WO2020233289A1 - 托拉塞米磷酸酯类前药、其制备方法及组合物 - Google Patents
托拉塞米磷酸酯类前药、其制备方法及组合物 Download PDFInfo
- Publication number
- WO2020233289A1 WO2020233289A1 PCT/CN2020/084803 CN2020084803W WO2020233289A1 WO 2020233289 A1 WO2020233289 A1 WO 2020233289A1 CN 2020084803 W CN2020084803 W CN 2020084803W WO 2020233289 A1 WO2020233289 A1 WO 2020233289A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- salt
- torsemide
- phosphate
- pharmaceutically acceptable
- torasemide
- Prior art date
Links
- 229960005461 torasemide Drugs 0.000 title claims abstract description 74
- NGBFQHCMQULJNZ-UHFFFAOYSA-N Torsemide Chemical compound CC(C)NC(=O)NS(=O)(=O)C1=CN=CC=C1NC1=CC=CC(C)=C1 NGBFQHCMQULJNZ-UHFFFAOYSA-N 0.000 title claims abstract description 50
- 229910019142 PO4 Inorganic materials 0.000 title claims abstract description 40
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 title claims abstract description 40
- 239000010452 phosphate Substances 0.000 title claims abstract description 40
- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- 229940002612 prodrug Drugs 0.000 title claims abstract description 24
- 239000000651 prodrug Substances 0.000 title claims abstract description 24
- 239000000203 mixture Substances 0.000 title abstract description 6
- 150000003839 salts Chemical class 0.000 claims abstract description 20
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 24
- 238000006243 chemical reaction Methods 0.000 claims description 18
- 150000001875 compounds Chemical class 0.000 claims description 13
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 11
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- -1 amine salt Chemical class 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 6
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical class CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 claims description 6
- 229940125782 compound 2 Drugs 0.000 claims description 5
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical class [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 claims description 4
- KCIDZIIHRGYJAE-YGFYJFDDSA-L dipotassium;[(2r,3r,4s,5r,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl] phosphate Chemical class [K+].[K+].OC[C@H]1O[C@H](OP([O-])([O-])=O)[C@H](O)[C@@H](O)[C@H]1O KCIDZIIHRGYJAE-YGFYJFDDSA-L 0.000 claims description 4
- 229930040373 Paraformaldehyde Natural products 0.000 claims description 3
- 229920002866 paraformaldehyde Polymers 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 230000001225 therapeutic effect Effects 0.000 claims description 3
- 159000000009 barium salts Chemical class 0.000 claims description 2
- 238000005660 chlorination reaction Methods 0.000 claims description 2
- 230000032050 esterification Effects 0.000 claims description 2
- 238000005886 esterification reaction Methods 0.000 claims description 2
- 238000005984 hydrogenation reaction Methods 0.000 claims description 2
- 150000002505 iron Chemical class 0.000 claims description 2
- BAUYGSIQEAFULO-UHFFFAOYSA-L iron(2+) sulfate (anhydrous) Chemical compound [Fe+2].[O-]S([O-])(=O)=O BAUYGSIQEAFULO-UHFFFAOYSA-L 0.000 claims description 2
- 229910003002 lithium salt Inorganic materials 0.000 claims description 2
- 159000000002 lithium salts Chemical class 0.000 claims description 2
- 159000000003 magnesium salts Chemical class 0.000 claims description 2
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 claims description 2
- 159000000000 sodium salts Chemical group 0.000 claims description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical group CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 claims description 2
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical class CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 claims description 2
- 150000003751 zinc Chemical class 0.000 claims description 2
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 10
- 238000003756 stirring Methods 0.000 description 9
- 239000012065 filter cake Substances 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- 238000002347 injection Methods 0.000 description 6
- 239000007924 injection Substances 0.000 description 6
- UBLQIESZTDNNAO-UHFFFAOYSA-N n,n-diethylethanamine;phosphoric acid Chemical compound [O-]P([O-])([O-])=O.CC[NH+](CC)CC.CC[NH+](CC)CC.CC[NH+](CC)CC UBLQIESZTDNNAO-UHFFFAOYSA-N 0.000 description 6
- HLUIWGCMLRIUNQ-UHFFFAOYSA-N tributylazanium;phosphate Chemical compound [O-]P([O-])([O-])=O.CCCC[NH+](CCCC)CCCC.CCCC[NH+](CCCC)CCCC.CCCC[NH+](CCCC)CCCC HLUIWGCMLRIUNQ-UHFFFAOYSA-N 0.000 description 6
- 208000004880 Polyuria Diseases 0.000 description 5
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 5
- 230000001882 diuretic effect Effects 0.000 description 5
- 239000008215 water for injection Substances 0.000 description 5
- HDFFVHSMHLDSLO-UHFFFAOYSA-M dibenzyl phosphate Chemical compound C=1C=CC=CC=1COP(=O)([O-])OCC1=CC=CC=C1 HDFFVHSMHLDSLO-UHFFFAOYSA-M 0.000 description 4
- 229910000397 disodium phosphate Inorganic materials 0.000 description 4
- 235000019800 disodium phosphate Nutrition 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 229940090044 injection Drugs 0.000 description 4
- 239000001488 sodium phosphate Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- 238000000859 sublimation Methods 0.000 description 3
- 230000008022 sublimation Effects 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 239000004695 Polyether sulfone Substances 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000004108 freeze drying Methods 0.000 description 2
- 239000013067 intermediate product Substances 0.000 description 2
- 239000002171 loop diuretic Substances 0.000 description 2
- 229920006393 polyether sulfone Polymers 0.000 description 2
- 229940068918 polyethylene glycol 400 Drugs 0.000 description 2
- 238000011045 prefiltration Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 2
- 229960000281 trometamol Drugs 0.000 description 2
- 210000002700 urine Anatomy 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical group OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 229940125890 compound Ia Drugs 0.000 description 1
- 239000006184 cosolvent Substances 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 229910000396 dipotassium phosphate Inorganic materials 0.000 description 1
- 235000019797 dipotassium phosphate Nutrition 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 229940030606 diuretics Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 238000003304 gavage Methods 0.000 description 1
- 229960000443 hydrochloric acid Drugs 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 230000005923 long-lasting effect Effects 0.000 description 1
- 239000008176 lyophilized powder Substances 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 230000027939 micturition Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- LWIHDJKSTIGBAC-UHFFFAOYSA-K potassium phosphate Substances [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229940083608 sodium hydroxide Drugs 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- QUFBGLCLSVONQA-UHFFFAOYSA-M sodium;dibenzyl phosphate Chemical compound [Na+].C=1C=CC=CC=1COP(=O)([O-])OCC1=CC=CC=C1 QUFBGLCLSVONQA-UHFFFAOYSA-M 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229940112088 torsemide injection Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/576—Six-membered rings
- C07F9/58—Pyridine rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/10—Antioedematous agents; Diuretics
Definitions
- the present invention relates to the technical field of biomedicine, in particular to torsemide phosphate prodrug, its preparation method and composition.
- torasemide is 1-[4-(3-methylphenyl)aminopyridin-3-yl]sulfonyl-3-isopropylurea. It is a new generation of high-efficiency loop diuretic with pKa value 6.44, almost insoluble in water, slightly soluble in 0.1mol/L sodium hydroxide solution. More than 20 years of clinical application has proved that torsemide has a wide range of indications, rapid, strong and long-lasting diuretic effects, and is a class of high-efficiency diuretics worth promoting in clinical practice.
- torasemide is marketed as injections, tablets, and capsules. In the preparation process of injections, it is hoped that the crude drug has high water solubility. Torasemide is very slightly soluble in water (European Journal of Pharmaceutics and Biopharmaceutics 53 (2002) 75-86). Sodium hydroxide and a large amount of excipients need to be added to help dissolve the torsemide injection.
- the excipients used include: Polyethylene glycol 400, tromethamine, sodium hydroxide, hydrochloric acid, etc.
- the present invention provides a compound of formula I torasemide phosphate or a pharmaceutically acceptable salt thereof.
- the torasemide phosphate prodrug of the present invention has the characteristics of high solubility, high stability, convenient preparation of preparations, etc., and is easy to be industrialized and used for medical purposes.
- the purpose of the present invention is to provide a torsemide phosphate prodrug and a pharmaceutically acceptable salt thereof.
- the torsemide phosphate prodrug is shown in formula I:
- the pharmaceutically acceptable salt of the torasemide phosphate prodrug includes a pharmaceutically acceptable salt, for example, it may be selected from sodium salt, potassium salt, barium salt, magnesium salt, zinc salt, lithium salt, and iron salt. , Ferrous salt or organic amine salt.
- the pharmaceutically acceptable salt is selected from disodium salt, dipotassium salt or organic amine salt of phosphoric acid group.
- organic amine salt is selected from trimethylamine salt, triethylamine salt, tripropylamine salt or tri-n-butylamine salt.
- the N-hydroxymethyl torsemide phosphate prodrug is selected from the following compounds:
- the second objective of the present invention is to provide the method for preparing the above-mentioned torsemide phosphate prodrug, which includes the following steps:
- Compound 2 is prepared by torsemide 1 and paraformaldehyde through methylolation reaction;
- the present invention also provides a method for preparing medicinal salts based on the above-mentioned torsemide phosphate prodrugs.
- the compound of formula I is then reacted with sodium hydroxide, potassium hydroxide, triethylamine or tri-n-butylamine, respectively.
- the third aspect of the present invention is to provide a pharmaceutical composition, which comprises a therapeutic amount of N-hydroxymethyl-torasemide phosphate and/or a pharmaceutically acceptable salt thereof, and other pharmaceutically acceptable excipients.
- the beneficial effect of the present invention is to provide a torsemide prodrug N-hydroxymethyl torsemide phosphate and/or its medicinal salt, the solubility is better than torsemide, and it has a good medicine sexual advantage.
- Preparation composition N-hydroxymethyl-torasemide phosphate disodium 10g, water for injection 2000mL.
- step (1) The solution A in step (1) is sterilized and filtered with two 0.22 ⁇ m polyethersulfone filter elements to obtain intermediate product B;
- Preparation composition N-hydroxymethyl-torasemide phosphate disodium 10g, water for injection 2000mL.
- the preparation process is as follows:
- step (2) The solution B in step (2) is sterilized and filtered with two 0.22 ⁇ m polyethersulfone filter elements to obtain solution C, filled and half-pressed to obtain intermediate product D;
- the intermediate D is subjected to a freeze-drying treatment under the conditions of a temperature of -40°C to -50°C and a pressure of 10Pa-22Pa, and the freeze-drying treatment adopts the following procedure to heat up:
- mice Male SD rats (body weight 180 ⁇ 20g) were randomly divided into 7 groups, 3 in each group, and each was given 30mL/kg normal saline by gavage. After intragastric administration of normal saline, except the blank control group, each group was given one drug (10mg/kg, iv, 1mg/mL, formulation prescription: 0.5% methylcellulose), and urination for 4 hours was collected. The results are shown in Table 2:
- Urine output (mL/kg, 4h) Blank control ⁇ 18.9 Torasemide 10mg/kg, iv 100.3 Compound I 10mg/kg, iv 105.4 Compound Ia 10mg/kg, iv 121.6 Compound Ib 10mg/kg, iv 116.8 Compound Ic 10mg/kg, iv 103.4 Compound Id 10mg/kg, iv 105.6
- the diuretic effect experiment results show that the N-hydroxymethyl torsemide phosphate prodrug in Examples 1 to 5 has a diuretic effect similar to torsemide, or better than torsemide diuretic effect, and has better Medicine advantage.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Hematology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Diabetes (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Enzymes And Modification Thereof (AREA)
Abstract
本发明涉及生物医药技术领域,具体涉及托拉塞米磷酸酯类前药、其制备方法及组合物。本发明提供的托拉塞米前药N-羟甲基-托拉塞米磷酸酯和/或其药用盐,溶解性优于托拉塞米,具有较好的成药性优势。
Description
本发明涉及生物医药技术领域,具体涉及托拉塞米磷酸酯类前药、其制备方法及组合物。
托拉塞米化学名为1-[4-(3-甲基苯基)氨基吡啶-3-基]磺酰-3-异丙基脲,是新一代高效髓袢利尿剂,其pKa值为6.44,在水中几乎不溶,略溶于0.1mol/L的氢氧化钠溶液。20多年临床应用证实,托拉塞米适应症广,利尿作用迅速、强大且持久,是临床上值得推广的一类高效利尿剂。
目前托拉塞米上市剂型有注射剂、片剂、胶囊剂。在注射剂的制备过程中,希望原料药具有较高的水溶性。托拉塞米在水中极微溶解(European Journal of Pharmaceutics and Biopharmaceutics 53(2002)75–86),在制备托拉塞米注射剂型时,需加入氢氧化钠及大量辅料助溶,所用辅料包括:聚乙二醇400、氨丁三醇、氢氧化钠、盐酸等。上述辅料的加入带来了诸多不利:1)氢氧化钠水溶液溶解托拉塞米过程中放热明显,易产生制剂降解杂质;2)聚乙二醇400、氨丁三醇等有机助溶剂的加入,对注射剂用药安全性带来隐患。人们总是期望减少配方的成分种类以便减少病人可能产生的副反应。
因此开发更高水溶性、更利于制剂制备的新型髓袢利尿剂成为一大挑战。
本发明提供了式I托拉塞米磷酸酯的化合物或其药用盐。
本发明托拉塞米磷酸酯前药具有溶解度高、稳定性高、制备制剂方便等特点,易于产业化放大并用于医药用途。
发明内容
本发明的目的在于提供一种托拉塞米磷酸酯类前药及其药用盐,具体的,所述托拉塞米磷酸酯类前药如式Ⅰ所示:
上述结构的化学名称为N-羟甲基-托拉塞米磷酸酯。
优选的,所述托拉塞米磷酸酯类前药的药用盐包括药学上可接受的盐,例如可以选自钠盐、钾盐、钡盐、镁盐、锌盐、锂盐、铁盐、亚铁盐或有机胺盐。
进一步优选的,所述药用盐选自磷酸基团的二钠盐、二钾盐或有机胺盐。
进一步的,所述有机胺盐选自三甲胺盐、三乙胺盐、三丙胺盐或三正丁胺盐。
作为本发明的优选实施方式,所述N-羟甲基-托拉塞米磷酸酯前药选自如下化合物:
本发明的第二目的在于提供上述托拉塞米磷酸酯类前药制备方法,包括以下步骤:
(1)托拉塞米1与多聚甲醛经羟甲基化反应制得化合物2;
(2)化合物2经氯化、酯化、氢化脱苄基制得式I化合物;
本发明还提供了上述托拉塞米磷酸酯类前药基础上制备药用盐的方法,将式I化合物再分别与氢氧化钠、氢氧化钾、三乙胺或三正丁胺反应,分别获得式Ia、Ib、Ic、Id:
本发明的第三方面在于提供一种药物组合物,其包括治疗量的N-羟甲基-托拉塞米磷酸酯和/或其药用盐,以及其他药学上可接受的辅料。
本发明的有益效果在于提供了一种托拉塞米前药N-羟甲基-托拉塞米磷酸酯和/或其药用盐,溶解性优于托拉塞米,具有较好的成药性优势。
以下结合实施例对本发明作进一步作具体描述,但不局限于此。
实施例1:N-羟甲基-托拉塞米磷酸酯(I)的制备
步骤1:N-羟甲基-托拉塞米(2)的制备
500mL反应瓶中加入无水乙醇(300mL)、托拉塞米(34.8g,0.1mol,1eq)、碳酸钠(15.9g,0.15mol,1.5eq),搅拌下分批加入多聚甲醛(15g,0.5mol,5eq)。加完后,升温至内温80-85℃反应2h,缓慢降至内温20-25℃,有白色固体析出,过滤、水洗。滤饼真空干燥(40℃)得N-羟甲基-托拉塞米(2)(32.5g,收率86%),MS:379[M+1]。
步骤2:N-氯甲基-托拉塞米(3)的制备
500mL反应瓶中加入二氯甲烷(200mL)、N,N-二甲基甲酰胺(2mL)、化合物2(30g,79.3mmol,1eq),搅拌下滴加二氯亚砜(28.3g,237.8mmol,3eq)。加完后,升温至内温60-65℃反应2h,反应结束后,倒入500mL烧杯中,冰浴下分批滴加入10%碳酸钠水溶液(50mL),分液漏斗分液除去水层,有机层再水洗2次(50mL x2)、饱和食盐水(50mL)洗涤一次,分液、无水硫酸钠干燥、浓缩至干。剩余物经乙酸乙酯(50mL)打浆洗涤,过滤,滤饼真空干燥(40℃)得N-氯甲基-托拉塞米(3)(29.9g,收率95%),MS:398[M+1]。
步骤3:N-羟甲基-托拉塞米磷酸二苄酯(5)的制备
500mL反应瓶中加入乙腈(300mL)、化合物3(29g,73.1mmol,1eq)、碳酸钠(15.5g,146.1mmol,2eq)、磷酸二苄酯钠盐4(24.1g,80.4mmol,1.1eq),搅拌下升温至内温80-85℃反应8h,趁热过滤去除无机盐,滤液浓缩至干。浓缩剩余物加甲苯(50mL)重结晶,过滤。滤饼真空干燥(50℃)得N-羟甲基-托拉塞米磷酸二苄酯(5)(21.5g,收率46%),MS:639[M+1]。
步骤4:N-羟甲基-托拉塞米磷酸酯(I)的制备
将无水乙醇(400mL)、化合物5(20g,31.3mmol,1eq)、10%钯碳(2g,10%重量比)加入高压反应釜中,氮气置换3次,通氢气至压力2MPa,搅拌下室温反应5h,反应结束,过滤,滤液浓缩至干,得白色固体N-羟甲基-托拉塞米磷酸酯(I)(11.5g,收率80%),MS:459[M+1]。
1H NMR(400MHz,D
2O)δ:8.56(s,1H),7.99-8.00(d,J=4.0Hz,1H),7.23-7.26(m,1H),6.98-7.03(m,3H),6.89-6.90(m,1H),5.91(s,2H),3.55-3.57(m,1H),2.25(s,3H),0.95(s,3H),0.94(s,3H)。
实施例2:N-羟甲基-托拉塞米磷酸酯二钠(Ia)的制备
100mL反应瓶中加入无水乙醇(50mL)、N-羟甲基-托拉塞米磷酸酯(I)(10g,21.8mol,1eq),搅拌下滴加25%氢氧化钠溶液(1.83g,45.8mol,2.1eq),加完后搅拌反应1h。向反应液中加入丙酮(50mL),并继续搅拌30min,过滤,得二钠盐粗品。所得粗品加入丙酮(50mL)/H
2O(5mL)体系重结晶,过滤,滤饼真空干燥(50℃)得N-羟甲基-托拉塞米磷酸酯二钠(Ia)(7.6g,收率69%),HPLC纯度99.90%。MS:503[M+1],
1H NMR(400MHz,D
2O)δ:8.55(s,1H),7.99(d,J=4.0Hz,1H),7.25(m,1H),6.98-7.05(m,3H),6.92(m,1H),5.92(s,2H),3.56(m,1H),2.24(s,3H),0.94(s,3H),0.93(s,3H)。钠含量:9.19%。
实施例3 N-羟甲基-托拉塞米磷酸酯二钾(Ib)的制备
100mL反应瓶中加入无水乙醇(50mL)、N-羟甲基-托拉塞米磷酸酯(I)(10g,21.8mol,1eq),搅拌下滴加20%氢氧化钠溶液(2.57g,45.8mol,2.1eq),加完后搅拌反应1h。向反应液中加入丙酮(50mL),并继续搅拌30min,过滤,得二钾盐粗品。所得粗品加入丙酮(50mL)/H
2O(5mL)体系重结晶,过滤,滤饼真空干燥(50℃)得N-羟甲基-托拉塞米磷酸酯二钾(Ib)(7.6g,收率65%),HPLC纯度99.92%。MS:535[M+1],
1H NMR(400MHz,D
2O)δ:8.57(s,1H),7.99(d,J=4.0Hz,1H),7.27(m,1H),6.99-7.04(m,3H),6.94(m,1H),5.91(s,2H),3.55(m,1H),2.23(s,3H),0.94(s,6H)。钾含量:14.58%。
实施例4:N-羟甲基-托拉塞米磷酸酯三乙铵盐(Ic)的制备
100mL反应瓶中加入无水乙醇(50mL)、N-羟甲基-托拉塞米磷酸酯(I)(10g,21.8mol,1eq)、三乙胺(2.2g,21.8mol,1eq),搅拌反应1h。浓缩溶剂至干得泡沫状固体,该固体经丙酮(30mL)重结晶,过滤,滤饼真空干燥(40℃)得N-羟甲基-托拉塞米磷酸酯三乙铵盐(Ic)(6.7g,收率55%),HPLC纯度99.85%。MS:459[M+1],
1H NMR(400MHz,D
2O)δ:8.55(s,1H),7.99(d,J=4.0Hz,1H),7.25(m,1H),6.97-7.04(m,3H),6.95(m,1H),5.91(s,2H),3.57(m,1H),3.07(m,6H),2.25(s,3H),1.07(m,9H),0.93(s,6H)。
实施例5 N-羟甲基-托拉塞米磷酸酯三正丁铵盐(Id)的制备
100mL反应瓶中加入无水乙醇(50mL)、N-羟甲基-托拉塞米磷酸酯(I)(10g,21.8mol,1eq)、三正丁胺(4.04g,21.8mol,1eq),搅拌反应1h。浓缩溶剂至干得泡沫状固体,该固体经丙酮(30mL)重结晶,过滤,滤饼真空干燥(40℃)得N-羟甲基-托拉塞米磷酸酯三正丁铵盐(Id)(7.2g,收率51%),HPLC纯度99.88%。MS:459[M+1],
1H NMR(400MHz, D
2O)δ:8.56(s,1H),8.01-8.02(d,J=4.0Hz,1H),7.26(m,1H),6.98-7.04(m,3H),6.94(m,1H),5.93(s,2H),3.55(m,1H),3.05(m,6H),2.23(s,3H),1.35-1.42(m,12H),0.93(s,6H),0.87(m,9H)。
实施例6 N-羟甲基-托拉塞米磷酸酯二钠注射液的制备
制剂组成:N-羟甲基-托拉塞米磷酸酯二钠10g,注射用水2000mL。
制备方法:
(1)量取注射用水2000mL,加入托拉塞米10g,搅拌均匀,经板框过滤器进行预过滤,得溶液A;
(2)将步骤(1)中溶液A用两道0.22μm聚醚砜滤芯进行除菌过滤,得中间产品B;
(3)中间体B经灌装、熔封、包装,既得产品。
实施例7 N-羟甲基-托拉塞米磷酸酯二钠冻干粉针制备
制剂组成:N-羟甲基-托拉塞米磷酸酯二钠10g,注射用水2000mL。
制备过程如下:
(1)取70%选定体积注射用水,加入选定重量的N-羟甲基-托拉塞米磷酸酯二钠,搅拌至完成溶解,得溶液A;
(2)取30%选定体积注射用水,加入至上述溶液A中,搅拌下调节pH值8.5至9.5,经板框过滤器进行预过滤,得溶液B;
(3)将步骤(2)中溶液B用两道0.22μm聚醚砜滤芯进行除菌过滤,得溶液C,灌装,半压塞,得中间产品D;
(4)将所述中间体D在温度为-40℃~-50℃,压力为10Pa~22Pa的条件下进行冷冻干燥处理,所述冷冻干燥处理采用如下程序进行升温:
(a)设置温度为-45℃~-30℃,进行预冻2.0h;
(b)升温至温度为-30℃~-20℃,进行升华4.0h;
(c)升温至温度为-20℃~-10℃,进行升华1.5h;
(d)升温至温度为-10℃~0℃,进行升华1.0h;
(e)升温至温度为0℃~15℃,进行升华1.5h;
(f)升温至温度为15℃~25℃,进行保温2.0h;
压塞、出箱、扎盖,即得N-羟甲基-托拉塞米磷酸酯二钠冻干粉针。
溶解性比较:
对托拉塞米、N-羟甲基-托拉塞米磷酸酯(I)、N-羟甲基-托拉塞米磷酸酯二钠(Ia)、N-羟甲基-托拉塞米磷酸酯二钾(Ib)、N-羟甲基-托拉塞米磷酸酯三乙铵盐(Ic)、N-羟甲基-托拉塞米磷酸酯三正丁铵盐(Id)进行了溶解性比较,结果如下:
表1、不同形式样品水溶性比较
溶解度实验结果表明,实施例1~5中N-羟甲基-托拉塞米磷酸酯前药溶解性优于托拉塞 米,具有较好的成药性优势。
利尿作用比较:
SD雄性大鼠(体重180±20g)随机分为7组,每组3只,每只给予30mL/kg生理盐水灌胃。生理盐水灌胃后,除空白对照组外,每组给予一种药物(10mg/kg,iv,1mg/mL,制剂处方:0.5%methylcellulose),收集4h排尿情况,结果如表2所示:
表2、不同化合物排尿量比较
化合物 | 给药剂量及方式 | 排尿量(mL/kg,4h) |
空白对照 | ‐‐ | 18.9 |
托拉塞米 | 10mg/kg,iv | 100.3 |
化合物I | 10mg/kg,iv | 105.4 |
化合物Ia | 10mg/kg,iv | 121.6 |
化合物Ib | 10mg/kg,iv | 116.8 |
化合物Ic | 10mg/kg,iv | 103.4 |
化合物Id | 10mg/kg,iv | 105.6 |
利尿作用实验结果表明,实施例1~5中N-羟甲基-托拉塞米磷酸酯前药具有与托拉塞米相似利尿作用,或优于托拉塞米利尿作用,具有较好的成药性优势。
本发明提及的所有文献都在本申请中引用作为参考,就如同每一篇文献被单独引用作为参考那样。
Claims (9)
- 如权利要求1所述的托拉塞米磷酸酯类前药及其药用盐,其特征在于,所述托拉塞米磷酸酯类前药的药用盐包括药学上可接受的盐,可以选自钠盐、钾盐、钡盐、镁盐、锌盐、锂盐、铁盐、亚铁盐或有机胺盐。
- 如权利要求2所述的托拉塞米磷酸酯类前药及其药用盐,其特征在于,所述托拉塞米磷酸酯类前药的药用盐选自磷酸基团的二钠盐、二钾盐或有机胺盐。
- 如权利要求3所述的托拉塞米磷酸酯类前药及其药用盐,其特征在于,所述有机胺盐选自三甲胺盐、三乙胺盐、三丙胺盐或三正丁胺盐。
- 一种药物组合物,其特征在于包括治疗量的如权利要求1~4任一项所述的N-羟甲基-托拉塞米磷酸酯和/或其药用盐,以及其他药学上可接受的辅料。
- 一种药物组合物,其特征在于包括治疗量的如权利要求5所述的N-羟甲基-托拉塞米磷酸酯和/或其药用盐,以及其他药学上可接受的辅料。
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2021569862A JP7226859B2 (ja) | 2019-05-23 | 2020-04-14 | トラセミドリン酸エステルプロドラッグ、その調製方法及び組成物 |
US17/482,827 US20220009951A1 (en) | 2019-05-23 | 2021-09-23 | Torsemide phosphate prodrug, preparation method and composition thereof |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201910435995.7 | 2019-05-23 | ||
CN201910435995.7A CN110054647B (zh) | 2019-05-23 | 2019-05-23 | 托拉塞米磷酸酯类前药、其制备方法及组合物 |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US17/482,827 Continuation US20220009951A1 (en) | 2019-05-23 | 2021-09-23 | Torsemide phosphate prodrug, preparation method and composition thereof |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2020233289A1 true WO2020233289A1 (zh) | 2020-11-26 |
Family
ID=67324334
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/CN2020/084803 WO2020233289A1 (zh) | 2019-05-23 | 2020-04-14 | 托拉塞米磷酸酯类前药、其制备方法及组合物 |
Country Status (4)
Country | Link |
---|---|
US (1) | US20220009951A1 (zh) |
JP (1) | JP7226859B2 (zh) |
CN (1) | CN110054647B (zh) |
WO (1) | WO2020233289A1 (zh) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN110054647B (zh) * | 2019-05-23 | 2021-06-15 | 上海勋和医药科技有限公司 | 托拉塞米磷酸酯类前药、其制备方法及组合物 |
CN110606860B (zh) * | 2019-09-29 | 2021-12-10 | 上海勋和医药科技有限公司 | 一种吡啶磺酰胺磷酸酯类化合物、其制备方法及其用途 |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1992019245A1 (de) * | 1991-04-27 | 1992-11-12 | Boehringer Mannheim Gmbh | Verwendung von torasemid zur behandlung von hirnödemen |
EP0618209A1 (fr) * | 1993-03-26 | 1994-10-05 | Adir Et Compagnie | Nouvelles pyridothiadiazines, leurs procédés de préparation et les compositions pharmaceutiques qui les contiennent |
US5914336A (en) * | 1998-06-02 | 1999-06-22 | Boehringer Mannheim Gmbh | Method of controlling the serum solubility of orally administered torasemide and composition relating thereto |
CN1623987A (zh) * | 2000-03-20 | 2005-06-08 | 特瓦制药工业有限公司 | 托拉塞米的制备方法 |
CN104744355A (zh) * | 2013-12-31 | 2015-07-01 | 南京长澳医药科技有限公司 | 一种托拉塞米及其衍生物的制备方法 |
CN110054647A (zh) * | 2019-05-23 | 2019-07-26 | 上海勋和医药科技有限公司 | 托拉塞米磷酸酯类前药、其制备方法及组合物 |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7378527B2 (en) * | 2004-03-16 | 2008-05-27 | Daqing Che | Process for the preparation of torsemide and related intermediates |
CN106146557A (zh) * | 2015-03-26 | 2016-11-23 | 北京健峤医药科技有限公司 | 一种具有抗肿瘤活性的磷酸酯衍生物的合成及应用 |
-
2019
- 2019-05-23 CN CN201910435995.7A patent/CN110054647B/zh active Active
-
2020
- 2020-04-14 JP JP2021569862A patent/JP7226859B2/ja active Active
- 2020-04-14 WO PCT/CN2020/084803 patent/WO2020233289A1/zh active Application Filing
-
2021
- 2021-09-23 US US17/482,827 patent/US20220009951A1/en active Pending
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1992019245A1 (de) * | 1991-04-27 | 1992-11-12 | Boehringer Mannheim Gmbh | Verwendung von torasemid zur behandlung von hirnödemen |
EP0618209A1 (fr) * | 1993-03-26 | 1994-10-05 | Adir Et Compagnie | Nouvelles pyridothiadiazines, leurs procédés de préparation et les compositions pharmaceutiques qui les contiennent |
US5914336A (en) * | 1998-06-02 | 1999-06-22 | Boehringer Mannheim Gmbh | Method of controlling the serum solubility of orally administered torasemide and composition relating thereto |
CN1623987A (zh) * | 2000-03-20 | 2005-06-08 | 特瓦制药工业有限公司 | 托拉塞米的制备方法 |
CN104744355A (zh) * | 2013-12-31 | 2015-07-01 | 南京长澳医药科技有限公司 | 一种托拉塞米及其衍生物的制备方法 |
CN110054647A (zh) * | 2019-05-23 | 2019-07-26 | 上海勋和医药科技有限公司 | 托拉塞米磷酸酯类前药、其制备方法及组合物 |
Also Published As
Publication number | Publication date |
---|---|
JP7226859B2 (ja) | 2023-02-21 |
US20220009951A1 (en) | 2022-01-13 |
CN110054647B (zh) | 2021-06-15 |
CN110054647A (zh) | 2019-07-26 |
JP2022533795A (ja) | 2022-07-25 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN110606860B (zh) | 一种吡啶磺酰胺磷酸酯类化合物、其制备方法及其用途 | |
CN103209966A (zh) | 6-氟-3-羟基-2-吡嗪甲酰胺的钠盐 | |
JP3087763B2 (ja) | 新規な複素環式化合物およびそれを含有する医薬組成物 | |
US11286259B2 (en) | Co-crystals of ribociclib and co-crystals of ribociclib monosuccinate, preparation method therefor, compositions thereof, and uses thereof | |
WO2020233289A1 (zh) | 托拉塞米磷酸酯类前药、其制备方法及组合物 | |
WO2020020231A1 (zh) | 一类双季铵化合物及其制备方法和用途 | |
KR20090114398A (ko) | (e)-2,6-다이알콕시스티릴 4-치환된 벤질설폰의 비경구 투여용 제형 | |
JP2021046404A (ja) | Olig2活性の阻害 | |
FI57408B (fi) | Foerfarande foer framstaellning av antiallergiska 3-(tetrazol-5-yl)-kromoner | |
KR20070072588A (ko) | 텔미사르탄 나트륨의 비정질형 및 다형 | |
CN107602546A (zh) | 化合物的晶型及其制备方法、组合物和应用 | |
PT100777B (pt) | Novas ureias 4-oxociclicas uteias como agentes anti-arritmicos e anti-fibrilatorios | |
JPS6242905B2 (zh) | ||
WO2020233288A1 (zh) | 托拉塞米钠一水合物、其晶型及组合物 | |
CN106478764B (zh) | 丹参酮iia磷酸衍生物、及其合成和作为药物的应用 | |
KR102103407B1 (ko) | (3s,3s') 4,4'-디설판디일비스(3-아미노부탄 1-설폰산)과 l-라이신과의 결정성 상 | |
JPS6256874B2 (zh) | ||
SK279677B6 (sk) | Cyklické deriváty močoviny a farmaceutický prostri | |
JPS62212386A (ja) | 2−ピリジルメチルベンズイミダゾ−ル誘導体 | |
GB2033900A (en) | Sulphonamides | |
CN109879839B (zh) | 6-哌嗪甲基-7-羟基苯并呋喃类化合物及其医药用途 | |
WO1993015717A1 (en) | Compositions for the treatment of glaucoma | |
CN116554127A (zh) | 哌嗪取代苯酚类衍生物及其用途 | |
CN116514868A (zh) | 一种用于治疗的磺酰胺类化合物其及制备方法和用途 | |
WO2017152846A1 (zh) | 2-[(2r)-2-甲基-2-吡咯烷基]-1h-苯并咪唑-7-甲酰胺二盐酸盐的晶型a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: 20809745 Country of ref document: EP Kind code of ref document: A1 |
|
ENP | Entry into the national phase |
Ref document number: 2021569862 Country of ref document: JP Kind code of ref document: A |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
122 | Ep: pct application non-entry in european phase |
Ref document number: 20809745 Country of ref document: EP Kind code of ref document: A1 |