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WO2010109008A1 - Promédicaments de 3-(4-hydroxyphényl)-indolin-2-ones substitués - Google Patents

Promédicaments de 3-(4-hydroxyphényl)-indolin-2-ones substitués Download PDF

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Publication number
WO2010109008A1
WO2010109008A1 PCT/EP2010/054000 EP2010054000W WO2010109008A1 WO 2010109008 A1 WO2010109008 A1 WO 2010109008A1 EP 2010054000 W EP2010054000 W EP 2010054000W WO 2010109008 A1 WO2010109008 A1 WO 2010109008A1
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Prior art keywords
optionally substituted
alkyl
amino
oxoindolin
phenyl
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Inventor
Fredrik Björkling
Mette Knark Christensen
Martins Ikaunieks
Andrei Zaichenko
Ilze Kaula
Einars Loza
Ivars Kalvinsh
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Onxeo DK
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Topotarget AS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/32—Oxygen atoms
    • C07D209/34—Oxygen atoms in position 2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/572—Five-membered rings
    • C07F9/5728—Five-membered rings condensed with carbocyclic rings or carbocyclic ring systems

Definitions

  • the present invention relates to novel prodrugs of substituted 3-(4- hydroxyphenyl)-indolin-2-one compounds (oxindole compounds), and the use of such compounds for the preparation of a medicament for the treatment of cancer in a mammal.
  • oxindole compounds substituted 3-(4- hydroxyphenyl)-indolin-2-one compounds
  • US 2004/0242563 Al discloses substituted diphenyl indanone, indane and indole compounds and analogues thereof useful for the treatment or prevention of diseases characterized by abnormal cell proliferation.
  • Felding et al. (WO 2005/097107) describe a number of oxindoles as anti-cancer agents, e.g. the following oxindoles: Halperin et al. (WO 2005/080335) describe a number of oxindoles as potential anti-cancer agents, e.g. the following oxindoles;
  • Baskakova et al. (SU 90-4875262) describe the following oxindole for the manufacture of optical articles.
  • Kornowski (Kornowski H (1963) Bulletin de Ia Societe Chimique de France 10: 2035-2036) describes the synthesis of the following oxindoles:
  • Luk et al. (WO 2006/136606) describe oxindoles as potential anticancer agents:
  • the present invention provides compounds of the general formulae (I) and (W), cf. claims 1 and 11.
  • the present invention further provides a pharmaceutical composition, cf. claim 13, the utilization of compounds of the general formulae (I) and (W) in medicine, cf. claims 15, 16 and 18.
  • the present invention La relates to particular prodrug compounds which are useful for the treatment of cancer in a mammal.
  • the useful prodrug compounds have the general formula (I), namely
  • D is selected from -CH 2 -, -O-, -S-, -S(O)-, -S(O) 2 - and -NR 5 -, wherein R 5 is selected from hydrogen and optionally substituted Ci -6 -alkyl;
  • E is selected from optionally substituted Ci-i 2 -alkyl, optionally substituted C M2 - cycloalkyl, optionally substituted C 2 -i2-alkenyl, optionally substituted C 3- I 2 - cycloalkenyl, optionally substituted C 2- i 2 -alkynyl, optionally substituted heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl; with the proviso that E is not optionally substituted phenyl when r is O;
  • X is selected from the groups (i)-(vi) :
  • Z is selected from optionally substituted Ci-e-alkyl, optionally substituted C 2- 6-alkenyl; aryl, heterocyclyl, heteroaryl, -OR 7 , -N(R 7 )R 8 , -(CH 2 ) 2 -N(R 7 )R 8 , and -CH(R 6 )-N(R 7 )R 8 , and wherein any aryl, heterocyclyl and heteroaryl may be optionally substituted,
  • A is selected from optionally substituted Ci -6 -alkylidene and optionally substituted benzylidene,
  • B is selected from a single bond, -O- and -NH-,
  • R 5 is selected from hydrogen, optionally substituted Ci-e-alkyl, optionally substituted Ci-e-alkoxy, optionally substituted Ci -6 - alkoxycarbonyl, optionally substituted Ci -6 -alkylcarbo ⁇ yl, mono- and ditCi-e-alkyOaminocarbonyl, amino, Ci-e-alkylcarbonylamino, mono- and di(Ci -6 -alkyl)amino, aryl, aryloxy, arylcarbonyl, arylamino, heterocyclyl, heterocyclyloxy, heterocyclylcarbonyl, heterocyclylamino, heteroaryl, heteroaryloxy, heteroarylcarbonyl, and heteroarylamino; where any Ci-e-alkyl as an amino substituent is optionally substituted with hydroxy, Ci-e-alkoxy, amino, mono- and di(Ci -6 -alkyl)amino, carboxy, Ci-e-alkylcarbon
  • R 6 is selected from hydrogen, optionally substituted Ci -6 -alkyl, optionally substituted C 2- 6-alkenyl, aryl, heterocyclyl, and heteroaryl, wherein any aryl, heterocyclyl and heteroaryl may be optionally substituted;
  • R 7 and R 8 are independently selected from hydrogen, optionally substituted Ci-e-alkyl, hydroxy, optionally substituted Ci-e-alkoxy, optionally substituted Ci -6 -alkoxycarbonyl, optionally substituted Ci -6 - alkylcarbonyl, formyl, mono- and di(Ci -6 -alkyl)aminocarbonyl, amino, Ci- 6 -alkylcarbonylamino, mono- and di(Ci -6 -alkyl)amino, Ci -6 - alkylsulphonyl, Ci -6 -alkylsulphinyl, aryl, aryloxy, arylcarbonyl, arylamino, heterocyclyl, heterocyclyloxy, heterocyclylcarbonyl, heterocyclylamino, heteroaryl, heteroaryloxy, heteroarylcarbonyl, and heteroarylamino; where any Ci-e-alkyl as an amino substituent is optionally substituted with hydroxy, Ci
  • R 10 is selected from hydroxy, optionally substituted Ci-e-alkyl, optionally substituted Ci-e-alkoxy, optionally substituted C 2-6 - alkenyloxy; aryloxy, heterocyclyloxy, and heteroaryloxy, wherein any aryl, heterocyclyl and heteroaryl may be optionally substituted; and
  • R 11 is selected from hydroxy, optionally substituted Ci-e-alkyl, optionally substituted C 2-6 -alkenyl, aryl, heterocyclyl, heteroaryl, optionally substituted Ci-e-alkoxy, optionally substituted C 2-6 - alkenyloxy; aryloxy, heterocyclyloxy, and heteroaryloxy, wherein any aryl, heterocyclyl and heteroaryl may be optionally substituted;
  • fir X is selected from hydrogen, hydroxy, optionally substituted Ci -6 alkoxy, optionally substituted Ci -6 alkyl, optionally substituted C 2- 6 alkenyl, carboxy, optionally substituted Ci -6 -alkoxycarbonyl, Ci -6 -alkylcarbonyloxy, optionally substituted Ci -6 alkylcarbonyl, formyl, amino, mono- and di(Ci -6 -alkyl)amino, Ci-6-alkylcarbonylamino, Ci -6 -alkylsulphonylamino, mono- and di(d -6 -alkyl)- aminocarbonylamino, carbamoyl, mono-and di (Ci -6 -alkyl)aminocarbonyl, mercapto, optionally substituted Ci -6 -alkylthio, Ci -6 -alkylsulfonyl, mono- and di(Ci -6 -alkyl)aminosulfonyl,
  • R N represents a prodrug group of any of the types (vii)-(viii)
  • A, B and R 5 are as defined above for prodrug groups (i)-(vi);
  • R N is selected from hydrogen, optionally substituted Ci -6 -alkyl, hydroxy, optionally substituted Ci -6 -alkoxy, optionally substituted Ci -6 -alkoxycarbonyl, optionally substituted Ci-e-alkylcarbonyl, formyl, mono- and di(Ci -6 -alkyl)amino- carbonyl, amino, Ci-e-alkylcarbonylamino, mono- and di(Ci -6 -alkyl)amino, Ci -6 - alkylsulphonyl, and Ci -6 -alkylsulphinyl; where any Ci-e-alkyl as an amino substituent is optionally substituted with hydroxy, Ci-e-alkoxy, amino, mono- and di(Ci -6 -alkyl)amino, carboxy, Ci-e-alkylcarbonylamino, Ci -6 -alkylamino- carbonyl, or halogen(s);
  • V 1 , V 2 , V 3 , and V 4 independently are selected from a carbon atom, a non- quaternary nitrogen atom, an oxygen atom, and a sulphur atom, and where V 4 further may be selected from a bond, so that -V 1 -V 2 -V 3 -V 4 - together with the atoms to which V 1 and V 4 are attached form an aromatic or heteroaromatic ring;
  • R 1 , R 2 , R 3 , and R 4 when attached to a carbon atom, independently are selected from hydrogen, optionally substituted Ci-i 2 -alkyl, optionally substituted C 3-I2 - cycloalkyl, optionally substituted C 2 -i2-alkenyl, optionally substituted C 3- I 2 - cycloalkenyl, hydroxy, optionally substituted d- 12 -alkoxy, optionally substituted C 2 -i2-alkenyloxy, carboxy, optionally substituted Ci-i 2 -alkoxycarbonyl, optionally substituted Ci-i 2 -alkylcarbonyl, optionally substituted Ci-12-alkylcarbonyloxy, formyl, amino, mono- and di(d-i2-alkyl)amino, carbamoyl, mono- and di(Ci-i 2 - alkyl)aminocarbonyl, Ci-12-alkylcarbonylamino, Ci-12-alkylsulphony
  • R 1 , R 2 , R 3 , and R 4 when attached to a nitrogen atom, independently are selected from hydrogen, optionally substituted Ci-i 2 -alkyl, hydroxy, oxide, optionally substituted Ci-i 2 -alkoxy, optionally substituted Ci-12-alkoxycarbonyl, optionally substituted Ci- 12 -alkylcarbonyl, formyl, mono- and di(Ci-i 2 -alkyl)aminocarbonyl, amino, Ci-12-alkylcarbonylamino, mono- and di(Ci-i 2 -alkyl)amino, Ci-I 2 - alkylsulphonyl, Ci-i 2 -alkylsulphinyl, aryl, aryloxy, arylcarbonyl, arylamino, heterocyclyl, heterocyclyloxy, heterocyclylcarbonyl, heterocyclylamino, heteroaryl, heteroaryloxy, heteroarylcarbonyl, and heteroarylamin
  • the compound comprises at least one of the prodrug groups (i)-(viii) and with the proviso that the compound is not l-acetyl-3- (acetyloxy)-3-[4-(acetyloxy)phenyl]-l,3-dihydro-2H-indol-2-one;
  • Ci- 12 -alkyl and “Ci -6 -alkyl” are intended to mean a linear, cyclic or branched hydrocarbon group having 1 to 12 carbon atoms and 1 to 6 carbon atoms, respectively, such as methyl, ethyl, propyl, iso- propyl, pentyl, cyclopentyl, hexyl, cyclohexyl.
  • the term "Ci -4 -alkyl” is intended to cover linear, cyclic or branched hydrocarbon groups having 1 to 4 carbon atoms, e.g. methyl, ethyl, propyl, /so-propyl, cyclopropyl, butyl, /so- butyl, tert- butyl, cyclobutyl.
  • C 3- i 2 -cycloalkyl is encompassed by the term it refers specifically to the mono- and bicyclic counterparts, including alkyl groups having exo-cyclic atoms, e.g. cyclohexyl-methyl.
  • C 2- i2-alkenyl and “C 2- 6-alkenyl” are intended to cover linear, cyclic or branched hydrocarbon groups having 2 to 12 carbon atoms and 2 to 6 carbon atoms, respectively, and comprising (at least) one unsaturated bond.
  • alkenyl groups are vinyl, allyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, heptadecaenyl.
  • Preferred examples of alkenyl are vinyl, allyl, butenyl, especially allyl.
  • C 3- i 2 -cycloalkenyl is encompassed by the term “C 2-I2 - alkenyl”, it refers specifically to the mono- and bicyclic counterparts, including alkenyl groups having exo-cyclic atoms, e.g. cyclohexenyl-methyl.
  • the term “optionally substituted” is intended to mean that the group in question may be substituted one or several times, preferably 1-3 times, with group(s) selected from hydroxy (which when bound to an unsaturated carbon atom may be present in the tautomeric keto form), Ci-e-alkoxy ⁇ i.e.
  • Ci -6 -alkyl-oxy C 2- 6-alkenyloxy, carboxy, oxo (forming a keto or aldehyde functionality), Ci -6 -alkoxycarbonyl, Ci -6 - alkylcarbonyl, formyl, aryl, aryloxy, arylamino, arylcarbonyl, aryloxycarbonyl, arylcarbonyloxy, arylaminocarbonyl, arylcarbonylamino, heteroaryl, heteroaryloxy, heteroarylamino, heteroarylcarbonyl, heteroaryloxycarbonyl, heteroarylcarbonyloxy, heteroarylaminocarbonyl, heteroarylcarbonylcarbonylamino, heterocyclyl, heterocyclyloxy, heterocyclylaminocarbonyl, heterocyclylcarbonyl, heterocyclyloxy, heterocyclylamino, heterocyclylcarbonyl, heterocyclyloxycarbonyl, heterocyclylcarbonyloxy, heterocyclyla
  • the substituents are selected from hydroxy (which when bound to an unsaturated carbon atom may be present in the tautomeric keto form), Ci -6 - alkoxy ⁇ i.e. Ci-e-alkyl-oxy), C 2-6 -alkenyloxy, carboxy, oxo (forming a keto or aldehyde functionality), Ci-e-alkylcarbonyl, formyl, aryl, aryloxy, arylamino, arylcarbonyl, heteroaryl, heteroaryloxy, heteroarylamino, heteroarylcarbonyl, heterocyclyl, heterocyclyloxy, heterocyclylamino, heterocyclylcarbonyl, amino, mono- and di(Ci -6 -alkyl)amino; carbamoyl, mono- and di(d -6 -alkyl)amino- carbonyl, amino-Ci-e-alkyl-aminocarbonyl, mono- and di(Ci -6 -alkyl
  • substituents are selected from hydroxy, Ci -6 -alkoxy, amino, mono- and di(Ci -6 -alkyl)amino, carboxy, Ci-e-alkylcarbonylamino, Ci -6 - alkylaminocarbonyl, or halogen.
  • halogen includes fluoro, chloro, bromo, and iodo.
  • aryl is intended to mean a fully or partially aromatic carbocyclic ring or ring system, such as phenyl, naphthyl, 1,2,3,4- tetrahydronaphthyl, anthracyl, phenanthracyl, pyrenyl, benzopyrenyl, fluorenyl and xanthenyl, among which phenyl is a preferred example.
  • heteroaryl groups are oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, coumaryl, furanyl, thienyl, quinolyl, benzo- thiazolyl, benzotriazolyl, benzodiazolyl, benzooxozolyl, phthalazinyl, phthalanyl, triazolyl, tetrazolyl, isoquinolyl, acridinyl, carbazolyl, dibenzazepinyl, indolyl, benzopyrazolyl, phenoxazonyl.
  • heteroaryl groups are benzimidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, furyl, thienyl, quinolyl, triazolyl, tetrazolyl, isoquinolyl, indolyl in particular benzimidazolyl, pyrrolyl, imidazolyl, pyridinyl, pyrimidinyl, furyl, thienyl, quinolyl, tetrazolyl, and isoquinolyl.
  • heterocyclyl groups examples include imidazolidine, piperazine, hexahydropyridazine, hexahydropyrimidine, diazepane, diazocane, pyrrolidine, piperidine, azepane, azocane, aziridine, azirine, azetidine, pyroline, tropane, oxazinane (morpholine), azepine, dihydroazepine, tetrahydroazepine, and hexahydroazepine, oxazolane, oxazepane, oxazocane, thiazolane, thiazinane, thiazepane, thiazocane, oxazetane, diazetane, thiazetane, tetrahydrofuran, tetrahydropyran, oxepane, tetrahydrothioph
  • the most interesting examples are tetrahydrofuran, imidazolidine, piperazine, hexahydropyridazine, hexahydropyrimidine, diazepane, diazocane, pyrrolidine, piperidine, azepane, azocane, azetidine, tropane, oxazinane (morpholine), oxazolane, oxazepane, thiazolane, thiazinane, and thiazepane, in particular tetrahydrofuran, imidazolidine, piperazine, hexahydropyridazine, hexahydropyrimidine, diazepane, pyrrolidine, piperidine, azepane, oxazinane (morpholine), and thiazinane.
  • the term “optionally substituted” is intended to mean that the group in question may be substituted one or several times, preferably 1-5 times, in particular 1-3 times, with group(s) selected from hydroxy (which when present in an enol system may be represented in the tautomeric keto form), Ci -6 -alkyl, Ci- 6 -alkoxy, C 2-6 -alkenyloxy, oxo (which may be represented in the tautomeric enol form), oxide (only relevant as the N-oxide), carboxy, Ci -6 -alkoxycarbonyl, Ci- 6 -alkylcarbonyl, formyl, aryl, aryloxy, arylamino, aryloxycarbonyl, arylcarbon
  • the substituents are selected from hydroxy, Ci -6 -alkyl, Ci -6 -alkoxy, oxo (which may be represented in the tautomeric enol form), carboxy, Ci -6 - alkylcarbonyl, formyl, amino, mono- and di(Ci -6 -alkyl)amino; carbamoyl, mono- and di(Ci- 6 -alkyl)aminocarbonyl, amino-Ci- 6 -alkyl-aminocarbonyl, Ci -6 - alkylcarbonylamino, guanidino, carbamido, Ci -6 -alkyl-sulphonyl-amino, aryl- sulphonyl-amino, heteroaryl-sulphonyl-amino, Ci -6 -alkyl-suphonyl, Ci -6 -alkyl- sulphinyl, Ci -6 -alkylsulphonyl,
  • the substituents are selected from Ci-e-alkyl, Ci-e-alkoxy, amino, mono- and di(Ci -6 -alkyl)amino, sulphanyl, carboxy or halogen, where any alkyl, alkoxy and the like, representing substituents may be substituted with hydroxy, Ci -6 -alkoxy, C 2- 6-alkenyloxy, amino, mono- and di(Ci -6 -alkyl)amino, carboxy, Ci-e-alkylcarbonylamino, halogen, Ci -6 -alkylthio, Ci -6 -alkyl-sulphonyl- amino, or guanidino.
  • N-substituted amino acid refers to an amino acid moiety wherein the ⁇ -nitrogen is represented by -N(R 7 )R 8 , wherein R 7 and R 8 are as defined herein.
  • a non-substituted variant is the one where R 7 and R 8 are both hydrogen.
  • salts is intended to include acid addition salts and basic salts.
  • acid addition salts are pharmaceutically acceptable salts formed with non-toxic acids.
  • organic salts are those with maleic, fumaric, benzoic, ascorbic, succinic, oxalic, bis-methylenesalicylic, methanesulphonic, ethanedisulphonic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulphonic, and theophylline acetic acids, as well as the 8-halotheophyllines, for example 8-bromotheophylline.
  • Exemplary of such inorganic salts are those with hydrochloric, hydrobromic, sulphuric, sulphamic, phosphoric, and nitric acids.
  • Examples of basic salts are salts where the (remaining) counter ion is selected from alkali metals, such as sodium and potassium, alkaline earth metals, such as calcium, and ammonium ions ( + N(R) 3 R', where R and R' independently designates optionally substituted Ci -6 - alkyl, optionally substituted C 2-6 -alkenyl, optionally substituted aryl, or optionally substituted heteroaryl).
  • Pharmaceutically acceptable salts are, e.g., those described in Remington's Pharmaceutical Sciences, 17. Ed. Alfonso R.
  • an acid addition salt or a basic salt thereof used herein is intended to comprise such salts.
  • the compounds as well as any intermediates or starting materials may also be present in hydrate form.
  • the compounds may be present as racemic mixtures or the individual stereoisomers such as enantiomers or diastereomers.
  • the present invention encompasses each and every of such possible stereoisomers (e.g. enantiomers and diastereomers) as well as racemates and mixtures enriched with respect to one of the possible stereoisomers.
  • the compound of the general formula (I) must include at least one prodrug group of any of the types (i), (ii), (iii), (iv), (v), (vi), (vii) and (viii).
  • the compound may comprise only one prodrug group, i.e. X is a prodrug group of any of the types (i)-(vi), or R N is a prodrug group of any of the types (vii)-(viii).
  • the compound may comprise more than one prodrug group, e.g. R N is a prodrug group of any of the types (vii)-(viii) while X is a prodrug group of any of the types (i)-(vi).
  • Particularly interesting meaning of Z are optionally substituted Ci -6 -alkyl, C 2 - 6 -alkenyl, and -N(R 7 )R 8 .
  • R 7 and R 8 are independently selected from hydrogen, optionally substituted Ci -6 -alkyl, hydroxy, optionally substituted Ci-e-alkoxy, optionally substituted Ci -6 -alkoxycarbonyl, optionally substituted Ci -6 -alkylcarbonyl, formyl, mono- and di(Ci-6-alkyl)aminocarbonyl, amino, Ci-e-alkylcarbonylamino, mono- and di(Ci -6 -alkyl)amino, Ci-e-alkylsulphonyl, Ci -6 -alkylsulphinyl, aryl, aryloxy, arylcarbonyl, arylamino, heterocyclyl, heterocyclyloxy, heterocyclylcarbonyl, heterocyclylamino, heteroaryl, heteroaryloxy, heteroarylcarbonyl, and heteroarylamino; where any Ci -6 -alkyl as an amino substituent is optionally substituted with hydroxy, Ci
  • R 6 is preferably selected from side chains of essential amino acids, or R 6 and R 8 together with the intervening carbon and nitrogen atoms to which they are attached form a heterocyclic ring.
  • R 6 is preferably selected from hydrogen (representing glycine), methyl (alanine), 2-propyl (valine), 2-methyl-l-propyl (leucine), 2-butyl (isoleucine), methylthioethyl (methionine), benzyl (phenylalanine), 3- indolylmethyl (tryptophan), hydroxymethyl (serine), 1-hydroxyethyl (threonine), mercaptomethyl (cysteine), 4-hydroxybenzyl (tyrosine), aminocarbonylmethyl (asparagine), 2-aminocarbonylethyl (glutamine), carboxymethyl (aspartic acid), 2-carboxyethyl (glutamic acid), 4-amino-l-butyl (lysine),
  • Z is -N(R 7 )R 8 , wherein R 7 and R 8 together with the nitrogen atoms to which they are attached form a heterocyclic ring.
  • Z is -(CH 2 V N(R 7 )R 8 , wherein R 7 and R 8 together with the nitrogen atoms to which they are attached form a heterocyclic ring.
  • A is selected from optionally substituted Ci -6 -alkylidene and optionally substituted benzylidene;
  • B is selected from a single bond, -O- and -NH-;
  • R 5 is selected from hydrogen, optionally substituted Ci -6 -alkyl, optionally substituted Ci -6 -alkoxy, optionally substituted Ci-e-alkoxycarbonyl, optionally substituted Ci-e-alkylcarbonyl, mono- and di(Ci -6 -alkyl)aminocarbonyl, amino, Ci- 6 -alkylcarbonylamino, mono- and di(Ci -6 -alkyl)amino, aryl, aryloxy, arylcarbonyl, arylamino, heterocyclyl, heterocyclyloxy, heterocyclylcarbonyl, heterocyclylamino, heteroaryl, heteroaryloxy, heteroarylcarbonyl, and heteroarylamino; where any Ci -6 -alkyl
  • R 5 is selected from hydrogen, optionally substituted Ci -6 -alkyl, optionally substituted Ci -6 -alkoxy, optionally substituted Ci -6 -alkoxycarbonyl, optionally substituted Ci -6 -alkylcarbonyl, mono- and di(Ci -6 -alkyl)aminocarbonyl, amino, Ci -6 -alkylcarbonylamino, mono- and di(Ci -6 -alkyl)amino, aryl, aryloxy, arylcarbonyl, arylamino, heterocyclyl, heterocyclyloxy, heterocyclylcarbonyl, heterocyclylamino, heteroaryl, heteroaryloxy, heteroarylcarbonyl, and heteroarylamino; where any Ci -6 -alkyl as an amino substituent is optionally substituted with hydroxy, Ci -6 -alkoxy, amino, mono- and di(Ci -6 -alkyl)amino, carboxy, Ci
  • R 6 is preferably selected from side chains of essential amino acids, or R 6 and R 8 together with the intervening carbon and nitrogen atoms to which they are attached form a pyrrolidine ring (see the examples above for prodrug groups (i) and (ii)).
  • A is selected from optionally substituted Ci -6 -alkylidene and optionally substituted benzylidene;
  • R 9 is selected from hydrogen, hydroxy, optionally substituted Ci -6 -alkyl, optionally substituted Ci -6 -alkoxy, and optionally substituted C 2-6 -alkenyloxy;
  • R 10 is selected from hydroxy, optionally substituted Ci-e-alkyl, optionally substituted Ci -6 -alkoxy, optionally substituted C 2 -6-alkenyloxy; aryloxy, heterocyclyloxy, and heteroaryloxy, wherein any aryl, heterocyclyl and heteroaryl may be optionally substituted; provided that R 9 and R 10 are not both selected from hydroxy and C 1-6 -alkoxy.
  • R 9 is preferably selected from hydrogen and hydroxy
  • R 10 is preferably selected from optionally substituted Ci-e-alkoxy, optionally substituted C 2-6 -alkenyloxy; aryloxy, heterocyclyloxy, and heteroaryloxy, wherein any aryl, heterocyclyl and heteroaryl may be optionally substituted.
  • R 9 is hydroxy
  • R 10 is selected from optionally substituted Ci-e-alkoxy, aryloxy, heterocyclyloxy, and heteroaryloxy, wherein any aryl, heterocyclyl and heteroaryl may be optionally substituted.
  • R N represents a prodrug group or any of the types (vii)-(viii).
  • R N is not an acetyl group.
  • A is selected from optionally substituted Ci -6 -alkylidene and optionally substituted benzylidene; B is selected from a single bond, -O-, and -NH-; and R 5 is selected from hydrogen, optionally substituted Ci-6-alkyl, optionally substituted Ci- 6 -alkoxy, optionally substituted Ci-6-alkoxycarbonyl, optionally substituted Ci -6 -alkylcarbonyl, mono- and di(Ci -6 -alkyl)aminocarbonyl, amino, Ci- 6 -alkylcarbonylamino, mono- and di(Ci -6 -alkyl)amino, aryl, aryloxy, arylcarbonyl, arylamino, heterocyclyl, heterocyclyloxy, heterocyclylcarbonyl, heterocyclylamino, heteroaryl, heteroaryloxy, heteroarylcarbonyl, and
  • R 6 is preferably selected from side chains of essential amino acids, or R 6 and R 8 together with the intervening carbon and nitrogen atoms to which they are attached form a pyrrolidine ring (see the examples above for prodrug groups (i) and (ii)).
  • V 1 , V 2 , V 3 , and V 4 are mainly believed to be of sterical character, i.e. determinative for the orientation of the groups R ⁇ R 4 . It is, however, also believed that the selection of a heteroatom as one or more of V 1 , V 2 , V 3 , and V 4 may create dipole interactions with other entities and thereby have influence on, e.g. , the solubility of the compounds of the general formula (I).
  • V 1 , V 2 , V 3 , and V 4 are independently selected from a carbon atom, a non- quaternary nitrogen atom, an oxygen atom, and a sulfur atom, and where V 4 further may be selected from a bond, so that -V 1 -V 2 -V 3 -V 4 - together with the atoms to which V 1 and V 4 are attached form an aromatic or heteroaromatic ring.
  • V 1 , V 2 , V 3 and V 4 for each heteroaromatic ring is merely specified for the purpose of illustrating that various orientations of the heteroatoms are possible.
  • the respective rings carry the substituents R 1 , R 2 , R 3 and R 4 (where applicable) in accordance with the general formula (I).
  • R 1 , R 2 , R 3 and R 4 substituents R 1 , R 2 , R 3 and R 4 (where applicable) in accordance with the general formula (I).
  • C(-)" and “N(-)" as possible meanings of V 1 , V 2 , V 3 and V 4 is made for the purpose of describing that the atoms in question carry a substituent (which may be hydrogen).
  • Specification of "N” means that the respective atoms do not carry an "R” substituent, i.e. the corresponding "R” substituent is absent.
  • -V 1 -V 2 -V 3 -V 4 - together with the atoms to which V 1 and V 4 are attached form a ring selected from a benzene ring, a thiophene ring, a furan ring, a pyrazole ring, an imidazole ring, a pyridine ring, a pyrimidine ring, pyrazines, and a pyridazine ring, in particular from a benzene ring and a pyridine ring where the nitrogen atom represents V 3 (see also the Examples).
  • the respective ring (aromatic or heteroaromatic) carries the substituents R*-R 4 (where applicable).
  • the substituents R*-R 4 (where applicable) are believed to be at least partly responsible for the biological effect, e.g. the ability of the compounds to inhibit cell proliferation in cancer cells.
  • R 1 , R 2 , R 3 , and R 4 are, when attached to a carbon atom, independently selected from hydrogen, optionally substituted Ci -6 -alkyl, optionally substituted C 2 -6-alkenyl, hydroxy, optionally substituted Ci -6 -alkoxy, optionally substituted C 2- 6-alkenyloxy, carboxy, optionally substituted Ci -6 - alkoxycarbonyl, optionally substituted Ci -6 -alkylcarbonyl, optionally substituted Ci- 6 -alkylcarbonyloxy, formyl, amino, mono- and di(Ci -6 -alkyl)amino, carbamoyl, mono- and di(Ci -6 -alkyl)aminocarbonyl, Ci-e-alkylcarbonylamino, Ci -6 - alkylsulphonylamino, cyano, carbamido, mono- and di(Ci -6 -alkyl)amino- carbony
  • R 1 , R 2 , R 3 , and R 4 are independently selected from hydrogen, halogen, optionally substituted Ci -6 -alkyl, hydroxy, optionally substituted Ci -6 - alkoxy, optionally substituted Ci-e-alkoxycarbonyl, optionally substituted Ci -6 - alkylcarbonyl, amino, Ci -6 -alkylcarbonylamino, Ci -6 -alkylcarbonylamino, Ci -6 - alkylsulphonylamino, mono- and di(Ci -6 -alkyl)aminosulfonyl, and mono- and di(Ci -6 -alkyl)amino, where any Ci -6 -alkyl as an amino substituent is optionally substituted with hydroxy, Ci -6 -alkoxy, amino, mono- and di(Ci- 6 -alkyl)amino, carboxy, Ci- 6 -alkylcarbonylamino, Ci- 6 -alkyl,
  • R 1 and R 2 may in one embodiment together with the carbon atoms to which they are attached form a heterocyclic ring or a heteroaromatic ring; and in another embodiment, R 1 and R 2 may together with the carbon atoms to which they are attached form an aromatic ring or a carbocyclic ring.
  • R 1 , R 2 , R 3 and R 4 are not all hydrogen.
  • R 1 and R 2 are both halogen, in particular, R 1 and R 2 are both fluoro.
  • R N , R 3 and R 4 are all hydrogen.
  • R N may be selected from a wide variety of substituents including the prodrug groups (vii) and (viii). If not being a prodrug group, R N may advantageous be selected from hydrogen, Ci-6-alkyl, amino, and Ci-6- alkylcarbonylamino. Most preferred is the variants wherein R N is selected from hydrogen and Ci -6 -alkyl, in particular from hydrogen and methyl, most typical hydrogen.
  • each of V 1 , V 2 , V 3 , and V 4 represents a carbon atom;
  • R 1 and R 2 are selected from halogen, Ci -6 -alkyl, Ci -6 -alkoxy, in particular both are fluoro;
  • R 3 and R 4 are both hydrogen
  • R N is hydrogen
  • X represents a prodrug group (i), (ii) or (iv),
  • R 1 is selected from hydrogen, halogen, Ci -6 -alkyl, trifluoromethyl and Ci-e-alkoxy, when V 1 is a carbon atom.
  • R 2 is selected from hydrogen, halogen, Ci-e-alkoxy, optionally substituted aryl, optionally substituted aryloxy, and optionally substituted heteroaryl, when V 2 is a carbon atom.
  • R 3 is selected from hydrogen, optionally substituted Ci-e-alkoxy, halogen, cyano, optionally substituted aryl, optionally substituted aryloxy, optionally substituted heteroaryl, amino, Ci-6-alkylcarbony- lamino, Ci- 6 -alkylsulphonylamino, and mono- and di(Ci-6-alkyl)aminosulfonyl, when V 3 is a carbon atom.
  • R 4 is hydrogen, when V 4 is a carbon atom.
  • relevant feature of the compounds of the formula (I) include that the group E is not optionally substituted phenyl when r is 0,.
  • the group E is not optionally substituted phenyl when r is 0,.
  • at least one of the substituents R 1 , R 2 , R 3 , and R 4 is not hydrogen; and preferably at least two of the substituents R 1 , R 2 , R 3 , and R 4 are not hydrogen.
  • E plays an important role for the optimization of the biological activity of the compounds.
  • E is in one interesting embodiment selected from optionally substituted d- 12 -alkyl, optionally substituted C 3- i 2 -cycloalkyl, optionally substituted C 2 -i 2 -alkenyl, optionally substituted C 3 -i2-cycloalkenyl, optionally substituted C 2 -i 2 -alkynyl, and optionally substituted heterocyclyl.
  • E is selected from Ci-i 2 -alkyl, C 3 -i2-cycloalkyl, C 2- I 2 - alkenyl, C 3- i 2 -cycloalkenyl, and C 2- i 2 -alkynyl.
  • E is selected from optionally substituted C 3- I 2 - cycloalkyl and optionally substituted heterocyclyl (e.g. piperidine and morpholine), in particular from C 3- i 2 -cycloalkyl, heterocyclyl, and mono- substituted heterocyclyl.
  • optionally substituted C 3- I 2 - cycloalkyl and optionally substituted heterocyclyl e.g. piperidine and morpholine
  • E is selected from optionally substituted C 3- i 2 -cycloalkyl, such as from cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
  • E is optionally substituted heteroaryl, in particular heteroaryl.
  • E is aryl or, alternatively, E is di- or tri- substituted aryl.
  • r is 1 and D is -CH 2 -.
  • r 0.
  • each of V 1 , V 2 , V 3 , and V 4 represents a carbon atom (a benzene ring), or V 3 represents a nitrogen atom and each of V 1 , V 2 , and V 4 represents a carbon atom (a pyridine ring).
  • each of V 1 , V 2 , V 3 , and V 4 represents a carbon atom ⁇ i.e. the ring is a benzene ring).
  • the substituents R 1 and R 2 of the substituents R 1 , R 2 , R 3 , and R 4 seem to play a particular role.
  • R 1 is selected from halogen, Ci -6 -alkyl, trifluoromethyl and Ci -6 - alkoxy, when V 1 is a carbon atom.
  • R 2 is selected from halogen, optionally substituted Ci -6 -alkyl, and optionally substituted Ci-e-alkoxy, when V 2 is a carbon atom.
  • R 3 is selected from hydrogen, optionally substituted Ci- 6 -alkoxy, halogen, cyano, optionally substituted aryl, optionally substituted aryloxy, optionally substituted heteroaryl, amino, Ci -6 -alkylcarbonylamino, Ci -6 - alkylsulphonylamino, and mono- and di(Ci -6 -alkyl)aminosulphonyl, when V 3 is a carbon atom.
  • R 4 is hydrogen, when V 4 is a carbon atom.
  • At least two of the substituents R 1 , R 2 , R 3 , and R 4 are not hydrogen.
  • R 3 and R 4 are both hydrogen.
  • R 1 and R 2 are hydrogen.
  • R 1 and R 2 are both selected from halogen and methyl.
  • R 1 and R 2 are both fluoro.
  • R 1 and R 2 together with the carbon atoms to which they are attached form a ring selected from aromatic rings, carbocyclic rings, heterocyclic rings and heteroaromatic rings, in particular aromatic rings, heterocyclic rings and heteroaromatic rings
  • each of V 1 , V 2 , V 3 , and V 4 represents a carbon atom ⁇ i.e. the ring is a benzene ring).
  • the compounds of the present invention can be prepared in a number of ways well known to those skilled in the art of organic synthesis.
  • the compounds of the present invention can be synthesized using the methods outline below and in the Examples section, together with methods known in the art of synthetic organic chemistry, or variations thereof as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below.
  • novel compounds of formula (I) may be prepared using the reactions and techniques described in this section.
  • the reactions are performed in solvents appropriate to the reagents and materials employed and suitable for the transformations being effected.
  • synthetic methods described below it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature duration of experiment and work-up procedures, are chosen to be conditions of standard for that reaction, which should be readily recognized by one skilled in the art. It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the educt molecule must be compatible with the reagents and reactions proposed. Not all molecules of formula (I) falling into a given class may be compatible with some of the reaction conditions required in some of the methods described. Such restrictions to the substituents which are compatible with the reaction conditions will be readily apparent to one skilled in the art and alternative methods can be used.
  • Compounds (I) according to the present invention in which X is an amino acid ester (Ia) may be prepared from phenols of general formula (II) by coupling with a protected amino acid and subsequent removal of the protecting groups, if any, to yield compounds of general formula (Ia).
  • the condensation is carried out using any of the many methods for the formation of ester bonds known to one skilled in the art of organic synthesis. These methods include, but are not limited to, use of Standard coupling procedures such as use of symmetric carbonic anhydrides, mixed carbonic anhydride method (e.g. isobutyl chloroformate) method, carbodiimides (e.g.
  • N,N-dimethylaminopropyl-N'-ethyl carbodiimide dicyclohexyl carbodiimide, diisopropyl carbodiimide
  • active ester e.g. pentaflurophenyl ester, p-nitrophenyl ester, N-hydroxysuccinic imido ester
  • carbonyldiimidazole method azide method
  • phosphorous reagents such as BOP- Cl
  • conversion of the protected amino acid derivative into an acid chloride Some of these methods (especially carbodiimide) can be enhanced by addition of e.g. 1-hydroxybenzotriazole or N,N-dimethylaminopyridine.
  • Protection groups as referred to above are well known per se, for example from the techniques of peptide chemistry.
  • Amino groups can often be protected by tert-butyloxycarbonyl, benzyloxycarbonyl or acetyl groups, or in the form of a phtalimido group.
  • Hydroxy groups are often protected as readily cleavable ethers such as the t-butyl or benzyl ether, or as readily cleavable esters such as the acetate.
  • Carboxylic acid groups are often protected as readily cleavable esters such as the t-butyl or benzyl ester.
  • Thiols are often protected as readily cleavable ethers such as the trityl ether.
  • R 7 and R 8 are both alkylgroups or hydrogen
  • compounds of general formula (Ia) can be converted into the corresponding trialkylammonium salts (Ib), e.g. by reaction with an alkyl halide and a base or alkyl methane sulfonate.
  • Compounds (I) according to the present invention in which X is a phosphonate group or a phosphinate group (Ic) may be prepared from phenols of general formula (II) e.g. by condensation with a phosphonochloridate or a phosphinic chloride in the presence of a base.
  • phenols of general formula (II) may be treated with dibenzyl phosphate in the presence of a base, followed by removal of the benzyl groups by hydrogenation.
  • the chloromethyl or iodomethyl esters of general formula (III) may be prepared as described in Bioorg. Med. Chem. Lett. (2005) 13 2491-2494.
  • compounds of general formula (Id) may prepared by similar methods to those described in Bioorg. Med. Chem. Lett. (2003) 1695-1698 after suitable protection of the amide group and subsequent removal of the protecting group, as described above.
  • a base e.g. potassium carbonate or caesium carbonate
  • Compounds (I) according to the present invention which are sulfates (II) can be prepared by treating phenols of general formula (II) with sulfuric acid and acetic acid anhydride in pyridine.
  • Compounds (I) according to the present invention which are acrylates (In) can be prepared by reaction of phenols of general formula (II) with acryloyl chloride in the presence of a base.
  • Compounds (I) which are 3-aminopropanoates (Io) can subsequently be obtained from acrylates of general formula (In) by reaction with an amine in the presence of a catalyst such as e.g. bismuth(III) trifluoromethanesulfonate.
  • cancer is typically describing cell growth not under strict control.
  • treatment of cancers in which inhibition of protein synthesis and/or inhibition of activation of the mTOR pathway is an effective method for reducing cell growth.
  • cancers include, but are not limited to, breast cancer, renal cancer, multiple myeloma, leukemia, glioblastoma, rhabdomyosarcoma, prostate, soft tissue sarcoma, colorectal sarcoma, gastric carcinoma, head and neck squamous cell carcinoma, uterine, cervical, melanoma, lymphoma, and pancreatic cancer.
  • Any type of cell may be treated, including but not limited to, lung, gastrointestinal (including e.g. bowel, colon), breast (mammary), ovarian, prostate, liver (hepatic), kidney (renal), bladder, pancreas, brain and skin.
  • gastrointestinal including e.g. bowel, colon
  • breast mammary
  • ovarian prostate
  • liver hepatic
  • kidney renal
  • bladder pancreas
  • brain and skin any type of cell may be treated, including but not limited to, lung, gastrointestinal (including e.g. bowel, colon), breast (mammary), ovarian, prostate, liver (hepatic), kidney (renal), bladder, pancreas, brain and skin.
  • the present invention generally provides a compound of the general formula (I) or (W) as defined herein for use as a medicament; more particular, the use of a compound of the general formula (I) or (W) as defined herein for the preparation of a medicament for the treatment of cancer in a mammal.
  • Such medicaments may further comprise one or more other chemotherapeutic agents.
  • the present invention provides a method of treating a mammal suffering from or being susceptible to cancer, the method comprising administering to the mammal a therapeutically effective amount of a compound of the general formula (I) or (W) as defined herein.
  • the compounds of the general formulae (I) and (W) are suitably formulated in a pharmaceutical composition so as to suit the desirable route of administration.
  • the administration route of the compounds may be any suitable route which leads to a concentration in the blood or tissue corresponding to a therapeutic effective concentration.
  • the following administration routes may be applicable although the invention is not limited thereto: the oral route, the parenteral route, the cutaneous route, the nasal route, the rectal route, the vaginal route and the ocular route.
  • the administration route is dependent on the particular compound in question; particularly the choice of administration route depends on the physico- chemical properties of the compound together with the age and weight of the patient and on the particular disease or condition and the severity of the same.
  • the compounds may be contained in any appropriate amount in a pharmaceutical composition, and are generally contained in an amount of about 1-95%, e.g. 1-10%, by weight of the total weight of the composition.
  • the composition may be presented in a dosage form which is suitable for the oral, parenteral, rectal, cutaneous, nasal, vaginal and/or ocular administration route.
  • the composition may be in form of, e.g., tablets, capsules, pills, powders, granulates, suspensions, emulsions, solutions, gels including hydrogels, pastes, ointments, creams, plasters, drenches, delivery devices, suppositories, enemas, injectables, implants, sprays, aerosols and in other suitable form.
  • compositions may be formulated according to conventional pharmaceutical practice, see, e.g., "Remington's Pharmaceutical Sciences” and “Encyclopedia of Pharmaceutical Technology", edited by Swarbrick, J. & J. C. Boylan, Marcel Dekker, Inc., New York, 1988.
  • the compounds defined herein are formulated with (at least) a pharmaceutically acceptable carrier or excipient.
  • Pharmaceutically acceptable carriers or excipients are those known by the person skilled in the art. Formation of suitable salts of the compounds of the Formulae (I) and (W) will also be evident in view of the before-mentioned.
  • the present invention provides in a further aspect a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the general Formula (I) or (W) in combination with a pharmaceutically acceptable carrier.
  • compositions according to the present invention may be formulated to release the active compound substantially immediately upon administration or at any substantially predetermined time or time period after administration.
  • the latter type of compositions is generally known as controlled release formulations.
  • controlled release formulation embraces i) formulations which create a substantially constant concentration of the drug within the body over an extended period of time, ii) formulations which after a predetermined lag time create a substantially constant concentration of the drug within the body over an extended period of time, iii) formulations which sustain drug action during a predetermined time period by maintaining a relatively, constant, effective drug level in the body with concomitant minimization of undesirable side effects associated with fluctuations in the plasma level of the active drug substance (saw-tooth kinetic pattern), iv) formulations which attempt to localize drug action by, e.g., spatial placement of a controlled release composition adjacent to or in the diseased tissue or organ, v) formulations which attempt to target drug action by using carriers or chemical derivatives to deliver the drug to a particular target cell type. Controlled release formulations may also be denoted "sustained release", “prolonged release”, “programmed release”, “time release”, “rate-controlled” and/or "targeted release” formulations
  • Controlled release pharmaceutical compositions may be presented in any suitable dosage forms, especially in dosage forms intended for oral, parenteral, cutaneous nasal, rectal, vaginal and/or ocular administration.
  • suitable dosage forms especially in dosage forms intended for oral, parenteral, cutaneous nasal, rectal, vaginal and/or ocular administration.
  • Examples include single or multiple unit tablet or capsule compositions, oil solutions, suspensions, emulsions, microcapsules, microspheres, nanoparticles, liposomes, delivery devices such as those intended for oral, parenteral, cutaneous, nasal, vaginal or ocular use.
  • Capsules, tablets and pills etc. may contain for example the following compounds: microcrystalline cellulose, gum or gelatin as binders; starch or lactose as excipients; stearates as lubricants; various sweetening or flavouring agents.
  • the dosage unit may contain a liquid carrier like fatty oils.
  • coatings of sugar or enteric agents may be part of the dosage unit.
  • the pharmaceutical compositions may also be emulsions of the compound(s) and a lipid forming a micellular emulsion.
  • the pharmaceutical composition may include a sterile diluent, buffers, regulators of tonicity and antibacterials.
  • the active compound may be prepared with carriers that protect against degradation or immediate elimination from the body, including implants or microcapsules with controlled release properties.
  • the preferred carriers are physiological saline or phosphate buffered saline.
  • the pharmaceutical composition is in unit dosage form.
  • each unit dosage form typically comprises 0.1-500 mg, such as 0.1-200 mg, e.g. 0.1-100 mg, of the compound.
  • the compound are preferably administered in an amount of about 0.1-250 mg per kg body weight per day, such as about 0.5-100 mg per kg body weight per day.
  • the dosage is normally 0.5 mg to 1 g per dose administered 1-4 times daily for 1 week to 12 months depending on the disease to be treated.
  • the dosage for oral administration of the composition in order to prevent diseases or conditions is normally 1 mg to 100 mg per kg body weight per day.
  • the dosage may be administered once or twice daily for a period starting 1 week before the exposure to the disease until 4 weeks after the exposure.
  • compositions adapted for rectal use for preventing diseases a somewhat higher amount of the compound is usually preferred, i.e. from approximately 1 mg to 100 mg per kg body weight per day.
  • a dose of about 0.1 mg to about 100 mg per kg body weight per day is convenient.
  • a dose of about 0.1 mg to about 20 mg per kg body weight per day administered for 1 day to 3 months is convenient.
  • a dose of about 0.1 mg to about 50 mg per kg body weight per day is usually preferable.
  • a solution in an aqueous medium of 0.5- 2% or more of the active ingredients may be employed.
  • a dose of about 1 mg to about 5 g administered 1-10 times daily for 1 week to 12 months is usually preferable.
  • the compound of the general formula (I) or (W) is used therapeutically in combination with one or more other chemotherapeutic agents.
  • chemotherapeutic agents are those selected from daunorubicin, docetaxel, prednisone, dexamethasone, decadron, altretamine, amifostine, aminoglutethimide, dactinomycin, anastrozole, asparaginase, bicalutamide, bleomycin, busulfan, carboplatin, carmustine, chlorambucil, chlorodeoxyadenosine, cisplatin, cytosine arabinoside, dacarbazine, doxorubicin, epirubicin, estramustine, diethylstilbestrol, fludarabine, flutamide, 5-fluorouracil, gemcitabine, goserelin, idarubicin, irinotecan, levamisole, lomustine, me
  • the medicament may further comprise one or more other chemotherapeutic agents.
  • MS was performed using an LC-MS using a Bruker Esquire 3000+ ESI Iontrap with an Agilent 1200 HPLC-system . Melting points are uncorrected .
  • the organic solvents used were anhydrous.
  • the reaction was exothermic and it was controlled by the addition rate; the internal temperature was kept below -1O 0 C.
  • the reaction mixture was stirred for approx. Ih (control by TLC, CH 2 CI 2 -EtOH, 10: 0.5), 0.5M aq. KH 2 PO 4 (8 ml) was added, and the mixture was allowed to warm to room temperature.
  • the mixture was extracted three times with EtOAc.
  • the combined organic phase was washed with H 2 O and brine, dried over Na 2 SO 4 , and concentrated.
  • the product was purified by column chromatography using system CH 2 CI 2 -EtOH (100:0.5) to afford the benzyl protected phosphate ester.
  • Example 1 4-(3-cyclohexyl-6,7-difluoro-2-oxoindolin-3-yQphenyl dihvdroqen phosphate (compound 1001).
  • Example 5 4-(3-cvclohexyl-6,7-difluoro-2-oxoindolin-3-vhphenyl sulfate (compound 1005).
  • Example 7 4-(3-cvclohexyl-6.7-difluoro-2-oxoindolin-3-v ⁇ phenyl 2,2- dichloroacetate (compound 1007).
  • Example 9 4-(3-cvdoheptyl-6-fluoro-7-methyl-2-oxoindolin-3-vQphenyl dimethylcarbamate (compound 1009).
  • Example 11 4-(3-cycloheptyl-6-methoxy-7-methyl-2-oxoindolin-3-v0phenyl morpholine-4-carboxylate (compound 1011).
  • Example 13 4-(3-cvcloheptyl-6-methoxy-7-methyl-2-oxoindolin-3-y0phenyl dihvdroqenphosphate (compound 1013 ⁇ .
  • Example 14 4-(3-cycloheptyl-6-fluoro-7-methyl-2-oxoindolin-3-yQphenyl acrylate (compound 1014).
  • Example 15 4-(3-cycloheptyl-6-fluoro-7-methyl-2-oxoindolin-3-yQphenyl 3- morpholinopropanoate (compound 1015).
  • Example 17 4-(3-cyclohexyl-6-fluoro-7-methyl-2-oxoindolin-3-yQphenyl 3- morpholinopropanoate (compound 1017).
  • Example 19 4-(3-cvclohexyl-6.7-difluoro-2-oxoindolin-3-y0phenyl 3- morpholinopropanoate (compound 1019).
  • Example 21 4-(3-cvclopentyl-6,7-difluoro-2-oxoindolin-3-v ⁇ phenyl morpholine- 4-carboxylate (compound 1021).
  • Example 23 4-(3-cyclohexyl-7-methyl-2-oxoindolin-3-y0phenyl dimethylcarbamate (compound 1023).
  • Example 25 4-(3-cycloheptyl-7-methyl-2-oxoindolin-3-yDphenyl morpholine-4- carboxylate (compound 1025 1 ).
  • Example 27 4-(6-chloro-3-cycloheptyl-7-methyl-2-oxoindolin-3-yQphenyl morpholine-4-carboxylate (compound 10271.
  • Example 29 4-(7-chloro-3-cvcloheptyl-6-methyl-2-oxoindolin-3-v ⁇ phenyl dimethylcarbamate (compound 1029).
  • Example 30 4-(7-chloro-3-cycloheptyl-6-methyl-2-oxoindolin-3-v ⁇ phenyl morpholine-4-carboxylate (compound 103C0.
  • Example 31 4-(3-cyclohexyl-2-oxo-7-(trifluoromethy0indolin-3-yQphenyl dimethylcarbamate (compound 1031).
  • Example 33 (25V4-(6.7-difluoro-2-oxo-3-(thiophen-2-y0indolin-3-y ⁇ phenyl 2- aminopropanoate hvdrochloride(compound 1033).

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Abstract

La présente invention concerne de nouveaux promédicaments de composés de 3-(4-hydroxyphényl)-indolin-2-ones substitués (composés oxindoles), et l'utilisation de tels composés pour l'élaboration d'un médicament destiné au traitement du cancer chez un mammifère. Ces composés de promédicaments sont représentés par la formule (I).
PCT/EP2010/054000 2009-03-26 2010-03-26 Promédicaments de 3-(4-hydroxyphényl)-indolin-2-ones substitués Ceased WO2010109008A1 (fr)

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US11046647B2 (en) 2018-07-03 2021-06-29 The Board Of Trustees Of The University Of Illinois Activators of the unfolded protein response
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US1624675A (en) 1927-04-12 O-o-diacyl derivatives of diphenolisatine and process for the manu
DE2451592A1 (de) 1973-11-28 1975-06-05 Esteve Labor Dr Neue aether und ester des 3,3-diphenol2-indolinons und verfahren zu ihrer herstellung
DE2521966A1 (de) 1974-05-18 1975-11-27 Andreu Sa Dr 3,3-bis-(4-hydroxyphenyl)-2-indolinon- derivate und verfahren zu deren herstellung
JPH06114510A (ja) 1992-10-05 1994-04-26 Nisshin Steel Co Ltd 非金属介在物の混入を抑制した連続注湯方法及び装置
US20040242563A1 (en) 1997-11-20 2004-12-02 Children's Medical Center Corporation Substituted diphenyl indanone, indane and indole compounds and analogues thereof useful for the treatment or prevention of diseases characterized by abnormal cell proliferation
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CN115490673B (zh) * 2022-01-11 2024-10-15 苏州浦合医药科技有限公司 3,3-二取代吲哚酮类化合物及其用途

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