[go: up one dir, main page]

WO2018058296A1 - Sels d'addition de ttp488, leurs formes cristallines, leurs procédés de préparation et leurs compositions pharmaceutiques - Google Patents

Sels d'addition de ttp488, leurs formes cristallines, leurs procédés de préparation et leurs compositions pharmaceutiques Download PDF

Info

Publication number
WO2018058296A1
WO2018058296A1 PCT/CN2016/100314 CN2016100314W WO2018058296A1 WO 2018058296 A1 WO2018058296 A1 WO 2018058296A1 CN 2016100314 W CN2016100314 W CN 2016100314W WO 2018058296 A1 WO2018058296 A1 WO 2018058296A1
Authority
WO
WIPO (PCT)
Prior art keywords
ttp488
crystal form
solvent
hours
characteristic peaks
Prior art date
Application number
PCT/CN2016/100314
Other languages
English (en)
Chinese (zh)
Inventor
盛晓红
盛晓霞
宋小叶
Original Assignee
杭州领业医药科技有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 杭州领业医药科技有限公司 filed Critical 杭州领业医药科技有限公司
Priority to PCT/CN2016/100314 priority Critical patent/WO2018058296A1/fr
Priority to CN201680060380.5A priority patent/CN108349903B/zh
Publication of WO2018058296A1 publication Critical patent/WO2018058296A1/fr

Links

Images

Classifications

    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C07D233/60—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms with hydrocarbon radicals, substituted by oxygen or sulfur atoms, attached to ring nitrogen atoms

Definitions

  • the invention relates to the field of medicinal chemical crystallization technology.
  • it relates to a TTP488 salt and a crystalline form thereof, and to a process for the preparation of the TTP488 salt and its crystalline form, a pharmaceutical composition thereof and use thereof.
  • TTP488 is a receptor for advanced glycation end-product (RAGE) and amyloid/amyloid inhibitor for the treatment and delay of Alzheimer's disease including
  • RAGE advanced glycation end-product
  • amyloid/amyloid inhibitor for the treatment and delay of Alzheimer's disease including
  • the main function of a disease or condition such as Alzheimer's disease is to reduce the degree of cognitive impairment in the brain of Alzheimer's disease patients by reducing brain inflammation, reducing amyloid aggregation and protein plaque formation in the brain.
  • the degree of development The clinical trial results of TTP488 showed that after 18 months of TTP488 in patients with Alzheimer's disease, the rate of memory and cognitive decline was significantly slower than in patients who had been taking placebo during the experiment.
  • TTP488 chemical name is [3-(4- ⁇ 2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl ⁇ -phenoxy)-prop Base]-diethyl-amine, English name is Azeliragon, also known as PF-04494700, its chemical structure is as follows:
  • TTP488, a process for its preparation and pharmaceutical compositions thereof, and solvates of TTP488, pharmaceutically acceptable salts thereof, and for the treatment and/or prevention of RAGE-mediated diseases and/or with starch are disclosed in the patent CN100525763C
  • TTP4808 Two crystal forms of TTP488, namely crystal forms I and II, are disclosed in the patent CN101663280A, and their preparation methods and their 13 C NMR spectrum, IR spectrum, Raman spectrum, and X-ray powder diffraction peak characterization data are disclosed.
  • the present inventors discovered during the research that the known TTP488 has hydrophobicity and poor solubility in water, and is not suitable for clinical use.
  • novel salt forms of the present invention have one or more improved properties compared to known TTP 488, particularly in the presence of good solubility and stability.
  • the TTP488 new salt form of the present invention has at least one or more superior properties compared to the known TTP488 solid form.
  • Specific improved properties include, for example, higher water solubility, higher dissolution rate, better stability, better flowability, and advantageous processing and handling characteristics.
  • the novel solid form of the invention has higher solubility and better stability.
  • TTP488 hydrochloride salt form 1 a preparation method thereof, a pharmaceutical composition and use thereof.
  • TTP488 hydrochloride salt form 1 which is a compound formed by TTP488 and HCl in a 1:1 molar ratio, and has the structural formula shown in formula (I):
  • the X-ray powder diffraction pattern of the TTP488 hydrochloride salt form 1 represented by 2 ⁇ angle has the following characteristic peaks: 8.0 ⁇ 0.2°, 12.1 ⁇ 0.2°, 16.1 ⁇ 0.2°, 18.6 ⁇ 0.2°, 19.6 ⁇ 0.2 ° and 20.3 ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of the TTP488 hydrochloride salt form 1 represented by the 2 ⁇ angle has characteristic peaks at the following positions: 8.0 ⁇ 0.2°, 12.1 ⁇ 0.2°, 13.1 ⁇ 0.2°, 16.1 ⁇ 0.2° 16.4 ⁇ 0.2°, 18.6 ⁇ 0.2°, 19.6 ⁇ 0.2°, 20.3 ⁇ 0.2°, 21.5 ⁇ 0.2°, 22.5 ⁇ 0.2°, 23.2 ⁇ 0.2° and 24.4 ⁇ 0.2°.
  • the TTP488 hydrochloride salt form 1 has an X-ray powder diffraction pattern having characteristic peaks and relative intensities at the following diffraction angle 2 ⁇ :
  • TTP488 hydrochloride salt form 1 has an X-ray powder diffraction (XRPD) pattern as shown in FIG.
  • the Fourier infrared spectrum of the TTP488 hydrochloride salt form 1 has characteristic peaks at wave numbers of 1503, 1482, 1245, 1226, 1174, 1063, 842, 816, and 797 cm -1 .
  • the present invention provides a method for preparing TTP488 hydrochloride salt form 1, which comprises the steps of separately forming a solution of TTP488 and hydrochloric acid in a solvent, mixing and stirring, separating and drying to obtain the TTP488 hydrochloride crystal.
  • the solvent is selected from the group consisting of C 1 -C 4 alcohols, C 3 -C 4 ketones, cyclic ethers, acetonitrile or mixtures thereof, and the molar ratio of the TTP488 to hydrochloric acid is 1:1 to 1:2.
  • the solvent is selected from the group consisting of isopropanol, acetone, 1,4-dioxane, acetonitrile or mixtures thereof.
  • the preparation method has an operating temperature of -10 to 50 ° C, more preferably room temperature.
  • the agitation time is from 1 to 24 hours, more preferably from 1 to 8 hours.
  • the drying temperature is from 10 to 60 ° C, more preferably from 10 to 40 ° C.
  • the drying time is from 10 to 48 hours, more preferably from 10 to 24 hours.
  • the concentration of the TTP488 in the solvent is 0.1 to 1.2 times, more preferably 0.5 to 1 times, the solubility in the solvent at the crystallization temperature.
  • the “hydrochloric acid” is an aqueous solution of hydrogen chloride at a concentration of 37% by weight, which is commercially available.
  • the TTP488 hydrochloride salt form 1 has the following beneficial effects:
  • TTP488 hydrochloride salt form 1 of the present invention in water at 25 ° C is higher than that of known TTP 488, indicating that the TTP488 hydrochloride salt form 1 of the present invention has better solubility and thus has better bioavailability. degree.
  • the TTP488 hydrochloride salt form 1 of the present invention was allowed to stand in a desiccator at room temperature and a relative humidity of 10% to 90% for 4 months, and its appearance, XRPD and melting point were unchanged. It is indicated that the TTP488 hydrochloride salt form 1 of the invention has good storage stability, can better ensure that the TTP-488 hydrochloride active ingredient itself and the formulation dosage form containing TTP-488 hydrochloride avoid or reduce the manufacture of the drug. Problems such as quality, safety, and stability in processes such as storage and/or storage, such as uneven content of active ingredients, impurities, and the like. Avoid special and expensive packaging.
  • the invention also provides a pharmaceutical composition comprising the TTP488 hydrochloride salt form 1 and at least one pharmaceutically acceptable excipient.
  • the invention also provides the use of the TTP488 hydrochloride salt form 1 in the manufacture of a medicament for the treatment and/or prevention of RAGE-mediated and/or amyloid-related diseases.
  • the second aspect of the technical problem to be solved by the present invention is to provide TTP488 phosphate crystal form 1 and a preparation method, pharmaceutical composition and use thereof.
  • TTP488 phosphate crystal form 1 which is a compound formed by TTP488 and H 3 PO 4 in a molar ratio of 1:1, and has the structural formula shown in formula (II):
  • the X-ray powder diffraction pattern of the TTP488 phosphate crystal form 1 represented by 2 ⁇ angle has the following characteristic peaks: 4.1 ⁇ 0.2°, 13.1 ⁇ 0.2°, 16.2 ⁇ 0.2°, 18.6 ⁇ 0.2°, 19.7 ⁇ 0.2 ° and 20.9 ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of the TTP488 phosphate crystal form 1 represented by the 2 ⁇ angle has characteristic peaks at the following positions: 4.1 ⁇ 0.2°, 10.2 ⁇ 0.2°, 13.1 ⁇ 0.2°, 16.2 ⁇ 0.2°, 18.6 ⁇ 0.2 °, 18.9 ⁇ 0.2 °, 19.7 ⁇ 0.2 °, 20.1 ⁇ 0.2 °, 20.9 ⁇ 0.2 °, 22.0 ⁇ 0.2 °, 22.6 ⁇ 0.2 ° and 23.1 ⁇ 0.2 °.
  • the TTP488 phosphate crystal form 1 has an X-ray powder diffraction pattern having characteristic peaks and relative intensities at the following diffraction angle 2 ⁇ :
  • TTP488 phosphate crystal form 1 has an X-ray powder diffraction (XRPD) pattern as shown in FIG.
  • the Fourier infrared spectrum of the TTP488 hydrochloride salt form 1 has characteristic peaks at wave numbers of 1506, 1482, 1225, 1173, 1087, 1061, 1007, 946, 858, and 836 cm -1 .
  • the present invention provides a method for preparing TTP488 phosphate crystal form 1, which comprises the steps of separately forming a solution of TTP488 and phosphoric acid in a solvent, mixing and stirring, separating and drying to obtain the TTP488 phosphate crystal form 1
  • the solvent is selected from the group consisting of C 1 -C 4 alcohols, C 3 -C 4 ketones, cyclic ethers, acetonitrile or mixtures thereof, and the molar ratio of the TTP488 to the phosphoric acid is 1:1 to 1:2.
  • the solvent is selected from the group consisting of isopropanol, acetone, tetrahydrofuran or mixtures thereof.
  • the preparation method has an operating temperature of -10 to 50 ° C, more preferably room temperature.
  • the agitation time is from 1 to 24 hours, more preferably from 1 to 8 hours.
  • the drying temperature is from 10 to 60 ° C, more preferably from 10 to 40 ° C.
  • the drying time is from 10 to 48 hours, more preferably from 10 to 24 hours.
  • the concentration of the TTP488 in the solvent is 0.1 to 1.2 times, more preferably 0.5 to 1 times, the solubility in the solvent at the crystallization temperature.
  • the "phosphoric acid” is an aqueous phosphoric acid solution having a concentration of 85% by weight, which is commercially available.
  • the TTP488 phosphate crystal form 1 has the following beneficial effects:
  • TTP488 phosphate crystal form 1 of the present invention has better solubility and thus better bioavailability.
  • the TTP488 phosphate crystal form 1 of the present invention was allowed to stand in a desiccator at room temperature and a relative humidity of 10% to 90% for 4 months, and its appearance, XRPD and melting point were unchanged. It is indicated that the TTP488 hydrochloride salt form 1 of the invention has good storage stability, can better ensure that the TTP488 phosphate pharmaceutically active ingredient itself and the formulation dosage form containing TTP488 phosphate avoid or reduce the process of drug manufacture and/or storage. Quality, safety and stability issues, such as uneven content of active ingredients, impurities, etc. Avoid special and expensive packaging.
  • the invention also provides a pharmaceutical composition comprising the TTP488 phosphate crystal form 1 and at least one pharmaceutically acceptable excipient.
  • the invention also provides the use of the TTP488 phosphate crystal form 1 in the manufacture of a medicament for the treatment and/or prevention of a RAGE mediated disease and/or amyloid associated.
  • the third solution to solve the technical problem of the present invention is to provide TTP488 maleate salt form 1 and a preparation method, pharmaceutical composition and use thereof.
  • TTP488 maleate salt form 1 which is a compound formed by TTP488 and maleic acid in a 1:1 molar ratio, and has the structural formula shown in formula (III):
  • the X-ray powder diffraction pattern of the TTP488 maleate salt crystal form 1 represented by 2 ⁇ angle has the following characteristic peaks: 8.0 ⁇ 0.2°, 9.2 ⁇ 0.2°, 16.1 ⁇ 0.2°, 16.4 ⁇ 0.2°, 18.5. ⁇ 0.2° and 19.9 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the TTP488 maleate salt form 1 represented by the 2 ⁇ angle has characteristic peaks at the following positions: 8.0 ⁇ 0.2°, 9.2 ⁇ 0.2°, 13.1 ⁇ 0.2°, 16.1 ⁇ 0.2 °, 16.4 ⁇ 0.2 °, 18.5 ⁇ 0.2 °, 19.9 ⁇ 0.2 °, 20.9 ⁇ 0.2 °, 22.5 ⁇ 0.2 °, 22.8 ⁇ 0.2 ° and 24.5 ⁇ 0.2 °.
  • the TTP488 maleate salt form 1 has an X-ray powder diffraction pattern having characteristic peaks and relative intensities at the following diffraction angle 2 ⁇ :
  • TTP488 maleate salt form 1 has an X-ray powder diffraction (XRPD) pattern as shown in FIG.
  • the Fourier infrared spectrum of the TTP488 maleate salt form 1 has characteristic peaks at wave numbers of 1506, 1484, 1466, 1354, 1235, 1175, 1087, 872, 840, and 647 cm -1 .
  • the present invention provides a process for the preparation of TTP488 maleate salt form 1, which comprises the steps of separately forming a solution of TTP488 and maleic acid in a solvent, mixing and stirring, separating and drying to obtain the TTP488 horse.
  • the salt crystal form 1; the solvent is selected from the group consisting of C 1 -C 4 alcohols, C 3 -C 4 ketones, C 4 -C 6 ethers, C 4 -C 5 esters, acetonitrile or mixtures thereof, the TTP488 and the horse
  • the molar ratio of acid to acid is 1:1 to 1:2.
  • the solvent is selected from the group consisting of isopropanol, acetone, diethyl ether, ethyl acetate or mixtures thereof.
  • the preparation method has an operating temperature of -10 to 50 ° C, more preferably room temperature.
  • the agitation time is from 1 to 7 days, more preferably from 1 to 3 days.
  • the drying temperature is from 10 to 60 ° C, more preferably from 10 to 40 ° C.
  • the drying time is from 10 to 48 hours, more preferably from 10 to 24 hours.
  • the concentration of the TTP488 in the solvent is 0.1 to 1.2 times, more preferably 0.5 to 1 times, the solubility in the solvent at the crystallization temperature.
  • the concentration of the maleic acid in the solvent is 0.5 to 1.2 times its solubility in the solvent at a crystallization temperature.
  • the TTP488 maleate salt form 1 has the following beneficial effects:
  • the TTP488 maleate salt form 1 of the present invention was allowed to stand in a desiccator at room temperature and a relative humidity of 10% to 90% for 4 months, and its appearance, XRPD and melting point were unchanged.
  • the TTP488 maleate salt form 1 of the present invention has good storage stability, and can better ensure that the TTP488 maleate active ingredient itself and the formulation containing TTP488 maleate are avoided or reduced in drug manufacture and / or quality, safety and stability issues in the process of storage, such as uneven content of active ingredients, impurities and so on. Avoid special and expensive packaging.
  • the invention also provides a pharmaceutical composition comprising the TTP488 maleate salt form 1 and at least one pharmaceutically acceptable excipient.
  • the invention also provides the use of the TTP488 maleate salt form 1 in the manufacture of a medicament for the treatment and/or prevention of a RAGE mediated disease and/or an amyloid associated disease.
  • the fourth solution to solve the technical problem of the present invention is to provide TTP488 citrate crystal form 1, a preparation method thereof, a pharmaceutical composition and use thereof.
  • TTP488 citrate crystal form 1 which is a compound formed by TTP488 and citric acid in a 1:1 molar ratio, and has the structural formula shown in formula (IV):
  • the X-ray powder diffraction pattern of the TTP488 citrate form 1 expressed in terms of 2 ⁇ angle has the following characteristic peaks: 8.0 ⁇ 0.2°, 13.1 ⁇ 0.2°, 16.0 ⁇ 0.2°, 18.7 ⁇ 0.2°, and 19.6 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the TTP488 citrate form 1 expressed in terms of 2 ⁇ angle has characteristic peaks at the following positions: 8.0 ⁇ 0.2°, 13.1 ⁇ 0.2°, 16.0 ⁇ 0.2°, 16.4 ⁇ 0.2° , 18.7 ⁇ 0.2 °, 19.6 ⁇ 0.2 °, 20.3 ⁇ 0.2 °, 21.5 ⁇ 0.2 ° and 22.5 ⁇ 0.2 °.
  • the TTP488 citrate crystal form 1 has an X-ray powder diffraction pattern having characteristic peaks and relative intensities at the following diffraction angle 2 ⁇ :
  • TTP488 citrate form 1 has an X-ray powder diffraction (XRPD) pattern as shown in FIG.
  • the Fourier infrared spectrum of the TTP488 citrate form 1 has characteristic peaks at wavenumbers of 1729, 1504, 1483, 1239, 1225, 1175, 1088, 1049, 837 and 667 cm -1 .
  • the present invention provides a method for preparing TTP488 citrate crystal form 1, which comprises the steps of separately forming a solution of TTP488 and citric acid in a solvent, mixing and stirring, separating and drying to obtain the TTP488 citrate.
  • Form 1 the solvent is selected from the group consisting of C 1 -C 4 alcohols, C 3 -C 4 ketones, cyclic ethers, C 4 -C 5 esters, acetonitrile or mixtures thereof, the molar ratio of TTP488 to citric acid is 1: 1 to 1:2.
  • the solvent is selected from the group consisting of isopropanol, acetone, acetonitrile or mixtures thereof.
  • the preparation method has an operating temperature of -10 to 50 ° C, more preferably room temperature.
  • the agitation time is from 1 to 7 days, more preferably from 1 to 3 days.
  • the drying temperature is from 10 to 60 ° C, more preferably from 10 to 40 ° C.
  • the drying time is from 10 to 48 hours, more preferably from 10 to 24 hours.
  • the concentration of the TTP488 in the solvent is 0.1 to 1.2 times, more preferably 0.5 to 1 times, the solubility in the solvent at the crystallization temperature.
  • the concentration of the citric acid in the solvent is 0.5 to 1.2 times the solubility in the solvent at a crystallization temperature.
  • the TTP488 citrate form 1 has the following beneficial effects:
  • TTP488 citrate form 1 of the present invention in water at 25 ° C is higher than that of the known TTP 488, indicating that the TTP488 maleate salt form 1 of the present invention has better solubility and thus has a better biological activity. Utilization.
  • TTP488 citrate form 1 of the present invention was allowed to stand in a desiccator at room temperature and a relative humidity of 10% to 90% for 4 months, and its appearance, XRPD and melting point were unchanged. It is indicated that the TTP488 maleate salt form 1 of the invention has better storage stability, and can better ensure that the TTP488 citrate active ingredient itself and the formulation dosage form containing TTP488 citrate avoid or reduce the manufacture of drugs and/or Problems such as quality, safety, and stability during storage, such as uneven content of active ingredients, impurities, and the like. Avoid special and expensive packaging.
  • the invention also provides a pharmaceutical composition comprising the TTP488 citrate form 1 and at least one pharmaceutically acceptable excipient.
  • the invention also provides the use of the TTP488 citrate form 1 in the manufacture of a medicament for the treatment and/or prevention of a RAGE mediated disease and/or an amyloid associated disease.
  • the fifth aspect of the present invention to solve the technical problem is to provide TTP488 tartrate crystal form 1, a preparation method thereof, a pharmaceutical composition and use thereof.
  • TTP488 tartrate crystal form 1 which is a compound formed by TTP488 and tartaric acid in a molar ratio of 1:1, and the structural formula is as shown in formula (V):
  • the X-ray powder diffraction pattern of the TTP488 tartrate crystal form 1 represented by 2 ⁇ angle has the following characteristic peaks: 4.1 ⁇ 0.2°, 18.2 ⁇ 0.2°, 19.2 ⁇ 0.2°, 19.5 ⁇ 0.2°, and 21.6 ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of the TTP488 tartrate crystal form 1 represented by the 2 ⁇ angle has characteristic peaks at the following positions: 4.1 ⁇ 0.2°, 14.1 ⁇ 0.2°, 16.4 ⁇ 0.2°, 18.2 ⁇ 0.2°, 19.2 ⁇ 0.2 °, 19.5 ⁇ 0.2 °, 20.5 ⁇ 0.2 °, 21.6 ⁇ 0.2 °, 24.2 ⁇ 0.2 ° and 25.0 ⁇ 0.2 °.
  • the TTP488 tartrate crystal form 1 has an X-ray powder diffraction pattern having characteristic peaks and relative intensities at the following diffraction angle 2 ⁇ :
  • TTP488 tartrate crystal form 1 has an X-ray powder diffraction (XRPD) pattern as shown in FIG.
  • the Fourier transform infrared spectrum of the TTP488 tartrate crystal form 1 has characteristic peaks at wave numbers of 1504, 1484, 1237, 1137, 1082, 835, 808, 748, and 665 cm -1 .
  • the present invention provides a method for preparing TTP488 tartrate crystal form 1, which comprises the steps of separately forming a solution of TTP488 and tartaric acid in a solvent, mixing and stirring, separating and drying to obtain the TTP488 tartrate crystal form 1
  • the solvent is selected from the group consisting of C 1 -C 4 alcohols, C 3 -C 4 ketones, C 4 -C 6 ethers, C 4 -C 5 esters, acetonitrile or mixtures thereof, and the molar ratio of TTP488 to tartaric acid is 1: 1 to 1:2.
  • the solvent is selected from the group consisting of isopropanol, acetone, diethyl ether, acetonitrile or mixtures thereof.
  • the preparation method has an operating temperature of -10 to 50 ° C, more preferably room temperature.
  • the agitation time is from 1 to 7 days, more preferably from 1 to 3 days.
  • the drying temperature is from 10 to 60 ° C, more preferably from 10 to 40 ° C.
  • the drying time is from 10 to 48 hours, more preferably from 10 to 24 hours.
  • the concentration of the TTP488 in the solvent is 0.1 to 1.2 times, preferably 0.5 to 1 times, the solubility in the solvent at the crystallization temperature.
  • the concentration of the tartaric acid in the solvent is 0.5 to 1.2 times its solubility in the solvent at a crystallization temperature.
  • the TTP488 tartrate crystal form 1 has the following beneficial effects:
  • TTP488 tartrate crystal form 1 of the present invention in water at 25 ° C is higher than that of the known TTP 488, indicating that the TTP488 maleate salt form 1 of the present invention has better solubility and thus has better bioavailability. degree.
  • TTP488 tartrate crystal form 1 of the present invention was allowed to stand in a desiccator at room temperature and a relative humidity of 10% to 90% for 4 months, and its appearance, XRPD and melting point were unchanged. It is indicated that the TTP488 maleate salt form 1 of the invention has good storage stability, can better ensure that the TTP488 tartrate medicinal active ingredient itself and the formulation dosage form containing TTP488 tartrate avoid or reduce the manufacture and/or storage of the drug. Problems such as quality, safety and stability in the process, such as uneven content of active ingredients, impurities, and the like. Avoid special and expensive packaging.
  • the invention also provides a pharmaceutical composition comprising the TTP488 tartrate salt form 1 and at least one pharmaceutically acceptable excipient.
  • the invention also provides the use of the TTP488 tartrate salt form 1 in the manufacture of a medicament for the treatment and/or prevention of a RAGE mediated disease and/or an amyloid associated disease.
  • the present inventors also developed TTP488 phosphate crystal form 2, TTP488 malate amorphate, TTP488 succinate amorphous, TTP488 sulfate amorphous, TTP488 fumarate amorphous, TTP488 methanesulfonate without research. Stereotypes and methods for their preparation.
  • the TTP488 phosphate crystal form 2 characterized in that the X-ray powder diffraction pattern of the crystal form represented by 2 ⁇ angle has the following characteristic peaks: 4.4 ⁇ 0.2°, 12.8 ⁇ 0.2°, 13.2 ⁇ 0.2°, 16.3 ⁇ 0.2°, 17.6 ⁇ 0.2°, 18.8 ⁇ 0.2°, 19.9 ⁇ 0.2°, 20.5 ⁇ 0.2°, 21.0 ⁇ 0.2°, and 22.7 ⁇ 0.2°.
  • TTP488 phosphate crystal form 2 has an X-ray powder diffraction (XRPD) pattern as shown in FIG.
  • the invention also provides a preparation method of TTP488 phosphate crystal form 2, comprising the following steps: adding TTP488 phosphoric acid
  • the salt crystal form 1 solid forms a suspension in a solvent, and is stirred and crystallized at a certain temperature, and the precipitated crystal is separated and dried to obtain the TTP488 phosphate crystal form 2.
  • the solvent is selected from the group consisting of ethers, esters, alkanes or mixtures thereof in a temperature of from -10 to 50 °C.
  • the TTP488 malate is amorphous, and the preparation method comprises the steps of separately forming a solution system of TTP488 and malic acid in a soluble solvent, wherein a molar ratio of TTP488 to malic acid is 1:1 to 1:2, and mixing two The system forms a suspension for reaction, and after the reaction is completed, the solvent is removed to obtain the amorphous form of the TTP488 malate.
  • the soluble solvent is selected from the group consisting of alcohols, esters, ketones, cyclic ethers, acetonitrile or mixtures thereof.
  • the TTP488 succinate is amorphous, and the preparation method comprises the steps of separately forming a solution system of TTP488 and succinic acid in a soluble solvent, wherein the molar ratio of TTP488 to succinic acid is 1:1 to 1:2, mixing two The system forms a suspension for reaction, and after the reaction is completed, the solvent is removed to obtain the amorphous form of the TTP488 succinate.
  • the soluble solvent is selected from the group consisting of alcohols, esters, ketones, ethers, acetonitrile or mixtures thereof.
  • the TTP488 sulfate is amorphous, and the preparation method comprises the steps of separately forming a solution system of TTP488 and sulfuric acid in a soluble solvent, wherein a molar ratio of TTP488 to sulfuric acid is 1:1 to 1:2, and two systems are formed.
  • the suspension is reacted, and after completion of the reaction, the solvent is removed to obtain the amorphous form of the TTP488 sulfate.
  • the soluble solvent is selected from the group consisting of alcohols, cyclic ethers, ketones, acetonitrile or mixtures thereof.
  • the TTP488 fumarate is amorphous, and the preparation method comprises the steps of separately forming a solution system of TTP488 and fumaric acid in a soluble solvent, wherein the molar ratio of TTP488 to fumaric acid is 1:1 to 1:2.
  • the two systems are mixed to form a suspension for reaction, and after the reaction is completed, the solvent is removed to obtain the TTP488 fumarate amorphous form.
  • the soluble solvent is selected from the group consisting of alcohols, esters, ketones, ethers, acetonitrile or mixtures thereof.
  • the TTP488 methanesulfonate is amorphous, and the preparation method comprises the steps of separately forming a solution system of TTP488 and methanesulfonic acid in a soluble solvent, wherein the molar ratio of TTP488 to methanesulfonic acid is 1:1 to 1:2.
  • the two systems are mixed to form a suspension for reaction, and after the reaction is completed, the solvent is removed to obtain the amorphous form of the TTP488 methanesulfonate.
  • the soluble solvent is selected from the group consisting of alcohols, ethers, ketones, acetonitrile or mixtures thereof.
  • TTP488 hydrochloride salt form 1 TTP488 phosphate crystal form 1, TTP488 maleate salt form 1, TTP488 citrate form 1, TTP488 tartrate crystal form 1, TTP488 Phosphate Form 2, TTP488 Malate Amorphous, TTP488 Succinate Amorph, TTP488 Sulfate Amorph, TTP488 Fumarate Amorph, and TP488 Methanesulfonate Amorph have one or more of the following Improved properties, such as: better solubility, dissolution rate, better thermal stability and storage stability, better flow and better processability, easier at room temperature or high temperature The preparation of the ground is more conducive to the industrialization of the product.
  • TTP488 hydrochloride salt crystal form of the invention 1, TTP488 phosphate crystal form 1, TTP488 maleate salt crystal form 1, TTP488 citrate crystal form 1, TTP488 tartrate crystal form 1, TTP488 phosphate crystal form 2, TTP488
  • TTP488 succinate amorphous, TTP488 sulfate amorphous, TTP488 fumarate amorphous and TP488 methanesulfonate amorphous
  • room temperature means a temperature of 10 to 30 °C.
  • the "cyclic ether” may be tetrahydrofuran, 1,4-dioxane or the like.
  • the “stirring” may be carried out by a conventional method in the art, for example, the stirring method includes magnetic stirring, mechanical stirring, and the stirring speed is 50 to 1800 rpm, preferably 300 to 900 rpm.
  • the "separation” can be carried out by conventional methods in the art, such as filtration, centrifugation or volatilization.
  • the vacuum filtration is preferably carried out by suction filtration at a pressure of less than atmospheric pressure at room temperature, preferably at a pressure of less than 0.09 MPa.
  • the specific operation of the "centrifugation” is to place the sample to be separated in a centrifuge tube, for example, at a rate of 6000 rpm until the solids all sink to the bottom of the centrifuge tube.
  • volatilization volatilizing the solvent contained in the sample to dryness at a certain temperature, and may be naturally volatilized or volatilized to dryness with the aid of nitrogen.
  • the "drying” can be accomplished using conventional techniques in the art, such as drying at ambient temperature, blast drying or reduced pressure drying. It may be reduced in pressure or at normal pressure, and preferably the pressure is less than 0.09 MPa.
  • the drying apparatus and method are not limited, and may be a fume hood, a blast oven, a spray dryer, a fluidized bed drying or a vacuum oven; it can be carried out under reduced pressure or under reduced pressure. The pressure was chosen to be less than 0.09 MPa.
  • crystalline means that the compound is characterized by the X-ray powder diffraction pattern indicated, having a unique ordered molecular arrangement or configuration within the crystal lattice. It is well known to those skilled in the art that the experimental error therein depends on instrument conditions, sample preparation, and sample purity.
  • the 2 ⁇ angle of the peaks in the XRD pattern will typically vary slightly from instrument to sample. The difference in peak angle may vary by 1°, 0.8°, 0.5°, 03°, 0.1°, etc. depending on the instrument, and the error is usually ⁇ 0.2°, so the difference in peak angle cannot be the sole criterion.
  • the relative intensity of the peaks may vary with sample, sample preparation, and other experimental conditions, so the order of peak intensities cannot be the sole or decisive factor.
  • the influence of experimental factors such as sample height causes an overall shift in the peak angle, which usually allows a certain offset.
  • any crystal form having the same or similar characteristic peaks as the X-ray powder diffraction pattern of the present invention is within the scope of the present invention.
  • Single crystal form means a single crystal form as detected by X-ray powder diffraction.
  • novel salt form of TTP488 of the present invention is substantially pure, singular, and substantially free of any other crystalline or amorphous form.
  • substantially pure when used in reference to a new crystalline form means that the new crystalline form comprises at least 80% by weight of the compound present, more preferably at least 90% by weight, especially at least 95% ( Weight), especially at least 99% by weight.
  • the starting material TTP 488 can be prepared by the method described in Example 406 of the patent document CN100525763C, and is also commercially available, which is incorporated herein by reference in its entirety.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically and/or prophylactically effective amount of one or more novel salt forms of TTP488 of the present invention or a novel salt form of TTP488 prepared by the method of the present invention.
  • at least one pharmaceutically acceptable carrier at least one pharmaceutically acceptable carrier.
  • the new salt forms of TTP488 include TTP488 hydrochloride crystal form 1, TTP488 phosphate crystal form 1, TTP488 maleate salt form 1, TTP488 citrate form 1 and TTP488 tartrate form 1.
  • the pharmaceutical composition may also comprise an amorphous form of the crystalline form or salt of another pharmaceutically acceptable salt or salt of TTP488.
  • the pharmaceutical composition may be in a form suitable for oral administration, for example, in the form of tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs, etc. form.
  • the composition for oral use can be prepared by any publicly known method, and such a composition may contain one or more agents selected from the group consisting of sweeteners, flavoring agents, coloring agents, and preservatives. Tablets may contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets.
  • excipients may be, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents such as corn starch or alginic acid; binders such as starch, gelatin or gum arabic And lubricants such as magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may also be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a long lasting effect.
  • a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.
  • the preparation for oral administration may also be in the form of a hard gelatin capsule in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or in the form of a soft gelatin capsule, wherein the active ingredient is in a water or oil medium such as Mix with peanut oil, liquid paraffin or olive oil.
  • an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin
  • a soft gelatin capsule wherein the active ingredient is in a water or oil medium such as Mix with peanut oil, liquid paraffin or olive oil.
  • the aqueous suspensions may contain the active compound in admixture with excipients suitable for the preparation of aqueous suspensions.
  • excipients are suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, and gum arabic; dispersing or wetting agents can be used Is a naturally occurring phospholipid such as lecithin, or a condensation product of an alkylene oxide with a fatty acid such as polyoxyethylene stearate, or a condensation product of ethylene oxide with a long chain fatty alcohol such as heptadecyl oxide cetyl alcohol Or a condensation product of ethylene oxide with a partial ester derived from a fatty acid and an hexitol dehydrate, such as polyoxyethylene sorbitan monooleate.
  • the aqueous suspensions may contain one or more coloring agents, one or more flavoring agents, and one or more sweetening agents such as sucrose
  • the oily suspension can be formulated by suspending the active ingredient in a vegetable oil such as peanut oil, olive oil, sesame oil or coconut oil, or suspension in a mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those described above, as well as flavoring agents, may be added. These compositions can be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Suitable dispersing or wetting agents and suspending agents are those already listed above. Additional excipients such as sweetening, flavoring, and coloring agents may also be present.
  • the pharmaceutical composition may also be in the form of an oil-in-water emulsion.
  • the oil phase may be a vegetable oil such as olive oil or peanut oil, or a mineral oil such as liquid paraffin, or a mixture thereof.
  • Suitable emulsifiers may be naturally occurring gums such as gum arabic or tragacanth, naturally occurring phospholipids such as soy, lecithin, esters derived from fatty acids and hexitol sugar dehydrates or partial esters such as sorbitan mono-oil The acid ester, and the condensation product of the partial ester with ethylene oxide, such as polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweeteners and flavoring agents.
  • Syrups and elixirs can be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain buffers, preservatives, and flavoring and coloring agents.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oily suspension. This suspension may be formulated according to known methods using the appropriate dispersing or wetting agents and suspending agents described above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a diluent or solvent which may be employed in the case of injections, for example, a 1,3-butanediol solution.
  • permissible carriers and solvents that may be used are water, Ringer's solution, and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspension medium.
  • non-volatile oils can be used, using synthetic mono- and diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectable solutions.
  • the pharmaceutical composition may also be in the form of a suppository for rectal administration.
  • These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ambient temperature but liquid at the rectal temperature and which will melt in the rectum.
  • suitable non-irritating excipient include, for example, cocoa butter and polyethylene glycol.
  • creams, ointments, gels, solutions or suspensions containing a crystalline form of the salt or salt of the present invention lotions, ophthalmic ointments and eye drops or ear drops, impregnated bandages and gas may be used. Aerosol and the like.
  • These topical formulations may contain suitable conventional additives such as preservatives, solvents which aid in the penetration of the drug, and lubricants used in ointments and creams.
  • the formulation may also contain compatible conventional carriers such as emulsion or ointment bases and ethanol or oleyl alcohol. Such carriers can be present in amounts of from about 1% up to about 99% of the formulation. More usually, they will be up to about 80% of the formula.
  • topical applications should include mouthwashes and gargles.
  • the crystalline form of the salt or salt of the invention may also be administered in the form of a liposome delivery system, such as small unilamellar vesicles or large unilamellar vesicles as well as multilamellar vesicles.
  • Liposomes can be made from a variety of phospholipids such as cholesterol, stearylamine or phosphatidylcholine.
  • the crystalline form of the salt or salt of the present invention can also be combined with a soluble polymer to form a drug carrier that can be targeted.
  • a polymer may include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamide, or polyoxyethylene polylysine substituted with palmitoyl residues. .
  • the crystalline form of the salt or salt of the present invention can be combined with a class of biodegradable polymers useful for drug controlled release, for example, polylactic acid, polyhydroxybutyric acid, polycarboxyaldehyde, polydihydropyran, A crosslinked or amphoteric block copolymer of polycyanoacrylate and hydrogel.
  • biodegradable polymers useful for drug controlled release, for example, polylactic acid, polyhydroxybutyric acid, polycarboxyaldehyde, polydihydropyran, A crosslinked or amphoteric block copolymer of polycyanoacrylate and hydrogel.
  • the crystalline form of the salt or salt of the present invention can be conveniently conveniently by means of a suitable volatile agent such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, tetrafluoroethane, Heptafluoropropane, carbon dioxide or other suitable gas is delivered in the form of an aerosol spray from a pressurized pack or nebulizer. Placed in a pressurized aerosol, the metering unit can be determined by providing a valve for pumping the metered amount.
  • jelly capsules and cartridges for use in an inhaler or insufflator can be used to create a crystalline form comprising a salt or salt of the invention and a suitable powder base such as a powder mixture of lactose or starch.
  • the present invention provides a crystalline form of one or more salts or salts of TTP488 of the present invention or a crystalline form of a salt or salt of TTP488 obtained by the process of the present invention for the preparation and/or prevention of RAGE-mediated diseases.
  • the crystalline form of the salt or salt of TTP488 comprises TTP488 hydrochloride crystal form 1, TTP488 phosphate crystal form 1, TTP488 maleic acid of the invention Salt crystal form 1, TTP488 citrate crystal form 1, TTP488 tartrate crystal form 1, TTP488 phosphate crystal form 2, TTP488 malate amorphous form, TTP488 succinate amorphous type, TTP488 sulfate amorphous type, TTP488 rich horse
  • the acid salt is amorphous and the TP488 methanesulfonate is amorphous.
  • the present invention provides a method of treating and/or preventing a RAGE-mediated disease and/or an amyloid-related disease, the method comprising administering to a patient in need thereof a therapeutically and/or prophylactically effective amount of the present invention.
  • Such patients include, but are not limited to, mammals.
  • 1 is a 1 H NMR chart of a known TTP488 prepared according to the method described in Example 406 of the patent document CN100525763C.
  • TTP488 hydrochloride salt form 1 is an X-ray powder diffraction pattern of TTP488 hydrochloride salt form 1 prepared according to Example 1.
  • TTP488 hydrochloride salt form 1 prepared according to Example 1.
  • Figure 5 is an X-ray powder diffraction pattern of TTP488 phosphate crystal form 1 prepared according to Example 7 of the present invention.
  • Figure 6 is a TGA pattern of TTP488 phosphate crystal form 1 prepared according to Example 7 of the present invention.
  • Figure 7 is an IR spectrum of TTP488 phosphate crystal form 1 prepared according to Example 7 of the present invention.
  • Figure 8 is an X-ray powder diffraction pattern of TTP488 maleate salt form 1 prepared according to Example 13 of the present invention.
  • Figure 9 is a TGA pattern of TTP488 maleate salt form 1 prepared according to Example 13 of the present invention.
  • Figure 10 is an IR spectrum of TTP488 maleate salt form 1 prepared according to Example 13 of the present invention.
  • Figure 11 is an X-ray powder diffraction pattern of TTP488 citrate crystal form 1 prepared according to Example 20 of the present invention.
  • Figure 12 is a TGA pattern of TTP488 citrate Form 1 prepared according to Example 20 of the present invention.
  • Figure 13 is an IR spectrum of TTP488 citrate crystal form 1 prepared according to Example 20 of the present invention.
  • Figure 14 is an X-ray powder diffraction pattern of TTP488 tartrate crystal form 1 prepared according to Example 26 of the present invention.
  • Figure 15 is a TGA pattern of TTP488 tartrate Form 1 prepared according to Example 26 of the present invention.
  • Figure 16 is an IR spectrum of TTP488 tartrate crystal form 1 prepared according to Example 26 of the present invention.
  • Figure 17 is an X-ray powder diffraction pattern of a typical TTP488 phosphate salt form 2 of the present invention.
  • X-ray powder diffraction (XRPD): The instrument was a Bruker D8 Advance diffractometer. The samples were tested at room temperature. The detection conditions are as follows, the angle range is 3 to 40 ° 2 ⁇ , the step size is 0.02 ° 2 ⁇ , and the speed is 0.2 second / step.
  • Thermogravimetric analysis data was taken from the TA Instruments Q500TGA.
  • the detection method is as follows: 5 to 15 mg of the sample is placed in a platinum crucible, and the sample is raised from room temperature to a temperature of 10 ° C/min under the protection of 40 mL/min dry N 2 by means of segmented high-resolution detection. 350 ° C.
  • Nuclear magnetic resonance spectroscopy data ( 1 H NMR) were taken from a Bruker Avance II DMX 400 MHZ NMR spectrometer. A sample of 1 to 5 mg was weighed and dissolved in a nuclear magnetic sample tube with about 0.5 mL of deuterated reagent for detection.
  • Infrared spectroscopy (IR) data was taken from Bruker Tensor 27, and instrument control software and data analysis software were OPUS.
  • the infrared absorption spectrum is usually collected in the range of 600 to 4000 cm -1 using an ATR apparatus.
  • HPLC High performance liquid chromatography
  • TTP488 was prepared by the method described in Example 406 of the patent document CN100525763C.
  • TTP488 prepared in Preparation Example 1, add 1.0 mL of isopropanol, and add hydrochloric acid solution (18.5 mg of 37% hydrochloric acid to 0.4 mL of isopropanol) to the TTP488 isopropanol solution under stirring.
  • the mixture was stirred at room temperature for 4 hours, filtered under reduced pressure, and dried under vacuum at 40 ° C for 10 hours to obtain 101.6 mg of the TTP488 hydrochloride salt form 1 of the present invention.
  • TTP488 hydrochloride salt form 1 of the present invention was obtained by: adding 1.25 mL of acetone, and add hydrochloric acid solution (20.4 mg of 37% hydrochloric acid to 0.5 mL of acetone) to a solution of TTP488 in acetone under stirring, and stir at room temperature for 1 hour. Filtration under reduced pressure and vacuum drying at 25 ° C for 15 hours gave 100.3 mg of TTP488 hydrochloride salt form 1 of the present invention.
  • TTP488 prepared in Preparation Example 1, add 2.0 mL of acetonitrile, and add hydrochloric acid solution (37.1 mg of 37% hydrochloric acid to 0.4 mL of acetonitrile) to a solution of TTP488 in acetonitrile under stirring, and stir at room temperature for 8 hours. It was filtered under reduced pressure and dried under vacuum at 10 ° C for 24 hours to obtain 98.9 mg of the TTP488 hydrochloride salt form of the present invention.
  • hydrochloric acid solution 37.1 mg of 37% hydrochloric acid to 0.4 mL of acetonitrile
  • TTP488 hydrochloric acid of the present invention 100 mg was weighed, and 2.5 mL of a mixed solvent of methanol: methyl ethyl ketone (1:1) was added. Under stirring, a hydrochloric acid solution (27.8 mg of 37% hydrochloric acid was added to 0.4 mL of methanol: methyl ethyl ketone ( 1:1)))
  • a hydrochloric acid solution 27.8 mg of 37% hydrochloric acid was added to 0.4 mL of methanol: methyl ethyl ketone ( 1:1))
  • Add dropwise to TTP488 in methanol: methyl ethyl ketone (1:1) solution stir at -10 ° C for 16 hours, filter under reduced pressure, and vacuum dry at 50 ° C for 36 hours to obtain 90.2 mg of TTP488 hydrochloric acid of the present invention.
  • TTP488 prepared in Preparation Example 1 was weighed, and 1.0 mL of a mixed solvent of tetrahydrofuran:isopropanol (1:2) was added. Under stirring, a hydrochloric acid solution (24.1 mg of 37% hydrochloric acid was added to 0.4 mL of tetrahydrofuran: isopropyl The alcohol (1:2) was added dropwise to a solution of TTP488 in tetrahydrofuran:isopropanol (1:2), stirred at 40 ° C for 20 hours, filtered under reduced pressure, and dried under vacuum at 10 ° C for 48 hours to obtain 85.6 mg of TTP488 of the present invention. Hydrochloride crystal form 1.
  • TTP488 hydrochloride salt form 1 of the present invention Weigh 100 mg of TTP488 prepared in Preparation Example 1, add 10.0 mL of a mixed solvent of 1,4-dioxane:acetonitrile (1:1), and add hydrochloric acid solution (33.4 mg of 37% hydrochloric acid to 0.4 mL1) under stirring. , 4-dioxane: acetonitrile (1:1)) was added dropwise to TTP488 in 1,4-dioxane:acetonitrile (1:1) solution, stirred at 50 ° C for 24 hours, filtered under reduced pressure, 60 Drying under vacuum for 30 hours afforded 80.3 mg of TTP488 hydrochloride salt form 1 of the present invention.
  • the samples prepared in Examples 2 to 6 had the same or similar XRPD patterns, TGA patterns, and IR patterns (not shown) as the samples of Example 1, indicating that the samples of Examples 2 to 6 and the sample of Example 1 were The same crystal form.
  • TTP488 prepared in Preparation Example 1, add 1.0 mL of isopropanol, and add a phosphoric acid solution (21.7 mg of 85% phosphoric acid to 0.4 mL of isopropanol) to the TTP488 isopropanol solution under stirring.
  • the mixture was stirred at room temperature for 1 hour, filtered under reduced pressure, and dried under vacuum at 30 ° C for 16 hours to obtain 112.5 mg of the TTP488 phosphate crystal form of the present invention.
  • TTP488 prepared in Preparation Example 1, add 1.5 mL of tetrahydrofuran, and stir the phosphoric acid.
  • the solution (26.0 mg of 85% phosphoric acid added to 0.4 mL of tetrahydrofuran) was added dropwise to a solution of TTP488 in tetrahydrofuran, stirred at room temperature for 5 hours, filtered under reduced pressure, and dried under vacuum at 40 ° C for 10 hours to obtain 108.6 mg of the TTP488 phosphate of the present invention.
  • Form 1 Form 1 .
  • TTP488 phosphate crystal form of the present invention 100 mg of TTP488 prepared in Preparation Example 1 was weighed, 2.0 mL of acetone was added, and a phosphoric acid solution (43.3 mg of 85% phosphoric acid was added to 0.4 mL of acetone) was added dropwise to an acetone solution of TTP488 under stirring, and stirred at room temperature for 8 hours. It was filtered under reduced pressure and dried under vacuum at 10 ° C for 24 hours to obtain 104.3 mg of the TTP488 phosphate crystal form of the present invention.
  • a phosphoric acid solution 43.3 mg of 85% phosphoric acid was added to 0.4 mL of acetone
  • TTP488 phosphate crystal form of the present invention 100 mg of TTP488 prepared in Preparation Example 1 was weighed out, and 3.0 mL of methanol: tetrahydrofuran (1:3) was added. Under stirring, a phosphoric acid solution (32.5 mg of 85% phosphoric acid was added to 0.3 mL of methanol: tetrahydrofuran (1:3)). The mixture was added dropwise to a solution of TTP488 in methanol: tetrahydrofuran (1:3), stirred at 40 ° C for 12 hours, filtered under reduced pressure, and dried under vacuum at 45 ° C for 30 hours to obtain 94.1 mg of the TTP488 phosphate crystal form of the present invention.
  • TTP488 prepared in Preparation Example 1, add 1.2 mL of methyl ethyl ketone: 1,4-dioxane (1:2), and add a phosphoric acid solution (36.8 mg of 85% phosphoric acid to 0.3 mL of Ding) under stirring.
  • Ketone: 1,4-dioxane (1:2)) was added dropwise to TTP488 in butanone: 1,4-dioxane (1:2) solution, stirred at 50 ° C for 12 hours, filtered under reduced pressure It was dried under vacuum at 45 ° C for 30 hours to obtain 90.2 mg of TTP488 phosphate crystal form 1 of the present invention.
  • TTP488 phosphate crystal of the present invention 100 mg of TTP488 prepared in Preparation Example 1 was weighed out, and 12 mL of acetonitrile:isopropanol (1:1) was added. Under stirring, a phosphoric acid solution (43.3 mg of 85% phosphoric acid was added to 0.3 mL of acetonitrile: isopropanol (1: 1))) dropwise addition to TTP488 in acetonitrile: isopropanol (1:1) solution, stirring at -10 ° C for 12 hours, filtration under reduced pressure, and vacuum drying at 45 ° C for 30 hours to obtain 84.4 mg of TTP488 phosphate crystal of the present invention.
  • Type 1 100 mg of TTP488 prepared in Preparation Example 1 was weighed out, and 12 mL of acetonitrile:isopropanol (1:1) was added. Under stirring, a phosphoric acid solution (43.3 mg of 85% phosphoric acid was added to 0.3 mL of
  • the samples prepared in Examples 8 to 12 had the same or similar XRPD patterns, TGA patterns, and IR patterns (not shown) as the samples of Example 7, indicating that the samples of Examples 8 to 12 and Example 7 were The same crystal form.
  • TTP488 prepared in Preparation Example 1 was weighed out, and 1.25 mL of acetone was added thereto. Under stirring, a maleic acid solution (26.2 mg of maleic acid dissolved in 0.1 mL of acetone) was added dropwise to an acetone solution of TTP488, and stirred at room temperature for 1 day. Filtration under reduced pressure and vacuum drying at 35 ° C for 20 hours gave 112.9 mg of the TTP488 maleate salt crystal form of the present invention.
  • TTP488 prepared in Preparation Example 1 was weighed, 1.0 mL of ethyl acetate was added, and a maleic acid solution (21.8 mg of maleic acid dissolved in 18 mL of ethyl acetate) was added dropwise to an ethyl acetate solution of TTP488 under stirring. The mixture was stirred at room temperature for 2 days, filtered under reduced pressure, and dried under vacuum at 40 ° C for 10 hours to obtain 110.1 mg of the TTP488 maleate salt crystal form of the present invention.
  • TTP488 prepared in Preparation Example 1, add 2.0 mL of isopropanol, and add a maleic acid solution (32.7 mg of maleic acid dissolved in 0.2 mL of isopropanol) to the TTP488 isopropanol solution under stirring. The mixture was stirred at room temperature for 3 days, filtered under reduced pressure, and dried under vacuum at 10 ° C for 24 hours to obtain 108.4 mg of the TTP488 maleate salt crystal form of the present invention.
  • a maleic acid solution 32.7 mg of maleic acid dissolved in 0.2 mL of isopropanol
  • TTP488 prepared in Preparation Example 1 100 mg was weighed, and 66.0 mL of diethyl ether was added thereto. Under stirring, a maleic acid solution (43.6 mg of maleic acid dissolved in 8.2 mL of diethyl ether) was added dropwise to a solution of TTP488 in diethyl ether, and stirred at room temperature. After filtration under reduced pressure and vacuum drying at 10 ° C for 24 hours, 104.9 mg of TTP488 maleate salt crystal form 1 of the present invention was obtained.
  • TTP488 prepared in Preparation Example 1 was weighed out, and 2.8 mL of methanol:ethyl acetate (1:1) was added thereto, and a maleic acid solution (34.9 mg of maleic acid was dissolved in 0.15 mL of methanol:ethyl acetate (1) was stirred under stirring. :1))) added dropwise to TTP488 in methanol: ethyl acetate (1:1) solution, stirred at -10 ° C for 4 days, filtered under reduced pressure, and vacuum dried at 50 ° C for 30 hours to obtain 97.2 mg of TTP488 Malay of the present invention. Salt crystal form 1.
  • TTP488 prepared in Preparation Example 1, add 1.7 mL of methyl tert-butyl ether: n-propanol (1:4), and dissolve the maleic acid solution (21.8 mg of maleic acid in 0.2 mL of methyl group) with stirring.
  • tert-Butyl ether: n-propanol (1:4) was added dropwise to TTP488 in methyl tert-butyl ether: n-propanol (1:4) solution, stirred at 6 ° C for 7 days, filtered under reduced pressure, 60 ° C Drying under vacuum for 48 hours gave 90.7 mg of TTP 488 maleate salt form 1 of the present invention.
  • TTP488 prepared in Preparation Example 1 was weighed, and 2.8 mL of acetonitrile: butanone (1:2) was added. Under stirring, a maleic acid solution (43.6 mg of maleic acid was dissolved in 0.6 mL of acetonitrile: butanone (1:2) Add) to TTP488 in acetonitrile:butanone (1:2) solution, stir at 50 ° C for 6 days, filter under reduced pressure, and vacuum dry at 50 ° C for 40 hours to obtain 84.5 mg of TTP488 maleate salt form of the present invention. 1.
  • the samples prepared in Examples 14 to 19 had the same or similar XRPD patterns, TGA patterns, and IR patterns (not shown) as the samples of Example 13, indicating that the samples of Examples 14 to 19 and Example 13 were The same crystal form.
  • TTP488 citrate salt form 1 of the present invention was obtained by filtration under pressure and dried under vacuum at 10 ° C for 16 hours.
  • TTP488 citrate salt form 1 of the present invention 100 mg of TTP488 prepared in Preparation Example 1 was weighed, 1.25 mL of isopropanol was added, and a citric acid solution (36.1 mg of citric acid dissolved in 0.7 mL of isopropanol) was added dropwise to a solution of TTP488 in isopropanol under stirring. The mixture was stirred at room temperature for 1 day, filtered under reduced pressure, and dried under vacuum at 10 ° C for 10 hours to obtain 122.7 mg of the TTP488 citrate salt form 1 of the present invention.
  • TTP488 citrate crystal form 1 of the present invention was obtained by stirring 100 mg of TTP488 in Preparation Example 1, add 2.0 mL of acetone:ethanol (1:1), and dilute the citric acid solution (50.6 mg of citric acid in 0.2 mL of acetone:ethanol (1:1)). It was added to a solution of TTP488 in acetone:ethanol (1:1), stirred at room temperature for 3 days, filtered under reduced pressure, and vacuum dried at 40 ° C for 24 hours to obtain 115.2 mg of TTP488 citrate crystal form 1 of the present invention.
  • TTP488 citrate crystal form 1 of the present invention was obtained by stirring 100 mg of TTP488 prepared in Preparation Example 1, add 18.0 mL of ethyl acetate: 1,4-dioxane (1:5), and stir the citric acid solution (50.6 mg of citric acid in 1.5 mL of acetic acid B). Ester: 1,4-dioxane (1:5)) added dropwise to TTP488 in ethyl acetate: 1,4-dioxane (1:5) solution, stirred at -10 ° C for 4 days, minus It was filtered under pressure and dried under vacuum at 45 ° C for 30 hours to obtain 102.7 mg of TTP488 citrate crystal form 1 of the present invention.
  • TTP488 citric acid solution (61.4 mg of citric acid in 0.23 mL of n-butanol: butanone (1) under stirring. :1))) added dropwise to TTP488 in n-butanol: butanone (1:1) solution, stirred at 45 ° C for 5 days, filtered under reduced pressure, and vacuum dried at 60 ° C for 48 hours to obtain 95.1 mg of TTP488 citric acid of the present invention.
  • TTP488 citric acid solution 72.2 mg of citric acid dissolved in 0.4 mL of methanol: isopropyl acetate
  • a citric acid solution 72.2 mg of citric acid dissolved in 0.4 mL of methanol: isopropyl acetate
  • :1)) dropwise added to TTP488 in methanol: isopropyl acetate (1:1) solution, stirred at 50 ° C for 7 days, filtered under reduced pressure, and vacuum dried at 60 ° C for 48 hours to obtain 88.5 mg of TTP488 citric acid of the present invention.
  • the samples prepared in Examples 21 to 25 had the same or similar XRPD patterns, TGA patterns, and IR patterns (not shown) as the samples of Example 20, indicating that the samples of Examples 21 to 25 and Example 20 were The same crystal form.
  • TTP488 prepared in Preparation Example 1, add 1.0 mL of isopropanol: acetone (1:1), and dissolve the tartaric acid solution (28.2 mg of tartaric acid in 0.1 mL of isopropanol: acetone (1:1) with stirring.
  • the solution was added dropwise to an isopropanol:acetone (1:1) solution of TTP488, stirred at room temperature for 1 day, filtered under reduced pressure, and dried under vacuum at 40 ° C for 24 hours to obtain 121.9 mg of the TTP488 tartrate salt form 1 of the present invention.
  • TTP488 prepared in Preparation Example 1 100 mg was weighed, 2.0 mL of acetonitrile was added, and a tartaric acid solution (50.8 mg of tartaric acid dissolved in 0.9 mL of acetonitrile) was added dropwise to a solution of TTP488 in acetonitrile under stirring, and stirred at room temperature for 3 days, and filtered under reduced pressure. It was dried under vacuum at 10 ° C for 10 hours to obtain 116.7 mg of TTP488 tartrate crystal form 1 of the present invention.
  • TTP488 prepared in Preparation Example 1 100 mg was weighed, and 1.0 mL of diethyl ether was added thereto. Under stirring, a tartaric acid solution (42.3 mg of tartaric acid dissolved in 0.1 mL of diethyl ether) was added dropwise to a solution of TTP488 in diethyl ether, and stirred at room temperature for 2 days, and filtered under reduced pressure. It was dried under vacuum at 25 ° C for 16 hours to obtain 110.6 mg of TTP488 tartrate crystal form 1 of the present invention.
  • TTP488 prepared in Preparation Example 1 100 mg was weighed, and 12.0 mL of methanol: tetrahydrofuran (1:1) was added thereto, and a tartaric acid solution (56.4 mg of tartaric acid dissolved in 0.1 mL of methanol: tetrahydrofuran (1:1)) was added dropwise thereto under stirring.
  • TTP488 in methanol: tetrahydrofuran (1:1) solution stirred at -10 ° C for 2 days, filtered under reduced pressure, and dried under vacuum at 40 ° C for 30 hours to obtain 98.5 mg of TTP488 tartrate salt form 1 of the present invention.
  • TTP488 prepared in Preparation Example 1 100 mg was weighed, 2.2 mL of sec-butanol:ethyl acetate (1:5) was added, and a tartaric acid solution (28.2 mg of tartaric acid dissolved in 0.3 mL of sec-butanol:ethyl acetate) was added under stirring. :5))) dropwise added to TTP488 in sec-butanol:ethyl acetate (1:5) solution, stirred at 50 ° C for 2 days, filtered under reduced pressure, and vacuum dried at 60 ° C for 40 hours to obtain 90.4 mg of TTP488 tartaric acid of the present invention. Salt crystal form 1.
  • TTP488 prepared in Preparation Example 1, add 26.0 mL of methyl ethyl ketone: isopropyl acetate (1:1), and dissolve the tartaric acid solution (36.7 mg of tartaric acid in 2.0 mL of methyl ethyl ketone: isopropyl acetate) under stirring. :1))) added dropwise to TTP488 butanone: isopropyl acetate (1:1) solution, stirred at 40 ° C for 2 days, filtered under reduced pressure, and vacuum dried at 50 ° C for 48 hours to obtain 82.5 mg of TTP488 tartaric acid of the present invention. Salt crystal form 1.
  • the samples prepared in Examples 27 to 31 had the same or similar XRPD patterns, TGA patterns, and IR patterns (not shown) as the samples of Example 26, indicating that the samples of Examples 27 to 31 and Example 26 were The same crystal form.
  • TTP488 phosphate crystal form 1 of the present invention prepared in Example 7 100 mg was weighed, 3.0 mL of ethyl acetate was added thereto, and the mixture was stirred at room temperature for 1 day, filtered under reduced pressure, and vacuum dried at 40 ° C for 24 hours to obtain a TTP488 phosphate of the present invention.
  • Form 2 100 mg of the TTP488 phosphate crystal form 1 of the present invention prepared in Example 7 was weighed, 3.0 mL of ethyl acetate was added thereto, and the mixture was stirred at room temperature for 1 day, filtered under reduced pressure, and vacuum dried at 40 ° C for 24 hours to obtain a TTP488 phosphate of the present invention.
  • Form 2 100 mg of the TTP488 phosphate crystal form 1 of the present invention prepared in Example 7 was weighed, 3.0 mL of ethyl acetate was added thereto, and the mixture was stirred at room temperature for 1 day, filtered under reduced pressure, and vacuum
  • TTP488 prepared in Preparation Example 1 was weighed out, and 1.0 mL of ethanol was added thereto. Under stirring, a malic acid solution (30.2 mg of malic acid dissolved in 0.1 mL of ethanol) was added dropwise to an ethanol solution of TTP488, and stirred at 0 ° C for 2 days. The mixture was filtered under reduced pressure and dried under vacuum at 40 ° C for 16 hours to obtain the TTP 488 malate salt of the present invention.
  • TTP488 prepared in Preparation Example 1, add 26.0 mL of acetone, and add succinic acid solution (24.4 mg of succinic acid in 2.0 mL of acetone) to the acetone solution of TTP488 under stirring, and stir at room temperature for 5 days.
  • the mixture was filtered under pressure and dried under vacuum at 25 ° C for 48 hours to obtain the amorphous form of TTP488 succinate of the present invention.
  • TTP488 prepared in Preparation Example 1, add 2.0 mL of isopropanol, and add a sulfuric acid solution (23.4 mg of concentrated sulfuric acid dissolved in 0.2 mL of isopropanol) to a solution of TTP488 in isopropanol under stirring, 40 The mixture was stirred at ° C for 2 days, filtered under reduced pressure, and dried under vacuum at 10 ° C for 48 hours to obtain an amorphous form of TTP488 sulfate of the present invention.
  • TTP488 prepared in Preparation Example 1, add 1.0 mL of methyl ethyl ketone: methanol (1:1), and stir the fumaric acid solution (23.8 mg of fumaric acid in 0.2 mL of butanone: methanol (1:1). The solution was added dropwise to a solution of TTP488 in methyl ethyl ketone (1:1), stirred at room temperature for 5 days, filtered under reduced pressure, and dried under vacuum at 25 ° C for 24 hours to obtain the amorphous form of TTP488 fumarate of the present invention.
  • TTP488 prepared in Preparation Example 1, add 26.0 mL of acetone, and add methanesulfonic acid solution (23.5 mg of methanesulfonic acid dissolved in 2.0 mL of acetone) to a solution of TTP488 in acetone under stirring, and stir at -10 °C. After 3 days, it was filtered under reduced pressure and dried under vacuum at 30 ° C for 16 hours to obtain an amorphous form of the TTP488 methanesulfonate of the present invention.
  • Hard shell capsules prepared by filling traditional two-piece hard capsules containing 20 mg of powdered active ingredient (21 mg TTP488 hydrochloride crystal form 1), 30 mg lactose, 10 mg cellulose and 1.1 mg magnesium stearate A large number of capsule particles.
  • Hard shell capsule The TTP488 hydrochloride salt form 1 of Example 38 was replaced with TTP488 phosphate crystal form 1, TTP488 maleate salt form 1, TTP488 citrate form 1, TTP488, respectively, as described herein.
  • Tartrate salt crystal form 1 TTP488 phosphate crystal form 2 TTP488 malate, TTP488 succinate, TTP488 sulfate, TTP488 fumarate and TTP488 methanesulfonate, the free base in various salt forms in the formulation
  • the molar amount of the free base in the p-toluenesulfonate was the same, and the total amount of the filler and the salt form in the various salt forms was the same as that of the TTP488 hydrochloride salt form 1, and the other operation was the same as in Example 38.
  • Soft gelatin capsules a mixture of active ingredients is prepared in a digestible oil such as soybean oil, cottonseed oil or olive oil by active displacement pumping molten gelatin to form a soft mass containing 20 mg of active ingredient (TTP488 hydrochloride salt form 1) Gelatin capsules. The capsules are washed and dried. The active ingredient can be dissolved in a mixture of polyethylene glycol, glycerin and sorbitol to prepare a drug mixture which can be mixed with water.
  • a digestible oil such as soybean oil, cottonseed oil or olive oil by active displacement pumping molten gelatin to form a soft mass containing 20 mg of active ingredient (TTP488 hydrochloride salt form 1) Gelatin capsules.
  • the capsules are washed and dried.
  • the active ingredient can be dissolved in a mixture of polyethylene glycol, glycerin and sorbitol to prepare a drug mixture which can be mixed with water.
  • TTP488 hydrochloride salt form 1 of Example 49 was replaced with TTP488 phosphate crystal form 1, TTP488 maleate salt form 1, TTP488 citrate form 1, TTP488, respectively, as described herein.
  • Tartrate salt crystal form 1 TTP488 phosphate crystal form 2 TTP488 malate, TTP488 succinate, TTP488 sulfate, TTP488 fumarate and TTP488 methanesulfonate, the free base in various salt forms in the formulation
  • the molar amount of the free base in the TTP488 hydrochloride salt form 1 was the same, and the total amount of the filler and the salt form in the various salt forms was the same as that of the TTP488 hydrochloride salt form 1, and the other operation was the same as in Example 49.
  • Tablets A large number of tablets are prepared by conventional techniques such that the dosage unit is 20 mg active ingredient (21 mg TTP488 hydrochloride crystal form 1), 0.04 mg colloidal silica, 1 mg magnesium stearate, 55 mg microcrystalline cellulose, 2.05 mg of starch and 19.7 mg of lactose.
  • active ingredient 21 mg TTP488 hydrochloride crystal form 1
  • colloidal silica 1 mg magnesium stearate
  • 55 mg microcrystalline cellulose 55 mg microcrystalline cellulose
  • 2.05 mg of starch 2.05 mg of starch
  • 19.7 mg of lactose lactose.
  • Appropriate aqueous or non-aqueous coatings can be used to increase palatability, improve appearance and stability, or delay absorption.
  • TTP488 hydrochloride salt form 1 of Example 60 was replaced with TTP488 phosphate crystal form 1, TTP488 maleate salt form 1, TTP488 citrate form 1, TTP488 tartrate, respectively, as described herein.
  • Form 1 TTP488 Phosphate Form 2
  • TTP488 Malate TTP488 Succinate
  • TTP488 Sulfate TTP488 Fumarate
  • TTP488 Mesylate free base and TTP488 salt in various salt forms in the formulation
  • the molar amount of the free base in the acid salt form 1 was the same, and the total amount of the filler and the salt form in the various salt forms was the same as that of the TTP488 hydrochloride salt form 1, and the other operation was the same as in Example 60.
  • TTP488 hydrochloride salt form of the present invention As is apparent from Table 1, the TTP488 hydrochloride salt form of the present invention, the TTP488 phosphate crystal form of the present invention, the TTP488 maleate salt form of the present invention 1, and the present invention are compared with the prior art TTP488. Both TTP488 citrate form 1 and TTP488 tartrate form 1 of the present invention have higher solubility and thus have better bioavailability.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Biomedical Technology (AREA)
  • Veterinary Medicine (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Psychiatry (AREA)
  • Hospice & Palliative Care (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne le chlorhydrate, le phosphate, le maléate, le citrate et le tartrate de TTP488 et les formes cristallines, les procédés de préparation des sels du TTP488 et leurs formes cristallines, des compositions pharmaceutiques de ceux-ci, et leurs utilisations dans la préparation de médicaments pour le traitement et/ou la prévention de maladies induites par RAGE et/ou de maladies associées à des protéines amyloïdes. Par comparaison avec les TTP488 connus et leurs formes cristallines, les sels de TTP488 et leurs formes cristallines présentent une ou plusieurs caractéristiques améliorées.
PCT/CN2016/100314 2016-09-27 2016-09-27 Sels d'addition de ttp488, leurs formes cristallines, leurs procédés de préparation et leurs compositions pharmaceutiques WO2018058296A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
PCT/CN2016/100314 WO2018058296A1 (fr) 2016-09-27 2016-09-27 Sels d'addition de ttp488, leurs formes cristallines, leurs procédés de préparation et leurs compositions pharmaceutiques
CN201680060380.5A CN108349903B (zh) 2016-09-27 2016-09-27 Ttp488加成盐及其晶型、制备方法及药物组合物

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/CN2016/100314 WO2018058296A1 (fr) 2016-09-27 2016-09-27 Sels d'addition de ttp488, leurs formes cristallines, leurs procédés de préparation et leurs compositions pharmaceutiques

Publications (1)

Publication Number Publication Date
WO2018058296A1 true WO2018058296A1 (fr) 2018-04-05

Family

ID=61763221

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2016/100314 WO2018058296A1 (fr) 2016-09-27 2016-09-27 Sels d'addition de ttp488, leurs formes cristallines, leurs procédés de préparation et leurs compositions pharmaceutiques

Country Status (2)

Country Link
CN (1) CN108349903B (fr)
WO (1) WO2018058296A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108349903A (zh) * 2016-09-27 2018-07-31 杭州领业医药科技有限公司 Ttp488加成盐及其晶型、制备方法及药物组合物
WO2019190823A1 (fr) * 2018-03-28 2019-10-03 Vtv Therapeutics Llc Sels pharmaceutiquement acceptables de [3-(4- {2-butyl-1-[4-(4-chlorophénoxy)-phényl]-1h-imidazol-4-yl} -phénoxy)-propyl]-diéthyl-amine

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1805743A (zh) * 2003-05-20 2006-07-19 特兰斯泰克制药公司 用作逆转淀粉样变性及其他与之相关疾病的rage拮抗剂
CN101663280A (zh) * 2007-04-05 2010-03-03 转化技术制药公司 [3-(4-{2-丁基-1-[4-(4-氯-苯氧基)-苯基]-1h-咪唑-4-基}-苯氧基)-丙基]-二乙基-胺的晶型ⅰ和ⅱ
WO2011041198A1 (fr) * 2009-09-30 2011-04-07 Transtech Pharma, Inc. Dérivés d'imidazole substitués pour traiter la maladie d'alzheimer

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108349903B (zh) * 2016-09-27 2021-07-13 杭州领业医药科技有限公司 Ttp488加成盐及其晶型、制备方法及药物组合物

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1805743A (zh) * 2003-05-20 2006-07-19 特兰斯泰克制药公司 用作逆转淀粉样变性及其他与之相关疾病的rage拮抗剂
CN101663280A (zh) * 2007-04-05 2010-03-03 转化技术制药公司 [3-(4-{2-丁基-1-[4-(4-氯-苯氧基)-苯基]-1h-咪唑-4-基}-苯氧基)-丙基]-二乙基-胺的晶型ⅰ和ⅱ
WO2011041198A1 (fr) * 2009-09-30 2011-04-07 Transtech Pharma, Inc. Dérivés d'imidazole substitués pour traiter la maladie d'alzheimer

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108349903A (zh) * 2016-09-27 2018-07-31 杭州领业医药科技有限公司 Ttp488加成盐及其晶型、制备方法及药物组合物
CN108349903B (zh) * 2016-09-27 2021-07-13 杭州领业医药科技有限公司 Ttp488加成盐及其晶型、制备方法及药物组合物
WO2019190823A1 (fr) * 2018-03-28 2019-10-03 Vtv Therapeutics Llc Sels pharmaceutiquement acceptables de [3-(4- {2-butyl-1-[4-(4-chlorophénoxy)-phényl]-1h-imidazol-4-yl} -phénoxy)-propyl]-diéthyl-amine
US11883383B2 (en) 2018-03-28 2024-01-30 Vtv Therapeutics Llc Pharmaceutically acceptable salts of [3-(4- {2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl} -phenoxy)-propyl]-diethyl-amine

Also Published As

Publication number Publication date
CN108349903B (zh) 2021-07-13
CN108349903A (zh) 2018-07-31

Similar Documents

Publication Publication Date Title
EP2603509B1 (fr) Forme crystalline d'un conpose de pyrimido[6,1-a] isoquinolin-4-on
JP2017128605A (ja) 抗ウイルス化合物の固体形態
WO2018108101A1 (fr) Nouvelles formes cristallines d'acide {[5-(3-chlorophényl)-3-hydroxypyridine-2-carbonyl]amino} acétique et leur procédé de préparation
WO2018184185A1 (fr) Cristal de sel d'addition d'ozanimod, procédé de préparation, composition pharmaceutique, et utilisations
RU2704795C2 (ru) Кристаллическая форма бисульфата ингибитора jak и способ ее получения
US11286259B2 (en) Co-crystals of ribociclib and co-crystals of ribociclib monosuccinate, preparation method therefor, compositions thereof, and uses thereof
WO2022258060A1 (fr) Forme cristalline de lanifibranor et son procédé de préparation
US8193216B2 (en) Polymorphic forms of a GABAA agonist
WO2019183916A1 (fr) Cristal eutectique de fruquintinib, son procédé de préparation, sa composition et ses applications
WO2018058296A1 (fr) Sels d'addition de ttp488, leurs formes cristallines, leurs procédés de préparation et leurs compositions pharmaceutiques
WO2015176591A1 (fr) Sels de betrixaban, procede de preparation et utilisation de ceux-ci
WO2019210511A1 (fr) Sel d'addition de l'agoniste du récepteur s1p1, forme cristalline de celui-ci, et composition pharmaceutique
WO2021143954A2 (fr) Forme cristalline de fluvatinib ou de méthanesulfonate de fluvatinib et son procédé de préparation
WO2019200502A1 (fr) Forme cristalline de mésylate d'abémaciclib, procédé de préparation et composition pharmaceutique associés
CN112778290B (zh) 一种s1p1受体激动剂的加成盐及其晶型和药物组合物
WO2023198197A1 (fr) Forme cristalline plx5622 à l'état libre et son procédé de préparation
EP3950679B1 (fr) Forme cristalline de tetramethylpyrazine nitrone, procédé de préparation et utilisation de celle-ci
WO2018170724A1 (fr) Cocristal de 2-(6-méthyl-pyridine-2-yl)-3-yl-[6-amide-quinoléine-4-yl]-5,6-dihydro-4h-pyrrole[1,2-b]pyrazole, son procédé de préparation et composition pharmaceutique
KR101640808B1 (ko) 4-[2-디메틸아미노-1-(1-하이드록시사이클로헥실)에틸]페닐 4-메틸벤조에이트 하이드로클로라이드의 다형체, 이의 제조 방법 및 이의 용도
WO2022144042A1 (fr) Forme cristalline de tas-116, son procédé de préparation, sa composition pharmaceutique et son utilisation
CN105315230B (zh) 无定型形态的匹维溴铵
JP7627683B2 (ja) Ｎ－Ｔｅｒｔ－ブチル－４［［２－（５－クロロ－２－ヒドロキシ－フェニル）アセチル］アミノ］ピリジン－２－カルボキサミドの固体形態
WO2022194160A1 (fr) Forme solide de fisogatinib et son procédé de préparation
WO2016155631A1 (fr) Nouvelle forme cristalline du topiroxostat et son procédé de préparation
CN116410168A (zh) 一种淫羊藿苷元一水合物晶体及其制备方法

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 16917056

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 16917056

Country of ref document: EP

Kind code of ref document: A1