CN1453278A - Omprazole compound and its prepn and application - Google Patents

Omprazole compound and its prepn and application Download PDF

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CN1453278A
CN1453278A CN 02117637 CN02117637A CN1453278A CN 1453278 A CN1453278 A CN 1453278A CN 02117637 CN02117637 CN 02117637 CN 02117637 A CN02117637 A CN 02117637A CN 1453278 A CN1453278 A CN 1453278A
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compound
salt
methoxyl group
formula
imidazo
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李庶心
赵砚瑾
郭金华
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Institute of Radiation Medicine of CAMMS
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Institute of Radiation Medicine of CAMMS
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Abstract

The present invention discloses one kind of Omeprazole compound and its preparation and application. The present invention aims at providing one kind of compound with relatively strong H+/K+-ATP enzyme inhibiting activity. The compound may be S-configuration non-racemate compound and its salt or R-configuration non-racemate compound and its salt.

Description

A kind of Omprazole compound and preparation method thereof and application
Technical field
The present invention relates to a kind of Omprazole compound and preparation method thereof and application.
Background technology
H +/ K +-atpase inhibitor, promptly proton pump inhibitor (PPI) is the novel gastric acid inhibitory excretory medicine of a class.H +/ K +-ATP enzyme (proton pump), be positioned on the tubulovesicle and secretion periosteum of parietal cell, participate in last link of gastric acid secretion, the activity that suppresses this enzyme, can suppress the gastric acid secretion that various factors causes, PPI is mainly used in treatment stomach ulcer, duodenal ulcer, reflux esophagitis and assistant-syndrome etc. and gastric acid secretion imbalance diseases associated.This class medicine is than histamine H 2-receptor antagonist and other gastric acid inhibitory excretory medicine have obvious superiority, as selectivity height, good effect, few side effects, can eliminate Hp (stomach ulcer pathogenic bacterium) etc. with the compound preparation of microbiotic compatibility.The proton pump inhibitor of existing approved listing has omeprazole (listing in 1988), orchid to tremnble to draw azoles (listing in 1991), dissolves appropriate azoles (listing in 1994) and the rabeprazole (listing in 1997) of drawing.5-methoxyl group-2-[(4-methoxyl group-3,5-dimethyl-2-pyridylmethyl) sulfinyl] imidazo [4,5-b] pyridine is a kind ofly can suppress stomach H +/ K +The raceme compound of-ATP enzyme relatively has with other kind of the same type and to suppress H more significantly +/ K +The activity of-ATP enzyme, all effective to various test ulcer, and steady quality.
Summary of the invention
The purpose of this invention is to provide a kind of strong H that has +/ K +The compound of-ATP enzyme inhibition activity.
Compound provided by the present invention is non-raceme formula (I) compound of S-configuration and salt or non-raceme formula (II) compound of R-configuration and the salt of this compound thereof of this compound thereof.
The formed salt of The compounds of this invention, its character does not have particular restriction, has only when they make therepic use, should be pharmaceutically acceptable.When as therepic use, can form salt with alkali, for example, with basic metal, as the salt of sodium, potassium or lithium formation; The salt that becomes with alkaline-earth metal such as barium or calcium; With other metal, as the salt of magnesium or aluminium formation; Also can form salt with organic bases, as with dicyclohexylamine, the salt that guanidine or triethylamine form; Also can form salt, as the salt that forms with Methionin or arginine with basic aminoacids.Simultaneously, owing to contain basic group in the The compounds of this invention molecule, thereby can form acid salt.The example of this class acid salt comprises: with mineral acid, and haloid acid (as hydrofluoric acid, Hydrogen bromide, hydroiodic acid HI, spirit of salt) especially, nitric acid, carbonic acid, sulfuric acid or phosphoric acid form salt; With low alkyl group sulfonic acid, as methylsulfonic acid, trifluoromethanesulfonic acid or monosulfonic acid form salt; With aryl sulfonic acid, form salt as Phenylsulfonic acid or tosic acid; With organic carboxyl acid, as acetate, fumaric acid, tartrate, oxalic acid, toxilic acid, oxysuccinic acid, succsinic acid or citric acid form salt; With amino acid, form salt as L-glutamic acid or aspartic acid.Above-mentioned salt can be handled with acid or alkali by known common means, changes into pharmacy acceptable salt.
Second purpose of the present invention provides a kind of method of production Omprazole compound of the present invention easily and effectively.
For achieving this end, the present invention by the following technical solutions:
A kind of preparation 5-methoxyl group-2-[(s)-(4-methoxyl group-3; 5-dimethyl-2-pyridylmethyl) sulfinyl] imidazo [4; 5-b] method of pyridine; be with 2-(4-methoxyl group-3; 5-dimethyl-2-pyridyl methylthio group)-5-methoxyl group-3H-imidazo [4; 5-b] pyridine and titanium isopropoxide, cumene hydroperoxide thing, reaction obtains the purpose product in the presence of (-)-D-diethyl tartrate.
The sulfinyl of a kind of preparation 5-methoxyl group-2-[(R)-(4-methoxyl group-3,5-dimethyl-2-pyridylmethyl)] method of imidazo [4,5-b] pyridine, be to be chiral support with cell biological lytic enzyme I immobilization silica gel (CBH I-Silica), NaH 2PO 4(pH4)/CH 3CN (1: 1) is that moving phase separates raceme 5-methoxyl group-2-[(4-methoxyl group-3,5-dimethyl-2-pyridylmethyl) sulfinyl] imidazo [4,5-b] pyridine obtains the purpose product.
In above-mentioned preparation method, raw material 2-(4-methoxyl group-3,5-dimethyl-2-pyridyl methylthio group)-5-methoxyl group-3H-imidazo [4,5-b] pyridine can be bought on market or synthesize according to following reaction formula:
Figure A0211763700051
In above-mentioned reaction, a:HNO 3, H 2SO 4B:NH 3/ C 2H 5OH; C:NaOCH 3/ THF; D:H 2/ Raney Ni/THF; E: sulphur ortho acid potassium/C 2H 5OH; F:2-chloromethyl-4-methoxyl group-3,5-lutidine muriate, NaOH/C 2H 5OH; G: titanium isopropoxide, cumene hydroperoxide thing, (-)-D-diethyl tartrate, DIEA.
The compounds of this invention is an optically active body, can improve the administration consistence, and improves curative effect.The compounds of this invention has the good restraining effect to H+/K+ATP enzyme, gastric acid secretion, thereby be that the medicine of activeconstituents can be used for prevention or treatment digestive system with it, as stomach ulcer, duodenal ulcer, reflux esophagitis and assistant-Emhorn syndromes etc. and gastric acid secretion imbalance diseases associated.
When needing, in said medicine, can also contain one or more pharmaceutically acceptable carriers.Described carrier comprises thinner, vehicle, weighting agent, tackiness agent, wetting agent, disintegrating agent, absorption enhancer, tensio-active agent, absorption carrier, lubricant of pharmaceutical field routine etc., can also add flavouring agent, sweeting agent etc. in case of necessity.
Medicine of the present invention can be made various ways such as tablet, pulvis, granula, capsule, oral liquid and injection liquid.The medicine of above-mentioned various formulations all can be according to the ordinary method preparation of pharmaceutical field.
The consumption of said medicine is generally 1-100mg/kg body weight every day.
The present invention will be further described below in conjunction with specific embodiment.
Embodiment
The sulfinyl of embodiment 1, preparation 5-methoxyl group-2-[(s)-(4-methoxyl group-3,5-dimethyl-2-pyridylmethyl)] imidazo [4,5-b] pyridine
1, preparation 3-nitro-2 ,-6-dichloropyridine
In the three neck round-bottomed flasks of 250ml, add oleum 30ml, the ice bath cooling adds 2 down, 6-dichloropyridine 10g, controlled temperature is about 40 ℃.Finish, be chilled to 5 ℃ after, slowly drip concentrated nitric acid/vitriol oil (30: 48) mixing solutions 20ml, controlled temperature is below 60 ℃, and feeding in raw material finishes stirring at room 1 hour, slowly be warmed up to 140 ℃ of reactions then, stirred 5 hours, thin-layer chromatography shows that raw material reaction finishes.Cool overnight is slowly poured in the pure ice next day, has a large amount of white solids to separate out.After leaving standstill 1 hour, filter, solid washes with water to neutrality, and the dry light yellow solid that gets gets white solid 3-nitro-2 with the sherwood oil recrystallization ,-6-dichloropyridine 10g, productive rate 76.7%, m.p.61-62 ℃.
2, preparation 2-amino-3-nitro-6-chloropyridine
In the three neck round-bottomed flasks of 250ml, add dehydrated alcohol 100ml, ice bath feeds ammonia down, near saturated after, add 3-nitro-2,6-dichloropyridine 20g stirs, solid dissolves rapidly.Behind the stir about 30 minutes, have solid to separate out, room temperature continued to stir after 3 hours, standing over night.Filter next day, solid washes with water 3 times with washing with alcohol 3 times, dry solid.After ethanol is concentrated into an amount of volume, pour in the water of 2 times of amount volumes, filter, handles the samely, merge common yellow solid 2-amino-3-nitro-6-chloropyridine 15.5g, productive rate 86.1%, m.p.196.5-197 ℃.
3, preparation 2-amino-3-nitro-6-methoxypyridine
In the three neck round-bottomed flasks of 1000ml, add tetrahydrofuran (THF) 450ml, stir adding 2-amino-3-nitro-6-chloropyridine 82g down, gradation adds sodium methylate, and heat release also becomes redness rapidly, adds sodium methylate 40g altogether.Finish, stirring at room is after 0.5 hour, and slowly temperature rising reflux is 3 hours.Leave standstill cooling, filter, solid is washed 3 times again and is got red solid with tetrahydrofuran (THF) washing 3 times.Tetrahydrofuran solution concentrates, and cooling has solid to separate out again in falling back, and filters and washing.Altogether solid 65.0g, productive rate 81.5%, m.p.213-6 ℃.
4, preparation 2,3-diamino-6-methoxypyridine
2-amino-3-nitro-6-methoxypyridine 100g, tetrahydrofuran (THF) 1000ml, Raney Ni 100g, under 20 normal atmosphere, logical hydrogen is not to inhaling till the hydrogen, cooling is filtered, concentrate brown oil 80g.
5, preparation 2-sulfydryl-5-methoxyl group-3H-imidazo [4,5-b] pyridine
In the single neck round-bottomed flask of 250ml, add 2,3-diamino-6-methoxypyridine 47.5g, sulphur ortho acid potassium 100g, ethanol 600ml.Oil bath 80-90 ℃ refluxed 3 hours after, the cooling standing over night, decolorizing with activated carbon, ice acetic acid is acidified to PH3-4, leaves standstill filtration, the frozen water washing, dry solid 38g, productive rate 61.8%.m.p.235-7℃。Ultimate analysis C 7H 6N 3OS calculated value: C 46.67% H 3.33% N 23.33% S17.78%, measured value: C46.52% H 3.21% N 23.44% S 17.82%.
6, preparation 2-(4-methoxyl group-3,5-dimethyl-2-pyridyl methylthio group)-5-methoxyl group-3H-imidazo [4,5-b] pyridine
In 1000ml three neck round-bottomed flasks, add 2-sulfydryl-5-methoxyl group-3H-imidazo [4,5-b] pyridine 26g, ethanol 300ml, water 30ml, sodium hydroxide 10.4g, ice bath is cooled to below 10 ℃, adds 2-chloromethyl-4-methoxyl group-3,5-lutidine muriate 32g, after 30 minutes, add sodium hydroxide 2g, ethanol 75ml continues to stir 2 hours, room temperature is placed and is spent the night, behind the thin up, ice acetic acid is separated out solid, chloroform extraction, organic layer washs with aqueous sodium carbonate, anhydrous sodium sulfate drying.Filter, concentrate brown oil, ethyl alcohol recrystallization, white solid 48g, m.p.156 ~ 8 ℃.MS (FAB) 330.9 (M+H) +. ultimate analysis C 16H 18N 4O 2S calculated value: C58.38% H 5.45% N 16.97% S 9.7%, measured value: C 58.32% H 5.36% N 16.88% S 9.81%.
7, the sulfinyl of preparation 5-methoxyl group-2-[(s)-(4-methoxyl group-3,5-dimethyl-2-pyridylmethyl)] imidazo [4,5-b] pyridine
In 1000ml three neck round-bottomed flasks, add 2-(4-methoxyl group-3,5-dimethyl-2-pyridyl methylthio group)-5-methoxyl group-3H-imidazo [4,5-b] pyridine 4g, titanium isopropoxide 10g, cumene hydroperoxide thing 2g, (-)-D-diethyl tartrate 1g, DIEA 2g, chloroform 10ml reacted 3 hours.Mixture concentrates to such an extent that residuum gets the sulfinyl of product 5-methoxyl group-2-[(s)-(4-methoxyl group-3,5-dimethyl-2-pyridylmethyl) through column chromatography] imidazo [4,5-b] pyridine 3g, productive rate 71.53%.m.p.170-2℃。MS(FAB)347.2(M+H) +。Ultimate analysis C 16H 18N 4O 3S calculated value: C 55.49% H 5.20% N16.24% S 9.25%, measured value: C 55.43% H 5.13% N 16.24%S 9.32%.Confirm that the gained compound is correct.
The sulfinyl of embodiment 2, preparation 5-methoxyl group-2-[(R)-(4-methoxyl group-3,5-dimethyl-2-pyridylmethyl)] imidazo [4,5-b] pyridine
In 250ml three neck round-bottomed flasks, add raw material 2-(4-methoxyl group-3,5-dimethyl-2-pyridyl methylthio group)-5-methoxyl group-3H-imidazo [4,5-b] pyridine 1.0g, chloroform 100ml, be cooled to 0 ℃ after, add metachloroperbenzoic acid 0.76g, finish stirring reaction 0.5 hour.The sodium bicarbonate aqueous solution washing, drying concentrates, and gets raceme 0.8g with re-crystallizing in ethyl acetate, productive rate 76.3%, m.p.173-4 ℃.It is an amount of to get above-mentioned raceme; the preparative chromatography post; with CHBI-Silica is chiral support; SODIUM PHOSPHATE, MONOBASIC (PH=4)/acetonitrile (1: 1) is a moving phase; separate and to obtain the sulfinyl of 5-methoxyl group-2-[(R)-(4-methoxyl group-3,5-dimethyl-2-pyridylmethyl)] imidazo [4,5-b] pyridine 0.3g; productive rate 37.5%, m.p.173-4 ℃.Ultimate analysis C 16H 18N 4O 3S calculated value: C 55.49%H 5.20% N 16.24% S 9.25%, measured value: C 55.35% H 5.13% N 16.24% S9.32%.Confirm that the gained compound is correct.
Embodiment 3, The compounds of this invention are to H +/ K +The restraining effect of ATP enzyme
With omeprazole and tenatoprazole is contrast, adds formula of the present invention (I) compound and formula (II) compound respectively and contains 200-400ug H in proteic matrix +/ K +In the solution of ATP enzyme, H wherein +/ K +The ATP enzyme extracts from the pig stomach, and The compounds of this invention is dissolved in the ethanol, and solution is added in the reactive system, and making test compound concentration is 1 * 10 -3M.By mixing MgCl 2With KCl and cultivation reaction mixture, add Triphosaden then, and cultivated 15-30 minute at 37 ℃, discharge the inorganic phosphate radical ionic concn by colorimetric method for determining, determine H +/ K +The activity of ATP enzyme.The result is as shown in table 1, from the table data as can be seen, formula of the present invention (I) compound have be higher than omeprazole and tenatoprazole to H +/ K +The restraining effect of ATP enzyme, formula (II) compound is to H +/ K +The restraining effect of ATP enzyme is higher than omeprazole and is suitable with tenatoprazole.
Table 1: The compounds of this invention is to H +/ K +The inhibition effect (1 * 10 of ATP enzyme -3M)
Experimental compound Inhibiting rate (%)
Omeprazole formula (I) compound formula (II) compound tenatoprazole ????46 ????100 ????90 ????95
Embodiment 4, The compounds of this invention are to the restraining effect of gastric acid secretion
Male Wistar rat, heavy 150g, 8 every group is contrast with omeprazole and tenatoprazole in one evening of rat fasting, and The compounds of this invention is suspended in the sodium cellulose glycolate, and the rat ligation gavaged in preceding 30 minutes, dosage 80mg/kg, ligation rat pylorus then.After 6 hours, collect gastric juice, adopt 0.2N sodium hydroxide neutralization titration, measure the total acid content of every rat.The result is as shown in table 2, the data from table as can be seen, compound of the present invention has and is higher than the restraining effect of omeprazole to gastric acid secretion, and suitable to the restraining effect of gastric acid secretion with tenatoprazole.
Table 2: test compound suppresses effect to hydrochloric acid in gastric juice
Experimental compound ????ED 50(mg/kg)
Omeprazole formula (I) compound formula (II) compound tenatoprazole ????28.0 ????6.6 ????7.5 ????7.0

Claims (10)

1, non-raceme formula (II) compound of the salt of non-raceme formula (I) compound of S-configuration and this compound thereof or R-configuration and the salt of this compound thereof.
2, compound according to claim 1 is characterized in that: the salt of described formula (I) compound or formula (II) compound is pharmaceutically acceptable inorganic base salts.
3, compound according to claim 2 is characterized in that: described inorganic base salts is sodium salt, sylvite, calcium salt, lithium salts, barium salt or magnesium salts.
4, compound according to claim 1 is characterized in that: the salt of described formula (I) compound or formula (II) compound is pharmaceutically acceptable inorganic acid salt.
5, compound according to claim 4 is characterized in that: described inorganic acid salt is hydrochloride, vitriol, halogen acid salt, nitrate or phosphoric acid salt.
6, compound according to claim 1 is characterized in that: the salt of described formula (I) compound or formula (II) compound is pharmaceutically acceptable organic acid salt.
7, compound according to claim 6 is characterized in that: described organic acid salt is acetate, fumarate, tartrate, oxalate, maleate, malate, succinate or Citrate trianion.
8, a kind of preparation 5-methoxyl group-2-[(s)-(4-methoxyl group-3; 5-dimethyl-2-pyridylmethyl) sulfinyl] imidazo [4; 5-b] method of pyridine; be with 2-(4-methoxyl group-3; 5-dimethyl-2-pyridyl methylthio group)-5-methoxyl group-3H-imidazo [4; 5-b] pyridine and titanium isopropoxide, cumene hydroperoxide thing, reaction obtains the purpose product in the presence of (-)-D-diethyl tartrate.
9, the sulfinyl of a kind of preparation 5-methoxyl group-2-[(R)-(4-methoxyl group-3,5-dimethyl-2-pyridylmethyl)] method of imidazo [4,5-b] pyridine, be to be chiral support with CBHI-Silica, NaH 2PO 4(pH4)/CH 3CN (1: 1) is that moving phase separates raceme 5-methoxyl group-2-[(4-methoxyl group-3,5-dimethyl-2-pyridylmethyl) sulfinyl] imidazo [4,5-b] pyridine obtains the purpose product.
10, a kind of medicine for the treatment of the gastric acid secretion imbalance, its activeconstituents is non-raceme formula (I) compound of the described S-configuration of claim 1 and non-raceme formula (II) compound and the pharmacy acceptable salt thereof of pharmacy acceptable salt or R-configuration thereof.
CN 02117637 2002-04-23 2002-05-10 Omprazole compound and its prepn and application Pending CN1453278A (en)

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7256295B2 (en) * 2004-10-15 2007-08-14 Jubilant Organosys Limited Process for producing 2,3-diamino-6-methoxypyridine
JP2008502665A (en) * 2004-06-17 2008-01-31 シデム ファーマ ソシエテ アノニム S-tenatoprazole sodium salt monohydrate and its use in therapy
CN100371327C (en) * 2005-11-17 2008-02-27 江苏工业学院 One-step synthesis method of 2-amido-6-alkoxy-3-nitropyridine
JP2008515860A (en) * 2004-10-05 2008-05-15 シデム ファーマ ソシエテ アノニム Mirror image selective method for producing sulfoxide derivatives
CN102304127A (en) * 2011-06-30 2012-01-04 福建省福抗药业股份有限公司 Novel method for preparing tenatoprazole
CN102584688A (en) * 2012-01-13 2012-07-18 江苏中邦制药有限公司 Preparing method of 2,6-dichloro-3-nitropyridine

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2008502665A (en) * 2004-06-17 2008-01-31 シデム ファーマ ソシエテ アノニム S-tenatoprazole sodium salt monohydrate and its use in therapy
US7402593B2 (en) * 2004-06-17 2008-07-22 Sidem Pharma Monohydrated sodium salt of S-tenatoprazole and the use thereof in therapy
JP2008515860A (en) * 2004-10-05 2008-05-15 シデム ファーマ ソシエテ アノニム Mirror image selective method for producing sulfoxide derivatives
US7256295B2 (en) * 2004-10-15 2007-08-14 Jubilant Organosys Limited Process for producing 2,3-diamino-6-methoxypyridine
CN100371327C (en) * 2005-11-17 2008-02-27 江苏工业学院 One-step synthesis method of 2-amido-6-alkoxy-3-nitropyridine
CN102304127A (en) * 2011-06-30 2012-01-04 福建省福抗药业股份有限公司 Novel method for preparing tenatoprazole
CN102584688A (en) * 2012-01-13 2012-07-18 江苏中邦制药有限公司 Preparing method of 2,6-dichloro-3-nitropyridine

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