DE1016705B - Process for the preparation of therapeutically active substituted 4-dimethylaminocyclohexylcarbinols - Google Patents

Description

Process for the preparation of therapeutically effective substituted 4-Dimethylaminocyclohexylcarbinols The present invention relates to a method for the production of new substituted 4-dimethylaminocyclohexylcarbinols with valuable pharmacological and physiological properties, especially spasmolytic and parasympatholytic activity, their non-toxic acid addition and quaternary Ammonium salts.

The substituted 4-dimethylaminocyclohexylcarbinols which can be prepared according to the invention can be represented by the following general formula: In this formula, R1 and R2 are identical or different lower alkyl or aralkyl radicals, saturated and unsaturated carbocyclic radicals such as cycloalkyl, cycloalkylene or aryl radicals, saturated and unsaturated heterocyclic and substituted by heterocyclic alkyl radicals, X is hydrogen or a lower alkyl radical, such as Methyl, ethyl or propyl, and n is an integer between 0 and 3.

R1 and R can e.g. B. ethyl, propyl, butyl, phenyl, benzyl, Thienyl, pyridyl, piperidyl, pyrimidyl, thiazyl, cyclohexyl, cyclohexenyl, Cyclopentyl or cyclopentenyl radicals, which are also characterized by chlorine, bromine, lower alkoxy or lower alkyl radicals in the ring can be substituted.

The quaternary ammonium salts are particularly valuable pharmacologically, for example methochloride, bromide, iodide or sulfate. For example are a, a'-Dithienyl-4-dimethylaminocyclohexylcarbinol methohalide is particularly valuable in the control of gastric secretion and gastric motility. Also salts, like the hydrochloride, tartrate, maleat, citrate and salicylate, point valuable therapeutic properties.

The compounds that can be prepared according to the invention are preferred administered orally in the form of tablets, elixirs or capsules. In tablet form they can contain an inert carrier, one or more of the usual Binders, such as sugar or starch, may contain. The connections can too can be incorporated into elixirs, which have the advantage that they can be obtained by adding a enable natural or synthetic flavorings to be aromatized. In in many cases it is desirable to administer an anticholinergic compound parenterally administered, and so the compounds preparable according to the invention are expedient as injection solutions together with non-toxic substances such as water, ethyl alcohol, Polyethylene glycol, which can be sterilized before administration, applied. In addition, these compounds can be incorporated into topical ointments or creams when absorption through the skin or mucous membrane is desired.

The new compounds can be prepared as follows: For example, the ethyl p-aminobenzoate can be hydrogenated in a known manner in alcoholic hydrochloric acid in the presence of platinum oxide to give ethyl 4-aminocyclohexanecarboxylate and then dimethylated in the usual way with the aid of formic acid and formaldehyde, or the p- Ethyl dimethylaminobenzoate is hydrogenated directly to the corresponding ethyl 4-dimethylaminocyclohexanecarboxylate using a platinum oxide catalyst in acetic acid. In addition to the ethyl ester, other esters such as the methyl or propyl ester of p-amino or p-dimethylaminobenzoic acid can of course also be used as starting material. The 4-dimethylaminocyclohexanecarboxylic acid esters obtained are then reacted in a known manner according to Grignard according to the following reaction scheme: Using phenylmagnesium bromide z. B. Diphenyl-4-dimethylaminocyclohexylcarbinol.

In a corresponding manner, the corresponding dialkyl, dithienyl or dicycloalkyl derivatives. It has been found that in some Cases where it is difficult, if not impossible, to perform a Grignard reaction, other organometallic compounds are used to introduce the radicals R, and R2 can be. For example, the C-dipyridyl compound is preferably selected from 4-dimethylaminocyclohexanecarboxylic acid ester and the pyridyl-lithium compound, which can be obtained from bromopyridine and lithium butyl. Although organolithium compounds, such as phenyllithium, thienyllithium or lithium alkyls for the preparation of the compounds of the general formula I can be used, a Grignard reaction is preferred.

In the preparation of compounds in which R1 and R2 are not identical, the following reaction scheme can be used A 4-dimethylaminocyclohexanecarboxylic acid ester, in particular the ethyl 4-dimethylaminocyclohexanecarboxylate, is heated with concentrated aqueous ammonia in a closed vessel at 50 to 100 °, and the corresponding acid amide is obtained. The acid amide is then z. B. dehydrated by heating with phosphorus pentoxide to 4-dimethylaminocyclohexanecarboxylic acid nitrile. Reaction of this nitrile with one mole of a Grignard compound, for example with phenylmagnesium bromide, leads in a known manner to phenyl-4-dimethylaminocyclohexyl ketone. If this asymmetrical ketone is reacted with another Grignard compound, carbinols of the general formula I are obtained, in which R 1 and R 2 have different meanings.

The acid addition salts of the compounds of the general formula I. can be prepared by any known method, for example by anhydrous Hydrochloric acid with an ethereal solution of the substituted 4-dimethylaminocyclohexylcarbinol is passed therethrough or by equivalent amounts of a substituted 4-dimethylaminocyclohexylcarbinol and an acid, for example maleic, tartaric or citric acid, in alcoholic Solution to be brought together. The solution can then be concentrated to the crystallized To get salt. The quaternary ammonium salts are e.g. B. expedient by heating a 4-dimethylaminocyclohexylcarbinol with a suitable alkyl halide in Presence or absence of a solvent obtained. Instead of alkyl halides It is also possible to use alkyl esters of sulfuric acid, for example dimethyl sulfate in benzene. By heating a quaternary ammonium iodide in methanol solution with the iodide can easily be absorbed by a slight excess of silver bromide or silver chloride be converted into the other halides.

The following examples explain the process according to the invention: Example 1 Diphenyl-4-dimethylaminocyclohexylcarbinol 33g of ethyl p-aminobenzoate, that in 300 cc of absolute ethanol, 16.8 cc of concentrated hydrochloric acid contains, are dissolved, are at 3.5 atm. Hydrogen pressure equivalent to 2 g Hydrogenated platinum oxide. The theoretical amount of hydrogen will be in several hours absorbed, the catalyst then filtered off and the filtrate to dryness in vacuo evaporated. The residue is dissolved in water, alkaline with ammonium hydroxide made and extracted with chloroform. After removing the solvent is the remaining oil is distilled and the ethyl 4-aminocyclohexanecarboxylate obtained, bp, o = 114 to 117 °.

A mixture of 49g of this ester, 76g 98 ° J @ ger formic acid and 68 ccm formalin solution is heated under reflux for 8 hours. The solvents are then removed in vacuo on the steam bath, the residue dissolved in water with ammonium hydroxide made alkaline and extracted with chloroform. After removing the solvent and distillation in vacuo is the ethyl 4-dimethylaminocyclohexanecarboxylate obtained, Kp.io = 122 to 125 °.

A solution of 0.2 mol of the dimethylamino compound in 50 cc of absolute Ether becomes a cooled, well-stirred ethereal solution of phenyl magnesium bromide (0.8 mole) prepared in the usual manner was added. One warms up the mixture to room temperature and stir it for an additional 6 hours. The reaction mixture is then decomposed with dilute ammonium chloride solution and extracted with ether. The combined ether extracts are carefully treated with 10% hydrochloric acid extracted and the acidic solution made alkaline with ammonium hydroxide. The watery one Solution is extracted with chloroform, which is then washed with water, dried and the chloroform solution evaporated in vacuo. By recrystallizing the residue hexane becomes diphenyl-4-dimethylaminocyclohexylcarbinol, melting point 150.5 to 151 °, obtain.

Example 2 a, a'-Dithienyl-4-dimethylaminocyclohexylcarbinol 39.8 g of ethyl 4-dimethylaminocyclohexanecarboxylate are added to a solution of thienyl magnesium bromide obtained from 21.4 g of magnesium and 144 g of 2-bromothiephen. According to the method of Example 1 a, -Dithienyl-4-dimethylaminocyclohexylcarbinol obtained ä; Melting point 156 ° to 157 ° after recrystallization from benzene.

To an ether solution of 5 g of this substance add 10 ccm of methyl iodide added and the mixture kept at 0-5 ° overnight. The quaternary quaternary The ammonium salt is filtered off and made from a mixture of absolute ethanol and absolute Ether recrystallized, the a, a'-dithienyl-4-dimethylaminocyclohexylcarbinol methoiodide, Mp. 251 to 252 °, is obtained.

A mixture of 10 cc of dimethyl sulfate with 5 g of a, a'-dithienyl-4-dimethylaminocyclohexylbarbinol refluxed in benzene for 10 to 15 minutes after the solution had cooled precipitated salt and recrystallized from absolute ethanol, one obtains the a, a'-Dithienyl-4-dimethylaminocyclohexylcarbinol methosulfate, m.p. 200 to 201 °.

A solution of 10 g of carbinol is saturated in 300 cc of anhydrous Benzene with methyl bromide and let the solution stand at room temperature, filtered the precipitated crystals from and recrystallize them from ethanol -ether, is obtained one a, a'-dithienyl-4-diinethylaminocyclohexylcarbinol methobromide, m.p. 231 to 232 °.

Example 3 a, a'-Dipyridyl-4-dimethylaminocyclohexylcarbinol To a Suspension of 2 gram atoms of lithium in 11 anhydrous ether are at 0 ° below 1.0 mole of n-butyl bromide was added dropwise with stirring. When the reaction ends is, the mixture is cooled in a dry ice bath to about -30 ° and 1.0 mol 2-bromopyridine added dropwise. To the cooled suspension of 2-pyridyllithium 0.25 mol of 4-dimethylaminocyclohexylcarboxylic acid ethyl ester are slowly added with stirring added. Then the mixture is warmed to room temperature and another 6 stirred for up to 8 hours. Then the reaction mixture is poured into ice water, which Layers are separated, and the ethereal solution of the carbinol is carefully mixed with water washed and dried with sodium carbonate. After evaporation of the solvent 0.12 moles of a, a'-dipyridyl-4-dimethylaminocyclohexylcarbinol are obtained. Kp.5 = 190 to 208 °.

A solution of 5 g of this carbinol in 50 cc of anhydrous ether is treated with 10 ccm of methyl iodide as described in Example 2. Recrystallize from ethanol - ether gives the a, ä -dipyridyl-4-dimethylaminocyclohexylcarbinol methoiodide, M.p. 272 to 274 '.

The corresponding maleic acid is made from the carbinol in a known manner Salt and the methobromide produced after recrystallization from ethanol - ether melt at 163 to 164 ° or at 260 to 262 °.

Example 4 Diethyl-4-dimethylaminocyclohexylcarbinol By use of ethyl magnesium bromide instead of phenyl magnesium bromide in the example 1 is the method described after recrystallization from hexane, the diethyl-4-dimethylaminocyclohexylcarbinol, Kp.2 = 158 to 165 °.

Example 5 p, p'-Dichlorodiphenyl-4-dimethylaminocyclohexylcarbinol By using 0.8 moles of p-chlorophenyl magnesium bromide in place of phenyl magnesium bromide in the method described in Example 1, p, p'-dichlorodiphenyl-4-dimethylaminocyclohexylcarbinol, which can be recrystallized from benzene - hexane obtained.

The corresponding hydrochloride is known from carbinol Way produced and recrystallized from ethanol-ether, m.p. 271 to 272 °.

Example 6 p, p'-Ditolyl-4-dimethylaminocyclohexylcarbinol By substitution of the phenyl magnesium bromide used in Example 1 by an equivalent amount p-Tolylmagnesium bromide becomes p, p'-ditolyl-4-dimethylaminocyclohexylcarbinol in a corresponding manner as a white crystalline solid substance that can be recrystallized from hexane, obtain.

Example 7 Phenyl- [pyridyl- (2)] -4-dimethylaminocyclohexylcarbinol A mixture of 100 g of ethyl 4-dimethylaminocyclohexanecarboxylate (as in the example 1) and 500 cc of concentrated aqueous ammonium hydroxide is in one closed bomb heated to 100 ° for 8 hours. After cooling, the excess will aqueous solvent removed by distillation and the residue recrystallized from hexane, 4-dimethylaminocyclohexanecarboxamide, melting point 112 ° to 114 °, is obtained.

A mixture of 50 g of this amide and 120 g of phosphorus pentoxide is Heated for 3 hours at 150 ° at a pressure of 200 mm Hg. The pressure will then be gradual reduced to 2 mm Hg and the distillate, which boils at bp 100 to 150 °, collected. This crude fraction is treated with 200 cc of water, extracted with ether and the ether solution washed with dilute sodium carbonate solution. The ethereal solution is then dried and distilled in vacuo, 4-dimethylaminocyclohexanecarboxylic acid nitrile, Kp.i = 82 to 85 °.

A solution of 0.20 moles of this nitrile becomes a dropwise addition Solution of 0.4 moles of phenyl magnesium bromide added in ether. To several hours of refluxing the reaction mixture with ice and ammonium chloride solution decomposed and extracted with ether. The ether solution is dried and in vacuo distilled, with phenyl-4-dimethylaminocyclohexyl ketone, bp.2 -. 160 to 170 °, is obtained.

To a cooled suspension of 0.111 <2o1 2-pyridyllithium in Ether prepared as described in Example 3 is added dropwise a solution of 0.1 mol of the above-described ketone in ether was added. The mixture is warmed to room temperature and stirred for a further 6 hours. Afterward it is worked up according to the procedure of Example 3. After evaporation of the solvent, a liquid, bp.l = 195 to 200 ', is obtained which contains the Represents phenyl- [pyridyl- (2)] -4-dimethylaminocyclohexylcarbinol.

Example 8 Diphenyl-3-methyl-4-dimethylaminocyclohexylcarbinol One Solution of 100 g of 3-methyl-4-aminobenzoic acid in 500 ml of ethanol and 25 ml of concentrated Sulfuric acid is refluxed for 6 hours. The mixture is cooled to concentrated to a small volume and the residue treated with dilute alkali. The alkaline mixture is extracted with ether, the ether solution is dried and distilled in vacuo. The ethyl ester of 3-methyl-4-aminobenzoic acid is obtained.

This ethyl ester is made according to the procedure described in Example 1 hydrogenated and methylated. The methyl 4-dimethylaminocyclohexanecarboxylic acid ethyl ester is then obtained. By treating with phenyl magnesium bromide according to that described in Example 1 The process becomes diphenyl-3-methyl-4-dimethylaminocyclohexy after recrystallization from hexane Obtain lcarbinol.

Example 9 a, u'-Dithienyl-3-methyl-4-dimethylaminocyclohexylcarbinol By reacting 3-methyl-4-dimethylaminocy clohexanecarboxylic acid ethyl ester and 2-bromothiophene following the procedure of Example 2 is made after recrystallization obtained from benzene the α, α-dithienyl-3-methyl-4-dimethylaminocyclohexylcarbinol. Propylcyclopentyl-2,6-diethyl-4-dimethylaminocyclohexylcarbinol can be prepared in the same way, a, ä - Dipyrrolyte 1- 4 - dimethylaminocyclohexylcarbinol and 2, 2-dithia7olidyl-4-dimethylaminocyclohexylcarbinol. The dosage of the compounds which can be prepared according to the invention for adults is between 5 mg to about 100 mg per day.

The advantageous therapeutic properties of the compounds obtainable according to the invention can be seen from the table below: Compilation of the pharmacological data of compounds of the formula Mouse: parasym- antiacetyl- Rl and R2 patholytic cholini effects Effect in vivo in vitro atropine "Prantal" * - 1 sulfate = 1 1. Diphenyl (; t. = 0) ... 3.3 to 6.4 2. Di- (2'-thienyl). (n = 0). . . . . . . . . . . . 5.5., 9; 5 1 3. Phenyl-2'-thienyl (n = 0). . . . . . . . . . . . 3.8 »8 1i 4th 4. Phenyl-2'-pyridyl (n = 0). . . . . . . . . . . . 10.0 1/8 5. Cyclohexyl-2'-thienyl (7a = 0). . . . . . . . . . . . I 13.0 1 / s *) »Prantal ,: has the structural formula

Claims (1)

PATENT CLAIM: Process for the preparation of therapeutically effective substituted 4-dimethylaminocyclohexylcarbinols of the general formula in which R1 and R2 are identical or different lower alkyl or aralkyl radicals, saturated or unsaturated carbocyclic radicals having 5 to 6 carbon atoms, heterocyclic or alkyl radicals substituted by heterocyclic radicals, X is hydrogen or lower alkyl radicals and n is an integer from 0 to 3, or Their salts and quaternary ammonium compounds, characterized in that a p-amino or p-dimethylaminobenzoic acid ester is hydrogenated in a known manner with hydrogen in the presence of Pt 02 and hydrochloric or acetic acid, the optionally obtained 4-aminocyclohexanecarboxylic acid ester in the customary manner with formaldehyde and Dimethylated formic acid, the resulting 4-dimethylaminocvclohexanecarboxylic acid ester either a) in a known manner with an organometallic compound, preferably a Grignard compound cerium general formula R, - Mg - Br or R, -Mg - J, and the organometallic compound obtained in the usual way hydrolyzed od he b) first converted into the 4-dimethylaminocyclohexanecarboxamide with ammonia at 50 to 100 ° and increased pressure, this dehydrated with P20, in the known `` "iron, the 4-dimethylaminocyclohexanecarboxonitrile obtained in the usual way according to Grignard with a compound R1 - Mg- Br or R1 - Mg -J reacted, hydrolyzed, the 4-dimethylaminocyclohexyl - R1 - substituted ketone obtained is subjected to a second Grignard reaction with a compound R2 - Mg - Br or R2 - Mg - I, the organometallic intermediate obtained is likewise hydrolyzed and finally the obtained 4-dimethylaminocyclohexylcarbinol substituted by R, 7 and / or R 2 radicals, if desired, is converted into salts or quaternary ammonium compounds in a known manner. Documents considered: German Patent No. 862 446; Swiss Patent No. 301 246; French Patent No. 1055 887; U.S. Patent Nos. 2,680,115, 2,538,794, 2,508,499, 2,437,711, 2,682,543, 2,558,020; Helv. Chimica Acta, Vol. 2, 1919, pp. 717 to 719; J. Karrer, Textbook of Organic Chemistry, 1954, 12th Edition, pp. 84 and 85, 53 and 54; Repertory of pharmaceutical special preparations, 1948, pp. 1159, 1160; Supplementary Volume I, 1948, p. 284; Supplementary volume 1I, 1950, p. 388.