WO2023280293A1 - 一种吡咯磺酰类衍生物、及其制备方法与应用 - Google Patents
一种吡咯磺酰类衍生物、及其制备方法与应用 Download PDFInfo
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- WO2023280293A1 WO2023280293A1 PCT/CN2022/104536 CN2022104536W WO2023280293A1 WO 2023280293 A1 WO2023280293 A1 WO 2023280293A1 CN 2022104536 W CN2022104536 W CN 2022104536W WO 2023280293 A1 WO2023280293 A1 WO 2023280293A1
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- WIPO (PCT)
- Prior art keywords
- alkyl
- pyrrolesulfonyl
- pharmaceutically acceptable
- derivatives
- compound
- Prior art date
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- LNPNQDXXFAWSCF-UHFFFAOYSA-N tert-butyl n-[(5-bromo-1h-pyrrol-3-yl)methyl]-n-methylcarbamate Chemical compound CC(C)(C)OC(=O)N(C)CC1=CNC(Br)=C1 LNPNQDXXFAWSCF-UHFFFAOYSA-N 0.000 description 1
- LVGYGKHOCUVSGX-UHFFFAOYSA-N tert-butyl n-[[5-(2,4-difluorophenyl)-1h-pyrrol-3-yl]methyl]-n-methylcarbamate Chemical compound CC(C)(C)OC(=O)N(C)CC1=CNC(C=2C(=CC(F)=CC=2)F)=C1 LVGYGKHOCUVSGX-UHFFFAOYSA-N 0.000 description 1
- GKDXQEQCKDCJCE-UHFFFAOYSA-N tert-butyl n-[[5-(2-fluorophenyl)-1h-pyrrol-3-yl]methyl]-n-methylcarbamate Chemical compound CC(C)(C)OC(=O)N(C)CC1=CNC(C=2C(=CC=CC=2)F)=C1 GKDXQEQCKDCJCE-UHFFFAOYSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 229960005371 tolbutamide Drugs 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 210000005239 tubule Anatomy 0.000 description 1
- 229910021642 ultra pure water Inorganic materials 0.000 description 1
- 239000012498 ultrapure water Substances 0.000 description 1
Classifications
-
- 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
-
- 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
-
- 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
- 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
- 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
-
- 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
- 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
-
- 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
- C07D403/12—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 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
- C07D405/12—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 linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Definitions
- the present invention relates to a new class of pyrrolesulfonyl derivatives, a preparation method thereof, a pharmaceutical composition containing the derivative and its use as a therapeutic agent, especially as a gastric acid secretion inhibitor and a potassium ion competitive acid blocker (P- CABs) in the use.
- a new class of pyrrolesulfonyl derivatives a preparation method thereof, a pharmaceutical composition containing the derivative and its use as a therapeutic agent, especially as a gastric acid secretion inhibitor and a potassium ion competitive acid blocker (P- CABs) in the use.
- P- CABs potassium ion competitive acid blocker
- Gastrointestinal-related tumors account for five of the six most common cancers in the world, including gastric cancer, liver cancer, esophageal cancer, intestinal cancer, and pancreatic cancer.
- PPIs proton pump Inhibitors
- omeprazole was successfully developed by AstraZenaca and first launched in Sweden. Pump inhibitors used to treat duodenal ulcers, Zoller-Ellison syndrome, gastric ulcers, and reflux esophagitis. Subsequently, several PPIs products were launched in the world. After years of clinical application, PPIs have become the drug of choice for the treatment of gastric acid-related diseases.
- Proton Pump also known as gastric acid pump
- H + /K + -adenosine triphosphatase H + /K + -ATPase
- H + /K + -ATPase H + /K + -adenosine triphosphatase
- ATP is degraded to provide energy for H and K + exchange, and H is specifically pumped into the gastric cavity, forming a strong acid state in the stomach.
- the first-generation PPIs have a significant inhibitory effect on gastric acid secretion stimulated by basal, nocturnal gastric acid and pentagastrin, and test meals.
- P-CABs Potassium-Competitive Acid Blockers
- P-CABs are immediately ionized, and the ionized form inhibits H + /K + -ATPase through ionic binding, preventing H + transport and acid secretion into the gastric cavity, without the need to concentrate on the microcapsules and parietal cells.
- the activation of microtubules and acid can rapidly increase the pH value in the stomach, and the enzyme activity will recover after dissociation. Humans and animals can absorb rapidly after oral administration and reach the peak plasma concentration.
- Clinical and animal experiments also show that P-CABs has a faster onset of action than PPIs or histamine receptor 2 (H2) blockers, a stronger effect of increasing pH, and a linearity of blood drug concentration with oral administration dose.
- the object of the present invention is to provide a new pyrrolesulfonyl derivative, its tautomer or its stereoisomer, and its pharmaceutically acceptable salt for screening
- Compounds that are used as gastric acid secretion inhibitors and potassium ion competitive acid blockers (P-CABs) have excellent properties in terms of efficacy, safety and selectivity.
- Another object of the present invention is to provide a preparation method of the derivative, its tautomer or its stereoisomer, and its pharmaceutically acceptable salt.
- the present invention provides a pyrrolesulfonyl derivative, its tautomer or its stereoisomer, and a pharmaceutically acceptable salt thereof.
- the structure of the pyrrolesulfonyl derivative is as follows: (I) as shown:
- A is phenyl or pyridyl
- alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl can be optionally further substituted by 1-3 hydroxyl, halogen, C 1-6 alkyl, C 1-6 alkoxy ;
- R 2 is selected from H, C 1-6 alkyl, C 1-6 alkoxy, halogen, cyano, C 2-6 alkynyl, C 2-6 alkenyl, -OC 1-6 alkyl-OC 1-6 alkyl, -NR c R d ;
- R 3 is selected from halogen, 5-8 membered aryl, 5-8 membered heteroaryl, cyano, C 2-6 alkynyl, C 2-6 alkenyl, -OC 1-6 alkyl-OC 1 -6 alkyl, -NR c R d ;
- the aryl, heteroaryl and condensed ring aryl can be optionally further replaced by 1-3 C 1-6 alkyl, C 1 -6 alkoxy, halogen, C 2-6 alkynyl, C 2-6 alkenyl, cyano, -OC 1-6 alkyl-OC 1-6 alkyl, -NR c R d ;
- R 4 is selected from C 1-6 alkyl; wherein the alkyl can be optionally further substituted by 1-3 deuterium, halogen;
- n is selected from 0, 1, 2, 3;
- n 0, 1, 2;
- R a , R b , R c , and R d are each independently selected from C 1-6 alkyl, C 1-6 alkoxy, and C 3-7 cycloalkyl.
- alkyl group, cycloalkyl group and heterocyclyl group may be optionally further substituted by halogen or C 1-6 alkyl group.
- Ring A is selected from phenyl
- the pyrrolesulfonyl derivatives have a general structural formula as shown in formula (II):
- the R 2 is selected from H, C 1-6 alkoxy, halogen.
- said R 3 is selected from halogen; R 4 is selected from C 1-6 alkyl.
- the pyrrolesulfonyl derivatives have a general structural formula as shown in formula (III):
- the pharmaceutically acceptable salts of pyrrolesulfonyl derivatives provided by the present invention can be hydrochloride or trifluoroacetate.
- pyrrolesulfonyl derivatives of the present invention can be selected from any one of the following structures:
- the present invention provides a pharmaceutical composition, which comprises the above-mentioned pyrrolesulfonyl derivatives, tautomers or stereoisomers thereof, and pharmaceutically acceptable salts and pharmaceutically acceptable carriers and/or excipients.
- the present invention provides a pyrrolesulfonyl derivative as described in the first aspect, its tautomer or its stereoisomer, and a pharmaceutically acceptable salt thereof as described in the third aspect
- a pharmaceutical composition of the invention in the preparation of gastric acid secretion inhibitors, H + /K + -ATPase inhibitors or potassium ion competitive acid blockers.
- the present invention provides a kind of above-mentioned pyrrolesulfonyl derivatives, its tautomer or its stereoisomer, and its pharmaceutically acceptable salt or the above-mentioned pharmaceutical composition.
- the pyrrolesulfonyl derivatives provided by the present invention have less toxic and side effects, and have excellent safety; meanwhile, they have good pharmacokinetic properties, a longer half-life, and more sustained acid-suppressing effect, and are expected to have a positive effect on nocturnal acid breakthrough phenomenon. better improvement.
- Cycloalkyl means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring comprising 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 6 carbon atoms.
- Non-limiting examples of monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl , cycloheptatrienyl, cyclooctyl, etc.; polycyclic cycloalkyl includes spiro ring, fused ring and bridged ring cycloalkyl. Cycloalkyl groups can be optionally substituted or unsubstituted.
- Heterocyclyl “heterocycle” or “heterocyclic” are used interchangeably in this application, and all refer to a saturated or partially unsaturated monocyclic ring containing 3-12 ring atoms , bicyclic or tricyclic non-aromatic heterocyclic group, wherein at least one ring atom is a heteroatom, such as oxygen, nitrogen, sulfur atom and the like. Preference is given to having a 5 to 7 membered monocyclic ring or a 7 to 10 membered bi- or tricyclic ring, which may contain 1, 2 or 3 atoms selected from nitrogen, oxygen and/or sulfur.
- heterocyclyl examples include, but are not limited to, morpholinyl, oxetanyl, thiomorpholinyl, tetrahydropyranyl, 1,1-dioxo-thiomorpholinyl, piperidine Base, 2-oxo-piperidinyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, piperazin-2-one, 8-oxa-3-aza-bicyclo[3.2.1]octyl and piperazinyl.
- the heterocyclyl ring may be fused to an aryl, heteroaryl, or cycloalkyl ring where the ring bonded to the parent structure is a heterocyclyl.
- a heterocyclyl group can be optionally substituted or unsubstituted.
- Aryl means a carbocyclic aromatic system containing one or two rings, wherein the rings may be joined together in a fused fashion.
- aryl includes aromatic groups such as phenyl, naphthyl, tetrahydronaphthyl. Preferred aryl groups are C 6 -10 aryl groups, more preferred aryl groups are phenyl and naphthyl, most preferably phenyl.
- Aryl groups can be substituted or unsubstituted.
- the "aryl” can be fused with a heteroaryl, heterocyclyl or cycloalkyl, wherein the aryl ring is attached to the parent structure, non-limiting examples include but are not limited to:
- Heteroaryl means an aromatic 5 to 6 membered monocyclic ring or 9 to 10 membered bicyclic ring which may contain 1 to 4 atoms selected from nitrogen, oxygen and/or sulfur.
- heteroaryl include, but are not limited to, furyl, pyridyl, 2-oxo-1,2-dihydropyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl , oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, benzo-isodi Oxolyl, benzimidazolyl, indolyl, isoindolyl, 1,3-dioxo-isoindolyl, quin
- Heteroaryl groups can be optionally substituted or unsubstituted.
- the heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is a heteroaryl ring, non-limiting examples include but are not limited to:
- the present invention provides a new structure of pyrrolesulfonyl derivatives, the test results show that the pyrrolesulfonyl derivatives exhibit excellent gastric acid secretion inhibition and potassium ion competitive acid blockers (P-CABs) activity, It can be used to prepare for the treatment or prevention of peptic ulcer, Zoller's syndrome, gastric 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, hyperacidity caused by postoperative stress or ulcers caused by postoperative stress; Drugs for upper gastrointestinal bleeding caused by irritation ulcers, hemorrhagic gastritis, or invasive stress.
- P-CABs potassium ion competitive acid blockers
- the pyrrolesulfonyl derivatives provided by the present invention have less toxic and side effects, and have excellent safety; meanwhile, they have good pharmacokinetic properties, a longer half-life, and more sustained acid-suppressing effect, and are expected to have a positive effect on nocturnal acid breakthrough phenomenon. better improvement.
- Figure 1 shows the manual patch clamp hERG current test instruction voltage program.
- the mass spectrum was measured by LC/MS instrument, and the ionization mode was ESI.
- CD 3 OD deuterated methanol
- the hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a volume of about 1L.
- the solution in the reaction refers to an aqueous solution.
- reaction temperature is room temperature, which is 20°C-30°C.
- Step 1 Synthesis of 1-(5-(2-fluorophenyl)-1H-pyrrol-3-yl)-N-methylmethylamine (Int 1-2)
- Step 2 Synthesis of tert-butyl ((5-(2-fluorophenyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (Int 1-3)
- Step 3 Synthesis of tert-butyl((1-((3-bromophenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl)methyl)(methyl)aminomethyl Ester (Int 1)
- Step 2 Synthesis of tert-butyl((5-bromo-1H-pyrrol-3-yl)methyl)(methyl)carbamate (Int 3-3)
- Step 3 Synthesis of tert-butyl ((5-(2,4-difluorophenyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (Int 3-5)
- Step 4 Synthesis of tert-butyl((1-((3-bromophenyl)sulfonyl)-5-(2,4-difluorophenyl)-1H-pyrrol-3-yl)methyl)(methyl ) carbamate (Int 3)
- Step 2 Synthesis of benzyl(3-bromo-5-(3-methoxypropoxy)phenyl)sulfane (Int 4-5)
- Step 4 Synthesis of tert-butyl((1-((3-bromo-5-(3-methoxypropoxy)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrole- 3-yl)methyl)(methyl)carbamate (Int 4)
- Step 1 Synthesis of tert-butyl((5-(2-fluorophenyl)-1-((3-(3-methoxyprop-1-yn-1-yl)phenyl)sulfonyl)-1H- Pyrrol-3-yl)methyl)(methyl)carbamate (1-2)
- Step 2 Synthesis of 1-(5-(2-fluorophenyl)-1-((3-(3-methoxyprop-1-yn-1-yl)phenyl)sulfonyl)-1H-pyrrole- 3-yl)-N-methylmethylamine hydrochloride (II-1)
- Step 1 Synthesis of tert-butyl ((5-(2-fluorophenyl)-1-((5-(3-methoxyprop-1-yn-1-yl)pyridin-3-yl)sulfonyl) -1H-pyrrol-3-yl)methyl))(methyl)carbamate (2-2)
- Step 2 Synthesis of 1-(5-(2-fluorophenyl)-1-((5-(3-methoxyprop-1-yn-1-yl)pyridin-3-yl)sulfonyl)-1H -pyrrol-3-yl)-N-methylamine hydrochloride (II-2)
- Step 1 Synthesis of tert-butyl ((5-(2-fluorophenyl)-1-((5-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-3-yl) Sulfonyl)-1H pyrrol-3-yl)methyl)(methyl)carbamate (3-2)
- Step 2 Synthesis of 4-(5-((2-(2-fluorophenyl)-4-((methylamino)methyl)-1H-pyrrol-1-yl)sulfonyl)pyridin-3-yl)- 2-Methylbut-3-yn-2-ol (II-3)
- Step 1 Synthesis of tert-butyl ((1-((5-(cyclopropylethynyl)pyridin-3-yl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl) Methyl)(methyl)carbamate (4-2)
- Step 2 Synthesis of 1-(1-((5-(cyclopropylethynyl)pyridin-3-yl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl)-N -Methylmethylamine (II-4)
- Step 1 Synthesis of tert-butyl((5-(2-fluorophenyl)-1-((3-(3-methylbut-1-yn-1-yl)phenyl)sulfonyl)-1H-pyrrole -3-yl)methyl)(methyl)carbamate (5-1)
- the compound Int 1 (500mg, 0.960mmol) was dissolved in DMF (5mL), and Pd(PPh 3 ) 2 Cl 2 (67mg, 0.096mmol), CuI (19mg, 0.096mmol), triethyl Amine (0.5 mL, 3.84 mmol) and 3-methylbut-1-yne (260 mg, 3.84 mmol) were sealed and heated to 80°C overnight with stirring. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the crude product was separated and purified by column chromatography (n-hexane/ethyl acetate) to obtain 400 mg of a yellow oil with a yield of 81.6%.
- Step 2 Synthesis of 1-(5-(2-fluorophenyl)-1-((3-(3-methylbut-1-yn-1-yl)phenyl)sulfonyl)-1H-pyrrole-3 -yl)-N-methylmethylamine (II-5)
- Step 1 Synthesis of tert-butyl ((5-(2-fluorophenyl)-1-((3-(3-hydroxy-3-methylbut-1-yn-1-yl)phenyl)sulfonyl) -1H-pyrrol-3-yl)methyl)(methyl)carbamate (6-1)
- Step 2 Synthesis of 4-(3-((2-(2-fluorophenyl)-4-((methylamino)methyl)-1H-pyrrol-1-yl)sulfonyl)phenyl)-2-methanol But-3-yn-2-ol (II-6)
- Step 1 Synthesis of tert-butyl((5-(2-fluorophenyl)-1-((3-(3-methoxyprop-1-en-1-yl)phenyl)sulfonyl)-1H- Pyrrol-3-yl)methyl)(methyl)carbamate (7-1)
- Step 2 Synthesis of 1-(5-(2-fluorophenyl)-1-((3-(3-methoxyprop-1-en-1-yl)phenyl)sulfonyl)-1H-pyrrole- 3-yl)-N-methylmethylamine (II-7)
- Step 1 Synthesis of (E)-((1-((3-(2-cyclopropylvinyl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl) Methyl)(methyl)carbamate tert-butyl ester (8-2)
- Step 2 Synthesis of (E)-1-(1-((3-(2-cyclopropylvinyl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl )-N-methylmethylamine hydrochloride (II-8)
- Step 1 Synthesis of (E)-3-(3-((4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-2-(2-fluorophenyl)-1H-pyrrole- 1-yl)sulfonyl)phenyl)ethyl acrylate (9-2)
- Step 2 Synthesis of (E)-3-(3-((4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-2-(2-fluorophenyl)-1H-pyrrole- 1-yl)sulfonyl)phenyl)acrylic acid (9-3)
- Step 3 Synthesis of tert-butyl (E)-((5-(2-fluorophenyl)-1-((3-(3-(methylamino)-3-oxoprop-1-ene-1- Base) phenyl) sulfonyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate (9-5)
- Step 4 Synthesis of (E)-3-(3-((2-(2-fluorophenyl)-4-((methylamino)methyl)-1H-pyrrol-1-yl)sulfonyl)phenyl) -N-methacrylamide 2,2,2-trifluoroacetate (II-9)
- Step 1 Synthesis of tert-butyl((5-(2-fluorophenyl)-1-((3-(3-(methylamino)prop-1-yn-1-yl)phenyl)sulfonyl)- 1H-pyrrol-3-yl)methyl)(methyl)carbamate (10-1)
- Step 2 Synthesis of 3-(3-((2-(2-fluorophenyl)-4-((methylamino)methyl)-1H-pyrrol-1-yl)sulfonyl)phenyl)-N-methyl Prop-2-yn-1-amine (II-10)
- Step 1 Synthesis of tert-butyl ((5-(2,4-difluorophenyl)-1-((3-(3-methoxyprop-1-yn-1-yl)phenyl)sulfonyl) -1H-pyrrol-3-yl)methyl)(methyl)carbamate (11-1)
- Step 2 Synthesis of 1-(5-(2,4-difluorophenyl)-1-((3-(3-methoxyprop-1-yn-1-yl)phenyl)sulfonyl)-1H -pyrrol-3-yl)-N-methylmethylamine (II-11)
- Step 1 Synthesis of tert-butyl ((1-((3-(cyclopropylethynyl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl)methyl) (Methyl) carbamate (12-1)
- Step 2 Synthesis of (1-((3-(cyclopropylethynyl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl)-N-methylmethylamine Hydrochloride (II-12)
- Step 1 Synthesis of tert-butyl ((5-(2-fluorophenyl)-1-((3-(3-methoxyprop-1-yn-1-yl)-5-(3-methoxy Propoxy)phenyl)sulfonyl)-1H-pyrrol-3)yl)methyl)(methyl)carbamate (14-1)
- Step 2 Synthesis of 1-(5-(2-fluorophenyl)-1-((3-(3-methoxyprop-1-yn-1-yl)-5-(3-methoxypropoxy Base) phenyl) sulfonyl) -1H-pyrrol-3-yl) -N-methylmethylamine (II-14)
- Step 1 Synthesis of ethyl (E)-3-(5-((4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-2-(2-fluorophenyl)-1H- Pyrrol-1-yl)sulfonyl)pyridine-3-acrylate (15-2)
- Step 2 Synthesis of (E)-3-(5-((4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-2-(2-fluorophenyl)-1H-pyrrole- 1-yl)sulfonyl)pyridin-3-yl)acrylic acid (15-3)
- Step 3 Synthesis of tert-butyl (E)-((5-(2-fluorophenyl)-1-((5-(3-(methylamino)-3-oxoprop-1-ene-1- Base) pyridin-3-yl) sulfonyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate (15-4)
- Step 4 Synthesis of (E)-3-(5-((2-(2-fluorophenyl)-4-((methylamino)methyl)-1H-pyrrol-1-yl)sulfonyl)pyridine-3 -yl)-N-methacrylamide hydrochloride (II-15)
- K + -free buffer 50mM Tris-HCl pH 6.5, 5mM magnesium chloride, 10 ⁇ M valinomycin
- K + containing buffer 50mM Tris-HCl pH 6.5, 5mM magnesium chloride, 10 ⁇ M valinomycin, 20mM KCl MLG chromogenic solution: 0.1% w/v malachite green, 1.5% w/v ammonium molybdate, 0.2% v/v Tween-20
- Rabbit gastric mucosal microsomes (rich in H + /K + -ATPase), the extraction method is sucrose gradient centrifugation: wash the rabbit stomach with tap water and 3M NaCl solution, and then remove the surface water with filter paper. Add pre-cooled homogenization buffer (4ml/g tissue), and homogenize in a tissue homogenizer for 2-5min.
- tissue particles After homogenization, if there are larger tissue particles, they can be removed by centrifugation (600g, 10min), then move the supernatant to a clean centrifuge tube and centrifuge at 20,000g for 30min, then move the supernatant to a clean centrifuge tube for further Centrifuge at 100,000g for 90min to collect the precipitate; use the homogenate to suspend the precipitate, blow it evenly, measure the protein concentration by the Bradford method, adjust the concentration to 10mg/ml; (H + /K + -ATPaseenriched gastric membranes) were collected in a clean centrifuge tube, diluted 4-5 times with the homogenate, and centrifuged at 100,000 g for 90 minutes to collect the precipitate; the homogenate was used to suspend the sediment, homogenate evenly, and the protein was measured by the Bradford method Concentration, adjust the concentration to 22.5mg/ml. Freeze at -80°C for later use.
- the IC 50 value of the compound is calculated by the inhibition rate at different concentrations.
- the compound of the present invention has obvious inhibitory activity on H + /K + -ATPase, and the IC 50 is 20 to 100 nM, preferably 20 to 50 nM.
- the control group 1 is selected from Vonoprazan (Vonoprazan), and its preparation method refers to the patent CN101300229A; the control group 2 is selected from the group with the following structural formula.
- the compound of the present invention has obvious inhibitory activity on H + /K + -ATPase.
- DMEM Dulbecco's modified Eagle medium
- the cell line HepG2 derived from human liver cancer was cultured and subcultured at 5% and 37°C, and the cells in the logarithmic growth phase were collected, counted, and the cells were resuspended with complete medium, Adjust the cell concentration to an appropriate concentration (determined according to the results of the cell density optimization test), inoculate a 96-well plate, and add 75 ⁇ l/well cell suspension according to the following platemap. Dilute the compound to be tested with the culture medium to the corresponding effect concentration set, and add to the cells according to the platemap25 ⁇ l/well.
- DMEM Dulbecco's modified Eagle medium
- the concentration of the compounds to be tested starts from 100 ⁇ M, and is serially diluted 4 times, with a total of 9 concentrations and 2 duplicate wells.
- Cells were incubated at 37°C, 100% relative humidity, 5% CO 2 incubator for 24h. Add 50 ⁇ L/well CellTiter Glo RT and incubate for 30min in the dark. After shaking gently, detect in Envision and calculate the inhibition rate.
- cell growth inhibition rate% (1-As/Ac) ⁇ 100.
- IC 50 >20 ⁇ M is +++
- 20 ⁇ M>IC 50 >10 ⁇ M is ++
- 10 ⁇ M>IC 50 is +.
- liver microsomes from the desired species (eg, mouse, rat, dog, monkey, or human). Using DMSO as diluent, prepare 10mM sample stock solution and positive control stock solution. All stocks were then diluted to a working concentration of 0.25 mM with 70% acetonitrile.
- the cofactor used in this study is the NADPH regeneration system, which consists of 6.5mM NADP, 16.5mM G-6-P, and 3U/mL G-6-PD.
- the quenching reagent was a solution of tolbutamide and propranolol in acetonitrile.
- the buffer used in this study was 100 mM potassium phosphate buffer.
- a mixture containing 0.2 mg/mL liver microsomal protein and 1 ⁇ M test article/positive control was incubated in 100 mM potassium phosphate buffer.
- the compound of the present invention has T 1/2 (min)>80min, preferably T 1/2 (min)>100min in liver microsomes, and has good metabolic stability of liver microsomes.
- the compound under study was administered orally or intravenously (vehicle 5% DMSO+10% Solutol (HS-15)+85% saline) to animals (such as mice, rats, dogs or monkeys) at a fixed time point.
- Animal 5% DMSO+10% Solutol (HS-15)+85% saline Animal 5% DMSO+10% Solutol (HS-15)+85% saline
- Blood Immediately after blood sample collection, gently invert the tube at least 5 times to ensure thorough mixing and place on ice.
- the blood was anticoagulated with heparin, and then centrifuged at 8000pm for 5 minutes to separate the serum from the red blood cells. Aspirate the serum with a pipette and transfer it to a 2mL polypropylene tube, mark the name and time point of the compound, and store it in a -40°C refrigerator before LC-MS analysis for testing.
- CHO-hERG cells Chinese hamster ovary (CHO) cell line, CHO-hERG cells were used in this experiment.
- the complete medium is F12 medium, supplemented with 10% fetal bovine serum, 1% Selective antibiotic (G418), 89 ⁇ g/mL hygromycin B (HB).
- the recovery medium is F12 medium supplemented with 10% fetal bovine serum.
- CHO-hERG cells were grown in a high humidity incubator at 37°C ( ⁇ 2°C), 5% CO 2 (4% to 8%). Cells were revived with recovery medium, passaged in complete medium, and cells used for patch clamp experiments were replaced with recovery medium at the last passage.
- Reagent External fluid mM
- Internal fluid mM
- CaCl2 2 5.37 MgCl2 1 1.75
- KCl 4 120 NaCl 145 - Glucose 10 - HEPES 10 10 EGTA - 5 Na2ATP - 4 pH 7.3-7.4 7.2-7.3
- the hERG current was recorded under the whole-cell patch clamp technique, and the recording temperature was room temperature.
- the output signal of the patch clamp amplifier is converted by digital to analog and filtered by 2.9KHz low pass. Data records were collected with Patchmaster Pro software.
- the cell species is placed on the inverted microscope stage in the cell recording tank, and a cell in the recording tank is randomly selected for the test.
- the perfusion system was fixed on the inverted microscope stage and cells were continuously perfused with ECS.
- Electrodes for manual patch clamp experiments were prepared from capillary glass tubes filled with intracellular fluid. On the day of the patch clamp test, electrodes were prepared using borosilicate glass tubes (BF150-117-10, SUTTER INSTRUMENT USA). After the electrode is filled with ICS, the resistance is between 2-5M ⁇ .
- the clamping voltage was -80mV, the first step depolarized to +60mV and maintained for 850ms to open the hERG channel. Then, the voltage is set to -50mV and maintained for 1275ms, resulting in rebound current or tail current, the peak value of tail current will be measured and used for analysis. Finally, the voltage returns to the clamping voltage (-80mV). During the test, this command voltage program is repeated every 15s.
- cisapride was tested at a concentration of 0.1 [mu]M in duplicates of the cells. According to scientific literature reports, cisapride at 0.1 ⁇ M inhibits hERG current by more than 50%. (Milnes, J.T., et al.).
- a good whole-cell recording should meet the following conditions: path resistance (Rs) less than 10M ⁇ ; membrane resistance (Rm) greater than 500M ⁇ and membrane capacitance (Cm) less than 100pF.
- Leakage current Under the clamping voltage of -80mV, the absolute value of the leakage current should be less than 200pA. The current amplitude will be corrected for the leakage current at -80mV. Scanning curves whose absolute value of leakage current is greater than 200pA cannot be used for analysis.
- the percentage inhibition of each concentration of the test product and the positive control was calculated from the recorded current response using the following formula: (1- tail peak current recorded after perfusion of the test product/positive control/vehicle control perfusion Recorded tail peak current (initial current)) x 100%.
- IC 50 >20 ⁇ M is +++
- 20 ⁇ M>IC 50 >10 ⁇ M is ++
- 10 ⁇ M>IC 50 >1 ⁇ M is +.
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Abstract
涉及一类吡咯磺酰类衍生物、其制备方法及含有该衍生物的药物组合物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)中的用途。具体地,吡咯磺酰类衍生物结构通式如式(I)所示。
Description
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物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)的中用途。
中国有肠胃病患者1.2亿,包括幽门螺杆菌感染、胃食管返流、消化性溃疡、十二指肠溃疡、胃溃疡以及食管炎,消化道溃疡发病率为10%,慢性胃炎发病率为30%。长期的胃肠道疾病可逐渐发展成胃肠道癌,在全球六大高发癌症中,消化道相关肿瘤就占据了五个,包括胃癌,肝癌,食管癌,肠癌,胰腺癌。随着社会发展人们生活方式的转变,因吸烟、饮酒、情绪紧张、熬夜、药物刺激以及中国人嗜酸辣等饮食习惯引起的胃部相关疾病发病率正逐渐增高,消化性溃疡正在严重影响人们的工作和生活。现在医学界对其确切的发病机制还不清楚,但是抑制胃酸分泌已成为治疗此类疾病公认的首选方法。
1987年第一个质子泵抑制剂(Proton Pump Inhibitors,PPIs)奥美拉唑由AstraZenaca公司研制开发成功并在瑞典首次上市,是世界上第一个应用于临床,抑制胃酸作用最强的的质子泵抑制剂,用来治疗十二指肠溃疡、卓-艾综合征、胃溃疡和反流性食管炎。后续全球陆续上市数个PPIs产品。经过多年的临床应用,PPIs已经成为治疗胃酸相关性疾病的首选药物。质子泵(Proton Pump)又称胃酸泵,其实质为H
+/K
+-腺苷三磷酸酶(H
+/K
+-ATPase),是胃分泌H
+的最终共同途径,它存在于胃壁细胞分泌小管的细胞膜上,借助ATP降解供能进行H、K
+交换,特异性地将H泵入胃腔,形成胃内强酸状态。第一代PPIs对基础、夜间胃酸和五肽胃泌素、试餐等刺激的胃酸分泌有明显的抑制作用。但因在药动学及药效学方面的局限性,包括生物利用度、给药时间对药效的影响、夜间酸突破起效慢(Nocturnal acid breakthrough,NAB)、酸性条件下不稳定(经常需配制成肠制剂,需要数小时才能表现出效果)、对CYP450酶的依赖性(胃酸分泌抑制效果个体差异显著)等因素,影响了治疗效果与临床应用。与第一代PPIs相比,新一代PPIs在治疗胃食管返流病(Gastroesophageal Reflux Disease,GERD)及其他酸相关性疾病时具有明显优势。
钾竞争性酸阻滞剂(Potassium-Competitive Acid Blockers,P-CABs)作为一类新型抑酸剂,通过竞争性、可逆地结合H
+而抑制H
+/K
+-ATPase的活性,其作用机制明显不同于传统的PPIs,因此可称为酸泵阻滞剂。P-CABs具有亲脂性、弱碱性、解离常数高、半衰期长、在酸性时稳定、不主要由CYP2C19代谢,耐受性和依存性较好的特点。在酸性环境下,P-CABs立刻离子化,离子化形式通过离子型结合抑制H
+/K
+-ATPase,阻止H
+运送以及酸分 泌到胃腔中,不需要集中于胃壁细胞的微囊和微管及酸的激活,能迅速升高胃内pH值,离解后酶活性恢复。人和动物口服后能吸收迅速,达到血浆浓度的峰值。临床和动物实验也表明,P-CABs比PPIs或组胺受体2(Histamine receptor 2,H2)阻滞剂起效更快,升高pH的作用更强,血药浓度与口服给药剂量线性相关,提示该类药物可以比较容易地达到最佳抑酸状态,具有明显的优势。Takeda(武田)的富马酸沃诺拉赞(Vonoprazan Fumarate)2014年12月在日本获批;于2019年12月中国获批进口,并有部分P-CABs制剂已进入临床研究。
目前公开了一系列的P-CABs的专利申请,其中包括W02005041961,W02006134460,W02009041447或W02010021149等。
尽管目前已公开了一系列的P-CABs药物或化合物,但仍需要开发结构类型更丰富,具有更好药效和更安全的新化合物,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作用效果和良好的安全性。
发明内容
为了解决现有技术的上述问题,本发明的目的在于提供一种新的吡咯磺酰类衍生物、其互变异构体或其立体异构体,及其药学上可接受的盐、以筛选出在有效性、安全性和选择性等性能方面均具有优异性能的用作胃酸分泌抑制剂和钾离子竞争性酸阻滞剂(P-CABs)的化合物。
本发明的另一个目的是提供所述衍生物、其互变异构体或其立体异构体,及其其药学上可接受的盐、的制备方法。
为达到此发明目的,本发明采用以下技术方案:
第一方面,本发明提供一种吡咯磺酰类衍生物、其互变异构体或其立体异构体,及其药学上可接受的盐,所述吡咯磺酰类衍生物的结构如式(I)所示:
其中:
A为苯基或吡啶基;
虚线表示任选地键;
R
1选自H、C
1-6的烷基、C
3-12的环烷基、3-12元的杂环基、5-12元的芳基或5-12元的杂 芳基、C
1-6烷基-NH-C
1-6烷基、C
1-6烷基-O-C
1-6烷基、-C(=O)NHR
a、-C(=O)R
b、-S(=O)
m-C
1-6烷基;
其中,所述烷基、环烷基、杂环基、芳基或杂芳基可任选进一步被1-3个羟基、卤素、C
1-6烷基、C
1-6烷氧基所取代;
R
2选自H、C
1-6的烷基、C
1-6烷氧基、卤素、氰基、C
2-6炔基、C
2-6烯基、-O-C
1-6烷基-O-C
1-6烷基、-NR
cR
d;
R
3选自卤素、5-8元的芳基、5-8元的杂芳基、氰基、C
2-6炔基、C
2-6烯基、-O-C
1-6烷基-O-C
1-6烷基、-NR
cR
d;
或者两个R
3连同它们连接的碳原子一起形成稠环芳基,所述芳基、杂芳基和稠环芳基可任选地进一步被1-3个C
1-6烷基、C
1-6烷氧基、卤素、C
2-6炔基、C
2-6烯基、氰基、-O-C
1-6烷基-O-C
1-6烷基、-NR
cR
d所取代;
R
4选自C
1-6的烷基;其中所述烷基可任选地进一步被1-3个氘、卤素所取代;
n选自0、1、2、3;
m选自0、1、2;
R
a、R
b、R
c、R
d各自独立的选自C
1-6的烷基、C
1-6烷氧基、C
3-7的环烷基。
在一些实施例方案中:R
1选自H、C
1-6的烷基、C
3-12的环烷基、C
1-6烷基-NH-C
1-6烷基、C
1-6烷基-O-C
1-6烷基、-C(=O)NHR
a、-C(=O)OR
b;
其中,所述烷基、环烷基、杂环基、可任选进一步被卤素、C
1-6烷基所取代。
在一些实施例方案中:环A选自苯基;
R
1选自C
1-6烷基-NH-C
1-6烷基、C
1-6烷基-O-C
1-6烷基、C
3-12的环烷基或-C(=O)NHR
a。
在一些实施例方案中:所述吡咯磺酰类衍生物具有如式(Ⅱ)所示结构通式:
在一些优选的实施方案中,所述R
2选自H、C
1-6烷氧基、卤素。
在一些优选的实施方案中,所述R
3选自卤素;R
4选自C
1-6的烷基。
在一些优选的实施方案中,所述吡咯磺酰类衍生物具有如式(Ⅲ)所示结构通式:
本发明提供的吡咯磺酰类衍生物其药学上可接受的盐,所述的盐可为盐酸盐或三氟乙酸盐。
进一步的,本发明所述吡咯磺酰类衍生物可选自如下结构的任意一种:
另一方面,本发明提供一种药物组合物,所述药物组合物包括如上所述的吡咯磺酰类衍生物、其互变异构体或其立体异构体,及其药学上可接受的盐和可药用载体和/或赋形剂。
另一方面,本发明提供一种如第一方面所述的吡咯磺酰类衍生物、其互变异构体或其立体异构体,及其药学上可接受的盐如第三方面所述的药物组合物在制备胃酸分泌抑制剂、H
+/K
+-ATPase抑制剂或钾离子竞争性酸阻滞剂中的用途。
本发明提供一种如上所述吡咯磺酰类衍生物、其互变异构体或其立体异构体,及其药学上可接受的盐或如上所述的药物组合物在制备治疗或预防如下疾病用药物中的用途:消化性溃疡、卓-艾综合征、胃糜烂性食管炎、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、手术后应激导致的胃酸过多或手术后应激导致的溃疡的药物中的用途;或者在制备抑制消化性溃疡、急应激性溃疡、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。本发明提供的吡咯磺酰类衍生物毒副作用小,具有优异的安全性;同时具有较好的药代动力学性质,半衰期较长,有更持续的抑酸效果,有望对夜间酸突破现象有更好的改善作用。
术语解释
除非有相反陈述,否则本发明在说明书和权利要求书中所使用的部分术语定义如下:
“环烷基”是指饱和或部分不饱和单环或多环环状烃取代基,环烷基环包括3至20个碳原子,优选包括3至12个碳原子,更优选包含3至6个碳原子。单环环烷基的非限制性实施例包括,但不限于环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等;多环环烷基包括螺环、稠环和桥环的环烷基。环烷基可以是任选取代的或未取代的。
“杂环基”、“杂环”或“杂环的”在本申请中可交换使用,本申请中可交换使用,都是指包含3-12个环原子的饱和或部分不饱和的单环、双环或三环的非芳香性杂环基,其中至少一个环原子原子是杂原子,如氧、氮、硫原子等。优选具有5至7元单环或7至10元双-或三环,其可以包含1,2或3个选自氮、氧和/或硫中的原子。“杂环基”的实例包括但不限于吗啉基,氧杂环丁烷基,硫代吗啉基,四氢吡喃基,1,1-二氧代-硫代吗啉基,哌啶基,2-氧代-哌啶基,吡咯烷基,2-氧代-吡咯烷基,哌嗪-2-酮,8-氧杂-3-氮杂-双环[3.2.1]辛基和哌嗪基。所述杂环基环可以稠合于芳基、杂芳基或环烷基环上,其中与母体结构连接在一起的环为杂环基。杂环基可以是任选取代的或未取代的。
“芳基”是指含有一个或者两个环的碳环芳香系统,其中所述环可以以稠合的方式连接在一起。术语“芳基”包括比如苯基、萘基、四氢萘基的芳香基团。优选芳基为C
6-
10芳基,更优选芳基为苯基和萘基,最优选为苯基。芳基可以是取代或未取代的。所述“芳基”可与杂芳基、杂环基或环烷基稠合,其中与母体结构连接在一起的为芳基环,非限制性实施例包括但不限于:
“杂芳基”是指芳香族5至6元单环或9至10元双环,其可以包含1至4个选自氮、氧和/或硫中的原子。“杂芳基”的实施例包括但不限于呋喃基,吡啶基,2-氧代-1,2-二氢吡啶基、哒嗪基、嘧啶基、吡嗪基、噻吩基、异噁唑基、噁唑基、噁二唑基、咪唑基、吡咯基、吡唑基、三唑基、四唑基、噻唑基、异噻唑基、1,2,3-噻二唑基、苯并间二氧杂环戊烯基、苯并咪唑基、吲哚基、异吲哚基、1,3-二氧代-异吲哚基、喹啉基、吲唑基、苯并异噻唑基、苯并噁唑基和苯并异噁唑基。杂芳基可以是任选取代或未取代的。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上,其中与母体结构连接在一起的环为杂芳基环,非限制性实施例 包括但不限于:
“任选”意味着其所描述的事件可以但不必发生。例如,“A任选地被1到多个R
2取代”该说明包含着A基团可以被1到多个R
2取代或者不被R
2取代的情形。
本发明提供了一种新结构的吡咯磺酰类衍生物,试验结果表明,该吡咯磺酰类衍生物表现出优异的胃酸分泌抑制和钾离子竞争性酸阻滞剂(P-CABs)活性,可用于制备治疗或预防消化性溃疡、卓一艾综合征、胃糜烂性食管炎、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、手术后应激导致的胃酸过多或手术后应激导致的溃疡的药物;或者在制备抑制肖化性溃疡、急应激性溃疡、出血性胃炎或侵入性应激造成的上消化道出血的药物。本发明提供的吡咯磺酰类衍生物毒副作用小,具有优异的安全性;同时具有较好的药代动力学性质,半衰期较长,有更持续的抑酸效果,有望对夜间酸突破现象有更好的改善作用。
图1为手动膜片钳hERG电流测试指令电压程序。
下面通过具体实施例对本发明的方法进行说明,以使本发明技术方案更易于理解、掌握,但本发明并不局限于此。下述实施例中
1HNMR图谱是用Bruker仪器(400MHz)测定而得,化学位移用ppm表示。使用四甲基硅烷内标准(0.00ppm)。
1HNMR的表示方法:s=单峰,d=双重峰,t=三重峰,q=四重峰,m=多重峰,br=变宽的,dd=双重峰的双重峰,dt=三重峰的双重峰。若提供偶合常数时,其单位为Hz。
质谱是用LC/MS仪测定得到,离子化方式为ESI。
在下列实例中,除非另有指明,所有温度为摄氏温度,除非另有指明,各种起始原料和试剂来自市售或者是根据已知的方法合成,市售原料和试剂均不经进一步纯化直接使用。
CD
3OD:氘代甲醇;
CDCl
3:氘代氯仿;
DMSO-d
6:氘代二甲基亚砜;
氢气氛围是指反应瓶连接一个约1L容积的氢气气球。
实施例中无特殊说明,反应中的溶液是指水溶液。
实施例中无特殊说明,反应的温度为室温,为20℃-30℃。
中间体的制备
中间体Int 1的合成
步骤1:合成1-(5-(2-氟苯基)-1H-吡咯-3-基)-N-甲基甲胺(Int 1-2)
在室温下,将化合物Int 1-1(3.8g,20.1mmol)溶于30%甲胺醇溶液(20mL),搅拌1小时后,分批加入NaBH
4(2.3g,60.3mmol),继续搅拌1小时。加水(20mL),用乙酸乙酯(100mL)萃取,有机相用饱和食盐水(50mL)洗涤,用无水硫酸钠干燥,过滤后减压浓缩,得到黄色固体4.1g,产率:97.6%。
步骤2:合成((5-(2-氟苯基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸叔丁酯(Int 1-3)
在室温下,将化合物Int 1-2(4.1g,20.6mmol)溶于二氯甲烷(50mL),分别加入三乙胺(11mL,78.9mmol),Boc
2O(9.0g,41.2mmol)。在室温下反应2小时,减压浓缩,粗品用柱层析分离纯化(正己烷/乙酸乙酯),得到白色固体5.2g,产率82.5%。
步骤3:合成叔丁基((1-((3-溴苯基)磺酰基)-5-(2-氟苯基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯(Int 1)
室温下,将化合物Int 1-3(3g,9.86mmol)溶于DMF(50mL)中,冷至0℃,加入氢化钠(600mg,14.8mmol),室温搅拌10分钟后,加入3-溴苯磺酰氯(3g,11.8mmol)。继续反应1小时,加水(50mL)猝灭反应,用乙酸乙酯(100mL)萃取,有机相用饱和食盐水(100mL)洗涤,无水硫酸钠干燥,过滤后减压浓缩,粗品用柱层析分离纯化(正己烷/乙酸乙酯),得到白色固体4.8g,产率93.0%。
中间体Int 2的合成
合成叔丁基((1-((5-溴吡啶-3-基)磺酰基)-5-(2-氟苯基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯(Int 2)
在冰浴下,将化合物Int 1-3(3.0g,9.87mmol)溶解在DMF(40ml)中,然后加入NaH(789mg,19.71mmol),搅拌半个小时,然后加入化合物Int 2-1(3.03g,11.83mmol),继续搅拌2h。反应完全后,加入乙酸乙酯(150mL)稀释,用饱和食盐水(100mL)洗涤两次,有机相用无水硫酸钠干燥,过滤,减压浓缩,通过柱层析(PE/EA=3:1)纯化得到4.5g黄色油状化合物,产率87.2%。
中间体Int 3的合成
步骤1:合成1-(5-溴-1H-吡咯-3-基)-N-甲基甲胺(Int 3-2)
在室温下,将化合物Int 3-1(5.0g,28.74mmol)溶解在甲胺的甲醇溶液(50mL)中,室温搅拌2h,然后冰水浴冷却,加入硼氢化钠(2.2g,57.47mmol),继续搅拌2h。待反应完成后,加入饱和氯化铵的水溶液淬灭反应,用二氯甲烷(100mL×2)萃取,合并有机相用饱和食盐水(150mL×1)洗涤,有机相用无水硫酸钠干燥,过滤,减压浓缩,得到5.43g 的黄色油状化合物,没有纯化直接进行下一步反应,[M+H]
+:189.1。
步骤2:合成叔丁基((5-溴-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯(Int 3-3)
在室温下,将化合物Int 3-2(15.43g,28.72mmol)和三乙胺(7.98mL,57.44mmol)溶解在二氯甲烷(50mL)中,然后缓慢加入Boc
2O(7.52g,34.47mmol),室温搅拌3h。待反应结束后,将反应液减压浓缩,通过柱层析(PE/EA=5:1)纯化得到8.2g无色油状化合物,产率98.60%,[M+H]
+:289.1。
步骤3:合成叔丁基((5-(2,4-二氟苯基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯(Int 3-5)
将化合物Int 3-3(8.0g,27.67mmol),Int 3-4(8.0g,33.20mmol),Pd(dppf)Cl
2(2.1g,2.77mmol),和碳酸钾(9.6g,69.16mmol)溶解在1,4-二氧六环和水(80/16mL)中,在氮气保护下,115℃下搅拌4h。待反应完成后,用二氯甲烷(100mL×2)萃取,合并有机相用饱和食盐水(150mL×1)洗涤,有机相用无水硫酸钠干燥,过滤,减压浓缩,通过柱层析(PE/EA=3:1)纯化得到6.2g棕色油状化合物,产率69.66%,[M+H]
+:323.2。
步骤4:合成叔丁基((1-((3-溴苯基)磺酰基)-5-(2,4-二氟苯基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯(Int 3)
在冰浴下,将化合物Int 3-5(2.0g,6.20mmol)溶解在DMF(15mL)中,加入氢化钠(373mg,9.31mmol),搅拌30分钟,然后向反应体系中加入化合物Int 3-6(1.9g,7.45mmol),继续搅拌2h。待反应完成后,加入饱和氯化铵的水溶液淬灭反应,用乙酸乙酯(30mL×2)萃取,合并有机相用饱和食盐水(50mL×1)洗涤,有机相用无水硫酸钠干燥,过滤,减压浓缩,通过柱层析(PE/EA=3:1)纯化得到3.0g棕色油状化合物,产率89.55%。
中间体Int 4的合成
步骤1:合成1,3-二溴-5-(3-甲氧基丙氧基)苯(Int 4-3)
在室温下,将化合物Int 4-1(3.0g,11.90mmol),Int 4-2(1.55g,14.28mmol)和碳酸钾(4.11g,29.78mmol)溶解在DMF(30mL)中,100℃下搅拌过夜。反应完全后,加水(100mL),用乙酸乙酯(50mL×2)萃取,合并有机相,用无水硫酸钠干燥,过滤,滤液通过减压浓缩,柱层析分离纯化(PE/EA=5:1)得到无色油状化合物3.5g,产率92.11%。
步骤2:合成苄基(3-溴-5-(3-甲氧基丙氧基)苯基)硫烷(Int 4-5)
在室温下,将化合物Int 4-3(3.5g,10.80mmol),Int 4-4(1.34g,10.80mmol),Pd
2(dba)
3,(495mg,0.54mmol),xantphos(313mg,0.54mmol)和DIEA(3.5g,27.13mmol)溶解在甲苯(40mL)中,100℃下搅拌4h。反应完全后,减压浓缩,柱层析分离纯化(PE/EA=10:1)得到无色油状化合物3.0g,产率75.02%。
步骤3:合成3-溴-5-(3-甲氧基丙氧基)苯磺酰氯(Int 4-7)
在室温下,将化合物Int 4-5(2.5g,6.81mmol),Int 4-6(2.68g,13.61mmol)溶解在乙腈(69mL),水(4.15mL)和乙酸(4.15mL)的溶液中,室温下反应1h,反应完全后,加水(100mL),用乙酸乙酯(50mL×2)萃取,合并有机相,用无水硫酸钠干燥,过滤,滤液通过减压浓缩,柱层析分离纯化(PE/EA=5:1)得到黄色油状物1.1g,产率47.03%,[M+H]
+:344.9。
步骤4:合成叔丁基((1-((3-溴-5-(3-甲氧基丙氧基)苯基)磺酰基)-5-(2-氟苯基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯(Int 4)
在室温下,将氢化钠(160.4mg,4.00mmol)加入到DMF(20mL)溶液。化合物Int 1-3(811.93mg,2.67mmol)加入到上述溶液中,室温下搅拌0.5h。将化合物Int 4-7(1.1g,3.20mmol)缓慢加入到反应溶液中,氮气保护下,室温反应2h,反应完全后,加水(100mL),用乙酸乙酯(30mL×2)萃取,合并有机相,用无水硫酸钠干燥,过滤,滤液通过减压浓缩,柱层析分离纯化(PE/EA=3:1)得到黄色稠状固体600mg,产率36.87%,[M+H]
+:613.1。
实施例1
1-(5-(2-氟苯基)-1-((3-(3-甲氧基丙-1-炔-1-基)苯基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺盐酸盐(Ⅱ-1)的合成
步骤1:合成叔丁基((5-(2-氟苯基)-1-((3-(3-甲氧基丙-1-炔-1-基)苯基)磺酰基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯(1-2)
于封管中加入化合物Int 1(260mg,0.5mmol),化合物1-1(70mg,1mmol),Pd(PPh
3)
2Cl
2(35mg,0.05mmol),CuI(19mg,0.1mmol),TEA(150mg,1.5mmol),DMF(3mL),搅拌,氮气置换3次,升温至80℃搅拌4h。TLC点板监测,反应完全,有新点产生(PE/EA=3/1,Rf=0.3)。加入水30mL,乙酸乙酯(30mL×2)萃取,有机相合并,饱和食盐水(30mL)水洗一次,有机相无水硫酸钠干燥,控温45℃减压浓缩,柱层析分离,(PE/EA=3:1淋洗)得220mg无色油状物。
步骤2:合成1-(5-(2-氟苯基)-1-((3-(3-甲氧基丙-1-yn-1-基)苯基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺盐酸盐(II-1)
在室温下,于反应瓶中加入化合物1-2(220mg),二氯甲烷(10mL),搅拌溶解,加入4M盐酸/1,4-二氧六环(4mL),室温反应1h,TLC点板监测,反应完全,有新点产生(DCM/MeOH=10:1,Rf=0.2)。旋干,加入正己烷,有固体析出,过滤,抽干,得100mg类白色固体。
1HNMR:(400MHz,DMSO-d
6)δ9.15(s,2H),7.85-7.78(m,2H),7.60(t,J=8.0Hz,1H),7.56-7.47(m,2H),7.36(s,1H),7.28-7.19(m,2H),7.08(t,J=1.6Hz,1H),6.57(s,1H),4.36(s,2H),3.99(s,2H),3.36(s,3H),3.34(s,3H).
实施例2
1-(5-(2-氟苯基)-1-((5-(3-甲氧基丙-1-炔-1-基)吡啶-3-基)磺酰基)-1H-吡咯-3-基)-N-甲胺盐酸盐(Ⅱ-2)的合成
步骤1:合成叔丁基((5-(2-氟苯基)-1-((5-(3-甲氧基丙-1-炔-1-基)吡啶-3-基)磺酰基)-1H-吡咯-3-基)甲基))(甲基)氨基甲酸酯(2-2)
于封管中加入化合物Int 2(260mg,0.5mmol),1-1(70mg,1mmol),Pd(PPh
3)
2Cl
2(35mg,0.05mmol),CuI(19mg,0.1mmol),TEA(150mg,1.5mmol),DMF(3mL),搅拌,氮气置换3次,升温至80℃搅拌4h。TLC点板监测,反应完全,有新点产生(PE/EA=3/1,Rf=0.3)。加入水30mL,乙酸乙酯(30mL×2)萃取,有机相合并,饱和食盐水(30mL)水洗一次,有机相无水硫酸钠干燥,控温45℃减压浓缩,柱层析分离(PE/EA=3:1淋洗)得220mg褐色油状物。
步骤2:合成1-(5-(2-氟苯基)-1-((5-(3-甲氧基丙-1-炔-1-基)吡啶-3-基)磺酰基)-1H-吡咯-3-基)-N-甲胺盐酸盐(II-2)
在室温下,于反应瓶中加入化合物2-2(220mg),二氯甲烷(10mL),搅拌溶解,加入4M盐酸/1,4-二氧六环(4mL),室温反应1h,TLC点板监测,反应完全,有新点产生(DCM/MeOH=10/1,Rf=0.2)。旋干,加入乙酸乙酯(2mL)溶清,加入正己烷(10mL),有固体析出,过滤,抽干,得130mg褐色固体。
1HNMR:(400MHz,DMSO-d
6)δ9.17(s,2H),8.99(s,1H),8.55(s,1H),7.87(d,J=1.6Hz,2H),7.60-7.53(m,1H),7.32-7.22(m,2H),7.13(t,J=7.2,1H),6.62(s,1H),4.40(s,2H),4.00(s,2H),3.57(s,3H),3.37(s,3H).
实施例3
4-(5-((2-(2-氟苯基)-4-((甲氨基)甲基)-1H-吡咯-1-基)磺酰基)吡啶-3-基)-2-甲基丁-3-炔-2-醇(Ⅱ-3)的合成
步骤1:合成叔丁基((5-(2-氟苯基)-1-((5-(3-羟基-3-甲基丁-1-炔-1-基)吡啶-3-基)磺酰基)-1H吡咯-3-基)甲基)(甲基)氨基甲酸酯(3-2)
于封管中加入化合物Int 2(210mg,0.4mmol),化合物3-1(68mg,0.8mmol),Pd(PPh
3)
2Cl
2(28mg,0.04mmol),CuI(16mg,0.08mmol),TEA(122mg,1.2mmol),DMF(3mL),搅拌,氮气置换3次,升温至80℃搅拌4h。TLC点板监测,反应完全,有新点产生(PE/EA=3:1, Rf=0.3)。加入水30mL,乙酸乙酯(30mL×2)萃取,有机相合并,饱和食盐水(30mL)水洗一次,有机相无水硫酸钠干燥,控温45℃减压浓缩,柱层析分离(PE/EA=3:1)得200mg无色油状物。
步骤2:合成4-(5-((2-(2-氟苯基)-4-((甲氨基)甲基)-1H-吡咯-1-基)磺酰基)吡啶-3-基)-2-甲基丁-3-炔-2-醇(II-3)
在室温下,于反应瓶中加入化合物3-2(200mg),二氯甲烷(4mL),搅拌溶解,加入4M盐酸/1,4-二氧六环(2mL),室温反应1h,TLC点板监测,反应完全,有新点产生(DCM/MeOH=10:1,Rf=0.2)。加入碳酸氢钠水溶液调节pH到8,乙酸乙酯萃取,有机相饱和食盐水水洗2次,无水硫酸钠干燥,TLC板分离,得50mg褐色固体。
1HNMR:(400MHz,CD
3OD)δ8.78(s,1H),8.49(s,1H),7.70(s,1H),7.57(s,1H),7.55-7.49(m,1H),7.28-7.21(m,1H),7.18-7.10(m,2H),6.39(s,1H),3.70(s,2H),2.44(s,3H),1.60(s,6H).
实施例4
1-(1-((5-(环丙基乙炔基)吡啶-3-基)磺酰基)-5-(2-氟苯基)-1H-吡咯-3-基)-N-甲基甲胺(Ⅱ-4)的合成
步骤1:合成叔丁基((1-((5-(环丙基乙炔基)吡啶-3-基)磺酰基)-5-(2-氟苯基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯(4-2)
于封管中加入化合物Int 2(210mg,0.4mmol),化合物4-1(53mg,0.8mmol),Pd(PPh
3)
2Cl
2(28mg,0.04mmol),CuI(16mg,0.08mmol),TEA(122mg,1.2mmol),DMF(3mL),搅拌,氮气置换3次,升温至80℃搅拌4h。TLC点板监测,反应完全,有新点产生(PE/EA=3:1,Rf=0.3)。加入水30mL,乙酸乙酯(30mL×2)萃取,有机相合并,饱和食盐水(30mL)水洗一次,有机相无水硫酸钠干燥,控温45℃减压浓缩,柱层析分离(PE/EA=3:1)得200mg褐色油状物。
步骤2:合成1-(1-((5-(环丙基乙炔基)吡啶-3-基)磺酰基)-5-(2-氟苯基)-1H-吡咯-3-基)-N-甲基甲胺(II-4)
在室温下,于反应瓶中加入化合物4-2(200mg),二氯甲烷(4mL),搅拌溶解,加入4M盐酸/1,4-二氧六环(2mL),室温反应1h,TLC点板监测,反应完全,有新点产生(DCM/MeOH=10:1,Rf=0.2)。加入碳酸氢钠水溶液调节pH到8,乙酸乙酯萃取,有机相饱和食盐水水洗2次,无水硫酸钠干燥,TLC板分离,得80mg褐色油。
1HNMR:(400MHz,CD
3OD)δ8.71(s,1H),8.41(s,1H),7.66(s,1H),7.60(s,1H),7.54-7.48(m,1H),7.22-7.09(m,3H),6.38(s,1H),3.70(s,2H),2.44(s,3H),1.60-1.50(m,1H),1.03-0.95(m,2H),0.88-0.81(m,2H).
实施例5
1-(5-(2-氟苯基)-1-((3-(3-甲基丁-1-炔-1-基)苯基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺(Ⅱ-5)的合成
步骤1:合成叔丁基((5-(2-氟苯基)-1-((3-(3-甲基丁-1-炔-1-基)苯基)磺酰基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯(5-1)
氮气保护室温下,将化合物Int 1(500mg,0.960mmol)溶于DMF(5mL)中,分别加入Pd(PPh
3)
2Cl
2(67mg,0.096mmol),CuI(19mg,0.096mmol),三乙胺(0.5mL,3.84mmol)和3-甲基丁-1-炔(260mg,3.84mmol)封管加热至80℃搅拌过夜。反应完全后反应液减压浓缩,粗品用柱层析分离纯化(正己烷/乙酸乙酯),得到黄色油状物400mg,产率81.6%。
步骤2:合成1-(5-(2-氟苯基)-1-((3-(3-甲基丁-1-炔-1-基)苯基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺(II-5)
在室温下,将化合物5-1(400mg,0.783mmol)溶于二氯甲烷(4mL)中,加入4M盐酸/1,4-二氧六环(2mL),室温下反应1小时。减压浓缩,加水(5mL),用饱和NaHCO
3溶液调节pH=7-8,用乙酸乙酯(20mL)萃取,有机相用饱和食盐水(10mL)洗涤,无水硫酸钠干燥,过滤后减压浓缩,粗品用柱层析分离纯化(DCM/MeOH),得到黄色油状物100mg,产率31.2%。
1HNMR:(400MHz,CDCl
3)δ7.51-7.49(m,1H),7.42-7.30(m,3H),7.29-7.28(m, 1H),7.26-7.24(m,1H),7.17-7.10(m,2H),7.07-7.03(m,1H),6.22(s,1H),3.62(s,2H),2.80-2.73(m,1H),2.45(s,3H),1.26(d,J=6.8Hz,6H).
实施例6
4-(3-((2-(2-氟苯基)-4-((甲氨基)甲基)-1H-吡咯-1-基)磺酰基)苯基)-2-甲基丁-3-炔-2-醇(Ⅱ-6)的合成
步骤1:合成叔丁基((5-(2-氟苯基)-1-((3-(3-羟基-3-甲基丁-1-炔-1-基)苯基)磺酰基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯(6-1)
于封管中加入化合物Int 1(210mg,0.4mmol),化合物3-1(68mg,0.8mmol),Pd(PPh
3)
2Cl
2(28mg,0.04mmol),CuI(16mg,0.08mmol),TEA(122mg,1.2mmol),DMF(3mL),搅拌,氮气置换3次,升温至80℃搅拌4h。TLC点板监测,反应完全,有新点产生(PE/EA=3:1,Rf=0.3)。加入水30mL,乙酸乙酯(30mL×2)萃取,有机相合并,饱和食盐水(30mL)水洗一次,有机相无水硫酸钠干燥,控温45℃减压浓缩,柱层析分离,(PE/EA=3:1)得200mg无色油状物。
步骤2:合成4-(3-((2-(2-氟苯基)-4-((甲氨基)甲基)-1H-吡咯-1-基)磺酰基)苯基)-2-甲基丁-3-炔-2-醇(II-6)
在室温下,于反应瓶中加入化合物6-1(200mg),二氯甲烷(4mL),搅拌溶解,加入4M盐酸/1,4-二氧六环(2mL),室温反应1h,TLC点板监测,反应完全,有新点产生(DCM/MeOH=10:1,Rf=0.2)。加入碳酸氢钠水溶液调节pH到8,乙酸乙酯(20mL×2)萃取,合并有机相饱和食盐水(20mL×2)水洗,无水硫酸钠干燥,过滤,滤液浓缩TLC板分离,得50mg褐色固体。
1HNMR:(400MHz,CD
3OD)δ7.69(s,1H),7.68-7.63(m,1H),7.55-7.44(m,3H),7.33(s,1H),7.21(t,J=8.0Hz,1H),7.16-7.06(m,2H),6.39(s,1H),3.95(s,2H),2.61(s,3H),1.59(s,6H).
实施例7
1-(5-(2-氟苯基)-1-((3-(3-甲氧基丙-1-烯-1-基)苯基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺(Ⅱ-7) 的合成
步骤1:合成叔丁基((5-(2-氟苯基)-1-((3-(3-甲氧基丙-1-烯-1-基)苯基)磺酰基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯(7-1)
在室温下,将化合物1-2(500mg,0.98mmol)溶解在乙酸乙酯(8mL)中,然后加入Pd/C(50mg),在H
2体系下,室温搅拌过夜,待反应完成后,过滤,滤液浓缩,通过反相制备纯化得到400mg无色油状化合物,产率79.68%。
步骤2:合成1-(5-(2-氟苯基)-1-((3-(3-甲氧基丙-1-烯-1-基)苯基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺(II-7)
在室温下,将化合物7-1(400mg,0.78mmol)溶解在二氯甲烷(5mL)溶液中,加入4M盐酸/1,4-二氧六环(5mL),搅拌两小时,待反应完全后,浓缩,通过反相制备纯化得到92mg黄色油状化合物,产率28.57%,纯度>95%,[M+H]
+:415.1。
1HNMR:(400MHz,CDCl
3)δ7.49(s,1H),7.40-7.33(m,4H),7.23(s,1H),7.16-7.09(m,2H),7.01(t,J=9.2Hz,1H),6.48(d,J=11.6Hz,1H),6.34(s,1H),5.96-5.92(m,1H),4.03(d,J=6.4Hz,2H),3.75(s,2H),3.35(s,3H),2.50(s,3H).
实施例8
(E)-1-(1-((3-(2-环丙基乙烯基)苯基)磺酰基)-5-(2-氟苯基)-1H-吡咯-3-基)-N-甲基甲胺盐酸盐(Ⅱ-8)的合成
步骤1:合成(E)-((1-((3-(2-环丙基乙烯基)苯基)磺酰基)-5-(2-氟苯基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸叔丁酯(8-2)
将化合物Int 1(300mg,0.57mmol),8-1(223mg,1.15mmol),Pd(dppf)Cl
2(42mg,0.06mmol)和碳酸钾(198mg,1.44mmol)溶解在1,4-二氧六环和水的混合(10/2mL)溶液中,在氮气保护下,100℃搅拌过夜。反应完全后,加入乙酸乙酯(20mL)稀释,用饱和食盐水(20mL×2)洗涤,有机相用无水硫酸钠干燥,过滤,减压浓缩,通过柱层析(PE/EA=3:1)纯化得到250mg黄色油状化合物,产率85.62%。
步骤2:合成(E)-1-(1-((3-(2-环丙基乙烯基)苯基)磺酰基)-5-(2-氟苯基)-1H-吡咯-3-基)-N-甲基甲胺盐酸盐(II-8)
在室温下,将化合物8-2(250mg,0.49mmol)溶解在二氯甲烷(3mL)溶液中,加入4M盐酸/1,4-二氧六环(3mL),搅拌两小时,待反应完全后,过滤得到140mg棕色固体化合物,产率70.01%,纯度>95%,[M+H]
+:411.1。
1HNMR:(400MHz,CD
3OD)δ7.77(s,1H),7.59(d,J=7.6Hz,1H),7.52-7.48(m,1H),7.38(t,J=8.0Hz,1H),7.32-7.29(m,1H),7.26(s,1H),7.17(t,J=7.6Hz,1H),7.12-7.06(m,2H),6.40(d,J=15.6Hz,1H),6.39(s,1H),5.76(q,J=9.2Hz,1H),4.10(s,2H),2.70(s,3H),1.63-1.59(m,1H),0.92-0.87(m,2H),0.60-0.56(m,2H).
实施例9
(E)-3-(3-((2-(2-氟苯基)-4-((甲氨基)甲基)-1H-吡咯-1-基)磺酰基)苯基)-N-甲基丙烯酰胺2,2,2-三氟乙酸盐(Ⅱ-9)的合成
步骤1:合成(E)-3-(3-((4-(((叔丁氧基羰基)(甲基)氨基)甲基)-2-(2-氟苯基)-1H-吡咯-1-基)磺酰基)苯基)丙烯酸乙酯(9-2)
将化合物Int 1(200mg,0.38mmol),9-1(90mg,0.57mmol),Pd(dppf)Cl
2(28mg,0.04mmol)和碳酸钾(132mg,0.96mmol)溶解在二氧六环和水(10/2mL)溶液中,在氮气保护下,100℃搅拌过夜。反应完全后,加入乙酸乙酯(20mL)稀释,用饱和食盐水(20mL×2)洗涤两次,有机相用无水硫酸钠干燥,过滤,减压浓缩,通过柱层析(PE/EA=1:1)纯化得到180mg黄色油状化合物,产率86.96%。
步骤2:合成(E)-3-(3-((4-(((叔丁氧基羰基)(甲基)氨基)甲基)-2-(2-氟苯基)-1H-吡咯-1-基)磺酰基)苯基)丙烯酸(9-3)
在室温下,将化合物9-2(500mg,0.92mmol),溶解在甲醇(10mL)溶液中,然后加 入LiOH(45mg,1.84mmol)的水溶液(5mL),室温搅拌过夜。浓缩移除甲醇溶剂,调节溶液pH=6,用二氯甲烷(20mL×3)萃取,有机相用无水硫酸钠干燥,过滤,减压浓缩得到黄色固体450mg,产率95.14%,[M+H]
+:515.2。
步骤3:合成叔丁基(E)-((5-(2-氟苯基)-1-((3-(3-(甲基氨基)-3-氧代丙-1-烯-1-基)苯基)磺酰基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯(9-5)
在室温下,将化合物9-3(450mg,0.87mmol),9-4(90mg,1.32mmol),HATU(399mg,1.05mmol)和DIEA(337mg,2.61mmol)溶解在DMF(6mL)溶液中,室温搅拌过夜。加水(20mL),用乙酸乙酯(15mL×2)萃取,合并有机相,用无水硫酸钠干燥,过滤,滤液通过减压浓缩,柱层析分离纯化(乙酸乙酯)得到黄色固体300mg,产率65.22%,[M+H]
+:528.2。
步骤4:合成(E)-3-(3-((2-(2-氟苯基)-4-((甲氨基)甲基)-1H-吡咯-1-基)磺酰基)苯基)-N-甲基丙烯酰胺2,2,2-三氟乙酸盐(II-9)
在室温下,将化合物9-5(250mg,0.47mmol)溶解在二氯甲烷(2mL)溶液中,然后加入4M盐酸/1,4-二氧六环(2mL)室温搅拌2h。加水(5mL)稀释,调节pH=8,二氯甲烷(15mL×2)萃取,合并有机相,用无水硫酸钠干燥,过滤,滤液通过减压浓缩,反相制备(5-100%乙腈/水(0.1%TFA))纯化得到白色固体60mg,产率23.44%,[M+H]
+:428.2。
1HNMR:(400MHz,CD
3OD)δ7.87(d,J=8.0Hz,1H),7.80(s,1H),7.56-7.48(m,4H),7.42(d,J=15.6Hz,1H),7.18(t,J=7.6Hz,1H),7.11-7.06(m,2H),6.54(d,J=16.0Hz,1H),6.40(s,1H),4.11(s,2H),2.88(s,3H),2.73(s,3H).
实施例10
3-(3-((2-(2-氟苯基)-4-((甲氨基)甲基)-1H-吡咯-1-基)磺酰基)苯基)-N-甲基丙-2-炔-1-胺(Ⅱ-10)的合成
步骤1:合成叔丁基((5-(2-氟苯基)-1-((3-(3-(甲基氨基)丙-1-炔-1-基)苯基)磺酰基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯(10-1)
在室温下,将化合物Int 1(200mg,0.382mmol)溶于THF(4mL),依次加入N-甲基丙-2-炔-1-胺(106mg,1.53mmol),Pd(PPh
3)
2Cl
2(27mg,0.038mmol),CuI(15mg,0.076mmol)和三乙胺(0.5mL)。N
2置换后将反应液密封,升温至80℃搅拌过夜。反应完全后,浓缩溶剂,柱层析分离纯化(石油醚/乙酸乙酯=10:1-1:1),得到黄色固体150mg,产率76.70%,[M+H]
+:512.7。
步骤2:合成3-(3-((2-(2-氟苯基)-4-((甲氨基)甲基)-1H-吡咯-1-基)磺酰基)苯基)-N-甲基丙-2-炔-1-胺(II-10)
在室温下,将化合物10-1(140mg,0.274mmol)溶于1,4-二氧六环(3mL)中,加入4M盐酸/1,4-二氧六环(3mL),室温反应1小时后,浓缩溶剂,粗品用正乙烷/乙酸乙酯打浆纯化,得到灰色固体100mg,产率81.39%,[M+H]
+:412.6。
1HNMR:(400MHz,CD
3OD)δ7.80-7.77(m,2H),7.54-7.51(m,3H),7.48(s,1H),7.22-7.18(m,1H),7.11-7.07(m,2H),6.42(d,J=2.0Hz,1H),4.20(s,2H),4.11(s,2H),2.83(s,3H),2.71(s,3H).
实施例11
1-(5-(2,4-二氟苯基)-1-((3-(3-甲氧基丙-1-炔-1-基)苯基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺(Ⅱ-11)的合成
步骤1:合成叔丁基((5-(2,4-二氟苯基)-1-((3-(3-甲氧基丙-1-炔-1-基)苯基)磺酰基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯(11-1)
将化合物Int 3(20mg,0.37mmol),1-1(78mg,1.11mmol),双三苯基膦二氯化钯(26mg,0.04mmol),碘化亚铜(7mg,0.04mmol)和三乙胺(187mg,1.85mmol)溶解在DMF(4mL)中。在封管中,80℃下反应过夜,待反应结束,加入水(10mL),乙酸乙酯(15mL×2)萃取,合并有机相用饱和食盐水(20mL×1)洗涤,有机相用无水硫酸钠干燥,过滤,减压浓缩,通过柱层析(PE/EA=3:1)纯化得到150mg黄色油状化合物,产率76.92%。
步骤2:合成1-(5-(2,4-二氟苯基)-1-((3-(3-甲氧基丙-1-炔-1-基)苯基)磺酰基)-1H-吡咯-3- 基)-N-甲基甲胺(II-11)
在室温下,将化合物11-1(150mg,0.28mmol)溶解在二氯甲烷(2mL)溶液中,然后加入4M盐酸/1,4-二氧六环(2mL)室温搅拌2h。减压浓缩,得到白色固体75mg,产率57.25%。
1HNMR:(400MHz,DMSO-d
6)δ8.76(br,2H),7.83-7.80(m,2H),7.61(t,J=8.0Hz,1H),7.49(d,J=8.0Hz,1H),7.39(s,1H),7.28(t,J=8.0Hz,1H),7.15-7.13(m,2H),6.49(s,1H),4.36(s,2H),4.01(s,2H),3.36(s,3H),2.55(s,3H)。
实施例12
1-(1-((3-(环丙基乙炔基)苯基)磺酰基)-5-(2-氟苯基)-1H-吡咯-3-基)-N-甲基甲胺盐酸盐(Ⅱ-12)的合成
步骤1:合成叔丁基((1-((3-(环丙基乙炔基)苯基)磺酰基)-5-(2-氟苯基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯(12-1)
室温下,将化合物Int 1(200mg,0.382mmol)溶于DMF(2mL)中,分别加入Pd(PPh
3)
2Cl
2(27mg,0.038mmol),CuI(8mg,0.038mmol),三乙胺(0.5mL,3.59mmol),4-1(102mg,1.54mmol)。N
2置换后封管加热至80℃搅拌过夜。减压浓缩,粗品用柱层析分离纯化(正己烷/乙酸乙酯),得到黄色油状物80mg,产率41.2%。
步骤2:合成(1-((3-(环丙基乙炔基)苯基)磺酰基)-5-(2-氟苯基)-1H-吡咯-3-基)-N-甲基甲胺盐酸盐(II-12)
在室温下,将化合物12-1(80mg,0.197mmol)溶于4M盐酸/1,4-二氧六环(2mL)中,室温下反应1小时。减压浓缩,粗品用DCM/MeOH打浆,得到白色固体30mg,产率:34.1%。
1HNMR:(400MHz,CDCl
3)δ9.82(s,2H),7.66(s,1H),7.49-7.47(m,1H),7.41-7.36(m,1H),7.31-7.24(m,3H),7.11-7.05(m,2H),6.99(t,J=8.8Hz,1H),6.59(s,1H),3.99(s,2H),1.46-1.40(m,1H),0.93-0.86(m,2H),0.83-0.79(m,2H).
实施例13
在室温下,将化合物9-2(180mg,0.33mmol)溶解在二氯甲烷(3mL)溶液中,加入4M盐酸/1,4-二氧六环(3mL),搅拌两小时,待反应完全后,过滤得到140mg粉色固体化合物,产率95.89%,纯度>95%,[M+H]
+:443.1。
1HNMR:(400MHz,DMSO-d
6)δ8.94(s,2H),8.11(d,J=8.0Hz,1H),7.82(s,1H),7.72(s,1H),7.65-7.59(m,2H),7.55-7.44(m,2H),7.24-7.78(m,2H),7.06(t,J=6.0Hz,1H),6.64(d,J=16.0Hz,1H),6.53(s,1H),4.22(q,J=6.8Hz,2H),3.97(s,2H),3.35(s,3H),1.28(t,J=7.2Hz,3H).
实施例14
1-(5-(2-氟苯基)-1-((3-(3-甲氧基丙-1-炔-1-基)-5-(3-甲氧基丙氧基)苯基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺(Ⅱ-14)的合成
步骤1:合成叔丁基((5-(2-氟苯基)-1-((3-(3-甲氧基丙-1-炔-1-基)-5-(3-甲氧基丙氧基)苯基)磺酰基)-1H-吡咯-3)基)甲基)(甲基)氨基甲酸酯(14-1)
在室温下,将化合物Int 4(200mg,327.05μmol),1-1(68.77mg,981.16μmol),Pd(PPh
3)
2Cl
2(11.86mg,32.71μmol),碘化亚铜(6.23mg,32.71μmol)和三乙胺(99.28mg,981.16μmol)溶解在四氢呋喃(5mL)溶液中,氮气保护下,80℃反应过夜,反应完全后,加水(8mL),用乙酸乙酯(5mL×2)萃取,合并有机相,用无水硫酸钠干燥,过滤,滤液通过减压浓缩,柱层析分离纯化(PE/EA=3:1)得到黄色稠状固体70mg,产率36.63%,[M+H]
+:601.2。
步骤2:合成1-(5-(2-氟苯基)-1-((3-(3-甲氧基丙-1-炔-1-基)-5-(3-甲氧基丙氧基)苯基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺(II-14)
在室温下,向10mL的单口瓶中加入化合物14-1(80mg,151.91μmol),4M盐酸/1,4-二氧六环(1mL),二氯甲烷(2mL)。室温下搅拌反应2h。反应完全后,减压浓缩除去溶剂。加入水(2mL)溶清后,用饱和碳酸氢钠溶液调剂pH=9。乙酸乙酯(3mL×2),合并有机相,饱和食盐水(5mL)洗涤一次,无水硫酸钠干燥,过滤,旋干得到油状物20mg,产率35.27%,[M+H]
+:487.2。
1HNMR:(400MHz,CDCl
3)δ7.50(s,1H),7.40-7.35(m,1H),7.14-7.08(m,3H),7.04-6.99(m,2H),6.82(s,1H),6.43(s,1H),4.27(s,2H),3.92(t,J=6.4Hz,2H),3.86(s,2H),3.50(t,J=6Hz,2H),3.43(s,3H),3.32(s,3H),2.53(s,3H),2.09-1.94(m,2H).
实施例15
(E)-3-(5-((2-(2-氟苯基)-4-((甲氨基)甲基)-1H-吡咯-1-基)磺酰基)吡啶-3-基)-N-甲基丙烯酰胺盐酸盐(Ⅱ-15)的合成
步骤1:合成乙基(E)-3-(5-((4-(((叔丁氧基羰基)(甲基)氨基)甲基)-2-(2-氟苯基)-1H-吡咯-1-基)磺酰基)吡啶-3-丙烯酸酯(15-2)
在室温下,将化合物Int 2(500mg,0.95mmol),9-1(180mg,1.24mmol),Pd(dppf)Cl
2(63mg,0.095mmol),Na
2CO
3(170mg,1.9mmol)加入1,4-二氧六环(10mL)中,加入水(2mL),氮气置换三次,氮气保护下,升温至95℃,搅拌过夜。反应结束后,将反应体系减压浓缩,柱层析分离纯化(PE/EA=2:1)得到油状物170mg,产率31.95%,[M+H]
+:488.2。
步骤2:合成(E)-3-(5-((4-(((叔丁氧基羰基)(甲基)氨基)甲基)-2-(2-氟苯基)-1H-吡咯-1-基)磺酰基)吡啶-3-基)丙烯酸(15-3)
在室温下,将NaOH(35mg,0.88mmol)加入到2mL水中,搅拌溶解,加入乙醇(8mL),加入化合物15-2(120mg,0.22mmol),室温搅拌30min,反应结束后,加入稀盐酸调节pH=7,将反应体系减压浓缩,加入乙酸乙酯(15mL×2)萃取,将有机相减压浓缩得到黄色油状物100mg,产率88.49%,[M+H]
+:460.2。
步骤3:合成叔丁基(E)-((5-(2-氟苯基)-1-((5-(3-(甲基氨基)-3-氧代丙-1-烯-1-基)吡啶-3-基) 磺酰基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯(15-4)
在室温下,将化合物15-3(100mg,0.19mmol)加入到5mL DMF中,加入HATU(88.5mg,0.23mmol),室温搅拌30min,加入盐酸甲胺(26.2mg,0.39mmol),DIPEA(100mg,0.78mmol),反应结束后,加入15mL乙酸乙酯,10mL水,分液得有机相,水相用乙酸乙酯(15mL×2),合并有机相,将反应体系减压浓缩,柱层析(PE/EA=2:1),得到黄色油状物60mg,产率59.74%,[M+H]
+:473.2。
步骤4:合成(E)-3-(5-((2-(2-氟苯基)-4-((甲氨基)甲基)-1H-吡咯-1-基)磺酰基)吡啶-3-基)-N-甲基丙烯酰胺盐酸盐(II-15)
在室温下,将化合物15-4(60mg,0.11mmol),溶解在二氯甲烷(5mL)溶液中,然后加入4M盐酸/1,4-二氧六环(1.0mL)室温搅拌2h。浓缩得到棕色化合物40mg,产率75.80%,[M+H]
+:429.2。
1HNMR:(400MHz,CD
3OD)δ9.00(s,1H),8.57(s,1H),7.90(s,2H),7.56-7.51(m,1H),7.47(s,1H),7.23(t,J=7.6,1H),7.15(t,J=7.6,1H),7.10(t,J=9.2Hz,1H),6.68(d,J=15.8Hz,1H),6.47(s,1H),4.14(s,2H),2.89(s,3H),2.74(s,3H).
H
+/K
+-ATPase生物学评价
下面的体外筛选试验是用来测定本发明化合物对于H
+/K
+-ATPase酶活性的抑制作用。
实验材料及仪器:
ATP、孔雀石绿、缬氨霉素、钼酸铵
无K
+缓冲液:50mM Tris-HCl pH 6.5,5mM magnesium chloride,10μM valinomycin
含K
+缓冲液:50mM Tris-HCl pH 6.5,5mM magnesium chloride,10μM valinomycin,20mM KCl MLG显色液:0.1%w/v孔雀石绿,1.5%w/v钼酸铵,0.2%v/v Tween-20
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100000g离心90min,收集沉淀;利用匀浆液悬浮沉淀,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:
45μL缓冲液(含K
+缓冲液:50mM Tris-HCl pH 6.5,5mM magnesium chloride,10μM valinomycin,20mM KCl)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IC
50值通过不同浓度下的抑制率计算得到,本发明的化合物对H
+/K
+-ATPase具有明显的抑制活性,IC
50为20至100nM,优选的为20至50nM。其中对照组1选自Vonoprazan(沃诺拉赞),其制备方法参照专利CN101300229A;对照组2选自具有如下结构式。
本发明的部分化合物的IC
50值(H
+/K
+ATP)示于下表1中:
表1
结论:本发明化合物对H
+/K
+-ATPase具有明显的抑制活性。
体外细胞毒实验
利用Dulbecco的改进Eagle培养基(DMEM;Invitrogen),将源于人肝癌的细胞系HepG2在5%和37℃下培养和传代,收集对数生长期细胞,计数,用完全培养基重新悬浮细胞,调整细胞浓度至合适浓度(依照细胞密度优化试验结果确定),接种96孔板,按照以下platemap加75μl/well细胞悬液。用培养基将待测化合物稀释至所设置的相应作用浓度,按照platemap25μl/well加入细胞。待测化合物的作用浓度均从100μM开始,4倍梯度稀释,共9个浓度,2个复孔。细胞置于37℃,100%相对湿度,5%CO
2培养箱中孵育24h。加入50μL/well CellTiter Glo RT避光孵育30min。轻轻震荡后在Envision进行检测,计算抑制率。
按下式计算药物对各细胞生长的抑制率:细胞生长抑制率%=(1-As/Ac)×100。
As:样品的OA(细胞+CTG+待测化合物),
Ac:正常生长细胞对照的OA(细胞+CTG+DMSO)。
运用软件Graphpad Prism 6并采用计算公式XY-analysis/Nonlinear regression(curve fit)/Dose response-Inhibition/log(inhibitor)vs.response-Variable slope(four parameters)进行IC
50曲线拟合并计算出IC
50值,实验发现本发明化合物IC
50大于20μM,具有低细胞毒性。
本发明部分化合物体外细胞毒测试实验结果,具体见下表(表2)
表2:
编号 | IC 50 |
II-2 | +++ |
II-7 | +++ |
II-9 | +++ |
II-11 | +++ |
对照组1 | +++ |
注:IC
50>20μM为+++,20μM>IC
50>10μM为++,10μM>IC
50为+。
肝微粒稳定性实验
制备获取所需的种属肝微粒体(例如小鼠、大鼠、犬、猴子或者人)。以DMSO为稀释剂,配制10mM浓度的试样原液和阳性对照原液。然后用70%乙腈将所有原液稀释至0.25mM的工作浓度。本研究使用的辅助因子为NADPH再生体系,该体系由6.5mM NADP、16.5mM G-6-P、3U/mL G-6-P D组成。淬火试剂为含甲苯磺丁脲和心得安的乙腈溶液。
本研究使用的缓冲液为100mM磷酸钾缓冲液。含0.2mg/mL肝微粒体蛋白和1μM试验品/阳性对照的混合物在100mM磷酸钾缓冲液中孵育。
每一种孵育液取80μL加入300μL猝灭试剂中沉淀蛋白,制备0分钟的样品。样品涡旋后,加入20μL的NADPH再生体系。每个孵育液520μL加入130μL的NADPH再生体系引发反应。650μL的最终孵育条件为:0.2mg/mL微粒体蛋白、1μM条带/阳性对照、1.3mM NADP、3.3mM 葡萄糖6磷酸、0.6U/mL葡萄糖6磷酸脱氢酶。将混合物放入37℃的水浴中,轻轻摇晃。分别于0、5、10、30、60分钟取100μL的混合物,置于包含300μL淬火试剂沉淀蛋白的96孔板上,离心(5000×g,10分钟)。取80μL上清液加入预先添加160μL超纯水的96孔检测板,用LC-MS/MS进行分析。数据处理获得消除半衰期(T
1/2,T
1/2=0.693/K)和体外清除率(Cl
int)。
本发明的部分化合物在SD大鼠肝微粒体稳定性结果具体见下表(表3)
表3:
实验发现本发明化合物在肝微粒体中T
1/2(min)>80min,优选的T
1/2(min)>100min,具有良好的肝微粒代谢稳定性。
药代动力学实验
被研究化合物单次口服或者静脉给药(溶媒5%DMSO+10%Solutol(HS-15)+85%saline)于动物(例如小鼠、大鼠、犬或者猴子),在固定的时间点取血。血样采集后,立即温和地颠倒试管至少5次,保证混合充分后放置于冰上。血液用肝素抗凝,然后8000pm离心5分钟,将血清与红细胞分离。用移液器吸岀血清转移至2mL的聚丙烯管,标明化合物的名称和时间点,在进行LC-MS分析前保存在-40℃冰箱,待测。髙浓度样品用空白血浆稀释测定时。样品处理后,用LCMS/MS对血浆中的物质进行定量分析。通过进行了验证的药动学计算机程序,用以这种方式获得的血浆浓度/时曲线来计算药动学参数。实验发现本发明化合物均具有较好的药代动力学性质。
SD雄性大鼠以表4组别剂量口服给药后(各组为等摩尔剂量给药,溶媒为5%DMSO+10%Solutol(HS-15)+85%saline,每组3只),在固定的时间点取血检测。本发明的部分化合物的在大鼠血浆中的原型游离分子药代动力学参数如下表4;
表4:
从表4中可以看出,实验发现本发明化合物在大鼠血浆中的原型游离分子的AUC相比对照组在血浆中的原型游离分子的AUC无显著性差异,但半衰期有显著延长,具有良好的药代动力学性质。
hERG钾离子通道作用的研究
试验系统
细胞:中国仓鼠卵巢(CHO)细胞系,CHO-hERG细胞用于本试验。
细胞培养液及培养条件:完全培养基为F12培养基,补充加入10%胎牛血清,1%
选择性抗生素(G418),89μg/mL潮霉素B(HB)。复苏培养基为F12培养基补充加入10%胎牛血清。CHO-hERG细胞生长在37℃(±2℃)、5%CO
2(4%至8%)的高湿度培养箱中。细胞用复苏培养基复苏,完全培养基传代,用于膜片钳试验的细胞在最后一次传代时换成复苏培养基。
细胞外液及内液成分:
试剂 | 外液(mM) | 内液(mM) |
CaCl2 | 2 | 5.37 |
MgCl2 | 1 | 1.75 |
KCl | 4 | 120 |
NaCl | 145 | - |
Glucose | 10 | - |
HEPES | 10 | 10 |
EGTA | - | 5 |
Na2ATP | - | 4 |
pH | 7.3-7.4 | 7.2-7.3 |
试验方法
(1)将处于指数生长期的CHO-hERG细胞收集并重悬在ECS中备用。
(2)手动膜片钳试验
全细胞膜片钳技术下记录hERG电流,记录温度为室温。膜片钳放大器输出信号通过数模转换以及2.9KHz低通滤波。数据记录用Patchmaster Pro软件采集。
细胞种在细胞记录槽中放置在倒置显微镜载物台上,随机选择记录槽中的一个细胞进行 试验。灌流系统固定在倒置显微镜载物台上用ECS持续灌流细胞。
用毛细玻璃管制备手动膜片钳试验记录微电极,其中充灌细胞內液。在膜片钳试验当天,使用硼硅酸盐玻璃管(BF150-117-10,SUTTER INSTRUMENT USA)制备电极。电极充灌ICS后电阻在2-5MΩ之间。
钳制电压为-80mV,第一步去极化至+60mV并维持850ms开放hERG通道。然后,电压设置为-50mV并维持1275ms,产生反弹电流或者称为尾电流,尾电流的峰值将被测量并用于分析。最后,电压恢复到钳制电压(-80mV)。试验过程中,这个指令电压程序每间隔15s重复一次。
手动膜片钳hERG电流测试指令电压程序
在溶媒对照工作溶液灌流的记录开始阶段,监测尾电流峰值直至稳定3条以上扫描曲线后则可以灌流待测试的供试品/阳性对照工作溶液,直到供试品/阳性对照工作溶液对hERG电流峰值的抑制作用达到稳定状态。一般以最近的连续3个电流曲线峰值基本重合作为判断是否稳定状态的标准。达到稳定态势以后继续灌流下一浓度供试品。一个细胞上可以测试一个或多个供试品/阳性对照,或者同一种药物的多个浓度,不同供试品/阳性对照之间需用溶媒对照工作液冲洗直到hERG电流回复到加药物之前80%以上的大小。同一浓度下各记录细胞抑制率的标准差不超过15%。
阳性对照西沙必利的测试浓度为0.1μM,重复测定两个细胞。根据科学文献报道,0.1μM的西沙必利抑制hERG电流超过50%。(Milnes,J.T.,et al.)。
(3)手动膜片钳数据接受标准
封接标准:全细胞模式形成后,施加钳制电压(-80mV),可以记录到细胞膜相关参数(Cm,Rm以及Ra)。一个好的的全细胞记录应该满足以下条件:路径电阻(Rs)小于10MΩ;膜电阻(Rm)大于500MΩ和膜电容(Cm)小于100pF。
电流大小:供试品/阳性对照品作用前峰电流幅度在400pA和5000pA之间。否则,放弃该细胞。
漏电流:在-80mV的钳制电压下,漏电流绝对值应该小于200pA。电流幅度将会用-80mV下的漏电流校正。漏电流绝对值大于200pA的扫描曲线不能用于分析。
数据分析
对于每个细胞,每一个浓度的供试品及阳性对照的抑制百分比由记录到的电流反应用以下公式算出:(1-供试品/阳性对照灌流后记录到的尾峰值电流/溶媒对照灌流记录到的尾峰值电流(起始电流))×100%。
对于每一个浓度记录到所有的细胞抑制百分比取均值,IC
50值由Hill拟合的方法由浓度效应曲线中得出。
试验结果
本发明部分化合物对hERG电流的抑制结果,具体见下表(表5)
表5:
化合物编号 | hERGIC 50 |
II-1 | +++ |
II-7 | ++ |
II-9 | ++ |
II-10 | +++ |
II-11 | ++ |
II-12 | +++ |
II-13 | + |
对照组1 | + |
注:IC
50>20μM为+++,20μM>IC
50>10μM为++,10μM>IC
50>1μM为+。
实验发现本发明化合物具有较高的hERG IC
50值,说明本发明化合物心脏毒性风险较低。
以上详细描述了本发明的优选实施方式,但是,本发明并不限于上述实施方式中的具体细节,在本发明的技术构思范围内,可以对本发明的技术方案进行多种简单变型,这些简单变型均属于本发明的保护范围。
另外需要说明的是,在上述具体实施方式中所描述的各个具体技术特征,在不矛盾的情况下,可以通过任何合适的方式进行组合,为了避免不必要的重复,本发明对各种可能的组合方式不再另行说明。
Claims (10)
- 一种吡咯磺酰类衍生物、其互变异构体或其立体异构体,及其药学上可接受的盐,其特征在于,所述吡咯磺酰类衍生物的结构通式如式(I)所示:其中:A为苯基或吡啶基;虚线表示任选地键;R 1选自H、C 1-6的烷基、C 3-12的环烷基、3-12元的杂环基、5-12元的芳基或5-12元的杂芳基、C 1-6烷基-NH-C 1-6烷基、C 1-6烷基-O-C 1-6烷基、-C(=O)NHR a、-C(=O)R b、-S(=O) m-C 1-6烷基;其中,所述烷基、环烷基、杂环基、芳基或杂芳基可任选进一步被1-3个羟基、卤素、C 1-6烷基、C 1-6烷氧基所取代;R 2选自H、C 1-6的烷基、C 1-6烷氧基、卤素、氰基、C 2-6炔基、C 2-6烯基、-O-C 1-6烷基-O-C 1-6烷基、-NR cR d;R 3选自卤素、5-8元的芳基、5-8元的杂芳基、氰基、C 2-6炔基、C 2-6烯基、-O-C 1-6烷基-O-C 1-6烷基、-NR cR d;或者两个R 3连同它们连接的碳原子一起形成稠环芳基,所述芳基、杂芳基和稠环芳基可任选地进一步被1-3个C 1-6烷基、C 1-6烷氧基、卤素、C 2-6炔基、C 2-6烯基、氰基、-O-C 1-6烷基-O-C 1-6烷基、-NR cR d所取代;R 4选自C 1-6的烷基;其中所述烷基可任选地进一步被1-3个氘、卤素所取代;n选自0、1、2、3;m选自0、1、2;R a、R b、R c、R d各自独立的选自C 1-6的烷基、C 1-6烷氧基、C 3-7的环烷基。
- 如权利要求1所述的吡咯磺酰类衍生物、其互变异构体或其立体异构体,及其药学上可接受的盐,其特征在于,所述R 1选自H、C 1-6的烷基、C 3-12的环烷基、C 1-6烷基-NH-C 1-6烷基、C 1-6烷基-O-C 1-6烷基、-C(=O)NHR a、-C(=O)OR b;其中,所述烷基、环烷基、杂环基、可任选进一步被卤素、C 1-6烷基所取代。
- 如权利要求1所述的吡咯磺酰类衍生物、其互变异构体或其立体异构体,及其药学上可接受的盐,其特征在于,所述环A选自苯基;R 1选自C 1-6烷基-NH-C 1-6烷基、C 1-6烷基-O-C 1-6烷基、C 3-12的环烷基或-C(=O)NHR a。
- 如权利要求1-4中任一项所述的吡咯磺酰类衍生物、其互变异构体或其立体异构体,及其药学上可接受的盐,其特征在于,所述R 2选自H、C 1-6烷氧基、卤素。
- 如权利要求1-4中任一项所述的吡咯磺酰类衍生物、其互变异构体或其立体异构体,及其药学上可接受的盐,其特征在于,所述R 3选自卤素;R 4选自C 1-6的烷基。
- 一种药物组合物,其特征在于,所述药物组合物包括如权利要求1-7中任一项所述的吡咯磺酰类衍生物、其互变异构体或其立体异构体,及其药学上可接受的盐和可药用载体和/或赋形剂。
- 如权利要求1-7中任一项所述的吡咯磺酰类衍生物、其互变异构体或其立体异构体,其药学上可接受的盐或如权利要求8所述的药物组合物在制备胃酸分泌抑制剂、H +/K +-ATPase 抑制剂或钾离子竞争性酸阻滞剂中的用途。
- 如权利要求1-7中任一项所述的吡咯磺酰类衍生物、其互变异构体或其立体异构体,其药学上可接受的盐或如权利要求8所述的药物组合物在制备治疗或预防如下疾病用药物中的用途:消化性溃疡、卓-艾综合征、胃糜烂性食管炎、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、手术后应激导致的胃酸过多或手术后应激导致的溃疡的药物中的用途;或者在制备抑制消化性溃疡、急应激性溃疡、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。
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Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20070060570A1 (en) * | 2003-05-26 | 2007-03-15 | Taleda Pharmaceutical Company Limited | Sulfopyrroles |
US20140343070A1 (en) * | 2004-09-30 | 2014-11-20 | Takeda Pharmaceutical Company Limited | Proton pump inhibitors |
CN105330647A (zh) * | 2014-08-14 | 2016-02-17 | 江苏柯菲平医药股份有限公司 | 吡咯磺酰类衍生物、其制备方法及其在医药上的应用 |
CN105985278A (zh) * | 2015-01-27 | 2016-10-05 | 江苏柯菲平医药股份有限公司 | 吡咯磺酰类衍生物、其制备方法及其在医药上的应用 |
Family Cites Families (8)
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RU2015122126A (ru) * | 2012-11-19 | 2017-01-10 | Цзянсу Хэнсох Фармасьютикал Ко., Лтд. | Производное пиррол сульфонамида, метод его получения и применение в медицине |
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CN115385845A (zh) * | 2016-09-12 | 2022-11-25 | 江苏柯菲平医药股份有限公司 | 一种吡咯磺酸类化合物盐型制备 |
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CN108117503B (zh) * | 2016-11-30 | 2022-09-02 | 江苏柯菲平医药股份有限公司 | 吡咯磺酰类新化学实体、制备方法及其用途 |
CN108203449A (zh) * | 2016-12-16 | 2018-06-26 | 天地人和生物科技有限公司 | 一种新型可逆性质子泵抑制剂及其制备方法和用途 |
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Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20070060570A1 (en) * | 2003-05-26 | 2007-03-15 | Taleda Pharmaceutical Company Limited | Sulfopyrroles |
US20140343070A1 (en) * | 2004-09-30 | 2014-11-20 | Takeda Pharmaceutical Company Limited | Proton pump inhibitors |
CN105330647A (zh) * | 2014-08-14 | 2016-02-17 | 江苏柯菲平医药股份有限公司 | 吡咯磺酰类衍生物、其制备方法及其在医药上的应用 |
CN105985278A (zh) * | 2015-01-27 | 2016-10-05 | 江苏柯菲平医药股份有限公司 | 吡咯磺酰类衍生物、其制备方法及其在医药上的应用 |
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