DK146257B - METHOD OF ANALOGUE FOR THE PREPARATION OF (+) - 3R-N-MONOMETHYLAMINO-4C-PHENYL-4T-ETHOXYCARBONYL-CYCLOHEXEN- (1) OR ACID ADDITION SALTS THEREOF - Google Patents

Description

(19) DENMARK

(12) PUBLICATION MANUAL (n) 146257B

DIRECTORATE OF THE PATENT AND TRADEMARKET SYSTEM

(21) Patent Application No: 2462/75 (51) Int.CI.3: C 07 C101 / 38 (22) Filing Date: 02 Jun 1975 (24) Running Date: 29 Jun 1972 (41) Aim. available: 02 Jun 1975 (44) Submitted: 15 Aug 1983 (86) International Application No: - (62) Stock Application No .: 3252/72 (30) Priority: 30 Jun 1971 DE 2132562 (71) Applicant: «WARNER- LAMBERT COMPANY; Morris Plains, US.

(72) Inventor: Gerhard «Satzinger; DE, Wolfgang Dieter «Herrmann; DE, Manfred Franz Relnhold «Herrmann; THE.

(74) Plenipotentiary: Engineer Budde, Schou A Co_ (54) Analogous Process for the Preparation of (+) - 3r-N-Monomethylamino-4c-phenyl-4t-ethoxycarbonyl-cyclohexene- (1) or Acid Addition Salts thereof

The present invention relates to an analogous process for the preparation of the novel compound (+) - 3r-N-monomethylamino-4c-phenyl-4t-ethoxycarbonyl-cyclohexene- (1) of formula D CH

* I H

S / V / / OOC2H5

0 rrC

1 [P.

or acid addition salts thereof.

2 146257

From the specification of Danish Patent Application No. 1010/71, a process for the preparation of 3r-N-monomethylamino-4c-phenyl-4t-ethoxycarbonyl-cyclohexene- (1) is known which has a strong analgesic effect.

The process of the invention is characterized in that DL-3r-N-monomethylamino-4c-phenyl-4t-ethoxycarbonyl-cyclohexene- (1) of the formula CH-3

N H

C00 COhc / reaction is reacted with (+) - 0,0-dibenzoyl-L-tartaric acid or {-) - 0,0-dibenzoyl-D - tartaric acid to form diastereomeric salts, which are then subjected to fractional crystallization to separate it. diastereomeric salt of (+) - 3r-N-monomethylamino-4c-phenyl-4t-ethoxycarbonyl-cyclohexene- (1), and if desired (+) - 3r-N-monomethylamino-4c-phenyl-4t-ethoxy- carbonyl-cyclohexene- (1) is released by treatment with base, and the compound formed is optionally transferred into an acid addition salt thereof.

In the process, the racemic DL-3r-N-monomethyl-amino-4c-phenyl-4t-ethoxycarbonyl-cyclohexene- (1) is reacted in a manner known per se, i.e. by (+) - 0,0-dibenzoyl-L-tartaric acid or (-) - 0,0-dibenzoyl-D-tartaric acid in acetone, lower alcohols such as methanol, ethanol and isopropanol or in water, and the diastereomers thus prepared salts are subjected to fractional crystallization which utilizes their various solubilities in the solvents used and, if desired, the base is released from the pure diastereomeric salt of (+) - 3r-N-monomethylamino-4c-phenyl-4t-ethoxycarbonyl-cyclohexene - (1) treatment with aqueous alkali hydroxide or ammonium hydroxide and the free base is optionally transferred into the hydrochloride or another acid addition salt in a manner known per se with hydrogen chloride gas or the acid acid salt corresponding to the desired acid in suitable solvents, e.g. ethyl acetate. The use of (+) - 0,0-di-benzoyl-L-tartaric acid or (-) - 0,0-dibenzoyl-D-tartaric acid for racial separation has been found to be particularly suitable for this purpose, as the first forms a highly soluble salt, which can be obtained optically pure by recrystallization, with the desired pharmacologically active right-turning enantiomeric base. The other forms a heavily soluble salt with the left-turn enantiomeric base, so that the desired right-turning base can be obtained from the mother liquor. Thus, in the first mentioned case, the pharmacologically active compound is obtained directly in pure crystalline form (cf. example 2 below), while in the latter case two crystallizations (cf. examples 1a), b) and c) below must be made. ).

Surprisingly, it has been found that (+) - 3r-N-monomethylamino ~ -4c-phenyl-4t-ethoxycarbonyl-cyclohexene- (1) -HCl ("D-HCl") in animal studies at subcutaneous, intravenous and intragastric administration stronger analgesic effect and also more advantageous therapeutic properties than is the case with DL-3r-N-monomethylamino-4c-phenyl-4t-ethoxycarbonyl-cyclohexene- (1) ("DL-HCl"). Of course, these beneficial properties do not depend on the acid specifically used for salt formation, but are due to the properties of the (+) base or its cation.

For use, the compound may be formulated with conventional pharmaceutical carriers to form typical oral or rectal dosage units such as tablets, capsules, solutions, suppositories and the like. An adult can be given from approx. 5 to approx.

30 mg of these compounds up to three times daily, and of course, smaller doses can be given to children.

The following describes the determination of the acute toxicity of the compound and its analgesic effect.

To determine the acute toxicity, male mice (NMRI) weighing 20-27 g are used as experimental animals. All test animals are fasted for 16-18 hours before the start of the trial. They have free access to water. Each experimental group consists of 6 animals. The dose is increased by a factor of 1.3.

The volume of liquid used is 2 ml. 100 g of body weight by intragastric administration and 1 ml per ml. 100 g body weight by subcutaneous and intravenous administration. The observations are made over 7 days. Statistical evaluation of the experimental results is carried out in accordance with the method of Litchfield and Wilcoxon, cf. Ther, Grundlagen der experiment. Drug Research, S. 82, Wiss. Publishing Company, Stuttg. 1965th

The analgesic effect is determined by the phenyl-β-quinone test. Each experimental group consists of 12 male mice (NMRI) weighing 17-23 g. Intraperitoneally 1.25 ml of a 0.02% phenyl-β-quinone solution is administered per day. 100 g of body weight at 15 and 30 minutes after administration of the test substance. In the intravenous trials, phenyl-β-quinone is injected immediately after administration of the drug. Only such animals that do not exhibit typical pain reactions during the subsequent 20 minutes are considered to be protected. The experiment is discarded if at least 4 out of 12 animals in the control group respond. Also in the present case, statistical evaluation of the test results according to Litchfield and Wilcoxon's method is performed.

The results of the experiments described above are given in it

AED

the following table. The morphine-like analgesic meperidine ("Dolan tin" 'i-'), currently the leading substance on the market, is used as the positive standard drug. For comparison, the results for related cyclohexene compounds are included.

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6 146257

The process according to the invention is explained in more detail in the following examples.

Example 1 a) 259.4 g, 1 mole, DL-3r-N-monomethylamino-4c-phenyl-4t-ethoxy-carbonyl-cyclohexene- (1) are dissolved in 0.5 liter of acetone and mixed at room temperature with a mixture of 375.3 g, 1 mole, (-) - 0,0-dibenzoyl-D-tartaric acid monohydrate in 1.5 liters of acetone. After standing overnight, the resulting precipitate is filtered off. It consists mainly of (-) - 3r-N-monomethylamino-4c-phenyl-4t-ethoxycarbonyl-cyclohexene- (1) -dibenzoyl-D-tartrate. The filtrate is evaporated to dryness. The crystalline residue is taken up in water, the base is released with ammonia solution and extracted with gasoline. After drying the organic base with anhydrous sodium sulfate, the solvent is equilibrated. A residue of 104 g (+) - 3r-N-monomethylamino-4c-phenyl-4t-ethoxycarbonyl-cyclohexene (1) in the form of a colorless oil is obtained, [a] +355 (5 g / 100 ml of methanol).

(b) To precipitate the hydrochloride, dissolve 100 g, 0.385 mol, of the (+) base prepared above under (a) in 400 ml of anhydrous ethyl acetate, and dropwise add a solution of 14 g, 0.385 mol, HCl in 400 ml of ethyl acetate. with stirring at room temperature. After cooling, the precipitate is aspirated and washed with ethyl acetate.

Yield: 97 g, 85% of theory (+) - 3r-N-mono-methylamino-4c-phenyl-4t-ethoxycarbonyl-cyclohexene (1) hydrochloride. Colorless crystals with m.p. 210-212 ° C, [α] 25 + 315 ° (10 g / 100 ml water).

c) dissolve 26 g, 0.1 mol, (+) - 3r-N-monomethylamino-4c-phenyl-4t- -ethoxycarbonyl-cyclohexene- (1) in 100 ml of acetone, and to this solution is added a solution of 37, 6 g, 0.1 mole, (-) - 0.0-dibenzoyl-D-tartaric acid monohydrate in 100 ml of acetone. The precipitate formed is filtered off 24 hours. 20.2 g of salt are obtained with [a] D +78 (10 g / 100 ml of methanol).

The salt is twice recrystallized from a small amount of methanol. The product then constitutes 8.5 g (+) - 3r-N-monomethylamino-4c-phenyl-4t-ethoxycarbonyl-cyclohexene- (1) -0,0-dibenzoyl-D-tartrate in the form of colorless crystals, m.p. 113 ° C and [α] 4 + 86.5 ° (10 g / 100 ml methanol).

Example 2 26 g, 0.1 mol, DL-3r-N-monomethylamino-4c-phenyl-4t-ethoxy-carbonyl-cyclohexene (1) are dissolved in 50 ml of acetone and a solution of 37.6 is added. g, 0.1 mole, (+) - 0.0-dibenzoyl-L-tartaric acid monohydrate in 150 ml of acetone at room temperature. After standing overnight, the precipitate is filtered off and washed with a small amount of acetone. The crude product is 32.3 g with m.p. 175-176 ° C and [a] p 2 + 208.5 ° (2 g / 100 ml methanol). The salt is recrystallized from 500 ml of methanol to give 22 g of (+) - 3r-monomethylamino-4c-phenyl-4t-ethoxycarbonyl-cyclohexene- (1) -0,0-dibenzoyl-L-tartrate, m.p. 185-186 ° C and [α] 22 + 220 ° (2 g / 100 ml methanol).