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WO1993015071A1 - Derives de thiazolyle-pyridine et leur utilisation comme inhibiteurs de secretion d'acide gastrique - Google Patents

Derives de thiazolyle-pyridine et leur utilisation comme inhibiteurs de secretion d'acide gastrique Download PDF

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Publication number
WO1993015071A1
WO1993015071A1 PCT/EP1993/000176 EP9300176W WO9315071A1 WO 1993015071 A1 WO1993015071 A1 WO 1993015071A1 EP 9300176 W EP9300176 W EP 9300176W WO 9315071 A1 WO9315071 A1 WO 9315071A1
Authority
WO
WIPO (PCT)
Prior art keywords
methylphenyl
pyridyl
hydrogen
compound
thiazole
Prior art date
Application number
PCT/EP1993/000176
Other languages
English (en)
Inventor
Robert John Ife
Colin Andrew Leach
Original Assignee
Smithkline Beecham Intercredit B.V.
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 Smithkline Beecham Intercredit B.V. filed Critical Smithkline Beecham Intercredit B.V.
Priority to JP5512931A priority Critical patent/JPH07503023A/ja
Priority to EP93903880A priority patent/EP0625151A1/fr
Publication of WO1993015071A1 publication Critical patent/WO1993015071A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
    • C07D213/46—Oxygen atoms
    • C07D213/50—Ketonic radicals

Definitions

  • the present invention relates to novel substituted thiazole compounds, processes for their preparation, intermediates useful in their preparation, pharmaceutical compositions containing them, and their use in therapy, in particular as gastric acid secretion inhibitors.
  • the present invention therefore provides, compounds of structure (I) :
  • R is optionally substituted phenyl
  • R is Ci-galkyl or (CH2) n Ar in which n is 0 to 2 and Ar is optionally substituted phenyl;
  • R 3 i.s hydrogen or C ⁇ _4alkyl
  • R is hydrogen, C ⁇ _4alkyl, NR 7 R 8 or OCi- ⁇ alkyl;
  • R 5 is hydrogen or C ⁇ _ alkyl;
  • R 6 is hydrogen, C ⁇ _4alkyl or NR 7 R 8 ;
  • R 7 and R 8 are the same or different and are each hydrogen or
  • C ⁇ _4alkyl or one of R 7 and R 8 is hydrogen and the other is hydroxyC ⁇ _4alkyl, or R 7 and R 8 ' together with the nitrogen atom to which they are attached, form a 5- or
  • 6-membered ring optionally containing one or more additional heteroatoms; and the salts thereof.
  • R is hydrogen or optionally substituted phenyl.
  • R is an optionally substituted phenyl group.
  • Suitable substituted phenyl groups R include phenyl groups substituted by 1 to 3 substituents selected from
  • substituted phenyl groups are those substituted by a single substituent, in particular a methyl group, most preferably in the 2-position of the ring.
  • R 2 is C ⁇ _galkyl or (C__2) n Ar; preferably R2 is C ⁇ _galkyl, in particular n-propyl.
  • n is 0 to 2, preferably n is 0 or 1.
  • Suitable substituted phenyl groups Ar are as defined for substituted phenyl groups R .
  • R 3 i.s hydrogen or C ⁇ _4alkyl; preferably R3 is hydrogen.
  • R 4 is hydrogen, C _4alkyl, NR 7 R 8 or OC ⁇ _4al l; preferably R 4 is NR 7 R 8 .
  • R ⁇ is hydrogen or C ⁇ _4al l; preferably R ⁇ is hydrogen.
  • R 6 is hydrogen, or NR 7 R 8 ; preferably R ⁇ is hydrogen.
  • R 7 and R 8 are the same or different and are each hydrogen or C ⁇ _ alk l or one of R 7 and R 8 is hydrogen and the other is hydroxyC ⁇ _4alkyl, or R 7 and R 8 , together with the nitrogen atom to which they are attached, form a 5- or 6-membered ring optionally containing one or more additional heteroatoms.
  • R 7 and R 8 are the same and are both hydrogen.
  • Suitable 5- or 6-membered rings formed by R 7 and R 8 , together with the nitrogen atom to which they are attached, include, for example, pyrrolidino, morpholino, piperidino and piperazino rings..
  • the compounds of structure (I) can be prepared by processes analogous to those known in the art.
  • the present invention provides in a further aspect a process for the preparation of a compound of structure (I) which comprises
  • R 1 , R ⁇ , R3 and R ⁇ are , as described for structure (I) and one of X 1 and X ⁇ is halogen and the other is R 4 or R ⁇ as appropriate, with a suitable amine of structure HNR 7 R 8 in which R 7 and R 8 are as described for structure (I) ;
  • X is halogen such as chlorine or bromine; preferably X is bromine.
  • X 1 or X is halogen such as chlorine or bromine; preferably X 1 or X is chlorine.
  • the reaction between a compound of structure (II) and a compound of structure (III) is carried out in a suitable solvent at a temperature of between ambient and the reflux temperature of the solvent used, until the reaction is complete.
  • suitable solvents include, for example, C ⁇ _4alkanols such as methanol and ethanol, in particular ethanol.
  • the reaction is carried out at the reflux temperature of the solvent used.
  • compounds of structure (II) can themselves be prepared according to procedures known to those skilled in the art.
  • compounds of structure (II) in which X is bromine can be prepared from the corresponding precursors in which X is hydrogen, by reaction with, for example, bromine/hydrobromic acid at elevated temperature, preferably at reflux temperature, or with copper (II) bromide, in a suitable solvent medium (for example chloroform/ethyl acetate) at elevated temperature, preferably reflux temperature.
  • a suitable solvent medium for example chloroform/ethyl acetate
  • the precursor compounds of structure (II) in which X is hydrogen can be prepared from the corresponding 2-cyanopyridine of structure (V) and corresponding Grignard reagent (VI) :
  • the starting compounds of structures (V) and (VI) are commercially available or can be prepared by standard techniques from commercially available precursors.
  • suitable amines of structure HNR R can be carried out in a suitable solvent such as industrial methylated spirits, at elevated temperature, preferably under pressure, for example in a sealed pressure vessel at elevated temperature.
  • a suitable solvent such as industrial methylated spirits
  • the intermediate compounds of structure (IV) are prepared by standard techniques, for example, by reaction of the corresponding pyridine-N-oxides (VII) with, for example phosphorous oxychloride.
  • the intermediates of structure (VII) can be prepared from the corresponding compounds of structure (I) in which R to R ⁇ are all hydrogen, by reaction with a suitable oxidising agent such as m-chloroperbenzoic acid.
  • the compounds of structure (I) and their pharmaceutically acceptable salts exert an anti-secretory effect by inhibition of the gastrointestinal H K ATPase enzyme (Fellenius, E., Berglindh, T., Sachs, G., Olke, L., Elander, B., Sjostrand, S.E., and allmark, B., 1981, Nature, 290, 159-61) .
  • the present invention provides compounds of structure (I) and pharmaceutically acceptable salts thereof for use in therapy.
  • the compounds of structure (I) and their pharmaceutically acceptable salts inhibit exogenously and endogenously stimulated gastric acid secretion and are useful in the treatment of gastrointestinal diseases in mammals, in particular humans.
  • Such diseases include, for example, gastric and duodenal ulcers, aspiration pneumonitis and Zollinger- Ellison Syndrome.
  • the compounds of structure (I) can be used in the treatment of other disorders where an anti-secretory effect is desirable for example in patients with gastritis, NSAID induced gastritis, acute upper intestinal bleeding, in patients with a history of chronic and excessive alcohol consumption, and in patients with gastro oesophageal reflux disease (GERD) .
  • gastritis NSAID induced gastritis
  • acute upper intestinal bleeding in patients with a history of chronic and excessive alcohol consumption
  • gastro oesophageal reflux disease GABA
  • the compounds of the present invention are usually administered in a standard pharmaceutical composition.
  • the present invention therefore provides in a further aspect pharmaceutical compositions comprising a compound of structure (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • the compounds of structure (I) and their pharmaceutically acceptable salts which are active when given orally can be formulated as liquids, for example syrups, suspensions or emulsions, tablets, capsules and lozenges.
  • a liquid formulation will generally consist of a suspension or solution of the compound or pharmaceutically acceptable salt in a suitable liquid carrier(s) for example, ethanol, glycerine, non-aqueous solvent, for example polyethylene glycol, oils, or water with a suspending agent, preservative, flavouring or colouring agent.
  • a suitable liquid carrier(s) for example, ethanol, glycerine, non-aqueous solvent, for example polyethylene glycol, oils, or water with a suspending agent, preservative, flavouring or colouring agent.
  • a composition in the form of a tablet can be prepared using any suitable pharmaceutical carrier(s) routinely used for preparing solid formulations.
  • suitable pharmaceutical carrier(s) include magnesium stearate, starch, lactose, sucrose and cellulose.
  • a composition in the form of a capsule can be prepared using routine encapsulation procedures.
  • pellets containing the active ingredient can be prepared using standard carriers and then filled into a hard gelatin capsule; alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical carrier(s), for example aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatin capsule.
  • Typical parenteral compositions consist of a solution or suspension of the compound Or pharmaceutically acceptable salt in a sterile aqueous carrier or parenterally acceptable oil, for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil.
  • a sterile aqueous carrier or parenterally acceptable oil for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil.
  • the solution can be lyophilised and then reconstituted with a suitable solvent just prior to administration.
  • a typical suppository formulation comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof which is active when administered in this way, with a binding and/or lubricating agent such as polymeric glycols, gelatins or cocoa butter or other low melting vegetable or synthetic waxes or fats.
  • a binding and/or lubricating agent such as polymeric glycols, gelatins or cocoa butter or other low melting vegetable or synthetic waxes or fats.
  • composition is in unit dose form such as a tablet or capsule.
  • Each dosage unit for oral administration contains suitably from 1 to 1000 mg, preferably from 1 to 500 mg (and for parenteral administration contains preferably from 0.1 to 25 mg) of a compound of the formula (I) or a pharmaceutically acceptable salt thereof calculated as the free base.
  • the present invention also provides a method of inhibiting gastric acid secretion which comprises administering to a mammal in need thereof an effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt thereof; and a method of treatment of diseases of the stomach or intestine based on increased acid secretion which comprises administering to a mammal in need thereof an effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt thereof.
  • the pharmaceutically acceptable compounds of the invention will normally be administered to a subject for the treatment of gastrointestinal diseases and other conditions caused or exacerbated by gastric acidity.
  • the daily dosage regimen for an adult patient may be, for example, an oral dose of between 1 mg and 1000 mg, preferably between 1 mg and 500 mg, or an intravenous, subcutaneous, or intramuscular dose of between 0.1 mg and 100 mg, preferably between 0.1 mg and 25 mg, of the compound of the formula (I) or a pharmaceutically acceptable salt thereof calculated as the free base, the compound being administered' 1 to 4 times per day.
  • the compounds will be administered for a period of continuous therapy, for example for a week or more.
  • the compounds of the present invention can be co-administered with further active ingredients, such as antacids (for example magnesium carbonate or hydroxide and aluminium hydroxide) , non-steroidal anti-flammatory drugs (for example indomethacin, aspirin or naproxen) , steroids, or nitrite scavengers (for example ascorbic acid or aminosulphonic acid) , or other drugs used for treating gastric ulcers (for example histamine . ⁇ -antagonists such as cimetidine) , or agents having activity against Helicobacter pylori organisms, for example antibiotics such as amoxicillin.
  • active ingredients such as antacids (for example magnesium carbonate or hydroxide and aluminium hydroxide) , non-steroidal anti-flammatory drugs (for example indomethacin, aspirin or naproxen) , steroids, or nitrite scavengers (for example ascorbic acid or aminosulphonic acid) , or other
  • Lyophilised gastric vesicles were prepared from pig fundic ucosa after the method of Keeling et. al. (Biochem. Pharmacol., 34, 2967, 1985).
  • K -stimulated ATPase activity was determined at 37°C in the presence of the following : 10 mM Pipes/Tris buffer pH 7.0, 2 mM MgSC.4, - mM K C1 " ⁇ a2A P and 3-6 ⁇ g protein/ml lyophilised gastric vesicles. After incubation for 30 minutes, the inorganic phosphate hydrolysed from ATP was determined by the method of
  • the compounds of the examples exhibited IC50 values in the range of between 1 and 100 ⁇ M.

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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)
  • Pyridine Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

Dérivés de pyridyle-thiazole de structure (I) dans laquelle T1 représente un phényle substitué; R2 représente un alkyleC¿1-6? ou (CH2)nAr dans lequel n varie de 0 à 2 et Ar représente un phényle éventuellement substitué; R?3¿ représente hydrogène ou alkyleC¿1-4; R?4 représente hydrogène, alkyleC¿1-4?, NR?7R8¿ ou alkyleOC¿1-4; R?5 représente hydrogène ou alkyleC¿1-4; R?6 représente hydrogène, alkyleC¿1-4? ou NR?7R8; R7 et R8¿ sont identiques ou différents et représentent chacun hydrogène ou alkyle C¿1-4? ou l'un de R?7¿ ou de R8 représente hydrogène et l'autre représente hydroxyalkyle C¿1-4?, ou bien R?7 et R8¿ conjointement avec l'atome d'azote auquel ils sont liés, forment un cycle à 5 ou 6 éléments contenant éventuellement un ou plusieurs hétéroatomes supplémentaires. L'invention concerne également un sel desdits dérivés ainsi que l'utilisation de ceux-ci en thérapie comme inhibiteurs de sécrétion d'acide gastrique.
PCT/EP1993/000176 1992-01-27 1993-01-26 Derives de thiazolyle-pyridine et leur utilisation comme inhibiteurs de secretion d'acide gastrique WO1993015071A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
JP5512931A JPH07503023A (ja) 1992-01-27 1993-01-26 チアゾリルピリジン誘導体およびその胃酸分泌阻害剤としての用途
EP93903880A EP0625151A1 (fr) 1992-01-27 1993-01-26 Derives de thiazolyle-pyridine et leur utilisation comme inhibiteurs de secretion d'acide gastrique

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB929201692A GB9201692D0 (en) 1992-01-27 1992-01-27 Compounds
GB9201692.2 1992-01-27

Publications (1)

Publication Number Publication Date
WO1993015071A1 true WO1993015071A1 (fr) 1993-08-05

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Country Link
EP (1) EP0625151A1 (fr)
JP (1) JPH07503023A (fr)
AU (1) AU3494293A (fr)
GB (1) GB9201692D0 (fr)
WO (1) WO1993015071A1 (fr)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999021555A3 (fr) * 1997-10-27 1999-07-22 Takeda Chemical Industries Ltd Antagonistes des recepteurs de l'adenosine a¿3?
WO2001074811A3 (fr) * 2000-03-30 2002-02-07 Takeda Chemical Industries Ltd Composes de 1,3-thiazole substitues, production et utilisation desdits composes
WO2002062776A1 (fr) * 2001-02-02 2002-08-15 Glaxo Group Limited Derives de 2-amino-4-(pyridine-2-yle)-thiazole en tant qu'inhibiteurs du facteur de croissance transformant beta (tgf-bêta)
WO2004026307A1 (fr) * 2002-09-18 2004-04-01 Pfizer Products Inc. Derives de triazole servant d'inhibiteurs du facteur de croissance transformant (tgf)
US7175854B2 (en) 2000-12-07 2007-02-13 Altana Pharma Ag Pharmaceutical preparation comprising an active dispersed on a matrix
US7273936B2 (en) 2002-09-18 2007-09-25 Pfizer Inc. Oxazole and thiazole compounds as transforming growth factor (TGF) inhibitors
US7951397B2 (en) 2002-02-20 2011-05-31 Nycomed Gmbh Oral dosage form containing a PDE 4 inhibitor as an active ingredient and polyvinylpyrrolidon as excipient

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0149884A2 (fr) * 1983-09-09 1985-07-31 Takeda Chemical Industries, Ltd. Dérivés de 5-pyridyle-1,3-thiazole, leur préparation et utilisation
EP0169502A2 (fr) * 1984-07-25 1986-01-29 Merck & Co. Inc. 2-Benzyl-4-(2-morpholino)-4-Pyriol)Thiazole
EP0325496A1 (fr) * 1988-01-22 1989-07-26 Sumitomo Pharmaceuticals Company, Limited Dérivés de 2-pyridylthiazolidine-4-one comme agents anti-ulcère

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0149884A2 (fr) * 1983-09-09 1985-07-31 Takeda Chemical Industries, Ltd. Dérivés de 5-pyridyle-1,3-thiazole, leur préparation et utilisation
EP0169502A2 (fr) * 1984-07-25 1986-01-29 Merck & Co. Inc. 2-Benzyl-4-(2-morpholino)-4-Pyriol)Thiazole
EP0325496A1 (fr) * 1988-01-22 1989-07-26 Sumitomo Pharmaceuticals Company, Limited Dérivés de 2-pyridylthiazolidine-4-one comme agents anti-ulcère

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
JOURNAL OF HETEROCYCLIC CHEMISTRY. vol. 22, no. 3, May 1985, PROVO US pages 669 - 671 WALTER KLOSE ET AL 'Synthese von Pyridylphenyl-imidazo[2,1-b]thiazolen' *

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999021555A3 (fr) * 1997-10-27 1999-07-22 Takeda Chemical Industries Ltd Antagonistes des recepteurs de l'adenosine a¿3?
US6620825B1 (en) 1997-10-27 2003-09-16 Takeda Chemical Industries, Ltd. Adenosine A3 receptor antagonists
WO2001074811A3 (fr) * 2000-03-30 2002-02-07 Takeda Chemical Industries Ltd Composes de 1,3-thiazole substitues, production et utilisation desdits composes
US7495018B2 (en) 2000-03-30 2009-02-24 Takeda Pharmaceutical Company Limited Substituted 1,3-thiazole compounds, their production and use
US7175854B2 (en) 2000-12-07 2007-02-13 Altana Pharma Ag Pharmaceutical preparation comprising an active dispersed on a matrix
US7951398B2 (en) 2000-12-07 2011-05-31 Nycomed Gmbh Pharmaceutical preparation comprising an active dispersed on a matrix
WO2002062776A1 (fr) * 2001-02-02 2002-08-15 Glaxo Group Limited Derives de 2-amino-4-(pyridine-2-yle)-thiazole en tant qu'inhibiteurs du facteur de croissance transformant beta (tgf-bêta)
US7951397B2 (en) 2002-02-20 2011-05-31 Nycomed Gmbh Oral dosage form containing a PDE 4 inhibitor as an active ingredient and polyvinylpyrrolidon as excipient
US9468598B2 (en) 2002-02-20 2016-10-18 Astrazeneca Ab Oral dosage form containing a PDE 4 inhibitor as an active ingredient and polyvinylpyrrolidon as excipient
WO2004026307A1 (fr) * 2002-09-18 2004-04-01 Pfizer Products Inc. Derives de triazole servant d'inhibiteurs du facteur de croissance transformant (tgf)
US7053095B2 (en) 2002-09-18 2006-05-30 Pfizer Inc. Triazole compounds as transforming growth factor (TGF) inhibitors
US7273936B2 (en) 2002-09-18 2007-09-25 Pfizer Inc. Oxazole and thiazole compounds as transforming growth factor (TGF) inhibitors

Also Published As

Publication number Publication date
AU3494293A (en) 1993-09-01
EP0625151A1 (fr) 1994-11-23
GB9201692D0 (en) 1992-03-11
JPH07503023A (ja) 1995-03-30

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