WO2016119505A1 - 吡咯磺酰类衍生物、其制备方法及其在医药上的应用 - Google Patents

吡咯磺酰类衍生物、其制备方法及其在医药上的应用 Download PDF

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WO2016119505A1
WO2016119505A1 PCT/CN2015/094255 CN2015094255W WO2016119505A1 WO 2016119505 A1 WO2016119505 A1 WO 2016119505A1 CN 2015094255 W CN2015094255 W CN 2015094255W WO 2016119505 A1 WO2016119505 A1 WO 2016119505A1
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group
compound
alkyl
acid
preparation
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PCT/CN2015/094255
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English (en)
French (fr)
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秦引林
苏梅
金秋
陈涛
蒋建华
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江苏柯菲平医药股份有限公司
南京柯菲平盛辉制药有限公司
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Priority to ES15879703T priority Critical patent/ES2751702T3/es
Priority to JP2017540775A priority patent/JP6412656B2/ja
Priority to EP15879703.5A priority patent/EP3248963B1/en
Priority to CN201580069871.1A priority patent/CN107207432B/zh
Priority to US15/547,522 priority patent/US10913714B2/en
Publication of WO2016119505A1 publication Critical patent/WO2016119505A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/46—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with hetero atoms directly attached to the ring nitrogen atom
    • C07D207/48—Sulfur atoms
    • 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
    • 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
    • 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
    • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
    • 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
    • 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
    • C07D405/02—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 two hetero rings
    • C07D405/04—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 two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D413/12—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 chain containing hetero atoms as chain links
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/402—1-aryl substituted, e.g. piretanide
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • 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
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to a novel class of pyrrolesulfonyl derivatives, a process for the preparation thereof, and a pharmaceutical combination containing the same, and as a therapeutic agent, particularly as a gastric acid secretion inhibitor and a potassium ion competitive acid blocker (P-CABs) )the use of.
  • a novel class of pyrrolesulfonyl derivatives a process for the preparation thereof, and a pharmaceutical combination containing the same, and as a therapeutic agent, particularly as a gastric acid secretion inhibitor and a potassium ion competitive acid blocker (P-CABs) )the use of.
  • P-CABs potassium ion competitive acid blocker
  • proton pump inhibitors represented by omeprazole have been widely used clinically by inhibiting gastric acid secretion for the treatment of peptic ulcer, reflux esophagitis and Zhuo-Ai syndrome.
  • Long-term clinical applications have found that existing proton pump inhibitors have limitations in pharmacokinetics and pharmacodynamics. For example, the effect of administration time on the efficacy of the drug; slow acid onset at night; unstable under acidic conditions (need to be formulated into intestinal preparations); dependence on CYP450 enzyme (resulting in significant individual differences).
  • Potassium competitive acid blocker (Potassium-Competitive Acid Blockers, P -CABs) is generated by direct action, reversible processes competitively inhibiting H + / K + -ATP enzyme of K +.
  • P-CABs are characterized by lipophilicity, weak basicity, high dissociation constant and stability under low pH conditions.
  • P-CABs bind to H + /K + -ATPase in an ionized form, preventing H + transport and acid secretion into the gastric cavity, and rapidly increasing the pH in the stomach.
  • Animal experiments and clinical studies have shown that P-CABs have rapid onset of action and can achieve maximum therapeutic effect within one hour; blood concentration is linearly related to oral dose, and it is easier to achieve the best acid suppression effect.
  • the structure provided by the present application is a compound represented by formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, Or a pharmaceutically acceptable salt:
  • a and B are independently selected from N or CR 4 , and R 4 is selected from the group consisting of hydrogen, halogen, and alkyl;
  • X is selected from O or NR 5 , and R 5 is selected from the group consisting of hydrogen and alkyl;
  • R 1 is selected from an alkyl group, a heterocycloalkyl group, wherein the alkyl group, heterocycloalkyl group is further substituted with one or more substituents selected from the group consisting of hydrogen, halogen, and alkyl;
  • R 2 is selected from an alkylsulfonyl group, a heterocycloalkyl group, an alkoxy group, an alkyl acyl group, a phenoxy group, an alkylamino group, wherein the alkylsulfonyl group, heterocycloalkyl group, alkoxy group, formyl group a phenoxy group, an alkylamino group, further substituted with one or more substituents selected from the group consisting of hydrogen, halogen, and alkyl;
  • R 3 is selected from the group consisting of hydrogen, halogen, and alkyl.
  • B is selected from CR 4 and R 4 is selected from hydrogen.
  • the invention further relates to a pharmaceutical composition
  • a pharmaceutical composition comprising an effective amount of a compound according to any one of claims 1 to 3 or a tautomer thereof, a mesogen, a racemate, a pair a conjugate, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier, excipient or diluent.
  • Another aspect of the invention relates to a method for inhibiting gastric acid secretion comprising administering to a patient in need of treatment an effective amount of a compound of the formula (I) or a tautomer thereof, a mesogen, a racemic thereof a form, a diastereomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt or a pharmaceutical composition comprising the same.
  • Another aspect of the invention relates to a compound represented by (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or Use of a pharmaceutically acceptable salt or a pharmaceutical composition comprising the same for the preparation of an H + /K + - adenosine triphosphatase (H + /K + -ATPase) inhibitor.
  • H + /K + - adenosine triphosphatase H + /K + -ATPase
  • Another aspect of the invention relates to a compound represented by (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or A pharmaceutically acceptable salt or a pharmaceutical composition comprising the same for preparing potassium ion competitive acid resistance Use in retardants (P-CABs).
  • P-CABs potassium ion competitive acid resistance Use in retardants
  • the invention provides for treating or preventing peptic ulcer, Zhuo-Ai syndrome, gastritis, erosive esophagitis, reflux esophagitis, symptomatic gastroesophageal reflux disease, Barrett's esophagitis, functional dyspepsia, Use of Helicobacter pylori infection, gastric cancer, gastric MALT lymphoma, ulcers caused by non-steroidal anti-inflammatory drugs or drugs for hyperacidity or ulceration caused by post-operative stress; or in the preparation of inhibition for peptic ulcer, acute A method of stress ulcers, hemorrhagic gastritis, or drugs for upper gastrointestinal bleeding caused by invasive stress.
  • the peptic ulcer is selected from the group consisting of a gastric ulcer, a duodenal ulcer or an anastomotic ulcer; and the symptomatic gastroesophageal reflux disease is selected from a non-erosive reflux disease or a gastroesophageal reflux disease without esophagitis. method.
  • Alkyl means a saturated aliphatic hydrocarbon group. A straight or branched chain group of 1 to 20 carbon atoms is included. Preference is given to medium-sized alkyl groups having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl, pentyl and the like. More preferred are lower alkyl groups having 1 to 4 carbon atoms such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl or t-butyl groups and the like.
  • the alkyl group may be substituted or unsubstituted, and when substituted, preferred groups are: halogen, C 2 -C 6 alkenyl, C 6 -C 10 aryl, C 5 -C 10 heteroaryl, halogen C 1 -C 6 alkyl, 4 to 8 membered heteroalicyclic, hydroxy, C 1 -C 6 alkoxy, C 6 -C 10 aryloxy.
  • Heterocycloalkyl means a monocyclic or fused ring radical having from 5 to 9 ring atoms in the ring wherein one or both of the ring atoms are selected from N, O or S(O) p (where p is A hetero atom of 0 to 2 integers, and the remaining ring atoms are C. These rings may have one or more double bonds, but these rings do not have a fully conjugated pi-electron system.
  • Non-limiting examples of unsubstituted heteroalicyclic groups are pyrrolidinyl, piperidino, piperazino, morpholino, thiomorpholino, homopiperazino and the like.
  • the heteroalicyclic group can be substituted or unsubstituted.
  • the substituent is preferably one or more, more preferably one, two or three, and even more preferably one or two, said substituent being selected from the group consisting of hydrogen, hydroxy, thiol, oxygen a lower alkyl group, a lower alkoxy group, a lower cycloalkyl group, a lower heteroalicyclic group, a lower haloalkoxy group, an alkylthio group, a halogen, a lower haloalkyl group, a lower hydroxyalkyl group, a lower cycloalkylalkylene group, Lower heteroalicyclic alkylene, aryl, heteroaryl, alkoxycarbonyl, amino, alkylamino, alkylsulfonyl, arylsulfonyl, alkylaminosulfonyl, arylaminosulfonyl, alkyl Sulfonylamino, arylsulfonylamino, alkylaminocarbony
  • heteroalicyclic groups include, but are not limited to, morpholinyl, piperazinyl, piperidinyl, azetidinyl, pyrrolidinyl, hexahydroaza , oxetanyl, tetrahydrofuranyl, tetrahydrothiophenyl, oxazolidinyl, thiazolidinyl, isoxazolidinyl, tetrahydropyranyl, thiomorphinyl, quinuclidinyl and imidazole
  • the morphyl group, each group as described above may also be bicyclic, such as, for example, 3,8-diaza-bicyclo[3.2.1]octane, 2,5-diazabicyclo[2.2. 2] Octane or octahydro-pyrazino[2,1-c][1,4]oxazine.
  • Its heteroalicyclic group (and derivatives) include
  • Alkoxy means -O-(unsubstituted alkyl) and -O (unsubstituted cycloalkyl). Representative examples include, but are not limited to, methoxy, Ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy and the like.
  • Alkylsulfonyl means -S(O 2 )-alkyl.
  • Alkylamino means -NH-alkyl.
  • alkyl acyl means R is a lower alkyl group.
  • Haldroxy means an -OH group.
  • Halogen means fluoro, chloro, bromo or iodo, preferably fluoro or chloro.
  • substituted by one or more groups means that one, two, three or four hydrogen atoms in a given atom or group are each selected from a specified range of groups. Replace the same or different groups.
  • “Pharmaceutically acceptable salt” means those salts which retain the biological effectiveness and properties of the parent compound. Such salts include:
  • a salt with an acid obtained by a reaction of a free base of a parent compound with an inorganic or organic acid includes hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, metaphosphoric acid, sulfuric acid, sulfurous acid, perchloric acid, etc.
  • Organic acids include acetic acid, propionic acid, acrylic acid, oxalic acid, (D) or (L) malic acid, fumaric acid, maleic acid, hydroxybenzoic acid, ⁇ -hydroxybutyric acid, methoxybenzoic acid, ortho-benzene Formic acid, methanesulfonic acid, ethanesulfonic acid, naphthalene-1-sulfonic acid, naphthalene-2-sulfonic acid, p-toluenesulfonic acid, salicylic acid, tartaric acid, citric acid, lactic acid, mandelic acid, succinic acid or malonic acid .
  • an organic base such as ethanolamine, diethanolamine, or the like. Ethanolamine, tromethamine, N-methylglucamine, and the like.
  • “Pharmaceutical composition” means that one or more of the compounds of the invention, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, is mixed with another chemical component, such as a pharmaceutically acceptable carrier. .
  • the purpose of the pharmaceutical composition is to facilitate the administration to the animal.
  • “Pharmaceutically acceptable carrier” refers to an inactive ingredient in a pharmaceutical composition that does not cause significant irritation to the organism and does not interfere with the biological activity and properties of the administered compound, such as, but not limited to, calcium carbonate, calcium phosphate, various Sugar (eg lactose, mannitol, etc.), starch, cyclodextrin, magnesium stearate, cellulose, magnesium carbonate, acrylic polymer or methacrylic acid polymer, gel, water, polyethylene glycol, propylene glycol, B Glycol, castor oil or hydrogenated castor oil or polyethoxylated hydrogenated castor oil, sesame oil, corn oil, peanut oil and the like.
  • the aforementioned pharmaceutical composition may include, in addition to a pharmaceutically acceptable carrier, an adjuvant which is commonly used in medicine, for example, an antibacterial agent, an antifungal agent, an antimicrobial agent, a quality agent, a tone.
  • an adjuvant which is commonly used in medicine, for example, an antibacterial agent, an antifungal agent, an antimicrobial agent, a quality agent, a tone.
  • Toner solubilizer, thickener, surfactant, complexing agent, Protein, amino acids, fats, sugars, vitamins, minerals, trace elements, sweeteners, colors, flavors or combinations thereof.
  • Example 2 a white solid compound 1-(3-(3-(2-fluorophenyl)-4-((methylamino)methyl)-1H-pyrrol-1-yl) was obtained. Sulfonyl)phenoxy)pyrrolidin-1-yl)ethyl-1-one (EXP 2) in a yield of 65%.
  • Rabbit gastric mucosa microsomes (rich in H+/K+-ATPase), the extraction method is sucrose gradient centrifugation: the rabbit stomach is washed with tap water, 3M NaCl solution, and then the surface water is removed by filter paper. Pre-cooled homogenization buffer (4 ml/g tissue) was added and homogenized in a tissue homogenizer for 2-5 min.
  • the present invention provides a half-inhibitory concentration (IC 50 ) of a compound of formula I for H + /K + -ATPase activity.
  • EXP 1 EXP 2 EXP 3 EXP 4 EXP5 EXP 6 EXP 7 EXP8 +++ +++ ++ ++ +++ ++ ++ ++ ++ ++ EXP 9 EXP10 EXP 11 EXP 12 EXP14 ++ +++ + +++ ++
  • +++ means IC 50 ⁇ 100nM; ++ means range 0.1 ⁇ 1 ⁇ M; + means range 1 ⁇ 5 ⁇ M
  • the hERG cell line was routinely cultured and passaged in DMEM containing 10% fetal calf serum and 250 ⁇ g/ml G418.
  • Liquid configuration The components of the extracellular fluid used in the whole cell patch clamp experiment were (mM): NaCl 145; MgCl21; KCl 4; Glucose 10; HEPES 10; and CaCl22, adjusted to pH 7.4 with NaOH, and infiltrated with sucrose The pressure is adjusted to 300mOsm.
  • the intracellular fluid composition was (mM): KCl 140; MgCl21; EGTA 5; HEPES 10 and Na2ATP 4, the pH was adjusted to 7.2 with KOH, and the osmotic pressure was adjusted to 290 mOsm with sucrose.
  • Electrophysiological recording One dish was taken out of each experiment, washed twice with extracellular fluid, and placed on an inverted microscope stage. Whole cell patch clamp experiments were performed at room temperature using a borosilicate glass microelectrode tip resistance of 3 to 5 M ⁇ .
  • the membrane resistance in the experiment is greater than 1,000 M ⁇ .
  • the initial current is greater than 300pA.
  • the series resistance is less than 12 M ⁇ after the whole cell recording mode is established.
  • the leakage current is less than 10% of the ion channel current (-80pA is the maximum).
  • % inhibition rate ⁇ 1 - (current residual amplitude) / (control current amplitude) ⁇ * 100
  • the inhibition rate (mean ⁇ standard deviation) of multiple concentrations of the test compound to hERG current was obtained, and the data was fitted using a logistic equation to obtain an IC 50 value.
  • Compound EXP1 was dissolved in a small amount of acetic acid (about 1.10 N EXP1) and 0.9% sodium chloride solution to a desired concentration of clarified liquid before use.
  • Compound TAK-438 was dissolved in a 0.9% sodium chloride solution to a desired concentration of clarified solution immediately before use.
  • Compound EXP14 was dissolved in a small amount of acetic acid (about 1.10 N EXP14) and 0.9% sodium chloride solution to a desired concentration of clarified liquid before use.
  • Histamine dihydrochloride aladdin, lot number: H110868.
  • Chloral hydrate Sinopharm Chemical Reagent Co., Ltd., batch number: 20130314, prepared with 3% chloral hydrate solution with 0.9% sodium chloride solution before use.
  • Phenolphthalein Sinopharm Chemical Reagent Co., Ltd., the batch number is F20110125, and 1% phenolphthalein solution is prepared with 95% ethanol before use.
  • test compound EXP1 group (2 mg/kg) and TAK-438 group (2 mg/kg, calculated as free base).
  • the EXP14 group (2 mg/kg), the negative control group (equal volume saline) and the model control group (equal volume saline), 12 rats in each group. Fasting for 24 hours, can not help but water.
  • the test group A, B, and C were administered by intragastric administration, and the administration volume was 1 ml/100 g, and each group was administered once.
  • the negative control group and the model control group were intragastrically administered with an equal volume of physiological saline.
  • the rats were anesthetized with chloral hydrate 300 mg/kg (1 ml/100 g), they were fixed on the rat plate, and the abdominal wall was cut from the sternal xiphoid along the midline of the ventral midline. The incision was about 2 to 3 cm. Use your finger to gently push up to expose the stomach to the incision. The pylorus is ligated under the pylorus (the other adjacent vessels are not ligated), and then the abdominal wall incision is sutured. The animal was administered subcutaneously with histamine dihydrochloride (30 mg/10 m/kg) 1 hour after the administration of the test compound or physiological saline.
  • Test drug compound EXP 1 (about 1.10N EXP1), TAK-438 (administered dose as free base)
  • Test contents Single dose: 2000 mg/kg, 600 mg/kg, once intragastric administration, administration volume: 10 ml/kg, observed for 14 days, and observed the behavior and body weight of the rats every day.
  • Animals SPF grade SD rats, weighing 180-220 g, provided by Zhejiang Experimental Animal Center, animal certificate number: SCXK (Zhejiang) 2014-0001.
  • Experimental group blank group, 600mg/kg group, 2000mg/kg group, 4 groups in each group, male and female.
  • TAK-438 2000 mg/kg: death in all cases; 600 mg/kg: inhibition of weight gain.

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Abstract

本发明涉及一类新的吡咯磺酰类衍生物、其制备方法及在医药上的应用。具体而言，本发明涉及一种通式(I)所示的吡咯磺酰类衍生物、其制备方法及含有该衍生物的药物组合以及作为治疗剂，特别是作为胃酸分泌抑制剂和钾离子竞争性酸阻滞剂（P-CABs）的用途，其通式(I)的各取代基与说明书中的定义相同。

Description

吡咯磺酰类衍生物、其制备方法及其在医药上的应用 技术领域
本发明涉及一类新的吡咯磺酰类衍生物、其制备方法及含有该衍生物的药物组合以及其作为治疗剂特别是作为胃酸分泌抑制剂和钾离子竞争性酸阻滞剂(P-CABs)的用途。
背景技术
自1988年以来，以奥美拉唑为代表的质子泵抑制剂通过抑制胃酸分泌以治疗消化性溃疡、反流性食管炎和卓-艾综合症等在临床上得到广泛应用。长期的临床应用发现，现有质子泵抑制剂在药代动力学、药效学方面还有局限性。如：给药时间对药效的影响；夜间酸突破起效慢；酸性条件下不稳定(需要配制成肠制剂)；对CYP450酶的依赖性(导致个体差异显著)等。
钾竞争性酸阻滞剂(Potassium-Competitive Acid Blockers，P-CABs)通过直接、可逆性的过程竞争性地抑制H+/K+-ATP酶中的K+而产生作用。与传统质子泵抑制剂相比，P-CABs具有亲脂性、弱碱性、解离常数高和在低pH条件下稳定的特点。在酸性环境下，P-CABs以离子化形式与H+/K+-ATP酶结合，阻止H+运送及酸分泌到胃腔中，迅速升高胃中pH值。动物实验和临床研究表明：P-CABs具备起效迅速，在1小时内就能达到最大治疗效果；血药浓度与口服给药剂量线性相关，比较容易达到最佳抑酸效果的优势。
尽管目前已公开了一系列钾竞争性酸阻滞剂，但仍需要开发结构类型更丰富，新的可能具有更好的成药性质的化合物，经过不断努力，本发明设计具有通式(I)所示的结构的化合物，并发现具有此类结构的化合物表现出优异的效果和作用。
发明内容
本申请提供结构如式(I)所示的胃酸分泌抑制剂，它的使用方法，如本文下面所述：
本申请提供的结构如式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或药学上可接受的盐：
Figure PCTCN2015094255-appb-000001
其中A、B独立的选自N或CR4，R4选自氢、卤素、烷基；
X选自O或NR5，R5选自氢、烷基；
R1选自烷基、杂环烷基，其中所述烷基、杂环烷基进一步被一个或多个选自氢、卤素、烷基的取 代基所取代；
R2选自烷基磺酰基、杂环烷基、烷氧基、烷基酰基、苯氧基、烷基胺基，其中所述烷基磺酰基、杂环烷基、烷氧基、甲酰基、苯氧基、烷基胺基进一步被一个或多个选自氢、卤素、烷基的取代基所取代；
R3选自氢、卤素、烷基。
进一步的A、B选自CR4，R4选自氢。
进一步的，上述所述化合物选自：
Figure PCTCN2015094255-appb-000002
本发明还涉及一种药用组合物，所述药物组合物含有有效量的权利要求1-3任意一项所述化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或药学上可接受的盐和药物可接受的载体、赋形剂或稀释剂。
本发明另一方面涉及一种抑制胃酸分泌的方法，该方法包括给予需要治疗的患者有效剂量的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或药学上可接受的盐或包含其的药物组合物。
本发明另一方面涉及(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或药学上可接受的盐或包含其的药物组合物在制备H+/K+-腺苷三磷酸酶(H+/K+-ATPase)抑制剂中的用途。
本发明另一方面涉及(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或药学上可接受的盐或包含其的药物组合物在制备钾离子竞争性酸阻 滞剂(P-CABs)中的用途。
本发明提供用于治疗或预防消化性溃疡，卓-艾综合症、胃炎、糜烂性食管炎、反流性食管炎、症状性胃食管反流疾病、巴雷特食管炎、功能性消化不良、幽门螺旋杆菌感染、胃癌、胃MALT淋巴瘤、非甾体抗炎药引起的溃疡或手术后应激导致的胃酸过多或溃疡的药物中的用途；或者在制备抑制用于消化性溃疡、急性应激性溃疡、出血性胃炎或侵入性应激造成的上消化道出血的药物中的方法。其中消化性溃疡选自胃溃疡、十二指肠溃疡或吻合口溃疡；所述的症状性胃食管反流疾病选自非糜烂性的反流性疾病或无食管炎的胃食管反流疾病的方法。
发明的详细说明
除非有相反陈述，下列用在说明书和权利要求中的术语具有下述含义。
“烷基”指饱和的脂族烃基团。包括1至20个碳原子的直链或支链基团。优选含有1至6个碳原子的中等大小烷基，例如甲基、乙基、丙基、2-丙基、正丁基、异丁基、叔丁基、戊基等。更优选的是含有1至4个碳原子的低级烷基，例如甲基、乙基、丙基、2-丙基、正丁基、异丁基或叔丁基等。烷基可以是取代的或未取代的，当被取代时，优选的基团为：卤素、C2-C6烯基、C6-C10芳基、C5-C10杂芳基、卤代C1-C6烷基、4至8元杂脂环基、羟基、C1-C6烷氧基、C6-C10芳氧基。
“杂环烷基”表示单环或稠和环基团，在环中具有5到9个环原子，其中一个或两个环原子是选自N、O或S(O)p(其中p是0至2的整数)的杂原子，其余环原子是C。这些环可以具有一条或多条双键，但这些环不具有完全共轭的π电子系统。未取代的杂脂环基的非限制性实例有吡咯烷基、哌啶子基、哌嗪子基、吗啉代基、硫代吗啉代基、高哌嗪子基等。杂脂环基可以是取代的或未取代的。当被取代时，取代基优选为一个或多个，更为优选为一个、两个或三个，进而更优选为一个或两个，所述的取代基选自:氢、羟基、巯基、氧代、低级烷基、低级烷氧基、低级环烷基、低级杂脂环基、低级卤代烷氧基、烷硫基、卤素、低级卤代烷基、低级羟烷基、低级环烷基亚烷基、低级杂脂环基亚烷、芳基、杂芳基、烷氧基羰基、氨基、烷基氨基、烷基磺酰基、芳基磺酰基、烷基氨基磺酰基、芳基氨基磺酰基、烷基磺酰基氨基、芳基磺酰基氨基、烷基氨基羰基、芳基氨基羰基、烷基羰基氨基、芳基羰基氨基。除非另外指出。杂脂环基的实例包括但不限于，吗啉基，哌嗪基，哌啶基，氮杂环丁烷基，吡咯烷基，六氢氮杂
Figure PCTCN2015094255-appb-000003
基，氧杂环丁烷基，四氢呋喃基，四氢噻吩基，噁唑烷基，噻唑烷基，异噁唑烷基，四氢吡喃基，硫代吗琳基，奎宁环基和咪唑啉基，各基团如前所述，实例还可以是双环的，诸如，例如，3，8-二氮杂-双环[3.2.1]辛烷、2，5-二氮杂双环[2.2.2]辛烷或八氢-吡嗪并[2，1-c][1,4]噁嗪。其杂脂环基(和衍生物)包括其离子形式。
“烷氧基”表示-O-(未取代的烷基)和-O(未取代的环烷基)。代表性的实例包括但不限于甲氧基、 乙氧基、丙氧基、丁氧基、环丙氧基、环丁氧基、环戊氧基、环己氧基等。
“烷基磺酰基”表示-S(O2)-烷基。
“烷基胺基”表示-NH-烷基。
“烷基酰基”表示
Figure PCTCN2015094255-appb-000004
R为低级烷基。
“羟基”表示-OH基团。
“卤素”表示氟、氯、溴或碘，优选为氟或氯。
所谓“任选地”的意思是指后续描述的事件或情形可能会也可能不会发生，并且该描述包括事物或情形可能会也可能不会发生，并且该描述包括事物或情形发生和不发生两种情况。
在一些实施方案中，“被一个或多个基团取代”是指在指定的原子或基团中的一个、两个、三个或四个氢原子分别被指定范围的基团中选出的相同或不同的基团替换。
“药学上可接受的盐”表示保留母体化合物的生物有效性和性质的那些盐。这类盐包括：
(1)与酸成盐，通过母体化合物的游离碱与无机酸或有机酸的反应而得，无机酸包括盐酸、氢溴酸、硝酸、磷酸、偏磷酸、硫酸、亚硫酸和高氯酸等，有机酸包括乙酸、丙酸、丙烯酸、草酸、(D)或(L)苹果酸、富马酸、马来酸、羟基苯甲酸、γ-羟基丁酸、甲氧基苯甲酸、邻苯二甲酸、甲磺酸、乙磺酸、萘-1-磺酸、萘-2-磺酸、对甲苯磺酸、水杨酸、酒石酸、柠檬酸、乳酸、扁桃酸、琥珀酸或丙二酸等。
(2)存在于母体化合物中的酸性质子被金属离子代替或者与有机碱配位化合所生成的盐，金属例子例如碱金属离子、碱土金属离子或铝离子，有机碱例如乙醇胺、二乙醇胺、三乙醇胺、氨丁三醇、N-甲基葡糖胺等。
“药物组合物”指将本发明中的化合物中的一个或多个或其药学上可接受的盐、溶剂化物、水合物或前药与别的化学成分，例如药学上可接受的载体，混合。药物组合物的目的是促进给药给动物的过程。
“药用载体”指的是对有机体不引起明显的刺激性和不干扰所给予化合物的生物活性和性质的药物组合物中的非活性成分，例如但不限于：碳酸钙、磷酸钙、各种糖(例如乳糖、甘露醇等)、淀粉、环糊精、硬脂酸镁、纤维素、碳酸镁、丙烯酸聚合物或甲基丙烯酸聚合物、凝胶、水、聚乙二醇、丙二醇、乙二醇、蓖麻油或氢化蓖麻油或多乙氧基氢化蓖麻油、芝麻油、玉米油、花生油等。
前述的药物组合物中，除了包括药学上可接受的载体外，还可以包括在药(剂)学上常用的辅剂，例如：抗细菌剂、抗真菌剂、抗微生物剂、保质剂、调色剂、增溶剂、增稠剂、表面活性剂、络合剂、 蛋白质、氨基酸、脂肪、糖类、维生素、矿物质、微量元素、甜味剂、色素、香精或它们的结合等。
具体实施方式
以下结合实施例用于进一步描述本发明，但这些实施例并非限制着本发明的范围。
实施例1：
1-(5-(2-氟苯)-1-((3-(3-甲氧基丙氧基)苯基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺(EXP 1)的制备
Figure PCTCN2015094255-appb-000005
1)1-(3-甲氧基丙氧基)-硝基苯(化合物2)的制备
将3-硝基苯酚(化合物1，1.0g，7.19mmol)，碳酸钾(2.9g，21.6mmol)和1-溴-3-甲氧基丙烷(1.65g，10.79)溶解在无水DMF(20mL)中，在90℃搅拌过夜，加水(50mL)，并用乙酸乙酯萃取(50mLx3).合并有机相干燥，浓缩，得黄色固体1-(3-甲氧基丙氧基)-硝基苯(化合物2，1.5g,收率100％)。
2)1-(3-甲氧基丙氧基)-苯胺(化合物3)的制备
1-(3-甲氧基丙氧基)-硝基苯(化合物2，1.0g，4.74mmol)，Raney Ni(100mg)溶解于无水甲醇(20mL)溶液中，在氢气氛、室温条件搅拌过夜。过滤，滤液旋干得固体1-(3-甲氧基丙氧基)-苯胺(化合物3，0.80g，91％yield)。
3)1-(3-甲氧基丙氧基)-苯磺酰氯(化合物4)的制备
在0℃下，分批将亚硝酸钠(571mg，8.29mmol)加到1-(3-甲氧基丙氧基)-苯胺(化合物3，1.0g,5.52mmol)的乙酸(10mL)和盐酸水溶液(2N，10mL)中。加料结束，在0℃搅拌25min，得溶液I。在0℃下，将氯化亚铜(190mg，1.1mmol)加到二氧化硫的乙酸溶液中(10mL，2N)得溶液II。在0℃下，把溶液I滴加到溶液II中，滴加结束，自然升温至室温，搅拌反应3小时。用乙酸乙酯萃取(150mLx3)，合并有机相干燥，浓缩，柱层析(石油醚：乙酸乙酯＝20:1)得黄色油状物1-(3-甲氧基丙氧基)- 苯磺酰氯(化合物4，800mg,收率55％)。
4)5-(2-氟苯)-1-((3-(3-甲氧基丙氧基)苯基)磺酰基)-1H-吡咯-3-甲醛(化合物5)的制备
在0℃下，将t-BuOK(233mg,2.08mmol)加到5-(2-氟苯)-1H-吡咯-3-甲醛(200mg,1.04mmol)的无水THF(5mL)溶液中，在0℃搅拌反应30min。反应结束，分别加入15-crown-5(542mg，2.08mmol)和1-(3-甲氧基丙氧基)-苯磺酰氯(化合物4，412mg,2.08mmol)。加料结束后，自然升温至室温，搅拌反应90min。反应结束后用冰水(50g)淬灭并用乙酸乙酯萃取(50mLx3)。合并有机相干燥，浓缩，柱层析(石油醚：乙酸乙酯＝8:1)得黄色固体5-(2-氟苯)-1-((3-(3-甲氧基丙氧基)苯基)磺酰基)-1H-吡咯-3-甲醛(260mg,收率60％)。
5)1-(5-(2-氟苯)-1-((3-(3-甲氧基丙氧基)苯基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺(EXP 1)的制备
将5-(2-氟苯)-1-((3-(3-甲氧基丙氧基)苯基)磺酰基)-1H-吡咯-3-甲醛(化合物5，500mg,1.19mmol),乙酸(144mg,2.39mmol),甲胺醇溶液(1mL)溶于无水甲醇3mL中，室温搅拌4h。加NaBH3CN(212mg,3.59mmol)。搅拌60min。加冰水(30g)淬灭反应，用乙酸乙酯(50mLx3)萃取。合并有机相干燥，浓缩，柱层析得白色固体1-(5-(2-氟苯)-1-((3-(3-甲氧基丙氧基)苯基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺(EXP 1，100mg,20％)。
HPLC:99.4％；MS(ESI)m/z:[M+H]+＝433.0；1H-NMR(400MHz,DMSO-d6)δ:8.72(s,1H),7.78(d,1H),7.46-7.55(m,2H),7.21-7.32(m,3H),6.85-7.11(m,2H),6.83-6.85(m,1H),6.44(d,1H),3.95-4.02(m,4H),3.47(t,2H),3.32(s,3H),2.52(m,3H),1.94(t,2H)ppm。
实施例2：1-(3-(3-((2-(2-氟苯)-4-((甲胺基)甲基)-1H-吡咯-1-基)磺酰基)苯氧基)吡咯烷-1-基)乙基-1-酮(EXP 2)的制备
Figure PCTCN2015094255-appb-000006
参照实施例1的制备方法，获得白色固体化合物1-(3-(3-((2-(2-氟苯)-4-((甲胺基)甲基)-1H-吡咯-1-基)磺酰基)苯氧基)吡咯烷-1-基)乙基-1-酮(EXP 2)，收率65％。HPLC:94.8％；MS(ESI)m/z:[M+H]+＝472.1；1H-NMR(400MHz,DMSO-d6)δ:8.75(s,1H),7.78(s,1H),7.48-7.53(m,2H),7.35(t,1H),7.22-7.25(m,2H),7.04-7.09(m,2H),6.86-6.88(m,1H),6.45(d,1H),4.77-4.79(m,1H),4.01(s,2H),3.39-3.64(m,4H),2.55(d,3H),1.86-2.09(m,4H)ppm。
实施例3：1-(5-(2-氟苯)-1-((3-(2-甲氧基乙氧基)苯基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺(EXP 3)的 制备
Figure PCTCN2015094255-appb-000007
参照实施例1的制备方法，获得化合物1-(5-(2-氟苯)-1-((3-(2-甲氧基乙氧基)苯基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺(EXP 3)80mg，收率10％。HPLC:96.5％；MS(ESI)m/z:[M+H]+＝419.2；1H-NMR(400MHz,MeOD)δ:7.44(d,1H),7.42(m,1H),7.37(t,1H),7.04-7.19(m,5H),6.89(t,1H),6.28(d,1H),4.03(t,2H),3.72(t,2H),3.63(s,2H),3.42(d,3H),2.38(s,3H)ppm。
实施例4：1-(5-(2-氟苯)-1-((3-(3-甲基磺酰基丙氧基)苯基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺(EXP 4)的制备
Figure PCTCN2015094255-appb-000008
参照实施例1的制备方法，获得化合物1-(5-(2-氟苯)-1-((3-(3-甲基磺酰基丙氧基)苯基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺(EXP 4)70mg,收率20％。HPLC:94.28％；MS(ESI)m/z:[M+H]+＝481.2；1H-NMR(400MHz,MeOD)δ:7.45(m,2H),7.34(t,1H),7.06-7.19(m,5H),6.89(t,1H),6.28(d,1H),4.06(t,2H),3.59(s,2H),3.34(m,2H),3.42(d,3H),3.01(s,3H),2.36(s,3H),2.27(m,2H)ppm。
实施例5：1-(5-(2-氟苯)-1-((3-(2-吗啉基乙氧基)苯基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺(EXP 5)的制备
Figure PCTCN2015094255-appb-000009
Figure PCTCN2015094255-appb-000010
1)4-(2-(3-溴苯氧基)乙基)吗啉(化合物A)的制备
将化合物3-溴苯酚(SM-1，5g，29mmol，1eq)，化合物N-(2-氯乙基)吗啉(SM-2，4.3g，29mmol，1eq)和碳酸钾(8g,58mmol,2eq)溶于干燥的DMF(50ml)中，在室温下搅拌过夜，TLC检测反应完全。加入水，用EA萃取，蒸干有机层，过柱分离得化合物A(9g，收率90％)
2)3-(2-吗啉基乙氧基)苯磺酰氯(化合物B)的制备
将化合物A(4g,14mmol,1eq)溶于无水THF(50ml)并冷却-78℃，加入n-BuLi(13ml,21mmol,1.5eq)在-78℃下搅拌1小时，向反应液中通入二氧化硫气体20分钟，并在2小时内从-78℃升到0℃。反应液浓缩蒸干并加入DCM(50ml)和N-氯丁二酰亚胺(NCS，2.8g,21mmol,1.5eq)，继续搅拌12h。反应液直接过柱分离得化合物B(2g，收率50％)
3)(5-(2-氟苯)-1-((3-(2-吗啉基乙氧基)苯基)磺酰基)-1H-吡咯-3甲醛(化合物C)的制备
将化合物SM-3(1.2g,6.5mmol,1eq)溶于THF(15ml)并冷却到0℃，加入NaH(0.4g,9.8mmol,1.5eq)在0℃下搅拌0.5小时。化合物B(2g,6.5mmol,1eq)和15-crown-5(2g)加入到反应液中在室温下搅拌0.5小时，加入水，用EA萃取，有机层蒸干，过柱分离得化合物C(700mg，收率30％)
4)1-(5-(2-氟苯)-1-((3-(2-吗啉基乙氧基)苯基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺(EXP 5)的制备
将化合物C(0.7g,1.53mmol,1eq)溶于甲醇(5ml)，加入甲胺醇溶液(4ml)，在0℃下加入醋酸(2ml)并搅拌2h，加入氰基硼氢化钠(0.9g,15.3mmol,10eq)，继续搅拌14h，LC-MS检测反应完全，加入碳酸氢钠水溶液，用EA萃取，有机层蒸干，制备得化合物EXP5(100mg,收率15％).
HPLC:96.06％；MS(ESI)m/z:[M+H]+＝474.6；1H-NMR(400MHz,DMSO-d6)δ:7.42-7.51(m,3H),7.17-7.27(m,3H),7.08-7.12(m,1H),7.02(d,1H),6.87(s,1H),6.32(s,1H),4.03(t,2H),3.57(t,4H),3.50(s,2H),2.66(t,2H),2.45-2.50(m,4H),2.24(s,3H)ppm。
实施例6：3-((2-(2-氟苯)-4-((甲基胺基)亚甲基)-1H-吡咯-1-基)磺酰基)-N-(2-吗啉基乙基)苯胺(EXP 6)的制备
Figure PCTCN2015094255-appb-000011
参照实施例5的制备方法，获得化合物3-((2-(2-氟苯)-4-((甲基胺基)亚甲基)-1H-吡咯-1-基)磺酰基)-N-(2-吗啉基乙基)苯胺(EXP 6)100mg,收率20％。HPLC:96.99％；MS(ESI)m/z:[M+H]+＝473.6；1H-NMR(400MHz,DMSO-d6)δ:7.57(d,1H),7.48(q,1H),7.17-7.24(m,3H),7.08-7.12(m,1H),6.85(d,1H),6.55-6.58(m,1H),6.38(s,1H),6.11(t,1H),3.83(s,2H),3.59(s,4H),3.03(q,2H),2.39-2.44(m,9H)ppm。
实施例7：3-(3-((2-(2-氟苯)-4-((甲胺基)亚甲基)-1H-吡咯-1-基)磺酰基)苯氧基)-N-甲基正丙胺(EXP7)的制备
Figure PCTCN2015094255-appb-000012
参照实施例5的制备方法，获得化合物3-(3-((2-(2-氟苯)-4-((甲胺基)亚甲基)-1H-吡咯-1-基)磺酰基)苯氧基)-N-甲基正丙胺(EXP7)80mg,收率40％。HPLC:95.84％；MS(ESI)m/z:[M+H]+＝432.2；1H-NMR(400MHz,DMSO-d6)δ:7.40-7.51(m,3H),7.18-7.25(m,3H),7.03-7.13(m,1H),6.83(s,1H),6.31(s,1H),3.39(t,2H),3.46(s,2H),2.59(t,2H),2.29(s,3H),1.81(m,2H)ppm。
实施例8：1-(5-(2-氟苯)-1-((3-(吗啉基-2-基甲氧基)苯基)磺酰基)-1H-吡咯-3-yl)-N-家基甲胺(EXP8)的制备
Figure PCTCN2015094255-appb-000013
参照实施例5的制备方法，获得化合物1-(5-(2-氟苯)-1-((3-(吗啉基-2-基甲氧基)苯基)磺酰基)-1H-吡咯-3-yl)-N-家基甲胺(EXP 8)100mg,收率20％。HPLC:95.75％；MS(ESI)m/z:[M+H]+＝460.2， [M+Na]+＝482.2；1H-NMR(400MHz,DMSO-d6)δ:7.44-7.47(m,3H),7.18-7.28(m,3H),7.04-7.13(m,1H),7.02(d,1H),6.86(s,1H),6.31(d,1H),3.86(d,2H),3.65-3.75(m,2H),3.44-3.48(m,3H),2.82-2.85(m,1H),2.64-2.67(m,3H),2.45-2.51(m,1H),2.23(s,3H)ppm。
实施例9：1-(5-(2-氟苯)-1-((3-(3-甲氧基-2,2-二甲基丙氧基)苯基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺(EXP 9)的制备
Figure PCTCN2015094255-appb-000014
参照实施例1的制备方法，获得化合物1-(5-(2-氟苯)-1-((3-(3-甲氧基-2,2-二甲基丙氧基)苯基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺(EXP 9)59mg,收率15％。HPLC:96.4％；MS(ESI)m/z:[M+H]+＝461.5；1H-NMR(400MHz,DMSO-d6)δ:7.85(t,1H),7.68-7.75(m,3H),7.46-7.49(m,2H),7.27-7.35(m,2H),6.80-6.83(m,1H),6.34(s,1H),3.79-3.85(m,4H),3.61(t,2H),3.26(s,3H),2.38(m,3H),0.89(s,6H)ppm。
实施例10：1-(5-(2-氟苯)-1-((3-(2-苯氧基乙氧基)苯基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺(EXP10)的制备
Figure PCTCN2015094255-appb-000015
参照实施例1的制备方法，获得化合物1-(5-(2-氟苯)-1-((3-(2-苯氧基乙氧基)苯基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺(EXP 10)74mg,收率25％。HPLC:98.4％；MS(ESI)m/z:[M+H]+＝481.5；1H-NMR(400MHz,DMSO-d6)δ:7.65-7.81(m,4H),7.46-7.50(m,2H),7.25-7.33(m,4H),6.89-6.93(m,4H),6.13(s,1H),4.51(s,4H),3.61(s,2H),3.21(s,3H)ppm。
实施例11：1-(5-(2-氟苯)-1-((3-(2-哌啶-1-基)乙氧基)苯基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺(EXP 11)的制备
Figure PCTCN2015094255-appb-000016
参照实施例1的制备方法，获得化合物1-(5-(2-氟苯)-1-((3-(2-哌啶-1基)乙氧基)苯基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺(EXP 11)174mg,收率35％。HPLC:98.1％；MS(ESI)m/z:[M+H]+＝472.6；1H-NMR(400MHz,DMSO-d6)δ:7.48-7.72(m,3H),7.18-7.32(m,3H),7.10-7.15(m,2H),6.87(s,1H),6.23(s,1H),4.03(t,2H),3.50(s,2H),2.66(t,2H),2.41-2.52(m,4H),2.28(s,3H),1.37-1.51(m,6H)ppm。
实施例12：1-(5-(2-氟苯)-1-((3-甲氧基苯基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺(EXP 12)的制备
Figure PCTCN2015094255-appb-000017
参照文献WO 2006036024，Journal of Medicinal Chemistry(2012),55(9),4446-4456.的制备方法，获得化合物1-(5-(2-氟苯)-1-((3-甲氧基苯基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺(EXP 12)105mg,收率20％。HPLC:95.4％；MS(ESI)m/z:[M+H]+＝375.5。
实施例13：5-(2-氟苯基)-N-甲基-1-(3-吡啶基磺酰基)-1H-吡咯-3-甲胺富马酸盐(TAK-438)的制备
Figure PCTCN2015094255-appb-000018
参照文献WO 2006036024，Journal of Medicinal Chemistry(2012),55(9),4446-4456.的制备方法，获得化合物5-(2-氟苯基)-N-甲基-1-(3-吡啶基磺酰基)-1H-吡咯-3-甲胺富马酸盐(TAK-438)5.0g,收率40％。HPLC:99.8％；MS(ESI)m/z:[M+H]+＝347.1。1H-NMR(500MHz,DMSO-d6)δ:10.71(s,3H),8.86(dd,1H),8.55(d,1H),7.83-7.85(m,1H),7.78(s,1H),7.55-7.60(m,1H),7.46-7.50(m,1H),7.13-7.19(m,1H),7.07-7.10(m,1H),6.49-6.51(m,3H),3.94(s,2H),2.50(s,3H)ppm。
实施例14：2-(3-((2-(2-氟苯基)-4-((甲胺)甲基)-1H-吡咯-1-基)磺酰基)苯氧基)-N-甲基乙酰胺(EXP 14)的制备
Figure PCTCN2015094255-appb-000019
参照文献WO 2014075575的制备方法，获得化合物2-(3-((2-(2-氟苯基)-4-((甲胺)甲基)-1H-吡咯-1-基)磺酰基)苯氧基)-N-甲基乙酰胺(EXP 14)50mg,收率40％。HPLC:96.4％；MS(ESI)m/z:[M+H]+＝432.3。1H-NMR(400MHz,DMSO-d6)δ:7.75(s,1H),7.39-7.49(m,2H),7.27-7.29(m,1H),7.05-7.17(m,4H),6.96(s,1H),6.39(d,1H),4.45(s,2H),4.09(s,2H),3.31(s,3H),2.79(s,3H),2.68(s,3H)ppm。
测试例1：
H+/K+-ATPase生物学评价
下面的体外筛选试验是用来评价本发明化合物对于H+/K+-ATPase酶活性抑制作用的。
实验材料和仪器：
1)兔胃粘膜微粒体(富含H+/K+-ATPase，自提)
2)5-三磷酸腺苷ATP(Sigma-Aldrich，货号：A2383)
3)孔雀石绿(百灵威化学技术有限公司，货号：913120)
4)钼酸铵(百灵威化学技术有限公司，货号：128321)
5)缬氨霉素(百灵威化学技术有限公司，货号：227304)
实验步骤：
试剂准备：
1)化合物用DMSO溶解配制成合适的浓度；
2)缓冲液:50mmol/L HEPEs-Tris，pH＝6.5，5mmol/L氯化镁，10μmol/L缬氨霉素；
3)缓冲液:50mmol/L HEPEs-Tris，pH＝6.5，5mmol/L氯化镁，10μmol/L缬氨霉素，5mmol/L氯化钾；
4)ATP：用缓冲液1稀释ATP至5mM；
5)孔雀石绿溶液：0.12％孔雀石绿溶于2.5mol/L硫酸，7.5％(V/V)钼酸铵和11％Tween 20(V/V)使用时按100:25:2比例混合；
6)兔胃黏膜微粒体(富含H+/K+-ATPase)，提取方法为蔗糖梯度离心：把兔胃用分别自来水，3M NaCl溶液洗净，然后用滤纸除去表面水分。加入预冷的匀浆缓冲液(4ml/g组织)，于组织匀浆机中匀浆2-5min。匀浆后，如果有较大的组织颗粒，可离心(600g,10min)去除，然后将上清移至干净的离心管中20000g离心30min后，然后将上清移至干净的离心管中，进一步离心，100000g离心90min，收集沉淀；利用匀浆液悬浮沉淀，吹散均匀，利用Bradford法测蛋白浓度，调整浓度为10mg/ml；等比例加入7.5％Ficoll分层液，100000g离心60min 后，将中层(H+/K+-ATPaseenriched gastric membranes)收集于洁净离心管中，利用匀浆液4-5倍稀释，继续100 000g离心90min，收集沉淀；利用匀浆液悬浮沉淀，玻璃匀浆器匀浆均匀，利用Bradford法测蛋白浓度，调整浓度22.5mg/ml。冻于-80℃备用。
实验过程：
向45μL缓冲液2中加入5μL的胃粘膜微粒体(H+/K+-ATPase)，再加入5μL的化合物溶液，然后加入5μL 5mM的ATP启动反应，在37℃预反应30min。加入15μL孔雀石绿溶液终止反应，室温平衡20min，在620nm处读吸收光值。
同时，进行相同体积，不加氯化钾的反应作为背景，在计算酶活性时减去。
化合物IC50值通过不同浓度下的抑制率计算得到。
实验结果：化合物IC50值
本发明提供结构如式I所示化合物对H+/K+-ATPase活性的半数抑制浓度(IC50)
表1化合物对H+/K+-ATPase活性的半数抑制浓度(IC50)
TAK-438 EXP 1 EXP 2 EXP 3 EXP 4 EXP5 EXP 6 EXP 7 EXP8
+++ +++ ++ ++ +++ ++ ++ ++ ++
EXP 9 EXP10 EXP 11 EXP 12 EXP14        
++ +++ + +++ ++        
+++表示IC50<100nM；++表示范围0.1～1μM；+表示范围1～5μM
测试例2：
化合物EXP 1,TAK-438,EXP12对hERG钾离子通道作用的研究
试验系统
1)细胞培养：hERG细胞系常规培养，传代在含有10％胎牛血清和250μg/ml G418的DMEM中。
2)液体配置：全细胞膜片钳实验所用细胞外液的成分为(mM)：NaCl 145；MgCl21；KCl 4；Glucose10；HEPES 10；and CaCl22，用NaOH将pH值调至7.4，用sucrose将渗透压值调至300mOsm。细胞内液成分为(mM)：KCl 140；MgCl21；EGTA 5；HEPES 10and Na2ATP 4，用KOH将pH值调至7.2，用sucrose将渗透压值调至290mOsm。
细胞内外液主要成分
Figure PCTCN2015094255-appb-000020
Figure PCTCN2015094255-appb-000021
试验方法
1)电生理记录：每次实验取出一个培养皿，用细胞外液清洗两次，放置于倒置显微镜载物台上。全细胞膜片钳实验在室温下进行，所用硼硅玻璃微电极尖端电阻为3～5MΩ。
2)电压刺激方案和电流记录：全细胞记录模式后，将膜电位钳制在-80mV，每隔30s给予细胞+50mV去极化电压刺激，持续2s后复极化至-50mV，持续3s，即可引出hERG尾电流。去极化电压刺激前，先给予细胞50ms，-50mV复极化电压，该电压下记录的电流作为计算hERG尾电流的基线。只有达到记录标准的细胞才会被应用于待测化合物的检测。加入化合物前，hERG尾电流在细胞外液中至少稳定记录3分钟。灌流给药后当hERG尾电流幅值变化小于<5％时，被认为药物作用达到稳态。如果电流在6分钟内未达到稳态，则亦结束该浓度化合物检测。
3)检测标准：实验中膜电阻大于1,000MΩ。初始电流大于300pA。全细胞记录模式建立后串联电阻小于12MΩ。漏电流少于离子通道电流的10％(-80pA为最大值)。
数据分析
原始数据使用Clampex 10.2记录，以*abf文件保存。数据采集和分析使用pCLAMP 10.1软件程序。选取加入化合物前电流处于稳态的4～5个sweep，计算峰值平均值，作为对照电流幅值。选取加入化合物后电流处于稳态的4～5个sweep，计算峰值平均值，作为电流被抑制后的剩余幅值。待测化合物对hERG电流的抑制率依据以下方程进行计算：
％抑制率＝{1-(电流剩余幅值)/(对照电流幅值)}*100
依据上述计算方法得到待测化合物多个浓度对hERG电流的抑制率(平均值±标准差)后，使用logistic方程对数据进行拟合，得到IC50值。
试验结果
表2 EXP 1,TAK-438,EXP 12对hERG电流的抑制结果
化合物名称 最高检测浓度 最高检测浓度抑制率 IC50值
EXP 1 100μM 86.21±1.67％ 18.69M
TAK-438 100μM 88.23±3.18％ 15.93M
EXP 12 30μM 90.33±2.16％ 3.95M
测试例3：
化合物EXP 1，TAK-438，EXP14对组胺诱导的胃酸分泌作用研究
实验材料
1)动物
SD大鼠，SPF级，雄性，180～220g，由浙江省实验动物中心提供，生产许可证号：SCXK(浙)2014-0001。
2)药物及试剂
化合物EXP 1，临用前用少量醋酸(约1.10N EXP1)、0.9％氯化钠溶液溶解至所需浓度的澄清药液。
化合物TAK-438，临用前用0.9％氯化钠溶液溶解至所需浓度的澄清药液。
化合物EXP14，临用前用少量醋酸(约1.10N EXP14)、0.9％氯化钠溶液溶解至所需浓度的澄清药液。
0.9％氯化钠溶液：安徽双鹤药业有限责任公司，批号：131202。
组胺二盐酸盐：aladdin，批号：H110868。
水合氯醛：国药集团化学试剂有限公司，批号：20130314，临用前用0.9％氯化钠溶液配成3％的水合氯醛溶液。
酚酞：国药集团化学试剂有限公司，批号是F20110125，临用前用95％乙醇配成1％的酚酞溶液。
3)仪器
电子天平：北京赛多利斯仪器系统有限公司生产。
离心机：上海医疗器械(集团)有限公司手术器械厂生产。
碱式滴定管：由中国药科大学分析教研室提供。
方法与结果
取体重180-220g的SPF级SD大鼠60只，将动物按体重随机分成5组，包括受试化合物EXP1组(2mg/kg)，TAK-438组(2mg/kg，按游离碱计)，EXP14组(2mg/kg)，阴性对照组(等容积生理盐水)和模型对照组(等容积生理盐水)，每组12只。禁食24h，不禁水。24h后，受试化合物A，B，C组采取灌胃给药，给药容积为1ml/100g，各组均给药一次，阴性对照组和模型对照组灌胃给予等体积的生理盐水。之后将大鼠用水合氯醛300mg/kg(1ml/100g)麻醉后，固定在大鼠板上，自胸骨剑突下沿腹中线切开腹壁，切口约2～3cm，在左侧肋缘部位，用指轻轻往上一推，使胃暴露于切口。在幽门下穿一线将幽门结扎(邻近的其它血管不结扎)，然后缝合腹壁切口。动物于灌胃受试化合物或生理盐水1h后皮下给予组胺二盐酸盐(30mg/10m/kg)。给予组胺3h后用过量CO2窒息处死大鼠，取胃，收 集为内容物，3000rpm/min离心10min，用0.1mol/L的NaOH滴定酸液至PH7.0，计算3h期间的总酸。结果见表3。
表3.受试化合物对组胺诱导的胃酸分泌作用
组别 剂量(mg/kg) 总酸量(10-4mol) 抑酸率％
阴性对照 / 0.33±0.12 /
模型对照 / 1.09±0.18 /
EXP 1 2 0.49±0.12** 55.4
TAK-438 2 0.52±0.10** 52.3
EXP14 2 0.65±0.20** 40.4
注：*p<0.05，**p<0.01，与模型组比较。
测试例4：
化合物EXP 1，TAK-438大鼠灌胃急性毒性试验报告
试验药物：化合物EXP 1(约1.10N EXP1)，TAK-438(给药剂量按游离碱计)
试验内容：单次给药剂量：2000mg/kg、600mg/kg，灌胃给药1次，给药容积：10ml/kg，观察14天，每天观察大鼠行为及体重。
动物：SPF级SD大鼠，体重180-220g，浙江省实验动物中心提供，动物合格证号：SCXK(浙)2014-0001。实验分组：空白组、600mg/kg组、2000mg/kg组，每组4只，雌雄各半。
试验结果：
EXP1单次口服600mg/Kg或2000mg/Kg，未见动物死亡。单次口服600mg/Kg，对动物体重影响不明显。
TAK-438：2000mg/kg:全例死亡；600mg/kg:体重增加抑制。
己经通过举例说明和实施例的方式比较详细地描述了上述发明，以用于阐述和理解的目的。对于本领域技术人员显而易见的是，可以在后附权利要求的范围内进行改变和改进。因此，应该理解上述说明意在是举例说明性的而不是限制性的。因此，本发明的范围不应该参考上述说明书而确定，而应该参考下列后附的权利要求以及由权利要求授权的等价物的全部范围而确定。

Claims (9)

  1. 如化学结构式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或药学上可接受的盐：
    Figure PCTCN2015094255-appb-100001
    其中A、B独立的选自N或CR4，R4选自氢、卤素、烷基；
    X选自O或NR5，R5选自氢、烷基；
    R1选自烷基、杂环烷基，其中所述烷基、杂环烷基进一步被一个或多个选自氢、卤素、烷基的取代基所取代；
    R2选自烷基磺酰基、杂环烷基、烷氧基、烷基酰基、苯氧基、烷基胺基，其中所述烷基磺酰基、杂环烷基、烷氧基、甲酰基、苯氧基、烷基胺基进一步被一个或多个选自氢、卤素、烷基的取代基所取代；
    R3选自氢、卤素、烷基。
  2. 根据权利要求1所述，A、B选自CR4，R4选自氢。
  3. 根据权利要求1、2，所述化合物任选自如下化合物：
    Figure PCTCN2015094255-appb-100002
  4. 一种药用组合物，所述药物组合物含有有效量的权利要求1-3任意一项所述化合物或其互变异构体、 内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或药学上可接受的盐和药物可接受的载体、赋形剂或稀释剂。
  5. 权利要求1～4的药物组合物，其特征为其为胃酸分泌抑制剂。
  6. 权利要求5的药物组合物在制备H+/K+-ATPase抑制剂药物中的用途。
  7. 权利要求6的药物组合物在制备钾离子竞争性酸阻滞剂(P-CABs)药物中的用途。
  8. 根据权利要求7的药物组合物在制备治疗或预防消化性溃疡、卓-艾综合症、胃炎、糜烂性食管炎、反流性食管炎、症状性胃食管反流疾病、巴雷特食管炎、功能性消化不良、幽门螺旋杆菌感染、胃癌、胃MALT淋巴瘤、非甾体抗炎药引起的溃疡或手术后应激导致的胃酸过多或溃疡的药物中的用途；或者在制备抑制用于消化性溃疡、急性应激性溃疡、出血性胃炎或侵入性应激造成的上消化道出血的药物中的用途。
  9. 根据权利要求8所述的用途，其中所述的消化性溃疡包括胃溃疡、十二指肠溃疡或吻合口溃疡；所述的症状性胃食管反流疾病包括非糜烂性的反流性疾病或无食管炎的胃食管反流疾病。
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