DE2755198A1 - DIHYDROXYBENZOESAEE DERIVATIVES AND THE SAME-CONTAINING PAIN AND INFLAMMATORY AGENT - Google Patents

Description

Our No. 21 4 * 19 Ka / be

The Procter & Gamble Company Cincinnati, Ohio, V.St.A.

Dihydroxybenzoic acid derivatives and pain and inflammation relievers containing the same

The present invention relates to dihydroxybenzoic acid derivatives, in particular 2,5-dihydroxybenzoic acid derivatives containing the same Agents and the topical and systemic, in particular oral, use thereof in living things, including humans, to achieve an analgesic and anti-inflammatory effect.

Tissue inflammation is the result of interrelated physiological events. An inflammation of the skin that involves tissue damage may be associated with various skin diseases, such as: B. eczema, psoriasis, seborrheic dermatitis, Contact dermatitis, allergic dermatitis, etc. Also with tissue damage caused by ultraviolet or heat rays or from an attack by certain microorganisms, insect bites, stings, etc., inflammation can occur be connected. Inflammation of the deeper parts of the muscles, tendons, bursae and joints that cause tissue damage connected may result from physical injuries, e.g. D. Sprains, dislocations, bruises, strenuous exercise uöw. originate. Such inflammations can lead to bursitis, Tendonitis and muscle pain. Inflammation can also be associated with tissue damage be affected by metabolic diseases such as B. gout, or

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of serological r'.rar.kr.ei-en, ζ. Ξ. rheur.atoidsr arthritis, or of changes in clocks associated with aging, z. B. Osteoarthritis.

Symptoms of inflammation are erythema (reddening) and edema (Swelling), the heat, the pain, and a puncture loss. The immediate consequence of tissue damage is the release of certain chemical substances, which are mediators inflammation, i.e. these substances trigger the incidents that lead to redness, swelling, pain and heat and intensify it. Examples of these chemical agents are histamine, serotonin, and the kinins.

Some of the major mediators of inflammation include certain prostaglandins. In contrast to histamine, serotonin and kinins, prostaglandins are continuously biosynthesized and released from cells at the site of the inflammation. Therefore the prostaglandins have a longer lasting effect. Various anti-inflammatory compounds are known inhibitors of prostaglandin synthesis. A commonly used anti-inflammatory analgesic is aspirin. Aspirin is a well-known oral agent; however, aspirin, when administered orally, is known to cause gastric irritation and bleeding in up to 70% of patients using aspirin-based products. However, recent experiments have shown that aspirin, when given topically, can delay and reduce inflammation in animals and humans . However, it has been found that locally relatively high concentrations of aspirin must be applied before it acts as a topical analgesic. Unfortunately, repeated use of high doses of aspirin causes primary irritation and peeling of the top layers of the skin (the stratum corneum).

Hence there is a need for a connection that is local can be used and provide relief from pain and relaxation

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zündur.jen causes no harmful secondary effects.

It is an object of the present invention to provide compounds which are useful as pain and inflammation relievers, as well as Compounds which can be administered systemically and topically to produce an analgesic effect and inflammation to heal, to provide.

According to the invention it has been found that derivatives of 2,5-dihydroxybenzoic acid superior pain and inflammation relieving properties without the negative side effects that come with many Salicylate compounds, e.g. B. Aspirin are associated. The compounds of the invention have the general formula

OCOR ₁ COYR ₂

wherein R. is an alkyl radical having 1 to 4 carbon atoms, Y is a radical of the formula O, NH or MRP "Rp ^e ^ ^NEN saturated or unsaturated aliphatic radical having 1 to I ^ carbon atoms, the benzyl radical or the phenyl radical and X is a hydrogen atom or a radical of the formula COR, where R is an alkyl radical having 1 to ¹ carbon atoms, with the proviso that R has at least 2 carbon atoms when Y is a radical 0, X is a radical of the formula COR, and R. and R, Mean methyl radicals.

The 2,5-dihydroxybenzoic acid derivatives (including those in which R _? Contains a carbon atom when Y is 0, X is a radical of the formula COR-, and R and R, methyl radicals), which are referred to herein

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can be formulated into a pharmaceutically acceptable carrier for topical application to the skin or can be administered systemically as described below.

New, according to the invention for providing anaesthetic effects useful dihydroxybenzoic acid derivatives have the following formula

OCOH ₁

wherein R _{1 is} an alkyl radical having 1 to 4 carbon atoms, Y is a radical of the formula O, NH or NR ₂ , R _{2 is} a saturated or unsaturated aliphatic radical having 1 to 14 carbon atoms, the benzyl radical or the phenyl radical and X is a hydrogen atom or a radical Formula COR_, where R, is an alkyl radical having 1 to 4 carbon atoms, with the proviso that R_ has at least 2 carbon atoms when YO, X is a radical of the formula COR and R ₁ and R, are methyl radicals. The saturated or unsaturated aliphatic group includes alkyl groups, alkenyl groups, alkadienyl groups, alkatrienyl groups, alkynyl groups and alkadiynyl groups.

The saturated or unsaturated aliphatic, benzyl or phenyl radicals represented by R ₂ according to the invention can be mixed with acetoxy, alkyloxy, e.g. Methoxy, ethoxy and butoxy, alkylamido, e.g. Methylamido, ethylamido and butylamido, halogen, e.g. B. chlorine, bromine and fluorine, amino, nitro, alkyl, z. B. methyl residues, propyl residues and butyl residues, amido residues and

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Hydroxy radicals without adversely affecting the effectiveness of the be substituted dihydroxybenzoic acid derivatives defined above. Such radicals can, if Rp is a benzyl radical or a Phenyl radical means that they are in the ortho, meta or para position.

In general, the compounds according to the invention are prepared from a dihydroxybenzoic acid. One hydroxy group is in the 2-position, while the second hydroxy group is in the 5-position. The dihydroxybenzoic acid is initially acylated with a suitable anhydride of the formula (RCO) pO, wherein R has 1 to k carbon atoms. Examples of the anhydride are acetic anhydride, propionic anhydride, butyric anhydride, valeric anhydride and pivalylic anhydride. If X is to represent a radical of the formula COR-, two moles of the appropriate anhydride are reacted with each mole of the dihydroxybenzoic acid. The reaction proceeds in the presence of sulfuric acid at a temperature of ¹ IO to 8o ° C. The resulting diacyloxybenzoic acid is then reacted to form an ester or an amide thereof. The ester is formed by reacting the diacyloxybenzoic acid with oxalyl chloride or sulfonyl chloride to provide a diacyloxybenzoyl chloride. This compound is then reacted with a suitable alcohol in the presence of pyridine to give the desired ester. Suitable alcohols include ethanol, propanol, sec-propanol and primary, secondary and tert-butanol, hexanol, decanol and dodecahol, unsaturated alcohols, e.g. B. allyl alcohol, crotyl alcohol, 3-hexenol, 2-hexenol, 2-octenol, 3-dodecenol, 2, it-hexadienol, 3,5-octadiene,, -2-ol, 9 »H ~ dodecadien-3-cl, ^, 6-heptadien-2-ol, benzyl alcohol and phenol.

The amide compounds according to the invention, i.e. H. the connections where Y of the formula NH or NR "are, by um-

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set the Acyloxybenzoylc'nlorides with a suitable amine obtain. This reaction takes place at a temperature of 0 to 30 ° C.

The dihydroxybenzoic acid derivatives according to the invention in which X is a hydrogen atom are derived from the known 2-acetoxy-5-hydroxybenzoic acid /see. M. Bergmann and P. Dangshot, Reports, 52, 371 * (1919J [7 prepared. Other as starting materials Acyloxy-substituted hydroxybenzoic acids used are described using the general, from Bergmann and Dangshot described method produced. The hydroxy group is protected by treatment with trimethylsilyl chloride. The protected Acid is then obtained by subsequent reaction with oxalyl chloride and an alcohol or amine, as described above, wherein X is the radical of the formula COR, converted into the ester or the amide. The desired connection is made by removal of the trimethylsilyl radical obtained with tetrabutylammonium fluoride in tetrahydrofuran.

Preferred dihydroxybenzoic acid derivatives are those in which Y is a radical of the formula 0 and X is a radical of the formula COR. Particularly preferred dihydroxybenzoic acid derivatives are those in which Y is a radical of the formula 0, X is a radical of the formula COR ,, R _{2 is} an alkyl radical having 6 to 8 carbon atoms or a benzyl radical and R ₁ and R are methyl radicals or tert-butyl radicals . Extremely preferred compounds are benzyl 2,5-diacetoxybenzoate and hexyl 2,5-diacetoxybenzoate.

The following compounds are examples of dihydroxybenzoic acid derivatives :

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Isopropyl 2 _> 5-diacetoxybenzoate Propy1-2,5-diacetoxybenzoate Hexyl-2,5-diacetoxybenzoate 2'-Ethylhexy1-2,5-diacetoxybenzoate Decyl-2,5-diacetoxybenzoate Dodecyl-2,5-diacetoxybenzoate Methyl-2,5 Dipropionoxybenzoate Octy1-2,5-dipropionoxybenzoate Hexyl-2,5-dipivaloxybenzoate Decyl-2,5-dibutyroxybenzoate Butyl-2-acetoxy-5-hydroxybenzoate Hexyl-2-propionoxy-5-hydroxybenzoate 3 ', 5'-Hexadieny1-2 , 5-diacetoxybenzoate 2-hexenyl-2,5-diacetoxybenzoate 9 ', 11 ^t -dodecadienyl-2,5-diacetoxybenzoate benzyl-2,5-dibutyroxybenzoate benzyl-2,5-diacetoxybenzoate benzyl-2,5-dipivaloxybenzoate benzyl- 2-acetoxy-5-hydroxybenzoate, pheny1-2,5-diacetoxybenzoate, phenyl-2-acetoxy-5-hydroxybenzoate, 2,5-diacetoxy-N-hexylbenzamide, 2,5-dipropionoxy-N-octylbenzamide, 2,5-diacetoxy-M-dibutylbenzamide p-Acetamidophenyl-2,5-diacetoxybenzoate 5'-Kydroxyhexyl-2,5-diacetoxybenzoate 6'-Acetoxyhexy1-2,5-diacetoxybenzoate 6'-Fluorohexy1-2,5-diacetoxybenzoate 6'-Mitrohexy1-2,5-diacetoxybenzoate - 6 '- "4ethylamld <3hexyl ~ 2,5- ^ iacetaxyberisGat 2'-Ethy1-2' _t k '-hexadienyl-2,5-diacetoxybenzoate 2'-acetoxybenzyl-2,5-dipropionoxybenzoate

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AS-

2'-fluoro'cenzyl-2,5-iiacet; xycenzoate

2'-hydroxybenzyl-2,5-iiacetoxybenzoat 2 ^{t-methoxybenzyl-2,5-ciacetoxybenzoat} 2 ', 4 · -Diacetoxybenzyl-2,5-diacetoxybenzoat 2'-Acetamidobenzy1-2,5-diacetoxybenzoat.

The following examples serve to illustrate the present Invention.

Example 1 describes a very convenient "one-pot" synthesis the particularly preferred compound, benzy1-2,5-diacetoxybenzoate .

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example 1 Esterification and acylation of 2,5-dihydroxybenzoic acid

A 5 1 three-necked flask equipped with a water-cooled Friedrichs condenser, a 500 ml addition funnel, a thermometer, a Teflon-coated magnetic stirring bar and heating mantle was charged with ¹ IOO g of 2,5-dihydroxybenzoic acid and 1200 ml of acetonitrile. The solution was heated to 40 ° C and 360 ml of triethylamine was added in a slow stream (about 10 minutes). The addition of triethylamine raised the temperature of the mixture to about 65 ° C. The addition funnel was rinsed with 200 ml of acetonitrile, which was then added to the reaction mixture. 316 ml of benzyl bromide were added to this reaction mixture in a slow stream (approx. 10 min.). The addition funnel was washed with 200 ml of acetonitrile, which was then added to the reaction mixture. The reaction mixture was heated to about 80 ° C. and stirred at this temperature for 2 hours.

The heating element was switched off. 522 ml of pyridine were left in the flask (temperature of the reaction mass 70 ° C., pot

flow
temperature)). To this mixture was added 516 ml of acetic anhydride dropwise over about 15 minutes. The mixture was again heated to reflux (approximately 8O ⁰ C) and 20 minutes at this temperature.

The flask was cooled, the solution was divided into 3 approximately equal portions, and the acetonitrile was removed on a rotary evaporator removed. Each part was then transferred to a separatory funnel containing 3 liters of ethyl ether, where it was subsequently twice with 750 ml of 1 N HCl, once with 1 liter of water,

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Washed once with 500-1 saturated aqueous 3icar'oonate, once with 1 liter of water and once with 500 ml of saline solution (brine). The ether solution was dried with anhydrous magnesium sulfate. The drying agent was filtered off and the ether was evaporated to give the product. The crude product was recrystallized from ethanol, filtered and dried in a vacuum desiccator. The benzyl-2,5-diacetoxybenzoic acid obtained has a melting point of 71 to 73 ° C. and was obtained in a yield of about 80 % .

Example 2 Benzy1-2,5-diacetoxybenzoate

A solution of 2,5-dihydroxybenzoic acid (87 ^ g, 5.7 mole), freshly distilled acetic anhydride (2315 g, 22.7 moles) and 2 ml of concentrated sulfuric acid was * J5 minutes at 8O ⁰ C and heated for 72 hours at ambient temperature touched. About 1,200 ml of acetic anhydride were removed by distillation at 70 ^{° C. and 30 mm pressure.} The residue was poured into 7.5 water. After stirring for 2 hours, it became colorless

söhPag
Lower / collected by suction filtration, washed with further 2 1 of water and dried under vacuum for 16 hours (8O ⁰ C and 1 mm pressure). The precipitate was slurried with 2 1 of hexane, collected by suction filtration and dried under vacuum (8O ⁰ C and 1 mm pressure) l6 hours. The precipitate was again stirred with 1,800 ml of water and allowed to settle. The purification process was repeated twice and then the precipitate was collected by suction filtration and dried under vacuum (8O ⁰ C and 1 mm pressure) 6 ¹ »hours. The dry, colorless crystals weighed 1052 g (yield 78 %) , had a melting point of 121.5 to 125 ° C. and were identified as 2,5-diacetoxybenzoic acid.

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The acetoxybenzoic acid (225.2 g, 0.95 mol) was mixed with 1,800 g (14.18 mol) oxalyl chloride and 250 ml dry chloroform. The oxalyl chloride and the dry chloroform were initially cooled to ^{0 ° C. before being added to the diacetoxybenzoic acid.} The resulting mixture was stirred under an argon atmosphere for 48 hours. The excess oxalyl chloride was removed by distillation under vacuum (45 ° C and 30 mm pressure). The colorless residue was washed with 2,100 ml of hexane and washed under vacuum (^ 5 C and 0.1 mm pressure). The resulting product was identified as 2,5-diacetoxybenzoyl chloride and had a melting point of 89 to 94.5 ° C.

A solution of the 2,5-diacetoxybenzoyl chloride (250.7 g, 0.98 mol) in 750 ml of dry chloroform was at 0 C with a solution of benzyl alcohol (100.63 g, 0.93 mol) and IMO g (1, 77 mol) of pyridine in 150 ml of dry chloroform were added. The addition was made dropwise over a period of 6 hours. The temperature was maintained at 0-5 ° C during the addition and the entire operation was carried out under an argon atmosphere. The reaction mixture was stirred for l6 hours at 26 ⁰ C and poured into 300 ml of cold water. The organic part was extracted with 3> 4 liters of ether and washed with 200 ml of 15% hydrochloric acid, 1,200 ml of water, 500 ml of sodium hydroxide (0.1 N) and 2,400 ml of water and dried over magnesium sulfate. After evaporation of the solvents, 292.6 g (89 # yield) of light pink crystals were obtained. The crystals were recrystallized twice from methanol to obtain 132 g (40 % yield) of colorless crystals having a melting point of 71 to 73 ° C, which were identified as benzyl 2,5-diacetoxybenzoate.

The NMR spectrum (CDCl ₃ ) showed signals at: Γ 2.25 (S, J = 2Hz) A,? 7 C-5 aromatic proton, C 2.6 (s) fi \, 8 / aromatic protons of benzyl ester, r 2,6-3,0 (m) ^ 2,3 ^ C-3 and 809825/0775

C-Ji aromatic? ? rctcr.er _1} ~ 4.7 (s) /2,3.7 benzyl protons, * 7.7 (s) / 2, ς? Acetate-methyl group, r 7.85 (s) / 2.87 acetate-methyl group.

Analysis : (for C _1fi K _{1 /;} Or) C% H%

Io 10 O

calc .: 65.85 ¹ 1.9 found: 65.83 5.05.

Example 3 Hexy1-2,5-diacetoxybenzoate

A solution of 2,5-diacetoxybenzoyl chloride (60 g, 0.23 ¹ mol) in 2 ¹ 10 ml of dry chloroform was added dropwise over 6 hours to a solution of hexyl alcohol (21.7 g, 0.202 mol) and 33, 61 g (0.425 mol) of pyridine in 100 ml of chloroform were added. The temperature was maintained at 0-5 ° C during the addition and the entire operation was carried out under an argon atmosphere. The reaction mixture was stirred at 26 ° C. for 16 hours and diluted with 800 ml of ether. The organic layer was washed successively with 280 ml of 1N hydrochloric acid, three times with 100 ml of water, 125 ml of 1N sodium hydrochloride and three times with 100 ml of water, and then dried over magnesium sulfate. After evaporation of the solvents, 68.1 g (99 %) of a light yellow liquid were obtained. After distillation in a (short-path) distillation unit, 46.2 g (68 %) of hexyl 2,5-diacetoxybenzoate were obtained as a colorless liquid with a boiling point of 165 ° C / 0.3 mm.

The NMR spectrum (CDCl,) showed signals at: r 2.38 (d, J = 2Hz) / 0.927 C-6 aromatic proton, £ 2.7-3.17 (m) / 2.117 C-3 and C- ¹ I aromatic protons, r 5.8 (t, J = 6Hz) / 1.837 methylene protons cc to the acidic off, χ 7.72 (s) and T7.77 (s) / "6.247 the two acetate methyl groups, ττ 8 , 1 - 9.15 (m) /11.017 residual protons.

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2755Ί98 - 20-

example k Benzyl 2,5-dipropionoxybenzoate

A solution of 2,5-dihydroxybenzoic acid (10 g, 0.065 mol), freshly distilled propionic anhydride (33.8 g, 0.26 mol) and 3 drops of concentrated sulfuric acid was heated at 60 ° C for 25 minutes , stirred at ambient temperature for 16 hours and then poured into 900 ml of water. After stirring for 2 hours, the colorless precipitate was collected by suction filtration, washed three times with 300 ml of water and for 16 hours under vacuum. (80 ° C. and 1 mm pressure)

with

dried. The precipitate was slurried / 2 l of hexane, collected by suction filtration and dried under vacuum (60 ° C. and 1 mm pressure) for 16 hours. The dried colorless crystals weighed 26 Ί g (88% yield)> had a melting point 132-13 ^f l and C were identified as 2,5-Dipropionoxybenzoesäure.

Oxalyl chloride (100 g, 0.79 mol) and 2,5-dipropionoxy benzoic acid (10 g, 0.038 mol) were combined and this mixture was stirred for 4 ^J 8 hours under an argon atmosphere. The excess oxalyl chloride was removed by distillation under vacuum (45 ° C./30 mm pressure). The colorless residue was washed twice with 10 ml of hexane and stripped under vacuum ( ^] 45 ° C. and 1 mm pressure). This procedure gave 10.33 g of a colorless liquid which was identified as 2,5-dipropionoxybenzoyl chloride . This material was used without further purification.

A solution of 2,5-dipropionoxybenzoyl chloride (10.3 g, 0.036 mol) in 30 ml of dry chloroform was at O ⁰ C dropwise within 6 hours with a solution of benzyl alcohol (3, ^ 5 g, 0.032 mol) and 5, 05 g (0.064 mol) of pyridine in δ ml of dry chloroform were added. The tempera-

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The door was kept at 0 to 5 C during the addition and the entire operation was performed under an argon atmosphere. The reaction mixture was stirred at 26 ° C. for 16 hours and poured into 50 ml of cold water / water. The organic portion was extracted with 450 ml of ether and the organic layer was washed with 80% hydrochloric acid, 100 ml of 1N sodium hydroxide three times, and 100 ml of water three times, and dried over magnesium sulfate. After evaporation of the solvents, 10.22 g (90% yield) of benzyl 2,5-dipropionoxybenzoate were obtained as a colorless liquid. After distillation in a Hickman distillation unit, 7.0 g (yield 60 %) of benzyl 2,5-dipropionoxybenzoate were obtained as a colorless liquid with a boiling point of 227 ° C./0.14 mm.

The NMR spectrum (CDCl ₃ ) showed signals at 2.37 (d, J = 2Hz ^ 0.847 C-6 aromatic proton, T 2.55-3.1 (m) Ci ₁ IuJ C-3, C- ¹ I and aromatic ester protons, f 4.72 (s) Zl, 86.7 benzyl protons, r 7.17 - 7.99 (overlapping Q) / 3.837 methylene protons o6 to propionyl carbonyl jtr 8.57 - 9 »1 (overlapping , t) iS> 257 methyl protons.

Example 5 Benzyl 2,5-dipivaloxybenzoate

A solution of 2,5-dihydroxybenzoic acid (10.34 g, 0.067 mol), freshly distilled pivalyl anhydride (50 g, 0.27 mol) and 6 drops of concentrated sulfuric acid was added for 1 hour 60 C and stirred for 2 hours at ambient temperature. The reaction mixture was poured into 900 μl of water and Stirred for 2 hours. The precipitated product was? With 800 ml Ether extracted. The ethereal layer was washed 4 times with 50 ml of warm water and dried over magnesium sulfate.

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-η-

dries. After evaporation of the ether, 7 g of a waxy solid were obtained. This pesticide was triturated 10 times with 100 ml v / water, collected by suction filtration and washed with a further 300 ml of water. After air drying and drying in a vacuum oven (60 ° C and 1 mm pressure) within 16 hours 12.0 ¹ I g (56%) of 2,5-Dipivaloxybenzoesäure were obtained as frablose crystals having a melting point 159-162 ° C.

Oxalyl chloride (100 g, 0.793 mol) and 2.5 dipivaloxybenzoic acid (10 g, 0.031 mol) were combined and stirred for 18 hours at 26 ° C under an argon atmosphere. The excess oxalyl chloride was removed by stripping for 4 hours (35 ° C. and 1 mm pressure). The colorless liquid thus obtained was used without further purification.

A solution of the 2,5-Dipivaloxybensylchlorides (10.65 g, Ό, 031 T1ol) in 30 ml dry chloroform was at 0 ⁰ C dropwise within 2 hours with a solution of benzyl alcohol (2.88 g, 0.027 mol) and pyridine (4.22 g, 0.053 mol) in 6 ml of dry chloroform were added. The temperature was maintained at 0-5 ° C during the addition and the entire operation was carried out under an argon atmosphere. The reaction was stirred for 16 hours at 26 ⁰ C and then the reaction mixture was poured into 50 ml of cold V / ater. The organic part was extracted with 50 ml of ether and washed successively with 80 ml of 15% hydrochloric acid, three times with 50 ml of water, 25 ml of sodium hydroxide (0.1 N) and four times with 50 ml of water and dried over magnesium sulfate. After evaporation of the solvents , 11.6 l g of colorless crystals were obtained. These crystals were recrystallized from 40 ml hexane to give 6.5 g (59%) of benzyl 2-j 5 dipivaloxybenzoat as colorless crystals having a melting point 90.5 to 91.8 ° C were obtained.

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-η -

The MMR spectra (CDCl,) showed signals at: C 2.37 (d, J = 3Hz) ZTl, 087 C-6 aromatic proton, X 2.53-3.13 (m) / 7.567 C-3 , Cl »and aromatic ester protons, τ 4.7 (s) £ 2.167 benzyl protons, t: 8.63 Cs) £ 17.29.7 methyl protons.

Example 6

2,5-diacetoxy-N-hexy-benzamide

A solution of 2,5-diacetoxybenzoyl chloride (2.56 g, 0.01 mol) in 10 ml of dry chloroform was at 0 C dropwise within one hour with a solution of N-hexylamine (2.12 g, 0.021 mol) in 10 ml of dry chloroform were added. The temperature was maintained at 0-5 ° C during the addition and the entire operation was carried out under an argon atmosphere. After the addition was complete, the solution was stirred at 26 ° C. for 16 hours. The organic portion was extracted with 80 ml of chloroform and washed with 30 ml of 0.1 N HCl, 20 ml of water, 10 ml of sodium hydroxide (0.25 N) and 20 ml of water and dried over magnesium sulfate. After evaporation of the solvents, 3.57 g of pink crystals were obtained. These crystals were recrystallized from 550 ml of hexane, 1.8 g (56 %) of 2,5-diacetoxy-N-hexy1-benzamide being obtained as colorless crystals having a melting point of 76.5 to 77 ° C.

The NMR spectrum (CDCI,) showed signals at x; 2.55 (d, J = 3Hz) £ 0.867 C-6 aromatic proton,? · 2.7 - 3.1 (m) £ 2.1 * 7 C-3 and C-4 aromatic protons, τ 3.7 (broad s) amide proton, T. 6.4 - 6.9 (m) /."2.04J methylene protons et to nitrogen, r 7.7 (s) £ 5.767 acetate methyl groups, r8.6 - 9.1 (m) £ 12.27 remaining protons.

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Example 7 p-acetamidophenyl 2,5-diacetoxybenzoate

A solution of 95 g (0.37 mol) of 2,5-diacetoxybenzoyl chloride in 320 ml of dry chloroform was added dropwise over 4 hours to a solution of 4-acetamidophenol (50.85 g, 0.34 mol) and 98.3 g ( 1.24 mol) of pyridine was added. The temperature was kept at 0 to 5 ^° C. during the addition and the entire operation was carried out under an argon atmosphere. After the addition, the reaction mixture was stirred at 26 ° C. for 16 hours. The organic part was extracted with 1.0 l of ether and washed with 950 ml of 15 percent HCl, 3 × 300 ml of water, 150 ml of IN sodium hydroxide and 3 × 10 ml of water and dried over magnesium sulfate. After evaporation of the solvents, 14.7 g of a colorless semi-solid material were obtained. Recrystallization from Mach 1.5 1 of benzene 59.24 g (47%) of p-acetamidophenyl-2,5-diacetoxybenzoat as colorless crystals having a melting point of 148 - 149.5 ⁰ C obtained.

The MMR spectrum (CDCl ₃ ) showed signals at τ 1.82 - 3.13 (m) ^ ~ 8.037 C-6, C-3, C-4 aromatic protons, aromatic phenyl ester protons and the amide Proton, τ 7.7 (2 overlap, s) _ / ~ 5.8 ^ 7 acetate methyl groups, τ 7.87 (s) /.~3,167 acetamido methyl group.

Example 8

2,4-hexadienyl-2,5-diacetoxybenzoate

A solution of 1.6 g (O, 0o64 mole) of 2,5-Diacetoxybenzoylchlorid in 8 ml of dry chloroform was added at 0 ⁰ C in one hour dropwise with a solution of 0.6 g (0.006 mole) of 2,4-hexadienol and 0.925 Z (0.012 mol) of pyridine in 8 ml of dry chlorine

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form shifted. The temperature was maintained at 0-5 ° C during the addition and the entire operation was carried out under an argon atmosphere. The reaction mixture was stirred for 16 hours at 26 ° C. and poured into 35 ml of cold water / water. The organic portion was extracted with 80 ml of chloroform and washed with 70 ml of 0.1 N HCl, 35 ml of water, 10 ml of sodium hydroxide (0.1 N) and 35 ml of v / ater and dried over magnesium sulfate, after which the solvents were evaporated 1.6 g (soft) crystals were obtained. These crystals were recrystallized from hexane to give 0.91 g (49 %) (soft) of colorless crystals identified as 2,4-hexadienyl-2,5-diacetoxybenzoate.

The NMR spectrum (CDCl,) showed signals at: ΐ 2.3 (d, J = 2Hz) C-6 aromatic protons, r 2.58 - 3.1 (m) / 2.57 C-3 and C- 4-aromatic protons, τ 3.4 - 4.77 (broad m) / 2.95_? olefinic protons, -; 5.3 (d, J = 7Hz) / 1.347 methylene protons (L to oxygen, τ 7.7 and 7.73 (two s) Cl , 157 acetate methyl groups,? 8.28 (d, J = 6 Hz ) / 2,557 methyl group.

Example 9

n-butyl 2,5-diacetoxybenzoate

A solution of 2.0 g (0.008 mol) of 2,5-diacetoxybenzoyl chloride in 15 ml of dry chloroform was added dropwise over 30 minutes with a solution of 2.567 g (0.008 Mol) n-butanol and 0.80 g (0.011 mol) pyridine in 25 ml dry chloroform were added. The entire operation was done carried out at room temperature and under an argon atmosphere. The reaction mixture was left at 26 ° C for 16 hours touched. The chloroform was removed on a rotary evaporator and the residue was taken up in 60 ml of ether,

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-2S-

placed in a separatory funnel and washed with 25 ml of water, three times with 25 ml of hydrochloric acid (1N), three times with 25 ml of saturated aqueous sodium bicarbonate, twice with 25 ml of water and 25 ml of brine. The remaining ether solution was dried over magnesium sulfate, filtered and evaporated to a light brown oil. The crude product was purified by bulb-to-bulb distillation in a Kugelrohr oven to yield 1.48 g (60%) of a colorless oil identified as the n-butyl 2,5-diacetoxybenzoate.

The NMR spectrum (CDCl,) showed signals at: V 2.27 (d, J = 2Hz, IH, aromatic), T 2.6-3.1 (m, 2H, C, and C _1. Aromatic), Γ5.75 (t, J = 6Hz, 2H, oxymethylene7.68 and 7.75 (s, 3 for each, acetate-methyl ), t 8.0-8.9 (m, IH, methylene), T9.06 (m, 3H, butyl-methyl).

Example 10 Benzyl 2-acetoxy-5-hydroxybenzoate

A flask fitted with a stir bar was charged with 5.0 g (0.0255 mol) of 2-acetoxy-5-hydroxybenzoic acid / M. Bergmann and P. Dangschat, Reports, 52, 371 (1919) 7. After the flask was purged with argon and cooled in an ice bath, a solution of t-butyldimethylsilyl chloride (9.23 g, 0.06122 mol) and imidazole (8> 5 g, 0.125 mol) was _> dissolved in 20 ml of anhydrous dimethylformaldehyde (DMF) added dropwise over a 30 minute period. The reaction mixture was stirred at room temperature overnight. The DMF was removed in vacuo. The residue was taken up in 75 ml of ether, placed in a separatory funnel and extracted with 1 η HCl (three times 25 ml), 5 mg NaOH (three times 25 ml), water (twice 10 ml) and brine (20 ml). The ether extract was dried over sodium sulfate, filtered and the solvents were removed in vacuo, 2-acetoxy-5-t-butyldimethylsilylbenzoic acid being obtained. 809825/0775

A solution of 2-Ace-cxy-5-t-butyldimethylsilylbenzoic acid in 20 ml of chloroform, cooled in an ice bath, 23.3 U (0.133 mol) of oxalyl chloride were added dropwise in 1 hour. The solution was stirred at room temperature overnight. The excess oxalyl chloride was on a The rotary evaporator was removed and the resulting product was immediately dissolved in 25 ml of chloroform, with argon covered and chilled in an ice bath. This solution was added dropwise with a solution of Benzyl alcohol, pyridine and chloroform were added. The reaction mixture was stirred for 4 hours at room temperature. That Chloroform was removed on a rotary evaporator, the residue dissolved in ether and transferred to a separatory funnel brought. The ether layer was then washed with In HCl, 5 JSigem sodium hydroxide, water and saline solution extracted. The ether was dried over magnesium sulfate, filtered and evaporated to give 3enzyl-2-acetoxy-5-t-butyldimethylsilylbenzoate was obtained. The above ester was dissolved in tetrahydrofuran and a solution of tetrabutylammonium fluoride and tetrahydrofuran was added.

The above ester was dissolved in tetrahydrofuran and a solution of tetrabutylammonium fluoride and tetrahydrofuran was added at room temperature. The reaction mixture was stirred overnight. The tetrahydrofuran was removed on a rotary evaporator, the residue was taken up in ether, placed in a separatory funnel, and extracted with water and brine. The remaining ether solution was dried over magnesium sulfate, filtered and evaporated to give benzyl 2-acetoxy-5-hydroxybenzoate.

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The dihydroxybenzoic acid derivatives described above are useful when applied topically to the skin. Mixtures, the dihydroxybenzoic acid derivatives, wherein R _?

contains a carbon atom when Y is a radical of the formula en '

0, X is a / radical of the formula COR, and R ₁ and R, are methyl radicals , are also useful for topical applications to the skin. The agents comprise an effective amount, preferably from 0.001 % to 10 %, of the dihydroxybenzoic acid derivative. The remainder of the agent further comprises a pharmaceutically acceptable carrier. Suitable carriers for the dihydroxybenzoic acid derivatives remain in place on the skin as a continuous film and resist easy washing off by perspiration or by immersion in water. In general, the carrier is of an organic nature and is able to dissolve or disperse the dihydroxybenzoic acid derivative; common physical forms for the compositions according to the invention are lotions, creams, solutions, gels and solid materials. These shapes are explained in more detail below.

By the term "topical application" herein is meant the direct depositing or spreading of the compounds and agents onto epidermal tissues (including outer skin and oral, gum, nasal, etc. tissue) at the affected sites on demepidermal tissue or on the epidermal tissue at or near the affected area when an analgesic or anti-inflammatory effect is sought for disorders of deeper structures.

Lotions comprise from 0.001 % to 10 % , preferably 0.01 % to 5 % of the dihydroxybenzoic acid derivative, from 1 to 25 %, preferably 3 to 15 % of an emollient and the balance water.

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-η -

Various emollients are known. Examples of class. of emollients and examples thereof are as follows:

1) Hydrocarbon oils and waxes. Examples of these are mineral oil, petrolatum, paraffin, ceresin, ozokerite, microcrystalline wax, polyethylene and perhydrosqualene.

2) silicone oils, such as dimethylpolysiloxanes, methylphenylpolysiloxanes, water-soluble and alcohol-soluble silicone glycol copolymers.

3) Triglyceride esters, e.g. vegetable and animal fats and oils. Examples include castor oil, safflower oil, cottonseed oil, Corn oil, olive oil, cod liver oil, almond oil, avocado oil, palm oil, sesame oil and soybean oil.

Acetoglyceride esters, such as acetylated monoglycerides.

5) Ethoxylated glycerides such as ethoxylated glyceryl monostearate.

6) alkyl esters of fatty acids having 10 to 20 carbon atoms. Are methyl, isopropyl and butyl esters of fatty acids useful in the invention. Examples include hexyl laurate, Isohexyl laurate, isohexyl palmitate, isopropyl palmitate, Decyl oleate, isodecyl oleate, hexadecyl stearate, decyl stearate, isopropyl isostearate, diisopropyl adipate, diisohexyl adipate, Dihexyl decyl adipate, diisopropyl sebacate, lauryl lactate, myristyl lactate and cetyl lactate.

7) Alkenyl esters of fatty acids having 10 to 20 carbon atoms. Examples thereof include oleyl myristate, Oleyl stearate and oleyl oleate.

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-so -

8) fatty acids -Lz IC up to 20 carbon atoms. Suitable examples include pelargonic, lauric, myristic, palmitic, stearic, isostearic, hydroxystearic, oleic, linoleic, ricinoleic, arachidic, 3ehenic and erucic acids.

9) Fatty alcohols with 10 to 20 carbon atoms. Lauryl, myriscyl, cetyl, hexadecyl, gtearyl, isostearyl, hydroxystearyl, oleyl, ricinoleyl, behenyl, erucyl and 2-octyldodecanol alcohol are examples of satisfactory fatty alcohols.

10. fatty alcohol ethers. Ethoxylated fatty alcohols having 10 to 20 carbon atoms include lauryl, cetyl, stearyl, isostearyl, oleyl and cholesterol alcohols having from 1 to 50 ethylene oxide groups or 1 to 50 propylene oxide groups.

11. Ether-esters, such as fatty acid esters of ethoxylated fatty alcohols.

12. Lanolin and derivatives. Lanolin, lanolin oil, lanolin wax, lanolin alcohols, lanolin fatty acid, isopropyl lanolate, ethoxylated lanolin, ethoxylated lanolin alcohols, ethoxylated cholesterol, propoxylated lanolin alcohols, acetylated lanolin, acetylated lanolin alcohols, linoleate of Lar.olinalkoholen, ricinoleate of lanolin alcohols, acetate of lanolin alcohols ricinoleate of, acetate of ethoxylated Alkoholestern , Hydrogenolysis product of lanolin, ethoxylated hydrogenated lanolin, ethoxylated sorbitol lanolin, and liquid and semi-solid lanolin absorbent bases are illustrative examples of lanolin-derived emollients.

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13. Polyhydric alcohols and polyether derivatives. Propylene glycol, dipropylene glycol, polypropylene glycol 2000, 4000, polyoxyethylene-polyoxypropylene glycols, polyoxypropylene-polyoxyethylene glycols, glycerine, ethoxylated glycerine, propoxylated glycerine, sorbitol, ethoxylated sorbitol, -Homopolymers (100,000 - 5,000,000), polyalkylene glycols and derivatives, hexylene glycol (2-methyl-2, ¹ l-pentadiol), 1,3-butylene glycol, 1,2,6-hexanetriol, ethohexadiol USP (2-ethyl-l, 3 -hexanediol), C ₁₅ - to C _lg vicinal glycol and polyoxypropylene derivatives of trimethylolpropane are examples of the same.

I ¹ J. Polyalcohol Esters. Ethylene glycol mono- and difatty acid esters, diethylene glycol mono- and difatty acid esters, polyethylene glycol (200-6000) mono- and difatty acid esters, propylene glycol mono- and difatty acid esters, polypropylene glycol 2000 monooleate, polypropylene glycol 2000 monostearate, ethlycolated propylene glycol monostearate, Glyceryl mono- and difatty acid esters, polyglycerin poly fatty acid esters, ethoxylated glyceryl monostearate, 1,3 ~ butylene glycol monostearate, 1,3-butylene glycol distearate, polyoxyethylene polyol fatty acid esters, sorbitan fatty acid esters and polyoxyethylene sorbitan fatty oleic esters are satisfactory.

15 Wax esters such as beeswax, whale rat, myristyl myristate, stearyl stearate.

16. Beeswax derivatives such as polyoxyethylene sorbitol beeswax. These are reaction products of beeswax with ethoxylated sorbitol with different ethylene oxide content, which form a mixture of ether-esters.

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17. Vegetable waxes such as carnauba wax and candelilla wax.

18. Phospholipids such as lecithin and derivatives.

19. Sterols. Cholesterol and cholesterol fatty acid esters are examples of the same.

20. Amides, such as fatty acid amides, ethoxylated fatty acid amides, solid fatty acid alkanolamides.

The lotions according to the invention can furthermore contain from 1 to 10 %, preferably 2 to 5 %, of an emulsifying agent. Such emulsifiers are nonionic, anionic or cationic emulsifiers. Examples of satisfactory nonionic emulsifiers include fatty alcohols with 10 to 20 carbon atoms, fatty alcohols with 10 to 20 carbon atoms, which are condensed with 2 to 20 moles of ethylene oxide or propylene oxide, alkylphenols with 6 to 12 carbon atoms in the alkyl chain, which nit 2 to 20 moles Ethylene oxide is condensed, mono- and di-fatty acid esters of ethylene glycol, where the fatty acid residue contains from 10 to 20 carbon atoms, fatty acid monoglyceride, where the fatty acid residue contains from 10 to 20 carbon atoms. contains diethylene glycol, polyethylene glycols with molecular weights from 200 to 600O, propylene glycol with molecular weights from 200 to 3000, glycerol, sorbitol, sorbitan, polyoxyethylene sorbitan, polyoxyethylene sorbitan and hydrophilic wax esters. Suitable anionic emulsifying agents include the fatty acid soaps, for example sodium, potassium and triethanolamine soaps, the fatty acid radical containing from 10 to 20 carbon atoms. Other suitable anionic emulsifiers include the alkali metal, ammonium or substituted ammonium alkyl sulfates, alkyl aryl sulfonates and alkyl ethoxy ether sulfonates having 10 to 30 carbon atoms in the alkyl radical. The alkyl ethoxy ether sulfonates contain from 1 to 10 ethylene oxide

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ce

units. Satisfactory cationic emulsifiers are those Quaternary Ar.nior.iu-, morpholinium and pyridinium compounds. Bestir-.te Emollienti / those already mentioned in the foregoing Paragraphs described also have emulsifying properties. If a lotion that has such a If emollients are formulated, a further emulsifier is not required, although it is still included in the agent can be incorporated.

The rest of the remedy consists of water. The lotions can be formulated by simply mixing all of the ingredients together. Preferably the dihydroxybenzoic acid derivative is dissolved in the emollient and the mixture is then added to the water. Various constituents, such as the emulsifier or customary additives, can be added. A common additive is a thickener, which can be added in an amount of 1 to 10% of the mixture. Examples of suitable thickeners are, for example, crosslinked carboxypolymethylene polymers, methyl cellulose, polyethylene glycols, tragacanth gum, kharaya gum, xanthan gums and bentonite.

The agents according to the invention can also be formulated into creams. These creams comprise from 0.001 to 10 %, preferably 0.01 to 5% of the dihydroxybenzoic acid derivative, from 5 to 50 %, preferably 10 to 25% of an emollient and water as the remainder. The emollients described above are also used in the cream form of the agent. The cream can optionally contain a suitable emulsifier. Emulsifiers as described above are useful in these creams. If an emulsifier is used, it is in the composition in an amount of 3 to 50% _t, preferably 5 to 20% is used.

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The agents according to the invention can also be formulated as a solution. The solution according to the present invention comprises from 0.001 to 10 %> preferably 0.01 % to 5% of the dihydroxybenzoic acid derivative and a suitable organic solvent balance. Suitable organic materials useful as a solvent or as part of a solvent system are as follows : Propylene glycol, polyethylene glycol (200-600), polypropylene glycol (425-2025), glycerin, sorbitol esters, 1,2,6-hexanetriol, ethanol, isopropanol, diethyl tartrate, butanediol, and mixtures thereof. Such solvent systems can also contain water.

These agents are applied to the skin in the form of the solution or the solutions can also be formulated in an aerosol form and then applied to the skin as a spray. The agents in aerosol form additionally contain from 25 to 80 %, preferably 30 to 50 %, of a suitable propellant. Examples of such propellants are: The chlorinated, fluorinated and chlorofluorinated hydrocarbons of low molecular weight. Nitrous oxide and carbon dioxide are also used as propellants. They are used in an amount sufficient to drive off the contents of the container.

The compositions of the invention are formulated in a gel form by simply mixing a suitable thickener with the above described solution mixed. Examples of suitable thickeners are above with regard to the solutions described.

The jülförmigen means comprise from 0.001 to 10% _t preferably 0,0l to 5% df.'f dihydroxybenzoic acid derivative, from 5 to 75%> Preference iv.eise-Iv) to 50% of an organic solvent, as described in understanding , from 0.5 to 20 % _t preferably

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1 to 10 % of the Verdiocurante and water as the remainder.

The agents according to the invention can also be in the form of a solid mass or a solid. Such solid shapes can be used as sticks that are applied to the lips or other parts of the body. Such compositions contain from 0.001 to 10% _t, preferably from 0.01% to 5% of dihydroxybenzoic acid derivative and from 50 to 98% _t preferably from 60 to 90% of the emollient described above. This agent can also contain from 1 to 20 %, preferably from 5 to 15%, of a suitable thickening agent and optionally emulsifiers and water. The thickeners described above in the explanation of the gel-like compositions are suitable herein.

Additives commonly used in topical or topical agents such as preservatives, z. B. methyl and ethyl parabens, dyes and perfumes can be incorporated into any of the compositions described above will.

The effective amount of the dihydroxybenzoic acid derivative to be applied topically will vary with the particular circumstances the application, the length of the anticipated suspension and similar factors. In general, from 0.01 μg to 500 pg

of the dihydroxybenzoic acid derivative applied per cm of epidermal area. Individual applications for the treatment of skin inflammation are preferably 0.01 μg to 50 μg of the dihydroxybenzoe

acid derivatives per cm of epidermal area. Bigger ones Amounts are uneconomical and do not give a noticeably increased effectiveness, while lower amounts do not give any noticeably beneficial one Result. Individual applications for the treatment of

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Joints

Inflammation of deeper structures, e.g. B. of muscles, tendons / and Bursa are preferably used with 0.1 μg to 500 jig of the di-

p
hydroxybenzoic acid derivatives per cm of skin area. The amount of topical agent (dihydroxybenzoic acid derivative plus carrier) applied to the affected epidermal areas can be readily determined from the amount of dihydroxybenzoic acid derivative present in the agent.

The following examples illustrate the agents of the present invention and their use.

Example 11

The agents according to the invention are anti-inflammatory in terms of their anti-inflammatory properties Properties investigated by doing an ultraviolet light-induced erythema test on guinea pigs performs.

Albino guinea pigs of Hartley strain weighing ¹ ^ OO to 5Ou were clipped on the back of the coat g and then using a cremsförmigen depilatories ·; depilated. Fifteen minutes after applying the hair remover, the depilated area was carefully washed using warm tap water and then dried with a towel. After a period of about 18 hours, the guinea pigs were irradiated in a wire cage for 30 minutes using a series of lamps (Westernhouse lights) at a distance of 31 cm. An irradiation time of 10 minutes is a minimum amount for Erythenic. A strip of adhesive plaster is applied to the middle of the back of the guinea pig in order to preserve a non-irradiated part of the skin. About 1 hour after the irradiation time, 3 preparations were applied to each side using a micropipette. The treated areas were about 1 χ ^ cm

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large and were arranged from near the center back down to the side in the vertical direction. The degree of fading was determined in hourly intervals.

The remedies described below have been formulated and tested:

Propylene glycol ** 9 »95 %

Ethanol ** 9> 95 %

Dihydroxybenzoic acid derivative 0.1 % of the formula

OCOCIi ₃ COOJ {

Comparisons of the anti-inflammatory effectiveness of the dihydroxy

en

Benzoic acid derivatives were made by determining their IC ^ Q values. That is, compounds usually exhibit a dosage versus response relationship such that higher concentrations produce a greater response and lower concentrations produce a less response. However, various compounds have steeper or flatter slopes in their dose-response curves so that comparing the efficacy at one or a few concentrations does not provide a realistic insight into their relative potencies. To compare the effectiveness of different compounds by a single number, the concentration of a compound that inhibits puncture by 50% is determined from the dose-response curve. This value is referred to as ΗΚ_ ₀ (the concentration that inhibits the puncture by 50% ). In the following table the ΗΚ, -Q-value refers

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to concentrations (expressed in mM) of the dihydroxybenzoic acid derivative which inhibit erythema induced by UV light by 50 %. This HK values are based on cumulative levels of fading over a period of 1 to ^1J hours after application of the dihydroxybenzoic acid derivative. The lower the HKj- value, the greater the effectiveness of the compound.

_R HK ₅₀

CH ₂ C ₆ H ₅ 0.4

CH ₃ 2.3

C ₂ H ₅ 1.8

C ₃ H ₇ 1.1

C ₄ H ₉ 1.2

C ₅ H ₁₃ x 0.3 ^

C ₈ H ₁₇ . 0.34

C ₁₀ H ₂₁ 0.65

C ₁₂ H ₂₅ 1.2

C ₂ H ₃ (C ₂ H ₅ ) C ₄ H ₉ 5.8

CH (C ₀ H ₅ ) CH ₃ 1.2

CH ₀ C ₆ H ₄ OCH 0.53

CH ₂ C ₆ H ₃ (OCH ₃ )., 5.0

CH ₂ C ₆ H ₄ CH ₃ 0.53

CH ₂ C ₆ H ₄ ? 0.60

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If aspirin is used instead of the dire hydroxybenzoic acid derivative becomes, becomes eir. HK - ^ - fourth obtained from 140mM. The above The results given show that the compounds according to the invention have significantly better anti-inflammatory properties possess as aspirin when applied topically.

Example 12

This example illustrates the analgesic effectiveness of the compounds and agents according to the present invention.

Male Sprague-Dawley rats were trimmed in fur, depilated, and then kept quiet for 16 to 20 hours. The depilated area was irradiated for 30 minutes using ultraviolet light from 1 lamp (FS ¹ JO Westinghouse lamps) placed 31 cm above the back of the rat. The irradiated rats were allowed to rest for 1 hour before treatment. At the end of the one hour rest period ^e of the back of the rat were subjected to a heat-irritant respectively the right and the left side, which was provided by a powered electric bulb 10 volts of 2.75 Amp.. The heat irritant causes a visible receding movement of the rat's skin muscle. The exposure time required to induce this response is taken as the control response time.

The rats were then topically treated with 0.05 ml of the agent, the equivalent volume of ethanol, propylene glycol and a known Concentration of the compound to be tested contained, treated.

2 The remedy was evenly spread over about 3 inches of the left side the back of the rat painted. The analgesic effectiveness was determined by 2 hours after the application of the By means of the increase in the threshold reaction time (in seconds)

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on the heat stimulant. The compound and analgesic potency, measured as the concentration (expressed in mM) at which a 50 percent increase in the threshold response time was observed, are listed below.

link

Benzyl 2,5-diacetoxybenzoate Hexyl 2,5-diacetoxybenzoate, ethyl p-aminobenzoic acid Acety! Salicylic acid (aspirin)

Analgesic Efficacy, ED

12.5 750 ineffective

Ethyl-p-aminobenzoic acid is the active ingredient of im
Commercially available preparations sold as local anesthetics.

The results given above show that the compounds used in accordance with the invention, d. H. the benzyl and hexyl diacetoxybenzoates have greater analgesic activity than the ethyl p-aminobenzoic acid or aspirin.

Example 13

This example illustrates the effectiveness of the dihydroxy benzoic acid derivatives according to the present invention in suppressing the inflammation associated with arthritis.

Male Sprague-Dawley rats weighing between l80 to 200 g
weighed were subcutaneously in the distal third of the tail a suspension of 0.8 mg of heat-killed mycobacterium
butyricun injected in 0.1 ml of mineral oil. This injection causes arthritis in rats, as demonstrated by foot edema (swelling) . The measurement of the relief of the inflammation that

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is associated with arthritis is made by being measures hind paw volume initially, 2 weeks later, and each subsequent week thereafter. The measurements of the paw volume are obtained by immersing each hind paw of the rat up to a predetermined mark in a mercury bath ^ that with connected to a Statham pressure transducer. The increase in pressure within the bath is proportional to that Volume of the immersed paw.

A solution of benzyl 2,5-diacetoxybenzoate was prepared. This solution contains a 1: 1 mixture of propylene glycol and ethanol and 2 % benzyl 2,5-diacetoxybenzoate. In one group, each rat was topically treated with 20 mg / kg / day of the benzyl 2,5-diacetoxybenzoate solution. The changes in paw volume after each treatment were compared with the control rats. At the end of 5 weeks of treatment, the rats treated with the benzyl 2,5-diacetoxybenzoate showed significant improvements compared to the untreated control group, as evidenced by a reduction in foot edema. The reduction in foot edema is comparable to that obtained in a control group given 200 mg / kg / day aspirin by an oral route of treatment (ie ten times the dose of the topically applied benzyl-2,5-diacetoxybenzoate).

The means in the following example are examples of several Forms of the agents according to the invention.

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- γ-

Example I ^

lotion

Isopropyl myristate 8 %

Corn oil 5 %

Propylene glycol 5 %

Triethanolamine oleate 5 %

Benzyl 2,5 ~ diacetoxybenzoate 0.25 %

Xanthan gum 0.5 %

V / ater rest

cream

Isopropyl myristate 3 %

Sorbitol 5 %

Propylene glycol 10 %

Triethanolamine stearate 17 %

Hexy1-2,5-diacetoxybenzoate 1 %

Water rest

gel

Oleyl alcohol 1 % Propylene glycol 19 % Ethyl 2,5-dipropionoxybenzoate 2 % Triethanolamine 0.5 % Ethaiol 57 % Carbüxy-vinyl-polymeres (Carbopol 9 ^ 0 » B.F. Goodrich Chemical Co.) 0.5 % water rest

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solution

Propylene glycol 10 %

Polyethylene glycol 400 2 %

Benzyl 2,5-diacetoxybenzoate 0.5

Ethanol * »8 %

Water rest

ointment

Oleyl alcohol 30 %

Cetyl alcohol 10%

Propylene glycol 26 %

Phenyl 2,5-diacetoxybenzoate 4 %

The agent of Example l ¹ "be applied topically to relieve the inflammation and irritation of acne and acne-like skin conditions.

The aforementioned 2,5-dihydroxybenzoic acid derivatives are also useful when used systemically, e.g. By oral or parenteral administration. The required Dose of the 2,5-dihydroxybenzoic acid derivative that is believed to be safe and effective will vary with the particular being treated Condition, the severity of the condition, the duration of treatment, the specific derivative applied and its concentration of use, and similar factors within the specific Knowledge and expertise of the patient or the treating artisan and a reasonable risk / benefit ratio,

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- ψ-

associated with the use of each medicinal product are appropriate. The systemic dosages and dosage ranges given herein are based on the administration of the 2,5-dihydroxybenzoic acid derivatives to a 70 kg / human and can be adjusted to provide equivalent dosages for patients of various body weights. Oral dosages range from about 0.05 g to about 50 g / day _7, usually and preferably in divided doses. Preferably, doses in the range from about 0.1 to about 20 g / day, in particular from about 0.25 g to about 10 g / day, are used when the 2,5-dihydroxybenzoic acid derivatives are administered orally.

The 2,5-dihydroxybenzoic acid derivatives can also be used parenterally in combination with a pharmaceutically acceptable carrier such as sterile water for injection, in from about 0.5 mg to about 200 mg of 2,5-dihydroxybenzoic acid derivative are administered per dose. Parenteral administration from 0.5 mg to 200 mg / day can through subcutaneous, intradermal, intramuscular, intraarticular or intravenous injection. The preferred dosage range for this mode of administration is usually in the range of about 1 to about 100 mg / day.

The 2,5-dihydroxybenzoic acid derivatives can be administered orally in the form of dosage units, such as pills, capsules, tablets, granules, solutions, elixirs, lozenges, chewing gum, chewable tablets and the like. Suppositories containing the compounds according to the invention, can also be formulated in a known manner. The oral dosage forms typically comprise the dihydroxybenzoic acid derivative and a pharmaceutical carrier, each dosage unit from about 15 mg to about 1 g of the derivative contains. The preferred amount of the derivative is in the dosage form intended for oral use in humans

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in the range from 25 ng to 70 mg, in particular from 100 mg to 500 mg.

The term "pharmaceutically acceptable carrier" as used herein includes a solid or liquid filler, diluent or an encapsulating substance. Some examples of the substances used as pharmaceutical carriers for 2,5-dihydroxybenzoic acid derivatives May serve include sugars such as lactose, glycose and sucrose, starches such as corn starch and potato starch, cellulose and their derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, Cellulose acetate, powdered tragacanth, malt, gelatin, talc, stearic acid, magnesium stearate, calcium sulfate, vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and theobroma oil, polyols such as propylene glycol, glycerine, sorbitol, mannitol and polyethylene glycol, agar, alginic acid, water for injection, isotonic saline, phosphate buffer solutions, cocoa butter (Suppository base) as well as other non-toxic, tolerable substances typically found in pharmaceutical formulations be used. Wetting agents and lubricants, such as sodium lauryl sulfate, as well as colorants, flavorings and preservatives can also be present. Well known enteric dressing agents can be used with such oral products, so that the 2,5-dihydroxybenzoic acid derivative in the acidic environment of the stomach is spared and can be absorbed through the walls of the intestines.

The pharmaceutical carrier used in conjunction with the dihydroxybenzoic acid derivatives is used in a concentration sufficient to provide a practical ratio between size and dose is sufficient. Preferably the pharmaceutical carrier makes up from about 0.1 to about 99 wt. the whole Composition from.

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The following examples serve to illustrate the invention Preparations for oral and parenteral use and their mode of use.

Example 15

Capsules were made from the following ingredients by conventional methods manufactured:

Benzyl 2,5-diacetoxybenzoate 300 mg / capsule

Strength 75 mg / capsule

Sodium Lauryl Sulphate 2.9 mg / capsule

The above capsules given orally reduced 2 capsules every 6 hours for a 70 kg patient inflammation and are important in the treatment of common diseases such as simple headache, arthritis, Reumathism, gout, bursitis, back pain, sciatica, toothache and strep throat have an analgesic effect.

Example 16

Tablets were prepared from the following ingredients according to conventional methods manufactured:

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p-Acetamidophenyl-2,5-2iacetoxybenzoate 60 mg / tablet

Lactose 40 mg / tablet

Strength 2.50 mg / tablet

Sodium carboxymethyl cellulose 1.00 mg / tablet

When the tablets were administered every h hours in an amount of 2 tablets, the tablets of the above composition reduced the pain of inflammation of the skin smaller by providing a significant analgesic effect.

The lactose used in this example was replaced by sucrose and the sodium carboxymethyl cellulose by magnesium stearate replaced without affecting the properties of the tablets.

Tablets made by conventional methods are effective in achieving an analgesic or anti-inflammatory effect Effect when the 2,5-diacetoxybenzoate of the above formulation by other derivatives of 2,5-dihydroxybenzoic acid, such as B.

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6'-r-'e ^ ethylamidohexyl-2,2-diacetoxybenzoate 2'-Ethy 1-2 ', 4'-hexadienyl-2,5-diacetoxybenzoate 2'-acetoxybenzyl-2,5-dipropionoxybenzoate 2'-fluorobenzyl-2 , 5-diacetoxybenzoate, 2'-hydroxybenzyl-2,5-diacetoxybenzoate, 2'-methoxybenzyl-2,5-diacetoxybenzoate 2 ', ^' - diacetoxybenzyl-2,5-diacetoxybenzoate, 2'-acetamidobenzyl-2,5-diacetoxybenzoate, isopropy1-2 , 5-diacetoxybenzoate propyl 2,5-diacetoxybenzoate 2'-ethylhexy1-2,5-diacetoxybenzoate decyl 2,5-diacetoxybenzoate dodecy1-2,5-diacetoxybenzoate methyl 2,5-dipropionoxybenzoate octyl-2,5-dipropionoxybenzoate hexy1 -2,5 ~ dipivaloxybenzoate Decyl-2,5-dibutyroxybenzoate Butyl-2-acetoxy-5-hydroxybenzoate Hexyl-2-propionoxy-5-hydroxybenzoate 3 ', 5'-Heχadieny1-2,5-diacetoxybenzoate 2'-Hexenyl-2 , 5-diacetoxybenzoate 9 ', 11'-dodecadieny1-2,5-diacetoxybenzoate Ben zj 1-2,5 -dibutyroxybenzoate Benzy 1- 2,5- <l iace to xy henzoat

Benzyl 2-acetoxy-5-hydroxybenzoate Phenyl-2,5-diacetoxybenzoate Phenyl-2-acetoxy-5-hydroxybenzoate 2,5-Diacetoxy-N-hexylbenzamide 2,5-Dipropionoxy-N-octylbenzamid 2, ^ j-Diacetoxy- N-dibutylbenzamide hexy1-2,5-diacetoxybenzaot 5'-hydroxyhexy1-2,5-diacetoxybenzoate 6'-acetoxyhexy1-2,5-diacetoxybenzoate 6'-fluorohexy 1-2,5- ^f 3iacetoxybenzoate and 6'-nitrohexyl-2, 5-diacetoxybenzoate

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«♦ 9

is replaced.
Example 17

Elixirs of Dihydrobenzoic Acid Derivatives for Children Aged over a year were prepared according to standard procedures with the following formulations:

Benzyl 2,5-diacetoxybenzoate 150 mg Compound tragacanth powder

(Compound tragacanth powder) 100 mg

Raspberry syrup 1 ml

Propylene glycol (1,2-propanediol) 10 ml

10 ml of the above composition was administered orally for the relief of toothache.

Example 18

Dihydroxybenzoic acid derivatives have been used for administration by injection formulated. The injection mixtures were prepared by the usual means immediately before administration and for one Single dose formulated as follows:

Benzyl 2,5-diacetoxybenzoate 10 mg

NaCl 90 mg

Water to bring the total volume to 10 ml, pH 6 to 6.5, sterilized

Patent formulations of the above compositions were intravenous to provide an analgesic

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or anti-inflammatory effect in patients who suffer from complaints, how to suffer post-operative pain or may have discomfort when oral administration is unsuitable or is counter-injected.

As can be seen from the foregoing, the topical and oral compositions according to the present invention comprise a safe and effective amount of a 2,5-dihydroxybenzoic acid derivative and are effective when applied systemically and topically. By the term "containing" or "comprising" used herein it is understood that various other inert ingredients, compatible drugs and medicaments and steps in the means and methods of the present invention can be used together so long as the critical 2.5 Dihydroxybenzoic acid derivatives are present in the agents and are used in the specified manner. The term "contain" or /. "comprising" thus encompasses the narrower terms "consisting essentially of" and "consisting of" which characterize the use of the essential 2,5-dihydroxybenzoic acid derivatives in the agents and methods of the invention.

The term "compatible" is used herein to mean that the Components of the remedies are able to unresponsive in a manner which increases the effectiveness of the entire remedy below ordinary Conditions of use would significantly reduce to be admixed.

It can also be seen from the foregoing that the present Invention comprises methods for providing an analgesic effect and for relieving inflammation, a safe and effective amount, usually of about 0.01 to about 50 g / patient / day of a 2,5-dihydroxybenzoe-

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acid derivative, usually with a pharmaceutically acceptable one Carrier applied topically or administered systemically. The methods, remedies and derivatives are used to treat acne and to treat acne-like skin conditions and for various Disorders of the deeper structures, muscles, tendons, bursae, and joints associated with disease and injury and in various other conditions in which salxcylate compounds such as aspirin have been used for relief the pain and discomfort were used an analgesic Provide effect and relieve inflammation.

The agents according to the invention are a, much more effective pain

^ Is aspirin and anti-inflammatory agents < when applied topically. When administered systemically, those are according to the invention Remedies at least as effective as aspirin, but considerably less toxic than aspirin and do not show any negative side effects (stomach bleeding, etc.), such as those associated with aspirin.

For: The Procter & Gamble Company Cincinnati, Ähio / jf.V.St.A.

Lawyer

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Claims (1)

ADLLC. . ".., .. 'J3 FRA. ! KPJ ^ Γ AM MAIN 80 Claims
"Λ
1 · Dihydroxybenzoic acid derivatives of the general formula COYR ₂ wherein R _{1 is} an alkyl radical with 1 to ^ carbon atoms, Y 0, NH or NR ₂ , R_ is a saturated or unsaturated aliphatic radical with 1 to 4 carbon atoms, a benzyl radical or a phenyl radical and X is a hydrogen atom or a radical COR ^, where R, an alkyl radical having 1 to ¹ carbon atoms darstel3t J, mean, with the proviso that Rp has at least 2 carbon atoms when Y is 0, X is a radical of the formula COR, and R ₁ and R_ methyl radicals. 2. A compound according to claim 1, characterized in that X of the formula is the radical COR. 3. A compound according to claim 2, characterized in that Y is 0 of the formula. ¹ I. Compound according to claim 3, characterized in that Rp of the formula is a benzyl radical. 5. A compound according to claim 3 »characterized in that Rp of the formula denotes a phenyl radical. 809825/0775 6. Connection na:;. Ar.cpr-.cr. 3> characterized in that R _? of the formula means an all-iylrasc. 7. A compound according to claim 6, characterized in that Rp of the formula denotes an alkyl radical having 6 to S carbon atoms. 8. A compound according to claim 7, characterized in that R " of the formula denotes a hexyl radical. 9. A compound according to claim 3, characterized in that Rp of the formula denotes an alkenyl radical. 10. A compound according to claim 3, characterized in that Rp of the formula denotes an alkadienyl radical. 11. A compound according to claim ^, characterized in that R ₁ and R, of the formula tert. . Mean butyl residues. 12. A compound according to claim 6, characterized in that R _{1 and R 1 of} the formula represent methyl radicals. 13. A compound according to claim 6, characterized in that R _{1 and R 1 of} the formula tert are butyl radicals. 1 ^. Compound according to Claim 13, characterized in that Rp of the formula denotes a kexyl radical. 15. A compound according to claim 2, characterized in that Y
of the formula NH or NR ₂ . 16. A compound according to claim 15, characterized in that Y of the formula is NH. 809825/0775 17. A compound according to claim 1, characterized in that X the formula a ".. 'means assstoffatoni. l3. Connection according to claim 17, characterized in that Y of the formula 0 means. 19. A compound according to claim 17, characterized in that Y of the formula is NH or NRp. 20. Benzyl 2,5-diacetoxybenzoate as a compound according to Claim 1. 21. Hexyl 2,5-diacetoxybenzoate as a compound according to Claim 1. 22. Agent that relieves pain and inflammation, characterized in that that it is essentially made up a) an effective amount of a 2,5-dihydroxybenzoic acid derivative the general formula OCOR. COYR ₂ wherein R _{1 is} an alkyl radical with 1 to k carbon atoms, Y is a radical of the formula O, NH or NR ₂ , Rp is a saturated or unsaturated aliphatic radical with 1 to 1Ί carbon atoms, a benzyl radical or a phenyl radical and X is a hydrogen atom or a radical of the formula COR ,, in which R, represents an alkyl radical having 1 to 4 carbon atoms, and b) the balance consists of a pharmaceutically acceptable carrier. 809825/0775 23 · Mictel according to claim 22, characterized in that X
of the formula is a radical of the formula COR. 2U. Means according to claim 23, characterized in that Y is the
Formula O means. 25. Composition according to claim 24, characterized in that Rp of the formula denotes the benzyl radical. 26. Means according to claim 24, characterized in that Rp
of the formula denotes the phenyl radical. 27. Agent according to Claim 2 ¹ I, characterized in that Rp of the formula denotes an alkyl radical. 28. Composition according to claim 27, characterized in that Rp of the formula is an alkyl radical having 6 to 8 carbon atoms. 29. Means according to claim 28, characterized in that Rp
of the formula denotes a hexyl radical. 30. Composition according to claim 24, characterized in that Rp of the formula is an alkenyl radical. 31. Composition according to claim 24, characterized in that R _{2 of} the formula is an alkadienyl radical. 32. Composition according to claim 25, characterized in that R ₁ and R, of the formula tert. Mean butyl residues. 809825/0775 33 · Means according to claim 27, characterized in that R ₁ and R-. of the formula mean kechyl radicals. 3 ¹ I. Agent according to claim 27, characterized in that R _{1 and R 1 of} the formula represent tert-butyl radicals. 35. Means according to claim 34, characterized in that wheels Formula means a hexyl radical. 36. Agent according to claim 23, characterized in that Y of the formula denotes a radical of the formula NH or NR_, 37 · Means according to claim 36 »characterized in that Y is a Radical of the formula NH. 38. Composition according to claim 22, characterized in that X of the formula denotes a hydrogen atom. 39. Means according to claim 22, characterized in that the
Dihydroxybenzoic acid derivative is benzyl 2,5-diacetoxybenzoate. 40. Means according to claim 22, characterized in that the
Dihydroxybenzoic acid derivative is hexyl 2,5-diacetoxybenzoate. ill. Composition according to claim 22 for topical application to the Skin, characterized in that the dihydroxybenzoic acid derivative makes up from 0.001 to 10% of the agent. 42. Composition according to claim ¹ Il in the form of a lotion, characterized in that it a) the dihydroxybenzoic acid derivative, b) from 1 to 25 % of an emollient and c) comprises water as the remainder. 809825/0775 43. Agent according to claim 42, characterized in that it additionally contains from 1 to 10 % of an emulsifier. 44. Agent according to claim 41 in the form of a cream, characterized in that that it a) the dihydroxybenzoic acid derivative, b) from 5 to 50 % of an emollient and c) contains water as the remainder. 45. Agent according to claim 44, characterized in that it additionally contains from 3 to 50 % of an emulsifier. 46. Means according to claim 41 in the form of a solution, characterized in that that it a) the dihydroxybenzoic acid derivative and b) contains an organic solvent as the remainder. 47. Agent according to claim 41 in the form of a gel, characterized in that that it a) the dihydroxybenzoic acid derivative, b) from 5 to 75 % of an organic solvent, c) from 0.5 to 20 % of a thickener and d) contains water as the remainder. 809825/0775 -ι- * 18. Agent according to claim 1 ir. The form of a solid, characterized marked dai it a) the dihydroxybenzoic acid derivative and b) contains from 50 to 98 % of an emollient. 49 ♦ Agent according to claim 22 for oral administration in the form of a Dosage unit, characterized in that it contains from about 15 mg to about 1 g of the dihydroxybenzoic acid derivative and contains a pharmaceutically acceptable carrier. 50. Composition according to claim 22 for parenteral administration, characterized characterized in that it contains from about 0.5 mg to about 200 mg of the dihydroxybenzoic acid derivative and a pharmaceutical contains acceptable carrier. 809825/0775