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    • 专利摘要:
    Procedure for the preparation of pirionium pamoate and its crystalline forms. The present invention relates to a process for the preparation of pyrvionium pamoate, which comprises reacting the pyrvionium methylsulfate salt of formula (II) with disodium pamoate of formula (III), in the presence of a base; to processes for the preparation of crystalline form A and crystalline form III of pyrvionium pamoate; as well as to a process for the purification of crystalline form III. It also refers to the crystalline form A and III of pirvinium pamoate and to the pharmaceutical compositions containing them. (Machine-translation by Google Translate, not legally binding)
    公开号:ES2689371A1
    申请号:ES201700479
    申请日:2017-03-29
    公开日:2018-11-13
    发明作者:Jose Luis Del Rio Pericacho；Josep Martí Via；Antonio De Padua CÁNOVAS PAREDES
    申请人:Urquima SA；
    IPC主号:
    专利说明:

    DESCRIPTION

    Procedure for the preparation of pyrvinium pamoate and its crystalline forms.

    Background of the invention 5

    The present invention relates to a new process for the preparation of pyrvinium pamoate and a process for its purification. It also refers to new crystalline forms of pyrvinium pamoate and procedures for its preparation, as well as the pharmaceutical composition that contains them. 10

    State of the art

    The pyrvinium pamoate salt is the name of the compound (E) -6-10 (dimethylamino) -2- [2- (2,5-dimethyl-1-phenyl-1H-pyrrole-3-yl) pamoate salt compound. ethenyl] -1-methyl quinolinium of formula (I) whose chemical structure is as follows:



    The pyrvinium pamoate salt of formula (I) (hereafter referred to as "20 pyrvinium pamoate") is an inhibitor of NADH-fumarate reductase (NADH-FR) activity in the anaerobic respiratory chain in parasitic worm mitochondria , and therefore, it is effective against parasitic nematodes, including the nematodes of the Enterobius and Stronglyloides genera. It is indicated as an anthelmintic drug for the treatment of enterobiosis caused by Enterobius vermicularis. 25

    United States patent US2925417 describes several processes for the preparation of pyrvinium pamoate. These procedures are mainly based on the preparation of pyrvinium pamoate from simple pyrvinium salts, such as for example iodide and chloride salts. On the other hand, PCT patent application WO 2006/078754 describes the preparation of the pyrvinium phosphate salt and the pyrvinium sulfate salt from pyrvinium pamoate.

    The different solid forms of a pharmaceutically active ingredient may have different characteristics, and offer certain advantages, for example, with respect to its stability, bioavailability, ease of formulation, ease of administration, among others. Since some solid forms are more suitable for one type of formulation, and other forms for other different formulations, the development of new solid forms makes it possible to improve the characteristics of the pharmaceutical formulations that comprise them. In addition, depending on the therapeutic indications, one or another pharmaceutical formulation may be preferred. 40

    Especially desirable improvements / advantages of the new polymorphic forms would include, for example, better stability, fluidity, solubility, traceability, or compressibility, improvement of physical-chemical properties in order to facilitate their manufacture or formulation, to improve absorption. and / or bioavailability, being able to obtain easily with more constant physicochemical properties, which allows greater flexibility while formulating, or facilitating its formulation, better dispersibility properties, allowing better rates
    of dispersion, especially if they are dispersed in a surrounding physiological aqueous medium, or by reducing hygroscopicity, allowing new routes of administration.

    Therefore, there is a need to develop a more economical and more easily scalable process for the preparation of the pyrvinium pamoate and, in particular, for the preparation of solid forms of the pyrvinium pamoate.

    Brief Description of the Invention

    The inventors have found a new process for the preparation of pyrvinium pamoate which comprises the use of the pyrvinium methylsulfate salt of formula (II) as a starting material and which has several advantages, especially in terms of yields, lower costs. of the procedure, environmental impact, and at the same time allow a simple industrialization.
     fifteen
    An advantage of the process of the present invention is that it avoids the use of unsuitable reagents such as for example halogenated alkanes. In addition, the process of the invention allows the use of a low amount of pyrvinium methylsulfate of formula (II) with respect to the amount of disodium pamoate. This has a clear impact on the purity of the product obtained. Therefore, another advantage of the process lies in the fact that pyrvinium pamoate can be obtained with high yields and high purity, and therefore, the purification of pyrvinium pamoate can be simplified or even avoided. which results in a simple and scalable procedure at the industrial level.

    The process can also comprise the preparation of a new crystalline form of pyrvinium pamoate, called Crystalline Form III which is obtained with high yields and high purity. The preparation of this crystalline form also has a clear impact on the purity of the product obtained. Finally, the process can also comprise additional purification steps that take place with the formation of a new crystalline form of the pyrvinium pamoate, called Crystalline Form A, which not only reduces the amount of impurity called pamoate of (E) -2 - [2- (2,5-Dimethyl-1-phenyl-1 H-pyrrol-3-yl) -vinyl] -1-methyl-6-methylamino-quinolinium, but also of some other unknown impurities.

    Therefore, one aspect of the invention relates to a process for the preparation of pyrvinium pamoate,




    which comprises the reaction of the pyrvinium methylsulfate salt of formula (II),



    With disodium pamoate of formula (III),



    Optionally, in the presence of a base. 5

    A second aspect of the invention relates to a process for the preparation of a crystalline Form A of the pyrvinium pamoate comprising: (c) suspending the crystalline Form III of the pyrvinium pamoate with ethanol at reflux temperature for the necessary period of time to convert crystalline Form III to crystalline Form A; and (d) cooling to a temperature ranging from 20 ° C to 30 ° C.

    A third aspect of the invention relates to the crystalline Form A of the pyrvinium pamoate characterized by having an X-ray diffractogram comprising characteristic peaks at 2.8,
    5.1, 7.2, 8.9, 9.6, 9, 9, 15, 9.16, 3.17, 9, 21.0 ± 0.2 degrees 2 theta measured on an X-ray diffractometer 15 with Ka de Cu radiation (1.5418 Á).

    A fourth aspect of the invention relates to a process for the preparation of the crystalline Form III of the pyrvinium pamoate comprising: (g) suspending the crystalline Form A of the pyrvinium pamoate with a mixture of water and ethanol at reflux temperature during the time necessary to convert crystalline Form A to crystalline Form III; (h) separating the crystalline Form III obtained in step (g) at a temperature of from 90 ° C to 95 ° C; and (i) washing the crystalline Form III of the pyrvinium pamoate salt first with hot water at a temperature of from 90 ° C to 95 ° C and then with ethanol.
     25
    A fifth aspect of the invention relates to a process for the purification of the crystalline Form III of the pyrvinium pamoate which comprises preparing the crystalline Form A of the pyrvinium pamoate from the crystalline Form III obtained by the procedure defined in the second aspect of the invention and then transform the crystalline form A into the crystalline form III by the procedure defined in the fourth aspect of the invention.

    A sixth aspect of the invention relates to the crystalline Form III of the pyrvinium pamoate characterized by having an X-ray diffractogram comprising characteristic peaks at 6.0,
    8.6, 9,5,10,3,10,5,14,3,14,9,16,6,17,4,18,1,19,1,19,7, 20,6, 21, 5, 22.0, 22.6, 23.6, 24.9 ± 35
    0.2 degrees 2 theta measured on an X-ray diffractometer with Ka de Cu radiation (1.5418 Á).

    Finally, a seventh aspect of the invention relates to a pharmaceutical composition comprising the crystalline form of pyrvinium pamoate as defined in the fifth and sixth aspects of the invention, together with one or more pharmaceutically acceptable excipients or vehicles.

    Brief description of the drawings

    FIG. 1 shows the powder X-ray diffraction pattern (intensity (counts) versus angle 2-theta (°)) of the crystalline Form A of the pyrvinium pamoate.

    FIG. 2 shows the infrared (IR) spectrum of crystalline Form A of pyrvinium pamoate. The curve expresses the transmittance (T) versus the wave number value (cnr1).

    Fig. 3 shows the powder X-ray diffraction pattern (intensity (counts) versus angle 2-theta (°)) of the crystalline Form III of the pyrvinium pamoate. 5

    Fig. 4 shows the infrared (IR) spectrum of crystalline Form III of pyrvinium pamoate. The curve expresses the transmittance (T) versus the wave number value (crrr1).

    Detailed Description of the Invention 10

    All terms used in this application, unless otherwise indicated, should be understood to have their ordinary meaning as known in the art. Other more specific definitions for certain terms that are used in the present application are those set forth below and are intended to be applied uniformly throughout the specification and claims unless another definition expressly provides a broader definition.

    For the purposes of the invention, any given range includes both the lower and upper end of the range. The given intervals, such as temperatures, times, and the like, 20 should be considered approximate, unless specifically indicated.

    The term "molar ratio" refers to the molar ratio between the starting material and the reagent necessary to carry out the reaction. For example, the molar ratio between the moles of base and the moles of the pyrvinium methylsulfate salt of formula (II); or the molar ratio between pyrvinium methylsulfate of formula (II) and the disodium pamoate of formula (III).

    The term "volumetric ratio" refers to the ratio of the volume of a first compound to the volume of a second compound. For example, the volumetric relationship between water and C1-C4 alcohol refers to the amount of water with respect to the amount of C1-C4 alcohol.

    The term "alkyl" refers to a linear or branched hydrocarbon chain containing the number of carbon atoms specified in the description or claims.
     35
    The term "alcohol" refers to a hydrocarbon derivative in which one or more hydrogen atoms have been substituted by one or more -OH groups. The term alcohol also includes glycol compounds. Examples of alcohols suitable for the present invention include, but are not limited to, ethanol, 2-propanol (ie, isopropanol), or n-propanol.
     40
    The term "reflux temperature" refers to the temperature at which the mixture bustles under conditions in which the solvent vapor returns to the liquid mixture after condensation.

    The term "effective therapeutic amount" refers to the amount of active ingredient 45 (pyrvinium pamoate) that provides the therapeutic effect after application.

    The term "pharmaceutically acceptable" refers to excipients or vehicles suitable for use in pharmaceutical technology for the preparation of compositions for medical use. fifty

    For the purposes of the invention, the water content is determined by Karl Titulometry.
    Fisher (KFT) as expressed in% by weight of water with respect to the weight of pyrvinium pamoate.
    When the values of the characteristic peaks of an X-ray diffractogram are given, they are said to be "approximate" values. It should be understood that the values are those shown in the corresponding lists or tables ± 0.2 degrees 2 theta measured on an X-ray diffractometer with radiation Ka of Cu A = 1.5406 Á.
     5
    As mentioned above, the first aspect of the present invention relates to a process for the preparation of pyrvinium pamoate, which comprises the reaction of the pyrvinium methylsulfate salt of formula (II), with disodium pamoate of formula (III ).

    In one embodiment, optionally in combination with one or more characteristics of the various embodiments described above or below, the procedure is performed in the presence of a base. In another embodiment, optionally in combination with one or more features of the various embodiments described above or below, the base is selected from the group consisting of ammonia, (C 1-C 4 alkyl-amines, (C 1-C 4 alkyl) ) 3-amines, cyclic amines, alkali metal hydroxides and alkaline earth metal hydroxides 15. Examples of suitable amines for the present invention may be diethylamine, triethylamine, piperidine, and sodium hydroxide In a preferred embodiment, optionally in combination with One or more characteristics of the various embodiments described above or below, the base is ammonia.
     twenty
    In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, the process is that where the molar ratio between the base and the pyrvinium methylsulfate salt of formula (II) is from 0, 32 to 6.51; preferably from 0.32 to 1.95. In a particular embodiment, optionally in combination with one or more features of the various embodiments described above or below, the process is carried out in the presence of ammonia where the molar ratio between ammonia and the pyrvinium methylsulfate salt of formula ( II) is from 0.32 to 6.51; preferably, the process is carried out in the presence of ammonia where the molar ratio between the ammonia and the pyrvinium methylsulfate salt of formula (II) is comprised from 0.32 to 1.95.

    In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, the process is that where the molar ratio between the pyrvinium methylsulfate of formula (II) and the disodium pamoate of formula (III) it is from 1.33 to 2.00; preferably it is from 1.66 to 1.96. The term "molar ratio" has been used to express the stoichiometric amount in moles of each of the starting materials (compounds of formula (II) and (III)).
     40
    In one embodiment, optionally in combination with one or more characteristics of the various embodiments described above or below, the process is carried out in the presence of a solvent selected from water, C1-C4 alcohol, dimethylformamide, C3-C6 cyclic ethers and their mixtures Examples of suitable C3-C6 cyclic ethers include tetrahydrofuran and dioxane. Four. Five

    In one embodiment, optionally in combination with one or more characteristics of the various embodiments described above or below, the process is carried out in the presence of a mixture of water and C1-C4 alcohol, and then the procedure gives Crystal Form III of pyrvinium pamoate. Examples of the appropriate C1-C4 alcohol as a solvent for the present invention include, but are not limited to, methanol, ethanol and isopropanol. In one embodiment, optionally in combination with one or more characteristics of the various embodiments described above or below, the process is carried out in the presence of a mixture of water and ethanol. In a particular embodiment,
    optionally in combination with one or more features of the various embodiments described above or below, the process is performed in a mixture of water and ethanol, where the volumetric ratio between water and C 1 -C 4 alcohol is comprised from 40 to 3; preferably from 25 to 10. Therefore, a process for the preparation of the crystalline Form III of the pyrvinium pamoate which comprises performing the procedure defined in the first aspect of the invention in the presence of the invention is also part of the invention. a mixture of water and C 1-C 4 alcohol.

    In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, the process is performed at the reflux temperature of the solvent.

    Normally, the pyrvinium pamoate obtained by the process of the first aspect of the invention has a chemical purity equal to or greater than 99.0% of surface; preferably, equal to or greater than 99.3% of surface. In one embodiment, where the process of the first aspect of the invention is carried out in the presence of a mixture of water and C1-C4 alcohol, the process allows obtaining crystalline Form III of the pyrvinium pamoate having a chemical purity. up to 99.5% surface area, measured by HPLC. The process of the invention also allows to obtain the crystalline Form III of the pyrvinium pamoate with a water content equal to or less than 6.0% by weight. In a preferred embodiment, the water content 20 is comprised from 4.0% to 6.0% by weight.

    In an alternative embodiment, optionally in combination with one or more features of the various embodiments described above or below, where the process of the invention gives a crystalline Form III of the pyrvinium pamoate having a water content greater than 6.0 % by weight, then the process further comprises an additional drying step of the pyrvinium pamoate to have a water content equal to or less than 6.0% by weight. In one embodiment, optionally in combination with one or more characteristics of the various embodiments described above or below, the additional drying step is carried out at a temperature ranging from 80 ° C to 90 ° C; preferably from 30 ° C to 88 ° C. In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, the additional drying step is performed in the period of time necessary to dry the pyrvinium pamoate; preferably for a period of time from 2 to 5 h, more preferably for 4 h. In a particular embodiment, optionally in combination with
    one or more characteristics of the various embodiments described above or below, the additional drying step is carried out at a temperature ranging from 80 ° C to 90 ° C for a period of time from 2 to 5 h; preferably at a temperature from 84 ° C to 88 ° C for 4 h. Drying can be performed by any method known in the art. Examples of drying methods suitable for the present invention may be oven drying and vacuum drying.

    In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, the process of the invention further comprises firstly preparing the pyrvinium methylsulfate of formula (II), then the process comprises: a) reacting a compound of formula (IV),


     fifty

    With dimethyl sulfate; and b) reacting the mixture obtained in step a) with a compound of formula (V),

        CHO
     5

    In the presence of a base.

    In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, step b) of the process 10 of the invention is carried out in the presence of a base selected from the group consisting of ammonia, ( C1-C4 alkyl-amines, (C1-C4 alkyl) 3-amines, cyclic amines and an alkali metal hydride Examples of amines suitable for the present invention may be diethylamine, diisopropylamine, piperidine, pyrrolidine, hexamethyldisilazane, lithium hexamethyldisilazane , sodium hydride, butyl lithium, hexyl lithium, sodium methoxide and sodium ethoxide In a preferred embodiment, optionally in combination with one or more characteristics of the various embodiments described above or below, the base is piperidine. In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, the process is that where the molar ratio between the base and the compound of formula (IV) is from 0.39 to 1.94; preferably from 0.58 to 0.97. In a particular embodiment, optionally in combination with one or more features of the various embodiments described above or below, the process is carried out in the presence of piperidine where the molar ratio between piperidine and the compound of formula (IV) is comprised from 0.39 to 1.94; preferably, the process is carried out in the presence of piperidine where the molar ratio between piperidine and the compound of formula (IV) is from 0.58 to 0.97.

    In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, steps (a) and (b) of the process for the preparation of the pyrvinium methylsulfate of formula (II) are performed in the presence of one or more solvents.

    In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, step (a) is performed in the presence of a solvent selected from the group consisting of C 1-C 4 hydrocarbon, C 3- C 6 cyclic ethers, C1-C3 alkyl-COO-Ci-C4 alkyl, C1-C4 halo-hydrocarbons, and mixtures thereof. Examples of solvents suitable for step (a) include toluene, tetrahydrofuran, dioxane, ethyl acetate, isopropyl acetate, dichloroethane and mixtures thereof. In one embodiment, the solvent of step (a) is toluene. 40

    In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, step (a) is carried out in the presence of a solvent in an amount ranging from 2 to 10 L of solvent with respect to the kilograms of the compound of formula (IV); preferably from 45 3 to 5 L of solvent with respect to the kilograms of the compound of formula (IV); more preferably the amount of solvent is 3.5 L of solvent with respect to the
    kilograms of the compound of formula (IV). In one embodiment, optionally in combination with one or more characteristics of the various embodiments described above or below, step (a) is carried out in the presence of toluene in an amount comprised from 2 to 10 L of toluene with respect to the kilograms of the compound of formula (IV); preferably from 3 to 5 L of toluene with respect to the kilograms of the compound of formula (IV); more preferably the amount of solvent is 3.5 L of toluene with respect to the kilograms of the compound of formula (IV).

    In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, step (b) is carried out in the presence of a solvent selected from the group consisting of Ci-C 4 alcohol, C3- C6 cyclic ethers; C1-C3alkyl-COO-Ci-C4 alkyl and mixtures thereof. Examples of solvents suitable for step (b) include methanol, tetrahydrofuran, dioxane, ethyl acetate, isopropyl acetate. In a preferred embodiment, step (b) is carried out in the presence of a solvent selected from the group consisting of methanol, tetrahydrofuran, ethyl acetate and mixtures thereof; preferably methanol.

    In one embodiment, optionally in combination with one or more characteristics of the various embodiments described above or below, step (b) is carried out in the presence of a solvent in an amount ranging from 0.5 to 5 L of solvent with 20 with respect to the kilograms of the compound of formula (IV); preferably from 1 to 3 L of solvent with respect to the kilograms of the compound of formula (IV); more preferably the amount of solvent is 1.4 L of solvent with respect to the kilograms of the compound of formula (IV). In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, step (b) is carried out in the presence of methanol in an amount ranging from 0.5 to 5 L of methanol with respect to to the kilograms of the compound of the formula (IV); preferably from 1 to 3 L of methanol with respect to the kilograms of the compound of formula (IV); more preferably the amount of solvent is 1.4 L of methanol with respect to the kilograms of the compound of formula (IV). 30

    In a particular embodiment, optionally in combination with one or more characteristics of the various embodiments described above or below, step (a) is carried out in the presence of toluene and step (b) is carried out in the presence of methanol.
     35
    As mentioned above, the second aspect of the invention relates to a process for the preparation of the crystalline Form A of the pyrvinium pamoate comprising: (c) suspending the crystalline Form III of the pyrvinium pamoate with ethanol at reflux temperature during the period of time necessary to convert crystalline Form III into crystalline Form A; and (d) cooling to a temperature from 20 ° C to 30 40 ° C. In one embodiment, optionally in combination with one or more characteristics of the various embodiments described above or below, step (c) of the process for the preparation of crystalline form A of the pyrvinium pamoate is carried out at the reflux temperature of the ethanol for a period of time from 1 to 5 h;
    5 preferably for 1 h. In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, the process for the preparation of the crystalline form A of the pyrvinium pamoate further comprises (e) separating the crystalline form A obtained in the stage (d); and (f) washing the crystalline Form A obtained in step (e) with ethanol. The crystalline form A thus obtained is also
    10 part of the invention. fifty

    In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, the process for the preparation of Crystal Form A comprises the preparation of Crystal Form III of the
    pyrvinium pamoate as defined in the present invention; followed by the conversion of crystalline Form III into crystalline Form A as defined in the present invention.

    As mentioned above, the third aspect of the invention relates to a crystalline Form A of the pyrvinium pamoate characterized by having an X-ray diffractogram 5 comprising characteristic peaks at 2.8, 5,1,7,2,8. , 9, 9.6, 9,9,15,9,16,3,17.9, and 21.0 ± 0.2 degrees 2 theta measured on an X-ray diffractometer with Ka de Cu radiation (1.5418 TO). In one embodiment, the crystalline Form A of the pyrvinium pamoate is characterized by having an X-ray diffractogram which further comprises characteristic peaks at 2.8, 5,1,7,2, 8,9, 9,6, 9,9 , 13,4,14,3,15,9,16,3,17,2,17,9,19,2,19.8, 21.0, 22.2, 22.7, and 24.1 ± 0.2 degrees 2 theta 10 measured on an X-ray diffractometer with Ka de Cu radiation (1.5418 Á). More specifically, this crystalline Form A is characterized by presenting a pattern of peaks in the powder X-ray diffractogram, expressed in units 2 theta in degrees, 20 (°), which is shown in the following Table 1.
     fifteen
    Table 1: List of characteristic peaks obtained by X-ray diffractogram of the crystalline Form A of the pyrvinium pamoate:

     Pos. [° 2Th.]  Int. Rel. [%] Pos. [º2Th.] Int. Rel [%]
     2.8  21.9 16.3 9.2
     5.1  7.5 17.2 6.8
     7.3  5.6 17.9 100
     8.9  32.1 19.2 12.0
     9.6  35.1 19.8 10.1
     9.9  18.3 21.0 16.8
     13.4  5.2 22.2 9.5
     14.3  6.8 22.7 12.6
     15.9  22.7 24.1 13.1

    In one embodiment, the crystalline Form A of the pyrvinium pamoate can also be characterized by having an X-ray diffractogram as shown in Fig. 1.

    In a particular embodiment, the crystalline Form A of the pyrvinium pamoate is characterized by having an infrared (IR) spectrum that shows the following peaks (± 5 cnr1): 1615,1586, 1571,1496,1450,1356,1295,1255 , 1220,1188,1162,1025,1007, 948, 809, 766 and 703 cnr1. In one embodiment, the crystalline Form A of the pyrvinium pamoate is characterized by having the infrared (IR) spectrum shown in Fig. 2.

    In one embodiment, the chemical purity of the crystalline Form A of the pyrvinium pamoate of the present invention is equal to or greater than 99% surface; preferably equal to or greater than 30
    99.5% area; more preferably equal to or greater than 99.8% area; in particular equal to or greater than 99.95% of surface area measured by HPLC. In one embodiment, the polymorphic purity of the crystalline Form A of the pyrvinium pamoate is such that no other crystalline forms of the pyrvinium pamoate are detectable by measuring the X-ray powder diffraction using an X-ray diffractometer with Ka Cu radiation A = 1,5406 Á. 35

    An advantage of the crystalline Form A of the pyrvinium pamoate of the present invention lies in the fact that it is obtained with high yields and high purity; and it has physicomechanical properties that allow good handling for the preparation of solid pharmaceutical formulations that meet the strict pharmaceutical standards for oral administration.
    Another advantage of the crystalline Form A of the pyrvinium pamoate of the present invention is that it allows the removal and / or reduction of the amount of impurities of the pyrvinium pamoate, in particular of the crystalline Form III of the pyrvinium pamoate. Next, Crystalline Form A is useful as an intermediate for the preparation of Crystalline Form III of pyrvinium pamoate.
     5
    The fourth aspect of the present invention relates to a process for the preparation of crystalline Form III of the pyrvinium pamoate. In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, the process for the preparation of the crystalline Form III of the pyrvinium pamoate comprises: (g) suspending the crystalline Form A of the pyrvinium pamoate 10 with a mixture of water and ethanol at reflux temperature for the period of time necessary to convert crystalline Form A into crystalline Form III; preferably for a period of time from 15 to 20 h; (h) separating the crystalline Form III obtained in step (g) at a temperature of from 90 ° C to 95 ° C; and (i) washing the crystalline Form III obtained in step (h) first with hot water at a temperature of from 90 ° C to 95 ° C and then with ethanol.

    In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, the volumetric ratio between water and ethanol in step (g) is comprised from 15: 1 to 10: 1; preferably from 14: 1 to 11: 1.

    The fifth aspect of the present invention relates to a process for the purification of crystalline Form III of pyrvinium pamoate. The process comprises the preparation of the crystalline Form A of the pyrvinium pamoate of the crystalline Form III by the process of the invention and then, transforming the crystalline Form A into the crystalline Form III by the procedure defined above. All of the embodiments described above for the preparation of pyrvinium pamoate, Crystalline Form III and Crystalline Form A also apply to the process for purification of Crystalline Form III of the fifth aspect of the invention. 30

    The process for the purification of the crystalline Form III of the pyrvinium pamoate which comprises the preparation of the crystalline Form A and then the transformation of the crystalline Form A into the crystalline Form III allows to reduce the amount of total impurities from 0, 66% to 0.24% by weight measured by HPLC. As shown in the examples, this particular procedure allows the reduction of the amount of the pamoate by-product of (E) -2- [2- (2,5-dimethyl-1-phenyl-1H-pyrrole-3-yl) -vinyl] -1-methyl-6-methylamino-quinolinium from 0.21% to 0.12% by weight measured by HPLC. Therefore, the chemical purity of the crystalline Form III of the pyrvinium pamoate obtained by the process of the fifth aspect of the invention is equal to or greater than 99% surface; preferably equal to or greater than 99.5% surface area; more preferably equal to or greater than 99.8% area; in particular equal to or greater than 99.95% of surface area measured by HPLC. In one embodiment, the polymorphic purity of the crystalline Form III of the pyrvinium pamoate is such that other crystalline forms of the pyrvinium pamoate are not detectable by measuring X-ray powder diffraction using an X-ray diffractometer with Ka Ka radiation. = 1,5406 Á. Four. Five

    As mentioned above, the sixth aspect of the invention relates to the crystalline Form III of the pyrvinium pamoate characterized by having an X-ray diffractogram comprising characteristic peaks at 6.0, 8.6, 9.5, 10, 3,10,5,14,3,14,9,16,6,17,4,18,1,19,1, 19.7, 20.6, 21.5, 22.0, 22.6, 23, 6, 24.9 ± 0.2 degrees 2 theta measured on a 50 x-ray diffractometer with Ka de Cu radiation (1.5418 Á). In one embodiment, the crystalline Form III of the pyrvinium pamoate is characterized by having an X-ray diffractogram which further comprises characteristic peaks at 6.0, 8.6, 9.5, 9.9, 10.3, 10.5 , 10.7, 11.2, 12.9, 14.3, 14.5, 14.9, 16.6, 16.9, 17.4, 18.1.19.1.19.7, 20.0, 20.6 , 21.5, 22.0, 22.6, 23.6, 24.5, 24.9, and 26.4 ± 0.2 degrees 2 theta
    measured on an X-ray diffractometer with Ka de Cu radiation (1.5418 Á). More specifically, this crystalline Form III is characterized by presenting a pattern of peaks in the powder X-ray diffractogram, expressed in units 2 theta in degrees, 20 (°), which is shown in the following Table 2.
     5
    Table 2: List of characteristic peaks obtained by X-ray diffractogram of crystalline Form III of pyrvinium pamoate:

     Pos. [º2Th.]  Int. Rel. [%] Pos. [º2Th]. Int. Rel. [%]
     6.0  36.7 17.4 45.7
     8.6  16.5 18.1 43.3
     9.5  100.0 19.1 16.6
     9.9  28.3 19.7 25.3
     10.3  39.0 20.0 25.5
     10.5  48.0 20.6 16.4
     10.7  24.1 21.5 14.0
     11.2  11.0 22.0 19.3
     12.9  4.9 22.6 33.9
     14.3  77.6 23.6 17.2
     14.5  13.3 24.5 16.9
     14.9  22.9 24.9 27.7
     16.6  36.4 26.4 17.9
     16.9  22.7

    In one embodiment, the crystalline Form III of the pyrvinium pamoate can also be characterized by having an X-ray diffractogram as shown in Fig. 3.

    In a particular embodiment, the crystalline Form III of the pyrvinium pamoate is characterized by having an infrared (IR) spectrum that has the following peaks (± 5 cm 1): 3360 (wide peak), 1618, 1590, 1573, 1500, 1450, 1382, 1357, 1298, 1254, 1224, 1192, 1162, 1031, 1008, 15 957, 859, 813, 755, and 707 cm-1. In one embodiment, the crystalline Form III of the pyrvinium pamoate is characterized by having the infrared (IR) spectrum as shown in Fig. 4.

    As mentioned above, the seventh aspect of the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of crystalline Form A or crystalline Form III of pyrvinium pamoate as defined herein, together with one or more pharmaceutically acceptable excipients or vehicles. In one embodiment, optionally in combination with one or more characteristics of the various embodiments described above or below, the pharmaceutical composition may be in the form of an oral pharmaceutical composition. The compositions of the present invention can be prepared according to methods well known in the state of the art. Suitable excipients and / or vehicles, and their amounts, can easily be determined by those skilled in the art according to the type of formulation to be prepared.
     30
    The crystalline forms A and III of pyrvinium pamoate are also part of the invention as defined herein for use as an anthelmintic, in particular for use in the treatment of enterobiasis. The use of crystalline forms A and III of pyrvinium pamoate for the manufacture of a medicament for the treatment of enterobiasis is also part of the invention. This aspect could also be formulated as a method for the treatment of enterobiasis, which comprises administering a pharmaceutically effective amount of crystalline forms A and III of pyrvinium pamoate, together with excipients or
    Pharmaceutically acceptable vehicles, to a subject in need, including a human being.

    Throughout the description and the claims the word "comprises" and its variations, are not intended to exclude other technical characteristics, additives, components or steps. In addition, the word "comprises" encompasses the case of "consisting of". Additional objects, advantages and features of the invention will be apparent to those skilled in the art upon examination of the description or can be learned with the implementation of the invention. The following examples and drawings are provided by way of illustration, and are not intended to be limiting of the present invention. In addition, the present invention covers all possible combinations of particular and preferred embodiments described herein.

    Examples

    General Considerations 15

    The chemical shifts of the proton (1H) and carbon (13C) were obtained with a Bruker nuclear magnetic resonance spectrometer. Chemical shifts are given in ppm, with internal reference to the deuterated solvent. The molecular mass has been confirmed by direct infusion on the Waters micromass ZQ 2000 spectrometer with a 20 spray electrode (ES) probe.

    Water content was performed on an 831 Karl Fischer Coulometer with a 774 Oven Sample Processor. The solid sample is heated in the oven; The released water is transported in a stream of dry carrier gas to the Karl 25 Fischer titration cell with a generator electrode without diaphragm, where it is determined with reactive Hydranal Coulomat E.

    X-ray powder diffraction analyzes (PXRD) were performed by interleaving dust samples between 10 micron thick polyester films or 15 micron thick polyamide (30 Kapton) films and analyzed on a PANalytical powder diffractometer X'Pert PRO MPD q / q of 240 mm radius, in a convergent beam configuration with a focusing mirror and a flat geometry of sample transmission, under the following experimental conditions: Ka radiation of Cu (A = 1, 5418 Á); working power: 45 kV and 40 mA; incident beam slits defining a beam height of 0.4 millimeters; 35 incident and diffracted beams of Soller slits of 0.02 radians; PIXcel detector: active length = 3,347 °; 20/0 sweeps from 2 to 40 ° 20 with a step size of 0.026 ° 20 and a measurement time of 76 seconds per step. The X-ray diffractogram shows the powder X-ray diffraction pattern (intensity (counts) vs. angle 2-theta (°)) of the crystalline form of the pamoate pyrvinium salt of formula (I). 40

    Fourier Transformed Infrared Spectra - Total attenuated reflectance (FT-IRATR) was recorded on a Perkin Elmer Spectrum Two FT-IR spectrometer with universal attenuated total reflectance (UATR) sampling accessory (UATR Two). The sample is placed on the ATR plate and the measurement is carried out in the range of 4000-450 cnr1. The term "IR or IR spectrum / spectra" when used in this context refers to the spectra recorded under the conditions mentioned above.

    High pressure liquid chromatography (HPLC). HPLC analyzes were performed with a Waters 2695 and a Waters 1525 separation module with a PDA 2996 or Dual 50 2487 UV detector; using the following conditions: solvents: ammonium formate (analytical quality); formic acid (analytical quality); acetonitrile (HPLC quality); methanol (HPLC quality); and purified water (Milli-Q quality); Column: XBridge C18 (waters; 150x4.6 mm) 3.5 microns; Flow:
    0.7 ml / min; Injection volume: 10 pil; Injection temperature: 25 ° C; UV detection: 344 nm; Sample dissolved in acetonitrile: 10 mM ammonium formate (pH 3.3); Gradient:

     Time (min)  % acetonitrile% curved ammonium formate
     0  35 65
     27  60 40 6
     30  75 25 1
     35 35  65 1

    Example 1. Preparation of crystalline Form III of pyrvinium pamoate 5

    Step 1. Preparation of pyrvinium methylsulfate of formula (II)


     10
    A mixture of 6-dimethylaminoquinaldine of formula (IV) (150 kg) in toluene (525 L) was heated at 45-50 ° C for 30 minutes until complete dissolution. After cooling to 25-30 ° C, dimethyl sulfate (105 kg) was added slowly and the mixture was maintained at 75-85 ° C for 1 hour. Next, a hot solution of 2,5-dimethyl-1-phenyl-1 H-pyrrol-3- carbaldehyde of formula (V) (126.45 kg) in methanol (210 L) was added. Then, piperidine (48 15 kg) was added, and the resulting mixture was heated at reflux for approximately 2.5 h and the solvent was distilled in vacuo to obtain pyrvinium methylsulfate of formula (II) as a pasty solid. Once the pasty solid obtained was cooled, methanol (114 L) and acetone (380.7 L) were added and the mixture was refluxed for approximately 1 hour. Then, the reactor contents were cooled to 0-10 ° C for at least 2 hours, centrifuged and the solid obtained was washed with acetone (40 L) to obtain the pyrvinium methylsulfate of formula (II) (240 kg, yield 60.8% and 77.2% with respect to compounds (IV) and (V), respectively).

    Pyrvinium Methyl Sulfate of Formula (II):
     25
    IR (ATR, cm * 1): 1616,1585 and 1571 (arom.), 1374,1354, 1228 and 1057 (CH3O-SO3-), 1012, 707. MS: 382 (M +)

    1H NMR (300 MHz; DMSO): 8.50 (d, J = 9 Hz, 1H, CH H (22)), 8.42 (d, J = 9 Hz, 1H, CH H (23)), 8 , 21 (d, J = 9 Hz, 1H, CH H (18)), 8.06 (d, J = 15 Hz, 1H, CH H (14) or HC (15)), 7.57 (m, 4H, CH 30 H (11) + H (19) + H (10) + H (12)), 7.35 (d, J = 6 Hz, 2H, CH H (9) + H (13)), 7.20 (j, J = 2.7 Hz, 1H, CH H (21)), 7.19 (d, J = 15 Hz, 1H, CH HC (15) or H (14)), 6.72 (s, 1H, CH HC (4)), 4.35 (s, 3H, CH3 MeS04 or H (26)), 3.37 (s, 3H, CH3 H (26) or MeS04), 3.09 and 3.02 (s, 6H CH3 H (27) + H (28)), 2.23 (s, 3H, CH3 H (6) or H (7)), 2.00 (s, 3H, CH3 H ( 7) or H (6)),
     35
    Stage 2. Preparation of pyrvinium pamoate



    A mixture of pyrvinium methylsulfate of formula (II) obtained in step 1 (40 kg) in water (1000 L) was refluxed for approximately 1 hour. Then, a hot solution of disodium pamoate of formula (III) (19.3 kg) in water (130 L) 5 and 2 0 ammonia (7 L) was added slowly over the reactor contents. After heating at reflux for 9-10 hours, the mixture was cooled to 50-60 ° C, ethanol (75 L) was added, again refluxed for approximately 1 hour and hot centrifuged. Then, the solid obtained is washed first with hot water (1000 L) and then with ethanol (35 L) to give pyrvinium pamoate, which was dried under vacuum for 14-17 hours at 84-88 ° C and finally it was ground to obtain the crystalline Form lll of the pyrvinium pamoate having a water content measured by the Karl Flsher method Equal to or less than 6.0% by weight (46 kg, 100% yield, KF
    4.5%) The crystalline Form lll of the pyrvinium pamoate has an HPLC purity of 99.34% of surface area, an impurity content with the pamoate formula of (E) -2- [2- (2,5-dimethyl-1-phenyl) -1 H-pyrrole-3-ll) -vinyl] -1-methyl-6-methylamino-quinollnio of 0.21% surface purity per 15 HPLC; and an unknown impurity content of 0.45% surface purity by HPLC.

    Pyrvinium Pamoate:
     twenty
    MS: 382.3 (M +)

    1H NMR (300 MHz, DMSO) (ppm): 8.49 (d, J = 9 Hz, 2H, H22), 8.43 (d, J = 9 Hz, 2H, Ha), 8.12 
    (2d, J = 10 Hz, 4H, H18.H37). 8.10 (s, 2H, H33), 8.08 (d, J = 15 Hz, 2H, His), 7.6-7.4 (m, 10H, 25 H10, H11, Hiz, H19, H34) , 7.37-7.34 (2d, 4H, H9, H «), 7.21 (d, J = 15 Hz, 2H Hu), 7.20 (s, 2H, H21), 7.06 (m , 2H, H »), 6.96 (m, 2H, H35), 6.72 (s, 2H, H4), 4.64 (s, 2H, H29 (CH2)), 4.34 (s, 6H , H26 (CHj)), 3.08 (s, 12H, H27 and H28 (CHs)), 2.23 (s, 6H, H7 (CHs), 2.00 (s, 6H, H6 (CH3)).
     30
    (E) -2- [2- (2,5-Dimethyl-1-phenyl-1H-pyrrol-3-yl) -vinyl] -1-methyl-6-methylamino-quinolinium pamoate:



    1H NMR (300 MHz, CDCI3) 5 (ppm): 8.48 (d, J = 9, 1H, HC (22)), 8.41 (d, J = 9, 1H, HC (23)), 8 , 20- 8.12 (m + s, 3H, HC (18) + HC (34) + HC (37)), 8.04 (d, J = 1 5, 1H, HC (15)), 7, 58 (m, 5H, HC (10), HC (11), HC (12), HC (19), HC (34)), 7.38 (m, 2H, HC (9), HC (13)) , 7.20 (d, J = 15.1H HC (14), 7.07 (t, J = 7 Hz, 1H, HC (35)), 6.95 (m, 2H, HC (19) + HC (21)), 6.82 (m, 1H, HC (Ar)), 6.70 (s, 1H, HC (4), 4.64 (s, 2H, H2C (29), 4.33 (s , 3H, H2C (26), 3.34 (s, H20), 2.82 (d, J-5 Hz, 3H, 5 H3C (27)), 2.22 (s, 3H, H3C (7)) , 2.00 (s, 3H, H3C (6)).

    Example 2. Purification of the lll crystalline form of pyrvinium pamoate

    Step 1. Preparation of crystalline form A of pyrvinium pamoate 10

    Crystal form lll of the pyrvinium pamoate obtained in step 2 of Example 1 (60 g) and ethanol (1500 ml) were mixed in a reactor. The resulting mixture was heated at reflux for at least 1 hour. Then, the reactor contents were cooled to 20-30 ° C and maintained at that temperature for at least 1 hour, and after that time, the ethanol was centrifuged. Then, the solid obtained was washed with ethanol (300 ml). The crystalline form A of the pyrvinium pamoate was obtained as a brown solid. The crystalline Form A of the pyrvinium pamoate has an HPLC purity of 99.69% surface area, an impurity content with the pamoate formula of (E) -2- [2- (2,5-dimethyl-1-phenyl -1H-pyrrol-3-yl) -vinyl] -1-methyl-6-methylamino-quinolinium of 0.12% surface purity by HPLC, and an unknown impurity content of 0.19 20% purity by HPLC .

    Stage 2. Conversion of crystalline Form A to crystalline Form III of Pirvinium pamoate.

    The crystalline Form A of the pyrvinium pamoate obtained in step 1 of Example 25 2, 96 ° ethanol (120 ml) and water (1500 ml) were mixed in a reactor. The resulting mixture was heated at reflux for 15 hours. Then, at the reflux temperature, the reactor contents were centrifuged. Then, the solid obtained was washed with hot water (1500 ml) and with ethanol (120 ml). The crystalline Form III of the pyrvinium pamoate was obtained as a red solid and dried in a vacuum oven at 85 ° C for 15 h (53.5 g, two stages with an overall yield of 89%, KF 5, 8%) The crystalline Form III of the pyrvinium pamoate has an HPLC purity of 99.76% of surface area, an impurity content with the pamoate formula of (E) -2- [2- (2,5-dimethyl-1-phenyl- 1 H-pyrrol-3-yl) -vinyl] -1-methyl-6-methylamino-quinolinium of 0.12% surface purity by HPLC, and an unknown impurity content of 0.12% surface purity per HPLC 35
    权利要求:
    Claims (15)
    [1]

    1. Procedure for the preparation of the pyrvinium pamoate salt of formula (I),
     5
    which comprises the reaction of the pyrvinium methylsulfate salt of formula (II),

     (H3C) 2N
     10
    with disodium pamoate of formula

     fifteen
    optionally, in the presence of a base.

    [2]
    2. The process according to claim 1, wherein the base is ammonia.

    [3]
    3. The process according to any of claims 1-2, wherein the 20 molar ratio between the compound of formula (II) and the compound of formula (III) is from 1.33 to 2.00.

    [4]
    4. The process according to any one of claims 1-3, wherein the process is carried out in the presence of a mixture of water and C1-C4 alcohol and then the process gives Crystal Form III of the pyrvinium pamoate salt of formula (I).

    [5]
    5. The process according to any of claims 1-4, wherein the process further comprises first the preparation of the compound of formula (II):
    a) reacting a compound of formula (IV),
     (H3C) 2N

    with dimethyl sulfate; Y
     5
    b) reacting the mixture obtained in step a) with a compound of formula (V)

    in the presence of a base. 10

    [6]
    6. The method according to claim. 5, where: step a) is carried out in the presence of a solvent selected from the group consisting of C1-C4 hydrocarbons, C3-C6 cyclic ethers, C1-C3 alkyl -COO-C1-C4 alkyl, C1-C4 halo hydrocarbons; and their mixtures; and step b) is carried out in the presence of a solvent selected from the group consisting of C1-C4 alcohol, C3-C6 cyclic ethers; C1-C3 alkyl-COO-Ci-C4 alkyl; and their mixtures.

    [7]
    7. The method according to any of claims 5-6, wherein:
    step a) is carried out in the presence of toluene; and 20
    step b) is carried out in the presence of methanol.

    [8]
    8. The process according to any of claims 5-7, wherein the basis of step b) is piperidine. 25

    [9]
    9. A process for the preparation of a crystalline Form A of the pyrvinium pamoate salt of formula (I) comprising:
    (c) suspend the crystalline Form III of the pyrvinium pamoate salt of formula (I) with ethanol at reflux temperature for the period of time necessary to convert the crystalline Form
    III in Crystalline Form A; Y
    (d) cool to a temperature from 20 ° C to 30 ° C.
     35
    [10]
    10. The process for the preparation of the crystalline Form A of the pyrvinium pamoate salt of formula (I) according to claim 9, wherein step (c) is carried out for a period of time from 1 to 5 h.

    [11]
    11. A process for the preparation of crystalline Form III of the pyrvinium pamoate salt of formula (I) comprising:
    (g) suspending the crystalline form A of the pyrvinium pamoate salt of formula (I) with a mixture of water and ethanol at reflux temperature for the period of time necessary to convert the crystalline form A into the crystalline form III;
    (h) separating the crystalline Form III obtained in step (g) at a temperature of from 90 ° C to 95 ° C; Y
    (i) wash the crystalline Form III obtained in step (h) first with hot water at a temperature from 90 ° C to 95 ° C and then with ethanol.
     10
    [12]
    12. A process for the purification of the crystalline Form III of the pyrvinium pamoate salt of formula (I), which comprises preparing the Crystalline Form A of the pyrvinium pamoate salt of formula (I) from the crystalline Form III obtained by the process of any one of claims 9-10 and then transforming the crystalline form A into the crystalline form III by the method of claim 11. 15

    [13]
    13. A crystalline Form A of the pyrvinium pamoate salt of formula (I) characterized by having an X-ray diffractogram comprising characteristic peaks at 2.8, 5.1, 7.2, 8.9, 9.6 , 9,9,15,9,16,3,17.9, 21.0 ± 0.2 degrees 2 theta measured on an X-ray diffractometer with Ka de Cu radiation (1.5418 Á). twenty

    [14]
    14. A crystalline Form III of the pyrvinium pamoate salt of formula (I) characterized by having an X-ray diffractogram comprising characteristic peaks at 6.0, 8.6, 9,5,10,3,10,5 , 14,3,14,9,16,6,17,4,18,1,19,1,19,7, 20.6, 21.5, 22.0, 22.6, 23.6, and 24.9 ± 0.2 degrees 2 theta measured on an X-ray diffractometer with Ka de Cu radiation (1.5418 Á). 25

    [15]
    15. A pharmaceutical composition comprising any of the crystalline forms of the pyrvinium pamoate salt of formula (I) defined in any of claims 13-14, together with one or more pharmaceutically acceptable excipients or carriers.
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    同族专利:
    公开号 | 公开日
    EP3231796A1|2017-10-18|
    ES2689371B1|2019-08-22|
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    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    US2925417A|1957-11-06|1960-02-16|Parke Davis & Co|Quinolinium salts of pamoic acid|
    WO2006078754A1|2005-01-18|2006-07-27|Immusol Incorporated|Novel quinolinium salts and derivatives|
    WO2021081081A1|2019-10-22|2021-04-29|Thomas Jefferson University|Methods of treating, ameliorating, and/or preventing cancer using pyrvinium compositions|
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