WO2018041112A1 - 一种四氢异喹啉的盐衍生物及其晶体的制备方法和应用 - Google Patents
一种四氢异喹啉的盐衍生物及其晶体的制备方法和应用 Download PDFInfo
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- WO2018041112A1 WO2018041112A1 PCT/CN2017/099549 CN2017099549W WO2018041112A1 WO 2018041112 A1 WO2018041112 A1 WO 2018041112A1 CN 2017099549 W CN2017099549 W CN 2017099549W WO 2018041112 A1 WO2018041112 A1 WO 2018041112A1
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- methanesulfonamidobenzyl
- methoxy
- benzyloxy
- salt derivative
- acid
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- 0 *c1cccc(CC2NCCc3cc(*)c(*)cc23)c1 Chemical compound *c1cccc(CC2NCCc3cc(*)c(*)cc23)c1 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
- C07D217/18—Aralkyl radicals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/472—Non-condensed isoquinolines, e.g. papaverine
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- 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
- A61P9/06—Antiarrhythmics
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- 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 present invention relates to a 1-(3-methanesulfonamidobenzyl)-6-methoxy, 7-benzyloxy-1,2,3,4-tetrahydroisoquinoline salt derivative and preparation thereof And a pharmaceutical composition comprising a salt derivative of 1-(3-methanesulfonamidobenzyl)-6-methoxy, 7-benzyloxy-1,2,3,4-tetrahydroisoquinoline .
- SCD Sudden cardiac death
- Antiarrhythmic drugs can be divided into four categories: Class I is a sodium channel blocker, which has three subtypes a, b, and c. Class Ia is a moderate block of sodium channel, representing the drug Quinidine, etc.; Class Ib is a mild block of sodium channel, which represents the drug beneficial to Lidocaine; Ic class is a significant block of sodium channel, Representative drugs include Flecainide and the like. Class II is a beta adrenergic blocker, and the representative drug is Propranolol. Class III is a drug that selectively prolongs the repolarization process, which prolongs the action potential duration (APD) and the effective refractory period (ERP), and represents a drug such as Amiodarone. Class IV is a calcium antagonist, and the representative drug is Verapamil.
- Class Ia is a moderate block of sodium channel, representing the drug Quinidine, etc.
- Class Ib is a mild block of sodium channel, which represents the drug beneficial to Lidocaine
- Ic class
- Isoquinoline alkaloids are widely found in natural plants, among which bisbenzylisoquinoline alkaloids (eg, berbamine, dauricine, tetrandrine, xylophylline, neferine), monobenzyl Isoquinoline alkaloids (such as norepinephrine) and protoberberine (Huangliansu) have anti-arrhythmia and other cardiovascular activities.
- bisbenzylisoquinoline alkaloids eg, berbamine, dauricine, tetrandrine, xylophylline, neferine
- monobenzyl Isoquinoline alkaloids such as norepinephrine
- protoberberine Huangliansu
- berberine exhibits class III antiarrhythmic activity and is clinically reported for the treatment of ventricular arrhythmias.
- Patent ZL200710181295.7 discloses 1-(3-methanesulfonamidobenzyl)-6-methoxy, 7-benzyloxy-1,2,3,4-tetrahydroisoquinoline (SIPI-409) and The structure and preparation method and application of SIPI-409 hydrochloride.
- the present invention aims to provide a SIPI-409 salt derivative having good solubility in water and a preparation method thereof.
- the solubility of the salt derivative in water is not less than 3.0 nmol/mL or 1.8 mg/mL.
- HA is selected from the group consisting of sulfuric acid, phosphoric acid, nicotinic acid, oxalic acid, glycolic acid, benzenesulfonic acid, or orotic acid; and X is selected from 1/3, 1/2, or 1.
- the salt of 1-(3-methanesulfonamidobenzyl)-6-methoxy, 7-benzyloxy-1,2,3,4-tetrahydroisoquinoline is a crystal.
- HA is sulfuric acid; and X is selected from 1/2 or 1.
- HA is oxalic acid
- X is selected from 1/2 or 1.
- the crystal form of the crystal is determined by X-ray diffraction technique (XRPD) and characterized by a Bragg 2 Theta angle (Bragg 2-Theta) as follows: 4.9 ⁇ 0.2 °, 7.1 ⁇ 0.2 °, 8.4 ⁇ 0.2 °, 9.7 ⁇ 0.2 °, 12.0 ⁇ 0.2 °, 15.4 ⁇ 0.2 °, 17.0 ⁇ 0.2 °, 19.5 ° ⁇ 0.2 °, 20.3 ⁇ 0.2 °, 20.9 ⁇ 0.2 °, 21.6 ⁇ 0.2°, 22.8 ⁇ 0.2°, 23.6 ⁇ 0.2°, 24.6 ⁇ 0.2°, 25.4 ⁇ 0.2°, 26.0 ⁇ 0.2°, 30.8 ⁇ 0.2°; or in DSC spectra when analyzed by differential scanning calorimetry (DSC) There is an endothermic peak at 130 ⁇ 5 °C.
- DSC differential scanning calorimetry
- the crystal form of the crystal is determined by X-ray diffraction technique (XRPD) and characterized by a Bragg 2 Theta angle (Bragg 2-Theta) as follows: 4.6 ⁇ 0.2 °, 7.6 ⁇ 0.2 °, 9.8 ⁇ 0.2 °, 10.2 ⁇ 0.2 °, 13.9 ⁇ 0.2 °, 14.4 ⁇ 0.2 °, 15.3 ⁇ 0.2 °, 18.1 ⁇ 0.2 °, 16.8 ⁇ 0.2 °, 20.5 ⁇ 0.2 °, 20.9 ⁇ 0.2 °, 21.9 ⁇ 0.2 °, 23.1 ⁇ 0.2 °, 23.5 ⁇ 0.2 °, 24.3 ⁇ 0.2 °, 27.1 ⁇ 0.2 °; more preferably, the X-powder diffraction pattern of the crystal is shown in Figure 1.
- the crystal form of the crystal when HA is nicotinic acid is determined by X-ray diffraction technique (XRPD) and characterized by a Bragg 2 Theta angle (Bragg 2-Theta) as follows: 5.0 ⁇ 0.2 °, 5.9 ⁇ 0.2 °, 7.2 ⁇ 0.2 °, 8.2 ⁇ 0.2 °, 10.9 ⁇ 0.2 °, 12.2 ⁇ 0.2 °, 13.4 ⁇ 0.2 °, 14.4 ° ⁇ 0.2 °, 15.1 ⁇ 0.2 °, 15.5 ⁇ 0.2°, 17.0 ⁇ 0.2°, 17.4 ⁇ 0.2°, 17.8 ⁇ 0.2°, 18.7 ⁇ 0.2°, 19.9 ⁇ 0.2°, 20.5 ⁇ 0.2°, 20.8 ⁇ 0.2°, 21.9 ⁇ 0.2°, 23.1 ⁇ 0.2°, 23.5 ⁇ 0.2 °, 24.8 ⁇ 0.2 °, 25.1 ⁇ 0.2 °, 25.6 ⁇ 0.2 °, 27.0 ⁇ 0.2 °, 27.6
- the crystal form of the crystal is determined by X-ray diffraction technique (XRPD) and characterized by a Bragg 2 Theta angle (Bragg 2-Theta) as follows: 3.4 ⁇ 0.2 °, 4.6 ⁇ 0.2 °, 5.5 ⁇ 0.2 °, 7.8 ⁇ 0.2 °, 9.2 ⁇ 0.2 °, 10.2 ⁇ 0.2 °, 10.8 ⁇ 0.2 °, 11.9 ° ⁇ 0.2 °, 13.1 ⁇ 0.2 °, 13.8 ⁇ 0.2 °, 14.6 ⁇ 0.2°, 16.4 ⁇ 0.2°, 17.0 ⁇ 0.2°, 18.4 ⁇ 0.2°, 19.0 ⁇ 0.2°, 20.2 ⁇ 0.2°, 21.9 ⁇ 0.2°, 23.6 ⁇ 0.2°, 25.8 ⁇ 0.2°, 27.3 ⁇ 0.2°, 30.0 ⁇ 0.2°, 31.9 ⁇ 0.2°; or when analyzed by differential scanning calorimetry (DSC), there is an endother
- the crystal form of the crystal when HA is glycolic acid is determined by X-ray diffraction technique (XRPD) and characterized by a Bragg 2 Theta angle (Bragg 2-Theta) as follows: 4.7 ⁇ 0.2 °, 7.5 ⁇ 0.2 °, 9.9 ⁇ 0.2 °, 10.3 ⁇ 0.2 °, 13.7 ⁇ 0.2 °, 14.3 ⁇ 0.2 °, 14.9 ⁇ 0.2 °, 15.3 ° ⁇ 0.2 °, 16.1 ⁇ 0.2 °, 16.9 ⁇ 0.2 °, 17.6 ⁇ 0.2 °, 18.1 ⁇ 0.2°, 18.9 ⁇ 0.2°, 19.3 ⁇ 0.2°, 20.4 ⁇ 0.2°, 20.8 ⁇ 0.2°, 21.8 ⁇ 0.2°, 22.5 ⁇ 0.2°, 22.9 ⁇ 0.2°, 24.3 ⁇ 0.2°, 24.9 ⁇ 0.2°, 25.3 ⁇ 0.2°, 25.9 ⁇ 0.2°, 27.7 ⁇ 0.2°; or when analyzed by differential scanning calorimetry (XRPD)
- the crystal form of the crystal when HA is benzenesulfonic acid is determined by X-ray diffraction technique (XRPD) and characterized by a Bragg 2 Theta angle (Bragg 2-Theta) as follows: 6.1 ⁇ 0.2 °, 6.8 ⁇ 0.2°, 8.2 ⁇ 0.2°, 8.8 ⁇ 0.2°, 11.5 ⁇ 0.2°, 12.7 ⁇ 0.2°, 14.4 ⁇ 0.2°, 15.0° ⁇ 0.2°, 15.5 ⁇ 0.2°, 16.5 ⁇ 0.2°, 17.0 ⁇ 0.2°, 17.4 ⁇ 0.2°, 17.7 ⁇ 0.2°, 18.7 ⁇ 0.2°, 19.4 ⁇ 0.2°, 19.8 ⁇ 0.2°, 20.3 ⁇ 0.2°, 21.3 ⁇ 0.2°, 21.7 ⁇ 0.2°, 22.6 ⁇ 0.2°, 23.0 ⁇ 0.2°, 23.5 ⁇ 0.2°, 24.2 ⁇ 0.2°, 29.1 ⁇ 0.2°; or when analyzed by differential scanning calorimetry (DSC), there is an endothermic peak in the DSC spectrum at 150 ⁇ 5°C, and there is an endother
- the crystal form of the crystal when HA is orotic acid is determined by X-ray diffraction technique (XRPD) and characterized by a Bragg 2 Theta angle (Bragg 2-Theta) as follows: 5.8 ⁇ 0.2 °, 8.7 ⁇ 0.2°, 9.9 ⁇ 0.2°, 11.2 ⁇ 0.2°, 12.5 ⁇ 0.2°, 13.9 ⁇ 0.2°, 14.1 ⁇ 0.2°, 15.2° ⁇ 0.2°, 16.2 ⁇ 0.2°, 17.0 ⁇ 0.2°, 17.4 ⁇ 0.2°, 17.8 ⁇ 0.2°, 18.7 ⁇ 0.2°, 19.0 ⁇ 0.2°, 20.4 ⁇ 0.2°, 21.9 ⁇ 0.2°, 23.5 ⁇ 0.2°, 24.0 ⁇ 0.2°, 24.9 ⁇ 0.2°, 25.9 ⁇ 0.2°, 27.6 ⁇ 0.2°, 29.5 ⁇ 0.2°, 31.0 ⁇ 0.2°, 31.4 ⁇ 0.2°; or one in the DSC spectrum when analyzed by differential scanning calorimetry (DSC) The endothermic peak is at 138 ⁇ 5 °C.
- DSC differential scanning calori
- a 1-(3-methanesulfonamidobenzyl)-6-methoxy, 7-benzyloxy-1,2,3 provided by the invention as described above a method for producing a salt derivative of 4-tetrahydroisoquinoline, which comprises: 1-(3-methanesulfonamidobenzyl)-6-methoxy, 7-benzyloxy-1,2,3 , 4-tetrahydroisoquinoline is reacted with the corresponding acid HA to form a salt derivative.
- the preparation method comprises: 1-(3-methanesulfonamidobenzyl)-6-methoxy, 7-benzyloxy-1,2 provided by the present invention as described above.
- the 3,4-tetrahydroisoquinoline is reacted with the corresponding acid in an organic solvent to form a salt derivative.
- the preparation method comprises: 1-(3-methanesulfonamidobenzyl)-6- when HA is nicotinic acid, oxalic acid, glycolic acid, benzenesulfonic acid, or orotic acid.
- HA nicotinic acid
- oxalic acid glycolic acid
- benzenesulfonic acid or orotic acid.
- the methoxy group, 7-benzyloxy-1,2,3,4-tetrahydroisoquinoline is dissolved in an organic solvent, and then the corresponding acid is added, and after cooling, it is crystallized to give a product.
- the preparation method comprises: 1-(3-methanesulfonamidobenzyl)-6-methoxy, 7-benzyloxy-1, when HA is sulfuric acid or phosphoric acid, The 2,3,4-tetrahydroisoquinoline is dissolved in an organic solvent, and then an organic solvent containing the corresponding acid is added, and after cooling, it is crystallized to obtain a product.
- the preparation method further comprises washing and drying the precipitated crystals or precipitate.
- reaction temperature of the reaction is from 0 to 80 °C.
- the organic solvent is methanol, ethanol, isopropanol, acetone, 2-butanone, methyl acetate, isopropyl acetate, methyl tertiary ether acetonitrile, or toluene.
- the reaction temperature is from 10 to 60 ° C; more preferably 40 ° C.
- a pharmaceutical composition comprising an effective amount of 1-(3-methanesulfonamidobenzyl)-6-methoxy, 7-benzyl provided by the invention as described above A salt derivative of oxy-1,2,3,4-tetrahydroisoquinoline and one or more pharmaceutically acceptable excipients.
- a 1-(3-methanesulfonamidobenzyl)-6-methoxy, 7-benzyloxy-1,2,3 provided by the invention as described above.
- a salt derivative of 4-tetrahydroisoquinoline for use in the preparation of an antiarrhythmic drug.
- the present invention provides a salt derivative of a corresponding compound which is soluble in water, thereby improving its bioavailability and improving its medicinal properties.
- Figure 1 shows the XRPD pattern of SIPI-409 phosphate crystal under the experimental conditions of Cu target radiation source; the horizontal axis is the diffraction peak position (2 ⁇ value) and the vertical axis is the diffraction peak intensity.
- Figure 2 is a DSC pattern of SIPI-409 phosphate crystal; the downward direction peak is indicated as an endothermic peak.
- Figure 3 is an XRPD pattern of SIPI-409 sulfate crystal under experimental conditions using a Cu target radiation source; the horizontal axis is the diffraction peak position (2 ⁇ value) and the vertical axis is the diffraction peak intensity.
- Figure 4 is a DSC pattern of SIPI-409 sulfate crystal; wherein the downward direction peak is represented as an endothermic peak.
- Figure 5 is an XRPD pattern of SIPI-409 nicotinate crystal under experimental conditions using a Cu target radiation source; the horizontal axis is the diffraction peak position (2 ⁇ value) and the vertical axis is the diffraction peak intensity.
- Figure 6 is a DSC pattern of SIPI-409 nicotinate crystals; wherein the downward direction peak is represented as an endothermic peak.
- Figure 7 is an XRPD pattern of SIPI-409 oxalate crystal under experimental conditions using a Cu target radiation source; the horizontal axis is the diffraction peak position (2 ⁇ value) and the vertical axis is the diffraction peak intensity.
- Figure 8 is a DSC pattern of SIPI-409 oxalate crystal; wherein the downward direction peak is represented as an endothermic peak.
- Figure 9 is an XRPD pattern of SIPI-409 glycolate crystal under experimental conditions using a Cu target radiation source; the horizontal axis is the diffraction peak position (2 ⁇ value) and the vertical axis is the diffraction peak intensity.
- Figure 10 is a DSC chart of SIPI-409 glycolate crystals; wherein the downward direction peak is represented as an endothermic peak.
- Figure 11 is an XRPD pattern of SIPI-409 besylate crystal under experimental conditions using a Cu target radiation source; the horizontal axis is the diffraction peak position (2 ⁇ value) and the vertical axis is the diffraction peak intensity.
- Figure 12 is a DSC chart of SIPI-409 besylate crystals; wherein the downward direction peak is represented as an endothermic peak.
- Figure 13 is an XRPD pattern of SIPI-409 orotate crystals under experimental conditions using a Cu target radiation source; the horizontal axis is the diffraction peak position (2 ⁇ value) and the vertical axis is the diffraction peak intensity.
- Figure 14 is a DSC spectrum of SIPI-409 orotate crystal; wherein the downward direction peak is expressed as Endothermic peak.
- Figure 15 is a comparison of the XRPD pattern of SIPI-409 reacted with 14 acids and the XRPD pattern of SIPI-409 material;
- A is an XRPD pattern of the SIPI-409 starting material and an XRPD pattern of the reaction product with hydrochloric acid;
- B is the XRPD pattern of the SIPI-409 starting material and its XRPD pattern with the reaction product of succinic acid;
- C is the XRPD pattern of the SIPI-409 starting material and its XRPD pattern of the reaction product with glycolic acid;
- D is the XRPD pattern of the SIPI-409 starting material and its XRPD pattern with the oxalic acid reaction product;
- E is the XRPD pattern of the SIPI-409 starting material and its XRPD pattern of the reaction product with orotate;
- F is the XRPD pattern of the SIPI-409 starting material and its XRPD pattern of the reaction product with fumaric acid;
- G is the XRPD pattern of the SIPI-409 starting material and its XRPD pattern of the reaction product with tartaric acid;
- H is the XRPD pattern of the SIPI-409 starting material and its XRPD pattern with the reaction product of ethanedisulfonic acid;
- I is the XRPD pattern of the SIPI-409 starting material and its XRPD pattern with the malic acid reaction product;
- J is the XRPD pattern of the SIPI-409 starting material and its XRPD pattern of the reaction product with hydrobromic acid;
- K is the XRPD pattern of the SIPI-409 starting material and its XRPD pattern with the phosphoric acid reaction product
- L is the XRPD pattern of the SIPI-409 starting material and its XRPD pattern of the reaction product with niacin;
- M is the XRPD pattern of the SIPI-409 starting material and its XRPD pattern with the sulfuric acid reaction product;
- N is the XRPD pattern of the SIPI-409 starting material and its XRPD pattern of the reaction product with benzenesulfonic acid.
- Figure 16 is a perspective view showing the stereostructure of a single crystal molecule of SIPI-409 sulfate crystal.
- Figure 17 is a solubility standard curve obtained using the SIPI-409 standard; R value 0.999932.
- Figure 18 is an XRPD pattern obtained by examining the crystal stability of various salt derivatives of SIPI-409;
- A is an XRPD pattern obtained by examining the stability of the crystal form of SIPI-409 phosphate
- B is an XRPD pattern obtained by examining the stability of the crystal form of SIPI-409 nicotinate
- C is an XRPD pattern obtained by examining the stability of the crystal form of SIPI-409 glycolate
- D is an XRPD pattern obtained by examining the stability of the crystal form of SIPI-409 oxalate
- E is the XRPD pattern obtained by examining the stability of the crystal form of SIPI-409 orotate
- F is an XRPD pattern obtained by examining the stability of the crystal form of SIPI-409 besylate
- G is an XRPD pattern obtained by examining the stability of the crystal form of SIPI-409 sulfate.
- the inventors have extensively and intensively studied to find 1-(3-methanesulfonamidobenzyl)-6-methoxy, 7-benzyloxy-1,2,3,4 as shown in formula I.
- the solubility of the tetrahydroisoquinoline salt derivative in water is significantly improved compared to the existing SIPI-409 and SIPI-409 hydrochloride, and further pharmacokinetic experiments indicate the salt derivatization of SIPI-409 of the present invention.
- the bioavailability of the material is significantly improved compared to the existing SIPI-409 hydrochloric acid. Taking phosphate as an example, its bioavailability can be increased by 329% compared with the existing SIPI-409 hydrochloride.
- the present invention provides a salt derivative of the compound SIPI-409 as shown in the formula (I).
- the salt formed with SIPI-40 may be a common organic or inorganic acid; it may be selected from the acids described in Table 1.
- XRPD was used to test the results of the salt-type preliminary screening experiment.
- SIPI-409 was combined with hydrochloric acid, succinic acid, fumaric acid, L-tartaric acid, ethanedisulfonic acid, glycolic acid, orotic acid, DL-malic acid.
- the XRPD pattern after the reaction of hydrobromic acid, oxalic acid, phosphoric acid, nicotinic acid, sulfuric acid, benzenesulfonic acid and the like was compared with the XRPD pattern of the SIPI-409 raw material, and the results are shown in Fig. 15.
- phosphoric acid, sulfuric acid, nicotinic acid, oxalic acid, glycolic acid, benzenesulfonic acid, or orotic acid is salted with SIPI-409; more preferred is sulfuric acid, phosphoric acid, nicotinic acid, or oxalic acid.
- the SIPI-409 phosphate crystal provided by the invention, wherein the ratio of SIPI-409 to phosphoric acid is 1:1, 2:1 or 3:1, when the ratio of SIPI-409 to phosphoric acid is 1:1, the crystal powder X- is obtained.
- Ray diffraction analysis when using Cu target radiation source experimental conditions, its 2 ⁇ characteristic diffraction peaks are: 4.6 ⁇ 0.2 °, 7.6 ⁇ 0.2 °, 9.8 ⁇ 0.2 °, 10.2 ⁇ 0.2 °, 13.9 ⁇ 0.2 °, 14.4 ⁇ 0.2 °, 15.3 ⁇ 0.2°, 18.1 ⁇ 0.2°, 16.8 ⁇ 0.2°, 20.5 ⁇ 0.2°, 20.9 ⁇ 0.2°, 21.9 ⁇ 0.2°, 23.1 ⁇ 0.2°, 23.5 ⁇ 0.2°, 24.3 ⁇ 0.2°, 27.1 ⁇ 0.2°; More preferably, its XRPD pattern is shown in Figure 1.
- the SIPI-409 sulfate crystal provided by the invention wherein the ratio of SIPI-409 to sulfuric acid is 1:1, 2:1, wherein when the ratio of SIPI-409 to sulfuric acid is 1:1, the powder is obtained by powder X-ray diffraction analysis.
- the 2 ⁇ characteristic diffraction peaks are: 4.9 ⁇ 0.2°, 7.1 ⁇ 0.2°, 8.4 ⁇ 0.2°, 9.7 ⁇ 0.2°, 12.0 ⁇ 0.2°, 15.4 ⁇ 0.2°, 17.0 ⁇ 0.2.
- the above SIPI-409 sulfate crystal when analyzed by differential scanning calorimetry (DSC), exhibits an endothermic peak at 130 ⁇ 5 ° C in the DSC spectrum at a heating rate of 10 ° C / min; more preferably, Its DSC spectrum is shown in Figure 4.
- the single crystal of the above SIPI-409 sulfate crystal (C 25 H 28 N 2 O 4 S ⁇ H 2 SO 4 ) is a colorless transparent block, has a crystal density of 1.361 g/cm 3 , and a space group of P-1, a unit cell.
- the SIPI-409 nicotinate crystal provided by the invention uses powder X-ray diffraction analysis, and the 2 ⁇ characteristic diffraction peaks of the Cu target radiation source are: 5.0 ⁇ 0.2°, 5.9 ⁇ 0.2°, 7.2 ⁇ 0.2°.
- the SIPI-409 nicotinate crystal provided by the present invention is analyzed by differential scanning calorimetry (DSC), and exhibits an endothermic peak at 152 ⁇ 5 ° C in the DSC spectrum with a heating rate of 10 ° C/min; More preferably, its DSC pattern is shown in Figure 6.
- DSC differential scanning calorimetry
- the invention provides SIPI-409 oxalate crystal, wherein the ratio of SIPI-409 to oxalic acid is 1:1 or 2:1, wherein when the ratio of SIPI-409 to oxalic acid is 1:1, the powder is obtained by powder X-ray diffraction.
- the above SIPI-409 oxalate crystals were analyzed by differential scanning calorimetry (DSC), and there was an endothermic peak in the DSC spectrum with a heating rate of 10 ° C/min at 161 ⁇ 5 ° C, and at 190 There is a broad endothermic peak in the range of -210 ° C; more preferably, its DSC spectrum is shown in FIG.
- the SIPI-409 glycolate crystal provided by the invention uses powder X-ray diffraction analysis, and adopts the Cu target radiation source experimental condition, and the 2 ⁇ characteristic diffraction peaks are: 4.7 ⁇ 0.2°, 7.5 ⁇ 0.2°, 9.9 ⁇ 0.2°.
- the SIPI-409 glycolate crystal provided by the present invention is analyzed by differential scanning calorimetry (DSC), and an endothermic peak exists in the DSC spectrum with a heating rate of 10 ° C/min at 187 ⁇ 5 ° C; More preferably, its DSC pattern is shown in FIG.
- the SIPI-409 besylate crystal provided by the invention adopts powder X-ray diffraction analysis, and when the experimental conditions of the Cu target radiation source are used, the 2 ⁇ characteristic diffraction peaks are: 6.1 ⁇ 0.2°, 6.8 ⁇ 0.2°, 8.2 ⁇ 0.2.
- the SIPI-409 besylate crystal provided by the present invention is analyzed by differential scanning calorimetry (DSC), and the DSC spectrum having a heating rate of 10 ° C/min has an endothermic peak at 150 ⁇ 5 ° C. And there is a shoulder near 160 ° C; more preferably, its DSC spectrum is shown in FIG.
- the SIPI-409 orotate crystal provided by the invention adopts powder X-ray diffraction analysis, and the experimental results of the Cu target radiation source have the 2 ⁇ characteristic diffraction peaks of 5.8 ⁇ 0.2°, 8.7 ⁇ 0.2°, and 9.9 ⁇ 0.2.
- the SIPI-409 orotate crystal provided by the present invention uses differential scanning calorimetry (DSC) At the time of analysis, there was an endothermic peak in the DSC spectrum showing a heating rate of 10 ° C/min at 138 ⁇ 5 ° C; more preferably, its DSC spectrum is shown in FIG.
- the SIPI-409 salt derivative crystals to which the present invention relates include single crystals, as well as polymorphs thereof.
- the invention also provides a salt derivative of SIPI-409 and a preparation method thereof, wherein SIPI-409 is dissolved in an organic solvent, an organic or inorganic acid is added, and after stirring, the crystal is cooled and crystallized to obtain a salt of SIPI-409. Derivative crystals.
- the solvent described above includes an alcohol solvent, a ketone solvent, an ether solvent, an ester solvent, an aromatic hydrocarbon solvent, and a nitrile solvent.
- the alcohol solvent includes methanol, ethanol, and isopropanol; preferably methanol; the ketone solvent includes acetone and 2-butanone; and the ether solvent includes methyl tertiary ether, tetrahydrofuran, and 2 methyltetrahydrofuran;
- the ester solvent includes ethyl acetate, methyl acetate, and isopropyl acetate; the aromatic hydrocarbon solvent includes toluene and xylene; and the nitrile solvent is acetonitrile.
- the reaction temperature for salt formation is from 0 to 80 ° C; preferably from 10 to 60 ° C; most preferably 40 ° C.
- the ratio of SIPI-409 to acid and the manner of addition can be adapted to the desired salt derivative without departing from the principles of the invention.
- the SIPI-409 salt derivative or the crystal thereof provided by the invention has certain stability, and can be used as an active ingredient to develop an oral dosage form anti-arrhythmia drug for clinical use.
- Common oral administration forms include ordinary tablets, capsules, dispersible tablets, pellets, etc. Excipients, lubricants, binders and the like described in the above dosage forms are all common excipients in the field.
- the main advantage of the present invention is that the novel SIPI-409 salt derivative and crystal thereof provided by the invention can significantly improve the water solubility thereof, thereby improving the bioavailability and the drug-forming property.
- the XRPD pattern in the experiment involved in the present invention was obtained under the experimental conditions using a Cu target radiation source.
- the DSC pattern was expressed as a map at a temperature elevation rate of 10 ° C/min.
- the stability of the SIPI-40 salt derivative according to the present invention means the temperature, humidity, light stability and hygroscopicity of the salt derivative crystals over a certain period of time.
- SIPI-409 0.5g (0.11mmol), put it into a 50mL flask, add 20mL methanol solvent, control the temperature of the water bath to 40 ° C, add 1M phosphate methanol solution 1.3mL (0.13mmol), continue to maintain 40 ° C and stir for 2 hours.
- SIPI-409 0.5g (0.11mmol), place it in a 50mL flask, add 20mL methanol solvent, control the temperature of the water bath at 40 °C, add 1.3M (0.13mmol) of 1M sulfuric acid methanol solution, continue After stirring at 40 ° C for 2 hours, it was cooled to 5 to 15 ° C for crystallization, and filtered to obtain 0.54 g of SIPI-409 sulfate white solid powder in a yield of 90%.
- SIPI-409: sulfuric acid 1:1 in the crystal, single The crystal data is as shown in the drawing. Its XRPD spectrum is shown in Figure 3, and the DSC spectrum is shown in Figure 4.
- SIPI-409 0.5g (0.11mmol), put it in a 50mL flask, add 20mL methanol solvent, control the temperature of the water bath to 40 ° C, add 0.205g (0.13mmol) of benzenesulfonic acid, continue to stir at 40 ° C for 2 hours, then cool to Crystallization was carried out at 5 to 15 ° C, and filtration was carried out to obtain 0.57 g of SIPI-409 besylate white solid powder, yield 84%. Its XRPD pattern is shown in Figure 11, and the DSC spectrum is shown in Figure 12.
- SIPI-409 0.5g (0.11mmol), place it in a 50mL flask, add 20mL methanol solvent, control the temperature of the water bath at 40 ° C, add 0.226g (0.13mmol) of orotate monohydrate, continue to stir at 40 ° C for 2 hours. The mixture was cooled to 5 to 15 ° C for crystallization, and filtered to obtain 0.52 g of a SIPI-409 orotate white solid powder, yield 77%.
- the XRPD pattern is shown in Figure 13, and the DSC spectrum is shown in Figure 14.
- Sample treatment The sample to be tested is made into a supersaturated aqueous solution (suspension), shaken at 30 ° C for 12 h, placed in the ultrasound system for 30 s, filtered, diluted by appropriate multiples, and analyzed by HPLC. The test results are shown in Table 3.
- the results show that the SIPI-409 phosphate, SIPI-409 sulfate, SIPI-409 nicotinate, SIPI-409 oxalate, SIPI-409 glycolate, SIPI-409 besylate, SIPI-409 of the present invention are shown.
- the solubility of orotate in water is significantly improved over existing SIPI-409 and SIPI-409 hydrochlorides.
- solubility test results in water show that the solubility of SIPI-409 phosphate in water is greatly improved compared with SIPI-409 and SIPI-409 hydrochloride, so further study on the pharmacokinetics of SIPI-409 phosphate, and SIPI-409 hydrochloride was compared.
- SIPI-409 hydrochloride and SIPI-409 phosphate were administered orally (PO), and their pharmacokinetic parameters and bioavailability in SD rats were studied.
- concentrations of SIPI-409 hydrochloride and SIPI-409 phosphate in plasma were determined by liquid chromatography-mass spectrometry-mass spectrometry.
- the obtained plasma concentration data were calculated using the pharmacokinetic processing software WinNonlin 5.2 non-compartment model to calculate the relevant pharmacokinetic parameters.
- SIPI-409 phosphate, nicotinate, glycolate, oxalate, orotate, benzenesulfonate, sulphate were placed in an oven at 60 ° C for 0 days, 5 days, 10 days, 20 days , 30 days sampling for XRPD testing.
- SIPI-409 phosphate, nicotinate, glycolate, oxalate, orotate, benzenesulfonate, sulfate were placed in 92.5% RH (saturated KNO 3 ) for 0 days, 5 days, respectively. Samples were taken for XRPD testing for 10 days, 20 days, and 30 days.
- SIPI-409 phosphate, nicotinate, glycolate, oxalate, orotate, benzenesulfonate, sulfate are placed in the light box, respectively, on 0 days, 5 days, 10 days, 20 days, 30 days sampling for XRPD test.
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Abstract
Description
分析项目 | 测定值/% | 理论值/% |
C | 66.17 | 66.35 |
H | 6.15 | 6.24 |
N | 6.22 | 6.19 |
S | 7.02 | 7.09 |
Claims (25)
- 根据权利要求1所述的1-(3-甲磺酰胺基苄基)-6-甲氧基,7-苄氧基-1,2,3,4-四氢异喹啉的盐衍生物,其中,HA选自硫酸、磷酸、烟酸、草酸、乙醇酸、苯磺酸、或乳清酸;X选自1/3、1/2、或1。
- 根据权利要求1或2所述的1-(3-甲磺酰胺基苄基)-6-甲氧基,7-苄氧基-1,2,3,4-四氢异喹啉的盐衍生物为晶体。
- 根据权利要求2所述的1-(3-甲磺酰胺基苄基)-6-甲氧基,7-苄氧基-1,2,3,4-四氢异喹啉的盐衍生物,HA为硫酸;X选自1/2或1。
- 根据权利要求2所述的1-(3-甲磺酰胺基苄基)-6-甲氧基,7-苄氧基-1,2,3,4-四氢异喹啉的盐衍生物,HA为草酸;X选自1/2或1。
- 根据权利要求4所述的1-(3-甲磺酰胺基苄基)-6-甲氧基,7-苄氧基-1,2,3,4-四氢异喹啉的盐衍生物,当X为1时,所述晶体的晶型通过X-粉末衍射技术(XRPD)测定并以布拉格2θ角(Bragg 2-Theta)表征如下:4.9±0.2°、7.1±0.2°、8.4±0.2°、9.7±0.2°、12.0±0.2°、15.4±0.2°、17.0±0.2°、19.5°±0.2°、 20.3±0.2°、20.9±0.2°、21.6±0.2°、22.8±0.2°、23.6±0.2°、24.6±0.2°、25.4±0.2°、26.0±0.2°、30.8±0.2°;或使用差示扫描量热技术(DSC)分析时,DSC图谱中存在一个吸热峰在130±5℃处。
- 根据权利要求3所述的1-(3-甲磺酰胺基苄基)-6-甲氧基,7-苄氧基-1,2,3,4-四氢异喹啉的盐衍生物,当X为1、HA为磷酸时,所述晶体的晶型通过X-粉末衍射技术(XRPD)测定并以布拉格2θ角(Bragg 2-Theta)表征如下:4.6±0.2°、7.6±0.2°、9.8±0.2°、10.2±0.2°、13.9±0.2°、14.4±0.2°、15.3±0.2°、18.1±0.2°、16.8±0.2°、20.5±0.2°、20.9±0.2°、21.9±0.2°、23.1±0.2°、23.5±0.2°、24.3±0.2°、27.1±0.2°。
- 根据权利要求7所述的1-(3-甲磺酰胺基苄基)-6-甲氧基,7-苄氧基-1,2,3,4-四氢异喹啉的盐衍生物,所述晶体的X-粉末衍射图谱如图1所示。
- 根据权利要求3所述的1-(3-甲磺酰胺基苄基)-6-甲氧基,7-苄氧基-1,2,3,4-四氢异喹啉的盐衍生物,当X为1、HA为磷酸时,所述晶体使用差示扫描量热技术(DSC)分析时,DSC图谱中存在一个吸热峰在201±5℃处。
- 根据权利要求9所述的1-(3-甲磺酰胺基苄基)-6-甲氧基,7-苄氧基-1,2,3,4-四氢异喹啉的盐衍生物,所述晶体的DSC图谱如图2所示。
- 根据权利要求3所述的1-(3-甲磺酰胺基苄基)-6-甲氧基,7-苄氧基-1,2,3,4-四氢异喹啉的盐衍生物,当HA为烟酸时的晶体的晶型通过X-粉末衍射技术(XRPD)测定并以布拉格2θ角(Bragg 2-Theta)表征如下:5.0±0.2°、5.9±0.2°、7.2±0.2°、8.2±0.2°、10.9±0.2°、12.2±0.2°、13.4±0.2°、14.4°±0.2°、15.1±0.2°、15.5±0.2°、17.0±0.2°、17.4±0.2°、17.8±0.2°、18.7±0.2°、19.9±0.2°、20.5±0.2°、20.8±0.2°、21.9±0.2°、23.1±0.2°、23.5±0.2°、24.8±0.2°、25.1±0.2°、25.6±0.2°、27.0±0.2°、27.6±0.2°;或使用差示扫描量热技术(DSC)分析时,DSC图谱中存在一个吸热峰在152±5℃。
- 根据权利要求5所述的1-(3-甲磺酰胺基苄基)-6-甲氧基,7-苄氧基 -1,2,3,4-四氢异喹啉的盐衍生物,当X为1时,所述晶体的晶型通过X-粉末衍射技术(XRPD)测定并以布拉格2θ角(Bragg 2-Theta)表征如下:3.4±0.2°、4.6±0.2°、5.5±0.2°、7.8±0.2°、9.2±0.2°、10.2±0.2°、10.8±0.2°、11.9°±0.2°、13.1±0.2°、13.8±0.2°、14.6±0.2°、16.4±0.2°、17.0±0.2°、18.4±0.2°、19.0±0.2°、20.2±0.2°、21.9±0.2°、23.6±0.2°、25.8±0.2°、27.3±0.2°、30.0±0.2°、31.9±0.2°;或使用差示扫描量热技术(DSC)分析时,DSC图谱中存在一个吸热峰在在161±5℃处,且在190~210℃范围存在一个较宽的吸热峰。
- 根据权利要求3所述的1-(3-甲磺酰胺基苄基)-6-甲氧基,7-苄氧基-1,2,3,4-四氢异喹啉的盐衍生物,当HA为乙醇酸时的晶体的晶型通过X-粉末衍射技术(XRPD)测定并以布拉格2θ角(Bragg 2-Theta)表征如下:4.7±0.2°、7.5±0.2°、9.9±0.2°、10.3±0.2°、13.7±0.2°、14.3±0.2°、14.9±0.2°、15.3°±0.2°、16.1±0.2°、16.9±0.2°、17.6±0.2°、18.1±0.2°、18.9±0.2°、19.3±0.2°、20.4±0.2°、20.8±0.2°、21.8±0.2°、22.5±0.2°、22.9±0.2°、24.3±0.2°、24.9±0.2°、25.3±0.2°、25.9±0.2°、27.7±0.2°;或使用差示扫描量热技术(DSC)分析时,DSC图谱中存在一个吸热峰在187±5℃处。
- 根据权利要求3所述的1-(3-甲磺酰胺基苄基)-6-甲氧基,7-苄氧基-1,2,3,4-四氢异喹啉的盐衍生物,当HA为苯磺酸时的晶体的晶型通过X-粉末衍射技术(XRPD)测定并以布拉格2θ角(Bragg 2-Theta)表征如下:6.1±0.2°、6.8±0.2°、8.2±0.2°、8.8±0.2°、11.5±0.2°、12.7±0.2°、14.4±0.2°、15.0°±0.2°、15.5±0.2°、16.5±0.2°、17.0±0.2°、17.4±0.2°、17.7±0.2°、18.7±0.2°、19.4±0.2°、19.8±0.2°、20.3±0.2°、21.3±0.2°、21.7±0.2°、22.6±0.2°、23.0±0.2°、23.5±0.2°、24.2±0.2°、29.1±0.2°;或使用差示扫描量热技术(DSC)分析时,DSC图谱中存在一个吸热峰在150±5℃处,且在160℃附近存在一个肩峰。
- 根据权利要求3所述的1-(3-甲磺酰胺基苄基)-6-甲氧基,7-苄氧基-1,2,3,4-四氢异喹啉的盐衍生物,当HA为乳清酸时的晶体的晶型通过X-粉末衍射技术(XRPD)测定并以布拉格2θ角(Bragg 2-Theta)表征如下:5.8±0.2°、8.7±0.2°、9.9±0.2°、11.2±0.2°、12.5±0.2°、13.9±0.2°、14.1±0.2°、15.2°±0.2°、16.2±0.2°、17.0±0.2°、17.4±0.2°、17.8±0.2°、18.7±0.2°、19.0±0.2°、20.4±0.2°、 21.9±0.2°、23.5±0.2°、24.0±0.2°、24.9±0.2°、25.9±0.2°、27.6±0.2°、29.5±0.2°、31.0±0.2°、31.4±0.2°;或使用差示扫描量热技术(DSC)分析时,DSC图谱中存在一个吸热峰在138±5℃处。
- 根据权利要求1-15任一项所述的1-(3-甲磺酰胺基苄基)-6-甲氧基,7-苄氧基-1,2,3,4-四氢异喹啉的盐衍生物的制备方法,其包括:将1-(3-甲磺酰胺基苄基)-6-甲氧基,7-苄氧基-1,2,3,4-四氢异喹啉与相应的酸HA反应形成盐衍生物。
- 根据权利要求16所述的1-(3-甲磺酰胺基苄基)-6-甲氧基,7-苄氧基-1,2,3,4-四氢异喹啉的盐衍生物的制备方法,其包括:将1-(3-甲磺酰胺基苄基)-6-甲氧基,7-苄氧基-1,2,3,4-四氢异喹啉与相应的酸在有机溶剂中反应形成盐衍生物。
- 根据权利要求17所述的1-(3-甲磺酰胺基苄基)-6-甲氧基,7-苄氧基-1,2,3,4-四氢异喹啉的盐衍生物的制备方法,其包括:HA为烟酸、草酸、乙醇酸、苯磺酸、或乳清酸时,将1-(3-甲磺酰胺基苄基)-6-甲氧基,7-苄氧基-1,2,3,4-四氢异喹啉溶解于有机溶剂,然后加入相应的酸,冷却后析晶得产物。
- 根据权利要求17所述的1-(3-甲磺酰胺基苄基)-6-甲氧基,7-苄氧基-1,2,3,4-四氢异喹啉的盐衍生物的制备方法,其包括:当HA为硫酸或磷酸时,将1-(3-甲磺酰胺基苄基)-6-甲氧基,7-苄氧基-1,2,3,4-四氢异喹啉溶解于有机溶剂,然后加入含有相应酸的有机溶剂,冷却后析晶得产物。
- 根据权利要求18或19所述的1-(3-甲磺酰胺基苄基)-6-甲氧基,7-苄氧基-1,2,3,4-四氢异喹啉的盐衍生物的制备方法,其还包括:将析出的结晶或沉淀洗涤、干燥。
- 根据权利要求16-20任一项所述的1-(3-甲磺酰胺基苄基)-6-甲氧基,7-苄氧基-1,2,3,4-四氢异喹啉的盐衍生物的制备方法,其特征在于,所述反应的反应温度为0-80℃。
- 根据权利要求17-20任一项所述的1-(3-甲磺酰胺基苄基)-6-甲氧基,7-苄氧基-1,2,3,4-四氢异喹啉的盐衍生物的制备方法,其特征在于,所述有机溶剂为甲醇、乙醇、异丙醇、丙酮、2-丁酮、乙酸甲酯、乙酸异丙脂、甲叔醚乙腈、或甲苯。
- 根据权利要求21所述的1-(3-甲磺酰胺基苄基)-6-甲氧基,7-苄氧基-1,2,3,4-四氢异喹啉的盐衍生物的制备方法,其特征在于,HA为磷酸时,所述反应温度为10-60℃;优选为40℃。
- 一种药物组合物,由有效量的权利要求1-15任一项所述的1-(3-甲磺酰胺基苄基)-6-甲氧基,7-苄氧基-1,2,3,4-四氢异喹啉的盐衍生物和一种或多种药学上可接受的辅料组成。
- 一种权利要求1-15任一项所述的1-(3-甲磺酰胺基苄基)-6-甲氧基,7-苄氧基-1,2,3,4-四氢异喹啉的盐衍生物,在制备抗心律失常的药物中的应用。
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EP3508478A4 (en) | 2020-04-22 |
KR102346338B1 (ko) | 2022-01-03 |
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