CN111320662A - N-benzyl substituted diamidinonazine derivative and pharmaceutical application thereof - Google Patents
N-benzyl substituted diamidinonazine derivative and pharmaceutical application thereof Download PDFInfo
- Publication number
- CN111320662A CN111320662A CN202010096598.4A CN202010096598A CN111320662A CN 111320662 A CN111320662 A CN 111320662A CN 202010096598 A CN202010096598 A CN 202010096598A CN 111320662 A CN111320662 A CN 111320662A
- Authority
- CN
- China
- Prior art keywords
- diamidinonazine
- protein
- ace2
- benzyl substituted
- derivative
- 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.)
- Granted
Links
- 108090000975 Angiotensin-converting enzyme 2 Proteins 0.000 claims abstract description 32
- 102000053723 Angiotensin-converting enzyme 2 Human genes 0.000 claims abstract description 30
- 239000003814 drug Substances 0.000 claims abstract description 21
- IWUCXVSUMQZMFG-AFCXAGJDSA-N Ribavirin Chemical group N1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 IWUCXVSUMQZMFG-AFCXAGJDSA-N 0.000 claims abstract description 12
- 229960000329 ribavirin Drugs 0.000 claims abstract description 12
- HZCAHMRRMINHDJ-DBRKOABJSA-N ribavirin Natural products O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1N=CN=C1 HZCAHMRRMINHDJ-DBRKOABJSA-N 0.000 claims abstract description 12
- 230000009385 viral infection Effects 0.000 claims abstract description 7
- 208000036142 Viral infection Diseases 0.000 claims abstract description 6
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 2
- 230000001419 dependent effect Effects 0.000 claims 2
- 239000004480 active ingredient Substances 0.000 claims 1
- 230000003993 interaction Effects 0.000 abstract description 11
- 229940079593 drug Drugs 0.000 abstract description 9
- 150000001875 compounds Chemical class 0.000 description 17
- 210000004072 lung Anatomy 0.000 description 14
- 229940096437 Protein S Drugs 0.000 description 11
- 102100031673 Corneodesmosin Human genes 0.000 description 9
- 241000711573 Coronaviridae Species 0.000 description 9
- 108010031318 Vitronectin Proteins 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
- 229940125904 compound 1 Drugs 0.000 description 8
- 239000008280 blood Substances 0.000 description 7
- 210000004369 blood Anatomy 0.000 description 7
- 238000003032 molecular docking Methods 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 229940125782 compound 2 Drugs 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 210000004185 liver Anatomy 0.000 description 4
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 229910019142 PO4 Inorganic materials 0.000 description 3
- 101000629318 Severe acute respiratory syndrome coronavirus 2 Spike glycoprotein Proteins 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 125000004185 ester group Chemical group 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 239000010452 phosphate Substances 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 102000005962 receptors Human genes 0.000 description 3
- 230000008685 targeting Effects 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- WHTVZRBIWZFKQO-AWEZNQCLSA-N (S)-chloroquine Chemical compound ClC1=CC=C2C(N[C@@H](C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-AWEZNQCLSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- YBAZINRZQSAIAY-UHFFFAOYSA-N 4-aminobenzonitrile Chemical compound NC1=CC=C(C#N)C=C1 YBAZINRZQSAIAY-UHFFFAOYSA-N 0.000 description 2
- 102100030988 Angiotensin-converting enzyme Human genes 0.000 description 2
- 102100035765 Angiotensin-converting enzyme 2 Human genes 0.000 description 2
- 208000001528 Coronaviridae Infections Diseases 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- KJHKTHWMRKYKJE-SUGCFTRWSA-N Kaletra Chemical compound N1([C@@H](C(C)C)C(=O)N[C@H](C[C@H](O)[C@H](CC=2C=CC=CC=2)NC(=O)COC=2C(=CC=CC=2C)C)CC=2C=CC=CC=2)CCCNC1=O KJHKTHWMRKYKJE-SUGCFTRWSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 101710198474 Spike protein Proteins 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 229960003677 chloroquine Drugs 0.000 description 2
- WHTVZRBIWZFKQO-UHFFFAOYSA-N chloroquine Natural products ClC1=CC=C2C(NC(C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-UHFFFAOYSA-N 0.000 description 2
- 238000005094 computer simulation Methods 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 208000019423 liver disease Diseases 0.000 description 2
- 229960004525 lopinavir Drugs 0.000 description 2
- 239000002207 metabolite Substances 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 2
- 229940002612 prodrug Drugs 0.000 description 2
- 239000000651 prodrug Substances 0.000 description 2
- 235000010288 sodium nitrite Nutrition 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- AMFDITJFBUXZQN-KUBHLMPHSA-N (2s,3s,4r,5r)-2-(4-amino-5h-pyrrolo[3,2-d]pyrimidin-7-yl)-5-(hydroxymethyl)pyrrolidine-3,4-diol Chemical compound C=1NC=2C(N)=NC=NC=2C=1[C@@H]1N[C@H](CO)[C@@H](O)[C@H]1O AMFDITJFBUXZQN-KUBHLMPHSA-N 0.000 description 1
- 238000004679 31P NMR spectroscopy Methods 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 206010003757 Atypical pneumonia Diseases 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 241001678559 COVID-19 virus Species 0.000 description 1
- 108010001857 Cell Surface Receptors Proteins 0.000 description 1
- 208000025370 Middle East respiratory syndrome Diseases 0.000 description 1
- 241000127282 Middle East respiratory syndrome-related coronavirus Species 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- CJBJHOAVZSMMDJ-HEXNFIEUSA-N darunavir Chemical compound C([C@@H]([C@H](O)CN(CC(C)C)S(=O)(=O)C=1C=CC(N)=CC=1)NC(=O)O[C@@H]1[C@@H]2CCO[C@@H]2OC1)C1=CC=CC=C1 CJBJHOAVZSMMDJ-HEXNFIEUSA-N 0.000 description 1
- 229960005107 darunavir Drugs 0.000 description 1
- 230000036267 drug metabolism Effects 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- WSFSSNUMVMOOMR-UHFFFAOYSA-N formaldehyde Substances O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 1
- 229950002031 galidesivir Drugs 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 238000000126 in silico method Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L magnesium sulphate Substances [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 102000006240 membrane receptors Human genes 0.000 description 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene chloride Substances ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 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 1
- 239000003208 petroleum Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- RWWYLEGWBNMMLJ-MEUHYHILSA-N remdesivir Drugs C([C@@H]1[C@H]([C@@H](O)[C@@](C#N)(O1)C=1N2N=CN=C(N)C2=CC=1)O)OP(=O)(N[C@@H](C)C(=O)OCC(CC)CC)OC1=CC=CC=C1 RWWYLEGWBNMMLJ-MEUHYHILSA-N 0.000 description 1
- RWWYLEGWBNMMLJ-YSOARWBDSA-N remdesivir Chemical compound NC1=NC=NN2C1=CC=C2[C@]1([C@@H]([C@@H]([C@H](O1)CO[P@](=O)(OC1=CC=CC=C1)N[C@H](C(=O)OCC(CC)CC)C)O)O)C#N RWWYLEGWBNMMLJ-YSOARWBDSA-N 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- NHKZSTHOYNWEEZ-AFCXAGJDSA-N taribavirin Chemical compound N1=C(C(=N)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 NHKZSTHOYNWEEZ-AFCXAGJDSA-N 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- KCFYEAOKVJSACF-UHFFFAOYSA-N umifenovir Chemical compound CN1C2=CC(Br)=C(O)C(CN(C)C)=C2C(C(=O)OCC)=C1CSC1=CC=CC=C1 KCFYEAOKVJSACF-UHFFFAOYSA-N 0.000 description 1
- 229960004626 umifenovir Drugs 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/056—Triazole or tetrazole radicals
-
- 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
- A61P31/12—Antivirals
-
- 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
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Virology (AREA)
- Molecular Biology (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Communicable Diseases (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- Genetics & Genomics (AREA)
- Engineering & Computer Science (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
N-benzyl substituted diamidinonazine derivative and its medicinal use, the structure is in accordance with general formula (I)
Wherein: r is ribavirin and Rudexilvir. The medicine can act on an interaction interface of the Spike and the ACE2 protein, and can be used for preparing medicines for treating viral infection depending on ACE2 enzyme.
Description
Technical Field
The invention belongs to the field of pharmacy, and provides an N-benzyl substituted diamidinonazine derivative and a pharmaceutical application thereof.
Background
Angiotensin converting enzyme 2(ACE enzyme 2) is a homologous protein of the ACE enzyme. Coronavirus such as novel coronavirus (SARS-CoV-2) and atypical pneumonia (SARS-CoV) and middle east respiratory syndrome (MERS-CoV) enter cells by taking ACE2 enzyme as a receptor, so that infection of coronavirus can be reduced if expression of ACE2 enzyme can be prevented, and unexpected toxic and side effects can be generated because ACE2 enzyme has important physiological function and expression of ACE2 enzyme is prevented.
Coronavirus is combined with host cell ACE2 protein through outer coating protein-spike protein (also called S-protein, coronavirus is invaded into cell by virtue of the binding of spike protein and host cell surface receptor), if the combination can be prevented, the coronavirus has good inhibitory effect, and ideal anti-coronavirus medicine is obtained.
The computer simulation technology is adopted to scan the known medicine, the stronger binding capacity of the diaminazine (diamazene) to the interaction interface of the S-protein and the ACE2 protein is found (the docking score 8.0891 is shown in table 1), and the compound LJ-01 (the docking score 8.3138 is shown in table 1) with stronger binding capacity to the interaction interface of the S-protein and the ACE2 protein is obtained for the structural modification of the diaminazine (diaminazine) so as to indicate that the LJ-01 can better interfere the interaction of the S-protein and the ACE2 protein.
The LJ-01 is linked with a medicament possibly effective to the coronavirus, and a novel compound resisting coronavirus infection, which has better binding capacity to an interaction interface of an S-protein and an ACE2 protein, is expected to be obtained, so that the targeting property of the compound is improved, and the medicament effect and the safety are improved. The drugs that may be effective against coronaviruses were selected: ribavirin (ribavirin), Galidesivir, Reindesivir (remdesivir), GS-441524 (Reindesivir is a phosphate prodrug of GS-441524), Abidol (arbidol), lopinavir (lopinavir), Darunavir (daronavir), chloroquine (chloroquine), and the like.
The LJ-01 and the antiviral drugs above are linked in an ester bond mode, the obtained compound is subjected to computer simulation on the binding capacity of the interaction interface of the S-protein and the ACE2 protein, and the binding capacity (docking score) of part of compounds shows remarkable improvement (see table 1). Wherein LJ-01, ribavirin and Reidexilvir are linked in an ester group mode, and the binding capacity of the obtained compounds LJ-02 and LJ-04 (shown in Table 1: docking scores: 10.0797 and 10.5261) is remarkably improved, which indicates that the 2 compounds have stronger binding capacity on an interaction interface of S-protein and ACE2 protein.
Considering that Reidesciclovir is a phosphate prodrug of GS-441524, we linked LJ-01 and GS-441524 in an ester group manner, the binding capacity of the obtained compound did not show a significant improvement (see Table 1: LJ-10 docking score: 8.1196), and the binding capacity of the obtained compound LJ-09, which is also not shown to be significantly improved compared with LJ-02, by linking LJ-01 and a phosphate prodrug of ribavirin in an ester group manner (see Table 1: LJ-09 docking score: 9.0412). Indicating that this link is specific.
Preliminary in vivo drug metabolism studies showed that the target compounds obtained had better distribution in the lungs with high expression of ACE2 protein. Considering that the target compound can better interfere the interaction of the S-protein and the ACE2 protein, thereby reducing the infection of coronavirus, the medicine has better efficacy and safety.
Disclosure of Invention
The technical problem to be solved is as follows: the N-benzyl substituted diamidinonazine derivatives can act on an interaction interface of Spike and ACE2 protein, increase the distribution of the drugs in high-expression lung of ACE2 protein, and can be used for preparing drugs for treating virus infection depending on ACE2 enzyme.
The technical scheme is as follows: a kind of N-benzyl substituted diamidinonazine derivative, the structure is in accordance with the general formula (I)
The preferred structure is as follows:
the application of the N-benzyl substituted diamidinonazine derivatives in preparing medicaments for treating viral infection depending on ACE2 enzyme.
The medicine for treating viral infection depending on ACE2 enzyme has the effective component of N-benzyl substituted diamidinonazine derivative or its pharmaceutically acceptable salt.
Has the advantages that: the medicine can act on an interaction interface of the Spike and the ACE2 protein, increases the distribution of the medicine in the high-expression lung of the ACE2 protein, and can be used for preparing medicines for treating viral infection depending on the ACE2 enzyme.
Drawings
FIG. 1 is a graph showing the binding pattern of 2019-nCoV S protein and the receptor ACE2 protein obtained by homology modeling. The dark color is the 2019-nCoV S protein (left), the light color is ACE2 (right), and the linker is an interacting residue in both proteins (central cavity).
Detailed Description
The following examples are given to enable a person skilled in the art to fully understand the invention, but do not limit it in any way.
Example 1 in silico screening of compounds for binding ability to the interaction interface of S-protein and ACE2 protein:
the binding mode of 2019-nCoV S protein and the receptor ACE2 protein obtained by homologous modeling is adopted. The residues that interact in both proteins of the compound and the binding pattern were docked and scored. The scoring results are shown in Table 1
Example 2 synthesis of the target Compound 2.1 synthetic route for the key intermediate M-01:
the operation is as follows:
in a 100m L eggplant-shaped bottle, 11.8g (0.1mol) of p-aminobenzonitrile, 200mL of absolute ethanol, and 15.0g (0.1mol) of 3-formaldehyde benzoic acid were added and reacted at 50 ℃ for 4 hours. Filtering, dispersing the solid by 200mL of absolute ethyl alcohol, adding 5.0g of sodium borohydride in batches at 0 ℃, and reacting for 1h at 50 ℃ after the addition is finished. Adjusting pH to 3-5 with hydrochloric acid, filtering, adding 20mL of water into the filtrate, and filtering to collect solid.
100mL of water was added to the solid, and 20g of concentrated sulfuric acid and 20g of sodium nitrite were added at-5 to 0 ℃ to react at-5 to 0 ℃ for 1 hour. Sodium sulfite was added to eliminate the remaining sodium nitrite, 11.8g (0.1mol) of p-aminobenzonitrile was added dropwise, and the reaction was continued for 2 hours. Filtering to obtain solid. Adding 20mL of absolute ethyl alcohol and 10mL of 37% hydrochloric acid into the solid, reacting at room temperature for 10 hours, adding 20mL of ammonia water, reacting at-5-0 ℃ for 24 hours, reacting at room temperature for 48 hours, introducing hydrogen chloride at 0 ℃ until no solid is generated, and filtering to obtain a key intermediate M-01.
M-01：1H NMR(400MHz,DMSO-d6)δ(ppm)8.48(s,1H)，8.37(s,1H)，7.92-7.66(m，10H)，4.24(s，2H)
2.2 Synthesis of target Compound 1:
the synthetic route is as follows:
the operation is as follows:
100m L A eggplant-shaped bottle was charged with 2.44g (10mmol) of ribavirin and anhydrous CH2Cl2100M L, ice bath, 5.63g (1.0mmol) of M-01 were added. DCC 2.4g (11.1mmol) dissolved in 50mL of anhydrous CH was added dropwise at 0 deg.C2Cl2After 1 hour of ice-bath reaction, 1.0g of DMAP was added and the reaction was carried out at room temperature for 12 hours. The precipitated DCU was filtered off, the solvent was evaporated off, and 100mL of ethyl acetate was added to dissolve it, and 5% NaHCO was used for each3Washing, washing with 5% citric acid, washing with saturated NaCl and anhydrous MgSO4And (5) drying. The solvent was evaporated off. And (4) performing column chromatography (petroleum ether-EtAc is 4: 1) to obtain the target compound 1.
Target compound 1:1H NMR(400MHz,DMSO-d6)δ(ppm)8.87(s,1H)，8.45(s,1H)，8.32(s,1H)，7.90-7.62(m，12H)，5.81(d,1H)，5.58(d,1H)，5.19(d,1H)，4.92(t,1H)，4.37-4.33(m，1H)，4.16-4.11(m，1H)，4.25(s，2H)，3.97-3.93(m，1H)，3.66-3.15(m，1H)，3.50-3.47(m，1H)
2.3 Synthesis of target Compound 2:
referring to the method of the target compound 1, the synthesis is carried out by using the Rudexilvir and the key intermediate M-01.
Target compound 2:1H NMR(400MHz,DMSO-d6)δ(ppm)：8.46(s,1H)，8.36(s,1H)，7.92-7.65(m，11H)，7.34-7.26(m,2H),7.21-7.11(m,3H),6.92(d,1H),6.88(d,1H),4.79(d,1H),4.43-4.33(m,2H),4.30-4.27(m,1H),4.24(s，2H)，4.17(t,1H),4.03-4.01(m,1H),3.98-3.84(m,2H),1.49–1.40(m,1H),1.35–1.27(m,8H),0.85(t,6H),0.72(d,3H),.31P NMR(162MHz,DMSO-d6)δ(ppm)3.66(s)
example 3: investigation of distribution of target compounds in animals
SPF grade SD rats, 6-8 weeks old, 180 g in weight, male, were injected intravenously with the target compound 1(12.8mg/kg, 2.0mmol/L) and 1 hour after administration, blood concentration and concentration in lung tissue were measured with ribavirin as a reference (4.88mg/kg, 2.0 mmol/L).
TABLE 2 comparison of ribavirin concentrations in blood, liver, and lungs 1 hour after intravenous administration of target Compound 1 (ribavirin as a control)
| Compound numbering | Blood, blood-enriching agent and method for producing the same | Liver disease | Lung (lung) |
| 1 | 0.6 | 0.7 | 2.8 |
| Ribavirin | 1.0 | 1.0 | 1.0 |
The above experimental results show that: after the target compound 1 is injected, compared with the ribavirin injection, the concentration degree of the drug in blood and liver is obviously reduced, and the drug concentration in lung tissue is obviously increased. The target compound 1 is proved to have a targeting effect on the lung with high expression of ACE2 enzyme.
The distribution of the target compound 2 in the animal body is investigated by the same method, and the results are shown in Table 3
Table 3 comparison of the concentrations of Reidesciclovir (containing its metabolites) in blood, liver and lung 1 hour after intravenous administration of object compound 2 (Redesciclovir as control)
| Compound numbering | Blood, blood-enriching agent and method for producing the same | Liver disease | Lung (lung) |
| 1 | 0.5 | 0.6 | 3.2 |
| Reidesciclovir and metabolites thereof | 1.0 | 1.0 | 1.0 |
The above experimental results show that: after the injection of the target compound 2, compared with the direct injection of the Reidesvir, the concentration of the drug in blood and liver is obviously reduced, and the concentration of the drug in lung tissue is obviously increased. The target compound 1 has a targeting effect on the lung with high expression of ACE2 enzyme.
Claims (4)
1. The N-benzyl substituted diamidinonazine derivative is characterized in that the structure conforms to the general formula (I)
2. A class of N-benzyl substituted diamidinonazine derivatives according to claim 1, characterized by the preferred structure as shown below:
3. use of a class of N-benzyl substituted diamidinonazine derivatives as claimed in claim 1 or claim 2 in the manufacture of a medicament for the treatment of ACE2 enzyme dependent viral infections.
4. A medicament for the treatment of ACE2 enzyme dependent viral infections characterized in that the active ingredient is a class of N-benzyl substituted diamidinonazine derivatives according to claim 1 or 2 or a pharmaceutically acceptable salt thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010096598.4A CN111320662B (en) | 2020-02-17 | 2020-02-17 | N-benzyl substituted diamidinonazine derivative and pharmaceutical application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010096598.4A CN111320662B (en) | 2020-02-17 | 2020-02-17 | N-benzyl substituted diamidinonazine derivative and pharmaceutical application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN111320662A true CN111320662A (en) | 2020-06-23 |
| CN111320662B CN111320662B (en) | 2022-11-25 |
Family
ID=71172104
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010096598.4A Active CN111320662B (en) | 2020-02-17 | 2020-02-17 | N-benzyl substituted diamidinonazine derivative and pharmaceutical application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN111320662B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111766317A (en) * | 2020-07-02 | 2020-10-13 | 盐城师范学院 | Method for measuring GS-441524 content in preparation by using polyethylene glycol and water |
Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3984396A (en) * | 1971-06-01 | 1976-10-05 | Icn Pharmaceuticals, Inc. | 1-(β,-D-ribofuranosyl)-1,2,4-triazole acid esters |
| US20020055473A1 (en) * | 2000-04-20 | 2002-05-09 | Ganguly Ashit K. | Ribavirin-interferon alfa combination therapy for eradicating detectable HCV-RNA in patients having chronic hepatitis C infection |
| US6403564B1 (en) * | 1998-10-16 | 2002-06-11 | Schering Corporation | Ribavirin-interferon alfa combination therapy for eradicating detectable HCV-RNA in patients having chronic hepatitis C infection |
| US20030004119A1 (en) * | 2001-04-18 | 2003-01-02 | Ganguly Ashit K. | Ribavirin-interferon alfa combination therapy for eradicating detectable HCV-RNA in patients having chronic hepatitis C infection |
| WO2008007153A2 (en) * | 2006-07-14 | 2008-01-17 | Iqur Ltd. | Antiviral compounds |
| CN101374539A (en) * | 2004-11-02 | 2009-02-25 | 夏尔有限责任公司 | Prodrugs of ribavirin with improved hepatic delivery |
| WO2011150288A1 (en) * | 2010-05-28 | 2011-12-01 | Gilead Sciences, Inc. | 1'-substituted-carba-nucleoside prodrugs for antiviral treatment |
| CN107513055A (en) * | 2017-08-11 | 2017-12-26 | 广东昊邦医药健康有限责任公司 | A kind of Ribavirin derivative compound and its pharmaceutical composition |
-
2020
- 2020-02-17 CN CN202010096598.4A patent/CN111320662B/en active Active
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3984396A (en) * | 1971-06-01 | 1976-10-05 | Icn Pharmaceuticals, Inc. | 1-(β,-D-ribofuranosyl)-1,2,4-triazole acid esters |
| US6403564B1 (en) * | 1998-10-16 | 2002-06-11 | Schering Corporation | Ribavirin-interferon alfa combination therapy for eradicating detectable HCV-RNA in patients having chronic hepatitis C infection |
| US20020055473A1 (en) * | 2000-04-20 | 2002-05-09 | Ganguly Ashit K. | Ribavirin-interferon alfa combination therapy for eradicating detectable HCV-RNA in patients having chronic hepatitis C infection |
| US20030004119A1 (en) * | 2001-04-18 | 2003-01-02 | Ganguly Ashit K. | Ribavirin-interferon alfa combination therapy for eradicating detectable HCV-RNA in patients having chronic hepatitis C infection |
| CN101374539A (en) * | 2004-11-02 | 2009-02-25 | 夏尔有限责任公司 | Prodrugs of ribavirin with improved hepatic delivery |
| WO2008007153A2 (en) * | 2006-07-14 | 2008-01-17 | Iqur Ltd. | Antiviral compounds |
| WO2011150288A1 (en) * | 2010-05-28 | 2011-12-01 | Gilead Sciences, Inc. | 1'-substituted-carba-nucleoside prodrugs for antiviral treatment |
| CN107513055A (en) * | 2017-08-11 | 2017-12-26 | 广东昊邦医药健康有限责任公司 | A kind of Ribavirin derivative compound and its pharmaceutical composition |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111766317A (en) * | 2020-07-02 | 2020-10-13 | 盐城师范学院 | Method for measuring GS-441524 content in preparation by using polyethylene glycol and water |
| CN111766317B (en) * | 2020-07-02 | 2022-06-03 | 盐城师范学院 | Method for measuring GS-441524 content in preparation by using polyethylene glycol and water |
Also Published As
| Publication number | Publication date |
|---|---|
| CN111320662B (en) | 2022-11-25 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP1040094B1 (en) | Substituted cyclopentane and cyclopentene compounds useful as neuraminidase inhibitors | |
| US7888330B2 (en) | Phosphoramidate derivatives of FAU | |
| KR102488479B1 (en) | Indoles for use in influenza virus infection | |
| EP2841066B1 (en) | Anti-influenza agent conjugated to anti-inflammatory agent | |
| US7875727B2 (en) | Benzimidazole vascular damaging agents | |
| EA019590B1 (en) | P38 mapk kinase inhibitor | |
| US11306399B2 (en) | Nanoparticle compositions | |
| JP6010196B2 (en) | Oxazolidinone-containing dimer compounds, compositions, and methods of making and using | |
| EA003509B1 (en) | Sulphonamide derivatives as prodrugs of aspartyl protease inhibitors | |
| US20090175792A1 (en) | Glycomimetic inhibitors of siglec-8 | |
| KR20150082633A (en) | Novel Orally Bioavailable Breathing Control Modulating Compounds, and Methods of Using Same | |
| CN114805478A (en) | Deuterated peptidomimetic compound and application thereof | |
| CN111320662B (en) | N-benzyl substituted diamidinonazine derivative and pharmaceutical application thereof | |
| US9828333B2 (en) | Compounds for the treatment of influenza | |
| EP3733669A1 (en) | Liver specific delivery-based entecavir prodrug, nucleoside cyclic phosphate compound, and application thereof | |
| KR20060127906A (en) | 4'-substituted carbovir-and abacavir-derivatives as well as related compounds with hiv and hcv antiviral activity | |
| CN105705150A (en) | Mutual prodrug comprising short chain fatty acids and zebularine or 1'-cyano-cytarabine for cancer treatment | |
| CN103848762A (en) | Neuraminidase inhibitor prodrug and its composition and use | |
| CN103183722B (en) | Glyoxalase I inhibitor, preparation method and medical application thereof | |
| CN115925640A (en) | ((3-carbamoyl-5-fluoropyrazin-2-yl) oxy) methyl isobutyrate and preparation method and application thereof | |
| US20040023928A1 (en) | Phosphonate nucleotide and thiadiazole compounds for the treatment of smallpox | |
| CN115697383A (en) | Methods of treating viral infections and health problems | |
| CA3153281A1 (en) | 4'-halogen containing nucleotide and nucleoside therapeutic compositions and uses related thereto | |
| US20170218001A1 (en) | Phosphonate nucleosides useful in the treatment of viral diseases | |
| CN111499623B (en) | Thiazolone urea derivatives of non-nucleoside antitumor drugs and pharmaceutical application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |