CS241459B2 - Method of new benzo (c) quinolines production - Google Patents

Description

The invention relates to a process for the preparation of novel benzo [c] quinolines, in particular 1,9-dlhydroxyoctahydrobenzo [c] quinolines and 1-hydroxyhexahydrobenzo [c] quinolin-9 (8H) -ones, which are useful as central nervous system agents, in particular then as analgesics and tranquilizing agents, as hyperpentants in mammals (including humans), as agents for treating glaucoma and its diuretics.

The above products are compounds of formula (A)

Re (A) in which Q represents a group \

C = O

Z or

H OH

R 1 represents a hydrogen atom, an acetyl group or a piperidinobutyryl group,

R 1 represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or the radical - (CH 2) _z - C 6 H 5, wherein z is an integer of 1 to 4,

R 5 represents a hydrogen atom, a methyl group or an ethyl group,

R 6 is hydrogen, C 1 -C 2 alkyl, benzoyl, acetyl or; an isobutyryl group,

Z represents an alkylene group having 1 to 9 carbon atoms or the radical - (alki) _m -O- (alkzine), where alk2 and alki are the same or different and each represents an alkyl group of up to 9 carbon atoms and each independently has a value of 0 or 1, and

W represents a hydrogen atom or a phenyl group, and pharmaceutically acceptable salts thereof.

These compounds as well as the starting materials for their preparation and the respective intermediates can also be illustrated by the formulas I, II, III, V, VI and VII below.

An alternative nomenclature for the compounds described herein is to replace the base "benzo [c] quinoline" with the base "phenanthridine". Thus, d, 1-trans-5,6,6a (S, 7,8,9,10,10aa-octahydro-1-acetoxy-9β-hydroxy-6,3-methyl-3- (5- Phenyl-2-pentyloxy) benzo [quinoline labeled as d, 1-trans-5,6,6a (3,7,8,9,10,10aa-octahydro-1-acetoxy-9) -hydroxy-6] 2-Methyl-3- (5-phenyl-2-pentyloxy) -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 alleviate 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, are addictive. Thus, there is a clear need for better and more potent analgesically active agents.

The analgesic properties of 9-nor-9H-hydroxyhexahydrocannabinol and other cannabinoid structures such as ^{8 8} -tetrahydrocannabinol and its primary metabolite, 11-hydroxy-A ⁸ -tetrahydrocannabinol, have been described by Wilson and May, Absts. Papers, Am. Chem. Soc., 168, Meet, Medi 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 chlorine, hydrocarbyliden, and intermediates thereof.

U.S. Patent 3,649,650 discloses a series of tetrahydro-6,6,9-trialkyl-6H-dibenzo [b, d] pyran derivatives bearing an ω-dialkylaminoalkoxy group at the 1-position, which are effective as psychotherapeutic agents.

No. 2,451,934 discloses 1,9-dlhydroxyhexahydrodibenzo [b, d] pyranes and certain 1-acyl derivatives thereof having an alkyl or alkylene group at the 3-position, which are effective as hypotensive, psychotropic, sedative and analgesic agents. The starting hexahydro-9H-dibenzo [b, d] pyran-9-ones used for the preparation of the above compounds for which the same applicability is reported as for the corresponding 9-hydroxy compounds are disclosed in DOS No. 2 451932 (07/05 75). ).

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.

Bergei et al., J. Chem. Soc., 286-287 (1943) investigated the substitution of the 3-position pentyl group 7,8,9,10-tetrahydro-3-pentyl-6,6,9-trimethyl-6H-dibenzo [b, d] pyran-1-ol various alkoxy groups (butoxy, pentyloxy, hexyloxy and octyloxy) and found that this substitution results in a loss of biological effect. These authors reported that the hexyloxy derivative exhibited 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, Loes et al., J. Med. Chem., 16, 1200-1206 (1973), comparison of 7,8,9,10-tetrahydro-3-substituted-6,6,9-trimethyl-6H-dibenzo [b, d] pyran-1-ol substituted in position 3 -OCH (CH3) C5Hh, —CH2CH (CH3) C5Hh, or —CH (CH3) C5Hu.

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, 2 995-2 996 (1968) described the preparation of 5-azaanalog A ^{6a (10a)} -tetrahydrocannabinol, which is described in this work as 7,8,9,10-tetrahydro-1-hydroxy-5,6 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.

Hárdman et al. Why. 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 ^{6a] (10a,} -tetrahydrocannabinoluj.

In the book "Marijuana". (ed. Mechoulam, Academic Press, New York, 1973) reported by Mechoulam and Edery on page 127 that major structural changes in the tetrahydrocannabinol molecule are likely to result in a deep 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 replacement of nitrogen in the pyran ring with oxygen results in a loss of activity.

It has now been found that certain benzole ejoquinolines, namely, 1,9-dlhydroxyoctahydro-6H-benzo [c] quinolines of the general formula I below and 1-hydroxyhexahydro-6-benzo [c] quinolin-9 (8H) -ones below Formula II are useful as central nervous system agents, in particular as analgesics and tranquilizers, as hypotensive, non-narcotic and non-addictive, and in particular as agents for the treatment of glaucoma and as diuretics. The invention also provides various derivatives of these compounds useful as dosage forms and intermediates for their preparation. The above compounds and their derivatives correspond to the general formulas I and II below. Compounds of formula III are precursors of compounds of formulas II and I.

In these general formulas

R represents a hydroxyl group, a (C 1 -C 5) alkanoyloxy group or a hydroxymethyl group,

R 1 represents a hydrogen atom, an acetyl or piperidinobutyryl group,

R4 represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or a radical of formula

- (CH ₂ ) _Z —C ₆ H _s , where z is an integer ranging from 1 to 4,

R 5 represents a hydrogen atom, a methyl or ethyl group,

Re represents a hydrogen atom, an alkanoyl group having 2 or 4 carbon atoms, an alkyl group having 1 or 2 carbon atoms or a benzoyl group,

Z represents an alkylene group having 1-9 carbon atoms or a radical of formula - (Alk _m -O- (alk _{2} 3} - where alk and alkanolamines are independently each an alkylene group having 1-9 carbon atoms with the proviso that the sum of carbon atoms in alki and alka residues not greater than 9, and m and n are each independently 0 or 1, and

W represents a hydrogen atom or a phenyl group.

It is an object of the present invention to provide a process for preparing compounds of formula (A) by reducing compounds of formula (III).

The invention also encompasses a process for preparing pharmaceutically acceptable acid addition salts of compounds of formulas I and II. 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 at positions 6a and / or 10a. 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 9/3 diastereomers are generally more preferred than the 9'-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. With respect to the compounds of formula (II) in which one of R 1 and R 5 is other than hydrogen, the corresponding cis-diastereomers are preferred because of their higher biological activity. Of the enantiomers of a given compound, due to its higher potency, one of the enantiomers is usually always more preferred than the other enantiomer and than the racemate. The more preferred enantiomer is determined by the procedures described below. For example, the 1-enantiomer of 5,6,6,7,7,7,9,9,10,10aa-octahydro-1-acetoxy-9/3-hydroxy-6/3-methyl-3- (5-phenyl-2- For convenience and convenience, the above formulas illustrate racemic compounds, but also include racemic modifications of the compounds corresponding to these formulas, mixtures of diastereomers as well as mixtures of diastereomers as well as racemic modifications. clean

241439 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.

The various intermediates and starting materials for the preparation of compounds of formulas I, II and III may be described by formulas V, VI and VII

AND

Re

in which

R 1, R 5, Re and Z-W are as defined above,

R 7 represents a hydrogen atom or a formyl group and

Y 1 represents a hydrogen atom or a hydroxyl protecting group, in particular a methyl, ethyl or benzyl group.

In the starting materials of formulas V, VI and VII, asymmetric centers may exist in position 2 and in the substituent in position 7 (—Z — W), and, of course, in other positions, for example in the sustituent in position 1. of formulas V, VI and VII correspond to positions 6 and 6, respectively. 3 compounds of formulas I, II and III.

In view of their higher biological activity compared to the other compounds described, those of the formulas I and II in which R is as defined above are preferred,

R 1 represents a hydrogen atom, an acetyl or piperidinobutyryl group,

R 5 represents a hydrogen atom, a methyl or ethyl group, each of R a and R 5 representing a hydrogen atom or an alkyl group as defined above,

Z and W have the following meanings:

(C až-C) alkylene (C alky-C alky) alkylene - (alk ₁ ) _m -O- (alkyl ₂ ) _{m m} W - - H - - C 6 H 5 - (alkmine-O- (alk ₂ ) _n

I 0 f

II H 0 1 H 1 0 H

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

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

R is a hydroxyl group (compounds of formula I only),

R 1 represents a hydrogen atom or an acetyl group,

R 5 represents a hydrogen atom,

R4 represents a methyl or, in particular, propyl group,

R 6 represents a hydrogen atom, a methyl or ethyl group when Z represents an alkylene group having 2 to 5 carbon atoms, W represents a phenyl or 4-pyridyl group when Z represents a radical of the formula - (alkj-O-) (alk) ₂ ): - where m is 0 and _n is 1, and (alk ₂ ) is a C 4 -C 9 alkylene group, W is a hydrogen atom or a phenyl group, and when Z is a 5 to 9 alkylene group carbon atoms, W represents a hydrogen atom.

Preference is further given to those compounds of the formulas III, V, VI and VII which serve as starting materials and intermediates for the preparation of the preferred compounds of the formulas I or II.

Compounds of formulas I and II in which R 6 is other than hydrogen or alkyl also serve as starting materials for the preparation of those compounds of formulas I and II in which R 6 is hydrogen or alkyl.

Compounds of formula V are prepared from appropriately substituted anilines, for example, the 3-hydroxy-5- (Z-W-substituted) anilines of formula VIII below, or derivatives thereof, wherein the hydroxyl group at the 3-position is protected with Y1 which it is readily cleaved to regenerate the hydroxyl group. Suitable protecting groups are those which do not adversely affect the subsequent reactions of said 5-substituted anilines bearing a protected hydroxyl group at the 3-position and which can be cleaved under conditions not causing undesired reactions at other sites of the above compounds or products made therefrom. Representative protecting groups for Y 1 include methyl, ethyl, and benzyl, substituted benzyl, with, for example, C 1 -C 4 alkyl, halogen (chloro, bromo, fluoro, iodo), and C 1 -C 4 alkoxy. up to 4 carbon atoms.

The precise chemical structure of the protecting group does not play a decisive role in the present case since its importance lies in its ability to perform the above functions.

Selection and identification of appropriate protecting groups will not cause problems for those skilled in the art. The suitability and efficacy of a given hydroxyl protecting group is determined by the utility of such a group in the reaction sequence described above. Thus, it is intended to be such a group that can be easily cleaved to regenerate the hydroxyl group. A preferred alkyl protecting group is a methyl group, as it is readily cleavable by treatment with pyridine hydrochloride. The benzyl group, which is also a preferred protecting group, is removed by catalytic hydrogenolysis or acid hydrolysis.

When Z is a radical of the formula - (alki _m -O- (alk ₂ i _{; i)} - Yi is preferably a benzyl or substituted benzyl group, since such a group can then be removed without damaging the Z radical.

The protected aniline derivative (VIII j) is then converted to the compound of formula (IX) below in a known manner as described below.

The following is a reaction scheme illustrating the preparation of representative compounds of formula V from 3-hydroxy-5- (Z-W-substituted) anilines protected with a hydroxyl group at the 3-position (VIII) in which Z-W is methoxy.

Scheme A

In the above reaction scheme, R 0 is C 1 -C 6 alkyl and PPA is polyphosphoric acid. In the reaction scheme, in the individual formulas, instead of R 5, there is a hydrogen atom, but in reactions VIII - X or VIII -> V - B, R 5 can be methyl or ethyl in addition to the hydrogen atom.

The substituent at the 5-position of the compounds of formula (VIII) may be a moiety -Z-W to be included in the resulting compounds of formula (II) or (I) or a residue which can be readily converted to that moiety. When Z in the group -Z-W is a radical of formula - (Alk -O- (alk ₂₎ ,, - wherein each of m and n is 0, wherein the substituent in position 5 in the case where W represents a hydrogen atom, -OH or a protected -OH radical corresponding to the formula -O-Y, wherein Y is as defined above. In case the group -Z-W is a radical of formula - (alk -O- (alk _{2) n} -W, wherein m is 1 n has the value 0 and W represents a hydrogen atom, then the substituent at the 5-position is, of course, the radical of the formula - (alki) _m -OH.

The —OH group is preferably protected as described above.

In accordance with the above scheme, the respective 3-hydroxy-5-substituted anilines discussed above are reacted, preferably in the form of derivatives in which the hydroxyl group at the 3-position (and the hydroxyl group at the 5-position, if present) is protected. as described above, to allow a satisfactory reaction to proceed, with the (3-ketoalkylester), for example with the alkali (II) acetoacetate, in the presence of acetic acid, to give the corresponding β- (3-hydroxy-5-substitutedanilino) -, β- The (R) -hydroxy-protected (R) -acrylate at position 3 (IX) The reaction is generally carried out in an inert solvent such as benzene or toluene at a temperature of about 50 ° C to the reflux temperature of the solvent. Conditions allowing removal of by-product water. When the reaction is carried out under reflux, benzene and toluene are suitable solvents because they allow

241439 azeotropic removal of water resulting from the reaction. Other means, such as molecular sieves, as well as other solvents allowing azeotropic removal of water may also be used to remove the reaction water.

Preferred protecting groups for the starting 3-hydroxy-5-substituted anilines are methyl, ethyl and benzyl, since such ethers are readily prepared, provide satisfactory yields of compounds of formulas IX and X, and can be cleaved appropriately to remove the ether protecting group.

(3-keto-alkyl-alkyl ester, preferably one in which the alkyl group contains 1 to 6 carbon atoms) is generally used in excess to ensure maximum conversion of the starting aniline to the corresponding alkyl (3-anilino- [3- (R 4) -acrylate ( IX) To achieve satisfactory conversions, it is usually sufficient to use a 10% to 20% excess of .alpha.-ketoester of alkyl.

The alkyl β-anilino- [3- (R 4) -acrylate (IX) is then reduced to the corresponding hydroxy-protected 3- (3-hydroxy-5-substituted-anilino) -3- (R 1) -propionate in the position 3 (X) using, for example, sodium borohydride-acetic acid and catalytic hydrogenation. A preferred catalyst is platinum (IV) oxide, which allows the reaction to be carried out at low pressures, i.e. pressures below 0.35 MPa. Other catalysts, such as noble metals, such as platinum, palladium or rhodium, whether or not supported, can be used at a hydrogen pressure ranging from about atmospheric pressure to superatmospheric pressure, for example 14 MPa. In addition to these catalysts, which are heterogeneous catalysts, this reaction can also be carried out using homogeneous catalysts such as Wilkinson's catalyst [tris (triphenylphosphine) chloride].

If the protecting group (or protecting groups) is a benzyl or substituted benzyl group, the catalytic hydrogenation will, of course, be removed. For this reason, methyl and ethyl groups are preferred protecting groups for hydroxyl functions at the 3 and / or 5 positions of the starting materials of the general formula (VIII).

Alternatively, compounds of formula X may be prepared directly from compounds of formula VIII by reacting compounds of formula VIII with alkyl-3,3-R4R5-acrylate in acetic acid. The reaction is conveniently carried out by reacting an equimolar amount of alkyl 3,3-R4R5-acrylate and disubstituted aniline (VIII) in 0.1 to 2 equivalents of glacial acetic acid at a temperature of from 0 ° C to reflux.

Alternatively, compounds of formula V-B may be prepared directly by condensation of equimolar amounts of compound of formula

VIII and appropriately substituted acrylic acids (R 4 R 5 C = CH-COOH) in pyridine hydrochloride at a temperature of 150 to 200 ° C.

In addition, when R4 and R5 are both alkyl, the reaction of a compound of formula VIII and an alkyl-R4, R5-acrylate in an inert solvent such as tetrahydrofuran with mercuric acetate followed by reduction with sodium borohydride results in a compound of formula X.

The direct conversion of compounds of formula VIII to compounds of formula X is also conveniently effected by reacting 3,5-dihydroxyaniline hydrochloride in which both hydroxyl groups are in protected form with an excess of alkyl acetate, for example ethyl acetate, in the presence of sodium cyanoborohydride in a solvent such as methanol. .

The alkyl 3-anilino-3- (R 4) -propionate (X) is then cyclized to the corresponding 2- (R 4) -quinolin-4-one (V-A or V-B) by treatment with a suitable cyclizing agent such as polyphosphoric acid , hydrogen bromide-acetic acid, sulfuric acid, oleum (fuming sulfuric acid), hydrogen fluoride, trifluoroacetic acid, phosphoric acid-formic acid, and other agents known in the art. In accordance with a modification of this conversion, the alkyl 3-anilino-3- (R 4) -propionate (X) can be converted to the corresponding acid, for example, by saponifying the ester before acidifying and then acidifying.

The ether protecting groups on the hydroxyl groups at the 3 (and 5) position can be removed during cyclization by using hydrobromic acid in acetic acid as the cyclizing agent and simultaneously leaving the protecting group (or groups). Usually 48% aqueous hydrobromic acid is used, which satisfactorily acts as both a cyclizing agent and an ether protecting group cleavage agent. The reaction is carried out at elevated temperature, preferably at reflux. However, when Z is a radical of the formula - (alki) _m --O - (alk ₂ ) _Ω - cyclization must be carried out under other conditions, such as using polyphosphoric acid or trifluoroacetic acid, to prevent the ether or thioether bond from being broken.

Alternatively, the protecting group (s) may be removed after the cyclization reaction. Hydrobromic acid in acetic acid is also a preferred deprotecting agent (s) at this stage of the synthesis. Said reaction is carried out as described above.

Other reagents such as hydroiodic acid, pyridine hydrochloride or hydrobromide can also be used to remove the ether protecting groups (such as methyl and ethyl groups). If the protecting groups are benzyl or substituted benzyl groups, they can be cleaved by catalytic hydrogenolysis. Suitable catalysts in this case are palladium or platinum, in particular supported on coal. Alternatively, these protecting groups may be cleaved by solvolysis using trifluoroacetic acid.

A preferred method of converting compounds of formula X to compounds of formula V, which provides satisfactory yields and allows relatively mild conditions to be used, is to convert compounds of formula X to N-alkoxycarbonyl derivatives wherein the N-alkoxycarbonyl group contains 2 to 5 carbon atoms; by reaction with the appropriate alkyl or benzyl chloroformate. The N-alkoxycarbonyl- or -benzyloxycarbonyl derivative of the compound of formula X is then cyclized by treatment of the corresponding N-alkoxycarbonyl or -benzyloxycarbonyl derivative of the compound of formula V with polyphosphoric acid. 3-Hydroxy-5-substituted-anilino] -3- (R 4) -propionic acid with a hydroxyl-protected 3-position. Polyphosphoric acid generally provides the best cyclization yields and is therefore a preferred cyclizing agent.

Compounds of formula V wherein the hydroxyl group or hydroxyl groups are protected and wherein the nitrogen atom is substituted with an alkoxycarbonyl group will provide compounds of formula V-A by treatment with hydrobromic acid in acetic acid. If the protecting groups of the hydroxyl function or hydroxyl functions are benzyl or substituted benzyl, the regeneration of the hydroxyl groups is carried out by catalytic hydrogenolysis. The alkoxycarbonyl group, if present on the nitrogen atom, remains intact in this reaction. If desired, this group can be cleaved additionally by treatment with hydrobromic acid in acetic acid or any other of a wide variety of acids or bases. Cleavage of the benzyl protecting group by trifluoroacetic acid also cleaves the N-alkoxycarbonyl group present.

When —Z — W in compounds of formula V is —OH, and if desired —Z — W in compounds of formula II or I is —O— (alk ₂ ) _n —W, wherein: W is as defined above, performs conversion of -OH to -O- (alk ₂ J-W, suitably and preferably exactly at this point the total reaction sequence. Thus a group of 7-OH in the compound of the formula V-B is converted by reaction with an appropriate Williams bromide [Br- (alk ₂₎ -W _3], mesylate or tosylate group at vzorC6 -O- (alk ₂₎ -W ₃ (formula V-C.

Similarly, when the —Z — W substituent in the compound of formula (V) represents a radical - (alkj —O — H), this radical is converted to a radical of the formula - (alk, J — O- [alk ₂ }. ₎ —W, wherein n is 0 or 1 and W is other than hydrogen, conveniently at this reaction stage of the entire synthesis by a Williamson reaction.

Instead of an alkoxycarbonyl or benzyloxycarbonyl group, a number of other groups, such as one of R 5, may be used to protect the nitrogen atom from protonation advantageously.

The group R 5, if not already present in the compounds of the general formulas V-A, V-B or. It is possible to introduce in V-C before formation of the hydroxymethylenderivative (VIJ by reaction with the appropriate reagent C1-Rs or Br-Rs in a manner known per se. However, in products of formula I or II Rs is to be an acyl group, e.g. This group is generally introduced after the formation of a compound of formula (V) in which Re represents a hydrogen atom, for example by acylation with the appropriate acyl halide in a manner known per se.

Compounds of formula V (and of course V-A, V-B and V-CJ) are converted to compounds of formulas I and II according to the following Reaction Scheme B, wherein hydrogen is used instead of R 5.

Scheme Β

CH 2 CO-CH-CH 3. ba'ze ^CH ^OH

The quinolines of the above general formula (V) are converted to the hydroxymethylene derivatives of the general formula (VI) by reaction with ethyl formate and sodium hydride. This formylation reaction affords the bis-formyl derivative of the Formula VI in excellent yield. Treatment of this bis-formyl derivative with methyl vinyl ketone gives a mixture of the corresponding mono-N-formulated Michael adduct VII and 1,3-bis-formulated Michael adduct.

The two products are conveniently separated by silica gel column chromatography.

The conversion of compounds of formula VII to compounds of formula III is effected by aldol condensation of the mono-N-formyl derivative of formula VII. The 1,3-bis-formulated Michael adduct provides aldol condensation as the main product of the compound of formula III-A with spiro-fused rings, in the sense of the following scheme:

z-w m / jH

However, the compound of formula VII-A can also be converted by treating the compound of formula VII with an equivalent amount of potassium carbonate in methanol.

In addition to the spiro-fused ring product, small amounts of the desired enone (Formula III) and compounds of Formula V are also formed.

The enon of formula III is converted by a Birch reduction to the compound of formula II to give the cis- and transisomer thereof. The metal suitable for this reduction is lithium, but sodium or potassium may also be used. The reaction is carried out at temperatures of -35 to -80 ^° C. The advantage of the Birch reduction lies in its stereoselectivity as it provides the desired trans-ketone of formula II as the main product. Catalytic noble metal reduction is preferred when the desired major product is the cis-diastereoisomer.

The hydroxyketones of formula II and the dihydroxy compounds of formula I appear to be somewhat unstable. On standing they undergo oxidation, which is manifested by the formation of purple to red coloration. These colored by-products are formed even when the hydroxyketones are subjected to sodium borohydride reduction. It has been found that the formation of colored by-products can be prevented by acylation, in particular acetylation, of the 1-hydroxy (ORi) acetic anhydride in pyridine and the formation of acid addition salts such as hydrochlorides. The acetyl derivatives are then stable both when stored and when subjected to further reactions.

The aforementioned byproducts appear to have a chinoid structure resulting from the oxidation of 1-hydroxy (ORi) to the oxo group and the simultaneous introduction of the second oxo group at the 2 or 4 position. These by-products are themselves central nervous system agents, in particular analgesics. and hypotensive agents, and are used in the same manner and in the same amounts as the compounds of formulas I and II.

Reduction of the 9-oxo group of a compound of formula II, or preferably an acetylated derivative of formula II (for reasons of stability mentioned above) with a metal hydride provides compounds of formula I wherein the hydroxyl group at position 1 is in the form of its acetylated derivative. A suitable reducing agent is sodium borohydride, since it not only provides sufficient yields of the desired product, but also preserves the acetoxy group at the 1-position and reacts fairly slowly with hydroxyl-containing solvents that can be used for this purpose (methanol, ethanol, water). The reaction usually proceeds at temperatures of about 0 to 30 ° C. Lower temperatures, even up to -70%, can be used to increase the selectivity of the reduction. Higher temperatures in turn induce the reaction of sodium borohydride with solvents containing hydroxyl groups and deacetylacyl. If higher temperatures are desired or required for the reaction, isopropyl alcohol or diethylene glycol dimethyl ether is used as the solvent. A preferred reducing agent is potassium tris-sec-butylborohydride since it promotes the stereoselective formation of the 9α-hydroxy group. The reduction is carried out in dry tetrahydrofuran at a temperature of about -50 ° C and using equimolar amounts of the reducing agent and the starting 9-oxo compound.

Reducing agents such as lithium borohydride and lithium aluminum hydride require anhydrous hydroxyl-free conditions and solvents such as dimethoxyethane, tetrahydrofuran, ether, and ethylene glycol dimethyl ether.

241439

Alternatively, and more preferably, compounds of formula III, particularly those in which the hydroxyl group at position 1 is protected in the form of an ester or benzyl ether, are converted by catalytic hydrogenation to compounds of formula I. A suitable procedure is catalytic hydrogenation using palladium, for example palladium on coal or other precious metal, either as such or deposited on. as a catalyst.

The acetylated derivatives of formula (I) thus obtained are converted to the corresponding hydroxy derivatives by cleavage of the acetyl group by standard methods.

Esters of formulas II and III wherein R 1 is acetyl or piperidinobutyryl are readily prepared by reacting the corresponding hydroxy compounds of formulas II and III with acetic or piperidinobutyric acid in the presence of a condensing agent such as dicyclohexylcarbodiimide. Alternatively, these esters are prepared by reacting the hydroxy compounds of formulas II and III with the chloride or anhydride of the appropriate acid, for example acetyl chloride or acetic anhydride, in the presence of a base such as pyridine.

The presence of a basic group in the ester moiety (ORi) of the compounds of the invention permits the formation of acid addition salts containing said basic group. When the basic esters described herein are prepared by condensation of a suitable amino acid hydrochloride (or other acid addition salt) with an appropriate compound of Formula I to III in the presence of a condensing agent, a base ester hydrochloride is obtained. The free base is prepared by careful neutralization. The free base form can then be converted in a known manner to another addition salt.

It will be understood that the acid addition salts are formed with the nitrogen of the benzoquinoline system. These salts are prepared by standard procedures. Of course, the basic ester derivatives can, with the presence of two basic functions, form acid addition mono- or disalts with acids.

The analgesic properties of the compounds of the invention are determined by assays using either thermal irritant stimuli (e.g., thermal oscillation of mouse oss) or chemical irritant stimuli (such as measuring the ability of test compounds to suppress benzoquinone-induced pain spasms in mice). These and other tests are described below.

Thermal irritant stimulus tests (a) Analgesic effect test on hot plate mice

The modified method described by Woolfe and Mac Donald [J. Pharmacol.

Exp. Ther., 80, 300-307 (1944)]. The controlled thermal stimulus is applied to the paws of mice placed on a 3.2 mm thick aluminum plate. A mirror infrared lamp (250 W) is placed under the aluminum plate. The thermal controller, which is connected to a thermistor placed on the surface of the plate, controls the operation of the bulb so as to maintain a constant temperature of 57 ° C. Each mouse is dropped into a 16.5 cm diameter glass cylinder set on a hot plate and time is measured as the mouse touches the paw of the plate. At 0.5 to 2 hours after administration of the test compound, the first movements of the mice are observed to remove one or both hind paws from the hot plate. It is determined whether these movements occur within 10 seconds. Morphine has an MPE 50 = 4-5.6 mg / kg (subcutaneous) in this test.

(bj Test for analgesic effect in thermal irritation of the mouse tail

The modified assay described by D‘Amour and Smith [J. Pharmacol. Exp.-Ther., 72, 74-79 (1941)], in which the tail of the mouse is subjected to controlled, high-intensity heating. Each mouse is placed in a sliding metal cylinder such that its tail protrudes at one end of the cylinder. The cylinder is arranged so that the protruding tail of the mouse is placed over a screened heating lamp. At the beginning of the test, the aluminum screen is removed from the lamp and the jet stream is concentrated through the slit at the tail end. At the same time, time begins to measure. It is determined whether the mouse pulls its tail away from the heat stimulus site. Untreated mice usually respond within 3 to 4 seconds after the lamp is exposed. The limit of the time period during which the mouse is protected from pain by the test substance is 10 seconds. The test mice are subjected to the above test at 0.5 and 2 hours after administration of the test compound or morphine as reference. In this test, morphine has an MPE 50 value of 3.2 to 5.6 mg / kg (subcutaneous administration).

Test using chemical stimuli

Suppressing phenylbenzoquinone-induced pain spasms

Groups of 5 mice (Carwort Farms CF-1) were each pre-administered subcutaneously or orally with sodium chloride solution, morphine, codeine or test substance. After 20 minutes (in the case of subcutaneous administration) or 50 minutes (in the case of oral administration), each group is injected intraperitoneally with phenylbenzoquinone, a known irritant inducing abdominal contractions. presence or absence of wall squeeze.

The MPE 50 value for blocking abdominal contractions is determined for each pre-administered agent.

The results of the test described above are expressed as a percentage of the maximum possible effect ('% MPE'). % MPE values of each time interval n / ..nn (test substance) ^- % MPE = -, ... λ ..—— total test time -

The following tables summarize the results of the analgesic activity tests of the compounds produced by the method of the invention, given in MPE 50 values, which are the doses at which half of the maximum possible analgesic effect is achieved in a given test.

groups were statistically compared with the% MPE values achieved with the standard comparator and the corresponding values observed in the non-active group of animals. The% MPE is calculated using the following formula:

time interval (control substance)

--- r-τ —- x 100 time interval (control substance)

Individual tests are indicated in the table with the following abbreviations:

FBCH = test for abdominal contraction induced by phenylbenzoquinone r = test of mouse tail irritation s = hot plate test

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The compounds of the invention are potent analgesics for both oral and parenteral administration. Said substances are expediently administered in the form of appropriate compositions. The compositions comprise a pharmaceutically acceptable carrier selected with respect to the route of administration chosen and standard pharmaceutical practice. For example, the compounds may be administered in the form of tablets, pills, powders or granules containing, for example, starch, milk sugar, certain types of clay, etc. as carriers _. The compounds may also be administered in the form of capsules containing the aforementioned or other equivalent carriers. substances. The disclosed compounds may further be administered in the form of suspensions, solutions, emulsions, syrups or elixirs for oral administration, which compositions may contain flavoring and coloring agents. For most applications of the therapeutic agents of the invention, tablets or capsules for oral administration containing the active ingredient in an amount of about 0.01 to 100 mg are suitable.

The most appropriate dosage for which patient, which varies depending on the patient's age, weight, response to the preparation being administered, and the manner in which the patient is administered, will be determined by the attending physician. Generally, initial analgesically effective doses for adult patients may range from 0.01 to 500 milligrams per day. This dose may be given as a single dose or in several divided doses. In many cases it is not necessary to exceed the daily dose of 100 mg. Suitable dosages for oral administration are from about 0.01 to 300 mg / day, preferably from about 0.10 to 50 mg / day. Suitable doses for parenteral administration are from about 0.01 to 100 mg / day, preferably from 0.01 to 20 mg / day.

The antihypertensive efficacy of the disclosed compounds is demonstrated by their ability to statistically significantly lower the blood pressure of awake hypertensive rats and dogs when administered orally at the above dosages.

The transquilizing activity of the disclosed compounds is demonstrated in rats, when administered orally, at doses of about 0.01 to 50 mg / / kg, resulting in a decrease in spontaneous motor activity. In mammals, daily dosages range from about 0.01 to 10 mg.

It is believed that the utility of the disclosed compounds for the treatment of glaucoma is due to their ability to lower intraocular pressure. The effects of these compounds on lowering intraocular pressure have been investigated in dogs. The test substance is dripped into the dog's eye as a solution or administered systemically at various time points, after which the eye is anesthetized by dropping 2 drops of 1/2% tetracaine hydrochloride. A few minutes after this local anesthesia, the intraocular pressure is read with the aid of a mechanical tonometer and after staining with fluorescein stains

Holberg hand tonometer. The test substance is conveniently used in the form of a solution having, for example, the following composition: 1 mg of test substance, 0.05 ml of ethanol, 50 mg of Tween 80 (polyoxyalkylene sorbitan monooleate) and saline (up to 1 ml), or of a solution in which the individual components are present in ratios of 10 mg, 0.10 ml, 100 mg and up to 1 ml. In human medicine, concentrations of active compound of from 0.01 mg / kg to 10 mg / kg are used.

The efficacy of the disclosed compounds as diuretics was demonstrated by the test described by Lipschitz et al. [J. Pharmacol., 79, (194)], using rats as test animals. The dosage range for this use is the same as the dosage given above in describing the analgesic effects of the compounds of the invention.

The invention also relates to pharmaceutical compositions, including unit dosage forms, suitable for use of the disclosed compounds as analgesics or for the other uses mentioned above. In order to achieve a daily dosage in which use, the preparations may be administered in a single dose or in multiple doses, as mentioned above.

The active compounds produced by the process according to the invention can be formulated as liquid or solid preparations suitable for oral or parenteral administration. The active ingredient capsules according to the invention are prepared by mixing 1 part by weight of the active ingredient with 9 parts of carrier, such as starch or milk sugar, and dividing the mixture into push-fit gelatin capsules so that each capsule contains 100 parts of the mixture. Tablets containing the active ingredient according to the invention are prepared by mixing the active ingredient with standard carriers and excipients used in the preparation of tablets, such as starches, binding agents and glidants, and compressing the tablets from this mixture so that each tablet contains 0.01 to 100 mg. active substance.

Suspensions and solutions of the active ingredients are generally formulated just prior to use to avoid problems associated with instability of the active ingredients (e.g., oxidation), or, for example, deposition of the active ingredient from solutions or suspensions in storage. then dissolve or suspend for injection.

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

In the examples, NMR abbreviations are used with the following meanings:

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

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

To a solution of 0.1 g lithium in 75 ml of liquid ammonia distilled through potassium hydroxide pellets, a suspension of 1.0 g (2.91 mmol) d, 1-5,6,6a, 7-tetrahydro was added dropwise from the dropping funnel with vigorous stirring. -1-hydroxy-6/3-methyl-3- (2-heptyloxy) benzo [c] quinolin-9 (8H) -one. Rinse the dropping funnel with 10 ml tetrahydrofuran. The reaction mixture was stirred for 10 minutes and then solid ammonium chloride was added to remove the blue color. The excess ammonia was evaporated, the residue was taken up in 100 ml of water and 50 ml of ethyl acetate, the ethyl acetate layer was separated and the aqueous phase was extracted twice with 50 ml of ethyl acetate each time. The combined ethyl acetate extracts were washed with brine, dried (MgSO4) and concentrated under reduced pressure. 1.35 g of a brown colored semi-solid are obtained, which, by trituration with a mixture of equal parts of pentane and ether, yields 0.884 g of a brownish solid, m.p. 130-138 ° C.

The above procedure was repeated using 1.84 g (5.36 mole) of benzoquinolin-9-one, 0.184 g of lithium, 140 ml of liquid ammonia and 45 ml of tetrahydrofuran. The residue (2.1 g) remaining after evaporation of the ammonia was dissolved in benzene and loaded onto a chromatography column (3.8 x 61 cm) containing 250 g of silica gel. The column was eluted first with the same volume as the column volume of the degassed benzene, and then eluted with 1700 mL of degassed benzene / efher (9: 1). Continued elution (1100 mL) gave a bright red eluate which, upon concentration under reduced pressure, gave 580 mg of a slightly purple solid, from which after trituration with a mixture of equal portions of benzene and ether, 370 mg of solid product were obtained. C. This product was stored under nitrogen and in the dark and isolated solids were mixtures of the cis and trans forms of the title compound, mass spectrum: m / e 345 (M ^& lt ^{; +} & gt ^; ).

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6.85 and 7.49 (1H, broad signal, OH),

5,67,

5,71,

5,85,

5.93 (d, J = 2 Hz, total 2H, aromatic hydrogen for cis / trans mixture),

0.90 (t, 3H, terminal methyl),

1.12 to 4.43 (m, remaining protons).

Example 2

-3- (2-heptyloxy) benzo [c] quinalin-9 (8H) -one

To a vigorously stirred solution of 0.1 g lithium in 750 ml of liquid ammonia is added dropwise a solution of 9.0 gd, 1-5,6,6a, 7-tetrahydro-1-hydroxy-3- (2-heptyloxy) benzo [] -9 (8H) -one. An additional 0.1 g of lithium was added portionwise during the above addition to ensure a lasting blue color of the mixture. The reaction mixture was stirred for 10 minutes and then the blue color was removed by adding excess ammonium chloride. The excess ammonia was allowed to evaporate and the residue was taken up in a mixture of water and ethyl acetate. The organic layer was separated and the aqueous phase was extracted twice more with ethyl acetate. The combined extracts were washed with water and brine, dried (MgSO4) and evaporated to give 8.45 g of crude product as a brown solid.

This crude product (8.0 g) was suspended in methylene chloride (48 ml) at 0 ^° C and N, Nethylamine (3.24 g) was added. After addition of 2.52 ml of acetic anhydride, the mixture is stirred at 0 ° C for 30 minutes, then diluted with 300 ml of methylene chloride, the methylene chloride layer is separated, washed three times with 150 ml of water, once with 100 ml of sodium and once with 100 ml of sodium chloride, dried over magnesium sulphate and the roethylene chloride was evaporated. 13.7 g of a dark colored oil are obtained, which is subjected to chromatography on a column of 450 g of silica gel. The column is eluted successively with a mixture of equal portions of ether and hexane, then with a 2: 1 mixture of ether and hexane and finally with ether. 18 ml fractions were collected. Fractions 176 to 224 are combined and concentrated to an oily residue which, after crystallization from hexane, yields 3.24 g (32% yield) of the trans-isomer of the title compound as yellowish crystals, m.p. 65.6-68. Deň: 32 ° C.

Mass Spectrum: m / e 373 (M ^& lt ^{; +} &^gt;

IR (KBr):

5.82 (ketone carbonyl),

5.75 (ester carbonyl),

295 (NH)?

Fractions 246-290 were combined and concentrated to give 0.55 g (5%) of the crude cis-isomer of the title compound as an oil. This material was further purified by column chromatography as described above to give the pure oily cis-isomer. Mass spectrum: m / e 373 (M ^& lt ^{; +} & gt ^; ).

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5.82 (ketone carbonyl),

5.67 ester carbonyl),

2.92 (NH) pin.

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Analysis calculated for: C C2áH3iONN:

% C, 70.75;% H, 8.37;% N, 3.75.

% C, 70.90;% H, 8.54;% N, 3.79.

Fractions 225-245 were combined and evaporated to give 2.69 g (26%) _; mixture of cis- and trans-isomers, which is separated as described above.

The following compounds were prepared in an analogous manner from d, 1-5,6,6a, 7-tetrahydro-1-hydroxy-3- (5-phenyl-2-pentyloxy) benzo [c] quinolin-9 (8H) -one:

d, 1-trans-5,6,6a, 7,10,10aa-hexahydro-1-acetoxy-3- (5-phenyl-2-pentyloxy) benzo [c] quinolin-9 (8H) -one; oil. Mass spectrum: m / e 421 (M ^& lt ^{; +} & gt ^; ). For C26H31O4N, calculated:

74.08% C, 7.41 θ / ο H, 3.32% N, found:

% C, 74.16;% H, 7.59;% N, 3.20.

Isomer Hydrochloride m / e (M ⁺ ) m.p. (° C, d, 1-5,6,6a / 3,7,10, 10α-4-hexyhydro-1-acetoxy-3- (5-phenyl-2-pentyloxy) ) benzo [c] quinolin-9 (8H) -one as an oil.

Mass spectrum: m / e (M ^& lt ^{; +} & gt ^; ).

For C2 & H31O4N, calculated:

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

- 74.04 O / o C, H 7.49, N 3.54%.

In an analogous manner, the d, l-5,6,6a, 7-tetrahydr o-1-hydroxy-6α-methyl-3- (5-phenyl-2-pentyloxy) benzo [c] quinolin-9 (8H) -one is converted to:

d, 1-5,6,6a / 3,7,10,10aa-hexahydro-1-acetoxy-6'-methyl-3- (5-phenyl-2-pentyloxy) benzo [c] -9 (8H) -one ad, 1-cis-5,6,6a (3,7,10,10a) 2-hexahydro-1-acetoxy-6a-methyl-3- (5-enyl-2-pentyloxy) benzo [c] quinolin-Ώ (8H) -one.

These isomeric products are converted into their hydrochlorides by a known method. The characteristics of these salts are given in the following overview.

R _f ^a) Analysis ^b)

C Η N trans 107 to 110 435 0.74 68.92 7.17 2.86 cis 94 to 102 435 0.72 68.74 6.93 3.12

Legend:

^and> thin layer chromatography in a solvent system consisting of a mixture of equal parts of benzene and ether, ^b) Analysis: for C 27 H 33 O 4 N. HCl: calculated: 68.71% C, 7.26% H, ^2.96% N.

The following compounds were prepared in a similar manner to Example 2:

EXAMPLE 3 d, 1-trans-5,6,68 / 3,7,8,9,10,10aa-octahydro-1-aceto: [eta] &lt; 9 &gt; -hydroxy-6S-methyl-3- ( 5-Phenyl-2-pentyloxy) benzo [quinoline]

To 200 ml of methanol under a nitrogen atmosphere was added 7.57 g (0.20 mol) of sodium borohydride, the mixture is cooled off in a bath of solid carbon dioxide in acetone at about -75 C and about ^C stirred for 20 minutes, whereby either all dissolved , or at least most sodium borohydride. A solution of 8.71 g (0.02 mol) of dl-trans-5,6,6α, 7,10,10α-hexahydro-1-aethoxy-6,3-methyl-3- (5-phenylpentyloxy) benzo [c] holine-9 (8H) -one in 88 ml of tetrahydrofuran was cooled to about -50 ^Q C and during 5 to 10 minutes was added dropwise to a solution of sodium borohydride. The reaction mixture is stirred at about -70 ^DEG C. for 30 minutes and then poured into a mixture of 1000 ml of water, 45 g (0.80 mol) of ammonium chloride, 250 ml of crushed ice and 250 ml of ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate (3 x 200 mL). The combined extracts were washed once with 100 ml of water, dried over magnesium sulphate, the dried extract was cooled to about 5 ° C and 15 ml added dropwise over 15 minutes.

Of a 1.5 N solution of hydrogen chloride in ethyl acetate (0.025 mol). The hydrochloride of the title compound precipitates from the mixtures with stirring at 0-5 ^° C. After stirring for half an hour, the mixture is filtered and the salt is dried at 25 DEG C. under a vacuum of 7.2 Pa. 6.378 g (67.3%) of product melting with decomposition at 195-198 ° C is obtained.

Alternatively, the title compound is prepared as follows.

d, 1-trans-5,6,6a / S, 7,8,9,10,10aa-octahydro-1-acetoxy-O / 1-hydroxy-.beta.-methyl-S- (5-phenyl-2) pentyloxy) benzo [c] quinoline

Heterogeneous mixture 3.0 g (7 mmol) of d, l-5,6,6a, 7-tetrahydro-1-acetyl-6/3-methyl-3- (5-phenyl-2-pentyloxy) benzo [ c] quinolin-9 (8H) -one and 3.0 g of 5% palladium on carbon in 30 ml of methanol are hydrogenated for 3 hours at room temperature in a Parr apparatus under 50 psi of hydrogen, the catalyst is filtered off and the methanolic filtrate is evaporated. under reduced pressure, the title compound is obtained.

The product was taken up in 300 mL of ethyl acetate, cooled to 0 ° C and an excess of a saturated solution of hydrogen chloride in ethyl acetate was added to precipitate the hydrochloride of the title compound as a white solid. The product was filtered off, washed with ethyl acetate and dried.

d, 1-5,6,6a, 7-tetrahydro-1-acetoxy-6,3-methyl-3- (5-phenyl-2-pentyloxy) benzo [c] quinolin-9 (8H) he was prepared by the following method .

To a solution of 4.5 g (0.0115 mol) d, 1-5,6,6a, 7-tetrahydro-1-hydroxy-6/3-methyl-3- (5-phenyl-2-pentyloxy) benzo [b] In 1 ml of quinolin-9 (8H) -one in 45 ml of pyridine, 45 ml of acetic anhydride are added at room temperature, the resulting solution is stirred for 3.5 hours, then poured into 250 ml of ice-water and extracted twice with 250 ml of diisopropyl ether. The combined extracts were washed three times with 200 ml of water each time, dried over magnesium sulphate and evaporated under reduced pressure to a tan oil which solidified upon scratching the sides of the vessel with a glass rod. Trituration of the solid with n-heptane gave 2.0 g 40% of 1-acetoxy derivative which, after recrystallization from a hot mixture of chloroform and n-hexane (1: 4), gives the pure ester, m.p. 136-140 ° C.

Mass Spectrum: m / e 433 (M ^& lt ^{; +} & gt ^; ).

1 H-NMR (60 MHz, CDCl 3, tetramethyisilane, δ ppm):

7.21 (bs 5H, aromatic protons),

6.62 (d, J = 1.5 Hz, 1H, C-C-H),

5.97 (d, J = 3 Hz, 1H, proton in meta-position),

5.86 (d, J = 3H, 1H, proton in meta position),

2.27 [s, 3H, CH2-C (= O)],

1.21 (d, I = 7Hz, 6H, CH3-C-N,

CH3 (C-O),

1.49-4.51 (m, 14H, remaining protons).

Example 4 d, 1-trans-5,6,6a (S, 7,8,9,10,10a-octahydro-1,9-dihydroxy-6,3-n) ethyl-3- (2-heptyloxy) benzo cl quinoline

Solution 130 mg d, 1-trans-5,6,6ad, 7,8,9,10,10a-octahydro-1-acetoxy-9-hydroxy-6H-methyl-3- (2-heptyloxy) benzo [c] quinoline and 46 mg of potassium carbonate in 35 ml of methanol are stirred at room temperature. After 30 minutes, the reaction mixture is neutralized with acetic acid and concentrated to a residue. reduced pressure. The residue was dissolved in 100 ml of ether, washed successively with 2 x 35 ml of water, once with 35 ml of saturated sodium bicarbonate solution and once with 40 ml of sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. 96 mg of d, 1-trans-5,6,6a, 6,7,8,9,10,10a-octahydro-1,9-dihydroxy-6, S-methyl-3- (2-heptyloxy) are obtained. benzo [c] quinoline as an amorphous solid melting at 80-100 ° C with decomposition.

Mass spectrum: m / e 347 (M ^& lt ^{; +} & gt ^; ).

The NMR spectrum (deuterochloroform, 60 MHz) contains no signal for acetate methyl and the IC spectrum (chloroform contains no absorption band for ester carbonyl).

In an analogous manner, d, 1-trans-5,6,6a / 3,7,8,9,10,10aia-octahydro-1,9-dihydroxy-6,6-methyl-3- (5-) is prepared from the corresponding 1-acetoxy derivative. phenyl-2-pentyloxy) benzo [quinoline.

Mass Spectrum: m / e 395 (M + 1).

Upon conversion to the hydrochloride, a white powder product is obtained, m.p. 151-156 ° C.

IR (KBr):

3.00, 4.00 (HN =), 6.10 and 6.25, m.

Similarly, d, 1-trans-5,6,6a, 7,10,10aa-hexahydro-1-acetoxy-5-methyl-6 (S-methyl-3- (2-heptyloxy) benzo [c] quinoline-9 ( 157 DEG-160 DEG C. Mass spectrum: m / e 359 (M @ ⁺ ) Analysis for C22 H33 O3 N Calcd:

% C, 73.50;% H, 9.25;% N, 3.90.

% C, 73.16;% H, 9.14;% N, 3.85.

Example 5 d, 1-trans-5,6,6a (3,7,10,10aa-hexahydro-1-acetoxy-3- (2-heptyloxy) -5-benzoyl-6 H -methylbenzofin-quinolin-9) (8H) -one

To a solution of 812 mg d, 1-trans-5,6,6aS, 7,10,10aa-hexahydro-1-acetoxy-6 (S-methyl-3- (2-heptyloxy) benzo [c] quinolin-9 (8H) j -on ve

A solution of 421 mg of benzoyl chloride in 5 ml of chloroform was added with stirring to 2.5 ml of pyridine. After 2 hours the reaction mixture was poured onto ice and extracted twice with ether. The combined ether extracts were washed with water and sodium bicarbonate solution, dried over magnesium sulfate, filtered, concentrated and the residue crystallized from a mixture of ether and petroleum ether. D, 1-trans-5,6,6a / 3-7,10,10a-hexahydro-1-acetoxy-3- (2-heptyloxy) -δ-β-β-π-β-β-benzo [c] was obtained. quinolin-9 (8H) -one, m.p. 108-110 ° C.

Mass spectrum: m / e 491 (M &lt; + &gt;).

By repeating this procedure using an equivalent amount of acetyl chloride instead of benzoyl chloride, the corresponding benzo [c] quinoline d., 1-trans-5,6,6a / 3,7,10,10aa-hexahydro-1-acetoxy-3- ( 2-heptyloxy) -5-acetyl-6H-methylbenzo [c] quinolin-9 (8H) -one. Mass spectrum: m / e 433 (M &lt; + &gt;).

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

To a solution of 387 mg d, 1-trans-5,6,6a / 3,7,10,10aa-hexahydro-1-acetoxy-6,3-methyl-3- (2-heptyloxy) benzo [c] quinolin-9 (8H) 1 -one in 3 ml of acetonitrile, cooled to 15 ° C, is added with stirring first 0.5 ml of 37% aqueous formaldehyde and then 100 mg of sodium cyanoborohydride. Addition of acetic acid keeps the pH neutral until the reaction is complete, i.e., no starting material is present in the mixture according to thin layer chromatography. The product is isolated as follows.

Ice-water and ether were added to the reaction mixture, the layers were separated and the aqueous layer was extracted once more with ether. The combined ether layers were dried and evaporated to give the desired d, 1-trans-5,6,6a (3,7,10,10aa-hexahydro-1-acetoxy-5-methyl-6/3-methyl-3). - (2-heptyloxy) benzo [c] quinolin-9 (8H) -one as an oil.

¹ H NMR spectrum (60 MHz), measured in deuterochloroform, contains a characteristic signal at 2.85 ppm for the?

N - CH3.

OF

The following compounds were prepared in an analogous manner from the appropriate reactants:

d, 1-trans-5,6,6a / 1,7,10,10aa-hexahydro-1-acetoxy-5-methyl-3- (2-heptyloxy) benzo [c] quinolin-9 (8H) -one in the form of oils.

d, 1-trans-5,6,6ad, 7,8,9,10,10aa-octahydro-1,9 diacetoxy-5-methyl-6,3-methyl-3- (2-heptyloxy) benzo [c] quinoline in the form of an oil. Mass spectrum: m / e 445 (M &lt; + &gt;).

The following compounds are also prepared in a similar manner:

—Z — w

R-Rs Re

Rs m / e melting point (° C) (M @ +

CH3-O-CH- (CHsbCeHs

CH 3 -O-CH- (CH 2) 3 C ₆ H ₅ -O- (CH ₂ ) 4 C ₆ H ₅

CPI3 h

CH3 and III η 94—97 ^υ 449

CH3 h

CH3 h

CH.3

CH3

HH oil ² '449

Η! IH 102 - 103 ^3> 435

Legend:

ⁿ as the hydrochloride;

Analysis: for C28H35O4N. HCl calculated:

69.19% C, found: 7.47% H, 2.88 % N, 68.72% c, 7.18% H, 2.74 % N. ²⁾ Analysis: for C28H35O4N calculated: 74.80% C, 7.85% H, 3.12 % N,

found:

74.66% C, 8.05% H, 2.66% N. The hydrochloride melts at 69-75 ° C.

³⁾ Analysis: calculated for C27H33O4N:

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

H, 7.51; N, 3.04.

A solution of 114 mg (1.07 mmol) of isobutyryl chloride in 20 mL of chloroform is slowly added under stirring at 0 ° C under nitrogen. The reaction mixture was stirred for 5 hours and then poured into 50 ml of ice-water. The chloroform layer was separated and the aqueous phase was extracted twice with 20 ml of chloroform each. The chloroform extracts were combined, washed with 10 ml of 10% hydrochloric acid twice and then once with 10 ml of sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. A yellow oily residue is obtained which solidifies on standing and, after trituration with hexane, gives a white crystalline product which is isolated by filtration. After drying, 400 mg of the desired product is obtained, m.p. 128-129 ° C. Concentration of the hexane filtrate gave an additional 121 mg of oily material.

Example 7

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

To a solution of 100 mg of lithium aluminum hydride in 5 ml of dry tetrahydrofuran cooled in a water / ice mixture is added dropwise a solution of 90 mg of d, 1-trans-5,6,6a / S, 7,8,9,10,10aa-octahydro- 1,9-dihydroxy-5-acetyl-6S-methyl-3- (2-heptyloxy) benzo [c] quinoline in ml of tetrahydrofuran. After the addition was complete, the reaction mixture was heated to reflux for 1 hour and then allowed to cool to room temperature. Firstly an equivalent amount of water and then an equivalent amount of 3N potassium hydroxide are added, the precipitate formed is filtered off and the filtrate is concentrated in vacuo to give the desired N-ethyl derivative as an oil. Mass spectrum: m / z 375 (M ⁺ ).

Example 8 d, 1-trans-5,6,6a / 3,7,10,10a-hexahydro-1-acetoxy-5-isobutyryl-3- (5-phenyl-2-pentyloxy) benzo [c] quinoline -9 (8H) -one

To a solution of 450 mg (1.07 mmol) of d, 1-trans-5,6,6,6,7,7,10,10aa-hexahydro-1-acetoxy-3- (5-phenyl-2-pentyloxy) benzo {c] quinolin-9 (8H) -one in 1.5 ml of dry pyridine is treated with d, 1-trans-5,6,6a-3,7,8,9,10,10a-octahydro-1,9 / 3-diacetoxy -5-isobutyryl-3- (5-phenyl-2-pentyloxy) benzofin-quinoline

To a suspension of 100 mg (2.6 mmol) of lithium aluminum hydride in 5 mL of tetrahydrofuran at room temperature under a nitrogen atmosphere was added a solution of 213 mg (0.432 mmol) of d, 1-trans-5,6,6a, α, 7,8,9, 10,10aia-octahydro-1-acetoxy-9, (3-hydroxy-5-lsobutyryl-3- (5-phenyl-2-pentyloxy) benzoylquinoline) in 5 ml of tetrahydrofuran. 1 ml of water, 0.1 ml of 15% sodium hydroxide solution and 0.3 ml of water, the resulting mixture is filtered under nitrogen and the filter cake is washed twice with 5 ml of tetrahydrofuran in each case, and the filtrate is combined with the washings and concentrated to a reddish oily residue. weighing 0.174 g.

The oil was dissolved under nitrogen in 1 mL of pyridine, cooled to 0 ^C and under stirring added thereto 1 ml of acetic anhydride. The reaction mixture was stirred at 0 ° C for 30 min, then poured into 25 mL and extracted with ethyl acetate (3 x 25 mL). The extracts were combined, washed with brine and dried over magnesium sulfate to concentrate to a brown oil (184 mg). This oil was purged with nitrogen and chromatographed on 40 g of silica gel using 9: 1 benzene / ether as eluent. Fractions of 10 ml are collected. Fractions 2-10 are combined and concentrated to an oil of 109 mg. Mass spectrum: m / e 521 (M ^& lt ^{; +} & gt ^; ). Calcd for C34H43O4N:

% C, 73.67;% H, 8.31;% N, 2.68.

H, 8.89; N, 2.23.

¹ H NMR (60 MHz, CDCl 3, tetramethylsilane, S-ppm):

7.22 (s, 5H, aromatic protons),

6.05 (d, 1H, aromatic proton),

5.90 (d, 1H, aromatic proton),

4.90 (bs, 1H), 4.30 (bs, 1H),

3.10 (d, II, _N-CH2)

2.90 (d, 2H, N - OH 2),

2.70 (bs, 2H),

2.40 and 2.15 (s, 6H, 2-CH 3 -COO-),

1.85 (bs, 2H, H7 and H5),

1.5 (m), 1.05 (d, 6H,

CH3 /

~ \),

CH3

1.0-3.0 (broad signal, remaining protons).

Example 10

A. d, 1-trans-5,6,6a (3,7,10,10ao; -hexahydro-1-hydroxy-5-acetyl-ε-methyl-g-methylene-3- (2-heptyloxy) benzo) c] quinoline

To a solution of 0.95 g (2.0 mmol) of sodium hydride in 50 ml of dimethylsulfoxide at 50 ^Q C was added 742 mg (2.12 mmol) of triphenylmethylphosphonium bromide. The reaction mixture was heated at 70 ° C for 3 h. A solution of 0.858 g (2.0 mmol) of d, 1-trans-5,6,6a, 7,10,10aa-hexahydro-1-acetoxy- 5-acetyl-η 5 -methyl-S- (2-heptyloxy) benzole] quinolin-9 (8H) -one in 50 mL of dimethylsulfoxide. The resulting mixture was heated at 70 ° C overnight, then cooled and poured into ice water containing 12.5 g of sodium bicarbonate. The aqueous mixture was extracted with benzene, the extract was dried over sodium sulfate and evaporated under reduced pressure. The crude product was purified by silica gel column chromatography using a mixture of equal parts of hexane and benzene as eluent.

B. d, 1-trans-5,6,6af1,7,10,10aa-hexahydro-5-acetyl-1-hydroxy-6,3-methyl-9-methylene-3- (5-phenyl-2- pentyloxy) benzo [c] quinoline

A suspension of 0.94 g (0.039 mol) of sodium hydride (obtained by washing 1.87 g of a 50% dispersion of sodium hydride in mineral oil with dry pentane) in 57 ml of dimethylsulfoxide was heated at 50 ° C for 2.5 hours. After the addition of 15.32 g (0.043 mol) of triphenylmethylphosphonium bromide, the mixture was heated at 60 ° C for 2 hours. , 10α-hexahydro-1-acetoxy-5-acetyl-6H-methyl-3- (5-phenyl-2-pentyloxy) benzo [c] quinolin-9 (8H) -one in 57 mL of dimethylsulfoxide, reaction mixture The mixture was heated at 60 ° C for 30 minutes, then cooled and poured into 200 ml of ice-water containing 20 g of sodium bicarbonate. The aqueous mixture was extracted with ethyl acetate (2 x 50 ml), the combined organic layers were washed with water (50 ml) and brine (50 ml), dried (MgSO4) and evaporated. An orange-colored oil is obtained which, according to thin layer chromatography, contains triphenylphosphine oxide. This product was purified by column chromatography (125 g silica gel, cyclohexane / ether 3: 1) to give 1.251 g (74% yield) of the title compound, m.p. 174-176 ° C.

Calcd for C28H35O3N:

% C, 77.56;% H, 8.14;% N, 3.23.

% C, 77.29;% H, 7.96;% N, 3.22.

IC (KB -r-technology) 2.98 (with), 3.34 (m), 3.38 (m), 3.44 (m), 6.10 (E), 6.24 (with), 6.58 (with), 6.90 (s) / grains

Mass spectrum: m / e 433 (M ^& lt ^{; +} & gt ^; ).

¹ H NMR (60. MHz, deuterochloroform, tetramethylsilane, δ in ppm):

8.80 (s, 1H, phenol);

7.16 (m, 5H, aromatic protons),

6.32 (d, 1H, C2-H),

6.09 (d, 1H, C4-H),

4.64 (bs, 2H, vinyl group),

1.96 and 1.93 (2 s, 3H, amidic methyl),

1.27 and 1.25 (2 d, 3H, C 6 -CH 3),

1.02 (d, 3H, methyl group in the side chain),

0.9 to 4.5 (various signals, remaining protons).

Analogously, d, 1-cis-5,6,6a (3,7,10,10a) -Miexahydro-5-acetyl-1-hydroxy-6 (3-methyl-9-methylene-3-) was prepared from the appropriate starting material. 168 DEG-169.5 DEG C. (5-phenyl-2-pentyloxy) benzo [c] quinoline, yield 88%.

Calcd for C.23H35O3N:

77.56% C, 8.14 ’% H, 3.23% N, found:

77.25% C, 8.14% H, 3.12 _0/0 N.

@ 1 H NMR (60 MHz, CDCl3, tetramethylsilane, < S in ppm):

8.82 (s, 1H), phenol),

7.16 (m, 5H, aromatic protons),

6.36 (d, 1H, C 5 -H),

6.12 (d, 1H, C 1 H),

4.68 (bs, 2H, vinyl group),

2.08 and 2.06 (2 s, 3H, amidic methyl),

1.22 and 1.20 (2 d, 3H, C 5 -CH 2),

1.10 (d, 3H, methyl group in the side chain),

1.50 to 4.50 (different signals, protons remaining).

IR (KBr):

2.95 (mj,

3.36 (s)

61.0 (s),

6.33 (s),

6.88 (s),

7.20 (s),

7.35 (s),

8.50 (s), µm.

Example 11 d, 1-trans-5,6,6a / J, 7,8,9,10,10aa-octahydro-1-hydroxy-5-ethyl-9-hydroxymethyl-6- (3-methyl-3- (2) (heptyloxy) benzo [c] quinoline

To a solution of 0.855 g (2 mmol) of 1,1-trans-5,6,63 (3,7,10,10aa-hexahydro-1-hydroxy-5-acetyl-6,3-methyl-9-methylene- 3- (2-heptyloxy) benzoquinoline in 30 ml of tetrahydrofuran was added dropwise at 0-5 ° C with 6 ml of a 1M solution of diborane in tetrahydrofuran (borane-tetrahydrofuran complex). After the addition, the reaction mixture was allowed to react for 30 minutes at room temperature and water was added to decompose the excess hydride.

The mixture was heated to 50 ^° C in a water bath and 3N sodium hydroxide (3 ml) was added first and then 3 ml of 30% hydrogen peroxide was added dropwise. After the addition was complete, the mixture was allowed to stand at room temperature for 1 hour, 1.5 g of potassium carbonate were added thereto, and the tetrahydrofuran layer was separated. The aqueous phase is extracted with 10 ml of tetrahydrofuran in each case, the extracts are combined and, after drying over magnesium sulphate, concentrated to the desired product, which is purified by silica gel column chromatography using a mixture of ether and hexane as eluent.

Example 12

D, 1-7,10-Dihydro-1-hydroxy-3- (2-heptyloxy) benzo [c] quinolin-9 (8H) -one ethylene ketal and ethylene ketal d, I-5,6,6a, 7,10, 10α-Hexahydro-1-hydroxy-3- (2-heptyloxy) benzo (c 1 quinolin-9 (8H) -one)

<T

Suspension of 0.50 g (1.52 mmol) of d, 1-trans-5 _with 6,6α, 3,7-tetrahydro-1-hydroxy-3- (2-heptyloxy) benzo [c] quinolin-9 (8H) ) -onu ,,

0.43 ml (7.70 mmol) of ethylene glycol and 0.28 g (1.46 mmol) of p-toluenesulfonic acid monohydrate in 25 ml of benzene were heated under reflux for 45 minutes while the by-product water was removed azeotropically. The resulting interesting suspension was taken up in a mixture of ether and saturated sodium bicarbonate solution, the organic layer was separated, washed with saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate and concentrated to an oily residue which was chromatographed on 50 g of silica gel using ether as eluent. reagents. Fractions of 10 ml are collected.

Fractions 12-18 were combined and evaporated to give 203 mg of ethylene ketal hexahydrate.

Mass spectrum: m / e 375 (M ^& lt ^{; +} & gt ^; ).

IR (KBr):

2.98 µm (overlapping bands for N - H and

O-H).

- NMR (SO MHz, deuterochloroform, tetramethylsilane, value in ppm):

5.7 (s, 2H, aromatic protons),

4.0 (s, 4H, ketal ethylene residue) and signals for remaining protons).

Fractions 42-65 are combined and concentrated to give 146 mg of a yellow solid which, by trituration with a mixture of equal portions of ether and pentane, affords 85 mg of 7,10-dihydro-1-hydroxy-3- (2-heptyloxy) ethylene ketal. 171 DEG-173 DEG C. benzo [clquinolin-9 (8M) -one.

Mass spectrum: m / e 371 (M ^& lt ^{; +} & gt ^; ).

IR (chloroform):

2.98 ym (0-H).

NMR (80 MHz, CDCl3, tetramethylsilane, δ ppm):

8.6 (s, 1H, aromatic proton on Cs),

6.6 and 7.0 (dd, 2H, aromatic protons),

4.1 (bs, 4H, ethylene ketal),

3.9 (bs, 2H, methylene to C 10),

3.1 (t, 2H, C2-ethylene),

2.0 (bt, 2H, C 5 -methylene), and other signals for the remaining protons).

Analysis for C22H29O4N calculated

71.13% C, 7.87% H, 3.77% N, found:

% C, 71.19;% H, 7.67;% N, 3.61.

In an analogous manner, the ethylene ketal d, l-5,6,6a, 7,10,10a-hexahydro-1-hydroxy-3- (2 heptyloxy) -6-methylbenzo [c] quinolin-9 (8M) -one is converted to ethylene ketal d, 1-7,10-dihydro-1-hydroxy-3- (2-heptyloxy) -6-methylbenzo [c] quinolin-9 (8H) -one. Mass spectrum: m / e 385 (M ^& lt ^{; +} & gt ^; ).

¹ H NMR (60 MHz, CDCl 3, tetramethylsilane, δ in ppm):

6.8 and 6.4 (2 doublets for 1H, aromatic protons),

5.7 (bs, 1H, phenolic proton),

4.0 (bs, 4H, ethylene ketal),

3.9 (bs, 2H, C10-methylene),

3.1 (bt, 2H, C 5 -methylene),

2.5 (s, 3H, 6-CH 3),

2.0 (bt, 2H, C7-methylene), additional signals for remaining protons.

Example 13 d, 1-5,6,6a / 3,7,10,10a-hexahydro-1-hydroxy-6H-methyl-3- (2-heptylsulfinyl) benzo [c] quinolin-9 (8H) )-he

Equimolar amounts of m-chloroperbenzoic acid and 1,1,1,6,6a, 6, 7,10,10aa-hexahydro-1-hydroxy-6S-methyl-3- (a) were added to a 2: 1 mixture of chloroform and acetic acid. 2-heptylthio] benzo [c] quinolin-9 (8H) -one and the reaction mixture was stirred at room temperature for 1 hour. The organic phase was separated and washed with water and dried over magnesium sulfate to evaporate to dryness to give the title compound. .

Example 14 d, 1-trans-5,6,6a, 7,10,10a-hexahydro-1-hydroxy-6,3-methyl-3- (2-heptylsulfonyl) benzo [c] quinolin-9 (8H) -one

The title compound is obtained by repeating the procedure described in Example 13, using two equivalents of m-chloroperbenzoic acid or another suitable oxidizing agent for each mole of starting thioether.

Example 15 d, 1-5,6,6a, 7-tetrahydro-1- (4-morpholinobutyryloxy) -6β-methyl-3- (2-heptyloxy) benzo [c] quinolin-9 (8H) -one

To a solution of 0.51 g (1.5 mmol) of d, 1-5,6,6a, 7-tetrahydro-hydroxy-6,3-methyl-3- (2-heptyloxy) benzo [c] quinolin-9 (8H) 0.35 g of 4-morpholinobutyric acid hydrochloride (1.5 mmol) is added in 25 ml of dry methylene chloride and the mixture is stirred at room temperature under a nitrogen atmosphere. Of a 1M solution of dicyclohexylcarbodiimide in methylene chloride, the reaction mixture was stirred for 24 hours, then filtered and evaporated to give the title compound which was purified by silica gel column chromatography.

Example 16 d, 1-trans-5,6,6a / 3,7,8,9,10,10aa-octahydro-1- (4-N-piperidylbutyryloxy) -9-hydroxy-6/3-methyl-3- (5-Phenyl-2-pentyloxy) benzolequinoline hydrochloride

To a solution of 1.0 g (2.53 mmol) of d, 1-trans-5,6,6a-R, 7,8,9,10,10a-octahydro-1,9-dihydroxy-6/5-methyl -3- (5-phenyl-2-pentyloxy) benzo [c] quinoline in 20 ml of methylene chloride at 25 ° C is added 0.524 g (2.53 mmol) of 4-N-plperidylbutyric acid hydrochloride and 0.573 g (2, The reaction mixture was stirred at 26 ° C for 6 hours, cooled for 12 hours, then filtered, and the filtrate was evaporated and the residue triturated with ether to give 1.3 g of solid monohydrochloride.

IR (KBr):

2,95,

3,70,

5.65 (ester carbonyl),

6.13,

6,27 μπι.

A portion of this solid was subjected to preparative chromatography on a 0.5 mm layer of silica gel in 10% methanol in methylene dichloride. D, 1-trans-5,6,6,6,7,8,9,10,10a-octahydro-1- (4-N-piperidylbutyryloxy) -9-hydroxy-6'-methyl-3- (5- phenyl-2-pentyloxy) benzo [c] quinoline in free base form.

¹ H NMR (60 MHz, CDCl 3, tetramethylsilane, δ ppm):

1.12 (d, J = 7 Hz, side chain methyl on Ca),

1.25 (d, J = 6 Hz, C 5 -methyl),

5.84 (s, 2 aryl protons),

7.16 (s, 5H).

Treatment of this free base with an excess of hydrogen chloride in ether gives the corresponding dihydrochloride as a hygroscopic powder.

Example 17 d, l-5,6,6a, 7-Tetra-1-l- (4-N-piperidylbutyryloxy) -6,3-methyl-3- (5-phenyl-2-pentyloxy) benzo [c] quinoline-9 (8H) -ort

To a solution of 550 mg (1.41 mmol) of d, 1-5,6,6a, 7-tetrahydro-1-hydroxy-6,3-methyl-3- (5-phenyl-2-pentyloxy) benzo [c] quinoline-9 (8H) -one in 26 ml of methylene chloride at 25 ° C was added 291 mg (1.41 mmol) of 4-N-piperidylbutyric acid hydrochloride and 319 mg (1.55 mmol) of dicyclohexylcarbodiimide. The reaction mixture was stirred for 18 hours, then cooled to 0 ° C and filtered. Evaporation of the filtrate and trituration of the residue with ether gave 800 mg of d, 1-5,6,6a, 7-tetrahydro-1- (4-N-piperidylbutyryloxy) -6 (3-methyl-3- (5-phenyl-2)). pentyloxy) benzo [quinolin-9 (8H) -one hydrochloride as a hygroscopic yellow powder.

IR (chloroform):

92

444 (HN + =)

5.69 (ester),

6,00,

6.20,

6,40 gm.

In an analogous manner, from 4-N-morpholinobutyric acid ad, 1-trans-5,6,6a / S, 7,8,9,10,10aa-octahydro-1,9-dihydroxy-6/3-methyl-3- (5-phenyl-2-pentyloxy) benzo [c] quinoline prepares d, 1-trans-5,6,63 (3,7,8,9,10,10a-octahydro-1- (4-N-) morpholinobutyryloxy) -O-hydroxy-N-methyl-5- (5-phenyl-2-pentyloxy) benzo [c] quinoline hydrochloride.

IR (KBr):

3,00,

3,75,

5.67 (ester carbonyl): 6.15,

6,30 μΐιι.

Example 18

D, 1-7,10-Dihydro-1-hydroxy-3- (2-heptyloxy) -6-methylbenzo [c] quinolin-9 (8H) -one ethylene ketal.

To an ice-cold solution of 44 mg (2.0 mmol) of methyllithium in 25 mL of ether was slowly added a solution of 371 mg (1.0 mmol) of ethylene ketal d, 1-7,10-dihydrol-hydroxy-3- (2-heptyloxy). benzo [c] quinolin-9 (8H) -one in 50 mL ether. The 5-lithio-6-methyl derivative thus obtained is dissolved in dry ether and dry oxygen is added to the solution. Filtration and evaporation of the solvent gave the title compound.

Example 19

General procedure for the preparation of hydrochlorides

An excess of hydrogen chloride is introduced into the solution of the appropriate benzoquinoline, the precipitate formed is separated and recrystallized from a suitable solvent, for example a 1: 10 mixture of methanol and ether.

For example, the following salt is prepared:

d, 1-trans-5,6,6a / 3,7,8,9,10,10a-octahydro-1-acetoxy-9 (3-hydroxy-6 (3-methyl-3- (5-phenyl-2)) m.p. 191-193 ° C.

Mass spectrum: m / e = 437 (M ^& lt ^{; +} & gt ^; ).

Calcd for C27H38O4NCI:

68.48% C, 7.70% H, 2.89% N, found:

H, 7.66; N, 2.96.

Example 20 dl-trans-5,6,6a, 3,7,10,10a-hexahydro-1-methyl-6- (3-methyl-3- (5-phenyl-2-pentyloxy) benzo [c] quinoline- 9 (8H) -one

3.49 g (0.008 mol) of dl-trans-5,6,6a, 3,7,8,9, -0,10a-octahydro-1-acetoxy-6 (3-ethyl-3- (5-f) enyl-2-pentyl-oxybenzo [c] quinolin-9 (8H) -one is dissolved in 20 ml of chloroform-free alcohol, cooled in ice-water and 14 ml of pyridine dried over potassium hydroxide pellets are added first and then 0.95 ml (0.013 mol) of acetyl chloride dissolved in 5 ml of chloroform, and the resulting homogeneous solution was stirred at room temperature for 18 hours, poured into 50 ml of ice-water and extracted twice with 25 ml of chloroform each. The layers were washed with 25 mL saturated potassium bicarbonate solution, 25 mL water, 25 mL brine, dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure. Purification of the residue by chromatography on 200 g silica gel using cyclohexane / ether ( 3: 1) 2.20 g (83.8 percent) of the title compound is obtained Analysis for C29H35O5N calculated:

72.90% C, 7.39% H, 2.80% N, found:

% C, 72.69;% H, 7.48;% N, 2.49.

IR (KBr):

2.90 f <m (m)

3,38 μία. (with),

3.48 ym (s)

5.62 / s (s),

5.78 ym (s)

6,00 min (s),

6.15 μϊίΐ (δ),

6.30 μΐη (s).

Mass spectrum: m / e 477 (M ^& lt ^{; +} & gt ^; ).

¹ H NMR (60 MHz, CDCl 3, tetramethylsilane, δ ppm):

⁷ .20 (m, 5H, aromatic H);

6.53 (d, 1H, C2-H),

6.39 (d, 1H, Ca-H),

4.71 to 4.08 (m, 2H, methines),

2.29 (s, 3H, acetate methyl),

2.02 2.04 (2s, 3H, amide methyl),

1.25 + 1.23 (2 d, 3H, methyl on Cs),

1.12 (d, 3H, methyl in the side chain),

3.20 to 1.36 (remaining protons).

In an analogous manner, dl-cis-5,6,6a (S, 7,10a) 3-hexahydro-1-acetoxy-6 / S-methyl-3- (5-phenyl-2-pentyloxy) benzo [c] quinoline -9 (8H) -one is converted to dl-cis-5,6,6aj3,7,10aj3-hexahydro-1-acetoxy-5-acetyl-6/3-methyl-3- (5-phenyl) in 82% yield. 2-pentyloxy) benzo [c] quinolin-9 (8H) -one, m.p. 125-128 ° C.

For C29H35O5N calculated:

72.90 ° C, 7.39% H, 2.80% N, found:

% C, 72.80;% H, 7.35;

¹ H NMR (60 MHz, CDCl 3, tetramethylsilane, δ ppm):

7.22 (m, 5H, aromatic protons),

6.55 (2 d, C 2 - + Cl - H),

5.02 to 4.62 (m, 1H, C 5 -methine),

4.52 to 4.12 (m, 1H, methine in the side chain),

2.28 (s, 3H, acetate methyl),

2.11 + 2.13 (3H, amide methyl),

1.26 + 1.28 (3H, methyl to C6),

1.22 (d, methyl in the side chain),

3.42 to 1.65 (remaining protons).

IR (KBr):

2.95 µm (s),

3.43.

5.65 µm (s),

5.81 jun (s),

6.02 μπι (s),

6.16 jun (s)

6.32 µm (s),

6.70 µm (s).

Mass spectrum: m / e 477 (M ^& lt ^{; +} & gt ^; ). Example 21 (2'R, 6S, 6aR, 9R, 10aR) - (-) -1-Acetoxy-5,6,6a, 7,8,9,10,10a-octahydro-9-hydroxy-5,6- dimethyl-3- (5-phenyl-2-pentyloxy) benzo [quinoline]

To a solution of 1.0 g (0.0021 mol) of (2'R, 6S, 6aR, 9R, 10aR) - (-) -1-acetoxy-5,6,6a, 7,8,9,10,10a- octahydro-9-hydroxy-6-methyl-346

- (5-Phenyl-2-pentyloxy) benzo [c] quinoline hydrochloride in 30 ml of chloroform, 30 ml of saturated sodium bicarbonate solution are added and the mixture is stirred at room temperature for 5 minutes, the layers are separated and the aqueous layer is extracted again with 20 ml. The combined chloroform layers were dried over magnesium sulfate, filtered, and the solvent was evaporated in vacuo to give the corresponding free base as a colorless foam.

The foam was dissolved in 40 mL of tetrahydrofuran, and 1.05 g of 5% palladium on carbon, 1.05 mL (0.018 mol = 8.7 equivalents) of glacial acetic acid and 15.8 mL (0.20 mol) were added. = 100 equivalents) of 37% aqueous formaldehyde was added to the Parr apparatus and hydrogenated at 50 psi for 50 minutes. The catalyst was filtered through a pad of diatomaceous earth, which was washed well with ethyl acetate. The filtrate was diluted with ethyl acetate to 150 ml and washed successively with saturated sodium bicarbonate (3 x 100 ml), water (3 x 75 ml) and brine (75 ml), dried (MgSO4), filtered and the solvent evaporated in vacuo. A viscous yellow oil is obtained, which is chromatographed on 50 g of silica gel (0.04-0.63 mm) using a mixture of equal parts of toluene and diethyl ether as eluent, and similar fractions are combined and evaporated in vacuo to a colorless oil. The residue was redissolved in diethyl ether (50 mL), dry hydrogen chloride was added under stirring under nitrogen, and the white solid which precipitated was filtered off under nitrogen and dried at room temperature under a vacuum of 13 Pa for 24 hours. 45 g (44%) of the title compound, melting at 90-95 ° C with decomposition.

NMR (CDCl3):

2.73 ppm (s, 3H, N - CH3).

IR (KBr):

4.25 m (—NH + C1 “),

CHS

5.61 µm (—O — C — CH3).

O

Analysis: for C28C37O4N. HCl calculated:

% C, 68.90;% H, 7.85;% N, 2.87.

% C, 68.60;% H, 7.92;% N, 2.77.

[Α] _D 25 ₌ -73 ° ( _c = 1 ₍ methanol)) Mass spectrum: m / e 451 (M ⁺ ).

The following compounds were prepared in a similar manner:

dl-acetoxy-5,6,6a / S, 7,8,9,10,10aa-octahydro-9H-hydroxy-5,6 / 3-dimethyl-3- {1,1-dimethylhephyl] benzo [b] c] quinoline hydrochloride, m.p. 129-130 ° (dec.).

Mass spectrum: m / e 415 (M ⁺ , 100%).

IR (KBr):

5.67 µm (—C-CH3).

! (o

dl-acetoxy-5,6,6a / 3,7,8,9,10aa-octahydro9R-hydroxy-5-methyl-6S-n-butyl-3- (5-phenyl-2-pentyloxy) benzo [c] chmoline hydrochloride, m.p. 106-108 ° C.

Mass spectrum: m / e 493.

Analysis: for HHHíDIN. HG1 calculated:

% C, 70.21;% H, 8.37;% N, 2.8%.

70.02% c, 8.43% II, 2.6% N.

Example 22

Preparation of dl-5,6,6a / 3,7,8,9a, 10,10aa-octahydro-1-acetoxy-5-benzoyl-9-benzoyloxy-6,3-methyl-3- (1-methyl-4-phenylbutoxy) benzo [c] quinoline

Suspension 47.4 g (0.10 mol) dl-5,6,6a, 5,7,8,9a, 10,10aa-octahydro-1-ocetoxy-9-hydroxy-6S-methyl-3- (1- methyl-4-enylbutoxyJbenzo [c] quinoline hydrochloride in 500 ml chloroform with stirring under a nitrogen atmosphere cooled to 0 ^DEG C. and was added to the first 250 ml of pyridine and then 58 ml (0.50 mol) of benzoyl chloride in ₅₀₀ The resulting homogeneous solution was heated to reflux for 1 hour on a steam bath, then poured onto crushed ice and extracted with chloroform The combined organic extracts were washed successively twice with 500 ml of water each time, 10% hydrochloric acid, 500 ml. ml of saturated sodium bicarbonate solution and 500 ml of saturated sodium chloride solution, dried over magnesium sulphate and evaporated to give 119 g of a yellowish oil which, after chromatography on 2000 g of silica gel eluting with 20% ethyl acetate in cyclohexane, gave

50.5 g (78%) dl-5,6,6a / S, 7,8,9a, 10,10a-octahydro-1-acetoxy-5-benzoyl-9-benzoyloxy-6/3-methyl- 3- (1-methyl-4-phenylbutoxy) benzo [c] quinoline, m.p.

130 [deg.] C.

Analysis calculated for C11H4305N:

% C, 76.24;% H, 6.72;% N, 2.17.

H, 8.92; N, 2.19.

The separation of dl-5.6,63,3,7,8,9a, 10,10a-octahydro-1-acetoxy-5-benzoyl-9-benzoyl-xy-6/3-methyl-3- ( 1,3-methyl-4-phenylbutoxy) benzo [c] quinoline and dl-5,6,6a / S, 7,8,9a, 10,10aa-octahydro-1-acetoxy-5 benzoyl-9-benzoyloxy-6 3-Methyl-3- (1α-methyl-4-phenylbutoxy) benzo [c] hop.

Recrystallization of 50.5 g of dI-5,6,6a / 3,8,8,10-9,10,10aa-octahydro-1-acetoxy-5-benzoyl-9-benzoyloxy-6H-methyl-3 (1-methyl-4-phenylbutoxy) benzoquinoline from 2 liters of 2-propanol gave 23.8 g of a white solid, m.p. 136-138 ° C, which, after recrystallization twice from 2-propanol and recrystallization twice from acetonitrile, yielded 7 g dl-5,6,63 / 3,7,8,93,10,10aa-octahydro-1-acetoxy-5-benzoyl-9-benzoyloxy-6,3-methyl-3- (1d-methyl- 148 DEG-149 DEG C. (4-phenylbutoxy) benzo [c] quinoline.

The filtrate from the first recrystallization of dl-5,6,6a / S, 7,8,9a, 10,10a-α-octahydro-1-acetoxy-5-benzoyl-9-benzoyl-xy-6/3-methyl-3- The (1-methyl-4-phenylbutoxy) benzo] c] quinoline from 2-propanol was evaporated to a white foamy residue which was triturated with 500 ml of ether to give 12.9 g of a white solid melting at 129-132 ° C. This solid material was triturated twice more with ether to give 3.8 g of the title compound as a white solid, 5 g of benzoyl-9-benzoyloxy-6- [3-]. methyl 3- (1α-methyl-4-phenylbutoxy) benzofinquinoline, m.p. 139-141 ° C.

Preparation of dl-5,6,6a / 3,7,8,9a, 10,10a3-octahydro-1-acetoxy-9-hydroxy-6/3-methyl-3- (1/3-methyl-4- phenylbutoxybenzo [c] quinoline hydrochloride

To a stirred solution of lithium aluminum hydride (2.0 g, 5.3 mmol) in tetrahydrofuran (150 ml) was added dropwise a solution of 5.7 g (8.8 mmol) dl-5.6.6a / 2, 7.8, under nitrogen atmosphere over 5 minutes. 93,10,10aa-octahydro-1-acetoxy-5-benzoyl-9-benzoyloxy-6,3-methyl-3- (1,3-methyl-4-phenylbutoxy) benzo [c] quinoline in 112 ml tetrahydrofuran. The resulting mixture was heated to reflux for 45 minutes, then cooled and poured carefully into an ice-cold mixture of 1125 mL of 5% aqueous acetic acid and 2,250 mL of ether. The biphasic mixture was stirred for 10 minutes and the layers were separated. The aqueous layer was extracted with an additional 500 ml of ether, the combined ether extracts were washed successively with water (3 x 500 ml), saturated sodium bicarbonate (2 x 500 ml) and brine (500 ml), dried (MgSO4) and evaporated. 5.4 g of dl-5-benzyl-5,6,6a / 3,7,8,9a, 10,10aa-octahydro-1,9-dihydroxy-6/3-methyl-3- (1S-) are obtained. methyl 4-phenyloxybutoxybenzofinquinoline as a reddish oil.

dl-5-benzyl-5,6,6aS, 7,8,9a, 10,10a-octahydro-1,9-dihydroxy-6/3-methyl-3- (1/3-methyl-4-f) benzy [c] quinoline is immediately taken up in 450 ml of methanol and hydrogenated in the presence of 4.27 g of palladium on carbon for 3 hours at atmospheric pressure, after filtering off the catalyst and evaporating the methanol to give dl-5,6,6a / 3,7 8,9a, 10,10aa-octahydro-1,9-dihydroxy-6/3-methyl-3- (1/3-methyl-4-phenylbutoxy) benzo [c] quinoline dl-5,6,6a (3,7,8,9a, 10,10a) -octahydro-1,9-dihydroxy 6/3-methyl-3- (1S-methyl-4-phenylbutoxy) benzo [c] quinoline is immediately dissolved in 210 ml methylene chloride, the solution was cooled to 0 ° C under nitrogen, and 1.35 ml of triethylamine, 1.19 g (9.7 mmol of 4-dimethylaminopyridine) and finally 0.834 ml (8.8 mmol of acetic anhydride) were added gradually. The reaction mixture was poured into 250 ml of water and the organic layer was separated, and the aqueous layer was extracted once more with methylene chloride, the combined methylene chloride layer was separated. The reaction mixture was washed successively with saturated sodium bicarbonate solution (2.times.150 ml). sodium chloride, 150 ml of water and saturated sodium chloride solution, dried over magnesium sulphate and evaporated. Chromatography of the residue on 300 g of silica gel using 33% ether in toluene as eluent gave 1.4 g of dl-5,6,6a / 3,7,8,9a, 10,10aa-octahydro-1-acetoxy-9- hydroxy-6/1-methyl-3- (1/350

methyl-4-phenylbutoxy) benzo [c] quinoline in free base form. Reaction dl-5,6,6a) / 3,7,8,9a, 10,10aa-octahydro-1-acetoxy-9-hydroxy-6/3-methyl-3- (1,3-methyl-4-f) enybutoxy) benzofinquinoline in hydrogen chloride ether afforded 795 mg of dl-5,6,6a / 3,7,8,9a, 10,10aa-octahydro-1-acetoxy-9-hydroxy-6H-methyl-3 - (1,3-Methyl-4-phenylbutoxy) benzo [c] quinoline hydrochloride melting after filtration and trituration with acetone at 213-215 ° C.

Mass spectrum: m / e 437 (M ⁺ , 100%).

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

% C, 68.42;% H, 7.66;% N, 2.96.

H, 7.63; N, 3.05.

In an analogous manner, from 3.8 g of dl-5,6,6a / 3,7,8,9a, 10,10aa-octahydro-1-acetoxy-5-benzoyl-9-benzoyloxy-6/3-methyl- Of 3- (1-methyl-4-phenylbutoxy) benzo [c] quinoline gives 1.1 g of dl-5,6,6a / 3,7,8,9a, 10,10aa-octahydro-1-acetoxy-9- hydroxy-6-methyl-3- (1α-methyl-4-phenylbutoxy) benzo [c] quinoline hydrochloride melting at 202-205 ° C with decomposition.

Mass spectrum: m / e 437 (M ⁺ , 100%).

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

% C, 68.42;% H, 7.66;% N, 2.96.

H, 7.56; N, 3.04.

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2A denotes one and 2B the other of the two possible diastereomers in the Z-W side chain whose absolute stereochemistry has not yet been detected "left" or "left", respectively. 'Dextro' refers to the mixture of optical rotation (-) and (b) respectively. (+ 1

Claims (3)

Subject A process for the preparation of novel benzo [clquinolines of the general formula A wherein Q represents a group \ C = O or OF H OH R1 represents a hydrogen atom, an acetyl group or a piperidinobutyryl group, R 1 represents a hydrogen atom, a C 1 -C 6 alkyl group or a radical - (CH 2 Z 2 -C 6 H 5 where z is a number of 1 to 4, R 5 represents a hydrogen atom, a methyl group or an ethyl group, R 5 represents a hydrogen atom, a C 1 -C 2 alkyl group, a benzoyl group, an acetyl group or an isobutyryl group, Z represents an alkylene group having 1 to 9 carbon atoms or the radical _ (alki) _m -O- (alk ₂ ) _n -, wherein alki and alkz are the same or different and each represents an alkyl group of up to 9 carbon atoms and independently of one another always a value of 0 or 1, and I invent W represents a hydrogen- or phenyl group, and pharmaceutically acceptable salts thereof, characterized in that a compound of formula III in which: R 1, R 1, R 5, R 5, Z and W are as defined above, and the resulting compound is optionally converted to its pharmaceutically acceptable salt. 2. A process as claimed in claim 1, wherein the corresponding starting materials are used to form compounds of formula (A) wherein Q is a group. C = O Z and R 1, R 1, R 5, R 5, Z and W are as defined in point 1, and pharmaceutically acceptable salts thereof. 3. A process according to claim 1, wherein the corresponding starting materials are used to form compounds of formula (A) wherein Q is a group. H OH \ Z C Z 1 and R 1, R 1, R 5, R e, Z and W are as defined in point 1, and pharmaceutically acceptable salts thereof.