WO2009009597A1 - Métathèse d'oléfines hydrosolubles - Google Patents
Métathèse d'oléfines hydrosolubles Download PDFInfo
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- WO2009009597A1 WO2009009597A1 PCT/US2008/069532 US2008069532W WO2009009597A1 WO 2009009597 A1 WO2009009597 A1 WO 2009009597A1 US 2008069532 W US2008069532 W US 2008069532W WO 2009009597 A1 WO2009009597 A1 WO 2009009597A1
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- 0 CC(*)=CCc1c(*)c(OC**)c(*)c(*)c1* Chemical compound CC(*)=CCc1c(*)c(OC**)c(*)c(*)c1* 0.000 description 11
- YNDPEFKHBGCWDR-UHFFFAOYSA-N C1C=CCOC1c1ccccc1 Chemical compound C1C=CCOC1c1ccccc1 YNDPEFKHBGCWDR-UHFFFAOYSA-N 0.000 description 1
- JFACYZKWFSCQRL-UHFFFAOYSA-N CC(C)(C(CC1)C2)C1(CS(N(CC=C)CC=C)(=O)=O)C2=O Chemical compound CC(C)(C(CC1)C2)C1(CS(N(CC=C)CC=C)(=O)=O)C2=O JFACYZKWFSCQRL-UHFFFAOYSA-N 0.000 description 1
- KIQVTWGCLKHJCB-UHFFFAOYSA-N CC(C1C2C)C1C=C(C)C2N(CC1)C(C)N1C1(C)C(C)=CC(C)=CC1C Chemical compound CC(C1C2C)C1C=C(C)C2N(CC1)C(C)N1C1(C)C(C)=CC(C)=CC1C KIQVTWGCLKHJCB-UHFFFAOYSA-N 0.000 description 1
- ZRBXQPCESSVCSO-QRIDDKLISA-N CC(CC(C)(C)[C@@H](O)ON(C(CC1)=O)C1=O)C(O)=O Chemical compound CC(CC(C)(C)[C@@H](O)ON(C(CC1)=O)C1=O)C(O)=O ZRBXQPCESSVCSO-QRIDDKLISA-N 0.000 description 1
- MNTXRXUEQUWGHF-UHFFFAOYSA-N O=C(c1ccccc1)ON1CC=CC1 Chemical compound O=C(c1ccccc1)ON1CC=CC1 MNTXRXUEQUWGHF-UHFFFAOYSA-N 0.000 description 1
Classifications
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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
- C08G61/00—Macromolecular compounds obtained by reactions forming a carbon-to-carbon link in the main chain of the macromolecule
- C08G61/02—Macromolecular compounds containing only carbon atoms in the main chain of the macromolecule, e.g. polyxylylenes
- C08G61/04—Macromolecular compounds containing only carbon atoms in the main chain of the macromolecule, e.g. polyxylylenes only aliphatic carbon atoms
- C08G61/06—Macromolecular compounds containing only carbon atoms in the main chain of the macromolecule, e.g. polyxylylenes only aliphatic carbon atoms prepared by ring-opening of carbocyclic compounds
- C08G61/08—Macromolecular compounds containing only carbon atoms in the main chain of the macromolecule, e.g. polyxylylenes only aliphatic carbon atoms prepared by ring-opening of carbocyclic compounds of carbocyclic compounds containing one or more carbon-to-carbon double bonds in the ring
Definitions
- the present invention provides a new method of carrying out solubilizing metathesis reactions, which overcomes many prior art drawbacks and limitations.
- the present invention provides a composition comprising (a) a catalyst; and (b) a solubilizing agent.
- a composition described herein is dissolved in an aqueous solution.
- the present invention provides a metathesis reaction which includes a composition comprising (a) a catalyst; and (b) a solubilizing agent.
- a composition described herein is dissolved in an aqueous solution.
- the present invention provides a composition
- a composition comprising (a) a catalyst; and (b) a solubilizing agent.
- a composition described herein is dissolved in an aqueous solution.
- the present invention provides a metathesis reaction which includes a composition comprising (a) a catalyst; and (b) a solubilizing agent.
- a composition described herein is dissolved in an aqueous solution.
- FIG. 1 provides structures screened in the invention.
- FIG. 2 provides structures of common catalysts used for olefin metathesis.
- FIG. 3 provides a photo of a Grubbs-2 catalyst in PTS/water.
- FIG. 4 provides structures of problematic olefins.
- FIG. 5 provides the Hydrophilic Lipophilic Balance (HLB) of surfactants.
- FIG. 6 provides a study of the surfactants used in the invention.
- alkyl by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain, or cyclic hydrocarbon radical, or combination thereof, which may be fully saturated, mono- or polyunsaturated and can include di- and multivalent radicals, having the number of carbon atoms designated ⁇ i.e. C 1 -C 10 means one to ten carbons).
- saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl)methyl, cyclopropylmethyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.
- An unsaturated alkyl group is one having one or more double bonds or triple bonds.
- alkyl groups examples include, but are not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4- pentadienyl, 3-(l,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs and isomers.
- alkyl unless otherwise noted, is also meant to include those derivatives of alkyl defined in more detail below, such as “heteroalkyl.”
- Alkyl groups, which are limited to hydrocarbon groups are termed "homoalkyl".
- alkylene by itself or as part of another substituent means a divalent radical derived from an alkane, as exemplified, but not limited, by -CH 2 CH 2 CH 2 CH 2 -, and further includes those groups described below as “heteroalkylene.”
- an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred in the present invention.
- a “lower alkyl” or “lower alkylene” is a shorter chain alkyl or alkylene group, generally having eight or fewer carbon atoms.
- alkoxy alkylamino and “alkylthio” (or thioalkoxy) are used in their conventional sense, and refer to those alkyl groups attached to the remainder of the molecule via an oxygen atom, an amino group, or a sulfur atom, respectively.
- heteroalkyl by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or cyclic hydrocarbon radical, or combinations thereof, consisting of the stated number of carbon atoms and at least one heteroatom selected from the group consisting of O, N, Si and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized.
- the heteroatom(s) O, N and S and Si may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule.
- heteroalkylene by itself or as part of another substituent means a divalent radical derived from heteroalkyl, as exemplified, but not limited by, -CH 2 -CH 2 -S-CH 2 -CH 2 - and -CH 2 -S-CH 2 -CH 2 -NH-CH 2 -.
- heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like). Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula -C(O) 2 R'- represents both -C(O) 2 R'- and -R 5 C(O) 2 -.
- an "acyl substituent” is also selected from the group set forth above.
- acyl subsituent refers to groups attached to, and fulfilling the valence of a carbonyl carbon that is either directly or indirectly attached to the polycyclic nucleus of the compounds of the present invention.
- cycloalkyl and “heterocycloalkyl”, by themselves or in combination with other terms, represent, unless otherwise stated, cyclic versions of “alkyl” and “heteroalkyl”, respectively. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of cycloalkyl include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3- cyclohexenyl, cycloheptyl, and the like.
- heterocycloalkyl examples include, but are not limited to, 1 -(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4- morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2- yl, tetrahydrothien-3-yl, 1 -piperazinyl, 2-piperazinyl, and the like.
- halo or halogen
- haloalkyl by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.
- terms such as “haloalkyl,” are meant to include monohaloalkyl and polyhaloalkyl.
- halo(Ci-C4)alkyl is mean to include, but not be limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.
- aryl means, unless otherwise stated, a polyunsaturated, aromatic, hydrocarbon substituent which can be a single ring or multiple rings (preferably from 1 to 3 rings) which are fused together or linked covalently.
- heteroaryl refers to aryl groups (or rings) that contain from one to four heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized.
- a heteroaryl group can be attached to the remainder of the molecule through a heteroatom.
- Non- limiting examples of aryl and heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2- imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5- oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2- furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquino
- aryl when used in combination with other terms (e.g. , aryloxy, arylthioxy, arylalkyl) includes both aryl and heteroaryl rings as defined above.
- arylalkyl is meant to include those radicals in which an aryl group is attached to an alkyl group (e.g.
- benzyl, phenethyl, pyridylmethyl and the like including those alkyl groups in which a carbon atom (e.g., a methylene group) has been replaced by, for example, an oxygen atom (e.g., phenoxymethyl, 2-pyridyloxymethyl, 3-(l- naphthyloxy)propyl, and the like).
- a carbon atom e.g., a methylene group
- an oxygen atom e.g., phenoxymethyl, 2-pyridyloxymethyl, 3-(l- naphthyloxy)propyl, and the like.
- R', R", R'" and R" each preferably independently refer to hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, e.g., aryl substituted with 1-3 halogens, substituted or unsubstituted alkyl, alkoxy or thioalkoxy groups, or arylalkyl groups.
- each of the R groups is independently selected as are each R', R", R'" and R"" groups when more than one of these groups is present.
- R' and R" are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 5-, 6-, or 7-membered ring.
- -NR'R is meant to include, but not be limited to, 1-pyrrolidinyl and 4- morpholinyl.
- alkyl is meant to include groups including carbon atoms bound to groups other than hydrogen groups, such as haloalkyl (e.g., -CF 3 and -CH 2 CF 3 ) and acyl (e.g., -C(O)CH 3 , -C(O)CF 3 , -C(O)CH 2 OCH 3 , and the like).
- -NR-C(NR'R") NR'", -S(O)R', -S(O) 2 R', -S(O) 2 NR 5 R", -NRSO 2 R', -CN and -NO 2 , -R', - N 3 , -CH(Ph) 2 , fluoro(Ci-C 4 )alkoxy, and fluoro(Ci-C 4 )alkyl, in a number ranging from zero to the total number of open valences on the aromatic ring system; and where R', R", R'" and R"" are preferably independently selected from hydrogen, (Ci-Cg)alkyl and heteroalkyl, unsubstituted aryl and heteroaryl, (unsubstituted aryl)-(Ci-C4)alkyl, and (unsubstituted aryl)oxy-(Ci-C 4 )alkyl.
- Two of the aryl substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -T-C(O)-(CRR') q -U-, wherein T and U are independently -NR-, -O-, -CRR'- or a single bond, and q is an integer of from 0 to 3.
- two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A-(CH 2 ) r -B-, wherein A and B are independently -CRR'-, -O-, -NR-, -S-, -S(O)-, -S(O) 2 -, -S(O) 2 NR'- or a single bond, and r is an integer of from 1 to 4.
- One of the single bonds of the new ring so formed may optionally be replaced with a double bond.
- two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula - (CRR') s -X-(CR"R'") d -, where s and d are independently integers of from 0 to 3, and X is - O-, -NR'-, -S-, -S(O)-, -S(O) 2 -, or -S(O) 2 NR'-.
- the substituents R, R', R" and R'" are preferably independently selected from hydrogen or substituted or unsubstituted (C 1 - C 6 )alkyl.
- heteroatom includes oxygen (O), nitrogen (N), sulfur (S), phosphorus (P) and silicon (Si).
- water-soluble refers to moieties that have a detectable degree of solubility in water. Methods to detect and/or quantify water solubility are well known in the art.
- Exemplary water-soluble polymers include peptides, saccharides, poly(ethers), poly(amines), poly(carboxylic acids) and the like. Peptides can have mixed sequences of be composed of a single amino acid, e.g., poly(lysine), poly(aspartic acid), and poly(glutamic acid).
- An exemplary polysaccharide is poly(sialic acid).
- An exemplary poly(ether) is poly(ethylene glycol), e.g., m-PEG (a mono methyl capped poly(ethylene glycol)).
- Poly(ethylene imine) is an exemplary polyamine
- poly(acrylic) acid is a representative poly(carboxylic acid).
- pharmaceutically acceptable carrier includes any material, which when combined with the conjugate retains the conjugates' activity and is non-reactive with the subject's immune systems.
- examples include, but are not limited to, any of the standard pharmaceutical carriers such as a phosphate buffered saline solution, water, emulsions such as oil/water emulsion, and various types of wetting agents.
- Other carriers may also include sterile solutions, tablets including coated tablets and capsules.
- Such carriers contain excipients such as starch, milk, sugar, certain types of clay, gelatin, stearic acid or salts thereof, magnesium or calcium stearate, talc, vegetable fats or oils, gums, glycols, or other known excipients.
- Such carriers may also include flavor and color additives or other ingredients. Compositions comprising such carriers are formulated by well known conventional methods.
- administering means oral administration, administration as a suppository, topical contact, intravenous, intraperitoneal, intramuscular, intralesional, or subcutaneous administration, administration by inhalation, or the implantation of a slow- release device, e.g., a mini-osmotic pump, to the subject.
- Administration is by any route including parenteral and transmucosal (e.g., oral, nasal, vaginal, rectal, or transdermal), particularly by inhalation.
- Parenteral administration includes, e.g., intravenous, intramuscular, intra-arteriole, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial.
- injection is to treat a tumor, e.g., induce apoptosis
- administration may be directly to the tumor and/or into tissues surrounding the tumor.
- Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, etc.
- Hydrotrope refers to a class of water soluble organic molecules that significantly increase the aqueous solubility of certain lipophilic compounds. Hydrotropes are similar to surfactants but typically possess a smaller hydrophobic moiety. The reduced hydrophobic moiety makes hydrotropes less prone to forming micelles.
- An example of a hydrotrope is sodium xylenesulfonate, which is used in the consumer product industry. Other examples include nicotinamide, sodium ascorbate, cyclodextrins, liposomes and nanoparticles.
- Aqueous solution refers to a solution in which a majority of the weight of the solution is water. In some embodiments, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 92%, at least about 95%, at least about 96%, at least about 98%, and at least about 99% of the weight of the solution is water.
- CM intermolecular Grubbs cross-metathesis
- the aqueous solution is essentially free of co- solvents.
- the aqueous solution does not contain a co-solvent.
- the invention provides compositions comprising a catalyst and a solubilizing agent.
- the catalyst and solubilizing agent are covalently linked, thus forming a catalyst-solubilizing agent.
- the composition further comprises water, thereby forming an aqueous solution.
- the catalyst and the solubilizing agent are dissolved in the aqueous solution.
- the catalyst and the solubilizing agent form a micelle in aqueous solution.
- the aqueous solution does not contain a co-solvent.
- the composition does not include an additional solubilizing agent.
- the catalyst and the solubilizing agent form a micelle in aqueous solution.
- the composition further comprises an alcohol, thereby forming an alcoholic solution.
- the catalyst and the solubilizing agent are dissolved in the alcoholic solution.
- the catalyst and the solubilizing agent form a micelle in alcoholic solution.
- the catalyst is a transition-metal catalyst.
- the catalyst comprises ruthenium.
- the catalyst is a catalyst commonly used in a Grubbs reaction.
- the solubilizing agent has a structure according to Formula II.
- n is 8.
- the solubilizing agent has a structure according to Formula Ilia.
- the solubilizing agent has a structure according to Formula IHb.
- the solubilizing agent has a structure according to Formula IHc.
- the solubilizing agent has a structure according to Formula IHd.
- the solubilizing agent has a structure according to Formula V.
- the solubilizing agent is a member selected from polyoxyethanyl-tocopherol-sebacate (PTS), polyoxyethanyl-sitosterol-sebacate (PSS), polyoxyethanyl-cholesterol-sebacate (PCS) and polyoxyethanyl-ubiquinol-sebacate (PQS).
- PTS polyoxyethanyl-tocopherol-sebacate
- PSS polyoxyethanyl-sitosterol-sebacate
- PCS polyoxyethanyl-cholesterol-sebacate
- PQS polyoxyethanyl-ubiquinol-sebacate
- the invention provides compositions comprising a compound including an olefin and a solubilizing agent.
- these compositions are dissolved in an aqueous solution.
- the composition further comprises water, thereby forming an aqueous solution.
- the compound including an olefin and the solubilizing agent are dissolved in the aqueous solution.
- the composition further comprises an alcohol, thereby forming an alcoholic solution.
- the compound including an olefin and the solubilizing agent are dissolved in the alcoholic solution.
- the compound including an olefin and the solubilizing agent form a micelle in alcoholic solution.
- the invention provides compositions comprising a catalyst, compound including an olefin and a solubilizing agent.
- these compositions are dissolved in an aqueous solution.
- the composition further comprises water, thereby forming an aqueous solution.
- the catalyst, compound including an olefin and the solubilizing agent are dissolved in the aqueous solution.
- the composition further comprises an alcohol, thereby forming an alcoholic solution.
- the catalyst, compound including an olefin and the solubilizing agent are dissolved in the alcoholic solution.
- the catalyst, compound including an olefin and the solubilizing agent form a micelle in alcoholic solution.
- the catalyst is a transition-metal catalyst.
- the catalyst comprises ruthenium.
- the catalyst is a catalyst commonly used in a Grubbs reaction.
- the solubilizing agent has a structure according to Formula II.
- n is 8.
- the solubilizing agent has a structure according to Formula Ilia.
- the solubilizing agent has a structure according to Formula IHb.
- the solubilizing agent has a structure according to Formula IHc. In another exemplary embodiment, the solubilizing agent has a structure according to Formula IHd. In another exemplary embodiment, the solubilizing agent has a structure according to Formula V. In another exemplary embodiment, the solubilizing agent is a member selected from polyoxyethanyl- tocopherol-sebacate (PTS), polyoxyethanyl-sitosterol-sebacate (PSS), polyoxyethanyl- cholesterol-sebacate (PCS) and polyoxyethanyl-ubiquinol-sebacate (PQS). ///. a) Catalysts
- the catalyst is involved in a metathesis reaction.
- the metathesis reaction is a member selected from olefin metathesis, alkyne metathesis, alkane metathesis, cross metathesis (CM), ring-opening metathesis (ROM), ring-opening metathesis polymerization (ROMP), ring-closing metathesis (RCM), enyne metathesis (EM) and acyclic diene metathesis (ADMET).
- the catalyst is dissolved in an aqueous solution.
- the catalyst is a member selected from a Grubbs catalyst, Hoyveda-Grubbs catalyst, Schrock catalyst and derivatives thereof.
- the catalyst is Grubbs catalyst which is a member selected from first generation Grubbs catalyst and second-generation Grubbs catalyst.
- the catalyst is a Hoyveda-Grubbs catalyst and derivatives thereof.
- the catalyst is a Hoyveda-Grubbs catalyst. [0038] In an exemplary embodiment, wherein said catalyst has a structure which is a member selected from
- halo is a member selected from F, Cl, Br, and I and R 1 is a member selected from substituted or unsubstituted aryl;
- R 2 comprises PEG;
- R 3 is a member selected from substituted or unsubstituted aryl
- R a and R b are members independently selected from halogen, nitro, substituted or unsubstituted alkyl and substituted or unsubstituted heteroalkyl wherein Cy is unsubstituted cyclohexyl and Cy* is a member selected from substituted or unsubstituted cyclohexyl; Mes corresponds to the following structure: and Mes* is a member selected from substituted or unsubstituted 1,3,5 trimethylphenyl.
- R a is a member selected from nitro, methoxy, halogen, substituted or unsubstituted alkyl.
- R a and R b are members independently selected from nitro, methoxy, halogen and substituted or unsubstituted alkyl.
- said catalyst has a structure which is a member selected from
- the invention provides a catalyst described herein and PTS. In an exemplary embodiment, the invention provides a catalyst described in this paragraph and PTS.
- solubilizing agents can be utilized in the invention.
- the solubilizing agent is a surfactant.
- the solubilizing agent has a structure according to Formula (II):
- X or Y is a residue of hydrophilic moiety
- p is 1 or 2
- m is 0 or 1
- n is an integer from 0 to 18.
- the hydrophobic moiety of the solubilizing agent is a hydrophobic (lipophilic) molecule having an esterifiable hydroxy group and is preferably a sterol, tocopherol, or ubiquinol, or derivatives thereof, in particular cholesterol, 7-dehydrocholesterol, campesterol, sitosterol, ergosterol, stigmasterol, or an ⁇ -, ⁇ -, J-, or ⁇ -tocopherol.
- Cholesterol and sitosterol are preferred sterols, sitosterol being particularly preferred.
- ⁇ -(+)- Tocopherol and ⁇ -(+)-tocopherol are preferred tocopherols, with synthetic DL tocopherol being particularly preferred for PTS.
- the residue of the hydrophobic moiety is the entire hydrophobic molecule, except for its esterif ⁇ ed hydroxy group, such as 3-b-hydroxy group of cholesterol or sitosterol or 6-hydroxy group of ⁇ -tocopherol.
- the hydrophilic moiety of the solubilizing agent is a hydrophilic molecule having a functional group, which can be used to chemically attach the hydrophilic molecule to the ubiquinol, either directly or through a linker moiety.
- said functional group include esterifiable hydroxy groups, carboxy groups, and amino groups.
- the hydrophilic molecule is preferably selected from the group consisting of polyalcohols, polyethers, polyanions, polycations, polyphosphoric acids, polyamines, polysaccharides, polyhydroxy compounds, polylysines, and derivatives thereof. Of those, polyethers are preferred, polyalkylene glycols being particularly preferred.
- polyalkylene glycol includes polymers of lower alkylene oxides, in particular polymers of ethylene oxide (polyethylene glycols) and propylene oxide (polypropylene glycols), having an esterifiable hydroxy group at least at one end of the polymer molecule, as well as derivatives of such polymers having esterifiable carboxy groups.
- the residue of the hydrophilic moiety is the entire hydrophilic molecule, except for the atom involved in forming the bond to the ubiquinol moiety or the linker moiety (i.e. an esterified hydroxy group, the oxygen molecule of an ether bond, a carboxy or amino group) or groups, such as terminal hydroxy groups of a polyethylene glycol molecule.
- the solubilizing agent has a structure according to Formula (II), when p and m are both equal to 1 and the hydrophobic moiety is cholesterol, n is greater than 4 and not equal to 8.
- the solubilizing agent has a structure according to Formula (II), when when p and m are both equal to 1 and the hydrophobic moiety is ⁇ -(+)-tocopherol, n is not equal 2.
- Compounds of formula (II) for which m is equal to 1 can be regarded as diesters of an alkanedioic acid of the general formula HOOC-(CH 2 )I 1 --COOH.
- alkanedioic acids with n from 0 to 18 are preferred, those with n from 6 to 10 being particularly preferred.
- Y is a hydrophobic moiety having the structure according to formula (Ha):
- R 11 , R 12 and R 13 are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl, wherein
- R 12 and R 13 along with the atoms to which they are attached, are optionally joined to form a 4- to 8-membered ring;
- R 16 is a member selected from OR 17 , SR 17 , NR 17 R 18 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl wherein
- L2 is a linker moiety, selected from substituted or unsubstituted alkyl and substituted or unsubstituted heteroalkyl;
- Y2 is a hydrophilic moiety, selected from polyethers, polyalcohols and derivatives thereof;
- Z2 and Z4 are members independently selected from 0 and 1.
- Z4 and Z2 are both 0, (L2)z4-(Y2)z2 is a member selected from H, a negative charge and a salt counterion.
- Y2 and L2 do not comprise a labeling moiety, a targeting moiety or a drug moiety.
- L2 has a structure according to a formula described herein.
- the solubilizing agent has a structure according to Formula (Ilia):
- R 20 , R 21 , R 22 , R 23 , R 24 and R 25 are members selected from OR 17 , SR 17 , NR 17 R 18 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl.
- R 24 and/or R 25 comprises an isoprene moiety.
- the solubilizing agent has a structure according to Formula (HIb): wherein R 24 and/or R 25 comprises an isoprene moiety, Z4 is 1 and Z2 is 1.
- the solubilizing agent has a structure according to Formula (IIIc):
- R 24 and/or R 25 comprises an isoprene moiety
- Z4 is 1 and Z2 is 1.
- L2 and Y2 is a PEG moiety.
- this PEG moiety has a molecular weight of between 800 Da and 1200 Da.
- the solubilizing agent is TPGS.
- TPGS is synthesized by esterifying d-alpha tocopheryl succinate with polyethylene glycol (PEG) 1000 (the molecular weight of PEG 1000 is approximately 1,000 daltons). It is a pale yellow, waxy solid substance that is amphipathic and hydrophilic. Its molecular weight is approximately 1,513 daltons.
- d-alpha-tocopherol comprises 26% of TPGS.
- TPGS is also known as d- alpha-tocopheryl polyethylene glycol 1000 succinate and d-alpha-tocopheryl PEG 1000 succinate.
- the solubilizing agent is a member selected from RRR-alpha-tocopheryl polyethylene glycol 1000 succinate, 2R, 4'R, 8'R-alpha- tocopheryl polyethylene glycol 1000 succinate and 2, 5, 7, 8-tertramethyl-2-(4',8',12'- trimethyltridecyl)-6-chromanyl polyethylene glycol 1000 succinate.
- the solubilizing agent has a structure according to Formula (HId):
- R 24 and/or R 25 comprises an isoprene moiety
- Z4 is 1
- Z2 is 1.
- Ll-Yl is a member selected from
- n is member selected from 1 to 20
- m is a member selected from 1 to 10,000.
- n is 4.
- m is a member selected from 1 to 2,500.
- the solubilizing agent has a structure according to Formula (HIe):
- the solubilizing agent has a structure according to Formula (IV):
- R 11 , R 12 and R 13 are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl.
- R 16 is a member selected from OR 17 , SR 17 , NR 17 R 18 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl.
- R 17 and R 18 are members independently selected from substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl.
- R 12 and R 13 along with the atoms to which they are attached, are optionally joined to form a 4- to 8-membered ring.
- Ll and L2 are linker moieties, which are members independently selected from substituted or unsubstituted alkyl and substituted or unsubstituted heteroalkyl.
- Yl and Y2 are polymeric hydrophilic moieties, which are members independently selected from polyethers, polyalcohols and derivatives thereof. In a preferred embodiment, Yl, Y2, Ll and L2 do not comprise a labeling moiety, a targeting moiety or a drug moiety.
- Zl, Z2, Z3 and Z4 are members independently selected from 0 and 1 with the proviso that at least one of Zl and Z2 is 1.
- (L2)z4-(Y2)z2 is preferably a member selected from H, a negative charge, and a salt counterion
- (Ll)z3-(Yl)zi is preferably a member selected from H, a negative charge, and a salt counterion.
- the hydrophobic moiety of the solubilizing agent is a hydrophobic molecule having an esterif ⁇ able hydroxy group and is preferably an ubiquinol or a derivative thereof.
- Ubiquinol is a reduced derivative of a ubiquinone.
- R 16 has a structure according to the following formula:
- k is an integer selected from 1 to 13. In an exemplary embodiment, k is a member selected from 1 to 15. In an exemplary embodiment, k is a member selected from 3 to 11. In an exemplary embodiment, k is a member selected from 8 to 12. In an exemplary embodiment, k is 10.
- Preferred ubiquinols are those of Formula (V):
- k is an integer of from 1 to 13.
- the ubiquinol with k equal to 10 (ubiquinol-50 or reduced coenzyme Q 10 ) is particularly preferred.
- R 11 in Formula (IV) is H.
- Exemplary ubiquinol analogs according to this aspect of the invention include:
- R 11 is a methyl group and R 12 and R 13 are members independently selected from H, unsubstituted alkyl, unsubstituted alkoxy, halogen substituted alkyl, and halogen substituted alkoxy.
- Exemplary compounds according to this aspect of the invention include:
- one or more of the substituents R 11 , R 12 and R 13 include halogen atoms.
- the halogen is fluoro.
- Exemplary fluoroalkyl and fluoroalkoxy groups according to this aspect of the invention include but are not limited to CF 3 , OCF 3 , CHF 2 , OCHF 2 , CH 2 F, and OCH 2 F.
- Exemplary compounds according to this aspect of the invention include:
- linker moieties Ll and L2 can serve to connect the ubiquinol to the hydrophilic moiety.
- Ll and L2 are members independently selected from the following formulae:
- n is selected from O to 18.
- Y3 is a member selected from Yl and Y2, and Y4 and Y5 are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted cycloalkyl and substituted or unsubstituted heterocycloalkyl.
- Preferred linkers include diesters derived from an alkanedioic acid of the general formula HOOC-(CH 2 ) n ⁇ COOH.
- alkanedioic acids with n from 0 to 18 are preferred, those with n from 6 to 10 being particularly preferred.
- Other preferred linkers include diethers derived from a substituted alkane.
- the substituted alkane has the general structure X-(CH 2 )D-X' wherein X and X' independently represent a leaving group such as a halogen atom or a tosylate group.
- substituted alkanes with n from 0 to 18 are preferred, those with n from 6 to 10 being particularly preferred.
- one or both of the phenolic hydroxy groups of the ubiquinol analog are derivatized with the hydrophilic moiety or the linker moiety.
- exemplary solubilizing agents have the formula:
- one of the phenolic hydroxy groups of the ubiquinol analog is derivatized with a hydrophilic moiety of the invention.
- exemplary solubilizing agents have the structure:
- Q is a member selected from H, a negative charge and a salt counter ion.
- Q is a member selected from H, a negative charge and a salt counter ion.
- one or both of the phenolic hydroxy groups of ubiquinol are esterif ⁇ ed with the hydrophilic moiety or the linker moiety.
- Exemplary solubilizing agents have a formula which is a member selected from:
- phenolic hydroxy groups of ubiquinol are part of an ether bond with the linker moiety.
- solubilizing agents have a formula, which is a member selected from:
- the invention provides a mixture including two or more solubilizing agents described herein.
- the solubilizing agents are as described in Formula (IV).
- the integer k may be constant, but some of the solubilizing agents include one hydrophilic moiety, while others include two hydrophilic moieties.
- the mixture includes two regioisomers.
- the invention provides a mixture including a solubilizing agent of the invention, wherein Zl and Z2 are each 1 and wherein the mixture further includes at least one member selected from:
- Q is a member selected from H, a negative charge and a salt counter ion.
- the invention provides a mixture including a solubilizing agent of the invention, wherein Z2 is 1 and Zl is 0, wherein the mixture further includes at least one member selected from:
- Q is a member selected from H, a negative charge and a salt counter ion.
- the invention provides a mixture comprising a solubilizing agent of the invention, wherein Zl is 1 and Z2 is 0, wherein the mixture further includes at least one member selected from: wherein Q is a member selected from H, a negative charge and a salt counter ion.
- the compounds in the mixture of solubilizing agents have structures according to Formulae (Ilia), (VI), (VII), (VIII), (IX), (X) and (XI).
- the present invention provides a water-soluble composition including the solubilizing agent according to Formula (IV) and a catalyst.
- the solubilizing agent is a member selected from polyoxyethanyl-tocopherol-sebacate (PTS), polyoxyethanyl-sitosterol-sebacate (PSS), polyoxyethanyl-cholesterol-sebacate (PCS), polyoxyethanyl-ubiquinol-sebacate (PQS) and combinations thereof.
- PTS polyoxyethanyl-tocopherol-sebacate
- PSS polyoxyethanyl-sitosterol-sebacate
- PCS polyoxyethanyl-cholesterol-sebacate
- PQS polyoxyethanyl-ubiquinol-sebacate
- the solubilizing agent is a member selected from:
- m is a member selected from 1 to 30.
- m is a member selected from 5-20.
- m is a member selected from 7-14.
- m is 9.
- m is 11.
- the solubilizing agent is sodium dodecyl sulfate/sodium lauryl sulfate.
- the solubilizing agent is a member selected from:
- n is a member selected from 1 to 30, and n is a member selected from 1 to 5500.
- m is a member selected from 5-20.
- m is a member selected from 8-15.
- m is a member selected from 9 (laureth sulfate) 11 and 13 (myreth sulfate).
- the solubilizing agent is sodium dodecyl sulfate/sodium lauryl sulfate.
- n is a member selected from 1000-5000.
- n is a member selected from 100-500.
- n is a member selected from 10-50.
- n is a member selected from 1- 25.
- n is a member selected from 5-100.
- n is a member selected from 1-500.
- the solubilizing agent is a member selected from:
- n is a member selected from 1 to 30, and n is a member selected from 1 to 2500.
- m is a member selected from 5-20.
- m is a member selected from 8-15.
- m is a member selected from 9 (laureth sulfate) 11 and 13 (myreth sulfate).
- n is a member selected from 1000-5000.
- n is a member selected from 100-500.
- n is a member selected from 10-50.
- n is a member selected from 1-25.
- n is a member selected from 5-100.
- n is a member selected from 1-500.
- m is 11 and n is 4 (Brij 30).
- the solubilizing agent is a member selected from:
- n is a member selected from 1 to 5500.
- n is a member selected from 5-20.
- n is a member selected from 8- 15.
- n is a member selected from 1000-5000.
- n is a member selected from 100-500.
- n is a member selected from 10-50.
- n is a member selected from 1- 25.
- n is a member selected from 5-100.
- n is a member selected from 1-500.
- n is a member selected from 9 and 10 (Triton X-100).
- polyethylene glycol is the solubilizing agent.
- Suitable polyethylene glycols may have a free hydroxy group at each end of the polymer molecule, or may have one hydroxy group etherif ⁇ ed with a lower alkyl, e.g., a methyl group.
- derivatives of polyethylene glycols having esterifiable carboxy groups or amino groups which may be used to form an amide bond.
- Polyethylene glycols are commercially available under the trade name PEG, usually as mixtures of polymers characterized by an average molecular weight.
- Polyethylene glycols having an average molecular weight from about 300 to about 5000 are preferred, those having an average molecular weight from about 600 to about 1000 being particularly preferred. Both linear and branched PEG molecules can be used as solubilizing agents in the practice of the invention.
- PEG has between 1000 and 5000 subunits. In an exemplary embodiment, PEG has between 100 and 500 subunits. In an exemplary embodiment, PEG has between 10 and 50 subunits. In an exemplary embodiment, PEG has between 1 and 25 subunits. PEG has between 5 and 100 subunits. In an exemplary embodiment, PEG has between 1 and 500 subunits.
- the formulations of the invention include from about 10% to about 50% by weight of a solubilizing agent, such as PTS.
- a solubilizing agent such as PTS.
- the formulations include from about 15% to about 40% (w/w) solubilizing agent, more preferably from about 20% to about 40% (w/w), and even more preferably from about 20 to about 35% (w/w).
- the invention includes from about 0.01% (w/w) to about 5% (w/w) of a solubilizing agent. In an exemplary embodiment, the invention includes from about 0.01% (w/w) to about 0.1% (w/w) of a solubilizing agent. In an exemplary embodiment, the invention includes from about 0.01% (w/w) to about 1% (w/w) of a solubilizing agent. In an exemplary embodiment, the invention includes from about 0.1% (w/w) to about 1% (w/w) of a solubilizing agent. In an exemplary embodiment, the invention includes from about 0.1% (w/w) to about 0.75% (w/w) of a solubilizing agent.
- the invention includes from about 1% (w/w) to about 3% (w/w) of a solubilizing agent. In an exemplary embodiment, the invention includes from about 0.05% (w/w) to about 0.25% (w/w) of a solubilizing agent.
- Solubilizing agents utilized in the compositions of the invention include those described in US Provisional Patent Application 60/773,951; and US Patents: 6,045,826; 6, 191 , 172 and 6,632,443 to Borowy-Borowski et al. , which are incorporated herein by reference for all purposes. These solubilizing agents can be purchased commercially from sources such as Zymes (New Jersey) or produced according to the methods described in the above documents.
- the solubilizing agent contributes to the formation of micelles once the composition is added to an aqueous solution.
- the size of the formed micelles in solution may be measured using a dynamic light scattering (DLS) detector.
- the compositions of the invention form particle sizes in aqueous solution.
- the average particle size formed by the compositions of the invention in aqueous solution is preferably below about lOOnm. In exemplary embodiment, the average particle size is from about IOnm to about 90nm.
- An exemplary average particle size is from about 5nm to about 70nm, preferably from about IOnm to about 50nm, more preferably from about IOnm to about 30nm, and most preferably from about 15nm to about 25nm.
- the solubilizing agent is PTS.
- formulations of the invention can be produced in a variety of ways.
- ubiquinol analogs described herein and their precursors of the corresponding ubiquinones can be prepared by art-recognized methods or modifications thereof. Methods for the synthesis of quinone analogs are described by Lipshutz (Lipshutz et al, J. Am. Chem. Soc. 121: 11664-11673 (1999)), the disclosure of which is incorporated herein by reference. In addition, the synthesis of substituted methylene aromatic moieties, such as phenols, can be accomplished using methods described by U.S. Patent No. 6,545,184 to Lipshutz et al., and U.S. Patent Application No. 20050148675 to Lipshutz et al; the disclosures of which are also herein incorporated by reference.
- Preferred linkers include diesters derived from an alkanedioic acid of the general formula HOOC-(CH 2 ) n -COOH.
- alkanedioic acids with n from 0 to 18 are preferred, those with n from 6 to 10 being particularly preferred.
- solubilizing agents can be prepared by reacting a hydrophilic compound of the general formula Y-OH with a spacer compound of the general formula Z-OC-(CH 2 ) D -CO-Z, wherein Z is a member selected from OH, a leaving group, and further reacting the product so obtained with a ubiquinol analog.
- Halogens, in particular Cl and Br are preferred as the leaving group Z.
- the spacer moiety is activated through an NHS ester moiety.
- Other preferred linkers include diethers derived from a substituted alkane.
- the substituted alkane has the general structure X-(CH 2 ) n -X' wherein X and X' independently represent a leaving group such as a halogen atom or a tosylate group.
- the halogen is Br.
- the invention provides an compound including an olefin and a solubilizing agent.
- the compound including an olefin is described herein.
- the compound including an olefin is described in Table 1.
- the compound including an olefin is described in Table 2.
- the compound including an olefin is described in Figure 3.
- the compound including an olefin is described in Table 3.
- the invention provides a compound including an olefin described herein and PTS.
- the invention provides a compound including an olefin described in Table 1 and PTS.
- the invention provides a compound including an olefin described in Table 2 and PTS. In an exemplary embodiment, the invention provides a compound including an olefin described in Figure 3 and PTS. In an exemplary embodiment, the invention provides a compound including an olefin described in Table 3 and PTS. ///. d) Catalyst-Solubilizing Agents
- the catalyst-solubilizing agent has a structure according to Formula (Va):
- R 11 , R 12 and R 13 are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl.
- R 16 is a member selected from OR 17 , SR 17 , NR 17 R 18 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl.
- R 17 and R 18 are members independently selected from substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl.
- R 12 and R 13 along with the atoms to which they are attached, are optionally joined to form a 4- to 8-membered ring.
- the composition has a proviso that at least one of [Ll, Z3, Yl and Zl] and [L2, Z4, Y2 and Z2] is a catalyst described herein.
- the catalyst is a member selected from a Grubbs catalyst and a Hoyveda-Grubbs catalyst. In another exemplary embodiment, the catalyst is a second-generation Grubbs catalyst. In another exemplary embodiment, the catalyst is a Hoyveda-Grubbs catalyst.
- R 12 is OCH 3 .
- R 13 is OCH 3 .
- R 11 is CH 3 .
- R 16 has a structure according to the following formula:
- k is an integer selected from 1 to 13. In an exemplary embodiment, k is a member selected from 1 to 15. In an exemplary embodiment, k is a member selected from 3 to 11. In an exemplary embodiment, k is a member selected from 8 to 12. In an exemplary embodiment, k is 10. In an exemplary embodiment, Zl is 1 and Yl has a structure according to
- each halo is chloro
- the catalyst-solubilizing agent has a structure according to Formula (Vb):
- nl is a member selected from 1 to 10.
- nl is a member selected from 2, 3 and 4.
- nl is 3.
- L2z4-Y2z2 has a structure according to the following formula:
- R , 30 is a member selected from H and CH 3
- n2 is an integer selected from 1 to 15
- n3 is an integer selected from 1 to 2000.
- n2 is a member selected from 4 to 14.
- n2 is a member selected from 6 to 10.
- n2 is 8.
- n3 is an integer selected from 10 to 200.
- n3 is an integer selected from 10 to 150.
- n3 is an integer selected from 23 to 150.
- n3 is an integer selected from 50 to 100.
- n3 is an integer selected from 10 to 60.
- n3 is an integer selected from 60 to 100. In an exemplary embodiment, n3 is an integer selected from 23 to 150. In an exemplary embodiment, n3 is an integer selected from 10 to 35. In an exemplary embodiment, n3 is an integer selected from 30 to 55. In an exemplary embodiment, n3 is an integer selected from 1000 to 5000. In an exemplary embodiment, n3 is an integer selected from 100 to 500. In an exemplary embodiment, n3 is an integer selected from 10 to 50. In an integer selected from 1 to 25. In an exemplary embodiment, n3 is an integer selected from 5 to 100. In an exemplary embodiment, n3 is an integer selected from 1 to 500. In an exemplary embodiment, R 12 is OCH 3 . In an exemplary embodiment, R 13 is OCH 3 . In an exemplary embodiment, R 11 is CH 3 . In an exemplary embodiment, Zl is 1 and Yl has a structure according to
- R a is as described herein.
- halo is chloro
- the catalyst-solubilizing agent has a structure according to Formula (Vb):
- the catalyst-solubilizing agent has a structure according to Formula (Vd):
- the catalyst-solubilizing agent has a structure according to Formula (Ve):
- R 30 , n3, n2, R 11 , R 12 , R 13 , R 16 , are as described herein, Zl is 1, Yl is a catalyst moiety described herein and nl is a integer selected from 1 to 10. In an exemplary embodiment, n2 is 8. In an exemplary embodiment, n3 is an integer selected from 750 to 1500. In an exemplary embodiment, R 12 is OCH 3 . In an exemplary embodiment, R 13 is OCH 3 . In an exemplary embodiment, R 11 is CH 3 .
- the catalyst-solubilizing agent is a compound described in the Examples section. In an exemplary embodiment, the compound has a structure according to the following formula: , wherein n3 is as described herein. In an exemplary embodiment, n3 is a member selected from 10 to 60.
- the compound is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N
- n3 is as described herein.
- ubiquinol (10, Scheme 1)
- hydroquinone form of coenzyme Q 10 which is formed quantitatively from its Zn/HOAc reduction
- the mixed, O-succinimide derivative 9 formed by esterification using commercially available Me-PEG-2000 (7) and mono-carbonyl-activated sebacic acid, 8.
- PQS is a colorless white solid, freely soluble in water in which it forms 9 nm micelles, as determined by dynamic light scattering measurements using a Brookhaven Laser Light Scattering instrument. Its critical micelle concentration is 0.06 mg/mL at 25 0 C, which correspond to 1.97 x 10 "5 M based on a molecular weight of 3046. Esterif ⁇ cation of the free phenolic group in 5 using Hoveyda's acid 11 (Garber, S. B., et al, J. Am. Chem. Soc. 2000, 122, 8168-8179) gave the carbene precursor 12 in good isolated yield (Scheme 2).
- Table 3 illustrates representative examples, highlighting several noteworthy features of this remarkably simple process: (a) all cases studied to date led to excellent isolated yields of the desired products; (b) the water need not be degassed prior to use; (c) these reactions can be run fully exposed to air; (d) reactions leading to 5-, 6-, and 7- membered rings proceed smoothly under identical conditions; (e) ring closures are fairly rapid, all taking place with two hours at ambient temperature; (f) workup and product isolation are especially straightforward, involving addition of an organic solvent to the aqueous mixture, followed by repetitive in-flask extraction and subsequent removal of organic solvent.
- the process could be repeated for an additional 10 recycles.
- PQS-derived carbene complex 6 retains > 92% of its original activity within this (arbitrarily chosen) time frame and concentration in water.
- the catalyst- so lubilizing agent has a structure according to Formula (Ilia):
- R 20 , R 21 , R 22 , R 23 , R 24 and R 25 are members selected from OR 17 , SR 17 , NR 17 R 18 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl, and L2, Z4, Y2 and Z2 is a catalyst described herein.
- the catalyst is a member selected from a Grubbs catalyst and a Hoyveda-Grubbs catalyst.
- the catalyst is a second-generation Grubbs catalyst.
- R 24 and/or R 25 comprises an isoprene moiety.
- the catalyst-solubilizing agent has a structure according to Formula (HIb):
- R 24 and/or R 25 comprises an isoprene moiety, Z4 is 1 and Z2 is 1.
- the catalyst-solubilizing agent has a structure according to Formula (IIIc): wherein R 24 and/or R 25 comprises an isoprene moiety, Z4 is 1 and Z2 is 1.
- R 24 and/or R 25 comprises an isoprene moiety
- Z4 is 1
- Z2 is 1.
- L2 and Y2 is a PEG moiety.
- this PEG moiety has a molecular weight of between 800 Da and 1200 Da.
- the catalyst- so lubilizing agent has a structure according to Formula (IIIc):
- R 24 and/or R 25 comprises an isoprene moiety
- Z4 is 1
- Z2 is 1.
- Ll-Yl is a member selected from
- n is member selected from 1 to 20
- m is a member selected from 1 to 10,000.
- n is 4.
- m is a member selected from 1 to 2,500.
- the catalyst- so lubilizing agent has a structure according to Formula (HId):
- linker moieties Ll and L2 can serve to connect the ubiquinol to the hydrophilic moiety.
- Ll and L2 are members independently selected from the following formulae:
- n is selected from 0 to 18.
- Y3 is a member selected from Yl and Y2, and Y4 and Y5 are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted cycloalkyl and substituted or unsubstituted heterocycloalkyl.
- Preferred linkers include diesters derived from an alkanedioic acid of the general formula HOOC-(CH 2 ) n ⁇ COOH.
- alkanedioic acids with n from 0 to 18 are preferred, those with n from 6 to 10 being particularly preferred.
- Other preferred linkers include diethers derived from a substituted alkane.
- the substituted alkane has the general structure X-(CH 2 )D-X' wherein X and X' independently represent a leaving group such as a halogen atom or a tosylate group.
- substituted alkanes with n from 0 to 18 are preferred, those with n from 6 to 10 being particularly preferred.
- phenolic hydroxy groups of the ubiquinol analog are derivatized with the hydrophilic moiety or the linker moiety.
- exemplary catalyst-solubilizing agents have the formula:
- compositions of the invention are made by first adding a catalyst to an medium, and then adding the solubilizing agent to the medium.
- the compositions are made by first adding the solubilizing agent to the aqueous solution, and then adding the catalyst to the medium.
- the compositions are made by first adding the solubilizing agent and the catalyst to a container without the medium, and then adding medium.
- compositions of the invention are made by first adding a compound containing an olefin to an medium, and then adding the solubilizing agent to the medium.
- the compositions are made by first adding the solubilizing agent to the aqueous solution, and then adding the compound containing an olefin to the medium.
- the compositions are made by first adding the solubilizing agent and the compound containing an olefin to a container without the medium, and then adding medium.
- the invention provides a catalyst and a solubilizing agent in an aqueous solution that does not contain a co-solvent.
- the composition does not include an additional solubilizing agent.
- the invention provides a catalyst and PTS in an aqueous solution that does not contain a co-solvent.
- the composition does not include an additional solubilizing agent.
- the invention provides a Grubbs catalyst and PTS in an aqueous solution that does not contain a co- solvent.
- the composition does not include an additional solubilizing agent.
- the invention provides a second- generation Grubbs catalyst and PTS in an aqueous solution that does not contain a co- solvent.
- the composition does not include an additional solubilizing agent.
- PTS hydrophilic lipophilic balance
- HLB hydrophilic lipophilic balance
- the invention provides a reaction system comprising a catalyst and solubilizing agent described herein and at least one alkene compound.
- the invention provides a reaction system comprising a catalyst described herein, a solubilizing agent described herein, two acyclic alkene compounds described herein, said system for a cross-metathesis reaction.
- the invention provides a reaction system comprising a catalyst described herein, a solubilizing agent described herein, a cyclic alkene compound and an acyclic alkene compound.
- the invention provides a reaction system comprising a catalyst described herein, a solubilizing agent described herein, and a cyclic alkene compound, said system for a ring-opening metathesis reaction or a ring-opening metathesis polymerization reaction.
- the invention provides a reaction system comprising a catalyst described herein, a solubilizing agent described herein, and a compound which comprises at least two alkenes, said system for a ring-closing metathesis reaction.
- a reaction system described in this paragraph further comprises water.
- the components of a reaction system described in this paragraph are dissolved in an aqueous solution.
- the aqueous solution does not contain a co-solvent. In another exemplary embodiment, the composition does not include an additional solubilizing agent.
- the invention provides a method of performing a cross-coupling metathesis reaction in an aqueous solution, said method comprising: (a) contacting a first alkene compound and a second alkene compound and a catalyst and a solubilizing agent in said aqueous solution, wherein said contacting is for a time sufficient for said cross-coupling metathesis reaction to occur.
- the aqueous solution does not contain a co-solvent.
- the composition does not include an additional solubilizing agent.
- the invention provides a method of performing a ring-opening metathesis reaction in an aqueous solution, said method comprising: (a) contacting a cyclic alkene compound and a catalyst and a solubilizing agent, wherein said contacting is for a time sufficient for said ring-opening metathesis reaction to occur, thereby converting said cyclic alkene into a compound comprising at least two alkenes.
- the aqueous solution does not contain a co-solvent.
- the composition does not include an additional solubilizing agent.
- the invention provides a method of performing a ring-closing metathesis reaction in an aqueous solution, said method comprising: (a) contacting a compound which comprises at least two alkenes and a catalyst and a solubilizing agent, wherein said contacting is for a time sufficient for said ring-closing metathesis reaction to occur, thereby converting said compound to a compound comprising a cyclic alkene.
- the aqueous solution does not contain a co-solvent.
- the composition does not include an additional solubilizing agent.
- the invention provides a composition comprising: (a) a catalyst; and (b) a solubilizing agent.
- the catalyst is utilized in a metathesis reaction.
- the metathesis reaction is a member selected from olefin metathesis, alkyne metathesis, alkane metathesis, cross metathesis (CM), ring-opening metathesis (ROM), ring-opening metathesis polymerization (ROMP), ring-closing metathesis (RCM), enyne metathesis (EM) and acyclic diene metathesis (ADMET).
- CM cross metathesis
- ROM ring-opening metathesis
- ROMP ring-opening metathesis polymerization
- RCM ring-closing metathesis
- EM enyne metathesis
- ADMET acyclic diene metathesis
- the catalyst comprises a transition metal.
- the catalyst comprises ruthenium.
- the catalyst is a member selected from Grubbs catalyst, Hoyveda-Grubbs catalyst, Schrock catalyst and derivatives thereof.
- the catalyst is Grubbs catalyst which is a member selected from first generation Grubbs catalyst and second-generation Grubbs catalyst.
- the catalyst has a structure which is a member selected from
- halo is a member selected from F, Cl, Br, and I; R 1 is a member selected from
- R is a PEG moiety
- R 3 is a member selected from substituted or unsubstituted aryl
- the solubilizing agent is a member selected from: wherein R 11 , R 12 and R 13 are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl, wherein R 12 and R 13 , along with the atoms to which they are attached, are optionally joined to form a 4- to 8-membered ring; R 16 is a member selected from OR 17 , SR 17 , NR 17 R 18 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalky
- the solubilizing agent has a structure according to Formula (II):
- the solubilizing agent has a structure according to Formula (Ilia):
- R 20 , R 21 , R 22 , R 23 , R 24 and R 25 are members selected from OR 17 , SR 17 , NR 17 R 18 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl.
- the solubilizing agent is a member selected from polyoxyethanyl-tocopherol-sebacate (PTS), polyoxyethanyl-sitosterol-sebacate (PSS), polyoxyethanyl-cholesterol-sebacate (PCS), polyoxyethanyl-ubiquinol-sebacate (PQS) and combinations thereof
- the solubilizing agent is a member selected from polyoxyethanyl-tocopherol-sebacate (PTS), polyoxyethanyl-sitosterol-sebacate (PSS), and combinations thereof [0139] In an exemplary embodiment, according to any of the above paragraphs, the solubilizing agent is polyoxyethanyl-tocopherol-sebacate (PTS).
- the solubilizing agent which is a member selected from Triton X-100, Brij 30, TPGS, PEG and SDS.
- the solubilizing agent is polyoxyethanyl-tocopherol-sebacate and the composition is dissolved in an aqueous solution.
- the solubilizing agent is polyoxyethanyl-tocopherol-sebacate and the catalyst comprises a transition metal.
- the solubilizing agent is polyoxyethanyl-tocopherol-sebacate and the catalyst comprises ruthenium.
- the solubilizing agent is polyoxyethanyl-tocopherol-sebacate and the catalyst is a member selected from Grubbs catalyst, Hoyveda-Grubbs catalyst, Schrock catalyst and derivatives thereof.
- the solubilizing agent is polyoxyethanyl-tocopherol-sebacate and the catalyst is Grubbs catalyst which is a member selected from first generation Grubbs catalyst and second-generation Grubbs catalyst.
- the solubilizing agent is polyoxyethanyl-tocopherol-sebacate and the catalyst has a structure which is a member selected from
- halo is a member selected from F, Cl, Br, and I;
- R 1 is substituted or unsubstituted aryl;
- R 2 is a PEG moiety;
- R 3 is a member selected from substituted or unsubstituted aryl;
- the catalyst and said solubilizing agent are covalently attached, thereby forming a catalyst- solubilizing agent.
- the invention provides a compound with a structure according to the following formula:
- R 11 , R 12 and R 13 are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl wherein R 12 and R 13 , along with the atoms to which they are attached, are optionally joined to form a 4- to 8-membered ring;
- R 16 is a member selected from OR 17 , SR 17 , NR 17 R 18 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl, wherein R 17
- the catalyst-solubilizing agent has a structure according to a formula described herein.
- the compound has a structure according to a formula described herein.
- Yl has a structure which is a member selected from:
- R a is a member selected from halogen, nitro, substituted or unsubstituted alkyl and substituted or unsubstituted heteroalkyl.
- the compound has the following structure:
- n3 is an integer selected from 10 to 60. In an exemplary embodiment, n3 is an integer selected from 10 to 30.
- the invention provides a reaction system comprising the composition described in an above paragraph and at least one alkene compound.
- the reaction system comprises two acyclic alkene compounds, said system for a cross-metathesis reaction.
- the reaction system comprises a cyclic alkene compound and an acyclic alkene compound, said system for a ring-opening cross-metathesis reaction.
- the reaction system comprises a cyclic alkene compound, said system for a ring-opening metathesis reaction or a ring-opening metathesis polymerization reaction.
- the reaction system comprises a compound which comprises at least two alkenes, said system for a ring-closing metathesis reaction.
- the invention provides a method of performing a cross-coupling metathesis reaction in an aqueous solution, said method comprising: (a) contacting a first alkene compound and a second alkene compound and a catalyst according to any of the above paragraphs and a solubilizing agent according to any of the above paragraphs, wherein said contacting is for a time sufficient for said cross-coupling metathesis reaction to occur.
- the invention provides a method of performing a ring-opening metathesis reaction in an aqueous solution, said method comprising: (a) contacting a cyclic alkene compound and a catalyst according to any of the above paragraphs and a solubilizing agent according to any of the above paragraphs, wherein said contacting is for a time sufficient for said ring-opening metathesis reaction to occur, thereby converting said cyclic alkene into a compound comprising at least two alkenes.
- the invention provides a method of performing a ring-closing metathesis reaction in an aqueous solution, said method comprising: (a) contacting a compound which comprises at least two alkenes and a catalyst according to any of the above paragraphs and a solubilizing agent according to any of the above paragraphs, wherein said contacting is for a time sufficient for said ring-closing metathesis reaction to occur, thereby converting said compound to a compound comprising a cyclic alkene.
- the invention provides a composition
- a composition comprising: (a) a catalyst; (b) a solubilizing agent, wherein said solubilizing agent is a member selected from wherein R 11 , R 12 and R 13 are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl; wherein R 12 and R 13 , along with the atoms to which they are attached, are optionally joined to form a 4- to 8-membered ring; R 16 is a member selected from OR 17 , SR 17 , NR 17 R 18 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted
- CoQio- coenzyme Q 10 Ub50 - ubiquinol-50 and PQS - polyoxyethanyl-ubiquinol-sebacate.
- the following compounds were synthesized and characterized according to the following procedures: Compounds 11 (Garber, S. B. et al., J. Am. Chem. Soc. 2000, 122, 8168-8179); 15 (Terada, Y. et al., Angew. Chem., Int. Ed. 2004, 43, 4063-4067); 16 (Van Ornum, S. G.; Cook, J. M. Tetrahedron Lett.
- a number following one of the above abbreviations indicates an average molecular weight of the polyoxyethanyl moiety of the compound.
- a number followed by Me abbreviation indicates a polyoxyethanyl moiety capped with a methyl group (methoxypolyoxyethanyl).
- Ub50 can be dissolved in 3 mL of dry toluene at 40 0 C, followed by addition of 1.33 mmole of triethylamine (TEA). 1.33 mmole of sebacoyl chloride dissolved in 2 mL of dry toluene can then be added (dropwise, while stirring, and under anhydrous conditions) to the CoQio-TEA solution. The reaction can be carried out for 10 min at room temperature, at which time 2 mmole of PEG-600 (polyethylene glycol, Sigma Chem.
- PEG-600 polyethylene glycol
- the reaction can be continued for additional 20 min at room temperature with constant stirring.
- the reaction mixture can be extracted four times with 3 mL each time of saturated solution of NaCl and toluene can be evaporated under reduced pressure.
- the product can be dissolved in 5 mL of water and the residual toluene can be further removed by co- evaporation with water under a reduced pressure.
- the final waxy product can be obtained by lyophilization.
- solubilizing agents can be obtained by linking polyethylene glycol (average molecular weight 1000, Sigma Chem. Co., product # P-3515) or methoxypolyethylene glycol (average molecular weight 750, Sigma Chem. Co., product # M-7018) to CoQio using adipoyl, suberoyl, azelaoyl or dodecanedioyl dichlorides. They can be synthesized according to the method of Example 2.
- a solubilizing agent prepared according to Examples 1 or 2 can be dissolved in water at 2: 1 v/v ratio.
- the solution can be heated in a boiling water bath for approximately 2 min, until a visible precipitation occurred. This can then be followed by a brief centrifugation (at least 2000 X g) of the hot mixture to achieve separation of the precipitated product which is insoluble in hot water.
- the water phase (supernatant) can then be removed by decantation leaving a clear pellet of the product containing approximately 10% of water.
- Grubbs and Grubbs-Hoveyda second generation catalyst were all obtained from Materia Inc. and stored in a glove box under an Ar atmosphere. Solvents and coupling partners were all obtained from commercial vendors and used with no further purification. Compounds were all synthesized and characterized according to known procedures and data. The spectroscopic data obtained from reaction products are in accord with those previously reported for these compounds.
- the homogeneous reaction mixture was then diluted with EtOAc (5 mL), filtered through a bed of silica gel layered over Celite, and the bed further washed (3 x 10 mL) with EtOAc to collect all of the cross-coupled material.
- the volatiles were removed in vacuo to afford the crude product which was subsequently purified by flash chromatography using silica gel (eluting with 10% EtOAc/Hexanes) to afford the title compound as a colorless oil (123 mg, 82%).
- the reported E/Z ratio (>20:l) was determined by the relative integrations of the resonances at 6.86 and 6.11 ppm.
- the homogeneous reaction mixture was then diluted with EtOAc (5 mL), filtered through a bed of silica gel layered over Celite, and the bed further washed (3 x 10 mL) with EtOAc to collect all of the cyclized material. The volatiles were removed in vacuo to afford the crude product which was subsequently purified by flash chromatography using silica gel (12% EtOAc/Hexanes) to afford the title compound as a colorless solid (41 mg, 96%).
- reaction mixtures can be analyzed via TLC directly from the reaction solution with no "mini work-up" needed. • Thorough stirring of the reaction mixture is needed for the success of the reported reactions, especially when using solid substrates.
- Reactions can be preformed either under an blanket of Ar, in an open system (ie., a vent needle is placed through the septum), or in a closed system. All conditions yield similar results at the reaction scale mentioned.
- reaction mixture was extracted (CH 2 Cl 2 ), and the organic layer washed with aqueous sodium bicarbonate, and dried over Na 2 SO 4 . Removal of the volatiles in vacuo afforded the crude residue, which, was purified by column chromatography using silica gel (eluting with 10% EtOAc/Hexane) to yield the title compound (1.22 g, 86%) as a colorless oil.
- Dialkene 27 24 mg, 0.10 mmol
- catalyst 6 7.5 mg, 0.002 mmol
- H 2 O 1.0 mL; all RCM reaction were conducted at 0.1 M unless stated otherwise
- the homogeneous reaction mixture was then diluted with EtOAc (5 mL), filtered through a bed of silica gel layered over Celite, and the bed further washed (2 x 10 mL) with EtOAc to collect all of the cyclized material. The volatiles were removed in vacuo to afford the crude product which was subsequently purified by flash chromatography using silica gel (4% EtOAc/Hexanes) to afford the title compound as a colorless liquid (19 mg, 92%).
- Reaction mixtures can be analyzed via TLC directly from the reaction solution with no "mini work-up" needed.
- reactions can be preformed either under an blanket of Ar, in an open system (ie., a vent needle is placed through the septum), or in a closed system. All conditions yield similar results at the reaction scale mentioned.
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Abstract
Cette invention concerne une composition comprenant (a) un catalyseur ; et (b) un agent solubilisant, dans laquelle le catalyseur est utilisé dans une réaction de métathèse.
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CN101831503A (zh) * | 2010-05-21 | 2010-09-15 | 北京欧凯纳斯科技有限公司 | 一种乙烯基修饰的基因芯片、其制备方法及应用 |
US8063232B2 (en) | 2009-11-09 | 2011-11-22 | Exxonmobil Chemical Patents Inc. | Metathesis catalyst and process for use thereof |
EP2498908A2 (fr) * | 2009-11-09 | 2012-09-19 | ExxonMobil Chemical Patents Inc. | Catalyseurs de métathèse et leurs procédés d'utilisation |
US8329921B2 (en) | 2009-11-09 | 2012-12-11 | Exxonmobil Chemical Patents Inc. | Metathesis catalyst and process for use thereof |
US8809563B2 (en) | 2009-11-09 | 2014-08-19 | Exxonmobil Chemical Patents Inc. | Metathesis catalyst and process for use thereof |
US9024034B2 (en) | 2009-11-09 | 2015-05-05 | Exxonmobil Chemical Patents Inc. | Metathesis catalysts and processes for use thereof |
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US8063232B2 (en) | 2009-11-09 | 2011-11-22 | Exxonmobil Chemical Patents Inc. | Metathesis catalyst and process for use thereof |
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EP2498908A4 (fr) * | 2009-11-09 | 2013-08-14 | Exxonmobil Chem Patents Inc | Catalyseurs de métathèse et leurs procédés d'utilisation |
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US8809563B2 (en) | 2009-11-09 | 2014-08-19 | Exxonmobil Chemical Patents Inc. | Metathesis catalyst and process for use thereof |
US9024034B2 (en) | 2009-11-09 | 2015-05-05 | Exxonmobil Chemical Patents Inc. | Metathesis catalysts and processes for use thereof |
CN101831503A (zh) * | 2010-05-21 | 2010-09-15 | 北京欧凯纳斯科技有限公司 | 一种乙烯基修饰的基因芯片、其制备方法及应用 |
CN101831503B (zh) * | 2010-05-21 | 2013-07-24 | 北京欧凯纳斯科技有限公司 | 一种乙烯基修饰的基因芯片、其制备方法及应用 |
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