CA1071651A - Styrylamidines - Google Patents

Abstract

Abstract of the Disclosure Styrylamidines are prepared by treating styrylsulfonylamidines with base. The styrylamidines of the invention are effective in the prevention of aggregation of blood platelets and as analgesiics. The styrylsulfonylanidines of the invention which serve as precursors to the styrylamidines also have analgesic properties. Illustrative of the styrylanidines of the present invention are 4-amino-N-(4-aminostyryl)-benzemidite and N-(3,4-dichlorostyryl)acetamidine. An example of a styrylsulfonylamidine is N-(styryl)sulfonylacetamidine.

Description

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 --.~

~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 (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) 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 ~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.
:

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.

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.

, , .

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.

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.

....

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.

-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 .

.. .

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 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.

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.

>~

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=.

. .

. :. , ,:

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.

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.

~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.

(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 .

:~ 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.

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;

',' ', ' ' , :-' ' :

~ 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 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).

~ 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~ -.. .

. ............ . . .

Claims (63)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. The process for the preparation of styrylamidines having Formula I

(I) and a non-toxic pharmaceutically acceptable acid addition salt thereof wherein:
R1 is selected from hydrogen, nitro, amino, halogen, cyclohexyl, carbamoyl, lower alkylsulfonyl from 1 to 4 carbon atoms inclusive, sulfamoyl or lower alkanoylamido of from 2 to 4 carbon atoms inclusive;
R2 is selected from hydrogen or halogen;
R3 is hydrogen or lower alkyl having 1 to 4 carbon atoms;
A is selected from lower alkyl of from 1 to 3 carbon atoms inclusive, di(lower)alkylaminophenyl, phenyl, benzyl, .beta.-naphthyl, styryl, phenylbutadienyl, or a substituted phenyl radical represented by the symbol (X)n wherein X is selected from (lower) alkoxy from 1 to 4 carbon atoms inclusive, halogen, nitro, amino, lower alkanoylamido of from 2 to 4 carbon atoms inclusive, and n represents the integer of 1 or 2;
which comprises a process from the group consisting of:

(a) contacting in a reaction inert solvent at room temperature a styrylsulfonylamidine having Formula V

(V) wherein:
R1, R2, R3 and A are the same as defined above, with at least one molecular proportion of sodium hydroxide in a reaction inert-solvent whereby SO2 is eliminated from the styrylsulfonylamidine of Formula V to yield the styrylamidine of Formula I, (b) when R1 and X of a Formula I styrylamidine are nitro, reducing same with sodium borohydride in the presence of 10% palladium-on-carbon catalyst, and (c) treating a Formula I styrylamidine wherein R1 is amino with acetic anhydride in acetic acid and if desired reacting the substance of Formula 1 with a suit-able acid to yield a non-toxic pharmaceutically acceptable acid addition salt thereof.

2. The styrylamidine compound having Formula I

(I) and a non-toxic pharmaceutically acceptable acid addition salt thereof wherein:
R1 is selected from hydrogen, nitro, amino, halogen, cyclohexyl, carbamoyl, lower alkylsulfonyl from 1 to 4 carbon atoms inclusive, sulfamoyl or lower alkanoylamido of from 2 to 4 carbon atoms inclusive;
R2 is selected from hydrogen or halogen;

R3 is hydrogen or lower alkyl having 1 to 4 carbon atoms;
A is selected from lower alkyl of from 1 to 3 carbon atoms inclusive, di(lower)alkylaminophenyl, phenyl, benzyl, .beta.-naphthyl, styryl, phenylbutadienyl, or a substituted phenyl radical represented by the symbol (X)n wherein X is selected from (lower) alkoxy from 1 to 4 carbon atoms inclusive, halogen, nitro, amino, lower alkanoylamido of from 2 to 4 carbon atoms inclusive, and n represents the integer of 1 or 2;
whenever prepared by the process of claim 1.

3. The process for the preparation of N-(4-chlorostyryl) acetamidine or a non-toxic pharmaceutically acceptable acid addition salt thereof in accordance with claim 1 wherein N-(4-chlorostyrylsulfonyl)acetamidine is treated with 1 molecular proportion of sodium hydroxide employing dimethylsulfoxide as a solvent.

4. N-(4-chlorostyryl)acetamidine or a non-toxic pharmaceutically acceptable acid addition salt thereof whenever prepared by the process of claim 3.

5. The process for the preparation of N-(3,4-dichlorostyryl)acetamidine or a non-toxic pharmaceutically acceptable acid addition salt thereof in accordance with claim 1 wherein N-(3,4-dichlorostyrylsulfonyl)acetamidine is treated with 1 molecular proportion of sodium hydroxide employing dimethylsulfoxide as a solvent.

6. N-(3,4-dichlorostyryl)acetamidine or a non-toxic pharmaceutically acceptable acid addition salt thereof whenever prepared by the process of claim 5.

7. The process for the preparation of N-(3,4-dichlorostyryl)benzamidine or a non-toxic pharmaceutically acceptable acid addition salt thereof in accordance with claim 1 wherein N-(3,4-dichlorostyrylsulfonyl)benzamidine is treated with 1 molecular proportion of sodium hydroxide employing dimethylsulfoxide as a solvent.

8. N-(3,4-dichlorostyryl)benzamidine or a non-toxic pharmaceutically acceptable acid addition salt thereof whenever prepared by the process of claim 7.

9. The process for the preparation of N-(3,4-dichlorostyryl)-3,4-dimethoxybenzamidine or a non-toxic pharmaceutically acceptable acid addition salt thereof in accor-dance with claim 1 wherein N-(3,4-dichlorostyrylsulfonyl)-3,4-dimethoxybenzamidine is treated with 1 molecular proportion of sodium hydroxide employing dimethylsulfoxide as a solvent.

10. N-(3,4-dichlorostyryl)-3,4-dimethoxybenzamidine or a non-toxic pharmaceutically acceptable acid addition salt thereof whenever prepared by the process of claim 9.

11. The process for the preparation of N-(2-nitrostyryl) acetamidine or a non-toxic pharmaceutically acceptable acid addition salt thereof in accordance with claim 1 wherein N-(2 nitrostyrylsulfonyl)acetamidine is contacted with 4 molecular proportions of sodium hydroxide employing 3:1 acetone:water mixture as solvent.

12. N-(2-nitrostyryl)acetamidine or a non-toxic pharmaceutically acceptable acid addition salt thereof whenever prepared by the process of claim 11.

13. The process for the preparation of N-(4-nitrostyryl) benzamidine or a non-toxic pharmaceutically acceptable acid addition salt thereof in accordance with claim 1 wherein N-(4-nitrostyrylsulfonyl)benzamidine is contacted with 4 molecular proportions of sodium hydroxide employing 3:1 acetone:water mixture as solvent.

14. N-(4-nitrostyryl)benzamidine or a non-toxic pharmaceutically acceptable acid addition salt thereof whenever prepared by the process of claim 13.

15. The process for the preparation of 4-nitro-N-(4-nitrostyryl)benzamidine or a non-toxic pharmaceutically acceptable acid addition salt thereof in accordance with claim 1 wherein 4-nitro-N-(4-nitrostyrylsulfonyl)benzamidine is contacted with 5 molecular proportions of sodium hydroxide employing a 2:1 acetone:water mixture as solvent.

16. 4-Nitro-N-(4-nitrostyryl)benzamidine or a non-toxic pharmaceutically acceptable acid addition salt thereof whenever prepared by the process of claim 15.

17. The process for the preparation of 3,5-diamino-N-(4-nitrostyryl)benzamidine or a non-toxic pharmaceutically acceptable acid addition salt thereof in accordance with claim 1 wherein 3,5-diamino-N-(4-nitrostyrylsulfonyl)benzamidine is contacted with 4 molecular proportions of sodium hydroxide employing 3:1 acetone:water mixture as solvent.

18. 3,5-diamino-N-(4-nitrostyryl)benzamidine or a non-toxic pharmaceutically acceptable acid addition salt thereof whenever prepared by the process of claim 17.

19. The process for the preparation of 3-nitro-N-(4-nitrostyryl)benzamidine or a non-toxic pharmaceutically acceptable acid addition salt thereof in accordance with claim 1 wherein 3-nitro-N-(4-nitrostyrylsulfonyl)benzamidine is contacted with 4 molecular proportions of sodium hydroxide employing 3:1 acetone:water mixture as solvent

20. 3-Nitro-N-(4-nitrostyryl)benzamidine or a non-toxic pharmaceutically acceptable acid addition salt thereof whenever prepared by the process of claim 19.

21. The process for the preparation of 3-amino-N-(4-nitrostyryl)benzamidine or a non toxic pharmaceutically acceptable acid addition salt thereof in accordance with claim 1 wherein 3-amino-N-(4-nitrostyrylsulfonyl)benzamidine is contacted with 4 molecular proportions of sodium hydroxide employing 3:1 acetone:water mixture as solvent.

22. 3-Amino-N-(4-nitrostyryl)benzamidine or a non-toxic pharmaceutically acceptable acid addition salt thereof whenever prepared by the process of claim 21.

23. The process for the preparation of 4-(dimethylamino)-N-(4-nitrostyryl)benzamidine or a non-toxic pharmaceutically acceptable acid addition salt thereof in accordance with claim 1 wherein 4-(dimethylamino)-N-(4-nitrostyrylsulfonyl)benzamidine is contacted with 4 molecular proportions of sodium hydroxide employing 3:1 acetone:water mixture as solvent.

24. 4-(Dimethylamino)-N-(4-nitrostyryl)benzamidine or a non-toxic pharmaceutically acceptable acid addition salt thereof, whenever prepared by the process of claim 23.

25. The process for the preparation of N-(2-nitrostyryl) benzamidine or a non-toxic pharmaceutically acceptable acid addition salt thereof in accordance with claim 1 wherein N-(2-nitrostyrylsulfonyl)benzamidine is contacted with 4 molecular proportions of sodium hydroxide employing 3:1 acetone:
water mixture as solvent.

26. N-(2-nitrostyryl)benzamidine or a non-toxic pharmaceutically acceptable acid addition salt thereof whenever prepared by the process of claim 25.

27. The process in accordance with claim 1 involving the further additional step of reducing the compound of Formula I
wherein R1 is nitro to a compound of Formula I wherein R1 is amino.

28. The compound of Formula I or a non-toxic pharmaceuti-cally acceptable acid addition salt thereof wherein R1 is amino, whenever prepared by the process of claim 27.

29. The process for the preparation of N-(4-aminostyryl) benzamidine or a non-toxic pharmaceutically acceptable acid addition salt thereof wherein N-(4-nitrostyryl)benzamidine, prepared in accordance with claim 13, is reduced with sodium borohydride in the presence of 10% palladium-on-carbon catalyst.

30. N-(4-aminostyryl)benzamidine or a non-toxic pharmaceutically acceptable acid addition salt thereof whenever prepared by the process of claim 29.

31. The process for the preparation of N-(2-aminostyryl) benzamidine or a non-toxic pharmaceutically acceptable acid addition salt thereof wherein N-(2-nitrostyryl)benzamidine, prepared in accordance with claim 25, is reduced with sodium borohydride in the presence of 10% palladium-on-carbon catalyst.

32. N-(2-aminostyryl)benzamidine or a non-toxic pharmaceutically acceptable acid addition salt thereof whenever prepared by the process of claim 31.

33. The process for the preparation of 4-amino-N-(4-aminostyryl)benzamidine or a non-toxic pharmaceutically acceptable acid addition salt thereof wherein 4-nitro-N-(4-nitrostyryl)benzamidine, prepared in accordance with claim 15, is reduced with sodium borohydride in the presence of 10%
palladium-on-carbon catalyst.

34. 4-Amino-N-(4-aminostyryl)benzamidine or a non-toxic pharmaceutically acceptable acid addition salt thereof whenever prepared by the process of claim 33.

35. The process for the preparation of 3,5-diamino-N-(4-aminostyryl)benzamidine or a non-toxic pharmaceutically acceptable acid addition salt thereof wherein 3,5-diamino-N-(4-nitrostyryl)benzamidine, prepared in accordance with claim 17, is reduced with sodium borohydride in the presence of 10%
palladium-on-carbon catalyst.

36. 3,5-Diamino-N-(4-aminostyryl)benzamidine or a non-toxic pharmaceutically acceptable acid addition salt thereof whenever prepared by the process of claim 35.

37. The process for the preparation of 3-amino-N-(4-aminostyryl)benzamidine or a non-toxic pharmaceutically acceptable acid addition salt thereof wherein 3-nitro-N-(4-nitrostyryl)benzamidine, prepared in accordance with claim 21, is reduced with sodium borohydride in the presence of 10%
palladium-on-carbon catalyst.

38. 3-Amino-N-(4-aminostyryl)benzamidine or a non-toxic pharmaceutically acceptable acid addition salt thereof whenever prepared by the process of claim 37.

39. The process in accordance with claim 1 involving the further additional step of reacting the compound of Formula I
wherein R1 is amino with alkanoyl chloride, bromide, or anhydride having 2 to 4 atoms in the alkanoyl group under acylating conditions thereby producing a compound of Formula I
wherein R1 is alkanoylamido.

40. The compound of Formula I wherein R1 is alkanoylamido whenever prepared by the process of claim 39.

41. The process of preparing N-(4-acetamidostyryl) benzamidine or a non-toxic pharmaceutically acceptable acid addition salt thereof wherein N-(4-aminostyryl)benzamidine, prepared in accordance with claim 27, is treated with acetic anhydride in acetic acid as reaction medium.

42. N-(4-acetamidostyryl)benzamidine or a non-toxic pharmaceutically acceptable acid addition salt thereof, whenever prepared by the process of claim 41.

43. The process of preparing N-(3-bromo-4-cyclohexylstyryl)acetamidine or a non-toxic pharmaceutically acceptable acid addition salt thereof in accordance with claim 1 wherein N-(3-bromo-4-cyclohexylstyrylsulfonyl)acetamidine is treated with 1 molecular proportion of sodium hydroxide employing dimethylsulfoxide as solvent.

44. N-(3-bromo-4-cyclohexylstyryl)acetamidine or a non-toxic pharmaceutically acceptable acid addition salt thereof whenever prepared by the process of claim 43.

45. The process of preparing N-methyl-N-(4-nitrostyryl) benzamidine or a non-toxic pharmaceutically acceptable acid addition salt thereof in accordance with claim 1 wherein N-methyl-N-(4-nitrostyrylsulfonyl)benzamidine is contacted with 4 molecular proportions of sodium hydroxide employing 3:1 acetone:
water as solvent.

46. N-methyl-N-(4-nitrostyryl)benzamidine or a non-toxic pharmaceutically acceptable acid addition salt thereof whenever prepared by the process of claim 45.

47. The process for the preparation of N-styrylbenzamidine or a non-toxic pharmaceutically acceptable acid addition salt thereof in accordance with claim 1 wherein N-styrylsulfonyl) benzamidine is treated with 1 molecular proportion of sodium hydroxide employing dimethylsulfoxide as a solvent.

48. N-Styrylbenzamidine or a non-toxic pharmaceutically acceptable acid addition salt thereof whenever prepared by the process of claim 47.

49. The process for the preparation of N-(styryl) acetamidine or a non-toxic pharmaceutically acceptable acid addition salt thereof in accordance with claim 1 wherein N-(styrylsulfonyl)acetamidine is treated with 1 molecular proportion of sodium hydroxide employing dimethylsulfoxide as a solvent.

50. N-(Styryl)acetamidine or a non-toxic pharmaceutically acceptable acid addition salt thereof whenever prepared by the process of claim 49.

51. The process for the preparation of N-(3,4-dichlorostyryl)phenylacetamidine or a non-toxic pharmaceutically acceptable acid addition salt thereof in accordance with claim 1 wherein N-(3,4-dichlorostyrylsulfonyl)-phenylacetamidine is treated with 1 molecular proportion of sodium hydroxide employing dimethylsulfoxide as a solvent.

52. N-(3,4-dichlorostyryl)phenylacetamidine or a non-toxic pharmaceutically acceptable acid addition salt thereof whenever prepared by the process of claim 51.

53. The process for the preparation of N-(4-nitrostyryl)-acetamidine or a non-toxic pharmaceutically acceptable acid addition salt thereof in accordance with claim 1 wherein N-(4-nitrostyrylsulfonyl)acetamidine is treated with 1 molecular proportion of sodium hydroxide employing dimethylsulfoxide as a solvent.

54. N-(4-Nitrostyryl)-acetamidine or a non-toxic pharmaceutically acceptable acid addition salt thereof whenever prepared by the process of claim 53.

55. The process for the preparation of N-amino-N-(4-nitrostyryl)benzamidine or a non-toxic pharmaceutically acceptable acid addition salt thereof in accordance with claim 1 wherein 4-amino-N-(4-nitrostyrylsulfonyl)-benzamidine is contacted with 4 molecular proportions of sodium hydroxide employing 3:1 acetone:water mixture as solvent.

56. N-Amino-N-(4-nitrostyryl)benzamidine or a non-toxic pharmaceutically acceptable acid addition salt thereof whenever prepared by the process of claim 55.

57. The process for the preparation of N-(4-nitrostyryl) cinnamamidine or a non-toxic pharmaceutically acceptable acid addition salt thereof in accordance with claim 1 wherein N-(4-nitrostyrylsulfonyl)cinnamamidine is contacted with 4 molecular proportions of sodium hydroxide employing 3:1 acetone:water mixture as solvent.

58. N-(4-Nitrostyryl)cinnamamidine or a non-toxic pharmaceutically acceptable acid addition salt thereof whenever prepared by the process of claim 57.

59. The process for the preparation of N-(2,6-dichlorostyryl)acetamidine or a non-toxic pharmaceutically acceptable acid addition salt thereof in accordance with claim 1 wherein N-[(2,6-dichlorostyryl)sulfonyl]acetamidine is treated with 1 molecular proportion of sodium hydroxide employing dimethylsulfoxide as solvent.

60. N-(2,6-dichlorostyryl)acetamidine or a non-toxic pharmaceutically acceptable acid addition salt thereof whenever prepared by the process of claim 59.

61. The process of claim 1 involving the further step of reducing the compound of Formula I wherein R1 is nitro to a compound of Formula I wherein R1 is amino.

62. The process for the preparation of N-(4-aminostyryl) -2-naphthamidine or a non-toxic pharmaceutically acceptable acid addition salt thereof in accordance with claim 61 wherein N-(4-nitrostyryl)-2-naphthamidine is reduced with sodium borohydride in the presence of 10% palladium-on-carbon catalyst.

63. N-(4-aminostyryl)-2-naphthamidine or a non-toxic pharmaceutically acceptable acid addition salt thereof whenever prepared by the process of claim 62.