Novel 3-substituted salicylamides having increased analgesic activity and prolonged analgesic activity are disclosed.

DESCRIPTION OF THE PREFERRED EMBODIMENTS 
The following general example illustrates the production of a 3-substituted 
salicylamide by the procedure described in Method A. 
GENERAL EXAMPLE 
N-(2-diethylaminoethyl)-3-fluorosalicylamide hydrochloride 
A mixture of 20 g (0.179 mole) 2-fluorophenol and 75 g (0.543 mole) 
anhydrous potassium carbonate was placed in an autoclave having a total 
volume of 320 ml. The autoclave was filled to the top with dry ice, sealed 
and heated to a temperature of about 175.degree. for about 7 hours. The 
autoclave was then allowed to cool to room temperature and the solid 
substituted salicylic acid present in the autoclave removed by dissolving 
the acid in hot water. The substituted salicylic acid solution obtained 
was acidified with concentrated hydrochloric acid and the resulting 
suspension extracted with ether. The ether layer was dried over anhydrous 
magnesium sulfate and evaporated in vacuo to obtain 3-fluorosalicylic 
acid. The fluorosalicylic acid had a melting point of 133.degree. to 
135.degree. . 
A 15.6 g (0.10 mole) portion of 3-fluorosalicylic acid was dissolved in a 
100 ml portion of absolute methanol. A 22 ml portion of 
borontrifluoride-methanol reagent (2 equivalents, 51% BF.sub.3) was added 
and the reaction allowed to reflux for about six hours. The reaction 
mixture was cooled and added carefully to a saturated solution of sodium 
bicarbonate. The resulting mixture was then extracted with ether, the 
ether layer dried over magnesium sulfate and evaporated in vacuo. The oil 
obtained was crystallized from methanol. The methyl-3-fluorosalicylate 
obtained had a melting point of 94.degree.-5.degree. C. 
A 5.10 gram portion of methyl-3-fluorosalicylate (0.03 mole) was refluxed 
with a 3.49 g portion of N,N-diethylethylenediamine (0.03 mole) for about 
four hours and evaporated in vacuo. The brown oil obtained was 
chromatographed on silica gel with ether and the desired product isolated 
as the hydrochloride, m.p. 108.degree.-110.degree. C. 
Calcd. for C.sub.13 H.sub.20 FClN.sub.2 O.sub.2 : C, 53.69; H, 6.93; N, 
9.64 Found: C, 52.58; H, 6.71; N, 9.58. 
The following example illustrates production of one of the compounds of the 
present invention by the procedure described in Method B. 
EXAMPLE 1 
N-(2-diethylaminoethyl)-3-isopropylsalicylamide hydrochloride 
A 13.7 gram portion (0.1 mole) of 2-isopropylphenol was added dropwise to a 
stirred refluxing mixture containing 4.6 grams granular sodium (0.2 mole) 
in 150 ml dry xylene to which a continuous stream of carbon dioxide was 
bubbled. For convenience, the reaction was allowed to continue overnight. 
After cooling the reaction mixture slightly, sufficient water was 
carefully added to the reaction mixuture to destroy the excess sodium and 
to dissolve the solids present in the reaction mixture. Acidification of 
the water layer with concentrated hydrochloric acid yielded a solution 
containing 3-isopropylsalicylic acid which was extracted with ether, dried 
over magnesium sulfate and evaporated in vacuo. 
A 14.4 g portion of the 3-isopropylsalicylic acid (0.08 mole) and 20 ml 
boron trifluoride-methanol complex was dissolved in 100 ml of absolute 
methanol and refluxed for six hours. The ester solution obtained was 
poured into a saturated solution of sodium bicarbonate and the ester 
extracted with ether. The ether layer was dried over anhydrous magnesium 
sulfate and evaporated in vacuo, producing a green-colored oil. 
A 13.5 gram portion of the ester was refluxed with a 8.1 gram portion of 
N,N-diethylethylenediamine (0.07 mole) for about four hours. The methanol 
formed was removed in vacuo. The light brown oil obtained was 
chromatographed on a silica gel column with ether. Addition of a solution 
of hydrochloric acid in methanol produced a white precipitate. The 
precipitate was recovered by filtration, dried, stirred with ethyl 
acetate, filtered and again dried. The product was isolated as the 
hydrochloride, m.p. 141.degree.-142.degree.. 
Calcd. for C.sub.16 H.sub.27 ClN.sub.2 O.sub.2 : C, 61.00; H, 8.64; N, 8.89 
Found: C, 61.13; H, 8.67; N, 8.99. 
EXAMPLE 2 
N-(2-diethylaminoethyl)-3-methylsalicylamide hydrochloride 
Commercially available 3-methylsalicylic acid was esterified and amidated 
by the procedure described in the General Example and Example 1. 
Alternately, the method described in Example 1 can be used, utilizing 
2-methylphenol as the starting material. After esterification and 
amidation, the desired product was isolated as the hydrochloride, m.p. 
134.degree.-135.degree. C. 
Calcd. for C.sub.14 H.sub.23 ClN.sub.2 O.sub.2 : C, 58.63; H, 8.09 N, 9.77 
Found: C, 58.66; H, 8.33; N, 9.87. 
EXAMPLE 3 
N-(2-diethylaminoethyl)-3-n-octylsalicylamide hydrochloride 
The method described in Example 1 was used to prepare the desired 
n-octyl-substituted salicylamide by adding a 71 g portion (0.345 mole) of 
2-n-octylphenol to a stirred refluxing mixture containing 16.3 g granular 
sodium (0.71 mole). After esterification and amidation, the desired 
product was isolated as the hydrochloride, m.p. 89.degree.-91.degree. C. 
Calcd. for C.sub.21 H.sub.37 ClN.sub.2 O.sub.2 : C, 65.49; H, 9.69; N, 7.28 
Found: C, 66.00; H, 10.11; N, 7.26. 
EXAMPLE 4 
N-(2-diethylaminoethyl)-3-n-butylsalicylamide oxalate 
The method described in the General Example was used to prepare the desired 
n-butyl-substituted salicylamide by mixing together a 15 g portion (0.10 
mole) of 2-n-butylphenol and 45 g (0.325 mole) anhydrous potassium 
carbonate and heating in an autoclave to a temperature of about 
175.degree. for about 7 hours. After esterification and amidation, the 
desired product was isolated as the oxalate, m.p. 104.degree.-106.degree. 
C. 
Calcd. for C.sub.19 H.sub.30 N.sub.2 O.sub.6 : C, 59.68; H, 7.71; N, 7.32 
Found: C, 58.49; H, 7.76; N, 7.47 
EXAMPLE 5 
N-(2-diethylaminoethyl)-3-isobutylsalicylamide hydrochloride 
The method described in the General Example was used to prepare the desired 
isobutyl-substituted salicylamide by mixing together a 14.0 g portion 
(0.093 mole) of 2-isobutylphenol and 45 g (0.325 mole) anhydrous potassium 
carbonate in an autoclave and heating to a temperature of about 
175.degree. for about 7 hours. After esterification and amidation, the 
desired product was isolated as the hydrochloride, m.p. 
111.degree.-113.degree. C. 
Calcd. for C.sub.17 H.sub.29 ClN.sub.2 O.sub.2 : C, 62.08; H, 8.89; N, 8.52 
Found: C, 61.42; H, 9.07; N, 8.46. 
EXAMPLE 6 
N-(2-diethylaminoethyl)-3-t-butylsalicylamide hydrochloride 
The method described in Example 1 was used to prepare the desired 
t-butyl-substituted salicylamide by adding a 90.0 g portion (0.60 mole) of 
2-t-butylphenol to a stirred refluxing mixture containing 27.6 g granular 
sodium (1.20 moles). After esterification and amidation, the desired 
product was isolated as the hydrochloride, m.p. 
139.5.degree.-140.5.degree. C. 
Calcd. for C.sub.17 H.sub.29 ClN.sub.2 O.sub.2 : C, 62.08; H, 8.89; N, 
8.52. Found: C, 61.06; H, 9.01; H, 8.66. 
EXAMPLE 7 
N-(2-diethylaminoethyl)-3-t-amylsalicylamide hydrochloride 
The method described in Example 1 was used to prepare the desired 
t-amyl-substituted salicylamide by adding a 98.0 g portion (0.60 mole) of 
2-t-amylphenol to a stirred refluxing mixture containing 27.6 g granular 
sodium (1.20 moles). After esterification and amidation, the desired 
product was isolated as the hydrochloride, m.p. 141.degree.-143.degree. C. 
Calcd. for C.sub.18 H.sub.31 ClN.sub.2 O.sub.2 : C, 63.05; H, 9.16; N, 8.22 
Found: C, 61.78; H, 9.07; N, 8.42. 
EXAMPLE 8 
N-(2-diethylaminoethyl)-3-allylsalicylamide oxalate 
The method described in the General Example was used to prepare the desired 
allyl-substituted salcylamide by mixing together a 13.4 g portion (0.10 
mole) of 2-allylphenol and 45 g (0.325 mole) anhydrous potassium carbonate 
in an autoclave and heating to a temperature of about 175.degree. for 
about 7 hours. After esterification and amidation, the desired product was 
isolated as the oxalate, m.p. 152.degree.153.degree. C. 
Calcd. for C.sub.18 H.sub.26 N.sub.2 O.sub.6 : C, 59.00; H, 6.60; N, 7.64 
Found: C, 58.07; H, 7.03; N, 7.87. 
EXAMPLE 9 
N-(2-diethylaminoethyl)-3-methallylsalicylamide oxalate 
The method described in the General Example was used to prepare the desired 
methallyl-substituted salicylamide by mixing together a 12.0 g portion 
(0.081 mole) of 2-methallylphenol and 45 g (0.325 mole) anhydrous 
potassium carbonate in an autoclave and heating to a temperature of about 
175.degree. for about 7 hours. After esterification and amidation, the 
desired product was isolated as the oxalate, m.p. 105.degree.-108.degree. 
C. 
Calcd. for C.sub.19 H.sub.28 N.sub.2 O.sub.6 : C, 59.99; H, 7.42; N, 7.36 
Found: C, 59.14; H, 7.34; N, 7.09. 
EXAMPLE 10 
N-(2-diethylaminoethyl)-3-chlorosalicylamide hydrochloride 
The method described in Example 1 was used to prepare the desired 
chloro-substituted salicylamide by mixing together a 12.9 g portion (0.10 
mole) of 2-chlorophenol and 45 g (0.325 mole) anhydrous potassium 
carbonate in an autoclave and heating to a temperature of about 
175.degree. for about 7 hours. After esterification and amidation, the 
desired product was isolated as the hydrochloride, m.p. 
143.5.degree.-145.degree. C. 
Calcd. for C.sub.13 H.sub.20 Cl.sub.2 N.sub.2 O.sub.2 : C, 50.83; H, 6.56; 
N, 9.13. Found: C, 51.64; H, 6.57; N, 9.35. 
The starting materials used are available commercially from chemical supply 
houses, for example, Aldrich Chemical Co., Inc., 940 W. Saint Paul Avenue, 
Milwaukee, Wisconsin, 53233, or can be manufactured according to 
procedures described in the literature. Table I indicates whether the 
starting materials are commercially available, or in the alternative, 
lists the literature reference to the method of synthesis. 
TABLE I 
______________________________________ 
Source of Starting Phenols 
Example Commercial Literature Reference 
______________________________________ 
General 
Example Yes 
1 Yes 
2 Yes 
3 Chem. Ab. 25, 1228 
4 Chem. Ab. 25, 1228 
5 By reduction of starting 
material of Example 10 
6 Yes 
7 Yes 
8 J.Am.Chem.Soc. 64, 607-612 
(1942) 
9 J.Am.Chem.Soc. 57, 371-376 
(1935) 
10 Yes 
______________________________________ 
In order for a drug to act, it must be absorbed, transported to the 
appropriate tissue or organ, penetrate to the responding subcellular 
structure and elicit a response for a desired period of time. The 
pharmaceutic and therapeutic implication of these enumerated factors is 
that the usefulness of a drug does not depend on a single effect of the 
drug in question. Thus standard pharmaceutical science texts usually point 
out that the potency of a drug has little utility other than to provide a 
means of comparing the relative activities of drugs in a series to 
determine relative potencies. As pointed out in Remington's Pharmaceutical 
Sciences, Fourteenth Edition (p. 729), the potency of a drug has little 
bearing on its clinical usefulness provided that the potency is not so low 
as to cause the dosage amount to be unmanageable or to increase the 
treatment cost over equivalent drugs. The main consideration in governing 
drug choices is the selectivity of the action of the drug. 
For example, assessment of an analgesic compound should include assessment 
of potency and relative potency, toxicity, and duration of activity. 
The compounds of the present invention were investigated not only to 
determine their relative analgesic potency in comparison with a control 
salicylamide unsubstituted at the 3-position and one that was chloro, 
methyl, amyl or n-octyl substituted at the 3-position but also to 
determine the duration of analgesic activity. 
The analgesic activity of the compounds of the present invention was tested 
in mice by means of the "abdominal constriction" response. The test is 
based on the observation that following interperitoneal injection of a 
noxious agent, such as acetylcholine chloride, mice show a response which 
consists of a wave of constriction and elongation passing caudally along 
the abdominal wall, sometimes accompanied by twisting of the trunk and 
followed by extension of the hind limbs. Compounds are then tested for 
analgesic activity by determining whether they are effective in 
suppressing this abdominal constriction response [See Collier et al., Br. 
J. Pharmac. Chemother., 32, 295-310 (1968)]. 
Non-fasted female mice, weighing between 20 and 25 g, were used in the 
studies. Compounds to be tested were administered subcutaneously at a dose 
of 20 mg/kg to groups of ten mice, ten minutes before the interperitoneal 
injection of acetylcholine chloride (3.2 mg/kg). The animals were then 
placed in a circular glass enclosure and the number of responses counted 
during a given time period. 
Compounds completely inhibiting the response to acetycholine in at least 
five out of ten animals were subsequently tested at reduced dosage levels, 
using groups of ten animals per dose. The dose required to produce a 
specified response, that is, analgesic effect, is termed the individual 
effective dose; the response is a quantal rather than a graded response, 
since it is either present or absent. The cumulative frequency 
distribution of individual effective doses obtained, plotted as a function 
of logarithm of dose, is known as a dose-percent or dose-response curve. 
The ED.sub.50 and ED.sub.90 is then calculated from the dose-response 
curve obtained in the above experiments. The expression ED.sub.50 
indicates the amount of compound required to produce analgesic effect in 
50 percent of animals tested and is known as the "median effective dose". 
The expression ED.sub.90 indicates the amount of compound required to 
produce an analgesic effect in 90 percent of animals tested. 
The duration of analgestic activity of the active salicylamides of the 
present invention was measured by determining the time necessary for 50 
percent decay of the analgesic effect of the ED.sub.90 dosage level to 
occur. 
Experimental results obtained are shown in Table II below. 
TABLE II 
______________________________________ 
Abdominal Constriction Response 
Duration of 
Activity 
1/2 T 
Example R ED.sub.50 (mg/kg) 
(Minutes)** 
______________________________________ 
Control* hydrogen 16.6 30 
2 methyl 14.2 &lt;40**** 
9 methallyl 23.8 60 
1 isopropyl 12.7 80 
8 allyl 17.2 80 
6 t-butyl 14.3 120 
4 n-butyl 31.0 125 
5 isobutyl 44.5 205 
3*** n-octyl no activity -- 
7*** amyl no activity -- 
10*** chloro no activity -- 
______________________________________ 
*N-(2-diethylaminoethyl)salicylamide hydrochloride 
**Pharmacologically equipotent doses administered to animals - Duration o 
activity based on ED.sub.90 dosages. 
***These compounds showed no analgesic activity at (20 mg/kg). 
****The analgesic effects of this compounds ED.sub.90 are practically gon 
40 minutes after injection. 
The experimental tests results summarized above provide the basis for the 
following conclusions. 
All of the compounds listed above with the exception of the chloro, amyl 
and n-octyl derivatives, exhibited analgesic activity, including the 
control compound, the 3-unsubstituted salicylamide, 
N-(2-diethylaminoethyl)salicylamide hydrochloride. The determination of 
ED.sub.50 dosage for Examples 1, 5, 6 and 9 are, within experimental 
accuracy, substantially at the same potency as that of the control 
compound. However, the duration of activity of these representative 
compounds increased dramatically by a factor of up to 4-fold with 
substitution at the 3-position of the ring. The data indicates that the 
compounds of Example 4 and 5 are both less active analgesics than the 
other examples and the control sample, but both compounds exhibit greatly 
increased duration of analgesic activity in comparison to the 
unsubstituted control compound, by a factor of greater than 5-fold. It is 
further noted that the 3-chloro, amyl and n-octyl compounds showed no 
analgesic activity at dosages of 20 mg/kg. The methyl compound of Example 
2 exhibited analgesic activity and a fairly low ED.sub.50 but no 
meaningful increase in the duration of analgesic activity.