Substituted (3-loweralkylamino-2-R.sub.1 O-propoxy)pyridines, their preparation and use

Novel cyano substituted (3-loweralkylamino-2-R.sub.1 O-propoxy)pyridines, their pharmaceutically acceptable salts and their preparation are disclosed. The pyridines are vasodilators having antihypertensive activity of rapid onset and extended duration and reduced tendency to cause undesirable tachychardia; they are also .beta.-adrenergic blocking agents.

BACKGROUND OF THE INVENTION 
The present invention concerns cyano substituted 
2-(3-loweralkylamino-2-R.sub.1 O-propoxy)pyridines which have 
antihypertensive activity of rapid onset and extended duration and are 
.beta.-adrenergic blocking agents. 
Hypertension in man and other animals can be treated with various chemical 
agents. One such class of agents is that known as the .beta.-adrenergic 
blocking agents or .beta.-blockers. While this class of agents can have 
antihypertensive activity, the onset of this activity is generally 
gradual. The structure and activity of .beta.-blockers is generally 
discussed in "Clinical Pharmacology and Therapeutics" 10, 252, 306 (1969). 
Substituted carbocyclic aryl .beta.-adrenergic blocking agents are 
disclosed in British Pat. Nos. 1,206,420, 1,304,303, U.S. Pat. Nos. 
3,644,636, 3,459,782, Belgian Pat. No. 707,050 and Netherlands Pat. No. 
69.0700. Substituted N-heteroaryl .beta.-adrenergic blocking agents are 
also disclosed in German application No. 2,406,930, its counterpart South 
African Pat. No. 74.28204, British Pat. No. 1,305,644, Journal of 
Medicinal Chemistry 16, 1113-1114 (1973) and Journal of Medicinal 
Chemistry 15, 1321 (1972). 
Another class of antihypertensive agents are the vasodilators. 
Vasodilators, however, normally cause undesirable tachychardia. 
Novel cyano substituted (3-loweralkylamino-2-R.sub.1 O-propoxy)pyridines 
have been discovered. These compounds have antihypertensive activity of 
rapid onset and extended duration and they are .beta.-adrenergic blocking 
agents. 
SUMMARY OF THE INVENTION 
Novel cyano substituted (3-loweralkylamino-2-R.sub.1 O-propoxy)pyridines 
and their pharmaceutically acceptable salts which have rapid and lasting 
antihypertensive effect and are also .beta.-adrenergic blocking agents. 
DESCRIPTION OF THE PREFERRED EMBODIMENTS 
An embodiment of the present invention is compounds selected from those 
having the formula: 
##STR1## 
wherein R is C.sub.3 -C.sub.4 branched alkyl, 
R.sub.1 is selected from H and 
##STR2## 
L is selected from C.sub.1 -C.sub.10 alkyl, phenyl, mono- and 
disubstituted phenyl wherein said substituents are independently selected 
from C.sub.1 -C.sub.4 alkyl, 
And pharmaceutically acceptable salts thereof. 
The L group includes linear and branched alkyl such as methyl, n-decyl, 
tert. butyl, isoamyl, n-heptyl and the like with C.sub.1 -C.sub.4 alkyl 
being preferred; mono and disubstituted phenyl such as 4-tert. 
butoxyphenyl, 2,6-dibromophenyl, 3-methylphenyl, 4-n-propylphenyl, 
3,5,di-methoxyphenyl, 4-iodophenyl, 2-methyl-4-chlorophenyl, 
p-fluorophenyl and the like: which mono-substituted phenyl preferred. The 
term halo includes Cl, Br F and I, with Cl being preferred. R is 
isopropyl, sec. butyl or tert. butyl, tert. butyl being preferred. 
Where R.sub.2 in Formula I is 
##STR3## 
the preferred compounds are those wherein L is --CH.sub.3, 
--C(CH.sub.3).sub.3 or p-methoxyphenyl, with --C(CH.sub.3).sub.3 being 
most preferred. 
More preferred compounds of Formula I are those wherein R.sub.1 is 
hydrogen. Most preferred Formula I compounds are those where R.sub.1 is 
hydrogen and R is tert. butyl. 
The substituted pyridines of the present invention include all the optical 
isomer forms, that is, mixtures of enantiomers, e.g., racemates as well as 
the individual enantiomers. These individual enantiomers are commonly 
designated according to the optical rotation they effect, by (+) and (-), 
(L) and (D), (l) and (d) or combinations of these symbols. The symbols (S) 
and (R) stand for sinister and rectus respectively and designate an 
absolute spatial configuration of the enantiomer. Where no isomer 
designation is given for a compound, the compound is the racemate. 
The pyridines of the present invention can be prepared by any convenient 
process. 
One such process involves the coupling of a halopyridine with a suitable 
substituted oxazolidine and hydrolysing the reaction product obtained. 
This process is illustrated by the set of reaction equations: 
REACTION 1 
______________________________________ 
##STR4## (a) 
##STR5## 
##STR6## (b) 
##STR7## 
Halo may be Cl, Br and, with Cl being preferred. M is an alkali metal, 
either potassium or sodium. Y can be hydrogen or the residue of any 
suitable aldehyde 
##STR8## 
e.g. arylaldehyde, such as benzaldehyde, naphthaldehyde and the like, or 
alkanal such as acetaldehyde, butyraldehyde and the like. The process for 
preparing oxazolidines where M is hydrogen is disclosed in U.S. Pat. Nos. 
3,718,647 and 3,657,237 and to the extent necessary the pertinent 
disclosure is incorporated herein by reference. The alkali metal salt of 
the oxazolidine is prepared in a conventional manner by reaction of the 
corresponding hydroxymethyloxazolidine with an appropriate amount of base 
reactant. However, Reaction 1 may also be carried out with in-situ 
formation of the alkali metal oxazolidine salt of Formula B by reacting 
the oxazolidine 
##STR9## 
with the Formula A pyridine in the presence of a strong base such as an 
alkali metal alkoxide (e.g. K--O--C--(CH.sub.3).sub.3) or sodium hydride. 
The coupling reaction can be carried out at temperatures ranging from about 
0.degree. to about 100.degree. C. A temperature range of about 10.degree. 
to about 50.degree. C is preferred. The reaction is generally carried out 
in a solvent. Any suitable solvent may be used. Examples of useful 
solvents are dimethylformamide, dimethylsulfoxide, 
hexamethylphosphoramide, t-butanol and the like. The hydrolysis is carried 
out using conventional acid hydrolysis reagent and techniques e.g. 
treatment with a solution of any strong mineral acid such as HCl or 
H.sub.2 SO.sub.4. The hydrolysis product can be directly obtained as the 
salt of the acid used for the hydrolysis. Ordinarily, the product D is 
recovered as the free base after conventional neutralization of the salt. 
The coupling reaction is ordinarily carried out at atmospheric pressure. 
Higher pressures may be used if desired. 
When the racemic oxazolidine (Formula B, C or E) is used as a reactant, the 
product is obtained as a racemate. The racemate may be separated into its 
individual enantiomers by conventional resolution techniques. 
By using a single optical isomer of solid oxazolidine in the above 
reactions, the product may be obtained directly as a single enantiomer. 
Thus, if the S-isomer of the oxazolidine is used, then the product 
obtained will be the S-isomer. This provides a convenient way for directly 
preparing individual isomers of the present pyridines. 
Pyridines of Formula I wherein R.sub.1 is other than hydrogen, are 
conveniently prepared by treating the corresponding pyridine where R.sub.1 
is hydrogen with an appropriate acylating agent such as an acyl halide, 
e.g. acetylchloride, pivaloylchloride, p-methoxybenzoylchloride, 
benzoylchloride, an anhydride, e.g., acetic anhydride and the like. The 
reaction is illustrated by the following equation: 
##STR10## 
The compounds of the present invention also include the pharmaceutically 
acceptable salts of the novel pyridines. These salts are generally salts 
of the Formula I pyridines and organic or inorganic acids. These salts are 
prepared by treating the pyridine with an appropriate amount of a useful 
acid, generally in a suitable solvent. Examples of useful organic acids 
are carboxylic acids such as maleic acid, acetic acid, tartaric acid, 
propionic acid, fumaric acid, isethionic acid, succinic acid, pamoic acid, 
oxalic acid, pivalic acid and the like; useful inorganic acids are 
hydrohalo acids such as HCl, HBr, HI, sulfuric acid, phosphoric acid and 
the like. 
The compounds of the present invention have antihypertensive activity of 
rapid onset and are also .beta.-adrenergic blocking agents. This 
antihypertensive activity is believed to be the result of peripheral 
vasodilation via a mechanism not directly related to .beta.-adrenergic 
blockade. One advantage the present pyridines have over ordinary 
.beta.-adrenergic agents is that the antihypertensive effect is immediate 
and generally of extended duration. 
This rapid onset antihypertensive activity is determined by administering a 
representative pyridine of the present invention to spontaneously 
hypertensive (SH) rats and measuring the effect on blood pressure. An 
example of a representative compound having this antihypertensive activity 
is (S)-3-(3-tert. butylamino-2-hydroxypropoxy)-4-cyanopyridine. 
The .beta.-adrenergic blocking activity of the present pyridines is 
determined by measuring the ability of a representative pyridine to block 
isoproterenol induced .beta.-adrenergic stimulant effects such as heart 
rate increase, hypotension and bronchodilatation, in animals. 
The ability of the present pyridines to reduce blood pressure, in an SH 
rat, rapidly and for extended duration, indicates that the present 
pyridines and their salts are useful to treat hypertension in humans. 
Likewise, the observed .beta.-adrenergic blocking activity of these 
pyridines indicates that they are useful in humans as .beta.-adrenergic 
blocking agents. 
For use as antihypertensives and/or .beta.-adrenergic blocking agents, the 
compounds of the present invention can be administered orally, by 
inhalation, by suppository or parenterally, i.e., intravenously, 
intraperitoneally, etc. and in any suitable dosage form. The compounds may 
be offered in a form (1) for oral administration, e.g., as tablets in 
combination with other compounding ingredients (diluents or carriers) 
customarily used such as talc, vegetable oils, polyols, benzyl alcohols, 
starches, gelatin and the like -- or dissolved, dispersed or emulsified in 
a suitable liquid carrier -- or in capsules or encapsulated in a suitable 
encapsulating material; or (2) for parenteral administration, dissolved, 
dispersed, or emulsified in a suitable liquid carrier or diluent or (3) as 
an aerosol or (4) as a suppository. The ratio of active ingredient 
(present pyridine) to compounding ingredients will vary as the dosage form 
required. Conventional procedures are used to prepare the pharmaceutical 
formulations. 
The dosage level for the present compounds may be varied from about 0.01 
mg. to about 50 mg. per kilogram of animal body weight per day. Daily 
doses ranging from about 0.04 to about 2.5 mg/kg are preferred, with about 
0.08 to about 1.25 mg/kg being a more preferred range. Oral administration 
is preferred. Either single or multiple daily doses may be administered 
depending on unit dosage. 
Thus, another embodiment of this invention is a pharmaceutical composition 
containing an antihypertensive and/or .beta.-adrenergic blocking amount of 
a compound of the present invention. 
The following examples illustrate the preparation of representative 
pyridines of the present invention. Where no isomer designation is 
indicated, the product is the racemate. All parts are by weight unless 
otherwise noted.

EXAMPLE 1 
S-2-(3-Tert. butylamino-2-hydroxypropoxy)-4-cyanopyridine 
To a solution of S-2-phenyl-3-tert. butyl-5-hydroxymethyloxazolidine (3.7 
g. - 0.16 m) in DMF (15 ml.) is added 57% NaH (0.65 g., .015 m) and 
stirred at room temperature for 15 minutes. To the above solution is added 
2-chloro-4-cyanopyridine (3.3 g., 0.016 m) in DMF (10 ml.) and heated to 
80.degree. C. for 3 hours. The mixture is poured into water (200 ml.) and 
extracted with ether (3 .times. 100 ml.), backwashed with water (2 .times. 
100 ml.) and saturated NaCl solution (100 ml.) the ether is dried over 
Na.sub.2 SO.sub.4, filtered and concentrated to dryness under reduced 
pressure (30 mm.). The residue is treated with 1N HCl (25 ml.), heated on 
a steam bath for 15 minutes, cooled to room temperature and extracted with 
ether (2 .times. 50 ml.). The aqueous layer is neutralized with saturated 
Na.sub.2 CO.sub.3 solution and extracted with EtOAc (2 .times. 50 ml.), 
dried over Na.sub.2 SO.sub.7, filtered and concentrated to dryness under 
reduced pressure (3 mm). The residue is crystallized from petroleum 
ether-ether to give 2.4 g. of S-2-(3-tert. 
butylamino-2-hydroxypropoxy)-4-cyanopyridine, melting at 
80.degree.-82.degree. C. 
Isopropyl or sec. butyl amino analogues of the compounds of the above 
example are prepared by substituting suitable oxazolidines e.g. 
2-phenyl-3-isopropyl-5-hydroxymethyloxazolidine, (S)-2-methyl-3-sec. 
butyl-5-hydroxymethyloxazolidine, 3-isopropyl-5-hydroxymethyloxazolidine 
for the (S)-2-phenyl-3-tert. butyl-5-hydroxymethyloxazolidine reactant. 
The pyridines of Formula I where R.sub.1 is 
##STR11## 
are prepared by acylation of the corresponding pyridine having R.sub.1 
.dbd. OH. For example, the compound having the formula 
##STR12## 
is prepared by treating the product of Example I with an appropriate 
amount of pivaloyl chloride (trimethylacetyl chloride). 
The present invention also includes the quaternary ammonium salts and 
N-pyridine oxides of the Formula I compounds. 
The quaternary ammonium salts have the formula 
##STR13## 
wherein R and R.sub.1 are defined as above, R.sup.1 is an alkyl (e.g. 
C.sub.1 -C.sub.4 alkyl) or aryl (e.g. benzyl) group and X is a halogen 
especially Cl, Br or I. These quaternary salts are prepared using any 
convenient method. For example, they can be prepared by treating the 
compound of formula I with an alkyl or aryl halide such as methyliodide or 
benzylchloride to obtain the corresponding quarternary salt of formula II. 
The N-pyridine oxides have the formula 
##STR14## 
with R and R.sub.1 as defined as above, including the acid addition salts 
and quaternary ammonium salts thereof. These N-oxides are also prepared 
using conventional reagents and procedure. For example, a convenient 
method of preparing these oxides is to treat the intermediate of Formula A 
with an oxidizing agent e.g. H.sub.2 O.sub.2 using conventional reaction 
conditions to produce the oxidized intermediate having the formula 
##STR15## 
The formula V.sup.1 compound is then substituted for the formula V 
compound in Reaction 1 above to obtain the N-pyridine oxide of Formula 
III. 
Claims to the invention follow: