EP0628049A1 - Substituted benzimidazoles, process for their preparation as well as their use - Google Patents

Substituted benzimidazoles, process for their preparation as well as their use

Info

Publication number
EP0628049A1
EP0628049A1 EP93900477A EP93900477A EP0628049A1 EP 0628049 A1 EP0628049 A1 EP 0628049A1 EP 93900477 A EP93900477 A EP 93900477A EP 93900477 A EP93900477 A EP 93900477A EP 0628049 A1 EP0628049 A1 EP 0628049A1
Authority
EP
European Patent Office
Prior art keywords
methyl
compound
formula
sulfinyl
pyridinyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP93900477A
Other languages
German (de)
English (en)
French (fr)
Inventor
Karl Björn Christer HOLSTEIN
Gunnel Elisabeth Sunden
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 EP0628049A1 publication Critical patent/EP0628049A1/en
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom

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
  • the compounds may be used for treatment of other gastrointestinal disorders where gastric antisecretory effect is
  • 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 .
  • the invention also relates to pharmaceutical compositions containing the compounds of the invention, as active ingredient.
  • the invention relates to processes for preparation of such new compounds and to the use of the active compounds for the preparation of pharmaceutical compositions for the medical use indicated above.
  • the compounds of the invention will not block the uptake of iodine into the thyroid gland. It has earlie been disclosed in several lectures from the company, where the inventors are working that thyroid toxicity depends on if the compounds are lipophilic or not. The inventors have now unexpectedly found that it is not the lipophilicity that is the critical parameter.
  • the claimed compounds which include rather hydrophilic compounds, do not give any thyroid toxic effect and have at the same time high acid secretion inhibitory effect.
  • the compounds of the invention will also exhibit a high solubility and a high chemical stability in water.
  • the compounds of the invention exhibit a high solubility and a high chemical stability in water.
  • the compounds of the invention are therefore
  • administration routes such as for instance oral and rectal administration.
  • R 1 and R 2 which are different, is each methyl, -C(O)-
  • the structural isomers of the compounds of the formula I may be used separately, or in equal or unequal mixtures.
  • the compounds of the invention of the formula I have an asymmetric centre in the sulfur atom, i.e. exists as two optical isomers (enantiomers). Both the pure enantiomers, racemic mixtures (50% of each enantiomer) and unequal mixtures of the two are within the scope of the present invention.
  • the compounds of the invention may be prepared
  • Z is halogen such as CI, Br or I or a functionally equivalent group, with a compound of the formula III
  • Q is a counter ion such as Na + , K + , Ag + or trialkylammonium.
  • Salts obtained may be transformed to a therapeutically suitable salt such as sodium and potassium salts, by addition of NaOH and KOH, respectively or by ion exchange.
  • a therapeutically suitable salt such as sodium and potassium salts, by addition of NaOH and KOH, respectively or by ion exchange.
  • This oxidation may be carried out by using an oxidizing agent such as nitric acid, hydrogen peroxide,
  • the oxidation may also be carried out enzymatically by using an oxidizing enzyme or microbiotically by using a suitable microorganism.
  • the structural isomers obtained may be separated by means of crystallization or chromatography.
  • Racemates obtained can be separated according to known methods, e.g. recrystallization from an optically active solvent.
  • 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.
  • formulation contains a compound of the invention in combination with a pharmaceutically acceptable carrier.
  • the carrier may be in the form of a solid, semi-solid or liquid diluent, or a capsule.
  • 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
  • the compound selected may be mixed with a solid, powdered carrier, such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives, gelatin, or another suitable carrier, as well as with lubricating agents such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylenglycol waxes.
  • a solid, powdered carrier such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives, gelatin, or another suitable carrier, as well as with lubricating agents such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylenglycol waxes.
  • lubricating agents such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylenglycol waxes.
  • 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.
  • enteric coating is chosen among
  • enteric-coating materials e.g. beeswax, shellac or anionic film-forming polymers such as cellulose acetate phtalate, hydroxypropyl- methylcellulose phthalate, partly methyl esterified methacrylic acid polymers and the like, if preferred in combination with a suitable plasticizer.
  • enteric-coating materials e.g. beeswax, shellac or anionic film-forming polymers such as cellulose acetate phtalate, hydroxypropyl- methylcellulose phthalate, partly methyl esterified methacrylic acid polymers and the like, if preferred in combination with a suitable plasticizer.
  • enteric-coating materials e.g. beeswax, shellac or anionic film-forming polymers such as cellulose acetate phtalate, hydroxypropyl- methylcellulose phthalate, partly methyl esterified methacrylic acid polymers and the like, if preferred in combination with a suitable plastic
  • Soft gelatine capsules may be prepared with capsules containing a mixture of the active compound or
  • Hard 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,
  • 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
  • compositions may contain colouring agents, flavouring agents, saccharine and carboxymethyl cellulose or other thickening agents.
  • Liquid preparations for oral may contain colouring agents, flavouring agents, saccharine and carboxymethyl cellulose or other thickening agents.
  • 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.
  • 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
  • the typical daily dose of the active substance varies within a wide range and will depend on various factors such as for example the individual requirement of each patient, the route of administration and the disease. In general, oral and parenteral dosages will be in the range of 5 to 500 mg per day of active substance.
  • Example 1 Preparation of phosphoric acid, [5-acetyl- 6-methyl-2-[[(3,4-dimethoxy-2- pyridinyl)methyl]sulfinyl]-1H-benzimidazole-1-yl]methyl ester, disodium salt or phosphoric acid, [6-acetyl-5- methyl-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]- 1H-benzimidazole-1-yl]methyl ester, disodium salt.
  • Tributylamine (1.7 ml, 7.0 mmol) was added with stirring to a solution of phosphoric acid, 85 per cent (0.24 ml, 3.6 mmol) in ethanol (2 ml). The solvent was evaporated and the residue taken up in methylene chloride (2.5 ml). The organic phase was dried over sodium sulphate, filtered and evaporated.
  • Example 2 Preparation of phosphoric acid, [5-carbo methoxy-6-methyl-2-[[(3,4-dimethoxy-2- pyridinyl)methyl]sulfinyl]-1H-benzimidazole-1-yl]methyl ester, disodium salt or phosphoric acid, [6- carbomethoxy-5-methyl-2-[[(3,4-dimethoxy-2- pyridinyl)methyl]sulfinyl]-1H-benzimidazole-1-yl]methyl ester, disodium salt.
  • Example I 1 Preparation of 5-acetyl-1-hydroxymethyl-6-methyl-2-[[(3 dimethoxy-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole 6-acetyl-1-hydroxymethyl-5-metyl-2-[[(3,4-dimethoxy-2-p dinyl)methyl]sulfinyl]-1H-benzimidazole To a mixture of 5-acetyl-6-methyl-2-[[(3,4-dimethoxy-2- pyridinyl)methyl]sulfinyl]-1H-benzimidazole (2.00 g,
  • compositions containing a compound of the invention as active ingredient are illustrated in the following formulations.
  • flavouring agents dissolved in ethanol were added. The mixture was diluted with water to a final volume of 100 ml. Enteric-coated tablets
  • a parenteral formulation for intravenous use is provided.
  • 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 ampoules were sealed. Tablets
  • Tablets containing 30 mg of active compound were prepared from the following ingredients: Compound according to Example 3 in Table 3 300 g
  • 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
  • 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.
  • 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.
  • 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 compound according to Example 2 60 mg Sterile injection vials and stoppers Sterile active compound, 60 mg, was dispensed into 10 ml sterile injection vials. The vials were stoppered with sterile rubberstoppers. The vokale filling operation was performed under aseptic conditions in a sterile production area under vertical laminar flow.
  • Test substances suspended in 0.5% buffered (pH 9) methocel, were administered by oral gavage in a volume of 5 ml/kg body weight. After 1 hour, 125 I (300kBq/kg,
  • test agent- and placebo- treated animals were assessed with the Mann-Whitney U- test (two-tailed). P ⁇ 0.05 was accepted as significant.
  • Table 4 give the test data available for the compounds of the invention.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
EP93900477A 1991-12-19 1992-12-08 Substituted benzimidazoles, process for their preparation as well as their use Withdrawn EP0628049A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
SE9103776 1991-12-19
SE9103776A SE9103776D0 (sv) 1991-12-19 1991-12-19 New compounds
PCT/SE1992/000844 WO1993012124A1 (en) 1991-12-19 1992-12-08 Substituted benzimidazoles, process for their preparation as well as their use

Publications (1)

Publication Number Publication Date
EP0628049A1 true EP0628049A1 (en) 1994-12-14

Family

ID=20384667

Family Applications (1)

Application Number Title Priority Date Filing Date
EP93900477A Withdrawn EP0628049A1 (en) 1991-12-19 1992-12-08 Substituted benzimidazoles, process for their preparation as well as their use

Country Status (25)

Country Link
EP (1) EP0628049A1 (no)
JP (1) JPH07502503A (no)
KR (1) KR940703840A (no)
CN (1) CN1031827C (no)
AP (1) AP397A (no)
AU (1) AU665043B2 (no)
CA (1) CA2124689A1 (no)
CZ (1) CZ146794A3 (no)
FI (1) FI942912A (no)
HR (1) HRP921400A2 (no)
HU (1) HUT68270A (no)
IL (1) IL104025A0 (no)
IS (2) IS4079A (no)
MA (1) MA22746A1 (no)
MX (1) MX9207269A (no)
NO (1) NO942230D0 (no)
NZ (1) NZ246220A (no)
SE (1) SE9103776D0 (no)
SI (1) SI9200402A (no)
SK (1) SK73594A3 (no)
TN (1) TNSN92115A1 (no)
TW (1) TW224100B (no)
WO (1) WO1993012124A1 (no)
YU (1) YU101692A (no)
ZA (1) ZA928836B (no)

Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19645974C1 (de) * 1996-11-07 1998-08-13 Andreas Johannes Kesel (Z)-5-[[3-Hydroxy-2-methyl-5-[(phosphonooxy)methyl]-4-pyridinyl]methylen]-2-thioxo-4- thiazolidinon, Verfahren zu dessen Herstellung und Verwendung
JP2001527083A (ja) * 1997-12-31 2001-12-25 ザ・ユニバーシティ・オブ・カンザス 第二級および第三級アミン含有薬剤の水溶性プロドラッグおよびその製造方法
PT1913009E (pt) 2005-07-28 2010-06-25 Intervet Int Bv Novos (tio)carbamatos de benzimidazole com actividade antiparasitária e sua síntese
TWI385169B (zh) 2005-10-31 2013-02-11 Eisai R&D Man Co Ltd 經雜環取代之吡啶衍生物及含有彼之抗真菌劑
KR101403135B1 (ko) 2006-06-14 2014-06-19 인터벳 인터내셔널 비.브이. 벤지미다졸 카르바메이트 및 폴리솔베이트를 포함하는 현탁물
TW200841879A (en) 2007-04-27 2008-11-01 Eisai R&D Man Co Ltd Pyridine derivatives substituted by heterocyclic ring and phosphonoamino group, and anti-fungal agent containing same
US8513287B2 (en) * 2007-12-27 2013-08-20 Eisai R&D Management Co., Ltd. Heterocyclic ring and phosphonoxymethyl group substituted pyridine derivatives and antifungal agent containing same
US8188119B2 (en) 2008-10-24 2012-05-29 Eisai R&D Management Co., Ltd Pyridine derivatives substituted with heterocyclic ring and γ-glutamylamino group, and antifungal agents containing same
MX365051B (es) 2014-11-26 2019-05-09 Univ Mexico Nac Autonoma Nuevos compuestos hidrosolubles derivados del bencimidazol, utiles para el tratamiento de la fasciolosis.

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NZ234564A (en) * 1986-11-21 1991-04-26 Haessle Ab 1-substituted benzimidazoles and pharmaceutical compositions
SE8801907D0 (sv) * 1988-05-20 1988-05-20 Haessle Ab Novel pharmacological compounds
SE9002206D0 (sv) * 1990-06-20 1990-06-20 Haessle Ab New compounds
ATE184602T1 (de) * 1990-06-20 1999-10-15 Astra Ab Dialkoxypyridinylbenzimidazolderivate, verfahren zur herstellung und ihre pharmazeutische verwendung

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9312124A1 *

Also Published As

Publication number Publication date
NZ246220A (en) 1996-02-27
CN1031827C (zh) 1996-05-22
SE9103776D0 (sv) 1991-12-19
IS3960A (is) 1993-06-20
NO942230L (no) 1994-06-14
AP397A (en) 1995-08-14
NO942230D0 (no) 1994-06-14
HRP921400A2 (en) 1994-08-31
AU3175293A (en) 1993-07-19
CZ146794A3 (en) 1996-02-14
JPH07502503A (ja) 1995-03-16
MX9207269A (es) 1993-06-01
CA2124689A1 (en) 1993-06-24
FI942912A0 (fi) 1994-06-17
TNSN92115A1 (fr) 1993-06-08
AP9200463A0 (en) 1993-01-31
KR940703840A (ko) 1994-12-12
YU101692A (sh) 1995-10-03
CN1073446A (zh) 1993-06-23
ZA928836B (en) 1993-07-05
HU9401840D0 (en) 1994-09-28
AU665043B2 (en) 1995-12-14
IS4079A (is) 1993-06-20
FI942912A (fi) 1994-06-17
IL104025A0 (en) 1993-05-13
SK73594A3 (en) 1995-02-08
SI9200402A (en) 1993-06-30
WO1993012124A1 (en) 1993-06-24
HUT68270A (en) 1995-06-28
TW224100B (no) 1994-05-21
MA22746A1 (fr) 1993-07-01

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