DE102014008070A1 - Cyanoformyloxybenzoesäuren, process for their preparation and their use as medicaments - Google Patents

Abstract

The present invention provides compounds of the general formula (I) which are arbitrarily substituted on the aromatic ring in which R has the meaning defined in claim 1, their salts, in particular their physiologically tolerable salts, which have valuable properties, their preparation, which are the pharmacologically active compounds contained medicinal products and their use.

Description

in der R wie in Anspruch 1 definiert ist und deren Salze, insbesondere deren physiologisch verträgliche Salze mit organischen Basen, welche wertvolle Eigenschaften aufweisen, deren Herstellung, die die pharmakologisch wirksamen Verbindungen enthaltenden Arzneimittel, deren Herstellung und deren Verwendung.The invention relates to Cyanoformyloxybenzoesäuren the general formula

in which R is as defined in claim 1 and their salts, in particular their physiologically acceptable salts with organic bases, which have valuable properties, their preparation, the medicaments containing the pharmacologically active compounds, their preparation and their use.

In the above general formula (I), in a first embodiment
R is a hydrogen atom, a straight-chain or branched C _1-6 -alkyl radical, a straight-chain or branched C _1-4 -alkenyl radical or a straight-chain or branched C _1-4 -alkoxy radical,
wherein the substitution pattern of R, the carboxy group and the cyanoformyloxy group is variable on the aromatic,
and their salts.

Examples of substitution patterns are 2- (cyanoformyloxy) benzoic acid, 3- (cyanoformyloxy) benzoic acid, 4- (cyanoformyloxy) benzoic acid, 2- (cyanoformyloxy) -4-methylbenzoic acid, 2- (cyanoformyloxy) -6-methylbenzoic acid, 2- (Cyanoformyloxy) -5-methylbenzoic acid, 2- (cyanoformyloxy) -4-ethylbenzoic acid, 2- (cyanoformyloxy) -3-methoxybenzoic acid, 2- (cyanoformyloxy) -4-ethyloxybenzoic acid, 2- (cyanoformyloxy) -5-isopropylbenzoic acid, 2- (Cyanoformyloxy) -4-isopropylbenzoic acid, 2- (cyanoformyloxy) -3-isopropylbenzoic acid, 2- (cyanoformyloxy) -4-pentylbenzoic acid 2- (cyanoformyloxy) -4-hexylbenzoic acid, 2- (cyanoformyloxy) -5-hexylbenzoic acid, 2- ( Cyanoformyloxy) -4-allylbenzoesäure.

Examples of the C _1-6 -alkyl radicals mentioned above in the definitions are the methyl, ethyl, 1-propyl, 2-propyl, n-butyl, sec-butyl, tert-butyl, 1-pentyl- , 2-pentyl, 3-pentyl, neo-pentyl, 1-hexyl, 2-heyl or 3-hexyl.

Examples of the above mentioned in the definitions C _1-4 alkenyl radical are the vinyl, 1-allyl, 2-allyl, 3-allyl, 1-buten-3-yl or 1-buten-4-yl group ,

Examples of the above-mentioned in the definitions C _1-4 alkoxy are the methoxy, ethoxy, 1-propyloxy, 2-propyloxy, n-butyloxy, sec-butyloxy or tert-butyloxy group.

• (1) Cyanoformylsalicylsäure
• (2) 4-(Cyanoformyloxy)-benzoesäure
• (3) 2-(Cyanoformyloxy)-4-methylbenzoesäure
• (4) 2-(Cyanoformyloxy)-6-methylbenzoesäure
• (5) 2-(Cyanoformyloxy)-5-methylbenzoesäure
• (6) 2-(Cyanoformyloxy)-3-methoxybenzoesäure
• (7) 2-(Cyanoformyloxy)-5-isopropylbenzoesäure
• (8) 2-(Cyanoformyloxy)-5-hexylbenzoesäure
• (9) 2-(Cyanoformyloxy)-4-allylbenzoesäure
• deren Gemische und deren Salze.

Examples of very particularly preferred compounds of the above general formula (I) include the following:

• (1) Cyanoformylsalicylic acid
• (2) 4- (Cyanoformyloxy) benzoic acid
• (3) 2- (Cyanoformyloxy) -4-methylbenzoic acid
• (4) 2- (Cyanoformyloxy) -6-methylbenzoic acid
• (5) 2- (Cyanoformyloxy) -5-methylbenzoic acid
• (6) 2- (Cyanoformyloxy) -3-methoxybenzoic acid
• (7) 2- (Cyanoformyloxy) -5-isopropylbenzoic acid
• (8) 2- (Cyanoformyloxy) -5-hexylbenzoic acid
• (9) 2- (Cyanoformyloxy) -4-allylbenzoic acid
• their mixtures and their salts.

in der R die in der allgemeinen Formel (I) erwähnte Bedeutung besitzt, mit Cyanformylchlorid.The compounds of general formula (I) are prepared by methods known in principle. The following process has proven particularly suitable for the preparation of the compounds of general formula (I) according to the invention:
Reaction of a phenol of the general formula

in which R has the meaning mentioned in general formula (I), with cyanoformyl chloride.

The reaction is preferably carried out at a temperature of -20 degrees Celsius to +50 degrees Celsius in dry diethyl ether. The reaction takes place in the presence of a base, such as triethylamine.

Possibilities for the preparation of the phenol of the general formula (II) are familiar to the person skilled in the art. The preparation of these blocks is carried out according to the literature known methods.

The preparation of cyanoformyl chloride is carried out according to a literature specification [ R. Appel and M. Siray, Angewandte Chemie 95 (1983) 807 ].

If desired, the resulting compounds of the general formula (I) can be converted into their physiologically compatible addition salts with their addition salts with organic bases, in particular for pharmaceutical use. Suitable bases for this example, ammonia, cyclohexylamine, dicyclohexylamine, ethanolamine, diethanolamine, and triethanolamine into consideration.

The novel compounds of the general formula (I) and their physiologically tolerated salts have valuable pharmacological properties. They are effective as a painkiller.

Painful suffering and illnesses are omnipresent in our society, which is why analgesics are among the best-selling and most sought-after drugs of the time. Many of these painkillers, however, sometimes have very strong side effects beyond their analgesic effects. While these are usually only mild in the administration of acetylsalicylic acid, such as nausea and heartburn, asthma can cause seizures. In children, acetylsalicylic acid should not be used, as it can sometimes trigger the deadly Reye syndrome. Other currently used analgesics, such as tramadol and morphine, in addition to their own partial extreme side effects, such as seizures or respiratory depression, also lead in part to severe addictive conditions or reduced effectiveness of the analgesic used by habituation effects with prolonged use, whereby higher dosages must be administered accordingly have an increasing effect on any side effects. In addition, pathogens may over time develop resistance to drugs, making the development of new drugs indispensable. Preparations Example 1 Cyanoformylsalicylic acid

13.8 g (0.1 mol) of salicylic acid are added in a 500 ml flask at room temperature with 100 ml of dry diethyl ether and 20.2 g (0.2 mol) of triethylamine with exclusion of moisture (calcium chloride) and cooled to -10 degrees Celsius. 100 ml of a previously prepared ethereal solution containing 8.95 g (0.1 mol) of cyanoformyl chloride is added dropwise to the suspension stirred with a magnetic stirrer at -10 to -5 degrees Celsius with exclusion of moisture in 20 minutes. The reaction mixture is stirred for 18 hours at 20 to 25 degrees Celsius and then treated with 250 ml of water and treated with 0.1 mol of dilute hydrochloric acid. The resulting mixture is separated in a separating funnel. The organic phase is added once with 0.5% treated hydrochloric acid. The organic phase is dried over anhydrous sodium sulfate, filtered and concentrated. The result is a colorless solid which is separated by means of a Büchner funnel and then dried. Yield: 18.1 g (95%) C ₉ H ₅ NO ₄ (191.02) Theory (%) C 56.55 H 2,64 N 7,33 Found (%) C 57.01 H 2,82 N 7,19 Production Example 2 4- (Cyanoformyloxy) benzoic acid

Production Example 1 is repeated, but instead of 13.8 g (0.1 mol) of salicylic acid, 13.8 g (0.1 mol) of 4-hydroxybenzoic acid are used. Yield: 16.7 g (87%) C ₉ H ₅ NO ₄ (191.02) Theory (%) C 56.55 H 2,64 N 7,33 Found (%) C 55.03 H 2,88 N 7.06 Production Example 3 2- (Cyanoformyloxy) -4-methylbenzoic acid

Production Example 1 is repeated, but instead of 13.8 g (0.1 mol) of salicylic acid, 15.2 g (0.1 mol) of 2-hydroxy-4-methylbenzoic acid are used. Yield: 16.5 g (80%) C ₁₀ H ₇ NO ₄ (205,17) Theory (%) C 58.54 H 3,44 N 6,83 Found (%) C 58.19 H 3.68 N 7.09 Preparation 4 2- (Cyanoformyloxy) -6-methylbenzoic acid

Production Example 3 is repeated, but instead of 15.2 g (0.1 mol) of 2-hydroxy-4-methylbenzoic acid, 15.2 g (0.1 mol) of 2-hydroxy-6-methylbenzoic acid are used. Yield: 14.7 g (72%) C ₁₀ H ₇ NO ₄ (205,17) Theory (%) C 58.54 H 3,44 N 6,83 Found (%) C 58.63 H 3,29 N 6.74 Production Example 5 2- (Cyanoformyloxy) -5-methylbenzoic acid

Preparation Example 3 is repeated, but instead of 15.2 g (0.1 mol) of 2-hydroxy-4-methylbenzoic acid, 15.2 g (0.1 mol) of 2-hydroxy-5-methylbenzoic acid are used. Yield: 14.1 g (69%) C ₁₀ H ₇ NO ₄ (205,17) Theory (%) C 58.54 H 3,44 N 6,83 Found (%) C 58,75 H 3,27 N 6.78 Production Example 6 2- (Cyanoformyloxy) -3-methoxybenzoic acid

Preparation Example 3 is repeated except that instead of 15.2 g (0.1 mol) of 2-hydroxy-4-methylbenzoic acid, 16.8 g (0.1 mol) of 2-hydroxy-3-methoxybenzoic acid are used. Yield: 15.1 g (68%) C ₁₀ H ₇ NO ₅ (221,17) Theory (%) C 55.31 H 3,19 N 6,33 Found (%) C 54.95 H 3,20 N 6.63 Preparation 7 2- (Cyanoformyloxy) -5-isopropylbenzoic acid

Preparation Example 3 is repeated, but instead of 15.2 g (0.1 mol) of 2-hydroxy-4-methylbenzoic acid, 18.0 g (0.1 mol) of 2-hydroxy-5-isopropylbenzoic acid are used. Yield: 16.8 g (72%) C ₁₀ H ₇ NO ₅ (233.07) Theory (%) C 61.80 H 4.75 N 6.01 Found (%) C 62.05 H 5.00 N 6.23 Preparation 8 2- (Cyanoformyloxy) -5-hexylbenzoic acid

Preparation Example 3 is repeated, but instead of 15.2 g (0.1 mol) of 2-hydroxy-4-methylbenzoic acid, 22.2 g (0.1 mol) of 2-hydroxy-5-hexylbenzoic acid are used. Yield: 23.8 g (87%) C ₁₅ H ₁₇ NO ₄ (275.12) Theory (%) C 66,44 H 6,22 N 5.09 Found (%) C 62.05 H 5.00 N 6.23 Preparation 9 2- (Cyanoformyloxy) -4-allylbenzoic acid

Preparation Example 3 is repeated except that instead of 15.2 g (0.1 mol) of 2-hydroxy-4-methylbenzoic acid, 22.2 g (0.1 mol) of 2-hydroxy-4-allylbenzoic acid are used. Yield: 17.5 g (76%) C ₁₅ H ₁₇ NO ₄ (231.05) Theory (%) C 62,84 H 3.92 N 6.06 Found (%) C 62,95 H 4.03 N 6.27

Analgesic effect

1. Randall Selitto test

For the determination of the antinoceptive in vivo effect in the Randall-Selitto test [ Arch. Int. Pharmacodyn. Ther. 111, 409 (1957) ] was injected by injecting 0.1 ml of a 20% baker's yeast suspension into a rat hind paw to induce edema which resulted in pronounced mechanohyperalgesia after four hours. Increasing pressure (0 to 450 g / mm ² ) with a puncture (0.2 mm tip diameter) on the inflamed rat hind paw was then used to generate pain, and as a measure, the pressure at which the rat vocalization reaction occurred. Animals that had not vocalized to the maximum permitted pressure were considered analgesic. The test substances were administered intraperitoneally at a dose of 10 ml / kg 5 and 30 minutes before the Randall-Selitto measurement. The test results are in MPE (maximum possible effect) in% according to the formula: [Post-substance measurement value - pre-substance measurement value] / maximum value-pre-substance measured value] × 100 shown.

ED50 calculations were done by linear regression, confidence intervals were calculated according to Lichtfield and Wilcoxon [ J. Pharmacol. Exp. Ther. 95, 99 (1949) ]. substance Dose [mg / kg] Antinociceptive in vivo activity [MPE (%)] In vivo Antinociceptive Activity [ED50 (mg / kg)] Vehicle (aqueous carboxymethylcellulose suspension) - -15.3 ± 7.4 Comparison of acetylsalicylic acid 464 36.3 ± 8.0 Cyanoformylsalicylsäure 100 10.2 ± 3.9 4- (Cyanoformyloxy) benzoic acid 46.6 (37.0-58.8) 2- (Cyanoformyloxy) -4-methylbenzoic 71.0 (58.5-87.3) 2- (Cyanoformyloxy) -6-methylbenzoic acid 100 15.5 ± 7.1 2- (Cyanoformyloxy) -5-methylbenzoic acid 128.6 (98.5-153.7) 2- (Cyanoformyloxy) -3-methoxybenzoic acid 100 35.3 ± 16.5 2- (Cyanoformyloxy) -5-isopropylbenzoic 128.4 (97.4-152.2) 2- (Cyanoformyloxy) -5-hexylbenzoic acid 120.9 (94.5-144.2) 2- (Cyanoformyloxy) -4-allylbenzoesäure 118.4 (98.5-139.9) Vehicle (aqueous carboxymethylcellulose suspension) 2.5 to 19.8 4- (Cyanoformyloxy) benzoic acid 46.4 15.5 ± 5.95 tramadol 2.15 13.5 ± 3.45 4- (cyanoformyloxy) benzoic acid and tramadol 46.4 and 2.15 47.9 ± 8.56 morphine 1.46 12.0 ± 4.62 4- (cyanoformyloxy) benzoic acid and morphine 46.4 and 1.46 23.4 ± 4.82 metamizole 21.5 5.1 ± 3.86 4- (cyanoformyloxy) benzoic acid and metamizole 46.4 and 21.5 41.5 ± 11.50 acetylsalicylic acid 464 1.2 ± 3.66 4- (cyanoformyloxy) benzoic acid and acetylsalicylic acid 46.4 and 464 43.6 ± 8.27 paracetamol 464 19.7 ± 2.99 4- (cyanoformyloxy) benzoic acid and paracetamol 46.4 and 464 27.9 ± 6.34

2. Hot Plate Test

With the hot-plate test arrangement [ J. Pharmacol Exp. Ther. 133, 400 (1944) ], the effect was tested for acute, non-inflammatory thermal stimulus. The spinal / supraspinal nonuceptive reaction time is measured. For 4- (Cyanoformyloxy) benzoic acid, an ED ₅₀ value of about 80 mg / kg ip for direct Antithermoperalgesiewirkung was determined in the mouse.

3. Formalin test

To test indication-related efficacy in chronic pain, the formalin test [ Pain 4, 161 (1977) ; Pain 30, 103 (1987) ] selected. In this case, after the injection of formalin into the hindpaw of rat or mouse, the pain reactions of the animal were recorded as complex behavior patterns by observation and quantified for the efficacy testing of 4- (cyanoformyloxy) benzoic acid (chemical example 2) according to a score system. This test is not limited to the detection of spinal escape reactions or supraspinal controlled individual reactions, but detects the analgesic effect in the behavior of the whole animal.

For 4- (cyanoformyloxy) benzoic acid in the rat an ED ₅₀ value of 25.6 mg / kg for the direct analgesic effect and an ED ₅₀ value of 23.8 mg / kg for the analgesic effect in the second chronic Phase determined. The rat gave an ED ₅₀ value of 22.6 mg / kg for the direct analgesic effect and an ED ₅₀ value of 23.1 mg / kg for the analgesic effect in the second chronic phase.

QUOTES INCLUDE IN THE DESCRIPTION

This list of the documents listed by the applicant has been generated automatically and is included solely for the better information of the reader. The list is not part of the German patent or utility model application. The DPMA assumes no liability for any errors or omissions.

Cited non-patent literature

• R. Appel and M. Siray, Angewandte Chemie 95 (1983) 807 [0011]
• Arch. Int. Pharmacodyn. Ther. 111, 409 (1957) [0024]
• J. Pharmacol. Exp. Ther. 95, 99 (1949) [0025]
• J. Pharmacol Exp. Ther. 133, 400 (1944) [0026]
• Pain 4, 161 (1977) [0027]
• Pain 30, 103 (1987) [0027]

Claims (7)

Compounds of the general formula

in which R represents a hydrogen atom, a straight-chain or branched C _1-6 -alkyl radical, a straight-chain or branched C _1-4 -alkenyl radical or a straight-chain or branched C _1-4 -alkoxy radical, the substitution pattern of R, the carboxy group and the cyanoformyloxy group is variable at the aromatic, and their salts. Compounds of general formula (I) according to claim 1 in which R is a methyl, ethyl, 1-propyl, 2-propyl, n-butyl, sec-butyl, tert-butyl, 1-pentyl. 2-pentyl, 3-pentyl, neo-pentyl, 1-hexyl, 2-heyl, 3-hexyl, vinyl, 1-allyl, 2-allyl, 3-allyl, 1 Butene-3-yl or 1-butene-4-yl, methoxy, ethoxy, 1-propyloxy, 2-propyloxy, n-butyloxy, sec-butyloxy or tert-butyloxy group. The following compounds of general formula (I) according to claim 1: (1) cyanoformylsalicylic acid, (2) 4- (cyanoformyloxy) benzoic acid, (3) 2- (cyanoformyloxy) -4-methylbenzoic acid, (4) 2- (cyanoformyloxy) -6-methylbenzoic acid, (5) 2- (cyanoformyloxy) -5-methylbenzoic acid, (6) 2- (cyanoformyloxy) -3-methoxybenzoic acid, (7) 2- (cyanoformyloxy) -5-isopropylbenzoic acid, (8) 2- (cyanoformyloxy) -5-hexylbenzoic acid, (9) 2- (Cyanoformyloxy) -4-allylbenzoic acid and its salts. Physiologically acceptable salts of the compounds according to any one of claims 1 to 3 with organic bases. A process for the preparation of the compounds of the general formula (I) according to at least one of claims 1 to 3, characterized in that a phenol of the general formula

in which R has the meaning mentioned in the general formula (I), is reacted with cyanoformyl chloride. A medicament containing a compound according to at least one of claims 1 to 3 or a physiologically acceptable salt according to claim 4, optionally together with one or more inert carriers and / or diluents. Use of a compound according to at least one of claims 1 to 3 for the manufacture of a medicament for the acute and prophylactic treatment of pain, in particular chronic pain, neuropathic pain, post-operative pain, inflammatory pain, perioperative pain, arthralgia, migraine, neurodegeneration, nerve injury, neurotic Skin diseases, stroke, urinary hypersensitivity, irritable bowel, respiratory diseases such as asthma or chronic obstructive pulmonary disease, skin irritation, irritation of the eyes or mucous membranes, gastric and duodenal ulcers, gastritis or other inflammatory diseases, pain from osteoarthritis or back pain.