WO2018059455A1 - 1-[(吡啶-3-基-磺酰基)-1h-吡咯-3-基]甲胺衍生物及其药物组合物和用途 - Google Patents

1-[(吡啶-3-基-磺酰基)-1h-吡咯-3-基]甲胺衍生物及其药物组合物和用途 Download PDF

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WO2018059455A1
WO2018059455A1 PCT/CN2017/103744 CN2017103744W WO2018059455A1 WO 2018059455 A1 WO2018059455 A1 WO 2018059455A1 CN 2017103744 W CN2017103744 W CN 2017103744W WO 2018059455 A1 WO2018059455 A1 WO 2018059455A1
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derivative
sulfonyl
compound
pyrrol
fluorophenyl
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PCT/CN2017/103744
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English (en)
French (fr)
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耿仲毅
陈兴海
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江苏吉贝尔药业股份有限公司
镇江圣安医药有限公司
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Priority to CN201780065181.8A priority Critical patent/CN109843869B/zh
Priority to PL17854905T priority patent/PL3521281T3/pl
Priority to EP17854905.1A priority patent/EP3521281B1/en
Priority to ES17854905T priority patent/ES2861498T3/es
Priority to US16/337,714 priority patent/US10912769B2/en
Publication of WO2018059455A1 publication Critical patent/WO2018059455A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention belongs to the field of medicine and provides a 1-[(pyridin-3-yl-sulfonyl)-1H-pyrrol-3-yl]methylamine derivative, and a pharmaceutical composition or preparation containing the same and Use in the preparation of a medicament for the treatment of gastric acid related diseases.
  • Gastric acid-related diseases are a class of upper gastrointestinal diseases in which gastric acid is closely related to the pathogenesis.
  • gastroesophageal reflux disease GEF
  • dyspepsia dyspepsia
  • gastrointestinal ulcers gastritis
  • duodenitis duodenitis
  • Zollinger-Ellison syndrome gastrointestinal diseases caused by non-steroidal anti-inflammatory drugs.
  • the incidence of gastric acid-related diseases worldwide has increased year by year.
  • gastric acid-related diseases are one of the most common digestive diseases.
  • the gastric proton pump enzyme (H + , K + -ATPase) is the main target for the treatment of gastric acid-related diseases.
  • the two main classes of drugs that act on gastric proton pump enzymes are potassium-competitive acid blockers (P-CABs) and proton pump inhibitors (PPIs).
  • P-CABs potassium-competitive acid blockers
  • PPIs proton pump inhibitors
  • proton pump inhibitors irreversibly bind to enzymes by forming covalent complexes on specific cysteine residues
  • potassium ion competitive acid blockers reversibly inhibit gastric acid by competing with K + on the lumen surface secretion.
  • Vonoprazan is a potassium ion competitive acid blocker that inhibits and prematurely terminates gastric acid secretion by inhibiting the binding of K + to H + , K + -ATPase (proton pump).
  • K + to H + , K + -ATPase proton pump
  • many adverse drug metabolism problems may occur during the treatment with Venolazan, and the resulting active metabolites may cause toxicity or cause side effects to the human body.
  • loose stools, diarrhea, bitterness, upper abdominal pain and rash may occur.
  • the present invention is to overcome the deficiencies in the prior art and meet the growing needs of patients. Out.
  • the present invention provides an improved compound having an excellent gastric acid secretion inhibiting action.
  • the compounds of the invention may exhibit better pharmacodynamic properties and lower toxicity than other known drugs.
  • the present invention provides a compound having a structure represented by the following formula (I) or a derivative thereof, which is a pharmaceutically acceptable salt, a prodrug, an N-oxide, an isomer, a solvate thereof or Hydrate,
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 and R 14 are each independently
  • the ground is hydrogen or helium, provided that at least one of them is strontium.
  • a compound according to the present invention or a derivative thereof wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 10 , R 11 , R 12 , R 13 , R 14 One or more of them are ⁇ , preferably, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 10 , R 11 , R 12 , R 13 , R 14 At least two of them are ⁇ .
  • a compound according to the invention or a derivative thereof, wherein the pharmaceutically acceptable salt is an acid addition salt of a compound of the formula (I), preferably a fumaric acid addition salt of the compound of the formula (I).
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound according to the present invention or a derivative thereof, and a pharmaceutically acceptable carrier, excipient, diluent, thickener, adjuvant, preservative Or a variety.
  • composition according to the present invention wherein the pharmaceutical composition further comprises other compounds including proton pump inhibitors, oral antacids, anti-acidic agents, calcium channel blockers, dopamine antagonists, nitrogen oxides One or more of a synthase inhibitor and an anti-inflammatory agent.
  • other compounds including proton pump inhibitors, oral antacids, anti-acidic agents, calcium channel blockers, dopamine antagonists, nitrogen oxides One or more of a synthase inhibitor and an anti-inflammatory agent.
  • the present invention also provides a pharmaceutical preparation comprising a compound according to the present invention or a derivative thereof, and one of a pharmaceutically acceptable carrier, excipient, diluent, thickener, adjuvant, preservative or A plurality of, preferably, the pharmaceutical preparation is in the form of a solid, a gel or a liquid.
  • the invention also provides the use of a compound according to the invention or a derivative thereof as a gastric acid secretion inhibitor.
  • the invention also provides the use of a compound according to the invention or a derivative thereof as a potassium competitive gastric acid blocker.
  • the invention also provides a compound according to the invention or a derivative thereof for preparing a gastric acid phase
  • the gastric acid-related diseases include gastrointestinal mucosal damage, Helicobacter pylori infection, gastroesophageal reflux, peptic ulcer, duodenal ulcer, esophagitis or gastric ulcer .
  • the 1-[(pyridin-3-yl-sulfonyl)-1H-pyrrol-3-yl]methylamine derivative provided by the invention has good gastric acid secretion inhibiting activity and excellent pharmacodynamic performance, and lower toxicity.
  • Figure 1 is a graph showing the effect of the vorolazan derivative of fumaric acid (Compound I-1a) and the vorolazan fumarate on basal gastric acid secretion in rats.
  • substituted means that one or more hydrogen atoms in a given structure may be substituted with a particular substituent. Unless otherwise indicated, an optional substituent group may have one substituent substituted at each substitutable position of the group. When more than one position in the given formula can be substituted by one or more substituents selected from a particular group, the substituents may be substituted at the various positions, either identically or differently.
  • hydrogen means a single hydrogen atom.
  • ⁇ means a single ruthenium atom.
  • One such atomic group is bonded to a methyl group to form a mono-deuterated methyl group (-CDH 2 ), and two deuterium atoms are bonded to a methyl group to form a di-deuterated methyl group or a di-deuterated methyl group (-CD 2 H). And three deuterium atoms are bonded to one methyl group to form a trideuteromethyl group (-CD 3 ).
  • a hydrazine substitution means that one or more hydrogens in the compound or group are substituted by deuterium, and the deuterium substitution may be monosubstituted, disubstituted, polysubstituted or fully substituted.
  • the cerium isotope content of the cerium at the cerium substitution site is at least greater than the natural strontium isotope content (0.015%), preferably greater than 30%, more preferably greater than 50%, more preferably greater than 75%, and even more preferably greater than 95%. More preferably greater than 99%.
  • the terms "one or more deuterated” are used interchangeably with "one or more deuterated”.
  • solvate means a physical association of a compound of the invention with one or more solvent molecules. This physical association includes various degrees of ionic and covalent bonding, including hydrogen bonding. In some cases, for example, when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid, the solvate can be separated.
  • solvent includes solution phases and isolatable solvates. Non-limiting examples of solvates include ethanolates, methanolates, and the like.
  • hydrate wherein the solvent molecule is H 2 O solvate.
  • the preparation of solvates is generally known.
  • a typical non-limiting method involves dissolving the compound in a desired amount of solvent (organic or water or a mixture thereof) above ambient temperature, cooling the solution at a rate sufficient to form crystallization, and then separating the crystals by standard methods.
  • Analytical techniques such as infrared spectroscopy can confirm the presence of a solvent (or water) in the crystallization of the solvate (or hydrate).
  • prodrug means a substance which is converted in vivo to form a compound having the structure of formula (I) or a pharmaceutically acceptable salt of the compound. Transformation can be accomplished by various mechanisms (eg, by metabolic or chemical treatment), such as by hydrolysis in the blood.
  • prodrug derivatives examples include “Design and Application of Prodrugs”, edited by H. Bundgaard, pp. 113-191 (1991); “Pro-drugs as Novel Delivery” Systems,” edited by T. Higuchi and W. Stella, Vol. 14 of the ACSSymposium Series, and “Bioreversible Carriers in Drug Design” by Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.
  • the present invention uses isomers including stereoisomers, geometric isomers or tautomers and the like.
  • stereoisomer includes all enantiomerically/stereomerically pure and enantiomerically/stereoisomerically enriched compounds of the invention.
  • the compound of formula (I) may have at least one asymmetric carbon atom. All isomers, including racemic mixtures.
  • the isomers can be prepared by reacting optically pure or optically enriched starting materials or by isolating the isomers of the compounds of formula (I) using conventional methods.
  • the present invention provides a 1-[(pyridin-3-yl-sulfonyl)-1H-pyrrol-3-yl]methylamine compound or a derivative thereof, which is a compound represented by formula (I) or a derivative thereof
  • the derivative is a pharmaceutically acceptable salt, prodrug, solvate thereof or hydrate thereof,
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 and R 14 are each independently
  • the ground is hydrogen or helium, provided that at least one of them is strontium.
  • the compounds, hydrates, solvates, pharmaceutical prodrugs, single crystals or polymorphs of the invention may be formulated as pharmaceutically acceptable salts suitable for use as a medicament.
  • a pharmaceutically acceptable salt suitable for use as a medicament means a salt suitable for use as a medicament, such as an inorganic salt and an organic salt, formed by the compound of the formula (I) and a non-toxic acid provided by the present invention.
  • a preferred class of salts are the salts of the compounds of the invention with acids.
  • suitable acids for forming salts include, but are not limited to, mineral acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid and phosphoric acid, formic acid, acetic acid, propionic acid, fumaric acid, malic acid, citric acid, mandelic acid, Organic acids such as maleic acid, gluconic acid, malonic acid, succinic acid, lactic acid, tartaric acid, picric acid, methanesulfonic acid, methylenesulfonic acid, benzyl methanesulfonic acid and benzenesulfonic acid; salts with acidic amino acids Preferred examples include aspartic acid, glutamic acid, etc. Salt.
  • the pharmaceutically acceptable salt is a fumaric acid addition salt of a compound of formula (I).
  • the 1-[(pyridin-3-yl-sulfonyl)-1H-pyrrol-3-yl]methylamine derivative of the present invention is a preferred compound selected from the group consisting of:
  • the present invention produces each compound used in the compound of the formula (I), a pharmaceutically acceptable salt thereof, a solvent compound, a hydrate, an isomer, an N-oxide, a single crystal or a polymorph, It can be obtained according to the preparation method provided by the present invention, but is not limited to the preparation method provided by the present invention.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound according to the present invention or a derivative thereof, and one or more of a pharmaceutically acceptable carrier, excipient, diluent, thickener, adjuvant, preservative kind.
  • the invention also provides a pharmaceutical preparation comprising a compound according to the invention or a derivative thereof, and one or more of a pharmaceutically acceptable carrier, excipient, diluent, thickener, adjuvant, preservative
  • a pharmaceutically acceptable carrier e.g., a pharmaceutically acceptable sulfate, a pharmaceutically acceptable sulfate, a pharmaceutically acceptable sulfate, a pharmaceutically acceptable sulfate, a pharmaceutically acceptable carrier, excipient, diluent, thickener, adjuvant, preservative
  • the pharmaceutical preparation is in the form of a solid, a gel or a liquid.
  • the pharmaceutical composition or the pharmaceutical preparation of the present invention may further include a lubricant, a binder, a disintegrant, a water-soluble polymer, a basic inorganic salt, a solvent, a dissolution aid, a suspending agent, an isotonic agent, a buffer, One or more of a soothing agent, an antioxidant, a coloring agent, a sweetener, a sour agent, a foaming agent, and a flavoring agent.
  • the pharmaceutical composition of the present invention can be administered in the form of tablets (including sugar-coated tablets and film-coated tablets), powders, granules, capsules (including soft capsules), orally disintegrating tablets, orally disintegrating films, and liquids. , injection, suppository, sustained release preparation, ointment and the like.
  • compositions and pharmaceutical preparations of the present invention reduce the problem of producing poor drug metabolism during treatment, reducing toxicity and other side effects.
  • the invention also provides the use of a compound according to the invention or a derivative thereof as a gastric acid secretion inhibitor.
  • the invention also provides the use of a compound according to the invention or a derivative thereof as a potassium competitive gastric acid block.
  • the medicament of the invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
  • Other compounds that may be selected include, but are not limited to: (1) proton pump inhibitors such as lansoprazole and omeprazole; and (2) oral antacids such as: (3) mucosal protective agents, such as: polyprene zinc; (4) anti-acidic agents, such as: itosamine; (5) calcium channel blockers, such as: propafenone; (6) dopamine antagonists, Such as: sulpiride; (7) nitric oxide synthase inhibitors, such as: hydrazine ethyl disulfide or nitroflupirprofen.
  • proton pump inhibitors such as lansoprazole and omeprazole
  • oral antacids such as: (3) mucosal protective agents, such as: polyprene zinc; (4) anti-acidic agents, such as: itosamine; (5) calcium channel blockers, such as: propafenone; (6) dopamine antagonists, Such as: sulpiride; (7)
  • acetylsalicylic acid ASA
  • flurbiprofen sodium salicylate
  • acetaminophen acetaminophen
  • ibuprofen ketoprofen
  • fentanic acid Thiaclosan
  • carprofen suprofen
  • piroxine fenbufen
  • indomethacin diclofenac
  • naproxen piroxicam
  • tertidine etodolac
  • nabidine Methotone tenidop
  • antipyrine aminopyrine, dipyridamole, aminopyrone, phenylbutazone, chlorpheniramine, hydroxybutan, azabine, fenfluramide, benzyl Daming, Buclon, Cinchon, Lonixine, Ipeptazole, Fenoprofen, Floctafeninl, Flufenamic Acid, Glycosquine, Ibupro
  • piroxicam piroxi
  • the present invention also provides the use of the above 1-[(pyridin-3-yl-sulfonyl)-1H-pyrrol-3-yl]methylamine derivative for the preparation of a medicament for treating a stomach acid-related disease.
  • the gastric acid-related diseases include gastrointestinal mucosal damage, Helicobacter pylori infection, Zollinger-Ellisonsyndrome syndrome, gastroesophageal reflux, peptic ulcer, duodenal ulcer, esophagus Inflammation or stomach ulcers.
  • Step 3 Preparation of the intermediate 5-(2-fluorophenyl)-1-(pyridin-3-yl-sulfonyl)-1H-pyrrole-3-deuteroformaldehyde (I-1-d)
  • Step 4 Preparation of 1-[5-(2-fluorophenyl)-1-(pyridin-3-yl-sulfonyl)-1H-pyrrol-3-yl]-N-methyldiindolemethylamine (I -1)
  • Example 2 The methylamine-N,N-d2 in Example 1 was replaced with methylamine-d5 according to the method of Example 1, thereby preparing 1-[5-(2-fluorophenyl)-1-(pyridine-3). -yl-sulfonyl)-1H-pyrrol-3-yl]-N-trideuteromethyldiindolemethylamine (I-2).
  • Example 1 The pyridine-3-sulfonyl chloride of Example 1 was replaced with tetradeuteropyridine-3-sulfonyl chloride according to the method of Example 1, thereby preparing 1-[5-(2-fluorophenyl)-1-( Tetradezinopyridin-3-yl-sulfonyl)-1H-pyrrol-3-yl]-N-methyldiindolemethylamine (I-3).
  • the preparation route is as follows:
  • 1H-pyrrole (Compound I-1-1, 17.4 g, 259 mmol) was dissolved in 200 ml of tetrahydrofuran (THF) under argon, and slowly added dropwise to sodium hydride (NaH, 13.7 g, 285 mmol) in THF. (400 ml) The solution was stirred at 0 ° C for 1.5 h, then triisopropylchlorosilane (TIPSCl, 50 g, 259 mmol) was slowly added dropwise to the reaction system, and the mixture was allowed to stand at room temperature overnight.
  • TIPSCl triisopropylchlorosilane
  • Step 5 Preparation of the intermediate 5-(2-fluorophenyl)-1-(pyridin-3-yl-sulfonyl)-1H-pyrrol-3-yl-deuterated formaldehyde (I-1-7)
  • Step 6 Preparation of 1-[5-(2-fluorophenyl)-1-(pyridin-3-yl-sulfonyl)-1H-pyrrol-3-yl]-N-methyldiindolemethylamine (I -1b)
  • Example 1-b The methylamine-N,N-d2 in Example 1-b was replaced with methylamine-d5 according to the procedure of Example 1-b to give 1-[5-(2-fluorophenyl)-1- (Pyridin-3-yl-sulfonyl)-1H-pyrrol-3-yl]-N-trideuteromethyldiindolemethylamine (I-2b).
  • Example 2-b 1-[5-(2-Fluorophenyl)-1-(pyridin-3-yl-sulfonyl)-1H-pyrrol-3-yl in Example 2-b was obtained according to the procedure of Example 2-b ]-N-methyldiindolemethylamine (I-1b) is replaced by 1-[5-(2-fluorophenyl)-1-(pyridin-3-yl-sulfonyl)-1H-pyrrole-3- 1-[5-(2-fluorophenyl)-1-(pyridin-3-yl-sulfonyl)- is prepared by the formation of 1-[5-(2-fluorophenyl)-1-(pyridin-3-yl-sulfonyl)- 1H-Pyrrol-3-yl]-N-tridehypo-methyldiindolemethylamine fumarate (I-2a).
  • Example 1-b The pyridine-3-sulfonyl chloride of Example 1-b was replaced with tetrakisidine pyridine-3-sulfonyl chloride according to the procedure of Example 1-b to give 1-[5-(2-fluorophenyl).
  • Example 2-b 1-[5-(2-Fluorophenyl)-1-(pyridin-3-yl-sulfonyl)-1H-pyrrol-3-yl in Example 2-b was obtained according to the procedure of Example 2-b ]-N-Methyldiguanidinomethylamine (I-1b) is replaced by 1-[5-(2-fluorophenyl)-1-(tetrahydropyridin-3-yl-sulfonyl)-1H-pyrrole -3-yl]-N-methyldiindolemethylamine (I-3b), which gives 1-[5-(2-fluorophenyl)-1-(tetradepyridin-3-yl-sulfonyl) -1H-pyrrol-3-yl]-N-methyldiindolemethylamine fumarate (I-3a).
  • Example 1-b Prepared according to the method described in Example 1-b, replacing methylamine-N,N-d2 in Example 1-b with methylamine-d5 and pyridine-3-sulfonyl chloride with tetrahydropyridine- 3-sulfonyl chloride, thereby preparing 1-[5-(2-fluorophenyl)-1-(tetrahydropyridin-3-yl-sulfonyl)-1H-pyrrol-3-yl]-N-triazine Generation of methyl dinonylmethylamine (I-4b).
  • Example 2-b 1-[5-(2-Fluorophenyl)-1-(pyridin-3-yl-sulfonyl)-1H-pyrrol-3-yl in Example 2-b was obtained according to the procedure of Example 2-b ]-N-Methyldiguanidinomethylamine (I-1b) is replaced by 1-[5-(2-fluorophenyl)-1-(tetrahydropyridin-3-yl-sulfonyl)-1H-pyrrole 3-[3-]]-N-trideuteromethyldiindolemethylamine (I-4b), which gives 1-[5-(2-fluorophenyl)-1-(tetradepyridin-3-yl) -sulfonyl)-1-H-pyrrol-3-yl]-N-triazine Methyl di-deuterated methylamine fumarate (I-4a)
  • deuterated fumaric acid vorolazan derivatives I-1a, I-2a, I-3a and I-4a and vonolazan fumarate (Wonolazan) were prepared in equal amounts of the examples.
  • SD rats were used in this experiment, SPF grade, weighing 180-200g. Randomly grouped, 10 in each group, half male and half female. Animals can not be forbidden to drink water for 16 hours.
  • isoflurane anesthesia fixed position on the back, abdominal shaving, routine disinfection, cut a 1.5 cm incision along the median line under the xiphoid process, gently take the stomach, in the stomach pylorus
  • the duodenal junction was ligated with a surgical line to suture the pylorus and suture the incision. Fasting and water-free after surgery.
  • anesthesia was intraperitoneally injected with 1% sodium pentobarbital, and the incision was opened and the gastric cardia was ligated.
  • the stomach was taken out, cut along the large curvature of the stomach, the gastric juice was collected, centrifuged at 3000 rpm for 10 minutes, and the supernatant was aspirated to measure the volume of the gastric juice.
  • the basal gastric acid secretion test of rats was inhibited by intragastric administration of vorolazan fumarate derivative and vorolazan fumarate.
  • the results are shown in Table 1 and Figure 1.
  • the results showed that compared with the model control group, the 2 mg/kg dose of vorolazide fumarate derivative (Compound I-1a) significantly inhibited the secretion of gastric juice (P ⁇ 0.01), 2 mg/kg, 1 mg/kg.
  • Dispensing method Weigh 16mg of drug (vonolazan fumarate derivative or vorolazan fumarate), dissolve it with 2mL of N-methylpyrrolidone, add 38mL of 5% glucose injection to make the concentration of 0.4mg /mL administration solution, administered by intragastric administration.
  • drug vonolazan fumarate derivative or vorolazan fumarate
  • Administration by intragastric administration 6 SD rats, male and female, administered orally (2 mg/kg), blood was collected after administration, and the time of blood collection was 0.083 hours, 0.25 hours, 0.5 hours, 1 after administration. Hours, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 24 hours, 36 hours, 48 hours.
  • Sample collection 200 ⁇ L of whole blood was taken at each time of blood collection, heparin was anticoagulated, centrifuged at 12000 rpm for 5 min at 4 ° C, 50 ⁇ L of plasma was placed in a polypropylene tube, and the rest were backed up and stored at -20 ° C for testing.
  • Plasma treatment method 50 ⁇ L of rat heparin anticoagulated plasma, add 50 ⁇ L of methanol and 100 ⁇ L of internal standard ethoxybenzamide (10 ng/mL) methanol solution, vortex for 1 min, centrifuge at 12000 rpm for 10 min at 4 ° C, and take 100 ⁇ L of supernatant for interpolation. In the tube, 1 ⁇ L was injected for LC-MS/MS analysis.
  • the pharmacokinetic parameters were calculated using WinNonlin 6.3 software non-compartment model statistical moment method.
  • the obtained vanorazozan derivative according to the preparation method of the embodiment of the present invention has an absolute bioavailability increase of 28.1%, an AUC 0-t increase of 25.3%, and the drug is in vivo.
  • the time required for metabolism to half (half-life, t 1/2 ) was extended by 23.5%.

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Abstract

本发明提供一种具备如下式(I)所示结构的1-[(吡啶-3-基-磺酰基)-1H-吡咯-3-基]甲胺衍生物及其药物组合物和用途。本发明提供的1-[(吡啶-3-基-磺酰基)-1H-吡咯-3-基]甲胺衍生物，具有良好的胃酸分泌抑制活性和优异的药效学性能，以及较低的毒性。

Description

1-[(吡啶-3-基-磺酰基)-1H-吡咯-3-基]甲胺衍生物及其药物组合物和用途 技术领域
本发明属于医药领域，提供了一种1-[(吡啶-3-基-磺酰基)-1H-吡咯-3-基]甲胺衍生物，以及含有此类化合物的药物组合物或制剂及其在制备治疗胃酸相关性疾病的药物中的用途。
背景技术
胃酸相关性疾病(ARDs)是一类胃酸与发病机理密切相关的上消化道疾病。例如：胃食管反流病(GERD)、消化不良、胃肠道溃疡、胃炎、十二指肠炎、佐-埃(Zollinger-Ellison)综合征及非甾体类抗炎药引发的消化道疾病。在全球范围内胃酸相关性疾病的发病率逐年上升。临床上，胃酸相关性疾病是最常见多发的消化系统疾病之一。
胃质子泵酶(H+，K+-ATP酶)是胃酸相关性疾病治疗药物的主要靶点。作用于胃质子泵酶的两大主要类别药物分别是钾离子竞争性酸阻滞剂(potassium-competitive acid blockers，P-CABs)和质子泵抑制剂(proton pump inhibitors，PPIs)。其中，质子泵抑制剂通过在特定的半胱氨酸残基上形成共价复合物与酶不可逆的结合；钾离子竞争性酸阻滞剂通过与管腔表面的K+竞争可逆性的抑制胃酸分泌。
沃诺拉赞(Vonoprazan)是一种钾离子竞争性酸阻滞剂，其通过抑制K+对H+、K+-ATP酶(质子泵)结合，来抑制并提前终止胃酸的分泌。但是，在使用沃诺拉赞治疗过程中可能会产生很多药物不良代谢问题，所产生的活性代谢物可能会产生毒性或者对人体产生副作用。在使用沃诺拉赞治疗过程中可能会产生稀便、腹泻、苦味、上腹疼痛和斑疹等现象。
本发明正是为了克服现有技术中的不足、满足患者日益增长的需求而提 出的。本发明提供改进的具有优异的胃酸分泌抑制作用的化合物。与其它已知药物相比，本发明的化合物可显示更好的药效学性质和更低的毒性。
发明内容
发明要解决的问题
本发明的目的是提供一种1-[(吡啶-3-基-磺酰基)-1H-吡咯-3-基]甲胺衍生物和用途；进一步地，本发明提供一种具有式(I)所示结构的1-[(吡啶-3-基-磺酰基)-1H-吡咯-3-基]甲胺衍生物、及其药物组合物、药物制剂及其在制备治疗胃酸相关疾病的药物中的用途。
用于解决问题的方案
本发明提供一种具备如下式(I)所示结构的化合物或其衍生物，所述衍生物为其药学可接受的盐、前药、N-氧化物、异构体、其溶剂化物或其水合物，
Figure PCTCN2017103744-appb-000001
其中，式(I)中R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14各自独立地为氢或氘，条件是其中至少之一为氘。
根据本发明的化合物或其衍生物，其中，R1、R2、R3、R4、R5、R6、R7、R8、R10、R11、R12、R13、R14中的一个或多个为氘，优选地，R1、R2、R3、R4、R5、R6、R7、R8、R10、R11、R12、R13、R14中的至少两个为氘。
根据本发明的化合物或其衍生物，包括下列的化合物：
1-[5-(2-氟苯基)-1-(吡啶-3-基-磺酰基)-1H-吡咯-3-基]-N-甲基二氘代甲 胺，
1-[5-(2-氟苯基)-1-(吡啶-3-基-磺酰基)-1H-吡咯-3-基]-N-三氘代甲基二氘代甲胺，
1-[5-(2-氟苯基)-1-(四氘代吡啶-3-基-磺酰基)-1H-吡咯-3-基]-N-甲基二氘代甲胺，
1-[5-(2-氟苯基)-1-(四氘代吡啶-3-基-磺酰基)-1H-吡咯-3-基]-N-三氘代甲基二氘代甲胺。
根据本发明的化合物或其衍生物，其中，所述药学可接受的盐为式(I)所示的化合物的酸加成盐，优选为式(I)化合物的富马酸加成盐。
根据本发明的化合物或其衍生物，其中，所述化合物或其衍生物为单晶或多晶型物。
本发明还提供一种药物组合物，其中，其包含根据本发明的化合物或其衍生物，和药学可接受的载体、赋形剂、稀释剂、增稠剂、辅料、防腐剂中的一种或多种。
根据本发明的组合物，其中，所述药物组合物还包括其它化合物，所述其它化合物包括质子泵抑制剂、口服抗酸药、抗胃酸剂、钙通道阻滞剂、多巴胺拮抗剂、氧化氮合酶抑制剂、抗炎剂中一种或多种。
本发明还提供一种药物制剂，其中，其包含根据本发明的化合物或其衍生物，和药学可接受的载体、赋形剂、稀释剂、增稠剂、辅料、防腐剂中的一种或多种，优选地，所述药物制剂的剂型为固体、凝胶或液体。
本发明还提供一种根据本发明的化合物或其衍生物作为胃酸分泌抑制剂的用途。
本发明还提供一种根据本发明的化合物或其衍生物作为钾竞争性胃酸阻滞剂的用途。
本发明还提供一种根据本发明的化合物或其衍生物在制备治疗胃酸相 关性疾病的药物中的用途，优选地，所述胃酸相关性疾病包括胃肠道粘膜损伤、幽门螺杆菌感染、胃食管反流、消化性溃疡、十二指肠溃疡、食管炎或胃溃疡。
发明的效果
本发明提供的1-[(吡啶-3-基-磺酰基)-1H-吡咯-3-基]甲胺衍生物，具有良好的胃酸分泌抑制活性和优异的药效学性能，以及较低的毒性。
附图说明
图1为富马酸沃诺拉赞衍生物(化合物I-1a)及富马酸沃诺拉赞对大鼠基础胃酸分泌的影响示意图。
具体实施方式
一般而言，术语“取代”表示所给结构中的一个或多个氢原子可以被具体取代基所取代。除非其他方面表明，一个任选的取代基团可以有一个取代基在基团各个可取代的位置进行取代。当所给出的结构式中不只一个位置能被选自具体基团的一个或多个取代基所取代，那么取代基可以相同或不同地在各个位置取代。术语“氢”表示单个氢原子。术语“氘”表示单个氘原子。一个这样的原子团与一个甲基相连，形成单氘代甲基(-CDH2)，两个氘原子与一个甲基相连，形成双氘代甲基或二氘代甲基(-CD2H)，以及三个氘原子与一个甲基相连，形成三氘代甲基(-CD3)。
在本发明中，氘取代指化合物或基团中的一个或多个氢被氘取代，氘取代可以是一取代、二取代、多取代或全取代。所述氘在氘取代位置的氘同位素含量至少是大于天然氘同位素含量(0.015％)，较佳地大于30％，更佳地大于50％，更佳地大于75％，更佳地大于95％，更佳地大于99％。术语“一个或多个氘代的”与“一次或多次氘代”可互换使用。
术语“溶剂化物”表示本发明化合物与一种或多种溶剂分子的物理缔合。该物理缔合包括各种程度的离子和共价结合，包括氢键合。在某些情况中，例如当一种或多种溶剂分子掺入结晶固体的晶格中时，能够分离溶剂化物。“溶剂化物”包括溶液相和可分离的溶剂化物。溶剂化物的非限制性实例包括乙醇化物、甲醇化物等。
术语“水合物”是其中溶剂分子是H2O的溶剂化物。溶剂化物的制备通常是已知的。典型的非限制性方法包括在高于环境温度下将化合物溶解于需要量的需要的溶剂中(有机物或水或者其混合物)，以足以形成结晶的速度冷却溶液，然后通过标准方法分离结晶。分析技术例如红外光谱可以证实作为溶剂化物(或水合物)的结晶中溶剂(或水)的存在。
术语“前药”表示在体内转化生成具有式(I)结构的化合物或者该化合物的药学可接受的盐的物质。转化可以通过各种机制(例如，通过代谢或化学处理)完成，例如通过在血液中水解发生。
各种形式的前药衍生物的实例可参见以下的现有技术文献：“前药的设计和应用”，编辑H.Bundgaard，第113-191页(1991年)；“Pro-drugs as Novel Delivery Systems，”编辑T.Higuchi和W.Stella，A.C.S.Symposium Series的第14卷，和“Bioreversible Carriers in Drug Design”编辑Edward B.Roche，American Pharmaceutical Association and Pergamon Press，1987。
本发明使用异构体，包括立体异构体、几何异构体或互变异构体等。其中“立体异构体”包括所有对映异构/立体异构纯的和对映异构/立体异构富集的本发明的化合物。具有式(I)的化合物可能具有至少一个不对称碳原子。所有的异构体，包括外消旋混合物。异构体可以使用传统方法，通过使旋光纯的或光学上富集的起始原料反应或者通过分离式(I)的化合物的异构体来制备。
除非其他方面表明，本发明提供的如式(I)所示化合物的所有药学上 可接受的盐、水合物、溶剂化物、前药、异构体、N-氧化物、单晶或多晶型物都属于本发明的范围。
本发明提供一种1-[(吡啶-3-基-磺酰基)-1H-吡咯-3-基]甲胺化合物或其衍生物，其为如式(I)所示的化合物或其衍生物，所述衍生物为其药学上可接受的盐、前药、其溶剂化物或其水合物，
Figure PCTCN2017103744-appb-000002
其中，式(I)中R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14各自独立地为氢或氘，条件是其中至少之一为氘。
上述1-[(吡啶-3-基-磺酰基)-1H-吡咯-3-基]甲胺衍生物，其中，R1、R2、R3、R4、R5、R6、R7、R8、R10、R11、R12、R13、R14中的一个或多个为氘，优选地，R1、R2、R3、R4、R5、R6、R7、R8、R10、R11、R12、R13、R14中的至少两个为氘。
优选地，本发明所述化合物、水合物、溶剂化物、药物前药、单晶或多晶型物可制成药学上可接受的适合用作药物的盐。药学上可接受的适合用作药物的盐是指本发明提供的如式(I)所示化合物与无毒的酸所形成的适合用作药物的盐，包括无机盐和有机盐。
一类优选的盐是本发明所述化合物与酸形成的盐。适合形成盐的酸包括但并不限于：盐酸、氢溴酸、氢氟酸、硫酸、硝酸和磷酸等无机酸，甲酸、乙酸、丙酸、富马酸、苹果酸、柠檬酸、杏仁酸、马来酸、葡糖酸草酸、丙二酸、琥珀酸、乳酸、酒石酸、苦味酸、甲磺酸、亚甲基磺酸、苯甲磺酸和苯磺酸等有机酸；与酸性氨基酸的盐的优选实例包括与天冬氨酸，谷氨酸等 的盐。
优选地，所述药学可接受的盐为式(I)化合物的富马酸加成盐。
上述式(I)所示的1-[(吡啶-3-基-磺酰基)-1H-吡咯-3-基]甲胺化合物或其衍生物，所述化合物或其衍生物可以为单晶或多晶型物。
本发明所述1-[(吡啶-3-基-磺酰基)-1H-吡咯-3-基]甲胺衍生物是选自下组的优选化合物：
化合物1：1-[5-(2-氟苯基)-1-(吡啶-3-基-磺酰基)-1H-吡咯-3-基]-N-甲基二氘代甲胺：
Figure PCTCN2017103744-appb-000003
化合物2：1-[5-(2-氟苯基)-1-(吡啶-3-基-磺酰基)-1H-吡咯-3-基]-N-三氘代甲基二氘代甲胺：
Figure PCTCN2017103744-appb-000004
化合物3：1-[5-(2-氟苯基)-1-(四氘代吡啶-3-基-磺酰基)-1H-吡咯-3-基]-N-甲基二氘代甲胺：
Figure PCTCN2017103744-appb-000005
化合物4：1-[5-(2-氟苯基)-1-(四氘代吡啶-3-基-磺酰基)-1H-吡咯-3-基]-N-三氘代甲基二氘代甲胺：
Figure PCTCN2017103744-appb-000006
本发明制备如式(I)所示化合物、其药学上可接受的盐、其溶剂化合物、水合物、异构体、N-氧化物、单晶或多晶型物中所用到的各个化合物，可以按照本发明提供的制备方法制备获得，但并不限于本发明提供的制备方法。
本发明还提供一种药物组合物，其包含根据本发明的化合物或其衍生物，和药学可接受的载体、赋形剂、稀释剂、增稠剂、辅料、防腐剂中的一种或多种。
本发明还提供一种药物制剂，其包含根据本发明的化合物或其衍生物，和药学可接受的载体、赋形剂、稀释剂、增稠剂、辅料、防腐剂中的一种或多种，优选地，所述药物制剂的剂型为固体、凝胶或液体。
本发明的药物组合物或药物制剂中还可以包括润滑剂、粘合剂、崩解剂、水溶性聚合物、碱性无机盐、溶剂、溶解助剂、悬浮剂、等渗剂、缓冲液、安抚剂、抗氧剂、着色剂、甜味剂、酸味剂、起泡剂和调味剂中的一种或多种。
本发明的药物组合物的给药形式可以是片剂(包括糖衣片剂和膜包衣片剂)，粉末，颗粒，胶囊(包括软胶囊)，口腔崩解片剂，口腔崩解膜，液体，注射剂，栓剂，缓释制剂，膏剂等。
本发明的药物组合物和药物制剂在治疗过程中降低产生药物不良代谢的问题，减少毒性和其它副作用。
本发明还提供一种根据本发明的化合物或其衍生物作为胃酸分泌抑制剂的用途。
本发明还提供一种根据本发明的化合物或其衍生物作为钾竞争性胃酸阻滞的用途。
优选地，本发明所述药物可以单独给药，或者与其他药学上可接受的化合物联合给药。
可选择的其他化合物包括但不限于：(1)质子泵抑制剂，如：兰索拉唑和奥美拉唑；(2)口服抗酸药，如：
Figure PCTCN2017103744-appb-000007
(3)粘膜保护剂，如：聚普瑞锌；(4)抗胃酸剂，如：伊曲谷胺；(5)钙通道阻滞剂，如：普罗帕酮；(6)多巴胺拮抗剂，如：左舒必利；(7)氧化氮合酶抑制剂，如：胍乙基二硫化物或硝基氟吡洛芬。
可选择的其他化合物还可以包括抗炎剂，所述抗炎剂包括乙酰水杨酸(ASA)、氟比洛芬、水杨酸钠、扑热息痛、布洛芬、酮洛芬、芬替酸、噻氯咪索、卡洛芬、舒洛芬、吡洛芬、芬布芬、吲哚美辛、双氯芬酸、萘普生、吡氧噻嗪(吡罗昔康)、特丁非隆、依托度酸、萘丁美酮、替尼达普、安替比林、氨基比林、安乃近、氨基比林(aminopyrone)、保泰松、氯非宗、羟布宗、阿扎丙宗、芬氯酸、苄达明、布可隆、辛可芬、氯尼辛、依匹唑、非诺洛芬、夫洛非宁(floctafeninl)、氟芬那酸、甘氨苯喹、吲哚洛芬、甲氯芬那酸、甲灭酸、尼氟酸、舒林酸、托美丁、阿氯芬酸、噻拉米特、普罗喹宗、丁苯羟酸、非那西丁、氟咪唑、替诺立定、替美加定、氨苯砜、二氟尼柳、 贝诺酯、磷酸柳酯、奥沙普秦、噻洛芬酸、非普拉宗或舒多昔康中的一种或几种。
本发明还提供上述1-[(吡啶-3-基-磺酰基)-1H-吡咯-3-基]甲胺衍生物在制备治疗胃酸相关性疾病的药物中的用途。优选地，所述胃酸相关性疾病包括胃肠道粘膜损伤、幽门螺杆菌感染、佐-埃二氏(Zollinger-Ellisonsyndrome)综合征、胃食管反流、消化性溃疡、十二指肠溃疡、食管炎或胃溃疡。
实施例
下面更具体地描述本发明式(I)结构化合物的制备方法，但这些具体方法不对本发明构成任何限制。本发明化合物还可以任选将在本说明书中描述的或本领域已知的各种合成方法组合起来而方便的制得，这样的组合可由本发明所属领域的技术人员容易的进行。
本发明提供的实施例中及测试所用到的试剂和原料均可由市场购得。
实施例1
制备1-[5-(2-氟苯基)-1-(吡啶-3-基-磺酰基)-1H-吡咯-3-基]-N-甲基二氘代甲胺(I-1)
步骤1：制备中间体5-(2-氟苯基)-1H-吡咯-3-二氘代甲醇(I-1-b)
在氩气的保护下，在无水无氧的干燥烧瓶中将5-(2-氟苯基)-1H-吡咯-3-羧酸乙酯(I-1-a)(1.0g，5.71mmol)溶解于四氢呋喃(20mL)中，冷却至-78℃，滴加氘化铝锂(0.24g，5.71mmol)的四氢呋喃(20mL)溶液，-78℃的温度下搅拌反应2小时后用硫酸镁溶液淬灭反应，并将该混合物在室温下搅拌0.5小时。加入乙酸乙酯，有机层分别用饱和食盐水洗涤，无水硫酸钠干燥、过滤和浓缩。通过硅胶柱层析分离纯化(洗脱液：己烷∶乙酸乙酯＝7∶3-1∶1)，得到中间体5-(2-氟苯基)-1H-吡咯-3-二氘代甲醇(I-1-b)。
MS(ES+)：m/z＝194.2(M+H)+.
步骤2：制备中间体5-(2-氟苯基)-1H-吡咯-3-氘代甲醛(I-1-c)
在氩气的保护下，在无水无氧的干燥烧瓶中将5-(2-氟苯基)-1H-吡咯-3-二氘代甲醇(I-1-b)(0.75g，3.88mmol)溶解于二氯甲烷(15mL)中。在室温下搅拌并滴加戴斯-马丁氧化剂(3.88mmol，0.3mol二氯甲烷溶液)，在室温下搅拌过夜。然后向反应液中慢慢滴加饱和碳酸氢钠溶液(15mL)和饱和硫代硫酸钠溶液淬灭反应。将所得混合物用二氯甲烷(15mL×3)萃取，合并有机相，并用饱和食盐水洗涤(15mL×3)。经无水硫酸镁干燥，过滤，减压浓缩得粗品。该粗品经硅胶柱层析分离纯化(洗脱液：己烷∶乙酸乙酯＝4∶1-1∶1)，得到5-(2-氟苯基)-1H-吡咯-3-氘代甲醛(I-1-c)。
LC/MS：m/z＝191.2(M+H)+.
步骤3：制备中间体5-(2-氟苯基)-1-(吡啶-3-基-磺酰基)-1H-吡咯-3-氘代甲醛(I-1-d)
在干燥烧瓶中将氢化钠(在油中60％，63.2mg，1.58mmol)用己烷洗涤两次，在无水无氧且氩气保护下，悬浮于四氢呋喃(10mL)中。在0℃下加入5-(2-氟苯基)-1H-吡咯-3-氘代甲醛(I-1-c)(202mg，1.01mmol)的四氢呋喃(5mL)溶液中，并将混合物在相同的温度下搅拌30分钟。加入15-冠-5(0.31mL，1.58mmol)和吡啶-3-磺酰氯(246mg，1.58mmol)四氢呋喃(5mL)的溶液，在室温下搅拌反应1小时。反应由薄层色谱法(TLC)监控，然后加水淬灭反应。将所得混合物用EtOAc(10mL×3)萃取，合并有机相并用饱和碳酸氢钠溶液，水和饱和食盐水洗涤。经无水硫酸钠干燥后，减压浓缩得粗品。该粗产品经硅胶柱层析(洗脱液：己烷∶乙酸乙酯＝19∶1-1∶1)提纯得到中间体5-(2-氟苯基)-1-(吡啶-3-基-磺酰基)-1H-吡咯-3-氘代甲醛(I-1-d)。
LC-MS：m/z＝332.3(M+H)+.
步骤4：制备1-[5-(2-氟苯基)-1-(吡啶-3-基-磺酰基)-1H-吡咯-3-基]-N-甲基二氘代甲胺(I-1)
在无水无氧并氩气保护下，在干燥烧瓶中将5-(2-氟苯基)-1-(吡啶-3-基-磺酰基)-1H-吡咯-3-氘代甲醛(I-1-d)(100mg，0.3mmol)溶解于二氯甲烷(5mL)中。在冰冷却下，滴加甲胺-N，N-d2(17mg，0.45mmol)的四氢呋喃(1mL)溶液，并将该混合物在室温下搅拌2小时。在冰冷却下，逐步加入硼氘化钠(0.07g)，并将该混合物在室温下搅拌1小时，反应经TLC监控。加入饱和碳酸氢钠水溶液淬灭反应，并将该混合物用二氯甲烷萃取。萃取液用饱和盐水洗涤，用无水硫酸钠干燥，浓缩。通过碱性硅胶柱色谱进行纯化(洗脱液：己烷∶乙酸乙酯＝1∶1；乙酸乙酯∶甲醇＝5∶1)，得到1-[5-(2-氟苯基)-1-(吡啶-3-基-磺酰基)-1H-吡咯-3-基]-N-甲基二氘代甲胺(I-1)。
LC-MS：348.4(M+1).
具体反应路线为：
Figure PCTCN2017103744-appb-000008
实施例2
制备1-[5-(2-氟苯基)-1-(吡啶-3-基-磺酰基)-1H-吡咯-3-基]-N-甲基二氘代甲胺富马酸盐(I-1a)
将1-[5-(2-氟苯基)-1-(吡啶-3-基-磺酰基)-1H-吡咯-3-基]-N-甲基二氘代甲胺(I-a)0.5g，溶于异丙醇(5mL)和无水乙醇(2mL)的混合溶剂中， 搅拌下加入富马酸0.13g，之后加热至50℃回流30分钟，搅拌下自然冷却至室温，再搅拌2小时，过滤，干燥得到1-[5-(2-氟苯基)-1-(吡啶-3-基-磺酰基)-1H-吡咯-3-基]-N-甲基二氘代甲胺富马酸盐(I-1a)0.45g。
LC-MS：348.4(M+1).
1H-NMR(DMSO-d6)δ2.46(s，3H)，6.45(s，2H)，6.52(s，1H)，7.07-7.15(m，1H)，7.21-7.23(m，2H)，7.49-7.64(m，2H)，7.78(d，J＝1.8Hz，1H)，7.82-7.90(m，1H)，8.56-8.57(m，1H)，8.88-8.89(m，1H).
实施例3
制备1-[5-(2-氟苯基)-1-(吡啶-3-基-磺酰基)-1H-吡咯-3-基]-N-三氘代甲基二氘代甲胺(I-2)
按照实施例1的方法，将实施例1中的甲胺-N，N-d2替换为甲胺-d5，从而制备得到1-[5-(2-氟苯基)-1-(吡啶-3-基-磺酰基)-1H-吡咯-3-基]-N-三氘代甲基二氘代甲胺(I-2)。
LC-MS：351.4(M+1).
实施例4
制备1-[5-(2-氟苯基)-1-(吡啶-3-基-磺酰基)-1H-吡咯-3-基]-N-三氘代甲基二氘代甲胺富马酸盐(I-2a)
按照实施例2的方法，从而制备得到1-[5-(2-氟苯基)-1-(吡啶-3-基-磺酰基)-1H-吡咯-3-基]-N-三氘代甲基二氘代甲胺富马酸盐(I-2a)。
LC-MS：351.4(M+1).
实施例5
制备1-[5-(2-氟苯基)-1-(四氘代吡啶-3-基-磺酰基)-1H-吡咯-3-基]-N-甲基二氘代甲胺(I-3)
按照实施例1的方法，将实施例1中的吡啶-3-磺酰氯替换为四氘代吡啶-3-磺酰氯，从而制备得到1-[5-(2-氟苯基)-1-(四氘代吡啶-3-基-磺酰基)-1H-吡咯-3-基]-N-甲基二氘代甲胺(I-3)。
LC-MS：352.4(M+1).
实施例6
制备1-[5-(2-氟苯基)-1-(四氘代吡啶-3-基-磺酰基)-1H-吡咯-3-基]-N-甲基二氘代甲胺富马酸盐(I-3a)
按照实施例2的方法，制备得到1-[5-(2-氟苯基)-1-(四氘代吡啶-3-基-磺酰基)-1H-吡咯-3-基]-N-甲基二氘代甲胺富马酸盐(I-3a)。
LC-MS：352.4(M+1).
实施例7
制备1-[5-(2-氟苯基)-1-(四氘代吡啶-3-基-磺酰基)-1H-吡咯-3-基]-N-三氘代甲基二氘代甲胺(I-4)
按实施例1中所述的方法制备，将实施例1中的甲胺-N，N-d2替换为甲胺-d5，将吡啶-3-磺酰氯替换为四氘代吡啶-3-磺酰氯，从而制备得到1-[5-(2-氟苯基)-1-(四氘代吡啶-3-基-磺酰基)-1H-吡咯-3-基]-N-三氘代甲基二氘代甲胺(I-4)。
LC-MS：355.5(M+1).
实施例8
按照实施例2的方法，制备得到1-[5-(2-氟苯基)-1-(四氘代吡啶-3-基-磺酰基)-1H-吡咯-3-基]-N-三氘代甲基二氘代甲胺富马酸盐(I-4a)
LC-MS：355.5(M+1).
实施例1-b
制备1-[5-(2-氟苯基)-1-(吡啶-3-基-磺酰基)-1H-吡咯-3-基]-N-甲基二氘代甲胺(I-1b)
制备路线如下：
Figure PCTCN2017103744-appb-000009
步骤1：制备中间体1-三异丙基甲硅烷基-吡咯(化合物I-1-2)
Figure PCTCN2017103744-appb-000010
在氩气的保护下，将1H-吡咯(化合物I-1-1，17.4g，259mmmol)溶解在200ml的四氢呋喃(THF)中，缓慢滴加到氢化钠(NaH，13.7g，285mmol)的THF(400ml)溶液中，保持0℃搅拌1.5h，然后将三异丙基氯甲硅烷(TIPSCl，50g，259mmol)缓慢滴加到反应体系中，滴加完毕后室温过夜。反应结束后，将反应体系倒入冰水中，加入乙酸乙酯，有机层分别用饱和食盐水洗涤，无水硫酸钠干燥、过滤和浓缩。通过硅胶柱层析分离纯化(洗脱液：己烷∶乙酯＝7∶3-1∶1)，得到中间体1-(三异丙基甲硅烷基)吡咯(化合物I-1-2)。
步骤2：制备中间体1H-吡咯-3-氘代甲醛(化合物I-1-3)
Figure PCTCN2017103744-appb-000011
在氩气的保护下，2M的N，N-二甲基甲酰胺-d7(DMF-d7)的二氯甲烷(DCM)溶液滴加到0℃的0.18M的草酰氯的DCM溶液，0℃搅拌30min后，化合物I-1-2迅速加入到反应体系中，然后50℃回流30min，旋干，加入1M的NaOH溶液，室温搅拌12h。加入乙酸乙酯，有机层分别用饱和食盐水洗涤，无水硫酸钠干燥、过滤和浓缩。该粗品经硅胶柱层析分离纯化(洗脱液：己烷∶乙酸乙酯＝4∶1-1∶1)，分离得中间体1-H-吡咯-3-氘代甲醛(化合物I-1-3)。
步骤3：制备中间体2-溴-1H-吡咯-4-基-氘代甲醛(化合物I-1-4)
Figure PCTCN2017103744-appb-000012
在氩气的保护下，称取中间体1H-吡咯-3-基-氘代甲醛(化合物I-1-3)(250mg)溶解在3.9ml的THF中，冷却到-78℃后，缓慢滴加N-溴代琥珀酰亚胺(NBS，473mg)的DMF溶液，反应液在-78℃下搅拌1h后，经过2h缓慢升温至-10℃。将反应液倒入到冰水体系中，乙酸乙酯萃取住，有机层分别用饱和食盐水洗涤，无水硫酸钠干燥、过滤和浓缩。该粗产品经硅胶柱层析(洗脱液：己烷∶乙酸乙酯＝19∶1-1∶1)提纯，分离得中间体2-溴-1H-吡咯-4-基-氘代甲醛(化合物I-1-4)。
步骤4：制备中间体5-(2-氟苯基)-1H-吡咯-3-基-氘代甲醛(I-1-5)
Figure PCTCN2017103744-appb-000013
在氮气的保护下，称取中间体1H-2-溴-吡咯-4-基-氘代甲醛(化合物I-1-4)(0.57mmol)，邻氟苯硼酸(0.69mmol)，和碳酸钠(1.38mmol)，分散到5ml的乙二醇二甲醚和2ml的水中；体系通过氮气充分交换三次后，加入0.029mmol的四(三苯基膦)钯；再次氮气充分交换三次后，105℃回流反应24h。反应结束后乙酸乙酯萃取，有机层分别用饱和食盐水洗涤，无水硫酸钠干燥、过滤和浓缩。该粗产品经硅胶柱层析(洗脱液：己烷∶乙酸乙酯＝19∶1-1∶1)提纯，得到中间体5-(2-氟苯基)-1H-吡咯-3-基-氘代甲醛(化合物I-1-5).
步骤5：制备中间体5-(2-氟苯基)-1-(吡啶-3-基-磺酰基)-1H-吡咯-3-基-氘代甲醛(I-1-7)
Figure PCTCN2017103744-appb-000014
在干燥烧瓶中，将氢化钠(在油中60％，5.9mmol)用己烷洗涤两次，在无水无氧且氩气保护下，悬浮于四氢呋喃(10ml)中。在0℃下加入5-(2-氟苯基)-1H-吡咯-3-基-氘代甲醛(化合物I-1-5)(3.9mmol)的四氢呋喃(10ml)溶液中，并将混合物在相同的温度下搅拌30分钟。加入15-冠-5(1.5mL)和吡啶-3-磺酰氯(化合物I-1-6)(5.7mmol)的四氢呋喃(5ml)溶液，在室温下搅拌反应1小时。反应由薄层色谱扫描仪(TLC)监控，然后加水淬灭反 应。将所得混合物用EtOAc萃取(10ml×3)，合并有机相并用饱和碳酸氢钠溶液、水和饱和食盐水洗涤。经无水硫酸钠干燥后，减压浓缩得粗品。该粗产品经硅胶柱层析(洗脱液：己烷∶乙酸乙酯＝19∶1-1∶1)提纯，得到中间体5-(2-氟苯基)-1-(吡啶-3-基-磺酰基)-1H-吡咯-3-基-氘代甲醛(化合物I-1-7)。
步骤6：制备1-[5-(2-氟苯基)-1-(吡啶-3-基-磺酰基)-1H-吡咯-3-基]-N-甲基二氘代甲胺(I-1b)
Figure PCTCN2017103744-appb-000015
在无水无氧并氩气保护下，在干燥烧瓶中将5-(2-氟苯基)-1-(吡啶-3-基-磺酰基)-1H-吡咯-3-基-氘代甲醛(化合物I-1-7)(8mmol)溶解于30ml的甲醇中。在冰冷却下，滴加甲胺-N，N-d2(35mmol)的四氢呋喃(10mL)溶液。并将该混合物在室温下搅拌2小时。在冰冷却下，逐步加入硼氘化钠(13mmol)，并将该混合物在室温下搅拌1小时。反应经TLC监控，加入50ml的1M的盐酸溶液淬灭反应，搅拌5min，调节pH至碱性，并将该混合物用二氯甲烷萃取。萃取液用饱和盐水洗涤，用无水硫酸钠干燥，浓缩。通过碱性硅胶柱色谱进行纯化(洗脱液：己烷∶乙酸乙酯＝1∶1；乙酸乙酯∶甲醇＝5∶1)，得到1-[5-(2-氟苯基)-1-(吡啶-3-基-磺酰基)-1H-吡咯-3-基]-N-甲基二氘代甲胺(I-1b)。
LC-MS：348.1(M+1)+
实施例2-b：
制备1-[5-(2-氟苯基)-1-(吡啶-3-基-磺酰基)-1H-吡咯-3-基]-N-甲基二氘代甲胺富马酸盐(I-1a)
将1-[5-(2-氟苯基)-1-(吡啶-3-基-磺酰基)-1H-吡咯-3-基]-N-甲基二氘代甲 胺(I-1b)0.75g，溶于异丙醇(5mL)和无水乙醇(2mL)的混合溶剂中，搅拌下加入278mg的富马酸的3ml甲醇溶液，之后加热至50℃回流30分钟，搅拌下自然冷却至室温，再搅拌2小时，过滤，干燥得到1-[5-(2-氟苯基)-1-(吡啶-3-基-磺酰基)-1H-吡咯-3-基]-N-甲基二氘代甲胺富马酸盐(I-1a)0.45g。
LC-MS：348.1(M+1)+.
1H-NMR(DMSO-d6)δ2.46(s，3H)，6.45(s，2H)，6.52(s，1H)，7.07-7.15(m，1H)，7.21-7.23(m，2H)，7.49-7.64(m，2H)，7.78(d，J＝1.8Hz，1H)，7.82-7.90(m，1H)，8.56-8.57(m，1H)，8.88-8.89(m，1H).
实施例3-b：
制备1-[5-(2-氟苯基)-1-(吡啶-3-基-磺酰基)-1H-吡咯-3-基]-N-三氘代甲基二氘代甲胺(I-2b)
按照实施例1-b的方法，将实施例1-b中的甲胺-N，N-d2替换为甲胺-d5，从而制备得到1-[5-(2-氟苯基)-1-(吡啶-3-基-磺酰基)-1H-吡咯-3-基]-N-三氘代甲基二氘代甲胺(I-2b)。
LC-MS：351.4(M+1).
实施例4-b：
制备1-[5-(2-氟苯基)-1-(吡啶-3-基-磺酰基)-1H-吡咯-3-基]-N-三氘代甲基二氘代甲胺富马酸盐(I-2a)
按照实施例2-b的方法，将实施例2-b中的1-[5-(2-氟苯基)-1-(吡啶-3-基-磺酰基)-1H-吡咯-3-基]-N-甲基二氘代甲胺(I-1b)替换为1-[5-(2-氟苯基)-1-(吡啶-3-基-磺酰基)-1H-吡咯-3-基]-N-三氘代甲基二氘代甲胺(I-2b)，从而制备得到1-[5-(2-氟苯基)-1-(吡啶-3-基-磺酰基)-1H-吡咯-3-基]-N-三氘代甲基二氘代甲胺富马酸盐(I-2a)。
LC-MS：351.4(M+1).
实施例5-b：
制备1-[5-(2-氟苯基)-1-(四氘代吡啶-3-基-磺酰基)-1H-吡咯-3-基]-N-甲基 二氘代甲胺(I-3)
按照实施例1-b的方法，将实施例1-b中的吡啶-3-磺酰氯替换为四氘代吡啶-3-磺酰氯，从而制备得到1-[5-(2-氟苯基)-1-(四氘代吡啶-3-基-磺酰基)-1H-吡咯-3-基]-N-甲基二氘代甲胺(I-3b)。
LC-MS：352.4(M+1).
实施例6-b：
制备1-[5-(2-氟苯基)-1-(四氘代吡啶-3-基-磺酰基)-1H-吡咯-3-基]-N-甲基二氘代甲胺富马酸盐(I-3a)
按照实施例2-b的方法，将实施例2-b中的1-[5-(2-氟苯基)-1-(吡啶-3-基-磺酰基)-1H-吡咯-3-基]-N-甲基二氘代甲胺(I-1b)替换为1-[5-(2-氟苯基)-1-(四氘代吡啶-3-基-磺酰基)-1H-吡咯-3-基]-N-甲基二氘代甲胺(I-3b)，制备得到1-[5-(2-氟苯基)-1-(四氘代吡啶-3-基-磺酰基)-1H-吡咯-3-基]-N-甲基二氘代甲胺富马酸盐(I-3a)。
LC-MS：352.4(M+1).
实施例7-b：
制备1-[5-(2-氟苯基)-1-(四氘代吡啶-3-基-磺酰基)-1H-吡咯-3-基]-N-三氘代甲基二氘代甲胺(I-4b)
按实施例1-b中所述的方法制备，将实施例1-b中的甲胺-N，N-d2替换为甲胺-d5，将吡啶-3-磺酰氯替换为四氘代吡啶-3-磺酰氯，从而制备得到1-[5-(2-氟苯基)-1-(四氘代吡啶-3-基-磺酰基)-1H-吡咯-3-基]-N-三氘代甲基二氘代甲胺(I-4b)。
LC-MS：355.5(M+1).
实施例8-b：
按照实施例2-b的方法，将实施例2-b中的1-[5-(2-氟苯基)-1-(吡啶-3-基-磺酰基)-1H-吡咯-3-基]-N-甲基二氘代甲胺(I-1b)替换为1-[5-(2-氟苯基)-1-(四氘代吡啶-3-基-磺酰基)-1H-吡咯-3-基]-N-三氘代甲基二氘代甲胺(I-4b)，制备得到1-[5-(2-氟苯基)-1-(四氘代吡啶-3-基-磺酰基)-1-H-吡咯-3-基]-N-三氘 代甲基二氘代甲胺富马酸盐(I-4a)
LC-MS：355.5(M+1).
药效学实验：
分别取等量的实施例制备获得的氘代富马酸沃诺拉赞衍生物I-1a，I-2a，I-3a以及I-4a和沃诺拉赞富马酸盐(沃诺拉赞为1-[5-(2-氟苯基)-1-(吡啶-3-基-磺酰基)-1H-吡咯-3-基]-N-甲基甲胺)，对其进行大鼠的胃酸分泌抑制活性实验。
本试验选用SD大鼠，SPF级，体重180～200g。随机分组，每组10只，雌雄各半。动物禁食不禁水16小时，给药1h后，异氟烷麻醉，仰位固定，腹部剃毛，常规消毒，于剑突下沿正中线剪一个约1.5cm切口，轻取胃，在胃幽门与十二指肠结合部用手术线结扎胃幽门，缝合切口。术后禁食、禁水。4小时后用1％戊巴比妥钠腹腔注射麻醉后，剖开切口，结扎胃贲门。取出胃，沿胃大弯剖开，收集胃液，于3000转离心10分钟，吸取上清液，测量胃液体积。取胃液0.5ml置入小锥形瓶中，加入酚酞指示剂一滴，以0.01mol/L氢氧化钠滴定至出现红色(颜色不再加深)为终点，按下面公式计算胃酸总量，将各给药组与模型对照组的平均胃液分泌量、胃液总酸量进行统计学检验。
Figure PCTCN2017103744-appb-000017
表1.富马酸沃诺拉赞衍生物及富马酸沃诺拉赞对大鼠基础胃酸分泌的影响
(
Figure PCTCN2017103744-appb-000018
n＝10)
Figure PCTCN2017103744-appb-000019
与模型对照组比较，*P＜0.05，**P＜0.01，***P＜0.001。
与同剂量的富马酸沃诺拉赞比较，ΔP＜0.05。
通过灌胃给予富马酸沃诺拉赞衍生物及富马酸沃诺拉赞后抑制大鼠基础胃酸分泌试验，结果如表1及图1所示。结果显示，与模型对照组比较，2mg/kg剂量的富马酸沃诺拉赞衍生物(化合物I-1a)对胃液分泌量有明显抑制作用(P＜0.01)，2mg/kg、1mg/kg剂量的富马酸沃诺拉赞衍生物(化合物I-1a)及2mg/kg剂量的富马酸沃诺拉赞均对胃液总酸量有明显抑制作用(P＜0.05或P＜0.01)；2mg/kg剂量的富马酸沃诺拉赞衍生物(化合物I-1a)对大鼠胃液分泌量和胃液总酸量的抑制作用强于同剂量(2mg/kg)的富马酸沃诺拉赞，二者比较有显著性差异(P＜0.05)。对比富马酸沃诺拉赞，相同剂量下富马酸沃诺拉赞衍生物抑制大鼠胃酸分泌的作用更强。
表2.富马酸沃诺拉赞衍生物及富马酸沃诺拉赞对大鼠基础胃酸分泌的影响
(
Figure PCTCN2017103744-appb-000020
n＝10)
Figure PCTCN2017103744-appb-000021
表2中的结果表明，灌胃给予富马酸沃诺拉赞衍生物能够对大鼠基础胃酸的分泌具有显著的抑制作用，对比富马酸沃诺拉赞，相同剂量下富马酸沃诺拉赞衍生物抑制大鼠胃酸分泌的作用更强。
药代动力学实验
分别取等量的实施例制备获得的化合物I-1a(1-[5-(2-氟苯基)-1-(吡啶-3-基-磺酰基)-1H-吡咯-3-基]-N-甲基二氘代甲胺富马酸盐)和沃诺拉赞富马酸盐，对其进行药代动力学实验。
配药方式：称取药物(富马酸沃诺拉赞衍生物或富马酸沃诺拉赞)16mg，用N-甲基吡咯烷酮2mL溶解，再加入5％葡萄糖注射液38mL制成浓度为0.4mg/mL给药溶液，灌胃给药。
灌胃给药：取SD大鼠6只，雌雄各半，单次口服给药(2mg/kg)，给药后采血，采血的时间点为给药后0.083小时、0.25小时、0.5小时、1小时、2小时、3小时、4小时、6小时、8小时、12小时、24小时、36小时、48小时。
样品采集：每一采血时间点取全血200μL，肝素抗凝，4℃12000rpm离心5min，取血浆50μL置于聚丙烯管中，其余备份，-20℃保存待测。
血浆处理方法：大鼠肝素抗凝血浆50μL，加入甲醇50μL和内标乙氧苯柳胺(10ng/mL)甲醇溶液100μL，涡旋1min，4℃12000rpm离心10min，取上清液100μL于内插管中，进样1μL，进行LC-MS/MS分析。
用WinNonlin 6.3软件非房室模型统计矩法计算药代动力学参数。
表3.大鼠灌胃给药2mg/kg后的药代参数(n＝6)
Figure PCTCN2017103744-appb-000022
从表3中的实验数据可知，血浆中1-[5-(2-氟苯基)-1-(吡啶-3-基-磺酰基)-1H-吡咯-3-基]-N-甲基二氘代甲胺(TAK-438-d2)的AUC0-t为56.4h*ng/mL，血浆中沃诺拉赞(TAK-438)的AUC0-t为45h*ng/mL。
同时可知，按照本发明实施例的制备方法制备获得的沃诺拉赞衍生物，相比沃诺拉赞的绝对生物利用度提高了28.1％，AUC0-t提高了25.3％，并且药物在体内的代谢到一半时所需要的时间(半衰期，t1/2)延长了23.5％。
以上描述仅是对本发明的举例性说明，不应理解为对发明的限制。可以理解，本发明并不限制于上述特定的具体实施方案。

Claims (11)

  1. 一种具备如下式(I)所示结构的化合物或其衍生物，所述衍生物为其药学可接受的盐、前药、N-氧化物、异构体、其溶剂化物或其水合物，
    Figure PCTCN2017103744-appb-100001
    其特征在于，式(I)中R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14各自独立地为氢或氘，条件是其中至少之一为氘。
  2. 根据权利要求1所述的化合物或其衍生物，其特征在于，R1、R2、R3、R4、R5、R6、R7、R8、R10、R11、R12、R13、R14中的一个或多个为氘，优选地，R1、R2、R3、R4、R5、R6、R7、R8、R10、R11、R12、R13、R14中的至少两个为氘。
  3. 根据权利要求1或2所述的化合物或其衍生物，其特征在于，包括下列的化合物：
    1-[5-(2-氟苯基)-1-(吡啶-3-基-磺酰基)-1H-吡咯-3-基]-N-甲基二氘代甲胺，
    1-[5-(2-氟苯基)-1-(吡啶-3-基-磺酰基)-1H-吡咯-3-基]-N-三氘代甲基二氘代甲胺，
    1-[5-(2-氟苯基)-1-(四氘代吡啶-3-基-磺酰基)-1H-吡咯-3-基]-N-甲基二氘代甲胺，
    1-[5-(2-氟苯基)-1-(四氘代吡啶-3-基-磺酰基)-1H-吡咯-3-基]-N-三氘代甲基二氘代甲胺。
  4. 根据权利要求1～3任一项所述的化合物或其衍生物，其特征在于，所述药学可接受的盐为式(I)所示的化合物的酸加成盐，优选为式(I)化合 物的富马酸加成盐。
  5. 根据权利要求1～4任一项所述的化合物或其衍生物，其特征在于，所述化合物或其衍生物为单晶或多晶型物。
  6. 一种药物组合物，其特征在于，其包含根据权利要求1～5任一项所述的化合物或其衍生物，和药学可接受的载体、赋形剂、稀释剂、增稠剂、辅料、防腐剂中的一种或多种。
  7. 根据权利要求6所述的组合物，其特征在于，所述药物组合物还包括其它化合物，所述其它化合物包括质子泵抑制剂、口服抗酸药、抗胃酸剂、钙通道阻滞剂、多巴胺拮抗剂、氧化氮合酶抑制剂、抗炎剂中一种或多种。
  8. 一种药物制剂，其特征在于，其包含根据权利要求1～5任一项所述的化合物或其衍生物，和药学可接受的载体、赋形剂、稀释剂、增稠剂、辅料、防腐剂中的一种或多种，优选地，所述药物制剂的剂型为固体、凝胶或液体。
  9. 一种根据权利要求的1～5任一项所述的化合物或其衍生物作为胃酸分泌抑制剂的用途。
  10. 一种根据权利要求的1～5任一项所述的化合物或其衍生物作为钾竞争性胃酸阻滞剂的用途。
  11. 一种根据权利要求1～5任一项所述的化合物或其衍生物在制备治疗胃酸相关性疾病的药物中的用途，优选地，所述胃酸相关性疾病包括胃肠道粘膜损伤、幽门螺杆菌感染、胃食管反流、消化性溃疡、十二指肠溃疡、食管炎或胃溃疡。
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