WO2002077037A2 - Monomeres biaryles et polymeres dendritiques derives - Google Patents

Monomeres biaryles et polymeres dendritiques derives Download PDF

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WO2002077037A2
WO2002077037A2 PCT/US2002/008997 US0208997W WO02077037A2 WO 2002077037 A2 WO2002077037 A2 WO 2002077037A2 US 0208997 W US0208997 W US 0208997W WO 02077037 A2 WO02077037 A2 WO 02077037A2
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alkyl
substituted
phenyl
nhr
substituent
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PCT/US2002/008997
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WO2002077037A3 (fr
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Sankaran Thayumanavan
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The Administrators Of The Tulane Educational Fund
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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G83/00—Macromolecular compounds not provided for in groups C08G2/00 - C08G81/00
    • C08G83/002—Dendritic macromolecules
    • C08G83/003—Dendrimers
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/582—Recycling of unreacted starting or intermediate materials

Definitions

  • This invention relates generally to biaryl monomers and hyperbranched polymers, dendrons, and dendrimers derived therefrom. More particularly this invention relates to biaryl monomers that are capable of bonding to three other monomers and hyperbranched polymers, dendrons and dendrimers derived therefrom.
  • a promising approach to gaining control over the orientation and spacial disposition of functional groups within a dendritic polymer involves rendering the polymer amphiphilic (see, e.g., Newkome et al. , at pages 59-68; 234-236; and 415-416, incorporated herein by reference).
  • amphiphilic dendritic polymers however, the amphiphilicity is the result of the difference in hydrophobicity between the macromolecular backbone and the peripheral moieties, or between different peripheral moieties.
  • the functional groups are not directed toward the interiors of the globular dendritic polymer. In fact, functionalization of dendrons and dendrimers is often only practically achievable at the peripheral monomers of the dendritic structure.
  • Functionality has been introduced into the interior of a dendrimer by functionalization of the core monomer, as for example, utilizing a porphyrin group as the core monomer to allow sequestration of a metal ion in the core of a dendrimer (see e.g., Newkome et al. at pages 475-476, incorporated herein by reference).
  • a porphyrin group as the core monomer to allow sequestration of a metal ion in the core of a dendrimer.
  • An advantage of globular dendritic materials is that these molecules can act as nanoscale containers. Since dendrimers may be synthesized in globular sizes in the range of about 2 to about 15 nm in diameter, these materials are useful as host molecules for a number of guest substances. For example, in controlled drug release a non-polar drug can be encapsulated within these globular containers. The drugs can then be slowly released by diffusion.
  • the size of the nanoparticle can be directly controlled by controlling the size of the globular dendrimer host in which the particle is assembled.
  • dendritic structures As potential biological mimics, however, requires the ability to incorporate functional structural elements into the dendrimer molecular structure in a controlled and selective manner.
  • a useful feature to incorporate into a dendrimer structure would be a functionalized interior region. It would be desirable to be able to selectively incorporate either hydrophobic or hydrophilic functionality, for example, on the exterior surface or interior region of a globular dendrimer. Such selective functionalization allows, for example, tailoring of the dendritic molecular structure to accommodate guest molecules in the interior of a dendrimer or binding of the exterior of a dendrimer to various substrates.
  • dendritic polymer in which the functional environment of the globular interior ' and exterior surfaces of the polymer could be predictably controlled and manipulated by environmental factors such as solvent polarity, pH, solution ionic strength, and the like.
  • the currently known amphiphilic dendritic polymers fall short of this goal.
  • these materials adopt either globular or open structures, depending on the solvent environment in which they are found.
  • These materials for example, generally do not have the capability of forming globular structures in which the interior functionality can be changed from hydrophobic (i.e. , lipophilic) to hydrophilic within a single dendritic molecular structure.
  • the dendritic polymers of the present invention fulfill this need.
  • a dendritic polymer of the present invention comprises at least one biaryl monomer unit having at least a first aryl group and a second aryl group directly covalently bonded to the first aryl group.
  • the first aryl group of the biaryl monomer defines a plane
  • the second aryl group includes a first functional substituent and a second functional substituent.
  • the first and second functional substituents are bonded to the second aryl group such that the substituents are oriented on opposite sides of the plane defined by the first aryl group.
  • the first functional substituent is hydrophilic and the second functional substituent is hydrophobic the hydrophilic and hydrophobic substituents are oriented on opposite sides of the plane defined by the first aryl group.
  • first aryl group has first and second branching substituents, each adapted for bonding to another monomer unit, and at least one of the first and second aryl group has a third branching substituent adapted for bonding to a third monomer unit.
  • the dendritic polymers of the present invention adopt a globular conformation having an exterior surface and an interior surface.
  • the bi- planar nature of the biaryl monomer units of the polymer necessarily orients the first and second functional substituents opposite surfaces of the globular polymer.
  • the first functional substituent of a monomer unit is directed to the exterior surface
  • the second functional substituent is directed toward the interior surface.
  • the first and second functional substituents can be selected such that specific groups will orient to specific surfaces of the polymer. For example, if the first functional substituent is hydrophilic and the second functional substituent is hydrophobic, the hydrophobic substituents will orient toward the interior surface of the polymer when the polymer is dissolved in a hydrophilic solvent such as water.
  • the ability of a preferred embodiment of the dendritic polymer of the present invention to spontaneously orient functional groups according to the hydrophobic or hydrophilic nature of the solvent (i.e., the solvent polarity) in which the dendritic polymer is dissolved provides distinct advantages and improvements over conventional amphiphilic dendritic materials.
  • Facially amphiphilic dendritic polymers have a functionalized interior region capable of selectively encapsulating guest materials and capable of releasing such materials by inversion of the dendritic polymer if the solvent polarity or the functional group hydrophilicity/hydrophobicity changes.
  • the functionality of the interior region of conventional amphiphilic dendrimers is not generally affected by the solvent polarity.
  • the chemical nature and identity of the hydrophilic and hydrophobic substituents of the dendritic polymers of the invention can be selected to achieve a desired functional environment on the exterior surface of the globular polymer, the interior cavity of the polymer, or both.
  • the dendritic polymers of the present invention are useful, for example, as agents for targeted delivery of pharmaceuticals; for encapsulation and controlled release of drugs and other chemical active agents such as pesticides; as solubilizing agents fbr pharmaceuticals, agrochemicals and dyes, as carriers for fluorescent imaging agents, and as demulsifiers.
  • FIGURE 1 diagrammatically illustrates the bi- planar nature of the biaryl monomers of the present invention and the resulting facial orientation of functional groups on the monomer;
  • FIGURE 2 depicts functional group orientation of a conventional amphiphilic dendritic material (A) and two possible facial orientations of functional groups in the facially amphiphilic dendritic polymers of the invention (B, and B 2 );
  • FIGURE 3 depicts the manner in which biaryl monomers affect functional group orientation;
  • FIGURE 4 depicts d e branching pattern of a 5th generation dendron derived from AB 2 monomers
  • FIGURE 5 diagrammatically illustrates a method for fluorocarbon solvent-based phase transfer catalysis utilizing a dendritic polymer of the invention
  • FIGURE 6 diagrammatically illustrates a method for pH controlled delivery and release of a pharmaceutical agent into a tumor cell.
  • the dendritic polymers of the present invention are derived from functionalized biaryl AB 2 monomers. These functionalized biaryl monomers are useful for the preparation dendritic polymers (e.g., hyperbranched polymers, dendrons and dendrimers) that have functional substituents oriented on the exterior and interior surfaces of the dendritic polymer when the polymer adopts a globular conformation in solution.
  • the inventive polymers can be rendered facially amphiphilic when the biaryl monomer includes both hydrophilic and hydrophobic functional groups. These facially amphiphilic dendritic polymers have both hydrophilic and hydrophobic functional groups that are facially orientable and can be distributed throughout the dendritic structure.
  • Dendritic polymers naturally adopt globular conformations in solution, having an external globular surface exposed to the solvent, and an interior region that can be substantially free of solvent. Globular dendritic polymers can be thought of as monomolecular micelles. Because the aryl groups in biaryl compounds, such as biphenyl, tend to orient themselves in substantially perpendicular planes, functional groups such as hydrophilic and hydrophobic groups on one aryl group can be oriented above and below the plane of the other aryl group of the biaryl, as illustrated in FIG. 1.
  • the functional groups of the amphiphilic biaryl-based dendritic polymers of the present invention orient themselves with substantially all of one type of functional group (e.g. , hydrophilic or hydrophobic) on the globular exterior and the other type of functional group in the interior, depending on the hydrophilic or hydrophobic character of the solvent in which the dendritic polymer is dissolved.
  • This orientation is due to the bi-planar nature of the biaryl monomer units, which necessarily orient functional groups in a plane perpendicular to the plane of the dendrimer backbone.
  • FIGS. 2 and 3 illustrate functional group orientation of a conventional amphiphilic dendritic polymer and a facially amphiphilic dendritic polymer of the invention.
  • configuration A illustrates a conventional dendritic material having a hydrophilic macromolecular backbone and hydrophobic end capping groups
  • configurations ⁇ and B 2 illustrate two possible orientations of a facially amphiphilic biaryl dendritic polymer of the present invention
  • Orientation B x is typical of the functional group orientation of the facially amphiphilic dendritic polymer in a hydrophilic solvent such as water, wherein the hydrophilic functional groups are oriented on the external globular surface of the polymer, whereas the hydrophobic functional groups are oriented toward the interior of the globular macromolecule.
  • orientation B 2 illustrates the functional group orientation of the same dendritic polymer of the present invention dissolved in a hydrophobic solvent such as a hydrocarbon, wherein the hydrophobic groups are oriented on the globular exterior and the hydrophilic groups are oriented on the interior.
  • FIG. 3 illustrates the manner in which the bi-planar nature of the biaryl monomer units of the inventive dendritic polymers necessarily orients the hydrophobic and hydrophilic substituents to opposite surfaces of the polymer.
  • the functional groups can be oriented above and below the plane of the backbone aryl groups. Like functional groups tend to orient on the same face of the polymer.
  • dendritic polymer In a hydrophilic solvent, the natural tendency of dendritic materials to fold in on themselves to form globular structures in solution leads to a globular dendritic polymer with hydrophilic substituents distributed over the exterior surface of the polymer and hydrophobic substituents lining the interior of the polymer.
  • dendritic polymer and grammatical variations thereof refers to hyperbranched polymers, dendrons and dendrimers, including such hyperbranched polymers, dendrons and dendrimers that are bound to a solid support such as polystyrene resins, and like materials.
  • hyperbranched polymer and grammatical variations thereof, refers to a polymer derived, at least in part, from a single polymerization reaction of monomers capable of bonding to three or more other monomers, which polymerization results in a high degree of branch points within the polymer. Hyperbranched polymers are typically poly disperse materials.
  • Dendron and grammatical variations thereof, is used herein to refer to oligomeric and polymeric materials substantially entirely composed of monomers having three or more functional groups capable of bonding to other monomers. Dendrons are typically prepared in a convergent fashion, utilizing several individual chemical reactions, to afford substantially monodisperse oligomers or polymers. Dendrons generally can be described as macromolecules that originate at a single core monomer unit having two or more points of connectivity available for addition of other monomers. Another multifunctional monomer is bound to each connection point of the core monomer, such that each additional monomer has two or more connection points available for further reaction.
  • FIG. 4 illustrates an example of the branching pattern of a dendron derived from an AB 2 monomer (e.g. , a monomer that has two points of connectivity available at each successive tier or generatibn of monomers).
  • the number of monomers doubles in each successive tier (labeled 1, 2, 3, etc.).
  • generation 5 there are 63 total monomer units in the dendron (including the core monomer).
  • 6th generation there are a total of 127 monomer units in such a dendron.
  • each successive tier of monomers would triple in its number of monomers units.
  • the term "dendrimer” refers to a polymer composed of a plurality of dendrons attached to a core molecule. Typically, dendrimers are composed of two, three, or four dendron segments attached to a central core monomer, although more are possible. For example, a dendrimer composed of three 6th generation, AB 2 -derived dendron units attached to a trivalent core monomer would have 382 total monomer units (127 x 3 + 1).
  • Monomers and polymers of the present invention that have basic substituents such as amino groups, nitrogen-heterocyclic groups, and like substituents also include organic acid and mineral acid of the basic substituents.
  • a dendritic polymer of the present invention comprises at least one biaryl monomer unit having at least a first aryl group and a second aryl group directly covalently bonded to the first aryl group.
  • the first aryl group of the biaryl monomer defines a plane
  • the second aryl group includes a first functional substituent and a second functional substituent.
  • Biaryl compounds naturally adopt a bi-planar conformation, with one aryl group defining a plane and the other aryl group oriented so as to roughly bisect the plane of the first aryl group.
  • the substituents are bonded to the second aryl group such that the first and second functional substituents are oriented on opposite sides of the plane defined by the first aryl group, as illustrated in FIG. 1, for example.
  • first aryl group has first and second branching substituents, each adapted for bonding to another monomer unit and at least one of the first and second aryl group has a third branching substituent adapted for bonding to a third monomer unit.
  • aryl includes C 6 - C 25 aromatic hydrocarbon groups such as phenyl, naphthyl, anthracenyl, triphenylenyl, phenanthrenyl, pyrenyl, and the like; and C 3 - C 9 oxygen, sulfur and nitrogen heteroaromatic groups such as a furan, an imidazole, a pyrrole, a thiophene, a thiazole, an azole, an oxazole, a pyridine, a pyrazine, a pyrimidine, an indole, a benzofuran, a benzothiophene, a benzothiazole, a benzoxazole, a quinoline, an isoquinoline, and like heterocyclic groups.
  • the aryl groups are phenyl or naphthyl groups. More preferably, at least one of the aryl groups is a phenyl group, e.g., the biaryl is a biphenyl or a phenylnaphthyl compound. Most preferably, both aryl groups of the biaryl are phenyl groups, e.g., the biaryl is a biphenyl.
  • the dendritic polymers of the present invention can be hyperbranched polymers, dendrons, or dendrimers.
  • Hyperbranched polymer embodiments of the dendritic polymers of the present invention can be prepared by a polymerization of biaryl monomers having reactive branching substituents.
  • Such hyperbranched polymers can be made in a single polymerization reaction and are typically polydisperse polymers, consisting of a large number of macromolecular structures of varying degrees of polymerization and varying degrees of branching. Because of the relatively simple manufacturing processes used to prepare hyperbranched polymers, these materials can be economically feasible for use in applications requiring low-cost materials. Synthetic strategies for the production of hyperbranched polymers are well known in the polymer art, and are extensively discussed in chapters 3 and 4 and 6, pages 51 - 190 and 331-
  • Reactive functional groups capable of participating in polymerization reactions to form hyperbranched polymers include, without being limited to, acids, acid halides, amines, alcohols, haloalkyl groups, sulfonyl halides, and like functional groups that are capable of participating in condensation reactions to form ester, amide, ether, or sulfonamide bonds, for example.
  • the dendritic polymers of the present invention are prepared by a convergent manufacturing strategy, to produce dendrons and dendrimers.
  • Convergent methodologies for the synthesis of dendrons and dendrimers are extensively discussed in chapter 5 of Newkome et al. , the relevant disclosures of which are incorporated herein by reference. Further illustration of such methods as applied to the synthesis of facially amphiphilic dendrons and dendrimers is provided below in the experimental methods section.
  • Convergent synthetic methods require a plurality of individual synthetic reactions to produce a single polymeric material.
  • One distinct advantage of convergent synthetic methods is that the dendritic polymers obtained by such methods can be substantially monodisperse, consisting essentially of a single chemical entity of well defined molecular structure. Dendrons and dendrimers derived from convergent syntheses can be ideally suited for pharmaceutical applications, or other applications that require, or preferably utilize substantially pure, monodisperse materials.
  • the dendritic polymers of the present invention can be homopolymers, consisting essentially of monomer units having a single molecular structure, or the inventive polymers can be copolymers consisting of monomer units having a plurality of molecular structures.
  • the facially amphiphilic dendritic polymers of the present invention are homopolymers.
  • a preferred dendritic polymer of the present invention comprises at least one biaryl monomer unit having the following structure (I):
  • a 1 and A 2 are each independently phenyl or naphthyl
  • X 1 , X 2 , Y 1 , and Y 2 are each independently OH, O, NHR 1 , NR ⁇ SH, S,
  • Z is OH, O, NHR 1 , NR 1 -, SH, S, a covalent bond, CI, Br, I, or OSO 2 -R 5 ;
  • Z 2 is CI, Br, I, or OSO 2 -R 5 ;
  • E 1 is CH 2 or CF 2 ;
  • E 3 is CHR 7 , CF 2 , or CFR 7 ;
  • L 1 is H, C r C 20 alkyl, phenyl, C r C 20 alkyl-substituted phenyl, benzyl, diphenylphosphine-substituted C r C 20 alkyl, C r C 20 perfluoroalkyl, or
  • L 2 is C 4 -C 20 alkyl, phenyl, -C ⁇ alkyl-substituted phenyl, benzyl, diphenylphosphine-substituted C r C 20 alkyl, C r C 20 perfluoroalkyl, or
  • R 1 and R 2 are each independently H or C r C 20 alkyl
  • C r C 10 alkyl an amino-substituted C r C 10 alkyl, a hydroxy-substituted C r C 10 alkyl, a sulfonic acid-substituted C r C 10 alkyl, a phosphinic acid-substituted C ⁇ _C 10 alkyl, a phosphonic acid-substituted C r C ⁇ 0 alkyl, a nitrogen-heterocycle, a nitrogen-heterocycle-substituted C,-C 10 alkyl, or a trialkylammonium-substituted
  • R 5 is C r C 20 alkyl, phenyl, methylphenyl, or CF 3 ;
  • R 6 is H, C r C 20 alkyl, or C r C 20 perfluoroalkyl
  • R 7 is H or C r C 3 alkyl
  • R 8 , R 9 , and R 10 are each independently H or C r C 3 alkyl
  • Y 2 is OH, O, NHR 1 , NR 1 , SH, S,
  • X 1 and X 2 are E V, E 2 L 2 , P(L 2 ) 2 , E 3 R 3 or E R 4 ; when A 1 is phenyl, A 2 is in the 1 position of the phenyl ring, X 1 is in the 2 or 3 position of the phenyl ring, and X 2 is in the 5 or 6 position of the phenyl ring; when A 1 is naphthyl, A 2 is in the 1 position of the naphthyl ring, X 1 is in the 2 or 3 position of the naphthyl ring, and X 2 is in the 6 or 7 position of the naphthyl ring; when A 2 is phenyl, A 1 is in the 1 position of the phenyl ring, Y 1 is in the 2 or 3 position of the phenyl ring,
  • the biaryl monomer units of structure (I) can comprise any of the following structures (II), (III), (IV), (V), (VI) and (VII).
  • both X groups in the structures (I), (II), (III), (IN), (V), (VI) and (VII) are functional substituents, or both X groups are branching substituents.
  • the Y groups are both branching substituents.
  • both Y groups are functional substituents.
  • X 1 is in the 2 or 3 position, and X 2 is in the 5 or 6 position;
  • Y 1 is in the 2' or 3' position, and Y 2 is in the 5' or 6" position, as the positions are indicated numerically in the structure;
  • X 1 is in the 2 or 3 position, and'X 2 is in the 5 or 6 position;
  • Y 1 is in the 2' or 3' position, and Y 2 is in the 6' or 7' position, as the positions are indicated numerically in the structures;
  • X 1 is in the 2 or 3 position, and X 2 is in the 6 or 7 position;
  • Y 1 is in the 2' or 3' position, and Y 2 is in the 5' or 6' position, as the positions are indicated numerically in the structure;
  • X 1 is in the 2 or 3 position, and X 2 is in the 6 or 7 position; Y 1 is in the 2' or 3' position, and Y 2 is in the 6' or 7' position, as the positions are indicated numerically in the structures;.
  • substituents X 1 , X 2 , Y 1 , Y 2 , D and Z are defined as, and have the same limitations as described for structure (I) above.
  • structures (I), (II), (III), (IV), (V), (VI) and (VII) can include a third functional substituent on the aryl group bearing the first and second functional substituents.
  • the third functional substituent can, for example, be a substrate binding substituent capable of binding to a pharmaceutical agent, agrochemical, or other useful materials.
  • Biaryl monomers, useful for the preparation of the dendritic polymers of the present invention comprise at least one biaryl monomer unit having at least a first aryl group and a second aryl group directly covalently bonded to the first aryl group.
  • the first aryl group of the biaryl monomer defines a plane
  • the second aryl group has a first functional substituent and a second functional substituent.
  • the first and second functional substituents are oriented on opposite sides of the plane defined by the first aryl group in the normal, bi-planar conformation adopted by biaryl compounds.
  • the first aryl group has first and second branching substituents, each adapted for bonding to another monomer unit and at least one of the first and second aryl group has a third branching substituent adapted for bonding to a third monomer unit.
  • the second aryl group can include a third functional substituent, bound to the aryl group on the same side as the second functional substituent.
  • the aryl groups can be C 6 - C 25 aromatic hydrocarbon groups such as phenyl, naphthyl, anthracenyl, triphenylenyl, phenanthrenyl, pyrenyl, and the like; and C 3 - C 9 oxygen, sulfur and nitrogen heteroaromatic groups such as a furan, an imidazole, a pyrrole, a thiophene, a thiazole, an azole, an oxazole, a pyridine, a pyrazine, a pyrimidine, an indole, a benzofuran, a benzomiophene, a benzothiazole, a benzoxazole, a quinoline, an isoquinoline, and like heterocyclic groups.
  • C 6 - C 25 aromatic hydrocarbon groups such as phenyl, naphthyl, anthracenyl, triphenylenyl, phenanthrenyl, pyr
  • the aryl groups are phenyl or naphthyl units. More preferably, at least one of the aryl groups is a phenyl group, e.g., the biaryl is a biphenyl or a phenylnaphthyl compound. Most preferably, both aryl groups of the biaryl are phenyl groups, e.g., the biaryl is a biphenyl.
  • Preferred biaryl monomers useful for the preparation of the dendritic polymers of the present invention have the following structure (VIII): wherein
  • Z* is OH, ⁇ HR 1 , SH, CI, Br, I, or OSO 2 -R 5 ;
  • Z 2 is CI, Br, I, or OSO 2 -R 5 ;
  • E 1 is CH 2 or CF 2 ;
  • E 3 is CHR 7 , CF 2 , or CFR 7 ;
  • L 1 is H, C x -C 20 alkyl, phenyl, C r C 20 alkyl-substituted phenyl, benzyl, diphenylphosphine-substituted C r C 20 alkyl, C r C 20 perfluoroalkyl, or
  • L 2 is C 4 -C 20 alkyl, phenyl, C r C 20 alkyl-substituted phenyl, benzyl, diphenylphosphine-substituted C r C 20 alkyl, C r C 20 perfluoroalkyl, or
  • R 1 and R 2 are each independently H or C r C 20 alkyl
  • R 4 is H, (CH 2 CH 2 O) x -R 8 , (CH 2 CH 2 O) x -CH 2 CH 2 -NR 9 R 10 ;
  • R 10 an amino acid, a polypeptide, a nucleic acid, a polynucleic acid, biotin, sugar, a polysaccharide, a carboxylic acid-substituted C r C 10 alkyl, an amino-substituted C r C 10 alkyl, a hydroxy-substituted C r C 10 alkyl, a sulfonic acid-substituted C r C 10 alkyl, a phosphinic acid-substituted C ⁇ C ⁇ alkyl, a phosphonic acid-substituted C r C 10 alkyl, a nitrogen-heterocycle, a nitrogen-heterocycle-substituted C,-C 10 alkyl, or a trialkylammonium-substituted C r C 10 alkyl;
  • R 5 is C r C 20 alkyl, phenyl, methylphenyl, or CF 3 ;
  • R 6 is H, C r C 20 alkyl, or C r C 20 perfluoroalkyl;
  • R 7 is H or C r C 3 alkyl;
  • biaryl monomers of the present invention comprise biaryl monomer units having any of the following structures (IX), (X), (XI), (XII), (XIII) and (XIV):
  • X 3 is in the 2 or 3 position, and X 4 is in the 5 or 6 position;
  • Y 3 is in the 2' or 3' position, and Y 4 is in the 5' or 6' position, as the positions are indicated numerically in the structure;
  • X 3 is in the 2 or 3 position, and X 4 is in the 5 or 6 position;
  • Y 3 is in the 2' or 3' position, and Y 4 is in the 6' or 7' position, as the positions are indicated numerically in the structures;
  • X 3 is in the 2 or 3 position, and X 4 is in the 6 or 7 position;
  • Y 3 is in the 2' or 3' position, and Y 4 is in the 5' or 6' position, as the positions are indicated numerically in the structure;
  • both X groups in the structures (I), (II), (III), (IV), (V), (VI) and (VII) are functional substituents, or both X groups are branching substituents.
  • the Y groups are both branching substituents.
  • both Y groups are functional substituents.
  • structures (I), (II), (III), (IV), (V), (VI) and (VII) can include a third functional substituent on the aryl group bearing the first and second functional substituents.
  • the third functional substituent can, for example, be a substrate binding substituent capable of binding to a pharmaceutical agent, agrochemical, or other useful materials.
  • specific biphenyl monomer-based examples f the present invention are provided below:
  • the dendritic polymer is a dendron having any of the following structures (XVI), (XVII), or (XVIII) and other dendrons and dendrimers derived therefrom.
  • L w , L x , L ⁇ , and L z are each independently C 4 -C 20 alkyl, phenyl, C r C 20 alkyl-substituted phenyl, benzyl, diphenylphosphine-substituted C r C 20 alkyl, C r C 20 perfluoroalkyl, or C r C 20 perfluoroalkyl-substituted phenyl;
  • Z is OH, NHR 1 , SH, CI, Br, I, or OSO 2 -R 5 ;
  • R 5 is C r C 20 alkyl, phenyl, methylphenyl, or CF 3 ;
  • R 6 is H, C C 20 alkyl, or C r C 20 perfluoroalkyl;
  • R 7 is H or C r C 3 alkyl;
  • R 8 , R 9 , and R 10 are each independently H or C r C 3 alkyl;
  • L w , L x , V, and L z are each independently (CH 2 CH 2 O) x -CH 3 or carboxylic acid-substituted C r C 20 alkyl; G , G x , G ⁇ , and G z are each independently C r C 20 alkyl; each of T 1 and T 2 is (3-OL x ,5-OG x )-benzyl; D is CH 2 ; Z is OH or Br; and x is an integer in the range of about 1 to about 20.
  • Such dendrons are exemplified by compounds 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, and 29 described below.
  • the dendritic polymers of the present invention are useful in a variety of applications including pH controlled targeted delivery of pharmaceutical agents, encapsulation of hydrophilic and hydrophobic pharmaceutical and agrochemical agents, controlled release of pharmaceutical, agrochemical and like active agents, phase transfer and other catalytic processes, as solubilizing agents for pharmaceuticals, agrochemicals, and medical diagnostic agents such as fluorescent imaging agents; as cell-cell adhesion agents in tissue engineering applications, as exipients for the preparation of nanoparticles, as demulsifying agents and for encapsulation of pharmaceutical agents, agrochemicals and dyes.
  • a preferred embodiment of the present invention is a globular dendritic polymer having an external surface and an interior surface.
  • the polymer is composed of a plurality of biaryl monomer units.
  • Each of the biaryl monomer units comprises at least a first aryl group and a second aryl group directly covalently bonded to the first aryl group.
  • the first aryl group defines a plane.
  • the second aryl group generally adopts a conformation that approximately bisects the plane of the first aryl group.
  • the second aryl group includes a first substituent and a second substituent.
  • the first substituent has an affinity for a solvent having a first solvent property and the second substituent has an affinity for a solvent having a second solvent property.
  • the first and second substituents are bound to the second aryl group such that the first and second substituents are oriented on opposite sides of the plane defined by the first aryl group.
  • the first aryl group has first and second branching substituents each adapted for bonding to another monomer unit; and at least one of said first and second aryl groups has a third branching substituent adapted for bonding to a third monomer unit.
  • each substituent can be selected to have an affinity for a solvent having a particular solvent property, such as, for example, hydrophobicity, hydrophilicity, solvent polarity, pH, ionic strength.
  • inversion The process whereby the exterior and interior surfaces exchange, due to change in pH or any other solvent parameter, is referred to herein as inversion.
  • the term inversion also includes the adoption of a random, non- globular conformation, from a globular conformation, or the adoption of a globular conformation from a random, non-globular conformation.
  • the first functional substituent is a hydrophilic substituent and second functional substituent is a hydrophobic substituent.
  • the dendritic polymer is facially amphiphilic in solution.
  • the first functional substituent is a perfluorinated substituent having an affinity for fluorocarbon solvents, and the second functional substituent can be either hydrophobic or hydrophilic in nature.
  • the dendritic polymers of this embodiment can be copolymers comprising some biaryl monomer units having a hydrophobic second functional substituent and some biaryl monomer units having a hydrophilic second functional monomer.
  • the second aryl group can comprise a perfluorinated first functional substituent, a hydrophilic second functional substituent and a hydrophobic third functional substituent. The second and third functional substituents both being bonded to the second aryl group on the side of the aryl group opposite the first functional substituent.
  • Preferred perfluorinated substituent groups include C r C 20 perfluoroalkyl and perfluoroalkyl-substituted phenyl.
  • the dendritic polymer is a copolymer having at least one biaryl monomer in which the first substituent of the polymer is a fluorocarbon substituent (fluorophilic) that provides solubility of the dendritic polymer in fluorocarbon or carbon dioxide solvents and the second substituent is hydrophobic; and at least one biaryl monomer unit in which the first substituent is fluorophilic and the second substituent is hydrophilic.
  • the hydrophobic and the hydrophilic substituents can be directed to the interior of the polymer.
  • the interior substituents act as solubilizing agents for polar and apolar solutes.
  • Dendritic polymers of the present invention which have biaryl monomers with a first substituent that is a C C 20 perfluoroalkyl hydrophobic substituent and a second substituent that is either hydrophobic or hydrophilic are useful for solubilization and phase transfer catalysis of hydrophilic and hydrophobic solutes in fluorocarbon solvents and in liquid or supercritical carbon dioxide.
  • FIG. 5 illustrates such a use.
  • a globular dendritic polymer has fluorophilic moieties (fluorocarbon substituents) on its exterior surface and the interior surface includes both lipophilic (Hydrophobic) and hydrophilic moieties.
  • the polymer is dissolved in a fluorocarbon solvent. Hydrophilic and lipophilic substrates in a fluorocarbon solvent are encapsulated by the dendritic polymer, which then facilitates chemical reactions between the substrates to for a reaction product. These polymers can be used for the destruction of chemical warfare agents by encapsulating the agent and a reagent that can react to detoxify the agent, or the polymers can be used as recyclable reaction catalysts, since the fluorocarbon solvent can be easily evaporated to recover the polymer.
  • the inventive dendritic polymer is a pH sensitive globular dendritic polymer having an external surface and an interior region comprising a plurality of biaryl monomer units.
  • Each of the biaryl monomer units comprises at least a first aryl group and a second aryl group directly covalently bonded to the first aryl group.
  • the first aryl group defines a plane, and the second aryl group can be oriented so as to roughly bisect the plane of the first aryl group.
  • the second aryl group has a first substituent and a second substituent, each of the first and second substituents having hydrophilic properties at selected pH values.
  • the first substituent is substantially more hydrophilic than the second substituent in solution having a first pH value
  • the second substituent is substantially more hydrophilic than the first substituent in a solution having a second pH value.
  • the first and second substituents are bound to the second aryl group such that they are oriented on opposite sides of the plane defined by the first aryl group.
  • the first aryl group has first and second branching substituents that are each adapted for bonding to another monomer unit; and at least one of said first and second aryl groups has a third branching substituent adapted for bonding to a third monomer unit.
  • the first substituent of the second aryl group is oriented to the exterior surface of the polymer, and the second substituent is oriented in the interior surface of the polymer.
  • the polymer inverts, and the first substituent becomes oriented on the interior surface of the polymer and the second substituent is oriented on the exterior surface of the polymer.
  • the polymer can adopt a random, non-globular conformation at the second pH, such that both the first and second substituents are exposed to the solvent (i.e., there is no "interior” surface, both surfaces are "exterior”).
  • the pH sensitive dendritic polymer has a second substituent comprising a basic functional group that has a pK b in the range of about y to about z and which is oriented to the interior surface of the polymer at a pH of about w or greater; wherein y has a numerical value in the range of about 3 to about 8, w has a numerical value at least about 0.5 greater than z; z has a numerical value least about 1 greater than y.
  • the basic functional group is an amino or nitrogen- heterocyclic functional group selected from primary, secondary or tertiary amino, amino-substituted O r C 10 alkyl, amino-aryl, nitrogen-heterocycle, nitrogen- heterocycle-substituted C r C 10 alkyl, basic amino acids and basic peptides.
  • the first substituent preferably is selected from oligomeric polyoxyethylene groups, carboxylic acids, and acidic or neutral polypeptides. Polypeptides that bind to proteins that are overexpressed on tumor cell surfaces are particularly useful as the first substituent, in that they can aid in targeting the dendritic polymer to the tumor.
  • High molecular weight materials up to 800 KDa have been reported to be capable of entering tumors. Tumor vessels are leaky, and thus allow macromolecular uptake that is generally not seen in healthy tissues.
  • Tumors typically also lack effective lymphatic drainage, promoting the accumulation of macromolecular materials in tumors.
  • macromolecule-drug conjugates have been reported to have a higher retention rate in tumors than the free drugs.
  • the pH sensitive dendritic polymers of the present invention as described above are useful for delivering drugs or prodrugs to tumors.
  • the pH of a healthy cell is about 7.4, whereas the pH of the interstitial space between tumor cells is about 6.7 and the pH of the tumor cell lysosome is about 5.
  • FIG. 6 illustrates the process of drug delivery to the tumor cell and release in the lysosome, in which the drug molecule has been covalently bound to the dendritic polymer.
  • Cleavage of the drug from the polymer is achieved through natural enzymatic processes within the cell.
  • the drug can be encapsulated without being covalently bound to the dendritic polymer.
  • a prodrug can be utilized in place of a drug, as well.
  • the pH at which half of the base is protonated is approximately equal to the pK b of the base.
  • basic substituents such as amino and heterocyclic substituents, having pK b values in the range of about 5 to about 6.5 will have less than about half of the basic functional groups protonated at a pH in the range of about of 6.7 to about 7.4.
  • the amino and nitrogen-heterocyclic substituents will preferably have a pK b in the range of about 5 to about 6.5, more preferably about 5 to about 6.
  • the first and the second aryl groups are phenyl groups; the first functional substituent is at the 2 or 3 position relative to the first aryl group of the monomer unit; and the second functional substituent is at the 5 or 6 position relative to the first aryl group of the monomer unit.
  • Another aspect of the present invention is a method of delivering an anti-tumor drug to a tumor utilizing a pH sensitive dendritic polymer of the invention.
  • a drug or prodrug is encapsulated or chemically bound to the dendritic polymer. If the drug is chemically bound to the polymer, binding can be through one of the functional substituents, or through an additional binding substituent that is attached to the second aryl group of the polymer on the same side of the aryl group as the basic substituent.
  • a preferred embodiment of the anti-tumor drug delivery method involves utilization of a dendritic polymer having a pH sensitive functional substituent and comprises the sequential steps of: (a) binding or encapsulating an anti-tumor drug or prodrug in the interior region of a pH sensitive dendritic polymer in an aqueous solution having a pH, w, of greater than about 7 to form a polymer-drug conjugate;
  • the polymer-drug conjugate can enter the interstitial space between the tumor cells or the lysosome of a tumor cell, and a substantial portion of amino or nitrogen-heterocyclic functional groups of the dendritic polymer are protonated upon entering the interstitial space or lysosome. Protonation of the functional groups render the basic functional group more hydrophilic than the first functional group, and the polymer inverts so that the drug released.
  • release of the drug is achieved by enzymatic cleavage after the polymer has inverted, exposing the bound drug or prodrug to the enzymes present in the lysosome, as is illustrated in FIG. 6.
  • the drug is exposed to enzymes n the lysosome that can cleave the drug from the polymer to release the drug.
  • Another method aspect of the present invention is a method of encapsulating a solute in the inventive dendritic polymers.
  • a dendritic polymer having a functional substituent that has a binding affinity for a solute is utilized in this embodiment.
  • the polymer and solute are brought into contact in a solvent in which the substituent with the binding affinity is oriented on the exterior surface of the polymer, or where the polymer adopts a random, non-globular conformation.
  • the solute is bound to the substituent.
  • a solvent parameter is changed that causes the polymer to invert, the solute becomes encapsulated in the interior of the polymer.
  • Each substituent can be selected to have an affinity for a solvent having a particular solvent property, such as, for example, hydrophobicity, hydrophilicity, solvent polarity, pH, ionic strength.
  • the polymer-encapsulated solute can be separated from the solution by a size dependent separation method, for example.
  • Preferred size dependent separation methods include membrane filtration, size exclusion chromatography, and ultracentrifugation.
  • the polymer- encapsulated solute can be separated by precipitation.
  • the first and the second aryl groups are phenyl groups; the first functional substituent is at the 2 or 3 position relative to the first aryl group of the monomer unit; and the second functional substituent is at the 5 or 6 position relative to the first aryl group of the monomer unit.
  • a preferred embodiment of the encapsulation method involves utilization of a dendritic polymer having functional substituent sensitive to a solvent parameter and comprises the sequential steps of:
  • the first substituent of the second aryl group of the polymer has a binding affinity for the solute and is substantially more hydrophilic than the second substituent in an aqueous solution having the first solvent parameter value.
  • the second substituent is substantially more hydrophilic than the first substituent in an aqueous solution having the second solvent parameter value.
  • the first substituent is oriented at the external surface of the dendritic polymer and binds to the solute when the polymer contacts the solute.
  • the dendritic polymer inverts upon adjustment of the solvent parameter to the second solvent parameter value, thereby encapsulating the solute by bringing the solute and the first substituent to which the solute is bound into the interior region of the polymer.
  • the sensitive substituent can be selected to have an affinity for a solvent having a particular solvent parameter, such as, for example, hydrophobicity, hydrophilicity, solvent polarity, pH, ionic strength.
  • a particular solvent parameter such as, for example, hydrophobicity, hydrophilicity, solvent polarity, pH, ionic strength.
  • the substituent is sensitive to pH.
  • Solutes that can be encapsulated include heavy metal ions, dyes, and recyclable catalysts, for example.
  • a basic functional groups that has an affinity for a heavy metals include, chelating functional groups such as poly amino compounds, and chelating nitrogen-heterocyclic groups such as bipyridines. Such basic functional groups are effective when the first pH is more acidic than the second pH.
  • the chelating acidic functional groups can be utilized to bind to the solute, such as poly carboxylic acids. Acidic functional groups are useful when the first pH is less acidic than the second pH.
  • Dendritic polymers of the present invention having first and second substituents with cell surface adhesion affinity.
  • Preferred substituents with cell adhesion affinity include polypeptides such as such as the tripeptide Arg-Gly-Asp (also abbreviated referred to as RGD peptide), the tetrapeptide Gly-Arg-Gly-Asp (GRGD, SEQ ID NO: 1) and pentapeptide Gly-Arg-Gly-Asp-Ser (GRGDS, SEQ ID NO: 2) are useful for tissue engineering applications wherein the cell surface affinity agent causes the dendritic polymer to adhere to a tissue surface and to promote binding between different tissues, for example in transplant applications.
  • the dendritic polymers can act as a cell-cell binding agent.
  • Such dendritic polymers can also be used to deliver pharmaceutically active agents to specific tissue sites.
  • the first and the second aryl groups are phenyl groups; the first functional substituent is at the 2 or 3 position relative to the first aryl group of the monomer unit; and the second functional substituent is at the 5 or 6 position relative to the first aryl group of the monomer unit.
  • the dendritic polymers of the present invention can be bound to a solid support, such as a polystyrene resin, or like material.
  • Suitable support resins and methods of binding dendritic polymers to supports are disclosed in Lebreton et al. , Aldrichimica Acta, 2001, 34 (3):75-83, the relevant disclosures of which are incorporated herein by reference.
  • Resin bound dendritic polymers are particularly useful as recyclable catalysts, carriers for reagents, scavengers in parallel solution-phase synthesis, and affinity chromatography supports, for example.
  • the following non-limiting examples illustrate the preparation of dendritic polymers of the present invention.
  • Scheme 1 depicts the synthesis of the aryl boronic acid 5, a key intermediate for the synthesis of biphenyl or phenylnaphthyl monomers.
  • 3,5-Dihydroxybenzoic acid 1 was reacted with three equivalents of tert-butyldimethylsilyl chloride (TBDMSC1) and imidazole in dimethylformamide (DMF) solvent to afford the trisilyl derivative 2 in about 81 % yield.
  • Compound 2 was converted to the acid chloride 3 by reaction with thionyl chloride and catalytic trimethylamine hydrochloride in dichloromethane solvent. The dichloromethane solvent was removed in vacuo and the crude acid chloride 3 was dissolved in bromotrichloromethane and reacted with catalytic
  • Scheme 2 illustrates the synthesis of bromobenzene intermediate 10.
  • 4-Bromo-3,5-dihydroxybenzoic acid 6 was esterified by refluxing in ethanol containing a catalytic amount of fuming sulfuric acid to afford ester 7 in about 95% yield.
  • Ester 7 was alkylated with a sub-stoichiometric amount of butyl iodide with potassium carbonate and 18-crown-6 in acetone to afford butyl ether 8 in about 46% yield.
  • Scheme 3 depicts the preparation of benzyl bromide intermediate 14.
  • 3 ,5-Dihydroxybenzyl alcohol 11 was reacted with a sub-stoichiometric amount of butyl iodide, following the procedure for the alkylation of 7 above to afford butyl ether 12 in about 54% yield.
  • Compound 12 was then reacted with TEG tosylate 9, as described above for triethoxylation of compound 8, to provide benzyl alcohol 13 in about 69% yield.
  • Compound 13 was then converted to the benzyl bromide 14 in about 82% yield by reaction with triphenylphosphine and carbon tetrabromide in tetrahydrofuran (THF) solvent.
  • THF tetrahydrofuran
  • first, second, third, and fourth generation dendrons having a core monomer derived from 17 is illustrated in Scheme 5.
  • a trimeric first generation dendron 18 was prepared by alkylation of the two phenolic hydroxyl groups of 17 with benzylbromide 14, in the presence of potassium carbonate and 18-crown-6 as base, in about 72% yield.
  • the benzylic alcohol 18 was converted to benzylic bromide 19 by treatment with triphenylphosphine and carbon tetrabromide in THF.
  • the crude bromide 19 was then converted to second generation dendritic alcohol 20 in about 61 % overall yield by alkylation of 17 with 2 equivalents of 19.
  • the benzylic alcohol group of 20 was converted to a benzylic bromide by treatment with triphenylphosphine and carbon tetrabromide in THF to provide the second generation dendritic bromide 21 which was utilized without purification.
  • Two equivalents of dendron 21 were reacted with monomer 17, by the procedure described above, to afford (15-mer) third generation dendritic alcohol 22 in about 21 % yield from 20.
  • 22 was converted to the bromide 23.
  • Core monomer 17 was alkylated with two equivalents of 23 to provide fourth generation dendritic alcohol 24 in about 39% yield.
  • Second generation dendrons 20 and 21 comprise 3 monomer units of the present invention (i.e. , a core biphenyl unit and 2 branch biphenyl units).
  • the peripheral dendrimer units are further capped with two functionalized benzylic groups, thus these dendrons can also be referred to as septimeric (7-mer) dendrons (i.e., a core, plus two biphenyl units, plus four benzylic capping units).
  • Third generation dendrons 22 and 23 comprise 7 biaryl monomer units of the present invention (i.e.
  • Fourth generation dendron 24 comprises 15 biaryl monomer units of the present invention (i.e., a core biphenyl unit, 2 first branch biphenyl units, 4 second branch biphenyl units and 8 third branch biphenyl units), as well as, 16 benzylic capping units for a total of 31 monomer units (i.e., a 31- mer).
  • Dendrons having structures (XVI), such as 20 and 21, (XVII), such as 22 and 23 and (XVIII), such as 24, are useful for the synthesis of larger dendritic polymers such as other dendrons or dendrimers.
  • reaction of 2 equivalents of compound 24 with a monomer 17 will provide a fifth generation dendron.
  • reaction of three equivalents of dendron 24 with a trifunctional core monomer will result in a dendrimer comprising 45 biaryl monomer units of the present invention.
  • dendritic materials prepared by the methods described above include compounds 25 - 29 below.
  • Second generation dendrons 28 and 29 were subsequently converted to the third and fourth generation dendrons by the methods described above for the synthesis of dendrons 22, 23, and 24. Hydrolysis of the ester groups of dendron 25 affords a dendron having a carboxylic acid-substituted alkyl substituent.
  • MALDI ToF mass spectra was obtained at the Coordinated Instrumentation Facility of Tulane University or at the mass spectrometric facility at the University of Notre Dame. Flash chromatography was performed with EM Science 37-75 mm silica gel. Analytical thin layer chromatography was performed on EM Science silica plates with F-254 indicator and the visualization was accomplished by UV lamp or using the molybdic acid stain mixture. THF was distilled over Na / Ph 2 CO ketyl. All other chemicals obtained from commercial sources were used without further purification, unless otherwise mentioned.
  • boronic acid 5 t-Butyl lithium ( 111.12 mmol, 65.4 mL of 1.7 M pentane solution) was added to a solution of bis-(O-t-butyldimethylsilyl)-5-bromo-resorcinol 4 (31.77 mmol, 13.27 g) in THF (about 300 mL) at about -78 °C and was stirred at this temperature for about 15 minutes. Trimethyl borate (B(OMe) 3 ; 62 mmol, 6.9 mL) was added to the reaction mixture, which was stirred at a temperature of about -78 to about 20 °C for about 8 hours. The reaction was quenched with a saturated NH 4 C1 solution and extracted with ethyl acetate. The solvent was removed in vacuo and the crude boronic acid 5 was utilized without further purification or characterization.
  • B(OMe) 3 Trimethyl borate
  • Ethyl-4-bromo-3-hydroxy-5-butyloxy-benzoate 8 (14.04 g, 0.04 mol), potassium carbonate (9.18 g, 0.07 mol), 18-crown-6 (0.59 g, 2.20 mmol), and triethyleneglycol monomethyl ether tosylate 9 (14.11 g, 0.04 mol) were dissolved in about 150 mL of acetone. The resulting solution was refluxed under nitrogen for about 12 hours. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel chromatography using ethyl acetate/CH 2 Cl 2 (20:80) to afford about 18.86 (92%) of triethoxylated bromide 10 as a colorless liquid.
  • Suzuki coupling of boronic acid 5 and bromide 10 Tetrakis- triphenylphosphine palladium (Pd(PPh 3 ) 4 ; 3.17 mmol, 3.66 g) was added to a solution of the crude boronic acid 5 (31.77 mmol), bromoester 10 (24.8 mmol, 11.5 g) and K 3 PO 4 (95.31 mmol, 20.23 g) in DME (about 200 mL) and the mixture was refluxed for about 30 hours.
  • Pd(PPh 3 ) 4 3.17 mmol, 3.66 g
  • Tetrabutylammonium fluoride (TBAF; 60 mmol, 60 mL of 1.0 M THF solution) was added to the solution of alcohol 16 (7 mmol, 4.75 g) in THF (125 mL) and the resulting mixture was stirred at room temperature under nitrogen for about 20 hours. The solvent was removed in vacuo, the residue was treated with 10% aqueous HC1 (50 mL), and the product was extracted with ethyl acetate.
  • Dendron 20 was prepared following the procedure for the preparation of 18 above. The reaction was carried out utilizing about 1.4 mmol of 17 and about 2.8 mmol of 19. Crude dendron 20 was chromatographically purified on silica gel using ethyl acetate/ 1,4-dioxane (80:20) as eluent to afford about 2.95 g, 88% yield of dendron 20.
  • Dendron 24 was prepared following the procedure for the preparation of 18 above. The reaction was carried out utilizing about 0.0105 mmol of 17 and about 0.021 mmol of 23. Crude dendron 24 was chromatographically purified on silica gel using ethyl acetate/ 1,4-dioxane (80:20) as eluent to afford about 0.061 g, 51 % yield of dendron 24.
  • Dendrons 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, and 29 are soluble in, for example, dichloromethane, chloroform, ethyl acetate, acetonitrile,

Abstract

L'invention concerne des polymères dendritiques globulaires présentant des groupes fonctionnels orientés sur les surfaces extérieures et intérieures du polymère. Les polymères selon l'invention sont composés d'unités monomères biaryles ayant au moins deux substituants, l'un orienté vers la surface extérieure du polymère dendritique globulaire, l'autre vers la surface intérieure du polymère. On peut choisir chaque substituant de façon à avoir une affinité pour un solvant présentant une propriété de solvant particulière, par exemple l'hydrophobicité, l'hydrophilicité, la polarité de solvant, le pH, la résistance ionique. Lorsqu'on dissout le polymère dans un solvant ayant un paramètre pour lequel un substituant présente une affinité, ledit substituant s'oriente vers la surface extérieure du polymère. Lorsqu'un substituant est hydrophile et un substituant hydrophobe, les polymères sont amphiphiles de manière faciale. Les polymères dendritiques servent à l'encapsulation et à la libération régulée d'agents pharmaceutiques et agrochimiques, à la catalyse et à l'administration de médicaments ciblée.
PCT/US2002/008997 2001-03-22 2002-03-22 Monomeres biaryles et polymeres dendritiques derives WO2002077037A2 (fr)

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WO2006018295A2 (fr) 2004-08-17 2006-02-23 Universität Dortmund Systeme de nanotransport a architecture dendritique
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GB2415959B (en) * 2004-07-07 2007-08-22 Seiko Epson Corp Fabrication of self-assembled dendron monolayers
GB2415959A (en) * 2004-07-07 2006-01-11 Seiko Epson Corp Fabrication of self-assembled dendron monolayers
US7524998B2 (en) 2004-07-07 2009-04-28 Seiko Epson Corporation Fabrication of self-assembled dendron monolayers
US7687600B2 (en) 2004-07-19 2010-03-30 University Of Massachusetts Invertible amphiphilic polymers
WO2006018295A2 (fr) 2004-08-17 2006-02-23 Universität Dortmund Systeme de nanotransport a architecture dendritique
US7794699B2 (en) * 2005-01-05 2010-09-14 Michigan Molecular Institute Nano-structured blood substitutes
US8586705B2 (en) 2005-10-25 2013-11-19 Starpharma Pty Limited Macromolecular compounds having controlled stoichiometry
US8258259B2 (en) 2005-10-25 2012-09-04 Starpharma Pty Limited Macromolecular compounds having controlled stoichiometry
DE102007026397A1 (de) 2007-06-06 2008-12-11 Fu Berlin Nanokomplexe mit dendritischer Struktur zur Einlagerung und/oder zum Transport von monovalenten Metallionen
WO2016038596A1 (fr) * 2014-09-09 2016-03-17 Ramot At Tel-Aviv University Ltd. Système d'administration agrochimique basé sur des hybrides peg-dendron amphiphiles réagissant aux enzymes ou au ph
US10869939B2 (en) 2015-08-03 2020-12-22 Ramot At Tel-Aviv University Ltd. Delivery system in micellar form having modular spectral response based on enzyme-responsive amphiphilic PEG-dendron hybrid polymers
KR20200078962A (ko) * 2018-12-24 2020-07-02 연세대학교 산학협력단 야누스 펩타이드 덴드리머 및 이의 용도
KR102136657B1 (ko) 2018-12-24 2020-07-22 연세대학교 산학협력단 야누스 펩타이드 덴드리머 및 이의 용도

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