CA2083714A1 - Substituted benzimidazoles, process for their preparation and their pharmaceutical use - Google Patents
Substituted benzimidazoles, process for their preparation and their pharmaceutical useInfo
- Publication number
- CA2083714A1 CA2083714A1 CA002083714A CA2083714A CA2083714A1 CA 2083714 A1 CA2083714 A1 CA 2083714A1 CA 002083714 A CA002083714 A CA 002083714A CA 2083714 A CA2083714 A CA 2083714A CA 2083714 A1 CA2083714 A1 CA 2083714A1
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- Prior art keywords
- methyl
- compound
- formula
- benzimidazole
- pyridinyl
- Prior art date
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- 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
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pyridine Compounds (AREA)
Abstract
The novel compounds of formula (I), wherein R1 and R2, which are different, is each H, alkyl containing 1-4 carbon atoms or -C(O)-R6; one of R1 or R2 is always selected from the group -C(O)-R6; wherein R6 is alkyl containing 1-4 carbon atoms or alkoxy containing 1-4 carbon atoms, R3 is the group -CH2OCOOR7, wherein R7 is alkyl containing 1-6 carbon atoms or benzyl;
R4 and R5 are the same or different and selected from -CH3, -C2H5, (a), (b) and -CH2CH2OCH3, or R4 and R5 form together with the adjacent oxygen atoms attached to the pyridine ring and the carbon atoms in the pyridine ring a ring, wherein the part constituted by R4 and R5 is -CH2CH2CH2-, -CH2CH2- or -CH2- as well as pharmaceutical compositions containing such compounds as active ingredient, and the use of the compounds in medicine.
R4 and R5 are the same or different and selected from -CH3, -C2H5, (a), (b) and -CH2CH2OCH3, or R4 and R5 form together with the adjacent oxygen atoms attached to the pyridine ring and the carbon atoms in the pyridine ring a ring, wherein the part constituted by R4 and R5 is -CH2CH2CH2-, -CH2CH2- or -CH2- as well as pharmaceutical compositions containing such compounds as active ingredient, and the use of the compounds in medicine.
Description
20~37 ~ ~
WO91/19711 PCT/SE91/~15 Substituted benzimidazoles, ~rocess for their PreParation and their ~har~aceutical use D~SCRIPTION
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 n mammals including man. In a more general sense, the compou~nds of the inYention may be used for prevention and treabment o$ gastrointeætinal inflammatory diseases, and gastric acid-related disease~ in mammals including man, ~uch 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 an~ 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 ~ay be specifically mentioned are rheumatoid arthritis and gout.
The compounds may also be useful in the treatment of diseases related to bone metabolism disorders as well as '~t~71~
WO91/l9711 PCT/SE91/~15 the treatment of glaucoma. The invention also relates to pharmaceutical compositions containing the ~ompounds of the invention, as active ingredient. In a further aspect, the invention relates to processe for preparation of such S new compounds and to the use of the active comFounds for the preparation of phar~aceutical compositions for the medical use indicated above.
It is a specific primary object of the invention to provide compounds with a high level of biovailability. The compounds of the invention will also exhibit good stability properties at neutral and acidic p~ and a good potency in regard to inhi~ition of gastric acid secretion. The compounds of the invention will not bloc~
the uptake of iodine into the thyroid gland. It has ear}ier been disclosed in several }ectures from the company, where the inventors are working that thyroid toxicity depends on if the com~:ounds are lipophilic or not. The inventors have now unexpecte~ly 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, good bioavailability and stability.
Prior art and backqround of the invention 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 2~8 452, EP 221 041, EP 279 149, EP 176 308 and Der~ent 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.
WO91/19711 PCT/SE91/~15 Substituted benzimidazoles, ~rocess for their PreParation and their ~har~aceutical use D~SCRIPTION
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 n mammals including man. In a more general sense, the compou~nds of the inYention may be used for prevention and treabment o$ gastrointeætinal inflammatory diseases, and gastric acid-related disease~ in mammals including man, ~uch 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 an~ 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 ~ay be specifically mentioned are rheumatoid arthritis and gout.
The compounds may also be useful in the treatment of diseases related to bone metabolism disorders as well as '~t~71~
WO91/l9711 PCT/SE91/~15 the treatment of glaucoma. The invention also relates to pharmaceutical compositions containing the ~ompounds of the invention, as active ingredient. In a further aspect, the invention relates to processe for preparation of such S new compounds and to the use of the active comFounds for the preparation of phar~aceutical compositions for the medical use indicated above.
It is a specific primary object of the invention to provide compounds with a high level of biovailability. The compounds of the invention will also exhibit good stability properties at neutral and acidic p~ and a good potency in regard to inhi~ition of gastric acid secretion. The compounds of the invention will not bloc~
the uptake of iodine into the thyroid gland. It has ear}ier been disclosed in several }ectures from the company, where the inventors are working that thyroid toxicity depends on if the com~:ounds are lipophilic or not. The inventors have now unexpecte~ly 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, good bioavailability and stability.
Prior art and backqround of the invention 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 2~8 452, EP 221 041, EP 279 149, EP 176 308 and Der~ent 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.
2~'~37~ ~
W091/19711 PCT/SE91/~15 The invention The csmpounds of the formula I 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. It has also been found that the compounds of the following formula I show high bioavailability. Further, the compounds of the invention exhibit a high chemical stability in solution at neutral and acidic p~. The high chemical stability also at acidic pH makes the compounds useful for non-enteric coated peroral formulations.
The compounds of the invention are of the following formula I:
oR5 1 . I
~ R4 N ~ 2 wherein Rl and R2, which are different, is each H, alkyl containing 1-4 carbon atoms or -C(O)-R6, one of Rl or R2 is always selected from the group -C~O)-R6;
wherein R6 is alkyl containing 1-4 carbon atoms or alkoxy containing 1-4 carbon atoms R3 is the group -CH20CooR7~ wherein R7 is alkyl containing 1-6 carbon atoms or benzyl;
R4 and R5 are the same or different and selected from 7 ~ i~
WO91/19711 PCT/SE91/~15 3 2 5~ H2 ~ , CH2 ~ 0~ , and -CH2C~20CH3,~or R4 and R5 form together with the adjacent oxygen atoms attached t~ the pyridine ring and the carbon atoms in the pyridine ring a ring, wherein the part constituted by R4 and R5 is -CH2CH2cH2-, -CH2CH2 2 It should be understood that the expressions "alkyl" and "alkoxy" include straight and branched structures.
The structural isomers of the invention descxibed in examples 1-6 may be used separately, or in egual or unequal mixtures.
The compounds of the invention of the for~ula I have an asymmetric centre in the sulfur atom, i.e. exists as two optical isomers (enantiomers) or if they also contain one or more asymmetric carbon atoms, the compounds have two or more diastereomeric forms, each existiny in the two enantiomeric forms. Both the pure enantiomers, racemic mixtures (50% of each enan~iomer) and unequal mixtures of the two are within the scope of the present invention. It should also be understood that all the diastereomeric forms possible (pùre enantiomers or racemic mixtures) are within the scope of the invention.
Preferred groups of compounds of the formula I are:
l. Compounds, wherein R3 is -CH2OCOOCH2CH3.
2. Compounds, wherein Rl and R are selected from H, methyl or -C(O)-R6, wherein R6 is alkyl containing l-4 carbon atoms or alkoxy containing 1-4 carbon atoms.
3. Especially preferred benzimidazole structures are:
WO91/19711 2 ~, 3 ~ PCT/SEgl/~lS
o o N~COCH3 ,~ ;~CH3 J~N ~ H J~N I~OCH3 N CH3 N~3~1CIH33 ~10CH~CH~
J~
N COCH2CH~
4. Especially preferred are compounds, wherein R4 and R5 are methyl.
W091/19711 PCT/SE91/~15 The invention The csmpounds of the formula I 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. It has also been found that the compounds of the following formula I show high bioavailability. Further, the compounds of the invention exhibit a high chemical stability in solution at neutral and acidic p~. The high chemical stability also at acidic pH makes the compounds useful for non-enteric coated peroral formulations.
The compounds of the invention are of the following formula I:
oR5 1 . I
~ R4 N ~ 2 wherein Rl and R2, which are different, is each H, alkyl containing 1-4 carbon atoms or -C(O)-R6, one of Rl or R2 is always selected from the group -C~O)-R6;
wherein R6 is alkyl containing 1-4 carbon atoms or alkoxy containing 1-4 carbon atoms R3 is the group -CH20CooR7~ wherein R7 is alkyl containing 1-6 carbon atoms or benzyl;
R4 and R5 are the same or different and selected from 7 ~ i~
WO91/19711 PCT/SE91/~15 3 2 5~ H2 ~ , CH2 ~ 0~ , and -CH2C~20CH3,~or R4 and R5 form together with the adjacent oxygen atoms attached t~ the pyridine ring and the carbon atoms in the pyridine ring a ring, wherein the part constituted by R4 and R5 is -CH2CH2cH2-, -CH2CH2 2 It should be understood that the expressions "alkyl" and "alkoxy" include straight and branched structures.
The structural isomers of the invention descxibed in examples 1-6 may be used separately, or in egual or unequal mixtures.
The compounds of the invention of the for~ula I have an asymmetric centre in the sulfur atom, i.e. exists as two optical isomers (enantiomers) or if they also contain one or more asymmetric carbon atoms, the compounds have two or more diastereomeric forms, each existiny in the two enantiomeric forms. Both the pure enantiomers, racemic mixtures (50% of each enan~iomer) and unequal mixtures of the two are within the scope of the present invention. It should also be understood that all the diastereomeric forms possible (pùre enantiomers or racemic mixtures) are within the scope of the invention.
Preferred groups of compounds of the formula I are:
l. Compounds, wherein R3 is -CH2OCOOCH2CH3.
2. Compounds, wherein Rl and R are selected from H, methyl or -C(O)-R6, wherein R6 is alkyl containing l-4 carbon atoms or alkoxy containing 1-4 carbon atoms.
3. Especially preferred benzimidazole structures are:
WO91/19711 2 ~, 3 ~ PCT/SEgl/~lS
o o N~COCH3 ,~ ;~CH3 J~N ~ H J~N I~OCH3 N CH3 N~3~1CIH33 ~10CH~CH~
J~
N COCH2CH~
4. Especially preferred are compounds, wherein R4 and R5 are methyl.
5. Especially preferred specific compounds of the invention are the compounds listed in the following tabulation X~ R3 R~ . R5 CH3 C(O)OCH3 CH2Ocoo 2 3 CH3 CH3 30 C(O)OCH3 CH3 CH2OCOOCH2CH3 CH3 CH3 CH3 C(O)CH3 CH2OCOOCH2CH3 CH3 CH3 C(O)C~3 CH3 CH2ocoocH2cH3 CH3 CH3 It is believed that compounds of formula I are metabolized W091/19711 PCT/SE91/~15 into the corresponding co~pounds, wherein R3 i8 ~ before exerting their effect.
Pre~aration The compounds of the invention may be prepared according to the following methods:
a) Reacting a compound of the formula II
1 0 oR5 1 ~ H2 50 ~ ~ 2 II
wherein Rl, R2, R4 and R5 are as defi~ed under for~ula I, and 2, is either a metal cation such as Na+, R+, Li+ or Ag+
or a quaternary ammonium ion, such as tetrabutyla~onium with alkyl chloromethyl carbonate or benzyl chloromethyl carbonate.
b) Reacting a compound of the formula II, wherein Rl , R2, R4 and R5 are as defined under formula I and Z is hydroxymethyl with a compound of the formula III, X-C(o)-o-R7 III
wherein R7 is as defined above and X is Cl or imidazole or p-nitrophenoxy or a functionally equivalent group, in the presence of a suitable base such as triethylamine.
The reactions according to a) and b) are suitably carried out under protective gas in absence of water. Suitable solvents are hydrocarbons such as toluene or benzene or halogenated hydrocarbons such as methylene chloride or 2 ~ " 3 ~
~091/19711 PCT/SE91/~415 chloroform, or acetone, acetonitrile or d~methylformæmide.
The reactions may be carried out at a temperature between the ambient temperature and the boiling temperature of the reaction mixture.
c) Oxilizing a compound of the formula IV
oR5 ~ ; ~ ~ R2 IV
wherein Rl, R2, R3, R4 and R5 are as defined under formula I.
This oxidation may be carried out by u~ing an oxidizing agent such as nitric acid, hydrogen pero~ide, ~optionally in the presence of vanadium compounds), peracids, peres~ers, ozone, dinitrogentetraoxide, iodosobenzene, N-halosuccinimide, l-chlorobenzotriazole, t-butylhypochlorite, diazabicyclo-t2,2,2]-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 WO91/19711 ' ~ ; PCT/SE91/~15 solvent. In the case of racemic diastereomeric mixtures these may be separated into diastereomeric pure enantiomers by means of chromatography or ~ractional crystall~zation.
The starting materials utilized in the methods a)-c) are in some cases unknown. These unknown starting materials may, be obtained according to processes known E~
Alkyl chloromethyl carbonate and benzyl chloromethyl carbonate may be obtained from the pertinent alcohol by treatment with chloromethyl chloroformate in the presence of pyridine.
Intermediates of the formula II, wherein Z is hydroxymethyl are obtained by reaction of the corresponding benzimidazole compound carrying H in the N-l position with formaldehyde.
Starting materials of the fonmula III ~ay be obtained by known methods, e.g. from an alcoho~ HoR7 by treatment with phosgene or l,ll-carbonyldiimidazole or p-nitrophenyl chloroformate.
For clinical use a compound of the invention is formulated into pharmaceutical formulations for oral, rectal, or other modes of administration. The pharmaceutical formulation contains a compound of the invention normally 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 compound is between 0.1-95% by weight of the preparation, and between 1-50% by weight in preparations for oral administration.
In the preparation of pharmaceutical formulations containing a compound of the present invention in the form Wosl/19711 PCT/SE91/00415 of dosage units for oral admini~tration a co~pound selected may be mixed with a solid, powdered carrier, such as lactose, saccharose, sorbitol, mannitol, ~tar~h, amylopectin, cellulose derivatives, gelatin, or another suitable carrier, stabilizing substances such as alkaline compounds e.g. carbonates, hydroxides and oxides of sodium, potassium, calcium, magnesium and the like, 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 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-formi~g polymers such as celluloce acetate phthalate, hydroxypropyl-methylcellulose phthalate, partly methyl esterified methacrylic acid polymers and the like, if preferred in combination with a suitable plasticizer. To the coating various dyes may be added in order to distin~uish amon~ 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 an active compound 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, amylopection, cellulose deriva~ives or gelatine. The hard gelatine capsules may be enteric-coated as described above.
WO91/19711 2 ~ ~ 3 ~ ~ ~ ` PCT~SE91/~415 Dosa~e units for rectal administration may be prep~red in the form of suppositories which co~tain an 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 vehi~le 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 qlycol and~or polyethylene glycol. If de~ired, such liquid preparations may contain colouring agents, flavouring agents, saccharine and carboxymethyl cellulose or other thickening agents. Liguid preparations for oral administration may also be prepared in the form of a dry p~wder to be reconstituted with a suitable solvent prior to use.
The typical daily dose of the active substance 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 dosages will be in the range of 5 to 500 mg per day of active substance.
The invention is illustrated by the following examples.
~xam~le l. Preparation of 5-carbomethoxy-6-methyl-2-tt(3,4-dimethoxy-2-pyridinyl)methyl3sulfinyl]-lH-benzimidazole-l-ylmethyl ethyl carbonate and 6-carbomethoxy-5-methyl-2-7 1~
WO91/19711 PCT/SE91/~15 [[~3,4-dimethoxy-2-pyridinyl)methyl3~ulfinyl]~
benzimidazole-l-ylmethyl ethyl carbonate, as an isomeric mixture.
To a suspension of 0.45 g (1.1 mmol) of 5-carbomethoxy-6-methyl-2-~(3,4-dimethoxy-2-pyridinyl)methyl~-sulfinyl]-lH-benzimidazole and 0.25 g (1.8 mmol) of potassiu~
carbonate anhydrous in 45 ml of dry aoetonitrile, 0.21 g (1.5 mmol) of chloromethyl ethyl carbonate dissolved in 5 ml of acetonitrile was added. The reaction mixture was stirred at room temperature over night. The solvent was then removed in vacuo and the residue was diluted with methylene chloride and water. The organic solvent was dried over anhydrous sodium sulfate. Removal of the solvent in Yacuo gave the crude product, which was chromatographed with silica gel and eluted with ethyl acetate to provide 0.94 g of a yellow oil which slowly crystallized. Recrystallization with ethanol yielded 0.25 g (44 %) of the title compounds a~
an isomeric mixture.
NMR data for the products are given below.
Exam~le 2. Preparation of 6-carbomethoxy-5-methyl-2-~[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-lH-benzimidazole-1-ylmethyl ethyl ~arbonate.
The title compound was obtained by crystallizing the isomeric mixture given in example 1 from ethanol.
NMR data are given below.
Exam~le 3. Preparation of 5-acetyl-6-methyl-2-t[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-lH-benzimidazole-1-ylmethyl ethyl carbonate and 6-acetyl-5-methyl-2-lt(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl~-lH-benzimidazole-1-yl~ethyl ethyl carbonate, as an isomeric mLxture.
To a magnetically stirred suspension of potassium carbonate 20~7~ 1 WO91/19711 PCT/SE91/~15 anhydrous (O.48 g, 3.47 mmol) in 80 ml of dry acetonitr~le 0.80 g (2.14 mmol) of 5-acetyl-6-methyl-2-~ E (3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-lH-benzimidazole and 0.39 g (2.8 mmol) of chloromethyl ethyl carbonate dissolved in 10 ml of acetonitrile was added dropwise. Stirring was continued at room temperature for 20 hours. The solvent was removed in vacuo, the residue diluted with methylene chloride, the methylene chloride solution washed with water and dried over anhydrous sodium sulfate. Removal of the solvent in vacuo gave the crude product which was chromatographed with silica gel and eluted with ethyl acetate to yield 0.63 g of an almost white crystalline solide. The product was recrystallized frGm ethyl acetate to give 0.50 g (49 %) of the title compounds as an isomeric mixture.
NMR data for the products are given below.
kxamPle 4. Preparation of 5-acetyl-6-methyl-2-[[(3,4-dimethoxy-2-pyridinyl~methyl]sulfinyl~_lH_benzimidazole-1-ylmethyl ethyl carbonate.
The title compound was isolated from the isomeric mixturegiven in example 3 by chromatography on a silica column with methylene chloride - acetonitrile ~ratio 6:4) as eluent. The title compound was crystallized from ethanol.
NMR data are given below.
ExamPle 5. Preparation of 6-acetyl-5-methyl-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-lH-benzimidazole-1-ylmethyl ethyl carbonate.
The title compound was isolated from the isomeric mixturegiven in example 3 by chromatography on a silica column with methylene chloride-acetonitrile (ratio 6:4) as eluent. The title compound was crystallized from ethanol.
NMR data are given below.
2Q837~ l~
~O91/19711 PCT/SE91/~15 ExamDle 6 Preparation of 5-carbethoxy-2-[[(3,~-dimetho~y-2-pyridinyl)methyl]sulfinyl]-lH-benzimidazole-1-yl~ethyl ethyl carbonate and 6-carbethozy-2-t[(3,4-dimethoxy-2-pyridinyl)methyl]s~lfinyl~-lH-benzimidazole-l-ylmethyl ethyl carbonate, as an isomeric mtxture.
To a suspension of 0.28 g (0.72 mmol) 5-carbethoxy-2-~t(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl~-l_ benzimida~ole and 0.16 g tl.2 mmol) anhydrous potassium carbonate in 20 ~1 of dry acetonitrile 0.16 g (1.2 mmol) chloromethyl ethyl carbonate dissolved in 2 ml dry acetonitri~e was added. The mixture was stirred at ambient temperature over night. The solvent was evaporated off and the crude product was chromatographed on a silica column using ethyl acetate as eluent. Crystallizing fr~m ethanol gave the title compounds as an isomeric mixture, (0.13 g, 37%).
NMR data for the products are given below.
Table 1 Ex. Solvent NMR data ~ P~m 1 CDC13 1.20-1.30 (m, 3H), 2.70 (s,1.8H), (300 MHz) 2.75 (s, 1.2H), 3.85-3.95 (m,9H), 4.15-4.25 (m,2H), 4.85-5.05 (m,2H), 6.40-6.55 (m,2H), 6.75 (d,lH), 7.45 (s, 0.6H), 7.65 (s, 0.4 H), 8.10 (d, lH), 8.20 (s, 0.4 H), 8.40 (s, 0.6 H).
2 CDCl3 1.30 (t, 3H), 2.70 (s, 3H) (300 MHz) 3.90 (s,3H), 3.90 (s, 3H), 3.95 (s, 3H), 4.25 (g, 2H), 4.95 (d, lH), 5.05 (d, lH), 6.50 (m, 2H), 6.75 (d, lH), 7.65 (s, lH), 8.10 (d, lH), 8.20 (s, 2 Q ~ 3 ~
WO91~19711 PCT/SE91/~15 lH) 3 CDC13 1.30 (t, 3H) 2.60-2.70 (m, 6~), (300 MHz) 3.85-3.90 (m, 6H), 4.25 (g,2H), 4.85-5.05 (m, 2H), 6.75 (d,lH), 7.45 (s, 0.7 H), 7.60 (s, 0.3H), 8.05 (s, 0.3H), 8.10 (d, lK), 8~20 (s, a.7H) 4 CDC13 1.30 (t, 3H), 2.60 (s, 3~), 2.70 (300 MHz) (s, 3H), 3.90 (8, 3H), 3.90 (s, 3H), 4.20 (g, 2H), 4.90 ~d, lH), 5.05 (d, lH), 6.50 (m, 2H), 6.80 (d, lH), 7.50 (s, lH), 8.15 (d, lH), 8.20 (s, lH) CDCl3 1.30 (t, 3H), 2.60 (~, 3H), 2.70 ~300 MHz) (s, 3H), 3.90 (s, 3H), 3.90 (s, 3 - H), 4.25 (q, 2~), 4.90 (d, 1~), 5.05 (d, lH), 6.55 Im, 2H), 6.80 (d, lH), 7.60 (s, lH), 8.05 (s, 1 H~, 8.15 (d, lH) 6 CDC13 1.30 (m, 3H), 1.45 (m, 3H), 3.90 (300 MHz) (s, 3H), 3.90 (s, 3~), 4.25 (m, 2H), 4.45 (m, 2H), 5.00 (m, 2H), 6.55 (m, 2H), 6.80 (d, lH), 7.70 (d, 0.55H), 7.80 (d, 0.45H), 8.10 (m, 2H), 8.35 (s, 0,45H), 8.50 (d, 0.55H).
2~3~ ~
091/19711 PCT/SE91/~15 Preparation of intRr~edi~tes ~xamDle I l S Preparation of 5-carbomethosy-6-Eethyl-2-[[(3,~-dimethosy-2-~.idinyl)~ethyl]thio]-l~-benz~oidazole 5-carbomethoxy-6-methyl-2-mercapto-lH-benzimida~ole ~0.67 g, 0.003 mol) and NaOH (0.12 g, 0.003 mol) in H2O (0.6 ml) were dissolved in CH30H (l5 ml). 3,4-dimethoxy-2-chloromethylpyIidine hydrochloride, (=0.0036 mol) as a crude material in CH3OH (l0 ml) and NaOH (0.144 g, 0.0036 mol) in H2O ~0.72 ml) were added. The mixture was heated to reflux and the reflux was continued for 1 hour. CH30H was lS evaporated off and the crude material was purified by chromatography on a silica column using C~2Cl2-CH3OH (98-2) as eluent, giving 1l.03 g, 92%) of the pure title compound.
NMR data are given below.
ExamDle I 2 Preparation of 5-carbomethQxy-6-~ethyl-2-tt(3,~-dimetko~y-2-pyridinyl)methyl]~lf ~ l1-lH-benzi~ida~ole 5-carbomethoxy-6-methyl-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]thio]-lH-benzimidazole (1.03 g, 0.00276 mol) was dissolved in CH2Cl2 (30 ml). NaHCO3 (0.46 g, 0.0055 mol) in H2O (l0 ml) was added and the mixture was cooled ~o 12C. m-chloroperbenzoic acid 69.5% (0.62 g, 0.0025 mol) dissolved in CH2Cl2 (5 ml) was added dropwise under stirring. Stirrin~ was continued at +2C for 15 min.
After separation the organic layer was extracted with an aqueous 0.2 M NaOH solution (3x15 ml, 0.009 mol). After separation the aqueous solutions were combined and neutralized wi~h methyl formate (0.56 ml, 0.009 mol) in the S ~
WO9~/19711 PCT/SE91/~415 presence of CH2C12 (25 ml). After separation the organic layer was dried over ~a2S04 and evaporated under reduced pressure. The residue was crystallized from CH3CN (l0 ml) giving the title compound (0.68 g, 70 %).
NMR data are given below.
Exam~le I 3 Preparation of 5-acetvl-6-~sthyl-2- U(3,4-di~etho ~-2-Rqridinyl)methYl]thio]-l~-beD~idaz~le 5-acetyl-6-~ethyl-2-mercapto-lH-benzimidazo}e (4.2 g, 20 mmol) and NaOH (0.8 g, 20 mmol) in H20 (l ml) were dissolved in 60 ml ethanol. 3,4-dimethoxy-2-chloromethylpyridine hydrochloride (z17 mmol) as a crude material was added and the mixture was heated to boiling. NaOH (0.7 g, 17 mmol) in H20 (1 m}) was added and the reflux was continued for 6 hours. The solvent was evaporated off and the residue was diluted with methylene chloride and water. The organic phase was dried over Na2SO4 and the solvent was removed under reduced pressure. Crystallizing from acetonitrile gave the title compound, ~3.75 g, 62%).
NMR data are given below.
Example I 4 Pre~aration of 5-acetYl-6-~ethyl-2-[1(3,4-dimethQ~y-2-Pqridi~yllmetbYl1sulfinvll-lff-ben~IEida~ole 5-acetyl-6-methyl-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]thio3-lH-benzimidazole (3.75 g, l0 mmol) was dissolved in CH2Cl2 (70 ml). NaHCO3 (1.76 g, 21 mmol) in H2O (25 ml) was added and the mixture was cooled to -+3C.
m-Chloroperbenzoic acid 69.5~ (2.43 5, 9.8 mmol) dissolved 2~37'~
WO91/19711 PCT/SE91/~15 in CH2C12 (20 ~l) was added dropwi~e under stirring.
Stirring was continued for l0 min. The phases were separat~d and the organic ~hase was dried over Na2SO4 and evaporated under reduced pressure. The residue was crystallized from CH3CN giving the title compound (2.25 g, 60%).
NMR data are given below.
Example I 5 Preparation of 5-carbetho~y-2-lt(3~4-di~etho~y-2 pyridinyl)meth~l]thiol- y-benzieida~ole 5-carbethoxy-2-mercapto-l~-benzimidazole (2.0 9, 9 mmol) and NaOH (0.36 g, 9 mmol) in H2O (l ml) were dissolved in ethanol (30 ml). 3,4-dimethoxy-2-chloromethylpyridine hydrochloride ( 6.6 mmol) as a crude material were added and the mixture was heated to boilin~. ~aO~ (0.26 g, 6.6 ~mol) in H20 (l ml) was added and the reflux was continued for 6 hours. The solvent was evaporated off and the residue was diluted with methylene chloride and water. The organic phase was dried over Na2SO4 and the solvent removed under reduced pressure. Crystallizing from CH3CN gave the desired product ~1.75 ~, 71 %).
NMR data are given below.
Exam~le I 6 Prepæration of 5~ betbo~y-2-[t(3r~-di~etho~y-2-pyridinyl)~ethyl]s~lfi~yl]-la-benzi~idazole 5-carbethoxy-2-[~(3,4-dLmethoxy-2-py~idinyl)methyl~thio]-l~-benzimidazole (95.2% pure) (1.4 g, 0.0036 mol) was dissolved in CH2C12 (30 ml). Na~C03 (0.6 g, 0.0072 mol in H2O (l0 ml) was added and the mixture was cooled to +2C.
~0~7~
WO91/19711 PCT/SE91/~15 m-Chloroperbenzoic acid 69.5 % (0.87 g, 0.0035 mol) dissolved in CH2C12 (5 ~1) was added dropwise under stirring. Stirring was continued at +2C for 10 min. The phases were separated and the organic phase was dried over Na2S04 and evaporated under reduced pressure. The residue was crystallized from CH3CN (15 ml ) giving the title compound (0.76 g, 54 %).
NMR data are given below.
Table 2 Ex Solvent NMR data ~ pPm 15 I 1 CDC13 2.70 (s, 3H), 3.95 ~s, 3H), ~300 MHz) 3.95 (s, 3~), 4.00 (s, 3H), 4.40 (s, 2H~, 6.90 (d, 1~), 7.35 (s, lH), 8.23 (s, lH), 8.25 (d,lH).
I 2 CDCl3 2.70 (s, 3H), 3.85 (s, 3H), (500 MHz) 3.90 (s, 3H), 3.95 (s, 3H), 4.70 (d, lH), 4.90 (d, lH), 6.8 (d, lH), 7.30 (b, lH), 8.20 - (d, lH), 8.35 (b, lH).
I 3 CDC13 2.60 (s, 3H), 2.65 (s, 3H), 3.90 (300 MHz) (s, 3H), 3.90 (s, 3H), 4.35 (s, 2H) 6.85 (d, lH), 7.25 (s,0.6H), 7.40 (s, 0.4H), 7.85 (s, 0.4H), 8.05 (s, 0.6H), 8.30 (m, lH) I 4 CDC13 2.60 (s, 6H), 3.85 (s, 3H), 3.85 (300 MHz) (s, 3H), 4.70 (d, lH), 4.90 (d, lH), 6.80 (d, lH), 7.30 (b, lH), 8.15 (d, lH), 8.20 (b, lH) ~ V ~
WO91/19711 PCT/SE91/~415 I 5 CDCl3 1.40 (m, 3H), 3.90 (s, 3H), 3.90 (300 MHz) (s, 3H), 4.40 ~m, 4H), 6.90 (dd, lH), 7.45 (d, 0.4H), 7.60 (d, 0.6H), 7.90 (m, lH), 8.20 (s, 0.6H), 8.25 (m, lH), 8.25 (s, 0.4H) lO I 6 CDCl3 1.45 (t, 3H), 3.8S (s, 3H), (300 MHz) 3.90 (s, 3H), 4.40 (g, 2H), 4.65 (d, lH), 4.40 (d, lH), 6.80 (d, lH), 7.50 7.80 (b, lH) 8.05 (d, lH), 8.20 (d, lH), 8.25, 8.55 (b, lH) The best mode of carrying o~t the invention known at present is to use the compound mixture according to Bxan~le 3 and the compound according to ~xample 4.
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A syrup containing 1% (weight per volume) of active substance was prepared from the following ingredients:
A compound according to Example 4 l.0 g Sugar, powder 30.0 g Saccharine 0.6 g Glycerol 5.0 g lO Tween l.0 g Flavouring agent 0.05 g Ethanol 96% 5.0 g Distilled water g.s. to a final volume of lO0 ml A solution of the compound mixture according to Example in ethanol and Tween was prepared. Sugar and saccharine were dissolved in 60 g of warm water. After cooling the solution of 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 lO0 ml.
Tablets A tablet containing 50 mg of active compound was prepared from the following ingredients:
I Compound mixture according to Example 3 500 g Lactose 700 g Methyl cellulose 6 g Polyvinylpyrrolidone cross-linked50 g Magnesium stearate 15 g Sodium carbonate 6 g Distilled water q.s.
2~3'7 ~
WO91/19711 PCT/SE91/~15 II Hydroxypropyl methylcellulose 36 g Polyethylene glyco l9 g Colour Titanium dioxide 4 g Purified water 313 g I Compound mixture according to ~xample 3, powder, was mixed with lactose and granulated with a water solution of methyl cellulose and sodium carbonate. The wet ~RSS 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 (lO 000 tablets), each tablet containing 50 mg of active substance, in a tabletting machine using 7 mm diameter punches.
II A solution of hydroxypropyl methylcellulose and polyethylene glycol in puIified water was prepared. After dispersion of titaniu~ dioxide the solution was sprayed onto the tablets I in an Accela cotaR, Manesty coating eguipment. A final tablet weight of 125 mg was obtained.
Ca~sules Capsules containing 30 mg of active compound were prepared from the following ingredients:
A compound according to Example 4 300 g Lactose 700 g 30 Microcrystalline cellulose 40 g Hydroxypropyl cellulose low-substituted 62 ~
Purified water q.s.
The active compound mixture was mixed with the dry ingredients and granulated with a solution of disodium 2~3'~
WO91/19711 PCT/SE91/~15 hydrogen phoæphate. The wet mass was forced through an extruder and spheronized and dried in a fluidi~ed bed dryer.
500 g of the pellets above were first coated with a solution of hydroxypropyl methylcellulose, 30 9, in water, 600 g, using a fluidized bed coater. After drying, the pellets were coated with a second coating as given below:
Coating solution:
Hydroxypropyl methylcellulose phthalate 70 g Cetyl alcohol 4 g Acetone 600 g Ethanol 200 g The final coated pellets were filled into capsules.
Su~Dositories Suppositories were prepared from the following ingredients using a welding procedure. Each suppository contained 40 mg of active compound.
Compound ~ixture a~cording to Example 4 4 g Witepsol ~-15 180 g The active compound mixture was homogenously mixed with Witepsol H-15 at a temperature of 41C. 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.
~ ~ 3 ~
WO91/19711 PCT/SE91/~M15 Bioloaical Effects Biovailabilitv Bioavailability, is assessed by calculating the quotient between the areas under plasma concentration (AUC) curve of a compound of the formula I wherein R3 is hydrogen (herein defined as compound A), following l) intraduodenal (id) or oral (po) administration of the corresponding compound according to the invention and 2) intravenous (iv) administration of compound A, from the rat and the dog. Low, therapeutically relevant doses, were used. Data are provided in Table 4.
Potency for inhibition of acid secretion The potency for inhibition of acid secretion is measured in the female rat orally and in the dog both intraduodenally and orally.
Potency data are provided in Table 4.
Effects on the u~take of iodine into the thvroid qland.
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 l25I in the thyroid gland of the corresponding compound of the formula I, wherein R3 is hydrogen, that is a metabolized compound of the formula I.
Bioloqical Tests Inhibition of Gastric Acid Secretion in the Conscious Female Rat.
~837 ~ ~1 WO91/19711 PCT/SE91/~15 Female rats of the Sprague-Dawley strain are used. They are equipped with cannulated fistulae in the ~tomach (lumen), for collection of gastric secretions. A fourteen days recovery period after surgery is allowed before testin~ is commenced.
Before secretory tests, the animals are deprived of food but not water for 20 h. The stomach is repeatedly washed through the gastric cannula, and 6 ml of Ringer-Glucose given s.c. Acid secretion is stLmulated with infusion during 2.5 h (1.2 ml/h, s.c.) of pentagastrin and carbachol (20 and 1~0 nmol~kg h, respectively), during which time gastric secretions are collected in 30-min fractions. Test substances or vehicle are given orally 120 min before starting the stimulation, in a volu~e of 5 ml/kg. Gastric jui~e samples are titrated to p~ 7.0 with NaOH, 0.1 mol/L, and acid output is calculated as the product of titrant volume and concentration. Further calculations are based on group mean responses from 4-7 rats. Percentage inhibition is calculated from absolute rates of acid output. ED50- values are obtained from graphical interpolation on log dose-response curves, or estimated from single-dose experiments ~ss-~;ng a si~;lar slope for all dose-response curves. The results are based on gastric acid secretion during the third hour after drug/vehicle administration.
Bioavailability in the Male Rat.
Male adult rats of the Sprague-Dawley strain were used.
One day, prior to the experiments, all rats were prepared by cannulation of the left carotid artery under anaesthesia. The rats used for the intravenous experiments, were also cannulated in the jugular vein.
2 ~
WO91/19711 PCT/SE91/~15 (~ef. V Popovic and P Popovic, J Appl Physiol 1960;15,727-728). The rats used for the intraduodenal experi~ents, were also cannulated in the upper part of the duodenum.
The cannulas were exteriorized at the nape of the neck.
The rats were housed individually after surgery and were deprived of food, but not water, before administration of the test substances. The same dose (4 ~mol/kg) were given iv and id as a bolus for about one minute (2 ml/kg).
Blood samples (0.l-0.4 g) were drawn repeatedly from the carotid artery at intervals up to 4 hours after given dose. The samples were frozen as soon as po~sible until analysis of the test compound.
The area under the blood concentration vs time curve, AUC, for the compound A, determined by the linear trapezoidal rule and extrapolated to infinity ~y dividing the last determined blood concentration by the eliminatio~ rate constant in the terminal phaæe. The systemic bioavailability (F%) of the compound A following intraduodenal administration of compounds of the invention of formula I was calculated as AUC(ComPUnd A)id(~ompound of the invention) F(%) = x lO0 AUC(ComPUnd A)iv(compound A) Inhibition of Gastric Acid Secretion and Bioavailability in the Conscious Dog Harrier-dogs of either sex were used. They were equipped with a duodenal fistula for the administration of test compounds or vehicle and a cannulated gastric fistula or a Heidenhain-pouch for the collection of gastric secretions.
~ ~`35 ~
WO91/19711 PCT/SE91/~15 Before secretory tests the animals were fasted for about 18 h but water was freely allowed. Gastric acid secretion was stimulated by a 4 h infusion of histamine dihydrochloride (12 ml/h) at a dose producing about 80% of the individual maximal secretory response, and gastric juice collected in consecutive 30-min fractions. Test substance or vehicle waæ given orally, id or iv 1 h after starting the histamine in~usion, in a volume of 0.5 ml/kg body weight. In the case of oral administration, it should be pointed out that the test compound is administered to the acid secreting main stomach of the Heidenhain-pouch dog.
The acidity of the gastric juice samples were determined by titration to pH 7.0, and the acid output calculated.
The acid ou~put in the collection periods after administration of test substance or vehicle were expressed as fractional responses, setting the acid output in the fraction preceding administration to lØ
Per~entage inhibition was calculated from fractional responses elicited by test com~ound and vehicle. EDSo~
values were obtained by graphical interpolation on log dose - response curves, or estimated from single-dose experiments under the assumption of the same slope of the dose-response curve for all test compounds. All results reported are based on acid output 2 h after dosing.
Blood samples for the analysis of test compound concentration in plasma were taken at intervals up to 3 h after dosing. Plasma was separated and frozen within 30 min after collection and later analyzed. AUC (area under the plasma concentration - time curve) frsm time zero to 3 h after dose for compou~d A, was calculated by the linear trapezoidal rule. The systemic bioavailability (F%) of the f l l compound A after oral or id admini~tr~tion of compound~ of the invention was calculated as described above in the rat model.
~ffect on t~e accumulation of 125I in the thyToid ~land 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 tPH 9) methocel, were administerd by oral gavage in a volumc of 5 ml/kg body weight.`After 1 hour, 125I (300kBq/ky, 3ml/kg) was administered by intrapexitoneal 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 (LgB-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. ~he statistical significanoe 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.
Chemical Stabilitv The chemical stability of the compounds of the invention has been followed kinetically at low concentration at 37C in aqueous buffer solution at different pH values.
The results in Table 5 show the half life (t 1/2) at p~ 7, that is the time period after which half the amount of the ~ ~ ~ 3 1 ~ 1 Wosl/19711 PCT/SE91/~
original compound romains unchanged, and ~10% at p~ 2, that is the time period ~fter which 10% of t~e origtn~l compound has decompoEed.
Results of biological and stabilitY tests Table 4 and 5 give a summary of the te~t data available for the compounds of the invention.
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Table 5, Stability Data Test compound Chemical Example No. stability at t 1/2 (h) t 10% (h) 879.S
2 506.5 3 517.5 4 82 1~
Pre~aration The compounds of the invention may be prepared according to the following methods:
a) Reacting a compound of the formula II
1 0 oR5 1 ~ H2 50 ~ ~ 2 II
wherein Rl, R2, R4 and R5 are as defi~ed under for~ula I, and 2, is either a metal cation such as Na+, R+, Li+ or Ag+
or a quaternary ammonium ion, such as tetrabutyla~onium with alkyl chloromethyl carbonate or benzyl chloromethyl carbonate.
b) Reacting a compound of the formula II, wherein Rl , R2, R4 and R5 are as defined under formula I and Z is hydroxymethyl with a compound of the formula III, X-C(o)-o-R7 III
wherein R7 is as defined above and X is Cl or imidazole or p-nitrophenoxy or a functionally equivalent group, in the presence of a suitable base such as triethylamine.
The reactions according to a) and b) are suitably carried out under protective gas in absence of water. Suitable solvents are hydrocarbons such as toluene or benzene or halogenated hydrocarbons such as methylene chloride or 2 ~ " 3 ~
~091/19711 PCT/SE91/~415 chloroform, or acetone, acetonitrile or d~methylformæmide.
The reactions may be carried out at a temperature between the ambient temperature and the boiling temperature of the reaction mixture.
c) Oxilizing a compound of the formula IV
oR5 ~ ; ~ ~ R2 IV
wherein Rl, R2, R3, R4 and R5 are as defined under formula I.
This oxidation may be carried out by u~ing an oxidizing agent such as nitric acid, hydrogen pero~ide, ~optionally in the presence of vanadium compounds), peracids, peres~ers, ozone, dinitrogentetraoxide, iodosobenzene, N-halosuccinimide, l-chlorobenzotriazole, t-butylhypochlorite, diazabicyclo-t2,2,2]-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 WO91/19711 ' ~ ; PCT/SE91/~15 solvent. In the case of racemic diastereomeric mixtures these may be separated into diastereomeric pure enantiomers by means of chromatography or ~ractional crystall~zation.
The starting materials utilized in the methods a)-c) are in some cases unknown. These unknown starting materials may, be obtained according to processes known E~
Alkyl chloromethyl carbonate and benzyl chloromethyl carbonate may be obtained from the pertinent alcohol by treatment with chloromethyl chloroformate in the presence of pyridine.
Intermediates of the formula II, wherein Z is hydroxymethyl are obtained by reaction of the corresponding benzimidazole compound carrying H in the N-l position with formaldehyde.
Starting materials of the fonmula III ~ay be obtained by known methods, e.g. from an alcoho~ HoR7 by treatment with phosgene or l,ll-carbonyldiimidazole or p-nitrophenyl chloroformate.
For clinical use a compound of the invention is formulated into pharmaceutical formulations for oral, rectal, or other modes of administration. The pharmaceutical formulation contains a compound of the invention normally 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 compound is between 0.1-95% by weight of the preparation, and between 1-50% by weight in preparations for oral administration.
In the preparation of pharmaceutical formulations containing a compound of the present invention in the form Wosl/19711 PCT/SE91/00415 of dosage units for oral admini~tration a co~pound selected may be mixed with a solid, powdered carrier, such as lactose, saccharose, sorbitol, mannitol, ~tar~h, amylopectin, cellulose derivatives, gelatin, or another suitable carrier, stabilizing substances such as alkaline compounds e.g. carbonates, hydroxides and oxides of sodium, potassium, calcium, magnesium and the like, 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 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-formi~g polymers such as celluloce acetate phthalate, hydroxypropyl-methylcellulose phthalate, partly methyl esterified methacrylic acid polymers and the like, if preferred in combination with a suitable plasticizer. To the coating various dyes may be added in order to distin~uish amon~ 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 an active compound 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, amylopection, cellulose deriva~ives or gelatine. The hard gelatine capsules may be enteric-coated as described above.
WO91/19711 2 ~ ~ 3 ~ ~ ~ ` PCT~SE91/~415 Dosa~e units for rectal administration may be prep~red in the form of suppositories which co~tain an 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 vehi~le 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 qlycol and~or polyethylene glycol. If de~ired, such liquid preparations may contain colouring agents, flavouring agents, saccharine and carboxymethyl cellulose or other thickening agents. Liguid preparations for oral administration may also be prepared in the form of a dry p~wder to be reconstituted with a suitable solvent prior to use.
The typical daily dose of the active substance 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 dosages will be in the range of 5 to 500 mg per day of active substance.
The invention is illustrated by the following examples.
~xam~le l. Preparation of 5-carbomethoxy-6-methyl-2-tt(3,4-dimethoxy-2-pyridinyl)methyl3sulfinyl]-lH-benzimidazole-l-ylmethyl ethyl carbonate and 6-carbomethoxy-5-methyl-2-7 1~
WO91/19711 PCT/SE91/~15 [[~3,4-dimethoxy-2-pyridinyl)methyl3~ulfinyl]~
benzimidazole-l-ylmethyl ethyl carbonate, as an isomeric mixture.
To a suspension of 0.45 g (1.1 mmol) of 5-carbomethoxy-6-methyl-2-~(3,4-dimethoxy-2-pyridinyl)methyl~-sulfinyl]-lH-benzimidazole and 0.25 g (1.8 mmol) of potassiu~
carbonate anhydrous in 45 ml of dry aoetonitrile, 0.21 g (1.5 mmol) of chloromethyl ethyl carbonate dissolved in 5 ml of acetonitrile was added. The reaction mixture was stirred at room temperature over night. The solvent was then removed in vacuo and the residue was diluted with methylene chloride and water. The organic solvent was dried over anhydrous sodium sulfate. Removal of the solvent in Yacuo gave the crude product, which was chromatographed with silica gel and eluted with ethyl acetate to provide 0.94 g of a yellow oil which slowly crystallized. Recrystallization with ethanol yielded 0.25 g (44 %) of the title compounds a~
an isomeric mixture.
NMR data for the products are given below.
Exam~le 2. Preparation of 6-carbomethoxy-5-methyl-2-~[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-lH-benzimidazole-1-ylmethyl ethyl ~arbonate.
The title compound was obtained by crystallizing the isomeric mixture given in example 1 from ethanol.
NMR data are given below.
Exam~le 3. Preparation of 5-acetyl-6-methyl-2-t[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-lH-benzimidazole-1-ylmethyl ethyl carbonate and 6-acetyl-5-methyl-2-lt(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl~-lH-benzimidazole-1-yl~ethyl ethyl carbonate, as an isomeric mLxture.
To a magnetically stirred suspension of potassium carbonate 20~7~ 1 WO91/19711 PCT/SE91/~15 anhydrous (O.48 g, 3.47 mmol) in 80 ml of dry acetonitr~le 0.80 g (2.14 mmol) of 5-acetyl-6-methyl-2-~ E (3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-lH-benzimidazole and 0.39 g (2.8 mmol) of chloromethyl ethyl carbonate dissolved in 10 ml of acetonitrile was added dropwise. Stirring was continued at room temperature for 20 hours. The solvent was removed in vacuo, the residue diluted with methylene chloride, the methylene chloride solution washed with water and dried over anhydrous sodium sulfate. Removal of the solvent in vacuo gave the crude product which was chromatographed with silica gel and eluted with ethyl acetate to yield 0.63 g of an almost white crystalline solide. The product was recrystallized frGm ethyl acetate to give 0.50 g (49 %) of the title compounds as an isomeric mixture.
NMR data for the products are given below.
kxamPle 4. Preparation of 5-acetyl-6-methyl-2-[[(3,4-dimethoxy-2-pyridinyl~methyl]sulfinyl~_lH_benzimidazole-1-ylmethyl ethyl carbonate.
The title compound was isolated from the isomeric mixturegiven in example 3 by chromatography on a silica column with methylene chloride - acetonitrile ~ratio 6:4) as eluent. The title compound was crystallized from ethanol.
NMR data are given below.
ExamPle 5. Preparation of 6-acetyl-5-methyl-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-lH-benzimidazole-1-ylmethyl ethyl carbonate.
The title compound was isolated from the isomeric mixturegiven in example 3 by chromatography on a silica column with methylene chloride-acetonitrile (ratio 6:4) as eluent. The title compound was crystallized from ethanol.
NMR data are given below.
2Q837~ l~
~O91/19711 PCT/SE91/~15 ExamDle 6 Preparation of 5-carbethoxy-2-[[(3,~-dimetho~y-2-pyridinyl)methyl]sulfinyl]-lH-benzimidazole-1-yl~ethyl ethyl carbonate and 6-carbethozy-2-t[(3,4-dimethoxy-2-pyridinyl)methyl]s~lfinyl~-lH-benzimidazole-l-ylmethyl ethyl carbonate, as an isomeric mtxture.
To a suspension of 0.28 g (0.72 mmol) 5-carbethoxy-2-~t(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl~-l_ benzimida~ole and 0.16 g tl.2 mmol) anhydrous potassium carbonate in 20 ~1 of dry acetonitrile 0.16 g (1.2 mmol) chloromethyl ethyl carbonate dissolved in 2 ml dry acetonitri~e was added. The mixture was stirred at ambient temperature over night. The solvent was evaporated off and the crude product was chromatographed on a silica column using ethyl acetate as eluent. Crystallizing fr~m ethanol gave the title compounds as an isomeric mixture, (0.13 g, 37%).
NMR data for the products are given below.
Table 1 Ex. Solvent NMR data ~ P~m 1 CDC13 1.20-1.30 (m, 3H), 2.70 (s,1.8H), (300 MHz) 2.75 (s, 1.2H), 3.85-3.95 (m,9H), 4.15-4.25 (m,2H), 4.85-5.05 (m,2H), 6.40-6.55 (m,2H), 6.75 (d,lH), 7.45 (s, 0.6H), 7.65 (s, 0.4 H), 8.10 (d, lH), 8.20 (s, 0.4 H), 8.40 (s, 0.6 H).
2 CDCl3 1.30 (t, 3H), 2.70 (s, 3H) (300 MHz) 3.90 (s,3H), 3.90 (s, 3H), 3.95 (s, 3H), 4.25 (g, 2H), 4.95 (d, lH), 5.05 (d, lH), 6.50 (m, 2H), 6.75 (d, lH), 7.65 (s, lH), 8.10 (d, lH), 8.20 (s, 2 Q ~ 3 ~
WO91~19711 PCT/SE91/~15 lH) 3 CDC13 1.30 (t, 3H) 2.60-2.70 (m, 6~), (300 MHz) 3.85-3.90 (m, 6H), 4.25 (g,2H), 4.85-5.05 (m, 2H), 6.75 (d,lH), 7.45 (s, 0.7 H), 7.60 (s, 0.3H), 8.05 (s, 0.3H), 8.10 (d, lK), 8~20 (s, a.7H) 4 CDC13 1.30 (t, 3H), 2.60 (s, 3~), 2.70 (300 MHz) (s, 3H), 3.90 (8, 3H), 3.90 (s, 3H), 4.20 (g, 2H), 4.90 ~d, lH), 5.05 (d, lH), 6.50 (m, 2H), 6.80 (d, lH), 7.50 (s, lH), 8.15 (d, lH), 8.20 (s, lH) CDCl3 1.30 (t, 3H), 2.60 (~, 3H), 2.70 ~300 MHz) (s, 3H), 3.90 (s, 3H), 3.90 (s, 3 - H), 4.25 (q, 2~), 4.90 (d, 1~), 5.05 (d, lH), 6.55 Im, 2H), 6.80 (d, lH), 7.60 (s, lH), 8.05 (s, 1 H~, 8.15 (d, lH) 6 CDC13 1.30 (m, 3H), 1.45 (m, 3H), 3.90 (300 MHz) (s, 3H), 3.90 (s, 3~), 4.25 (m, 2H), 4.45 (m, 2H), 5.00 (m, 2H), 6.55 (m, 2H), 6.80 (d, lH), 7.70 (d, 0.55H), 7.80 (d, 0.45H), 8.10 (m, 2H), 8.35 (s, 0,45H), 8.50 (d, 0.55H).
2~3~ ~
091/19711 PCT/SE91/~15 Preparation of intRr~edi~tes ~xamDle I l S Preparation of 5-carbomethosy-6-Eethyl-2-[[(3,~-dimethosy-2-~.idinyl)~ethyl]thio]-l~-benz~oidazole 5-carbomethoxy-6-methyl-2-mercapto-lH-benzimida~ole ~0.67 g, 0.003 mol) and NaOH (0.12 g, 0.003 mol) in H2O (0.6 ml) were dissolved in CH30H (l5 ml). 3,4-dimethoxy-2-chloromethylpyIidine hydrochloride, (=0.0036 mol) as a crude material in CH3OH (l0 ml) and NaOH (0.144 g, 0.0036 mol) in H2O ~0.72 ml) were added. The mixture was heated to reflux and the reflux was continued for 1 hour. CH30H was lS evaporated off and the crude material was purified by chromatography on a silica column using C~2Cl2-CH3OH (98-2) as eluent, giving 1l.03 g, 92%) of the pure title compound.
NMR data are given below.
ExamDle I 2 Preparation of 5-carbomethQxy-6-~ethyl-2-tt(3,~-dimetko~y-2-pyridinyl)methyl]~lf ~ l1-lH-benzi~ida~ole 5-carbomethoxy-6-methyl-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]thio]-lH-benzimidazole (1.03 g, 0.00276 mol) was dissolved in CH2Cl2 (30 ml). NaHCO3 (0.46 g, 0.0055 mol) in H2O (l0 ml) was added and the mixture was cooled ~o 12C. m-chloroperbenzoic acid 69.5% (0.62 g, 0.0025 mol) dissolved in CH2Cl2 (5 ml) was added dropwise under stirring. Stirrin~ was continued at +2C for 15 min.
After separation the organic layer was extracted with an aqueous 0.2 M NaOH solution (3x15 ml, 0.009 mol). After separation the aqueous solutions were combined and neutralized wi~h methyl formate (0.56 ml, 0.009 mol) in the S ~
WO9~/19711 PCT/SE91/~415 presence of CH2C12 (25 ml). After separation the organic layer was dried over ~a2S04 and evaporated under reduced pressure. The residue was crystallized from CH3CN (l0 ml) giving the title compound (0.68 g, 70 %).
NMR data are given below.
Exam~le I 3 Preparation of 5-acetvl-6-~sthyl-2- U(3,4-di~etho ~-2-Rqridinyl)methYl]thio]-l~-beD~idaz~le 5-acetyl-6-~ethyl-2-mercapto-lH-benzimidazo}e (4.2 g, 20 mmol) and NaOH (0.8 g, 20 mmol) in H20 (l ml) were dissolved in 60 ml ethanol. 3,4-dimethoxy-2-chloromethylpyridine hydrochloride (z17 mmol) as a crude material was added and the mixture was heated to boiling. NaOH (0.7 g, 17 mmol) in H20 (1 m}) was added and the reflux was continued for 6 hours. The solvent was evaporated off and the residue was diluted with methylene chloride and water. The organic phase was dried over Na2SO4 and the solvent was removed under reduced pressure. Crystallizing from acetonitrile gave the title compound, ~3.75 g, 62%).
NMR data are given below.
Example I 4 Pre~aration of 5-acetYl-6-~ethyl-2-[1(3,4-dimethQ~y-2-Pqridi~yllmetbYl1sulfinvll-lff-ben~IEida~ole 5-acetyl-6-methyl-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]thio3-lH-benzimidazole (3.75 g, l0 mmol) was dissolved in CH2Cl2 (70 ml). NaHCO3 (1.76 g, 21 mmol) in H2O (25 ml) was added and the mixture was cooled to -+3C.
m-Chloroperbenzoic acid 69.5~ (2.43 5, 9.8 mmol) dissolved 2~37'~
WO91/19711 PCT/SE91/~15 in CH2C12 (20 ~l) was added dropwi~e under stirring.
Stirring was continued for l0 min. The phases were separat~d and the organic ~hase was dried over Na2SO4 and evaporated under reduced pressure. The residue was crystallized from CH3CN giving the title compound (2.25 g, 60%).
NMR data are given below.
Example I 5 Preparation of 5-carbetho~y-2-lt(3~4-di~etho~y-2 pyridinyl)meth~l]thiol- y-benzieida~ole 5-carbethoxy-2-mercapto-l~-benzimidazole (2.0 9, 9 mmol) and NaOH (0.36 g, 9 mmol) in H2O (l ml) were dissolved in ethanol (30 ml). 3,4-dimethoxy-2-chloromethylpyridine hydrochloride ( 6.6 mmol) as a crude material were added and the mixture was heated to boilin~. ~aO~ (0.26 g, 6.6 ~mol) in H20 (l ml) was added and the reflux was continued for 6 hours. The solvent was evaporated off and the residue was diluted with methylene chloride and water. The organic phase was dried over Na2SO4 and the solvent removed under reduced pressure. Crystallizing from CH3CN gave the desired product ~1.75 ~, 71 %).
NMR data are given below.
Exam~le I 6 Prepæration of 5~ betbo~y-2-[t(3r~-di~etho~y-2-pyridinyl)~ethyl]s~lfi~yl]-la-benzi~idazole 5-carbethoxy-2-[~(3,4-dLmethoxy-2-py~idinyl)methyl~thio]-l~-benzimidazole (95.2% pure) (1.4 g, 0.0036 mol) was dissolved in CH2C12 (30 ml). Na~C03 (0.6 g, 0.0072 mol in H2O (l0 ml) was added and the mixture was cooled to +2C.
~0~7~
WO91/19711 PCT/SE91/~15 m-Chloroperbenzoic acid 69.5 % (0.87 g, 0.0035 mol) dissolved in CH2C12 (5 ~1) was added dropwise under stirring. Stirring was continued at +2C for 10 min. The phases were separated and the organic phase was dried over Na2S04 and evaporated under reduced pressure. The residue was crystallized from CH3CN (15 ml ) giving the title compound (0.76 g, 54 %).
NMR data are given below.
Table 2 Ex Solvent NMR data ~ pPm 15 I 1 CDC13 2.70 (s, 3H), 3.95 ~s, 3H), ~300 MHz) 3.95 (s, 3~), 4.00 (s, 3H), 4.40 (s, 2H~, 6.90 (d, 1~), 7.35 (s, lH), 8.23 (s, lH), 8.25 (d,lH).
I 2 CDCl3 2.70 (s, 3H), 3.85 (s, 3H), (500 MHz) 3.90 (s, 3H), 3.95 (s, 3H), 4.70 (d, lH), 4.90 (d, lH), 6.8 (d, lH), 7.30 (b, lH), 8.20 - (d, lH), 8.35 (b, lH).
I 3 CDC13 2.60 (s, 3H), 2.65 (s, 3H), 3.90 (300 MHz) (s, 3H), 3.90 (s, 3H), 4.35 (s, 2H) 6.85 (d, lH), 7.25 (s,0.6H), 7.40 (s, 0.4H), 7.85 (s, 0.4H), 8.05 (s, 0.6H), 8.30 (m, lH) I 4 CDC13 2.60 (s, 6H), 3.85 (s, 3H), 3.85 (300 MHz) (s, 3H), 4.70 (d, lH), 4.90 (d, lH), 6.80 (d, lH), 7.30 (b, lH), 8.15 (d, lH), 8.20 (b, lH) ~ V ~
WO91/19711 PCT/SE91/~415 I 5 CDCl3 1.40 (m, 3H), 3.90 (s, 3H), 3.90 (300 MHz) (s, 3H), 4.40 ~m, 4H), 6.90 (dd, lH), 7.45 (d, 0.4H), 7.60 (d, 0.6H), 7.90 (m, lH), 8.20 (s, 0.6H), 8.25 (m, lH), 8.25 (s, 0.4H) lO I 6 CDCl3 1.45 (t, 3H), 3.8S (s, 3H), (300 MHz) 3.90 (s, 3H), 4.40 (g, 2H), 4.65 (d, lH), 4.40 (d, lH), 6.80 (d, lH), 7.50 7.80 (b, lH) 8.05 (d, lH), 8.20 (d, lH), 8.25, 8.55 (b, lH) The best mode of carrying o~t the invention known at present is to use the compound mixture according to Bxan~le 3 and the compound according to ~xample 4.
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A syrup containing 1% (weight per volume) of active substance was prepared from the following ingredients:
A compound according to Example 4 l.0 g Sugar, powder 30.0 g Saccharine 0.6 g Glycerol 5.0 g lO Tween l.0 g Flavouring agent 0.05 g Ethanol 96% 5.0 g Distilled water g.s. to a final volume of lO0 ml A solution of the compound mixture according to Example in ethanol and Tween was prepared. Sugar and saccharine were dissolved in 60 g of warm water. After cooling the solution of 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 lO0 ml.
Tablets A tablet containing 50 mg of active compound was prepared from the following ingredients:
I Compound mixture according to Example 3 500 g Lactose 700 g Methyl cellulose 6 g Polyvinylpyrrolidone cross-linked50 g Magnesium stearate 15 g Sodium carbonate 6 g Distilled water q.s.
2~3'7 ~
WO91/19711 PCT/SE91/~15 II Hydroxypropyl methylcellulose 36 g Polyethylene glyco l9 g Colour Titanium dioxide 4 g Purified water 313 g I Compound mixture according to ~xample 3, powder, was mixed with lactose and granulated with a water solution of methyl cellulose and sodium carbonate. The wet ~RSS 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 (lO 000 tablets), each tablet containing 50 mg of active substance, in a tabletting machine using 7 mm diameter punches.
II A solution of hydroxypropyl methylcellulose and polyethylene glycol in puIified water was prepared. After dispersion of titaniu~ dioxide the solution was sprayed onto the tablets I in an Accela cotaR, Manesty coating eguipment. A final tablet weight of 125 mg was obtained.
Ca~sules Capsules containing 30 mg of active compound were prepared from the following ingredients:
A compound according to Example 4 300 g Lactose 700 g 30 Microcrystalline cellulose 40 g Hydroxypropyl cellulose low-substituted 62 ~
Purified water q.s.
The active compound mixture was mixed with the dry ingredients and granulated with a solution of disodium 2~3'~
WO91/19711 PCT/SE91/~15 hydrogen phoæphate. The wet mass was forced through an extruder and spheronized and dried in a fluidi~ed bed dryer.
500 g of the pellets above were first coated with a solution of hydroxypropyl methylcellulose, 30 9, in water, 600 g, using a fluidized bed coater. After drying, the pellets were coated with a second coating as given below:
Coating solution:
Hydroxypropyl methylcellulose phthalate 70 g Cetyl alcohol 4 g Acetone 600 g Ethanol 200 g The final coated pellets were filled into capsules.
Su~Dositories Suppositories were prepared from the following ingredients using a welding procedure. Each suppository contained 40 mg of active compound.
Compound ~ixture a~cording to Example 4 4 g Witepsol ~-15 180 g The active compound mixture was homogenously mixed with Witepsol H-15 at a temperature of 41C. 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.
~ ~ 3 ~
WO91/19711 PCT/SE91/~M15 Bioloaical Effects Biovailabilitv Bioavailability, is assessed by calculating the quotient between the areas under plasma concentration (AUC) curve of a compound of the formula I wherein R3 is hydrogen (herein defined as compound A), following l) intraduodenal (id) or oral (po) administration of the corresponding compound according to the invention and 2) intravenous (iv) administration of compound A, from the rat and the dog. Low, therapeutically relevant doses, were used. Data are provided in Table 4.
Potency for inhibition of acid secretion The potency for inhibition of acid secretion is measured in the female rat orally and in the dog both intraduodenally and orally.
Potency data are provided in Table 4.
Effects on the u~take of iodine into the thvroid qland.
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 l25I in the thyroid gland of the corresponding compound of the formula I, wherein R3 is hydrogen, that is a metabolized compound of the formula I.
Bioloqical Tests Inhibition of Gastric Acid Secretion in the Conscious Female Rat.
~837 ~ ~1 WO91/19711 PCT/SE91/~15 Female rats of the Sprague-Dawley strain are used. They are equipped with cannulated fistulae in the ~tomach (lumen), for collection of gastric secretions. A fourteen days recovery period after surgery is allowed before testin~ is commenced.
Before secretory tests, the animals are deprived of food but not water for 20 h. The stomach is repeatedly washed through the gastric cannula, and 6 ml of Ringer-Glucose given s.c. Acid secretion is stLmulated with infusion during 2.5 h (1.2 ml/h, s.c.) of pentagastrin and carbachol (20 and 1~0 nmol~kg h, respectively), during which time gastric secretions are collected in 30-min fractions. Test substances or vehicle are given orally 120 min before starting the stimulation, in a volu~e of 5 ml/kg. Gastric jui~e samples are titrated to p~ 7.0 with NaOH, 0.1 mol/L, and acid output is calculated as the product of titrant volume and concentration. Further calculations are based on group mean responses from 4-7 rats. Percentage inhibition is calculated from absolute rates of acid output. ED50- values are obtained from graphical interpolation on log dose-response curves, or estimated from single-dose experiments ~ss-~;ng a si~;lar slope for all dose-response curves. The results are based on gastric acid secretion during the third hour after drug/vehicle administration.
Bioavailability in the Male Rat.
Male adult rats of the Sprague-Dawley strain were used.
One day, prior to the experiments, all rats were prepared by cannulation of the left carotid artery under anaesthesia. The rats used for the intravenous experiments, were also cannulated in the jugular vein.
2 ~
WO91/19711 PCT/SE91/~15 (~ef. V Popovic and P Popovic, J Appl Physiol 1960;15,727-728). The rats used for the intraduodenal experi~ents, were also cannulated in the upper part of the duodenum.
The cannulas were exteriorized at the nape of the neck.
The rats were housed individually after surgery and were deprived of food, but not water, before administration of the test substances. The same dose (4 ~mol/kg) were given iv and id as a bolus for about one minute (2 ml/kg).
Blood samples (0.l-0.4 g) were drawn repeatedly from the carotid artery at intervals up to 4 hours after given dose. The samples were frozen as soon as po~sible until analysis of the test compound.
The area under the blood concentration vs time curve, AUC, for the compound A, determined by the linear trapezoidal rule and extrapolated to infinity ~y dividing the last determined blood concentration by the eliminatio~ rate constant in the terminal phaæe. The systemic bioavailability (F%) of the compound A following intraduodenal administration of compounds of the invention of formula I was calculated as AUC(ComPUnd A)id(~ompound of the invention) F(%) = x lO0 AUC(ComPUnd A)iv(compound A) Inhibition of Gastric Acid Secretion and Bioavailability in the Conscious Dog Harrier-dogs of either sex were used. They were equipped with a duodenal fistula for the administration of test compounds or vehicle and a cannulated gastric fistula or a Heidenhain-pouch for the collection of gastric secretions.
~ ~`35 ~
WO91/19711 PCT/SE91/~15 Before secretory tests the animals were fasted for about 18 h but water was freely allowed. Gastric acid secretion was stimulated by a 4 h infusion of histamine dihydrochloride (12 ml/h) at a dose producing about 80% of the individual maximal secretory response, and gastric juice collected in consecutive 30-min fractions. Test substance or vehicle waæ given orally, id or iv 1 h after starting the histamine in~usion, in a volume of 0.5 ml/kg body weight. In the case of oral administration, it should be pointed out that the test compound is administered to the acid secreting main stomach of the Heidenhain-pouch dog.
The acidity of the gastric juice samples were determined by titration to pH 7.0, and the acid output calculated.
The acid ou~put in the collection periods after administration of test substance or vehicle were expressed as fractional responses, setting the acid output in the fraction preceding administration to lØ
Per~entage inhibition was calculated from fractional responses elicited by test com~ound and vehicle. EDSo~
values were obtained by graphical interpolation on log dose - response curves, or estimated from single-dose experiments under the assumption of the same slope of the dose-response curve for all test compounds. All results reported are based on acid output 2 h after dosing.
Blood samples for the analysis of test compound concentration in plasma were taken at intervals up to 3 h after dosing. Plasma was separated and frozen within 30 min after collection and later analyzed. AUC (area under the plasma concentration - time curve) frsm time zero to 3 h after dose for compou~d A, was calculated by the linear trapezoidal rule. The systemic bioavailability (F%) of the f l l compound A after oral or id admini~tr~tion of compound~ of the invention was calculated as described above in the rat model.
~ffect on t~e accumulation of 125I in the thyToid ~land 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 tPH 9) methocel, were administerd by oral gavage in a volumc of 5 ml/kg body weight.`After 1 hour, 125I (300kBq/ky, 3ml/kg) was administered by intrapexitoneal 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 (LgB-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. ~he statistical significanoe 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.
Chemical Stabilitv The chemical stability of the compounds of the invention has been followed kinetically at low concentration at 37C in aqueous buffer solution at different pH values.
The results in Table 5 show the half life (t 1/2) at p~ 7, that is the time period after which half the amount of the ~ ~ ~ 3 1 ~ 1 Wosl/19711 PCT/SE91/~
original compound romains unchanged, and ~10% at p~ 2, that is the time period ~fter which 10% of t~e origtn~l compound has decompoEed.
Results of biological and stabilitY tests Table 4 and 5 give a summary of the te~t data available for the compounds of the invention.
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~o ~ ~ O ~s I I~n q ~c E~J' a~ c o .4 R R R ~ a~
.rl O ~ O Ul C.e ~ ~n N ~ R
~a~
c c U a~
I
E~ E~ X
WO 91/19711 2 9 ~ 3 'i' i ~i PCr/SE91/004lS
Table 5, Stability Data Test compound Chemical Example No. stability at t 1/2 (h) t 10% (h) 879.S
2 506.5 3 517.5 4 82 1~
Claims (18)
1. Compounds of the formula I
wherein R1 and R2, which are different, is each H, alkyl containing 1-4 carbon atoms or -C(O)-R6; one of R1 or R2 is always selected from the group -C(O)-R6;
wherein R6 is alkyl containing 1-4 carbon atoms or alkoxy containing 1-4 carbon atoms, R3 is the group -CH2OCOOR7, wherein R7 is alkyl containing 1-6 carbon atoms or benzyl;
R4 and R5 are the same or different and selected from -CH3, -C2H5, , and -CH2CH2OCH3, or R4 and R5 form together with the adjacent oxygen atoms attached to the pyridine ring and the carbon atoms in the pyridine ring a ring, wherein the part constituted by R4 and R5 is -CH2CH2 -CH2-, -CH2CH2- or -CH2-.
wherein R1 and R2, which are different, is each H, alkyl containing 1-4 carbon atoms or -C(O)-R6; one of R1 or R2 is always selected from the group -C(O)-R6;
wherein R6 is alkyl containing 1-4 carbon atoms or alkoxy containing 1-4 carbon atoms, R3 is the group -CH2OCOOR7, wherein R7 is alkyl containing 1-6 carbon atoms or benzyl;
R4 and R5 are the same or different and selected from -CH3, -C2H5, , and -CH2CH2OCH3, or R4 and R5 form together with the adjacent oxygen atoms attached to the pyridine ring and the carbon atoms in the pyridine ring a ring, wherein the part constituted by R4 and R5 is -CH2CH2 -CH2-, -CH2CH2- or -CH2-.
2. Compounds according to formula I of claim 1, namely a mixture of 5-carbomethoxy-6-methyl-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole-1-ylmethyl ethyl carbonate and 6-carbomethoxy-5-methyl-2-[](3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-H-benzimidazole-1-ylmethyl ethyl carbonate.
3. Compounds according to formula I of claim 1, namely mixture of 5-acetyl-6-methyl-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole-1-ylmethyl ethyl carbonate and 6-acetyl-5-methyl-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole-1-ylmethyl ethyl carbonate.
4. A compound according to claim 1, namely 5-carbomethoxy-6-methyl-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole-1-ylmethyl ethyl carbonate.
5. A compound according to claim 1, namely 6-carbomethoxy-5-methyl-2-[[(3,4-dimethoxy-2-pyridinyl) methyl]sulfinyl]-1H-benzimidazole-1-ylmethyl ethyl carbonate.
6. A compound according to claim 1, namely 5-acetyl-6-methyl-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole-1-ylmethyl ethyl carbonate.
7. A compound according to claim 1, namely 6-acetyl-5-methyl-2-[[(3,4-dimethoxy-2-pyridinyl)-methyl]sufinyl]-1H-benzimidazole-1-ylmethyl ethyl carbonate.
8. A compound according to claim 1, wherein R3 is the group CH2OCOOCH2CH3.
9. A compound according to claim 1, wherein R1 and R2 is each H, methyl or -C(O)R6, wherein R6 is alkyl containing 1-4 carbon atoms or alkoxy containing 1-4 carbon atoms.
10. A pharmaceutical composition containing as active ingredient a compound according to claim 1.
11. A compound as defined in claim 1 for use in therapy.
12. A compound as defined in claim 1 for use in inhibiting gastric acid secretion in mammals including man.
13. A compound as defined in claim 1 for use in the treatment of gastrointestinal inflammatory deseases in mammals including man.
14. A method for inhibiting gastric acid secretion by administering to mammals including man a compound as defined in claim 1.
15. A method for the treatment of gastrointestinal infammatory diseases in mammals including man by administering a compound as defined in claim 1.
16. Use of a compound according to claim 1 in the manufacture of a medicament for inhibiting gastric acid secretion in mammals including man.
17. Use of a compound according to claim 1 in the manufacture of a medicament for the treatment of gastrointestinal inflammatory diseases in mammals including man.
18. 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
II
wherein R1, R2, R4 and R5 are as defined under formula I and Z is either a metal cation such as Na+, R+, Li+ or Ag+ or a quaternary ammonium ion, such as tetrabutylammonium with alkyl chloromethyl carbonate or benzyl chloromethyl carbonate or;
b) reacting a compound of the formula II, wherein R1, R2, R4 and R5 are as defined under formula I and Z is hydroxymethyl with a compound of the formula III
X-C(O)-O-R7 wherein R is as defined above and X is Cl or imidazole or p-nitrophenoxy or a functionally equivalent group in the presence of a suitable base such as triethylamine or;
c) oxidizing a compound of the formula IV
wherein R1, R2, R3, R4 and R5 are as defined under formula I.
II
wherein R1, R2, R4 and R5 are as defined under formula I and Z is either a metal cation such as Na+, R+, Li+ or Ag+ or a quaternary ammonium ion, such as tetrabutylammonium with alkyl chloromethyl carbonate or benzyl chloromethyl carbonate or;
b) reacting a compound of the formula II, wherein R1, R2, R4 and R5 are as defined under formula I and Z is hydroxymethyl with a compound of the formula III
X-C(O)-O-R7 wherein R is as defined above and X is Cl or imidazole or p-nitrophenoxy or a functionally equivalent group in the presence of a suitable base such as triethylamine or;
c) oxidizing a compound of the formula IV
wherein R1, R2, R3, R4 and R5 are as defined under formula I.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE9002206-2 | 1990-06-20 | ||
| SE9002206A SE9002206D0 (en) | 1990-06-20 | 1990-06-20 | NEW COMPOUNDS |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2083714A1 true CA2083714A1 (en) | 1991-12-21 |
Family
ID=20379831
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002083714A Abandoned CA2083714A1 (en) | 1990-06-20 | 1991-06-11 | Substituted benzimidazoles, process for their preparation and their pharmaceutical use |
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| Country | Link |
|---|---|
| EP (1) | EP0535081A1 (en) |
| JP (1) | JPH05507713A (en) |
| CN (1) | CN1058212A (en) |
| AP (1) | AP215A (en) |
| AU (1) | AU649453B2 (en) |
| CA (1) | CA2083714A1 (en) |
| CZ (1) | CZ279772B6 (en) |
| FI (1) | FI925766A0 (en) |
| HU (1) | HUT62881A (en) |
| IE (1) | IE912025A1 (en) |
| IL (1) | IL98470A0 (en) |
| IS (1) | IS3721A7 (en) |
| LT (2) | LT3952B (en) |
| LV (1) | LV10953A (en) |
| MA (1) | MA22199A1 (en) |
| NO (1) | NO924775L (en) |
| NZ (1) | NZ238546A (en) |
| OA (1) | OA09682A (en) |
| PT (1) | PT98035A (en) |
| RO (1) | RO110493B1 (en) |
| SE (1) | SE9002206D0 (en) |
| TN (1) | TNSN91049A1 (en) |
| TW (1) | TW216418B (en) |
| WO (1) | WO1991019711A1 (en) |
| YU (1) | YU104191A (en) |
| ZA (2) | ZA914297B (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| SE9002043D0 (en) * | 1990-06-07 | 1990-06-07 | Astra Ab | IMPROVED METHOD FOR SYNTHESIS |
| SE9103776D0 (en) * | 1991-12-19 | 1991-12-19 | Astra Ab | NEW COMPOUNDS |
| IS4232A (en) * | 1993-12-06 | 1995-06-07 | Astra Aktiebolag | Substituted benzimidazole, its methods of manufacture and pharmacological use |
| SE9500422D0 (en) * | 1995-02-06 | 1995-02-06 | Astra Ab | New oral pharmaceutical dosage forms |
| SE9500478D0 (en) * | 1995-02-09 | 1995-02-09 | Astra Ab | New pharmaceutical formulation and process |
| SE9600070D0 (en) | 1996-01-08 | 1996-01-08 | Astra Ab | New oral pharmaceutical dosage forms |
| MXPA02008232A (en) | 2000-02-24 | 2004-04-05 | Kopran Res Lab Ltd | Orally administrable acid stable anti ulcer benzimidazole derivatives. |
| SE0101379D0 (en) | 2001-04-18 | 2001-04-18 | Diabact Ab | Composition that inhibits gastric acid secretion |
| US8206741B2 (en) | 2001-06-01 | 2012-06-26 | Pozen Inc. | Pharmaceutical compositions for the coordinated delivery of NSAIDs |
| WO2003084518A2 (en) | 2002-04-09 | 2003-10-16 | Flamel Technologies | Oral suspension of active principle microcapsules |
| SE0203065D0 (en) | 2002-10-16 | 2002-10-16 | Diabact Ab | Gastric acid secretion inhibiting composition |
| CA2540308C (en) | 2003-09-26 | 2013-08-06 | Alza Corporation | Drug coating providing high drug loading and methods for providing the same |
| TW200606163A (en) | 2004-04-22 | 2006-02-16 | Eisai Co Ltd | Imidazopyridine compound |
| US8541026B2 (en) | 2004-09-24 | 2013-09-24 | Abbvie Inc. | Sustained release formulations of opioid and nonopioid analgesics |
| US20070015782A1 (en) | 2005-04-15 | 2007-01-18 | Eisai Co., Ltd. | Benzimidazole compound |
| US9040564B2 (en) | 2005-04-28 | 2015-05-26 | Eisai R&D Management Co., Ltd. | Stabilized composition |
| US7803817B2 (en) | 2005-05-11 | 2010-09-28 | Vecta, Ltd. | Composition and methods for inhibiting gastric acid secretion |
| US7981908B2 (en) | 2005-05-11 | 2011-07-19 | Vecta, Ltd. | Compositions and methods for inhibiting gastric acid secretion |
| WO2007122686A1 (en) * | 2006-04-14 | 2007-11-01 | Eisai R & D Management Co., Ltd. | Benzimidazole compounds |
| PL2046334T3 (en) | 2006-07-25 | 2015-02-27 | Vecta Ltd | Compositions and meth0ds for inhibiting gastric acide secretion using derivatives of small dicarboxylic acids in combination with ppi |
| EP2065379A4 (en) * | 2006-10-13 | 2011-01-19 | Eisai R&D Man Co Ltd | Benzimidazole compound having gastric acid secretion inhibitory activity |
| AU2009290712A1 (en) | 2008-09-09 | 2010-03-18 | Astrazeneca Ab | Method for delivering a pharmaceutical composition to patient in need thereof |
| CA2764963C (en) | 2009-06-25 | 2016-11-01 | Astrazeneca Ab | Method for treating a patient at risk for developing an nsaid-associated ulcer |
| WO2011080500A2 (en) | 2009-12-29 | 2011-07-07 | Orexo Ab | New pharmaceutical dosage form for the treatment of gastric acid-related disorders |
| WO2011080502A2 (en) | 2009-12-29 | 2011-07-07 | Orexo Ab | New pharmaceutical dosage form for the treatment of gastric acid-related disorders |
| WO2011080501A2 (en) | 2009-12-29 | 2011-07-07 | Orexo Ab | New pharmaceutical dosage form for the treatment of gastric acid-related disorders |
| EP2601947A1 (en) | 2011-12-05 | 2013-06-12 | Abo Bakr Mohammed Ali Al-Mehdar | Fixed-dose combination for treatment of helicobacter pylori associated diseases |
| CA2860231A1 (en) | 2011-12-28 | 2013-07-04 | Pozen Inc. | Improved compositions and methods for delivery of omeprazole plus acetylsalicylic acid |
| EP3512840B1 (en) * | 2016-09-14 | 2024-03-06 | Yufeng Jane Tseng | Novel substituted benzimidazole derivatives as d-amino acid oxidase (daao) inhibitors |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SE418966B (en) | 1974-02-18 | 1981-07-06 | Haessle Ab | ANALOGY PROCEDURE FOR THE PREPARATION OF COMPOUNDS WITH Gastric Acid Secretion Inhibitory Effects |
| SE416649B (en) | 1974-05-16 | 1981-01-26 | Haessle Ab | PROCEDURE FOR THE PREPARATION OF SUBSTANCES WHICH PREVENT Gastric acid secretion |
| IN148930B (en) | 1977-09-19 | 1981-07-25 | Hoffmann La Roche | |
| SE7804231L (en) | 1978-04-14 | 1979-10-15 | Haessle Ab | Gastric acid secretion |
| US4359465A (en) | 1980-07-28 | 1982-11-16 | The Upjohn Company | Methods for treating gastrointestinal inflammation |
| CH644116A5 (en) | 1980-08-21 | 1984-07-13 | Hoffmann La Roche | IMIDAZOLE DERIVATIVES. |
| SE8300736D0 (en) | 1983-02-11 | 1983-02-11 | Haessle Ab | NOVEL PHARMACOLOGICALLY ACTIVE COMPOUNDS |
| SE8301182D0 (en) | 1983-03-04 | 1983-03-04 | Haessle Ab | NOVEL COMPOUNDS |
| IL75400A (en) * | 1984-06-16 | 1988-10-31 | Byk Gulden Lomberg Chem Fab | Dialkoxypyridine methyl(sulfinyl or sulfonyl)benzimidazoles,processes for the preparation thereof and pharmaceutical compositions containing the same |
| AU568441B2 (en) * | 1984-09-24 | 1987-12-24 | Upjohn Company, The | 2-(pyridylalkenesulfinyl) benzimidazole derivatives |
| IL76839A (en) * | 1984-10-31 | 1988-08-31 | Byk Gulden Lomberg Chem Fab | Picoline derivatives,processes for the preparation thereof and pharmaceutical compositions containing the same |
| US4738975A (en) | 1985-07-02 | 1988-04-19 | Takeda Chemical Industries, Ltd. | Pyridine derivatives, and use as anti-ulcer agents |
| SE8505112D0 (en) * | 1985-10-29 | 1985-10-29 | Haessle Ab | NOVEL PHARMACOLOGICAL COMPOUNDS |
| NZ234564A (en) | 1986-11-21 | 1991-04-26 | Haessle Ab | 1-substituted benzimidazoles and pharmaceutical compositions |
| DE3722810A1 (en) * | 1987-07-10 | 1989-01-19 | Hoechst Ag | SUBSTITUTED BENZIMIDAZOLES, METHOD FOR THE PRODUCTION THEREOF, THE PHARMACEUTICAL PREPARATIONS CONTAINING THEM AND THE USE THEREOF |
| WO1989003830A1 (en) * | 1987-10-30 | 1989-05-05 | Aktiebolaget Hässle | 2-pyridinylmethyl (sulfinyl or thio)benzimidazoles for treatment of diseases related to bone loss |
| WO1989005299A1 (en) * | 1987-12-11 | 1989-06-15 | Byk Gulden Lomberg Chemische Fabrik Gmbh | Novel benzimidazole derivatives |
| JPH03504497A (en) * | 1988-05-25 | 1991-10-03 | ビイク グルデン ロンベルク ヒエーミツシエ フアブリーク ゲゼルシヤフト ミツト ベシユレンクテル ハフツング | New fluoroalkoxy compound |
-
1990
- 1990-06-20 SE SE9002206A patent/SE9002206D0/en unknown
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1991
- 1991-06-05 ZA ZA914297A patent/ZA914297B/en unknown
- 1991-06-05 ZA ZA914296A patent/ZA914296B/en unknown
- 1991-06-11 CA CA002083714A patent/CA2083714A1/en not_active Abandoned
- 1991-06-11 HU HU924033A patent/HUT62881A/en unknown
- 1991-06-11 RO RO92-01581A patent/RO110493B1/en unknown
- 1991-06-11 WO PCT/SE1991/000415 patent/WO1991019711A1/en not_active Application Discontinuation
- 1991-06-11 EP EP91911659A patent/EP0535081A1/en not_active Withdrawn
- 1991-06-11 JP JP91511435A patent/JPH05507713A/en active Pending
- 1991-06-11 AU AU80097/91A patent/AU649453B2/en not_active Ceased
- 1991-06-12 YU YU104191A patent/YU104191A/en unknown
- 1991-06-12 IL IL98470A patent/IL98470A0/en unknown
- 1991-06-12 TW TW080104582A patent/TW216418B/zh active
- 1991-06-14 IE IE202591A patent/IE912025A1/en unknown
- 1991-06-14 NZ NZ238546A patent/NZ238546A/en unknown
- 1991-06-18 MA MA22462A patent/MA22199A1/en unknown
- 1991-06-19 PT PT98035A patent/PT98035A/en not_active Application Discontinuation
- 1991-06-19 TN TNTNSN91049A patent/TNSN91049A1/en unknown
- 1991-06-19 AP APAP/P/1991/000285A patent/AP215A/en active
- 1991-06-20 IS IS3721A patent/IS3721A7/en unknown
- 1991-06-20 CN CN91105024A patent/CN1058212A/en active Pending
- 1991-06-20 CZ CS911894A patent/CZ279772B6/en unknown
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1992
- 1992-11-27 OA OA60306A patent/OA09682A/en unknown
- 1992-12-10 NO NO92924775A patent/NO924775L/en unknown
- 1992-12-18 FI FI925766A patent/FI925766A0/en not_active Application Discontinuation
-
1993
- 1993-08-27 LV LV931045A patent/LV10953A/en unknown
- 1993-12-30 LT LTIP1712A patent/LT3952B/en not_active IP Right Cessation
- 1993-12-30 LT LTIP1713A patent/LT3977B/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| IE912025A1 (en) | 1992-01-01 |
| CN1058212A (en) | 1992-01-29 |
| YU104191A (en) | 1994-01-20 |
| NO924775D0 (en) | 1992-12-10 |
| OA09682A (en) | 1993-05-15 |
| CZ279772B6 (en) | 1995-06-14 |
| SE9002206D0 (en) | 1990-06-20 |
| AP215A (en) | 1992-09-02 |
| LT3952B (en) | 1996-05-27 |
| NO924775L (en) | 1992-12-10 |
| RO110493B1 (en) | 1996-01-30 |
| IS3721A7 (en) | 1991-12-21 |
| ZA914297B (en) | 1992-03-25 |
| MA22199A1 (en) | 1992-04-01 |
| TW216418B (en) | 1993-11-21 |
| FI925766A (en) | 1992-12-18 |
| IL98470A0 (en) | 1992-07-15 |
| TNSN91049A1 (en) | 1992-10-25 |
| JPH05507713A (en) | 1993-11-04 |
| LV10953A (en) | 1995-12-20 |
| AU8009791A (en) | 1992-01-07 |
| HUT62881A (en) | 1993-06-28 |
| NZ238546A (en) | 1994-03-25 |
| PT98035A (en) | 1992-03-31 |
| FI925766A0 (en) | 1992-12-18 |
| LTIP1713A (en) | 1995-08-25 |
| ZA914296B (en) | 1992-03-25 |
| HU9204033D0 (en) | 1993-03-29 |
| EP0535081A1 (en) | 1993-04-07 |
| AP9100285A0 (en) | 1991-07-31 |
| WO1991019711A1 (en) | 1991-12-26 |
| LT3977B (en) | 1996-06-25 |
| AU649453B2 (en) | 1994-05-26 |
| LTIP1712A (en) | 1995-08-25 |
| CS189491A3 (en) | 1992-04-15 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued |