KR830000834B1 - 2.6-Metano-3-benzazosin preparation method - Google Patents

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Description

2.6-Metano-3-benzazosin preparation method

The present invention is a specially selected 3,6 (eq) -11 (aX) -trimethyl-8-hydroxy-11 (eq)-(CH ₂ CH _{2 which} is useful as an analgesic and anesthetic antagonist but has little anesthetic properties of morphine. COR) -1,2,3,4,5,6-pysahydro-2,6-methano-3-benzazosin.

US 3-R ₁ -6- (eq) in Patent 3,932,422, 11 (aX) - dimethyl-8-hydroxy _{-11 (eq) - (CH 2} CH 2 COR) -1,2,3,4,5, 6-hexahydro-2,6-methano-3-benzazocin is described extensively, wherein R ₁ is lower alkyl group, lower alkenyl group, lower alkynyl group, cycloalkyl group, cycloalkyl-lower-alkyl group and A phenyl-lower alkyl group or a substituted phenyl-lower alkyl group, and R is, among others, a lower alkyl group, a phenyl group or a phenyl-lower-alkyl group. Although the patent gives a general description of the properties of the same compound as an anesthetic antagonist, in fact, all kinds of compounds exhibiting anesthetic antagonism have a cyclopropylmethyl group on the benzazosin nitrogen atom.

This anesthetic antagonistic ability found in N-cyclopropylmethyl-substituted hexahydro-2,6-methano-3-benzazosin is entirely consistent with what is known in the past, because in the prior art, the methyl group on the nitrogen atom nucleus A potent anesthetic antagonist could be expected only in hexahydro-2,6-methano-3-benzazosine compounds in which special groups such as lower alkenyl, halo-lower alkenyl, cyclopropylmethyl, or cyclobutylmethyl groups were introduced. Because. This empirical rule that lower alkenyl, etc. is required in nitrogen atom hex to obtain anesthetic antagonistic properties is known as nalofine and naloxone, such as N-allylnormolophine and N-allyl-7,8-dihydro-14-. The same applies to two compounds known as relatively morphine-type anesthetic antagonists, known as hydroxynormolipins.

Therefore, the discovery of anesthetics of strong analgesics, including hexahydro-2,6-methano-3-benzazocins with methyl groups on nitrogen atoms, is unique to the present.

For example, Michne et al. J.Med. Anesthesia was found in the 3-methyl-hexahydro-2,6-methano-3-benzazocin class with lower alkyl carbinol side chains at position 11 (eq), published in Chem 20, 682 (1977) and ager And J. Med. Chem. 12, 288 (1969) reported a 3-methyl-2,6-methano-3-benzazosin family of effects of 2-20% of nalphaline on morphine-addicted monkeys, but these N-methyl antagonists Has a relatively low effect.

Surprisingly we have 3,6 (eq), 11 (aX) -trimethyl-8-hydroxy-11 (eq)-(CH ₂ CH ₂ COR) -1,2,3,4,5,6-hexahydro- It has been found that some of 2,6-methano-3-benzazosin and its acid addition salts have very high anesthetic antagonistic effects. Wherein R represents any selected lower alkyl group, phenyl-lower alkyl group or cycloalkyl-lower alkyl group.

These compounds are represented by the following structural formula.

Provided that R is pentyl, 3-methylbutyl or 2-phenylethyl.

The anesthetic antagonistic properties of the compounds defined above are in stark contrast to the properties of the compounds that are homologous to them in the lower alkyl moieties of the R group, which have the opposite properties as strong antagonists, with the antagonistic effect being significantly reduced.

Preparation of the compound of formula (I) is carried out with formic acid or benzyl-di-lower alkyl-ammonium formate or tri-lower alkyl ammonium in an organic solvent such as suluene, xylene or mesitylene, as in US Pat. No. 3,932,422. 7-Yo-1,4-aα, 5α-trimethyl-3-COR-1,2,3,4,4a, 5,10,10a-octahydro-2,5 of formula (II) with formate -Methanobenzo [g] quinoline can be prepared by decomposing the lower alkoxy group (YO) when Y is lower alkyl with aqueous hydrobromic acid or sodium propyl sulfide solution as described below.

With the proviso that Y represents hydrogen or lower alkyl and R has the same meaning as described above.

As another preferred method, the preparation of the compound of formula (I) may be modified by the above-described method, formic acid or benzyl-di-lower alkyl ammonium formate or tri-lower alkyl ammonium in an organic solvent such as toluene, xylene or mesitylene. Lower alkyl 1,4aα, 5α-trimethyl-7-YO-3-RCO-1,2,3,4,4a, 5,10a-octahydro-2,5-methano of formula (III) using formate It can be prepared by heating benzo [g] quinoline-3-carboxylate.

In which AlK 'represents lower alkyl and R and Y have the meanings described above.

When Y is lower alkyl, lower alkoxy (Y-O) is decomposed to hydrobromic acid or aqueous sodium propyl sulfide solution. When water-soluble hydrobromic acid is used as a disintegrant, the reaction is carried out by refluxing an ether solution in water-soluble hydrobromic acid, and it is effective to separate from the reaction mixture in the form of hydrobromide or free base in a neutral solution. When the ether is decomposed using sodium propyl sulfide, dimethylformamide (DMF) is refluxed in an inert organic solvent with an excess of sodium propyl sulfide, where propyl sodium sulfide is added propanethiol to caustic soda. To prepare. As a starting material, Y is a lower alkyl group, and thus, a compound of formula (II) or (III), which requires separation of ether later, is preferable.

Compounds of formula (II) and methods for their preparation are described in US Pat. No. 3,932,422. The compound of formula III is lower alkyl-1,4aα, -5α-trimethyl-7-YO-1,2,3,4,4a, 5,10,10a-octahydro-2,5-methanobenzo [ g] Quinoline (Formula II, R is lower alkoxy) is an alkali metal amide such as sodium amide or lithium diisopropylimide, and the resulting alkali metal salt is reacted with an appropriate acyl halide, R-CO in an inert organic solvent. Prepared by reaction with -X or 1,4aα, 5α-trimethyl-7-YO-1,2,3,4,4a, 5,10,10a-octahydro-2,5-methanobenzo [g] quinoline (Formula II, wherein R has the meaning as described above) is prepared by reacting the alkali metal amide with the lower alkyl haloformate after reacting with the alkali metal amide according to any of the above-described methods.

Due to the presence of the basic amino group, the free base product represented by the above formula (I) reacts with organic and inorganic acids to form acid addition salts. Acid addition salt products are prepared from any organic or inorganic acid. They are prepared by conventional methods, for example, by mixing the base directly with an acid or, if it is not suitable, by mixing both the base and the acid or separately in water or an organic solvent and then mixing the two solutions or dissolving the base and the acid together in a solvent. There is this. The acid addition salts formed are separated by filtration when insoluble in the reaction medium or the acid addition salts are obtained as a residue by evaporation of the reaction medium. The acid moiety of these salts or the anions themselves are not novel or critical, so any acid anion or any acid analog that can produce salts with bases is acceptable.

Acid addition salts are all useful as generators in free base form by reacting with inorganic bases. Therefore, any of the solubility, molecular weight, physical properties, toxicity or similar properties of a given base or acid addition salt can be easily converted into a more suitable form if it is unsuitable for a particular purpose. For the manufacture of pharmaceuticals, acid addition salts of relatively less toxic and pharmaceutically suitable acids are used, for example, hydrochloric acid, methanesulfonic acid, lactic acid, tartaric acid and the like.

The compounds of the present invention may also exist in the form of a colon, which can be separated into the colon. If desired, certain colony forms can be glassed or manufactured by applying the general principles known in the art. In the index used for the compound of formula I, "aX" is used in the vertical direction, "eq" is used in the horizontal direction, and the atomic arrangement is based on the hydrogen aromatic ring. Thus, the 6 (eq) and 11 (aX) compounds of formula (I) are cis-arranged while the 6 (eq) and 11 (eq) compounds are trans-arrays.

Since the useful properties of the compounds of the present invention are implemented by standard pharmacological methods that can be easily performed by those skilled in the art of pharmacological test methods, the experiments can be extended to actually determine the numerical biological data for a specific test substance. There is no need to check.

Test methods for determining analgesic and anesthetic antagonism of the compounds of the present invention are described in the prior art and in the following. The acetylcholine-induced peritoneal convergence test, designed to measure the inhibitory ability of a sample against rat peritoneal convergence by acetylcholine induction, is a bird published by Collier et al. J. Pharmacol. Chemot-herap. 32, 295 (1968), and the anti-bradykinin assay, which is one of the primary analgesic selection tests, is reported by J. Pharmacol. Exp. Therap. 177, 500-508 (1971), J. Pharm. Reported by Blane et al. Pharmacol. 19, 367-373 (1976), Eur. Reported by Botha et al. J. Pharmacol. 6, 312-321 (1969) and Deffenu et al. J. Phrm. Pharmacol. 18, 135 (1966) and J. Pharmacol., Reported by Pearl and Harris, for a mouse phenyl-P-quinone induced convulsion test. Exp. Therap. 154, 319-323 (1966), and J. Pharmacol. J. Pharmacol. Exp. Therap. 72, 74 (1941), the improvement was reported by J. Am. Pharm. Assoc. Sci. Ed. 41, 569 (1959) and anesthesia antagonists (e.g., phenazosin, morphine, and mapperidin antagonist tests) soothe the effects of phenazosin, morphine, or meperidine in the above-described murine oscillatory muscle group test. J. Pharmacol., Reported by Harris and Pierson. Exp. Therap. 143, 141 (1964), and the Straub tail test is reported by Straub in Dtsch. med. wochr. (1911), p. 1426 and Brit. Reported by Aceto et al. J. Pharmacol. 36, 225-239 (1969), which leads to the conclusion that there is a morphine-type anesthesia when positive as an observational test.

The structures of the compounds of the present invention are completed by synthesis, elemental analysis, and by ultraviolet, infrared and nuclear magnetic resonance spectroscopy. The path of reaction and homogeneity of the product was confirmed by thin layer chromatography.

Example 1

27.5 g (0.064 moles) of ethyl 1,4aα, 5α-trimethyl-7-methoxy-3-hexanoyl-1,2,3,4,4a, 5,10,10a-octahydro-2,5-meta A solution of nobenzo [g] quinoline-3-carboxylate in 275 ml of mesitylene and 37 ml of 98% formic acid was heated to reflux with stirring for 24 hours and then dried in vacuo. The oily residue was treated with 200 ml of basified with pH 10 with concentrated ammonia water, and the mixture was extracted with diethyl ether. The organic extract was washed with water and then brine, dried over anhydrous sodium sulfate and evaporated to dryness. The 30 g residue was treated with a solution of 6.0 g of oxalic acid dissolved in 50 ml of ethanol. As a result, 27 g of 3,6 (eq), 11 (aX) -trimethyl-8-methoxy-11 (eq)-(3-oxooctyl) -1,2,3,4,5,6-hexahydro- 2,6-Metano-3-benzazocinoxalate was obtained with a melting point of 95-97 ° C.

The latter was dissolved in 1.9 g (0.0047 mol) of hydrochloric acid in 25 ml of 48% hydrobromic acid, heated to reflux for 24 hours, dried in vacuo, and the residue was converted to basic with water-soluble alkali and extracted with diethyl ether. The ether extract was concentrated to dryness and the solid residue was converted to hydrochloride with etheric hydrogen chloride to obtain 2.5 g of crude material, which was recrystallized from isopropanol to 1.7 g of 3,6 (eq), 11 (aX) -trimethyl-8. -Hydroxy-11 (eq)-(3-oxooctyl) -1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazosin hydrochloride with a melting point of 252- It was 255 degreeC.

The conversion of a small amount of hydrochloride sample to basic and then to methanesulfonate resulted in a melting point of 178-179 ° C. (from acetone).

The other sample was converted to 2-naphthalene sulfonate and the melting point was 195-198 ° C. (from methanol / diethyl ether).

In the same manner as described in Example 1, the following compounds of formula (I) were prepared in the same manner.

Example 2

3,6 (eq), 11 (aX) -trimethyl-8-hydroxy-11 (eq)-(3-oxo-6-methylheptyl) -1,2,3,4,5,6-hexahydro- 2,6-methano-3-benzazosine hydrochloride, melting point 260-263 ° C. (3.6 g from isopropanol) is 20 g (0.045 mol) of ethyl 1.4aα, 5α-trimethyl-7-methoxy-3- (4- Methylpentanoyl) -1,2,3,4,4a, 5,10,10a-octahydro-2,5-methanozeno [g] quinoline-3-carboxylate in 1 l of mesitylene and 70 ml of formic acid And heated to 17.8 g of 3.6 (eq), 11 (aX) -trimethyl-8-methoxy-11 (eq)-(3-oxo-6-methylheptyl) -1,2,3,4,5,6 Hexahydro-2,6-methano-3-benzazocin hydrochloride (melting point 222-229 ° C., from diethyl ether) was decomposed with 40 ml of 48% hydrobromic acid to obtain the latter 4.0 g (0.0098 mol). It was prepared by the method.

The free base was liberated from the hydrochloride to convert the base to the corresponding methanesulfonate with a melting point of 189-191 ° C. (from acetone / diethyl).

Example 3

3.6 (eq), 11 (aX) -trimethyl-8-hydroxy-11 (eq)-(3-oxo-5-phenylpentyl) -1,2,3,4,5,6-hexahydro-2, 6-Methano-3-benzazosin methanesulfonate, melting point 233-235 ° C. (from ethanol, 1.6 g) is 26.2 g (0.055 mol) of ethyl 1,4aα, 5α-trimethyl-7-methoxy-3- (3-phenylpropionyl) -1,2,3,4,4a, 5,10,10a-octahydro-2,5-methanobenzo [g] quinoline-3-carboxylate with 990 ml of mesitylene and It was added to 41.5 ml of formic acid solution and heated to give 3,6 (eq), 11 (aX) -trimethyl-8-methoxy-11 (eq)-(3-oxo-5-phenylpentyl) -1,2,3, Obtain 4,5,6-hexahydro-2,6-methano-3-benzazosin-P-toluenesulfonate (melting point 170-179 ° C) and then use 81 ml of 48% hydrobromic acid to correspond to the latter free base. Prepared by digesting 8.1 g (0.02 mol).

A series of reference compounds generally described in US Pat. No. 3.932.422 for comparison were prepared by the above-described method as follows.

Reference compound 1: 3.6 (eq), 11 (aX) -trimethyl-8-hydroxy-11 (eq)-(3-oxophenyl) -1,2,3,4,5,6-hexahydro-2, 6-methano-3-benzazocin (R is C ₂ H ₅ );

Reference compound 2: 3.6 (eq), 11 (aX) -trimethyl-8-hydroxy-11 (eq)-(3-oxoheptyl) -1,2,3,4,5,6-hexahydro-2, 6-methano-3-benzazocin hydrochloride [R is (CH ₂ ) ₂ CH ₃ ];

Reference compound 3: 3.6 (eq), 11 (aX) -trimethyl-8-hydroxy-11 (eq)-(3-oxoheptyl) -1,2,3,4,5,6-hexahydro-2, 6-methano-3-benzazocin hydrochloride [R is (CH ₂ ) ₃ CH ₃ ];

Reference compound 4: 3,6 (eq), 11 (aX) -trimethyl-8-hydroxy-11 (eq)-(3-oxononyl) -1,2,3,4,5,6-hexahydro -2,6-methano-3-benzazocin [R is (CH ₂ ) ₅ CH ₃ ];

Reference compound 5: 3,6 (eq), 11 (aX) -trimethyl-8-hydroxy-11 (eq)-(3-oxo-5-methylheptyl) -1,2,3,4,5,6 Hexahydro-2,6-methano-3-benzazocin hydrochloride [R is CH ₂ CH (CH ₃ ) ₂ ];

Reference compound 6: 3,6 (eq), 11 (aX) -trimethyl-8-hydroxy-11 (eq)-(3-oxo-7-methyloxyl) -1,2,3,4,5,6 -Hexahydro-2,6-methano-3-benzazocin [R is (CH ₂ ) ₃ CH (CH ₃ ) ₂ ];

Reference compound 7: 3,6 (eq), 11 (aX) -trimethyl-8-hydroxy-11 (eq)-(3-oxo-3-phenylpropyl) -1,2,3,4,5,6 -Hexahydro-2,6-methano-3-benzazocin (R is C ₆ H ₅ );

Reference compound 8: 3,6 (eq (, 11 (aX) -trimethyl-8-hydroxy-11 (eq)-(3-oxo-4-phenylbutyl) -1,2,3,4,5,6 Hexahydro-2,6-methano-3-benzazosin methanesulfonate (R is CH ₂ C ₆ H ₅ );

[Biological test results]

The data obtained from the compounds of the present invention are described in the following table, the example numbers are as described above and the reference compounds are the same as the above reference numbers. The abbreviations Ach, Bk, PPQ, Phen, Mor, Mep, TF Ag and Straub are acetylcholine induced abdominal convergence test, anti-bradykinin test, phenyl-P-quinone induced convulsion test, phenazosin, morphine and meperidine tail vibration The main root muscle test and the straube test are indicated. The result is Ach. Bk. PPQ and TF Ag test indicated ED ₅₀ (mg / kg) and Phen. The Mor and Mep test or percent suppression terms indicate AD ₅₀ . Letter I means inert and all results not stated otherwise are obtained as a result of subcutaneous administration. All doses are expressed in milligrams per kilogram (mg / kg).

TABLE I

The tail oscillation main muscle group activity was inhibited with 1.0 mg / kg (SC) of nallopine, respectively, for the reference compounds 1,2,3,5, and 7, but 1.0 mg / nalol for the compound of Example 2 (hydrochloride). Partially inhibited by kg (SC). This result indicates the properties of the reference compounds 1,2,3,5 and 7 as anesthetics, which is further evident by the observation of the Straub tail response with relatively small doses of these compounds. The data regarding the compound of Example 2 is clearly shown to have a strong antagonist in anesthesia antagonist test (pentazosin, morphine and meperidine), which shows no weak main muscle group activity in tail oscillation main muscle group test and therefore it is morphine It turns out that it has type activity. This property is further evident in the observation of the Straub tail response with doses above the effective antagonist dose.

In general, it can be seen that the above-mentioned data show a considerable difference in each property depending on the selection of the compounds of the present invention and their higher and lower rapid flow products. Thus, Reference compound 1-3 is a lower equivalent of the compound of Example 1, which has no antagonistic effect on the main root muscle group, whereas the compound of Example 1 shows a strong antagonistic effect on all antagonistic tests but is completely inactive to the main root muscle group. . Its high class derivative, Reference compound 4, also has antagonistic activity, but it is only one fifth the effect of the compound of the example in the lung nazosin antagonism test and only one-fifth activity in the isetylcholine and anti-bradykinin tests. Indicated.

Likewise, the compound of Example 2 has very weak activity against the main myocardium. While all three antagonists showed strong antagonism, the reference compound 5, the lower class of 2, had clearly opposite activities, the latter being active in the tail oscillation main muscle group test, but inactive in the lung nazosin antagonist test. . When the compound of Example 1 was compared with the next higher class of compounds of Reference compound 4, Reference compound 6, and Example 2, the compound was inactive in the tail oscillation main muscle group test and active in the phenazosin antagonistic test, thus showing its activity as an antagonist. . However, the compound is 60 to 100 times less active in the acetylcholine test.

Compared with the reference compounds 7 and 8, which are the lower equivalents of Example 3, the compound of Example 3 had a very strong main root group or anesthesia characteristic of the reference compound 7, but was completely reversed in the second higher equivalents, namely the compound of Example 3. The data of Example 3 show that the data are pure antagonists.

Example 4

3,6 (eq), 11 (aX) -trimethyl-8-hydroxy-11 (eq)-(3-oxobutyl) -1,2,3,4,5,6-hexahydro-2,6- Metano-3-benzazosin was prepared by the following method.

57.1 g (0.148 moles) of ethyl 1,4aα, 5α-trimethyl-7-methoxy-3-acetyl-1,2,3,4,4a, 5,10,10a-octahydro-2,5-methano -Benzo [g] quinoline-3-carboxylate was added to a solution containing 72.5 ml of formic acid and 571 ml of mesitylene. The mixture was heated and refluxed for 24 hours, cooled, added with an aqueous solution of excess caustic soda and made basic. Extract with ether. The mixed ether extract was washed with brine washed with water, washed with brine, dried, filtered and dried in vacuo to distill the residue into steam. After steam distillation, the residue was extracted again with ether, washed with brine, washed again with brine, dried, filtered and evaporated to dryness to obtain 42.4 g of crude product which was then converted to hydrochloride. 6.6 g of 3,6 (eq), 11 (aX) -trimethyl-8-methoxy-11 (eq)-) 3-oxobutyl) -1,2,3,4,5,6-hexahydro -2,6-methano-3-benzazocin hydrochloride was obtained with a melting point of 182.5-187.5 ° C.

The latter (5.8 g, 0.0018 mol) was digested under reflux for 2 hours in 58 ml of 48% hydrobromic acid solution. The product was liberated to free base and recrystallized from ethanol to 1.3 g of 3,6 (eq), 11 (aX) -trimethyl-8-hydroxy-11 (eq)-(3-oxobutyl) -1,2 , 3,4,5,6-hexahydro-2,6-methano-3-benzazosin was obtained and the melting point was 170-173 ° C.

The free base sample was converted to methanesulfonate to obtain a material having a melting point of 265-268 ° C. (from ethanol).

Acetylcholine induced peritoneal convergence (Ach), anti-bradykinin (Bk), phenyl-P-quinone induced cramps (PPQ), tail oscillation phenazosin antagonism (Phen), tail oscillation main muscle group (TFAg) and strau tail The data obtained from the test results are listed in Table 2, where the dosage is expressed in milligrams per kilogram, and data not otherwise stated are obtained by subcutaneous administration.

[Table 2]

These data indicate that the sample is an anesthetic analgesic, which is found to be inactive in the phenazosin antagonist test, the main muscle group activity in the tail oscillation main muscle group test, and furthermore, the observation of the Straub tail reaction. .

The activity of the tail oscillator muscle group of the compound is not disturbed by nallopine 1.0 mg / kg (SC) or naloxone 0.1 mg / kg (S.C.). The low sensitivity of the compound to anesthetic antagonists is surprising in terms of pharmaceutical limitations. On the other hand, morphine's tail oscillation agonist muscle activity is completely reversed when administered the same as these anesthetic antagonists.

Claims (1)

The compound of formula (III) was heated with formic acid, benzyl-di-lower alkylammonium formate or tri-lower-alkylammonium formate in an organic solvent to obtain 3,6 (eq), 11 (aX). ) -Trimethyl-8-lower-alkoxy-11 (eq)-(CH ₂ CH ₂ COR) -1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazosin A process for producing benzazosin of formula (I) and acid addition salts thereof, wherein the lower alkoxy group is decomposed.

Wherein R is a pentyl group, 3-methylbutyl group or 2-phenylethyl group, Y is a lower alkyl group and Alk 'is a lower alkyl group.