DE1802568A1 - Sydnone derivs - Google Patents

Abstract

(A) Cpds. (I) R1 is a hydrocarbon group (1-6C) R2 and R3 are alkyl (1-5C), alkenyl (2-5C) or aralkyl (7-9C), or R2 and R3 together with the N atom to which they are joined form a heterocyclic ring of 5-7 atoms. The aralkyl ring may be substd. by OH, methoxy, NO2 or halogen or the heterocyclic ring by alkoxy (1-5C), alkyl (1-3C), phenyl, halophenyl, benzyl, formyl or phenethyl. (B) Acid-addition salts of cpds. (I). Analgesics of low toxicity, without secondary effects, useful for treating post-operative pain, toothache and stomach-ache.

Description

Sydnone Derivatives and Processes for Their Preparation The invention relates to new valuable sydnone derivatives of the formula in which Ri is a hydrocarbon radical with 1 to 6 carbon atoms, R2 and R3 each stand for an alkyl radical with 1 to 5 carbon atoms, an alkenyl radical with 2 to 5 carbon atoms, an aralkyl radical with 7 to 9 carbon atoms or together with the neighboring nitrogen atom a five- to seven-membered heterocyclic ring, pharmaceutically acceptable salts of these derivatives, pharmaceutical preparations which contain at least one sydnone derivative of the formula (I), and a new process for the preparation of the sydnone derivatives. The new compounds are prepared by reacting VeX compounds of the formula in which R1 has the meaning already mentioned, with formaldehyde and a secondary amine of the formula in which R2 and R3 have the meaning already mentioned.

As hydrocarbon radicals for which R1 in formulas (I) and (II) is, for example, alkyl radicals with 1 to 6 carbon atoms, e.g. methyl, Ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, isopentyl, sec-amyl, n-Hexyl and isohexyl radicals, alkenyl radicals with 2 to 6 carbon atoms, e.g. vinyl, Allyl, butenyl and divinylmethyl radicals, alicyclic radicals of a five- or see-membered Ring, e.g. cyclopentyl, cyclohexyl, cyclopentadienyl and cyclohexadienyl radicals, and aromatic radicals such as phenyl radicals in question, and these radicals can be a or more substituents, e.g.

Hydroxyl groups, methoxy groups, nitro groups and halogen atoms (e.g. F, Cl, Br, J) included.

As alkyl radicals for which R2 and R3 in formulas (I) and (III) stand, come, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl and isopentyl radicals and, as alkenyl radicals, for example vinyl, allyl and butenyl residues in question. An example of an aralkyl radical is one with a lower one Alkyl radical, substituted phenyl radical, zOB benzyl, phenylethyl, phenylpropyl usaz0 in question If R2 and R3 together with the neighboring nitrogen atom form a five- to seven-membered heterocyclic ring, the heterocyclic radical bet for example Morpholino, piperidino, piperazino, pyrrolidino and Be hexamethyleneimino, and the remainder can be one or more substituents on the ring, s.B. Alkoxy with 1 to 5 carbon atoms, alkyl with 1 to 3 carbon atoms, Phenyl, halophenyl (e.g. chlorophenyl or fluorophenyl), benzyl, formyl, phenylethyl etc., which are not involved in the reaction according to the invention.

The starting compound of the formula (II) can easily be prepared, for example, by the following reaction sequence: R1 - SH - Cn2 C i X NaNO2 in sour nedjum I. R1-4HCH2C0Or R1 -; l - CH2 - cr NaO in see also alkaline hydrolysis Medium 1 (, aOR) (i; a Oi) R, - CH2COOH R1 - 1§ - CW2COO, ia NO N0 Ring closure 1 \ R1 - N - C-. 0+ 1 r; O- O Here, R1 has the meaning given above.

In the method according to the invention, formaldehyde can be used as an aqueous solution can be used, but it is preferably used in For: of p-formaldehyde.

The reaction is carried out under acidic conditions.

A solvent, e.g. water, alcohols, ethers, organic acids etc., or mixtures thereof, can be used so long as this supports the reaction is not disturbed 0 However, it becomes more useful for the reaction according to the invention a weak organic acid, e.g. acetic acid, as such or as a mixture with other solvents used to If the starting compound (III) is in the form of a Acid addition salt is used, the acidification of the reaction solution is not necessary.

The other reaction conditions, e.g. the reaction temperature and the reaction time, are different depending on the sydnones and secondary used Amines, but generally the reaction will take place at about 0 to 150 ° C for a period carried out from 30 minutes to a few hours.

If necessary, further formaldehyde and further secondary Amine can be added.

The final product is usually obtained in the form of its free base and, if necessary, into the pharmaceutically acceptable salt, e.g. the hydrochloride, Picrate, nitrate, sulfate, phosphate, toluene sulfonate, methanesulfonate, citrate, nethiodide etc. converted.

The sydnone derivatives according to the invention and their pharmaceutically acceptable ones Salts have a strong analgesic effect, and rather low toxicity few side effects. The connections saad. effective against a wide variety of pains, e.g. post-operative pain, toothache and abdominal pain.

The superiority of the compounds according to the invention is demonstrated by illustrated the following experiments.

Experiment 1: Acute Toxicity A 10% (w / w / yola) solution of the test compound (3-Isopropyl-4-morpholinomethylsydnone) in physiological saline solution became groups administered orally in different doses of 5 male mice each weighing about 18 g each The mice treated in this way were left at 2300 and 60% relative humidity for 24 hours whereupon the mean lethal dose according to the Litchfield-Wilcoxon method (see The Journal of Pharmacology and Experimental herapeutics, 96, 99 (1949)) from Number of surviving mice was calculated, mean lethal dose (LD50) = 1425 mg / kg 95% confidential limits: 1177.7 to 1724.2 mg / kg.

In contrast, the LD50 determined by the same method for aminopyrine was 458 mg / kgX Experiment 2: Analgesic effect The analgesic effect of the compound was determined using the method developed by R. Koster and co-workers in Federation Proceeding 18, 412 (1959).

A solution of the test compound in physiological saline solution was given in different doses in groups of 5 male mice each weighing about 18 g administered orally.

Thirty minutes after the tracing, each mouse was given a 0.7% acetic acid solution (on a volume basis) in an amount of 0.1 ml / 10 g body weight intraperitoneally administered. After the administration of acetic acid, the convulsions became convulsive observed each mouse for 20 minutes.

The results are shown in the following table together with the results of a control experiment in which pure saline was administered became. The percentages in the table are based on the frequency of, convulsive Curvatures in the comparison animals Test compound dose frequency of mg / kg of body convulsive weight curvatures,% None (control experiment) - 100 3-n-hexyl-4-morpholino- 25 78 methylsydnone 50 34 100 3 3-isopropyl-4-morpholino- 25 67 methylsydnon 5Q 12 100 1 aminopyrine 1 100 66 pharmaceutical preparations, which can contain one or more of the compounds according to the invention according to for the production of capsules, syrups, oils, injection liquids, etc. customary processes.

In the various dosage forms mentioned above, the effective Ingredients in a lesser amount with a greater amount of a carrier exist, but the reverse relationship is also possible.

An effective daily dose of the sydnone derivatives according to the invention for adult people, e.g. for relieving toothache or the like, is usually about 0.1 to 3.0 g, expediently 0.15 to 0.30 g, but a higher or higher is also possible smaller daily dose effective depending on the symptoms.

In the following examples, the percentages relate to the Weight.

Example 1 A mixture of 7.0 g of 3-isopropylsydnone, 1.5 g of p-formaldehyde, 4.0 g of morpholine and 50 ml of acetic acid are heated to 100 ° C. for 3 hours. After After cooling, the acetic acid is distilled off under reduced pressure. The residue is dissolved in ethyl acetate. A dilute hydrochloric acid solution is added to the solution, to transfer the desired compound into the aqueous phase. The aqueous phase - is neutralized with sodium hydrogen carbonate, becoming an oily substance separates, which is extracted with ethyl acetate. The extract is washed with water and dried. After the solvent has been removed, 4.0 g of 3-isopropyl-4-morpholinomethyl aydnone are added obtained in the form of crystals with a melting point of 820C.

Elemental analysis: C H N Calculated for C10H17li303: 52.84 7.54 18.49 Found: 52.84 7.56 18.56 This compound is converted into that at 19200 with decomposition Melting hydrochloride converted by putting it in a small amount of methanol dissolved and added to the solution methanolic hydrochloric acid with cooling.

Elemental analysis: C H y Calculated for C1 0H17N3O3.HCl: 45.54 6.88 15.93 Found: 45.30 6.74 16.02 Example 2 3.4 g of 3-cyclohexylsydnone, 0.75 g of p-formaldehyde and 2.0 g of morpholine are added to a mixture of 5 ml of ethanol and 5 ml of acetic acid given. The mixture is heated to 950 ° C. for 5 hours. After adding 5 ml of acetic acid, 0.75 g of p-formaldehyde and 2.0 g of ilopholine for the reaction mixture is this additional Heated for 6 hours. After cooling, the ethanol is under reduced pressure distilled off and the residue with an aqueous bicarbonate solution neutralized, whereupon the aqueous solution is extracted with ethyl acetate. The extract is dehydrated and concentrated, leaving 5.9 g of crude crystals which be recrystallized from ligroin. This gives 2.0 g of 3-cyclohexyl-4-morpholinomethylsydnone Elemental analysis obtained as colorless crystals from melting point 127 to 128 ° C: 0 H N Calculated for 013H21N303: 58.41 7.92 15.72 Found: 58.37 7.92 15.74 These Compound is dissolved in a small amount of methanol. Methanolisene becomes the solution Added hydrochloric acid, with crystals separating out of the solution. The crystals are filtered off and recrystallized from methanol, 3-cyclohexyl-4-morpholinomethylsydnonhydrochlorid in the form of colorless needles with a melting point of 206 to 2080C (decomp.) Example 3 1.0 g of 3-cyclohexylsydnone and 0.5 g of p-formaldehyde are dissolved in 10 ml of ethanol suspended, after adding 1 ml of piperidine and 3 ml of acetic acid to the suspension the mixture kept for 10 hours at 1000C, the ethanol and acetic acid are distilled off from the reaction mixture under reduced pressure. The residue will by column chromatography on silica gel using ether as the eluent cleaned. After evaporation of the solution by means of the eluate, crude crystals become obtained, which are recrystallized from ligroin. This is 3-cyclohexyl-4-piperidinomethylsydnone obtained in the form of colorless crystals with a melting point of 124 to 12600.

Elemental analysis: C H N Calculated for C14H23N3O2: 63.37 8.74 15.83 Found: 63.04- 8.74 15973 To that described in Examples 1-3 The following compounds are obtained in the manner: 3-Cyclohexyl-4-morpholinomethylsydnone (Melting point 127 to 128 ° C; melting point of the hydrochloride 206 to 2080 ° C) 3-n-Hexyl-4-morpholinomethylsydnone (Melting point 83-85 ° C.) 3-phenyl-4-piperadinomethylsydnone (melting point 13500) 3-phenyl-4-diethylaminomethylsydnone (Melting point 10500) 3-phenyl-4-morpholinomethylsydnone (melting point 129-130 ° C) 3-phenyl-4- (4'-benzyl-piperazino) methylsydnone (melting point 143 ° C) 3-p-fluorophenyl-4-morpholinomethylsydnone (Hydrochloride, melting point 19800 3-n-Butyl-4-morpholinomethylsydnone (melting point 75 ° C.) 3-isobutyl-4-morpholinomethylsydnone (melting point 950 ° C.) 3-sec-butyl-4-morpholinomethylsydnone (Picrat, melting point 199 ° C (dec.)).

3-Allyl-4-morpholinomethylsydnone (melting point 87 ° C) 3iIsopropyl-4-diallylaminomethylsydnone (Picrat, melting point 122-123 ° C) 3-Isopropyl-4-dimethylaminomethylsydnone (Picrat, Melting point 156-158 ° C) Typical preparations containing an active ingredient of the formula (I) according to the invention are described below.

Preparation 1 mg / g powder 1) 3-Cyclohexyl-4-morpholinomethylsydnone 200 2) Lactose 600 3) Starch 200 1000 All ingredients are mixed well. That The resulting mixture is suitable as a powder to be administered orally.

Preparation 2 mg / tablet 1) 3-isopropyl-4-morpholinomethylsydnone 250 2) Microcrystalline Cellulose 142 3) Calcium Salt of Carboxymethyl Cellulose 20 4) Lactose 70 5) Talc 15 6) Magnesium stearate 500 The compound (1), half of (2) and the compound (4) are kneaded with methanol. The mixture is taken under dried under reduced pressure and then granulated.

The remaining half of (2) and the connections (3) (5) and (6) are added to the granules and the mixture becomes too. Compressed tablets. The so The tablets produced can also be coated with sugar, for example0 Preparation 3 mg / cap 1) 3-isopropyl-4-morpholinomethylsydnon 250 2) gelatin capsule 55 305 The powdery compound (1) is filled into the gelatin capsule.

In the preparations mentioned above as examples, 3-cyclohexyl-4-morpholinomethylsydnone can be used and 3-isopropyl-4 morpholinomethylsydnone by any other compounds (I) according to the invention - or their salts can be replaced on the same molar basis.

Claims (13)

Claims 1) Sydnone derivatives of the general formula in which R1 denotes a hydrocarbon residue with 1 to 6 carbon atoms, each of the residues R2 and R3 denotes an alkyl residue with 1 to 5 carbon atoms, alkenyl residue with 2 to 5 carbon atoms, aralkyl residue with 7 to 9 carbon atoms, or R2 and R3 together with the adjacent nitrogen atom for represents a 5- to 7-membered heterocyclic ring. 2) Compounds according to claim in the form of their pharmaceutically compatible Salts, preferably in the form of their hydrochlorides. 3) Compounds according to claim l, wherein the radical R1 in the general Formula denotes an alkyl radical. 4) Compounds according to claim 1, wherein the radical R1 in the general Formula means an alicyclic radical of the 5- or 6-membered ring. 5) Compounds according to claim l, wherein R2 and R3 in general Formula together with the neighboring nitrogen atom stand for a morpholino group. 6) 3-isopropyl-4-morpholinomethylsydnone. 7) 3-Cyclohexyl-4-morpholinomethylsydnone. 8) 3-n-hexyl-4-morpholinomethylsydnone. 9) 3-isopropyl-4-dialylaminomethylsydnone. 10) Process for the preparation of sydnone derivatives of the general formula in which R1 is a hydrocarbon radical with 1 to 6 carbon atoms, each of the radicals R2 and R3 is an alkyl radical with 1 to 5 carbon atoms, alkenyl radical with 2 to 5 carbon atoms, aralkyl radical with 7 to 9 carbon atoms, or R2 and R3 together with the adjacent nitrogen atom for a 5- to 7-membered heterocyclic ring, characterized in that compounds of the formula wherein R1 has the abovementioned meaning with formaldehyde and secondary amines of the formula in which R2 and R likewise have the abovementioned meaning. 11) Method according to claim 10, characterized in that one dadurc-h Sydney derivatives converted into their pharmaceutically acceptable salts. 12) Pharmaceutical mixture, characterized by a low, However Analgesic component of ßydnonderivaten according to claim 1. 13) Pharmaceutical mixture, characterized by a content of Sydnone derivatives according to claim 1 as the main component and a minor amount a pharmaceutical carrier.