WO2022083476A1 - Forme cristalline du citrate de géfapixant, son procédé de préparation et son utilisation - Google Patents

Forme cristalline du citrate de géfapixant, son procédé de préparation et son utilisation Download PDF

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Publication number
WO2022083476A1
WO2022083476A1 PCT/CN2021/123311 CN2021123311W WO2022083476A1 WO 2022083476 A1 WO2022083476 A1 WO 2022083476A1 CN 2021123311 W CN2021123311 W CN 2021123311W WO 2022083476 A1 WO2022083476 A1 WO 2022083476A1
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Prior art keywords
crystal form
csi
citrate
form csi
compound
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PCT/CN2021/123311
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English (en)
Chinese (zh)
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陈敏华
朱宏艳
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苏州科睿思制药有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/14—Antitussive agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms

Definitions

  • the present invention relates to the field of crystal chemistry. Specifically, it relates to the crystalline form of Gefapixant citrate and its preparation method and use.
  • Chronic cough is a cough that persists for more than eight weeks and can be caused by lung disease (eg, asthma, chronic obstructive pulmonary disease, or idiopathic pulmonary fibrosis), extrapulmonary disease (allergic rhinitis, gastroesophageal reflux), certain A side effect of the drug, or an unrecognized cause.
  • Chronic cough is characterized by high frequency of coughs (10-100 per hour) and long duration (months or years).
  • the P2X3 receptor is an adenosine triphosphate (ATP)-gated ion channel expressed by sensory neurons and is a target for the treatment of chronic sensitization disorders.
  • P2X3 receptors play a key role in the sensitization of certain sensory nerves. Triggered by injury or infection in the airways and lungs, these sensory nerves are activated or sensitized in pathological conditions mediated by common cellular signaling (ATP), resulting in excessive, persistent, and frequent cough urges, known as chronic cough.
  • ATP common cellular signaling
  • Gefapixant is the first non-narcotic P2X3 receptor blocker that selectively blocks ATP activation of P2X3 receptors and is potentially useful for the treatment of cough, chronic cough and cough in respiratory conditions and disorders, among other conditions impulse.
  • Compound I 5-(2,4-diamino-pyrimidin-5-yloxy)-4-isopropyl-2-methoxy-benzenesulfonamide
  • a crystal is a solid in which the molecules of a compound are arranged in a three-dimensional order in a microstructure to form a crystal lattice.
  • Polymorphism is the phenomenon in which a compound exists in more than one crystal form. Compounds may exist in one or more crystalline forms, but their existence and identity cannot be specifically expected. APIs with different crystal forms have different physicochemical properties, which may lead to different dissolution and absorption of the drug in the body, thereby affecting the clinical efficacy of the drug to a certain extent. Especially for some insoluble oral solid or semi-solid preparations, the crystal form is very important to the product performance. In addition to this, the physicochemical properties of the crystal form are crucial to the production process. Therefore, polymorphism is an important part of drug research and drug quality control.
  • WO2019209607A1 discloses Compound I citrate methanol solvate crystal form 1, isopropanol solvate crystal form 1 and hydrated methanol solvate crystal form 1.
  • WO2019209607A1 also discloses that Compound I citrate can form a solvate with ethanol/water, isopropanol/water, tetrahydrofuran or N-methylpyrrolidone.
  • Q3C Impurities: Guidelines for Residual Solvents" issued by ICH, methanol, tetrahydrofuran and N-methylpyrrolidone belong to class 2 solvents.
  • Class 2 solvents are solvents that are carcinogenic to animals and need to be strictly restricted in pharmaceutical products to protect patients protected from potential adverse reactions.
  • ethanol is metabolized by the liver to acetaldehyde.
  • acetaldehyde is a class 1 carcinogen.
  • Isopropyl alcohol is a potent central nervous system depressant, and poisoning by ingestion or inhalation may cause coma and respiratory arrest. Its metabolite is acetone, which may cause and prolong central nervous system depression.
  • the compound I citrate solvate disclosed in WO2019209607A1 is not suitable for drug development, and to a certain extent, it shows that the compound I citrate solvate is easy to obtain solvate.
  • WO2018118668A1 discloses Compound I citrate crystal form A and crystal form B, and its specification also discloses "It is speculated that crystal form A may be the most thermodynamically stable anhydrous form of citrate".
  • NMR data showed that both Form A and Form B had solvent residues. Residual solvents may lead to drug transcrystallization or impurity formation during production and storage, resulting in changes in drug bioavailability and toxic side effects. In addition, the residual solvent itself can also affect the safety of the drug.
  • Compound I citrate easily forms a solvate, and it is very difficult to obtain a new crystal form that meets the pharmaceutical standards.
  • the inventors of the present application have found that, in addition to the solvate disclosed in the WO2019209607A1 patent, Compound I citrate can also interact with various other solvents (2-methyltetrahydrofuran, trifluoroethanol, dibromomethane, p-xylene, benzoyl ether, n-butanol, toluene, etc.) form solvates or hydrated solvates.
  • the inventors of the present application tried a variety of experimental methods (such as volatilization, cooling, humidity induction, anti-solvent addition, gas-liquid diffusion and gas-solid diffusion, etc.), and carried out more than 1,000 experiments, but no new crystal forms that meet the pharmaceutical standards have been obtained. .
  • the experimental method of volatilization is very easy to obtain the amorphous form of Compound I citrate, even if the inventor of the present application has conducted a large number of experimental studies, including trying a variety of single or mixed solvents, changing the initial concentration of volatilization, the mixing ratio of solvents and It is also difficult to obtain a new crystal form that meets the pharmaceutical standards by changing the volume of the volatilized solution and the temperature of volatilization.
  • the crystal form CSI of the present invention was finally found creatively. It has advantages in at least one aspect of dissolution residue, solubility, hygroscopicity, purification effect, stability, adhesion, compressibility, fluidity, in vitro and in vivo dissolution, bioavailability, etc., especially without dissolution residue, solubility, etc. High, solves the problems existing in the prior art, and has very important significance for the development of drugs containing compound I.
  • the present invention provides a new crystal form of compound I citrate, a preparation method and use of the new crystal form, and a pharmaceutical composition thereof.
  • the present invention provides Compound I citrate crystal form CSI (hereinafter referred to as "crystal form CSI").
  • the X-ray powder diffraction pattern of the crystalline form CSI has characteristic peaks at diffraction angle 2 ⁇ values of 6.6° ⁇ 0.2°, 11.7° ⁇ 0.2°, and 20.0° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form CSI is characterized at any one of the diffraction angle 2 ⁇ values of 10.5° ⁇ 0.2°, 13.9° ⁇ 0.2°, and 18.5° ⁇ 0.2° peaks; preferably, the X-ray powder diffraction pattern of the crystalline form CSI has characteristic peaks at 3 positions in the diffraction angle 2 ⁇ of 10.5° ⁇ 0.2°, 13.9° ⁇ 0.2°, and 18.5° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form CSI has features at any one of the diffraction angle 2 ⁇ values of 18.0° ⁇ 0.2°, 23.8° ⁇ 0.2°, and 24.7° ⁇ 0.2° peaks; preferably, the X-ray powder diffraction pattern of the crystalline form CSI has characteristic peaks at 3 positions in the diffraction angle 2 ⁇ of 18.0° ⁇ 0.2°, 23.8° ⁇ 0.2°, and 24.7° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form CSI has diffraction angle 2 ⁇ values of 6.6° ⁇ 0.2°, 11.7° ⁇ 0.2°, 20.0° ⁇ 0.2°, 10.5° ⁇ 0.2° , 13.9° ⁇ 0.2°, 18.5° ⁇ 0.2°, 18.0° ⁇ 0.2°, 23.8° ⁇ 0.2°, 24.7° ⁇ 0.2°, 9.9° ⁇ 0.2°, 16.7° ⁇ 0.2°, 22.6° ⁇ 0.2°
  • the X-ray powder diffraction pattern of the crystalline form CSI is substantially as shown in FIG. 1 .
  • differential scanning calorimetry analysis diagram of the crystalline form CSI is basically shown in FIG. 2 .
  • thermogravimetric analysis diagram of the crystalline form CSI is basically as shown in FIG. 3 , heating to 100° C. has a mass loss of about 3.5%, corresponding to the desorption of water.
  • the crystal form CSI is a hydrate crystal form.
  • the present invention also provides a preparation method of crystal form CSI, characterized in that the preparation method comprises: dissolving the solid compound I citrate in a mixed solvent of water and alcohols, and slowly volatilizing to obtain crystal form CSI .
  • the alcohols are preferably trifluoroethanol; the temperature of the slow volatilization is preferably 2-40° C.; the ratio of the mixed solvent (water:alcohols, v:v) is 1:25-1:2.
  • the present invention also provides a pharmaceutical composition comprising an effective therapeutic amount of crystalline form CSI and pharmaceutically acceptable excipients.
  • crystal form CSI provided by the present invention in the preparation of a P2X3 receptor blocker medicine.
  • the crystalline form CSI provided by the present invention has no solvent residue. Residual solvents not only affect the safety of the drug, but also have an impact on the quality and stability of the drug. Residual solvents may lead to drug transcrystallization or impurity formation during production and storage, resulting in changes in drug bioavailability and toxic side effects.
  • the crystal form CSI provided by the invention has no solvent residue, and effectively overcomes the disadvantages of low drug stability, poor curative effect and high toxicity caused by low drug purity or high solvent residue.
  • the crystalline form CSI provided by the present invention has higher solubility.
  • the solubility of the crystal form CSI is 1.5 times that of the crystal form A of the prior art WO2018118668A1.
  • Higher solubility is beneficial to improve the absorption of drugs in the human body and improve bioavailability; in addition, higher solubility can reduce the dosage of drugs while ensuring the efficacy of drugs, thereby reducing the side effects of drugs and improving the safety of drugs.
  • the crystal form CSI API provided by the present invention has better physical and chemical stability and humidity stability. After the crystalline form of CSI APIs are separately packaged and placed under the conditions of 25°C/60%RH, the crystal form has not changed for at least 6 months, and the purity remains basically unchanged during storage. It shows that the crystalline CSI API has good stability under long-term conditions, which is beneficial to the storage of the drug.
  • the crystal form CSI API After the crystalline form CSI API has been sealed and packaged, the crystal form has not changed under the condition of 40°C/75%RH for at least 6 months, and the crystal form has not changed under the condition of 60°C/75%RH for at least 1 month, and The purity remains essentially unchanged during storage. It shows that the crystalline form CSI API has better stability under accelerated conditions and more severe conditions. Meanwhile, the crystalline form CSI has good humidity stability. After the crystal form CSI of the present invention is cycled once under a relative humidity of 40%-95%-0%-95%, the crystal form does not change. Furthermore, the crystalline form CSI did not deliquescence after being placed at room temperature/97%RH for 14 days, indicating that the crystalline form CSI has better stability under high humidity conditions.
  • CSI API High temperature and high humidity conditions caused by seasonal differences, climate differences in different regions and environmental factors will affect the storage, transportation and production of APIs. Therefore, the stability of the drug substance under accelerated and more severe conditions is critical for the drug.
  • the crystalline form of CSI API has better stability under harsh conditions, which is beneficial to avoid the influence on the quality of the drug due to transcrystallization or decrease in purity during drug storage.
  • Crystalline CSI has good physical and chemical stability, ensuring consistent and controllable quality of APIs and preparations, and reducing drug quality changes, bioavailability changes and toxic side effects caused by changes in crystal form or impurities.
  • the crystal form CSI API provided by the present invention has good mechanical stability. After grinding, the crystalline form CSI API did not transform into crystals and the crystallinity did not decrease, and had good physical stability. In the process of preparation processing, it is often necessary to grind and pulverize the API, and good physical stability can reduce the risk of lowering the crystallinity of the API and the risk of crystal transformation during the preparation process.
  • Figure 1 shows the XRPD pattern of crystalline form CSI
  • Figure 2 is the DSC diagram of the crystal form CSI
  • Figure 3 is the TGA diagram of the crystal form CSI
  • Figure 4 is the 1 H NMR chart of the crystalline form CSI
  • Figure 5 is the XRPD comparison chart of crystalline CSI before and after being placed under different conditions (from top to bottom: before placing, placed at 25°C/60%RH for 6 months (airtight packaging), placed at 25°C/60%RH for 6 months month (open packaging), 6 months at 40°C/75%RH (airtight packaging), 1 month at 60°C/75%RH (airtight packaging))
  • Figure 6 is the XRPD comparison chart of crystal form CSI before and after DVS test (top: before DVS, bottom: after DVS)
  • Figure 7 is the XRPD comparison chart of the crystal form CSI before and after grinding (top: before grinding, bottom: after grinding)
  • the X-ray powder diffraction pattern of Example 6 of the present invention was collected on a Bruker D8 DISCOVER X-ray powder diffractometer.
  • the method parameters of X-ray powder diffraction of the present invention are as follows:
  • X-ray powder diffraction patterns of other examples described herein were collected on a Bruker D2 PHASER X-ray powder diffractometer.
  • the method parameters of X-ray powder diffraction of the present invention are as follows:
  • DSC Differential Scanning Calorimetry
  • thermogravimetric analysis (TGA) plots described in the present invention were collected on a TA Q500.
  • the method parameters of thermogravimetric analysis (TGA) of the present invention are as follows:
  • the dynamic moisture adsorption (DVS) map of the present invention is collected on the Intrinsic dynamic moisture adsorption instrument produced by SMS company (Surface Measurement Systems Ltd.).
  • the instrument control software is DVS-Intrinsic control software.
  • the method parameters of the described dynamic moisture adsorption instrument are as follows:
  • Relative humidity range 0%RH-95%RH
  • Hydrogen nuclear magnetic resonance data ( 1 H NMR) were obtained from a Bruker Avance II DMX 400M HZ nuclear magnetic resonance spectrometer. Weigh 1-5 mg of the sample, dissolve it with 0.5 mL of deuterated dimethyl sulfoxide, and prepare a solution of 2-10 mg/mL.
  • test parameters for the detection of crystalline CSI related substances of the present invention are shown in Table 2:
  • the "stirring" is accomplished by conventional methods in the art, such as magnetic stirring or mechanical stirring, and the stirring speed is 50-1800 rev/min, wherein the magnetic stirring speed is preferably 300-900 rev/min, and the mechanical stirring The speed is preferably 100-300 revolutions per minute.
  • the "volatilization” is accomplished by conventional methods in the art, such as slow volatilization or rapid volatilization.
  • the slow volatilization can be by sealing the container with a sealing film, puncturing the holes, and standing to volatilize; the fast volatilization can be by leaving the container open to volatilize.
  • the "cooling" is accomplished by conventional methods in the art, such as slow cooling and rapid cooling.
  • the slow cooling is usually carried out at 0.1°C/min.
  • Rapid cooling usually involves transferring the sample directly from an environment not lower than room temperature, such as a refrigerator, for cooling.
  • the “humidity induction” is accomplished by conventional methods in the art, such as induction by placing the solid under a certain humidity condition.
  • gas-liquid diffusion is accomplished by conventional methods in the art, such as inducing a solution containing a compound in a solvent atmosphere.
  • gas-solid diffusion is accomplished by conventional methods in the art, for example, placing the solid in a solvent atmosphere to induce it.
  • anti-solvent addition is accomplished by conventional methods in the art, such as adding another solvent to the solution containing the compound.
  • the "drying” is accomplished by conventional methods in the art, such as vacuum drying, blast drying or natural air drying.
  • the drying temperature may be room temperature or higher, preferably room temperature to about 60°C, or to 50°C, or to 40°C. Drying time can be 2-48 hours, or overnight. Drying takes place in a fume hood, blast oven or vacuum oven.
  • the "open packaging" is accomplished by conventional methods in the art, such as placing the sample in a glass vial, covering the bottle opening with a layer of aluminum foil and making 5-10 small holes in the aluminum foil.
  • the "airtight packaging" is accomplished by conventional methods in the art, such as placing the sample in a glass vial, closing the bottle cap and sealing it in an aluminum foil bag.
  • the “characteristic peak” refers to a representative diffraction peak used to identify crystals.
  • the peak position can usually have an error of ⁇ 0.2°.
  • crystal or “crystal form” can be characterized by X-ray powder diffraction.
  • X-ray powder diffraction pattern will vary depending on the conditions of the instrument, the preparation of the sample, and the purity of the sample.
  • the relative intensities of the diffraction peaks in the X-ray powder diffraction pattern may also vary with the experimental conditions, so the intensity of the diffraction peaks cannot be used as the only or decisive factor for determining the crystal form.
  • the relative intensities of the diffraction peaks in the X-ray powder diffraction pattern are related to the preferred orientation of the crystals, and the diffraction peak intensities shown in the present invention are illustrative and not for absolute comparison. Therefore, those skilled in the art can understand that the X-ray powder diffraction pattern of the crystal form protected by the present invention does not have to be completely consistent with the X-ray powder diffraction pattern in the embodiments referred to here, and any X-ray powder diffraction pattern with the characteristic peaks in these patterns Crystal forms with the same or similar X-ray powder diffraction patterns all fall within the scope of the present invention. Those skilled in the art can compare the X-ray powder diffraction pattern listed in the present invention with an X-ray powder diffraction pattern of an unknown crystal form to confirm whether the two sets of images reflect the same or different crystal forms.
  • the crystalline form CSI of the present invention is pure, substantially free from admixture with any other crystalline form.
  • substantially free when used to refer to a new crystal form means that the crystal form contains less than 20% by weight of other crystal forms, especially less than 10% by weight of other crystal forms, and even less More than 5% (weight) of other crystal forms, more than 1% (weight) of other crystal forms.
  • room temperature is not a specific temperature value, but refers to a temperature range of 10-30°C.
  • the compound I and/or its salts as raw materials include, but are not limited to, solid form (crystalline or amorphous), oily, liquid form and solution.
  • the compound I and/or its salts as starting materials are in solid form.
  • Compound I and/or its salts used in the following examples may be solids/crystal forms disclosed in the prior art, such as those disclosed in WO2018118668A1.
  • Embodiment 2-3 the preparation method of crystal form CSI
  • the crystalline solids obtained in Examples 2-3 are all of the crystal form CSI of the present invention.
  • the X-ray powder diffraction pattern of the crystal form CSI obtained in Example 2 is shown in FIG. 1
  • the X-ray powder diffraction data is shown in Table 6.
  • the DSC chart of the crystal form CSI obtained in Example 2 is shown in FIG. 2 .
  • the TGA diagram of the crystal form CSI obtained in Example 2 is shown in FIG. 3 , when it is heated to 100° C., it has a mass loss of about 3.5%, which corresponds to the removal of water.
  • one hydrogen with a chemical shift ⁇ of 3.34 was covered by the water peak, and four active hydrogens did not appear.
  • the NMR results showed that the crystalline form CSI was the monocitrate of compound I, and did not contain solvent residues.
  • Placement conditions packing condition put time Crystal form purity start —— —— Form CSI 99.45%
  • the crystalline form CSI can be stable for at least 6 months at 25°C/60%RH; after airtight packaging, the crystalline form CSI can be stable at 40°C/75%RH for at least 6 months. months, it can be seen that the crystalline form CSI can maintain good stability under both long-term and accelerated conditions. After airtight packaging, the crystalline form of CSI is stable for at least 1 month at 60°C/75%RH, and it can be seen that the stability is also very good under more severe conditions.
  • the crystalline form CSI was placed in a mortar and manually ground for 5 minutes. XRPD tests were performed before and after grinding. The test results are shown in Figure 7. The results showed that after grinding, the crystal form and crystallinity of crystalline form CSI did not change, and had good stability.

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Abstract

L'invention concerne une nouvelle forme cristalline du citrate de géfapixant (appelé "composé I") et son procédé de préparation, une composition pharmaceutique contenant la forme cristalline et une utilisation de la forme cristalline dans la préparation de médicaments antagonistes du récepteur P2X3 et de médicaments pour le traitement de la toux chronique. La nouvelle forme cristalline du citrate (composé I) selon l'invention présente une ou plusieurs propriétés améliorées par rapport à l'état de la technique, résout les problèmes existant dans l'état de la technique et possède une valeur importante en matière d'optimisation et de développement de médicaments contenant le citrate (composé I).
PCT/CN2021/123311 2020-10-19 2021-10-12 Forme cristalline du citrate de géfapixant, son procédé de préparation et son utilisation WO2022083476A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110087654A (zh) * 2016-12-20 2019-08-02 传入制药公司 P2x3拮抗剂的结晶盐和多晶型物
WO2019209607A1 (fr) * 2018-04-23 2019-10-31 Merck Sharp & Dohme Corp. Nouveau procédé de synthèse d'un composé phénoxy diaminopyrimidine

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110087654A (zh) * 2016-12-20 2019-08-02 传入制药公司 P2x3拮抗剂的结晶盐和多晶型物
WO2019209607A1 (fr) * 2018-04-23 2019-10-31 Merck Sharp & Dohme Corp. Nouveau procédé de synthèse d'un composé phénoxy diaminopyrimidine

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
MALONEY, K.M. ET AL.: "Development of a Green and Sustainable Manufacturing Process for Gefapixant Citrate (MK-7264). Part 6: Development of an Improved Commercial Salt Formation Process", ORGANIC PROCESS RESEARCH & DEVELOPMENT, vol. 24, 23 October 2020 (2020-10-23), XP055862885 *
MOHAN ANNE E., DIBENEDETTO MICHAEL, ALWEDI EMBAREK, ANG YEE SWAN, ASI SIHOMBING MUHAMMAD SOFIAN BIN, CHANG HSIEH YAO D., COTE AARO: "Development and Demonstration of a Co-feed Process to Address Form and Physical Attribute Control of the Gefapixant (MK-7264) Citrate Active Pharmaceutical Ingredient", ORGANIC PROCESS RESEARCH & DEVELOPMENT, AMERICAN CHEMICAL SOCIETY, US, vol. 25, no. 3, 19 March 2021 (2021-03-19), US , pages 541 - 551, XP055922952, ISSN: 1083-6160, DOI: 10.1021/acs.oprd.0c00488 *
REN, H. ET AL.: "Development of a Green and Sustainable Manufacturing Process for Gefapixant Citrate (MK-7264) Part 1: Introduction and Process Overview", ORGANIC PROCESS RESEARCH & DEVELOPMENT, vol. 24, 16 October 2020 (2020-10-16), XP055859791 *

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