CA1244049A - Compounds and compositions useful for producing analgesia - Google Patents
Compounds and compositions useful for producing analgesiaInfo
- Publication number
- CA1244049A CA1244049A CA000458769A CA458769A CA1244049A CA 1244049 A CA1244049 A CA 1244049A CA 000458769 A CA000458769 A CA 000458769A CA 458769 A CA458769 A CA 458769A CA 1244049 A CA1244049 A CA 1244049A
- Authority
- CA
- Canada
- Prior art keywords
- alkynamide
- compound
- och3
- pharmaceutically
- vanillyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
Abstract
NOVEL COMPOUNDS AND COMPOSITIONS
USEFUL FOR PRODUCING ANALGESIA
ABSTRACT
Alkynamide compounds, and pharmaceutically-acceptable salts thereof, of the formula:
wherein X is O or S; R is straight or branched alkyne having from 11 to 23 carbon atoms; R1 is H, OH, or OCH3; R2 is OH or a short-chain ester; and wherein at least one of R1 and R2 is OH
or OCH3. 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.
USEFUL FOR PRODUCING ANALGESIA
ABSTRACT
Alkynamide compounds, and pharmaceutically-acceptable salts thereof, of the formula:
wherein X is O or S; R is straight or branched alkyne having from 11 to 23 carbon atoms; R1 is H, OH, or OCH3; R2 is OH or a short-chain ester; and wherein at least one of R1 and R2 is OH
or OCH3. 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.
Description
NOVEL COMPOUNDS AND COMPOSITIONS
USEFUL FOR PRODUCING ANALGESIA
John M. Janusz Thomas R. LaHann BACKGROUND OF THE INV~NTION
-This invention relates to compositions, containing certain N-phenylmethylalkynamides, having analgesic activity.
While "pain" is incapable of precise definlition 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, ancl others directed to ~locking 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 uncon-sciousness. 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, phenace-tin, acetaminophen, phenylbutazone, and indomethacin.
Although the precise pharmacological action of these analge-sics is uncertain, there are certain effects which readily distin-guish the opioid analgesics from the antipyretics. In particular, the antipyretics are weak analgesics, with 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 narco~ics, 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.
3~
It has been recently discovered that capsaicin, a natural product of certain species of the genus Capsicum, induces anal-gesia in animals. Capsaicin (8-methyl-N-vanillyl-6E-nonenamide) and "synthetic" capsaicin (N-vanillylnonanamide) are disclosed as analgesics in U.S. Patent 4,313,958, LaHann, issued February 2, 1982. Analgesic activity of ca~saicin has also been discusseci in the chemical and medical literature, including' Yaksh, et al., Science, 206, 481-483 (1979). The use of capsaicin to prevent diDilatory irritation is also disclosed in U.S. Patent No.
4,546,1~12/ LaHann, et al., issued October 8, 1985.
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 cate-gories of analgesics, described above.
Compounds structurally similar to capsaicin have been de-scribed 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 tl954) lists the relative pun-gency of approximately 164 compounds, including N-vanillylole-amide and other alkenamide derivatives of capsaicin. Ott and Zimmermann, Liebigs Ann., 425, 314-337 t1921 ) discloses a syn-thesis for N-vanillyloleamide. A synthesis for N-vanillyllinole-amide is disclosed in Ferris, Australian C mmonwealth, Dep.
Supply, Def. Stand. Lab., No 89 t1966) (Chem. Abs. 67:22919).
U.S. Patent 4,238,505, Nelson, issued December 9, 1980, discloses 3-hydroxyacetanilide for use in producing analgesia in animals. U.S. Patent No. 4,424,205, LaHann, et al., issued January 3, 1984, describes hydroxyphenylacetamides with analgesic and anti-irritant activity. Similarly, analgesic and anti-irritant activity is disciosed for N-vanillylsulfonamides in U.S. Patent No. 4,401,663, Buckwalter, et al., issued July 17, 1984; N-vanillylureas in U.S. Patent No.
4,460,602, Buckwalter, et al., issued July 17, 1984; and N-vanillylcarbamates in U.S. Patent No. 4,443,473, Buckwalter~ et al., issued April 17, 1984.
It has now been discovered that certain N-phenylmethyl alkynamides have analgesic activity in humans and lower animals. In paeticular, these alkynamides have potent analgesic activity similar to that of capsaicin, but are substantially less toxic.
SUMMARY OF THE INVENTION
____.________________ I'he present invention provides compounds useful for producing analgesia in humans and lower animals, of the formula:
NHC--R
Rl wherein X is 0 or S, R is straight or branched alkyne having from 11 to 23 carbon atoms, Rl is H, OH, or OCH3, R2 is OH or a short-chain ester, and wherein at least one of Rl and R2 is OFI or OCH3; and pharmaceutically-acceptable salts thereoE.
This invention also provides a method for preparing such compounds by reacting a compound of the formula ,[~,CH2NH2 Rl in which Rl and R2 have the above meanings;
- 3a -with a compound of the formula Y _ ~ - R
where Y is a halogen, preferably chlorine and X and R have the above meanings, and, when required, converting the product obtained into a pharmaceutically-acceptable salt thereof.
~ his 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 admini-stering the compounds and compositions of this invention.
DESCRIPTION OF THE INVENTION
The compositions and method of this invention incorpo-rate certain N-[(substituted phenyl)methyl] alkynylamides (e.g., N~vanillyl-alkynylamides), or pharmaceutically-acceptable salts thereof, (hereinafter "alkynamides") of the formula:
~''i S R~ ~_ Ch2N~C--R
Rl ~
wherein X is O or S; R is straigh~ or branched alkyne having from 11 to 23 carbon atoms; R1 is H, OH or OCH3; R2 is OH or a short-chain ester; and wherein at least one of R1 and R2 is OH
or OCH3. 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 pre-ferred are alkynamides wherein X is O, alkynamides wherein R1 is OCH3 and R2 is OH, and alkynamides wherein R2 is a short-chain (i.e., Cl-C6) ester, e.g., acetoxy.
A preferred alkynamide is N-vanillyl-9-octadecynamide.
Preferred pharmaceutically-acceptable alkynamide salts include the sodium, potassium, calcium, magnesium, and ammonium salts.
The alkynamides described herein can be readily prepared by the following general synthetic scheme:
USEFUL FOR PRODUCING ANALGESIA
John M. Janusz Thomas R. LaHann BACKGROUND OF THE INV~NTION
-This invention relates to compositions, containing certain N-phenylmethylalkynamides, having analgesic activity.
While "pain" is incapable of precise definlition 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, ancl others directed to ~locking 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 uncon-sciousness. 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, phenace-tin, acetaminophen, phenylbutazone, and indomethacin.
Although the precise pharmacological action of these analge-sics is uncertain, there are certain effects which readily distin-guish the opioid analgesics from the antipyretics. In particular, the antipyretics are weak analgesics, with 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 narco~ics, 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.
3~
It has been recently discovered that capsaicin, a natural product of certain species of the genus Capsicum, induces anal-gesia in animals. Capsaicin (8-methyl-N-vanillyl-6E-nonenamide) and "synthetic" capsaicin (N-vanillylnonanamide) are disclosed as analgesics in U.S. Patent 4,313,958, LaHann, issued February 2, 1982. Analgesic activity of ca~saicin has also been discusseci in the chemical and medical literature, including' Yaksh, et al., Science, 206, 481-483 (1979). The use of capsaicin to prevent diDilatory irritation is also disclosed in U.S. Patent No.
4,546,1~12/ LaHann, et al., issued October 8, 1985.
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 cate-gories of analgesics, described above.
Compounds structurally similar to capsaicin have been de-scribed 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 tl954) lists the relative pun-gency of approximately 164 compounds, including N-vanillylole-amide and other alkenamide derivatives of capsaicin. Ott and Zimmermann, Liebigs Ann., 425, 314-337 t1921 ) discloses a syn-thesis for N-vanillyloleamide. A synthesis for N-vanillyllinole-amide is disclosed in Ferris, Australian C mmonwealth, Dep.
Supply, Def. Stand. Lab., No 89 t1966) (Chem. Abs. 67:22919).
U.S. Patent 4,238,505, Nelson, issued December 9, 1980, discloses 3-hydroxyacetanilide for use in producing analgesia in animals. U.S. Patent No. 4,424,205, LaHann, et al., issued January 3, 1984, describes hydroxyphenylacetamides with analgesic and anti-irritant activity. Similarly, analgesic and anti-irritant activity is disciosed for N-vanillylsulfonamides in U.S. Patent No. 4,401,663, Buckwalter, et al., issued July 17, 1984; N-vanillylureas in U.S. Patent No.
4,460,602, Buckwalter, et al., issued July 17, 1984; and N-vanillylcarbamates in U.S. Patent No. 4,443,473, Buckwalter~ et al., issued April 17, 1984.
It has now been discovered that certain N-phenylmethyl alkynamides have analgesic activity in humans and lower animals. In paeticular, these alkynamides have potent analgesic activity similar to that of capsaicin, but are substantially less toxic.
SUMMARY OF THE INVENTION
____.________________ I'he present invention provides compounds useful for producing analgesia in humans and lower animals, of the formula:
NHC--R
Rl wherein X is 0 or S, R is straight or branched alkyne having from 11 to 23 carbon atoms, Rl is H, OH, or OCH3, R2 is OH or a short-chain ester, and wherein at least one of Rl and R2 is OFI or OCH3; and pharmaceutically-acceptable salts thereoE.
This invention also provides a method for preparing such compounds by reacting a compound of the formula ,[~,CH2NH2 Rl in which Rl and R2 have the above meanings;
- 3a -with a compound of the formula Y _ ~ - R
where Y is a halogen, preferably chlorine and X and R have the above meanings, and, when required, converting the product obtained into a pharmaceutically-acceptable salt thereof.
~ his 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 admini-stering the compounds and compositions of this invention.
DESCRIPTION OF THE INVENTION
The compositions and method of this invention incorpo-rate certain N-[(substituted phenyl)methyl] alkynylamides (e.g., N~vanillyl-alkynylamides), or pharmaceutically-acceptable salts thereof, (hereinafter "alkynamides") of the formula:
~''i S R~ ~_ Ch2N~C--R
Rl ~
wherein X is O or S; R is straigh~ or branched alkyne having from 11 to 23 carbon atoms; R1 is H, OH or OCH3; R2 is OH or a short-chain ester; and wherein at least one of R1 and R2 is OH
or OCH3. 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 pre-ferred are alkynamides wherein X is O, alkynamides wherein R1 is OCH3 and R2 is OH, and alkynamides wherein R2 is a short-chain (i.e., Cl-C6) ester, e.g., acetoxy.
A preferred alkynamide is N-vanillyl-9-octadecynamide.
Preferred pharmaceutically-acceptable alkynamide salts include the sodium, potassium, calcium, magnesium, and ammonium salts.
The alkynamides described herein can be readily prepared by the following general synthetic scheme:
2$ R2~ CH2NH ~ R
Rl 1 ~[~, CN;~I;HC--R
_ 5 ~ 3~?
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 inten--'^ ' with any medical treatment. Obviously, the amount of alkyn-amide will vary with such factors as the particular condition that is being treated, the sevPrity 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 solubility and concentration of alkynamide 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-actlve agents, and encapsulating substan-ces, The amount of the carrier employed in conjunction with the alkynamide is sufficient to provlde a practical quantity of material per unlt dose of analgesic.
Pharmaceutically-acceptable carriers for systemic adrninistra-tion, that may be incorporated into the compositions of this invention, include sugars, starches, cellulose and its derlvatives, malt, gelatin, talc, calcium sulfate, vegetable oils, synthetic oils, polyols, alginic acid, phosphate buffer solutions, emulsifiers, isotonic saline, and pyrogen-free water. Specific pharmaceutic-ally-acceptable carriers are described in the following U.S. Patents:
U.S. Patent Nos. 4,424,205; 4,401,663;.4,460,602 and - 4,443,473. P.referred carriers for
Rl 1 ~[~, CN;~I;HC--R
_ 5 ~ 3~?
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 inten--'^ ' with any medical treatment. Obviously, the amount of alkyn-amide will vary with such factors as the particular condition that is being treated, the sevPrity 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 solubility and concentration of alkynamide 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-actlve agents, and encapsulating substan-ces, The amount of the carrier employed in conjunction with the alkynamide is sufficient to provlde a practical quantity of material per unlt dose of analgesic.
Pharmaceutically-acceptable carriers for systemic adrninistra-tion, that may be incorporated into the compositions of this invention, include sugars, starches, cellulose and its derlvatives, malt, gelatin, talc, calcium sulfate, vegetable oils, synthetic oils, polyols, alginic acid, phosphate buffer solutions, emulsifiers, isotonic saline, and pyrogen-free water. Specific pharmaceutic-ally-acceptable carriers are described in the following U.S. Patents:
U.S. Patent Nos. 4,424,205; 4,401,663;.4,460,602 and - 4,443,473. P.referred carriers for
3~
parenteral administration include propylene glycol, ethyl oleate, pyrrolidone, ethanol, and sesame oil. Preferably, the pharmaceu-tically-acceptable carrier, in compositions for parenteral admin-istration, 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 50Q~ of the alkynamide. Tablets can be compressed, tablet triturates, en-teric-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 fr om effervescent granules, containing suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, melting agents, coloring, and flavoring agents. Preferred carriers for oral administration 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 alkyn-amides, are described in U.S. Patent 3,903,297, Robert, issued September 2, 1975. Techniques and compositions for making solid oral dosage forms are described in Marshall, "Solid Oral Dosage Forms," odern Pharmaceutics, Vol 7, (Banker and Rhodes, editors), 359-42? (1979), The compositions of the present invention can also be admin-istered topically to a bioiogic 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 effec-tive amount, usually at l~ast about O . 5~, and preferably fror~
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 waterl Generally, the carrier is organic in nature and capable of having dispersed or dissolved therein the alkynamide. The carrier may include phar-maceutically-acceptable emollients, emulsifiers, thickening agents, and solvents.
Specific systemic and topical formulations useful in this invention are described in the following U.S. Patents:
U.S. Patent Nos. 4,424,205; 4,401,663; 4,460,602 and
parenteral administration include propylene glycol, ethyl oleate, pyrrolidone, ethanol, and sesame oil. Preferably, the pharmaceu-tically-acceptable carrier, in compositions for parenteral admin-istration, 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 50Q~ of the alkynamide. Tablets can be compressed, tablet triturates, en-teric-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 fr om effervescent granules, containing suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, melting agents, coloring, and flavoring agents. Preferred carriers for oral administration 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 alkyn-amides, are described in U.S. Patent 3,903,297, Robert, issued September 2, 1975. Techniques and compositions for making solid oral dosage forms are described in Marshall, "Solid Oral Dosage Forms," odern Pharmaceutics, Vol 7, (Banker and Rhodes, editors), 359-42? (1979), The compositions of the present invention can also be admin-istered topically to a bioiogic 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 effec-tive amount, usually at l~ast about O . 5~, and preferably fror~
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 waterl Generally, the carrier is organic in nature and capable of having dispersed or dissolved therein the alkynamide. The carrier may include phar-maceutically-acceptable emollients, emulsifiers, thickening agents, and solvents.
Specific systemic and topical formulations useful in this invention are described in the following U.S. Patents:
U.S. Patent Nos. 4,424,205; 4,401,663; 4,460,602 and
4,443,473. Topical vehicles, useful herein, are disclosed in the ~ollowing U.S. Patents: U.S. Patent 4,557,934, Cooper, issued December 10, 1985; and U.S. Patent No.
4,537,776, Cooper, iæsued August 27, 1985. Additional ~ormulations, useful for parenteral, oral, and topical administration of alkynamides, are disclosed in the ~ollowing U.S. Patents: U.S. Patent Mo. 4,493,848, LaHann and Buckwalter, issued January 15, 1985; U.S. Patent No.
4,544,669, La~lann, Janusz and Buckwalter, issued October 1, 1985; and U.S. Patent No. 4,544,668, Janusz, ~uckwalter and LaHann, issued October 1, 1985.
~ ~CA~
Methods for Producing Analgesia The present invention also encompasses methods of producing analgesia in humans or lower animals throùgh administering, to the human or lower animal, a safe and effective amount, usually
4,537,776, Cooper, iæsued August 27, 1985. Additional ~ormulations, useful for parenteral, oral, and topical administration of alkynamides, are disclosed in the ~ollowing U.S. Patents: U.S. Patent Mo. 4,493,848, LaHann and Buckwalter, issued January 15, 1985; U.S. Patent No.
4,544,669, La~lann, Janusz and Buckwalter, issued October 1, 1985; and U.S. Patent No. 4,544,668, Janusz, ~uckwalter and LaHann, issued October 1, 1985.
~ ~CA~
Methods for Producing Analgesia The present invention also encompasses methods of producing analgesia in humans or lower animals throùgh administering, to the human or lower animal, a safe and effective amount, usually
5 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 dos-ages higher than the foregoing are effective to produce analgesia, care must be taken in some individuals to prevent adverse side t-, 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 applica-tion includes any rnethod of introducing the alkynamide into the tissues of the body, e.g., intrathecai, epidural, intramuscular, transdermal, intravenous, intraperitoneal, subcutaneous, sublin-gual, 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 approxirnate 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 alkyn-amides is through oral administration. For mammals, especially humans, (assuming an approximate body weight of 70 kg) indivi-dual 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.
:~2~
g Topical administration can be used to produce local or sys-temic 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 alkyn-amide 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 ~,a, .icular alkynamide to be administered as well as the particular disorder to be treated and the extent to which systemic (as distinguished from local) analgesic effec~s 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 1 5 tissues.
The following non-limiting Examples illustrate the composi-tions, processes, ancl uses of the present invention.
EXAMPLE I
N-vanillyl-9-octadecynamide was synthesized by the following method:
Br2 Cr Bl r HOOC(cH2)7cH=cH(cH2)7cH3~ HOOC(CH2)7 H-CH(CH2~ CH
~0 ~ ~0 ~
OC~ OCH ~ lC(CH2)~ ~ C(C~2)7CH3 O
--H2NHC(C~2)7C--C(C~2)7 3 q~
SpecTfically, 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 remain-ing ) the solvent and excess bromine were evaporated, yielding 8 9 of 9 ,1 0-dibromooctadecanoic acid. A 30~ solution of potassium hydroxide in ethylene glycol (13 ml) was added to this dlbromi-nated oleic acid product, and refluxed at 185-1 90C for six hours, The mixture was stirred overnight, then acidified with 10~ H~l. The 9-octadecynoic acid (stearolic acid) was extracted into 100 ml petroleum ether, chilled, and the 4 9 of resulting product crystals were filtered and dried. 15 ml of oxalyl chloride were added to 3. 5 9 of the stearolic acid product and the mixture refluxed for one hour. The excess oxalyl chloride was eva-porated, yielding 9-octadecynyl chloride (stearoyl chloride) ~.4 9 of 4-hydroxy-3-methoxybenzylamine-HCI was suspended in 35 ml of N,M-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 HCI, sodium bicarbonate, water, and brine, and then dried and filtered. 5.3 9 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-van-illyl-9-hexadecynamide, N-vanillyl-6-octadecynamide, N-vanil-lyl-11-octadecynamide, N-vanillyl-10-nonadecynamide, and N-van-illyl-13-docosynamide are each made by substituting the respective n-alkynoic acid for 9-octadecynoic acid in the above synthesis.
,Using the 9-octadecynyl chloride:and substituting a corresponding reactant for the 4-hydroxy-3-methoxyben~yl-amine-HCl there may be obtained N-[(4-acetoxy-3-methoxy-phènyl)-methyl]-9-octadecynamide.
EXAMPLE I I
An analgesic composition, according to the present invention, was made comprising:
N-vani I Iyl-9-octadecynamide 127 . 2 mg ethanol 0 . 3 ml Tween 80 (polyoxyethylene 20 0.3 ml sorbitan mono-eleate) Sal ine 2 . 4 ml The composition was made by simple dissolution of the alkyn-amide in the liquid solvents. A mouse weighing 30 g, was inject-ed subcutaneously with 0.2 ml of the composition, producing ana Igesia .
EXAMPLE l l I
A composition, according to the instant invention, ~or paren-teral administration, is made with the following ingredients:
N-vanillyl-1 0-nonadecynamide1 OOmg/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 composi~ion 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-van-illyl 6-octadecynamide, N-vanillyl-11-octadecynamide, 12-methyl-N-vanillyl-9-octadecynamide, and 12-ethyl-N-vanillyl-9-octadecyn-amide are substituted, respectively, for N-vanillyl-10-nonadecyn-amide, with substantially similar results.
EXAMPLE !V
A composition, according to the instant invention, for paren-teral administration, is made with the following components:
N-vanillyl-9-octadecynamide 1 OOmg/ml of carrier carrier (percent-by-weight):
sesame oil 98%
benzyl alcohol ~ 2%
A human subject, weighing 70 kg, is injected via deep-intramus-cu!ar injection, with 1.0 ml of the composition prepared above, producing analgesia.
In the above example, N-vanillyl-l 0-non3decynamide, N-van-illyl-9-dodecynamide, N-vanillyl-13-docosynamide, 12-hydroxy-N-vanillyl-9-octadecynamide, N-vanillyl-9-octadecynethioamide, N-l (3,4-dihydroxyphenyl)methyl]-9-octadecynamide, N-[ (3-methoxyphenyl)methyl]-6-octadecynamide are substituted, respec-tively, for N-vanillyl-9-octadecynamide, with substantially similar resu I ts .
EXAMPLi V
A composition, accordin,g to the instant invention, for par--enteral administration, is made by admixing the following compo-nents:
N-[ (~I-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 in jection, with 3 . 0 ml of the composition prepared above, pro-ducing analgesia.
EXAMPLE Vl A composition, according to the instant invention, is made with the following components:
N-vanillyl-9-octadecynamide 20 mg sesame oil 0.5 ml ~a2~
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 anal-gesia .
S EXAMPLE Vl I
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 preserva-tives such as glycerin, methyl paraben, propylparaben, benzoic acid, sodium benzoate and alcohol, are added, singly or in com-bination, to the composition formed above, with substantially simi la r results .
EXAMPLE Vl l l 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 approx-imately 70 kg, is orally administered three of the tablets, for a total dose of 1500 mg of alkynamide, producing analgesia.
:~2'~
EXAMPLE I X
A composition, according to the instant invention, for oral administration, is made with the following components:
N-vanillyl~ octadecynamide 1000 mg starch 10.2 magnesi um stearate ~ 5~.1 A capsule is made by filling with the above ingredients, and administered to a human subject, weighing approximately 70 kg, ,or~ cing 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-octadecynamide2 . 0%
isopropyl myristate 8 . 0%
corn oi l 5 . 0%
propylene glycol 5, 0%
triethanolamine oleate 5 . 0%
xanthan gum 0, 5 water 76 . 0~
Approximately 4 ml of the lotion formed is applied to a 80 cm2 portion of the skin of a human subject, produciny analgesia.
In the above example, N-vanillyl-9-octadecynamide is sub-stituted for N-vanillyl-6-octadecynamide, with substantially similar ~S results.
The alkynamides and compositions of the instant invention can be administered topically or systemically. Systemic applica-tion includes any rnethod of introducing the alkynamide into the tissues of the body, e.g., intrathecai, epidural, intramuscular, transdermal, intravenous, intraperitoneal, subcutaneous, sublin-gual, 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 approxirnate 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 alkyn-amides is through oral administration. For mammals, especially humans, (assuming an approximate body weight of 70 kg) indivi-dual 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.
:~2~
g Topical administration can be used to produce local or sys-temic 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 alkyn-amide 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 ~,a, .icular alkynamide to be administered as well as the particular disorder to be treated and the extent to which systemic (as distinguished from local) analgesic effec~s 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 1 5 tissues.
The following non-limiting Examples illustrate the composi-tions, processes, ancl uses of the present invention.
EXAMPLE I
N-vanillyl-9-octadecynamide was synthesized by the following method:
Br2 Cr Bl r HOOC(cH2)7cH=cH(cH2)7cH3~ HOOC(CH2)7 H-CH(CH2~ CH
~0 ~ ~0 ~
OC~ OCH ~ lC(CH2)~ ~ C(C~2)7CH3 O
--H2NHC(C~2)7C--C(C~2)7 3 q~
SpecTfically, 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 remain-ing ) the solvent and excess bromine were evaporated, yielding 8 9 of 9 ,1 0-dibromooctadecanoic acid. A 30~ solution of potassium hydroxide in ethylene glycol (13 ml) was added to this dlbromi-nated oleic acid product, and refluxed at 185-1 90C for six hours, The mixture was stirred overnight, then acidified with 10~ H~l. The 9-octadecynoic acid (stearolic acid) was extracted into 100 ml petroleum ether, chilled, and the 4 9 of resulting product crystals were filtered and dried. 15 ml of oxalyl chloride were added to 3. 5 9 of the stearolic acid product and the mixture refluxed for one hour. The excess oxalyl chloride was eva-porated, yielding 9-octadecynyl chloride (stearoyl chloride) ~.4 9 of 4-hydroxy-3-methoxybenzylamine-HCI was suspended in 35 ml of N,M-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 HCI, sodium bicarbonate, water, and brine, and then dried and filtered. 5.3 9 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-van-illyl-9-hexadecynamide, N-vanillyl-6-octadecynamide, N-vanil-lyl-11-octadecynamide, N-vanillyl-10-nonadecynamide, and N-van-illyl-13-docosynamide are each made by substituting the respective n-alkynoic acid for 9-octadecynoic acid in the above synthesis.
,Using the 9-octadecynyl chloride:and substituting a corresponding reactant for the 4-hydroxy-3-methoxyben~yl-amine-HCl there may be obtained N-[(4-acetoxy-3-methoxy-phènyl)-methyl]-9-octadecynamide.
EXAMPLE I I
An analgesic composition, according to the present invention, was made comprising:
N-vani I Iyl-9-octadecynamide 127 . 2 mg ethanol 0 . 3 ml Tween 80 (polyoxyethylene 20 0.3 ml sorbitan mono-eleate) Sal ine 2 . 4 ml The composition was made by simple dissolution of the alkyn-amide in the liquid solvents. A mouse weighing 30 g, was inject-ed subcutaneously with 0.2 ml of the composition, producing ana Igesia .
EXAMPLE l l I
A composition, according to the instant invention, ~or paren-teral administration, is made with the following ingredients:
N-vanillyl-1 0-nonadecynamide1 OOmg/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 composi~ion 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-van-illyl 6-octadecynamide, N-vanillyl-11-octadecynamide, 12-methyl-N-vanillyl-9-octadecynamide, and 12-ethyl-N-vanillyl-9-octadecyn-amide are substituted, respectively, for N-vanillyl-10-nonadecyn-amide, with substantially similar results.
EXAMPLE !V
A composition, according to the instant invention, for paren-teral administration, is made with the following components:
N-vanillyl-9-octadecynamide 1 OOmg/ml of carrier carrier (percent-by-weight):
sesame oil 98%
benzyl alcohol ~ 2%
A human subject, weighing 70 kg, is injected via deep-intramus-cu!ar injection, with 1.0 ml of the composition prepared above, producing analgesia.
In the above example, N-vanillyl-l 0-non3decynamide, N-van-illyl-9-dodecynamide, N-vanillyl-13-docosynamide, 12-hydroxy-N-vanillyl-9-octadecynamide, N-vanillyl-9-octadecynethioamide, N-l (3,4-dihydroxyphenyl)methyl]-9-octadecynamide, N-[ (3-methoxyphenyl)methyl]-6-octadecynamide are substituted, respec-tively, for N-vanillyl-9-octadecynamide, with substantially similar resu I ts .
EXAMPLi V
A composition, accordin,g to the instant invention, for par--enteral administration, is made by admixing the following compo-nents:
N-[ (~I-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 in jection, with 3 . 0 ml of the composition prepared above, pro-ducing analgesia.
EXAMPLE Vl A composition, according to the instant invention, is made with the following components:
N-vanillyl-9-octadecynamide 20 mg sesame oil 0.5 ml ~a2~
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 anal-gesia .
S EXAMPLE Vl I
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 preserva-tives such as glycerin, methyl paraben, propylparaben, benzoic acid, sodium benzoate and alcohol, are added, singly or in com-bination, to the composition formed above, with substantially simi la r results .
EXAMPLE Vl l l 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 approx-imately 70 kg, is orally administered three of the tablets, for a total dose of 1500 mg of alkynamide, producing analgesia.
:~2'~
EXAMPLE I X
A composition, according to the instant invention, for oral administration, is made with the following components:
N-vanillyl~ octadecynamide 1000 mg starch 10.2 magnesi um stearate ~ 5~.1 A capsule is made by filling with the above ingredients, and administered to a human subject, weighing approximately 70 kg, ,or~ cing 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-octadecynamide2 . 0%
isopropyl myristate 8 . 0%
corn oi l 5 . 0%
propylene glycol 5, 0%
triethanolamine oleate 5 . 0%
xanthan gum 0, 5 water 76 . 0~
Approximately 4 ml of the lotion formed is applied to a 80 cm2 portion of the skin of a human subject, produciny analgesia.
In the above example, N-vanillyl-9-octadecynamide is sub-stituted for N-vanillyl-6-octadecynamide, with substantially similar ~S results.
Claims (14)
1. A process for producing an alkynamide compound or pharmaceutically-acceptable salts thereof, or mixtures thereof of the formula:
wherein X is O or S; R is straight or branched alkyne having from 11 to 23 carbon atoms; R1 is H, OH or OCH3; R2 is OH or a short chain ester, and wherein at least one of R1 and R2 is OH or OCH3; which comprises reacting a compound of the formula in which R1 and R2 have the above meanings;
with a compound of the formula where Y is a halogen and X and R have the above meanings, and, when required, converting the product obtained into a pharmaceutically-acceptable salt thereof.
wherein X is O or S; R is straight or branched alkyne having from 11 to 23 carbon atoms; R1 is H, OH or OCH3; R2 is OH or a short chain ester, and wherein at least one of R1 and R2 is OH or OCH3; which comprises reacting a compound of the formula in which R1 and R2 have the above meanings;
with a compound of the formula where Y is a halogen and X and R have the above meanings, and, when required, converting the product obtained into a pharmaceutically-acceptable salt thereof.
2 A process according to Claim 1 wherein R is straight or branched alkyne having from 16 to 21 carbon atoms.
3. A process according to Claim 1 wherein R1 is OCH3 and R2 is OH.
4. A process according to Claim 1 wherein R2 is a short chain ester.
5. A process according to Claim 1 wherein said alkynamide compound is converted into a salt selected from the group consisting of sodium, potassium, calcium, magnesium and ammonium salts.
6. A process according to Claim 3 which comprises reacting 4-hydroxy-3-methyoxybenzylamine with 9-octadecynyl chloride.
7. A process according to Claim 4 which comprises reacting 4-acetoxy-3-methoxybenzylamine with 9-octadecynyl chloride.
8. An alkynamide compound or pharmaceutically acceptable salt thereof, or mixtures thereof, of the formula:
wherein X is O or S; R is straight or branched alkyne having from 11 to 23 carbon atoms; R1 is H, OH or OCH3; R2 is OH
or a short-chain ester, and wherein at least one of R1 and R2 is OH or OCH3.
wherein X is O or S; R is straight or branched alkyne having from 11 to 23 carbon atoms; R1 is H, OH or OCH3; R2 is OH
or a short-chain ester, and wherein at least one of R1 and R2 is OH or OCH3.
9. An alkynamide compound as defined in Claim 8, wherein R is a straight or branched alkyne having from 16 to 21 carbon atoms.
10. An alkynamide compound as defined in Claim 8, wherein R1 is OCH3 and R2 is OH.
11. An alkynamide compound as defined in Claim 8, wherein R2 is a short-chain ester.
12. An alkynamide compound as defined in Claim 8, in the form of a sodium, potassium, calcium, magnesium or ammonium salt.
13. N-vanillyl-9-octadecynamide.
14. N-[(4-acetoxy-3-methoxyphenyl)methyl]-9-octadecynamide.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US06/514,204 US4532139A (en) | 1983-07-14 | 1983-07-14 | Compounds and compositions useful for producing analgesia |
| US514,204 | 1983-07-14 |
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|---|---|
| CA1244049A true CA1244049A (en) | 1988-11-01 |
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|---|---|---|---|
| CA000458769A Expired CA1244049A (en) | 1983-07-14 | 1984-07-12 | Compounds and compositions useful for producing analgesia |
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|---|---|
| US (1) | US4532139A (en) |
| EP (1) | EP0132114B1 (en) |
| JP (1) | JPS6084251A (en) |
| AU (1) | AU566192B2 (en) |
| CA (1) | CA1244049A (en) |
| DE (1) | DE3460820D1 (en) |
| DK (1) | DK345884A (en) |
| GB (1) | GB2144415B (en) |
| HK (1) | HK74990A (en) |
| IE (1) | IE57567B1 (en) |
| MY (1) | MY101021A (en) |
| NZ (1) | NZ208899A (en) |
| PH (1) | PH20512A (en) |
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| ZA (1) | ZA845348B (en) |
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| US4493848A (en) * | 1983-07-14 | 1985-01-15 | The Procter & Gamble Company | Compositions and methods useful for producing analgesia |
| US4681897A (en) * | 1984-01-16 | 1987-07-21 | The Procter & Gamble Company | Pharmaceutical products providing enhanced analgesia |
| DE3520761A1 (en) * | 1984-06-11 | 1985-12-12 | Ajinomoto Co., Inc., Tokio/Tokyo | USE OF VANILLYLAMINE OR VANILLYLAMIDES TO PROMOTE FAT METABOLISM |
| US5013759A (en) * | 1985-06-10 | 1991-05-07 | The Procter & Gamble Company | Compounds and compositions having anti-inflammatory and analgesic activity |
| GB2178031B (en) | 1985-06-10 | 1989-07-26 | Procter & Gamble | Phenylacetic acid amides having anti-inflammatory and analgesic activity |
| US4990533A (en) * | 1985-12-20 | 1991-02-05 | Warner-Lambert Co. | Benzoic acid and benzoic acid ester derivatives having anti-inflammatory and analgesic activity |
| US4689182A (en) * | 1985-12-20 | 1987-08-25 | Warner-Lambert Company | Benzoic acid and benzoic acid ester derivatives having anti-inflammatory and analgesic activity |
| US4980366A (en) * | 1986-08-19 | 1990-12-25 | Warner-Lambert Co. | Amide, sulfonamide, urea, carbamate, thiocarbamate, and thiourea derivatives of 4'hydroxybenzylamine having anti-inflammatory and analgesic activity |
| US5045565A (en) * | 1987-03-09 | 1991-09-03 | The Procter & Gamble Company | Novel compounds, pharmaceutical compositions, and methods for treating inflammation and pain |
| US5099030A (en) * | 1987-03-09 | 1992-03-24 | The Procter & Gamble Company | Novel compounds, pharmaceutical compositions, and methods for treating inflammation and pain |
| US5461075A (en) * | 1988-06-17 | 1995-10-24 | The Procter & Gamble Company | Use of vanilloids for the prevention of lesions due to herpes simplex infections |
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| US3024281A (en) * | 1962-03-06 | Amidomethylation of aromatic | ||
| US2710299A (en) * | 1950-10-21 | 1955-06-07 | Thomae Gmbh Dr K | Process for the production of crystalline vanillyl amides |
| DE938014C (en) * | 1952-11-05 | 1956-01-19 | Beiersdorf & Co A G P | Process for the production of crystallized vanillylamides |
| US2845449A (en) * | 1956-07-11 | 1958-07-29 | California Research Corp | Thioamide production |
| NL269079A (en) * | 1960-09-09 | 1964-06-25 | ||
| US3108038A (en) * | 1962-01-08 | 1963-10-22 | Du Pont | Anilide nematocides |
| US3192213A (en) * | 1962-10-12 | 1965-06-29 | Olin Mathieson | Aminoalkyl anilides |
| US3167556A (en) * | 1963-11-19 | 1965-01-26 | Olin Mathieson | Basic derivatives of anilides |
| SE353319B (en) * | 1964-08-15 | 1973-01-29 | Sumitomo Chemical Co | |
| US3201401A (en) * | 1964-09-17 | 1965-08-17 | Olin Mathieson | Aminoalkoxy and aminoalkylthioanilide compounds |
| GB1150051A (en) * | 1966-03-11 | 1969-04-30 | Science Union & Cie | New Phenylisopropylamide Derivatives and Process for Preparing Them |
| US3780103A (en) * | 1967-03-30 | 1973-12-18 | Ciba Geigy Corp | Alkylhydroxybenzylamides |
| US4031186A (en) * | 1975-07-10 | 1977-06-21 | Rohm And Haas Company | Arylaminoalkylthioamides |
| DE2752366A1 (en) * | 1977-11-24 | 1979-05-31 | Bayer Ag | 3,3-Di:methyl-4-pentene thio acid derivs. - are intermediates for cyclopropane carboxylic acid insecticides |
| US4244730A (en) * | 1979-07-02 | 1981-01-13 | Chevron Research Company | Herbicidal N-haloacetyl-2-alkyl-6-acylanilines |
| US4372972A (en) * | 1979-09-14 | 1983-02-08 | Rohm And Haas Company | N-Substituted alkynyl anilines |
-
1983
- 1983-07-14 US US06/514,204 patent/US4532139A/en not_active Expired - Lifetime
-
1984
- 1984-07-11 DE DE8484304729T patent/DE3460820D1/en not_active Expired
- 1984-07-11 GB GB08417625A patent/GB2144415B/en not_active Expired
- 1984-07-11 ZA ZA845348A patent/ZA845348B/en unknown
- 1984-07-11 EP EP84304729A patent/EP0132114B1/en not_active Expired
- 1984-07-12 CA CA000458769A patent/CA1244049A/en not_active Expired
- 1984-07-13 DK DK345884A patent/DK345884A/en not_active Application Discontinuation
- 1984-07-13 JP JP59145860A patent/JPS6084251A/en active Granted
- 1984-07-13 AU AU30586/84A patent/AU566192B2/en not_active Ceased
- 1984-07-13 NZ NZ208899A patent/NZ208899A/en unknown
- 1984-07-13 IE IE1814/84A patent/IE57567B1/en not_active IP Right Cessation
- 1984-07-13 PH PH30981A patent/PH20512A/en unknown
-
1987
- 1987-09-21 MY MYPI87001814A patent/MY101021A/en unknown
-
1990
- 1990-06-26 SG SG45190A patent/SG45190G/en unknown
- 1990-09-20 HK HK749/90A patent/HK74990A/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| MY101021A (en) | 1991-06-29 |
| PH20512A (en) | 1987-01-26 |
| HK74990A (en) | 1990-09-28 |
| DE3460820D1 (en) | 1986-10-30 |
| JPH0472820B2 (en) | 1992-11-19 |
| GB8417625D0 (en) | 1984-08-15 |
| DK345884A (en) | 1985-01-15 |
| ZA845348B (en) | 1985-03-27 |
| JPS6084251A (en) | 1985-05-13 |
| EP0132114B1 (en) | 1986-09-24 |
| SG45190G (en) | 1990-08-17 |
| EP0132114A1 (en) | 1985-01-23 |
| AU566192B2 (en) | 1987-10-08 |
| AU3058684A (en) | 1985-01-17 |
| NZ208899A (en) | 1988-03-30 |
| GB2144415A (en) | 1985-03-06 |
| US4532139A (en) | 1985-07-30 |
| IE841814L (en) | 1985-01-14 |
| DK345884D0 (en) | 1984-07-13 |
| GB2144415B (en) | 1987-11-25 |
| IE57567B1 (en) | 1992-12-16 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKEX | Expiry |