United S ta tes P a tent [ 1 9 ;

S eo et 2 1 1 .
4 , 6 3 6 , 5 1 9
J a n. 1 3 , 1 9 8 7
[ 1 1 ] P a tent Number:
[ 4 5 ] Da te of P a tent:
[ 5 4 ] KETENE S , S - A C ETA L DERIVA TIVE, A
P ROC ES S FOR MA NUFA C TURING
THEREOF A ND A METHOD FOR C URING
MYC OS IS BY A DMINIS TERING IT
[ 7 5 ] Inv entors : A k ira S eo, Ya ma tota k a da ; Hideo
Ka nno, Iba ra k i; Nobu Ha s eg a w a ,
Nis h inomiy a ; Yuk io Miy a g i, Os a k a ;
A k ira Nis h imura , Ka w a c h ina g a no;
S h ig eo Kona k a , Ha bik ino; Tets uto
Oh mi, Ka w a c h ina g a no; Yuk imi
Munec h ik a , ' Ha s h imoto; Ma ta z a emon
Uc h ida , Ka w a c h ina g a no; Kenic h i
Ik eda , C h iba , a l l of J a p a n
[ 7 3 ] A s s ig nee: Nih on Noh y a k u C o. , L td. , Tok y o,
J a p a n
[ 2 1 ] A p p l . No. : 7 8 6 , 1 2 3
[ 2 2 ] Fil ed: Oc t. 1 0 , 1 9 8 5
[ 5 1 ] Int. C l . 4 . . . . . . . . . . . . . . . . . . . A 6 1 K 3 1 / 4 1 5 ; A 6 1 K 3 1 / 4 4 ;
C 0 7 D 4 0 3 / 0 0 ; C 0 7 D 4 0 1 / 0 0
[ 5 2 ] US . C l . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 1 4 / 3 9 7 ; 5 4 8 / 3 3 6 ;
5 4 6 / 2 7 8 ; 5 1 4 / 3 4 1
[ 5 8 ] Fiel d of S ea rc h . . . . . . . . . . . . . . . . . . . . . . . . 5 4 8 / 3 3 6 ; 5 4 6 / 2 7 8 ;
5 1 4 / 3 4 1 , 3 9 7
[ 5 6 ] Ref erenc es C ited
U. S . P A TENT DOC UMENTS
3 , 8 6 4 , 1 1 5 2 / 1 9 7 5 S c h ra der et a l . . . . . . . . . . . . . . . . . . . . 5 4 9 / 2 2 0
4 , 0 8 7 , 5 3 6 5 / 1 9 7 8 Budde et a l . .
4 , 4 6 5 , 6 8 0 8 / 1 9 8 4 Kra a tz et a 1 . 5 4 8 / 3 3 6
4 , 4 8 3 , 8 6 5 1 1 / 1 9 8 4 Heeres et a l . 5 4 8 / 3 3 6
4 , 5 2 4 , 1 1 0 6 / 1 9 8 5 Heeres et a 1 . . . . . . . . . . . . . . . . . . . . . . . . 5 4 8 / 3 3 6
FOREIGN P A TENT DOC UMENTS
2 0 2 7 1 3 8 / 1 9 8 1 Fed. Rep . of Germa ny . . . . . . 5 4 8 / 3 3 6
5 8 - 9 6 0 7 3 6 / 1 9 8 3 J a p a n . . . . . . . . . . . 5 4 8 / 3 3 6
5 9 - 1 6 8 8 7 V1 9 8 4 J a p a n . . . . . . . . . . . 5 4 8 / 3 3 6
P rima ry Ex a miner- - Henry R. J il es
A s s is ta nt Ex a miner- Robert C . W h ittenba ug h
5 4 8 / 3 3 6
A ttorney , A g ent, or Firm- C us h ma n, Da rby & C us h ma n
[ 5 7 ] ' A BS TRA C T
A nov el k etene S , S - a c eta l deriv a tiv e w h ic h is us ef ul a s
a n a ntimy c otic a g ent a nd a n a g ric ul tura l c h emic a l of
f ung ic ida l , p l a nt g row th reg ul a ting or ins ec tic ida l p rop
erties rep res ented by th e g enera l f ormul a ( I) :
a l ia s a
( 1 )
w h erein R rep res ents a h y drog en a tom; a n a l k y l g roup
h a v ing 1 to 8 c a rbon a toms ; a c y c l oa l k y l g roup h a v ing
3 to 6 c a rbon a toms ; a meth y l ene g roup ; a l ow er a l k eny l
g roup ; a l ow er a l k y l g roup s ubs tituted by a h a l og en
a tom, a c y a no g roup , a l ow er a l k ox y g roup , a l ow er
a l k y l th io g roup ; a c a rba rnoy l g roup , a n a c y l g roup , or
a n a l k enoy l ox y g roup ; a p h eny l g roup rep res ented by
@ 0 1 1 ) " .
( in w h ic h R1 rep res ents a h y drog en a tom, a h a l og en
a tom, a s tra ig h t or bra nc h ed c h a in l ow er a l k y l g roup , a
l ow er a l k ox y l g roup w h ic h ma y be s ubs tituted by one
or more h a l og en a toms , a p h enox y g roup or a meth y l
enediox y g roup , a nd m rep res ents a n integ er of 1 to 3 ) ;
a benz y l g roup ; a meth y l enediox y benz y l g roup ; a p h e
nox y a l k y l g roup ; a p h enox y a l k y l g roup s ubs tituted by a
h a l og en a tom; a na p h th y l g roup ; or a s ubs tituted or
uns ubs tituted p y ridy l g roup . - '
1 2 C l a ims , No Dra w ing s
4 , 6 3 6 , 5 1 9
1
KETENE S , S - A C ETA L DERIVA TIVE, A P ROC ES S
FOR MA NUFA C TURING THEREOF A ND A
METHOD FOR C URING MYC OS IS BY
A DMINIS TERING IT
BA C KGROUND OF THE INVENTION
Th is inv ention rel a tes to a nov el k etene S , S - a c eta l
deriv a tiv es w h ic h a re us ef ul a s a ntimy c otic a g ents a nd
a g ric ul tura l c h emic a l s .
More p a rtic ul a rl y , th is inv ention rel a tes to k etene
S , S - a c eta l deriv a tiv es rep res ented by th e g enera l f or
mul a ( I) :
NC S ( I)
> = < 3 *
W s
N = /
w h erein R rep res ents a h y drog en a tom; a n a l k y l g roup
h a v ing 1 to 8 c a rbon a tom; a c y c l oa l k y l g roup h a v ing 3
to 6 c a rbon a toms ; a meth y l ene g roup ; a l ow er a l k eny l
g roup ; a l ow er a l k y l g roup s ubs tituted by a h a l og en
a tom, a c y a no g roup , a l ow er a l k ox y l g roup , a l ow er
a l k y l th io g roup , a c a rba moy l g roup , a n a c y l g roup , or
a n a l k enoy l ox y g roup ; a p h eny l g roup rep res ented by
( Rom
( in w h ic h R1 rep res ents a h y drog en a tom, a h a l og en
a tom, a s tra ig h t or bra nc h ed c h a in l ow er a l k y l g roup , a
l ow er a l k ox y l g roup w h ic h ma y be s ubs tituted by one
or more h a l og en a toms , a p h enox y g roup or a meth y l
enediox y g roup , a nd m rep res ents a n integ er of l to 3 ) ;
a benz y l g roup ; a meth y l enediox y benz y l g roup ; a p h e
nox y a l k y l g roup ; a p h enox y a l k y l g roup s ubs tituted by a
h a l og en a tom; a na p h th y l g roup ; or a s ubs tituted or
uns ubs tituted p y ridy l g roup .
S UMMA RY OF INVENTION
Th e p res ent inv entors h a v e dev oted th ems el v es to
res ea rc h in order to inv ent a nov el k etene S , S - a c eta l
deriv a tiv e, a nd h a v e c ons eq uentl y f ound th a t c om
p ounds rep res ented by th e g enera l f ormul a ( I) a re nov el
c omp ounds not des c ribed in l itera tures a nd a re us ef ul a s
a ntimy c otic a g ents a nd a g ric ul tura l c h emic a l s ; in p a rtic
ul a r, not onl y f ung ic ides a nd p l a nt g row th reg ul a tors
but a l s o ins ec tic ides , w h ereby th is inv ention h a s been
a c c omp l is h ed
Th e s ubs tituent R in th e a bov e g enera l f ormul a ( I)
inc l udes h y drog en a tom; s tra ig h t or bra nc h ed c h a in
a l k y l g roup s s uc h a s meth y l , eth y l , n- p rop y l , i- p rop y l ,
n~ buty l , i- buty l , s - buty l , t- buty l , u- p enty l , i- p enty l , neo
p enty l , n- h ex y l , n- oc ty l a nd th e l ik e; c y c l oa l k y l g roup s
s uc h a s c y c l op rop y l , c y c l oh ex y l a nd th e l ik e; meth y l ene
g roup ; l ow er a l k eny l g roup s s uc h a s v iny l , a l l y l a nd th e
l ik e; l ow er a l k y l g roup s s ubs tituted by a h a l og en a tom
s uc h a s c h l orometh y l , dic h l oroeth y l a nd th e l ik e; l ow er
a l k y l g roup s s ubs tituted by a c y a no g roup s uc h a s
c y a nometh y l a nd th e l ik e; l ow er a l k y l g roup s s ubs ti
tuted by a l ow er a l k ox y l s uc h a s meth ox y meth y l , me
th ox y eth y l a nd th e l ik e or a l ow er a l k y l th io g roup s uc h
a s meth y l th iometh y l a nd th e l ik e: l ow er a l k y l g roup
1 5
2 0
2 5
3 0
3 5
4 5
5 0
5 5
6 0
6 5
2
s ubs tituted by c a rba moy l g roup s uc h a s c a rba moy l
meth y l a nd th e l ik e; l ow er a l k y l g roup s s ubs tituted by
a n a c y l g roup ; l ow er a l k y l g roup s s ubs tituted by a n
a l k enoy l ox y g roup s s uc h a s a c ry l oy l meth y l a nd th e
l ik e; p h eny l g roup s rep res ented by
( Rum
( in w h ic h R1 rep res ents a h y drog en a tom, a h a l og en
a tom, a s tra ig h t or bra nc h ed c h a in l ow er a l k y l g roup , a
l ow er a l k ox y l g roup w h ic h ma y be s ubs tituted by one
or more h a l og en a toms , a p h enox y g roup or a meth y l
enediox y g roup , a nd m rep res ents a n integ er of l to 3 ) ;
a benz y l g roup ; a meth y l enediox y benz y l g roup ; a p h e
nox y a l k y l g roup s uc h a s p h enox y meth y l a nd th e l ik e; a
p h enox y a l k y l g roup s ubs tituted by a h a l og en a tom;
na p h th y l g roup ; s ubs tituted or uns ubs tituted p y ridy l
g roup ; etc .
DETA IL ED DES C RIP TION OF INVENTION
Th e c omp ound rep res ented by th e g enera l f ormul a
( I) of th is inv ention c a n be s y nth es iz ed, f or ex a mp l e, by
th e p roc es s s h ow n bel ow :
NC C HZ N I + c s ; 3 %
\= N
( 1 1 )
NC S e 1 ' 1
H x c nc nz x
N 5 9 ( Il l ) >
N = /
( IV)
NC S
F > = < %
N s
N = /
( I)
w h erein R is a s def ined a bov e, a nd X rep res ents a h a l o
g en a tom, a mes y l ox y or a tos y l ox y g roup . Th a t is to
s a y , th e c omp ound rep res ented by th e g enera l f ormul a
( I) c a n be obta ined by rea c ting l - c y a nometh y l imida z ol e
rep res ented by th e s truc tura l f ormul a ( II) w ith c a rbon
dis ul ? de in th e p res enc e of a ba s e a nd a s ol v ent to f orm
a n intermedia te rep res ented by th e s truc tura l f ormul a
( IV) , a nd rea c ting th e intermedia te w ith a c omp ound
rep res ented by th e g enera l f ormul a ( III) w ith out is ol a t
ing th e s a me.
A s th e s ol v ent us a bl e in th e inv ention, a ny s ol v ent
ma y be us ed s o l ong a s it does not inh ibit th e p rog res s of
th e rea c tion, a nd th ere c a n be ex emp l i? ed, f or ex a mp l e,
a l c oh ol s s uc h a s meth a nol , eth a nol , is op rop a nol a nd th e
l ik e, dimeth y l s ul f ox ide, dimeth y l f orma mide, h ex a me
4 , 6 3 6 , 5 1 9
3
th y l enep h os p h oroa mide, w a ter, etc . Th es e s ol v ents c a n
be us ed a l one or a s a mix ture th ereof .
A s th e ba s e us a bl e in th is inv ention, th ere c a n be
ex emp l i? ed s odium c a rbona te, p ota s s ium c a rbona te,
s odium h y drog enc a rbona te, p ota s s ium h y drog enc a r
bona te, s odium h y drox ide, p ota s s ium h y drox ide, p ota s
s ium t- butox ide, etc . Th es e c a n be us ed in s ol id s ta te or
in s ol ution.
A l th oug h it is s uf ? c ient th a t th e rea c tion temp era ture
is s el ec ted in th e ra ng e of 0 to 1 0 0 C . , it is p a rtic ul a rl y
p ref era bl e to c a rry out th e rea c tion a t a temp era ture
nea r room temp era ture.
It is s uf ? c ient th a t th e rea c tion time is p rop erl y s e
l ec ted in th e ra ng e of 0 . 5 to 2 4 h ours .
It is s uf ? c ient th a t th e a mount of th e ba s e us ed is
s el ec ted in th e ra ng e of 2 to 4 mol es p er mol e of l
c y a nometh y l imida z ol e rep res ented by th e s truc tura l
f ormul a ( IV) .
It is s uf ? c ient th a t a f ter c omp l etion of th e rea c tion,
th e rea c tion s ol ution is trea ted in th e us ua l w a y . For
ex a mp l e, th e rea c tion p roduc t is ex tra c ted a nd s ep a
ra ted w ith a s uita bl e s ol v ent a nd th en c a n be p uri? ed by
rec ry s ta l l iz a tion or c ol umn c h roma tog ra p h y .
Th e c omp ound rep res ented by th e g enera l f ormul a
( I) is of ten obta ined a s a mix ture of tw o k inds of th e
g eometric a l is omers s h ow n bel ow .
NC S l NC S ] / R
i N s R l N s
N = / N = /
( Z is omer) ( E is omer)
Th e a f ores a id mix ture of th e Z a nd E is omers c a n
of ten be is ol a ted into th e tw o is omers by a s uita bl e
s ep a ra tion meth od, f or ex a mp l e, rec ry s ta l l iz a tion, c h ro
ma tog ra p h y or th e l ik e.
Th is inv ention inc l udes th e g eometric a l is omers , i. e. ,
th e E a nd Z is omers , a nd a l l mix tures of th e tw o is omers
in a ny ra tio.
Ty p ic a l ex a mp l es of th e c omp ounds rep res ented by
th e g enera l f ormul a ( I) a re s h ow n in Ta bl e l , but th is
inv ention is not l imited th ereto.
TA BL E 1
NC S
F H } R
N S
( 1 )
P h y s ic a l p rop erty ,
mel ting p oint,
ref ra c tiv e index ,
MNR 6 v a l ue
( TMS / C DC 1 3 )
1 H Mel ting p oint l 2 6 . 5 C .
2 C H3 Mel ting p oint 9 7 . 6 " C .
3 c 2 1 1 5 rip " 1 . 6 2 4 6
4 n- C 3 H7 r1 0 1 7 1 . 6 0 6 5
5 i- C 3 H7 Mel ting p oint 8 6 . 7 C .
( Z is omer)
Mel ting p oint 5 5 . 8 C .
( E is omer)
1 1 D 1 . 5 2 3 0
Mel ting p oint 7 3 . 3 C .
( 2 is omer)
Mel ting p oint 1 1 8 . 1 C .
2 0
2 5
3 5
4 5
5 0
5 5
6 0
6 5
TA BL E l - c ontinued
NC
( I)
> = < Err
EN s
P h y s ic a l p rop erty ,
mel ting p oint,
C om ref ra c tiv e index ,
p ound MNR 6 v a l ue
No. R ( TMS / C DC 1 3 )
( E is omer)
1 0 s C 4 H9 ri D1 6 1 . 6 0 1 1 ( 2 is omer)
1 1 s - C 4 H9 r1 0 1 6 1 . 6 0 8 9 ( E is omer)
1 2 t- C 4 l - l 9 Mel ting p oint 1 5 1 . 7 . C .
1 3 n- C 5 HH DDM' S 1 . 5 9 3 1 ( 2 is omer)
1 4 1 1 - 0 5 1 1 n D1 6 5 1 . 5 9 4 9 ( E is omer)
l 5 i- C 5 H1 1 Mel ting p oint 7 4 . 3 C .
( Z is omer)
1 6 i- C 5 HH Mel ting p oint 1 1 1 . 4 C .
( E is omer)
1 7 neo- C 5 Hu Mel ting p oint 9 6 . 2 C .
( Z is omer)
l 8 neo- C 5 H1 1 Mel ting p oint l 0 7 . 7 C .
( E is omer)
1 9 ri- c 6 1 1 i3 r1 9 1 7 1 . 5 9 0 2 ( 2 is omer)
2 0 n- C 5 H1 3 Mel ting p oint 4 8 . 2 C .
( E is omer)
2 1 Mel ting p oint 1 1 3 . 9 C .
( Z is omer)
2 2 Mel ting p oint 1 0 3 . 8 C .
( E is omer)
2 3 = C H2 Mel ting p oint 1 1 5 . 7 C .
2 4 - C H= C H2 D1 7 1 . 6 4 2 2
2 5 C H2 C l Mel ting p oint 9 6 . 2 C .
2 6 - c 1 1 c 1 c 1 1 2 c 1 rip 1 6 1 . 6 1 0 3
2 7 = - C 1 - 1 2 C N n1 ) l 8 1 . 6 1 6 7
2 s - c 1 1 2 c 1 1 2 oc 1 - 1 2 c 1 - 1 3 1 1 D2 4 1 . 6 0 0 9
2 9 - - c r1 2 s c 1 - 1 3 Il Dl 3 5 1 . 6 4 1 2
3 0 C H; C ONH2 Vis c ous oil y s ubs ta nc e
3 . 6 4 ( m, 2 H) , 4 . 2 0
( m, 3 H) , 5 . 2 7 ( br, 2 H)
6 . 9 6 , 7 . 0 5 , 7 . 5 2 ( 1 1 - 1 on
h etero ring f or ea c h )
3 1 C H2 C H2 C OC H3 nDl s 1 . 6 0 8 6
3 2 c 1 r1 2 o2 c c 1 - 1 = c 1 1 2 r1 9 1 8 1 . 6 0 8 2
3 3 on 1 . 6 4 1 7
3 4 C l Mel ting p oint 1 1 9 . 4 C .
C l
( Z is omer)
Mel ting p oint 1 4 1 . 5 C .
( E is omer)
C om
p ound
No.
5
4 , 6 3 6 , 5 1 9
TA BL E l - c ontinued
RH. }
( 1 )
P h y s ic a l p rop erty ,
mel ting p oint,
ref ra c tiv e index ,
MNR 8 v a l ue
( T MS / C DC I 3 )
6 6 6 6 1 6 8 6 6 9 6 :
4 2
4 3
4 5
m f W
. 1
0
@
Q
1 1 0 2 4 1 . 6 0 8 3
Vis c ous oil y s ubs ta nc e
( Z is omer)
3 . 5 4 - 4 . 2 0 ( m, 2 H) ,
5 . 6 9 ( DD, 1 H)
7 . 0 0 - 7 . 7 5 ( m, 7 H)
Vis c ous oil y s ubs ta nc e
( E is omer)
3 . 4 5 - 4 . 1 0 ( rn, 2 H) ,
5 . 7 6 ( dd, 1 H)
7 . 0 0 - 7 . 8 5 ( m, 7 H)
Vis c ous oil y s ubs ta nc e
( 2 is omer)
3 . 6 - 4 . 0 ( m, 2 H) , 5 . 2 2 ( dd,
1 H) 6 . 9 - 7 . 8 1 ( m, 7 H)
Mel ting p oint 1 4 8 . 8 C .
( E is omer)
Vis c ous oil y s ubs ta nc e
( Z is omer)
Mel ting p oint 1 1 9 C .
( E is omer)
Vis c ous oil y s ubs ta nc e
3 . 6 - 3 . 9 ( m, 2 H) ,
5 . 1 - 5 . 5 ( m, 1 H)
6 . 9 - 7 . 8 ( m, 7 H)
D1 8 1 . 6 3 1 3 ( 2 is omer)
Mel ting p oint 1 2 3 . 3 C .
( E is omer)
1 0
2 0
2 5
3 0 ,
3 5
4 5
5 0
5 5
6 5
TA BL E l - c ontinued
NC
a ?
N
N
( 1 )
P h y s ic a l p rop erty ,
mel ting p oint,
C om- ref ra c tiv e index ,
p ound MNR 8 v a l ue
No. R ( TMS / C DC 1 3 )
4 6 D1 4 1 . 6 3 6 0
@ C H:
4 7 up 1 . 6 1 9 6
5 0
5 2
5 4
f og @ 9 @ 9 K? @
o n 7 '
f eis s 9
o of ?
OC H3
OC H3
C l
C l
Vis c ous oil y s ubs ta nc e
( Z is omer)
Vis c ous oil y s ubs ta nc e
( E is omer)
3 . 7 1 ( d, 2 H) , 3 . 8 2
( s , 3 H) , 5 . 6 8 ( t, 1 H)
6 . 8 7 , 7 . 0 0 , 6 . 7 2 ( 1 H f or
ea c h , H on a z ol e ring )
7 . 0 0 - 7 . 6 0 ( m, 4 H)
Vis c ous oil y s ubs ta nc e
( Z is omer)
3 . 7 5 ( d, 2 H) , 3 . 7 7
( s , 3 H) , 5 . 1 7 ( t, 1 H) ,
6 . 7 4 - 7 . 6 0 ( m, 7 H)
Vis c ous oil y s ubs ta nc e
( E is omer)
3 . 6 7 ( d, 2 H) , 3 . 8 0
( s , 3 H) , 5 . 2 4 ( t, 1 H) ,
6 . 7 0 - 7 . 6 5 ( m, 7 H)
Mel ting p oint 1 1 0 . 5 " C .
( Z is omer)
Mel ting p oint l 0 0 . 4 C .
( E is omer)
Vis c ous oil y s ubs ta nc e
( 2 is omer)
4 , 6 3 6 , 5 1 9
TA BL E l - c ontinued
C om
p ound
No.
5 7
N
N
1 7
C H3
C H3
C H3
C H2
H_ R '
P h y s ic a l p rop erty ,
mel ting p oint,
ref ra c tiv e index ,
MNR 8 v a l ue
( TMS / C DC 1 3 )
Vis c ous oil y s ubs ta nc e
( E is omer)
3 . 4 2 ( dd, 1 H) , 4 . 4 3
( t, 1 H) , 6 . 1 6 ( dd, 1 H) ,
7 . 1 8 - 7 . 4 0 ( m, 3 H) ,
6 . 9 8 , 7 . 0 8 , 7 . 5 6 ( l l - I f or
ea c h , H on a z ol e ring )
Vis c ous oil y s ubs ta nc e
3 . 6 - 3 . 9 ( m, 2 H) , 5 . 0 - 5 . 4
( m, 1 H) , 6 . 9 - 7 . 8 ( m, 6 H)
Vis c ous oil y s ubs ta nc e
3 . 6 4 , 3 . 7 2 ( d, 2 H f or
ea c h ) , 5 . 1 1 , 5 . 1 9 ( t, 1 H
f or ea c h ) , 5 . 9 2 , 5 . 9 5 ( s ,
( 1 )
2 H f or ea c h ) , 6 . 6 0 - 6 . 9 5 _
( m, 3 H) , 7 . 0 0 , 7 . 0 8 ,
7 . 5 3 ( 1 H f or ea c h , H on
a z ol e ring )
Mel ting p oint 1 8 7 . 5 C .
( Z is omer)
Mel ting p oint 2 1 4 . 0 C .
( E is omer)
Mel ting p oint 1 0 2 . 7 C .
D1 7 1 . 6 2 5 8
M1 8 1 . 6 3 1 5
1 1 D 1 . 6 2 1 3
2 0
2 5
3 0
3 5
4 5
5 0
5 5
6 5
6 6
7 0
TA BL E l - c ontinued
NC S
> = < %
F. .
C 1 C l
( 1 )
P h y s ic a l p rop erty ,
mel ting p oint,
ref ra c tiv e index ,
MNR 6 v a l ue
( TMS / C DC 1 3 )
Mel ting p oint 1 3 5 . 0 C . -
Vis c ous oil y s ubs ta nc e
3 . 6 5 - 4 . 3 8 ( m, 2 H) ,
5 . 2 2 - 5 . 6 0 ( m, 1 H) ,
7 . 0 0 - 7 . 9 5 ( m, 6 H) ,
8 . 5 4 - 8 . 7 6 ( m, 1 H)
Vis c ous oil y s ubs ta nc e
3 . 7 5 ( m, 2 H) ,
5 . 2 0 ( m, 1 H) ,
6 . 8 0 - 7 . 8 0 ( m, 7 H)
mix - 5 1 . 6 0 6 3
Vis c ous oil y s ubs ta nc e
( Z is omer)
3 . 8 3 ( m, 2 H) ,
5 . 4 6 ( dd, 1 H)
6 . 7 0 - 7 . 8 0 ( m, 6 H)
Vis c ous oil y s ubs ta nc e
( E is omer)
3 . 7 5 ( m, 2 H) ,
5 . 5 2 ( dd, 1 H) ,
6 . 6 0 - 7 . 8 0 ( m, 6 H)
D1 7 5 1 . 6 3 5 8 ( E is omer)
nD1 7 ~ 5 1 . 6 4 5 8 ( Z is omer)
Vis c ous oil y s ubs ta nc e
( 2 is omer)
3 . 8 3 ( m, 2 H) ,
5 . 5 9 ( dd, 1 H) ,
6 . 7 5 - 7 . 7 0 ( m, 6 H)
4 , 6 3 6 , 5 1 9
9
TA BL E l - c ontinued
1 7
P h y s ic a l p rop erty ,
mel ting p oint,
C om- ref ra c tiv e index ,
p ound MNR 5 v a l ue
No. R ( TMS / C DC 1 3 )
7 3 C l mel ting p oint
1 4 6 - 1 5 2 C . ( E is omer)
F
7 4 F Vis c ous oil y s ubs ta nc e
( Z is omer)
3 . 8 3 ( m, 2 H) ,
C l 5 . 4 2 ( dd, 1 H) ,
6 . 9 0 - 7 . 7 0 ( m, 6 H)
7 5 F mel ting p oint
1 1 4 - 1 1 7 C . ( E is omer)
C l
7 6 " D2 1 0 1 . 6 4 0 1
@ 0
7 7 nDZ Z - O 1 . 6 2 6 2
: 0
7 8 6 9 2 5 - 5 1 . 6 4 3 2
G
C H3
7 9 1 1 0 2 5 - 5 1 . 6 3 3 2
i?
P ref erred c omp ounds a re th es e in w h ic h R rep res ents
a l ow er a l k y l g roup , a l ow er a l k y l g roup s ubs tituted by
a l ow er a l k ox y l or a l k y l th io g roup , or
( R1 ) ! ! !
in w h ic h R1 rep res ents a h a l og en a tom, es p ec ia l l y c h l o
rine or bromine a tom, or a s tra ig h t or bra nc h ed c h a in
l ow er a l k y l g roup , es p ec ia l l y meth y l , a nd 1 1 1 rep res ents
a n integ er of 1 to 3 .
1 0
2 0
2 5
3 0
3 5
4 5
5 0
5 5
6 5
1 0
Ex a mp l es of th is inv ention a re s h ow n bel ow .
EXA MP L E 1
S y nth es is of
2 - ( 1 - imida z ol y l ) - 2 - ( 4 ~ is obuty l - 1 , 3 - dith iol on- 2
y l idene) a c et. onitril e ( C omp ound Nos . 8 a nd 9 )
To a mix ed s ol ution of 0 . 5 5 g ( 0 . 0 0 5 mol e) of l
c y a nometh y l imida z ol e, 0 . 4 g ( 0 . 0 0 5 mol e) of c a rbon
dis ul ? de a nd 1 0 ml of dimeth y l s ul f ox ide w a s a dded 0 . 8
g ( 0 . 0 1 4 mol e) of p ota s s ium h y drox ide p ow der w ith
s tirring , a nd th e rea c tion w a s c a rried out a t room tem
p era ture f or 1 h our. Th en, 1 . 5 g ( 0 . 0 0 6 mol e) of 1 , 2
dibromo- 4 - meth y l p enta ne w a s a dded drop w is e w ith
s tirring , a nd th e res ul ting s ol ution w a s s ubj ec ted to
rea c tion f or 2 h ours . A f ter c omp l etion of th e rea c tion,
2 0 ml of w a ter w a s a dded to th e rea c tion s ol ution, a f ter
w h ic h th e res ul ting mix ture w a s s ubj ec ted to ex tra c tion
w ith eth y l a c eta te, a nd th e org a nic l a y er w a s w a s h ed
w ith w a ter a nd dried. Th e s ol v ent w a s dis til l ed of f a nd
th e res idue w a s p uri? ed by s il ic a g el c h roma tog ra p h y to
obta in 0 . 4 5 g of th e Z is omer a nd 0 . 3 g on th e E is omer
indiv idua l l y in th e f orm of c ol orl es s c ry s ta l s .
Th e Z is omer ( C omp ound No. 8 ) : mel ting p oint 7 3 . 3
C . , y iel d 3 4 %.
Th e E is omer ( C omp ound No. 9 ) : mel ting p oint
l l 8 . l C . , y iel d 2 3 %.
EXA MP L E 2
S y nth es is of 2 - ( l - imida z ol y l ) - 2 - ( 4 - c h l orometh y l - 1 , 3
dith iol a n- 2 - y l idene) a c etonitril e ( C omp ound No. 2 5 )
To a mix ed s ol ution of 0 . 5 5 g ( 0 . 0 0 5 mol e) of l
c y a nometh y l imida z ol e, 0 . 4 g ( 0 . 0 0 5 mol e) of c a rbon
dis ul ? de a nd 1 0 ml of dimeth y l s ul f ox ide w a s a dded 0 . 8
g ( 0 . 0 1 4 mol e) of p ota s s ium h y drox ide p ow der w ith
s tirring , a nd th e rea c tion w a s c a rried out a t room tem
p era ture f or 1 h our. Th en, 1 . 4 g ( 0 . 0 0 6 mol e) of 1 , 2
dibromo- 3 - c h l orop rop a ne w a s a dded drop w is e w ith
s tirring , a nd th e res ul ting s ol ution w a s s ubj ec ted to
rea c tion f or 2 h ours . A f ter c omp l etion of th e rea c tion,
2 0 ml of w a ter w a s a dded to th e rea c tion s ol ution, a f ter
w h ic h th e res ul ting mix ture w a s s ubj ec ted to ex tra c tion
w ith eth y l a c eta te, a nd th e org a nic l a y er w a s w a s h ed
w ith w a ter a nd dried. Th e s ol v ent w a s dis til l ed of f a nd
th e res idue w a s p urif ied by s il ic a g el c h roma tog ra p h y
a nd rec ry s ta l l iz ed f rom eth y l a c eta te- n- h ex a ne to obta in
0 . 8 g of th e des ired c omp ound in th e f orm of c ol orl es s
c ry s ta l s : mel ting p oint 9 6 . 2 C . , y iel d 6 2 %.
EXA MP L E 3
S y nth es is of 2 - ( l - imida z ol y l ) - 2 - ( 4 - meth y l idene- 1 , 3
dith iol a n- 2 - y l idene) a c etonitril e ( C omp ound No. 2 3 )
In 1 0 ml of tetra h y drof ura n w ere dis s ol v ed 0 . 5 2 g
( 0 . 0 0 2 mol e) of th e 2 - ( l - imida z ol y l ) - 2 - ( 4 ~ c h l oro- meth
y l - l , 3 - dith iol a n- 2 - y l idene) a c etonitril e obta ined in Ex
a mp l e 2 a nd 0 . 3 1 g of l , 8 - dia z a bic y c l o- [ 5 , 4 , 0 ] - 7 - undec
ene, a nd th e rea c tion w a s c a rried out w ith h ea ting
under re? ux f or 1 h our. A f ter th e rea c tion s ol ution w a s
a l l ow ed to c ool , th e dep os ited s a l t w a s s ep a ra ted by
? l tra tion a nd th e ? l tra te w a s c onc entra ted to obta in
c rude c ry s ta l s , w h ic h w ere th en rec ry s ta l l iz ed f rom
eth y l a c eta te- n- h ex a ne to obta in 0 . 3 5 g of th e des ired
c omp ound in th e f orm of c ry s ta l s : mel ting p oint 1 1 5 . 7
0 . , y iel d 7 9 %.
l l l l
EXA MP L E 4
S y nth es is of 2 - ( 1 - imida z ol y l ) - 2 - [ 4 - ( 2 , 4 - dic h l oro
p h eny l ) - l , 3 - dith iol a n~ 2 - y l idenel ] a c etonitril e
( C omp ound Nos . 5 2 a nd 5 3 )
To a mix ed s ol ution of 0 . 5 5 g ( 0 . 0 0 5 mol e) of 1
c y a nometh y l imida z ol e, 0 . 4 g ( 0 . 0 0 5 mol e) of c a rbon
dis ul ? de a nd 1 0 ml of dimeth y l s ul f ox ide w a s a dded 0 . 8
g ( 0 . 0 1 4 mol e) of p ota s s ium h y drox ide p ow der w ith
s tirring , a nd th e rea c tion w a s c a rried out a t room tem
p era ture f or 1 h our. Th en, 2 . 0 g ( 0 . 0 0 6 mol e) of 2 ' , 4 '
dic h l oro- l , 2 - dibromoeth y l benz ene w a s a dded drop w is e
w ith s tirring , a nd th e res ul ting s ol ution w a s s ubj ec ted to
rea c tion f or 2 h ours . A f ter c omp l etion of th e rea c tion,
2 0 ml of w a ter w a s a dded to th e rea c tion s ol ution, a nd
th e res ul ting mix ture w a s s ubj ec ted to ex tra c tion w ith
eth y l a c eta te, a nd th e org a nic l a y er w a s w a s h ed w ith
w a ter a nd dried. Th e s ol v ent w a s dis til l ed of f a nd th e
res idue w a s p uri? ed by s il ic a g el c h roma tog ra p h y to
obta in 0 . 2 5 g of th e Z is omer a nd 0 . 5 g of th e E is omer
indiv idua l l y in th e f orm of a y el l ow v is c ous s ubs ta nc e:
y iel d ( tota l y iel d of th e Z a nd E is omers ) 4 2 %, mel ting
p oints 1 1 0 . 5 " C . ( th e Z is omer) a nd 1 0 0 . 4 " C . ( th e E
is omer) .
EXA MP L E 5
S y nth es is of
- - 2 - ( 1 - imida z ol y l ) - 2 - [ 4 ( 2 - is op rop y l - p h eny l ) - l , 3 - dith io
l a n- 2 - y l idene] a c etonitril e ( C omp ound No. 4 7 )
To mix ed s ol ution of 0 . 5 5 g ( 0 . 0 0 5 mol e) of l
c y a nometh y l imida z ol e, 0 . 4 ( 0 . 0 0 5 mol e) of c a rbon dis ul
? de a nd 1 0 ml of dimeth y l f orma mide w a s a dded 0 . 8 g
( 0 . 0 1 4 mol e) of p ota s s ium h y drox ide p ow der, a nd th e
rea c tion w a s c a rried out w ith s tirring a t room temp era
ture f or 1 h our. Th en, 1 . 8 g ( 0 . 0 0 6 mol e) of 2 - is op rop y l
1 , 2 - dibromoeth y l benz ene w a s a dded drop w is e w ith
s tirring , a nd th e res ul ting s ol ution w a s s ubj ec ted to
rea c tion f or a noth er 2 h ours . A f ter c omp l etion of th e
rea c tion, 2 0 ml of w a ter w a s a ddd to th e rea c tion s ol u
tion, a nd th e res ul ting mix ture w a s s ubj ec ted to ex tra c
tion w ith eth y l a c eta te, a nd th e org a nic l a y er w a s
w a s h ed w ith w a ter a nd dried. Th e s ol v ent w a s dis til l ed
of f a nd th e res idue w a s p uri? ed by s il ic a g el c h roma tog =
ra p h y to obta in th e des ired c omp ound in th e f orm of a
l ig h t- y el l ow oil y s ubs ta nc e: np 1 6 l . 6 l 9 6 , y iel d 3 4 %.
EXA MP L E 6
' S y nth es is of '
2 - ( l - imida z ol y l ) - 2 - [ 4 - ( 2 - c h l orop h eny l ) 1 , 3 - dith iol a n- 2
y l idenej a c etonitril e ( C omp ound Nos . 3 4 a nd 3 5 )
To a mix ed s ol ution of 2 . 2 g ( 0 . 0 2 mol e) of l
c y a nometh y l imida z ol e, 1 . 6 0 g ( 0 . 0 2 mol e) of c a rbon
dis ul ? de a nd 1 0 ml of dimeth y l s ul f ox ide w a s a dded 3 . 0
g ( 0 . 0 5 mol e) of p ota s s ium h y drox ide p ow der, a nd th e
rea c tion w a s c a rried out w ith s tirring a t room temp era
ture f or 1 h our. Th en, 4 . 2 g ( 0 . 0 2 mol e) of 2 ' - c h l oro- ( 1 , 2 <
dic h l oroeth y Dbenz ene w a s a dded drop w is e w ith s tir
ring , a nd th e res ul ting s ol ution w a s s ubj ec ted to rea c
tion f or a noth er 2 h ours . A f ter c omp l etion of th e rea c
tion, 2 0 ml of w a ter w a s a dded to th e rea c tion s ol ution,
a f ter w h ic h th e res ul ting mix ture w a s s ubj ec ted to ex
tra c tion w ith eth y l a c eta te, a nd th e org a nic l a y er w a s
w a s h ed w ith w a ter a nd dried. Th e s ol v ent w a s dis til l ed
of f a nd th e res idue w a s p uri? ed by s il ic a g el c h roma tog
ra p h y to obta in 2 . 0 g of th e Z is omer a nd 2 . 4 g of th e E
is omer indiv idua l l y in th e f orm of l ig h t- y el l ow c ry s ta l s .
4 , 6 3 6 , 5 1 9
l o
2 0
2 5
3 0
3 5
1 2
Th e Z is omer: mel ting p oint 1 1 9 . 4 C . y iel d 3 1 %.
Th e E is omer: mel ting p oint 1 4 1 . 5 " C . , y iel d 3 8 %.
EXA MP L E 7
S y nth es is of 2 - ( 1 - imida z ol y l ) ~ 2 - [ 4
( 2 - c h l orop h eny l ) l , 3 - dith iol a n- 2 - y l idene] a c etonitril e
( C omp ound Nos . 3 4 a nd 3 5 )
To a mix ed s ol ution of 2 . 2 g ( 0 . 0 2 mol e) of l c y a nome
th y l imida z ol e, 1 . 6 0 g ( 0 . 0 2 mol e) of c a rbon dis ul ? de a nd
1 0 ml of dimeth y l s ul f ox ide w a a dded 3 . 0 g ( 0 . 0 5 mol e)
of p ota s s ium h y drox ide p ow der, a nd th e rea c tion w a s
c a rried out w ith s tirring a t room temp era ture f or 1
h our. Th en, 6 . 0 g ( 0 . 0 2 mol e) of 2 ' - c h l oro- ( l , 2 - dibromo
eth y l ) benz ene w a s a dded drop w is e w ith s tirring , a nd
th e res ul ting s ol ution w a s s ubj ec ted to rea c tion f or
a noth er 2 h ours . A f ter c omp l etion of th e rea c tion, 2 0 ml
of w a ter w a s a dded to th e rea c tion s ol ution, a f ter w h ic h
th e res ul ting mix ture w a s s ubj ec ted to ex tra c tion w ith
eth y l a c eta te, a nd th e org a nic l a y er w a s w a s h ed w ith
w a ter a nd dried. Th e s ol v ent w a s dis til l ed of f a nd th e
res idue w a s p uri? ed by s il ia g el c h roma tog ra p h y to
obta in 0 . 3 g of th e Z is omer a nd 1 . 3 g of th e E is omer
indiv idua l l y in th e f orm of l ig h t- y el l ow c ry s ta l s .
Th e Z is omer: mel ting p oint 1 l 9 . 4 C . , y iel d 5 %.
Th e E is omer: mel ting p oint 1 4 1 . 5 C . , y iel d 2 0 %.
EXA MP L E 8
S y nth es is of
2 - ( 1 - imida z ol y l ) - 2 - [ 4 - ( 2 - c h l orop h eny l ) 1 , 3 - dith iol a n- 2
y l idene] a c etonitril e ( C omp ound Nos . 3 4 a nd 3 5 )
To a mix ed s ol ution of 2 . 2 g ( 0 . 0 2 mol e) of l
c y a nometh y l imida z ol e, 1 . 6 0 g ( 0 . 0 2 mol e) of c a rbon
dis ul ? de a nd 1 0 ml of dimeth y l s ul f ox ide w a s a dded 3 . 0
g ( 0 . 0 5 mol e) of p ota s s ium h y drox ide p ow der, a nd th e
rea c tion w a s c a rried out w ith s tirring a t room temp era
ture f or 1 h our. Th en, 6 . 6 g ( 0 . 0 2 mol e) of 2 ' - c h l oro( l , 2
dimes y l ox y eth y l ) benz ene w a s a dded drop w is e w ith
s tirring , a nd th e res ul ting s ol ution w a s s ubj ec ted to
4 0 rea c tion f or a noth er 2 h ours . A f ter c omp l etion of th e
4 5
5 0
5 5
6 0
6 5
rea c tion, 2 0 ml of w a ter w a s a dded to th e rea c tion s ol u
tion, a f ter w h ic h th e res ul ting mix ture w a s s ubj ec ted to
ex tra c tion w ith eth y l a c eta te, a nd th e org a nic l a y er w a s
w a s h ed w ith w a ter a nd dried. Th e s ol v ent w a s dis til l ed
of f a nd th e res idue w a s p uri? ed by s il ic a g el c h roma tog
ra p h y to obta in 1 . 3 g of th e Z is omer a nd 1 . 8 g of th e E
is omer indiv idua l l y in th e f orm of l ig h t- y el l ow c ry s ta l s .
Th e Z is omer: mel ting p oint l l 9 . 4 C . , y iel d 2 0 %.
Th e E is omer: mel ting p oint 1 4 1 . 5 C . , y iel d 2 8 %.
Th e c omp ounds of th is inv ention a re a ntimy c otic
a g ents us ef ul f or p rev enting f ung ous inf ec tion of h uma n
being s a nd a nima l s . For ex a mp l e, th es e c omp ounds c a n
be us ed f or c uring my c os es s uc h a s l oc a l my c otic inf ec
tion, muc os a l my c otic inf ec tion, s y s temic my c otic in
f ec tion a nd th e l ik e w h ic h a re c a us ed by Derma to
p h y tes s uc h a s Mic ros p orum, Ep idermop h y ton, Tric h o
p h y ton a nd th e l ik e a nd C a ndida .
Th e c omp ounds of th is inv ention c a n be mix ed w ith
c onv entiona l c h emoth era p eutic a l l y a c c ep ta bl e dil uents
or c a rriers a nd if des ired, oth er ex c ip ients , a nd c a n be
us ed in p h a rma c eutic a l f orms s uc h a s s ol utions , c rea ms ,
s up p os itories , ointments , ta bl ets , etc .
W h en us ed a s a ntimy c otic a g ents , th e c omp ounds of
th is inv ention c a n be us ed a s l oc a l l iniments in p h a rma
c eutic a l f orms s uc h a s c rea ms , ointments , s ol ution, etc .
W h en th ey a re us ed in th e f orm of a n endermic s ol ution,
th eir p ra c tic a l c onc entra tion is c ons idered to be s uita bl y
0 . 1 %or more.
4 , 6 3 6 , 5 1 9
1 3
Th e p res ent drug s ma y be us ed, of c ours e, in a n a d
mix ture w ith oth er a ntiba c teria l a g ents s uc h a s a mp h o
teric in B, ny s ta tin, tric h omy c in, v a riotin, c l otrima z ol e
a nd th e l ik e.
Furth er, th e c omp ounds of th is inv ention a re us ef ul a s
a g ric ul tura l a nd h ortic ul tura l f ung ic ides . For ex a mp l e,
th ey a re v ery ef f ec tiv e a g a ins t v a rious p h y top a th og enic
dis ea s es , e. g . , ric e bl a s t ( P iric ul a ria ory z a e) ; p ow dery
mil dew of ba rl ey a nd w h ea t ( Ery s l l p h e g ra minis ) , a nd
oth er p ow dery mil dew s of v a rious h os t p l a nts s uc h a s
th a t of c uc umber ( S p h a eroth ec a f ul g inea ) , th a t of a p p l e
( P odos p h a era Ieuc otric h a ) a nd th a t of g ra p e ( Unc inul a
nec a tor) ; rus t of w h ea t ( P uc c inia v ec ondita ) ; C row n rus t
of oa ts ( P uc c inia c orona te) a nd rus t of oth er h os t p l a nts :
l a te bl ig h t of toma to ( p h y ta p h th ora c a p s ic i) a nd p h y top h
th ora rot of oth er h os t p l a nts ; etc .
W h en th e c omp ound of th is inv ention is us ed a s a c
tiv e ing redient in a n a g ric ul tura l a nd a h ortic ul tura l
f ung ic ide, th e f ung ic ide is p rep a red into a f ormul a tion
s uita bl e f or us e in a c onv entiona l ma nner a s a n a g ric ul
tura l c h emic a l . For ex a mp l e, th e f ung ic ide is p rep a red
in th e f orm of dus t, g ra nul es , ? ne g ra nul es , w etta bl e
p ow der, emul s i? a bl e c onc entra te, oil y s ol ution, a eros ol ,
? oa ting dus t, f umig a nts , p rep a ra tions s uita bl e f or v a
p oriz ing th e a c tiv e ing redient by h ea t or oth er p h y s ic a l
mea ns , ta bl ets or th e l ik e by mix ing th e c omp ound of
th e inv ention w ith a dj uv a nts , a nd is a p p l ied to s ta l k s
a nd l ea v es of v eg eta bl es , ? ow ering p l a nts , c rop s f or
indus tria l us e, f ruit trees , oth er trees a nd th e l ik e a s it is
or a f ter dil uted to a s uita bl e v ol ume w ith w a ter. A l
th oug h in th is inv ention th e dos a g e of th e a c tiv e ing re
dient v a ries dep ending on th e k ind of th e c omp ound,
p l a nt to be trea ted, th e w a y of us ing , a nd th e l ik e, it c a n
be s el ec ted in th e ra ng e of 5 to 5 0 0 g p er 1 0 a res .
W h en a p p l ied, th e c omp ound of th is inv ention c a n
a l s o be us ed in a dmix ture w ith or in c ombina tion w ith
oth er a g ric ul tura l c h emic a l s , f ertil iz ers , p l a nt nutrients
a nd th e l ik e w h ic h c a n be us ed s imil a rl y to th e c om
p ound.
For ex a mp l e, w h en a p h y top a th og enic dis ea s e is c on
trol l ed by us ing a n a g ric ul tura l a nd h ortic ul tura l f ung i
c ide c omp ris ing th e c omp ound of th is inv ention a s a c
tiv e ing redient, th e f ung ic ide c a n be ma de into a mul ti
p l e- p urp os e p rev enting a nd c uring a g ent by mix ing
th erew ith a n a g ent f or p rev enting a nd c uring oth er
dis ea s es a nd/ or v ermin ins ec ts w h ic h brea k out s imul ta
neous l y w ith a f ores a id dis ea s e.
Nex t, s ome Tes t Ex a mp l es a nd Formul a tion Ex a m
p l es a re g iv en bel ow in order to demons tra te th e us ef ul
nes s of th e c omp ounds of th is inv ention, but th is inv en
tion is not intended to be l imited th ereto.
Tes t Ex a mp l e 1
Tes t f or a ntif ung a l a c tiv ity a g a ins t Tric h op h y ton menta
g rop h y tes
In 1 l iter of w a ter w ere dis s ol v ed 1 0 g of p ep tone a nd
4 . 0 g of g l uc os e a nd th e res ul ting s ol ution w a s a dj us ted
to p H 6 . 0 , a f ter w h ic h a drug c onta ining 5 0 p p b ( 1 %
DMS O s ol ution) of ea c h a c tiv e ing redient w a s a dded.
Into a 3 . 5 q b c m P etri dis h w a s p oured 3 0 ml of th e th us
obta ined S a boura ud medium to p rep a re a n a g a r p l a te.
Th en, th e inoc ul um of th e f ung us p rec ul tured w a s
p oured onto th e p l a te in a n a mount of 0 . 1 ml p er P etri
dis h . Th us p rep a red p l a tes w ere inc uba ted a t 2 8 C . f or
4 - 6 da y s . Th e tes t w a s c a rried out in dup l ic a tion f or
ea c h c omp ound a nd th e res ul ts p er dis h ev a l ua ted ma c
ros c op ic a l l y a re s h ow n in Ta bl e 2 .
2 5
3 0
3 5
5 0
5 5
6 5
1 4
Ev a l ua tion c riterion
+ Mul tip l ic a tion of c el l s w a s c omp l etel y inh ibited.
+ Mul tip l ic a tion of c el l s w a s inh ibited.
- + t- W h ite c ol onies w ere f ormed.
- \+ + Th e dia meter of w h ite c ol onied inc rea s ed.
TA BL E 2
C omp ound No.
6 5
C ontrol
( no c omp ound a dded)
TES T EXA MP L E 2
C uring ef f ec t tes t a g a ins t tric h op h y tos is w h ic h w a s
a rti? c ia l l y inf ec ted in g uinea p ig s
Ha rtl ey s tra in w h ite ma l e g uinea p ig s ( 4 0 0 to 6 0 0 g )
w ere us ed a s tes t a nima l s . Th e h a ir in th ree s p ots on th e
ba c k of ea c h g uinea p ig w a s s h ea red a nd th en remov ed
in a c irc l e h a v ing a dia meter of a bout 3 c m by us e of
dep il a tory c rea m, a f ter w h ic h th e s k in in th e dep il a ted
s p ots w a s l ig h tl y rubbed w ith s a ndp a p er. Th us trea ted
s p ots w ere inoc ul a ted w ith 0 . 1 ml ( 1 0 6 s p ores / s p ot) of
c ul ture of Tric h op h y ton menta g rop h y tes IFO- 5 4 6 6 s tra in
g row n on S a boura ud g l uc os e a g a r media . Ea c h tes t
drug p rep a red by us ing p ol y eth y l ene g l y c ol 3 0 0 a s ba s e
w a s a p p l ied to th e inoc ul a tion s p ots onc e da il y f or 1 1
c ons ec utiv e da y s in a n a mount of 0 . 2 ml p er inoc ul a tion
s p ot, s ta rting 7 2 h ours a f ter th e inoc ul a tion. Th e ev a l ua
tion w a s c onduc ted by ma c ros c op ic a l j udg ement a nd
rev ers e c ul ture tes t.
( a ) Ma c ros c op ic a l j udg ement:
A f ter th e inoc ul a tion, th e a l l ev ia tion a nd dev el op
ment of s y mp toms in th e a bov e- mentioned s p ots w ere
obs erv ed ev ery da y f or 1 5 da y s . Th e res ul ts a re s h ow n
in Ta bl e 3 .
0 : No s y mp tom w a s obs erv ed.
1 : A f ew s ma l l ery th ema s w ere obs erv ed.
2 : Ery th ema s w ere ins ul a rl y s c a ttered or f us ed into
one, a nd rubef a c tion w a s obs erv ed a round th em.
3 : S c a l es w ere obs erv ed, a nd th en f orma tion of th ic k
l es ion w a s obs erv ed.
4 : L es ion rea c h ed to a n ex treme s ta g e w ith
bl eeding . Th e res ul ts obta ined a re s h ow n in Ta bl e 3 .
( b) Rev ers e c ul ture tes t
Ea c h g uinea p ig w a s s a c ri? ed 1 5 da y s a f ter th e inoc u
l a tion, a f ter w h ic h th e s k in in th e w h ol e inoc ul a tion
s p ots w a s c ut of f a nd th e s k in c ut- of f w a s f urth er c ut
into s ma l l p iec es ( a bout 5 mm s q ua re) . Th e p iec es th us
p rep a red w ere p l a c ed on S a boura ud g l uc os e a g a r me
dium c onta ining 2 0 i. u. / ml of p enic il l in G a nd 4 0 ug / ml
of s trep tomy c in, a nd th en c ul tured a t 2 7 C . f or 2
4 , 6 3 6 , 5 1 9
1 1 5 1 6
w eek s . Th e ev a ul a tion w a s c a rried out by inv es tig a ting _ -
th e c ol onies . Th e res ul ts obta ined a re s h ow n in Ta bl e TA BL E 5 c ommued
C omp ound C onc entra tion C ontrol l ing
TA BL E 3 s No. ( p p m) ef f ec ts
( Ma c ros c op ic a l j udg ement! 5 2 2 4
Drug 2 4 4
tes ted 2 5 I, 4
( C onc en- Da y s 2 6 I 4
tra tion) 4 5 6 7 s 9 1 0 1 1 1 2 1 3 1 4 1 5 , , i
C omp ound 5 3 2 9 " 4
l 0 3 0 u 2
( 1 %) 0 . 5 l l l l l l 1 . 5 1 . 5 1 . 5 2 . 5 2
( 0 . 1 %) 1 2 2 2 2 . 5 3 3 3 . 5 3 . 5 3 . 5 3 . 5 3 . 5 3 2 H 2
C omp ound 3 5 3 3 H 4
( 1 %) 1 1 1 1 1 1 1 . 5 1 . 5 1 . 5 1 . 5 3 3 , , 1
( 0 . 1 %) 0 . 5 l 1 . 5 1 . 5 2 . 2 . 5 3 3 . 5 3 . 5 3 . 5 3 . 5 4 3 6 , , 4
C om ound 3 8 1 5 3 7 , , 4
( 1 %) 1 1 . 5 1 . 5 l l 1 1 . 5 2 2 2 2 2 3 8 H 4
( 0 . 1 %) 0 . 5 2 2 2 2 . 5 2 . 5 3 3 3 . 5 3 . 5 3 . 5 4 4 2 1 ' 4
M 4 3 " 4
( 1 %) l l l 1 . 5 l l 1 . 5 2 2 . 5 2 . 5 3 . 5 3 . 5 4 5 " 4
( 0 . 1 %) 0 1 . 5 1 . 5 2 2 . 5 3 3 3 3 3 3 3 4 6 " 4
C ontrol 1 2 2 2 3 3 . 5 3 . 5 3 . 5 3 . 5 4 4 4 2 0 4 7 " 4
( N0 ' 4 8 " 4
c omp ound 5 0 " 4
trea ted) 5 3 " 4
5 4 " 4
5 6 " 4
TA BL E 4 2 5 g ; , , :
( Ees ul ts of rev ers e c ul ture tes t! 6 1 " 4
Drug C onc entra tion 2 2 " 4
_ - _ ' _ _ ' _ I! 4
Tes ted 1 % 0 . 1 % 6 5 , , 4
C omp ound 5 3 0 / 2 0 7 / 2 0 3 0 6 7 " 4
C omp ound 3 5 0 / 2 0 6 / 2 0 7 2 " 4
C omp ound 3 8 0 / 2 0 6 / 2 0 7 5 4
Tol na f ta te 0 / 2 0 1 6 / 2 0 7 6 " 4
C ontrol 2 0 / 2 0 7 7 " 4
( No c omp ound 7 8 " 4
trea ted) 3 5 7 9 4
1 TES T EXA MP L E 3 TES T EXA MP L E 4
C ontrol l ing Ef f ec ts on P ow dery Mil dew of Ba rl ey C ontrol l ing Ef f ec ts on s eed- borne Fus a rium
Young ba rl ey p l a nts ( v a riety : Ka nto No. 6 , 2 - l ea f 4 0 C uc umber s eeds inf es ted w ith Fus a n' um ox y s p orum
s ta g e) c ul tiv a ted in th e p orc el a in p ots ( 1 2 c m in dia rne- f s p . c uc umerinum w ere s oa k ed in s ol utions ( 2 0 0 p p m) of
ter) w ere inoc ul a ted by c onidia of Ery s ip h e g ra minis th e p res ent c omp ounds f or 2 0 h r. Th e trea ted s eeds
g ra minis F. S p . h ordei, th e c a us a l f ung us of p ow edery w ere th en p l a c ed on th e s el ec tiv e medium f or Fus a rium
mil dew . Th e da y a f ter inoc ul a tion, th e p l a nts w ere s p p . ( Koma da medium) . A f tera w eek - inc uba tion a t 2 5
trea ted on th e turn ta bl e by s p ra y ing s ol utions ( 2 0 0 4 5 C . , th e my c el ia l g row th a round th e trea ted s eeds w a s
p p m) of th e p res ent c omp ounds by s p ra y g un. Th e a s s es s ed a nd th e c ontrol l ing ef f ec ts w ere c a l c ul a ted in
trea ted p l a nts w ere k ep t a t 2 5 C . f or 6 da y s in a g reen- c omp a ris on w ith untrea ted I p l ots . Th e c riteria f or
h ous e a nd th e dev el op ment of l es ions w a s a s s es s ed. Th e c ntrol l ing ef f ec ts a re a s s a me a s in Tes t Ex a rnl e 3 .
c ontrol l ing ef f ec ts of th e c omp ounds w ere c a l c ul a ted in Th e res ul ts a re s h ow n in Ta bl e 6 .
c omp a ris on w ith th e untrea ted p l ots . Th e c riteria f or 5 0 TA BL E 6
th e c ontrol l ing ef f ec ts a re: . .
4 ~ l 0 0 _ 9 5 7 c ontrol C omp ound C onc entra tl on Oontrol l mg
5 0 No. ( p p m) ef f ec ts
3 ; 9 4 - 8 0 %c ontrol 3 2 0 0 4
2 ; 7 9 - 6 0 %c ontrol 4 . . 4
1 ; 5 9 - 0 %c ontrol 5 5 6 " 4
Th e res ul ts a re s h ow n in Ta bl e 5 . 1 ( 7 ) 3
TA BL E 5 1 1 I, 4 1
C omp ound C onc entra tion C ontrol l ing , : Z
No. ( p p m) ef f ec ts 6 0 1 8 . 1 4
1 2 0 0 3 2 0 " 4
3 " 4 2 1 " 4
5 u 4 2 4 " 3
8 u 4 2 6 " 2
9 " 4 2 9 " 4
1 2 " 3 6 5 3 3 " 4
1 5 " 4 3 5 " 4
1 7 " 4 3 7 " 4
2 0 " 4 3 9 " 4
2 1 " 4 4 0 u 4
4 , 6 3 6 , 5 1 9
1 7 1 8
TA BL E 6 _ c ominued Th e rec ip es s h ow n in Formul a tion Ex a mp l es 4 to a re
. f or a g ric ul tura l c h emic a l s . In th es e ex a mp l es , a l l p a rts
a re by w eig h t a s in Formul a tion Ex a mp l es 1 to 3 .
C omp ound C onc entra tion C ontrol l ing
No. ( P P ! ! ! ) ef f ec ts
" 4 5 FORMUL A TION EXA MP L E 4
W etta bl e p ow der
" C omp ound 1 2 5 0 p a rts
" l 0 Mix ture of dia toma c eous 4 5 p a rts
" ea rth a nd c l a y
P ol y ox y eth y l ene nony l - 5 p a rts
" p h eny l eth er
Th es e ing redients a re h omog eneous l y mix ed a nd th en
p ul v eriz ed to p rep a re a w etta bl e p ow der.
FORMUL A TION EXA MP L E 5
6 6 1 ' Emul s i? a bl e c onc entra te
6 7 "
6 8 " 2 0
6 9 " C omp ound 2 3 2 0 p a rts
7 0 " Tetra h y drof ura n 2 0 p a rts
7 1 Xy l ene 4 5 p a rts
7 3 " Mix ture of p ol y ox y eth y l ene 1 5 p a rts
7 5 " nony l p h eny l eth er a nd a l k y l
7 6 " 2 5 benz enes ul f ona te
7 7 "
7 8 " 0 I a
7 9 " Th es e ing redients a re h omog eneous l y mix ed to p re
p a re a n emul s i? a bl e c onc entra te.
Th e rec ip es s h ow n bel ow a s Formul a tion Ex a mp l es 1 3 0 FORMUL A TION EXA MP L E 6
to 3 a re f or medic a l p urp os es . For th es e p urp os es , th e D
v a rious a dj uv a nts a nd c ons tituents to be us ed s h oul d be S t
of p h a rma c eutic a l l y a c c ep ta bl e g ra de. In Formul a tion
Ex a mp l es 1 to 3 , a l l p a rts a re by w eig h t. C omp ound 2 9 4 p m
3 5 M' : f d' : 9 5 a rts
FORMUL A TION EXA MP L E 1 ea r t h ? ' f l g 8 :1 1 3 ?
C a l c ium s tea ra te 1 p a rt
C omp ound 3 5 1 p a rt . ' _
P ol y eth y l ene g l y c ol 3 0 0 9 5 p a rts Th es e mg ra dl ents a re h omog eneous l y mix ed a nd th en
. 4 p ul v eriz ed to p rep a re a dus t.
Th es e ing redients a re mix ed to p rep a re a n endermic FORMUL A TION EXA MP L E 7
s ol ution.
Gra nul es
FORMUL A TION EXA MP L E 2 4 5
C omp ound 4 6 3 p a rts
c omp ound 5 3 2 p a ns Mix ture of bentonite a nd c l a y 9 2 p a rts
P ol y eth y l ene g l y c ol 4 0 0 4 0 p a rts C a l c ium l ig nin s ul f ona te 5 p a rts
P ol y eth y l ene g l y c ol 1 5 0 0 5 8 p a rts
5 0 Th es e ing rea dients a re h omog eneous mix ed a nd th en
Th es e ing redients a re mix ed w ith h ea ting to obta in a p ul v eriz ed, a f ter w h ic h a n a deq ua te a mount of w a ter is
s ol ution, w h ic h is th en c ol l ed to p rep a re a n ointment. a dded, a nd th e res ul ting mix ture is s uf f ic ientl y k nea ded
a nd th en g ra nul a ted to p rep a re g ra nul es .
FORMUL A TION EXA MP L E 3 w h a t is c l a imed is :
5 5 l . A k etene S , S - a c eta 1 deriv a tiv e rep res ented by th e
C omp ound 3 8 2 p a rts g enera l f ormul a ( I) :
1 , 2 - P rop a nediol 5 p a rts
Gl y c erol s tea ra te 5 p a rts ( I)
S p erma c eti 5 p a rts NC 5
Is op rop y l my ris ta te 1 0 p a rts 6 0
P ol y s orba te 6 0 4 p a rts > ' = < R
N s
A mix ture of th em is h ea ted a nd th en c ool ed, a f ter N = /
w h ic h 6 9 p a rts of w a ter is a dded w ith s tirring to p rep a re
c 1 c a m 6 5 w h erein R rep res ents a h y drog en a tom; a n a l k y l g roup
1 ? a ddition to th e p l l a ml a c eutic a l f omml a tions ( 1 6 ' h a v ing 1 to 8 c a rbon a toms ; a c y c l oa l k y l g roup h a v ing
s c nbed a bov e, Ql ' eRa l ' a tl on " 1 p h a rma c el f uc f l uy us f l bl e 3 to 6 c a rbon a toms ; a meth y l ene g roup ; a l ow er a l k eny l
f orms s uc h a s l Xl J C C tl OIl S , ta bl ets a nd th e l ik e 1 s p os s ibl e. g roup ; a l ow er A l k y l g ronp s ubs tituted by a h a l og en
4 , 6 3 6 , 5 1 9
1 9
a tom, a c y a no g roup , a l ow er a l k ox y l g roup , a l ow er
a l k y l th io g roup , a c a rba moy l g roup , a l ow er a l k a noy l
g roup , or a n a l k enoy l ox y g roup s ; a p l eny l g roup rep re
s ented by
( ROM ,
( in w h ic h R1 rep res ents a h y drog en a tom, a h a l og en
a tom, a s tra ig h t or bra nc h ed c h a in l ow er a l k y l g roup , a
l ow er a l k ox y l g roup w ith w h ic h ma y be s ubs tituted by
one or more h a l og en a toms , a p h enox y g roup or a meth
y l enediox y g roup , a nd m rep res ents a n integ er of l to 3 ) ;
a benz y l g roup ; a meth y l enediox y benz y l g roup ; a p h e
nox y a l k y l g roup ; a p h enox y a l k y l g roup s ubs tituted by a
h a l og en a tom; a na p h th y l g roup ; a p y ridy l g roup or a
p y ridy l g roup s ubs tituted by a l ow er a l k y l g roup .
2 . A k etene S , S - a c eta l deriv a tiv e a c c ording to c l a im
1 , w h erein R rep res ents a l ow er a l k y l g roup , a l ow er
a l k y l g roup s ubs tituted by a l ow er a l k ox y l or a l k y l th io
g roup , or
in w h ic h R1 rep res ents a h a l og en a tom, or a s tra ig h t or
bra nc h ed c h a in l ow er a l k y l g roup , a nd m rep res ents a n
integ er of l to 3 .
3 . A k etene S , S - a c eta l deriv a tiv e a c c ording to c l a im
1 , w h erein R rep res ents
in w h ic h R1 rep res ents a h a l og en a tom or meth y l g roup ,
a nd m rep res ents a n integ er of l to 3 .
4 . A k etene S , S - a c eta l deriv a tiv e a c c ording to c l a im
1 , w h ic h is 2 - ( l - imida z ol y l ) - 2 - [ 4 - ( 2 , 4 - dic h l oro- p h eny l )
1 , 3 - dith iol a n- 2 - y l idene] a c etonitril e ( E is omer) .
5 . A k etene S , S - a c eta l deriv a tiv e a c c ording to c l a im
1 , w h ic h is 2 - ( l - imida z ol y l ) - 2 - [ 4 - ( 2 - c h l oro- p h eny l ) - 1 , 3
dith iol a n- Z - y l idene] a c etonitril e ( E is omer) .
6 . A k etene S , S - a c eta l deriv a tiv e a c c ording to c l a im
1 , w h ic h is 2 - ( 1 - imida z ol y l ) - 2 - [ 4 - ( 2 - bromo- p h eny l ) - 1 , 3
dith iol a n- Z - y l idene] a c etonitril e ( E is omer) .
7 . A k etene S , S - a c eta l deriv a tiv e a c c ording to c l a im
1 , w h ic h is 2 - ( l - imida z ol y l ) - 2 - [ 4 - ( 4 - c h l oro- p h eny l ) - 1 , 3
c l ith iol a n- Z - y l idene] a c etonitril e ( E is omer) .
8 . A p roc es s f or p roduc ing a k etene S , S - a c eta l deriv a
tiv e rep res ented by th e g enera l f ormul a ( I) :
w h erein R1 rep res ents a h y drog en a tom; a n a l k y l g roup
h a v ing 1 to 8 c a rbon a tom; a c y c l oa l k y l g roup h a v ing 3
to 6 c a rbon a toms ; a meth y l ene g roup ; a l ow er a l k eny l
1 0
1 5
2 0
2 5
3 5
4 5
5 0
5 5
6 0
2 0
g roup s ; a l ow er a l k y l g roup s ubs tituted by a h a l og en
a tom, a c y a no g roup , a l ow er a l k ox y l g roup , a l ow er
a l k y l th io g roup , a c a rba moy l g roup , a l ow er a l k a noy l
g roup , or a n a l k enoy l ox y g roup ; a p h eny l g roup rep re
s ented by
( Rom
( in w h ic h R1 rep res ents a h y drog en a tom, a h a l og en
a tom, a s tra ig h t or bra nc h ed c h a in l ow er a l k y l g roup , a
l ow er a l k ox y l g roup w h ic h ma y be s ubs tituted by one
or more h a l og en a toms , a p h enox y g roup or a meth y l
enediox y g roup , a nd m rep res ents a n integ er of l to 3 ) ;
a benz y l g roup ; a meth y l enediox y benz y l g roup : a p h e
nox y a l k y l g roup ; a p h enox y a l k y l g roup s ubs tituted by a
h a l og en a tom; a na p h th y l g roup ; a p y ridy l g roup or a
p y ridy l g roup s ubs tituted by a l ow er a l k y l g roup , w h ic h
c omp ris es rea c ting l - c y a nometh y l imida z ol e rep re
s ented by th e s truc tura l f ormul a ( II) :
NOC HZ N %
( II)
w ith c a rbon dis ul ? de in th e p res enc e of a ba s e, a nd th en
rea c ting th e rea c tion p roduc t w ith a c omp ound rep re
s ented by th e g enera l f ormul a ( III) :
R ( 1 1 1 )
I
x c uc nz x
w h erein R is a s de? ned a bov e, a nd X rep res ents a h a l o
g en a tom, a mes y l ox y or a tos y l ox y g roup .
9 . A meth od f or c uring my c os is w h ic h c omp ris es
a dminis tering a p h a rma c eutic a l p rep a ra tion c onta ining
a p h a rma c eutic a l l y ef f ec tiv e a mount of a k etene S , S
a c eta l deriv a tiv e rep res ented by th e g enera l f ormul a ( I) :
NC 8 ( I)
> = < 5 %
W S
N :/
w h erein R rep res ents a h y drog en a tom; a n a l k y l g roup
h a v ing 1 to 8 c a rbon a toms ; a c y c l oa l k y l g roup h a v ing
3 to 6 c a rbon a toms ; a meth y l ene g roup ; a l ow er a l k eny l
g roup ; a l ow er a l k y l g roup s ubs tituted by a h a l og en
a tom; a c y a no g roup ; a l ow er a l k ox y l g roup , a l ow er
a l k y l th io g roup , a c a rba moy l g roup , a l ow er a l k a noy l
g roup , or a n a l k enoy l ox y g roup ; a p h eny l g roup rep re
s ented by
ml ) " :
( in w h ic h R1 rep res ents a h y drog en a tom, a h a l og en
a tom, a s tra ig h t or bra nc h ed c h a in l ow er a l k y l g roup , a
4 , 6 3 6 , 5 1 9
2 1 2 2
l ow er a l k ox y l g roup w h ic h ma y be s ubs tituted by one iml da z ol y l ' z ' [ 4 ' ( 2 , 4 ' d1 h 1 T P h eny 1 ) - 1 , 3 - dl l h i0 1 a n- 2
. _ y l idene] a c etonitril e ( E is omer) .
of 1 . 0 m h a l og en a toms 3 p h enox y g r_ oup or a meth y l 1 1 . A meth od f or c uring my c os is a c c ording to c l a im
enedl ox y g roup a nd m rep res ents a n l meg a of 1 to 3 ) ; 9 , w h erein th e k etene S , S - a c eta l deriv a tiv e is 2 - ( 1
a benz y l g roup , a meth y l enediox y benz y l g roup ; a p h e- 5 imida z ol y l ) - 2 - [ 4 - ( 2 - c h l orop h eny l ) - 1 , 3 - dith iol a n- 2 - y l i
nox y a l k y l g roup ; a p h enox y a l k y l g roup s ubs tituted by a dene) a c ew nitl ' il e ( E is omer)
h t . h th 1 . - d 1 1 2 . A meth od f or c uring my c os is a c c ording to c l a im
a p g en a Om a a ? y g roup a p y n y g roup or a 9 , w h erein th e k etene S , S - a c eta l deriv a tiv e is 2 - ( 1
p y ndy ] g roup s ubs tituted by a l ow er a l k y l g roup . imida z o1 y l ) _ 2 _ [ 4 _ ( 2 _ bmm0 p h eny l ) _ 1 3 _ dith iol a n_ 2 _
1 0 . A meth od f or c uring my c os is a c c ording to c l a im 1 0 y l idenek c etoniml e ( E is omer)
9 w h erein th e k etene S , S - a c eta l deriv a tiv e is 2 - ( 1 - * ' * * * *
1 5
2 0
2 5
3 0
3 5
4 5
5 0
5 5
6 5