WO2024077650A1 - 磺酰脲环取代的化合物的盐型及其晶型 - Google Patents
磺酰脲环取代的化合物的盐型及其晶型 Download PDFInfo
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- 230000004071 biological effect Effects 0.000 description 1
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- 230000037396 body weight Effects 0.000 description 1
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- YZBQHRLRFGPBSL-RXMQYKEDSA-N carbapenem Chemical compound C1C=CN2C(=O)C[C@H]21 YZBQHRLRFGPBSL-RXMQYKEDSA-N 0.000 description 1
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- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 229940124587 cephalosporin Drugs 0.000 description 1
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- 239000011521 glass Substances 0.000 description 1
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- 125000001072 heteroaryl group Chemical group 0.000 description 1
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- 230000001404 mediated effect Effects 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 230000036457 multidrug resistance Effects 0.000 description 1
- AFDQGRURHDVABZ-UHFFFAOYSA-N n,n-dimethylformamide;sulfur trioxide Chemical compound O=S(=O)=O.CN(C)C=O AFDQGRURHDVABZ-UHFFFAOYSA-N 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 150000002960 penicillins Chemical class 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 229940085991 phosphate ion Drugs 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- USHAGKDGDHPEEY-UHFFFAOYSA-L potassium persulfate Chemical compound [K+].[K+].[O-]S(=O)(=O)OOS([O-])(=O)=O USHAGKDGDHPEEY-UHFFFAOYSA-L 0.000 description 1
- XTUSEBKMEQERQV-UHFFFAOYSA-N propan-2-ol;hydrate Chemical compound O.CC(C)O XTUSEBKMEQERQV-UHFFFAOYSA-N 0.000 description 1
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- 239000002994 raw material Substances 0.000 description 1
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- 229910052708 sodium Inorganic materials 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 229910001415 sodium ion Inorganic materials 0.000 description 1
- 238000007711 solidification Methods 0.000 description 1
- 230000008023 solidification Effects 0.000 description 1
- 238000000547 structure data Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
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- 125000001424 substituent group Chemical group 0.000 description 1
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- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/433—Thidiazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- 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
- C07B2200/07—Optical isomers
-
- 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 class of salt forms and crystal forms of sulfonylurea ring-substituted compounds, and specifically discloses a compound represented by formula (I), its crystal form, its preparation method, its pharmaceutically acceptable salt and its application in the preparation and treatment of related diseases.
- ⁇ -lactam antibiotics are important antibiotics.
- antibiotic hydrolases such as extended-spectrum serine ⁇ -lactamases (ESBLs) and serine carbapenemases (such as KPCs)
- ESBLs extended-spectrum serine ⁇ -lactamases
- KPCs serine carbapenemases
- traditional antibiotics such as penicillins, cephalosporins, and carbapenems are no longer able to cope with infections caused by these resistant bacteria.
- monocyclic ⁇ -lactam antibiotics represented by aztreonam are naturally stable to metallo- ⁇ -lactamases (MBLs) and are a highly advantageous chemical series.
- the marketed drug aztreonam has disadvantages such as poor permeability, strong efflux effect, narrow antibacterial spectrum, and instability against extended-spectrum serine ⁇ -lactamases (ESBLs).
- ESBLs extended-spectrum serine ⁇ -lactamases
- a strategy of enhancing permeability through iron carriers has been introduced, such as Basilea (WO 2007065288) and Naeja Pharmaceuticals (WO 2002022613).
- Novartis (WO 2015148379) reported a study on overcoming drug resistance by modifying the substituents on the aztreonam molecule.
- the general formula of the compound is shown below, where the group Het is a heteroaromatic ring or a heterocycle substituted with 1-2 heteroatoms.
- Patent PCT/CN2020/130568 describes a sulfonylurea ring-substituted monocyclic ⁇ -lactam compound, which is mainly used to treat diseases related to bacterial infection. Its structure is shown in formula (B-I):
- the present invention provides a crystal form A of a compound of formula (I), whose X-ray powder diffraction spectrum has characteristic diffraction peaks at the following 2 ⁇ angles: 15.05 ⁇ 0.20°, 19.11 ⁇ 0.20°, and 21.15 ⁇ 0.20°.
- the X-ray powder diffraction pattern of the above-mentioned crystal form A has characteristic diffraction peaks at the following 2 ⁇ angles: 15.05 ⁇ 0.20°, 19.11 ⁇ 0.20°, 20.41 ⁇ 0.20°, 21.15 ⁇ 0.20°, 22.62 ⁇ 0.20°, 23.48 ⁇ 0.20°, 27.32 ⁇ 0.20°, and 29.25 ⁇ 0.20°.
- the X-ray powder diffraction pattern of the above-mentioned crystal form A has characteristic diffraction peaks at the following 2 ⁇ angles: 9.10 ⁇ 0.20°, 11.29 ⁇ 0.20°, 12.76 ⁇ 0.20°, 15.05 ⁇ 0.20°, 16.39 ⁇ 0.20°, 19.11 ⁇ 0.20°, 20.41 ⁇ 0.20°, 21.15 ⁇ 0.20°, 22.62 ⁇ 0.20°, and 23.68 ⁇ 0.20°.
- the X-ray powder diffraction pattern of the above-mentioned crystal form A has characteristic diffraction peaks at the following 2 ⁇ angles: 6.90 ⁇ 0.20°, 9.10 ⁇ 0.20°, 11.29 ⁇ 0.20°, 11.83 ⁇ 0.20°, 12.76 ⁇ 0.20°, 13.73 ⁇ 0.20°, 14.57 ⁇ 0.20°, 15.05 ⁇ 0.20°, 16.10 ⁇ 0.20°, 16.39 ⁇ 0.20°, 17.81 ⁇ 0.20°, 18.25 ⁇ 0.20°, 19.11 ⁇ 0.20°, 20.41 ⁇ 0.20°, and 21.15 ⁇ 0.20°.
- the X-ray powder diffraction pattern of the above-mentioned crystal form A has characteristic diffraction peaks at the following 2 ⁇ angles: 6.90 ⁇ 0.20°, 9.10 ⁇ 0.20°, 11.29 ⁇ 0.20°, 11.83 ⁇ 0.20°, 12.76 ⁇ 0.20°, 13.73 ⁇ 0.20°, 15.05 ⁇ 0.20°, 16.39 ⁇ 0.20°, 17.81 ⁇ 0.20°, 19.11 ⁇ 0.20°, 20.41 ⁇ 0.20°, 21.15 ⁇ 0.20°, 21.64 ⁇ 0.20°, 22.62 ⁇ 0.20°, and 23.48 ⁇ 0.20°.
- the X-ray powder diffraction pattern of the above-mentioned crystal form A has characteristic diffraction peaks at the following 2 ⁇ angles: 6.90 ⁇ 0.20°, 9.10 ⁇ 0.20°, 11.29 ⁇ 0.20°, 11.83 ⁇ 0.20°, 12.76 ⁇ 0.20°, 13.73 ⁇ 0.20°, 15.05 ⁇ 0.20°, 16.39 ⁇ 0.20°, 17.8 1 ⁇ 0.20°, 19.11 ⁇ 0.20°, 20.41 ⁇ 0.20°, 21.15 ⁇ 0.20°, 21.64 ⁇ 0.20°, 22.62 ⁇ 0.20°, 23.48 ⁇ 0.20°, 25.73 ⁇ 0.20°, 26.43 ⁇ 0.20°, 27.32 ⁇ 0.20°, 28.42 ⁇ 0.20°, 29.25 ⁇ 0.20°.
- the X-ray powder diffraction pattern of the above-mentioned crystal form A has characteristic diffraction peaks at the following 2 ⁇ angles: 15.05 ⁇ 0.20°, 19.11 ⁇ 0.20°, 21.15 ⁇ 0.20°, and/or 6.90 ⁇ 0.20°, and/or 9.10 ⁇ 0.20°, and/or 11.29 ⁇ 0.20°, and/or 11.83 ⁇ 0.20°, and/or 12.76 ⁇ 0.20°, and/or 13.73 ⁇ 0.20°, and/or 14.57 ⁇ 0.20°, and/or 16.1 0 ⁇ 0.20°, and/or 16.39 ⁇ 0.20°, and/or 17.81 ⁇ 0.20°, and/or 18.25 ⁇ 0.20°, and/or 20.41 ⁇ 0.20°, and/or 20.79 ⁇ 0.20°, and/or 21.64 ⁇ 0.20°, and/or 22.62 ⁇ 0.20°, and/or 23.48 ⁇ 0.20°, and/or 23.68 ⁇ 0.20°, and/or 24.00 ⁇ 0.20°
- the X-ray powder diffraction pattern of the above-mentioned crystal form A has characteristic diffraction peaks at the following 2 ⁇ angles: 6.904°, 9.095°, 11.285°, 11.833°, 12.757°, 13.732°, 14.573°, 15.050°, 16.100°, 16.389°, 17.807°, 18.251°, 19.113°, 20.413°, 20.790°, 21.147°, 21.641°, 22.615°, 23.484°, 23.676°, 24.002°, 24.8 12°, 25.728°, 26.433°, 26.655°, 27.323°, 27.636°, 28.420°, 29.248°, 29.922°, 30.358°, 30.733°, 31.507°, 31.830°, 32.049°, 32.509°, 32.843°, 33.130°, 33.837°, 34.346°, 34.895°, 35.500
- the XRPD pattern of the above-mentioned Form A is substantially as shown in Figure 1.
- the X-ray powder diffraction pattern analysis data of the above-mentioned A crystal form is shown in Table 1.
- thermogravimetric analysis curve of the above-mentioned crystal type A shows a weight loss of 6.657% at 140.000°C ⁇ 3.000°C and a weight loss of 12.576% at 205.000°C ⁇ 3.000°C.
- thermogravimetric analysis curve of the above-mentioned crystal form A is basically as shown in Figure 2.
- the above-mentioned crystal form A has a differential scanning calorimetry curve with an endothermic peak at 100.28°C ⁇ 3.00°C, an endothermic peak at 127.61°C ⁇ 3.00°C, an exothermic peak at 200.70°C ⁇ 3.00°C, and an endothermic peak at 266.36°C ⁇ 3.00°C.
- the differential scanning calorimetry curve of the above-mentioned Form A is substantially as shown in FIG3 .
- the present invention also provides the use of the compound of formula (I) or its crystal form A in the preparation of a compound for treating diseases related to bacterial infection.
- the crystal form A of the compound of formula (I) of the present invention is easy to obtain, has good physical stability and chemical stability, and has high industrial application value and economic value.
- the present invention discloses a new class of sulfonylurea ring-substituted monocyclic ⁇ -lactam compounds, which are stable to serine ⁇ -lactamase and metallo ⁇ -lactamase. It has a wide antibacterial spectrum against Gram-negative bacteria, especially has outstanding antibacterial activity against various carbapenem-resistant Enterobacteriaceae super bacteria expressing ⁇ -lactamase.
- the compound disclosed by the present invention has good water solubility, is suitable for intravenous administration, has excellent pharmacokinetic properties, good safety, and good efficacy, and will be used to treat diseases related to bacterial infections.
- aq represents water
- BOC represents tert-butyloxycarbonyl, which is an amine protecting group
- TEMPO represents 2,2,6,6-tetramethylpiperidine nitrogen oxide
- TCCA represents trichloroisocyanuric acid
- HCl represents hydrochloric acid
- Pd/C represents palladium on carbon
- TFA represents trifluoroacetic acid
- DCM represents dichloromethane
- MeCN represents acetonitrile
- (n-Bu) 4 NHSO 4 represents tetrabutylammonium hydrogen sulfate
- IPA represents isopropanol
- eq represents equivalent
- CBz represents benzyloxycarbonyl, which is an amine protecting group.
- FIG1 is an XRPD spectrum of the crystalline form A of the compound of formula (I);
- FIG2 is a TGA spectrum of the crystalline form A of the compound of formula (I);
- Figure 3 is a DSC spectrum of the crystal form A of the compound of formula (I) (specific information of peak A: total heat release (endothermic) amount -189.19mJ standard heat release (endothermic) amount -82.26Jg ⁇ -1 initial melting temperature 74.62°C peak 100.28°C final melting temperature 120.89°C left limit temperature 47.75°C right limit temperature 113.15°C; specific information of peak B: total heat release (endothermic) amount -113.80mJ standard heat release (endothermic) amount -49.48Jg ⁇ -1 initial melting temperature 105.72°C peak 127.61°C final melting temperature 136.22°C left limit temperature 113.15°C right limit temperature 136.62°C; C peak specific information: total heat release (absorption) 1374.45mJ standard heat release (absorption) 597.59Jg ⁇ -1 initial melting temperature 170.56°C peak 200.70°C final melting temperature 215.91°C left limit temperature 136.62°C right
- the present invention is described in detail below by examples, but it is not intended to limit the present invention in any adverse way.
- the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by the combination thereof with other chemical synthesis methods, and equivalent substitutions well known to those skilled in the art, and preferred embodiments include but are not limited to the embodiments of the present invention. It will be apparent to those skilled in the art that various changes and improvements are made to the specific embodiments of the present invention without departing from the spirit and scope of the present invention.
- Dissolve compound A-1 (1.00 kg, 6.85 mol, 1 eq) in methanol (4 L), slowly drop Boc anhydride (1.63 kg, 7.46 mol, 1.71 L, 1.09 eq) at 20 ° C.
- Dissolve potassium carbonate (1.09 kg, 7.88 mol, 1.15 eq) in water (2 L), slowly drop it into the reaction system, and stir at 20-30 ° C for 1 hour.
- Add ethyl acetate (8 L) to the reaction solution and extract twice, combine the organic phases and concentrate under reduced pressure.
- Add ethyl acetate (15 L) to the residue, wash once with water (10 L), dry over anhydrous sodium sulfate, filter, and concentrate in vacuo to obtain compound A-2.
- 1.8-diazabicyclo[5.4.0]undecane-7-ene (536.8g, 3.53mol, 531.5mL, 1.2eq) was added to a toluene (3.5L) solution of compound C-1 (300.0g, 2.94mol, 1eq) and bromodiphenylmethane (835.2g, 3.38mol, 1.15eq), and then the temperature was raised to 75-80°C for reaction for 5 hours.
- the reaction solution was concentrated under reduced pressure to obtain a residue, and then ethyl acetate (400 mL) was added and heated to 65-70°C and stirred for 0.5 hours, and then n-heptane (1.6 L) was added, and then the mixture was cooled to room temperature and stirred in an ice bath for 0.5 hours, filtered, and the filter cake was rinsed with ethyl acetate/n-heptane (400 mL, 1/3), and dried under reduced pressure with an oil pump to obtain a residue.
- the residue was added to acetonitrile (580 mL) and acetone (1.45 L), stirred at 55-60° C. for 3 hours, concentrated under reduced pressure at 40° C.
- Dissolve compound 1-4 (2.47 kg, 11.82 mol, 1.3 eq) in dichloromethane (12.8 L), cool to -40 ° C, add triethylamine (3.59 kg, 35.46 mol, 4.94 L, 3.9 eq) and isobutyl chloroformate (4.84 kg, 35.46 mol, 4.66 L, 3.9 eq), stir at -30 to -20 ° C for 30 minutes, slowly add the dichloromethane solution of the above compound 1-3 at -20 to -30 ° C, then raise the temperature to -20 to 10 ° C, and continue stirring for 6 hours.
- Triethylamine (25.09 g, 247.96 mmol, 34.51 mL, 2 eq) was added to anhydrous tetrahydrofuran (1.08 L) of compound 1-9 (97.43 g, 123.98 mmol, 1 eq), and methanesulfonyl chloride (17.31 g, 151.11 mmol, 11.70 mL, 1.22 eq) was added dropwise at 0-10°C, and stirred for 3 hours.
- the reaction solution was poured into 1.5 L of ice water and stirred for 10 minutes, then filtered, the filter cake was washed with water (300 mL ⁇ 2), and the filtrate was extracted with ethyl acetate (500 mL ⁇ 2).
- the filter cake was dissolved in the organic phase, washed with dilute hydrochloric acid (0.5N, 100 mL ⁇ 2), saturated sodium bicarbonate (100 mL ⁇ 2) and brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a residue.
- the lower phosphoric acid phase in the mixture was dropped into tetrahydrofuran (300 mL) and stirred at 0-5°C for 1 hour, filtered under nitrogen protection, and the filter cake was rinsed with tetrahydrofuran (100 mL ⁇ 2) to obtain a crude product of the compound of formula (I), which was an amorphous powder as detected by XRPD.
- the crude product was dissolved in water (4 mL), filtered, and the filtrate was dropped into tetrahydrofuran (80 mL).
- the crude product of the compound of formula (I) (0.50 g, 685.33 ⁇ mol) was dissolved in water (0.5 mL), insoluble impurities were filtered out, and the mixture was added dropwise into tetrahydrofuran (10 mL) at 25-30° C., and stirred at 25-30° C. for 4 hours. After 4 hours, the mixture was evenly dispersed, filtered under nitrogen protection, and dried to obtain a crystalline form A of the compound of formula (I).
- the compound of formula (I) (100 mg, 137.07 ⁇ mol) was dissolved in water (0.1 mL), tetrahydrofuran (2 mL) was added dropwise to the solution until solid precipitated, and the mixture was stirred for about 2 hours until solidification began and the mixture gradually dispersed. After 4 hours, the mixture was evenly dispersed. The mixture was filtered under nitrogen protection and dried to obtain the crystalline form A of the compound of formula (I).
- the compound of formula (I) (500 mg, 685.33 ⁇ mol) was dissolved in water (1.0 mL), 85% phosphoric acid (67.16 mg, 685.33 mmol) was added, tetrahydrofuran (20.0 mL) was added dropwise to the solution, and the mixture was stirred at 15-25° C. for 12 hours. The mixture was filtered under nitrogen protection and dried to obtain a crystalline form A of the compound of formula (I).
- the compound of formula (I) (500 mg, 685.33 ⁇ mol) was dissolved in water (1.0 mL), 85% phosphoric acid (67.16 mg, 685.33 mmol) was added, isopropanol (6.0 mL) was added dropwise to the solution, and the mixture was stirred at 15-25° C. for 12 hours. The mixture was filtered under nitrogen protection and dried to obtain a crystalline form A of the compound of formula (I).
- the simulated XRPD of the needle-shaped crystals is shown in FIG4 , and the structural data and parameters are shown in Tables 2 to 7.
- the lower aqueous phase/TFA was added dropwise to a cooled solution of MeCN (8 mL) at 0-5°C. The mixture was then stirred at 0-5°C for 0.5 hours. The product was filtered under vacuum nitrogen protection to obtain a crude product (110 mg, 168.67 ⁇ mol, 54.59% yield, 89.33% purity) as an off-white solid. The solid was dissolved in 5 mL of water, then adjusted to pH 7-8 with saturated sodium bicarbonate at 0°C, and then treated with (n-Bu) 4 NHSO 4 to pH 4-5.
- the starting material was completely consumed, but no product was generated.
- the starting material was completely consumed, but no product was generated.
- the starting material was completely consumed, but no product was generated.
- Example 5 Stability test of the crystalline form A of compound of formula (I) in different solvents
- the crystalline form A of compound of formula (I) can be stably present in a variety of solvents, has good reproducibility, and is easy to obtain.
- the A crystal form of the compound of formula (I) is spread into a thin layer, and is completely exposed to high temperature, normal temperature and high humidity, light, and high temperature and high humidity conditions. Samples are taken at specified time points to detect XRPD, appearance, content and related substances, and compared with the results of the 0-day sample.
- Crystal form A of the compound of formula (I) is stable under high temperature, high humidity and light conditions, and the related substances and contents do not change significantly under 60°C, 25°C/75% RH and light conditions.
- the minimum inhibitory concentration (MIC) of each compound was determined by the microdilution method in accordance with the requirements of the Clinical and Laboratory Standards Institute (CLSI) using three strains of Klebsiella pneumoniae ATCC BAA-205 (TEM-1/SHV-1/SHV-12), ATCC BAA-1705 (KPC-2), ATCC BAA-2470 (NDM-1), Enterobacter cloacae ATCC BAA-1143 (AmpC), and two strains of Escherichia coli ATCC BAA-2523 (OXA- 48 ), and ATCC 25922.
- CLSI Clinical and Laboratory Standards Institute
- CFU Colony-Forming Units
- the pharmacokinetic characteristics of the compound after intravenous administration in rodents were tested using a standard protocol. Specifically, the candidate compound was intravenously administered to 7- to 10-week-old SD male rats. The compound was dissolved in saline to form a clear solution. Plasma samples were collected, analyzed by LC-MS/MS, and pharmacokinetic parameters were calculated. The pharmacokinetic parameters of the crystalline form of compound A of formula (I) are shown in Table 12.
- the A crystal form of the compound (I) provided by the present invention has stable properties, good solubility and good hygroscopicity, and has good drug development prospects.
- the A crystal form of compound (I) provided by the present invention is easy to prepare, and the reagents used are common, easily available on the market and inexpensive; a variety of preparation methods can obtain a single stable crystal form; the operation is simple, the conditions are mild; the purity is good, and the yield is high.
- the strain Klebsiella pneumoniae ATCC-BAA 2470 was revived on the MHA plate.
- the revived colonies were picked and dissolved in sterile saline to prepare a bacterial solution with a concentration of 5.95E+07 CFU/mL for infection of the thigh muscles of mice.
- the infection start time was calculated to be 0h, and 100 ⁇ L of bacterial solution was injected into each thigh muscle at 0h, that is, the inoculation volume was 5.95E+06 CFU/mouse. 2h after infection, the drug was administered according to the experimental plan.
- the specific experimental plan is as follows (see Table 14):
- Cages 1 to 24 were given subcutaneous injection of the crystalline form of compound A of formula (I) at a volume of 10 mL/kg of mouse body weight.
- the total dose for cages 1 to 4 was 1600 mg/kg
- the total dose for cages 5 to 8 was 480 mg/kg
- the total dose for cages 9 to 12 was 160 mg/kg
- the total dose for cages 13 to 16 was 48 mg/kg
- the total dose for cages 17 to 20 was 16 mg/kg
- the total dose for cages 21 to 24 was 4.8 mg/kg.
- Each dose group was administered in four different dose fractions, namely q3h, q6h, q12h and q24h.
- mice (3) 26 hours after infection: The test endpoint was 26 hours after infection. Thigh muscle tissues were taken from the 1st to 26th cages of mice and placed in 10 mL of sterile saline. The homogenate was homogenized by a homogenizer and the homogenate was graded and plated. Each mouse was replicated twice. The bacterial load in the thigh muscle tissues of mice was counted. The experimental results are shown in Table 15.
- the crystal form A of the compound of formula (I) of the present invention has a significant bactericidal effect in vivo, and the dose-effect relationship is significant. Under the same daily dose, shortening the dosing interval can significantly improve the in vivo efficacy.
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明提供一种磺酰脲环取代的化合物的盐型及其晶型,及其特定的A晶型,还提供其在制备治疗与细菌感染相关疾病的药物中的应用;化合物的A晶型易于获得、物理稳定性和化学稳定性均较好,具有很高的工业应用价值和经济价值;本发明公开的化合物水溶性好,适合静脉给药,药代动力学性质优异;安全性好;具有良好的药效,将用于治疗细菌感染相关的疾病。
Description
本发明涉及一类磺酰脲环取代的化合物的盐型及其晶型,具体公开了式(I)所示化合物、其晶型、其制备方法、其药学上可接受的盐以及其在制备治疗相关疾病中的应用。
β-内酰胺类抗生素是重要抗生素,然而随着耐药基因及抗生素水解酶如超广谱丝氨酸β-内酰胺酶(ESBLs),丝氨酸碳青霉烯酶(如KPCs)的不断涌现,现有抗生素药效已不能满足要求。尤其对于金属β-内酰胺酶(MBLs)介导的严重甚至多药耐药性,使得传统抗生素如青霉素类、头孢菌素类、碳青霉烯类等已无法应对这些耐药菌引起的感染。作为对策,以氨曲南为代表的单环β-内酰胺环类抗生素对金属β-内酰胺酶(MBLs)天然稳定,是极具优势的化学系列。
上市药物氨曲南存在渗透性差,外排作用强,抑菌谱窄,对超广谱丝氨酸β-内酰胺酶(ESBLs)不稳定等劣势,为克服这些临床问题,通过铁载体增强通透性的策略被引入,如Basilea(WO 2007065288),Naeja Pharmaceuticals(WO 2002022613)报道了相应系列分子;最近Novartis(WO 2015148379)报道了通过修饰氨曲南分子上的取代基来克服耐药性的研究,化合物通式如下所示,其中基团Het为杂芳环或1-2个杂原子取代的杂环。
基于严峻的耐药形势,开发出新一代的单环β-内酰胺抗生素,解决目前的耐药问题是当务之急,本发明中的磺酰脲环取代的单环β-内酰胺类分子具备相应潜质。
PCT/CN2020/130568的专利记载了一种磺酰脲环取代的单环β-内酰胺类化合物,其主要用于治疗与细菌感染相关疾病中的应用症。其结构如式(B-I)所示:
发明内容
本发明提供式(I)化合物的A晶型,其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:15.05±0.20°、19.11±0.20°、21.15±0.20°。
在本发明的一些方案中,上述A晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:15.05±0.20°、19.11±0.20°、20.41±0.20°、21.15±0.20°、22.62±0.20°、23.48±0.20°、27.32±0.20°、29.25±0.20°。
在本发明的一些方案中,上述A晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:9.10±0.20°、11.29±0.20°、12.76±0.20°、15.05±0.20°、16.39±0.20°、19.11±0.20°、20.41±0.20°、21.15±0.20°、22.62±0.20°、23.68±0.20°。
在本发明的一些方案中,上述A晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:6.90±0.20°、9.10±0.20°、11.29±0.20°、11.83±0.20°、12.76±0.20°、13.73±0.20°、14.57±0.20°、15.05±0.20°、16.10±0.20°、16.39±0.20°、17.81±0.20°、18.25±0.20°、19.11±0.20°、20.41±0.20°、21.15±0.20°。
在本发明的一些方案中,上述A晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:6.90±0.20°、9.10±0.20°、11.29±0.20°、11.83±0.20°、12.76±0.20°、13.73±0.20°、15.05±0.20°、16.39±0.20°、17.81±0.20°、19.11±0.20°、20.41±0.20°、21.15±0.20°、21.64±0.20°、22.62±0.20°、23.48±0.20°。
在本发明的一些方案中,上述A晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:6.90±0.20°、9.10±0.20°、11.29±0.20°、11.83±0.20°、12.76±0.20°、13.73±0.20°、15.05±0.20°、16.39±0.20°、17.81±0.20°、19.11±0.20°、20.41±0.20°、21.15±0.20°、21.64±0.20°、22.62±0.20°、23.48±0.20°、25.73±0.20°、26.43±0.20°、27.32±0.20°、28.42±0.20°、29.25±0.20°。
在本发明的一些方案中,上述A晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:15.05±0.20°、19.11±0.20°、21.15±0.20°、和/或6.90±0.20°、和/或9.10±0.20°、和/或11.29±0.20°、和/或11.83±0.20°、和/或12.76±0.20°、和/或13.73±0.20°、和/或14.57±0.20°、和/或16.10±0.20°、和/或16.39±0.20°、和/或17.81±0.20°、和/或18.25±0.20°、和/或20.41±0.20°、和/或20.79±0.20°、和/或21.64±0.20°、和/或22.62±0.20°、和/或23.48±0.20°、和/或23.68±0.20°、和/或24.00±0.20°、和/或24.81±0.20°、和/或25.73±0.20°、 和/或26.43±0.20°、和/或26.66±0.20°、和/或27.32±0.20°、和/或27.64±0.20°、和/或28.42±0.20°、和/或29.25±0.20°、和/或29.92±0.20°、和/或30.36±0.20°、和/或30.73±0.20°、和/或31.51±0.20°、和/或31.83±0.20°、和/或32.05±0.20°、和/或32.51±0.20°、和/或32.84±0.20°、和/或33.13±0.20°、和/或33.84±0.20°、和/或34.35±0.20°、和/或34.90±0.20°、和/或35.50±0.20°、和/或36.04±0.20°、和/或36.47±0.20°、和/或37.10±0.20°、和/或37.57±0.20°、和/或37.88±0.20°、和/或38.80±0.20°。
在本发明的一些方案中,上述A晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:6.904°、9.095°、11.285°、11.833°、12.757°、13.732°、14.573°、15.050°、16.100°、16.389°、17.807°、18.251°、19.113°、20.413°、20.790°、21.147°、21.641°、22.615°、23.484°、23.676°、24.002°、24.812°、25.728°、26.433°、26.655°、27.323°、27.636°、28.420°、29.248°、29.922°、30.358°、30.733°、31.507°、31.830°、32.049°、32.509°、32.843°、33.130°、33.837°、34.346°、34.895°、35.500°、36.037°、36.467°、37.098°、37.573°、37.875°、38.797°。
在本发明的一些方案中,上述A晶型的XRPD图谱基本上如图1所示。
在本发明的一些方案中,上述A晶型的X射线粉末衍射图谱解析数据见表1。
表1式(I)化合物A晶型的X射线粉末衍射图谱解析数据
在本发明的一些方案中,上述A晶型,其热重分析曲线在140.000℃±3.000℃时失重达6.657%,在205.000℃±3.000℃时失重达12.576%。
在本发明的一些方案中,上述A晶型,其热重分析曲线基本上如图2所示。
在本发明的一些方案中,上述A晶型,其差示扫描量热曲线在100.28℃±3.00℃处具有吸热峰、在127.61℃±3.00℃处具有吸热峰、在200.70℃±3.00℃处具有放热峰、在266.36℃±3.00℃处具有吸热峰。
在本发明的一些方案中,上述A晶型,其差示扫描量热曲线基本上如图3所示。
本发明还提供式(I)化合物或其A晶型在制备治疗与细菌感染相关疾病中的应用。
技术效果
本发明式(I)化合物的A晶型易于获得、物理稳定性和化学稳定性均较好,具有很高的工业应用价值和经济价值。本发明公开了一类新的磺酰脲环取代的单环β-内酰胺类化合物,对丝氨酸β-内酰胺酶和金属β- 内酰胺酶稳定。对革兰氏阴性菌具有广泛的抑菌谱,尤其对各种表达β-内酰胺酶的耐碳青霉烯类肠科杆菌超级细菌具有突出的抑菌活性。本发明公开的化合物水溶性好,适合静脉给药,药代动力学性质优异;安全性好;具有良好的药效,将用于治疗细菌感染相关的疾病。
定义和说明
本发明采用下述缩略词:aq代表水;BOC代表叔丁氧羰基是一种胺保护基团;TEMPO代表2,2,6,6-四甲基哌啶氮氧化物;TCCA代表三氯异氰尿酸;HCl代表盐酸;Pd/C代表钯碳;TFA代表三氟乙酸;DCM代表二氯甲烷;MeCN代表乙腈;(n-Bu)
4NHSO
4代表四丁基硫酸氢铵;IPA代表异丙醇;eq代表当量、等量;CBz代表苄氧羰基,是一种胺保护基团。
图1为式(I)化合物A晶型的XRPD谱图;
图2为式(I)化合物A晶型的TGA谱图;
图3为式(I)化合物A晶型的DSC谱图(A峰具体信息:总放热(吸热)量-189.19mJ标准放热(吸热)量-82.26Jg^-1初熔温度74.62℃峰值100.28℃终熔温度120.89℃左极限温度47.75℃右极限温度113.15℃;B峰具体信息:总放热(吸热)量-113.80mJ标准放热(吸热)量-49.48Jg^-1初熔温度105.72℃峰值127.61℃终熔温度136.22℃左极限温度113.15℃右极限温度136.62℃;C峰具体信息:总放热(吸热)量1374.45mJ标准放热(吸热)量597.59Jg^-1初熔温度170.56℃峰值200.70℃终熔温度215.91℃左极限温度136.62℃右极限温度228.98℃;D峰具体信息:总放热(吸热)量-888.43mJ标准放热(吸热)量-386.27Jg^-1初熔温度229.07℃峰值266.36℃终熔温度299.00℃左极限温度228.98℃右极限温度350.12℃);
图4为式(I)化合物单晶的模拟XRPD谱图(波长1.54056;14.585,10366;h,k,l=4,0,-1)。
下面通过实施例对本发明进行详细描述,但并不意味着对本发明任何不利限制。本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备,包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式,优选的实施方式包括但不限于本发明的实施例。对本领域的技术人员而言,在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。
实施例1:式(I)化合物
中间体A的制备:
步骤一:化合物A-2的制备
将化合物A-1(1.00kg,6.85mol,1eq)溶在甲醇(4L)中,在20℃下缓慢滴入Boc酸酐(1.63kg,7.46mol,1.71L,1.09eq)。将碳酸钾(1.09kg,7.88mol,1.15eq)溶在水(2L)中,缓慢滴加至反应体系,在20~30℃下搅拌1小时。向反应液中加入乙酸乙酯(8L)萃取两次,合并有机相减压浓缩。向剩余物中加入乙酸乙酯(15L),加水(10L)洗涤一次,无水硫酸钠干燥,过滤,真空浓缩得到化合物A-2。
1H NMR(400MHz,CDCl
3)δ=5.01(br s,1H),3.93(br s,1H),3.65-3.50(m,2H),3.44(br d,J=14.0Hz,1H),3.33-3.19(m,1H),1.46(d,J=1.9Hz,9H)。
步骤二:化合物A-3的制备
将化合物A-2(1.15kg,5.48mol,1eq)溶在乙醇(1.5L)中,降温至0~5℃。将氢氧化钠(338.50g,6.03mol,1.1eq)溶在乙醇(4L)中缓慢滴加至反应体系中,加毕缓慢升温至25℃并在25℃搅拌1小时。向反应液中加入1N HCl调节pH=7,减压浓缩。往剩余物中加入乙酸乙酯(5L×2)萃取,盐水(1L)洗涤一次,合并有机相经无水硫酸钠干燥,过滤,减压浓缩。将剩余物溶在石油醚:乙酸乙酯=3:1(5L)的混合溶剂中,在15℃下加入100-200目硅胶(1.50kg),搅拌0.5小时,过滤,滤饼用石油醚/乙酸乙酯=1/3的混合溶剂(5L)洗涤三次,合并滤液真空浓缩得到化合物A-3。
1H NMR(400MHz,CDCl
3)δ=4.76(br s,1H),3.62-3.50(m,1H),3.28-3.19(m,1H),3.11(br s,1H),2.80(t,J=4.3Hz,1H),2.61(dd,J=2.6,4.7Hz,1H),1.46(s,9H)。
步骤三:中间体A的制备
将化合物A-3溶在乙醇(5L)中,在0~5℃下加入氨水(4.55kg,32.46mol,5L,25%纯度,5.62eq),加毕升温至20℃搅拌16小时。反应液减压蒸馏,向剩余物中加入固体氯化钠,在25℃下搅拌0.5小时。加入乙酸乙酯(2L)萃取一次,水相用乙酸乙酯(500mL)萃取,合并有机相经无水硫酸钠干燥,过滤, 减压浓缩。剩余物在20℃下经石油醚/叔丁基甲基醚=1/1打浆1小时,过滤,滤饼真空干燥得到中间体A。
1H NMR(400MHz,CDCl
3)δ=5.46-5.08(m,1H),3.79-3.54(m,1H),3.32-3.19(m,1H),3.13-2.99(m,1H),2.79(dd,J=4.0,12.7Hz,1H),1.43(s,9H)。
中间体B的制备:
将化合物B-1(84.00g,593.50mmol,1eq)溶于二氯甲烷(590mL)中,在0~10℃,氮气氛围下缓慢滴加到苯甲醇(66.11g,661.30mmol,1.03eq)的二氯甲烷(590mL)溶液中,反应液在冰浴下反应0.5小时。将反应液真空浓缩得到粗品,粗品使用石油醚(600mL)25℃下打浆15分钟,过滤得到中间体B。
1H NMR(400MHz,CDCl
3)δ=7.51-7.36(m,5H),5.33(s,2H)。
中间体C的制备:
步骤一:化合物C-2的制备
在20~30℃下,向化合物C-1(300.0g,2.94mol,1eq)和溴代二苯甲烷(835.2g,3.38mol,1.15eq)的甲苯(3.5L)溶液中加入1.8-二氮杂二环[5.4.0]十一烷-7-烯(536.8g,3.53mol,531.5mL,1.2eq),然后升温至75~80℃反应5小时。反应液冷却至室温,加入水(1L)搅拌0.5小时,分离有机相,在用水(1L×2)洗涤,减压下浓缩至约500mL,加入正庚烷(2L),加热至75~80℃得到澄清溶液,降至室温并在冰水中搅拌1小时,过滤,滤饼用甲苯/正庚烷(600mL,1/5)和正庚烷(300mL)洗涤,固体用油泵干燥 得化合物C-2。
1H NMR(400MHz,CDCl
3)δ=7.40-7.29(m,11H),6.95(s,1H),1.46-1.39(m,2H),1.27-1.19(m,2H)。
步骤二:化合物C-3的制备
将化合物C-2(150.0g,559.1mmol,1eq)和二苯基膦酰羟胺(156.5g,670.9mmol,1.2eq)的四氢呋喃(1.5L)溶液中,在0~10℃下分批加入叔丁醇钠,控制温度范围在0~10℃,然后在0~10℃氮气保护下反应2小时。向反应液中加入5%氯化钠溶液(1L)并搅拌0.5小时,分离有机相,水相用乙酸乙酯(500mL×2)萃取,合并有机相,用5%氯化钠溶液(1L×2)洗涤,用无水硫酸钠干燥,过滤得到化合物C-3的2.5L四氢呋喃/乙酸乙酯溶液,直接用于下一步反应。
步骤三:中间体C的制备
向上述化合物C-3(158.4g,559.1mmol,1eq)的2.5L四氢呋喃/乙酸乙酯溶液中加入化合物C-4(106.6g,391.3mmol,0.7eq),20~30℃下反应18小时。反应液减压浓缩,得到残余物,然后加入乙酸乙酯(400mL)加热至65~70℃搅拌0.5小时,然后加入正庚烷(1.6L),然后降至室温,并在冰浴下搅拌0.5小时,过滤,滤饼用乙酸乙酯/正庚烷(400mL,1/3)淋洗,用油泵减压干燥,得到残余物。将残余物加入到乙腈(580mL)和丙酮(1.45L)中在55~60℃搅拌3小时,40℃下减压浓缩出去丙酮,重复加入乙腈(400mL)两次减压浓缩,然后加入乙腈(360mL),加热至60℃,然后滴加水(580mL),降至室温后继续搅拌1小时,过滤,滤饼依次用乙腈/水(300mL,1/1)和冰乙腈(100mL)淋洗,固体用油泵减压干燥,得到残余物。
1H NMR(400MHz,DMSO-d
6)δ=11.83(br s,1H),7.49(s,1H),7.45(dd,J=1.8,7.6Hz,4H),7.30-7.21(m,6H),6.88(s,1H),1.51(br d,J=3.0Hz,2H),1.48(s,9H),1.45-1.40(m,2H)。
式(I)化合物的制备:
步骤一:化合物1-2的制备
将1-1(1.5kg,11.35mol,1eq)溶解在DCM(15L)中,氮气保护下在10~20℃一次性加入TEMPO(4.46g,28.38mmol,0.0025eq)和乙酸钠(1.40kg,17.03mol,1.5eq),然后在0~10℃下历经1小时分批加入TCCA(1.06kg,4.54mol,0.4eq),将反应液升温到10~20℃,继续搅拌1小时,将反应液过滤,滤液为化合物1-2的二氯甲烷溶液,直接用于下一步反应。
步骤二:化合物1-3的制备
向上述化合物1-2的二氯甲烷溶液中加入1当量的碳酸钠水溶液,然后加入2,4-二甲氧基苄胺(1.52kg,9.10mol,1.37L,1eq),该混合物在10~15℃下搅拌0.5小时。停止反应,分液,有机相用饱和食盐水(5.0L)洗涤,无水硫酸钠干燥,过滤,滤液为化合物1-3的二氯甲烷溶液,直接用于下一步反应。
步骤三:化合物1-5的制备
将化合物1-4(2.47kg,11.82mol,1.3eq)溶解在二氯甲烷(12.8L)中,降温到-40℃,加入三乙胺(3.59kg,35.46mol,4.94L,3.9eq)和氯甲酸异丁酯(4.84kg,35.46mol,4.66L,3.9eq),在-30~-20℃下搅拌30分钟,将上述化合物1-3的二氯甲烷溶液在-20~-30℃下缓慢加入,然后升温至-20~10℃,继续搅拌6小时。停止反应,依次用3M HCl(6L),饱和碳酸氢钠水溶液(6L)和食盐水(6L)洗涤,用无水硫酸钠干燥, 过滤,滤液经减压浓缩得到粗品,该粗品在悬浮在甲醇中,于-30~-20℃悬浮搅拌2小时,过滤得到化合物1-5(880.0g,三步总收率18.5%)。
步骤四:化合物1-6的制备
在20~30℃下将化合物1-5(131.0g,278.42mmol,1eq)加入至四氢呋喃(1.2L)和水(300mL)中,加入一水合对甲苯磺酸(37.07g,194.89mmol,0.7eq),在65℃下搅拌4小时。冷却至20℃,使用饱和碳酸氢钠溶液调节pH至7,40℃下减压浓缩除去四氢呋喃,向剩余混合物中加入水(1.2L),在20~30℃下搅拌1小时,过滤,滤饼使用水(600mL)淋洗得到化合物1-6。
步骤五:化合物1-7的制备
20~30℃下将化合物1-6(119.85g,278.43mmol,1eq)加入至乙酸乙酯(1.2L)和水(400mL)中,加入高碘酸钠(65.51g,306.27mmol,1.1eq),将混合物在50℃下搅拌2小时。降温至20~25℃,分离有机相和水相,水相使用乙酸乙酯(300mL×2)萃取,合并有机相,使用5%氯化钠溶液(300mL)洗涤,减压浓缩,粗品产物使用乙酸乙酯(350mL)在20~30℃下搅拌5小时,过滤得到化合物1-7。
1H NMR(400MHz,CDCl
3)δ=9.35(d,J=3.3Hz,1H),8.22(d,J=8.4Hz,1H),7.42-.27(m,6H),7.19(d,J=8.3Hz,1H),6.57(d,J=2.1Hz,1H),6.51(dd,J=2.3,8.3Hz,1H),5.01(s,2H),4.97-4.90(m,1H),4.47-4.24(m,2H),4.08(dd,J=3.3,5.8Hz,1H),3.76(s,3H),3.73(s,3H)。
步骤六:化合物1-8的制备
0℃将化合物1-7(78.00g,195.80mmol,1eq)和4A分子筛(150.00g)加入至无水二氯甲烷(780mL),滴加中间体A(55.87g,293.67mmol,1.5eq)的二氯甲烷(200mL)溶液,在氮气保护下搅拌1小时,过滤,将滤液滴加至醋酸硼氢化钠(82.99g,391.56mmol,2eq)的醋酸(200mL)溶液中,氮气保护下在15~25℃搅拌16小时。35℃下减压浓缩,然后用水(1L)稀释,使用乙酸乙酯(800mL×2)萃取,使用无水硫酸钠干燥,过滤,向滤液中加入石油醚(1.5L),在15~25℃下搅拌1小时,析出白色固体,过滤得到化合物1-8。
1H NMR(400MHz,DMSO)δ=9.57-8.96(m,1H),8.88-8.41(m,1H),8.17(br d,J=9.3Hz,1H),7.44-7.28(m,5H),7.19(d,J=8.3Hz,1H),6.90(br s,1H),6.58(d,J=2.3Hz,1H),6.50(dd,J=2.3,8.3Hz,1H),5.61(br s,1H),5.15-5.01(m,2H),4.99(dd,J=5.1,9.4Hz,1H),4.45-4.20(m,2H),3.98(br s,1H),3.80(s,3H),3.76(s,3H),3.15(br s,1H),3.06(br s,1H),2.99-2.90(m,2H),2.84(br d,J=10.9Hz,1H),2.64(br t,J=10.2Hz,1H),1.38(s,9H)。
步骤七:化合物1-9的制备
将化合物1-8(70.00g,122.24mmol,1eq)和三乙胺(49.48g,488.96mmol,68.06mL,4eq)加入至无水四氢呋喃(700mL),在0℃条件下滴加中间体B(46.69g,187.03mmol,1.53eq)的无水四氢呋喃(300mL)溶液,混合物在0~5℃下搅拌1小时。向混合物中滴加中间体B(6.10g,24.45mmol,0.2eq)的无水四氢呋喃溶液(50mL),在15~25℃下搅拌1小时,得到化合物1-9的四氢呋喃溶液,将 直接用于下一步反应。
步骤八:化合物1-11的制备
向化合物1-9(97.43g,123.98mmol,1eq)的无水四氢呋喃(1.08L)中加入三乙胺(25.09g,247.96mmol,34.51mL,2eq),在0~10℃条件下滴加甲烷磺酰氯(17.31g,151.11mmol,11.70mL,1.22eq),搅拌3小时,向混合物中滴加甲烷磺酰氯(16.16g,141.07mmol,10.92mL,1.14eq),0~10℃下搅拌1小时,加入三乙胺(25.09g,247.96mmol,34.51mL,2eq),在80℃条件下搅拌1小时,降温至15~20℃,将混合物倒入冰水(1.5L)中,乙酸乙酯(1L×2)萃取,合并的有机相使用盐水(1L)洗涤,无水硫酸钠干燥,减压浓缩后加入乙酸乙酯(500mL),15~25℃下搅拌16小时,过滤得到化合物1-11。LCMS(ESI)m/z:768.4(M+1)。
步骤九:化合物1-12的制备
将化合物1-11(20.00g,26.05mmol,1eq)溶于乙腈(200mL)和水(100mL)中,在油浴100℃下升温至内温65~70℃,一次性加入过硫酸钾(31.68g,117.21mmol,4.5eq)和磷酸二氢钾(18.15g,104.19mmol,4eq),回流反应1.5小时。然后降至室温,过滤,加入饱和碳酸氢钠(200mL),乙酸乙酯(200mL×2)萃取。有机层用盐水(200mL)洗涤,用无水硫酸钠干燥,过滤并减压浓缩,得到残余物。通过硅胶快速柱色谱法(石油醚/乙酸乙酯=3/1至1/3,10%二氯甲烷)纯化残余物,得到化合物1-12。
1H NMR(400MHz,CDCl
3)δ=7.44-7.20(m,11H),6.02-5.50(m,1H),5.31-5.16(m,2H),5.11-4.90(m,4H),4.02-3.97(m,1H),3.97-3.86(m,1H),3.70-3.44(m,2H),3.43-3.09(m,3H),2.97-2.81(m,1H),1.89-1.57(m,1H),1.36(s,9H)。
步骤十:化合物1-13的制备
向5L玻璃反应瓶中投入化合物1-12(300.0g)和3.0L甲醇,开始搅拌,加热升温至40℃,搅拌至原料溶解。氮气保护下加入Pd/C(15.0g,10%纯度),开始滴加564.8g三乙基硅氢,保持氮气流环境继续搅拌。氮气保护下加入Pd/C(15.0g,10%纯度),保持滴加三乙基硅氢,加毕保持氮气保护,关闭加热,继续搅拌20分钟。反应液经硅藻土抽滤,滤饼用甲醇(500ml×2)淋洗两次,45℃下浓缩滤液。向残留物中加入5.0L叔丁基甲基醚,15~30℃搅拌打浆18小时,氮气保护下抽滤,用1.0L叔丁基甲基醚淋洗滤饼,抽滤,滤饼经油泵旋蒸拉干(温度:50℃,时间:2小时)得到化合物1-13。
步骤十一:化合物1-14的制备
将化合物1-13(20.50g,58.67mmol,1eq)和中间体C(28.39g,52.80mmol,0.9eq)溶到N,N-二甲基甲酰胺(200mL)中,加入N,N-二异丙基乙胺(22.75g,176.01mmol,30.66mL,3eq)和1-羟基苯并三氮唑(10.31g,76.27mmol,1.3eq),随后加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(14.62g,76.27mmol,1.3eq),反应液在15~25℃氮气保护下反应16小时。将反应液倒入1.5L的冰水中搅拌10分钟,然后过滤,滤饼用水洗(300mL×2),滤液用乙酸乙酯(500mL×2)萃取。滤饼溶到有机相中,依次用稀盐酸 (0.5N,100mL×2),饱和碳酸氢钠(100mL×2)和盐水(200mL)洗涤,用无水硫酸钠干燥,过滤并在减压下浓缩,得到残余物。通过硅胶快速柱色谱法(石油醚/乙酸乙酯=2/1至1/2,10%二氯甲烷)纯化残余物,得到化合物1-14。
步骤十二:化合物1-15的制备
将化合物1-14(10.00g,11.51mmol,1eq)溶于N,N-二甲基甲酰胺(50mL)中,在0~5℃下加入三氧化硫的N,N-二甲基甲酰胺络合物(13.63g,46.03mmol,47%纯度,4eq),在0~5℃下搅拌3小时。将混合物倒入水(80mL)和乙酸乙酯(150mL)的混合溶剂中,分液,水相用乙酸乙酯(100mL×3)萃取。有机层用盐水(150mL×3)洗涤,用无水硫酸钠干燥,过滤并减压浓缩,得到残余物。残余物通过硅胶柱色谱法纯化(石油醚/乙酸乙酯=2/1至0/1+10%二氯甲烷),得到化合物1-15。LCMS(ESI)m/z:949.1(M+1)。
步骤十三:式(I)化合物的制备
将化合物1-15(6.20g,6.53mmol,1eq)和苯甲醚(7.06g,65.33mmol,7.10mL,10eq)溶于二氯甲烷(60mL)中,在0~5℃下加入磷酸(50.40g,437.14mmol,85%纯度,66.91eq),在0~5℃下搅拌1.5小时。在0~5℃下,将混合物中的下层磷酸相滴入四氢呋喃(300mL)并在0~5℃下搅拌1小时,在氮气保护下过滤,滤饼用四氢呋喃(100mL×2)淋洗,得到式(I)化合物粗产品,经XRPD检测为无定形粉末。将粗产品溶于水(4mL)中,过滤,将滤液滴到四氢呋喃(80mL)中,混合物在25~30℃下搅拌4小时,在氮气保护下过滤,滤饼用四氢呋喃(50mL×2)淋洗,干燥,得到式(I)化合物。经XRPD检测式(I)化合物为A晶型。经ICPMS检测,钠离子含量为1.59%,磷酸根离子含量为19.4%,卡尔费休水分测定检测显示水含量为7.5%,确定式(I)化合物为含有0.5个钠,1.5个磷酸的盐型和含有三个结晶水的A晶型。LCMS(ESI)m/z:583.1(M+1)。1H NMR(400MHz,DMSO-d
6+D
2O)δ=6.80(s,1H),5.23(d,J=5.7Hz,1H),4.17(q,J=5.7Hz,1H),3.84-3.76(m,2H),3.67(br t,J=8.9Hz,1H),3.42(br dd,J=5.1,14.4Hz,1H),3.16(br dd,J=6.2,14.2Hz,1H),3.04(br dd,J=5.4,9.9Hz,1H),2.98-2.89(m,1H),2.88-2.79(m,1H),1.29(br d,J=9.4Hz,4H)。
实施例2:式(I)化合物A晶型
方法一:
将式(I)化合物(0.50g,685.33μmol)的粗产品溶解到水(0.5mL)中,过滤掉不溶性杂质,在25~30℃下滴加到四氢呋喃(10mL)中,在25~30℃下搅拌4小时,4小时后分散均匀,在氮气保护下过滤,干燥,得到式(I)化合物A晶型。
方法二:
将式(I)化合物(100mg,137.07μmol)溶解到水(0.1mL)中,向溶液中滴加四氢呋喃(2mL),滴到有固体析出,搅拌约2小时开始固化,逐渐分散,4小时后分散均匀,在氮气保护下过滤,干燥,得 到式(I)化合物A晶型。
方法三:
向式(I)化合物(20.00mg,27.4μmol)中分别加入水和四氢呋喃的混合溶剂,分别加入水/四氢呋喃(1/15=0.5mL)、(1/20=0.5mL)、(1/25=0.5mL),在25~30℃下搅拌,约5小时固体分散均匀,在氮气保护下过滤,干燥,得到式(I)化合物A晶型。
方法四:
将式(I)化合物(500mg,685.33μmol)溶解到水(1.0mL)中,加入85%的磷酸(67.16mg,685.33mmol),向溶液中滴加四氢呋喃(20.0mL),15~25℃下搅拌12小时,在氮气保护下过滤,干燥,得到式(I)化合物A晶型。
方法五:
将式(I)化合物(500mg,685.33μmol)溶解到水(1.0mL)中,加入85%的磷酸(67.16mg,685.33mmol),向溶液中滴加异丙醇(6.0mL),15~25℃下搅拌12小时,在氮气保护下过滤,干燥,得到式(I)化合物A晶型。
实施例3:式(I)化合物立体构型确证
取16mg式(I)A晶型样品在室温条件下溶解于900μL甲醇/乙醇/水(1:1:1)中,将样品溶液置于4mL半密封样品瓶中,在室温条件下缓慢挥发。第二天得到无色针状晶体。
检测晶体为无色针状(0.30×0.10×0.10mm
3),属于单斜晶系C2空间群。晶胞参数
α=90°,β=90.224(2)°,γ=90°,
Z=2。计算密度Dc=1.728g/cm
3,单胞中电子数F(000)=1648.0,单胞的线性吸收系数μ(Cu Kα)=3.918mm
–1,衍射实验温度T=149.99(11)K。
上述针状晶体的模拟XRPD见图4,结构数据和参数见表2~7。
表2式(I)化合物的晶体结构数据和测定参数
12-X,+Y,1-Z;
21-X,+Y,-Z
表5式(I)化合物晶体的键角
原子 | 原子 | 原子 | 键角/° | 原子 | 原子 | 原子 | 键角/° |
O(9) | S(3) | O(10) | 114.6(4) | C(12) | N(5) | S(2) | 129.8(6) |
O(9) | S(3) | N(6) | 109.2(3) | C(13) | N(6) | S(3) | 112.6(5) |
O(9) | S(3) | N(7) | 110.1(5) | C(14) | N(6) | S(3) | 107.5(5) |
O(10) | S(3) | N(6) | 112.0(4) | C(14) | N(6) | C(13) | 116.1(7) |
O(10) | S(3) | N(7) | 115.9(5) | S(2) | O(8) | Na(1) | 131.5(7) |
N(7) | S(3) | N(6) | 93.0(4) | C(1) | N(2) | C(3) | 114.9(8) |
C(2) | S(1) | C(1) | 91.3(5) | O(4) | C(9) | N(4) | 123.5(7) |
O(16) 1 | P(2) | O(16) | 114.4(7) | O(4) | C(9) | C(4) | 119.8(7) |
O(16) | P(2) | O(15) 1 | 114.1(5) | N(4) | C(9) | C(4) | 116.7(7) |
O(16) | P(2) | O(15) | 100.8(6) | O(5) | C(10) | N(5) | 133.5(9) |
O(16) 1 | P(2) | O(15) 1 | 100.8(6) | O(5) | C(10) | C(11) | 135.3(9) |
O(16) 1 | P(2) | O(15) | 114.1(5) | N(5) | C(10) | C(11) | 91.2(6) |
O(15) 1 | P(2) | O(15) | 113.2(9) | N(6) | C(13) | C(12) | 109.4(6) |
O(8) | S(2) | N(5) | 104.0(5) | C(15) | N(7) | S(3) | 112.5(7) |
O(8) | S(2) | O(6) | 113.3(7) | O(3) | C(5) | C(8) | 117.7(7) |
O(8) | S(2) | O(7) | 117.0(7) | O(3) | C(5) | C(7) | 112.7(7) |
O(6) | S(2) | N(5) | 104.9(5) | O(3) | C(5) | C(6) | 118.7(8) |
O(7) | S(2) | N(5) | 107.7(5) | C(7) | C(5) | C(8) | 116.5(8) |
O(7) | S(2) | O(6) | 109.0(7) | C(7) | C(5) | C(6) | 59.0(6) |
O(14) | P(1) | O(12) | 102.1(6) | C(6) | C(5) | C(8) | 118.4(7) |
O(11) | P(1) | O(14) | 118.4(7) | N(7) | C(15) | C(16) | 113.2(8) |
O(11) | P(1) | O(12) | 109.0(6) | N(7) | C(15) | C(14) | 106.0(7) |
O(11) | P(1) | O(13) | 108.6(6) | C(14) | C(15) | C(16) | 110.6(8) |
O(13) | P(1) | O(14) | 110.0(6) | N(4) | C(11) | C(10) | 119.0(6) |
O(13) | P(1) | O(12) | 108.2(6) | N(4) | C(11) | C(12) | 120.2(6) |
O(5) | Na(1) | O(5) 2 | 115.2(5) | C(10) | C(11) | C(12) | 85.6(6) |
O(8) 2 | Na(1) | O(5) 2 | 79.3(3) | N(5) | C(12) | C(13) | 111.9(7) |
O(8) | Na(1) | O(5) | 79.3(3) | N(5) | C(12) | C(11) | 87.7(6) |
O(8) | Na(1) | O(5) 2 | 165.5(4) | C(13) | C(12) | C(11) | 120.9(6) |
O(8) 2 | Na(1) | O(5) | 165.5(4) | O(2) | C(8) | O(1) | 127.1(9) |
O(8) | Na(1) | O(8) 2 | 86.2(6) | O(2) | C(8) | C(5) | 123.2(8) |
O(17) 2 | Na(1) | O(5) | 79.9(3) | O(1) | C(8) | C(5) | 109.7(5) |
O(17) 2 | Na(1) | O(5) 2 | 70.6(3) | C(6) | C(7) | C(5) | 61.0(6) |
O(17) | Na(1) | O(5) | 70.6(3) | N(3) | C(4) | C(9) | 122.2(7) |
O(17) | Na(1) | O(5) 2 | 79.9(3) | N(3) | C(4) | C(3) | 118.8(7) |
O(17) 2 | Na(1) | O(8) 2 | 106.2(4) | C(3) | C(4) | C(9) | 118.6(7) |
O(17) 2 | Na(1) | O(8) | 114.5(4) | N(2) | C(1) | S(1) | 110.2(7) |
O(17) | Na(1) | O(8) 2 | 114.5(4) | N(1) | C(1) | S(1) | 125.6(9) |
O(17) | Na(1) | O(8) | 106.2(4) | N(1) | C(1) | N(2) | 124.2(10) |
O(17) | Na(1) | O(17) 2 | 123.3(7) | N(2) | C(3) | C(4) | 120.0(7) |
N(3) | O(3) | C(5) | 110.2(6) | C(2) | C(3) | N(2) | 113.2(8) |
C(9) | N(4) | C(11) | 123.0(7) | C(2) | C(3) | C(4) | 126.8(8) |
C(10) | O(5) | Na(1) | 114.9(7) | C(7) | C(6) | C(5) | 60.0(6) |
C(4) | N(3) | O(3) | 108.6(6) | C(3) | C(2) | S(1) | 110.4(7) |
C(10) | N(5) | S(2) | 132.4(6) | N(8) | C(16) | C(15) | 113.4(8) |
C(10) | N(5) | C(12) | 95.5(7) | N(6) | C(14) | C(15) | 104.8(7) |
12-X,+Y,1-Z;
21-X,+Y,-Z
表6式(I)化合物晶体的氢键
1+X,1+Y,+Z;
21/2+X,1/2+Y,+Z;
31/2+X,-1/2+Y,+Z;
41-X,+Y,1-Z;
53/2-X,-1/2+Y,1-Z;
63/2-X,1/2+Y,1-Z;
71-X,1+Y,1-Z
表7式(I)化合物晶体的扭转角
A | B | C | D | 角/° | A | B | C | D | 角/° |
S(3) | N(6) | C(13) | C(12) | -151.4(6) | N(2) | C(3) | C(2) | S(1) | 0.6(10) |
S(3) | N(6) | C(14) | C(15) | 41.5(8) | O(6) | S(2) | N(5) | C(10) | -174.3(9) |
S(3) | N(7) | C(15) | C(16) | 123.6(8) | O(6) | S(2) | N(5) | C(12) | 27.2(9) |
S(3) | N(7) | C(15) | C(14) | 2.2(10) | O(6) | S(2) | O(8) | Na(1) | 163.0(7) |
S(2) | N(5) | C(10) | O(5) | 14.4(16) | C(9) | N(4) | C(11) | C(10) | 28.7(11) |
S(2) | N(5) | C(10) | C(11) | -164.1(7) | C(9) | N(4) | C(11) | C(12) | -74.0(10) |
S(2) | N(5) | C(12) | C(13) | -72.7(9) | C(9) | C(4) | C(3) | N(2) | 172.0(8) |
S(2) | N(5) | C(12) | C(11) | 164.7(6) | C(9) | C(4) | C(3) | C(2) | -8.5(13) |
O(9) | S(3) | N(6) | C(13) | 82.1(6) | C(10) | N(5) | C(12) | C(13) | 123.1(7) |
O(9) | S(3) | N(6) | C(14) | -148.8(6) | C(10) | N(5) | C(12) | C(11) | 0.5(6) |
O(9) | S(3) | N(7) | C(15) | 131.3(7) | C(10) | C(11) | C(12) | N(5) | -0.4(5) |
O(4) | C(9) | C(4) | N(3) | 91.2(10) | C(10) | C(11) | C(12) | C(13) | -114.8(8) |
O(4) | C(9) | C(4) | C(3) | -82.1(10) | C(13) | N(6) | C(14) | C(15) | 168.6(6) |
Na(1) | O(5) | C(10) | N(5) | 24.0(13) | N(7) | S(3) | N(6) | C(13) | -165.4(6) |
Na(1) | O(5) | C(10) | C(11) | -158.2(8) | N(7) | S(3) | N(6) | C(14) | -36.4(7) |
O(3) | N(3) | C(4) | C(9) | 4.4(11) | N(7) | C(15) | C(16) | N(8) | 83.1(11) |
O(3) | N(3) | C(4) | C(3) | 177.7(7) | N(7) | C(15) | C(14) | N(6) | -26.9(10) |
O(3) | C(5) | C(8) | O(2) | -177.0(9) | C(5) | O(3) | N(3) | C(4) | 174.1(7) |
O(3) | C(5) | C(8) | O(1) | 2.8(11) | C(11) | N(4) | C(9) | O(4) | 3.6(12) |
O(3) | C(5) | C(7) | C(6) | -110.9(8) | C(11) | N(4) | C(9) | C(4) | -174.8(7) |
O(3) | C(5) | C(6) | C(7) | 100.5(9) | C(12) | N(5) | C(10) | O(5) | 177.9(10) |
O(10) | S(3) | N(6) | C(13) | -45.9(6) | C(12) | N(5) | C(10) | C(11) | -0.5(6) |
O(10) | S(3) | N(6) | C(14) | 83.2(6) | C(8) | C(5) | C(7) | C(6) | 108.7(8) |
O(10) | S(3) | N(7) | C(15) | -96.7(8) | C(8) | C(5) | C(6) | C(7) | -105.4(9) |
N(4) | C(9) | C(4) | N(3) | -90.3(10) | C(7) | C(5) | C(8) | O(2) | -38.6(12) |
N(4) | C(9) | C(4) | C(3) | 96.4(9) | C(7) | C(5) | C(8) | O(1) | 141.2(7) |
N(4) | C(11) | C(12) | N(5) | 120.7(7) | C(4) | C(3) | C(2) | S(1) | -178.9(7) |
N(4) | C(11) | C(12) | C(13) | 6.4(11) | C(1) | S(1) | C(2) | C(3) | -0.6(8) |
O(5) | C(10) | C(11) | N(4) | 59.8(13) | C(1) | N(2) | C(3) | C(4) | 179.3(8) |
O(5) | C(10) | C(11) | C(12) | -177.9(10) | C(1) | N(2) | C(3) | C(2) | -0.3(12) |
N(3) | O(3) | C(5) | C(8) | -79.5(9) | C(3) | N(2) | C(1) | S(1) | -0.2(10) |
N(3) | O(3) | C(5) | C(7) | 140.6(8) | C(3) | N(2) | C(1) | N(1) | 178.9(9) |
N(3) | O(3) | C(5) | C(6) | 74.7(9) | C(6) | C(5) | C(8) | O(2) | 28.7(14) |
N(3) | C(4) | C(3) | N(2) | -1.6(12) | C(6) | C(5) | C(8) | O(1) | -151.5(8) |
N(3) | C(4) | C(3) | C(2) | 177.9(9) | O(7) | S(2) | N(5) | C(10) | 69.7(10) |
N(5) | S(2) | O(8) | Na(1) | 49.7(9) | O(7) | S(2) | N(5) | C(12) | -88.8(9) |
N(5) | C(10) | C(11) | N(4) | -121.8(8) | O(7) | S(2) | O(8) | Na(1) | -68.9(10) |
N(5) | C(10) | C(11) | C(12) | 0.5(6) | C(2) | S(1) | C(1) | N(2) | 0.5(7) |
N(6) | S(3) | N(7) | C(15) | 19.6(8) | C(2) | S(1) | C(1) | N(1) | -178.6(9) |
N(6) | C(13) | C(12) | N(5) | 150.3(7) | C(16) | C(15) | C(14) | N(6) | -150.0(7) |
N(6) | C(13) | C(12) | C(11) | -108.6(8) | C(14) | N(6) | C(13) | C(12) | 84.1(8) |
O(8) | S(2) | N(5) | C(10) | -55.1(10) | C(14) | C(15) | C(16) | N(8) | -158.1(9) |
O(8) | S(2) | N(5) | C(12) | 146.4(8) | - | - | - | - | - |
实施例4:式(I)化合物的其他盐型的制备
(1)三氟乙酸盐(TFA)的制备:
将中间体1-15(300mg,308.95μmol,1eq)和苯甲醚(66.82mg,617.91μmol,67.16μL,2eq)溶于DCM(3mL)中,在0℃向的混合物中加入TFA(704.54mg,6.18mmol,457.49μL,20eq)。然后将混合物在0~5℃下搅拌1小时。然后向混合物中加入H
2O(140.04mg,7.77mmol,140.04μL,25.15eq)在0℃下并在25℃下搅拌24小时。在0~5℃下将下层水相/TFA滴加到MeCN(8mL)的冷却溶液中。然后将混合物在0~5℃下搅拌0.5小时。在真空氮气保护下过滤产物,得到粗品(110mg,168.67μmol,54.59%产率,89.33%纯度),为灰白色固体,将固体溶于5mL水中,然后在0℃下用饱和碳酸氢钠调节pH=7~8,然后用(n-Bu)
4NHSO
4处理至pH=4~5。通过制备型HPLC(柱:Waters Xbridge BEH C
18 250*50mm*10μm;流动相:乙腈/水(10mM NH
4HCO
3);乙腈的百分比从5%至30%,21分钟)纯化。然后通过制备型HPLC(柱:Phenomenex Synergi Max-RP 250*50mm*10μm;流动相:乙腈/水(0.1%TFA),乙腈的百分比从0%至25%,21分钟)纯化,得到式(II)化合物,经XRPD检测为无定形粉末。LCMS (ESI)m/z:583.1(M+1)。
1H NMR(400MHz,D
2O)δ=6.80(s,1H),5.23(d,J=5.7Hz,1H),4.17(q,J=5.7Hz,1H),3.84-3.76(m,2H),3.67(br t,J=8.9Hz,1H),3.42(br dd,J=5.1,14.4Hz,1H),3.16(br dd,J=6.2,14.2Hz,1H),3.04(br dd,J=5.4,9.9Hz,1H),2.98-2.89(m,1H),2.88-2.79(m,1H),1.29(br d,J=9.4Hz,4H)。
(2)硫酸盐(H
2SO
4)的制备:
反应变杂,未获得硫酸盐。
(3)盐酸盐(HCl)的制备
原料消耗完全,但无产物生成。
(4)乙酸盐(AcOH)的制备
原料消耗完全,但无产物生成。
(5)对甲苯磺酸盐(TsOH)的制备
原料消耗完全,但无产物生成。
结论:式(I)化合物的一些其他盐型不能直接获得。
实施例5:式(I)化合物A晶型在不同溶剂中的稳定性试验
将式(I)化合物A晶型(30.00mg,44.08μmol,1eq)分别在乙醇(0.2mL),异丙醇(0.2mL),乙腈(0.2mL),乙酸乙酯(0.2mL),四氢呋喃(0.2mL),乙醇\水=20/1(0.2mL),异丙醇/水=20/1(0.2mL),乙腈/水=20/1(0.2mL)中于20~30度悬浮两天,在氮气保护下过滤,干燥,测试晶型结果如表8所示。
表8式(I)化合物A晶型在不用溶剂中的稳定性实验
序号 | 溶剂 | 外观(2天) | 结果 |
1 | 乙醇 | 混悬液 | A晶型 |
2 | 异丙醇 | 混悬液 | A晶型 |
3 | 乙腈 | 混悬液 | A晶型 |
4 | 乙酸乙酯 | 混悬液 | A晶型 |
5 | 四氢呋喃 | 混悬液 | A晶型 |
6 | 乙醇-水(20:1) | 混悬液 | A晶型 |
7 | 异丙醇-水(20:1) | 混悬液 | A晶型 |
8 | 乙腈-水(20:1) | 混悬液 | A晶型 |
结论:式(I)化合物A晶型在多种溶剂种均能稳定存在,重现性好,容易获得。
实施例6:式(I)化合物其他晶型探索
目的:通过改变结晶条件,探索获得其他晶型。
表9式(I)化合物其他晶型探索
结论:使用式(I)化合物A晶型在不同含水体系中,先溶解后结晶均未获得其他晶型。
实施例7:式(I)化合物A晶型的固体稳定性研究
将式(I)化合物的A晶型摊成一薄层,在高温、常温高湿、光照、高温高湿条件下完全暴露放置,并按规定的时间点取样检测XRPD、外观、含量及有关物质,与0天样品的结果做比对。
表10式(I)化合物A晶型的固体稳定性研究结果
结论:将式(I)化合物的A晶型在高温、高湿、光照条件下稳定,在60℃、25℃/75%RH和光照条件下,有关物质和含量均未发生显著变化。
式(I)化合物A晶型的生物活性评估
实验例1:式(I)化合物A晶型抑菌作用检测(MIC)
用3株肺炎克雷伯菌ATCC BAA-205(TEM-1/SHV-1/SHV-12)、ATCC BAA-1705(KPC-2)、ATCC BAA-2470(NDM-1)、阴沟肠杆菌ATCC BAA-1143(AmpC)、2株大肠杆菌ATCC BAA-2523(OXA-48)、ATCC 25922,按照临床和实验室标准协会(Institute of clinical and laboratory standard,CLSI)要求通过微量液体稀释法测定各化合物的最低抑菌浓度(Minimum
Inhibitory Concentration,MIC)。在圆底96-孔板(Catalog#3788,Corning)中加入2倍系列梯度稀释化合物(终浓度范围0.125μg/mL-128μg/mL),从过夜辛顿米勒琼脂培养基Mueller Hinton II Agar(MHA,Cat.No.211438,BD BBL
TM)平板上挑取新鲜细菌单克隆,悬浮于灭菌生理盐水,调节浓度为1×10
8CFU/mL,再用阳离子调节的辛顿米勒培养基Cation-Adjusted Mueller Hinton II Broth(MHB,Catalog#212332,BD BBL
TM)稀释到5×10
5CFU/mL,取100μL加入到含有药物的圆底96-孔板。平板倒置于37℃培养20-24h后读取MIC值,将抑制细菌生长的 最低药物浓度定为MIC。结果见表8。菌落形成单位(CFU,Colony-Forming Units)指单位体积中的细菌群落总数。
表11式(I)化合物A晶型抑菌作用检测MIC(μg/mL)数据
结论:式(I)化合物A晶型对多种菌都具有良好的抑制效果。
实验例2:式(I)化合物A晶型大鼠体内的药代动力学研究
以标准方案测试化合物静脉注射给药后的啮齿类动物药代特征。具体来说,实验中候选化合物静脉注射给药7到10周龄的SD雄性大鼠。将化合物溶解在食盐水中配成澄清溶液。收集血浆样品,以LC-MS/MS方法分析,并计算药代参数。式(I)化合物A晶型的药代参数见表12。
表12式(I)化合物A晶型大鼠体内的药代动力学数据
结论:本发明化合物暴露量呈线性增长,在后期研究中,安全范围内,能发挥药物的最大给药量优势,获得更好的临床效果,具有良好的成药前景。
实验例3:式(I)化合物A晶型对大肠埃希菌ATCC 25922的自发耐药突变率(FOR)
用大肠埃希菌ATCC 25922,按照临床和实验室标准协会(Institute of clinical and laboratory standard,CLSI)要求通过微量液体稀释法,选取菌落总量为2.60E+08CFU的筛选用菌落,菌落形成单位(CFU,Colony-Forming Units),以2、4、8、16、32倍MIC最低抑菌浓度(Minimum Inhibitory Concentration,MIC),分别培养24及48小时,计算耐药频率,具体见表13。
表13式(I)化合物A晶型自发耐药突变率
结论:化合物(I)在两倍MIC时具有更小的耐药发生率,具有更好的临床使用前景。
本发明所提供的化合物(I)的A晶型性质稳定、溶解度好、引湿性好,具有良好的成药前景。
本发明给出的化合物(I)的A晶型制备容易,所用试剂常见,在市场上容易获得且价格低廉;多种制备方法均能获得单一稳定晶型;操作简单,条件温和;纯度较好,收率高。
实验例4:式(I)化合物A晶型大腿肌肉感染模型体内药效
78只CD-1雌鼠分成26笼,每笼3只;计感染当天为第0天。
于Day-4天腹腔注射免疫抑制剂环磷酰胺150mg/kg,Day-1再次腹腔注射免疫抑制剂环磷酰胺100mg/kg造成免疫缺陷小鼠。
于Day-1在MHA平板复苏菌株Klebsiella pneumoniae ATCC-BAA 2470(NDM+)。挑取复苏的菌落溶于无菌生理盐水中,制备浓度为5.95E+07CFU/mL的菌液用于小鼠大腿肌肉感染。计感染开始时间为0h,于0h通过大腿肌肉每只注射100μL菌液,即接种量为5.95E+06CFU/mouse。感染后2h,根据实验方案进行给药。具体实验方案如下(见表14):
(1)感染后2h:第25笼小鼠终点,取大腿肌肉组织置于10mL无菌生理盐水中,匀质机组织匀浆并将匀浆液进行梯度稀释点板,每只小鼠两个重复。
(2)感染后2h:第1~24笼按照小鼠体重10mL/kg的体积分别皮下注射给予式(I)化合物A晶型治疗,第1~4笼日给药总剂量为1600mg/kg,第5~8笼日给药总剂量为480mg/kg,第9~12笼日给药总剂量为160mg/kg,第13~16笼日给药总剂量为48mg/kg,第17~20笼日给药总剂量为16mg/kg,第21~24笼日给药总剂量为4.8mg/kg,每个剂量组分别采用四种不同的剂量分割方式进行给药,分别为q3h、q6h、q12h和q24h。
(3)感染后26h:试验终点为感染后26h,第1~26笼小鼠,取大腿肌肉组织置于10mL无菌生理盐水中,匀质机组织匀浆并将匀浆液进行梯度稀释点板,每只小鼠两个重复。对小鼠大腿肌肉组织载菌量进行计数,实验结果见表15。
表14实验方案
表15 26h终点时小鼠大腿肌肉组织载菌量实验结果
结论:本发明式(I)化合物A晶型具有显著体内杀菌效果,量效关系显著,同等日剂量下,缩短给药间隔,可以显著提高体内药效。
Claims (19)
- 根据权利要求2所述的A晶型,其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:15.05±0.20°、19.11±0.20°、20.41±0.20°、21.15±0.20°、22.62±0.20°、23.48±0.20°、27.32±0.20°、29.25±0.20°。
- 根据权利要求2所述的A晶型,其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:9.10±0.20°、11.29±0.20°、12.76±0.20°、15.05±0.20°、16.39±0.20°、19.11±0.20°、20.41±0.20°、21.15±0.20°、22.62±0.20°、23.68±0.20°。
- 根据权利要求2所述的A晶型,其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:6.90±0.20°、9.10±0.20°、11.29±0.20°、11.83±0.20°、12.76±0.20°、13.73±0.20°、14.57±0.20°、15.05±0.20°、16.10±0.20°、16.39±0.20°、17.81±0.20°、18.25±0.20°、19.11±0.20°、20.41±0.20°、21.15±0.20°。
- 根据权利要求2所述的A晶型,其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:6.90±0.20°、9.10±0.20°、11.29±0.20°、11.83±0.20°、12.76±0.20°、13.73±0.20°、15.05±0.20°、16.39±0.20°、17.81±0.20°、19.11±0.20°、20.41±0.20°、21.15±0.20°、21.64±0.20°、22.62±0.20°、23.48±0.20°。
- 根据权利要求2所述的A晶型,其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:6.90±0.20°、 9.10±0.20°、11.29±0.20°、11.83±0.20°、12.76±0.20°、13.73±0.20°、15.05±0.20°、16.39±0.20°、17.81±0.20°、19.11±0.20°、20.41±0.20°、21.15±0.20°、21.64±0.20°、22.62±0.20°、23.48±0.20°、25.73±0.20°、26.43±0.20°、27.32±0.20°、28.42±0.20°、29.25±0.20°。
- 根据权利要求2所述的A晶型,其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:6.904°、9.095°、11.285°、11.833°、12.757°、13.732°、14.573°、15.050°、16.100°、16.389°、17.807°、18.251°、19.113°、20.413°、20.790°、21.147°、21.641°、22.615°、23.484°、23.676°、24.002°、24.812°、25.728°、26.433°、26.655°、27.323°、27.636°、28.420°、29.248°、29.922°、30.358°、30.733°、31.507°、31.830°、32.049°、32.509°、32.843°、33.130°、33.837°、34.346°、34.895°、35.500°、36.037°、36.467°、37.098°、37.573°、37.875°、38.797°。
- 根据权利要求2~8中的任意一项所述的A晶型,其热重分析曲线在140.000℃±3.000℃时失重达6.657%,在205.000℃±3.000℃时失重达12.576%。
- 根据权利要求2~8中的任意一项所述的A晶型,其热重分析曲线基本上如图2所示。
- 根据权利要求2~8中的任意一项所述的A晶型,其差示扫描量热曲线在100.28℃±3.00℃处具有吸热峰、在127.61℃±3.00℃处具有吸热峰、在200.70℃±3.00℃处具有放热峰、在266.36℃±3.00℃处具有吸热峰。
- 根据权利要求2~8中的任意一项所述的A晶型,其差示扫描量热曲线基本上如图3所示。
- 根据权利要求13所述的A晶型,其热重分析曲线在140.000℃±3.000℃时失重达6.657%,在205.000℃±3.000℃时失重达12.576%。
- 根据权利要求13所述的A晶型,其热重分析曲线基本上如图2所示。
- 根据权利要求13所述的A晶型,其差示扫描量热曲线在100.28℃±3.00℃处具有吸热峰、在127.61℃±3.00℃处具有吸热峰、在200.70℃±3.00℃处具有放热峰、在266.36℃±3.00℃处具有吸热峰。
- 根据权利要求13所述的A晶型,其差示扫描量热曲线基本上如图3所示。
- 权利要求1所述的可药用盐及其晶型在制备治疗与细菌感染相关疾病的药物中的应用。
- 权利要求2~17中任意一项所述的A晶型在制备治疗与细菌感染相关疾病的药物中的应用。
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WO2002022613A1 (en) | 2000-09-14 | 2002-03-21 | Pantherix Limited | 3-(heteroaryl acetamido)-2-oxo-azetidine-1-sulfonic acids derivatives as antibacterial agents |
WO2007065288A2 (en) | 2005-12-07 | 2007-06-14 | Basilea Pharmaceutica Ag | Useful combinations of monobactam antibiotics with beta-lactamase inhibitors |
CN103228652A (zh) * | 2010-11-29 | 2013-07-31 | 辉瑞大药厂 | 单环内酰胺类 |
WO2015148379A1 (en) | 2014-03-24 | 2015-10-01 | Novartis Ag | Monobactam organic compounds for the treatment of bacterial infections |
CN108137573A (zh) * | 2015-09-23 | 2018-06-08 | 诺华股份有限公司 | 单环内酰胺抗生素的盐和固体形式 |
WO2021098840A1 (zh) * | 2019-11-22 | 2021-05-27 | 南京明德新药研发有限公司 | 磺酰脲环取代的单环β-内酰胺类抗生素 |
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2002022613A1 (en) | 2000-09-14 | 2002-03-21 | Pantherix Limited | 3-(heteroaryl acetamido)-2-oxo-azetidine-1-sulfonic acids derivatives as antibacterial agents |
WO2007065288A2 (en) | 2005-12-07 | 2007-06-14 | Basilea Pharmaceutica Ag | Useful combinations of monobactam antibiotics with beta-lactamase inhibitors |
CN103228652A (zh) * | 2010-11-29 | 2013-07-31 | 辉瑞大药厂 | 单环内酰胺类 |
WO2015148379A1 (en) | 2014-03-24 | 2015-10-01 | Novartis Ag | Monobactam organic compounds for the treatment of bacterial infections |
CN108137573A (zh) * | 2015-09-23 | 2018-06-08 | 诺华股份有限公司 | 单环内酰胺抗生素的盐和固体形式 |
WO2021098840A1 (zh) * | 2019-11-22 | 2021-05-27 | 南京明德新药研发有限公司 | 磺酰脲环取代的单环β-内酰胺类抗生素 |
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