WO1995011884A1 - Composes et procedes de prevention de la formation de la cataracte - Google Patents
Composes et procedes de prevention de la formation de la cataracte Download PDFInfo
- Publication number
- WO1995011884A1 WO1995011884A1 PCT/US1994/012301 US9412301W WO9511884A1 WO 1995011884 A1 WO1995011884 A1 WO 1995011884A1 US 9412301 W US9412301 W US 9412301W WO 9511884 A1 WO9511884 A1 WO 9511884A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- pantetheine
- pantethine
- compounds
- cataract
- compound
- Prior art date
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- 208000002177 Cataract Diseases 0.000 title claims abstract description 41
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- AHJWSRRHTXRLAQ-UHFFFAOYSA-N tetramethoxymethane Chemical compound COC(OC)(OC)OC AHJWSRRHTXRLAQ-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- DHCDFWKWKRSZHF-UHFFFAOYSA-L thiosulfate(2-) Chemical compound [O-]S([S-])(=O)=O DHCDFWKWKRSZHF-UHFFFAOYSA-L 0.000 description 1
- GWIKYPMLNBTJHR-UHFFFAOYSA-M thiosulfonate group Chemical group S(=S)(=O)[O-] GWIKYPMLNBTJHR-UHFFFAOYSA-M 0.000 description 1
- 238000000108 ultra-filtration Methods 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 210000004127 vitreous body Anatomy 0.000 description 1
- 238000001075 voltammogram Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
- C07C323/24—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
- C07C323/25—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C329/00—Thiocarbonic acids; Halides, esters or anhydrides thereof
- C07C329/02—Monothiocarbonic acids; Derivatives thereof
- C07C329/04—Esters of monothiocarbonic acids
- C07C329/06—Esters of monothiocarbonic acids having sulfur atoms of thiocarbonic groups bound to acyclic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D319/04—1,3-Dioxanes; Hydrogenated 1,3-dioxanes
- C07D319/06—1,3-Dioxanes; Hydrogenated 1,3-dioxanes not condensed with other rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
- C07F9/6552—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a six-membered ring
Definitions
- This invention relates generally to compounds which are useful for preventing or inhibiting cataract formation in warm-blooded animals and, more specifically, to compounds which function as anti-cataract agents and/or prodrugs to anti-cataract agents.
- Cataract is the general term for any pathological condition in which the normal transparency of the ocular lens is substantially diminished. Although often regarded as an inevitable accompaniment of age, cataracts may develop at any time in life, even before birth. Risk factors for cataract formation include metabolic disorders (e.g., diabetes) , exposure to toxic agents in the environment (e.g., ultraviolet radiation, ionizing radiation) , drug side effects, and inherited traits. Due to the wide variety of causative agents and conditions, the pathogenesis of cataract has been the subject of much debate.
- the cellular structure of the lens is well characterized.
- the lens exhibits a high degree of regularity, consisting of fiber cells with hexagonal cross sections packed together to create a very regular parallel array of fiber cells which stretch from anterior to posterior pole.
- the lens fiber cells lose all intracellular organelles that could contribute to light scattering during the process of differentiation and the cytoplasmic protein concentration increases markedly.
- Approximately 35%-60% of the total mass of the lens consists of structural proteins, the remainder being water. More than 90% of the total lens protein consists of alpha, beta and gamma crystallins, a group of structural proteins found at extremely high concentrations (in excess of 300 mg/ml) in the lens cell cytoplasm.
- the cytoplasmic concentration of the crystallins throughout the lens occurs along a continuous radial concentration gradient, in which the concentration is greatest in cells at the nucleus and decreases in peripheral cells of the lens cortex.
- the crystallin distribution determines the mean index of refraction and index gradient, which are in turn responsible for the special optical properties of the animal lens .
- An important optical property is lens transparency. In the normal lens, incident light is scattered in all directions by the macromolecular constituents of the lens. If the individual wavelets of the scattered light interfere destructively with one another, the lens is transparent. Destructive interference takes place in the normal lens because of the existence of short range order in the relative positions of the crystallins.
- opacity is responsible for the visual impairment in cataract disease.
- Cataracts are the leading cause of blindness in humans worldwide, and surgery remains the primary form of treatment. More than one million cataract extractions are performed annually in the United States, and it is estimated that 5-10 million individuals become visually disabled each year due to cataracts. Cataracts in animals also pose a significant veterinary problem. Accordingly, significant effort is underway to identify compounds which can treat or inhibit cataract formation, thus avoiding or delaying the need for surgical lens replacement.
- the present invention is directed to compounds and methods for preventing or inhibiting cataract formation in warm-blooded animals, including humans.
- the compounds of this invention function as anti-cataract agents and/or prodrugs to anti- cataract agents, including pantethine and pantetheine.
- a method for inhibiting cataract formation in the lens of a warm ⁇ blooded animal by administering to the animal an effective amount of a compound of this invention.
- the compounds of the present invention are derivatives of pantethine or pantetheine where one or more of the alcohol groups have been modified, and/or are derivatives of pantetheine where the terminal sulfhydryl has been modified.
- the compounds are thioester or thiocarbamate derivatives of pantetheine.
- Figure 1 shows the HPLC elution of standard samples of both pantethine and pantetheine (Figure 1A) and pantethine alone ( Figure IB) .
- Figure 2A shows the HPLC elution of a representative compound of this invention (S-pivaloyl-D- pantetheine) after incubation with a corneal homogenate.
- Figure 2B shows that no pantetheine was detected when a corresponding sample of corneal homogentate was incubated without S-pivaloyl-D-pantetheine.
- Figure 3A shows the HPLC elution of pantetheine after incubation of serum with S-pivaloyl-D-pantetheine.
- Figure 3B shows that no pantethine was detected when a corresponding sample of serum was incubated without S- pivaloyl-D-pantetheine.
- Figure 4 illustrates the enhanced corneal permeability S-pivaloyl-D-pantetheine (corneas #3 and #4) compared to pantethine (corneas #1 and #2) .
- Figure 5 illustrates the steady state corneal penetration of S-pivaloyl-D-pantetheine.
- Figure 6 illustrates the steady state corneal penetration of pantethine.
- the compounds and methods of this invention are useful for the prevention or inhibition of cataract formation in a warm-blooded animal, including a human.
- the compounds of this invention serve as prodrugs to anti-cataract agents, including pantethine or pantetheine.
- prodrug means a compound which, when administered to the animal, will be converted within the animal's body to a biologically active anti-cataract agent.
- the compounds of this invention may also possess utility as anti-cataract agents prior to conversion to pantethine or pantetheine.
- the combined effect of the compounds i.e., in vivo conversion to pantethine or pantetheine, as well as in vivo activity as anti-cataract agents) accounts for the effectiveness of the compounds of this invention.
- the compounds of this invention may generally be represented by the following structures 1 and 2:
- X, Y and Z are the same or different, and are selected from hydrogen or a chemical group which is susceptible to enzymatic cleavage within the body of a patient, with the proviso that X, Y and Z of structure JL are not all hydrogen, and with the further proviso that X and Y of structure 2, are not all hydrogen (since the compounds of structure 2. are dimers, this proviso applies when both X moieties and both Y moieties are hydrogen) .
- the individual X moieties may be the same or different, and the individual Y moieties may be the same or different.
- the compounds of the present invention may generally be described as derivatives of pantethine or pantetheine in which one or more of the alcohol groups have been modified
- panthethine i.e, X and/or Y modifications
- derivatives of panthethine were the terminal sulfhydryl has been modified (i.e., Z modifications) .
- X, Y and Z are the same or different, and are selected from hydrogen and structures through £:
- esters of structures _L and 2 are formed, and when X and/or Y is structure __-, carbamates result.
- X and/or Y is structure __. or £
- phosphate esters or sulphonate esters are formed, respectively.
- Z is structure 2
- thioesters of structure _ result, and when Z is structure 4.
- thiocarbamates are formed.
- Z is structure 5_ or £, phosphate or sulfonate thioesters of structure 1 are formed, respectively.
- X and Y taken together form a single carbon bridge between the oxygen atoms as represented by structures through _L__:
- X and Y taken together may form a phosphate bridge having structure 11, or a sulfone bridge having structure 12:
- X and Y taken together may form a cyclic carbonate having structure 12, or a cyclic oxalate having structure 14 :
- each R moiety may be the same or different chemical species, and are selected from hydrogen or saturated or unsaturated, branched or unbranched, substituted or unsubstituted C ⁇ to C25 alkyl moieties, C3 to C25 cycloalkyl moieties, Cg to C25 aryl moieties, and combinations thereof.
- C ] _ to C5 alkyl moieties include methyl, ethyl, propyl, isopropyl, butyl, sec-buty, tert-butyl, pentyl, isopentyl, sec-pentyl and neopentyl;
- C3 to Cg cycloalkyl moieties include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl;
- Cg and C7 aryl moieties include phenyl, benzyl and tolyl .
- Substituted aryl moieties include substituted phenyl (such as p-acetylphenyl and p- acetimidylphenyl) and heteroaryl groups (such as furyl, thienyl and pyridyl) .
- suitable R moieties of this invention are listed in Table 1 Table 1 Representative R Moieties
- Z is a sulfur-containing compound linked to the terminal sulfur atom of structure 1 by a disulfide linkage (i.e., -S-S-) .
- Suitable sulfur-containing compounds of this invention include the compounds disclosed in PCT Publication No. WO 93/06832 (hereby incorporated by reference in its entirety) .
- Representative examples of such sulfur- containing compounds include (but are not limited to) the compounds listed in Table 2.
- the compounds have the ability to serve as prodrugs to biologically active anti-cataract agents, including pantethine and pantetheine.
- the compounds of this invention are believed to undergo hydrolysis due to esterase activity within the body of the animal, including ocular tissues and fluids (such as the cornea, iris-ciliary complex, lens, aqueous humor and vitreous humor) , as well as upon contact with tissue and fluid of the blood, liver and kidney.
- the compounds of this invention may thus be assayed for their ability to convert to the biologically active form upon, for example, contact with corneal tissue and serum.
- assays may be accomplished by the procedures set forth below in Example 6. In that assay, corneal tissue and serum was collected from an animal, and contacted with the compound for a period of time. After precipitation of protein by addition of acid, the samples were centrifuged and the resulting solution analyzed by
- the compounds of this invention may be administered to an animal in any manner which results in the delivery of an effective amount of the compound to the lens of the eye. Suitable modes of administration of the compounds (and salts thereof) include topical, as well as oral, parenteral and other systemic forms of delivery.
- the compounds may be formulated in a variety of pharmaceutically acceptable forms, including liquid, semi-solid, solid and aerosol forms. Representative examples of such forms include liquids, ointments, tablets, pills, capsules, powders, suspensions and the like.
- One or more conventional pharmaceutical carriers or excipients may also be present in addition to the compounds of this invention (or pharmaceutically acceptable salt thereof) .
- the amount or dosage of compound administered to an animal will depend on a number of factors, including the animal's age and weight, the stage of cataract development and mode of administration. Dosage may be monitored for effectiveness in vivo by monitoring the initial stage of cataract by, for example, the apparatus and techniques disclosed in U.S. Patent Nos. 4,957,113, 4,993,827 and 5,072,731, followed by subsequent monitoring of the animal.
- an effective dosage of the compounds of this invention may be in the range of 0.1 to 2,000 mg/kg/day if administered systemically (for a 70 kg human, this would amount to 7 mg to 14g/day) .
- the animal which is to be treated may also be an important consideration. For example, dosages may be higher in veterinary applications, such as for horses, dogs and cats, and may be more prolonged than might be possible or desirable with humans.
- the compounds of this invention are administered before the formation of detectable levels of high molecular weight protein aggregates in the lens cell cytoplasm, although it may also be applied up to and including the time that vision is noticeably impaired. It should also be applied as soon as possible after detection of any rise in phase separation temperature in the lens cell cytoplasm.
- the amount required for effective prophylaxis or treatment may be determined by measuring the decrease in phase separation temperature per mole. For in vivo application, it is necessary to decrease and maintain the phase separation temperature of the lens cell cytoplasm at less than body temperature while inhibiting the formation of high molecular weight aggregates.
- the compounds of this invention are particularly useful when administered prior to a cataract insult, including (but not limited to) insults associated with both radiation and steroid therapy, as well as cataract surgery, such as vitrectomy.
- the compounds ' used may be in the form of solid, semisolid, or liquid dosage forms, such as, for example, ointments, tablets, pills, capsules, powders, liquids, suspensions, or the like, preferably in unit dosage forms suitable for single administration of precise dosages.
- Such formulations will include a conventional pharmaceutical carrier or excipient in combination with the compound (or a pharmaceutically acceptable salt thereof) and may further include other medicinal agents, pharmaceutical agents, carriers, adjuvants, etc. More than one compound may be included in the formulation to achieve advantages not available from the separate administration of such compounds.
- Parenteral administration of the compound is generally characterized by injection, either subcutaneously, intramuscularly or intravenously.
- Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions.
- Suitable excipients are, for example, water, saline, dextrose, glycerol, ethanol, or the like.
- the formulations may also contain minor amounts of nontoxic auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, and the like, such as, for example, sodium acetate, sorbitan monolaurate, triethanolamine oleate, and the like.
- liquid formulations For administration of a solid formulation, conventional nontoxic solid carriers may be used including, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like.
- Liquid formulations can, for example, be prepared by dissolving or dispersing a compound of this invention in a carrier, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like, to form a solution or suspension.
- the formulation may also contain minor amounts of nontoxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents, and the like, for example, sodium acetate, sorbitan monolaurate, triethanolamine sodium acetate and triethanolamine oleate.
- auxiliary substances such as wetting or emulsifying agents, pH buffering agents, and the like, for example, sodium acetate, sorbitan monolaurate, triethanolamine sodium acetate and triethanolamine oleate.
- the formulation to be administered will, in any event, contain a quantity of the compound(s) in an amount effective to prevent or inhibit the further development of cataract in the animal being tested.
- a pharmaceutically acceptable nontoxic formulation is made by the incorporation of any of the normally employed excipients, such as, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like.
- excipients such as, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like.
- Such formulations include solutions, suspensions, tablets, pills, capsules, powders, sustained release formulations, and the like, and may contain 10%- 95% active ingredient, preferably 25%-70%.
- Another approach for parenteral administration employs the implantation of a slow-release or sustained- release system, such that a constant level of dosage is maintained (see. e.g. , U.S. Patent No. 3,710,795) .
- a contact lens delivery system may be employed.
- Lacrimal fluid is isotonic with blood, having an isotonicity value corresponding to that of a 0.9% sodium chloride solution.
- an ophthalmic solution should have this isotonicity value, but the eye can tolerate isotonicity values as low as that of a 0.6% sodium chloride solution and as high as that of a 3.0% sodium chloride solution without marked discomfort .
- Some ophthalmic solutions are necessarily hypertonic in order to enhance absorption and provide a concentration of the pharmaceutically active ingredient (s) strong enough to exert a prompt and effective action.
- a boric acid vehicle which is preferred in some ophthalmic preparations, has a pH slightly below 5.0. It may be prepared by dissolving 1.9 g of boric acid in sufficient water to make 100 mL of solution. A phosphate buffer system may also be employed, and adjusted for isotonicity provides a choice of pH ranging from 5.9 to 8.0. A pharmaceutical grade of methylcellulose (e.g., 1% if the viscosity is 25 centipoises, or 0.25% if 4000 centipoises) or other suitable thickening agents such as hydroxypropyl methylcellulose or polyvinyl alcohol occasionally are added to ophthalmic solutions to increase the viscosity and prolong contact of the compound with the tissue of the eye.
- methylcellulose e.g., 1% if the viscosity is 25 centipoises, or 0.25% if 4000 centipoises
- suitable thickening agents such as hydroxypropyl methylcellulose or polyvinyl alcohol occasionally are
- the compounds of this invention have increased corneal permeability compared to their biologically active forms.
- the compounds are formulated for topical application to the animal's eye.
- the efficacy of the compounds of this invention to penetrate the cornea may be demonstrated with a Ussing Chamber in combination with a suitable analytical technique for the quantitation of pantethine or pantetheine.
- the Ussing Chamber contains two fluid-filled chambers which are separated by an excised cornea, and is described, for example, by Schoenwald and Huang, J. Pharm. Sci. 22.:1266-1272, 1978 (hereby incorporated by reference) .
- the cornea is kept in a viable state with appropriate buffers perfused with both oxygen and carbon dioxide.
- a buffer solution containing a known concentration of compound (C 0 ) is placed on the epithelial side of the cornea, and the concentration of the compound appearing of the endothelial side (Cn.) is assayed as a function of time (C-j_(t)) .
- the steady state rate of increase of the endothelial concentration (expressed as dC- (t)/dt) is calculated from the data.
- the steady state penetration coefficient (K) may be approximated calculated by the following equation (1) :
- Equation (1) above assumes that C 0 is essentially constant and that C ⁇ is much smaller than C 0 , conditions which were satisfied in this assay.
- a more detailed treatment of the corneal penetration of the compounds of this invention is set forth in Example 7.
- the ability of the compounds of the present invention to be converted in vivo to a biologically active form is demonstrated in Example 8.
- the ability of pantethine to convert to pantetheine upon contact with ocular tissue is demonstrated.
- other compounds having structure 1 (where Z is a sulfur-containing compound joined to the terminal sulfur atom via a disulfide bond) would be expected to undergo similar conversion to pantetheine.
- the following disclosure is directed to the general synthesis of the compounds of this invention.
- ester compounds may be prepared by reaction of pantetheine or pantethine with a suitable carboxylic acid to form the corresponding ester.
- suitable carboxylic acids include carboxylic acids themselves, or reactive derivatives of carboxylic acids, such as acid chlorides, mixed anhydride derivatives, or N- hydroxysuccinimide esters of carboxylic acid derivatives. Suitable carboxylic acids or their reactive derivatives are available from a variety of commercial sources.
- treatment of pantethine with a carboxylic acid or reactive derivative thereof yields a pantethine ester according to structure 2.
- R corresponds to the substituent of the carboxylic acid utilized in the esterification reaction.
- treatment of pantetheine or pantethine with isobutyric acid chloride produces ester compounds where R is an isopropyl group.
- ester-containing compounds of this invention may be made by esterification or carbamate formation.
- the X moieties and Y moieties may be the same or different (i.e., a compound of structure 2. has two X moieties and 2 Y moieties) .
- further asymmetry may be imparted to the compounds by varying the individual X moieties, Y moieties, or both.
- esterification is a stepwise process, the above esters are readily achieved.
- a secondary alcohol slightly more severe reaction conditions are necessary.
- esterification of the secondary alcohol with the same carboxylic acid derivative as utilized in esterification of the primary alcohol results in symmetric diesters, while esterification with a different carboxylic acid or reactive derivative produces the asymmetric esters.
- the symmetric and asymmetric dicarbamates may be prepared in the same manner using either the same or different carbamic acid derivatives, respectively.
- the compounds of the present invention are cyclic derivatives in which both alcohol groups have been modified.
- the 1,3-diol of pantetheine or pantethine may be modified with a reagent which effectively bridges the alcohol groups with one or more carbon atoms.
- X and Y taken together form the bridge between the alcohol groups.
- Preferred embodiments of these cyclic prodrugs include cyclic ketals, cyclic acetals, cyclic orthoesters, cyclic carbamate, and cyclic oxalates.
- cyclic ketones such as cyclopentanone or cyclohexanone provides a spiro-bridged prodrug, while condensation with an acyclic ketone, such as acetone, yields a compound of structure 2 where both R moieties are methyl .
- Suitable ketones include dialkyl ketones, such as acetone or methyl ethyl ketone; alkyl aryl ketones, such as acetophenone; and diaryl ketones, such as benzophenone.
- Cyclic acetal compounds may be prepared from the condensation of pantetheine or pantethine with a suitable aldehyde (e.g., R-CHO) .
- Suitable aldehydes include alkyl aldehydes, such as formaldehyde or ethanal; cycloalkyl aldehydes; and aryl aldehydes, such as benzaldehyde.
- Cyclic orthoesters are those compounds in which
- X and Y taken together form a single carbon bridge, as illustrated in structures £ and J£ above.
- Treatment of pantetheine or pantethine with the appropriate orthoester reagent provides such cyclic compounds.
- treatment of pantetheine or pantethine with trimethyl orthoformate yields a cyclic orthoester compound according to structures _L and 2.
- Similar treatment with trimethyl orthoacetate or trimethyl orthobenzoate provide cyclic orthoester prodrugs (where R methyl and phenyl, respectively, and OR is OCH3) .
- the compounds of the present invention may also be pantetheine or pantethine cyclic carbonates.
- the carbon bridge is a single carbonyl group as illustrated in structure 13.
- Such cyclic carbonates may be prepared by treating pantetheine or pantethine with phosgene or its synthetic equivalent.
- pantetheine or pantethine cyclic oxalates may also be formed.
- the carbon bridge comprises two carbonyl groups as represented in structure ______
- Such cyclic oxalates may be prepared by treatment of pantetheine or pantethine with oxalic acid or a suitable reactive derivative thereof.
- compounds of structure _L and 2 are synthesized according to the disclosure of U.S. Patent Application Serial No. (awaiting serial number), filed October 27, 1993, entitled “Compounds and Methods for Synthesizing Pantethine, Pantetheine and Derivatives Thereof" (which application is hereby incorporated by reference in its entirety) .
- pantothenic acid may serve as the starting point for the chemical synthesis of the compounds of this invention.
- the crystalline ketal intermediates may be subjected to recrystallization, as necessary, to afford ketals of high purity. Ketal purity may be ascertained by any one of a variety of techniques, including melting point determination, as well as spectrographic or chromatographic analysis. Hydrolysis of the ketal, if desired, regenerates the 1,3-diol functional group.
- the first synthesis step involves the ketalization of pantothenic acid.
- Sodium pantothenate (Aldrich Chemical Co., Milwaukee, I) is treated with acetone under acidic conditions to yield the acetone ketal of pantothenic aid, 1, 3-isopropylidene pantothenic acid.
- a solution of sodium pantothenate in acetone may be treated with either a catalytic or stoichiometric amount of an acid, such as sulfuric acid, and heated at reflux for several hours to effect conversion of the diol to the corresponding ketal.
- the ketal may be then be isolated via crystallization by dilution of the solution with a nonpolar solvent such as hexane.
- the crystallized ketal may be collected by filtration, washed with an appropriate solvent, and recrystallized as necessary to afford the purified ketal synthetic intermediate.
- the formation of the acetone ketal of pantothenic acid by the process described above may be referred to as direct ketalization.
- pantothenic acid may be treated with a ketal of acetone such as 2,2-dimethoxypropane
- trans-ketalization acetone dimethyl ketal
- the acetone ketal is exchanged or transferred from the ketalizing reagent, 2,2-dimethoxypropane, to pantothenic acid.
- a solution of sodium pantothenate in acetone may be treated with a single molar equivalent of sulfuric acid followed by treatment with 2, 2-dimethoxypropane.
- the crude product may be isolated by an aqueous extractive process utilizing methylene chloride and water.
- the ketal thus obtained may be recrystallized from a suitable solvent system such as acetone-hexane (1:1) to provide highly pure 1, 3-isopropylidene-D-pantothenic acid.
- a suitable solvent system such as acetone-hexane (1:1)
- a representative experimental procedure for the formation of the acetone ketal of pantothenic acid is described in detail in Example 1.
- the acetone ketal of pantothenic acid, 1,3- isopropylidene-D-pantothenic acid may be represented by structure 15 :
- pantothenic acid ketals may be utilized which are derived from a variety of ketones .
- Suitable ketones are those which provide pantothenic acid ketals which are crystalline and capable of recrystallization to provide highly pure ketals.
- Preferred ketones include dialkyl ketones containing from four to eight carbons, such as methyl ethyl ketone (2-butanone) ; cyclic ketones containing from three to seven carbon atoms, such as cyclopentanone and cyclohexanone; alkyl aryl ketones, such as methyl phenyl ketone (acetophenone) ; and diaryl ketones, such as diphenyl ketone (benzophenone) .
- the pantothenic acid ketals derived from the above-mentioned ketones may be generally represented by structure 15 ' :
- R ⁇ and R2 individually represent alkyl groups of a dialkyl ketone, alkyl and aryl groups of an alkyl aryl ketone, and aryl groups of a diaryl ketone as disclosed above, or wherein R]_ and R2 taken together represent the carbocyle of a cyclic ketone as disclosed above.
- Ketal formation is accomplished under acidic conditions. Suitable acids for these conditions include organic acids and mineral acids .
- Organic acids include carboxylic acids, ammonium salts, sulfinic acids, and sulfonic acids.
- Mineral acids include hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid. In a preferred embodiment, ketal formation utilizes sulfuric acid.
- the coupling of either cystamine or cysteamine to the ketal of pantothenic acid is then performed.
- the amino group of either cystamine or cysteamine is coupled to the carboxy group of the pantothenic acid ketal to form an amide bond to produce the ketal of pantethine or pantetheine, respectively.
- This coupling reaction may optionally utilize a coupling agent to effect amide bond formation.
- Such coupling agents include those reagents which activate carboxylic acid groups toward nucleophilic substitution.
- Suitable reagents include thionyl chloride (which transforms carboxylic acids to acid chlorides) , various chloroformates (which convert carboxylic acids into reactive anhydrides) , and diimide reagents such as dicyclohexyl carbodiimide (DCC) and 1- (3- dimethylaminopropyl) -3-ethyl carbodiimide (EDC) (which convert carboxylic acids to active ester derivatives) .
- DCC dicyclohexyl carbodiimide
- EDC 1- (3- dimethylaminopropyl) -3-ethyl carbodiimide
- a preferred coupling agent is carbonyl diimidazole (CDI) which converts carboxylic acids to carbonyl imidazoles.
- the coupling of cystamine or cysteamine to the ketal of pantothenic acid may be accomplished by esterifying the ketal by refluxing in methanol with a catalytic amount of concentrated sulfuric acid.
- cysteamine (1 equivalent) or cysteamine (0.5 equivalents)
- cysteamine 0.5 equivalents
- the mixture is then evaporated to dryness, redissolved in methylene chloride and washed with dilute HCl, saturated NaHC ⁇ 3 and brine, and then dried (e.g., using MgS ⁇ 4) , filtered and evaporated to dryness.
- pantothenic acid ketal i.e., structure 15 ' above
- cystamine is coupled with cystamine to yield the pantethine ketal of structure _L__.
- cysteamine to yield the pantetheine ketal of structure 12-
- the coupling of cystamine or cysteamine to a representative pantothenic acid ketal i.e., 1,3- isopropylidene-D-pantothenic acid
- carbonyl diimidazole to produce the 1, 3-isopropylidenes of pantethine and pantetheine are described in detail in Examples 2 and 3, respectively.
- these coupling reactions may be represented schematically as follows:
- the purity of the ketals of pantethine and pantetheine may be enhanced by recrystallization in a manner similar to that of the starting material, the pantothenic acid ketal.
- the pantetheine ketal of structure 12 may be further esterified.
- the sulfhydryl group of the pantetheine ketal is esterified with an esterifying agent to provide a pantetheine ketal thioester.
- esterifying agent refers to any reactive acid derivative which is capable of reacting with a sulfhydryl group to form a thioester.
- a thioester may be thought of as resulting from the condensation of a sulfhydryl containing compound, a thiol, with an acid much in the same way that an ester results from the condensation of an alcohol with an acid.
- the pantetheine ketal thioesters produced by the methods of the present invention may be prepared from esterifying agents derived from carboxylic, carbamic, phosphoric, and sulfuric acid derivatives, and are represented by structure IS.:
- R ⁇ and R2 are as described above, and R3 represents the residual portion of the esterifying agent.
- the residual portion of the esterifying agent, R3, is the portion of the esterifying agent which corresponds to the acid from which the esterifying group is derived, less the -OH group of the acid.
- the esterifying agent is a carboxylic acid derivative, such as an acid chloride
- the esterifying group is a phosphoric acid (H3PO4) or sulfuric acid (H2SO4) derivative, the residual portion of the esterifying group, R3, is -PO3H2 and -SO3H, respectively.
- Esterifying agents derived from carboxylic acids include reactive carboxylic acid derivatives such as acid halides, carboxylic acid anhydrides, and reactive carboxylic ester derivatives, including p-nitrophenyl esters and N-hydroxysuccinimide ester.
- Suitable acid halide esterifying agents include acid chlorides such as acetyl chloride and benzyl chloride.
- the thioesters produced from carboxylic acid-derived esterifying agents by the methods of the present invention are represented by structure formula ________:
- R ⁇ and R2 as are as described above, and R represents the side chain of the carboxylic acid from which the esterifying agent is derived.
- Suitable R groups included hydrogen or saturated or unsaturated, branched or unbranched, substituted or unsubstituted C ] _ to C25 alkyl moieties, C3 to C25 cycloalkyl moieties, Cg to C25 aryl moieties, and combinations thereof.
- C ⁇ to C5 alkyl moieties include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, isopentyl, sec- pentyl and neopentyl;
- C3 to Cg cycloalkyl moieties include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl;
- Cg and C7 aryl moieties include phenyl, benzyl and tolyl .
- Substituted aryl moieties include substituted phenyl (such as p-acetylphenyl and p-acetimidylphenyl) and heteroaryl groups (such as furyl, thienyl and pyridyl) .
- substituted phenyl such as p-acetylphenyl and p-acetimidylphenyl
- heteroaryl groups such as furyl, thienyl and pyridyl
- esterifying groups derived from carbamic acid are esterifying groups derived from carbamic acid. These esterifying agents produce pantetheine ketal thioesters, which may also be referred to as pantetheine ketal thiocarbamates.
- the thioesters produced from carbamic acid-derived esterifying agents by the method of the present invention may be represented by formula 18b:
- R ⁇ , R2, and R are as described above.
- the pantetheine ketal thioesters of the present invention derived from phosphoric and sulfuric acid derivatives may also be referred to as pantetheine ketal thiophosphonate and thiosulfonate esters, respectively.
- the thioesters produced from phosphoric and sulfuric acid- derived esterifying agents by the methods of the present invention are represented by formulas 18c and 18d f respectively:
- structure 18c may be accomplished by reacting structure 17 with phosphoryl chloride.
- structure 18d may be synthesized by reacting thiosulfate with the reaction product of structure 12 or its sulfenyl chloride.
- the compounds of this invention also include other 1,3-diol derivatives of pantethine and pantetheine.
- 1,3-diols may be condensed with aldehydes (R-CHO) to provide acetals.
- R-CHO aldehydes
- the 1,3-diols of pantothenic acid may be treated with orthoester reagents.
- Orthoester reagents are classified according to the ester and alcohols from which they are derived. Orthoester reagents derived from formate esters (R]-, is hydrogen) are referred to as orthoformates, and orthoester reagents derived from all other esters (R- Q not hydrogen) are referred to as the originating ester. For example, orthoester derived from acetates (R- Q is methyl) and benzoates (R ⁇ is phenyl) are referred to as orthoacetates and orthobenzoates, respectively.
- Suitable orthoester reagents of this invention include orthoesters derived from esters and alcohols wherein Rj-, and R a are as described above for R ⁇ _ (and R2) regarding the synthesis of ketals.
- Preferred orthoesters include trimethyl orthoformate, trimethyl orthoacetate, and trimethyl orthobenzoate.
- orthocarbonate reagents C(0R a ) 4
- Suitable orthocarbonate reagents are derived from alcohols (R a -0H) wherein R a is as described above for the orthoesters.
- the slurry was partitioned in 250 mL methylene chloride and 250 mL saturated aqueous sodium chloride.
- the methylene chloride layer was separated and washed with 100 mL saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. Filtration of the drying agent and concentration to dryness produced a white powder (85% yield) . Recrystallization from acetone-hexane (1:1 v/v) gave 1, 3-isopropylidene-D-pantothenic acid as a white crystalline solid, melting point 90-91°C (HPLC purity > 99%) .
- the solution was concentrated under reduced pressure and the resulting white solid was dissolved in 150 mL methylene chloride.
- the methylene chloride solution was washed sequentially with solutions of saturated aqueous sodium chloride, dilute hydrochloric acid, saturated sodium bicarbonate, again with saturated aqueous sodium chloride, and dried over anhydrous sodium sulfate.
- the solution was filtered, diluted with 150 mL hexanes, and allowed to stand overnight at room temperature.
- Example 5 Synthesis of S-Trimeth ⁇ lacetyl-D-Pantetheine S-trimethylacetyl-D-pantetheine was prepared by hydrolysis of its corresponding acetone ketal. Specifically, a solution of 0.010 mole S-trimethylacetyl- 1, 3-isopropylidene-D-pantetheine (prepared as described above in Example 4) in 100 mL 80% aqueous acetic acid was heated for 6 hours at 65°C. The solution was concentrated to dryness under reduced pressure to provide a glassy solid. The solid was dissolved in 100 mL distilled water and washed with two 100 mL portions of methylene chloride. The aqueous layer was collected and freeze-dried to yield S-trimethylacetyl-D-pantethine as glassy material (93% yield, HPLC purity > 99%) .
- This example illustrates the ability of corneal tissue and serum to convert a representative compound of this invention, S-pivaloyl pantetheine, to pantetheine.
- the HPLC included a Bioanalytical Systems PM-80 HPLC pump, LC-4C dual amperometric electrochemical detector, LC-44 thin layer flow cell, and LC-26 vacuum degasser.
- the analytical column was a Bioanalytical Systems 3.2 x 100 mm, 3 ⁇ m, Phase II ODS cartridge column.
- An SGE 4.1 x 10 mm, 5 ⁇ m, ODS-Iguard column was employed.
- Mobile phase A was a 50 mM, pH 2.8 phosphate buffer.
- Mobile phase B was prepared by adding 100 mL of a 500 mM, pH 2.8 phosphate buffer to a 1 L volumetric flask, then adding 200 mL of acetonitrile and diluting to the mark with HPLC-grade water.
- the mobile phase was degassed and maintained under 2 psig of helium using a Kontes sparging manifold. The flow was set to 1.0 mL/minute.
- the mobile phase composition was changed linearly from 90%A:10%B to 10%A:90%B in 10 minutes, followed by holding at this composition for 10 minutes before equilibrating the system with 90%A:10%B.
- a dual HG/Au electrode was prepared and equilibrated overnight in the system.
- a potential of - 1.250 V was applied to the upstream electrode and a potential of +0.250 was applied to the upstream electrode.
- the optimum potentials were determined by performing hydrodynamic voltammograms at the upstream and downstream electrode.
- Figures 1A and IB display standard samples showing elution times of both pantetheine ( Figures 1A and IB) and pantethine ( Figure 1A) under the chromatographic conditions employed.
- Figures 2A and 2B show results of HPLC analyses of corneal homogenates demonstrating hydrolysis of the S- pivaloyl pantetheine by the cornea tissue.
- Figure 2A shows the elution of S-pivaloyl pantetheine after incubation of corneal homogenates with S-pivaloyl pantetheine as described above.
- Figure 2B illustrates that no pantetheine was detected when a corresponding sample of corneal homogenate which was incubated without S-pivaloyl pantetheine present.
- Figures 3A and 3B presents the results of HPLC analysis of control samples and of serum, demonstrating conversion of S-pivaloyl pantetheine to pantetheine in serum.
- Figure 3A illustrates the elution of pantetheine after incubation of serum with S-pivaloyl pantetheine as described above.
- Figure 3B shows a corresponding sample of serum which was incubated without S-pivaloyl pantetheine, and no pantetheine was detected.
- This example illustrates the ability of a representative compound of this invention, S-pivaloyl pantetheine, to penetrate the cornea of an animal lens.
- S-pivaloyl pantetheine For each compound tested (i.e., pantethine and
- the conjunctival and scleral tissue served as a gasket and permitted the cornea to be suspended within the corneal ring, which was then positioned between two large rings and placed in the center of the perfusion chamber.
- the chamber was put in a water bath to maintain the cornea and the perfusion solution at 37°C.
- Bicarbonated Ringer's solution was modified as described by Schoenwald and Huang (J. Pharm. Sci. 22:1266-1272, 1978) to preserve the integrity of the tissue of the excised cornea over 6 hours and used through the perfusion study.
- the first cornea was mounted and clamped between two cylindrical compartments of the perfusion chamber.
- a measured volume (7.0 mL) of bicarbonated Ringer's solution was added first to the endothelial side (i.e., the "receiving solution") to prevent the cornea from buckling.
- Fluid was circulated inside each half- chamber by bubbling a mixture of O2-CO2 (95:5) through at a rate of 3-5 bubbles per second. This served not only to provide oxygen to the excised corneas, but also maintained the solution at a constant pH of about 7.7.
- Samples were withdrawn (0.5 mL) from the receiving chamber at 2, 15, 30, 60, 90, 120, 150, 180, 210 and 240 minutes after the compound was added to the epithelial side. After each sample was withdrawn, an equal volume (0.5 mL) of solution was immediately added to the receiving solution to maintain a constant volume. The first sample, withdrawn at 2 minutes, served as a control to detect leakage and rapid penetration. Sample solutions were transferred into autosampler vials for HPLC analysis immediately after finishing the collection of each sample.
- the HPLC system included of the following components: Rainin solvent delivery module, Rainin Dynamax automatic sample injection (Model AI-1) , Rainin reversed phase C18 column, 5 ⁇ m particle diameter, pore size 100 Angstroms, 15 cm long with an I.D. of 4.6 mm, and a Rainin Dynamax ultraviolet absorbance detection (Model UV-D) detecting at a wavelength of 230 nm. Data was collected and processed with a Waters 860 System Data Station on a Digital Equipment MicroVax 3100 computer. The mobile phase consisted of methanol and water in the volumetric ratios 40:60 for pantethine and 60:40 for S- pivaloyl pantetheine, and was delivered at a rate of 1.0 mL/minute from a reservoir.
- Rainin solvent delivery module Model AI-1
- Rainin reversed phase C18 column 5 ⁇ m particle diameter, pore size 100 Angstroms, 15 cm long with an I.D. of 4.6 mm
- a Rainin Dynamax ultraviolet absorbance detection Model UV
- the column temperature was set to 25°C, injected sample volume was 20 ⁇ l, and run time was 10 minutes.
- the corneas were trimmed of excess scleral tissue and conjunctiva, weighed, and dried in an oven overnight at 100°C. After each cornea was dried, it was reweighed so that the hydration level of the cornea could be determined. Each cornea had a hydration level of between 77-79%. A normal, undamaged cornea gives a hydration level of 76-80% following this same procedure, indicating the hydration levels in the test corneas were within satisfactory hydration limits.
- Figure 4 illustrates the data collected for corneas #1 through #4 of Table 4. More specifically, Figure 4 is a plot of the receiving chamber concentration of pantethine as a function of time (C-j_(t)) for the data collected from 0 to 120 minutes. This figure graphically illustrates the enhanced corneal permeability achieved in corneas #3 and #4 by S-pivaloyl pantetheine (i.e., the upper two lines) , compared to the corneal permeability of corneas #1 and #2 by pantethine (i.e., the lower two lines) .
- S-pivaloyl pantetheine i.e., the upper two lines
- pantethine i.e., the lower two lines
- the steady state penetration coefficient (K) may be calculated for both pantethine and S-pivaloyl pantetheine.
- penetration coefficient for S-pivaloyl pantetheine was 2.0 x 10 ⁇ 5 cm/seconds (see Figure 5)
- for pantethine was 2.6 x 10 ⁇ 6 cm/seconds (see Figure 6) .
- K s . pivaloyl p an t et h was approximately 7 to 8 times greater than pan t e th ine' demonstrating that corneal permeability of representative compound of this invention was superior compared to that of pantethine.
- This example illustrates the conversion of the disulfide bond of pantethine to its sulfhydryl form, pantetheine, upon contact with various lens tissue.
- this example illustrates the ability of compounds having structure 1 (where Z is a sulfur- containing compound joined to the terminal sulfur via a disulfide linkage) and structure 2, to be converted in vivo to the biologically active anti-cataract agent, pantetheine.
- calf lens homogenate (2) unfractionated alpha-, beta- and gamma-crystallin solutions, and (3) purified gamma-II crystallin and gamma- IV crystallin solutions.
- These solutions were prepared by homogenizing bovine calf lenses, separating the various constituents by gel filtration and ion exchange chromatography, and concentrating by ultrafiltration and/or centrifugation.
- the protein solutions were then mixed with pantethine (7.5 mM) and incubated at 37°C for either 30 or 180 minutes. After incubation, proteins were precipitated by the addition of 2 parts methanol to 1 part reaction mixture, allowed to stand for 30 minutes, and centrifuged for 15 minutes (Beckman JA-20 rotor, 15,000 rpm, 4°C) . The supernatant from each tube was recentrifuged for 5 minutes and the final supernatant was placed into HPLC vials for analysis of pantethine and pantetheine concentrations.
- the HPLC system included the following components: Rainin solvent delivery module, Rainin Dynamax automatic sample injector (Model AI-1) , Rainin reversed phase C18 column, 5 ⁇ m particle diameter, pore size 100 Angstroms, 15 cm x 4.6 mm (L x I.D.) , and Rainin Cynamax ultraviolet absorbance detector (Model UV-D) set to a wavelength of 230 nm. Data was collected and processed with a Waters 860 System Data Station on a Digital Equipment MicroVax 3100 computer. The mobile phase contained methanol and water in the volumetric ratios of 40:60, and was delivered at a rated of 1.0 ml per minute from a reservoir. The column temperature was set to 25°C, the injected sample volume was 20 ⁇ L, and the run time was 10 minutes.
- samples containing the relevant protein(s) but with no added pantethine were employed: (1) samples containing the relevant protein(s) but with no added pantethine, (2) samples containing pantethine but with no protein, and (3) samples containing water only.
- Each control was treated in identical fashion to the pantethine/protein(s) samples described above, including incubation, addition of methanol and centrifugation. No pantethine or pantetheine was detected in those sample which did not receive the addition of pantethine. Moreover, no pantetheine was detected in samples containing pantethine but no protein. The results of this experiment are summarized in
- Table 5 illustrate the ability of compounds of structure 1 (where Z is a sulfur-containing compound linked via a disulfide bridge to the terminal sulfur atom) and structure 2 to convert to a biologically active anti- cataract agent upon contact with ocular lens protein.
- This example illustrates the efficacy of a representative compound of this invention, S-pivaloyl pantetheine, to prevent or inhibit cataract formation in the selenium-induced animal cataract model (pantethine was also used in this experiment for comparative purposes) .
- a mature cataract forms four or five days after a single subcutaneous injection of selenium, and has been described, for example, by Bunce and Hess, Exp. Eye Res. _____:505-514, 1981, and reviewed by Shearer et al. , Curr. Eye Res. ⁇ :289-300, 1987 (which references are hereby incorporated by reference) .
- Rats treated with S-pivaloyl pantetheine or pantetheine were dosed one day prior to selenite injection, and on the day of selenite injection. On each day of dosing, four 10 ⁇ l drops of either 2% S-pivaloyl pantetheine or 40% pantethine were adinistered to each eye.
- the drops were administered over an eight hour period, two in the morning and two in the afternoon.
- two drops were administered before injection, and two drops after injection.
- the rats were divided into three groups: selenite only group (control group) , selenium plus S-pivaloyl pantetheine treatment, and selenite plus pantethine treatment.
- Stage 0 One day prior to selenite injection, gross opthalmic observations were performed to scale each eye from Stage 0 to Stage 6 as follows: Stage 0, completely clear lens; Stage 1, barely visible haziness at lens necleus; Stage 2, diffusely hazy nucleus; Stage 3, densely hazy nucleus; Stage 4, opaque (white) nucleus, small cataract; Stage 5, opaque nucleas, large cataract; and Stage 6, completely opaque lens.
- S-pivaloyl pantetheine to inhibit the onset of cataract associated with this cataract model is believed to be due, at least in part, to its enhanced corneal permeability compared to that of pantethine (as demonstrated above in Example 7) .
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Abstract
La présente invention concerne des composés et des procédés de prévention de formation de la cataracte sur le cristallin de l'oeil d'un animal à sang chaud. Le composé est généralement constitué de dérivés de la pantéthine ou de pantéthéine dont un ou plusieurs groupes alcool ont été modifiés, et de dérivés de la pantéthéine à terminaison sulfhydryle modifiée. Ces composés possèdent une activité anti-cataractique, et ils peuvent en outre s'utiliser comme bioprécurseurs activant biologiquement les agents anti-cataractiques tels que la pantéthine et la pantéthéine. La présente invention concerne également les procédés incluant l'administration d'une quantité suffisante d'un composé destiné à prévenir ou empêcher la formation de cataracte.
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AU80928/94A AU8092894A (en) | 1993-10-27 | 1994-10-26 | Compounds and methods for inhibiting cataract formation |
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WO2014080309A2 (fr) * | 2012-11-21 | 2014-05-30 | Mahesh Kandula | Compositions et procédés pour le traitement de troubles inflammatoires et lipidiques |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
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JPS50126884A (fr) * | 1974-03-29 | 1975-10-06 | ||
JPS60139618A (ja) * | 1983-12-28 | 1985-07-24 | Sogo Yatsukou Kk | 白内障治療薬 |
US5053426A (en) * | 1990-03-29 | 1991-10-01 | American Cyanamid Company | Simplified thioester and isostere analogs of oleoyl coenzyme a as hypocholesterolemic agents |
US5120738A (en) * | 1989-10-06 | 1992-06-09 | Fujirebio Inc. | Pantothenic acid derivatives |
-
1994
- 1994-10-26 AU AU80928/94A patent/AU8092894A/en not_active Abandoned
- 1994-10-26 WO PCT/US1994/012301 patent/WO1995011884A1/fr active Application Filing
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS50126884A (fr) * | 1974-03-29 | 1975-10-06 | ||
JPS60139618A (ja) * | 1983-12-28 | 1985-07-24 | Sogo Yatsukou Kk | 白内障治療薬 |
US5120738A (en) * | 1989-10-06 | 1992-06-09 | Fujirebio Inc. | Pantothenic acid derivatives |
US5053426A (en) * | 1990-03-29 | 1991-10-01 | American Cyanamid Company | Simplified thioester and isostere analogs of oleoyl coenzyme a as hypocholesterolemic agents |
Non-Patent Citations (7)
Title |
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CHEMICAL ABSTRACTS, vol. 70, no. 1, 6 January 1969, Columbus, Ohio, US; abstract no. 3481p, V.M. KOPELEVICH: "Coenzyme A. VI. Synthesis of (+)-S-benzoylpantetheine phosphates" page 313; * |
CHEMICAL ABSTRACTS, vol. 84, no. 7, 16 February 1976, Columbus, Ohio, US; abstract no. 42027d, page 332; * |
H. NAKAMURA, ET AL.:: "Growth responses of Bifidobacterium bifidum to S-sulphonic acid-type panthethein related compounds", JAPANESE JOURNAL OF MICROBIOLOGY, vol. 16, no. 3, TOKYO, JP, pages 239 - 242 * |
J.T. DAVIS, ET AL.:: "Biosynthetic thiolase from Zoogloea ramigera", JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 262, no. 1, 5 January 1987 (1987-01-05), BALTIMORE, MD US, pages 82 - 89 * |
PATENT ABSTRACTS OF JAPAN vol. 9, no. 301 (C - 316) 28 November 1985 (1985-11-28) * |
R. SCHWYZER: "Coenzym A: Eine enfacehe Synthese von S-Acylderivaten des Patnethins", HELVETICA CHIMICA ACTA, vol. 35, no. 6, 15 October 1952 (1952-10-15), BASEL CH, pages 1903 - 1907 * |
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Cited By (2)
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WO2014080309A2 (fr) * | 2012-11-21 | 2014-05-30 | Mahesh Kandula | Compositions et procédés pour le traitement de troubles inflammatoires et lipidiques |
WO2014080309A3 (fr) * | 2012-11-21 | 2014-12-24 | Mahesh Kandula | Compositions et procédés pour le traitement de troubles inflammatoires et lipidiques |
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