CN1128997A - Novel dialkoxy-pyridinyl-benzymidazole derivatives - Google Patents
Novel dialkoxy-pyridinyl-benzymidazole derivatives Download PDFInfo
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- CN1128997A CN1128997A CN95190482A CN95190482A CN1128997A CN 1128997 A CN1128997 A CN 1128997A CN 95190482 A CN95190482 A CN 95190482A CN 95190482 A CN95190482 A CN 95190482A CN 1128997 A CN1128997 A CN 1128997A
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- methyl
- compound
- benzoglyoxaline
- methoxycarbonyl
- sulfinyl
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
Abstract
The novel optically pure compounds, i.e. the single enantiomeric compounds, (+)-5-carbomethoxy-6-methyl-2-(3,4-dimethoxy-2-pyridinyl)methyl!sulfinyl!-1H-benzimidazole and (-)-5-carbomethoxy-6-methyl-2-(3,4-dimethoxy-2-pyridinyl)methyl!sulfinyl!-1H-benzimidazole or a therapeutically acceptable salt thereof, such as Na+, Mg2+, Li+, K+, Ca2+ and N+(R)4 salts, where R is an alkyl group with 1-4 carbon atoms, processes for the preparation thereof and pharmaceutical preparations containing the compounds as active ingredients, as well as the use of the compounds in pharmaceutical preparations and intermediates obtained by preparing the compounds.
Description
Invention field
The present invention relates to have high optically pure new compound and pharmaceutical use thereof, preparation method and the purposes in useful in preparing drug formulations.The invention still further relates to the new intermediate in the The compounds of this invention preparation.
Background of invention
Compound 5-methoxycarbonyl-6-methyl-2-[[(3,4-dimethoxy-2 pyridyl) methyl] sulfinyl]-to be described in application number be among the EP91911618.6 for 1H-benzoglyoxaline and pharmacologically acceptable salt thereof.This compound and salt thereof are effective gastric acid secretion inhibitor, as anti ulcer agent.Sulfoxide compound has the sulphur atom asymmetric center, promptly has two optically active isomers (enantiomorph).People's expectation obtains having the pharmacokinetics of improvement and the compound of metabolisming property, and described character can be improved result of treatment.The invention provides such compound, they are 5-methoxycarbonyl-6-methyl-2-[[(3,4-dimethoxy-2-pyridyl) methyl] sulfinyl]-the new salt of the single enantiomer of 1H-benzoglyoxaline and the new single enantiomer of described compound neutral form.
The analytical scale of the enantiomorph of the sulfoxide class of therapeutic activity is separated; the benzimidazoles of Qu Daiing for example; as omeprazole (is 5-methoxyl group-2-[[(4-methoxyl group-3; 5-dimethyl-2-pyridyl) methyl] sulfinyl]-the 1H-benzoglyoxaline) be described in for example J.Chromatography; 532 (1990), among the 305-19.The separation of sulfoxide medicine R018-5364 single enantiomer is described among the Euro.J.Biochem.166 (1987) 453459.In addition, the separation of the preparative-scale of omeprazole enantiomer is described among the DE 4035455.The latter is undertaken by using diastereomer ether, separates this ether earlier, holds hydrolysis in the liquid in acidity then.Fall under the required acidic conditions of this linking group in hydrolysis, the active compound omeprazole is very responsive, and should acid must neutralize with alkali very soon, decomposes to avoid described acid sensitive compound.Be to add in the dense NaOH solution by the reaction mixture that will contain the vitriol oil to carry out in above-mentioned application.This is imperfect, because exist great danger, promptly the part reaches pH1-6, and it can make material damage.Moreover neutralizing effect at once will be created in unmanageable heat in the scale operation.
The invention provides the novel method of mass preparation new compound of the present invention on the other hand.Therefore, this novel method can be used for the single enantiomer of scale operation with the The compounds of this invention that obtains neutral form and pharmaceutical acceptable salt.
Sulfoxide class new compound of the present invention is expected under neutral and the alkaline pH condition can experience the racemization effect, and for example referring to Brandstrom et al, Acta Chemica Scandinavica43 (1989) P.536-547.The present inventor is surprisingly found out that: 5-methoxycarbonyl-6-methyl-2-[[(3,4-dimethoxy-2-pyridyl) methyl] sulfinyl]-the external racemization role of new single enantiomer of 1H-benzoglyoxaline and pharmacologically acceptable salt thereof is stable.
In prior art without any separating or the example of the single enantiomer of characterization The compounds of this invention.In addition, the present inventor does not know the description of any separated salt of any single enantiomer about the requirement type yet in scientific literature.
The detailed description of invention
The present invention relates to 5-methoxycarbonyl-6-methyl-2-[[(3 of Compound I a and Ib, 4-dimethoxy-2-pyridyl) methyl] sulfinyl]-the new single enantiomer and the pharmaceutically useful salt thereof of 1H-benzoglyoxaline:
Ia (+)-enantiomorph
Ib (-)-enantiomorph
The example of described salt is the Na of the single enantiomer of described compound
+, Mg
2+, Ca
2+, Li
+, K
+And N
+(R)
4Salt, wherein R is the alkyl that 1 to 4 carbon atom is arranged.It is that The compounds of this invention is: (+)-5-methoxycarbonyl-6-methyl-2-[[(3; 4-dimethoxy-2-pyridyl) methyl] sulfinyl]-1H-benzoglyoxaline and (-)-5-methoxycarbonyl-6-methyl-2-[[(3,4-dimethoxy-2-pyridyl) methyl] sulfinyl]-1H-benzoglyoxaline and their Na
+, Mg
2+, Ca
2+, Ll
+, K
+And N
+(R)
4Salt, wherein R is the alkyl with 1-4 carbon atom.
The particularly preferred salt of The compounds of this invention is 5-methoxycarbonyl 6-methyl-2-[[(3,4-dimethoxy-2-pyridyl) methyl] sulfinyl]-Na of the single enantiomer of 1H-benzoglyoxaline
+, Mg
2+And Ca
2+Salt.
Most preferred of the present invention is optically pure 5-methoxycarbonyl-6-methyl-2-[[(3 of above-mentioned formula Ia and Ib, 4-dimethoxy-2-pyridyl) methyl] sulfinyl]-the 1H-benzoglyoxaline.5-methoxycarbonyl-6-methyl-2-[[(3 that more preferred compound is Compound I Ia and IIb, 4-dimethoxy-2-pyridyl) methyl] sulfinyl]-the optically pure Na of 1H-benzoglyoxaline
+Salt:
IIa (+)-enantiomorph
IIb (-)-enantiomorph and have formula III a and the optically pure magnesium salts of the described compound of IIIb structure:
IIIa (+)-enantiomorph
IIIb (-)-enantiomorph
" the optically pure compound of the present invention " means (+)-enantiomorph of the described compound that does not contain corresponding (-)-enantiomorph substantially and do not contain (-)-enantiomorph of the described compound of corresponding (+)-enantiomorph substantially.Therefore, each simplification compound of the present invention all obtains with high polarimetry purity.According to an aspect of the present invention, the new special method by single enantiomer is easy to obtain The compounds of this invention.In addition, as mentioned above, new optically pure compound of the present invention is stable to the racemization effect under neutral pH and alkaline pH condition.The former is wonderful, because comprising reversible reaction by chiral intermediate, decomposition reaction mechanism this class sulfoxide omeprazole analogue under condition of neutral pH) [sees: Brandstrom et al.Acta Chemica Scandinavica 43 (1989) for example, P.536-547), especially P.538].Clearly, get back to the such reversible reaction meeting of sulfoxide by chiral intermediate and produce racemic product.In addition, the new optically pure compound of the present invention is stable to the racemization effect of alkaline pH condition, this also is wonderful, and expection can cause the racemization effect under the alkaline condition because act in the known deprotonation on the carbon atom between pyridine ring and the chiral sulfur atom.This high stability to racemization effect under neutral pH and alkaline pH condition makes single enantiomer compound of the present invention be applied to become possibility in the treatment with the form of neutral form and its salt.
As mentioned above, the concrete grammar of the single enantiomer of preparation The compounds of this invention also is one aspect of the present invention, and it can be used for obtaining the single enantiomer compound and the salt form thereof of neutral form.
Single enantiomer compound of the present invention and racemic modification demonstrate very high biological effectiveness; And described compound is highly effective gastric acid secretion inhibitor, and presents high chemical stability in neutral pH solution.
The compounds of this invention can be used for suppressing Mammals and human gastric acid secretion.More common meaning is that single enantiomer compound of the present invention can be used for Mammals and human hydrochloric acid in gastric juice diseases related and the treatment of inflammatory diseases of gastro-intestinal tract, for example routed soup of stomach, duodenal ulcer, backflow esophagitis and gastritis.In addition, The compounds of this invention also can be used for the gastrointestinal dysfunction of the anti-stomachial secretion effect of needs, for example is used for patient, gastric tumor patient and the acute hemorrhage of upper gastrointestinal tract patient of NSAID treatment.They also can be used for the patient who strengthens nursing and art is preceding and postoperative prevents that acid from sucking and the patient of stress ulcer.Chemical combination of the present invention further also can be used for the Mammals inflammation of (comprising the people), particularly relates to the treatment or the prevention of the inflammation of bacteriolyze ferment enzyme.The inflammation that can mention especially is rheumatic arthritis and gout.The compounds of this invention also can be used for the treatment of psoriasis treatment and helicobacter infection.
Of the present invention is the non-enantiomer mixture of the regional isomerism mixture of formula IV more on the one hand, and it is a used intermediate among the concrete preparation method of the present invention, and wherein the methoxycarbonyl and the methyl substituents of benzoglyoxaline part are in 5 or 6 respectively.
Preparation
Optically pure compound of the present invention; it is single enantiomer; can be prepared as follows: the 5-methoxycarbonyl-6-methyl-2-[[that separates following formula V; (3; 4-dimethoxy-2-pyridyl) methyl]-; (R/S)-sulfinyl]-1-[; (1R)-the acyloxy methyl]-1H-benzoglyoxaline and 6-methoxycarbonyl-5-methyl-2-[[; (3; 4-dimethoxy-2-pyridyl) methyl]-; (R/S)-sulfinyl]-1-[; (1R)-the acyloxy methyl]-the non-enantiomer mixture steric isomer of the regional isomerism mixture of 1H-benzoglyoxaline
Wherein the methoxycarbonyl of benzoglyoxaline part and methyl substituents lay respectively at 5 or 6 and acyl group is following defines; Each isolating diastereomer of solvolysis in basic solution then.Then, by using in the neutralizing agent and the aqueous solution of the salt of described compound, isolate the single enantiomer compound of the present invention of the neutral form of formation, described neutralizing agent can be acid or ester, as methyl-formiate.
Acyl moiety in the diastereomer ester can be the chirality acyl group, and as mandeloyl, and the asymmetric center of this chirality acyl group can have R or S configuration.
Can separate the diastereomer ester by chromatography or fractionation crystallization.
The logical common alkali of solvolysis is in proton transfer solvent (as alcohols or water); or in the mixture of proton transfer and non-proton transmission mixed solvent such as acetonitrile and water, carry out, but by in aprotonic solvent such as dimethyl sulfoxide (DMSO) or dimethyl formamide, falling acyl group with alkali also hydrolyzable with alkali.The alkali of reaction can be OH-or R
1O-, wherein R
1It is any alkyl or aryl.
In order to obtain the optically pure sodium salt of the present invention, the sodium salt of single enantiomer compound promptly of the present invention in water or non-aqueous media, with a kind of alkali such as NaOH, or is used NaOR
2, R wherein
2Be the alkyl that contains 1 to 4 carbon atom, or use NaNH
2, the compound of the neutral form that processing obtains.With the lithium or the sylvite of above-mentioned alkali, also can making wherein, positively charged ion is Li
+Or K
+Basic salt.For the crystallized form of the single enantiomer that obtains sodium salt, the mixture of 2-butanone and toluene is added in the optically pure sodium salt slurry.By adding NaOH in the mixture of the single enantiomer compound of neutral form of the present invention and non-aqueous media (as the mixture of 2-butanone and toluene), also can make the crystallized form of the single enantiomer of sodium salt.
In order to obtain the pure Mg of optically-active of the present invention
2+Salt uses inorganic magnesium salt (as MgCl
2) the aqueous solution handle the optically pure sodium salt of the present invention, this moment, magnesium salts was settled out.With a kind of alkali such as Mg (OR
3)
2, R wherein
3Be the alkyl that contains 1 to 4 carbon atom, in non-aqueous solvent [as alcohols (only to alkoxide), for example ROH; Ethers, for example tetrahydrofuran (THF)] in, handle single enantiomer compound of the present invention, also can make optically pure Mg
2+Salt.With similar method, use inorganic calcium salt (as CaCl
2) the aqueous solution, also can preparing wherein, positively charged ion is Ca
2+Basic salt.
As mentioned above, except sodium salt (Compound I Ia and IIb) and magnesium salts (compound III a and IIIb), the example of the basic salt of single enantiomer of the present invention also has L1
+, K
+, Ca
2+And N
+(R)
4Salt, wherein R is the alkyl that contains 1-4 carbon atom.
With regard to clinical application, with single enantiomer of the present invention, promptly optically pure compound is mixed with the pharmaceutical preparation for oral, rectum, non-enteron aisle or other form of medication.Pharmaceutical preparation of the present invention contains single enantiomer of the present invention, also has pharmaceutical carrier usually.This carrier is solid, semisolid, liquid diluent or capsule form.These pharmaceutical preparations also are one object of the present invention.The amount of activeconstituents normally accounts for 0.1～95% of weight of formulation; When using, account for the 0.2-20% of weight of formulation for non-enteron aisle; During oral administration, account for 1～50% of weight of formulation.For the preparation that non-enteron aisle is used, requiring active compound is the form that high-dissolvability is arranged in water; For oral preparation, active compound is fit to the low solubility form.
When the pharmaceutical preparation of preparation dosage unit form for oral administration, the enantiomeric compounds that the present invention is pure is mixed with following substances: solid or powder carrier, for example lactose, sucrose, Sorbitol Powder, mannitol, starch, amylopectin, derivatived cellulose, gelatin or other suitable carrier; Stablizer, as basic cpd, for example carbonate of sodium, potassium, calcium, magnesium, oxyhydroxide and oxide compound etc.; And lubricant, as Magnesium Stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol wax.Then this mixture is processed into particle or is pressed into tablet.Particle and tablet can be used the enteric coating dressing, and preparation this enteric coating protection active compound between gastric phase is avoided acid catalyzed decomposition.Enteric coating is selected from pharmaceutically useful enteric coating material, as beeswax, lac or negatively charged ion film-forming polymer etc., preferably adds softening agent.Various dyestuffs can add tablet or the particle that has different amount activeconstituentss in the dressing with differentiation.
With the mixture of the carrier that contains active compound, vegetables oil, fat or other suitable soft gelatin capsule, can prepare soft gelatin capsule.As mentioned above, soft gelatin capsule also can be the enteric coating dressing.
Hard gelatin capsule can contain the particle or the enteric coating coated granules of active compound of the present invention.Hard gelatin capsule also can contain active compound and solid-state powder carrier, as lactose, sucrose, Sorbitol Powder, mannitol, potato starch, amylopectin, derivatived cellulose or gelatin.As mentioned above, capsule can be the enteric coating dressing.
The dosage device of rectal administration can be prepared into suppository form, and this suppository contains active substance and neutral fat matrix; Perhaps also can be prepared into the gelatin rectal capsule form, wherein contain active substance and be mixed with vegetables oil, paraffin oil or be suitable for other carrier of gelatin rectal capsule; Perhaps also can be prepared into dried particulate enema agent, before administration, prepare again with suitable solvent.
The liquid preparation of oral administration can be prepared into syrup or suspension form, for example solution or suspension, the activeconstituents that wherein contains 0.2% to 20% (weight), all the other materials are made up of the mixture of sugar or sugar alcohol and ethanol, water, glycerine, propylene glycol and/or polyoxyethylene glycol.In case of necessity, this class I liquid I preparation can contain tinting material, seasonings, asccharin and carboxymethyl cellulose or other thickening material.The dry powder form of preparing again with the adaptation solvent before the liquid preparation of oral administration also can be prepared into and use.
But the solution of solution preparation cost invention optically pure compound in acceptable solvent of parenterai administration, concentration is preferably 0.1% to 10% (weight).These solution can contain stablizer and/or buffer reagent, and can manufacture the ampoule or the bottle of different units dosage.The dry powder formulations of temporarily preparing with suitable solvent before the solution of parenterai administration also can be prepared into and use.
The common per daily dose of active compound of the present invention depends on various factors, as patient's individual need, medicine-feeding way and the state of an illness.Usually, oral and parenteral dosage is 5～500mg active substance every day.
Following embodiment explains the present invention.
Embodiment 1:(+)-and 5-methoxycarbonyl-6-methyl-2-[[(3,4-dimethyl-2-pyridyl) methyl] sulfinyl]-preparation of 1H-benzoglyoxaline
Diastereomer crude product with the mandelate mixture of two kinds of regional isomerisms; be 5-methoxycarbonyl-6-methyl-2-[[(3; 4-dimethoxy-2-pyridyl) methyl]-(R/S)-sulfinyl]-1-(R)-almond acyl-oxygen ylmethyl]-1H-benzoglyoxaline and 6-methoxycarbonyl-5-methyl-2-[[(3; 4-dimethoxy-2-pyridyl) methyl]-(R/S)-sulfinyl]-1-[(R-almond acyl-oxygen ylmethyl]-1H-benzoglyoxaline (1.8g; 3.3mmol); be divided into 3 parts; every part at reversed-phase column (HPLC; Kromasil C8) enterprising circumstances in which people get things ready for a trip spectrum is separated, to separate diastereomer.Mixture (70/30) wash-out by with 0.1M ammonium acetate solution and acetonitrile is easy to separate described steric isomer.Yet each isolating diastereomer is made up of the mixture of two regional isomers.These intermediates are directly used with its solution at hydrolysing step.In acetonitrile/more lipophilic diastereomer aqueous solution, add the 1M NaOH aqueous solution, reach 12-13 until pH.Use 3.0M NH after 5 minutes
4The Cl aqueous solution this solution that neutralizes.Merge the solution of each preparation, use dichloromethane extraction, use Na
2SO
4Dry organic phase.Remove and desolvate, resistates flash chromatography method is separated (silica gel, ethanol/methylene, 1～8% gradient), gets the 250mg yellow oil.Add the 3ml acetonitrile and make the product crystallization, get 210mg (32%) title compound, white crystals, m.p.171 °-173 ℃ after the filtration.[α]
D 20=+153.1 ° (c=0.5%, chloroform).The NMR data are seen below.
Embodiment 2:(-)-and 5-methoxycarbonyl-6-methyl-2-[[(3,4-dimethoxy-2-pyridyl) methyl] sulfinyl]-preparation of 1H-benzoglyoxaline
To acetonitrile/more alipotropic diastereomer 5-methoxycarbonyl-6-methyl-2-[[3; 4-dimethoxy-2-pyridyl) methyl]-(R/S)-sulfinyl]-1-[(R)-almond acyl-oxygen ylmethyl]-1H-benzoglyoxaline and 6-methoxycarbonyl-5-methyl-2-[[(3; 4-dimethoxy-2-pyridyl) methyl]-(R/S)-sulfinyl]-1-[(R)-almond acyl-oxygen ylmethyl]-add 1.0M NaOH in the aqueous solution of 1H-benzoglyoxaline (deriving from the very identical reverse-phase chromatography preparation that embodiment 1 describes), be 12-13 until pH.Use 3.0M NH after 5 minutes
4The Cl aqueous solution this solution that neutralizes.Merge the solution of each preparation and use dichloromethane extraction, use Na
2SO
4Dry organic phase is removed and is desolvated, and resistates flash chromatography method is separated (silica gel, ethanol/methylene, 1～8% gradient), gets the 270mg yellow oil.Add the 3ml acetonitrile and make the product crystallization, get 210mg (32%) title compound, white crystals, m.p.173 °-174 ℃ after the filtration.[α]
D 20=-150.0 ° (c=0.5%, chloroform).The NMR data are seen below.
Embodiment 3:(+)-and 5-methoxycarbonyl-6-methyl-2-[[(3,4-dimethoxy-2-pyridyl) methyl] sulfinyl]-preparation of 1H-benzoglyoxaline sodium salt
To (+)-5-methoxycarbonyl-6-methyl-2-[[(3,4-dimethoxy-2-pyridyl) methyl] sulfinyl]-the 1H-benzoglyoxaline (200mg, 0.51mmol) and add in the mixture of ethanol (10ml) the 2.0M NaOH aqueous solution (0.26ml, 0.51mmol).Thin film evaporation is removed and is desolvated, and resistates is dissolved in the 2-butanone (1ml), splashes into toluene (5ml) under stirring.Centrifugation goes out the precipitation of generation and washes with ether, gets 170mg (81%) title compound, white crystals, m.p.170-173 ℃ (decomposition).[α]
D 20=+ 93.6 ° (c=1.0%, methyl alcohol).The NMR data are seen below.
Embodiment 4:(-)-and 5-methoxycarbonyl-6-methyl-2-[[(3,4-dimethoxy-2-pyridyl) methyl] sulfinyl]-preparation of 1H-benzoglyoxaline sodium salt
To (-)-5-methoxycarbonyl-6-methyl-2-[[(3,4-dimethoxy-2-pyridyl) methyl] sulfinyl]-the 1H-benzoglyoxaline (200mg, 0.51mmol) and add in the mixture of ethanol (10ml) the 2.0M NaOH aqueous solution (0.26ml, 0.51mmol).Thin film evaporation is removed and is desolvated, and resistates is dissolved in the 2-butanone (1ml), splashes into toluene (5ml) under stirring.Filter to isolate the precipitation of generation and wash with ether, 200mg (96%) title compound, white crystals, m.p.172-175 ℃ (decomposition).[α]
D 20=-93.8 ° (c=1.0%, methyl alcohol).The NMR data are seen below.
Embodiment 5:(+)-and 5-methoxycarbonyl-6-methyl-2-[[(3,4-dimethoxy-2-pyridyl) methyl] sulfinyl]-preparation of 1H-benzoglyoxaline magnesium salts
With (+)-5-methoxycarbonyl-6-methyl-2-[[(3 that embodiment 3 obtains, 4-dimethoxy-2-pyridyl) methyl] sulfinyl]-(100mg 0.24mmol) in water-soluble (2ml), splashes into MgCl to 1H-benzoglyoxaline sodium salt
2.6H
2O (25mg, 0.12mmol) solution in 1ml water.The precipitation that centrifugation forms washes with water.Product is dry in moisture eliminator, gets 84mg (87%) white powder.[α]
D 20＝+170°(c＝0.5％，DMSO)。
Embodiment 6:(-)-and 5-methoxycarbonyl-6-methyl-2-[[(3,4-dimethoxy-2-pyridyl) methyl] sulfinyl]-preparation of 1H-benzoglyoxaline magnesium salts
With (-)-5-methoxycarbonyl-6-methyl-2-[[(3 that embodiment 3 obtains, 4-dimethoxy-2-pyridyl) methyl] sulfinyl]-(100mg 0.24mmol) in water-soluble (2ml), splashes into MgCl to 1H-benzoglyoxaline sodium salt
26H
2O (25mg, 0.12mmol) solution in 1ml water.The precipitation that centrifugation forms washes with water.Product is dry in moisture eliminator, gets 84mg (87%) white powder.[α]
D 20＝-178.8°(c＝0.5％，DMSO)。
Table 1 embodiment solvent NMR data δ (ppm) are DMSO-d 1.
62.62 (s, 3H), 3.75 (s, 3H), 3.84 (s, 3H), 3.88 (s, 3H),
300MHz 4.68(s，2H)，7.09(d，1H)，7.53(s，1H)，8.11(s，1H)，
8.12(d，1H)，13.75(b，1H).2. DMSO-d
6 2.62(s，3H)，3.75(s，3H)，3.84(s，3H)，3.88(s，3H)，
300MHz 4.68(s，2H)，7.09(d，1H)，7.53(s，1H)，8.11(s，1H)，
8.12(d，1H)，13.75(b，1H).3. DMSO-d
6 2.58(s，3H)，3.77(s，3H)，3.79(s，3H)，3.89(s，3H)，
300MHz 4.36(d，1H)，4.74(d，1H)，7.07(d，1H)，7.31(s，1H)，
8.10(s，1H)，8.21(d，1H).4. DMSO-d
6 2.58(s，3H)，3.77(s，3H)，3.79(s，3H)，3.89(s，3H)，
300MHz 4.34(d，1H)，4.74(d，1H)，7.07(d，1H)，7.29(s，1H)，
8.11(s，1H)，8.22(d，1H).
Following examples are described the preparation of synthetic intermediate of the present invention.
Embodiment 7:5-methoxycarbonyl-6-methyl-2-[[(3; 4-dimethoxy-2-pyridyl) methyl]-(R/S)-sulfinyl]-1-[(R)-almond acyl-oxygen ylmethyl]-1H-benzoglyoxaline and 6-methoxycarbonyl-5-methyl-2-[[(3,4-dimethoxy-2-pyridyl) methyl]-(R/S)-sulfinyl]-1-[(R)-almond acyl-oxygen ylmethyl]-preparation of 1H-benzoglyoxaline
With the solution of 0.33g (8.2mmol) NaOH in 1.6ml water add 1.4g (4.1mmol) hydrogen sulfate 4-butyl ammonium and 0.62g (4.1mmol) (R)-(-)-mixture of amygdalic acid in.Add chloroform (50ml) and 5-methoxycarbonyl-6-methyl-2-[[(3; 4-dimethoxy-2-adjoins car) methyl]-sulfinyl]-1-(chloromethyl)-1H-benzoglyoxaline] and 6-methoxycarbonyl-5-methyl-2-[[(3; 4-dimethoxy-2-pyridine) methyl]-sulfinyl]-mixture (racemic modification) of 1-(chloromethyl)-1H-benzoglyoxaline, this mixture refluxed 3 hours.The reaction mixture cooling, and be allocated in ethyl acetate and the water, layering also washes organic phase with water, uses Na
2SO
4Dry.Remove the non-enantiomer mixture that gets the mandelate of two regional isomerisms after desolvating.Crude product is directly used in chromatrographic separation step, separates diastereomer (embodiment 1 and 2).Get the 2.4g product, 62%.The NMR data are as follows.
Table 2 embodiment solvent NMR data δ (ppm)
7. CDCl
3 2.6-2.8(m，3H)，3.8-4.1(m，9H)，4.75-4.95(m，1H)，
500MHz 5.00-5.15(m，1H)，5.3-5.4(m，1H)，6.45-6.70(m，
2H)，6.70-6.80(m，1H)，7.1-8.4(m，8H).
Present known enforcement best mode of the present invention is to use the magnesium salts of optically pure compound of the present invention, so these compounds are described in embodiment 5 and 6.
Following preparation is explained and is contained the pharmaceutical preparation of The compounds of this invention as activeconstituents.
Syrup
The syrup that is contained 1% (w/v) active material by the following ingredients preparation: embodiment 1 compound 1.0g sugar, powder 30.0g asccharin 0.6g glycerine 5.0g flavor enhancement 0.05g ethanol 96% 5.0g distilled water adds to final volume 100ml
Sugar and asccharin are dissolved in the 60ml warm water, and the cooling back adds active compound in sugar soln, and adds glycerine and the seasonings that is dissolved in the ethanol.It is 100ml that mixture is diluted with water to final volume.
The tablet of enteric coating dressing
The enteric coating coated tablet that is contained the 50mg reactive compound by the following ingredients preparation: an amount of II of polyvinylpyrrolidone 50g dolomol 15g sodium carbonate 6g distilled water that I: embodiment 2 compound 500g lactose 700g methylcellulose 6g are crosslinked: sour O-phthalic acid cellulose 200g hexadecanol 15g isopropyl alcohol 2000g carrene 2000g
Embodiment 7 compound powders are mixed with lactose, and granulate with the aqueous solution of methylcellulose gum and yellow soda ash.Wet solids forces by a screen cloth, and the particle that drying obtains in baking oven.After the drying particle is mixed with polyvinylpyrrolidone and Magnesium Stearate.With dry mixture drift tablet forming stamen (1000) with the 7mm diameter in tabletting machine, every contains the 50mg active substance.
At Accela Cota
R, in the Manesty dressing equipment, the solution spraying in Virahol/methylene dichloride obtains the tablet of the heavy 110mg of final sheet on above-mentioned sheet stamen with Cellacefate and cetyl alcohol.
The solution of intravenously administrable
Make the parenteral formulation that supplies vein to use that contains the 4mg/ml active compound by following ingredients:
Embodiment 3 compound 4g
It is 1000ml that sterilized water adds to final volume
Active compound is water-soluble, to final volume be 1000ml.This solution filters by 0.22 μ m filter, and sealed ampoule is gone in the 10ml sterilization ampoule in packing immediately.
Capsule
The capsule that is contained the 30mg reactive compound by the following ingredients preparation: embodiment 6 compound 300g lactose 700g microcrystalline cellulose 40g LH-21 62g sodium hydrogen phosphate 2g purified water are an amount of
Active compound is mixed with dry ingredients, and granulate with disodium phosphate soln, wet solids is extruded by forcing machine, nodularization, and dry in fluidized bed dryer.
Above-mentioned 500g piller uses fluidized bed coating equipment dressing with the solution of Vltra tears (30g) in 750g water earlier.Dry back piller is with the following material package second layer clothing that is coated with.
Coating solution: Hydroxypropyl Methylcellulose Phathalate 70g cetyl alcohol 4g acetone 200g ethanol 600g
At last the piller of dressing is inserted in the capsule.
Suppository
Make suppository with a combining method by following ingredients.Every bolt contains the 40mg active compound.Embodiment 2 compound 4gWitepsol H-15 180g
Active compound is mixed with Witepsol H-15 in 41 ℃.The mixture of fusing is packed in the previously prepared suppository bag, makes net weight 1.84g, after the cooling, heated sealant suppository bag.Every bolt contains the 40mg active compound.
The stability of external racemization role under different pH
37 ℃ in the water damping fluid of pH7 and pH11, measured the stability of the external racemization role of optically pure compound of the present invention with lower concentration (10-5M).By (-)-enantiomorph 5-methoxycarbonyl-6-methyl-2-[[(3 relatively, 4-dimethoxy-2-pyridyl) methyl] sulfinyl]-1H-benzoglyoxaline dissolved in buffered soln measures its stereochemistry stability with the specific rotation of dissolving back a few hours at once.Test compound all finds no the racemization effect at pH[7 and pH11 even after 24 hours, and this fact illustrates that as an example The compounds of this invention has surprising high stereochemistry stability at neutral and alkaline condition.Yet, after 28 hours under the pH7 condition decomposition of The compounds of this invention be tangible.
Claims (19)
1. the single enantiomer compound and the pharmaceutically useful salt thereof that have following formula I a and Ib:
I (a) enantiomorph
Ib (-)-enantiomorph
2. the compound of claim 1 is characterized in that this compound is (+)-5-methoxycarbonyl-6-methyl-2-[[(3 that does not contain its (-)-enantiomorph substantially, 4-dimethoxy-2-pyridyl) methyl] sulfinyl]-1H-benzoglyoxaline or its pharmaceutically useful salt.
3. the compound of claim 1 is characterized in that this compound is (-)-5-methoxycarbonyl-6-methyl-2-[[(3 that does not contain its (+)-enantiomorph substantially, 4-dimethoxy-2-pyridyl) methyl] sulfinyl]-1H-benzoglyoxaline or its pharmaceutically useful salt.
4. the compound of arbitrary claim among the claim 1-3 is characterized in that pharmacologically acceptable salt is Na
+, Mg
2+, Ca
2+, Li, K
+And N
+(R)
4Salt, wherein R is the alkyl that contains 1-4 carbon atom.
5. the compound of arbitrary claim among the claim 1-4; it is characterized in that described compound is (+)-5-methoxycarbonyl-6-methyl-2-[[(3; 4-dimethoxy-2-pyridyl) methyl] sulfinyl]-1H-benzoglyoxaline sodium salt; (-)-5-methoxycarbonyl-6-methyl-2-[[(3; 4-dimethoxy-2-pyridyl) methyl] sulfinyl]-1H-benzoglyoxaline sodium salt; (+)-5-methoxycarbonyl-6-methyl-2-[[(3; 4-dimethoxy-2-pyridyl) methyl] sulfinyl]-1H-benzoglyoxaline magnesium salts and (-)-5-methoxycarbonyl-6-methyl-2-[[(3,4-dimethoxy-2-pyridyl) methyl] sulfinyl]-1H-benzoglyoxaline magnesium salts.
6. the compound of arbitrary claim among the claim 1-3; it is characterized in that described compound is with its crystallized form (+)-5-methoxycarbonyl-6-methyl-2-[[(3; 4-dimethoxy-2-pyridyl) methyl] sulfinyl]-1H-benzoglyoxaline or its magnesium salts and (-)-5-methoxycarbonyl-6-methyl-2-[[(3,4-dimethoxy-2-pyridyl) methyl] sulfinyl]-1H-benzoglyoxaline or its magnesium salts.
7. claim 1 and 2 compound; it is characterized in that described compound is respectively (+)-5-methoxycarbonyl-6-methyl-2-[[(3 that does not contain the crystallized form of its (-)-enantiomorph substantially, 4-dimethoxy-2-pyridyl) methyl] sulfinyl]-1H-benzoglyoxaline or its magnesium salts.
8. claim 1 and 3 compound; it is characterized in that described compound is respectively (-)-5-methoxycarbonyl-6-methyl-2-[[(3 that does not contain the crystallized form of its (+)-enantiomorph substantially, 4-dimethoxy-2-pyridyl) methyl] sulfinyl]-1H-benzoglyoxaline or its magnesium salts.
9. prepare the method for claim 1 compound, it is characterized in that: separate the non-enantiomer ester of the formula V with R or S configuration,
Methoxycarbonyl in the formula on the benzoglyoxaline ring and methyl substituents lay respectively at 5 or 6, and acyl group represents the chirality acyl group, as mandeloyl; And make each isolating diastereomer stand solvolysis with basic solution, wherein the acyl-oxygen methyl is hydrolyzed, with in the neutralizing agent and after, obtain the enantiomeric compounds of neutral form; And at random the enantiomeric compounds of this neutral form is transformed into pharmacologically acceptable salt.
10. the method for claim 9 is characterized in that described diastereomer separates by chromatography or fractionation crystallization.
11. the method for claim 9, it is characterized in that described solvolysis carries out in alkalescence is held liquid, this basic solution is the solution of alkali in proton transfer solvent such as alcohols or water, or the solution of alkali in aprotonic solvent such as dimethyl sulfoxide (DMSO) or dimethyl formamide, or alkali is at the mixture of proton transfer solvent and aprotonic solvent such as the solution in water and the acetonitrile.
12. the method for the compound of the crystallized form of arbitrary claim among the preparation claim 1-4 is characterized in that handling the neutral form that claim 9 obtains or the product of pharmaceutical acceptable salt with non-aqueous solvent, is settled out crystallized product.
13. (+)-5-methoxycarbonyl-6-methyl-2-[[(3 of preparation crystallized form; 4-dimethoxy-2-pyridyl) methyl] sulfinyl]-1H-benzoglyoxaline or its sodium salt and (-)-5-methoxycarbonyl-6-methyl-2-[[(3; 4-dimethoxy-2-pyridyl) methyl] sulfinyl]-method of 1H-benzoglyoxaline or its sodium salt; it is characterized in that using non-aqueous media; as 2-butanone and toluene; handle (+)-5-methoxycarbonyl-6-methyl-2-[[(3 respectively; 4-dimethoxy-2-pyridyl) methyl] sulfinyl]-1H-benzoglyoxaline or its sodium salt and (-)-5-methoxycarbonyl-6-methyl-2-[[(3, the pyridyl of 4-dimethoxy-2-)) methyl] sulfinyl]-1H-benzoglyoxaline or its sodium salt crude product.
14. contain the pharmaceutical preparation of the single enantiomer compound of arbitrary claim among the claim 1-8 as activeconstituents.
15. the application of single enantiomer compound in treatment of arbitrary claim among the claim 1-8.
16. the purposes of the single enantiomer compound of arbitrary claim in preparation gastric acid inhibitory secretion medicine preparation among the claim 1-8.
17. the purposes of the single enantiomer compound of arbitrary claim in the pharmaceutical preparation of preparation treatment gastrointestinal inflammation disease among the claim 1-8.
18. gastric acid inhibitory excretory method comprises the enantiomeric compounds of arbitrary claim among the claim 1-8 that needs Mammals (the comprising the people) significant quantity that this smelting treats.
19. the method for treatment gastrointestinal tract inflammation disease comprises the enantiomeric compounds of arbitrary claim among the claim 1-8 of Mammals (the comprising the people) significant quantity that needs this treatment.
20. compound 5-methoxycarbonyl-6-methyl-2-[[(3; 4-dimethoxy-2-pyridyl) methyl] sulfinyl]-1-[almond acyl-oxygen ylmethyl]-1H-benzoglyoxaline and 6-methoxycarbonyl-5-methyl-2-[[(3,4-dimethoxy-2-pyridyl) methyl] sulfinyl]-1-[almond acyl-oxygen ylmethyl]-the 1H-benzoglyoxaline.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| WOPCT/SE94/00511 | 1994-05-27 | ||
| SE9400511 | 1994-05-27 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1128997A true CN1128997A (en) | 1996-08-14 |
Family
ID=20392945
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN95190482A Pending CN1128997A (en) | 1994-05-27 | 1995-05-11 | Novel dialkoxy-pyridinyl-benzymidazole derivatives |
Country Status (18)
| Country | Link |
|---|---|
| EP (1) | EP0712401A1 (en) |
| JP (1) | JPH09504557A (en) |
| CN (1) | CN1128997A (en) |
| AU (1) | AU2633095A (en) |
| BR (1) | BR9506235A (en) |
| CA (1) | CA2166988A1 (en) |
| CZ (1) | CZ24396A3 (en) |
| EE (1) | EE9600011A (en) |
| FI (1) | FI960367A (en) |
| HU (1) | HU9600005D0 (en) |
| IL (1) | IL113604A0 (en) |
| IS (1) | IS4321A (en) |
| MA (1) | MA23563A1 (en) |
| NO (1) | NO960268D0 (en) |
| PL (1) | PL312692A1 (en) |
| TN (1) | TNSN95062A1 (en) |
| WO (1) | WO1995032959A1 (en) |
| ZA (1) | ZA954125B (en) |
Families Citing this family (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9423970D0 (en) * | 1994-11-28 | 1995-01-11 | Astra Ab | Oxidation |
| GB9423968D0 (en) * | 1994-11-28 | 1995-01-11 | Astra Ab | Resolution |
| US6489346B1 (en) | 1996-01-04 | 2002-12-03 | The Curators Of The University Of Missouri | Substituted benzimidazole dosage forms and method of using same |
| US5840737A (en) | 1996-01-04 | 1998-11-24 | The Curators Of The University Of Missouri | Omeprazole solution and method for using same |
| EP1131316B1 (en) | 1998-11-18 | 2004-07-21 | AstraZeneca AB | Improved chemical process and pharmaceutical formulation |
| US8206741B2 (en) | 2001-06-01 | 2012-06-26 | Pozen Inc. | Pharmaceutical compositions for the coordinated delivery of NSAIDs |
| US8993599B2 (en) | 2003-07-18 | 2015-03-31 | Santarus, Inc. | Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them |
| US8906940B2 (en) | 2004-05-25 | 2014-12-09 | Santarus, Inc. | Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them |
| MX2009004475A (en) | 2006-10-27 | 2009-08-12 | Univ Missouri | Compositions comprising acid labile proton pump inhibiting agents, at least one other pharmaceutically active agent and methods of using same. |
| CA2716367C (en) | 2008-02-20 | 2015-05-26 | The Curators Of The University Of Missouri | Composition comprising a combination of omeprazole and lansoprazole, and a buffering agent, and methods of using same |
| US9220698B2 (en) | 2008-09-09 | 2015-12-29 | Pozen Inc. | Method for delivering a pharmaceutical composition to patient in need thereof |
| EA201290026A1 (en) | 2009-06-25 | 2012-07-30 | Астразенека Аб | A METHOD FOR TREATING A PATIENT THAT HAS A RISK OF DEVELOPMENT OF ANALISM ASSOCIATED WITH THE RECEPTION OF NONSTEROID ANTI-INFLAMMATORY MEDIA |
| UA115139C2 (en) | 2011-12-28 | 2017-09-25 | Поузен Інк. | Improved compositions and methods for delivery of omeprazole plus acetylsalicylic acid |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1991019712A1 (en) * | 1990-06-20 | 1991-12-26 | Aktiebolaget Astra | Dialkoxy-pyridinyl-benzimidazole derivatives, process for their preparation and their pharmaceutical use |
| DE4035455A1 (en) * | 1990-11-08 | 1992-05-14 | Byk Gulden Lomberg Chem Fab | ENANTIOMER SEPARATION |
-
1994
- 1994-05-29 TN TNTNSN95062A patent/TNSN95062A1/en unknown
-
1995
- 1995-05-03 IL IL11360495A patent/IL113604A0/en unknown
- 1995-05-11 PL PL95312692A patent/PL312692A1/en unknown
- 1995-05-11 BR BR9506235A patent/BR9506235A/en not_active Application Discontinuation
- 1995-05-11 EE EE9600011A patent/EE9600011A/en unknown
- 1995-05-11 AU AU26330/95A patent/AU2633095A/en not_active Abandoned
- 1995-05-11 WO PCT/SE1995/000519 patent/WO1995032959A1/en not_active Application Discontinuation
- 1995-05-11 CN CN95190482A patent/CN1128997A/en active Pending
- 1995-05-11 CZ CZ96243A patent/CZ24396A3/en unknown
- 1995-05-11 JP JP8500730A patent/JPH09504557A/en active Pending
- 1995-05-11 HU HU9600005A patent/HU9600005D0/en unknown
- 1995-05-11 EP EP95921187A patent/EP0712401A1/en not_active Withdrawn
- 1995-05-11 CA CA002166988A patent/CA2166988A1/en not_active Abandoned
- 1995-05-19 ZA ZA954125A patent/ZA954125B/en unknown
- 1995-05-26 MA MA23901A patent/MA23563A1/en unknown
-
1996
- 1996-01-17 IS IS4321A patent/IS4321A/en unknown
- 1996-01-23 NO NO960268A patent/NO960268D0/en unknown
- 1996-01-26 FI FI960367A patent/FI960367A/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| NO960268L (en) | 1996-01-23 |
| JPH09504557A (en) | 1997-05-06 |
| IL113604A0 (en) | 1995-08-31 |
| EP0712401A1 (en) | 1996-05-22 |
| IS4321A (en) | 1996-01-17 |
| PL312692A1 (en) | 1996-05-13 |
| NO960268D0 (en) | 1996-01-23 |
| FI960367A0 (en) | 1996-01-26 |
| FI960367A (en) | 1996-01-26 |
| AU2633095A (en) | 1995-12-21 |
| BR9506235A (en) | 1997-08-12 |
| HU9600005D0 (en) | 1996-03-28 |
| EE9600011A (en) | 1996-04-15 |
| CZ24396A3 (en) | 1996-06-12 |
| MA23563A1 (en) | 1995-12-31 |
| TNSN95062A1 (en) | 1996-02-06 |
| ZA954125B (en) | 1995-11-27 |
| WO1995032959A1 (en) | 1995-12-07 |
| CA2166988A1 (en) | 1995-12-07 |
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