EP0332647A1 - Nouveaux derives de benzimidazole, procede de production desdits derives et composition pharmaceutique les contenant - Google Patents

Nouveaux derives de benzimidazole, procede de production desdits derives et composition pharmaceutique les contenant

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Publication number
EP0332647A1
EP0332647A1 EP87908006A EP87908006A EP0332647A1 EP 0332647 A1 EP0332647 A1 EP 0332647A1 EP 87908006 A EP87908006 A EP 87908006A EP 87908006 A EP87908006 A EP 87908006A EP 0332647 A1 EP0332647 A1 EP 0332647A1
Authority
EP
European Patent Office
Prior art keywords
carbon atoms
alkyl
compound
alkoxy
methoxy
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.)
Pending
Application number
EP87908006A
Other languages
German (de)
English (en)
Inventor
Tomas Börje ALMINGER
Rolf Axel Bergman
Hans Bundgaard
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.)
Hassle AB
Original Assignee
Hassle 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
Priority claimed from SE8604998A external-priority patent/SE8604998D0/xx
Priority claimed from SE8605551A external-priority patent/SE8605551D0/xx
Priority claimed from SE8704049A external-priority patent/SE8704049D0/xx
Application filed by Hassle AB filed Critical Hassle AB
Publication of EP0332647A1 publication Critical patent/EP0332647A1/fr
Pending legal-status Critical Current

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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • C07D401/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom

Definitions

  • New benzimidazole derivatives a process for production thereof and a pharmaceutical composition containing the same.
  • the object of the present invention is to provide novel compounds, and therapeutically acceptable salts thereof, 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 relates to the use of the compounds of the invention, especially therapeutically acceptable salts thereof, for inhibiting gastric acid secretion in mammals and man.
  • the compounds of the invention may be used for prevention and treatment of gastrointestinal inflammatory diseases, and gastric acid-related diseases in mammals and man, such as gastritis, gastric ulcer, duodenal ulcer, and reflux esophagitis.
  • 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 preand postoperatively to prevent acid aspiration and stress ulceration.
  • the invention also relates to pharmaceutical compositions containing at least one compound of the invention, or a therapeutically acceptable salt thereof, as active ingredient.
  • the invention relates to processes for preparation of such new compounds, to novel intermediates in the preparation of the compounds of the invention, and to the use of the active compounds for the preparation of pharmaceutical compositions for the medical use indicated above.
  • Benzimidazole derivatives intended for inhibiting gastric acid secretion are disclosed in numerous patent documents. Among these can be mentioned GB 1 500043, GB 1 525958, US 4 182756, EP 0005 129, and BE 890024.
  • Benzimidazole derivatives proposed for use in the treatment or prevention of special gastrointestinal inflammatory diseases are disclosed in EP-A-0045200.
  • N-substituted 2-(pyridylalkylenesulfinyl)- benzimidazoles are disclosed in EP-A-0 175308.
  • the compounds in the prior art generally have a low water solubility, which does not admit manufacture of such highly concentrated water solution which are needed for intravenous and intramuscular injections.
  • the compounds presented in the European patent application, publication no. 0176308, disclosing N-substituted benzimidazole derivatives have low water solubility and are thus not suitable for the above-mentioned parenteral use.
  • the compounds of the invention wherein X is SO generally show higher chemical stability in water solutions at the pH where they exhibit optimal stability compared to the corresponding compounds without the N-1 substitution, at the same pH. Some of the compounds of the invention show exceedingly high chemical stability in solution.
  • the compounds of the formula I are therefore particularly suitable for parenteral, especially intravenous and intramuscular administration.
  • the high solubility and chemical stability also render the compounds of the invention suitable for other administration routes, such as for instance oral and rectal administration.
  • X is -S- or -SO-; R 1 , R 2 , R 3 and R 4 , which are the same or different, are
  • alkylthio containing 1-6 carbon atoms in the alkyl part
  • alkylsulfinyl containing 1-7 carbon atoms in the alkyl part
  • aryl-thio -sulfinyl, -sulfonyl, -sulfonyloxy, -oxysulfonyl
  • -sulfonami do or -aminosulfonyl
  • each aryl group optionally is substituted b y 1-3 substituents, the same or different and selected from halogen, CF 3 , (1-5C)alkyl and (1-5C)alkoxy (n) arylalkyl or arylalkoxy, containing 1-6 carbon atoms in the alkyl and alkoxy parts, respectively whereby the aryl part optionally is substituted by 1-3 substituents, the same or different and selected from halogen , CF 3 , ( 1-5C) alkyl and (1-5C)alkoxy
  • each aryl group optionally is substituted by 1-3 substituents, the same or different and selected from halogen, CF 3 , (1-5C)alkyl and (1-5C)alkoxy
  • each ring may be saturated or unsaturated and may contain 0-3 hetero atoms selected from N , S and 0 , and whereby each ring may be optionally substituted with 1-10, suitably 1-6, or 1-4 substituents selected from alkyl groups with 1-3 carbon atoms and halogen, or two or four of the mentioned substituents
  • R 6 is (a) H
  • R 8 is (a) H
  • alkyl containing 1-8 especially 1-6 carbon atoms
  • alkoxy containing 1-8 especially 1-6 carbon atoms
  • halogen e
  • R 7 is (a) H
  • R 9 is (a) H
  • R 10 is (a) alkyl containing 1-6 carbon atoms (b) alkoxy containing 1-6 carbon atoms
  • A is (a) straight or branched (1-8C)alkylene
  • E is (a) - O - or (b) - NH -
  • Z 2 is (a) - CH 2 -
  • R a , R b , R c , R d and R q are the same or different and selected from
  • R e is (a) H
  • R f is the side chain of an amino acid; m is an integer 0, 1, 2, 3, 4, 5, 6, 7 or 8; p is an integer 1, 2, 3 or 4; q is an integer 1, 2, 3 or 4; r is an integer 0, 1, 2, 3, 4, 5, 6, 7, 8; s is an integer 0 or 1; t is an integer 0 or 1; u is an integer 1 or 2; v is an integer 0 or 1;
  • R 5 may also be in a zwitter-ionic form; with the provisos that
  • A is (3-7C) cycloalkylene or (4-9C) alkylene containing a cycloalkylene group when the following conditions are fulfilled simultaneously:
  • R a is H, (1-3C)alkyl
  • R b is H, (1-3C)alkyl
  • R 6 and R 8 Either or both of R 6 and R 8 is halogen when R 7 is dialkylamino, morpholino, piperidino, M-methyl-piperazino or pyrrolidino.
  • R 7 dialkylamino, morpholino, piperidino, M-methyl-piperazino or pyrrolidino.
  • alkyl and alkoxy include straight, branched, and cyclic structures including cycloalkylalkyl and cycloalkylalkoxy, respectively.
  • the compounds of the invention that are sulfoxides have an asymmetric centre in the sulfur atom, i.e. these compounds exist 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 two enantiomeric forms.
  • the different diastereomeric forms possible as well as the pure enantiomers and racemic mixtures are within the scope of the invention.
  • R 1 , R 2 , R 3 and R 4 are the same or different and selected from hydrogen, (1-4C)alkyl, (5-6C)cycloalkyl, (1-4C)alkoxy, (1-2C)alkoxy(1-2C)alkyl, (1-2C)alkoxy(1-2C)alkoxy, halogen, CF 3 , (2-4C)alkanoyl, arylcarbonyl, (1-2C)alkoxycarbonyl, aryl(1-3C)alkoxy, aryl, halo(1-4C)alkoxy, hydroxy(1-4C)alkyl, (2-4C)alkanoyl(1-3C)alkyl, or wherein R 2 and R 3 together with the ring carbons form a 5- or 6-membered saturated, oxygen-containing or carbocylic, ring, optionally substituted by 1-6 substituents, the same or different and selected from halogen, (1-2C)alkyl, or two of the substituents together form an o
  • R 1 , R 2 , R 3 and R 4 are the same or different and selected from hydrogen, (1-4C)alkyl, (1-4C)alkoxy, (1-2C)alkoxy(1-2C)alkyl, fluorine, CF 3 , (2-4C)alkanoyl, (1-2C)alkoxycarbonyl, fluoro(1-4C)alkoxy, hydroxy(1-4C)alkyl, or wherein R 2 and R 3 form a group -OCH 2 O, -OCF 2 O, -OCF 2 -CHFO-, or
  • R 1 , R 2 , R 3 and R 4 are the same or different and selected from hydrogen, methyl, ethyl, isopropyl, t-butyl, methoxy, ethoxy, methoxymethyl, ethoxymethyl, fluorine, trifluoromethoxy, tetrafluoroethoxy, hydroxymethyl, or wherein R 2 and R 3 form a group
  • R 1 , R 2 , R 3 and R 4 are the same or different and selected from hydrogen, t-butyl, methoxy, ethoxy, methoxymethyl, ethoxymethyl, fluorine, trifluoromethoxy, tetrafluoroethoxy, hydroxymethyl or hydroxyethyl.
  • R 1 and R 4 are H and R 2 and R 3 are selected from t-butyl, methoxy, methoxymethyl, fluorine, trifluoromethoxy, hydroxymethyl and hydroxyethyl.
  • R 1 , R 2 , R 3 and R 4 are H, alkyl containing 1-6 carbon atoms, or alkoxy containing 1-6 carbon atoms.
  • R 1 and R 4 are alkoxy containing 1-3 carbon atoms and R 2 and R 3 are H or hydroxyalkyl containing 1-3 carbon atoms.
  • R 7 is H, alkyl containing 1-6 carbon atoms, alkoxy containing 1-6 carbon atoms.
  • R 7 is aryloxy or arylalkoxy, optionally substituted.
  • R 9 is H or CH 3 , especially H.
  • Preferred substituents in position 1 of the benzimidazole nucleus are those where R 9 is H and D is as exemplified in Table 1 below.
  • Preferred benzimidazole structures are: unsubstituted, 5-methoxy and 6-methoxy-substituted.
  • Preferred of the pyridine fragments are: 3,5-dimethyl-4-methoxy-, 3-methyl-4-methoxy-, 5-ethyl-4-methoxy-, 4-methoxy-, 4-ethoxy-, 4-isopropoxy-, 3,5-diwethyl-, 3,4-dimethyl-, 4,5-dimethyl-, 3-methyl-4-(2,2,2-trifluoro)ethoxy-, 3,4-dimethoxy-, 4,5-dimethoxy-, 3-methyl-4-ethylthio-, 3-methyl-4,5-dimethoxy-, 3,4,5-trimethyl, 3-ethyl-4-methoxy-, 3-n-propyl-4-methoxy-, 3-isopro ⁇ yl- -4-wethoxy-, 3-t-butyl-4-methoxy-substituted.
  • Preferred groups of the radicals R 6 and R 8 are H, CH 3 , C 2 H 5 . n-C 3 H 7 , i -C 3 H 7 , and t-C 4 H 9 . 38.
  • the most preferred compounds of the invention are
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R a , R b , R c , R d , R e and R q are exemplified by methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, n-hexyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopentylmethyl, cyclopentylethyl, and cyclohexylmethyl.
  • Lower alkyl groups containing 1-4 carbon atoms are especially preferred.
  • the group alkoxy in the defintions of R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 and R 10 are exemplified by methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, n-pentoxy, i-pentoxy, n-hexoxy, cyclopropoxy, cyclopentoxy, cyclohexoxy, cyclopropylmethoxy, cyclo- pentylmethoxy, cyclopentylethoxy, and cyclohexylmethoxy.
  • Lower alkoxy groups are preferred, especially those containing 1-4 carbon atoms, preferably a lower alkoxy group having especially preferred 1-3 carbon atoms, e.g. methoxy, ethoxy, n-propoxy or isopropoxy.
  • Halogen in the definitions of R 1 , R 2 , R 3 , R 5 , R 6 andR 8 is chloro, bromo , fluoro and iodo, preferably chloro, bromo, and fluoro.
  • R 1 , R 2 , R 3 , R 4 and R 7 when representing alkylthio or alkylsulfinyl is the alkyl preferably a lower alkyl having especially preferred 1-4 carbon atoms, e.g. methylthio, methylsulfinyl, ethylthio, ethylsulfinyl, isopropylthio, n-butylsulfinyl or isobutylthio.
  • the group aryl when present in R 1 , R 2 , R 3 , R 4 , R 7 , R 10 and R e has preferably up to 10 carbon atoms, especially preferred up to 6 carbon atoms, e.g. a phenyl group.
  • R 1 , R 2 , R 3 ,R 4 , and R 7 representing an aryloxy or arylthio group have preferably up to 10 carbon atoms, especially preferred up to 6 carbon atoms, e.g. a phenoxy or phenylthio group.
  • the groups arylalkyl, arylalkoxy, and arylalkylthio, when present in R 1 , R 2 , R 3 , R 4 , R 7 , R 8 and R e have preferably up to 10 carbon atoms in the aryl group. Especially preferred are 6 carbon atoms in the aryl group and 1-3 carbon atoms in the alkyl group or alkoxy group, respectively, e.g. phenylmethyl, phenylethyl, phenylmethoxy, phenylethoxy, phenylpropyl, phenylisopropoxy, phenylmethylthio, and phenylethylthio.
  • the group "(4-9C)alkylen containing a cycloalkylene group" when present in A is especially / R 1 , R 2 , R 3 , R 4 , and R 7 representing an alkoxy alkyl or alkoxyalkoxy group are exemplified by methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, propoxyethyl, methoxymethoxy, methoxyethoxy, methoxypropoxy, ethoxyethoxy and propoxyethoxy.
  • R 7 representing an alkenyl ⁇ xy or alkynyloxy group has preferably 2-7 carbon atoms, especially preferred 3-4 carbon atoms, e.g. allyloxy, propargyloxy, 2-butenyloxy and 2-butynyloxy.
  • R 3 and R 3 and R 4 are -CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 -, -CH 2 C(CH 3 )-CH 2 -,
  • R 6 and R 7 , or R 7 and R 8 representing a 5- or 6-membered saturated or unsaturated ring is preferably a saturated carbocyclic ring or a saturated ring containing an oxygen or a sulphur atom in the 4-position in the pyridine ring, e.g. -CH 2 CH-CH 2 -, -CH 2 CH 2 CH 2 CH 2 -, -O-CH-CH 2 -,
  • R 1 , R 2 , R 3 and R 4 when representing haloalkoxy is preferably a lower haloalkoxy.
  • Especially preferred are lower fluoroalkoxy, or fluorochloroalkoxy groups, e.g. OCF 3 , OCHF 2 , OCF 2 CHF 2 , OCF 2 CF 3 , OCF 2 Cl,
  • R 7 when representing fluoroalkoxy is exemplified by OCH 2 CF 3 , OCH 2 CF 2 CF 3 and OCH 2 CF 2 CHF 2 .
  • R 1 , R 2 , R 3 and R 4 representing hydroxyalkyl is exemplified by CH 2 OH, CH 2 CH 2 OH, CH 2 CH 2 CH 2 OH, and (CH 2 ) 4 OH.
  • R 7 when representing a dialkylamino group is preferably -N(CH 3 ) 2 , or -N(C 2 H 5 ) 2 .
  • R f which represents the side chain of an amino acid is e.g. CH 3 derived from alanine or (CH 2 ) 2 COOH derived from glutamic acid.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and X are as defined under formula I with a compound of the formula III
  • R 5 is as defined under formula I above.
  • reaction of a compound of formula II with a compound of formula III is suitably carried out either directly in the presence of dicyclohexyl- carbodiimide and if desired also in the presence of N,N-dimethylamino- pyridine (DMAP) or with an activated form of compound III, such as an acid halide or a mixed anhydride or a carbonate.
  • Suitable solvents are hydrocarbons such as toluene and benzene or halogenated hydrocarbons such as methylen chloride and chloroform or polar solvents such as acetone, dimethyl formamide (DMF), acetonitrile tetrahydrofuran (THF) and pyridine.
  • the reaction of the compounds of formulas II and III may be carried out at a temperature between -15°C and the boiling temperature of the reaction mixture.
  • R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 and X are as defined under formula I, and Z is halogen such as Cl, Br or I or a functionally equivalent group, with a compound of the formula V, VI, VII, VIII, IX, X,XI, XII, or XIII:
  • R p is a suitable protecting group such as cyanoethyl, benzyl or p-nitrophenyl
  • M is a counter ion such as Na + , K + , Ag + or trialkylammonium.
  • a protecting group such protecting group is removed after the coupling reaction (see under E below).
  • X is S
  • R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R 9 and D have the meanings given, to give a compound of the same formula I wherein X is SO.
  • This oxidation may be carried out by using an oxidizing agent selected from the group consisting of nitric acid, hydrogen peroxide, peracids, peresters, ozone, dinitrogentetraoxide, iodosobenzene, N-halosuccini- mide, 1-chlorobenzotriazole, t-butylhypochlorite, diazabicyclo-
  • the oxidation usually takes place in a solvent wherein the oxidizing agent is present in some excess in relation
  • the oxidation may also be carried out enzymatically by using an oxidating enzyme or microbiotically by using a suitable microorganism.
  • R 1 , R 2 , R 3 , R 4 , R 6 ,R 7 , R 8 and X are as defined under formula I and M a is either a metal cation such as Na + , K + , Li + or Ag + or a quaternary ammonium ion, such as tetrabutylammonium with a compound of the formula
  • D and R 9 are as defined under formula I and Y is halogen such as Cl, Br or I, or a functionally equivalent group.
  • reaction of a compound of formula IIA with a compound of formula XII- is suitably carried out under protective gas in absence of water.
  • Suitable solvents are hydrocarbons such as toluene and benzene and halogenated hydrocarbons such as methylene chloride and chloroform.
  • the reaction of the compounds of formula IIA and XII may be carried out at a temperature between the ambient temperature and the boiling temperature of the reaction mixture.
  • the phosphates may be protected as dibenzyl- or diphenyl esters, which can be cleaved by basic hydrolysis.
  • the dibenzyl esters may also be cleaved by sodium iodide in acetone.
  • the cyanoethyl protecting group may be removed by treatment with base such as NaOH.
  • the end products of the formula I are obtained either in neutral or salt form. Both the neutral compounds and the salts of these end products are included within the scope of the invention.
  • salts may be obtained as well as hemi, mono, sesqui or polyhydrates.
  • Acid addition salts of the amino-containing compounds may in a manner known per se be transformed into free base using basic agents such as alkali or by ion exchange. The free bases obtained may then be converted into salts with organic or inorganic acids. In the preparation of acid addition salts preferably such acids are used which form suitable therapeutically acceptable salts.
  • acids examples include hydrohalogen acids, sulfonic acid, phosphoric acid, nitric acid, and perchloric acid; aliphatic, alicyclic, aromatic or heterocyclic carboxyl or sulfonic acids, such as formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, hydroxymaleic acid, pyruvic acid, phenyl- acetic acid, benzoic acid, p-aminobenzoic acid, p-hydroxybenzoic acid, salicylic acid or p-aminosalicylic acid, embonic acid, methanesulfonic acid, ethanesulifonic acid, hydroxyethanesulfonic acid, ethylenesulfonic acid, halogenbenzenesulfonic acid, toluenesulfonic acid, napthylsulfonic acid or sulfanilic
  • Base addition salts of the carboxylic acid - or phosphorous - containing compounds may in a corresponding way be transformed into the acid form, and then reconverted to a therapeutically suitable salt such as sodium and potassium salts.
  • Racemates obtained can be separated according to known methods, e.g. recrystallization from an optically active solvent.
  • racemate mixtures these may be separated into stereoisomeric (diastereomeric) pure racemates by means of chromatography or fractional crystallization.
  • the starting materials utilized in the methods A-E are in some cases novel. These novel starting materials may, however, be obtained according to processes known per se.
  • the invention relates to the use, as means for increasing the aqueous solubility of gastric acid-inhibiting benzimidazole derivatives, of a radical of the formula
  • the invention also relates to gastric acid-inhibiting benzimidazole derivatives having in position N-l of the benzimidazole nucleus a radical of the formula D-CH( R 9 )-, where D and R 9 are as defined in formula I
  • the invention also relates to the use as agent to be linked to position N-1 of the benzimidazole nucleus, for increasing the aqueous solubility of benzimidazole derivatives having gastric acid inhibiting effect, of a compound of the formula where D, R 9 and Y are as defined elsewhere in this specification.
  • the compounds of the invention are formulated into pharmaceutical formulations for oral, rectal, parenteral or other mode of administration. It is especially preferred to formulate the compounds of the invention into pharmaceutical formulations for parenteral administration.
  • the pharmaceutical formulation contains a compound of tne invention in combination with a pharmaceutically acceptable carrier.
  • the carrier may be in the form of a solid, semi-solid or liquid diluent, or a capsule.
  • These pharmaceutical preparations are a further object of the invention.
  • the amount of active compounds is between 0.1-95% by weight of the preparation, between 0.2-20% by weight in preparations for parenteral use and between 1 and 50% by weight in preparations for oral administration.
  • the compound selected may be mixed with a solid, powdered carrier, such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives, gelatin, or another suitable carrier, as well as with lubricating agents such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylenglyc ⁇ l waxes.
  • a solid, powdered carrier such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives, gelatin, or another suitable carrier, as well as with lubricating agents such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylenglyc ⁇ l waxes.
  • lubricating agents such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylenglyc ⁇ l waxes.
  • Granules and tablets containing sulfoxides may be coated with an enteric coating which protects the active compound from acid catalyzed degradation as long as the dosage form remains in the stomach.
  • the enteric coating is chosen among pharmaceutically acceptable enteric- coating materials e.g. beeswax, shellac or anionic film-forming polymers such as cellulose acetate phthalate, hydroxypropyl-methylcellulose phthalate, partly methyl esterified methacrylic acid polymers and the like, if preferred in combination with a suitable plasticizer.
  • enteric- coating materials e.g. beeswax, shellac or anionic film-forming polymers such as cellulose acetate phthalate, hydroxypropyl-methylcellulose phthalate, partly methyl esterified methacrylic acid polymers and the like, if preferred in combination with a suitable plasticizer.
  • To this coating various dyes may be added in order to distinguish among tablets or granules with different active compounds or with different amounts of the active
  • Soft gelatine capsules may be prepared with capsules containing a mixture of the active compound or compounds of the invention, vegetable oil, fat, or other suitable vehicle for soft gelatine capsules. Soft gelatine capsules may also be enteric-coated as described above. Hard gelatine capsules may contain granules or enteric-coated granules of the active compound. Hard gelatine capsules may also contain the active compound in combination with a solid powdered carrier such as lactose, saccharose, sorbitol, mannitol, potato starch, amylopectin, cellulose derivatives or gelatine. The hard gelatine capsules may be enteric- coated as described above.
  • Dosage units for rectal administration may be prepared in the form of suppositories which contain the active substance mixed with a neutral fat base, or they may be prepared in the form of a gelatine rectal capsule which contains the active substance in a mixture with a vegetable oil, paraffin oil or other suitable vehicle for gelatine rectal capsules, or they may be prepared in the form of a ready-made micro enema, or they may be prepared in the form of a dry micro enema formulation to be reconstituted in a suitable solvent just prior to administration.
  • Liquid preparation for oral administration may be prepared in the form of syrups or suspensions, e.g solutions or suspensions containing from 0.2% to 20% by weight of the active ingredient and the remainder consisting of sugar or sugar alcohols and a mixture of ethanol, water, glycerol, propylene glycol and polyethylene glycol. If desired, such liquid preparations may contain colouring agents, flavouring agents, saccharine and carboxymethyl cellulose or other thickening agents.
  • Liquid preparations for oral administration may also be prepared in the form of a dry powder to be reconstituted with a suitable solvent prior to use.
  • Solutions for parenteral administration may be prepared as a solution of a compound of the invention in a pharmaceutically acceptable solvent, preferably in a concentration from 0.1% to 10% by weight. These solutions may also contain stabilizing agents and/or buffering agents and may be manufactured in different unit dose ampoules or vials. Solutions for parenteral administration may also be prepared as a dry preparation to be reconstituted with a suitable solvent extemporaneously before use.
  • the typical daily dose of the active substance varies within a wide range and will depend on various factors such as for example the individual requirement of each patient, the route of administration and the disease. In general, oral and parenteral dosages will be in the range of 5 to 500 rug per day of active substance.
  • the compound of this example is identified in Table 1, and was prepared by Method A as exemplified in Example 1.
  • Phosphoric acid, dibenzyl-[2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl]sulfinyl]-1H-benzimidazoie-1-yl]methyl triester (90 mg, 0.15 mmoles) was dissolved in methanol/water (2 ml, 1:1). Sodium hydrogen carbonate (58 mg, 0,7 mmoles) was added and the mixture was refluxed for 2 hours on a waterbath. Concentration of the mixture at reduced pressure and chromatography of the residue on silica gel (ethyl acetate-methanol-water; 20:4:3) gave the essentially pure title compound. Yield: 30 mg (37 %).
  • Example 14 These compounds are identified in Table 1 and were prepared by Method A as exemplified in Example 14.
  • Example 14 These compounds are identified in Table 1 and were prepared by Method A as exemplified in Example 14.
  • Example 14
  • the title compound is prepared by alkylation of 2-[[(4-Methoxy-3,5-dimethyl-2 pyridinyl)methyl]sulfinyl]-1H- benzimidazole-1-yl]methyl-3-(1-methyl piperzine-4-yl)propyl carbonate with methyl iodide by conventional methods.
  • Tributylamine 14 ml, 0.059 mol was added with stirring to a solution of phosphoric acid, 85 per cent (2 ml, 0.030 mol) in ethanol (10 ml). The solvent was evaporated and the residue taken up in methylene chloride (25 ml). The organic phase was dried over sodium sulphate, filterered and evaporated.
  • tributyl, ammonium salts prepared in step a) above phosphoric acid [5-methoxy- [2[[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl]sulfinyl] -1H-benzimidazole-1-yl]]methyl ester, tributylammonium salt was obtained through chromatography on a reversed phase column, eluted with 15 per cent acetonitrilein water. After freeze drying the compound was dissolved in methylene chloride acid treated with sodiumhydroxide as described above.
  • Butandioic acid anhydride (4 g 0.04 mol), N-methyl piperazine (4 g 0.04 mol) and triethylamine (4 g 0.04 mol) was added to dichloromethane ⁇ 250 ml). The mixture was stirred for 10 min. at room temperature. The mixture was cooled to -15°C and methylchloroformate (3.78 g 0.04 mol) was added.
  • This compound is identified in Table 1 and was prepared by method B as exemplified in Examples 63 and 64, with the exception that potassium hydroxide was used instead of sodium hydroxide.
  • the preparation of the precursors no. I 21 and I 22 results in the formation of an isomeric mixture in the ratio 1:2.
  • the target compounds no. 32 and 29 are formed as isomers in the same ratio 1:2.
  • the isomeric ratios are sometimes different from 1:2 and are dependent on the substituents, especially the substituents on the benzimidazole nucleus.
  • compositions containing a compound of the invention as active ingredient are illustrated in the following formulations.
  • a syrup containing 1 % (weight per volume) of active substance was prepared from the following ingredients:
  • An enteric coated tablet containing 20 mg of active compound was prepared from the following ingredients:
  • a parenteral formulation for intravenous use containing 4 mg of active compound per ml-, was prepared from the following ingredients:
  • the active compound was dissolved in water to a final volume of 1000 ml, The solution was filtered through a 0.22 ⁇ m filter and immediately dispensed into 10 ml sterile ampoules. The a ⁇ poules were sealed.
  • Tablets containing 30 mg of active compound were prepared from the following ingredients:
  • the active compound was mixed with lactose and part of the PVP-XL and granulated with a solution of methyl cellulose and disodium hydrogen phosphate.
  • the wet mass was forced through a screen and dried in a fluidized bed dryer. After adding magnesium stearate and the remainder in PVP-XL and mixing, the drug mixture was compressed into tablets with a mean weight of 110 mg, each tablet containing 30 mg of the active compound.
  • Suppositories were prepared from the following ingredients using a welding procedure. Each suppository contained 40 mg of active compound.
  • the active compound 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.
  • a syrup containing 1% of active substance was prepared from the following ingredients:
  • the active compound was dissolved in water to a final volume of 1000 ml.
  • the solution was filtered through a sterile 0.22 ⁇ m filter and aseptically dispensed into 1 ml sterile ampoules. The ampoules were sealed.
  • Sterile active compound 60 mg was dispensed into 10 ml sterile injection vials.
  • the vials were stoppered with sterile rubber stoppers.
  • the whole filling operation was performed under aseptic conditions in a sterile production area under vertical laminar flow.
  • the active compound dissolved in 10 ml of sterile water is transferred into 100 ml of normal saline solution for infusion to give a total volume of about 110 ml.
  • the solution is administered as an intravenous infusion during a time period of about 30 minutes.
  • Chronic gastric fistula dog were used. These dogs have been surgically provided with a gastric cannula in the stomach and a duodenal fistula, used for direct intraduodenal administration of test compounds. Following a 4 weeks' recovery period after surgery, tests were performed once a week on each dog. Food and water were withdrawn 18 hours before each test.
  • Gastric acid secretion was induced by a continuous 4 h infusion of histamine at individual doses (400-600 nmol/kg ⁇ h,iv) resulting in approximately 90% of maximal secretion of gastric acid.
  • the gastric juice was collected by free flow from the gastric cannula in consecutive 30 min. samples during the duration of the histamine infusion.
  • the samples were titrated to pH 7.0 with 0.1 M or 1.0 M NaOH using an automatic titrator and the acid output was calculated.
  • the acid output during the periods after administration of test compound or vehicle was expressed as the fraction of the output during the period preceding these administrations, and the per cent inhibition of acid secretion was calculated by comparing in each dog the fractional responses induced by the test compound to the corresponding vehicle-induced fractional responses.
  • test results given in Table 5 below represent inhibition during the 2nd hour after dose.
  • Omeprazole-Na 5-methoxy-2- [[(4-methoxy-3 ,5-dimethyl-2-pyridinyl ) - methyl]sulfinyl]-1H-benzimidazole sodium salt

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Abstract

Nouveaux composés représentés par la formule (I), compositions pharmaceutiques contenant de tels composés comme ingrédient actif et utilisation desdits composés en medecine.
EP87908006A 1986-11-21 1987-11-20 Nouveaux derives de benzimidazole, procede de production desdits derives et composition pharmaceutique les contenant Pending EP0332647A1 (fr)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
SE8604998A SE8604998D0 (sv) 1986-11-21 1986-11-21 Novel pharmacological compounds
SE8604998 1986-11-21
SE8605551A SE8605551D0 (sv) 1986-12-23 1986-12-23 Novel pharmacological compounds
SE8605551 1986-12-23
SE8704049 1987-10-16
SE8704049A SE8704049D0 (sv) 1987-10-16 1987-10-16 Novel pharmacological compounds

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EP0332647A1 true EP0332647A1 (fr) 1989-09-20

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EP87850362A Expired - Lifetime EP0279149B1 (fr) 1986-11-21 1987-11-20 Dérivés du benzimidazole, leur procédé de préparation et compositions pharmaceutiques les contenant
EP92108817A Withdrawn EP0510719A1 (fr) 1986-11-21 1987-11-20 Dérivés de benzimidazol substitués par un group radical et leur utilisation pour l'inhibition de la sécrétion gastrique
EP87908006A Pending EP0332647A1 (fr) 1986-11-21 1987-11-20 Nouveaux derives de benzimidazole, procede de production desdits derives et composition pharmaceutique les contenant

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EP87850362A Expired - Lifetime EP0279149B1 (fr) 1986-11-21 1987-11-20 Dérivés du benzimidazole, leur procédé de préparation et compositions pharmaceutiques les contenant
EP92108817A Withdrawn EP0510719A1 (fr) 1986-11-21 1987-11-20 Dérivés de benzimidazol substitués par un group radical et leur utilisation pour l'inhibition de la sécrétion gastrique

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EP (3) EP0279149B1 (fr)
JP (1) JPH02500744A (fr)
KR (1) KR890700125A (fr)
AT (1) ATE84032T1 (fr)
AU (1) AU612129B2 (fr)
DE (1) DE3783356T2 (fr)
DK (1) DK365488A (fr)
EG (1) EG18379A (fr)
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FI (1) FI892454A (fr)
GR (1) GR3007385T3 (fr)
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MY (1) MY101784A (fr)
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PL (1) PL157655B1 (fr)
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SE9103776D0 (sv) * 1991-12-19 1991-12-19 Astra Ab New compounds
CA2113561C (fr) * 1992-05-21 1999-09-14 Kazuyoshi Miyata Derive de diester d'acide phosphonique
WO1994026279A1 (fr) * 1993-05-18 1994-11-24 The Upjohn Company Esters de biphosphonate pour traiter les troubles gastriques
US6875872B1 (en) 1993-05-28 2005-04-05 Astrazeneca Compounds
EP0983263A1 (fr) * 1997-05-30 2000-03-08 Dr. Reddy's Research Foundation Nouveaux benzimidazoles utilises comme agents antiulcereux, leur procede de preparation et compositions pharmaceutiques les contenant
KR20010033811A (ko) * 1997-12-31 2001-04-25 토마스 안 빅토리아 2차 및 3차 아민을 함유하는 약제의 물에 용해가능한프로드럭 및 그것의 제조방법
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AU2001294228A1 (en) * 2000-10-12 2002-04-22 Takeda Chemical Industries Ltd. Benzimidazole compounds, process for producing the same and use thereof
US20040248941A1 (en) * 2001-09-25 2004-12-09 Keiji Kamiyama Benzimidazone compound, process for producing the same, and use thereof
ATE467637T1 (de) * 2005-07-28 2010-05-15 Intervet Int Bv Neue benzimidazol(thio)carbamate mit antiparasitischer wirkung und ihre synthese
CA3000985C (fr) 2014-10-14 2023-01-31 The Board Of Trustees Of The Leland Stanford Junior University Procede pour le traitement de maladies neurodegeneratives
KR20180094989A (ko) 2015-12-15 2018-08-24 더 보드 오브 트러스티스 오브 더 리랜드 스탠포드 주니어 유니버시티 노화 관련 인지장애 및 신경염증의 예방 및/또는 치료 방법
TW202019410A (zh) 2018-08-06 2020-06-01 小利蘭史丹佛大學董事會 作為用於治療神經退化性疾病的ppargc1a活化劑的2-芳基苯并咪唑
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NO883229D0 (no) 1988-07-20
ES2052603T3 (es) 1994-07-16
LV10954B (en) 1996-08-20
PL157655B1 (pl) 1992-06-30
NO883229L (no) 1988-09-16
IS1565B (is) 1994-12-13
IE873125L (en) 1988-05-21
EP0279149A2 (fr) 1988-08-24
DK365488D0 (da) 1988-07-01
EP0279149B1 (fr) 1992-12-30
IE61178B1 (en) 1994-10-05
NZ234564A (en) 1991-04-26
YU211087A (en) 1988-12-31
PL268927A1 (en) 1989-01-23
DE3783356D1 (de) 1993-02-11
WO1988003921A1 (fr) 1988-06-02
HU204814B (en) 1992-02-28
DK365488A (da) 1988-07-01
EG18379A (en) 1992-11-30
DE3783356T2 (de) 1993-04-15
IS3284A7 (is) 1988-05-22
FI892454A0 (fi) 1989-05-19
NO173998C (no) 1994-03-02
AU612129B2 (en) 1991-07-04
RU2062778C1 (ru) 1996-06-27
LV10954A (lv) 1995-12-20
KR890700125A (ko) 1989-03-02
NZ222495A (en) 1991-04-26
EP0279149A3 (en) 1988-08-31
IE940326L (en) 1988-05-21
MY101784A (en) 1992-01-17
JPH02500744A (ja) 1990-03-15
GR3007385T3 (fr) 1993-07-30
HUT51269A (en) 1990-04-28
YU47116B (sh) 1994-12-28
PT86186B (pt) 1990-08-31
FI892454A (fi) 1989-05-19
ATE84032T1 (de) 1993-01-15
IL84504A (en) 1994-10-07
NO173998B (no) 1993-11-22
PT86186A (en) 1987-12-01
AU8330287A (en) 1988-06-16
EP0510719A1 (fr) 1992-10-28

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