CN104447490B - A kind of crystal formation of proton pump inhibitor, prepare intermediate and its synthetic method and medical usage - Google Patents
A kind of crystal formation of proton pump inhibitor, prepare intermediate and its synthetic method and medical usage Download PDFInfo
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- CN104447490B CN104447490B CN201410664394.0A CN201410664394A CN104447490B CN 104447490 B CN104447490 B CN 104447490B CN 201410664394 A CN201410664394 A CN 201410664394A CN 104447490 B CN104447490 B CN 104447490B
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- fluorophenyls
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- WDKWVUQFMHVYIY-WAYWQWQTSA-N CC(C(C)NC)/C=C\C(F)=C Chemical compound CC(C(C)NC)/C=C\C(F)=C WDKWVUQFMHVYIY-WAYWQWQTSA-N 0.000 description 1
- DHVCQCJBSCDDDT-UHFFFAOYSA-N CC(C)(C)OC(N(C)Cc(cc1-c(cccc2)c2F)c[n]1S(c1cc(C[IH]C2CCC2)cc(OCC(NC)=O)c1)(=O)=O)=O Chemical compound CC(C)(C)OC(N(C)Cc(cc1-c(cccc2)c2F)c[n]1S(c1cc(C[IH]C2CCC2)cc(OCC(NC)=O)c1)(=O)=O)=O DHVCQCJBSCDDDT-UHFFFAOYSA-N 0.000 description 1
- 0 CCNCc(cc1C*(C(C)=C)=*=*(/C=C/C)F)c[n]1[S-]([N+]=*)(/[S+](/CC1=C/C1=C(/C*C)\*C(NC)=O)=C/*C)=O Chemical compound CCNCc(cc1C*(C(C)=C)=*=*(/C=C/C)F)c[n]1[S-]([N+]=*)(/[S+](/CC1=C/C1=C(/C*C)\*C(NC)=O)=C/*C)=O 0.000 description 1
- XUQIXISAJNKQBZ-UHFFFAOYSA-N CNC(COc1cccc(S=O)c1)=O Chemical compound CNC(COc1cccc(S=O)c1)=O XUQIXISAJNKQBZ-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/46—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with hetero atoms directly attached to the ring nitrogen atom
- C07D207/48—Sulfur atoms
Abstract
The invention discloses a kind of crystal formation of proton pump inhibitor, prepare intermediate and its synthetic method and medical usage.Specifically, the present invention relates to a kind of proton pump inhibitor containing pyrrole ring formula (1) shown in hemifumarate crystal formation, intermediate and preparation method thereof and medical usage, it is 7.858 that the XRD spectrum characteristic peak of the hemifumarate crystal formation has (± 0.2 °) of 2 θ angles, 9.456,13.202,14.836,15.099,15.749,15.050,19.948.Novel crystal forms of the invention have drug effect significantly, the advantages of Small side effects.
Description
Technical field
The present invention relates to field of medicaments, and in particular to a kind of proton pump inhibitor is 2- (3- ((2- (2- fluorophenyls) -4-
((methylamino) methyl) -1H- pyrroles -1- bases) sulfonyl) phenoxy group)-N- methylacetamide hemifumarates crystal formation, prepare in
Mesosome and preparation method thereof, and the crystal formation containing therapeutically effective amount medical composition and its use.
Background technology
Peptic ulcer refers to the tissue damage more than muscular layer of mucosa that gastrointestinal mucosa is caused by peptic digest liquid autodigestion,
Gastral any position can be betided, wherein most commonly seen with stomach and duodenum, i.e. gastric ulcer and duodenal ulcer, its
The cause of disease, clinical symptoms and treatment method are substantially similar, clarify a diagnosis mainly by gastrocopy.Gastric ulcer be in peptic ulcer most
Common one kind, is primarily referred to as the tissue damage more than muscular layer of mucosa that stomach lining is caused by peptic digest liquid autodigestion.
Gastric ulcer is one of common disease, frequently-occurring disease in population of China.As the common type in peptic ulcer, gastric ulcer
Geographical distribution substantially there is the north south to raise trend, and be apt to occur in the larger winter and spring of climate change.Additionally, male sends out
Sick rate apparently higher than women, may with smoking, life and diet it is irregular, work and ambient pressure and psychologic factors it is close
Cut is closed.In recent years, the incidence of disease of gastric ulcer starts on a declining curve, but it still belongs to most common disease in disease of digestive system
One of disease.Mainly loss of equilibrium has and the damage factor and mucous membrane self-defense reparation factor of gastroduodenal mucous membrane between for its generation
Close.Helicobacter pylori (H.pylori) infection, NSAIDs (NSAID, such as aspirin), gastric acid secretion cause extremely
The common disease factor of ulcer.The characteristics of typical canker sores have chronicity, periodicity and rhythmicity.Wherein, how good gastric ulcer is
Send out in small curved at stomach angle and antrum, be more common in Elderly male patient, its morbidity has certain relation with seasonal variations.
In gastral cavity, hydrochloric acid in gastric juice and pepsin are important digestion materials in gastric juice.Hydrochloric acid in gastric juice is highly acid material, with stronger
Aggressivity；Pepsin has the effect of aminosal, the protein that can be destroyed on coat of the stomach, however, these erosion because
In the presence of element, intestines and stomach remain to the integrality and the function of itself for resisting and maintaining mucous membrane, and it is primarily due to stomach, 12 fingers
Intestinal mucosa also has series of defence and repair mechanism.The harmful aggressive of hydrochloric acid in gastric juice and pepsin is referred to as damage machine by us
System, and defence that intestines and stomach itself are had and repair mechanism referred to as protection mechanism.It is now recognized that the stomach 12 of normal person refers to
The protection mechanism of intestinal mucosa, it is sufficient to resist the erosion of hydrochloric acid in gastric juice and pepsin.But, in some factors compromise protection mechanism
Certain link hydrochloric acid in gastric juice may occur and protease corrodes itself mucous membrane and causes the formation of ulcer.When excessive gastric acid secretion is remote
The defence and repair for exceeding well over mucous membrane are likely to cause ulcer to occur.In recent years research it has been shown that helicobacter pylori and
NSAIDs is to damage stomach and intestine protection mechanism to cause the most commonly encountered diseases that ulcer is fallen ill because hydrochloric acid in gastric juice plays key in ulcer is formed
Effect.Additionally, medicine, stress, hormone may also lead to the generation of ulcer, and various psychological factors and bad dietary life habits can
The appearance of induced ulcer.
Clinically mainly there are bisfentidine (H2-RA) and proton pump inhibitor (PPI) at present.H2-RA can suppress base
Plinth and the gastric acid secretion of stimulation, it is conventional such as Cimetidine, ranitidine, famotidine and nizatidine；It is thin that PPI acts on wall
Born of the same parents' gastric acid secretion key enzyme H+-K+ATP enzymes eventually in the step of end, make its irreversible inactivation, and Acidinhibitor is stronger and persistent.
PPI promotes the speed of ulcer healing, healing rate higher, it is adaptable to which various intractable ulcers or NSAID ulcers can not
Treatment during NSAID is disabled, can also can be used for Helicobacter pylori eradication for treatment with the synergy of antibiotic, therefore be gastric ulcer
First-selected medication.Conventional PPI has Omeprazole, Lansoprazole, Rabeprazole, esomeprazole, Iprazole etc..
2- (3- ((2- (2- fluorophenyls) -4- ((methylamino) methyl) -1H- pyrroles -1- bases) sulfonyl) phenoxy group)-N- first
Yl acetamide hemifumarate is a kind of proton pump inhibitor containing pyrrole ring, with drug effect significantly, the advantages of Small side effects,
There are huge potentiality in Gastric Ulcer Treatment is treated.
The content of the invention
It is an object of the invention to provide 2- (3- ((2- (2- fluorophenyls) -4- ((methylamino) first shown in a kind of formula (1)
Base) -1H- pyrroles -1- bases) sulfonyl) phenoxy group)-N- methylacetamide hemifumarates crystal formation, be that one kind contains pyrrole ring
Proton pump inhibitor.
Formula (1)
It is 7.858,9.456,13.202,14.836,15.099 that the XRD spectrum of the crystal formation has (± 0.2 °) of 2 θ angles,
15.749,15.050,19.948 characteristic peak, it is preferred that (± 0.2 °) is 19.901,20.922,22.423 also containing 2 θ angles,
24.867 characteristic peak, particularly preferred, the XRD spectrum of the crystal formation is as shown in Figure 2.
Preparation method another object of the present invention is to provide the hemifumarate shown in a kind of formula (1), by that will change
Compound (2) 2- (3- ((2- (2- fluorophenyls) -4- ((methylamino) methyl) -1H- pyrroles -1- bases) sulfonyl) phenoxy group)-N- first
Yl acetamide is obtained in organic solvent with fumaric acid into salt crystallization.
Preferably, the preparation method comprises the following steps：
1. by formula (2) compound 2- (3- ((2- (2- fluorophenyls) -4- ((methylamino) methyl) -1H- pyrroles -1- bases) sulphonyl
Base) phenoxy group)-N- methylacetamides are dissolved in organic solvent, add fumarate solid or fumaric acid solution；
2. by above-mentioned reaction solution agitating heating；
3. cooling crystallization obtains formula (1).
Preferably, described organic solvent is alcohols solvent.
Preferably, the alcohols solvent is selected from one or two in isopropanol or absolute ethyl alcohol, it is furthermore preferred that working as alcohols
When solvent is isopropanol/absolute ethyl alcohol mixed solvent, wherein the ratio of isopropanol is 0.1%~100%.
Preferably, the mixed solvent system is isopropanol/absolute ethyl alcohol, and both volume ratios are 4:1.
Preferably, the fumaric acid solution is the ethanol solution of fumaric acid.
Preferably, the molar equivalent of the fumaric acid is 0.1~0.8 equivalent of formula (2) compound, more preferably 0.4~0.5
Equivalent, more preferably 0.45~0.47 equivalent.
Preferably, the temperature of agitating heating is 50~82 DEG C, preferably reflux temperature.
Another object of the present invention also resides in a kind of medicine group comprising the crystal formation and one or more excipient of offer
Compound.
Preferably, the existence form of said composition is tablet or capsule.
Another object of the present invention also resides in the offer crystal formation or the pharmaceutical composition comprising the crystal formation and is preparing treatment
Purposes in gastroesophageal reflux, peptic ulcer, gastric ulcer, duodenal bulbar ulcer or esophagitis medicine.
The present invention is obtained the compound crystal form first, and gained crystal formation is stable in properties, is adapted to medical applications, with good city
Field prospect.
Another object of the present invention to be also resided in and prepare 2- (3- ((2- (2- fluorophenyls) -4- shown in a kind of formula (III) of offer
((methylamino) methyl) -1H- pyrroles -1- bases) sulfonyl) phenoxy group) and-N- methylacetamide hemifumarates intermediate
Another object of the present invention also resides in the method for providing and preparing the intermediate, including by the tert-butyl group ((5- (2- fluorine
Phenyl) -1H- pyrroles -3- bases) methyl) (methyl) carbonic ester and 3- (2- (methylamino) -2- oxoethoxies) phenyl -1- sulphonyl
Chlorine is condensed prepared in organic solvent.
Preferably, the organic solvent is selected from benzene,toluene,xylene, acetonitrile or DMF.
Another object of the present invention also resides in a kind of method for preparing the intermediate free bases of offer, including by the formula
(III) compound is passed through hydrogen chloride gas, and pH to alkalescence is adjusted with alkaline matter.
Preferably, the alkaline matter is selected from sodium acid carbonate, NaOH or sodium carbonate.
Crystal formation of the present invention is stable in properties, is especially suitable for pharmaceutical preparation application.
Brief description of the drawings
Fig. 1：2- (3- ((2- (2- fluorophenyls) -4- ((methylamino) methyl) -1H- pyrroles -1- bases) sulfonyl) benzene of the present invention
Epoxide)-N- methylacetamide hemifumarates 1H-NMR collection of illustrative plates.
Fig. 2：2- (3- ((2- (2- fluorophenyls) -4- ((methylamino) methyl) -1H- pyrroles -1- bases) sulfonyl) benzene of the present invention
Epoxide)-N- methylacetamide hemifumarate crystal formations XRD spectrum.
Specific embodiment
Embodiment one：By 2- (3- ((2- (2- fluorophenyls) -4- ((methylamino) methyl) -1H- pyrroles -1- bases) sulfonyl)
Phenoxy group)-N- methylacetamide 10g, it is dissolved in the mixed solvent of isopropanol (80ml) and absolute ethyl alcohol (20ml), in stirring
Under the conditions of add fumaric acid 1.26g, be heated to afterwards 50 DEG C flow back 30 minutes, room temperature is naturally cooled under conditions of stirring,
Stirring 2 hours, filtering, is dried to obtain 2- (3- ((2- (2- fluorophenyls) -4- ((methylamino) methyl) -1H- pyrroles -1- bases) sulphonyl
Base) phenoxy group)-N- methylacetamide hemifumarates, target crystal formation is obtained, crystal formation 1 is named as, weigh 9.8g, mass yield
98%, its 1H-NMR collection of illustrative plates is as shown in figure 1, XRD spectrum is as shown in Figure 2.
Embodiment two：By 2- (3- ((2- (2- fluorophenyls) -4- ((methylamino) methyl) -1H- pyrroles -1- bases) sulfonyl)
Phenoxy group)-N- methylacetamide 10g, isopropanol (80ml) is dissolved in, the ethanol solution (1.26g/20ml) of fumaric acid is added, plus
To flowing back, solid is all dissolved heat, and room temperature is naturally cooled under conditions of stirring, is stirred 2 hours, and filtering is dried to obtain 2- (3-
((2- (2- fluorophenyls) -4- ((methylamino) methyl) -1H- pyrroles -1- bases) sulfonyl) phenoxy group) richness of-N- methylacetamides half
Horse hydrochlorate, obtains target crystal formation, is named as crystal formation 1, and weigh 9.6g, mass yield 96%, its 1H-NMR collection of illustrative plates substantially with Fig. 1 phases
Together, XRD spectrum is coincide with Fig. 2 substantially, meets the feature of crystal formation 1.
Embodiment 3：2- (3- ((2- (2- fluorophenyls) -4- ((methylamino) methyl) -1H- pyrroles -1- bases) sulfonyl) benzene oxygen
Base)-N- methylacetamide hemifumarate intermediates and free alkali preparation
The first step
By the tert-butyl group ((5- (2- fluorophenyls) -1H- pyrroles -3- bases) methyl) (methyl) carbonic ester (3.0g, 10mmol) and
3- (2- (methylamino) -2- oxoethoxies) phenyl -1- sulfonic acid chlorides (2.64mg, 10mmol), adds in acetonitrile, adds DIEA to stir
Mix reaction 2~5 hours.Reaction solution is lowered the temperature, and adds watery hydrochloric acid regulation pH to 4~5, adds purified water crystallization, obtains compound III,
4.9g, yield：92.3%.
Second step
Compound III (4.5g) is dissolved in the ethyl acetate of 15mL, ice bath cools down reacting liquid temperature to 10 DEG C, input
Hydrogen chloride gas, stirring reaction 1 hour.PH is adjusted to alkalescence for sodium acid carbonate, is washed with saturated nacl aqueous solution, anhydrous sodium sulfate
Dry, filtering, filtrate decompression concentration is purified with silica gel column chromatography with eluant, eluent system B (n-hexane and ethyl acetate system)
Gained residue, obtains 2- (3- ((2- (2- fluorophenyls) -4- ((methylamino) methyl) -1H- pyrroles -1- bases) sulfonyl) benzene oxygen
Base)-N- methylacetamides (3.0g, colorless oil), yield：82.2%.
The study on the stability of experimental example one, crystal formation：
Crystal formation of the present invention 1 (embodiment 1 be obtained) is carried out 3 months accelerated stabilities (setting-out condition is 40 DEG C ± 2 DEG C,
The experiment investigation of RH75 ± 5%), sample is provided by Jiangsu Haosen Pharmaceutical Co., Ltd, three crystal formation products difference of batch
VP-130401, VP-130402 and VP-130403 are named as, 1 is see the table below with the initial X-ray powder diffraction Data Comparison of sample
~2, relevant material stability is shown in Table 3.
The accelerated stability X-ray powder diffraction Data Comparison (- 2 θ) of table 1.
Accelerated stability X-ray powder diffraction Data Comparison (- d) of table 2.
The accelerated stability qualitative data of table 3. is contrasted
Above-mentioned 3 months accelerated stability as shown by data, crystal formation 1 has good stabilization.
Claims (19)
1. a kind of 2- (3- ((2- (2- fluorophenyls) -4- ((methylamino) methyl) -1H- pyrroles -1- bases) sulfonyl) phenoxy group)-N-
Methylacetamide hemifumarate crystal formation, structural formula such as formula (1),
It is 7.858,9.456,13.202,14.836,15.099,15.749 that its XRD spectrum characteristic peak has (± 0.2 °) of 2 θ angles,
15.050,19.948,19.901,20.922,22.423,24.867.
2. 2- (3- ((2- (2- fluorophenyls) -4- ((methylamino) methyl) -1H- pyrroles -1- bases) sulphurs according to claim 1
Acyl group) phenoxy group)-N- methylacetamide hemifumarate crystal formations, it is characterised in that the XRD spectrum of the crystal formation such as specification
Shown in accompanying drawing 2.
3. 2- (3- ((2- (2- fluorophenyls) -4- ((methylamino) methyl) -1H- pyrroles -1- bases) sulphurs according to claim 1
Acyl group) phenoxy group)-N- methylacetamide hemifumarate crystal formations preparation method, methods described is by formula (2) compound 2- (3-
((2- (2- fluorophenyls) -4- ((methylamino) methyl) -1H- pyrroles -1- bases) sulfonyl) phenoxy group)-N- methylacetamides with it is rich
Horse acid is obtained in organic solvent into salt crystallization, and the organic solvent is alcohols solvent,
4. preparation method according to claim 3, comprises the following steps：
1) by formula (2) compound 2- (3- ((2- (2- fluorophenyls) -4- ((methylamino) methyl) -1H- pyrroles -1- bases) sulfonyl)
Phenoxy group)-N- methylacetamides are dissolved in organic solvent, add fumarate solid or fumaric acid solution, the organic solvent
It is alcohols solvent；
2) by above-mentioned reaction solution agitating heating；
3) cooling crystallization obtains formula (1).
5. the preparation method according to any one of claim 3 or 4, it is characterised in that the alcohols solvent is selected from isopropyl
One or two in alcohol or absolute ethyl alcohol.
6. preparation method according to claim 5, it is characterised in that when alcohols solvent is that isopropanol and absolute ethyl alcohol mix
During solvent, wherein the ratio of isopropanol is 0.1%~100%.
7. preparation method according to claim 6, it is characterised in that the mixed solvent system is isopropanol and anhydrous second
Alcohol, both volume ratios are 4:1.
8. preparation method according to claim 4, it is characterised in that the fumaric acid solution is that the ethanol of fumaric acid is molten
Liquid.
9. preparation method according to claim 4, it is characterised in that the molar equivalent of fumaric acid for formula (2) 0.1~
0.8 equivalent.
10. preparation method according to claim 9, it is characterised in that the molar equivalent of fumaric acid for formula (2) 0.4~
0.5 equivalent.
11. preparation methods according to claim 10, it is characterised in that the molar equivalent of fumaric acid is the 0.45 of formula (2)
~0.47 equivalent.
12. preparation methods according to claim 4, it is characterised in that the temperature of agitating heating is 50~82 DEG C.
13. preparation methods according to claim 12, it is characterised in that the temperature of agitating heating is reflux temperature.
14. a kind of pharmaceutical compositions, comprising 2- according to claim 1 (3- ((2- (2- fluorophenyls) -4- ((methylamino)
Methyl) -1H- pyrroles -1- bases) sulfonyl) phenoxy group)-N- methylacetamide hemifumarate crystal formations and one or more figuration
Agent.
15. pharmaceutical compositions according to claim 14, the existence form of said composition is tablet or capsule.
16. 2- (3- ((2- (2- fluorophenyls) -4- ((methylamino) methyl) -1H- pyrroles -1- bases) according to claim 1
Sulfonyl) phenoxy group)-N- methylacetamide hemifumarate crystal formations or the pharmaceutical composition described in claim 16 control in preparation
Treat gastroesophageal reflux, peptic ulcer, gastric ulcer, the application in duodenal bulbar ulcer or esophagitis medicine.
17. prepare 2- (3- ((2- (2- fluorophenyls) -4- ((methylamino) the methyl) -1H- pyrroles -1- bases) sulphurs shown in formula (III)
Acyl group) phenoxy group)-N- methylacetamide hemifumarate intermediates method, including by the tert-butyl group ((5- (2- fluorophenyls)-
1H- pyrroles -3- bases) methyl) (methyl) carbonic ester having with 3- (2- (methylamino) -2- oxoethoxies) phenyl -1- sulfonic acid chlorides
It is condensed in machine solvent and is obtained,
The organic solvent is acetonitrile.
18. prepare 2- (3- ((2- (2- fluorophenyls) -4- ((methylamino) the methyl) -1H- pyrroles -1- bases) sulphurs shown in formula (III)
Acyl group) phenoxy group)-N- methylacetamide hemifumarate intermediates free alkali method, including by the formula (III) chemical combination
Thing is passed through hydrogen chloride gas, and pH to alkalescence is adjusted with alkaline matter.
19. preparation methods according to claim 18, it is characterised in that the alkaline matter is selected from sodium acid carbonate, hydrogen-oxygen
Change sodium or sodium carbonate.
Priority Applications (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710107080.4A CN106957252B (en) | 2014-11-19 | 2014-11-19 | A kind of proton pump inhibitor intermediate and preparation method thereof |
| CN201410664394.0A CN104447490B (en) | 2014-11-19 | 2014-11-19 | A kind of crystal formation of proton pump inhibitor, prepare intermediate and its synthetic method and medical usage |
| CN201580059766.XA CN107001262A (en) | 2014-11-19 | 2015-11-18 | The hemifumarate and its crystal formation of the proton pump inhibitor containing pyrrole ring, intermediate and medical usage |
| PCT/CN2015/094958 WO2016078594A1 (en) | 2014-11-19 | 2015-11-18 | Pyrrole ring-containing proton pump inhibitor being hemifumarate and crystal form thereof, intermediate and medical use thereof |
| TW104138403A TW201619129A (en) | 2014-11-19 | 2015-11-19 | A hemifumarate of a proton pump inhibitor with pyrrole, crystal form, intermediate and medical use thereof |
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| CN201410664394.0A CN104447490B (en) | 2014-11-19 | 2014-11-19 | A kind of crystal formation of proton pump inhibitor, prepare intermediate and its synthetic method and medical usage |
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| WO2016078594A1 (en) * | 2014-11-19 | 2016-05-26 | 江苏豪森药业集团有限公司 | Pyrrole ring-containing proton pump inhibitor being hemifumarate and crystal form thereof, intermediate and medical use thereof |
| KR102081920B1 (en) * | 2016-03-25 | 2020-02-26 | 주식회사 대웅제약 | Novel crystalline form of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1h-pyrrol-3-yl)-n-methylmethanamine salt |
| KR20170113040A (en) * | 2016-03-25 | 2017-10-12 | 주식회사 대웅제약 | Novel acid addition salt of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1h-pyrrol-3-yl)-n-methylmethanamine |
| FI3625213T3 (en) * | 2017-05-19 | 2023-05-29 | Integrative Res Laboratories Sweden Ab | (+)-3-(2,3-difluorophenyl)-3-methoxypyrrolidine fumarate, a process for its preparation and uses thereof |
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| NZ536444A (en) * | 2002-05-17 | 2006-12-22 | Merckle Gmbh | Annelated pyrrole compounds as gastric proton pump inhibitors for treating ulcer |
| NZ566378A (en) * | 2005-08-30 | 2011-03-31 | Takeda Pharmaceutical | 1-Heterocyclylsulfonyl, 2-aminomethyl, 5-(hetero-) aryl substituted 1-H-pyrrole derivatives as acid secretion inhibitors |
| SG178557A1 (en) * | 2009-09-14 | 2012-03-29 | Suven Life Sciences Ltd | L -dihydro-2-oxoquinoline compounds a 5-ht4 receptor ligands |
| WO2011036130A1 (en) * | 2009-09-24 | 2011-03-31 | F. Hoffmann-La Roche Ag | Indole derivatives as crac modulators |
| WO2014075575A1 (en) * | 2012-11-19 | 2014-05-22 | 江苏豪森药业股份有限公司 | Pyrrole sulfonamide derivative, preparation method for same, and medical application thereof |
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