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WO1991006569A1 - Polymeres d'iodothyronine - Google Patents

Polymeres d'iodothyronine Download PDF

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Publication number
WO1991006569A1
WO1991006569A1 PCT/US1990/006213 US9006213W WO9106569A1 WO 1991006569 A1 WO1991006569 A1 WO 1991006569A1 US 9006213 W US9006213 W US 9006213W WO 9106569 A1 WO9106569 A1 WO 9106569A1
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Prior art keywords
iodo
polymer
iodothyronine
formula
recurring units
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PCT/US1990/006213
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English (en)
Inventor
Keith Roger Latham
Vincent Ernest Latham
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Boots Pharmaceuticals Inc.
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Priority to CA002072613A priority Critical patent/CA2072613C/fr
Publication of WO1991006569A1 publication Critical patent/WO1991006569A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/44—Two oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/575—Hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • This invention relates to iodothyronine polymers which have utility in the treatment of thyroid hormone deficiencies, to pharmaceutical compositions containing iodothyronine polymers and to the use of iodothyronine polymers in the treatment of thyroid hormone deficiencies.
  • the iodothyronine polymers of the present invention contain recurring units linked by -NHCO- bridging groups and are therefore polypeptides.
  • Thyroid hormone deficiencies are disease states in which insufficient thyroid hormone is released in the body causing a slowing down of all the metabolic processes of the body and, in children, causing poor mental and physical development.
  • Dessicated thyroid glands obtained from the ox, sheep or pig have been used for many years to treat thyroid hormone deficiencies.
  • the actual thyroid hormone dose from dessicated thyroid glands is difficult to regulate due to variations in iodine content between preparations.
  • More recently synthetic levothyroxine (LT.) has been used to treat thyroid hormone deficiencies.
  • the present invention provides a substantially pure synthetic iodothyronine polymer having a plurality of recurring units, which may be the same or different, of formula I
  • A is iodo and B, C and D are independently H or iodo.
  • iodothyronine polymers substantially all of the recurring units of formula I are in the same stereoisomeric form.
  • substantially all of the recurring units of formula I are L-stereoisomers.
  • a and C are iodo and B and D are independently H or iodo.
  • a and C are iodo and at least one of B and D is iodo.
  • the average number of the recurring units may vary from about 5 to about 400, preferably from about 10 to about 400, more preferably from about 20 to about 200, or from about 30 to about 150 or from about 80 to about 120.
  • the recurring units of formula I are derivatives of one or more iodothyronine compounds selected from the group consisting of 3-T.- , 3,3'-T 2 , 3,5-T 2 , rT 3 , T 3 and T. as defined in Table I below.
  • Table I
  • the iodothyronine polymers of the present invention are used to treat thyroid hormone deficiencies, substantially all of the recurring units of formula I are the physiologic L-stereroisomer. That is, at least 90%, preferably 95%, and most preferably greater than 99% of the recurring units are the physiologic L-stereoisomer.
  • the recurring units of formula I are derivatives of the pharmacologically active iodothyronine compounds identified in Table II.
  • the iodothyro ⁇ nine polymer is a homopolymer as defined below in Table III.
  • substantially all of the recurring units will be those identified above. That is, at least 90%, preferably at least 95%, and most preferably at least 99% of the recurring units of each homopolymer will contain the substituents identified in Table III.
  • the iodothyronine homopolymers in which substantially all of the recurring units of formula I are L-stereoisomers and in which A, B, C and D are iodo, or in which A, B and C are iodo and D is H have utility in the treatment of thyroid hormone deficiency.
  • the preferred homopolymers for use in therapy are poly-LT. and poly-LT, .
  • the iodothyronine polymers of the present invention in which substantially all of the recurring units of formula I are L-stereoisomers and A and C are iodo and B and D are independently H or iodo have utility in the treatment of thyroid hormone deficiencies in human and other mammals.
  • LT. is the primary thyroid hormone in mammals, but LT, is also released by the thyroid gland and is also active as a thyroid hormone. LT and LT are found in the blood in an approximate 4:1 ratio.
  • the iodo-thyronine polymer contains recurring units derived from both L . and LT, to form a copolymer of these units.
  • the LT. derivatives Preferably, from about 70 to about 90% of the recurring units are the LT. derivatives and about 10 to about 30% of the recurring units are the LT, derivatives. Most preferably, the ratio is approximately 4:1 i.e. about 80% of the recurring units are LT. and approximately 20% of such units are LT,.
  • This copolymer is referred to herein as poly-LT 4 /LT 3 .
  • a further aspect of the present invention provides an iodothyronine polymer in which a fraction of the recurring units are derived from rLT,.
  • a fraction of the recurring units are derived from rLT, approximately 70-89% of the recurring units are derived from LT., approximately
  • a further aspect of the present invention provides iodothyronine polymers which contain further recurring units of formula II
  • R is a residue of any of the amino acids commonly found in nature.
  • amino acids are listed by Lehninger in Principles of Biochemistry (1982) published by Worth Publishers Inc of New York (see page 96) as alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine.
  • the properties of the iodothyronine polymers are modified by copolymerization with these amino acids.
  • hydrophilic amino acids like lysine, arginine, aspartic acid, glutamic acid, serine or threonine can be copolymerized into the polypeptide chain.
  • the amount of amino acid incorporated will be dependent upon the particular iodothyronine/amino acid copolymer(s) , and the properties desired.
  • the recurring units of formula II may comprise up to 50%, preferably up to 66%, most preferably up to 80% of the recurring units in the copolymers.
  • Iodothyronine polymers of the present invention in which substantially all of the recurring units of formula I are the L-stereoisomers and in which the recurring units are of formula I in which A and C are iodo and B and D are independently H or iodo have utility in the treatment of thyroid hormone deficiencies.
  • a further aspect of the present invention therefore provides a pharmaceutical composition suitable for treating thyroid hormone deficiencies which comprises a pharmaceutically acceptable diluent or carrier and a pharmacologically active ingredient consisting of a pharmaceutically effective amount of a substantially pure synthetic iodothyronine polymer having a plurality of recurring units, which .
  • the iodothyronine polymer in these pharmaceutical compositions may be poly-LT., poly-LT 3 , poly-LT 4 /LT 3 , poly-LT./LT 3 /rLT 3 or mixtures thereof.
  • compositions are those in which the iodothyronine polymer is poly-LT., poly-LT,, a mixture of poly-LT. and poly-LT, in which the ratio of poly-LT. to poly-LT lies in the range 7:3 to 9:1 preferably about 4:1 or a mixture of poly-LT., poly-LT, and poly-rLT 3 in which the ratio of poly-LT. to poly-LT and poly-rLT is approximately 80:15:5.
  • the iodothyronine polymer is preferably administered orally.
  • the therapeutic compositions of the present invention may take the form of any of the known pharmaceutical compositions for oral administration.
  • Pharmaceutically acceptable carriers are well known in the art of pharmacy.
  • the compositions of the invention may contain 0.1-90% by weight of iodothyronine polymer.
  • the compositions of the invention are generally prepared in unit dosage form.
  • compositions for oral administration are the known pharmaceutical forms for such administration, for example tablets, capsules, syrups and aqueous or oily suspensions.
  • the diluent or carrier used in the preparation of these compositions can be any of the materials known in the pharmacists' art.
  • Tablets may be prepared by mixing the iodothyronine polymer with an inert diluent such as calcium phosphate in the presence of disintegrating agents, for example maize starch, and lubricating agents, for example magnesium stearate, and tableting the mixture by known methods.
  • the tablets may be formulated in a manner known to those skilled in the art so as to give a sustained release of the compounds of the present invention.
  • Such tablets may, if desired, be provided with enteric coatings by known methods, for example by the use of cellulose acetate phthalate.
  • capsules for example hard or soft gelatin capsules, containing the active compound with or without added excipients, may be prepared by conventional means and, if desired, provided with enteric coatings in a known manner.
  • the tablets and capsules may conveniently each contain 12.5 to 500 microgrammes of the iodothyronine polymer.
  • compositions for oral administration include, for example, aqueous suspensions containing the iodothyronine polymer in an aqueous medium in the presence of a non-toxic suspending agent such as sodium carboxymethylcellulose, and oily suspensions containing a compound of the present invention in a suitable vegetable oil, for example arachis oil.
  • a non-toxic suspending agent such as sodium carboxymethylcellulose
  • oily suspensions containing a compound of the present invention in a suitable vegetable oil for example arachis oil.
  • An alternative route of administration of the iodothyronine polymer is by means of an implant.
  • a pellet containing iodothyronine polymers containing large numbers of recurring units is implanted under the skin of the patient and pharmacologically active amounts of the iodothyronine polymer are then released over an extended period of time, suitably over several weeks or months.
  • the compounds of the present invention in the form of particles of very small size, for example as obtained by fluid energy milling.
  • compositions containing a therapeutically effective amount of the iodothyronine polymers of the present invention in which substantially all of the recurring units of formula I are the L-stereoisomers may be used to treat thyroid hormone deficiencies in warm blooded animals including human beings.
  • the amount of the iodothyronine polymer administered per day is under the control of the prescribing physician and will depend inter alia on the age of the patient and on the severity of the condition to be treated but will usually lie in the range 12.5 to 1000 micrograms per day, preferably 25 to 400 micro-grams per day, most preferably 50 to 300 micrograms per day given in single or divided doses at one or more times during the day.
  • the amount of the polymer administered may be higher than quoted above but will be such as to give rise to equivalent amounts of the pharmacologically active iodothyronine moieties.
  • a preferred method of synthesizing the iodothyro ⁇ nine polymers of the present invention comprises the polymerisation of one or more N-carboxyanhydride ⁇ (NCA) of formula III
  • the N-carboxyanhydride of formula III should be substantially all in that same stereoisomeric form.
  • the desired iodothyronine polymer is a homopolymer
  • one N-carboxyanhydride of formula III is used.
  • two or more N-carboxyanhydrides of formula III are used in the same molar proportions as is desired in the iodothyronine polymer.
  • the desired iodothyronine polymer is a copolymer of LT. and LT
  • the N-carboxy ⁇ anhydrides of LT when the desired iodothyronine polymer is a copolymer of LT. and LT, the N-carboxy ⁇ anhydrides of LT.
  • the iodothyronine copolymer and of LT, are used in the molar ratio desired in the iodothyronine copolymer and when the desired iodothyronine polymer is a heteropolymer of LT., LT and rLT,, the N-carboxyanhydrides of LT ⁇ , LT 3 and rLT. are used in the molar ratio desired in the final copolymer.
  • the iodothyronine polymer also contains one or more further recurring units of formula II, an N-carboxyanhydride of formula IV R
  • N-carboxyanhydride of formula III may be used in addition to the N-carboxyanhydride of formula III.
  • the N-carboxyanhydrides of formula III and formula IV are used in the molar ratio desired in the final iodothyronine polymer
  • the polymerization preferably comprises reacting one or more compounds of formula III in an anhydrous solvent, preferably at a concentration of about 5-40% and a temperature from about 0°C to the boiling point of the solvent for sufficient time to complete the polymerisation.
  • the reaction is continued until polymerisation is complete as indicated, for example, by product precipitation, cessation of CO ⁇ evolution, the attainment of maximum viscosity or the absence of the starting material, as indicated for example, by spectroscopic examination of the reaction mixture.
  • anhydrous solvents examples include ethers, such as dioxane or tetrahydrofuran, aromatic solvents, such as benzene, chlorobenzene, and toluene, and other solvents, such as dimethyl formamide, ethyl acetate and dimethyl sulphoxide.
  • ethers such as dioxane or tetrahydrofuran
  • aromatic solvents such as benzene, chlorobenzene, and toluene
  • other solvents such as dimethyl formamide, ethyl acetate and dimethyl sulphoxide.
  • a preferred solvent is dioxane or tetrahydrofuran.
  • a base is used as an initiator in the above reaction.
  • An inorganic or organic base may be used, although an organic base is preferred.
  • suitable bases include organic amines such as n-butylamine, triethylamine, tributylamine, triamyl- amine, diisopropylethylamine or alkali metal alkoxides such as sodium methoxide or sodium ethoxide.
  • the III to the initiator lies in the range 20 to 400 preferably 30 to 150 more preferably 50 to 100.
  • the base is sodium methoxide.
  • the iodothyronine polymers of the present invention may be prepared by the further iodination of iodothyronine polymers having recurring units of formula I in which A is iodo, B is H or iodo and C and D are H.
  • iodothyronine polymer starting materials are identified in Table III as poly-3,5-T ? and poly-3-T. respectively. If these polymers are subjected to vigorous iodination conditions, for example by the use of excess potassium triiodide or of iodine monochloride as the iodinating agent, iodothyronine polymers can be produced in which both C and D are iodo.
  • poly-3,5-LT gives poly-LT.
  • poly-3-LT gives poly-rLT_.
  • poly-3,5-LT 2 would give poly-LT..
  • poly-3-LT. would give poly-3,3'-LT_.
  • copolymers of LT. and LT may be prepared by partial iodination of poly-3,5-LT 2 .
  • the iodothyronine polymers of the present invention may also be prepared by the condensation of the amino acids from which the recurring units of formula I are derived in the presence of a dehydrating agent such as dicyclohexylcarbodiimide which is converted into dicyclohexylurea when it removes the elements of water from two amino acid residues to form a peptide bond between them.
  • a dehydrating agent such as dicyclohexylcarbodiimide which is converted into dicyclohexylurea when it removes the elements of water from two amino acid residues to form a peptide bond between them.
  • Copolymers and hetero- polymers may be prepared by condensing mixtures of two or more amino acids.
  • hetero- polymers Homogeneous polymerizations to form hetero- polymers result in a random distribution of each component in the polymer.
  • sequence- specific copolymer or heteropolymer combinations are desired, a solid phase synthesis of the Merrifield type is useful.
  • the preferred method of synthesis is through the t-BOC or f-MOC intermediates of the iodothyronines and other amino acids if applicable. Synthesis proceeds as previously described in Groginski, Amer. Biotech. Lab., May/June:38-51 (1986), incorporated herein by reference.
  • the N-carboxyanhydride of formula III may be prepared by reacting the appropriate iodothyronine with a carbonylating reagent to form the N-carboxyanhydride.
  • a preferred carbonylating reagent is hexachlorodimethylcarbonate, (CC1,0) 2 C0. This normally solid chemical is commercially available from Aldrich Chemicals under the trade name Triphosgene.
  • the iodothyronine is suspended in the anhydrous solvent and the hexachlorodimethylcarbonate is added. An excess of the hexachlorodimethylcarbonate is used.
  • phosgene gas may be used as the carbonylating agent.
  • the iodothyronine polymer may be precipitated and the resulting solid collected by filtration and may be further purified, if necessary, by recrystallisation.
  • the product is advantageously dried by lyophilisation.
  • the precipitated iodothyronine polymer if necessary following recrystallisation, is prefrozen or frozen in situ by evaporative cooling in vacuo with sufficient external heat provided to obtain a product with the desired, preferably less than 0.1%, moisture content.
  • N-carboxyanhydrides of formula III obtained by the above synthesis are typically recrystallised to obtain intermediates of pharmaceutical purity. Since the prepared anhydrides are moisture sensitive, special care to ensure anhydrous conditions of the reaction, recovery and storage of the N-carboxyanhydrides is important. This synthetic procedure may also be used to prepare the N-carboxyanhydride derivatives of formula IV for copolymerization or heteropolymerisation with the N-carboxyanhydride derivatives of formula III to prepare iodothyronine polymers having further recurring units of formula II.
  • Compounds of formula V are prepared by methods which are well known in the art such as those described, for example, in US Patents 2579668, 2886592, 2889363, 2889364, 3477954 and 3577535.
  • the iodothyronine polymers of the present invention provide a method of delivering thyroid hormones to a patient in need thereof. Because the thyroid hormones are released by digestive proteolysis of the iodothyronine polymers of this invention, it is expected that the use of the iodothyronine polymers would have a long physiologic effect because of the sustained release from the polymers of the monomeric thyroid hormones.
  • the use of copolymers containing recurring units derived from two or more thyroid hormones or mixtures of homopolymers of the thyroid hormones in the appropriate ratio provides a means whereby the naturally occurring ratio of thyroid hormones may be duplicated. Attempts have been made before to duplicate this naturally occurring ratio by administering a mixture of LT, and LT. (see for example
  • LT 3 has a short half life in the blood compared to the half life of LT. and so the desired ratio cannot be maintained over a long period of time.
  • the iodothyronine polymers of the present invention are solid materials which may be readily handled and formulated to give stable, consistent pharmaceutical compositions for the treatment of thyroid hormone deficiencies.
  • Hexachlorodimethylcarbonate (10 g) was added to a suspension of 3,5-diodo-L-thyronine (26.3) in anhydrous tetrahydrofuran (125 ml) and the mixture was heated to 67°C for 15 minutes.
  • Anhydrous tetrahydrofuran (500 ml) and then anhydrous hexane (3000 ml) were added and the mixture stored at 20°C for three hours.
  • 3,5-Diodo-L-thyronine N-carboxyanhydride (3,5-LT 2 ⁇ NCA) was collected by filtration. Yield 24 g.
  • the product was precipitated from the reaction mixture by addition of petroleum ether (2 volumes) and the precipitate dried in vacuo. Yield
  • Polymeric 3,5-diiodo-L-thyronine (poly-3,5-LT - 22 g prepared in a similar manner to that described in Example 2) was dissolved in a 33% aqueous solution of diethylamine at 16 to 22°C.
  • the mixture was stirred at 4 to 10°C for 2 hours.
  • a precipitate formed which was collected by filtration and washed with water.
  • the filter cake was dissolved in a mixture of ethanol (25 ml) and 2N aqueous sodium hydroxide solution (100 ml).
  • Polymeric 3,5-diiodo-L-thyronine (poly-3,5-LT_ - 18.4 g prepared in a similar manner to that described in Example 2) was dissolved in 33% aqueous diethylamine (185 ml).
  • a solution of potassium triiodide [82 ml of a solution prepared from iodine (26.2 g) , potassium iodide (67.8 g) and water (90 ml)] was added with stirring over 30 minutes. Stirring was continued for 15 minutes and water (111 ml) and then 2N hydrochloric acid were added to cause precipitation.
  • the brown precipitate was collected by filtration and the filter cake dissolved in a mixture of ethanol (1332 ml) and IN aqueous sodium hydroxide solutions (111 ml) .
  • the solution was filtered, heated to boiling and treated with 30% aqueous acetic acid until precipitation commenced.
  • the mixture was cooled in ice and the precipitate collected by filtration and washed with water.
  • the wet filter cake was placed in a freeze drying chamber in vacuo (less than 0.3 mm Hg) to freeze the cake via evaporative cooling. Sufficient heat was provided (shelf temperature 40°C) to reduce the moisture content to less than 0.1% in 24 hours. (Yield 24.6 g) .
  • the product was hydrolysed with acid and high performance liquid chromatography (HPLC) of the hydrolysed product showed the presence of 83.3% LT., 16.4% L 3 and less than 0.1% of 3,5-LT 2 indicating that the product was a polymer containing recurring units derived from LT 4 and L 3 (poly LT 4 /L 3 ) .
  • polymeric 3-iodo-L-thyronine (poly-3LT-. ) was diiodinated to give polymeric 3,5,5 '-triiodo-L-thyro ⁇ nine (poly-rLT,) in 96% yield.
  • Polymeric 3-iodo-L- thyronine was prepared in a similar manner to that described in Example 2 by polymerisation of 3-iodo-L- thyronine N-carboxyanhydride (3-LT -NCA) which was prepared in 93% yield in a similar manner to that described in Example 1.
  • Example 1 1
  • Boc-protected LT and glycine are prepared as described in Tam et al., Int. J. Peptide Protein Res., 21:57 (1983), and polymerized by standard sequential additions on polystyrene beads as an immobilized support. The following coupling sequence is used as described in Spatola, Amer. Biotech Lab., Dec. 14-22 (1984) .
  • Steps 7 through 18 are repeated 25 or more times to obtain a polymer of 50 or more residues in length.
  • the copolymer is isolated by cleavage from the resin using HF.
  • the copolymer formed by this reaction has alternating recurring units derived from LT 4 and glycine.
  • Polymeric 3,5-diodo-L-thyronine (0.715 g) was ground to a fine powder and dissolved with gentle warming in a mixture of dimethylformamide (8.6 ml), water (5.7 ml) and diethylamine (4.3 ml) and the solution was cooled to 5-10°C.
  • a solution of potassium triodide was prepared from iodine (31.5 g) and a 40% solution of potassium iodide in water (100 ml of solution) .
  • Four portions of the resulting solution (0.8 ml each) were added over 30 minutes. The reaction mixture was stirred overnight as the temperature rose to ambient and then poured into acetone (200 ml) .
  • Polymeric 3,5-diido-L-thyronine (1 g) was ground to a fine powder and dissolved with gentle warming in dimethylformamide (5 ml) .
  • a mixture of glacial acetic acid (2 ml) and iodine monochloride (0.8 g) was added over twenty minutes with rapid mixing and the resulting mixture heated to 60°C.
  • Glacial acetic acid (5 ml) and then water (12 ml) were added dropwise ⁇ nd the mixture was reheated to 60°C.
  • Potassium bisulphite (0.3 g) was added and the mixture cooled in ice. The resulting precipitate was collected by filtration and washed with water.
  • the washed solid was frozen on dry ice and lyophilised under vacuum (less than 0.3 mm Hg) using a shelf temperature of 35°C to give polymeric 3,3',5,5'- tetraiodo-L-thyronine (poly-LT . Yield 1.56 g.
  • the finely powdered iodothyronine polymer is blended to uniformity with corn starch, lactose, PVP and ascorbate, mixed into an aqueous paste with 1.0 ml H O and freeze dried (30° shelf temperature, 0.03 mm Hg) .
  • the resulting powder is mixed uniformly with talcum and pressed into tablets.
  • hypothyroid male rats which were 2 months old and had an average weight of 95 g were prepared by surgical removal of the thyroid gland. Six to eight weeks were allowed for clearance of endogenous thyroid hormones and rats were bled from the tail vein and serum levels of LT, and LT. were measured by radioimmunoassay (RIA) . Rats having high levels of LT. due to inadequate thyroidectomy were removed from the study. A control, untreated group of four thyroidectomized rats was used to test for thyroid remnant regeneration during the course of the experiment. The treatment group of six rats received 10 ⁇ g/day of the iodothyronine polymer (poly-T 4 /T,) prepared in Example 9 slurried in corn syrup orally by gavage.
  • poly-T 4 /T iodothyronine polymer
  • the sodium salt of 3,3' ,5,5'-tetraiodo-L-thyronine was suspended in water and dilute (IN) hydrochloric acid was added to give a pH of between 4 and 5. The mixture was shaken for 5 minutes and the solid formed was collected by filtration, washed with water and dried under vacuo at a temperature in the range 30-50°C. The solid was 3,3',5,5'-tetraiodo-L- thyronine.
  • 3,3',5,5'-Tetraiodo-L-thyronine (46.1 g) was suspended in tetrahydrofuran (400 ml) in a metal foil-wrapped vessel. The mixture was heated at 50-55°C under slightly reduced pressure and solvent (100 ml) was removed by distilltion. A further portion of tetrahydrofuran (100 ml) was added and the distillation repeated to collect a total of 200 ml of solvent. A solution of hexachlorodimethylcarbonate (12 g) in tetrahydrofuran (35 ml) was added at 55°C over a period of twenty minutes and the mixture heated at 55°C for 2 hours.
  • a sample (35 g) of the dried product was dissolved in a mixture of ethyl acetate (240 ml) and tetrahydro ⁇ furan (90 ml) with warming. The mixture was filtered through charcoal and the tetrahydrofuran removed by distillation under reduced pressure. Additional ethyl acetate (100 ml) was added and 100 ml of solvent was removed by distillation under reduced pressure. This addition/distillation cycle was repeated twice. The volume was then reduced to 50 ml by evaporation and the solution stored at 2°C for two hours. The resulting solid was collected by filtration, washed with ethyl acetate and dried in vacuo at 40°C.
  • the dried solid was dissolved in a mixture of ethyl acetate (170 ml) and tetrahydrofuran (90 ml) .
  • the solvent was removed by evaporation.
  • the residue was dissolved in ethyl acetate (100 ml) and the solvent removed by evaporation. This dissolution/evaporation cycle was repeated and the residue dissolved in ethyl acetate (100 ml).
  • the volume was reduced to 50 ml by evaporation and the solution stored at 2°C for two hours.
  • Example 24 A sample (50 microlitres) of one of these sodium methoxide solutions was added to each of the solutions of 3,3' ,5,5'-tetraiodo-L-thyronine N-carboxyanhydride and the resulting mixtures were stored at 48-50°C for 23 hours. In Example 24 a further portion (50 micro ⁇ litres) of the sodium methoxide solution was added after 1 hour. The mixtures were then stored at ambient temperature for 48 hours and the solid which had been formed was collected by filtration and dried at 40°C in vacuo to give dioxane-insoluble fractions of polymeric 3,3 ' ,5,5'-tetraiodo-L-thyronine.

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Abstract

Des polymères d'iodothyronine possédant une pluralité d'unités récurrentes dont la formula est (I), où A est iodo et B, C, et D sont indépendamment iodo ou H. Des polymères dans lesquels A et C sont iodo et B et D sont indépendamment H ou iodo, et dans lesquels sensiblement toutes les unités récurrentes sont des L-stéréoisomères, sont utiles au traitement de la déficience d'hormones thyroïdiennes. De préférence, on prépare les polymères par la polymérisation des N-carboxyanhydrides dont la formule est (III).
PCT/US1990/006213 1989-11-03 1990-10-31 Polymeres d'iodothyronine WO1991006569A1 (fr)

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US7514419B2 (en) 2003-11-19 2009-04-07 Metabasis Therapeutics, Inc. Phosphorus-containing thyromimetics
US10087285B2 (en) 2014-12-23 2018-10-02 Rutgers, The State University Of New Jersey Biocompatible iodinated diphenol monomers and polymers
US10130643B2 (en) 2005-05-26 2018-11-20 Metabasis Therapeutics, Inc. Thyromimetics for the treatment of fatty liver diseases
US10202490B2 (en) 2009-10-11 2019-02-12 Rutgers, The State University Of New Jersey Biocompatible polymers for medical devices
US10774030B2 (en) 2014-12-23 2020-09-15 Rutgers, The State University Of New Jersey Polymeric biomaterials derived from phenolic monomers and their medical uses
US11124603B2 (en) 2012-02-03 2021-09-21 Rutgers, The State University Of New Jersey Polymeric biomaterials derived from phenolic monomers and their medical uses
US11202789B2 (en) 2016-11-21 2021-12-21 Viking Therapeutics, Inc. Method of treating glycogen storage disease
US11472918B2 (en) 2012-02-03 2022-10-18 Rutgers, The State University Of New Jersey Polymeric biomaterials derived from phenolic monomers and their medical uses
US11707472B2 (en) 2017-06-05 2023-07-25 Viking Therapeutics, Inc. Compositions for the treatment of fibrosis
US11787828B2 (en) 2018-03-22 2023-10-17 Viking Therapeutics, Inc. Crystalline forms and methods of producing crystalline forms of a compound
US12102646B2 (en) 2018-12-05 2024-10-01 Viking Therapeutics, Inc. Compositions for the treatment of fibrosis and inflammation

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Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7829552B2 (en) 2003-11-19 2010-11-09 Metabasis Therapeutics, Inc. Phosphorus-containing thyromimetics
US7514419B2 (en) 2003-11-19 2009-04-07 Metabasis Therapeutics, Inc. Phosphorus-containing thyromimetics
US10925885B2 (en) 2005-05-26 2021-02-23 Metabasis Therapeutics, Inc. Thyromimetics for the treatment of fatty liver diseases
US10130643B2 (en) 2005-05-26 2018-11-20 Metabasis Therapeutics, Inc. Thyromimetics for the treatment of fatty liver diseases
US11118011B2 (en) 2009-10-11 2021-09-14 Rutgers, The State University Of New Jersey Biocompatible polymers for medical devices
US10202490B2 (en) 2009-10-11 2019-02-12 Rutgers, The State University Of New Jersey Biocompatible polymers for medical devices
US11124603B2 (en) 2012-02-03 2021-09-21 Rutgers, The State University Of New Jersey Polymeric biomaterials derived from phenolic monomers and their medical uses
US12030983B2 (en) 2012-02-03 2024-07-09 Rutgers, The State University Of New Jersey Polymeric biomaterials derived from phenolic monomers and their medical uses
US11472918B2 (en) 2012-02-03 2022-10-18 Rutgers, The State University Of New Jersey Polymeric biomaterials derived from phenolic monomers and their medical uses
US10087285B2 (en) 2014-12-23 2018-10-02 Rutgers, The State University Of New Jersey Biocompatible iodinated diphenol monomers and polymers
US10266647B2 (en) 2014-12-23 2019-04-23 Rutgers, The State University Of New Jersey Biocompatible iodinated diphenol monomers and polymers
US11649203B2 (en) 2014-12-23 2023-05-16 Rutgers, The State University Of New Jersey Polymeric biomaterials derived from phenolic monomers and their medical uses
US10774030B2 (en) 2014-12-23 2020-09-15 Rutgers, The State University Of New Jersey Polymeric biomaterials derived from phenolic monomers and their medical uses
US11202789B2 (en) 2016-11-21 2021-12-21 Viking Therapeutics, Inc. Method of treating glycogen storage disease
US11707472B2 (en) 2017-06-05 2023-07-25 Viking Therapeutics, Inc. Compositions for the treatment of fibrosis
US11787828B2 (en) 2018-03-22 2023-10-17 Viking Therapeutics, Inc. Crystalline forms and methods of producing crystalline forms of a compound
US12227533B2 (en) 2018-03-22 2025-02-18 Viking Therapeutics, Inc. Crystalline forms and methods of producing crystalline forms of a compound
US12102646B2 (en) 2018-12-05 2024-10-01 Viking Therapeutics, Inc. Compositions for the treatment of fibrosis and inflammation

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PT95773A (pt) 1991-09-13
ZA908802B (en) 1991-06-26
IE903851A1 (en) 1991-05-08
AU6639790A (en) 1991-05-31
CA2072613C (fr) 2002-02-05
YU207990A (sh) 1993-05-28
PL287594A1 (en) 1992-01-27
CA2072613A1 (fr) 1991-05-04
IL96226A0 (en) 1991-08-16

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