CN101268050B - Isotopically substituted pantoprazole - Google Patents
Isotopically substituted pantoprazole Download PDFInfo
- Publication number
- CN101268050B CN101268050B CN2006800344239A CN200680034423A CN101268050B CN 101268050 B CN101268050 B CN 101268050B CN 2006800344239 A CN2006800344239 A CN 2006800344239A CN 200680034423 A CN200680034423 A CN 200680034423A CN 101268050 B CN101268050 B CN 101268050B
- Authority
- CN
- China
- Prior art keywords
- compound
- methoxy
- methoxyl group
- formula
- pyridyl
- 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.)
- Expired - Fee Related
Links
- 229960005019 pantoprazole Drugs 0.000 title description 13
- IQPSEEYGBUAQFF-UHFFFAOYSA-N Pantoprazole Chemical class COC1=CC=NC(CS(=O)C=2NC3=CC=C(OC(F)F)C=C3N=2)=C1OC IQPSEEYGBUAQFF-UHFFFAOYSA-N 0.000 title description 11
- 150000001875 compounds Chemical class 0.000 claims abstract description 206
- 239000003814 drug Substances 0.000 claims abstract description 16
- 150000003839 salts Chemical class 0.000 claims description 76
- 125000006216 methylsulfinyl group Chemical group [H]C([H])([H])S(*)=O 0.000 claims description 64
- -1 3-methoxy-4-trideuteromethoxy-2-pyridyl Chemical group 0.000 claims description 42
- 238000000034 method Methods 0.000 claims description 40
- 229910052805 deuterium Inorganic materials 0.000 claims description 26
- 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 claims description 14
- 238000004519 manufacturing process Methods 0.000 claims description 13
- 238000002360 preparation method Methods 0.000 claims description 12
- 239000000460 chlorine Substances 0.000 claims description 11
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- 150000002367 halogens Chemical group 0.000 claims description 8
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- 230000001590 oxidative effect Effects 0.000 claims description 5
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical group II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 2
- 230000002265 prevention Effects 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims 8
- 125000004431 deuterium atom Chemical group 0.000 claims 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 5
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 claims 2
- 239000008194 pharmaceutical composition Substances 0.000 claims 2
- 208000018522 Gastrointestinal disease Diseases 0.000 claims 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims 1
- 150000002460 imidazoles Chemical class 0.000 claims 1
- 239000000543 intermediate Substances 0.000 abstract 1
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 94
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- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 48
- 239000007787 solid Substances 0.000 description 42
- 239000000243 solution Substances 0.000 description 33
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 32
- 239000000203 mixture Substances 0.000 description 32
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 30
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- 239000000463 material Substances 0.000 description 22
- 230000002496 gastric effect Effects 0.000 description 21
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 20
- 125000004429 atom Chemical group 0.000 description 20
- 235000011121 sodium hydroxide Nutrition 0.000 description 20
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- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 18
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- IWTFOFMTUOBLHG-UHFFFAOYSA-N 2-methoxypyridine Chemical class COC1=CC=CC=N1 IWTFOFMTUOBLHG-UHFFFAOYSA-N 0.000 description 12
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- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
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- NASFKTWZWDYFER-UHFFFAOYSA-N sodium;hydrate Chemical compound O.[Na] NASFKTWZWDYFER-UHFFFAOYSA-N 0.000 description 7
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
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- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 5
- 206010013710 Drug interaction Diseases 0.000 description 5
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 5
- 201000010099 disease Diseases 0.000 description 5
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- 150000004684 trihydrates Chemical class 0.000 description 5
- 108010081668 Cytochrome P-450 CYP3A Proteins 0.000 description 4
- 102000002004 Cytochrome P-450 Enzyme System Human genes 0.000 description 4
- 108010015742 Cytochrome P-450 Enzyme System Proteins 0.000 description 4
- 108010037444 diisopropylglutathione ester Proteins 0.000 description 4
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
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- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
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- KPQDKAMSAVONFC-UHFFFAOYSA-N 4-chloro-2-(chloromethyl)-3-methoxypyridine Chemical compound COC1=C(Cl)C=CN=C1CCl KPQDKAMSAVONFC-UHFFFAOYSA-N 0.000 description 3
- IQPSEEYGBUAQFF-SANMLTNESA-N 6-(difluoromethoxy)-2-[(s)-(3,4-dimethoxypyridin-2-yl)methylsulfinyl]-1h-benzimidazole Chemical compound COC1=CC=NC(C[S@](=O)C=2NC3=CC=C(OC(F)F)C=C3N=2)=C1OC IQPSEEYGBUAQFF-SANMLTNESA-N 0.000 description 3
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- 108010026925 Cytochrome P-450 CYP2C19 Proteins 0.000 description 3
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- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 238000003109 Karl Fischer titration Methods 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
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- AGOYDEPGAOXOCK-KCBOHYOISA-N clarithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@](C)([C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)OC)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 AGOYDEPGAOXOCK-KCBOHYOISA-N 0.000 description 3
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- PODWXQQNRWNDGD-UHFFFAOYSA-L sodium thiosulfate pentahydrate Chemical compound O.O.O.O.O.[Na+].[Na+].[O-]S([S-])(=O)=O PODWXQQNRWNDGD-UHFFFAOYSA-L 0.000 description 3
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Abstract
本发明涉及式1化合物和包含这些化合物的药物，还涉及式2和式3中间体。
The present invention relates to compounds of formula 1 and medicaments comprising these compounds, as well as intermediates of formula 2 and formula 3.
Description
Subject matter
The present invention relates to the substituted pantoprazole of isotropic substance and (R)-with (S)-enantiomorph.These compounds can be used for pharmaceutical industry and prepare medicinal compsns.
Background of invention
Because its H
+/ K
+-ATP enzyme-restraining effect; Pyridine-2-ylmethyl sulfinyl-1 H-benzimidazole; For example known those; Like among EP-A-0005129, EP-A-0166287, EP-A-0174726, EP-A-0254588 and the EP-A-0268956 those, increase in the diseases associated with gastric acid secretion in treatment and to have suitable importance.
The example that this type could can buy or be in the active compound in the clinical development has: 5-methoxyl group-2-[(4-methoxyl group-3; 5-dimethyl--2-pyridyl) methylsulfinyl]-omeprazole), (S)-5-methoxyl group-2-[(4-methoxyl group-3 1H-benzoglyoxaline (INN:; 5-dimethyl--2-pyridyl) methylsulfinyl]-Chinese mugwort department omeprazole), 5-difluoro-methoxy-2-[(3 1H-benzoglyoxaline (INN:; 4-dimethoxy-2-pyridyl) methylsulfinyl]-pantoprazole), 2-[3-methyl-4-(2 1H-benzoglyoxaline (INN:; 2; The 2-trifluoro ethoxy)-and the 2-pyridyl) methylsulfinyl]-1H-benzoglyoxaline (INN: lansoprazole); 2-{ [4-(3-methoxy propoxy)-3-picoline-2-yl] methylsulfinyl }-rabeprazole) and 5-methoxyl group-2-((4-methoxyl group-3,5-dimethyl--2-pyridylmethyl) sulfinyl)-1H-imidazo [4,5-b] pyridine (INN: TU-199) 1H-benzoglyoxaline (INN:.
Because its mechanism of action, above-mentioned sulfinyl verivate are also referred to as proton pump inhibitor or are abbreviated as PPI.
Description of Related Art
USP the 6th, 818 discloses wherein at least one Wasserstoffatoms for No. 200 by substituted dihydropyridine compound of D atom and microbiotic.React under H-type compound and water-d2 and the suitable vigorous reaction condition of mixture of catalysts in sealed vessel, just, can obtain the deuterated compound in high temperature (60 to 80 ℃) long-time reaction (reaching 190 hours) down.This patent also discloses H/D exchange some influences that pharmacological properties produced to these compounds.
Disclosure of the Invention
Find surprisingly that now the isotropic substance substitution compound that details below suppresses sour excretory character to these compounds and produced remarkably influenced.
The present invention relates to general formula 1 compound and salt thereof, solvolyte (preferably water compound), with and the solvolyte (the preferably hydrate of its salt) of salt
Wherein R1 is a difluoro-methoxy, and R2 is a methoxyl group, and R3 is a methoxyl group,
Wherein at least one Wasserstoffatoms is replaced by D atom in R1, R2, R3 or R1, R2 and the R3 arbitrary combination.Possible is combined as: R1 and R2, R1 and R3, R2 and R3 or R1 and R2 and R3.
According to the present invention, the meaning of salt comprises all inorganic base salts and organic alkali salt, particularly an alkali metal salt (for example lithium salts, sodium salt and sylvite), perhaps alkaline earth salt (for example magnesium salts and calcium salt), and other pharmaceutically-compatible salt, for example aluminium salt or zinc salt.Special particular certain cancers and magnesium salts.
For production of medicine; Available method known to those skilled in the art changes into the salt that can tolerate on the pharmacology with inconsistent salt on the pharmacology (it can be used as the for example process product of industrial-scale production The compounds of this invention (process product) acquisition at first, and this process product is also within category of the present invention).
What those skilled in the art were known is that The compounds of this invention and salt thereof for example, if they are to separate with crystallized form to obtain, then can contain various amounts of solvent.Therefore, the present invention also comprises all solvolytes (particularly all hydrates) of formula 1 compound, and all solvolytes of formula 1 compound salt (particularly all hydrates).The meaning of solvolyte comprises that all generate the pharmaceutically acceptable solvent of this solvolyte.
According to the present invention, term " at least one " is meant 1 to 3 Wasserstoffatoms of R2 or R3, and it can be replaced by D atom.
About the name of The compounds of this invention, " deuterium " speech should refer to D atom ([
2H]).Similarly, " three " of front should refer in special groups (like three deuterate methoxyl groups), occur three for example D atoms.
Within the scope of the invention, preferably wherein among R2, R3 or R2 and the R3 at least one Wasserstoffatoms by the substituted compound of D atom.Also preferred wherein R1 is the compound of deuterate difluoro-methoxy.The example of this compound can be: 5-difluoro-methoxy-2-[(3-methoxyl group-4-one deuterate methoxyl group)-2-pyridyl) methylsulfinyl]-1H-benzoglyoxaline, 5-difluoro-methoxy-2-[(3-methoxyl group-4-two deuterate methoxyl groups)-2-pyridyl) methylsulfinyl]-1H-benzoglyoxaline, 5-difluoro-methoxy-2-[3-one deuterate methoxyl group-4-methoxyl group)-the 2-pyridyl) methylsulfinyl]-1H-benzoglyoxaline, 5-difluoro-methoxy-2-[(3-two deuterates methoxyl group-4-methoxyl group)-2-pyridyl) methylsulfinyl]-1H-benzoglyoxaline, 5-difluoro-methoxy-2-[(3; 4-two (a deuterate methoxyl group)-2-pyridyl) methylsulfinyl]-1H-benzoglyoxaline or 5-difluoro-methoxy-2-[(3,4-two (two deuterate methoxyl groups)-2-pyridyl) methylsulfinyl]-1H-benzoglyoxaline.
Also preferred wherein R2, R3 or R2 and R3 are the compound of three deuterate methoxyl groups.More preferably wherein R3 is the compound of three deuterate methoxyl groups.The example of these compounds can be: 5-difluoro-methoxy-2-[(3-three deuterates methoxyl group-4-methoxyl group-2-pyridyl) methylsulfinyl]-1H-benzoglyoxaline, 5-difluoro-methoxy-2-[(3-methoxyl group-4-three deuterates methoxyl group-2-pyridyl) methylsulfinyl]-1H-benzoglyoxaline or 5-difluoro-methoxy-2-[(3,4-two (three deuterate methoxyl groups)-2-pyridyl) methylsulfinyl]-1H-benzoglyoxaline.
Most preferably wherein R1 is that difluoro-methoxy, R2 are that methoxyl group and R3 are the compound of two deuterate methoxyl groups or three deuterate methoxyl groups.
The sodium salt or the magnesium salts of preferred formula 1 compound.Sodium salt is monohydrate salt preferably, is more preferably the sesquialter hydrate salt.Magnesium salts is trihydrate salt preferably, is more preferably dihydrate salt.
The compounds of this invention can significantly improve the character that known compound influences gastric acid secretion.
The compounds of this invention is a chipal compounds.Therefore, the present invention relates to the mixture of racemic modification and enantiomorph and any required ratio thereof.The medical science viewpoint thinks that some chipal compounds possibly be favourable with one or another kind of enantiomeric form administration; In view of this fact; The preferred theme of the present invention is the enantiomorph of formula 1 compound, and preferably, said enantiomorph does not contain another enantiomorph of opposite configuration separately basically.
Therefore, particularly preferably be compound on the one hand with general formula 1a (S)-configuration,
Wherein, the meaning of R1, R2 and R3 as stated.
Within the scope of the present invention; Preferred especially (S)-configuration of compound is: compound (S)-5-difluoro-methoxy-2-[(3-methoxyl group-4-three deuterates methoxyl group-2-pyridylmethyl) sulfinyl]-1H-benzoglyoxaline, the solvolyte (preferably water compound) of this compound, the salt of this compound, and the solvolyte of this compound salt (preferably water compound).Within the scope of the present invention; Another preferred especially (S)-configuration of compound is: compound (S)-5-difluoro-methoxy-2-[(3-methoxyl group-4-two deuterates methoxyl group-2-pyridylmethyl) sulfinyl]-1H-benzoglyoxaline, the solvolyte (preferably water compound) of this compound, the salt of this compound, and the solvolyte of this compound salt (preferably water compound).
The sodium salt of preferred formula 1a compound or magnesium salts.Preferably, the sodium salt of S-enantiomorph or magnesium salts are trihydrates.
On the other hand, the compound of special preferred formula 1b (R)-configuration
Wherein the meaning of R1, R2 and R3 as stated.
Within the scope of the present invention; Preferred especially (R)-configuration of compound is: compound (R)-5-difluoro-methoxy-2-[(3-methoxyl group-4-three deuterates methoxyl group-2-pyridylmethyl) sulfinyl]-1H-benzoglyoxaline, the solvolyte (preferably water compound) of this compound, the salt of this compound, and the solvolyte of this compound salt (preferably water compound).Within the scope of the present invention; Another preferred especially (R)-configuration of compound is: compound (R)-5-difluoro-methoxy-2-[(3-methoxyl group-4-two deuterates methoxyl group-2-pyridylmethyl) sulfinyl]-1H-benzoglyoxaline, the solvolyte (preferably water compound) of this compound, the salt of this compound, and the solvolyte of this compound salt (preferably water compound).
The whole bag of tricks described in the available for example International Patent Application WO 92/08716 is perhaps used column chromatography, and formula 1 compound is split into enantiomorph.Perhaps, can carry out chiral oxidization, obtain formula 1a and 1b compound the sulfide described in the International Patent Application WO 2004/052881.
The salt of formula 1,1a and 1b compound can prepare with currently known methods; Make formula 1,1a and 1b compound (can be used as weak acid) and suitable alkali reaction; For example, perhaps react with alkaline-earth alkoxides (like magnesium methylate) with alkali metal hydroxide or alkoxide (like sodium hydroxide or sodium methylate) reaction.For instance, the magnesium salts of formula 1,1a and 1b compound (preferred salt except that sodium salt) can prepare with currently known methods, makes formula 1,1a and 1b compound and magnesium alkali (for example magnesium alkoxide) prepared in reaction; Perhaps at water or water and polar organic solvent (alcohol for example; Particular methanol, ethanol or Virahol, perhaps ketone, preferred acetone) mixture in; Use magnesium salts, by lyotropic salt (for example sodium salt) preparation of formula 1,1a and 1b compound.
According to the present invention, " (S)-configuration of compound " is understood to include " (the S)-configuration of compound that does not contain (R)-configuration of compound basically ".
In context of the present invention, " not containing basically " is meant that the solvolyte of (S)-configuration of compound and/or its salt, its solvolyte or its salt contains (the R)-configuration of compound that is less than 10% weight and/or the solvolyte of its salt, its solvolyte or its salt.Preferably, " do not contain " solvolyte that is meant (S)-configuration of compound and/or its salt, its solvolyte or its salt basically and contain (the R)-configuration of compound that is less than 5% weight and/or the solvolyte of its salt, its solvolyte or its salt.More preferably, " do not contain " solvolyte that is meant (S)-configuration of compound and/or its salt, its solvolyte or its salt basically and contain (the R)-configuration of compound that is less than 2% weight and/or the solvolyte of its salt, its solvolyte or its salt.In most preferred embodiments, " do not contain " solvolyte that is meant (S)-configuration of compound and/or its salt, its solvolyte or its salt basically and contain (the R)-configuration of compound that is less than 1% weight and/or the solvolyte of its salt, its solvolyte or its salt.
According to the present invention, " (R)-configuration of compound " is understood to include " (the R)-configuration of compound that does not contain (S)-configuration of compound basically ".
In context of the present invention, " not containing basically " is meant that the solvolyte of (R)-configuration of compound and/or its salt, its solvolyte or its salt contains (the S)-configuration of compound that is less than 10% weight and/or the solvolyte of its salt, its solvolyte or its salt.Preferably, " do not contain " solvolyte that is meant (R)-configuration of compound and/or its salt, its solvolyte or its salt basically and contain (the S)-configuration of compound that is less than 5% weight and/or the solvolyte of its salt, its solvolyte or its salt.More preferably, " do not contain " solvolyte that is meant (R)-configuration of compound and/or its salt, its solvolyte or its salt basically and contain (the S)-configuration of compound that is less than 2% weight and/or the solvolyte of its salt, its solvolyte or its salt.In most preferred embodiments, " do not contain " solvolyte that is meant (R)-configuration of compound and/or its salt, its solvolyte or its salt basically and contain (the S)-configuration of compound that is less than 1% weight and/or the solvolyte of its salt, its solvolyte or its salt.
According to the present invention, term " Wasserstoffatoms is replaced by D atom " is interpreted as limiting large quantities of raw materials and is at least 80% degree of deuterium, and wherein all these corresponding Wasserstoffatomss of mentioning are replaced by D atom.For example, if substituent R 2 or R3 are meant the methoxyl group of whole three " Wasserstoffatoms is replaced by D atom ", then according to what above-mentioned definition should be understood be, at least 80% of all R2 or R3 methoxyl group is-OCD in large quantities of raw materials
3100% comprises-OCHD with interior remainder
2,-OCH
2D or-OCH
3
The degree of deuterium of specific Wasserstoffatoms is preferably at least 90% in large quantities of raw materials, this means that at least 90% said substituted Wasserstoffatoms should be D atom.The degree of deuterium of specific Wasserstoffatoms more preferably at least 92% in large quantities of raw materials.The degree of deuterium of specific Wasserstoffatoms further more preferably at least 94% in large quantities of raw materials, and the degree of deuterium of specific Wasserstoffatoms most preferably is at least 96% in large quantities of raw materials.
Another theme of the present invention is formula 2 compounds
Wherein the meaning of R1, R2 and R3 as stated, and wherein in R1, R2, R3 or R1, R2 and the R3 arbitrary combination at least one Wasserstoffatoms replaced by D atom.Possible is combined as: R1 and R2, R1 and R3, R2 and R3 or R1 and R2 and R3.Formula 2 compounds also comprise itself and sour salt (preferably salt hydrochlorate, vitriol or phosphoric acid salt) and/or solvolyte.These compounds can be used for producing general formula 1,1a or 1b compound.Formula 2 compounds are particularly suitable for the starting raw material as the oxidizing reaction of production formula 1,1a or 1b compound.
Another aspect of the present invention is formula 3 compounds
Wherein X is halogen or is pure activated derivatives, and the meaning of R2 and R3 as stated, and wherein at least one Wasserstoffatoms is replaced by D atom among R2, R3 or R2 and the R3.
For the purposes of the present invention, halogen is iodine, bromine, chlorine and fluorine.X is preferably chlorine.For the purposes of the present invention, the activated derivatives of alcohol is alkylsulphonic acid base (a for example methylsulfonic acid base), or aryl sulfonic acid groups (for example toluenesulphonic acids base or Phenylsulfonic acid base), or perfluoroalkane sulfonate base (for example trifluoromethayl sulfonic acid base).
Formula 3 compounds can be used for production formula 1,1a or 1b compound.Preferably, at first make the nitrogen-atoms of formula 3 compounds quaternized, and then react with formula 4 compounds
Wherein the meaning of R1 as stated, thereby obtain aforesaid formula 2 compounds.
The deuterium homologue of R/S pantoprazole and S-pantoprazole; Can use document (people such as Kohl for example, J.Med.Chem.1992,35; 1049 ff. or WO 2004/052881) in currently known methods; Corresponding selective oxidation of sulfur containing compounds in particular is prepared, perhaps go up to the substituent corresponding sulfoxide of halogen (like chlorine, bromine or nitro), prepare through halogen being replaced as three deuterate methoxyl groups by the position (particularly pyridyl 4-position) of final three deuterate methoxyl groups.
Similarly; The preparation of sulfocompound; Perhaps through replace the halogen on final three deuterates methoxyl group-substituting group position with three deuterate methoxyl groups, perhaps through making 5-difluoro-methoxy-2-mercaptobenzimidazole and corresponding substituted chlorination 2-chloromethyl-3-methoxyl group-4-three deuterate methoxyl group-pyridines
coupling.The said route that openly prepares also can be used for using two deuterate methoxyl groups or a deuterate methoxyl group (rather than three above-mentioned deuterate methoxyl groups) to replace halogen.These compound methods can generate corresponding deuterate compound.
Can prepare formula 1 compound with following reaction scheme:
Prepare the salt of sulfoxide and mineral alkali according to diplomatic currently known methods, make sulfoxide in the mixture of organic solvent or organic solvent and water with corresponding oxyhydroxide or pure reactant salt.
Perhaps, the preparation method of salt is following: sulfoxide and alkali metal hydroxide reaction obtain corresponding alkali metal salt (Na, K, Li), further react with for example magnesium salts, calcium salt, aluminium salt, zinc salt again.
Following examples are used for illustrating in more detail the present invention, but not it is limited.Clear and definite described new compound among the embodiment, any salt, solvolyte (preferably water compound), perhaps the solvolyte of these compound salt (preferably water compound) is the preferred theme of the present invention.
Embodiment
Methyl alcohol-the d4 of D atom＞99.8% atom is as three deuterate methoxylation agent.The ownership system gets the substituent isomery purity of three deuterate methoxyl groups＞98.0% in the product (measuring with NMR and MS).Methyl alcohol-the d1 of the methyl alcohol-d2 of D atom＞98.0% atom and D atom＞98.0% atom is also as the deuterate agent.Two deuterate methoxyl groups and the substituent isomery purity of a deuterate methoxyl group＞96.0% in the products therefrom (measuring) with NMR and MS.
Embodiment 1
(R/S)-5-difluoro-methoxy-2-[(3-methoxyl group-4-three deuterates methoxyl group-2-pyridyl) methylsulfinyl]-1H-benzoglyoxaline
Under 30 to 35 ℃ of stirrings; (1.0 restrained to 5-difluoro-methoxy-2-[(3-methoxyl group-4-three deuterates methoxyl group-2-pyridyl) methylthio group]-1H-benzoglyoxaline with 1 to 2 hour; 2.7 mmole) at water (20 milliliters), 2-propyl alcohol (10 milliliters) and the sodium hydroxide (solution of 0.5 milliliter of 40% concentration; 7.1 in slurry mmole), add chlorine bleach liquor's (10% concentration) (3.3mmol).After said temperature 30 to 60 minutes, add Sulfothiorine (0.3 gram is dissolved in 5 ml waters), continue again to stir 15 to 30 minutes.
Reaction mixture vacuum (30 to 40 ℃) is concentrated into the about 1/3 of original volume, adds entry (about 70 milliliters).
Water adds methylene dichloride (50 milliliters) once more with after methylene dichloride (2 times, the each 10 milliliters) extraction, stirs down to add potassium dihydrogen phosphate aqueous solution, and pH is transferred to 7 to 8.Be separated, water is used methylene dichloride (20 milliliters) extraction again, and dried over mgso is used in the organic phase water of merging (20 milliliters) washing, removes by filter siccative, obtains the solution of thick title compound.
Add sherwood oil (50/70; 150 milliliters), and, be concentrated into about 30 ml volumes at 30 to 40 ℃ of rotary evaporation in vacuo; Filter the solid of separating out then; Clean (20 milliliters) with sherwood oil 50/70, and vacuum-drying (35 ℃, 5 hours); Obtain off-white color solid title compound (R/S)-5-difluoro-methoxy-2-[(3-methoxyl group-4-three deuterates methoxyl group-2-pyridyl) methylsulfinyl]-1H-benzoglyoxaline, fusing point: 135 to 136 ℃ (decomposition); Output 1.0 gram (theoretical value 95%).
1H-NMR(400MHz，DMSO?d-6)：d＝3,78(s，3H，OMe)，4,68(d，1H，J(CHa，CHb)＝13Hz，S-CH2-Py)，4,73(d，1H，J(CHb，CHa)＝13Hz，S-CH2-Py)，7,10(d，1H，J(H5’，H6’)＝5Hz，H5’)7,18(bd，1H，H6)，7,24(t，1H，J(H，F)＝74Hz，OCHF2)，7,4(bs，1H，H4)，7,70(bs，1H，H7)，8,15(d，1H，J(H6’，H5’)＝5Hz)H6’)，13,7(s，1H，NH)。
Embodiment 2
(S) (-)-5-difluoro-methoxy-2-[(3-methoxyl group-4-three deuterates methoxyl group-2-pyridyl) methylsulfinyl]-1H-benzoglyoxaline
Under the room temperature; 2.0 gram 5-difluoro-methoxy-2-[(3-methoxyl group-4-three deuterates methoxyl group-2-pyridyl) methylthio group]-1H-benzoglyoxalines are suspended in 20 milliliters the mibk; Together with (+)-L-tartrate two-(N-tetramethyleneimine acid amides) (2.3 gram) and n-propyl alcohol zirconium (IV) (1.0 restrain 70%/propyl alcohol) together.Mixture 40 ℃ of heating 1 hour, is formed almost clear soln.After being cooled to room temperature, add N-ethyl diisopropylamine (0.07 milliliter) and Cumene Hydroperoxide 80 (1.05 milliliters).Stir this mixture under the room temperature and finish (10 to 24 hours, TLC inspects with tlc) until oxidizing reaction.Said settled solution dilutes with 10 milliliters of mibks, and with 0.08 gram Sulfothiorine/14 milliliter saturated sodium bicarbonate solution quencher, restir 2 hours.After being separated, mixture is with 5 milliliters of saturated sodium bicarbonate solution washed twice.Add 15 ml waters to mibk in mutually, pH is transferred to pH=13 with the sodium hydroxide solution of 40% weight concentration.After being separated, mibk extracts with the water of 5 milliliters of pH 13 mutually again.Merge water, and the initial distillation of under 40 ℃, reducing pressure.Adding is filtered after stirring 1 hour under 20 to 25 ℃ as the Hyflo Super Cell (0.05 gram) of flocculating aids.Under 40 to 45 ℃, the acetic acid that in filtrating, adds 10% concentration is separated out thick title compound to pH=9.0.With mixture restir 12 hours, during monitor pH.Filter cream-coloured crystallization, and wash with 10 ml waters.About 1.6 grams (theoretical value 75%) of the output of gained title compound, optical purity＞98%.
In order to increase purity, with (-) pantoprazole water-soluble/aqueous sodium hydroxide solution in, pH is 13, makes it to precipitate once more when the pH=9.0 with acetic acid (10%).
Recrystallization from methylene dichloride/t-butyl methyl ether; Obtain off-white color solid title compound (S) (-)-5-difluoro-methoxy-2-[(3-methoxyl group-4-three deuterates methoxyl group-2-pyridyl) methylsulfinyl]-1H-benzoglyoxaline, fusing point: 146 to 148 ℃ (decomposition); Output 1.6 grams.
Embodiment 3
5-difluoro-methoxy-2-[(3-methoxyl group-4-three deuterates methoxyl group-2-pyridyl) methylthio group]-1H-benzoglyoxaline
Under 50 to 60 ℃; (D4 made by deuterate methyl alcohol with 30 to 60 fens clockwise three deuterate sodium methylates; 7.8 restrain) and sodium hydride (8.6 grams; 60% concentration/paraffin) in N-methyl-pyrrolidin-2-one (150 milliliters) solution, divide to add 2-[(4-chloro-3-methoxyl group-2-pyridyl)-methylthio group]-5-difluoro-methoxy-1H-benzoglyoxaline (20 gram) for four times.
Under said temperature, after 4 hours, make reaction mixture be cooled to 20 to 25 ℃, stir down with adding entry (500 milliliters) in 1 to 2 hour.Transfer to after the pH7 with the 2N aqueous hydrochloric acid, at 20 to 25 ℃ with this mixture restir 1 hour.
The suction filtration deposition, cleaning several times of water (200 milliliters) branch and drying (35 ℃, 20 millibars, 20 hours).At 80 to 85 ℃ exsiccant bullion (22 gram) is dissolved in toluene (250 milliliters), and adds aluminum oxide (Merck, 90 active alkalescence (active basic); 10g).After said temperature stirs 30 minutes, filtering mixt, and clear filtrate is concentrated into 50 ml volumes in vacuum (40 to 50 ℃).
Be cooled to 10 ℃ 2 hours, suction filtration is isolated colourless deposition, cleans and dry (40 ℃, 20 millibars, 20 hours) with toluene (10 milliliters).
Obtain title compound 5-difluoro-methoxy-2-[(3-methoxyl group-4-three deuterates methoxyl group-2-pyridyl) the methylthio group]-1H-benzoglyoxaline of 16 gram (theoretical value 80%) off-white color crystalline solid, fusing point: 119 to 120 ℃.
The alternative synthesis method of embodiment 3
In the solution of 2.08 gram 2-sulfydryl-5-difluoro-methoxy-1H-benzoglyoxaline/40 milliliter ethanol and 20 milliliters of 1N sodium hydroxide solutions; Add 2.12 gram chlorination 2-chloromethyl-3-methoxyl group-4-three deuterate methoxypyridines
; This mixture stirred 2 hours at 20 ℃, then 40 ℃ of restir 1 hour.Rotary evaporation (10 millibars/40 ℃) boils off ethanol, and suction filtration is isolated colourless deposition.Clean and drying with 1N sodium hydroxide solution and water.According to embodiment 3, recrystallization from toluene obtains the title compound of off-white color crystalline solid, output 2.9 grams; Fusing point: 118 to 120 ℃.
Embodiment 4
Synthesizing of starting raw material chlorination 2-chloromethyl-3-methoxyl group-4-three deuterate methoxypyridines
The preparation of 3-methoxyl group-2-methyl-4-three deuterate methoxypyridine N-oxide compounds
In deuterate methyl alcohol d4 (20 milliliters), reflux 4-chloro-3-methoxyl group-2-methylpyridine N oxide (10 gram) and three deuterate sodium methylates (6.2 gram).After 15 hours, vacuum evaporating solvent, resistates filters insolubles with toluene (50 milliliters) extraction of heat.Add Di Iso Propyl Ether to filtrating, separate out solid, obtain 3-methoxyl group-2-methyl-4-three deuterate methoxypyridine N-oxide compounds of 8.1 gram light brown powder after the vacuum-drying.It is used for following steps subsequently.
The preparation of 2-methylol-3-methoxyl group-4-three deuterate methoxypyridines
The product (8.1 gram) of preceding step is dissolved in the aceticanhydride (50 milliliters), and 90 ℃ of heating 2 hours.After the vacuum-evaporation, dark oil resistates and 2N NaOH (20 milliliters) were stirred 2 hours at 80 ℃.After the cooling, product gets in the methylene dichloride through extraction, dry (K
2CO
3), vacuum concentration is to smaller size smaller.Add sherwood oil (50/70), after filtration and the vacuum-drying, obtain 2-hydroxyl-3-methoxyl group-4-three deuterate methoxypyridines of light brown solid (5.5 gram), it is used for following steps.
The preparation of chlorination 2-chloromethyl-3-methoxyl group-4-three deuterate methoxypyridines
The product (5.5 gram) of preceding step is dissolved in the anhydrous methylene chloride (40 milliliters) thionyl chloride (3 milliliters) under 5 to 10 ℃ of stirrings.Make mixture be warming up to 20 ℃, final vacuum was evaporated to dried in 3 hours.
Add toluene (20 milliliters), obtain 6.6 gram light brown solid title compound chlorination 2-chloromethyl-3-methoxyl group-4-three deuterate methoxypyridines
.
The synthetic raw material contains the impurity that some are difficult to remove by this way, and these impurity might be brought in the next step of preparation general formula (2) compound and final general formula (1) compound thereof.Therefore, for general formula (1) compound for preparing extreme high purity, the deuterate alkoxide method described in the preferred usually employing embodiment 3 and 14.
Embodiment 5
(S)-{ [5-(difluoro-methoxy)]-2-[(3-methoxyl group-4-three deuterates methoxyl group-2-pyridyl) methylsulfinyl]-1H-benzoglyoxaline } sodium hydrate is synthetic
5.0 gram (S) { [5-(difluoro-methoxy)]-2-[(3-methoxyl group-4-three deuterates methoxyl group-2-pyridyl) methylsulfinyl]-1H-benzoglyoxaline } are suspended in 25ml isobutyl ketone (MIBK) and the 2.5 milliliters of 2-propyl alcohol, and being heated to internal temperature is 45 ℃.This temperature stirred suspension 15 minutes.At 45 ℃, in this suspension-s, slowly drip 1.25 gram 40% (w/w) aqueous sodium hydroxide solution and 0.25 ml waters.Make solution be cooled to room temperature gradually.Crystallization between 45 to 30 ℃, but put into the crystal seed accelerate crystallisation.Gained suspension-s is ℃ following restir 18 hours in internal temperature＜20.Filtering suspension liquid then, crystal washs with 2 milliliters of MIBK.Dry in the vacuum drying oven of＜50 millibars and 35 ℃.Obtain the title compound of white to off-white color crystalline solid; Output 5.9 grams, 99% of theoretical value; Water cut is 12 to 14%, corresponding to trihydrate; Fusing point: begin to decompose purity HPLC＞99.7%, chirality HPLC＞98.0%ee at 95 ℃; [α]
20 D=-89.0 ° (c=0.5, methyl alcohol).
Embodiment 6
(R/S)-{ [5-(difluoro-methoxy)]-2-[(3-methoxyl group-4-three deuterates methoxyl group-2-pyridyl) methylsulfinyl]-1H-benzoglyoxaline } sodium hydrate is synthetic
9.5 grams { [5-(difluoro-methoxy)]-2-[(3-methoxyl group-4-three deuterates methoxyl group-2-pyridyl) methylsulfinyl]-1H-benzoglyoxaline } are suspended in 57 milliliters of acetone, and being heated to internal temperature is 45 ℃.This temperature stirred suspension 15 minutes.At 45 ℃, in this suspension-s, slowly add 2.4 gram 40% (w/w) aqueous sodium hydroxide solutions.Make solution be cooled to room temperature gradually.Crystallization between 30 to 25 ℃, but put into the crystal seed accelerate crystallisation.Add 4 ml waters.Gained suspension-s is ℃ following the stirring 18 hours in internal temperature＜20.Filtering suspension liquid then, crystal is with 5 milliliters of washing with acetones.Dry in the vacuum drying oven of＜50 millibars and 40 ℃.Obtain the title compound of white to off-white color crystalline solid; Output 8.8 grams, 88% of theoretical value; Water cut is 5.2% (Karl Fischer titration), corresponding to monohydrate; Fusing point: 155 to 158 ℃ (decomposition), purity＞99.3% (HPLC).
1H-NMR(200MHz，DMSO-d6)：δ＝3.78(s，3H)，4.34(d，12.9Hz，1H)，4.68(d，12.9Hz，1H)，6.72(dd，8.6Hz，2.4Hz，1H)，7.02(t，75.8Hz，1H)，7.07(d，5.6Hz，1H)，7.24(d，2.2Hz，1H)，7.44(d，8.6Hz，1H)，8.22(d，5.5Hz，1H)；LC-MS：MNa
+＝409，MH
+＝387。
Embodiment 7
(S)-two-{ [5-(difluoro-methoxy)]-2-[(3-methoxyl group-4-three deuterates methoxyl group-2-pyridyl) methylsulfinyl]-1H-benzoglyoxaline } the magnesium hydrate is synthetic
3.0 gram (S)-{ [5-(difluoro-methoxy)]-2-[(3-methoxyl group-4-three deuterates methoxyl group-2-pyridyl) methylsulfinyl]-1H-benzoglyoxaline } sodium (calculating with anhydride) are suspended in 26 ml waters.Suspension-s is heated to 35 to 40 ℃, restir 10 minutes.Obtain clear soln.Make this settled solution be cooled to 22 to 27 ℃.1.43 gram Magnesium dichloride hexahydrates are dissolved in 10 ml waters, under stirring at room, this solution slowly are added drop-wise in the sodium salt solution.Then with gained suspension-s restir 18 hours at room temperature.Filtering suspension liquid, product is with 10 ml water washed twice.Dry in the vacuum drying oven of＜50 millibars and 40 to 45 ℃, obtain 2.2 gram (74%) title compounds; Fusing point: begin to decompose at 169 ℃; Water cut is 6.4% (KarlFischer titration), corresponding to trihydrate; Purity＞99.7%HPLC, chirality HPLC＞99.0%ee; [α]
20 D=-122 ° (c=0.5, methyl alcohol).
Embodiment 8
(R/S)-two-{ [5-(difluoro-methoxy)]-2-[(3-methoxyl group-4-three deuterates methoxyl group-2-pyridyl) methylsulfinyl]-1H-benzoglyoxaline } the magnesium hydrate is synthetic
3.0 gram (R/S)-{ [5-(difluoro-methoxy)]-2-[(3-methoxyl group-4-three deuterates methoxyl group-2-pyridyl) methylsulfinyl]-1H-benzoglyoxaline } sodium (calculating with anhydride) are suspended in 26 ml waters.Suspension-s is heated to 35 to 40 ℃, and 35 to 40 ℃ of restir 10 minutes.Obtain clear soln.Make this settled solution be cooled to 22 to 27 ℃.1.43 gram Magnesium dichloride hexahydrates are dissolved in 10 ml waters, under stirring at room, this solution slowly are added dropwise in the sodium salt solution.Then with gained suspension-s restir 4 hours at room temperature.Filtering suspension liquid, product is with 15 ml water washed twice.Dry in the vacuum drying oven of＜50 millibars and 40 to 45 ℃, obtain 2.1 gram (70%) title compounds; Fusing point: 179 to 181 ℃ (decomposition).Water cut is 4.7% (Karl Fischer titration), corresponding to duohydrate; Purity: 99.5%HPLC.
Embodiment 9
Chlorination 4-chloro-2-chloromethyl-3-Methoxy Pyridine
At 85 to 95 ℃, with toluene (148 liters) solution that in aceticanhydride (71 liters), added 4-chloro-3-methoxyl group-2-methylpyridine N oxide (19.2 kilograms, 111 moles) in 5 to 7 hours.Under about 60 ℃ vacuum, concentrated reaction mixture is until boiling off about 170 liters.Add toluene (160 liters) and boil off solvent (160 liters).The final step operation repeats once.Add the toluene (14 liters) and the 40%NaOH aqueous solution (14.6 liters) at 35 to 45 ℃ then, reaction mixture was kept under this temperature 2 to 3 hours.If this moment, pH was lower than 13, then adds NaOH again, and continued reheat 2 hours.The two-phase reaction mixture of gained is separated with toluene (26 liters) and saturated sodium bicarbonate aqueous solution (26 liters) dilution, and water layer is with toluene (26 liters and 2 * 13 liters) extraction three times.At last, the organic phase of merging is with saturated sodium bicarbonate aqueous solution (13 liters) washing, at 50 to 65 ℃ of vacuum concentration until boiling off about 115 liters.After toluene (100 liters) dilution, boil off 100 liters of solvents again.
4-chloro-2-methylol-3-Methoxy Pyridine (about 30% concentration) solution of gained is used CH
2Cl
2(48 liters) dilution.Disposable adding DMF (65.5 grams, 0.896 mole) is then at 15 to 30 ℃, with 3 to 5 hours adding THIONYL CHLORIDE 97s (11.1 kilograms, 93.2 moles).After the restir 1.5 hours, boil off about 45 liters of solvents.Add toluene (20 liters), boil off 20 liters of solvents again.In the thick slurry of gained, add ethanol (1.5 liters) then.10 to 15 ℃ of solids filtered; Wash with toluene (17 liters); 30 ℃ in vacuum is dry down, obtains off-white color solid chlorination 4-chloro-2-chloromethyl-3-Methoxy Pyridine
(132 ℃ of fusing points); 15.0 kilograms of output (59%).
1H-NMR(200MHz，CDCl
3)：δ＝4.19(s，3H)，5.14(s，2H)，7.92(d，6.0Hz，1H)，8.59(d，6.0Hz，1H)，11.64(br?s，1H)；LC-MS：MH
+＝192/194/196。
Chlorination 4-chloro-2-chloromethyl-3-three deuterate methoxypyridines
Starting raw material, the preparation method of 4-chloro-2-methyl-3-three deuterates methoxypyridine-N-oxide compound sees J.Med.Chem.1992,35, the method D of non-deuterate congener among the 1049-1057:
Begin from 3-hydroxy-2-methyl-pyrokomane; In the presence of salt of wormwood in DMF; Transform with three deuterate methyl iodide, (productive rate: 83 to 96%), it heats with ammonia at 150 ℃ in ethanol to obtain 2-methyl-3-three deuterate methoxyl group-pyrokomanes; From acetone/isopropanol 4: 1, after the crystallization, obtain 4-hydroxy-2-methyl-three deuterate methoxypyridine (productive rate: 52 to 60%).This raw material is handled with phosphoryl chloride, forms 4-chloro-2-methyl-three deuterate methoxypyridine (productive rate: 64 to 81%).In acetic acid, carry out oxidation then, obtain the 4-chloro-2-methyl-3-three deuterates methoxypyridine-N-oxide compound (productive rate: 87 to 89%) of light yellow solid with hydrogen peroxide.
After the conversion of 4-chloro-2-methylol-3-three deuterate methoxypyridines such as embodiment 9 said carrying out, obtain chlorination 4-chloro-2-chloromethyl-3-three deuterate methoxypyridines
(129 to 130 ℃ of fusing points) of colourless crystalline solid; Productive rate 19.6 grams (42%).
Embodiment 11
Chlorination 2-chloromethyl-3,4-two (three deuterate methoxyl groups) pyridine
According to the foregoing description 4 described methods, with 4-chloro-2-methyl-3-three deuterates methoxypyridine-N-oxide compound (25.3 grams, 144 mmoles; Embodiment 10 is seen in its preparation) be converted into 2-methyl-3; 4-two (three deuterate methoxyl groups) pyridine-N-oxide (output: 23.5 grams; 96%), obtains 2-methylol-3 again, 4-two (three deuterate methoxyl groups) pyridine (output: 13.0 grams; 56%); The final off-white color crystalline solid chlorination 2-chloromethyl-3 that generates, 4-two (three deuterate methoxyl groups) pyridine
(output: 15.4 grams, 89%).
Embodiment 12
5-difluoro-methoxy-2-[(4-chloro-3-methoxyl group-2-pyridyl) methylthio group]-1H-benzoglyoxaline
At 55 to 65 ℃; With 2 to 3 hours to (8.84 kilograms of 5-difluoro-methoxies-1H-benzimidazolyl-2 radicals-mercaptan; 40.9 mole), toluene (43 liters), water (21 liters) and the 40%NaOH aqueous solution are (10.3 kilograms; 103 moles) mixture in; Water (20 liters) solution that adds chlorination 4-chloro-2-chloromethyl-3-Methoxy Pyridine
(10.0 kilograms, 43.8 moles).Continue to stir 2 to 3 hours at 60 ℃, make reaction mixture be cooled to 10 to 15 ℃ again.The centrifugal deposition that obtains is with toluene (16 liters) washing, pulp once more in water (122 liters).Centrifugal back water (32 liters) cleans, and 35 ℃ of following vacuum-dryings, obtains off-white color solid 5-difluoro-methoxy-2-[(4-chloro-3-methoxyl group-2-pyridyl) methylthio group]-1H-benzoglyoxaline monohydrate (KF=4.6%) (95 to 99 ℃ of fusing points); 14.2 kilograms of output (92%).
1H-NMR(200MHz，DMSO-d6)：δ＝3.55(br?s，NH+H
2O)，3.92(s，3H)，4.79(s，2H)，6.97(dd，8.6Hz，2.3Hz，1H)，7.16(t，74.8Hz，1H)，7.28(d，2.2Hz，1H)，7.47(d，8.7Hz，1H)，7.55(d，5.3Hz，1H)，8.25(d，5.2Hz，1H)；LC-MS：MH
+＝372/374。
Embodiment 13
5-difluoro-methoxy-2-[(4-chloro-3-three deuterates methoxyl group-2-pyridyl) methylthio group]-1H-benzoglyoxaline
From chlorination 4-chloro-2-chloromethyl-3-three deuterate methoxypyridines
(5.00 grams; 21.6 mmole; Embodiment 10) beginning; According to embodiment 12 described methods, obtain off-white color solid 5-difluoro-methoxy-2-[(4-chloro-3-three deuterates methoxyl group-2-pyridyl) methylthio group]-1H-benzoglyoxaline monohydrate (KF=4.7%) (94 to 99 ℃ of fusing points); Output 7.24 grams (85%).
1H-NMR(200MHz，DMSO-d6)：δ＝4.79(s，2H)，6.98(dd，8.7Hz，2.3Hz，1H)，7.16(t，74.8Hz，1H)，7.28(d，2.0Hz，1H)，7.47(d，8.6Hz，1H)，7.55(d，5.2Hz，1H)，8.25(d，5.2Hz，1H)，12.75(brs，1H)；LC-MS：MH
+＝375/377。
Embodiment 14
The alternative method of 5-difluoro-methoxy-2-[(3-methoxyl group-4-three deuterates methoxyl group-2-pyridyl) methylthio group]-1H-benzoglyoxaline
At 15 to 30 ℃, with 30 to 60 minutes the clockwise sodium tert-butoxide (6.00 kilograms, 62.4 moles) DMAc (27 liters) mixture in, add methyl alcohol-d4 (2.26 kilograms, 62.7 moles).Be heated to after 57 to 65 ℃, with DMAc (10 liters) solution that added 5-difluoro-methoxy-2-[(4-chloro-3-methoxyl group-2-pyridyl) methylthio group]-1H-benzoglyoxaline monohydrate (6.08 kilograms, 15.6 moles) in 30 to 60 minutes.Continued stir about 10 hours at 57 to 65 ℃.Make reaction mixture be cooled to 20 to 30 ℃, water (21 liters) dilution uses the 20%HCl aqueous solution (about 7.5 liters) that pH is transferred to 7 to 8 then.With adding entry (75h) in about 4 hours, obtain the product deposition.With the gained slurry be heated to 35 to 45 ℃ 1.5 hours, be cooled to 10 to 15 ℃ then.Centrifugal (comprising that water (58 liters) cleans); Pulp once more in water (78 liters); Recentrifuge (comprising that again water (58 liters) cleans), the brown solid of the water-wet of acquisition 5-difluoro-methoxy-2-[(3-methoxyl group-4-three deuterates methoxyl group-2-pyridyl) methylthio group]-1H-benzoglyoxaline; 10.4 kilograms of output, KF=49.7% (91%).
Sample (16.2 grams at the product of 25 ℃ of vacuum-drying water-wets; KF=49.7%); Obtain unformed solid, its crystallization from toluene (30 milliliters) obtains the anhydrous 5-difluoro-methoxy-2-of off-white color solid [(3-methoxyl group-4-three deuterates methoxyl group-2-pyridyl) methylthio group]-1H-benzoglyoxaline (5.80 grams; 71% recovery, fusing point=115 are to 116 ℃).
1H-NMR(200MHz，DMSO-d6)：δ＝3.82(s，3H)，4.68(s，2H)，6.97(dd，8.6Hz，2.1Hz，1H)，7.08(d，5.6Hz，1H)，7.16(t，74.8Hz，1H)，7.28(br?s，1H)，7.47(br?d，～8.3Hz，1H)，8.16(d，5.6Hz，1H)，12.75(br?s，1H)；LC-MS：MH
+＝371。
Embodiment 15
5-difluoro-methoxy-2-[(3-methoxyl group-4-two deuterates methoxyl group-2-pyridyl) methylthio group]-1H-benzoglyoxaline
From 5-difluoro-methoxy-2-[(4-chloro-3-methoxyl group-2-pyridyl) methylthio group]-1H-benzoglyoxaline monohydrate (28.6 grams; 73.4 mmole) and methyl alcohol-d2 (10.0 the gram; 294 mmoles) beginning; According to embodiment 14 described methods, obtain 5-difluoro-methoxy-2-[(3-methoxyl group-4-two deuterates methoxyl group-2-pyridyl) the methylthio group]-1H-benzoglyoxaline of the brown solid of water-wet; Output 46.4 grams, KF=51.6% (82%).
1H-NMR(400MHz，DMSO-d6)：δ＝3.81(s，3H)，3.86(s，1H)，4.67(s，2H)，6.97(dd，8.4Hz，2.0Hz，1H)，7.08(d，5.5Hz，1H)，7.16(t，74.7Hz，1H)，7.21-7.53(br?m，2H)，8.16(d，5.5Hz，1H)，12.78(br?s，1H)；LC-MS：MH
+＝370。
Embodiment 16
5-difluoro-methoxy-2-[(3-methoxyl group-4-one deuterate methoxyl group-2-pyridyl) methylthio group]-1H-benzoglyoxaline
From 5-difluoro-methoxy-2-[(4-chloro-3-methoxyl group-2-pyridyl) methylthio group]-1H-benzoglyoxaline monohydrate (29.5 grams; 75.6 mmole) and methyl alcohol-d1 (10.0 the gram; 303 mmoles) beginning; According to embodiment 14 described methods, obtain 5-difluoro-methoxy-2-[(3-methoxyl group-4-one deuterate methoxyl group-2-pyridyl) the methylthio group]-1H-benzoglyoxaline of the brown solid of water-wet; Output 50.3 grams, KF=50.8% (89%).
1H-NMR(200MHz，DMSO-d6)：δ＝3.82(s，3H)，3.88(s，2H)，4.67(s，2H)，6.98(dd，8.6Hz，2.2Hz，1H)，7.08(d，5.6Hz，1H)，7.15(t，74.8Hz，1H)，7.22-7.53(br?m，2H)，8.16(d，5.6Hz，1H)，12.79(br?s，1H)；LC-MS：MH
+＝369。
Embodiment 17
5-difluoro-methoxy-2-[(4-methoxyl group-3-three deuterates methoxyl group-2-pyridyl) methylthio group]-1H-benzoglyoxaline
From 5-difluoro-methoxy-2-[(4-chloro-3-three deuterates methoxyl group-2-pyridyl) methylthio group]-1H-benzoglyoxaline monohydrate (6.97 grams; 17.7 mmole) and methyl alcohol (2.28 the gram; 71.2 beginning mmole); According to embodiment 14 described methods, obtain 5-difluoro-methoxy-2-[(4-methoxyl group-3-three deuterates methoxyl group-2-pyridyl) the methylthio group]-1H-benzoglyoxaline of the brown solid of water-wet; Output 7.01 grams, KF=19.1% (87%).
1H-NMR(200MHz，DMSO-d6)：δ＝3.89(s，3H)，4.68(s，2H)，6.97(dd，8.6Hz，2.0Hz，1H)，7.08(d，5.5Hz，1H)，7.16(t，74.7Hz，1H)，7.18-7.47(br?m，2H)，8.16(d，5.6Hz，1H)，12.76(br?s，1H)；LC-MS：MH
+＝371。
Embodiment 18
5-difluoro-methoxy-2-[(3,4-two (three deuterate methoxyl groups)-2-pyridyl) methylthio group]-1H-benzoglyoxaline
At 50 to 55 ℃; With 30 fens clockwise 5-difluoro-methoxy-1H-benzimidazolyl-2 radicals-mercaptan (14.5 grams; 66.8 mmole), the ethanol (133 milliliters) and the 2M NaOH aqueous solution are (73.5 milliliters; 147 mmoles) in the mixture; Gradation adds chlorination 2-chloromethyl-3,4-two (three deuterate methoxyl groups) pyridine
(15.4 grams, 66.8 mmoles).Continue to stir 1 to 2 hour at 50 to 55 ℃, boil off ethanol in 40 ℃ of vacuum then.Surplus water emulsion water (50 milliliters) dilution, and with methylene dichloride (165 milliliters each) extraction three times.The organic phase that merges is with the 0.1M NaOH aqueous solution (165 milliliters) washing, through Na
2SO
4Dry and be evaporated to driedly, obtain brown buttery 5-difluoro-methoxy-2-[(3,4-two (three deuterate methoxyl groups)-2-pyridyl) methylthio group]-1H-benzoglyoxaline; Output 23.8 grams (95%).
Embodiment 19
Racemize-5-difluoro-methoxy-2-[(3-methoxyl group-4-three deuterates methoxyl group-2-pyridyl) methylsulfinyl]-1H-benzoglyoxaline-large-scale methods
At 25 to 35 ℃; With 3 to 4 hours to (10.4 kilograms of 5-difluoro-methoxy-2-[(3-methoxyl group-4-three deuterates methoxyl group-2-pyridyl) methylthio group]-1H-benzoglyoxaline; KF=49.7%, 14.2 moles) and the solution of the 40%NaOH aqueous solution (2.84 kilograms) in water (49 liters) and Virahol (49 liters) mixture in, add (10.5 kilograms of aqueous sodium hypochlorite solutions; 10% concentration, 14.2 moles).Continue to stir 0.5 to 1 hour at 25 to 35 ℃, add 1%Na then
2S
2O
3The aqueous solution (4.3 liters) makes the reaction quencher.Boil off about 65 liters of solvents in 30 to 45 ℃ of vacuum then.After water (55 liters) dilution, boil off a part of solvent (8 to 10 liters) again.Make reaction mixture remain on 40 to 45 ℃, added 10% aqueous acetic acid (about 13 liters) with 1.5 hours and reach 8.5 to 9.5 until pH.Crystallization Once you begin adds 10% aqueous acetic acid (about 0.6 liter) again and makes pH slowly transfer to 6.8 to 7.2.Be cooled to 20 to 25 ℃, filter bullion, water (7.5 liters) washing, water-soluble once more (80 liters), the 40%NaOH aqueous solution (1.6 liters) and Na
2S
2O
3In the mixture of (60 gram).The summary turbidity solution of gained is with MIBK (each 12 liters) washed twice, and handles (0.40 kilogram) with Hyflo and make clarification, adds 10% aqueous acetic acids (about 8 liters) at 40 to 45 ℃ then and makes pH transfer to 9.0 to 9.5.In case product begins crystallization, adding 10% acetic acid again is 9.0 to 9.5 to continue keeping pH.At last; 20 to 25 ℃ centrifugal (comprising that water (7.5 liters) cleans); In about 50 ℃ of vacuum-dryings; Obtain off-white color solid racemize-5-difluoro-methoxy-2-[(3-methoxyl group-4-three deuterates methoxyl group-2-pyridyl) methylsulfinyl]-1H-benzoglyoxaline (decompose to 135 ℃ fusing point=134); 3.59 kilograms of output (65%).
1H-NMR(400MHz，DMSO-d6)：δ＝3.78(s，3H)，4.67(d，13.1Hz，1H)，4.73(d，13.1Hz，1H)，7.10(d，5.5Hz，1H)，7.18(br?d，8.7Hz，1H)，7.24(t，74.4Hz，1H)，7.44(br?s，1H)，7.70(br?s，1H)，8.15(d，5.5Hz，1H)，13.73(br?s，1H)；LC-MS：MH
+＝387。
Racemize-5-difluoro-methoxy-2-[(3-methoxyl group-4-two deuterates methoxyl group-2-pyridyl) methylsulfinyl]-1H-benzoglyoxaline
From wet 5-difluoro-methoxy-2-[(3-methoxyl group-4-two deuterates methoxyl group-2-pyridyl) methylthio group]-1H-benzoglyoxaline (32.7 grams; KF=51.6%; 42.8 beginning mmole); According to embodiment 19 described methods, obtain off-white color solid racemize-5-difluoro-methoxy-2-[(3-methoxyl group-4-two deuterates methoxyl group-2-pyridyl) methylsulfinyl]-1H-benzoglyoxaline (decompose to 135 ℃ fusing point=133); Output 10.8 grams (65%).
1H-NMR(200MHz，DMSO-d6)：δ＝3.32(br?s，NH+H
2O)，3.77(s，3H)，3.86(s，1H)，4.65(d，13.1Hz，1H)，4.73(d，13.1Hz，1H)，7.10(d，5.5Hz，1H)，7.15(dd，8.8Hz，2.4Hz，1H)，7.23(t，74.4Hz，1H)，7.44(d，2.2Hz，1H)，7.69(d，8.8Hz，1H)，8.15(d，5.5Hz，1H)；LC-MS：MH
+＝386。
Embodiment 21
Racemize-5-difluoro-methoxy-2-[(3-methoxyl group-4-one deuterate methoxyl group-2-pyridyl) methylsulfinyl]-1H-benzoglyoxaline
From wet 5-difluoro-methoxy-2-[(3-methoxyl group-4-one deuterate methoxyl group-2-pyridyl) methylthio group]-1H-benzoglyoxaline (34.8 grams; KF=50.8%; 46.5 beginning mmole); According to embodiment 19 described methods, obtain off-white color solid racemize-5-difluoro-methoxy-2-[(3-methoxyl group-4-one deuterate methoxyl group-2-pyridyl) methylsulfinyl]-1H-benzoglyoxaline (decompose to 135 ℃ fusing point=134); Output 14.0 grams (78%).
1H-NMR(200MHz，DMSO-d6)：δ＝3.78(s，3H)，3.88(s，2H)，4.66(d，13.2Hz，1H)，4.73(d，13.1Hz，1H)，7.10(d，5.6Hz，1H)，7.16(dd，8.8Hz，2.4Hz，1H)，7.24(t，74.4Hz，1H)，7.45(d，2.2Hz，1H)，7.69(d，8.8Hz，1H)，8.15(d，5.5Hz，1H)，13.77(br?s，1H)；LC-MS：MH
+＝385。
Embodiment 22
Racemize-5-difluoro-methoxy-2-[(4-methoxyl group-3-three deuterates methoxyl group-2-pyridyl) methylsulfinyl]-1H-benzoglyoxaline
From wet 5-difluoro-methoxy-2-[(4-methoxyl group-3-three deuterates methoxyl group-2-pyridyl) methylthio group]-1H-benzoglyoxaline (3.00 grams; KF=19.1%; 6.55 beginning mmole) is according to embodiment 23 described methods, from TBME (10 milliliters) after the crystallization; Obtain off-white color solid racemize-5-difluoro-methoxy-2-[(4-methoxyl group-3-three deuterates methoxyl group-2-pyridyl) methylsulfinyl]-1H-benzoglyoxaline (decompose to 134 ℃ fusing point=133); Output 1.83 grams (72%).
1H-NMR(200MHz，DMSO-d6)：δ＝3.90(s，3H)，4.66(d，13.1Hz，1H)，4.73(d，13.1Hz，1H)，7.10(d，5.6Hz，1H)，7.15(dd，8.9Hz，2.4Hz，1H)，7.24(t，74.4Hz，1H)，7.45(d，2.1Hz，1H)，7.69(d，8.8Hz，1H)，8.15(d，5.5Hz，1H)，13.77(br?s，1H)；LC-MS：MH
+＝387。
Embodiment 23
Racemize-5-difluoro-methoxy-2-[(3,4-two (three deuterate methoxyl groups)-2-pyridyl) methylsulfinyl]-1H-benzoglyoxaline
5-difluoro-methoxy-2-[(3,4-two (three deuterate methoxyl groups)-2-pyridyl) methylthio group]-1H-benzoglyoxaline (23.8 grams, 63.7 mmoles) is dissolved in CH
2Cl
2(210 milliliters), and be cooled to-55 to-40 ℃.Under this temperature, with the CH that slowly added 3-chloroperoxybenzoic acid (wet, 77% concentration, 15.8 grams, 70.5 mmoles) in 1.5 hours
2Cl
2(110 milliliters) solution.-55 to-40 ℃ after 1 hour, add triethylamine (12.3 milliliters, 88.5 mmoles) and 6%Na in succession
2CO
3The aqueous solution and 2%Na
2S
2O
31: 1 mixture of the aqueous solution (140 milliliters) makes mixture be warming up to about 0 ℃ simultaneously.Normal temperature continues down to stir 1 hour.Separate phase, organic layer is used 6%Na
2CO
3The aqueous solution and 2%Na
2S
2O
31: 1 mixture washed twice of the aqueous solution, water (140 milliliters each) washing once is evaporated to dried then again.From DIPE (700 milliliters), after the crystallization, obtain off-white color solid racemize-5-difluoro-methoxy-2-[(3,4-two (three deuterate methoxyl groups)-2-pyridyl) methylsulfinyl]-1H-benzoglyoxaline; Output 20.9 grams (84%).
Embodiment 24
Racemize-5-difluoro-methoxy-2-[(3-methoxyl group-4-two deuterates methoxyl group-2-pyridyl) methylsulfinyl]-1H-benzoglyoxaline sodium salt monohydrate
From racemize-5-difluoro-methoxy-2-[(3-methoxyl group-4-two deuterates methoxyl group-2-pyridyl) methylsulfinyl]-1H-benzoglyoxaline (8.10 grams; 21.0 beginning mmole); According to embodiment 6 described methods; [(3-methoxyl group-4-two deuterates methoxyl group-2-pyridyl) methylsulfinyl]-(fusing point=150 are to 152 ℃ (decomposition), KF=4.8%) for 1H-benzoglyoxaline sodium salt monohydrate to obtain off-white color solid racemize-5-difluoro-methoxy-2-; Output 6.05 grams (68%).
1H-NMR(200MHz，DMSO-d6)：δ＝3.77(s，3H)，3.85(s，1H)，4.36(d，12.9Hz，1H)，4.66(d，12.9Hz，1H)，6.73(dd，8.6Hz，2.4Hz，1H)，7.02(t，75.8Hz，1H)，7.07(d，5.6Hz，1H)，7.25(d，2.3Hz，1H)，7.45(d，8.6Hz，1H)，8.22(d，5.5Hz，1H)；LC-MS：MNa
+＝408，MH
+＝386。
Embodiment 25
Racemize-5-difluoro-methoxy-2-[(3-methoxyl group-4-one deuterate methoxyl group-2-pyridyl) methylsulfinyl]-1H-benzoglyoxaline sodium salt monohydrate
From racemize-5-difluoro-methoxy-2-[(3-methoxyl group-4-one deuterate methoxyl group-2-pyridyl) methylsulfinyl]-1H-benzoglyoxaline (10.2 grams; 26.5 beginning mmole); According to embodiment 6 described methods; [(3-methoxyl group-4-one deuterate methoxyl group-2-pyridyl) methylsulfinyl]-(fusing point=151 are to 152 ℃ (decomposition), KF=4.1%) for 1H-benzoglyoxaline sodium salt monohydrate to obtain off-white color solid racemize-5-difluoro-methoxy-2-; Output 8.95 grams (79%).
1H-NMR(200MHz，DMSO-d6)：δ＝3.78(s，3H)，3.88(s，2H)，4.34(d，12.9Hz，1H)，4.68(d，12.9Hz，1H)，6.73(dd，8.6Hz，2.4Hz，1H)，7.03(t，75.8Hz，1H)，7.08(d，5.5Hz，1H)，7.24(d，2.2Hz，1H)，7.44(d，8.6Hz，1H)，8.22(d，5.5Hz，1H)；LC-MS：MNa
+＝407，MH
+＝385。
Embodiment 26
Racemize-5-difluoro-methoxy-2-[(3,4-two (three deuterate methoxyl groups)-2-pyridyl) methylsulfinyl]-1H-benzoglyoxaline sodium salt monohydrate
At 15 to 25 ℃; With about 15 minutes to racemize-5-difluoro-methoxy-2-[(3; 4-two (three deuterate methoxyl groups)-2-pyridyl) methylsulfinyl]-1H-benzoglyoxaline (21.0 grams; 53.9 mmole) in the solution of ethanol/dichloromethane 6: 1 mixture (725 milliliters), add the 6M NaOH aqueous solution (8.92 milliliters, 53.5 mmoles).Restir is 10 minutes under the room temperature, boils off most of solvent.Gained enriched material (115 gram) dilutes with DIPE (1.7 liters).Some black wax shape resistates is insoluble, pours out yellow supernatant.In this solution, add a part of DIPE (3.4 liters) again, generate the product deposition.Make suspension-s be cooled to 0 ℃.Solids filtered; Wash with DIPE (100 milliliters); And, obtain off-white color solid racemize-5-difluoro-methoxy-2-[(3,4-two (three deuterate methoxyl groups)-2-pyridyl) methylsulfinyl]-1H-benzoglyoxaline sodium salt monohydrate (KF=4.0%) 40 ℃ of vacuum-dryings; Output 18.9 grams (82%).
1H-NMR(400MHz，DMSO-d6)：δ＝4.32(d，12.9Hz，1H)，4.70(d，12.9Hz，1H)，6.72(dd，8.6Hz，2.4Hz，1H)，7.04(t，75.8Hz，1H)，7.08(d，5.5Hz，1H)，7.23(d，2.4Hz，1H)，7.44(d，8.6Hz，1H)，8.22(d，5.5Hz，1H)；LC-MS：MNa
+＝412，MH
+＝390。
Embodiment 27
Racemize-5-difluoro-methoxy-2-[(3-methoxyl group-4-three deuterates methoxyl group-2-pyridyl) methylsulfinyl]-1H-benzoglyoxaline sodium salt sesquialter hydrate
At 48 to 55 ℃; Racemize-5-difluoro-methoxy-2-[(3-methoxyl group-4-three deuterates methoxyl group-2-pyridyl) methylsulfinyl]-1H-benzoglyoxaline sodium salt monohydrate (2.93 kilograms, 6.87 moles) is dissolved in the mixture of Virahol (12 liters) and water (0.50 liter).Handle and be cooled to 18 to 25 ℃ with Hyflo SuperCel (56 gram), add true product sample crystal seed after, stir 40h at 18 to 25 ℃, and 10 to 15 ℃ of restir 5 hours to accomplish crystallization.Centrifugal; 45 ℃ of vacuum-dryings; [(3-methoxyl group-4-three deuterates methoxyl group-2-pyridyl) methylsulfinyl]-(fusing point=140 are to 142 ℃ (decomposition), KF=6.6%) for 1H-benzoglyoxaline sodium salt sesquialter hydrate to obtain the racemize-5-difluoro-methoxy-2-of white solid; 2.28 kilograms of output (78%).
Embodiment 28
(S)-large-scale methods of dry starting raw material of 5-difluoro-methoxy-2-[(3-methoxyl group-4-three deuterates methoxyl group-2-pyridyl) methylsulfinyl]-1H-benzoglyoxaline-not
In room temperature; With wet 5-difluoro-methoxy-2-[(3-methoxyl group-4-three deuterates methoxyl group-2-pyridyl) the methylthio group]-1H-benzoglyoxaline (KF=47.6% of 382 grams; 0.540 mole) be suspended in 2.44 liters of mibks, together together with (+)-L-tartrate two-(N-tetramethyleneimine acid amides) (55.0 gram).With mixture heating up to 40 ℃, vacuum boils off about 1.25 liters of solvents and anhydrates to remove.Then, add n-propyl alcohol zirconium (IV) (24.0 milliliters, the 70%/n-propyl alcohol), and continued restir 1 hour at 40 ℃.After being cooled to 30 ℃, add N-ethyl diisopropylamine (6.5 milliliters) and Cumene Hydroperoxide 80 (103 milliliters, about 80% concentration).After 30 ℃ of stir abouts 18 hours, tlc shows does not have starting raw material further to be transformed.Clarifying reaction mixture dilutes with 500 milliliters of mibks, and with 7.0 gram Sulfothiorine/800 milliliter saturated sodium bicarbonate solution quenchers.After being separated, organic layer is with 400 milliliters of saturated sodium bicarbonate solution washed twice.In organic phase, add 1.5 premium on currency, and pH is transferred to pH=13 with 40% aqueous sodium hydroxide solution.Organic layer extracts with the water of 400 milliliters of pH13 again.After handling with Hyflo Super Cel (5.0 gram), add pH that 10% aqueous acetic acids will merge water at 40 to 45 ℃ and transfer to and be about 9.In case product deposition beginning with mixture restir 12 hours, is transferred pH at last once more.Filter (comprising that water (200 milliliters) cleans), obtain the bullion (160g, 75% productive rate) of optical purity＞98%.
In order further to increase purity, bullion is dissolved in the methylene dichloride (2.0 liters), and water (400 milliliters) washing.Chase (solvent chase) with TBME through solvent and carry out crystallization (about 1.1 liters of final volume).Filter crystal at about 0 ℃; Wash with TBME (400 milliliters); And, obtain off-white color solid (S)-5-difluoro-methoxy-2-[(3-methoxyl group-4-three deuterates methoxyl group-2-pyridyl) methylsulfinyl]-1H-benzoglyoxaline (146 to 148 ℃ of fusing points (decomposition) 30 ℃ of vacuum-dryings; KF=0.8%); Output 135 grams (64%).
Chirality HPLC:＞98.0%ee; Specific rotation: [α]
D=-98 ° (methyl alcohol, c=0.50).
1H-NMR(200MHz，DMSO-d6)：δ＝3.41(br?s，NH+H
2O)，3.77(s，3H)，4.65(d，13.0Hz，1H)，4.73(d，13.1Hz，1H)，7.09(d，5.6Hz，1H)，7.15(dd，8.9Hz，2.4Hz，1H)，7.23(t，74.4Hz，1H)，7.44(d，2.1Hz，1H)，7.68(d，8.9Hz，1H)，8.14(d，5.5Hz，1H)；LC-MS：MH
+＝387。
Embodiment 29
(R)-5-difluoro-methoxy-2-[(3-methoxyl group-4-three deuterates methoxyl group-2-pyridyl) methylsulfinyl]-1H-benzoglyoxaline
From 5-difluoro-methoxy-2-[(3-methoxyl group-4-three deuterates methoxyl group-2-pyridyl) methylthio group]-1H-benzoglyoxaline (70.7 grams; KF=47.6%; 100 mmoles) beginning; And with (-)-D-tartrate two-(N-tetramethyleneimine acid amides) (10.3 gram, 40.0 mmoles) as chiral ligand, according to embodiment 28 described methods; From TBME, after the recrystallization, obtain off-white color solid (R)-5-difluoro-methoxy-2-[(3-methoxyl group-4-three deuterates methoxyl group-2-pyridyl) methylsulfinyl]-1H-benzoglyoxaline (fusing point: 140 to 142 ℃ (decomposition); KF=0.8%); Output 22.2 grams (57%).
Chirality HPLC:＞98.0%ee; Specific rotation: [α]
D=+97 ° (methyl alcohol, c=0.50).
1H-NMR(200MHz，DMSO-d6)：δ＝3.77(s，3H)，4.65(d，13.2Hz，1H)，4.73(d，13.1Hz，1H)，7.09(d，5.5Hz，1H)，7.16(br?d，～10.3Hz，1H)，7.23(t，74.4Hz，1H)，7.44(br?s，1H)，7.68(br?s，1H)，8.14(d，5.5Hz，1H)，13.73(br?s，1H)；LC-MS：MH
+＝387。
(R)-5-difluoro-methoxy-2-[(3-methoxyl group-4-three deuterates methoxyl group-2-pyridyl) methylsulfinyl]-1H-benzoglyoxaline sodium salt trihydrate
From (R)-5-difluoro-methoxy-2-[(3-methoxyl group-4-three deuterates methoxyl group-2-pyridyl) methylsulfinyl]-1H-benzoglyoxaline (15.5 grams; 40.1 beginning mmole); According to embodiment 5 described methods, obtain (R)-5-difluoro-methoxy-2-[(3-methoxyl group-4-three deuterates methoxyl group-2-pyridyl) methylsulfinyl]-1H-benzoglyoxaline sodium salt trihydrate (98 to 103 ℃ of the fusing points (decomposition) of white solid; KF=11.3%); Output 17.4 grams (94%).
Chirality HPLC:＞98.0%ee; Specific rotation: [α]
D=+91 ° (methyl alcohol, c=0.50).
Embodiment 31
Two-[(R)-and 5-difluoro-methoxy-2-[(3-methoxyl group-4-three deuterates methoxyl group-2-pyridyl) methylsulfinyl]-1H-benzoglyoxaline] the magnesium salts trihydrate
From (R)-5-difluoro-methoxy-2-[(3-methoxyl group-4-three deuterates methoxyl group-2-pyridyl) methylsulfinyl]-1H-benzoglyoxaline sodium salt (2.30 grams; KF=11.3%; 5.00 beginning mmole); According to embodiment 7 described methods, obtain two of white solid-[(R)-5-difluoro-methoxy-2-[(3-methoxyl group-4-three deuterates methoxyl group-2-pyridyl) methylsulfinyl]-1H-benzoglyoxaline] magnesium salts trihydrate (fusing point: 141 to 145 ℃ (decomposition); KF=6.9%); Output 1.23 grams (58%).
Chirality HPLC:＞99.0%ee; Specific rotation: [α]
D=+120 ° (methyl alcohol, c=0.50).
Commercial use
General formula 1 compound and salt thereof and solvolyte (preferably water compound), with and the useful pharmacological property of solvolyte (preferably water compound) (hereinafter referred to as " The compounds of this invention ") of salt make it have commercial use.Especially, they have significant inhibitory effect to gastric acid secretion, and the stomach and intestine of warm-blooded animal (particularly human) are had fabulous provide protection.Here, the characteristic of The compounds of this invention is: acting duration, bioavailability that selectivity is high, favourable are high especially, and interindividual metabolism overview is consistent, do not have apparent side effect, and the treatment spectrum width.
In this context; " stomach and intestine protection " is interpreted as prevention and treatment gastrointestinal illness; Particularly gastrointestinal inflammation disease and damage are (for example; Stomach ulcer, duodenal ulcer, gastritis, owing to produce Yi Jichang, GERD, segmental enteritis, the IBD that acid increases or drug effect causes), the reason that causes these diseases can be for example mikrobe (for example helicobacter pylori), bacteriotoxin, medicine (for example some antiphlogistic and antirheumatic), chemical (for example ethanol), hydrochloric acid in gastric juice or pressure.
In the various models of measuring antiulcer agent and secretion inhibitor character, find that surprisingly The compounds of this invention has advantageous property, obviously is superior to the prior art compound, particularly its metabolisming property.The metabolisming property of these improvement can for example reduce The compounds of this invention and be used to the dosage of treating or preventing.Perhaps, can obtain long working lipe through the The compounds of this invention of use with prior art compound same dose.Relevant with these character is the advantage of relevant patient safety or economic aspect (for example, medicine valency or the like).Because these character, The compounds of this invention is highly suitable in people's medication and veterinary medicine, using, and is specially adapted to treat and/or prevent gastrointestinal illness.
Therefore, the present invention also provides The compounds of this invention to be used to treat and/or prevent the purposes of above-mentioned disease.
The present invention comprises that also The compounds of this invention preparation is used to treat and/or prevent the purposes of the medicinal compsns of above-mentioned disease.
The present invention also provides the medicinal compsns that contains The compounds of this invention.Especially, the invention provides and contain its pharmaceutically-acceptable salts form (particularly sodium salt or magnesium salts form), and/or the medicinal compsns of the formula 1 of the hydrate forms of these salt, 1a or 1b compound.
Said medicinal compsns can prepare with the currently known methods that those skilled in the art are familiar with.As medicinal compsns; The compounds of this invention can directly use; Perhaps preferred and suitable pharmaceutical excipient or carrier combinations are used; Formulation has tablet, coated tablet, capsule, suppository, paste (for example as TTS), emulsion, suspension-s or solution; Wherein the content of active compound is favourable is about 0.1% to about 95%, and through selecting suitable auxiliary material and carrier, can process the pharmaceutical dosage form (for example slow release type or enteric solubility) that is suitable for active compound and/or required onset time and/or acting duration.
The auxiliary material or the carrier that are applicable to required medicinal prepns are well known by persons skilled in the art.Except solvent, gel forming agent, suppository base, compressing tablet auxiliary material and other are used for the carrier of active compound; Can also use for example oxidation inhibitor, dispersion agent, emulsifying agent, antifoams, odor masking agent (flavour-masking agents), sanitas, solubilizing agent, tinting material; Perhaps especially, penetration enhancer and mixture form agent (for example Schardinger dextrins).
The compounds of this invention can be taken orally, administered parenterally or percutaneous dosing.The administration of The compounds of this invention preferred oral.
In people's medication, find usually, advantageously; During the The compounds of this invention oral administration, daily dosage about 0.01 is to about 1 mg/kg body weight, and preferred about 0.02 to about 0.5 mg/kg body weight; Preferred about 0.04 to about 0.3 mg/kg body weight [free state (promptly not being the form of salt ,=" free cpds ") with The compounds of this invention is a basic calculation], if suitable especially; With a plurality of, the form administration of preferred 1 to 4 single dose is to obtain required effect.For the parenteral treatment, can use similar dosage or usually lower dosage (especially when vein gives active compound).The required optimal dose and the administering mode of active compound under every kind of situation, those skilled in the art can confirm easily.
Therefore, another aspect of the present invention is the medicinal compsns that comprises one or more The compounds of this invention and one or more conventional auxiliary materials, and wherein single dose comprises about 2 to about 60 milligrams free cpds.
Another aspect of the present invention is the medicinal compsns that comprises one or more The compounds of this invention and one or more conventional auxiliary materials, and wherein single dose comprises about 4 to about 40 milligrams free cpds.
Another aspect of the present invention is the purposes that The compounds of this invention is used to treat gastrointestinal illness.
Another aspect of the present invention is the purposes that The compounds of this invention production is used to treat or prevent the medicinal compsns of gastrointestinal illness.
Another aspect of the present invention is the method for treating gastrointestinal illness through the medicinal compsns that comprises one or more The compounds of this invention.
Another aspect of the present invention is the purposes of The compounds of this invention treatment for patient's gastrointestinal illness of poor metabolizer.
Another aspect of the present invention is the purposes that the The compounds of this invention treatment has patient's gastrointestinal illness of drug interaction risk.
Another aspect of the present invention is that the The compounds of this invention treatment needs the long-time purposes that suppresses sour excretory patient gastrointestinal illness.
Another aspect of the present invention is to be used to treat the medicinal compsns into patient's gastrointestinal illness of poor metabolizer, and it comprises one or more The compounds of this invention and one or more conventional auxiliary materials, and wherein single dose comprises about 2 to about 60 milligrams free cpds.
Another aspect of the present invention is to be used to treat the medicinal compsns into patient's gastrointestinal illness of poor metabolizer, and it comprises one or more The compounds of this invention and one or more conventional auxiliary materials, and wherein single dose comprises about 4 to about 40 milligrams free cpds.
Another aspect of the present invention is the medicinal compsns that is used to treat patient's gastrointestinal illness of drug interaction risk; It comprises one or more The compounds of this invention and one or more conventional auxiliary materials, and wherein single dose comprises about 2 to about 60 milligrams free cpds.
Another aspect of the present invention is the medicinal compsns that is used to treat patient's gastrointestinal illness of drug interaction risk; It comprises one or more The compounds of this invention and one or more conventional auxiliary materials, and wherein single dose comprises about 4 to about 40 milligrams free cpds.
Another aspect of the present invention is to be used to treat the long-time medicinal compsns that suppresses sour excretory patient gastrointestinal illness of needs; It comprises one or more The compounds of this invention and one or more conventional auxiliary materials, and wherein single dose comprises about 2 to about 60 milligrams free cpds.
Another aspect of the present invention is to be used to treat the long-time medicinal compsns that suppresses sour excretory patient gastrointestinal illness of needs; It comprises one or more The compounds of this invention and one or more conventional auxiliary materials, and wherein single dose comprises about 4 to about 40 milligrams free cpds.
Another aspect of the present invention is to be used to treat the medicinal compsns into patient's gastrointestinal illness of poor metabolizer; Comprise pharmacy acceptable salt of the present invention or its hydrate and one or more conventional auxiliary materials in its oral administration solid application forms, wherein single dose comprises about 2 to about 60 milligrams free cpds.
Another aspect of the present invention is to be used to treat the medicinal compsns into patient's gastrointestinal illness of poor metabolizer; Comprise pharmacy acceptable salt of the present invention or its hydrate and one or more conventional auxiliary materials in its oral administration solid application forms, wherein single dose comprises about 4 to about 40 milligrams free cpds.
Another aspect of the present invention is the medicinal compsns that is used to treat patient's gastrointestinal illness of drug interaction risk; Comprise pharmacy acceptable salt of the present invention or its hydrate and one or more conventional auxiliary materials in its oral administration solid application forms, wherein single dose comprises about 2 to about 60 milligrams free cpds.
Another aspect of the present invention is the medicinal compsns that is used to treat patient's gastrointestinal illness of drug interaction risk; Comprise pharmacy acceptable salt of the present invention or its hydrate and one or more conventional auxiliary materials in its oral administration solid application forms, wherein single dose comprises about 4 to about 40 milligrams free cpds.
Another aspect of the present invention is to be used to treat the long-time medicinal compsns that suppresses sour excretory patient gastrointestinal illness of needs; Comprise pharmacy acceptable salt of the present invention or its hydrate and one or more conventional auxiliary materials in its oral administration solid application forms, wherein single dose comprises about 2 to about 60 milligrams free cpds.
Another aspect of the present invention is to be used to treat the long-time medicinal compsns that suppresses sour excretory patient gastrointestinal illness of needs; Comprise pharmacy acceptable salt of the present invention or its hydrate and one or more conventional auxiliary materials in its oral administration solid application forms, wherein single dose comprises about 4 to about 40 milligrams free cpds.
If The compounds of this invention is used to treat above-mentioned disease, then medicinal prepns can also comprise one or more pharmacological components from other classification medicine.The example that can mention comprises Tranqilliser (benzodiazepine
type for example; As stable), spasmolytic (for example bietamiverine (bietamiverine) or Camylofin (camylofine)), anticholinergic (for example; Oxyphencyclimine or fencarbamide), local anesthetic (for example; Tetracaine or PROCAINE HCL, PHARMA GRADE), optional enzyme, VITAMINs or the amino acid of also comprising.
In this context, the lay special stress on The compounds of this invention with play buffering or in hydrochloric acid in gastric juice or suppress the combination of secretory other medicine of acid, for example antacid (like Ripon) or H
2Blocker (like Cimitidine Type A/AB, Ranitidine HCL), and with the combination of gastrin antagonists, with additional or ultra strengthen main effect with adding and/or eliminate or minimizing spinoff or onset faster.Also have with NSAID (for example; Etofenamate, diclofenac, indomethacin, Ibuprofen BP/EP or piroxicam) fixing or independent assortment; With the gastrointestinal damage that prevents to cause by NSAID; Perhaps fix or independent assortment with the compound that changes digestive tract power; Perhaps with reduce by one cross property relaxation of lower esophageal sphincter (TLOSR) incidence compound fix or independent assortment, perhaps with antimicrobial drug (for example cynnematin, tsiklomitsin, penicillium mould, Macrolide, nitroimidazole or bismuth salt) fixing or independent assortment with the control Helicobacter pylori.Can be used as comprising of antibacterial combination part, for example mezlocillin, Ampicillin Trihydrate, amoxycilline Trihydrate bp, cefoxitin, cefoxitin, cefotaxime, imipenum, qingfengmeisu qiong, amikacin, Oxacyclotetradecane,erythromycin deriv, CIPROFLOXACIN USP 24, metronidazole, clarithromycin, Azythromycin and compsn thereof (for example clarithromycin+metronidazole or amoxycilline Trihydrate bp+clarithromycin).
During embodiment of the present invention; In combined therapy; The compounds of this invention can separate with above-mentioned one or more standard care medicines, continuously, simultaneously or give (for example, as the unit dosage of combination, as the unit dosage that separates, as contiguous discontinuous unit dosage, as fixing or revocable combination, as the medicine box of forming (kit-of-parts) or as mixture) in chronological order alternately.
Term of the present invention " combination " can be the medicine box (kit-of-parts) of fixed combination, on-fixed combination or composition.
" fixed combination " is defined as a kind of combination, and wherein first activeconstituents and second activeconstituents are present in a unit formulation or the single entity together.An example of " fixed combination " is a kind of medicinal compsns, and wherein said first activeconstituents and said second activeconstituents are present in the mixture (like preparation) of administration simultaneously.Another example of " fixed combination " is a kind of medicinal compsns, and wherein said first activeconstituents and said second activeconstituents are present in the unit but do not mix.
" medicine box of composition " is defined as a kind of combination, and wherein said first activeconstituents and said second activeconstituents are present in the above unit.An example of " medicine box of composition " is a kind of combination, and wherein said first activeconstituents and said second activeconstituents separately exist.The component of the medicine box of forming can separate, continuously, give alternately simultaneously or in chronological order.
Pharmacology
Metabolism in the hepatomicrosome
Material and method
Pantoprazole or embodiment 1 or 2 (each 10 μ M) are incubated with hepatomicrosome (source: remove minipig (Mini Pig) from the TEBU, from GenTest), at 1 mg/ml albumen, 100mM Tris-HCl, pH7.4,1mM NADPH
2Condition under be incubated.Use the liquid nitrogen termination reaction after 90 minutes, detect parent compound (10mM KH with HPLC
2PO
4, pH 7.4, acetonitrile gradient 20 to 44%).
Table 1:
Be incubated after 90 minutes the comparison (kind dependency) of microsome metabolism H-pantoprazole and metabolism deuterate compound (embodiment 1 or 2)
MCR
In order to assess the character of The compounds of this invention, compare with non-deuterate compound, measured the inherent clearance rate of compound among recombinant human Cytochrome P450 (CYP) isozyme CYP1A2, CYP2C8, CYP2C19, CYP2D6, CYP3A4 and the CYP3A5.
Material and method
Under 37 ℃; Compound described in embodiment 5,6,22,24,25 and 30 and [1H] racemize Pantoprazole Sodium sesquialter hydrate and corresponding S-thereof and R-enantiomorph are being contained the 1nmol/mL P450 (Cypex that recombinates; Dundee, UK), be incubated 0,3,6,12 and 15 or 30 minute in the damping fluid of 4mg/mL microsomal protein, 100mMol/L Tris-HCl (pH7.4) and 1mMol/LNADPH.Insulation is triplicate.Measure inherent clearance rate based on the rate of disappearance of parent compound.Measure pantoprazole and deuterate congener with HPLC-UV.Lower bound based on the detection resolution (resolution) of testing variability is 17.6 μ l/min/nmol P450.
The result
Find that CYP2C19 and CYP3A4 help the oxidative metabolism of pantoprazole and deuterate congener thereof.Other all cells cytochrome p 450 isozyme (CYP1A2, CYP2C8, CYP2C9, CYP2D6, CYP3A5) does not have help to the metabolism of any research compound of being higher than the detection resolution lower bound.
Pantoprazole M2 (5-(difluoro-methoxy)-2-[[(3-methoxyl group-4-sulfate-2-pyridine
The base)-methyl] sulfinyl]-the 1H-benzoglyoxaline) formation kinetics
Behind MCR with P450 enzyme assessment The compounds of this invention; Be determined at the formation kinetics of the major metabolite of confirming in the human body (that is M2 (5-(difluoro-methoxy)-2-[[(3-methoxyl group-4-sulfate-2-pyridyl)-methyl] sulfinyl]-1H-benzoglyoxaline)).Because the generation of M2 comprises: through CYP2C19 oxidation 4-methoxyl group-pyridyl; And combine with 3'-phosphoadenosine-5'-phosphosulfate (PAPS) through unacknowledged sulfotransferase subsequently; So use frozen human liver cell, this be since in this vitro system I stage and II stage enzyme all be acting.
Material and method
With compound described in embodiment 5,6,22,24,25 and 30 and racemize [
1H] Pantoprazole Sodium sesquialter hydrate and corresponding S-thereof be 10 with the R-enantiomorph containing 84 μ g/mL amikacins, 1mMol/L calcium chloride, 20mMol/L Hepes, 4.2 μ Mol/L hepatonic sour (hepatonic acid), 28.5mMol/L sodium hydrogencarbonate and concentration
6The frozen liver cell of the people of cell/mL (10 donor storehouses (donor pool), InVitro Technologies, insulation among the Baltimore, Krebs Henseleit Puffer (KHB) MDUSA).The formation speed of M2 is linear until 60 minutes under these conditions.The M2 that has measured under 9 different compound concentrations (0,0.5,1.0,2.5,5.0,10.0,25.0,50.0 and 100 μ Mol/L) of 60 minutes of 37 ℃ of duplicate insulations forms speed.With LC-MS/MS M2 is carried out quantitatively.Isolated M2 is as external standard from people's urine.Through nonlinear regression analysis, obtain to reach the maximum concentration (K that forms speed of half with the Michaelis-Menten equation
M-be worth) and the maximum speed (V that forms
Max).Use V
MaxDivided by K
MObtain inherent clearance rate (Cl
Int).
The result
By compound formation M2 described in pantoprazole, its enantiomorph and embodiment 5,6,22,24,25 and 30, demonstrate and receive the inhibition that is higher than 100 μ M concentration of substrate.Therefore, the insulation data of 100 and 250 μ M concentration of substrate are got rid of at K
mAnd V
MaxCalculating outside.By racemize [
1H] pantoprazole and enantiomorph formation M2, show stereospecificity difference (Figure 1A).Compare with its non-deuterated counterpart, deuterated racemize, (R) and (S) on 4-methoxyl group-pyridyl position-congener (embodiment 6,30 and 5) shows that forming speed is reduced to 1/2.5th (Figure 1B) at least.Compare with its non-deuterated counterpart, the inherent clearance rate of deuterated racemize, (R) and (S) on 4-methoxyl group-pyridyl position-congener (embodiment 6,30 and 5) is reduced to 1/4.7th (tables 2) at least.From [
1H] the observed M2 of the pantoprazole congener stereospecificity difference that forms speed do not have on 4-methoxyl group-pyridyl position deuterated congener significantly (Figure 1B).Surprisingly, compare with non-deuterate compound, the reduction of M2 formation speed demonstrates and depends on the position (Fig. 2) of three deuterate methoxyl groups in molecule pyridyl part.Increase in the molecule on 4-methoxyl group-pyridyl position by [
2H] atom substituted [
1H] atom number ([
1H], [
2H
1] embodiment 25, [
2H
2] embodiment 24 and [
2H
3] embodiment 6), can reduce the formation speed (Fig. 3) of M2.
Table 2:
What obtain with the insulation of pantoprazole and The compounds of this invention mixes the inherent clearance rate (Cl in (pooled) human liver cell
Int).
Claims (26)
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| EP05106874 | 2005-07-26 | ||
| EP05106874.0 | 2005-07-26 | ||
| PCT/EP2006/064669 WO2007012651A1 (en) | 2005-07-26 | 2006-07-26 | Isotopically substituted pantoprazole |
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| JP (1) | JP5289951B2 (en) |
| CN (1) | CN101268050B (en) |
| AR (1) | AR054583A1 (en) |
| AU (1) | AU2006274037B2 (en) |
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| MX2008000901A (en) * | 2005-07-26 | 2008-03-26 | Nycomed Gmbh | Isotopically substituted proton pump inhibitors. |
| JP2009511481A (en) * | 2005-10-06 | 2009-03-19 | オースペックス・ファーマシューティカルズ・インコーポレイテッド | Gastric H +, K + -ATPase deuteration inhibitors with enhanced therapeutic properties |
| CA2703011A1 (en) * | 2006-10-23 | 2008-10-23 | Concert Pharmaceuticals Inc. | Oxazolidinone derivatives and methods of use |
| ES2395241T3 (en) * | 2007-03-07 | 2013-02-11 | Concert Pharmaceuticals Inc. | Deuterated piperazine derivatives as antianginal compounds |
| PT2522668E (en) | 2007-05-01 | 2015-06-09 | Concert Pharmaceuticals Inc | MORFINAN COMPOUNDS |
| PL2152709T3 (en) * | 2007-05-01 | 2012-07-31 | Concert Pharmaceuticals Inc | Morphinan compounds |
| EP2155697B1 (en) * | 2007-06-13 | 2012-11-28 | Auspex Pharmaceuticals, Inc. | Substituted piperazines |
| JP2011510079A (en) * | 2008-01-22 | 2011-03-31 | コンサート ファーマシューティカルズ インコーポレイテッド | Gefitinib derivative |
| JP5770997B2 (en) * | 2009-12-09 | 2015-08-26 | 大塚製薬株式会社 | Method for measuring metabolic function of CYP3A4 |
| CN103349655B (en) * | 2013-07-22 | 2015-04-29 | 南通广泰生化制品有限公司 | Tamoxifen citrate enteric capsules |
| JP2017527614A (en) * | 2014-09-02 | 2017-09-21 | ブピンダー シン | Deuterated or non-deuterated molecules and pharmaceutical formulations |
| GB2560750A (en) * | 2017-03-24 | 2018-09-26 | Taher Darreh Shori | Biological methods |
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| EP0005129A1 (en) * | 1978-04-14 | 1979-10-31 | Aktiebolaget Hässle | Substituted pyridylsulfinylbenzimidazoles having gastric acid secretion properties, pharmaceutical preparations containing same, and intermediates for their preparation |
| US6818200B2 (en) * | 1994-03-25 | 2004-11-16 | Isotechnika Inc. | Method of using deuterated calcium channel blockers |
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| ZA854287B (en) * | 1984-06-16 | 1986-02-26 | Byk Gulden Lomberg Chem Fab | Dialkoxypyridines,process for their preparation,their use and medicaments containing them |
| EP0751926B1 (en) * | 1994-03-25 | 2007-09-12 | Isotechnika,Inc. | Enhancement of the efficacy of drugs by deuteration |
| US6884429B2 (en) * | 1997-09-05 | 2005-04-26 | Isotechnika International Inc. | Medical devices incorporating deuterated rapamycin for controlled delivery thereof |
| NO309305B1 (en) * | 1999-02-19 | 2001-01-15 | Norsk Hydro As | Use of benzaldehyde derivatives in the manufacture of pharmaceutical preparations for the prevention and / or treatment of cancer, as well as certain new benzaldehyde derivatives |
| DE10123129A1 (en) * | 2001-05-02 | 2002-11-14 | Berolina Drug Dev Ab Svedala | Deuterated 3-piperidinopropiophenones and medicinal products containing these compounds |
| DE10162121A1 (en) * | 2001-12-12 | 2003-06-18 | Berolina Drug Dev Ab Svedala | Deuterated substituted pyrazolyl-benzenesulfonamides and drugs containing these compounds |
| MX2008000901A (en) * | 2005-07-26 | 2008-03-26 | Nycomed Gmbh | Isotopically substituted proton pump inhibitors. |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0005129A1 (en) * | 1978-04-14 | 1979-10-31 | Aktiebolaget Hässle | Substituted pyridylsulfinylbenzimidazoles having gastric acid secretion properties, pharmaceutical preparations containing same, and intermediates for their preparation |
| US6818200B2 (en) * | 1994-03-25 | 2004-11-16 | Isotechnika Inc. | Method of using deuterated calcium channel blockers |
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| TW200745039A (en) | 2007-12-16 |
| CA2615678A1 (en) | 2007-02-01 |
| EP1912947A1 (en) | 2008-04-23 |
| JP5289951B2 (en) | 2013-09-11 |
| TWI410409B (en) | 2013-10-01 |
| AU2006274037B2 (en) | 2012-04-26 |
| CA2615678C (en) | 2015-01-20 |
| AR054583A1 (en) | 2007-06-27 |
| WO2007012651A1 (en) | 2007-02-01 |
| AU2006274037A1 (en) | 2007-02-01 |
| CN101268050A (en) | 2008-09-17 |
| JP2009502872A (en) | 2009-01-29 |
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