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WO1996002531A1 - Chelateur du fer hydrosoluble efficace oralement - Google Patents

Chelateur du fer hydrosoluble efficace oralement Download PDF

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Publication number
WO1996002531A1
WO1996002531A1 PCT/US1995/008519 US9508519W WO9602531A1 WO 1996002531 A1 WO1996002531 A1 WO 1996002531A1 US 9508519 W US9508519 W US 9508519W WO 9602531 A1 WO9602531 A1 WO 9602531A1
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WIPO (PCT)
Prior art keywords
compound
pih
dpa
acid
iron
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PCT/US1995/008519
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English (en)
Inventor
Neil Lewis
Vithal Patel
Jacek Terpinski
Robert Bliss
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Jacobus Pharmaceutical Co Inc
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Jacobus Pharmaceutical Co Inc
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Priority to PCT/US1995/008519 priority Critical patent/WO1996002531A1/fr
Priority to US08/765,369 priority patent/US5834492A/en
Publication of WO1996002531A1 publication Critical patent/WO1996002531A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/86—Hydrazides; Thio or imino analogues thereof

Definitions

  • This invention relates to the synthesis, isolation and novel pharmaceutical formulation of a chemically distinct and pharmaceutically unique class of compounds, namely pyridoxal isonicotinoyl hydrazone polyprotic salts, that have heretofore been unattainable due to the complex chemical characteristics of the free base precursor, pyridoxal isonicotinoyl hydrazone (PIH).
  • PHI pyridoxal isonicotinoyl hydrazone
  • These compounds are generally crystalline and generally free of associated water.
  • the solubility and stability properties of these salts makes them particularly suitable as orally administered chelators that can complex and remove pharmacologically significant levels of iron at dosages that are pharmaceutically meaningful.
  • PIH pyridoxal isonicotinoyl hydrazone
  • Literature reports have specifically referred to the dihydrate (D. Libermann, N. Rist, F. Grumbach, M. Moyeux, B. Gauthier, A. Rouaix, J. Maillard, J. Himbert and S. Cals. Bull. Soc. Chim. Fr. 1430-43 (1954)), a monohydrate (H.C. Beyerman, J.S. Bontekoe, W.J. Van der Burg and W.L.C. Veer. Reel. Trav. Chim. Pavs-Bas. 73:109-17 (1954)), (S. Avramovici- Grisaru, supra) the monohydro-chloride hydrate and the 0.5 hydrochloride and the monohydrochloride (J.
  • Example 1 of Bernstein et al supra patent closely parallels, but is not totally identical with the Archer et al su p ra method which yields the intermediate manganous complex.
  • solubility characteristics of such crystalline polyprotic polycharged species have not been defined with regard to their potential for efficacious pharmaceutical oral activity despite the recognition that PIH itself was potentially useful as an orally effective chelator, specifically for iron overload.
  • X is suitably chloride, bromide, iodide, ethanesulfonate, hydrogen succinate or hydrogen sulfate
  • H 2 Y is suitably dihydrogen sulfate, or 1 ,2-ethanedisulfonic or any other pharmaceutically acceptable diprotic sulfonic acid.
  • X is chloride to yield the anhydrous PIH dihydrochloride (hereinafter abbreviated as PIHDH (la) or PIH.2HCI can be used interchangeably).
  • associated water is intended to encompass any elements of water revealed by analysis. Such elements comprise, but are not limited to absorbed water, water occluded in the crystal lattice, water of hydration or crystallization or similar mode of association, whether stoichiometric or otherwise.
  • compositions for reducing the level of iron in the cells of living subjects in need of such reduction comprising a reductively effective amount of PIH.DPA (I), suitably PIHDH, and an orally administrable carrier. It is especially desirable to provide these compositions in a dosage form formulated for administration as enterically coated granules, tablets or capsules.
  • the invention also includes a method of reducing the level of iron in the cells of living subjects in need of such reduction comprising administering to said subject a reductively effective amount of PIH.
  • qDPA suitably PIHDH.
  • Such methods include administering to said subject a reductively effective amount of these materials in a dosage form formulated for administration as enterically coated granules, tablets or capsules or else in conjunction with sufficient pharmaceutically acceptable buffer to adjust the pH of the stomach of said subject to a level that will minimize acid hydrolysis of the PIH moiety while maintaining a suitable degree of water solubility. Specifically, this requires a pH adjustment of not less than about 3 and not more than approximately a pH of 8.
  • the invention also includes a method of synthesizing the compounds of Formula I which comprises the steps of reacting
  • salt (IV) which is a hemiacid salt where 0.5 DPA is a monoprotic acid with an anhydrous alkali metal hydroxide M.OH, suitably sodium or potassium hydroxide, in the said anhydrous alkanol to yield CH 2 OH
  • the M. salt is removed and the above anhydrous alkanolic solution of free base (V) treated with at least two equivalents of anhydrous DPA in said anhydrous alkanol to yield the desired polyprotic acid salt (I).
  • DPA is a diprotic acid and q in Formula I is 2, then at least four (4) equivalents, i.e., two (2) relative molecules of the acid are needed.
  • DPA there may be used any strong mono- or diprotic pharmaceutically acceptable acid, whose salts are orally administrable and which is of sufficient strength to diprotonate the PIH molecule.
  • hydrohalic acids such as succinic acid will form, say a dihydrogen-disuccinate.
  • the thus produced hemihydrochloride salt is reacted with at least two equivalents of anhydrous hydrochloric acid in said anhydrous alkanol to yield the desired dihydrochloride salt (IA).
  • PIHDH IA
  • certain other PIH.DPA salts free of associated water have heretofore unreported high levels of water solubility so as to make them pharmaceutically useful compositions of matter for oral administration and absorption into subjects suffering from overload of iron; said PIHDH by virtue of its water solubility provides the iron chelator PIH in a solubilized form which is 450 times more water soluble than PIH itself and which preserves its ability to complex iron in aqueous solutions in vitro and in vivo.
  • the previously unreported pyridoxal isonicotinyl hydrazone hydrochloride 1.5 hydrate (VI) is prepared by permitting a saturated aqueous solution of PIHDH (IA) to stand at ambient temperature whereby crystals of said monohydrochloride 1.5 hydrate are precipitated.
  • PIH.DPA especially PIHDH is most suitable for absorption at a pH of 6-7 with virtually little to virtually no decomposition when buffered above 3.0 to 7.0.
  • Such stabilizing of the pH of the environment can be carried out in different ways.
  • Increasing the pH of the stomach prior to or concurrently with administra-tion of the invention can be accomplished with virtually any pharmaceutically acceptable buffer including, for example a phosphate buffer, a citrate buffer, the pharmaceutically acceptable amino acid glycine, or any combination of buffering agent so as to stabilize the pH of the environment to raise the acidic pH which causes decomposition of the drug.
  • This invention demonstrates that adjustment of stomach pH to 3-4 still allows sufficient concentration of the chelator to be absorbed as to allow for increased iron excretion from patients afflicted with iron overload (Table III).
  • a protective coating to delay the dissolution of the active principle until after the drug has passed through the stomach and is introduced into the upper intestinal tract where the pH is sufficiently high to begin dissolution of the protective enteric coating. Once such dissolution begins, the highly water soluble drug rapidly goes into solution in an environment where it tends to be in a form that is both more stable to environmental pH and less highly ionized - which increases the ratio of readily absorbed form of the drug to the highly charged fully protonated form.
  • the first approach includes the provision of a buffer sachet or packet with sufficient number of milliequivalents of buffer to effectively raise the pH of the stomach.
  • Other standard antacids could be used as well and could include phosphate-citrate buffers ⁇
  • a combined buffered tablet could also be given.
  • a chewable drug/buffer combination would be unlikely to be well received by users.
  • Figure 1 is a plot of in vivo biliary excretion of iron after oral administration of saline versus iron chelators.
  • Figure 2 is an infrared absorption spectrum (KBr, pellet) of PIH dihydrochloride (anh) (i.e. PIH.2HCI).
  • Figure 3 is an infrared absorption spectrum (KBr, pellet) of PIH monohydrochloride trihemihydrate (i.e. PIH.HCI 1.5 H 2 O).
  • Figure 4 is an infrared absorption spectrum (KBr, pellet) of PIH hemihydrochloride (anh) (i.e. PIH.0.5 HCI).
  • Figure 5 is an infrared absorption spectrum (KBr, pellet) of PIH free base (anh) (i.e. PIH).
  • Figure 6 is an infrared absorption spectrum (KBr, pellet) of PIH free base hydrate (i.e. PIH.H 2 O).
  • Figure 7 is an infrared absorption spectrum (KBr, pellet) of PIH hemidihydrogen sulfate) (i.e. PIH. 0.5 HSO 4 H).
  • Figure 8 is an infrared absorption spectrum (KBr, pellet) of PIH di(dihydrogen sulfate) (i.e. PIH. 2HSO 4 H).
  • Figure 9 is an infrared absorption spectrum (KBr, pellet) of PIH dihydrogen sulfate (i.e. PIH. HSO 4 H).
  • Figure 10 is an infrared absorption spectrum (KBr, pellet) of PIH dihydro-bromide (i.e. PIH.2HBr).
  • Figure 11 is an infrared absorption spectrum (KBr, pellet) of PIH di(hydrogenethanesulfonate) (i.e. PIH.2EtSO 3 H).
  • Figure 12 is an infrared absorption spectrum (KBr, pellet) of PIH di(hydrogen nitrate) (i.e. PIH.2HNO 3) .
  • Figure 13 is an infrared absorption spectrum (KBr, pellet) of PIH dihydrogen disuccinate (i.e. PIH.2(CH 2 CO 2 H) 2 ).
  • Figure 14 is an infrared absorption spectrum (KBr, pellet) of PIH tri- hydrogenphosphate (i.e. PIH.H 3 PO 4 ).
  • Figure 15 is an infrared absorption spectrum (KBr, pellet) of PIH ise- thionate (i.e. PIH.HO(CH 2 ) 2 SO 3 H).
  • Figure 16 is a Table showing solubilities of various PIH salts
  • Figure 17 is a Table showing in vivo biliary iron excretion in test animals.
  • Figure 18 is a Table showing Iron excretion in Iron Overload Patients DESCRIPTION OF THE PREFERRED EMBODIMENTS
  • anhydrous DPA such as fuming sulfuric acid
  • anhydrous DPA such as fuming sulfuric acid
  • anhydrous DPA such as fuming sulfuric acid
  • sulfuric acid there may be utilized other acids such as hydrochloric, hydrobromic, hydriodic, ethane sulfonic, trichloracetic or toluene sulfonic acids or similar strong acids capable of forming the corresponding anhydrous diprotic salt.
  • the PIH.2DPA is required, such as the PIH.2H 2 SO 4 , 2 equivalents of acid, i.e., sulfuric acid are added.
  • PIHDH is synthesized in high purity in our process in > 95% yield in the following manner.
  • SDA specially denatured
  • ethyl alcohol modifications of the previously reported syntheses of PIH from isonicotinic acid hydrazide (II, isoniazid; INH) and pyridoxal hydrochloride (III, 3-hydroxy-5-hydroxymethyl-2- methyl-4-pyridinylcarboxaldehyde hydrochloride)
  • the hemihydrochloride is generated in situ. This is then reacted in situ with a minimum of 2 equivalents of anhydrous hydrogen chloride in anhydrous ethyl alcohol.
  • PIHDH demonstrates better water solubility than the free base and its related hydrated species at 25°C.
  • the HCI.1.5 hydrate is isolated as an equilibrium product from concentrated aqueous solutions of PIHDH.
  • Use of a strong inorganic acid such as H 2 SO 4 in aqueous media can lead to decomposition of the product to pyridoxal hydrazone which can be readily seen, but by substituting a nonprotonic solvent such as ether (THF for example), other pure salts can be isolated.
  • PIH.qDPAs when free of associated water, provides unique and highly useful crystalline forms of PIH as polyprotic salts which can become bioavailable rapidly once they are released in the gastro- intestinal tract.
  • PIH.2HCI is specially prepared in a formulation for oral administration as enteric coated layered granules that protect the PIH.2HCI from extended exposure to stomach acid.
  • enteric coated layered granules that protect the PIH.2HCI from extended exposure to stomach acid.
  • the extensive solubility at higher pH makes this formulation suitable for oral use in capsules, coated tablets, or when given directly as a suspension of granules in an appropriate liquid.
  • any other PIH. qDPA salt or derivative thereof can be formulated to protect the active chelating species from decomposition in stomach acid.
  • PIH was first synthesized by Sah supra. S. Archer and M.E. Auerbach, received US Patent 2,775,598 for a method of making PIH via a manganous complex.
  • US Patent 2,810,725 to Bernstein is the second patent directed to yet another synthesis of PIH. This synthesis is based on the formation of an intermediate stated in this latter patent to be pyridoxal isonicotinoyl hydrazone sulfate (hereinafter PIH.S"). The reaction of PIH.S" with hydrochloric acid and barium hydroxide is stated to yield pyridoxal isonicotinoyl hydrazone (hereinafter PIH"). There is further disclosure of the conversion of PIH" to the corresponding mono- and dihydrochlorides. As summarized above, and reported in detail in the experimental section below, the findings of applicants herein do not support the disclosure of US Patent 2,810,725.
  • Example 2 of US 2,810,725 discloses that PIH is synthesized from the product obtained above, "prepared as in Example 1 " by treatment of a solution of his first product, in a two molar excess of hydrochloric acid, with 1 mole equivalent of barium hydroxide. As discussed above this would be expected to produce the yellow-brown manganese complex of PIH rather than free PIH. This is precisely what applicants found and we were able to confirm again by elemental analysis. Thus, the disclosure of synthesis in US 2,810,725 of the PIH sulfate and of PIH by the methods described appears unsupported by experimental fact.
  • Example 6 of US 2,810,725 were undertaken using equimolar reaction conditions in an effort to duplicate the disclosure of that patents. There was utilized PIH synthesized independently and structurally confirmed beforehand since no reproducible source of PIH was seen to be disclosed in the given in US 2,810,725.
  • PIH Monohydrochloride The PIH hydrochloride preparation disclosed in Example 6 of the patent uses a 1 :1 molar ratio of PIH to ethereal HCI. The preparation recites " to a solution of 28.6 grams (0.1 M) pyridoxal isonicotinoyl hydrazone in 5 500 cc absolute ethanol is added 25 cc 4 N (0.1 M) ethereal HCI. After the addition of 500 cc dry ether, the hydrochloride precipitates out. It is filtered off and recrystallized from a mixture of absolute ethanol and ether.”
  • PIH has very limited solubility in water and ethanol, and in fact, to 0 solubilize 28.6 grams of PIH would require 30,000 cc of absolute ethanol. Nevertheless, the aforesaid molar concentrations were used to produce a suspension to which was added the ethereal HCI solution. The "product” was filtered and an attempt was made to recrystallize it according to the disclosure - - which required the volume of 2.5 liters of ethanol per 1 gram 5 of recovered solid (a ratio of 2000:1 IID.The product thus obtained failed to analyze for PIH monohydrochloride or any of its hydrates or solvates.
  • Example 6 of Patent No. 2,810,725 the syntheses of other pyridoxal isonicotinoyl hydrazone acid-addition salts are recited but it is apparent that the methodology, as described - - even when utilizing PIH synthesized by a provable route and the structure of said PIH confirmed prior to derivatization - - do not substantiate any of the known solubility properties of PIH or more specifically, its polyacid addition salts.
  • the recitations, in Example 6, concerning the recrystallization of the mono and dihydrochloride salts of PIH do not support the structures allocated to them.
  • the purpose of the present invention was to enhance the immediate water solubility of the active principle and thus develop an effective and efficient way to deliver the pharmacologically active chelating species, which has excellent partition in lipids.
  • the enhanced solubility thus encourages absorption from the gastrointestinal tract and the proper enteric formulation carries the active principle through the stomach where it eliminates exposure to aqueous acid which can decompose PIH and PIHDH.
  • Some decomposition has been observed for PIHDH in strongly acidic medium but the PIHDH is more stable with no degradation at pH 6.8, 17.7% at pH 2.78 and 44.1 % at pH 1.29 after three hours.
  • FIGURE 1 The superior in vivo efficacy of the highly water soluble PIHDH can be seen in FIGURE 1 and the table in Figure 17. This demonstrates that the
  • mice Male Sprague-Dawley rats weighing approximately 200 g were housed in cages and randomly assigned to three groups containing at least 6 animals. The groups received (i) one ml of saline alone administered by gavage (ii) 1 mL saline with PIH as the free base, 100 mg/kg body weight, added just prior to administration by gavage and (iii) 1 mL saline with PIHDH, 100 mg/kg body weight, added just prior to administration by gavage. The doses of chelators tested are chosen to provide direct comparisons with previous assay data. Animals receiving the chelators or saline by gavage receive doses 45 minutes prior to surgery.
  • the active compounds of this invention are administered orally in such a manner that degradation in the stomach is avoided or substantially reduced. This may be done by administration as enterically coated dosage forms such as granules, tablets or capsules. Alternatively, where such coating is not used, the compounds are administered either together with or after preadministration of a buffer to increase the pH of the stomach into the range of above 3 to about 7.5, suitably about 4 to 7.
  • a buffer to increase the pH of the stomach into the range of above 3 to about 7.5, suitably about 4 to 7.
  • Such buffers are well known to include single or multiple components such as those listed in the US Pharmacopoeia XXII, specifically for example, ammonium, potassium and/or sodium salts of phosphoric acid, in con-junction with citric acid.
  • a pharmaceutically acceptable antacid such as aluminum and/or magnesium hydroxide or calcium carbonate or glycine USP/NF sufficient to neutralize the normally present 0.1 N HCI in the 200 to 600 ml of stomach fluids (20 to 60 meq of base).
  • a specific example of phosphate-citrate buffer, pH 6.8, would result from 9.1 ml of 0.1 M citric acid combined with 40.9 ml 0.2M dibasic sodium phosphate solutions.
  • a further example is prior adminis-tration of 3.0 grams of glycine (Aminoacetic acid) USP/NF which demonstrably raises the pH of the stomach contents with 100 mL of water to pH 3.0 to 4.0 as measured by a clinically accepted pH indicator string test (for example, Gastro-test device for rapid measurement of gastric pH and screening for esophageal and gastric bleeding, US Patent Nos. 3,683,890-3,528,429, HDC Corp., San Jose, CA 95131 ).
  • glycine Aminacetic acid
  • Table III shows the total daily iron excretion, measured in mg/day, in iron overloaded patients after a resting period.
  • Five human subjects were administered PIHDH (PIH(HCI) 2 ) as either enteric coated granules at 546 mg three times daily representing the lowest dose tested at 20 mg/kg per day.
  • three subjects were also given 546 mg capsules of the same active chelating drug, three times daily, for six days immediately after administration of 3.0 grams of glycine USP/NF to bring the stomach pH approximately to 3-4 as measured by gastric string pH test. All tests were performed on patients kept in hospital and excreta were collected with total iron excretion determined by laboratory extraction methods comparable to those reported for other in vivo testing using the methods of Brittenham supra.
  • PIH. qDPA suitably as the PIHDH is utilized to deliver the equivalent of 250-1500 mg of chelator up to three times daily depending upon the speed of absorption of the drug and the severity of the clinical symptoms requiring chelation therapy. This is also controlled by enteric coating which can slow dissolution and provide a delayed release formulation.
  • the target dosage is 15-60 mg/kg total per day of active chelator which can complex sufficient iron or other target ions so as to be pharmaceutically effective.
  • a chemical reactor system fitted with an efficient reflux condenser and efficient mechanical stirrer, is charged with 27.2 kg of anhydrous ethyl alcohol and 1000 g. (7.30 Mol) of isoniazid (II) and the solids fully dissolved by gradual heating and stirring. Pyridoxal Hydrochloride (III; 1651 g., 7.76 Mol) is then added with stirring and the mixture refluxed for one hour during which time the highly insoluble orange colored crystalline PIH-0.5HCI is formed. Stirring is continued for one hour and 1900 mL of anhydrous ethyl alcohol saturated with 830 g. of HCI gas is added to the mixture.
  • a saturated water solution of PIHDH (63 mg/mL) when allowed to stand undisturbed for one hour forms white crystals of the heretofore unreported hydrochloride-1.5 hydrate of PIH which retains water solubility of 34 mg/mL, mp 253°C (decomposition).
  • I.R. (KBr Pellet): 3432, 3251 , 2079, 1687, 1550, 1368, 1268, 1 156, 1062, 1026, 1009, 691 cm 1
  • Pyridoxal isonicotinoyl hydrazone free base (as an anhydrous intermediate for diprotic salts).
  • a cooled suspension of pyridoxal isonicotinoyl hydrazone 0.5 hydrochloride (254 g., 0.72 Mol) formed in Example 1. in 2.7 liter of water is added slowly with stirring a solution of 14.4 g (0.36 Mol, 1 equivalent) anhydrous sodium hydroxide in 150 mL water.
  • the resultant suspension of PIH hydrate is filtered, dried and dissolved in 9 liters of hot anhydrous methanol.
  • the solution is allowed to cool thus precipitating the anhydrous pyridoxal isonicotinoyl hydrazone as the free base (160 g., 77.7% first crop).
  • Example 3 To the free base prepared in Example 3 were added 2 equivalents of anhydrous ethane sulfonic acid in absolute ethanol. The title product precipitated from the reaction mixture as off white crystals m.p. 182-4°C (dec). I.R. (KBr Pellet): 3446, 2661 (vbr), 2070, 1698, 1563, 1303, 1272, 1255, 1187, 1149, 1032, 996, 751 , 743, 582, 530 cm 1
  • Example 3 To the free base prepared in Example 3 was added 1 mole of fuming sulfuric acid in anhydrous ethanol. The title product precipitated from the reaction mixture as off white crystals m.p. 200-205°C (dec). I.R. (KBr Pellet): 3236, 3088, 2660, 2069, 1685, 1638, 1598, 1579, 1307, 1282, 1 158, 1 136, 1093, 1055, 985, 966, 882, 852, 746, 607 Cm '1 Calculated for C 14 H 14 N 4 O 3 .H 2 SO 4 .
  • Example 3 To the free base prepared in Example 3 were added 2 moles of fuming sulfuric acid in tetrahydrofuran. The title product precipitated from the reaction mixture as off white crystals m.p. 181-183°C . I.R. (KBr Pellet): 3372, 3106, 3006, 2825, 1662, 1623, 1559, 1479, 1257, 1204, 1176, 1160, 1058, 1027, 880, 857, 581 cm '1 Calculated for C 14 H 14 N 4 O 3 .2H 2 SO 4 .
  • Example 3 To the free base prepared in Example 3 was added 1 mole of fuming sulfuric acid in tetrahydrofuran. The title product precipitated from the reaction mixture as off white crystals m.p. 200-205°C (dec).
  • Example 3 To the free base prepared in Example 3 were added (340 mg,1.2mM) was added 1.0 ml of a 1.2 molar solution of isethionic acid (1.2 mMoOin ethanol and 20ml of methanol. The mixture was heated to boiling wherein all solids were soluble. The solution was allowed to cool to 25°C and the resultant precipitate filtered off, washed with ethanol (1 x 3ml) and the orange solid vacuum dried to give 420mg (100%) of the title product with water solubility of 2.7ml/mg and solubility in 0.1 NHCI-36mg/ml, mp 203- 205°C. 2 equivalents of anhydrous ethane sulfonic acid in absolute ethanol. The title product precipitated from the reaction mixture as off white crystals m.p. 203-5°C (dec).
  • the disclosure calls for a solution of 57.2 mg pyridoxal isonicotinoyl hydrazone per 1 cc of absolute ethanol (28.6 g, 100 mMol in 500 cc) to which is then added an equimolar amount (100 mMol) of 4 N ethereal HCI.
  • Example 9 Pyridoxal isonicotinoyl hydrazone dihydrochloride Since Example 9 above did not yield PIH, analytically pure PIH was synthesized by the method of Sah supra. The synthesis of PIH dihydrochloride was attempted under the experimental conditions of molar concentration dis-closed in Example 6 of U.S. PATENT 2 810 725.
  • the disclosure calls for a solution of 28.6 mg pyridoxal isonicotinoyl hydrazone per 1 cc of absolute ethanol (28.6 g, 100 mMol in 500 cc) to which is then added a twice equimolar amount (200 mMol) of 4 N ethereal HCI.
  • Nonpareils (support spherules) 20/40 mesh 60-80% Povidone K32 5-10%
  • the PIH.DPA drug is combined with sufficient ethanol to make it into a slightly damp thick paste which is further mixed with povidone and mechanically applied as a layered coating over a spherical support of defined mesh size.
  • the supports themselves, if desired, are usually pharmacologically inactive, but an active support may also be utilized.
  • the spherical matrix could be an acid resistant, biocompatible polymer. Examples are polycarbonate, polyethylene, teflon, microcrystalline cellulose, or other palstics. Other biocompatible polymers can also be used.
  • Enteric polymers and plasticizers are combined in ethanol to form a solution which is carefully sprayed over the support as a film which covers the active drug and protects it from premature dissolution in an environmental pH which is un-favorable for best absorption.
  • the ensuing product is mechanically dried while preserving the uniformity of the enteric coating.
  • PIH.2HCI (or other PIH.qDPH) 1.75 Kg 25.0% (20-30) Povidone K32 0.645 Kg 9.2% (8-10)
  • Nonpareils (support spherules) 20/40 mesh 2.60 Kg 37.1 % (32-40)
  • the enteric coatings are similarly applied using the same technology as in Example 12, for example ethanol, Povidone, PIH.2HCI are appropriately combined and diluted with further pharmaceutically acceptable alcohol and used to coat the nonpareils (beads). Proportionally larger amounts to 100 kg PIH.2HCI are readily prepared by this method.
  • the enteric layer preparation for example, would consist of ethanol, acetyl triethylcitrate, Talc (USP), Eudragit L100, and the material appropriately diluted to a predetermined weight of 7.0 kg.

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Abstract

L'invention concerne des dérivés de diacides diprotonés de la pyridoxal isonicotinoyle hydrazone (PIH) de la formule (I) ainsi que leur synthèse. Dans cette formule, q est 1 ou 2, DPA correspond à 2 moles d'un acide monoprotonique HX ou à 1 mole d'un acide diprotonique H2Y, où X est un anion monovalent, Y est un anion divalent et HX et H2Y sont tous deux des acides acceptables sur le plan pharmaceutique. Les propriétés uniques de la molécule PIH.DPA, sa grande solubilité dans l'eau et son acceptabilité pharmaceutique la rendent particulièrement utile pour la réalisation de formes galéniques orales. L'invention concerne en outre des procédés d'utilisation de ces composés cristallins chimiquement uniques que l'on peut isoler tels que PIH.2HCl, comme agents chélateurs à usage pharmaceutique. Enfin, l'invention concerne des formulations pharmaceutiques destinées spécifiquement à réduire la surcharge en fer et en métaux similaires se prêtant à une chélation, chez des sujets présentant une telle surcharge.
PCT/US1995/008519 1994-07-14 1995-07-10 Chelateur du fer hydrosoluble efficace oralement Ceased WO1996002531A1 (fr)

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PCT/US1995/008519 WO1996002531A1 (fr) 1994-07-14 1995-07-10 Chelateur du fer hydrosoluble efficace oralement
US08/765,369 US5834492A (en) 1995-07-10 1995-07-10 Water soluble orally effective iron chelator

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Application Number Priority Date Filing Date Title
US27523594A 1994-07-14 1994-07-14
US08/275,235 1994-07-14
PCT/US1995/008519 WO1996002531A1 (fr) 1994-07-14 1995-07-10 Chelateur du fer hydrosoluble efficace oralement

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WO1996002531A1 true WO1996002531A1 (fr) 1996-02-01

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PCT/US1995/008519 Ceased WO1996002531A1 (fr) 1994-07-14 1995-07-10 Chelateur du fer hydrosoluble efficace oralement

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998012094A1 (fr) * 1996-09-20 1998-03-26 Jiangsu Goodbaby Group, Inc. Poussette
FR2764290A1 (fr) * 1997-06-04 1998-12-11 Nihon Bayer Agrochem Kk Derives d'hydrazide d'acide isonicotinique
US6589966B1 (en) 1998-03-18 2003-07-08 Wake Forest University Health Sciences Cytotoxic metal chelators and methods for making and using same

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2775598A (en) * 1955-04-14 1956-12-25 Sterling Drug Inc Process of preparing pyridoxal isonicotinoylhydrazone and intermediate used therein
US2810725A (en) * 1954-12-20 1957-10-22 Olin Mathieson Pyridoxal derivatives of isonicotinic acid hydrazide

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2810725A (en) * 1954-12-20 1957-10-22 Olin Mathieson Pyridoxal derivatives of isonicotinic acid hydrazide
US2775598A (en) * 1955-04-14 1956-12-25 Sterling Drug Inc Process of preparing pyridoxal isonicotinoylhydrazone and intermediate used therein

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
BIRTH DEFECTS, Volume 23, Number 5B, issued 1988, WEBB et al., "Pyridoxal Isonicontinoyl Hydrazone (PIH): A Promising New Iron Chelator", pages 63-70. *
J. PHARM. EXP. THER., Volume 221, No. 2, issued 1982, JOHNSON et al., "An in Vivo Evaluation of Iron-Chelating Drugs Derived from Pyridoxal and Its Analogs", pages 399-403. *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998012094A1 (fr) * 1996-09-20 1998-03-26 Jiangsu Goodbaby Group, Inc. Poussette
FR2764290A1 (fr) * 1997-06-04 1998-12-11 Nihon Bayer Agrochem Kk Derives d'hydrazide d'acide isonicotinique
US6589966B1 (en) 1998-03-18 2003-07-08 Wake Forest University Health Sciences Cytotoxic metal chelators and methods for making and using same

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