Note: Descriptions are shown in the official language in which they were submitted.
STYR~L ~ IDI~ES
Background of the Invention
- This invention is broadly concerned with amldines having drug
and bio-affecting prop~rties. More particularly, the invention relates to -~styryla~idines and to sty.ylsulfonylamidine intermediates therefor. The
~tyrylamidines inhibit aggregation of blood platelets and also possess
~nalgesic activity. Apart from being precursors to the styrylamidines,
the styrylsul~onyla~idines of the inven~ion have analgesic ac~iv~ty.
With respec~ to ?rior art amidines, the styrylsulfonylamidines
~nd the styryla~idines of this invention are distinct and ncvel. The
following publications are cited by way of illustrating the closes~
prior art known to the inven~ors.
A. ~Iarxer, HPlvetica Chlmlca Acta, 55, 430 (1972) describes
a new synthesi6 of benæamidlnes substituted at tl~e imlde nltrogen by
~ .
.
. .
a 1,2-diphenyl-vinyl group. None of the amidines of the instant
invention whlch have a styryl or styrylsulfonyl radical at that
position are described.
B. G. Advani, et al., Tetrahedron Letters No. 56, 5825-5828
(1968) describes N-~-styrylamidines having pyrrolidino or morpholino
groups in place of the NH2 moiety of the amidino group whereas the
amidines of the present invention do not.
K. Hasegawa and S. Hirooka, Bulletin Chemical Society of
Japan, 45, 1893-1896 (1972~ disclose S-methylthioureas containing
phenylethene~l-sulfonyl substituents useful in the synthesis of
1,2,4-thiadiazine-1,1-dioxides. The styrylsulfonylamidines and
styrylamidines of the instant invention are not disclosed and are
structurally unrelated in that they are classified as amidines
rather than "S-methylthioureas".
French Patent 2,036,528 teaches that certain "ethene-
sulfonamides" are useful as intermediates in the preparation of
dioxothiadiazines. "Ethenesulfonamides" wherein the amidino nitrogen
is part of a nitrogen heterocycle are specifically disclosed.
Summary of the Invention
This invention is concerned with a group of styrylamidines
and the preparation thereof, which styrylamidines produce an analgesic
and an~ithrombogenic effect when administered. More particularly,
the invention pertains to the preparation of styrylamidines of
Formula I and non-toxic pharmzceutically acceptable acid addition
salts ~hereof.
Rl 3
CH=CH-N-C-A (I)
NH
.
' ' ' ' : . . .
The substances represcnted by Formul~ T are novel eomposltions of
matter and are effective as central nervous system analgesics and a5
inhibitors of blood platelet aggregation in mammals.
In the above formula, the symbols "Rl, R2, ~ and A" have the
followirlg meanings:
Rl represents a member of the group consisting of hydrogen, nitro,
amino, halogen, cyclohexyl, carbamoyl, lower alkylsulfonyl ~rom 1 to ~ carbon
atoms inclusive, sulfamoyl, and lower alkanoylamido of from 2 to 4 carbon
atoms inclusive. R2 represents hydrogen or halogen and R3 represents hydroge
or lower alkyl having 1 to 4 carbon atoms.
The symbol "A" represents a member of the group consisting of lower
alkyl of from 1 to 3 carbon atoms inclusive, di(lower)alkylaminophenyl,
phenyl, benzyl, ~-naphthyl, styryl, phenylbutadienyl, or a (X) -phenyl radical
which is represented by the symbol (X) ~ wherein X signifies
a member of the group consisting of ~owe~ alkoxy from 1 to 4 atoms inclusive,
halogen, nitro, amino, lower alkanoylamido of from 2 to 4 carbon atoms
inclusive, and n signifies an integer of 1 or 2.
It is to be understood that by employment of the terms "lower
alkyl", "lower alkoxy" and "lower alkanoylamido" herein, it is meant that the
carbon chains of each group include both straight and branched carbon
radicals of the designated number of carbon atoms. Exemplary of carbon chain
radicals containing 1 to 4 carbon atoms are methyl, ethyl, propyl, isopropyl,
l-butyl, l-methylpropyl, 2-methylpropyl, and _ert.-butyl. The term "lower
alkanoylamido of from ~ to 4 carbon atoms inclusive" comprehends both
straight and branched chain carbon radicals whereln the total number of
carbon atoms includes the carbonyl divalent radicaL. By the term "halogen"
as used herein, it is meant to connote all members of that group, i.e.,
chlorine, bromine, fluorine, and iodine.
,r~ . -- 3 --
33
.~
~dJ~
Those skilled in the art will recognize that the sub~ect
styrylamidines of Formula I and their salts wherein R3 is hydrogen
can exist in more than one tautomeric modification as depicted by
Formulas II and III wherein Rl, R2 and A have the meaning previously
defined.
Rl R
~CH=CH-N=C-A = ~ CH=CH-N-C-A
k~:J 2
R2 R2
(II) (III)
~ithout being bound by any theory9 it is believed that the protonated
styrylamidines of the present in~entlon, as is the case with the acid
addition salts, are best represented by a delocalized double bond
illustrated by Formula IV
Rl ~ R,3
2 C~C -N = C - A (1~)
ln Wherein X symbolizes an anion rather than fixed double bonds shown
in the foregoing tautomeric forms.
It will also be recognized that compounds of Formula I
exist as cis or trans geometrical isomers as the result of different
arrangements of groups around the ethylenic double bond. According
to nuclear ~agnetic resonance studies, the compounds of Formula I
are belived to have the trans~configuration on the basis of vinyl
proton coupling constants.
The compounds of this invention characterized by Pormula I are
obtained by a method which comprises tr~ating a styrylsulfonylamidine o~
Formula
Rl
5~ CH=CHS02-N=C-A (V)
2 NHR3
wherein Rl, R2, R3 and A are as herein defined with at least one molecular
proportion of sodium hydroxide in a reaction-inert solvent whereby S02 is
eliminated and thereafter ~rom the styrylsulfonylamidine of Formula (V)~and
if desired, reacting the resulting product in free base form with an acid to
form an acid addition salt thereof.
An alternate method of providing compounds of Formula I wherein R2
is amino involves reducing the corresponding nitro substituted styrylamidine.
Reduction of nitrostyrylamidines of Formula I to the corresponding amino
compounds is accomplished by selective reduction with sodium borohydride in
the presence of 10% palladium-on-carbon catalyst according to the method of
T. Neilson, et al., J. Chem. Soc., 371, (1962). ~
Compounds of Formula I containing lower alkanoylamido radicals can
also be obtained by acylating the corresponding amino substituted
styrylamidine with a lower alkanoyl halide or anhydride.
By reaction-inert solvent is meant a solvent wherein the
reactants are soluble and does not interfere with their interaction.
In this respect, acetone and dimethylsulfoxide are particularly
preferred. When acetone is selected as the reaction solvent, 2 to lO
moles of base per mole of styrylsulfonylamtdine is preferably employed
with a reaction perlod of from about 1 to 3 hr. at a temperaLure oE
-`~0
,.: :. ' ` ' '
~.~7~
abo-lt 25C. ~hen dimeehylsulfoxlde is selected as ~he reaction
~olvent, an equi-molar r~tio of ba~e to the styrylsulfonylamidine
18 employed with a longer reaction period of from 24 to prPferably
64 hours. Styrylsulfonylamldines containing electron withdrawing R,
or R~ substituen~s provide higher yields of the correspondlng
6tyrylamidine product compared to yields of styrylsulfonylamidines
wherein R~ and R~ are hydrogen.
The compounds characterized by Formula I ha~e basic properties
and are converted to corresponding non-toxic pharmaceutically acceptable
acid addition salts by admixture of the base with a selected acid in
an inert organic solvent such as ethanol, ben2ene, ethyl acetate, ether,
hslogenated hydrocarbons (e.g.~ dlchloroethane), and the like. A
preferred method of salt preparation is to ~reat the base with substantially
one chemical equivalent of an acid such as hydrogen chloride or isathionic
acid in ethanol solutlon. The salt is isolated from the ethanolic solution
~y chilling or the addition of an appropriate co-solvent such as ether.
Both ~ha free base and salt forms of the products of Formula I are
useul for the purpose of the invention although salts are par~icularly
preferred becau~e of thnir increased watEr solubility. It is to be
understood that the term "pharmaceutically acceptable acid ~ddition
salts" as used herein is construed to mean a combination of the compounds
of the present invention with a relatively non-toxic inorganic or organic
acid, the anion of which is pharmaceutically ineffective in the usual
do6sge. Some exam~le~ of inorganic or organic acids which may be
employed to providc a non-toxlc pharmaceutically acceptable acid addition
~alt of the compounds of Formula I are: ~ulfuric, pho~phoric, hydrochloric,
hydrobromic, hydrolodic, sulfamic, acetic, lactic, maleic, 6uccinic~
malic, fumaric, tartarlc, citric, gluconic, glutaric, ascorbic, ben20ic,
cinnamic, i~ethionic, and r~lated acids.
~ .
!
The ~tyrylsulforylamidine pxecuraors of the compou~ds of the
pres~nt invention char2cterlzed by For~ula I are obtained by reactin~ a
~tyrylsulfonyl chloride of the formula
R ~ CH=CHS02Cl (VI)
R~
wherein R~ and Rl are as herein defined but excluding amino with an
amidine of the formula
NH
H2N-C-A (VII)
~herein A is as herein defined ~o yield the new styrylsulfonylamidines
illustrated by general Formula V.
An alternate procedure for preparin~ styrylsulfonylamidines of
Formula V comprises reacting a N-styrylsulfonylimldoyl chloride of For~ula VIII
R~ Cl
~CH=CHSO ~N=C-A (VIII)
R~
with an R3NH2 amine wherein Rl, R2, R3, and A are as he.ein defined.
Styrene inte mediates employed in the preparation of styryl-
sulfonyl chlorid~ of Formula VI are obtalned from the corresponding
benzaldehydes by thP procedure of L. A. 8roo~s~ J. ~er. Chem. Soc.,
66, 1295 (1944). Conversion of the styrene intermediates to styryl-
sulfonyl chlorldes i9 carried out by the method of F. G. Bordwell, et al.,J. Amer. Che~. Soc., 6&, 139, 177~ (1946).
Illustrative of styrylsulfonyl chlorides of Formula VI
wh~ch are useful in the preparation o~ the styrylsulEonylamidine
precursors of Formula V of the present inven~ion are:
8tyryl~ulfonyl chloride,
4-chlorostyrylsulfonyl chlorlde,
3,4-dlchlorostyryl~ulfonyl chloride,
2-nitrostyrylsulfonyl chloride,
4-nitro 8 tyryl~ulfonyl chlorid~,
~ .
~ 3~'~
4-carbamoylstyrylsulfonyl chloride,
4-sulfamoylstyrylsulfonyl ehloride,
4-(methanesulfonyl)styrylsulfonyl chlorlde,
4 cyclohexylstyrylsulfonyl chloride,
3-bromo-4-cyclohexylstyryl~ulfonyl chlorlde,
4-acetamidostyrylsulfonyl chloride,
2-fluorostyrylsulfonyl chloride,
2,5-dichlo.ostyrylsulfonyl chloride,
4-(2-methylpropionamido~styrylsulfonyl chloride,
2,6-dichlorostyrylsulfonyl chloride.
The amldine intermediates of Formula VII are generally known
compounds which are available rom co~erciel sources or are conveniently
prepared accurding to the methods of L. Weintraub, et al., J. Org. Chem.,
339 1679 (1968) and P. O~l~y, et al. J. Chem. Soc., 147 (1945), 303 (1948).
Illustrative of ~uitable amidine intermedlates of Formula VXI
which reacted with ~he styrylsulfor.yl chlorides of Formula VI provide
styrylsulfonylamidines of Formula V are~
4-nitrobenzamidine,
acstamidine,
; 20 benzamidine,
' . phenylacetamidiIIe~
4-nitrobenzamidine,
3~nitrobenzamidine,
4 aminobenzamidine,
3-am~nobenzamidine,
2-ni~robenzamidine,
2-sminobenzamldine,
4-dimethylamirobenzamidlne,
j;7~
cinna~amidine,
beta-naphthamidine,
4-chlorobenzamidine,
3-acetamldobenza~idine~
3,4-dichlorobenzamidine,
4-styrylbenzamidine,
4-phenylbut.adienylbenzamidine,
4-(dibutylamino)benzamidine,
2-methylpropionamidine.
The compounds of this invent$on cha~acterized by Formula I
are therapeutically actlve substances whicn possess antithrombogenic
snd analgesic actlvities when present in an effective amount in the
mam~alian circulatory system.
Measurement o~ the antithrombogenic activity of the compounds
of Formula I is carried out by standard pharmacological tssts essentially
described by Born, Nature, 194, 927 (1962) and O'Brien, J. Clin. Path.,
15, 446 (1~62). This test comprises a nephelometric method in which
the change ln turbidity of a specimen of platelet rich plasma (human
or ra~bit) is meas~red on causation of platelet aggregation by addiLion
of a thrombogeni& inducing agent such a~ adenosine cliphosphate or
collagen. The compounds of the present invention are effective
ahtithrom~ogenic agent~ according to this test at concentrations in
the order of about 0.5 to 90 mcg.t3~5 ml. platelet rich plasmaO In
the ~ntact animal, the antithrombogenic effect is readily observed
2S by applying the above test to blood samples withdrawn p~i¢r to and
Qfeer adminiPtration of a compound of the present invention. While
compounds of Formula I generally exhiblt significant antithrombogenic
activity, compounds ~thlch reduce ~he thrombo~enic capacity o collagen
or adenosine diphosphate lnduced platelet aggregation by 50~ or more
at concentrations of less than 15 mcg./0.5 ml. of platelet rich plasma
are preferred and by way of example there can be mentioned:
N-styrylbenzamidine hydrochloride,
N-(3,4-dichlorostyryl)acetamidine hydrochloride,
3,5-diamino-N-(4-nitrostyryl)benzamidine trihydrochloride,
;~ 4-amino-N-(4-nitros~yryl~benzamidine hydrochloride,
4-(dimethylamino)-N-(4-nitrostyryl)benzamidine isethionate,
N-(4-aminos~yryl~benzamidine dihydrochloride,
~-(2-aminostyryl)benzamidine dihydrochloride,
4-amino-N-(4-aminostyryl)benzamidine trihydrochloride,
3-amino-N-(4-aminostyryl)benzamidine trihydrochloride,
N-~4-acetamidos~yryl)benzamidine hydrochloride,
N-(3-bromo-4-cyclohexylstyryl)acetamidine hydrochloride.
A particularly preferred group of styrylamidines of Formula I
comprises styrylbenzamidines wherein Rl and R2 are hydrophilic sub-
stituents such as sulfamoyl, carbamoyl, amino, and the like~ and the
X substituent is a radical whose electrons are capable of being
delocalized such as dialkylamino, amino, nitro, styryl, phenylbuta-
dienyl, and the like.
Another preferred group of styrylamidines of Formula I com-
prises styrylalkylamidines wherein Rl and R2 are lipophilic sub-
stituents such as alkyl, cycloalkyl, halogen, and the like.
A still further preferred group of compounds comprises
Formula I styrylamidines whereln A is methyl, R2 and Rl are halogen
and R3 is hydrogen.
Apart from the antithrombogenic activity, the compounds of
the present invention of Formula I have central nervous system analgesic
activity as demonstrated by preve~tion of the phenylquinone writhing
syndrome in mice. In this test, groups o~ 10-20 mlce are in~ected
-- 10 --
~L~7~
subcutaneously or orally with different doses of the test compound.
At predetermlned time intervals, the mice receive 2.5 mg./kg. phenylquinone
intraperltoneally. The total number of wr~thlng episode6 is counted
for each mou6e for 10 min. and the average percent decrease in writhing
recorded for each dose.
The novel styrylsulfonylamidines of Formula V in addition to
being useful as precursors to the styrylamidine products of Formula IV
have analgesic utility as measured in the foregoing phenylquinone
writhing test. A preferred class of styrylsulfonylamidines of Formula V
having particularly significant analgesic activity are those wherein
R, and R2 are each hydrogan, nitro ~r halogen ~nd A is phenyl or
lower alkyl of from 1 to 3 carbon atoms inclusive. Analgesic activity
at the time interval indicated following administra~ion of compounds
representative or this clas~ are given in Table I below.
~ABLE I.
ANALGESIC ACTIVITY OF STYRY~SULFONYL-
AMIDINES
Percent Inhibition
Subcutaneous Oral Tlme
70 Name ~6 mg./kg.~ ~100 mg./kg.) Interval
- N-(styryl~sulfonyl)acetamidine 38 __ 15 min.
~-(4-nitrostyrylsulfonyl)- 36 __ 60 min.
acetamidine
N-C(3,4-dlchlorostyryl)sulfonyl]- 28 ~~ 30 min.
acetamidine
N-~(3,4-dichlorostyryl)sulfonyl]- -- 36 120 m~nO
acet~midine
N-(styrylsulfonyl)benzamldine 36 ~_ 30 min.
N-(styrylsulfonyl)benz~midine -- 26 60 min.
:
-- 11 --
According to the present invention, the antithrombogenic
process is carried out in mammals by systemic administration of a
non-toxic effective dose of the styrylamidines of Formula I ranging
from about 0.01 to lO mg./kg. of body weight of a mammal. By
systemic administration it is intended to include both oral and
parentaral routes. Examples of parenteral administration are
intramuscular, intravenous, intraperitoneal and subcutaneous. As
would be expected, the dosage will vary with the form of administratlon
and par~icular compound chosen.
It is to be understood that the term "non-toxic effective
dose" as used herein refers to quantity of active in8redient necessary
to produce the desired therapeu~ic effect without causing any harmful
or deleterious side effects.
The styrylamidines of Formula I can be formulated according
to conventional pharmaceutical practice to provide pharmaceutical
co~positions of unit dosage form which may include solid preparat~ons
suitable for oral administration such as tablets, capsules, powders,
granules, emulsions~ suspensions, and the like. The solid
preparation may comprise an inorganic carrier, e.g., talc, or an
organic carrier such as lactose or starch. Additives such as magnesium
stearate ta lubricant) can also be includPd. Liquid preparations
suitable for parenteral administration include solutions, suspensions
or emulsions of the compounds of Formula I in combination with the
usual diluent such as water, petroleum jelly, and the like; a
suspension media such as polyoxyethyleneglycol, vegetable oils and the
like. The compositions may also contain other additional ingredients
such as absorbing agents, stabilizing agents, and buffers.
- 12 -
The compounds which constitute this ln~ention and ~heir
methods of prep2ration ~ill appear more fully from a consider~-~ion of
the following exampleq and append~d claims ~7hich are giYen for the
purpose of illustration only and are not to be construed as limiting
~he inven~ion in splrit or in scope.
In regard to "N~R" da~a give~ belo~, chemic~l shift del~a
values are in parts per million and the following multiplicity notations
employed: s~singlet, d=doublet, t=triplet, m-multiplet (center listed),
bs=broad singlet, bd=broadened doublet (one J value listed), bm=very broad
lines (either a multiplet or more than one singlet). Sol-~ent and internal
referenc~ peak are also identified: TMS=te~ramethylsilane, DSS=3-(trimethyl-
silyl)-l-propanesulfonic acid sodium salt.
Example 1.- N-(Styrylsulfonyl)berlzamidine (4.3 g. 9 0.015 mole)
ls added portion-wise to a stirred mixture of 50% sodium hydroxide
(1.2 g., 0.015 mole) in 25 ml. of dimethylsulfo~ide. After ~tirring the
mixture for 64 hr., at 25C., the mixture is poured into 250 ml. of
cold water and made strongly basic with 5% sodium hydroxide. The basified
solution is ex~racted several times with ether, the ethereal extracts
comblned, washed ~l.h water, dried over pota~sium carbona~e, and
concentrated to provide the N-styrylben2amidine free base as a yello
olly residue. The free base oil is taken up in ethanol, acidifled
- with ethanolic hydrogen chloride and the hydrochloride salt isolated
by dllution with ether. Trituration of the salt with acPtone affords
0.25 g. (6.5% yield) of N-STYRYL~ENZAMIDINE HYDROCHLORIDE, m.p.
226.5-228.0C. (corr.).
Analysis. Calcd. for C~5Hl4N2~HCl (percent): C, 69.60;
H, 5.84; N, 10.82, Found (percent): C, 69.34 ~1~ 5.80; N, 10.79.
NMR (D~SO~da~ T~S): 6.95d (14.0 }I~), 7.10m, 8.25bd (14.0 H~),
10.33bs, 12.03bs.
,
-- 13
,
.
Example ~.- N-(S-tyrylsulfonyl)acetamidine is treated
with sodium hydroxide according -to the procedure of Example 1.
Isolation of the styrylamidine product is carried out by r-
quenching the reaction mixture in water, acidifying -~he aqueous
mixture with 3N hydrochloric acid and filtering. The filtrate
is made basic with sodium hydroxide and extracted w1th
chloroform. Concentration of the chloroform extract provides
the N-(styryl)acetamidine free base as a gum. The free base is
converted to the hydrochloride in acetone with ethanolic
hydrogen chloride. Acetone trituration of the crude
hydrochloride and crystallization from isopropyl alcohol affords
a 3% analytical yield of N-(STYRYL)ACETAMIDINE HYDROCHLORIDE
having a capillary melting point of 167.0 - 183.0C. when '
inserted in bath at 95C.
Analysis. Calcd. for CloHl2N~-HCl (percent): C,
61.05; H, 6.66; N, 14.24. Found (percent): C, 61.16; H, 6.76;
N, 14.20
NMR (DMSO-d6, TMS): 2.33s, 6.65d (14~0 Hz), 7.~8m,
8.00bd (14.0 H2), 9.~7bs, 11~88bs.
~0 Example 3.- N-(4-chlorostyrylsulfonyl)acetamidine
treated with sodium hydroxide according to the procedure of
Example 1 provides a 12% analytical yield of N-(4-CHLOROSTYRYL)
ACETAMIDINE HYDROCHLORIDE, m.p. ~28 - 234.5C. (corr.), from
methanol-isopropyl ether.
Ana~ysis. Calcd. for CloHl1ClN2-HCl (percent): C,
51.96; H, 5.24; N, 1~.13. Found (percent): C, 51.79; H, 5.27;
N, 11.94.
NMR (DMSO-d6, TMS): 2.38s, 6.66d (14.2 Hz), 7.57m,
8.10bd (14.2 Hz), 9.83bs, 11.88bs.
- 14 -
r~l~ ,
Example 4.- Trea~ment of N (3~4-dlchlorostyrylsulfon~
acetamidine with sodl~m h~droxlde accordlng to the procedure of
Example l affords N-(3,4-dichlorostyryl)acctamidine free base, m.p.
125-128C. Conversion of the free base to the hydrochloride salt with
ethanolic hydrogen chloride in metha~ol provides N-(3,4-DICHLOROSTYRYL)-
ACETAMID~NE HYDROCHLORIDE, m.p. 215-224C. (dec.)(corr.), from
methanol-acetone.
Analysis. Calcd. for CloHlo U 2N2-HCl (percent): C, 45.22;
~, 4.18; N, 10.55. Found (percent): C, 45.33; H, 4.39; N, 10.47.
NMR ~DMSO-d6, TMS): 2.31s, 6.48d (14.0 Hz), 7.51m, 7.82m,
7.99bd (14.0 Hz), 9.83bs, 11.67bs.
Example 5.- Treatment of N~(3,4-dichlorosty~ylsulfonyl)~
phenylacet~midine with ~odium hydroxide according to the procedure of
Exsmple l affords a 41~ yield of N~(3,4-dichlorostyryl)ph~nylac~tamidlne
15 hydrochloride, m.p. 216-219C., from isopropanol. The hydrochloride 1s
taken up in acetone, ~ade basic with ammonium hydroxlde and the free
~ase e~tracted with e~hyl acetate. After washing with water, the ethyl
acetate extract is dried and made acid with isethionic acid to prcvide
- the lsethionate ~alt. Analytically pu~e N_~3J4_DICHLOROSTYRYL)PHENYL-
ACETAMIDINE ISETHIONATE i9 obtained by crystalliza~ion from ac~tonltrile,
m.p. 132.5-134.5C.
Analysi~s. Calcd. for Cl6H~4Cl2N~C2H604S (percent): C, 50.12;
H, 4.67; N, 6.50. ~ound (p~r~ent): C, 50.30; H, 4.78; N, 6.64.
N~R (DMSO-d6, TMS): 2.69t (6.6 Hz), 3.67t (6.6 Hz), 3.82m,
25 6.52d (13.9 Hz), 7.47m, 9.42bs, 9.i8bs, 11.55bs.
-- 15 -
....
Example h . - N- (3,4-dichloros~yrylsulfonyl)benzamldine
treated with sodium hydroxlde according to ~he procedure of ExamplP 1
provides N-(3,4-~ICHLOROSTYRYL)BENZAMIDINE HYDROCHJ.ORIDE, m.p. 243.0-
248.5C. (dec.)(corr.), fro~ ethanol-~ethanol-isopropyl Pther.
Analysis. Caled. for Cl~H,2ClqN2-HCl (percent): C, 54.99;
~, 4.00; N; 8.56. Found (percent): C, 55.09; H, 4.00, N, 8.55.
NMR ~DMSO-d6, ~S): 6.89d (14.0 Hz), 7.83m, 8.38bd ~14.0 H2),
10.35bs, 12.10bs.
~xample 7.- N-(3,4-dichlorostyrylsulfonyl)-3,4-dimetho~y-
benzamidine treated wlth sodium hydroxide accordlng to the procPdure
of Example 1 provides a 64% yield of N-(3~4-DICHLOROSTYRYL)-3~4-
D~THOXYBENZAMIDINE ~YDROCHLORIDE, m.p. 239.0-240.0C., (corr.),
from methanol-lsopropyl ethsr.
~ ysis. Calcd. for Cl7HI6Cl2NaO2-HCl (psrcent): C, 52.66;
H, 4.42; N, 7.23. Found (~ercent): C, 52.56; H, 4.45; N, 7.220
NMR ~DM50-d6, TMS): 3.92s, 6.93d (14.0 Hz~, 7.65m, 8.21bd
~14.0 Hz), 10.20bs, 11.93bs.
~ e $.- N-(4~n~tros~yrylsulfQnyl)acetamidine treated
wlth sodiu~ hvdroxide accordir.g to the procedure of Example 1 provides
~-(4-nitrostyryl)acetamidine free base, m.p. 142-143C. Conversion of
the free base to the hydrochloride salt affords N-(4-NITROS~YR~L)-
ACETAMIDINE HYDROCHLORIDE, m.p. 247.0-247.5C. (dec.)(corr.), from
methanol.
AnalYsis. Calcd. for CloHl~N90~-HCl (pereent): C, 49.69;
2~ H, S.Ol; N, 17.39. Found ~percent): C, 49.69; H, 4.95; N, 17.33.
NMR (DMSO-d~, ~IS): 2.39s, 6.73d (14.1 Hz), 8.04d (14.1 H7)~
8.07m, 9.92bs, 11.95bs.
-- 16 --
-
r~
~ A suspension of 4-amino-N-~4-nitrostyrylsulfonyl)-
benzamidin2 (6.9 g.~ 0.02 mole) in 120 ml. of acetone is stirred with
50X sodium hy~oxide (6.4 g., 0.08 mole) in 40 ml. of water for ]. hr.
Concentratio~. of the reaction mixture affords a residue which i6
stirred wlth 50 ml. of water, fil~ered, washed with water, and dried.
Trituration of the dried filter ca~e ui~h isopropyl alcohol yields 5.3 g.
(95%) of N-(4-nitrostyryl)--4-aminobenzamidine free b~se, m.p. 195-197C.
(dec.). The free base (5.0 g.) dissolved in 400 ml. of hot 1:1 methanol
scetone and acidified with ethanolic hydrogen chloride provides 3.5 g. of
analytically pure 4-AMINO-N-(4-~ITROSTYRYL)B~NZAMIDINE HYDROCHLORIDE
as a yellow solid, m.p. 247~248C. (dec.)(corr.). Concentration of
the mother liquors and trituration of the residue provided an additional
2.6 g. of the hydrochloride salt.
Analysis. Calcd. for C,5Hl4N~02-HCl (percent): C, 5~.50;
H, 4.74; N, 17.58. Found (percent): C, 56.89; H, 4.70; N, 17.74.
NMR (DMSO-d 6 , TMS ): 3.83bs 9 6.76m, 7.88m, 9.68b~, 11.37bs.
.
Example 10.~ N-(2-nitrostyrylsulfonyl)acetamidine trea~ed
w~th sodiu~ hydroxlde according to the procedure of E~ample ~ provides
N-~2-NITROSTYR~L)ACET.4MIDI~E HYDROCHLORIDE, m.p. 227-229C. (dec.)(cor~.),
from ethanol-isopropyl ether.
Analysis. Calcd. for C~oHl~N302~HCl ~percent): C, 49.69;
H, 5.01; N, 17.39. Found (percen~): C, 49.39; H, 5.14; N, 17.10.
~ ~ (DMSO-d6, TMS): 2.36s, 7.02d (13.9 ~z), 7.93m, lO.l~bs,
11.97bs.
Example 11.- N-(2-nitrostyrylsulfonyl)benzamidine trea~ed
wlth sodium hydroxide according to the procedure of Example 9 provides
.
17 -
.. .
a 7870 analytical yield of N-~2-NITROSTYRYL)BENZAMIDIN~ HYDROCHIORIDE,
m.p. 219.5-221.5C. (dec.)(corr.), from methanol-isopropyl ether.
Analysis. Calcd- for C15~13N302-HCl (percent): C, 59.32;
H, 4.65; N, 13.84. Found (percent): C, 59.04; ~9 4.83, N, 13.72.
NM~ (DMSO-d6, TMS): 7.25d (13.9 Hz), 7.87m, 10.50bs,
11.83bs.
Example 12.- N-(4-nitrostyrylsulfonyl)benzamidine treated
with sodium hydroxide according to the procedure of Example 9 provides
N-(4-nitrostyryl)benzamidine free base, m.p. 163-165C. ~-(4-Nitro-
styryl)benzamidine hydrochloride obtained from the free base in ~he
usual manner has a melting point of 2S5-257C. The free base treated
with a slight excess of isethionic acid in methanol affords N-(4-
NITROSTYRYL)BENZA~IDINE ISETHIONATE, m.p. 204-206.5C. (dec.)(corr.),
from methanol-isopropyl ether.
Analysis- Calcd- for ClsH13~302 C2H6 4 (p
H, 4.86; N, 10.69. Found (percent): C, 51.56; H, 4.94; N, 10.54.
NMR (DMSO-d6, TMS): 2.68t (6.7 Hz), 3.52t (6.7 Hz)~ 4.43s,
6.89d (14.0 Hz), 8.05m, 10.17bs, 11.83bs.
Example 13.- A solution of 4-ni~ro-N-(4-nitrostyryl-
sulfonyl)benzamidine (15.0 g., 0.04 mole) and 100 ml. of 2N sodiumhydroxide in 200 ml. of acetone is stirred at 25C. for a period of
1 hr. Acetone i9 removed under reduced pressure, the mixture filtered
and ~he filter cake washed with water and dried affo~ding 8.4 8. (68
yield) of 4-nitro-N-(4-nitrostyryl)benzamidine free base, m.p. 214~
216C. 4-Nitro-N-(4-nitrostyryl)benzamidine hydrochloride obtained in
the usual manner has a melting point of 243-244C. (dec.). The free
base taken up in methanol and acidified with isethionic acid provides
- 18 -
4-NITRO-N-~4-NITROSTYRYL)B~MZ~MIDIN~ ISETHIONATE, m,p. 206.5 208C.,
(corr . ) .
nalYsis. Calcd. for C,,Hl2N4O4~C2H6O4S (percent): C, 'l6.57;
H, 4.14; N, 12.77. Found (percent): C, 46.17; H, 4.27; N, 12.71.
NMR (DMSO-d6, TMS): 2.63t (6.7 Hz), 3.62t (6.7 Hz), 3.88s,
6.78d (14.0 Hz), 7.93m, 8~37bd (14.0 Hz), 10.33bs.
~ .- 3,5-Diamino-N-t4-nitrostyryl~ulfonyl)benzamidine
treated wlth sodium hydroxide according to the procedure of Example 9
- affords 3,5-diamino-N-(4-nitrostyryl)benzsmidine free base, m.p. lZl-126C.
(dec.) in a yield of 75%. Conversion of the free base with ethanolic
- hydrogen chloridP in acetone affords 3,5-DIA~IINO-N-(4~NITROSTYRYL)-BENZAMIDINE TRI~DROCHLORIDE, m.p. 210.5-214.5C. (dec.)(corr.), from 90%
ethanol.
Analysis. Calcd. for C~,Hl5N~O~-3HCl ~percen~): C, 44.29;
H, 4.46; N7 17.22. Found ~percent): C, 44.35; H, 4.86; N, 17.06.
NMR (DMSO-d~, TMS): 5.82bs, 6.73m, 7.97m, 10.08bs, 10.45bs.
_ample 15.- 3-Nitro-N-(4-nitros~yrylsulfonyl)benzamidine
~reated with sodlum hydroxid2 according to ~he procedure of Example 9
provides 3-nitro-N-(4-nitrostyryl)benzamidine free base, ~.p. 152-155C.
2Q The free base in acetone acidified with isethionic acid provides
3-NITRO-N-(4-NITROSTY~YL)BENZAMIDINE ISETHIONATE MONO~YDRAT~, ~.p.
195.0-198.0C. (corr.), from ethanol.
Analysis. Calcd. for Cl~Hl2N4O4HOC~H4SO3HH2O (percent):
C, 44.73; H, 4.42; N, 12.27. ~ound (percent~: C, 44.90; H, 4.20;
N, 12.05.
N~R (DMSO-d69 TMS): 2.62t (6.7 Hz), 3.62t (6.7 Hz), 3.79s,
6.80d (14.0 Hz), 8.07m, 10.25bs.
~ 19 --
,, ~.
Example 16.- 3-Amino-N-(4-nitrostyrylsulfonyl)benzamidine
treated w~th sodium h~droxide slccording to the procedure of Example 9
provides 3-amino-N-(4-ni~rostyryl)benzamidine frPe base, m.p. 146-148C.
in 79% yield, from isopropyl alcohol-ether. Conversion of the free base
to the hydrochloride ssllt with ethanolic hydrogen chloride afords
3-AMINO-N-(4-NITROSTYRYL)BENZA~IDINE DIHYDROCHLORIDE MONOHYDRATE, m.p.
lA3.0-19~.5C. (dec.)(corr.).
Analysis. Calcd. for Cl3H~N4O~-2HCl-H~O (percent): C, 48.27;
~, 4.86; N, 15.02. Found (percent): C, 47.99; H, ~.55; N, 14.96.
NMR (DMSO-d6, TMS): 6.80d (14.0 Hz), 7.77m, 3.90bs, 10.25bs.
E~g@~ .- 4-(Dime~hylamino)-N-(4-nitrostyrylsulfonyl)-
ben~amidine treated wi~h sodium hydroxide a^cording to the procedure
of Example 9 provides 4-(dimethylamino)-N-(4-nitrostyryl)b~nzamidine
free base, m.p. 191-193C. Acidification of the free base in ~ethanoI
with isethionic acid affords 4-(DIMETHYLAMINO)-N-(4-NITROSTYRYL)-
BENZAMIDINE ISETHI0NATE, m.p. 260.5-262.5C. (dsc.~(corr.), from
methanol-isopropyl ether.
alysis. Calcd. for C. 7H~ 02~HOCaH4SO3H (percent): C, 52.28,
N, 5.54; N, 12O83. Found (percent): C, 52.44; H, 5.54; N, 12.82.
NMR (DMS0-d6, TMS): 2.63t (6.7 Hz), 3.64t (6.7 Hz)9 4;38s,
3.04s, 6.73m9 7.92m, 11.17bs.
E m~e 18.- N-(4-Ni~rostyrylsulfonyl)clnnamamidine
treated with sodium hydroxide according to the procedure of Example 9
provides N-(4-nitrostyryl)c~nnamamidine free base, m.p. 120-125C.
(dec.). Acidification of the free base in acetone with iseth~onic
acid affQrds N-(4-NITR0STYRYL)CINNAMA~IDINE ISETHIONATE, m.p.
224.5-228.0C. (corr.), from meths~nol.
20 ~
Analysls. Calcd. for Cl7Hl5NgO~HOC2H4SO3H (percent):
C, 54.41; H, 5.05; N, 10.02. Found (percent): C, 54.29; H, 5.09;
N, 9.84.
N~ (DMSO-d6, TMS): 2.73t (6.7 Hz), 3.69t (6.7 Hz), 4.1&bs,
6.69d (13.9 Hz), 6.85d (16.2 Hz), 7.83m, 9.63bs.
Example 19.- A nitrogen atmosphere is employed throughout
the reaction. A ~olution of sodium borohydride (3.8 g., 0.1 mole) in
10 ml. of wa~er i8 added to a suspension of about 200 mg. of 10%
palladium on carbon in 10 ml. of water. After 5 min., 200 ml. of
methanol is added followed by portion-wlse addition of finely powdered
N-(4-nitrostyryl)benzamidine (8.0 g., 0.03 mole) over a period of
5 min. During the addition, the mixture refluxes and continues to
boil for about 5-10 min. thereafter. The reaction mixture ~s stirred
withou~ ex~ernal heating for 0.5 hr., filtered through CE~ITE
concentrated under reduced pressure and the residue 6tirred with
25 ml. of water and filtered. The filter cake washed with cold water,
drled, and triturated with isopropyl alcohol provides 6.8 g. (86% yield)
of N-(~-aminostyryl)benzamidine free base, m.p. 166-168C. Treating
the free base in methanol with ethanolic hydrogen chloride and
: 20 evaporating the solvent under reduced pressure provides the crude
hydrochloride. Analytically pure N-(4-AMINOSTYRYL)~ENZ~IIDINE DI-
HYDROCHLOP~IDE, m.p. 217.5-219.53C. (dec.)(corr.), (60% yield) is
obtained by first triturating the crude hydrochloride with ace~one
and then recrystallizing from methanol-lsopropyl ether.
Analysis. Calcd. for Cl5H~Nar2HCl (percent): C, 58.05;
Il, 5.53; N, 13.55. Found (percent~: C, 58.43; }1, 5.60; n, 13.36.
N~ (DMSO-d~, ~MS): 6.97d (14.0 llz), 7.7~1, 9.53bs, 10.18bs,
10.57bs, 12.00bs.
21 -
Example 20.- Reduction of N-(2-nitrostyryl)benzamidine with sodiun~
borohydride according to the procedure of Example 19 provides N-(2-
AMINOSTYRYL)BENz~MIDINE DIHYDROCHLORIDE, m.p. 226.5 - 227.5 C. (dec.)
(corr.), from methanol-isopropyl ether.
Analysis. Calcd. fo~ ClsH,sN3-2HCl (percent): C, 58.06; H, 5.53;
N, 13.55. Found (percent): C, 58.30; H, 5.44; N, 13.71.
NMR (DMSO-d6, TMS): 6.84d (14.0 Hz), 7.58m, 9.92bm, 11.75bs.
Example 21.- Reduction of 4-nitro-N-(4-nitrostyryl)benzamidine
with sodium borohydride according to the procedure of Example 19 affords 4-
~MINO-N-(4-AMINOSTYRYL)BENZ~MIDINE TRIHYDROCHLORIDE, m.p. 259.0 C. (dec.)
(corr.), from methanol-isopropyl ether.
Analysis. Calcd. for ClsHl6N4-3HCl (percent): C, 49.80; H, 5.30;
N, 15.49. Found (percent): C, 49.60; H, 5.34; N, 15.66.
NMR (DMSO-d6, TMS): 6.80m, 7.62m, 9.53bs, 9.75bs, 11.33bs.
Example 22.- Reduction of 3,5-diamino-N-(4-nitrostyryl~-
benzamidine with sodium borohydride according to the procedure of Example 19
provides 3,5-DIAMINO-N-(4-AMINOSTYRYL)BENZAMIDINE TRIHYDROCHLORIDE, m.p.
286.5 - 288.0 C. (dec.) (corr.), from aqueous ethanol.
Analysis. Calcd. for ClsHl7Ns-3Hcl (percent): C, 47.82; H, 5.35;
N, 18.60. Found (percent): C, 47.60; H, 5.44; N, 18.54.
NMR (D20, DSS): 4.67s, 6.70d (14.0 H~), 7.47m.
Example 23.- Reduction of 3-nitro-N-(4-aminostyryl)ben~amidine
with sodium borohydride according to the procedure of Example 19 provides 3-
AMINO-N-(4-AMINOSTYRYL)BENZAMIDINE TRIHYDROCHLORLDI: MONOHYDRATE, m.p. 224.5 -
226.5 C. (dec.) (corr.), from methanol-isopropyl acetate.
- 22 -
>~
Analysis. Calcd. for C~Hl6N4~3HClsH~O (percent~: C, 47.44;
5.58; N, 14.76; H~O, 4.74. Found (pe~cent): C, 47.40; H, 5.65;
N~ 14.56; H~O, 4.68.
NMR (D20, DSS): 4.67SJ 6.68d (14.0 Hz), 7.43m.
E mple Z4.- Reduction of N-(4-nitrostyryl)-2-naphthamidine
according to the procedure of Example 19 wi~h sodium borohydride provides
N-(4-aminostyryl)-2-naphthamidine free base, m.p. 151-153C. Acidification
of the free base in acetone with 5N hydrochloric a-cid affords N-(4~
AMINOSTYRYL)-2-NAPHTHAMIDINE DIHYDROCHLORIDE, m.p. 235-237C. (dec.)
(corr.), from methanol-isopropyl ether.
Analysis. Calcd. for Cl9Hl7~3-2HCl (percent): C, S3.33;
H, 5.32; N, 11.66. Found (percent): C, 63.41; Hg 5.25; N, 11.65.
NMR (DMSO-d6, TMS): 6.86d (14 0 Hz), 7071m, 8.50d ~2.0 Hz),
9.13bs, 10.08bs, 10.42bs, 11.85bQ.
Exam~le 25.- A solution of N-(4-aminostyryl)ben~amidine
(2.4 g~3 0.01 mGle) in 25 ml. of acetic acid and 5 ml. of acetic
a~hytride is heated at 100C. for a per$od of 15 min., coolsd and
quenched ir. 50 ~1. of ~ced-~atPr. The yellow solution thus obtained
i6 acidifled wi~h 3N hydrochloric acid providing a y2110w precipitate
which is collected, trltura~cd with ace!one and crystalIized from
methanol-ethanol to yield 2.C g., (~3%) of analytically pure N-(4-
- ACET.~IIDOSTYRYL)BENZ~MIDIN~ HYDROC~LORIDE, m.p. 249-251C. (dec.)(corr.).
Analysis. Calcd. for Cl~HI,N30~HCl (percent): C, 64.66;
B~ 5.74; N, 13.30. Found (percent): C, 64.72; H, 6.05; N, 13.11.
~ 25 NMR (DMSO-d6, T~S): 2.05s, 6.74d (13.5 Hz~, 7.64m, 9.83bm,
`- 10.05s, 11.55b=.
. .
- 23
. :. , ,:
Example 26.~ The following s~yrylami~ine products of
Fo~mula I are obt~ined by tre~ting the enumerated styrylsulfonyl-
a~idine precursor with sodium hydro~lde in dimethyl~ulfoxid~
aeeording to the pr~cedure of Example 1:
(a) N-(4-CARBAMOYLSTYRYL)ACETAMIDINE from N-(4-carbamoyl-
styrylsulfonyl)acetamidine;
~b) N-(4-SULFAMOYLSTYRYL~ACETAMIDINE ~rom N-(4-sulfamoylstyryl-
sulfonyl)acetamidine;
(e) N-(3-MET~IYLSUT.FONYLSTY~YL~ACETAMIDINE from N-(3-methyl-
sulfonylstyrylsulfonyl)acetamidine;
td) N-(4-CYCLOHEXYLSTYRYLjACETAMIDINE from N-(4-cyclohexyl-
styrylsulfonyl)acetamidlne;
(~) N-(3-Bromo~4-eyclohexylstyrylsulfonyl)acetamidine provides
N-(3-BROMO-4-CYCLOHEYYLSTYRYL)ACETAMIDINE HYDROCHLORLDE,
m.p. 212-215C. (dec.)~corr.).
Analysis, Found (~ercent): C3 53.46; H, 6.22; N, 7.72.
NMR (DMSO-d6, TMS): 1.60m, 2.29g, 2.82m, 6.46d (14.0 Hz~,
7.5bm, 10.25bs.
(f) N-(STYRYL)-4-CHLOROBEN~AMIDINE from N-(styryl~ulfonyl)-4-
ehlorobenzamidine;
(g) N-(STYRYL)-3-ACETAMIDOBENZAMIDINE from N-(styrylsulfonyl)-3-
aeetamidobenzamidine;
~h) N-(STYRYL)-3,4-DICHLOROBENZAMIDINE from N-(styrylsulfonyl~-
3,4-dichlorobenzamidine;
(i) N-(4-~ITROSTYRYL)-4-STYRYLBENZ~IIDINE from ~-(4-nitros~yryl-
8ulfonyl)-4~styrylbenzamidine;
.. 24 -
.
~;) N-(4-NITROSTYRYL)-4-(PHENYLBUTADIENYI)BENZAMIDINE from
N-(4-nitrostyrylsulfonyl)-4-(phenylbutadienyl)benzamidine;
~k) N-(2~FLUOROSTYRYL)BENZAMIDINE from N-(2-fluorostyryl-
sulfonyl)benzamidine,
(1) N-(2,5-DICHLOROSTYRYL)BENZAMIDINE from N-(2,4-dichloro-
styrylsulfonyl)benzamidine;
(m) N-(STYRYL)-4-(di-n-BUTYLAMINO)BENZAMIDINE from N-(styryl-
sulfonyl)-4-(di-n-butylamino)benzamidine;
(n) N-[3-(2-METHXEPROPIONAMIDO)STYRYL]ACETAMIDINE from
N-r3-(2-methylpropionamido)styrylsulfonyl]acetamidine;
(o) N-(STYRYL)-2-sec.-BUTYRAMIDINE from N-(styrylsulfonyl~-
sec.-butyramidine;
(p~ N-~(2,6-DICHLOROSTYRYL)SULFONYL]ACETAMIDINE provideR
N-t2,6-dichlorostyryl)acetamidine hydrochloride, m.p.
154.5-158.5C. (corr.). Analysis. Found (percent):
C, 45.20; H, 4.13; N, 10.66. ~MR (DMSO-d6, TMS): 2.35s,
6.65d (13.8 Hz), 7.40m, 9.5bs, 9.8bs, 12Ø
Example 27.- Reaction of the aminos~yrylamidines enumerated
below wlth acetic anhydride according ~o the procedure o~ Example 25
provides the following acetamidostyrylamidine products of Formula I:
ta) N-(4-AcETAMIDosTyRyL)-4-sTyRyLBENzAMIDINE from
N-t4-aminostyryl)-4-styrylbenzamidine;
tb) N-t4-AcETAMIDosTyRyL)-4-tpHE~yLBuTADIENyL)BENzAMIDINE
from N-t4-aminostyryl)-4-tphenylbutadienyl)benzamidlne.
Example 28.- Reduction of the nitrostyrylamidines enumera~ed
below with sodium borohydride according to the procedure of Example 19
provides the following aminos~yrylamidines of Formula I:
ta) N-(4-AMINOSTYRYL)-4-STYRYIBENZAMIDINE from N-(4-nitro-
~tyryl)-4-styrylbenzamidine;
tb) N-t4-AMINOSTYRYL)-4-tPHENYLBUTADIEN~L)BENZAMIDINE from
- N-t4-nitrostyry~)-4-tphenylbutadienyl)benzamidine.
- 25 -
Example 29. PRE~RATION OF STYRYLSULFO~r~LAMIDINES.
(a) 4-Nitrobenzamidine hydrochloride obtained according to
method of L. Weintraub, et al., J. Org. Chem., 33, 1679 (1968) is
hydrogenated in methanol ~olution in a Parr Apparatus employing a
10% palladium on carbon catalyst to provide 4-aminobenzamidlne
hydrochloride.
Addition of 50% sodium hydroxide (4.0 ~ " 0.05 mole) to
a 801utlon of 4-aminobenzamidine hydrochloride (0.5 mole) in 10 ml.
of water affords 4-aminobenzamidine free base. Acetone (50 ml.) is
added to the liberated free base and the mixture cooled to 5C.
4-Nitrostyrylsulfonyl chloride is added to the mixture in a period of
5 min. whlle maintaining a temperature below 15C. The mixture is
stlrred for 10 min., the reaction mi~ture concentrated under reduced
pressure provides a residue which diluted with 100 ml. of water and
neutralized wi~h 3N hydrochloric acid affords a pale yellow solid
precipitata. The precipitate ls collected, washed thoroughly with
water and then triturated first with isopropanol and ~hen with ether
to yield 7.3 g. (84~) of N-(4-NITROSTYRYLSULFONYL)-4-AMINOBENZAMIDINE,
m.p. 188-189C.
(b) A mixture of ac&tamidine hydrochloride (28.8 g., 0.15 mole)
~nd 50% sodium hydroxide (12.0 g., 0~15 mole) in 150 ml. of ace~one is
stirred for a period of 10 min. to liberate ~he free base. A solution of
etyryl&ul'~onyl chlor~de (10.1 g., 0.05 mole) in 50 ml. o aceton~ is
added dropwise to the mlxture at a temperature of 20-25C. with s~lrring.
After further stirring for 10 min., the mixture i~ concentrated under
reduced pressure to remove acstone, the concentrate diluted with
200 ml~ of water and acidified with 3N hydrochloric acid to provide
a precipitate. The precipitate is colle.cted, dissolved in chloroform
- ~6 -
, _
.~.q.;~ .9;~
and the chlsroform extract drled. Evapora~ion of thc chloroform
601vent under reduced pressure provldes a ~hite solid, m.s. 130-134C.
wh~ch ~9 crystalliz~d from isopropyl acetate affording 8.5 ~. (76~
: yield) of N-tSTYRYLSULFONYL)ACETAMIDINE, m.p. 134.5-137.0C. (corr.).
A~nalysis. Calcd. for CloH1~N203S (percent): C, 53.55;
H, 5.39; N, 12.49. Found (percent): C, 53037; H, 5.30; N, 12.54.
NMR (CDCl3, TMS): 2.16s, 6.73bs, 6.92d (15.5 Hz~, 7.45m,
7 . 64d (15 . 5 Hz), 7 . 84b s .
(c) Reaction of benzamtdine and styrylsulfor.yl chloride
according to tha above procedure pro~ides N-(STYRYLSULFONYL)BENZAMIDINE,
m.p. 192.5-194.5C. (corr.), crystalli~ed from acetone.
Analysis. Calcd. for Cl~Hl4N~02S (percent): C, 62.91, H, 4.93;
N, 9.79. Found (perc~nt): C, 63.13; ~, 5.06; N, 9.64.
NMR (DMSO-d~, TMS): 7.4-8.1m, 8.20bs, 9.20bs.
(d~ Reaction of acetamidine with 4-n~trostyrylsulfonyl
chloride according to the above procedure provides N-(4-NITROSTYRYL-
SULFONYL)ACETA~IIDINE, m.p. 203.0-20305C. (dec.)(corr.), crystallized
` fronl acetonitrile.
Analysis. Calcd. Eor CloH~N3o4s (percent): C, 44.59;
H, 4.12, N, 15.61. Found (percent): C, 44.85; H, 4.21, N, 15.74.
NMR (DMSO-d6, I~S~: 2.16s, 7.56s, 8.15m, 8.62bs.
(e) Reaction of acetamidine with 394-dichloros~yrylsulfonyl
chloride according to the abo~e procedure affords N~C(3l4-DICHLORO-
STYRYL)SULFOWYI~AC~T~MIDINE, m.p. 197.5-198.5C. (corr.), crystallized
from acetone-isopropanol.
Analys_s. Calcd. for CloHlocl2N~o2s (percent): C, 40.96;
~, 3.44; N, 9.56. Found (percent): C, 41.15; H, 3.64; N, 9.49.
27 -
~R tDMSO-d6, TMS): 2.14s, 7.43s, 7.73m, 7.g6bs, 8.08m,
8.57bs.
(f) Reaction of acetamidine with 4-chlorostyrylsulfonyl
chloride according to the above procedure affords N-[(li-CHLOROSTYRYL)-
SULFONYLlACETA}fIDINE, m.p. 161-1~3C., crystallized from ethyl acetate.
tg) Reaction of phenylacetamidina benzenesulfonate, obtained
according to the method of P. Oxley and W. F. Short, J. Chem. Soc.,
147 (1~46), with 3,4-dichlorostyrylsulfonyl chlorids according to the
above procedure affords N-~(3,4-DICHLOROSTYRYL)SULFONYL]PHENYLACETAMIDIN~,
m.p. 151-155C.
~ h~ Reaction of ben~amitine with 3,4-di~hlorostyrylsulfonyl
chloride according to the above procedure affords N-[(3,4-DICHLOROSTYRYL)-
SUL~DNYL~BENZAMIDINE, m.p. 144-146C.
(i) Reaction of acetamidine with 2-nitro~tyrylsulfonyl
chloride according to the above procedure affords N-(2-~TITROSTYRYL~
SULFONYL)ACETAMIDINE, m.p. 175-178C.
(~ Reaction of benzamidine with 4-nitrostyrylsulfonyl
chloride according to tne above procedure affords N-(4-NITROSTYRYL-
SULFONYL~BENZ~iIDINE, m.p. 173-175C., by tri~ura~ing with methanol.
tk) 4-Nitrostyrylsulfonyl chloride (2.5 g., ~.01 mole) is
added portion-~ise to a solution of 4-nltrobenzamidine (1.65 g.,
0.01 mole), prepared according to the procedure of L. Weintraub, et al.,
J. Org. Chem., 33, 1679 (1968~, and triethylamine (l.Ol g., 0.01 mole)
in 50 ml. of acetone at 10C. After stlrring for a period oE 1 hr. at
25C., the mixture ls concentrated under reduced pressure and the
residual material stlrred with water and collected. Triturqting the
filter caXe with acetone provides N (4-NITROSTY~YLSULFO~L)-4-NITRO-
BENZA~IIDINE, m.p. 173-177C.
- 2
(1) Reaction of 3~nitrobenzamidine with 4-nitrostyrylsulforlyl
chlQrlde accordi~g to th~ above procedure provlde~ N-(4-NITROSTY~YL
SULFONYL)-3-NITROBENZAMIDINE, m.p. 230-232C.
(~) Reaction of 3-amlnobenzamidine9 obtained by catalytic
reduction of 3-nltrobenzamidine in methanol in a Parr Appara~us
employing 10% palladium on carbon catalyst, with 4-nitrostyrylsulfonyl
chloride according to ~he abova procedure affords N-(4-NITROSTYRYL-
SULFONYL)-3-AMINOBENZ~IIDINE, m.p. 162-170C., by triturating with
isopropanol.
(n) Reaction of 4-(N,N-dimethylamino)benzamidine 3 obtained
according to the procedure of "Organic Synthesisl', Coll. Vol. 1, 2nd
Ed., page 5, (Wiley, 1932), with 4-nitrostyrylsulfonyl chloride
according to the above procedure affords N-t4-NITROSTYRYLSULFONYL)-4
Dr~ETHYLAMINO~ENZAMIDINE, m.p. lg2-196C., by triturating with acetone.
(o) Resction of cinnamamldine, obtained according to the
procedure of "Organic Synthesis", Coll. ~ol. 1, 2nd, Ed. page 5,
(Wiley, 1932), with 4-nitrostyrylsulfonyl chlorlde by the above
procedure affords N-(4-NITROSTY~YLSULFONYL)CI~N~MAMIDTNE, m.p. 188-192C.,
by tritursting wi~h ethyl acetate.
(p) Reaction of ~-naphthamidine with 4-nitrostyrylsulfonyl
chloride accor~ing to the above procedure affords N-(4-NITROSTYRYL-
SULFONYLj-~-NAPHTHAMIDINE, m.p. 180-182.5C.~ by triturating with
isopropanol.
(~) Reaction of 3,5-diaminobenzamidine obtained by catalytic
reduction of 3,5-dinitrubenzamidine benzenesulfonate, with 4-nitrostyryl-
sulfonyl chloride accord~ng to the above procedure affords N-(4-NITRO-
STYRYLSULFONYL)-3~5-DT~II~OBENZAMIDINE.
.~
;3~
~ r) Hydrogen chlorlde 19 bubbled through a mixture of
4-cyanostilbene (13.5 g., 0.~65 mole), obtained according tc the
method of Belgian Patent 641,415 (Chem. Abs. 63: 3092g (1965)),
in 35 ml. of dry benzene and 17.5 ml. of absolute ethar.ol at
0 to 5C for a period of 3 hr. The reaction is maintained at
O to 5C. for 48 hr. and the solvent and excess hydrogen chloride
re~oved under raduced pressure. The residue stirred with 50 ml.
of dry be~zene and collected provides 13.0 g. of ethyl-4-styryl-
benzimidate hydrochloride. A methanol solution of the benzimidate
~alt is cooled to S eo 10C., saturated with ammonia and heated
at a temperature of 100C. for a period of 3 hr. in an enclosed
container. Concen~ration of the reaction mixture provides 4-styryl-
benzamidine hydrochloride.
Reaction of 4-styrylbenzamidine ~ith 4-nitrostyrylsulfonyl
chloride according to the procedure of Example 29 (a) provides
N-(4-NITROSTYRYLSULFONYL)-4-STYRYLBENZAMIDINE.
(B~ By sub~titu~ing 4-(4-phenylbuta-1,3-dienyl)benzonitrile
for 4-cyanostilbene ~ccording to Example 29 (r) there is obtained
e~hyl-4-(4-phenylbuta-1,3-dienyl)benzi~idate hydrochloride, m.p.
20 ~45-260C. (dec.) by triturating with acetone. The ethylber.~lmidate
8alt is converted to 4-(4-phenylbuta-1,3-dienyl)benzamidine hydrochloride
by dissolving in methanol saturated with am~onia.
~eaction of 4-(4-phenylbu~a-1,3-dienyl)benzamidine with
4-nltrostyrylsulfonyl chloride according to the procedure of Example
29 (a) provides N-(4-NITROSTYRYLSULFO~L)-4-PHENYL~UTADIE~m ~ENZAMI~INE.
(t) Ammonia is bubbled through a solutio~ of 3,4-dichlorostyryl-
sulfonyl chloride t27.2 g., 0.1 mole) in 250 ml. of ether for a period
of 30 min. at about 20C. The solvent is evaporated and the residue stirred
.
30 -
:~ g3'~
with water, collected aad dried at 100C. under vacuum ~ffords 24.6 g.
(97~ yield) oE 3,4-dlchloroseyrylsulfonamide, m.p. 127-130C.
A mlxture of 3,4-dlchlorostyrylsulfonamide (12.6 g., 0.05 mole)
~nd 3,4-dimethoxyb~nzoyl chlo~lde (11.0 g., 0.055 mole~ in 15 ml. of
S phosphorus oxychloride is heated at steam bath temperature for a period
of 30 min. Excess phosphorus oxychloride i~ removed under reduced
pressure and dry benzene sdded. T'ne benzene is eva~orated and the
treatment repeated two times. ~enzene (50 ml.~ is added to ~he residue
thus obtained and the insoluble solid collected providln~ 14.6 g.
(70~ yield) of N-(3,4-dichlorostyrylsulfony~)-3,4-dimethoxybenzamide,
.p. 145-147C.
A ~uspension of N-(3,4-di~hlorostyrylsulfo~yl)-3,4-dimethoxy-
ben2amide (8.3 g., 0.02 mole) in 100 ml. of dry benzene is stirred
and refluxed with phosphorus pentachloride (4.6 g., 04022 mole) f~r a
period of 1.5 hrt provlding a clesr solution which is concentrated
under reduced pressure. Lenze~e is added to the residue and evaporated.
The benzene treatment is repeated æeveral tlmes and ~ne residue thus
obtained triturated with isopropyl ether provides a quantitative yield
of N-(3,4-dichlorost~rylsulfo~yl)-3,4-dimethoxyben~imidoy~ chloride,
20 ~.p. 120-125C.
Ammonium gas is bubbled through a solution of N-(3,4-dichloro-
styrylsulfonyl)-3,4-dimethoxy~enz$midoyl chloride (8~7 g., 0.02 mole)
in 100 ml. of dry benz.ene for a period of 1 hr. The solven~ evaporated
under reduced pressure and the sol$d residue stirrPd w~th 50 ml. of
25 w&ter and filtered affords 8.0 g. (96% yield) of N-(3,4-DICHLOROSTYRYL-
SULFONYL)-3,4-DIMET~OXYBENZ~MIDINE, m.p. 205-210C. A ~ample crystalllzed
from acetonitrile has a melting point of 208-211C.
-- 31 --
3'~
tu) ~eaction of acetamidine with 2,6-dichlorostyrylsulfonyl
chloride according to the procedure of Example 29(b) affords N'-~(2,6-dichloro-
~tyryl)sulfonyl]acetamidine, m.p. 154.5-158.5C. (corr.), from absolute
ethanol.
Analysis. Calcd. for C~oHlocl2N2o2s (percent): C, 40.96,
~, 3.44; N, 9.56. Found (percent~: C, 40.60; H, 3.36; N, 9.37.
Example 30.- Reaction of the s~yrylsulfonyl chlorides and
amidines enumerated below according to the proced~res set forth in
Example 29 provides the following styrylsulfonylamidine precursors
of the products of Formula I:
(a) N-(4-CARB~MOYLSTYRYLSULFONYL)ACETAMIDINE from 4-carbamoyl-
- styrylsulfonyl chloride and acetamidine;
(b) N-t4-SULFAMOYLSTYRYLSULFONYL)ACETAMIDINE from 4-sulfamoyl~
ctyrylsulfonyl ~hloride and acet~midine;
~c) N-(3-METHYLSULFONYLSTYRYLSULFONYL)ACETAMIDINE from 3-methyl-
sulfonylstyrylsulfonyl chloride and acetamidine,
(d) N-~4-CYCLOHE.YYLSTYRYLSULFOMYL)ACETAMIDIN~ from 4-cyclohexyl-
styrylsulfonyl chlorida and acetamidine;
(e) N-(3-BROMO-4-CY5LOHEXYLSTYRYLSULFONYL)ACET~IDINE, m.p.
148-156C., from 3-bromo-4-cyclohexyls~yrylsulfonyl
chloride and acetamidine;
~f) N-(STYRYLSULFO~IYL)-4-CHLOROBENZAMIDINE from styrylsulfonyl
chloride and 4-chlorobenzamidine;
(g) N-(STY~YLSULFONYL)-3-ACET~IIDOBENZ~IIDINE from qtyrylsulfonyl
chloride and 3-a~etamidobenza~idine;
(h) N-(STYRYLSULFONYL)-3,4-DIC~ILOROBENZAMIDINE from styrylsulfonyl
~hloride and 3,~-dichlorobenzamidine;
- 32 -
',' ', ' ' , :-' ' :
~ 7~ J~
.
(4-~ITROSTYRYLSULFON~L)-4-STYRYLBENZAMIDIN~ from 4-nitro-
styryl~ulfonyl chloride and 4~styrylben~amidine;
(~) N-(4-NITROSTYRYLSULFONYL)-4-PHENYLBUTADIENYLBENZAMIDINE
from 4-nltrostyrylsulfonyl chloride and 4-phenylbutadienyl-
benzamldine;
(k) M-(2-FLUOROSTYRYLSULFONYL)BENZ.AMIDINE from 2~fluorostyryl-
sulfonyl chloride and b~nzamidine;
(1) N-(2,5-DICHLOROSTYRYLSULFONYL)BENZAMIDINE from 2,5-dichloro-
styrylsulfonyl chloride and benzamidine;
(m) N-(STYRYLSULFONYL)-4-~di-n-BUTYLAMINO)BENZAMIDINE from
styryl6ulfonyl chloride and 4-(di-n-butylamino)benzamidine;
~n) N-[3-(2-METaYLPROPIONAMIDO)STYRYLSULFON~L~ACETAMIDINE from
3-~2-methylpropionamido)styrylsulfonyl chloride and
acetamid.ne;
(o) N-(STYRYLSULFONYL)-sec.-BUTYRAMIDIN~ from styrylsulfonyl
chloride and sec.-butyramidine.
Example 31.- PREPARATION OF STY~YLSULFONYL C~LORIDES
ta~ 3,4-DICHLOROSTYRYLSULFONYL CHLORIDE.- Sulfur trioxide
(20.0 ~., 0.25 mole) is distilled from 20% fuming sulfuric acid
into a flask containing 200 ml. of dry dichloroethane. Dioxane
(21.0 g., 0.25 ~ole) is added dropwise to the solution of sulfur
tr~oxide while maintaining a temperature of from -10 to 0C. After
the addition of dioxane, a solution of 3,4-dichloros~yrene (43.8 g.,
0.25 mole) in 50 ml. of dlchloroethane ls added over a 10 min.
period at 0C. The solu~io~ ls stirred for 3 hr. at 25C., refluxed
' for 0.5 hr. and then poured into 400 ml. of cold water. The
reaction mixture i5 extracted wlth ether, basified with 50~ ~odium
hydroxide, and the aqueous ~raction concentrated under reduced pres3ure
- 33 -~
','' . :
to a small volu~ ylelding 35.4 g. (51%) of the sodiu~ salt of 3,4-
dichloros~yrylsulfonic acid.
A mlxture of the sodium sulfonate salt (35 g., 0.126 mole)
and phosphorus pentachloride (30 g., 0.144 mole) is he~ted at a
temperature of 100C. for a period of 5 hr. After removal of the
phosphorus oxychloride by-product under vacuum the reaction mixture
is added to ice water, the resulting mass broken up and the mixture
filtered. Tha fllter cake is dissolved in ether, the ethereal
` solution, washed with water and dried over magnesium sulfate.
EvaporatiGn of the ether solvent provides 3,4-dichlorostyrylsulfonyl
chloride, m.p. 91-96C. in 92~ yield. A sample crystallized from
chloroform melts at 95-98C.
(b) Subst`itu~ing 4-chlorostyrene for 394-dichlorostyre~e
in the above pro?edure provides 4-CHLOROSTYRYISULFONYL CHLORIDE, m.p,
lS 133-135C. in 88% yield.
(c) Substituting styrene in the abGve procedure for 3,4-
dichlorostyrene provides STYRENESULFONYL CHLOP~IDE, m.p. 86-89C. ln
95% yie.ld~
(d) Nitration of styrellesulfonyl chloride accordlng
2~ to the procedure of F.G. ~ordwell, e~ al., J. Amer. Chem. Soc., 68,
1778 (1~46) provides 2-NITROSTYRYLSULFONYL CHLORIDE9 m.p. 102-105C. 9
and 4-NITROSTYRYI,SULFONYL CHLORIDE, m~p. 171-174C.
(e) Substltuting 4-carbamoylstyrene for 3,4-dichloros~yren
in the above procedure provides 4-CARBAMOYLSTYRYLSULFONYL CEILORIDE~
~5 (f) Substituting 4-~ulfa~.oylstyrene for 334-dichlorostyrene
~n the above procedure provides 4-SULF~'~oYLSTYRYLSULFoNYL CHLORIDE.
~ g) Substitutlng 3-methylsulfo~ylstyrene for 3,4-dlchloro-
styrene in the above procedure provides 3-METHYLSULFONYLSTYRYLSULFONYL
C}n.ORIDE .
'
~ 34 ~
(h) Substituting 4-cyclohexylstyrene for 3,4-dichloro-
styrene in the above procedure provides 4-CYCLOHE m STYRYLSULFONYI
CHLORIDE.
(i) Substituting 3-bromo-4-cyclohexylstyrene for 3,4-di-
chlorostyrene in the abo~e procedure provides 3-BROMO-4-CYCLOHEXYL-
STYRYLSULFONYL CHIORIDE, m.p. 93-97C.
(j) Substituting 2-fluorostyrene for 3,4-dichlorostyrene in
the above proedure provides 2-FLUOROSTYRYLSULPONYL CHIORIDE.
(k) Substituting 2,5-dichlorostyrene ~or 3,4-dichlorostyrene
in the abo~e procedure provides 2,5-DICHLOROSTYRYISULFONYL CHLORIDE.
(1) Substituting 3-(2-methylpropionamido)styrene for 3,4-
dichlorostyrene in the above procedure provides 3-(2-METHYLPROPION-
AMIDO)STYRYLSULFONYL CELORIDE.
(m) Substltuting 2,6-dichlorostyrene for 3,4-dichloro-
styrene in the above procedure provides 2,6-DICHLOROSTYRYLSULFONYL
CHLORIDE, m.p. 88-90C.
Example 32.- Prepa ation of N-Methyl-N-(4-nitro~y~y~)
benzamidine ~ydrochloride.-
(a) N-(4-Nitrostyrylsulfonyl)benzimidoyl chloride.-
A mixture of 4 nitrostyrylsulfonamide (18.2 g., 0.08 mole)~ benzoylchloride (12.6 g.7 0.09 mole) and phosphorus oxychloride (13.8 g.,
0.09 mole) i5 heated at steam bath temperature for 1.5 hr. The
reaction mixture diluted with 20 ml. of ethyl acetate, cooled and
filtered affords 19.0 g. (76% yield) of N (4-nitrostyrylsulfonyl)-
benzamide, m.p. 192-195C., from ethyl acetate-hexane.
A suspension of N-(4-nitrostyrylsulfonyl)benzamide (14~9 g.,
0.045 mole) in 500 ml. o~ dry benzene is refluxed and stirred r7ith
phosphorus pentachloride (10.4 g., 0.05 mole) for 8 hr. ~he reaction
- 35 -
mixture after st~ndin2 overnlght at 25C. provldes 8.2 g. of solid,
m.p. 158-166C. Concentratlon of the mother liquor to abou~ 100 ml.
provides an additional 2.5 g. of solid, m.p. 158-161C. The combined
crude solid crystallized from ethyl acetate affords analytically pure
N-t4-nitrostyrylsulfonyl)benzimldoyl chloride, m.p. 168-175C.
Anal. ~ound: C, 51.46; H~ 3.09; N, 7.79.
(b) N-Methyl-N'-(4-nitrostyrylsulfonyl)benzamidlne.-
Methylamine is passed slowly into a solution of N-t4-nitrostyryl-
8ulfonyl)benzimidoyl chloride (6.3 g., 0.018 mole) in 50 ml. of dry
acetone for 5 min. at 25C. After stirring the mixture for 25 min.
at 25C., the mixture is concentrated ant 50 ml. water and 150 mlO
of chloroform added. The resulting mixture ls shaken vigorously and
filtered. Insoluble material is triturated with 200 ml. of hot
chloroform, cooled and fi~tered providing 0.6 g. of N-methyl-N7-(4-
nitrostyrylsulfonyl)be~zamidine. The chloroform fraction~ are combined,
- washed with water~ drled over magnesium sulfate and concentrated
under reduced pressure. Trituration of the residue thus obtained
with ~ethanol affords an additional 3.5 g. of the benzamldine.
Analytically pure N-methyl-N'-(4-nitrostyrylsulfonyl)benzan~i~in~ has a
melting point of 155.5-157C. ~dec.) from acetonitrile.
Anal. Calcd. for C~6H,~N304S: C, 55.65; H, 4.38; N, 12.17.
Found: C, 55.29; H, 4.24; N, 12.16.
N~R tD~SO-d6, ~IS): 2.92d (4.0 Hæ~, 7.12d (15.0 Hz),
` 7.70-7.25m, 7.85d (9.0 Hz), 8.21d (9.0 Hz), 9.00bs.
~c) N~Methyl-N-(4-nitrostyryl)benzamldine.- A mixture of
N-methyl-N ~4-nitrostyrylsulfonyl)benza~idine (3.45 g., 0.01 mole)
in 100 ml. of acetone and 25 ml. of 10~ aqueous sodium hydroxide ls
- ~tirred at 25C. for 30 min. The solvent is removed under reduced
- ~6
pressure and the residue diluted wi~h water and extracted with
chloroform. The chloroform extract is washed with ~ater~ dried
over potassium carbonate and concentrated affording the benzamidine
free base. The free base is taken up in ethanol, acidified with
ethanolic hydrogen chloride and the hydrochloride salt isolated by
dilution with ether. Trituration of the crude salt with acetone
and crystallization from methanol-isopropyl ether provides 2.4 g.
(75~) of analytically pure N-methyl-N-(4-nitrostyryl)benzamidine
hydrochloride, m.p. 247.5-249.5C. (dec.)(corr.).
Anal- Calcd- for Cl6~l5N3o2.Hcl C, 60.47; H, 5.08;
N9 13.22. Found: C, 60.66; H, 5.03; N, 13.35.
NMR (DMSO-d6, T~S): 3044s, 6.90d, 7.6-8.0m, 8.22d (9.0 Hz),
10.70bs.
~ xample 33. 1 aration_of 5,6-dihydro-4-methyl-5-(4-
nitrophenyl?-3-phenyl-4~-1,2,4-thiadiaæine l,l-dioxide.- Methylamine
is bubbled into a solution of N-(4-nitrostyrylsulfonyl)benæimidoyl
chloride (5.25 g., 0.015 mole) in 100 ml. of acetone for a period of
2.5 hr. The reaction mixture is concentrated under reduced pressure,
diluted with 50 ml. of water and acidified with 3N hydrochloric acid.
After stirring for several minutes the acidified mixture is filtered
and insolubles air dried. Trituration of this crude product with
30 ml. of isopropanol and then isopropyl ether affords 3.2 g. (61~)
of 5~6-dihydro-4-methyl-5-(4-nitrGphenyl)-3-phenyl-4H-1,2,4-
thiadiazine l,l-dioxide, m.p. 179.5-181C., (dec.)(corr.), from
acetonitrile.
Anal- Calcd- ~or C16H15N304S: C, 55.64; H, 4.38; N, 12.17.
Found: C, 55.77; H, 4.32; N, 12.23.
~ R (DMS0-d6, TMS): 3.02s, 3.40m, 5.03dd (8.5 Hæ, 6.0 Hz),
7.50s, 7.66d (8.5 Hz), 8.15d (8.5 Hæ).
- 37 -
~ q ~ ff,~ r,D ;~
Oral or lntraperi~oneal admlnistratiGn of 5,6-dlhydro-4-
methyl-5-(4-nitrophenyl)-3~phpnyl-4H-l~2~4-thiadia~lna l,l-dioxide
to the ~ouse produced non-specif ic CNS depresslon. 5~6-Dihydro-4-
methyl-5-(4-nitrophenyl)-3-phenyl-4H-1,2,4-thiadiazine l,l-dioxide
was not effective in preventing the phenylquinone writhing syndrome
in mice at an oral dose of 100 mg./kg. body weight or subcutaneous
dose of 6 mg./~g. body weight.
Example 34.- Treating N-isopropyl-N'-(3,4-dichlorostyrylsulfonyl)-
acetamidine with aqueous sodium hydroxide in ace~one according to the
procedure of Example 32 (c) provides N-isopropyl-N-(3,4-dichlorostyryl)-
acetamidlne.
Exam~ 3S. Treating N-methyl-N'-t3,4-dichlorostyrylsulfonyl)-
acetamidine with aqueous sodium hydroxide in acetone according to the
procedure of E~ample 32 (c) provides N-methyl-N-(3,4-dichlorostyryl)-
acetamidine.
: - 3~ -
.. .
. ............ . . .
