EP2079704A2 - Composés thérapeutiques - Google Patents

Composés thérapeutiques

Info

Publication number
EP2079704A2
EP2079704A2 EP07755933A EP07755933A EP2079704A2 EP 2079704 A2 EP2079704 A2 EP 2079704A2 EP 07755933 A EP07755933 A EP 07755933A EP 07755933 A EP07755933 A EP 07755933A EP 2079704 A2 EP2079704 A2 EP 2079704A2
Authority
EP
European Patent Office
Prior art keywords
compound
independently
formula
alkoxy
group
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP07755933A
Other languages
German (de)
English (en)
Other versions
EP2079704A4 (fr
Inventor
Edmond J. Lavoie
Joseph E. Rice
Leroy F. Liu
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Rutgers State University of New Jersey
Rutgers Health
Original Assignee
Liu Leroy Fong
Rutgers State University of New Jersey
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Liu Leroy Fong, Rutgers State University of New Jersey filed Critical Liu Leroy Fong
Publication of EP2079704A2 publication Critical patent/EP2079704A2/fr
Publication of EP2079704A4 publication Critical patent/EP2079704A4/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains four or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D515/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D515/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains four or more hetero rings

Definitions

  • a diverse array of compounds including anthra ⁇ iinones, acridines, cationic porphyrins, perylenes, thidium derivatives, fluor ⁇ iones, pentacyclic acridinium salts, fluoroquinophenoxazines, and other specflsc miscellaneous polycyclic compounds, have been reported to stabilize G-qujickuplex DNA. Most of these compounds have little or no selectivity for G ⁇ iadruplex vs. duplex DNA. Telomestatin is a natural product isolated from Streptomyces anulatus
  • telomestatin was viewed as the most potent inhibitor- of telomerase. In vitro, telomestatin stabilizes G-quadruplex vs. duplex DNA in a 70:1 ratio (Kim et al, Cancer Res., 2003, 63, 3247-3256). It has been suggested that telomestatin also inhibits telomerase function in vivo, since cells treated with the natural product exhibit a cellular senescence phenotype. Like telomere dysfunction, telomestatin activates the ATM signaling pathway.
  • telomestatin While the precise mechanism by which telomestatin interacts with a G-quadruplex has not been definitively elucidated, telomestatin does suppress the plating efficiency of K62 leukemia cells but has a much lesser effect on burst-forming units - erythrocyte (BFU-E) and colony-forming units - granulocyte/macrophage (CFU- GM) from natural bone marrow CD34-positive cells (Tauchi et al., Oncogene, 2003, 22, 5338-5347).
  • BFU-E burst-forming units - erythrocyte
  • CFU- GM colony-forming units - granulocyte/macrophage
  • telomestatin The anticancer potential of telomestatin resides in its telomerase inhibitory activity (IC50 5 nM) and in its ability to enhance apoptosis.
  • Telomestatin has been evaluated for cytotoxicity in the human neuroblastoma cell lines SK-N-AS 5 LAN5, WAC2, and LANl with IC 50 values of 0.8, 2.5, 3.2, and 4.0 ⁇ M respectively (Binz et al, Eur. J. Cancer, 2005, 41, 2873-2881) and in the human pancreatic carcinoma MiaPaCa with an IC5 0 value of 0.5 ⁇ M (Liu et at., Nucleosides, Nucleotides, and Nucleic Acids, 2005, 24, 1801-1815).
  • Such agents may have improved binding affinity for G-quadruplex DNA and/or they may have advantageous drug-like properties.
  • the present invention provides compounds that stabalize G-quadruplex DNA and that possess anti-cancer properties. Accordingly there is provided a compound of the invention which is compound of formula I:
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable diluent or carrier.
  • the invention provides a therapeutic method for treating cancer comprising administering to a mammal (e.g., a human male or female) in need of such therapy, an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof.
  • a mammal e.g., a human male or female
  • the invention provides a compound of formula I or a pharmaceutically acceptable salt thereof for use in medical therapy (e.g., for use in treating cancer), as well as the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament useful for the treatment of cancer in a mammal, such as a human.
  • the invention also provides processes and intermediated disclosed herein
  • halo is fluoro, chloro, bromo, or iodo.
  • Alkyl, alkoxy, etc. denote both straight and branched groups; but reference to an individual radical such as propyl embraces • only the straight chain radical, a branched chain isomer such as isopropyl being specifically referred to.
  • Aryl denotes a phenyl radical or an ortho-fused bicyclic carbocyclic radical having about nine to ten ring atoms in which at least one ring is aromatic.
  • (Ci-Ce)alkyl can be methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec-butyl, pentyl, 3-pentyl, or hexyl;
  • (Ci-Ce)alkoxy can be methoxy, ethoxy, propoxy, isopropoxy, butoxy, iso-butoxy, sec-butoxy, pentoxy, 3- pentoxy, or hexyloxy; and aryl can be phenyl, indenyl, or naphthyl.
  • a specific group of compounds are compounds wherein A and D are each independently a group of the following formula:
  • a specific value for X is O.
  • a specific value for the bond represented by is a double bond.
  • Ra is H, methyl, isopropyl, 2-methylpropyl, benzyl, 3- (N,N-dime1hylammo)propyl, or 4-(NJV-dimethylamino)butyl.
  • a specific group of compounds are compounds wherein A, B, and D are each independently a group of the following formula:
  • a specific group of compounds are compounds wherein A, B, D 5 and E are each independently a group of the following formula:
  • R ⁇ , R 2 , R 3 , R 4 , and R 5 is independently H or (Ci- C 6 )alkyl that is substituted with OH, (Ci-C 6 )alkoxy, (Ci-C 6 )alkylthio, aryl, NR 0 Rd,
  • a specific group of compounds are compounds wherein each B and E is independently a group of the formula:
  • a specific value for Z is N.
  • a specific value for Z is CH.
  • a specific group of compounds are compounds wherein each A, B. D, and E is independently " a group of the formula:
  • a specific group of compounds are compounds wherein A and D are each independently a group of the following formula:
  • a specific group of compounds are compounds wherein A and D are each independently a group of the following formula:
  • a specific compound of the invention is a compound of formula (II):
  • This series of compounds can be prepared by using intermediates comprised of alternating oxazole and amino acid units as outlined in Scheme 1. Initially, cyclic tetraoxazole intermediates are synthesized from which further interconnected oxazole rings can be generated.
  • Such intermediates can be prepared by condensation of the N-Boc derivatives of amino acids such as valine, leucine, alanine or an appropriately substituted ⁇ -amino acid (assuming that appropriate protecting groups are employed) and an O-protected serine methyl ester employing either l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) in the presence of 1-hydroxybenzotriazole (HOBt) and base, or benzorriazol-l-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) with triethylamine.
  • EDC l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
  • HOBt 1-hydroxybenzotriazole
  • BOP benzorriazol-l-yloxytris(dimethylamino)phosphonium hexaflu
  • Cyclodehydration can be achieved using (diethylamino)sulfur trifluoride (DAST) giving the corresponding oxazolines 102.
  • Dehydrogenation to the oxazole derivatives 103 can be performed using brornotrichloromethane in the presence of 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU).
  • DBU 1,8- diazabicyclo[5.4.0]undec-7-ene
  • One portion of each of the oxazoles can then be hydrolyzed to carboxylic acids 104 using lithium hydroxide in aqueous methanol or THF. Another portion can be treated with equal amounts of trifluoroacetic acid (TFA) in methylene chloride to afford the deprotected amines 105.
  • TFA trifluoroacetic acid
  • Oxazoles having a free amino group, such as 105 can be coupled with others having a 4-carboxylic acid moiety, such as 104, using BOP to provide the key structural intermediate 106 possessing two oxazole rings separated by an ⁇ - amino acid residue. Again, portions of these intermediates can be treated with either LiOH to give the 4'-carboxylic acid derivatives 107 or with TFA to give the unprotected amino derivatives 108. Coupling of 107 and 108 with BOP will provide 109, which can be deprotected sequentially with TFA, and then LiOH to provide 110.
  • Macrocyclization of 110 can be achieved using BOP in the presence of diisopropylethylamine (DIPEA) in DMF/acetonitrile (7:1) under high dilution (0.007M) conditions to yield the appropriately substituted tetra-oxazole, 111.
  • DIPEA diisopropylethylamine
  • Hexa-oxazole compounds can be prepared from tetra-oxazoles where two of the R-substituents consist of a hydroxymethyl group as outlined in Scheme 2.
  • the hydroxyl group in such instances can be protected by the formation of tert- butyldiphenylsilyl (TBDPS) ethers as represented by the specific intermediate Ilia.
  • TDPS tert- butyldiphenylsilyl
  • Methods for the preparation of 114a and 114b illustrate the general method by which one can convert such tetra-oxazoles intermediates into hexa- oxazoles. Treatment of Ilia with BDF will efficiently remove the tert- butyldiphenylsilyl (TBDPS) ethers.
  • the resulting diol 112a can then be cyclodehydrated using DAST to give the resulting bis-oxazoline 113a, which can be aromatized to 114a upon treatment with bromotrichloromethane and DBU.
  • the macrocycle 111b which is illustrated with two different silyl ether protecting groups on the hydroxymethyl groups designated as Ri and R 2 can be treated with camphorsulfonic acid (CSA) in methanol and methylene chloride to selectively remove the te/?-butyldimethylsilyl (TBS) groups to give diol 112b.
  • Treatment of 112b with DAST can provide 113b. Aromatization of the two oxazoline rings would yield 114b.
  • Macrocyclic dihydroheptaoxazoles 120 and heptaoxazoles 121 containing varied R substituents can be prepared as illustrated in Scheme 3.
  • R 4 is a benzyl ether on intermediate 108 (whose synthesis was described in Scheme 1) one has intermediate 108a, which can be hydrogenolyzed over palladium hydroxide to give its corresponding alcohol derivative.
  • Such hydroxymethyl groups upon treatment with DAST will cyclize to a dihydrooxazole which can be dehydrogenated with bromotrichloromethane to give the teroxazole 115, where R is a number of varied alpha-substituents, which have standard protecting groups as required.
  • Treatment of 115 with TFA will remove the Boc-protecting group and provide the amine 116.
  • Treatment of a mixture of 116 and 117 with BOP provides the amide 118.
  • the Boc group can then be removed with TFA, the ester hydrolyzed and the resulting compound macrocyclized using BOP to give lactam 119.
  • the TIPS group can be removed by treatment with concentrated HCl in methanol and methylene chloride to give the alcohol.
  • the alcohol can be oxidized to an aldehyde using Dess-Martin periodinate and cyclized to hepatoxazole 121 using triphenylphosphine and iodine with triethylamine.
  • Teroxazole 122 (which was prepared by fo ⁇ ning the benzyl ester from acid 117) will be treated with HF -pyridine complex to remove the TIPS group. The resulting alcohol will be oxidized with RuCI 3 ZNaIO 4 to give a carboxylic acid that will then be converted into methyl ester 123. A portion of 123 will be treated with TFA to remove the Boc group to give amine 124. Another portion of 123 will be converted into carboxylic acid 125 by selective hydro genolysis of the benzyl ester. Coupling of 124 and 125 will give amide 126.
  • alkyl side chains possessing basic functional groups may stabilize the interaction between the substrate and the G-quadruplex structure by providing for hydrogen bonding with the phosphate backbone.
  • the presence of these substituents should also improve water solubility by providing a handle for salt formation. Two such groups on non-adjacent oxazole rings may magnify the binding affinity for G-quadruplex relative to duplex DNA.
  • Similar methodology can be used to prepare macrocyclic hexa-, hepta- or octaoxazoles having one or two ⁇ -aminoalkyl chains in which the amine is substituted with H, alkyl, acetyl, or Boc groups.
  • bromomethyl derivative 136 Treatment with bromine and CsF at low temperature, followed by a quench with excess cyclohexene to prevent ring bromination is expected to give bromomethyl derivative 136 directly.
  • An alternative preparation of 136 from methyl derivative 130 is possible by treatment with N-bromosuccinimide and a free-radical initiator in a non-protic solvent, conditions under which the dithiane is stable. Stille coupling of 136 with l-(N 5 N-dimethylamino)methyltributylstannane will lead to bisoxazole 137. This will be elaborated into teroxazole 138.
  • Amide 139 will be oxidized to an aldehyde and converted into ⁇ - hydroxysilane 140 as described above. Oxidation to the ketone and cyclodehydration using WipFs procedure will furnish teroxazole 141. Bromodesilylation and Stille coupling, as detailed previously, followed by ester hydrolysis will give 142.
  • Section B Methods to Convert a Hexa- or Hepta- Oxazole MacroHde into a Hepta- or Octa Oxazole, which Possesses a 4-[2-(N-N-
  • Macrocycle 125 will be oxidized with Dess-Martin periodinane (DMP) and the resulting aldehyde reacted chemoselectively with (trimethylsilyl)methyl- titaniumtriisopropoxide to give alcohol 143.
  • DMP Dess-Martin periodinane
  • a second Dess-Martin oxidation followed by treatment with triphenylphosphine and iodine will form heptaoxazole 144.
  • Replacement of the silane with bromine, and Stille coupling with l-(N,N-dimethylamino)methyltributylstannane will furnish key intermediate 145 which will then be converted as described.
  • torands 160-162 can be prepared as illustrated below. The synthesis of torands consisting of two pyridine rings are detailed. N- Cbz-O-TBDPS serine will be converted into an acid choride and then reacted with silver isocyanate followed by treatment with diazomethane to give oxazolone 146. This will be treated immediately with triflic anhydride and base to form oxazole triflate 147. This will be joined with 2,6-dibromopyridine via a Stille coupling to give intermediate 148.
  • the second oxazole coupling partner will be prepared by reaction of the zinc enolate of methyl N-Boc glycinate with 3-(N 3 N- dimethylamino)propionaldehyde.
  • Alcohol 149 will be oxidized with Dess
  • ketone 150 Condensation with phosgene in the presence of base will give oxazolone 151, which will be converted into triflate 152 using the procedure of Panek.
  • amide 156 Hydrogenolysis of the Cbz group, hydrolysis of the ester and macrolactamization with BOP will give 157.
  • Macrocyclic pentaoxazole 158 will be formed by cyclodehydration of the primary alcohol with DAST 3 dehydrogenation with bromotrichloromethane, and removal of the silyl group with TBAF.
  • Series A analogs 159, 160, and 161 are prepared from common intermediate 158. Treatment with DAST and then bromotrichloromethane and DBU -will give oxazole 159. Thiazole 160 will result from treatment of 158 with Lawesson's reagent, followed by DAST and BrCCl 3 /DBU. Dess Martin oxidation of 158 and then reaction with HMDS in the presence of TMSOTf will give imidazole 161.
  • Macrocycle 157 will serve as common intermediate to several Series A analogs such as 159, 162, and 163.
  • Treatment of 157 with TBDPSCl and then Lawesson's reagent will give a bis(thiolactam).
  • methyl 6-bromopyridine-2-carboxylate can be converted into an organozinc derivative using Rieke zinc. This can be coupled with benryloxyacetyl chloride in the presence of copper cyanide to give ketone 169. Conversion into an oxime followed by reduction will give amine 170. One can then protect the amine as a 9-fluorenylmethyl carbamate (Fmoc) followed by hydroylsis of the ester with ultimate conversion of the hydrolysis product into acid chloride 171.
  • Fmoc 9-fluorenylmethyl carbamate
  • Benzyl 6-formyl-2-pyridinecarboxylate 172 can be prepared from 2,6-pyridinedicarboxylic acid by a known three-step procedure. ' A portion of 173 will be treated briefly with morpholine to remove the Fmoc group, to give amine 174. A second portion of 173 will be hydrolyzed to acid 175. Coupling of 174 and 175 with BOP will give amide 176.
  • N- silylimine 182 derived from aldehyde 181 will attack the amide carbonyl in the presence of TMSOTf or another Lewis acid, and after N- to O- transfer of the silyl group, the electron pair from the amide nitrogen will eliminate the O-TMS group.
  • a [1,3] sigmatropic hydrogen shift will complete the imidazole synthesis, with the driving force being establishment of aromaticity in the ring.
  • Use of appropriately substituted naphthalene and isoquinoline derivatives provides a convenient route wherein R$ and R 7 or R 7 and Rg represent a benzo- fused ring in the general structure provided below for these mixed torands.
  • suitably substituted teroxazoles will be coupled using BOP or similar acylation catalyst. After protecting group removal, cyclization with BOP will give the macrocyclic hexaoxazole analogs.
  • group R' is a carboxylic acid group
  • treatment with acetic anhydride or similar dehydrating agent will provide the cyclic hydroxyheptaoxazole or its 5-oxazolone tautomer.
  • a substituent can be appended to the hydroxy group using a base such as triethylamine and an alkyl halide or alkyl sulfonate.
  • a cyclic hexaoxazole having identical groups R and R' will be prepared using methods described previously. Removal of the protecting groups will lead to the bis (carboxylic acid) derivative which will be treated with acetic anhydride or similar dehydrating agent to give the symmetrical dihydroxyoctaoxazole compound or the bis(5-oxazolone) tautomers. Substituents can be appended to the hydroxy groups using a base such as triethylamine and an alkyl halide or alkyl sulfonate. Unsymmetrical analogs can be prepared starting from teroxazoles having differently protected carboxyl groups.
  • the differentially protected dihydroxyoctaoxazole can be prepared. Selective removal of one protecting group followed by attachment of a substituent to the hydroxy group will give the monoderivatized analog. Removal of the second protecting group and attachment of a different substituent will give the unsymmetrical octaoxazole derivative.
  • R 1 R' CH 2 OH, iPr, CH 2 IPr, CH 2 Ph, CH 2 CH 2 CH 2 CH 2 NMe 2
  • a salt of a compound of formula I can be useful as an intermediate for isolating or purifying a compound of formula I.
  • administration of a compound of formula I as a pharmaceutically acceptable acid or base salt may be appropriate.
  • pharmaceutically acceptable salts are organic acid addition salts formed with acids which form a physiological acceptable anion, for example, tosylate, methanesulfonate, acetate, citrate, malonate, tartarate, succinate, benzoate, ascorbate, ⁇ -ketoglutarate, and ⁇ -glycerophosphate.
  • Suitable inorganic salts may also be formed, including hydrochloride, sulfate, nitrate, bicarbonate, and carbonate salts.
  • salts may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound such as an amine with a suitable acid affording a physiologically acceptable anion.
  • a sufficiently basic compound such as an amine
  • a suitable acid affording a physiologically acceptable anion.
  • Alkali metal (for example, sodium, potassium or lithium) or alkaline earth metal (for example calcium) salts of carboxylic acids can also be made.
  • the compounds of formula I can be formulated as pharmaceutical compositions and administered to a mammalian host, such as a human patient in a variety of forms adapted to the chosen route of administration, e.g., orally or parenterally, by intravenous, intramuscular, topical or subcutaneous routes.
  • the present compounds may be systemically administered, e.g., orally, in combination with a pharmaceutically acceptable vehicle such as an inert diluent or an assimilable edible carrier. They may be enclosed in hard or soft shell gelatin capsules, may be compressed into tablets, or may be incorporated directly with the food of the patient's diet.
  • a pharmaceutically acceptable vehicle such as an inert diluent or an assimilable edible carrier.
  • the active compound may be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
  • Such compositions and preparations should contain at least 0.1% of active compound.
  • the percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 2 to about 60% of the weight of a given unit dosage form.
  • the amount of active compound in such therapeutically useful compositions is such that an effective dosage level will be obtained.
  • the tablets, troches, pills, capsules, and the like may also contain the following: binders such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, fructose, lactose or aspartame or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring may be added.
  • a liquid carrier such as a vegetable oil or a polyethylene glycol.
  • any material used in preparing any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts employed.
  • the active compound may be incorporated into sustained-release preparations and devices.
  • the active compound may also be administered intravenously or intraperitoneally by infusion or injection.
  • Solutions of the active compound or its salts can be prepared in water, optionally mixed with a nontoxic surfactant.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • the pharmaceutical dosage forms suitable for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders comprising the active ingredient which are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes.
  • the ultimate dosage form should be sterile, fluid and stable under the conditions of manufacture and storage.
  • the liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), a vegetable oil, a nontoxic glyceryl ester, and suitable mixtures thereof.
  • the proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions or by the use of surfactants.
  • the prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, buffers or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.
  • Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filter sterilization.
  • the preferred methods of preparation are vacuum drying and the freeze drying techniques, which yield a powder of the active ingredient plus any additional desired ingredient present in the previously sterile-filtered solutions.
  • the present compounds may be applied in pure form, e.g., when they are liquids. However, it will generally be desirable to administer them to the skin as compositions or formulations, in combination with a dermatologically acceptable carrier, which may be a solid or a liquid.
  • a dermatologically acceptable carrier which may be a solid or a liquid.
  • Useful solid carriers include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina and the like.
  • Useful liquid carriers include water, alcohols or glycols or water-alcohol/glycol blends, in which the present compounds can be dissolved or dispersed at effective levels, optionally with the aid of non-toxic surfactants.
  • Adjuvants such as fragrances and additional antimicrobial agents can be added to optimize the properties for a given use.
  • the resultant liquid compositions can be applied from absorbent pads, used to impregnate bandages and other dressings, or sprayed onto the affected area using pump-type or aerosol sprayers.
  • Thickeners such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified celluloses or modified mineral materials can also be employed with liquid carriers to form spreadable pastes, gels, ointments, soaps, and the like, for application directly to the skin of the user.
  • compositions which can be used to deliver the compounds of formula I to the skin are known to the art; for example, see Jacquet et al. (U.S. Pat. No. 4,608,392), Geria (U.S. Pat. No. 4,992,478),
  • the concentration of the compound(s) of formula I in a liquid composition will be from about 0.1-25 wt-%, preferably from about 0.5-10 wt-%.
  • concentration in a semi-solid or solid composition such as a gel or a powder will be about 0.1-5 wt-%, preferably about 0.5-2.5 wt-%.
  • the amount of the compound, or an active salt or derivative thereof, required for use in treatment will vary not only with the particular salt selected but also with the route of administration, the nature of the condition being treated and the age and condition of the patient and will be ultimately at the discretion of the attendant physician or clinician.
  • a suitable dose will be in the range of from about 0.5 to about 100 mg/kg, e.g., from about 10 to about 75 mg/kg of body weight per day, such as 3 to about 50 mg per kilogram body weight of the recipient per day, preferably in the range of 6 to 90 mg/kg/day, most preferably in the range of 15 to 60 mg/kg/day.
  • the compound is conveniently administered in unit dosage form; for example, containing 5 to 1000 mg, conveniently 10 to 750 mg, most conveniently, 50 to 500 mg of active ingredient per unit dosage form.
  • the active ingredient should be administered to achieve peak plasma concentrations of the active compound of from about 0.5 to about 75 uM, preferably, about 1 to 50 ⁇ M, most preferably, about 2 to about 30 ⁇ M. This may be achieved, for example, by the intravenous injection of a 0.05 to 5% solution of the active ingredient, optionally in saline, or orally administered as a bolus containing about 1-100 mg of the active ingredient. Desirable blood levels may be maintained by continuous infusion to provide about 0.01-5.0 mg/kg/hr or by intermittent infusions containing about 0.4-15 mg/kg of the active ingredient(s).
  • the desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day.
  • the sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations; such as multiple inhalations from an insufflator or by application of a plurality of drops into the eye.
  • Compounds of the invention can also be administered in combination with other therapeutic agents, for example, other agents that are useful for the treatment of cancer. Accordingly, in one embodiment the invention also provides a composition comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, at least one other therapeutic agent, and a pharmaceutically acceptable diluent or carrier.
  • the invention also provides a kit comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, at least one other therapeutic agent, packaging material, and instructions for administering the compound of formula I or the pharmaceutically acceptable salt thereof and the other therapeutic agent or agents to an animal to treat cancer.
  • a kit comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, at least one other therapeutic agent, packaging material, and instructions for administering the compound of formula I or the pharmaceutically acceptable salt thereof and the other therapeutic agent or agents to an animal to treat cancer.
  • DNA may be determined using pharmacological models which are well known to the art, or using Test A described below.
  • Test A Stabilization of G-quadruplex DNA Analyses can be performed to determine the ability of the agents to bind and thermally stabilize the duplex, triplex, and quadruplex forms of nucleic acids. Toward this end, the UV absorbances of the nucleic acids as a function of temperature in the absence and presence of HXDV was monitored. The melting of duplex and triplex nucleic acids is generally associated with a hyperchromic shift at 260 ran (76,77), while the melting of quadruplex nucleic acids is associated with a hypochromic shift at 295 nm (26,78).
  • Test B Temperature-dependent spectrophotometry
  • AVTV Model 14DS Spectrophotometer (Aviv Biomedical, Lakewood, NJ) equipped with a thermoelectrically controlled cell holder. Quartz cells with a pathlength of 1.0 cm were used for all the absorbance studies. Temperature- dependent absorption profiles were acquired at either 260 (for duplex and triplex) or 295 (for quadruplex) nm with a 5 sec averaging time. The temperature was raised in 0.5 0 C increments, and the samples were allowed to equilibrate for 1.5 min at each temperature setting.
  • the concentrations of d(T 2 AG 3 ) 4 , 9AP, 15AP, and 21AP were 5 ⁇ M in strand (120 ⁇ M in nucleotide), while the concentration of r(UG 4 U) was 20 ⁇ M in strand (120 ⁇ M in nucleotide).
  • compound 219 concentration was 20 ⁇ M.
  • the nucleic acid concentration was 15 ⁇ M in base pair (30 ⁇ M in nucleotide) or 15 ⁇ M in base triple (45 ⁇ M in nucleotide) and the HXDV concentration, when present, was 15 ⁇ M.
  • the buffer for all the UV melting experiments contained 10 mM EPPS (pH 7.5). In addition, sufficient KCl was added to each solution to bring
  • nucleic acid solutions Prior to their use in UV melting experiments, all. nucleic acid solutions are preheated at 90 0 C for 5 min and slowly cooled to room temperature over a-period of 4 hr.
  • the antiproliferative activity of a compound of the invention may be determined using pharmacological models which are well known to the art, or using Test C described below.
  • Test C Evaluation of G-quadruplex stabilizers using the MTT assay.
  • MTT MTT-3-[4,5- dimethylthiozol-2-yl]-2,5-diphenyltetrazolium bromide (Sigma) (0.1 mg/ml). Cells were treated with MTT for 3 hrs and then dissolved in 100 ⁇ l 100% DMSO. Absorbance was measured at ODs 70 using a microplate reader (Model 3550 UV from BIO-RAD).
  • the MTT value was normalized to OD 570 of cells treated with Cellfectin alone. Stock solutions of each compound were prepared. MTT assays were performed using spectrometric analysis and 96 well plates. Representative compounds of Formula I were evaluated and were found to demonstrate antiproliferative activity in Test C. The invention will now be illustrated by the following non-limiting
  • Compound 15 A representative compound of the invention (Compound 15) was prepared as illustrated and described below.
  • N- ⁇ -Cbz-(S)-Lysine (5g, 17.85mmol) was dissolved in a mixture of THF (5OmL) and water (5OmL). To this sodium bicarbonate (3g, 35.5mmol, 2eq) and a solution OfBoC 2 O (9g, 41mmol, 2.3eq) in THF (5OmL). After stirring at room temperature overnight, the THF was removed under reduced pressure and the resulting aqueous solution was neutralized with 2N HCl. This was extracted with ethyl acetate and the combined organic layers were washed with brine. The organic layer was dried with sodium sulfate and concentrated to a clear oil.
  • IR thin film, NaCl 3336, 3068, 3014, 2981, 2937, 2866, 1693, 1525, 1455, 1392, 1366, 1250, 1170, 1061, 912, 849, 755, 698, 666 cm '1
  • TR thin film, NaCl 3349, 3069, 3034, 2981, 2953, 2866, 2249, 1705, 1666, 1519, 1455, 1439, 1392, 1366, 1337, 1249, 1174, 1060, 988, 912, 848, 777, 733, 698, 647 cm '1
  • reaction mixture turned from orange to dark brown in color and was allowed to warm to room temperature overnight. It was then poured into a solution of saturated ammonium chloride and extracted with CH 2 CI2. The organic layers were dried with sodium sulfate and concentrated to a brown oil. This was flash chromatographed on SiO 2 with 1-5% methanol/chloroform which gave the product as an amber oil weighing 7.Og, 85%.
  • ER thin film, NaCl 3337, 3167, 3069, 3034, 2975, 2952, 2866, 2250, 1705, 1585, 1523, 1455, 1439, 1392, 1366, 1325, 1249, 1170, 1111, 1044, 1002, 912, 863, 805, 733, 698, 647 cm "1
  • the TIPS oxazole 28 (3.58g, 10.47mmol) was dissolved in dry CH 2 Cl 2 (2OmL) and placed under argon. To this was added freshly distilled 2, 6-lutidine (6.ImL, 52.4mmol, 5eq) and the flask was cooled to O 0 C. Then a solution of 5 (4.68g, 10.47mmol, leq), EDC (4.02& 20.94mmol, 1.2eq) and HOBT (2.83g, 20.94mmol, 1.2eq) in CH 2 Cb (4OmL) was added. The reaction warmed to room temperature overnight and then the solvent was removed under reduced pressure.
  • valine teroxazole 200mg, 0.6mmol
  • lysine teroxazole 10 350mg, 0.6mmol
  • EDC 230mg, 1.2mmol, 2eq
  • HOBT 2.3mmol, 2eq
  • 2,6-lutidine O.lmL, 0.6mmol, lOeq
  • Boc-O-benzyl-L-serine (4.13g, 14mmol), serine methyl ester (2.18g, 14mmol) and BOP (6.19 g, 14mmol) were dissolved in CH 3 CN (40 mL). Then triethylamine (4.2mL, 30.8mmol, 2.2eq) was added. The reaction stirred overnight at room temperature. The solvent was removed and the residue was dissolved in CH 2 Ck and washed successively with brine, 2N HCl, 0.5N NaHCO 3 , water and brine. The organic extract was dried over Na 2 SO 4 and concentrated to a clear oil weighing 5.54g, 100%.
  • Oxazoline 24 (5.28g, 14mmol) in CH 2 CI 2 (2OmL) was placed under argon and cooled to 0 0 C.
  • DBU (3.2 mL, 2mmol, 1.6eq) was added dropwise and the solution turned yellow.
  • BrCCb (2.2mL, 22.4mmol) was added dropwise and the solution became brown. This warmed to room temperature overnight and then poured into saturated ammonium chloride. The aqueous layer was extracted with CH 2 Cl 2 . The organic layers were dried over Na 2 SO 4 and concentrated to a brown oil. This was flash chromatographed on SiO 2 with 15- 50% EtOAc/hexane. The product was obtained as a clear oil 3.1 Og, 59%.
  • IR thin film NaCl 3447, 3353, 3159, 3112, 2944, 2892, 2867, 2756, 2723, 2251, 1720, 1585, 1500, 1463, 1391, 1367, 1324, 1250, 1171, 1113, 1068, 998, 920, 882, 804, 766, 733. 684, 660 cm "1
  • the residue was triturated with ethanol and filtered to remove precipitated NaCl.
  • the residue was dissolved in 1OmL of methanol and half of the solution was stirred with Amberlyst A-15 resin. After stirring for 1 hour the solvent was removed and the resin was washed with methanol. The resin was then stirred with a solution of methanolic ammonia to release the product from the resin. After stirring for 2 hours the resin was filtered and the filtrate was concentrated to give 2mg of product. The other half of the methanol solution was concentrated and triturated with 30% hexane/chlorofo ⁇ n. The organic solvent was removed by pipette to give the product as a white solid weighing lOmg. Total product obtained was 12mg, 67%.
  • Compound 22 will be converted to Compound 50 by removing the protecting groups.
  • R iPr, CH 2 IPr, CH 3 , CH 2 OTBS
  • Example 8 The following illustrate representative pharmaceutical dosage forms, containing a compound of formula I ('Compound X 1 ), for therapeutic or prophylactic use in humans.

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Abstract

La présente invention concerne des composés de formule I : où A, B, D, E, R1, R2, R3, R4, R5, X et ----- prennent l'une quelconque des valeurs définies dans la présente invention, ainsi que leurs sels. Les composés sont actifs en tant que stabilisants d'ADN G-quadruplex et en tant qu'agents antiproliférants.
EP07755933A 2006-04-25 2007-04-24 Composés thérapeutiques Withdrawn EP2079704A4 (fr)

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US8093235B2 (en) 2006-04-25 2012-01-10 Rutgers, The State University Of New Jersey Macrocyclic compounds which stabilize G-Quadruplex DNA and RNA
JP2010535204A (ja) 2007-08-02 2010-11-18 ラトガーズ， ザ ステイト ユニバーシティ オブ ニュー ジャージー 治療用化合物
JP5476541B2 (ja) * 2008-06-25 2014-04-23 国立大学法人東京農工大学 テロメラーゼ阻害剤
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