CS241466B2 - Method of new benzo (c) quinolines production - Google Patents

Description

The present invention relates to a process for the preparation of novel benzo [c] quinolines, in particular acylated 1-hydroxyhexahydrobenzo [c] quinolin-9 (8H) -one derivatives, used to prepare 1,9-dihydroxyoctahydrobenzo [c (quinolines) useful as centrally acting agents the nervous system, particularly as analgesics and tranquilizing agents, as hypotensive agents in mammals (including humans), as agents for treating glaucoma, and as diuretics.

An alternative nomenclature for the compounds described herein is to replace the "benzo [quinoline" base with the "phenanthridine" base. Thus, the following d, 1-trans-S.alpha.VASACUaaa-octahydro-1-acetyl-9/3-hydroxy-6,1-methyl-3- (5-phenyl-2-pentyloxy) may be used. benzo [quinoline] denote d, 1-trans-5,6,6a, 7,8,9,10,10aa-octahydro-1-acetoxy-.gamma.-hydroxy-.epsilon. -S-methyl-S-S-phenyl-2- pentyloxy is phenanthridine.

Although a wide variety of analgesic agents are commercially available, there is a continuing search for new and improved agents of this type that can be used to relieve pains of all kinds and with minimal side effects. The most commonly used substance, aspirin, is virtually worthless for the control of severe pain and is known to cause various unwanted side effects. Other more potent analgesics such as d-propoxyphene, codeine and morphine induce addiction. Is therefore. the evident need for better and stronger analgesic active agents.

The analgesic properties of 9-nor-9/3-hydroxyhexahydrocannabinol and other cannabinoid structures, such as ^{8 8} -tetrahydrocannabinol and its primary metabolite, 11-hydroxy- ^{8 8} -tetrahydrocannabinol, have been described by Wilson and May, Absts. Papers, Am. Chem. Soc., 168 Meet., MEDIA 11 (1974), J. Med. Chem. 17, 475-476 (1974) and J. Med. Chem. 18, 700-703 (1975).

U.S. Patent Nos. 3,507,885 and 3,636,058 disclose various 1-hydroxy-3-alkyl-6H-dibenzo [b, d] pyranes bearing substituents at the 9-position such as oxo, hydrocarbyl, hydroxyl, atom chloro, hydrocarbylidene and intermediates thereof.

U.S. Pat. No. 3,649,650 discloses a series of tetrahydro-6,6,9-trialkyl-6H-dibenzo [b, d] pyran derivatives carrying a ω-dialkylaminoalkoxy group at the 1-position which are effective as psychotherapeutic agents.

In DOS No. 2,451,934 they are. disclosed 1,9-dihydroxyhexahydrodibenzo [b, d] pyranes and certain 1-acyl derivatives thereof having an alkyl or alkylene group at position 141466 that are effective as hypotensive, psychotropic, sedative and analgesic agents. The starting hexahydro-9H-dibeiizo [b, d] pyran-9-ones used for the preparation of the above compounds, for which the same usability as for the corresponding 9-hydroxy compounds is reported, are described in DOS No. 2,451,932.

U.S. Pat. No. 3,856,821 discloses a series of 3-alkoxy-substituted dibenzo [b, d] pyranes exhibiting antiarthritic, anti-inflammatory, and central nervous system activity.

Bergel et al., J. Chem. Soc., 286-287 (1943) investigated the 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- They were found by various alkoxy groups (butoxy, pentyloxy, hexyloxy and octyloxy) and found that this substitution resulted in a loss of biological effect. These authors reported that the hexyloxy derivative showed a slight hashish effect at doses of 10 to 20 mg / kg. The remaining ethers were then ineffective at doses up to 20 mg / kg.

In a more recent study, Loev et al., J. Med. Chem., 16, 1,200-1,206 (1973) Comparison of 7,8,9,10-tetrahydro-3-subst.-6,6,9-trimethyl-6H-dibenzo [b, d] pyran-1-oles substituted at the 3-position with -OCH (CH 3) C 5 H 11, -CH 2 CH (CH 3) C 5 H 11, or -CH (CH 3) C 5 H 11.

A compound containing a side ether chain had a 50% lower central nervous system effect than a corresponding compound in which the alkyl side chain is attached directly to the aromatic nucleus (ie not via an oxygen atom) and five times more potent than the compound in which the oxygen atom is replaced by a methylene group. Hoops et al., J. Org. Chem., 33, -2995-2996 (1968) described the preparation of 5-azaanalog A ^{6a (10a)} -tetrahydrocannabinol, which is described as 7,8,9,10-tetrahydro-1-hydroxy-5 in this work. 6,6,9-tetramethyl-3-n-pentylphenanthridine, but do not disclose any use for this substance. In "Psychomimetic Drugs" (ed. Efron, Raven Press, New York, 1970), Beil states on page 336 that this compound is completely inert in animal pharmacology.

Hardman et al., Proc. West. Pharmacol. Soc., 14, 14-20 (1971) mentions certain pharmacological activities of 7,8,9,10-tetrahydro-1-hydroxy-6,6,9-trimethyl-3-n-pentylphenanthridine [5-aza-A] ^6a10a) -tetrahydrocannabinol.

In "Marijuana," published by Mechoulam, Academic Press, New York, 1973, Mechoulam and Edery report on page 127 that major structural changes in the tetrahydrocannabinol molecule are likely to result in a profound decrease in analgesic efficacy.

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

It has now been found that certain benzo [c] quinolines, namely, 1,9-dihydroxyoctahydro-6H-benzo [c] quinolines of the general formula 1,1-hydroxy-hexahydro-6H-benzo [c] quinolin-9 (8H) -one of formula II and the 1-hydroxytetrahydroquinolines of formula IV are useful as central nervous system agents, in particular analgesics and tranquilizers, as non-narcotic and non-narcotic hypotensive agents, and in particular as agents for the treatment of glaucoma and as diuretics. Further, various derivatives of these compounds, useful as dosage forms, and intermediates for their preparation have been prepared. The above compounds and their derivatives correspond to the general formulas I, II and IV below. Compounds of formula III and IV are precursors of compounds of formulas II and I.

241468

The compounds of the above formulas (I) to (IV), their preparation and their interconversions are described in our related Czechoslovak patents Nos. 241,459, 241,463 and 241,465.

In formulas I to IV

R represents a hydroxyl group, an alkanoyloxy group having 1 to 5 carbon atoms or a hydroxymethyl group,

R * represents a radical R or an oxo, methylene or C 2 -C 4 alkylenedioxy group and

R 1, R 1, R 5, Re, Z and W preferably have the meanings given above for R 1 ', R 1', R 5 ', R 5', Z 'and W', but may also have other meanings listed in the cited related Czechoslovak patents cited above. .

Pharmaceutical acid addition salts of the compounds of formulas I and II are also suitable for the aforementioned purposes. Representative examples of such salts include salts with mineral acids such as hydrochlorides, hydrobromides, sulfates, nitrates and phosphates, and salts with organic acids such as citrates, acetates, sulfosalicylates, tartrates, glycolates, malonates, maleates, fumarates, salts with malic acid, 2-hydroxy-3-naphthoates, pamoates, salicylates, stearates, phthalates, succinates, gluconates, mandelic acid salts, lactic acid salts, and methanesulfonates.

The compounds of the above formulas I, II and III contain centers of asymmetry in the 6a and / or 10a fields. The asymmetric centers may furthermore be located at the 3-position of the -Z-W substituent and at the 5, 6 and 9 positions. Because of their greater biological effect (quantitatively), the diastereomers of configuration 9 (3 are generally more preferred than the 9α-isomers). in general, the trans (6a, 10a) diastereomers of the compounds of formula I are more preferred than the corresponding cis (6a, 10a) diastereomers For compounds of formula II wherein one of R a and R 5 is other than hydrogen, For the compounds of formula (IV), there are centers of asymmetry in the substituents at the 9 and 3 positions. Of the enantiomers of a given compound, one of the enantiomers is usually always preferable to the other enantiomer of the other and the racemate The more preferred enantiomer is determined by the methods described herein, for example, the 1-enantiomer 5,6,6a / 3,7,8,9,10,10a-. octahydro-1-acetoxy-9 (3-hydroxy-6-methyl-3- (5-phenyl-2-pentyloxy) benzo [choline] is preferable to the d-enantiomer and the racemate because of its higher analgesic activity. For convenience and convenience, the above formulas illustrate racemic compounds, but include racemic modifications of the compounds corresponding to these formulas, mixtures of diastereomers, as well as pure enantiomers and diastereomers. The usefulness and usefulness of racemic mixtures, diastereomeric mixtures, as well as the pure enantiomers and diastereomers are determined by the biological activity tests described below.

In view of their higher biological activity compared to the other compounds described, the corresponding 1,9-dihydroxy derivatives corresponding to the general formula I are particularly preferred, in which:

R představuje is hydrogen, methyl or ethyl, each of R a and R znamená is hydrogen or alkyl;

Z and W have the following meanings:

Z W is C 5 -C 9 alkylene; H is C 2 -C 5 alkylene

-O-alk-C 6 H 8 - (alk-O- (alk) - H wherein alk, alki and alkz are C 1 -C 9 alkylene groups.

Among the preferred compounds of formula I described above, those in which R is a hydroxyl group and which have a trans-configuration are particularly preferred.

Particularly preferred are those compounds of formulas I and II wherein:.

R is a hydroxyl group (only compounds of formula Ij,

R 1 represents a hydrogen atom or an acetyl group,

R 5 represents a hydrogen atom,

R 1 represents a methyl or especially propyl group,

Re represents a hydrogen atom or a methyl group when Z represents an alkylene group of 2 to 5 carbon atoms, W represents a phenyl group, when Z represents a radical of the formula -O-alk- wherein alk represents an alkylene group of 4 to 9 carbon atoms, W represents a hydrogen atom or a phenyl group, and when Z represents an alkylene group of 5 to 9 carbon atoms, W represents a hydrogen atom.

Compounds of formulas I and II in which R e is other than hydrogen. or an alkyl group also serves as starting materials for the preparation of those compounds of formulas I and II in which R e represents a hydrogen atom or an alkyl group.

The object of the invention is to provide a process for the preparation of compounds of the formula II

in which

R 11 represents an acetyl group or a 4-N-piperidylbutyryl group,

Rd ‘represents an alkyl group having 1 to 6 carbon atoms,

R 5 represents a hydrogen atom, a benzyl group or a phenylethyl group,

R 5 represents a hydrogen atom, a methyl group, an isobutyryl group or a benzoyl group,

Z ‘is C 1 -C 9 alkyleneoxy;

W ^! represents a phenyl group or a hydrogen atom, characterized in that the compound of formula (V) is:

in which

Rd ‘, R s‘, R s ‘, Z‘ and W mají, as defined above, acylates to convert the hydrogen atom in the hydroxyl group at the 1-position to the above-defined radical R 1 ‘.

In accordance with the invention, esters of formula II ‘in which R 1‘ is acetyl or 4-N-piperidylbutyryl can be prepared from compounds of formula V by reaction with the corresponding acid in the presence of a condensing agent such as dicyclohexylcarbodiimide. In addition, these may be prepared by reaction

Compounds of formula V with an appropriate acid chloride or anhydride, for example acetyl chloride or acetic anhydride, in the presence of a base such as pyridine.

Esters of formula I in which only the 9-hydroxy group is acylated are obtained by mild hydrolysis of the corresponding 1,9-diacyl derivatives. Here, an easier hydrolysis of the phenolic acyl group is utilized. Compounds of formula I in which only 1-hydroxy is esterified are obtained from ketones of formula II esterified at the 1-position by reduction with borohydride. The thus prepared 1-acyl-9-hydroxy- or 1-hydroxy-9-acyl-substituted compounds of formula I can be further acylated with various acylating agents to give diesterified compounds of formula I in which the ester groups at positions 1 and 9 are different.

The presence of a basic group in the ester moiety (OR 1 ') of the compounds of the invention [or (OR; j in the above-mentioned compounds of formulas I-IV] allows the formation of acid addition salts containing said basic group. esters are prepared by condensation of a suitable amino acid hydrochloride (or other acid addition salt) with the appropriate compound of formula I-IV in the presence of a condensing agent, to obtain the base ester hydrochloride, by careful neutralization to prepare the free base. addition salt.

In the procedures described in our above-cited Czechoslovak patents, it is often preferred to use acylated derivatives of compounds of formulas II, III and IV, since acyl groups increase the stability of both the starting materials and products.

The pharmacological properties of the compounds of the formulas I-IV, methods for their application and their processing into the corresponding pharmaceutical compositions are described in our above-cited related Czechoslovak patents.

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

In the examples, NMR spectra are used with abbreviations as follows:

s = singlet d = doublet t = triplet q = quartet m = multiplet w = broad signal TMS = tetramethylsilane Et = ethyl.

He did

Isomeric 5,6,6a, 7,10,10a-hexahydro-1-acetoxy-6H-methyl-3- (2-heptyloxy) benzo [c] quinolin-9 (8H) -ones

24X488

Pyridine (2.2 mL) was added under a nitrogen atmosphere to a suspension of 222.6 mg (0.624 mmol of 5,6,6a, 7,10,10a-hexahydro-1-hydroxy-6/3-methyl-3- (2-heptyloxy) benzo [b]). c] quinolin-9 (8H) -one in 2.2 ml of acetic anhydride The mixture was stirred at room temperature for 1.5 hours and then poured onto 50 ml of ice and the precipitated gum product was extracted with ether (3 x 50 ml), combined the extracts were washed first with water (4 x 50 ml) and then with brine (1 x 60 ml). The extract was dried (MgSO4) and evaporated under reduced pressure to give 250 mg of a red oil.

This oil was dissolved in a minimum amount of ether and the ether solution was applied to a 45 g silica gel column. The column was washed with 200 mL of a mixture of pentane and ether (3: 1). The elution is then continued with 10 ml fractions being collected. Fractions 22-32 were combined and concentrated to give 113.5 mg of a foam which crystallized from petroleum ether as white crystals melting at 112-114 ° C.

Combination of fractions 33-50 and concentration gives 89.7 mg of a foam which crystallizes from petroleum ether also as white crystals, but melting at 78-82 ° C.

The products are isomeric monoacetyl compounds.

Example 2 d, 1-5,6,6a, 7,10,10a-hexahydro-1-hydroxy-6; S-methyl-3- (2-heptyloxy) benzo [c] quinolin-9 (8H) -one

Suspension 1.0 g (2.91 mmol) of d, l-5,6,6a, 7-tetrahydro-1-hydroxy-6,3-methyl-3- (2-heptyloxybenzo) c] quinolin-9 (8H) - In 20 ml of tetrahydrofuran was added dropwise from a separatory funnel to a rapidly stirred solution of 0.1 g of lithium in 75 ml of liquid ammonia (distilled through potassium hydroxide pellets). The separating funnel is then rinsed with 10 ml of tetrahydrofuran. The mixture was stirred for 10 minutes and then solid ammonium chloride was added to remove the blue color of the solution. The excess ammonia was evaporated and the residue was dissolved in a mixture of 100 ml of water and 50 ml of ethyl acetate. The ethyl acetate layer was separated and the aqueous phase was extracted with ethyl acetate (2 x 50 mL). The combined extracts were washed with brine, dried (MgSO 4) and concentrated under reduced pressure to give a brown semisolid product (1.35 g). Trituration of the semi-solid in 1: 1 foam-ether gave 0.884 g of a light brown solid melting at 130-138 ° C.

The above procedure was repeated using 1.84 g (5.36 mmol) of the starting benzo [c] quinolin-9-one, 0.184 g of lithium, 140 ml of liquid ammonia and 45 ml of tetnahydrofuran. The ammonia evaporation residue (2.1 g) was dissolved in benzene and the solution was applied to a chromatography column (3.8 x 61 cm) packed with silica gel (250 g). The column is eluted with benzene equal to that of the column and then with 1700 ml of 9: 1 benzene-ether system, free of dissolved gases. Continued elution with 1100 ml) gave a shimmering red eluate which was evaporated under reduced pressure to give 580 mg of a reddish solid. Trituration of this material in benzene ether (1: 1) gave 370 mg of the product melting at 154-156 ° C, which was stored under nitrogen in the dark. The isolated product is a mixture of the cis and trans forms of the title product, m / e - 345 (m ⁺ ).

Ή NMR (100MHz) <$ ™ ® _ΐ5 (PPm):

6.85 and 7.49 (1H, br, OH),

5.67, 5.71, 5.85, 5.93 (d, J = 2 Hz, total 2H, aromatic hydrogen of the cis / trans mixture),

0.90 (t, 3H, terminal CH3),

11.12 to 4.43 (m, remaining protons).

EXAMPLE 3 d, 1-cis-5,6,6a / 3,7,8,9,10,10ai / S-octahydro-1-acetoxy-9a-hydroxy-6 / J-methyl-3 - (5-Phenyl-2-pentyloxy) benzo [quinoline]

To a solution of 1.0 g (2.296 mmol) of d, 1-cis-5.6,6afi, 7.10, 10a (S) -hexahydro-1-acetoxy-6H-methyl-3- (5-phenyl-2-pentyloxy) 4-Benzo-quinolin-9 (8H) -one in 100 mL dry tetrahydrofuran was added dropwise over 5 minutes at -78 ° C with 4.6 mL (2.296 mmol) of 0.5 M potassium tri-sec-butylborohydride. The reaction mixture was stirred at -78 ° C for an additional 30 minutes and then poured into a mixture of 250 ml of 5% acetic acid and 500 ml of ether, which had been pre-cooled to 0 ° C, with stirring. The layers were separated and the aqueous phase was extracted with 250 mL of ether. The combined ether extracts were washed successively with water (2 x 250 mL), saturated sodium bicarbonate solution (1 x 250 mL), and brine (1 x 250 mL), then dried over magnesium sulfate and concentrated in vacuo to give 1 g of the title compound. , 4 g of yellow oil. The crude oil was chromatographed on 100 g of silica gel using benzene ether (3: 1) as eluent. After washing the low-polar impurities, the title compound is isolated as a clear oil (700 mg). This oil was dissolved in ether (35 mL) and treated with HCl saturated ether to give 448 mg of the title compound hydrochloride, mp 115-124 ° C (recrystallized from ether-chloroform), m / e = 437 (m ⁺ ).

IR (KBr):

5.58 μ (ester carbonyl).

.tl

Analysis: for C 27 H 35 O 4 N. HCl calculated:

% C, 68.41;% H, 7.66;% N, 2.96.

% C, 68.52;% H, 7.91;% N, 2.73.

Example 4 d, 1-5,6,6a, 7,10,10a-hexahydro-1-acetoxy-6- (3-methyl-3- (2-heptyloxy) benzo [c] quinolin-9 (8H) -one

The procedure described in Example 2 was repeated, but using twice the amount of the reactants. The product (2.22 g) is then acetylated as described in Example 3 to give 2.35 g of the acetylated product. This product was triturated in pentane-ether (3: 1) to give 905 mg of a tan solid. Recrystallization from ethanol gave 404 mg of slightly yellow-brown crystals, melting at 112-113.5 ^and C.

The mother liquors from which the above solids were separated were combined and concentrated. The residue was dissolved in a minimum amount of benzene-ether-methylene chloride (1: 1: 1) and applied to 275 g of silica gel. The column is eluted first with 2 liters of petroleum ether-ether (3: 1), then with 1.5 liters of petroleum ether (2: 1) and then with 2 liters of petroleum ether (1: 1), collecting fractions of 50 ml. Fractions 2-11 eluted with a 1: 1 solvent system were combined and concentrated under reduced pressure to give 496 mg of a foam. Crystallization from petroleum ether gave white crystals (410 mg) melting at 100 ^DEG- 113 ^DEG C. Recrystallization from ethanol-water (1: 1j) gave d, 1-trans-5,6,6a / 3,7,10, 10aa-hexahydro-1-acetoxy-6/3-methyl-3- (2-heptyloxy) benzophenylquinolin-9 (8H) -one, melting at 111-112 ° C.

m / e = 387 (m ^&lt; ^{+ &gt;} ).

For C23H33O1N calculated:

71.29% C, 8.58% H, 3.61 θ / ο N, found:

% C, 70.95;% H, 8.64;

The collected fractions 12-18 and 19-27 (50 ml each) were concentrated to give 273 mg and 208 mg of the acetylated product, respectively. Crystallization of the residue from fractions 19-27 from petroleum ether gave 119 mg of a white crystalline solid, melting at 84-88 ° C. Recrystallization from ethyl acetate-hexane (1:

10) yielding d, 1-cis-5,6,6a (3,7,10,10a) 3-hexahydro-1-acetoxy-3- (2-heptyloxy) -6,3-methylbenzo [c) quinoline -9 (8H) -one melting at 84-86 ° C.

For C23H33O4N calculated:

71.29 θ / o C, 8.58 θ / ο H, 3.61% N, found:

H, 9.48; N, 3.56.

In a similar manner, the following compounds were prepared from the appropriate reactants:

d, 1-trans-5,6,6a, a, 7,10,10aa-hexahydro-1-acetoxy-6/3-methyl-3- (5-phenyl-2-pentyloxy) benzo [c] quinolin-9 (8H j-one, m.p. 80-82 ° C).

m / e = 435 (m &lt; + &gt;).

For C27H33O.IN calculated:

% C, 74.45;% H, 7.64;% N, 3.22.

74.43% C, 7.73% I-I, 3.28% N.

d, 1-cis-5,6,63 (3,7,10,10a) 3-hexahydro-1-acetoxy-6/3-methyl-3- (5-phenyl-2-pentyloxy) benzo (c) quinoline -9 (8H) -one, m.p. 172-176 ° C [hydrochloride after crystallization from acetone-ether (1: 1)]. Analysis: for C 27 H 33 O 4 N. HCl calculated:

68.71 θ / ο C, 7.26% H, 2.97% N, found:

H, 7.16; N, 2.97.

d, 1-trans-5,6,6a / 3,7,10,10aa-hexahydro-1-acetoxy-3- (5-phenyl-2-pentyloxy) -O- (5-propylbenzophenyl) quinolin-9 (8H) mp 79-80 ° C.

m / e = 483 (m &lt; ⁴ &gt;).

d, 1-cis-5,6,6a (3,7,1,10,10a) 3-hexahydro-1-acetoxy-3- (5-phenyl-2-pentyloxy) -6 / 3-propylbenzo [c] quinoline -9 (8H) -one hydrochloride, m.p. 144-146 ° C. m / e = 483 (m ^&lt; ^{+ &gt;} ).

d, lcis-5,6,6a, 7,10,10a / 3-hexahydro-1-acetoxy-3- (5-phenyl-2-pentyloxy) -6,3-methylbenzo [c] quinolin-9 (8H) 1 -one as the hydrochloride melting at 90-94 ° C with decomposition.

[α] _D ²⁵ = + 22.8 ° (c - 0.31; CH 3 OH). m / e = 435 (m ^&lt; ^{+ &gt;} ).

Analysis: for C 27 H 33 O 4 N. HCl calculated:

<58.71% C, 7.26% H, 2.97% N, found:

% C, 69.24;% H, 7.30;

d-trans-S, S, S, S, S, S, H-hexahydrol-acetoxy-3- (5-phenyl-2-pentyloxy) -6- (3-methyl-benzo [c] quinolin-9 (8H) -one, as the hydrochloride, m.p. decomposition at 90 DEG-95 DEG C. [ _.alpha .] _D @ ²⁵ = + 78.46 DEG (c = 0.13; CH3 OH) m / e = 435 (m + j).

Analysis: for C 27 H 33 O.JN. HCl calculated:

68.71 0/0 C, 7.26% H, 2.97 «/ o N, found ¹ :

H, 7.23; N, 3.07.

1-cis-5,6,6a (3,7,10,10a-3-hexahydro-1-acetoxy-3- (5-phenyl-2-pentyloxy) -6,6S-methylbenzo [c] quinolin-9 (8H-1-one) as hydrochloride, m.p. 90-92 ^° C.

( _.alpha. ) _D @ ²⁵ = -20.5 ^{DEG C.} (c = 0.19; CH3 OH) m / e = 435 (m + j).

Analysis: for C 27 H 33 O 4 N. HCl calculated:

68.71% C, 7.26% H, 2.97% N, found:

H, 7.23; N, 3.09.

1-trans-5,6,6a, 3,7,10,10a0-hexahydro-1-acetoxy-3- (5-phenyl-2-pentyloxy) -6,3-methylbenzophenyl] quinolin-9 (8H) - he as the hydrochloride, m.p. 92-96 ° C.

[α] _D ²⁵ ₌ -79 ° ( _C = 0.10; CH 3 OH). m / e = 435 (m &lt; + &gt;).

Analysis: for C 27 H 33 O 1 N. HG1 calculated:

68.71 0 / oC, 7.26% H, 2.97% N, found ·:

H, 7.23; N, 3.02.

Example 5

Trans- and cis-isomers of dl-5,6,6a, 7,10,10a-hexahydro-acetoxy-ol DJS-methyl-3- (5-phenyl-2-pentyloxy j benzo ^[c] quinoline 9 (8H) -one

To a three-liter, three-necked, flame-dried flask equipped with a mechanical stirrer and 500 ml separatory funnel, cooled to about -75 ° C with solid carbon dioxide-acetone, is directly condensed with 1,150 ml of ammonia under nitrogen. 2 grams of lithium wire in 0.62 millimeter pieces to give a characteristic blue color. To this blue solution was added dropwise 21.5 g (0.055 mol) of d, 1-5,6,6a, 7-tetrahydro-1-hydroxy-6, d-methyl- 3- (5-phenyl-2-pentyloxy) benzo [c] quinolin-9 (8H) -one dissolved in 250 mL of tetrahydrofuran. After addition of the tetrahydrofuran solution was complete, the reaction mixture was stirred for an additional 5 minutes at -78 ° C. The reaction process was terminated by the addition of 20 g of solid dry ammonium chloride. Cooling is discontinued and the reaction mixture is slowly heated on a steam bath to evaporate the ammonia. When the reaction mixture is evaporated to near dryness, 2 liters of ethyl acetate and 1 liter of water are added, and the mixture is stirred for 10 minutes. The layers were separated and the aqueous phase was extracted once more with 500 mL of ethyl acetate. The combined organic extracts were washed once with 1 liter of water, dried over magnesium sulfate and concentrated to give 28 g of a brown semi-solid. This material was immediately dissolved in 200 mL of methylene chloride, 7.5 g (0.061 mol) of triethylamine was added, and the solution was cooled to 0 ° C (ice-water cooling bath) under stirring under nitrogen. Acetic anhydride (6.1 g, 0.061 mol) was added dropwise with vigorous stirring, and after stirring for 30 minutes at 0 ° C, the reaction mixture was diluted with 2 L of ethyl acetate and 1 L of water and stirred for 10 minutes. The organic extracts were washed with water (4 x 1 liter), saturated sodium bicarbonate solution (1 x 1 liter), brine (1 x 1 liter), dried over magnesium sulfate and concentrated to a light brown oil (ca. 27 g). 1.8 kg of silica gel, eluting with 15% benzene in ethyl acetate.

After washing off the less polar impurities, fractions 16-20 are combined and evaporated, and the residue is crystallized from a mixture of ether and petroleum ether. Thus, 5.6 g (23.4%) of the trans-isomer of the title product are obtained. Combination of fractions 21 to 27 yielded 7.6 g (31.8%) of the trans-cis isomer mixture, and fractions 28 to 32 yielded 2.5 g (10.4%) of the cis-isomer.

The trans-isomer has the following characteristics:

m / e = 435 (m &lt; + &gt;).

@ ¹ H NMR (60 MHz) .delta.

7.24 (s, 5H, aromatic protons),

5.97 (s, 2H, meta-hydrogens),

2.28 (s, 3H, CH2-COO),

1.23 (d, 3H, CH 3 - CH - O -),

1.20 (d, 3H, GH5-CH-N),

1.3 to 4.5 (m, 17H, remaining protons).

Mp 81-83 ° C.

Calcd for C27H33O4N:

74.45% C, 7.64% H, 3.22 O / o N, πα1ρ7ΡΠΠ *

H, 7.68; N, 3.18.

The cis-isomer has the following characteristics: m / e = 435 (m ⁺ ).

The hydrochloride melts after crystallization from a mixture of acetone and ether with decomposition at 172-176 ^° C.

Analysis: for C 27 H 33 O 4 N. HCl calculated:

% C, 68.71;% H, 7.26;% N = 2.97.

H, 7.18; H, 2.97;

Example 6

Trans- and cis-isomers of d, l-5,6,6a, 7,10,10a-hexahydro-1-acetoxy-6 (S-methyl-3- (4-phenylbutyloxy) benzo [c] quinolin-9 ( 8H j -one

The preparation method described in Example 4 was repeated. D, 1-5,6,6a, 7-tetrahydro-1-hydroxy-6,3-methyl-3- (4-phenylbutyloxy) benzo [c] quinolin-9 (8H) - it is first reduced with lithium in liquid ammonia and then acylated to give the desired hexahydroisomers.TLC on silica gel using ether as the eluent first separates d, 1-trans-5,6,6a (3,1,10,10aa). hexahydro-1-acetoxy-6/1-methyl-3- (4-phenylbutoxy) benzo [c] quinolin-9 (8H) -one, having a recrystallization from ethyl acetate-pentane (1: 5), m.p. 156 DEG C. Analysis for C23 H31 O1 N calculated:

74.08% C, 7.41% H, 3.32% N, found:

H, 7.47; N, 3.22. M / e = 421 (m + j).

If cyclohexane-ether (1: 1) is used as the eluent, the isomeric d, 1-cis-5,6,63 (3,7,10,10a / J-hexahydro-1-) isomeric is obtained by chromatographic purification of these fractions. acetoxy-6/3-methyl-3- (4-phenylbutyloxy) -1'-benzoyl] quinolin-9 (8M) -one, melting point 95-96 ° C after recrystallization from ethyl acetate-hexane (1: 5) m / e = 421 (m + e).

For C2GH31O4N, calculated:

74.08% C, 7.41% H, 3.32% N,

n.qlpypn.n ·

% C, 73.95;% H, 7.51;

Example 1 a d 7

d.l-trans-5,6,6a (3,7,8,9,10,10aa-octahydro-1-acetoxyl-9-hydroxy-5-methyl-3- (5-phenyl-2-psytyloxy) benzo [c] quinoline

To a solution of d, 1 trans-5,6,6,6,7,7,10,1Daa-hexahydro-1-acetoxy-3- (5-phenyl-2-pentyloxy) benzoquinoline in 15 ml of acetonitrile is gradually added first at room temperature, 1 ml of 37% aqueous formaldehyde and then 0.262 g of sodium borohydride. The reaction mixture was stirred for 1 hour, during which time the pH was kept neutral if necessary by addition of acetic acid. An additional 0.262 g of sodium cyanoborohydride and 15 ml of methanol was added to the reaction solution, the mixture was acidified to pH 3 and stirred for 2 hours. Concentration under reduced pressure yielded an oil which was dissolved in 50 ml of water, adjusted to pH 9-10 with aqueous sodium hydroxide solution, and extracted with ether (8 x 200 ml). The combined ethereal solutions were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The clear oily residue was dissolved in ether-hexane (1: 1) and applied to a silica gel column. The column was eluted first with 50% ether in hexane and then sequentially with 60%, 70% and 75% ether in hexane. The eluate was monitored by thin layer chromatography (ether-hexane, 10: 1). First, 0.125 gd, 1-trans-5,6,6a, 7,10,10a-hexahydro-1-acetoxy-5-methyl-3- (5-phenyl-2-pentyloxy) benzo [c] quinoline- 9 (8H) -one. m / e = 435 (m ^&lt; ^{+ &gt;} ).

For C27H33O N calculated:

% C, 74.45;% H, 7.64;% N, 3.22.

% C, 74.06;% H, 7.77;% N, 3.31.

The second product is the 9α-hydroxy diastereomer of the title compound (25 mg), m / e - 437 (m +).

241463

For C27H35O1N calculated:

H, 8.06; N, 3.20.

TI. 31.6 Z θ 3 · O *

73.96% C, 8.34% H, 3.00% N.

The third product is the 9β-hydroxydiastereomer of the title compound (0.7 g). m / e = 437 (m ^&lt; ^{+ &gt;} ).

Calcd for C27H35O4N:

H, 8.06; N, 3.20.

73.56% C, 7.86% H, 3.21% N.

Similarly, d, 1-trans-5,6,6a / 3,7,10,10a * α-hexahydro-1-acetoxy-6- (3-methyl-3- (5-phenyl-2-pentyloxy) benzoic acid) may be used. ] quinolin-9 (8H) -one convert to:

d, 1-trans-5,6,6a / 3,7,10,10a-hexahydro-1-acetoxy-5-methyl-6-methyl-3- (5-phenyl-2-pentyloxy) benzo [c] quinolin-9 (8H) -one and 1,1-trans-5,6,6a / 3,7,8,9,10,10aa-octahydro-1-acetoxy-9/3-hydroxy-5-methyl 6-methyl-3- (5-phenyl-2-pentyloxy) benzo [c] quinoline, which is isolated in the form of the hydrochloride, m.p. 163-165 ° C.

m / e = 451 (m ^&lt; ^{+ &gt;} ).

Example d, 1-trans-5,6,6a / S, 7,8,9,10,10aa-octahydro-1,9-diacetoxy-6,3-methyl-3- (2-heptyloxy) benzo [quinoline]

1.2 g of unchromatographed product of d, 1-trans-5,6,6a0,7,10, 10aa-hexahydrol-acetoxy-6,3-methyl-3- (2-heptyloxy) benzo [c] quinolin-9 (8HJ) The mixture of Example 7 was stirred overnight at room temperature with excess acetic anhydride and pyridine, then poured into ice-water and extracted with ether (3 x 100 mL) .The combined ether extracts were washed with water and brine. The residue is chromatographed on a column of 40 g of silica gel, eluting with benzene ether (9: 1), to give 680 mg of the desired d, L-trans-5,6,6aS, m.p. 7,8,9,10,10aa-octahydro-1,9-diacetoxy-6/3-methyl-3- (2-heptyloxy) benzoquinoline, which crystallizes upon addition of hexane and ethyl acetate, melting at 86-87 ° C.

m / e = 431 (m ^&lt; ^{+ &gt;} ).

IC (KBr):

5.73 μ (ester carbonyl).

1 H NMR (60 MHz) <5 (PPm):

5.88 (bs, Hz, Hd-2H),

2.28 and 2.05 [two seconds after 3H, CH3-C (= O)], about 0.8 to 5.0 (m, remaining protons).

Calcd for C28H31NiO:

69.57% C, 8.64% Η, 3.25% N, found:

% C, 69.51;% H, 8.54;

In an analogous manner, from 60 mg of d, 1-trans-5,6,6a / 3,7,8,9,10,10aa-octahydro-1-acetoxy-9 / S-hydroxy-6 / S-methyl-3- (4-phenylbutyloxy) benzo (c) quinoline in 1 ml pyridine and 1 ml acetic anhydride prepared by stirring for one hour at room temperature the desired d, 1-trans-5,6,6a / 3,7,8,9,10,10aa-octahydro 1'-d-diacetoxy-η 5 -methyl-5- (4-phenylbutyloxy) benzofc] quinoline, which melts at 146-147 ° C after recrystallization from ethyl acetate-hexane (1: 1).

m / e = 465 (m ^&lt; ^{+ &gt;} ).

Calcd for C28H35OSN:

% C, 72.23;% H, 7.58;% N, 3.01.

% C, 72.17;% H, 7.61;% N, 3.08.

Claims (1)

SUBSTITUTE Process for the preparation of the novel benzo [c] quinolines of the general formula O OF THE INVENTION in which R 1 represents an acetyl group or a 4-N-piperidylbutyryl group, R1 * represents an alkyl group having 1 to 6 carbon atoms, R 5 represents a hydrogen atom, a benzyl group or a phenylethyl group, R 5 represents a hydrogen atom, a methyl group, an isobutyryl group or a benzoyl group, Z ‘is C 1 -C 9 alkyleneoxy; W ‘represents a phenyl group or a hydrogen atom, characterized in that the compound of the general formula V. in which R a ‘, R s‘, R ‘, Z and W‘ are as defined above, acylating to convert the hydrogen atom in the hydroxyl group at the 1-position to the above-defined radical R 1 ‘.