EP0535081A1 - Substituted benzimidazoles, process for their preparation and their pharmaceutical use - Google Patents

Substituted benzimidazoles, process for their preparation and their pharmaceutical use

Info

Publication number
EP0535081A1
EP0535081A1 EP91911659A EP91911659A EP0535081A1 EP 0535081 A1 EP0535081 A1 EP 0535081A1 EP 91911659 A EP91911659 A EP 91911659A EP 91911659 A EP91911659 A EP 91911659A EP 0535081 A1 EP0535081 A1 EP 0535081A1
Authority
EP
European Patent Office
Prior art keywords
methyl
compound
formula
pyridinyl
dimethoxy
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP91911659A
Other languages
German (de)
English (en)
French (fr)
Inventor
Arne Elof BRÄNDSTRÖM
Per Lennart Lindberg
Gunnel Elisabeth Sund N
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
AstraZeneca AB
Original Assignee
Astra AB
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Astra AB filed Critical Astra AB
Publication of EP0535081A1 publication Critical patent/EP0535081A1/en
Withdrawn legal-status Critical Current

Links

Classifications

    • 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

Definitions

  • the object of the present invention is to provide novel compounds, which inhibit exogenously or endogenously stimulated gastric acid secretion and thus can be used in the prevention and treatment of peptic ulcer.
  • the present invention also relates to the use of the compounds of the invention for inhibiting gastric acid secretion in mammals including man.
  • the compounds of the invention may be used for prevention and treatment of gastrointestinal inflammatory diseases, and gastric acid-related diseases in mammals including man, such as gastritis, gastric ulcer, duodenal ulcer, reflux esophagitis, and Zollinger-Ellison syndrome.
  • 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
  • the compounds of the invention may also be used for treatment or prophylaxis of inflammatory disorders
  • the invention also relates to pharmaceutical compositions containing the compounds of the invention, as active ingredient. In a further aspect, the invention relates to processes for preparation of such new compounds and to the use of the active compounds for the preparation of pharmaceutical compositions for the medical use indicated above.
  • the compounds of the invention will also exhibit good
  • the compounds of the invention will not block the uptake of iodine into the thyroid gland. It has earlier been disclosed in several lectures from the company, where the inventors are working that thyroid toxicity depends on if the compounds are lipophilic or not. The inventors have now unexpectedly found that it is not the lipophilicity that is the critical parameter.
  • the claimed compounds which include rather hydrophilic compounds, do not give any thyroid toxic effect and have at the same time high acid secretion inhibitory effect, good bioavailability and stability.
  • Benzimidazole derivatives intended for inhibiting gastric acid secretion are disclosed in numerous patent documents. Among these can be mentioned GB 1 500 043, GB 1 525 958, US 4 182 766, US 4 255 431, US 4 599 347, BE 898 880, EP 124 495, EP 208 452, EP 221 041, EP 279 149, EP 176 308 and Derwent abstract 87-294449/42.
  • the compounds of the invention exhibit a high chemical stability in solution at neutral and acidic pH.
  • 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:
  • R 1 and R 2 which are different, is each H, alkyl
  • R 1 or R 2 is always selected from the group -C(O)-R 6 ;
  • R 6 is alkyl containing 1-4 carbon atoms or alkoxy
  • R 3 is the group -CH 2 OCCOR 7 , wherein R 7 is alkyl containing
  • R 4 and R 5 are the same or different and selected from
  • R 4 and R 5 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 R 4 and R 5 is -CH 2 CH 2 CH 2 -, -CH 2 CH 2 - or -CH 2 -.
  • alkyl and “alkoxy” include straight and branched structures.
  • the compounds of the invention of the formula I have an asymmetric centre in the sulfur atom, i.e. exists as two optical isomers (enantiomers) or if they also contain one or more asymmetric carbon atoms, the compounds have two or more diastereomeric forms, each existing in the two enantiomeric forms.
  • Both the pure enantiomers, racemic mixtures (50% of each enantiomer) and unequal mixtures of the two are within the scope of the present invention. It should also be understood that all the diastereomeric forms possible (pure enantiomers or racemic mixtures) are within the scope of the invention.
  • Preferred groups of compounds of the formula I are: 1. Compounds, wherein R 3 is -CH 2 OCOOCH 2 CH 3 .
  • R 1 and R 2 are selected from H, methyl or -C(O)-R 6 , wherein R 6 is alkyl containing 1-
  • Benzimidazole structures are:
  • the compounds of the invention may be prepared according to the following methods: a) Reacting a compound of the formula II
  • R 1 , R 2 , R 4 and R 5 are as definedw under formula I, and Z, is either a metal cation such as Na+, K+, Li+ or Ag+ or a quaternary ammonium ion, such as tetrabutylammonium with alkyl chloromethyl carbonate or benzyl chloromethyl carbonate.
  • 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 chloroform, or acetone, acetonitrile or dimethyIformamide.
  • the reactions may be carried out at a temperature between the ambient temperature and the boiling temperature of the reaction mixture.
  • R 1 , R 2 , R 3 , R 4 and R 5 are as defined under formula I.
  • This oxidation may be carried out by using an oxidizing agent such as nitric acid, hydrogen peroxide, (optionally in the presence of vanadium compounds), peracids, peresters, ozone, dinitrogentetraoxide, iodosobenzene, Nhalosuccinimide, 1-chlorobenzotriazole, tbutylhypochlorite, diazabicyclo-[2,2,2]-octane bromine complex, sodium metaperiodate, selenium dioxide, manganese dioxide, chromic acid, cericammonium nitrate, bromine, chlorine, and sulfuryl chloride.
  • the oxidation usually takes place in a solvent such as halogenated hydrocarbons, alcohols, ethers, ketones.
  • the oxidation may also be carried out enzymatically by using an oxidizing enzyme or microbiotically by using a suitable microorganism.
  • the structural isomers obtained may be separated by means of crystallization or
  • Racemates obtained can be separated according to known methods, e.g. recrystallization from an optically active solvent. In the case of racemic diastereomeric mixtures these may be separated into diastereomeric pure enantiomers by means of chromatography or fractional crystallization.
  • 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 per se.
  • Alkyl chloromethyl carbonate and benzyl chloromethyl carbonate may be obtained from the pertinent alcohol by treatment with chloromethyl chloroformate in the presence of pyridine.
  • Starting materials of the formula III may be obtained by known methods, e.g. from an alcohol HOR 7 by treatment with phosgene or 1,1 1 -carbonyldiimidazole or p-nitrophenyl chloroformate.
  • 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 combinatio with a pharmaceutically acceptable carrier.
  • the carrier may be in the form of a solid, semi-solid or liquid diluent, or a capsule.
  • a compound selected may be mixed with a solid, powdered carrier, such as lactose, saccharose, sorbitol, mannitol, starch,
  • 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.
  • soft gelatine capsules 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
  • Dosage units for rectal administration may be prepared in the form of suppositories which contain 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 vehicle for gelatine rectal capsules, or they may be prepared in the form of a ready-made micro enema, or they may be prepared in the form of a dry micro enema formulation to be reconstituted in a suitable solvent just prior to administration.
  • Liquid preparation for oral administration may be prepared in the form of syrups or suspensions, e.g. solutions or suspensions containing from 0.2% to 20% by weight of the active ingredient and the remainder consisting of sugar or sugar alcohols and a mixture of ethanol, water, glycerol, propylene glycol and/or polyethylene glycol. If desired, such liquid preparations may contain colouring agents, flavouring agents, saccharine and carboxymethyl cellulose or other thickening agents.
  • Liquid preparations for oral administration may also be prepared in the form of a dry powder to be reconstituted with a suitable solvent prior to use.
  • 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.
  • Example 1 Preparation 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]-1H-benzimidazole-1-ylmethyl ethyl carbonate, as an isomeric mixture.
  • the title compound was isolated from the isomeric mixture given 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.
  • the title compound was isolated from the isomeric mixture given 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.
  • a syrup containing 1% (weight per volume) of active substance was prepared from the following ingredients:
  • a compound according to Example 4 1. 0 g Sugar, powder 30. 0 g Saccharine 0.6 g Glycerol 5. 0 g Tween 1.0 g
  • Tablets A tablet containing 50 mg of active compound was prepared from the following ingredients:
  • Capsules containing 30 mg of active compound were prepared from the following ingredients:
  • the active compound mixture was mixed with the dry ingredients and granulated with a solution of disodium hydrogen phosphate.
  • the wet mass was forced through an extruder and spheronized and dried in a fluidized bed dryer.
  • 500 g of the pellets above were first coated with a solution of hydroxypropyl methylcellulose, 30 g, in water, 600 g, using a fluidized bed coater. After drying, the pellets were coated with a second coating as given below: Coating solution:
  • the final coated pellets were filled into capsules.
  • Suppositories Suppositories were prepared from the following ingredients using a welding procedure. Each suppository contained 40 mg of active compound.
  • the active compound mixture was homogenously mixed with Witepsol H-15 at a temperature of 41°C.
  • the molten mass was volume filled into pre-fabricated suppository packages to a net weight of 1.84 g. After cooling the packages were heat sealed.
  • Each suppository contained 40 mg of active compound.
  • Bioavailability is assessed by calculating the quotient between the areas under plasma concentration (AUC) curve of a compound of the formula I wherein R 3 is hydrogen
  • compound A (herein defined as compound A), following 1) intraduodenal (id) or oral (po) administration of the corresponding compound according to the invention and 2) intravenous
  • the potency for inhibition of acid secretion is measured in the female rat orally and in the dog both
  • the effect of a compound within the invention of the formula I on the uptake of iodine into the thyroid gland is measured as an effect on the accumulation of 125 I in the thyroid gland of the corresponding compound of the formula I, wherein R 3 is hydrogen, that is a metabolized compound of the formula I.
  • the samples were frozen as soon as possible 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 by dividing the last determined blood concentration by the elimination rate constant in the terminal phase.
  • 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. 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
  • test substance or vehicle was given orally, id or iv 1 h after starting the histamine infusion, in a volume of 0.5 ml/kg body weight.
  • 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 output in the collection periods after
  • Percentage inhibition was calculated from fractional responses elicited by test compound and vehicle. ED 50 -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.
  • methocel were administerd by oral gavage in a volume of 5 ml/kg body weight. After 1 hour, 125 I (300kBq/kg, 3ml/kg) was administered by intraperitoneal injection. Four hours after 125I-administration, the animals were killed by
  • Table 4 and 5 give a sumnary of the test data available for the compounds of the invention.

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (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)
EP91911659A 1990-06-20 1991-06-11 Substituted benzimidazoles, process for their preparation and their pharmaceutical use Withdrawn EP0535081A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SE9002206 1990-06-20
SE9002206A SE9002206D0 (sv) 1990-06-20 1990-06-20 New compounds

Publications (1)

Publication Number Publication Date
EP0535081A1 true EP0535081A1 (en) 1993-04-07

Family

ID=20379831

Family Applications (1)

Application Number Title Priority Date Filing Date
EP91911659A Withdrawn EP0535081A1 (en) 1990-06-20 1991-06-11 Substituted benzimidazoles, process for their preparation and their pharmaceutical use

Country Status (27)

Country Link
EP (1) EP0535081A1 (enrdf_load_stackoverflow)
JP (1) JPH05507713A (enrdf_load_stackoverflow)
CN (1) CN1058212A (enrdf_load_stackoverflow)
AP (1) AP215A (enrdf_load_stackoverflow)
AU (1) AU649453B2 (enrdf_load_stackoverflow)
BG (1) BG97200A (enrdf_load_stackoverflow)
CA (1) CA2083714A1 (enrdf_load_stackoverflow)
CZ (1) CZ279772B6 (enrdf_load_stackoverflow)
FI (1) FI925766A7 (enrdf_load_stackoverflow)
HU (1) HUT62881A (enrdf_load_stackoverflow)
IE (1) IE912025A1 (enrdf_load_stackoverflow)
IL (1) IL98470A0 (enrdf_load_stackoverflow)
IS (1) IS3721A7 (enrdf_load_stackoverflow)
LT (2) LT3952B (enrdf_load_stackoverflow)
LV (1) LV10953A (enrdf_load_stackoverflow)
MA (1) MA22199A1 (enrdf_load_stackoverflow)
NO (1) NO924775L (enrdf_load_stackoverflow)
NZ (1) NZ238546A (enrdf_load_stackoverflow)
OA (1) OA09682A (enrdf_load_stackoverflow)
PT (1) PT98035A (enrdf_load_stackoverflow)
RO (1) RO110493B1 (enrdf_load_stackoverflow)
SE (1) SE9002206D0 (enrdf_load_stackoverflow)
TN (1) TNSN91049A1 (enrdf_load_stackoverflow)
TW (1) TW216418B (enrdf_load_stackoverflow)
WO (1) WO1991019711A1 (enrdf_load_stackoverflow)
YU (1) YU104191A (enrdf_load_stackoverflow)
ZA (2) ZA914297B (enrdf_load_stackoverflow)

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WO2007122686A1 (ja) * 2006-04-14 2007-11-01 Eisai R & D Management Co., Ltd. ベンズイミダゾール化合物
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JP2012531409A (ja) 2009-06-25 2012-12-10 アストラゼネカ・アクチエボラーグ Ｎｓａｉｄ関連潰瘍を発症するリスクがある患者の処置方法
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Also Published As

Publication number Publication date
PT98035A (pt) 1992-03-31
TNSN91049A1 (fr) 1992-10-25
FI925766A0 (fi) 1992-12-18
SE9002206D0 (sv) 1990-06-20
AU8009791A (en) 1992-01-07
LT3952B (en) 1996-05-27
CZ279772B6 (cs) 1995-06-14
YU104191A (sh) 1994-01-20
MA22199A1 (fr) 1992-04-01
LV10953A (lv) 1995-12-20
IL98470A0 (en) 1992-07-15
LTIP1712A (en) 1995-08-25
AP215A (en) 1992-09-02
FI925766A7 (fi) 1992-12-18
BG97200A (bg) 1993-12-24
LTIP1713A (en) 1995-08-25
ZA914296B (en) 1992-03-25
AP9100285A0 (en) 1991-07-31
IS3721A7 (is) 1991-12-21
LT3977B (en) 1996-06-25
IE912025A1 (en) 1992-01-01
TW216418B (enrdf_load_stackoverflow) 1993-11-21
CA2083714A1 (en) 1991-12-21
JPH05507713A (ja) 1993-11-04
NO924775D0 (no) 1992-12-10
OA09682A (en) 1993-05-15
HUT62881A (en) 1993-06-28
ZA914297B (en) 1992-03-25
HU9204033D0 (en) 1993-03-29
CS189491A3 (en) 1992-04-15
AU649453B2 (en) 1994-05-26
RO110493B1 (ro) 1996-01-30
WO1991019711A1 (en) 1991-12-26
NO924775L (no) 1992-12-10
CN1058212A (zh) 1992-01-29
NZ238546A (en) 1994-03-25

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