US3532704A - Anesthetic butoxydimethylbenzamides - Google Patents
Anesthetic butoxydimethylbenzamides Download PDFInfo
- Publication number
- US3532704A US3532704A US759505A US3532704DA US3532704A US 3532704 A US3532704 A US 3532704A US 759505 A US759505 A US 759505A US 3532704D A US3532704D A US 3532704DA US 3532704 A US3532704 A US 3532704A
- Authority
- US
- United States
- Prior art keywords
- butoxy
- methyl
- solution
- compound
- dimethylbenzoylamino
- 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 - Lifetime
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Classifications
-
- 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
- C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/36—Radicals substituted by singly-bound nitrogen atoms
- C07D213/40—Acylated substituent nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
- C07D207/09—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/02—Preparation by ring-closure or hydrogenation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
- C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
Definitions
- This invention relates to anesthetic agents, and particularly to butoxydimethylbenzamides and salts thereof which have anesthetic effects.
- piperidine and pyrrolidine bases of the formula and their salts with physiologically tolerated acids are safe and effective anesthetic agents, X in the formula being N-methyl-Z-piperidyl, N-methyl-3-piperidyl, or N- methylpyrrolidyl.
- the bases and salts are strongly neurotropic even when applied to living organisms in minute concentrations, and are therefore useful in local anesthesia, particularly as surface anesthetics. Their etfects in surface anesthesia are greatly superior to those of chemically similar known anesthetics in comparable dosage.
- the hydrochloride of l-N-methyl- 2-(4' butoxy 2,6' dimethylbenzoylamino) methylpiperidine (Compound I) in 2.5 millimolar solution in Tasaki-Ringer solution has the same reaction blocking eifect on the isolated frog nerve as a millimolar solution of the known anesthetic agent w-diethylamino-2,6- dimethylacetanilide, (Compound IV, Lidocaine) as the hydrochloride, both solutions having a pH of 7.4.
- Toxicities were determined for Compounds I and III to VI by applying solutions of the several hydrochlorides in Ringer solution to mice by intravenous injection (i.v.), intramuscular injection (i.m.) or intraperitoneal injection (i.p.).
- the median lethal dosis DL was calculated from deaths within 12 days by the method of Litchfield and Wilkoxon. Eight white mice having a weight of 18 to 24 g. were used for each set of conditions.
- the duration of anesthesia in rabbit corneas was determined by the method of Regnier-Hotovy by measuring the elimination of the lid closing reflex. Solutions of the hydrochlorides of the six compounds listed above in Ringer solution were instilled in the connective tissue bag at the eye and permitted to act on the cornea for two minutes. The eye was then washed with much physiological saline solution. The lid was touched with a rabbit whisker twenty times at a rate of twelve contacts per minute and the presence or absence of the reflex was observed. The results are listed in Table II. The relative effectiveness of the several compounds was calculated, assigning to Lidocaine (Compound IV) a value of 1.
- the reaction time of untreated rats to the applied heat was 2 to 4 seconds. An extension of the reaction time to at least 30 seconds was considered indicative of anesthesia.
- the minimum concentration of active agent which produced anesthesia in 50% of the test animals was determined.
- Compound IV was compared with Compounds I to III (values listed in Table III without parentheses).
- Compound IV was compared with Compounds V and VI (values in parentheses). Because of ditferences in experimental technique between the two sets, their results cannot be compared directly.
- the values for relative effectiveness, derived from the concentration figures by assigning a value of 1 to Compound IV are not significantly affected.
- Nerve endings in the third distal region of blackened rat tails were blocked by infiltration with 0.4 ml. of the several anesthetic solutions, the infiltrated region was exposed to the afore-described electric lamp, and the minimum concentration producing anesthesia in 50% of the animals (CE was determined in two series of tests as described with reference to Table III.
- the compounds of the invention compare favorably in their toxicity with the known anesthetic agent Lidocaine (Compound IV).
- the known Compounds V and VI are more toxic than Lidocaine.
- the anesthetic effects of the compounds of the invention are superior to Lidocaine in equal concentrations, superior in most tests to the known Compounds V and VI in equal amounts, and superior or equal under all tested conditions at equal toxicity.
- the superiority of the butoxydimethylbenzamides of the invention over all tested known compounds is particularly great in surface anesthesia.
- the base compounds of the invention are readily prepared in good yields.
- the salts, whose anesthetic effects are approximately equal to those of the bases in equimolecular amounts, are obtained from the bases in a conventional manner.
- 4-butoxy-2,6-dimethylbenzoic acid or a reactive derivative thereof, as described above, may also be condensed with an aminomethylpyridine or an aminomethylpyrrol of one of the formulas to the corresponding amide, whereupon the heterocyclic ring of the product is hydrogenated. Hydrogen attached 4 to the nitrogen atom of the ring may be replaced by methyl prior to or after hydrogenation.
- EXAMPLE 1 300 g. N-methylpyridinium-2-aldoxime iodide were suspended in a mixture of 65 ml. glacial acetic acid and 600 ml. water, and hydrogenated at a gage pressure of 1 to 2 atmospheres in the presence of a catalyst mixture of 30 g. 5% platinum on carbon and 30 g. 5% rhodium on carbon. The hydrogenation reaction was exothermic. More than 0f the hydrogen theoretically required was consumed after about 3 hours, and more than after about 8 hours. I
- the contents of the hydrogenation vessel were then filtered to remove the catalyst, and the filtrate was evaporated to dryness in a vacuum.
- the residue was dissolved in a large excess of concentrated sodium hydroxide solution, and 1-N-methyl-2-aminomethylpiperidine was extracted with ether from the alkaline medium.
- the compound was obtained from the dried ether extract by distillation as a liquid boiling at 101-102 C. at 55 mm. Hg. The yield in several runs was between 89 and 105 g. (56-72%).
- the compound which is a base, also dissolves in aqueous solutions of stoichiometric amounts of strong acids, such as hydrochloric acid, sulfuric acid, hydrobromic acid, oxalic acid, or fumaric acid, and the corresponding salts can be recovered from the aqueous solutions by careful vacuum evaporation.
- the acid oxalate identified as having the formula C H N O melts at 94 C. It dissolves in very small amounts of water.
- the above condensation reaction is readily modified in a known manner to substitute free 4-butoxy-2,6-dimethylbenzoic acid, its anhydride, or its ethyl ester for the acyl chloride in the reaction with N-methyl-Z-aminomethylpiperidine.
- the yields are not quite as high, and the acyl halides are therefore preferred, the bromide being as useful as the chloride.
- EXAMPLE 2 36.1 g. 4-butoxy 2,6 dimethylbenzoyl chloride dissolved in 70 ml. chloroform were added dropwise with agitation to a solution of 33.6 g. Z-aminomethylpyridine in 180 ml. chloroform. The reaction was terminated two hours after mixing was completed. The chloroform was distilled oflf, and the residue was taken up in water and ether. The ether phase was repeatedly washed with water, dried, and evaporated to dryness.
- EXAMPLE 3 72.2 g. 4-butoxy 2,6 dimethylbenzoyl chloride (0.3 mole) were dissolved in 140 ml. pure chloroform, and the solution was added dropwise with stirring to a solution of 67.2 g. 3-aminomethylpyridine (0.62 g.) in 220 ml. chloroform While the heat of reaction was absorbed in ice water. The reaction mixture was evaporated to dryness in a vacuum and further worked up as described in Example 2 to produce 72.6 g. crude 3-(4'-butoxy-2,6'- dimethylbenzoylamino)-methylpyridine (79% yield). The compound boiled at 190 to 196 C. at 0.2 mm., and it had a melting point of 73 -74 C. when recrystallized from diisopropyl ether.
- the crude base was purified by passing its ether solution over a chromatographic column packed with aluminum oxide.
- the column was washer with ether, and the combined ether solutions were carefully evaporated, whereby 15.1 g. of a crystalline material were obtained (66.5% yield).
- the crystals sintered at 805 C. and melted at 81-82 C.
- the compound was identified by its equivalent weight, determined as 334.2 (calculated for C H N O 332.47).
- l-N-methyl 3-(4' butoxy 2', 6' dimethylbenzoylamino)-methylpiperidine is insoluble in water, but dissolves readily in aqueous solutions of strong acids and in all usual organic solvents.
- EXAMPLE 4 120.4 g. 4-butoxy-2, 6-dimethylbenzoyl chloride were dissolved in 150 ml. chloroform, and the solution was stirred drop by drop into a solution of 62.8 g. l-N- methyl-3-aminomethylpyrrolidine. The reaction mixture was stirred at ambient temperature for several hours, partly evaporated in a vacuum, and shaken with 400 ml. 2.5 N sodium hydroxide solution and much diethyl ether until two distinct phases formed. The ether phase was washed with water, dried, and evaporated, and the residue was purified by high-Vacuum distillation.
- the salts of the base are formed by dissolving the base in stoichiometrically equivalent solutions of strong acids and evaporating the water in a vacuum.
- the acid oxalate melts at about 92 C., the acid fumarate at about C.
- the salts very readily dissolve in water and also in the lower alkanols.
- hydrochlorides of the several bases of the invention are preferred for use in injectable solutions, but other physiologically tolerated acids may be combined with the bases.
- Aqueous solutions containing 0.25% to 2% of the free bases in the form of the hydrochlorides and enough of a disodium phosphate/monopotassium phosphate buffer to adjust the pH to 6 have been used successfully.
- the free bases may be employed in surface anesthesia, using dispersions or solutions in fatty ointments or in oily solution as is conventional in pharmacy.
- the salts are preferably applied to the skin or to mucous membranes in aqueous solution containing up to 5% of the active agents of the invention.
- a substance having anesthetic effects said substarlice being a piperidine or pyrrolidine base of the formu a:
- G-T-TODD,ASSiStaIltEXaminel substance is 1-N-methy1-3-(4'-butoxy-2',6-dimethylbenzoylamino)-methy1piperidine or a salt thereof with said acid. 10 260326.3;424-267, 274
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Hydrogenated Pyridines (AREA)
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CH1472667A CH487145A (de) | 1967-10-20 | 1967-10-20 | Verfahren zur Herstellung von neuen Butoxy-dimethylbenzamiden |
Publications (1)
Publication Number | Publication Date |
---|---|
US3532704A true US3532704A (en) | 1970-10-06 |
Family
ID=4403338
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US759505A Expired - Lifetime US3532704A (en) | 1967-10-20 | 1968-09-12 | Anesthetic butoxydimethylbenzamides |
Country Status (9)
Country | Link |
---|---|
US (1) | US3532704A (xx) |
BE (1) | BE722579A (xx) |
BR (1) | BR6803205D0 (xx) |
CH (2) | CH488691A (xx) |
DE (1) | DE1803569A1 (xx) |
ES (1) | ES359321A1 (xx) |
FR (2) | FR1603755A (xx) |
GB (1) | GB1218793A (xx) |
SE (1) | SE332637B (xx) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4035373A (en) * | 1976-02-23 | 1977-07-12 | The University Of Toledo | Preparation of piperidinyl-alkyl-benzamides |
US4069224A (en) * | 1973-12-26 | 1978-01-17 | The Upjohn Company | Novel benzamides |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5254569A (en) * | 1991-01-14 | 1993-10-19 | The Du Pont Merck Pharmaceutical Company | (Amidomethyl)nitrogen heterocyclic analgesics |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB877846A (en) * | 1959-02-07 | 1961-09-20 | Laeaeketehdas Orion Oy | Improvements in or relating to the preparation of aromatic ortho-disubstituted acid amides and salts and quaternary ammonium compounds of said acid amides |
-
1967
- 1967-10-20 CH CH101570A patent/CH488691A/de not_active IP Right Cessation
- 1967-10-20 CH CH1472667A patent/CH487145A/de not_active IP Right Cessation
-
1968
- 1968-09-12 US US759505A patent/US3532704A/en not_active Expired - Lifetime
- 1968-09-20 SE SE12696/68A patent/SE332637B/xx unknown
- 1968-09-25 GB GB45490/68A patent/GB1218793A/en not_active Expired
- 1968-10-16 FR FR1603755D patent/FR1603755A/fr not_active Expired
- 1968-10-16 FR FR170048A patent/FR7864M/fr not_active Expired
- 1968-10-17 BR BR203205/68A patent/BR6803205D0/pt unknown
- 1968-10-17 DE DE19681803569 patent/DE1803569A1/de active Pending
- 1968-10-18 BE BE722579D patent/BE722579A/xx unknown
- 1968-10-18 ES ES359321A patent/ES359321A1/es not_active Expired
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB877846A (en) * | 1959-02-07 | 1961-09-20 | Laeaeketehdas Orion Oy | Improvements in or relating to the preparation of aromatic ortho-disubstituted acid amides and salts and quaternary ammonium compounds of said acid amides |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4069224A (en) * | 1973-12-26 | 1978-01-17 | The Upjohn Company | Novel benzamides |
US4035373A (en) * | 1976-02-23 | 1977-07-12 | The University Of Toledo | Preparation of piperidinyl-alkyl-benzamides |
Also Published As
Publication number | Publication date |
---|---|
SE332637B (xx) | 1971-02-15 |
DE1803569A1 (de) | 1969-06-19 |
CH487145A (de) | 1970-03-15 |
ES359321A0 (es) | 1970-06-01 |
BR6803205D0 (pt) | 1973-03-08 |
FR1603755A (xx) | 1971-05-24 |
BE722579A (xx) | 1969-04-18 |
ES359321A1 (es) | 1970-06-01 |
CH488691A (de) | 1970-04-15 |
GB1218793A (en) | 1971-01-13 |
FR7864M (xx) | 1970-04-27 |
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