WO2020118715A1 - Sels de scy-635 et leurs utilisations en médecine - Google Patents

Sels de scy-635 et leurs utilisations en médecine Download PDF

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Publication number
WO2020118715A1
WO2020118715A1 PCT/CN2018/121301 CN2018121301W WO2020118715A1 WO 2020118715 A1 WO2020118715 A1 WO 2020118715A1 CN 2018121301 W CN2018121301 W CN 2018121301W WO 2020118715 A1 WO2020118715 A1 WO 2020118715A1
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WO
WIPO (PCT)
Prior art keywords
salt
compound
formula
hepatitis
salts
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PCT/CN2018/121301
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English (en)
Inventor
Jian Cui
Yao Yu
Minglong HU
Original Assignee
Waterstone Pharmaceuticals (Wuhan) Co., Ltd.
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Filing date
Publication date
Application filed by Waterstone Pharmaceuticals (Wuhan) Co., Ltd. filed Critical Waterstone Pharmaceuticals (Wuhan) Co., Ltd.
Priority to PCT/CN2018/121301 priority Critical patent/WO2020118715A1/fr
Publication of WO2020118715A1 publication Critical patent/WO2020118715A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/64—Cyclic peptides containing only normal peptide links
    • C07K7/645—Cyclosporins; Related peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention belongs to the field of medicine. Specifically, it relates to a v ariety of salts of (3S, 6S, 9S, 12R, 15S, 18S, 21S, 24S, 27R, 30S, 33S) -27- ( (2- (dimethylamino) ethyl) thio) -30-ethyl-33- ( (1R, 2R, E) -1-hydroxy-2-methylhex-4-en-1-yl) -24- (2-hydroxy-2-methylpropyl) -6, 9, 18-triisobutyl-3, 21-diisopropyl-1, 4, 7, 10, 12, 15, 19, 25, 28-nonamethyl-1, 4, 7, 10, 13, 16, 19, 22, 25, 28, 31-undecaazacyclotritriacontan-2, 5, 8, 11, 14, 17, 20, 23, 26, 29, 32-undecaone (I) (SCY-635) , and pharmaceutically composition thereof.
  • SCY-635 (the compound of formula (I) ) is a novel non-immunosuppressive cyclosporine-based analog that exhibits potent suppression of hepatitis C virus (HCV) replication in vitro.
  • SCY-635 inhibited the peptidyl prolyl isomerase activity of cyclophilin A at nanomolar concentrations but showed no detectable inhibition of calcineurin phosphatase activity at concentrations up to 2 ⁇ M.
  • SCY-635 was a weak inhibitor and a poor substrate for P-glycoprotein.
  • SCY-635 is a weaker inhibitor of interleukin-2 secretion than cyclosporine.
  • a series of two-drug combination studies was performed in vitro.
  • SCY-635 exhibited synergistic antiviral activity with alpha interferon 2b and additive antiviral activity with ribavirin.
  • SCY-635 was shown to be orally bioavailable in multiple animal species and produced blood and liver concentrations of parent drug that exceeded the 50%effective dose determined in the bicistronic con1b-derived replicon assay.
  • Different salts of a pharmaceutically active ingredient may have different properties.
  • the change of properties of different salts can provide improved formulations, such as improvement of dissolution rate or stability and shelf life.
  • the final dosage form can also be improved due to changes in properties caused by different salts, for example if such changes can increase exposure, bioavailability or prolong half-life. Therefore, salts research on compounds can provide a basis for the subsequent pharmaceutical use of the said compounds.
  • the present invention relates to acid addition salt form of (3S, 6S, 9S, 12R, 15S, 18S, 21S, 24S, 27R, 30S, 33S) -27- ( (2- (dimethylamino) ethyl) thio) -30-ethyl-33- ( (1R, 2R, E) -1-hydroxy-2-methylhex-4-en-1-yl) -24- (2-hydroxy-2-methylpropyl) -6, 9, 18-triisobutyl-3 , 21-diisopropyl-1, 4, 7, 10, 12, 15, 19, 25, 28-nonamethyl-1, 4, 7, 10, 13, 16, 19, 22, 25, 28, 31-undecaazacyc lotritriacontan-2, 5, 8, 11, 14, 17, 20, 23, 26, 29, 32-undecaone (I) (SCY-635) , and pharmaceutically compositions thereof.
  • a salt of a compound of formula (I) wherein the salt is a pharmaceutically acceptable acid addition salt; and wherein the pharmaceutically acceptable acid addition salt is an inorganic acid salt or an organic acid salt, and wherein the inorganic acid salt is phosphate or sulfate, and wherein the organic acid salt is napadisylate.
  • the inventors did a lot of experiments, including screening a variety of salts and screening a variety of solvents, and finally found that only the said three salts can make the compound of formula (I) to be a stable salt.
  • the said salts of the compound of formula (I) have better water solubility, stability and pharmacokinetic properties than the compound of formula (I) itself.
  • the salt is a phosphate
  • the mole ratio of the compound of formula (I) to phosphoric acid in the phosphate of the compound of formula (I) is from 1: 0.9 to 1: 1.5.
  • the said mole ratio is 1: 1.
  • the salt is a sulfate
  • the mole ratio of the compound of formula (I) to sulfuric acid in the sulfate of the compound of formula (I) is from 1: 0.9 to 1: 1.5.
  • the said mole ratio is 1: 1.
  • the salt is a napadisylate
  • the mole ratio of the compound of formula (I) to 1, 5-naphthalenedisulfonic acid in the napadisylate of the compound of formula (I) is from 1: 0.8 to 1: 1.2.
  • the said mole ratio is 1: 1.
  • a pharmaceutical composition comprising the said salts of the compound of formula (I) above, and a pharmaceutically acceptable excipient.
  • the said pharmaceutical composition is stable and can be used in preventing, managing, treating or lessening chronic hepatitis C and hepatitis C infection in a patient.
  • a medicament for preventing, managing, treating or lessening chronic hepatitis C and hepatitis C infection in a patient.
  • provided herein is a method of preventing, managing, treating or lessening chronic hepatitis C and hepatitis C infection, comprising administering to a patient in need of such treatment a therapeutically effective amount of the salts said above, or the pharmaceutical composition said above.
  • provided herein is the salts said above, or the pharmaceutical composition said above, for use in preventing, managing, treating or lessening chronic hepatitis C and hepatitis C infection in a patient.
  • Fig. 1 shows the Ion chromatogram (IC) of the phosphate of the compound of formula (I) ,
  • Fig. 2 shows the HPLC of the phosphate of the compound of formula (I) .
  • Fig. 3 shows the Ion chromatogram (IC) of the sulfate of the compound of formula (I) .
  • Fig. 4 shows the HPLC of the sulfate of the compound of formula (I) .
  • Fig. 5 shows the 1 H NMR of the napadisylate of the compound of formula (I) .
  • the compound of formula (I) may contain solvent.
  • the solvent contained herein contributes to the internal stability of the acid addition salt thereof.
  • Common solvents include, water, ethanol, methanol, isopropanol, acetone, isopropyl ether, ethyl ether, isopropyl acetate, n-heptane, tetrahydrofuran, dichloromethane, ethyl acetate, etc.
  • room temperature refers to a temperature from about 10 °C to about 40 °C. In some embodiments, “room temperature” refers to a temperature from about 20 °C to about 30 °C; in other embodiments, “room temperature” refers to a temperature from about 25 °Cto about 30 °C.
  • pharmaceutically acceptable means a substance is acceptable from the standpoint of toxicology for pharmaceutical applications and does not adversely interact with active ingredients.
  • polycrystalline form or “polymorphism” is defined as the possibility that there are at least two different crystalline arrangements for the same chemical molecule.
  • “Amorphism” or “amorphous form” refers to substance forming by particle (such as molecule, atom, ion) arranged in no periodic in three-dimensional space, which is characterized by a diffused X-ray powder diffraction pattern with no sharp peaks.
  • Amorphism is a special physical form of solid substance, the ordered structural characteristics in a part of amorphous substance imply there are innumerable links between amorphous substance and crystal substance.
  • Amorphous form of a substance can be obtained by a number of methods as known in the art.
  • These methods include, but are not limited to, rapid freezing method, anti-solvent flocculence, ball-milling method, spray drying method, freeze-drying method, wet granulating method and solid dispersion technique, and the like.
  • solvent means a substance, typically a liquid, that is capable of completely or partially dissolving another substance, typically a solid.
  • Solvents for the practice of the invention include, but are not limited to, water, acetic acid, ethyl ether, isopropyl ether, petroleum ether, isopropyl acetate, methyl tert-butyl ether, n-heptane, acetone, acetonitrile, benzene, chloroform, tetrachloromethane, dichloromethane, dimethyl sulfoxide, 1, 4-dioxane, ethanol, ethyl acetate, n-butanol, tert-butanol, N, N-dimethylacetamide, N, N-dimethylformamide, formamide, formic acid, hexane, isopropanol, methanol, methyl ethyl ketone, 1-methyl-2
  • equivalent is the equivalent amount of other raw materials needed according to the chemical reaction equivalent relationship, wherein the basic raw material is used as the base (1 equivalent) in each step.
  • structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational) forms of the structure; for example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, or geometric mixtures of the present compounds are within the scope disclosed herein.
  • a specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture.
  • a 50: 50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process.
  • patient refers to a human (including adults and children) or other animal. In one embodiment, “patient” refers to a human.
  • the term “treat” , “treating” or “treatment” of any disease or disorder refers in one embodiment, to ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof) .
  • “treat” , “treating” or “treatment” refers to alleviating or ameliorating at least one physical parameter including those which may not be discernible by the patient.
  • “treat” , “treating” or “treatment” refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom) , physiologically, (e.g., stabilization of a physical parameter) , or both.
  • “treat” , “treating” or “treatment” refers to preventing or delaying the onset or development or progression of the disease or disorder.
  • compositions disclosed herein further comprise a pharmaceutically acceptable excipient, which, as used herein, includes any and all solvents, solid excipients, diluent, adhesives, disintegrant or other liquid vehicle, dispersion, flavoring agents or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, glidants, lubricants and the like, as suited to the particular dosage form desired.
  • a pharmaceutically acceptable excipient includes any and all solvents, solid excipients, diluent, adhesives, disintegrant or other liquid vehicle, dispersion, flavoring agents or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, glidants, lubricants and the like, as suited to the particular dosage form desired.
  • a pharmaceutically acceptable excipient includes any and all solvents, solid excipients, diluent,
  • Some non-limiting examples of materials which can serve as pharmaceutically acceptable excipients include ion exchangers; aluminium; aluminum stearate; lecithin; serum proteins such as human serum albumin; buffer substances such as phosphates; glycine; sorbic acid; potassium sorbate; partial glyceride mixtures of saturated vegetable fatty acids; water; salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride and zinc salts; colloidal silica; magnesium trisilicate; polyvinyl pyrrolidone; polyacrylates; waxes; polyethylene-polyoxypropylene-block polymers; wool fat; sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipient
  • the compound, salts, or pharmaceutical compositions disclosed herein are suitable for the treatment of acute and chronic viral infections of infectious hepatitis, particularly can inhibit hepatitis C virus (HCV) effectively, and are suitable for treating or lessening diseases induced by viruses in a patient, especially chronic HCV infections.
  • HCV hepatitis C virus
  • the compound, salts or pharmaceutical composition disclosed herein may be administered in any of the following routes: orally, inhaled by spray, locally, rectally, nasally, vaginally, parenterally such as subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intraventricular, intrasternal, or intracranial injection or infusion, or administered with the aid of an explanted reservoir.
  • routes by orally, intramuscular, intraperitoneal or intravenous injection are preferred.
  • the compound, salts or pharmaceutically acceptable composition thereof may be administered in a unit dosage form.
  • the dosage form may be in a liquid form, or a solid form.
  • the liquid form includes true solutions, colloids, particulates, suspensions.
  • Other dosage forms include tablets, capsules, dropping pills, aerosols, pills, powders, solutions, suspensions, emulsions, granules, suppositories, freeze-dried powder injection, and the like.
  • Oral tablets and capsules may comprise excipients, e.g., binders, such as syrup, arabic gum, sorbitol, tragacanth or polyvinylpyrrolidone; fillers, such as lactose, sucrose, corn starch, calcium phosphate, sorbitol, glycine; lubricants such as magnesium stearate, talc, polyethylene glycol, silica; disintegrating agents, such as potato starch; or acceptable moisturizing agents such as sodium lauryl sulfate. Tablets may be coated by using known methods in pharmaceutics.
  • binders such as syrup, arabic gum, sorbitol, tragacanth or polyvinylpyrrolidone
  • fillers such as lactose, sucrose, corn starch, calcium phosphate, sorbitol, glycine
  • lubricants such as magnesium stearate, talc, polyethylene glycol, silica
  • disintegrating agents such
  • Oral solution may be made as a suspension of water and oil, a solution, an emulsion, syrup or an elixir, or made as a dried product to which water or other suitable medium is added before use.
  • This liquid preparation may comprise conventional additives, e.g., suspending agents, sorbitol, cellulose methyl ether, glucose syrup, gel, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel, hydrogenated edible greases; emulsifying agents such as lecithin, sorbitan monoleate, arabic gum; or non-aqueous carriers (possibly including edible oil) , such as almond oil, grease such as glycerin, ethylene glycol, or ethanol; antiseptics such as methyl or propyl p-hydroxybenzoate, sorbic acid.
  • a flavoring agent or a colorant may be added.
  • Suppositories may comprise a conventional suppository base, such as cocoa butter or other glyceride.
  • the liquid dosage form is usually made from the compound and a sterilized carrier.
  • the preferred carrier is water.
  • the compound can be either dissolved in the carrier or made into a supernatant solution.
  • the compound is firstly dissolved in water, and then filtered and sterilized before being packaged into a sealed bottle or an ampoule.
  • the salts of the compound disclosed herein may be made into a suitable form of ointments, lotions or creams, wherein the active ingredient is suspended or dissolved in one or more carrier (s) .
  • carriers used for an ointment preparation include, but are not limited to: mineral oil, liquid vaseline, white vaseline, propylene glycol, polyoxyethylene, polyoxypropylene, emulsified wax and water;
  • carriers used for a lotion and a cream include, but are not limited to: mineral oil, sorbitan monostearate, Tween 60, cetyl ester wax, hexadecylene aromatic alcohol, 2-octyl dodecanol, benzyl alcohol and water.
  • the pharmaceutical composition provided herein further comprises anti-HCV drugs, and the anti-HCV drug is an HCV polymerase inhibitor, immunomodulator or interferon.
  • HCV disease is a hepatic disease caused by hepatitis C virus infection or hepatitis C infection, including acute hepatitis, chronic hepatitis, cirrhosis and hepatocellular carcinoma.
  • the symptoms of acute hepatitis C virus infection may be asymptomatic or manifested as acute hepatitis symptoms.
  • a patient with chronic virus infection suffers an active disease, which can progress to cirrhosis and liver cancer.
  • an “effective amount” , "a therapeutically effective amount” or “effective dose” of the compound, salt, crystalline form, complex or pharmaceutically acceptable composition disclosed herein is an amount that is effective in treating or lessening the severity of one or more of the aforementioned disorders.
  • the complex and pharmaceutically acceptable compositions are effective administered in a fairly wide dose range.
  • the daily dose is from about 0.1 mg to 1000 mg per person, the compounds or pharmaceutically acceptable compositions can be administered in a single dose or in several divided doses a day.
  • the salts and compositions, according to the method disclosed herein, may be administered using any amount and any route of administration which is effective for treating or lessening the severity of the disorder or disease.
  • the exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular agent, its mode of administration, and the like.
  • the compound, salt or pharmaceutical composition disclosed herein can also be administered with one or more other therapeutic agents as discussed above.
  • XRPD refers to X-ray powder diffraction. Some informations such as change in crystalline form, crystallinity, crystal structure state, etc., can be obtained through detection of X-ray powder diffraction (XRPD) which is a common method used for identifying crystalline form.
  • XRPD X-ray powder diffraction
  • the term "X-ray powder diffraction pattern" or “XRPD pattern” refers to the experimentally observed diffractogram or parameters derived therefrom.
  • the X-ray powder diffraction (XRPD) is characterized by the peak position (abscissa) and the peak intensity (ordinate) .
  • the peak position of XRPD pattern mainly depends on the crystal structure, which is relatively insensitive to experimental details, and the relative peak height depends on many factors related to sample preparation and the geometry of the instrument.
  • the crystalline form disclosed herein is characterized by an X-ray powder diffraction pattern having some peaks in certain positions, which is substantially the same as the XRPD pattern provided in appended figures of the present invention.
  • Table 2 IC method for counter-ion content measurement
  • the compound of formula (I) (SCY-635) can be prepared refer to the method described in any reasonable synthetic methods, or through commercial purchase.
  • Fig. 1 shows the Ion chromatogram (IC) of the phosphate of the compound of formula (I)
  • Fig. 3 shows the Ion chromatogram (IC) of the sulfate of the compound of formula (I)
  • Fig. 5 shows the 1 H NMR (DMSO-d6) of the napadisylate of the compound of formula (I) .

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Abstract

La présente invention concerne des sels d'un composé de formule (I) et leurs utilisations en médecine. Plus particulièrement, l'invention concerne un sel d'addition d'acide du composé de formule (I) et des compositions pharmaceutiques de celui-ci. En outre, l'invention concerne des utilisations du sel d'addition d'acide et des compositions pharmaceutiques de celui-ci dans la fabrication d'un médicament, en particulier dans la fabrication d'un médicament pour la prévention, la gestion, le traitement ou l'atténuation d'une infection par le virus de l'hépatite C (VHC). (I)
PCT/CN2018/121301 2018-12-14 2018-12-14 Sels de scy-635 et leurs utilisations en médecine WO2020118715A1 (fr)

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PCT/CN2018/121301 WO2020118715A1 (fr) 2018-12-14 2018-12-14 Sels de scy-635 et leurs utilisations en médecine

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5994299A (en) * 1996-12-24 1999-11-30 Rhone-Poulenc Rorer, S.A. Cyclosporin compounds, their preparation and the pharmaceutical compositions which contain them
CN101068829A (zh) * 2004-10-01 2007-11-07 西尼克斯公司 用于治疗和预防丙型肝炎病毒感染的3－醚和3－硫醚取代的环孢菌素衍生物
CN101316606A (zh) * 2005-09-30 2008-12-03 西尼克斯公司 治疗和预防丙型肝炎感染的方法和药物组合物
CN102834409A (zh) * 2009-12-30 2012-12-19 西尼克斯公司 环孢菌素类似物
CN103153330A (zh) * 2010-08-12 2013-06-12 美国科技环球有限公司 新的环孢霉素衍生物在病毒感染的治疗和预防中的应用

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5994299A (en) * 1996-12-24 1999-11-30 Rhone-Poulenc Rorer, S.A. Cyclosporin compounds, their preparation and the pharmaceutical compositions which contain them
CN101068829A (zh) * 2004-10-01 2007-11-07 西尼克斯公司 用于治疗和预防丙型肝炎病毒感染的3－醚和3－硫醚取代的环孢菌素衍生物
CN101316606A (zh) * 2005-09-30 2008-12-03 西尼克斯公司 治疗和预防丙型肝炎感染的方法和药物组合物
CN102834409A (zh) * 2009-12-30 2012-12-19 西尼克斯公司 环孢菌素类似物
CN103153330A (zh) * 2010-08-12 2013-06-12 美国科技环球有限公司 新的环孢霉素衍生物在病毒感染的治疗和预防中的应用

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