CS228543B2 - Method for the production of new trans-/6a,10a/diastereomeric 9-amino-1-acetoxyoktahydrobenzo/c/quinoline derivates - Google Patents

Description

BACKGROUND OF THE INVENTION The present invention relates to a process for the preparation of certain novel benzofin-quinolines, in particular trans- (6a, 10a) diastereomeric 9-amino-1-acetoxyoctahydrobenzo [c] quinolines and derivatives thereof, and particularly certain 5S-methylamide derivatives on pharmaceutically acceptable acid addition salts useful as central nervous system agents, particularly as analgesics and antiemetics for administration to mammals, including humans, methods of use thereof, and pharmaceutical compositions containing the disclosed compounds as active agents.

An acceptable alternative nomenclature for the disclosed compounds of Formula I below is based on the replacement of the term "benzoquinoline" by "phenanthridine". Thus dl-trans-5,6,6a, 7,8,9,10,10a-octahydro-1-acetoxy-9 (5-acetamido-5,6 (3-dimethyl-3- (5-phenyl-2- pentyloxy] benzo [c] quinoline may alternatively be called dl-trans-5,6,6a, 7,8,9,10,10a-octahydro-1-acetoxy-9,6-acetamido-5,6'-dimethyl-3 - (5-Phenyl-2-pentyloxy) -phenanthridine.

Although a number of analgesics are currently available, there is a continuing search for new and improved formulations, as there is no agent suitable for the treatment of a wide range of pain conditions that at the same time would have minimal side effects. The most commonly used substance, aspirin, is of no practical significance for the treatment of major pain and, moreover, is known to exhibit various undesirable side effects. Other, more potent analgesics, such as d-propoxyphene, codeine, and morphine, are addictive. This clearly implies a need for better and more effective analgesics.

Belgian Patent Specification No. 854,655, issued November 16, 1977, discloses compounds of formulas II and III.

in which

R 1, R 4, R 5, R 6, Z and W are as defined below, and the corresponding 9-hydroxy compounds. The ketones of formula II and the corresponding 9-hydroxy compounds are said to be useful as central nervous system agents, particularly as analgesics and tranquilizers, such as hypotensives, diuretics and glaucoma treatment agents. U.S. Pat. No. 4,222,816, issued October 14, 1980, discloses compounds of Formula II and the corresponding 1,9-dlhydroxy-octahydrobenzo [c] quinolines as antiemetics.

Wilson and May, Abst. Papers, Am. Chem. Soc., 168 Meet., Medi 11 (1974), J. Med. Chem. 17, 475-476 (1974) and J. Med. Chem. 18, 700-703 (1975), described the analgesic properties of 9-nor-9β-hydroxyhexahydrocanabinol and other cannabinoid structures such as (S-8-tetrahydrocanabinol and its primary metabolite, 11-hydroxy-δ-8-tetrahydrocanabinol).

U.S. Pat

507 885, 3,636,058, 3,649,650, 3,856,821,

Nos. 928,598, 3,944,673, 3,953,603 and 4,143,139 disclose a series of structurally related dibenzo [b, d] pyranes bearing substituents at the 9-position such as alkyl, hydroxy and oxo. Of particular interest is dl-trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-6,6a, 7,8,9,10,10a-hexahydro-9H-dibenzo [b, d] pyran-9-one, which in animals acts as an anti-emetic and an anxiety agent exhibiting analgesic properties, now known by the generic name nabilone.

U.S. Pat. No. 4,152,450 discloses certain 3-alkyl-1-hydroxy-tetrahydro- and -bexahydrodibenzo [b, d] pyranes containing an amino or amido group at the 9-position which are useful as analgesics, antidepressants, anxiolytics and hypotensives .

U.S. Patent No. 3,878,219 discloses 5H- [1] benzopyrano [3,4-d] pyridines useful as analgesics, and U.S. Patent No. 3,888,946 discloses a corresponding group of compounds in which the carbon ring is not six-membered but five-membered.

Bergel et al., J. Chem. Soc., 286 (1943) investigated the effect of substitution of the pentyl group at the 3-position 7,8,9,10-tetrahydro-3-pentyl-6,6,9-trimethyl-6H-dibenzo [b, d] pyran-1-ol C 4 -C 8 alkoxy groups have been found to have little or no hashish activity at a dose of 10 to 20 mg / kg.

In a newer work [J. Copper. Chem. 16, 1200-1206 (1973) described by Loev et al. comparison of the activity of 7,8,9,10-tetrahydro-3-substituted-6,6,9-trimethyl-6H-dibenzo [b, d] pyran-1-ol, in which the 3-position substituent is -OCH ( CH3) C5H11, - CH2CH (CH3) C5H11, or —CH (CH3) C5H11.

A compound containing an ether side chain is 50% less effective on the central nervous system than the corresponding compound in which the alkyl side chain is attached to the aromatic ring directly and not through an oxygen atom and five times more potent than the compound in which the oxygen is replaced by a methylene group.

Hoops et al. in J. Org. Chem. 33, 2995-2996 (1968) described the preparation of the 5-aza-analog 5-6a (10α) -tetrahydrocannabinol, which is referred to herein as 7,8,9,10-tetrahydro-1-hydroxy-5,6,6, 9-tetramethyl-3-n-pentylphenanthridine, but reported no use for this compound, Beil in "Psychomimetic Drugs" (ed. Efron, Raven Press, New York, 1970, p. 336) reports that it is the pharmacology of the animal is completely inert.

Hardman et al. v Why. West. Pharmacol. Soc. 14, 14-20 (1971) report some pharmacological activity for 7,8,9,10-tetrahydro-1-hydroxy-6,6,9-trimethyl-2-n-pentylphenanthridine [5-aza-a-6a (10a). j-tetrahydrocannabinol].

Mechoulam and Edery in "Marijuana" (ed. Mechoulam, Academic Press, New York, 1973, p. 127) report their observation that major structural changes in the tetrahydrocannabinol molecule are likely to lead to a sharp decrease in analgesic efficacy.

Paton in the Annual Review of Pharmacology, 15, 192 (1975) describes a generalization of the structure-activity relationships of cannabinoid-type agents. The presence of a geminal dimethyl moiety in the pyran ring is critical for cannabinoid activity and the replacement of oxygen in the pyran ring with nitrogen results in a loss of activity.

U.S. Pat. No. 4,087,545 discloses anti-methyl and antinauseal properties of 1-hydroxy-3-alkyl-6,6a, 7,8,10,10a-hexahydro-9H-dibenzo [b, d] pyran-9-ones .

Sallan et al. in N. E. J. Med. 293, 795 (1975) report that 5-9-tetrahydrocannabinol exhibits anti-emetic properties when administered orally in patients receiving anticancer chemotherapy.

Shannon et al. (Life Sciences 23, 49-54, 1978) have reported that 5-9-tetrahydrocannabinol has no anti-emetic effects in the case of dog-induced vomiting by apomorphine. Borisnn et al. described in N. England J. of Med. 298, 1480 (1978) the use of non-anesthetized cats as model animals for detecting the antiemetic effect of the compounds, particularly with regard to vomiting induced by drugs used for cancer chemotherapy. The cited authors found that premedication of non-anesthetized cats 1-hydroxy-3- (1 ', 1'-dimethylheptyl) -6,6-dimethyl-6,6a, 7,8,10,10a-hexahydro-9H-dibenzo [b, d] pyran-9 (9H) -one (nabilone) explicitly protects against vomiting after injection of an antineoplastic drug.

In our related Czechoslovak patent specification 228 515, certain benzo [c] quinolines, namely 9-amino-1-hydroxy-oxy-octahydro-6H-benzo [c] quinolines and their amides, of formula I below, are effective. central nervous system agents useful in mammals as tranquilizers, anticonvulsants, diuretics, antidiarrheal agents, antitussives, and glaucoma treatment agents, which are particularly effective as analgesics and as treatment agents in mammals, including humans, and prevention of vomiting and nausea, in particular induced by antineoplastic drugs. The above-mentioned substances, which are non-narcotic and non-addictive, are compounds of formula I nhr

in which

R is hydrogen, COR 7 or SO 2 R 8, wherein R 7 is hydrogen, C 1 -C 5 alkyl, trifluoromethyl or phenyl, and R 8 is methyl or p-tolyl,

R1 represents a hydrogen atom, a benzyl group or an alkanoyl group having 1 to 5 carbon atoms,

Rd represents a hydrogen atom or a methyl group,

R 5 represents a hydrogen atom or a methyl group,

R6 represents a hydrogen atom or a methyl group,

Z represents the remainder of the formula

- (alki) _m -O- (alk2) _n wherein alki and alk2 each independently represent an alkylene group having 1 to 9 carbon atoms, provided that the sum of the carbon atoms in the alki and alk2 radicals is at most 9, and m independently of one another have always 0 or 1 a

W represents a phenyl group, and pharmaceutically acceptable acid addition salts thereof.

Representative examples of pharmaceutically acceptable acid addition salts of the compounds of formula (I) include salts with mineral acids such as hydrochlorides, hydrobromides,

B sulfates, nitrates and phosphates, and salts with organic acids such as citrates, acetates, sulfosalicylates, tartrates, glycolates, malonates, maleates, fumarates, malts,

2-hydroxy-3-naphthoates, pamoates, salicylates, stearates, phthalates, succinates, gluconates, salts with mandelic acid, lactates and methanesulfonates.

The compounds of formula I above have asymmetric centers at the 9, 6a, and 10a positions. Other centers of asymmetry may exist in the substituent at the 3-position — Z-W] and at the 6-position. Because of the quantitatively greater biological activity, diastereoisomers with a β-configuration are generally preferable to the corresponding 9α-isomers. For the same reason, the trans (6a, 10a) diastereomers of the compounds of formula (I) are generally more preferred than the corresponding cis (6a, 10a) diastereomers, and generally one of the enantiomers of the compound is more preferred than the other enantiomer and racemate. For example, the d-enantiomer of 5,8,6'-, 7,8,9,10,10aa-octahydro-1-acetoxy-9,3-amino-5,6,3-dimethyl -3- (5-phenyl-2-pentyloxy) benzo [c] quinoline is superior to the 1-enantiomer and to the racemate due to its higher analgesic activity.

Of the diastereomers with respect to the 3-position (ZWJ is always one more preferred than the remaining one) For example, compounds of formula 1 in which ZW is a radical of formula

H

Because of their greater analgesic activity, the OC-1CH2Cfls are preferable to the corresponding compounds in which ZW represents a radical of formula

CHz

Τ

-O-C-CH3C4s

Η

For simplicity and convenience, all of these modifications are designated by a single general formula (I), which thus includes both racemic forms of the compounds and mixtures of diastereomers, pure enantiomers and diastereomers. The usefulness and usefulness of racemic mixtures, mixtures of diastereomers as well as pure enantiomers and diastereomers are determined by the biological assays described below.

The present invention describes a process for the preparation of those compounds of the above general formula (I) in which the R6 substituent at the 5-position is a β-methyl group, wherein the additional substituents present in the compounds produced by the process of the invention are given by Formula II below.

Accordingly, the present invention provides a process for the preparation of novel trans (6a, 10a) diastereomeric 9-amino-1-acetoxyoctahydrobenzo [c] quinoline derivatives of formula II

wherein one of R 10 and R 10 is hydrogen and the other is methyl and their pharmaceutically acceptable acid addition salts, characterized in that the trans- (6a, 10a) is a di-stereoisomeric compound of formula III

in which

R 10 and R 11 are as defined above, methylated on nitrogen to give the desired 5 H -methyl derivative of the general formula II, and optionally converted by acid treatment to its pharmaceutically acceptable acid addition salt.

The methylation according to the invention is preferably carried out using formaldehyde and hydrogen in the presence of a noble metal catalyst and in the presence of an inert solvent. Even more preferably, a molar excess of formaldehyde is used in the presence of palladium on carbon as a catalyst and methanol as an inert solvent, the reaction being carried out at room temperature at a pressure of 1 to 50 bar.

The preparation of the starting materials of the general formula III is described in our related Czechoslovak patent specification 228 515.

A particularly preferred compound of formula (II) is the individual enantiomer with the absolute configuration [3 (1R), 6S, 6aR, 9R, 10aR] in which R 10 represents a hydrogen atom and Ru represents a methyl group.

The compounds of formula II are particularly useful as analgesics, and as antiemetics and antinauseal agents for mammals, including humans. The compounds can be used to induce analgesia in a mammal and to prevent or treat nausea in mammals, either by oral or parenteral administration of an effective amount of a compound of formula (II) or a pharmaceutically acceptable salt thereof.

The present compounds may be administered as analgesics as well as agents for the prevention and treatment of nausea in the form of pharmaceutical compositions comprising an effective amount of a compound of Formula II and a pharmaceutically acceptable carrier.

The presence of a basic group in the ester moiety (OCOCH 3) in the compounds of formula II allows the preparation of acid addition salts on this basic group. When the above basic esters are prepared by condensation of the hydrochloride (or other acid addition salt) of the corresponding amino acid with the corresponding compound of formula I in the presence of a condensing agent, the base ester hydrochloride is obtained which by careful neutralization affords the free base. The free base can then be converted into other acid addition salts in a known manner.

Acid addition salts may be formed on the nitrogen of the benzo [c] quinoline system. These salts are prepared by standard procedures. However, derivatives of the basic ester type abruptly move mice to remove the tail from forming acid addition mono- or disalts.

The analgesic properties of the compounds of formula (II) are determined using thermal irritant stimulation tests, such as a test in which mice abruptly remove the tail from the thermal irritation site, or using chemical irritant stimuli such as the ability of test compound po228543 to ) induced in mice by phenylbenzoquinone. These and other assays are set forth below.

Tests using thermal stimuli

(a) Hot plate analgesic efficacy test

A modification of the procedure described by Woolfe and MacDonald [J. Pharmacol. Exp. Ther. 80, 300-307 (1944)]. The test mice are placed on a 0.3 cm thick aluminum plate, which is heated in a controlled manner to irritate the mouse paws with heat. Under the aluminum plate there is an infrared radiator with a power input of 250 W. The radiator operation is controlled by a thermal regulator connected to the thermistors on the surface of the plate so that the plate temperature is maintained at a constant value of 57 ° C. Each experimental mouse is placed in a glass cylinder (16.5 cm diameter) seated on a hot plate and time is counted as soon as the animal's paw touches the plate, and are observed 0.5 and 2 hours after administration of the test compound. Morphine has an MPE50 value of 4 to 5.6 mg / kg (subcutaneous administration) in this test.

(b) Mouse analgesic efficacy test, in which animals vigorously remove the tail from the site of thermal irritation

This test is a modification of the procedure described by D‘Amour and Smith [J. Pharmacol. Exp. Ther. 72, 74-79 (1941)], and utilizes thermal irritation of the tail of a controlled intensity mouse. Each mouse is placed in a sliding metal cylinder such that its tail protrudes at one end of the cylinder. The cylinder is arranged such that the protruding tail of the animal is in a horizontal position above the covered heat emitter. At the beginning of the test, the aluminum screen is removed from the emitter and the beam of light with the slit and focus is directed to the end of the animal's tail. At the same time the clocks start. An increase in the time required for the mouse to respond to thermal irritation by tail twitching is observed. Untreated mice usually respond to thermal irritation in 3 to 4 seconds. The endpoint of protection provided by the test substance is 10 seconds. Each mouse is tested at 0.5 to 2 hours after administration of morphine or test compound. Morphine has an MPE 50 value of 3.2 to 5.6 mg / kg (subcutaneous administration).

c) Tests in submerged tail mice

The method used is a modification of the procedure developed by Benbasset et al. [Sheet. int. Pharmacodyn. 122, 434 (1959)]. Male white mice (Charles River CD-I strain, weighing 19-21 g) were weighed and labeled. Each substance was tested per group of 5 animals, each animal serving as its own control. For general efficacy, the new test substance is first administered intraperitoneally or subcutaneously at a dose of 56 mg / kg administered in a volume of 10 ml / kg. Before administration of the drug and at 0.5 and 2 hours after drug administration, each animal is placed in a cylinder provided with adequate ventilation openings and closed with a circular nylon closure through which the animal's tail protrudes from the cylinder. The cylinder is held in an upright position, with the animal's protruding tail fully immersed in a water bath heated to a constant temperature of 56 ° C. The experiment always ends with an energetic twitch or tail-pull associated with the motor response. In some cases, this may be less vigorous after administration of the test substance. To prevent unwanted tissue damage, the experiment is terminated and the animal's tail is removed from the bath after 10 seconds. The response time is recorded in seconds, rounded to 0.5 seconds. In parallel, the test is performed after application of only the vehicle and standard of known efficacy. If the efficacy of the test substance does not decrease to baseline within 2 hours after administration, the latency of the response is determined 4 to 6 hours after administration. If, at the end of the test day, the test compound still shows efficacy, a final measurement is made 24 hours after administration.

Test using chemical stimuli

Suppression of painful convulsions (writhing) induced by phenylbenzoquinone

Groups of 5 mice (Carworth Farms CF-1) are each pre-treated by subcutaneous or oral administration of saline, morphine, codeine or test compound. Phenylbenzoquinone, which is known to induce abdominal contractions, is then administered intraperitoneally to all groups of test animals after 20 minutes (for subcutaneous administration) or 50 minutes (for oral administration). Five minutes after injection of the compound, mice are observed for 5 minutes to determine whether or not they experience painful convulsions. MPE50 values are determined for each test substance to prevent painful convulsions when administered prematurely.

Tests using pressure stimuli

Efficiency in the Haffner test

A modification of the procedure described by Haffner [Experimentelle Prufung Schmerzstillender Mittel, Deutsch, Med. Wschr., 55, 731-732 (1929)].

Male white rats (50-60 µg Charles River (Sprague-Dawley) CD) are used for the test. Before the test substance is administered and again at 0.5, 1, 2 and 3 hours after drug administration, the rat's tail is clamped ( John-Hopkins, 6.35 cm "bulldog" clamp) The end point of each experiment is explicitly offensive behavior and biting towards a pain-inducing tool, recording the latency of the response in seconds, unless the attack takes 30 seconds, the clamp The morphine is effective in intraperitoneal administration at a dose of 17.8 milligrams / kg.

Tests using electrical stimuli

Test in which test animals bounce from the site of an electrical irritant stimulus

A modification of the procedure described by Tenen [Psychopharmacologia, 12, 278-285 (1968)] is used to provide a threshold of pain, using male white rats (175-200 g) of the Charles River (Sprague-Dawley) CD strain to test. the test substances are immersed in the paws of all rats in a 20% glycerin solution in saline, and the animals are then introduced into the cage and pawed at 30-second intervals with one second electric shocks at increasing current intensity. 39, 0.52, 0.78, 1.05, 1.31, 1.58, 1.86, 2.13, 2.42, 2.72 and 3.04 mA. whether electric shock occurs

a) to bounce backwards,

b) screeching and / or cj to jump or fast forward.

One rat of shocks at increasing current intensity is given to each rat just prior to administration of the test substance and at 0.5, 2, 4 and 24 hours after administration of the test substance.

The results of the above tests are recorded as the maximum possible effect in% (% MPE). The% MPE values for each group are statistically compared to the percent MPE values for the standard and the control values observed prior to drug administration. The% MPE values are calculated using the following formula:

_n / measured time - check time% MPE = -z --—; -; -; break time - check time

The following table shows analgesic activities for representative trans-5,6,6a, 7,8,9,10,10a-octahydro-1-acetoxy-9-amido-3- (5-phenyl-2-pentyloxy) benzo [c] The quinolines according to the invention, which were found in a mouse test in painful cramps induced by phenylbenzoquinone, were reported as MPE50 values, the doses at which half the maximum possible analgesic effect was observed in the test.

the compound ~ NHR ^b> from example number

Rio Rii MPE 50 mg / kg (phenylbenzoquinone - induced convulsions)

NHCOCH2

NHCOCHt. 1 H CH3 CH3 CH3 H H NHCOCHa 1 H CH3 CH3 H 3 *> Bl NHCOCH2 H CH3 Legend: sa b) = racemic mixture «x = dextrorotatory enantiomer, fi [a] _D = + 154,88 ° = i / 3-configuration - <3-configuration

(a) = mixture of equal parts of the side chain diastereomers in position 3

As mentioned above, the compounds of formula II are particularly useful as antiemetics and antinauseal agents in mammals. The disclosed compounds are particularly suitable for preventing vomiting and nausea induced by the application of antineoplastic agents.

The anti-emetic properties of the compounds of formula II are determined on non-anesthetized cats using the procedure described in Proc. Soc. Exptl. Biol. and Med., 180, 437-440 (1979).

The compounds of the present invention are potent analgesics, antiemetics, and antinauseal agents for both oral and parenteral administration, and are conveniently used in the form of suitable compositions. These compositions comprise a pharmaceutical carrier selected with consideration. the intended mode of administration and standard pharmaceutical practice. The active compounds may be administered, for example, in the form of tablets, pills, powders or granules containing as carriers and excipients, for example, starch, milk sugar, certain types of sugar, etc. The said compounds may further be administered in capsules containing them or equivalent carriers and excipients. The active compounds described may also be administered in the form of suspensions, solutions, emulsions, syrups and elixirs for oral administration, which dosage forms may contain flavoring and coloring agents. Tablets or capsules containing from about 0.01 to 100 milligrams of active ingredient are suitable for the vast majority of oral applications of the active ingredients.

Suspensions and solutions of the disclosed compounds are generally prepared just prior to use to avoid storage stability problems (e.g., oxidation) or suspensions or solutions (e.g., solid precipitation) of the active ingredient. Compositions suitable for such use are generally dry solid compositions which are reconstituted for injection.

The dosage most appropriate for each patient will be determined by the attending physician, and will vary depending upon the age, weight and response of the patient as well as the route of administration. In general, however, the initial analgesic doses, as well as the initial doses for use in the prevention or treatment of nausea in adults, may range from 0.01 to 500 mg per day, the total dose being administered in single or divided doses. In many cases it is not necessary to exceed a daily dose of 100 mg. A suitable dosage range for oral administration is from about 0.01 to 300 mg / day, preferably from about 0.10 to 50 mg / day. A suitable dosage range for parenteral administration is from about 0.01 to 100 mg / day, preferably from about 0.01 to 20 mg / day.

The invention is illustrated by the following non-limiting examples.

Example 1 dl-9α-acetamido-1-acetoxy-5,6,6a, 7,8,9,10,10aof-octahydro-5,6 (3-dimethyl-3- (5-phenyl-2-pentyloxy) ) benzo [c] quinoline hydrochloride

To a mixture of 475 mg of 5% palladium on carbon and 10 ml of nitrogen purged methanol was added a solution of 475 mg (0.99 mmol) of dl-9α-acetamido-1-acetoxy-5,6,6a3,7,8,9, 10,10aa-octahydro-6H-methyl-3- (5-phenyl-2-pentyloxy) benzo [c] quinoline, prepared as described in Czechoslovak Patent Specification No. 228 515 in 10 ml methanol, 7.5 ml 37 % formaldehyde and 0.5 ml acetic acid. The resulting mixture is hydrogenated at atmospheric pressure at normal temperature. The theoretical amount of hydrogen (22 mL) was consumed in 20 minutes. The reaction mixture is filtered and the filtrate is poured into a mixture of 100 ml of water and 50 ml of methylene chloride. The aqueous phase was separated, extracted with 50 ml of methylene chloride, the combined organic layers were washed with 50 ml of sodium bicarbonate solution, water and brine each time, dried over anhydrous magnesium sulfate and evaporated. The colorless oily residue is purified by chromatography on 60 g of silica gel using a mixture of equal volumes of toluene and ethyl ether as eluent. Product containing fractions were combined and evaporated. The colorless oily residue is dissolved in 20 ml of ether, filtered and ethyl acetate solution of hydrogen chloride is added to the filtrate until the mixture is acidic to litmus paper. The precipitated product is filtered off and dried at 24 DEG C. under a vacuum of 6.7 Pa for 2 days. The yield of the desired product is 316 mg (75.7%), mp 115-116 ° C.

Mass Spectrum: m / e = 492 (M &lt; + &gt;),

478, 391,375,286,244,230,190.

IR (KBr-technique, values in, um):

2.95, 3.45, 4.20, (wide band),

5.65, 6.00, 6.14, 6.52, 7.30, 8.35.

Analysis:

for C30H40N2O4. HCl calculated:

% C, 68.08;% H, 7.81;% N, 5.30%;

H, 7.88; N, 5.28. Example 2

Diastereomeric dl-trans-9 (3-acetamido-1-acetoxy-5,6,6a1 (3,7,8,9,10,10a-octahydro-5,6'-dimethyl-3- (1 H-) -) methyl-4-phenylbutoxy) benzo [c] quinoline hydrochloride and its mixture with the corresponding -3- (N-methyl-4-phenylbutoxy) diastereomer

A mixture of 741 mg of dl-trans-9,3-acetamido-1-acetoxy-5α, 4α, 4α, 10α, 10α-octahydro-15S-methyl-3- (5-phenyl-2-pentyloxy) benzo [c] quinoline, prepared as described in Czechoslovak Patent Specification No. 228,515, 25 ml of freshly distilled tetrahydrofuran, 7.5 ml of 37% formaldehyde. 550 mg of palladium on carbon and 0.55 ml of acetic acid were hydrogenated at 50 psi for 1 hour. The catalyst is filtered off, washed with ethyl acetate, the filtrate is washed four times with 150 ml each of sodium bicarbonate solution, twice with 150 ml of water each, with 200 ml of sodium chloride solution, dried over magnesium sulfate and the solvent is evaporated off under vacuum. 800 mg of a colorless foam are obtained, containing a mixture of racemic diastereomers 9 / β-acetamido-1-acetoxy-5,6,6a / 3,7,8,9,10,10aa-octahydro-5,6,3-dimethyl-3- ( 1-methyl-4-phenylbutoxy) benzo [c] quinoline. This mixture is chromatographed on a column of 40 g of silica gel, which is initially eluted with a mixture of equal volumes of ethyl ether and toluene, collecting 15 ml fractions. After 170 fractions were collected, a mixture of equal volumes of ethyl acetate and toluene was used as eluent. A total of 350 fractions were collected.

A. Fractions 171-300 were combined and concentrated in vacuo to dryness to give 445 mg of a colorless oil which, upon addition of ethyl ether, yielded 175 mg of 3- (1S-methyl-4-phenylbutoxy) diastereomer free base m.p. 121 ° C. This free base was dissolved in 20 mL of ethyl acetate and the solution was saturated with dry hydrogen chloride. After addition of ether, 190 mg of hydrochloride with a melting point of 105 DEG-120 DEG C. are precipitated. 1 H-NMR spectroscopy is the product of the 3- (1 [(5-methyl-4-phenylbutoxy) diastereomer (racemic)).

Analysis:

for C30H40O4N2. HCl calculated:

H, 7.81; N, 5.30. Found:

H, 8.01; N, 5.26.

B. The ethereal mother liquor from the above isolation was evaporated to dryness to give 300 mg of an oily residue which was dissolved in 50 ml of ether and saturated with dry hydrogen chloride. 240 mg of hydrochloride mixture are obtained ^; Of the [3- (N-methyl- and N-3-methyl-4-phenylbutoxy)] diastereomers of the title compound, m.p. 105-120 ° C. 1 H-NMR spectroscopy is a mixture of equal parts of the above two racemic diastereomers.

Analysis:

for C30H40O4N2. HCl calculated:

% C, 68.11;% H, 7.81;% N, 5.30.

67, 50% C, 7.58% H, 5.24% N.

The structure of the two products isolated above was confirmed by mass spectroscopy.

Example 3 (+) [3 (IR), 6S, 6aR, 9R, 10aR] -9-Acetamido-1-acetoxy-5,6,6a, 7,8,9,10,10a-octahydro-5,6- dimethyl-3- (1-methyl-4-phenoxybutoxy) benzo [c] quinoline

Hydrogenation of a mixture of 0.71 g (1.48 mmol) of [3 (IR), 6S, 6aR, 9R, 10aR] -9-acetamido-1-acetoxy-5,6,6a, 7,8,9,10,10a -octahydro-6-methyl-3- (1-methyl-4-phenylbutoxy) benzo [c] quinoline prepared according to the procedure described in Czechoslovak patent specification 228 515, 0.71 g 5% palladium on carbon, 12.0 g 37 % formaldehyde and 0.7 ml of acetic acid, using the procedure described in Example 1, gave 750 mg of a crude oil which was purified by chromatography on a column of 35 g of silica gel (0.04-0.063 μπι) eluting with ethyl ether containing 2% by volume. of methanol. Fractions containing product gave 0.27 g (37%) of the desired N-methyl derivative as a colorless solid, mp 120-122 ° C. Mass Spectrum: m / e = 492 (M ^& lt ^{; +} & gt ^; ),

304, 230.

IR (KBr-technique, values in m):

3.02, 3.41, 5.71, 6.15, 8.17, 13.41, 14.36.

[α] D ²⁵ = + 154.88 ⁰ (c = 0.1, methanol).

Analysis:

Calcd for C30H40N2O4:

% C, 73.14;% H, 8.18;% N, 5.69.

H, 8.00; N, 5.58.

Claims (3)

SUBJECT VYNALEZU A process for the preparation of novel trans (6a, 10a) diastereomeric 9-amino-1-acetoxyoctahydrobenzo [c] quinoline derivatives of the general formula II in which: R 10 and R 11 are as defined above, methylated on nitrogen to give the desired 5 H -methyl derivative of the general formula II and optionally converted by acid treatment to its pharmaceutically acceptable acid addition salt. 2. The process according to claim 1, wherein the methylation on nitrogen is carried out using formaldehyde and hydrogen in the presence of a noble metal catalyst and in the presence of an inert solvent. 3. A process according to claim 2, wherein a molar excess of formaldehyde is used in the presence of palladium on carbon as the catalyst, methanol is used as the solvent, and the reaction is carried out at room temperature under a pressure of 1 to 50 bar. wherein one of R 10 and R 11 is hydrogen and the other is methyl and their pharmaceutically acceptable acid addition salts, characterized in that the trans- (6a, 10a) is a di-stereomeric compound of formula III