AP397A - Substituted benzimidazoles, process for their preparation as well as their use. - Google Patents
Substituted benzimidazoles, process for their preparation as well as their use. Download PDFInfo
- Publication number
- AP397A AP397A APAP/P/1992/000463A AP9200463A AP397A AP 397 A AP397 A AP 397A AP 9200463 A AP9200463 A AP 9200463A AP 397 A AP397 A AP 397A
- Authority
- AP
- ARIPO
- Prior art keywords
- methyl
- compound
- dimethoxy
- phosphoric acid
- mixture
- Prior art date
Links
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- 238000000034 method Methods 0.000 title claims abstract description 12
- 150000001556 benzimidazoles Chemical class 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 100
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 39
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- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 31
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 24
- -1 [5-acetyl-6methyl-2- [ [ (3,4-dimethoxy-2-pyridinyl)methyl] sulfinyl] -1Hbenzimidazole-l-yl]methyl Chemical group 0.000 claims description 20
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- 229910052717 sulfur Inorganic materials 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- IXZDIALLLMRYOU-UHFFFAOYSA-N tert-butyl hypochlorite Chemical compound CC(C)(C)OCl IXZDIALLLMRYOU-UHFFFAOYSA-N 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 231100000967 thyroidotoxicity Toxicity 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 210000003437 trachea Anatomy 0.000 description 1
- 230000036269 ulceration Effects 0.000 description 1
- 150000003682 vanadium compounds Chemical class 0.000 description 1
- 235000019871 vegetable fat Nutrition 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 238000003466 welding Methods 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
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- 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
- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
-
- 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
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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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
- C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
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- Bioinformatics & Cheminformatics (AREA)
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- Molecular Biology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
There are provided novel compounds of the formula wherein r1 and r2 which are different, is each methyl, -c(o)-ch3 or -c(o)-och3 and whereby one r1 and r2 is methyl but r1 and r2 are not both methyl, and m is a physiologically acceptable cation, as well as processes for the preparation of said compounds, pharmaceutical compositions containing said compounds as active ingredient, and the use of the compounds in medicine.
Description
DESCRIPTION
Field of the invention
The object of the present invention is to provide novel compounds, which inhibit exogenously or endogenously stimulated gastric acid secretion and thus can be used in the prevention and treatment of peptic ulcer.
The present invention also relates to the use of the compounds of the invention for inhibiting gastric acid secretion in mammals including man. In a more general sense, the compounds of the invention may be used for prevention and treatment of gastrointestinal inflammatory diseases, and gastric acid-related diseases in mammals including man, such as gastritis, gastric ulcer, duodenal ulcer, reflux esophagitis, and Zollinger-Ellison syndrome. Furthermore, the compounds may be used for treatment of other gastrointestinal disorders where gastric antisecretory effect is desirable e.g. in patients with gastrinomas, and in patients with acute upper gastrointestinal bleeding. They may also be used in patients in intensive care situations, and pre- and postoperatively to prevent acid aspiration and stress ulceration. The compounds of the invention may also be used for treatment or prophylaxis of inflammatory conditions in mammals, including man, especially those involving lysozymal enzymes. Conditions that may be specifically mentioned are rheumatoid arthritis and gout. The invention also relates to pharmaceutical compositions containing the compounds of the invention, as active ingredient. In a further aspect, the invention relates to processes for
BAD ORIGINAL preparation of such new compounds and to the use of the active compounds for the preparation of pharmaceutical compositions for the medical use indicated above.
The compounds of the invention will not block the uptake of iodine into the thyroid gland, it has earlier been disclosed in several lectures from the company, where the inventors are working that thyroid toxicity depends on if the compounds are lipophilic or not. The inventors have now unexpectedly found that it is not the lipophilicity that is the critical parameter. The claimed compounds, which include rather hydrophilic compounds, do not give any thyroid toxic effect and have at the same time high acid secretion inhibitory effect.
The compounds of the invention will also exhibit a high solubility and a high chemical stability in water.
Background of the invention
Similar disubstituted 2-[ [ ( 3,4-dialkoxy-2-pyridinyl)methyl]sulfinyl]-lH-benzimidazole-l-yl compounds are described in PCT/SE91/00415, which was not publically available at the time of filing the basic application in Sweden, but was published shortly thereafter.
Prior art
Benzimidazole derivatives intended for inhibiting gastric acid secretion are disclosed in numerous patent documents.
Among these can be mentioned GB 1 500 043,
GB 1 525 958, US 4 182 766, US 4 255 431, US 4 599 347, BE 898 880, EP 124 495, EP 208 452, EP 221 041,
EP 279 149, EP 176 308 and Derwent abstract 87-294449/42. Benzimidazole derivatives proposed for
BADORIGINAL $
AP ο 0 0 3 9 7 use in the treatment or prevention of special gastrointestinal inflammatory diseases are disclosed in US 4 359 465.
The invention
The compounds of the invention are effective as inhibitors of gastric acid secretion in mammals including man and in addition do not block the uptake of iodine into the thyroid gland.
Further, the compounds of the invention exhibit a high solubility and a high chemical stability in water.
The compounds of the invention are therefore particularly suitable for parenteral, especially intravenous and intramuscular administration. The high solubility and chemical stability also render the compounds of the invention suitable for other administration routes, such as for instance oral and rectal administration.
The compounds of the invention are of the following formula I:
BAD ORIGINAL 0$) wherein
R* and R2, which are different, is each methyl, -C(O)-CH3 or -C(0)-OCH} and whereby one of R* or R2 is methyl but R* and R2 are not both methyl, and M is a physiologically acceptable cation.
The structural isomers of the compounds of the formula I may be used separately, or in equal or unequal mixtures.
The compounds of the invention of the formula I have an asymmetric centre in the sulfur atom, i.e. exists as two optical isomers (enantiomers). Both the pure enantiomers, racemic mixtures (50% of each enantiomer) and unequal mixtures of the two are within the scope of the present invention.
It is believed that compounds of formula I are metabolized before exerting their effect. Such metabolism occur in the N-substituent, the phosphorous containing group, in position 1 in the benzimidazole nucleus.
Preparation
The compounds of the invention may be prepared according to the following methods:
a) Reacting a compound of the formula II
BAD ORIGINAL ft
AP 0 0 0 3 9 7
II
ch2z
2 wherein R and R are as defined under formula I, and
Z, is halogen such as Cl, Br or I or a functionally equivalent group, with a compound of the formula III
HO-P-O Q
111 wherein Q is a counter ion such as Na+, K+, Ag+ or trialkylammonium.
Salts obtained may be transformed to a therapeutically suitable salt such as sodium and potassium salts, by addition of NaOH and KOH, respectively or by ion exchange.
b) Oxidizing a compound of the formula IV
OCH
iv
BAD ORIGINAL
2 wherein R , R and M have the meanings given, to give a compound of formula I.
This oxidation may be carried out by using an oxidizing agent such as nitric acid, hydrogen peroxide, (optionally in the presence of vanadium compounds), peracids, peresters, ozone, dinitrogentetraoxide, iodosobenzene, N-halosuccinimide, 1chlorobenzotriazole, t-butylhypochlorite, diazabicyclo[2,2,2]-octane bromine complex, sodium metaperiodate, selenium dioxide, manganese dioxide, chromic acid, cericammonium nitrate, bromine, chlorine, and sulfuryl chloride. The oxidation usually takes place in a solvent such as halogenated hydrocarbons, alcohols, ethers, ketones.
The oxidation may also be carried out enzymatically by using an oxidizing enzyme or microbiotically by using a suitable microorganism.
The structural isomers obtained, may be separated by means of crystallization or chromatography.
Racemates obtained can be separated according to known methods, e.g. recrystallization from an optically active solvent.
For clinical use the compounds of the invention are formulated into pharmaceutical formulations for oral, rectal, parenteral or other mode of administration. It
BAD ORIGINAL $
AP 0 0 0 3 9 7 is especially preferred to formulate the compounds of the invention into pharmaceutical formulations for parenteral administration. The pharmaceutical formulation contains a compound of the invention in combination with a pharmaceutically acceptable carrier. The carrier may be in the form of a solid, serai-solid or liquid diluent, or a capsule. These pharmaceutical preparations are a further object of the invention. Usually the amount of active compounds is between 0.195% by weight of the preparation, between 0.2-20% by weight in preparations for parenteral use and between 1 and 50% by weight in preparations for oral administration.
In the preparation of pharmaceutical formulations containing a compound of the present invention in the form of dosage units for oral administration the compound selected may be mixed with a solid, powdered carrier, such as lactose, saccharose, sorbitol, mannitol, starch, arnylopectin, cellulose derivatives, gelatin, or another suitable carrier, as well as with lubricating agents such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylenglycol waxes.
The mixture is then processed into granules or pressed into tablets. Granules and tablets containing sulfoxides may be coated with an enteric coating, which protects the active compound from acid catalyzed degradation as long as the dosage form remains in the stomach. The enteric coating is chosen among pharmaceutically acceptable enteric-coating materials e.g. beeswax, shellac or anionic film-forming polymers such as cellulose acetate phtalate, hydroxypropylmethylcellulose phthalate, partly methyl esterified methacrylic acid polymers and the like, if preferred in combination with a suitable plasticizer. To this
BAD ORIGINAL coating various dyes may be added in order to distinguish among tablets or granules with different active compounds or with different amounts of the active compound present.
Soft gelatine capsules may be prepared with capsules containing a mixture of the active compound or compounds of the invention, vegetable oil, fat, or other suitable vehicle for soft gelatine capsules. Soft gelatine capsules may also be enteric-coated as described above. Hard gelatine capsules may contain granules or enteric-coated granules of the active compound. Hard gelatine capsules may also contain the active compound in combination with a solid powdered carrier such as lactose, saccharose, sorbitol, mannitol, potato starch, amylopectin, cellulose derivatives or gelatine. The hard gelatine capsules may be enteric-coated as described above.
Dosage units for rectal administration may be prepared in the form of suppositories which contain the active substance mixed with a neutral fat base, or they may be prepared in the form of a gelatine rectal capsule which contains the active substance in a mixture with a vegetable oil, paraffin oil or other suitable vehicle for gelatine rectal capsules, or they may be prepared in the form of a ready-made micro enema, or they may be prepared in the form of a dry micro enema formulation to be reconstituted in a suitable solvent just prior to administration.
Liquid preparation for oral administration may be prepared in the form of syrups or suspensions, e.g. solutions or suspensions containing from 0.2% to 20% by weight of the active ingredient and the remainder
BAD ORIGINAL
AP 0 0 0 3 9 7 consisting of sugar or sugar alcohols and a mixture of ethanol, water, glycerol, propylene glycol and polyethylene glycol. If desired, such liquid preparations may contain colouring agents, flavouring agents, saccharine and carboxymethyl cellulose or other thickening agents. Liquid preparations for oral administration may also be prepared in the form of a dry powder to be reconstituted with a suitable solvent prior to use.
Solutions for parenteral administration may be prepared as a solution of a compound of the invention in a pharmaceutically acceptable solvent, preferably in a concentration from 0.1% to 10% by weight. These solutions may also contain stabilizing agents and/or buffering agents and may be manufactured in different unit dose ampoules or vials. Solutions for parenteral administration may also be prepared as a dry preparation to be reconstituted with a suitable solvent extemporaneously before use.
The typical daily dose of the active substance varies within a wide range and will depend on various factors such as for example the individual requirement of each patient, the route of administration and the disease.
In general, oral and parenteral dosages will be in the range of 5 to 500 mg per day of active substance.
The invention is illustrated by the following examples.
Example 1 Preparation of phosphoric acid, (5-acetyl6-methyl-2-[[(3,4-dimethoxy-2pyr idinyl) methyl ] sulf inyl ] -lH-benzimidazole-l-yl Imethyl ester, disodium salt or phosphoric acid, (6-acetyl-5methyl-2-[ [ ( 3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]BAD ORIGINAL
ΙΗ-benzimidazole-l-yllmethyl ester, disodiura salt.
Tributylamine (1.7 ml, 7.0 mmol) was added with stirring to a solution of phosphoric acid, 85 per cent (0.24 ml, 3.6 mmol) in ethanol (2 ml). The solvent was evaporated and the residue taken up in methylene chloride (2.5 ml). The organic phase was dried over sodium sulphate, filtered and evaporated. 5-acetyl-lchloromethyl-6-methyl-2-[[(3,4-dimethoxy-2pyridinyl)methyl]sulfinyl]-ΙΗ-benzimidazole or 6acetyl-l-chloromethyl-5-methyl-2- [ [ ( 3,4-dimethoxy-2pyridinyl)methyl)sulfinyl]-lH-benzimidazole (0.12 g, 0,28 mmol) and the tributylammonium salt of phosphoric acid, prepared above, were dissolved in methylene chloride (6 ml). The methylene chloride was distilled off and the residue was heated on a waterbath for 5 minutes at 60eC. The residue was dissolved in methylene chloride (6 ml) and again the methylene chloride was distilled off and the oily product mixture was heated on a waterbath for 5 minutes at 60®C. This procedure was repeated four times until the reaction was completed. The residue was dissolved in methylene chloride (4 ml) and washed with three (4 ml) portions of water. A solution of sodium hydroxide (0.2M), was added to the organic phase with stirring while pH of the aqueous layer was carefully controlled. When pH reached 9-9.5 in the aqueous phase the mixture was centrifuged. The aqueous layer was washed with three portions (4 ml) of methylene chloride and then freeze dried to give 40 mg, 27% of the title compound.
NMR data are given below.
Example 2. Preparation of phosphoric acid, [5-carboBAD ORIGINAL A
AP 0 0 0 3 9 7 methoxy-6-methyl-2-[ [(3,4-dimethoxy-2pyridiny1)methyl]sulfinyl]-ΙΗ-benzimidazole-1-ylImethyl ester, disodium salt or phosphoric acid, [6carbomethoxy-5-methyl-2-[[(3,4-dimethoxy-2pyridinyl)methyl]sulf inyl)-ΙΗ-benzimidazole-1-yl]methyl ester, disodium salt.
Tributylamine (1.8 ml, 7.8 mmol) was added with stirring to a solution of phosphoric acid, 85% (0.26 ml, 3.9 mmol) in ethanol (2.5 ml). The solvent was evaporated and the residue taken up in methylene chloride (3 ml). The organic phase was dried over sodium sulphate, filtered and evaporated. 5carbomethoxy-l-chloromethyl-6-methyl-2-[[(3,4dimethoxy-2-pyridinyl)methyl]sulfinyl]-lH-benzimidazole or 6-carbomethoxy-l-chloromethyl-5-methyl-2-[[(3,4dimethoxy-2-pyr idiny 1)methyl]sulf inyl]-ΙΗ-benz imidazole (0.14 g, 0.32 mmol, and the tributylammonium salt of phosphoric acid, prepared above, were dissolved in methylene chloride (6.5 ml). The methylene chloride was distilled off and the residue was heated on a waterbath for 5 minutes at 60°C. The residue was dissolved in methylene chloride (6.5 ml) and again the methylene chloride was distilled off and the oily product mixture was heated on a waterbath for 5 minutes at 60 ®C. This procedure was repeated four times until the reaction was completed. The residue was dissolved in methylene chloride (4 ml) and washed with three (4 ml) portions of water. A solution of sodium hydroxide (0.2M), was added to the organic phase with stirring while pH of the aqueous layer was carefully controlled. When pH reached 9-9.5 in the aqueous phase the mixture was centrifuged. The aqueous layer was washed with three portions (4 ml) of methylene chloride and then freeze dried to give 11 mg, 6% of the title compound.
BAD ORIGINAL 0*
NMR date are given below.
Table 1
Protons in water set to 4.80. | ||
Ex. | Solvent | NMR data δ ppm |
1 | d2o | 2.67 (s,3H), 2.78 (s, 3H), 3.85 (s, 3H), |
(300 MHz) | 3.98 (s, 3H), 4.98 (d, IH), 5.08 (d, IH), 5.98 (m, 2H), 7.15 (d, IH), 7.78 (s, IH), 8.12 (d, IH), 8.18 (s, IH). | |
2 | D2° | 2.75 (s, 3H), 3.83 (s, 3H), 3.97 (s, 3H) , |
(300 MHZ) | 4.05 (s, 3H), 4.98 (d, IH), 5.08 (d, IH), 5,95 (m, 2H), 7.15 (d, IH), 7.83 (s, IH), 8.15 (d, IH), 8.28 (s, IH). |
Preparation of intermediates
Example I 1
Preparation of 5-acetyl-l-hydroxyraethyl-6-roethyl-2-[[(3,4diraethoxy-2-pyridinyl) methyl ] sulf inyl ] - IH-benz imida zole or
6-acetyl-l-hydroxymethyl-5-metyl-2-[ [ (3,4-dimethoxy-2-pyridinyl Jmethyl ]sulfinyl]-lH-benzimidazole
To a mixture of 5-acetyl-6-methyl-2-[ [ (3,4-dimethoxy-2BAD ORIGINAL fi
AP 0 0 0 3 9 7 pyridinyl)methyl]sulfinyl]-lH-benzimidazole (2.00 g,
5.4 mmol) and methylene chloride (100 ml) aqueous 5 M formaldehyde (5.0 ml, 25 mmol) was added. The mixture was
After separation the organic solution and evaporated under reduced pressure giving a red syrup (1.7 g, 78%). The product consisted mainly of one of the structure isomers of the title compound as well as small amounts of starting material.
shaken for 3 minutes, was dried over
NMR data are given below.
Example I 2
Preparation of 5-acetyl-l-chlororoethyl-6-roethyl-2-[[(3,4dimethoxy-2-pyridinyl)methyl]sulfinyl] -ΙΗ-benzimidazole or
6-acetyl-l-chlororoethyl-5-roethyl-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-ΙΗ-benz imidazole
A suspension of 5-acetyl-l-hydroxymethyl-6-methyl-2-[[(3,4dimethoxy-2-pyr idinyl)methyl]sulf inyl]-ΙΗ-benz imidazole and
6-acetyl-l-hydroxymethyl-5-methyl-2-[[(3,4-dimethoxy-2pyridinyl)methyl]sulfinyl]-lH-benzimidazole (1.7 g,
4.2 mmol) in acetonitrile (40 ml) was chilled to -15°C. Thionyl chloride (0.50 g, 4.2 mmol) and triethylamine (0.50 g, 4.2 mmol) were added dropwise in the given order. The mixture was stirred at room temperature for five minutes and then evaporated under reduced pressure. The residue was chromatographed on silica gel (70 g) using a mixture of ethyl acetate and methylene chloride as eluent. The amount of ethyl acetate was increased during the chromatography. The product 0.14 g (8%) consisted mainly of one of the structure isomers.
NMR data are given below.
BAD ORIGINAL A
Example I 3
Preparation of 5-carboroethoxy-l-hydroxymethyl-6-roethyl-2[ [ ( 3,4-dimethoxy-2-pyridinyl Jmethyl] sulf inyl]-1Hbenzimidazole or 6-carbomethoxy-l-hydroxyroethyl-5-roethyl-2[ [ (3,4-dimethoxy-2-pyridinylJmethyl]sulfinyl]-lHbenzimidazole
To a solution of 5-carbomethoxy-6-methyl-2-[[(3,4dime thoxy-2-pyr idinyl) methyl ]sulf inyl ]-ΙΗ-benzimidazole (0.34 g, 0.87 mmol) in methylene chloride (25 ml) 5 M aqueous formaldehyde (1.7 ml, 8.5 mmol) was added. The mixture was shaken for 3 minutes. After separation the organic solution was dried over Na2SO^ and evaporated under reduced pressure giving a red syrup (0.36 g, 100%). The product consisted mainly of one of the structure isomers of the title compound as well as small amounts of starting material.
NMR data are given below.
Example I 4
Preparation of 5-carboroethoxy-1-chlorcroethy1-6-methy 1-2[ [ (3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-lHbenziroidazole or 6-carbomethoxy-l-chlororoethyl-5-methyl-2t [ (3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-lHbenziroidazole
A solution of 5-carbomethoxy-l-hydroxymethyl-6-methyl-2t [ (3,4-diroethoxy-2-pyridinyljmethyl]sulfinyl]-lHbenzimidazole and 6-carbomethoxy-l-hydroxymethyl-5-methyl2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-lHbenzimidazole (0.36 g, 0.87 mmol) in acetonitril (20 ml) was chilled to -20°C. Thionyl chloride (0.066 ml,
BAD ORIGINAL
AP 0 0 0 3 9 7
0.90 mmol) and triethylamine (0.10 g, 1.0 mmol) were added dropwise in the given order. The mixture was stirred at room temperature for five minutes and then evaporated under reduced pressure. The residue was chromatographed on silica gel (20 g) using a mixture of ethyl acetate and methylene chloride as eluent. The amount of ethyl acetate was increased during the chromatography. The product 0.16 g (43%) consisted mainly of one of the structure isomers.
NMR data are given below.
Table 2
Ex | Solvent | NMR data δ ppra |
I 1 | cdci3 | 2.60 (sz 3H), 2.70(s, 3H), 3.90 (s, 3H), 3.95 (sz 3H), 4.8-5.1 (m, 2H), 5.70 (d, IH), 6.10 (d, IH) 6.75 (d, IH), 7.40 (s, 1H), 7.90 (d, IH), 8.10 (s, IH,. |
I 2 | cdci3 | 2.66 (sz 3H), 2.72 (s, 3H), 3.90 (s, 3H), 3.91 (sz 3H), 4.91 (d, IH), 5.02 (d, 1H), 6.23 (d, IH), 6.55 (d, 1H), 6.80 (d, IH), 7.39 (sz IH), 8.15 (d, IH), 8.20 (sz IH). |
I 3 | cdci3 | 2.75 (s, 3H)Z 3.8-4.0 (mz 9H)Z 4.7-5.1 (m, 2H)Z 5.75 (dz IH), 6.10 (dz IH), 6.75 (d, 1H)Z 7.40 (sz IH), 7.90 (dz IH), 8.30 (sz IH). |
I 4 | CDC13 | 2.79 (sz 3H), 3.89 (sz 3H), 3.91 (sz 3H)Z 3.93 (sz 3H), 4.90 (d, IH), 5.02 (dz 1H)Z 6.23 (dz IH), 6.57 (dz IH), 6.80 (dz IH), 7.39 (sz IH), 8.15 (d, IH), 8.40 (sz IH). |
BAD ORIGINAL 0,
Table 3
Examples of compounds included in the formula I are given
in the | following | table. | ||||
Yield | Ident. | Re- | ||||
Example | R1 | R2 | M | % | data | marks |
1 | ch3 | C(O)CH3 | ||||
or | Na + | 27 | NMR | Isolated | ||
C(O)CH3 | CH3 | isomer | ||||
2 | ch3 | C(O)OCH3 | ||||
or | Na | 6 | NMR | Isolated | ||
isomer | ||||||
c(o)och3 | ch3 | |||||
3 | c(o)ch3 | CH3 | ||||
or | Na+ | - | - | Isolated | ||
isomer | ||||||
CH3 | C(O)CH3 | |||||
4 | C(O)OCH3 | CH3 | ||||
or | Na+ | - | - | Isolated | ||
isomer | ||||||
C(O)OCH3 | CH3 | |||||
5 | CH3 | C(O)CH3 | Na+ | - | - | Isomeric |
C(O)CH3 | CH3 | mixture |
bad original
AP 0 0 0 3 9 7
CH-j C(O)OCH3 Na+ c(o)och3 ch3
Isomeri mixture
The best mode of carrying out the invention known at present is to use a compound according to Example 2.
Pharmaceutical preparations containing a compound of the invention as active ingredient are illustrated in the following formulations.
Syrup
A syrup containing 1% (weight per volume) of active substance was prepared from the following ingredients:
Compound according to Example 1
Sugar, powder
Saccharine
Glycerol
Flavouring agent
Ethanol 96%
1.0 g 30.0 g 0.6 g 5.0 g 0.05 g 5.0 g
Distilled water q.s. to a final volume of 100 ml
Sugar and saccharine were dissolved in 60 g of warm water. After cooling the active compound was added to the sugar solution and glycerol and a solution of flavouring agents dissolved in ethanol were added. The mixture was diluted with water to a final volume of 100 ml.
Enteric-coated tablets
An enteric coated tablet containing 20 mg of active compound was prepared from the following ingredients:
BAD ORIGINAL $
I
II
200 g
700 g
Compound mixture according to
Example 2
Lactose
Methyl cellulose
Polyvinylpyrrolidone cross-linked Magnesium stearate Sodium carbonate Distilled water g
g 15 g 6 g q.s.
Cellulose acetate phthalate Cetyl alcohol Isopropanol Methylene chloride
200 g 15 g
2000 g 2000 g
I Compound according to Example 1, powder, was mixed with lactose and granulated with a water solution of methyl cellulose and sodium carbonate. The wet mass was forced through a sieve and the granulate dried in an oven. After drying the granulate was mixed with polyvinylpyrrolidone and magnesium stearate. The dry mixture was pressed into tablet cores (10 000 tablets), each tablet containing 20 mg of active substance, in a tabletting machine using 6 mm diameter punches.
II A solution of cellulose acetate phthalate and cetyl alcohol in isopropanol/methylene chloride was sprayed onto the tablets in an Accela Cota , Manesty coating equipment. A final tablet weight of 110 mg was obtained.
Solution for intravenous administration
A parenteral formulation for intravenous use, containing 4 mg of active compound per ml, was prepared from the following ingredients:
BAD ORIGINAL
AP 0 0 0 3 9 7
Compound according to Example 2 Sterile water to a final volume of g
1000 ml
The active compound was dissolved in water to a final volume of 1000 ml. The solution was filtered through a 0.22 urn filter and immediately dispensed into 10 ml sterile ampoules. The ampoules were sealed.
Tablets
Tablets containing 30 mg of active compound were prepared from the following ingredients:
Compound according to Example 3 in Table 3 300 g
Lactose 700 g
Methyl cellulose 6 g
Polyvinyl pyrrolidone, cross-linked (PVP-XL) 62 g
Disodium hydrogen phosphate 2 g
Magnesium stearate 30 g
Purified water q.s.
The active compound was mixed with lactose and part of the PVP-XL and granulated with a solution of methyl cellulose and disodium hydrogen phosphate. The wet mass was forced through a screen and dried in a fluidized bed dryer. After adding magnesium stearate and the remainder in PVP-XL and mixing, the drug mixture was compressed into tablets with a mean weight of 110 mg, each tablet containing 30 mg of the active compound.
Enteric coated tablets
500 g of the tablets above were enteric-coated. A solution of the composition below was sprayed onto the
BAD ORIGINAL fi tablets in a fluidized bed apparatus using Wurster coating technique.
Coating solution:
Cellulose acetate phthalate Cetyl alcohol Isopropanol Dichloromethane g 2 g
400 g 400 g
The final coated tablet weighed 117 mg.
Suppositories
Suppositories were prepared from the following ingredients using a welding procedure. Each suppository contained 40 mg of active compound.
Compound mixture according to Example 4 in Table 3 4 g
Witepsol H-15 180 g
The active compound mixture was homogenously mixed with Witepsol H-15 at a temperature of 41®C. The molten mass was volume filled into pre-fabricated suppository packages to a net weight of 1.84 g. After cooling the packages were heat sealed. Each suppository contained 40 mg of active compound.
Just before use, the active compound dissolved in 10 ml of sterile water is transferred into 100 ml of normal saline solution for infusion to give a total volume of about 110 ml. The solution is administered as an intravenous infusion during a time period of about 30 minutes.
BAD ORIGINAL
APO00397
Syrup
A syrup containing from the following
1% of active substance was prepared ingredients:
Compound according to Example 3 in
Table 3
Sugar, powder
Saccharine
Flavouring agent
Ethanol 96%
Purified water q.s.
1.0 g 30.0 g
0.6 g 0.05 g
5.0 g to 100 ml
Sugar and saccharine were dissolved in 60 g of warm water. After cooling the active compound was added to the sugar solution and a solution of flavouring agents dissolved in ethanol was added. The mixture was diluted with water to a final volume of 100 ml.
Solution for intravenous or intramuscular injection
Compound according to Example 1 60 g
Water for injection to make 1000 ml
The active compound was dissolved in water to a final volume of 1000 ml. The solution was filtered through a sterile 0.22 um filter and aseptically dispensed into 1 ml sterile ampoules. The ampoules were sealed.
Formulation for intravenous infusion
Sterile compound according to Example 2 60 mg
Sterile injection vials and stoppers
BAD ORIGINAL
Sterile active compound, 60 mg, was dispensed into 10 ml sterile injection vials. The vials were stoppered with sterile rubberstoppers. The vokale filling operation was performed under aseptic conditions in a sterile production area under vertical laminar flow.
Biological Effects
Effects on the uptake of iodine into the thyroid gland
The effect of a compound within the invention of the formula I on the uptake of iodine into the thyroid gland is measured as an effect on the accumulation of 125
I in the thyroid gland of the active compounds generated in the metabolism of the compounds within the invention.
125
Effect on the accumulation of I in the thyroid gland
125
The accumulation of I in the thyroid gland was studied in male, Sprague-Dawley rats which were deprived of food for 24 hours before the test. The experimental protocol of Searle, CE et al. (Biochem J 1950; 47:77-81) was followed.
Test substances, suspended in 0.5% buffered (pH 9) methocel, were administered by oral gavage in a volume
125 of 5 ml/kg body weight. After 1 hour, I (300kBq/kg,
3ml/kg) was administered by intraperitoneal injection. 125
Four hours after I-administration, the animals were killed by CO 2-asphyxiation and bled. The thyroid gland together with a piece of the trachea was dissected out and placed in a small test tube for the assay of bAD ORIGINAL
AP 0 0 0 3 9 7 radioactivity in a gamma counter (LKB-Wallac model 1282 Compugamma). Percentage inhibition was calculated according to the formula 100 (1-T/P), where T and P is the mean radioactivity of thyroid glands from animals treated with test agent and placebo (buffered methocel), respectively. The statistical significance for a difference between test agent- and placebotreated animals was assessed with the Mann-Whitney Utest (two-tailed). P<0.05 was accepted as significant.
Results of biological tests
Table 4 give the test data available for the compounds of the invention.
Table 4, Biological Test Data | ||
Test compound (number of animals) | Per cent inhibition of 400 umol/kg on the uptake 125 of I in the thyroid gland | |
Active metabolite of Examples No 1, 3 and (n = 5) | 5 | -7 |
Active metabolite of Examples No 2, 4 and (n = 5) | 6 | 0 |
BAD ORIGINAL ft
Hiring now particul ;.-<y described kfl3 Moartained my .iur '-A iierncon aod b what manner 4 c <-t-»- ··. ι * r«-r(onndl IZwe declare dial what i ~< uiai;r> · —
Claims (20)
1. A compound of the formula I wherein
R1 and R2, which are different, is each methyl, -C(O)-CH3 or 5 -C(O)-OCH3 and whereby one of R1 or R2 is methyl but R* and R2 are not both methyl, and M is a physiologically acceptable cation.
2. A compound according to claim 1 wherein M is Na, K, Ag or trialkylammonium.
10
3. A mixture of phosphoric acid, [5-acetyl-6methyl-2- [ [ (3,4-dimethoxy-2-pyridinyl)methyl] sulfinyl] -1Hbenzimidazole-l-yl]methyl ester, disodium salt and phosphoric acid, (6-acetyl-5-methyl-2-[ ( (3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-lH-benzimidazole-l-yl]methyl ester, disodium
15 salt.
4. A mixture of phosphoric acid, [5carbomethoxy-6-methyl-2- [ [ (3,4-dimethoxy-2-pyridinyl) methyljsulfinyl]-lH-benzimidazole-l-yl]roethyl ester, disodium salt and phosphoric acid, [6-carbomethoxy-5-methyl-2-[((3,420 dimethoxy-2-pyridinyl)methyl ]sulf inyl] -lH-benzimidazole-1yljmethyl ester, disodium salt.
5. Phosphoric acid, (5-acetyl-6-methy1-2([(3,4-dimethoxy-2-pyridiny1)methy1]sulfiny1]-1HBAD ORIGINAL ά
AP 0 0 0 3 9 7
-25benzimidazole-l-yl]methy1 ester, disodium salt.
6. Phosphoric acid, [6-acetyl-5-methyl-2[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinylj-lHbenzimidazole-l-yl]methy1 ester, disodium salt.
7. Phosphoric acid, (5-carboraethoxy-6-methyl-2[ [ (3,4-dimethoxy-2-pyr idinyl) methyl ] sulf inyl ]-1Hbenzimidazole-l-yl]methyl ester, disodium salt.
8. Phosphoric acid, (6-carbomethoxy-5-methyl-2( [ ( 3 , 4-dimethoxy-2-pyridinyl)methyl] sulfinyl)-lHbenzimidazole-l-yl]methy1 ester, disodium salt.
9. A compound according to claim 1 specifically identified herein.
10. A pharmaceutical composition containing as active ingredient one or more compounds as claimed in any one of claims 1 to 9 together with a pharmaceutically acceptable carrier or diluent.
11. A compound or compound mixture as defined in any one of claims 1 to 9 for use in therapy.
12. A compound or compound mixture as defined in any one of claims 1 to 9 for use in inhibiting gastric acid secretion in mammals including man.
13. A compound or compound mixture as defined in any one of claims 1 to 9 for use in the treatment of gastrointestinal inflammatory diseases in mammals including man.
14. Use of a compound or compound mixture according to any one of claims 1 to 9 in the manufacture of a medicament for inhibiting gastric acid secretion in mammals including man.
15. Use of a compound or compound mixture according to any one of claims 1 to 9 in the manufacture of a medicament for the treatment of gastrointestinal inflammatory diseases in mammals including man.
16. A process for the preparation of a compound of the formula I as claimed in claim 1, which process comprises
BAD ORIGINAL
a) reacting a compound of the formula II
R1
R2
II wherein R1 and R2 are as defined in claim 1 and Z is halogen such as Cl, Br or I or a functionally equivalent group, with a compound of the formula III
O
II
HO-P-O 0 ι o Q
5 wherein Q is a cation such as Na*, K*, Ag* or trialkylammonium, or
b) Oxidizing a compound of the formula IV
BAD ORIGINAL A
AP Ο Ο Ο 3 9 7
- 27 wherein R1, R2 and M are as defined in claim 1, to give a conpound of formula I.
17. A process for preparing a compound as claimed in claim 1 substantially as described in any one of
5 the Examples.
18. A compound according to claim 1 prepared by the process claimed in claim 16 or 17.
19. A compound of the formula II
II wherein R1 and R2 are as defined in claim 1 and Z is halogen, 10 such as Cl, Br or I or a functionally equivalent group.
20. A compound according to claim 19, wherein Z is Cl or OH.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
SE9103776A SE9103776D0 (en) | 1991-12-19 | 1991-12-19 | NEW COMPOUNDS |
Publications (2)
Publication Number | Publication Date |
---|---|
AP9200463A0 AP9200463A0 (en) | 1993-01-31 |
AP397A true AP397A (en) | 1995-08-14 |
Family
ID=20384667
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
APAP/P/1992/000463A AP397A (en) | 1991-12-19 | 1992-12-14 | Substituted benzimidazoles, process for their preparation as well as their use. |
Country Status (25)
Country | Link |
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EP (1) | EP0628049A1 (en) |
JP (1) | JPH07502503A (en) |
KR (1) | KR940703840A (en) |
CN (1) | CN1031827C (en) |
AP (1) | AP397A (en) |
AU (1) | AU665043B2 (en) |
CA (1) | CA2124689A1 (en) |
CZ (1) | CZ146794A3 (en) |
FI (1) | FI942912A0 (en) |
HR (1) | HRP921400A2 (en) |
HU (1) | HUT68270A (en) |
IL (1) | IL104025A0 (en) |
IS (2) | IS4079A (en) |
MA (1) | MA22746A1 (en) |
MX (1) | MX9207269A (en) |
NO (1) | NO942230D0 (en) |
NZ (1) | NZ246220A (en) |
SE (1) | SE9103776D0 (en) |
SI (1) | SI9200402A (en) |
SK (1) | SK73594A3 (en) |
TN (1) | TNSN92115A1 (en) |
TW (1) | TW224100B (en) |
WO (1) | WO1993012124A1 (en) |
YU (1) | YU101692A (en) |
ZA (1) | ZA928836B (en) |
Families Citing this family (9)
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DE19645974C1 (en) * | 1996-11-07 | 1998-08-13 | Andreas Johannes Kesel | (Z) -5 - [[3-Hydroxy-2-methyl-5 - [(phosphonooxy) methyl] -4-pyridinyl] methylene] -2-thioxo-4-thiazolidinone, process for its preparation and use |
US5985856A (en) * | 1997-12-31 | 1999-11-16 | University Of Kansas | Water soluble prodrugs of secondary and tertiary amine containing drugs and methods of making thereof |
PL1913009T3 (en) | 2005-07-28 | 2010-10-29 | Intervet Int Bv | Novel benzimidazole (thio) carbamates with antiparasitic activity and the synthesis thereof |
TWI385169B (en) | 2005-10-31 | 2013-02-11 | Eisai R&D Man Co Ltd | Heterocyclic substituted pyridine derivatives and antifungal agent containing same |
EP2037914B1 (en) | 2006-06-14 | 2013-10-23 | Intervet International BV | A suspension comprising benzimidazole carbamate and a polysorbate |
TW200841879A (en) | 2007-04-27 | 2008-11-01 | Eisai R&D Man Co Ltd | Pyridine derivatives substituted by heterocyclic ring and phosphonoamino group, and anti-fungal agent containing same |
US8513287B2 (en) * | 2007-12-27 | 2013-08-20 | Eisai R&D Management Co., Ltd. | Heterocyclic ring and phosphonoxymethyl group substituted pyridine derivatives and antifungal agent containing same |
US8188119B2 (en) | 2008-10-24 | 2012-05-29 | Eisai R&D Management Co., Ltd | Pyridine derivatives substituted with heterocyclic ring and γ-glutamylamino group, and antifungal agents containing same |
MX365051B (en) | 2014-11-26 | 2019-05-09 | Univ Mexico Nac Autonoma | Novel hydrosoluble compounds derived from benzimidazole used in treating fasciolosis. |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
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EP0279149A2 (en) * | 1986-11-21 | 1988-08-24 | Aktiebolaget Hässle | Benzimidazole derivatives, process for their production and a pharmaceutical composition containing the same |
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SE8801907D0 (en) * | 1988-05-20 | 1988-05-20 | Haessle Ab | NOVEL PHARMACOLOGICAL COMPOUNDS |
CA2083606C (en) * | 1990-06-20 | 2001-08-21 | Arne Elof Brandstrom | Dialkoxy-pyridinyl-benzimidazole derivatives, process for their preparation and their pharmaceutical use |
SE9002206D0 (en) * | 1990-06-20 | 1990-06-20 | Haessle Ab | NEW COMPOUNDS |
-
1991
- 1991-12-19 SE SE9103776A patent/SE9103776D0/en unknown
-
1992
- 1992-10-06 IS IS4079A patent/IS4079A/en unknown
- 1992-11-11 TW TW081109053A patent/TW224100B/zh active
- 1992-11-16 ZA ZA928836A patent/ZA928836B/en unknown
- 1992-11-25 YU YU101692A patent/YU101692A/en unknown
- 1992-12-07 HR HR921400A patent/HRP921400A2/en not_active Application Discontinuation
- 1992-12-08 CA CA002124689A patent/CA2124689A1/en not_active Abandoned
- 1992-12-08 WO PCT/SE1992/000844 patent/WO1993012124A1/en not_active Application Discontinuation
- 1992-12-08 EP EP93900477A patent/EP0628049A1/en not_active Withdrawn
- 1992-12-08 HU HU9401840A patent/HUT68270A/en unknown
- 1992-12-08 CZ CZ941467A patent/CZ146794A3/en unknown
- 1992-12-08 SK SK735-94A patent/SK73594A3/en unknown
- 1992-12-08 KR KR1019940702131A patent/KR940703840A/en not_active Application Discontinuation
- 1992-12-08 IL IL104025A patent/IL104025A0/en unknown
- 1992-12-08 AU AU31752/93A patent/AU665043B2/en not_active Ceased
- 1992-12-08 NZ NZ246220A patent/NZ246220A/en unknown
- 1992-12-08 JP JP5510832A patent/JPH07502503A/en active Pending
- 1992-12-14 AP APAP/P/1992/000463A patent/AP397A/en active
- 1992-12-15 MX MX9207269A patent/MX9207269A/en unknown
- 1992-12-16 MA MA23036A patent/MA22746A1/en unknown
- 1992-12-18 TN TNTNSN92115A patent/TNSN92115A1/en unknown
- 1992-12-18 SI SI19929200402A patent/SI9200402A/en unknown
- 1992-12-18 CN CN92114364A patent/CN1031827C/en not_active Expired - Fee Related
- 1992-12-18 IS IS3960A patent/IS3960A/en unknown
-
1994
- 1994-06-14 NO NO942230A patent/NO942230D0/en unknown
- 1994-06-17 FI FI942912A patent/FI942912A0/en not_active Application Discontinuation
Patent Citations (1)
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EP0279149A2 (en) * | 1986-11-21 | 1988-08-24 | Aktiebolaget Hässle | Benzimidazole derivatives, process for their production and a pharmaceutical composition containing the same |
Also Published As
Publication number | Publication date |
---|---|
IS4079A (en) | 1993-06-20 |
ZA928836B (en) | 1993-07-05 |
NZ246220A (en) | 1996-02-27 |
AU665043B2 (en) | 1995-12-14 |
IL104025A0 (en) | 1993-05-13 |
YU101692A (en) | 1995-10-03 |
CZ146794A3 (en) | 1996-02-14 |
FI942912A (en) | 1994-06-17 |
AU3175293A (en) | 1993-07-19 |
IS3960A (en) | 1993-06-20 |
SI9200402A (en) | 1993-06-30 |
SK73594A3 (en) | 1995-02-08 |
HRP921400A2 (en) | 1994-08-31 |
EP0628049A1 (en) | 1994-12-14 |
WO1993012124A1 (en) | 1993-06-24 |
TW224100B (en) | 1994-05-21 |
HUT68270A (en) | 1995-06-28 |
KR940703840A (en) | 1994-12-12 |
MA22746A1 (en) | 1993-07-01 |
AP9200463A0 (en) | 1993-01-31 |
NO942230L (en) | 1994-06-14 |
FI942912A0 (en) | 1994-06-17 |
TNSN92115A1 (en) | 1993-06-08 |
SE9103776D0 (en) | 1991-12-19 |
CN1073446A (en) | 1993-06-23 |
JPH07502503A (en) | 1995-03-16 |
CN1031827C (en) | 1996-05-22 |
MX9207269A (en) | 1993-06-01 |
HU9401840D0 (en) | 1994-09-28 |
CA2124689A1 (en) | 1993-06-24 |
NO942230D0 (en) | 1994-06-14 |
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