Method of treating senile cognitive decline with N'-substituted aminopyridine adrenergic agents

A method is disclosed for the treatment or amelioration of the symptoms of cerebral insufficiency characterized by decreased central adrenergic and/or cholinergic function employing certain N-substituted aminopyridines.

BACKGROUND OF THE INVENTION 
The present invention relates to a medical method of treatment. More 
particularly, it concerns the use of certain N'-substituted aminopyridine 
compounds having adrenergic activity for ameliorating the symptoms of 
cognitive decline in the elderly. 
U.S. Pat. No. 3,450,707 discloses 2-(3-fluoroanilino)-, and 
2-(3-trifluoromethylanilino)pyridine and their N-oxides as 
antiinflammatory agents. 
U.S. Pat. No. 3,624,096 discloses a process for preparing 2-aminopyridine 
compounds in which the amino group is substituted with phenyl, benzyl, 
p-tolyl, p-chlorophenyl, or p-nitrophenyl. 
U.S. Pat. No. 3,928,341 discloses 4-[(2-chlorophenyl)amino]pyridine, 
4-[(3-chlorophenyl)amino]pyridine, 4-[(3,5-dichlorophenyl)-amino]pyridine, 
4-[(3-trifluoromethylphenyl)amino]pyridine, 
4-[(2-methylphenyl)amino]pyridine, 4-[(2-ethylphenyl)amino]-pyridine, and 
4-[(2,6-dimethylphenyl)amino]pyridine as intermediates for the preparation 
of certain N-aminoalkyl-4-anilino pyridines having central nervous system 
activity as excitants and antidepressants. 
U.S. Pat. No. 4,206,215 discloses 4-[(4-chlorophenyl]amino]pyridine and 
4-[(4-fluorophenyl)-amino]pyridine as intermediates for the preparation of 
bis-[4-[(substituted)amino]-1-pyridinium]alkanes having antimicrobial 
activity. 
U.S. Pat. No. 4,331,670 discloses certain pyridylanilines having utility as 
agents for combatting insects, mites, fungi, or bacteria. 
European patent application EP No. 0 000 816 to Baggaley discloses certain 
[[(substituted)phenyl]-amino]pyridines having hypoglycemic, hypolipidemic, 
and/or antilipolytic activity. 
Hirota et al, Bull. Soc. Chem. (Japan), 54: 1583-1584 discloses several 
2-[[2-, 2-[[3-, and 2-[[(4-substituted)phenyl]amino]pyridines in a study 
of the effect of substitution patterns on the N-H stretching frequency in 
the infrared spectrum of the compounds. 
Sammes, et al, J. Chem. Soc. Perkin Trans. I, (1983), 973-978 discloses a 
synthetic route to several 4-[[2-, 4-[[3-, and 
4-[[4-(substituted)phenyl]amino]-pyridines. 
SUMMARY OF THE INVENTION 
The present invention provides a method of treating the symptoms of senile 
cognitive decline in the elderly characterized by decreased cerebral 
adrenergic and cholinergic function. The treatment comprises administering 
to a patient an effective amount of a compound having the structure 
##STR1## 
wherein R.sub.1 is selected from hydrogen; alkyl of from one to six carbon 
atoms; alkanoyl of from two to six carbon atoms; benzoyl; carboxyl; 
carboxyalkyl; 2-, 3-, or 4-pyridinyl; phenyl; phenyl substituted with 
fluorine, chlorine, hydroxy, alkyl of from one to four carbon atoms, or 
alkoxy of from one to four carbon atoms; or phenylmethyl. 
R.sub.2 and R.sub.3 are independently hydrogen; alkyl of from one to six 
carbon atoms; alkoxyl of from one to six carbon atoms; alkanoyl of from 
two to six carbon atoms; carboxyl; carboxyalkyl in which alkyl contains 
from one to six carbon atoms; halogen; hydroxy; cyano; trifluoromethyl; 
nitro; --SO.sub.3 H; amino; alkylamino, or dialkylamino in which alkyl 
contains from one to four carbon atoms. 
DETAILED DESCRIPTION 
Memory problems are perhaps the most conspicuous psychological problems of 
aging, ranging from persistent forgetfulness to clinical dementia. 
Age-associated memory impairment (AAMI) is characterized by a transient 
failure to recall details about recent events. Simple primary degenerative 
dementia (SPDD) is characterized by a profound loss of recent memory, 
relatively selective cholinergic deficit and late onset, generally after 
65 years of age. Complex primary degenerative dementia (CPDD) is 
characterized by adrenergic and global cognitive deficits and early age of 
onset. 
Together, AAMI, SPDD, and CPD represent a large percentage of senile 
cognitive decline (SCD), which is defined as the variety of cognitive 
disorders that accompany aging, constituting a major and growing public 
health problem. Presently, 5-10% of the population at 65 years of age and 
up to 20% of the population over 80 years of age are affected. 
While cholinergic dysfunction contributes in part to SCD, other 
neutrotransmitter systems are clearly involved. Consistent reductions in 
noradrenergic function arising from neuropathological abnormalities in 
noradrenergic containing cell bodies in the locus coeruleus accompany SCD. 
This results in decreases in the levels of norepinephrine and numbers of 
.alpha. adrenergic receptors in the cerebral cortex and basal forebrain of 
aged humans and patients with dementia. 
Agents which increase central noradrenergic function ameliorate these 
neurochemical abnormalities and are useful in the treatment of SCD. Thus, 
.alpha.2-adrenergic antagonists, which increase the availability of 
norepinephrine, represent potentially effective therapy for SCD. In 
addition, agent which increase central noradrenergic function may also 
indirectly activate cholinergic function. 
Cognitive deficits are not restricted to the aged. These deficits are found 
at all ages and in a variety of clinical situations, including head 
trauma, hypoxic and pharmacologic insult, convulsive disorders, mental 
retardation, and learning disorders. An agent which enhances central 
adrenergic and/or cholinergic function may also be useful in treating 
cognitive dysfunction associated with these disorders. 
The compounds in the present invention are selective .alpha.2 antagonists, 
with additional effects on the cholinergic system, and are thus effective 
in the treatment or amelioration of cognitive dysfunction. The compounds 
in this invention are 4-aminopyridines in which the 4-amino group may be 
monosubstituted (i.e., a secondary amine) or disubstituted (i.e., a 
tertiary amine). The preferred secondary amines are 
N-((substituted)-phenyl)-4-pyridinamines in which the phenyl group may be 
mono-, or disubstituted with alkyl of from one to six carbon atoms; 
alkoxyl of from one to six carbon atoms; alkanoyl of from two to six 
carbon atoms; carboxyl; carboxyalkyl in which alkyl contains from one to 
six carbon atoms; halogen; hydroxy; cyano; trifluoromethyl; nitro; 
--SO.sub.3 H; amino; alkylamino or dialkylamino in which alkyl contains 
from one to four carbon atoms. 
The tertiary amines are substituted on the 4-amino nitrogen atom as 
described just above, with the 4-amino nitrogen atom additionally bearing 
a substituent selected from alkyl of from one to six carbon atoms; 
alkanoyl of from two to six carbon atoms; benzoyl; carboxyl; carboalkoxy; 
2-, 3-, or 4-pyridinyl; (substituted)phenyl; or phenylmethyl. 
The term "alkyl of from one to six carbon atoms" denotes a substituent 
group derived from a saturated hydrocarbon by removal of a single hydrogen 
atom. The term includes methyl, ethyl, n-propyl, iso-propyl, n-butyl, 
sec-butyl, iso-butyl, tert-butyl, and the various isomeric forms of pentyl 
and hexyl. 
The term "alkoxy" denotes a substituent group derived by removal of the 
hydrogen from the oxygen atom of a saturated alcohol and attached to the 
parent molecular moiety through the oxygen atom. Such groups include 
methoxyl, ethoxyl, 1- and 2-propoxyl, and similar branched and unbranched 
alkoxy groups of up to four carbon atoms. 
The term "alkanonyl" denotes an alkyl group as previously defined, attached 
to the parent molecular moiety through a carbonyl group. 
The term "carboxyl" denotes the acidic functional group --COOH, while 
carboxyalkyl denotes the ester function --COO--alkyl where alkyl is as 
previously defined. 
Examples of compounds contemplated as falling within the scope of the 
present invention include, but are not limited to the following: 
N-Phenyl-4-pyridinamine. 
N-(3-Methylphenyl)-4-pyridinamine. 
N-(4-Methylphenyl)-4-pyridinamine. 
N-(4-Methyl-2-nitrophenyl)-4-pyridinamine. 
N-(3-Methoxyphenyl)-4-pyridinamine. 
N-(4-Methoxyphenyl)-4-pyridinamine. 
N-(3,4-Dimethoxyphenyl)-4-pyridinamine. 
N-(2-Chlorophenyl)-4-pyridinamine. 
N-(3-Chlorophenyl)-4-pyridinamine. 
N-(4-Chlorophenyl)-4-pyridinamine. 
N-(3-Chlorophenyl)-N-methyl-4-pyridinamine. 
N-(4-Chlorophenyl)-N-methyl-4-pyridinamine. 
N-(2,4-Dichlorophenyl)-4-pyridinamine. 
N-(3,4-Dichlorophenyl)-4-pyridinamine. 
N-(4-Chloro-3-nitrophenyl)-4-pyridinamine. 
N-(2-Nitrophenyl)-4-pyridinamine. 
N-(3-Nitrophenyl)-4-pyridinamine. 
N-4-Pyridinyl-1,2-benzenediamine. 
N-4-Pyridinyl-1,3-benzenediamine. 
N,N-Dimethyl-N'-4-pyridinyl-1,3-benzene-diamine. 
N-[3-(Trifluoromethyl)phenyl]-4-pyridin-amine. 
N-[4-(Trifluoromethyl)phenyl]-4-pyridin-amine. 
3-(4-Pyridinylamiino)-benzonitrile. 
3-(4-Pyridinylamino)benzoic acid, methyl ester. 
3-(4-Pyridinylamino)benzoic acid, ethyl ester. 
3-(4-Pyridinylamino)benzenesulfonic acid. 
N-(3,4-Dichlorophenyl)-N-4-pyridinyl-4-pyridinamine. 
N-(3,4-Dichlorophenyl)-N-4-pyridinylacet-amide. 
N-(4-Methylphenyl)-N-4-pyridinylacetamide. 
N-(3,4-Dichlorophenyl)-N-4-pyridinylbenz-amide. 
(3,4-Dichlorophenyl)-4-pyridinylcarbamic acid, methyl ester. 
(4-Methylphenyl)-4-pyridinylcarbamic acid, methyl ester. 
Compounds of the present invention are prepared by one of the following 
general synthetic methods, A or B. 
In Method A, N-(4-pyridyl)pyridinium chloride hydrochloride is heated to a 
temperature of about 150.degree. C. with the desired aniline. Pyridine is 
distilled from the reaction mixture, and the crude product is further 
purified, if needed, by recrystallization. This method is exemplified by 
the production of N-(4-methoxyphenyl)-4-pyridinamine, Example 1, below. 
In Method B, 4-chloropyridine hydrochloride is reacted in glacial acetic 
acid at about 100.degree. C. for a period of from about six to ten hours 
with an approximately equimolar amount of the desired aniline. The crude 
product is isolated as the hydrochloride salt which is purified by 
recrystallization or which can be converted to the free base and purified. 
This method is exemplified by Examples 2-5 below. 
The compounds of the present invention form pharmaceutically acceptable 
acid addition salts with organic and inorganic acids. Examples of suitable 
acids for the formation of pharmaceutically acceptable salts are 
hydrochloric, sulfuric, phosphoric, acetic, benzoic, citric, malonic, 
salicylic, malic, fumaric, oxalic, succinic, tartaric, lactic, gluconic, 
ascorbic, maleic, aspartic, benzenesulfonic, methane- and ethanesulfonic, 
hydroxymethane- and hydroxyethanesulfonic, and the like. (See for example, 
"Pharmaceutical Salts,"J. Pharm. Sci. 66(1): 1-19 (1977)). 
The salts are prepared by contacting the free base form of the compounds of 
this invention with a sufficient amount of the desired acid to produce the 
salt in the conventional manner. The free base forms may be regenerated, 
if desired, by treating the salt form with a base. For example, dilute 
aqueous solutions of such bases, as sodium hydroxide, potassium carbonate, 
ammonia, and sodium bicarbonate may be utilized for this purpose. 
The free base forms of the compounds of this invention differ somewhat from 
their respective salt forms in such physical properties as melting point 
and solubility in polar solvents, but the salts are othewise equivalent to 
their respective free acid or base forms for the purpose of the invention. 
The biological activity of compounds of the present invention was evaluated 
using the "scopolamine induced swimming test" (SIS). This screen evaluated 
the ability of the test compounds to reverse the hyperactive swimming 
behavior of laboratory rats given scopolamine. in this test, untreated 
rats will generally swim between 20 to 30 meters during a five-minute test 
period. Rats given scopolamine at doses of 0.1 mg/kg develop a 
stereotypical swimming hyperactivity with the swimming distances generally 
increasing by 75-125% above baseline values. This increase in swimming 
hyperactivity can be reversed by administration of the 
acetylcholinesterase inhibitor physostigmine of the cholinergic agonist, 
arecoline. The effect of scopolamine on swimming behavior was determined 
to be centrally mediated since (1) the quaternary amine of scopolamine, 
scopolamine methyl nitrate, does not produce any behavioral changes under 
the same conditions, and (2) neostigmine, a quaternary amine analog of 
physostigmine, does not reverse the effect of scopolamine. We have 
discovered unexpectedly that .alpha.2-adrenergic antagonists including the 
compounds in this application also reverse this swimming hyperactivity, 
perhaps through indirect stimulation of the cholinergic system. 
SIS values are reported as the percent reversal of scopolamine, and are 
determined as follows: 
##EQU1## 
where U, SDT, and ST represent, respectively, the mean activity level in 
meters swum of untreated, scopolamine-and-drug-treated, and 
scopolamine-treated mice. Representative results are presented in Table 1. 
TABLE 1 
__________________________________________________________________________ 
Reversal of Scopolamine-Induced 
Swimming Hyperactivity 
##STR2## 
Percent Reversal 
Swimming Hyperactivity 
Dose (mg/kg, SC) 
Compound 
R.sub.1 
R.sub.2 
R.sub.3 
0.32 3.2 32 
__________________________________________________________________________ 
1 H H H 27 22 57 
2 H H 3-CH.sub.3 
52 36 66 
3 H H 4-CH.sub.3 
10 25 100 
4 H H 3-Cl 0 27 75 
5 H H 3-CF.sub.3 
0 0 57 
6 H H 4-CF.sub.3 
0 16 55 
7 H H 3-OCH.sub.3 
23 62 31 
8 H H 3-NO.sub.2 
40 39 70 
9 H H 2-NH.sub.2 
15 18 72 
10 H H 3-NH.sub.2 
47 0 41 
11 H H 3-N(CH.sub.3).sub.2 
15 4 61 
12 H H 3-COOCH.sub.3 
15 0 8 
13 H 2-Cl 
4-Cl 0 24 0 
14 H 3-Cl 
4-Cl 31 37 64 
15 H 3-NO.sub.2 
4-Cl 26 0 0 
16 H 2-NO.sub.2 
4-CH.sub.3 
0 3 14 
17 Ac H 4-CH.sub.3 
35 56 21 
18 Ac 3-Cl 
4-Cl 33 34 30 
19 COOCH.sub.3 
H 4-CH.sub.3 
36 20 17 
20 COOCH.sub.3 
3-Cl 
4-Cl 6 0 9 
__________________________________________________________________________ 
The compounds of the present invention also demonstrate selective 
antagonism at the .alpha.2-adrenergic binding site in the brain. The 
.alpha.2 binding sites are presynaptic and are involved in the control of 
release of norepinephrine. A compound which acts selectively as an 
.alpha.2-adrenergic antagonist acts to increase noradrenergic activity. 
Such increases in noradrenergic activity are related to improved cognitive 
function in animals. 
The binding of representative compounds of this invention at the 
.alpha.1-adrenergic binding site was measured using the protocol described 
by Hornung, R., et al, Archiv. Pharm., 308:223 (1979). Similarly, the 
binding at the .alpha.2:adrenergic binding site was measured using the 
method of Rouot, B. R., et al, Life Sci., 25: 769 (1979). The data are 
presented in Table 2 and illustrate the .alpha.2 selectivity of the 
compounds. 
TABLE 2 
______________________________________ 
Selective Binding at the .alpha.l- and 
.alpha.2-Adrenergic Binding Sites 
##STR3## 
.alpha.1 
.alpha.2 
.alpha.1/.alpha.2 
Compound R.sub.1 
R.sub.2 
R.sub.3 
IC.sub.50 (Nanomolar) 
______________________________________ 
3 H H 4-CH.sub.3 
1600 37 43 
4 H H 3-Cl 7500 133 56 
14 H 3-Cl 4-Cl &gt;1000 118 &gt;8.5 
17 Ac H 4-CH.sub.3 
&gt;10000 5400 &gt;1.9 
______________________________________ 
As seen from the data in Table 2, Compound 4 demonstrates a high degree of 
selectivity for binding at the .alpha.2-adrenergic site. This compound was 
tested in the Mouse Water Maze (MWM) test which is a direct test of 
spatial cognitive skill in laboratory mice. This test, which is described 
in Morris, R., J. Neurosci. Meth., 11: 47-60 (1984), measures the effect 
of a test drug on spatial working memory in hippocamally-deficient mice. 
In this test, Compound 4 demonstrated a minimal effective dose (MED) of 
3.2 mg/kg. 
In therapeutic use as agents for treating cerebral insufficiency, the 
compounds utilized in the pharmaceutical method of this invention are 
administered to the patient at dosage levels of from 0.001 mg to 100 mg 
per day. The specific dosages employed, however, may be varied depending 
upon the requirement of the patient, the severity of the condition being 
treated, and the activity of the compound being employed. The 
determination of optimum dosages for a particular situation is within the 
skill of the art. 
For preparing pharmaceutical compositions from the compounds of this 
invention, inert, pharmaceutically acceptable carriers can be either solid 
or liquid. Solid form preparations include powders, tablets, dispersible 
granules, capsules, cachets, and suppositories. 
A solid carrier can be one or more substances which may also act as 
diluents, flavoring agents, solubilizers, lubricants, suspending agents, 
binders, or tablet disintegrating agents; it can also be an encapsulating 
material. 
In powders, the carrier is a finely divided solid which is in a mixture 
with the finely divided active component. In tablets, the active compound 
is mixed with the carrier having the necessary binding properties in 
suitable proportions and compacted in the shape and size desired. 
For preparing suppositories, a low-melting was such as a mixture of fatty 
acid glycerides and cocoa butter is first melted, and the active 
ingredient is dispersed therein by, for example, stirring. The molten 
homogeneous mixture is then poured into convenient sized molds and allowed 
to cool and solidify. 
Powders and tablets preferably contain between about 5 to about 70% by 
weight of the active ingredient. Suitable carriers are magnesium 
carbonate, magnesium stearate, talc, lactose, sugar, pectin, dextrin, 
starch, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a 
low-melting wax, cocoa butter, and the like. 
The term "preparation" is intended to include the formulation of the active 
compound with encapsulating material as a carrier providing a capsule in 
which the active component (with or without other carriers) is surrounded 
by a carrier, which is thus in association with it. In a similar manner, 
cachets are also included. 
Tablets, powders, cachets, and capsules can be used as solid dosage forms 
suitable for oral administration. 
Liquid form preparations include solutions suitable for oral or parenteral 
administration, or suspensions, and emulsions suitable for oral 
administration. Sterile water solutions of the active component or sterile 
solutions of the active component in solvents comprising water, ethanol, 
or propylene glycol may be mentioned as examples of liquid preparations 
suitable for parenteral administration. 
Sterile solutions may be prepared by dissolving the active component in the 
desired solvent system, and then passing the resulting solution through a 
membrane filter to sterilize it or, alternatively, by dissolving the 
sterile compound in a previously sterilized solvent under sterile 
conditions. 
Aqueous solutions for oral administration can be prepared by dissolving the 
active compound in water and adding suitable flavorable, coloring agents, 
stabilizers, and thickening agents as desired. Aqueous suspensions for 
oral use can be made by dispersing the finely divided active component in 
water together with a viscous material such as natural or synthetic gums, 
resins, methyl cellulose, sodium carboxymethyl cellulose, and other 
suspending agents known to the pharmaceutical formulation art. 
Preferably, the pharmaceutical preparation is in unit dosage form. In such 
form, the preparation is divided into unit doses containing appropriate 
quantities of the active component. The unit dosage form can be a packaged 
preparation, the package containing discrete quantities of the 
preparation, for example, packeted tablets, capsules, and powders in vials 
or ampoules. The unit dosage form can also be a capsule, cachet, or tablet 
itself, or it can be the appropriate number of any of these packaged 
forms.

The following preparative examples are provided to enable one skilled in 
the art to practice the invention. They are illustrative of the present 
invention and are not to be read as limiting the scope of the invention as 
it is defined by the appended claims. 
EXAMPLE 1 
Preparation of N-(4-methoxyphenyl)-4-pyridinamine 
A mixture of 1-(4-pyridinium chloride hydrochloride (10.0 g, 0.04 mol) and 
p-anisidine (4.9 g, 0.04 mol) is heated at 150.degree. C. until the 
pyridine stops distilling. The resulting black oil is allowed to cool to 
room temperature during which time it solidifies. The solid is broken into 
a powder and repeatedly washed with acetone until the color is light 
brown. Recrystallization from isopropanol gives the product as a yellow 
powder, mp 129.degree.-134.degree. C. 
EXAMPLE 2 
Preparation of N-(3,4-dichlorophenyl)-4-pyridinamine 
4-Chloropyridine hydrochloride (15.0 g, 0.10 mol) is dissolved in glacial 
acetic acid (150 ml) and 3,4-dichloroanailine (16.2 g, 0.10 mol) is added. 
The solution is heated to 100.degree. C. for a period of eight hours. 
After cooling the solution to room temperature, the acetic acid is remove 
under vacuum to give the crude product as an off-white solid. The solid is 
washed with acetone and collected by filtration. Recrystallization from 
isopropanol yields N-(3,4-dichlorophenyl)-4-pyridinamine as the 
hydrochloride salt, as an offwhite powder, mp 240.degree.-241.degree. C. 
EXAMPLE 3 
Preparation of N-(3-chlorophenyl)-4-pyridinamine 
3-Chloroaniline (12.8 g, 0.10 mol) is added to a solution of 
4-chloropyridine hydrochloride (15.0 g, 0110 mol) in 150 ml of glacial 
acetic acid. The resulting solution is heated at 100.degree. C. for eight 
hours. After cooling the mixture to room temperature, the acetic acid is 
removed under vacuum. The resulting solid is triturated with acetone, 
collected by filtration, and washed with diethyl ether. 
Water (100 ml) is added to the pale yellow solid, and the undissolved 
material is filtered off. The aqueous layer is made basic with 6M sodium 
hydroxide solution and the solid which forms is collected by filtration 
and washed with acetone and then with diethyl ether. 
The solid product is dried under vacuum at 100.degree. C. for eight hours 
to produce an off-white solid, mp 123.degree.-125.degree. C. 
EXAMPLE 4 
Preparation of 3-(4-pyridinylamino)benzoic acid, methyl ester 
3-Aminobenzoic acid, methyl ester (15.2 g, 0.10 mol) is added to a solution 
of 4-chloropyridine hydrochloride (15.0 g, 0.10 mol) in 150 ml of glacial 
acetic acid. The resulting mixture is heated to 100.degree. C. for six 
hours and then cooled to room temperature. 
The acetic acid is removed under vacuum to yield the crude product as an 
orange oil. The oil is taken up in 150 ml of water and the resulting 
solution is made basic with 6M sodium hydroxide solution. The aqueous 
solution is extracted three times with 100-ml portions of chloroform and 
the organic extracts are combined and dried over anhydrous magnesium 
sulfate. The chloroform is removed under vacuum to give the crude product, 
which is purified by recrystallization from ethyl acetate to yield a pale 
yellow powder, mp 139.degree.-142.degree. C. 
EXAMPLE 5 
Preparation of 3-(4-pyridinylamino)benzonitrile 
3-Aminobenzonitrile (11.8 g, 0.10 mol) is added to a solution of 
4-chloropyridine hydrochloride (15.0 g, 0.10 mol) in 100 ml of glacial 
acetic acid. The solution is heated at 100.degree. C. for nine hours, 
after which time the solution is cooled to room temperature and the acetic 
acid is removed under vacuum to yield the crude product as an orange oil. 
The oil is taken up in 100 ml of water and the resulting solution made 
basic with 6M sodium hydroxide solution. The resulting hygroscopic solid 
is collected by filtration and dissolved in 50 ml of acetone. Diethyl 
ether (50 ml) is added and gaseous hydrogen chloride is bubbled through 
the solution. The solid which forms is collected by filtration and 
recrystallized from isopropanol to yield 3-(4-pyridinylamino)benzonitrile 
as the hydrochloride salt, mp 228.degree.-291.degree. C. 
Employing the general synthetic methods described above, the following 
additional compounds were prepared as described in Table 3. 
TABLE 3 
______________________________________ 
##STR4## 
Ex- 
am- 
ple R.sub.1 R.sub.2 R.sub.3 MP(.degree.C.) 
______________________________________ 
6 H H H 215-218* 
7 H H 4-CH.sub.3 
233-235* 
8 H H 3-NO.sub.2 
193-14 197 
9 H H 3-(COOCH.sub.3) 
139-142 
10 H 3-CH.sub.3 H 164-168 
11 H 4-CH.sub.3 3-NO.sub.2 
&gt;250 
12 H 3-OCH.sub.3 H 203-205* 
13 H 2-Cl H 123-125 
14 H 3-Cl H 189-190 
15 H 3-Cl H 165-166* 
16 H 3-Cl H 204-207.sup.1 
17 H 3-Cl H 150-152.sup.2 
18 H 3-Cl H 147-149.sup.3 
19 H 3-Cl H 133-135.sup.4 
20 H 2-Cl 4-Cl 195-200 
21 H 4-Cl 3-NO.sub.2 
276-279* 
22 H 3-CF.sub.3 H 210-215* 
23 H 4-CF.sub.3 H 230-234* 
24 H 2-NO.sub.2 H 99-101 
25 H 2-NH.sub.2 H 195- 197 
26 H 3-NH.sub.2 H &gt;275* 
27 H 3-(N(CH.sub.3).sub.2) 
H 135-137 
28 H 3-(COOC.sub.2 H.sub.5) 
H 110-112 
29 H 4-SO.sub.3 H 
H &gt;275 
30 COOCH.sub.3 3-Cl 4-Cl 86-89 
31 COOCH.sub.3 H 4-CH.sub.3 
132-133 
32 COCH.sub.3 3-Cl 4-Cl 195-197* 
33 COCH.sub.3 H 4-CH.sub.3 
&gt;210* 
34 CO(Phenyl) 3-Cl 4-Cl 131-134 
______________________________________ 
*Monohydrochloride salt 
.sup.1 Sesquihydrochloride salt 
.sup.2 Mononitrate salt 
.sup.3 Nitrate salt 
.sup.4 Methanesulfonate salt