WO2007058630A1 - Composes d'agregat de bis(amino)-ortho-dicarbaborane - Google Patents

Composes d'agregat de bis(amino)-ortho-dicarbaborane Download PDF

Info

Publication number
WO2007058630A1
WO2007058630A1 PCT/SG2006/000355 SG2006000355W WO2007058630A1 WO 2007058630 A1 WO2007058630 A1 WO 2007058630A1 SG 2006000355 W SG2006000355 W SG 2006000355W WO 2007058630 A1 WO2007058630 A1 WO 2007058630A1
Authority
WO
WIPO (PCT)
Prior art keywords
bis
amino
dicarbaborane
optionally substituted
group
Prior art date
Application number
PCT/SG2006/000355
Other languages
English (en)
Inventor
Yinghuai Zhu
Original Assignee
Agency For Science, Technology And Research
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 Agency For Science, Technology And Research filed Critical Agency For Science, Technology And Research
Publication of WO2007058630A1 publication Critical patent/WO2007058630A1/fr

Links

Classifications

    • 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
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds
    • C07F5/027—Organoboranes and organoborohydrides
    • 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
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/0803—Compounds with Si-C or Si-Si linkages
    • C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
    • C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring

Definitions

  • the invention relates to bis(amino)-o/t/70-dicarbaborane cluster compounds which are, for example, suitable for the treatment of cancer, for example, in boron neutron capture therapy.
  • the invention also relates to pharmaceutical compositions of such bis(amino)-orf/7o-dicarbaborane cluster compounds and various uses of such compounds.
  • a neutron capture agent is injected into the patient and is selectively taken into the malignant tissue.
  • the administration of a pharmaceutical containing the neutron capture agent is preferably direct administration into the bloodstream of the patient.
  • the treatment volume i.e., the anatomical structure to be treated
  • the technology has come to be known as boron neutron capture therapy, or BNCT.
  • BNCT Boron Neutron Capture Therapy
  • the thermal neutrons interact with the boron-IO in the compound, which has a very high capture cross-section in the thermal energy range.
  • the boron-IO is present only in the malignant cells so that boron-neutron interactions will occur only in malignant cells.
  • nonradioactive 10 B in nature 20% of elemental boron
  • thermal neutrons 0.025 eV
  • Helium-4 (alpha particles) and Lithium-7 nuclei emanate from this reaction with a range of 4 - 9 micrometers, sharing between them 2.3-2.8 MeV.
  • the main effect is due to the alpha particle, due to its longer range compared to the 7 Li nucleus.
  • the gamma radiation produced contributes very little to the local or normal tissue effect. Since these nuclei only travel a very short range (about one cellular diameter) and deposit all their energy in the tumor, thereby damage is done to the tumor cell only, while largely sparing healthy tissue (A H. Soloway, et al., Chem. Rev. 1998, 98 (No 4), 1515-1562; V. I. Bregadze, Chem. Rev. 1992, 92, 209-223; J. F. Valliant, et al, Coordination Chem. Rev., 2002, 232, 173-230).
  • boron-neutron interaction provides a high probability of cell inactivation by direct DNA damage.
  • BNCT treatment has an excellent response in a patient with head and neck cancer for whom there was no other treatment available. The treatment has been successful in improving the quality of life for patients with head and neck cancer (M. Kouri, et al., Radiotherapy and Oncology, 2004, 72, 83-85).
  • the BNCT technique requires targeting malignant tumor with a carrier of 10 B, then exposing the area to a beam of neutrons. To meet the criteria of selectivity and effectiveness, there must be a significant differential boron-10 concentration in tumor vs. normal tissues ( 10 B concentration ratio should be 5/1) and approximately 20-30 micrograms per gram of 10 B in cancer cells.
  • BSH Sodium borocaptate
  • BPA Boronophenylalanine
  • BNCT treatment kills tumor cells based on the produced higher kinetic energy of ⁇ particles. If BNCT agents are close to DNA of tumor cells, the killing effectiveness should be dramatically improved. This is based on the concept of nucleus and may constitute only about 20% of total cellular mass, if BNCT agents are confined to nuclear DNA, the absolute boron concentrations of effective killing tumor will be dramatically decreased to about 6 ⁇ g 10 B/g tissue. However, the type agents are limited by their cytotoxicity, so discovery of new DNA-binding agents remains a challenge target in BNCT research (M. F. Hawthorne; M. W. Lee, J. Neuro-Oncol., 2003, 62, 33-45). Design and synthesis of low molecular weight BNCT reagents is still urgently required.
  • the present invention refers to a bis(amino)-or#7o- dicarbaborane cluster compound according to the general formula (I)
  • A is 1 ,2-[C 2 B z H z ];
  • R 1 and R 2 may be the same or different and may be selected from the group consisting of (-C n (R 3 R 4 )Si m (R 5 R 6 )-) y NH 2 and [(-Cn(R 3 R 4 )Si m (R 5 R 6 )-) y NH 3 )] + [X ' ]; said R 1 and R 2 being each attached to a different carbon atom of A;
  • R 3 , R 4 , R 5 and R 6 may be the same or different and may be selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, cyano, nitro, OH 1 amino and halide;
  • R d is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted O-alkyl, optionally substituted N-alkyl and optionally substituted aryl; and i is an integer from 0 to 5, said R d being attached to a boron atom of A;
  • X is a pharmaceutically acceptable anion; n is an integer from 0 to 5 and m is an integer from 0 to 5, wherein at least one of n and m is 1 ; y is an integer from 1 to 5; and z is an integer from 5 to 12; with the proviso that:
  • the present invention refers to a pharmaceutical composition
  • a pharmaceutical composition comprising a bis(amino)-o/f/7O-dicarbaborane cluster compound as defined above.
  • Another embodiment of the present invention is directed to the use of a bis(amino)-orf/7o-dicarbaborane cluster compound for the manufacture of a medicament, wherein the bis(amino)-orf/?o-dicarbaborane cluster compound is of the general formula (I):
  • A is [C 2 B 2 H z ]
  • R 1 and R 2 may be the same or different and may be selected from the group consisting of (-C n (R 3 R 4 )Si m (R 5 R 6 )-) y NH 2 and [(-C n (R 3 R 4 )Si m (R 5 R 6 )-) y NH 3 )] + [X " L said R 1 and R 2 being attached to different carbon atoms of A; R 3 , R 4 , R 5 and R 6 may be the same or different and may be selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, cyano, nitro, OH, amino and halide;
  • R d is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted O-alkyl, optionally substituted N-alkyl and optionally substituted aryl; and i is an integer from 0 to 5, said R d being attached to a boron atom of A;
  • X is a pharmaceutically acceptable anion
  • n and m are an integer from 0 to 5, wherein at least one of n and m is 1 ; y is an integer from 1 to 5; and z is an integer from 5 to 12.
  • the present invention is directed to a method of preparing a bis(amino)-orf/?o-dicarbaborane cluster compound comprising: a) reacting a disubstituted acetylene compound with 2 equivalents of a protected amine compound; b) reacting the product obtained in step a) with a borane-solvent adduct; and c) reacting the product obtained in step b) with an acid.
  • the present invention refers to a method of treating cancer comprising administering to a patient in need thereof a therapeutically effective amount of a bis(amino)-orf/7O-dicarbaborane cluster compound of the general formula (I):
  • A is [C 2 B 2 HJ;
  • R 1 and R 2 may be the same or different and may be selected from the group consisting of (-C n (R 3 R 4 )Si m (R 5 R 6 )-) y NH 2 and [(-C n (R 3 R 4 )Si m (R 5 R 6 )-) y NH 3 )] + [X-], said R 1 and R 2 being attached to different carbon atoms of A;
  • R 3 , R 4 , R 5 and R 6 may be the same or different and may be selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, cyano, nitro, OH, amino and halide;
  • R d is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted . O-alkyl, optionally substituted N-alkyl and optionally substituted aryl; and i is an integer from 0 to 5, said R d being attached to a boron atom of A;
  • X is a pharmaceutically acceptable anion
  • n and m are an integer from 0 to 5, wherein at least one of n and m is 1 ;
  • y is an integer from 1 to 5; and
  • z is an integer from 5 to 12.
  • Figure 1 shows the 10 B[n, a] 7 Li reaction, which is the basis of Boron Neutron Capture Therapy.
  • Figure 2 is a schematic sketch of the interaction reaction of the thermal neutrons with the boron-IO in the compound showing the relative ranges the reaction products.
  • Figure 3 illustrates the general formula of bis(short-chain-amino)-o/f/7O- dicarbaborane hydrochlorides (I) and corresponding ⁇ /do-derivates (II).
  • Figure 4 illustrates a precursor compound according to formula (IV) used in the preparation of bis(amino)-orf/7o-dicarbaboranes according to an embodiment of the invention.
  • Figure 5 illustrates a precursor compound according to formula (VII) used in the the preparation of bis(amino)-orf/7 ⁇ -dicarbaboranes according to an embodiment of the invention.
  • Figure 6 shows an exemplary reaction scheme for the preparation of an 1 ,6-diphthaIimido-3-hexyne precursor according to an embodiment of the invention.
  • Figure 7 shows an exemplary reaction scheme for the preparation of 1 ,4- diphthalimido-(1 ,2-(dimethyl)silyl)ethyne precursor according to an embodiment of the invention.
  • Figure 8 shows an exemplary reaction scheme for precursor compounds according to formula (IV) having -Si- and -Si-C- chains used in the preparation of bis(amino)-o/t/7O-dicarbaboranes according to an embodiment of the invention.
  • Figure 9 shows a reaction scheme of the preparation of 1 ,2- bis(aminomethyl)-orf/7O-dicarbaborane according to an embodiment of the invention.
  • Figure 10 is a graph showing the survival fraction of C6 gliosarcoma cells against irradiation time at 3 MW treated with bis(aminomethyl)-ortho-carborane hydrochloride (compound Ia) (filled triangles) as an illustrative compound of the invention compared to Sodium borocaptate (circles).
  • Figure 11 is a graph showing the biodistribution of compound (Ia) in healthy animals.
  • Figure 12 shows an example of a magnetic nanoparticle that can be used with a compound according to the present invention as a BNCT agent.
  • the present invention provides new bis(amino)-orf ⁇ o-dicarbaboranes and bis(amino)-or#7o-dicarbaborane compounds, the preparation thereof and their use in pharmaceutical compositions.
  • the present invention provides a novel bis(amino)-o/t/7o-dicarbaborane cluster compound according to the general formula (I)
  • A is 1 ,2-[C 2 B 2 H 2 ];
  • R 1 and R 2 may be the same or different and may be selected from the group consisting of (-C n (R 3 R 4 )Si m (R 5 R 6 )-)NH 2 and [(-C n (R 3 R 4 )Si m (R 5 R 6 )-)NH 3 )] +
  • R 3 , R 4 , R 5 and R 6 may be the same or different and may be selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, cyano, nitro, OH, amino and halide;
  • R d is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted O-alkyl, optionally substituted N-alkyl and optionally substituted aryl; and i is an integer from 0 to 5, said R d being attached to a boron atom of A;
  • X is a pharmaceutically acceptable anion; n is an integer from 0 to 5 and m is an integer from 0 to 5, wherein at least one of n and m is 1 ; y is an integer from 1 to 5; and z is an integer from 5 to 12; with the proviso that:
  • A is a (substituted) 1 ,2-[C 2 B z H z ] carborane cluster compound.
  • Z may be an integer from 5 to 12, wherein in one embodiment A is an ortf70-1 ,2-C 2 BioHio cluster compound, "ortho" in this respect means that the two carbon atoms in the boron cluster structure are adjacent to each other.
  • A is a 1 ,2-[C 2 B z -iH z .i] ' carborane cluster anion, in particular an open-cage [nido-1 , 2-[C 2 B 2-1 H z _i] " ] anion which results by decapitation reaction of [closo-1 ,2-[C 2 B z H z ]] with an alkaline compound and further deprotonation with an organic base, as will be explained in detail below.
  • A is a 1 ,2-[C 2 B 9 Hg] " anion. The nido-derivates dissolve in water easily due to the additional negative charge in the molecule structure.
  • R 1 and R 2 may be the same or different and may be selected from the group consisting of (-C n (R 3 R 4 )Si m (R 5 R 6 )-) y NH 2 and [(-C n (R 3 R 4 )Si m (R 5 R 6 )-) y NH 3 )] + [X " ]; said R 1 and R 2 being each attached to a different carbon atom of A.
  • n is an integer from 0 to 5 and m is an integer from 0 to 5, wherein at least one of n and m is 1.
  • y is an integer from 1 to 5. In one embodiment of the present invention y is 1 or 2. It should be noted, that every possible combination of n, m and y is within the scope of the present invention. Only the compound 1 ,2-bis(aminopropyl)-o/t/7o-dicarbaborane is not included.
  • n can be 0, 1 ,or 2
  • m can be 0, 1 , 2 or 3 and y can also be 1 or 2.
  • n can 1 , 2, 4 or 5 and m and y are 0.
  • m can be 1 , 2, 3, 4 or 5 and n and y are 0.
  • R 1 and R 2 independently from each other include, but are not limited to, -CH 2 -NH 2 , -C 2 H 4 -NH 2 , -CH 2 -NH 3 + X " and -C 2 H 4 -NH 3 + X " .
  • R 1 and R 2 can independently from each other also include, but are not limited to, -SiH 2 -NH 2 , -Si 2 H 4 -NH 2 , -Si(CHs) 2 -NH 2 , -Si 2 (CHs) 4 -NH 2 , -SiH 2 - NH 3 + X " , -Si 2 H 4 -NH 3 + X " , -Si(CHs) 2 -NH 3 + X " and -Si 2 (CHs) 4 -NH 3 + .
  • R 1 and R 2 may independently from each other be -CH 2 -Si(CHs) 2 - NH 2 , -Si(CHs) 2 -CH 2 -NH 2 -CH 2 -Si(CHs) 2 -NH 3 + or -Si(CHs) 2 -CH 2 -NH 3 + .
  • R 1 can for example be -C 2 H 4 -NH 2 and R2 can for example by -CH 2 -NH 2 or -SiH 2 -NH 2 .
  • R 3 , R 4 , R 5 and R 6 may be the same or different and may be selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, cyano, nitro, OH, amino and halide.
  • suitable alkly groups include, but are not limited to, are methyl, ethyl, propyl, isopropyl, butyl and isobutyl.
  • exemplary alkynyl groups include, but are not limited to, are -C ⁇ CH and - CH 2 -C ⁇ CH.
  • aromatic groups include, but are not limited to, are benzyl, phenyl, toluenyl and naphthyl.
  • the heteroaryl may be selected from pyridyl, thienyl or the like.
  • the halide may be selected from fluoride, chloride or bromide.
  • Optionally substituted means that the respective substituent may be further substituted with an alkyl or aromatic group defined as above.
  • substituents R 3 , R 4 , R 5 and R 6 can be hydrophilic substituents, for example hydrogen, OH or amino, in order to further increase the water solubility compared to known carborane compounds.
  • R 3 , R 4 , R 5 and R 6 are all -H.
  • R d may be selected from hydrogen, optionally substituted alkyl, optionally substituted O-alkyl, optionally substituted N-alkyl and optionally substituted aryl; and i is an integer from 0 to 5.
  • the substituent R d is attached to a boron atom of A.
  • suitable alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl.
  • Exemplary aromatic groups that can be used as group R d include, but are not limited to, phenyl, toluoyl and naphthyl.
  • suitable O-alkyl groups include, but are not limited to, methoxy, ethoxy, propoxy or butoxy, whereas the N-alkyl group is selected from - NHMe, -N(Me) 2 , -N(ethyl)2 or -N(propyl)2.
  • N-alkyl substiuents may be advantageous since also they can also be protonated and thus further increase the water solubility of the compounds of the invention.
  • X can be any pharmaceutically acceptable anion in the above formula (I).
  • pharmaceutical anions include, but are not limited to, CP, Br “ , CN “ , SCN “ , OH “ , NO 2 “ , NO 3 “ , MeO “ , EtO “ , citrate, oxalate, tatrate or CH 3 COO " .
  • X is Cl " . It should be noted that the water solubility of these ammonium salts have been significantly improved compared with pristine carborane clusters.
  • a further embodiment of the present invention is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising a bis(amino)-orf/7o-dicarbaborane cluster compound as defined above, wherein the compound 1 ,2-bis(.aminopropyl)-or_ ⁇ o- dicarbaborane is also included.
  • a "pharmaceutical composition” refers to a mixture of one or more of the compounds described herein, or physiologically/pharmaceutically acceptable salts thereof, with other chemical components, such as physiologically/pharmaceutically acceptable carriers, excipients and diluents.
  • the purpose of a pharmaceutical composition is to facilitate administration of a compound to an organism.
  • the pharmaceutical composition may be used in the treatment of diseases, such as cancer, as will be explained in more detail below.
  • the pharmaceutical composition may comprise further pharmaceutically active compounds which will be useful in the treatment of the respective disease.
  • a compound of the present invention or a pharmaceutically acceptable salt thereof can be administered as such to a human patient or can be administered in pharmaceutical compositions in which the foregoing materials are mixed with suitable carriers, excipient(s) or diluents.
  • suitable carriers excipient(s) or diluents.
  • administer refers to the delivery of a compound of Formula (I) or a pharmaceutically acceptable salt thereof or of a pharmaceutical composition containing a compound of Formula (I) or a pharmaceutically acceptable salt thereof of this invention to an organism.
  • Suitable routes of administration may include, without limitation, oral, rectal, transmucosal or intestinal administration or intramuscular, subcutaneous, intramedullary, intrathecal, direct intraventricular, intravenous, intravitreal, intraperitoneal, intranasal, or intraocular injections.
  • a compound of the invention can either be administered in a systemic or also in a rather manner, for example, via injection of the compound directly into a solid tumour. This can, for example, be done using a depot or sustained release formulation or using magnetic nanoparticles as explained below (cf., also Fig. 12).
  • the compounds of the invention can be targeted to the desired site/tumour by applying an external magnetic field as described in Alexiou et al., Locoreginal Cancer Treatment with Magnetic Drug Targeting, Cancer Research, 60, 6641-6648, December 2000).
  • the present invention is also directed to use of a bis(amino)- or/ ⁇ o-dicarbaborane cluster compound for the manufacture of a medicament, wherein the bis(amino)-ortfjo-dicarbaborane cluster compound is of the general formula (I):
  • A is [C 2 B 2 H 2 ]
  • R 1 and R 2 may be the same or different and may be selected from the group consisting of (-C n (R 3 R 4 )Si m (R 5 R 6 )-) y NH 2 and [(-C n (R 3 R 4 )Si m (R 5 R 6 )-) y NH 3 )] + pq, said R 1 and R 2 being each attached to a different carbon atom of A;
  • R 3 , R 4 , R 5 and R 6 may be the same or different and may be selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, cyano, nitro, OH, amino and halide;
  • R d is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted O-alkyl, optionally substituted N-alkyl and optionally substituted aryl; and i is an integer from 0 to 5, said R d being attached to a boron atom of A;
  • X is a pharmaceutically acceptable anion
  • n and m are an integer from 0 to 5, wherein at least one of n and m is 1 ; y is an integer from 1 to 5; and z is an integer from 5 to 12.
  • the present invention is directed to the use of nido- derivatives of the bis(amino)-orf/7o-dicarbaborane cluster compound of the general formula (I).
  • a in formula (I) is 1 ,2-[C 2 Bz-I H z -i] " , in particular 1 ,2-[C 2 B 9 H 9 ]-.
  • the bis(amino)-or_/?o-dicarbaborane cluster compound can be used for the manufacture of a medicament for the treatment of various diseases.
  • the bis(amino)-o/t/7o-dicarbaborane cluster compound can be used for the manufacture of a medicament for the treatment of cancer.
  • the cancer can, for example, be malignant brain tumor, head cancer or neck cancer.
  • the bis(amino)-orf ⁇ o-dicarbaborane cluster compounds of the present invention ca be used for the treatment in conjunction with boron neutron capture therapy.
  • the boron neutron capture therapy may be carried out in a manner known to the skilled man in the art (for review see Soloway et al., "The chemistry of neutron capture therapy", Chem. Rev. 1998, 98 (No 4), 1515-1562.
  • BNCT is an experimental form of radiotherapy that utilizes a neutron beam that interacts with boron injected to a patient and that BNCT depends on the interaction of slow neutrons with boron-10 to produce alpha particles
  • patients can first be given, for example, an intravenous injection of a boron-10 tagged compound according to the present invention that preferentially binds tumor cells.
  • the neutrons are created either in a nuclear reactor or by colliding high-energy protons into a lithium target.
  • the neutrons pass through a moderator, which shapes the neutron energy spectrum suitable for BNCT treatment.
  • the neutron beam is shaped by a beam collimator.
  • the neutrons While passing through the tissue of the patient, the neutrons are slowed by collisions and become low energy thermal neutrons.
  • the thermal neutrons undergo reaction with the boron-10 nuclei, forming a compound nucleus (excited boron-11) which then promptly disintegrates to lithium-7 and an alpha particle.
  • Both the alpha particle and the lithium ion produce closely spaced ionizations in the immediate vicinity of the reaction, with a range of approximately 10 micrometres, or one cell diameter. This technique is advantageous since the radiation damage occurs over a short range and thus normal tissues can be spared.
  • there are two mechanisms for tumor selectivity since both the boron compound is made to bind to tumor cells and the neutron beam is aimed at the location of the tumor. Further methods known in the art with respect to BNCT are also applicable to the compounds of the present invention.
  • the compounds of the present invention can be used in a charged form in the therapy of, for example, cancer. Due to the disubstitution of the carborane cluster with two quaternary ammonium substituents a high charge density is present on the molecule. This leads to an improved solubility and therefore provides the chance of a better distribution in the body of the patient. Further, as it is known that amines are important DNA active constituents of biochemicals as they bind through electrostatic interactions to the DNA, the interaction of the bis(amino)orf/70-dicarbaborane compounds of the present invention with the DNA is potentially stronger than that of known monoamines.
  • the reactivity of the compounds in the boron neutron capture therapy should also be improved as the alpha particle which is built during the radiation process has to travel only a very short distance to get to destroy the tumor cell. Therefore, a more effective treatment of cancer is possible.
  • Example 2 and Figure 10 it can be taken from Example 2 and Figure 10, that the activity and effectiveness of the compounds of the present invention in BNCT is increased compared with the compounds known in the art, in particular compared to sodium borocaptate (BSH).
  • BSH sodium borocaptate
  • the dicarbaboranes of the present invention show a suitable bioavailability and biodistribution in healthy and diseased animals (cf. Example 2 and Figure 11).
  • the compounds of the present invention are readily absorbed into the bloodstream so that the respective boron concentration in the blood can be detected at an early stage in a very high amount.
  • the carbaboranes may enter into cells via a receptor mediate with a high affinity as their concentration in lung and spleen samples are high.
  • the bis(amino)-or#7o-dicarbaboranes and bis(amino)-or#7o- dicarbaboranes compounds and their n/ ⁇ fo-derivates can be used as boron neutron capture therapy agents alone or with other BNCT agents known in the art.
  • the dicarbaboranes can also be used as building blocks to constitute natural biochemicals or nanoparticles.
  • the bis(amino)-ortf7odicarbaboranes and bis(amino)-o/?/7o-dicarbaboranes compounds can be chemically or physically coupled to such biochemicals or contained or coupled to such nanoparticles.
  • the biochemicals which may be covalently or non-covalently coupled may include, but are not limited to, carbohydrates, folic acids or nucleosides. These compounds may be catabolized, i.e. that for example a nucleoside to which a dicarbaborane compound of the invention is coupled, will be integrated into DNA of a cancer cell and can selectively exercise its effect directly at the DNA of the respective cell.
  • Nanoparticles in the meaning of the present invention may be used as drug carriers.
  • the nanoparticles may be magnetic particles bearing, for example, a phosphate group or a sulfonate group being negatively charged.
  • the positively charged compounds of the present invention may then be immobilized on the nanoparticle by electrostatic interactions with negatively charged groups.
  • Those negatively charged groups can be provided by long chain compounds having, for example, a hydrophobic moiety that binds the nanoparticles surface through non covalent interaction and that has a charged moiety such as a carboxylate, sulphonate or phosphate group that is solvent exposed as illustrated in Fig. 12.
  • so obtained magnetic particles may, for example, be directly injected into the tumor tissue or into the blood stream of the patient with a pharmaceutical composition as explained above. With the aid of a magnetic source outside the body of the patient, the particles may be successfully directed to the advanced sarcomas without the associated organ toxicity. Thus, the amount of systemic distribution of the cytotoxic drug may be reduced and thus, the associated side-effects are also reduced. Further, the dosage required for a more efficient, localized targeting of the drug can also be reduced.
  • the use of nanoparticles is generally well tolerated in most of the patients treated with such a method. Examples of nanoparticles include, but are not limited to, carbon nanotubes, fullerenes, layered double hydroxides and dendrimers.
  • the compounds of the invention may also be encapsulated in polymeric nanoparticles that are suitable as dug delivery systems, as described, for example, in US patent application US 2005/0277739, the content thereof is incorporated herein by reference.
  • the bis(amino)-orf/7o-dicarbaboranes compounds of the invention can also be coordinated with transition metal centers that have pharmaceutical activity on their own, for example as anti-tumour/cancer agent (reviewed, for example, in K ⁇ pf-Maier, Complexes of metals other than platinum as antitumour agents, European Journal of Clinical Pharmacology, Vol. 47, No. 1 , 1994, 1-16 or Dyson & Sava, Metal-based antitumour drugs in the post genomic era, Dalton Trans., 2006, 1929-1933).
  • Suitable transition metal centers include, but are not limited to Pt, Gd, Ru, Co, Zn or Ga, to name only few.
  • Such transition metals can form coordination complexes with a carborane compound of the invention via the two n-terminal amino groups of the substituents R 1 and R 2 .
  • the bis(amino)-or#7O-dicarbaborane cluster compounds of the present invention can be prepared in a process comprising: a) reacting a disubstituted acetylene compound with 2 equivalents of a protected amine compound; b) reacting the product obtained in a) with a borane-solvent adduct; and c) reacting the product obtained in b) with an acid.
  • advantages of this method are the unlimited variety of attaching a short chain with a terminal amine group, for example a -CH 2 NH 2 chain or any other chain as explained above, to the borane cluster forming the bis(amino)carbaborane cluster compounds of the present invention. Further, the occurrence of decapitation reactions, nucleophilic addition reactions or elimination reactions can be avoided. Moreover, the carborane cage in a bis(amino)-orf/7O-dicarbaborane cluster compound can be decapitated in a controlled manner under the reaction conditions as given below into n/ ⁇ fo-derivates which dissolve in water easily and therefore, enhance the bioavailabilty of the compounds.
  • a disubstituted acetylene compound is reacted with 2 equivalents of a protected amine compound.
  • every disubstituted acetylene compound may be used for the purpose of the present invention.
  • the disubstituted acetylene is X- (C n (R 3 R 4 )Si m (R 5 R 6 )) y -C ⁇ C-(C n (R 3 R 4 )Si m (R 5 R 6 )) y -X, wherein
  • R 3 , R 4 , R 5 and R 6 may be the same or different and may be selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl and halide; X is Cl, Br or I; n and m are an integer from 0 to 5, wherein at least one of n and m is 1 ; and y is an integer from 1 to 5.
  • R 3 , R 4 , R 5 and R 6 may further be selected as defined above.
  • the protected amine compound is a compound which is capable of reacting with the disubstituted acetylene and wherein the nitrogen atom is further protected by substituents protecting the nitrogen atom from further reaction with other compounds.
  • the protected amine compound is of the following formula (Vl)
  • Y is a Na or K
  • R a and R b are electron withdrawing substituents and may together with 2-4 carbon atoms form a ring system.
  • R a and R b can, for example, be chosen from phthalimide potassium, phthalimide sodium, pyrryl potassium or pyrryl sodium.
  • the protected amine compound may be HN(C(O)OBu-t) 2 .
  • the reaction between the disubstituted acetylene and the protected amine compound is typically carried out in an organic solution, for example in DMF, THF or the like.
  • a precursor-compound (IV) is prepared (cf. Fig. 4).
  • the moiety E can be, for example, (-C n (R 3 R 4 )Si m (R 5 R 6 )-) wherein the substituents are as defined above.
  • Various disubstituted acetylene compounds may be used in the present invention.
  • a dihalogenoalkyne compound X-(CR 3 R 4 ) n -C ⁇ C-(CR 3 R 4 ) n -X, wherein X, R 3 , R 4 and n are as defined above is used as the disubstituted acetylene compound.
  • An illustrative example of this kind of disubstituted acetylene compound is shown in Fig. 9 (compound (Va) in Fig. 9).
  • this X-(CR 3 R 4 )n-C ⁇ €-(CR 3 R 4 ) n -X compound may further be reacted with, for example, N-halogenalkyl phthalimide.
  • the halogenalkyl includes, but is not limited to, -(CR 3 R 4 ) n -X, wherein X, R 3 , R 4 and n are as defined above.
  • An example of such a N-halogenalkyl phthalimide is given in Fig. 5, an exemplary reaction scheme can be taken from Fig. 6.
  • a suitable phthalimide is 2-chloro-1-hydroxy-N-phthalimide which is commercially available from Sigma.
  • the protected amine compound in this case may, for example, be N-chloroethyl phthalimide, N- chloropropyl phthalimide, N-chlorobutyl phthalimide or N-chloropenyl phthalimide, to name only a few possible compounds.
  • These compounds are easily available by reaction of the respective amino, for example, 1-amino-2 chloro-ethane with phthalic acid anhydride.
  • the disubstituted acetylene compound may be prepared by reaction of a disilane substituted acetylene with Cl 2 and CCI 4 .
  • the disilane substituted acetylene compound may be (H)(Si(R 5 R e )) m -C ⁇ C-(Si(R 5 R 6 )) m (H), wherein R 5 , R 6 and m are as defined above.
  • the disilane substituted acetylene can be SiH 3 -CsC-SiH 3 or SiH(CH 3 )2- C ⁇ C-SiH(CH 3 ) 2 .
  • the preparation of the disubstituted acetylene compound starts with a silane or carbosilane compound selected from X-(Si(R 5 R 6 )) m -X or X-(C(R 3 R 4 )) n (Si(R 5 R 6 )) m -X, wherein R 3 , R 4 , R 5 , R 6 , n and m are as defined above.
  • the silane or carbosilane compounds are further reacted with dilithiumacetylene to obtain the respective disubstituted acetylene compound.
  • An exemplary reaction scheme can be seen in Fig. 8.
  • disubstituted acetylene compounds include, but are not limited to, CI-(Si(CH 3 ) 2 ) 2 -C ⁇ C-(Si(CH 3 ) 2 ) 2 -CI or CI-CH 2 -Si(CH 3 ) 2 -C ⁇ C-Si(CH 3 ) 2 -CH 2 -CI.
  • Further disubstituted acetylene compounds with mixed -C-Si- chains may be prepared according to this method.
  • a borane-solvent adduct is a complex of a boran cluster having two solvent molecules attached thereon.
  • Examples of such borane-solvent adducts are BioHi 2 (MeCN) 2 and BiOHi 2 (Me 3 S) 2 .
  • a 1 ,2-bis(phthalimidomethyl)-1 ,2-dicarba- c/oso-dodecaborane (Ilia) is formed in the process b) (cf. also Fig. 9).
  • Suitable acids include, but are not limited to, mineral acids such as HCI or HBr, or glacial acid and HNO 3 and mixtures thereof. In one exemplary embodiment of the present invention a mixture of HCI and glacial acid is used.
  • the prepared bis(amino)-or_/jo-dicarbaborane salt (I) can then be subjected to a decapitation reaction by the treatment with an alkaline compound in a polar solvent, thereby forming a nido-derivative of the bis(amino)-o/t/?o-dicarbaborane.
  • a polar solvent any suitable alkaline compound can be used, example of alkaline compounds (bases) include NaOH, KOH, Csf, Et ⁇ N or piperidine, to name only a few.
  • any suitable polar solvent can be used in this process. Examples of the polar solvent include, but are not limited to, methanol, ethanol and tetrahydrofuran.
  • C6 gliosarcoma cells were incubated in subconfluent condition in standard MEM (Nissui, Tokyo, Japan) supplemented with 10% FCS, in 36°C, 5% carbondioxicide atmosphere for overnight. Aliquots of the boron samples solution (bis(aminomethyl)-ortho-carborane hydrochloride and BSH respectively) were added for 6 hrs into the Petri dishes respectively for uptaking of tumor cells in dose-dependent manners. Boron 10 concentrations in mediums was planned at 20ppm 10 B and confirmed by prompt ⁇ spectroscopy (PGA). The tumour cells were washed twice after boron loading.
  • the neutron absorbed dose (Gy) was calculated using the flux-to-dose conversion factor (9).
  • the chemical composition of the tumors was assumed to be 10.7% hydrogen, 12.1 % carbon, 2% nitrogen, 71.4% oxygen and 3.8% others (10).
  • the ⁇ -ray dose was monitored by thermoluminescent dosimeters (TLDs) attached to the tubes and ranged from 0 to 5 Sv.
  • TLDs thermoluminescent dosimeters
  • 500 cells were seeded in 6-cm Petri dishes (Corning, NY, USA) and incubated for 10 days in a humidified 37°C atmosphere of 98% air/5% carbon dioxide to allow colony formation. The colonies were fixed and stained with a 10% formaldehyde/1 % toluidine blue solution and then counted microscopically.
  • the IC 50 (moles/liter, M), i.e. the concentration that inhibited the growth of C6 gliosarcoma cells by 50% after 3 days of continuous exposure, was determined. Suspensions of 10 5 C6 cells/200 ⁇ l MEM containing 20% FCS were incubated for 3 days in 96-well culture plates with various concentrations of the samples. The damaged cells were detected at 490nm optical absorbance by aqueous one Solution Cell Proliferation Assay. The IC 50 for compound I is 7.88x10 " 3 M.
  • mice The Balb/C inbred strain of the species Mus musculus (mouse) was used as the animal model for this study. Each mouse was treatedas per guidelines of the Institutional Animal Care and Use Committee (IACUC) of the National University of Singapore (NUS). Six-weeks-old female mice, each weighing approximately 2Og at the time of administration, were used in this study.
  • the boron compound being studied was bis(aminomethyl)-orf/7O-dicarbaborane hydrochloride (compound (Ia) being synthesized according to the present invention. All the solutions were made up to a concentration of 23 mg/ml.
  • mice 200 ⁇ l of the solution containing the boron compound was each administered to 5 mice via the intra-peritoneal route, after which the mice were observed for 5 to 10 minutes for any signs of distress.
  • the mice were sacrificed after either 8, 16, 30 or 48 hours after administration.
  • the mice were anesthetized with diethyl ether, and blood was collected in heparinized syringes by cardiac puncture. Following cardiac puncture, the mice were sacrificed by cervical dislocation (while still under anesthesia), and whole organs of lungs, liver and spleen were collected.
  • Tissue distributions of compound (Ia) is shown in Figure 11. It can be taken from Fig. 11 that the compound concentration can be measured much earlier in all the organs (ca. 8 hrs) except in the blood, which shows a general decreasing trend. Thus, compound (Ia) is expected to be absorbed into the circulatory system, from which it seems to be distributed to other parts of the body. Hence, boron concentrations in the blood peak rapidly, and then decrease over time.
  • receptor-mediated absorption governs the process of cellular uptake.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des composés de bis(amino)-ortho-dicarbaboranes et de bis(amino)-ortho-dicarbaborane et les dérivés nido de ceux-ci, utiles comme agents de thérapie par capture neutronique du bore. L'invention concerne également un procédé de synthèse des agrégats de bis(amino)-ortho-dicarbaborane à partir de bis(phthalimido)acétylènes correspondants, ainsi que des compositions pharmaceutiques et l'utilisation des composés.
PCT/SG2006/000355 2005-11-17 2006-11-17 Composes d'agregat de bis(amino)-ortho-dicarbaborane WO2007058630A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US73782705P 2005-11-17 2005-11-17
US60/737,827 2005-11-17

Publications (1)

Publication Number Publication Date
WO2007058630A1 true WO2007058630A1 (fr) 2007-05-24

Family

ID=38048929

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/SG2006/000355 WO2007058630A1 (fr) 2005-11-17 2006-11-17 Composes d'agregat de bis(amino)-ortho-dicarbaborane

Country Status (1)

Country Link
WO (1) WO2007058630A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103044312A (zh) * 2012-11-26 2013-04-17 北京航空航天大学 含碳癸硼烷聚酰亚胺单体及其制备方法
CN105770898A (zh) * 2016-04-05 2016-07-20 佳木斯大学 恩诺沙星柱撑水滑石的制备方法
TWI602594B (zh) * 2014-09-17 2017-10-21 進安 陳 處理生物組織的反應物及系統
US10004805B2 (en) 2014-09-17 2018-06-26 James Chinan Chen Proton induced boron capture therapy

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3377370A (en) * 1964-06-24 1968-04-09 Olin Mathieson Bis-diorganosilylamine carboranes

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3377370A (en) * 1964-06-24 1968-04-09 Olin Mathieson Bis-diorganosilylamine carboranes

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
WU Y. ET AL.: "Synthesis, characterization and reactivity of isocyanato dicarbaboranes obtained from omicron-carborane", INORGANIC CHEMISTRY, vol. 36, 1997, pages 4753 - 4761, XP003013120 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103044312A (zh) * 2012-11-26 2013-04-17 北京航空航天大学 含碳癸硼烷聚酰亚胺单体及其制备方法
TWI602594B (zh) * 2014-09-17 2017-10-21 進安 陳 處理生物組織的反應物及系統
US10004805B2 (en) 2014-09-17 2018-06-26 James Chinan Chen Proton induced boron capture therapy
CN105770898A (zh) * 2016-04-05 2016-07-20 佳木斯大学 恩诺沙星柱撑水滑石的制备方法

Similar Documents

Publication Publication Date Title
ES2774330T3 (es) Polímero de suministro de fármaco y usos del mismo
CN108619511B (zh) 一种基于阿糖胞苷小分子前药的金属有机框架载药系统的制备方法和应用
EP1420022A1 (fr) Complexes de pyridinopentaazamacrocycle substitué à activité de superoxyde dismutase
EP0729363A1 (fr) Analogues d'hormone contenant du bore et procedes d'utilisation de ces derniers pour visualiser ou eliminer des cellules pourvues de recepteurs d'hormones
JPH06502647A (ja) 薬物供給のポルフィリン組成物と方法
RU2477161C2 (ru) Карборанилпорферины и их применение
Satapathy et al. New developments in the medicinal chemistry of carboranes
JP5053277B2 (ja) Ｂｎｃｔに有用なホウ素化合物
AU2003244843B2 (en) Conjugates of N-hydroxypropymethacrylamide-methacrylate copolymer with nuclide activation agent and/or anti-cancer compounds
US8648205B2 (en) Metal complexes of N-heterocyclic carbenes
US6017902A (en) Boron containing amino acid compounds and methods for their use
US20080182834A1 (en) Multi-Nuclear Metal Complexes Partially Encapsulated by Cucurbit[7-12]Urils
WO2007058630A1 (fr) Composes d'agregat de bis(amino)-ortho-dicarbaborane
Bregadze et al. Polyhedral boron compounds for BNCT
US8519146B2 (en) Metal complexes of N-heterocyclic carbenes as antibiotics
CA2490298A1 (fr) Conjugue de porphyrine-polyamine pour la cancerotherapie
Zhu et al. Synthesis and in vitro anti-tumor activity of carboranyl levodopa
US20080267867A1 (en) Metal Complexes of N-Heterocyclic Carbenes as Radiopharmaceuticals and Antibiotics
CN111434352B (zh) 一种具有肿瘤靶向能力的含硼药物及其制备方法和应用
WO2008018838A1 (fr) Procédé de préparation d'amas de bore polyédriques enrichis 10b
AU2010306994B2 (en) Metal complexes of N-heterocyclic carbenes
Zhu Frontiers in boron-based medicinal chemistry
JP7154528B2 (ja) ホウ素含有葉酸誘導体
Hou et al. GSH-activatable camptothecin prodrug-loaded gold nanostars coated with hyaluronic acid for targeted breast cancer therapy via multiple radiosensitization strategies
CN113318227B (zh) 一种掺硼肿瘤靶向药物及其制备方法和应用

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application
DPE1 Request for preliminary examination filed after expiration of 19th month from priority date (pct application filed from 20040101)
NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 06813135

Country of ref document: EP

Kind code of ref document: A1