AU3175293A - Substituted benzimidazoles, process for their preparation as well as their use - Google Patents
Substituted benzimidazoles, process for their preparation as well as their useInfo
- Publication number
- AU3175293A AU3175293A AU31752/93A AU3175293A AU3175293A AU 3175293 A AU3175293 A AU 3175293A AU 31752/93 A AU31752/93 A AU 31752/93A AU 3175293 A AU3175293 A AU 3175293A AU 3175293 A AU3175293 A AU 3175293A
- Authority
- AU
- Australia
- Prior art keywords
- methyl
- compound
- formula
- sulfinyl
- pyridinyl
- 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.)
- Granted
Links
- 238000002360 preparation method Methods 0.000 title claims description 21
- 238000000034 method Methods 0.000 title claims description 12
- 150000001556 benzimidazoles Chemical class 0.000 title description 5
- 150000001875 compounds Chemical class 0.000 claims description 97
- 239000000203 mixture Substances 0.000 claims description 33
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 29
- -1 [5-acetyl-6-methyl-2- [[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-1H- benzimidazole-l-yl]methyl Chemical group 0.000 claims description 16
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 14
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical class [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 claims description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
- 241000124008 Mammalia Species 0.000 claims description 10
- 238000011282 treatment Methods 0.000 claims description 8
- 230000027119 gastric acid secretion Effects 0.000 claims description 7
- 229910052740 iodine Inorganic materials 0.000 claims description 7
- 230000002401 inhibitory effect Effects 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 6
- 239000004480 active ingredient Substances 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 208000017189 Gastrointestinal inflammatory disease Diseases 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 3
- 201000010099 disease Diseases 0.000 claims description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 3
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- 150000002367 halogens Chemical class 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 230000001590 oxidative effect Effects 0.000 claims description 3
- 125000005208 trialkylammonium group Chemical group 0.000 claims description 3
- 150000001768 cations Chemical class 0.000 claims description 2
- 150000002500 ions Chemical class 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
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- 150000004702 methyl esters Chemical class 0.000 claims 2
- 150000002148 esters Chemical class 0.000 claims 1
- 238000002560 therapeutic procedure Methods 0.000 claims 1
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- MPYBSSHBMZXTHH-UHFFFAOYSA-N 1-[1-(chloromethyl)-2-[(3,4-dimethoxypyridin-2-yl)methylsulfinyl]-6-methylbenzimidazol-5-yl]ethanone Chemical compound COC1=CC=NC(CS(=O)C=2N(C3=CC(C)=C(C(C)=O)C=C3N=2)CCl)=C1OC MPYBSSHBMZXTHH-UHFFFAOYSA-N 0.000 description 2
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- LDLOYSGTGFZHQN-UHFFFAOYSA-N methyl 2-[(3,4-dimethoxypyridin-2-yl)methylsulfinyl]-1-(hydroxymethyl)-6-methylbenzimidazole-5-carboxylate Chemical compound OCN1C=2C=C(C)C(C(=O)OC)=CC=2N=C1S(=O)CC1=NC=CC(OC)=C1OC LDLOYSGTGFZHQN-UHFFFAOYSA-N 0.000 description 2
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- BHEPBYXIRTUNPN-UHFFFAOYSA-N hydridophosphorus(.) (triplet) Chemical compound [PH] BHEPBYXIRTUNPN-UHFFFAOYSA-N 0.000 description 1
- 150000002433 hydrophilic molecules Chemical class 0.000 description 1
- 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 description 1
- 229940031704 hydroxypropyl methylcellulose phthalate Drugs 0.000 description 1
- 230000004968 inflammatory condition Effects 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- JYJVVHFRSFVEJM-UHFFFAOYSA-N iodosobenzene Chemical compound O=IC1=CC=CC=C1 JYJVVHFRSFVEJM-UHFFFAOYSA-N 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- OUNSCXAXAHZWQE-UHFFFAOYSA-N methyl 1-(chloromethyl)-2-[(3,4-dimethoxypyridin-2-yl)methylsulfinyl]-6-methylbenzimidazole-5-carboxylate Chemical compound ClCN1C=2C=C(C)C(C(=O)OC)=CC=2N=C1S(=O)CC1=NC=CC(OC)=C1OC OUNSCXAXAHZWQE-UHFFFAOYSA-N 0.000 description 1
- USQNQXCBFGFDKP-UHFFFAOYSA-N methyl 2-[(3,4-dimethoxypyridin-2-yl)methylsulfinyl]-3-(hydroxymethyl)-6-methylbenzimidazole-5-carboxylate Chemical compound N=1C=2C=C(C)C(C(=O)OC)=CC=2N(CO)C=1S(=O)CC1=NC=CC(OC)=C1OC USQNQXCBFGFDKP-UHFFFAOYSA-N 0.000 description 1
- RFJGNWGMCBFYTP-UHFFFAOYSA-N methyl 2-[(3,4-dimethoxypyridin-2-yl)methylsulfinyl]-6-methyl-1h-benzimidazole-5-carboxylate Chemical compound N1C=2C=C(C)C(C(=O)OC)=CC=2N=C1S(=O)CC1=NC=CC(OC)=C1OC RFJGNWGMCBFYTP-UHFFFAOYSA-N 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 229940006093 opthalmologic coloring agent diagnostic Drugs 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 238000003305 oral gavage Methods 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 208000000689 peptic esophagitis Diseases 0.000 description 1
- 208000011906 peptic ulcer disease Diseases 0.000 description 1
- 150000002976 peresters Chemical class 0.000 description 1
- 150000004965 peroxy acids Chemical class 0.000 description 1
- 125000005498 phthalate group Chemical group 0.000 description 1
- 239000000902 placebo Substances 0.000 description 1
- 229940068196 placebo Drugs 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 1
- 238000012453 sprague-dawley rat model Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Chemical class 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 150000005846 sugar alcohols Chemical class 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 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
-
- 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
-
- 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
-
- 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
-
- 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
-
- 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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- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Molecular Biology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
SUBSTITUTED BENZIMIDAZOLES, PROCESS FOR THEIR
PREPARATION AS WELL AS THEIR USE.
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
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 earlie 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]-1H-benzimidazole-1-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 1525 958, US 4182766, US 4255 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
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:
I
wherein
R1 and R2, which are different, is each methyl, -C(O)-
CH3 or -C(O)-OCH3 and whereby one of R1or R2 is always methyl, and M is a physiologically acceptable counter 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
wherein R1 and R2 are as defined under formula I, and
Z, is halogen such as CI, Br or I or a functionally equivalent group, with a compound of the formula III
O
|
HO-P-O Q III
|
O Q 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
wherein R1, R2 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, 1- chlorobenzotriazole, 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
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, semi-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 0.1- 95% 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, amylopectin, 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, hydroxypropyl- methylcellulose phthalate, partly methyl esterified methacrylic acid polymers and the like, if preferred in combination with a suitable plasticizer. To this
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
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-acetyl- 6-methyl-2-[[(3,4-dimethoxy-2- pyridinyl)methyl]sulfinyl]-1H-benzimidazole-1-yl]methyl ester, disodium salt or phosphoric acid, [6-acetyl-5- methyl-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-
1H-benzimidazole-1-yl]methyl ester, disodium 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-1- chloromethyl-6-methyl-2-[[(3,4-dimethoxy-2- pyridinyl)methyl]sulfinyl]-1H-benzimidazole or 6- acetyl-1-chloromethyl-5-methyl-2-[[(3,4-dimethoxy-2- pyridinyl)methyl]sulfinyl]-1H-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 60°C. 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-carbo
methoxy-6-methyl-2-[[(3,4-dimethoxy-2- pyridinyl)methyl]sulfinyl]-1H-benzimidazole-1-yl]methyl ester, disodium salt or phosphoric acid, [6- carbomethoxy-5-methyl-2-[[(3,4-dimethoxy-2- pyridinyl)methyl]sulfinyl]-1H-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. 5- carbomethoxy-1-chloromethyl-6-methyl-2-[[(3,4- dimethoxy-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole or 6-carbomethoxy-1-chloromethyl-5-methyl-2-[[(3,4- dimethoxy-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole (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.
NMR date are given below.
Table 1
Protons in water set to 4.80.
Ex. Solvent NMR data 6 ppm
1 D2O 2.67 (s,3H), 2.78 (s, 3H), 3.85
(s, 3H),
(300 MHz) 3.98 (s, 3H), 4.98 (d, 1H), 5.08 (d
1H), 5.98 (m, 2H), 7.15 (d, 1H), 7.
(s, 1H), 8.12 (d, 1H), 8.18 (s, 1H)
2 D2O 2.75 (s, 3H), 3.83 (s, 3H), 3.97 (s
3H),
(300 MHz) 4.05 (s, 3H), 4.98 (d, 1H), 5.08 (d
1H), 5,95 (m, 2H), 7.15 (d, 1H), 7.
(s, 1H), 8.15 (d, 1H), 8.28 (s, 1H)
Preparation of intermediates
Example I 1 Preparation of 5-acetyl-1-hydroxymethyl-6-methyl-2-[[(3 dimethoxy-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole 6-acetyl-1-hydroxymethyl-5-metyl-2-[[(3,4-dimethoxy-2-p dinyl)methyl]sulfinyl]-1H-benzimidazole To a mixture of 5-acetyl-6-methyl-2-[[(3,4-dimethoxy-2-
pyridinyl)methyl]sulfinyl]-1H-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 shaken for 3 minutes. After separation the organic solution was dried over Na2SO4 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. NMR data are given below.
Example I 2
Preparation of 5-acetyl-1-chloromethyl-6-methyl-2-[[(3,4- dimethoxy-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole or 6-acetyl-1-chloromethyl-5-methyl-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole
A suspension of 5-acetyl-1-hydroxymethyl-6-methyl-2-[[(3,4- dimethoxy-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole and 6-acetyl-1-hydroxymethyl-5-methyl-2-[[(3,4-dimethoxy-2- pyridinyl)methyl]sulfinyl]-1H-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.
Example I 3
Preparation of 5-carbomethoxy-1-hydroxymethyl-6-methyl-2- [[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-1H- benzimidazole or 6-carbomethoxy-1-hydroxymethyl-5-methyl-2- [[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-1H- benziraidazole
To a solution of 5-carbomethoxy-6-methyl-2-[[(3,4- dimethoxy-2-pyridinyl)methyl]sulfinyl]-1H-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 Na2SO4 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-carbcfnethoxy-1-chloromethyl-6-methyl-2- [[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-1H- benzimidazole or 6-carbomethoxy-1-chloromethyl-5-methyl-2- [[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-1H- benzimidazole A solution of 5-carbomethoxy-1-hydroxymethyl-6-methyl-2- [[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-1H- benzimidazole and 6-carbomethoxy-1-hydroxymethyl-5-methyl- 2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-1H- benzimidazole (0.36 g, 0.87 mmol) in aσetonitril (20 ml) was chilled to -20°C. Thionyl chloride (0.066 ml.
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 ppm
I 1 CDCl3 2.60 (s, 3H), 2.70(s, 3H), 3.90 (s, 3H),
3.95 (s, 3H), 4.8-5.1 (m, 2H), 5.70 (d,
1H), 6.10 (d, 1H) 6.75 (d, 1H), 7.40 (s, 1H),
7.90 (d, 1H), 8.10 (s, 1H).
I 2 CDCl3 2.66 (s, 3H), 2.72 (s, 3H), 3.90 (s, 3H) ,
3.91 (s, 3H), 4.91 (d, 1H), 5.02 (d, 1H),
6.23 (d, 1H), 6.55 (d, 1H), 6.80 (d, 1H), 7.39 (s, 1H), 8.15 (d, 1H), 8.20 (s, 1H) .
I 3 CDCl3 2.75 (s, 3H), 3.8-4.0 (m, 9H), 4.7-5.1 (m,
2H), 5.75 (d, 1H), 6.10 (d, 1H),
6.75 (d, 1H), 7.40 (s, 1H), 7.90 (d, 1H), 8.30 (s, 1H).
I 4 CDCl3 2.79 (s, 3H), 3.89 (s, 3H), 3.91 (s, 3H),
3.93 (s, 3H), 4.90 (d, 1H), 5.02 (d, 1H),
6.23 (d, 1H), 6.57 (d, 1H), 6.80 (d, 1H), 7.39 (s, 1H), 8.15 (d, 1H), 8.40 (s, 1H) .
Table 3
Examples of compounds included in the formula I are given in the following table.
ric re
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 1 . 0 g
Sugar, powder 30 . 0 g
Saccharine 0. 6 g
Glycerol 5 . 0 g
Flavouring agent 0 . 05 g
Ethanol 96% 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:
I Compound mixture according to
Example 2 200 g
Lactose 700 g
Methyl cellulose 6 g
Polyvinylpyrrolidone cross-linked 50 g
Magnesium stearate 15 g
Sodium carbonate 6 g
Distilled water q.s.
II Cellulose acetate phthalate 200 g
Cetyl alcohol 15 g
Isopropanol 2000 g
Methylene chloride 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 CotaR, 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:
Compound according to Example 2 4 g
Sterile water to a final volume of 1000 ml
The active compound was dissolved in water to a final volume of 1000 ml. The solution was filtered through a 0.22 μm 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
tablets in a fluidized bed apparatus using Wurster coating technique.
Coating solution:
Cellulose acetate phthalate 40 g
Cetyl alcohol 2 g
Isopropanol 400 g
Dichloromethane 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.
Syrup
A syrup containing 1% of active substance was prepared from the following ingredients:
Compound according to Example 3 in
Table 3 1.0 g
Sugar, powder 30.0 g Saccharine 0.6 g
Flavouring agent 0.05 g
Ethanol 96% 5.0 g Purified water q.s. 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 μm 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
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.
Effect on the accumulation of 125I in the thyroid gland The accumulation of 125I 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 of 5 ml/kg body weight. After 1 hour, 125I (300kBq/kg,
3ml/kg) was administered by intraperitoneal injection. Four hours after 125I-administration, the animals were killed by CO2-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
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 placebo- treated animals was assessed with the Mann-Whitney U- test (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 Per cent inhibition of
(number of animals) 400 μmol/kg on the uptake
ooff 125I in the thyroid
gland
Active metabolite of
Examples No 1, 3 and 5
(n = 5) -7 Active metabolite of
Examples No 2, 4 and 6
(n = 5) 0
Claims (19)
1. Compounds of the formula I
wherein
R1 and R2, which are different, is each methyl, -C(O)-CH3 or -C(O)-OCH3 and whereby one of R1 or R2 is always methyl and M is a physiologically acceptable counter cation.
2. A compound according to claim 1 wherein M is Na, K, Ag or trialkylammonium.
3. Compounds according to formula I of claim 1, namely a mixture of phosphoric acid, [5-acetyl-6-methyl-2- [[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-1H- benzimidazole-l-yl]methyl ester, disodium salt and phosphoric acid, [6-acetyl-5-methyl-2-[[(3,4-dimethoxy-2- pyridinyl)methyl]sulfinyl]-1H-benzimidazole-1-yl]methyl ester, disodium salt.
4. Compounds as according to formula I of claim 1, namely a mixture of phosphoric acid, [5-carbomethoxy-6- methyl-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]- 1H-benzimidazole-1-γl]methγl ester, disodium salt and pho phoric acid, [6-carbomethoxy-5-methyl-2-[[(3,4- dimethoxy-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole2 1-yl]methyl ester, disodium salt.
5. A compound according to claim 1, namely phosphoric acid, (5-acetyl-6-methyl-2-[[(3,4-dimethoxy-2-pyridinyl)- methyl]sulfinyl]-1H-benzimidazole-1-yl]methyl ester, disodium salt.
6. A compound according to claim 1, namely phosphoric acid, [6-acetyl-5-methyl-2-[[(3,4-dimethoxy-2-pyridinyl)- methyl]sulfinyl]-1H-benzimidazole-1-yl]methyl ester, disodium salt.
7. A compound according to claim 1 namely phosphoric acid, [5-carbomethoxy-6-methyl-2-[[(3,4-dimethoxy-2- pyridinyl)methyl]sulfinyl]-1H-benzimidazole-1-yl]methyl ester, disodium salt.
8. A compound according to claim 1, namely phosphoric acid, [6-carbomethoxy-5-methyl-2-[[(3,4-dimethoxy-2- pyridinyl)methyl]sulfinyl]-1H-benzimidazole-1-yl]methyl ester, disodium salt.
9. A pharmaceutical composition containing as active ingredient a compound according to claim 1.
10. A compound as defined in claim 1 for use in therapy.
11. A compound as defined in claim 1 for use in
inhibiting gastric acid secretion in mammals including man.
12. A compound as defined in claim 1 for use in the treatment of gastrointestinal inflammatory diseases in mammals including man.
13. A method for inhibiting gastric acid secretion by administering to mammals including man a compound as defined in claim 1.
14. A method for the treatment of gastrointestinal inflammatory diseases in mammals including man by administering a compound as defined in claim 1.
15. Use of a compound according to claim 1 in the manufacture of a medicament for inhibiting gastric acid secretion in mammals including man.
16. Use of a compound according to claim 1 in the manufacture of a medicament for the treatment of
gastrointestinal infiammatory diseases in mammals
including man.
17. A process for the preparation of a compound of the formula I according to claim 1, by
a) reacting a compound of the formula II
wherein R1 and R2 are as defined under formula I and Z halogen such as CI, Br or I or a functionally equivalent group, with a compound of the formula III O
II HO-P-O Q III
I O Q wherein Q is a counter ion such as Na+, K+, Ag+ or trialkylammonium, or b) Oxidizing a compound of the formula IV
wherein R1, R2 and M have the meanings given, to give a compound of formula I.
18. A compound of the formula II
wherein R1 and R2 are as defined under formula I and Z is halogen, such as CI, Br or I or a functionally equivalent group.
19. A compound according to claim 18, wherein R1 and
R2 are as defined above and Z is CI or OH.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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SE9103776A SE9103776D0 (en) | 1991-12-19 | 1991-12-19 | NEW COMPOUNDS |
SE9103776 | 1991-12-19 | ||
PCT/SE1992/000844 WO1993012124A1 (en) | 1991-12-19 | 1992-12-08 | Substituted benzimidazoles, process for their preparation as well as their use |
Publications (2)
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AU3175293A true AU3175293A (en) | 1993-07-19 |
AU665043B2 AU665043B2 (en) | 1995-12-14 |
Family
ID=20384667
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AU31752/93A Ceased AU665043B2 (en) | 1991-12-19 | 1992-12-08 | Substituted benzimidazoles, process for their preparation as well as their use |
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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) | NO942230L (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) |
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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 |
EP1051181B1 (en) * | 1997-12-31 | 2004-03-17 | The University Of Kansas | Water soluble prodrugs of tertiary amine containing drugs and methods of making thereof |
TW200740838A (en) | 2005-07-28 | 2007-11-01 | 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 |
WO2007144362A1 (en) | 2006-06-14 | 2007-12-21 | Intervet International B.V. | 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. |
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SE8801907D0 (en) * | 1988-05-20 | 1988-05-20 | Haessle Ab | NOVEL PHARMACOLOGICAL COMPOUNDS |
SE9002206D0 (en) * | 1990-06-20 | 1990-06-20 | Haessle Ab | NEW COMPOUNDS |
HUT62882A (en) * | 1990-06-20 | 1993-06-28 | Astra Ab | Process for producing dialkoxy pyridylmethyl sulfinyl benzimidazole derivatives and pharmaceutical compositions comprising same |
-
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 EP EP93900477A patent/EP0628049A1/en not_active Withdrawn
- 1992-12-08 WO PCT/SE1992/000844 patent/WO1993012124A1/en not_active Application Discontinuation
- 1992-12-08 NZ NZ246220A patent/NZ246220A/en unknown
- 1992-12-08 CZ CZ941467A patent/CZ146794A3/en unknown
- 1992-12-08 IL IL104025A patent/IL104025A0/en unknown
- 1992-12-08 CA CA002124689A patent/CA2124689A1/en not_active Abandoned
- 1992-12-08 SK SK735-94A patent/SK73594A3/en unknown
- 1992-12-08 JP JP5510832A patent/JPH07502503A/en active Pending
- 1992-12-08 HU HU9401840A patent/HUT68270A/en unknown
- 1992-12-08 AU AU31752/93A patent/AU665043B2/en not_active Ceased
- 1992-12-08 KR KR1019940702131A patent/KR940703840A/en not_active Application Discontinuation
- 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 IS IS3960A patent/IS3960A/en unknown
- 1992-12-18 CN CN92114364A patent/CN1031827C/en not_active Expired - Fee Related
- 1992-12-18 SI SI19929200402A patent/SI9200402A/en unknown
-
1994
- 1994-06-14 NO NO942230A patent/NO942230L/en unknown
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CZ146794A3 (en) | 1996-02-14 |
MX9207269A (en) | 1993-06-01 |
ZA928836B (en) | 1993-07-05 |
WO1993012124A1 (en) | 1993-06-24 |
NO942230D0 (en) | 1994-06-14 |
MA22746A1 (en) | 1993-07-01 |
AU665043B2 (en) | 1995-12-14 |
YU101692A (en) | 1995-10-03 |
NO942230L (en) | 1994-06-14 |
CN1031827C (en) | 1996-05-22 |
TW224100B (en) | 1994-05-21 |
SI9200402A (en) | 1993-06-30 |
FI942912A (en) | 1994-06-17 |
KR940703840A (en) | 1994-12-12 |
CN1073446A (en) | 1993-06-23 |
JPH07502503A (en) | 1995-03-16 |
AP397A (en) | 1995-08-14 |
CA2124689A1 (en) | 1993-06-24 |
HRP921400A2 (en) | 1994-08-31 |
AP9200463A0 (en) | 1993-01-31 |
SE9103776D0 (en) | 1991-12-19 |
IS3960A (en) | 1993-06-20 |
EP0628049A1 (en) | 1994-12-14 |
TNSN92115A1 (en) | 1993-06-08 |
IL104025A0 (en) | 1993-05-13 |
SK73594A3 (en) | 1995-02-08 |
HUT68270A (en) | 1995-06-28 |
HU9401840D0 (en) | 1994-09-28 |
IS4079A (en) | 1993-06-20 |
NZ246220A (en) | 1996-02-27 |
FI942912A0 (en) | 1994-06-17 |
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