4 - alkynyl, aryl, F, Cl, Br, I, trifluoromethoxy, C 2 -C 4 -alkoxy, cycloalkoxy, heterocycloalkoxy, d-C 4 -alkanoyl, d-C 4 -alkanoyloxy, OH, NH 2 , NHd-C 4 -alkyl, N(d-C 4 -alkyl) 2 , CF 3 , CN, N 3 , Sd-C 4 -alkyl, SH, COOH, COOd-C 4 -al
  • R 1 represents H, OCH 3 , ethylamine, propylamine, butylamine, pentylamine, hexylamine, heptylamine, octylamine, allylamine, ⁇ -hydroxyethylamine, ⁇ -chloroethylamine, ⁇ -fluoroethylamine, v- hydroxypropylamine, ⁇ -chloropropylamine, ⁇ -fluoropropylamine, dimethylaminoethylamine, diethylaminoethylamine, dimethylaminopropylamine, diethylaminopropylamine, pyrrolidinoethylamine, piperidinoethylamine, morpholinoethylamine, azetidinoethylamine.
  • the compounds, their stereoisomers, tautomers and their physiologically compatible salts selected from the group comprising the compounds of the examples and the compounds that have combinations of the various substituents of the compounds of these examples are quite especially preferred.
  • compositions containing the above compounds of formula I or II along with the usual vehicles and additives are preferred.
  • the aforementioned medicinal products in combination with other active substances for tumour treatment are also preferred.
  • These compounds according to the invention are used for the production of a medicament for the treatment of tumours, in particular those that can be treated by inhibition of Hsp90.
  • these compounds according to the invention are used for the production of a medicament for the treatment of fungal infections.
  • These compounds according to the invention are used alone or in combination with other therapeutic agents for the production of a medicament for the treatment of diseases caused by parasites, in particular for the treatment of malaria.
  • a and “an” are used herein to refer to one or to more than one (i.e. at least one) of the grammatical objects of the article.
  • a compound means one compound or more than one compound.
  • Alkyl in itself or as part of another substituent, means a linear or branched alkyl chain radical of the length stated in each case.
  • Ci -4 -alkyl denotes e.g. methyl, ethyl, 1- propyl, 2-propyl, 2-methyl-2-propyl, 2-methyl-l-propyl, 1-butyl, 2-butyl
  • Ci -6 -alkyl denotes e.g. Ci- 4 -alkyl, pentyl, 1-pentyl, 2-pentyl, 3-pentyl, 1-hexyl, 2-hexyl, 3-hexyl, 4-methyl-l- pentyl or 3,3-dimethyl-butyl.
  • C 2 , 6 -alkenyl denotes e.g.
  • ethenyl 1-propenyl, 2-propenyl, 2-methyl-2-propenyl, 2-methyl-l-propenyl, 1-butenyl, 2- butenyl, 1,3-butdienyl, 2,4-butdienyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 1,3-pentdienyl, 2,4-pentdienyl, 1,4-pentdienyl, 1-hexenyl, 2-hexenyl, 1,3-hediexyl, 4-methyl-l-pentenyl or 3,3-dimethyl-butenyl.
  • Alkynyl in itself or as part of another substituent, means a linear or branched alkyl chain radical with one or more C-C-triple bonds of the length stated in each case, optionally with additional double bonds also present.
  • C 2 , 6 -alkynyl denotes e.g.
  • ethinyl 1-propynyl, 2-propynyl, 2-methyl-2-propynyl, 2-methyl-l-propynyl, 1-butynyl, 2-butynyl, 1- pentynyl, 2-pentynyl, 3-pentynyl, 1,4-pentdiinyl, l-pentin-4-enyl, 1-hexynyl, 2-hexynyl, 1,3- hexdiinyl, 4-methyl-l-pentynyl or 3,3-dimethyl-butynyl.
  • Halogen stands for fluorine, chlorine, bromine, iodine, preferably bromine and chlorine.
  • NR x R y also stands for a dialkylamino group, where the two alkyl groups together with the N can also form a 5- or 6-membered ring.
  • Cycloalkyl in itself or as part of another substituent, comprises saturated, cyclic hydrocarbon groups, with 3 to 8 carbon atoms, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4-methyl-cyclohexyl, cyclohexyl methylene, cycloheptyl or cyclooctyl.
  • Heterocycloalkyl in itself or as part of another substituent, comprises cycloalkyl groups in which up to two CH 2 groups can be replaced with oxygen, sulphur or nitrogen atoms and another CH 2 group can be replaced with a carbonyl function, e.g. pyrrolidine, piperidine, morpholine or
  • ring system generally refers to 3, 4, 5, 6, 7, 8, 9 or 10 membered rings. 5 and 6 membered rings are preferred. Moreover, ring systems with 1 or 2 fused rings are preferred.
  • tumor 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 tumour may also 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.
  • the present invention provides prodrugs and derivatives of the compounds according to the formulae above.
  • Prodrugs are derivatives of the compounds of the invention, which have metabolically cleavable groups and become by solvolysis or under physiological conditions the compounds of the invention, which are pharmaceutically active, in vivo.
  • Such examples include, but are not limited to, choline ester derivatives and the like, N-alkylmorpholine esters and the like.
  • Other derivatives of the compounds of this invention have activity in both their acid and acid derivative forms, but the acid sensitive form often offers advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (see, Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985).
  • Prodrugs include acid derivatives well know to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides and anhydrides derived from acidic groups pendant on the compounds of this invention are preferred prodrugs. In some cases it is desirable to prepare double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters.
  • Ci to C 8 alkyl, C 2 -C 8 alkenyl, aryl, C 7 -Ci 2 substituted aryl, and C 7 -Ci 2 arylalkyl esters of the compounds of the invention are particularly useful.
  • the compounds according to the invention of formulae I and II can be as they are, as their tautomers, as hydrates or, if they have acidic or basic groups, in the form of their salts with physiologically compatible bases or acids.
  • acids are: hydrochloric acid, citric acid, trifluoroacetic acid, tartaric acid, lactic acid, phosphoric acid, methanesulphonic acid, acetic acid, formic acid, maleic acid, fumaric acid, succinic acid, hydroxysuccinic acid, sulphuric acid, glutaric acid, aspartic acid, pyruvic acid, benzoic acid, glucuronic acid, oxalic acid, ascorbic acid and acetylglycine.
  • bases are alkali ions, preferably Na, K, alkaline-earth ions, preferably Ca, Mg, ammonium ions.
  • compositions When employed as pharmaceuticals, the compounds of this invention are typically administered in the form of a pharmaceutical composition.
  • Such compositions can be prepared in a manner well known in the pharmaceutical art and comprise at least one active compound.
  • the compounds of this invention are administered in a pharmaceutically effective amount.
  • the amount of the compound actually administered will typically be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound -administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.
  • compositions of this invention can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal.
  • routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal.
  • the compounds of this invention are preferably formulated as either injectable or oral compositions or as salves, as lotions or as patches all for transdermal administration.
  • compositions for oral administration can take the form of bulk liquid solutions or suspensions, or bulk powders. More commonly, however, the compositions are presented in unit dosage forms to facilitate accurate dosing.
  • unit dosage forms refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
  • Typical unit dosage forms include prefilled, premeasured ampules or syringes of the liquid compositions or pills, tablets, capsules or the like in the case of solid compositions.
  • the furansulfonic acid compound is usually a minor component (from about 0.1 to about 50% by weight or preferably from about 1 to about 40% by weight) with the remainder being various vehicles or carriers and processing aids helpful for forming the desired dosing form.
  • Liquid forms suitable for oral administration may include a suitable aqueous or nonaqueous vehicle with buffers, suspending and dispensing agents, colorants, flavors and the like.
  • Solid forms may include, for example, any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
  • a binder such as microcrystalline cellulose, gum tragacanth or gelatin
  • an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch
  • Injectable compositions are typically based upon injectable sterile saline or phosphate- buffered saline or other injectable carriers known in the art.
  • the active compound in such compositions is typically a minor component, often being from about 0.05 to 10% by weight with the remainder being the injectable carrier and the like.
  • Transdermal compositions are typically formulated as a topical ointment or cream containing the active ingredient(s), generally in an amount ranging from about 0.01 to about 20% by weight, preferably from about 0.1 to about 20% by weight, preferably from about 0.1 to about 10% by weight, and more preferably from about 0.5 to about 15% by weight.
  • the active ingredients When formulated as a ointment, the active ingredients will typically be combined with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with, for example an oil-in-water cream base.
  • Such transdermal formulations are well-known in the art and generally include additional ingredients to enhance the dermal penetration of stability of the active ingredients or the formulation. All such known transdermal formulations and ingredients are included within the scope of this invention.
  • transdermal administration can be accomplished using a patch either of the reservoir or porous membrane type, or of a solid matrix variety.
  • the compounds of this invention can also be administered in sustained release forms or from sustained release drug delivery systems.
  • sustained release materials can be found in Remington's Pharmaceutical Sciences.
  • the following formulation examples illustrate representative pharmaceutical compositions of this invention.
  • the present invention is not limited to the following pharmaceutical compositions.
  • a compound of the invention is admixed as a dry powder with a dry gelatin binder in an approximate 1:2 weight ratio.
  • a minor amount of magnesium stearate is added as a lubricant.
  • the mixture is formed into 240-270 mg tablets (80-90 mg of active amide compound per tablet) in a tablet press.
  • a compound of the invention is admixed as a dry powder with a starch diluent in an approximate 1:1 weight ratio.
  • the mixture is filled into 250 mg capsules (125 mg of active amide compound per capsule).
  • a compound of the invention (125 mg), sucrose (1.75 g) and xanthan gum (4 mg) are blended, passed through a No. 10 mesh U.S. sieve, and then mixed with a previously made solution of microcrystalline cellulose and sodium carboxymethyl cellulose (11:89, 50 mg) in water.
  • Sodium benzoate (10 mg) flavor, and color are diluted with water and added with stirring. Sufficient water is then added to produce a total volume of 5 ml_.
  • a compound of the invention is admixed as a dry powder with a dry gelatin binder in an approximate 1 :2 weight ratio.
  • a minor amount of magnesium stearate is added as a lubricant.
  • the mixture is formed into 450-900 mg tablets (150-300 mg of active amide compound) in a tablet press.
  • a compound of the invention is dissolved or suspended in a buffered sterile saline injectable aqueous medium to a concentration of approximately 5 mg/mL.
  • Stearyl alcohol (250 g) and a white petrolatum (250 g) are melted at about 75 0 C and then a mixture of a compound of the invention (50 g) methylparaben (0.25 g), propylparaben (0.15 g), sodium lauryl sulfate (10 g), and propylene glycol (120 g) dissolved in water (about 370 g) is added and the resulting mixture is stirred until it congeals.
  • the present compounds are used as therapeutic agents for the treatment of tumours, fungal infections and/or malaria in mammals, in particular the treatment of tumours. Accordingly, the compounds and pharmaceutical compositions of this invention find use as therapeutics for preventing and/or treating tumours, fungal infections and/or malaria in mammals including humans.
  • this invention provides a method of treatment or prophylaxis in a mammal susceptible to or afflicted with a tumour, which method comprises administering a therapeutically effective amount of a compound according to the invention, or one or more of the pharmaceutical compositions just described.
  • the present compounds for use as a pharmaceutical especially in the treatment or prevention of the aforementioned conditions and diseases. Also provided herein is the use of the present compounds in the manufacture of a medicament for the treatment or prevention of one of the aforementioned conditions and diseases.
  • Injection dose levels range from about 0.1 mg/kg/hour to at least 10 mg/kg/hour, all for from about 1 to about 120 hours and especially 24 to 96 hours.
  • a preloading bolus of from about 0.1 mg/kg to about 10 mg/kg or more may also be administered to achieve adequate steady state levels.
  • the maximum total dose is not expected to exceed about 2 g/day for a 40 to 80 kg human patient.
  • each dose provides from about 0.01 to about 20 mg/kg of the compound of the invention, with preferred doses each providing from about 0.1 to about 10 mg/kg and especially about 1 to about 5 mg/kg.
  • Transdermal doses are generally selected to provide similar or lower blood levels than are achieved using injection doses.
  • the compounds of this invention When used to prevent the onset of a condition, for example a tumour, a fungal infection or malaria, the compounds of this invention will be administered to a patient at risk for developing the condition, typically on the advice and under the supervision of a physician, at the dosage levels described above.
  • Patients at risk for developing a tumour, a fungal infection or malaria generally include those who have been identified by genetic testing or screening to be particularly susceptible to developing said condition.
  • the compounds of this invention can be administered as the sole active agent or they can be administered in combination with other agents, including other compounds that demonstrate the same or a similar therapeutic activity, and that are determined to safe and efficacious for such combined administration.
  • Geldanamycin and herbimycin may be obtained commercially, by fermentation or by total synthesis using methods known to those of skill in the art.
  • the geldanamycin derivatives according to the invention can be produced either from geldanamycin or from known geldanamycin derivatives by the stated methods directly or by variation of the stated methods.
  • the production of geldanamycin is carried out for example by fermentation of the soil bacterium Streptomyces hygroscopicus.
  • the herbimycin derivatives according to the invention can be produced either from herbimycin or from known herbimycin derivatives by the stated methods directly or by variation of the stated methods.
  • the production of herbimycin is carried out for example by fermentation of the soil bacterium Streptomyces hygroscopicus strain No. AM-3672.
  • geldanamycin-18-oxime derivatives When geldanamycin is reacted with hydroxylamine or O-alkyl- or O-arylhydroxylamines, geldanamycin-18-oxime derivatives are formed. Halogenation then yields the corresponding 19-halogengeldanamycin-18-oxime derivatives (see Scheme 1).
  • the C17 methoxy group of geldanamycin can be reacted with electron donors, for example amines, to the 17-aminogeldanamycin derivatives. Subsequent reaction with hydroxylamine or O-alkyl- or O-arylhydroxylamines provides the 17-amino-17-demethoxygeldanamycin-18- oximes, which can also be halogenated in the C-19 position (see Scheme 2).
  • geldanamycin can be oxidized to 11-oxogeldanamycin. This can be converted by subsequent condensation with hydroxylamine, O-alkyl- or O-arylhydroxylamines to geldanamycin-ll,18-dioxime, which can in turn be halogenated at C-19 (see Scheme 3).
  • geldanamycin can be converted at very good yields to herbimycin B (17-demethoxygeldanamycin). Further reaction of herbimycin B with hydroxylamine or O-alkyl- or O-arylhydroxylamines gives the herbimycin B-18-oximes, which can then be converted by halogenation to the 19- halogenherbimycin B 18-oxime derivatives (see Scheme 4).
  • 17-Demethoxy-17-(dimethylaminoethylamino)geldanamycin 300 mg, 0.5 mmol
  • hydroxylamine hydrochloride 210 mg, 3 mmol
  • the reaction product is then distributed between 60 ml dichloromethane and 100 ml of 0.5 M hydrochloric acid.
  • the organic phase is separated, and the aqueous phase is extracted again with 20 ml dichloromethane.
  • the combined dichloromethane phases are dried over sodium sulphate and the solvent is removed.
  • 17-Demethoxy-17-(2-dimethylaminoethylamino)geldanamycin (385 mg, 0.60 mmol) and hydroxylamine hydrochloride (420 mg, 6 mmol) are suspended in 5 ml dry pyridine. The mixture is stirred for 16h at 60 0 C. The reaction mixture is then distributed between 60 ml dichloromethane and 100 ml water. The organic phase is removed and the aqueous phase is extracted with 20 ml dichloromethane. The combined dichloromethane phases are dried over sodium sulphate and the solvent is removed under vacuum.
  • 17-Amino-17-demethoxygeldanamycin 115 mg, 0.21 mmol
  • semicarbazide hydrochloride 111 mg, 1.0 mmol
  • the reaction product is then distributed between 50 ml dichloromethane and 50 ml of IM hydrochloric acid solution.
  • the organic phase is separated, dried over sodium sulphate and the solvent is removed under vacuum.
  • Purification on Sephadex LH-20 with methanol gives ⁇ -demethoxy- ⁇ -aminogeldanamycin-lS-semicarbazone (82 mg, 64.5 % yield).
  • Oximes of herbimycin B may be produced using methods as described for geldamycim compounds 1-4 above.
  • herbimycin B 53 mg, 0.1 mmol
  • pyridine 1 mL
  • hydroxylamine 1.5 mmol
  • hydroxylamine derivative 1.5 mmol
  • Hydroxylamine hydrochloride (34.7 mg, 0.5 mmol) is suspended in 10 ml dry pyridine. After adding 34.6 mg potassium carbonate the mixture is stirred for 8h at room temperature. After adding 17-demethoxy-17-(2,3-dihydroxypropylamino)geldanamycin (200 mg, 0.32 mmol) the reaction mixture is stirred for 18h at 60 0 C. The pyridine is removed in the rotary evaporator and the residue is distributed between 60 ml IN hydrochloric acid and 100 ml ethyl acetate. The organic phase is separated, dried over Na 2 SO 4 and concentrated to dryness.
  • 17-Demethoxy-17-(2-phosphorylhydroxyethylamino)geldanamycin (280.0 mg, 0.42 mmol) is dissolved under inert gas in 10 mL pyridine. After adding hydroxylamine hydrochloride (1400 mg, 20.0 mmol) it is stirred for 15 minutes at room temperature and then for 16 h at 50 0 C. The pyridine is removed in the rotary evaporator and the residue is taken up in ethyl acetate. Filter and then concentrate the filtrate to dryness.
  • 17-Demethoxy-17-(2-sulphatohydroxyethylamino)geldanamycin 320.0 mg, 0.48 mmol is dissolved under inert gas in 10 ml pyridine. After adding hydroxylamine hydrochloride (700 mg, 10.0 mmol) it is stirred for 2h at room temperature and then for 16 h at 50 0 C. The pyridine is removed in the rotary evaporator and the residue is taken up in ethyl acetate. Filter and then concentrate the filtrate to dryness.
  • Example A Biological activity of selected ansamvcin derivatives
  • a competitive assay was set up, in which the binding of biotinylated geldanamycin to the ATP binding site of Hsp90 is converted to a measurement signal.
  • Compounds of the invention or unlabelled geldanamycin compete with the biotinylated geldanamycin for binding and reduce the signal.
  • the percentage inhibition and an IC 5 O value are calculated.
  • the IC 50 value is a measure of the strength of binding of the derivatives to Hsp90 and therefore of the biological action (e.g. Hsp90 inhibition).
  • the assay is based on a published assay by V. Zhou et al. (Anal. Biochem.
  • concentration of the components in the assay 5O mM Hepes pH 7.3, 5O mM NaCI, 10O mM KF, I mM EDTA, I mM DTT, 0.1% Triton-X-100, 1 nM anti-His-antibody-EuK, 40 nM Hsp90, 40 nM streptavidin-allophycocyanin,
  • the compounds according to the invention display very strong Hsp90 binding.
  • the compounds according to the invention display greatly improved solubility in water.
  • 17-DMAG x HCI is only soluble in aqueous solutions at about 10 mg/mL
  • 17-DMAG-18-oxime x HCI Compound 3
  • Solubility in water correlates with oral bioavailability.

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  • Organic Chemistry (AREA)
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Abstract

La présente invention concerne de nouveaux dérivés d'ansamycine de Formule (I) ou (II) : des produits médicinaux qui contiennent des dérivés ou des sels de ces dérivés, et l'utilisation de dérivés de geldanamycine pour le traitement de maladies, en particulier des maladies néoplastiques.
PCT/EP2007/060032 2006-09-21 2007-09-21 dérivés d'ansamycine WO2008034895A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102006044472.8 2006-09-21
DE200610044472 DE102006044472A1 (de) 2006-09-21 2006-09-21 Geldanamycin-Derivate

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WO2008034895A2 true WO2008034895A2 (fr) 2008-03-27
WO2008034895A3 WO2008034895A3 (fr) 2008-05-08

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109295125A (zh) * 2018-10-08 2019-02-01 中国科学院南海海洋研究所 安莎霉素类化合物及其制备方法与应用

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6870049B1 (en) * 2003-11-12 2005-03-22 Kosan Biosciences, Inc. 11-O-methylgeldanamycin compounds
WO2007059116A2 (fr) * 2005-11-14 2007-05-24 Abraxis Bioscience, Inc. Derives de geldanamycine et compositions pharmaceutiques associees

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109295125A (zh) * 2018-10-08 2019-02-01 中国科学院南海海洋研究所 安莎霉素类化合物及其制备方法与应用
CN109295125B (zh) * 2018-10-08 2020-12-18 中国科学院南海海洋研究所 安莎霉素类化合物及其制备方法与应用

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