WO2021017069A1 - 吡咯并吡唑类衍生物、其制备方法及其在医药上的应用 - Google Patents

吡咯并吡唑类衍生物、其制备方法及其在医药上的应用 Download PDF

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WO2021017069A1
WO2021017069A1 PCT/CN2019/102527 CN2019102527W WO2021017069A1 WO 2021017069 A1 WO2021017069 A1 WO 2021017069A1 CN 2019102527 W CN2019102527 W CN 2019102527W WO 2021017069 A1 WO2021017069 A1 WO 2021017069A1
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methyl
compound
pyrazole
fluorophenyl
pharmaceutically acceptable
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PCT/CN2019/102527
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English (en)
French (fr)
Inventor
任峰
王显连
徐咏梅
陈春麟
蔡金娜
Original Assignee
上海美迪西生物医药股份有限公司
美迪西普亚医药科技(上海)有限公司
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Priority to US17/630,127 priority Critical patent/US20220259215A1/en
Publication of WO2021017069A1 publication Critical patent/WO2021017069A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4162—1,2-Diazoles condensed with heterocyclic ring systems
    • 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
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present invention relates to a new class of pyrrolopyrazole derivatives, their preparation method and their own or pharmaceutical compositions containing such derivatives as therapeutic agents, especially as gastric acid secretion inhibitors and potassium ion competitive acid blockers (P-CABs) purpose.
  • P-CABs potassium ion competitive acid blockers
  • Peptic ulcer mainly refers to chronic ulcers that occur in the stomach and duodenum. Although there are regional differences, the incidence of peptic ulcer usually accounts for 10% to 20% of the total population. It is a frequently-occurring and common disease. There are various factors for the formation of ulcers, among which the digestive effect of acidic gastric juice on the mucosa is the basic factor for ulcer formation. Therefore, inhibiting gastric acid secretion has gradually become the first choice for the treatment of peptic ulcer diseases.
  • Proton Pump Inhibitors PPIs
  • omeprazole was launched in 1988, several PPIs have been launched worldwide, including lansoprazole, pantoprazole, rabeprazole, and imeprazole. Someprazole and so on. PPIs have become the drug of choice for the treatment of gastric acid-related diseases including peptic ulcer, reflux esophagitis and Zollinger-Edyne syndrome.
  • Proton pump is essentially H + /K + -adenosine triphosphatase (H + /K + -ATPase), which specifically pumps protons (H+) into the stomach cavity to form strong acidity in the stomach.
  • Proton pump inhibitors can inhibit the activity of the proton pump to regulate the secretion of gastric acid mediated by the proton pump.
  • P-CABs Potassium-Competitive Acid Blockers
  • K + potassium ions
  • K + potassium ions
  • P-CABs are lipophilic, weakly alkaline, and stable under acidic (low pH) conditions.
  • P-CABs have the advantages of rapid onset and relatively easy to achieve acid suppression effect.
  • Voronolazan the first new P-CABs drug, was launched in Japan in 2014 for the treatment of gastric acid-related diseases such as peptic ulcers.
  • a series of potassium ion-competitive acid blockers have also been published.
  • the object of the present invention is to provide a compound for the treatment of gastric acid-related diseases such as peptic ulcer with a new structure type and excellent effects and effects.
  • the present invention provides a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof,
  • X is NR a , wherein R a is selected from a hydrogen atom or an alkyl group;
  • R 1 is selected from hydrogen atom, halogen or alkyl
  • R 2 is selected from a hydrogen atom, a halogen, a hydroxyl group or an alkyl group.
  • X is NR a, wherein R a is selected from a hydrogen atom or a C 1 ⁇ 3 alkyl group;
  • R 1 is selected from a hydrogen atom or a fluorine atom
  • R 2 is selected from a hydrogen atom, a fluorine atom or a hydroxyl group.
  • X is NH
  • R 1 is a fluorine atom
  • R 2 is a hydrogen atom.
  • the compound is selected from:
  • the present invention provides a pharmaceutical composition, comprising a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient or diluent.
  • the present invention provides the use of the compound represented by general formula (I) or its pharmaceutically acceptable salt or the above-mentioned pharmaceutical composition in the preparation of a gastric acid secretion inhibitor.
  • the present invention provides a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof or the above-mentioned pharmaceutical composition for preparing H + /K + -adenosine triphosphatase (H + /K + -ATPase ) Use in inhibitors.
  • the present invention provides the use of the compound represented by general formula (I) or its pharmaceutically acceptable salt or the above-mentioned pharmaceutical composition in the preparation of potassium ion competitive acid blockers (P-CABs).
  • the present invention provides the use of a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof or the above-mentioned pharmaceutical composition in the preparation of a medicine for the treatment and/or prevention of peptic ulcer, Zollinger-Eye syndrome, gastritis, erosive esophagitis, reflux esophagitis, symptomatic gastroesophageal reflux disease, Barrett's esophagitis, functional dyspepsia, Helicobacter pylori infection, gastric cancer, gastric MALT lymphoma, Ulcers caused by non-steroidal anti-inflammatory drugs or hyperacidity or ulcers caused by post-operative stress; or suppressing peptic ulcer, acute stress ulcer, hemorrhagic gastritis or upper gastrointestinal bleeding caused by invasive stress.
  • general formula (I) or a pharmaceutically acceptable salt thereof or the above-mentioned pharmaceutical composition in the preparation of a medicine for the treatment and/or prevention of peptic ulcer, Zollinger-Eye
  • alkyl refers to saturated aliphatic hydrocarbon groups, including straight or branched chain groups of 1 to 10 carbon atoms. Preference is given to alkyl groups containing 1 to 5 carbon atoms. More preferred are alkyl groups containing 1 to 3 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl.
  • C i ⁇ j indicate that the number of carbon atoms in this part is an integer "i" to an integer "j” (Including i and j).
  • C 1 ⁇ 3 alkyl refers to alkyl of 1 to 3 carbon atoms (including 1 and 3).
  • alkyl refers to -O-alkyl, where the alkyl is as defined herein.
  • hydroxy refers to the -OH group.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • heterocyclic ring refers to a ring having at least one saturated or unsaturated ring.
  • the atoms constituting the ring also contain at least one heteroatom, such as nitrogen, oxygen, and sulfur atoms.
  • heterocycles include non-aromatic heterocycles (or aliphatic heterocycles), such as morpholine, piperidine, and pyrrolidine; and heteroaromatic rings (or aromatic heterocycles), such as furan, benzofuran, thiophene, and benzene.
  • compound of the present invention refers to a compound represented by general formula (I).
  • the term also includes various crystalline forms, pharmaceutically acceptable salts, hydrates or solvates of the compound of general formula (I).
  • pharmaceutically acceptable salt refers to a salt formed by the compound of the present invention and an acid or a base suitable for use as a medicine.
  • Pharmaceutically acceptable salts include inorganic salts and organic salts.
  • a preferred class of salts are the salts of the compounds of this invention with acids.
  • Acids suitable for salt formation include but are not limited to: hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid and other inorganic acids, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, horse Organic acids such as lactic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, toluenesulfonic acid, and benzenesulfonic acid; and acidic amino acids such as aspartic acid and glutamic acid.
  • pharmaceutically acceptable carrier means a carrier that can be used to prepare pharmaceutical compositions. They are generally safe, non-toxic, not biologically or otherwise unexpected, and include those that can be pharmaceutically acceptable by animals and humans. Carrier.
  • pharmaceutically acceptable carrier used in the specification and claims includes one or more such carriers.
  • prevention refers to, for example, preventing the development of clinical symptoms of a disease in a mammal that may be exposed to or pre-treated with the disease but has not experienced or displayed symptoms of the disease.
  • treatment may refer to inhibiting the disease, such as preventing or reducing the development of the disease or its clinical symptoms, or alleviating the disease, such as regressing the disease or its clinical symptoms.
  • R 1 is selected from a hydrogen atom, a halogen or an alkyl group. In a preferred embodiment, R 1 is selected from a hydrogen atom or a fluorine atom. In a more preferred embodiment, R 1 is a fluorine atom. The substitution position of R 1 is preferably the 2 position.
  • R 2 is selected from a hydrogen atom, a halogen, a hydroxyl group or an alkyl group. In a preferred embodiment, R 2 is selected from a hydrogen atom, a fluorine atom or a hydroxyl group. In a more preferred embodiment, R 2 is a hydrogen atom.
  • X is NR a, wherein R a is selected from a hydrogen atom or an alkyl group.
  • R a is selected from a hydrogen atom or a C 1 ⁇ 3 alkyl group.
  • X is NH.
  • R b is selected from hydrogen atom, halogen, hydroxyl, alkyl, alkoxy, NR c R d , five-membered or six-membered saturated heterocyclic ring, wherein R c and R d are each independently selected from hydrogen atom or C 1 ⁇ 3 alkyl.
  • the compound of general formula (I) is selected from the compounds shown in Table 1.
  • the compound of the general formula (I) is the compound of the following formula (Ia) or the compound of the formula (Ib), and the following general synthetic routes can be used for preparation:
  • X, Y, Z, U , V, R 1, R 2, R a is as defined above.
  • the P 1 group may be a well-known amino protecting group in the art, for example, it may be selected from substituted C7-11 aralkyl groups such as benzyl, p-methoxyphenylmethyl, o-nitrophenylmethyl, etc.; acetyl , Trifluoroacetyl and other substituted C1-6 alkylcarbonyl groups; benzoyl and other substituted C6-10 aromatic carbonyl groups; methoxycarbonyl, ethoxycarbonyl, Boc (tert-butoxycarbonyl), Cbz group ( Benzyloxycarbonyl), Fmoc group (fluorenylmethyloxycarbonyl), Teoc group (trimethylsilylethoxycarbonyl) and other substituted C1-6 alkoxycarbonyl groups; Alloc group (allyloxycarbonyl) and other alkylene oxides Carbonyl; alkylsulfonyl such as methylsulfonyl; C6-10 arylsulfonyl
  • the X 1 group may be a leaving group known in the art, for example, it may be selected from halogen atoms such as fluorine atom, chlorine atom, bromine atom, and iodine atom.
  • the X 2 group can be selected from halogen atoms such as chlorine atoms, bromine atoms, and iodine atoms.
  • the X 3 group can be selected from halogen atoms such as chlorine atoms, bromine atoms, and iodine atoms.
  • the X 4 group may be a leaving group known in the art, for example, it may be selected from halogen atoms such as fluorine atom, chlorine atom, bromine atom, and iodine atom.
  • step (a) a compound of formula I-1 is reacted with a compound of formula I-2 to obtain a compound of formula I-3.
  • the molar ratio of the compound of formula I-1 to the compound of formula I-2 may be 1: (0.5-3.0).
  • the reaction solvent can be acetonitrile, acetone, tetrahydrofuran, dioxane, N,N-dimethylformamide and the like.
  • the reaction of step (a) can be carried out in the presence of a base.
  • the base may be selected from: cesium carbonate, potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide and the like.
  • the molar ratio of the compound of formula I-1 to the base may be 1: (1.0 to 6.0).
  • the reaction temperature of step (a) can be appropriately set by those skilled in the art, and can be, for example, 0-100°C.
  • step (b) a compound of formula I-3 is reacted with a compound of formula I-4 to obtain a compound of formula I-5.
  • the molar ratio of the compound of formula I-3 to the compound of formula I-4 may be 1: (0.5-3.0).
  • the reaction solvent can be N,N-dimethylacetamide, N,N-dimethylformamide, toluene, acetonitrile and the like.
  • Step (b) can be carried out in the presence of a palladium catalyst.
  • the palladium catalyst can be selected from: allylpalladium(II) chloride dimer, tris(dibenzylideneacetone)dipalladium, [1,1'-bis(diphenylphosphino)ferrocene] Palladium dichloride, palladium chloride, etc.
  • the reaction of step (b) can be carried out in the presence of a base.
  • the base can be selected from: potassium acetate, sodium acetate, potassium phosphate, potassium dihydrogen phosphate, potassium bistrimethylsilylamine, sodium bistrimethylsilylamine, and the like.
  • the molar ratio of the compound of formula I-3 to the base may be 1: (0.5-3.0).
  • the reaction temperature of step (b) can be appropriately set by those skilled in the art, and can be, for example, 40 to 150°C.
  • step (c) the P 1 protecting group is removed.
  • the reaction conditions can be the reaction conditions commonly used in the art for removing the amino protective group.
  • P 1 is Boc
  • it can be treated with a protic acid (for example, trifluoroacetic acid) or Lewis acid.
  • step (d) the compound of formula I-6 is subjected to an aminomethylation reaction to obtain the compound of formula I-7.
  • This step can use aminomethylation reaction conditions known in the art.
  • the compound of formula I-6 is stirred with formaldehyde for a period of time to generate a Schiff base, then a reducing agent such as sodium acetate borohydride is added to react for a period of time to obtain the compound of formula I-7.
  • step (e) the nitro group in the compound of formula I-7 is reduced to an amino group to obtain the compound of formula I-8.
  • This step can adopt reaction conditions known in the art for reducing the nitro group to the amino group.
  • the compound of formula I-7 is reacted with hydrazine hydrate in the presence of a Raney-Ni catalyst to obtain the compound of formula I-8.
  • step (f) a compound of formula I-8 is reacted with a compound of formula I-9 to obtain a compound of formula Ia.
  • step (e) can be carried out in the presence of a palladium catalyst.
  • the palladium catalyst can be selected from: tris(dibenzylideneacetone) dipalladium (Pd 2 (dba) 3 ), allyl palladium(II) chloride dimer, [1,1'-bis(diphenyl) Phosphonyl) ferrocene] palladium dichloride, palladium chloride, etc.
  • the reaction solvent can be dioxane, tetrahydrofuran, toluene, N,N-dimethylformamide and the like.
  • phosphine ligands can be added to the reaction of step (e), such as 2-dicyclohexylphosphorus-2',4',6'-triisopropylbiphenyl (X-phos), 1,1'- Binaphthyl-2,2'-bisdiphenylphosphine (BINAP), 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (Xant-phos), tricyclohexylphosphine, etc.
  • the reaction of step (e) can be carried out in the presence of a base.
  • the base can be selected from: sodium tert-butoxide, cesium carbonate, sodium carbonate, sodium bicarbonate, potassium phosphate and the like.
  • the molar ratio of the compound of formula I-8 to the base can be 1: (0.5-5.0).
  • the reaction temperature of step (e) can be appropriately set by those skilled in the art, and can be, for example, 40 to 150°C.
  • the amino group in the compound of formula I-8 can be changed to an iodine atom (for example, the compound of formula I-8 is reacted with sodium nitrite and potassium iodide), and then the compound of formula I-9 (where X 3 is an amino group) The reaction yields the compound of formula Ia.
  • step (e) can be performed under acidic conditions.
  • step (g) the compound of formula Ia is reacted with the compound of formula I-10 to obtain the compound of formula Ib.
  • the molar ratio of the compound of formula Ia to the compound of formula I-10 may be 1: (0.5-3.0).
  • the reaction solvent can be acetonitrile, acetone, tetrahydrofuran, dioxane, N,N-dimethylformamide and the like.
  • the reaction of step (a) can be carried out in the presence of a base.
  • the base may be selected from: cesium carbonate, potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide and the like.
  • the molar ratio of the compound of formula Ia to the base may be 1: (1.0 to 6.0).
  • the reaction temperature of step (g) can be appropriately set by those skilled in the art, and can be, for example, 0-100°C.
  • the compound of general formula (I) can be used as an inhibitor of gastric acid secretion.
  • a compound of formula (I) may be used as H + / K + - adenosine triphosphatase (H + / K + -ATPase) inhibitors.
  • the compounds of general formula (I) can be used as potassium ion competitive acid blockers (P-CABs).
  • the compound of general formula (I) can be used for the treatment and/or prevention of peptic ulcer, Zollinger-Eddle syndrome, gastritis, erosive esophagitis, reflux esophagitis, symptomatic gastroesophageal reflux disease, Barrett's esophagitis, Functional dyspepsia, Helicobacter pylori infection, gastric cancer, gastric MALT lymphoma, ulcers caused by non-steroidal anti-inflammatory drugs, or hyperacidity or ulcers caused by postoperative stress; or suppress peptic ulcers, acute stress ulcers , Hemorrhagic gastritis or upper gastrointestinal bleeding caused by invasive stress.
  • the above-mentioned peptic ulcer includes but is not limited to gastric ulcer, duodenal ulcer or anastomotic ulcer.
  • Symptomatic gastroesophageal reflux disease includes but is not limited to non-erosive reflux disease or gastroesophageal reflux disease without esophagitis.
  • the pharmaceutical composition of the present invention contains an effective amount of a compound represented by the general formula (I) or its tautomers, enantiomers, diastereomers, and mixtures thereof, and pharmaceutically acceptable Salt, and a pharmaceutically acceptable carrier or excipient or diluent.
  • Effective amount means the compound of the present invention: (i) treat a specific disease, condition or disorder, (ii) attenuate, ameliorate or eliminate one or more symptoms of a specific disease, condition or disorder, or (iii) prevent or delay herein The amount of onset of one or more symptoms of the particular disease, condition or disorder.
  • Examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, and solid lubricants (such as stearic acid). , Magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers Wetting agents (such as sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
  • cellulose and its derivatives such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.
  • gelatin such as sodium stearic acid
  • talc such as stearic acid
  • solid lubricants such as
  • the method of administration of the compound or pharmaceutical composition of the present invention is not particularly limited.
  • Representative administration methods include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration .
  • the compound of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds.
  • Another aspect of the present invention relates to a method for inhibiting the secretion of gastric acid, which comprises administering an effective dose of a compound represented by general formula (I) or its tautomers, enantiomers, or diastereomers to patients in need of treatment.
  • a compound represented by general formula (I) or its tautomers, enantiomers, or diastereomers to patients in need of treatment.
  • Another aspect of the present invention relates to a method for inhibiting H + /K + -adenosine triphosphatase (H + /K + -ATPase), the method comprising administering to a patient in need of treatment an effective dose of the formula (I)
  • the compound shown or its tautomers, enantiomers, diastereomers, and mixtures thereof, and pharmaceutically acceptable salts or pharmaceutical compositions thereof are shown or its tautomers, enantiomers, diastereomers, and mixtures thereof, and pharmaceutically acceptable salts or pharmaceutical compositions thereof.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS), and the purity of the compound is determined by liquid high pressure chromatography (HPLC).
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • HPLC liquid high pressure chromatography
  • the third step 3-(2-fluorophenyl)-2-(3-nitrobenzyl)-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole
  • reaction solution was concentrated and prepared by HPLC (acetonitrile/water (containing 0.05% NH 3 ) gradient washing) to obtain compound 3-(2-fluorophenyl)-5-methyl-2-(3-nitrobenzyl)-2 ,4,5,6-Tetrahydropyrrolo[3,4-c]pyrazole 1e (160mg, yellow oily liquid), yield: 71.0%.
  • Step 5 3-((3-(2-Fluorophenyl)-5-methyl-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-yl)methyl )aniline
  • the sixth step 2-chloro-N-(3-((3-(2-fluorophenyl)-5-methyl-5,6-dihydropyrrolo[3,4-c]pyrazole-2( 4H)-yl)methyl)phenyl)-6-methoxypyridin-3-amine
  • reaction solution was poured into water (40 mL), and extracted with ethyl acetate (20 mL ⁇ 3). The organic phase was washed with brine (20 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, and concentrated.
  • the first step 3-(2-fluorophenyl)-2-(3-iodobenzyl)-5-methyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole
  • the second step 2-chloro-N-(3-((3-(2-fluorophenyl)-5-methyl-5,6-dihydropyrrolo[3,4-c]pyrazole-2( 4H)-yl)methyl)phenyl)-6-methylpyridin-3-amine
  • reaction solution was poured into water (40 mL), and extracted with ethyl acetate (20 mL ⁇ 3). The organic phase was washed with brine (20 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, and concentrated.
  • Test example Determination of the compound's inhibition of H+/K+ATPase activity
  • Enzyme working solution titrate the enzyme, dilute the enzyme with buffer 1, and during the reaction, take 5 ⁇ l of the diluted solution into the 50 ⁇ l reaction system
  • ATP solution 100mM ATP is diluted to 5mM with no K + buffer, and 5 ⁇ l of the diluted solution is added to a 50 ⁇ l reaction system, that is, the final concentration of ATP is 500 ⁇ M
  • MLG color developing solution mix 0.12% MLG, 7.5% ammonium molybdate, 11% Tween-20 in a volume of 100:25:2, and add 15 ⁇ l to each well during detection
  • Buffer 1 50mM Tris-HCl pH 6.5, 5mM magnesium chloride (magnesium chloride), 10 ⁇ M valinomycin (valinomycin)
  • Buffer 2 50mM Tris-HCl pH 6.5, 5mM magnesium chloride (magnesium chloride), 10 ⁇ M valinomycin (valinomycin), 20mM KCl
  • Homogenization buffer 10mmol/L Tris-HCl, pH 6.8, 0.25M sucrose, 1mmol/LEDTA 7.5%
  • Ficoll Layering solution homogenization buffer + 7.5% (W/W) 400 (Ficoll 400).
  • tissue particles After homogenization, if there are larger tissue particles, they can be removed by centrifugation (600g, 10min), then transfer the supernatant to a clean centrifuge tube, centrifuge at 20000g for 30min, and then transfer the supernatant to a clean centrifuge In the tube, further centrifuge, centrifuge at 100000g for 90 minutes, and collect the precipitate;
  • M5 instrument detects 620nm reading.
  • the inhibition rate is calculated with the following formula:
  • Inhibition rate (IC 50 ) [OD (sample well)-OD (full enzyme well containing potassium chloride)] / [(OD (full enzyme well containing potassium chloride)-(OD (no potassium chloride Enzyme hole) ⁇ 100%
  • the inhibition rate (IC 50 ) of each example compound is shown in Table 2.
  • the compound of the present invention has excellent H + /K + ATPase inhibitory activity and can be used to prepare gastric acid secretion inhibitors.

Abstract

一种吡咯并吡唑类衍生物、其制备方法及其在医药上的应用。具体的说，涉及一类通式(I)所示的吡咯并吡唑类衍生物、其制备方法以及其本身或含有此类衍生物的药物组合物作为治疗剂，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)在生物医药中的用途。

Description

吡咯并吡唑类衍生物、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并吡唑类衍生物、其制备方法以及其本身或含有此类衍生物的药物组合物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
消化性溃疡主要指发生于胃和十二指肠的慢性溃疡。虽然有地区差异，但消化性溃疡发病率通常占总人口的10％～20％，是一多发病、常见病。溃疡的形成有各种因素，其中酸性胃液对黏膜的消化作用是溃疡形成的基本因素。因此，抑制胃酸分泌逐渐成为治疗消化性溃疡类疾病的首选方法。
自1988年第一个质子泵抑制剂(Proton Pump Inhibitors，PPIs)奥美拉唑上市以来，至今全球已有数个PPIs产品上市，包括兰索拉唑、泮托拉唑、雷贝拉唑和艾司奥美拉唑等。PPIs已经成为治疗胃酸相关性疾病包括消化性溃疡、反流性食管炎和卓-艾综合征等疾病的首选药物。质子泵(Proton Pump)实质为H +/K +-腺苷三磷酸酶(H +/K +-ATPase)，它特异性的将质子(H+)泵入胃腔从而形成胃内的强酸性。质子泵抑制剂可以抑制质子泵的活性从而调节质子泵介导的胃酸分泌。
钾离子竞争性酸阻滞剂(Potassium-Competitive Acid Blockers，P-CABs)是一类新型的胃酸阻滞剂，它通过可逆的、与钾离子(K +)竞争性的结合H +/K +-ATPase从而起到抑制H +/K +-ATPase酶活性的作用。与PPIs相比较，P-CABs具有亲脂性、弱碱性以及在酸性(低pH)条件下稳定等特点。同时，P-CABs具有起效迅速以及比较容易达到抑酸效果等优势。
第一款P-CABs新药沃诺拉赞于2014年在日本上市，用于治疗胃酸相关疾病如消化性溃疡。一系列的钾离子竞争性酸阻滞剂结构也已经被公开。但仍然需要开发结构类型多样性的具有更好成药性的新化合物。
发明内容
针对上述问题，本发明的目的在于提供新的结构类型且具有优异的效果和作用的用于治疗胃酸相关疾病如消化性溃疡的化合物。
一方面，本发明提供一种通式(I)所示的化合物或其药学上可接受的盐，
Figure PCTCN2019102527-appb-000001
其中：
X为NR a，其中R a选自氢原子或烷基；
Y、Z、U和V各自独立选自N、NH、CR b或C(＝O)，并且Y、Z、U和V有且只有一个或两个同时含有N，其中R b选自氢原子、卤素、羟基、烷基、烷氧基、NR cR d、五元或六元饱和杂环，其中R c和R d各自独立选自氢原子或C 1～3烷基；
R 1选自氢原子、卤素或烷基；
R 2选自氢原子、卤素、羟基或烷基。
优选地，X为NR a，其中R a选自氢原子或C 1～3烷基；
Y、Z、U和V各自独立选自N、NH、CR b或C(＝O)，并且Y、Z、U和V有且只有一个或两个同时含有N，其中R b选自氢原子、卤素、羟基、烷基、C 1～3烷氧基、NR cR d、六元饱和杂环，其中R c和R d中一者为氢，另一者选自氢原子或C 1～3烷基；
R 1选自氢原子或氟原子；
R 2选自氢原子、氟原子或羟基。
优选地，X为NH；
Y、Z、U和V各自独立选自N、NH、CR b或C(＝O)，并且Y、Z、U和V有且只有一个或两个同时含有N，其中R b选自氢原子、氯原子、羟基、甲基、甲氧基、NHCH 3或吗啉；
R 1为氟原子；
R 2为氢原子。
优选地，所述化合物选自：
2-氯-N-(3-((3-(2-氟苯基)-5-甲基-5,6-二氢吡咯并[3,4-c]吡唑-2(4H)-基)甲基)苯基)-6-甲氧基吡啶-3-胺；
2-氯-N-(3-((3-(2-氟苯基)-5-甲基-5,6-二氢吡咯并[3,4-c]吡唑-2(4H)-基)甲基)苯基)-6-甲基吡啶-3-胺；
2-氯-N-(3-((3-(2-氟苯基)-5-甲基-5,6-二氢吡咯并[3,4-c]吡唑-2(4H)-基)甲基)苯 基)嘧啶-4-胺；
4-((3-((3-(2-氟苯基)-5-甲基-5,6-二氢吡咯并[3,4-c]吡唑-2(4H)-基)甲基)苯基)氨基)嘧啶-2-(1H)-酮；
N 4-(3-((3-(2-氟苯基)-5-甲基-5,6-二氢吡咯并[3,4-c]吡唑-2(4H)-基)甲基)苯基)-N 2-甲基嘧啶-2,4-二胺；
N-(3-((3-(2-氟苯基)-5-甲基-5,6-二氢吡咯并[3,4-c]吡唑-2(4H)-基)甲基)苯基)-2-吗啉代嘧啶-4-胺；
6-氯-N-(3-((3-(2-氟苯基)-5-甲基-5,6-二氢吡咯并[3,4-c]吡唑-2(4H)-基)甲基)苯基)吡嗪-2-胺。
第二方面，本发明提供一种药物组合物，包括通式(I)所示的化合物或其药学上可接受的盐以及药学上可接受的载体、赋形剂或稀释剂。
第三方面，本发明提供通式(I)所示的化合物或其药学上可接受的盐或上述药物组合物在制备胃酸分泌抑制剂中的用途。
第四方面，本发明提供通式(I)所示的化合物或其药学上可接受的盐或上述药物组合物在制备H +/K +-腺苷三磷酸酶(H +/K +-ATPase)抑制剂中的用途。
第五方面，本发明提供通式(I)所示的化合物或其药学上可接受的盐或上述药物组合物在制备钾离子竞争性酸阻滞剂(P-CABs)中的用途。
第六方面，本发明提供通式(I)所示的化合物或其药学上可接受的盐或上述药物组合物在制备药物中的用途，所述药物用于治疗和/或预防消化性溃疡、卓-艾综合征、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；或者抑制消化性溃疡、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。
具体实施方式
以下通过下述实施方式进一步说明本发明，应理解，下述实施方式仅用于说明本发明，而非限制本发明。
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。
术语“烷基”指饱和的脂族烃基团，包括1至10个碳原子的直链或支链基团。优选含有1至5个碳原子的烷基。更优选含有1至3个碳原子的烷基，例如甲基，乙基，正丙基，异丙基。
各种含碳氢结构部分的碳原子含量由该部分的标有最小和最大碳原子数目的前缀表示，即前缀C i～j表示该部分的碳原子数为整数“i”至整数“j”(包括i和j)。因此，例如，C 1～3烷基是指1至3个碳原子的烷基(包括1和3)。
术语“烷基”指-O-烷基，其中所述烷基如本文所定义。
术语“羟基”指-OH基团。
术语“卤素”指氟、氯、溴或碘。
术语“杂环”指具有至少一个饱和或不饱和的环，构成环的原子除碳原子外，还至少含有一个杂原子，例如氮、氧、硫原子。杂环的实例包括非芳族杂环(或称脂杂环)，诸如吗啉、哌啶、吡咯烷；以及杂芳环(或称芳杂环)，诸如呋喃、苯并呋喃、噻吩、苯并噻吩、吡咯、吡啶、嘧啶、吡嗪、喹啉、异喹啉、酞嗪、苯并-1,2,5-噻二唑、苯并噻唑、吲哚、苯并三唑、苯并二氧戊环、苯并二噁唑、咔唑及喹唑啉。
除非特别说明，本发明中，所有出现的化合物均意在包括所有可能的异构体，例如互变异构体、对映异构体、非对映异构体、及其混合物形式。
术语“本发明化合物”指通式(I)所示的化合物。该术语还包括通式(I)化合物的各种晶型形式、药学上可接受的盐、水合物或溶剂合物。
术语“药学上可接受的盐”指本发明化合物与酸或碱所形成的适合用作药物的盐。药学上可接受的盐包括无机盐和有机盐。一类优选的盐是本发明化合物与酸形成的盐。适合形成盐的酸包括但不限于：盐酸、氢溴酸、氢氟酸、硫酸、硝酸、磷酸等无机酸，甲酸、乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、甲磺酸、苯甲磺酸，苯磺酸等有机酸；以及天冬氨酸、谷氨酸等酸性氨基酸。
术语“药学上可接受的载体”表示能用于制备药物组合物的载体，它们一般是安全的、无毒性的，不是生物上或其他方面不期待的，且包括能被动物和人类药学上接受的载体。在说明书和权利要求书中使用的“药学上可接受的载体”包括一种或一种以上的这类载体。
术语“含有”、“包含”或“包括”表示各种成分可一起应用于本发明的混合物或组合物中。因此，术语“主要由...组成”和“由...组成”包含在术语“含有”中。
术语“预防”例如是指在可能暴露或预先处置于疾病但尚未经历或显示疾病症状的哺乳动物中使疾病临床症状不发展。
术语“治疗”可指抑制疾病，例如阻止或降低疾病或其临床症状的发展，或者缓 解疾病，例如使疾病或其临床症状退化。
通式(I)化合物
Figure PCTCN2019102527-appb-000002
本发明一些实施方式中，R 1选自氢原子、卤素或烷基。优选实施方式中，R 1选自氢原子或氟原子。更优选实施方式中，R 1为氟原子。R 1的取代位点优选为2位。
本发明一些实施方式中，R 2选自氢原子、卤素、羟基或烷基。优选实施方式中，R 2选自氢原子、氟原子或羟基。更优选实施方式中，R 2为氢原子。
本发明一些实施方式中，X为NR a，其中R a选自氢原子或烷基。优选实施方式中，X为NR a，其中R a选自氢原子或C 1～3烷基。更优选实施方式中，X为NH。
本发明一些实施方式中，Y、Z、U和V各自独立选自N、NH、CR b或C(＝O)，并且Y、Z、U和V有且只有一个或两个同时含有N，其中R b选自氢原子、卤素、羟基、烷基、烷氧基、NR cR d、五元或六元饱和杂环，其中R c和R d各自独立选自氢原子或C 1～3烷基。
优选实施方式中，Y、Z、U和V各自独立选自N、NH、CR b或C(＝O)，并且Y、Z、U和V有且只有一个或两个同时含有N，其中R b选自氢原子、卤素、羟基、烷基、C 1～3烷氧基、NR cR d、六元饱和杂环，其中R c和R d中一者为氢，另一者选自氢原子或C 1～3烷基。
更优选实施方式中，Y、Z、U和V各自独立选自N、NH、CR b或C(＝O)，并且Y、Z、U和V有且只有一个或两个同时含有N，其中R b选自氢原子、氯原子、羟基、甲基、甲氧基、NHCH 3或吗啉。
进一步优选实施方式中，
Figure PCTCN2019102527-appb-000003
选自如下基团：
Figure PCTCN2019102527-appb-000004
本发明一些实施方式中，通式(I)化合物选自表1中所示的化合物。
表1
Figure PCTCN2019102527-appb-000005
Figure PCTCN2019102527-appb-000006
通式(I)化合物的制备方法
本发明一些实施方式中，通式(I)化合物为下述式(Ia)化合物或式(Ib)化合物，制备可采用如下通用合成路线：
Figure PCTCN2019102527-appb-000007
其中，X、Y、Z、U、V、R 1、R 2、R a的定义如上所述。
P 1基可为本领域公知的氨基保护基，例如可选自苄基、对甲氧基苯基甲基、邻硝基苯基甲基等可被取代的C7-11芳烷基；乙酰基、三氟乙酰基等可被取代的C1-6烷羰基；苯甲酰基等可被取代的C6-10芳羰基；甲氧羰基、乙氧羰基、Boc基(叔丁氧羰基)、Cbz基(苄氧羰基)、Fmoc基(芴甲氧羰基)、Teoc基(三甲基甲硅烷基乙氧羰基)等可被取代的C1-6烷氧羰基；Alloc基(烯丙氧羰基)等烯氧羰基；甲磺酰基等烷基磺酰基；对甲苯磺酰基等可被取代的C6-10芳基磺酰基。
X 1基可为本领域公知的离去基团，例如可选自氟原子、氯原子、溴原子、碘原子等卤素原子。
X 2基可选自氯原子、溴原子、碘原子等卤素原子。
X 3基可选自氯原子、溴原子、碘原子等卤素原子。
X 4基可为本领域公知的离去基团，例如可选自氟原子、氯原子、溴原子、碘原子等卤素原子。
步骤(a)中，用式I-1化合物和式I-2化合物反应，得到式I-3化合物。
式I-1化合物和式I-2化合物的摩尔比可为1：(0.5～3.0)。反应溶剂可为乙腈、丙酮、四氢呋喃、二氧六环、N，N-二甲基甲酰胺等。步骤(a)的反应可在碱存在下进行。所述碱可选自：碳酸铯、碳酸钾、碳酸钠、氢氧化钾、氢氧化钠等。式I-1化合物与碱的摩尔比可为1：(1.0～6.0)。步骤(a)的反应温度可以由本领域技术人员适当设定，例如可为0～100℃。
步骤(b)中，用式I-3化合物和式I-4化合物反应，得到式I-5化合物。
式I-3化合物和式I-4化合物的摩尔比可为1：(0.5～3.0)。反应溶剂可为N，N-二甲基乙酰胺、N，N-二甲基甲酰胺、甲苯、乙腈等。步骤(b)可在钯催化剂存在下进行。所述钯催化剂可选自：氯化烯丙基钯(II)二聚物、三(二亚苄基丙酮)二钯、[1,1'-双(二苯基膦基)二茂铁]二氯化钯、氯化钯等。另外，步骤(b)的反应可在碱存在下进行。所述碱可选自：乙酸钾、乙酸钠、磷酸钾、磷酸二氢钾、双三甲基硅基胺基钾、双三甲基硅基胺基钠等。式I-3化合物与碱的摩尔比可为1：(0.5～3.0)。步骤(b)的反应温度可以由本领域技术人员适当设定，例如可为40～150℃。
步骤(c)中，脱除P 1保护基。反应条件可采用本领域常用的脱除氨基保护基的反应条件。例如，P 1为Boc时，可以用质子酸(例如三氟乙酸)或路易斯酸进行处理。
步骤(d)中，对式I-6化合物进行氨基甲基化反应，得到式I-7化合物。该步骤可采用本领域公知的氨基甲基化反应条件。一些实施方式中，将式I-6化合物与甲醛搅 拌一段时间生成席夫碱，然后加入还原剂例如醋酸硼氢化钠反应一段时间，得到式I-7化合物。
步骤(e)中，将式I-7化合物中的硝基还原为氨基，得到式I-8化合物。该步骤可采用本领域公知的将硝基还原为氨基的反应条件。一些实施方式中，将式I-7化合物在Raney-Ni催化剂存在下与水合肼反应，得到式I-8化合物。
步骤(f)中，用式I-8化合物和式I-9化合物反应，得到式Ia化合物。
式I-8化合物与式I-9化合物的摩尔比可为1：(0.5～3.0)。一些实施方式中，步骤(e)可在钯催化剂存在下进行。所述钯催化剂可选自：三(二亚苄基丙酮)二钯(Pd 2(dba) 3)、氯化烯丙基钯(II)二聚物、[1,1'-双(二苯基膦基)二茂铁]二氯化钯、氯化钯等。反应溶剂可为二氧六环、四氢呋喃、甲苯、N，N-二甲基甲酰胺等。另外，步骤(e)的反应中还可以加入膦配体，例如2-二环己基磷-2',4',6'-三异丙基联苯(X-phos)、1,1'-联萘-2,2'-双二苯膦(BINAP)、4,5-双二苯基膦-9,9-二甲基氧杂蒽(Xant-phos)、三环己基膦等。步骤(e)的反应可在碱存在下进行。所述碱可选自：叔丁醇钠、碳酸铯、碳酸钠、碳酸氢钠、磷酸钾等。式I-8化合物与碱的摩尔比可为1：(0.5～5.0)。步骤(e)的反应温度可以由本领域技术人员适当设定，例如可为40～150℃。
一些实施方式中，可将式I-8化合物中的氨基变成碘原子(例如将式I-8化合物与亚硝酸钠和碘化钾反应)，再与式I-9化合物(其中X 3为氨基)反应，得到式Ia化合物。
一些实施方式中，步骤(e)可在酸性条件下进行。
步骤(g)中，式Ia化合物与式I-10化合物反应，得到式Ib化合物。
式Ia化合物和式I-10化合物的摩尔比可为1：(0.5～3.0)。反应溶剂可为乙腈、丙酮、四氢呋喃、二氧六环、N，N-二甲基甲酰胺等。步骤(a)的反应可在碱存在下进行。所述碱可选自：碳酸铯、碳酸钾、碳酸钠、氢氧化钾、氢氧化钠等。式Ia化合物与碱的摩尔比可为1：(1.0～6.0)。步骤(g)的反应温度可以由本领域技术人员适当设定，例如可为0～100℃。
通式(I)化合物的应用
通式(I)化合物可作为胃酸分泌抑制剂。
通式(I)化合物可作为H +/K +-腺苷三磷酸酶(H +/K +-ATPase)抑制剂。
通式(I)化合物可作为钾离子竞争性酸阻滞剂(P-CABs)。
通式(I)化合物可用于治疗和/或预防消化性溃疡、卓-艾综合征、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；或者抑制消化性溃疡、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。上述消化性溃疡包括但不限于胃溃疡、十二指肠溃疡或吻合口溃疡。症状性胃食管反流疾病包括但不限于非糜烂性的反流性疾病或无食管炎的胃食管反流疾病。
药物组合物
本发明的药物组合物包含有效量的通式(I)所示的化合物或其互变异构体、对映异构体、非对映异构体、及其混合物形式、及其可药用的盐、及其药学上可接受的载体或赋形剂或稀释剂。
“有效量”意指本发明化合物：(i)治疗特定疾病、病症或障碍，(ii)减弱、改善或消除特定疾病、病症或障碍的一或多种症状，或(iii)预防或延迟本文所述特定疾病、病症或障碍的一或多种症状发作的量。
药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂
Figure PCTCN2019102527-appb-000008
润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
本发明化合物或药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：口服、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)、和局部给药。
本发明化合物可以单独给药，或者与其他药学上可接受的化合物联合给药。
本发明的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、对映异构体、非对映异构体、及其混合物形式、及其可药用的盐或其药物组合物。
本发明的另一方面涉及一种抑制H +/K +-腺苷三磷酸酶(H +/K +-ATPase)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、对映异构体、非对映异构体、及其混合物形式、及其可药用的盐或其药物组合物。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。
化合物的结构是通过核磁共振(NMR)或质谱(MS)来确定的，化合物的纯度 是通过液相高压色谱仪(HPLC)测定的。NMR的测定是用Bruker AVANCE-400核磁共振仪，溶剂为氘代二甲基亚砜(DMSO-d6)或氘代甲醇(MeOH-d4)，内标为四甲基硅烷(TMS)，化学位移以ppm为单位。MS的测定使用安捷伦6120质谱仪。HPLC使用安捷伦1200DAD高压液相色谱仪测定。
实施例1：2-氯-N-(3-((3-(2-氟苯基)-5-甲基-5,6-二氢吡咯并[3,4-c]吡唑-2(4H)-基)甲基)苯基)-6-甲氧基吡啶-3-胺
Figure PCTCN2019102527-appb-000009
第一步：2-(3-硝基苄基)-2,6-二氢吡咯并[3,4-c]吡唑-5(4H)-羧酸叔丁酯
化合物2,6-二氢吡咯并[3,4-c]吡唑-5(4H)-羧酸叔丁酯1a(1g，4.78mmol)溶于乙腈(50mL)中，加入3-硝基溴苄(1.23g，5.74mmol)，碳酸铯(4.67g，14.345mmol)，在氩气气氛中于80℃反应过夜。反应液直接过滤，浓缩，残余物通过柱层析分离(石油醚/乙酸乙酯＝4/1)得到粗品化合物2-(3-硝基苄基)-2,6-二氢吡咯并[3,4-c]吡唑-5(4H)-羧酸叔丁酯1b(1.1g，黄色油状物)，产率：66.8％。MS m/z(ESI)：345.2[M+1]。
第二步：3-(2-氟苯基)-2-(3-硝基苄基)-2,6-二氢吡咯并[3,4-c]吡唑-5(4H)-羧酸叔丁酯
化合物2-(3-硝基苄基)-2,6-二氢吡咯并[3,4-c]吡唑-5(4H)-羧酸叔丁酯1b(1g，2.91mmol)，醋酸钾(1.71g，17.46mmol)，氯化烯丙基钯(II)二聚物(106mg，0.291mmol)，邻氟碘苯(1.292g，5.82mmol)，DMA(30mL)依次加入反应器中，在氩气气氛中于100℃反应3小时。将反应液倒入水(80mL)中，用乙酸乙酯(30mL×3)萃取。有机相用饱和氯化钠水溶液(50mL×2)洗涤，无水硫酸钠干燥，过滤，浓缩，残 余物经柱层析分离(石油醚/乙酸乙酯＝2/1)得到化合物3-(2-氟苯基)-2-(3-硝基苄基)-2,6-二氢吡咯并[3,4-c]吡唑-5(4H)-羧酸叔丁酯1c(300mg，黄色油状物)，产率：23.5％。
第三步：3-(2-氟苯基)-2-(3-硝基苄基)-2,4,5,6-四氢吡咯并[3,4-c]吡唑
化合物3-(2-氟苯基)-2-(3-硝基苄基)-2,6-二氢吡咯并[3,4-c]吡唑-5(4H)-羧酸叔丁酯1c(300mg，0.685mmol)溶于二氯甲烷(9mL)，加入三氟乙酸(3mL)，室温反应2小时。将反应液浓缩得到化合物3-(2-氟苯基)-2-(3-硝基苄基)-2,4,5,6-四氢吡咯并[3,4-c]吡唑1d(220mg，棕色液体)，产率：94.5％。MS m/z(ESI)：339.2[M+1]。
第四步：3-(2-氟苯基)-5-甲基-2-(3-硝基苄基)-2,4,5,6-四氢吡咯并[3,4-c]吡唑
化合物3-(2-氟苯基)-2-(3-硝基苄基)-2,4,5,6-四氢吡咯并[3,4-c]吡唑1d(220mg，0.65mmol)溶于二氯甲烷/甲醇(2/1，24mL)溶液中，加入甲醛水溶液(37％，460mg，5.68mmol)，室温搅拌1小时，然后加入醋酸硼氢化钠(1.2g，5.68mmol)，再室温反应2小时。反应液浓缩后经HPLC制备(乙腈/水(含0.05％NH 3)梯度冲洗)得到化合物3-(2-氟苯基)-5-甲基-2-(3-硝基苄基)-2,4,5,6-四氢吡咯并[3,4-c]吡唑1e(160mg，黄色油状液体)，产率：71.0％。MS m/z(ESI):353.3[M+1]。 1H NMR(400MHz,CDCl 3)δ8.00(d,J＝7.9Hz,1H),7.81(s,1H),7.33(dt,J＝7.7,5.2Hz,2H),7.27(d,J＝7.6Hz,1H),7.19-7.03(m,3H),5.23(s,2H),3.73(d,J＝39.1Hz,4H),2.57(s,3H)。
第五步：3-((3-(2-氟苯基)-5-甲基-5,6-二氢吡咯并[3,4-c]吡唑-2(4H)-基)甲基)苯胺
将化合物3-(2-氟苯基)-5-甲基-2-(3-硝基苄基)-2,4,5,6-四氢吡咯并[3,4-c]吡唑1e(120mg，0.34mmol)溶解于溶剂甲醇(15mL)中，加入Raney-Ni催化剂(1.0mL)。反应液加热到40℃，滴加水合肼(50％，1.0mL，10mmol)。滴加完毕后，加热搅拌2小时。将反应液过滤，滤液浓缩得到化合物3-((3-(2-氟苯基)-5-甲基-5,6-二氢吡咯并[3,4-c]吡唑-2(4H)-基)甲基)苯胺1f(80mg，灰白色固体)。MS m/z(ESI)：323.2[M+H]。 1H NMR(400MHz,CDCl 3)δ7.36(s,1H),7.18(m,2H),7.01(m,1H),6.52(m,1H),6.46–6.10(m,2H),5.15(s,2H),3.80(d,J＝42.7Hz,4H),3.53(s,2H),2.64(s,3H)。
第六步：2-氯-N-(3-((3-(2-氟苯基)-5-甲基-5,6-二氢吡咯并[3,4-c]吡唑-2(4H)-基)甲基)苯基)-6-甲氧基吡啶-3-胺
依次在反应瓶中加入化合物3-((3-(2-氟苯基)-5-甲基-5,6-二氢吡咯并[3,4-c]吡唑-2(4H)-基)甲基)苯胺1f(100mg，1.31mmol)、碳酸铯(0.41g，1.24mmol)、三(二亚苄基丙酮)二钯(28mg，0.031mmol)、2-二环己基磷-2，4，6-三异丙基联苯(29.5mg，0.062mmol)、N，N-二甲基甲酰胺(10mL)、2-氯-3-碘-6-甲氧基吡啶(0.18g，0.62mmol)，在氩气气氛中于110℃反应16小时。反应液恢复至室温后倒入水(40mL)中，用乙酸乙酯(20mL×3)萃取。有机相用盐水(20mL×2)洗，无水硫酸钠干燥、过滤、浓缩。残留物用HPLC制备(乙腈/水(含0.05％三氟乙酸)得到化合物2-氯-N-(3-((3-(2-氟苯基)-5-甲基-5,6-二氢吡咯并[3,4-c]吡唑-2(4H)-基)甲基)苯基)-6-甲氧基吡啶-3-胺1(三氟乙酸盐，盐系数＝2，17.2mg，黑棕色油状物)，产率：3.3％。MS m/z(ESI)：464.1[M+1]。 1H NMR(400MHz,CDCl 3)δ7.47-7.33(m,2H),7.20-7.06(m,4H),6.75(dd,J＝8.0,1.6Hz,1H),6.57(d,J＝8.6Hz,1H),6.55-6.42(m,2H),5.15(d,J＝7.2Hz,2H),4.90(s,2H),3.98(dd,J＝27.8,11.1Hz,2H),3.85(s,3H),3.05(s,3H)。
实施例2：2-氯-N-(3-((3-(2-氟苯基)-5-甲基-5,6-二氢吡咯并[3,4-c]吡唑-2(4H)-基)甲基)苯基)-6-甲基吡啶-3-胺
Figure PCTCN2019102527-appb-000010
第一步：3-(2-氟苯基)-2-(3-碘苄基)-5-甲基-2,4,5,6-四氢吡咯并[3,4-c]吡唑
将化合物3-(2-氟苯基)-5-甲基-2-(3-硝基苄基)-2,4,5,6-四氢吡咯并[3,4-c]吡唑1e(350mg，1.09mmol)溶于浓硫酸/水(11mL，10/1)溶液中，加入溶于水(1mL)的亚硝酸钠(90mg，1.30mmol)，在0℃反应1h后，加入溶于水(1mL)的碘化钾(325mg，1.96mmol)，于15℃以下反应2h。反应液恢复至室温后倒入水(10mL)中，用乙酸乙酯(20mL×3)萃取。有机相合并后用饱和食盐水(15mL×2)洗涤，无水硫酸钠干燥、过滤并浓缩得化合物3-(2-氟苯基)-2-(3-碘苄基)-5-甲基-2,4,5,6-四氢吡咯并 [3,4-c]吡唑2a(300mg，浅黄色油状物)，产率：63.5％。MS m/z(ESI)：434.3[M+1]。1H NMR(400MHz,CDCl3)δ7.61(d,1H),7.52-7.46(m,1H),7.40(s,1H),7.25-7.20(m,3H),7.05-6.99(m,2H),5.21(s,2H),4.97(t,2H),4.12-4.01(m,2H),3.13(s,3H)。
第二步：2-氯-N-(3-((3-(2-氟苯基)-5-甲基-5,6-二氢吡咯并[3,4-c]吡唑-2(4H)-基)甲基)苯基)-6-甲基吡啶-3-胺
依次在反应瓶中加入化合物3-(2-氟苯基)-2-(3-碘苄基)-5-甲基-2,4,5,6-四氢吡咯并[3,4-c]吡唑2a(300mg，0.69mmol)、2-氯-6-甲基吡啶-3-胺(200mg，1.39mmol)、碳酸铯(900mg，2.76mmol)、三(二亚苄基丙酮)二钯(63mg，0.07mmol)、2-二环己基磷-2，4，6-三异丙基联苯(69mg，0.14mmol)、N，N-二甲基甲酰胺(20mL)，氩气气氛中于110℃反应过夜。反应液冷却至室温后倒入水(100mL)中，用乙酸乙酯(50mL×3)萃取。有机相合并后用饱和食盐水(50mL×2)洗涤，用无水硫酸钠干燥、过滤并浓缩。残留物用HPLC制备(乙腈/水(含0.05％NH3)梯度冲洗)得到化合物2-氯-N-(3-((3-(2-氟苯基)-5-甲基-5,6-二氢吡咯并[3,4-c]吡唑-2(4H)-基)甲基)苯基)-6-甲基吡啶-3-胺2(35mg，黄色粉末)，产率：10.6％。MS m/z(ESI)：478.3[M+1]。 1H NMR(400MHz,CDCl 3)δ7.36(d,J＝8.0Hz,1H),7.30(d,J＝8.2Hz,1H),7.18-7.07(m,4H),6.90(t,J＝6.6Hz,2H),6.67(s,1H),6.61(d,J＝7.6Hz,1H),5.87(s,1H),5.15(s,2H),4.08(d,J＝33.0Hz,4H),2.80(s,3H),2.40(s,3H),2.10(s,1H)。
实施例3：2-氯-N-(3-((3-(2-氟苯基)-5-甲基-5,6-二氢吡咯并[3,4-c]吡唑-2(4H)-基)甲基)苯基)嘧啶-4-胺
Figure PCTCN2019102527-appb-000011
将化合物3-(2-氟苯基)-5-甲基-2-(3-硝基苄基)-2,4,5,6-四氢吡咯并[3,4-c]吡唑1e(320mg，1.0mmol)、水(5mL)、盐酸(1滴)、2,4-二氯嘧啶(179mg，1.2mmol)混合，室温反应48小时。反应结束后冻干，取50mg用HPLC制备(乙腈/水(含0.05％ 三氟乙酸)得到粗品，粗品用TLC制备板(二氯甲烷/甲醇＝10/1)纯化得到化合物2-氯-N-(3-((3-(2-氟苯基)-5-甲基-5,6-二氢吡咯并[3,4-c]吡唑-2(4H)-基)甲基)苯基)嘧啶-4-胺3(5mg，黄色油状物)，产率：1.2％。MS m/z(ESI)：435.1[M+1]。 1H NMR(400MHz,CDCl 3)δ8.01(d,J＝5.8Hz,1H),7.48(s,1H),7.33(d,J＝4.8Hz,2H),7.17(dd,J＝9.7,6.7Hz,2H),7.14-7.04(m,2H),6.78(d,J＝7.6Hz,1H),6.67(s,1H),6.50(d,J＝5.8Hz,1H),5.19(s,2H),3.92(d,J＝33.4Hz,4H),2.69(s,3H)。
实施例4：4-((3-((3-(2-氟苯基)-5-甲基-5,6-二氢吡咯并[3,4-c]吡唑-2(4H)-基)甲基)苯基)氨基)嘧啶-2-(1H)-酮
Figure PCTCN2019102527-appb-000012
在反应瓶中加入化合物2-氯-N-(3-((3-(2-氟苯基)-5-甲基-5,6-二氢吡咯并[3,4-c]吡唑-2(4H)-基)甲基)苯基)嘧啶-4-胺3(100mg，0.23mmol)和甲酸(1ml)，65℃反应6小时，反应结束后，用乙酸乙酯(10mL×3)萃取。有机相用盐水(10mL×2)洗，无水硫酸钠干燥、过滤、浓缩。残留物用HPLC制备(乙腈/水(含0.05％三氟乙酸)得到化合物4-((3-((3-(2-氟苯基)-5-甲基-5,6-二氢吡咯并[3,4-c]吡唑-2(4H)-基)甲基)苯基)氨基)嘧啶-2-(1H)-酮4(三氟乙酸盐，盐系数＝4，3mg，黄色油状物)，产率：3.1％。MS m/z(ESI)：417.1[M+1]。 1H NMR(400MHz,MeOD)δ7.48(d,J＝7.1Hz,3H),7.40(s,1H),7.23(dd,J＝23.9,10.3Hz,4H),6.76(s,1H),5.97(d,J＝7.1Hz,1H),5.37(s,2H),4.47(d,J＝31.9Hz,4H),3.11(s,3H)。
实施例5：N 4-(3-((3-(2-氟苯基)-5-甲基-5,6-二氢吡咯并[3,4-c]吡唑-2(4H)-基)甲基)苯基)-N 2-甲基嘧啶-2,4-二胺
Figure PCTCN2019102527-appb-000013
Figure PCTCN2019102527-appb-000014
将化合物2-氯-N-(3-((3-(2-氟苯基)-5-甲基-5,6-二氢吡咯并[3,4-c]吡唑-2(4H)-基)甲基)苯基)嘧啶-4-胺3(100mg，0.23mmol)与甲胺醇溶液(2ml)混合，100℃反应过夜，反应结束后，反应液用乙酸乙酯(10mL×3)萃取。有机相用盐水(10mL×2)洗，无水硫酸钠干燥、过滤、浓缩。残留物用HPLC制备(乙腈/水(含0.05％三氟乙酸)得到化合物N 4-(3-((3-(2-氟苯基)-5-甲基-5,6-二氢吡咯并[3,4-c]吡唑-2(4H)-基)甲基)苯基)-N 2-甲基嘧啶-2,4-二胺5(三氟乙酸盐，盐系数＝1.6，5mg，黄色油状物)，产率：5.1％。MS m/z(ESI)：430.2[M+1]。 1H NMR(400MHz,CDCl 3)δ7.67(s,1H),7.45(s,1H),7.39-7.30(m,1H),7.19-7.06(m,4H),6.79(d,J＝7.5Hz,1H),6.63(s,1H),6.00(d,J＝6.3Hz,1H),5.23(s,2H),4.10(d,J＝32.6Hz,4H),2.96-2.77(m,6H)。
实施例6：N-(3-((3-(2-氟苯基)-5-甲基-5,6-二氢吡咯并[3,4-c]吡唑-2(4H)-基)甲基)苯基)-2-吗啉代嘧啶-4-胺
Figure PCTCN2019102527-appb-000015
将化合物2-氯-N-(3-((3-(2-氟苯基)-5-甲基-5,6-二氢吡咯并[3,4-c]吡唑-2(4H)-基)甲基)苯基)嘧啶-4-胺3(100mg，0.23mmol)于封管内，加入DIEA(1mL)、叔丁醇(1mL)，吗啡啉(3mL)，加热100℃反应过夜，反应结束后，用乙酸乙酯(10mLx3)萃取。有机相用盐水(10mLx2)洗，然后用无水硫酸钠干燥、过滤、浓缩。将有机层浓缩后用高压液相色谱制备(乙腈/水(含0.05％三氟乙酸)得到N-(3-((3-(2-氟苯基)-5-甲基-5,6-二氢吡咯并[3,4-c]吡唑-2(4H)-基)甲基)苯基)-2-吗啉代嘧啶-4-胺6(5mg，黄色油状物)，产率：4.4％。MS m/z(ESI)：486.2[M+1]。 1H NMR(400MHz,CDCl 3)δ7.88(d,J＝5.7Hz,1H),7.43(d,J＝7.9Hz,1H),7.37–7.28(m,1H),7.20–7.05(m,4H),7.01(s,1H),6.75(s,1H),6.65(d,J＝7.6Hz,1H),5.98(d,J＝5.7Hz,1H),5.18(s,2H),4.08(d,J＝32.9Hz,4H),3.67(s,8H),2.79(s,3H)。
实施例7：6-氯-N-(3-((3-(2-氟苯基)-5-甲基-5,6-二氢吡咯并[3,4-c]吡唑-2(4H)-基)甲基)苯基)吡嗪-2-胺
Figure PCTCN2019102527-appb-000016
依次在反应瓶中加入化合物3-(2-氟苯基)-5-甲基-2-(3-硝基苄基)-2,4,5,6-四氢吡咯并[3,4-c]吡唑1e(100mg，0.31mmol)、叔丁醇钠(0.041g，0.43mmol)、三(二亚苄基丙酮)二钯(2.8mg，0.0031mmol)、BINAP(7.7mg，0.012mmol)、1,4-二氧六环(2mL)、2，6-二氯吡嗪(0.055g，0.37mmol)，在氩气气氛中于90℃反应16小时。反应液恢复至室温后倒入水(40mL)中，用乙酸乙酯(20mL×3)萃取。有机相用盐水(20mL×2)洗，无水硫酸钠干燥、过滤、浓缩。残留物用HPLC制备(乙腈/水(含0.05％三氟乙酸)得到粗品，粗品用TLC制备板(二氯甲烷/甲醇＝10/1)纯化得到化合物6-氯-N-(3-((3-(2-氟苯基)-5-甲基-5,6-二氢吡咯并[3,4-c]吡唑-2(4H)-基)甲基)苯基)吡嗪-2-胺7(6mg，黄棕色固体)，产率：4.5％。MS m/z(ESI)：435.1[M+1]。 1H NMR(400MHz,CDCl 3)δ7.98(s,1H),7.86(s,1H),7.41(d,J＝7.9Hz,1H),7.32(d,J＝7.0Hz,1H),7.18-7.12(m,2H),7.13-7.05(m,2H),6.78(s,1H),6.69(d,J＝7.5Hz,1H),5.18(s,2H),3.88(d,J＝35.3Hz,4H),2.66(s,3H)。
测试例：化合物对H+/K+ATPase酶活性抑制的测定
下面的实验是用来测定本发明化合物对H+/K+ATPase酶活性的抑制作用。
1.实验材料
Plate reader:SpectraMax M5(MD)
孔雀石绿(Sigma Aldrich,213020-25G)
钼酸铵(Sigma Aldrich,277908-20G)
ATP(Sigma Aldrich,A1852-1VL)。
2.缓冲液配制
酶工作液：对酶进行滴定，用缓冲液1将酶稀释，反应时，取5μl稀释液至50μl的反应体系中
ATP溶液：100mM的ATP用无K +buffer稀释至5mM，取5μl稀释液至50μl的反应体系中，即ATP的终浓度为500μM
MLG显色液：将0.12％的MLG、7.5％钼酸铵、11％的Tween-20按100：25：2的体积混匀，检测时每孔加入15μl
缓冲液1:50mM Tris-HCl pH 6.5,5mM氯化镁(magnesium chloride),10μM缬氨霉素(valinomycin)
缓冲液2:50mM Tris-HCl pH 6.5,5mM氯化镁(magnesium chloride),10μM缬氨霉素(valinomycin),20mM KCl
匀浆缓冲液：10mmol/L Tris-HCl,pH 6.8，0.25M蔗糖(sucrose),1mmol/LEDTA 7.5％Ficoll分层液：匀浆缓冲液+7.5％(W/W)
Figure PCTCN2019102527-appb-000017
400(聚蔗糖400)。
3.实验步骤
3.1.H +/K +ATP酶提取
(1)分离出兔胃组织，自来水冲洗血迹，食物残留；
(2)利用预冷的NaCl溶液彻底清洗胃底部位，去除表面粘液；
(3)将剥离的粘膜，装于样品袋或50ml离心管，迅速冻于液氮罐中；
(4)取出组织，用手术剪刀剪碎，加入预冷的匀浆缓冲液(4ml/g组织)，于组织匀浆机中匀浆2-10min；
(5)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；
(6)利用匀浆缓冲液重悬沉淀，吹散均匀，等比例加入7.5％Ficoll分层液，100000g离心90min，收集沉淀；
(7)匀浆缓冲液重悬沉淀，吹散均匀，用Bradford测蛋白浓度。分管冻存于-80℃备用。
3.2.H +/K +ATP酶活性实验
(1)每个实验孔中加入35μl反应缓冲液，再加入35μl的缓冲液1
(2)全酶和缓冲液孔中，加入5μl含10％DMSO的缓冲液1
(3)化合物孔中，加入5μl10X化合物工作液混匀
(4)缓冲液孔中加入5μl的缓冲液1
(5)其余孔中，加入5μl 10X酶工作液混匀于37℃孵育30min
(6)向所有实验孔中加入5μl 10XATP工作液，并混匀于37℃孵育20min
(7)向所有实验孔中加入15μl MLG显色液，并混匀于室温孵5-30min
(8)M5仪器检测620nm的读数。
4.数据分析
抑制率用以下公式计算：
抑制率(IC 50)＝【OD(样品孔)-OD(含氯化钾的全酶孔)】/【(OD(含氯化钾的全酶孔)-(OD(不含氯化钾的全酶孔)】×100％
5.实验结果
各实施例化合物的抑制率(IC 50)在表2中示出
表2
化合物编号 IC 50(μM)
实施例1 0.4154
实施例2 0.6688
实施例3 0.9658
实施例4 0.7293
实施例5 0.2789
实施例6 2.847
实施例7 0.3254
从表2可以看出，本发明化合物具有优异的H +/K +ATPase酶抑制活性，可用于制备胃酸分泌抑制剂。

Claims (9)

  1. 一种通式(I)所示的化合物或其药学上可接受的盐，
    Figure PCTCN2019102527-appb-100001
    其中：
    X为NR a，其中R a选自氢原子或烷基；
    Y、Z、U和V各自独立选自N、NH、CR b或C(＝O)，并且Y、Z、U和V有且只有一个或两个同时含有N，其中R b选自氢原子、卤素、羟基、烷基、烷氧基、NR cR d、五元或六元饱和杂环，其中R c和R d各自独立选自氢原子或C 1～3烷基；
    R 1选自氢原子、卤素或烷基；
    R 2选自氢原子、卤素、羟基或烷基。
  2. 根据权利要求1所述的化合物或其药学上可接受的盐，其特征在于，
    X为NR a，其中R a选自氢原子或C 1～3烷基；
    Y、Z、U和V各自独立选自N、NH、CR b或C(＝O)，并且Y、Z、U和V有且只有一个或两个同时含有N，其中R b选自氢原子、卤素、羟基、烷基、C 1～3烷氧基、NR cR d、六元饱和杂环，其中R c和R d中一者为氢，另一者选自氢原子或C 1～3烷基；
    R 1选自氢原子或氟原子；
    R 2选自氢原子、氟原子或羟基。
  3. 根据权利要求1或2所述的化合物或其药学上可接受的盐，其特征在于，
    X为NH；
    Y、Z、U和V各自独立选自N、NH、CR b或C(＝O)，并且Y、Z、U和V有且只有一个或两个同时含有N，其中R b选自氢原子、氯原子、羟基、甲基、甲氧基、NHCH 3或吗啉；
    R 1为氟原子；
    R 2为氢原子。
  4. 根据权利要求1至3中任一项所述的化合物或其药学上可接受的盐，其特征在于，所述化合物选自：
    2-氯-N-(3-((3-(2-氟苯基)-5-甲基-5,6-二氢吡咯并[3,4-c]吡唑-2(4H)-基)甲基)苯基)-6-甲氧基吡啶-3-胺；
    2-氯-N-(3-((3-(2-氟苯基)-5-甲基-5,6-二氢吡咯并[3,4-c]吡唑-2(4H)-基)甲基)苯基)-6-甲基吡啶-3-胺；
    2-氯-N-(3-((3-(2-氟苯基)-5-甲基-5,6-二氢吡咯并[3,4-c]吡唑-2(4H)-基)甲基)苯基)嘧啶-4-胺；
    4-((3-((3-(2-氟苯基)-5-甲基-5,6-二氢吡咯并[3,4-c]吡唑-2(4H)-基)甲基)苯基)氨基)嘧啶-2-(1H)-酮；
    N 4-(3-((3-(2-氟苯基)-5-甲基-5,6-二氢吡咯并[3,4-c]吡唑-2(4H)-基)甲基)苯基)-N 2-甲基嘧啶-2,4-二胺；
    N-(3-((3-(2-氟苯基)-5-甲基-5,6-二氢吡咯并[3,4-c]吡唑-2(4H)-基)甲基)苯基)-2-吗啉代嘧啶-4-胺；
    6-氯-N-(3-((3-(2-氟苯基)-5-甲基-5,6-二氢吡咯并[3,4-c]吡唑-2(4H)-基)甲基)苯基)吡嗪-2-胺。
  5. 一种药物组合物，包括权利要求1至4中任一项所述的化合物或其药学上可接受的盐以及药学上可接受的载体、赋形剂或稀释剂。
  6. 权利要求1至4中任一项所述的化合物或其药学上可接受的盐或权利要求5所述的药物组合物在制备胃酸分泌抑制剂中的用途。
  7. 权利要求1至4中任一项所述的化合物或其药学上可接受的盐或权利要求5所述的药物组合物在制备H +/K +-腺苷三磷酸酶抑制剂中的用途。
  8. 权利要求1至4中任一项所述的化合物或其药学上可接受的盐或权利要求5所述的药物组合物在制备钾离子竞争性酸阻滞剂中的用途。
  9. 权利要求1至4中任一项所述的化合物或其药学上可接受的盐或权利要求5所述的药物组合物在制备药物中的用途，所述药物用于治疗和/或预防消化性溃疡、卓-艾综合征、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；或者抑制消化性溃疡、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。
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