CA1181080A

CA1181080A - Imidazolylphenyl amidines, processes for their preparation and their pharmaceutical use, and intermediates of preparation

Info

Publication number: CA1181080A
Application number: CA000448583A
Authority: CA
Inventors: Enzo Cereda; Piero Del Soldato; Mario Bergamaschi; Arturo Donetti
Original assignee: Instituto de Angeli SpA
Current assignee: Instituto de Angeli SpA
Priority date: 1980-11-28
Filing date: 1984-02-29
Publication date: 1985-01-15

Abstract

ABSTRACT OF THE DISCLOSURE

The invention relates to a process for preparing a compound of formula IX

(IX) in which R and R1, which may be the same or different, each represents a hydrogen atom or a lower alkyl group, and B represents a cyano, acetyl, carbethoxy or carbamyl group, or an acid addition salt thereof, which process comprises reacting an amine of formula II

(II) (wherein R is as defined above) with a compound of formula X

(X) wherein R1 and B are as defined above, or in the case where B represents a cyano group, reacting an amine of formula II with cyanamide in the presence of a compound of formula VII

(VII) where R1 is as defined above and Y is a lower alkyl group and, where required, forming an acid addition salt thereof.

The invention further relates to compounds of formula (IX) as defined above or acid addition salts thereof. Compounds of formula (IX) are useful as intermediates in the preparation of pharmacologically active substituted imidazolylphenyl amidines which are H2 receptor blocking agents inhibiting gastric acid secretion (as antiulcer agents).

Description

~ 27086-3D

The present invention relates to novel intermediates useful in the preparation of substituted imidazolylphenyl amidines and a process for the preparation of the novel intermediates. This application is divided out of the parent application Canadian application serial No.391,057 filed on November 27, 1981.
The invention of the parent application relates to new substituted imida~olylphenyl amidines, to processes for their preparation, and to pharmaceutical compositions containing them. The new compounds are H2 receptor blocking agents and may be used as gastric acid secretion inhibi-tors and antiulcer agents.
The ineffectiveness of the ordinary antihistaminic drugs in blocking the stimulating effect of histamine on gastric secretion has prompted a search for histaminic antagonists. This effect of histamine, which is recogni~ed as a powerful agonist of gastric secretion is mediated through H2 receptors (Black, et al, Nature 236, 385, 1972) and is not inhibited by ~he classical antihistamines, Hl receptor blockers (Ash and Schild, Brit. J.
Pharmacol., 27, 427, 1966). Investigations in this direction culminated in the synthesis of a class of substances (G.J. Durant, et al, J. Med. Chem.
20, 901, 1977) typified by burimamide the first clinically effective H2 receptor antagonist. Although burimamide was sufficiently selective pharmacologically it seemed to lack sufficient oral bioavailability. Metiamide a subsequently evaluated H2 antagonist, proved more potent than burimamide and orally active in man. However, metiamide could not be introduced into therapy owing to its toxic side effects (agranulocytosis).
Cimetidine, a congener of metiamide bearing a cyanoguanidino instead of a thioureido group, proved as potent as metiamide as an H2 antagonist but is devoid of the toxic side effects of metiamide.

8/94 DIV.I. - 1 -Cimetidine has been recently introduced into therapy as an antiulcer drug. Its half-life however is relatively short and administration of several daily doses of 200-300 mg tablets is required. This shortcoming has prompted further research in the field of H2 receptor blockers aimed at finding longer acting and/or more potent substances. Recently, two new H2-receptor antagonists [ranitidine ~AH 19065) and tiotidine (ICI 125,225~]have been reported possessing chemical features analogous to cimetidine, i.e. a linear methylthioethyl side-chain bearing neutral polar groups. The main chemical variation in the latter compounds with respect to cimetidine consists in the replacement of the imidazole ring by an aminoalkyl furan and a 2-guanidino-thiazole ring, respectively. Both ranitidine ~Bradshaw, et al, Brit. J. Pharmacol. 66, 464 P, 1979) and tiotidine (TØ Yellin, Life Sci., 25, 2001-9, 1979) have been reported to be more potent than cimetidine either as H2 receptor antagonists in "in vitro" tests or as inhibitors of gastric acid secretion "in vivo".
We have now discovered that by substituting the linear side-chain, present in the classical as well as the two more recent H2 receptor antagonists, with a phenyl ring possessing optionally substituted amidino groups, new substances endowed wi~th potent H2-blocking activity, which inhibit gastric acid secretion, may be obtained.
The H2 receptor antagonists besides being use:Eul in blocking gastric secretion agents are potentially useful as therapeutically active agents in the treatment of inflammation [Yoshioka T., Monafo IV.W., Ayvazian et al. (Am J. Surg. 136, 681(1978)] and of cardiovascular disorders [Jerome P., Trzechiakowski and R. Levi [J. Pharmacol. Exp. Ther. 214, 629-634, ~1980)].
In some conditions a combination of Hl and H2 antagonist activity would be useEul [Barry L. Tepperman, Eugene D. Jacobson et al. (Life Sciences, vol.24, 2301-2308(1979)]. Some compounds disclosed herein show both these receptorial interactions.
According to one feature of the invention of the parent application there are provided compounds of general formula 1 R

~IN C -- _ ~ N = C - N (I) \ C~l ~ Rl R3 in which R, Rl and R3, which may be the same or different, each represents a hydrogen atom or a lower alkyl group, and R2 represents a linear or branched alkyl, alkenyl or alkynyl group, a cyano group, a hydroxyl group, a substituted or unsubstituted cycloalkyl or cycloaliphatic alkyl group, a bicyclic group, an aralkyl or aryl group (optionally substituted by halogen, methyl, methoxy or methylenedioxy groups) or a substituted or unsubstituted heterocycloalkyl or heterocyclic group which may optionally also contain a further hete~o atom; tautomers thereof; and acid addition salts of the aforesaid compounds.
For pharmaceutical use, the acid addition salts reEerred to above will of course be physiologically compatible acid addition salts but other acid addition salts may find use in the preparation of the compounds of formula I and their physiologically compatible acid addition salts. The term "acid addition salts" includes salts with inorganic and organic acids. Suitable physiologically compatible acid addition salts include, for example, salts formed with hydrochloric, maleic, fumaric, methanesul~onic, citric, tartaric or acetic acids.
It is to be understood that although in the formula I given above the double bond in the amidine radical and in the imidazole ring have been , "

-~8111i~8~

shown in a particular position, various other tautomeric forms are possible, and the invention of the parent application includes such tautomeric forms within its scope, both in terms of the compounds of the inventions and in terms of the manufacturing processes.
When in the compounds of formula I R, Rl and/or R3 represent lower alkyl groups these may, for example be, alkyl groups containing from 1 to 3 carbon atoms, e.g. methyl. When R2 represents a linear or branched alkyl group it may, for example, be an alkyl group containing from 1 to 8 carbon atoms; when R2 is a linear or branched alkenyl group it may, for example, be an alkenyl group containing from 2 to 5 carbon atoms; when R2 represents a linear or branched alkynyl group it may, for example be an alkynyl group containing 3 or 4 carbon atoms; when R2 is a bicyclic group it may, or example, be a norbornyl group; when R2 represents an aralkyl group it may, for example, be a benzyl group; when R2 represents an aryl group it may, for example, be a phenyl group optionally substituted by a halogen atom, e.g.
chlorine; when R2 represents substituted or unsubstituted cyclo-alkyl or cycloaliphatic alkyl groups they may, for example, contain from 3 to 6 carbon atoms; when R2 represents a substituted or unsubstituted heterocycycloalkyl or heterocyclic group this may, for example, be an unsaturated five-member ring which may also contain a further heteroatom. In the above mentioned formula ~I) the amidine radical may be in the ortho, meta or para position of the ben~ene ring.
Preferred compounds according to the invention o:E the parent application include those wherein the amidine radical is in the para position of the ben~ene ring, R, Rl and R3 all represent hydrogen atoms and R2 is a hydroxyl, methyl~ ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, neopentyl, hexyl, heptyl, octyl, allyl, ~-methylallyl, prenyl ~i.e. 3-~8~

me-thyl-but-2-enyl), propargyl, ~-methylpropargyl, cyano, norbornyl, benzyl, cyclopropyl, cyclopropylmethyl, dimethylcyclopropylmethyl, menthyl~
cyclohexyi, cyclohexylmethyl, phenyl, p-chlorophenyl, p-methylphenyl, p-methoxy-phenyl, methylenedioxyphenyl or 2-furylmethylgroup and their physiologically compatible acid addition salts. Such compounds generally have better activity and are therefore preferred as antiulcer agents and for treatment of disorders of the gastrointestinal tract.
The compounds of general formula I as hereinbefore defined may, for example, be prepared by the following processes, which processes constitute further features of the invention of the parent application.
A. Reaction of a compound of formula II
R

\ C C ~ (II) \ NH2 N N
\ CH- ~
(wherein R is as hereinbefore defined) with a reactive derivative of a compound of formula III

A C = NH - R2 X (~ (III) where Rl and R2 are as hereinbefore defined, X(~ represents the anion of an inorganic acid such as the chloride or fluoroborate ion, and A represents a benzyloxy group, a lower alkoxy group such as methoxy or ethoxy, or a chlorine atom. The compound of formula III may optionally be made to react as a base. Preferred temperatures are those between 0 and 100C and preferably from 20 to 60C. The reaction may, for example be carried out in the presence of an inert organic solvent such as, an alcohol having 1 to 3 carbon atoms such as methanol or ethanol or a halogenated hydrocarbon such as o dichloromethane, dioxan or acetone.
The compounds of formula III used as starting materials in the above process may be obtained by conventional methods, e.g., by reacting a carboxamide of the formula IV

Rl C - NH - R2 ~IV) o (wherein Rl and R2 are as hereinbefore defined) with benzoyl chloride, triethyloxonium fluoroborate, ethyl chloroformate, phosphorous oxychloride or phosphorous pentachloride.
B. Reaction of a compound of formula V
R

\ C--C_~ (V) HN N ~ N = C - oY
\ CH / Rl wherein R and Rl are as hereinbefore defined and Y represents a lower alkyl group, such as methyl or ethyl, with an amine of formula VI
H2N - R2 (VI) wherein R2 is as hereinbefore defined.
The reaction is conveniently carried out in the presence of an inert organic solvent. Suitable solvents include, for example, alcohols such as methanol, ethanol, or dioxane.
The reaction may, however, be carried out in the absence of a solvent of an excess of the amine of formula VI may optionally be used as a solvent. Preferred temperatures are those between 20 and 80C.
The compound of formula V may for example, be prepared in situ, by reacting an amine of formula II as herebefore defined with a c~mpound of formula VII

~83L~

oY
Rl - C \ OY (VII) OY

where Rl and Y are as hereinbefore defined, in the presence of an inorganic acid, for example sulfuric acid) as catalyst. Preferred temperatures are those between 60 and 120C. After a few hours the amine of formula VI is added to the reaction mixture.
The compound of the general formula V used as starting material may be prepared by methods known in the literature, for example by reacting an amine of the formula II with a compound of formula VII in the absence of a solvent and distilling off ~he alcohol formed during the reaction.
C. Reaction of a compound of formula VIII

/ \ (VIII) Y O Rl wherein Rl, R2, R3 and Y are as hereinbefore defined, with an amine of formula II as hereinbefore defined. Preferred temperatures are those between 20 and 80C. The alcohol formed during the reaction, is distilled off.

D. Reaction of a compound of formula IX
R
~ C C - _ ~ N~l - C = N - B (IX) \\ C~l~ Rl (wherein R and Rl are as hereinbefore defined and B represents a cyano, acetyl, carbethoxy or carbamyl group) with an amine of formula (VI) as herein-before defined.
The reaction may conveniently be performed in the presence of water or an inert organic solvent, for example an alcohol such as methanol or ethanol, LBl~

formamide, dioxane or acetonitrile. Preferred temperatures are those between 10 and 50C and preferably room temperature.
The compound of formula IX used as starting material in the above process is a novel intermediate and may be prepared by processes that are known in the literature.
According to one aspect of the present invention there is provided a compound of formula IX as defined above or an acid addition salt thereof.
According to a further aspect of the present invention there is provided a process for preparing a compolmd of formula IX

/ C ~ (IX) N N Nil - C = N - B
\ CH~ Rl in which R and Rl, which may be the same or different, each represents a hydrogen atom or a lower alkyl group, and B represents a cyano, acetyl, carbethoxy or carbamyl group, or an acid addition salt thereof, which process comprises reacting an amine of formula II

C C\ ~ (II) N NH
~ CH~ 2 (wherein R is as defined above) with a compound of formula X
Rl,~
/ ~ - N - B (X) P.~5 wherein Rl and B are as defined above, or in the case where B represents a cyano group, reacting an amine of formula II with cyanamide in the presence o a compound of formula VII / OY
Rl - C - Y (VII) \ OY

where Rl is a defined above and Y is a lower alkyl group and) where requiredJ
forming an acid addition salt thereof.
The reaction may conveniently be carried out in the presence of a suitable inert organic solvent for example a lower alcohol, ethers, ethylacetate, acetonitrile or dioxan or without a solvent at a temperature of from 20 to 80C. The compound of formula X may be prepared by conventional methods.
. Reaction of a compound of formula XI

C =C____~
I ~ N NH - C = N~ - R2 (XI) `\ C~l~ S~2 (where R and R2 are as hereinbefore defined) with a weak organic acid, for example formic, acetic or propionic acid.
The compound of formula XI may be obtained by convcntional methods, for example by oxidizing the corresponding thiourea by means of hydrogen peroxide in the presence of a lower alcohol preferably at temperatures between 20 and 50C.
F. To prepare a compound of formula I wherein Rl and R3 both represent hydrogen atoms: reaction in a single step of a compound of formula XII
Cll _ - CH l N N - Cll = N - R2 (XII) `~CII~ .

(wherein R2 is as hereinbefore defined) (an intermediate obtained without isol.ation in situ from an isonitrile of formula Ct- N - R2 and imidazole in the presence of AgCl according to T. Saegusa et al. [Tetrah~ Letters 1283 (1974)~) with an amine of formula II; or reaction of an amine of formula II with an iso-nitrile of formula C ~ N-R2 in the presence of CuCl. The reaction may be carried out without solvent, or in the presence of, for example, ethanol or dioxane. Compounds of formulae III, V, IX and XI are new compounds.
Preferred temperatures are those between 100-150C.
The compounds of formula I prepared according to the processes A to F may optionally be converted with inorganic or organic acids into physiologically compatible acid addition salts, for example by conventional methods such as by reacting the compounds as bases with a solution of the corresponding acids in a suitable solvent.
Particularly preferred acids include for example hydrochloricJ
maleic, fumaric and methanesulfonic acids. The salts thus obtained are normally soluble in water. The compounds of general formula I and their physiologically compatible acid addition salts are H2 receptor blocking agents which inhibit gastric acid secretion.
Particularly preferred compounds are the following:
N-Ethyl-N'-[4-~midazol-4-yl)-phenyl]-formamidine (Compound 11) N-Isopropyl-N'-[4-(imidazol-4-yl)-phenyl]-formamidine ~Compound 13) N-Allyl-N'-[4-(imidazol-4-yl)-phenyl]-formamidine ~Compound 14) N-n.Propyl-N'-[4-~imidazol-4-yl)-phenyl]-formamidine (Compound 18) N-sec.Butyl-N'-[4-(imidazol-4-yl)-phenyl]-formamidine (Compound 19) N-Isobuty]-N'~[4-(imidazol-4-yl)-phenyl]-formamidine (Compound 20) N-Prenyl-N'-[4-(lmidazol-4-yl)-phenyl]-formamidine ~Compound 23) N-Cyclopropylmethyl-N'-[4-(imidazol-4-yl)-phenyl]-formamidine (Compound 26) N-Cyclopropyl-N'-[4-(imidazol-4-yl)-phenyl]-formamidine (Compound 32) N~ ethylallyl)-~'-[4-(imidazol-~-yl)-phenyl]-formamidine (Compound 3~) N-Neopentyl-N'-[~-(imidazol-4-yl)-phenyl]-formamidine (Compo~md 36) N-(2,2-Dimethyl)-cyclopropylmethyl-N'-[4-(imidazol-4-yl)-phenyl]-formamidine (Compound 37) The antagonistic activity of compounds according to the invention of the parent application on histamine H2 receptors may be demonstrated either in vitro or in vivo by their inhibition of H -dependent biological _ _ _ _ _ 2 effects which include the histamine induced chronotropic effect and the histamine induced gastric secretion of acid respectively.
The positive chronotropic effect has been investigated in vitro in isolated guinea pig atria suspended in an organ bath (50 ml) containing oxygenated (02:95%-C02:5%) Krebs - Henseleit solution (pH 7.4) maintained at 32C. The myocardial preparation, loaded to 1 g isometric tension, is allowed to stabilize for 60 min., and then myocardial contractions are recorded through an isometric lever connected to a strain-gauge coupler, and the instantaneous rate is monitored with a cardiotachymeter, and a heat-writing pen recorder. After control, responses ~tachycardia) to histamine ~10 6 g/ml) are obtained three times at 30 minute intervals, the test compounds are added to the bath to the desired final concentration, and the atria are again treated with histamine. The chronotropic response obtained in the presence of the antagonist is then compared to the control response to histamine and the percent reduction of the histamine H2-evoked response is calculated. The average effective concen~ration (EC50) of the H2 antagonists is then calculated by the standard procedure according to D.R. Waud, Analysis of dose-response curves, in "Methods in Pharmacology"
Vol. 3 smooth muscle, Ed Daniel E.E. Paton, M., Plenum Press. New York (1975);
Ash and Schild, Br. J. Pharmacol. Chemother. 27, ~27-~39, 1966.

"In vitro" inhibitory activity in histamine induced tachycardia (guinea pig atria).

Compound EC50 10.
11 30 .
13 9,~ . .
1~ ~3.3 . 18 . 4.4 19 15 . 0 6.5 23 .7.~
26 4.8~
32 . 37.9 34 . 16 .8 36 12.1 .

. _ . _ CIMETIDINE 3 40 . O
_ _ _ _ 8~

Some compounds or ~ormula I have been found to effectively inhibit a~50 the spasmodic action of histamine which is inhibited by classical Hl anti-histamines, such as diphenhydramine and pyrilamine, in the isolated guinea-pig ileum.
The ability of the test compounds to inhibit histamine induced gastric acid secretion, has been investigated in vivo after intravenous or intraduodenal adminlstration in stomach perfused rats, according to Gosh and Shild (Br. J. Pharmacol, Chemother. 13, 54, 1958).
The preparation or tne animals under general anaesthesia (urethane, 1 g. Kg 1 i.p.~ and constant temperature, was achieved by inserting and tying in place polyethylene tubes (PE 50) in the aesophagus and in the pyloric-antral region. After the stomach was washed to remove remains of food, continuous perfusion of the stomach was started with saline, 0.5. ml.
min l (37~C), pri~ed by a Jobling peristaltic pump. After 30 min. of perfusion adaptation, the stomach perfusate was collected at 30. min intervals, and titrated for acic content, expressed as ~Eq of NaOH 1 N.
As con~rol acid output became constant, intravenous perfusion of histamine (1 mg.kg lhr 1) was started and maintained throughout the experimental period.
After the acid secretion ha2 reached a steady higher level, increasing doses of the test compounds were iniected intravenously in order to obtain dose response functions. ED50 values were then calculated by standard procedures. The compounds tested by this procedure showed a very potent antisecretory activity when administered intravenously at or below 100 ~g/kg 1; the results are reported in the following table II:

T~BL~3 II
"In vivo" antisecretory activity in histamine induced gastric secretion (stomach perfused rat).

Compound E D~o mg/kg 1 (i.v.)*
_ ll 0.02 13 O.Ol~g 14 0.0~4 18 ~.0111 19 0.0223 0.02~9 23 0.0559 26 0.0235 32 0.036 34 0.04~
36 0.030 - 37 0.034 : -CIMETIDINE -- - -- F -* The values of activi~y are expressed taking the compound as a base.

The acute toxicity of the particularly preferred compounds of general formula I was approximately determined by oral administration of a single dose to groups of 5 Swiss mice pre-fasted for 18 hours.
The resultant incidence of mortality after 14 days was evaluated. The results are reported in the following table, in which the values are expressed taking the compound as a base.

.

-TAB~E III
_ _ ~ _ _ CO~SPO~ND No. Dead/No. Treated Mice 11 3/5 at 500 mg/kg 13 2/5 at 500 mg/kg 14 1/5 at 500 mg/kg 1~ 2/5 at 375 mg~ks 19 2/5 at 500 mg/kg 20 2/5 at 250 mg/kg 23 1/5 at 250 mg/kg 26 4/5 ~t 500 mg/kg 32 0/5 at 500 mg/kg 34 2/5 at 500 mg/kg 36 2/5 at 250 mg/kg 37 5/5 a~ 25Q mg/kg _ _ . _ _ _ According to yet a further feature of the invention is a novel inter-mediate and there are provided pharmaceutical compositions comprising as active ingredient at least one compound of formu].a I, as hereinbefore defined, or a physiologically compatible acid addition salt thereof in association with a pharmaceutical carrier or excipient.
For pharmaceutical administration the compound of general formula I
or its physiologically compatible acid addition salt may be incorporated into convantional pharmaceutical preparations in either so~id or liquid form. The compositions may, for example, be presented in a form suitable for oral or parenteral administration. Preferred forms include, for example, capsules~ plain tablets, coated tablets and vials.
The active ingredient may be incorporated in excipients or carriers conventionally used in pharmaceutical compositions such as for example talc, gum arabic, lactose, gelatine, magnesium stearate, corn starch and aqueous or non-aqueous vehicles, compositions may be formulated as dosage lmits, each dosage unit being adapted to supply a fixed dose of the active ingredient. Each dosage unit may conveniently contain for example from 10 mg to 500 mg and preferably 20 mg to 150 mgJ of active ingredient according to the invention.

The following non-limiting examples serve to illustrate the present invention and the invention of the divisional applioation.

8~

_~ample l 5 Methvl-4-(3-amino~henyl)-l-H-imidazole 5-Methyl-4-(3-nitxophenyl)-l-H-imidazole [R. Morgenstern, et al. Pharmazie 30, 103 (1975)] (84 g) dissolved in methanol was hydrogenated in the presence o Pd/C 5% (0.8 g) at atmospheric pressure and at room temperature. When the calculated amount of hydrogen had been taken up, the catalyst was filtered off and the solution was evaporated to dryness to afford 62.5 g of the desired compound. M.p.
198-199C.
Analysis:
CloHl1N3 : found % C 69.12; H 6.43; N 24.40 calc. % C 69.34; H 6.40; N 24,26.
Example 2 (a) 5-Methyl-4-(4-nitrophenyl)-l-H-imidazole 5-Methyl-4-phenyl-1-H-imidazole as a nitrate salt ~R.
Morgenstern, et al. Pharmazie 30, 103 (1975)] (50 g) was added in po~tions to 96% H2SO4 (100 ml). The thick solution so obtained was heated at 100C for two hours, diluted with water (1000 ml) and again heated to 70 C
~or twenty hours. After cooling, the sol~tion was neutralized with 30 % NaOH and 17~ Na2CO3 aqueous solu-tions.- The solid precipitated (a mixture of the o- and -~-nitro derivatives) was filtered and converted into its nitrate salt by means of 30% nitric acid. The mixture of salts of the o~ and _-nitro isomers so obtained was re-crystallized from water to afford the pure para-isomer.
Neutralization of an aqueous solution of the para-nitro derivative yielded 30 g of 5 methyl-4-(4-nitrophenyl)-1-H-imidazole as a base sufficiently pure to be used in the next step. M.p. l9o-l9loc.
Analysis:
CloHgN3O2 : found % C 58.94; H 4.42; N 20.81.
calc. ~ C 59.10; H 4.46; N 20.68.
(b) 5-Methyl-4-(4-aminophenyl)-l-H-imidazole 5-Methyl-4-(4-nitrophenyl~ H-imidazole (80 g) dissolved in methanol was hydrogenated in the presence of Pd/C 5% ~0.7 g) at atmos-pheric press~.~re and at room temperature. When the calculated amount of hydrogen had been taken up, the catalyst was filtered off and the solution was evaporated to dryness to afford 43 g of 5-methyl-4-~4-aminophenyl)-1-1-1-imidazole. M.p. 215-216C.
Analysis:
CloH11N3 : found % C 69.12; ll 6.29; N 24.15.
calc. % C 69.34; H 6.40; N 24.26.
Example 3 (a) N-[3-~Imidazol-~-yl)-phenyl]-acetimidate A mixture of 4-(3-aminophenyl)-1-H-imidazole (15.9 g) [W. Schunack, et al, Arch. Pharm. 306~934 (1973)] and triethyl orthoacetate (18.17 g) was heated until the calculated amount of ethanol was distilled. The resulting solid was recrystallized from petroleum ether-diethyl ether (1:1 v/v) to give 21.6 g of N-[3-(imidazol-4-yl)-phenyl]-ethyl acetimidate. M.p. 126-127 C.
Analysis:
C13H15N30 : found % C 68.14; H 6.64; N 18.01.
calc. % C 68.1Q; H 6.59; N 18.33.
The following intermediates were prepared in a similar manner:
N-~3-(5-Methylimidazol-4-yl)-phenyl]-ethyl acetimidate was obtained starting from 5-Methyl-4-~3-amino-phenyl~-1-H-imidazole and tri-ethylorthoacetate. M.p. 130-131 C ~Et20).
Analysis:
C14H17N3O : found % C 69.32; H 7.08; N 17.15.
calc. % C 69.11; H 7.04; N 17.27.

-~83lql8~

N-[4-~5-Methylimidazol-4-yl)-phenyl]-ethyl acetimidate was obtained starting from 5-Methyl-4-(4-amino-phenyl)-l-H~imidazole and tri-ethylorthoacetate. M.p. 171-172C (Et20).
Analysis:
Cl4H17N30 : found % C 69.43; H 7.09; N 17.34.
calc. % C 69.11; H 7.04; N 17.27.

- l~a -.., ,~

~L~8~)8~J

N-l4-(Imidazol-4-Yl)-phenyl] ethyl acetimidate was obtained starting from 4-(4-amino-phenyl)-l-H-imidazole ~E. Balaban et al. J.Chem. Soc. 2701 ~1925~]
and triethylorthoacetate. M.p. 144-147C (Et2O).
Analysis:
Cl3Hl5N3O found % C 68.21; ~1 6060; N 18.14 calc. ~ C 68.10 H 6.59; N 18.33 (b) N-Methyl-N'-[4-(imidazol-4-Yl)-phenvl] acetamidine .
(Compound l) To a solution of N-[4-(imidazol-4-yl)-phenyl~ ethyl-acetimidate (8.02 g) in ethanol (20 ml) three portions of 33% methylamine in ethanol (8 g each; 24 g total) were added in a period of six days. The solution was evaporated to dryness and the residue was dissolved in 10~ hydrochloric acid. The acid solution was washed with ethyl acetate and basified to pH 10 with 10~ NaOH. The solid which separated was collected by filtration and dried to give the title compound (5.5g)O
M.p. 226-227 C.
Anaylsis:
C12Hl4N4 found % C 67.53; H 6.53; N 25.98.
calc. % C 67.26j H 6.59; N 26.15.
Maleate salt. M.p. 170-171 C.

The following acetamidines were prepared in a similar manner, starting from the appropriate ethyl acetimi-date as above described.
N-Methyl-N'-[3-(5-methylimidazol-4-yl)-phenyl]-acetamidine (Compound 2 M.p. 201-202 C.
Analysis:
Cl3Hl6N4 found ~ C 67.77; H 7.05; N 24.18.
calc. ~ C 68.39: H 7.06, N 24.54.
Hydrochloride salt. M.p. 260-261C.

N-Methyl-N'-[3-(imidazol-4-yl)-~henyl]-ace~amidine ICompound 3) ~I.p. 117-120C, Analysis:
C12H14N4 : found % C 66.86; H 6.81; N 25.82.
calc. % C 67.26; H 6.59; N 26.15.
Hydrochloride salt. M.p. 288-290 C.
N-Methyl-N'-[4-~5-methylimidazol-4-yl)-phenyl]-acetamidine (Compound 4) M.p. 223-226 C.
Analysis:
C13H16N4 : found % C 68.45; H 7.08; N 24.36.
calc. % C 68.39; H 7.06; N 24.54.
Hydrochloride salt. M.p. 283-285C.
Example_ N-Methyl-N'-~4-(imidazol-4-yl)-phenyl]-~ormamidine ~Compound 5) To a solution of N-methylformamide (2.36 g) in anhydrous diethyl ether (10 ml) was slowly added at O C a solution of benzoyl chloride (5.62 g) in anhydrous diethyl ether (30 ml). After one hour stirringJ the white solid which formed was filtered and immediately added to a suspension of 4-(4-aminophenyl)-1-H-imidazole (1.59 g) in dioxan (50 ml). The mixture was stirred overnight and then evaporated to dryness. The residue was taken up in water and the solution was basified to pH 10 with 10% NaOH and -the product which separated was ex-tracted with ethylacetate. The organic solution was dried (MgS04) and evapor-ated to dryness to give 0.75 g of the crude amidine which was recrystallized from acetone. M.p. 189-190 C.
Analysis:
CllH12N4 : found % C 65.55; ll 5.92; N 27.56.
calc. % C 65.98; H 6.04; N 27.98.
Fumarate salt. M.p. 188-189 C.

., .

E~amle S
N-~5ethvl-N'-[4-(imidazol)-4-yl)-phznyl]-formamidine (Compound 5) To a solution of N-met~yl formamide (1.48 g) in 15 ml of di-chlorome-thane, was slo~ly added at 0C a solution of 4.78 g of triethyloxonium fluoroborate ~H. Meerwein, Org. Synth.
46, 113 (1966)] in dichloromethane (25 ml). After six hr.
stirring at room temperature, 4-(4-aminophenyl)-1-H-imidazole (2 g) in ethanol (10 ml) was added dropwise. The mixture was stirred overnight, and then evaporated to dryness. The fluoroborate salt of N-me~hyl-N'- L4 ~imidazol-4-yl)-phenyl]-formamidine was dissolved in water and the solution was basi-fied to pH 10 with 10~ NaOH. The product which crystallized off was collected by filtration to give 1.4 g of the title formamidine. M.p. 189-190 C.
The following compounds were prepared in a similar manner, starting from the appropriate imidazolylphenylamine and from the suitable N-substitllted formamide:
N-tert-Butyl-N'-[4-(imidazol-4-yl?-phenyl]-formamidine (Compound 21) Fumarate salt. M.p. 192-194C (Ethanol).
Analysis:
C22H26N4O8 found % C 55.94; H 5.67; N 11.68.
calc. % C 55.69; H 5.52; N 11,81.
N-Menthyl-N'-¦4-(imidazol-4-yl)-p'~enyl]-formamidi~e (Compound 38) Tartrate salt. M.p. 106-109 C.
Analysis:
C28H40N4O12 found 6 C 53.99; H 6.48; N~8O94~
30- calc. ~6 C 53.84; H 6.45; N 8.97.
Example 6 (a) N-Methyl-N'-[4-(imidazol-4-yl)-phenyl]-formamidine (Compound 5) A suspension of 4-(4-aminophenyl)-1-H-imidazole (0.8 g) and ethyl N-methyl-formimidate hydrochloride (1.86 g) [F.H. Suydam, et al., J. Org. Chem. 34,292 (1969)] in 20 ml of anhydrous ethanol was stirred at room temperature for two days.
The clear solution was evaporated to dryness, and the oily residue was dis-solved in water. The solution so obtained was basified to pH 10 with 10%
NaOII. The product which separated was extrac*ed with ethyl acetate, the organic solution was evaporated to dryness and the product obtained was puri-fied through its hydrochloride salt to give 0.35 g of the title compound as a crystalline solid. M.p. 280-282 C ~ethanol).
Analysis:
Clllll4Cl2N4: found % C 47.98; ll 5.26; Cl 25.78; N 20.21.
calc. % C 48.36; H 5.17; Cl 25.96; N 20.51.
(b) N-Phenyl-N'- [4-(imidazol-4-yl)-phenyl]-formamidine (Compound 30) 5 g of 4-(4-aminophenyl)-l-H-imidazole were added to a solution of ethyl N-phenyl-formimidate [Org. Synth., 35, 65 ~1955)] ~4.6 g) in acetone (25 ml).
After stirring for 4 hours at room ~emperature the solid which separated was filtered and dried under vacuum. The product was treated with acetone and acidiEied with glacial acetic acid. N-Phenyl-N'-[4-(imidazol-4-yl)]-form-amidine crystallized as its acetate salt which was filtered to give 4.6 g of the title product. M.p. 123-124C.
Analysis:
C20H22N4O4: found % C 62.58; H 5.72; N 14.69.
calc. % C 62.81; 1l 5.80; N 14.65.
The following compounds were prepared in a similar manner, starting -from the appropriate imidazolphenylamine and from the suitable ethyl formimidates:
N-3,4-Methylenedioxyphenyl-N'- [4- (imidazol- 4-yl)-phenyl]-formamidine _ (Compound 39) Fumarate salt. M.p. 140 141 C.

Analysis:
C25H22N4Olo : found % C 55.48; H 4.15; N 10.50.
calc. % C 55.76; H 4.12; N 10.41.
N-4-Chlorophenyl-N'-[4-(imidazol-4-yl)-phenyl]-formamidine ~Compound 41) Acetate salt. M.p. 78-79 C.
Analysis:
C20ll21ClN4O~ : found % C 57.73; H 5.12; Cl 8.63; N 13.36.
calc. % C 57.62; H 5.08; Cl 8.50; N 13.44.
N-4-Tolyl-N'-[4-(imidazol-4-yl)-phenyl]-formamidine (Compound 42) Acetate salt. M.p. 91-92C.
Analysis:
C21ll24N404 : found % C 62.98; H 6.13; N 14.08.
calc. % C 63.62; H 6.10; N 14.13.
N-4-Anisyl-N'-[4-(imidazol-4-yl)-phenyl]-formamidine ~Compound 43 Fumarate salt. M.p. 131-132 C.
Analysis:
C25H24N409 : found % C 57.01; H 4.64; N 10.71.
calc. % C 57.25; H 4.61; N 10.68.
N-(3,4-Dimethylisoxazol-5-yl?-N'-[4-(imidazol-4-yl)-phenyl]-formamidine (Compound 44) M.p. 204-205 C.
Analysis:
Cl5Hl5N50 : found % C 63.91; H 5.40; N 24.85.
calc. % C 64.04; ll 5.37; N 24.90.
Exam ~
~a) N-Cyano-N'-[4-(imidazol-4-yl)-~henyl]-formamidine (Compound 6) A solution of 4-(4-aminophenyl)-1-H-imidazole (25.3 g) cmd ethyl N-cyano formimidate ~18.7 g) IK.R. Huffman et al., J. Org. Chem. 28, 1816, ~1963)]
in ethanol was stirred at room temperature overnight. The product which crystallized at the end of the reaction was collected by filtration, washed ~ith cold ethanol to give 30.7 g of the title compound. M.p. 234-235 C.
Analysis:
ClllllgN5 : found % C 61.94; H 4.36; N 32.95.
calc. % C 62.55; H 4.30; N 33.16.

- 23a -~8~

The following compounds were prepared in a similar man-ner starting from the appropriate imidazolyl phenyl amine.
N-Cyano-N'-[3-(imidazol-4-yl)-phenyl¦-formamidine (Compound 7) ~.p. 206-207C.
Analysis:
Cl1HgN5 found % C 62,60; ~ 4.22; N 32.84.
calc. % C 62.55; H 4.30; N 33~16.
N-Cyano-N'-[4-(5-meth~limidazol-4-y~ phenyl]
formamidine M.p. 236-238 C.
Analysis:
C12HllN5 found ~ C 63.44; H 5.04; N 30O94.
calc. % C 63.98; H 4.92; N 31.09.
N-Cyano-N'-~3-(5-methylimidazol-4-yl)-phenyl]-formamidine M.p. 221-223 CO
Analysis:
C12HllN5 found ~ C 63.96; ~ 5,06; N 30.820 calc. : C 63.98; H 4.92; N 31.09.
(a') N-Cyano-N'-[4-imidazol-4-yl)-,ohenyl]-formamidine. -(~ompound 6) A mixture of 4-(p-aminophenyl)~l-H-imidazole (113.8 g), ethyl orthoformate (132.4 g) and cyana~mide (30.7 g~ was heated at 100C for 20 minutes and stirred at room temperature for 3 hours. The solid was filtered and dried to give 130 g of the title compound. Mp. 236-238C.
(b) N-Methyl-N'-[4-(imidazol~4-yl)-phenyll-formamidine (Compound 5) ~-Cyano-N'-[4~(imidazol-4-yl)-phenyl]-formamidine (20 g) was added in one portion to 359O methylamine in water (70 ml). After few minutes, the solid N-methyl-N'-[4-(imidazol-4-yl)-phenyl]-form~midine separated out of the solution. This solid was filtered, washed with water and dried to give 13.45 g of the title product t which was re-crystallized from acetone. M.p. 189-190C.

:- -Fumarate sal-t. M.p. 188 -189 C.
The following compounds ~ere prepared in a similar manner, starting from the appropriate N cyano ~ormamidine derivatives.
N-l~ethyl-N'-[3-(imidazol-4-yl)~phenyl]-formamidine (Compound 8) Maleate salt. M.p. 149-150 C. (ethanol).
Analysis:
ClgH20N4O8 found % C 51.93; H 4.73; N 13.15.
calc. % C 52.78; H 4.66; N 12.96.
N-Methvl-N'-[3-(5-methylimidazol-4-yl)-phenyl]-~ormamidine (Com ound 9) M,p. 180-181 C.
Analysis C12H14N4 found % C 67.40; H 6.67; N 26.40 calc. % C 67.26; H 6.59; N 26.15.
N-Methyl-N'-[4-(5-methylimidazol-4-yl)-phenyl3-formamidine ~Compound 10) M.p. 225-226 C.
Analysis C12H14N4 found % C 66.81; H 6~70; N 25.82.
calc. % C 67.26; H 6.59; N 26.15.
N-Ethyl-N'-[4-(imidazol-4-yl)-phenyll-formamidine,(Compound 11) Hydrochloride salt. M.p. 253-254 C.
Analysis:
C12H16C12N4 found % C 49.92; H 5.70; Cl 25.00; N 19.56.
calc. % C 50.18; H 5.61; Cl 24.69; N 19.51.
N-Butyl~N'-[4-(imidazol-4-yl)-phenxl]-formamidine_(Compound 12) Hydrochloride salt. M.p. 206-208 C.
Analysis:
C14H20C12N4 found ~O C 53~48; H 6.51; Cl 22.63; N 17.59~
- 30 calc. % C 53.34; H 6.39i Cl 22.49; N 17.77.
N-Isopr~ _N'-[4-(imidazol-4-yl)-phenyl]-formamidine , (Compour.d 13) Fumarate salk. M.p. 130-133 C.
Analysis:
C21EI~4N4O8 found ~ C 53.91; Y. 5.30; N 12.36~ -~alc. % C 54.78; H 5.25; N 12.17.

~3L8~
.
N-Allyl=N'-[4-(imidazol-4-vl)-phenyl]-formamidine (Com~ound 14) l~aleate salt. M.p. 153-154C
Analysis:
C21~22N48 found ~ C 54.85; H 4.71;N 11.93.
caic % C 55.02; H 4L84; N 12.22.

N-HYdroxy-N'-[4-(imidazol-4-Yl)-Phenvll-formamidine (Co~ound 15) Hydrochloride salt. M.p. 207-208 C.
Analysis:
C1oH12C12N4O found % C 43.70; H 4.34; Cl 25.48; N 20.45 calc. ~ C 43.65; H 4.39; Cl 25.76; N 20.36.

N-n-Propyl-N'-t4-(imidazol-4-yl)-phenvl]-formamidine_ (_m?ound 13) Hydrochloride salt. M.p. 220-221C. (Ethanol).
Analysis C13H18Cl2N2 found ~C 51.13; H 6.10; Cl 23.30; N 18.51.
calc. ~C 51.83; H 6.02; Cl 23.54; N 13.60.

N-sec-Butyl-N'-[4-(imidazol-4~1)-phenyl~-formamidine (Com~ound 19) Hydrochloride salt. M.p. 196 197C. (Ethanol).
Analysis H20cl2N4 found % C 52.97; H 6.51; Cl 22.08; N 17.44.
calc. % C 53.33; H 6.39; Cl 22.49; N 17.77.

N-Isobutyl-NI-t4-(imidazol-4-yl)-phenyl]-formamidine (Com~ound 20) .
Hydrochloride salt. M.p. 238-240 C. (Ethanol) Analysis C14 20 2 4 found % C 52.69; H 6;54; Cl 22.04; N 17.38.
calc % C 53.33; H 6.39; Cl 22.49; N 17.77 :~8~
N~ ethvl)n hexyl-N'-[4-(lmidazol-4-yl)-phenyl]-formamidine __ (Com~ound 2_) Maleate salt. M~p. 150-151 C. (Acetone) Analysis C25H32 48 found ~ C 59.09; H 6.08; N 10.63.
calc % C 58.13; H 6.24; N 10.85.

N-Pren~l-N'-[4-(imidazol-4-~1)-phenyl]-formamidine (Compound 23). Fumarate salt. M.p. 174-175 C. (Ethanol).
Analysis C23 26 4 8 found % C 56.94; H 5.48; N 11.67.
calc. % C 56.78; H 5.39; N 11052.

N-Propar~v~1-N'-[4-('imidazol-4-yl)-phenvl]-formamidine (Com~ound 2 4) _ Methanesulfonate salt. M.p. 184-135 C. (Ethanol).
Analysis.
ClsH2oN4o6s2 found ~ C 42.75; H 4.93; N 13.20; S 15-29-calc. ~ C 43.26; H 4.84; N 13.45; S 15.39.

N-n Hexyl-N'-[4-(imidazol-4-yl)-ehenyl]-formamidine (Compound 25) Hydrochloride salt M.p. ~270 C. (Ethanol).
Analysis C16H24Cl2N4 found % C 55.35; H 7.00; Cl 20.39; N 16.00.
- calc. ~ C 55.97; H 7005; Cl 20.66; N 16032.

N-C~cloprop~ylmethyl-N'-[4-(imidazol-4-yl)-phen~l]-formamidine (Com~nd 26) Fumarate salt. M.p. 127 128 C.
- Analysis C22H2~N408 found % C 56.21; H 5.09; N 11.99.
calc. % C 55.93; H 5.12; N 11.86.

~ .

o N-sic~clo-[2~2~l]-He t-2-vl-N'~4-~imi~zol-4-yl)-phenyl3-p _ _ _ _ formamidine (Com~oun~ 27) Maleate salt. M.p. 182-lB3 C.
_ Analysis C25H28N4O8 fo~d ~C 57.90; H 5.43; N 10.94.
calc. ~C 58.58; H 5.Sl; N 10.93.

F -f l-N'-~4-(imidazol-4-vl)- hen l]--formamidine N~ Ul ury p y (Compo~nd 28~
~ydrochloride salt. M.p. 215-217 C (Ethanol).
Analysis:
Cl5Hl6cl2N4o found % C 52.80; H 4.87; Cl 20.62; N 16.27.
calc. % C 53.11; H ~.75; Cl 20.90; N 16.52.

N-Cvcloh~ l-N'-~4-'imidazol-4- l)-~hen l]-formamidine -- --' Y ~ y (Com~ound 29) Fumarate salt. M.p. 139-141 C. (Ethanol).-Analysis C24H28N4O8 fo~nd % C 57.89; H 5.68; N 10.99.
calc. ~ C 57.59; H 5.64. N 11.20.

N-Ben~yl-N'-[4-(imidazol-4-yl)-phenyl3-formamidine (_m ound 31) Hydrochloride salt. M.p. 210-212 C. (Ethanol) Analysis C17H18Cl2N4 found % C 57.91; H 5.29; Cl 19.94; N 15.87.
calc. % C 58.46; H 5.19; Cl 20.30; N 16.04.

N-Cy~lopropyl-N~-[4-(imidazol-4-yl)-phenyl]-ormamidin~
(Compound 32) Fumarate salt. M.p. 185-186 C. (Ethanol).
Anal~sis C21H22N4O8 found ~ C 55.09; H 4;74; N 12.48.
calc. ~ C 55,02; H 4.84; N 12.22.

N~ ethYl~ro~arqvl)-N'-[4-(imidazol-4~ henY1]-formamidine (Com~ou~d 33) Maleate salt. M.p. 188 C.
Analysis C22H22N4O8 found % C 56.28; H 4.15; N 11.87.
calc. % C 56.16; H 4.17; N 11.91.

N-(~-Meth~laily~-N'-r4-(imidazol-4-yl)-phenyl]-ormamidine (Com?ound 34) Maleate salt. M.p. 185 C.
Analysis C22H24N4O8 found % C. 55.87; H 5.04; N 11 76.
calc. ~ C 55.93; H 5.12; N 11.86.

N-n.Octyl-~'-[4-(imidazol-a-vl)-~henYl]-formamidine (ComPound 35) Fumarate salt. M.p. 152-153 C.
Analysis C26H34N4O8 found % C 58.52; H &.35; N 10.72~
calc. % C 58.85; H 6.46; N 10.56.

N-Neopentyl-N'-[4-(imidazol-4-~ -phenyl]-formamidi~
(Compound 36) Fumarate salt. M.p. 251-252C.

Analysis C23H28N4O8 found % C 56.67; H 5.81; N 11.40.
calc. ~ C 56.55; H 5.78; N 11.47.

N-(2,2-Dimethyl)-cyclo~ropylmethyl-NI-[4-(imida2Ol-4-yl)-~_enyl]~formamidine (Com~ound 37) - -Hydrochloride salt. M.p. 246~248C.
Analysis C16~22Cl2N4 found ~ C 55.90; H 6.53; Cl 20.88; N 16.30.
calc. % C 56.30, H 6.50; Gl 20.78; N 16.42.

~L~L89~

~-CycloheYylmethyl-N'-[4-~imidaæol-4-~1)-phenyl)-formamidine ~om~ound 40) Fumarate salt. M.p. 154-155C.

Analysis C25 30 4 8 ~ound 6 C.57.79; H 5.91, N 10.75.
calc. % C 58.36; H 5.88; N 10.89.

Exam~le 8 N,N-Dimethyl-N'-~4-(imidazol-4-yl)-phenyl]-formamidine ~Compound 16) A solution of 4-(4-aminophenyl)-1-H-imidazole (3.18 g) in N,N-dimethyl-formamide diethylacetal (8.82 g) was stirred at room temperaiure for two days. Addition of diethyl ether afforded precipitation o~ the formamidine (Compound 16) which was collected by filtration ~3.9 g) M~po 141-142C.
Analysis C12H14 4 found % C 67.02; H 6.50; N 26.28.
calc. % C 67.26; H 6~59; N 26.15.

N,N-Dimethyl-N'-[4-(5-methYlimidazol-4~ phenyl]-form~Tnidine (Compound 17) was prepared in a similar manner starting from 5-Methyl-4-(4-aminophenyl)-1-H-imidazoleO Mop~ 228-229C.
Analysis Cl3Hl6M~ found % C 69.08; H 7.16; N 24.28.
calc. % C 68.39; H 7.06; N 24.54.

Example 9 Methvl-N'~4-~imidazol-~-yl)-phenyl]-formamidine ~Compound 5) A mixture of 4-(4-aminophenyl)-1-H-imidazole (1.59 g) and triethyl orthoformate (2.22 g) was heated for 30 min. at 100 C in the presence oi catalytic amounts oE 96~ H2SO4.
solution of methylamine 336 in etha~ol (9.5 g) was then added dropwise to the cooled reaction mixture. The solution was stirred at room temperature for twenty hours and then evaporated to dryness. The residue obtained was dissolved in 10~6 hydrochloric acid and the acid solution was washed with ethyl acetate and then ~asified -to pEI10 wi-th 10% NaOH. The product which separated was extracted with ethyl acetateto give, after evapo~ation of the sol~ent, 0.45 g of the compound 5.
M.p. 188-189 CO

E~am~le 10 (a) N _ethyl-N'-[4-(imidazol-4-vl)-~henyl]-thiourea A solution of 4-~4-aminophenyl~l-H-imidazole (2.3g) and methyl isothiocyanate (1.15 g) in 30 ml of ethanol was refluxed for 0.5 hour and evaporated to dryness. The oily ~ase so obtained was pl-rified by conversion into the corresponding hydrochloride salt by bubbling hydrogen chloride through it, in isopropanol. The desired thiourea was obtained as a white solid (2 g) M~p. 210-211C.
Analysis:
CllH13ClN4S found % C 49.23; H 4.98; Cl 13.20;N20.64;S11.72.
calc. % C 49.15; H 4.87j Cl 13.19;N20.84;S11.92.
(b) N-Methyl-N'-[4-(imidazol-4-yl~-phenYl]-formamidine sulfinic acid Hydrogen peroxide (31~o~ 1.08 g) was added dropwise in 30 min.to A stirred,ice-cooled solution of N-methyl-N'-~4-(imidazol-4-yl)-phenyl] thiourea (1.16 g) in S ml of methanol. After two hr stirring the mixture was evaporated to dryness and the residue so obtained was crystallized from ethanol to afford 0.95 g of the desired compound.
Analysis:
CllHl2N~O2S found % C S0.17; H 4.55; N 21.41; S 12.04.
calc. % C 49.98; ~ 4.57; N 21.20; S 12.12.
Acetate salt. M.p. 194-195 C (acetone).
30 (C) N-Meths~l~N'-[4-(imidazol-4~yl)-~he~y~ll-formamidine -(Co~ound 5) N-Methyl-N'-[4-~imidazol-4-yl)-phenyl]-formamidine sulfinic acid (0.9 g) was dissolved in 15 ml of glacial acetic acid and reflu:ced for one hr. The concentrated solution was basified to pH 10 with 10% NaOH and extracted with ethyl acetate. The organic solution ., was eYaporated to dryness to af~ord 0.3 g of N-me~hyl-N'-[4-(imidazol-4-yll-phenyl]-formamidine. M.p. 187-189 C.

Exam~le }-~N-t. ~ut~1-N'~[4-(~midazol-4-yl)-~henyl]-formamidine (~omPound 21) A mixture of 4-~p-aminophenyl)-1-H-imidazole (2.3 g), t-butvlisonitrile (1.25 g), AgCl (0.2 g) and imidazole (O.lly)was h~ated a-t 100 C for 13 hours. The thick reaction mixture was treated with 10% HCl and ethyl acetate. The acid solution was taken to pH 6.5 with 10% NaOH, treated with charcoal, filtered and completely basiiied. The layer which separated was extracted with ethyl acetate. After drying,the organic soluticn was evaporated to give 0.38 g of the title compound. Fumarate salt.
M.p. 192-194 C.
Example 12 N-Cyclohexyl-N'-~4-(imida201-4-yl)-phenYl]-formamidine (Com~ound 29) A mixture o 4-(p-aminophenyl)-1-H-imida~ole (l.S9 g) cyclohexyl isonitrile (1.2 g) and CuC1 (0.99 g) was heated at 150C for 3 hours. The thick reaction mixture was extracted into methanol. The methanol solution after treated with charcoal was evaporated to dryness and extracted into ethyl acetate and 10~ hydrochloric acid.
The acid solution ~as basified to pH 7.5 with 17% Na2C03 and extracted into ethyl acetate. The organic solution was evaporated to dryness. The residue, aft~-r recrystallization from acetone gave 0.25 g of the title product. M.p. 220-221 C.
Fumarate salt. M.p. 139-141 C.

Exc~n~le 13 Tablets. One tablet contains:
-active ingredient 50 mg -lactose 217 mg -corn starch 30 mg -magnesium stearate 3 mg E~am~le lg Capsules. One capsule contains ~ active ingredient 50 mg 10 - corn starch 17C mg - magnesium stearate 2 mg Exam~le 15 Vials. One vial contains - active ingredient 50 mg - water for injection q.s.5 ml

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for preparing a compound of formula IX

(IX) in which R and R1, which may be the same or different, each represents a hydrogen atom or a lower alkyl group, and B represents a cyano acetyl, carbethoxy or carbamyl group, or an acid addition salt thereof, which process comprises reacting an amine of formula II

(II) (wherein R is as defined above) with a compound of formula X

(X) wherein R1 and B are as defined above, or in the case where B represents a cyano group, reacting an amine of formula II with cyanamide in the presence of a compound of formula VII

(VII) where R1 is as defined above and Y is a lower alkyl group and, where required, forming an acid addition salt thereof.

2. A process according to claim 1 wherein in the starting materials Y is methyl or ethyl.

3. A process according to claim 1 wherein the reaction is carried out in the presence of an inert organic solvent.

4. A process according to claim 3 wherein the solvent is a lower alcohol, an ether, ethylacetate, acetonitrile or dioxane.

5. A process according to claim 1 wherein the reaction is carried out at a temperature of from 20 to 80°C.

6. A process according to claim 1 wherein in the starting materials R
and R1 are each hydrogen.

7. A compound of the formula IX as defined in claim 1 or an acid addition salt thereof whenever prepared by a process according to claim 1 or 3 or by an obvious chemical equivalent thereof.

8. A compound of the formula IX as defined in claim 1 or an acid addition salt thereof whenever prepared by a process according to claim 4 or S or by an obvious chemical equivalent thereof.

9. A compound of the formula IX as defined in claim 1 wherein Y is methyl or ethyl or an acid addition salt thereof whenever prepared by a process according to claim 2 or by an obvious chemical equivalent thereof.

10. A compound of the formula IX as defined in claim 1 wherein R and R1 are each hydrogen, or an acid addition salt thereof whenever prepared by a process according to claim 6 or by an obvious chemical equivalent thereof.

11. A process according to claim 1 wherein in the starting materials R and R1 are each hydrogen and B is cyano.

12. A process for preparing N-Cyano-N'-[4-(imidazol-4-yl)-phenyl]-formamidine which comprises reacting 4-(4-aminophenyl)-1-H-imidazole with ethyl N-cyano formimidate.

13. A process for preparing N-Cyano-N'-[4-(imidazol-4-yl)-phenyl]-formamidine which comprises reacting 4-(p-aminophenyl)-1-H-imidazole with ethyl orthoformate and cyanamide.

14. The compound N-Cyano-N'-[4-(imidazol-4-yl)-phenyl]-formamidine or an acid addition salt thereof whenever prepared by a process according to claim 11, 12 or 13, or by an obvious chemical equivalent thereof.