Compounds and compositions useful for producing analgesia

Alkynamide compounds, and pharmaceutically-acceptable salts thereof, of the formula: ##STR1## wherein X is O or S; R is straight or branched alkyne having from 11 to 23 carbon atoms; R.sub.1 is H, OH, or OCH.sub.3 ; R.sub.2 is OH or a short-chain ester; and wherein at least one of R.sub.1 and R.sub.2 is OH or OCH.sub.3. Compositions, useful for producing analgesia in humans or lower animals, comprise a safe and effective amount of: an alkynamide, pharmaceutically-acceptable salts thereof, or mixtures thereof; and a pharmaceutically-acceptable carrier. Preferably, these alkynamides are N-vanillyl-alkynamides. Methods of treatment, comprising administering a safe and effective amount of these alkynamides, pharmaceutically-acceptable salts thereof, or mixtures thereof, include methods of parenteral, oral, and topical administration.

BACKGROUND OF THE INVENTION 
This invention relates to compositions, containing certain 
N-phenylmethylalkynamides, having analgesic activity. 
While "pain" is incapable of precise definition due to its basically 
subjective nature, it can generally be said that the term refers to 
feelings of distress or suffering caused by stimulation of specialized 
nerve endings. A great variety of drugs have been developed to reduce pain 
in man and other animals; some directed to eliminating pain at its source, 
and others directed to blocking the assimilation of pain by the brain. 
Among the latter group of drugs that are designed to block the sensation 
of pain, are the analgesics, which generally relieve pain without causing 
unconsciousness. Analgesics can be further classified in two main 
categories: opioid analgesics, including morphine, codeine, levorphanol, 
and the morphine-like analgesics meperidine, and methadone; and 
antipyretic analgesics, such as aspirin, phenacetin, acetaminophen, 
phenylbutazone, and indomethacin. 
Although the precise pharmacological action of these analgesics is 
uncertain, there are certain effects which readily distinguish the opoid 
analgesics from the antipyretics. In particular, the antipyretics are weak 
analgesics, which much of their effect in the peripheral nervous system, 
so that behavioral changes do not usually occur. Generally, these 
analgesics relieve only somatic pain originating from muscles, joints, 
tendons and fasciae, and are ineffective against deep visceral pain. 
However, the opioid analgesics are quite effective against all types of 
pain, with broad based action in the central nervous system. Aside from 
potent analgesia, the opioids, also known as narcotics, often produce 
effects on mood and other behavioral changes. Perhaps the most notable 
side effect of the opioid analgesics is the fact that their repeated use 
is associated with tolerance as well as psychic and physical dependence. 
It has been recently discovered that capsaicin, a natural product of 
certain species of the genus Capsicum, induces analgesia in animals. 
Capsaicin (8-methyl-N-vanillyl-6E-nonenamide) and "synthetic" capsaicin 
(N-vanillylnonanamide) are disclosed as analgesics in U.S. Pat. No. 
4,313,958, LaHann, issued Feb. 2, 1982. Analgesic activity of capsaicin 
has also been discussed in the chemical and medical literature, including 
Yaksh, et al., Science, 206, 481-483 (1979). The use of capsaicin to 
prevent dipilatory irritation is also disclosed in U.S. patent application 
Ser. No. 330,731, LaHann, et al., filed Dec. 14, 1981. 
Specifically, capsaicin prevents the development of cutaneous hyperalgesia 
and also provides relief of deep visceral pain and severe pain. In certain 
tests, capsaicin produces a level of analgesia comparable to morphine, yet 
it is not antagonized by such narcotic antagonists as nalorphine and 
naloxone. Thus, capsaicin does not appear to belong to either of the major 
categories of analgesics, described above. 
Compounds structurally similar to capsaicin have been described in the 
chemical literature. These references, though, do not suggest analgesic 
activity for these compounds. For example, Newman, "Natural and Synthetic 
Pepper-Flavored Substances (6)," Chemical Products, 102-106 (1954) lists 
the relative pungency of approximately 164 compounds, including 
N-vanillyloleamide and other alkenamide derivatives of capsaicin. Ott and 
Zimmermann, Liebigs Ann., 425, 314-337 (1921) discloses a synthesis for 
N-vanillyloleamide. A synthesis for N-vanillyllinoleamide is disclosed in 
Ferris, Australian Commonwealth, Dep. Supply, Def. Stand. Lab., No. 89 
(1966) (Chem. Abs. 67:22919). 
U.S. Pat. No. 4,238,505, Nelson, issued Dec. 9, 1980, discloses 
3-hydroxyacetanilide for use in producing analgesia in animals. U.S. 
patent application Ser. No. 359,464, LaHann, et al., filed Mar. 18, 1982, 
describes hydroxyphenylacetamides with analgesic and anti-irritant 
activity. Similarly, analgesic and anti-irritant activity is disclosed for 
N-vanillylsulfonamides in U.S. patent application Ser. No. 360,953, 
Buckwalter, et al., filed Mar. 23, 1982, now U.S. Pat. No. 4,401,663; 
N-vanillylureas in U.S. patent application Ser. No. 381,672, Buckwalter, 
et al., filed May 25, 1982, now U.S. Pat. No. 4,460,602; and 
N-vanillylcarbamates in U.S. patent application Ser. No. 384,685, 
Buckwalter, et al., filed June 3, 1982, now U.S. Pat. No. 4,434,473. 
It has now been discovered that certain N-phenylmethyl alkynamides have 
analgesic activity in humans and lower animals. In particular, these 
alkynamides have potent analgesic activity similar to that of capsaicin, 
but are substantially less toxic. 
SUMMARY OF THE INVENTION 
The present invention provides compounds useful for producing analgesia in 
humans and lower animals, of the formula: 
##STR2## 
wherein X is O or S, R is straight or branched alkyne having from 11 to 23 
carbon atoms, R.sub.1 is H, OH, or OCH.sub.3, R.sub.2 is OH or a 
short-chain ester, and wherein at least one of R.sub.1 and R.sub.2 is OH 
or OCH.sub.3 ; and pharmaceutically-acceptable salts thereof. 
This invention also provides compositions comprising a safe and effective 
amount of these compounds, or mixtures thereof, and a 
pharmaceutically-acceptable carrier. Also provided are methods for 
producing analgesia by administering the compounds and compositions of 
this invention. 
DESCRIPTION OF THE INVENTION 
The compositions and methods of this invention incorporate certain 
N-[(substituted phenyl)methyl]alkynylamides (e.g., 
N-vanillyl-alkynylamides), or pharmaceutically-acceptable salts thereof, 
(herein "alkynamides") of the formula: 
##STR3## 
wherein X is O or S; R is straight or branched alkyne having from 11 to 23 
carbon atoms; R.sub.1 is H, OH or OCH.sub.3 ; R.sub.2 is OH or a 
short-chain ester; and wherein at least one of R.sub.1 and R.sub.2 is OH 
or OCH.sub.3. R preferably contains from 16 to 21 carbon atoms and, 
preferably, the unsaturated bonds are at position six or greater, i.e., 
wherein R is a (n-alkyne), n is at least six. Also preferred are 
alkynamides wherein X is O, alkylnamides wherein R.sub.1 is OCH.sub.3 and 
R.sub.2 is OH, and alkylnamides wherein R.sub.2 is a short-chain (i.e., 
C.sub.1 -C.sub.6) ester, e.g., acetoxy. 
A preferred alkynamide is N-vanillyl-9-octadecynamide. Preferred 
pharmaceutically-acceptable alkylnamide salts include the sodium, 
potassium, calcium, magnesium, and ammonium salts. 
The alkynamides described herein can be readily prepared by the following 
general synthetic scheme: 
##STR4## 
COMPOSITIONS 
The compositions of the present invention comprise: 
(a) a safe and effective amount of an alkynamide; and 
(b) a pharmaceutically-acceptable carrier. 
A safe and effective amount of alkynamide is that amount which provides 
analgesia, thereby alleviating or preventing the pain being treated at a 
reasonable benefit/risk ratio, as is intended with any medical treatment. 
Obviously, the amount of alkynamide will vary with such factors as the 
particular condition that is being treated, the severity of the condition, 
the duration of the treatment, the physical condition of the patient, the 
nature of concurrent therapy (if any), the specific formulation and 
carrier employed, and the solublity and concentration of alkylnamide 
therein. 
Depending upon the particular route of administration, a variety of 
pharmaceutically-acceptable carriers, well known in the art, may be used. 
These include solid or liquid fillers, diluents, hydrotropes, 
surface-active agents, and encapsulating substances. The amount of the 
carrier employed in conjunction with the alkynamide is sufficient to 
provide a practical quantity of material per unit dose of analgesic. 
Pharmaceutically-acceptable carriers for systemic administration, that may 
be incorporated into the compositions of this invention, include sugars, 
starches, cellulose and its derivatives, malt, gelatin, talc, calcium 
sulfate, vegetable oils, synthetic oils, polyols, alginic acid, phosphate 
buffer solutions, emulsifiers, isotonic saline, and pyrogen-free water. 
Specific pharmaceutically-acceptable carriers are described in the 
following U.S. patent applications, all incorporated by reference herein: 
Ser. No. 359,464, LaHann, et al., filed Mar. 18, 1982; Ser. No. 360,953, 
Buckwalter, et al., filed Mar. 23, 1982; Ser. No. 381,672, Buckwalter, et 
al., filed May 25, 1982; and Ser. No. 384,685, Buckwalter, et al., filed 
June 3, 1982. Preferred carriers for parenteral administration include 
propylene glycol, ethyl oleate, pyrrolidone, ethanol, and sesame oil. 
Preferably, the pharmaceutically-acceptable carrier, in compositions for 
parenteral administration, comprises at least about 90% by weight of the 
total composition. 
Various oral dosage forms can be used, including such solid forms as 
tablets, capsules, granules and bulk powders. These oral forms comprise a 
safe and effective amount, usually at least about 5%, and preferably from 
about 25% to about 50% of the alkynamide. Tablets can be compressed, 
tablet triturates, enteric-coated, sugar-coated, film-coated or multiple 
compressed, containing suitable binders, lubricants, diluents, 
disintegrating agents, coloring agents, flavoring agents, flow-inducing 
agents, and melting agents. Liquid oral dosage forms include aqueous 
solutions, emulsions, suspensions, solutions and/or suspensions 
reconstituted from non-effervescent granules and effervescent preparations 
reconstituted from effervescent granules, containing suitable solvents, 
preservatives, emulsifying agents, suspending agents, diluents, 
sweeteners, melting agents, coloring, and flavoring agents. Preferred 
carriers for oral adminstration include gelatin, propylene glycol, 
cottonseed oil and sesame oil. Specific examples of 
pharmaceutically-acceptable carriers and excipients that may be used to 
formulate oral dosage forms, which may be used in formulating oral dosage 
forms containing alkynamides, are described in U.S. Pat. No. 3,903,297, 
Robert, issued Sept. 2, 1975, incorporated by reference herein. Techniques 
and compositions for making solid oral dosage forms are described in 
Marshall, "Solid Oral Dosage Forms," Modern Pharmaceutics , Vol. 7, 
(Banker and Rhodes, editors), 359-427 (1979), incorporated by reference 
herein. 
The compositions of the present invention can also be administered 
topically to a biologic subject, i.e., by the direct laying on or 
spreading of the composition on epidermal or epithelial tissue. Such 
compositions include lotions, creams, solutions, gels and solids. These 
topical compositions comprise a safe and effective amount, usually at 
least about 0.5%, and preferably from about 1% to about 2%, of the 
alkynamide. Suitable carriers for topical administration of the alkynamide 
preferably remain in place on the skin as a continuous film and resist 
being washed off easily by perspiration or by immersion in water. 
Generally, the carrier is organic in nature and capable of having 
dispersed or dissolved therein the alkynamide. The carrier may include 
pharmaceutically-acceptable emollients, emulsifiers, thickening agents, 
and solvents. 
Specific systemic and topical formulations useful in this invention are 
described in the following U.S. patent applications, all incorporated by 
reference herein: Ser. No. 359,464, LaHann, et al., filed Mar. 18, 1982; 
Ser. No. 360,953, Buckwalter, et al., filed Mar. 23, 1982; Ser. No. 
381,672, Buckwalter, et al., filed May 25, 1982; and Ser. No. 384,685, 
Buckwalter, et al., filed June 3, 1982. Topical vehicles, useful herein, 
are disclosed in the following U.S. patent applications, incorporated by 
reference herein: "Improved Penetrating Topical Pharmaceutical 
Compositions Containing 1-dodecylazacycloheptan-2-one", Ser. No. 506,275, 
Cooper, filed June 21, 1983; and "Penetrating Topical Pharmaceutical 
Compositions Containing N-(2-hydroxyethyl)-pyrrolidone", Ser. No. 506,273, 
Cooper, filed June 21, 1983. Additional formulations, useful for 
parenteral, oral, and topical administration of alkynamides, are disclosed 
in the following U.S. patent applications concurrently filed herewith, all 
incorporated by reference herein: "Compositions Useful for Producing 
Analgesia", Ser. No. 514,206, LaHann and Buckwalter; "Novel Compounds and 
Compositions Useful for Producing Analgesia", Ser. No. 514,207, LaHann, 
Janusz and Buckwalter; and Novel Compounds and Compositions Useful for 
Producing Analgesia", Ser. No. 514,208, Janusz, Buckwalter and LaHann. 
METHODS FOR PRODUCING ANALGESIA 
The present invention also encompasses methods of producing analgesia in 
humans or lower animals through administering, to the human or lower 
animal, a safe and effective amount, usually from about 1 mg to about 3600 
mg per day, preferably from about 200 mg to about 2000 mg per day, of an 
alkynamide. While dosages higher than the foregoing are effective to 
produce analgesia, care must be taken in some individuals to prevent 
adverse side effects. The alkynamides and compositions of this invention 
can be used to treat and prevent pain, and to provide analgesia in various 
disorders at the deeper structures, muscles, tendons, bursa and joints 
associated with disease and trauma, and in various other conditions in 
which compounds such as aspirin, codeine, and morphine have heretofore 
been used to alleviate pain and discomfort. 
The alkynamides and compositions of the instant invention can be 
administered topically or systemically. Systemic application includes any 
method of introducing the alkynamides into the tissues of the body, e.g., 
intrathecal, epidural, intramuscular, transdermal, intravenous, 
intraperitoneal, subcutaneous, sublingual, and oral administration. 
A preferred method of parenteral administration is through intramuscular 
injection. As is known and practiced in the art, all formulations for 
parenteral administration must be sterile. For mammals, especially humans, 
(assuming an approximate body weight of 70 kg) individual doses of from 
about 2 mg to about 400 mg of alkynamide are acceptable. Individual doses 
of from about 50 mg to about 200 mg are preferred. 
A preferred method of systemic application of the alkynamides is through 
oral administration. For mammals, especially humans, (assuming an 
approximate body weight of 70 kg) individual doses of from about 1 mg to 
about 900 mg of alkynamide are acceptable. Individual doses of from about 
50 mg to about 600 mg are especially preferred. 
Topical administration can be used to produce local or systemic analgesia, 
through directly laying on or spreading a safe and effective amount of the 
alkynamide, or composition containing an alkynamide, on epidermal or 
epithelial tissue, including outer skin and oral, gingival, and nasal 
tissue. The amount of alkynamide to be topically administered depends upon 
such factors as the sensitivity, type and location of tissue to be 
treated, the composition and carrier (if any) to be administered, and the 
particular alkynamide to be administered as well as the particular 
disorder to be treated and the extent to which systemic (as distinguished 
from local) analgesic effects are desired. The extent of systemic 
analgesia also depends upon such factors as the amount of alkynamide, the 
area of tissue to be covered, and the ability of the alkynamide 
composition to penetrate the skin tissues.

The following non-limiting Examples illustrate the compositions, processes, 
and uses of the present invention. 
EXAMPLE I 
N-vanillyl-9-octadecynamide was synthesized by the following method: 
##STR5## 
Specifically, 9-octadecenoic acid (oleic acid) (5 g) was dissolved in 
ether and chilled in a water bath, while stirring. Bromine was added, 
dropwise, allowing color to disappear after every four to five drops. When 
there was an excess of bromine (color remaining) the solvent and excess 
bromine were evaporated, yielding 8 g of 9,10-dibromooctadecanoic acid. A 
30% solution of potassium hydroxide in ethylene glycol (13 ml) was added 
to this dibrominated oleic acid product, and refluxed at 
185.degree.-190.degree. C. for six hours. The mixture was stirred 
overnight, then acidified with 10% HCl. The 9-octadecynoic acid (stearolic 
acid) was extracted into 100 ml petroleum ether, chilled, and the 4 g of 
resulting product crystals were filtered and dried. 15 ml of oxalyl 
chloride were added to 3.5 g of the stearolic acid product and the mixture 
refluxed for one hour. The excess oxalyl chloride was evaporated, yielding 
9-octadecynyl chloride (stearoyl chloride) 
2.4 g of 4-hydroxy-3-methoxybenzylamine-HCl was suspended in 35 ml of 
N,N-dimethylformamide (DMF), and stirred. Added were 5 ml of a 5N solution 
of NaOH, and the mixture was stirred for an additional 10 to 15 minutes. 
The DMF mixture was chilled in an ice bath, and the stearoyl chloride, 
prepared above and dissolved in ether, was added dropwise. The mixture was 
then stirred for 3 hours, allowing it to come to room temperature. The 
mixture was then poured into 300 ml water, layers separated, and the 
aqueous layer extracted with ethyl ether. The extracts were washed with 
HCl, sodium bicarbonate, water, and brine, and then dried and filtered. 
5.3 g of crude N-vanillyl-9-octadecynamide was obtained. Purification by 
recrystallization from toluene and hexane, and then benzene and hexane, 
gave 2.8 g of analytically pure product. Its structure was confirmed via 
nuclear magnetic resonance and infrared spectroscopy. 
In the above example, N-vanillyl-9-tetradecynamide, 
N-vanillyl-9-hexadecynamide, N-vanillyl-6-octadecynamide, 
N-vanillyl-11-octadecynamide, N-vanillyl-10-nonadecynamide, and 
N-vanillyl-13-docosynamide are each made by substituting the respective 
n-alkynoic acid for 9-octadecynoic acid in the above synthesis. 
EXAMPLE II 
An analgesic composition, according to the present invention, was made 
comprising: 
______________________________________ 
N--vanillyl-9-octadecynamide 
127.2 mg 
ethanol 0.3 ml 
Tween 80 (polyoxyethylene 20 
0.3 ml 
sorbitan mono-eleate) 
Saline 2.4 ml 
______________________________________ 
The composition was made by simple dissolution of the alkynamide in the 
liquid solvents. A mouse weighing 30 g, was injected subcutaneously with 
0.2 ml of the composition, producing analgesia. 
EXAMPLE III 
A composition, according to the instant invention, for parenteral 
administration, is made with the following ingredients: 
______________________________________ 
N--vanillyl-10-nonadecynamide 
100 mg/ml of carrier 
carrier (percent-by-weight): 
propylene glycol 72% 
polyethylene glycol 17% 
water 10% 
benzyl alcohol 1% 
______________________________________ 
The alkynamide is dissolved in the carrier and a human subject, weighing 70 
kg, is injected subcutaneously with 1.0 ml of the composition thereby 
prepared, producing analgesia. At eight-hour intervals, two more 
subcutaneous injections are made, of 1.0 ml of the composition per 
administration, for a total of 300 mg N-vanillyl-10-nonadecynamide 
administered over a twenty-four hour period. 
In the above example, N-vanillyl-9-tetradecynamide, 
N-vanillyl-6-octadecynamide, N-vanillyl-11-octadecynamide, 
12-methyl-N-vanillyl-9-octadecynamide, and 
12-ethyl-N-vanillyl-9-octadecynamide are substituted, respectively, for 
N-vanillyl-10-nonadecynamide, with substantially similar results. 
EXAMPLE IV 
A composition, according to the instant invention, for parenteral 
administration, is made with the following components: 
______________________________________ 
N--vanillyl-9-octadecynamide 
100 mg/ml of carrier 
carrier (percent-by-weight): 
sesame oil 98% 
benzyl alcohol 2% 
______________________________________ 
A human subject, weighing 70 kg, is injected via deep-intramuscular 
injection, with 1.0 ml of the composition prepared above, producing 
analgesia. 
In the above example, N-vanillyl-10-nonadecynamide, 
N-vanillyl-9-dodecynamide, N-vanillyl-13-dodosynamide, 
12-hydroxy-N-vanillyl-9-octadecynamide, N-vanillyl-9-octadecynethioamide, 
N-[(3,4-dihydroxyphenyl)methyl]-9-octadecynamide, 
N-[(3-methoxyphenyl)methyl]-6-octadecynamide are substituted, 
respectively, for N-vanillyl-9-octadecynamide, with substantially similar 
results. 
EXAMPLE V 
A composition, according to the instant invention, for parenteral 
administration, is made by admixing the following components: 
______________________________________ 
N--[(4-acetoxy-3-methoxyphenyl)- 
100 mg/ml of carrier 
methyl]-9-octadecynamide 
carrier (percent by weight): 
ethyl oleate 98.0% 
benzyl alcohol 2.0% 
______________________________________ 
A human subject, weighing 70 kg, is injected via intramuscular injection, 
with 3.0 ml of the composition prepared above, producing analgesia. 
EXAMPLE VI 
A composition, according to the instant invention, is made with the 
following components: 
______________________________________ 
N--vanillyl-9-octadecynamide 
20 mg 
sesame oil 0.5 ml 
______________________________________ 
The alkynamide is dissolved in the sesame oil carrier and the solution thus 
obtained is administered orally to a rat, weighing 100 g, (resulting in a 
dose of 200 mg per kg) producing analgesia. 
EXAMPLE VII 
A composition, according to the instant invention, for oral administration, 
is made with the following components: 
______________________________________ 
N--vanillyl-9-octadecynamide 
100 mg/ml of carrier 
carrier (percent-by-weight): 
propylene glycol 100% 
______________________________________ 
5.0 ml of the syrup thereby prepared is administered orally to a human 
subject, producing analgesia. 
In the above example, flavoring agents, sweetening agents such as sucrose, 
lactose, mannitol and saccharin, and preservatives such as glycerin, 
methyl paraben, propylparaben, benzoic acid, sodium benzoate and alcohol, 
are added, singly or in combination, to the composition formed above, with 
substantially similar results. 
EXAMPLE VIII 
A composition, according to the instant invention, for oral administration, 
is made with the following components: 
______________________________________ 
Component Bulk Individual Tablet 
______________________________________ 
N--vanillyl-9-octadecynamide 
100 500 mg 
mannitol 97.2 486 
acacia 5.86 29.3 
starch 9.62 48.1 
talc 3.2 16.0 
calcium stearate 0.42 2.1 
orange flavor mix 1.06 5.3 
______________________________________ 
The above ingredients are admixed into a bulk mixture totalling 17.4 g. 
Chewable tablets are formed, using tabletting methods known in the art, 
each containing 1.09 g of the bulk mixture, for a total of 200 tablets 
formed. A human subject, weighing approximately 70 kg, is orally 
administered three of the tablets, for a total dose of 1500 mg of 
alkynamide, producing analgesia. 
EXAMPLE IX 
A composition, according to the instant invention, for oral administration, 
is made with the following components: 
______________________________________ 
N--vanillyl-11-octadecynamide 
1000 mg 
starch 10.2 
magnesium stearate 5.1 
______________________________________ 
A capsule is made by filling with the above ingredients, and administered 
to a human subject, weighing approximately 70 kg, producing analgesia. 
EXAMPLE X 
A lotion composition, according to the instant invention, for topical 
administration, is formed through admixing the following components 
(percentages-by-weight): 
______________________________________ 
N--vanillyl-6-octadecynamide 
2.0% 
isopropyl myristate 8.0% 
corn oil 5.0% 
propylene glycol 5.0% 
triethanolamide oleate 
5.0% 
xanthan gum 0.5% 
water 76.0% 
______________________________________ 
Approximately 4 ml of the lotion formed is applied to a 80 cm.sup.2 portion 
of the skin of a human subject, producing analgesia. 
In the above example, N-vanillyl-9-octadecynamide is substituted for 
N-vanillyl-6-octadecynamide, with substantially similar results.