CN108203449A - 一种新型可逆性质子泵抑制剂及其制备方法和用途 - Google Patents
一种新型可逆性质子泵抑制剂及其制备方法和用途 Download PDFInfo
- Publication number
- CN108203449A CN108203449A CN201611170710.4A CN201611170710A CN108203449A CN 108203449 A CN108203449 A CN 108203449A CN 201611170710 A CN201611170710 A CN 201611170710A CN 108203449 A CN108203449 A CN 108203449A
- Authority
- CN
- China
- Prior art keywords
- methyl
- compound
- methoxyl group
- methoxy
- difluoro
- 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.)
- Pending
Links
- 229940126409 proton pump inhibitor Drugs 0.000 title claims abstract description 15
- 239000000612 proton pump inhibitor Substances 0.000 title claims abstract description 15
- 230000002441 reversible effect Effects 0.000 title claims abstract description 13
- 238000002360 preparation method Methods 0.000 title abstract description 13
- 150000001875 compounds Chemical class 0.000 claims abstract description 51
- 239000003814 drug Substances 0.000 claims abstract description 15
- 150000003839 salts Chemical class 0.000 claims abstract description 11
- 238000011282 treatment Methods 0.000 claims abstract description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 6
- 206010063655 Erosive oesophagitis Diseases 0.000 claims abstract description 4
- 208000007107 Stomach Ulcer Diseases 0.000 claims abstract description 4
- 201000005917 gastric ulcer Diseases 0.000 claims abstract description 4
- 208000000718 duodenal ulcer Diseases 0.000 claims abstract description 3
- 230000005496 eutectics Effects 0.000 claims abstract description 3
- 239000012453 solvate Substances 0.000 claims abstract 2
- -1 eutectic Substances 0.000 claims description 20
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
- 229940079593 drug Drugs 0.000 claims description 11
- ZRNSSRODJSSVEJ-UHFFFAOYSA-N 2-methylpentacosane Chemical compound CCCCCCCCCCCCCCCCCCCCCCCC(C)C ZRNSSRODJSSVEJ-UHFFFAOYSA-N 0.000 claims description 8
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims description 8
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- 150000002367 halogens Chemical class 0.000 claims description 8
- NBVXSUQYWXRMNV-UHFFFAOYSA-N monofluoromethane Natural products FC NBVXSUQYWXRMNV-UHFFFAOYSA-N 0.000 claims description 8
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 8
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 7
- 239000001103 potassium chloride Substances 0.000 claims description 5
- 235000011164 potassium chloride Nutrition 0.000 claims description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 claims description 4
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 claims description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 3
- 229910002651 NO3 Inorganic materials 0.000 claims description 3
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 claims description 3
- 229910019142 PO4 Inorganic materials 0.000 claims description 3
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 3
- 229940072056 alginate Drugs 0.000 claims description 3
- 235000010443 alginic acid Nutrition 0.000 claims description 3
- 229920000615 alginic acid Polymers 0.000 claims description 3
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 3
- VFNGKCDDZUSWLR-UHFFFAOYSA-L disulfate(2-) Chemical compound [O-]S(=O)(=O)OS([O-])(=O)=O VFNGKCDDZUSWLR-UHFFFAOYSA-L 0.000 claims description 3
- 229950005627 embonate Drugs 0.000 claims description 3
- 229940049920 malate Drugs 0.000 claims description 3
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 3
- PSZYNBSKGUBXEH-UHFFFAOYSA-M naphthalene-1-sulfonate Chemical compound C1=CC=C2C(S(=O)(=O)[O-])=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-M 0.000 claims description 3
- 150000003891 oxalate salts Chemical class 0.000 claims description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 3
- 239000010452 phosphate Substances 0.000 claims description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 159000000007 calcium salts Chemical class 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 159000000003 magnesium salts Chemical class 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 159000000000 sodium salts Chemical class 0.000 claims description 2
- 150000003892 tartrate salts Chemical class 0.000 claims description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims 1
- 229940050390 benzoate Drugs 0.000 claims 1
- 239000003085 diluting agent Substances 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- PQIOSYKVBBWRRI-UHFFFAOYSA-N methylphosphonyl difluoride Chemical group CP(F)(F)=O PQIOSYKVBBWRRI-UHFFFAOYSA-N 0.000 claims 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical class OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims 1
- 229940095064 tartrate Drugs 0.000 claims 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 239000000243 solution Substances 0.000 description 12
- 238000000034 method Methods 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- 102000004190 Enzymes Human genes 0.000 description 9
- 108090000790 Enzymes Proteins 0.000 description 9
- 230000000694 effects Effects 0.000 description 9
- 229920000333 poly(propyleneimine) Polymers 0.000 description 9
- ZKHQWZAMYRWXGA-KQYNXXCUSA-N Adenosine triphosphate Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O ZKHQWZAMYRWXGA-KQYNXXCUSA-N 0.000 description 8
- 229920006217 cellulose acetate butyrate Polymers 0.000 description 8
- ROGSHYHKHPCCJW-WLHGVMLRSA-N (e)-but-2-enedioic acid;1-[5-(2-fluorophenyl)-1-pyridin-3-ylsulfonylpyrrol-3-yl]-n-methylmethanamine Chemical compound OC(=O)\C=C\C(O)=O.C=1C=CN=CC=1S(=O)(=O)N1C=C(CNC)C=C1C1=CC=CC=C1F ROGSHYHKHPCCJW-WLHGVMLRSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 241000699666 Mus <mouse, genus> Species 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 210000004369 blood Anatomy 0.000 description 6
- 239000008280 blood Substances 0.000 description 6
- 229910052731 fluorine Inorganic materials 0.000 description 6
- 239000011737 fluorine Substances 0.000 description 6
- 229950003825 vonoprazan Drugs 0.000 description 6
- 229930006000 Sucrose Natural products 0.000 description 5
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 239000005720 sucrose Substances 0.000 description 5
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
- 239000003340 retarding agent Substances 0.000 description 4
- 210000002784 stomach Anatomy 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- 108030003004 Triphosphatases Proteins 0.000 description 3
- 239000007983 Tris buffer Substances 0.000 description 3
- LXKFVPKKRVKNIJ-MCDZGGTQSA-N [K].C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O Chemical compound [K].C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O LXKFVPKKRVKNIJ-MCDZGGTQSA-N 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 230000000857 drug effect Effects 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 230000027119 gastric acid secretion Effects 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- FDZZZRQASAIRJF-UHFFFAOYSA-M malachite green Chemical compound [Cl-].C1=CC(N(C)C)=CC=C1C(C=1C=CC=CC=1)=C1C=CC(=[N+](C)C)C=C1 FDZZZRQASAIRJF-UHFFFAOYSA-M 0.000 description 3
- 229940107698 malachite green Drugs 0.000 description 3
- 231100000668 minimum lethal dose Toxicity 0.000 description 3
- 210000004400 mucous membrane Anatomy 0.000 description 3
- 210000002381 plasma Anatomy 0.000 description 3
- 239000011591 potassium Substances 0.000 description 3
- 229910052700 potassium Inorganic materials 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- DAEPDZWVDSPTHF-UHFFFAOYSA-M sodium pyruvate Chemical class [Na+].CC(=O)C([O-])=O DAEPDZWVDSPTHF-UHFFFAOYSA-M 0.000 description 3
- 238000010792 warming Methods 0.000 description 3
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 229920001917 Ficoll Polymers 0.000 description 2
- 150000008540 L-glutamines Chemical class 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical class [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- 229930182555 Penicillin Natural products 0.000 description 2
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 2
- 208000008469 Peptic Ulcer Diseases 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- NPYPAHLBTDXSSS-UHFFFAOYSA-N Potassium ion Chemical compound [K+] NPYPAHLBTDXSSS-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 238000007605 air drying Methods 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 230000002860 competitive effect Effects 0.000 description 2
- 238000006911 enzymatic reaction Methods 0.000 description 2
- 210000004211 gastric acid Anatomy 0.000 description 2
- 208000021302 gastroesophageal reflux disease Diseases 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 238000011221 initial treatment Methods 0.000 description 2
- 229910052816 inorganic phosphate Inorganic materials 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 235000011147 magnesium chloride Nutrition 0.000 description 2
- 230000003228 microsomal effect Effects 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N mono-methylamine Natural products NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- 230000000422 nocturnal effect Effects 0.000 description 2
- 210000001711 oxyntic cell Anatomy 0.000 description 2
- 229940049954 penicillin Drugs 0.000 description 2
- 208000000689 peptic esophagitis Diseases 0.000 description 2
- 208000011906 peptic ulcer disease Diseases 0.000 description 2
- 229910001414 potassium ion Inorganic materials 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 230000001629 suppression Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 210000003462 vein Anatomy 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 101710181757 1,2-dihydroxy-3-keto-5-methylthiopentene dioxygenase Proteins 0.000 description 1
- ATRQECRSCHYSNP-UHFFFAOYSA-N 2-(trifluoromethyl)pyridine Chemical class FC(F)(F)C1=CC=CC=N1 ATRQECRSCHYSNP-UHFFFAOYSA-N 0.000 description 1
- GKWLIQDHWRWNRS-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC(N)(CO)CO.OCCN1CCN(CCS(O)(=O)=O)CC1 GKWLIQDHWRWNRS-UHFFFAOYSA-N 0.000 description 1
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
- 101710094863 Acireductone dioxygenase Proteins 0.000 description 1
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical class N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 101100111800 Caenorhabditis elegans best-24 gene Proteins 0.000 description 1
- 206010011224 Cough Diseases 0.000 description 1
- 102000019057 Cytochrome P-450 CYP2C19 Human genes 0.000 description 1
- 108010026925 Cytochrome P-450 CYP2C19 Proteins 0.000 description 1
- 241000167880 Hirundinidae Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- YLUGBQJQQLZZNL-UHFFFAOYSA-N O.O.O.O.O.O.O.[Na].[Na] Chemical compound O.O.O.O.O.O.O.[Na].[Na] YLUGBQJQQLZZNL-UHFFFAOYSA-N 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- 102100021904 Potassium-transporting ATPase alpha chain 1 Human genes 0.000 description 1
- 108010083204 Proton Pumps Proteins 0.000 description 1
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical class C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 239000011609 ammonium molybdate Substances 0.000 description 1
- APUPEJJSWDHEBO-UHFFFAOYSA-P ammonium molybdate Chemical compound [NH4+].[NH4+].[O-][Mo]([O-])(=O)=O APUPEJJSWDHEBO-UHFFFAOYSA-P 0.000 description 1
- 235000018660 ammonium molybdate Nutrition 0.000 description 1
- 229940010552 ammonium molybdate Drugs 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000001262 anti-secretory effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000012752 auxiliary agent Substances 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004737 colorimetric analysis Methods 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- KCIDZIIHRGYJAE-YGFYJFDDSA-L dipotassium;[(2r,3r,4s,5r,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl] phosphate Chemical compound [K+].[K+].OC[C@H]1O[C@H](OP([O-])([O-])=O)[C@H](O)[C@@H](O)[C@H]1O KCIDZIIHRGYJAE-YGFYJFDDSA-L 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 230000036267 drug metabolism Effects 0.000 description 1
- 210000001198 duodenum Anatomy 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000012894 fetal calf serum Substances 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 230000030136 gastric emptying Effects 0.000 description 1
- 210000001156 gastric mucosa Anatomy 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 230000003862 health status Effects 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000003485 histamine H2 receptor antagonist Substances 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000010813 internal standard method Methods 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 231100000225 lethality Toxicity 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 238000011866 long-term treatment Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000037323 metabolic rate Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 230000035764 nutrition Effects 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Substances OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 150000003109 potassium Chemical class 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 150000003233 pyrroles Chemical class 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000009938 salting Methods 0.000 description 1
- 239000013049 sediment Substances 0.000 description 1
- 229940054269 sodium pyruvate Drugs 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000006190 sub-lingual tablet Substances 0.000 description 1
- 229940098466 sublingual tablet Drugs 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000008399 tap water Substances 0.000 description 1
- 235000020679 tap water Nutrition 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000012549 training Methods 0.000 description 1
- WKMXOPXIVBEXRR-UHFFFAOYSA-H tricalcium;diphosphate;dihydrate Chemical compound O.O.[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O WKMXOPXIVBEXRR-UHFFFAOYSA-H 0.000 description 1
- 210000005239 tubule Anatomy 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
Classifications
-
- 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
- C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
- C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及一种新型可逆性质子泵抑制剂及其在临床上的用途,本发明所述新型可逆性质子泵抑制剂具有下式(I)所示的结构。本发明还包括式(I)所示的化合物或水合物、溶剂化物、共晶体、药学上可接受的盐、其制备方法。该类化合物的药物组合物在医药上的用途,特别是用于糜烂性食管炎、胃溃疡、十二指肠溃疡的治疗。
Description
技术领域
本发明涉及一种新型可逆性质子泵抑制剂及其非毒性药学可接受的盐、制备方法、含它们的药物组合物和临床上用途,特别是用于糜烂性食管炎、胃溃疡、十二指肠溃疡的治疗。
背景技术
胃酸分泌过多可引起消化性溃疡、反流性食管炎及其他胃酸分泌相关疾病。抑制胃酸分泌是该类疾病的主要治疗方法。临床上常用的抑酸药物有组胺H2受体拮抗剂(H2-Ras)和质子泵抑制剂(proton pump inhibitors,PPIs)。H2-Ras治疗反流性食管炎和胃肠出血的疗效不如治疗消化性溃疡的疗效好,且机体会对其快速产生耐受,这一点也限制此类药物在长期治疗及大量静脉注射中的应用。在临床上,质子泵抑制剂(PPIs)已被广泛应用于ARDs的治疗,是此类疾病的主要治疗药物。但是PPIs仍有一些局限性需要进一步改进:①所有的PPIs都是酸不稳定性的,因此需要做成酸保护的剂型,如肠衣片等,它们的起效速度和药效受到胃排空的较大影响;②PPIs需要H+激活转化,起效较慢,通常需要3~5天时间且多次给药,才能达到稳定的最大疗效;③由于人群中肝脏CYP2C19代谢系统的基因多样性,PPIs在不同病人中疗效差异较大,而且有可能与其他药物存在药物代谢上的相互作用;④药效与给药剂量成线性关系,血浆中代谢较快,即使一天两次给药,PPIs也很难持续24小时控制胃酸分泌。因此,PPIs对于某些病人的夜间胃酸分泌的抑制作用是不足的,夜间酸突破现象普遍存在。
钾竞争性酸阻滞剂(potassium-competitive acid blockers,P-CABs)为一类新型抑酸剂,P-CABs能够以钾离子竞争性的方式可逆性的抑制胃壁细胞上的H+,K+-ATP酶,是一种可逆性K+拮抗剂,该类药物具有更高的pKa,在强酸性环境中较为稳定,可以高度富集在泌酸小管壁细胞H+,K+-ATP酶的管腔侧表面,迅速质子化,以离子的形式非共价结合并抑制H+,K+-ATP酶,由于不需要类似PPIs的强酸依赖性激活转化,因此P-CABs在应用中具有更快的起效速度。P-CABs可以特异性的结合到H+,K+-ATP酶的E2P构型上,这种机理导致对质子泵迅速的抑制,因为抑制作用在酶催化循环的中问即可发生。由于此类药物的抑酸作用与H+,K+-ATP酶的活化状态无关,临床应用中可以显著降低夜间酸突破的发生。在动物和人体试验中也表明,P-CABs口服后可迅速达到稳定的血药浓度,因此此类药物的抑酸作用起效更快,且作用持续时间与血浆中药物的半衰期有关,首次口服后即可达到最大的抑酸效果。目前部分新型钾离子竞争性阻滞剂(P-CABs)的制剂已进入临床研究或已上市。
目前公开了一系列的钾竞争性阻滞剂(P-CABs)的专利申请,主要有WO2005041961、WO2006134460、WO2009041447、WO2010021149和WO2014075575等。
尽管目前已公开了一系列的吡咯类衍生物,但是仍需开发新的具有更好药效和更少不良反应的钾竞争性酸阻滞剂(P-CABs)。本发明通过设计具有通式(Ⅰ)所示结构的化合物,并发现具有此类结构的化合物表现出优异的效果。
发明内容
本发明提供了如下通式I所示的可逆性质子泵抑制剂,同时还提供了一系列通式I的化合物在药学上可接受的盐、水合物、溶剂化合物、共晶体。
(Ⅰ)
其中:
n 为0至10的整数;
R1选自H、甲氧基、甲基、三氟乙氧基、甲氧基丙氧基、卤素、三氟甲氧基、二氟甲氧基、氟甲氧基、三氟甲基、二氟甲基、氟甲基;
R2选自H、甲氧基、甲基、三氟乙氧基、甲氧基丙氧基、卤素、三氟甲氧基、二氟甲氧基、氟甲氧基、三氟甲基、二氟甲基、氟甲基;
R3选自H、甲氧基、甲基、三氟乙氧基、甲氧基丙氧基、卤素、三氟甲氧基、二氟甲氧基、氟甲氧基、三氟甲基、二氟甲基、氟甲基;
R4选自氢基、甲基、、(结构式中的波浪线表示连接位置);
R5选自甲基、羟基、(结构式中的波浪线表示连接位置);
R6选自甲基、甲氧基、羟基、卤素、三氟甲氧基、二氟甲氧基、氟甲氧基、三氟甲基、二氟甲基、氟甲基;
Y为盐酸盐,氢溴酸盐,硫酸盐,硫酸氢盐、磷酸盐,硝酸盐,以及醋酸盐,草酸盐,酒石酸盐,琥珀酸盐,苹果酸盐,苯甲酸盐,双羟萘酸盐,海藻酸盐,枸橼酸盐,丁二酸盐,富马酸盐,甲磺酸盐,萘磺酸盐。
所述R4基团的X可以为钠盐、钾盐、镁盐、钙盐;
上述通式I的化合物包括消旋体、S构型、R构型。
本发明提供通式I的化合物、其立体异构体或药学上可以接受的盐,其中,所述通式I的化合物括下列化合物:
本发明第二方面提供制备可逆性质子泵抑制剂、其立体异构体或药学上可接受的盐的方法。步骤如下:
上述化合物包括消旋体、S构型、R构型。
本发明还提供可逆性质子泵抑制剂或其药用盐在糜烂性食管炎、胃溃疡、十二指肠溃疡中的用途。
本发明还提供含有本发明可逆性质子泵抑制剂和立体异构体或药用盐的药物组合物,其包括临床有效剂量的本发明可逆性质子泵抑制剂、其立体异构体或药用盐以及任选的药学可接受的载体。本发明所获得的可逆性质子泵抑制剂、其立体异构体或药用盐可以单独或以药物组合的形式给药。本发明药物组合可根据给药途径配成各种适宜的剂型。使用一种或多种生理上可接受的载体,包含赋形剂和助剂,它们有利于将活性化合物加工成可以在药学上使用的制剂。适当的制剂形式取决于所选择的给药途径,可以按照本领域熟知的常识进行制造。
给药途径可以是口服、非肠道或局部给药,优选口服和注射形式给药。可以口服的给药制剂包括胶囊剂、颗粒剂和片剂等。患者吞咽有困难时,也可以采用舌下片或者其它非吞咽的方式给药。本发明化合物也可以用于配制用于胃肠外给药或者透皮给药或者经黏膜给药。或者采用栓剂或者埋植剂的方式给药。本领域技术人员可以理解,本发明化合物可以采用合适的药物释放系统以得到更有利的效果。
另外需要指出,本发明化合物使用剂量和使用方法取决于诸多因素,包括患者的年龄、体重、性别、健康状况、营养状况、化合物的活性强度、使用时间、代谢速率、病症的严重程度以及诊治医生的主观判断。优选的使用剂量介于2~1200mg/kg;最好24小时的给药量为每公斤 1~100mg,也可采用多次给药方式。
下面结合实施例对本发明作进一步详细说明,但应理解本发明的范围非仅限于这些实施例的范围。
实施例1: 5-(2-氟苯基)-N-甲基-1-(3-磺酰基吡啶基)-1H-吡咯-3-甲胺磷酸酯的制备
取1L三口瓶,称取5-(2-氟苯基)-N-甲基-1-(3-磺酰基吡啶基)-1H-吡咯-3-甲胺100g,加入瓶中,加入乙腈100ml中,搅拌,冰水浴降温,控温0℃,加入三氯氧磷10g,搅拌30min,升温至25-35℃反应6小时,再降温至0℃,慢慢加入水20ml,加完后用氢氧化钠溶液调节pH至4.0,60℃减压蒸干,加入无水乙醇100ml,搅拌30分钟,过滤,滤液减压蒸干,得类白色固体64.6g,收率71.2%。
实施例2:5-(5-甲氧基苯基)-N-甲基-1-(5-甲基-3-磺酰基吡啶基)-1H-吡咯-3-甲胺磷酸二丙酯的制备
取1L三口瓶,称取5-(5-甲氧基苯基)-N-甲基-1-(5-甲基-3-磺酰基吡啶基)-1H-吡咯-3-甲胺 100g,加入瓶中,加入二氯甲烷100ml中,搅拌,冰水浴降温,控温0℃,加入双丙基磷酰氯16g,搅拌30min,升温至25-35℃反应10小时,再降温至0℃,搅拌3小时,过滤,滤饼用适量水洗涤,40℃鼓风干燥,得类白色固体68.2g,收率77.2%。
实施例3:5-(4-三氟甲基苯基)-N-甲基-1-(3-磺酰基-4-氟基-6-三氟甲基吡啶基)-1H-吡咯-3-甲胺磷酸酯二钠三水合物的制备
取1L三口瓶,称:5-(4-三氟甲基苯基)-N-甲基-1-(3-磺酰基-4-氟基-6-三氟甲基吡啶基)-1H-吡咯-3-甲胺 100g,加入瓶中,加入乙腈100ml中,搅拌,冰水浴降温,控温0℃,加入三氯氧磷17g,搅拌30min,升温至25-35℃反应6小时,再降温至0℃,慢慢加入水20ml,加完后用氢氧化钠溶液调节pH至4.0,60℃减压蒸干,加入无水乙醇100ml,搅拌30分钟,过滤,滤液用氢氧化钠调节pH至7.0-8.0,搅拌1小时,过滤,40℃鼓风干燥,得类白色固体73.9g,收率84.2%。
实施例4:5-(2-甲基苯基)-N-甲基-1-(3-磺酰基-5-三氟甲基乙氧基吡啶基)-1H-吡咯-3-甲胺磷酸酯二钾六水合物的制备
同实施例3方法制备,区别在于将5-(4-三氟甲基苯基)-N-甲基-1-(3-磺酰基-4-氟基-6-三氟甲基吡啶基)-1H-吡咯-3-甲胺替换为5-(2-甲基苯基)-N-甲基-1-(3-磺酰基-5-三氟甲基乙氧基吡啶基)-1H-吡咯-3-甲胺和氢氧化钠替换成氢氧化钾。
实施例5 :5-(2-氯苯基)-N-甲基-1-(2-甲氧基-3-磺酰基-6-甲基吡啶基)-1H-吡咯-3-甲胺磷酸酯二钾八水合物的制备
同实施例3方法制备,区别在于将5-(4-三氟甲基苯基)-N-甲基-1-(3-磺酰基-4-氟基-6-三氟甲基吡啶基)-1H-吡咯-3-甲胺替换为5-(2-氯苯基)-N-甲基-1-(2-甲氧基-3-磺酰基-6-甲基吡啶基)-1H-吡咯-3-甲胺和氢氧化钠替换成氢氧化钾。
实施例6:5-(3-三氟甲基苯基)-N-乙基-1-(-3-磺酰基-5-氯吡啶基)-1H-吡咯-3-甲胺磷酸酯钙二水合物的制备
同实施例3方法制备,区别在于将5-(4-三氟甲基苯基)-N-甲基-1-(3-磺酰基-4-氟基-6-三氟甲基吡啶基)-1H-吡咯-3-甲胺替换为5-(3-三氟甲基苯基)-N-乙基-1-(-3-磺酰基-5-氯吡啶基)-1H-吡咯-3-甲胺和氢氧化钠替换成氢氧化钙。
实施例7:5-(2-氟苯基)-N-乙基-1-(-3-磺酰基-4-溴吡啶基)-1H-吡咯-3-甲胺磷酸酯二钠七水合物的制备
同实施例3方法制备,区别在于将5-(4-三氟甲基苯基)-N-甲基-1-(3-磺酰基-4-氟基-6-三氟甲基吡啶基)-1H-吡咯-3-甲胺替换为5-(2-氟苯基)-N-乙基-1-(-3-磺酰基-4-溴吡啶基)-1H-吡咯-3-甲胺。
实施例8:本发明的化合物对小鼠静脉给药的急性毒性测试
将200 毫克选实施例制备的化合物组成的组中的一种的混合物对5只ICR小鼠给药 (5周大,雄性,体重 20 克±2 克的小鼠 )。然后观察 2 周后的致死率、体重、症状等,以确定最小致死量 (Minimum Lethal Dose,MLD, mg/Kg )。使用的富马酸沃诺拉赞作为对照。结果如表1所示。
表1:
化合物 | 最小致死量(MLD,mg/Kg) |
富马酸沃诺拉赞 | >110 |
实施例1化合物 | >150 |
实施例2化合物 | >150 |
实施例3化合物 | >150 |
实施例4化合物 | >150 |
实施例5化合物 | >150 |
实施例6化合物 | >150 |
实施例7化合物 | >150 |
根据存活率、体重变化、血液测试和中毒综合症的观察结果证明本发明的可逆性质子泵抑制剂毒性小于富马酸沃诺拉赞。
实施例9:本发明化合物的体内药代动力学试验
方法:
实验动物为雄性小鼠,6 至8 周龄,体重190-215 克,购自北京维利通华实验动物技术有限公司。基于小鼠体重随机分成16组,每组3 只动物。各组小鼠的给药剂量和途径见表2:
在药代动力学试验前,将小鼠禁食16 小时。然后按照表2中所示经静脉(1mL/kg;10mg/kg) 给药单个剂量的化合物。采取颈静脉穿刺的方式在给药后定时收集血液200μL,其中对于经静脉给药的动物组,在给药后0、15 分钟、30 分钟、1 小时、2 小时、4 小时、8 小时和24 小时收集血液。将血样收集于具有EDTA 的样品管中,立即在4℃下以4000rpm 离心血样5 分钟,然后将血浆转移到另一个样品管中,储存于-20 摄氏度下。
采用的方法和仪器如下:
HPLC :Shimadzu
MS:AB API4000Q
柱子:Phenomenex Luna5μC18
流动相:100%乙腈和100%水(3mM 乙酸铵)
定量方法:内标法
表3
由表3中数据可知,实施例中各化合物与富马酸沃诺拉赞对比,其本发明的化合物半衰期明显长于富马酸沃诺拉赞,说明同等剂量本发明的化合物的作用时间更长,优势明显。
实验例10:质子、钾-腺苷三磷酸酶(H+,K+-ATP酶)抑制活性试验
根据Wallmark等人的方法[Biochim. Biophys. Acta,728,31 (1983)],用猪胃制备胃粘膜微粒体级分。首先,移除胃,用自来水冲洗,浸于3mol/L盐水中,并用纸巾擦拭粘膜表面。将胃粘膜剥离、破碎并利用polytron (Kinematica)匀浆于0.25mol/L的蔗糖溶液(pH6.8)中,该蔗糖溶液中含有1mmol/L的EDTA和lOmmol/L的tris-盐酸。将所得均浆以20000×g离心30分钟,并特上清液以100000×g离心90分钟。将沉淀物悬浮于0.25mol/L的蔗糖溶液中,添加(superimposed on)含7.5%聚蔗糖(Ficoll)的0.25mol/L的蔗糖溶液,并以100000×g离心5小时。回收包含两层之间的界面的级分,并用0. 25mol/L的蔗糖溶液离心洗涤。
利用所得微粒体级分作为质子、钾-腺苷三磷酸酶标准制品。
向40 uL含2.5 u g/mL(基于蛋白浓度)酶标准制品的50mmol/LHEPES-tris缓冲液(5mmol/L氯化镁,lOmmol/L氯化钾,10 u mol/L缬氨霉素,pH=6.5)中加入溶解于10%二甲亚砜水溶液中的实施例化合物(5 ul),并将该混合物在37℃培养30分钟。通过加入5ul的2mmol/L三磷酸腺苷tris盐溶液(50mmol/L HEPES-tris缓冲液(5mmol/L氯化镁,pH6.5))启动酶反应。该酶反应在37℃进行20分钟,并加入15ul的孔雀石绿溶液(0.12%孔雀石绿溶液于硫酸中(2.5mol/L),7.5%钼酸铵和11%的Tween 20以100:25:2的比例混合),以淬灭反应。使之在室温下静置15分钟之后,将所得无机磷与孔雀石绿的反应产物在610nm波长下进行比色法测定。另外,以同样的方式测量不含氯化钾的反应溶液中的无机磷酸的量,并将其从存在氯化钾时的无机磷酸的量中减去,以测定质子、钾-腺苷三磷酸酶活性。由对照的活性值和不同浓度实施例化合物的活性值确定抑制率(%),并测定质子、钾-腺苷三磷酸酶的50%抑制浓度(IC50)。结果见表4。
实验例11:利用Dulbecco的改进Eagle培养基(DMEM;Invitrogen),将源于人肝癌的细
胞系HepG2 (ATCC No.HB-8065)在5%CO2和37℃下传代,所述培养基含有10%胎牛血清(FBS;
TRACE SCIENTIFIC LTD.),1mmol/L丙酮酸钠(Invitrogen),2mmol/L L-谷氨酰胺
(Invitrogen),50IU/mL青霉素(Invitrogen)和50 ug/mL链霉素(Invitrogen)。用DMSO制备
lOmM的试验试剂,并用DMEM培养基进一步稀释至DMSO终浓度为0.1%,所述DMEM培养基含有
0.5% FBS,1mmol/L丙酮酸钠,2mmol/L L-谷氨酰胺,50IU/mL青霉素和50 ug/mL链霉素。将
HepG2(2×104个细胞/孔)在96孔无色板(Costar)中用试验试剂于5% CO2和37℃下培养。培
养l天之后,利用ATPLiterTM(PerkinElmer Life Sciences)测量细胞内的ATP含量。结果示
于表4(n≥3,平均值±SD),其为30uM时相对于对照(不加药物)的相对值(%)。
药物 | H+/K+-ATP酶抑制活性(IC50,nM) | ATP含量(%,30uM) |
富马酸沃诺拉赞 | 13 | 25.2 |
实施例1化合物 | 86 | 74.0 |
实施例2化合物 | 120 | 85.8 |
实施例3化合物 | 48 | 59.3 |
实施例4化合物 | 46 | 73.2 |
实施例5化合物 | 110 | 88.5 |
实施例6化合物 | 93 | 94.3 |
实施例7化合物 | 63 | 68.3 |
从表4的结果可以看出,本发明的化合物(I)具有优异的H+lK+-ATP酶抑制活性,而且还具有低毒性。
Claims (6)
1.可逆性质子泵抑制剂结构为I所示,所示化合物包括其水合物、溶剂化物、共晶体、药学上可接受的盐;
Ⅰ
其中:
n 为0至10的整数;
R1选自H、甲氧基、甲基、三氟乙氧基、甲氧基丙氧基、卤素、三氟甲氧基、二氟甲氧基、氟甲氧基、三氟甲基、二氟甲基、氟甲基;
R2选自H、甲氧基、甲基、三氟乙氧基、甲氧基丙氧基、卤素、三氟甲氧基、二氟甲氧基、氟甲氧基、三氟甲基、二氟甲基、氟甲基;
R3选自H、甲氧基、甲基、三氟乙氧基、甲氧基丙氧基、卤素、三氟甲氧基、二氟甲氧基、氟甲氧基、三氟甲基、二氟甲基、氟甲基;
R4选自氢基、甲基、、(结构式中的波浪线表示连接位置);
R5选自甲基、羟基、(结构式中的波浪线表示连接位置)n为1-4;
R6选自甲基、甲氧基、羟基、卤素、三氟甲氧基、二氟甲氧基、氟甲氧基、三氟甲基、二氟甲基、氟甲基;
Y为盐酸盐,氢溴酸盐,硫酸盐,硫酸氢盐、磷酸盐,硝酸盐,以及醋酸盐,草酸盐,酒石酸盐,琥珀酸盐,苹果酸盐,苯甲酸盐,双羟萘酸盐,海藻酸盐,枸橼酸盐,丁二酸盐,富马酸盐,甲磺酸盐,萘磺酸盐;
所述R4基团的X可以为钠盐、钾盐、镁盐、钙盐。
2.根据权利要求1所述的通式I所示化合物,其特征在化合物构型包括消旋体、S构型、R构型。
3.根据权利要求1所述的通式I所示化合物,其特征在于药学上可接受的盐,选自:盐酸盐,氢溴酸盐,硫酸盐,硫酸氢盐、磷酸盐,硝酸盐,以及醋酸盐,草酸盐,酒石酸盐,琥珀酸盐,苹果酸盐,苯甲酸盐,双羟萘酸盐,海藻酸盐,甲磺酸盐,萘磺酸盐。
4.根据权利要求1至3所述通式I所示化合物,其特征在于,具有代表性的化合物如下:
。
5.根据权利要求1所述的通式I所示化合物,其特征在于,通式I所示化合物包括一种或多种药学上可接受的载体、赋形剂或稀释剂的组合物。
6.权利要求 1-5中任一项所述的化合物或药物组合物,其特征在于所述的化合物或药物组合物在治疗糜烂性食管炎、胃溃疡、十二指肠溃疡的相关药物中的用途。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201611170710.4A CN108203449A (zh) | 2016-12-16 | 2016-12-16 | 一种新型可逆性质子泵抑制剂及其制备方法和用途 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201611170710.4A CN108203449A (zh) | 2016-12-16 | 2016-12-16 | 一种新型可逆性质子泵抑制剂及其制备方法和用途 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN108203449A true CN108203449A (zh) | 2018-06-26 |
Family
ID=62601865
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201611170710.4A Pending CN108203449A (zh) | 2016-12-16 | 2016-12-16 | 一种新型可逆性质子泵抑制剂及其制备方法和用途 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN108203449A (zh) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2023280288A1 (zh) * | 2021-07-09 | 2023-01-12 | 天地恒一制药股份有限公司 | 一种吡咯磺酰类衍生物、及其制备方法与应用 |
CN115594623A (zh) * | 2021-07-09 | 2023-01-13 | 天地恒一制药股份有限公司(Cn) | 一种吡咯磺酰类衍生物、及其制备方法与应用 |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105693693A (zh) * | 2014-11-27 | 2016-06-22 | 江苏柯菲平医药股份有限公司 | 一种吡咯类胃酸分泌和抑制剂化合物盐的制备 |
CN106031710A (zh) * | 2015-03-16 | 2016-10-19 | 南京优科制药有限公司 | 一种富马酸氟呐普拉赞的注射剂及其制备方法 |
-
2016
- 2016-12-16 CN CN201611170710.4A patent/CN108203449A/zh active Pending
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105693693A (zh) * | 2014-11-27 | 2016-06-22 | 江苏柯菲平医药股份有限公司 | 一种吡咯类胃酸分泌和抑制剂化合物盐的制备 |
CN106031710A (zh) * | 2015-03-16 | 2016-10-19 | 南京优科制药有限公司 | 一种富马酸氟呐普拉赞的注射剂及其制备方法 |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2023280288A1 (zh) * | 2021-07-09 | 2023-01-12 | 天地恒一制药股份有限公司 | 一种吡咯磺酰类衍生物、及其制备方法与应用 |
CN115594623A (zh) * | 2021-07-09 | 2023-01-13 | 天地恒一制药股份有限公司(Cn) | 一种吡咯磺酰类衍生物、及其制备方法与应用 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN108349981A (zh) | 新型的吡唑并[3,4-d]嘧啶化合物或其盐 | |
CN107072985A (zh) | 治疗性抑制化合物 | |
US20090220621A1 (en) | Pharmaceutical compositions of a non-enteric coated proton pump inhibitor with a carbonate salt and bicarbonate salt combination | |
CN101309917A (zh) | 具有增强治疗性质的胃h+,k+-atp酶氘代抑制剂 | |
TW200817001A (en) | New indications for direct thrombin inhibitors in the cardiovascular field | |
CN102617567A (zh) | 含有内酰胺的化合物及其衍生物作为Xa因子的抑制剂 | |
CN101553480B (zh) | 兼具抑制胃酸分泌作用的幽门螺杆菌除菌剂 | |
CN109153672A (zh) | Trpv4拮抗剂 | |
CN108530444A (zh) | 一种新型nampt和ido双重抑制剂及其制备方法和医药用途 | |
CN108203449A (zh) | 一种新型可逆性质子泵抑制剂及其制备方法和用途 | |
CN107207510B (zh) | 联合疗法 | |
CN104955801B (zh) | 取代的二芳基磺酰胺及其用途 | |
PL160767B1 (pl) | Sposób wytwarzania nowego 4-fluoro-2- [(4-metoksypirydynylo-2)metylosulfinylo]--1 H-benzimidazolu PL PL | |
CN107108526A (zh) | 双功能化合物及用于降低尿酸水平的用途 | |
CN106794180A (zh) | 联合疗法 | |
JPH03141221A (ja) | トランスグルタミナーゼ阻害剤としての一定のイミダゾール化合物類 | |
TW200811136A (en) | Dicarboxamide derivatives | |
CZ146794A3 (en) | Substituted benzimidazoles, process of their preparation and their use | |
CN108203430A (zh) | 一种新型可逆性质子泵抑制剂及其制备方法和用途 | |
KR101191733B1 (ko) | 파골세포 분화 억제 효과를 갖는 신규한 화합물 및 이를 포함하는 약학적 조성물 | |
EP1353624B1 (en) | Pharmaceutical compositions of a non-enteric coated proton pump inhibitor with a carbonate salt and bicarbonate salt combination | |
CN111670188B (zh) | 用于治疗纤维化的化合物和组合物 | |
CN107304215A (zh) | 噻吩吡啶类衍生物及其制备方法和用途 | |
CN107556294A (zh) | 一种新型抗真菌感染药物及其制备方法和用途 | |
KR20130120635A (ko) | 정족수 감지 억제 활성 및 항균 활성을 갖는 항균용 조성물 |
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 | ||
TA01 | Transfer of patent application right |
Effective date of registration: 20210122 Address after: Room 30803, Haijia Yunding commercial and residential building, No.2, Gaoxin Third Road, high tech Zone, Xi'an City, Shaanxi Province Applicant after: Huachuang Synthetic Pharmaceutical Co.,Ltd. Address before: 225300 room 811, building 1 (Building 8), No.1 Yaocheng Avenue, Taizhou City, Jiangsu Province Applicant before: SMART-LIFESCIENCES TECHNOLOGY Co.,Ltd. |
|
TA01 | Transfer of patent application right | ||
WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20180626 |
|
WD01 | Invention patent application deemed withdrawn after publication |