JPS59501461A - N-alkyl-4'-hydroxyacetanilides, pharmaceutical compositions containing them and their uses - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] N-alkyl-4゛　-hydroxyacetanilides, pharmaceutical compositions containing them and and their uses Kimitsu Gai ■Gimi 1. Honyosho ■ Branch The present invention has analgesic, antipyretic, anti-inflammatory and sedative activity, but N-alkyl-4゛　-hydroxyacetic acid that does not have the nephrotoxicity and hepatotoxicity of Novel pharmaceutical compositions containing toanilides. The invention further provides for administration of these compounds. The present invention relates to a method for alleviating pain by giving.

2. Touji skin Acetaminophene (valacetamol) has been reported in the literature since 1966 for its hepatotoxicity. However, it is increasingly being recommended for therapeutic use as an analgesic. Continuous ingestion of large amounts over a long period of time has been shown to cause extensive liver necrosis. A, J , Ware et al, Annals of Internal Medicine ine 88: 267-268 (1978); D, M, Rosen berg, F.A.

: 302-303 (1977). Individuals with liver damage or disease should use acetaminol. Phen medication was found to be particularly susceptible to hepatotoxicity. D.M.

1? osenberg et al, 5othern Medical Jo urnal 70: 600-601 (1977); H, L, Bonk owsky et al, Lancet 2: 1016-1018 (1 978); V.

5choenfelf et al, New En 1 and Journal of Medicine 303: 47 (1980); D, P, G olden et at, 0ral Sur er 51: 385-389 (1981).

In addition, conditions that induce liver enzymes responsible for acetaminophen metabolism, such as alcohol Consumption of chole or barbyrates can significantly enhance the hepatotoxicity of this compound. Probably.

9-541 (1978). Also, acetaminophene has recently been linked to a possible human carcinogen. They are related as substances. M, 1. Mihatash et a’l, Sc Medizonische Wochenchrif t 110:225-264 (1980), thus the public and prescription Acetaminophen, a ubiquitous component of the drug, is known for its liver and other toxic effects. The effects pose a significant risk to the general user and susceptible user population. obtain.

The mechanism of acetaminophene toxicity has not been completely elucidated in the prior art. Ed itorial, Lancet 2 = 1189 (1975); B, E, Walker etal, C11nical 5science & Mo 1ecular Medicine 47: 449-459 (1974) .

However, recent studies discussed below show that acetaminophen is a common metabolite. suggesting the involvement of certain liver enzymes that convert There is.

UK Patent Application No. 2. ．． No. 040.164 and U.S. Pat. No. 4,292,293 (assigned to Beecham, Group, Limited) are both combined with ascorbic acid. Composition for reducing acute hepatotoxicity of acetaminophen by oral administration of a combination formulation and how they claim it. The US patent describes a non-extended release form of ascorbic acid 30 0■/kg has no protective effect against 450■/kir (oral) of valacetamol. However, the same amount of ascorbic acid in sustained release form had a substantial protective effect; It is disclosed that 600-w1/kg had a larger effect.

However, in human experimental studies, vitamin C has been shown to be associated with acetaminophen. produced a rapid and significant decrease in the excretion rate of sulfate, but itself in the urine. or by its excretion rate as glucuronide or its sulfate. It was proven that the drug's appearance did not affect its half-life. J, B, Housto n, G, Levy, Journalof Pharmaceutical 5science 65: 1218-1221 (1976), acetamino The specific reaction between phene and ascorbic acid occurs under normal conditions, i.e. acetaminof When the drug is administered as an analgesic or antipyretic in a single recommended dose, it is likely that It is stated that it is not clinically significant.

Other researchers believe that the protective effects shown by these vitamins are due to vitamin E and Propyl gallate is an antioxidant in vitro, although it reduces hepatotoxicity. and diphenyl-p-phenylenediamine, which confers protection against Cα4 hepatotoxicity. C0DPD) enhance acetaminophen hepatotoxicity, so their antioxidant activity It is concluded that no attribution can be made. Kelleher et al supra . These authors suggested that the modification of hepatotoxicity may be due to changes in the activity of specific components of the granular drug-metabolizing enzyme system. It is assumed that this may occur.

Surprisingly, and published literature suggests that certain antioxidants include aceminophene. Despite reports that it may provide protection against the hepatotoxic effects of is the ubiquitous BIT (butylated hydroxyl) used to prevent food spoilage. toluene) and BHA (butylated hydroxyanisole) have significant hepatotoxicity. I discovered that it strengthens the Their presence in a wide variety of foods makes it difficult for the general population to Since large amounts of these drugs are ingested every day, acetaminophen is often taken continuously. The risk of increased frequency of hepatotoxicity in people with cancer is self-evident.

Other approaches to reducing acetaminophen medication hepatotoxicity have also been considered. example For example, a press release states that N-acetylcysteine should be administered within 16 hours of an overdose. The Me reported a clinical study showing that it is effective in preventing liver toxicity if I quoted the announcement of the dical Letter. Akira Saigaki (Dachi Uyo 1979) December 7th, A9 page. The author focuses on glutamate, a substance that the body uses to detoxify drugs. N-acetylcysteine was chosen because of its chemical similarity to thione.

Dimethyl sulfoxide (DMSO) after administration of acutely toxic doses of acetaminophen When administered within 1 hour, mice were protected against the hepatotoxic effects of acetaminophen. showed protection. C, P, Seigers, Journal of Ph. armacolo 30: 375-377 (1978), its activity is Granule oxidation of drugs by the hepatic mixed-function oxidase system with chemically active alkylating agents. was attributed to the inhibition of On the other hand, this theory suggests that DMSO is effective against CO24 hepatotoxicity in mice. cannot explain why it is impossible to protect Kedashiko compounds are also mixed-function oxidative enzymes. This is because it is activated by the elementary system. Acetaminophen anti-liver in DMSO A mechanism of toxicity could not be provided.

Based on the above, there are no effective methods to protect humans against acute acetaminophen hepatotoxicity. It is clear that this has not been established by technology.

Additionally, acetaminophen is more effective than simply administering acetaminophen at the same time as a reducer. It may be preferable to allocate the use of the button itself.

Like many other toxic compounds, once acetaminophen begins to cause hepatotoxicity Once the mechanism is elucidated, the potential for human health from acute and chronic exposure to this drug will be risks can be better screened and avoided.

The risk of M liver damage is due to the use of acetaminophen and cytochrome P-450 (=acetaminophen). It is possible to induce the enzyme S) responsible for converting nophene into its toxic intermediate. Higher in patients taking concomitant drugs with known drugs. N. Buchanan + G, P, Moodley', Br1tish Medical Jou rnal2:307-308 (1979); N, Wr’i’ght, L”, F, ^rthurs, J, F, Fielding.

Journal of the Ir1sh Medical As5ocia tion 73: 273-'274 (1980).

Therefore, hepatotoxicity caused by acetaminophen administration is more pronounced due to chronic use of ethanol. It is not surprising that the increase in D, J, Emby, B, N.

Fraser, 5outh African Medical Journal l 51: 208-209 (1977); R, Goldfinger et al, American Journal of Ga5trolo 7Q: 385-388 (1978); C, J, McCiain e t al, Journal of the American Medical As5ocation 224:251-253 (1980); H, Light et al.

Annals of the Internal Medicine 92: 511 (1980).

Currently, over 300 genes have been shown to induce cytochrome P-450. drugs have been used, thereby enhancing the hepatotoxicity of acetaminophen. It must be. For example, phenol, a well-known cytochrome P-450 inducer, Barbital is an effective and widely prescribed drug for some types of epilepsy It is a drug. Therefore, chronic use of acetaminophen by individuals with grand mal seizures is contraindicated. Should. Tobacco is also known to induce cytochrome P-450; In 973, Mt tchel 1 and co-workers discovered that acetaminophen Published a series of papers on the subject. J. R. Mitchell et al.

HaμmaI　bμ! Parallel rank I and snoring stop” Company crime 1 cod swordsmith IT, hdan fallen friend and Uri E 187:185-194 (1973); D, J, Jollow et. al, Journal of Pharmacolou-andExe r’mental Thera eutics 187: 195-202 (1973); W, Z.

Potter et al, Journal of Pharmacolo and Ex erimenta11ha anal and abdominal string competition 187':'203-217 (1973). However, the nature of this metabolite and the fact that acetaminophen is As a result, no mechanism for initiating hepatotoxicity was established.

Initially, cytochrome P-450 converts acetaminophen into N-hydroxyacetaminophen. oxidation to phene, which loses water to form the hypothetical intermediate N-acetyl-p-benzo. It was proposed that it would provide quinone imine.

(GSH) to produce 3-(glutathione-8-yl)-acetaminphen. You can detox by responding. J, A, Hinson et al+ Loss ■Met abolism Dis position 10: 47-50 (1982 ) o When GSH is depleted, this quinone imine becomes a cellular macromolecule. join to. -1Z, Potter et al+ Phaa+acolo 12: 129-143 (1974) e Based on these findings, N-A An intracellular macromolecule of cetyl-p-benzoquinone imine was proposed. Potter et alfi. J, A, Hins6n et al, Life 5science 24:2133-2138 (1979): S. D. Nelson et. 　Al、Biochemical anal bile parallel ■29: 1617-1f320 (1980) has cast doubt on this aspect of the mechanism. These studies If biosynthesized by a route that does not include N-acetyl-acetaminophen, showed that.

An alternative hypothesis is that the formation of N-acetyl-p-benzoquinoneimine is unsuccessful. Imagine epoxidation of acetaminophen followed by ring opening with loss of water. If like this If the mechanism is correct, the addition of heavy oxygen (0”2) to the reaction mixture will result in Nr acetyl- This would lead to the incorporation of O]8 into half of the p-benzoquinone imine. But long When conducting such studies, researchers found that none of the acetaminophen metabolites 0]8 could not be detected. S, D, Nelson et al, l; J , A, former n5onet al, Dru Metabolism Dis os ition 8: 289-294 (1980).

The third mechanism is that cytochrome P-450 initiates one-electron oxidation of acetaminophen. It is suggested that aceminophen free radicals are produced. S, D, ~el son et al, Mo1ecular Pharmacolo 20: 195-199 (1981). This transfer of electrons from free radicals to oxygen is , superoxide free radical and N-acetyl-p-benzoquinone will produce min. Such a hypothesis and this reaction pathway in hepatotoxicity Participating support is given to the electronic properties of acetaquinophene as a hypothesized toxic intermediate. This comes from the observation that all of the compounds can be oxidized to free radicals that exert their effects. S, D. Nelson et al.

Hadan Seiyuan Shiha Rainbow Next Day ■ 20: 195-199 (1981). Liver toxicity J = possibility of radical mechanism is promethazine 3, which is a free radical scavenger ^,E,M,McLean,L,Nuttall,Biochemic al Pharmacolo 21:425-430 (1979); Gluta Thione, M, 5trolin-Beneditte et al+Jour nal of Pharmaceutics and Pharmacolo 27:629-632 (1975) lA, RlBurkitt et al. , Biochemical Pharmacolo 28: 2941-29 46 (1979); and β-dimethylaminoethanol, C, P, Si egerS+M, Young, Arzneimittel Forschu na 29: 520-523 (1979) on acetaminophene toxicity. further supported by proof that it achieves protection.

I believe that acetaminophen medication chronic and acute toxicity is due to the following mechanisms: This may be due to the generation of superoxide free radicals. I discovered that.

Acetaminophen was initially converted into acetaminophen by cytochrome P-450. It is metabolized by being converted to lee radicals. This toxic free radical It is oxidized to N-acetyl-p-benziquinone imine, and the imine is absorbed into glucose in the liver. It is converted to glutathione-acetaminophenthioether by tathione. excluded by. N-acetyl-p- of acetaminophen free radical Oxidation to henzoquinone ions is eliminated by peroxidase enzymes. H Generates toxic superoxide free radicals which are disproportionated to 2O2. deer However, when the N-on concentration generated by this mechanism is insufficient1, it can be reconverted to acetaminophene free radicals by reductases. , thus generating additional toxic superoxide free radicals. acetami This cyclical regeneration of nophene free radicals Generates enough superoxide free radicals to overwhelm dodismutase , thereby enhancing hepatotoxicity through lipid peroxidation.

In my U.S. Patent No. 4,314,989, I am free of toxic acetaminophen. methionine to destroy the radical before it has a chance to react with oxygen. Methods for preventing acetaminophen-induced hepatotoxicity by using Phoxide and A composition is disclosed.

The present invention relates to certain types of N-alkyl-4'-hydroxya-! ! l-Arid The compound produces radicals with analgesic activity comparable to acetaminophen. In some embodiments, it is not metabolized by hepatic enzymatic reactions.

Some members of this genus are covered by British patents 749,907 (1956) and is disclosed as a starting material for other compounds. 0 in 1894. old ns berg, G, Treuple, Archives of Ex eri mental ha holo and Pharmacolo 33:’216 -250 (1894) c. Many 77) Synthesized mono-amide phenols; Their antipyretic and analgesic activities were investigated. Among the compounds tested was N-ethyl -4”-Hydroxyacetanilide. In this paper, the authors However, they provided data on the antipyretic activity of this compound. I concluded that there was no. He also reported, without supporting data, that N-ethyl-4゛　- He said hydroxyacetanilide has no analgesic effect. This is recognized This is the opposite of my findings using the plate analgesic model. In the same year, N-E A, M, H’och for the synthesis of thyl-4゛　-hydroxyacetanilide German Patent No. 79°098 was granted to st. This patent indicates that it has utility. The product may be useful as a medicine without specifying the conditions and methods of use under which it may be used. It states that there is. In 1899, the former NSBERG .

305:276-289 (1899) found in his 1894 paper. A more detailed synthesis of N-ethyl-4'-hydroxyacetanilide than announced the establishment of This paper does not discuss biological activity.

The object of the present invention is to provide a drug that has the analgesic activity of acetaminophen, but is non-hepatotoxic. To provide novel pharmaceutical compositions and methods for their use. It is. Another purpose is to prepare novel N-alkyl-4゛　-hydroxyacetanilides. It is to provide.

Honkohada Summer Retirement I In terms of composition, the present invention provides a pharmaceutically acceptable carrier in unit dosage form. In a mixture with the body, the formula % formula % Analgesic efficacy of acetanilide compounds (wherein R is alkyl of up to 8 carbon atoms) per unit dose.

Such compositions are preferably taken orally, most preferably as tablets or It is in the form of a capsule.

In other composition aspects, the present invention provides N-isopropyl-4''-hydroxyacetic acid Novel N-alkyl-4゛　-hydroxyacetanilides, including toanilides Regarding seeds.

In terms of methods of use, the present invention provides for the analgesic effects of the compositions of the present invention on humans suffering from pain. The present invention relates to a method of pain relief comprising administering an effective amount.

In a second method of use, the present invention provides a method of administering the acetaniline of the present invention to a human with a fever. The present invention relates to a method for alleviating fever, which comprises administering an effective amount of antipyretic.

In another method of use, the present invention provides a method of administering an acetate of the present invention to a human having a systemic inflammatory condition. A method of reducing a systemic inflammatory condition comprising administering an anti-inflammatory effective amount of toanilide Regarding.

In yet another method of use, the present invention provides sedation of the acetanilides of the present invention in humans. A method of sedating a human comprising administering a statically effective dose.

dwarf To be commercially acceptable for use by the general public, an analgesic and antipyretic compound must be Fat must be non-toxic. i.e. is it in its therapeutic dose? It should also have virtually no significant toxic effects.

Q) It must be stable. i.e. single-use drug forms, i.e. tablets, caps. in cells, pills, elixirs and other aqueous vehicles for at least 6 months, preferably have a fly life of at least 1 year, and more preferably at least 2 years. Two.

(C) Must be non-volatile. i.e. exhibits significant vapor pressure under environmental conditions. It should not be liquid or preferably solid.

! There must be virtually no DL symptoms. i.e. people who take painkillers The patient does not develop any significant symptoms that may be of benefit to the patient.

tel liver non-hepatic toxicity. That is, its metabolism is toxic in the liver. Does not result in the formation of sulfur peroxide free radicals or other toxic metabolites.

N-alkyl-4”-hydroxoacetanilide used in the composition of the invention The compound meets all of the above criteria. In addition to their analgesic activity, these compounds It is an effective antipyretic at the same dosage.

have systemic anti-inflammatory activity and, at high doses, sedative activity.

In the compounds of the present invention, the acetamide nitrogen atom preferably Attaches 2 to 8 carbon atoms that block metabolic conversion to cetaminophene metabolites. It has a lukyl group. An example is that R is ethyl, or each straight or branched chain Polymers such as propyl, butyl, amyl, hexyl, heptyl or octyl -Bonalkyl compound. As mentioned above, although not preferred, R is Methyl may also be used.

The compounds of the present invention can be used as is, or when particularly high water solubility is desired, with a strong Na or K1 concentration. It can be used as its salt, such as a base. These salts convert the free acid into hydroxyl by mixing with an aqueous solution of molar equivalents of sodium or potassium Mol of hesodium or potassium ethoxide in solution of free acid in anhydrous organic solvent It can be produced by adding an equivalent amount.

Contemplated equivalents of the compounds used in the compositions of the invention include the toxic acetate of the compounds. Compounds with other R groups that block metabolic conversion to minophene metabolites. So The blocking activity of the group is more important to the present invention than the exact chemical structure of Therefore, those skilled in the art will know that other examples of R groups include high carbon atoms, such as 9 to 16 carbon atoms. cycloalkyl, cyclopropyl, cyclopentyl and cyclohexyl. Other hydrocarbon groups such as chloroalkyl, and their unsaturated analogs. one Generally speaking, the latter is less desirable. In addition, the N-hydrocarbon group also It is possible to have simple substituents that do not interfere with the analgesic activity of the compound. Compounds of the invention In order to become nephrotoxic and hepatotoxic, such as in Converted in vivo to acetaminophen and then metabolized to toxic free radicals. must be In the case of N-methyl-4゛　-hydroxyacetanilide, This compound must be N-methylated to produce acetaminophen. stomach. Demethylation of amines is not very difficult, but demethylation of amides (in this case De-N-methylation of , only limited amounts of acetaminophen are produced. In this way, acetamino Smaller amounts of toxic metabolites are ultimately produced than when feeding phene directly. N -Methyl-4°-Hydroxyacetanilide is used for analgesia with acetaminophen. Comparatively reduced - poses an increased toxicity risk, but the degree of protection is less when the alkyl is methyl of the larger N-alkyl-4'-hydroxyacetanilide compounds of the present invention. Less perfect than that.

The best known N-hypothesis methylation of amides in humans is diazepam. , which produces N-desmethyldiazepam. However, for example, N-ethyl oxidative N-ethylation for Ru-4'-hydroxyacetanilide. Cetaminophen is not produced.

Below are animal studies demonstrating the utility of the claimed compounds as painkillers.

It was used for the test. The untreated control group was incubated at a plate temperature of 54°C□. It took an average of 44 seconds to lick a foot. N-ethyl-4゛-hydro administered intraperitoneally dose of xyacetanilide (30 μ/kg) and 10 minutes later at 54°C. The test group that had their stomachs on the hot plate took an average of 64 seconds to lick their hind paws. Showed the time. The analgesic activity of this compound thus reduces the pain response time to almost 5. Increased by 0%.

Further experiments demonstrated the absence of hepatotoxicity of this compound compared to acetaminophen. Indicated. BBA, a strain known to be resistant to acetaminophen hepatotoxicity. Three groups of /2H mice received acetaminophen (400 μg/kg in aqueous vehicle), or N-ethyl-4゛　-hydroxyacetanilide (propylene glycol 500 tng/kg) or saline as a control group. I received it. (The acetaminophene LDIIXl dose is sensitive to certain mice. For example, in outbred Swiss Army mice, the weight is 400 kg/kg. Ru. ) No immediate symptomatic effects were observed in acetaminophene-treated mice.

Mice treated with N-ethyl-4°-hydroxyacetanilide had a sedative effect, i.e. Approximately 15 minutes later ■ Leg ataxia and approximately 25 minutes later a state of drowsiness, which is approximately 3 Lasted 0 minutes. Oral administration of the same compound at 600 μ/kg (aqueous vehicle, pH 12) Upon administration, mice fell asleep for approximately 25 to 40 minutes. 24 hours later , all three groups of mice were sacrificed. Histopathological examination of liver sections revealed control and N-ethyl-4゛〛　-hydroxyacetanilide group (i, p, and p.

0, both) did not show fatty changes and other signs of hepatotoxicity, but acetamine The nofen group showed significant hepatic necrosis (estimated 60% of the liver was necrotic). acetami The oral LDso of Nophene is approximately 400 ■/kg, with significant Hepatotoxicity is indicated. In a similar experiment, N-methyl-4°-hydroxyacetate Mice treated with anilide (400 μ/+r) showed pre-necrotic liver lesions and no protection. Proved the level of incompleteness.

The toxicity of N-isopropylacetaminophen ranges from 100 to 400 Mice were injected at various doses of ■/kg, i, p, and 24 hours later the animals killed and evaluated by measuring histopathology of the liver, kidneys, and lungs. I valued it. In all cases, no organs showed signs of injury.

Of interest is that at high doses (250-400 μ/kl, i, p,), It was discovered that all mice exhibited significant CNS sedation.

The higher the dose, the longer the sedation. Does this give the same sedative activity? Ma This was also found to be the case when mice were given the drug orally. this medicine The sedative effect of the drug is 30 minutes at 250■/kg, and the sedative effect at 400■/kg. It lasted for about 1.5 hours. At high doses, the mice fell asleep.

Once the mice recovered from this sedative effect, no further CNS effects were observed. Ta.

The analgesic properties of N-isopropylacetaminophyne were reported by Ankier (Eur, J. .

Pharmacol, 27: 1-4 (1974)). tested using a hot plate test. Two groups of 6 mice per group were used. .

The first group was placed individually onto a hot plate and the time required to lick the hindpaw was time was recorded and found to be 44 seconds (average) at 54°C. Ma The second group of mice each received 30 μ/kg (i,p,) of N-isopropylaceta. received minofene and was placed on a 54°C hot plate after 1o min. rear The time taken to lick the paw was measured and found to be 64 seconds (on average) Thus, the response time was increased by 50%.

1. The enemy of the deceased Compounds used in the claimed composition: It can be synthesized according to the following procedures. I also have N-ethyl and N-isopropyl hydroxyacetani and dimethylformamide (D) as follows. MF　50mI! , p-aminophenol 5 g' (0,0459 mol) To the solution was slowly added 8.67 ml (0,097 mol) of acetic anhydride. reaction mixture The mixture was heated at 60°C for 3 hours, then the crushed G' was poured onto ice. Zero solid precipitation did. The remaining liquid was extracted with chloroform, dried over anhydrous magnesium sulfate, Evaporated to dryness.

Pour the remaining liquid over crushed ice.) Solid force (precipitated. All solid matter The mixture was dried to obtain 5.5 g of 4''-acetoxyacetani IJ.

5 g (0,0259 mol) of 4-acetoxyacetanilide was added to dry tetrahydrofuranate. Solvent A was applied during run (T) IF) 200d. Add lithium aluminum hydride to this mixture. 1.97 g (0,0518 mol) of minium was added slowly over 1 hour. . After addition of this reagent, reflux for 3 hours, cool and drain saturated ammonium chloride solution. I added some ice cream. The resulting mixture was filtered, evaporated to dryness and the remaining oil was dissolved in dilute 1iC1. G. This solution was extracted several times with chloroform. Carbonate the remaining aqueous phase ) + Jum to make it basic so that it becomes pill O2, and then make it basic with chloroform. Extracted once. Dry the chloroform solution over anhydrous magnesium sulfate and evaporate to dryness. Ta. This acidic/basic extraction process is repeated several times, resulting in an oil that solidifies when left to stand. 2.2 g of p-ethylaminophenol was obtained.

Dissolve 2g (0,0146 mol) of p-ethylaminophenol in 50% DMF. Ta. To this, 2.98 g (0,0292 mol) of acetic anhydride was added and the oil was diluted with chloroform. Extracted, dried over anhydrous magnesium sulfate and evaporated to dryness leaving a residual oil. . To this oil was added 5% sodium hydroxide and the mixture was heated at 60° C. for 1 hour. melt The liquid was cooled and then extracted with chloroform. The remaining aqueous phase was brought to a pH of approximately 4 with dilute H&O. The mixture was acidified until dry and then extracted with chloroform. Liquid over anhydrous magnesium sulfate and then evaporated to dryness. Pour the remaining brown solid substance into an ethanol-water mixture. recrystallized from N-ethyl-4゛-hydroxyacetanilide (m, p, 18 3-185°C) was obtained.

According to the operation of Weight Hong 31: L901-1908 (1'1131)), N-I Sopropyl-p-hydroxyaniline, m, p,' 143℃ 1g (41% ) was obtained.

Dissolve 13.5 g of acetic anhydride (0.132 mol) in 50 d of acetic acid and add to this mixture 13.5 g of acetic anhydride (0.132 mol). ) was added. The reaction mixture was heated at 50° C. for 5 hours and poured onto crushed ice.

Sodium carbonate was added until the pH was approximately 8.5, then the solution was extracted with chloroform. The mixture was taken out, dried over anhydrous magnesium sulfate, and heated at 70°C for 5 hours. Mix after cooling Extract the substance with chloroform and add 10% HCl until the pH of the solution becomes 2 to 3. Acidified. The solution was then extracted with chloroform and dried over anhydrous magnesium sulfate. and evaporated to dryness to give N-isopropyl-4°-hydroxy-acetic acid as a white solid. 7.6 g (60%) of toanilide was obtained, which was recrystallized from water.

m, p, 152-153°C, 1. R, 3300-3200cm-' (OH) and by reacting equimolar amounts thereof with sodium hydroxide in water. Ta. The water was evaporated to dryness leaving the sodium salt as a solid and further dried. m, p , 52'54℃.

p-ethylaminophenol in the previous production example was replaced with other p-fulkylaminophenol. such as p-n-propylaminophenol, p~ -Octylaminophenol makes N-isopropyl-p-hyperoxypropyl Replacement of droxyaniline by another N-alkyl-p-hydroxyaniline Other N-alkylacetanilides used in the present invention by changing is generated. They follow the method described in British Patent 749.907 (1956). The disclosure of that patent is hereby incorporated by reference.

The acetanilides of the present invention are preferably mixed with a pharmaceutically acceptable carrier. It is preferably formulated in unit dosage form. The composition of the present invention provides , an analgesic effective amount of acetanilide of the formula given above, i.e., simple untreatable pain. Pain, such as pain that can be relieved with aspirin, acetaminophen or other antipyretic analgesics. Pain, such as headaches, arthritis, flu, colds, simple sprains, strains and other minor An effective amount to reduce minor trauma, for example, 2 for the smallest person (10 kg). 5■ (pediatric dose N) to 750■ (adult dose).

Preferably from 100 to 5 per unit dose, preferably per oral unit dose. Contains 00■. The compositions are available in sterile injectable powders and solutions, suppositories, buccal and and preferably oral dosage forms such as gunpowder, tablets, capsules, dragees, sweetened syrups. It can be in the form of soups and elixirs. Tablets, capsules and oral aqueous solutions is preferred. Preferred formulations are those commonly used by those skilled in the art of formulation. , most preferably those used for the administration of acetaminophene.

The acetanilide of the present invention is in an analgesic, antipyretic, antiinflammatory or sedative effective amount; It alleviates simple pain in people who suffer from simple pain, such as the one described above, and reduces the body temperature of people with fever. and reduce the symptoms of systemic terminal illnesses, such as arthritis, and is administered to a human in an amount effective to sedate the human. The sedative effect is substantially higher than the dosage required to achieve analgesic, antipyretic and anti-inflammatory effects . Although the present invention is primarily directed to the treatment of humans in its methods of use, it will be apparent to those skilled in the art that As mentioned above, the acetanilides of the present invention can be used in other mammals suffering from similar conditions. It can be administered to species or to sedate them. individual sushi The daily dosage rates are comparable to those commonly used for acetaminophen. do. The preferred dosage rate is about 5 ■/k+- to 15 ■/kg. oral When administered, the dosage rate is preferably 150 to 50 mg per dose for children. 00■, and for adults it is about 300 to 1000■ per dose, which is necessary. It is repeated up to about 6 times a day as needed. To obtain a sedative effect, use the minimum of the above range. About 3 to 5 times the value is generally required. To obtain surgical sedation, intravenous infusion is preferred. Other routes of administration of these compositions are readily available to those skilled in the pharmaceutical arts. those used, most preferably those used in acetaminophene. be.

From the above description, a person skilled in the art can easily ascertain the essential features of the invention and and adapt it to various uses and conditions without departing from its spirit and scope. Various changes and modifications can be made to the present invention to make it more flexible. Therefore, the following preference It should be understood that the preferred specific examples are merely illustrative and are not intended to limit the description in any way. It is.

Example 1 In the conventional manner, capsules or tablets or N-ethyl-4°-hydroxya Cetanilide or N-isopropyl-4°-hydroxyacetanilide 25 Fill capsules or make compressed tablets containing 0,350 or 500 μl.

For the relief of pain or fever or both, 1 to 2 doses 3 or 4 times for adults Administer capsules or tablets.

Example 2 N-ethyl-4”-hydroxyacetanilide per fluid ounce (30d) or N-isopropyl-4゛　-hydroxyacetanilide 500,750 or Prepare an alcoholic (8-2/1%) honey-scented sweet solution of Yo. 2/3 fluid ounce every 4 to 6 hours up to 6 times a day to reduce pain , or 1 fluid ounce up to 4 times per day.

Example 3 In a conventional manner, N-ethyl-4'-hydroxyacetanilide or N -Isopropyl-4°-Sugar-coated containing 80μ of hydroxyacetanilide Manufacture cracked chewable fruit-flavored tablets. 3 for children due to pain 1 or 2 tablets for children up to 1 year old; 2 or 3 tablets for children 4 to 5 years old; For children aged 9 to 12 years, a dose of 4 tablets may relieve pain or fever or both. Administer up to 3 or 4 times a day for relief.

Examples 4 to 11 The following have less frantic side effects than corresponding compositions containing acetaminophen. 1 is an illustration of a claimed composition of the present invention having a frequency.

(Margin below) Examples 12 to 22 Repeat each operation of the example procedure 11. However, the N-ethyl- or N-isopropyl-4”-hydroxyacetanilide in an equal amount of N-methyl Substitute with 4-hydroxyacetanilide. The resulting composition is as in Example 1. It is highly sensitive at higher doses and for longer periods of time than compositions used in the eyes or in the eye. 4) They are more likely to express rapture, but they are more susceptible to acetaminophene. It develops much less frenzy than a corresponding composition containing the same amount. Furthermore, that They have sedative and anti-inflammatory activity that acetaminophene-based compositions do not have. As such, they can be used if the latter is not available.

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Claims (1)

[Claims] ■ In unit dose form, H Analgesic acetanilide compounds (wherein R is alkyl of up to 8 carbon atoms) A pharmaceutical composition containing an effective amount per unit dose. 2. The pharmaceutical composition of item 1, wherein R is alkyl having 2 to 4 carbon atoms. 3. The acetanilide compound is N-ethyl-4゛-hydroxyacetanilide The pharmaceutical composition of item 2, which is. 4. The acetanilide compound is N-isopropyl-4゛-hydroxyaceto The pharmaceutical composition of clause 2 which is a nilide. 5. The pharmaceutical composition of item 1, which is suitable for oral ingestion. 6. The pharmaceutical composition of item 5 in the form of tablets or capsules. 7. The pharmaceutical composition of item 1 in the form of an aqueous solution suitable for oral ingestion. 8. The pharmaceutical composition of paragraph 1 in the form of a sterile aqueous solution suitable for parenteral administration. 9. The pharmaceutical composition of item 3, which is suitable for oral ingestion. 10. The pharmaceutical composition of paragraph 9 in the form of tablets or capsules. 11. The pharmaceutical composition of paragraph 4 in the form of a sterile aqueous solution suitable for parenteral administration. 12. The pharmaceutical composition of paragraph 4 in the form of tablets or capsules. 13. For humans in pain, in a mixture with a pharmaceutically acceptable carrier. ,formula Analgesic acetanilide compounds (wherein R is alkyl of up to 8 carbon atoms) A method for alleviating pain comprising administering an effective amount. 14. The method of item 13, wherein R is alkyl having 2 to 4 carbon atoms. 15. The acetanilide compound is N-ethyl-4”-hydroxyacetanilide The method of paragraph 13, which is 16, H acetanilide compound is N-isopropyl-4゛-hydroxyacetate The method of paragraph 13, wherein toanilide. 17. The method of paragraph 13, wherein the composition is suitable for oral ingestion and is administered orally. 18. The acetanilide compound is N-ethyl-4゛-hydroxyacetoani The method of paragraph 17, which is lido. 19. The acetanilide compound is N-isopropyl-4”-hydroxyacetate. The method of paragraph 17, wherein the anilide is an anilide. 20. The method of paragraph 13, wherein the composition is suitable for parenteral administration and is administered orally. . 21, N-isopropyl-4'-hydroxyacetanilide.