US3276960A - Analgesic methods and compositions - Google Patents
Analgesic methods and compositions Download PDFInfo
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- US3276960A US3276960A US377111A US37711164A US3276960A US 3276960 A US3276960 A US 3276960A US 377111 A US377111 A US 377111A US 37711164 A US37711164 A US 37711164A US 3276960 A US3276960 A US 3276960A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/80—Acids; Esters in position 3
Definitions
- This invention relates to a new analgesically active compound and compositions containing the compound suitable for use in the treatment of muscular aches and pains.
- Analgesic compositions are topically applied in the treatment of muscular soreness due to muscular bruises, sprains and the like. Although the exact mechanism by which these compositions exert their pain-relieving effect is not fully understood, there is general agreement that the active agents in the analgesic compositions must be capable of passing through the skin and effect a vasodilation in the skin and deeper tissues. It has been shown that vasodilation is brought about by stimulation of nerve fibers which cause a dilating response in the arterioles and precapillary arteriolar sphincters. Capillaries and non-muscular venules do not dilate, but because of the arteriolar dilation have an increase in flow rate with a small accompanying distension. In addition, some capillaries previously devoid of blood become filled.
- the increase in the supply and flow of blood removes toxins and metabolites in the treated areas.
- the new blood in the treated areas also brings in a supply of nutrients.
- the removal of toxins and metabolites and the supply of nutrients contribute to relief of muscular soreness and pain.
- vasodilating effect of analgesically active com pounds is accompanied by an increase in the temperature of the skin and erythemic reaction (redness); These changes of temperature and color of the skin can be observed and serve as a measure of the vasodilatory activity of the analgesica'lly active compounds.
- the intensity of the change in skin temperature induced by the compounds should not be so great as to be uncomfortable for the patient.
- a chemically induced increase in skin temperature of several degrees is tolerable.
- a large increase in temperature does not in itself qualify a compound as a suitable ingredient for analgesic compositions.
- the length of time of the chemically induced vasodilation is of considerable importance.
- the new compound of this invention is bicyclo-(2.2.1)- hept-S-ene-Zcarbinylnicotinate.
- This nicotinate ester (occasionally referred to hereafter simply as the bicyclo nicotinate) produces a comfortable sensation of warmth when applied to the skin, producing an increase in temperature of between about 3 F. to 4 F. in the skin within about the first half hour after application. The temperature of the skin then gradually decreases, and after about 3 hours is still approximately 1 F. higher than other comparable skin portions of the body. A condition of erythema remains for as long as 24 hours after application, indicating increased blood flow and supply in the region of the treated area.
- the bicyclo-(2.2.1)-hept-5-ene-2 carbinylnicotinate is substantially less odoriferous than many of the presently commercially used analgesically active compounds.
- the bicyclo-(2.2.1)-hept-5-ene-2-carbinylnicotinate may be compounded with various carriers normally used in liniment and balm formulations.
- the activity of the bicyclo-(2.2.1)-hept-5-ene-2-car-' binylnicotinate as an analgesic compound can be objectively illustrated by the occurrence of erythema and rise in temperature of the skin in the locale of application. This activity and comparison thereof with other compounds is hereinafter illustrated.
- the methyl salicylate (more commonly known as oil of Wintergreen) produced only a very minor amount of erythema.
- the bicyclo nicotinate compound of this invention produced a greater amount of erythema than either of the two commonly used analgesically active compounds: methyl nicotinate and methyl salicyla-te. Most significantly, however, the bicyclo nicotinate ester produced a greater efiFect for a much longer period of time than either of the other compounds.
- this bicyclo nicotinate ester is greater than the activity of formulations containing mixtures of methyl nicotinate and methyl salicylate either together or with other ingredients to compliment the analgesic function of these two compounds.
- the liniment solution containing 5% bicyclo-(2.2.1)-hept-5-ene-2-carbinylnicotinate in the isopropanol-water carrier was also compared with several commercial analgesic preparations.
- formulation A is the isopropanol-water solution of the bicyclo-(2.2.1)-hept-5-ene-2-carbinylnicotinate.
- Skin temperatures were measured with a thermistor temperature measuring device, sensitive to changes of at least 0.01 8 F.
- the formulation was applied to a one square inch skin area on the outer aspect of the upper arm. The resulting temperature rise was measured as the difference between the test spot and a control spot on the other arm. Basal temperatures were first obtained on both arms before the application of the formulations. Basal temperatures at periodic times after the application of the formulation were determined by measuring the temperature of a similar spot on the opposite arm using a third thermistor. In order to avoid errors, the measuring devices were taped in place and moved only for the application of the test formulations.
- the results of toxicity measurements by intraperitoneal injection show that the bicyclo-(2.2.1)-hept-5-ene-2-carbinylnicotinate of this invention is less toxic than the methyl nicotinate and methyl salicylate.
- the LD (mg/kg.) of the bicyclo-(2.2.1)-hept-5-ene-2-carbinylnicotinate is 1440.
- the IJD (mg/kg.) values for the methyl esters of nicotinic acid and methyl salicylic acid are, respectively, 1225 and 500.
- analgesic preparation should contain at least about 0.5% by weight of bicyclo- (2.2.1) hept S-ene-Z-carbinylnicotinate. Less may be used, particularly when combined with other analgesics. Ordinarily the use of as much as 5% of this active ingredient in the analgesic preparation would be wasteful. Increasing the concentration of the bicyclo-(2.2.l)-hept- S-ene-Z-carbinylnicotinate from 0.5% to 2.5% produced only a slight effect on the degree of erythema observed. From the standpoint of economics and effectiveness, analgesic preparations containing from 0. 5% to 2.5% of the compound of this invention are preferred.
- the bicyclo (2.2.1) hept-5-ene-Z-carbinylnicotinate may be compounded with liquids and semisolid and solid vehicles conventionally employed in analgesic lotions, liniments and balms.
- suitable vehicles for the formulation of such analgesic compositions are alcohols, such as isopropanol and ethyl alcohol; mineral oil; squalene; limonene; polyalcohols, such as glycerol, including glycols such as ethylene glycol and propylene glycol; petrolatum; licosane; fatty acid esters of polyethylene glycol, such as polyethylene glycol monostearate; and vanishing creams.
- the bicyclo (2.2.1) hept-5-ene-2-carbinylnicotinate may be simply prepared by well-known esterification methods.
- bicyclo (2.2.l)-hept-5-ene-2-carbin-o1 (sometimes alternatively referred to as bicyclo- (2.-2.l)-hept 5-ene-2rnethylol) may be reacted with nicotinic acid in the presence of boron trioxide as a catalyst at a temperature Within the range of C. to 200 C.
- the bicycloheptenecarbinol starting material acts as a solvent and preferably should be present in an amount greater than a 1:1 molar ratio with the nicotinic acid.
- An analgesic composition for application to skin comprising a minor amount of bicyclo-(2.2.l)-hept-5- ene-Z-carbinylnicotinate and a major amount of carrier therefor, said bicyclo compound being present in said composition in an amount at least sufiicient to produce a. condition of erythema on the skin for a duration of at least about 24 hours in the locale of application.
- An analgesic composition for application to skin comprising a minor amount, at least about 0.5% by weight of bicyclo-(2.2.1) hept-S-ene-2-carbinylnicotinate and a major amount of a carrier therefor.
- An analgesic composition for application to skin comprising a minor amount, about 0.5% to about 5% by weight, of bicyclo-(2.2.1)-hept-5-ene-Z-carbinylnicotinate and a predominantly major amount of a carrier therefor.
- An analgesic composition for application to skin comprising a minor amount, about 0.5 to about 2.5 by weight, of bicyclo (2.2.l)-hept-5-ene-2-carbinylnicotinate and a carrier therefor in a predominantly major amount.
- composition of claim 1 wherein the carrier is a liquid.
- composition of claim 1 wherein the carrier is a spreada-ble solid.
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Description
United States Patent 9 Claims. (Cl. 167-65) This application is a division of parent application Serial No. 162,545, filed August 21, 1961, now US. Patent No. 3,185,697, granted May 25, 1965.
This invention relates to a new analgesically active compound and compositions containing the compound suitable for use in the treatment of muscular aches and pains.
Analgesic compositions are topically applied in the treatment of muscular soreness due to muscular bruises, sprains and the like. Although the exact mechanism by which these compositions exert their pain-relieving effect is not fully understood, there is general agreement that the active agents in the analgesic compositions must be capable of passing through the skin and effect a vasodilation in the skin and deeper tissues. It has been shown that vasodilation is brought about by stimulation of nerve fibers which cause a dilating response in the arterioles and precapillary arteriolar sphincters. Capillaries and non-muscular venules do not dilate, but because of the arteriolar dilation have an increase in flow rate with a small accompanying distension. In addition, some capillaries previously devoid of blood become filled.
The increase in the supply and flow of blood removes toxins and metabolites in the treated areas. The new blood in the treated areas also brings in a supply of nutrients. The removal of toxins and metabolites and the supply of nutrients contribute to relief of muscular soreness and pain.
The vasodilating effect of analgesically active com pounds is accompanied by an increase in the temperature of the skin and erythemic reaction (redness); These changes of temperature and color of the skin can be observed and serve as a measure of the vasodilatory activity of the analgesica'lly active compounds.
The intensity of the change in skin temperature induced by the compounds should not be so great as to be uncomfortable for the patient. Generally, a chemically induced increase in skin temperature of several degrees is tolerable. A large increase in temperature does not in itself qualify a compound as a suitable ingredient for analgesic compositions. The length of time of the chemically induced vasodilation is of considerable importance.
The new compound of this invention is bicyclo-(2.2.1)- hept-S-ene-Zcarbinylnicotinate. This nicotinate ester (occasionally referred to hereafter simply as the bicyclo nicotinate) produces a comfortable sensation of warmth when applied to the skin, producing an increase in temperature of between about 3 F. to 4 F. in the skin within about the first half hour after application. The temperature of the skin then gradually decreases, and after about 3 hours is still approximately 1 F. higher than other comparable skin portions of the body. A condition of erythema remains for as long as 24 hours after application, indicating increased blood flow and supply in the region of the treated area.
ice
Advantageously, the bicyclo-(2.2.1)-hept-5-ene-2 carbinylnicotinate is substantially less odoriferous than many of the presently commercially used analgesically active compounds.
The bicyclo-(2.2.1)-hept-5-ene-2-carbinylnicotinate may be compounded with various carriers normally used in liniment and balm formulations.
The activity of the bicyclo-(2.2.1)-hept-5-ene-2-car-' binylnicotinate as an analgesic compound can be objectively illustrated by the occurrence of erythema and rise in temperature of the skin in the locale of application. This activity and comparison thereof with other compounds is hereinafter illustrated.
Erythema The chemical tested was applied on the inner aspect of the forearm over a previously marked-out one square inch area. The degree of erythema produced was then evaluated at various intervals according to the following scale:-
0-no erythema 1slight erythema 2clear erythema 3strong erythema 4-very strong erythema.
TAB LE I Maximum lDuration Value at; 4 Active Compound Erythema in Hours 1 24 Hours Value Methyl Nicotinate 2. 3 e. 0 0 Methyl Salicylate 0. 5 0 Bicyclo-(2.2.1)-hept-5-eue-2-c binylnicotinate 3. 0 '7. 5 0. 6 Control- 0. 0 0. 0 0. 0
1 Time after application at which erythema rating at least 1.0.
In all instances the skin remained uncovered. .The methyl salicylate (more commonly known as oil of Wintergreen) produced only a very minor amount of erythema. The bicyclo nicotinate compound of this invention produced a greater amount of erythema than either of the two commonly used analgesically active compounds: methyl nicotinate and methyl salicyla-te. Most significantly, however, the bicyclo nicotinate ester produced a greater efiFect for a much longer period of time than either of the other compounds.
Furthermore, the activity of this bicyclo nicotinate ester is greater than the activity of formulations containing mixtures of methyl nicotinate and methyl salicylate either together or with other ingredients to compliment the analgesic function of these two compounds. The liniment solution containing 5% bicyclo-(2.2.1)-hept-5-ene-2-carbinylnicotinate in the isopropanol-water carrier was also compared with several commercial analgesic preparations.
The measurements of erythema were made in the manner described above. Again the compound of this invention exhibited a greater degree and duration of erythemic reaction. These results are tabulated in Table II. In Table II, formulation A is the isopropanol-water solution of the bicyclo-(2.2.1)-hept-5-ene-2-carbinylnicotinate.
TABLE II Maximum Duration Value at Product Erythema in Hours 1 24 Hours Rating Formulation E I I Time after application at which erythema rating at least 1.0.
Skin temperature The skin temperature studies clearly illustrate the superiority of the bicyclo-(2.2.1)-hept-5-ene-2-carbinylnicotinate over methyl salicylate and methyl nicotinate. The relative activity of these compounds and two commercial balms in this respect is shown in Table III. Formulations B and C in Table Ill are the same as those previously described.
TABLE III Temperature Rise/Time After Application F.: minutes) Analgesic Compound Blcyclo-(2.2.1)-hept-5-ene-2- carbinylnicotinate 1 3. 6 2. 9 1. 8 1. 1 0. 9 0. 9 Methyl Nicctinate 2. 9 1. 1 0. Methyl Salicylate 1. 6 0. 7 0. O Formulation B 2. 1. 1 0. 5 0. 4 Formulation C 2. 5 1. 7 0. 5 0. 0
1 5% solution in isopropanol-water (1:1).
A maximum increase in temperature of 3.6 F. was produced in the skin at about 30 minutes after application'. All of the other preparations in Table III reached a maximum temperature increase in slightly less than 30 minutes, but in no case did the temperature exceed the temperature produced by the bicyclo nicotinate compound.
Skin temperatures were measured with a thermistor temperature measuring device, sensitive to changes of at least 0.01 8 F. The formulation was applied to a one square inch skin area on the outer aspect of the upper arm. The resulting temperature rise was measured as the difference between the test spot and a control spot on the other arm. Basal temperatures were first obtained on both arms before the application of the formulations. Basal temperatures at periodic times after the application of the formulation were determined by measuring the temperature of a similar spot on the opposite arm using a third thermistor. In order to avoid errors, the measuring devices were taped in place and moved only for the application of the test formulations.
The results of toxicity measurements by intraperitoneal injection show that the bicyclo-(2.2.1)-hept-5-ene-2-carbinylnicotinate of this invention is less toxic than the methyl nicotinate and methyl salicylate. Thus, the LD (mg/kg.) of the bicyclo-(2.2.1)-hept-5-ene-2-carbinylnicotinate is 1440. The IJD (mg/kg.) values for the methyl esters of nicotinic acid and methyl salicylic acid are, respectively, 1225 and 500.
Only very minor amounts of the compound of this invention need be employed in the analgesic compositions. Generally, for practical utility the analgesic preparation should contain at least about 0.5% by weight of bicyclo- (2.2.1) hept S-ene-Z-carbinylnicotinate. Less may be used, particularly when combined with other analgesics. Ordinarily the use of as much as 5% of this active ingredient in the analgesic preparation would be wasteful. Increasing the concentration of the bicyclo-(2.2.l)-hept- S-ene-Z-carbinylnicotinate from 0.5% to 2.5% produced only a slight effect on the degree of erythema observed. From the standpoint of economics and effectiveness, analgesic preparations containing from 0. 5% to 2.5% of the compound of this invention are preferred.
The bicyclo (2.2.1) hept-5-ene-Z-carbinylnicotinate may be compounded with liquids and semisolid and solid vehicles conventionally employed in analgesic lotions, liniments and balms. Examples of suitable vehicles for the formulation of such analgesic compositions are alcohols, such as isopropanol and ethyl alcohol; mineral oil; squalene; limonene; polyalcohols, such as glycerol, including glycols such as ethylene glycol and propylene glycol; petrolatum; licosane; fatty acid esters of polyethylene glycol, such as polyethylene glycol monostearate; and vanishing creams. These are illustrative of substantially inert materials applicable to skin which may serve as a vehicle or carrier for the :bicyclo nicotinate ester in analgesic preparations. Various embodiments of such preparations utilizing the compound of this invention will be obvious to those skilled in the art and accordingly, it is to be understood that all materials disclosed are to be interpreted as illustrative and not in a limiting sense.
The bicyclo (2.2.1) hept-5-ene-2-carbinylnicotinate may be simply prepared by well-known esterification methods. For example, bicyclo (2.2.l)-hept-5-ene-2-carbin-o1 (sometimes alternatively referred to as bicyclo- (2.-2.l)-hept 5-ene-2rnethylol) may be reacted with nicotinic acid in the presence of boron trioxide as a catalyst at a temperature Within the range of C. to 200 C. The bicycloheptenecarbinol starting material acts as a solvent and preferably should be present in an amount greater than a 1:1 molar ratio with the nicotinic acid.
What is claimed is:
1. An analgesic composition for application to skin comprising a minor amount of bicyclo-(2.2.l)-hept-5- ene-Z-carbinylnicotinate and a major amount of carrier therefor, said bicyclo compound being present in said composition in an amount at least sufiicient to produce a. condition of erythema on the skin for a duration of at least about 24 hours in the locale of application.
2. An analgesic composition for application to skin comprising a minor amount, at least about 0.5% by weight of bicyclo-(2.2.1) hept-S-ene-2-carbinylnicotinate and a major amount of a carrier therefor.
3. An analgesic composition for application to skin comprising a minor amount, about 0.5% to about 5% by weight, of bicyclo-(2.2.1)-hept-5-ene-Z-carbinylnicotinate and a predominantly major amount of a carrier therefor.
4. An analgesic composition for application to skin comprising a minor amount, about 0.5 to about 2.5 by weight, of bicyclo (2.2.l)-hept-5-ene-2-carbinylnicotinate and a carrier therefor in a predominantly major amount.
5. The composition of claim 1 wherein the carrier is a liquid.
6. The composition of claim 1 wherein the carrier is a spreada-ble solid.
5 6 7. The method comprising applying a composition References Cited by the Examiner containing bicycle-(2.2.1)-hept:5-ene-2-carbinylnicotinate FOREIGN PATENTS and a carrier therefor to the skin. v
8. The method comprising applying the composition of 620,687 3/1949 Great Bmam' claim 2 to the skin. 5
9. The method comprising applying the composition of JULIAN LEVITT Primary Examiner claim 4 to the skin. STANLEY J. FRIEDMAN, Assistant Examiner
Claims (1)
- 4. AN ANALGESTIC COMPOSITION FOR APPLYCATION TO SKIN COMPRISING A MINOR AMOUNT, ABOUT 0.5% TO ABOUT 2.5% BY WEIGHT, OF BICYCLO-(2.2.1)-HEPT-5-ENE-2-CARBINYLINICOTINATE AND A CARRIER THEREFOR IN A PREDOMINANTLY MAJOR AMOUNT.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US377111A US3276960A (en) | 1961-08-21 | 1964-06-22 | Analgesic methods and compositions |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US132545A US3185697A (en) | 1961-08-21 | 1961-08-21 | Bicyclo-(2.2.1)-hept-5-ene-2-carbinyl-nicotinate |
| US377111A US3276960A (en) | 1961-08-21 | 1964-06-22 | Analgesic methods and compositions |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| US3276960A true US3276960A (en) | 1966-10-04 |
Family
ID=26830469
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US377111A Expired - Lifetime US3276960A (en) | 1961-08-21 | 1964-06-22 | Analgesic methods and compositions |
Country Status (1)
| Country | Link |
|---|---|
| US (1) | US3276960A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6337065B1 (en) | 1998-12-01 | 2002-01-08 | University Of Kentucky Research Foundation | Method for enhancing protective cellular responses to genotoxic stress in skin |
| FR2959131A1 (en) * | 2010-04-23 | 2011-10-28 | Francois Forestier | Composition, useful for limiting a replication of heat-sensitive virus such as rhinovirus, treating common cold and to inhibit inflammatory response, comprises at least one rubefacient and a carrier |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB620687A (en) * | 1945-05-22 | 1949-03-29 | Winthrop Chem Co Inc | Improvements in or relating to alkyl esters of nicotinic acid |
-
1964
- 1964-06-22 US US377111A patent/US3276960A/en not_active Expired - Lifetime
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB620687A (en) * | 1945-05-22 | 1949-03-29 | Winthrop Chem Co Inc | Improvements in or relating to alkyl esters of nicotinic acid |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6337065B1 (en) | 1998-12-01 | 2002-01-08 | University Of Kentucky Research Foundation | Method for enhancing protective cellular responses to genotoxic stress in skin |
| US6552050B2 (en) | 1998-12-01 | 2003-04-22 | University Of Kentucky Research Foundation | Method for enhancing protective cellular responses to genotoxic stress in skin |
| FR2959131A1 (en) * | 2010-04-23 | 2011-10-28 | Francois Forestier | Composition, useful for limiting a replication of heat-sensitive virus such as rhinovirus, treating common cold and to inhibit inflammatory response, comprises at least one rubefacient and a carrier |
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