EP0625151A1 - Thiazolyl-pyridine derivatives and their use as gastric acid secretion inhibitors - Google Patents
Thiazolyl-pyridine derivatives and their use as gastric acid secretion inhibitorsInfo
- Publication number
- EP0625151A1 EP0625151A1 EP93903880A EP93903880A EP0625151A1 EP 0625151 A1 EP0625151 A1 EP 0625151A1 EP 93903880 A EP93903880 A EP 93903880A EP 93903880 A EP93903880 A EP 93903880A EP 0625151 A1 EP0625151 A1 EP 0625151A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- methylphenyl
- pyridyl
- compound
- thiazole
- propyl
- 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.)
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Classifications
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- 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
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- 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
Abstract
Dérivés de pyridyle-thiazole de structure (I) dans laquelle T1 représente un phényle substitué; R2 représente un alkyleC1-6 ou (CH2)nAr dans lequel n varie de 0 à 2 et Ar représente un phényle éventuellement substitué; R3 représente hydrogène ou alkyleC1-4; R4 représente hydrogène, alkyleC1-4, NR7R8 ou alkyleOC1-4; R5 représente hydrogène ou alkyleC1-4; R6 représente hydrogène, alkyleC1-4 ou NR7R8; R7 et R8 sont identiques ou différents et représentent chacun hydrogène ou alkyle C1-4 ou l'un de R7 ou de R8 représente hydrogène et l'autre représente hydroxyalkyle C1-4, ou bien R7 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.Pyridyl-thiazole derivatives of structure (I) in which T1 represents a substituted phenyl; R2 represents C1-6 alkyl or (CH2) nAr in which n varies from 0 to 2 and Ar represents an optionally substituted phenyl; R3 represents hydrogen or C1-4alkyl; R4 represents hydrogen, C1-4alkyl, NR7R8 or OC1-4alkyl; R5 represents hydrogen or C1-4alkyl; R6 represents hydrogen, C1-4alkyl or NR7R8; R7 and R8 are the same or different and each represents hydrogen or C1-4 alkyl or one of R7 or R8 represents hydrogen and the other represents C1-4 hydroxyalkyl, or else R7 and R8 together with the nitrogen atom to which they are linked, form a 5 or 6 element ring possibly containing one or more additional heteroatoms. The invention also relates to a salt of said derivatives and to the use thereof in therapy as inhibitors of gastric acid secretion.
Description
Thiazolyl-pyridlne derivatives and their use as gastric add secretion In¬ hibitors
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) :
n which
1 R is optionally substituted phenyl;
2 .
R is Ci-galkyl or (CH2)nAr in which n is 0 to 2 and Ar is optionally substituted phenyl;
R 3 i.s hydrogen or Cι_4alkyl;
R is hydrogen, Cι_4alkyl, NR7R8 or OCi-^alkyl; R5 is hydrogen or Cχ_ alkyl;
R6 is hydrogen, Cι_4alkyl or NR7R8;
R7 and R8 are the same or different and are each hydrogen or
Cι_4alkyl or one of R7 and R8 is hydrogen and the other is hydroxyCι_4alkyl, or R7 and R8' 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.
Suitably, R is hydrogen or optionally substituted phenyl. Preferably R is an optionally substituted phenyl group.
1 Suitable substituted phenyl groups R include phenyl groups substituted by 1 to 3 substituents selected from
C^-galkyl, C^-galkoxy, amino, Cι_galkylthio, halogen, cyano, hydroxy, carbamoyl, carboxy, C^-galkanoyl or trifluoromethyl. Preferred substituted phenyl groups are those substituted by a single substituent, in particular a methyl group, most preferably in the 2-position of the ring.
Suitably, R 2 is Cχ_galkyl or (C__2)nAr; preferably R2 is Cχ_galkyl, in particular n-propyl.
Suitably, n is 0 to 2, preferably n is 0 or 1.
Suitable substituted phenyl groups Ar are as defined for substituted phenyl groups R .
Suitably, R 3 i.s hydrogen or Cχ_4alkyl; preferably R3 is hydrogen.
Suitably R4 is hydrogen, C _4alkyl, NR7R8 or OCι_4al l; preferably R4 is NR7R8.
Suitably R^ is hydrogen or Cι_4al l; preferably R^ is hydrogen.
Suitably R6 is hydrogen,
or NR7R8; preferably R^ is hydrogen.
Suitably, R7 and R8 are the same or different and are each hydrogen or Cι_ alk l or one of R7 and R8 is hydrogen and the other is hydroxyCχ_4alkyl, or R7 and R8, together with the nitrogen atom to which they are attached, form a 5- or 6-membered ring optionally containing one or more additional heteroatoms. Preferably R7 and R8 are the same and are both hydrogen.
Suitable 5- or 6-membered rings formed by R7 and R8, 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
a) reaction of a compound of structure (II) with a compound of structure (III) :
in which R to R> are as described for structure (I), and X is halogen;
b) for compounds in which one of R4 or R^ is NR7R8, reaction of a compound of structure (IV) :
in which R1, R^, R3 and R^ are, as described for structure (I) and one of X1 and X^ is halogen and the other is R4 or
R^ as appropriate, with a suitable amine of structure HNR7R8 in which R7 and R8 are as described for structure (I) ;
c) for compounds in which one of R4 or R^ is NH?, reduction of a compound of structure (IV) in which X or X^ is N3; and
optionally thereafter, forming a salt.
Suitably, X is halogen such as chlorine or bromine; preferably X is bromine. Suitably 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, Cι_4alkanols such as methanol and ethanol, in particular ethanol. Preferably 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. For example, 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. 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) :
in which R and R to R^ are as described for structure (I) and X is halogen.
The starting compounds of structures (V) and (VI) are commercially available or can be prepared by standard techniques from commercially available precursors.
The reaction between compounds of structure (IV) and
4 5 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.
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 reduction of compounds of structure (IV) in which X is azide is carried out by hydrogenation over a noble metal catalyst, such as palladium on carbon. The intermediates of structure (IV) in which X is azide can be
prepared from the corresponding compounds of structure (VII) by reaction with (PhO)2P (0)N3<
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) .
In a further aspect therefore 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.
Further, 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) .
In therapeutic use, 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 composition in the form of a tablet can be prepared using any suitable pharmaceutical carrier(s) routinely used for preparing solid formulations. Examples of such carriers include magnesium stearate, starch, lactose, sucrose and cellulose.
A composition in the form of a capsule can be prepared using routine encapsulation procedures. For example, 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. Alternatively, 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.
Preferably the 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.
Suitably the compounds will be administered for a period of continuous therapy, for example for a week or more.
In addition, 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.
The following examples illustrate the invention. Temperatures are recorded in degrees centigrade.
Example 1 2-Propyl- -(2-pyridyl)-5-(2- ethylphβnyl)thiazole dihydrobromide
(i) 2-(2- ethylphenylacetyl)pyridine
A solution of α-bromo-o-xylene (9.25 g, 0.05 mol) in anhydrous ether (50 ml) was added dropwise under nitrogen to a stirred mixture of magnesium turnings (1.21 g, 0.05 mol) and anhydrous ether (15 ml) so as to maintain a gentle reflux. After a further 10 min, a solution of 2-cyano- pyridine (5.2 g, 0.05 mol) in anhydrous ether (50 ml) was added dropwise over 15 min. The mixture was stirred for a further 2 hours, left to stand for 16 hours, then cooled in ice and a 20% aqueous ammonium chloride solution added dropwise, followed by cone, hydrochloric acid (14 ml) to give two clear layers. The aqueous layer was separated and extracted with chloroform. The combined organic layers were dried and evaporated to a dark oil, which was purified by flash chromatography (silica, dichloromethane) to give the title compound as an oil (4.86 g) .
(ii) 2-(2-Methylphenylbromoacetyl)pyridine
A solution of 2- (2-methylphenylacetyl)pyridine (21.26 g,
0.1 mol) in 48% aqueous hydrobromic acid (100 ml) was heated at 100 °C whilst bromine (17.7 g. 0.11 mol) was added dropwise over 5 min. After a further 10 min the solution was allowed to cool, and the resulting solid filtered off and washed with acetonitrile, then converted to the free base and crystallised from pet. ether to give the product (15.88 g) , m.p. 53-55°C.
(iii) 2-Propyl-4- (2-pyridyl)-5-(2-methylphenyl)thiazole dihydrobromide
A solution of 2-(2-methylphenylbromoacetyl)pyridine (1.82 g, 6.27 mmol) and thiobutyra ide (0.65 g, 6.27 mmol) in ethanol
(40 ml) was heated under reflux for 4 hours. The solvent was evaporated and the residue triturated with ether, slowly giving a crystalline solid. Conversion to the dihydrobromide and recrystallisation from ethanol/ether then from methanol/ether gave the title compound as a yellow solid (1.25 g) , m.p. 200-201°C.
C18H18N2S -2HBr Found C 47.28, H 4.46, N 6.05, Br 34.72, S 6.83 Requires C 47.39, H 4.42, N 6.14, Br 35.03, S 7.03
Example 2
2-Propyl- -(6-methylamino-2-pyridyl)-5-(2- methylphenyl) hiazole
(i) 2-Propyl-4- (l-oxo-2-pyridyl)-5- (2-methylphenyl)thiazole
2-Propyl-4- (2-pyridyl)-5- (2-methylphenyl)thiazole dihydrobromide (10.74 g, 28.6 mmol) was converted to the free base by treatment with sodium bicarbonate and extraction into dichloromethane. _?-Chloroperbenzoic acid (55.93 g, 34.4 mmol) was added to the organic solution portionwise over about 5 min with stirring. The clear solution was left to stand for 16 hours, then cooled in ice, ammonia gas bubbled through, the precipitate filtered off and the filtrate evaporated to a brown oil. Flash chromatography (silica, methanol/dichloromethane) and crystallisation from pet. ether gave the title compound (6.87 g) , m.p. 80-82°C.
(ii) 2-Propyl-4-(6-chloro-2-pyridyl)-5-(2-methylphenyl) - thiazole and 2-propyl-4- (4-chloro-2-pyridyl)-5- (2- methylphenyl)thiazole
2-Propyl-4- (l-oxo-2-pyridyl)-5- (2-methylphenyl)thiazole (2.15 g, 6.93 mmol) and phosphoryl chloride (5 ml, excess) were heated at 120 °C for 1 hour. The excess phosphoryl chloride was evaporated, and the residue treated with ice- water, basified with sodium bicarbonate and extracted with dichloromethane, then the extracts dried and evaporated.
Chromatography (silica, dichloromethane/methanol) gave 2- propyl-4-(6-chloro-2-pyridyl)-5- (2-methylphenyl)thiazole as a low-melting solid (1.19 g) , m.p. 64-66°C, and 2-propyl-4- (4-chloro-2-pyridyl)-5-(2-methylphenyl)thiazole as an oil (0.62 g) .
(iii) 2-Propyl-4- (6-methylamino-2-pyridyl)-5-(2- methylphenyl)thiazole
2-Propyl-4-(6-chloro-2-pyridyl)-5-(2-methylphenyl)thiazole (2.0 g, 6.1 mmol) and a 33% solution of methylamine in IMS (50 ml) were heated together in a pressure vessel at 185 °C for 16 hours. After cooling, the solvent was evaporated, the residue treated with dilute aqueous sodium carbonate solution, and extracted several times with dichloromethane. The combined extracts were dried and evaporated to an oil, which was purified by flash chromatography (silica, dichloromethane/methanol) to give the title compound (1.21 g) as an oil. C 9_i2 N2S
Found C 70.49, H 6.38, N 12.93 Requires C 70.55, H 6.54, N 12.99
Example 3 2-Propyl-4-(6-(2-hydroxyethylamino)-2-pyridyl)-5-(2- methylphenyl) hiazole
2-Propyl-4-(6-chloro-2-pyridyl)-5- (2-methylphenyl)thiazole (1.0 g, 3.04 mmol) and ethanolamine (5 ml, excess) were heated under reflux for 16 hours. The solution was diluted with water and extracted several times with dichloromethane. The combined extracts were washed with water, dried and evaporated to an oil, which was purified by flash chromatography (silica, dichloromethane/methanol) , then crystallisation from acetone/water to give the title compound (0.69 g) as a hydrate', m.p. indeterminate.
C20H23N3θS -1.27H20 Found C 63.85, H 6.77, N 11.06 Requires C 63.82, H 6.84, N 11.17
Example 4
2-Propyl-4-(6-amino-2-pyridyl)-5-(2-methylphenyl)thiazole
(i) 2-Propyl-4- (6-azido-2-pyridyl)-5- (2-methylphenyl)- thiazole
2-Propyl-4- (l-oxo-2-pyridyl)-5- (2-methylphenyl)thiazole (2.0 g, 6.44 mmol) and diphenylphosphoryl azide (3.55 g, 12.9 mmol) were heated at 155-160°C for 3 hours. After cooling, the residue was treated with aqueous sodium hydroxide and extracted with dichloromethane. The extracts were dried and evaporated to an oil, which was purified by flash chromatography (silica, ether/pet. ether) and crystallisation from ether/pet. ether to give the title compound (0.38 g) , m.p. 70-72°C.
(ii) 2-Propyl-4- (6-amino-2-pyridyl)-5- (2-methylphenyl)- thiazole
A solution of 2-propyl-4- (6-azido-2-pyridyl)-5- (2- methylphenyl)thiazole (0.5 g, 1.5 mmol) in ethanol (50 ml) was hydrogenated over 10% palladium on charcoal (0.1 g) at 50 p.s.i. for 2.5 hours. The catalyst was filtered off and the filtrate evaporated. Recrystallisation from ether/ pet. ether gave the title compound (0.22 g) , m.p. 80-81°C. Cχ8Hl9N3S
Found C 69.91, H 6.25, N 13.58 Requires C 69.87, H 6.19, N 13.58
Example 5 2-Propyl-4-(4-a_nino-2-pyridyl)-5-(2-methylphenyl)thiazole
2-Propyl-4- (4-chloro-2-pyridyl)-5- (2-methylphenyl)thiazole (0.62 g, 1.88 mmol) and phenol (8g, excess) were heated with
stirring at 200 °C, whilst ammonia gas was bubbled through for 3 hours. The excess phenol was distilled off under reduced pressure, and the residue treated with aqueous sodium hydroxide and extracted with ether. The combined extracts were dried and evaporated to an oil, which was purified by flash chromatography (silica, methanolic ammonia/dichloromethane) then crystallised from pet. ether to give the title compound (0.2 g) , m.p. 135-136°C.
C18H19N3S Found C 69.73, H 6.17, N 13.45
Requires C 69.87, H 6.19, N 13.58
Example 6 2-Methyl-4-(2-pyridyl)-5-(2-methylphenyl) hiazole hydrobromide
A solution of 2- (2-methylphenylbromoacetyl)pyridine (1.3 g, 4.48 mmol) and thioacetamide (0.4 g, 5.4 mmol) in ethanol (25 ml) was heated under reflux for 5 hours. The solvent was evaporated and the residue triturated with ether to give a yellow solid which after recrystallisation from methanol/acetone then from acetonitrile gave the title compound (0.56 g) , m.p. 209-212°C.
C16H14N2S *HBr Found C 55.37, H 4.35, N 8.13
Requires C 55.34, H 4.35, N 8.07
Example 7 2-(2-Methylphenyl)-4-(2-pyridyl)-5-(2-methylphenyl) hiazole hydrobromide
A solution of 2- (2-methylphenylbromoacetyl)pyridine (0.7 g, 2.41 mmol) and 2-methylthiobenzamide (0.44 g, 2.89 mmol) in ethanol (15 ml) was heated under reflux for 4 hours. The solvent was evaporated and the residue triturated with ether to give a yellow solid which after recrystallisation from acetonitrile gave the title compound (0.51 g) , m.p. 221-223°C.
C22Hχ8N2S -HBr Found C 62.05, H 4.58, N 6.70 Requires C 62.41, H 4.52, N 6.62
Example 8 2-(Phenylmethyl)-4-(2-pyridyl)-5-(2-methylphenyl)thiazole
A solution of 2- (2-methylphenylbromoacetyl)pyridine (1.03 g, 3.55 mmol) and phenylthioacetamide (0.64 g, 4.26 mmol) in ethanol (20 ml) was heated under reflux for 4 hours. The solvent was evaporated and the residue treated with aqueous sodium bicarbonate and extracted with dichloromethane.
Drying and evaporation of the organic layer followed by flash chromatography (silica, dichloromethane/ethyl acetate) and crystallisation from pet. ether gave the title compound
(0.86 g) , m.p. 94-95°C.
C22H18N2S Found C 77.21, H 5.33, N 8.27 Requires C 77.16, H 5.30, N 8.18
Example 9 2-Propyl-4-(2-pyridyl)-5-phenylthiazole hydrobro ide
(i) 2- (Phenylbromoacetyl)pyridine
To a stirring solution of 2-phenylacetylpyridine (5.0 g, 0.025 mol) in cone. HBr (48-50% w/w, 25 ml) at 100°C was added bromine (1.42 ml, 0.0275 mol) dropwise over a period of 5 mins. The solution was maintained at 100°C for a further 10 mins then cooled to room temperature, diluted with water and extracted with dichloromethane. The combined organic layers were washed with dilute sodium bicarbonate, dried and evaporated to an oil which was crystallised from petroleum ether to give the title compound (4.25 g) m.p. 54-55°C.
(ii) 2-Propyl-4-(2-pyridyl)-5-phenylthiazole
2- (Phenylbromoacetyl)pyridine (4.0 g, 0.0145 mol) and thiobutyramide (1.79 g, 0.0174 mol) were dissolved in ethanol (50 ml) and refluxed for 4 hrs. The solvent was evaporated off and the residue triturated with ether to give buff coloured crystals. These were filtered off, recrystallised from acetonitrile/ether and dried to yield the title compound (2.58 g) , m.p. 130-133°C.
C 7 H16 N2 S -HBr Found: C 56.05 H 4.76 N 7.83 Requires: C 56.51 H 4.74 N 7.75
Biological Data.
H K ATPase Activity.
The effects of a single high concentration (100 μM) of a compound of structure (I) on K-stimulated ATPase activity in lyophilised gastric vesicles was determined. Preferred compounds of structure (I) were also tested over a range of concentrations to determine IC50 values.
(i) Preparation of lyophilised gastric vesicles (H/K-ATPase) .
Lyophilised gastric vesicles were prepared from pig fundic ucosa after the method of Keeling et. al. (Biochem. Pharmacol., 34, 2967, 1985).
(ii) K -stimulated ATPase activity.
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 KC1 "^ a2A P and 3-6 μg protein/ml lyophilised gastric vesicles. After incubation for 30 minutes, the inorganic phosphate hydrolysed from ATP was determined by the method of
Yoda and Hokin (Biochem. Biophys. Res. Commun. 40, 880, 1970) .
Compounds of structure (I) were dissolved in dimethylsulphoxide which up to the highest concentration used had no effect on K -stimulated ATPase activity. The effect of the highest concentration of each compound of structure (I) on the recovery of a standard amount of inorganic phosphate was also determined.
Results
The compounds of the examples exhibited IC50 values in the range of between 1 and 100 μM.
Claims
Claims :
A compound of structure (I) :
in which
R is optionally substituted phenyl;
2 .
R is Cχ_galkyl or (CH2)nAr in which n is 0 to 2 and Ar is optionally substituted phenyl;
R 3 i■s hydrogen or Cχ_4alkyl;
R4 is hydrogen, Cχ_4alkyl, NR7R8 or 0Cχ_4alkyl; R5 is hydrogen or C _4 alkyl; R6 is hydrogen, Cχ_4alkyl or NR7R8; R7 and R8 are the same or different and are each hydrogen or Cχ_4alkyl or one of R7 and R8 is hydrogen and the other is hydroxyCχ_4alkyl, or R7 and R8' together with the nitrogen atom to which they are attached, form a 5- or 6-membered ring optionally containing one or more additional heteroatoms; or a salt thereof.
2. A compound according to claim 1 in which R- is o- methylphenyl.
3. A compound according to claim 2 in which R2 is n- propyl.
4. A compound according to claim 3 in which R^ is NR7R8 in which R7 and R8 are both hydrogen.
A compound of structure (I) which is: 2-propyl-4- (2-pyridyl) -5- (2-methylphenyl)thiazole dihydrobromide;
2-propyl-4- (6-methylamino-2-pyridyl) -5- (2-methylphenyl) - thiazole; 2-propyl-4-(6-(2-hydroxyethylamino) -2-pyridyl) -5-(2- methylphenyl)thiazole;
2-propyl-4- (6-amino-2-pyridyl) -5- (2-methylphenyl)thiazole;
2-propyl-4- (4-amino-2-pyridyl) -5- (2-methylphenyl)thiazole;
2-methyl-4- (2-pyridyl) -5- (2-methylphenyl)thiazole hydrobromide;
2- (2-methylphenyl) -4- (2-pyridyl) -5- (2-methylphenyl)- thiazole;
2- (phenylmethyl) -4- (2-pyridyl) -5- (2-methylphenyl)thiazole; or 2-propyl-4- (2-pyridyl) -5-phenylthiazole hydrobromide.
6. A process for preparing a compound of structure (I) which comprises
a) reaction of a compound of structure (II) with a compound of structure (III) :
in which R to R^ are as described for structure (I) , and X is halogen;
b) for compounds in which one of R4 or R^ is NR7R8, reaction of a compound of structure (IV) :
in which R1, R2, R^ and R5 are as described for structure (I) and one of X1 and X2 is halogen and the other is R4 or R^ as appropriate, with a suitable amine of structure HNR R8 in which R7 and R8 are as described for structure (I) ;
c) for compounds in which one of R4 or R^ is N__2, reduction of a compound of structure (IV) in which X 1 or is N3; and
optionally thereafter, forming a salt.
7. A pharmaceutical composition comprising a compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier.
8. A compound according to any one of claims 1 to 5 for use in therapy, in particular in the treatment of gastrointestinal disorders.
9. A compound of structure (II) as defined in claim
10. A compound of structure (IV) as defined in claim
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9201692 | 1992-01-27 | ||
| GB929201692A GB9201692D0 (en) | 1992-01-27 | 1992-01-27 | Compounds |
| PCT/EP1993/000176 WO1993015071A1 (en) | 1992-01-27 | 1993-01-26 | Thiazolyl-pyridine derivatives and their use as gastric acid secretion inhibitors |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP0625151A1 true EP0625151A1 (en) | 1994-11-23 |
Family
ID=10709305
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP93903880A Withdrawn EP0625151A1 (en) | 1992-01-27 | 1993-01-26 | Thiazolyl-pyridine derivatives and their use as gastric acid secretion inhibitors |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP0625151A1 (en) |
| JP (1) | JPH07503023A (en) |
| AU (1) | AU3494293A (en) |
| GB (1) | GB9201692D0 (en) |
| WO (1) | WO1993015071A1 (en) |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6436966B1 (en) | 1997-10-27 | 2002-08-20 | Takeda Chemical Ind., Ltd. | Adenosine A3 receptor antagonists |
| AU2001244618A1 (en) | 2000-03-30 | 2001-10-15 | Takeda Chemical Industries Ltd. | Substituted 1,3-thiazole compounds, their production and use |
| UA80393C2 (en) | 2000-12-07 | 2007-09-25 | Алтана Фарма Аг | Pharmaceutical preparation comprising an pde inhibitor dispersed on a matrix |
| GB0102668D0 (en) * | 2001-02-02 | 2001-03-21 | Glaxo Group Ltd | Compounds |
| MY140561A (en) | 2002-02-20 | 2009-12-31 | Nycomed Gmbh | Dosage form containing pde 4 inhibitor as active ingredient |
| AU2003256003A1 (en) | 2002-09-18 | 2004-04-08 | Pfizer Products Inc. | Novel oxazole and thiazole compounds as transforming growth factor (TGF) inhibitors |
| MXPA05002982A (en) * | 2002-09-18 | 2005-06-22 | Pfizer Prod Inc | Triazole derivatives as transforming growth factor (tgf) inhibitors. |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0149884B1 (en) * | 1983-09-09 | 1992-12-16 | Takeda Chemical Industries, Ltd. | 5-pyridyl-1,3-thiazole derivatives, their production and use |
| US4697012A (en) * | 1984-07-25 | 1987-09-29 | Merck & Co., Inc. | Morpholino pyridyl thiazole compound |
| US5021435A (en) * | 1988-01-22 | 1991-06-04 | Sumitomo Pharmaceuticals Company, Limited | Certain pyridyl-thiazolidin-4-one having anti-ulcer activity |
-
1992
- 1992-01-27 GB GB929201692A patent/GB9201692D0/en active Pending
-
1993
- 1993-01-26 JP JP5512931A patent/JPH07503023A/en active Pending
- 1993-01-26 AU AU34942/93A patent/AU3494293A/en not_active Abandoned
- 1993-01-26 WO PCT/EP1993/000176 patent/WO1993015071A1/en not_active Application Discontinuation
- 1993-01-26 EP EP93903880A patent/EP0625151A1/en not_active Withdrawn
Non-Patent Citations (1)
| Title |
|---|
| See references of WO9315071A1 * |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH07503023A (en) | 1995-03-30 |
| WO1993015071A1 (en) | 1993-08-05 |
| AU3494293A (en) | 1993-09-01 |
| GB9201692D0 (en) | 1992-03-11 |
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