Potent DBH inhibitors having the formula ##STR1## can be used to inhibit DBH activity in mammals.

FIELD OF THE INVENTION 
This invention relates to inhibitors of dopamine-.beta.-hydroxylase. 
BACKGROUND OF THE INVENTION 
In the catecholamine biosynthetic pathway, tyrosine is converted in three 
steps to norepinephrine (NE). Intermediates are dihydroxyphenylalanine 
(DOPA) and dopamine (DA). The latter is hydroxylated to norepinephrine by 
dopamine-.beta.-hydroxylase (DBH) in the presence of oxygen and ascorbic 
acid. 
Inhibition of catecholamine activity has been found to decrease 
hypertension. See, for example, Matta et al., Clin. Pharm. Ther. 14, 541 
(1973), and Teresawa et al., Japan Circ. J. 35, 339 (1971). Weinshilboum, 
Mayo Clin. Proc. 55, 39 (1980), reviews compounds which inhibit 
catecholamine activity by interfering with adrenergic receptors. 
Alternatively, the catecholamine biosynthetic pathway can be suppressed at 
any of the three steps, resulting in decreased levels of NE. In addition 
to decreasing hypertension, inhibitors of NE synthesis are active as 
diuretics, natriuretics, cardiotonics and vasodilators.. Inhibition of DBH 
activity can have the added advantage of increasing levels of DA, which as 
reported by Ehrreich et al., "New Antihypertensive Drugs," Spectrum 
Publishing, 1976, pp. 409-432, has been found to have selective 
vasodilator activity at certain concentrations. 
DBH inhibitors have also been shown to reduce or prevent formation of 
gastric ulcers in rats by Hidaka et al., "Catecholamine and Stress," edit. 
by Usdin et al., Permagon Press, Oxford, 1976, pp. 159-165 and by Osumi et 
al., Japan. J. Pharmacol. 23, 904 (1973). 
A number of DBH inhibitors are known. These are generally divided into two 
classes, namely, metal chelating agents, which bind to copper in the 
enzyme, and phenethylamine analogues. Rosenberg et al., "Essays in 
Neurochemistry and Neuropharmacology, Vol. 4," edit. by Youdim et al., 
John Wiley & Sons, 1980, pp. 179-192, and Goldstein, Pharmacol. Rev. 
18(1), 77 (1966), review DBH inhibitors. The former report that many of 
the potent DBH inhibitors have a hydrophobic side chain of size comparable 
to the aromatic ring of DA, leading the authors to suggest that 
incorporation of a terminal hydroxyl group on a 4- to 6- carbon side chain 
on a phenethylamine analogue might yield a potent inhibitor. 
Known inhibitors include: 
5-alkylpicolinic acids [See, Suda et al., Chem. Pharm. Bull. 17, 2377 
(1969); Umezawa et al., Biochem. Pharmacol 19, 35 (1969); Hidaka et al., 
Mol. Pharmacol. 9, 172 (1973); Miyano et al., Chem. Pharm. Bull. 26, 2328 
(1978); Miyano et al., Heterocycles 14, 755 (1980); Claxton et al., Eur. 
J. Pharmacol. 37, 179 (1976)]; 
BRL 8242 [See, Claxton et al., Eur. J. Pharmacol. 37, 179 (1976)]; 
1-alkyl-2-mercaptoimidazole [See, Hanlon et al., Life Sci. 12, 417 (1973); 
Fuller et al., Adv. Enzyme Regul. 15, 267 (1976)]; 
substituted thioureas [See, Johnson et al., J. Pharmacol. Exp. Ther. 168, 
229 (1969)]; and 
benzyloxyamine and benzylhydrazine [See, Creveling et al., Biochim. 
Biophys. Acta 64, 125 (1; Creveling et al., Biochim. Bioohvs. Res. Commun. 
8, 215 (1962); van der Schoot et al., J. Pharmacol. Exp. Ther. 141, 74 
(1963). Bloom, Ann. N. Y. Acad. Sci. 107, 878 (1963)]. 
All of the above compounds except benzyloxyamine and benzylhydrazine 
apparently owe their inhibitory effect to metal chelating properties. 
Alkyl derivatives of 2-mercaptoimidazole are more potent, presumably due 
to non-specific interaction of the alkyl substituent with the enzyme. 
Benzyloxyamine and benzylhydrazine are phenethylamine derivatives which 
apparently act as competitive inhibitors. 
In addition to the above compounds, Runti et al., Il Farmaco Ed. Sc. 36, 
260 (1980), report that other fusaric acid derivatives and analogues 
inhibit DBH. These include phenypicdlinic acid, which is reported to have 
twice the inhibitory activity of fusaric acid, and 
5-(4-chlorobutyl)picolinic acid, and others such as substituted amides of 
fusaric acid and acids and amides of 5-butyroylpicolinic acid, 
5-aminopicolinic acid and 5-hydrazinopicolinic acid, and derivatives 
thereof. 
Hidaka et al., Molecular Pharmacology, 9, 172-177 (1973) report that 
5-(3,4-dibromo)butyl picolinic acid and 5-(dimethyldithiocarbamoyl)methyl 
picolinic acid are DBH inhibitors. 
Bupicomide, 5-(n-butyl)picolinamide, is reported by Ehrreich et al., "New 
Antihypertensive Drugs," Spectrum Publications, 1976, pg. 409-432, to be a 
DBH inhibitor and to have antihypertensive activity. Friedman et al. 
Psychosomatic Med. 40, 107 (1978), report that patients treated with 
alpha-methyl-DOPA, guanethidine and reserpine, but not propanolol and 
diuretics, have lowered DBH levels, although the significance of the 
observation is uncertain. 
Although there are many known inhibitors of DBH, most of these agents have 
not found clinical application because of non-specific, often toxic, 
properties they possess. Fusaric acid, for example, is hepatotoxic. See, 
for example, Teresawa et al., Japan. Cir. J. 35, 339 (1971) and references 
cited therein. Presumably, the picolinic acid structure interacts with a 
number of metalloproteins and enzymes in non-specific fashion to produce 
observed side effects. 
In U.K. specification 1,555,580 are disclosed compounds having the formula: 
##STR2## 
wherein .sup.2 and R.sup.3 can be H and R.sup.1 can be substituted phenyl. 
The compounds are said to have analgesic, antiinflammatory and antipyretic 
properties. Gebert et al., U.S Patent 3,915,980, disclose such compounds 
wherein R.sup.1 can be phenyl or phen(C.sub.1-3) alkyl, as intermediates 
to imidazolyl-2-thioalkanoic acid estcrs. 
Iverson, Acta Chem. Scand. 21, 279 (1967) reports a compound having the 
formula: 
##STR3## 
herein R can be --CO.sub.2 H or --CH.sub.2 NCH.sub.6 H.sub.5, but does not 
report a pharmaceutical use for the compound. 
In European Patent Application No. 125,033 (published Nov. 14, 1984) a 
series of 1-phenyl and 1-phenylalkylimidazole compounds having a mercapto 
or alkylthio group in the 2-position are disclosed. These compounds are 
described as having DBH inhibiting activity. 
U.S. Pat. No. 4,532,331 describes various 1-benzyl-2-aminomethylimidazole 
derivatives that inhibit DBH activity and includes pharmaceutical 
compositions containing these derivatives and methods of using these 
derivatives to inhibit DBH activity. 
SUMMARY OF THE INVENTION 
The invention resides in the discovery that DBH is inhibited by a compound 
having a mercaptoimidazole moiety and a phenethylamine analogue moiety. 
More particularly, the invention is selected novel compounds having the 
formula: 
##STR4## 
wherein: 
X is --H, --OH, halogen, C.sub.l-4 alkyl, --CN,--NO.sub.2, --SO.sub.2 
NH.sub.2, --CO.sub.2 H, --CONH.sub.2, --CHO, --CH.sub.2 OH, -CF.sub.3, 
C.sub.1-4 alkoxy, --SO.sub.2 C.sub.l-4 alkyl, --SO.sub.2 C.sub.1-4 
fluoroalkyl, --CO.sub.2 C.sub.1-4 aIkyI or any accessible combination 
thereof up to four substituents; 
Y is --H, --OH, C.sub.1-4 alkoxy, halogen, C.sub.1-4 alkyl, --CN, 
--NO.sub.2 --SO.sub.2 CONH.sub.2, -C02H, --CHO, --CH.sub.2 OH, --CF.sub.3, 
--SO.sub.2 C.sub.1-4 alkyl, --SO.sub.2 C.sub.1-4 fluoroalkyl, or 
--CO.sub.2 C.sub.1-4 alkyl; 
R is --H or C.sub.1-4 alkyl; and 
n is 0-4, 
or a hydrate or, when R is C.sub.1-4 alkyl, a pharmaceutically acceptable 
acid addition salt thereof, provided that when n is 0, Y is --OH and when 
n is 1-3, at least one of Y and X is not --H. As used herein, "accessible 
combination thereof" means any other stable combination of substituents 
available by chemical synthesis. 
In preferred compounds of the invention, Y is --OHH or --OCH.sub.3; R is 
--H; n is 1 or 3; and X is --H, --OH or halogen (in particular, 
3,5-dichloro, 3,5-difluoro, 3-chloro, or 3-fluoro) or Y is --H; R is --H; 
n is 1 or 3 and X is halogen (in particular, 3,5-dichloro, 3,5-difluoro, 
3-chloro, or 3-fluoro). In the most preferred compound of the invention, Y 
is --H, X is 3,5-difluoro, R is --H and n is 1. 
The invention is also a method of inhibiting DBH activity in mammals which 
comprises administering internally to a subject an effective amount of a 
compound having the formula: 
##STR5## 
wherein: 
X is --H, --OH, halogen, C.sub.1-4 alkyl, --CN, --NO.sub.2, --SO.sub.2 
--CONH.sub.2, --CHO, --CH.sub.2, OH, --CF.sub.3, C.sub.1-4 alkoxy, 
--SO.sub.2 C.sub.1-4 alkyl, --SO.sub.2 C.sub.1-4 fluoroalkyl, --CO.sub.2 
C.sub.1-4 alkyl or any accessible combination thereof up to four 
substituents; 
Y is --H, --OH, C.sub.1-4 alkoxy, halogen, C.sub.1-4 alkyl, --CN, 
--NO.sub.2, --SO.sub.2 NH.sub.2, --CO.sub.2 H, --CONH.sub.2, --CHO, 
--CH.sub.2 OH, --CF.sub.3, --SO.sub.2 C.sub.1-4 alkyl, --SO.sub.2 
C.sub.1-4 fluoroalkyl, or --CO.sub.2 C.sub.1-4 alkyl; 
R is --H or C.sub.1-4 alkyl; and 
n is 0-4, or a hydrate or, when R is C.sub.1-4 alkyl, a pharmaceutically 
acceptable acid addition salt thereof. 
Compounds found to be especially potent, and therefore preferred in the 
method of invention, are those in which Y is --OH or OCH.sub.3; R is --H; 
n is 1 or 3; and X is --H, --OH or halogen (in particular, 3,5-dichloro 
3,5-difluoro, 3-chloro or 3-fluoro) or Y is --H; R is --H; n is 1 or 3 and 
X is halogen (in particular, 3,5-dichloro, 3,5-difluoro, 3-chloro, or 
3-fluoro). In the most preferred method of the invention, Y is --H; X is 
3,5-difluoro, R is --H and n is 1. 
It is intended that the above formulae include the tautomer of the 
compounds wherein R is --H, that is, the compounds having the above 
formulae wherein the imidazole moiety has the formula: 
##STR6## 
The above formulae also include hydrates of the compounds and 
pharmaceutically acceptable acid addition salts of the compounds wherein R 
is C.sub.1-4 alkyl. The invention also includes pharmaceutical 
compositions comprising the compounds having the above formulae, provided 
that when n is 0, Y is --OH, and pharmaceutical carriers. 
The invention is also intermediates to the compound of the invention, said 
intermediates having the formula: 
##STR7## 
wherein Y.sup.1 and X.sup.1 are the same as Y and X but are not --OH and n 
is 0-4 and 
##STR8## 
wherein X.sup.1 is the same as X but is not --OH, Y.sup.1 is C.sub.1-4 
alkoxy, preferably --OCH3 and n is 0. 
The invention is also a process for preparing the compound of the invention 
which comprises contacting and reacting compound II, above, with acidic 
thiocyanate and such process which comprises contacting and reacting 
compound II A, above, with an acid to cyclize the compound. In both 
processes, when Y.sup.1 and/or X.sup.1 are C.sub.1-4 alkoxy, Y and/or X 
are optionally deprotected to prepare the compound wherein Y and/or X are 
--OH. 
DETAILED DESCRIPTION OF THE INVENTION 
The compounds of the present invention contain weak metal-chelating 
functional groups derived from N-methyl-2-mercaptoimidazole which is known 
to be a weak DBH inhibitor. The compounds of the invention also contain 
phenyl moieties as do phenethylamine analogue inhibitors such as 
benzyloxyamine, benzylhydrazine, tryptamine and serotonin. 
The compounds of the invention and the compounds used in the method of the 
invention can be prepared from corresponding starting benzyl or phenyl 
compounds such as benzaldehydes, which are known and described in 
published references or are readily accessible, by known techniques such 
as illustrated in Scheme I, below, wherein X.sup.1 and Y.sup.1 are X and 
Y, respectively, except that when Y is --OH, Y.sup.1 is C.sub.1-4 alkoxy, 
preferably --OCH.sub.3, and when X is --OH, X.sup.1 is C.sub.1-4 alkoxy, 
preferably --OCH.sub.3 As illustrated, n is one, although n can be 0-4. 
Scheme I illustrates reductive amination of benzaldehydes (I) with an 
aminoacetaldehyde acetal followed by reduction by, for example, catalytic 
hydrogenation or treatment with a reducing agent such as NaBH.sub.4, 
LiAlH.sub.4 or AlH.sub.3, to provide intermediate substituted benzylamines 
(II). Upon reaction with acidic thiocyanante, the intermediates (II) yield 
mercaptoimidazole products (III). The mercaptoimidazole products can be 
prepared from other than benzaldehydes, as illustrated in Examples 1 and 
4, below. 
##STR9## 
The 1-phenyl substituted 2-mercaptoimidazoles (n is 0) are preferably 
prepared by reaction of an appropriately substituted phenyl isothiocyanate 
with an aminoacetaldehyde acetal followed by strong acid catalyzed 
cyclization, as illustrated in Example 1, below. 
The compounds wherein n is 2, 3 or 4 are preferably prepared as illustrated 
in Example 4 and in Examples 23 and 24, below. Coupling of substituted 
phenyalkanoic acids as the acid halides, preferably chlorides, with 
aminoacetaldehyde acetals and subsequent reduction provided such 
intermediate substituted phenylalkylamines. 
Y.sup.1 in Scheme I is the same as Y except that when Y is --OH, Y.sup.1 is 
C.sub.1-4 alkoxy, preferably --OCH3, optional deprotection of the 4-alkoxy 
group with, for example, BBr.sub.3 or HBr, or nucleophilic aromatic 
substitution with dilute hydroxide, provides the phenol (Y is --OH). 
X.sup.1 may be one or more substituents at the 2-, 3-, 5- or 6- positions, 
provided the combination of substituents is accessible, that is, does not 
result insignificant instability due to steric hindrance. When Xl is 
C.sub.1-4 alkoxy, preferably --OCH.sub.3, it can be deprotected as 
described above for Y.sup.1 
The compounds in which R is C.sub.1-4 alkyl are preferably prepared by 
allowing the deprotection with, for example, BBr.sub.3, in an alkanol to 
proceed to formation of an alkyl bromide which alkylates the mercapto 
group as illustrated in Example 6, below. Alternatively, a solution or 
suspension of an appropriately substituted mercaptoimidazole in an inert 
solvent, for example, methanol, tetrahydrofuran or aqueous 
dimethylformamide, can be reacted with an alkylating agent, for example, 
alkyl iodide, bromide or tosylate. Methyl iodide is preferred in this 
alternative procedure. 
The pharmaceutically acceptable acid addition salts of the compounds 
wherein R is C.sub.1-4 alkyl are formed with strong or moderately strong 
organic or inorganic acids by methods known to the art. For example, the 
base is reacted with an inorganic or organic acid in an aqueous miscible 
solvent such as ethanol with isolation of the salt by removing the solvent 
or in an aqueous immiscible solvent when the acid is soluble therein, such 
as ethyl ether or chloroform, with the desired salt separating directly or 
isolated by removing the solvent. Exemplary of the salts which are 
included in this invention are maleate, fumarate, lactate, oxalate, 
methanesulfonate, ethanesulfonate, benzenesulfonate, tartrate, citrate, 
hydrochloride, hydrobromide, sulfate, phosphate and nitrate salts. 
The compounds of the invention, because they can be used to inhibit DBH 
activity, have therapeutic value as diuretic, natriuretic, cardiotonic, 
antihypertensive and vasodilator agents, as well as antiulcerogenic and 
antiparkinson disease agents. 
Compounds of the invention and other compounds useful in the method of the 
invention were screened for in vitro DBH inhibition by a standard 
procedure for assaying conversion of tyramine to octopamine in the 
presence of DBH. Octopamine was assayed following sodium periodate 
oxidation to p-hydroxybenzaldehyde by measuring spectrophotometric 
absorbance at 330 nm. Results are given in Table I, below. Inhibition is 
given in molar concentration of compound at which DBH activity was halved 
(IC.sub.50 Melting points (mp) are given in .degree. C. By this procedure 
fusaric acid was found to have an IC.sub.50 of about 8.times.10.sup.-7. 
TABLE I 
______________________________________ 
n X Y R mp IC.sub.50 
______________________________________ 
1 3-Br OH H 181 1.2 .times. 10.sup.-5 
1 3-F OH H 172 1.4 .times. 10.sup.-6 
1 3-F OCH.sub.3 
H 156-157 10.sup.-4 (67% 
inhibition) 
1 3-OH H H 167 1.5 .times. 10.sup.-4 
1 2-OH H H 158 5.8 .times. 10.sup.-4 
1 3-CH.sub.3 
OH H 214-216 4.8 .times. 10.sup.-5 
1 2-OCH.sub.3 
H H 159 10.sup.-4 (68% 
inhibition) 
1 3-OCH.sub.3 
H H 118-121 10.sup.-4 (72% 
inhibition) 
4 H OH H 132-134 10.sup.-4 (12% 
inhibition) 
3 H OH CH.sub.3 
140-142 7.9 .times. 10.sup.-5 
1 3,5-Cl.sub.2 
OH H 220-222 (dec) 
7.4 .times. 10.sup.-7 
1 3-NO.sub.2 
OH H 224-227 2.0 .times. 10.sup.-5 
1 2,6-Cl.sub.2 
OH H &gt;235 (dec) 
7.5 .times. 10.sup.-5 
1 3,5-F.sub.2 
OH H 213-215 7.4 .times. 10.sup.-8 
1 3,5-F.sub.2 
OCH.sub.3 
H 160-161 3.6 .times. 10.sup.-5 
1 3-CF.sub.3 
OH H 220 (dec) 1.2 .times. 10.sup.-4 
1 2,3,5,6-F.sub.4 
OH H 203-5 6.2 .times. 10.sup.-5 
1 H H H 144-5 1.1 .times. 10.sup.-5 
2 H OH H 181-184 1.8 .times. 10.sup.-5 
0 H H H 180-182 1.0 .times. 10.sup.-4 
1 H OH H 188-190 2.3 .times. 10.sup.-6 
3 H OH H 183-185 2.0 .times. 10.sup.-6 
1 3-OH OH H 209-212 4.0 .times. 10.sup.-6 
0 H OH H 260-264 3.2 .times. 10.sup.-4 
1 3-Cl OH H 186-190 2 .times. 10.sup.-6 
1 2,6-Cl.sub.2 
H H 242-243 10.sup.-4 (7% 
inhibition) 
1 2-Cl H H 206-207 10.sup.-4 (14% 
inhbition) 
1 2,5-Cl.sub.2 
H H 265 (dec) 9.7 .times. 10.sup.- 5 
1 4-Cl H H 187-189 9.6 .times. 10.sup.-5 
1 2,3-Cl.sub.2 
H H 195-197 5.2 .times. 10.sup.-5 
1 H F H 167-169 4.7 .times. 10.sup.-5 
1 3,4-Cl.sub.2 
H H 178-181 2.8 .times. 10.sup.-5 
1 2,4-Cl.sub.2 
H H 185-187 1.7 .times. 10.sup.-5 
1 3-Cl H H 129-131 1.2 .times. 10.sup.-5 
1 3,5-Cl.sub.2 
H H 209-211 2.4 .times. 10.sup.-6 
1 2,4,6-Cl.sub.3 
H H 240-244 1.0 .times. 10.sup.-4 
1 3-F H H 113-114 5.6 .times. 10.sup.-6 
1 3,5-F.sub.2 
H H 140-141 1.2 .times. 10.sup.-6 
3 3,5-Cl.sub.2 
H H 98-99 2.0 .times. 10.sup.-6 
3 3,5-F.sub.2 
H H 131-132 4.7 .times. 10.sup.-6 
______________________________________ 
The above results illustrate that compounds of the invention and other 
compounds useful in the method of the invention inhibit DBH activity. 
The following procedure was used to screen compounds of the invention for 
activity in vivo. Male Okamoto-Aoki strain spontaneously hypertensive rats 
(SHR), 270-340 g, aged 16-20 weeks, were used for testing. The afternoon 
before testing, the animals were fasted and the following morning the 
first dose .fo the test compound was administered, p.o., along with a 25 
ml/kg, load of normal saline. The animals were then placed in metabolism 
cages, three per cage, and urine was collected for three h4 and 
subsequently analyzed for sodium, potassium, and creatinine. Indirect 
systolic blood pressure and heart rate were measured via a tail-cuff 
method and, within 24 hr of the first dose, the animals received an 
identical second dose of the test compound. Two hr after the second dose, 
the systolic blood pressure and heart rate were again determined. Drugs 
were administered intraperitoneally as a solution or suspension in 0.9% 
NaCl with 0.02% ascorbic acid. The dose volume was 5 ml. 
Averaged results of the in vivo screens are given in Table II. In all 
compounds tested, R is --H and Y is --OH. Except where otherwise 
indicated, the concentration was 50 mg/kg. Averaged results with control 
animals are listed in parentheses below results of treated animals. 
TABLE II 
__________________________________________________________________________ 
Systolic Blood 
Electrolytes Pressure 
Heart Rate 
Execrated Urine (mmHg) (beats/min) 
Compound 
No. of 
(mEq/rat) Vol. Na.sup.+ /K.sup.+ 
First 
Second 
First 
Second 
x n Animals 
Na.sup.+ 
K.sup.+ 
(ml/rat) 
Ratio 
Dose 
Dose 
Dose 
Dose 
__________________________________________________________________________ 
3-Cl 1 3 280.33 
182.22 
8 1.538 
173 180 400 
440 
(3) (381.56) 
(133.79) 
(8) (2.852) 
(174) 
(170) 
(440) 
(460) 
3-F 1 3 162.07 
134.81 
3 1.202 
177 191 460 
420 
(3) (214.16) 
(198.80) 
(6) (1.077) 
(188) 
(189) 
(460) 
(440) 
H .sup. 3.sup.(1) 
3 185.81 
160.59 
5 1.157 
181 185 440 
440 
H .sup. 3.sup.(2) 
3 339.19 
231.19 
8 1.467 
187 180 380 
440 
(3) (390.84) 
(231.19) 
(8) (1.691) 
(193) 
(192) 
(480) 
(460) 
H 3 3 334.84 
104.72 
8 3.197 
181 163 460 
460 
(3) (183.41) 
(91.11) 
(4) (2.013) 
(183) 
(180) 
(460) 
(460) 
3,5-Cl.sub.2 
1 3 541.03 
293.07 
13.0 
1.846 
167 160 440 
500 
(3) (333.42) 
(153.17) 
(6.5) 
(2.177) 
(167) 
(176) 
(400) 
(460) 
3-OH 1 3 149.10 
174.26 
4 0.856 
185 173 460 
480 
(3) (161.19) 
(154.61) 
(4) (1.043) 
(180) 
(185) 
(480) 
(400) 
3-OH .sup. 1.sup.(2) 
3 383.61 
205.29 
10 1.869 
173 178 440 
440 
(3) (395.72) 
(164.23) 
(8) (2.409) 
(171) 
(199) 
(420) 
(480) 
H 1 3 369.40 
251.79 
11 1.467 
181 183 400 
440 
.sup. 1.sup.(1) 
3 495.00 
229.27 
11 2.159 
193 182 480 
480 
(3) (344.55) 
(137.84) 
(9) (2.500) 
(171) 
(183) 
(380) 
(440) 
3,5-Cl.sub.2 * 
3 3 103.46 
53.34 
1 1.940 
147 153 320 
400 
(3) (146.06) 
(20.11) 
(2) (7.264) 
(179) 
(186) 
(420) 
(460) 
3,5-Cl.sub.2 * 
3 3 86.67 
54.32 
3.5 
1.596 
159 141 360 
360 
(3) 128.60 
77.25 
3 1.665 
172 182 400 
480 
__________________________________________________________________________ 
.sup.(1) dose concentration = 12.5 mg/kg. 
.sup.(2) dose concentration = 25.0 mg/kg. 
*Y is H. 
It is apparent from Table II that the compounds tested have significant 
diuretic and/or cardiotonic activity. The compounds in which X is 
3,5-dichloro showed significant natriuretic activity as well as diuretic, 
antihypertensive and cardiotonic activity. Compounds having diuretic 
activity are known to be useful as antihypertensives. 
In additional experiments carried out substantially by the above procedure, 
the compound in which X is 3,5--F.sub.2, Y is --H, R is --H and n is 1 (50 
mg/kg) was found to have an especially pronounced effect on urine 
excretion, increasing urine volume about four fold over controls. Heart 
rate was generally decreased by administration of the compound. 
Various compounds of the invention, as well as various known DBH 
inhibitors, were tested for their effects on peripheral dopamine and 
norepinephrine levels substantially by the procedure of DaPrada and 
Zurcher, Life Sci. 19, 1161 (1976). Spontaneously hypertensive rats were 
dosed twice, the second dose being about 18 hr after the first, and were 
sacrificed about 2 hr after the second dose. Averaged results, expressed 
in micrograms of DA per gram of tissue, are given in Table III and in 
Table III A, which follow. In Table III, R=--H, Y=--OH and n=1; in Table 
III A, R=--H, Y=--H and n=1; in Table III B, R=--H, Y=--OCH.sub.3, and 
n=1. 
TABLE III 
______________________________________ 
No. of DA DA/NE 
Compound Animals (.mu.g/g) Ratio 
______________________________________ 
Control (H.sub.2 O) 
11 .260 .019 .040 .002 
Fusaric Acid 
11 .520 .053.sup.(1) 
.100 .007.sup.(1) 
Control 3 .219 .044 .035 .002 
Hydralazine 
(25 mg/kg) 
3 .417 .026.sup.(2) 
.078 .015.sup.(2) 
(50 mg/kg) 
1 .835 .127 .098 .018 
Control 1 .299 .038 .039 .004 
X = 3-F 1 .476 .023.sup.(3) 
.064 .004.sup.(2) 
(50 mg/kg) 
Control 1 .261 .046 .041 .007 
X = 3-F 
(50 mg/kg) 
1 .430 .027.sup.(3) 
.082 .005.sup.(3) 
(100 mg/kg) 
1 .619 .071.sup.(3) 
.099 .003.sup.(1) 
Control 1 .273 .019 .040 .002 
X = 3,5-Cl.sub.2 
1 .241 .031.sup.(3) 
.045 .006.sup.(3) 
(50 mg/kg) 
Control 1 .242 .014 .030 .002 
(cold-stressed) 
X = 3,5-Cl.sub.2 
1 .313 .019.sup.(2) 
.038 .003.sup.(2) 
(50 mg/kg) 
(cold-stressed) 
Control 5 .270 .025 .0307 .0019 
Fusaric Acid 
5 .675 .030.sup.(1) 
.0871 .0047.sup.(1) 
(50 mg/kg) 
X = 3,5-F.sub.2 
5 .708 .068.sup.(1) 
.0824 .0128.sup.(2) 
(50 mg/kg) 
______________________________________ 
.sup.(1) P &lt; 0.001 
.sup. (2) P &lt; 0.05 
.sup.(3) P &lt; 0.01 
TABLE IIIA 
______________________________________ 
No. of DA DA/NE 
Compound Animals (.mu.g/g) Ratio 
______________________________________ 
Control 4 .319 .+-. .104 
.042 .+-. .012 
Fusaric Acid 
5 .642 .+-. .114 
.sup. .1240 .+-. .0140.sup.(1) 
X = 3-F 5 1.096 .+-. .080 
.sup. .1946 .+-. .0112.sup.(1) 
n = 1 
(50 mg/kg) 
X = 3,5-F.sub.2 
5 2.109 .+-. .123 
.sup. .4485 .+-. .0532.sup.(1) 
(50 mg/kg) 
Control 5 .250 .+-. .014 
.037 .+-. .003 
X = 3,5-Cl.sub.2 
5 .670 .+-. .065 
.sup. .110 .+-. .008.sup.(1) 
(50 mg/kg) 
Control 5 .308 .+-. .023 
.045 .+-. .004 
X = 3,5-Cl.sub.2 
5 .688 .+-. .020 
.sup. .103 .+-. .002.sup.(1) 
(50 mg/kg) 
______________________________________ 
.sup.(1) P &lt; 0.001 
TABLE IIIB 
______________________________________ 
No. of DA DA/NE 
Compound Animals (.mu.g/g) Ratio 
______________________________________ 
Control 6 .318 .+-. .008 
.0393 
X = 3-F 6 1.397 .+-. .111 
.239.sup.(1) 
X = 3,5-F.sub.2 
6 1.178 .+-. .087 
.204.sup.(1) 
______________________________________ 
.sup.(1) P 0.001 
The above results illustrate that the compounds of the invention inhibit 
DBH activity in mammals when administered internally in effective amounts. 
The compound of the invention in which X is --H, Y is --OH, R is --H and n 
is 3 was also tested in one rat. The results did not indicate significant 
inhibition of DBH activity. Nevertheless, because only a single experiment 
was run, because other compounds of the invention show such activity, and 
because the compound has a low in vitro IC.sub.50 (See Table I), the 
compound is believed to be useful in inhibiting DBH activity in mammals. 
The compounds in which Y is --H and X is halogen, especially difluoro and 
dichloro, show high in vivo activity, as shown in Table IIIA. The compound 
in which X is 3,5 difluoro, Y is --H, R is --H and n is 1 (IC.sub.50 =1.2 
.times.10.sup.-6) showed an especially pronounced effect on the DA/NE 
ratio in vivo. Additionally, although relatively weak in vitro DBH 
inhibitors, as indicated by the data in Table IIIB, compounds in which Y 
is --OCH.sub.3, n is 1, and X is 3--F or 3,5--F.sub.2 proved very potent 
DBH inhibitors in vivo. 
In a study on the effect on blood pressure in spontaneously hypertensive 
rats of daily doses of compounds of the invention (50 mg/kg, i.p.), the 
compound in which X is 3,5-dichloro, Y is --H, R is --H and n is 1 
exhibited a cumulative effect, that is, blood pressure continued to 
decrease on each day of the four day study period. 
Another study was conducted to compare the effects on blood pressure of 
compounds wherein Y is --OH, X is 3--F or 3,5--F.sub.2 and n is 1 to their 
Y is --OCH3 analogues. The maximum blood pressure reduction observed after 
administration of the hydroxy compound in which X is 3--F was 18%, whereas 
one-half the dose of its methoxy analogue produced a 35% blood pressure 
reduction. Also, equivalent doses of the compound in which Y is --OH, X is 
3,5--F.sub.2, and n is 1 and its Y is --OCH3 analogue produced, 
respectively, 20% and 35% blood pressure reductions. 
The compounds can be incorporated into convenient dosage unit forms such as 
capsules, tablets or injectable preparations. Pharmaceutical carriers 
which can be employed can be solid or liquid. Solid carriers include, 
among others, lactose, terra alba, sucrose, talc, gelatin, agar, pectin, 
acacia, magnesium stearate, and stearic acid Liquid carriers include, 
among others, syrup, peanut oil, olive oil and water. Similarly, the 
carrier or diluent may include any delayed release material, such as 
glyceryl monostearate or glyceryl distearate, alone or with a wax. The 
amount of solid carrier will vary widely but, preferably, will be from 
about 25 mg to about 1 g per dosage unit. If a liquid carrier is used, the 
preparation will be in the form of a syrup, emulsion, soft gelatin 
capsule, sterile injectable liquid such as an ampule, or an aqueous or 
nonaqueous liquid suspension. 
The pharmaceutical preparations are made following conventional techniques 
of a pharmaceutical chemist involving mixing, granulating and compressing, 
when necessary, for tablet forms, or mixing, filling and dissolving the 
ingredients, as appropriate, to give the desired oral or parenteral end 
products. 
Doses of the present compounds in a pharmaceutical dosage unit will be an 
effective amount, that is, a nontoxic quantity selected from the range of 
0.1-1,000 mg/kg of active compound, preferably 10-100 mg/kg. The selected 
dose is administered to a patient in need of treatment from 1-5 times 
daily, orally, rectally, by injection or by infusion. Parenteral 
administration, which uses a low dose, is preferred. However, oral 
administration, at a higher dose, can also be used when safe and 
convenient for the patient. Use of lowest effective doses is recommended 
because toxicity has been associated with sulfur-containing compounds.

The following examples are illustrative df preparation of compounds of the 
invention or intermediates therefor. The starting compounds are 
commercially available or are prepared by known techniques. The Examples 
are not intended to limit the scope of the invention as defined herein 
above and as claimed below. The compounds listed in Tables I, II and III, 
above, were prepared substantially by the illustrated procedures. All 
temperatures and melting points (mp) are in degrees Celsius (.degree. C). 
EXAMPLE 1 
1-(4-Methoxyphenyl)-2-mercaptoimidazole 
A solution of 10 g (.06 mole) of p-methoxyphenyl isothiocyanate in 100 ml 
of CHCl.sub.3 was treated with 6.3 g (.06 mole) of aminoacetaldehyde 
dimethyl acetal. The solvent was evaporated and the residue was 
recrystallized from ethanol to yield 
N-(p-methoxyphenyl)-N'-(.beta.,.beta.-dimethoxyethyl)thiourea, 9.2 g 
(57%). A suspension of this thiourea in a solution of 5 ml of concentrated 
H.sub.2 SO.sub.4 and 20 ml of H.sub.2 O was refluxed for 3 hours. The 
mixture was cooled and a solid was filtered, washed with H.sub.2 O and 
dried. Recrystallization from ethanol gave 
1-(4-methoxyphenyl)-2-mercaptomidazole, 4.9 g (70%), mp 215-7.degree. . 
The compound can be deprotected, for example, as illustrated in Example 5 
and 6, below, to prepare the phenol, Y is --OH. 
EXAMPLE 2 
1-(4-Methoxybenzyl)-2-mercaptoimidazole 
A mixture of 13.6 g (0.1 mole) of anisaldehyde, 3.3 g (0.1 mole) of 
aminoacetaldehyde diethyl acetal and ml of CH.sub.3 OH was heated at 
95.degree. for 10 minutes. A residue was dissolved in 150 ml of ethanol 
and hydrogenated over 10% Pd on carbon at 50 psi (0.34 MPa) until H.sub.2 
uptake was complete. The catalyst was filtered and the filtrate was 
treated with 10.4 g (0.107 mole) of KSCN, 0 ml of 3N HCl and 40 ml of 
H.sub.2 O. The mixture was refluxed, letting the solvent evaporate until 
the volume of the reaction mixture was 100 ml. After 45 minutes, the 
mixture was cooled, and a solid was filtered, washed with H.sub.2 O and 
dried. Recrystallization from ethanol gave 
(1-(4-methoxybenzyl)-2-mercaptoimidazole, 15.0 g (68%), mp 
140-142.degree.. 
EXAMPLE 3 
1-(3-Bromo-4-methoxybenzyl)-2-mercaptoimidazole 
A solution of 10.75 g (.05 mole) of 3-bromo-4methoxybenzaldehyde and 6.65 g 
(.05 mole) of aminoacetaldehyde diethyl acetal in 25 ml of ethanol was 
refluxed for 30 minutes. The solvent was evaporated and the residue was 
dissolved in CH.sub.2 Cl.sub.2. The CH.sub.2 Cl.sub.2 solution of the 
Schiff base was washed with saturated aqueous NaCl, dried (K.sub.2 
CO.sub.3) and filtered, and the solvent was evaporated. Residual Schiff 
base was dissolved in 100 ml of methanol, cooled to 5.degree. , and 
treated with 5.0 g of NaBH.sub.4. The reaction mixture was allowed to warm 
to 22.degree. and, after 4 hr, the solvent was evaporated. The residue was 
taken up in diethyl ether, washed with H.sub.2 O, dried (MgS.sub.SO.sub.4) 
and filtered, and the solvent was evaporated. A solution of the residue in 
CHC13, upon treatment with ethereal HCl, gave, on standing, crystals of 
N-(3-bromo-4-methoxybenzyl)aminoacetaldehyde diethylacetal hydrochloride, 
10.75 g (58%), mp 112-120.degree.. 
A solution of 10.74 g (.029 mole) of 
N-(3-bromo4-methoxybenzyl)aminoacetaldehyde diethyl acetal hydrochloride 
and 3.37 g (0.35 mole) of KSCN in 50 ml of H20, 50 ml of ethanol and 5 ml 
of 3N HCl was refluxed for 4.5 hours. One hundred ml of H.sub.2 O was 
added and the mixture was cooled. A solid was filtered, washed with 
H.sub.2 O and dried. Recrystallization from ethanol gave 
1-(3-bromo-4-methoxybenzyl)-2-mercaptoimidazole, 6.3 g (72%), mp 
188.degree.. 
EXAMPLE 4 
1-[3-(4-Methoxyphenyl)-propyl]-2-mercaptoimidazole 
A solution of 12.5 g (.07 mole) of p-methoxyphenylpropionic acid in 100 ml 
of CH.sub.2 Cl.sub.2 and one drop of pyridine was treated with 9.8 g (.077 
mole) of oxalyl chloride. After 2.5 hours, the solvents were thoroughly 
evaporated to give the acid chloride as an oil. A solution of the acid 
chloride in 100 ml of CH.sub.2 Cl.sub.2 was slowly added to a cold 
(0.degree.) solution of 14.7 g (0.14 mole) of aminoacetaldehyde dimethyl 
acetal in 300 ml of CH.sub.2 Cl.sub.2 at a rate such that the temperature 
stayed below 20.degree.. After 1 hr, the reaction mixture was poured into 
H20, and the CH.sub.2 C12 layer was separated and washed with aqueous 
Na.sub.2 CO.sub.3, 0.5 N HCl and H.sub.2 O. Following drying and 
evaporation of the solvent, N-(.beta., 
.beta.B-dimethoxyethyl)-p-methoxyphenylpropionamide was obtained as a 
solid, 10.3 g (55%). A solution of this amide in 300 ml of diethyl ether 
was slowly added to a slurry of 4.0 g of LiAlH.sub.4 in 400 ml of diethyl 
ether and 350 ml of tetrahydrofuran (THF). After 3.5 hours at 22.degree., 
excess LiAlH.sub.4 was cautiously destroyed, the reaction mixture was 
filtered and the filtrate was evaporated. The residue was dissolved in 100 
ml of 0.15N HCl, washed with diethyl ether, basified with NaHCO.sub.3 and 
extracted with diethyl ether. The extracts were dried (MgSO.sub.4) and the 
solvent was evaporated to give N-[3-(4-methoxyphenyl)propyl] 
aminoacetaldehyde dimethyl acetal, 4.6 g (52%), as an unstable oil. 
A solution of 3.62 g (.014 mole) of 
N-[3-(4-methoxyphenyl)propyl]aminoacetaldehyde dimethyl acetal and 1.4 g 
(.0144 mole) of KSCN in 20 ml of ethanol, 5 ml of H.sub.2 O and 2 ml of 
concentrated HCl was refluxed for five hours. Fifty ml of H.sub.2 O was 
added, the mixture was cooled and a solid was filtered, washed with 
H.sub.2 O and dried. Recrystallization from ethanol gave 
1-[3-(4-methoxyphenyl)propyl]-2-mercaptoimidazole, 2.4 g (69%), mp 
108-109.degree.. 
Example 5 
1-(3--Fluoro-4-methoxybenzyl)-2-mercaptoimidazole 
3--Fluoro-4-methoxybenzaldehyde (5.0 g, 0.0324 mole) was added to 
aminoacetaldehyde dimethyl acetal (3.53 ml, 0.0324 mole) and the mixture 
was heated at 100.degree. C. for 2 hours. The reaction mixture was cooled 
in ice, diluted with ethyl alcohol (50 ml) and sodium borohydride (1.23 g, 
0.0324 mole) was added and the mixture was stirred overnight at 25.degree. 
C. The solvent was removed under reduced pressure and the residue was 
dissolved in ethyl acetate and the solution was washed with water and 
brine and then dried with sodium sulfate. The mixture was filtered and the 
solvent removed under reduced pressure to give 
N-(3-fluoro-4-methoxybenzyl)-aminoacetaldehyde dimethyl acetal as an oil 
(6.68 g, 85%). 
To a solution of 1-(3-fluoro-4-methoxybenzyl)aminoacetaldehyde dimethyl 
acetal (6.68 g, 0.0275 mole) in ethyl alcohol (40 ml) was added potassium 
thiocyanate (2.94 g, 0.0302 mole) in water (65 ml) followed by 12 N 
hydrochloric acid (6 ml) and the reaction mixture was heated under reflux 
for 3 hours. The solvent was partially removed under reduced pressure and 
the mixture was cooled in ice and the product filtered. The product was 
recrystallized from ethyl alcohol to give 
1-(3-fluoro4-methoxybenzyl)-2-mercaptoimidazole as a solid melting at 
156-157.degree. (3.98 g, 61%). 
Example 6 
1-(3,5-Difluoro-4-methoxybenzyl)-2-mercaptoimidazole 
A mixture of 3,5-difluoro-4-methoxybenzonitrile (3.50 g, 0.0207 mole) and 
Raney catalyst powder (3.5 g) in 90% formic acid (35 ml) was stirred and 
heated under reflux for 2.5 hours and the catalyst was filtered and washed 
with hot water and hexane. The hexane layer was separated and the aqueous 
solution was extracted an additional three times with hexane. The combined 
hexane extracts were washed with water and brine, dried and the solvent 
was removed to give 3,5-difluoro-4-methoxybenzaldehyde as an oil (3.38 g, 
95%). 
3,5-Difluoro-4-methoxybenzaldehyde (3.38 g, 0.0196 mole) was added to 
aminoacetaldehyde dimethyl acetal (2.14 ml, 0.0196 mole) and the mixture 
was heated at 100.degree. C. for 2 hours. The reaction mixture was cooled 
in ice, diluted with ethyl alcohol (35 ml), and sodium borohydride (0.743 
g., 0.0196 mole) was added and the mixture was stirred overnight at 
25.degree. C. The solvent was removed under reduced pressure, the residue 
was dissolved in ethyl acetate, and the solution was washed with water and 
brine and then dried with sodium sulfate. The mixture was filtered, and 
the solvent removed under reduced pressure to give 
N-(3,5-difluoro-4-methoxybenzyl)-aminoacetaldehyde dimethyl acetal as an 
oil (4.94 g, 96%). 
To a solution of N-(3,5-difluoro-4-methoxybenzyl)-aminoacetaldehyde 
dimethyl acetal (4.94 g, 0.0189 mole) in ethyl alcohol (30 ml) was added 
potassium thiocyanate (2.10 g, 0.0216 mole) in water (48 ml) followed by 
12 N hydrochloric acid (4 ml), and the reaction mixture was heated under 
reflux for 3.5 hours. The solvent was partially removed under reduced 
pressure, the mixture was cooled in ice, and the product was filtered. The 
product was recrystallized from ethyl alcohol - hexane to give 
1-(3,5-difluoro-4-methoxybenzyl)-2-mercaptoimidazole as a solid melting at 
160-161.degree. (2.22 g, 46%). 
EXAMPLE 7 
1-[3-(4--Hydroxyphenyl)propyl]-2-mercaptoimidazole 
A solution of 1.75 g (0.007 mole) of 
1-[3-(4methoxyphenyl)propyl]-2-mercaptoimidazole in 60 ml of CH.sub.2 
Cl.sub.2 was deprotected by treatment with a solution of 7.0 g (0.028 
mole) of BBr.sub.3 in 10 ml of CH.sub.2 Cl.sub.2. After 1 5 hr, the 
reaction mixture was cooled to 0.degree. , and methanol was cautiously 
added. After a vigorous reaction subsided, the solvents were evaporated. 
The residue was recrystallized from ethanol to give 
1-[3-(4-hydroxyphenyl)-propyl]-2-mercaptoimidazole, 1.02 g (67%), mp 
185.degree. . 
EXAMPLE 8 
1-[3-(4--Hydroxyphenyl)propyl]-2-thiomethylimidazole 
A solution of 1.2 g (.0046 mole) of 
1-[3-(4methoxyphenyl)propyl]-2-mercaptoimidazole in 40 ml of CH.sub.2 
Cl.sub.2 was treated with a solution of 3.5 g (.014 mole) of BBr.sub.3 in 
10 ml of CH.sub.2 Cl.sub.2. After 4 hours, methanol was cautiously added, 
the mixture was stirred for an additional 18 hours, and the solvents were 
evaporated. The residue was dissolved in H.sub.2 O, washed with ethyl 
acetate, neutralized with NaHCO and extracted with ethyl acetate. The 
extracts were dried (MgSO.sub.4) and filtered and the solvent was 
evaporated. The residue was dissolved in 5 ml of ethanol, and treated with 
ethereal HCl. A crystalline product was filtered and recrystallized from 
ethanol, to give 1-[3-(4-hydroxyphenyl)propyl]-2-thiomethylimidazole 
hydrochloride, 0.61 g (45%), mp 140-142.degree.. 
EXAMPLE 9 
1-(3-Nitro-4-hydroxybenzyl)-2-mercaptoimidazole 
A solution of 1-[3'-nitro-4'-methoxybenzyl]-2mercaptoimidazole (1.59 g, 6.0 
moles) in 10% aqueous NaOH (200 ml) was refluxed for two hours, cooled, 
acidified with concentrated HCl, cooled and filtered. The crystalline 
product was washed with water. Recrystallization from ethanol provided 
1.25 g (80%) of product as yellow prisms: mp 225-227.degree. (dec). 
EXAMPLE 10 
1-(2,6-Dichloro-4-hydroxybenzyl)-2-mercaptoimidazole 
A mixture of 1-[2',6'-dichloro-4'-methoxybenzyl]2-mercaptoimidazole (1 g) 
in concentrated aqueous hydrobromic acid (50 ml) was heated at reflux 
under argon for 1.25 hr, and then cooled. The product was collected by 
filtration. Washing with concentrated aqueous hydrobromic acid and water 
and drying yielded 0.64 g (60%) of product as light yellow crystals: mp 
235.degree. (dec). 
EXAMPLE 11 
1-(3-Trifluoromethyl-4-hydroxybenzyl)-2-mercaptoimidazole 
A mixture of 1-(3'-trifluoromethyl-4'-methoxy- benzyl)-2-mercaptoimidazole 
(2.0 g) and pyridine hydrochloride (15 g) was melted at 210.degree. for 30 
minutes, cooled, diluted with water and extracted with ethyl acetate. The 
ethyl acetate extracts were treated with charcoal, dried over sodium 
sulfate and concentrated to give a thick oil. Addition of THF (3 ml), 
ether (6 ml), and hexane (15 ml) produced yellow crystals. 
Recrystallization from ethyl acetate/hexane yielded 0.7 g (37%) of cream 
colored crystals: mp 220.degree. (dec). 
EXAMPLE 12 
3',5'-Dichlorobenzyl)-2-mercaptoimidazole 
A mixture of 3,5-dichlorobenzaldehyde (17.5 g, 0.1 mole) and 
aminoacetaldehyde diethylacetal (13.3 g, 0.1 mole) was heated on a steam 
bath. The resulting solution was stirred at room temperature during slow 
addition of sodium borohydride (3 g, 0.08 mole) and the mixture was 
stirred overnight at room temperature. The mixture was concentrated under 
reduced pressure, and the residue was partitioned between ethyl acetate 
and water. The ethyl acetate layer was washed sequentially with water and 
brine, and then dried over anhydrous sodium sulfate, and concentrated 
under reduced pressure. The resulting oil was heated at reflux with water 
(100 ml), concentrated hydrochloric acid (22 ml), ethanol (41 ml), and 
potassium thiocyanante (10.7 g, 0.11 mole) for 2 hours. The mixture was 
cooled and diluted with water (250 ml), and the crude product was 
collected by filtration and dried. Recrystallization twice from acetic 
acid provided 7.3 g (30%) of the title compound as light yellow crystals: 
mp 209-211.degree.. 
EXAMPLE 13 
1-(2',6'-Dichlorobenzyl)-2-mercaptoimidazole 
Reaction of 2,6-dichlorobenzaldehyde (17.5 g, 0.1 mole) and 
aminoacetaldehyde diethyl acetal (13.3 g, 0.1 mole) substantially as above 
yielded 5.4 g (21%) of the title compound as white needles: mp 
242-3.degree. (ethanol/ether). 
EXAMPLE 14 
1-(2'--Chlorobenzyl)-2-mercaptoimidazole 
Reaction of 2-chlorobenzaldehyde (14 g, 0.1 mole) and aminoacetaldehyde 
diethylacetal (13.3 g, 0.1 mole) substantially as above yielded 11.2 g 
(50%) of the title compound as white crystals: mp 206-7.degree. 
(acetone/ethanol). 
EXAMPLE 15 
1-(2',5'-Dichlorobenzyl)-2-mercaptoimidazole 
Reaction of 2,5-dichlorobenzaldehyde (10.25 g, 0.059 mole) and 
aminoacetaldehyde diethyl acetal (7.79 g, 0.059 mole) substantially as 
above yielded 5.2 g (34%) of the title compound as white crystals: mp 
265.degree. (dec) (propionic acid). 
EXAMPLE 16 
1-(4'--Chlorobenzyl)-2-mercaptoimidazole 
Reaction of 4-chlorobenzaldehyde (14 g, 0.1 mole) and aminoacetaldehyde 
diethyl acetal (13.3 g, 0.1 mole) substantially as above yielded 8.3 g 
(36%) of the title compound as white crystals: mp 187-9.degree. 
(acetonitrile). 
EXAMPLE 17 
1-(2',3'-Dichlorobenzyl)-2-mercaptoimidazole Reaction of 
2,3-dichlorobenzaldehyde (8.7 g, 0.05 mole) and aminoacetaldehyde diethyl 
acetal (6.65 g, 0.05 mole) substantially as above yielded 3.0 g (23%) of 
the title compound as white crystals: mp 195-7.degree. (ethanol). 
EXAMPLE 18 
1-(4'--Fluorobenzyl)-2-mercaptoimidazole Reaction of 4-fluorobenzaldehyde 
(12.4 g, 0.1 mole) and aminoacetaldehyde diethyl acetal (13.3 g, 0.1 mole) 
substantially as above yielded 13.0 g (62.5%) of the title compound as 
white crystals: mp 167-9.degree. (ethanol). 
EXAMPLE 19 
1-(3',4'-Dichlorobenzyl)-2-mercaptoimidazole Reaction of 
3,4-dichlorobenzaldehyde (17.5 g, 0.1 mole) and aminoacetaldehyde diethyl 
acetal (13.3 g, 0.1 mole) substantially as above yielded 10 g (39%) of the 
title compound as white crystals: mp 178-81.degree. (ethanol). 
EXAMPLE 20 
(2',4'-Dichlorobenzyl)-2-mercaptoimidazole Reaction of 
2,4-dichlorobenzaldehyde (17.5 g, 0.1 mole) and aminoacetaldehyde diethyl 
acetal (13.3 g, 0.1 mole) substantially as above yielded 8.5 g (33%) of 
the title compound as of white crystals: mp 185-7.degree. (2-propanol). 
EXAMPLE 21 
1-(3'--Chlorobenzyl)-2-mercaptoimidazole Reaction of 3-chlorobenzaldehyde 
(14 g, 0.1 mole) and aminoacetaldehyde diethyl acetal (13.3 g, 0.1 mole) 
substantially as above yielded 14 g (62.5%) of the title compound as white 
crystals: mp 129-131.degree. (acetonitrile). 
EXAMPLE 22 
(2',4',6'-Trichlorobenzyl)-2-mercaptoimidazole Reaction of 
2,4,6-trichlorobenzaldehyde (20.9 g, 0.1 mole) and aminoacetaldehyde 
diethylacetal (13.3 g, 0.1 mole) substantially as above yielded 12 g (46%) 
of the title compound as white crystals: mp 240-4.degree. (ethanol). 
EXAMPLE 23 
1-(3--Fluorobenzyl)-2-mercaptoimidazole Reaction of 3-fluorobenzaldehyde 
(24.8 g, 0.2 mole) and aminoacetaldehyde diethyl acetal (26.6 g, 0.2 mole) 
substantially as above yielded 28 g (67%) of the title compound as white 
crystals: mp 112.5-114.degree. (2-propanol/water). 
EXAMPLE 24 
1-(3',5'-Difluorobenzyl)-2-mercaptoimidazole Reaction of 
3,5-difluorobenzaldehyde (14.7 g, 0.104 mole) and aminoacetaldehyde 
dimethyl acetal (10.8 g, 0.104 mole) substantially as above yielded 10.0 g 
(43%) of the title compound as white crystals: mp 140-141.degree. (ethyl 
acetate/hexane). 
EXAMPLE 25 
1-[3-(3',5'-Difluorophenyl)propyl]-2-mercaptoimidazole 
3,5-Difluorobenzaldehyde (5.5 g, 0.039 mole), malonic acid (6.06 g, 0.058 
mole), pyridine (2.1 ml) and piperidine (0.105 ml) were heated on a steam 
bath for 2 hours and then at 155.degree. for 1 hour. The reaction mixture 
was poured into cold 3N aqueous hydrochloric acid, and then filtered. 
Recrystallization from ethanol provided 4.7 g (66%) of 
3,5-difluorocinnamic acid as buff needles: mp 199-201.degree.. 
3-5-Difluorocinnamic acid (4.6 g, 0.025 mole) was dissolved in 
tetrahydrofuran (50 ml) and added to a slurry of 0.75 g palladium/carbon 
in ethyl acetate. The mixture was shaken under 50 psi (.34 MPa) hydrogen 
for 5 hours and then was filtered and concentrated to provide 4.5 g (97%) 
of 3-(3',5'-difluorophenyl)propanoic acid as colorless crystals: mp 
56.degree. (methanol). 
A solution of 3-(3'5'-difluorophenyl) propanoic acid (4.4 g, 0.024 mole) 
N,N-dimethylformamide (one drop) and thionyl chloride (15 ml) was heated 
at 60.degree. for 3 hours. Excess thionyl chloride was removed by 
distillation at reduced pressure. Distillation (Kugelrohr) at reduced 
pressure (about 0.25 mm [33 Pa]) yielded 4.1 g (85%) of 
3-(3',5'-difluorophenyl)propionyl chloride as an oil. 
A solution of 3-(3',5'-difluorophenyl)propionyl chloride (4 g, 0.0196 mole) 
in methylene chloride (40 ml) was slowly added to a 0.degree. solution of 
amino acetaldehyde dimethyl acetal (4.3 g, 0.0412 mole) in methylene 
chloride (100 ml) at a rate such that the temperature did not exceed 
20.degree.. The reaction mixture was stirred for 1 hour. Then it was 
poured into water and the layers were separated. The organic layer was 
washed with 5% aqueous sodium carbonate, 0.05% aqueous hydrogen chloride, 
and water and then was dried over sodium sulfate and concentrated to yield 
5.5 g (103%) of 3-(3',5'difluorophenyl))propanamide N-acetaldehyde 
dimethyl acetal as an oil. 
A solution of 3-(3',5'-difluorophenyl)propanamide N-acetaldehyde dimethyl 
acetal (5.3 g, 0.0194 mole) in diethyl ether (100 ml) was slowly added to 
a slurry of lithium aluminum hydride (4.4 g, 0.116 mole) in diethyl ether 
(200 ml). The reaction mixture was stirred at ambient temperature 
(20-25.degree. ) for 18 hours. Then water (4.5 ml) was carefully added, 
followed by 10% aqueous sodium hydroxide (7 ml) and water (11 ml). The 
mixture was filtered and the filtrate was dried over sodium sulfate and 
concentrated to yield 4.4 g (88%) of (3',5'-difluorophenyl)propanamine 
N-acetaldehyde dimethyl acetal as colorless oil. 
A solution of 3-(3',5'-difluorophenyl)propanamine N-acetaldehyde dimethyl 
acetal (4.3 g, 0.0166 mole) and potassium thiocyanate (1.6 g, 0.0166 mol) 
in ethanol (12 ml), water (20 ml), and concentrated hydrochloric acid (4 
ml) was refluxed for 1 hour and then cooled and a large volume of water 
was added. The product was filtered and recrystallized to yield 2.2 g 
(55%) of 1-[3-(3',5'difluorophenyl)propyl]2-mercaptoimidazole as white 
needles: mp 131-132.degree. (ethanol). 
EXAMPLE 26 
3-(3', 5'-Dichlorophenyl)propyl-2-mercaptoimidazole 
Reaction of 3,5-dichlorobenzaldehyde (26.9 g, 0.154 mole), malonic acid 
(24.1 g, 0.232 mole), pyridine (8 ml) and piperidine (0.4 ml) 
substantially as above yielded 22.9 g (69%) of 3,5-dichlorocinnamic acid 
as white needles: mp 169-170.degree. (ethanol). 
Reaction of 3,5-dichlorocinnamic acid (22.9 g, 0.106 mol) and 3 g 
palladium/carbon substantially as above yielded 23 g (99%) of 
3-(3',5'-dichlorophenyl)propanoic acid as an oil. 
A one molar solution of borane in tetrahydrofuran (233 ml) was added 
dropwise to a cooled (0.degree. ) solution of 
3-(3',5'-dichlorophenyl)propanoic acid (23 g, 0.106 mole) in distilled 
tetrahydrofuran (200 ml). The reaction was stirred at room temperature for 
2 hours. Then methanol was added and the solution was concentrated to 
yield 21.2 g (98%) of 1-[3-(3',5'-dichlorophenyl)]propanol as a clear oil. 
Dimethyl sulfoxide (6.75 g, 0.083 mole) in dry methylene chloride (15 ml) 
was added dropwise to a solution of oxalylchloride (6.2 g, 0.049 mole) in 
dry methylene chloride (15 ml) at -78.degree. . The reaction mixture was 
stirred for 2 minutes. Then 1-[3-(3',5'dichlorophenyl)]-propanol (5 g, 
0.0245 mole) in dry methylene chloride (20 ml) was slowly added, keeping 
the temperature below -60.degree. . After stirring for 15 minutes at 
-70.degree. , triethylamine (16 g, 0.160 mol) was added dropwise. The 
reaction mixture was stirred for an additional 5 minutes at -60.degree. 
and then was warmed to room temperature and diluted with water. The 
organic layer was separated, washed with 3N hydrogen chloride and then 
with brine, and was dried over sodium sulfate. The solution was 
concentrated to give 5.0 g (100%) of 3-(3' ,5'dichlorophenyl) 
propionaldehyde as a yellow oil. 
Amino acetaldehyde dimethyl acetal (2.1 g, 0.0197 mole) was added with 
stirring to a solution of 3-(3',5'-dichlorophenyl)propionaldehyde (5 g, 
0.025 mole) in hexane (10 ml). After stirring for 1 hour at room 
temperature, sodium borohydride (7.3 g, 0.193 mole) in ethanol (25 ml) was 
added. The reaction mixture was stirred for 18 hours and then was diluted 
with water and concentrated. The residue was taken up in ethyl acetate, 
washed with water, dried over sodium sulfate and concentrated to yield 6.8 
g (93%) of 3-(3',5'- dichlorphenyl)propanimide N-acetaldehyde dimethyl 
acetal as a yellow oil. 
A solution of 3-(3',5'-dichlorophenyl)propanamide N-acetaldehyde dimethyl 
acetal and potassium thiocynate (2.2 g, 0.0223 mole) in ethanol (20 ml), 
water (30 ml), and concentrated hydrochloric acid was refluxed for 1 hour. 
The reaction mixture was cooled and diluted with water. After standing for 
3 hours, the crude product solidified and was filtered. Chromatography on 
silica, eluting with 0.5 to 1% methanol in methylene chloride, provided 
2.0 g (31%) of 3-(3',5'-dichlorophenyl)propyl-2mercaptoimidazole as white 
crystals: mp 98-99.degree. (ethanol). 
EXAMPLES 27-58 
The compounds listed in Table IV, below, are prepared substantially by the 
procedures illustrated in the preceding Examples except that equivalent 
molar amounts of appropriate starting compounds and of other reactants and 
reagents are used. 
The compounds in which X and/or Y is --OH are prepared from corresponding 
methoxy-substituted compounds which are deprotected as illustrated above. 
In particular, the compounds of Examples 29, 32, 36 and 38 are prepared 
from mercaptoimidazoles as follows: 
______________________________________ 
Example Mercaptoimidazoles 
______________________________________ 
30 1-[3-(3-carboxamido-4-methoxyphenyl)- 
propyl]-2-mercaptoimidazole 
33 1-[2-(2,3-di(trifluoromethyl)-4- 
methoxyphenylethyl]-2-mercapto- 
imidazole 
36 1-[2-(3-cyano-4-methoxyphenyl)- 
ethyl]-2-mercaptoimidazole 
38 1-[3-(2-methoxy-4-carbomethoxyphenyl)- 
propyl]-2-mercaptoimidazole 
______________________________________ 
The compound of Example 33, in which R is --(CH.sub.2).sub.3 CH.sub.3 is 
prepared by allowing the deprotection with BBr.sub.3 in butanol to proceed 
to formation of butyl bromide The butyl bromide alkylates the mercapto 
moiety as in Example 6, above. 
TABLE IV 
______________________________________ 
EXAM- 
PLE n X Y R 
______________________________________ 
27 0 3-CH.sub.3,5-CH.sub.3 
CH.sub.3 H 
28 3 2-CN CH.sub.2 OH 
H 
29 1 3-SO.sub.2 NH.sub.2 
H H 
30 3 3-CONH.sub.2 OH H 
31 4 2-CHO H H 
32 4 2-CH.sub.2 OH,3-CH.sub.3 
CF.sub.3 H 
33 2 2-CF.sub.3,3-CF.sub.3 
OH (CH.sub.2).sub.3 CH.sub.3 
34 1 3-SO.sub.2 CF.sub.3 
H H 
35 1 3-CO.sub.2 (CH.sub.2).sub.3 CH.sub.3 
H H 
36 2 3-CN OH H 
37 4 H SO.sub.2 NH.sub.2 
H 
38 3 2-OH CO.sub.2 H 
H 
39 0 H CONH.sub.2 
H 
40 1 3-OCH.sub.3 SO.sub.2 CH.sub.2 CH.sub.3 
H 
41 1 H SO.sub.2 (CF.sub.2).sub.3 CF.sub.3 
H 
42 1 3-(CF.sub.2).sub.3 CF.sub.3 
CO.sub.2 CH.sub.3 
H 
43 1 2,3,5,6-F.sub.4 
F 
44 3 2,3,5,6-F.sub.4 
F H 
45 1 2,3-F.sub.2 H H 
46 1 2-F F H 
47 1 2,5-F.sub.2 H H 
48 1 2,6-F.sub.2 H H 
49 1 3-F F H 
50 1 3,5-F.sub.2 F H 
51 4 3,5-F.sub.2 H H 
52 3 3-Cl,5-F H H 
53 1 3-Cl,5-F H H 
54 2 3,5-F.sub.2 H H 
55 0 3,5-F.sub.2 H H 
56 1 3-Cl,5-F F H 
57 1 3-Br,5-F H H 
58 1 3-I,5-F H H 
______________________________________ 
EXAMPLES 59-68 
The compounds shown in V, below, are prepared by alkylating corresponding 
mercaptoimidazoles of the invention with methyl iodide in methanol by 
known techniques. Other alkyl halides, for example, methyl bromide, methyl 
chloride and butyl iodide, are substituted for methyl iodide in an 
appropriate solvent. The salts are neutralized to the free base with, for 
example, sodium hydroxide or sodium carbonate, and can be converted to 
another pharmacologically acceptable acid addition salt. 
TABLE V 
______________________________________ 
Compound 
EXAMPLE n X Y R 
______________________________________ 
59 1 3-(CH.sub.2).sub.3 CH.sub.3 
F CH.sub.3 
60 1 3-SO.sub.2 CH.sub.3 
(CH.sub.2).sub.3 CH.sub.3 
CH.sub.3 
61 4 2-CHO CHO CH.sub.3 
62 1 3,5-F.sub.2 H CH.sub.3 
63 1 2,4-F.sub.2 H CH.sub.3 
64 3 3,5-F.sub.2 H CH.sub.3 
65 4 3,5-F.sub.2 H CH.sub.3 
66 3 3,5-F.sub.2 H CH.sub.2 CH.sub.3 
67 1 3,5-F.sub.2 H (CH.sub.2).sub.3 CH 
68 1 3,5-F.sub.2 H CH.sub.2 CH.sub.3 
______________________________________ 
EXAMPLE 69 
The ingredients in Table VI, below, are screened, mixed and filled into a 
hard gelatin capsule. 
TABLE VI 
______________________________________ 
Ingredients Amounts 
______________________________________ 
1-[3-(4-hydroxyphenyl)-propyl]-2- 
50 mg 
mercaptoimidazole 
magnesium stearate 5 mg 
lactose 75 mg 
______________________________________ 
EXAMPLE 70 
The sucrose, calcium sulfate dihydrate and imidazole shown in Table VII, 
below, are mixed and granulated with a 10% gelatin solution. The wet 
granules are screened, dried, mixed with the starch, talc and stearic 
acid, screened and compressed into a tablet. 
TABLE VII 
______________________________________ 
Ingredients Amounts 
______________________________________ 
1-[2',6'-dichloro-4'-hydroxybenzyl]- 
100 mg 
2-mercaptoimidazole 
calcium sulfate dihydrate 
150 mg 
sucrose 20 mg 
starch 10 mg 
talc 5 mg 
stearic acid 3 mg 
______________________________________ 
EXAMPLE 71 
1-3-(4--Hydroxyphenyl)propyl]-2-thiomethylimidazole 
75 mg, is dissolved in z5 ml of normal saline to prepare an injectable 
preparation. 
While the preferred embodiments of the invention are illustrated by the 
above, it is to be understood that the invention is not limited to the 
precise constructions herein disclosed and that the right to all 
modifications coming within the scope of the following claims is reserved.