Claims
- 1. A compound of the formula ##STR5## and pharmacologically acceptable, non-toxic salts thereof wherein: R is a member selected from the group consisting of methallyl, isopropyl, allyl, t-butyl, n-butyl, and isobutyl.
- 2. A compound as claimed in claim 1, wherein R is methallyl.
- 3. A compound as claimed in claim 1, wherein R is isopropyl.
- 4. A compound as claimed in claim 1, wherein R is allyl.
- 5. A compound as claimed in claim 1, wherein R is t-butyl.
- 6. A compound as claimed in claim 1, wherein R is n-butyl.
- 7. A compound as claimed in claim 1, wherein R is isobutyl.
- 8. A therapeutic method for treating algia in an individual for whom such therapy is indicated comprising: administering to the individual an effective analgesic amount of a compound of the formula ##STR6## or pharmacologically acceptable, non-toxic salts thereof wherein: R is a member selected from the group consisting of methallyl, isopropyl, allyl, t-butyl, n-butyl and isobutyl.
- 9. A method as claimed in claim 8, wherein R is methallyl.
- 10. A method as claimed in claim 8, wherein R is isopropyl.
- 11. A method as claimed in claim 8, wherein R is allyl.
- 12. A method as claimed in claim 8 wherein R is t-butyl.
- 13. A method as claimed in claim 8, wherein R is n-butyl.
- 14. A method as claimed in claim 8, wherein R is isobutyl.
BACKGROUND OF THE INVENTION
1. Related Applications
This application is a continuation-in-part of co-pending application Ser. No. 753,645 filed on Dec. 23, 1976, and now abandoned.
2. Field of the Invention
This invention is related to 3-substituted salicylamides which demonstrate increased analgesic activity accompanied by a prolongation of such activity when compared with prior art compounds having similar chemical structures.
3. Prior Art
Because salicylic acid is so irritating that it can only be used externally, various derivatives of the acid have been synthesized for systemic use. In general, the derivatives synthesized comprise two main classes, namely salicylate esters, such as aspirin, obtained by substitution on the phenol group, and amides of salicylic acid, obtained by substitution on the carboxyl group, for example, amide group substitution. Both types of derivatives are referred to collectively as "salicylates" or "salicylamide" compounds.
Another class of derivatives can be prepared from the salicylates described above by substitution on the benzene ring.
The salicyl compounds are widely used as analgesics because the compounds have lower maximal effects than do the narcotic analgesics. Hence they are used extensively for pain of slight-to-moderate intensity. They have the advantage that chronic use does not lead to tolerance or addiction. Their toxicity is lower than that of more potent analgesics. Types of pain amenable to treatment with salicyl compounds are low intensity, either circumscribed or widespread in origin, and include headache, myalgia and arthralgia.
Many of the salicylates are too toxic to be employed as general analgesics; however, because of the usefulness of aspirin and other salicylates, research to discover potent-acting salicylates, with reduced toxicity is continuing. Another disadvantage of various salicylates is their short duration of activity, due to rapid biotransformation by conjugation with endogenous glucuronic acid.
U.S. Pat. No. 2,810,718 discloses salicyl compounds substituted on the phenol group and substituted on the carboxyl group by piperazyl and piperadyl moieties, having local anesthetic and fungicidal activity. J. Chem. Soc. 1961, pp. 661-667; J. Org. Chem., 19, 510 (1954) J. Gen. Chem., 8, 427 (1938) and J. Org. Chem., 2, 253-259 (1937) all merely disclose the laboratory preparation of salicyl compounds substituted on the benzene nucleus; no pharmaceutical properties are disclosed.
U.S. Pat. Nos. 2,751,410; 2,751,411; and 2,751,412 disclose 3-phenysalicylamides; U.S. Pat. No. 2,879,290 discloses analgesic compounds which are 3-[N,N-Di(loweralkyl)carbamoyl]-2-acyloxybiphenyl; J. Am. Pharm. Assoc. Sci. Ed., 45, 277-81 (1956) discloses analgesic compounds which are derivatives of 3-, 4- and 5-phenylsalicylamides; Chem. Ab., 70, p. 28655M discloses analgesic compounds which are salicylic acid derivatives; and U.S. Pat. Nos. 3,219,528; 3,177,252; and 3,312,739 disclose 3-substituted 2-diethylaminoethyl benzamide tranquilizers.
British Pat. No. 994,023 discloses dialkylaminoethyl derivatives of salicylamides of the formula: ##STR1## This patent further discloses that W can be (CH.sub.2).sub.2, R.sub.1 and R.sub.2 can be CH.sub.3, Z and Y can be H and that X can be chlorine.
The present invention is directed to 3-substituted salicylamides, having prolonged analgesic or antinociceptive activity. The salicylamides and pharmacologically acceptable, non-toxic salts thereof, are represented by the formula: ##STR2## R can be; methallyl, isopropyl, allyl, t-butyl, n-butyl and isobutyl.
These compounds exhibit good analgesic activity and a longer duration of such activity when compared to structurally similar prior art compounds.
The compounds described and claimed are effective in treating algia by producing an analgesic effect, i.e., reduction of pain, in an individual.
The term "individual" as utilized in this specification means a human being or an experimental animal that is a model for a human being. Medical indications for the use of the analgesics of the present invention are any conditions in which it is desired to treat algia in an individual. Although the amount will vary from individual to individual and from indication to indication, it is easily determined by one skilled in the art without undue experimentation. Dose forms for administration of the analgesic can be prepared by recognized methods in the pharmaceutical sciences.
The compounds of the present invention can be prepared by the methods described hereinafter and designated as Method A and Method B.
Method A [See J. Org. Chem., 15, 232-236 (1950)] involves mixing together potassium carbonate and a substituted phenol in about a 2:1 to 3:1 molar ratio of carbonate/phenol, and heating in the presence of CO.sub.2. The pressure can vary between about 100 and 1580 psi; the temperature can vary between about 110.degree. and 250.degree. C. A high yield can be obtained at a temperature of 125.degree. for 8 hours at a pressure of about 250 psi. Pressures as low as 100 psi can be used when operating at higher temperatures, e.g. 175.degree. C. The substituted salicylic acid formed is dissolved in hot water and unreacted phenol removed by extraction with ether. The substituted salicylic acid is obtained by precipitation with an acid, e.g., concentrated HCl. The substituted acid can be dried in an oven, or extracted with ether, dried over MgSO.sub.4 and evaporated.
The substituted salicylic acid intermediate is then esterified in the carboxyl group by treating the acid with a mixture of absolute methanol and boron trifluoride and the reaction mixture heated to reflux [See J. Chem. Soc., 577 (1965)]. The esterification can be accomplished in high yield by using about two equivalents of commercially available boron trifluoride-methanol complex in an excess of methanol, e.g., about two equivalents of the complex in an excess of about 5 volumes of methanol has been found to be satisfactory. Alternately, the esterification can be accomplished by standard organic chemical procedures involving the use of a methanol-dilute acid mixture, e.g., CH.sub.3 OH/HCl.
The reaction mixture, containing the esterified salicylate compound is then added to a saturated solution of sodium bicarbonate and extracted with an organic solvent, such as ether, dried and evaporated. The extracted salicylate, usually present as an oil, is crystallized or chromatographed by standard techniques. For example, the oil can be crystallized from methanol or can be chromatographed on silica gel.
The salicylate obtained is then converted to the desired salicylamide by refluxing with N,N-diethylethylenediamine in about a 1:1 ester/amine molar ratio. [See U.S. Pat. No. 2,810,718 and CA 52, 2918a].
The method described is shown schematically below: ##STR3##
The compounds of the instant invention can also be prepared by Method B [See J. Am. Pharm. Assoc. Sci. Ed., 41, 155 (1952)] which involves refluxing together a mixture of granulated sodium, a solvent such as dry xylene, and a substituted phenol while continuously bubbling carbon dioxide through the refluxing mixture. The phenol/sodium molar ratio can be from about 2:1 to 3:1. The granulated sodium is added in small amounts while the mixture is refluxing, over a period of about 1 to 3 hours, while a continual stream of dry carbon dioxide gas is bubbled into the reaction mixture. The reaction mixture is then refluxed for about 9 hours or, if convenient, overnight. After cooling, sufficient water is added slowly to destroy any excess sodium present; the substituted salicylic acid intermediate can be recovered, esterified and amidated as described in Method A hereinbefore.
The method described is shown schematically below: ##STR4##
US Referenced Citations (6)
Foreign Referenced Citations (4)
| Number |
Date |
Country |
| 1313758 |
Nov 1962 |
FRX |
| 395959 |
Jul 1965 |
CHX |
| 862721 |
Mar 1961 |
GBX |
| 994023 |
Jun 1965 |
GBX |
Continuation in Parts (1)
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Number |
Date |
Country |
| Parent |
753645 |
Dec 1976 |
|
Patent Grant
4140769
