GB2025416A - Mercaptopyridazinethione antifungal agents - Google Patents
Mercaptopyridazinethione antifungal agents Download PDFInfo
- Publication number
- GB2025416A GB2025416A GB7924241A GB7924241A GB2025416A GB 2025416 A GB2025416 A GB 2025416A GB 7924241 A GB7924241 A GB 7924241A GB 7924241 A GB7924241 A GB 7924241A GB 2025416 A GB2025416 A GB 2025416A
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- GB
- United Kingdom
- Prior art keywords
- compound
- formula
- pharmaceutically acceptable
- zinc
- zinc complex
- 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
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F3/00—Compounds containing elements of Groups 2 or 12 of the Periodic System
- C07F3/003—Compounds containing elements of Groups 2 or 12 of the Periodic System without C-Metal linkages
Abstract
Novel mercaptopyridazinethione antifungal agents of the formula: <IMAGE> wherein R is H, CH3, C2H5 or benzyl, their pharmaceutically acceptable metal or ammonium salts, zinc complexes, or bioprecursors are prepared by introduction of the mercapto and thione groups.
Description
SPECIFICATION
Therapeutic agents
This invention relates to novel pyridazine derivatives and in particular to 4-mercapto-3(2H)pyridazinethione and certain derivatives thereof which possess antifungal activity.
Thus, the present invention provides novel pyridazines of the formula:
wherein R is hydrogen, methyl, ethyl or benzyl: or the pharmaceutically acceptable metal or ammonium salts thereof; or the zinc complexes thereof; or the pharmaceutically acceptable bioprecursors of the above.
The compounds of the formula (IA) and (IB), as stated above, form complexes with zinc which possess antifungal activity. These zinc complexes have the stoichiometric formula (R. C4H2N2S2)2Zn.
The pharmaceutically acceptable metal salts of the compounds of the formula (IA) and (IB) are the non-toxic metal, particularly the alkali metal, salts.
Preferred compounds are those of the formula (IA) in which R is hydrogen or methyl, and the zinc complexes thereof.
The compounds of the formula (IA) and (IB) may exist in tautomeric forms, and such tautomers are also within the scope of the invention. The following tautomerisms are for example possible when R is hydrogen:
When R is hydrogen, then it will be noted that the compounds of the formula (IA) and (IB) are tautomers.
Also, the following tautomers are for example possible when R is methyl, ethyl or benzyl:-
The term "pharmaceutically acceptable bioprecursor" used above requires some explanation. It is of course, common practice in pharmaceutical chemistry to overcome some undesirable physical or chemical property of a drug by converting the drug into a chemical derivative which does not suffer from that undesirable property, but which, upon administration to an animal or human being, is converted back to the parent drug. For example, if a drug is not well absorbed when given to the animal or patient, by the oral route, it may be possible to convert it into a chemical derivative which is well absorbed and which in the serum or tissues is reconverted to the parent drug.Again, if a drug is unstable in solution, it may be possible to prepare a chemical derivative of it which is stable and may be administered in solution, but which is reconverted in the body to give the parent drug. The pharmaceutical chemist is well aware of the possibility of overcoming intrinsic deficiencies in a drug by chemical modifications which are only temporary and are reversible upon administration to the animal or patient.
For the purpose of this specification the term "pharmaceutically acceptable bioprecursor" of a compound, salt or complex of the invention means a compound having a structural formula different from the said compound, salt or complex but which nonetheless, upon administration to an animal or human being, is converted in the patient's body to the compound, salt or complex.
The compounds of the invention may be prepared by a number of routes, including the following, (1) The compounds of the formula (IA) may be prepared by the following route:
In a typical reaction, the pyridazine (II) and phosphorus pentasulfide or the phenylthionophosphine sulphide are heated together e.g. under reflux, in a suitable organic solvent, e.g. dry pyridine in the case of phosphorus pentasulphide, or toluene or xylene in the case of the phenylthionophosphine sulphide.
Generally long reaction times are necessary in the case of phosphorus pentasulphide, e.g. 100 hours, although lesser reaction times are usually necessary in the case of the phenylthionophosphine sulphide, e.g. 12 hours. The product may then be isolated and purified by conventional procedures.
The starting materials of the formula (II) are either known compounds or may be prepared by methods analogous to those of the prior art. For example, 4-chloro-pyridazin-3(2H)-one may be prepared by the oxidation of 4-chloro-5-hydrazino-pyridazin-3(2H)-one with cupric sulphate according to the method of M. Yanai and T. Kinoshita, J. Pharm. Soc. Jap., 85, 344 352 (1965). The bromo compound may prepared similarly. 4-Hydroxypyridazin-3(2H)-one may be prepared by the method described below.The starting materials in which R is methyl, ethyl or benzyl may be prepared by the methylation, ethylation or benzylation respectively of 4-chloro- or bromo-pyridazin-3(2H)-one, e.g. using methyl or ethyl iodide and potassium carbonate in methanol, dimethyl or diethyl sulphate in aqueous caustic soda, or benzyl chloride, bromide or iodide and potassium carbonate in ethanol.
(2) The compounds of the formula (IB) in which R is methyl, ethyl or benzyl may be prepared by the reaction of a compound of the formula:
with phosphorus pentasulphide in a similar manner to route (1).
The compound of the formula (IB) in which R is hydrogen is of course a tautomer of the corresponding compound of the formula (IA) and thus may be prepared as described in route (1).
The starting materials of the formula (III) may be prepared by the methylation, ethylation or benzylation of the corresponding compound of the formula (III) in which R is H in a similar manner to that described in route (1), followed by separation of the N-substituted isomers by chromatography. The starting material of the formula (III) in which R is H may be prepared by conventional procedures, e.g. as follows:
(3) The zinc complexes may be prepared by reacting the compounds of the formula (IA) or (IB) with zinc, preferably as zinc dust, in the presence of a dilute acid, preferably dilute acetic acid. Typically the organic extract was washed twice with water, dried over anhydrous magnesium sulphate, filtered and the filtrate reduced in volume to 10 ml under reduced pressure.On cooling in ice, a dark yellow crystalline solid was deposited (3.2 g). A further reduction in volume yielded a further amount of bright yellow solid (1.0 g). These two crops of 4-mercapto-3(2H)-pyridazinethione were of similar purity as judged by t.l.c. and were combined, 4.2 g (76%) m.p. 1 55-1 650C.
Analysis %:
Found: C, 32.8; H, 2.79; N, 18.7; S, 44.4 C4H4N2S2requires: C, 33.3; H, 2.80; N, 19.4; S, 44.4 EXAMPLE 2
Preparation of the Zinc Complex of 4-Mercapto-3(2H)-pyridazinethione 4-Mercapto-3(2H)-pyridazinethione (75 mg) was stirred in methanol (2.5 ml) and acetic acid (1.0 ml) whilst zinc dust (80 mg) was added. The mixture was then stirred and heated under reflux for two hours.
The reaction mixture was cooled and the solvents removed under reduced pressure. The solid residue was stirred in water (2 ml), and the mixture made basic to pH 14 with sodium hydroxide solution to give a red solution. This solution was filtered and acidified with concentrated hydrochloric acid to pH 1 to give the zinc complex as a yellow solid, which was filtered off, washed well with water and dried, 56 mg, m.p. > 3000.
Analysis %:
Found: C, 28.4; H, 1.8; N, 15.3 (C4H3N2S2)2Znrequires: C,27.3; H, 1.7; N, 15.9 EXAMPLE 3
Preparation of 4-Mercapto-2-methyl-3-pyridazinethione (i) 4-Hydroxy-2-methyipyridazine-3-one was prepared by methylation of 4-hydroxypyridazine-3
(2H)-one with dimethyl sulphate in sodium hydroxide solution. Acidification followed by chloroform extraction gave the title compound of (i) as a colourless crystalline solid, m,p. 1 58-1 600C.
Analysis %:
Found: C, 46.7; H, 4.73; N, 22.1 C5H6N202 requires: C, 47.6; H, 4.80; N, 22.2 (ii) 4-Hydroxy-2-methylpyridazine-3-one (2.52 g) and the dimer of pmethoxyphenylthionophosphine sulphide (40.2 g) were heated under reflux in xylene (250 ml) for 12 hours.
On cooling to room temperature (200), yellow crystals of unreacted thiating agent were deposited.
These were filtered off and the filtrate extracted three times with sodium hydroxide solution (100 mi portions, 2N).
The aqueous extract was extracted with chloroform (2 x 100 ml) and then acidified to pH 2 with concentrated hydrochloric acid. The acid solution was extracted three times with chloroform (70 mr portions), the chloroform extract washed with water, dried over magnesium sulphate, and evaporated to a brown solid, 0.81 g. This was recrystailised from cyclohexane to give yellow crystals of 4-mercapto-2- methyl-3-pyridezinethione (0.64 g) m.p. 69--710.
Analysis %:
Found: C, 38.4; H, 3.87; N, 15.76; S, 38.0
C5H6N2S2requires: C, 38.0; H, 3.82; N, 17.7; S, 40.5
EXAMPLE 4
Preparation of the Zinc Complex of 4-Mercapto-2-methyl-3-pyridazinethione
4-Mercapto-2-methyl-3-pyridazinethione (0.3 g) and zinc dust (0.28 g) were heated under reflux in methanol (6 ml) and acetic acid (3 ml) for two hours. The reaction mixture was cooled and the green
precipitate was filtered off, suspended in sodium hydroxide solution (5 ml, 2N), filtered off, washed well with water, re-suspended in dimethylformamide (3 ml), filtered off and dried under vacuum at 600 to give the title zinc complex (136 mg), m.p. > 3000.
Analysis %:
Found: C,31.15; H,2.40; N,14.5; S,33.1 (C5H5N2S2)2.Znrequires: C,31.3; H, 2.63; N,14.6; S, 33.4 reaction is carried out in a suitable organic solvent, e.g. methanol, with heating, e.g. under reflux, for up to about 4 hours. The product may be recovered by conventional procedures.
(4) The salts of the invention may be prepared by conventional procedures. For example, the alkali metal salts may generally be obtained by adding the compound of the formula (IA) or (IB) to a solution of the alkali metal hydroxide in a suitable solvent, stirring and collecting and drying the resulting precipitate of the alkali metal salt. The ammonium salts may generally be prepared by suspending the compound in a suitable solvent, passing ammonia through the resulting solution, stirring, and collecting the resulting precipitate of the ammonium salt.
The compounds of the invention and their pharmaceutically acceptable metal and ammonium salts and zinc complexes are anti-fungal agents, useful in combating fungal infections in animals, including humans.
The in vitro evaluation of the anti-fungal activity of the compounds of the invention may be performed by determining the minimum inhibitory concentration (m.i.c.) of the test compounds in a suitable medium at which growth of the particular micro-organism fails to occur.
In practice a series of agar plates, each having the test compound incorporated at a particular concentration, are inoculated with a standard cuiture of Candida albicans and each plate is then incubated for 24 hours at 370 C. The plates are then examined for the presence or absence of growth of the fungus and the appropriate m.i.c. value is noted. Other micro-organisms used in such tests include
Cryptococcus neoformans, Aspergillus fumigatus, Trichophyton rubrum, Epidermophyton floccosum,
Blastomyces dermatitidis, and Torulopsis glabrata.
The in vivo evaluation of the compounds may also be carried out at a series of dose levels by intraperitoneal or intravenous injection or by oral administration, to mice which are inoculated with a strain of Candida albicans. Activity is based on the survival of a treated group of mice after the death of an untreated group of mice following 48 hours observation. The dose level at which the compound provides 50% protection against the lethal effect of the infection may be calcuiated.
For human use, the anti-fungal compounds, salts and complexes of the invention can be administered alone, but will generally be administered in admixture with a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice. For example, they may be administered orally in the form of tablets containing such excipients as starch or lactose, or in capsules either alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavouring or colouring agents, or in the form of suppositories or pessaries.They may be injected parenterally, for example, intravenously, intramuscularly or subcutaneously. For parenteral administration, they are best used in the form of a sterile aqueous solution which may contain other solutes, for example, enough salts or glucose to make the solution isotonic. They may also be applied topically in an ointment.
For oral and parenteral administration to human patients, it is expected that the daily dosage level of the anti-fungal compounds, salts and complexes of the invention will be from 0.5 to 20 mg/kg (in divided doses), when administered by the oral or parenteral route. Thus tablets, capsules or dosage units for parenteral administration (e.g. ampoules) containing the compounds can be expected to contain from 30 mg to 0.5 g of active compound. The physician in any event will determine the actual dosage which will be most suitable for an individual patient and it will vary with the age, weight and response of the particular patient. The above dosages are exemplary of the average host. There can, of course, be individual cases where higher or lower dosage ranges are merited, and such are within the scope of this invention.
Thus the invention provides a pharmaceutical composition comprising a compound, salt, or zinc complex according to the invention together with a pharmaceutically acceptable diluent or carrier.
As stated above, the anti-fungal compounds of the invention may be applied topically, e.g. in the form of a cream or ointment. For example they may be incorporated into a cream consisting of an aqueous emulsion of polyethylene glycol or liquid paraffin; or they may be incorporated, at a concentration between 1 and 10%, into an ointment consisting of a white wax or white soft paraffin base together with such stabilisers and preservatives as may be required.
The invention also provides an anti-fungal composition for topical administration comprising a compound, salt, or zinc complex according to the invention together with a topically-acceptable diluent or carrier.
The following Examples illustrate the invention. All temperatures are given in OC.
EXAMPLE 1
Preparation of 4-Mercapto-3(2H)-pyridazinethione 4-Chloropyridazin-3(2H)-one (5.0 g) and phosphorus pentasulphide (45 g) were heated under reflux in dry pyridine (450 ml) for 100 hours with the exclusion of moisture.
The reaction mixture was then cooled and the pyridine removed under reduced pressure to give a black viscous oil. This oil was heated for two hours with water (70 ml) on a steam bath with the evolution of hydrogen sulphide.
The resulting solution was cooled to room temperature (200), acidified to pH 1 with concentrated hydrochloric acid, and extracted with three successive portions of ethyl acetate (3 x 250 ml). The
wherein R is hydrogen, methyl, ethyl or benzyl; or the pharmaceutically acceptable metal or ammonium salts thereof; or the zinc complexes thereof.
2. A compound of the formula (IA) as claimed in claim 1 in which R is hydrogen or methyl; or a zinc complex thereof.
3. A process for preparing a compound of the formula (IA) as claimed in claim 1, which comprises reacting a compound of the formula:
wherein R is as defined in claim 1, with either phosphorus pentasulphide or the dimer of p-methoxyphenylthionophosphine sulphide.
4. A process for preparing a compound of the formula (IB) as claimed in claim 1 which comprises reacting a compound of the formula:
wherein R is as defined in claim 1, with phosphorus pentasulphide.
5. A process for preparing a zinc complex of a compound of the formula (IA) or (IB) as claimed in claim 1, which comprises reacting the said compound with zinc dust in the presence of dilute acetic acid.
6. A process as claimed in claim 3 substantially as hereinbefore described in either of Examples 1 and 3.
7. A process as claimed in claim 5 substantially as hereinbefore described in either of Examples 2 and 4.
8. A compound of the formula (IA) or (IB) as claimed in claim 1 or a zinc complex thereof which has been prepared by a process as claimed in any one of claims 3 to 7.
9. A pharmaceutical composition comprising a compound of the formula (IA) or (IB) as claimed in claim 1, or a pharmaceutically acceptable metal or ammonium salt thereof, or a zinc complex thereof, together with a pharmaceutically acceptable diluent or carrier.
10. An anti-fungal composition for topical administration comprising a compound of the formula (IA) or (IB) as claimed in claim 1, or a pharmaceutically acceptable metal or ammonium salt thereof, or a zinc complex thereof, together with a topically acceptable diluent or carrier.
11. A pharmaceutically acceptable bioprecursor of a compound of the formula (IA) or (IB) as claimed in claim 1, or of a pharmaceutically acceptable metal or ammonium salt thereof, or of a zinc complex thereof.
**WARNING** end of DESC field may overlap start of CLMS **.
Claims (11)
- **WARNING** start of CLMS field may overlap end of DESC **.wherein R is hydrogen, methyl, ethyl or benzyl; or the pharmaceutically acceptable metal or ammonium salts thereof; or the zinc complexes thereof.
- 2. A compound of the formula (IA) as claimed in claim 1 in which R is hydrogen or methyl; or a zinc complex thereof.
- 3. A process for preparing a compound of the formula (IA) as claimed in claim 1, which comprises reacting a compound of the formula:wherein R is as defined in claim 1, with either phosphorus pentasulphide or the dimer of p-methoxyphenylthionophosphine sulphide.
- 4. A process for preparing a compound of the formula (IB) as claimed in claim 1 which comprises reacting a compound of the formula:wherein R is as defined in claim 1, with phosphorus pentasulphide.
- 5. A process for preparing a zinc complex of a compound of the formula (IA) or (IB) as claimed in claim 1, which comprises reacting the said compound with zinc dust in the presence of dilute acetic acid.
- 6. A process as claimed in claim 3 substantially as hereinbefore described in either of Examples 1 and 3.
- 7. A process as claimed in claim 5 substantially as hereinbefore described in either of Examples 2 and 4.
- 8. A compound of the formula (IA) or (IB) as claimed in claim 1 or a zinc complex thereof which has been prepared by a process as claimed in any one of claims 3 to 7.
- 9. A pharmaceutical composition comprising a compound of the formula (IA) or (IB) as claimed in claim 1, or a pharmaceutically acceptable metal or ammonium salt thereof, or a zinc complex thereof, together with a pharmaceutically acceptable diluent or carrier.
- 10. An anti-fungal composition for topical administration comprising a compound of the formula (IA) or (IB) as claimed in claim 1, or a pharmaceutically acceptable metal or ammonium salt thereof, or a zinc complex thereof, together with a topically acceptable diluent or carrier.
- 11. A pharmaceutically acceptable bioprecursor of a compound of the formula (IA) or (IB) as claimed in claim 1, or of a pharmaceutically acceptable metal or ammonium salt thereof, or of a zinc complex thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB7924241A GB2025416A (en) | 1978-07-14 | 1979-07-12 | Mercaptopyridazinethione antifungal agents |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB7829899 | 1978-07-14 | ||
| GB7924241A GB2025416A (en) | 1978-07-14 | 1979-07-12 | Mercaptopyridazinethione antifungal agents |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| GB2025416A true GB2025416A (en) | 1980-01-23 |
Family
ID=26268214
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB7924241A Withdrawn GB2025416A (en) | 1978-07-14 | 1979-07-12 | Mercaptopyridazinethione antifungal agents |
Country Status (1)
| Country | Link |
|---|---|
| GB (1) | GB2025416A (en) |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0014562A1 (en) * | 1979-01-31 | 1980-08-20 | Pfizer Limited | Pyridazines for use in treating fungal infections, pharmaceutical compositions containing them, and processes for their preparation |
| WO1995026357A1 (en) * | 1994-03-29 | 1995-10-05 | Monsanto Company | Thionation process using elemental phosphorus and sulfur |
| WO2013073577A1 (en) * | 2011-11-15 | 2013-05-23 | アステラス製薬株式会社 | Dihydroxy aromatic heterocyclic compound |
| US9180122B2 (en) | 2011-07-07 | 2015-11-10 | Takeda Pharmaceutical Company Limited | 5- or 6-substituted 3-hydroxy-2 (1 H)-pyridinones as D-amino acid oxidase (DAAO) inhibitors in therapy of diseases such as schizophrenia, cognitive disorder and pain |
| US9290456B2 (en) | 2011-08-22 | 2016-03-22 | Takeda Pharmaceutical Company Limited | Pyridazinone compounds and their use as DAAO inhibitors |
| US9750748B2 (en) | 2012-12-17 | 2017-09-05 | Takeda Pharmaceutical Company Limited | Pyridazinones as DAAO enzyme inhibitors |
| US10085986B2 (en) | 2011-07-07 | 2018-10-02 | Takeda Pharmaceutical Company Limited | Pyrimidinone compounds and their use |
-
1979
- 1979-07-12 GB GB7924241A patent/GB2025416A/en not_active Withdrawn
Cited By (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0014562A1 (en) * | 1979-01-31 | 1980-08-20 | Pfizer Limited | Pyridazines for use in treating fungal infections, pharmaceutical compositions containing them, and processes for their preparation |
| WO1995026357A1 (en) * | 1994-03-29 | 1995-10-05 | Monsanto Company | Thionation process using elemental phosphorus and sulfur |
| US10085986B2 (en) | 2011-07-07 | 2018-10-02 | Takeda Pharmaceutical Company Limited | Pyrimidinone compounds and their use |
| US9180122B2 (en) | 2011-07-07 | 2015-11-10 | Takeda Pharmaceutical Company Limited | 5- or 6-substituted 3-hydroxy-2 (1 H)-pyridinones as D-amino acid oxidase (DAAO) inhibitors in therapy of diseases such as schizophrenia, cognitive disorder and pain |
| US9290456B2 (en) | 2011-08-22 | 2016-03-22 | Takeda Pharmaceutical Company Limited | Pyridazinone compounds and their use as DAAO inhibitors |
| US9931340B2 (en) | 2011-08-22 | 2018-04-03 | Takeda Pharmaceutical Company Limited | Pyridazinone compounds and their use as DAAO inhibitors |
| US10463663B2 (en) | 2011-08-22 | 2019-11-05 | Takeda Pharmaceutical Company Limited | Pyridazinone compounds and their use as DAAO inhibitors |
| US11129828B2 (en) | 2011-08-22 | 2021-09-28 | Takeda Pharmaceutical Company Limited | Pyridazinone compounds and their use as DAAO inhibitors |
| US9212147B2 (en) | 2011-11-15 | 2015-12-15 | Takeda Pharmaceutical Company Limited | Dihydroxy aromatic heterocyclic compound |
| US9562020B2 (en) | 2011-11-15 | 2017-02-07 | Takeda Pharmaceutical Company Limited | Dihydroxy aromatic heterocyclic compound |
| WO2013073577A1 (en) * | 2011-11-15 | 2013-05-23 | アステラス製薬株式会社 | Dihydroxy aromatic heterocyclic compound |
| US10202399B2 (en) | 2011-11-15 | 2019-02-12 | Takeda Pharmaceutical Company Limited | Dihydroxy aromatic heterocyclic compound |
| US9750748B2 (en) | 2012-12-17 | 2017-09-05 | Takeda Pharmaceutical Company Limited | Pyridazinones as DAAO enzyme inhibitors |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| WAP | Application withdrawn, taken to be withdrawn or refused ** after publication under section 16(1) |