KR20020032421A - Cobalamin conjugates useful as antitumor agents - Google Patents

Abstract

The present invention relates to cobalamin compounds in which neutron capture therapeutic targets (eg, boron-10 or gadolinium-157) and detectable sites are bound, as well as pharmaceutical compositions comprising such compounds and methods of using the compounds in medical diagnosis and treatment to provide.

Description

Cobalamin conjugates useful as antitumor agents

Boron neutron capture therapy is a nuclear reaction that produces helium nuclei (α-particles) and ⁷ Li nuclei when ¹⁰ B, a stable isotope, is irradiated with low energy (0.025 eV) or thermal neutrons. Based on.

Therapeutic potential of this response has been recognized by Locher 50 years ago (Locher, GL et al . , Am. J. Roentgenol. Radium Ther. , 36 , 1-13 (1936)), and Sweet is a boron neutron capture therapy (BNCT). Has been proposed for the first time in the treatment of brain tumors (Javid, M, et al. , J. Clin. Invest. , 31 , 603-610 (1952); Sweet, WH, N. Engl. J. Med. , 245 , 875-878 (1951); Sweet, WH, et al . , J. Neurosurg. , 9 , 200-209 (1952)).

Subsequently, there have been clinical trials using borax as a capture agent in Brookhaven National Laboratory, in collaboration with Sweet and other researchers at Massachusetts General Hospital (Farr, LE et al . , Am. J. Roentgenol). ., 71, 279~291 (1954) ; Godwin, JT and so on, Cancer (. Phila), 8 , 601~615 (1955)). The aim of this trial is the use of BNCT as an additive to surgery for the treatment of patients with all brain tumors, glioblastoma multiforme, which are very malignant and difficult to treat.

Another attempt was made in the early 1960s, but failed to demonstrate therapeutic effects (Farr, LC et al ., Supra ; Godwin, JT et al ., Supra ; Asbury, AK et al., J Neuropathol, Exp. Neurol. , 31 , 248-303 (1972), which showed adverse effects on normal tissues (Asbury, AK et al., Supra ). Encouraging clinical studies for the treatment of malignant gliomas by Hantanka et al. (Hatanaka, HA, J. Neurol. , 209 , 81-94 (1975); Hatanaka, H. et al., Boron Neutron Capture Therapy for Tumors , Melanoma by Chap. 25, pp. 349-378. Niigata, Japan: Nishimura Co., Ltd (1986) and Mishima et al. (Mishima, Y et al . , Lancet. , 2, 388-289 (1989)) The study for the treatment of) triggered new national and international interest in BNCT.

The therapeutic benefits of BNCT are two components or two systems consisting of ¹⁰ B and thermal neutrons, which, when combined together, can provide high linear energy transfer that can selectively destroy tumor cells without significant damage to normal tissue. energy transfer (LET) irradiation. BNCT must be transported to each tumor cell to achieve a critical amount of ¹⁰ B and a sufficient number of thermal neutrons.

The Department of Energy and the NIH have newly funded research related to BNCT for several years, and this funding has supported the increasing research of many other researchers. There is an advantage of BNCT in the field of desired compound distribution and pharmacokinetics over the use of radio-labeled antibodies for the treatment of cancer used in physiological targeting and other novel therapeutic methods such as photon activity therapy, photo-dynamic therapy.

There are many nuclides that have a high tendency to absorb low energy or thermal neutrons, and this property, referred to as neutron capture cross-sectional area (σ), is measured in half (1b = 10 ^-24 cm 2). In various nuclides with high neutron capture cross-sectional areas, ¹⁰ B is of most interest for the following reasons: (a) It has no radioactivity, is readily available, and contains about 20% of naturally occurring boron: (b) Particles released by the capture reaction [ ¹⁰ B (n, α) ⁷ Li] are very high LETs: (c) Their orbit lengths are about 1 cell radius (10-14 μm), which is theoretically sufficient for ¹⁰ The radiation effect is limited on tumor cells ingesting B and at the same time does not affect normal cells, and (d) the extensive chemistry of boron can be incorporated into a variety of different chemical structures.

⁷ Li and α-particles are the primary cleavage products of neutron capture reactions with ¹⁰ B. α-particles are relatively slow and cause closely spaced ionization phenomena that make up a very limited track of columns. They have an orbital length of about 10 μm, are high LETs, and destroy various biologically active molecules including DNA, RNA and proteins. In this reaction, there is very little cellular damage, if any, from α-particle-induced radiation damage.

^{Since the 10} B (n, α) ⁷ Li reaction produces significant biological effects when there is sufficient flow of thermal neutrons and critical amounts of ¹⁰ B localized in the pericellular, cellular, and intracellular areas, the resulting radiation produces normal tissue composition It can be very localized without damaging the element. As such, the selectivity is one of the advantages and disadvantages of BNCT at the same time, since it is necessary to transport larger amounts of boron-10 to tumor cells than normal cells.

Ideally, the boron compounds used for BNCT should have low concentrations in adjacent normal tissue and blood and at the same time high selectivity for tumor cells. Since it is desirable to limit radiation only to these cells, intracellular or optionally intranuclear localization of boron is preferred.

Chlorpromazine derivatives containing various boron have been synthesized (Nakagawa, T. et al., Chem. Pharm. Bull. (Tokyo), 24, 778-781 (1976); Alam, F. et al., Sthralenther. Onkol., 165 , 121-125 (1989)). p-boronophenylalanine is another compound studied as a potential capture agent for treating melanoma. The basis for its use is the phagocytosis of melanoma to aromatic amino acids and the continuous insertion into melanin (Ichihashi, M. et al., J. Invest. Dermatol., 78, 215-218 (1982); Mishima, Y. et al., Neutral Capture Therapy, 230-236, Niigata, Japan: Nishimura Co., Ltd. (1986)).

Tumor localization has been demonstrated by intravenous administration by means of systemic radiographs (Coderre, JA et al., Cancer Res., 48, 6313-6316 (1988)), and patients with cutaneous melanoma by perioperative injection (Mishima, Y. et al., Sthralenther. Onkol., 165, 251-254 (1989)). Stimulated by Mishima's experiments, it is possible that amino acids containing many different boron are synthesized, and a large amount can be inserted into proteins of malignant cells (Hall, IH et al., J. Pharm. Sci., 68, 685). 688 (1979)).

Another study of the selective targeting of boron to melanoma is based on the observation that thiouracil is preferably inserted into melanogenic melanoma during melanin formation (Whittacker, JR, J. Biol. Chem., 246, 6217-6226 (1971). This observation provided a stimulus to the synthesis of thiouracil containing various boron (Gabel, D., Clinical Aspects of Neutron Capture Therapy, 233-241, New York: Plenum Publishing Co. (1989)). It is evaluated in animals.

Two other classes of compounds that tend to be ubiquitous in malignant tumors are phthalocyanine associated with porphyrin. The biochemical basis for the elevated levels of these compounds into malignant tumors is unknown, but the observations provide a basis for the use of derivatives of hematopopyrine in photo-mechanical treatment of cancer (Dougherty, TJ et al. , Porphyrin Photosensitization, 3-13, New York: Plenum Publishing Corp. (1981).

High concentrations of these compounds in tumors, their intracellular ubiquity and persistence have been demonstrated as potential capturing agents for boronated polpyrine (Kahl, SB et al., Neutron Capture Therapy, 61-67, Niigata, Japan: Nishimura Co., Ltd. (1986) ) And phthalocyanine (Alam, F. et al., Strahlenther. Oncol., 165, 121-123 (1989)). Borated polpyrins show three to four times the effect per unit dose in cell culture than monomers or dimers of Na ₂ B ₁₂ H ₁₁ SH (Laster, BH et al., Strahlenther. Oncol., 165, 203-205 (1989) ). Although liver concentrations for these compounds are very high (Kahl, SB et al., Supra), they do not limit their use as capture agents for the treatment of brain tumors.

One desired category of low molecular boron compounds is purine and pyrimidine containing boron and their nucleosides. The basis for their development is that the compounds can be selectively inserted into proliferating tumor cells quickly and captured into the cells after conversion to the corresponding nucleotides. Their bases and their nucleosides can also function as analogs of naturally occurring precursors of nucleic acids and can be inserted into the DNA of the nucleus.

Since the heavy particles resulting from the capture reaction can transfer a large portion of their energy to intranuclear targeting, the cytoplasm or preferably the nuclear localization of all of the boron compounds can be advantageous and therefore required when the compound is present outside the cell. Less boron concentrations are allowed (Gabel, D. et al., Radiat. Res., 111, 14-25 (1987); Fairchild, RG et al., Int. J. Radiat, Oncol. Biol. Phys., 11, 831 840 (1985)). Schinazi and Prusoff (Shinazi, RF et al., Tetrahedron Lett., 50,4981-4984 (1978)) have been described for nucleosides containing boron, 5-dihydroloxyboryl-2'-deoxyuridine, thymidine. The analog was synthesized for the first time and found to be cytotoxic to African green monkeys (Vero) at a concentration level of 1600 μM (Laster, BH et al., Neutron Capture Therapy, 46-54, Niigata, Japan: Nishimura Co., Ltd.). (1986)). In Vitro neutron radiation studies on cell growth in the presence of 5-dihydroxy-2'-deoxyuridine, ˜6 μg ¹⁰ B / g, sufficient for BNCT, if achievable in vivo, Biological effects equal to concentration occurred.

In the 1960s and early 1970s, attention was focused on the potential use of polyclonal antibodies directed against tumor-binding antigens for the delivery of drugs and radioisotopes to tumors (Pressman, D. et al., Cancer Res. , 40, 3001-3007 (1957); Ghose, T. et al., Br. Med. J., 1, 90-93 (1967); Ghose, T. et al., Cancer (Phila.), 29, 1398-1400 ( 1972)). In 1964 Soloway suggested that antibodies could be used for selective targeting of ¹⁰ B to tumors (Soloway, AH, supra ). Hawthorne et al. (Hawthorne, MF et al., J. Medicinal Chem., 15, 449-452 (1972)) are diazonium from 1- (4-aminophenyl) -1,2-dicarbo-closo-dodecaborane. The insertion of salts directly into antibodies against bovine serum albumin and directly into polyclonal antibodies against human and mouse histocompatibility antigens (Hawthorne, MF et al ., Supra ).

In vitro experiments have shown that these immunoconjugates enable the transport of sufficient boron to human and rat lymphocytes to maintain a lethal ¹⁰ B (n, α) ⁷ response, demonstrating reduced viability by neutron stimulation. Claimed. However, the immune conjugate contains only 0.2% by weight of natural boron, which is equivalent to 6 atoms of ¹⁰ B / antibody molecule. Looking back, it seems that there must be another explanation for the observed reduced cell viability. Sneath et al. (Sneath, RL, Jr., J. Medicinal Chem., 17, 796-799 (1974)) indicated that if protein solubility is maintained in an aqueous system, water-soluble groups should be inserted into protein-bound polyhedron boron.

Subsequently, a group of polyhedral boron derivatives containing protein-binding functional groups were bound to IgG molecules by means of carbodiimide reactions without any signs of precipitation (Sneath, RL et al., J. Medicinal Chem., 19, 1290-). 1294 (1976).

One desired category of macromolecular species that is probably useful for the transport of ¹⁰ B is the so-called "encapsulation complex" such as, for example, liposomes, microspheres and low concentration lipoproteins (Kahl, SB et al., Strahlenther, Onkol., 165, 137- 139 (1989)). In theory, large amounts of ¹⁰ B can be encapsulated, and if the encapsulation complex can be targeted to the tumor by binding to monoclonal antibodies using current methodology or targeting of endogenously expressed cell surface receptors, They can be very powerful delivery systems and can also be advantageously localized in the reticuloendothelial system and develop methodologies to minimize this and maximize tumor intake.

Cobalamin

In the years following the separation of vitamin B ₁₂ as cyanocobalamin in 1984, it has been assumed that cyanocobalamin and the photolysis product, possible hydroxyloxbalamin, appear in humans. Cyanocobalamin is an isolated processed product of vitamin B ₁₂ and it has been demonstrated that hydroxylcobalamin and two coenzyme forms, methylcobalamin and adenosylcobalamin, are naturally occurring forms of vitamins.

Its various forms of structure are shown in Figure 1, where X is CN, OH, CH ₃ or adenosyl, respectively. The term cobalamin is then used to refer to all molecules except the X group. The basic ring system without cobalt (Co) or side chains is called corrin and octadehydrocorin is called corrole. 1 is taken from the Merck Index (Merck & Co. 11th Edition, 1989), where X is the top of the plane defined by the Corinne ring and the nucleotide is the bottom of the plane of the ring. The Corining Ring has six attached amidoalkyl (H ₂ NC (O) Alk) substituents at positions 2, 3, 7, 8, 13 and 18, and may be defined as a to e and g, respectively (DL Anton et al., J. Amer Chem. Soc., 102, 2215 (1980)).

Methylcobalamin acts as a cytoplasmic coenzyme for ⁵ N-methyltetrahydrofolate: homocysteine methyl transferase (methionine synthetase, EC 2.1.1.13), which catalyzes the formation of methionine from homocysteine.

All forms of vitamin B ₁₂ (adenosyl-, cyano-, hydroxyl-, or methylcobalamin) must be bound by transfer proteins, endogenous factors and transcobalamin II to be biologically active. Specifically, gastrointestinal absorption of vitamin B ₁₂ is an intrinsic factor binding by the intrinsic factor receptors in the terminal ileum (ileum) - dependent on vitamin B ₁₂ conjugate. As such, vascular metastasis and continued cellular uptake of vitamin B ₁₂ through the human body depends on transcobalamin II and membrane transcobalamin II receptors, respectively. After internalizing the transcobalamin II-vitamin B ₁₂ complex, the transfer protein undergoes lysosomal degradation, which releases vitamin B ₁₂ into the cytoplasm. Thereafter, all forms of vitamin B ₁₂ can be converted to adenosyl-, hydroxyl- or methylcobalamin, depending on the needs of the cell. See, eg, AE Finkler et al., Arch Biochem. Biophys., 120, 79 (1967); C. Hall et al., J. Cell Physiol., 133, 187 (1987); See ME Rappazzo et al., J. Clin, Invest., 51, 1915 (1972) and R. Soda et al., Blood, 65, 795 (1985).

Fast proliferating cells showed increased uptake of thymidine and methionine (ME van Eijkeren et al., Acta Ocologica, 31, 539 (1992); K. Kobota et al., J. Nucl. Med., 32, 2118 ( 1991) and K. Higashi et al., J. Nucl. Med., 34, 773 (1993). Because methylcobalamin is directly involved in methionine synthesis and indirectly in the synthesis of thymidylate and DNA, it is surprising that methylcobalamin, as well as cobalt-57-cyanocobalamin, exhibits increased absorption in rapidly differentiated tissues. (BA Cooper et al., Nature, 191, 393 (1961); H. Flodh, Acta Radiol. Suppl., 284, 55 (1968); L. Bloomquist et al., Experientia, 25, 294 (1969)). In addition, upregulation of the number of transcobalamin II receptors has been demonstrated in several malignant cell lines during their increased thymidine uptake and DNA synthesis (J. Lindemans et al., Exp. Cell. Res., 184, 449 (1989); Amagasaki et al., Blood, 26, 138 (1990) and JA Begly et al., J. Cell Physiol., 156, 43 (1993).

Vitamin B ₁₂ has several properties that are of potential interest as a therapeutic agent for tumors in vivo. Vitamin B ₁₂ is water soluble, has no known toxicity, and excess is released from glomerular filtration. The absorption of vitamin B ₁₂ may also be modulated by the administration of nitric oxide and other pharmacological agents (D. Swanson et al., Pharmaceuticals in Medical Imaging, MacMillan Pub. Co., NY (1990) page 621). ˜628).

Methods for preparing ¹²⁵ I-vitamin B ₁₂ derivatives are disclosed in US Pat. No. 3,981,863, filed by Niswender et al. In this method, vitamin B ₁₂ first forms a mixture of monocarboxylic acids by mild hydrolysis, and the following Houts find that it contains mostly (e) -isomers. The mixture was then reacted with p- (aminoalkyl) phenol (via reaction with one free carboxylic acid group) to introduce phenol groups into the B ₁₂ acid. The mixed substituent B ₁₂ derivatives were then iodized in phenol-group substituents. This US patent teaches that the generated and mixed ¹²⁵ I-vitamin B ₁₂ derivatives are useful in radioimmunoassay of B ₁₂ using increased antibodies to the mixture.

US Pat. No. 4,465,775, filed by TMHouts, reported that members of the antiseptic labeled mixtures of Niswender et al. Did not bind with the same affinity to IF. Houts disclosed that radioactive iodide derivatives of pure monocarboxy (d) -isomers are useful for the analysis of B ₁₂ where IF is used. However, although Houts have generally disclosed that monocarboxyl (d) -isomers can be labeled by fluoropores or enzymes and used in competitive assays for vitamin B ₁₂ in solution, tumor and tissue imaging and treatment There remains a need for a labeled vitamin B ₁₂ derivative suitable for.

U.S. Pat.No. 5,739,313, filed by Collins and Hogenkamp, discloses cobalamin analogs, including linking and chelating groups, containing any detectable radionuclide or paramagnetic ions are ubiquitous in tumor cells and imaging of tumors. Reported to be valid.

Despite previous efforts to find high concentrations of neutron capture agents in tumor cells and useful for treating tumors, neutron capture agents are still needed to treat tumors.

Summary of the invention

The present invention relates to compounds wherein the residues of the compounds of general formula I of FIG. 1 are bonded to the residues of molecules comprising boron-10 (ie, B-10), wherein X is CN, OH, CH ₃ , adenosyl or B Molecule, including -10), or a pharmaceutically acceptable salt thereof.

The present invention also relates to compounds wherein the residues of the compounds of formula I in FIG. 1 are attached to the group of formula QLW-Det, wherein X is a molecule comprising Q, CN, OH, CH ₃ , adenosyl, B-10 Det is a chelating group comprising Gd-157, L is a linker or lacking, and W and Q are each independently -N (R) C (= 0)-, -C (= 0) N (R)-, -OC (= O)-, -C (= O) O-, -O-, -S-, -S (O)-, -S (O) _2- , -C (= O )-, -N (R)-, or a direct bond; each R is independently H or (C ₁ -C ₆ ) alkyl) or a pharmaceutically acceptable salt thereof.

The invention also relates to compounds in which the residues of the compounds of formula I in Figure 1 are linked to the residues of molecules comprising B-10, wherein the residues in the compounds of formula I are also linked to the group of formula QLW-Det Wherein X is a molecule comprising CN, OH, CH ₃ , a group of formula QLW-Det, or B-10, wherein Det is a kill containing a therapeutic radionuclide or diagnostic radionuclide Is a rating group, L is a linker or absent, and Q and W are each independently -N (R) C (= 0)-, -C (= 0) N (R)-, -OC (= 0)- , -C (= O) O-, -O-, -S-, -S (O)-, -S (O) _2- , -C (= O)-, -N (R)-, or direct Each R is independently H or (C ₁ -C ₆ ) alkyl) or a pharmaceutically acceptable salt thereof.

The invention also relates to compounds in which the residues of the compounds of formula I in Figure 1 are bound to the residues of the molecule comprising B-10, wherein the residues in the compounds of formula I are also linked to the group of formula QLW-Det Where X is CN, OH, CH ₃ , a group of the general formula QLW-Det, or a molecule comprising B-10; Det is a chelating group comprising Gd-157, L is a linker or absent , Q and W are each independently -N (R) C (= O)-, -C (= O) N (R)-, -OC (= O)-, -C (= O) O-,- O—, —S—, —S (O) —, —S (O) ₂ —, —C (═O) —, —N (R) —, or a direct bond; each R is independently H or (C ₁ -C ₆ ) alkyl) or a pharmaceutically acceptable salt thereof.

The present invention also relates to compounds wherein the residues of the compounds of general formula I of FIG. 1 are bound to detectable radionuclides and also to residues of molecules comprising boron-10 (ie B-10), wherein X is CN , OH, CH ₃ , adenosyl, or a molecule comprising B-10), or a pharmaceutically acceptable salt thereof.

The invention also relates to a residue of the compound of general formula I of FIG. 1 bound to a detectable radionuclide; Or a compound bound to a group comprising Gd-157, wherein X is a molecule comprising CN, OH, CH ₃ , B-10 or a group comprising Gd-157, or a pharmaceutically acceptable salt thereof To provide. In particular the group comprising Gd-157 may have the general formula QLW-Det; Wherein Det is a chelating group comprising Gd-157; L is a linker or absent; W and Q are each independently -N (R) C (= O)-, -C (= O) N (R)-, -OC (= O)-, -C (= O) O-, -O —, —S—, —S (O) —, —S (O) ₂ —, —C (═O) —, —N (R) —, or a direct bond; Each R is independently H or (C ₁ -C ₆ ) alkyl.

The present invention also relates to a moiety wherein the residue of the compound of formula I of FIG. To each compound, wherein each Det is independently a chelating group comprising a metal radionuclide; each L is a linker or absent, and W and Q are each independently -N (R) C (= 0) -, -C (= O) N (R)-, -OC (= O)-, -C (= O) O-, -O-, -S-, -S (O)-, -S (O ) _2- , -C (= 0)-, -N (R)-, or a direct bond; each R is independently H or (C ₁ -C ₆ ) alkyl) or a pharmaceutically acceptable salt thereof To provide.

The present invention also provides a pharmaceutical composition comprising the compound of the present invention and a pharmaceutically suitable carrier.

The present invention also provides a method of treating a tumor in a mammal in need of such treatment, comprising administering to said mammal an effective amount of a compound of the invention, and performing neutron capture treatment.

The invention also requires administering such a detectable amount of the compound of the invention to a mammal and detecting the presence of the compound, in combination with a pharmaceutically acceptable vehicle effective for imaging the tumor. Provided are methods for imaging tumors of a mammal.

The invention also provides a compound of the invention for use in medical treatment or diagnosis.

The invention also provides the use of a compound of the invention for the manufacture of a medicament for imaging a tumor in a mammal (especially a human).

The invention also provides the use of a compound of the invention for the manufacture of a medicament for treating a tumor in a mammal (especially a human).

The present invention also provides synthetic methods for the preparation of the compounds of the present invention, as well as intermediates disclosed herein useful for the compounds of the present invention.

Related Applications

This application claims the priority of US Provisional Application No. 60 / 129,733, filed April 16, 1999 and US Provisional Application No. 60 / 159,873, filed October 15, 1999.

Figure 1 shows the structure of cobalamin when X is CN (cyano), OH, CH ₃ or adenosyl,

2 shows the synthesis of cyanocobalamin-nido-carborane conjugates,

Figure 3 shows the synthesis of representative compounds of the present invention.

Applicants have found that some cobalamin analogs are useful in the treatment of tumors in combination with neutron capture therapy. Applicants have also found that some cobalamin analogs are useful as neutron capture agents and tumor imaging agents.

Unless stated otherwise, the following definitions are used:

Halo is fluoro, chloro, bromo or iodine. Alkyl, alkoxy, alkenyl, alkynyl and the like represent linear and branched groups; Individual radicals, such as "propyl" only include straight chain radicals, and branched chain isomers such as "isopropyl" are specifically mentioned. Aryl is defined as an ortho-fused bicyclic carbocyclic radical having a phenyl radical or at least one ring is aromatic and having about 9 to 10 ring atoms.

The optional and preferred listed below for radicals, substituents, and ranges are illustrative only and do not exclude other definitions or anything within the scope defined for radicals and substituents.

Those skilled in the art will appreciate that there may be compounds of the invention having chiral centers and that they can be separated into optically active and racemic forms. Some compounds may exist in polymorphism. It is to be understood that the present invention may include any racemic, optically active, polymorphic, stereoisomeric form or mixtures thereof of the present invention having the useful properties described herein, of optically active form Preparation methods (e.g., by fractionation of racemic forms by recrystallization techniques, by synthesis from optically active starting materials, by chiral synthesis, by chromatographic separation using chiral stationary phases), and Methods of measuring antitumor activity or utility as antitumor imaging agents by use of standard tests described herein or similarly known tests in the art are well known in the art.

In particular, (C ₁ -C ₁₄ ) alkyl is methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec-butyl, pentyl, 3-pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodec It may be yarn, tridecyl or tetradecyl.

In particular, (C ₂ -C ₁₄ ) alkenyl is vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl , 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl , 4-heptenyl, 5-heptenyl, 6-heptenyl, 1-octenyl, 2-octenyl, 3-octenyl, 4-octenyl, 5-octenyl, 6-octenyl, 7-octenyl , 1-nonenyl, 2-nonenyl, 3-nonenyl, 4-nonenyl, 5-nonenyl, 6-nonenyl, 7-nonenyl, 8-nonenyl, 1-decenyl, 2-decenyl , 3-decenyl, 4-decenyl, 5-decenyl, 6-decenyl, 7-decenyl, 8-decenyl, 9-decenyl, 1-undecenyl, 2-undecenyl, 3-undecenyl , 4-undecenyl, 5-undecenyl, 6-undecenyl, 7-undecenyl, 8-undecenyl, 9-undecenyl, 10-undecenyl, 1-dodecenyl, 2-dodecenyl, 3-dodecenyl , 4-dodecenyl, 5-dodecenyl, 6-dodecenyl, 7-dodecenyl, 8-dodecenyl, 9-dodecenyl, 10-dodecenyl, 11-dodecenyl, 1-tridecenyl, 2-tri place Nil, 3-tridecenyl, 4-tridecenyl, 5-tridecenyl, 6-tridecenyl, 7-tridecenyl, 8-tridecenyl, 9-tridecenyl, 10-tridecenyl, 11-tridecenyl, 12-tridecenyl, 1-tetradecenyl, 2-tetradecenyl, 3-tetradecenyl, 4-tetradecenyl, 5-tetradecenyl, 6-tetradecenyl, 7- Tetradecenyl, 8-tetradecenyl, 9-tetradecenyl, 10-tetradecenyl, 11-tetradecenyl, 12-tetradecenyl, or 13-tetradecenyl.

In particular, (C ₂ -C ₁₄ ) alkynyl is ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-heptinyl, 2-heptinyl, 3-heptinyl, 4-heptinyl, 5-heptinyl, 6-heptinyl, 1-octinyl, 2-octinyl, 3-octinyl, 4-octinyl, 5-octinyl, 6-octinyl, 7-octinyl, 1-noninyl, 2-noninyl, 3-noninyl, 4-noninyl, 5-noninyl, 6-noninyl, 7-noninyl, 8-noninyl, 1-decynyl, 2-decynyl, 3-decynyl, 4-decynyl, 5-decynyl, 6-decynyl, 7-decynyl, 8-decynyl, 9-decynyl, 1-undecynyl, 2-undecynyl, 3-unde Cynyl, 4-undecynyl, 5-undecynyl, 6-undecynyl, 7-undecynyl, 8-undecynyl, 9-undecynyl, 10-undecynyl, 1-dodecynyl , 2-dodecynyl, 3-dodecynyl, 4-dodecynyl, 5-dodecynyl, 6-dodecynyl, 7-dodecynyl, 8-dodecynyl, 9-dodecynyl, 10 Dodecynyl, 11-dodecynyl, 1-tridecynyl, 2-tridecynyl, 3-tridesinyl, 4-tridesinyl, 5-tridesinyl, 6-tridesinyl, 7-tridesinyl, 8-tridesinyl, 9-tridesinyl, 10-tridesinyl, 11- Tridecynyl, 12-tridecynyl, 1-tetradecynyl, 2-tetradecynyl, 3-tetradecynyl, 4-tetradecynyl, 5-tetradecynyl, 6-tetradecynyl, 7-tetradecyl Yl, 8-tetradecynyl, 9-tetradecynyl, 10-tetradecynyl, 11-tetradecynyl, 12-tetradecynyl, or 13-tetradecynyl.

In particular "aryl" may be phenyl, indenyl or naphthyl.

In particular (C ₃ -C ₈ ) cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.

As used herein, "amino acid" refers to a natural amino acid group in the form of D or L having one or more open valences (e.g., Ala, Arg, Asn, Asp, Cys, Glu, Gln, Gly, His, Hyl , Hyp, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr and Val), as well as non-natural amino acids (eg, phosphoserine; phosphoreonine; phosphotyrosine; hydroxyproline; gamma- Carboxyglutamate; hippuric acid; octahydroindole-2-carboxylic acid; statin; 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid; penicillamine; ornithine; citrulline; α-methyl-alanine Para-benzoylphenylalanine; polyglycine; propargylglycine; salcosine; and tert-butylglycine) groups. The term also includes carboxy-protected (eg, (C ₁ ) natural and unnatural amino acids having conventional amino acid protecting groups (eg, acetyl, acyl, trifluoroacetyl, or benzyloxycarbonyl) as well as conventional protecting groups. ~C ₆₎ alkyl, and a phenyl or benzyl ester or amide include protection) natural and unnatural amino acids. Other suitable amino and carboxy protecting groups are known to those skilled in the art (eg, TW Greene, Protecting Groups In Organic Synthesis ; Wiley: New York, 1981; D. Voet, Biochemistry , Wiley: New York, 1990; L. Stryer , Biochemistry , (3rd Ed.), WH Freeman and Co .: New York, 1975; J. March, Advanced Organic Chemistry, Reactions, Mechanisms and Structure , (2nd Ed.), McGraw Hill: New York, 1977; F. Carey and R. Sundberg, Advanced Organic Chemistry, Part B: Reactions and Synthesis , (2nd Ed.), Plenum: New York, 1977; and references cited therein). According to the invention, the amino or carboxy protecting group may also comprise radionuclides (eg fluorine-18, iodine-123 or iodine-124).

As used herein, a "peptide" is a sequence or peptide residue of 2 to 25 amino acids (eg, as defined above) having one or more open valences. The sequence is straight or circular. For example, circular peptides can be prepared or produced by the formation of disulfide bonds between two cysteine residues in a sequence. Peptides may be linked via carboxy terminus, amino terminus or any other useful conjugation site such as sulfur of cysteine and the like. Peptide derivatives are described in US Pat. No. 4,612,302; 4,853,371; It may be prepared by the method disclosed in 4,684,620 or by the methods described in the examples herein. Peptide sequences specifically mentioned herein list the amino terminus on the left and the carboxy terminus on the right.

The particular and optional ones listed below for radicals, substituents and ranges are illustrative only and do not exclude other definitions or anything within the scope defined for radicals and substituents.

In particular, the peptides are poly-L-lysine, poly-L-glutamic acid, poly-L-aspartic acid, poly-L-histidine, poly-L-ornithine, poly-L-serine, poly-L-threonine, poly -L-tyrosine, poly-L-lysine-L-phenylalanine or poly-L-lysine-L-tyrosine).

As used herein, "residue of a compound of formula I" is a residue of a compound of formula I having one or more open valences. Atoms or atoms that are easy to synthesize any of the compounds of Formula I may migrate to provide a hot valence, and the resulting compound may be local to or near the tumor. Based on the necessary binding, one skilled in the art can select suitable functional starting materials that can be derived from the compounds of general formula I using known methods. Suitable atoms that can move, for example, is a hydrogen atom, b- carboxamide (FIG. 1 from the NH ₂ group or a- carboxamide (carboxamide) NH ₂ group of the a- carboxamide (also appears in Figure 1) It appears) of the NH ₂ group or a hydrogen atom b-, d- from the carboxamide group of the NH _{2-carboxamide} (also a hydrogen atom from the NH ₂ group or NH ₂ group of the d- carboxamide of appears in Figure 1) , hydrogen atom from NH ₂ group of e-carboxamide (shown in FIG. 1) or NH ₂ group of e-carboxamide, and X in 6-position (shown in FIG. 1). Further, a hydrogen atom of the hydroxy group at the 3 'position of the sugar, a hydrogen atom from the hydroxy group at the 3' position of the sugar, a hydrogen atom of the CH ₂ OH at the 5 'position of the ring of the sugar, or a 5' position of the ring of the sugar Hydrogen atoms from hydroxy groups can be moved.

As used herein, "adenosyl" is an adenosine radical in which any synthesizable atom or group of atoms moves to provide an open valence. Removable synthesizable atoms include hydrogen atoms of hydroxy groups at the 5 'position. Thus, adenosine can conveniently attach to the 6-position of the compound of Formula I via the 5 'position of adenosyl.

As used herein, “molecule comprising B-10” may be any compound comprising at least one B-10 atom. However, the compound must be non-toxic and must be able to enter tumor cells and be able to be present near tumor cells when a molecule comprising B-10 is attached.

As used herein, “residue of a molecule comprising B-10” is a residue of a molecule comprising B-10 having one or more open valences. Any atom or atoms that are readily synthesized, including B-10, may migrate to provide a degraded valency and retain substantially bioactivity. Based on the necessary binding, one of ordinary skill in the art can select appropriate functionalized starting materials that can be derived from molecules comprising B-10 using known methods.

As used herein, an “o-carborane group”, “m-carborane group” or “p-carborane group” refers to each o-carborane group, m-carborate having one or more open valences Borane groups or p-carborane groups. Any atom or atoms that can be readily synthesized of an o-carborane group, an m-carborane group or a p-carborane group can migrate to provide a degraded valency and retain substantially bioactivity. Based on the necessary binding, one of ordinary skill in the art can select suitable functionalized starting materials that can be derived from molecules comprising -10 using known methods.

Boron Compounds Useful for Treating Neutron Capture

The present invention relates to compounds of general formula I (FIG. 1) bound to one or more molecules comprising B-10 (where X is a molecule comprising CN, OH, CH ₃ , adenosyl or B-10), or It is to provide a pharmaceutically acceptable salt thereof.

Various known molecules, including B-10, are useful in the present invention. The molecules may vary considerably in structure, but are suitable for practicing the present invention. Suitable species include boron containing not only carborane but also amino acids, carbohydrates and nucleosides. Various compounds including boron are commercially available and are known. Various molecules including B-10 are commercially available from Boron Biologicals, Inc., Raleigh, North Carolian, and RysCor Science, Inc., Raleigh, North Carolina.

In particular, at least one molecule comprising B-10 may be o-carborane, m-carborane, or p-carborane. More specifically, at least one molecule comprising B-10 may be selected from o-carborane, o-carborane [1,2-dicarbado decaborane (12)]; Commercially available m-carborane [1,7-dicarbado decaborane (12)] or p-carborane [1,12-dicarbado decaborane (12)] from Aldrich, Milwaukee, WI have.

In particular, each molecule comprising B-10 may be independently o-carborane, m-carborane, or p-carborane. More specifically, each molecule comprising B-10 is o-carborane.

Molecules Containing Compound of Formula I / B-10

Residues of molecules comprising B-10 include amides (eg, -N (R) C (= 0)-or -C (= 0) N (R)-), esters (eg, , -OC (= O)-or -C (= O) O-), ether (e.g. -O-), amino (e.g. -N (R)-), ketone (e.g. -C (= O) -), Through a thioether (e.g. -S-), sulfinyl (e.g. -S (O)-), sulfonyl (e.g. -S (O) _2- ) or a direct bond (e.g. CC bond) Wherein each R is independently H or (C ₁ -C ₆ ) alkyl. Such bonds can be formed from suitably functionalized starting materials using known synthetic methods. Based on the necessary binding, those skilled in the art will use known methods to select appropriate functionalized starting materials that can be derived from the residues of the compounds of Formula I and the residues of the molecule comprising the given B-10. Can be.

The residues of the molecule comprising B-10 may bind directly to any position that is easy to synthesize on the residues of the compound of general formula (I). Appropriate sites of attachment are possible, although other attachment sites are possible, for example b-carboxamide, d-carboxamide, e-carboxamide (shown in FIG. 1) as well as the 6-position (by X in FIG. Occupied) and 5'-hydroxy and 3'-hydroxy groups of 5-membered ring sugars. U.S. Pat.No. 5,739,313 discloses compounds which are useful intermediates for the preparation of the compounds of the invention (e.g., cyanocobalamin-b- (4-aminobutyl) amide, methylcobalamin-b- (4-aminobutyl) amide and adenosyl). Cobalamin-b- (4-aminobutyl) amide) is disclosed.

Compounds in which the residue of the molecule comprising B-10 is linked to the 6-position of the compound of formula I reduce the corresponding Co (II) compound of formula I to form a nucleophilic Co (I) compound, Co (I) compounds can be prepared by treating with a residue (or derivative thereof) of a molecule comprising B-10, including a suitable leaving group such as a halide (eg chloride).

The present invention also provides compounds having one or more residues of the molecule comprising B-10 linked directly to a compound of formula (I). For example, a residue of a molecule comprising B-10 may be directly attached to a residue of b-carboxamide of a compound of Formula I, and a residue of another molecule comprising B-10 may be a d of a compound of Formula I May be directly attached to the residue of the carboxamide. In addition, the residues of the molecule comprising B-10 may be bonded directly to the 6-position of the compound of formula I, and the residues of other molecules comprising B-10 may be d- or may be directly linked to the residue of the e-carboxamide.

Molecules comprising a compound of formula I / linker / B-10 linker

In addition to being directly linked to the residue of the compound of formula I, the residue of the molecule comprising B-10 may also be linked by a linker appropriate to the residue of the compound of formula I. The structure of the linker is not critical and is provided to produce a compound of the invention that has an effective therapeutic index for the target cell and can be localized in or near the tumor molecule.

Suitable linkers include linkers that separate the residues of the compound of Formula I and the residues of the molecule comprising B-10 into about 5 to about 200 angstroms. Other suitable linkers include linkers that separate residues of compounds of Formula I and residues of molecules comprising B-10 into about 5 to about 100 angstroms, as well as molecules comprising residues of compounds of Formula I and B-10. Linkers that separate the residues of from about 5 to about 50 angstroms, or about 5 to about 25 angstroms. Suitable linkers are disclosed, for example, in US Pat. No. 5,735,313.

The linker may be linked to any position that is easy to synthesize to the moiety of the compound of formula (I). Suitable sites of attachment may be other attachment sites, for example, residues of b-carboxamide, residues of d-carboxamide and residues of e-carboxamide, 6-position (ie, X in Formula I). Position), as well as 5'-hydroxy and 3'-hydroxy groups of 5-membered ring sugars. Based on the necessary binding, one skilled in the art can use known methods to select suitable functionalized starting materials that can be derived from a compound of Formula I and a molecule comprising a given B-10.

The linker can be easily linked to an amide (eg, -N (R) C (= 0)-or -C (= 0) N (R)-) at a residue of a compound of Formula I or a residue of a molecule comprising B-10). ), Esters (e.g. -OC (= O)-or -C (= O) O-), ethers (e.g. -O-), ketones (e.g. -C (= O)-), thioethers (e.g. , -S-), sulfinyl (e.g. -S (O)-), sulfonyl (e.g. -S (O) _2- ), amino (e.g. -N (R)-) or a direct bond (e.g. CC bond), wherein each R is independently H or (C ₁ -C ₆ ) alkyl. The linkage may be formed from suitably functionalized starting materials using known synthetic methods. Based on the necessary binding, those skilled in the art will use known methods to select appropriate functionalized starting materials that can be derived from the residues of the compounds of Formula I and the residues of the molecule comprising the given B-10. Can be.

In particular, the linker may be a divalent moiety of the formula WAQ, wherein A is (C ₁ -C ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl, (C ₂ -C ₆ ) alkynyl, ( C ₃ -C ₈ ) cycloalkyl, (C ₆ -C ₁₀ ) aryl, W and Q are each independently -N (R) C (= 0)-, -C (= 0) N (R)-, -OC (= O)-, -C (= O) O-, -O-, -S-, -S (O)-, -S (O) _2- , -N (R)-, -C ( = O)-or a direct bond (ie, no W and Q); Each R is independently H or (C ₁ -C ₆ ) alkyl.

In particular, the linker may be a divalent residue of the general formula W- (CH ₂ ) _n -Q, wherein n is about 1 to about 20, about 1 to about 15, about 2 to about 10, about 2 to about 6, about 4 to about 6, and W and Q are each independently -N (R) C (= 0)-, -C (= 0) N (R)-, -OC (= 0)-, -C (= O) O-, -O-, -S-, -S (O)-, -S (O) _2- , -C (= O)-, -N (R)-, or a direct bond (i.e. , W and Q are absent); Each R is independently H or (C ₁ -C ₆ ) alkyl.

Specifically, W and Q are each independently -N (R) C (= 0)-, -C (= 0) N (R)-, -OC (= 0)-, -N (R)-, -C (= O) O- or a direct bond (ie, no W and Q).

In particular, the linker is a divalent radical, ie a divalent radical formed from a peptide or an amino acid, ie a 1, ω-2 valent radical. The peptide may comprise 2 to about 20 amino acids, 2 to about 15 amino acids, 2 to about 12 amino acids.

In particular, the peptide is a poly-L-lysine (ie, [-NHCH [(CH ₂ ) ₄ NH ₂ ] CO-] _m -Q, wherein Q is H, (C ₁ -C ₁₄ ) alkyl, or suitable carboxy And a protecting group, m is about 2 to about 20. In particular, the poly-L-lysine may comprise about 5 to about 15 residues (ie, m is about 5 to about 15). , Poly-L-lysine may comprise about 8 to about 11 residues (ie, m is about 8 to about 11).

In particular, the peptides are poly-L-glutamic acid, poly-L-aspartic acid, poly-L-histidine, poly-L-ornithine, poly-L-serine, poly-L-threonine, poly-L-tyrosine, poly -L-lysine-L-phenylalanine or poly-L-lysine-L-tyrosine.

In particular, the linker is 1,6-diaminohexane H ₂ N (CH ₂ ) ₆ NH ₂ , 1,5-diaminopentane H ₂ N (CH ₂ ) ₅ NH ₂ , 1,4-diaminobutane H ₂ N (CH ₂ ) ₄ NH ₂ , or 1,3-diaminopropane H ₂ N (CH ₂ ) ₃ NH ₂ .

The linker may comprise one or more non-metal radionuclides. In particular, the linker may comprise one or more non-metallic radionuclides. More preferably, the Syick linker may comprise 2 to about 10, 2 to about 8, 2 to about 6, 2 to about 4 non-metallic radioisotopes.

Specific residues (ie, linkers) of the peptides may include one or more non-metal radionuclides having the formula and pharmaceutically acceptable salts thereof, wherein each M is independently a non-metal radionuclide High; Each R is independently (C ₁ -C ₁₄ ) alkyl, (C ₂ -C ₁₄ ) alkenyl, (C ₂ -C ₁₄ ) alkynyl, (C ₁ -C ₁₄ ) alkoxy, hydroxy, cyano, Nitro, halo, trifluoromethyl, N (R _a ) (R _b ), (C ₁ -C ₁₄ ) alkanoyl, (C ₂ -C ₁₄ ) alkanoyloxy, (C ₆ -C ₁₀ ) aryl or ( C ₃ -C ₈ ) cycloalkyl, R _a and R _b are each independently H or (C ₁ -C ₁₄ ) alkyl; P and Q are H, (C ₁ -C ₁₄ ) alkyl or a suitable carboxy protecting group, n is from 2 to about 20; i is 1-5, j is 0-4, and i + j is <5.

In particular, i may be 1, j may be 0, M may be fluorine-18, bromine-76, or iodine-123, and n may be about 6 to about 12.

The molecule comprising B-10 may include one or more boron atoms. Suitable molecules comprising B-10 may comprise from 1 to about 20, 1 to about 15, 1 to about 10, or 1 to about 5 boron atoms. In addition, the molecule comprising B-10 may comprise one or more B-10 atoms. Suitable molecules comprising B-10 may comprise 1 to about 20, 1 to about 15, 1 to about 10, 1 to about 5 B-10 atoms.

The molecule comprising B-10 may be an amino acid, carbohydrate, nucleoside or carborane. Particularly the molecule comprising B-10 is o-carborane, m-carborane, or p-carborane.

Compounds in which the linker is bonded at the 6-position of the compound of formula I produce the nucleophilic Co (I) species described above and react with a linker comprising a suitable leaving group such as a halide (e.g. chloride) It can manufacture.

The present invention also provides compounds having one or more molecules, each comprising B-10 to which a compound of formula I is attached via a linker. For example, residues of a molecule comprising B-10 can be easily linked via a linker to residues of b-carboxamide of a compound of Formula I, while residues of other molecules comprising B-10 are linked through a linker. And can easily be linked to the residues of the d-, or e-carboxamide of the compound of general formula (I). In addition, residues of a molecule comprising B-10 can be readily linked to the 6-position of the compound of formula I via a linker, and residues of other molecules comprising B-10 can easily be attached via a linker Or a residue of b-, d-, or e-carboxamide of a compound of.

The present invention also provides compounds having one or more molecules comprising B-10 to which the compound of formula I is attached directly or through a linker. For example, residues of a molecule comprising B-10 can be readily linked to a residue of b-carboxamide of a compound of Formula I, either directly or via a linker, and residues of other molecules comprising B-10 are directly Or via a linker to easily bind to the d-, or e-carboxamide residue of the compound of general formula (I). In addition, residues of a molecule comprising B-10 may be readily attached at the 6-position of the compound of Formula I, either directly or via a linker, and residues of other molecules comprising B-10 may be directly or via a linker. Can be easily attached to the residues of b-, d-, or e-carboxamide of the compound of general formula (I).

Chelating Groups Containing Compound Of Formula I / Gadolinium-157

US Pat. No. 5,739,313 discloses cobalamin analogs comprising a compound of Formula I, a linking group and a chelating group comprising detectable radionuclide or paramagnetic ions. The compounds are disclosed to be localized into tumor cells after administration and are useful for imaging tumors.

Metal radionuclide gadolinium-157 is a very useful ion for performing magnetic resonance imaging. This is also a useful target ion for neutron capture therapy. The inventors have found that the insertion of Gd-157 into one chelating molecule described in US Pat. No. 5,739,313 is particularly useful for performing magnetic resonance imaging of the compound, as well as for the compound to treat neutron capture for the treatment of tumors. It has been found that it can be used in combination.

As such, the present invention provides residues of a compound of Formula I wherein at least one residue of Formula QLW-Det is bonded, wherein each Det is independently a chelating group comprising Gd-157; L is independently a linker (as defined above) or lacks; each W and Q are each independently -N (R) C (= 0)-, -C (= 0) N (R)- , -OC (= O)-, -C (= O) O-, -O-, -S-, -S (O)-, -S (O) _2- , -C (= O)-,- N (R)-, or a direct bond (ie W and Q are absent); each R is independently H or (C ₁ -C ₆ ) alkyl.

Chelating Groups Containing Compounds Of Formula I / Radionuclides

The inventors also note that by inserting one or more neutron capture target atoms (e.g., B-10 or Gd-157) into a compound comprising a searchable radionuclide, compounds can be prepared simultaneously useful for imaging and treatment of tumors. Found. Thus, the present invention relates to one or more residues of a molecule comprising B-10; Also provided are residues of a compound of Formula I, or a pharmaceutically acceptable salt thereof, linked to one or more groups of Formula QLW-Det, wherein each Det is independently a chelating group comprising Gd-157 ( As defined herein; each L is independently a linker (as defined herein) or lacks; each W and Q is each independently -N (R) C (= 0)- , -C (= O) N (R)-, -OC (= O)-, -C (= O) O-, -O-, -S-, -S (O)-, -S (O) _2- , -C (= 0)-, -N (R)-, or a direct bond (ie, no W and Q); each R is independently H or (C ₁ -C ₆ ) alkyl) .

The present invention provides residues of a compound of formula I linked to a molecule comprising B-10 or to a chelating group comprising Gd-157, wherein the residues of the compound of formula I are of formula QLW- Is bound to at least one residue of Det, wherein each Det is independently a chelating group (as defined above) comprising a metal radionuclide; each L is independently a linker (as defined above) The same) or lacking; each W and Q are each independently -N (R) C (= 0)-, -C (= 0) N (R)-, -OC (= 0)-, -C ( = O) O-, -O-, -S-, -S (O)-, -S (O) _2- , -C (= O)-, -N (R)-, or a direct bond (i.e. W and Q are absent) and each R is independently H or (C ₁ -C ₆ ) alkyl).

Molecule / detectable radionuclide comprising Compound of Formula I / B-10

The present invention also relates to compounds in which the residues of the compounds of formula I (FIG. 1) are bound to 1) residues of molecules comprising B-10 and 2) detectable radionuclides, wherein X is CN, OH, CH ₃ , Adenosyl or a molecule comprising B-10), or a pharmaceutically acceptable salt thereof.

The detectable radionuclide can be directly bound to the residue of the compound of formula I and can also be linked to the residue of the compound of formula I by a linker. The linker may be any suitable linker described herein. In particular, the linker may be of the general formula WA, wherein A is (C ₁ -C ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl, (C ₂ -C ₆ ) alkynyl, (C ₃ -C ₈ ) cycloalkyl, or (C ₆ -C ₁₀ ) aryl, W is -N (R) C (= 0)-, -C (= 0) N (R)-, -OC (= 0)-, -C (= 0) O-, -O-, -S-, -S (O)-, -S (O) _2- , -N (R)-, -C (= O)-or directly ; Each R is independently H or (C ₁ -C ₆ ) alkyl; A is substituted with one or more non-metallic radionuclides. The linker may also be a peptide or an amino acid.

Group / detectable radionuclide comprising compound of formula I / Gd-157

The present invention also provides that the residues of the compound of Formula I (FIG. 1) are 1) detectable radionuclide; And 2) a compound bound to a group comprising Gd-157, or a pharmaceutically acceptable salt thereof.

Gd-157 may be linked to the residue of the compound of formula I by any suitable means. For example, residues of a compound of Formula I may be attached to a group comprising Gd-157 having the formula QLW-Det. Any suitable chelator can be used, where Det is a chelating group comprising Gd-157, L is a linker or absent, and W and Q are each independently -N (R) C (= 0)- , -C (= O) N (R)-, -OC (= O)-, -C (= O) O-, -O-, -S-, -S (O)-, -S (O) _2- , -C (= 0)-, -N (R)-, or a direct bond; each R is independently H or (C ₁ -C ₆ ) alkyl.

The detectable radionuclide may be directly linked to the residue of the compound of formula I, or may be linked by a linker to the residue of the compound of formula I. The linker may be any suitable linker described herein. In particular the linker may be of the general formula WA, wherein A is (C ₁ -C ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl, (C ₂ -C ₆ ) alkynyl, (C ₃ -C ₈ ) Cycloalkyl, or (C ₆ -C ₁₀ ) aryl, W is -N (R) C (= 0)-, -C (= 0) N (R)-, -OC (= 0)-, -C (═O) O—, —O—, —S—, —S (O) —, —S (O) ₂ —, —N (R) —, —C (═O) — or directly bonds; Each R is independently H or (C ₁ -C ₆ ) alkyl; A is substituted with one or more non-metallic radionuclides. The linker may also be a peptide or an amino acid.

Non-metallic radionuclide

Any detectable non-metallic radionuclide suitable for imaging can be used with the compounds of the present invention. For example, suitable non-metallic radionuclides include carbon-11, fluorine-18, bromine-76, and iodine-123. In particular, the non-metallic radionuclide is a non-metallic paramagnetic (eg fluorine-19); Or non-metal positron emitting radionuclides (eg, carbon-11, fluorine-18, iodine-123 or bromine-76).

Metal radionuclide

Suitable metal radionuclides (i.e. metal radioisotopes or metal paramagnetic ions) are antimony-124, antimony-125, Arsenic-74, barium-103, barium-140, beryllium ) -7, Bismuth-206, Bismuth-207, Cadmium-109, Cadmium-115m, Calcium-45, Cerium-139, Cerium-141, Cerium-144, Cesium- 137, Chromium-51, Cobalt-55, Cobalt-56, Cobalt-57, Cobalt-58, Cobalt-60, Cobalt-64, Copper-67, Erbium-169, Europium ) -152, gallium-64, gallium-68, gadolinium-153, gadolinium-157 gold-195, gold-199, hafnium-175, hafnium-175-181 , Holmium-166, Indium-110, Indium-111, Iridium-192, Iron-55, Iron-59, Krypton-85, Lead-210, Magnesium- 54, Mercury-197, Mercury-203, Molybdenum-99, Neodymium-147, Neptunium-237, Nickel-63, Niobium-95, Osmium-185 + 191, Palladium-103, Platinum-195m, Plasodymium-143, Promethium-147, Promethium Protactinium-233, Radium-226, Rhenium-186, Rhenium-188, Rubidium-86, Ruthenium-103, Ruthenium-106, Scandium-44 , Scandium-46, selenium-75, silver-110m, silver-111, sodium-22, strontium-85, strontium-89, strontium-90, sulfur- 35, Tantalum-182, Decnetium-99m, Tellurium-125, Tellurium-132, Thallium-204, Thorium-228, Thorium-232, Tlium (Thallium) -170, Tin-113, Tin-114, Tin-117m, Titanium-44, Tungsten-185, Vanadium-48, Vanadium-49, Ytterbium -169, Yttrium-86, yttrium-88, yttrium-90, yttrium-91, Zinc-65, and zirconium-95.

As used herein, “detectable radionuclide” is any suitable radionuclide (ie, radioisotope) capable of detecting cancer or other tumor cells in a diagnostic method in vivo or in vitro. Suitable detectable radionuclides include metal radionuclides (ie metal radioisotopes) and non-metal radionuclides (ie metal radioisotopes).

As used herein, “therapeutic radionuclide” is any suitable radionuclide (ie, radioisotope) that has a therapeutic effect on cancer or other tumor cells in vivo or in vitro. Suitable therapeutic radionuclides include metal radionuclides (ie metal radioisotopes).

Chelating group

Any suitable chelating group can be inserted into the compound of the present invention. Suitable chelating groups include those disclosed in US Pat. No. 5,739,313. In particular, the chelating group can be NTA, HEDTA, DCTA, RP414, MDP, DOTATOC, CDTA, HYNIC, EDTA, DTPA, TETA, DOTA, DOTMP, DCTA, 15N4, 9N3, 12N3 or MAG3, described herein below. (Or other suitable polyamino acid chelator), or may be a phosphonate chelator (eg, EDMT). More preferably, the chelate group may be DTPA.

DTPA is diethylenetriaminepentaacetic acid; TETA is 1,4,8,11-tetraazacyclotetradecane-N, N ', N ", N" -tetraacetic acid; DOTA is 1,4,7,10-tetraazacyclododecane-N, N ', N ", N" -tetraacetic acid; 15N4 is 1,4,8,12-tetraazacyclopentadecane-N, N ', N ", N" -tetraacetic acid; 9N3 is 1,4,7-triazacyclononane-N, N ', N "-triacetic acid 12N3 is 1,5,9-triazacyclododecane-N, N', N" -triacetic acid; MAG3 is (N- [N- [N-[(benzoylthio) acetyl] glycyl] glysyl] glycine) and DCTA is a metal chelator based on cyclohexane of the formula

Wherein R ³ may be (C ₁ -C ₄ ) alkyl or CH ₂ CO ₂ — and may be attached via position 4 or 5, or R ₃ , and from 1 to 4 detectable metal or nonmetallic cations (M ), Monovalent cations, or alkaline earth metals. As such, when the metal is in the +1 oxidation state, each individual cyclohexane-based molecule can carry up to four metal cations, where the R ³ group is CH ₂ COOM. Similarly, in a high oxidation state, the number of metals decreases by 2 or 1 per cyclohexane skeleton. The above formula is not intended to limit the molecule by any particular stereochemistry.

NTA, HEDTA, and DCTA are members of the Poster Division, Proceeding of the 46th Annual Meeting, J. Nuc. Med ., P. 31, No. 1386. RP414 is an academic paper, Proceeding of the 46th Annual Meeting, J. Nuc. Med ., P. 123, No. 466. MDP is an academic paper, Proceeding of the 46th Annual Meeting, J. Nuc. Med ., P. 102, No. 413. DOTATOC is an academic paper, Proceeding of the 46th Annual Meeting, J. Nuc. Med ., P. 102, No. 414 and academic papers, Proceeding of the 46th Annual Meeting, J. Nuc. Med ., P. 103, No. 415. The CDTA is in the Poster Division, Proceeding of the 46th Annual Meeting, J. Nuc. Med ., P.318, No. 1396. HYNIC is pleased to announce the poster division, Proceeding of the 46th Annual Meeting, J. Nuc. Med ., P.319, No.1398.

Bifunctional chelators based on macrocyclic ligands (i.e. chelating groups), via an activated arm where conjugation is attached to the ligand's carbon backbone, can also be applied as chelating groups, M Moi et al., J. Amer, Chem., Soc., 49, 2639 (1989) (2-p-nitrobenzyl-1,4,7,10-tetraazacyclododecane-N, N ', N ", N "'-tetraacetic acid); S. V. Deshpande et al., J. Nucl. Med., 31, 473 (1990); G. Kuser et al., Bioconj. Chem., 1, 345 (1990); In C. J. Broan et al., J. C. S. Chem. Comm., 23, 1739 (1990); and C. J. Anderson et al., J. Nucl. Med. 36, 850 (1995) (6-Bromoacetamido-benzyl-1,4,8,11-tetraazacyclotetadecan-N, N ', N ", N"'-tetraacetic acid (BAT)) It is described in

In addition, diagnostic chelators or therapeutic chelating groups can be found in the journal Proceedings of the 46th Annual Meeting, J. Nuc. Med ., Wednesday, June 9, 1999, p. 124, No. Any chelating group described in 500.

A "detectable group" is a chelating group that includes metal radionuclides (ie, metal radioisotopes) that can detect cancer or other tumor cells in vivo or in vitro.

In particular, the chelating group is Waibel et al ., Nature Biotechnology , 897-901, Vol. 17, September 1999; Or any one of the carbonyl complexes described in Sattelberger et al ., Nature Biotechnology , 849-850, Vol, 17, September 1999.

In particular, the detectable group is described in Waibel et al ., Nature Biotechnology , 897-901, Vol, 17, September 1999; Or Sattelberger et al ., Nature Biotechnology , 849-850, Vol. May be any one of the carbonyl complexes described in 17, September 1999. More preferably, the detectable chelating group is Waibel et al ., Nature Biotechnology , 897-901, Vol. 17, September 1999; Or Technetium-99m, further comprising Nature Biotechnology , 849-850, Vol. May be any one of the carbonyl complexes described in 17, September 1999,

As used herein, “therapeutic chelating group” is a chelating group comprising metal radionuclides (eg, radioisotopes) that have a therapeutic effect on cancer or other tumor cells in vivo or in vitro. Any suitable chelating group can be applied.

In particular, the therapeutic chelating group is described in Waibel et al ., Nature Biotechnology , 897-901, Vol. 17, September 1999; Or Sattelberger et al ., Nature Biotechnology , 849-850, Vol. It may be any carbonyl complex described in 17, September 1999. More preferably, the therapeutic chelating group is Waibel et al ., Nature Biotechnology , 897-901, Vol. 17, September 1999; Or Sattelberger et al ., Nature Biotechnology , 849-850, Vol. 2, further comprising metal Rhenium-186 or rhenium-188. It may be any carbonyl complex described in 17, September 1999.

Tumors that can be treated with the compounds and methods of the invention can be present in any site of a mammal. In particular, the tumor may include the chest, lungs, thyroid gland, lymph nodes, urogenital system (e.g. kidney, urethra, bladder, ovary, testis or prostate), musculoskeletal system (e.g. bone, skeletal muscle or bone marrow), gastrointestinal tract (e.g. stomach, esophagus, Located in the small intestine, colon, rectum, pancreas, liver or smooth muscle), central or peripheral nervous system (e.g. brain, spine or nerve), head and neck tumors (e.g. ear, eye, nasopharynx, oropharyngeal or acupuncture) or heart can do.

Compounds disclosed herein can be prepared using methods disclosed in US Pat. No. 5,739,313 or methods similar to those disclosed herein. The residue of the molecule comprising B-10 may be linked to the residue of the compound of formula I as above. Additional intermediates and synthetic methods useful for the preparation of the compounds of the present invention are described, for example, in Hogenkamp, H. et al., Synthesis and Characterization of nido-Carborane-Cobalamin Conjugates , Nucl. Med. & Biol., 2000, 27, 89-92; Collins, D., et al., Tumor Imaging Via Indium 111-Labeled DTPA-Adenosylcobalamin , Mayo Clinic Proc., 1999, 74: 687-691; US Patent Application 60 / 129,733, filed April 16, 1999; US Application 60 / 159,874, filed October 15, 1999; US Application 60 / 159,753, filed October 15, 1999; US Application 60 / 159,873, filed October 15, 1999; and the references cited therein.

If the compounds are sufficiently basic or acidic to form stable non-toxic acid or base salts, administration of the compounds as salts may be appropriate. Examples of pharmaceutically acceptable salts are organic acid addition salts with acids, such as tosylate, methanesulfonate, acetate, citrate, malonate, tartarate, succinate, benzoate, which form physiologically suitable anions, Ascorbate, α-ketoglutarate and α-glycerophosphate. Suitable inorganic salts may also be formed and include hydrogen chloride, sulfate, nitrate, bicarbotate and carbonate salts.

Pharmaceutically acceptable salts can be obtained using standard methods known in the art, for example, by reaction of a suitable basic compound such as an amine with a suitable acid capable of bringing about a physiologically suitable anion. Alkali earth metal (eg calcium) salts of alkali metals (eg sodium, potassium or lithium) or carboxylic acids can also be prepared.

The compounds of the present invention may be formulated as pharmaceutical compositions and suitable for route selected appropriately for administration to a mammalian host such as a human patient, ie, oral or parenteral (eg, intravenous, intramuscular, intraperitoneal). It can be administered in various forms. Preferably, the compound is administered parenterally.

The active compound may also be administered intravenously or intraperitoneally by infusion or injection. Solutions of the active substance or salts thereof can be prepared in water, optionally mixed with non-toxic surfactants. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin or mixtures thereof and in oils. Under ordinary conditions of storage and use, these agents contain a preservative to prevent the growth of microorganisms.

Pharmaceutical dosage forms suitable for injection or infusion are sterile aqueous solutions or dispersants or sterile agents comprising the active ingredient, optionally encapsulated in liposomes, which are employed for the immediate preparation of a sterile injectable solution or dispersant for injection. It may include powder. In all cases, the final dosage form must be sterile, fluid and stable under the conditions of manufacture and storage. The liquid carrier or vehicle may be a solvent or liquid dispersion medium comprising water, ethanol, polyols (eg, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, non-toxic glycerol esters, and suitable mixtures thereof. Proper fluidity can be maintained, for example, by the formation of liposomes, in the case of dispersants, by the maintenance of the required particle size, or by the use of surfactants. In order to prevent the action of microorganisms, various antibiotics and antifungal agents can be applied, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal and the like. In many cases, it is preferable to include isotonic agents, for example, sugars, buffers or sodium chloride. Sustained absorption of the injectable compositions can be achieved by the use of compositions of retardation agents such as aluminum monostearate and gelatin.

Sterile injectable solutions are prepared, if necessary, by insertion of the required amount of the active compound into a suitable solvent comprising the various other ingredients described above and by sterilization by filtration. In the case of sterile powders for the preparation of sterile injectable solvents, the preferred preparation is a reduced pressure drying and freeze drying technique which produces a powder of the active ingredient with any additional necessary ingredients already present in the sterile filtered solvent.

Specifically, in combination with neutron capture, suitable doses of the compounds of the invention for use in therapy range from about 0.1 to about 100 μg, such as from about 0.5 to about 50 μg, or about 0.5 to 15 μg per treatment. Include. Suitable doses for use in imaging or for use in imaging and treatment are in the range of about 0.1 mg to about 50 g, such as 0.5 mg to 10 g, about 0.5 mg to 2 g per treatment.

The required dose may conveniently be administered in a single dose or in divided doses at appropriate intervals, such as two, three, four or more sub-doses per day. The sub-dose itself can be further divided by the number of separate spaced doses.

The compound may preferably be dissolved or dispersed in the required concentration in a non-toxic liquid vehicle such as physiological saline or similar aqueous vehicle. The preselected therapeutic unit dose is then administered to experimental animals or humans by oral administration or ingestion to achieve the necessary in vivo concentrations by intravenous or intraperitoneal infusion or injection. Dosages useful for treating tumors are derived, for example, from amounts found to be effective for treating tumors in human or animal models in vitro, or from doses of other labeled vitamin B ₁₂ molecules already employed in animal treatment, such as: Can be.

2 and 3 show the four steps of synthesis used to prepare three cyanocobalamin-nido-carborane conjugates, respectively. The o-carborane carboxylic acid (2) was prepared by reacting o-carborane, n-butyllithium and carbon dioxide at -78 ° C for about 1 hour in ether. Treatment of thionyl chloride affords o-carborane carboxylic acid chloride (3) and reaction with 1,4-butanediamine in pyridine to give the amide-bonded nido-carboranoyl (4-aminobutyl) amide (4) Prepared. Compound (4) was bound to b-monocarboxylic acid of cyanocobalamin, d-monocarboxylic acid of cyanocobalamin, or b- and d-monocarboxylic acid of cyanocobalamin. In each reaction, hydroxybenzotriazole and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide were added to promote the formation of amide bonds.

The invention can be explained in more detail by the following examples.

UV-visible spectra were recorded by a diode array spectrophotometer. ¹¹ B NMR spectra with ¹ H decoupling at 192.656 MHZ were recorded on a Varian 1NOVA 600MHZ spectrometer using an 8 mm wide band probe. About 10 mg cobalamin-conjugate was dissolved in 1 ml pyridine d ₆ in a 5 mm NMR tube. 500 scans were collected with a 0.133 second acquisition time and 1 second relaxation delay. Chemical shifts are given relative to BF ₃ : (CH ₃ CH ₂ ) ₂ O.

Weight spectral data were obtained on a Sciex API 365 LC-MS / MS system (Toronto, Canada). Separation was performed on two LC-10AD pumps and an SCI-10Avp regulator (Shimadzu Scientific Instruments, Colombia, MD). The assay was monitored by UV at 214 NM with ABI 785 detector. HPLC separation was performed using a BDS-Hypersil C8 column (150 × 4.6 mm; 120A, Keystone Scientific, Inc., Bellefonte, PA). The fluidized bed consisted of water: methanol (98: 2 v: v) in pump A and water: methanol (2:92 v: v) in pump B. The linear gradient used 5% B-30% B for 10 minutes and was maintained at 30% B for 20 minutes before returning to initial conditions (mono-carborane synthesis). Di-carborane used the same fluidized bed and required a longer gradient: held at 5% B-65% B for 25 minutes and at 65% B for 15 minutes before returning to initial conditions. Separation was monitored by UV absorption at 214 NM. The flow rate was 1.0 ml / min and the post-columns were cleaved to allow ˜10 μl to flow into the mass spectrometer.

Mass spectral data were collected using electronspray ionization in positive mode over a weight range of 300-2300 AMU at a dwell time of 0.3 ms / 0.1 AMU. Synthetic samples were prepared at 5 or 10 mg / ml in the Pump A fluidized bed and fractions were injected on HPLC (1-5 μl). The retention times of the mono- and di-carborane products were determined to be 13.3 minutes and 16.2 minutes, respectively. Purification of the b- and d mono-carborane products was achieved by collecting fractions at the elution time by multiple injections. The collected fractions were combined and dried to a powder. A portion of the purification product was dissolved in metalol: H ₂ O (1: 1) and reanalyzed by HPLC-MS to confirm purification.

o-Carborane, butyllithium (1.6M solution in hexane) and putrescine were purchased from Aldrich Chemical Company (Milwiki, WI). Water-soluble carbodiimide 1-ethyl-3 (3'-dimethylaminopropyl) carbodiimide and 1-hydroxybenzotriazole were purchased from Sigma (St. Louis, MO). Thin layer chromatography (TLC) silica gel plates were purchased from Eastman Kodak. Cyanocobalamin-b, d and e monocarboxylic acids and b, d-dicarboxylic acids were prepared as described above (US Pat. Nos. 5,739,313 and DLAnton et al. , J. Am. Chem. Soc ., 1980 , 102 , 2212-2219). ), Provided by Professor Kahl of the School of Medical Chemistry at the University of California, San Francisco.

Example 1 Cyanocobalamin-Nido-Carborane Conjugate (5, FIG. 2)

1 g (-0.66 mmol) of b-monocarboxylic acid, d-monocarboxylic acid or b, d-dicarboxylic acid, hydroxybenzotriazole (810 mg) in 100 ml of water-acetone mixture (2: 1) , 6.0 mmol), a separation reaction mixture comprising 1-ethyl-3 (3-dimethylaminopropyl) carbodiimide (11.4 g, 6.0 mmol) and 4 (600 mg, 2.0 mmol) to pH 6.9 using 1N NaOH. Adjusted. The reaction was stirred at room temperature and the reaction progress was monitored by TLC. After 3 hours, the mixture was concentrated to remove acetone and the resulting aqueous suspension was extracted into 92% aqueous phenol. The phenol phase was washed with water to remove the water soluble reactant. One part of acetone and 3 parts of ether were added on each phenol and the desired cyanocobalamin-nido-carborane conjugate was extracted again into water. The aqueous layer was extracted three times with ether to remove residual phenol and unreacted material (4). Finally, the aqueous solution was evaporated for drying. The residue was triturated with acetone and the desired conjugate was isolated as an orange-red powder (yield was 90-95% based on cyanocobalamin-carboxylic acid).

The isotope ratios of the final products were also theoretically compared as follows:

Theoretical M + H ⁺ of mono product

Theoretical M + H ⁺ of die product-(C77H129CoB18O16PN16)-

The results include the identification of b and d carborane cyanocobalamin (CCC) analogs by LC-MS. The identified products continued to be separated and purified by HPLC. Purified products were reanalyzed by LC-MS and no starting material was found. MS / MS data were also obtained for the b and d CCCs to provide further structural properties. The purified product was then tested for biological assays. The e -CCC analog and the di -CCC analog were also separated and identified by LC-MS, but the preparation included one or more reaction additive products resulting from difficult purification. To provide more information for identification, the isotope ratios of the b -and d -CCC analogs as well as the di -CCC analogs were compared with the theoretical isotope ratios.

The weight spectrum demonstrated the presence of each cyanocobalamin-nido-carborane conjugate. ¹¹ B NMR, as well as volumetric spectroscopy assay 3 4 (FIG. 2 and 3) during the transition to, o- carboxylic borane nuclei Nido-carboxylic borane derivative (4, 3) lost the boron atom to produce a Yin was shown. The UV-visible spectroscopy of the final product represents the largest typical of cyanocobalamin, shows that the corin nucleus is intact and that the 5,6-dimethyl benzimidazole nucleus remains attached to the cobalt atom.

Starting material ( 4 ) was prepared as follows (see FIG. 2):

a. o-carborane carboxylic acid (2).

A solution of o-carborane (1) (5.0 g, 34.7 mmol) in 500 ml of dry ether in a 1 L round bottom flask was cooled to -78 ° C in a dry ice-acetone vessel. Argon was poured into the solution and the flask was sealed with a serum stopper. n-butyllithium (24 ml in nucleic acid, 1.6 M) was slowly injected through the syringe for about 20 minutes and the reaction stirred for an additional 30 minutes. Crushed dry ice (10-15 g) was then added and the mixture was stirred for 1 hour. The dry ice-acetone vessel was removed and the reaction left at room temperature. Ether and hexane were removed on a rotary evaporator, water (150 ml) was added and unreacted o-carborane was extracted by hexane (2 x 100 ml). The aqueous phase was oxidized with concentrated HCl and the desired product was extracted with hexane (4 x 100 ml). The combined extracts were dried over Na ₂ SO ₄ , evaporated to dryness to give 5.8 g (88.7 g) of o-carborane carboxylic acid (2), which was used without further purification.

b. o-carborane carboxylic acid chloride (3).

O-Carborane carboxylic acid (2.0 g, 10.6 mmol), dried at P ₂ O ₅ , was dissolved in 30 ml of thionylchloride and heated at reflux for 3 hours. The solution was cooled to room temperature, evaporated to dryness, dried over P ₂ O ₅ (2.05 g, 9.9 mmol, 93%) to prepare (3) and used without further purification.

c. Nido-carboranoyl (4-aminobutyl) amide (4).

The acid chloride (3) was dissolved in 15 ml of dry pyridine and 1,4-diaminobutane (1.12 g, 12.7 mmol) was added. The reaction mixture was heated to reflux for 3 hours, cooled to room temperature and concentrated. Water (10 ml) was added and the suspension was acidified with 3M HCl. The desired product was extracted with ethyl acetate (4 x 50 ml), the combined organic layers were washed once with water, dried over Na ₂ S0 ₄ and evaporated for drying to give 2.35 g (8.0 mmol, 75%) of (4) Got. As such, the product was recrystallized from various solvent mixtures, but TLC (2-propanol-NH ₄ OH-H ₂ O; 7: 1: 2) on silica gel plates showed only one ninhydrin positive compound that was distinguished from diamine It was.

Example 2 6-Carboranoylamidopropyl cobalamin

6- (3-aminoprop-1-yl) cobalamin (300 mg), hydroxybenzotriazole (270 mg), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (382 mg) and o-carr Borane monocarboxylic acid was dissolved in water (50 ml) and acetone (20 ml) and left at room temperature for 3 hours. The reaction mixture was concentrated to remove acetone and desalted via phenol extraction. The concentrated aqueous solution was crystallized from aqueous acetone to give the title compound.

Intermediate 6- (3-aminoprop-1-yl) cobalamin was prepared as follows.

a. 6- (3-aminoprop-1-yl) cobalamin

Cyano cobalamin (500 mg) was dissolved in 100 ml deoxygenated water containing 10 mg of CoC _l2 and reduced with sodium borohydride to produce the corresponding Co (I) compound. After 30 minutes, hydrochloric acid 3-chloropropyl amine (130 mg) dissolved in 5 ml of deoxygenated ethanol was added. After 1 hour, the mixture was desalted through phenol extraction at room temperature. The aminopropylcarbolamine was extracted again in water after addition of 1 part of acetone and 3 parts of ether. The aqueous solution was concentrated and the desired 6- (3-aminoprop-1-yl) cobalamin crystallized from aqueous acetone (510 mg production).

Example 3 DTPA-aminopropylcarbalamin (DAPC)

Similar to the coupling method described in Example 2, the title compound was prepared by coupling 2,6- (3-aminoprop-1-yl) cobalamin and DTPA in the presence of hydroxybenzotriazole.

Example 4 Biological Activity in vitro of Carborane Cyanocobalamin Analogues

The binding capacity of unsaturated vitamin B ₁₂ (UBBC) for carborane cyanocobalamin (Example 1, CCC) and DTPA-aminopropylcobalamin (Example 3, DAPC) analogs to measure in vitro the binding to transcobalamin protein Analyzes were performed (see DACollins and HPCHogenkamp, J. Nuclear Medicine, 1997, 38, 717-723). Serum from 5 patients evaluated for pernicious anemia in Mayo Clinic was obtained. The serum of the patient underwent such typical clinical UBBC. To determine if CCC and DAPC analogs inhibited Co-57 cyanocobalamin from binding to transcobalamin protein, UBBC modified with excess serum from 5 patients was performed.

In particular, 4 μl (ml normal saline glucose concentration 10 μg CCC) 2 CCC analogues, carborane-d-cyanocobalamin and carborane-b-cyanocobalamin and DAPC were treated with 0.4 ml serum in dim light. The analogs were incubated with the patient's serum for 20 minutes at room temperature. Clinical performed and analogue treated samples were analyzed by UBBC as defined.

The analogs completely blocked Co-57 cyanocobalamin from binding of the transcobalamin protein. Thus, the cpm of the modified UBBC assay was significantly lower than that of the clinical performer. The percent PB of the analogs to the _{transcobalamin} protein is calculated as follows (PB = 100-CCC _UBBC cpm / clinical UBBC cpm x 100). The average percent binding (PB) of 5 solutions to carborane-d-cyanocobalamin and carborane-b-cyanocobalamin (n = 10 for each solution, ie two modified UBBR analyzes per patient), respectively 35.75% and 92.93%, and 98.21% for DAPC.

Although incorporated by reference, all publications, patient and patient records herein are incorporated by reference. The present invention has been described by reference to various specific and preferred embodiments and techniques. However, it should be understood that many changes and modifications may be made within the spirit and scope of the invention.

Claims (74)

1, or a pharmaceutically acceptable salt thereof, wherein the residue of the compound of Formula I is bound to the residue of a molecule comprising B-10, wherein X is CN, OH, CH ₃ , adenosyl or B- Molecule containing 10). The moiety of claim 1, wherein the residue of the molecule comprising B-10 is bonded directly to the 6-position of the compound of formula I, or to the residue of b-, d- or e-carboxamide of the compound of formula I Directly bound compounds. The compound of claim 1, wherein the residues of the molecule comprising B-10 are linked by a linker at the 6-position of the compound of formula I, or a-, b-, d- or e-ka of the compound of formula I A compound bound by a linker to a residue of a copying midgroup. The compound of claim 1, wherein the residues of the molecule comprising B-10 are linked to the residues of the b-carboxamide group of the compound of formula (I). The compound of claim 1, wherein the residue of the molecule comprising B-10 is bonded to the residue of the d-carboxamide group of the compound of formula I. The compound of claim 1, wherein the residues of the molecule comprising B-10 are linked to the residues of the e-carboxamide group of the compound of formula (I). The compound of claim 1, wherein the residues of the molecule comprising B-10 are linked to the residues of the b-carboxamide group, and the second residue of the molecule comprising B-10 is a d-carbox of the compound of formula I Compounds bound to residues of the mid group. The compound of claim 1, wherein the residues of the molecule comprising B-10 are bonded at the 6-position of the compound of Formula I. The compound of claim 1, wherein the molecule comprising B-10 comprises 1 to about 20 boron atoms. The compound of claim 1, wherein the molecule comprising B-10 is an amino acid, carbohydrate, nucleoside or carborane. The compound of claim 1, wherein the molecule comprising B-10 is o-carborane, m-carborane, or p-carborane. The compound of claim 1, wherein the molecule comprising B-10 is o-carborane. The compound of claim 3, wherein at least one linker is of the general formula WAQ, wherein A is (C ₁ -C ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl, (C ₂ -C ₆ ) alkynyl, ( C ₃ -C ₈ ) cycloalkyl, (C ₆ -C ₁₀ ) aryl, W and Q are each independently -N (R) C (= 0)-, -C (= 0) N (R)-, -OC (= O)-, -C (= O) O-, -O-, -S-, -S (O)-, -S (O) _2- , -N (R)-, -C ( = O)-or a direct bond; Each R is independently H or (C ₁ -C ₆ ) alkyl. The compound of claim 13, wherein W is NH ₂ or COOH and Q is NH ₂ or COOH. The compound of claim 13, wherein A is (C ₁ -C ₆ ) alkyl. The compound of claim 3, wherein the at least one linker is about 5 to about 50 angstroms. The compound of claim 3, wherein the at least one linker comprises a therapeutic radionuclide or a diagnostic radionuclide. The compound of claim 17, wherein the therapeutic radionuclide is a metal radionuclide. The compound of claim 17, wherein the diagnostic radionuclide is a metal radionuclide. The compound of claim 17, wherein the diagnostic radionuclide is a non-metal radionuclide. The compound of claim 3, wherein the at least one linker is a divalent radical formed from a peptide. The compound of claim 3, wherein the at least one linker is a divalent radical formed from an amino acid. The method of claim 3, wherein the at least one linker is poly-L-glutamic acid, poly-L-aspartic acid, poly-L-histidine, poly-L-ornithine, poly-L-serine, poly-L-threonine, poly -L-tyrosine, poly-L-lysine-L-phenylalanine, poly-L-lysine or poly-L-lysine-L-tyrosine. The compound of claim 1, wherein the residue of the compound of formula I is also bound to a linker comprising a detectable radionuclide or therapeutic radionuclide. A compound in which the residue of the compound of formula I of FIG. 1 is bound to a group of formula QLW-Det, or a pharmaceutically acceptable salt thereof, wherein X represents CN, OH, CH ₃ , adenosyl, B-10 Is a containing molecule or QLW-Det; Det is a chelating group comprising Gd-157, L is a linker or absent, and W and Q are each independently -N (R) C (= 0)-,- C (= O) N (R)-, -OC (= O)-, -C (= O) O-, -O-, -S-, -S (O)-, -S (O) _2- , —C (═O) —, —N (R) —, or a direct bond; each R is independently H or (C ₁ -C ₆ ) alkyl. The group of claim 25, wherein the group of formula QLW-Det is a residue of the b-carboxamide group, a residue of the d-carboxamide group, a residue of the e-carboxamide group, or 6- of the compound of formula I Compound bound to position. 27. The compound of claim 25, wherein the group of formula QLW-Det is bonded to the residue of the b-carboxamide group of the compound of formula I, and the second group of formula QLW-Det is d- of the compound of formula I Compound bound to a residue of a carboxamide group. The compound of claim 25, wherein the group of formula Q-L-W-Det is about 20 to about 500 angstroms in length. The compound of claim 25, wherein the at least one chelating group is EDTA, DTPA, DOTA, DOTMP, TETA, MAG3, or DCTA. The compound of claim 25, wherein the at least one chelating group is DTPA comprising Gd-157. 1, or a pharmaceutically acceptable salt thereof, wherein the residue of the compound of Formula I is bound to the residue of a molecule comprising B-10, wherein the residue of the compound of Formula I is also a group of QLW-Det Wherein X is a molecule comprising CN, OH, CH ₃ , adenosyl, a group of formula QLW-Det, or B-10; Det is a chelating group comprising a therapeutic radionuclide or a diagnostic radionuclide; L is a linker or absent; Q and W are each independently -N (R) C (= O)-, -C (= O) N (R)-, -OC (= O)-, -C (= O) O-, -O —, —S—, —S (O) —, —S (O) ₂ —, —C (═O) —, —N (R) —, or a direct bond; Each R is independently H or (C ₁ -C ₆ ) alkyl. The compound of claim 31, wherein the at least one radionuclide is Tc ^99m , In ¹¹¹ , In ¹¹⁰ , Gd ¹⁵⁷ or Y ⁸⁶ . The molecule of claim 31, wherein the molecule comprising B-10 is a residue of a b-carboxamide group, a residue of a d-carboxamide group, a residue of an e-carboxamide group, or 6- of a compound of Formula I Compound bound to position. 32. The compound of claim 31, wherein the chelating group is DTA, DTPA, DOTA, TETA, DOTMP, MAG3, or DCTA. 32. The compound of claim 31, wherein the chelating group is DTPA. The compound of claim 31, wherein the residue of the molecule comprising B-10 comprises 1 to about 20 boron elements. 32. The compound of claim 31, wherein the residue of the molecule comprising B-10 is a carbohydrate, amino acid, nucleoside or carborane. The compound of claim 31, wherein the molecule comprising B-10 is o-nido-carborane, m-nido-carborane, or p-nido-carborane. The compound of claim 31, wherein the molecule comprising B-10 is o-nido-carborane. The compound of claim 31, wherein the residue of the molecule comprising B-10 is bonded directly to the 6-position of the compound of Formula I or to a residue of the b-, d- or e-carboxamide group. The compound of claim 31, wherein the residue of the compound of formula I is linked to a residue of a molecule comprising B-10 via a linker. The compound of claim 41, wherein the linker comprises a non-metal radionuclide. 42. The compound of claim 41, wherein the linker is about 5 to about 50 angstroms. The compound of claim 1, further comprising a detectable radionuclide. The compound of claim 2, wherein the detectable radionuclide is a non-metal radionuclide. The compound of claim 3, wherein the non-metallic radionuclide is carbon-11, fluorine-18, bromine-76, iodine-123 or iodine-124. The compound of claim 2, wherein the detectable radionuclide is directly linked to the compound of general formula (I). The compound of claim 2, wherein the detectable radionuclide is bound to a compound of formula I by a linker. The compound of claim 6, wherein the linker is of formula WA, wherein A is (C ₁ -C ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl, (C ₂ -C ₆ ) alkynyl, (C ₃ -C ₈ ) cycloalkyl or (C ₆ -C ₁₀ ) aryl, W is -N (R) C (= 0)-, -C (= 0) N (R)-, -OC (= 0)- , -C (= O) O-, -O-, -S-, -S (O)-, -S (O) _2- , -N (R)-, -C (= O)-or direct bond Is; Each R is independently H or (C ₁ -C ₆ ) alkyl and A is substituted with one or more non-metallic radionuclides. 49. The compound of claim 48, wherein said linker is about 5 to about 50 angstroms. 49. The compound of claim 48, wherein said linker is a divalent peptide or amino acid. 49. The method of claim 48, wherein the linker is poly-L-glutamic acid, poly-L-aspartic acid, poly-L-histidine, poly-L-ornithine, poly-L-serine, poly-L-threonine, poly-L A compound that is -tyrosine, poly-L-lysine-L-phenylalanine, poly-L-lysine or poly-L-lysine-L-tyrosine. The compound of claim 48, wherein the linker is bonded to the 6-position of the compound of Formula I or to a residue of an a-, b-, d- or e-carboxamide group. 1 or a pharmaceutically acceptable salt thereof, wherein the moiety of the compound of general formula I of FIG. 1 is linked to a detectable radionuclide and 2) to a group comprising Gd-157. 55. The group of claim 54, wherein the group comprising Gd-157 has the general formula QLW-Det; Wherein X is a molecule comprising CN, OH, CH ₃ , adenosyl, B-10 or QLW-Det; Det is a chelating group comprising Gd-157, L is a linker or absent, and W and Q are each independently -N (R) C (= 0)-, -C (= 0) N (R) -, -OC (= O)-, -C (= O) O-, -O-, -S-, -S (O)-, -S (O) _2- , -C (= O)-, -N (R)-, or a direct bond; Each R is independently H or (C ₁ -C ₆ ) alkyl. 55. The compound of claim 54, wherein the detectable radionuclide is a non-metal radionuclide. The compound of claim 56, wherein the non-metallic radionuclide is carbon-11, fluorine-18, bromine-76, iodine-123 or iodine-124. 55. The compound of claim 54, wherein the detectable radionuclide is directly linked to the compound of general formula (I). 55. The compound of claim 54, wherein the detectable radionuclide is bound to a compound of formula I by a linker. The compound of claim 59, wherein the linker is of formula WA, wherein A is (C ₁ -C ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl, (C ₂ -C ₆ ) alkynyl, (C ₃ -C ₈ ) cycloalkyl, (C ₆ -C ₁₀ ) aryl, W is -N (R) C (= 0)-, -C (= 0) N (R)-, -OC (= 0)- , -C (= O) O-, -O-, -S-, -S (O)-, -S (O) _2- , -N (R)-, -C (= O)-or direct bond Is; Each R is independently H or (C ₁ -C ₆ ) alkyl and A is substituted with one or more non-metallic radionuclides. 60. The compound of claim 59, wherein the linker is about 5 to about 50 angstroms. 60. The compound of claim 59, wherein said linker is a divalent peptide or amino acid. 59. The method of claim 58, wherein the linker is poly-L-glutamic acid, poly-L-aspartic acid, poly-L-histidine, poly-L-ornithine, poly-L-serine, poly-L-threonine, poly-L A compound that is -tyrosine, poly-L-lysine-L-phenylalanine, poly-L-lysine or poly-L-lysine-L-tyrosine. 60. The compound of claim 59, wherein said linker is attached to the 6-position of the compound of Formula I or to a residue of an a-, b-, d- or e-carboxamide group. 1 wherein the residue of the compound of Formula I is 1) a molecule comprising B-10 or a chelating group comprising Gd-157, and 2) a compound bound to at least one residue of Formula QLW-Det, or Pharmaceutically acceptable salts thereof, wherein each Det is independently a chelating group comprising a metal radionuclide; each L is a linker or absent, and W and Q are each independently -N (R) C (= O)-, -C (= O) N (R)-, -OC (= O)-, -C (= O) O-, -O-, -S-, -S (O)-, -S (O) _2- , -C (= 0)-, -N (R)-, or a direct bond; each R is independently H or (C ₁ -C ₆ ) alkyl. 45. The compound of claim 1 or 44, wherein the moiety of the compound of formula I is also bound to a group comprising Gd-157. 67. The group of claim 66, wherein the group comprising Gd-157 has the general formula QLW-Det, wherein X is a molecule comprising CN, OH, CH ₃ , adenosyl, B-10 or QLW-Det; Det is a chelating group comprising Gd-157, L is a linker or absent, and W and Q are each independently -N (R) C (= 0)-, -C (= 0) N (R) -, -OC (= O)-, -C (= O) O-, -O-, -S-, -S (O)-, -S (O) _2- , -C (= O)-, -N (R)-, or a direct bond; Each R is independently H or (C ₁ -C ₆ ) alkyl. A pharmaceutical composition comprising the compound of any one of claims 1-67 and a pharmaceutically acceptable carrier. 67. A mammal is administered an effective amount of a compound of any one of claims 1 to 67 in combination with a pharmaceutically acceptable vehicle; A method of treating tumors in a mammal in need of such treatment comprising performing neutron capture treatment. Administering to the mammal a detectable amount of a compound of any one of claims 1-67; A method of imaging tumors in a mammal comprising detection of the presence of said compound. The method of claim 70, further comprising treating the tumor with neutron capture treatment. 68. The compound of any one of claims 1-67 for use in medical treatment or diagnosis. Use of a compound of any one of claims 1 to 67 for the manufacture of a medicament for imaging a tumor in a mammal. Use of a compound of any one of claims 1 to 67 for the manufacture of a medicament for treating a tumor in a mammal in need thereof.