GB2038327A - Bis-(pyridiniumthio) quarternary compounds as anti-ulcer agents - Google Patents
Bis-(pyridiniumthio) quarternary compounds as anti-ulcer agents Download PDFInfo
- Publication number
- GB2038327A GB2038327A GB7941030A GB7941030A GB2038327A GB 2038327 A GB2038327 A GB 2038327A GB 7941030 A GB7941030 A GB 7941030A GB 7941030 A GB7941030 A GB 7941030A GB 2038327 A GB2038327 A GB 2038327A
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- GB
- United Kingdom
- Prior art keywords
- ulcer agent
- lower alkyl
- alkyl
- ulcer
- pharmaceutical composition
- 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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- 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
- C07D213/60—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/70—Sulfur atoms
Abstract
The invention provides, as an anti- ulcer agent, a compound of formula I <IMAGE> wherein R is alkyl, aryl or aralkyl, R<1> is hydrogen, lower alkyl, hydroxyloweralkyl, loweralkoxyloweralkyl, loweralkoxy, halogen, formyl, phenyl, phenylalkyl or acetal [CH(OR<4>)2 where R<4> is lower alkyl or two R<4> radicals are joined to form a lower alkylene chain], n and m are 1 or 2, Z<-> is an anion and R and R<1> radicals may be the same or different, and A represents a methylene or ethylene radical which may be substituted by lower alkyl of 1 to 6 carbon atoms, oxo or hydroxy, and S is sulphur. Pharmaceutical compositions containing the anti-ulcer agents are also described.
Description
SPECIFICATION
Anti-ulcer agents
The invention relates to novel anti-ulcer agents and pharmaceutical compositions containing them.
During the course of a search for novel anti-ulcer agents we have prepared and tested certain pyridinium compounds which have two pyridinium rings linked through two sulphur atoms and an alkylene chain. We have found that representative examples of this class of compounds possess anti-ulcer and/or anti-secretory activity. Some of these compounds are known but others are novel. So far as we are aware no specific pharmaceutical use for these compounds has previously been reported.
Accordingly in one aspect the invention provides as an anti-ulcer agent, a compound of the formula
wherein R is alkyl, aryl or aralkyl, R1 is hydrogen, lower alkyl, hydroxylower alkyl, lower alkoxylower alkyl, lowerakoxy, halogen, formyl, phenyl, phenylalkyl oracetal [CH(OR4)2where R4 is lower alkyl or two R4 radicals are joined to form a lower alkylene chain, n and m are 1 or 2, Z is an anion and R and R1 radicals may be the same or different, and A represents a methylene or ethylene radical which may be substituted by lower alkyl of 1 to 6 carbon atoms, oxo or hydroxy, and S is sulphur.
The radical A is preferably unsubstituted methylene or ethylene.
Z- may be a halide ion, eg chloride, bromide, iodide or fluoride or an organic sulphonate ion eg, a lower alkylsulphonate such as methylsulphonate(mesyl) or an aryl sulphonate, eg p-toluene sulphonate (tosyl).
In this specification when a group is substituted by alkyl, this is preferably lower alkyl of 1 to 6 carbon atoms e.g. methyl, ethyl, n-propyl; isopropyl, n-butyl, s-butyl, t-butyl, n-pentyl and n-hexyl. An alkoxy substituent is preferably lower alkoxy in which the alkyl portion is as defined for a lower alkyl group.
Whenever the term lower alkyl is used as part of another radical e.g. arylloweralkyl, the lower alkyl portion has 1 to 6 carbon atoms.
The invention includes a pharmaceutical composition in a form suitable for therapeutic administration comprising a compound of formula I and a pharmaceutically acceptable carrier. Preferably the pharmaceutical composition is in unit dosage form.
For the pharmaceutical carrier any suitable carrier known in the art can be used to prepare the pharmaceutical compositions. In such a composition, the carrier may be a solid, liquid, or mixture of a solid and a liquid. Solid form compositions include powders, tablets and capsules. A solid carrier can be one or more substances which may also act as flavouring agents, lubricants, solubilisers, suspending agents, binders, or tablet disintegrating agents; it can also be an encapsulating material. In powders the carrier is a finely divided solid which is in admixture with the finely divided active ingredient. In tablets the active ingredient is mixed with a carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain from 5 to 99, preferably 10-80% of the active ingredient.Suitable solid carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a low melting wax and cocoa butter. The term "composition" is intended to include the formulation of an active ingredient with encapsulating material as carrier to give a capsule in which the active ingredient (with or without other carriers) is surrounded by carriers, which is thus in association with it. Similarly cachets are included.
Sterile liquid form compositions include sterile solutions, suspensions, emulsions, syrups and elixirs. The active ingredient can be dissolved or suspended in a pharmaceutically acceptable carrier, such as sterile water, sterile organic solvent or mixture of both. The active ingredient can often be dissolved in a suitable organic solvent, for instance aqueous propylene glycol containing from 10 to 75% of the glycol by weight is generally suitable. In other instances compositions can be made by dispersing the finely-divided active ingredient in aqueous starch or sodium carboxymethyl cellulose solution, or in a suitable oil, for instance arachis oil.
Preferably the pharmaceutical composition is in unit dosage form, the composition is sub-divided in unit doses containing appropriate quantities of the active ingredient; the unit dosage form can be a packaged composition, the package containing specific quantities of compositions, for example packeted powders or vials or ampoules. The unit dosage form can be a capsule, cachet or tablet itself, or it can be the appropriate number of any of these in packaged form. The quantity of active ingredient in a unit dose of composition may be varied or adjusted from 10 to 500 mg or more e.g. 25 mg to 250 mg, according to the particular need and the activity of the active ingredient. The invention also includes the compounds in the absence of carrier where the compounds are in unit dosage from.
The anti-ulcer compositions of the invention will be administered orally in either liquid or solid composition form. These compositions may include one or more antacid ingredients e.g. aluminium hydroxide, magnesium hydroxide or bismuth carbonate, aluminium glycinate, calcium carbonate, magnesium trisilicate, sodium bicarbonate, or the alumina gel described in British Specification No.
1,284,394.
Anti-ulcer activity was determined by the stress-induced erosion test of Senay & Levine, Proc.Soc.Exp.Biol.Med., 124, 1221-3 (1967) and anti-secretory activity by the test of H. Shay, D. Sun and H. Greenstein, Gastroenterology, 1954,26, 903-13 as exemplified by Beattie et al in J.Med.Chem, 20,714 (1977).
Compounds which possess one or both these activities are considered to be antilulcer agents which can be used for the treatment of ulcers or hyper-secretion of mammals.
Some compounds of formula I are known, namely those in which R1 is hydrogen, R is methyl, A is a polymethylene chain and Z is halogen. These compounds are described in Chim.Ther. 1966(5-6), 337 mainly for their chemical interest. However, this publication does state that the compounds may exhibit possible pharmacological uses. We have found no reports of any tests having been carried out on these compounds.
In view of the several hundreds of pharmacological tests which are available this statement is considered to be meaningless since it gives the reader no guidance as to what, if any, pharmacological activity the compounds might possess. In our view these compounds have not been described for use in a method of treatment of the human or animal body by surgery or therapy. Our discovery that these compounds have anti-ulcer and/or anti-secretory activity which renders them useful for treatment of ulcers or hypersecretion in mammals is therefore the firsttherepeutical treatment application.
We have also found that compounds of formula I wherein A is propylene, butylene or pentylene are inactive as anti-secretory or anti-ulcer agents.
A few compounds of formula I wherein R is methyl, R1 is hydrogen and A is ethylene substituted by phenethyl are disclosed as chemical intermediates in Synthesis, 1977, 884-885.
The compounds of formula I may be prepared by reacting a pyridothione of formula II
wherein R, R1 and n are as previously defined, with a dihaloalkylene compound of formula
Hal-A-Hal Ill wherein Hal represents a halogen, which may be chlorine, bromine or iodine. The invention includes the preparation of the above described novel compounds by this method.
Alternatively a dipyridine compound of formula IV
wherein R1, n and A are as defined in connection with formula I may be treated with an alkyl, aryl or aralkylating agent containing Rand Z wherein R and Z are as defined in connection with formula I. For example the alkylating, arylating or aralkylating agent may be an alkyl, or aralkyl halide or alkyl, or aryl sulphonic acid lower alkyl or aralkyl ester.
The invention is illustrated by the following examples.
EXAMPLE 1
Methylene bis/7-methylpyridinium-2-yl)-thio) dilo dide A solution of 1-methyl-2-pyridothione (2.5g) in hot ethanol (20 ml) was added to di-iodomethane (0.81 ml).
The mixture was heated under reflux for 31/2 hours and then allowed to cool to room temperature. The resulting solid was removed by filtration and dried to give the title compound as a hemihydrate (4.7g; 89%) mp 191-3"C (Found: C, 29.6; H, 3.3; N, 5.05% C13H1612N2S2.1/2H2O requires: C, 29.6; H, 3.25; N, 5.3%).
EXAMPLE 2 1,2-di-(1-methylpyridinium-2-yI)thio)ethane dibromide
A solution of 1 -methyl-2-pyridothione (1 .25g) in ethanol (10 ml) was treated with dibromoethane (0.43 ml).
The mixture was heated under reflux for 6 hours and then allowed to cool to room temperature. The resulting solid was removed by filtration, washed with ether and dried to give the title compound as hemihydrate (1.4g; 63%) mp 204-5.5 C (Found: C, 37.3; H, 4.6; N, 6.0% C14H1sBr2N2S2.H2O requires: C, 37.6; H,4.3; N, 6.3%).
EXAMPLE 3
Methylene bis((l-methylpyridinium-2-yl)thio) ditosylate
2-(((2-pyridylthio)methyl)thio)pyridine is reacted with 2-molar equivalents of methyl tosylate at 100"C to give the title compound.
EXAMPLE 4
Methylene bis { benzylpyridinium-2-yl)-thio)dichloride Following the procedure of Example 3 but substituting benzylchloride for methyltosylate the title compound is prepared.
Pharmacological test results
Compound Stress Induced erosion Aniti-Secretory [Product of (Senay & Levine) (Shayetal
Example No] Dose mg/kg % inhibition Dose % change
mg/kg in viol 1 100 71 30 -62
10 -32 2 100 67 30 -48
Pharmaceutical compositions
The following examples illustrate the preparation of unit dosage form of pharmaceutical compositions according to the invention.
EXAMPLE A
Antacid table (chewable) Saccharin 1.Omg.
Hydrated alumina sucrose powder 750.0 mg.
Methylene bis ((1-methylpyridinium -2yl)thio) di-iodide 100.0 mg.
Mannitol B.P. 170.0 mg.
Maize starch B.P. dried 30.0 mg.
Talc purified B.P. 28.0 mg.
Magnesium stearate B.P. 20.0 mg.
Peppermint oil B.P. 1.0 mg.
1100.0 mg.
Antacid tablets of the above formulation are prepared by the following procedure. Triturate peppermint oil with talc (screen 40 mesh). Add the triturate, and other ingredients to a blender and mix thoroughly. Slug the powder to large hard slugs. Granulate the slugs through a 14 mesh screen. Compress the granules on a suitable compression machine to give tablets of the required size.
EXAMPLE B
Anti-ulcer tablet (without antacid) mg/tabiet 1 ,2-Di-((1 -methylpyridinium-2-yl)thio)-ethane dibromide 100 mg.
Celutab 147.5 mg.
Mg. Stearate 2.5 mg.
250.0 mg.
The tablets are prepared by the following method. Blend the ingredients in a suitable blender. Compress the blended ingredients on a suitable compression machine to form tablets of the above composition. Celutab is a commercial product comprising 90-2% dextrose, 3-5% maltose, the remainder being higher glucose saccharides. The product is spray crystallised.
Claims (11)
1. As an anti-ulcer agent, a compound of the formula
wherein R is alkyl, aryl or aralkyl, Rl is hydrogen, lower alkyl, hydroxylower alkyl, loweralkoxyloweralkyl, lower-alkoxy, halogen, formyl, phenyl, phenylalkyl oracetal [CH(OR4)2where R4is lower alkyl or two R4 radicals are joined to form a lower alkylene chainl, n and m are 1 or 2 Z is an anion and R and R1 radicals may be the same or different, and A represents a methylene or ethylene radical which may be substituted by lower alkyl of 1 to 6 carbon atoms, oxo or hydroxy, and S is sulphur.
2. An anti-ulcer agent as claimed in claim 1, wherein R is lower alkyl of 1 to 6 carbon atoms.
3. An anti-ulcer agent as claimed in claim 1, wherein R is methyl.
4. An anti-ulcer agent as claimed in claim 1, claim 2, or claim 3 wherein A is methylene or ethylene and R1 is hydrogen.
5. An anti-ulcer agent as clamed in any one of the preceding claims wherein Z- is a halide or organic sulphonate ion.
6. As an anti-ulcer agent methylene bis((1-methylpyridinium-2-yl)-thio di-iodide.
7. As an anti-ulcer agent 1,2-di-((1 -methylpyridinium-2-yl)thio)ethane di bromide.
8. A pharmaceutical composition for treatment of ulcers or hypersecretion comprising an anti-ulcer agent as claimed in any one of claims 1 to 6 and a pharmaceutically acceptable carrier.
9. A pharmaceutical composition as claimed in claim 8 in unit dosage form.
10. A pharmaceutical composition as claimed in claim 8 or claim 9 which also includes an antacid ingredient.
11. A pharmaceutical composition substantially as hereinbefore described with reference to Example A or B.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB7941030A GB2038327B (en) | 1978-11-30 | 1979-11-28 | Bis-(pyridiniumthio)quaternary compounds as anti-ulcer agents |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB7846724 | 1978-11-30 | ||
GB7941030A GB2038327B (en) | 1978-11-30 | 1979-11-28 | Bis-(pyridiniumthio)quaternary compounds as anti-ulcer agents |
Publications (2)
Publication Number | Publication Date |
---|---|
GB2038327A true GB2038327A (en) | 1980-07-23 |
GB2038327B GB2038327B (en) | 1983-01-19 |
Family
ID=26269809
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GB7941030A Expired GB2038327B (en) | 1978-11-30 | 1979-11-28 | Bis-(pyridiniumthio)quaternary compounds as anti-ulcer agents |
Country Status (1)
Country | Link |
---|---|
GB (1) | GB2038327B (en) |
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1979
- 1979-11-28 GB GB7941030A patent/GB2038327B/en not_active Expired
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Publication number | Publication date |
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GB2038327B (en) | 1983-01-19 |
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Date | Code | Title | Description |
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PCNP | Patent ceased through non-payment of renewal fee |