CN114437033A - Salt of nitroxoline prodrug, pharmaceutical composition containing salt, preparation method and application of salt - Google Patents
Salt of nitroxoline prodrug, pharmaceutical composition containing salt, preparation method and application of salt Download PDFInfo
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- CN114437033A CN114437033A CN202011189484.0A CN202011189484A CN114437033A CN 114437033 A CN114437033 A CN 114437033A CN 202011189484 A CN202011189484 A CN 202011189484A CN 114437033 A CN114437033 A CN 114437033A
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- yloxy
- methyl
- isopropionylpyrrolidine
- nitroquinolin
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- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 13
- 150000003839 salts Chemical class 0.000 title abstract description 21
- RJIWZDNTCBHXAL-UHFFFAOYSA-N nitroxoline Chemical compound C1=CN=C2C(O)=CC=C([N+]([O-])=O)C2=C1 RJIWZDNTCBHXAL-UHFFFAOYSA-N 0.000 title abstract description 14
- 229960005131 nitroxoline Drugs 0.000 title abstract description 13
- 239000000651 prodrug Substances 0.000 title abstract description 11
- 229940002612 prodrug Drugs 0.000 title abstract description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 37
- 239000003814 drug Substances 0.000 claims abstract description 14
- 229940079593 drug Drugs 0.000 claims abstract description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 21
- 150000001875 compounds Chemical class 0.000 claims description 17
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 16
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 11
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 8
- 206010028980 Neoplasm Diseases 0.000 claims description 7
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 claims description 6
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 6
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- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
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- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 8
- 238000004458 analytical method Methods 0.000 description 8
- 229940125904 compound 1 Drugs 0.000 description 8
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 8
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- 206010005003 Bladder cancer Diseases 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
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- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 239000007836 KH2PO4 Substances 0.000 description 3
- 206010060862 Prostate cancer Diseases 0.000 description 3
- 206010038389 Renal cancer Diseases 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical class OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 229960001193 diclofenac sodium Drugs 0.000 description 3
- 238000007865 diluting Methods 0.000 description 3
- 201000010982 kidney cancer Diseases 0.000 description 3
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 3
- JGMJQSFLQWGYMQ-UHFFFAOYSA-M sodium;2,6-dichloro-n-phenylaniline;acetate Chemical compound [Na+].CC([O-])=O.ClC1=CC=CC(Cl)=C1NC1=CC=CC=C1 JGMJQSFLQWGYMQ-UHFFFAOYSA-M 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
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- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
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- 239000003826 tablet Substances 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 101710181812 Methionine aminopeptidase Proteins 0.000 description 1
- 102100031455 NAD-dependent protein deacetylase sirtuin-1 Human genes 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 108010041191 Sirtuin 1 Proteins 0.000 description 1
- 102000000477 Sirtuin 2 Human genes 0.000 description 1
- 108010041216 Sirtuin 2 Proteins 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- XBJFCYDKBDVADW-UHFFFAOYSA-N acetonitrile;formic acid Chemical compound CC#N.OC=O XBJFCYDKBDVADW-UHFFFAOYSA-N 0.000 description 1
- PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
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- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
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- 238000002715 modification method Methods 0.000 description 1
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- 229940127249 oral antibiotic Drugs 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
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- 229920001343 polytetrafluoroethylene Polymers 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Urology & Nephrology (AREA)
- Engineering & Computer Science (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention discloses a salt of a nitroxoline prodrug, a pharmaceutical composition containing the salt, a preparation method and application of the salt. The salt of the nitroxoline prodrug is the hydrochloride of (S) - (5-nitroquinolin-8-yloxy) methyl 1-isopropionylpyrrolidine-2-carboxylate. The hydrochloride has solubility far higher than that of free (S) - (5-nitroquinolin-8-yloxy) methyl 1-isopropionylpyrrolidine-2-carboxylate and other salts, such as hydrobromide, methanesulfonate, bisulfate, so that the hydrochloride is easier to absorb and has higher bioavailability, and is more favorable for developing medicines suitable for human bodies.
Description
Technical Field
The invention relates to a salt of a nitroxoline prodrug, a pharmaceutical composition containing the salt, a preparation method and application of the salt.
Background
Nitroxoline, the british name Nitroxoline, the chemical name 5-nitro-8-hydroxyquinoline, was developed in the sixties as an oral antibiotic drug, mainly for urinary infections, with a safer history of use, and was later replaced by the discovery and use of new antibiotics.
In recent years, new researches show that the nitroxoline can simultaneously inhibit methionine aminopeptidase MetAP2 and a sirtuin 2-related enzyme SIRT1 in vascular endothelial cells to play a synergistic inhibition effect on tumor angiogenesis and simultaneously inhibit the proliferation of tumor cells. Thus, nitroxoline has been newly developed for the treatment of tumors including bladder cancer.
The prodrug is a compound obtained by chemically modifying an active drug, and is converted into the original drug by the action of an enzyme in vivo to exert the drug effect. The prodrug has wide application in drug research and development, is a modification method of drugs, can overcome various adverse characteristics and properties, and mainly can bring the following advantages: increase drug solubility, improve drug absorption and distribution, increase drug stability, reduce toxicity or adverse reactions, prolong drug action time, eliminate drug unsuitable properties, and the like.
The prior art has reported on nitroxoline prodrugs, however, there is no report on salts of nitroxoline prodrugs.
Disclosure of Invention
In order to solve the technical problem that no salt of a nitroxoline prodrug exists in the prior art, the invention provides a salt of a nitroxoline prodrug, a pharmaceutical composition containing the salt, a preparation method and application of the salt.
The invention solves the technical problems through the following technical scheme:
the present invention provides a hydrochloride salt of (S) - (5-nitroquinolin-8-yloxy) methyl 1-isopropionylpyrrolidine-2-carboxylate.
In some preferred embodiments, the molar ratio of (S) - (5-nitroquinolin-8-yloxy) methyl 1-isopropionylpyrrolidine-2-carboxylate to HCl is from 0.5:1 to 1.5: 1.
In some preferred embodiments, the molar ratio of (S) - (5-nitroquinolin-8-yloxy) methyl 1-isopropionylpyrrolidine-2-carboxylate to HCl is 1:1, i.e.
The present invention also provides a method for preparing the hydrochloride of the aforementioned (S) - (5-nitroquinolin-8-yloxy) methyl 1-isopropionylpyrrolidine-2-carboxylate, which comprises the steps of:
reacting the mixture of (S) - (5-nitroquinolin-8-yloxy) methyl 1-isopropionylpyrrolidine-2-carboxylate and organic solvent with a solution containing hydrochloric acid, and carrying out solid-liquid separation to obtain the compound.
In some preferred above processes, the organic solvent is selected from one or more of tetrahydrofuran, methanol, ethanol, n-propanol, isopropanol, acetone and ethyl acetate, preferably tetrahydrofuran.
In some preferred above processes, the solvent in the hydrochloric acid-containing solution is selected from one or more of ethyl acetate, water, methanol, ethanol, n-propanol, isopropanol and acetone, preferably ethyl acetate.
In some preferred above processes, the equivalent ratio of (S) - (5-nitroquinolin-8-yloxy) methyl 1-isopropionylpyrrolidine-2-carboxylate to hydrogen chloride in the hydrochloric acid-containing solution is from 1:5 to 5:1, preferably from 1:1.5 to 1:3, more preferably from 1:1.5 to 1:2.5, even more preferably 1:2.
In some preferred above-mentioned processes, the temperature of the reaction is 10-30 ℃, preferably 20-30 ℃, e.g. 25 ℃.
In some preferred above-mentioned methods, the reaction time is 10min to 3h, preferably 10 to 60min, more preferably 25 to 35min, still more preferably 30 min.
In some preferred above processes, the solid-liquid separation is filtration.
The invention also provides a pharmaceutical composition, which comprises the hydrochloride of the (S) - (5-nitroquinolin-8-yloxy) methyl 1-isopropionylpyrrolidine-2-carboxylate and a pharmaceutically acceptable carrier.
The pharmaceutical composition can be prepared into tablets, pills, powder, granules, capsules or emulsions, and can also be prepared into quick-release preparations or sustained-release preparations.
The pharmaceutical compositions of the present invention may be used for various routes of administration, such as oral or parenteral administration.
The invention also provides application of the hydrochloride of the (S) - (5-nitroquinolin-8-yloxy) methyl 1-isopropionylpyrrolidine-2-carboxylate or the pharmaceutical composition in preparing anti-infective and/or anti-tumor drugs.
Wherein the infection is preferably a urinary tract infection.
Wherein the tumor is preferably selected from the group consisting of bladder cancer, prostate cancer and renal cancer.
The invention also provides a hydrochloride of the aforementioned (S) - (5-nitroquinolin-8-yloxy) methyl 1-isopropionylpyrrolidine-2-carboxylate or a pharmaceutical composition of the aforementioned, for use against infection and/or tumor.
Wherein the infection is preferably a urinary tract infection.
Wherein the tumor is preferably selected from the group consisting of bladder cancer, prostate cancer and renal cancer.
The present invention also provides a method of treating an infection and/or tumor comprising administering to a patient in need thereof a therapeutically effective amount of the hydrochloride salt of the aforementioned (S) - (5-nitroquinolin-8-yloxy) methyl 1-isopropionylpyrrolidine-2-carboxylate or the aforementioned pharmaceutical composition.
Wherein the infection is preferably a urinary tract infection.
Wherein the tumor is preferably selected from the group consisting of bladder cancer, prostate cancer and renal cancer.
It will be understood by those skilled in the art that the optimum dosage and interval will depend upon the nature and extent of the condition being treated, the form, route and site of administration, and the particular patient being treated, and that such optimum may be determined by conventional techniques. It will also be appreciated by those skilled in the art that the optimal course of treatment, i.e. the number of doses of active ingredient administered per day over a given period of time, can be determined by those skilled in the art using routine tests to determine the course of treatment.
Compared with the prior art, the technical scheme of the invention has the following advantages: the hydrochloride of the (S) - (5-nitroquinolin-8-yloxy) methyl 1-isopropionylpyrrolidine-2-carboxylate has much higher solubility than free (S) - (5-nitroquinolin-8-yloxy) methyl 1-isopropionylpyrrolidine-2-carboxylate and other salts, such as hydrobromide, methanesulfonate, bisulfate, so that the hydrochloride is easier to absorb and has higher bioavailability, and is more beneficial to developing medicaments suitable for human bodies.
Detailed Description
Terms not defined herein have meanings as commonly understood by one of ordinary skill in the art to which the present invention belongs. For the terms defined herein, they have the meanings set forth in the specification.
The term "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable excipient, such as one or more of a binder, filler, disintegrant, and lubricant in a tablet, for delivering the hydrochloride salt of (S) - (5-nitroquinolin-8-yloxy) methyl 1-isopropionylpyrrolidine-2-carboxylate herein to a subject; semisolid formulations include the base portion of ointments and creams; one or more of preservatives, antioxidants, flavoring agents, fragrances, cosolvents, emulsifiers, solubilizers, tonicity adjusting agents and colorants in the liquid formulation.
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions. Known reagents, solvents, materials in the examples can be synthesized using or according to methods known in the art, or are commercially available.
Hereinafter, the purity analysis method is as follows: using a Kinetex EVO C18(50 x 4.6mm, 5 μm,
) And (3) carrying out gradient elution by using acetonitrile-water as a mobile phase on a chromatographic column, wherein the flow rate is 1.5mL/min, and the detection wavelength is 220 nm. Determination of MS Using an LC (Agilent 1260Infinity II)/MS (G6125B single quadrupole) mass spectrometer (manufacturer: Agilent) (Photodiode Array Detector). The structure of the compound is determined by hydrogen spectrum, and the model of the device is WNMR-I-400 MHz.
Hereinafter, compound 1 is (S) - (5-nitroquinolin-8-yloxy) methyl 1-isopropionylpyrrolidine-2-carboxylate, prepared according to the method disclosed in example 20 of patent application publication No. WO2020/063824A 1.
Example 1: synthesis of hydrochloride of (S) - (5-nitroquinolin-8-yloxy) methyl 1-isopropionylpyrrolidine-2-carboxylate (Compound 2)
(S) - (5-Nitro-quinolin-8-yloxy) methyl 1-isopropionyl-pyrrolidine-2-carboxylate (compound 1) (200mg, 0.517mmol, 1eq) was dissolved in 5mL of THF, HCl/ethyl acetate solution (1.02mL, 1.02mmol, 2.0eq) was added, and the mixture was stirred at 25 ℃ for 30min to precipitate a solid, which was filtered and the cake was dried to constant weight, yielding 180mg of (S) - (5-Nitro-quinolin-8-yloxy) methyl 1-isopropionyl-pyrrolidine-2-carboxylate hydrochloride (compound 2) as a yellow solid with a purity of 99% in 82.5% yield.
Molecular weight: m + H+＝388.2(ESI)。
1H-NMR(400MHz,DMSO-d6):δ：9.10(d,J＝2.8Hz,1H),9.07(d,J＝8.4Hz,1H),8.56(d,J＝8.8Hz,1H),7.90(dd,J＝4.0Hz,8.8Hz,1H),7.58(d,J＝8.8Hz,1H),6.21(d,J＝6.4Hz,1H),6.17(d,J＝6.4Hz,1H),4.36-4.33(m,1H),3.58-3.55(m,2H),2.73-2.65(m,1H),2.17-2.14(m,1H),1.91-1.86(m,2H),1.83-1.74(m,1H),0.98(d,J＝6.8Hz,3H),0.87(d,J＝6.8Hz,3H)。
Comparative example 1: synthesis of hydrobromide salt of (S) - (5-nitroquinolin-8-yloxy) methyl 1-isopropionylpyrrolidine-2-carboxylate (Compound 3)
(S) - (5-Nitro-quinolin-8-yloxy) methyl 1-isopropionylpyrrolidine-2-carboxylate (compound 1) (200mg, 0.517mmol, 1eq) was dissolved in 5mL of THF, aqueous HBr (156.8mg, 0.776mmol, 1.5eq, 40 wt%) was added and stirred at 25 ℃ for 30min to precipitate a solid, which was filtered and the cake was dried to constant weight to give 193mg of (S) - (5-Nitro-quinolin-8-yloxy) methyl 1-isopropionylpyrrolidine-2-carboxylate hydrobromide salt (compound 3) as a yellow solid with a purity of 99% in 80% yield.
Molecular weight: m + H+＝388.2(ESI)。
1H-NMR(400MHz,DMSO-d6):δ：9.06(d,J＝2.8Hz,1H),9.03(d,J＝8.4Hz,1H),8.58(d,J＝8.8Hz,1H),7.90(dd,J＝4.0Hz,8.8Hz,1H),7.55(d,J＝8.8Hz,1H),6.20(d,J＝6.4Hz,1H),6.14(d,J＝6.4Hz,1H),4.36-4.33(m,1H),3.58-3.55(m,2H),2.70-2.63(m,1H),2.19-2.14(m,1H),1.92-1.87(m,2H),1.82-1.77(m,1H),0.95(d,J＝6.8Hz,3H),0.89(d,J＝6.8Hz,3H)。
Comparative example 2: synthesis of methanesulfonic acid salt of (S) - (5-nitroquinolin-8-yloxy) methyl 1-isopropionylpyrrolidine-2-carboxylic acid ester (Compound 4)
(S) - (5-Nitro-quinolin-8-yloxy) methyl 1-isopropionyl-pyrrolidine-2-carboxylate (compound 1) (200mg, 0.517mmol, 1eq) was dissolved in 5mL of THF, methanesulfonic acid (50mg, 0.51mmol, 1.0eq) was added, and the mixture was stirred at 25 ℃ for 30min to precipitate a solid, which was filtered and the cake was dried to constant weight to give 135mg of (S) - (5-Nitro-quinolin-8-yloxy) methyl 1-isopropionyl-pyrrolidine-2-carboxylate methanesulfonate (compound 4) as a yellow solid with a purity of 99% and a yield of 54%.
Molecular weight: m + H+＝388.2(ESI)。
1H-NMR(400MHz,DMSO-d6):δ：9.09(d,J＝2.8Hz,1H),9.04(d,J＝8.4Hz,1H),8.58(d,J＝8.8Hz,1H),7.91(dd,J＝4.0Hz,8.8Hz,1H),7.56(d,J＝8.8Hz,1H),6.24(d,J＝6.4Hz,1H),6.14(d,J＝6.4Hz,1H),4.36-4.33(m,1H),3.58-3.55(m,2H),2.73-2.64(m,1H),2.19-2.14(m,1H),1.91-1.86(m,2H),1.83-1.76(m,1H),0.96(d,J＝6.8Hz,3H),0.90(d,J＝6.8Hz,3H)。
Comparative example 3: synthesis of hydrogen sulfate salt of (S) - (5-nitroquinolin-8-yloxy) methyl 1-isopropionylpyrrolidine-2-carboxylic acid ester (Compound 5)
(S) - (5-Nitro-quinolin-8-yloxy) methyl 1-isopropionyl-pyrrolidine-2-carboxylate (compound 1) (200mg, 0.517mmol, 1eq) was dissolved in 5mL of THF, sulfuric acid (50mg, 0.517mmol, 1.0eq, 98 wt%) was added and stirred at 25 ℃ for 30min to precipitate a solid, which was filtered and the cake was dried to constant weight to give 135mg of (S) - (5-Nitro-quinolin-8-yloxy) methyl 1-isopropionyl-pyrrolidine-2-carboxylate hydrogen sulfate salt (compound 5) as a yellow solid with a purity of 99% and a yield of 44.6%.
Molecular weight: m + H+＝388.2(ESI)。
1H-NMR(400MHz,DMSO-d6):δ：9.08(d,J＝2.8Hz,1H),9.05(d,J＝8.4Hz,1H),8.55(d,J＝8.8Hz,1H),7.94(dd,J＝4.0Hz,8.8Hz,1H),7.55(d,J＝8.8Hz,1H),6.23(d,J＝6.4Hz,1H),6.15(d,J＝6.4Hz,1H),4.36-4.33(m,1H),3.58-3.55(m,2H),2.76-2.64(m,1H),2.24-2.14(m,1H),1.97-1.86(m,2H),1.85-1.77(m,1H),0.97(d,J＝6.8Hz,3H),0.90(d,J＝6.8Hz,3H)。
Test example 1 solubility test method and test results
Test method
I. In the following test methods, specific parameters of LC-MS/MS are as follows:
liquid chromatography system: shimadzu; mass spectrometry analysis: API 4000 instrument from AB Inc (canada) with ESI interface; column temperature: 25 ℃; sample introduction amount: 3. mu.L or 10. mu.L; a chromatographic column: ACE Ultra Core 2.5 Super C18(3.0 x 50mm) XP chromatography column in combination with a preguard chromatography column; mobile phase: 0.1 v% aqueous formic acid (A) and 0.1 v% acetonitrile formic acid (B); elution speed: 1 mL/min.
| Time (min) | 0.00 | 0.30 | 0.60 | 0.90 | 0.91 | 1.20 |
| ％B | 5 | 5 | 100 | 100 | 5 | 5 |
The MS parameters were as follows: an ion source: turbo spraying; ionization model: ESI; the scanning type is as follows: MRM; collision gas: 10L/min; curtain gas: 30L/min; atomizing gas: 60L/min; auxiliary gas: 60L/min; temperature: 550 ℃; ion spray voltage: +5500V (positive MRM).
II. The specific operation steps of the test are as follows:
1. preparation of hydrochloric acid solution pH 1.2
Dissolving 7.65mL of HCl in ultrapure water, diluting to 1000mL with ultrapure water, and stirring.
2. preparation of acetate buffer solution of pH 4.5
(1) Preparation of 2mol/L CH3COOH
120.0g (114mL) of CH3Dissolving COOH in ultrapure water, and diluting with ultrapure water to 1000 mL.
(2)CH3Preparation of COONa
2.99g of CH3COONa is dissolved in ultrapure water and usedDiluting with ultrapure water to 1000 mL.
(3) 1000mL of CH3COONa and 14.0mL of 2mol/L CH3And uniformly mixing the COOH solution.
3. preparation of phosphate buffer solution of pH 6.8
(1) Preparation of 0.2mol/L KH2PO4Solutions of
Mixing 27.22g KH2PO4Dissolving in ultrapure water, and diluting to 1000mL with ultrapure water.
(2) Preparation of 0.2mol/L NaOH solution
8.00g of NaOH was dissolved in ultrapure water and diluted to 1000mL with ultrapure water.
(3) 250mL of 0.2mol/L KH2PO4The solution is mixed with 112mL of 0.2mol/L NaOH solution, diluted to 1000mL by ultrapure water and mixed evenly.
4. The test compound and the control compound diclofenac sodium (purchased from Sigma Chemical co., which is used to verify the accuracy and reliability of the test method) were weighed to measure solubility (for compound 2, three samples were weighed at one specific test condition, wherein 30mg of two samples were each placed in a 1.5mL glass vial as a test article, 3.0mg of a sample were placed in a 1.5mL glass vial as a standard article; for diclofenac sodium, compound 1, compound 3, compound 4, compound 5, each compound was also weighed at one specific test condition, about 1.0mg each, were each placed in three independent 1.5mL glass vials).
5. One vial was used as the standard and two other vials were used as the test article for each compound under the specified test conditions.
6. Each compound was placed in a 96-well rack in order, with standards placed in one 96-well rack and test items placed in the other 96-well rack.
7. To the test article, 1000 μ L of hydrochloric acid solution at pH 1.2, acetate buffer solution at pH 4.5, or phosphate buffer solution at pH 6.8 was added using a pipette gun, a stir bar was placed in each glass vial, and the glass vial was sealed using a PTFE/silica gel plug.
8. The test article was transferred to an Eppendorf Thermomixer Comfort plate shaker and shaken for 24 hours at 25 ℃ and 1100 RPM.
9. After 24 hours, the stir bar was removed using a large magnet, and the vial of test article was transferred to a filter plate using a pipette and filtered using a vacuum manifold. The filtrate was diluted 1000 times with acetonitrile to obtain test solution I. 100 μ L of test solution I was transferred to a new 96-well plate (designated as well plate I) along with 100 μ L of water for LC-MS/MS analysis. Dilution factor was varied according to solubility values and LC-MS signal response.
10. For the standard, a standard solution I (concentration of standard solution I is 3.0mg/mL for Compound 2; concentration of standard solution I is 1.0mg/mL for diclofenac sodium, Compound 1, Compound 3, Compound 4, Compound 5) was prepared, wherein the solvent was DMSO.
11. The standard vial was covered with a 96-well plate lid and the standard was placed on an Eppendorf Thermomixer Comfort plate shaker at 25 ℃ and 1100RPM for 5 minutes.
12. After 5 minutes, each compound was completely dissolved.
13. mu.L of the standard solution I was transferred to a new well plate A, and 495. mu.L of acetonitrile was added to the well plate to obtain a standard solution II. 50. mu.L of the standard solution II was transferred to a new well plate B, and 450. mu.L of acetonitrile was added to the well plate to obtain a standard solution III. 100 μ L of standard solution III was transferred to a new 96-well plate (designated as well plate II) along with 100 μ L of water for LC-MS/MS analysis. The concentration of the standard was adjusted according to the LC-MS signal response.
14. Well plate I and well plate II were placed in a well plate autosampler and evaluated by LC-MS/MS analysis at 4 ℃.
15. The solubility value of the test compound is calculated by the formula:
wherein S isTestingSolubility of the test Compound, ATestingTest solutions for LC-MS/MS analysis in step 9Peak area corresponding to liquid I, VTestingSample volume, DF, of test solution I to be subjected to LC-MS/MS analysis in step 9TestingDilution factor of the filtrate in step 9, CStandard of meritIs the concentration of the test compound in the standard solution I, AStandard of meritPeak area, V, corresponding to standard solution III sent to LC-MS/MS analysis in step 13Standard of referenceThe sample volume of standard solution III sent for LC-MS/MS analysis in step 13.
Note: q1: mass-to-charge ratio of parent ions; q2: the mass-to-charge ratio of the daughter ions; DP: de-clustering voltage; EP: an entrance voltage to direct and focus ions through a high voltage Q0 region; CE: collision energy; CXP: the collision cell exit voltage is used to focus and accelerate ions out of the Q2 region for Q3 region scanning and MS/MS.
Second, test results
From the above table, it can be seen that the hydrochloride salt of example 1 has much higher solubility than compound 1 of the prior art, as well as other salts, such as the hydrobromide, mesylate, bisulfate salts. Therefore, the hydrochloride is easier to absorb and has higher bioavailability, and is more beneficial to developing into medicaments suitable for human bodies.
While specific embodiments of the invention have been described above, it will be appreciated by those skilled in the art that this is by way of example only, and that the scope of the invention is defined by the appended claims. Various changes and modifications to these embodiments may be made by those skilled in the art without departing from the spirit and scope of the invention, and these changes and modifications are within the scope of the invention.
Claims (10)
- Hydrochloride of (S) - (5-nitroquinolin-8-yloxy) methyl 1-isopropionylpyrrolidine-2-carboxylate.
- 2. The hydrochloride salt of (S) - (5-nitroquinolin-8-yloxy) methyl 1-isopropionylpyrrolidine-2-carboxylate according to claim 1, having the formula:
- 3. a process for the preparation of the hydrochloride salt of (S) - (5-nitroquinolin-8-yloxy) methyl 1-isopropionylpyrrolidine-2-carboxylic acid ester according to claim 1 or 2, comprising the steps of:reacting the mixture of (S) - (5-nitroquinolin-8-yloxy) methyl 1-isopropionylpyrrolidine-2-carboxylate and organic solvent with a solution containing hydrochloric acid, and carrying out solid-liquid separation to obtain the compound.
- 4. The preparation method according to claim 3, wherein the organic solvent is one or more selected from tetrahydrofuran, methanol, ethanol, n-propanol, isopropanol, acetone and ethyl acetate, preferably tetrahydrofuran.
- 5. The production method according to claim 3 or 4, wherein the solvent in the hydrochloric acid-containing solution is one or more selected from the group consisting of ethyl acetate, water, methanol, ethanol, n-propanol, isopropanol and acetone, and preferably ethyl acetate.
- 6. The production method according to any one of claims 3 to 5, wherein the equivalent ratio of (S) - (5-nitroquinolin-8-yloxy) methyl 1-isopropionylpyrrolidine-2-carboxylate to hydrogen chloride in the hydrochloric acid-containing solution is 1:5 to 5:1, preferably 1:1.5 to 1:3, more preferably 1:1.5 to 1:2.5, still more preferably 1:2.
- 7. The production method according to any one of claims 3 to 6, wherein the reaction temperature is 10 to 30 ℃, preferably 20 to 30 ℃, and more preferably 25 ℃;and/or the reaction time is 10min-3h, preferably 10-60min, more preferably 25-35min, and even more preferably 30 min.
- 8. A pharmaceutical composition comprising the hydrochloride of (S) - (5-nitroquinolin-8-yloxy) methyl 1-isopropionylpyrrolidine-2-carboxylate according to claim 1 or 2, and a pharmaceutically acceptable carrier.
- 9. Use of the hydrochloride of (S) - (5-nitroquinolin-8-yloxy) methyl 1-isopropionylpyrrolidine-2-carboxylate according to claim 1 or 2, or the pharmaceutical composition according to claim 8, for the preparation of an anti-infective and/or anti-tumoral drug.
- 10. Use according to claim 9, the infection being a urinary tract infection, and/or the tumour being selected from bladder, prostate and renal cancers.
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| CN111514142A (en) * | 2020-05-29 | 2020-08-11 | 江苏亚虹医药科技有限公司 | Pharmaceutical composition containing nitroxoline prodrug and preparation method and application thereof |
| CN111646936A (en) * | 2020-06-22 | 2020-09-11 | 江苏亚虹医药科技有限公司 | Process for producing aromatic ether compound |
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| CN111514142A (en) * | 2020-05-29 | 2020-08-11 | 江苏亚虹医药科技有限公司 | Pharmaceutical composition containing nitroxoline prodrug and preparation method and application thereof |
| CN111646936A (en) * | 2020-06-22 | 2020-09-11 | 江苏亚虹医药科技有限公司 | Process for producing aromatic ether compound |
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