Benzimidazol-5-yl alanine derivatives useful as antihypertensive agents are disclosed as well as methods for their preparation.

BACKGROUND OF THE INVENTION 
The present application is concerned with novel substituted 
benzimidazolylalanines which are useful as antihypertensive agents. 
Unsubstituted 3-(benzimidazol-5-yl)-alanine and 
3-(benzimidazol-5-yl)-2-methylalanine are known [see Journal of Medicinal 
Chemistry 13, 741 (1970); Fifth International Congress on Pharmacology, 
Abstract 964, July-23-28, 1972]. Each of these alanines is known to effect 
in vivo depletion of norepinephrine in the brain and heart. Neither of 
these alanines is known to have substantial antihypertensive activity. 
3,4-Dihydroxyphenyl-2-methylalanine, also commonly known as methyldopa, is 
a well known antihypertensive agent. It also is known to effect a 
substantial depletion of norepinepherine, in vivo, in both the brain and 
heart. 
Novel substituted benzimidazole alanines, specifically 
3-(6-hydroxybenzimidazol-5-yl)alanine, 
3-(6-hydroxybenzimidazol-2-one-5-yl)alanine and 
3-(6-methoxybenzimidazol-2-one-5-yl)alanine have been prepared. These 
compounds exhibit antihypertensive activity. 
SUMMARY OF THE INVENTION 
3-(6-Hydroxybenzimidazol-5-yl)alanine, 
3-(6-hydroxybenzimidazol-2-one-5-yl)alanine and 
3-(6-methoxybenzimidazol-2-one-5-yl)alanine their pharmaceutically 
acceptable salts and use as antihypertensive agents. 
DESCRIPTION OF THE PREFERRED EMBODIMENTS 
The present invention is embodied in compounds having the formulae 
##STR1## 
and pharmaceutically acceptable salts thereof. Since each of the Formula 
I, through IIIa compounds has an asymmetric carbon atom, it is optically 
active. Thus, these compounds include the individual optical isomers as 
well as the racemate and other isomer mixtures. 
These individual optical isomers are variously designated as 1 and d, D and 
L, - and + or by combinations of these symbols. These isomers may also be 
designated S (sinister) and R (rectus), symbols which indicate the 
absolute spatial configuration of the isomer molecule. 
An appropriate isomer designation may be used in naming a compound. Where 
no symbol is given, then the compound named includes the individual 
isomers, the racemate and all isomer mixtures. 
Pharmaceutically acceptable salts include metal salts, e.g. sodium, 
potassium, etc., and the salts of the Formula I-IIIa compound with 
suitable acids. These acids include inorganic and organic acids. Useful 
inorganic acids encompass the hydrohalide acids e.g. HCl, HBr, HI, 
sulfuric acid and phosphoric acid. The organic acids include carboxylic 
and non-carboxylic acids. The carboxylic acids may contain from 2 to about 
24 carbon atoms. Useful carboxylic acids are exemplified by acetic acid, 
cyclohexylcarboxylic acid, maleic acid, citric acid, hexanoic acid, 
tetracosanoic acid, oxalic acid, succinic acid, tartaric acid, the fatty 
acids e.g. palmitic, oleic, stearic, pamoic and the like, fumaric acid, 
malic acid, ascorbic acid, pivalic acid and the like. An especially useful 
non-carboxylic acid is isethionic acid. Pharmaceutically acceptable means 
that the salts are substantially non-toxic and retain the required 
pharmaceutical activity. 
Preferred salts are the hydrohalides and especially the hydrochlorides and 
hydrobromides. 
Representative salts of the compounds of Formulae I, II and III have been 
found to effect a reduction in blood pressure when administered to 
spontaneously hypertensive rats. It is believed that the compounds of the 
present invention are useful to treat hypertension in animals, including 
humans. Hypertension manifests itself, and is commonly referred to, as 
"high blood pressure". Thus, the present compounds are useful in lowering 
the blood pressure of hypertensive patients. 
A representative salt of the Formula I compound has also been found to 
reduce norepinephrine in the brain and heart of rats using a conventional 
test procedure. 
The dosage required to effect lowering of blood pressure in the 
hypertensive patient will vary. Daily dosage ranging from 10 to 3500 mg of 
a compound of Formula I to IIIa is useful. A preferred daily dosage range 
is 50-1000 mg, with 100-750 mg being more preferred. 
The compounds may be administered alone or in combination with suitable 
pharmaceutical compounding ingredients. Useful dosage forms include those 
suitable for oral administration e.g. tablets, capsules, suspensions, 
emulsions and the like, as well as for parenteral administration e.g. 
solution, suspension, emulsion and the like. The dosage forms are prepared 
using conventional procedures, equipment and compounding ingredients i.e. 
diluents, carriers, excipients, encapsulating materials etc. 
In addition to the more conventional administration modes and dosage forms, 
the present compounds may also be administered in a form which will 
dispense the compound to the patient continuously over an extended period 
of time. This method of administration is embodied in a carrier device or 
means which is imbedded, inserted, attached, ingested or otherwise 
provided to the patient. An advantage of this form of administration is 
that it ensures continuous, regulated and convenient administration of the 
hypertensive agent to the patient.

The following examples illustrates preparation of a representative 
compounds of the present invention. While the example products obtained 
are racemates (D,L), they may be separated into the D and L enantiomers by 
conventional procedures such as resolution using an optically active acid 
(e.g. tartaric acid) in a suitable solvent system. All temperatures in the 
example are in degrees centigrade. 
EXAMPLE 1 
Preparation of D,L-3-(6-hydroxybenzimidazole-5-yl)alanine-.multidot.2HBr 
A. Diethyl-2-Methoxy-5-Nitrobenzyl acetamido malonate 
##STR2## 
Molar amounts of 2-chloromethyl-4-nitroanisole and freshly prepared 
sodiodiethylacetamidomalonate were refluxed in ethanol for 5 hrs. and the 
turbid solution filtered hot. The filtrate was allowed to cool and 
refiltered to yield 2-methoxy-5-nitrobenzyl acetamidomalonate A in 70-75% 
crude yield, m.p. 161.degree.-163.degree.. This crude product was used for 
the next step as such. 
B. Diethyl-2-Methoxy-5-Acetylaminobenzyl-acetamidomalonate 
##STR3## 
The crude nitro compound A (15g) from the previous step was dissolved in 
absolute ethanol (200 ml), Pd-C (10%, 0.8g) was added and the mixture 
hydrogenated in a Paar bottle at 40 psi until no more hydrogen was 
absorbed (2-3 hrs.). The mixture was filtered through Celite (to remove 
Pd-C) and the filtrate evaporated in vacuo to give the colorless solid 
amine m.p. 129.degree.-131.degree.. The amine was in all cases directly 
acetylated by refluxing with acetic acid (5 ml) and acetic anhydride (25 
ml) for 1 hour. The mixture was then poured into ice water (100 ml), 
cooled in the refrigerator for 1 hour, then filtered and the solid washed 
with water. Drying in vacuo at 60.degree. yielded 13.5 g of the desired 
acetate B (88%), mp 143.degree.-145.degree.. The crude acetate B was taken 
up for nitration without further purification. Recrystallization from 
ethyl acetate yielded an analytical sample of B mp 150.degree.-51.degree.. 
C. Diethyl-2-Methoxy-4-Nitro-5-Acetamidobenzylacetamidomalonate: 
##STR4## 
The crude acetate B from the previous step (15g) was stirred in a 250 ml 
3-necked flask with a 1:1 mixture of acetic acid and acetic anhydride (45 
ml). The solution was cooled externally in ice to 0.degree.-5.degree.. 
Through a dropping funnel, conc. HNO.sub.3 (30 ml) was gradually added 
while maintaining the temp. below 10.degree. (1Hr). After stirring for an 
additional 1 hour at 10.degree.-15.degree., the reaction mixture was 
gradually added with rapid stirring to NaHCO.sub.3 (120g) in 400 ml cold 
water to bring it to pH 7. The mixture was stirred (30 min.), filtered and 
washed with water to give 18-20 g of a dark yellow solid, mp 
157.degree.-158.degree.. Recrystallization from CHCl.sub.3 :Hexane (1:1, 
200 ml) yielded 14.7 g (88%) of crystalline yellow compound C, mp 
159.degree.-161.degree.. 
D. 2-Methoxy-5-Amino-4-Nitrophenylalanine 
##STR5## 
Compound C (10g) was refluxed with 5N HCl (90 ml) for 6 hours. The solution 
was then cooled in ice and neutralized with 30% NH.sub.4 OH to pH 6, 
cooled in the refrigerator overnight, filtered and dried in a vacuum oven, 
or at room temperature, yielding 5.5 g of the crude compound D, mp 
232.degree.-234.degree.. However, the compound contained 1 mol of water of 
crystallization. The yield as hydrate was 88%. The amino acid D was 
directly used without further purification in most cases. A small amount 
of the sample was recrystallized from CH.sub.3 OH:H.sub.2 O (1:1) giving 
bright red crystals of the hydrate of D m.p. (color changing to pale 
yellow around 110.degree.) 239.degree.-240.degree. (dec). 
E. 5-(6) Methoxy Benzimidazole 6-(5) alanine .multidot.HCl 
##STR6## 
The crude amino acid D (1.0 g) was dissolved in 5N HCl (40 ml) in a Paar 
bottle, 5% Pd-C (0.1 g) was added and the mixture hydrogenated (1.5-2 
hours) at 35-40 psi until no additional H.sub.2 was absorbed. The Paar 
Bottle was then flushed with N.sub.2 and the contents transferred to a 250 
ml flask containing 7 ml formic acid (97%) and 5 ml of 5N HCl. The mixture 
was refluxed for 3.5 hours with exclusion of air (Hg trap used) and was 
then stirred (30 minutes) with Norit (a charcoal) and filtered through 
Celite to give a pale yellow mother liquor. The solvent was then removed 
in vacuo and the solid obtained was co-evaporated in vacuo twice with 5 ml 
isopropyl alcohol each time (to remove excess H--COOH and HCl). Finally 
isopropyl alcohol was added and the mixture refrigerated overnight. The 
solid was then filtered, washed well with cold isopropyl alcohol, and 
dried at 110.degree., 0.1 mm Hg for 5 hours giving 970 mgs of a pale 
yellow solid, mp 271.degree. (dec.) which was recrystallized from 
ethanol:water and dried in vacuo to give 620 mgs (51.1%) of compound E, mp 
275.degree. (dec.). 
F. D,L-3(6-dihydroxybenzimidazol-5-yl) alanine .multidot.2HBR 
##STR7## 
The amino acid E (1.35 g) was refluxed with 48% HBr (25 ml) for 6.5 hours 
using a Hg trap to exclude air. The solution was cooled in a freezer 
overnight. The solid that separated on cooling was filtered, washed first 
with acetone and then with ether. On drying the solid in vacuo at 
110.degree., crude compound F (1.6g), decomposing at 279.degree., was 
obtained. The solid was dissolved in ethanol:H.sub.2 O (45:5 ml) and 
treated with neutral Norit (a charcoal) for 4 hours. After filtering 
through Celite to remove charcoal, the mother liquor was evaporated in 
vacuo and the solid recrystallized from ethanol:acetonitrile (1:2) to 
yield 0.9g (53.6%) of colorless product F, decomposing at 273.degree.. 
EXAMPLE 2 
Preparation of D,L-3-(6-hydroxybenzimidazol-2-one-5-yl)-alanine 
.multidot.HBr 
A. 3-(6-Methoxybenzimidazol-2-one-5-yl)alanine 
##STR8## 
The crude amino acid D (2.5g) was dissolved in 5N HCl (175 ml), 5% Pd-C 
(0.25g) was added and the mixture hydrogenated at 35-40 psi until no more 
H.sub.2 was absorbed (1.5-2 hrs). The Paar bottle was flushed with N.sub.2 
and the contents trasferred to a 3-necked flask; phosgene gas was passed 
through the solution for 1 hour and the solution was then heated for 30 
min on a steam bath. The solid which precipitated during the reaction was 
collected on a Buchner funnel and the mother liquor evaporated in vacuo to 
give additional product. The combined solids (containing Pd-C) were 
carefully dissolved in ethanol (25 ml) and water (10 ml) and stirred with 
Norit for about 1 hr. Filtration through Celite and concentration in vacuo 
yielded an almost colorless solid, (1.1g). Recrystallization from 
ethanol:water (5:1) yielded 0.85g (32.3%) of the desired product G mp 
288.degree. (dec.). 
B. D,L-3-(6-hydroxybenzimidazol-2-one-5-yl)alanine .multidot.HBr 
##STR9## 
The amino acid G (0.600 g) was refluxed with 48% HBr (23 ml) for 6.5 hrs. 
using a Hg trap to exclude air. The solution was then evaporated in vacuo 
and the solid was dissolved in CH.sub.3 OH (40 ml) and treated with Norit 
for 1 hr. After filtering through Celite, the mother liquor was 
concentrated in vacuo to give a solid. The solid was recrystallized from 
CH.sub.3 OH:CH.sub.3 CN (1:2) to yield 432 mg (65%) of a colorless, solid 
compound H mp 268.degree. (dec.). 
The G and H compounds also include their tautomers. 
HI can be used in place of HBr to effect the ether cleavage in Example 1, 
step F, or Example 2, step B and the resultant product will then be the HI 
salt. 
The benzimidazole alanine product in Example 1, Step F or Example 2, step B 
is obtained as the HBr or HI salt. This salt may be conventionally 
neutralized to provide the free alanine base. The base can then be used as 
such as an antihypertensive agent or converted to any other suitable salt 
by treatment with appropriate acid or base. 
Claims to the invention follow.