WO2011019882A1 - Conjugués bêtabloquants nanostructurés - Google Patents

Conjugués bêtabloquants nanostructurés Download PDF

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Publication number
WO2011019882A1
WO2011019882A1 PCT/US2010/045279 US2010045279W WO2011019882A1 WO 2011019882 A1 WO2011019882 A1 WO 2011019882A1 US 2010045279 W US2010045279 W US 2010045279W WO 2011019882 A1 WO2011019882 A1 WO 2011019882A1
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beta
blocker
carrier
bone
bisphosphonate
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PCT/US2010/045279
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English (en)
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Lon J. Wilson
Ivana Romina Guadalupe Peralta
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William Marsh Rice University
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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y30/00—Nanotechnology for materials or surface science, e.g. nanocomposites
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6921—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere
    • A61K47/6925—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a microcapsule, nanocapsule, microbubble or nanobubble

Definitions

  • Bone is the hard form of connective tissue that makes up most of the skeleton; it consists of an organic component, the cells and matrix, and an inorganic, or mineral component. Living bone is continuously recycled by the processes of bone formation and resorption. During an animal's growth years, bone formation exceeds resorption and the skeletal mass increases. In humans, bone mass reaches a peak between ages 20 and 30 years. After that time, the rate of formation and resorption stabilize the bone mass until age 35 to 40 years, at which time resorption begins to exceed formation, and the total mass slowly decreases. The process of bone turnover in adults is known as remodeling. Up to 15 percent of the total bone mass turns over every year in the remodeling process.
  • osteoclasts and osteoblasts.
  • Osteoclasts absorb and remove mineralized bone, releasing calcium and phosphate.
  • Osteoblasts assimilate calcium and phosphate to slowly produce crystals, or mineralized bone. As the mineralized bone accumulates and surrounds the osteoblast, that cell slows its activity and becomes an interior osteocyte.
  • a cement line containing bone matrix material which delineates the zones of resorption and new bone formation. Bone formation takes place in areas where bone undergoes the greatest stress. Therefore, a bone that is underutilized, such as a leg that is immobilized, is prone to resorption.
  • Bone remodeling not only alters the architecture of the bone, it also enables the body to regulate the levels of calcium ions in the blood and interstitial fluid. These calcium levels must remain within a fairly narrow range in order to ensure the proper functioning of nerve transmission, the integrity and permeability of cellular membranes, and the ability of the blood to clot. Bone contains about 99 percent of the body's calcium. When fluid calcium levels fall too low, parathyroid hormone stimulates osteoclast activity (causing increased bone resorption) and the subsequent release of calcium into the bloodstream. When fluid calcium levels rise excessively, the hormone calcitonin inhibits resorption (acting against the parathyroid hormone), thereby restricting the release of calcium from the bones.
  • Vitamin D is also essential, as it makes possible the body's use of ingested calcium. Estrogen also inhibits bone resorption.
  • osteosclerosis when a bone has much more bone tissue than average, it is termed osteosclerosis; when there is less, it is called osteopenia. If bone suffers from a lack of mineral content, it is called rickets in children and osteomalacia in adults. The afflicted bones become malleable and vulnerable to deformities. In children, this condition is often the result of vitamin D deficiency.
  • osteoporosis a generalized osteopenia, is the most common. This disease primarily affects the aged and is more serious in women than men. Osteoporosis is responsible for many of the fractures encountered by the elderly. Another disease that often afflicts the elderly is Paget' s disease, characterized by bone deformity and calcium imbalance.
  • bone cells can be killed by a lack of blood supply; this tissue death is termed necrosis or osteonecrosis. It can be brought on by injury, the blockage of an artery, circulatory problems, the administration of corticosteroid hormones for the treatment of another affliction, or by a disease of the metabolic system.
  • Osteomyelitis refers to a bone infection, which can be acquired through an open wound, or from an infection elsewhere in the body. Tumors can also develop in bone tissue.
  • Congenital bone diseases refer to abnormalities which are present at birth; some are genetically transferred but most occur due to problems during pregnancy or delivery.
  • bone fractures are the result of a force greater than the strength and resistance of the bone. Age and disease are factors that determine whether a given force will cause a fracture.
  • compositions that mitigate bone loss and/or encourage bone growth are the subject of ongoing research.
  • the present disclosure relates generally to nanostructure-beta-blocker conjugates. More particularly, in some embodiments, the present disclosure relates to nanostructure-beta-blocker conjugates, methods of their synthesis, and their use in the treatment and prevention of bone disease, such as osteoporosis.
  • the present disclosure provides a composition
  • a composition comprising: a C n carrier, wherein C n refers to a fullerene moiety or nanotube comprising n carbon atoms, a bone targeting agent, and a beta-blocker.
  • the present disclosure provides a method comprising administering a therapeutically effective amount of a composition comprising a C n carrier, wherein C n refers to a fullerene moiety or nanotube comprising n carbon atoms, a bone targeting agent, and a beta-blocker to a mammal.
  • the present disclosure provides a method comprising providing a C n carrier, wherein C n refers to a fullerene moiety or nanotube comprising n carbon atoms, and allowing a bone targeting agent and a beta-blocker to react with the carrier so as to form a nanostructure-beta-blocker conjugate.
  • FIGURE 1 shows the chemical structures of certain beta-blockers, where * designates the chiral center.
  • FIGURE 2 shows the synthesis and Chemical Structure of levobunolol, where * designates the chiral center.
  • FIGURE 3 shows the two dimensional structure of a C 60 -bisphosphonate-beta-blocker conjugate, according to one embodiment.
  • FIGURE 4 shows the synthesis of a model C 60 hydrazone compound (3).
  • FIGURE 5 shows the Synthesis of tert-bxxty ⁇ 3-[(4-hydrazinyl-4-oxobutyl)amino]-3- oxopropanoate (5).
  • FIGURE 6 shows the synthesis of a second model C 60 hydrazone compound (7).
  • FIGURE 7 shows the protection of levobunolol (8).
  • FIGURE 8 shows the synthesis of a C 60 -beta-blocker conjugate (11), according to one embodiment, (a) anhydrous N 2 H 4 , methanol, (b) protected levobunolol, 2-methoxy-ethanol, (c) CBr 4 , DBU, toluene; CH 2 C1 2 (2:1).
  • FIGURE 9 shows the synthesis of a C 6 o-Bisphosphonate-Beta-blocker Conjugate (13), according to one embodiment, (a) CBr 4 , DBU, toluene;CH 2 Cl 2 (2:l), (b) Si(CH 3 ) 3 I, CCl 4 , H 2 O, NaOH, TFA, NaCl. Only one possible geometrical isomer of 12 is shown.
  • FIGURE 10 is an image depicting the MALDI-TOF MS of 12.
  • the present disclosure relates generally to nanostructure-beta-blocker conjugates. More particularly, in some embodiments, the present disclosure relates to nanostructure-beta-blocker conjugates, methods of their synthesis, and their use in the treatment and prevention of osteoporosis.
  • Beta-adrenergic antagonists or beta-blockers comprise a group of drugs that are mostly used to treat cardiovascular disorders such as hypertension, cardiac arrhythmia, or ischemic heart disease. They possess a natural high degree of enantioselectivity in binding to ⁇ ( ⁇ i and/or ⁇ 2 ) receptors, and they competitively inhibit the beta effects of endogenous catecholamines, which are "fight-or-flight" hormones (adrenaline, noradrenaline and dopamine) that the adrenal glands release in response to stress.
  • catecholamines which are "fight-or-flight" hormones (adrenaline, noradrenaline and dopamine) that the adrenal glands release in response to stress.
  • beta-blockers are so active, they cannot be administered systemically for the treatment of osteoporosis.
  • beta-blockers to be used as a therapy for osteoporosis or other bone disorders, they should be targeted and delivered mainly to bone to minimize cardiovascular side effects. Accordingly, in some embodiments, the present disclosure provides a nanostructure-beta-blocker conjugate that may provide a targeted therapy for bone disease, such as osteoporosis.
  • the present disclosure provides a composition comprising: a C n carrier, wherein C n refers to a fullerene moiety or nanotube comprising n carbon atoms, a bone targeting agent, and a beta-blocker.
  • a C n carrier refers to a fullerene moiety comprising n carbon atoms or a nanotube moiety comprising at least n carbon atoms.
  • a C n carrier may act as an ideal scaffold for targeted beta-blocker delivery because it is a biologically stable molecule that is non-toxic, non-immunogenic and efficiently cleared in mammals when it is properly derivatized.
  • Suitable C n carriers for use in conjunction with the compositions of the present disclosure include, but are not limited to, buckminsterfullerenes, gadofullerenes, single walled carbon nanotubes (SWNTs), and ultra-short carbon nanotubes (US-tubes).
  • Buckminsterfullerenes also known as fullerenes or more colloquially, buckyballs, are closed- cage molecules consisting essentially of sp 2 -hybridized carbons.
  • Fullerenes are the third form of pure carbon, in addition to diamond and graphite. Typically, fullerenes are arranged in hexagons, pentagons, or both.
  • fullerenes have 12 pentagons and varying numbers of hexagons, depending on the size of the molecule.
  • SWNTs also known as single walled tubular fullerenes
  • SWNTs are cylindrical molecules consisting essentially of sp 2 hybridized carbons.
  • Single walled tubular fullerenes are distinguished from each other by a double index (x,y), where x and y are integers that describe how to cut a single strip of hexagonal graphite such that its edges join seamlessly when the strip is wrapped onto the surface of a cylinder.
  • x ⁇ y and y ⁇ O the resulting tube has chirality.
  • the electronic properties of the nanotube are dependent on the conformation, for example, arm-chair tubes are metallic and have extremely high electrical conductivity. Other tube types are metallic, semi-metals, or semiconductors, depending on their conformation. Regardless of tube type, all SWNTs have extremely high thermal conductivity and tensile strength.
  • the SWNT may be a cylinder with two open ends, a cylinder with one closed end, or a cylinder with two closed ends. Generally, an end of an SWNT can be closed by a hemifullerene, e.g. a (10,10) carbon nanotube can be closed by a 30-carbon hemifullerene.
  • the open ends can have any valences unfilled by carbon-carbon bonds within the single wall carbon nanotube filled by bonds with hydrogen, hydroxyl groups, carboxyl groups, or other groups.
  • SWNTs can also be cut into ultra-short pieces, thereby forming US-tubes.
  • US-tubes refers to ultra short carbon nanotubes with lengths from about 20 nm to about 100 nm.
  • a C n carrier can be substituted or unsubstituted.
  • substituted it is meant that a group of one or more atoms is covalently linked to one or more atoms of a C n carrier.
  • in situ Bingel chemistry may be used to substitute a C n carrier with appropriate groups to form the targeted nanostructures of the present disclosure.
  • groups suitable for use include, but are not limited to, malonate groups, serinol malonates, groups derived from malonates, serinol groups, carboxylic acid, polyethyleneglycol (PEG), and the like.
  • a C n carrier is substituted with one or more water-solubilizing groups.
  • Water-solubilizing groups are polar groups (that is, groups having a net dipole moment) that render the generally hydrophobic fullerene core soluble in water.
  • the addition of such groups allow for greater biocompatibility of a C n carrier.
  • a C n carrier may contain from 1 to 4 addends.
  • a C n carrier can be substituted with any water solubilizing group to allow for sufficient water solubility and biocompatibility, but the spectroscopic properties of the C n carrier should not be compromised.
  • a C n carrier may be further substituted with either a thiol (-SH) or an amine (-NH 2 ) group.
  • compositions of the present disclosure further comprise a bone targeting agent.
  • a suitable bone targeting agent may include, but is not limited to, a bisphosphonate.
  • Bisphosphonates are compounds generally characterized by two C-P bonds.
  • suitable bisphosphonates may include etidronate, clodronate, tiludronate, pamidronate, neridronate, olpadronate, alendronate, ibandronate, risedronate, zoledronate and a combination thereof.
  • bisphosphonates While not bound to any particular theory, it is currently believed that all bisphosphonates generally act in a similar manner on bone: they bind permanently to mineralized bone surfaces and inhibit subsequent osteoclastic activity, namely the removal of bone during the process of bone remodeling. Because they reduce the amount of bone tissue degraded during the remodeling cycle, they are sometimes referred to as "antiresorptive agents.” The application of bisphosphonates usually reduces bone loss and, correspondingly, the risk of broken bones, and sometime increases bone mass.
  • the bisphosphonates may offer several advantages over estrogens in treating osteoporosis. They are bone-tissue specific, have minimal side effects (e.g., nausea, abdominal pain and loose bowel movements), cause no known risk of carcinogenesis, and have antiresorptive efficacy that is equivalent to or greater than estrogens. Furthermore, there is some evidence that the use of bisphosphonates can cause a reduction in incident vertebral fractures.
  • Nanostructure-beta-blocker conjugates of the present disclosure further comprise a beta- blocker.
  • a suitable beta-blocker possesses at least one chiral center and at least one of the chiral carbon atoms on the alkyl side chain is directly attached to a hydroxyl group.
  • suitable beta-blockers have at least one aromatic ring structure attached to a side alkyl chain possessing a secondary hydroxyl and amine functional group.
  • the amine may have an isopropyl or bulkier substituent group which appears to favor the interaction with beta-receptors. In general, it is believed that the nature of the substituents on the aromatic ring determines whether the effect will be predominantly activation or blockage.
  • beta-blockers e.g., propranolol, metoprolol, atenolol, and pindolol
  • beta-blockers e.g., propranolol, metoprolol, atenolol, and pindolol
  • beta-blockers may include, but are not limited to, dichloroisoproterenol, propanolol, atenolol, pindolol, metoprolol, timolol, bunolol, levobunolol, isomers thereof and combinations thereof ( Figure 1).
  • Pharmacologically, beta-blockers are distinguished based on their selectivity for beta-receptors.
  • the non-selective beta-blockers including propranolol, pindolol, and timolol, block both ⁇ i- and ⁇ 2 -adrenergic receptors.
  • selective beta-blockers including metoprolol and atenolol, have greater affinity for ⁇ i receptors.
  • beta-blockers are non-stereoselectively absorbed from the gastrointestinal tract via passive diffusion.
  • the lipophilic beta-blockers are eventually metabolized and therefore eliminated.
  • the more hydrophilic beta-blockers are usually excreted unchanged in urine.
  • Levobunolol (-)-5-[3-(tert-Butylamino)-2-hydroxypropoxy]-3,4-dihydro-l(2H)- naphthalenone, is the levorotatory and pharmacologically active isomer of bunolol. It is a potent non-selective beta-blocker which may be synthesized by the reaction of epichlorohydrin with 5- hydroxy- 1 -tetralone in the presence of NaOH ( Figure 2). It is currently marketed as a hydrochloride ophthalmic solution for the treatment of glaucoma as AKBeta® and Betagan®.
  • nanostructure-beta-blocker conjugate of the present disclosure comprises a C 60 fullerene, bisphosphonate, and levobunolol.
  • the carboxyl group of the tetralone of levobunolol was reacted with a malonic hydrazide and then coupled to the C 6 o-Bis(bisphosphonate) compound via a Bingel reaction.
  • the nanostructure-beta-blocker conjugates of the present disclosure may be synthesized using Bingel-Hirsch additions to the carbon nanostructure. Furthermore, in certain embodiments, the nanostructure-beta-blocker conjugates of the present disclosure may be used for treating a disease. For example, the nanostructure-beta-blocker conjugates of the present disclosure may be used for the treatment of, among other things, osteoporosis.
  • DIPEA Alfa Aesar
  • levobunolol ⁇ Cl BalPharma
  • di-tert-butyl dicarbonate Wisher
  • the N 2 (Trigas, prepurified) was purified by passing though a column containing R3-11 catalyst
  • Flash chromatography was carried out using silica gel (70-230 mesh from EM science) after activation at 200 0 C for at least 24 hours. TLC analyses were carried out using Whatman 250 ⁇ m layer silica gel with fluorescent indicator on polyester backing (PE SIL G/UV). HPLC was performed on a Hitachi L-6200A Intelligent Pump HPLC system with a Hitachi Model L- 3000 UV-vis photodiode array detector using various columns as specified in the synthesis section. All samples were filtered with a 0.2 ⁇ m nylon syringe filter (Fisher) prior to injections.
  • Mass spectra were obtained on a Bruker MS Reflex IV MALDI-TOF mass spectrometer.
  • MALDI-TOF spectra unless otherwise specified, trans-2-[3-(4-tert-Butylphenyl)-2- rnethyl-2-propenylidene]malononitrile (DCTB) was used as matrix.
  • DCTB trans-2-[3-(4-tert-Butylphenyl)-2- rnethyl-2-propenylidene]malononitrile
  • FT-IR spectra of the neat compounds were collected on a Nicolet Avatar FT-IR spectrometer, and the acquired data was processed using Origin" 7.5.
  • the strategy for the synthesis of a nanostructure-bisphosphonate-beta- blocker conjugate involved the synthesis of a malonohydrazide derivative and coupling it to levobunolol via a hydrazone bond, followed by the attachment to C 60 . Since hydrazide compounds have not been previously coupled to C 60 , two model compounds were first prepared. This synthetic sequence was designed to minimize the number of steps involving levobunolol due to its high cost.
  • the first synthesis involved the preparation of malonodihydrazide 1 according to Jung et. al and its reaction with acetone to form a hydrazone 2.
  • the Bingel reaction of 2 with C 60 with in situ generation of the brominated intermediate gave compound 3.
  • the Bingel reaction (nucleophilic cyclopropanation) was used since it was by far the simplest and most versatile method of C 60 derivatization. This reaction, like most fullerene derivatization procedures, afforded a mixture of mono, bis, tris a tetraaducts.
  • a hydrazone could be coupled to C 60 via a Bingel reaction
  • a second model compound reaction was designed.
  • the ketone chosen had a tetralone group similar to the levobunolol molecule.
  • Malonate 4 was formed by reacting mono-tert-butyl malonate and methyl-4-aminobutyrate HCl in the presence of DCC. After addition of dry hydrazine, hydrazide 5 was formed. As shown in Figure 6, 5-methoxy-l- tetralone was then coupled to 5 forming hydrazone 6.
  • C 60 [C(PO 3 iPr 2 ) 2 ]2 (50 mg, 0.0357 mmol) was dissolved in 100 mL of toluene: CH 2 Cl 2 (2:1), and then 10 (19.5 mg, 0.036 mmol), CBr 4 (11.8 mg, 0.036 mmol), and DBU (5.5 mg, 0.036 mmol) were added. After stirring at room temperature for two hours, the reaction mixture was filtered and the solvent was removed in vacuo.
  • MALDI-TOF MS calcd. 1950.91. Found 1949.97 [M + H + ].

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Abstract

L'invention porte sur des conjugués bêtabloquants nanostructurés. De plus, l'invention porte sur des procédés de synthèse de conjugués bêtabloquants nanostructurés et sur leur utilisation dans le traitement et la prévention de maladies osseuses telles que l'ostéoporose.
PCT/US2010/045279 2009-08-12 2010-08-12 Conjugués bêtabloquants nanostructurés WO2011019882A1 (fr)

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013157833A1 (fr) * 2012-04-18 2013-10-24 서울대학교산학협력단 Composition comprenant un bêta-bloquant comme principe actif pour traiter ou diminuer l'obésité, les maladies métaboliques et l'ostéopénie.
JP2016194513A (ja) * 2015-03-31 2016-11-17 日油株式会社 高分子量ポリオキシエチレン誘導体のマトリクス支援レーザー脱離質量分析法
CN108578705A (zh) * 2018-05-18 2018-09-28 浙江医药高等专科学校 叶酸接枝富勒醇载阿霉素前药及其制备方法与应用
WO2019119141A1 (fr) 2017-12-22 2019-06-27 Ontario Institute For Cancer Research (Oicr) Lieurs d'acylhydrazone hétérocycliques, procédés et utilisations associés
WO2021150256A1 (fr) * 2020-01-26 2021-07-29 Butzloff Peter Robert Phosphonates de fullerènes, procédé et médicament
US11576981B2 (en) 2017-12-06 2023-02-14 Ontario Institute For Cancer Research (Oicr) Acyl hydrazone linkers, methods and uses thereof

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040038946A1 (en) * 2001-04-27 2004-02-26 Wilson Lon J. Fullerene-based drugs targeted to bone
US20070049616A1 (en) * 2005-08-25 2007-03-01 Ksander Gary M Organic compounds

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040038946A1 (en) * 2001-04-27 2004-02-26 Wilson Lon J. Fullerene-based drugs targeted to bone
US20070049616A1 (en) * 2005-08-25 2007-03-01 Ksander Gary M Organic compounds

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013157833A1 (fr) * 2012-04-18 2013-10-24 서울대학교산학협력단 Composition comprenant un bêta-bloquant comme principe actif pour traiter ou diminuer l'obésité, les maladies métaboliques et l'ostéopénie.
JP2016194513A (ja) * 2015-03-31 2016-11-17 日油株式会社 高分子量ポリオキシエチレン誘導体のマトリクス支援レーザー脱離質量分析法
US11576981B2 (en) 2017-12-06 2023-02-14 Ontario Institute For Cancer Research (Oicr) Acyl hydrazone linkers, methods and uses thereof
WO2019119141A1 (fr) 2017-12-22 2019-06-27 Ontario Institute For Cancer Research (Oicr) Lieurs d'acylhydrazone hétérocycliques, procédés et utilisations associés
EP3728273A4 (fr) * 2017-12-22 2021-12-29 Ontario Institute for Cancer Research (OICR) Lieurs d'acylhydrazone hétérocycliques, procédés et utilisations associés
US11850287B2 (en) 2017-12-22 2023-12-26 Ontario Institute For Cancer Search (Oicr) Heterocyclic acyl hydrazone linkers, methods and uses thereof
CN108578705A (zh) * 2018-05-18 2018-09-28 浙江医药高等专科学校 叶酸接枝富勒醇载阿霉素前药及其制备方法与应用
CN108578705B (zh) * 2018-05-18 2021-10-15 浙江医药高等专科学校 叶酸接枝富勒醇载阿霉素前药及其制备方法与应用
WO2021150256A1 (fr) * 2020-01-26 2021-07-29 Butzloff Peter Robert Phosphonates de fullerènes, procédé et médicament

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