`ICC
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`l.
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`2,831,866
`HETEROCYCLIC COMPOUNDS
`Wilfred Arthur Freeman, East Barnet, David Lord Pain,
`Rainham, and Ronald Slack, Chelsea, London, Eng
`land, assignors to May & Baker Limited, Dagenham,
`Essex, England, a British company
`No Drawing. Application May 14, 1956
`Serial No. 584,431
`Claims priority, application Great Britain May 12, 1955
`6 Claims. (Cl. 260-310)
`
`This invention relates to heterocyclic compounds and
`more particularly to new and useful nitrosopyrazoles, a
`process for their production and to fungicidal composi
`trons containing them.
`According to the present invention there are provided
`pyridyl-4-nitrosopyrazoles of the general formula:
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`10
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`15
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`20
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`25
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`2,831,866
`‘Patented Apr. 22,1958
`2
`names of the compounds in alternative form, e. g. 3(5)
`methyl-4-nitroso-l-phenyl-S ( 3 ) -4'-pyridyl-pyrazole.
`Example I
`Z-pyridylhydrazine (13.5 g.) is dissolved in water
`(200 ml.) containing 2 N acetic acid (123 ml.) and the
`solution is cooled in ice. A solution of isonitrosoacetyl~
`acetone (15.9 g.) in water (90 ml.) is added slowly with
`stirring. The mixture is stirred for a further 1 hour and
`then allowed to stand at 0° C. The 3:5-dimethyl-4
`nitroso-1-2'-pyridylpyrazole formed is collected and
`crystallised from a large volume of light petroleum (B. P.
`60-80“ C.) (some white insolublesolid is removed), giv
`ing turquoise needles, M. P. 93—94° C.
`Example 11
`Isonicotinoylacetone (16.3 g.) is dissolved in water
`(100 ml.) containing concentrated hydrochloric acid
`(20 ml.) and the solution is cooled in ice. A solution of
`sodium nitrite (7.1 g.) in water (35 ml.) is added drop
`wise with stirring, keeping the temperature at 0° to 5° C.
`The white isonicotinoyl-isonitrosoacetone which separates
`is collected and crystallised from ethanol, giving colour
`less needles, M. P. 162" C. A mixture of this 'isonitroso
`compound (17.5 g.), phenylhydrazine (8 ml.) and ethanol
`(50 ml.) is heated under re?ux for 30 minutes. The prod
`uct is diluted to 100 ml. with ethanol, the solution is boiled
`with charcoal and ?ltered. The orange solid which sep
`arates on cooling is recrystallised from ethanol giving
`yellow needles of the phenylhydrazone of isonicotinoyl
`isonitrosoacctone, M. P. 134-1350 C. (d.).
`The latter compound (5.5 g.) is dissolved in chloro
`benzene (350 ml.) and the solution is very slowly distilled
`(150 ml. collected during 11/2 hours). The residue is
`evaporated to dryness in vacuo and the 3(5)-methyl-4
`nitroso-1-phenyl-5(3)-4'-pyridylpyrazole obtained crystal
`lised from light petroleum (B. P. 60-80° C.) giving tur
`quoise plates, M. P. 153—154° C.
`Example 111
`
`A 50% by weight wettable powder was made up with
`the addition to the product of Example I of an inert pow
`dered carrier in the form of a silicaceous earth and a
`wetting agent in the form of “Sulphonated Lorol.” This
`powder was added to water to give a suspension contain
`ing 0.1% by weight of the active compound.
`Example IV
`A paint for veterinary use was prepared by dissolving
`0.5 g. of the compound of Example I in suf?cient 75%
`industrial methylated spirit to bring the volume to 100 cc.
`The preparation is particularly useful for topical appli
`cation in the cure of ringworm invcattle.
`Example V
`
`A preparation in the form of a cream for topical use on
`the human body was made up as follows: castor oil
`(24 g.), stearyl alcohol (10 g.) and polyethyleneglycol
`(600 monostearate) were melted together at 70° C. and
`the mixture poured into distilled water (60 g.), This
`mixture was passed through a homogeniser and the very
`?nely powdered compound of Example I (1.0 g.) was
`added. The cream was then milled.
`We claim:
`1. A pyridyl-4-nitrosopyrazole having the formula:
`
`wherein R and R1 are chosen from the group consisting of
`4-pyridyl and lower alkyl groups containing not more than
`6 carbon atoms, and R2 is chosen from the group con
`sisting of 2-pyridyl and phenyl, one of R, R1 and R2
`being pyridyl.
`_
`The new compounds which are of low toxicity are use
`ful agents in combatting fungi and are also active against
`virulent strains of Mycobacterium tuberculosis. They are
`of use in the topical treatment of pathogenic fungi of
`humans and cattle, particularly against ringworm caused
`by, for example, the following dermatophytes: Micro
`sporum audouini and Trichophyton tansumns, discOideS,
`quinckeanum, mentagrophytes and rubrum. They are also
`active against fungal pathogens in plants and in particular
`against the chocolate spot fungus of broad beans (Botrytis
`cinerea) and Sclerotinea loxa.
`According to a feature of the present invention, com
`pounds of the aforesaid general formula are prepared by
`nitrosating a compound of the general formula
`R.CO.CH2.CO.R1
`and condensing the resulting isonitrosoketone
`R.CO.CH(NO).CO.R1 (or R.CO.C: (NOH).CO.R1)
`with hydrazine or a substituted hydrazine of the formula
`Nl-I2NHR2 wherein R, R1 and R2 are as de?ned above.
`When R2 is other than hydrogen and R is not the same as
`R1 two isomers may be formed and, if required, isolated.
`The present invention includes within its scope fungi
`cidal preparations containing the new compound in associ
`ation with a diluent or carrier which may be either a solid
`material or a liquid. The precise mode of formulation
`and nature of diluent will vary according to the intended
`purpose of the composition. For therapeutic application,
`formulations of the type customary for the topical appli
`cation of anti-fungal compounds will be employed; exam
`ples are solutions (paints) in volatile solvents and creams.
`For horticultural purposes, again formulations of conven
`tional type are applicable; by way of illustration an aque- a
`ous suspension containing a wetting agent is a convenient
`formulation for spraying. Whichever type of formulation
`is employed, it is preferred that the concentration of the
`active compound shall be not less than 0.05% by weight,
`based upon the total weight of the composition.
`‘The invention is illustrated by the following examples
`in which isomeric con?guration is indicated by writing the
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`50
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`55
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`60
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`CFAD Exhibit 1020
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`2,831,866
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`wherein’ R and R1 are chosen from the group consisting
`of 4-pyridyl and lower alkyl groups containing not more
`than 6 carbon atoms, and R2 is chosen from the group
`consisting of 2-pyridyl and phenyl, one of R, R1 and R2
`being pyridyl.
`2. 3:S-dirnethylA-nitroso-1-2'-pyridylpyrazole.
`3. 3-methyi-4-nitroso-1-phenyl>5-4’-pyridylpyrazole.
`4. 5-methyl-4-nitroso-1-phenyl-3-4'-pyridy1pyrazole.
`5. A fungicidal composition containing at least 0.05%
`by Weight of at least one pyridyl-4-nitr0sopyrazole as
`claimed in claim 1 in association with a diluent.
`6. A therapeutic composition containing, in association
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`with a diluent, a therapeutically e?'ective amount of a
`nitrosopyrazole as de?ned in claim 1.
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`References Cited in the ?le of this patent
`UNITED STATES PATENTS
`Sundholm ____________ .. June 6, 1950
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`2,510,724
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`10
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`OTHER REFERENCES
`Lund: Chem. Abstracts, vol. 29, col. 4,359 (1935).
`' McNew et aL: Chem. Abstracts, vol. 44, cols. 4,183-4
`(1950).