Note: Descriptions are shown in the official language in which they were submitted.
- 1 - 16588
TITLE OF THE INVENTION
DIAMINO ISOTHIAZOLE -l~OXIDES AND ~ DI~XIDES AS
GASTRIC SECRETION INHIBITORS
BACKGROUND OF THE INVENTION
Inhibitors of qastric aci~ secretion
functioning by antagonism of the histamine H2-
receptor are effective antiulcer agent~
Structurally, such compounds are tYpically viewe~ as
molecules having three substituents or fragments;
i.e., A-B-C, each of which can independentlv affect
the antisecretory activity. The "A" portion may be a
substituted or unsubstituted aromatic or hetero-
aromatic group such as are disclosed in, for exam~le,
U.S. Patent 3,950,333 to Durant et. al., U.S. Patent
4,128,658 to Price et. al., and Belgian Patents
867,106 and 875,846 (Derwent Abstracts 84065A/47 and
79110B/44, respectively).
The central, or "B" Portion, mav he a
connecting chain joined to A such as A-CH2SCH2CH2-,
AOCH2CH2CH2, and the like.
- 2 16588IA
The remaininq terminal substituent "C" is
structurally distinct from either the A or B portions
and may be, for example, a substituted quanidine, a
substituted 1,1-diamino e~hylene, or a 3,5-diamino-
l-alkyl triazole as disclosed in the aforementione~
U.S. Patents to Durant et. al., and Price et. ~1., a~
well as in Belgian Patent 875,846.
The present invention is directed to uni~ue
"C" moieties which confer antisecretorv activity when
combined with the A-R moleclllar fraqments comprisinq
these antiulcer aqents. These novel "C" moietiPs,
i.e., 3,4-diaminoisothiazole-1-oxides and
-1,1-dioxides, when incorporated into the A-B
molecular fragments, afford compounds that exhibit
gastric antisecretory activitv comparahle to or
greater than known prior art compounds, includin~
those disclosed in the above-identified U.S., Belgian
and European patents. The disclosure of
4-isothiazolin-3-one-1-oxides and -l,l-dioxides in
U.S. Patent 4,062,859 does not teacl~ or sugqe~st how
to synthesize the novel compounds of this invention
as no appropriate precursors nor amine displacement
reactions are disclosed.
SUMMARY OF THE INVENTION
This inventi~n is directed to diamino
isothiazole -1-oxides and l,1-dioxides and related
compounds as well as ~rocesses for the pre~arati~n of
such compounds.
D~scRIplrIoN OF THE INVENTION
The compounds of this invention are
represented by the following structural formulae:
~ 3 ~
- 3 ~ 16588I~
( l)p
~ ( 2)n X(cH2)m-HN~L h~ -
(Ia)
and
1~ R2 I P
R- ~ ~(CH2)n-X-~CH2)m HN~I ~ n
R
(Ib)
wherein in both of the above structural formulae:
R is hydrogen, loweralkyl,
/ R5 / NH_R7a
( 2)k \ 6 or \ NH-R7
wherein
R5 an~ R6 are independently hv~roqen,
loweralkyl, cycloloweralkyl or phenylloweralkyl or
R5and R6 may be joined to form, alonq with the
nitrogen to which they are attached, a 5- or
6-membered heterocycle, which may also contain an
oxygen, sulfur, SO, SO2, or an N-R8 linkage
wherein R is hydrog~n, lo~eralkyl of from 1 to 3
carbon atoms, loweralkenyl~ or loweralkynyl;
143t~
- 4 - 16588IA
R7~ and R7b are independelltly hydroqen,
or loweralkyl, 3,3,3-trifluoroethyl or
R7a and R7b may b~ ~oined toqether to
form a cyclic structure through an
-(CH2)k-linlca~e;
p is 1 or 2;
n is 0 or 1,
m is 2 to 4;
k is 0 to 4;
X is oxvgen, sulfur or methvlenP:
R is hvdrogen; hal~gen; 1~7eralk~
loweralkoxy; aryl; substituted aryl wherein the
substituent~s are loweralkyl, halogen, lo~eralkoxy,
trifluoromethylthio, and trifluoromethylsulfonyl;
CH2OH; CN; CONR 3R3; So2NR3R7~; wherein
R7a is as defined a~hove and R3 is as Aefined
below; or COR9; CO2R9, cor~R3R9; and
SO2R whPrein R can be hvdrogen~ loweralkvl,
substitutPd loweralkyl wherein the suhs~ituent is
hydroxy, loweralkoxy, NHCoR7a wherein R7a is as
deJined above; aryl, substitut~d arylo and,
arylloweralkyl;
R3 and R4 are indepPndentlY hydroqen,
loweralkyl, loweralkenyl, loweralkynyl, cyclo
lol~eralkyl, phenyl, pyridvl, or suhstituted
loweralkyl or .substituted l~weralkynYl wherein the
alkyl and alkynyl substituents are phenyl,
substituted phenyl, sycloloweralkYl, pyridyl,
imidazolyl, morpholino, hydroxy, loweralkoxy,
loweralkylthio; di(~oweralkyl)amino, or NCoR3R7a
or R3 and R4 may be joined to form, alonq with
the nitrogen to which they are attached, a 5- or
- 5 - 16588IA
6-membered heterocycle which ma~ also c~ntain an
oxygen, sulfur, SO, SO2, N-R , or an NOR
linkage wherein R8 is as define~ above;
~ is phenylene or a 5- or 6-membered
heterocycle containinq one to three heteroatoms
selected from oxvgen, sulfur or nitrogen, ~hich m~v
optionally have a benzo ring fused thereon; and, a
substituted 5-membered heterocycle wherein the
substituents are loweralkyl, lower alkoxy carbonyl,
halo, car~amoyl, substituted carhamoyl,
provided that when ~ in Formulae Ia and Ib
above is a 5-membered heterocycle, or a benzo fused
5-membered heterocycle containing one heteroatom, n
is l; and, the physiologically acceptable salts and
N-oxides thereof.
Exampl~s of ~ in Formulae Ia or Ib are
furan, thiophene, pyrrole, oxazole, oxadiazole,
thiadiazole, thiazole, triazol~, pvrazole, imi~azole,
pyridine, pyrimidine, pyrazine, and the like and the
fused benzo derivative.s thereof sl]ch as h~nzofuran,
benzoxazole, benzimidazole, and the like.
It is further provided that when R ~ in
either Formulae Ia or Ib is a furan or a thiazole
having the structures:
R10 R10
then R is as defined above and R10 is loweralkyl,
hydroxvloweralkyl, alkoxyalkyl, alkoxycarhonyl,
- 6 - 16588IA
O~CNR R a wherein R and R are as defined
above; halo, preferably ehlorine or bromine, or aryl,
preferably phenyl.
Examples of the 5- or 6-membered
heteroeyeles represented by R3 and R4 when joined
and by R5 and R6 when joined are pyrrolidino,
piperidino, morpholino, thiomorpholino, piperazino,
and N-loweralkyl piperazino~
In the instant invention, unless speeified
otherwise, the term "loweralkyl" is intended to
inelude those alkyl groups eontaining from 1 to 5
carbon atoms in either a straight or branehed
eonfiguration. Examples of sueh alkyl groups are
methyl, ethyl, propyl, iso-propyl, butyl, sec-butyl,
pentyl and the like.
The term "cycloloweralkyl" is intendecl to
include those cycloalkyl groups of from 3 to 7 earbon
atoms. Examples of such cycloalkyl groups are
eyclopropyl, cyclobutyl, eyelopentyl, cvelohexyl, and
cycloheptyl.
The term "loweralkenyl" is intended to
include those alkenyl groups of from 3 to 7 carbon
atoms of either a straight or hranche~ configuration.
Examples of sueh alkenyl qroups are ~ropenyl,
butenyl, ~entenyl, ancl the like.
The term "loweralkynyl" is intended to
include those alkynyl groups of from 3 to 7 carbon
atoms of either a straight or branehed
eonfiguration. Examples of sueh alkynyl groups are
propargyl, butynyl, ~ent~nyl, and the like.
The terms "alkoxyalkyl", "hyc3roxyalkyl" and
"alkoxycarhonyl" are intended to inelude those normal
- 7 - 16588IA
and hranched alkyl qroups containinq from 1 to 5
carbon atoms. Thus, the term "alkoxyalkyl" is
exemplified by such compounds as ~ethoxymethvl,
ethoxy methyl, methoxy propyl, methoxy butyl, and the
like; the term "hydroxyalkyl" is ex~mp~i~ied by such
substituents as hydro~y methyl, hy~roxy ethvl,
hydroxypropyl, hydroxybutyl, and the like; and, the
term "alkoxycarbonyl" is exem~lified by such
compounds as methoxycarbonyl, ethoxycarbonyl,
propoxycarbonyl, butoxycarbonyl, and the like. ~he
preferred com?ounds of the instant invention will
have definitions which vary with the nature of the
compounds of Formulae Ia and Ib.
Compounds Ia are the preferred compounds of
this invention.
Preferred Ia compounds of the invention are
realized when R3 and R4 are independentl~
hydrogen, loweralkyl, loweralkynyl, substituted
loweralkyl, or suhstituted loweralkynyl wherein the
substituents in the alkyl and alkynyl groups are
loweralkoxy, phenyl, pyridyl or imidazolyl; and R5
and R6 are indep~ndently hydrogen, loweralkyl,
cycloloweralkyl or when R5 and R~ are joined to
form a piperidine heterocyclic ring.
Further such preferred compounds are those
wherein ~ is m-phenylene or a 6-memhered heterocycle
as defined above, n is O, X is oxygen, m is 3 and R
i s :
~ R5
( 2)k N
~ R
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In such cases it is fur~her preferred that k
be 1 and R5 and R6 be loweralkyl, preferably
methyl, or joined to form a morpholine,
thiomorpholine, thiomorpholine ~-oxide,
thiomorpholine S-dioxide, piperidine or N-loweralkyl
piperazine, heterocyclic ring.
Additional preferred variations oE ~ are
those wherein ~ is furan, imidazole, thiazole,
oxazole, thiophene, triazole, thiadiazole, oxadiazole
or benæofuran.
When ~ is heterocyclic containing one
heteroatom, it is preferred that n=l, X=sulfur and
m=2.
Preferred variations of R2 are carboxy,
loweralkoxycarbonyl, benzyloxycarbonyl, carbamoyl,
substitl3ted carbamoyl, cyano, sulfamovl, phenyl, and
loweralkyl.
The preferred values of R ~ill depend upon
and vary with the definition of ~ . When ~ is
furan or benzofuran, R is preferred to he:
~ R
(CH2)k N ~ R6
wherein it is further preferred that k=l and R5 and
R6 be hydrogen or loweralkyl, preferablv hydrogen
or methyl, or joined to form a morpholine~
thiomorpholine, piperidine, or N-meth~l piperazine
ring.
~HR7a
When ~ is thiazolyl, R is preferably -N=C
~ HR7b
wherein R7a'7b are most preferably hydrog~n.
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The preferred compounds of the invention
described above also include the physiologically
acceptable salts and the N- and S-oxldes thereof.
Examples of the compounds of this invention
are:
(1) 3-N-[2-[4-methyl-5-imidazolyl)methylthiol-
ethyl]amino-4-methylamino-5-methoxycarbonyl-
isothiazole-l,l-dioxide
(2) 3-N-[2-[(5-dimethylaminomethyl-2-furanyl)-
methylthio]ethyl]amino-4-propynylamino-5-
carbamoylisothiazole-l,l-dioxide
(3) 3-N-[2-[(2-guanidino-4-thiazolyl)methylthiol-
ethyl]amino-4-amino-5-(N-methylcarbamoyl)-
isothiazole-l,l-d;oxide
(4) 3-N-[3-[3-(dimethylaminomethyl)phenoxy]propyl~-
amino-9-methylamino-5-cyanoisothiazole-1,1-
dioxide
(5) 3-N-[2-[(9-methyl-5-imidazolyl)methylthiol-
ethyl]amino-4-amino-5-(ethoxycarbonyl)-
isothiazole-l,l-dioxide
(6) 3-N-~2-~(5-dimethylaminomethyl-2-furanyl)-
methylthio]ethyl]amino-4-amino-5-benzyloxy-
carbonylisothiazole-l/l-dioxide
(7) 3-N-~2-l(2-guanidino-4-thiazolyl)methylthiol-
ethyllamino-4-dimethylamino-5-carhamoY]iso-
thiazole-l,l-dioxide
- 10 - 16588IA
(8) 3-N-~3-[3-(dimethylaminomethyl)phenoxvl~ropvl]-
amino-4-(2-methoxyethyl~amino-5-ethoxycarbonyl-
isothiazole-l,l-dioxide
5 (9) 3-N-[2-[(4-methyl-5-imidazolyl)methylthio]-
ethyl]amino-4-(2-pyridylethyl)amino-5-ethoxv
carbonylisothiazole-l,l-dioxide
(10) 3-N-[2-1(5-dimethylaminomethyl-2-furanyl)methyl-
thio]ethyl]amino-4-amino-5-sulfamoylisothiazole-
l,l-dioxide
(11) 3-N-[2-l(2-auanidino--4-thiaZol~l)m~thylthinl-
ethyl]amino-4-methylamino--5-(N-methylsulfamoyl)
i~othia~ole-l,l-dioxide
(12) 3-N-~3-T3-(dimethylaminometh~l)phen~xy]prnpYl]-
amino-4-amino-5-(N,N-dimethylsulfamoyl)iso-
thiazole-l,l-dinxide
(13) 3-N-[2-[(4-methyl-5-imidazolyl)methylthio]-
ethyl]-amino-4-amino-5-carbamoylisothiazole-1,1-
dioxide
(14) 3-N-[2-[(5-dimethylaminnmethyl-2-EuranYl)methvl-
thiolethyl~amino-4-amino-5-benz~yli.cothi~znle-
l,l-dioxide
(15) 3-N-~2-[(2-guanidino-4-thlazolyl)-methylthiol-
ethyl]amino-4-methylamino-5-acetylisothiazole-
l,l-dioxide
~ 16588IA
(16) 3-N-[3-~3-(dimethvlaminomethvl)phenoxy]Propvl]-
amino-4-amino-5-acetylisothiazole]~ dioxide
(17) 3-N-~2-~(5-dimethvlaminomethyl-2-fl1ranyl)m~thyl-
thio]ethyl]amino-4-amino-5-ethoxycarbonyliso-
thiazole-l,l-dioxide
(18) 3-N-[3-[3-(1-piPeridinvlmethyl)phenoxyl~ro~vl]-
amino-4-amino-5~ethoxycarbonylisothiazole-1,1-
dioxide
(19) 3-N-[3-[3-(dimethylaminomethv1~Dhenoxvlpropyll-
amino-4-amino-5-sulfamoylisothiazole-1,1-dioxide
(20) 3-N-~2-~(5-dimethylaminomethyl-2-f~lranvl)methyl-
thio]ethyl]amino-4-amino-5-cyannisothiazole-1,1-
dioxide
(21) 3-N-[3-[3-(cyclopropylaminomethvl)phenoxvl-
propyl]amino-4-amino-5-carbamoylisothiazole-1,1-
dioxide
(22) 3-N-[2-[[6-(4-morpholinylmethyl)-2-benz~-
furanyl]methylthio]ethyl]amino-4-amino-5-carboxy
isothiazole-l,l-dioxide
(23) 3-N-[3-[3-(dimethvlaminomethyl!phenoxy]pro~yl]-
amino-4-amino-5-carboxyisothiazole-1,1-dioxide
~24) 3-N-[2-[(5-dimethylaminometh~1-2-furanvl)methvl-
thio]ethyl]amino-4-amino-5-N-[(2-dimethy].amino)-
ethyl]carbamoylisothiazole-l,l-dioxide
- 12 - 16588IA
(25) 3-N-[2-[(4-methyl-5-oxazolvl)met.hylthio]ethvll-
amino-4-amino-5-N-(2-hydroxyethyl)carbamoyl.iso-
thiazole-l,l-dioxide
(26) 3-N-~2-~[6-(4-morpholinylmethyl)-2-benzo-
furanvl~methylthio]ethyllamino-4-amino-5-N-(2-
hydroxyethyl)carbamoylisothiazole-l,l-dioxide
(27~ 3-N-~2-~(5-dimethylaminomethyl-2-furanyl!meth
thio]ethyl]amino-4-amino-5-methylisothiazole-
l,l-dioxide
(28) 3-N-[2-[l2-guanidino--4-thiazolyl)methvlthiol-
ethyl]amino-4-amino-5-methylisothiazole-1,1-
dioxide
(29) 3-N-[2-[(2-guanidino-5-methyl-4-thiazolvl)-
methylthio]ethyl3amino-4-amino-5-ethoxycarbonyl-
isothiazole-l,l-dioxide
(30~ 3-N-~2-[(4-methyl-5-imid,~zolyl)methvlthio3-
ethyl]amino-4-methylaminoisothiazole-1-oxide
(31) 3-N-~2-[(5-dimethylamin~methyl-2-furanvl)methvl-
thio]ethyl]am.ino-4-methylamino-5-ethoxycarbonyl-
isothiazole-l,l-dioxide
(32) 3-N [2-[(2-guanidino-4-thiazolyl)methylthio]-
ethyl]amino-4-methylamino-5-carbamoyliso-
thiazole-l-oxide
l33) 3-N-[3-~3-(dimethylaminomethyl)phenoxy]pro~yll-
amino-4-amino-5-ethoxycarbonyl-isothiazole-1-
oxide
- 13 - 16588IA
(34) 3-N-[3-[3-tl-piperidinylmethyl)phenoxvlpr~yll-
amino-4-amino-5-carbamoylisothiazole-1-oxide
(35) 3-N-[2-[~5-methylaminomethyl-2-furanyl)methvl
thio]ethyl]amino-4-amino-5-sulfamoylisothiazole-
l-oxide
(36) 3-N-[2-(4-methyl-5-imidazolyl)methvlthio]ethvl]-
amino-4-amino-5-carboxyisothiazole-1-oxide
(37) 3-N-[2-[(2-gl~anidino-4-thiazolyl)methylthio]
ethyl]amino-4-methylamino 5-(N-methylcarbamoyl)-
isothiazole-l-oxide
(38) 3-N-[3-[3-(dimethylaminomethyl)phenoxylpr
amino-4-amino-5-(N-methylsulfamoYl)iso th iaz~le-
l-oxide
(39) 3-N-[2-[(5-dimethylaminomethyl-2-thienyl)methyl-
thio]ethyl]amino-4-amino-5-cyanoisothiazole-1-
oxide
(40) 3-N-[2-(2-pyridylmethvlthio)ethyl]amino-4-amino-
5-ethoxycarbonylisothiazole-1-oxide
(41) 3-N-[2-[(5-dimethylaminomethyl-2-thienyl)methyl-
thio]ethyl]amino-4-methylamino 5-carbamoyliso-
thiazole-l,l-dioxide
(42) 3-N-[2-(2-pvridylmethylthio)ethyl]amino-4-amino-
5-carhamoylisothiazole-1,1-dioxide
- 14 - 16588IA
(43) 3-N-12-~(2-dimethylaminomethyl-5-thiazolyl)-
methyl-thio]ethyl]amino-4-amino-5-ethoxycarbonyl
isothiazole-l,l-dioxide
~44) 3-N-[3-[4~(4-methylpiperazinyl)-3-thiadiazolyl-
oxy]propyl]amino-4-amino-5-ethoxYcarbonvl-i~o-
thiazole-l,l-dioxide
(45) 3-N-[3-~3-(1-piperidinvlmethvl)phen~xv]Pr~yll~
amino-4-amino-5-benzyloxycarbonylisothiazole-
1,1 dioxide
(46) 3-N-[2-[(2-guanidino-4-thiazolyl)methylthiol-
ethyl]amino-4-amino-5-ethoxycarbonylisothiazole-
l,l-dioxide
(47) 3-N-[3-[5-(dimethvlaminomethyl)-2-ox~zolvloxy7-
propyl]amino-4-(3-propynyl)amino-5-ethoxy-
carbonylisothiazole-l,l-dioxide
(48) 3-N-[2-[(5-dimethylaminomethyl-2-fl~ranvl)m~thyl-
thio]ethyl]amino-4-amino-5-methanesulfonyliso-
thiazole-l-oxide
(49) 3-N-[2-[(5-dimethylaminomethvl-2-furanvl)methyl-
thio]ethyl]amino-4-amino-5-methanesulfon~liso-
thiazole-l,l-dioxide
(50) 4-N-[2-~(5-dimethylaminomethyl-2-fl~ranvl)methyl-
thio]ethyl]amino-3-amino-5-carbamoylisothiazole-
l-oxide
- 15 - 16588IA
(51) 4-N-~2-~(5-dimethylaminomethyl-2-furanyl)methyl-
thio]ethyl]amino-3-amino-5-carbamoylisothiazole-
l,l-dioxide
152) 3-N-[2-[(3-dimethylaminomethyl-2-furanyl)meth
thio]ethyl]amino-4-amino-5-ethoxycarb~nvliso-
thiazole-l-oxide
(53) 3-N-[2-[(5-dimethylaminomethyl-2-furanvl)methvl-
thio]ethyl]amino-4-amino-5-carboxyisothiazole-
l-oxide
(54) 3-N-[2-[(5-dimethylaminomethyl-2-furanyl)methyl-
thio]ethyl]amino-4-amino-5-carboxyisothiazole-
l,l-dioxide
(55) 3-N-[2-[5-(dimethylaminomethyl-^-furanyl)methyl-
thio]ethyl]amino-4-methylthio-5-ethoxycarbonyl-
isothiazole-l,l-dioxicle
(56) 3-N-[2-[5-(dimethylaminomethyl-2-furanyl)methyl-
thio]ethyl]amino-4-amino-5-benzyloxycarbonyl-
isothiazole-l-oxide
(57) 3-N-[2-[5-(dimethylaminomethyl-2-furanyl)methyl-
thio]ethyl]amino-4-amino-5-N,N-dimethvlcarbamoyl-
isothiazole-l,l-dioxide
(58) 3-N-[2-[5-(dimethylaminomethyl-2-furanyl)-
methylthio]ethyl]amino-4-amino-5-(2-hydroxy-
ethoxy)carbonylisothiazole-1,1-clioxide
- 16 - 16588IA
(59) 3-N-[2-[5-(dimethylaminomethyl-2-fllranyl)methyl-
thio]ethyl]amino-4-amino-5-(2-acetamidoethoxy)-
carbonylisothiazole-l,l-dioxi~?e
(60) 3-N-[2-[2-guanidino-5-chloro 4-thiazole)methyl-
thio]ethyl]amino-4-amino-5-ethoxycarbonylis~-
thiazole~ dioxide
(61) 3-N-~2-[5-(dimethylamin~methyl-2-furanyl)-
methylthio]ethyl]amino-4-amino-5-t-butyl-
oxycarbonylisothiazole-l,]-dioxide.
The compounds according to the invention
readilv form physiologically acceptable salts. Such
salts include salts with inorganic acids such as
hydrochlorides, hydrobromides, sulfates, nitrates and
phosphates. Particularly useful salts of organic
acids are formed with aliphatic mono- or dicarboxylic
or sulfonic acidsO Examples of such salts are
acetates, maleates, fumarates, tartrates, citrates,
benzoates, succinates, methane sulfonates, and
isethionates. The compounds and their salts may also
form hydrates and solvates. In addition, the
nitrogen atoms in groups R, ~ , R3 and R4 mav
also form quaternary salts and N-oxides. Such
derivatives are also deemed to be included in the
compounds of the present invention.
It will also be appreciated by th~se skilled
in the art that the compounds of this invention will
have a tautomeric isomerism about the nitrogen and
ring carbon atoms of the isothiazole rinq; i.e., the
exo-imino structure may exist at one or both of the
~-atoms attacned at the 3- and 4- positions of the
isothiazole ring as shown below:
- 17 - 16588IA
( O ) p ". ( O ) p ,,"~_ _ ( fJ ) p ,,,~ ( O ) D
T~
-N N- -~ N~ - N~ -N~ J-N_
H H
All of the various tautomeric structures of
the instant compo~nds are intended to be included in
this invention. In addition, when R is quanidino,
three tautomers are possible as determined in the
art, and all such tautomers are included in this
invention.
In addition, there exists the possihility of
stereoisomerism in the instant compounds when p=l.
These stereoisomers correspond to an R or S absolute
configuration at the sulfur atom of the isothiazole
ring. It is intended that all such stereoisomers are
included within the instant invention.
As stated above, the compounds of this
invention have been found to have pharmacoloqical
activity in the animal body as antagonists to certain
actions of histamine which are not blocked by
"antihistamines" such as mepyramine. For example,
they have been found to inhibit selectively the
histamine-stimulated secretion of gastric aciA in the
stomach of chronic fistula dogs at doses of from D.nl
to 10 mg per kilogram intravenously or orally from
0.01 to 50 mg per kilogramO Similarly, the action of
these compounds is de nstrated by their antagonism
to the effects of histamine on other tissues which
are not affected by histamine Hl antagonists. An
example of such tissue is the isolated guinea-pig
right atrium.
4~
- 18 - 16588IA
These compounds have heen found to be up to
lO0 times more active in animal models than
cimetidine.
The pharmaceutical carrier employed may be,
for example, either a solid or liquid. Exemplary of
solid carriers are lactose, terra alba, sucrose,
talc, gelatin, agar, pectin, acacia, magnesium
stearate, stearic acid and the like. Exemplary of
liquid carriers are syrup, peanut oil, olive oil,
water and the like.
A wide variety of pharmaceutical forms can
be employed. Thus, if a solid carrier is used, the
preparation can be tableted, placed in a hard qelatin
capsule in powder or pellet form, or in the form of a
troche or lozenge. The amount of solid carrier will
vary widely but preferably will be from about 15 mg
to about 0.4 gm. If a liquid carrier is used, the
preparation may be in the form of a svrup, emulsion,
soft gelatin capsule, sterile injectable liquid such
as an ampoule, or an aqueous or nonaqueous liquid
suspension.
The pharmaceutical compositions are prepared
by conventional techniques involving procedures such
as mixing, granulating and compressinq or dissolvinq
the ingredients as appropriate to obtain the desired
preparation.
The active ingredient w;ll be present in the
composition in an amount effective to inhibit
histamine gastric acid secretory activity. The route
of administration may be orally or parenterally.
Preferably, each ~aily dosage will contain
the active ingredient in an amount of from about 5 mg
to about 500 mg, most preferably from about 15 mg to
- 19 - 1658~IA
about 150 mg given in a single dose or multiple
divided doses.
For therapeutic use, the pharmacologically
active compounds of the present invention will
normally be administered as a pharmaceutical
composition comPrising at least one such com~ound a~
the sole or an essential active ingredient in the
basic form or in the form of an addition salt with a
pharmaceutically acceptable acid and in association
with a pharmaceutical carrier therefor. Such
addition salts include those mentioned ahove.
Other pharmacologically active compounds
may, in certain cases, be included in the comp~si-
tion. It may be appropriate to combine the instant
compound or compounds with anticholinergic agents
such as propantheline; Hl antihistamines such as
mepyramine, pyribenzamine chlorpheniramine and the
like; or prostanoids.
Advantageously the composition will be made
up in a dosage unit form appropriate to the desired
mode of administration such as, for exa~ple, a
tablet, capsule or injectable solution.
The compounds of this invention are
synthesized by sequential reaction of the amines
R ~Rl and R ~ (CH2)n X (CH2)mNHRl with
R4
either an isothiazole-l-oxide or l,l-dioxide each
substituted with an appropriate leaving group (Y, Z)
in the 3- and 4-positions. (In intermediates II, Y
and 7 may be lower alkoxy, aryloxy, loweralkylthio,
loweralkylsulfonyl, arylthio, arylsulfonyl, halo (F,
Cl, Br, I), di-loweralkylamino and cyclicamino such
as piperidino, morpholino, and the like.) It will be
noted in the Reaction Schemes outlined below that
- 20 - 16588IA
position isomers Ia and Ib can be obtained from these
reactions. The isomer Ia or Ib which results depends
on several factors. These inclufle the order of
addition of the amine reagents mentioned above, the
relative reactivity of the leaving groups (Y, Z) at
positons -3 and -4, respectively, and the electro-
negativity of the substituent at the 5-position
(R ). The synthethic strategies outlined helow
demonstrate preparation of specific examples of Ia
and Ib compounds by constructive utilization of the
aforementioned considerations.
When R2 is an electroneqative suhstitutent
such as carboxy, carboalkoxy, cyano, carbamoyl,
substituted carbamovl, sulfamoyl, subslituted
sulfamoyl, alkanoyl, aroyl, and the like, compounds
Ia and Ib are synthesized by addition ~f the amines
III and IV to the isothiazoles of formula II as in
Reaction Scheme I. When Y, Z are indeDendently ~1,
Br, loweralkoxy, or aryloxy and R2=CO2R or
SO2R9, the amine III or IV preferentially
displaces Z. When R =CN, aryl or CONR R
amines III or IV selectively displace Y. In the case
where R2=CONH2 or SO2NH2, mixtures of
intermedi-
ates V and VI can be obtained and separated hymethods known in the art, such as column chromato-
graphy on silica gel or aluminum oxide. In Reaction
Scheme I, Rl is hydrogPn or trimethylsilyl and R9
R , R , ~ , X, m and n are as previously
defined.
The isothiazole intermediate II wherein p=2
is synthesized according to Reaction Schemes II-VI.
The isothiazole intermediate II (Reaction
Scheme III) wherein p=l and, for example,
- 21 - 16588IA
R2=CO2R9, is synthesized by oxidation of the
precursor XIV with one mole of alkyl, haloalkyl, or
arylpercarboxylic acid (R' = CH3, CF3,
m-chlorophenyl), dinitrogen tetroxide or chromic
anhydride. Also, as outlined in Reaction ,Scheme IV,
XXI is similarly converted to XXII and thence to
XXIII.
In R~action Scheme ITI, i~ can he seen tha~
the leaving group Z can be introduced bv electrophilic
suhstitution of isothiazoles XVI hy reaction with a
suitab'e electrophile such as Y-Z (e.q. Br2)
Some intPrmediates in Reaction Schemes I-III
such as IIa, IIb, IIc, V, VI, IX, X, XI, XTI, XTII
and XIV are unknown in the art and are thus ~referre~
intermediat~s an~ compounds of the instant
inventi~n. In particular, interme~iates VIa an~ ~TIb
(Reaction Scheme I) also possess the desired ~astric
antisecret~ry activitv and are thus ~otentiallv
useful in the treatment of gasti~ hypersecretorv
diseases such as peptic ulcers.
- 22 - 16588IA
REACI'I ON SCHEME
1~2 ~ 1PCR2 ( IVl ~ R
IV) ~ VI b)
t~V) (III)
15R~ cH2)nx(cH2)m ~; ~z R3N~r3[ 2 2)mX~)H2)n
()p ( ~p
(IV) ¦ (VIa) lIb)
(III)
~I
2 5 R- (~) - ( CH 2 ) nX ( CE3 2 ) mN ~cNR 3
( )p
(Ia)
I I I = RlNR3R4
30 IV = RlNH(CH2)mX(CH2)n- A -R
.~Z6~L43~
- 23 - 16588IA
REACTION SCHEM~ II
R2CH2S02Cl 1) 1 (_H3) 35i] 2_ ~l2c~l2so2NH2
(VII) 2) E:tOH~VIII)
ÇOCl
~CO2Et) 2 \~02~8
Base ~
R CH2so2NHcoco2R
/ (X)
Cl /Cl MO OM /Base
~R or ~R2
2 phosphorous O~
~XI) halide (IX)
1) AgN03
2) 2R8Y
R8q;~ ~ Base~f ~a2
(IIa) (IIb)
3~
- 24 - 16588IA
REACTION SCHEME III
R~O ~
XVI
) R8 = H; Z-y 2) R X, base
(e.g.,; Br) 1 ,
R80 ~ R2
XV
R8s SR8 R~s2 0l-2R8
b~L HOAc ~ R
(XII) (XIII)
R8OH, Base
R o OR R8O oR8
~ ArCO H Ll
N\ ~LR or N204 \S~L
(IIC) XIV
8 3 N204 or CrO3 2 ArCO3H
2. ) R OH base
R R8O oR8
N~ ~ 1 ) 2 ArCO3H
(XV) (IIb)
~¢~
25 - 16588IA
In Reaction Scheme I, wherein Y, Z of II are
halogen and/or lower alkoxy, preferred compounds Ia
are obtained by reacting II with the amines or
N-trimethylsilyl amines III in inert solvents such as
hydrocarbons or halocarbons, preferablv methylene
chloride, at temperatures of about -30QC to ~60C,
preferably 0-25C and for one to 24 hours. If R' of
III is trimethylsilyl, then the crude products V are
treated with a lower alkanol, preferably ethanol, to
remove trimethylsilyl groups. The compounds V are
then reacted with complex amines or N-trimethylsilyl
derivatives IV in hydrocarbon or halocarbon solvents,
preferably methylene chloride, or in polar aprotic
solvents such as acetonitrile, dimethyl sulfoxide,
N,N-dimethylformamide, and the like, at temperatures
of about OC to the reflux temperature of the solvent
for one to 24 hours to give preferred compounds Ia.
In Reaction Scheme II, intermediates IX can
be formed by reaction of ~-substituted methane-
sulfonamides VIII with oxalic esters, preferablYdiethyl oxalate, in lower alkanol solvents,
preferably ethanol, at temperatures of about 25C to
100C, preferably reflux temperature of the solvent,
in the presence of from 2-2.5 equivalents of metal
lower alkoxide, preferably sodium ethoxide, for 1 to
48 hours, or until precipitation of the desired
dialkali metal salts IX is complete and thin layer
chromatographic analysis shows no unreacted VIII.
Alternatively, oxamate X can be formed by reaction of
the ~-substituted methanesulfonamides VIII with alkyl
oxalyl chloride, preferably ethvloxalyl chloride, at
25 to 150C, preferably 120C, for 1~8 hours,
preferably 2 hours. Intermediates X can bP cvcli~ed
3~
- 26 - 16588IA
to IX in the presence of strong bases such as, for
example, alkali metal alkoxides, preferably sodium
t_ -butoxide, in polar aprotic solvents, preferably
N,N-dimethylformamide, at 0 to 60~C, preferably
25C, for 1 to 2~ hours. The intermediates IX can ~e
reacted with phosphorus halides, such as phosphorus
pentachloride and oxychloride, or reactive acyl
halides, preferably oxalyl chloride, in hydrocarbon
or halocarbon solvent or, in the absence of solvent,
at 60C-150C for 1 to 48 hours. The desired
dichloro intermediates XI are then reacted with
loweralkanols, preferably ethanol (one equivalent),
at -30C to 60C in halocarbon solvents for 30
minutes to 24 hours, preferably one hour, to give
haloalkoxy intermediates IIa. The l~tter can be
further reacted with alkanol, preferably ethanol, in
the presence of bases, such as alkali carbonates and
bicarbonates, pyridine, and loweralkylamines,
preferably triethylamine, in aprotic solvents,
preferably methylene chloride, at -30C to 50C
preferably 0C, to give diloweralkoxy intermediates
IIb. The latter can also be synthesized by reactinq
intermediates IX with two equivalents of silver
nitrate followed by two equivalents of alkylating
agents R8-Y in which Y is preferably OSO20R8,
bromine, iodine and OSO2aryl and substituted aryl,
in polar aprotic solvents such as acetonitrile,
N,N-dialkylcarboxamides, diloweralkvlsulfoxides, and
the like, at temperatures of about 0C to 100C,
preferably 50-80C. By this method, a mixture of
the desired IIb and its N-alkylated isomers are
obtained and this mixture is separated by methods
known to those skilled in the art.
4~;
~ 27 - 165~8IA
Compounds XV required in Reaction Sch~me III
are obtained by electrophilic substitution of the
4-unsu~tituted compound.s XVI with reaqent~ YZ,
preferably bromine, in halocarbon or acetic acid
solvent at a temperature of ahout 0 to 50C.
In Reaction Scheme III, his loweralkylthio
intermediates XII are oxidized with hydrogen peroxide
in acetic acid at temperatures of ab~ut 0C to 6noc
to give the bis-sulfones XIII. The latter can be
reacted with lower alkanols in the presence of base,
preferabl~7 sodium ethoxide in ethanol, at 0C to
reflux to give intermediates XIVo The latter are
oxidized to S-oxides IIc wih oxidizinq aaent.s ~uch as
aromatic peroxycarboxylic acids, dinitroqen tetroxide,
alkali metal persulfates, or chromic anhvdride, in
solvents such as halocarbons at 0C to 60C.
Alternatively, XIV may be oxidized to 1,1-dioxides
IIb with two equi~7alents of aromat.ic peroxycarboxylic
acids in halocarbon solvent at 0C to 60C. The same
intermediates (IIb, IIc) can be synthesi.zed bv similar
oxidation of int~rmediates XV foll.owed hv rea^tion
with lower alkanols in the presence of base under
similar conditions to those emploved in the con~7er-
sion of XIII to XIV. In general, the route from XII
is preferred when R2 is an electron withdra~inq
substitutent such as alkoxycarbonyl, carbamoyl,
sulfamoyl, cyano, and the like. When R2 is
hydrogen, loweralkyl, and the like, the route from
XVI is preferred.
3L ~ L~
- 28 - 16588IA
REAC~ION SCHEME IV
-
R8O Br R8O r R8~ OAr
~ R'CO3H ~ ArOTl ~ ~
CONH2 ~ CONH2 ~CONH2
Op
XVA \ XVII XVIIa
HO ~ HONO
RRQ 8r RaQ~ ~rRRo Br
~ MOH ~ SOC12
fiOM Y O2H ~-Cl
O Op
XIX XVIII XX
1) 1~CH3)35i~2NH,NH3 9
R9X 2) EtOH R OH
R8 ~ ~ CO2R ~ OzH ~ C2R
XXI y ~R2=co2H) XXI
¦ ; ~ ClO ~, base~
NHR3R7a
1~Z631 ~
- 29 - 16588IA
C~ /NH2
~co~3
7a, 7b XXI
XXI
R'CO H V
3 / 1. ArCO H
~/ 2. R'NR~R4
R8~r ~( 9 II
XXII XXIII
R8~B R aNHR3 ~ 7a
XX XX IV
~ R 'C03H
R ~4 RB Br
R7
XXVI XXV
l ~Zq~
- 30 - 16588IA
Reaction Scheme IV illustrates th~ conversion
of 5-carbamoyl isothiazoles to useful synthons XVIII,
XXII and XXV which are converte~, respectivelv, to
5-carboxy, 5-alkoxycarbonyl and 5-substituted
carbamoyl analogues of preferred compounds Ia and
Ib. The key features of the transformations nf
Reaction Scheme IV are nitrous acid hydrolysis of the
5-carbamoyl function to a ~-carboxvl function anA
transformation of the 5-carboxyl function to esters
and amides by methods known to those skille~ in the
art. Alternatively the carboxy svnthon is converteA
to preferred compound Ia (R2=CO2H) which is then
converted to other Ia compounds in which
2 ~ ~
(R = ~INR ~ lso by methods known in the art.
In certain cases for svnthes-.s of ~referreA
Ib compounds, intermediate XVII is preferentiallv
first reacted with a metal (preferahlv thall;um)
phenoxide to displace Br and form XVIIa (Reaction
Scheme IV) ~Jhich ic then sequentiall~ reacte~ with N-
trimethylsilylated amine IV (Rl=(CH3)~Si) and
ammonia to form Ib compounds (e.g. R =CONH2).
- 31 - 16588IA
Reaction Scheme V
Q 1 ) HONO CN
~C 3) 3CO CH2CN 2)Tosyl Chloride tCH3) 3CO fi
~1 - OTS
~ XXVI I ) /( XXVI I I )
(CH3) 3COC NH2 ~SCH2R, Base
\S/ R
(XXIX)
TFA
HOOC ~ NH2
~(R 2
/ (XXX)
BH3/ \~R~(l. )
f \~
(XXXI) (XXXII)
- 32 - 1~588IA
HOCH2~H22 MnO2 OH(~ ~22
/
XXXI \ / XXXII
H2O2 ,H ~(OX. )
~3L
(~) p
XXXIII
1) R8Y, bas~ ¦ 2) ArCO3H, N2O4 CrO3,
o M2S208
R8O_~H22
(l,p
Va
- 33 - 16588IA
Compounds Ia, wherein R3=R =H and p=l or
2, can also be made by addition oE amines IV to
intermediates Va, the latter being prepared accordinq
to Reaction Scheme V~ Tert-butylcvanoacetate is
converted to intermediates XXVIII, XXIX by procedures
identified by K. Gewald and P. Bellmann (Li~hiqs Ann.
Chem. 1979, 1534).
Selective solvolvsis of the tert-hutyl ester
group of XXIX is achieved by dissolving it in
trifluroacetic acid, preferablv at 10 to ~0C. The
re~ulting carboxylic acid function of XXX can then he
reduced to either the carboxaldehyde qroup of XXXII
or the hydroxymethyl qroup of XXXI, either of which
can be subjected to oxidative rearrangements
resultinq in intermeAiates XXXIII (r~=0 or 1). For
examr~le, treatment of the h~v~lroxy methyl comp~und
XXXI with hydrogen peroxide under acidic conditions
at 0 to 60 gives the rearranqed intermediates
XXXIII as a mixture wherein p=0 and p=1. The mixture
is separated by methods known to those skilleA in the
art.
Alternatively, oxidative rrarranq~ment of
the carboxaldehyde XXXII under Baeyer-Villiger
conditions, such as reaction with an eaui~7alPnt of an
aromatic peroxycarboxylic acid in a halocarbon
solvent, preferably methylene chloride, at no t~ ~,
leads to intermediate XXXIII wherein p=0. These
rearrangement ~roducts XXXIII can b~ alkvlated witk
an equivalent of an alkylating agent R -Y, as
described above for Reaction ~ch~me II, in Polar
aprotic solvents at 0 to lOn to form interme~iates
Va (p=0 or 1). The latter can be further oxidized at
sulfur to p=l or 2 with oxidi~inq aqents such as
- 34 - 16588IA
aromatic peroxycarboxylic acids, dinitrogen
tetroxide, chromic anhydri~e or alkali metal
persulfates.
~ 35 - 16588IA
REACTION SCHEME VI
~3LCl HO~ l EtI
XXX IV 2 3/DMF
EtO~l NaSO C~EtOl!~--Cl EtO 02CH3
~--~02CH3 ~02CH ~
XV XXXVI XXXVII
CH3Na DMF -F3~CrO3H
MCP8A
~ E tO~2~H3
XXXVI I I
i )p XL
MCP3A
I (CH3 ~ 35i ] 2NH
EtO~ OCCH3 EtO~; 3~sNoR2c43
XXXIX XLI
Ia
t R 2=5O2CH3 )
~2~
- 36 - 16588IA
EtO~7CC1
XXXIX
s
[ (CH3) 3Si] 2NH
EtO NR3R4
~OCH3
V
R ' NH t CH 2 ) mX ( CH 2 ) n~ A - R
2 Ia
( R =OCH 3 )
- 37 - 16588IA
Reaction Scheme VI illustrates the ~rinciple
of displacement of a 5-halogen substituent of a
suitably ~ubstituted isothiazole (e.q~, XXXV) with
nucleophiles such as loweralkoxide, loweralkyl-
sulfenate, and loweralkylmercaptide in a polaraprotic solvent such as N,N-dimethylformamide at
0-120C, preferably 80-120C. The displacement
products, XXXVI and XXXVIII, are converted to useful
synthons, XXXIX and XII, by the methods described
hereinaboveO These useful synthons are converted to
preferred compounds Ia by methods descri~ed in
Reaction Scheme I.
The following examples are provided to
further illustrate the invention, but they are not to
be construed as limitative of the invention. Unless
otherwise indicated, all temperatures are in de~rees
Celsius.
EXAMPLE 1
Ethoxycarbonylmethane Sulfonamide
A sol~tion of 54.6 g (0.29 mole) ethoxv
carbonyl methanesulfonyl chloride in 250 ml methylene
chloride was stirred at 0 under a nitroqen atmosphere
while 46.8 9 (0.29 mole) hexamethyldisilazane was
added dropwise. The resulting cloudy solution was
allowed to warm to 25 over one hour and then
evaporated in vacuo to an oil which crystallizes:
yield of the title product is 48.4 g (100%), mp
63-67; lit.l mp S7-68, lit2 mp 66-68.
1.) JACS 1959, 81, 5655 R. L. Hinman, L.
Locatelli, Jr.
2.) Bull. Soc. Chim. Fr. 1975 (3-4), 807 A.
LeBerre, A. Etienne, B. Desmazieres
- 38 - 16588IA
EXAMPLE 2
Disodium salt of 3,4-Dihydroxy-5-ethoxycarbonyl-
isothiazole-l,l-dioxide
A solution of sodium ethoxide was pre~ared
from 7.6 g (0.33 g-atom) sodium (spheres) in 200 ~1
ahs. ethanol under a nitroaen atmosPherP. At 25 a
solution of 27.6 g (0.165 mole) ethoxycarbonyl
methane sulfonamide in 200 ml ethan~l was adde~ to
the ethoxide solution, following which was added
dro~wise a solution of 24.1 g (O.lh5 mole) diethyl-
oxalate in 50 ml ethanol. The rPsulting thick
suspension was warmed to reflux and stirred under
reflux overnight. The mixture was cooled to 2~,
filtered and the white solid washed with 100 ml abs.
ethanol. The disodillm salt, 41.4 g (~5~, c~n h~
recrystallized from 95% ethanol. ~he s~lt was sta~le
as a hemihydrate (after drying at 95/0.3 mm ~lg over
P2O5 for 24 hours); mp 265-285 (dec).
Anal. Calcd. for C6H5NO6SNA2ol/2H2O:
C, 26.28; H, 2.21,; N, 5.11.
Found: C, 26.08; H, ?.4q; N, 5.12.
EXAMPLE 3
3-Ethoxy-4-chloro-5-ethoxycarbonylisothiazole-
l,l-dioxide
In a drv flask fitted with a maqnetic
stirrer, condenser and calcium sulfate drying tube
were placed 3.2 g (.011 mole) of the Exam~le 2
disodium salt and 11.0 g (.053 mole) phosphorous
pentachloride. The flask was immersed in a ~reh~at~d
100 oil bath and the mixture was stirred for 18
hours, following ~hich phosphorous oxychloride was
distilled off under aspirat~r ~ressureD The solid
~Z¢~436
- 39 - 16588IA
residue was slurried in 100 ml ether, the ether
supernatant filtered rapidly into a clean, dry flask
containinq 15 ml ahsolute ethanol. The ether
extraction of the residual solid was repeated three
times with all ether-ethanol fjltrates comhine~.
After stirring at ro~m temperature for 3n minutes,
the ether-ethanol solution was concentrated in vacuo
to an oily solid which was collected hy suction
filtration after trituration with a small amount of
ether. This solid title compound weighed ~gn mq
(30%); mp 134-136, MS:m/e 267 (M ), 222
(M-OC2H5), 135 (M-OC2H5
- [Cl-C=C=C-O ]), 87 (Cl-C=C=C-O ).
Anal. Calcd. for C8~ll0ClNO5S: C, 35.~0; ~,
3.77; N, 5.23.
Found: C, 35.70,; H, 3.8a N, 5.48.
Alternatively, five grams (18.9 mmol) of the
dry disodium salt of Example 2 was ~reated with 5.0
ml of distilled oxalyl chloride under a nitrogen
atmosphere. The resultinq mixture was tre~ted, ~ith
vigorous stirrinq, with a solution of 1 ml dry
pyridine in 50 ml of toluene. The vigorously stirred
mixture was heated by a heat qun until qas evolution
began. The reaction was then allowed to proceed
exothermically until gas evolution ceased. Warming
was then resumed and continued until there wa~ no
more gas evolution. The resultant dark mixture was
concentrated _ vacuo and the residue taken up in lnO
ml of methylene chloride. The solution was then
added to a magnetically stirred sus~ension of 70-230
MESH silica qel (25 g), previously stirred in
absolute ethanol, the ethanol decanted off, and the
silica gel then washed with 2x50 ml ~ortions of
:~20~43~i
- 40 - 16588IA
methvlene chloride bv decantAtion) and the su~sp~nsi~n
stirred for one hour at room temperature. The silica
gel mixture was filtered throuqh qlass iber paper,
the filtrate evaporated in vacuo and the residue
taken up in chloroform. Filtration throuah a column
of silica gel, eluting with chloroform, gave 2.4 g of
3-ethoxy-4-chloro-5-echoxycarbonylisothiazole-1,1-
dioxide as a white solid, mp 134-136.
XAMPLE 4
3,4-Diethoxy-5-ethoxycarhonvl isothiazole-l,l-~ioxide
Triethylamine (1.05 ml, 7.5 mmol) ~issolved
in 10 ml methylene chloride was added dropwise to a
stirred solution of 2.0 q (7.5 mmol) of the Exam~le 3
compound and 2.5 ml absolute ethanol in 10 ml
methylene chl~ri~e at 0C. When the ad~ition was
complete, the resulting solution was stirred an
additional 3n minutes and then evaporated at 35 ln
vacuo to an oil. Chromatography over silica gel
(elutant, rnethylene chloride) produced tlc homo-
genous, title material, 1.6 g (80%), m~ 129-133.
alcd- for ClOH15N6S C, 43-31;
H, 5.45; N, 5.05.
Found: C, 43.21; H, 5.60; ~, 5.30.
EXA~PLE 5
3-Ethoxy-4-amino-5-ethoxycarbonyl isothiazole-
l,l-dioxi~e
. _ _
Under a nitrogen atmosphere, a solution of
1.41 9 (5.3 mmol) of the Example 3 compound in 15 ml
of mPthylene chloride was stirred in an ice hath
while a solution of 1.2 g (7.9 mmol) hexamethyldi-
silazane in 10 ml ~ethylene chloride was ~dded
l~V~36;
- 41 - 16588IA
dropwise. The solution was allowed to warm to room
temperature at which temperature stirrin~ was
continued for 18 hours. The solution was then
evaporated ln vacuo to an oil which was redissolved
in 20 ml of a mixture of methylene chloride tl5)
-ethanol (5). After stirrinq at room temperature for
one hour, the solution was again concentrated in
vacuo, leaving a solid, 1.1 g (85%), mn 1~3-165.
Recrystallization from ethyl acetate provided
analytically pure title compoundr m~ 172.~-173.
8 12N25S: C, 38.71,
H, 4.87; N, 11.28.
Found: C, 38.76, H, 4.91; N, lloaO~
The title compound can also be prepared by
an alternate route employing the Examnle 4 ~omnound
and hexamethyldisilazane followinq the above
procedure.
From 690 mq (2.5 mmole) of tlle Example 4
compound and 600 mg ~3.75 mmole) hexamethyldisilazane
there was obtained 525 mg (8~) of the title
compound, mp lh8-172. Thin layer chromatoqraphy
(silica GF, 95:5 CHC13:CH30H) showed this to be
identical with the material prepared from the
3-ethoxy-4-chloro- compound; a mixed meltinq noint
was undepressed (169-173).
EX~MPLE 6
3,4-Diethoxy-5-cyanoisothiazole-1,1-dioxide
Step A Disodium 3,4-dihydroxy-5-cyanoisothiazole-
l,l-dioxide
To a suspension of sodium hydride (1.~ g, 45
mmol) in dimethylformamide (10 ml) at 70 was added a
solution of sulfamylacetonitrile (27 q, 22.5 mmol) in
- 42 - 16588IA
dimethylformamide (12 ml). Then a solution of
diethyl oxalate (3.0 ml, 23 mmol) in dimethylform-
amide (10 ml) was added dropwise and the reaction
temperature was raised to 100. After 1 hour, the
temperature was raised to 120 an-l maintained at that
temperature for 15-20 hours. The reaction was th~n
cooled, diluted with a small volume of ethanol,
solids were filtered off, and the filtrate diluted
with ethanol and diethyl ether to afford a gummy
precipitate. This precipitate was dissolved in
methanol, filtered and then diluted with diethyl
ether to give the title compound as a tan solid (3.5
g) which wa.s used without further purification.
Step B 3,4-Dihydroxy-5-cyanoisothiazole~ dioxide
disilver salt
To a solution of disodium 3,4-dihvdroxy-5-
cyanoisothiazole-l,l-dioxide (7.4 g, 34 mmol) in
water (60 ml) there was added a solut;on of silver
nitrate (11.5 g, 68 mmol) in water (40 ml). The
resulting suspension was stirre~ for 2-3 hours and
the precipitate collected by filtration and washed
with ethanol, diethyl ether and dried to give 11.4 q
of title compound which was used without further
purification.
Step C 3,4-Diethoxy-5-cvanoisothiaznle-1,1-dioxide
A solution of ethyl io~ide (5.15 ml, ~4
mmol) in acetonitrile t5 ml) was added dropwise to a
suspension of diargento 3,4-dihydroxy-5-cyanoiso-
thia7O1e-l,l-dioxide (11.4 g, 29 mmol) in aceto-
nitrile (75 ml). This mixture was stirred for 2-3
days and then the silver salts were filtered and the
- 43 - 16588IA
filtrate evaporated. This residue was dissolved in
chloroform and passed through a short column of
silica gel to qive 3.4 9 of a 2:3 mixture nf 3,a-
diethoxy-S-cyanoisothiazole-l,l-dioxide and ethoxy-5-
S cyano-2-ethylisothiazole-3-one-1,1-dioxide.
This mixture (2.65 g, 11.5 mmol) was then
dissolved in acetonitrile (10 ml) cooled in an
ice-bath, and a solution of hexamethyldisilizane
(1.37 ml, 0.0065 mmol) in acetonitrile (2 ml) was
added dropwise. The solution waS warmed to ambient
temperature and then heated at 50 for qO minutes.
After cooling to ambient temperature, the solution
was concentrated to dryness in vacuoO Methylene
chloride (4 ml) was added and the charge was cooled
in an ice-bath. Absolute ethan~l (25 ml) was added,
the mixture was warmed to ambient tem~erature and
stirred for 30 min. The solution was concentrated to
dryness _ vacuo to give 2.44 g of a yellow solid
which was chromatographed on a column of E. Merck
silica gel hO. Fro~ the fractions eluted with
chloroform followed hy 2% acetonitrile/chloroform
there was obtained 0.97 g 3,4-diethoxy-5-cyanoisothi-
azole~ dioxide. This 90% pure product was ( qO%
pure by NMR) recrystallized from 2:1 n-butylchloride:
hexane to give 0.84 g (78% of theoretical) ~ure title
compound, mp 147-148.5.
TLC (10% methanol/chloroform, silica): Rf=0.7
Calc'd for ~8HlON204S N~ 12-17; C, 41-73
H, 4.38.
Found: N, 12.29; C, 41.88; H, 4.50.
3~
- 44 - 16588IA
EXAMPLE 7
3-Ethoxy-4-amino-5-ethoxycarbonylisothiaz le-l-oxide
Step A 3-Ethoxy-4-bromo-5-chlorocarbonylisothiazole
3-Ethoxy-4-bromo-5-carboxvisothiazole (2.52
g, 0.01 mol) was heated at reflux in 25 ml of thionyl
chloride for 3/4 hour. Removal of the excess thionyl
chloride in vacuo gave 207 g of the title compound as
an off white solid, mp 58. 5-61C.
Step B 3-Ethoxy-4-bromo-5-ethoxycarbonylisothiazole
-
3-Ethox~-4-bromo-5-chlorocarbonvlisothiazole
(2. 7 g, 0.01 mol) in 25 ml of absolute ethanol was
heated at reflux for 1/2 hour. Removal nf the
ethanol ln vacuo gave 2.8 g of off white solid, mp
40-43C.
Step C 3-Ethoxy-4-bromo-5-ethoxycarhonylisothiazole-
l-oxide and l,l-dioxide
_
3-Ethoxy 4-bromo-5-ethoxycarbonylisothiazole
(9~ mg, 0.34 mmol) was dissolved in 2 ml of m~thylene
chloride and m-chloroperbenzoic acid (58.7 mg, 0.34
mmol) was added in small portions over ten minutes.
The reaction mixture was stirreA at rnom tempera'ur~
over night. The reaction mixture was then concen
trated _ vacuo and the residue was chromatoqraphed
on silica gel using chloroform. There wa~ nhtaine~
22 mg of the l,l-dioxide melting at 145-146 and 17
mg of the l-oxide melting at 93-94C.
0 Step D 3-Ethoxy-4-amino-5-ethoxycarbonylisothiaz~le-
l-o~ide
. _ .
3-Ethoxy-4-bromo-5-ethoxycarbonylisothiazole-
l-oxide (1.48 g, 5.0 mmol) was dissolved in fifteen ml
4~3~
~ 45 - 16588IA
of dry acetonitrile. The solution was cooled in ice
and a solution of anhydrous ammonia in cold
acetonitrile (n.105 mol in 5 ml) was added dropwis~
in excess. After stirring in the ice bath for 4-1/4
hours the reaction was complete. 'rhe title compound
(1.16 g 78~, mp 153.5-155C) was obtained as a yellow
solid by chro~atography on silica gel (chloroform).
EXAMPLE 8
3-Amino-4-ethoxy-5-cyanoisothiazole-l,ldioxide
To a suspension of 3,4-diethoxy-5-cyano-
isothiazole-l,l-dioxide (0.85 g, 0.0037 mol) in 40 ml
of ethanol was added 2.6 ml of 1.7M ammonia in
ethanol (0.0044 mol) with stirring. A clear yellow
lS solution formed and a white precipitate separated in
5 minutes. After 2 hours at room temperature, the
title compound (0.61 9, 82~, mp 232-233.5) was
collected and a sample recrystallized from e~hanol to
give analytically pure material, mp 236-238.5, Rf
20 0.26 (10% methanol-chloroform, silica gel).
Calc'd for C6H7N3O3S: N, 20.89; C, 35.81;
H, 3.51.
Found: N, 21.02, C, 35.91; ~l, 3.59.
EXAMPLE 9
3-Ethoxy-4-amino-5-cvanoisothiazole-1,1-dioxide
Step A 3-Ethov-4-chloro-5-cyanoisothiazole-
l,l-dioxide
-
3,4-Dihydroxy-5-cyanoisothiazole-1,1-
dioxide disodium salt from Example 6, Step A (23.~ q~
0.10 mol) was reacted with oxalyl chloride (45 ml)
according to the alternate procedure of Example 3 to
give crude 3-ethoxy-4-chloro-5-cyanoisothiazole-
l,l-dioxide.
- 46 - lh588IA
Step ~ 3-Ethoxy-4-amino-5-cyanoisothiazole-
l,l-dioxide
The product from Step A was reacted with
hexamethyldisilazane followed by ethanol according to
the procedure of Example 5. After recrystallization
of the crude product from ethanol, there was ~htaineA
pure title compound, mp 228-229.
EXAMPLE 10
3-Amino-4-ethoxy-5-N,N-dimethylcarbamoylisothiazole-
l,l-dioxide
Step A Disodium 3,4-Dihydroxy-5-dimethylcarbamyliso-
thiazole~ dioxide
To a suspension of 60% NaH (5.0 g, 0.125
mol) in dry DMF (10 ml) under a nitrogen atmosphere
at 70C was added dropwise a warmed solution of N,N-
dimethyl-~-sulfanylacetamide (10.1 g, 0.061 mol) in
DMF (55 ml). After 1/2 hour, a solution nf di~thyl
oxalate (8.7 ml, 0.064 mol) in DMF (20 ml) was added
dropwise and the solution was allowed to heat at
120C for 12-lh hours. After cooling the reaction,
it was diluted with ethanol and the precipitated
product collected by filtration, washed with ethanol,
ether and dried in vacuum oven at 70C for several
hours to give 16.5 g of crude title comPound.
Step B 3,4-Dihydroxy-5-dimethylcarbamylisothiaznle-
l,l-dioxide Disilver salt
The cr~de disodium salt from part A was
dissolved in water (150 ml) and added dropwise to a
soluticn of silver nitrate (23.0 q, 0.135 mol) in
water tl50 ml). An immediate gelatinous precipitate
formed, but after stirring for 3-5 hours, a more
- 47 - 16588IA
granular hrownish precipitate was obtained. This was
filtered, washed with water, ~thanol, ether and dried
in a vacuum oven at 70C for several hours to aive
11.6 g of crude title compound.
Step C 3,4-Diethoxy-5-dimethylcarbamvlisothiazole-
l,l-dioxide
To a suspension of 3,4-dihydroxy-5-dimethyl-
carbamylisothiazole-1,1-dioxide disilver salt (8.0 q,
17.9 mmol) in acetonitrile (30 ml) was added ethyl
iodide (4.3 ml, 54 mmol). This mixture was stirred
at ambient temperature for 2-3 days. The precipi-
tated silver salts were removed by filtration and the
acetonitrile solution evaporated to give 5.4 g of
residue containing the title compound at a ratio of
2:3 to its isomeric 2-ethyl-4-ethoxy-S-dimethyl-
carbamyl-3-isothiazolone. This residue was chromato-
graphed on silica gel eluting with chlorofrom to qive
1.3 g of purified isomeric mixture enriched in the
title compound (60%). No further attempt ~7as made to
purify this material.
S ep D 3-Amino-4-ethoxy-5-dimethylcarbamylisothia-
zole-l,l-dioxide
To a solution of 60% pure 3,4-diethoxy-5
dimethylcarbamylisothiazole-l,l-dioxide (103 q) ~rom
Part C in acetonitrile (7 ml), under nitroqen, was
added hexamethyldisilizane (0.90%, 4.3 mmol). This
solution was heated at 50 for four hours. The
reaction was then quench~d with methanol (0.5 ml) and
the solvent evaporated. This residue was chromato-
graphed on silica gel eluting with 40% methanol/
chloroform and the collected product residue
iZ~ 36
- 48 - 16588IA
triturated with ether to qive 0.61 g, of title
compound (mp 221-223).
EXAMPLE 11
3-Ethoxy-4-chloro-5-methylsulfonylisothiazole
Step A 3-Ethoxy-4,5-dichlor_isothiazole
To a mixture of 4,5-dichloro-3-hvdroxyiso-
thiazole (17.00 9, 0.100 mol) and potassium carbonate
(13.82 g, 0.100 mol) in dry DMF (80 ml) was adde~
dropwise a solution of ethyl iodide (8.84 ml, 0.110
mol) in dry DMF (20 ml). The mixture was stirr~d 18
hours at ambient temperature. Water (500 ml) was
added and the mixture was extracted with ether (3x400
ml). The combined ether extracts were dried over
sodium sulfate, filtered, and concentrated in vacuo
to give the crude product (18.35 g). The crude
product was distilled to give 4,5-dichloro-3-ethoxy-
isothiazole (14.63 q, 74%r b.p. 64-66/0.1 mm). TLC
(2% methanol/chloroform, silica): Rf=0.72.
Step B 3-Ethoxv-4-chloro-5-methyl lfonylisothia?.ole
To a solution of 3-ethoxy-4,5-dichloro-
isothiazole (19.8 g, 0.10 mol) in DMF (50 ml) under a
nitrogen atmosphere was added sodium methanesulfenate
(20.4 g, 0.20 mol). The mixture was warmed to 100C
and stirred for two days. The reaction mixture was
then cooled, diluted with diethyl ether, washed with
water, dried over anhydrous sodium sulfate, filtered,
and concentrated in vacuo. The residue was chromato-
graphed on a silica gel column, elutinq with
chloroform, to give 7.1 g of the title compound, mp
85-87, crystallized from cyclohexane. A by-product,
3-ethoxy-4,5-bis(methylsulfonyl)isothiazole (3.9 q)
- 49 16588IA
was also obtained, mp 158-160 (crystallized from
cyclohexane).
EXAMPLE 12
3-Ethoxy-4-chloro-5-methoxvisothiaæole-1-oxide
Step A 3-Ethoxy-4-chloro-5-methoxyisothiaæole
To a solution of 3-ethoxy-4,5-dichloro-
isothiazole (1.0 g, 5.1 mmol) in DMF (5 ml) under a
nitrogen atmosphere was added sodium methoxide (570
mg, 10.5 mmol). The mixture was warmed to 100C and
stirred for eight hours. The reaction mixture was
then cooled, diluted with diethyl ether, washed with
water, dried over anhydrous sodium sulfate, filtered,
and concentrated in vacuo. The residue was chromato-
_
graphed on a silica qel column, eluting with
cyclohexane and then toluene, to qive 170 mq ~f the
title compound.
Step B 3-Ethoxy-4-chloro-5-methoxyisothiazo e-l-oxide
A solution of m-chloroperoxyhenæoic acid
(100 mg, 0.49 mmol) in methylene chloride (1.5 ml)
wad added dropwise with stirring to an ice-cooled
solution of 3-ethoxy-4-chloro-5-methoxvisothiazole
(87 mg, 0.45 mmol) in methylene chloride (1.0 ml)~
The solution was then stirred for 12 hours at room
temperature. The m-chlorobenzoic acid, which precipi-
tated out of solution, was filtered off~ The filtrate
was concentrat~d in vacuo, and the residue was chroma-
tographed on a silica gel column, eluting with toluene
followed by chloroform, to give 40 mg of the title
compound.
~ 50 - 1658~IA
Alternate synthesis of: 3-Ethoxy-4-chloro-
5-methoxyisothiazole-1-oxide
To the solution of 3-ethoxy-4,5-dichloro-
isothiazole-l-oxide (0.12 g, 0.0005~ mol) in methanol
S (1 ml) cooled in an ice-bath was added a solution of
sodium methoxide (0.032 g, 0.00060 mol) methanol (1
ml). The solution was warmed to ambient temperature
and stirred overniqht. The solution was concentrated
to dryness in vacuo and the residue was partitioned
between chloroform (10 ml) and water (5 ml). The
aqueous layer was washed with chloroform rlO ml) and
the combined organic layers were washed with saturated
sodium chlorate solution (2 ml) dried o~er sodium
sulfate, filtered, and concentrated to dryness to
give 0.14 g oranqe liquid. Thi~ liquid was chromato-
graphed on a column of E. Merck~silica qel 60. From
the fraction eluted with n-butylchloride, there was
obtained 0.06 g of a mixture of startin~ material and
3-methoxy-4,5-dichloroisothiazole-1-oxide. From the
fractions eluted with methylene chloride, there was
obtained 0.03 g (25~) of the title compound.
TLC (methylene chloride silica): Rf=0.43 (identical
to product of Step B above.
EXAMPLE 13
Step A 3-Ethoxy-4-chloro-5-methylsulfonylisothiazo~e-
l-oxide
To a solution of 3-ethoxy-4-chloro-5-methyl-
sulfonvlisothiazole (1.9 q, 8 mmol) in methylene
chloride (10 ml), cooled in an ice bath was added
dropwise a solution of pertrifluoroacetic acid ( ~
mmol) in methylene chloride (10 ml). After stirring
for 2 hours, the reaction was diluted with methvlene
- 51 - 16588I~
chloride and washed with sodium bisulfite solution,
sodium bicarbonate solution, dried over anhydrous
sodium sulfate, filtered and evaporated. The residue
obtained from diethyl ether gave 1.5 g of a 1:1
mixture of the title compound and starting material.
This material was used in subsequent reacti~ns.
Repeated recrystallizations from diethyl ether gave
pure product, mp 38-102.
Step B 3-Ethoxy-4-amino-5-methylsulfonvlisothia~ole-
l-oxide
To a solution of crude 3-ethoxv-4-chloro-5-
methylsulfonylsiothiazole-l-oxide (0O90 g, 1.6 mmol)
in acetonitrile (10 ml) under a nitrogen atmosphere
15 was added hexamethyldisilizane (0.70 ml, 3.3 mmol).
The reaction mixture was heated at 70 for 1-1/2
hours, cooled to room temperature and methanol (loO
ml) was added. The reaction was filtered and
evaporated. The residue was triturated with methanol/
ethyl acetate to afford crude title compound (n.3
g). Recrystallization from methanol/ethyl acetate
after treatment with charcoal gave 0.23 g of pure
product, mp 191-193.
EXAMPLE 14
3-Ethoxy-4-amino-5-methylsulfonylisothiazole-1,1-
dioxide
Step A 3-Ethoxy-4-chloro-5-methylsulfonylisothiazole-
-
l,l-dioxide
To a solution of 3-ethoxy-4-chloro-5-methyl-
sulfonylisothiazole (2.0 g, 8.3 mmol) in chloro~orm
(40 ml) was added 80% pure m~chloroperbenzoic acid
(3.9 g, 18.2 mmol). This solution was stirred for
i2~
- 52 - 16588IA
2-3 day~ as the m-chlorobenzoic acid by-product
precipitated. The entire mixture was evaporated and
the residue treated with diethyl ether. The
crystalline title compound remained undissolved and
S was collected by filtration (1.5 g), mp 181-1~4.
Step B 3-Ethoxv-4-amino-5-methylsulfonylisothiazole-
l,l-dioxide
To a solution of 3-ethoxy-4-chloro-5-methyl-
sulfonylisothiazole-l,l-dioxide (1.1 9, 4.0 mmol) in
acetonitrile (15 ml) under a nitroclen atmosphere was
added hexamethyldisilizane (0.85 ml, 4.0 mmol).
After an immediate exothermic reaction, the solution
was heated at gentle reflux for 1 hourO Upon cooling
to room temperature, methanol (1.0 ml) was added and
any solid removed by filtration. The orqanic
solution was evaporated and the solid residue
triturated with ethyl acetate/methanol to aive
crystalline title compound (0.81 g), mp 214-217.
EXAMPLE_15
3-Ethoxy-4,5-dichloroisothia~ole-1-oxide
.
To a solution of 3-ethoxy-4,5-dichloro-
isothiazole (13.86 g, 0.070 mol) in chloroform (100
ml) cooled in an ice-bath was added dropwise over 2
hours 8596 m-chloroperbenzoic acid (14.21 g, 0.070
mol) in chloroform (200 ml). The mixture was warmed
to ambient temperature and stirred for 18 hours. The
mixture was cooled to 5 and filtered to remove 8.1 9
m-chloroban~oic acid. The filtrate was concentrated
to dryness in vacuo, the residue triturated with 3C
ml chloroform, and filtered to remove 3.8 g acid.
The filtrate was concentrated and the residue was
~1 ~1d f~1 4 ;3 ~
~ 53 - 16588IA
chromatoqraphed on a column of E. Merck silica ~1
60. From the fraction eluted with n-butylchloride,
there was recovered 4.62 g (33~) startinq material.
From the fractions eluted with 1 1 n-butylchloride:
5 methylene chloride there was ohtaineA 4.56 q of ~
mixture of starting material, product, and ~-ethoxy-
4,5-dichloro-isothiazole-1,1-dioxide. From the
fraction eluted with 1:1 n-butvl-chloride:
methylene chloride followed by methylene chloride
there was obtained 7.48 g (50%) Droduct, mP ca: 20~.
TLC (CH2C12, silica): Rf=0.53.
EXAMPLE 16
3-Ethoxy-4,5-dichloroisothiazole-1,1-dioxide
To a mixture of 3-ethoxy-4,5-dichloroiso-
thiazole, isothiazole-1-ox;d~, and isothiazole-l,l-
dioxide (5.26 g) obtained as in Example 15 dissolved
in chloroform (50 ml) was added dropwise dllrinq 20
minutes a solution of 85% n-chloroperbenzoic acid
(5.08 g, o.n250 mol) in chloroform (70 ml) at ambient
temperature. The resultinq solution was stirred 2-5
days then concentrated to dryness ln vacuo. The
residue was triturated with chloroform (15 ml) an~
filtered to remove 2.5 g m-chlorobenzoic acid. The
filtrate was concentrated to dryness to qive 7.6 q
residue which was chromatographed on a column of E.
Merck silica gel 60. From the fractions eluted with
n-hutylchloride there was obtained 2.89 g of the
title product, mp 120-122.5. TLC (methylene
chloride, silica): Rf=0.73. A sample was
recrystallized from n-butylchloride, mp 122.5-123.5.
Calc'd for C5H5C12NO3S N, 6.09; C, 26.10;
H, 2.19.
Found: N, 5.97; C, 26.44; H, 2.18.
- 54 - 16588IA
EXAMPLE 17
-
3-Hydroxy-4-bromo-5-carbamoyl_sothiazole
3-Hydroxy-5-carbamoylisothiazole (1.44, 0.01
mmol) was dissolved in 15 mol of trifluoroacetic
acid. Bromine (2.4 g, 0.015 mmol) in 5 ml of
trifluoroacetic acid was added dropwise over a 20
minute period. Simultaneously, at the same rate,
wa~er was added dropwise until 20 ml was added.
Yellow solid separated when most of the water ~as
added. The resulting suspension was stirred for two
hours at room temperature, poured into 100 ml of ice
water, and filtered to give the title compound as a
white solid (1.5 g, 67%, mp 250-251C, dec).
EXA~lPLE 18
3-Ethoxy-4-bromo-5-carbamoylisothiazole
3-Hydroxy~4-bromo-5-carbamoylisothiazole
(0.6 g, 2.7 mmol) was dissolved in 5 ml of dry
20 dimethylformamide. Potassium carbonate (0.37 g~ 2.7
mmol) and ethyl iodide (0.46 g, 2.9 mmol) were added
and the mixture stirred at room temperature for
sixteen hours overnight. The dimethylformamide was
removed in vacuo and the solid residue stirred in
25 10-15 ml of ice water. Filtration gave 0.5 g of
white solid; mp 157-162C (from methylene chloride);
yield, 74%.
- 55 - 16588IA
EXAMPLE 19
3-Ethoxy-4-bromo-5-carboxyisothiazole
3-Ethoxy-4-bromo-5-carbamoylisothiazole
(2.51 g, 0.01 mol) was dissolved in 20 ml of
trifluoroacetic acid and the solution cooled to 0 to
5C. Sodium nitrite (2.76 q, 0.04 mol) ~as added in
small portions to the stirred solution over a five
minute period. Stirrinq was continued for 10 minutes
at the same temperature and the reaction mixture
poured into 150 ml of ice water~ The title compound
separated as a white solid (2.2 q, 88%, mp
151-152.5C) and was filtered, washed with ice water
and dried.
EXAMPLE 20
3-Ethoxy-4-brom~-5-chlorocarbonyl;sothiazole
A suspension of 3-ethoxv 4-bromo-5-carboxy-
isothiazole (5.0 g, 0.0198 mol) in 35 ml of thionyl
chloride was stirred at reflux for 1 hour. The
resulting yellow solution was concentrated in vacuo
to obtain 5.3 g of the acid chloride as a pale vellow
solid, m.p. 60-62C.
EXAMPLE 21
.
3-Ethoxy-4-bromo-5~t-hutyloxycarbonylisothiazole
To a solution of dry t-butyl alcohol (l.h3
g, 0.022 mol) in 5 ml of tetrahydrofuran was added
dropwise 14.3 ml (0.021 mol) of n butyl lithium
reagent tlo47 M in hexane) at ice bath temperature
stirred for an additional 1/2 hour at room
temperature and then added dropwise a solution of
3-ethoxy-4-bromo-5-chlorocarbonylisothiazole (5.4 g,
0.0198 mol) in 10 ml of THF. The mixture ~as heated
- 56 - 16588IA
at reflux for 1/2 hour after which it was
concentrated in vacuo. The residual oil-solid
mixture was taken up in 50 ml of ether and was washed
with a little ice-water and with cold saturated
NaHCO3 solution. The ether extract was dried over
anhydrous Na2SO4, filtered and concentrated in
vacuo to obtain 5.9 g of the t-butyl ester as a
yellow solid. Recrystallized m.p. was 46-47.5C
(pet. ether).
10 Calc'd for ClOH4BrNO3S N, 4-55; C, 38097; H~
4.58.
Found: N, 4.62; C, 39.28; H, 4.90.
EXAMPLE 22
15 3-Ethoxy-4-bromo-5-t-butyloxycarbonylisothiazole-1,1-
dioxide
A solution of peroxytrifluoroacetic acid was
prepared by standard procedures from 90% H2O2
(1.4 ml, 0.05 mol) and trifluoroacetic anhydride
20 (12.6 g, 0.06 mol) in 25 ml o~ methylene chloride.
To a stirred solution of
3-ethoxy-4-bromo-5-t-butyloxycarbonylisothiazole
(3.03 q, 0.01 mol) in 25 ml of methylene chloride ~as
added anhydrous Na2CO3 (21.2 ~, 0.2 mol) followed
by the dropwise addition at O~C of the
peroxytrifluoroacetic acid solution prepared above~
The reaction mixture was filtered and the filtrate
was cooled and washed quickly with cold sodium
bicarbonate solution and with ice water. The
methylene chloride solution was dried over anhydrous
Na2SO4, filtered and concentrated in vacuo to
- 57 - 16588IA
obtain 3.0 g of the sulfone as a yellow solid. The
product recrystallized from n-butyl chloride hexane,
m.p. 143-145C with dec.
10 14 5S ~ 4.12; C, 35.30; H,
4.15.
Found: N, 4.00; C, 35.~7; H, 4.19.
EXAMPLE 23
3-Ethoxy-4-amino-5-t-butyloxycarbonylisothiazole-1,1-
dioxide
To 3-ethoxy-4-bromo-5-t-butvloxycarbonyliso-
thiazole-l,l-dioxide (340 mg, 1.0 mmol) in 5 ml of
dry acetonitrile was added hexamethyldisilazane (242
mg, 1.5 mmol) and the solution was stirred at reflux
for 7 hours. The reaction mixture was evaporated in
vacuo and the residue was refluxed in 10 ml of
ethanol for 3/4 hr. Removal of ~he ethanol in vacuo
gave a crude oil which was chromatographed on silica
gel. The product was recovered as a viscous yellow
oil (210 mg). Trituration in petroleum ether gave a
yellow solid, m.p. 128-130C. Mass spectral analysis
confirmed the structure.
EXAMPLE 24
3-Ethoxy-4-bromo-5-carbamoylisothiazole-1-oxide and
l,l-dioxide
Pertrifluoroacetic acid was prepared from
0.36 ml of 90% hydrogen peroxide and 1.44 ml of
trifluoroacetic anhydride in 10 ml of dry methylene
chloride. This solution was added dropwise over a
3/4 hour period to 3-ethoxy-4-hromo-5-carbamoyl-
isothiazole (1.8 g, 7.0 mmol) in 50 ml of dry
14~
- 58 - 16588IA
methylene chloride. After the solution was stirred
at room temperature overnight, it was concentrated in
vacuo to a volume of 5 ml. Chromatographv of this
concentrate on silica gel gave the title compounds.
The l-oxide (0.94 g) melts at 179 181.5C while the
l,l-dioxide (0.6 g) melts at 168-172C.
EXAMPLE 25
3-Ethoxy-4-bromo-5-carboxyisothiazole-1-oxide
3-Ethoxy-4-bromo-5-carbamoylisothiazole-1-
oxide (267 mg, 1.0 mmol) was dissolved in 2 ml of
trifluoroacetic acid and sodium nitrite (138 mg, 2.0
mmol) was added in sm~ll portions over a two minute
period with stirring. Stirring was continued for two
minutes at room temperature and then the solvent was
removed _ vacuo. The residual gum was stirred in 5
ml of ice water for five minutes. ~iltration gave
174 mg (65% yield) of yellow solid; mp 158 160C, dec.
EXAMPLE 26
3-Ethoxy-4-bromo-5-[N(2-dimethylamir~o)ethyllcarba-
moylisothiazole-l-oxide
The product from Example 25 r ( 4.4 g, 0.02
mol) can be added to a solution of dicyclohexyl-
25 carbodiimide (4.1 g, 0.02 mol) in 100 ml of dry
acetonitrile. After about one hour, a solution of
N,N-dimethylethylenediamine (1.8 g, 0.02 mol) in 25
ml of acetonitrile can be added dropwise at 0C. The
mixture can then be stirred at 0 for about four
hours, filtered, and concentrated under vacuum at
25C. The residue can be triturated with ice water
and the solid title compound can be collected by
suction.
- 59 - 16588IA
EX~MPLE 27
3-Ethoxy-4-amino-5-lN[(2-hydroxy)ethyl[carbamoyl]-iso-
thiazole-l-oxide
The product from Example 25, (5.8 q, 0.02
mole) can be added to a solutin of triethylamine (28
ml, 0.02 mol) and diphenylphosphorylazide (5.5 q,
0 02 mol) in 100 ml of dry a~etonitrile at 0C. A
solution of ethanolamine (1.23 g, 0.02 mol) in 25 ml
of acetonitrile can then be added dropwise with
stirring under N2 at 0. The mixture can then be
stirred for about four hours at 0C, diluted with one
volume of ice water and the precipitated title
compound can be collected by suctionO
EXAMPLE 28
3-Methoxy-4 amino-5-methylisothiazole-1,1-dioxide
Step A 3-Hydroxy-4-amino-5-methylisothiazole-1,1-
~ e ~t=s~i~r S-lt
4-Chloro-5-methylisothiazoline-3-one-1,1-
dioxide (S. N. Lewis et al., J. Heterocyclic Chem. 8,
1971, 591) (9.0 q, 0.05 mol) can be added to a
sol~tion of ammonia in absolute ethanol (200 ml of
.06 molar). The suspension can then be stirred for
about four hours at room temperature and then added
to a solution of potassium hydroxide (5.6 9, 0.10
mol) in 200 ml of ethanol. The resulting sus~ension
should then he stirred for about one hour at room
temDerature and filtered. The resulting so]id can
then be recrystallized from water to give the
postassium salt of 4-amino-5-methylisothiazoline-
3-one-1,1-dioxide which can be subsequently dried at
about 80 under high vacuum.
- 60 - 16588IA
Step B 3-Methoxy-4-amino-5-methylisothiazole-1,1-
dioxide
_
The product from Step A, (60 g, 0.03 mol)
can be dissolved in 50 ml of dimethylsulfoxide under
N2 at 50C and the stirred solution can be treated
with dimethylsulfate (3.78 g, 0.03 mol) at about
50~. The stirred mixture can be kept at about 50C
for about 3 hours, concentrated under vacuum and the
residual semi-solid triturated with ice water and
filtered to give the title compound.
EXAMPLE 2 9
3-Methoxy-4-bromoisothiazole-1-oxide
To a solution of 3-methoxy-4-bromoiso-
thiazole (2.9 g, 15 mmol) in methylene chloride (15
ml) there can be was added, in portions,
3,5-dinitroperbenzoic acid (3O4 g, 15 mmol) with ice
bath cooling. After about one hour, the precipitated
3,5-dinitrobenzoic acid can be filtered off and the
solvent evaporated in vacuo. By triturating the
residue with diethyl ether, a crystalline product,
3-methoxy-4-bromoisothiazole-1-oxide, can be
obtained. Additional material can be obtained hy
chromatographing the mother liquors on silica gel,
eluting with chloroform.
EXAMPLE 30
3-Methoxy-4-bromoisothiazole-1,1-dioxide
To a solution o~ 3-methoxy-4-bromoisothia-
zole (2.9 g, 15 mmol) in methylene chloride (10 ml)
there can be added dropwise with ice-bath cooling a
solution of 85% pure 3-chloroperbenzoic acid (6.09 q,
30 mmol) in methylene chloride (25 ml). When the
4~3~
- 61 - 16588IA
addition is complete, the reaction mixture can be
concentrated to one-half volume on a rotary
evaporator, the mixture cooled in an ice bath, and
3-chlorobenzoic acid can be filtered off. The
solvent can he evaporated ln vacuo and the residue
triturated with diethyl ether to afford the title
compound. Additional product can be obtained by
chromatography on silica gel, eluting with chloroform.
EXAMPLE 31
.
3,4-Dimethoxyisothiazole-l-oxide
To a solution of the Example 29 compound
(1.05 g, 5 mmol) in methylene chloride (10 ml3 there
can be added with ice bath cooling, excess methanol
(2.0 ml), followed by triethylamine (0.5 ml, 5
mmol). Upon stirring at ambient temperature for
about 5 hours, the reaction mixture can be diluted
with diethylether and the triethylamine hvdrobromide
removed by suction filtration. The filtrate can then
be evaporated ln vacuo to afford the title compound.
XAMPLE 32
3,4-Dimethoxyisothiazole-l_,l-dioxide
The title compound can be obtained following
the procedures described in Example 31 except that
the compound of Example 30 should be used in place of
the compound of Example 29.
EXAMPLE 33
_ . _
3-Amino-4-methoxyiSothiazole-l-oxide
A solution containing 800 mg (5.0 mmol) of
the Example 31 compound and 800 mg (5.0 mmol)
hexamethyldisilazane in 10 ml drv acetonitrile can he
- 62 - 16588IA
stirred under nitrogen in an oil bath at about 50Co
After about 18 hours the solution can be evaporated
to dryness in vacuo and the residue dissolved in 10
ml methanol. After stirring for about one hour, the
mixture can then be concentrated in vacuo and the
residue triturated with diethyl ether to afford the
title compound.
EXAMPLE 34
3-Amino-4-me~hoxyisothiazole-1,1-dioxide
To a solution of the Example 32 compound
(1~15 9~ 6.5 mmol) in 15 ml of methylene chloride
there can be added, under a nitrogen atmosphere,
hexamethyldisilazane (1.0 g, 6.5 mmol) dissolved in 5
ml methylene chloride. After stirring at room
temperature for about four hours, the ~solvent can be
removed under aspirator pressure and the residue
dissolved in 10 ml methanol. Upon stirring for about
one hour, the solution can then be eva orated to
dryness in vacuo to give the title compound.
EXA~PLE 35
3,4-Bis(methylsulfonvl)isothiazole-5-carbonitrile
To a suspension of 5.10 g (0.025 mole) of
3,4-bis(methylthio)isothiazole carbonitrile in 20 ml
of acetic anhydride and 20 ml of qlacial acetic acid
was added, over 90 minutes with stirrinq, 11.90 g
(0.105 mole) of 30% hydrogen peroxide. An ice bath
was used intermittently throughout the addition to
moderate the exothermic reaction. After 2 days at
room tem~erature, the solid mass was diluted with
water (500 ml) and filtered to afford 4.0 g of the
title compound.
- 63 16588IA
EXAMPLE 36
3,4-Dimethoxyisothiazole-5-carbonitrile
A mixture of the compound of Example 35
(3.95 g, 0.015 mol) and sodium carbonate (1.58 q,
0.015 mole) in 40 ml methanol can be stirred at
reflux for 6 hours. On cooling, the mixture can be
poured into water and the precipitate collected by
suction filtration. Recrystallization of the solid
from ethanol can give the pure title compound.
EXAMPLE 37
3,4-Dimethoxy-5-cyanoisothiazole-1-oxide
The title compound can be obtained by
following the procedure of Exam~le 29 usinq the
compound of Example 36 in place of 3-methoxy-4-bromo-
isothiazole.
EXA~-~PLE 38
3,4-Dimethoxy-5-cyanoisothiazole-1,1-dioxide
.. . ..
The title compound can be obtained by
following the procedure of Example 30 using the
compound of Example 36 in place of 3-methoxy-4-bromo-
isothiazole.
EXA~PLE 39
3-[2-[5-Dimethylaminomethyl)-2-furanylmethylthio]
ethyl~amino-4-amino-5-ethoxycarbonylisothiazole
l,l-dioxide
.
To a solution of 510 mg (2.0 mmol) of the
Example 5 compound in 4 ml dry acetonitrile under a
nitrogen atmosphere there was added 440 mq (2 0 mmol)
2-[5-~dimethylaminomethyl)furanylmethylthio]ethylamine.
A slight exothermicity was noted on mixing of the
- 64 - 16588IA
reactants. After 30 minutes at room temperature, the
reaction was completed by tlc (Alumina 6F, 95:5
CHC13:CH30H). ITpon evaporation of the solvent,
the oily residue was triturated in a mixture of
S cyclohexane:ethanol (10:1) from which there was
obtained 760 mg of analyticallv pure title product,
mp 90-95, as an ethanol solvate.
Anal. Calcd. for C16H24N4O5S2. 2 5
N, 12.11; H, 6.54; S, 13086.
Found: N, 12.39; H, 6.44; S, 14.20.
EXAMPLE 40
3-N-[3-[3-(1-piperidinylmethyl)phenoxy]propyl~amino-
4-amino-5-ethoxycarbonylisothiazole-1,1-dioxide
Following the procedure of Example 39,
3-[3-(1-piperidinylmethyl)phenoxv]propaneamine was
reacted with the compound of Example 5 in
acetonitrile to give the title com~ound as a
crystalline hydrate, mp 111-118.
Anal. Calc'd for C21H30N4O5S-H2O:
C,53.83; N, 11.96; H, 6.88.
Found: C, 53.91; N, 11.80; H, 7.04.
EXAMPLE 41
N-Trimethylsilyl-2-[5-(dimethylaminomethyl)-2-furanyl-
methylthio]ethyl amine
The dihydrochloride salt of 2-[5-(dimethyl-
aminomethyl)-2-furanylmethylthio~ethylamine (10.0 g,
34.8 mmol) and 15 ml of hexamethyldisilazane were
combined in 50 ml dry toluene and the mixture was
stirred under vigorous reflux under a nitroqen
atmosphere. After four hours, the toluene was
distilled at atmospheric pressure, followed by hexa-
4~3~
- 65 - 16588IA
methyldisilazane at a slight vacuum and then the
title product distilled as a yellow oil, bp 140-145/
0.5 mm; 7.9 g. Further purification can be achieved
by redistillation: bp 95-96/0.1 mm. H NMR
(CDC13, no tetramethylsilane added) 6.0s (sinqlet
-2 protons-furan), 3.64 (sinqlet -2 protons-
furan-CH2-S-), 3.38 (singlet -2 protons- furan-
CH2-N-), 2.90-2.40 (multiplet, 4 protons-CH2-
CH2)-, 2.20 (singlet -6 protons- N(CH3)2), 1.60
(singlet, 1 proton, NH) and 0.0 (sinqlet -9 protons-
(C 3)3).
EXAMPLE 42
3-Amino-4-[2-(5-dimethylaminomethyl)-2-furanylmethyl-
thio]ethylamino-5-ethoxycarbonylisothiazole-
l,l-dioxide
.
Under a nitrogen atrnosphere, a solution of
900 mg (3.2 mmol) of the Example 4 compound in 20 ml
dry tetrahydrofl~ran was stirred in a dry ice -
acetonitrile bath (-35) while being treated with a 3
ml solution containing 825 mg (3.2 mmol) of the
trimethylsilylamine of Example 41 in tetrahydrofuran.
The mixture was allowed to warm to 0-15 and, after
three hours, a tlc analysis (silica GF, 9:1 CHC13:
C2H5OH) showed the reaction to be complete. An
ammonia-tetrahydrofuran solution (7.0 ml of 0.465 M,
3.2 mmol NH3) was added dropwise and the resul~in~
solution was stirred at ambient temperature for la
hours. The white solid, which precipitated was
collected an~ washed with ether to qive 480 mg of the
title product, mp 101-103.
16 24~4O5S: C, 46.14;
H, 5.80.
Found: C, 46.16; H, 6.10.
3~;
- 66 - 16588IA
EXAMPLE 43
3-N [3-[3-(cyclopropylaminomethyl)phenoxy]propyl]-
amino-4-amino-5-carbamoylisothiazole-1,1-dioxide
hvdrochloride
.. .
To an ice-cold solution of 1.53 g (7.0 mmol)
of 3-ethoxy-4-amino-5-carbamoylisothiazole-1,1-
dioxide in 10 ml acetonitrile there can be added
dropwise, under nitrogen, a solution of 3-[3-(cvclo-
propylaminomethyl)phenoxy]propane amine (1.56 g, 7.0
mmol) in 10 ml acetonitrile. The mixture can then be
stirred at room temperature for about two hours, the
solvent evaporated in vacuo, and the residue
chromatographed on silica gel using 1-2% ethanol in
chloroform as elutant. Fractions containing the
product-free base can then be combined and the
solvent evaporated to give the title compound.
EXAMPLE 44
3-N-[2-16-(4-morpholinylmethyl)-2-benzofuranylmethyl-
thio]ethyl]amino-4-amino-5-ethoxycarbonylisothiazole-
l,l-dioxide
.
The title compol]nd can be obtained by
reaction of 4.0 mmol each of 2-[[6-(4-morpholinyl-
methyl)-2-benzofuranyllmethylthio]ethyl amine and the
compound of Example 5 in 8 ml of acetonitrileO The
pure product can then be crystallized from the
reaction solution and collected by filtration.
EXAMPL~ 45
3-N-[2-[5-(dimethylaminomethyl)-2-furanylmethvlthio]-
ethyl]amino-4-amino-5-N-[(2-dimethylamino)-ethyl]car-
bamoylisothiazole-l-oxide __ _
Following the procedure in Example 39 with
the reagent of Example 26 and 2-[(5-dimethylamino-
3tLi
67 - 16588IA
methyl-2-furanyl)methylthio)ethylamine, the pure
title compound can be obtained.
EXAMPLE 46
3-N-[2-[(4-methyl-5-oxaæolyl)methylthio)ethyllamino-4-
amino-5-N-[2-hydroxyethyl3carbamoylisothiazole-1-oxide
The title compound can be obtained as
described in Example 39 using the product of Example
27 and 2 [(4-methyl-5-oxazolyl)methylthio]-ethane
amine.
EXAMPLE 47
3-N-[2-[[6-(morpholinylmethyl)-2-benzofuranyl]methvl-
thio]ethyl]amino-4-amino-5-N-[2-hydroxyethyl]carbamoyl-
isothiazole-l-oxide
The title compound can be obtained as
described in Example 39 using the product from
Example 27 and 2-[~6-(4-morpholinylmethyl)-2-benzo-
furanyl]methylthio]-ethyl amine.
EXAMPLE 48
3-N-[2-[5-(dimethvlaminomethyl)-2-furanylmethylthiol-
ethyl]-amino-4-amino-5-methylisothiazole-1,1-dioxide
The title compound can be obtained as
described in Example 39 using the compound of Example
28 in place of that of Example 5.
EXAM~LE 49
3-N-[2-[(2-guanidino-4-thiazolyl)methylthio~ethyl]-
amino-4-amino-5-methylisothiazole l,l-dioxide
The title compound can be obtained as
described in Example 39 using equimolar amounts of
2-[(2-guanidino-4-thiazolyl)methylthio]ethanamine and
the product of Example 28.
- 68 - 16588IA
EXAMPLE 50
3-N-[2-~(4-methyl-5-imidazolyl)methylthio~ethyl]-
amino-4-methoxy isothiazole-l-oxide
To a solution of 1.61 g (0.01 mol) of the
Example 31 compound in 20 ml dry tetrahydrofuran at
-20 under a nitrogen atmosphere, there can be added
1.71 g (0.01 mol) of 2-[(4-methyl-5-imidazolyl)-
methylthio]ethylamine dissolved in 10 ml dry
tetrahydrofuran. The mixture can then be allowed to
warm to room temperature andl after about 18 hours,
can be concentrated to one-half volume to afford the
title compound as a precipitate.
~XAMPLE 51
3-N-[2-~(4-methyl-5-imidazolyl)-methylthio]ethylamino-
4-methylamino-isothiazole-1-oxide hydrochlori~e
A solution of anhydrou~ methylamine in
tetrahydrofuran (10 ml, 0.55 M) can be added dropwise
to a solution of the Example 50 compound (1.63 g, 5.5
mmol) dissolved in 20 ml dry tetrahydrofuran at about
0 under a nitrogen atmosphere. When the addition ;s
complete, the ice bath can be removed and the
solution slowly warmed to room temperature. After
about 24 hours, the solvent can be evaporated in
vacuo and the crude oily residue can be
chromatographed using silica qel flash
chromatography, eluting with 1-5~ methanol in
chloroform. The product fractions can then be
combined, the solvent evaporatd in vacuo, and the
residual gum dissolved in a mixture of
ethanol-tetrahydrofuran. Addition of 0.45 ml of
concentrated hydrochloric acid should then
precipitate the title compound.
- 69 - 16588IA
EXAMPLE 52
3-Amino-4-N~[3-[3-(4-morpholinylmethyl)phenoxy~-
propyl]aminoisothiazole-l,l-dioxide
By the method of Example 42, using equimolar
amounts of 3-[3-(4-morpholinylmethyl)phenoxy]propan-
amine and the compound of Example 34, the title
compound can be obtained.
EXAMPLE 53
~-tert-Butyloxycarbonyl-a-tosyloximinoacetonitrile
A mixture of tert-butylcyanoacetate (5.0 g,
.035 mole), sodium acetate (3.4 g, .042 mole), and
sodium nitrite (2.9 g, .042 mole) in 15 ml water was
stirred in an ice bath during dropwise addition of
acetic acid (2.6 ml, .045 mole). Stirring was then
continued at room temperature overnight. A yellow
waxy solid was collected (4.2 g) which contained
unreacted tert-butyl cyanoacetate by ~mr. This
material was recycled with fresh sodium nitrite (1.2
g, .0175 mole~, sodium acetate (1.4 g, .0175 mole)
and acetic acid (1.0 ml, .018 mole). The waxy solid
which resulted, (a mixture of (~-oximino)tert-butyl
cyanoacetate and the sodium salt thereof) was washed
with water and dried. The solid (3~2 g, approxi-
mately .0179 mole) was dissolved in 15 ml dry
pyridine and to this solutin at -5C there was added
protionwise _-toluenesulfonyl chloride (3.4 g, .0179
mole). After one hour, the suspension was poured
into 100 ml ice water and the solid which
crystallized was collected and Aried: 5.2 g of the
title compound, mp 101-102C.
9 - 70 - 16588IA
EXAMPLE 54
.
3-tert-Butyloxycarbonyl-4-amino-5-ethoxycarbonyliso-
thiazole
,
Pyridine (1.62 ml, .020 mole) was added
dropwise to a solution of 5.15 9 (.016 mole) (~-tosyl-
oximino)tert-butyl cyanoacetate and 2.66 ml (.024
mole) ethyl-2-mercapto acetate in 6 ml absolute
ethanol at such a rate as to maintain a reaction
temperature of 35-40. When the addition was
completed, the solution was stirred one hour before
pouring it into 80 ml ice water. Ether extraction
afforded 2-cyano-2-tert-butyloxycarbonylmethyl-
thioimino acetic acid ethyl ester as an oil. This
material was cyclized directly by dissolving it in 50
ml acetonitrile and treating the solution with 2.6 g
(.026 mole) triethylamine under a nitrogen atmosphere.
After 1.5 hours, the mixture was concentrated in
vacuo to 1/3 its original volume, the residue poured
into water and the product extracted into ether. The
dried (Na2SO4) ether extract was evaporated to an
oil which was chromatographed over silica qel (chloro-
form elution). The title compound was obtained as an
oily solid in 87% yield (3.8 gl. Washing the solid
with an ether-hexane mixture afforded analytically
pure material, mp 68-69.
EXAMPLE 55
3-Carboxylic acid-4-amino-5-ethoxycarbonylisothiazole
Nine grams (.033 mole) of the diester of
Example 54 was dissolved in 30 ml trifluoroacetic
acid and the solution allowed to stand at room
temperature for two hoursO The 7.5 9 of yellow solid
that remained upon evaporation of the solvent had a
- 71 - 16588I~
mp 144-147. Recrystallization of this crude
3-carboxylic acid-4-amino-5-ethoxycarbonylisothiazole
from n-butylchloride afforded analytically pure
material, mp 146-148.
EXAMPLE 56
3-Hydroxymethyl-4-amino-5 ethoxycarbonylisothiazole
A solution containing 6~0 ~ (.0277 mole) o~
3-carboxylic acid ~-amino-S-ethoxycarbonylisothiazole
in 60 ml of dry tetrahydrofuran was stirred at -10
to 0 under a nitrogen atmosphere while a solution of
borane in tetrahydrofuran (83 ml, lN) was added drop-
wise. The mixture was allowed to waem to room
temperaturey then stirred at reflux for two hours
before chilling in an ice bath and quenching with
dropwise addition of lN HCl. The resultant mixture
was concentrated on a rotary evaporator to a semi-
solid which was then extracted into ethyl acetate.
Upon washing the organic phase with water, aqueous
sodium bicarbonate, then brine, the ethvl acetate was
dried (sodium sulfate), filtered, and evaporated in
vacuo to give the title compound as a solid, mp
82-85C. An analytical sample, mp 84 86 was
prepared by recrystallization from n-butylchloride.
EXAMPLE 57
4-Amino-5-ethoxvcarbonylisothiazolin-3-one-1-oxitlP
To a solution of 3-hvdroxymethyl-4-amino-5-
ethoxycarbonylisothiazole (2.0 g, .010 mole) in 40 ml
acetic acid-water (28:12) was a~ded 0~10 ml perchloric
acid (70%) and the solution was warmed to 40. Over
ten minutes there was added dropwise 2.~ ml 30%
hydrogen peroxide solution t.025 mole) dissolved in
36
- 72 - 16588IA
10 ml 70% aqueous acetic acid. After one hour, the
reaction temperature was raised to 60 and the
solution stlrred for 24 hours at this temperature. A
test with potassium iodide/starch paper revealed no
peroxide left. The solution was then cooled, poured
onto crushed ice, and extracted with methvlene
chloride to remove any unreacted starting material.
The aqueous phase was then treated with sodium
chloride and extracted with ethyl acetate (4x50 ml)~
The combined ethyl acetate extracts were dried over
sodium sulfate before concentratinq in vacuo to an
oily solid which was triturated with ethanol to
afford the title comp~und, mp 197-198
EXAMPLE 58
.
3-Ethoxy-4-amino-5-ethoxycarbonvlisothiazole-1-oxide
A mixture of 1.55 g (7.6 mmole) of
4-amino-5-ethoxycarbonylisothiazolin-3-one-1-oxide,
1.3~ q (10.0 mmole) of potassium carhonate, and 0.64
ml (8.0 mmole) of ethyl iodide in 6 ml dimethyl-
sulfoxide was stirred at room temperature for 18
hours. The suspension was then poured onto crushed
ice and extracted with ethyl acetate (3x30 ml). The
combined organic phases were washed one time each
with ice water and brine, then dried over sodium
sulfate. The title compound, which was obtained upon
removal of the solvent, was identical to the product
of Example 7.
EXAMPLE 59
. .
3-[2-[5-(Dimethylaminomethyl)-2 furanylmethylthiol-
ethyl]amino-4-amino-5-ethoxycarbonylisothiazole-1-oxide
The title compound was obtained by effecting
a tetrahydrofuran solution of equimolar amounts of
36
~ 73 - 16588IA
2-[5-(dimethvlaminomethyl)furanylmethvlthiolethvlamine
and the compound of Example 58 and allowing the
mixture to stir at ambient temperature under nitrnqen
for 48 hoursO Removal of the solvent in vacuo
afforded the title compound a~ a crystalline soli~
which was recrvstallized from ethanol and was
identical to the product of Example 70.
EXAMPLE10 Methyl N-(benzylsulfonyl)oxamate
A mixture of benzylsulfonamide (16.7 q,
0.0975 mole) and methyloxalylchloride (38 ml, 0.41
mol) was heated at 100-120C for 2 hours. Upon
evaporation, there was obtained the title compound,
20.6 g, mp 119-124C.
EXA~1PLE _
3-[2-[5-(Dimethylaminomethyl)-2-furanylmethylthiol
ethyl]amino-4-amino-5-phenylisothiazole-1,1-dioxide
Step A Disodium salt of 3,4-~ih~droxY-5-phenvliso-
thiazole-l,l-dioxide
-
A solution of sodium tert-butoxide was
prepared by adding dropl~ise, under nitrogen, a
solution of tert-butanol (7.2 ml, 00078 mol) in dry
N,N-dimethylformamide (15 ml) to a stirred mixture of
sodium hydride (3.7 g of a 50~ dispersion in mineral
oil, 0.078 mol) in dry N,N-dimethylformamide (10 ml).
External cooling was required to maintain a reaction
temperature of 15 to 25. The mixture was then
stirred at 25 until ~as evolution ceased (20-30
minutes). To this mixture, there was added dropwise
a solution of methyl N-(ben~ylsul~onyl)oxama~e (10.0
~Z~14~6
- 74 - 16588IA
g, 0.039 mol) in N,~-dimethylformamide (25 ml),
maintaining a reaction temperature of 15 to 25C.
The solution was then stirred overnight at room
temperature. Evaporation of the solvent at 55/0.1
mm Hg left the title compound as a sol;d.
Step B Disilver Salt of 3,4-dihydroxv-5-~henyliso-
thiazole-l,l-dioxide
The product from Step A (16.6 g, .062 mol)
was dissolved in 250 ml water, the solution filtere~,
ad the filtrate treated with 21.2 g (.125 mol\ silver
nitrate dissolved in 50 ml water. The mixture was
stirred under nitrogen for 24 hours and the ~roduct
collected by filtration. The solid title compound
was dried at 100 in vacuo for 24 hours: yielA, ~4.8
g (91%).
Step C 3,4-Diethoxy-5-phenylisothiazole-1,1-dioxi~e
A suspension of the disilver salt from Step
B (24.3 g, .055 mol) in 70 ml dry acetonitrile was
stirred under nitrogen in a fiO oil bath while a
soluion of iodoethane (19.5 g, .125 mol) in 30 ml dry
acetonitrile was added dropwise. When the addition
was complete the heat was removed and the mixture
allowed to stir at am~ient temperature for two days.
Filtration of the mixture throuqh Celite, followed by
evaporation of the clear filtrate gave an oily solid
(13 g, 85%) which was a mixture of the title compound
and its isomer, 2-ethyl-4-ethoxy-5-phenyl-3-
isothiazolinone, in a 35:65 ratio. Chromatoqraphv onsilica gel eluting with ethyl acetate:hexane (1:4)
gave 3.3 g of pure title compound, m.p. 133-134.
~XQ~
~ 75 - 16588IA
Step D 3-N-[2-[5-(Dimethylaminomethyl)-2-furanyl-
methylthio]ethyl]amino-4-ethoxy-5-phenyliso-
thiazole-l,l-dioxide
_.
A solution of the compound from Step C (1.2
9, 4.2 mmol) in 25 mL acetonitrile was treated with
2-[5-~dimethylaminomethyl)furanylmethylthio]ethvlamine
(0~90 g, 4.2 mmol). ~fter stirring under nitrogen at
ambient temperature for 2 hours, the solvent was
evaporated in vacuo to give an oil which crystallized
from ethanol-ethyl ether: 1.5 g (81~) of the title
compound, mp 92-98.
Step E 3-N ~2-[5-(Dimethylaminomethyl)-2-furanyl-
methylthio]ethyl]amino-4-amino-5-phenyliso-
thiazole~ dioxide
_ .
A 90 mL capacity glass pressure bottl~ wascharged with 1.0 9 (2.2 mmol) of the compound of Step
D. The bottle was immersed in a dry ice-acetone ~ath
and ammonia gas (ca~ 3 mL) was condensed in the
bottle. After sealing the bottle with a pressure
valve, the cooling bath was removed and the solution
stirred at ambient temperature for lB hours. The
residue left after venting off the reaction vessel
and evaporation of excess ammonia was taken up in
ethyl acetate and the solution washed with brine.
The organic phase was concentrated in vacuo and the
residue chromatographed over silica gel, eluting with
chloroform saturated with ammonia (0 to 10~
methanol)~ The title compound, 430 mg; was obtained
as tlc homogeneous white solid which was
recrystallized from acetonitrile. The pure compound
was an amorphous hemihydrate, mp 74-77.
3~i
- 76 - 16588IA
EXAMPLh 62
3-N [2-[(2-Guanidino-5-methyl-4 thiazolyl)methYlthi
ethyl]amino-4-amino-5-ethoxycarbonylisothiazole-
l,l-dioxide tetrahYdrofuran solvate hemihydrate Step A 4,5-Dimethyl-2-guanidinothiazole hydro-
bromide
Amidinothiourea hydrobromide (15.4 q, 0.10
mol) was slurried in 100 ml of ice water and the
stirred suspension treated with 7.d ml of concen-
trated aqueous ammonia. The mixture was stirred for30 minutes at 0-5 and filtered to qive lOo 8 q (n ~ 091
mol) of amidinothiourea. This was slurried in a
solution of 13.5 9 (0.089 mol) of 3-bromo-2-hutanon~
in 100 ml of acetone and the mixture was kept at room
temperature overn;ght (a mild ex~therm gave a clear
solution which de~sited crvstals of th~ title
compound). The title compound, 17 g, mp 268-269,
was collected by suction.
Step B 4-Bromomethyl-5-me~hvl-2-quanidin~thia7Ole
hv(lrohromide
.
A solution of the product from ~Step A (5.0
g, 0.020 mol) in 25 ml of trifluroacetic acid was
heated to reflux and treated with bromine adde~/ hy
way of a teflon tube, below the surface of the
refluxing mixture. A total of 2.2 ml of bromine ~^~as
added during 6 hours reflux after which an nmr
spectrum showed complete con~7ersion of the m~thyl
signal of starting material at 2.5 to a CH2 signal
at 4.53. The mixture was concentrated in vacuo and
the solvent replaced hy isopropanol saturated with
hydrogen bromide. The crude product, which crystal-
lized (3.9 g), was recrystallized from qlacial acetic
3~;
~ 77 - 16588IA
acid to give the pure titl~ compound (2.8 q, 42~), m~
188-188.5C.
Step C 2-~(2-Guanidino-5-methyl-4-thiazolvl)methvl-
thio]ethvla_ine maleate
To a stirred solution of cvsteamine hydro-
chloride (1.7 g, 0.017 mol) in 25 ml of methanol was
added a solution of 1.7 g (0.031 mol) of sodillm
methoxide in 15 ml of methanol under nitr~gen at 0 to
-15C. To the resulting mixture there was adde~ a
solution of 2.5 g (0.0075 m~l) of the ~roduct from
Step B in 40 ml of methanol at 0C. The resultinq
mixture was warmed to r~om temperature during 4 hours
and then concentrated under vacuum. The residue was
partitioned ~etween aqueous sodium hydroxid~
(s~turate~ with sodillm chloride) and methvlene
chloride. The methylene chloride extract was dried
(so~ m sulfate), filtered and concentrated un~er
vacuum to an oil which was crystallized from aceto-
nitrile to gi~re the crude title amine. This wasboiled in 50 ml of acetonitrile and the solution
filtered through diatomaceous earth. The filtrate
was treated with a solution of .065 q of maleic ACid
in 25 ml of acetonitrile and the title salt, which
crystallized, was collected ~y sUction; vi~ld 1.4 q,
mp 232-234C.
Step D 3-N-[2-[(2-Guanidino-5-meth~rl-4-thiazolvl~
methylthio]ethyl]amino-4-amino-5-ethoxy-
carbonylisothiazole-l,l-dioxide tetrahvdro-
furan solvate h~mihvdrate
.
The salt from Step C (1.3 q, o.On36 mol\ was
partitioned between a mixture of 2 ml of lON sodium
43~
- 78 - 16588IA
hydroxide and 3 ml of 5% ethanol-methylene chl~ride.
The layers were separated and the extraction
repeated. The combined methylene chloride lavers
were dried (sodium sulfate), filtered, and
concentrated under vacuum. The residue was dissolved
in 20 ml of dry tetraht~drofuran and the cloudY
solution filtered through diatomaceous earth into a
solution of 3-ethoxv-4-amino-5-ethoxy carbonyliso-
thiazole-l,l-dioxide in 20 ml of dry tetrahydro-
furan. The resulting clear solution was stirredoverniqht at room temperature and the ~recipitated
3-N-[2-[(2-guanidino-S-methyl-4-thiazolylmethylthio]-
ethyl]amino-4-amino-5-ethoxycarbonylisothiazole-1,1-
dioxide tetrahydrofuran solvate hemihydrate collected
by suction mp 150-152C (dec).
RXAMPLE 63
3-N-[2-[(2-Guanidino-4-thiazolyl)methylthio]ethyl]-
amino-4-amino-5-ethoxycarbonylisothiazole-1,1-
dioxide h drate
Y
To the suspension of 3-etho~y-4-amino-5-
ethoxycarbonylisothiazole-l,l-dioxide (0.74 g, 0.0030
mol) in ethanol (3 ml) there ^7as added a solution of
2-[(2-guanidino-4-thiazolyl)methythio]ethylamine
(0.69 g, 0.0030 mol) in ethanol (4 ml) resulting in a
clear yellow solution. A gum was deposited after 30
min. After 24 hours, the mixture was concentrated to
dryness in vacuo and the residue wa.s chromatoqraphed
on a column of E. Merck silica gel 60. From the
fraction eluted with 10% methanol/chlorofrom ~ollowed
by 20~ and 30% methanol/chloroform, there was ~htaine~
l.i2 g glassy solid. The glass was triturated with
hot acetonitrile and the solid filtered and dried to
give 0.80 g glassy solid. After recrystallization
3~i
- 79 - 16588I~
from isopropanol followed by recrystallization from
methanol 0.35 g (27~) of the title product was
obtained, mp 201-203. TLC (30~ methanol/chloroform,
silica): Rf=0.61.
Calc'd for C13~19N74S3H2
C, 34.57; H, 4.33.
Found: N, 21.72; C, 34.58; H, 4.69.
EXAMPLE 64
-
3-Amino-4-[2-(5-dimethylaminomethyl)-2-furanyl-
methylthio]ethyl~amino-5-cyano-isothiazole-
l,l-dioxide
To a suspension of 3-amino-4-ethoxy-5-cyano-
isothiazole-l,l-dioxide (0.60 q, 0.0030 mol) in
acetonitrile (20 ml) there was added dropwise a
solution of 2-~5-(dimethylaminomethyl)furanyl-
thio]ethylamine (0064 g, 0.0030 mol) in acetonitrile
(3 ml) to give an orange solution. A ~reciPitate
formed within 30 minutes and the reaction was
completed within 120 minutes by TLC. The precipitate
was filtered off, washed with ether, and dried to
give 0.85 g (77~) of the title compound; mp
165.5-167.5(d) TLC (20~ methanol/chloroform,
silica): Rf=0.30.
EXAMPLE 65
3-N-[2-(5-Dimethylaminomethyl-2-furanylmethyl-
thio)ethyl]amino-4-amino-5-cyanoisothiazole-1,1-
dioxide 1/2CH3CN
-~
To a solution of 3,4-diethoxy-5-cyano-
isothiazole-1,1-dioxide (1.25 g, 0.0050 mol) in
acetonitrile (15 ml) cooled in an ice/methanol hath
there was added dropwise a solution of 2-[5-
43~;
- 80 - 16588IA
(dimethylaminomethyl)-furanylthio]ethylamine tl.07 q,
0.0050 mol) in acetonitrile (5 ml). The solution was
warmed to ambient temperature and stirred for ~0 min.
at which time no further reaction was noted by TLC.
Dry ammonia was then bubbled into the solution cooled
in an ice bath for 10 minutes. The solution was then
warmed to ambient temperature and stirred for 60
minutes. The solution was concentrated to dryness in
vacuo to give an orange glass which was triturated
with acetonitrile to give a solid. The mixture was
cooled in an ice bath and the solid filtered off to
give crude product, mp 137-139. The crude product
(1.48 g) was dissolved in methanol and concentrated
to dryness. The residue was tri-turated with
acetonitrile, filtered off, and dried to obtain 1.29
g of product; mp 142-143 ~d). TLC (20%
methanol/chloroform, silica): Rf=0.38.
Calc'd for Cl4Hl9N5o3~2.l/2cH3cN
N, 19.76; C, 46.14; H, 5.30.
Found: N, 19.78; C, 46.22; H, 5.32.
EXA~1PL~ 66
3-[2-[(5-Dimethylaminomethyl-2-furanyl)methylth;o]-
ethyl]amino-4~amino-5-methylsulfonylisothiazole-
1-oxide
To a solution of 2-[(5-dimethvlaminomethyl-2-
furanyl)methylthio]ethylamine (440 mg, 2 mmol) in
acetonitrile (6 ml) there was ad~ed 3-ethoxv-4-amino-
5-methylsulfonylisothiazole-1-oxide (480 mg, 2
mmol). This mixture was stirred under a nitrogen
atmosphere for 15 hours as product slowly crystal-
lized out. Precipitate was collected by filtration,
washed with acetonitrile, diethyl ether and air dried
to give 650 mg, of title compound, mp 134-137.
36
- 81 - 16588IA
EXAMPLE 67
3-[2-[(5-Dimethylaminomethyl-2-furanyl)methylthio]-
ethyl]amino-4-amino-5-methvlsulfonylisothiazole-1,1-
dioxide _ _ _
To a solution of 2-[(5-dimethylaminomethyl-2-
furanyl)methylthio]ethvlamine (0.66 a, 3.08 mmol) in
acetonitrile (5 ml) under a nitrogen atmosphere there
was added solid 3-ethoxy-4-amino-5-methvlsulfony~iso-
thiazole-l,l-dioxide (0.77 9, 3.01 mmol) to give an
immediate sol~tion and exothermic reaction. After
1/4 hour, the product began to crystallize and after
stirring for 15 hours, was collected by filtration
(102 g). The title compound was recrystallized bv
dissolving in hot methanol and diluting with several
volumes of ether (1.0 g), mp 187 189.
EXAtlPLE 68
3-Amino-4-[2-[(5-dimethylaminomethyl 2-furanyl)methyl-
thio]ethyl]amino-5-dimethylcarbamylisothiazole-1,1-
dioxide
Step A 3-amino-4-[2-[(5-dimethylaminomethvl-2-
furanyl)methylthio]ethylamino]-4-ethoxy-5 di
methylcarbamvl-4,5-dihydroisothiazole-1~1 di-
oxide
To a solution of 3-amino-4-ethoxy-5-dimethyl-
carbamylisothiazole-l,l-dioxide (0.62 g, 2.5 mmol) in
acetonitrile (6 ml) there was added dropwise a
solution of 2-[(5-dimethvlaminomethyl-2-fl1ran~!l)meth-
ylthio]ethylamine (0.55 g, 2.6 mmol) in acetonitrile
(5 ml). After stirring at ambient temperature for
16-20 hours, precipitated material was collected to
give 0.9 g of title compound, mp 143-144~
36
- 82 16588IA
Step B 3-Amino-4-~2-[(5-dimethyla~inomethyl-2-
furanyl)methylthio]ethyl]amino-5-dimethylcar-
bamvlisothiazole-l,l-dioxi~e
-
The compound from Step A was dissolved (n.
g, 1.9 mmol) in acetonitrile (20 ml) and methylene
chloride (10 ml) and silica qel added in portions
(4.0 g) until all of compound was adsorbed on silica
gel. Then, solvent was evaporated, coate~ silica gel
was packed on top of silica gel column, and the title
compound eluted with 7-8% methanol/chloroform to give
0.4 g of a qlassy solid.
_AMPLE 69
3-[2-[(5-Dimethylaminomethvl-2-furanyl)methylthio]-
ethyl]amino-4-amino-5-N,N-dlmethylcarbamoylisothiazole-
l,l-dioxide
~ .
Step A 3-[2-[(5-Dimethylaminomethyl-2-furanvl1meth-
ylthio]ethyl]amino-4-ethoxy-5-dimethylcar-
bamylisothiazole-l,1-dioxide
.
To a solution of ~0% pure 3,4-diethoxy-5-
dimethylcarbamylisothiazole-l,l-dioxide (1.7 q from
Example 10, Step C) in acetonitrile (7 ml) there was
added dropwise a solution of 2-[(5-dimethylamino-
methyl-2-furanyl)methylthio]ethylamine (0.81 g, 3.8
mmol) in acetonitrile (5 ml). After stirrina at
ambient temperature for 1-2 hours, sol~ent was
evaporated and the residue chromatographed on silica
gel, eluting with 4% methanol/chloroform, to oive lo~
g of purified oily title compound.
i2~ 6
- 83 - 16588IA
Step B 3-[2-~(5-Dimethylaminomethyl-2-furanvl)meth-
ylthio]ethyl]amino-4-amino-5-dimethylcar-
bamylisothiazole-l,l-dioxide
Into a solution of 3-~2-[(5-dimethylamino-
methyl-2-furanyl)methylthio]ethyl]amino-4-ethoxy-5-
dimethylcarbamylisothiazole~ dioxide (1.4 q, 3.2
mmol) in acetonitrile (12 ml) warmed at 65C, ammonia
gas was slowly bubbled over a 1-2 hour Perio~.
Solvent was evaporated, residue chromatographed on
silica gel eluting with 3-5% methanol/chloroform to
give 0.96 g of title compound which could be
crystallized from nitromethane/ether, mp 101-104.
EXAMPLE 70
3-[2-[5-Dimethylaminomethyl)-2-furanylmethylthiolethyl]
amino-4-amino-5-ethoxycarbonylisothiazole-1-oxi~e
3-Ethoxy-4-amino-5-ethox~carhonylisothiazole-
l-oxide ~0.5 g, 2.15 mmol) was stirred in 3 ml of dry
acetonitrile under nitrogen atmosPhere and 2-[5-(di-
methylaminomethyl)furanylmethylthio]ethylamine t0.46g, 2.15 mmol) in 2 ml of dry acetonitrile was added
dropwise over five minutes. Stirring was continued
at ambient temperature overnight. The product
precipitated to give 0.8 g of the title compound as a
white solid, mp 88-94.
EXAMPLE 71
3-[2-[(5-Dimethylaminomethyl-2-furanylmethylthiOlethVll
amino-4-amino-5-carbamoylisothiazole-1-oxide0 Step A 3-Ethoxy-4-bromo-5-(trimethylsilyloxycarbonyl)
isothiazole-l-oxide
3 Ethoxy-4-bromo-5-carboxyisothiazole-1-oxide
(4.02 g, 0.015 mol) was silylated with trimethyl-
436
- 84 - 1658~IA
chlorosilane in 10% excess ~1.79 q, 0.01~5 mol! in an
anhydrous inert solvent (dry acetonitrile) using the
standard literature silylation ~rocedure. Solvent
and excess reagent were removed in vacuo and the
crude silyl ester was used ~tithout further
purification.
Step B 3- E2- [5-(Dimethylaminomethyl)-2-furanyl-
methylthio]ethyl]amino-4-amino-5-carboxyiso-
thiazole-l-oxide
3-Ethoxv-4-bromo-5-(trimethylsilyloxycarbonyl)
isothiazole-l-oxide (0.68 g, 2.0 mmol) was dissolved
in 3 ml of dry acetonitrile and aminateA by the
careful addition of anhydrous ammonia in acetonitrile
added at ice bath temperature. When no more starting
material remained ~by TLC), an equivalent of 2-~5-(di-
methylaminomethyl-2-furanylmethylthio]ethylamine
(0.43 g, 2.0 mmol) was aAded dropwise and the
reaction mixture stirred under nitrogen atmosphere
for 24 hours. The solvent was then rem~veA ln vacuo
and the residue heated at reflux in 10 ml of methanol
for ten minutes. Removal of the solvent in vacuo
gave the crude title compound which was purifieA hy
crystallization.5
3-[2-[5-(Dimethylaminomethyl)-2-furanYlmethyl-
thio]ethylamino]-4-amino-5-carbamoylisothia-
zole-l-oxide
The Woodward's ester of 3-[2-[5-(dirnethyl-
aminomethyl)-2-furanylinethylthio]ethyl]amino-4-amino-
5-carboxyisothiazole-1-oxide was prepared frorn the
carboxylic acid (0.37 g, 1.0 mmol) by reaction with
N-t-butyl-5-methylisoxazolium perchlorate (0.24 q,
`` .~2~436
- 85 - 16588IA
1.0 mmol) in 3 ml of dry DMF using literature
methodology. Reaction ~ the "active ester" with
excess anhydrous ammonia in absolute ethanol gave the
amide title compound.
EXAMPLE 72
3-[2-[5-(Dimethylaminomethyl)-2-furanylmethylthio]-
ethyl]amino-4-amino-5-carbamoylisothiazole-1,1-dioxide
Step A 3-Ethoxy-4-bromo-5-carboxyisothiazole-1,1-
dioxide
3-Ethoxy-4-bromo-5-carbamovlisothiazole-1,1-
dioxide (283 mg, 1.0 mmol) was dissolved in 2 ml of
trifluoroacetic acid and sodium nitrite (138 mg, 2.0
mmol) was added in small portions over a two minute
period with stirring. Stirring was continued for two
minutes at room temerature and then the solvent was
removed in vacuo. The residual gum was stirred in
ice water and the solid title compound was quickly
filtered and dried _ vacuo.
Step B 3-Ethoxy-4-bromo-5-(trimethylsilyloxycarbonvl)
isothiazole-l,l-dioxide
3-Ethoxy-4-bromo-5-carboxyisothiazole-1,1-
dioxide (5.68 q, 0.02 mol) was silylated in aceto-
nitrile using the procedure described for the
preparation of the l-oxide analog in Example 71.
Standard work up gave the title compound.
Step C 3-[2-[5-(Dimethylaminomethyl)-2-~uranylmethyl-
thio]ethyl]amino-4-amino-5-carboxyisothiazole-
l,l-dioxide
3-Ethoxy-4-bromo-5-(trimethylsilyloxvcarbonyl)
isothiazole-l,l-dioxide (0.89 g, 2.5 mmol) was
3~
- 86 - 16588IA
aminated in 5 ml o dry acetonitrile accordinq to the
procedure used for the l-oxide analog in Example 71.
Addition of an equivalent of 2-[5-(dimethylamino-
methyl-2-furanylmethylthio]ethylamine (0.54 g, 2.0
S mmol) ~ollowed by hydrolysis of the silyl ester as in
Example 71 qave the title compound. Purification was
accomplished by chromatography on silica gel.
Step D 3-[2-[5-(Dimethylaminomethyl)-2-furanvlmethyl-
thio]ethyl]amino-4-amino-5-carbamoylisothia-
zole-l,l-dioxide
The ~oodward's ester of 3-[2-[5-(dimethyl-
aminomethyl)-2-furanylmethylthio]ethyl]amino-4-amino-5-
carboxyisothiazole-l,l-dioxide was Prepared from the
carboxylic acid (0.39 g, 1.0 mmol) by reaction with
N-t-butyl-5-methylisoxazolium perchlorate to (0.24 q,
1.0 mmol) as in Example 71 for the l-oxide analoq.
Conversion of the "active ester" to the carboxamide
was accomplished with excess ammonia as in Example 71.
EXAMPLE 73
3-Amino-4-[2-[5-(dimethylaminomethyl)-2-furanylmethyl-
thio]ethyl]amino-5-carbamoylisothiazole-1,1-dioxide
Step ~ 3-Ethoxy-4-phenoxy-5-carbamoylisothiazole-
l,l-dioxide
A solution of 3-ethoxv-4-bromo-5-carbamoyl-
isothiazole-l,l-dioxide (283 mg, 1.0 mmol) in 15 ml
of dry T~F was cooled in ice and stirred as thallous
phenoxide (279 mg, 1.0 mmol) was added in small
portions over ten minutes. The mixture was stirred
for 1-1/2 hours at ambient temPerature. The
resulting suspension was cooled in ice and filtered.
The solid was purified by chromatography on silica
1~ 3~;
- 87 - 16588IA
gel followed by recrystallization from chlorofrom.
The pure white solid melts at 1~3-186C.
Step B 3-Amino-4[2-[5-(dimethylaminomethyl)-2-
furanylmethylthio]ethyl]amino-5-carbamoyliso-
thiazole-l,l-dioxide __ ___
3-Ethoxv-4-phenoxy-5-carbamoylisothiazole-
l,l-dioxide (0.46 g, 1.5S mmol) in 5 ml of THF was
stirred at ice bath temperature while N-trimethyl-
silyl 2-[5-(dimethylaminomethyl)-2-furanylmethylthio]-
ethylamine (0.44 9, 1.55 mmol) in 2 ml of THF was
added dropwise over 20 minutes. After an additional
10 minutes, the solution was concentrated to dryness
in vacuo. The residual solid was taken up in 10 ml
of T~F and 10 ml of chloroform and ~as saturated with
anhydrous ammonia. This mixture was stirred at
ambient temperature for 1-1/2 hours then the solvent
was removed in vacuo. The crude yellow solid was
purified by chromatography on silica gel and
recrystalliæed from acetonitrile. The yellow solid
melts at 128-130C.
EXAMPLE 74
-
3-N-[2-[5-(Dimethylaminomethyl)-2-furanylmethylthio]-
ethyl]amino-4-amino-5-benzyloxycarbonylisothiazole-1,1-
dioxide
.
Step A 3-Ethoxy-4-bromoisothiazole-5-carboxylic
acid potassium salt
-
To a solution of 3-ethoxy-4-bromoisothiazole-
30 5-carboxylic acid (2.02 g, 0.0080 mol) in methanol (8
ml~ there l~as added a solution of potassium hydroxide
(0.45 g, 0.0080 mol) in methanol (8 ml). The
resulting solution was stirred at amhient temperature
- 88 - 16588IA
for 10 minutes and concentrated to dryness in vacuo
The residue was dried (60, 0.1 mm) to give
4-bromo-3-ethoxyisothiazole-5-carboxylic acid
potassium salt (2.24 g, 97%, mp 265-268 (d)).
Step B 3-Ethoxy-4-bromo-5-benzyloxycarbonvliso-
thiazole
To a suspension of 3-ethoxy-4-bromoisothia-
zole-5-carboxylic acid potassium salt (2.32 g, 0.0080
mol) in dry DMF (~3 ml) there was added benzyl
bromide (1.10 ml, 0.0093 mol). All solids ~issolved
and a fine precipitate formedD After 90 minutes, the
mixture was filtered and the filtrate poure~ into
ice-water (40 ml). The mixture was extracted with
ether (2x50 ml). The combined ether extracts were
washed with saturated soæium bicarbonate solution (15
ml), dried over sodium sulfate, and filtered. Hexane
(100 ml) was added to the filtrate causing crystalli-
zation of the product. The mixture was cooled to 5
and the crystals filtered off and dried to qive the
product (2.06 g, 75%, mp 48-49.5~. TLC (2% methanol/
chloroform, silica): Rf=0.90.
13 12 NO3S: N, 4.09; C, 5.62;
H, 3.53.
Found: N, 3.92, C, 45.44; H, 3.51.
Step C 3-Ethoxv-4-bromo-5-benzyloxycarhonvl-
isothiazole-l,l-dioxide
To cold methylene chloride (15 ml) there was
added 90% hydrogen peroxide (0.51 g, 0.0134 mol). To
the resulting suspension, cooled in an ice-bath, was
added, dropwise with stirring, trifluoroacetic
anhydride (2.07 ml, 0.0147 mol) at 7-10 over 20
- 89 - 16588IA
minutes. The resulting solution was warmed to 15,
stirred for 15 minutes, and then cooled in an
ice-bath. The solution of 3-ethoxy-4-bromoisothia-
zole-5-carboxylic benzyl ester (2.02 g, 0.0059 mol)
in methylene chloride (6 ml) was added dropwise at
3-6 over 20 minutes. The solution was stirred at
10-15 for 2 hours and then at ambient temperature
for 6 hours. The solution was concentrated ln vacuo
at ambient temperature to a small volume (5 ml) and
chromatographed on a column of E. Merck silica geL hO
eluted with chloroform. A white solid (1.95 g) w~s
obtained which was recrystallized from n-butyl-
chloride/hexane (1:1) to give the product (1.80 q,
81~, mp 123-124). TLC (chlorofrom, silica):
Rf=0.71.
Calc'd for C13H12BrNO5S: N, 3.74; C, 41.72,
H, 3.23.
Found: N, 3.72; C, 41.90; H, 3.170
Step D 3-Ethoxy-4-amino-5-benzyloxycarbonylisothia-
zole-l,l-dioxide
To a suspension of 3-ethoxy-4-bromo-5-
benzyloxycarbonylisothiazole-l,l-dioxide (1.50 9,
0.0040 mol) in acetonitrile (6 ml) there was added
hexamethyldisilazane (O.91 ml, 0.0043 mol). The
mixture was heated at 70 for 3.5 hours. Additional
hexamethyldisilazane (0.21 ml, O.O010 mol) was added
and the solution stirred at 70 for 1.5 hours. The
mixture was then concentrated to dryness ln vacuo and
the residue dissolved in ethanol (50 ml) and stirred
for 15 minutes. The solution was concentrated to
dryness in vacuo and the residue recrystallized from
ethanol to give the title product (0.95 g, 77%r mp
149-151).
3~i
- 90 - 16588IA
The mother liquors were concentrated to
dryness and the residue placed in acetonit~ile (3
ml). HexamethylAisilazane (0.21 ml, 0.0010 mol) was
added and the solution heated at 70 for 1.5 hours.
After concentration, treatment with ethanol, and
recrystallization as described above, a second crop
of product was obtained (0.11 g, 9%, mp 144-147).
TLC (5% methanol/chloroform, silica): Rf=0.78.
c 13 14 2OsS N~ 9-03, C, 50.31;
H, 4.55.
Found: N, 9.14, C, 50.45; H, 4.60
Step E 3-N-[2-[5-(Dimethylaminomethyl)-2-furanyl-
methylthio]ethyl]amino-4-amino-5-benzyloxy-
carbonylisothiazole-l,l-dioxide ethanolate
To a suspension of 3-ethoxy-4-amino-5-benzyl-
oxycarbonylisothiazole-l,l-dioxide (0.43 g, 0.0020
mol) in ethanol (10 ml) there was added a solution of
2-(5-dimethylaminomethyl-2-furanylmethylthio)ethyl-
amine (0.62 9, 0.0020 mol) in ethanol (2 ml). All
solids dissolved within 10 minutes and precipita~ion
of a pink solid began after 30 minutes. After 1
hour, the mixture was cooled and the precipitate
(0.96 g) filtered off. After three
recrystalliæations from ethanol, the title product
was obtained (0.69 9, 66~, mp 82-91). TLC (10%
methanol/chloroform, silica): Rf=0.30.
Calc'd for C21H26H~O5S2C2 5
N, 10.68; C, 52.65; H, 6.18~
Found: N, 10.69; C, 52.51; H, 6.12.
- 91 - 16588IA
EXAMPLE 75
3-[3-[3-(1-Piperidinylmethyl)phenoxylpropylamino]-4-
amino-5-carboxyisothiazole~ dioxide
A mixture of 3-ethoxy-4-amino-5-t-butyloxy-
carhonvlisothia~ole-l,l-dioxide (276 mq, 1.0 mmol)
and 3-[3-(1-piperi~inylmethyl)phenoxylprop~lam;ne
(273 mg, 1.1 mmol) can be heated to about 150C for
several hours under a nitroqen atmosphere with
stirring using an oil bath~ The residue can then be
wa~shed bv trituration wit~ petroleum ether and ~xane
several times followed bv recrystallization of the
product.
EXAMPLE 7 6
3-N- [2-~(4-Methvl-5-imidazolyl)methvlthiolethyllam;no-
4-amin~-5-ethnxycarbonylisothiazole-1,1-d i OY; ~e
Th~ title comp~1lnd was obtalne~ from
equimolar amounts of the compound of Exam~le 5 and 2-
[(4-methyl-5-imidazolyl)methvlthio~ethvlamine
according to the procedure of Example 39. The
analytically pure material was isolateA as a hvdrate,
mp 116-119 dec.
EXAMPLE 77
3-N-~2-[5-(Dimethylaminomethyl)-2-furanylmethylthio]
ethyl~amino-4-amino-~-t-butyloxycarbony]isothiazole-
l,l-dioxide
The title compound, a yellow solid, mp
126-129 ~ec., was obtained hv the ~rocedure of
Example 39 using the compound of Example 23 in place
of the comp~und of Exam~le 5.
