WO2009127815A1 - Aminoallylimidazotétrazines pour le traitement de cancers - Google Patents

Aminoallylimidazotétrazines pour le traitement de cancers Download PDF

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Publication number
WO2009127815A1
WO2009127815A1 PCT/GB2009/000957 GB2009000957W WO2009127815A1 WO 2009127815 A1 WO2009127815 A1 WO 2009127815A1 GB 2009000957 W GB2009000957 W GB 2009000957W WO 2009127815 A1 WO2009127815 A1 WO 2009127815A1
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compound
hydrogen
halogen
cyano
hydrocarbyl
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PCT/GB2009/000957
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English (en)
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Richard Thomas Wheelhouse
Dimitrios Pletsas
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The University Of Bradford
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Publication of WO2009127815A1 publication Critical patent/WO2009127815A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • 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 compounds, in particular imidazotetrazines, useful in the treatment of cancer.
  • Mitzolomide a member of the N(3) substituted family of 8-carbamoylimidazo[5,l-d]- [1,2,3,5] tetrazin-4(3H)-ones, had curative activity against murine tumour models but it proved unpredictably myelosuppressive in humans so was replaced by the less toxic analogue Temozolomide.
  • the range of tumours that can be treated with Temozolomide is strictly limited, some tumours are tolerant of the drug and others are actively resistant.
  • Temozolomide (Temodal®, Temodar®) is currently licensed for the treatment of malignant melanoma and glioma.
  • Temozolomide is a DNA methylating agent and clinical response depends on two major DNA repair systems. Susceptibility to the drug depends on the presence of active mismatch repair (MMR). Without this a cell line is not susceptible to the drug so the tumour cannot respond to the drug. A low level of MMR is notably characteristic of certain tumours including colon, ovarian and bladder tumours. There is a need for new DNA modifying agents whose therapeutic effect is independent of active MMR in the tumour cells.
  • MMR active mismatch repair
  • MGMT O6-alkylguanine-DNA alkyltransferase
  • the present inventors have prepared DNA alkylating agents whose activity is independent of the MMR and MGMT status of the cell lines without the use of an adjuvant. Such agents can be used to treat those tumours that were previously either not susceptible to DNA methylating agents or which were actively resistant to them.
  • R and R 1 are each independently selected from hydrogen or R 12 ; or R and R 1 taken together with the atoms to which they are attached form a carbocycle or a heterocycle, optionally substituted with one or more R 12 ;
  • A is selected from N, O or S;
  • X is selected from the group consisting of hydrogen, halogen, halide, and hydrocarbyl optionally substituted with R 12 ;
  • Y which may be absent, is selected from the group consisting of hydrogen, halogen, halide and hydrocarbyl optionally substituted with R 12 ,
  • R 13 and R 14 are each independently selected from hydrogen or R 15 ; wherein R 15 is selected from hydrocarbyl and -(CH 2 ) q -heterocyclyl, and each R 15 is optionally and independently substituted with one or more of halogen, cyano, amino, hydroxy, C 1-6 alkyl and C 1-6 alkoxy;
  • the compounds of the invention can exist in different forms, such as free acids, free bases, esters and other prodrugs, salts and tautomers, for example, and the invention includes all variant forms of the compounds.
  • hydrocarbyl as used herein includes reference to moieties consisting exclusively of hydrogen and carbon atoms; such a moiety may comprise an aliphatic and/or an aromatic moiety. The moiety may comprise 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms.
  • hydrocarbyl groups include Ci -6 alkyl (e.g. Ci, C 2 , C 3 or C 4 alkyl, for example methyl, ethyl, propyl, isopropyl, n- butyl, sec-butyl or tert-butyl); Ci -6 alkyl substituted by aryl (e.g.
  • benzyl or by cycloalkyl (e.g. cyclopropylmethyl); cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl); alkenyl (e.g. 2-butenyl); alkynyl (e.g. 2-butynyl); aryl (e.g. phenyl, naphthyl or fluorenyl) and the like.
  • cycloalkyl e.g. cyclopropylmethyl
  • cycloalkyl e.g. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl
  • alkenyl e.g. 2-butenyl
  • alkynyl e.g. 2-butynyl
  • aryl e.g. phenyl, naphthyl or fluorenyl
  • alkyl and C 1-6 alkyl as used herein include reference to a straight or branched chain alkyl moiety having 1, 2, 3, 4, 5 or 6 carbon atoms. This term includes reference to groups such as methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl or tert-butyl), pentyl, hexyl and the like. In particular, alkyl may have 1, 2, 3 or 4 carbon atoms. Alkenyl
  • alkenyl and C 2 -6 alkenyl as used herein include reference to a straight or branched chain alkyl moiety having 2, 3, 4, 5 or 6 carbon atoms and having, in addition, at least one double bond, of either E or Z stereochemistry where applicable. This term includes reference to groups such as ethenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3- ⁇ entenyl, 1-hexenyl, 2-hexenyl and 3-hexenyl and the like.
  • alkynyl and C 2-6 alkynyl as used herein include reference to a straight or branched chain alkyl moiety having 2, 3, 4, 5 or 6 carbon atoms and having, in addition, at least one triple bond. This term includes reference to groups such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 1- hexynyl, 2-hexynyl and 3-hexynyl and the like.
  • alkoxy and C 1-6 alkoxy as used herein include reference to -O-alkyl, wherein alkyl is straight or branched chain and comprises 1, 2, 3, 4, 5 or 6 carbon atoms. In one class of embodiments, alkoxy has 1 , 2, 3 or 4 carbon atoms. This term includes reference to groups such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentoxy, hexoxy and the like.
  • cycloalkyl as used herein includes reference to an alicyclic moiety having 3, 4,
  • the group may be a bridged or polycyclic ring system. More often cycloalkyl groups are monocyclic. This term includes reference to groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, bicyclo[2.2.2]octyl and the like.
  • aryl as used herein includes reference to an aromatic ring system comprising
  • Aryl is often phenyl but may be a polycyclic ring system, having two or more rings, at least one of which is aromatic. This term includes reference to groups such as phenyl, naphthyl, fluorenyl, azulenyl, indenyl, anthryl and the like.
  • aryl includes heteroaryl.
  • carbocyclyl as used herein includes reference to a saturated (e.g. cycloalkyl) or unsaturated (e.g. aryl) ring moiety having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 carbon ring atoms.
  • carbocyclyl includes a 3- to 10-membered ring or ring system and, in particular, a 5- or 6-membered ring, which may be saturated or unsaturated.
  • a carbocyclic moiety is, for example, selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, bicyclo[2.2.2]octyl, phenyl, naphthyl, fluorenyl, azulenyl, indenyl, anthryl and the like.
  • heterocyclyl as used herein includes reference to a saturated (e.g. heterocycloalkyl) or unsaturated (e.g. heteroaryl) heterocyclic ring moiety having from 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 ring atoms, at least one of which is selected from nitrogen, oxygen, phosphorus, silicon and sulphur.
  • heterocyclyl includes a 3- to 10-membered ring or ring system and more particularly a 5- or 6-or 7- membered ring, which may be saturated or unsaturated.
  • a heterocyclic moiety is, for example, selected from oxiranyl, azirinyl, 1 ,2-oxathiolanyl, imidazolyl, thienyl, furyl, tetrahydrofuryl, pyranyl, thiopyranyl, thianthrenyl, isoben- zofuranyl, benzofuranyl, chromenyl, 2H-pyrrolyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolidinyl, benzimidazolyl, pyrazolyl, pyrazinyl, pyrazolidinyl, thiazolyl, isothiazolyl, dithiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, piperidyl, piperazinyl, pyridazinyl, mo ⁇ holin
  • heterocycloalkyl as used herein includes reference to a saturated heterocyclic moiety having 3, 4, 5, 6 or 7 ring carbon atoms and 1, 2, 3, 4 or 5 ring heteroatoms selected from nitrogen, oxygen, phosphorus and sulphur.
  • the group may be a polycyclic ring system but more often is monocyclic.
  • This term includes reference to groups such as azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, oxiranyl, pyrazolidinyl, imidazolyl, indolizidinyl, piperazinyl, thiazolidinyl, morpholinyl, thiomorpholinyl, quinolinidinyl and the like.
  • heteroaryl as used herein includes reference to an aromatic heterocyclic ring system having 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 ring atoms, at least one of which is selected from nitrogen, oxygen and sulphur.
  • the group may be a polycyclic ring system, having two or more rings, at least one of which is aromatic, but is more often monocyclic.
  • This term includes reference to groups such as pyrimidinyl, furanyl, benzo[b]thiophenyl, thiophenyl, pyrrolyl, imidazolyl, pyrrolidinyl, pyridinyl, benzo[b]furanyl, pyrazinyl, purinyl, indolyl, benzimidazolyl, quinolinyl, phenothiazinyl, triazinyl, phthalazinyl, 2H- chromenyl, oxazolyl, isoxazolyl, thiazolyl, isoindolyl, indazolyl, purinyl, isoquinolinyl, quinazolinyl, pteridinyl and the like.
  • halogen as used herein includes reference to F, Cl, Br or I. In particular, halogen may be F or Cl.
  • halide refers to a moiety containing a halogen as the anion. Examples include a hydrogen halide such as HBr and HI.
  • substituted as used herein in reference to a moiety means that one or more, especially up to 5, more especially 1, 2 or 3, of the hydrogen atoms in said moiety are replaced independently of each other by the corresponding number of the described substituents.
  • optionally substituted as used herein means substituted or unsubstituted.
  • amino or hydroxy groups with free hydrogen may be unstable if bound to carbon atoms with unsaturated (e.g. olefinic) bonds.
  • substituents described herein may themselves be substituted by any substituent, subject to the aforementioned restriction to appropriate substitutions as recognised by the skilled man.
  • X may be cyclohydrocarbyl, for example aryl or heteroaryl, optionally substituted with R 12 .
  • X is aryl, for example phenyl, optionally substituted with R 12 .
  • X is preferably a group
  • R 18 is selected from hydrocarbyl and -(CH 2 ) r -heterocyclyl, and each R 18 is optionally and independently substituted with one or more of halogen, cyano, amino, hydroxy, C 1-6 alkyl and Cj -6 alkoxy;
  • r is 0, 1, 2, 3, 4, 5 or 6.
  • D and/or E and/or J and/or K and/or L are hydrogen. In a preferred embodiment of the invention D, E, J, K and L are all hydrogen.
  • D or E is nitro
  • J or K is an amine or an amide.
  • examples include amide, thioamide and sulphonamide.
  • L is an electron withdrawing group.
  • L may be selected from groups comprising fluorine, cyano and nitro.
  • L may be selected from nitro, fluorine atoms, fluoroalkyl, fluoroaryl and fluoroheteroaryl. In an embodiment of the invention L is nitro.
  • D or E and/or L are independently selected from electron rich groups including amino, sulfide, hydroxyl, alkoxy or hydrocarbyl for example alkyl (e.g. C 1-6 alkyl).
  • D or E and/or L may be selected -OR 16 , -C(O)R 16 , -C(O)OR 16 , -OC(O)R 16 , -S(O) 1 R 16 , - N(R 16 )R 17 , -C(O)N(R 16 )R 17 , -SO 2 N(R 16 )R 17 and R 18 .
  • L is an electron rich group for example amino, sulfide, hydroxyl, alkoxy or hydrocarbyl for example alkyl (e.g. C 1-6 alkyl such as methyl).
  • R and R 1 taken together with the atoms to which they are attached form a heterocycle, optionally substituted with one or more R 12 .
  • the heterocycle may be a five membered heterocycle containing from 1 to 5 heteroatoms independently selected from N, S or O wherein each substitutable carbon or heteroatom in the heterocycle is optionally and independently substituted by one or more R 12 .
  • the heterocycle is a five membered heterocycle containing from 1 to 2 N atoms wherein each substitutable carbon or N in the heterocycle is optionally and independently substituted by one or more R 12 .
  • the compound is of formula (H)
  • R 19 and R 20 are each independently selected from hydrogen or R 21 ;
  • R 21 is selected from hydrocarbyl and -(CH 2 ) t -heterocyclyl, and each R 21 is optionally and independently substituted with one or more of halogen, cyano, amino, hydroxy, C 1-6 alkyl and Ci -6 alkoxy;
  • the compound is of formula (lib)
  • R 19 and R 20 are each independently selected from hydrogen or R 21 ;
  • R 21 is selected from hydrocarbyl and -(CthVheterocyclyl, and each R 21 is optionally and independently substituted with one or more of halogen, cyano, amino, hydroxy, C 1-6 alkyl and Ci -6 alkoxy;
  • t 0, 1, 2, 3, 4, 5 or 6;
  • the compound is of formula II or Hb and R 4 is amide for example CONH 2 .
  • A is selected from O or S.
  • A is O.
  • Y is hydrogen, halogen, halide or an aliphatic hydrocarbyl group for example alkyl (e.g. C 1-6 alklyl).
  • Y is cylohydrocarbyl for example aryl such as heteroaryl.
  • the compound of the invention may be of formula III
  • B is selected from N, O or S;
  • R 2 and R 3 are each independently selected from hydrogen or R 22 ; or R 2 and R 3 taken together with the atoms to which they are attached form a carbocycle or a heterocycle, optionally substituted with one or more R 22 ;
  • R 23 and R 24 are each independently selected from hydrogen or R 25 ;
  • R 25 is selected from hydrocarbyl and -(CH 2 ) u -heterocyclyl, and each R 25 is optionally and independently substituted with one or more of halogen, cyano, amino, hydroxy, Ci -6 alkyl and C 1-6 alkoxy;
  • a and B are independently selected from O or S.
  • a and B are O.
  • n is 1, 2 or 3 for example 1.
  • n is 1 and m is 1.
  • R and R and/or R and R taken together with the atoms to which they are attached form a heterocycle, optionally substituted with one or more R 12 .
  • the heterocycle may be a five membered heterocycle containing from 1 to 5 heteroatoms independently selected from N, S or O wherein each substitutable carbon or heteroatom in the heterocycle is optionally and independently substituted by one or more R 12 .
  • the invention provides a compound of formula (IV)
  • R 4 , A, B, X, n and m are as defined herein;
  • R is selected from hydrocarbyl and -(CH 2 ) u -heterocyclyl, and each R is optionally and independently substituted with one or more of halogen, cyano, amino, hydroxy, C 1-6 alkyl and C 1 ⁇ alkoxy;
  • u is O, 1, 2, 3, 4, 5 or 6;
  • the compound is an anilinoethyl imidazotetrazine.
  • the compound is an anilino (e.g. diethylanilino) linked bis imidazotetrazine.
  • anilino e.g. diethylanilino
  • Compounds of the invention may exist in different forms, such as free acids, free bases, esters and other prodrugs, salts and tautomers, for example, and the disclosure includes all variant forms of the compounds.
  • packages which include a description or instructions which indicate that the package contains a species or pharmaceutical formulation of the invention and a product which is or comprises, or purports to be or comprise, such a formulation or species.
  • packages may be, but are not necessarily, counterfeit or fraudulent.
  • each compound may be in the form of the free compound, an acid or base addition salt, or a prodrug.
  • compounds of the invention may be in the form of pharmaceutically acceptable salts.
  • pharmaceutically acceptable includes reference to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings or animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. This term includes acceptability for both human and veterinary purposes.
  • Pharmaceutically acceptable salts can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods.
  • such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.
  • nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.
  • Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., US, 1985, p. 1418, the disclosure of which is hereby incorporated by reference; see also Stahl et al, Eds, "Handbook of Pharmaceutical Salts Properties Selection and Use", Verlag Helvetica Chimica Acta and Wiley-VCH, 2002.
  • the disclosure thus includes pharmaceutically-acceptable salts of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof, for example the conventional non-toxic salts or the quaternary ammonium salts which are formed, e.g. from inorganic or organic acids or bases.
  • acid addition salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3- phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate,
  • Base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N-methyl-D-glucamine, and salts with amino acids such as arginine, lysine, and so forth.
  • the basic nitrogen- containing groups may be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides and others.
  • lower alkyl halides such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides
  • dialkyl sulfates like dimethyl, diethyl, dibutyl
  • diamyl sulfates long chain halides
  • the invention includes prodrugs for the active pharmaceutical species of the invention, for example in which one or more functional groups are protected or derivatised but can be converted in vivo to the functional group, as in the case of esters of carboxylic acids convertible in vivo to the free acid, or in the case of protected amines, to the free amino group.
  • prodrug represents in particular compounds which are rapidly transformed in vivo to the parent compound, for example, by hydrolysis in blood.
  • Prodrugs therefore include drugs having a functional group which has been transformed into a reversible derivative thereof. Typically, such prodrugs are transformed to the active drug by hydrolysis. As examples may be mentioned the following:
  • Prodrugs also include compounds convertible to the active drug by an oxidative or reductive reaction.
  • oxidative activation e.g. N- and O- dealkylation, oxidative deamination, N-oxidation or epoxidation
  • reductive activation e.g. azo reduction, sulfoxide reduction, disulfide reduction, bioreductive alkylation or nitro reduction.
  • metabolic activations of prodrugs are nucleotide activation, phosphorylation activation and decarboxylation activation.
  • the compounds of the disclosure may also contain one or more asymmetric carbon atoms and may therefore exhibit optical and/or diastereoisomerism. All diastereoisomers may be separated using conventional techniques, e.g. chromatography or fractional crystallisation. The various stereoisomers may be isolated by separation of a racemic or other mixture of the compounds using conventional, e.g. fractional crystallisation or HPLC, techniques. Alternatively the desired optical isomers may be made by reaction of the appropriate optically active starting materials under conditions which will not cause racemisation or epimerisation, or by derivatisation, for example with a homochiral acid followed by separation of the diastereomeric derivatives by conventional means (e.g. HPLC, chromatography over silica).
  • HPLC chromatography over silica
  • Geometric isomers may also exist in the compounds of the present disclosure.
  • the present disclosure contemplates the various geometric isomers and mixtures thereof resulting from the arrangement of substituents around a carbon-carbon double bond and designates such isomers as of the Z or E configuration, wherein the term "Z” represents substituents on the same side of the carbon-carbon double bond and the term “E” represents substituents on opposite sides of the carbon-carbon double bond.
  • the disclosure therefore includes all variant forms of the defined compounds, for example any tautomer or any pharmaceutically acceptable salt, ester, acid or other variant of the defined compounds and their tautomers as well as substances which, upon administration, are capable of providing directly or indirectly a compound as defined above or providing a species which is capable of existing in equilibrium with such a compound.
  • analogous mono-functional agents 5 were also prepared; an example with an aliphatic amine 8 is also shown.
  • Reagents and conditions (i) CuCI, AcOH, ⁇ ; (ii) NH 2 NH 2 IxH 2 O / IPA, ⁇ ; (iii) NaNO 2 , AcOH, H 2 O/CH 2 CI 2 , O DC; (iv) PhMe, ⁇ , [>95%]; (v) DMSO, RT, days; (vi) TFA, CH 3 CN, O DC, 2 h.
  • Reagents and conditions (i) NH 2 NH 2 xH2O / IPA, ⁇ ; (ii) NaNO 2 , AcOH, H 2 O/CH 2 CI 2 , O 0 C; (iii) PhMe, ⁇ , [>95%]; (iv) DMSO, 30 0 C, 36 h; (vi) HBr, CH 3 CN, RT, 12 h.
  • Reagents and conditions (i) HNO 3 / H 2 SO 4 , 0-10 0 C; (ii) NH 2 (CH 2 J 2 CO 2 Me / Et 3 N / CH 3 CN, ⁇ ; (iii) NH 2 NH 2 XH 2 O / IPA, ⁇ ; (iv) NaNO 2 , AcOH, H 2 O/CH 2 CI 2 , 0 0 C; (v) PhMe, ⁇ ; (vi) 2 / DMSO, RT, 24 h; (vii) HNO 3 / H 2 SO 4 , 0-70 0 C 12 h; (viii) SOCI 2 / DME / DMF, 50 0 C, 18 h; (ix) 27 / Et 3 N / THF / 100 0 C, 12 h; (x) -20 0 C, 12 h.
  • Any mixtures of final products or intermediates obtained can be separated on the basis of the physico-chemical differences of the constituents, in a known manner, into the pure final products or intermediates, for example by chromatography, distillation, fractional crystallisation, or by the formation of a salt if appropriate or possible under the circumstances.
  • the present inventors have found that yields of the compounds of the invention can be improved by purifying the crude isocyanate prior to reacting it with 5-diazoimidazole-4- carboxamide.
  • the invention provides a process for the preparation of a compound according to the invention, the process comprising the steps of
  • R' is hydrogen, C 1-6 alkyl (for example methyl) optionally substituted with NCO; and wherein X' has the same meaning as X as defined herein; (ii) contacting the product of (i) with a diazoimidazole.
  • the diazoimidazole may be S-diazoimidazole ⁇ -carboxamide.
  • R' is hydrogen or methyl
  • (i) is carried out with heating.
  • the ether extract is separated from an oily residue and then evaporated to give the product (i).
  • step (ii) is performed in the presence of a solvent such as DMSO.
  • DMSO is generally dry DMSO at room temperature.
  • Step (ii) may be carried out under nitrogen and may be carried out in the absence of light.
  • the invention provides a compound, or pharmaceutically acceptable salt or prodrug thereof, as hereinbefore described for use as a medicament.
  • the use of compounds of the invention as medicaments may be desirable over known DNA alkylating agents due, inter alia, to the former being more effective in the treatment of resistant cancers and cancers which were previously shown not to be susceptible to DNA alkylating agents.
  • a pharmaceutical formulation comprising a compound, or pharmaceutically acceptable salt or prodrug, as hereinbefore described.
  • the formulation may contain at least one additional pharmaceutically acceptable component, e.g. an excipient, diluent or carrier.
  • additional pharmaceutically acceptable component e.g. an excipient, diluent or carrier.
  • the formulation is intended for parenteral administration.
  • a pharmaceutical composition comprising a compound, or pharmaceutically acceptable salt or prodrug thereof, according to the invention.
  • a pharmaceutical composition is formulated to be compatible with its intended route of administration. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (topical), transmucosal, and rectal administration.
  • Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide.
  • the parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.
  • compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion.
  • Oral compositions generally include an inert diluent or an edible carrier.
  • the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules, e.g., gelatin capsules.
  • the tablets, pills, capsules, troches and the like can contain 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 or
  • Sterotes 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 glidant such as colloidal silicon dioxide
  • a sweetening agent such as sucrose or saccharin
  • a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
  • Actual dosage levels of active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active compound(s) that is effective to achieve the desired therapeutic response for a particular patient, compositions, and mode of administration.
  • the selected dosage level will depend upon the activity of the particular compound, the route of administration, the severity of the condition being treated and the condition and prior medical history of the patient being treated. However, it is within the skill of the art to start doses of the compound at levels lower than required for to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.
  • the compound, or pharmaceutical composition, of the invention may be used to treat cancer.
  • a compound according to the invention, or a pharmaceutically acceptable salt or prodrug thereof, for use in the treatment of cancer in a patient is provided.
  • Another aspect of the invention concerns the use of a compound according to the invention, or a pharmaceutically acceptable salt or prodrug thereof, for the manufacture of a medicament for the treatment of cancer.
  • a method to treat cancer in a subject comprising administering an effective amount of a compound according to the invention.
  • said subject is human.
  • cancer refers to cells having the capacity for autonomous growth, i.e., an abnormal state or condition characterized by rapidly proliferating cell growth.
  • the term is meant to include all types of cancerous growths or oncogenic processes, metastatic tissues or malignantly transformed . cells, tissues, or organs, irrespective of histopathologic type or stage of invasiveness.
  • cancer includes malignancies of the various organ systems, such as those affecting, for example, lung, breast, thyroid, lymphoid, gastrointestinal, and genito-urinary tract, as well as adenocarcinomas which include malignancies such as most colon cancers, renal-cell carcinoma, prostate cancer and/or testicular tumours, non-small cell carcinoma of the lung, cancer of the small intestine and cancer of the esophagus.
  • carcinoma is art recognized and refers to malignancies of epithelial or endocrine tissues including respiratory system carcinomas, gastrointestinal system carcinomas, genitourinary system carcinomas, testicular carcinomas, breast carcinomas, prostatic carcinomas, endocrine system carcinomas, and melanomas.
  • exemplary carcinomas include those forming from tissue of the cervix, ovarian, bladder, colon, skin, prostate, breast and central nervous system for example the brain.
  • a compound or composition according to the invention may be useful in the treatment of colon, prostate, ovary and skin.
  • carcinosarcoma also includes carcinosarcomas, e.g., which include malignant tumours composed of carcinomatous and sarcomatous tissues.
  • An "adenocarcinoma” refers to a carcinoma derived from glandular tissue or in which the tumor cells form recognizable glandular structures.
  • the term “sarcoma” is art recognized and refers to malignant tumors of mesenchymal derivation. Further types of cancer include leukaemia, skin, intracranial and brain cancer.
  • a pharmaceutical formulation comprising a compound of the present invention may be administered in combination, either sequentially or at a substantially similar time as a chemotherapeutic agent.
  • treatment refers to clinical intervention in an attempt to alter the natural course of the individual or cell being treated, and may be performed either for prophylaxis or during the course of clinical pathology. Desirable effects include preventing occurrence or recurrence of disease, alleviation of symptoms, diminishment of any direct or indirect pathological consequences of the disease, lowering the rate of disease progression, amelioration or palliation of the disease state, and remission or improved prognosis.
  • treatment as used herein is intended to include the treatment and prevention of the indicated conditions/disorders
  • the package defined herein may comprise more than one dosage unit, in order to provide for repeat dosing. If more than one dosage unit is present, such units may be the same, or may be different in terms of the dose of active agent composition and/or physical form.
  • FIG. 1 IC 50 values ( ⁇ M) of selected compounds against A2780 (MMR+) and A2780- cp70 (MMR-) cells in the absence (MGMT+) and presence (MGMT-) of the MGMT inactivator PaTrin2 (10 mM). All data are the means of at least three determinations. TMZ, temozolomide Ia; MTZ, mitozolomide Ib. * IC 50 >250 ⁇ M.
  • the novel compounds may be considered under three categories: Group 1, mono-functional agents 5; Group 2, bi-functional agents 6; Group 3, CB 1954 analogues 7.
  • the hot solution was decanted leaving a residue of oily imputies behind.
  • the ether was evaporated to leave pure isocyanate as pale yellow oil (v max 2260s).
  • the isocyanate (0.29g, 1.03 mmol) was mixed with diazo-IC 2 (0.3 g, 2.17 mmol, 2.1 eq) in dry DMSO (0.1 mL) under N 2 at room temperature in the absence of light for 24 h.
  • the bis-imidazotetrazine was purified by flash column chromatography eluting with CHCl 3 : AcOH (1 :1) to give imidazotetrazine 6e as a light brown solid (0.1 g, 6%): m.p. 143-144 °C.
  • the oil was diluted with toluene (100 mL) and heated under reflux for 1 h under N 2 .
  • the volatile components were removed in vacuo to give the crude isocyanate 13g as an oil.
  • Diethylether 150 mL was added and the mixture was heated with strong agitation.
  • the hot ether solution was decanted leaving an oily residue of impurities behind.
  • the ether layer was evaporated to leave pure isocyanate as pale yellow oil v max 2260s).
  • the isocyanate (0.21 g, 0.70 mmol) was mixed with diazo-IC 2 (0.19 g, 1.39 mmol, 2 eq) in dry DMSO (0.3 mL) under N 2 .
  • Ester 14e (3.7g, ll. ⁇ mmol, 1 eq) was mixed with hydrazine hydrate (5.9g, l l ⁇ mmol, 10 eq) in propan-2-ol (1OmL) for 48h at room temperature. The volatile components were removed by evaporation to leave hydrazide 15e as colourless oil (3.5 g, 95%).
  • Hydrazide 15b was obtained as a colourless oil (6.4 g, 93%).
  • Hydrazide 15f was obtained as a yellow oil (2.16 g, 97%).
  • Hydrazide 15a (0.3g, 1.6 mmol) was dissolved in a mixture of DCM (10 ml) and HCl (10 ml, 14.8%), the solution was stirred in a CaCl 2 -ice bath at 0 0 C, a solution of NaNO 2 (0.66 g, 9.6 mmol) in H 2 O (10 ml) was added gradually and the exthothermic reaction was kept at 0-5 0 C. A further amount of DCM (15ml) was added, the DCM layer separated, washed with two portions of H 2 O (20ml) dried with on MgSO 4 , then filtered. Formation of the azide 16k was confirmed by IR and 1 H NMR.
  • the DCM solution of the crude azide 16k was stirred under nitrogen at rt overnight.
  • the isocyanate formation was confirmed by IR.
  • the DCM was evaporated under reduced pressure at low temperature (an ice bath was used to lower the temperature) and the crude isocyanate 17k collected as a yellow oil (0.27 g, 90 %).
  • the crude mixture of isocyanate 17k (0.27 g, 1.22 mmol) was diluted with DMSO (1.5 ml), under nitrogen then added to a suspension of diazo-IC (0.17 g, 1.22 mmol) in DMSO (1.5 ml), the mixture was stirred at r.t protected from light for 48 h.
  • the reaction mixture was then suspended in water (30 ml) and filtered.
  • the solid on the filter was washed with copious amounts of water until the washings came through colourless, then with ether.
  • Column chromatography on silica with gradient elution with 5-20 % acetic acid in chloroform was used for the purification.
  • the imidazotetrazine 5k was then dissolved in DMF and the solution filtered, water was added the imidazotetrazine precipitated as a yellow solid which was collected by filtration, washed with copious amount of water and dried, m.p. 179-180 0 C.
  • JV-Nitroso-iV-(3-azido-3-oxopropyl)carbainic acid-/-butyl ester 30 The hydrazide 29 (1.8 g, 8.86 mmol) was suspended in a mixture of water (10 ml) and DCM (10 ml) and left to stir in an ice bath at 0 °C, HCl (5 ml, 10 M) was added gradually followed by NaNO 2 (3.67 g, 53.13 mmol) solution in water (10 ml) added dropwise, keeping the exothermic reaction at 0-5 °C.
  • the isocyanate 31 (0.80 g, 4.37 mmol) was added to a suspension of diazo-IC 2 (0.6 g, 4.37 mmol) in DMSO (1.8 ml), the mixture was stirred at 30 0 C protected from light. The reaction was complete after 36 h as monitored by 1 H NMR. Water (10 ml) was added and the mixture filtered. The residue was washed with copious amounts of water until the washings came through colourless. The solid was washed with /-propanol and left to dry on the filter.
  • Isopropyl isocyanate (0.3 g, 3.45 mmol) (Aldrich) was reacted with diazo-IC 2 (0.43 g, 3.14 mmol) in dry DMSO (1 mL) for 24 h at room temperature. The reaction mixture was quenched with water and the product purified by flash column chromatography (3% methanol/ether). The imidazotetrazine 9 was obtained as a white crystalline solid (0.35g, 55%): m.p. 129-130 °C.
  • 3-Fluorobenzamide 18 3-Fluorobenzoic acid (54.4 g, 0.39 mol) was suspended in DME (150 mL), thionyl chloride (98.4g, 0.83 mol, 2.1 eq) and DMF (1 mL). The reaction mixture was stirred at 50 °C for 18 h. The reaction was quenched with ammonia solution (35% aq., 500 g) and the volatile components were removed by evaporation. The crude solid was suspended in ethylacetate and heated under reflux for 2 h with vigorous agitation. The mixture was filtered hot to remove the inorganics and the volume was reduced to approximately 150 mL.
  • Acid 25 (26.7 g, 0.11 mol) was mixed with thionylchloride (140 g, 1.1 mol, 10 eq) and heated at 100 °C for 3 h. Volatile components were removed by evaporation and the crude residue was dissolved in tetrahydrofuran and cooled to -20 0 C. Ammonia solution (35% aq, 7Og) in tetrahydrofuran (300 mL) was added slowly keeping the temperature ⁇ 0 °C. The reaction mixture was partitioned between brine and ethylacetate. The organic layer was washed with brine, dried (MgSO 4 ) and evaporated to dryness. The resulting solid was triturated with chloroform to give amide 26 as a solid (19.1 g, 72%).
  • 3-(Methylamino)propanoate 27 was prepared by slow addition of methylamine (3.8 g, 122 mmol, 1 eq) to methylacrylate (11.6 g, 135 mmol, 1.1 eq) while keeping the temperature ⁇ -20 0 C. The mixture was allowed to stand in the freezer overnight. The mixture was evaporated to leave an oil containing methyl 3-(methylamino)propanoate in a 1 :1 mixture with dimethyl-3,3'-(methylazanediyl)dipropanoate that was used directly.
  • Fluorobenzamide 19 (0.25g, 1.36mmol, 1 eq) was mixed with 3- (methylamino)propanoate (50%, 1.2 g, 5.4 mmol, 4 eq) and triethylamine (1.1 g, 10.8 mmol, 8 eq) in CH 3 CN (25 mL) and heated at 100 °C overnight. The mixture was evaporated to dryness and the residue recrystallised from methanol :diethylether:petroleum ether (1 :2:3) to obtain aniline 20a as a yellow solid (0.32 g, 84%): m.p. 125-126 0 C.
  • Methyl 3-(5-carbamoyl-2-nkrophenylamino)propanoate 20b ⁇ - Alanine methyl ester (0.2 g, 1.09 mmol) was mixed with triethylamine (0.17 g, 1.62 mmol, 1.5 eq) in CH 3 CN (5 mL) and added to a solution of fluoroamide 19 in CH 3 CN (10 mL). The mixture was heated under reflux for 2 h. The volatile components were removed and the crude residue re-suspended in ethyl acetate (20 mL), filtered and evaporated to dryness. The crude product was recrystallised from CHaCN/ether to give ester 20b as orange crystals: m.p. 154-155.
  • Ester 20b (2.7 g, 10.1 mmol) was mixed with hydrazine hydrate (1.52 g, 30.3 mmol, 3 eq) in propan-2-ol (20 mL) and stirred at room temperature overnight. The resultant solid was collected by filtration and washed with propan-2-ol to give hydrazide 21b as a yellow solid (2.1 Ig, 78%).
  • ester 20c (2.0 g, 6.41 mmol) in tetrahydrofuran (100 mL) was added hydrazine hydrate (10.0 g, 200 mmol, 20 eq) in CH 3 CN (100 mL). The mixture was heated at 115 0 C overnight. The mixture was evaporated to an oily residue which was suspended in methanol, a solid formed that was collected by filtration and washed with methanol to give hydrazide 21c as a yellow/green solid (0.67 g, 34%): m.p. 279-280 0 C.
  • Cells were plated into 96 well culture plates at 1 x 10 3 cells per well and incubated over night at 37 0 C in a CO 2 enriched (5%) atmosphere to enable cells to adhere to the plate.
  • Culture media was removed and replaced with fresh media containing test compound concentrations ranging from 0 (controls) to a 250 ⁇ M. Following 5 days incubation at 37 0 C, cell survival was determined using the MTT assay. All compounds were dissolved in DMSO (with the exception of salt 8 which is water soluble) and the final concentration of DMSO in the culture plates was ⁇ 0.1% (v/v).
  • Patrin-2 was used as an inhibitor of MGMT and cells were incubated with test compounds in the presence or absence of 10 ⁇ M Patrin-2 as described above.
  • test compounds were incubated in the presence or absence of an NRH analogue (reduced l-(carbamoylmethyl)pyridinium-3- carboxamide,100 ⁇ M) and cell survival following continuous 5 day exposure was determined as described above.
  • temozolomide was >30-fold more potent when MGMT was inactivated whilst for the new agents, this ratio was 0.5-5-fold for the bi-functional and 1.1-2.9-fold for the mono-functional agents.
  • all compounds showed activity greater than temozolomide irrespective of the MGMT status of the cells (yellow bars and pale blue bars) showing that MMR-dependent toxicity and MGMT-mediated resistance are now only a minor determinants of the anti-tumour effect.
  • the putative CB 1954 precursors were evaluated in a test system using RTl 12 cells in the presence and absence of a synthetic analogue of the non-biogenic cofactor NRH which activates latent NQO2 in tumour cells (Knox et al, Cancer Res., 2000, 60, 4179—4186).
  • CB 1954 showed a 290-fold potentiation whilst the tetrazinone analogue 7c was 22-fold more potent against the cells with activated NQO2.

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Abstract

La présente invention concerne des imidazotétrazines de formule (I) et leur utilisation dans le traitement de cancers.
PCT/GB2009/000957 2008-04-18 2009-04-14 Aminoallylimidazotétrazines pour le traitement de cancers WO2009127815A1 (fr)

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Cited By (6)

* Cited by examiner, † Cited by third party
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US8450479B2 (en) 2007-12-18 2013-05-28 Pharminox Limited 3-substituted-4-oxo-3,4-dihydro-imidazo[5,1-d][1,2,3,5-tetrazine-8-carboxylic acid amides and their use
EP2777702A1 (fr) * 2013-03-14 2014-09-17 Hikma Pharmaceuticals Formulations pharmaceutiques stabilisées comprenant des composés antinéoplasiques
US9024018B2 (en) 2009-06-23 2015-05-05 Pharminox Limited 3-substituted-8-substituted-3H-imidazo[5,1-d][1,2,3,5]tetrazin-4-one compounds and their use
WO2020033359A1 (fr) * 2018-08-06 2020-02-13 The Board Of Trustees Of The Leland Stanford Junior University 2-arylbenzimidazoles utiles en tant qu'activateurs de ppargc1a pour le traitement de maladies neurodégénératives
US10583125B2 (en) 2014-10-14 2020-03-10 The Board Of Trustees Of The Leland Stanford Junio Method for treating neurodegenerative diseases
US10653669B2 (en) 2015-12-15 2020-05-19 The Board Of Trustees Of The Leland Stanford Junior University Method for preventing and/or treating aging-associated cognitive impairment and neuroinflammation

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Title
ARROWSMITH J ET AL: "ANTITUMOUR IMIDAZOTETRAZINES.PART 39.1 SYNTHESIS OF BIS(IMIDAZOTETRAZINE)S WITH SATURATED SPACER GROUPS", JOURNAL OF THE CHEMICAL SOCIETY, PERKIN TRANSACTIONS 1, CHEMICAL SOCIETY. LETCHWORTH, GB, vol. 24, 1 January 2000 (2000-01-01), pages 4432 - 4438, XP001069597, ISSN: 0300-922X *

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8450479B2 (en) 2007-12-18 2013-05-28 Pharminox Limited 3-substituted-4-oxo-3,4-dihydro-imidazo[5,1-d][1,2,3,5-tetrazine-8-carboxylic acid amides and their use
US9024018B2 (en) 2009-06-23 2015-05-05 Pharminox Limited 3-substituted-8-substituted-3H-imidazo[5,1-d][1,2,3,5]tetrazin-4-one compounds and their use
EP2777702A1 (fr) * 2013-03-14 2014-09-17 Hikma Pharmaceuticals Formulations pharmaceutiques stabilisées comprenant des composés antinéoplasiques
US8974811B2 (en) 2013-03-14 2015-03-10 Hikma Pharmaceuticals Stabilized pharmaceutical formulations comprising antineoplastic compounds
US9211335B2 (en) 2013-03-14 2015-12-15 Hikma Pharmaceuticals Stabilized pharmaceutical formulations comprising antineoplastic compounds
US9211336B2 (en) 2013-03-14 2015-12-15 Hikma Pharmaceuticals Antioxidant stabilized pharmaceutical formulations comprising antineoplastic compounds
US10583125B2 (en) 2014-10-14 2020-03-10 The Board Of Trustees Of The Leland Stanford Junio Method for treating neurodegenerative diseases
US10966962B2 (en) 2014-10-14 2021-04-06 The Board Of Trustees Of The Leland Stanford Junior University Method for treating neurodegenerative diseases
US10653669B2 (en) 2015-12-15 2020-05-19 The Board Of Trustees Of The Leland Stanford Junior University Method for preventing and/or treating aging-associated cognitive impairment and neuroinflammation
WO2020033359A1 (fr) * 2018-08-06 2020-02-13 The Board Of Trustees Of The Leland Stanford Junior University 2-arylbenzimidazoles utiles en tant qu'activateurs de ppargc1a pour le traitement de maladies neurodégénératives
US10851066B2 (en) 2018-08-06 2020-12-01 The Board Of Trustees Of The Leland Stanford Junior University 2-arylbenzimidazoles as PPARGC1A activators for treating neurodegenerative diseases
US11111217B2 (en) 2018-08-06 2021-09-07 The Board Of Trustees Of The Leland Stanford Junior University 2-arylbenzimidazoles as Ppargc1a activators for treating neurodegenerative diseases

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