WO2021175290A1 - 杂环类化合物 - Google Patents
杂环类化合物 Download PDFInfo
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- WO2021175290A1 WO2021175290A1 PCT/CN2021/079093 CN2021079093W WO2021175290A1 WO 2021175290 A1 WO2021175290 A1 WO 2021175290A1 CN 2021079093 W CN2021079093 W CN 2021079093W WO 2021175290 A1 WO2021175290 A1 WO 2021175290A1
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- 238000001035 drying Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- MSMGXWFHBSCQFB-UHFFFAOYSA-N ethyl cyanoformate Chemical compound CCOC(=O)C#N MSMGXWFHBSCQFB-UHFFFAOYSA-N 0.000 description 1
- PQVSTLUFSYVLTO-UHFFFAOYSA-N ethyl n-ethoxycarbonylcarbamate Chemical compound CCOC(=O)NC(=O)OCC PQVSTLUFSYVLTO-UHFFFAOYSA-N 0.000 description 1
- 238000013401 experimental design Methods 0.000 description 1
- 230000020764 fibrinolysis Effects 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 238000003304 gavage Methods 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 229940097043 glucuronic acid Drugs 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 210000003494 hepatocyte Anatomy 0.000 description 1
- 125000001183 hydrocarbyl group Chemical group 0.000 description 1
- 150000003840 hydrochlorides Chemical group 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- XMBWDFGMSWQBCA-YPZZEJLDSA-N iodane Chemical compound [125IH] XMBWDFGMSWQBCA-YPZZEJLDSA-N 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229940044173 iodine-125 Drugs 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000000155 isotopic effect Effects 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 229940040692 lithium hydroxide monohydrate Drugs 0.000 description 1
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium hydroxide monohydrate Substances [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 1
- 125000001434 methanylylidene group Chemical group [H]C#[*] 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 239000002637 mydriatic agent Substances 0.000 description 1
- 201000000050 myeloid neoplasm Diseases 0.000 description 1
- XCVNDBIXFPGMIW-UHFFFAOYSA-N n-ethylpropan-1-amine Chemical compound CCCNCC XCVNDBIXFPGMIW-UHFFFAOYSA-N 0.000 description 1
- 125000003506 n-propoxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 229960002446 octanoic acid Drugs 0.000 description 1
- 231100000822 oral exposure Toxicity 0.000 description 1
- 235000005985 organic acids Nutrition 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
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000223 polyglycerol Polymers 0.000 description 1
- 238000011533 pre-incubation Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 210000001747 pupil Anatomy 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 239000011535 reaction buffer Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 210000003786 sclera Anatomy 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 238000004467 single crystal X-ray diffraction Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical class [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 125000001273 sulfonato group Chemical group [O-]S(*)(=O)=O 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- WRECIMRULFAWHA-UHFFFAOYSA-N trimethyl borate Chemical compound COB(OC)OC WRECIMRULFAWHA-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 230000008728 vascular permeability Effects 0.000 description 1
- 230000006442 vascular tone Effects 0.000 description 1
- 230000024883 vasodilation Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- GTLDTDOJJJZVBW-UHFFFAOYSA-N zinc cyanide Chemical compound [Zn+2].N#[C-].N#[C-] GTLDTDOJJJZVBW-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- 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
-
- 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
-
- 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
- C07D401/14—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 three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
Definitions
- This application belongs to the field of medicine, and specifically relates to a compound of formula (I), a preparation method thereof, and a pharmaceutical composition containing the compound.
- Plasma kallikrein also known as Fletcher factor
- Fletcher factor Plasma kallikrein
- PKal Plasma kallikrein
- FXIIa acting on prokallikrein and can mediate the cleavage of kallikrein.
- BK bradykinin
- BK activates its B1 and B2 receptors, regulate vascular tone, inflammation, and endogenous blood coagulation and fibrinolysis processes.
- PKal is often highly expressed in diabetic patients, leading to vasodilation and blood vessels Permeability (RVP) increases, causing diabetic retinopathy (DR) and diabetic macular edema (DME).
- RVP vasodilation and blood vessels Permeability
- DR diabetic retinopathy
- DME diabetic macular edema
- the main function of plasma kallikrein inhibitors is to reduce the level of plasma kallikrein in the body, reduce the activation of bradykinin on the two receptors, thereby alleviating vascular permeability and inflammation, and achieving the treatment of diabetic retinopathy and diabetic macular
- the plasma kallikrein inhibitor KVD001 (WO2013005045), developed by KalVista Pharmaceuticals, is in clinical phase II. It is administered through intravitreal injection to treat diabetic macular edema, and patient compliance needs to be improved.
- plasma kallikrein inhibitors In view of the important role of plasma kallikrein inhibitors, as well as the patient compliance problem of current administration methods, it is particularly important to develop plasma kallikrein inhibitors suitable for oral therapeutic drugs.
- the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof,
- R 1 is H, F, Cl, Br, I, OH or NH 2 ;
- R 2 is H, F, Cl, Br, I, OH or NH 2 ;
- R 3 is H, F, Cl, Br, I, OH, C 1-3 alkyl or C 1-3 alkoxy, wherein the C 1-3 alkyl and C 1-3 alkoxy are each independently optionally substituted with 1, 2 or 3 R a;
- R 4 is H or C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with 1, 2 or 3 R b ;
- T 1 is N or CR 5 ;
- T 2 is N or CR 6 ;
- T 3 is N or CR 7 ;
- E 1 is O or NR 8 ;
- R 5 , R 6 and R 7 are each independently H, F, Cl, Br, I, OH or NH 2 ;
- R a , R b and R c are each independently F, Cl, Br, I, OH or NH 2 .
- R 3 is H, F, Cl, Br, I, OH, CH 3 or -O-CH 3 , wherein the CH 3 and -O-CH 3 are each independently optionally selected by 1 , 2 or 3 substituents R a, R a, and the other variables are as defined in the present invention.
- R 3 is -O-CH 3 , and other variables are as defined in the present invention.
- R 4 is H or CH 3 , wherein the CH 3 is optionally substituted with 1, 2, or 3 R b , and R b and other variables are as defined in the present invention.
- R 4 is H or CH 3 , and other variables are as defined in the present invention.
- the above-mentioned compound has the structure (I-1) or (I-2)
- T 1 , T 2 , T 3 , R 1 , R 2 , R 3 , R 4 and R 8 are as defined in the present invention.
- the present invention also provides a compound of the following formula or a pharmaceutically acceptable salt thereof:
- the above-mentioned compound or a pharmaceutically acceptable salt thereof, wherein the salt is hydrochloride.
- the present invention also provides the use of the above-mentioned compound or its pharmaceutically acceptable salt in the preparation of plasma kallikrein inhibitor-related drugs.
- the above-mentioned hydrochloride is used in the preparation of drugs related to plasma kallikrein inhibitors.
- the compound of the present invention has significant plasma kallikrein inhibitory activity.
- the compound of the present invention has good oral PK properties and appropriate ocular exposure, and has an obvious alleviating effect on retinal edema in an animal model of diabetic macular edema induced by carbonic anhydrase (CA-1) by oral administration.
- pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms that are within the scope of reliable medical judgment and are suitable for use in contact with human and animal tissues. , Without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
- pharmaceutically acceptable salt refers to a salt of the compound of the present invention, which is prepared from a compound with specific substituents discovered in the present invention and a relatively non-toxic acid or base.
- a base addition salt can be obtained by contacting the compound with a sufficient amount of base in a pure solution or a suitable inert solvent.
- Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salt or similar salts.
- the acid addition salt can be obtained by contacting the compound with a sufficient amount of acid in a pure solution or a suitable inert solvent.
- Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, hydrogen carbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts, the organic acid includes, for example, acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid and methanesulfonic acid; also include salts of amino acids (such as arginine, etc.) , And salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain basic and
- the pharmaceutically acceptable salt of the present invention can be synthesized from the parent compound containing acid or base by conventional chemical methods. In general, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of appropriate base or acid in water or organic solvent or a mixture of both.
- the compound of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms constituting the compound.
- compounds can be labeled with radioisotopes, such as tritium ( 3 H), iodine-125 ( 125 I), or C-14 ( 14 C).
- deuterium can be substituted for hydrogen to form deuterated drugs.
- the bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon.
- deuterated drugs can reduce toxic side effects and increase drug stability. , Enhance the efficacy, extend the biological half-life of drugs and other advantages. All changes in the isotopic composition of the compounds of the present invention, whether radioactive or not, are included in the scope of the present invention.
- substituted means that any one or more hydrogen atoms on a specific atom are replaced by a substituent.
- the substituent may include deuterium and hydrogen variants, as long as the valence of the specific atom is normal and the compound after substitution Is stable.
- Oxygen substitution does not occur on aromatic groups.
- optionally substituted means that it can be substituted or unsubstituted. Unless otherwise specified, the type and number of substituents can be arbitrary on the basis that they can be chemically realized.
- any variable such as R
- its definition in each case is independent.
- the group can optionally be substituted with up to two Rs, and R has independent options in each case.
- combinations of substituents and/or variants thereof are only permitted if such combinations result in stable compounds.
- linking group When the number of a linking group is 0, such as -(CRR) 0 -, it means that the linking group is a single bond.
- substituents When a substituent is vacant, it means that the substituent is absent. For example, when X in A-X is vacant, it means that the structure is actually A.
- substituents do not indicate which atom is connected to the substituted group, such substituents can be bonded via any atom.
- a pyridyl group can pass through any one of the pyridine ring as a substituent. The carbon atom is attached to the substituted group.
- C 1-3 alkyl is used to indicate a linear or branched saturated hydrocarbon group composed of 1 to 3 carbon atoms.
- the C 1-3 alkyl group includes C 1-2 and C 2-3 alkyl groups, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or multivalent (such as methine) .
- Examples of C 1-3 alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.
- C 1-3 alkoxy refers to those alkyl groups containing 1 to 3 carbon atoms that are attached to the rest of the molecule through an oxygen atom.
- the C 1-3 alkoxy group includes C 1-2 , C 2-3 , C 3 and C 2 alkoxy groups and the like.
- Examples of C 1-3 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.
- C n-n+m or C n -C n+m includes any specific case of n to n+m carbons, for example, C 1-12 includes C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , and C 12 , including any range from n to n+m, for example, C 1-12 includes C 1-3 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 , and C 9-12, etc.; similarly, from n to n +m member means that the number of atoms in the ring is from n to n+m, for example, 3-12 membered ring includes 3-membered ring, 4-membered ring, 5-membered ring, 6-membered ring, 7-membered ring, 8-membered ring, 9-membered
- leaving group refers to a functional group or atom that can be replaced by another functional group or atom through a substitution reaction (for example, a nucleophilic substitution reaction).
- representative leaving groups include trifluoromethanesulfonate; chlorine, bromine, iodine; sulfonate groups, such as mesylate, tosylate, p-bromobenzenesulfonate, p-toluenesulfonic acid Esters, etc.; acyloxy groups, such as acetoxy, trifluoroacetoxy and the like.
- protecting group includes, but is not limited to, "amino protecting group", “hydroxy protecting group” or “thiol protecting group”.
- amino protecting group refers to a protecting group suitable for preventing side reactions at the amino nitrogen position.
- Representative amino protecting groups include, but are not limited to: formyl; acyl, such as alkanoyl (such as acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, such as tert-butoxycarbonyl (Boc) ; Arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethyloxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1,1-di -(4'-Methoxyphenyl)methyl; silyl groups, such as trimethylsilyl (TMS) and tert-butyld
- hydroxy protecting group refers to a protecting group suitable for preventing side reactions of the hydroxyl group.
- Representative hydroxy protecting groups include but are not limited to: alkyl groups, such as methyl, ethyl, and tert-butyl; acyl groups, such as alkanoyl groups (such as acetyl); arylmethyl groups, such as benzyl (Bn), p-methyl Oxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyl Dimethylsilyl (TBS) and so on.
- alkyl groups such as methyl, ethyl, and tert-butyl
- acyl groups such as alkanoyl groups (such as acetyl)
- arylmethyl groups such as benzyl (Bn), p-methyl Oxybenzyl (P
- the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by combining them with other chemical synthesis methods, and those well known to those skilled in the art Equivalent alternatives, preferred implementations include but are not limited to the embodiments of the present invention.
- the structure of the compound of the present invention can be confirmed by conventional methods well known to those skilled in the art. If the present invention relates to the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art.
- the single crystal X-ray diffraction method uses the Bruker D8 venture diffractometer to collect the diffraction intensity data of the cultured single crystal.
- the light source is CuK ⁇ radiation
- the scanning method After scanning and collecting relevant data, the direct method (Shelxs97) is further used to analyze the crystal structure to confirm the absolute configuration.
- the solvent used in the present invention is commercially available.
- the present invention uses the following abbreviations: aq stands for water.
- N,N-dimethylformamide (5mL), compound 1-4 (389mg, 1.99mmol), 1-5 (0.5g, 1.99mmol), potassium carbonate (549mg, 3.97mmol) ), reacted at 80°C for 16 hours, the system was reduced to 20°C, then water (10 mL) was added to the system, filtered, the filter cake was washed with water (20 mL), the filter cake was collected and dried under vacuum to obtain compound 1-6.
- Tetrahydrofuran (12 mL), methanol (3 mL), compound 1-6 (0.65 g, 1.58 mmol), water (3 mL), and lithium hydroxide monohydrate (199 mg, 4.74 mmol) were added to the pre-dried reaction flask. After stirring at 70°C for 2 hours, the system was reduced to 20°C, then an aqueous citric acid solution (0.5M) was added to adjust the pH to 4 to 5, concentrated, the organic solvent was removed, filtered, and the filter cake was collected and dried under vacuum to obtain compound 1-7.
- aqueous citric acid solution 0.5M
- a saturated aqueous ammonium chloride solution (200 mL) was added to the system to quench the system, ethyl acetate (200 mL) was added and stirred for 30 minutes, the aqueous phase was separated and collected, and concentrated under reduced pressure to obtain the crude product 2-1b.
- N,N-dimethylformamide (1mL), compound 1-7 (50mg, 130.42 ⁇ mol), compound 2-1 (28mg, 143.46 ⁇ mol), N,N -Diisopropylethylamine (135 mg, 1.04 mmol).
- 2-(7-azobenzotriazole)-N,N,N,N-tetramethylurea hexafluorophosphate (74mg, 194 ⁇ mol) was added and stirred at 20°C for 2 hours.
- reaction system was filtered, and the filtrate was subjected to preparative high performance liquid chromatography (column: Welch Xtimate C18 150*25mm*5 ⁇ m; mobile phase: [A-10mM ammonium bicarbonate aqueous solution; B-acetonitrile B%: 20%-50%, 10.5min ) Purification to obtain compound 5.
- the reaction was naturally heated to 27°C, water (10mL) and ethyl acetate (20mL) were added, the liquids were extracted and separated, the organic phase was collected, and concentrated under reduced pressure to obtain the crude product.
- the crude product was obtained by preparative high performance liquid chromatography (column: Welch Xtimate C18 150* 25mm*5 ⁇ m; mobile phase: [A-10mM ammonium bicarbonate aqueous solution; B-acetonitrile; B%: 25%-55%, 10.5min) purified to obtain compound 6.
- reaction solution passed through preparative high performance liquid chromatography (column: Waters Xbridge Prep OBD C18 150*40mm*10 ⁇ m; mobile phase: [A-0.05% ammonia + 10mM ammonium bicarbonate aqueous solution; B-acetonitrile; B%: 25%-55 %, 8min) to obtain the target compound 8.
- the reaction flask was placed in an ice bath and quenched with sodium hydroxide solid (2.4 g), stirred for 3 minutes, methyl tertiary ether (20 mL) was added, extraction was performed twice, and the aqueous phase was collected.
- the water phase was placed in an ice bath to cool to 0°C, and hydrochloric acid (12M) was added to adjust the pH of the solution to 3.
- Methyl tertiary ether (20 mL) was added, the layers were separated by extraction, and the organic phase was collected. Add tertiary methyl ether (20 mL) to the aqueous phase, extract and separate the layers, and collect the organic phase.
- reaction solution was filtered and concentrated under reduced pressure to obtain the crude product, which was subjected to preparative high performance liquid chromatography (column: Waters Xbridge BEH C18 100*30mm*10 ⁇ m; mobile phase: [A-10mM ammonium bicarbonate aqueous solution; B-acetonitrile; B%: 20 %-50%, 8min) to obtain compound 10.
- N,N-diisopropylethylamine (1.41g, 10.95mmol) and 2-(7-azobenzotriazole)-N,N,N,N-tetramethylurea hexafluorophosphate (3.12g, 8.21mmol).
- compound 1- 8 (1g, 5.78mmol)
- the resulting mixture was naturally raised to room temperature and 25°C and stirred for 16 hours.
- Ethyl acetate (100mL) and water (50mL) were added to the reaction solution and stirred for 10 minutes.
- the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product.
- PKal reaction buffer 25mM Tris-HCl (Tris-hydroxymethylaminomethane-HCl), pH 8.0, 100mM NaCl, pH 8.5, 0.01% Brij35 (polyoxyethylene laureth), and 1% DMSO (final concentration ).
- PKal R&D Systems Cat#2497-SE
- Enzyme activation (1) Dilute rhPKal to 200 ⁇ g/mL activation buffer (100mM Tris, 10mM CaCl 2 , 150mM NaCl, pH 7.5 (TCN)); (2) Dilute thermolysin (Thermolysin) to 20 ⁇ g /mL activation buffer; (3) mix rhPKal (200 ⁇ g/mL) and thermolysin (20 ⁇ g/mL) in equal volumes; (4) incubate at 37°C for 30min; (5) use 50 ⁇ M EDTA (ethylene diamine) Tetraacetic acid) terminates the reaction.
- EDTA ethylene diamine
- Matrix (Enzo Cat#P-139): 10 ⁇ M Z-FR-AMC (AMC: 7-amino-4-methylcoumarin).
- Reaction process (1) Prepare the designated enzyme and substrate in the newly prepared activation buffer; (2) Inject the enzyme solution into the reaction well; (3) Use acoustic technology (Echo 550, LabCyte Inc. Sunnyvale, CA) ) Inject the DMSO solution of the test product into the reaction mixture and control it within the nanoliter range; (4) After pre-incubation for 10 minutes, inject the matrix solution into the reaction well to start the reaction; (5) The enzyme activity can be measured by fluorescence The fluorescent signal of the labeled peptide matrix increases as an indicator, and it is monitored every 5 minutes for 120 minutes at room temperature; (6) Data analysis: measure the slope of the straight line* (fluorescence signal/time), the slope can be calculated by excel, and the curve can be fitted by Prism software .
- the test results of the inhibitory effect of the compounds on plasma kallikrein (PKal) are shown in Table 1 below.
- the compound of the present invention has a significant inhibitory effect on plasma kallikrein (PKal).
- the LC-MS/MS method was used to determine the drug concentration in plasma at different times after intravenous and intragastric administration of the test compound. Study the pharmacokinetic behavior of the compound in rats and evaluate its pharmacokinetic characteristics.
- Test drug test compound.
- the LC-MS/MS method was used to determine the content of the test compound in the rat plasma after intravenous and intragastric administration.
- the linear range of the method is 2.00 ⁇ 6000nmol/L; plasma samples are analyzed after acetonitrile-precipitated protein treatment.
- the pharmacokinetic test results of the compounds are shown in Table 2 below.
- the compound of the present invention has a low clearance rate, a certain amount of oral exposure and oral bioavailability.
- the LC-MS/MS method was used to determine the drug concentration in the eye tissues at different times after intragastric administration of the test compound.
- the pharmacokinetic behavior of the compound in the eyes of rats after intragastric administration was studied, and its pharmacokinetic characteristics were evaluated.
- Test animals 6 healthy adult male rats were divided into 3 groups with 4 eyes in each group. The animals were purchased from Beijing Weitong Lihua Laboratory Animal Technology Co., Ltd.
- Drug preparation Weigh an appropriate amount of samples, add appropriate amounts of DMSO and caprylic acid polyglycerol glyceride in a volume ratio of 10:90, stir and ultrasound to reach a clear liquid state of 15mg/mL for intragastric administration.
- the LC-MS/MS method was used to determine the content of the test compound in the eye tissue of the rat after intragastric administration.
- the linear range of the method is 2.00 ⁇ 6000nmol/L; the eye tissue concentration data is presented in Table 3, where each eye tissue concentration data is obtained by combining the left and right eyes of two rats.
- Table 3 The results of the ocular pharmacokinetic test of the compound of the present invention are shown in Table 3 below.
- the compound of the present invention has a certain amount of drug exposure in the retina and choroid of the rat fundus.
- Twenty male SD rats were selected from 25 male SD rats and divided into 5 groups according to their body weights, 4 in each group, and 1 spare animal in each group. All animals were treated before, 48 hours and 72 hours after the model. Perform retinal optical coherence tomography. Select the appropriate scanning position to measure and mark the retinal thickness. Through the changes of retinal thickness in each group, the effects of the test products on improving retinal edema were compared, and active compounds were screened. The above experimental operation of model building and inspection must follow the order of right eye first, then left eye.
- OCT optical coherence tomography
- the retinas of the animals in each group were checked by OCT before modeling, and the retinas of the animals in each group were normal. 48 hours and 72 hours after modeling, the retinas of rats injected with saline were significantly thickened, and the thickening of the retinas of rats in the oral administration group was relieved to varying degrees.
- Compound 1 low-dose group 50mg/kg partially relieved retinal thickening at 48 hours (remission rate of 19%), and significantly relieved retinal thickening at 72h (remission rate of 79%); compound 1 high-dose group (75mg /kg) completely relieved the thickening of the retina caused by carbonic anhydrase-1 at 48 hours and 72 hours (remission rate 100%).
- Compound 8 (75mg/kg) partially relieved retinal thickening at 48 hours (remission rate 84%), and completely relieved retinal thickening caused by carbonic anhydrase-1 at 72 hours (remission rate 116%). The compounds are well tolerated.
Abstract
本申请属于医药领域,具体而言公开了式(I)化合物、其制备方法以及含有该化合物的药物组合物。
Description
本申请主张如下优先权
CN202010144412.8,申请日:2020.03.04。
本申请属于医药领域,具体而言涉及式(I)化合物、其制备方法以及含有该化合物的药物组合物。
血浆激肽释放酶(plasma kallikrein,PKal)又称Fletcher因子,特异地在肝细胞表达,是一种高分子量糖蛋白,是FXIIa作用于激肽释放酶原生成的,可介导激肽原裂解产生缓激肽(BK),激活其B1受体和B2受体,调节血管紧张性、炎症反应以及内源性血液凝固和纤维蛋白溶解过程,糖尿病患者体内PKal往往高表达,导致血管舒张及血管通透性(RVP)增加,从而引起糖尿病视网膜病变(DR)和糖尿病黄斑水肿(DME)。血浆激肽释放酶抑制剂的主要作用是降低体内血浆激肽释放酶水平,降低缓激肽对两种受体的激活作用,从而缓解血管通透性及炎症,达到治疗糖尿病视网膜病变和糖尿病黄斑水肿的重要作用。由KalVista Pharmaceuticals公司开发的血浆激肽释放酶抑制剂KVD001(WO2013005045)正在临床二期阶段,通过玻璃体腔注射给药来治疗糖尿病黄斑水肿,患者依从性有待改善。
鉴于血浆激肽释放酶抑制剂的重要作用,以及目前给药方式患者依从性问题,开发适用作口服治疗药物的血浆激肽释放酶抑制剂显得尤为重要。
发明内容
本发明提供了式(Ⅰ)化合物或其药学上可接受的盐,
其中,
R
1为H、F、Cl、Br、I、OH或NH
2;
R
2为H、F、Cl、Br、I、OH或NH
2;
R
3为H、F、Cl、Br、I、OH、C
1-3烷基或C
1-3烷氧基,其中所述C
1-3烷基和C
1-3烷氧基分别独立地任选被1、2或3个R
a取代;
R
4为H或C
1-3烷基,其中所述C
1-3烷基任选被1、2或3个R
b取代;
T
1为N或CR
5;
T
2为N或CR
6;
T
3为N或CR
7;
E
1为O或NR
8;
R
5、R
6和R
7分别独立地为H、F、Cl、Br、I、OH或NH
2;
R
8为H、C
1-3烷基、C
1-3烷氧基、-C(=O)C
1-3烷基或-S(=O)
2C
1-3烷基,其中所述C
1-3烷基、-C
1-3烷氧基、-C(=O)C
1-3烷基和-S(=O)
2C
1-3烷基分别独立地任选被1、2或3个R
c取代;
R
a、R
b和R
c分别独立地为F、Cl、Br、I、OH或NH
2。
本发明的一些方案中,上述R
3为H、F、Cl、Br、I、OH、CH
3或-O-CH
3,其中所述CH
3和-O-CH
3分别独立地任选被1、2或3个R
a取代,R
a及其他变量如本发明所定义。
本发明的一些方案中,上述R
3为-O-CH
3,其他变量如本发明所定义。
本发明的一些方案中,上述R
4为H或CH
3,其中所述CH
3任选被1、2或3个R
b取代,R
b及其他变量如本发明所定义。
本发明的一些方案中,上述R
4为H或CH
3,其他变量如本发明所定义。
本发明的一些方案中,上述R
8为H、CH
3、CH
2-CH
3、-C(=O)-CH
3或-S(=O)
2-CH
3,其中所述CH
3、CH
2-CH
3、-C(=O)-CH
3或-S(=O)
2-CH
3任选被1、2或3个R
c取代,R
c及其他变量如本发明所定义。
本发明的一些方案中,上述R
8为H、CH
3、CH
2-CF
3、-C(=O)-CH
3或-S(=O)
2-CH
3,其他变量如本发明所定义。
本发明还有一些方案是由上述各变量任意组合而来。
本发明的一些方案中,上述化合物具有(Ⅰ-1)或(Ⅰ-2)的结构
其中,
T
1、T
2、T
3、R
1、R
2、R
3、R
4和R
8如本发明所定义。
本发明还提供了下式化合物或其药学上可接受的盐:
本发明的一些方案中,上述化合物或其药学上可接受的盐,其中所述的盐为盐酸盐。
本发明还提供了上述化合物或其药学上可接受的盐在制备血浆激肽释放酶抑制剂相关药物的用途。
本发明的一些方案中,上述的盐酸盐在制备血浆激肽释放酶抑制剂相关药物的用途。
技术效果
本发明化合物具有显著的血浆激肽释放酶抑制活性。本发明化合物具有良好的口服PK性质,以及合适的眼部暴露量,以口服给药的方式在碳酸酐酶(CA-1)诱导的糖尿病黄斑水肿动物模型上对视网膜水肿的缓解效果明显。
定义和说明
除非另有说明,本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的,而应该按照普通的含义去理解。当本文中出现商品名时,意在指代其对应的商品或其活性成分。
这里所采用的术语“药学上可接受的”,是针对那些化合物、材料、组合物和/或剂型而言,它们在可靠的医学判断的范围之内,适用于与人类和动物的组织接触使用,而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症,与合理的利益/风险比相称。
术语“药学上可接受的盐”是指本发明化合物的盐,由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时,可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物接触的方式获得碱加成盐。药学上可接受的碱加成盐包括钠、钾、钙、铵、有机胺或镁盐或类似的盐。当本发明的化合物中含有相对碱性的官能团时,可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物接触的方式获得酸加成盐。药学上可接受的酸加成盐的实例包括无机酸盐,所述无机酸包括例如盐酸、氢溴酸、硝酸、碳酸,碳酸氢根,磷酸、磷酸一氢根、磷酸二氢根、硫酸、硫酸氢根、氢碘酸、亚磷酸等;以及有机酸盐,所述有机酸包括如乙酸、丙酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸和甲磺酸等类似的酸;还包括氨基酸(如精氨酸 等)的盐,以及如葡糖醛酸等有机酸的盐。本发明的某些特定的化合物含有碱性和酸性的官能团,从而可以被转换成任一碱或酸加成盐。
本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下,这样的盐的制备方法是:在水或有机溶剂或两者的混合物中,经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如,可用放射性同位素标记化合物,比如氚(
3H),碘-125(
125I)或C-14(
14C)。又例如,可用重氢取代氢形成氘代药物,氘与碳构成的键比普通氢与碳构成的键更坚固,相比于未氘化药物,氘代药物有降低毒副作用、增加药物稳定性、增强疗效、延长药物生物半衰期等优势。本发明的化合物的所有同位素组成的变换,无论放射性与否,都包括在本发明的范围之内。
“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现的,并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。
术语“被取代的”是指特定原子上的任意一个或多个氢原子被取代基取代,取代基可以包括重氢和氢的变体,只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为氧(即=O)时,意味着两个氢原子被取代。氧取代不会发生在芳香基上。术语“任选被取代的”是指可以被取代,也可以不被取代,除非另有规定,取代基的种类和数目在化学上可以实现的基础上可以是任意的。
当任何变量(例如R)在化合物的组成或结构中出现一次以上时,其在每一种情况下的定义都是独立的。因此,例如,如果一个基团被0-2个R所取代,则所述基团可以任选地至多被两个R所取代,并且每种情况下的R都有独立的选项。此外,取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
当一个连接基团的数量为0时,比如-(CRR)
0-,表示该连接基团为单键。
当其中一个变量选自单键时,表示其连接的两个基团直接相连,比如A-L-Z中L代表单键时表示该结构实际上是A-Z。
当一个取代基为空缺时,表示该取代基是不存在的,比如A-X中X为空缺时表示该结构实际上是A。当所列举的取代基中没有指明其通过哪一个原子连接到被取代的基团上时,这种取代基可以通过其任何原子相键合,例如,吡啶基作为取代基可以通过吡啶环上任意一个碳原子连接到被取代的基团上。
除非另有规定,术语“C
1-3烷基”用于表示直链或支链的由1至3个碳原子组成的饱和碳氢基团。所述C
1-3烷基包括C
1-2和C
2-3烷基等;其可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。C
1-3烷基的实例包括但不限于甲基(Me)、乙基(Et)、丙基(包括n-丙基和异丙基)等。
除非另有规定,术语“C
1-3烷氧基”表示通过一个氧原子连接到分子的其余部分的那些包含1至3个碳原子的烷基基团。所述C
1-3烷氧基包括C
1-2、C
2-3、C
3和C
2烷氧基等。C
1-3烷氧基的实例包括但不限于甲氧基、乙氧基、丙氧基(包括正丙氧基和异丙氧基)等。
除非另有规定,C
n-n+m或C
n-C
n+m包括n至n+m个碳的任何一种具体情况,例如C
1-12包括C
1、C
2、C
3、C
4、C
5、C
6、C
7、C
8、C
9、C
10、C
11、和C
12,也包括n至n+m中的任何一个范围,例如C
1-12 包括C
1-3、C
1-6、C
1-9、C
3-6、C
3-9、C
3-12、C
6-9、C
6-12、和C
9-12等;同理,n元至n+m元表示环上原子数为n至n+m个,例如3-12元环包括3元环、4元环、5元环、6元环、7元环、8元环、9元环、10元环、11元环、和12元环,也包括n至n+m中的任何一个范围,例如3-12元环包括3-6元环、3-9元环、5-6元环、5-7元环、6-7元环、6-8元环、和6-10元环等。
术语“离去基团”是指可以被另一种官能团或原子通过取代反应(例如亲核取代反应)所取代的官能团或原子。例如,代表性的离去基团包括三氟甲磺酸酯;氯、溴、碘;磺酸酯基,如甲磺酸酯、甲苯磺酸酯、对溴苯磺酸酯、对甲苯磺酸酯等;酰氧基,如乙酰氧基、三氟乙酰氧基等等。
术语“保护基”包括但不限于“氨基保护基”、“羟基保护基”或“巯基保护基”。术语“氨基保护基”是指适合用于阻止氨基氮位上副反应的保护基团。代表性的氨基保护基包括但不限于:甲酰基;酰基,例如链烷酰基(如乙酰基、三氯乙酰基或三氟乙酰基);烷氧基羰基,如叔丁氧基羰基(Boc);芳基甲氧羰基,如苄氧羰基(Cbz)和9-芴甲氧羰基(Fmoc);芳基甲基,如苄基(Bn)、三苯甲基(Tr)、1,1-二-(4'-甲氧基苯基)甲基;甲硅烷基,如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。术语“羟基保护基”是指适合用于阻止羟基副反应的保护基。代表性羟基保护基包括但不限于:烷基,如甲基、乙基和叔丁基;酰基,例如链烷酰基(如乙酰基);芳基甲基,如苄基(Bn),对甲氧基苄基(PMB)、9-芴基甲基(Fm)和二苯基甲基(二苯甲基,DPM);甲硅烷基,如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。
本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备,包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式,优选的实施方式包括但不限于本发明的实施例。
本发明的化合物可以通过本领域技术人员所熟知的常规方法来确认结构,如果本发明涉及化合物的绝对构型,则该绝对构型可以通过本领域常规技术手段予以确证。例如单晶X射线衍射法(SXRD),把培养出的单晶用Bruker D8 venture衍射仪收集衍射强度数据,光源为CuKα辐射,扫描方式:
扫描,收集相关数据后,进一步采用直接法(Shelxs97)解析晶体结构,便可以确证绝对构型。
本发明所使用的溶剂可经市售获得。本发明采用下述缩略词:aq代表水。
下面通过实施例对本发明进行详细描述,但并不意味着对本发明任何不利限制。本文已经详细地描述了本申请,其中也公开了其具体实施例方式,对本领域的技术人员而言,在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。本申请所使用的所有溶剂是市售的,无需进一步纯化即可使用。本申请用于合成的初始化合物原料通过市售获得,也可以通过现有技术的方法制备。
实施例1
合成路线:
1)化合物1-2的合成
在三口瓶中加入化合物1-1(92g,665.88mmol),盐酸(12M,277.45mL)和无水甲苯(920mL),25℃下搅拌4小时。加入饱和碳酸氢钠溶液调pH至7,加入乙酸乙酯(300mL*3)萃取,收集合并有机相加入饱和食盐水(500mL)洗,分离有机相加入无水硫酸钠干燥,过滤,滤液减压浓缩得到化合物1-2。LCMS(ESI)m/z:139[M-17]
+。
2)化合物1-3的合成
向预先干燥的单口瓶中加入5-氟-2-羟基吡啶(14.7g,130.26mmol),化合物1-2(17.0g,108.55mmol),N,N-二甲基甲酰胺(160mL),碳酸钾(15.0g,108.55mmol),65℃搅拌18小时。待体系自然回温至40℃后,将体系过滤,滤饼用乙酸乙酯(100mL*3)淋洗,收集滤液加入饱和食盐水(200mL),乙酸乙酯(300mL*3)萃取,收集有机相加入无水硫酸钠干燥过滤,滤液减压浓缩至干得到油状粗品。粗品中加入乙酸乙酯(40mL),25℃,搅拌10分钟,过滤,滤饼乙酸乙酯(10mL*3)淋洗,收集滤饼,真空干燥得到化合物1-3。LCMS(ESI)m/z:234[M+1]
+。
3)化合物1-4的合成
向预先干燥的反应瓶中加入二氯甲烷(25mL),化合物1-3(2.2g,8.49mmol),三乙胺(1.3g,12.73mmol),降温至0℃,滴加甲基磺酰氯(1.4g,11.88mmol)。滴加完毕,升温至20℃搅拌16小时。反应液用二氯甲烷(20mL)稀释,加入水(50mL),搅拌10分钟,除去水相,有机相用无水硫酸钠干燥,过滤,减压浓缩,得到化合物1-4。
1HNMR(400MHz,CDCl
3)δppm 7.36-7.43(m,2H),7.31(d,J=8.2Hz,2H),7.24-7.29(m,1H),7.16(t,J=3.6Hz,1H),6.61(dd,J=5.4,10.0Hz,1H),5.10(s,2H),4.58(s,2H);LCMS(ESI)m/z:252[M+1]
+。
4)化合物1-5b的合成
在圆底烧瓶中加入化合物1-5a(0.5g,4.90mmol),羰基二咪唑(953mg,5.88mmol),四氢呋喃(5mL),室温25℃搅拌2小时,然后加入丙二酸单乙酯钾盐(1.0g,5.88mmol),氯化镁(574mg,6.02mmol),25℃搅拌16小时,向反应液中加入乙酸乙酯(20mL)和水(10mL),除去水相,有机相用无水硫酸钠干燥,过滤,减压浓缩得到粗品。粗品经柱层析(梯度洗脱:0~100%乙酸乙酯/石油醚,流速20mL/min)纯化得到化合物1-5b。
1HNMR(400MHz,CDCl
3)δppm 4.75-4.87(m,4H),4.20(m,2H),4.07-4.16(m,1H),3.47(s,2H),1.22-1.33(m,3H)。
5)化合物1-5c的合成
向预先干燥的反应瓶中加入溶于N,N-二甲基甲酰胺(35mL)的化合物1-5b(3.5g,20.33mmol),然后加入N,N-二甲基甲酰胺二甲缩醛(4.8g,40.66mmol)。120℃搅拌2小时,体系降温至20℃,减压浓缩,得到化合物1-5c。
1HNMR(400MHz,CDCl
3)δppm 7.80(s,1H),4.80(s,2H),4.78(s,2H),4..23-4.35(m,1H),4.15(m,2H),3.21-3.36(m,3H),2.80-2.90(m,3H),1.29(m,3H)。
6)化合物1-5的合成
向预先干燥的反应瓶中加入正丁醇(10mL),1-5c(4.6g,20.24mmol),一水合肼(1.3g,24.29mmol),乙酸(1.5g,24.29mmol),120℃搅拌2小时,体系降温至20℃,向反应液中加入乙酸乙酯(50mL)和饱和碳酸氢钠水溶液(50mL)搅拌10分钟,除去水相,有机相用无水硫酸钠干燥,过滤,减压浓 缩得到化合物1-5。
1HNMR(400MHz,CD
3OD)δppm 7.85-8.23(m,1H),5.00-5.06(m,2H),4.93(m,2H),4.57-4.84(m,1H),4.25(m,2H),1.33(t,J=7.2Hz,3H)。
7)化合物1-6的合成
向预先干燥的反应瓶中加入N,N-二甲基甲酰胺(5mL),化合物1-4(389mg,1.99mmol),1-5(0.5g,1.99mmol),碳酸钾(549mg,3.97mmol),80℃反应16小时,体系降至20℃,然后向体系中加入水(10mL),过滤,用水(20mL)洗滤饼,收集滤饼真空干燥,得到化合物1-6。
1HNMR(400MHz,CDCl
3)δppm 7.83(s,1H),7.32-7.37(m,2H),7.26-7.31(m,3H),7.18(t,J=3.6Hz,1H),6.62(dd,J=5.4,10.0Hz,1H),5.29(s,2H),5.11(s,2H),4.94-5.08(m,4H),4.65(m,1H),4.24(m,2H),1.33(t,J=7.2Hz,3H)。
8)化合物1-7的合成
向预先干燥的反应瓶中加入四氢呋喃(12mL),甲醇(3mL),化合物1-6(0.65g,1.58mmol),水(3mL),一水合氢氧化锂(199mg,4.74mmol)。70℃搅拌2小时,体系降至20℃,然后加入柠檬酸水溶液(0.5M)调节pH至4~5,浓缩,除去有机溶剂,过滤,收集滤饼真空干燥,得到化合物1-7。
1HNMR(400MHz,CDCl
3)δppm 8.31(s,1H),7.91-8.07(m,1H),7.57(m,1H),7.20-7.39(m,4H),6.44(m,1H),5.31(s,2H),5.02(s,2H),4.61-4.87(m,4H),4.44-4.60(m,1H)。
9)化合物1-8b的合成
向预先干燥的反应瓶加入化合物1-8a(23.0g,159.59mmol),四氢呋喃(460mL)氮气保护下反应降温至-78℃后,加入二异丙基胺锂2M四氢呋喃正庚烷混合溶液(2M,119.69mL)反应2小时后,向反应液中加入氰基甲酸乙酯(39.5g,398.98mmol,39.14mL)的四氢呋喃(230mL)溶液,继续反应0.5小时,将反应液缓慢升至15℃,向反应液中加入饱和氯化铵水溶液(700mL),乙酸乙酯(700mL*2)萃取,合并有机相,加入饱和食盐水(300mL)洗涤,收集有机相加入无水硫酸钠干燥过滤,滤液减压浓缩,粗品通过柱层析(梯度洗脱:乙酸乙酯/石油醚,乙酸乙酯%:0~100%,流速20mL/min)纯化得到化合物1-8b。LCMS(ESI)m/z:217[M+1]
+。
10)化合物1-8c的合成
向预先干燥的三口瓶中加入硼氢化锂(9.3g,427.42mmol),无水四氢呋喃(220mL),氮气保护,降温至0℃加入化合物1-8b(22 0g,101.77mmol)和无水四氢呋喃(20mL)的混合溶液,自然回温至25℃后移至油浴40℃搅拌17小时。将合并体系缓慢倒入装有饱和氯化铵(1L)的溶液中淬灭,缓慢搅拌至无气泡产生。加入乙酸乙酯(200mL*3)萃取分液,收集有机相加入饱和食盐水(100mL)洗涤,有机相用无水硫酸钠干燥过滤,滤液减压浓缩得到化合物1-8c。LCMS(ESI)m/z:157[M-17]
+。
11)化合物1-8d的合成
向预先干燥的单口瓶中加入化合物1-8c(14.0g,80.39mmol),N,N-二甲基甲酰胺(140mL),二氯亚砜(44.0g,369.81mmol,26.83mL),25℃搅拌0.5小时,后体系升温至40℃,冰浴降温至25℃继续搅拌0.5小时。向体系中加入乙酸乙酯(100mL),饱和氯化钠水溶液(100mL*3)洗涤,收集有机相加入无水硫酸钠干燥过滤,滤液减压浓缩,得到化合物1-8d。
12)化合物1-8的合成
向预先干燥的单口瓶中加入化合物1-8d(15.4g,79.96mmol),氨气/甲醇(14M,150mL),25℃搅拌24小时。将体系旋干,加入无水二氯甲烷(100mL),25℃搅拌0.5小时,过滤,滤饼用二氯甲烷(10mL*3)淋洗,收集滤出固体减压浓缩,得到化合物1-8。
1HNMR(400MHz,DMSO-d
6)δppm 7.28(dt,J=5.4,9.4Hz,1H),7.14(dt,J=1.8,9.2Hz,1H),4.03(s,2H),3.85(s,3H);LCMS(ESI)m/z:174[M+1]
+。
13)化合物1的合成
在三口瓶中加入化合物1-7(50mg,130.42μmol),化合物1-8(22mg,130.42μmol),N,N-二甲基甲酰胺(2mL),二异丙基乙基胺(75mg,86.90μmol)降温至0℃加入2-(7-偶氮苯并三氮唑)-N,N,N,N-四甲基脲六氟磷酸酯(74mg,194μmol),0℃搅拌2小时。粗品经制备高效液相色谱(色谱柱:Welch Xtimate C18 150*25mm*5μm;流动相:[A-10mM碳酸氢铵水溶液;B-乙腈;B%:30%-50%,10.5min)纯化得到化合物1。
1HNMR(400MHz,DMSO-d
6)δppm 8.25(t,J=5.14Hz,1H),8.21(s,1H),8.01-8.05(m,1H),7.56(ddd,J=10.13,7.12,3.33Hz,1H),7.27-7.33(m,2H),7.20-7.26(m,2H),7.11(td,J=9.35,5.27Hz,1H),6.95-7.04(m,1H),6.43(dd,J=10.04,5.40Hz,1H),5.28(s,2H),5.01(s,2H),4.80(dd,J=8.47,5.58Hz,2H),4.67(t,J=6.27Hz,2H),4.46-4.56(m,1H),4.37(d,J=4.89Hz,2H),3.81(s,3H);LCMS(ESI)m/z:539[M+1]
+。
实施例2
合成路线:
1)化合物2-1b的合成
在氮气保护下向预先干燥的三口瓶中加入化合物2-1a(25.0g,190.06mmol)的四氢呋喃(200mL)溶液,降温至-78℃滴加二异丙基胺锂2M四氢呋喃正庚烷混合溶液(2M,104.53mL),搅拌2小时后滴加原料硼酸三甲酯(39.5g,380.13mmol,42.93mL),自然升至室温25℃继续搅拌22小时。向体系中加入饱和氯化铵水溶液(200mL)将体系淬灭,加入乙酸乙酯(200mL)搅拌30分钟,分离收集水相,减压浓缩得粗品2-1b。
2)化合物2-1c的合成
0-5℃下,向化合物2-1b(33.3g,189.90mmol)的乙醇溶液(330mL)中滴加双氧水(59.0g,520.36mmol,50mL,30%纯度),得到的混合物自然升至室温25℃搅拌4.5小时。补加双氧水(118.0g,1.04mol,100mL,30%纯度)继续搅拌18小时。向饱和亚硫酸钠水溶液(500mL)中缓慢加入反应体系,搅拌1小时,至淀粉碘化钾试纸不变色,乙酸乙酯(300mL*3)萃取,收集合并有机相,加入无水硫酸钠干燥过滤,滤液减压浓缩,得到化合物2-1c。LCMS(ESI)m/z:148[M+1]
+。
3)化合物2-1d的合成
向预先干燥的单口瓶中加入化合物2-1c(7.9g,53.41mmol),N,N-二甲基甲酰胺(80mL),碳酸钾(14.8g,106.82mmol),碘甲烷(11.4g,80.12mmol,4.99mL),25℃搅拌18小时。向体系中加入乙酸乙酯(30mL)搅拌10分钟后,通过布氏漏斗将体系过滤,滤饼通过乙酸乙酯(15mL*3)淋洗,收集滤液加入饱和食盐水(40mL*3)洗涤,分离出有机相加入无水硫酸钠干燥过滤,滤液减压浓缩,粗品通过柱层析(梯度洗脱:乙酸乙酯/石油醚,乙酸乙酯%:0~30%,流速30mL/min)纯化得到化合物2-1d。LCMS(ESI)m/z:162[M+1]
+。
4)化合物2-1e的合成
向预先干燥的单口瓶中加入化合物2-1d(2.9g,17.95mmol),N,N-二甲基甲酰胺(30mL),氰化锌(2.1g,17.95mmol,1.14mL),1,1-双(二苯基膦基)二茂铁(995mg,1.79mmol),三(二亚苄基丙酮)二钯(822mg,897.49μmol),氮气置换三次120℃搅拌16小时。将体系过滤,滤饼用乙酸乙酯(30mL*5)淋洗,滤液中加入饱和食盐水搅拌20分钟,使用分液漏斗分离,有机相加入无水硫酸钠干燥过滤,滤液减压浓缩,粗品通过柱层析(梯度洗脱:乙酸乙酯/石油醚,乙酸乙酯%:0~50%,流速30mL/min)纯化得到化合物2-1e。LCMS(ESI)m/z:153[M+1]
+。
5)化合物2-1的合成
向预先干燥的单口瓶中加入化合物2-1e(1.8g,11.83mmol),无水乙醇(10mL),无水四氢呋喃(10mL),盐酸(1.20g,11.83mmol,1.17mL,36%纯度),钯/碳(500mg,10%纯度),15psi通入氢气(23.85mg,11.83mmol),25℃搅拌4小时。体系通过硅藻土过滤,滤饼用甲醇(20mL*4)淋洗至无产物残留,滤液减压浓缩得到化合物2-1。
1HNMR(400MHz,DMSO-d
6)δppm 8.36(d,J=5.6Hz,1H),7.34(t,J=6.2Hz,1H),4.20-4.15(m,2H),3.96(s,3H);LCMS(ESI)m/z:156[M+1]
+。
6)化合物2的合成
0℃下,向预先干燥的反应瓶中加入N,N-二甲基甲酰胺(1mL),化合物1-7(50mg,130.42μmol),化合物2-1(28mg,143.46μmol),N,N-二异丙基乙胺(135mg,1.04mmol)。然后加入2-(7-偶氮苯 并三氮唑)-N,N,N,N-四甲基脲六氟磷酸酯(74mg,194μmol),20℃搅拌2小时。体系过滤,粗品经制备高效液相色谱(色谱柱:Welch Xtimate C18 150*25mm*5μm;流动相:[A-10mM碳酸氢铵水溶液;B-乙腈,B%:25%-55%,10.5min)纯化得到化合物2。
1HNMR(400MHz,CD
3OD)δppm 8.16(d,J=5.6Hz,1H),8.10(s,1H),7.77(t,J=3.8Hz,1H),7.54(m,1H),7.25-7.37(m,4H),7.11(t,J=6.2Hz,1H),6.57(dd,J=5.2,10.0Hz,1H),5.32(s,2H),5.14(s,2H),4.93-5.02(m,2H),4.88-4.92(m,2H),4.60-4.70(m,1H),4.57(d,J=2.0Hz,2H),3.95(s,3H)。
实施例3
合成路线:
化合物3的合成
0℃下,向预先干燥的反应瓶中加入N,N-二甲基甲酰胺(1mL),化合物1-7(50mg,130.42μmol),化合物3-1(30mg,156.51μmol),N,N-二异丙基乙基胺(76mg,586.90μmol),然后加入2-(7-偶氮苯并三氮唑)-N,N,N,N-四甲基脲六氟磷酸酯(74mg,194μmol),25℃搅拌2小时。体系过滤,粗品经制备高效液相色谱(色谱柱:Welch Xtimate C18 150*25mm*5μm;流动相:[A-10mM碳酸氢铵水溶液;B-乙腈B%:30%-60%,10.5min)纯化得到化合物3。
1HNMR(400MHz,CDCl
3)δppm 8.21(s,1H),8.10-8.18(m,1H),7.97-8.08(m,1H),7.56(m,1H),7.27-7.33(m,2H),7.20-7.26(m,3H),7.10-7.18(m,1H),6.43(dd,J=5.4,10.0Hz,1H),5.28(s,2H),5.01(s,2H),4.80(dd,J=5.6,8.6Hz,2H),4.64-4.71(m,2H),4.48-4.59(m,1H),4.43(m,2H),3.81-3.86(m,3H);LCMS(ESI)m/z:555[M+1]
+。
实施例4
合成路线:
1)化合物4-2的合成
向化合物1-5(3.1g,15.80mmol)和化合物4-1(3.7g,15.96mmol)的N,N-二甲基甲酰胺(50mL)溶液中加入碳酸钾(4.6g,33.64mmol),得到的混合物加热到65℃搅拌4小时。向反应液中加入乙酸乙酯(100mL)和水(50mL)搅拌10分钟,除去水相,有机相减压浓缩,残余物加入乙酸乙酯(6mL)搅拌10分钟,过滤得到4-2。
1HNMR(400MHz,CDCl
3)δppm 7.80(s,1H),7.25-7.37(m,6H),6.62(d,J=8.0Hz,1H),6.17(td,J=6.8,1.3Hz,1H),5.30(s,1H),5.25(s,2H),5.15(s,2H),4.93-5.06(m,4H),4.63(t,J=7.8Hz,1H),4.22(q,J=7.2Hz,2H),1.31(t,J=7.2Hz,3H)。
2)化合物4-3的合成
向化合物4-2(6.2g,15.76mmol)的乙醇(70mL)溶液中加入氢氧化钠水溶液(2.5M,18.91mL),得到的混合物加热到35℃搅拌16小时。向反应液中滴加0.5M柠檬酸水溶液调节pH值至4~5,有大量白色固体析出,过滤收集固体,加入乙醇(30mL)搅拌10分钟,过滤得到化合物4-3。
1HNMR(400MHz,CDCl
3)δppm 7.84(s,1H),7.23-7.38(m,6H),6.66(d,J=8.8Hz,1H),6.16-6.23(m,1H),5.27(s,2H),5.16(s,2H),4.94-5.07(m,4H),4.64(t,J=7.7Hz,1H)。
3)化合物4的合成
在三口瓶中加入化合物4-3(50mg,136.84μmol),化合物3-1(25mg,136.84μmol),N,N-二甲基甲酰胺(2mL),二异丙基乙基胺(79mg,615.78μmol),降温至0℃加入2-(7-偶氮苯并三氮唑)-N,N,N,N-四甲基脲六氟磷酸酯(78mg,205.26μmol),0℃搅拌2小时。粗品经制备高效液相色谱(色谱柱:Welch Xtimate C18 150*25mm*5μm;流动相:[A-10mM碳酸氢铵水溶液;B-乙腈;B%:40%-70%,10.5min)纯化得到化合物4。
1HNMR(DMSO-d
6,400MHz)δppm 8.20(s,1H),8.08-8.14(m,1H),7.72-7.78(m,1H),7.37-7.44(m,1H),7.11-7.30(m,6H),6.39(d,J=9.16Hz,1H),6.17-6.25(m,1H),5.27(s,2H),5.06(s,2H),4.80(dd,J=8.41,5.52Hz,2H),4.68(t,J=6.27Hz,2H),4.48-4.59(m,1H),4.43(br d,J=3.26Hz,2H),3.84(s,3H);LCMS(ESI)m/z:537[M+1]
+。
实施例5
合成路线:
1)化合物5-2的合成
向预先干燥的反应瓶中加入化合物5-1(3.0g,13.44mmol),无水氯化钙(6.0g,53.76mmol),无水乙醇(33mL),无水四氢呋喃(35mL)。冷却至0℃加入硼氢化钠(1.0g,26.88mmol),并在0℃下搅拌5小时。向反应瓶中加入饱和氯化铵溶液(150mL),搅拌10分钟。自然升温到27℃,向反应瓶中加入二氯甲烷(250mL和水(250mL),萃取分液,收集有机相。向水相中加入二氯甲烷(250mL),萃取分液,有机相经无水硫酸钠干燥,过滤,减压浓缩。得到化合物5-2。LCMS(ESI)m/z:182[M+1]
+。
2)化合物5-3的合成
向预先干燥的反应瓶中加入化合物5-2(2.2g,12.14mmol),无水二氯甲烷(25mL)降温至0℃,并在0℃时加入氯化亚砜(7.7g,64.35mmol,4.67mL)。自然升温到27℃,搅拌3小时。将反应液加入饱和碳酸氢钠溶液(100mL),再加入二氯甲烷(200mL),萃取分液,收集有机相。向水相中加入二氯甲烷(200mL),收集有机相,合并有机相,经无水硫酸钠干燥,过滤,减压浓缩得到化合 物5-3。
1HNMR(400MHz,CDCl
3)δppm 9.11(d,J=1.62Hz,1H),8.28(dd,J=8.08,2.06Hz,1H),7.54(d,J=8.16Hz,1H),4.62-4.75(m,2H),4.31-4.45(m,2H),1.29-1.45(m,3H);LCMS(ESI)m/z:200[M+1]
+。
3)化合物5-4的合成
27℃时向预先干燥的反应瓶中加入化合物5-3(1.7g,8.47mmol),无水四氢呋喃(20mL),降温至-78℃加入二异丁基氢化铝(1M,29.63mL),保持-78℃反应搅拌3小时。加入氢氧化钠溶液(30mL),搅拌5分钟。硅藻土过滤,收集滤液。向滤液加入乙酸乙酯(50mL),萃取分液,收集有机相。经无水硫酸钠干燥,过滤,减压浓缩。经柱层析纯化得到化合物5-4。LCMS(ESI)m/z:158[M+1]
+。
4)化合物5-5的合成
向预先干燥的反应瓶中加入化合物5-4(600mg,3.68mmol),1-5(737mg,3.75mmol),N,N-二甲基甲酰胺(6mL),无水碳酸钾(1.1g,8.10mmol),升温到65℃搅拌12小时。自然降温到27℃,向反应瓶中加入二氯甲烷(20mL),搅拌10分钟,过滤,滤液减压浓缩。残留物经柱层析纯化得到化合物5-5。LCMS(ESI)m/z:318[M+1]
+。
5)化合物5-6的合成
预先干燥的反应瓶中,加入化合物5-5(300mg,945.36μmol),无水二氯甲烷(4mL)和三乙胺(383mg,3.78mmol,526.33μL),并在0℃时加入甲基磺酰氯(161mg,1.40mmol,108.59μL),自然升温到27℃搅拌7小时。向反应液中加入水(50mL)搅拌10分钟,萃取分液除去水相,得到有机相,经无水硫酸钠干燥,抽滤,减压浓缩。得到化合物5-6。LCMS(ESI)m/z:336[M+1]
+。
6)化合物5-7的合成
向预先干燥的反应瓶中加入化合物5-6(300mg,744.52μmol),2-羟基吡啶(74mg,781.75μmol),N,N-二甲基甲酰胺(3mL)和无水碳酸钾(103mg,744.52μmol)。反应加热至70℃并反应12小时。自然降温到27℃,加入N,N-二甲基甲酰胺(2mL),过滤,滤液减压浓缩后经制备高效液相色谱(中性体系)纯化得到化合物5-7。LCMS(ESI)m/z:395[M+1]
+。
7)化合物5-9的合成
向预先干燥的单口瓶中加入化合物5-7(54mg,136.91μmol),氢氧化钠(16mg,410.73μmol),无水乙醇(1mL),无水四氢呋喃(1mL),水(0.3mL),75℃搅拌20小时。将体系减压浓缩至干,得到粗品化合物5-9。LCMS(ESI)m/z:366[M-22]
+。
8)化合物5的合成
向预先干燥的三口瓶中加入化合物1-9(44mg,120.10μmol),1-8(21mg,120.10μmol),N,N-二异丙基乙胺(70mg,540.44μmol,94.13μL),N,N-二甲基甲酰胺(0.6mL),降温至0℃加入2-(7-偶氮苯并三氮唑)-N,N,N,N-四甲基脲六氟磷酸酯(69mg,180.15μmol),0℃搅拌3小时。反应体系过滤,滤液经制备高效液相色谱(色谱柱:Welch Xtimate C18 150*25mm*5μm;流动相:[A-10mM碳酸氢铵水溶液;B-乙腈B%:20%-50%,10.5min)纯化得到化合物5。
1HNMR(400MHz,CDCl
3)δppm8.55(d,J=1.8Hz,1H),7.76(s,1H),7.66(dd,J=2.2,8.0Hz,1H),7.37-7.28(m,2H),7.15(d,J=8.2Hz,1H),6.91-6.78(m,2H),6.61(d,J=9.2Hz,1H),6.20(t,J=6.2Hz,1H),6.02(br s,1H),5.36(s,2H),5.13(s,2H),5.03(dd,J=5.8,8.6Hz,2H),4.92(t,J=6.2Hz,2H),4.67-4.61(m,3H),3.87(s,3H)。
实施例6
合成路线:
1)化合物6-5的合成
向预先干燥的反应瓶中加入化合物5-4(0.5g,3.49mmol),5-氟-2-羟基吡啶(414mg,3.66mmol),乙腈(6mL),无水碳酸钾(482mg,3.49mmol)。升温到65℃搅拌12小时。自然降温到27℃,向反应瓶中加入二氯甲烷(50mL),搅拌10分钟,过滤,减压浓缩,得到化合物6-5。
1HNMR(400MHz,CDCl
3)δppm 8.55(s,1H),7.35-7.53(m,5H),6.50-6.69(m,5H),5.18(s,2H),4.70-4.76(m,2H).3.51(s,1H);LCMS(ESI)m/z:235[M+1]
+。
2)化合物6-6的合成
向预先干燥的反应瓶中加入化合物6-5(0.1g,426.9μmol),二氯甲烷(1.5mL))将反应降温至0℃,并加入二氯亚砜(253mg,2.13mmol,154.8μL)。自然升温到27℃并反应3小时。将反应体系倒于饱和碳酸氢钠溶液(20mL)中淬灭,静置5分钟,加入二氯甲烷(10mL)和水(10mL),萃取分液,收集有机相。再向水相中加入二氯甲烷(10mL),萃取分液,合并有机相。经无水硫酸钠干燥,过滤,减压浓缩,得到化合物6-6。
1HNMR(400MHz,CDCl
3)δppm 8.57(d,J=1.75Hz,1H),7.73(dd,J=7.89,2.19Hz,1H),7.41-7.49(m,2H),7.28-7.33(m,1H),6.57(dd,J=10.09,5.26Hz,1H),5.18(s,2H),4.58(s,2H);LCMS(ESI)m/z:253[M+1]
+。
3)化合物6-7的合成
在25℃时,向预先干燥的拇指瓶中加入化合物6-6(0.1g,395.7μmol),化合物1-5(78mg,,399.3μmol),无水碳酸钾(116mg,842.9μmol),N,N-二甲基甲酰胺(2mL)。油浴加热到65℃并搅拌12小时。自然降温到27℃,向反应瓶中加入二氯甲烷(20mL)和水(20mL),萃取分液,收集有机相。向水相中加入二氯甲烷(20mL),萃取分液,合并有机相。经无水硫酸钠干燥,过滤,减压浓缩,得到化合物6-7。
1HNMR(400MHz,CDCl
3)δppm 8.38-8.58(m,1H),7.78-8.08(m,1H),7.49-7.67(m,1H),5.12-5.35(m,2H),4.78-5.06(m,2H),4.12-4.38(m,1H),3.51(s,2H),1.22-1.38(m,3H);LCMS(ESI)m/z:413[M+1]
+。
4)化合物6-8的合成
在27℃时向预先干燥的反应瓶中加入化合物6-7(0.1g,193.9μmol),并溶于无水四氢呋喃(2mL),再向体系加入氢氧化钠溶液(2M,387.9μL)和乙醇(2mL)。升温到40℃并搅拌12小时。反应自然降温到27℃,向反应瓶中加入盐酸(1M,10mL)将溶液调整pH至6,向反应瓶中加入二氯甲烷(10mL)和水(10mL),萃取分液,收集有机相。向水相中加入二氯甲烷(10mL),萃取分液,合并有机相,经无水硫酸钠干燥,过滤,减压浓缩,得到化合物6-8。LCMS(ESI)m/z:385[M+1]
+。
5)化合物6的合成
27℃时,在预先干燥的单口瓶中加入化合物6-8(36mg,93.6μmol),化合物1-8(16mg,93.6μmol),N,N-二异丙基乙胺(54mg,421.8μmol,73.4μL),N,N-二甲基甲酰胺(1mL),降温至0℃加入2-(7-偶氮苯并三氮唑)-N,N,N,N-四甲基脲六氟磷酸酯(53mg,140.5μmol),0℃下搅拌5小时。将反应自然升温到27℃,加入水(10mL)和乙酸乙酯(20mL),萃取分液,收集有机相,减压浓缩得到粗品,经制备高效液相色谱(色谱柱:Welch Xtimate C18 150*25mm*5μm;流动相:[A-10mM碳酸氢铵水溶液;B-乙腈;B%:25%-55%,10.5min)纯化得到化合物6。
1HNMR(400MHz,DMSO-d
6)δppm8.37-8.51(m,1H),7.34-7.63(m,5H),6.84(d,J=8.33Hz,1H),5.16(s,2H),5.04(dd,J=8.33,6.14Hz,2H),4.88-4.94(m,2H),4.64(d,J=5.26Hz,2H),3.86(s,2H),3.54(s,6H);LCMS(ESI)m/z:541[M+1]
+。
实施例7
合成路线:
1)化合物7-2的合成
向预先干燥的三口瓶中加入N,N-二甲基甲酰胺(40mL),无水碳酸钾(3.4g,24.29mmol),化合物7-1(4g,16.19mmol),2-羟基吡啶(1.6g,17.00mmol)。70℃加热搅拌4小时,加入乙酸乙酯(150mL)和水(300mL)稀释,分液后收集有机相,水相用乙酸乙酯(100mL)萃取。合并有机相,用饱和食盐水(200mL)洗涤,经无水硫酸钠干燥,过滤,减压浓缩得到粗品,经柱层析纯化得到化合物7-2。
1HNMR(400MHz,CDCl
3)δppm 7.79(dd,J=7.89,1.75Hz,1H),7.73(dd,J=10.52,1.32Hz,1H),7.48(t,J=7.67Hz,1H),7.31-7.40(m,2H),6.60(d,J=9.21Hz,1H),6.19(td,J=6.80,1.32Hz,1H),5.21(s,2H),3.92(s,3H);LCMS(ESI)m/z:162[M+1]
+。
2)化合物7-3的合成
向预先干燥的反应瓶中加入7-2(2.3g,,8.82mmol),无水四氢呋喃(30mL)。0℃在冰浴中向反应瓶加入硼氢化锂(2M,,22.06mL),自然升温到27℃搅拌12小时。将反应体系冷却至0℃,加入乙酸乙酯(50mL)和水(50mL)稀释,分液后收集有机相,水相用乙酸乙酯(50mL)萃取。合并有机相,用饱和食盐水(50mL)洗涤,经无水硫酸钠干燥,过滤,减压浓缩得到粗品,经柱层析纯化得到化合物7-3。
1HNMR(400MHz,CDCl
3)δppm 7.35-7.46(m,2H),7.27-7.35(m,1H),7.04-7.16(m,2H),6.56(d,J=9.21Hz,1H),6.16(td,J=6.80,1.32Hz,1H),5.13(s,2H),4.60-4.74(m,2H);LCMS(ESI)m/z:234[M+1]
+。
3)化合物7-4的合成
在27℃时,向预先干燥的反应瓶中,加入化合物7-3(1.8g,7.72mmol),二氯甲烷(20mL)和三乙胺(1.6g,15.43mmol,2.2mL),并在0℃时加入甲基磺酰氯(1.1g,9.26mmol,716.8μL),自然升温到27℃搅拌12小时。向反应液中加入水(100mL)搅拌10分钟,萃取分液除去水相,得到有机相,减压浓缩得到粗品,经柱层析纯化得到化合物7-4。LCMS(ESI)m/z:252[M+1]
+。
4)化合物7-5的合成
在25℃时,向预先干燥的拇指瓶中加入化合物7-4(0.2g,794.7μmol),1-5(157mg,802.6μmol),无水碳酸钾(234mg,1.69mmol),N,N二甲基甲酰胺(3mL)。油浴加热到65℃并搅拌12小时。将反应体系冷却至0℃,加入乙酸乙酯(50mL)和水(30mL)稀释,分液后收集有机相,水相用乙酸乙酯(30mL)萃取。合并有机相,用饱和食盐水(10mL)洗涤2次,经无水硫酸钠干燥,过滤,减压浓缩得到粗品,经柱层析纯化得到化合物7-5。LCMS(ESI)m/z:412[M+1]
+。
5)化合物7-6的合成
在27℃时向预先干燥的反应瓶中加入化合物7-5(0.2g,529.8μmol),并溶于无水四氢呋喃(3mL),再向体系加入氢氧化钠溶液(2M,1.1mL)和乙醇(4mL),升温到40℃并搅拌6小时。将反应自然冷却至27℃,加入盐酸(1M,10mL),调节反应液pH至1。加入二氯甲烷(10mL)与水(10mL),萃取分液,收集有机相。水相再次加入二氯甲烷(20mL),萃取分液,合并有机相。经无水硫酸钠干燥,过滤,减压浓缩,得到化合物7-6。
1HNMR(400MHz,CDCl
3)δppm 7.48(t,J=7.84Hz,1H),7.40(br d,J=7.03Hz,1H),7.30-7.37(m,1H),6.93-7.07(m,2H),6.61(d,J=8.78Hz,1H),5.22-5.33(m,2H),5.16(s,2H),5.00-5.07(m,2H),4.91-5.00(m,2H),4.65(t,J=7.65Hz,1H);LCMS(ESI)m/z:384[M+1]
+。
6)化合物7的合成
27℃时,在预先干燥的单口瓶中加入化合物1-8(22mg,130.4μmol),化合物7-6(0.1g,130.4μmol),N,N-二异丙基乙胺(75mg,586.9μmol,102.2μL),N,N二甲基甲酰胺(2mL),降温至0℃加入2-(7-偶氮苯并三氮唑)-N,N,N,N-四甲基脲六氟磷酸酯(74mg,194μmol),0℃下搅拌6小时。将反应自然升温到27℃,加入水(10mL)和乙酸乙酯(20mL),萃取分液,收集有机相。经无水硫酸钠干燥,过滤,减压浓缩,得到粗品,经制备高效液相色谱(色谱柱:Welch Xtimate C18 150*25mm*5μm;流动相:[A-10mM碳酸氢铵水溶液;B-乙腈B%:30%-50%,10.5min)纯化得到化合物7。
1HNMR(400MHz,CDCl
3)δppm 7.60(s,1H),7.29-7.46(m,3H),6.90-7.02(m,2H),6.78-6.89(m,2H),6.57(d,J=9.21Hz,1H),6.13-6.22(m,1H),6.06(br s,1H),5.22(s,2H),5.13(s,2H),5.04(dd,J=8.33,5.70Hz,2H),4.93(t,J=6.36Hz,2H),4.58-4.68(m,3H),3.86(s,3H);LCMS(ESI)m/z:539[M+1]
+。
实施例8
合成路线:
1)化合物8-2的合成
向预先干燥的单口瓶中加入化合物7-1(1g,4.05mmol),5-氟-2-羟基吡啶(503mg,4.45mmol),碳酸钾(1.1g,8.50mmol),N,N-二甲基甲酰胺(15mL),65℃搅拌20小时。将体系过滤,滤饼用乙酸乙酯(15mL*3)淋洗,收集滤液加入水(30mL*3)洗涤,分离出有机相加入无水硫酸钠干燥,过滤,滤液减压浓缩至干,粗品经柱层析纯化得到化合物8-2。
1HNMR(400MHz,CD
3OD)δppm7.84-7.78(m,2H),7.73(dd,J=1.4,10.7Hz,1H),7.59(ddd,J=3.2,7.0,10.1Hz,1H),7.35(t,J=7.8Hz,1H),6.58(dd,J=5.0,10.0Hz,1H),5.25(s,2H),3.90(s,3H)。
2)化合物8-3的合成
向预先干燥的单口瓶中加入化合物8-2(523mg,1.87mmol),无水四氢呋喃(2mL),0℃加入硼氢化锂(285.6mg,13.11mmol),自然回温至25℃搅拌48小时。向体系中加入饱和氯化铵水溶液(10mL)将体系淬灭。加入乙酸乙酯(15mL*3)萃取,分液,合并有机相,加入无水硫酸钠干燥,过滤,滤液减压浓缩至干得到化合物8-3。LCMS(ESI)m/z:252[M+1]
+。
3)化合物8-4的合成
向预先干燥的单口瓶中加入化合物8-3(543mg,2.16mmol),无水二氯甲烷(6mL),降温至0℃加入二氯亚砜(1.2g,9.94mmol,721.24μL),25℃搅拌20小时。体系加入饱和食盐水(10mL),乙酸乙酯(15mL*3)萃取,收集合并有机相,加入无水硫酸钠干燥,过滤,滤液减压浓缩至干得到化合物8-4。LCMS(ESI)m/z:270[M+1]
+。
4)化合物8-6的合成
向预先干燥的单口瓶中加入化合物8-4(503mg,1.87mmol),化合物1-5(366mg,1.87mmol),碳酸钾(516mg,3.73mmol),N,N-二甲基甲酰胺(5mL),65℃搅拌5小时。将体系过滤,滤饼用乙酸乙酯(10mL*3)淋洗。收集滤液加入饱和食盐水(10mL*3)洗涤,有机相减压浓缩至干,粗品经柱层析纯化得到化合物8-6。LCMS(ESI)m/z:430[M+1]
+。
5)化合物8-7的合成
向预先干燥的单口瓶中加入化合物8-6(450mg,1.05mmol),无水乙醇(5mL),无水四氢呋喃(5mL),水(1.6mL),氢氧化钠(126mg,3.14mmol)65℃搅拌17小时。向体系中加入0.5M柠檬酸将体系调pH至3,减压浓缩将体系中有机溶剂旋干,过滤,滤饼用水(3mL*3)淋洗,收集滤饼,真空干燥得到化合物8-7。LCMS(ESI)m/z:402[M+1]
+。
6)化合物8的合成
向预先干燥的单口瓶中加入化合物8-7(322mg,802.27μmol),1-8(180mg,1.04mmol),N,N-二甲基甲酰胺(3mL),N,N-二异丙基乙胺(467mg,3.61mmol,628.83μL),2-(7-偶氮苯并三氮唑)-N,N,N,N-四甲基脲六氟磷酸酯(458mg,1.20mmol)25℃搅拌5小时。反应液通过制备高效液相色谱(色谱柱:Waters Xbridge Prep OBD C18 150*40mm*10μm;流动相:[A-0.05%氨水+10mM碳酸氢铵水溶液;B-乙腈;B%:25%-55%,8min)纯化得到目标化合物8。
1HNMR(400MHz,DMSO-d
6)δppm8.27(t,J=5.2Hz,1H),7.96(t,J=4.0Hz,1H),7.60(m,1H),7.19-7.07(m,3H),7.06-6.94(m,2H),6.43(dd,J=5.6,10.0Hz,1H),5.32(s,2H),5.05(s,2H),4.80(dd,J=5.6,8.4Hz,2H),4.67(t,J=6.2Hz,2H),4.59-4.47(m,1H),4.38(br d,J=5.0Hz,2H),3.81(s,3H);LCMS(ESI)m/z:557[M+1]
+。
实施例9
合成路线:
1)化合物9-2的合成
向预先干燥的反应瓶中加入化合物9-1(1g,9.79mmol,970.8μL),二乙酰氧基碘苯(6.3g,19.58 mmol),水(10mL),乙腈(10mL)。冰浴降温至0℃,并加入2,2,6,6-四甲基哌啶氧化物(307mg,1.96mmol)。自然升温到20℃搅拌12小时。将反应瓶置于冰浴中加入氢氧化钠固体(2.4g)淬灭,搅拌3分钟,加入甲叔醚(20mL),萃取分液2次,收集水相。将水相置于冰浴中降温至0℃,加入盐酸(12M)调节溶液pH至3。加入甲叔醚(20mL),萃取分液,收集有机相。向水相中加入甲叔醚(20mL),萃取分液,收集有机相。合并有机相,经无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经柱层析纯化得到化合物9-2。
1HNMR(400MHz,CDCl
3)δppm 4.98(d,J=5.70Hz,2H),4.42(d,J=5.70Hz,2H),1.61(s,4H);LCMS(ESI)m/z:115[M-1]
-。
2)化合物9-3的合成
在20℃下向预先干燥的反应瓶中加入化合物9-2(20mg,172.2μmol),无水四氢呋喃(1mL)和N,N-羰基二吡唑(33mg,206.6μmol)。搅拌2小时,随后加入氯化镁(20mg,211.8μmol,8.6μL)和丙二酸单乙酯钾盐(35mg,206.6μmol)搅拌4小时。加入乙酸乙酯(5mL)和水(5mL),搅拌5分钟,萃取分液,收集有机相。向水相中加乙酸乙酯(10mL*3),合并有机相,向有机相中加入饱和食盐水(30mL),萃取分液,有机相减压浓缩至干得到化合物9-3。
1HNMR(400MHz,CDCl
3)δppm4.34-4.61(m,4H),3.34-3.77(m,2H),1.32-1.53(m,8H);LCMS(ESI)m/z:185[M-1]
-。
3)化合物9-4的合成
向预先干燥的反应瓶中加入化合物9-3(0.1g,537.1μmol),N,N-二甲基甲酰胺(2mL),1,1-二甲氧基三甲胺(128mg,1.07mmol,142.7μL),将反应升温至120℃反应2小时。降温到20℃,减压浓缩,得到化合物9-4。LCMS(ESI)m/z:242[M+1]
+。
4)化合物9-5的合成
向化合物9-4(120mg,497.3μmol)和水合肼(30mg,596.8μmol,29.6μL)的正丁醇(1mL)溶液中加入醋酸(30mg,507.3μmol,29.1μL)的混合物在110℃下搅拌2小时。加入乙酸乙酯(5mL)和饱和碳酸氢钠水溶液(5mL),搅拌分钟。萃取分液,除去水相,有机相减压浓缩得到化合物9-5。
1HNMR(400MHz,CDCl
3)δppm 8.04(s,1H),5.11(d,J=6.14Hz,2H),4.69(d,J=6.14Hz,2H),4.22-4.38(m,3H),1.76(s,4H),1.35-1.43(m,3H);LCMS(ESI)m/z:211[M+1]
+。
5)化合物9-6的合成
在25℃时,向预先干燥的拇指瓶中加入化合物1-4(118mg,470.9μmol),化合物9-5(0.1g,475.6μmol),无水碳酸钾(138mg,1.00mmol),N,N-二甲基甲酰胺(2mL)。油浴加热到65℃并搅拌12小时。自然降温到20℃,向反应瓶中加入二氯甲烷(10mL)和水(10mL),萃取分液,收集有机相。向水相中加入二氯甲烷(10mL),收集有机相,合并有机相。经无水硫酸钠干燥,过滤,减压浓缩得到化合物9-6。
1HNMR(400MHz,CDCl
3)δppm 8.02(s,1H),7.79(s,1H),7.10-7.41(m,6H),6.49-6.65(m,1H),5.17-5.28(m,1H),5.01-5.13(m,3H),4.64(d,J=6.02Hz,1H),4.13-4.32(m,2H),1.73(s,3H),1.16-1.38(m,3H);LCMS(ESI)m/z:426[M+1]
+。
6)化合物9-7的合成
在20℃时向预先干燥的反应瓶中加入化合物9-6(0.3g,705.1μmol),并溶于无水四氢呋喃(2mL),再向体系加入固体氢氧化钠(282mg,7.05mmol)和乙醇(2mL),水(2mL)。升温到60℃并搅拌 12小时。反应自然降温到27℃,向反应瓶中加入盐酸(1M,10mL)将溶液调节pH至6,向反应瓶中加入二氯甲烷(10mL)和水(10mL),萃取分液,收集有机相。向水相中加入二氯甲烷(10mL),萃取分液收集有机相,合并有机相,经无水硫酸钠干燥,过滤,减压浓缩得到化合物9-7。LCMS(ESI)m/z:398[M+1]
+。
7)化合物9的合成
20℃时,在预先干燥的单口瓶中加入化合物9-7(50mg,125.8μmol),2-1(20mg,125.8μmol),N,N-二异丙基乙胺(73mg,566.1μmol,98.6μL),N,N-二甲基甲酰胺(1.5mL),降温至0℃加入2-(7-偶氮苯并三氮唑)-N,N,N,N-四甲基脲六氟磷酸酯(71mg,188.7μmol),0℃下搅拌6小时。自然升温到20℃,减压浓缩得粗品。粗品经制备高效液相色谱(色谱柱:Waters Xbridge BEH C18 100*25mm*5μm;流动相:[A-10mM碳酸氢铵水溶液;B-乙腈;B%:15%-50%,10min)纯化得到化合物9。
1HNMR(400MHz,DMSO-d
6)δppm 8.36-8.43(m,1H),8.24(s,1H),8.20(d,J=5.29Hz,1H),8.02-8.08(m,1H),7.52-7.65(m,1H),7.29-7.33(m,2H),7.23-7.28(m,2H),7.14-7.19(m,1H),6.44(dd,J=10.14,5.29Hz,1H),5.27(s,2H),5.02(s,2H),4.80(d,J=6.17Hz,2H),4.45(br d,J=3.75Hz,2H),4.40(d,J=5.95Hz,2H),3.90(s,3H),1.54(s,3H);LCMS(ESI)m/z:536[M+1]
+。
实施例10
合成路线:
化合物10的合成
20℃时,在预先干燥的单口瓶中加入化合物9-7(49mg,125.5μmol),1-8(26mg,150.6μmol),N,N-二异丙基乙胺(72mg,564.7μmol,98.3μL),N,N-二甲基甲酰胺(1.5mL),降温至0℃加入2-(7-偶氮苯并三氮唑)-N,N,N,N-四甲基脲六氟磷酸酯(71mg,188.2μmol),搅拌2小时。反应液过滤,减压浓缩得到粗品,经制备高效液相色谱(色谱柱:Waters Xbridge BEH C18 100*30mm*10μm;流动相:[A-10mM碳酸氢铵水溶液;B-乙腈;B%:20%-50%,8min)纯化得到化合物10。
1HNMR(400MHz,DMSO-d
6)δppm 8.82(d,J=5.87Hz,1H),8.52(d,J=6.36Hz,3H),8.32(s,1H),7.87-8.12(m,3H),7.47-7.73(m,1H),5.93(s,1H),5.63-5.83(m,3H),5.15-5.34(m,3H),4.57(d,J=6.24Hz,2H),3.88(s, J=6.24Hz,6H),1.97(s,1H);LCMS(ESI)m/z:553[M+1]
+。
实施例11
合成路线:
1)化合物11-1b的合成
向预先干燥的单口瓶中加入化合物11-1a(24.0g,119.27mmol),1,1-羰基二咪唑(23.2g,143.13mmol),四氢呋喃(250mL),氮气置换三次,25℃搅拌2小时,加入氯化镁(13.2g,146.71mmol),丙二酸单乙酯钾盐(24.3g,143.13mmol),25℃搅拌4小时。将体系旋干,加入乙酸乙酯(300mL),加入水(200mL*4)分液,收集有机相,经无水硫酸钠干燥,过滤,滤液减压浓缩至干,经柱层析纯化得到化合物11-1b。LCMS(ESI)m/z:216[M-55]
+。
2)化合物11-1c的合成
向预先干燥的单口瓶中加入化合物11-1b(28.0g,103.20mmol),N,N-二甲基甲酰胺二甲基缩醛(24.6g,206.41mmol,27.42mL),N,N-二甲基甲酰胺(280mL),120℃搅拌18小时,待体系降温至60℃, 减压浓缩至干,得到粗品化合物11-1c。LCMS(ESI)m/z:327[M+1]
+。
3)化合物11-1的合成
在反应瓶中加入化合物11-1c(32.0g,98.04mmol),正丁醇(320mL),冰乙酸(6.0g,100.00mmol,5.72mL),水合肼(5.7g,107.85mmol,5.52mL),氮气置换三次,110℃反应7小时。减压浓缩将体系旋干。加入饱和碳酸氢钠水溶液将体系调节pH至8,加入乙酸乙酯(100mL*3)萃取,收集合并有机相,加入无水硫酸钠干燥,过滤,滤液减压浓缩至干,粗品经柱层析纯化得到化合物11-1。
1HNMR(400MHz,CDCl
3)δppm 8.06(s,1H),4.38-4.12(m,7H),1.45(s,9H),1.35(t,J=7.0Hz,3H);LCMS(ESI)m/z:240[M-55]
+。
4)化合物11-2的合成
在拇指瓶中加入化合物化合物4-1(330mg,1.41mmol),化合物11-1(500mg,1.69mmol),N,N-二甲基甲酰胺(5mL),碳酸钾(415mg,3.01mmol)氮气置换三次,65℃反应4小时。向反应液中加入乙酸乙酯(20mL)和饱和食盐水(10mL)溶液搅拌5分钟,分液,有机相用无水硫酸钠干燥,过滤,减压浓缩得到粗品,粗品经柱层析纯化得到化合物11-2。
1HNMR(400MHz,DMSO-d
6)δppm8.39(s,1H),7.75(dd,J=6.78,1.88Hz,1H),7.40(ddd,J=8.97,6.71,2.01Hz,1H),7.25(s,4H),6.39(d,J=9.03Hz,1H),6.19-6.25(m,1H),5.30(s,2H),5.06(s,2H),3.84-4.15(m,7H),1.36(s,9H),1.24(t,J=7.09Hz,3H)。
5)化合物11-3的合成
在拇指瓶中加入化合物11-2(450mg,913.58μmol),氢氧化钠(109mg,2.74mmol),乙醇(6mL),水(2mL),氮气置换三次,25℃反应16小时,补加氢氧化钠(36mg,913.58μmol),25℃继续反应4小时。向反应液中滴加柠檬酸水溶液(0.5M)调节pH值至4~5,向反应液中加入乙酸乙酯(20mL),有机相用无水硫酸钠干燥,过滤,减压浓缩得到粗品,粗品经柱层析纯化得到化合物11-3。
1HNMR(400MHz,MeOD)δppm 8.11(s,1H),7.69(d,J=4.52Hz,1H),7.48-7.58(m,1H),7.24-7.35(m,4H),6.57(d,J=9.03Hz,1H),6.39(t,J=6.27Hz,1H),5.31(s,2H),5.19(s,2H),4.06-4.29(m,5H),1.44(s,9H)。
6)化合物11-4的合成
在三口瓶中加入化合物11-3(200mg,430.56μmol),化合物1-8(74mg,430.56μmol),N,N-二甲基甲酰胺(2mL),二异丙基乙基胺(250mg,1.94mmol)降温至0℃加入2-(7-偶氮苯并三氮唑)-N,N,N,N-四甲基脲六氟磷酸酯(245mg,645.84μmol),自然升温至25℃反应1小时。向反应液中加入20mL乙酸乙酯和10mL饱和食盐水溶液搅拌5分钟,分液,有机相用无水硫酸钠干燥,过滤,减压浓缩得到粗品,粗品经薄层层析硅胶板纯化得到化合物11-4。LCMS(ESI)m/z:620[M+1]
+。
7)化合物11盐酸盐的合成
在反应瓶中加入化合物11-4(50mg,80.69μmol),盐酸/乙酸乙酯(6M,12.49mL),氮气置换三次,25℃反应1小时。反应液进行减压浓缩得到粗品,粗品经制备高效液相色谱(色谱柱:Phenomenex Luna C18 100*30mm*5μm;流动相:[A-0.04%盐酸水溶液;B-乙腈;B%:10%-40%,10min)纯化得到化合物11盐酸盐。
1HNMR(400MHz,DMSO-d
6)δppm 8.98(br s,1H),8.53-8.72(m,1H),8.42(t,J=5.08Hz,1H),8.29(s,1H),7.78(dd,J=6.78,1.88Hz,1H),7.41(ddd,J=9.00,6.68,2.01Hz,1H),7.20-7.33(m,4H),7.12 (td,J=9.32,5.21Hz,1H),6.96-7.05(m,1H),6.39(d,J=9.16Hz,1H),6.23(td,J=6.65,1.13Hz,1H),5.29(s,2H),5.06(s,2H),4.28-4.44(m,3H),4.04-4.21(m,4H),3.81(s,3H);LCMS(ESI)m/z:520[M+1]
+。
实施例12
合成路线:
1)化合物12的合成
在反应瓶中加入化合物11(15mg,28.87μmol),甲醇(1mL),多聚甲醛(26mg,288.72μmol),搅拌0.5小时加入氰基硼氢化钠(9mg,144.36μmol),25℃搅拌0.5小时。反应液中加入稀盐酸水溶液(1M,1mL)搅拌1分钟后过滤,收集滤液。减压浓缩得粗品,粗品经制备高效液相色谱(色谱柱:Phenomenex Luna C18 100*30mm*5μm;流动相:[A-0.04%盐酸水溶液;B-乙腈B%:15%-45%,10min))纯化得到化合物12盐酸盐。
1HNMR(400MHz,D
2O)δppm 7.98-8.08(m,1H),7.56(br d,J=7.15Hz,2H),7.10(br s,4H),6.97(br d,J=5.90Hz,1H),6.78-6.88(m,1H),6.54(br d,J=8.41Hz,1H),6.43(br d,J=5.40Hz,1H),5.22(br s,2H),5.06(br s,2H),4.98-5.12(m,1H),4.37-4.54(m,4H),3.98-4.35(m,3H),3.75(br s,3H),2.90(s,1H),2.77(s,2H);LCMS(ESI)m/z:534[M+1]
+。
实施例13
合成路线:
1)化合物13的合成
在反应瓶中加入化合物11(10mg,19.25μmol),N,N-二甲基甲酰胺(1mL),三乙胺(2mg,19.25μmol),降温至0℃加入乙酸酐(2mg,19.25μmol),自然升温至25℃反应2小时。反应液减压浓缩后得粗品,粗品经制备高效液相色谱(色谱柱:Phenomenex Luna C18 100*30mm*5μm;流动相:[A-0.04%盐酸水溶液;B-乙腈;B%:20%-50%,10min)纯化得到化合物13。
1HNMR(400MHz,DMSO-d
6)δppm 8.29(br t,J=5.02Hz,1H),8.21(s,1H),7.76(dd,J=6.71,1.69Hz,1H),7.41(ddd,J=8.94,6.74,1.88Hz,1H),7.24(q,J=8.24Hz,4H),7.07-7.16(m,1H),6.96-7.05(m,1H),6.39(d,J=9.03Hz,1H),6.22(t,J=6.65Hz,1H),5.27(s,2H),5.06(s,2H),4.32-4.44(m,3H),4.03-4.18(m,3H),3.94(br d,J=3.76Hz,1H),3.81(s,3H),1.73(s,3H);LCMS(ESI)m/z:562[M+1]
+。
实施例14
合成路线:
化合物14的合成
在反应瓶中加入化合物11(70mg,134.73μmol),二氯甲烷(1mL),三乙胺(41mg,404.20μmol),降温至0℃加入甲基磺酰氯(38mg,336.84μmol),0℃搅拌3小时。反应液中加入饱和碳酸氢钠水溶液(2mL),二氯甲烷萃取(5mL*3),分液,合并有机相,有机相用饱和食盐水洗涤(2mL*3),经无水硫酸钠干燥,过滤,减压浓缩得到粗品,粗品经制备高效液相色谱(色谱柱:Phenomenex Gemini-NX C18 75*30mm*3μm;流动相:[A-10mM碳酸氢铵水溶液;B-甲醇;B%:45%-75%,10.5min)纯化得到化合物14。
1HNMR(400MHz,DMSO-d
6)δppm 8.33(t,J=5.08Hz,1H),8.22(s,1H),7.76(dd,J=6.71,1.95Hz,1H),7.41(ddd,J=9.00,6.68,2.01Hz,1H),7.20-7.30(m,4H),7.11(td,J=9.32,5.33Hz,1H),6.96-7.04(m,1H),6.39(d,J=9.16Hz,1H),6.22(td,J=6.65,1.25Hz,1H),5.28(s,2H),5.06(s,2H),4.38(br d,J=4.89Hz,2H),4.09-4.15(m,3H),3.95-4.01(m,2H),3.81(s,3H),2.92(s,3H);LCMS(ESI)m/z:598[M+1]
+。
实施例15
合成路线:
1)化合物15-1的合成
向预先干燥的单口瓶中加入化合物11-1(1.3g,5.17mmol),化合物1-4(1.7g,5.68mmol),碳酸钾(1.5g,11.00mmol),N,N-二甲基甲酰胺(10mL),65℃搅拌3小时。将体系过滤,滤饼用乙酸乙酯(10mL*3)淋洗,收集滤液加入饱和食盐水(10mL*2)洗涤,收集有机相,经无水硫酸钠干燥过滤,滤液减压浓缩得粗品,粗品经柱层析纯化得到化合物15-1。LCMS(ESI)m/z:511[M+1]
+。
2)化合物15-2的合成
向预先干燥的单口瓶中加入化合物15-1(1.0g,1.96mmol),氢氧化钠(235mg,5.88mmol),乙醇(5mL),四氢呋喃(5mL),水(1.6mL),75℃搅拌16小时。向体系中加入饱和柠檬酸水溶液调节pH至3,用乙酸乙酯(10mL*3)萃取,收集合并有机相,加入饱和食盐水(20mL)洗涤,有机相经无水硫酸钠干燥,过滤,滤液减压浓缩得到化合物15-2。LCMS(ESI)m/z:383[M-99]
+。
3)化合物15-3的合成
向预先干燥的三口瓶中加入化合物15-2(797mg,1.65mmol),化合物2-1(258mg,1.65mmol),N,N-二甲基甲酰胺(0.9mL),N,N-二异丙基乙胺(961mg,7.43mmol,1.29mL),2-(7-偶氮苯并三氮唑)-N,N,N,N-四甲基脲六氟磷酸酯(942mg,2.48mmol),0℃搅拌2小时。向体系中加入饱和食盐水(20mL),乙酸乙酯(15mL*3)萃取,收集有机相经无水硫酸钠干燥,过滤,滤液加减压浓缩得 粗品,粗品经柱层析纯化得到化合物15-3。LCMS(ESI)m/z:621[M+1]
+。
4)化合物15-4的合成
向预先干燥的单口瓶中加入化合物15-3(503mg,810.45μmol),乙酸乙酯(1mL),盐酸/乙酸乙酯(4M,5mL),23℃搅拌1小时。将体系中溶剂减压浓缩得到化合物15-4。
5)化合物15的合成
向预先干燥的单口瓶中加入化合物15-4(169mg,303.42μmol),三氟甲磺酸三氟乙酯(176mg,758.54μmol),N,N-二异丙基乙胺(137mg,1.06mmol,184.97μL),四氢呋喃(0.8mL),N,N-二甲基甲酰胺(0.8mL),27℃搅拌4小时。反应液减压浓缩得粗品,粗品经薄层色谱法(二氯甲烷/甲醇=20/1)纯化得到化合物15。
1HNMR(400MHz,DMSO-d
6)δppm 8.34(s,1H),8.24-8.17(m,2H),8.04(br d,J=3.8Hz,1H),7.63-7.54(m,1H),7.35-7.22(m,4H),7.17(t,J=5.8Hz,1H),6.45(dd,J=5.6,10.2Hz,1H),5.28(s,2H),5.03(s,2H),4.47(br d,J=3.4Hz,2H),4.07-3.95(m,1H),3.92(s,3H),3.68(br t,J=7.2Hz,2H),3.41(br t,J=7.4Hz,3H),3.16(q,J=9.8Hz,2H);LCMS(ESI)m/z:603[M+1]
+。
实施例16
合成路线:
化合物16的合成
冰水浴0℃氮气保护下,向化合物4-3(2.0g,5.47mmol)的N,N-二甲基甲酰胺(20mL)溶液中加入N,N-二异丙基乙胺(1.41g,10.95mmol)和2-(7-偶氮苯并三氮唑)-N,N,N,N-四甲基脲六氟磷酸酯(3.12g,8.21mmol),搅拌30分钟后加入化合物1-8(1g,5.78mmol),得到的混合物自然升至室温25℃搅拌16小时。向反应液中加入乙酸乙酯(100mL)和水(50mL)搅拌10分钟,收集有机相,无水硫酸钠干燥,过滤,减压浓缩后得到粗品,粗品通过柱层析(梯度洗脱:甲醇/二氯甲烷,甲醇%:0~10%,流速60mL/min)纯化得到化合物16。
1HNMR(400MHz,CD
3OD)δppm 8.02(s,1H),7.69(dd,J=6.7,1.8Hz,1H),7.52(ddd,J=9.0,6.8,2.0Hz,1H),7.29(q,J=8.4Hz,4H),7.03(br d,J=5.1Hz,1H),6.88(br d,J=2.0Hz,1H),6.57(d,J=9.0Hz,1H),6.35-6.41(m,1H),5.29(s,2H),5.18(s,2H),4.98(dd,J=8.5,5.8Hz,2H),4.90(br s,2H),4.65(s,1H),4.51(s,2H),3.84ppm(s,3H);LCMS(ESI)m/z:521[M+1]
+。
实施例17
合成路线:
化合物17的合成
室温25℃氮气保护下,向化合物4-3(100mg,273.7μmol)和化合物2-1(63.2mg,328.4μmol)的N,N-二甲基甲酰胺(1mL)溶液中加入N,N-二异丙基乙基胺(106.2mg,821.6μmol)和2-(7-偶氮苯并三氮唑)-N,N,N,N-四甲基脲六氟磷酸酯(124.9mg,328.4μmol),得到的混合物搅拌16小时。向反应液中加入乙酸乙酯(5mL)和水(3mL)搅拌5分钟,除去水相,有机相减压浓缩,粗品经制备高效液相色谱(色谱柱:Welch Xtimate C18 150*25mm*5μm;流动相:[A-10mM碳酸氢铵水溶液;B-乙腈;B%:25%-55%,10.5min)纯化得到化合物17。
1HNMR(400MHz,CD
3OD)δppm 8.17(d,J=5.6,1H),8.10(s,1H),7.70(m,1H),7.52(m,1H),7.28-7.34(m,4H),7.11-7.14(m,1H),6.56-6.58(m,1H),6.38-6.40(m,1H),5.32(s,1H),5.19(s,1H),4.97-4.99(m,4H),4.62-4.66(m,2H),4.57(s,2H),3.96(s,3H);LCMS(ESI)m/z:504[M+1]
+。
实施例18
合成路线:
1)化合物18的合成
向预先干燥的单口瓶中加入化合物8-7(200mg,498.30μmol),四氢呋喃(3mL),然后加入N,N-二异丙基乙胺(225.41mg,1.74mmol,303.78μL),N,N’羰基二咪唑(105.04mg,647.79mmol)50℃搅拌1小时后,加入化合物2-1(115.18mg,597.96μmol),50℃搅拌16小时后,补加2-1(23.34mg,121.09μmol),50℃搅拌3小时后,补加化合物2-1(22mg,114.22μmol),50℃搅拌16小时。反应液减压浓缩后,加入N,N二甲基甲酰胺(3mL)溶解,过滤,滤液减压浓缩后经制备高效液相色谱(色谱柱:Waters Xbridge BEH C18 100*30mm*10μm;流动相:[A-10mM碳酸氢铵水溶液;B-乙腈B%:15%-45%,8min)纯化得到目标化合物18。
1HNMR(400MHz,DMSO-d
6)δppm 8.39(t,J=5.7Hz,1H),8.29(s,1H),8.21(d,J=5.7Hz,1H),7.98-7.93(m,1H),7.60(ddd,J=3.5,7.0,10.1Hz,1H),7.19-7.12(m,3H),7.09-7.05(m,1H),6.44(dd,J=5.7,10.1Hz,1H),6.10-6.08(m,1H),5.34(s,2H),5.06(s,2H),4.81-4.76(m,2H),4.67(dd,J=5.7,7.0Hz,2H),4.56-4.43(m,3H),3.91(s,3H)。
2)化合物18盐酸盐的制备
向预先干燥的单口瓶中加入化合物18(42.8mg,79.33μmol),乙腈(20mL),超声溶清后加入稀盐酸(1.1M,72.12μL),15℃搅拌3小时,反应液抽滤,并用乙腈(5mL)淋洗滤饼,滤干后继续减压抽滤2小时,去除残留乙腈,收集滤饼,干燥后得到化合物18的盐酸盐。
1HNMR(400MHz,DMSO-d
6)δppm 8.46(s,1H),8.34-8.23(m,2H),7.97(t,J=3.9Hz,1H),7.61(s,1H),7.25(s,1H),7.19-7.11(m,2H),7.09-7.04(m,1H),6.44(dd,J=5.3,10.1Hz,1H),5.35(s,2H),5.06(s,2H),4.78(dd,J=5.7,8.3Hz,2H),4.71-4.64(m,2H),4.53-4.44(m,3H),3.95(s,3H);LCMS(ESI)m/z:540[M+1]
+。
实验例1:测试化合物对血浆激肽释放酶(PKal)的抑制作用
1.PKal反应缓冲液:25mM Tris-HCl(三羟甲基氨基甲烷-HCl),pH 8.0,100mM NaCl,pH 8.5,0.01%Brij35(月桂醇聚氧乙烯醚),and 1%DMSO(最终浓度)。
2.酶:PKal(R&D Systems Cat#2497-SE),在小鼠骨髓瘤细胞株中表达的重组人源血浆激肽释放酶,由NS0-衍生的Gly20-Ala638,C-端带有60-His附属物,MW=70kDa。酶的活化:(1)将rhPKal稀释为200μg/mL的激活缓冲液(100mM Tris,10mM CaCl
2,150mM NaCl,pH 7.5(TCN));(2)将嗜热菌蛋白酶(Thermolysin)稀释为20μg/mL的激活缓冲液;(3)将rhPKal(200μg/mL)和嗜热菌蛋白酶(20μg/mL)等体积混合;(4)37℃孵育30min;(5)再用50μM EDTA(乙二胺四乙酸)终止反应。
3.基质(Enzo Cat#P-139):10μM Z-FR-AMC(AMC:7-氨基-4-甲基香豆素)。
4.检测:EnVision(PE),Ex/Em 355/460nm。
5.反应过程:(1)准备指定的酶和基质在新配制的激活缓冲液中;(2)将酶溶液注入反应孔中;(3)采用声学技术(Echo 550,LabCyte Inc.Sunnyvale,CA)将供试品的DMSO溶液注入反应混合液中,并控制在纳升范围内;(4)预培养10min后,将基质溶液注入到反应孔中开始反应;(5)酶的活性可通过荧光标记肽基质的荧光信号增加来指示,每5min监测一次,室温下持续120min;(6)数据分析:测量直线的斜率*(荧光信号/时间),斜率可由excel计算出来,通过Prism软件拟合曲线。化合物对血浆激肽释放酶(PKal)的抑制作用测试结果如下表1所示。
表1化合物对血浆激肽释放酶的抑制作用测试结果
化合物编号 | IC 50(人PKal)nM | 化合物编号 | IC 50(人PKal)nM |
化合物1 | 0.139 | 化合物10 | 0.344 |
化合物2 | 1.53 | 化合物11盐酸盐 | 0.268 |
化合物3 | 0.264 | 化合物12盐酸盐 | 1.08 |
化合物4 | 0.052 | 化合物13 | 0.833 |
化合物5 | 18.7 | 化合物14 | 0.717 |
化合物6 | 2.63 | 化合物15 | 2.24 |
化合物7 | 0.552 | 化合物16 | 0.62 |
化合物8 | 0.465 | 化合物17 | 0.053 |
化合物9 | 1.03 | 化合物18盐酸盐 | 2.31 |
实验结论:本发明化合物对血浆激肽释放酶(PKal)的抑制作用显著。
实验例2:本发明化合物的药代动力学测试
1.摘要
以雄性SD大鼠为受试动物,应用LC-MS/MS法测定大鼠静脉和灌胃给予受试化合物后不同时刻血浆中的药物浓度。研究化合物在大鼠体内的药代动力学行为,评价其药动学特征。
2.实验方案
2.1试验药品:受试化合物。
2.2试验动物:健康成年雄性SD大鼠28只,分成14组,每组2只。动物购买自北京维通利华实验动物技术有限公司
2.3药物配制
称取适量样品,按照体积比例10:10:80依次加入适量DMSO、聚氧乙烯蓖麻油和无菌注射用水,搅拌超声后达到0.5mg/mL的澄清状态用于静脉给药。
称取适量样品,按照体积比例10:10:80依次加入适量DMSO、聚氧乙烯蓖麻油和无菌注射用水,搅拌超声后达到0.4mg/mL的澄清或混悬液状态用于灌胃给药。
称取适量样品,按照体积比例10:10:80依次加入适量DMSO、聚氧乙烯蓖麻油和无菌注射用水,搅拌超声后达到3mg/mL的澄清状态用于静脉给药。
2.4给药:雄性SD大鼠28只,分成14组,禁食一夜后,静脉给药组,给药体积为2mL/kg,剂量为1mg/kg;灌胃给药组1,给药体积为5mL/kg,剂量为2mg/kg。灌胃给药组2,给药体积为10mL/kg,剂量为30mg/kg。
3.实验操作及结果
雄性SD大鼠静脉给予化合物后,分别在0.0833,0.25,0.5,1,2,4,8及24小时采血40μL,置于含有2μL EDTA-K
2的试管中。灌胃给药组给予化合物后,分别在0.25,0.5,1,2,4,6,10及24小时采血40μL,置于含有2μL EDTA-K
2的试管中。试管在4000rpm离心15分钟分离血浆,并于-60℃保存。给药2小时后动物可进食。
用LC-MS/MS法测定大鼠静脉和灌胃给药后,血浆中待测化合物的含量。方法的线性范围为2.00~6000nmol/L;血浆样品经乙腈沉淀蛋白处理后进行分析。化合物的药代动力学测试结果如下表2所示。
表2化合物的药代动力学测试结果
注:“—”表示该项不用检测。
实验结论:本发明化合物清除率较低,有一定的口服暴露量和口服生物利用度。
实验例3:本发明化合物在大鼠眼中药代动力学测试
1.摘要
以雄性大鼠为受试动物,应用LC-MS/MS法测定灌胃给予待测化合物后不同时刻眼组织中的药物浓度。研究化合物灌胃给药后在大鼠眼中的药代动力学行为,评价其药动学特征。
2.实验方案
2.1试验药品:受试化合物
2.2试验动物:健康成年雄性大鼠6只,分成3组,每组4只眼睛。动物购买自北京维通利华实验动物技术有限公司。
2.3药物配制:称取适量样品,按照体积比例10:90依次加入适量DMSO和辛酸癸酸聚乙二醇甘油酯,搅拌超声后达到15mg/mL的澄清液状态用于灌胃给药。
2.4给药:雄性SD大鼠6只,分成3组,禁食一夜后,灌胃给药组,给药体积为5mL/kg,剂量为75mg/kg。
3.实验操作及结果
雄性大鼠灌胃给予化合物1后,分别在1,4及8小时使一组(2只)大鼠安乐死,每只大鼠的2只眼睛合并眼组织,测量在视网膜、脉络膜/巩膜中化合物的浓度。
用LC-MS/MS法测定大鼠灌胃给药后,眼组织中待测化合物的含量。方法的线性范围为2.00~6000nmol/L;眼组织浓度数据呈现在表3,其中每个眼组织浓度数据是2只大鼠的左右眼合并后检测所得。本发明化合物的眼中药代动力学测试结果如下表3所示。
表3本发明化合物在大鼠眼中药代动力学测试结果
注:“_”表示用于计算该参数的有效数值不足,无法计算(可定量值小于3个)。
“ND”表示未测出。
实验结论:本发明化合物在大鼠眼底视网膜和脉络膜都有一定的药物暴露量。
实验例4本发明化合物对CA-1(100ng)诱导的大鼠DME模型的体内药效学研究
1.实验设计
从25只雄性SD大鼠中选择20只,根据体重分入5组,每组4只,每组各1只备用动物,在造模前、造模后48小时和72小时,分别对所有动物进行视网膜光学相干断层扫描检查。选择合适的扫描位置进行测量并标记视网膜厚度。通过各组视网膜厚度的变化,对供试品改善视网膜水肿的作用进行比较,筛选活性化合物。以上造模及检查的实验操作,须遵循先右眼后左眼的顺序。
表4本发明化合物对CA-1诱导的大鼠DME模型实验方案
2.实验材料
2.1实验动物
种属:大鼠
品系:SD大鼠,SPF级
周龄及体重:7-8周龄,体重250-300克
性别:雄性
供应商:浙江维通利华实验动物技术有限公司
动物合格证号:
2.2造模剂
碳酸酐酶-1(CA-1,Sigma)
3.实验方法与步骤
3.1给药及造模
造模当天,所有动物先口服给予溶媒或供试品,大约4小时后,对动物进行双眼玻璃体腔注射生理盐水(5μL/眼)或CA-I(100ng/眼)进行造模,将第二只眼注射结束时间记为0小时,造模后4±0.5、20±0.5小时、28±0.5小时、44±0.5小时、52±0.5小时和68±0.5小时分别对所有动物口服给予溶媒(10%DMSO+90%辛酸癸酸聚乙二醇甘油酯)或供试品。
3.2光学相干断层扫描(OCT)检查
造模前、造模后48小时和72小时,先对动物麻醉,然后进行光学相干断层扫描(OCT)检查,麻 醉前使用适当的散瞳剂,确保动物的瞳孔已完全散开,采用舒泰(5mg/kg)和噻拉嗪溶液(3mg/kg)联合肌肉注射的方法进行麻醉。OCT检查要求如下:
1)数据采集时须将视盘置于红外眼底图像正中位置;
2)采用“米字”形,交叉点过视盘,以最宽长度进行视网膜扫描。
3)在尽可能的情况下采用软件追踪功能,进行给药前后视网膜厚度的比较,如果无法使用追踪功能,则尽可能调节眼位与给药前一致,并尽量保证断层扫描图像的清晰,以利于给药前后视网膜厚度的比较。
4.实验结果
造模前OCT检查各组动物的视网膜显示正常,造模后48小时和72小时观察到只注射生理盐水的大鼠视网膜明显增厚,口服给药组的大鼠视网膜增厚有不同程度的缓解,化合物1低剂量组(50mg/kg)在48小时对视网膜增厚部分缓解(缓解率19%),在72h小时对视网膜增厚显著缓解(缓解率79%);化合物1高剂量组(75mg/kg)在48小时和72h小时均完全缓解了碳酸酐酶-1引起的视网膜增厚(缓解率100%)。化合物8(75mg/kg)在48小时对视网膜增厚部分缓解(缓解率84%),72h小时完全缓解了碳酸酐酶-1引起的视网膜增厚(缓解率116%)同时动物对上述受试化合物都具有良好的耐受性。
Claims (12)
- 式(Ⅰ)化合物或其药学上可接受的盐,其中,R 1为H、F、Cl、Br、I、OH或NH 2;R 2为H、F、Cl、Br、I、OH或NH 2;R 3为H、F、Cl、Br、I、OH、C 1-3烷基或C 1-3烷氧基,其中所述C 1-3烷基和C 1-3烷氧基分别独立地任选被1、2或3个R a取代;R 4为H或C 1-3烷基,其中所述C 1-3烷基任选被1、2或3个R b取代;T 1为N或CR 5;T 2为N或CR 6;T 3为N或CR 7;E 1为O或NR 8;R 5、R 6和R 7分别独立地为H、F、Cl、Br、I、OH或NH 2;R 8为H、C 1-3烷基、C 1-3烷氧基、-C(=O)C 1-3烷基或-S(=O) 2C 1-3烷基,其中所述C 1-3烷基、-C 1-3烷氧基、-C(=O)C 1-3烷基和-S(=O) 2C 1-3烷基分别独立地任选被1、2或3个R c取代;R a、R b和R c分别独立地为F、Cl、Br、I、OH或NH 2。
- 根据权利要求1所述化合物或其药学上可接受的盐,其中,R 3为H、F、Cl、Br、I、OH、CH 3或-O-CH 3,其中所述CH 3和-O-CH 3分别独立地任选被1、2或3个R a取代。
- 根据权利要求2所述化合物或其药学上可接受的盐,其中,R 3为-O-CH 3。
- 根据权利要求1所述化合物或其药学上可接受的盐,其中,R 4为H或CH 3,其中所述CH 3任选被1、2或3个R b取代。
- 根据权利要求4所述化合物或其药学上可接受的盐,其中,R 4为H或CH 3。
- 根据权利要求1所述化合物或其药学上可接受的盐,其中,R 8为H、CH 3、CH 2-CH 3、-C(=O)-CH 3或-S(=O) 2-CH 3,其中所述CH 3、CH 2-CH 3、-C(=O)-CH 3或-S(=O) 2-CH 3任选被1、2或3个R c取代。
- 根据权利要求6所述化合物或其药学上可接受的盐,其中,R 8为H、CH 3、CH 2-CF 3、-C(=O)-CH 3或-S(=O) 2-CH 3。
- 根据权利要求1-9任意一项所述的化合物或其药学上可接受的盐,其中所述的盐为盐酸盐。
- 根据权利要求1-9任意一项所述的化合物或其药学上可接受的盐在制备血浆激肽释放酶抑制剂相关药物的用途。
- 根据权利要求10所述的盐酸盐在制备血浆激肽释放酶抑制剂相关药物的用途。
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JP2022552856A JP7245397B2 (ja) | 2020-03-04 | 2021-03-04 | 複素環化合物 |
US17/905,538 US11814371B2 (en) | 2020-03-04 | 2021-03-04 | Heterocyclic compound |
CN202180018862.5A CN115210230A (zh) | 2020-03-04 | 2021-03-04 | 杂环类化合物 |
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