WO2017114456A1 - 吗啉衍生物的盐及其晶型、其制备方法及药物组合物、用途 - Google Patents

吗啉衍生物的盐及其晶型、其制备方法及药物组合物、用途 Download PDF

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WO2017114456A1
WO2017114456A1 PCT/CN2016/112966 CN2016112966W WO2017114456A1 WO 2017114456 A1 WO2017114456 A1 WO 2017114456A1 CN 2016112966 W CN2016112966 W CN 2016112966W WO 2017114456 A1 WO2017114456 A1 WO 2017114456A1
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Prior art keywords
morpholine derivative
morpholine
tartrate
free base
acetone
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PCT/CN2016/112966
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English (en)
French (fr)
Inventor
夏广新
谢建树
贾国慧
韩建生
上田直子
饭嶋彻
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Shanghai Pharmaceuticals Holding Co Ltd
Tanabe Pharma Corp
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Shanghai Pharmaceuticals Holding Co Ltd
Mitsubishi Tanabe Pharma Corp
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Priority to ES16881245T priority Critical patent/ES2918674T3/es
Priority to US16/066,490 priority patent/US10519150B2/en
Priority to JP2018534034A priority patent/JP6818031B2/ja
Priority to DK16881245.1T priority patent/DK3398946T3/da
Priority to PL16881245.1T priority patent/PL3398946T3/pl
Priority to EP16881245.1A priority patent/EP3398946B1/en
Publication of WO2017114456A1 publication Critical patent/WO2017114456A1/zh
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
    • C07C309/28—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C309/33—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of six-membered aromatic rings being part of condensed ring systems
    • C07C309/34—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of six-membered aromatic rings being part of condensed ring systems formed by two rings
    • C07C309/35—Naphthalene sulfonic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/41—Preparation of salts of carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/42—Separation; Purification; Stabilisation; Use of additives
    • C07C51/43—Separation; Purification; Stabilisation; Use of additives by change of the physical state, e.g. crystallisation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C53/00—Saturated compounds having only one carboxyl group bound to an acyclic carbon atom or hydrogen
    • C07C53/08—Acetic acid
    • C07C53/10—Salts thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/235—Saturated compounds containing more than one carboxyl group
    • C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/235—Saturated compounds containing more than one carboxyl group
    • C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
    • C07C59/255—Tartaric acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the invention belongs to the technical field of medicinal chemistry, in particular to a salt of a morpholine derivative and a crystal form thereof, a preparation method thereof, and a pharmaceutical composition and use thereof.
  • CN103562191 discloses a free base form of the morpholine derivative, a process for its preparation, and a renin inhibitory activity.
  • the free base is a semi-solid or amorphous powder, is poorly water-soluble, and is more susceptible to oxidation and is not suitable for long-term storage.
  • the present invention provides novel pharmaceutically acceptable salts of morpholine derivatives, including malate, tartrate, hydrochloride, acetate and naphthalene diphosphate, of which tartrate has A crystal form (tetrahydrate), B crystal form (anhydrous) and dihydrate three crystalline salt forms, malate, hydrochloride, acetate each have a crystalline salt type, naphthalene Phosphate is amorphous.
  • the present invention has one or more improved properties compared to the free base of known morpholine derivatives.
  • the present invention further provides a process for the preparation of a salt and a crystalline form of the morpholine derivative, a pharmaceutical composition and use thereof.
  • One of the contents of the present invention is to provide a morpholine derivative malate and a process for the preparation thereof.
  • the morpholine derivative malate is a compound formed by a morpholine derivative and L-malic acid in a 1:1 molar ratio, and has the following structural formula:
  • the morpholine derivative malate has a crystalline form, and its X-ray powder diffraction pattern is 7.767° ⁇ 0.2°, 13.897° ⁇ 0.2°, 14.775° ⁇ 0.2°, 17.098° ⁇ 0.2°, 18.999° ⁇ at 2 ⁇ . Characteristic peaks are present at 0.2°, 20.153 ⁇ 0.2°, 20.960° ⁇ 0.2°, 21.423° ⁇ 0.2°, 26.348° ⁇ 0.2°, 27.892° ⁇ 0.2°.
  • the crystalline form of the morpholine derivative malate has an X-ray powder diffraction pattern of 2.598° ⁇ 0.2°, 7.357° ⁇ 0.2°, 7.767° ⁇ 0.2°, 10.395° ⁇ 0.2°, 11.108 at 2 ⁇ .
  • the morpholine derivative malate has an X-ray powder diffraction (XRPD) pattern as shown in FIG.
  • the morpholine derivative malate has a polarizing light microscope (PLM) pattern as shown in FIG. 2.
  • PLM polarizing light microscope
  • the morpholine derivative malate has a thermogravimetric analysis (TGA) pattern as shown in FIG. 3, and the TGA pattern shows that the morpholine derivative malate is decomposed at about 185.8 ° C, and the sample has no weight loss before decomposition. .
  • TGA thermogravimetric analysis
  • the morpholine derivative malate has a differential thermal analysis (DSC) spectrum as shown in Fig. 4, and its DSC spectrum shows an endothermic peak (95 J/g) at around 121 °C.
  • DSC differential thermal analysis
  • the morpholine derivative malate has a dynamic moisture adsorption analysis (DVS) spectrum as shown in FIG. 5, and the DVS spectrum thereof shows that the morpholine derivative malate is in a range of 20% to 80% humidity.
  • the internal weight change is approximately 1.2%.
  • the method for preparing the morpholine derivative malate comprises the steps of dissolving a morpholine derivative free base in acetone, chloroform, acetonitrile, ethyl acetate, methanol or tetrahydrofuran (preferably acetone) to obtain a morpholine-containing compound.
  • the molar ratio of the morpholine derivative free base to malic acid is from 1:1.1 to 1:3.3, preferably 1:1.1.
  • the morpholine derivative malate has one or more improved properties, for example, a better crystalline state, it is difficult to absorb moisture at 20%-80% RH, and the water solubility is greatly improved. ( ⁇ 100 mg/mL) and good stability under conditions of light and oxidation.
  • a second aspect of the present invention provides a morpholine derivative tartrate salt and a crystal form thereof, and a process for the preparation thereof.
  • the morpholine derivative tartrate is a compound formed by a morphine ratio of a morpholine derivative and L-tartaric acid, and has the following structural formula:
  • the method for preparing the morpholine derivative tartrate comprises the steps of dissolving L-tartaric acid by dissolving the morpholine derivative free base in acetone, chloroform, acetonitrile, ethyl acetate, methanol or tetrahydrofuran (preferably acetone) Water, an aqueous solution of L-tartaric acid was added dropwise to a solution of the morpholine derivative free base in acetone, chloroform, acetonitrile, ethyl acetate, methanol or tetrahydrofuran, and stirred at room temperature overnight to precipitate a white solid.
  • the molar ratio of the morpholine derivative to L-tartaric acid is 1:1.03-1:2.2, preferably 1:1.03.
  • the morpholine derivative tartrate is a morpholine derivative tartrate crystal form B, and its X-ray powder diffraction pattern is 3.339° ⁇ 0.2°, 6.562° ⁇ 0.2°, 11.331° ⁇ 0.2°, 16.396° ⁇ 0.2 at 2 ⁇ . Characteristic peaks at °, 22.041 ° ⁇ 0.2 °.
  • the morpholine derivative tartrate crystal form B has an X-ray powder diffraction pattern at 2.39° ⁇ 0.2°, 5.078° ⁇ 0.2°, 6.562° ⁇ 0.2°, 6.864° ⁇ 0.2°, 8.250° at 2 ⁇ .
  • the morpholine derivative tartrate crystal form B has an XRPD pattern as shown in FIG.
  • the morpholine derivative tartrate crystal form B has a PLM pattern as shown in FIG.
  • the morpholine derivative tartrate crystal form B has a TGA pattern as shown in FIG. 8, and the TGA pattern shows that the morpholine derivative tartrate crystal form B decomposes at around 186.0 ° C, and has a 2.5% slow weight loss before decomposition. (The weight loss starts from around 150 °C).
  • the morpholine derivative tartrate crystal form B has a DSC spectrum as shown in FIG. 9 and a DSC spectrum It is shown that the morpholine derivative tartrate crystal form B has an endothermic peak (38 J/g) at around 161.5 °C.
  • the morpholine derivative tartrate crystal form B has a DVS spectrum as shown in FIG. 10, and the DVS spectrum shows that the weight change is about 7% in a humidity range of 20% to 80%, which is relatively easy to absorb moisture. It may also become a hydrate.
  • the morpholine derivative tartrate crystal form B is added to a mixed solvent of acetone and water, stirred at room temperature for 2 days, and then filtered to obtain a morpholine derivative tartrate dihydrate; the volume ratio of acetone to water is preferably 30:1.
  • the crystalline form of the morpholine derivative tartrate dihydrate has an X-ray powder diffraction pattern of 9.851° ⁇ 0.2°, 13.434° ⁇ 0.2°, 14.410° ⁇ 0.2°, 14.774° ⁇ 0.2° at 2 ⁇ .
  • the morpholine derivative tartrate dihydrate has an XRPD pattern as shown in FIG.
  • the morpholine derivative tartrate dihydrate has a PLM pattern as shown in FIG.
  • the morpholine derivative tartrate dihydrate has a TGA pattern as shown in FIG. 13, and the TGA pattern shows that the morpholine derivative tartrate dihydrate is decomposed at about 189.6 ° C, and has a gradient of 6.95% before decomposition. weightlessness.
  • the morpholine derivative tartrate dihydrate has a DSC spectrum as shown in FIG. 14, and the DSC spectrum shows that the morpholine derivative tartrate dihydrate has an endothermic peak at about 29.5 ° C (112 J / g), there is an exothermic peak (27 J/g) around 99 °C, and an endothermic peak (19 J/g) around 154 °C.
  • the morpholine derivative tartrate dihydrate has a DVS spectrum as shown in FIG. 15, and the DVS spectrum shows a weight change of about 11.06% in a humidity range of 0% to 80%, which is relatively easy to absorb moisture.
  • the invention also discloses a morpholine derivative tartrate tetrahydrate, which is a crystalline form A, and its X-ray powder diffraction pattern is 9.082° ⁇ 0.2°, 14.426° ⁇ 0.2°, 14.802° ⁇ 0.2°, 16.275° ⁇ at 2 ⁇ . There are characteristic peaks at 0.2°, 20.085° ⁇ 0.2°, 20.872° ⁇ 0.2°, 21.978° ⁇ 0.2°, 23.236° ⁇ 0.2°.
  • the morpholine derivative tartrate crystal form A has an X-ray powder diffraction pattern at 9.82° ⁇ 0.2°, 11.964° ⁇ 0.2°, 13.558° ⁇ 0.2°, 14.426° ⁇ 0.2°, 14.802° at 2 ⁇ .
  • the morpholine derivative tartrate crystal form A has an XRPD pattern as shown in FIG.
  • the morpholine derivative tartrate crystal form A has a PLM pattern as shown in FIG.
  • the morpholine derivative tartrate crystal form A has a TGA pattern as shown in FIG.
  • the morpholine derivative tartrate crystal form A has a DSC pattern as shown in FIG.
  • the morpholine derivative tartrate crystal form A has a DVS pattern as shown in FIG.
  • the invention also discloses a preparation method of the morpholine derivative tartrate crystal form A, which comprises the steps of dissolving the morpholine derivative free base in acetone, chloroform, acetonitrile, ethyl acetate, methanol or tetrahydrofuran (preferably Acetone), obtaining a solution of the morpholine derivative free base in acetone, chloroform, acetonitrile, ethyl acetate, methanol or tetrahydrofuran, dissolving L-tartaric acid in water to obtain an aqueous solution of tartaric acid, and adding the aqueous solution of the L-tartaric acid to the solution
  • the morpholine derivative free base is stirred in a solution of acetone, chloroform, acetonitrile, ethyl acetate, methanol or tetrahydrofuran at room temperature for not less than 48 h, and a white solid is precipitated and filtered.
  • the morpholine derivative tartrate has one or more improved properties, for example, both crystal forms A and B have a better crystalline state, but crystal form A is very high at 20%-80% RH. It is difficult to absorb moisture, and Form B is easy to absorb moisture. At the same time, it improves water solubility (50-300mg/mL), and under oxidizing conditions, Form B has better stability than Form A and is stable under light conditions. Sex is equal.
  • a third aspect of the present invention provides a morpholine derivative hydrochloride and a process for the preparation thereof.
  • the morpholine derivative hydrochloride is a compound formed of a morpholine derivative and hydrochloric acid in a molar ratio of 1:2, and has the following structural formula:
  • the morpholine derivative hydrochloride has a crystalline form, and its X-ray powder diffraction pattern is 3.981° ⁇ 0.2°, 7.784° ⁇ 0.2°, 8.667° ⁇ 0.2°, 13.634° ⁇ 0.2°, 18.238° ⁇ at 2 ⁇ . Characteristic peaks are present at 0.2°, 19.620° ⁇ 0.2°, 24.624° ⁇ 0.2°, 24.987° ⁇ 0.2°, 28.072° ⁇ 0.2°, 31.815° ⁇ 0.2°.
  • the crystalline form of the morpholine derivative hydrochloride has an X-ray powder diffraction pattern at 2.81 ° ⁇ 0.2 °, 7.784 ° ⁇ 0.2 °, 8.667 ° ⁇ 0.2 °, 10.914 ° ⁇ 0.2 °, 11.557.
  • the morpholine derivative hydrochloride has an X-ray powder diffraction (XRPD) pattern as shown in FIG.
  • the morpholine derivative hydrochloride has a polarizing light microscope (PLM) pattern as shown in FIG.
  • PLM polarizing light microscope
  • the morpholine derivative hydrochloride has a thermogravimetric analysis (TGA) spectrum as shown in FIG. 23, and the TGA spectrum thereof shows that the morpholine derivative hydrochloride continuously loses weight during the temperature rise, and the decomposition temperature is 207. °C, there are two stages of weight loss before decomposition, a total of about 9.1%.
  • TGA thermogravimetric analysis
  • the morpholine derivative hydrochloride has a differential thermal analysis (DSC) spectrum as shown in Fig. 24, and its DSC spectrum shows a broad endothermic peak between 25 and 115 ° C (57.68 J). /g), having an endothermic peak at 133 ° C (57.65 J/g).
  • DSC differential thermal analysis
  • the morpholine derivative hydrochloride has a dynamic moisture adsorption analysis (DVS) spectrum as shown in FIG. 25, and the DVS spectrum thereof shows that the morpholine derivative hydrochloride is absorbed at 0%-60% RH. It is 15% water, which is deliquescent in this humidity range.
  • DVS dynamic moisture adsorption analysis
  • the method for preparing the morpholine derivative hydrochloride comprises the steps of dissolving the morpholine derivative free base in acetone, chloroform, acetonitrile, ethyl acetate, methanol or tetrahydrofuran (preferably acetone) to obtain morpholine.
  • the free base was stirred in a solution of acetone, chloroform, acetonitrile, ethyl acetate, methanol or tetrahydrofuran at room temperature overnight to precipitate a white solid.
  • the molar ratio of the morpholine derivative free base to hydrochloric acid is from 1:1.03 to 1:3.5, preferably 1:3.4.
  • the morpholine derivative hydrochloride has one or more improved properties, for example, having a better crystalline state, greatly improving water solubility (>500 mg/mL), but very easy It absorbs moisture and has good thermal stability under light conditions.
  • a fourth aspect of the present invention provides a morpholine derivative acetate and a process for the preparation thereof.
  • the morpholine derivative acetate is a compound formed of a morpholine derivative and acetic acid in a molar ratio of 1:1, and has the following structural formula:
  • the morpholine derivative acetate has a crystalline form, and its X-ray powder diffraction pattern is 7.784° ⁇ 0.2°, 11.429° ⁇ 0.2°, 14.455° ⁇ 0.2°, 16.874° ⁇ 0.2°, 19.899° ⁇ at 2 ⁇ . There are characteristic peaks at 0.2°, 21.146° ⁇ 0.2°, and 24.887° ⁇ 0.2°.
  • the crystalline form of the morpholine derivative acetate has an X-ray powder diffraction pattern of 6.012° ⁇ 0.2°, 7.457° ⁇ 0.2°, 7.784° ⁇ 0.2°, 10.391° ⁇ 0.2°, 10.768 in 2 ⁇ .
  • the morpholine derivative acetate has an X-ray powder diffraction (XRPD) pattern as shown in FIG.
  • the morpholine derivative acetate has a polarizing light microscope (PLM) pattern as shown in FIG.
  • PLM polarizing light microscope
  • the morpholine derivative acetate has a thermogravimetric analysis (TGA) pattern as shown in FIG. 28, and the TGA pattern shows that the morpholine derivative acetate has a step ladder at 50 ° C and 75 ° C respectively. Weight loss was 4.0% and 9.5%, respectively.
  • TGA thermogravimetric analysis
  • the morpholine derivative acetate has a differential thermal analysis (DSC) spectrum as shown in Fig. 29, and its DSC spectrum shows an endothermic peak (61 J/g) at 95 °C.
  • DSC differential thermal analysis
  • the morpholine derivative acetate has a dynamic moisture adsorption analysis (DVS) spectrum as shown in FIG. 30, and the DVS spectrum thereof shows that the morpholine derivative hydrochloride is dried at an initial humidity of 0%. At the stage, there is about 5% weight loss, and then 20%-60% of the humidity absorbs 6.4% of the water, and absorbs 40% of the water at 90% humidity, indicating deliquescence.
  • DVS dynamic moisture adsorption analysis
  • the method for preparing the morpholine derivative acetate comprises the steps of dissolving the morpholine derivative free base in acetone, chloroform, acetonitrile, ethyl acetate, methanol or tetrahydrofuran (preferably acetone) to obtain morpholine.
  • Derivative free base Acetone, chloroform, acetonitrile, ethyl acetate, methanol or tetrahydrofuran solution
  • the acetic acid is dissolved in acetone to obtain an acetone solution of acetic acid
  • the acetone solution of the acetic acid is added dropwise to the acetone containing the free base of the morpholine derivative.
  • the molar ratio of the morpholine derivative free base to acetic acid is from 1:1.1 to 1:3.1, preferably 1:1.4.
  • the morpholine derivative acetate has one or more improved properties, for example, having a better crystalline state and greatly improving the water solubility (150 to 300 mg/mL), but very It is easy to absorb moisture and has good thermal stability under light conditions.
  • a fifth aspect of the present invention provides a morpholine derivative naphthalene disulfonate and a process for the preparation thereof.
  • the morpholine derivative naphthalene disulfonate is a compound formed by a morpholine derivative and naphthalene disulfonic acid in a 1:1 molar ratio, and has the following structural formula:
  • the morpholine derivative naphthalene disulfonate is amorphous.
  • the morpholine derivative naphthalene disulfonate has an X-ray powder diffraction (XRPD) pattern as shown in FIG.
  • the preparation method of the morpholine derivative naphthalene disulfonate comprises the steps of dissolving a morpholine derivative free base in ethyl acetate, dissolving naphthalene disulfonic acid in ethanol, and reacting naphthalene disulfonic acid in ethanol.
  • the solution was added dropwise to an ethyl acetate solution containing the free base of the morpholine derivative, and stirred at room temperature to obtain a white flocculent precipitate, which was filtered.
  • the molar ratio of the morpholine derivative free base to naphthalene disulfonic acid is from 1:1.1 to 1:3, preferably 1:1.4.
  • the morpholine derivative naphthalene disulfonate has one or more improved properties, for example, having a better crystalline state and greatly improving water solubility (>500 mg/mL), but It is very easy to absorb moisture and has good thermal stability under light conditions.
  • the "stirring" described in any of the above-described preparation methods of the present invention can be accomplished by conventional techniques such as magnetic stirring and mechanical stirring.
  • the stirring speed is 50 to 1800 rpm, preferably 300 to 900 rpm.
  • room temperature means 15-25 °C.
  • overnight means 24 hours or more.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically and/or prophylactically effective amount of one or more morpholine derivative salts of the present invention or a crystalline form thereof, or prepared by the method of the present invention
  • the morpholine derivative salt or a crystal form thereof is selected from the group consisting of a malate salt of a morpholine derivative, a tartrate salt, a tartrate salt form A, a tartrate salt form B, a hydrochloride salt, an acetate salt, and a naphthalene disulfonate.
  • the acid salt, in addition, the pharmaceutical composition may further comprise other pharmaceutically acceptable salt forms, crystal forms or amorphous forms of the morpholine derivative.
  • Excipients in the pharmaceutical composition include sugars, cellulose and derivatives thereof, starch or modified starch, solid inorganic substances such as calcium phosphate, dicalcium phosphate, hydroxyapatite, calcium sulfate, calcium carbonate, semi-solid Such as lipid or paraffin, binders such as microcrystalline cellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, glidants such as colloidal silica, Light anhydrous silicic acid, crystalline cellulose, talc or magnesium stearate, disintegrants such as sodium starch glycolate, crospovidone, croscarmellose, sodium carboxymethylcellulose, dried corn Starch, lubricants such as stearic acid, magnesium stearate, sodium stearyl fumarate, polyethylene glycol.
  • solid inorganic substances such as calcium phosphate, dicalcium phosphate, hydroxyapatite, calcium sulfate
  • the pharmaceutical composition may be in a solid or liquid form, such as a solid oral dosage form, including tablets, granules, powders, pills, and capsules; liquid oral dosage forms including solutions, syrups, suspensions, dispersions, and emulsions; Injectable preparations, including solutions, dispersions, and lyophilizates.
  • the formulation may be adapted for rapid release, delayed release or modified release of the active ingredient. It may be a conventional, dispersible, chewable, orally dissolved or rapidly melted formulation. Routes of administration include oral, intravenous subcutaneous injection, injection into tissue, transdermal administration, rectal administration, intranasal administration, and the like.
  • the pharmaceutical composition can be prepared using methods well known to those skilled in the art.
  • the morpholine derivative salt of the present invention or a crystalline form thereof is mixed with one or more pharmaceutically acceptable carriers, optionally with other crystalline forms of pharmaceutically acceptable morpholine derivatives, Other amorphous or salt forms are mixed, optionally in admixture with one or more other active ingredients.
  • the solid preparation can be prepared by a process such as direct mixing, granulation, or the like.
  • the present invention provides the use of the aforementioned morpholine derivative salt of the present invention or a crystal form thereof as a renin inhibitor, and the use thereof for the preparation of a therapeutic and/or preventive hypertension, cardiac insufficiency, diabetic nephropathy, etc. Use in medicines for diseases.
  • Figure 1 is an XRPD pattern of a morpholine derivative malate
  • Figure 2 is a PLM spectrum of a morpholine derivative malate
  • Figure 3 is a TGA map of the morpholine derivative malate
  • Figure 4 is a DSC spectrum of a morpholine derivative malate
  • Figure 5 is a DVS spectrum of the morpholine derivative malate
  • Figure 6 is an XRPD pattern of the morpholine derivative tartrate crystal form B
  • Figure 7 is a PLM spectrum of the morpholine derivative tartrate crystal form B
  • Figure 8 is a TGA spectrum of the morpholine derivative tartrate salt form B
  • Figure 9 is a DSC spectrum of the morpholine derivative tartrate crystal form B
  • Figure 10 is a DVS spectrum of the morpholine derivative tartrate salt form B
  • Figure 11 is an XRPD pattern of the morpholine derivative tartrate dihydrate
  • Figure 12 is a PLM spectrum of the morpholine derivative tartrate dihydrate
  • Figure 13 is a TGA spectrum of the morpholine derivative tartrate dihydrate
  • Figure 14 is a DSC spectrum of the morpholine derivative tartrate dihydrate
  • Figure 15 is a DVS spectrum of the morpholine derivative tartrate dihydrate
  • Figure 16 is an XRPD pattern of the morpholine derivative tartrate crystal form A
  • Figure 17 is a PLM spectrum of the morpholine derivative tartrate crystal form A
  • Figure 18 is a TGA spectrum of the morpholine derivative tartrate crystal form A
  • Figure 19 is a DSC chart of the morpholine derivative tartrate crystal form A
  • Figure 20 is a DVS spectrum of the morpholine derivative tartrate crystal form A
  • Figure 21 is an XRPD pattern of the morpholine derivative hydrochloride
  • Figure 22 is a PLM spectrum of the morpholine derivative hydrochloride
  • Figure 23 is a TGA spectrum of the morpholine derivative hydrochloride
  • Figure 24 is a DSC chart of the morpholine derivative hydrochloride
  • Figure 25 is a DVS spectrum of the morpholine derivative hydrochloride
  • Figure 26 is an XRPD pattern of the morpholine derivative acetate
  • Figure 27 is a PLM spectrum of the morpholine derivative acetate
  • Figure 28 is a TGA spectrum of the morpholine derivative acetate
  • Figure 29 is a DSC spectrum of the morpholine derivative acetate
  • Figure 30 is a DVS spectrum of the morpholine derivative acetate
  • Figure 31 is an XRPD pattern of the morpholine derivative naphthalene disulfonate.
  • the instrument used for X-ray powder diffraction was a Bruker D8 Advance diffractometer with K X-rays with a copper target wavelength of 1.54 nm, a ⁇ -2 ⁇ goniometer, a Mo monochromator at 40 kV and 40 mA operating conditions, Lynxeye detector.
  • the instrument is used to correct the peak position with the standard sample supplied with the instrument before use.
  • the acquisition software is Diffrac Plus XRD Commander and the analysis software is MDI Jade 5.0.
  • the sample is tested at room temperature and the sample to be tested is placed on an organic slide.
  • the detailed detection conditions are as follows: angle range: 3 to 4 ° 2 ⁇ ; step size: 0.02 ° 2 ⁇ ; speed: 0.2 s / step. Samples were not ground prior to testing unless otherwise stated.
  • Polarized light microscopy (PLM) spectra were taken from an XP-500E polarized light microscope (Shanghai Changfang Optical Instrument Co., Ltd.). Take a small amount of powder sample on the glass slide, add a small amount of mineral oil to better disperse the powder sample, cover the cover glass, and then place the sample on the XP-500E polarized light microscope (Shanghai Changfang Optical Instrument Co., Ltd.) On the stage, select the appropriate magnification to observe the shape of the sample and take a picture.
  • PLM Polarized light microscopy
  • the differential thermal analysis (DSC) data was taken from the TA Instruments Q200MDSC, the instrument control software was Thermal Advantage, and the analysis software was Universal Analysis. Usually take 1 ⁇ 10 mg of the sample in the aluminum crucible with capping (unless otherwise specified), raise the sample from room temperature to 200 at a heating rate of 10 ° C / min under the protection of 50 mL / min dry N 2 °C or 300 °C, while the TA software records the change in heat during the temperature rise of the sample. In the present application, the melting point is reported as the starting temperature.
  • Thermogravimetric analysis (TGA) data was taken from the TA Instruments Q500TGA, the instrument control software was Thermal Advantage, and the analysis software was Universal Analysis. Usually, 5 to 15 mg of the sample is placed in a platinum crucible, and the sample is raised from room temperature to 300 ° C under the protection of 50 mL/min dry N 2 at a heating rate of 10 ° C/min using a segmented high-resolution detection method. At the same time, the TA software records the change in weight of the sample during the heating process.
  • Dynamic moisture adsorption analysis (DVS) data was taken from the TA Instruments Q5000TGA, the instrument control software was Thermal Advantage, and the analysis software was Universal Analysis. A sample of 1 to 10 mg is usually placed in a platinum crucible. Typically, the TA software records the change in weight of the sample during a change in relative humidity from 0% to 80% to 0%. Depending on the specifics of the sample, different adsorption and desorption steps are also applied to the sample.
  • the starting material morpholine derivative free base of the present invention is prepared according to the method disclosed in the document CN103562191 (WO2012124775), and the morpholine derivative free base in the following examples is referred to as free base.
  • the morpholine derivative malate has an X-ray powder diffraction (XRPD) pattern as shown in FIG.
  • the morpholine derivative malate has a polarizing light microscope (PLM) pattern as shown in FIG.
  • the morpholine derivative malate has a thermogravimetric analysis (TGA) pattern as shown in FIG. 3, and its TGA pattern shows that the morpholine derivative malate decomposes at around 185.8 ° C, and the sample has no weight loss before decomposition.
  • TGA thermogravimetric analysis
  • the morpholine derivative malate has a differential thermal analysis (DSC) pattern as shown in Fig. 4, and its DSC spectrum shows an endothermic peak (95 J/g) at around 121 °C.
  • DSC differential thermal analysis
  • DVS dynamic moisture adsorption analysis
  • the morpholine derivative tartrate crystal form B has an XRPD pattern as shown in FIG.
  • the morpholine derivative tartrate crystal form B has a PLM pattern as shown in FIG.
  • the morpholine derivative tartrate crystal form B has a TGA pattern as shown in Fig. 8.
  • the TGA pattern shows that the morpholine derivative tartrate crystal form B decomposes at around 186.0 ° C, and has a 2.5% slow weight loss before decomposition (weight loss from Start around 150 °C).
  • the morpholine derivative tartrate crystal form B has a DSC pattern as shown in Fig. 9, and the DSC pattern shows that the morpholine derivative tartrate crystal form B has an endothermic peak (38 J/g) at around 161.5 °C.
  • the morpholine derivative tartrate crystal form B has a DVS spectrum as shown in FIG. 10, and the DVS spectrum shows a weight change of about 7% in a humidity range of 20% to 80%, which is relatively easy to absorb moisture and may also change. Hydrate.
  • the morpholine derivative tartrate salt form B obtained in Example 2 was 10 mg, 50 ml of a mixed solvent of acetone and water in a volume ratio of 30:1 was added, and the mixture was stirred at room temperature for 2 days, and then filtered and characterized.
  • the morpholine derivative tartrate dihydrate has an XRPD pattern as shown in FIG.
  • the morpholine derivative tartrate dihydrate has a PLM pattern as shown in FIG.
  • the morpholine derivative tartrate dihydrate has a TGA pattern as shown in FIG. 13, and the TGA pattern shows that the morpholine derivative tartrate dihydrate is decomposed at about 189.6 ° C, and has a gradient weight loss of 6.95% before decomposition.
  • the morpholine derivative tartrate dihydrate has a DSC spectrum as shown in FIG. 14, and the DSC spectrum shows that the morpholine derivative tartrate dihydrate has an endothermic peak (112 J/g) at around 29.5 °C. There is an exothermic peak (27 J/g) around 99 °C and an endothermic peak (19 J/g) around 154 °C.
  • the morpholine derivative tartrate dihydrate has a DVS spectrum as shown in FIG. 15, and the DVS spectrum shows a weight change of about 11.06% in a humidity range of 0% to 80%, which is relatively easy to absorb moisture.
  • the morpholine derivative tartrate crystal form A has an X-ray powder diffraction (XRPD) pattern as shown in FIG.
  • the morpholine derivative tartrate crystal form A has a polarizing light microscope (PLM) pattern as shown in FIG.
  • the morpholine derivative tartrate crystal form A has a thermogravimetric analysis (TGA) pattern as shown in Fig. 18, and its TGA pattern shows that the morpholine derivative tartrate tetrahydrate has a weight loss of 10.0-10.4%.
  • TGA thermogravimetric analysis
  • the morpholine derivative tartrate crystal form A has a differential thermal analysis (DSC) spectrum as shown in FIG. 19, and its DSC spectrum shows an endothermic peak at 62.7 ° C and a melting endothermic peak at 159.3 ° C. Decomposed after 191 °C.
  • DSC differential thermal analysis
  • the morpholine derivative tartrate crystal form A has a dynamic moisture adsorption analysis (DVS) pattern as shown in FIG. 20, and its DVS spectrum shows that the morpholine derivative tartrate crystal form A is in the range of 20% to 80% humidity.
  • the weight change in the range is about 1.5%, which is not easy to absorb moisture.
  • the morpholine derivative hydrochloride has an X-ray powder diffraction (XRPD) pattern as shown in FIG.
  • the morpholine derivative hydrochloride has a polarizing light microscope (PLM) pattern as shown in FIG.
  • PLM polarizing light microscope
  • the morpholine derivative hydrochloride has a thermogravimetric analysis (TGA) spectrum as shown in FIG. 23, and the TGA spectrum thereof shows that the morpholine derivative hydrochloride continuously loses weight during the temperature rise, and the decomposition temperature is 207 ° C, and the decomposition There are two sections of weight loss before, totaling about 9.1%.
  • TGA thermogravimetric analysis
  • the morpholine derivative hydrochloride has a differential thermal analysis (DSC) pattern as shown in Fig. 24, and its DSC spectrum shows a broad endothermic peak (57.68 J/g) between 25 and 115 °C. It has an endothermic peak at 133 ° C (57.65 J / g).
  • DSC differential thermal analysis
  • DVS dynamic moisture adsorption analysis
  • the morpholine derivative acetate has an X-ray powder diffraction (XRPD) pattern as shown in FIG.
  • the morpholine derivative acetate has a polarizing light microscope (PLM) pattern as shown in FIG.
  • PLM polarizing light microscope
  • the morpholine derivative acetate has a thermogravimetric analysis (TGA) spectrum as shown in FIG. 28, and the TGA spectrum thereof shows that the morpholine derivative acetate has a step weight loss at 50 ° C and 75 ° C, respectively. They are 4.0% and 9.5% respectively.
  • TGA thermogravimetric analysis
  • the morpholine derivative acetate had a differential thermal analysis (DSC) spectrum as shown in Fig. 29, and its DSC spectrum showed an endothermic peak (61 J/g) at 95 °C.
  • DSC differential thermal analysis
  • the weight loss around % then absorbs 6.4% of the water in the humidity range of 20%-60%, and absorbs 40% of the water in 90% humidity, indicating deliquescence.
  • the morpholine derivative naphthalene disulfonate has an X-ray powder diffraction (XRPD) pattern as shown in Fig. 31 and is an amorphous salt.
  • XRPD X-ray powder diffraction
  • the free base, the salt of the morpholine derivative of Example 1-7 was each taken 5 mg, and pure water was gradually added to each sample at 25 ° C until the sample was completely dissolved, and the sample was calculated according to the actual weight of the sample and the amount of water. Solubility. The results are shown in Table 1. The parallel test showed that the sample did not undergo crystal transformation during the test.
  • the salt of the morpholine derivative of the examples was each taken 5 mg, the humidity was increased from 20% to 80%, and the weight change was tested. The results are shown in Table 2.

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Abstract

本发明提供了新型的可药用的吗啉衍生物的盐，包括其苹果酸盐、酒石酸盐、盐酸盐、醋酸盐和萘二磷酸盐，其中酒石酸盐有A晶型、B晶型和二水合物3种晶态盐型，苹果酸盐、盐酸盐、醋酸盐各有1种晶态盐型，萘二磷酸盐为无定形。与已知的吗啉衍生物的游离碱相比，本发明具有一种或多种的改进性能，如具有较好的晶态，极大程度地提高了水溶解度、光稳定性及热稳定性等。本发明进一步提供了所述吗啉衍生物的盐和晶型的制备方法、药物组合物和用途。

Description

吗啉衍生物的盐及其晶型、其制备方法及药物组合物、用途 技术领域
本发明属于药物化学技术领域，具体而言，涉及一种吗啉衍生物的盐及其晶型、其制备方法，以及其药物组合物和用途。
背景技术
一种吗啉衍生物，其化学名称为甲基(3-(3-((R)-1-((R)-N-环丙基吗啉-2-甲酰胺)乙基)-6-甲基-1H-吡唑[3,4-b]吡啶-1-基)正丙基)氨基甲酸甲酯，其分子式为C22H32N6O4，其结构式如下所示：
Figure PCTCN2016112966-appb-000001
CN103562191(201280013626.5)公开了该吗啉衍生物的游离碱形式、其制备方法和肾素抑制活性。该游离碱为半固体或无定形粉末，水溶性较差，且较易被氧化、不适合长期存储。
发明内容
针对现有技术的不足，本发明提供了新型的可药用的吗啉衍生物的盐，包括其苹果酸盐、酒石酸盐、盐酸盐、醋酸盐和萘二磷酸盐，其中酒石酸盐有A晶型(四水合物)、B晶型(无水物)和二水合物3种晶态盐型，苹果酸盐、盐酸盐、醋酸盐各有1种晶态盐型，萘二磷酸盐为无定形。与已知的吗啉衍生物的游离碱相比，本发明具有一种或多种的改进性能。本发明进一步提供了所述吗啉衍生物的盐和晶型的制备方法、药物组合物和用途。
本发明的内容之一是提供吗啉衍生物苹果酸盐及其制备方法。
所述吗啉衍生物苹果酸盐是吗啉衍生物和L-苹果酸以1:1摩尔比形成的化合物，其结构式如下：
Figure PCTCN2016112966-appb-000002
所述吗啉衍生物苹果酸盐具有晶型形态，其X射线粉末衍射图谱在2θ为7.767°±0.2°、13.897°±0.2°、14.775°±0.2°、17.098°±0.2°、18.999°±0.2°、20.153±0.2°、20.960°±0.2°、21.423°±0.2°、26.348°±0.2°、27.892°±0.2°处具有特征峰。
优选的，所述吗啉衍生物苹果酸盐的晶型，其X射线粉末衍射图谱在2θ为5.598°±0.2°、7.357°±0.2°、7.767°±0.2°、10.395°±0.2°、11.108°±0.2°、13.897°±0.2°、14.775°±0.2°、16.037°±0.2°、16.523°±0.2°、17.098°±0.2°、18.999°±0.2°、19.410°±0.2°、20.153°±0.2°、20.960°±0.2°、21.423°±0.2°、22.645°±0.2°、26.348°±0.2°、26.630°±0.2°、26.891°±0.2°、27.380°±0.2°、27.892°±0.2°、31.056°±0.2°、33.306°±0.2°、33.775°±0.2°、39.231°±0.2°处具有特征峰。
进一步的，所述吗啉衍生物苹果酸盐，具有如图1所示的X射线粉末衍射(XRPD)图谱。
进一步的，所述吗啉衍生物苹果酸盐，具有如图2所示的偏振光显微镜(PLM)图谱。
进一步的，所述吗啉衍生物苹果酸盐，具有如图3所示的热重分析(TGA)图谱，其TGA图谱显示吗啉衍生物苹果酸盐在185.8℃左右分解，分解前样品无失重。
进一步的，所述吗啉衍生物苹果酸盐，具有如图4所示的差热分析(DSC)图谱，其DSC图谱显示，在121℃左右具有一个吸热峰(95J/g)。
进一步的，所述吗啉衍生物苹果酸盐，其具有如图5所示的动态水份吸附分析(DVS)图谱，其DVS图谱显示吗啉衍生物苹果酸盐在20％-80％湿度范围内重量变化约为1.2％。
所述吗啉衍生物苹果酸盐的制备方法，包括以下步骤：将吗啉衍生物游离碱溶于丙酮、氯仿、乙腈、乙酸乙酯、甲醇或四氢呋喃(优选为丙酮)中，得到含有吗啉衍生物游离碱的丙酮、氯仿、乙腈、乙酸乙酯、甲醇或四氢呋喃溶液，将L-苹果酸溶于乙醇中，得到L-苹果酸的乙醇溶液，将所述L-苹果酸的乙醇溶液滴加到所述含有吗啉衍生物游离碱的丙酮、氯仿、乙腈、乙酸乙酯、甲醇或四氢呋喃溶液中，室温下搅拌过夜，析出白色固体，过滤。优选的，所述吗啉衍生物游离碱与苹果酸的摩尔比为1:1.1～1:3.3，优选为1:1.1。
与现有技术比较，吗啉衍生物苹果酸盐具有一种或多种改进的特性，例如：有较好的晶态，在20％-80％RH下很难吸湿，同时大大提高了水溶性(～100mg/mL)，且在光照和氧化的条件下有较好的稳定性。
本发明的内容之二是提供吗啉衍生物酒石酸盐及其晶型、以及它们的制备方法。
所述吗啉衍生物酒石酸盐，是吗啉衍生物和L-酒石酸以1:1摩尔比形成的化合物，其结构式如下：
Figure PCTCN2016112966-appb-000003
所述吗啉衍生物酒石酸盐的制备方法，包括以下步骤：将吗啉衍生物游离碱溶于丙酮、氯仿、乙腈、乙酸乙酯、甲醇或四氢呋喃(优选为丙酮)，将L-酒石酸溶于水，将L-酒石酸的水溶液滴加至吗啉衍生物游离碱的丙酮、氯仿、乙腈、乙酸乙酯、甲醇或四氢呋喃溶液中，室温搅拌过夜，析出白色固体，过滤。
所述吗啉衍生物和L-酒石酸的摩尔比为1:1.03-1:2.2，优选为1:1.03。
所述吗啉衍生物酒石酸盐为吗啉衍生物酒石酸盐晶型B，其X射线粉末衍射图谱在2θ为3.339°±0.2°、6.562°±0.2°、11.331°±0.2°、16.396°±0.2°、22.041°±0.2°处具有特征峰。
优选的，所述吗啉衍生物酒石酸盐晶型B，其X射线粉末衍射图谱在2θ为3.339°±0.2°、5.078°±0.2°、6.562°±0.2°、6.864°±0.2°、8.250°±0.2°、8.444°±0.2°、11.030°±0.2°、11.331°±0.2°、12.864°±0.2°、13.907°±0.2°、14.642°±0.2°、16.396°±0.2°、19.100°±0.2°、19.359°±0.2°、22.041°±0.2°、25.251°±0.2°、26.768°±0.2°、27.894°±0.2°、29.510°±0.2°、38.343°±0.2°处具有特征峰。
进一步的，所述吗啉衍生物酒石酸盐晶型B，具有如图6所示的XRPD图谱。
进一步的，所述吗啉衍生物酒石酸盐晶型B，具有如图7所示的PLM图谱。
进一步的，所述吗啉衍生物酒石酸盐晶型B，具有如图8所示的TGA图谱，TGA图谱显示吗啉衍生物酒石酸盐晶型B在186.0℃左右分解，分解前有2.5％缓慢失重(失重从150℃左右开始)。
进一步的，所述吗啉衍生物酒石酸盐晶型B，具有如图9所示的DSC图谱，DSC图谱 显示，吗啉衍生物酒石酸盐晶型B在161.5℃左右有一个吸热峰(38J/g)。
进一步的，所述吗啉衍生物酒石酸盐晶型B，具有如图10所示的DVS图谱，DVS图谱显示在20％-80％的湿度范围内重量变化为7％左右，较易吸潮，也可能变成水合物。
将所述吗啉衍生物酒石酸盐晶型B加入丙酮和水的混合溶剂中，室温下搅拌2天后，过滤，得到吗啉衍生物酒石酸盐二水合物；所述丙酮和水的体积比优选为30:1。
所述吗啉衍生物酒石酸盐二水合物，其具有晶型，其X射线粉末衍射图谱在2θ为9.851°±0.2°、14.410°±0.2°、14.774°±0.2°、15.052°±0.2°、16.254°±0.2°、20.847°±0.2°、23.225°±0.2°处具有特征峰。
优选的，所述吗啉衍生物酒石酸盐二水合物的晶型，其X射线粉末衍射图谱在2θ为9.851°±0.2°、13.434°±0.2°、14.410°±0.2°、14.774°±0.2°、15.052°±0.2°、15.415°±0.2°、15.701°±0.2°、16.254°±0.2°、16.755°±0.2°、17.283°±0.2°、18.079°±0.2°、18.576°±0.2°、20.077°±0.2°、20.847°±0.2°、21.960°±0.2°、23.225°±0.2°、24.351°±0.2°、27.046°±0.2°、27.865°±0.2°、38.458°±0.2°处具有特征峰。
进一步的，所述吗啉衍生物酒石酸盐二水合物，具有如图11所示的XRPD图谱。
进一步的，所述吗啉衍生物酒石酸盐二水合物，具有如图12所示的PLM图谱。
进一步的，所述吗啉衍生物酒石酸盐二水合物，具有如图13所示的TGA图谱，TGA图谱显示吗啉衍生物酒石酸盐二水合物在189.6℃左右分解，分解前有6.95％的梯度失重。
进一步的，所述吗啉衍生物酒石酸盐二水合物，具有如图14所示的DSC图谱，DSC图谱显示，吗啉衍生物酒石酸盐二水合物在29.5℃左右有一个吸热峰(112J/g)，在99℃左右有一个放热峰(27J/g)，在154℃左右有一个吸热峰(19J/g)。
进一步的，所述吗啉衍生物酒石酸盐二水合物，具有如图15所示的DVS图谱，DVS图谱显示在0％-80％的湿度范围内重量变化为11.06％左右，较易吸潮。
本发明还公开了吗啉衍生物酒石酸盐四水合物，为晶型A，其X射线粉末衍射图谱在2θ为9.882°±0.2°、14.426°±0.2°、14.802°±0.2°、16.275°±0.2°、20.085°±0.2°、20.872°±0.2°、21.978°±0.2°、23.236°±0.2°处具有特征峰。
优选的，所述吗啉衍生物酒石酸盐晶型A，其X射线粉末衍射图谱在2θ为9.882°±0.2°、11.964°±0.2°、13.558°±0.2°、14.426°±0.2°、14.802°±0.2°、15.076°±0.2°、15.450°±0.2°、16.046°±0.2°、16.275°±0.2°、16.754°±0.2°、17.320°±0.2°、18.450°±0.2°、18.790°±0.2°、19.728°±0.2°、20.085°±0.2°、20.577°±0.2°、20.872°±0.2°、21.978°±0.2°、22.426°±0.2°、23.236°±0.2°、23.704°±0.2°、24.399°±0.2°、25.346°±0.2°、25.913°±0.2°、26.991°±0.2°、28.199°±0.2°、28.445°±0.2°、29.030°±0.2°、30.209°±0.2°、30.480°±0.2°、32.791°±0.2°、34.796°±0.2°、 36.226°±0.2°、38.472°±0.2°处具有特征峰。
所述吗啉衍生物酒石酸盐晶型A，具有如图16所示的XRPD图谱。
所述吗啉衍生物酒石酸盐晶型A，具有如图17所示的PLM图谱。
所述吗啉衍生物酒石酸盐晶型A，具有如图18所示的TGA图谱。
所述吗啉衍生物酒石酸盐晶型A，具有如图19所示的DSC图谱。
所述吗啉衍生物酒石酸盐晶型A，具有如图20所示的DVS图谱。
本发明还公开了所述吗啉衍生物酒石酸盐晶型A的制备方法，其包括如下步骤：将吗啉衍生物游离碱溶于丙酮、氯仿、乙腈、乙酸乙酯、甲醇或四氢呋喃(优选为丙酮)，得到吗啉衍生物游离碱的丙酮、氯仿、乙腈、乙酸乙酯、甲醇或四氢呋喃溶液，将L-酒石酸溶于水，得到酒石酸的水溶液，将所述L-酒石酸的水溶液滴加至所述吗啉衍生物游离碱的丙酮、氯仿、乙腈、乙酸乙酯、甲醇或四氢呋喃溶液中，室温搅拌不少于48h，析出白色固体，过滤。所述酒石酸盐游离碱与L-酒石酸的摩尔比为1:2.2，丙酮与水的体积比为20:1。
与现有技术比较，吗啉衍生物酒石酸盐具有一种或多种改进的特性，例如：晶型A和B都具有较好的晶态，但在20％-80％RH下晶型A很难吸湿，晶型B则容易吸湿，同时都改善了水溶解度(50～300mg/mL)，且在氧化的条件下晶型B较晶型A有较好的稳定性，在光照的条件下稳定性两者相当。
本发明的内容之三是提供吗啉衍生物盐酸盐及其制备方法。
所述吗啉衍生物盐酸盐是吗啉衍生物和盐酸以1:2摩尔比形成的化合物，其结构式如下：
Figure PCTCN2016112966-appb-000004
所述吗啉衍生物盐酸盐具有晶型形态，其X射线粉末衍射图谱在2θ为3.981°±0.2°、7.784°±0.2°、8.667°±0.2°、13.634°±0.2°、18.238°±0.2°、19.620°±0.2°、24.624°±0.2°、24.987°±0.2°、28.072°±0.2°、31.815°±0.2°处具有特征峰。
优选的，所述吗啉衍生物盐酸盐的晶型，其X射线粉末衍射图谱在2θ为3.981°±0.2°、7.784°±0.2°、8.667°±0.2°、10.914°±0.2°、11.557°±0.2°、12.211°±0.2°、13.634°±0.2°、14.675° ±0.2°、15.419°±0.2°、15.817°±0.2°、17.158°±0.2°、18.238°±0.2°、19.116°±0.2°、19.620°±0.2°、20.618°±0.2°、21.261°±0.2°、21.901°±0.2°、22.428°±0.2°、22.548°±0.2°、23.342°±0.2°、24.624°±0.2°、24.987°±0.2°、25.902°±0.2°、26.267°±0.2°、26.730°±0.2°、26.946°±0.2°、28.072°±0.2°、29.994°±0.2°、31.154°±0.2°、31.815°±0.2°、33.220°±0.2°、34.670°±0.2°、35.201°±0.2°处具有特征峰。
进一步的，所述吗啉衍生物盐酸盐，具有如图21所示的X射线粉末衍射(XRPD)图谱。
进一步的，所述吗啉衍生物盐酸盐，具有如图22所示的偏振光显微镜(PLM)图谱。
进一步的，所述吗啉衍生物盐酸盐，具有如图23所示的热重分析(TGA)图谱，其TGA图谱显示吗啉衍生物盐酸盐在升温过程中持续失重，分解温度为207℃，分解前有两段失重，共计9.1％左右。
进一步的，所述吗啉衍生物盐酸盐，具有如图24所示的差热分析(DSC)图谱，其DSC图谱显示，在25-115℃间具有一个很宽的吸热峰(57.68J/g)，在133℃具有一个吸热峰(57.65J/g)。
进一步的，所述吗啉衍生物盐酸盐，其具有如图25所示的动态水份吸附分析(DVS)图谱，其DVS图谱显示吗啉衍生物盐酸盐在0％-60％RH吸收了为15％的水，在此湿度范围内易潮解。
所述吗啉衍生物盐酸盐的制备方法，包括以下步骤：将吗啉衍生物游离碱溶于丙酮、氯仿、乙腈、乙酸乙酯、甲醇或四氢呋喃(优选为丙酮)中，得到含有吗啉衍生物游离碱的丙酮、氯仿、乙腈、乙酸乙酯、甲醇或四氢呋喃溶液，将盐酸溶于丙酮中，得到盐酸的丙酮溶液，将所述盐酸的丙酮溶液滴加到所述含有吗啉衍生物游离碱的丙酮、氯仿、乙腈、乙酸乙酯、甲醇或四氢呋喃溶液中，室温下搅拌过夜，析出白色固体，过滤。优选的，所述吗啉衍生物游离碱与盐酸的摩尔比为1:1.03～1:3.5，优选为1:3.4。
与现有技术比较，吗啉衍生物盐酸盐具有一种或多种改进的特性，例如：具有较好的晶态，极大程度地提高了水溶解度(>500mg/mL)，但非常容易吸湿，在光照条件下有较好的热稳定性。
本发明的内容之四是提供吗啉衍生物醋酸盐及其制备方法。
所述吗啉衍生物醋酸盐是吗啉衍生物和醋酸以1:1摩尔比形成的化合物，其结构式如下：
Figure PCTCN2016112966-appb-000005
所述吗啉衍生物醋酸盐具有晶型形态，其X射线粉末衍射图谱在2θ为7.784°±0.2°、11.429°±0.2°、14.455°±0.2°、16.874°±0.2°、19.899°±0.2°、21.146°±0.2°、24.887°±0.2°处具有特征峰。
优选的，所述吗啉衍生物醋酸盐的晶型，其X射线粉末衍射图谱在2θ为6.012°±0.2°、7.457°±0.2°、7.784°±0.2°、10.391°±0.2°、10.768°±0.2°、11.429°±0.2°、13.652°±0.2°、14.089°±0.2°、14.455°±0.2°、14.841°±0.2°、15.516°±0.2°、16.301°±0.2°、16.874°±0.2°、17.592°±0.2°、18.777°±0.2°、19.375°±0.2°、19.899°±0.2°、20.521°±0.2°、21.146°±0.2°、21.541°±0.2°、22.346°±0.2°、22.966°±0.2°、23.347°±0.2°、24.585°±0.2°、24.887°±0.2°、25.546°±0.2°、26.028°±0.2°、26.328°±0.2°、27.484°±0.2°、27.753°±0.2°、29.206°±0.2°、30.611°±0.2°、30.972°±0.2°、31.233°±0.2°、31.801°±0.2°、33.696°±0.2°、34.699°±0.2°、35.313°±0.2°、36.441°±0.2°、37.961°±0.2°，38.179°±0.2°、39.325°±0.2°处具有特征峰。
进一步的，所述吗啉衍生物醋酸盐，具有如图26所示的X射线粉末衍射(XRPD)图谱。
进一步的，所述吗啉衍生物醋酸盐，具有如图27所示的偏振光显微镜(PLM)图谱。
进一步的，所述吗啉衍生物醋酸盐，具有如图28所示的热重分析(TGA)图谱，其TGA图谱显示吗啉衍生物醋酸盐在50℃和75℃左右各有一步阶梯式失重，分别为4.0％和9.5％。
进一步的，所述吗啉衍生物醋酸盐，具有如图29所示的差热分析(DSC)图谱，其DSC图谱显示，在95℃具有一个吸热峰(61J/g)。
进一步的，所述吗啉衍生物醋酸盐，其具有如图30所示的动态水份吸附分析(DVS)图谱，其DVS图谱显示吗啉衍生物盐酸盐在初始湿度为0％的干燥阶段有5％左右的失重，之后再20％-60％的湿度范围内吸收了占其质量百分比6.4％的水，在90％湿度下吸收了占其质量百分比40％的水，表明已潮解。
所述吗啉衍生物醋酸盐的制备方法，包括以下步骤：将吗啉衍生物游离碱溶于丙酮、氯仿、乙腈、乙酸乙酯、甲醇或四氢呋喃(优选为丙酮)中，得到含有吗啉衍生物游离碱 的丙酮、氯仿、乙腈、乙酸乙酯、甲醇或四氢呋喃溶液，将醋酸溶于丙酮中，得到醋酸的丙酮溶液，将所述醋酸的丙酮溶液滴加到所述含有吗啉衍生物游离碱的丙酮、氯仿、乙腈、乙酸乙酯、甲醇或四氢呋喃溶液中，室温下搅拌过夜，析出白色固体，过滤。优选的，所述吗啉衍生物游离碱与醋酸的摩尔比为1:1.1～1:3.1，优选为1:1.4。
与现有技术比较，吗啉衍生物醋酸盐具有一种或多种改进的特性，例如：具有较好的晶态，极大程度地提高了水溶解度(150～300mg/mL)，但非常容易吸湿，在光照条件下有较好的热稳定性。
本发明的内容之五是提供吗啉衍生物萘二磺酸盐及其制备方法。
所述吗啉衍生物萘二磺酸盐是吗啉衍生物和萘二磺酸以1:1摩尔比形成的化合物，其结构式如下：
Figure PCTCN2016112966-appb-000006
所述吗啉衍生物萘二磺酸盐为无定形。
进一步的，所述吗啉衍生物萘二磺酸盐，具有如图31所示的X射线粉末衍射(XRPD)图谱。
所述吗啉衍生物萘二磺酸盐的制备方法，包括以下步骤：将吗啉衍生物游离碱溶于乙酸乙酯中，将萘二磺酸溶于乙醇中，将萘二磺酸的乙醇溶液滴加到含有吗啉衍生物游离碱的乙酸乙酯溶液中，室温下搅拌，得到白色絮状沉淀，过滤。优选的，所述吗啉衍生物游离碱与萘二磺酸的摩尔比为1:1.1～1:3，优选为1:1.4。
与现有技术比较，吗啉衍生物萘二磺酸盐具有一种或多种改进的特性，例如：具有较好的晶态，极大程度地提高了水溶解度(>500mg/mL)，但非常容易吸湿，在光照条件下有较好的热稳定性。
本发明上述任何制备方法中描述的“搅拌”可用常规技术完成，例如磁力搅拌和机械搅拌。搅拌速度为50～1800转/分，优选300～900转/分。
本发明中，“室温”指15-25℃。
本发明中，“过夜”是指24h以上。
进一步地，本发明提供一种药物组合物，所述药物组合物包含治疗和/或预防有效量的一种或多种本发明所述的吗啉衍生物盐或其晶型或者由本发明方法制备得到的吗啉衍生物盐或其晶型，以及至少一种药学上可接受的赋形剂。其中，所述吗啉衍生物盐或其晶型选自吗啉衍生物的苹果酸盐、酒石酸盐、酒石酸盐晶型A、酒石酸盐晶型B、盐酸盐、醋酸盐、萘二磺酸盐，此外，所述药物组合物还可以包含吗啉衍生物其它可药用的盐型、晶型或无定形。
所述药物组合物中的辅料包括糖类，纤维素及其衍生物，淀粉或改性淀粉，固体无机物如磷酸钙、磷酸氢二钙、羟基磷灰石、硫酸钙、碳酸钙，半固体如脂质或石蜡，粘合剂如微晶纤维素、乙基纤维素、羟甲基纤维素、羟丙基甲基纤维素、羟乙基纤维素，助流剂如胶态二氧化硅、轻质无水硅酸、结晶纤维素、滑石粉或硬脂酸镁，崩解剂如乙醇酸淀粉钠、交聚维酮、交联羧甲基纤维素、羧甲基纤维素钠、干玉米淀粉，润滑剂如硬脂酸、硬脂酸镁、硬脂酰富马酸钠、聚乙二醇。
所述药物组合物可为固态或液态，例如固体口服剂型，包括片剂、颗粒剂、散剂、丸剂和胶囊剂；液体口服剂型，包括溶液剂、糖浆剂、混悬剂、分散剂和乳剂；可注射制剂，包括溶液剂、分散剂和冻干剂。配方可适于活性成分的快速释放、延迟释放或调节释放。可以是常规的、可分散的、可咀嚼的、口腔溶解的或快速熔化的制剂。给药途径包括口服、静脉皮下注射、注射入组织给药、透皮给药、直肠给药、滴鼻给药等。
所述药物组合物可以使用本领域技术人员公知的方法来制备。制备药物组合物时，本发明的吗啉衍生物盐或其晶型与一种或多种药学上可接受的载体相混合，任选的与可药用的吗啉衍生物的其它晶型、其它无定形或盐型相混合，任选的与一种或多种其他的活性成分相混合。固体制剂可以通过直接混合、制粒等工艺来制备。
进一步地，本发明提供了本发明前述的吗啉衍生物盐或其晶型作为肾素抑制剂的用途，以及其在用于制备治疗和/或预防高血压、心功能不全、糖尿病性肾病等疾病的药物中的用途。
附图说明
图1是吗啉衍生物苹果酸盐的XRPD图谱；
图2是吗啉衍生物苹果酸盐的PLM图谱；
图3是吗啉衍生物苹果酸盐的TGA图谱；
图4是吗啉衍生物苹果酸盐的DSC图谱；
图5是吗啉衍生物苹果酸盐的DVS图谱；
图6是吗啉衍生物酒石酸盐晶型B的XRPD图谱；
图7是吗啉衍生物酒石酸盐晶型B的PLM图谱；
图8是吗啉衍生物酒石酸盐晶型B的TGA图谱；
图9是吗啉衍生物酒石酸盐晶型B的DSC图谱；
图10是吗啉衍生物酒石酸盐晶型B的DVS图谱；
图11是吗啉衍生物酒石酸盐二水合物的XRPD图谱；
图12是吗啉衍生物酒石酸盐二水合物的PLM图谱；
图13是吗啉衍生物酒石酸盐二水合物的TGA图谱；
图14是吗啉衍生物酒石酸盐二水合物的DSC图谱；
图15是吗啉衍生物酒石酸盐二水合物的DVS图谱；
图16是吗啉衍生物酒石酸盐晶型A的XRPD图谱；
图17是吗啉衍生物酒石酸盐晶型A的PLM图谱；
图18是吗啉衍生物酒石酸盐晶型A的TGA图谱；
图19是吗啉衍生物酒石酸盐晶型A的DSC图谱；
图20是吗啉衍生物酒石酸盐晶型A的DVS图谱；
图21是吗啉衍生物盐酸盐的XRPD图谱；
图22是吗啉衍生物盐酸盐的PLM图谱；
图23是吗啉衍生物盐酸盐的TGA图谱；
图24是吗啉衍生物盐酸盐的DSC图谱；
图25是吗啉衍生物盐酸盐的DVS图谱；
图26是吗啉衍生物醋酸盐的XRPD图谱；
图27是吗啉衍生物醋酸盐的PLM图谱；
图28是吗啉衍生物醋酸盐的TGA图谱；
图29是吗啉衍生物醋酸盐的DSC图谱；
图30是吗啉衍生物醋酸盐的DVS图谱；
图31是吗啉衍生物萘二磺酸盐的XRPD图谱。
具体实施方式
本发明进一步参考以下实施例，所述实施例详细描述本发明的盐及晶型的制备和应用。 对本领域技术人员显而易见的是，对于材料和方法两者其中的许多改变可在不脱离本发明范围的情况下实施。
检测仪器及方法：
X射线粉末衍射(XPRD)所使用的仪器为Bruker D8Advance diffractometer，采用铜靶波长为1.54nm的K X-射线，在40kV和40mA的操作条件下、θ-2θ测角仪、Mo单色仪、Lynxeye探测器。仪器在使用前用仪器自带的标准样品校正峰位。采集软件是Diffrac Plus XRD Commander，分析软件是MDI Jade 5.0。样品在室温条件下测试，把需要检测的样品放在有机玻片上。详细检测条件如下：角度范围：3～4°2θ；步长：0.02°2θ；速度：0.2s/步。除非特别说明，样品在检测前未经研磨。
偏振光显微镜(PLM)图谱采自于XP-500E偏振光显微镜(上海长方光学仪器有限公司)。取少量粉末样品置于载玻片上，滴加少量矿物油以更好地分散粉末样品，盖上盖玻片，然后将样品放置在XP-500E偏振光显微镜(上海长方光学仪器有限公司)的载物台上，选择合适的放大倍数观测样品的形貌并拍照。
差热分析(DSC)数据采自于TA Instruments Q200MDSC，仪器控制软件是Thermal Advantage，分析软件是Universal Analysis。通常取1～10毫克的样品放置于加盖打孔(除非特别说明)的铝坩埚内，以10℃/min的升温速度在50mL/min干燥N2的保护下将样品从室温升至200℃或300℃，同时TA软件记录样品在升温过程中的热量变化。在本申请中，熔点是按起始温度来报告的。
热重分析(TGA)数据采自于TA Instruments Q500TGA，仪器控制软件是Thermal Advantage，分析软件是Universal Analysis。通常取5～15mg的样品放置于白金坩埚内，采用分段高分辨检测的方式，以10℃/min的升温速度在50mL/min干燥N2的保护下将样品从室温升至300℃，同时TA软件记录样品在升温过程中的重量变化。
动态水份吸附分析(DVS)数据采自于TA Instruments Q5000TGA，仪器控制软件是Thermal Advantage，分析软件是Universal Analysis。通常取1～10mg的样品放置于白金坩埚内，通常TA软件记录样品在相对湿度从0％到80％到0％变化过程中的重量变化。根据样品的具体情况，也会对样品采用不同的吸附和脱吸附步骤。
本发明的起始原料吗啉衍生物游离碱按照文献CN103562191(WO2012124775)公开的方法制备，以下实施例中吗啉衍生物游离碱简称游离碱。
实施例1 吗啉衍生物苹果酸盐的制备
取10.64mg(0.024mmol，1eq)游离碱溶于0.6ml丙酮中，取3.63mg(0.027mmol，1.1eq)L-苹果酸溶于0.04ml乙醇中，再将配制的乙醇溶液滴加至丙酮溶液中，室温搅拌过夜，析 出白色固体，过滤，表征。
所述吗啉衍生物苹果酸盐，具有如图1所示的X射线粉末衍射(XRPD)图谱。
所述吗啉衍生物苹果酸盐，具有如图2所示的偏振光显微镜(PLM)图谱。
所述吗啉衍生物苹果酸盐，具有如图3所示的热重分析(TGA)图谱，其TGA图谱显示吗啉衍生物苹果酸盐在185.8℃左右分解，分解前样品无失重。
所述吗啉衍生物苹果酸盐，具有如图4所示的差热分析(DSC)图谱，其DSC图谱显示，在121℃左右具有一个吸热峰(95J/g)。
所述吗啉衍生物苹果酸盐，其具有如图5所示的动态水份吸附分析(DVS)图谱，其DVS图谱显示吗啉衍生物苹果酸盐在20％-80％湿度范围内重量变化约为1.2％。
实施例2 吗啉衍生物酒石酸盐晶型B的制备
取42.72mg(0.096mmol，1eq)游离碱溶于1.0ml丙酮中，取14.86mg(0.099mmol，1.03eq)L-酒石酸溶于0.048ml水中，再将配制的L-酒石酸的水溶液滴加至游离碱的丙酮溶液中，室温搅拌过夜，析出白色固体，过滤，表征。
所述吗啉衍生物酒石酸盐晶型B，具有如图6所示的XRPD图谱。
所述吗啉衍生物酒石酸盐晶型B，具有如图7所示的PLM图谱。
所述吗啉衍生物酒石酸盐晶型B，具有如图8所示的TGA图谱，TGA图谱显示吗啉衍生物酒石酸盐晶型B在186.0℃左右分解，分解前有2.5％缓慢失重(失重从150℃左右开始)。
所述吗啉衍生物酒石酸盐晶型B，具有如图9所示的DSC图谱，DSC图谱显示，吗啉衍生物酒石酸盐晶型B在161.5℃左右有一个吸热峰(38J/g)。
所述吗啉衍生物酒石酸盐晶型B，具有如图10所示的DVS图谱，DVS图谱显示在20％-80％的湿度范围内重量变化为7％左右，较易吸潮，也可能变成水合物。
实施例3 吗啉衍生物酒石酸盐二水合物的制备
取实施例2制得的吗啉衍生物酒石酸盐晶型B 10mg，加入丙酮和水体积比为30:1的混合溶剂共50ml，室温下搅拌2天后，过滤，表征。
所述吗啉衍生物酒石酸盐二水合物，具有如图11所示的XRPD图谱。
所述吗啉衍生物酒石酸盐二水合物，具有如图12所示的PLM图谱。
所述吗啉衍生物酒石酸盐二水合物，具有如图13所示的TGA图谱，TGA图谱显示吗啉衍生物酒石酸盐二水合物在189.6℃左右分解，分解前有6.95％的梯度失重。
所述吗啉衍生物酒石酸盐二水合物，具有如图14所示的DSC图谱，DSC图谱显示，吗啉衍生物酒石酸盐二水合物在29.5℃左右有一个吸热峰(112J/g)，在99℃左右有一个放热峰(27J/g)，在154℃左右有一个吸热峰(19J/g)。
所述吗啉衍生物酒石酸盐二水合物，具有如图15所示的DVS图谱，DVS图谱显示在0％-80％的湿度范围内重量变化为11.06％左右，较易吸潮。
实施例4 吗啉衍生物酒石酸盐晶型A(四水合物)的制备
取1.0g游离碱(2.25mmol，1eq)溶于丙酮，超声使其全溶，取0.74g L-酒石酸(4.93mmol，2.2eq 20:1)。将酸溶液缓慢滴加至碱溶液中，室温搅拌不小于48h，过滤得到的酒石酸盐水合物固体1.01g。
所述吗啉衍生物酒石酸盐晶型A，具有如图16所示的X射线粉末衍射(XRPD)图谱。
所述吗啉衍生物酒石酸盐晶型A，具有如图17所示的偏振光显微镜(PLM)图谱。
所述吗啉衍生物酒石酸盐晶型A，具有如图18所示的热重分析(TGA)图谱，其TGA图谱显示吗啉衍生物酒石酸盐四水合物有10.0-10.4％的失重。
所述吗啉衍生物酒石酸盐晶型A，具有如图19所示的差热分析(DSC)图谱，其DSC图谱显示，在62.7℃有吸热峰，在159.3℃有熔融吸热峰，在191℃以后分解。
所述吗啉衍生物酒石酸盐晶型A，其具有如图20所示的动态水份吸附分析(DVS)图谱，其DVS图谱显示吗啉衍生物酒石酸盐晶型A在20％-80％湿度范围内重量变化约为1.5％，不易吸潮。
实施例5 吗啉衍生物盐酸盐的制备
取1.5g游离碱(3.38mmol，1eq)溶于50mL丙酮中，超声使其全溶，取1.1g 36.5％的盐酸(10.8mmol，3.3eq)水溶液，然后将酸溶液缓慢滴加至碱溶液中，室温搅拌过夜。过滤得到盐酸盐固体。
所述吗啉衍生物盐酸盐，具有如图21所示的X射线粉末衍射(XRPD)图谱。
所述吗啉衍生物盐酸盐，具有如图22所示的偏振光显微镜(PLM)图谱。
所述吗啉衍生物盐酸盐，具有如图23所示的热重分析(TGA)图谱，其TGA图谱显示吗啉衍生物盐酸盐在升温过程中持续失重，分解温度为207℃，分解前有两段失重，共计9.1％左右。
所述吗啉衍生物盐酸盐，具有如图24所示的差热分析(DSC)图谱，其DSC图谱显示，在25-115℃间具有一个很宽的吸热峰(57.68J/g)，在133℃具有一个吸热峰(57.65J/g)。
所述吗啉衍生物盐酸盐，其具有如图25所示的动态水份吸附分析(DVS)图谱，其DVS图谱显示吗啉衍生物盐酸盐在0％-60％RH吸收了为15％的水，在此湿度范围内易潮解。
实施例6 吗啉衍生物醋酸盐的制备
取10.64mg(0.024mmol，1eq)游离碱溶于0.4ml丙酮中，取2.03mg(0.033mmol，1.4eq)醋酸溶于0.1ml丙酮中，再将配制的醋酸的丙酮溶液滴加至游离碱的丙酮溶液中，室温搅拌过夜，析出白色固体，过滤，表征。
所述吗啉衍生物醋酸盐，具有如图26所示的X射线粉末衍射(XRPD)图谱。
所述吗啉衍生物醋酸盐，具有如图27所示的偏振光显微镜(PLM)图谱。
所述吗啉衍生物醋酸盐，具有如图28所示的热重分析(TGA)图谱，其TGA图谱显示吗啉衍生物醋酸盐在50℃和75℃左右各有一步阶梯式失重，分别为4.0％和9.5％。
所述吗啉衍生物醋酸盐，具有如图29所示的差热分析(DSC)图谱，其DSC图谱显示，在95℃具有一个吸热峰(61J/g)。
所述吗啉衍生物醋酸盐，其具有如图30所示的动态水份吸附分析(DVS)图谱，其DVS图谱显示吗啉衍生物盐酸盐在初始湿度为0％的干燥阶段有5％左右的失重，之后再20％-60％的湿度范围内吸收了占其质量百分比6.4％的水，在90％湿度下吸收了占其质量百分比40％的水，表明已潮解。
实施例7 萘二磺酸盐的制备
取10.68mg(0.024mmol，1eq)游离碱溶于2ml乙酸乙酯中，取12.17mg(0.034mmol，1.4eq)萘二磺酸溶于1ml乙醇中，再将配制的萘二磺酸的乙醇溶液滴加至游离碱的乙酸乙酯溶液中，搅拌，得到白色絮状沉淀，过滤，表征。
所述吗啉衍生物萘二磺酸盐，具有如图31所示的X射线粉末衍射(XRPD)图谱，为无定形盐。
测试例1 溶解度的测试
将游离碱、实施例1-7的吗啉衍生物的盐各取5mg，25℃下逐步向每份样品中添加纯水直至样品全部溶清，根据样品的实际重量和水的量计算得样品的溶解度。结果见表1，平行试验表明样品在该检测过程中未发生转晶。
表1吗啉衍生物的各类盐的溶解度测试
测试样品 溶解度(mg/ml)
吗啉衍生物苹果酸盐 100
吗啉衍生物酒石酸盐晶型B 150-300
吗啉衍生物酒石酸盐二水合物 100
吗啉衍生物酒石酸盐晶型A 100
吗啉衍生物盐酸盐 ＞500
吗啉衍生物醋酸盐 150-300
吗啉衍生物萘二磺酸盐 ＞500
吗啉衍生物游离碱 5-10
测试例2 稳定性的测试
将实施例的吗啉衍生物的盐各取5mg，将湿度从20％提高到80％，测试重量变化，结果见表2。
表2吗啉衍生物的各类盐的吸湿性测试
测试样品 20％～80％吸湿重量变化 难易程度
吗啉衍生物苹果酸盐 1.70％ 难
吗啉衍生物酒石酸盐晶型B 6.58％ 易
吗啉衍生物酒石酸盐二水合物 9.05％ 易
吗啉衍生物酒石酸盐晶型A 1.50％ 难
吗啉衍生物盐酸盐 31.80％ 非常容易
吗啉衍生物醋酸盐 21.30％ 非常容易
吗啉衍生物萘二磺酸盐 N/A 非常容易
吗啉衍生物游离碱 N/A 难
注：N/A代表无效
将游离碱、实施例的吗啉衍生物的盐各取10mg，在氧化条件下，进行稳定性测试，结果见表3。
表3吗啉衍生物的各类盐在氧化条件下稳定性测试
测试样品 分解量(％) 新杂质种类(种)
吗啉衍生物苹果酸盐 8.46％ 2
吗啉衍生物酒石酸盐晶型B 3.24％ 4
吗啉衍生物酒石酸盐晶型A 17.93％ 6
吗啉衍生物游离碱 38.0％ 6
吗啉衍生物萘二磺酸盐 51.47％ 7
吗啉衍生物盐酸盐 63.53％ 6
吗啉衍生物醋酸盐 95.71％ 5
吗啉衍生物酒石酸盐二水合物 N/A N/A
注：N/A代表无效
*氧化条件：取原料药适量置于表面皿中，厚度约为3-5毫米，置于盛有过氧化氢脲的密闭容器中，在40℃环境下放置12天，取样，做固态表征、手性HPLC测定供试品的含量，与第0天样品比较。
将游离碱、实施例1-6的吗啉衍生物的盐各取10mg，在光照条件下，进行稳定性测试，结果见表4。
表4吗啉衍生物的各类盐在光照条件下稳定性测试
测试样品 分解量(％)
吗啉衍生物苹果酸盐 2.05％
吗啉衍生物酒石酸盐晶型B 3.61％
吗啉衍生物酒石酸盐晶型A 2.14％
吗啉衍生物盐酸盐 5.27％
吗啉衍生物醋酸盐 100％
吗啉衍生物萘二磺酸盐 12.58％
吗啉衍生物游离碱 100％
*光照条件：取原料药适量置于表面皿中，铺成3-5毫米厚度，置于光照箱内，与照度为4500Lx±500Lx(25℃)的条件下放置12天，取样，做固态表征、手性HPLC测定供试品的含量，与第0天样品比较。
以上所述，仅为本发明的具体实施方式，但本发明的保护范围并不局限于此，任何熟悉本领域的技术人员在本发明所揭露的技术范围内，可不经过创造性劳动想到的变化或替换，都应涵盖在本发明的保护范围之内。

Claims (39)

  1. 一种吗啉衍生物苹果酸盐，其特征在于：所述吗啉衍生物苹果酸盐是吗啉衍生物和L-苹果酸以1:1摩尔比形成的化合物，其结构式如下：
    Figure PCTCN2016112966-appb-100001
  2. 如权利要求1所述的吗啉衍生物苹果酸盐，其特征在于：所述吗啉衍生物苹果酸盐为晶型，其X射线粉末衍射图谱在2θ为7.767°±0.2°、13.897°±0.2°、14.775°±0.2°、17.098°±0.2°、18.999°±0.2°、20.153±0.2°、20.960°±0.2°、21.423°±0.2°、26.348°±0.2°、27.892°±0.2°处具有特征峰。
  3. 如权利要求2所述的吗啉衍生物苹果酸盐，其特征在于：所述的晶型，其X射线粉末衍射图谱还在2θ为5.598°±0.2°、7.357°±0.2°、10.395°±0.2°、11.108°±0.2°、16.037°±0.2°、16.523°±0.2°、19.410°±0.2°、22.645°±0.2°、26.630°±0.2°、26.891°±0.2°、27.380°±0.2°、31.056°±0.2°、33.306°±0.2°、33.775°±0.2°、39.231°±0.2°处具有特征峰。
  4. 如权利要求2或3所述的吗啉衍生物苹果酸盐，其特征在于：其具有如图1所示的X射线粉末衍射图谱。
  5. 权利要求1-4中任一项所述吗啉衍生物苹果酸盐的制备方法，其特征在于，包括以下步骤：将吗啉衍生物游离碱溶于丙酮中，将L-苹果酸溶于乙醇中，将L-苹果酸的乙醇溶液滴加到含有吗啉衍生物游离碱的丙酮溶液中，室温下搅拌过夜，析出白色固体，过滤。
  6. 根据权利要求5所述的制备方法，其特征在于：所述吗啉衍生物游离碱与苹果酸的摩尔比为1:1.1～1:3.3。
  7. 一种吗啉衍生物酒石酸盐，其特征在于：是吗啉衍生物和L-酒石酸以1:1摩尔比形成的化合物，其结构式如下：
    Figure PCTCN2016112966-appb-100002
  8. 如权利要求7所述的吗啉衍生物酒石酸盐，其特征在于：所述吗啉衍生物酒石酸盐为吗啉衍生物酒石酸盐晶型B，其X射线粉末衍射图谱在2θ为3.339°±0.2°、6.562°±0.2°、11.331°±0.2°、16.396°±0.2°、22.041°±0.2°处具有特征峰。
  9. 如权利要求8所述的吗啉衍生物酒石酸盐，其特征在于：所述的晶型B，其X射线粉末衍射图谱还在2θ为5.078°±0.2°、6.864°±0.2°、8.250°±0.2°、8.444°±0.2°、11.030°±0.2°、12.864°±0.2°、13.907°±0.2°、14.642°±0.2°、19.100°±0.2°、19.359°±0.2°、25.251°±0.2°、26.768°±0.2°、27.894°±0.2°、29.510°±0.2°、38.343°±0.2°处具有特征峰。
  10. 如权利要求8或9所述的吗啉衍生物酒石酸盐，其特征在于：所述吗啉衍生物酒石酸盐晶型B，具有如图6所示的XRPD图谱。
  11. 如权利要求7-10中任一项所述的吗啉衍生物酒石酸盐的制备方法，包括以下步骤：将吗啉衍生物游离碱溶于丙酮，将L-酒石酸溶于水，将L-酒石酸的水溶液滴加至吗啉衍生物游离碱的丙酮溶液中，室温搅拌过夜，析出白色固体，过滤。
  12. 如权利要求11所述的制备方法，其特征在于：所述吗啉衍生物游离碱与L-酒石酸的摩尔比为1:1.03。
  13. 权利要求7所述的吗啉衍生物酒石酸盐的二水合物，其特征在于：其X射线粉末衍射图谱在2θ为9.851°±0.2°、14.410°±0.2°、14.774°±0.2°、15.052°±0.2°、16.254°±0.2°、20.847°±0.2°、23.225°±0.2°处具有特征峰。
  14. 如权利要求13所述的吗啉衍生物酒石酸盐的二水合物，其特征在于：其X射线粉 末衍射图谱还在2θ为13.434°±0.2°、15.415°±0.2°、15.701°±0.2°、16.755°±0.2°、17.283°±0.2°、18.079°±0.2°、18.576°±0.2°、20.077°±0.2°、21.960°±0.2°、24.351°±0.2°、27.046°±0.2°、27.865°±0.2°、38.458°±0.2°处具有特征峰。
  15. 如权利要求13或14所述的吗啉衍生物酒石酸盐的二水合物，其特征在于具有如图11所示的XRPD图谱。
  16. 如权利要求13、14或15所述的吗啉衍生物酒石酸盐的二水合物的制备方法，其特征在于，包括如下步骤：将吗啉衍生物酒石酸盐晶型B加入丙酮和水的混合溶剂中，室温下搅拌2天后，过滤，得到吗啉衍生物酒石酸盐二水合物。
  17. 如权利要求16所述的制备方法，其特征在于：所述丙酮和水的体积比为30:1。
  18. 权利要求7所述的吗啉衍生物酒石酸盐的四水合物，其特征在于：其为吗啉衍生物酒石酸盐晶型A，其X射线粉末衍射图谱在2θ为9.882°±0.2°、14.426°±0.2°、14.802°±0.2°、16.275°±0.2°、20.085°±0.2°、20.872°±0.2°、21.978°±0.2°、23.236°±0.2°处具有特征峰。
  19. 如权利要求18所述的吗啉衍生物酒石酸盐的四水合物，其特征在于：所述的晶型A，其X射线粉末衍射图谱还在2θ为11.964°±0.2°、13.558°±0.2°、15.076°±0.2°、15.450°±0.2°、16.046°±0.2°、16.754°±0.2°、17.320°±0.2°、18.450°±0.2°、18.790°±0.2°、19.728°±0.2°、20.577°±0.2°、22.426°±0.2°、23.704°±0.2°、24.399°±0.2°、25.346°±0.2°、25.913°±0.2°、26.991°±0.2°、28.199°±0.2°、28.445°±0.2°、29.030°±0.2°、30.209°±0.2°、30.480°±0.2°、32.791°±0.2°、34.796°±0.2°、36.226°±0.2°、38.472°±0.2°处具有特征峰。
  20. 如权利要求18或19所述的吗啉衍生物酒石酸盐的四水合物，其特征在于具有如图16所示的XRPD图谱。
  21. 如权利要求18、19或20所述的吗啉衍生物酒石酸盐的四水合物的制备方法，其特征在于，包括如下步骤：将吗啉衍生物游离碱溶于丙酮，将L-酒石酸溶于水，将L-酒石酸的水溶液滴加至吗啉衍生物游离碱的丙酮溶液中，室温搅拌，析出白色固体，过滤。
  22. 如权利要求21所述的制备方法，其特征在于：所述吗啉衍生物游离碱与L-酒石酸 的摩尔比为1:2.2，所述丙酮与水的体积比为20:1。
  23. 一种吗啉衍生物盐酸盐，其特征在于：所述吗啉衍生物盐酸盐是吗啉衍生物和盐酸以1:2摩尔比形成的化合物，其结构式如下：
    Figure PCTCN2016112966-appb-100003
  24. 如权利要求23所述的吗啉衍生物盐酸盐，其特征在于：所述吗啉衍生物盐酸盐具有晶型形态，其X射线粉末衍射图谱在2θ为3.981°±0.2°、7.784°±0.2°、8.667°±0.2°、13.634°±0.2°、18.238°±0.2°、19.620°±0.2°、24.624°±0.2°、24.987°±0.2°、28.072°±0.2°、31.815°±0.2°处具有特征峰。
  25. 如权利要求24所述的吗啉衍生物盐酸盐，其特征在于：所述的晶型，其X射线粉末衍射图谱还在2θ为10.914°±0.2°、11.557°±0.2°、12.211°±0.2°、14.675°±0.2°、15.419°±0.2°、15.817°±0.2°、17.158°±0.2°、19.116°±0.2°、20.618°±0.2°、21.261°±0.2°、21.901°±0.2°、22.428°±0.2°、22.548°±0.2°、23.342°±0.2°、25.902°±0.2°、26.267°±0.2°、26.730°±0.2°、26.946°±0.2°、29.994°±0.2°、31.154°±0.2°、33.220°±0.2°、34.670°±0.2°、35.201°±0.2°处具有特征峰。
  26. 如权利要求24或25所述的吗啉衍生物盐酸盐，其特征在于所述吗啉衍生物盐酸盐具有如图21所示的XRPD图谱。
  27. 如权利要求23-26中任一项所述的吗啉衍生物盐酸盐的制备方法，包括以下步骤：将吗啉衍生物游离碱溶于丙酮中，将盐酸溶于丙酮中，然后向含吗啉衍生物游离碱的丙酮溶液中滴加盐酸的丙酮溶液，室温下搅拌过夜，析出白色固体，过滤。
  28. 如权利要求27所述的制备方法，所述吗啉衍生物游离碱与盐酸的摩尔比为 1:1.03～1:3.5。
  29. 一种吗啉衍生物醋酸盐，其特在在于：是吗啉衍生物和醋酸以1:1摩尔比形成的化合物，其结构式如下：
    Figure PCTCN2016112966-appb-100004
  30. 如权利要求29所述的吗啉衍生物醋酸盐，其特在在于，所述吗啉衍生物醋酸盐具有晶型形态，其X射线粉末衍射图谱在2θ为7.784°±0.2°、11.429°±0.2°、14.455°±0.2°、16.874°±0.2°、19.899°±0.2°、21.146±0.2°、24.887°±0.2°处具有特征峰。
  31. 如权利要求30所述的吗啉衍生物醋酸盐，其特征在于：所述的晶型，其X射线粉末衍射图谱还在2θ为6.012°±0.2°、7.457°±0.2°、10.391°±0.2°、10.768°±0.2°、13.652°±0.2°、14.089°±0.2°、14.841°±0.2°、15.516°±0.2°、16.301°±0.2°、17.592°±0.2°、18.777°±0.2°、19.375°±0.2°、20.521°±0.2°、21.541°±0.2°、22.346°±0.2°、22.966°±0.2°、23.347°±0.2°、24.585°±0.2°、25.546°±0.2°、26.028°±0.2°、26.328°±0.2°、27.484°±0.2°、27.753°±0.2°、29.206°±0.2°、30.611°±0.2°、30.972°±0.2°、31.233°±0.2°、31.801°±0.2°、33.696°±0.2°、34.699°±0.2°、35.313°±0.2°、36.441°±0.2°、37.961°±0.2°、38.179°±0.2°、39.325°±0.2°处具有特征峰。
  32. 如权利要求30或31所述的吗啉衍生物醋酸盐，其特在在于，所述吗啉衍生物醋酸盐具有如图26所示的XRPD图谱。
  33. 权利要求29-32中任一项所述的吗啉衍生物醋酸盐的制备方法，其特征在于，包括如下步骤：将吗啉衍生物游离碱溶于丙酮中，将醋酸溶于丙酮中，然后向含吗啉衍生物游离碱的丙酮溶液中滴加醋酸的丙酮溶液，室温下搅拌过夜，析出白色固体，过滤。
  34. 如权利要求33所示的制备方法，其特征在于：所述吗啉衍生物游离碱与醋酸的摩尔比为1:1.1～1:3.1。
  35. 一种吗啉衍生物萘二磺酸盐，其特征在于，是吗啉衍生物和萘二磺酸以1:1摩尔比形成的化合物，其结构式如下：
    Figure PCTCN2016112966-appb-100005
  36. 如权利要求35所述吗啉衍生物萘二磺酸盐，其特征在于为无定形盐。
  37. 如权利要求36所述吗啉衍生物萘二磺酸盐，其特征在于：具有如图31所示的XRPD图谱。
  38. 如权利要求35-37中任一项所述的吗啉衍生物萘二磺酸盐的制备方法，其特征在于，包括如下步骤：将吗啉衍生物游离碱溶于乙酸乙酯中，将萘二磺酸溶于乙醇中，将萘二磺酸的乙醇溶液滴加到含有吗啉衍生物游离碱的乙酸乙酯溶液中，室温下搅拌，得到白色絮状沉淀，过滤。
  39. 如权利要求38所述的制备方法，其特征在在于：所述吗啉衍生物游离碱与萘二磺酸的摩尔比为1:1.1～1:3。
PCT/CN2016/112966 2015-12-29 2016-12-29 吗啉衍生物的盐及其晶型、其制备方法及药物组合物、用途 Ceased WO2017114456A1 (zh)

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