US20080262077A1 - Pharmaceutical formulations containing lipoic acid derivatives - Google Patents

Pharmaceutical formulations containing lipoic acid derivatives Download PDF

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US20080262077A1
US20080262077A1 US12/105,100 US10510008A US2008262077A1 US 20080262077 A1 US20080262077 A1 US 20080262077A1 US 10510008 A US10510008 A US 10510008A US 2008262077 A1 US2008262077 A1 US 2008262077A1
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Prior art keywords
pharmaceutical formulation
lipoic acid
acid derivative
group
alkyl
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Robert G.L. Shorr
Robert J. Rodriguez
Rajinder Bhasin
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Cornerstone Pharmaceuticals Inc
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Individual
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Priority to US12/105,100 priority Critical patent/US20080262077A1/en
Application filed by Individual filed Critical Individual
Priority to TW097114308A priority patent/TWI459944B/zh
Assigned to CORNERSTONE PHARMACEUTICALS, INC. reassignment CORNERSTONE PHARMACEUTICALS, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BHASIN, RAJINDER, RODRIGUEZ, ROBERT J., SHORR, ROBERT G.L.
Publication of US20080262077A1 publication Critical patent/US20080262077A1/en
Priority to US12/604,763 priority patent/US8263653B2/en
Priority to US13/253,503 priority patent/US8691873B2/en
Priority to US13/569,654 priority patent/US20130150445A1/en
Priority to US14/227,148 priority patent/US9320726B2/en
Priority to US14/857,192 priority patent/US9839691B2/en
Priority to US15/134,896 priority patent/US9872845B2/en
Priority to US15/662,612 priority patent/US10098955B2/en
Priority to US16/039,799 priority patent/US10391177B2/en
Priority to US16/508,630 priority patent/US11065335B2/en
Priority to US17/375,678 priority patent/US20220184212A1/en
Abandoned legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/205—Amine addition salts of organic acids; Inner quaternary ammonium salts, e.g. betaine, carnitine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/385—Heterocyclic compounds having sulfur as a ring hetero atom having two or more sulfur atoms in the same ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/541—Organic ions forming an ion pair complex with the pharmacologically or therapeutically active agent
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention is directed to pharmaceutical formulations containing lipoic acid derivatives or salts thereof which selectively kill tumor cells by altering cancer cell metabolism and signal transduction pathways linked to the Warburg Effect, as well as to methods of treating a subject with such pharmaceutical formulations.
  • TCA tricarboxylic acid
  • PDH pyruvate dehydrogenase
  • acetaldehyde A number of these metabolites are known to be cytotoxic, e.g., acetaldehyde.
  • PDC in cancer along with other related enzymes plays a major role in managing and/or detoxifying the excess pyruvate and metabolites. For example, the joining of two acetyl molecules to form the neutral compound acetoin. This generation of acetoin is catalyzed by a tumor-specific form of PDC.
  • lipoic acid acts as a cofactor with PDC and related lipoamide using enzymes in detoxifying these otherwise toxic metabolites. Whether lipoic acid is made by healthy and cancer cells or whether it is an essential nutrient is debated in the literature, and both may be the case.
  • the genes required to produce lipoic acid have been identified in mammalian cells. Whether mitochondrial pumps or uptake mechanisms are present in healthy or cancer cells or whether they differ in diverse tissues is not known. Although the TCA cycle still functions in cancer cells, the tumor cell TCA cycle is a variant cycle which depends on glutamine as the primary energy source. Inhibition or inactivation of tumor-specific PDC and related enzymes that detoxify metabolites may promote apoptosis or necrosis and cell death.
  • U.S. Pat. Nos. 6,331,559 and 6,951,887 disclose a novel class of therapeutic agents which selectively targets and kills tumor cells and certain other types of diseased cells. These patents further disclose pharmaceutical compositions comprising an effective amount of a lipoic acid derivative according to its invention along with a pharmaceutically acceptable carrier. However, these patents provide no specific guidance with regard to the selection of suitable pharmaceutically acceptable carriers. As the present inventors have now discovered, the pharmaceutical formulation of the lipoic acid derivatives has proved pivotal in achieving efficacy for these agents.
  • the present invention is directed to a pharmaceutical formulation comprising (a) at least one lipoic acid derivative or salt thereof and (b) at least one ion pairing agent and optionally (c) a pharmaceutically acceptable diluent.
  • the lipoic acid derivative has the formula (I):
  • R 1 and R 2 are independently selected from the group consisting of acyl defined as R 3 C(O)—, alkyl defined as C n H 2n+1 , alkenyl defined as C m H 2m ⁇ 1 , alkynyl defined as C m H 2m ⁇ 3 , aryl, heteroaryl, alkyl sulfide defined as CH 3 (CH 2 ) n —S—, imidoyl defined as R 3 C( ⁇ NH)—, hemiacetal defined as R 4 CH(OH)—S—, and hydrogen provided that at least one of R 1 and R 2 is not hydrogen; wherein R 1 and R 2 as defined above can be unsubstituted or substituted; wherein R 3 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkylaryl, heteroaryl, or heterocyclyl, any of which can be substituted or unsubstituted; wherein R 4 is CCl 3 or COOH
  • R 1 and R 2 are both a benzyl group, i.e., both R 1 and R 2 are independently —CH 2 C 6 H 5 .
  • the lipoic acid derivative has the formula (II):
  • M is a metal chelate, —[C(R 1 )(R 2 )] z — or other metal complex; wherein R 1 and R 2 are independently selected from the group consisting of acyl defined as R 3 C(O)—, alkyl defined as C n H 2n+1 , alkenyl defined as C m H 2m ⁇ 1 , alkynyl defined as C m H 2m ⁇ 3 , aryl, alkyl sulfide defined as CH 3 (CH 2 ) n —S—, imidoyl defined as R 3 C( ⁇ NH)—, hemiacetal defined as R 4 CH(OH)—S— and hydrogen; wherein R 1 and R 2 as defined above can be unsubstituted or substituted; wherein R 3 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkylaryl, heteroaryl, or heterocyclyl, any of which can be substituted or unsubsti
  • Further preferred embodiments of this invention include those in which the lipoic acid derivative is present in a therapeutically effective amount. Still further preferred embodiments of this invention include those in which the ion pairing agent is selected from the group consisting of triethanolamine, polyethyleneimine, monoethanolamine, diethanolamine, mefanamic acid, tromethamine and combinations thereof, those in which the ion pairing agent is a polymer-conjugated ion pairing agent, and those in which the ion pairing agent and the at least one lipoic acid derivative is present in a ratio ranging from about 1000:1 to about 1:1000. Further preferred embodiments of the present invention also include those in which the diluent is selected from the group consisting of saline, a sugar solution, an alcohol, dimethylformamide, dimethylsulfoxide, dimethylacetamide and combinations thereof.
  • the present invention is directed to a method of treating a disease characterized by disease cells that are sensitive to lipoic acid derivatives comprising administering to a patient in need thereof a pharmaceutical formulation comprising at least one lipoic acid derivative or salt thereof, at least one ion pairing agent, and optionally a pharmaceutically acceptable diluent.
  • the present invention is directed to a method of preventing a disease characterized by disease cells that are sensitive to lipoic acid derivatives comprising administering to a patient in need thereof a pharmaceutical formulation comprising at least one lipoic acid derivative, at least one ion pairing agent, and optionally a pharmaceutically acceptable diluent.
  • the disease is a cancer such as a carcinoma, sarcoma, myeloma, lymphoma, leukemia, or a mixed cancer type.
  • the invention is directed to an ion pair consisting of (a) at least one lipoic acid derivative and (b) at least one ion pairing agent, most preferably bis-benzyl lipoate and triethanolamine, respectively.
  • FIGS. 1A and 1B show the tumor volume and body weight, respectively, in H-460 tumor-bearing mice treated with bis-benzyl lipoate in a Tween 80/ethanol pharmaceutical formulation.
  • FIGS. 2A , 2 B and 2 C show the tumor volume in H-460 tumor-bearing mice treated with bis-benzyl lipoate in a triethanolamine/dextrose pharmaceutical formulation at 3 different dosage levels.
  • the present invention is directed to pharmaceutical formulations containing lipoic acid derivatives which are effective to target and kill tumor cells. While the pharmaceutical formulation of many therapeutic agents is quite conventional, the present inventors have found that the pharmaceutical formulation of lipoic acid derivatives is not. In fact, the particular pharmaceutical formulation in which a lipoic acid derivative is placed may well be the determining factor between inactivity and activity for its intended purpose. Accordingly, in a first embodiment, the present invention is directed to a pharmaceutical formulation comprising (a) at least one lipoic acid derivative and (b) at least one ion pairing agent and optionally (c) a pharmaceutically acceptable diluent.
  • Lipoic acid derivatives suitable for use in the present invention include those described in full detail in each of U.S. Pat. Nos. 6,331,559 and 6,951,887 and those described in co-pending U.S. Provisional Application No. 60/912,598, filed Apr. 18, 2007 [Attorney Docket No. 03459.000110.PV] and corresponding co-pending U.S. patent application Ser. No. ______, filed Apr. __, 2008 [Attorney Docket No. 03459.000110.], the disclosure of each of which is incorporated by reference herein.
  • Lipoic acid derivatives suitable for use in the present invention can be made according to known procedures such as those set forth in the aforementioned patents. In a preferred embodiment of this invention, the lipoic acid derivative has the formula (I):
  • R 1 and R 2 are independently selected from the group consisting of acyl defined as R 3 C(O), alkyl defined as C n H 2n+1 , alkenyl defined as C m H 2m ⁇ 1 , alkynyl defined as C m H 2m ⁇ 3 , aryl, heteroaryl, alkyl sulfide defined as CH 3 (CH 2 ) n —S—, imidoyl defined as R 3 C( ⁇ NH)—, hemiacetal defined as R 4 CH(OH)—S—, and hydrogen provided that at least one of R 1 and R 2 is not hydrogen;
  • R 1 and R 2 as defined above can be unsubstituted or substituted
  • R 3 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkylaryl, heteroaryl, or heterocyclyl, any of which can be substituted or unsubstituted;
  • R 4 is CCl 3 or COOH
  • x is 0-16, n is 0-10 and m is 2-10.
  • acyl refers to an R 3 C(O)— group, where R 3 can be, without limitation, hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkylaryl, heteroaryl, or heterocyclyl, any of which can be substituted or unsubstituted.
  • R 3 can be, without limitation, hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkylaryl, heteroaryl, or heterocyclyl, any of which can be substituted or unsubstituted.
  • R 3 groups is linked to the carbon backbone of formula (I) through a thio-ester linkage.
  • acyl groups include, without limitation, acetyl, benzoyl and benzoyl derivatives, 4-fluorobenzoyl and 1-methylpyrrole-2-carboxyl.
  • lipoic acid derivatives containing an acyl group include, without limitation, bis-acety
  • alkyl refers to a C n H 2n+1 group, wherein n is 1-10, more preferably 1-6 and most preferably 1-4, i.e., an alkyl group linked to the carbon backbone of formula (I) through a thio-ether linkage.
  • Alkyl groups can be either aliphatic (straight or branched chain) or alicyclic; alicyclic groups may have additions or substitutions on any of the carbons to form heterocyclics. At least one heteroatom such as N, O or S may be present in a given alkyl group, i.e., in the carbon chain. Alkyl groups may be substituted or unsubstituted on any of their carbons.
  • a preferred alkyl group is an alkyl group substituted with an aryl or heteroaryl group, i.e., wherein R 1 or R 2 is an alkylaryl or alkylheteroaryl group; the aryl or heteroaryl group may be substituted or unsubstituted.
  • alkyl groups include, without limitation, methyl, ethyl, butyl, decanyl, cyclopropyl, 4-pyridine methyl, 2-anthraquinone methyl, N-phenylacetamide, phenylethyl, 2-ethanoic acid, 2-acetamido, 4-(2-acetamido-pyridinyl)methyl, N-[(2-fluorophenyl)methyl]acetamide, N-[(6-methoxy-3-pyridyl)methyl]acetamide, 5-(acetylamino)pyridine-2-carboxamide, 5-(6,8-diaza-7-oxo-3-thiabicyclo[3.3.0]oct-2-yl)-N-(2-carbonylaminoethyl)pentanamide and 5-(6,8-diaza-7-oxo-3-thiabicyclo[3.3.0]oct-2-yl)pentacarboxyl.
  • lipo methyl
  • alkenyl refers to a C m H 2m ⁇ 1 group, wherein m is 2-10, i.e., an alkenyl group linked to the carbon backbone of formula (I) through a thioether linkage.
  • Alkenyl groups can be either aliphatic (straight or branched chain) or alicyclic; alicyclic groups may have additions or substitutions on any of the carbons to form heterocyclics. At least one heteroatom such as N, O or S may be present in a given alkenyl group, i.e., in the carbon chain.
  • Alkenyl groups may be substituted or unsubstituted on any of their carbons. Examples of alkenyl groups include, without limitation, propenyl, 2,3 dimethyl-2-butenyl, heptenyl and cyclopentenyl.
  • alkynyl refers to a C m H 2m ⁇ 3 , where m is 2-10, i.e., an alkynyl group linked to the carbon backbone of formula (I) through a thio-ether linkage.
  • Alkynyl groups can be either aliphatic (straight or branched chain) or alicyclic; alicyclic groups may have additions or substitutions on any of the carbons to form heterocyclics. At least one heteroatom such as N, O or S may be present in a given alkynyl group, i.e., in the carbon chain.
  • Alkynyl groups may be substituted or unsubstituted on any of their carbons. Examples of alkynyl groups include, without limitation, acetylenyl, propynyl and octynyl.
  • aryl refers to an aromatic or aryl group linked to the carbon backbone of formula (I) through a thio-ether linkage.
  • Aryl is preferably an unsaturated ring system having 6-10 carbon atoms.
  • Aryl also includes organometallic aryl groups such as ferrocene. Aryl groups may be substituted or unsubstituted on any of their carbons.
  • aryl groups include, without limitation, benzyl (—CH 2 C 6 H 5 ), benzyl derivatives such as methylbenzyl and aminobenzyl, (1,2,3,4,5-pentafluorophenyl)methyl, triphenylmethyl, 4-methyl benzoic acid, ferrocene methyl, 2-naphthylmethyl, 4,4-biphenylmethyl, and stilbene (or 1-((1E)-2-phenylvinyl)-4-methyl benzene).
  • a specific example of a lipoic acid derivative containing an aryl group is bis-benzyl lipoate.
  • heteroaryl refers to an aromatic heterocyclic ring system (monocyclic or bicyclic) where the heteroaryl moieties are five or six membered rings containing 1 to 4 heteroatoms selected from the group consisting of S, N, and O; the heteroaryl group is linked to the carbon backbone of formula (I) through a thio-ether linkage.
  • Heteroaryl groups may be substituted or unsubstituted on any of their atoms especially on the carbon atoms.
  • heteroaryl groups include, without limitation, benzothiazole, quinoline, 7-chloroquinoline, furan, thiophene, indole, azaindole, oxazole, thiazole, isoxazole, isothiazole, imidazole, N-methylimidazole, pyridine, pyrimidine, pyrazine, pyrrole, N-methylpyrrole, pyrazole, N-methylpyrazole, 1,3,4-oxadiazole, 1,2,4-triazole, 1-methyl-1,2,4-triazole, 1H-tetrazole, 1-methyltetrazole, benzoxazole, benzofuran, benzisoxazole, benzimidazole, N-methylbenzimidazole, azabenzimidazole, indazole, quinazoline and pyrrolidinyl.
  • alkyl sulfide refers to a CH 3 (CH 2 ) n —S— group, where n is 0-9.
  • an alkyl group is linked to the carbon backbone of formula (I) through a disulfide linkage.
  • the alkyl group i.e., CH 3 (CH 2 ) n
  • CH 3 (CH 2 ) n can be substituted or unsubstituted on any of its carbons and shares the same features as set forth above with regard to the C n H 2n+1 alkyl group.
  • imidoyl refers to a R 3 C( ⁇ NH)— group, where R 3 can be, without limitation, hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkylaryl, heteroaryl, or heterocyclyl, any of which can be substituted or unsubstituted.
  • R 3 can be, without limitation, hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkylaryl, heteroaryl, or heterocyclyl, any of which can be substituted or unsubstituted.
  • one of the listed R 3 groups is linked to the carbon backbone of formula (I) through a thio-imide linkage.
  • hemiacetal refers to an R 4 CH(OH)—S— group, where R 4 is a compound with strongly electron withdrawing substituents such as, without limitation, CF 3 , CCl 3 or COOH.
  • substituents include, without limitation, alkyl, alkenyl, alkynyl, aryl, heteroaryl, acyl, alkoxycarbonyl, alkoxy, alkoxyalkyl, alkoxyalkoxy, cyano, halogen, hydroxy, nitro, oxo, trifluoromethyl, trifluoromethoxy, trifluoropropyl, amino, amido, alkylamino, dialkylamino, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, alkylthio, —SO 3 H, —SO 2 NH 2 , —SO 2 NHalkyl, —SO 2 N(alkyl) 2 , —CO 2 H, CO 2 NH 2 , CO 2 NHalkyl, and —CO 2 N(alkyl) 2 .
  • any number of substitutions may be made on any of the above-described groups; in other words, it is possible to have a mono-, di-, tri-, etc. substituted R 1 or R 2 group, and the substituents themselves may also be substituted.
  • any of the R 1 or R 2 groups may be appropriately generally substituted with any of a carbohydrate, a lipid, a nucleic acid, an amino acid or a polymer of any of those, or a single or branched chain synthetic polymer (having a molecular weight ranging from about 350 to about 40,000).
  • the thio-ester or thio-ether linkage by which the R 1 and R 2 are linked to the backbone can be oxidized to produce sulfoxides or sulfones; in other words, the —S— in the linkage could be —S(O)— or —S(O) 2 .
  • the thio-ester or thio-ether linkage by which the R 1 and R 2 are linked to the backbone may further comprise disulfides that can be oxidized to thiosulfinic or thiosulfonic acids; in other words, instead of —S— in a linkage, the linkage could be —S(O)—S— or —S(O) 2 —S—.
  • the lipoic acid derivative has the formula (II):
  • M is a metal chelate, —[C(R 1 )(R 2 )] z — or other metal complex.
  • R 1 and R 2 are independently selected from the group consisting of acyl defined as R 3 C(O)—, alkyl defined as C n H 2n+1 , alkenyl defined as C m H 2m ⁇ 1 , alkynyl defined as C m H 2m ⁇ 3 , aryl, heteroaryl, alkyl sulfide defined as CH 3 (CH 2 ) n —S—, imidoyl defined as R 3 C( ⁇ NH)—, hemiacetal defined as R 4 CH(OH)—S— and hydrogen, wherein R 1 and R 2 as defined above can be unsubstituted or substituted.
  • R 3 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkylaryl, heteroaryl, or heterocyclyl, any of which can be substituted or unsubstituted;
  • R 4 is CCl 3 or COOH.
  • x is 0-16
  • z is preferably 0-5, more preferably 0-3, n is 0-10 and m is 2-10.
  • Suitable —[C(R 1 )(R 2 )] z — groups include, without limitation, —CH 2 , —CH(CH 3 ), —C(CH 3 ) 2 , —CH(C 6 H 5 ) and —CH(pyridine).
  • a metal or metal salt can be added to one or both sulfhydryls through a bond in which a metal or metal salt forms a covalent or coordination or chelated complex with the thiol group(s) of the lipoic acid molecule.
  • metals include, platinum, nickel, silver, rhodium, cadmium, gold, palladium or cobalt.
  • Metal salts include, for example, platinum bromide, platinum chloride, platinum iodide, nickel borate, nickel boride, nickel bromide, nickel chloride, nickel iodide, nickel fluoride, silver bromate, silver bromide, silver chloride, silver fluoride, silver iodide, rhodium chloride, cadmium bromide, cadmium chloride, cadmium fluoride, cadmium iodide, gold bromide, gold chloride, gold iodide, cobalt bromide, cobalt bromide, cobalt chloride, cobalt fluoride, cobalt iodide, palladium chloride, palladium iodide, and palladium bromide.
  • Such salts include various metal oxidation states such as, for example, platinum (II) chloride and platinum (IV) chloride.
  • the structure of the lipoic acid-metal complex described herein is likely to be (metal) m (lipoic acid) n where m and n are both one or where m is one and n is two.
  • lipoic acid derivative may include lipoic acid derivatives in which one or both of the thiols have been replaced with a selenium molecule, a sulfur analog, or in which one or both of the thiols have been oxidized to sulfate or related groups.
  • the lipoic acid derivative is one selected from the following:
  • the at least one lipoic acid derivative is a salt
  • an ion pairing agent such as triethanolamine could displace the anion without the need for ion exchange.
  • the at least one lipoic acid derivative is present in a pharmaceutical formulation of the present invention in a therapeutically effective amount.
  • the pharmaceutical formulation of the present invention may contain a unit dose or multiple doses of the lipoic acid derivative.
  • a “therapeutically effective amount” is intended to mean the amount of a lipoic acid derivative that, when administered to a subject in need thereof, is sufficient to effect treatment for (or prevent) disease conditions characterized by disease cells that are sensitive to lipoic acid derivatives.
  • the amount of a given lipoic acid derivative that will be therapeutically effective will vary depending upon factors such as the disease condition and the severity thereof, the identity of the subject in need thereof, etc., which amount may be routinely determined by those of ordinary skill in the art.
  • the quantity of lipoic acid derivative in a unit dose should be sufficient to inhibit or kill tumor cells while leaving normal cells substantially unharmed.
  • the at least one lipoic acid derivative is preferably present in a pharmaceutical formulation of the present invention in an amount to provide from about 0.001 mg/m 2 to about 10 g/m 2 , more preferably about 0.01 mg/m 2 to about 5 g/m 2 , still more preferably from about 0.25 mg/m 2 to about 3 g/m 2 , and most preferably from about 20 mg/m 2 to about 500 mg/m 2 of the at least one lipoic acid derivative per dose.
  • the pharmaceutical formulations of the present invention includes at least one ion pairing agent.
  • ion pairing agent refers to any agent which is capable of forming a “salt bridge” or an “ion pair” with a given lipoic acid derivative.
  • salt bridge or “ion pair” refers to not only a salt (weak or strong) formed between an ion pairing agent and a given lipoic acid derivative, but also to other ionic associations (weak or strong) that do not rise to the level of actual salt formation between an ion pairing agent and a given lipoic acid derivative.
  • an ion pairing agent such as triethanolamine forms a salt bridge, i.e., forms a salt in situ, with a lipoic acid derivative such as bis-benzyl lipoate, which then enables the lipoic acid deriviative to achieve its cell kill effect in vivo.
  • Ion pairing agents particularly suitable for use in the present invention include, without limitation, tertiary amines such as triethanolamine and polyethyleneimine, other amines such as diethanolamine, monoethanolamine, mefenamic acid and tromethamine, and combinations thereof.
  • a preferred ion pairing agent is triethanolamine.
  • Additional ion pairing agents suitable for use in this invention include polymer-conjugated ion pairing agents which employ, without limitation, polyethylene glycol, polyglutamic acid and sugar-based polymers such as dextrans in combination with any of the above-noted ion pairing agents or any other known ion pairing agent.
  • Still further ion pairing agents can be selected with guidance from Handbook of Pharmaceutical Salts: Properties, Selection and Use, IUPAC, Wiley-VCH, P.H. Stahl, ed., the entire disclosure of which is incorporated by reference herein.
  • Ion pairing agents of particular note therein include, without limitation, those listed in Table 5, p.
  • the ion pairing agent may be hydrophilic or hydrophobic (such as acylated triethanolamine).
  • the ion pairing agent is present in an amount sufficient to achieve substantial solubility of the at least one lipoic acid derivative in a solvent suitable for intravenous administration, which is most preferably an aqueous medium.
  • the ion pairing agent and lipoic acid derivative are present in a molar ratio ranging from about 1000:1 to about 1:1000, more preferably from about 500:1 to about 1:500, still more preferably from about 50:1 to about 1:50, still further more preferably from about 20:1 to about 1:20, and most preferably of about 1:1.
  • the pharmaceutical formulations of the present invention optionally include (c) a pharmaceutically acceptable diluent.
  • a pharmaceutically acceptable diluent such as saline, a sugar solution, alcohols such as ethyl alcohol, methanol and isopropyl alcohol, polar aprotic solvents such as dimethylformamide (DMF), dimethylsulfoxide (DMSO) and dimethylacetamide (DMA), and combinations thereof.
  • a pharmaceutically acceptable diluents include, without limitation, saline, a sugar solution, alcohols such as ethyl alcohol, methanol and isopropyl alcohol, polar aprotic solvents such as dimethylformamide (DMF), dimethylsulfoxide (DMSO) and dimethylacetamide (DMA), and combinations thereof.
  • DMF dimethylformamide
  • DMSO dimethylsulfoxide
  • DMA dimethylacetamide
  • a preferred pharmaceutically acceptable diluent is a dextrose solution, more preferably a dextrose solution containing from about 2.5% to about 10%, more preferably about 5%, dextrose by weight.
  • the pharmaceutically acceptable diluent is typically employed in a non-homolysis generating amount; one of ordinary skill in the art can readily determine an amount of diluent suitable for use in a pharmaceutical formulation according to the present invention.
  • the pharmaceutical formulation comprises bis-benzyl lipoate, triethanolamine and a dextrose solution containing about 5% dextrose by weight.
  • the pharmaceutical formulations of the present invention may optionally include at least one other pharmaceutically acceptable additive.
  • suitable additives include, without limitation, solvents, diluents, surfactants, solubilizers, preservatives, buffers, and combinations thereof, as well as any other additives particularly suited for use in parenteral administration forms. It is well within the skill of one of ordinary skill in the art to determine suitable amounts of these other pharmaceutically acceptable additives.
  • Solvents particularly suitable for use herein include benzyl alcohol, dimethylamine, isopropyl alcohol and combinations thereof; one of ordinary skill in the art would readily recognize that it may be desirable to first dissolve the at least one lipoic acid derivative in a suitable solvent and then to dilute the solution into an ion pairing agent and finally to dilute with a diluent.
  • the pharmaceutical formulations of the present invention can be prepared according to conventional formulation techniques.
  • a stock solution of the at least one lipoic acid derivative and the ion pairing agent can be prepared according to conventional techniques and then diluted as desired by a pharmaceutically acceptable diluent.
  • the pharmaceutical formulations of the present invention are liquid preparations such as sterile parenteral solutions.
  • the pharmaceutical formulations of the present invention may be contained in any suitable vessel such as a vial or ampoule and are suitable for administration via one of several routes including, without limitation, intravenous, intramuscular, subcutaneous, intradermally, intraperitoneal, intrathoracic, intrapleural, intrauterine or intratumor.
  • a second embodiment of the invention is directed to a method of treating a disease characterized by disease cells that are sensitive to lipoic acid derivatives comprising administering to a patient in need thereof a pharmaceutical formulation according to the first embodiment of the invention.
  • a third embodiment of the invention is directed to a method of preventing a disease characterized by disease cells that are sensitive to lipoic acid derivatives comprising administering to a patient in need thereof a pharmaceutical formulation according to the first embodiment of the invention.
  • compositions of lipoic acid derivatives may be used to prevent or inhibit diseases involving altered or distinct cellular PDC activity, i.e., diseases characterized by disease cells that are sensitive to lipoic acid derivatives.
  • Cells with appropriately altered or deranged energy metabolism, i.e., altered PDC activity are particularly targeted and killed, while surrounding healthy tissues remain unharmed by the lipoic acid derivative.
  • diseases having altered PDC activity are particularly targeted and killed, while surrounding healthy tissues remain unharmed by the lipoic acid derivative.
  • the skilled artisan can readily identify diseases having altered PDC activity.
  • the skilled artisan can readily screen the disease of interest for sensitivity to lipoic acid derivatives.
  • the disease treated or prevented includes cancer, such as carcinoma, sarcoma, myeloma, lymphoma, leukemia and mixed types thereof.
  • the pharmaceutical formulations of the present invention are effective against both primary and metastatic cancers and effective against cancers of the, without limitation, lung, liver, uterus, cervix, bladder, kidney, colon, breast, prostate, ovary, and pancreas.
  • the pharmaceutical formulations of the present invention can be used in the treatment of diseases associated with altered energy metabolism such as Alzheimer's disease, hyperproliferative diseases such as psoriasis and other diseases such as diabetic neuropathy.
  • a pharmaceutical formulation according to the first embodiment of the invention is administered directly to a patient, typically in a unit dose form.
  • the pharmaceutical formulation comprising the lipoic acid derivative may be administered via one of several routes including, without limitation, intravenous, intramuscular, subcutaneous, intradermally, intraperitoneal, intrathoracic, intrapleural, intrauterine or intratumor.
  • routes including, without limitation, intravenous, intramuscular, subcutaneous, intradermally, intraperitoneal, intrathoracic, intrapleural, intrauterine or intratumor.
  • the mode of administering the lipoic acid derivative depends on the type of cancer or symptom to be treated. For example, a preferred mode of administering the lipoic acid for treatment of leukemia would involve intravenous administration.
  • the pharmaceutical formulations of the present invention may also be used in methods for treating diseases other than cancer, where the disease-causing cells exhibit altered metabolic patterns.
  • diseases other than cancer where the disease-causing cells exhibit altered metabolic patterns.
  • eukaryotic pathogens of humans and other animals are generally much more difficult to treat than bacterial pathogens because eukaryotic cells are so much more similar to animal cells than are bacterial cells.
  • eukaryotic pathogens include protozoans such as those causing malaria as well as fungal and algal pathogens.
  • the pharmaceutical formulations of the present invention can be used to kill bacterial PDCs.
  • Yet another embodiment of the present invention is directed to an ion pair, be it a true salt or some other lesser ionic association, consisting of (a) at least one lipoic acid derivative and (b) an ion pairing agent.
  • the ion pair consists of bis-benzyl lipoate and triethanolamine.
  • the present invention includes all ion pairs, whether in situ as formed or isolated by some conventional method. All of the details regarding amounts of (a) and (b) and possible materials suitable for use are the same as those set forth above with regard to the first embodiment.
  • Bis-benzyl lipoate was provided in a concentrated form at a concentration of 50 mg/mL dissolved in 1 M triethanolamine (TEA).
  • TAA triethanolamine
  • the stability of the drug product was assessed by visual observation and by high-performance liquid chromatography (HPLC) assessment, performed at the beginning and the end of the study. The physical appearance did not change and the purity was found to be >99% pure, both at the beginning and the end of the study.
  • the concentrated bis-benzyl lipoate solution was diluted to an appropriate concentration with 5% dextrose (D 5 W) to formulate 0.1, 1 and 10 mg/kg doses of bis-benzyl lipoate.
  • Bis-benzyl lipoate was dissolved to a concentration of 40 mg/mL in a conventional mixture of Tween 80 and ethanol (1:1 by volume ratio). The concentrated bis-benzyl lipoate solution was diluted to an appropriate concentration with saline.
  • the protocol was revised by subdividing each treatment group into two subgroups, as shown in Table 2 below. Specifically, both subgroups of each treatment group were treated with the same dose of bis-benzyl lipoate as in the original protocol; however, one of the two subgroups was treated with a pharmaceutical formulation of bis-benzyl lipoate according to Comparative Example 1, i.e., bis-benzyl lipoate dissolved in 1:1 Tween 80:ethanol and diluted with saline, and the other subgroup was treated with a pharmaceutical formulation of bis-benzyl lipoate according to Example 1, i.e., dissolved in TEA and diluted with D5W.
  • H-460 tumors in mice treated with 0.1-10 mg/kg of bis-benzyl lipoate in pharmaceutical formulations made according to Example 1 may be similar among each other, but may be smaller than that in mice treated with 10 mg/kg of bis-benzyl lipoate in a pharmaceutical formulation made according to Comparative Example 1.

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US12/105,100 US20080262077A1 (en) 2007-04-18 2008-04-17 Pharmaceutical formulations containing lipoic acid derivatives
TW097114308A TWI459944B (zh) 2007-04-18 2008-04-18 含有硫辛酸衍生物之醫藥調配物
US12/604,763 US8263653B2 (en) 2007-04-18 2009-10-23 Pharmaceutical formulations containing lipoic acid derivatives
US13/253,503 US8691873B2 (en) 2007-04-18 2011-10-05 Pharmaceutical formulations containing lipoic acid derivatives
US13/569,654 US20130150445A1 (en) 2007-04-18 2012-08-08 Pharmaceutical Formulations Containing Lipoic Acid Derivatives
US14/227,148 US9320726B2 (en) 2007-04-18 2014-03-27 Methods of treating colon, lung, and liver cancers using compositions containing an ion pair of a lipoic acid derivative
US14/857,192 US9839691B2 (en) 2007-04-18 2015-09-17 Methods of treating pancreatic and ovarian cancers using compositions containing an ion pair of a lipoic acid derivative
US15/134,896 US9872845B2 (en) 2007-04-18 2016-04-21 Methods of treating myeloma and lymphoma using compositions containing an ion pair of a lipoic acid derivative
US15/662,612 US10098955B2 (en) 2007-04-18 2017-07-28 Pharmaceutical formulations containing lipoic acid derivatives
US16/039,799 US10391177B2 (en) 2007-04-18 2018-07-19 Methods for treating cancer using 6,8-bis (benzylthio) octanonic acid
US16/508,630 US11065335B2 (en) 2007-04-18 2019-07-11 Methods of treating leukemia using compositions containing bis(benzylthio)octanoic acid and ion pairs thereof
US17/375,678 US20220184212A1 (en) 2007-04-18 2021-07-14 Pharmaceutical formulations containing lipoic acid derivatives

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