DE2811849C2 - - Google Patents

Description

The invention relates to certain selected 3.6 (eq), 11 (ax) - Trimethyl-8-hydroxy-11 (eq) - (2-acyl-ethyl) -1,2,3,4,5,6-hexa hydro-2,6-methano-3-benzazocine, used as an analgesic and Antagonists are suitable for narcotics and low or have no morphine-like narcotic properties.

The US-PS 39 32 422 broadly describes a variety of 3-R₁-6- (eq), 11 (ax) -dimethyl-8-hydroxy-11 (eq) - (CH₂CH₂COR) - 1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocines, wherein R₁ a variety of substituents including lower alkyl, low alkenyl, low alkynyl, cycloalkyl, cycloalkyl low alkyl and phenyl lower alkyl or substituted phenyl is lower alkyl and in which R includes low alkyl, Phenyl or phenyl-lower alkyl means. Although this patent the general statement contains that the connections Have narcotic-antagonistic properties, actually contains any species for which narcotics are antagonistic Efficacy data are given for a cyclopropylmethyl group on the benzazocin nitrogen atom. That N-cyclopropylmethyl substituted hexahydro-2,6-methano-benzazocine have a narcotic-antagonistic effect, true with the technical knowledge, because up to the present time has been taught that a strong narcotic-antagonistic activity only in compounds of hexahydro-2,6-methano-3-benzazocin Class can be expected by introducing special Groups that differ from the methyl group on the nitrogen atom distinguish how groups including low alkenyl,  Halogen-lower-alkenyl, cyclopropylmethyl or cyclobutyl- methyl (see, for example, US Pat. Nos. 32 50 678, 33 72 165, 33 45 373 and 35 14 463). This empirical rule, for example a low alkenyl group on the nitrogen atom for Narcotics-antagonistic properties required, even goes on the morphine class about what is caused by nalorphine and naloxone is made clear d. H. N-allylnormorphin or N-allyl-7,8-dihydro- 14-hydroxynormorphinone, two well-known anesthetic antagonists of the morphine type. Therefore, it was up to the present Time very unusual, narcotic-antagonistic Properties in strong analgesics including analgesics the hexahydro-2,6-methano-3-benzazocin class to find the have a methyl group on the nitrogen atom. For example Michne et al., J. Med. Chem. 20, 682 (1977) a Narcotics-antagonistic activity in a species of 3-methyl-hexahydro-2,6-methano-3-benzazocin with a low Alkyl carbinol side chain found in the 11 (eq) position, and Ager et al., J. Med. Chem. 12, 288 (1969) described one Series of 3-methyl-2,6-methano-3-benzazocines, ranging from 2 to 20% of the effectiveness of nalorphine in morphine addicts Have monkeys, but they have N-methyl antagonists a relatively low effectiveness.

It has now surprisingly been found that one particular Species of 3.6 (eq), 11 (ax) trimethyl-8-hydroxy-11 (eq) - 2-acyl-ethyl) -1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocines, where R denotes certain selected groups, and whose acid addition salts have potent anesthetic antagonists are. These compounds have the formula

on, wherein R is pentyl, 3-methylbutyl, 2-phenylethyl, 2-cyclopropylethyl or 2-cyclopentylethyl. The narcotic-antagonistic properties that the above identified group are clearly Contrast with the properties of homologous compounds in the lower alkyl part of the R group because these compounds have exactly the opposite effectiveness and strong analgesics with either no antagonistic properties are or their antagonistic properties are greatly reduced are.

The compounds of the formula I are either prepared by the process of US Pat. No. 3,932,422, which consists of using formic acid in an organic solvent, such as, for example, toluene, xylene or mesitylene, or using a benzyl-di-lower-alkyl-ammonium formate or a tri-lower-alkyl-ammonium formate a 7-YO-1,4-a α , 5 α- trimethyl-3-COR-1,2,3,4,4a, 5,10,10a-octahydro-2, 5-methanobenzo [g] quinoline of the formula II

to heat, where Y is hydrogen or lower alkyl and R has the meanings given above, whereupon one with aqueous hydrobromic acid or with sodium propyl sulfide, as described below, the lower alkoxy group (Alk-O) cleaves in the event that Y is lower alkyl.

Alternatively and preferably, the compounds of the formula I are prepared by modifying the above process, which consists in formic acid in an organic solvent, for example toluene, xylene or mesitylene, or with a benzyl-di-lower-alkylammonium formate or Tri-lower-alkylammonium formate a lower-alkyl-1,4a α , 5 a -trimethyl-7-YO-3-RCO-1,2,3,4,4a, 5,10,10a- octahydro-2,5- methanobenzo [g] quinoline-3-carboxylate of the formula III

to heat, wherein Alk 'denotes lower alkyl and R and Alk have the meanings given above, as in the DE-OS 27 42 715.2 described. In the event that Y is lower alkyl, the lower alkoxy group is split (Alk-O), such as with aqueous hydrobromic acid or sodium propyl sulfide. If you use aqueous hydrobromic acid effective cleavage, the reaction is carried out by reflux in a solution of the ether in aqueous hydrobromic acid and isolating the connection either directly from the Reaction mixture in the form of the hydrobromide salt or from a neutral solution in the form of the free base. One uses Sodium propyl sulfide to cleave the ether, so you do that Reaction by refluxing a solution of the ether in one inert organic solvents, for example dimethylformamide (DMF), with a molar excess of sodium propyl sulfide, that by adding propanethiol to sodium hydride manufactures. The starting material is preferably used of formula II or III, wherein Y is lower alkyl, whereby the following ether cleavage is required.

The compounds of formula II and the processes for their preparation are described in US Pat. No. 3,932,422. As described in DE-OS 27 42 715.2, the compounds of the formula III are prepared either by reacting a lower-alkyl-1,4a α , 5 α- trimethyl-7-YO-1,2,3,4,4a, 5,10,10a-octahydro-2,5-methanobenzo [g] quinoline-3-carboxylate (formula II, wherein R is lower alkoxy) with an alkali metal amide, for example sodium amide or lithium diisopropyl amide, in an inert organic solvent and reaction of the so formed alkali metal salt with a corresponding acyl halide, R-CO-X, or by reacting a 1,4a α , 5 α -trimethyl-7-YO-3-RCO-1,2,3,4,4a, 5,10,10a -oxtahydro-2,5-methanobenzo [g] - quinolins (formula II, in which R has the meanings given above) with an alkali metal amide, as in the above alternative, and reaction of the resulting alkali metal salt with a lower alkyl haloformate.

React thanks to the presence of a basic amino group the forms of the represented by the above formula I. free base with organic and inorganic acids under Formation of acid addition salts. The forms of the acid addition salts are made from any organic or inorganic Acid produced. You get them in the usual way, for example, either by directly mixing the base with the acid or, if this is not appropriate, by Dissolve either or both of the base and components Acid separated in water or an organic solvent and mixing the two solutions or by dissolving both the base as well as the acid together in a solvent. The resulting acid addition salt is filtered isolated if it is insoluble in the reaction medium, or by evaporation of the reaction medium, the acid addition salt is left behind. The acid residues or anions these salt forms are neither new nor critical in themselves and can therefore be any acid anion or any acid-like Substance that is suitable for salt formation with the base is.

All acid addition salts are available as sources for the forms of free base by reaction with an inorganic base.  It can be seen that if one or more the characteristics such as solubility, molecular weight, physical Appearance, toxicity and the like, of a given Base or an acid addition salt thereof this form for the makes each purpose unsuitable, easily into another more suitable form can be converted. It goes without saying that for pharmaceutical purposes acid addition salts of relative non-toxic, pharmaceutically usable or compatible Acids, for example hydrochloric acid, methanesulfonic acid, Lactic acid, tartaric acid and the like are used.

The compounds of the invention can be in enantiomers Forms are present that can be split into enantiomers. If desired, the isolation or manufacture of a special enantiomeric form can be achieved using general, principles known to those skilled in the art. At the for the Compounds of formula I used nomenclature "ax" axial and "equ" equatorial, and the configurations are given with regard to the hydroaromatic ring. Thus the 6 (eq), 11 (ax) compounds of the formula I are in the cis configuration, whereas the 6 (eq), 11 (eq) connections exist in the trans configuration.

The useful properties of the compounds of the invention were through standard pharmacological procedures demonstrates how easy it is by technicians with normal Experience in pharmacological investigations can be, so that the current determination of the numerical biological data for a particular test compound can be done without undue experimentation.

The one used to determine the analgesic and narcotic-antagonistic Activities of the compounds according to the invention used test procedures were described in more detail in the literature; these are the following: the acetylcholine induced abdominal constriction test, which is a primary  analgesic screening test is used to measure ability a test compound to suppress acetylcholine induced abdominal cramps or constriction Mice and by Collier et al., Brit. J. Pharmacol. Chemotherapist 32, 295 (1968); a modification the anti-bradykinin test, which is also a primary analgesic Screening test is described by Berkowitz et al. J. Pharmacol. Exp. Therap. 177: 500-508 (1971), Blane et al., J. Pharm. Pharmacol. 19, 367-373 (1967), Botha et al. Eur. J. Pharmacol. 6, 312-321 (1969) and Deffenu et al., J. Pharm. Pharmacol. 18, 135 (1966); the one induced by phenyl-p-quinone Cramp test, also a primary analgesic Screening test, designed to measure the ability of a patient Test agent for preventing phenyl-p-quinone induced Convulsions in mice described by Pearl and Harris, J. Pharmacol. Exp. Therap. 154, 319-323 (1966); the rat tail Shock thermal radiation analgesia (agonist) test, described by D'Amour and Smith, J. Pharmacol. Exp. Therap. 72, 74 (1941) modified by Bass and Van der Brook, J. Am. Pharm. Assoc. Sci. Ed. 41, 569 (1956); the narcotic antagonism test (e.g. phenazocin, morphine and meperidine antagonist test), which is intended to test the ability of a test agent to antagonize the effects of phenazocin, morphine or meperidine in the rat tail blow agonist Determine test described by Harris and Pierson, J. Pharmacol. Exp. Therap. 143, 141 (1964); and Straub's Tail test, described by Straub, German medical Wochenschrift (1911), page 1426, and Aceto et al., Brit. J. Pharmacol. 36, 225-239 (1969), which is an observation test the, if positive, a clue for a conclusion for morphine-like narcotic properties.

The structures of the compounds according to the invention were determined by the synthesis methods, through the elementary analyzes and the ultraviolet, Infrared and nuclear magnetic resonance spectra assigned. The course of the reactions and the homogeneity of the Products were monitored by thin layer chromatography.  

Example 1

A solution of 27.5 g (0.064 mol) of ethyl 1,4- α , 5 α- trimethyl-7-methoxy-3-hexanoyl-1,2,3,4,4a, 5,10,10a-octahydro-2 , 5-methano-benzo [g] quinoline-3-carboxylate in 275 ml of mesitylene and 37 ml of 98% formic acid was heated under reflux with stirring for 24 hours and then brought to dryness in vacuo. The oily residue was triturated with 200 ml of water, basified to pH 10 with concentrated ammonium hydroxide and the mixture was extracted with diethyl ether. The organic extracts, when washed with water and then with brine, dried over anhydrous sodium sulfate and evaporated to dryness, gave 30 g of a residue which was treated with a solution of 6.0 g of oxalic acid in 50 ml of ethanol. This gave 27 g of 3.6 (eq), 11 (ax) trimethyl-8-methoxy-11 (eq) - (3-oxooctyl) -1,2,3,4,5,6-hexahydro-2, 5-methano-3-benzazocin oxalate, F 95-97 ° C.

A solution of 1.9 g (0.0047 mol) of the latter in the form of the hydrochloride salt in 25 ml of 48% hydrobromic acid was heated under reflux for 2 hours, in vacuo to dryness concentrated and the residue became basic with aqueous alkali made and extracted with diethyl ether. By concentrating the ethereal extracts for drying and conversion the remaining solid in the hydrochloride salt with ethereal Hydrogen chloride was obtained 2.5 g of raw material, the was recrystallized from isopropanol to give 1.7 g 3.6 (eq), 11 (ax) trimethyl-8-hydroxy-11 (eq) - (3-oxooctyl) - 1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocin hydrochloride, F 252-255 ° C.

A small sample of the hydrochloride salt was added to the base converted, and the latter was converted into the methanesulfonate from F 178-179 ° C (from acetone) converted.

Another sample was in the 2-naphthalene sulfonate, F 195- 198 ° C, (from methanol / diethyl ether) converted.  

Following a procedure similar to that described in Example 1 were the following compounds of formula I in the same Manufactured way.

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-benzazocin hydrochloride, F 260-263 ° C (3.6 g from isopropanol), prepared by heating 20.0 g (0.045 mol) of ethyl 1,4a α , 5 α -trimethyl- 7- methoxy-3- (4-methylpentanoyl) -1,2,3,4,4a, 5,10,10a-octahydro-2,5-methanobenzo [g] quinoline-3-carboxylate in 1 liter of mesitylene and 70 ml of formic acid Formation of 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 (F 222-229 ° C from diethyl ether) and cleavage with 40 ml of 48% hydrobromic acid of 4.0 g (0.0098 mol) of the latter.

A sample of the free base was made from the hydrochloride salt isolated, and the base was converted into the corresponding methanesulfonate from F 189-191 ° C (from acetone / diethyl ether) converted.

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-benzazocin methanesulfonate, F 233-235 ° C (1.6 g from ethanol), prepared by heating 26.2 g (0.055 mol) of ethyl 1,4a α , 5 α - trimethyl-7-methoxy- 3- (3-phenylpropionyl) -1,2,3,4,4a, 5,10,10a-octahydro-2,5-methanobenzo [g] quinoline-3-carboxylate in a solution of 990 ml mesitylene and 41.5 ml formic acid to form 3.6 (eq), 11 (ax) -trimethyl-8-methoxy-11 (eq) - (3-oxo-5-phenylpentyl) -1,2,3,4,5,6- hexahydro-2,6-methano-3-benzazocin p-toluenesulfonate, F 176-179 ° C, and cleavage of 8.1 g (0.02 mol) of the free base corresponding to the latter with 81 ml of 48% aqueous hydrobromic acid .

Example 4

3,6 (eq), 11 (ax) -trimethyl-8-hydroxy-11 (eq) - (3-oxo-5-cyclopropylpentyl -) - 1,2,3,4,5,6-hexahydro-2, 6-methano-3-benzazocin of F 128-130 ° C (0.9 g, from ethyl acetate / hexane), prepared by heating 14.9 g (0.034 mol) of ethyl 1,4- α , 5 α -trimethyl- 7-methoxy-3- (3-cyclopropylpropionyl) -1,2,3,4,4a, 5,10,10a-octahydro-2,5-methanobenzo [g] quinoline-3-carboxylate in a solution of 680 ml mesitylene and 26 ml of formic acid to give 6.2 g of 3.6 (eq), 11 (ax) trimethyl-8-methoxy-11 (eq) - (3-oxo-5-cyclopropylpentyl) -1,2,3, 4,5,6-hexahydro-2,6-methano-3-benzazocin hydrochloride, F 224-226 ° C (from ethanol / diethyl ether) and cleavage of the latter with 0.065 mol of sodium propyl sulfide (prepared by adding 2.7 g of one 50% dispersion of sodium hydride in mineral oil to 5.9 ml propanethiol) in 65 ml dimethylformamide (DMF).

A sample of the free base was converted to the hydrochloride salt to form a product of F 271-273 ° C (from Ethanol / diethyl ether).

Example 5

3,6 (eq), 11 (ax) trimethyl-8-hydroxy-11 (eq) - (3-oxo-5-cyclopentylpentyl -) - 1,2,3,4,5,6-hexahydro-2, 6-methano-3-benzazocine sulfate of F 230-235 ° C (4.8 g, from ethanol), prepared by heating 43.7 g (0.094 mol) of ethyl 1,4a α , 5 α -trimethyl- 7- methoxy-3- (3-cyclopentylpropionyl) -1,2,3,4,4a, 5,10,10a-octahydro-2,5-methanobenzo [g] quinoline-3-carboxylate in a solution of 35.3 ml formic acid in 437 ml of mesitylene to give 19.5 g of 3.6 (eq), 11 (ax) trimethyl-8-methoxy-11 (eq) - (3-oxo-5-cyclopentylpentyl) -1,2,3, 4,5,6-hexahydro-2,6-methano-3-benzazocin hydrochloride of F 219-223 ° C (from ethanol / diethyl ether), followed by the cleavage of 12.7 g of the latter with 127 ml of 48% Hydrobromic acid.

For comparison purposes with the claimed species, a Series of reference connections made as they are general are described in US Pat. No. 3,932,422, using the above working methods:

Comparative compound 1:
3,6 (eq), 11 (ax) trimethyl-8-hydroxy-11 (eq) - (3-oxopentyl) -1,2,3,4,5,6-hexahydro-2,6-methano-3 -benzazocin (R = C₂H₅);

Comparative compound 2:
3,6 (eq), 11 (ax) trimethyl-8-hydroxy-11 (eq) - (3-oxohexyl) -1,2,3,4,5,6-hexahydro-2,6-methano-3 -benzazocine hydrochloride [R = (CH₂) ₂CH₃];

Comparative 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 = (CH₂) ₃CH₃];

Comparative 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 = (CH₂) ₅CH₃];

Comparative compound 5:
3,6 (eq), 11 (ax) trimethyl-8-hydroxy-11 (eq) - (3-oxo-5-methylhexyl) -1,2,3,4,5,6-hexahydro-2,6 -methano- 3-benzazocin hydrochloride [R = CH₂CH (CH₃) ₂];

Comparative compound 6:
3,6 (eq), 11 (ax) trimethyl-8-hydroxy-11 (eq) - (3-oxo-7-methyloctyl) -1,2,3,4,5,6-hexahydro-2,6 -methano- 3-benzazocin [R = (CH₂) ₃CH (CH₃) ₂];

Comparative 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 = C₆H₅); and

Comparative 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-benzazocin methanesulfonate (R = CH₂C₆H₅).

Results of the biological studies

The data obtained with the compounds according to the invention, which are denoted by the above numbers of the preparation examples and the comparative compounds, which are denoted by the above comparison numbers, are listed in the table below. The abbreviations Ach, BK, PPQ, Phen, Mor, Mep, TF Ag and Straub each mean the abdominal constriction test induced by acetylcholine, the anti-bradykinin test, the cramp test induced by phenyl-p-quinone, the phenazocin , Morphine and meperidine tail-beat antagonist test, the tail-beat agonist test and the Straub test. The results are given either as ED₅₀ (mg / kg) for the Ach, BK, PPQ and TF Ag tests or as AD₅₀ for the Phen, Mor and Mep tests or as a percentage inhibition. The letter "I" means inactive and, unless otherwise stated, all results have been achieved by subcutaneous administration. All doses are given in mg / kg.

Tail agonist activities of each of the control compounds 1,2,3,5 and 7 were in each case prevented by 1.0 mg / kg (subcutaneous) nalorphine, whereas the same activity of the compound of Example 2 (hydrochloride) partially 1.0 mg / kg (subcutaneous) nalorphine prevented has been. These results show that the comparative compounds 1,2,3,5 and 7 are similar to narcotics, an indication later by observing Straub's Tail reaction in any case of this species at relatively low levels Dosages is confirmed. The data regarding the Species from Example 2 show that while the compound a strong antagonist is what is caused by the activity in everyone of narcotic antagonist studies is confirmed (Pentazocin, morphine and meperidine), they nonetheless a weak agonistic effectiveness in tail beating Owns agonist test and therefore to some extent is characterized by having morphine-like activity. This latter sign continues through observation the Straub tail reaction at a low dose level clarified above the effective antagonist dose.

In general, the above data show considerable Differences in properties between each of the chosen Species according to the invention and their higher and lower ones Homologues. This shows for each of the comparison compounds 1 to 3, the lower homologues of the species of Example 1 are that they are agonists with no visible antagonistic properties whereas the compound of Example 1 is a is a strong antagonist in all antagonism studies and is completely ineffective as an agonist. Although she is a higher one Comparative compound 4 also shows homologous features an activity as an antagonist, but the effectiveness is only a fifth that of the compound of Example 1 in the phenazocin antagonism test and only a fifteenth in the acetylcholine and anti-bradykinin tests.  

In the same way, the connection of Example 2 shows one very little agonistic effect, but a strong antagonistic Effectiveness in all three antagonism studies, whereas their lower homologue, the comparison compound 5, exactly the opposite spectrum of effectiveness having; the latter is effective in tail striking Agonism test and inactive in the phenazocin antagonism test. As in the case of the comparison between the compounds of example 1 and the comparative compound 4 shows the comparative compound 6, the next higher homolog of the type of Example 2, an efficacy profile as an antagonist. Agonism test ineffective and with phenazocin antagonism Test is effective. However, the connection is about 60- to 100 times less active in the acetylcholine examination.

In the case of the connection of example 3 in comparison with theirs lower homologues, comparative compounds 7 and 8 very strong agonism or become narcotic-like Properties of comparative compound 7 in the second higher Homologues, d. H. with the connection of example 3, completely vice versa, which is characterized by its data as a pure antagonist identifies.

The compounds of Examples 4 and 5 that are not homologous with are any currently known compounds wherein R is cycloalkyl-lower alkyl, are shown by the data also as antagonists, but as with the compound Example 2 also shows very low agonism or have very low properties similar to narcotics, what the tail flap agonism test and the observation of the Straub's tail reaction show that at high doses being found.

Claims (2)

1. 3,6 (eq), 11 (ax) -trimethyl-8-hydroxy-11 (eq) - (2-acyl-ethyl) - 1,2,3,4,5,6-hexahydro-2,6 -methano-3-benzazocin of the general formula I. wherein R is pentyl, 3-methylbutyl, 2-phenylethyl, 2-cyclopropylethyl or 2-cyclopentylethyl or an acid addition salt thereof. 2. Use of the compounds according to claim 1 as anesthetic Antagonists.