CN105330647A - Pyrrole sulfonamide derivative, preparation method and medical application thereof - Google Patents
Pyrrole sulfonamide derivative, preparation method and medical application thereof Download PDFInfo
- Publication number
- CN105330647A CN105330647A CN201410399065.8A CN201410399065A CN105330647A CN 105330647 A CN105330647 A CN 105330647A CN 201410399065 A CN201410399065 A CN 201410399065A CN 105330647 A CN105330647 A CN 105330647A
- Authority
- CN
- China
- Prior art keywords
- heteroaryl
- cycloalkyl
- alkyl
- aryl
- heterocyclylalkyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
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
- A61K31/435—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
- A61K31/435—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
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4709—Non-condensed quinolines 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
- A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
-
- 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
- C07D405/14—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 three or more hetero rings
-
- 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
- C07D417/14—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 three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
Abstract
The present invention relates to a pyrrole sulfonamide derivative, a preparation method and a medical application thereof. Concretely, the present invention relates to the pyrrole sulfonamide derivative shown in a formula (I), the preparation method for the derivative, a pharmaceutical composition comprising the derivative, and uses of same as therapeutic agents, and particularly as a gastric acid secretion inhibitor and potassium-competitive acid blockers (P-CABs), where each substituent of formula (I) is as defined in the description.
Description
Technical field
The present invention relates to the new pyrroles's sulphonyl analog derivative of a class, its preparation method and containing the drug regimen of this derivative and its as therapeutical agent particularly as the purposes of gastric acid secretion inhibitor and the competitive sour retarding agent (P-CABs) of potassium ion.
Background technology
Since 1988, be that the proton pump inhibitor of representative is used widely to treat peptide ulceration, reflux esophagitis and Zollinger-Eillison syndrome etc. clinically by gastric acid secretion inhibiting with omeprazole.Long-term clinical application finds, existing proton pump inhibitor also has limitation in pharmacokinetics, pharmacodynamics.As: administration time is on the impact of drug effect; Control of Nocturnal Gastric Acid Breakthrough onset is slow; Under acidic conditions unstable (needing to be mixed with Enteral formulations); To dependency of CYP450 enzyme (cause individual difference remarkable) etc.
The competitive sour retarding agent (Potassium-CompetitiveAcidBlockers, P-CABs) of potassium suppresses H competitively by direct, reversible process
+/ K
+k in-ATP enzyme
+and generation effect.Compared with traditional proton pump inhibitor, P-CABs has lipotropy, weakly alkaline, feature that dissociation constant is high and stable at low ph conditions.Under sour environment, P-CABs is with ionized form and H
+/ K
+-ATP enzyme combines, and stops H
+transport and acid are secreted in gastral cavity, raise pH value in stomach rapidly.Experimentation on animals and clinical study show: it is rapid that P-CABs possesses onset, in 1 hour, just can reach maximum hospital benefit; Plasma Concentration and qf oral administration dosage linear dependence, than being easier to the advantage reaching best acid suppression effect.
Although disclosed the competitive sour retarding agent of a series of potassium at present, but still need development structure type abundanter, the new compound may with better patent medicine character, through continuous effort, the present invention's design has the compound of the structure shown in general formula (I), and finds that the compounds exhibit with this class formation goes out excellent effect and effect.
Summary of the invention
The application provides structure gastric acid secretion inhibitor as shown in the formula (I), its using method, as described herein below:
The structure that the application provides compound as shown in the formula (I) or its tautomer, mesomeride, racemic modification, enantiomer, diastereomer or its form of mixtures or pharmacy acceptable salt:
In formula,
X, Y are selected from CR independently of one another
2or N;
R
1be selected from alkyl, cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl, wherein said alkyl, cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl are optionally selected from hydrogen, halogen, cyano group, hydroxyl, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl ,-OR by one or more
3,-NR
3r
4,-C (O) NR
3r
4,-S (O)
mr
3,-C (O) R
3,-OC (O) R
3or-C (O) OR
3substituting group replaced;
For fused rings, wherein ring A is cycloalkyl, Heterocyclylalkyl, phenyl, heteroaryl; Ring B is cycloalkyl, Heterocyclylalkyl, phenyl, heteroaryl; A, B are phenyl time different.Wherein optionally be selected from hydrogen, halogen, cyano group, hydroxyl, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl ,-OR by one or more
3,-NR
3r
4,-C (O) NR
3r
4,-S (O)
mr
3,-C (O) R
3,-OC (O) R
3or-C (O) OR
3substituting group replaced;
R
2be selected from hydrogen, halogen, alkyl;
R
3or R
4be selected from hydrogen atom, alkyl, cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl independently of one another, wherein said alkyl, cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl optionally by one or more be selected from the substituting group of halogen, cyano group, hydroxyl, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxyl group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, carboxyl, amide group or carboxylic acid ester groups replace;
M is selected from 0,1 or 2.
Further, the invention provides structure compound as shown in the formula (I) or its tautomer, mesomeride, racemic modification, enantiomer, diastereomer or its form of mixtures or pharmacy acceptable salt, wherein R
1be selected from aryl or heteroaryl, wherein said aryl or heteroaryl are optionally selected from hydrogen, halogen, cyano group, hydroxyl, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl ,-OR by one or more
3,-NR
3r
4,-C (O) NR
3r
4,-S (O)
mr
3,-C (O) R
3,-OC (O) R
3or-C (O) OR
3substituting group replaced;
R
3or R
4be selected from hydrogen atom, alkyl, cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl independently of one another, wherein said alkyl, cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl optionally by one or more be selected from the substituting group of halogen, cyano group, hydroxyl, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxyl group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, carboxyl, amide group or carboxylic acid ester groups replace;
M is selected from 0,1 or 2.
Further, the invention provides structure such as formula (I) compound or its tautomer, mesomeride, racemic modification, enantiomer, diastereomer or its form of mixtures or pharmacy acceptable salt, wherein, A is selected from phenyl, heteroaryl; B is cycloalkyl, Heterocyclylalkyl, phenyl, heteroaryl; A, B are phenyl time different.Wherein said cycloalkyl, Heterocyclylalkyl, phenyl, heteroaryl are optionally selected from hydrogen, halogen, cyano group, hydroxyl, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl ,-OR by one or more
3,-NR
3r
4,-C (O) NR
3r
4,-S (O)
mr
3,-C (O) R
3,-OC (O) R
3or-C (O) OR
3substituting group replaced;
R
3or R
4be selected from hydrogen atom, alkyl, cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl independently of one another, wherein said alkyl, cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl optionally by one or more be selected from the substituting group of halogen, cyano group, hydroxyl, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxyl group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, carboxyl, amide group or carboxylic acid ester groups replace;
M is selected from 0,1 or 2.
Further, the invention provides structure such as formula (I) compound or its tautomer, mesomeride, racemic modification, enantiomer, diastereomer or its form of mixtures or pharmacy acceptable salt, wherein X, Y are selected from CH or N independently of one another.
Further, the invention provides structure such as formula (I) compound or its tautomer, mesomeride, racemic modification, enantiomer, diastereomer or its form of mixtures or pharmacy acceptable salt, be wherein selected from:
deng.
Further, the invention provides structure as shown in the formula (I) compound be selected from:
Further, the invention provides structure compound as shown in the formula (I), typical compound is selected from:
。
The invention still further relates to a kind of medicinal compositions, described pharmaceutical composition contains the compound shown in general formula (I) of significant quantity or its tautomer, mesomeride, racemic modification, enantiomer, diastereomer or its form of mixtures or pharmacy acceptable salt and medicine acceptable carrier, vehicle or thinner.
The invention still further relates to the compound shown in general formula (I) or its tautomer, mesomeride, racemic modification, enantiomer, diastereomer or its form of mixtures or pharmacy acceptable salt or the pharmaceutical composition that comprises it is preparing the purposes in gastric acid secretion inhibitor.
The present invention relates to a kind of method of gastric acid secretion inhibiting on the other hand, and the method comprises the compound shown in general formula (I) or its tautomer, mesomeride, racemic modification, enantiomer, diastereomer or its form of mixtures or pharmacy acceptable salt that give patient's effective dose that needs are treated or the pharmaceutical composition comprising it.
The pharmaceutical composition that the present invention relates on the other hand the compound shown in (I) or its tautomer, mesomeride, racemic modification, enantiomer, diastereomer or its form of mixtures or pharmacy acceptable salt or comprises it is at preparation H
+/ K
+-adenosine triphosphatase (H
+/ K
+-ATPase) purposes in inhibitor.
The present invention relates on the other hand the compound shown in (I) or its tautomer, mesomeride, racemic modification, enantiomer, diastereomer or its form of mixtures or pharmacy acceptable salt or the pharmaceutical composition that comprises it is preparing the purposes in the competitive sour retarding agent (P-CABs) of potassium ion.
The invention provides and be used for the treatment of or prevent peptide ulceration, the purposes in the medicine of the ulcer that Zollinger-Eillison syndrome, gastritis, erosive esophagitis, reflux esophagitis, symptomatic gastroesophageal reflux disease, Barrett esophagus inflammation, functional dyspepsia, Helicobacter pylori infection, cancer of the stomach, gastric MALT lymphoma, NSAID (non-steroidal anti-inflammatory drug) cause or the hyperchlorhydria that Post operation stress cause or ulcer; Or the method be used in the medicine of the upper gastrointestinal hemorrhage that peptide ulceration, acute stress ulcer, hemorrhagic gastritis or invasive stress cause is suppressed in preparation.Wherein peptide ulceration is selected from stomach ulcer, duodenal ulcer or stoma ulcer; Described symptomatic gastroesophageal reflux disease is selected from the method for the reflux diseases of Non-erosive or the gastroesophageal reflux disease without esophagitis.
detailed description of the invention
Unless stated to the contrary, following use term in the specification and in the claims has following implication.
" alkyl " refers to saturated aliphatic hydrocarbon group.Comprise the straight or branched group of 1 to 20 carbon atom.Median size alkyl preferably containing 1 to 6 carbon atom, such as methyl, ethyl, propyl group, 2-propyl group, normal-butyl, isobutyl-, the tertiary butyl, amyl group etc.Low alkyl group more preferably containing 1 to 4 carbon atom, such as methyl, ethyl, propyl group, 2-propyl group, normal-butyl, isobutyl-or the tertiary butyl etc.Alkyl can be replacement or unsubstituted, and when substituted, preferred group is: halogen, C
2-C
6thiazolinyl, C
6-C
10aryl, C
5-C
10heteroaryl, halo C
1-C
6alkyl, 4 to 8 yuan of heteroalicyclyl, hydroxyl, C
1-C
6alkoxyl group, C
6-C
10aryloxy.
" cycloalkyl " refers to 3 to 8 yuan of full carbon monocycles, complete 5 yuan/6 yuan, carbon or 6 yuan/6 yuan thick and rings or many rings are thick and ring (" thick and " ring means that each ring in system and other ring in system share a pair carbon atom adjoined) group, wherein one or more rings have the electronic system connected completely, and the example (being not limited to) of cycloalkyl is cyclopropane, tetramethylene, pentamethylene, cyclopentenes, hexanaphthene, diamantane, cyclohexadiene, suberane and cycloheptatriene.Cycloalkyl is commutable and is what replace.When substituted, substituting group is preferably one or more is selected from following group separately, comprise: hydrogen, hydroxyl, sulfydryl, oxo, low alkyl group, lower alkoxy, low-grade cycloalkyl, rudimentary heteroalicyclyl, elementary halogenated alkoxy, alkylthio, halogen, low-grade halogenated alkyl, Lower hydroxy alkyl, low-grade cycloalkyl alkylidene group, rudimentary heteroalicyclyl alkylene, aryl, heteroaryl, alkoxy carbonyl, amino, alkylamino, alkyl sulphonyl, aryl sulfonyl, alkyl amino sulfonyl, n-aryl sulfonyl, alkyl sulfonyl-amino, arlysulfonylamino, alkyl amino-carbonyl, aromatic yl aminocarbonyl, alkyl-carbonyl-amino, aryl-amino-carbonyl.
" aryl " represents full carbon monocycle or the fused polycycle group of 6 to 14 carbon atoms, has the π-electron system of total conjugated." aryl " comprising:
Hexa-atomic carbon aromatic nucleus, e.g., benzene;
Dicyclo, wherein has at least a ring to be carbon aromatic nucleus, e.g., and naphthalene, indenes and 1,2,3,4-tetrahydroquinoline; And
Three rings, wherein have at least a ring to be carbon aromatic nucleus, e.g., and fluorenes.
Such as, aryl comprises containing hexa-atomic carbon aromatic nucleus and a hexa-member heterocycle, and this heterocycle comprises one or more heteroatoms being selected from nitrogen, oxygen and sulphur, and condition is that tie point is on carbon aromatic nucleus.But aryl does not comprise, also not overlapping with the heterocyclic aryl defined respectively below by any mode.Therefore, in this definition, if one or more carbon aromatic nucleus and an assorted aromatic nucleus ring, consequent loop systems is heteroaryl, instead of aryl.The limiting examples of aryl has phenyl, naphthyl.Aryl can be replacement or unsubstituted.When substituted, preferred group is: hydrogen, hydroxyl, nitro, cyano group, oxo, low alkyl group, lower alkoxy, low-grade cycloalkyl, rudimentary heteroalicyclyl, elementary halogenated alkoxy, alkylthio, halogen, low-grade halogenated alkyl, Lower hydroxy alkyl, low-grade cycloalkyl alkylidene group, rudimentary heteroalicyclyl alkylene, aryl, heteroaryl, alkoxy carbonyl, amino, alkylamino, alkyl sulphonyl, aryl sulfonyl, alkyl amino sulfonyl, n-aryl sulfonyl, alkyl sulfonyl-amino, arlysulfonylamino, alkyl amino-carbonyl, aromatic yl aminocarbonyl, alkyl-carbonyl-amino, aryl-amino-carbonyl.
" heteroaryl " represents monocycle or the fused ring group of 5 to 14 annular atomses, and be selected from the ring hetero atom of N, O or S containing one, two, three or four, all the other annular atomses are C, has the π-electron system of total conjugated in addition.Heteroaryl refers to:
The mononuclear aromatics of 5-8 unit, containing one or more heteroatoms being selected from N, O and S, as 1-4 heteroatoms, in some embodiments, 1-3 heteroatoms, on ring, other atoms are carbon atoms;
The double ring arene of 8-12 unit, containing one or more heteroatoms being selected from N, O and S, as 1-4 heteroatoms, in some embodiments, 1-3 heteroatoms, on ring, other atoms are carbon atoms; A ring is wherein had at least to be aromatic nucleus; And
The thrcylic aromatic hydrocarbon of 11-14 unit, containing one or more heteroatoms being selected from N, O and S, as 1-4 heteroatoms, in some embodiments, 1-3 heteroatoms, on ring, other atoms are carbon atoms; A ring is wherein had at least to be aromatic nucleus.
Such as, heteroaryl comprises the assorted aromatic nucleus of a 5-6 unit and the cycloalkyl of a 5-6 unit.For such dicyclo and the heteroaryl got up, wherein only have a ring to contain one or more heteroatoms, connection site is on assorted aromatic nucleus.
When the sulphur atom on heteroaryl and Sauerstoffatom sum are more than 1, these heteroatomss can not be adjacent one by one.In some embodiments, sulphur atom and the Sauerstoffatom sum in heteroaryl is no more than 2.In some embodiments, sulphur atom and the Sauerstoffatom sum in heteroaryl is no more than 1.
The example of heteroaryl, include but not limited to, pyrroles, furans, thiophene, imidazoles, oxazole, thiazole, pyrazoles, triazole, pyrimidine, pyridine, pyridone, miaow pyridine, pyrazine, pyridazine, indoles, azaindole, benzoglyoxaline, benzotriazole, indoline, indolone, quinoline, isoquinoline 99.9, quinazoline, thienopyridine, Thienopyrimidine etc.The preferred embodiment of this type of group is pyrryl, pyrazolyl, imidazolyl, triazol radical, furyl, oxazolyl, thienyl, thiazolyl, benzimidazolyl-, benzotriazole.One or all hydrogen atom in heteroaryl can be replaced by following groups: hydrogen, hydroxyl, nitro, cyano group, oxo, low alkyl group, lower alkoxy, low-grade cycloalkyl, rudimentary heteroalicyclyl, elementary halogenated alkoxy, alkylthio, halogen, low-grade halogenated alkyl, Lower hydroxy alkyl, low-grade cycloalkyl alkylidene group, rudimentary heteroalicyclyl alkylene, aryl, heteroaryl, alkoxy carbonyl, amino, alkylamino, alkyl sulphonyl, aryl sulfonyl, alkyl amino sulfonyl, n-aryl sulfonyl, alkyl sulfonyl-amino, arlysulfonylamino, alkyl amino-carbonyl, aromatic yl aminocarbonyl, alkyl-carbonyl-amino, aryl-amino-carbonyl.
" Heterocyclylalkyl " represents monocycle or thick and cyclic group, has 5 to 9 annular atomses in ring, and wherein one or two annular atoms is selected from N, O or S (O)
pthe heteroatoms of (wherein p is the integer of 0 to 2), all the other annular atomses are C.These rings can have one or more double bond, but these rings do not have the π-electron system of total conjugated.The limiting examples of unsubstituted heteroalicyclyl has pyrrolidyl, piperidino-(1-position only), Piperazino, morpholino base, thiomorpholine for base, homopiperazino etc.Heteroalicyclyl can be replacement or unsubstituted.When substituted, substituting group is preferably one or more, more be preferably one, two or three, and then be more preferably one or two, described substituting group is selected from: hydrogen, hydroxyl, sulfydryl, oxo, low alkyl group, lower alkoxy, low-grade cycloalkyl, rudimentary heteroalicyclyl, elementary halogenated alkoxy, alkylthio, halogen, low-grade halogenated alkyl, Lower hydroxy alkyl, low-grade cycloalkyl alkylidene group, rudimentary heteroalicyclyl alkylene, aryl, heteroaryl, alkoxy carbonyl, amino, alkylamino, alkyl sulphonyl, aryl sulfonyl, alkyl amino sulfonyl, n-aryl sulfonyl, alkyl sulfonyl-amino, arlysulfonylamino, alkyl amino-carbonyl, aromatic yl aminocarbonyl, alkyl-carbonyl-amino, aryl-amino-carbonyl.Unless otherwise noted.The example of heteroalicyclyl includes but not limited to, morpholinyl, piperazinyl, piperidyl, azetidinyl, pyrrolidyl, six hydrogen azepine bases, oxetanyl, tetrahydrofuran base, tetrahydro-thienyl, oxazolidinyl, thiazolidyl, isoxazole alkyl, THP trtrahydropyranyl, sulfo-Lin Ji, quinuclidinyl and imidazolinyl, each group as previously mentioned, example can also be dicyclo, such as, such as, 3, 8-diaza-dicyclo [3.2.1] octane, 2, 5-diazabicyclo [2.2.2] octane or octahydro-pyrazine also [2, 1-c] [1, 4] oxazines.Its heteroalicyclyl (and derivative) comprises its ionic species.
" alkoxyl group " represents the unsubstituted alkyl of-O-() and the unsubstituted cycloalkyl of-O().Representational example includes but not limited to methoxyl group, oxyethyl group, propoxy-, butoxy, ring propoxy-, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy etc.
" hydroxyl " represents-OH group.
" halogen " represents fluorine, chlorine, bromine or iodine, is preferably fluorine or chlorine.
" haloalkyl " represents alkyl, preferably low alkyl group as defined above, and it is replaced by one or more identical or different halogen atom, such as-CH
2cl ,-CF
3,-CCl
3,-CH
2cF
3,-CH
2cCl
3deng.
" cyano group " represents-CN group.
" amino " expression-NH
2group.
The meaning of so-called " optionally " refers to that the event of subsequent descriptions or situation may also may can not occur, and this description comprises things or situation may also may can not occur, and this description comprises things or situation occurs and two kinds of situations do not occur.
In some embodiments, " replaced " of referring in the atom of specifying or group by one or more group, two, three or four hydrogen atoms are designated the identical or different group selected in the group of scope respectively and replace.
" pharmacy acceptable salt " represents the reservation biological effectiveness of parent compound and those salt of character.This kind of salt comprises:
(1) with sour salify, react by the free alkali of parent compound and mineral acid or organic acid and obtain, mineral acid comprises hydrochloric acid, Hydrogen bromide, nitric acid, phosphoric acid, metaphosphoric acid, sulfuric acid, sulfurous acid and perchloric acid etc., organic acid comprises acetic acid, propionic acid, vinylformic acid, oxalic acid, or (L) oxysuccinic acid (D), fumaric acid, toxilic acid, hydroxy-benzoic acid, gamma-hydroxybutyric acid, methoxybenzoic acid, phthalic acid, methylsulfonic acid, ethyl sulfonic acid, naphthalene-1-sulfonic acid, naphthalene-2-sulfonic acid, tosic acid, Whitfield's ointment, tartrate, citric acid, lactic acid, amygdalic acid, succsinic acid or propanedioic acid etc.,
(2) acid proton be present in parent compound replaced by metal ion or with organic bases ligand compound the salt that generates, metal ion is alkalimetal ion, alkaline-earth metal ions or aluminum ion such as, and organic bases is as thanomin, diethanolamine, trolamine, Trometamol, N-METHYL-ALPHA-L-GLUCOSAMINE etc.;
" pharmaceutical composition " refers to such as, by one or more or its pharmacy acceptable salt, solvate, hydrate or the prodrug in the compound in the present invention and other chemical composition, pharmaceutically acceptable carrier, mixing.The object of pharmaceutical composition promotes that administration is to the process of animal;
" pharmaceutical carrier " refers to and does not cause obvious pungency to organism and do not disturb the non-active ingredient in the biological activity of given compound and the pharmaceutical composition of character, such as but not limited to: calcium carbonate, calcium phosphate, various sugar (such as lactose, N.F,USP MANNITOL etc.), starch, cyclodextrin, Magnesium Stearate, Mierocrystalline cellulose, magnesiumcarbonate, acrylate copolymer or methacrylate polymer, gel, water, polyoxyethylene glycol, propylene glycol, ethylene glycol, Viscotrol C or hydrogenated castor oil or many ethoxy aluminium Viscotrol C, sesame oil, Semen Maydis oil, peanut wet goods;
In aforesaid pharmaceutical composition, except comprising pharmaceutically acceptable carrier, assistant agent conventional in medicine (agent) can also be included in, such as: antibacterial agent, anti-mycotic agent, biocide, preservative, toning agent, solubilizing agent, thickening material, tensio-active agent, complexing agent, protein, amino acid, fat, carbohydrate, VITAMIN, mineral substance, trace element, sweeting agent, pigment, essence or their combination etc.
Embodiment
Be used for further describing the present invention below in conjunction with embodiment, but these embodiments not limit scope of the present invention.
the preparation of embodiment 1:1-(5-(benzo [d] [1,3] dioxole-5-base)-1-(pyridin-3-yl-alkylsulfonyl)-1H-pyrroles-3-base)-N-methyl methylamine (compound 1)
1) preparation of 5-(benzo [d] [1,3] dioxole-5-base)-1H-pyrroles-3-formaldehyde (Compound C)
By the bromo-1H-pyrroles of 5--3-formaldehyde (compd A, 0.25g, 1.45mmol), benzo [d] [1,3] dioxole-5-ylboronic acid (compd B, 0.3g, 1.81mmol), Pd (PPh
3)
4(0.12g, 0.10mmol), Na
2cO
3(367mg, 3.46mmol), DME (5mL), water (2mL) is added in 25mL eggplant type bottle, stirs, is warming up to backflow, reaction 2h.Stopped reaction, naturally cools to room temperature, impouring frozen water (50mL), and EA (50mL*3) extracts.Merge organic relevant dry, concentrated, column chromatography (sherwood oil: ethyl acetate=2:1) obtains off-white color solid chemical compound
c(38mg, 12.23%), MS (ESI) m/z:[M+H]
+=216.1.
2) preparation of 5-(benzo [d] [1,3] dioxole-5-base)-1-(pyridin-3-yl-alkylsulfonyl)-1H-pyrroles-3-base formaldehyde (Compound D)
By 5-(benzo [d] [1,3] dioxole-5-base)-1H-pyrroles-3-formaldehyde (Compound C, 38mg, 0.17mmol), THF(2mL) wiring solution-forming, is added drop-wise to t-BuOK (61mg, 0.544mmol) at 0 DEG C, THF(2mL), in solution, drip and terminate rear continuation reaction 0.5h.Drip pyridine-3-SULPHURYL CHLORIDE (47.5mg, 0.267mmol) subsequently, the mixing solutions of 15-crown-5 (59mg, 0.268mmol).Drip and terminate, be naturally warming up to 25 DEG C of reaction 0.5h.Add frozen water 20mL after reaction terminates, ethyl acetate (20mL*3) extracts.Merge organic relevant dry, concentrated, column chromatography (sherwood oil: ethyl acetate=1:1) obtains yellow solid compound
d(40mg, yield 63.5%), MS (ESI) m/z:[M+H]
+=357.1.
3) preparation of 1-(5-(benzo [d] [1,3] dioxole-5-base)-1-(pyridin-3-yl-alkylsulfonyl)-1H-pyrroles-3-base)-N-methyl methylamine (compound 1)
By methylamine alcohol solution (96mg), Compound D (60mg, 0.1685mmol), acetic acid (0.5mL), methyl alcohol (2mL) is added in 25mL eggplant type bottle, 25 DEG C of stirring reaction 1h.Be cooled to 0 DEG C, slowly add NaBH
3cN (20mg, 0.337).Reaction 0.5h is continued after reinforced end.Poured into by reaction solution in 10mL frozen water, ethyl acetate (20mLx3) extracts.Merge organic relevant dry, concentrated, column chromatography (sherwood oil: ethyl acetate=1:1) obtains compound as white solid
1(15mg, 24%)
HPLC:95.3%;MS(ESI)m/z:[M+H]
+=372.2;
1H-NMR(400MHz,MeOD)δ:8.77(s,1H),8.50(s,1H),7.81(d,1H),7.72(s,1H),7.51(t,1H),6.78(d,1H),6.58(m,2H),6.30(d,1H),6.02(s,2H),4.07(s,2H),2.70(s,3H)ppm。
the preparation of embodiment 2:1-(5-(1H-indoles-5-base)-1-(pyridin-3-yl-alkylsulfonyl)-1H-pyrroles-3-base)-N-methyl methylamine (compound 2)
The preparation method of reference compound 1, obtains compound as white solid
2, yield 30%.HPLC:98.1%;MS(ESI)m/z:[M+H]
+=367.0;
1H-NMR(400MHz,DMSO-
d6)δ:11.21(s,1H),8.78(d,1H),8.39(s,1H),7.72(d,1H),7.51(m,1H),7.39(m,3H),7.34(m,1H),6.87(d,1H),6.43(s,1H),6.20(s,1H),3.45(s,2H),2.32(s,3H)ppm。
the preparation of embodiment 3:1-(5-(2,3-Dihydrobenzofuranes-5-base)-1-(pyridin-3-yl-alkylsulfonyl)-1H-pyrroles-3-base)-N-methyl methylamine (compound 3)
The preparation method of reference compound 1, obtains compound as white solid
3, yield 28%.HPLC:96.8%;MS(ESI)m/z:[M+H]
+=370.0;
1H-NMR(400MHz,DMSO-
d6)δ:8.82(d,1H),8.47(d,1H),7.76(d,1H),7.57(d,1H),7.35(s,1H),6.97(s,1H),6.87(d,1H),6.74(d,1H),6.19(s,1H),4.58(t,2H),3.45(s,2H),3.16(t,2H),2.21(s,3H)ppm。
test case:
h
+
/ K
+
-ATPase biological assessment
Body outer screening test is below used to evaluate the compounds of this invention for H
+/ K
+the effect of-ATPase inhibition of enzyme activity:
Experiment material and instrument:
1) rabbit gastric mucosa microsome (is rich in H
+/ K
+-ATPase, carries certainly)
2) 5-adenosine triphosphate atp (Sigma-Aldrich, article No.: A2383)
3) (lark waffle learns a skill company limited malachite green, article No.: 913120)
4) (lark waffle learns a skill company limited ammonium molybdate, article No.: 128321)
5) (lark waffle learns a skill company limited valinomycin, article No.: 227304)
Experimental procedure:
Reagent prepares:
1) compound DMSO dissolves and is mixed with suitable concentration;
2) damping fluid: 50mmol/LHEPEs-Tris, pH=6.5,5mmol/L magnesium chloride, 10 μm of ol/L valinomycin;
3) damping fluid: 50mmol/LHEPEs-Tris, pH=6.5,5mmol/L magnesium chloride, 10 μm of ol/L valinomycin, 5mmol/L Repone K;
4) ATP: dilute ATP to 5mM with damping fluid 1;
5) malachite green solution: 0.12% malachite green is dissolved in 2.5mol/L sulfuric acid, mixes in 100:25:2 ratio when 7.5% (V/V) ammonium molybdate and 11%Tween20 (V/V) use;
6) rabbit gastric mucosa microsome (being rich in H+/K+-ATPase), extracting method is sucrose gradient centrifugation: rabbit stomach tap water respectively, 3MNaCl solution is cleaned, and then removes surface-moisture with filter paper.Add the homogenate buffer (4ml/g tissue) of precooling, homogenate 2-5min in tissue refiner.After homogenate, if there is larger tissue particles, can centrifugal (600g, 10min) remove, then supernatant is moved in clean centrifuge tube after the centrifugal 30min of 20000g, then supernatant is moved in clean centrifuge tube, centrifugal further, the centrifugal 90min of 100000g, collecting precipitation; Utilize homogenate to suspend to precipitate, dispel evenly, utilize Bradford method to survey protein concentration, adjustment concentration is 10mg/ml; Equal proportion adds 7.5%Ficoll layering liquid, after the centrifugal 60min of 100000g, middle level (H+/K+-ATPaseenrichedgastricmembranes) is collected in clean centrifuge tube, utilizes homogenate 4-5 doubly to dilute, continue the centrifugal 90min of 100000g, collecting precipitation; Utilize homogenate to suspend to precipitate, glass homogenizer homogenate is even, utilizes Bradford method to survey protein concentration, adjustment concentration 22.5mg/ml.Freeze in-80 ° of C for subsequent use.
Experimentation:
Stomach mucous membrane microsome (the H of 5 μ L is added in 45 μ L damping fluids 2
+/ K
+-ATPase), then add the compound solution of 5 μ L, the ATP then adding 5 μ L5mM starts reaction, at 37 DEG C of pre-reaction 30min.Add 15 μ L malachite green solution termination reactions, equilibrium at room temperature 20min, read at 620nm place to absorb light value;
Meanwhile, carry out same volume, the reaction not adding Repone K as a setting, deducts when calculating enzymic activity;
Compound I C
50value is calculated by the inhibiting rate under different concns;
Experimental result: Compound I C
50value
The invention provides structure such as formula compound shown in I to H
+/ K
+half-inhibition concentration (the IC of-ATPase activity
50)
| TAK-438 | Compound 1 | Compound 2 | Compound 3 |
| +++ | ++ | +++ | ++ |
+++ represent IC
50<100nM; ++ represent scope 0.1 ~ 1 μM; + represent scope 1 ~ 5 μM.
Oneself is through to illustrate by way of example and the Method compare of embodiment describe in detail foregoing invention, for setting forth and the object of understanding.It will be apparent to one skilled in the art that and can carry out changes and improvements in the scope of appended claim.Therefore, should be appreciated that above-mentioned explanation is intended to is illustrative instead of restrictive.Therefore, scope of the present invention should not determined with reference to above-mentioned specification sheets, and with reference to following accompanying claim and should be determined by the four corner of the Equivalent of claims issue.
Claims (13)
1. structure compound as shown in the formula (I) or its tautomer, mesomeride, racemic modification, enantiomer, diastereomer or its form of mixtures or pharmacy acceptable salt:
In formula,
X, Y are selected from CR independently of one another
2or N;
R
1be selected from alkyl, cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl, wherein said alkyl, cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl are optionally selected from hydrogen, halogen, cyano group, hydroxyl, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl ,-OR by one or more
3,-NR
3r
4,-C (O) NR
3r
4,-S (O)
mr
3,-C (O) R
3,-OC (O) R
3or-C (O) OR
3substituting group replaced;
For fused rings, wherein ring A is cycloalkyl, Heterocyclylalkyl, phenyl, heteroaryl; Ring B is cycloalkyl, Heterocyclylalkyl, phenyl, heteroaryl; A, B are phenyl time different; Wherein optionally be selected from hydrogen, halogen, cyano group, hydroxyl, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl ,-OR by one or more
3,-NR
3r
4,-C (O) NR
3r
4,-S (O)
mr
3,-C (O) R
3,-OC (O) R
3or-C (O) OR
3substituting group replaced;
R
2be selected from hydrogen, halogen, alkyl;
R
3or R
4be selected from hydrogen atom, alkyl, cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl independently of one another, wherein said alkyl, cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl optionally by one or more be selected from the substituting group of halogen, cyano group, hydroxyl, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxyl group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, carboxyl, amide group or carboxylic acid ester groups replace;
M is selected from 0,1 or 2.
2. formula according to claim 1 (I) compound or its tautomer, mesomeride, racemic modification, enantiomer, diastereomer or its form of mixtures or pharmacy acceptable salt, wherein R
1be selected from aryl or heteroaryl, wherein said aryl or heteroaryl are optionally selected from hydrogen, halogen, cyano group, hydroxyl, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl ,-OR by one or more
3,-NR
3r
4,-C (O) NR
3r
4,-S (O)
mr
3,-C (O) R
3,-OC (O) R
3or-C (O) OR
3substituting group replaced;
R
3or R
4be selected from hydrogen atom, alkyl, cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl independently of one another, wherein said alkyl, cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl optionally by one or more be selected from the substituting group of halogen, cyano group, hydroxyl, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxyl group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, carboxyl, amide group or carboxylic acid ester groups replace;
M is selected from 0,1 or 2.
3., according to formula (I) compound of claim 1 ~ 2 or its tautomer, mesomeride, racemic modification, enantiomer, diastereomer or its form of mixtures or pharmacy acceptable salt, wherein, A is selected from phenyl, heteroaryl; B is cycloalkyl, Heterocyclylalkyl, phenyl, heteroaryl; A, B are phenyl time different; Wherein said cycloalkyl, Heterocyclylalkyl, phenyl, heteroaryl are optionally selected from hydrogen, halogen, cyano group, hydroxyl, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl ,-OR by one or more
3,-NR
3r
4,-C (O) NR
3r
4,-S (O)
mr
3,-C (O) R
3,-OC (O) R
3or-C (O) OR
3substituting group replaced;
R
3or R
4be selected from hydrogen atom, alkyl, cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl independently of one another, wherein said alkyl, cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl optionally by one or more be selected from the substituting group of halogen, cyano group, hydroxyl, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxyl group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, carboxyl, amide group or carboxylic acid ester groups replace;
M is selected from 0,1 or 2.
4., according to formula (I) compound of claim 1 ~ 3 or its tautomer, mesomeride, racemic modification, enantiomer, diastereomer or its form of mixtures or pharmacy acceptable salt, wherein X, Y are selected from CH or N independently of one another.
5., according to formula (I) compound of claim 1 ~ 4 or its tautomer, mesomeride, racemic modification, enantiomer, diastereomer or its form of mixtures or pharmacy acceptable salt, be wherein selected from:
deng.
6., according to formula (I) compound of claim 1 ~ 5 or its tautomer, mesomeride, racemic modification, enantiomer, diastereomer or its form of mixtures or pharmacy acceptable salt, described compound is selected from:
。
7., according to the compound shown in claim 6 or its tautomer, mesomeride, racemic modification, enantiomer, diastereomer or its form of mixtures or pharmacy acceptable salt, described compound is selected from:
。
8. a medicinal compositions, described pharmaceutical composition contains the compound shown in general formula (I) described in claim 1 ~ 6 any one of significant quantity or its tautomer, mesomeride, racemic modification, enantiomer, diastereomer or its form of mixtures or pharmacy acceptable salt and medicine acceptable carrier, vehicle or thinner.
9. the pharmaceutical composition of claim 7, it is gastric acid secretion inhibitor.
10. the pharmaceutical composition of claim 7, it is preparation H
+/ K
+purposes in-ATPase inhibitor.
The pharmaceutical composition of 11. claims 7, it is for preparing the purposes in the competitive sour retarding agent (P-CABs) of potassium ion.
12. pharmaceutical compositions according to claim 7, the purposes in the medicine of the ulcer that it is treatment or prevention peptide ulceration, Zollinger-Eillison syndrome, gastritis, erosive esophagitis, reflux esophagitis, symptomatic gastroesophageal reflux disease, Barrett esophagus inflammation, functional dyspepsia, Helicobacter pylori infection, cancer of the stomach, gastric MALT lymphoma, NSAID (non-steroidal anti-inflammatory drug) cause or the hyperchlorhydria that Post operation stress cause or ulcer; Or the purposes be used in the medicine of the upper gastrointestinal hemorrhage that peptide ulceration, acute stress ulcer, hemorrhagic gastritis or invasive stress cause is suppressed in preparation.
13. purposes according to claim 11, wherein said peptide ulceration is selected from stomach ulcer, duodenal ulcer or stoma ulcer; Described symptomatic gastroesophageal reflux disease is selected from the reflux diseases of Non-erosive or the gastroesophageal reflux disease without esophagitis.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410399065.8A CN105330647A (en) | 2014-08-14 | 2014-08-14 | Pyrrole sulfonamide derivative, preparation method and medical application thereof |
| PCT/CN2015/086603 WO2016023459A1 (en) | 2014-08-14 | 2015-08-11 | Pyrrole sulfonyl derivative, preparation method and medical use thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410399065.8A CN105330647A (en) | 2014-08-14 | 2014-08-14 | Pyrrole sulfonamide derivative, preparation method and medical application thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN105330647A true CN105330647A (en) | 2016-02-17 |
Family
ID=55281438
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410399065.8A Pending CN105330647A (en) | 2014-08-14 | 2014-08-14 | Pyrrole sulfonamide derivative, preparation method and medical application thereof |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN105330647A (en) |
| WO (1) | WO2016023459A1 (en) |
Cited By (17)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107875387A (en) * | 2016-09-29 | 2018-04-06 | 江苏柯菲平医药股份有限公司 | A kind of compound medicine containing pyrroles's sulphonyl analog derivative and application thereof |
| CN110117284A (en) * | 2018-02-06 | 2019-08-13 | 江苏奥赛康药业有限公司 | Nitrogen-containing hetero cyclics and its preparation method and application |
| CN111943932A (en) * | 2020-08-06 | 2020-11-17 | 四川国康药业有限公司 | 3-pyridine sulfonyl-1-N-heteropyrrole derivative capable of treating peptic ulcer and preparation method and application thereof |
| CN112300168A (en) * | 2019-07-26 | 2021-02-02 | 上海美迪西生物医药股份有限公司 | Pyrrolopyrazole derivative, preparation method and medical application thereof |
| CN112300167A (en) * | 2019-07-26 | 2021-02-02 | 上海美迪西生物医药股份有限公司 | Pyrrolopyrazole derivative, preparation method and medical application thereof |
| CN112300170A (en) * | 2019-07-26 | 2021-02-02 | 上海美迪西生物医药股份有限公司 | Pyrrolopyrazole derivative, preparation method and medical application thereof |
| CN112300169A (en) * | 2019-07-26 | 2021-02-02 | 上海美迪西生物医药股份有限公司 | Pyrrolopyrazole derivative, preparation method and medical application thereof |
| WO2021017065A1 (en) * | 2019-07-26 | 2021-02-04 | 上海美迪西生物医药股份有限公司 | Pyrrolopyrazole derivatives, preparation method therefor and application thereof in medicine |
| CN112390801A (en) * | 2019-08-15 | 2021-02-23 | 上海美迪西生物医药股份有限公司 | Pyrrolopyrazole derivative, preparation method and medical application thereof |
| CN112390802A (en) * | 2019-08-15 | 2021-02-23 | 上海美迪西生物医药股份有限公司 | Pyrrolopyrazole derivative, preparation method and medical application thereof |
| CN112480118A (en) * | 2019-09-12 | 2021-03-12 | 上海美迪西生物医药股份有限公司 | Pyrrolopyrazole derivative, preparation method and medical application thereof |
| CN112480117A (en) * | 2019-09-12 | 2021-03-12 | 上海美迪西生物医药股份有限公司 | Pyrrolopyrazole derivative, preparation method and medical application thereof |
| CN112480119A (en) * | 2019-09-12 | 2021-03-12 | 上海美迪西生物医药股份有限公司 | Pyrrolopyrazole derivative, preparation method and medical application thereof |
| WO2021104256A1 (en) * | 2019-11-25 | 2021-06-03 | 杭州华东医药集团新药研究院有限公司 | Heterocyclic derivative, pharmaceutical composition thereof and use thereof |
| CN115557876A (en) * | 2022-10-26 | 2023-01-03 | 四川国康药业有限公司 | 3-arylcyclylsulfonyl-1-N-heteropyrrole derivative for treating peptic ulcer, and its preparing process and application |
| WO2023280293A1 (en) * | 2021-07-09 | 2023-01-12 | 天地恒一制药股份有限公司 | Pyrrole sulfonyl derivative, preparation method therefor, and application thereof |
| WO2023280290A1 (en) * | 2021-07-09 | 2023-01-12 | 天地恒一制药股份有限公司 | Pyrrole sulfonyl derivative, and preparation method therefor and use thereof |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108794449B (en) * | 2017-05-05 | 2023-08-04 | 广东东阳光药业有限公司 | Synthetic method of deuterated fumaric acid vorofacian metabolite |
| CN112300123B (en) * | 2019-08-02 | 2023-07-18 | 上海天慈国际药业有限公司 | Preparation method of voronoi intermediate |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20110028476A1 (en) * | 2004-09-30 | 2011-02-03 | Masahiro Kajino | Proton pump inhibitors |
| CN102164581A (en) * | 2008-07-28 | 2011-08-24 | 武田药品工业株式会社 | Pharmaceutical composition |
-
2014
- 2014-08-14 CN CN201410399065.8A patent/CN105330647A/en active Pending
-
2015
- 2015-08-11 WO PCT/CN2015/086603 patent/WO2016023459A1/en active Application Filing
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20110028476A1 (en) * | 2004-09-30 | 2011-02-03 | Masahiro Kajino | Proton pump inhibitors |
| CN102164581A (en) * | 2008-07-28 | 2011-08-24 | 武田药品工业株式会社 | Pharmaceutical composition |
Non-Patent Citations (2)
| Title |
|---|
| HARUYUKI NISHIDA,ET AL.: "Discovery, synthesis, and biological evaluation of novel pyrrole derivatives as highly selective potassium-competitive acid blockers", 《BIOORGANIC & MEDICINAL CHEMISTRY》 * |
| MITSUYO KONDO,ET AL.: "High-Throughput Screening of Potassium-Competitive Acid Blockers", 《JOURNAL OF BIOMOLECULAR SCREENING》 * |
Cited By (29)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107875387A (en) * | 2016-09-29 | 2018-04-06 | 江苏柯菲平医药股份有限公司 | A kind of compound medicine containing pyrroles's sulphonyl analog derivative and application thereof |
| CN110117284B (en) * | 2018-02-06 | 2021-11-19 | 江苏奥赛康药业有限公司 | Nitrogen-containing heterocyclic compound and preparation method and application thereof |
| CN110117284A (en) * | 2018-02-06 | 2019-08-13 | 江苏奥赛康药业有限公司 | Nitrogen-containing hetero cyclics and its preparation method and application |
| WO2019154366A1 (en) * | 2018-02-06 | 2019-08-15 | 江苏奥赛康药业有限公司 | Nitrogen-containing heterocyclic compound, preparation method therefor and use thereof |
| CN112300169B (en) * | 2019-07-26 | 2022-03-04 | 上海美迪西生物医药股份有限公司 | Pyrrolopyrazole derivative, preparation method and medical application thereof |
| CN112300168A (en) * | 2019-07-26 | 2021-02-02 | 上海美迪西生物医药股份有限公司 | Pyrrolopyrazole derivative, preparation method and medical application thereof |
| CN112300170A (en) * | 2019-07-26 | 2021-02-02 | 上海美迪西生物医药股份有限公司 | Pyrrolopyrazole derivative, preparation method and medical application thereof |
| CN112300169A (en) * | 2019-07-26 | 2021-02-02 | 上海美迪西生物医药股份有限公司 | Pyrrolopyrazole derivative, preparation method and medical application thereof |
| WO2021017065A1 (en) * | 2019-07-26 | 2021-02-04 | 上海美迪西生物医药股份有限公司 | Pyrrolopyrazole derivatives, preparation method therefor and application thereof in medicine |
| WO2021017069A1 (en) * | 2019-07-26 | 2021-02-04 | 上海美迪西生物医药股份有限公司 | Pyrrolopyrazole derivative, preparation method therefor, and application thereof in medicine |
| WO2021017068A1 (en) * | 2019-07-26 | 2021-02-04 | 上海美迪西生物医药股份有限公司 | Pyrrolo-pyrazol derivatives, preparation method therefor and medical use thereof |
| CN112300167A (en) * | 2019-07-26 | 2021-02-02 | 上海美迪西生物医药股份有限公司 | Pyrrolopyrazole derivative, preparation method and medical application thereof |
| CN112300168B (en) * | 2019-07-26 | 2022-02-25 | 上海美迪西生物医药股份有限公司 | Pyrrolopyrazole derivative, preparation method and medical application thereof |
| CN112300170B (en) * | 2019-07-26 | 2022-01-21 | 上海美迪西生物医药股份有限公司 | Pyrrolopyrazole derivative, preparation method and medical application thereof |
| CN112300167B (en) * | 2019-07-26 | 2022-01-21 | 上海美迪西生物医药股份有限公司 | Pyrrolopyrazole derivative, preparation method and medical application thereof |
| CN112390801A (en) * | 2019-08-15 | 2021-02-23 | 上海美迪西生物医药股份有限公司 | Pyrrolopyrazole derivative, preparation method and medical application thereof |
| CN112390802A (en) * | 2019-08-15 | 2021-02-23 | 上海美迪西生物医药股份有限公司 | Pyrrolopyrazole derivative, preparation method and medical application thereof |
| CN112480118B (en) * | 2019-09-12 | 2022-03-11 | 上海美迪西生物医药股份有限公司 | Pyrrolopyrazole derivative, preparation method and medical application thereof |
| CN112480117A (en) * | 2019-09-12 | 2021-03-12 | 上海美迪西生物医药股份有限公司 | Pyrrolopyrazole derivative, preparation method and medical application thereof |
| CN112480118A (en) * | 2019-09-12 | 2021-03-12 | 上海美迪西生物医药股份有限公司 | Pyrrolopyrazole derivative, preparation method and medical application thereof |
| CN112480119A (en) * | 2019-09-12 | 2021-03-12 | 上海美迪西生物医药股份有限公司 | Pyrrolopyrazole derivative, preparation method and medical application thereof |
| CN112480117B (en) * | 2019-09-12 | 2022-03-29 | 上海美迪西生物医药股份有限公司 | Pyrrolopyrazole derivative, preparation method and medical application thereof |
| CN112480119B (en) * | 2019-09-12 | 2022-04-01 | 上海美迪西生物医药股份有限公司 | Pyrrolopyrazole derivative, preparation method and medical application thereof |
| WO2021104256A1 (en) * | 2019-11-25 | 2021-06-03 | 杭州华东医药集团新药研究院有限公司 | Heterocyclic derivative, pharmaceutical composition thereof and use thereof |
| CN111943932A (en) * | 2020-08-06 | 2020-11-17 | 四川国康药业有限公司 | 3-pyridine sulfonyl-1-N-heteropyrrole derivative capable of treating peptic ulcer and preparation method and application thereof |
| WO2023280293A1 (en) * | 2021-07-09 | 2023-01-12 | 天地恒一制药股份有限公司 | Pyrrole sulfonyl derivative, preparation method therefor, and application thereof |
| WO2023280290A1 (en) * | 2021-07-09 | 2023-01-12 | 天地恒一制药股份有限公司 | Pyrrole sulfonyl derivative, and preparation method therefor and use thereof |
| CN115594622A (en) * | 2021-07-09 | 2023-01-13 | 天地恒一制药股份有限公司（Cn） | Pyrrole sulfonyl derivative, and preparation method and application thereof |
| CN115557876A (en) * | 2022-10-26 | 2023-01-03 | 四川国康药业有限公司 | 3-arylcyclylsulfonyl-1-N-heteropyrrole derivative for treating peptic ulcer, and its preparing process and application |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2016023459A1 (en) | 2016-02-18 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN105330647A (en) | Pyrrole sulfonamide derivative, preparation method and medical application thereof | |
| CN105985278A (en) | Pyrrole sulfonyl derivatives, preparation method and medicinal application thereof | |
| CN105367550A (en) | Tetrahydrocyclopenta[c]pyrrole derivative, preparation method and medical applications thereof | |
| JP6445684B2 (en) | Indazole compounds as FGFR kinase inhibitors and their production and use | |
| CN105777756B (en) | Heteroaryl compound and its application in drug | |
| ES2392570T3 (en) | Quinoxaline derivatives as inhibitors of Janus tyrosine kinase kinase activity. | |
| CN102727498B (en) | Use the Therapeutic Method of Pyridopyrimidinone PI3K alpha inhibitor | |
| KR101538822B1 (en) | Specific inhibitors for vascular endothelial growth factor receptors | |
| CN105934248A (en) | Substituted pyroolopyridines and pyrrolopyrazines for treating cancer or inflammatory diseases | |
| CN106892916A (en) | The indazole inhibitors and its treatment use of WNT signal paths | |
| WO2023051716A1 (en) | Heteroaryl derivative parp inhibitor and use thereof | |
| CN105085483A (en) | Kinase inhibitor and application thereof | |
| CN107922340B (en) | 1,2,3, 4-tetrahydroisoquinoline derivatives, preparation method and application thereof | |
| CN104447740B (en) | Imidazolone derivative as well as drug composition and application thereof | |
| CN102712649B (en) | Benzimidazole derivatives and pharmaceutical compositions and uses thereof | |
| NO331505B1 (en) | (-) The enantiomer of tenatoprazole, a pharmaceutical composition containing it and its use for the preparation of a medical preparation for the treatment of disease | |
| CN108779089A (en) | Griseofulvin compounds | |
| CN105732615A (en) | CDK kinase inhibitor | |
| CN105524067A (en) | 4-substituted pyrrolo[2,3-d]pyrimidine compound and uses thereof | |
| WO2017045612A1 (en) | Pyrimidine derivative pim kinase inhibitor, preparation method therefor, and application thereof in medicine preparation | |
| CN105440016A (en) | Indole and azaindole derivative and preparation method and application thereof in medicines | |
| CN104203958B (en) | Bicyclic heterocycles derivative, its preparation and therapeutical uses | |
| CN104098551A (en) | Substituted quinazoline derivative as aurora kinase inhibitor | |
| CN105906616B (en) | The crystal form and preparation method thereof of LDE225 monophosphates | |
| CN105272963A (en) | 2-oxo-4-thio-3,4-dihydropyrimidine derivatives as dipeptidyl peptidase IV (DPP-IV) inhibitors |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20160217 |
|
| WD01 | Invention patent application deemed withdrawn after publication |