CN116621856A - Novel carbamate compound and application thereof - Google Patents
Novel carbamate compound and application thereof Download PDFInfo
- Publication number
- CN116621856A CN116621856A CN202310647868.XA CN202310647868A CN116621856A CN 116621856 A CN116621856 A CN 116621856A CN 202310647868 A CN202310647868 A CN 202310647868A CN 116621856 A CN116621856 A CN 116621856A
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- China
- Prior art keywords
- compound
- pharmaceutically acceptable
- acceptable salt
- platelet aggregation
- solvate
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- -1 carbamate compound Chemical class 0.000 title description 11
- 150000001875 compounds Chemical class 0.000 claims abstract description 42
- 208000010110 spontaneous platelet aggregation Diseases 0.000 claims abstract description 24
- 150000003839 salts Chemical class 0.000 claims abstract description 13
- 239000003814 drug Substances 0.000 claims abstract description 11
- 239000012453 solvate Substances 0.000 claims abstract description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 11
- 230000001154 acute effect Effects 0.000 claims description 10
- 210000004556 brain Anatomy 0.000 claims description 5
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 208000011580 syndromic disease Diseases 0.000 claims description 4
- 230000001732 thrombotic effect Effects 0.000 claims description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 3
- 201000001320 Atherosclerosis Diseases 0.000 claims description 3
- 201000010099 disease Diseases 0.000 claims description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 2
- 229910002651 NO3 Inorganic materials 0.000 claims description 2
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 claims description 2
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 2
- 229910019142 PO4 Inorganic materials 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 2
- 229940072107 ascorbate Drugs 0.000 claims description 2
- 235000010323 ascorbic acid Nutrition 0.000 claims description 2
- 239000011668 ascorbic acid Substances 0.000 claims description 2
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- 229940077388 benzenesulfonate Drugs 0.000 claims description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 2
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- GKTWGGQPFAXNFI-HNNXBMFYSA-N clopidogrel Chemical compound C1([C@H](N2CC=3C=CSC=3CC2)C(=O)OC)=CC=CC=C1Cl GKTWGGQPFAXNFI-HNNXBMFYSA-N 0.000 description 8
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- GNHHCBSBCDGWND-KRWDZBQOSA-N methyl (2s)-2-(2-acetyloxy-6,7-dihydro-4h-thieno[3,2-c]pyridin-5-yl)-2-(2-chlorophenyl)acetate Chemical compound C1([C@H](N2CC=3C=C(OC(C)=O)SC=3CC2)C(=O)OC)=CC=CC=C1Cl GNHHCBSBCDGWND-KRWDZBQOSA-N 0.000 description 5
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- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
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- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
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- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
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- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
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- 206010002091 Anaesthesia Diseases 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 2
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- QGMRQYFBGABWDR-UHFFFAOYSA-M Pentobarbital sodium Chemical compound [Na+].CCCC(C)C1(CC)C(=O)NC(=O)[N-]C1=O QGMRQYFBGABWDR-UHFFFAOYSA-M 0.000 description 2
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- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 2
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- CWUDNVCEAAXNQA-AWGNNQSZSA-N (2z)-2-[1-[(1s)-1-(2-chlorophenyl)-2-methoxy-2-oxoethyl]-4-sulfanylpiperidin-3-ylidene]acetic acid Chemical compound N1([C@H](C(=O)OC)C=2C(=CC=CC=2)Cl)CCC(S)\C(=C/C(O)=O)C1 CWUDNVCEAAXNQA-AWGNNQSZSA-N 0.000 description 1
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 1
- JXRGUPLJCCDGKG-UHFFFAOYSA-N 4-nitrobenzenesulfonyl chloride Chemical compound [O-][N+](=O)C1=CC=C(S(Cl)(=O)=O)C=C1 JXRGUPLJCCDGKG-UHFFFAOYSA-N 0.000 description 1
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- AFCARXCZXQIEQB-UHFFFAOYSA-N N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CCNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 AFCARXCZXQIEQB-UHFFFAOYSA-N 0.000 description 1
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- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
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- 230000008588 hemolysis Effects 0.000 description 1
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- WICNYNXYKZNNSN-UHFFFAOYSA-N hydron;4-methylpiperazine-1-carbonyl chloride;chloride Chemical compound Cl.CN1CCN(C(Cl)=O)CC1 WICNYNXYKZNNSN-UHFFFAOYSA-N 0.000 description 1
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- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
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- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
- C07B59/002—Heterocyclic compounds
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Abstract
The invention relates to an anti-platelet aggregation medicine and application thereof. The medicine is a compound with a structure shown in a formula I, or pharmaceutically acceptable salt, solvate or deuterated compound thereof; the compound has obvious platelet aggregation resisting effect, proper water solubility and good stability, and is expected to become a new kind of injectable platelet aggregation resisting medicine.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a carbamate compound and application of the carbamate compound in preparation of anti-platelet aggregation medicines.
Background
Platelet aggregation is known in the art to cause a range of cardiovascular and cerebrovascular and other arterial circulatory disorders, including (1) Acute Coronary Syndrome (ACS), such as Unstable Angina (UA), acute ST elevation myocardial infarction (STEMI), and acute non-ST elevation myocardial infarction (NSTEMI); (2) Atherosclerosis diseases such as myocardial infarction, ischemic stroke, peripheral arterial disease; (3) thrombotic complications, etc. Aiming at the current anti-platelet aggregation medicine, clopidogrel is of great concern because of the small bleeding risk, but the effect time and application scene of the medicine, such as acute thrombus, are greatly limited because of the phenomenon of 'clopidogrel resistance'. Although the prior art also tries to prepare injection formulations of clopidogrel in order to achieve rapid onset of action and overcome the defects of slow onset of action in acute treatment environments, such as ASD-002 nanoemulsion from ascndia corporation, MDCO-157 (cyclodextrin inclusion) injection from CyDex corporation and JIN-2013 nanoliposome injection from Jina Pharmaceuticals corporation; however, the problems of solubility of clopidogrel, water, light and heat stability have all been failed. In addition, the clopidogrel metabolic intermediate 2-oxo clopidogrel developed by Chengdu Shi Beikang biological medicine technology Co., ltd, although overcoming the adverse reaction of 'clopidogrel resistance', has the advantages of quick effect, higher bioavailability and the like; however, in the research, 2-oxo clopidogrel still has the defect of instability in water, and has great challenges and limitations for development into injection dosage forms. Therefore, the development of the intermediate metabolite 2-oxoclopidogrel derivative has attracted extensive attention from the society.
Currently, only Vicagrel in 2-oxoclopidogrel-based prodrug molecules is in the clinic and is in tablet form. However, in comparative studies, the Vicagrel still has a plurality of limitations, such as unsatisfactory solubility, thermal stability and the like, and the administration form and clinical application scene of the Vicagrel are also limited to a great extent.
In conclusion, development of a prodrug molecule capable of continuously releasing clopidogrel active metabolite component (H4) for a long time in vivo and having good water solubility and stability, and solving the characteristic that clopidogrel is not injectable, is a difficult problem to be solved clinically at present.
Disclosure of Invention
An object of the present invention is to provide a 2-oxoclopidogrel prodrug molecular compound having excellent solubility in water.
It is another object of the present invention to provide a method for preventing and treating heart, brain and other arterial circulatory disorders caused by platelet aggregation.
The technical scheme of the invention is as follows:
the invention provides a compound shown in a formula I, or pharmaceutically acceptable salt, solvate or deuterated compound thereof:
。
further, the pharmaceutically acceptable salts include fumarate, acetate, ascorbate, benzoate, benzenesulfonate, citrate, hydrochloride, hydrobromide, maleate, methanesulfonate, sulfate, bisulfate, nitrate, oxalate, phosphate, or succinate.
Further, the pharmaceutically acceptable salt is selected from hydrochloride, wherein the molar ratio of hydrochloric acid to the compound shown in formula I is 1:1 or 2:1.
the invention provides a pharmaceutical composition containing any one of the compounds, or pharmaceutically acceptable salts, solvates or deuterated compounds thereof, and the pharmaceutical composition also contains pharmaceutically acceptable auxiliary materials.
The invention also provides application of the compound or pharmaceutically acceptable salt, solvate or deuterated compound thereof in preparing medicaments for preventing and/or treating heart, brain and other arterial circulatory disorders caused by platelet aggregation.
Further, the above-mentioned diseases of heart, brain and other arterial circulatory disorders caused by platelet aggregation include, but are not limited to, acute coronary arterial syndrome, atherosclerosis diseases, or thrombotic complications.
Further, the above-mentioned acute coronary arterial syndrome includes, but is not limited to, angina pectoris or myocardial infarction.
Still further, the acute coronary arterial syndrome includes, but is not limited to, unstable Angina (UA), acute ST elevation myocardial infarction (STEMI), or acute non-ST elevation myocardial infarction (NSTEMI).
Further, the above-mentioned atherosclerotic diseases include, but are not limited to, myocardial infarction, ischemic stroke or peripheral arterial disease.
Still further, the ischemic stroke includes, but is not limited to, cerebral stroke.
Further, the thrombotic complications described above include, but are not limited to, pulmonary infarction.
The beneficial technical effects are as follows:
the compound of the invention has better in vitro efficacy and better pharmacokinetic characteristics. Specifically, the compound has strong platelet aggregation resisting effect, quick effect, high blood concentration and bioavailability of in vivo drug generations, longer half-life period and better drug effect. In addition, the compound disclosed by the invention has the advantages of good in-vitro solubility, high stability, small hemolysis risk, no cardiotoxicity, small vascular irritation risk and high safety, is more favorable for preparing injection and makes up for clinical defects.
Description of the embodiments
The present invention will be described in further detail with reference to the following examples and test examples, which are only for the purpose of illustrating the technical aspects of the present invention, but are not to be construed as limiting the present invention, and any equivalent substitution in the art according to the present disclosure is intended to be within the scope of the present invention.
The compounds of the present invention, stereoisomers or pharmaceutically acceptable salts thereof may be prepared by the synthetic routes of the examples, and the conventional conditions of the reaction starting materials and reaction solvents may be adjusted according to the substituents or salt-forming requirements, which may be accomplished by one skilled in the art based on the present disclosure. In addition, the column chromatography of the present invention refers to silica gel column chromatography unless otherwise specified, and the eluting solvent may be a single or mixed eluting solvent determined by combining the reaction solvent with common knowledge or common means of a person skilled in the art.
The structure of the compound is nuclear magnetic resonance 1 H NMR) or liquid mass spectrometry (LC-MS).
The liquid chromatography-mass spectrometer (LC-MS) is Agilent G6120B (matched with liquid phase Agilent 1260); nuclear magnetic resonance apparatus 1 H NMR) of Bruker AVANCE-400 or Bruker AVANCE-800, nuclear magnetic resonance 1 H NMR) shift [ ]δ) Given in parts per million (ppm), the assay solvent is DMSO-d 6 Or CDCl 3 The internal standard is Tetramethylsilane (TMS), and the chemical shift is 10 -6 (ppm) is given as a unit.
The term "room temperature" according to the invention means a temperature between 10 and 25 ℃.
Example 1: preparation of (S) -5- (1- (2-chlorophenyl) -2- (methoxy-d 3) -2-oxoethyl) -4,5,6, 7-tetrahydrothieno [3,2-c ] pyridin-2-yl [1,4 '-dipiperidine ] -1' -carboxylate (Compound 1)
Step 1: preparation of (R) -2- (2-chlorophenyl) -2-hydroxyacetic acid methyl-d 3-ester (intermediate b)
4g of (R) -o-chloromandelic acid was put into a 50mL three-necked flask at room temperature, 12mL of anhydrous deuterated methanol was added thereto, and the mixture was stirred and dissolved, followed by slowly adding 0.17g of concentrated sulfuric acid dropwise. After the dripping, the mixture was heated in an oil bath to raise the temperature to 78℃and refluxed for 2 hours. The reaction was monitored by TLC (developing reagent: ethyl acetate/petroleum ether=1/3, development under a 254nm UV lamp). The mixture was concentrated under reduced pressure at 45℃to remove methanol, and 12mL of ethyl acetate was added to the residue and dissolved with stirring. The ethyl acetate layer was washed twice with 10mL of x 2 water, then with 10mL of saturated sodium hydrogencarbonate and 10mL of saturated brine, respectively, and the ethyl acetate layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure at 45℃to remove ethyl acetate, yielding 0.415g of a yellowish transparent oily liquid as intermediate b. Yield: 95.1%.
ESI-MS: m/z = 204.1(M+H) + 。
1 HNMR (400 MHz, CDCl 3 ) δ:7.4 (m,1H),7.35 (m, 1H), 7.23 (m, 2H), 5.58 (s, 1H) , 4.06 (brs, 1H)。
Step 2: preparation of methyl-d 3-ester of (R) -2- (2-chlorophenyl) -2- (((4-nitrophenyl) sulfonyl) oxy) acetate (intermediate d)
4.15g of intermediate I and 15mL of methylene dichloride are put into a 30mL single-port bottle at room temperature, stirred and dissolved in an ice bath, 2.51g of triethylamine is added, the temperature is reduced, and the internal temperature is controlled to be not higher than 5 ℃. 4.35g of p-nitrobenzenesulfonyl chloride dissolved in 15mL of methylene chloride was slowly dropped into the vessel at a constant pressure, and after the dropping was completed, the ice bath was maintained for 0.5 hour. The reaction was quenched by dropping 4M glacial hydrochloric acid 5mL in a constant pressure dropping funnel under ice bath, and the system was vigorously stirred until it became bright yellow, and then stopped, and the solution was separated. The dichloromethane layer was washed with 10mL of water, 10 mL. Times.2 saturated brine, and concentrated under reduced pressure at 35℃to remove dichloromethane to give crude intermediate d as a yellow paste. The crude product was poured into a 50mL beaker and slurried with 10mL of ice methanol under an ice bath for 0.5 hour, during which time a large amount of white solid precipitated. The solid was filtered to give 5.61g of a white powdery solid as intermediate d in a yield of 70.8%. .
ESI-MS: m/z = 389.1(M+H) + 。
1 HNMR (400 MHz, CDCl 3 ) δ: 8.31 (d, J = 8.9 Hz，2H),8.07 (d，J = 8.9 Hz, 2H), 7.31 (m, 4H), 6.39 (s, 1H)。
Step 3: preparation of methyl-d 3-ester of (S) -2- (2-chlorophenyl) -2- ((S) 2-oxo-2, 6,7 a-tetrahydrothieno [3,2-c ] pyridin-5 (4H) -yl) acetate (intermediate f)
The reaction: 5.61g of intermediate b,3.19g of compound e,5.39g of anhydrous sodium carbonate and 100mL of acetonitrile are placed in a 200mL three-necked flask at room temperature, the temperature is raised to 38℃and the reaction is vigorously stirred under nitrogen for 5 hours. The reaction solution was filtered through celite, and concentrated under reduced pressure at an external temperature of 45℃to remove acetonitrile. The residue was dissolved in 20mL of methylene chloride, and the methylene chloride layers were washed with 10 mL. Times.2 water and 10mL of saturated brine, respectively, and separated. Filtering, concentrating the filtrate under reduced pressure to obtain partially crystallized brown cream semisolid 4.18g, putting 4.18g of sbk002 crude product and 10mL of acetone into a 20mL beaker at 60 ℃ in water bath, and fully stirring for 10 minutes. Basically dissolving, filtering while the solution is hot, crystallizing to obtain 2.95g of white crystalline powder with the yield of 60.0%.
ESI-MS: m/z = 341.1(M+H) + 。
Step 4: preparation of (S) -5- (1- (2-chlorophenyl) -2- (methoxy-d 3) -2-oxoethyl) -4,5,6, 7-tetrahydrothieno [3,2-c ] pyridin-2-yl [1,4 '-dipiperidine ] -1' -carboxylate (Compound 1)
To a 50ml three-necked flask were added intermediate f (1 g,3 mmol) and 4-methylpiperazine-1-carbonyl chloride hydrochloride (884 mg,4.44 mmol), DMF (20 ml), stirred and cooled to 0℃and DBU (1.37 g,9 mmol) was added dropwise. After the completion of the dropwise addition, the reaction was completed at room temperature for 2 hours. EA was added, washed twice with water and once with brine. Anhydrous Na for organic phase 2 SO 4 Dried and concentrated. ConcentrateThe product was collected by separation and purification using a column, and concentrated to give 1.2g of compound 1 in a yield of 87.6% and a purity of 98.34%.
ESI-MS: m/z = 535.2(M+H) + 。
1 HNMR (400 MHz, DMSO-d6) δ: 7.52～7.43 (m, 1H), 7.43～7.34 (m, 1H), 7.32～ 7.21 (m, 2H), 6.29 (s, 1H), 4.75 (d, 1H), 3.90 (d, 2H), 3.69～ 3.59 (m, 2H), 3.39 (m, 2H), 3.15～3.08 (m, 1H), 3.02 (t, 1H), 2.91 (t, 2H), 2.68 (m, 2H), 2.39 (q, 1H), 2.31 (m, 2H), 1.74～1.37 (m, 10H)。
Example 2: preparation of (S) -5- (1- (2-chlorophenyl) -2-methoxy-2-oxoethyl) -4,5,6, 7-tetrahydrothieno [3,2-c ] pyridin-2-yl 4-methylpiperazine-1-carboxylate fumarate (Compound 2)
To a 25ml flask was added (S) -5- (1- (2-chlorophenyl) -2- (methoxy-d 3) -2-oxoethyl) -4,5,6, 7-tetrahydrothieno [3,2-c ] pyridin-2-yl-4-methylpiperazine-1-carboxylate (1 g,1.87 mmol), EA (2.5 ml) was added to dissolve, and 1.87mmol hydrochloric acid was added to stir and a large amount of solid was precipitated. After stirring for 3h, filtration and drying gave the title compound 671 mg. The yield was 62.7% and the purity was 98.75%.
ESI-MS: m/z = 535.2(M+H) + 。
1 HNMR (400 MHz, DMSO-d6) δ: 7.58～7.46 (m, 1H), 7.46～7.34 (m, 1H), 7.39～ 7.24 (m, 2H), 6.29 (s, 1H), 4.75 (d, 1H), 3.90 (d, 2H), 3.71～3.60 (m, 2H), 3.35 (m, 2H), 3.15～3.08 (m, 1H), 3.02 (t, 1H), 2.91 (t, 2H), 2.68 (m, 2H), 2.39 (q, 1H), 2.31 (m, 2H), 1.74～1.37 (m, 10H)。
Comparative example 1: 2-Oxoclopgrel (metabolic intermediate in clopidogrel activation process)
Chengdu Shi Beikang, manufactured by biomedical technologies, inc., ee=98.8%.
Comparative example 2: vicagrel (in clinical research)
Prepared according to CN201010624329.7, purity 98.22%.
Test example 1: anti-platelet aggregation study
Test purpose: the therapeutic effect of each compound against platelet aggregation after equimolar administration was evaluated and compared.
Test method
(1) Grouping
The 40 rats were randomly and evenly divided into 4 groups: solvent control group, comparative example 1 (2-oxoclopidogrel), comparative example 2 (vicagrel) and compound 1.
(2) Anesthesia induction
Rats were anesthetized by intraperitoneal injection with 1.5% sodium pentobarbital.
(3) Fixing
The anesthetized animals were transferred to the console and observed for palpebral reflex and pain response in rats, and surgery was initiated after palpebral reflex and pain response in the extremities and tail had disappeared.
(4) Blood is taken from abdominal aorta of rat
After anesthetic is injected, the rat can be fixed on the operating table on the back until the whole body becomes soft, the abdominal cavity is cut off along the abdominal midline by using surgical scissors after conventional sterilization, fat around blood vessels is gently scraped off by using small forceps, and the superfluous fat covered on the blood vessels is wiped off by using cotton balls until the blood vessels are clearly seen (abdominal aorta is positioned above the spinal column; abdominal vein blood vessels are thicker than abdominal aorta and have darker color). The blood vessel is fixed firstly, the displacement of the blood vessel is avoided as much as possible, the fat and other viscera at the two sides of the blood vessel are fixed by the thumb and the index finger of the left hand, the upper end of the needle inlet point of the blood vessel is pressed by the ring finger, the blood pressure is reduced, the blood injection can be avoided, the right hand holds the puncture needle, the inclined plane of the needle point faces downwards, the needle inlet angle is about 30 degrees, the needle end is penetrated towards the direction of the heart end, the depth is preferably about 5mm, and the other end of the blood taking needle is penetrated into the vacuum tube after the blood returns. After the needle is inserted, the hemostatic clamp can be used for clamping the needle head, so that the phenomenon that blood vessels are punctured by the needle head due to insufficient struggling of anesthesia can be avoided.
(5) Platelet preparation
3 hours after administration, the rats are anesthetized by pentobarbital sodium, then the abdominal aorta is sampled, 3.8% sodium citrate is anticoagulated 1:9, and after uniform mixing, the rats are centrifuged for 10 minutes by 200 g, and the supernatant is Platelet Rich Plasma (PRP); the remaining plasma was centrifuged at 1600 a g a for 15min and the supernatant was taken as Platelet Poor Plasma (PPP).
(6) ADP-induced platelet aggregation
Platelet aggregation rate was measured using a platelet aggregation meter (model: agg RAM, halna, usa): the PPP corresponding to the PRP to be measured in each channel is firstly taken for light transmittance correction, PPP is taken out after correction, then a cuvette with 225 mu l of PRP to be measured is put into each channel, a stirrer is added, ADP (final concentration is 20 mu M) is added, and platelet aggregation rate detection is immediately started.
Test results
Platelet aggregation rate data for each group after equimolar administration are detailed in table 1.
The results show that: (1) the platelet aggregation ratio (%) of the solvent control group was: 76.06 + -3.29; the platelet aggregation rates (%) of the comparative example 1 group, the comparative example 2 group and the compound 1 group are 31.32 +/-6.07, 39.32 +/-12.38 and 20.06+/-5.32 respectively, and each administration group has obvious effect of inhibiting the platelet aggregation of rats induced by ADP (P is less than 0.01) compared with the solvent control group.
(2) Compared with the group 2 of the comparative example, the group 1 of the compound has significant advantage (P < 0.01) in inhibiting the ADP-induced platelet aggregation of rats, and has statistical significance.
(3) From the test results, the effect of the compound 1 in inhibiting the ADP-induced platelet aggregation of rats is obviously superior to that of the compound of the comparative example 2 and is also obviously superior to that of the compound of the comparative example 1 after single intravenous injection administration at the same dosage.
Test example 2: effect of Compounds on stable over-expressed hERG channel currents
Test sample
Compound 1, control compound Cisapride.
Test method
The inhibition of hERG potassium channel by test compound 1 was studied using manual patch clamp technique (gold standard for hERG safety assessment) and evaluated for risk of eliciting ventricular repolarization toxicity.
Test results
The present study utilizes manual patch clamp technique to detect the concentration effect relationship of blocking effect of test compound 1 on hERG channels, thereby evaluating the risk of test compound on cardiac hERG potassium channel inhibition. The test results are shown in Table 2.
The test results show that the compound of the invention has small risk of inducing ventricular repolarization toxicity and high safety.
Test example 3: pharmacokinetic studies
Purpose of test
The pharmacokinetic profile of each compound after a single intragastric administration in rats was examined at equimolar doses and compared to the prevailing pharmacokinetic parameters.
Materials and methods
(1) Test article
Comparative example 1 (2-oxoclopidogrel), compound 1.
(2) Formulation of the administration preparation
Respectively and accurately weighing the tested compounds in a clean administration container, adding a proper amount of Solutol for dissolution, carrying out vortex vibration, adding pure water, carrying out ultrasonic treatment, and carrying out vortex vibration until the compounds are completely dissolved; the administration formulations were all freshly prepared on the day of administration.
(3) Test group and dosing regimen
12 healthy adult SD rats were given by gavage. The specific scheme is shown in Table 3.
(4) Test method
Grouping and fasted: SD rats, randomly grouped, 6 per group, were given the corresponding compounds by gavage according to table 3.
Sample collection and processing: blood is collected for 0.2 ml at different time points for 5min, 15min, 30 min, 1 h, 2h, 4h, 8h and 24h before administration (0 h), and after anticoagulation with EDTA-K2, centrifugation is carried out at 4deg.C for 5min, and the separated blood plasma is stored at-80deg.C for testing.
And (3) detection: the plasma concentrations of 2-oxoclopidogrel in all PK plasma samples were detected by LC/MS method and pharmacokinetic parameters of each compound were calculated using winnonlin7.2 software.
Test results
After equimolar administration, T of Compound 1 is compared to Compound 1 of comparative example 1 1/2 、C max And AUC 0-last Has obvious extension and improvement, has statistical significance and P<0.01. It was demonstrated that the absorption of compound 1 in rats was significantly better than that of the compound of comparative example 1, with better pharmacokinetic profile.
In conclusion, the compound of the invention has better absorption and high bioavailability, and is expected to fully exert the drug effect.
Test example 4: solubility study
Samples of example 2 and comparative example 2 (Visugrel) were accurately weighed, 1ml each of the samples was taken with physiological saline and buffer solution of pH1.2 at 25-30℃and each of the samples was added with 10 mg, and solubility data were measured as shown in the following table: the compound 2 of the invention has excellent solubility, can meet the requirement of injection prepared into effective concentration clinically, and the solubility of the comparative example 2 is extremely low, does not meet the requirement of injection, and can bring potential safety risk if other cosolvent is added.
。
Test example 5: influence factor test study
The test method comprises the following steps: the compound 2 and comparative example 2 (Visugrel) samples were weighed separately and placed in weighing flasks under high temperature (60 ℃), high humidity (RH 80%) and light (5000 Lux) conditions, respectively.
The test results for compound 2 are shown in the following table: the compound 2 has small content change, no obvious change in appearance shape and good stability under the conditions of high temperature, high humidity and illumination for 10 days.
Whereas comparative example 2 was left at high temperature (60 ℃) for two days, the behavior changed significantly from a white solid to a yellowish brown oil, indicating poor stability of comparative example 2 at high temperature. In summary, the compounds of the present invention have warm, wet, light stability and are superior to comparative example 2.
Numerous modifications and variations may be made to the compounds, compositions, and methods of the present invention by those of ordinary skill in the art without departing from the spirit of the invention, which fall within the same or equivalent scope of the invention.
Claims (6)
1. A compound of formula I, or a pharmaceutically acceptable salt, solvate or deuterated thereof:
。
2. the compound of claim 1, or a pharmaceutically acceptable salt, solvate, or deuterated thereof, wherein the pharmaceutically acceptable salt comprises a fumarate, acetate, ascorbate, benzoate, benzenesulfonate, citrate, hydrochloride, hydrobromide, maleate, methanesulfonate, sulfate, bisulfate, nitrate, oxalate, phosphate, or succinate.
3. The compound of claim 2, or a pharmaceutically acceptable salt, solvate or deuterated thereof, wherein the compound is selected from the group consisting of hydrochloride salts wherein the molar ratio of hydrochloric acid to the compound of formula I is 1:1 or 2:1.
4. a pharmaceutical composition comprising a compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, solvate or deuterated thereof, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable adjuvant.
5. The use of a compound according to claims 1-3, or a pharmaceutically acceptable salt, solvate or deuterate thereof, for the manufacture of a medicament for the prevention and/or treatment of heart, brain and other arterial circulatory disorders caused by platelet aggregation.
6. The use according to claim 5, wherein the diseases of heart, brain and other arterial circulatory disorders caused by platelet aggregation include, but are not limited to, acute coronary arterial syndrome, atherosclerosis diseases, or thrombotic complications.
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