FI64141C - FREQUENCY REQUIREMENT FOR THERAPEUTIC THERAPEUTIC ACTIVATION OF BENZO (C) - Google Patents

Description

[B] _KUUUTUSJULKA.su ,,

Ma '' utlAggningsskrift o4l41 c (45) j * ^ --3 ^ (51) Ky.ik.3 / mt.ci.3 C 07 D 221/12 FINLAND — FINLAND (21) |, tt ,, 'ttlh' k, mu · -p «tMt» jekninj 771550 (22) Hikemispiivt - Ansekninpdag 16.05 77 (23) Initial Cloud - Glltlghettdig g γγ (41) Become Public - Blivlt offentllg g ^

National Board of Patents and Registration (44 \ Nihtivik * ip »non j» kuL | ulk »i * un pvm. -, Γι,

Patent and registration authorities Ansöksn utlagd och utUkrHten publicsnd ou.ub. oj (32) (33) (31) Privilege claimed — Begird priority i7.O5.76 22.12.76, 15.03.77 USA 687332, 753619, 777928 (71) Pfizer Inc., 235 East U2nd Street, New York , New York, IJSA (US) (7 <.) Michael Ross Johnson, Gales Perry, Connecticut, USA (UG).

The present invention relates to a process for the preparation of new benzo / c / quinolines, and in particular to 1,9-benzo / c / quinolines. This invention relates to a process for the preparation of new benzo / c / quinolines, and in particular to 1,9. -dihydroxyoctahydrobenzo [c] quinolines and their derivatives useful as central nervous system (CNS) agents, in particular as analgesics and sedatives, as antihypertensive agents in animals, including humans, as greening agents and as therapeutic agents for greenery.

These new therapeutically active benzo / c-7-quinoline derivatives have the formula I

0Ri sJwL (I)

R / I

o R.

D

2 6 414 "· wherein R is hydroxy or alkanoyloxy of 2 to 6 carbon atoms is hydrogen, alkanoyl of 2 to 6 carbon atoms or -CO- (C 1-4), where p is an integer from 1 to 4; R 0 and form a bond to them with nitrogen A 5- or 5-membered saturated cyclic amine group; is hydrogen or alkyl having 1 to 6 carbon atoms; R 1 is hydrogen, methyl or ethyl; R 1 is hydrogen, alkanoyl having 2 to 6 carbon atoms,

O

Alkyl of 1 to 6 carbon atoms or - (CH 2) -C 1 H 2 or -CO (CH 2) wherein x is an integer from 1 to 4; Z is alkylene of 1 to 9 carbon-2 x -16 'or -O- (alk) -, wherein (alk) is alkylene of 1 to 9 carbon atoms; and W is hydrogen, methyl or phenyl.

An acceptable alternative designation for the compounds described herein is based on the replacement of the strain "benzo / c7quinol.ine" with "phenanthride". Thus, d, 1-trans-5,6,6a β-, Ί, 8,9,10,10ac? -Octahydro-1-acetoxy-9β-hydroxy-5,6-methyl-3- (5-phenyl- 2-Pentyloxy) -benzo / jc_7 The quinoline is d, 1-trans-5,6,6a / g, 7,8,9,10,10a? -Octa-hydro-1-acetoxy- 9,5-hydroxy-6,6-methyl-3- (5-phenyl-2-pentyloxy) -phenanthridine.

Although numerous painkillers are available today, the search for new and better agents continues. This indicates the lack of a substance that is effective over a wide range of pain with minimal side effects. The most widely used substance, aspirin, is not effective for severe pain and is known to be associated with a variety of unwanted side effects. Other more effective analgesics, such as d-propoxyphene, codeine, and morphine, are addictive. Thus, the need for better and more effective analgesics is obvious.

Pain and palliative properties of 9-nor-9/6-hydroxyhexahydrocannabinol and other cannabinoid structures such as Δ -tetrahydrocannabinol (Δ -THC) and its g-primary metabolite, 11-hydroxy-Δ-THC have been described by Wilson and May, Absts. Papers, Am. Chem. 3cc., 168 Meet., MEDI 11 (1974), J. Med. Chem., 17 (1974) 475-476 and J. Med. Chem., 18 (1975) 700-703.

U.S. Patent Nos. 3,507,885 and 3,636,058 describe a variety of 1-hydroxy-3-alkyl-6H-dibenzo [b, d] pyrans having oxo, hydrocarbyl and hydroxy or chlorine, hydrocarbylidene substituents at the 9-position, and intermediates thereof.

CS Patent 3,649,650 describes a number of tetrahydro-6,6,9-trialkyl-6H-dibenzo-3,644 '/ b, d7pyran derivatives having a 60-dialkyl Liam in the 1-position as a mental therapy. no-alkoxy.

DE 2 451 934 has the lowest antihypertensive effect; '. 1,9-dihydroxyhexahydrodibenzo [b] d7pyrans and some of their 1-acyl derivatives having an alkyl or alkylene group in the 3-position described as psychoactive, sedative and analgesic. The precursors used in their preparation, hexahydro-9H-dibenzo [b] d7pyran-9-ones, which have been reported to be as useful as the corresponding 9-hydroxy compounds, are described in DE-A-2 451 932.

U.S. Patent No. 3,856,821 describes a group of 3-initial-substituted dibenzo [b, d] pyrans that are effective in arthritis, inflammation, and the central nervous system.

Bergel et al., J. Chem. Soc. , 286-287 (1943) investigated the replacement of the 3-position pentyl group of 7,3,9,1 u · tetrahydro-3-pentyl-6,6,9-trimethyl-6H-dibenzo [b, d] pyran-1-ol with alkoxy (butoxy ., a, peryloxy, hexyloxy and octyloxy) and found this to lead to biological inactivity. The hexyloxy derivative was reported to have a mild hashish effect at a dose of 10-20 τ.η / kv. Other ethers were not active even at doses of 20 mg / kg.

In a more recent study, Loev et al., J. Med. Chem., 16 (1973) 1200-1206 compare 7,8,9,10-tetrahydro-3-substituted-6,6,9-trimethyl-6H-dibenzo [B, d] pyran-1-ols with 3-substituents. supported by -OCH (CH3) C5K11, -CH2CH (CH3) C8H or -CH (CH3) C5K.

The potency of the compound containing the ether side chain, i.e., with respect to the central nervous system, is 50% lower than that of the corresponding compound whose alkyl side chain is directly attached to the aromatic ring without a mediating oxygen atom, and five times more potent than the compound replaced by methylene.

Koop et al., J. Org. Chem., 33 (1968) 2995-2996 describes the preparation of the 5-aza analog of? 6a ('Oa) -tetrahydrocannabinol, which they call 7,8,9,10-tetrahydro-1-hydroxy-5, 6,6,9-tetramethyl to 1 to 3-n-pentyl ifenanthridine, but do not mention the utility of the compound. Beil in "Psychomimetic Drugs," ed. Anu. Efron, Raven Press, New York, 1970, p. 336 mentions that the compound was completely ineffective in animal pharmacology.

Hardman et al., Proc. West. Pharmacol. Soc., 14 (19 71) 14--20 report 7,8,9,10-tetrahydro-1-hydroxy-6,6,9-trimethyl-3-r-644,141 with pentylphenanthridine, a 5-aza-α -tetrahydrocannabinol has some pharmacological effect.

Mechoulam and Edery, in "Marijuana," edited by Mechoulam, Academic Press, New York, 1973, p. 127, found that major structural changes in the tetrahydrocannabinol molecule appear to lead to a sharp decrease in analgesic efficacy.

Paton, Annual Review of Pharmacology, 15 (1975) 192 provides an overview of the effect of cannabinoid structure. The presence of the necessary dimethyl group in the pyran ring is critical for cannabinoid potency, and replacement of oxygen with nitrogen in the pyran ring eliminates the potency.

It has now been found that certain benzo [c] quinolines, namely 1,9-dihydroxyoctahydro-6H-benzo [c] quinolines (I), are effective CNS agents, in particular as analgesic, sedative and antihypertensive agents which are non-narcotic and non-addictive. and as urinary excretion enhancers. In addition, the present invention encompasses various derivatives of these compounds that are useful dosage forms, as well as intermediates thereof. The above compounds and their derivatives are of formula I. The compounds of formulas II and III are precursors of the compounds of formulas II and I. The preparation of compounds of formula II is described in this application by division 820,202.

HR R O

> C 1 jj 8 f 9> 0 0¾ "1 9 * 1 i I] 9 * 1

TJjoX

* 6 (I) (II) (III)

In the above formulas, the substituents R 1, R 2, R 2, R 2, R 2,

Rj, Rg, Z and W have the same meaning as above.

The present invention also includes pharmaceutically acceptable acid addition salts of the compounds of formula I. Examples of such salts are mineral acid salts such as hydrochloride, li 5 64141 hydrobromide, sulphate, nitrate and phosphate and salts of organic acids such as citrate, acetate, sulphosalicylate, tartrate, gluconate, malonate, maleate, fumarate-3-hydrate, 2-hydrate , pamoate, salicylate, stearate, phthalate, succinate, gluconate, mandelate, lactate and methanesulfonate.

The compounds of formulas I, II and III above have centers of asymmetry at the 6a and / or 10a position. Additional asymmetric centers may be present at the 3-position substituent (-Z-W) and at the 5-, 6-, and 9-positions. In general, diastereomers with a 9/6 structure are more preferred than 9i * isomers because they have (quantitatively) higher biological potency. For the same reason, the trans (6a, 10a) diastereomers of the compounds of formula I are generally more preferred than the cis- (6a, 10a) diastereomers. Compounds of formula II in which either or R 1. is other than hydrogen, cis diastereomers are more preferred due to their higher biological potency. One of the enantiomers of a given compound is generally more preferred than the other and the racemate due to its greater biological potency. The preferred enantiomer can be determined by the methods described herein. E.g.

5,6,6α, 7,8,9,10,10ack-octahydro-1-acetoxy-9β-hydroxy-6H-methyl-3- (5-phenyl-2-pentyloxy) -benzo [c] quinoline 1-enantiomer is more preferred than the d-enantiomer and the racemate due to its greater analgesic potency. For simplicity, the above formulas represent racemic compounds. However, the general formulas set forth above are also considered to include racemic modifications, diastereomeric mixtures, pure enantiomers, and diastereomers of the compounds of this invention. The utility of racemic mixtures, diastereomeric mixtures, and pure enantiomers and diastereomers can be determined by the biological methods described later.

Due to their higher biological potency compared to the other compounds described herein, those compounds of formula I are preferred in which R 1 is hydrogen or alkanoyl, R 1 is hydrogen, methyl or ethyl, R 1 and R 8 are hydrogen or alkyl and Z and W are as follows: 6 64141! ! ~~ Ί, ζ i w ι ι --1-1: alkylene containing 5-9 carbon atoms j H or CH-,!

(Alkylene containing 2 to 5 carbon atoms

I .65; —O- (alk) -I C, Hr i I! o 3;

: -O- (alk) -J H or CH 1

; _ι__i

Preferred compounds of formula I are those Preferred compounds described above wherein R is hydroxy and has a trans structure.

Particularly preferred compounds of formula I are those wherein R is hydroxy; is hydrogen or acetyl; R 2 is hydrogen; is methyl or propyl; Rg is hydrogen, methyl or ethyl; when Z is alkylene of 2 to 5 carbon atoms, W is phenyl; when Z is -O- (alk) -, wherein (alk) is alkylene of 4 to 9 carbon atoms, W is hydrogen or phenyl; and when Z is alkylene of 5 to 9 carbon atoms, W is hydrogen.

The process according to the invention is characterized in that a) a compound of the formula II1 0 ij Γ t .; 'No'; —Z_w R_ Γ ^ o R6 wherein, R1, Rg, Rg, Z and W are as defined above, is reduced by reacting it with a metal hydride, or

b) a compound of formula III

0

X

'll Γ h j. ι (III) * ‘5 |

R

II

6 7 641 41 wherein R 1, R q, R 9, Z and H are as defined above is reduced by catalytic hydrogenation and, if desired, acylated at the 1- and / or 9-position to give a compound in which R and R 4 do not represent hydrogen, and, if desired, preparing a compound in which R 1 is not hydrogen, reacting a compound in which R 1 is hydrogen with formaldehyde or an alkyl or acyl halide, and, if desired, reducing the compound thus obtained to an alkali metal borohydride to give a compound in which R 8 is alkyl or phenylalkyl, and if desired converted to an acid addition salt.

Compounds of formula I in which Rg is other than hydrogen

alkyl or - (CH_) -C-H-, may be modified if desired

2x65 compounds wherein Rg is hydrogen, alkyl or - () -C8H.

In the preparation of compounds of formula I, compounds of formula V and of course formulas V-A, V-B and V-C are converted to exemplary compounds of formula I according to the following series of examples (Reaction Scheme A) (in the example R ~ = H).

641 41 8

Reaction scheme Ά

OH O O OH O OH

ιοΛ

W-Z / A \ ^^ v'N '^' R4 r4 ^ Z-W

(V) jj CH0 (VI)

CH 3 CO-CH = CH? base, CH 2 OH

Λ \

Il fH 1 u f

Tl ^ L / Öök L \ 1

H CHO

(m), (VII) E + 1,3-bisformyl-

Li / NH-, H, / kata derivative (VII-A) J

N / or X ^ iyysi ji x.

OH H | "iiisL ->

r / Nj ^ nx ^ z-w r4 * f Z-W

1H H (n) / + - cis-isomer7 (I)

The quinolines of formula V are converted to the hydroxymethylene derivatives of formula VI by reacting them with ethyl formate and sodium hydride. In this formylation reaction, the bis-formylated derivative (VI) is formed in excellent yields.

li 9 64141 Treatment of the bis-formylated derivative with methyl vinyl ketone gives a mixture of the corresponding mono-N-formylated Michael adduct (VII) and 1,3-bis-formylated Michael adduct. Both products can be conveniently separated by column chromatography on silica gel.

Conversion of compounds of formula VII to compounds of formula III is accomplished by aldol condensation of a mono-N-formyl compound of formula VII. In this case, the 1,3-bis-formylated Michael adduct is formed as the main product spiro-annelation product (III-A). But a compound of formula VII-A can be converted to a compound of formula VII by treating with an equivalent amount of potassium carbonate in methanol.

(VII-A) (III-A) 0

0 OH 0 OH

LAA - LAAA h-A created A fol

H Z-W

CHO H

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

The enone of formula III is converted to the compound of formula II by Birch reduction. Both the cis and trans isomers are formed. This reduction is conveniently done with lithium metal.

Sodium or potassium may also be used. The reaction is carried out at a temperature between about -35 ° C and about -80 ° C. Birch reduction is preferred because it is stereoselective and the desired trans-ketone of formula II is formed as the major product. Catalytic reduction with a noble metal is recommended if desired as the major product cis diastereomers.

The hydroxyketones of formula II (compounds in which Rq is oxo and Rj1 is hydrogen) and the dihydroxy compounds of formula I (R = OR · ^ = OH) appear to be quite unstable. When standing, they oxidize, as evidenced by a color that varies from purple to red. Colored by-products are formed even upon reduction of the hydroxy ketone with sodium borohydride. It has been found that the formation of colored by-products can be prevented by acylation and in particular by acetylation of the 1-hydroxyl group (OF 4) with acetic anhydride in pyridine and the formation of acid addition salts, for example the hydrochloride. Lethyl derivatives, when standing, are also stable in the extended ring.

The above-mentioned colored by-products are believed to have a kincr.oid structure due to the oxidation of the 1-hydroxy group (0Ρ.Ί) to the cesex and the incorporation of another o2zo group into its 2- or 4-arms. The by-products are themselves effective CNS substances, in particular as analgesics and sedatives and antihypertensives, and are used in the same way and at the same dosage level as the compounds of the formula I.

Reduction of the 9-oxo group of the compounds of formula II and preferably the acetylated derivative of the formula II metal hydride 11a for the reasons of stability mentioned above gives compounds of the formula I in which the hydroxyl group in the 1-position is in the form of its acetated derivative. At this stage, sodium borohydride is the preferred reducing agent because it not only produces the desired product in satisfactory yields, but retains the acetoxy group in the 1-position and reacts slowly enough with hydroxyl solvents (methanes, ethanol, water) to allow their use as solvents. The temperature is usually about 0 ° to about 30 ° C. Lower temperatures, up to about -70 ° C, can be used to improve the selectivity of the reduction. Higher temperatures cause sodium borohydride to react with the hydroxyl solvent and deacetylate. If higher temperatures are desired or a certain reduction is required, isopropyl alcohol or diethylene glycol cimethyl ether is used as the solvent. Potassium tri-sec-butyl borohydride is the preferred wood fiber because it promotes stereoselective formation of the 9C-hydroxy group. The reduction is performed in dry tetrahydrofuran at a temperature below about -50 ° C using equimolar amounts of the 9-oxo compound and the reducing agent.

Reducing agents such as lithium borohydride and lithium aluminum hydride require anhydrous conditions and hydroxyl-free solvents such as 1,2-dimethoxyethane, tetrahydrofuran, ether or dimethyl ether of ethyl ether glycol.

Alternatively, and more preferably, the compounds of formula III, and in particular those in which the 1-hydroxy group is protected as an ester or a polycotor, are converted to the compounds of formula I by catalytic hydrogenation. In a suitable process, the catalyst is hydrogenated with or without palladium, for example palladium on carbon or another noble metal support.

The acetylated derivatives of formula I thus formed are converted into the corresponding hydroxy derivatives by cleavage of the acetyl group by standard methods.

The following intermediates are useful in the preparation of the starting materials (V) (VI) 0 0 * 1 HO O 0Y7 'used in the process of the invention! A lv il 1 ^ V / j L, _ jOj.

RS I, V j

Rr 6 (VII) 60; i and 0 OY, r4 ^ Y ^ z-w R5 R7 wherein R4, Rg, Rg and Z-W have the same meaning as above, R? is hydrogen or formyl and is a hydrogen or hydroxy protecting group, especially methyl, ethyl or benzyl.

The intermediates of formulas V, VI and VII may have centers of asymmetry at the 2-position and the 7-position substituent (-Z-N) and, of course, at other positions, for example in the 1-position substituent. The 2- and 7-positions of the compounds of formulas V-VII correspond to the 6- and 3-positions of the compounds of formulas I, II, III and IV.

Compounds of formula V are prepared from appropriately substituted anilines, for example 3-hydroxy-5- (Zw-substituted) anilines (VIII) or derivatives thereof, in which the 3-hydroxy group is protected by a group (Y 1) which is easily removed to restore the hydroxy group . Suitable protecting groups do not interfere with the further reactions of said 3- (protected hydroxy) -5-substituted anilines and can be removed under conditions which do not cause undesired reactions at other sites of said compound or in products made therefrom. ^) are methyl, ethyl, benzyl, substituted benzyl, in which the substituent is, for example, alkyl having 1 to 4 carbon atoms, halogen (Cl, Br, F, I) or alkoxy having 1 to 4 carbon atoms.

The exact chemical structure of the protecting group is not critical to the present invention, but its ability to function as described above is important.

The expert can easily select and identify suitable protecting groups. The suitability and potency of the group as a hydroxy protecting group is determined using this in the reaction sequence described above. Thus, it must be a group that is easily removable to restore the hydroxy groups. Methyl is preferred as the alkyl protecting group because it is readily removed by treatment with pyridine hydrochloride. The benzyl group is also a preferred protecting group which can be removed catalytically by hydrogenation or acid hydrolysis.

When Z is -O- (alk) -, it is preferably a benzyl or substituted benzyl group, since it can be subsequently removed without interfering with the group Z.

The protected aniline derivative (VIII) is converted to a compound of formula IX by the prior art described herein. The following Reaction Scheme B shows a truncated reaction sequence for the preparation of compounds of formula V starting from 3- (protected hydroxy) -5- (Z-W-substituted) -aniline (VIII) wherein -Z-W is OCH 2: 11 13 41 41

Reaction Scheme B: (VIII) (IX) 0 OCR., II OCH-, I 3 II o [3 JL R4-C-CH2COQ R ^ COOR ° C)] HOAo * JOj 1 CH3CT ^ NH2 CH3O

B

j r4r5c = ch-coor ° / or / Xs \ ^ 4 ~ coch2coor ° H2 / \ + NaCNBH4 v / (V-A) / Ni (X) / OCH 0 OCH ^ / I (1) ClCOOC-Hq

/ 0H "Λ ^ co ° R

/ ACX <- <3i-p-AA

/ CH3O I R4 CH3O4R4 / COOC2H5 H (R5 = H) \! HBr- / 7 HBr- \! HO Ac / HO Ac \ 1 / (V-B) \ (V-C) OH O OH 0

Br- (alk2) n-ws Jv / L

FoY 'l koh (pj j HO ΆίR W- (alk0) -0 A "Ar \ jR-

I I

H H

In Reaction Scheme B, R 0 is alkyl of 1 to 6 carbon atoms. (By way of example, in the general reaction scheme, hydrogen is present, but in Step VIII-^ X or VIII- ^ V-3 R ^ may be hydrogen, methyl or ethyl).

i4 6 41 41

The 5-substituent of the compounds of formula VIII may be a desired group of a compound of formula I or II, or a group which can be readily converted to that desired group. When the z part of the group -Z-W is -O- (alk) -, the 5-substituent is an OH group or a protected OR group when W is hydrogen.

Suitable 3-hydroxy-5-substituted anilines are preferably reacted as a derivative in which the 3-hydroxy group (and any 5-hydroxy group present) is protected as described above to give satisfactory reactions with alkyl β-ketoesters, e.g. alkylacetoacetate. with, in the presence of acetic acid, to give the corresponding (5- (J3-protected hydroxy) -5-substituted anilino-7 ', P (R) acrylate (IX). The reaction is carried out in a reaction-inert solvent such as benzene or toluene at a temperature between about 50 ° C and the reflux temperature of the solvent under conditions in which the by-product water is removed from the reaction mixture.

Benzene and toluene are effective solvents when the reaction is carried out at reflux temperature because they allow the azeotropic removal of water formed as a by-product. Other means of dewatering can be used, such as molecular sieves, as can other solvents suitable for azeotropic dewatering.

Preferred protecting groups for 3-hydroxy-5-substituted anilines are methyl, ethyl and benzyl because ethers are readily prepared to give compounds of formulas IX and X in satisfactory yields and which are then deprotected by conventional means.

An alkyl-β-keto ester, preferably one having 1 to 6 carbon atoms in the alkyl group, is generally used in excess to ensure maximum conversion of the reactive aniline to the corresponding alkyl-anilino-β- (R 2) -acrylate (IX). To achieve a satisfactory conversion, an excess of 10-20% alkyl β-ketoester is usually used. Catalytic amounts of acetic acid are used to promote the reaction.

The alkyl p-anilino-β- (R 1) -acrylate (IX) is then reduced to the corresponding alkyl 3- (13-protected hydroxy) -5-substituted anilinoyl-3- (R 4) -propionate (X) with, for example, sodium borohydride-acetic acid and catalytic hydrogenation. The preferred catalyst is platinum dioxide because it allows the reaction to be carried out at low pressure, for example below 3.5 kp / cm. Can be used for other l! 15 641 41 catalysts, for example noble metals such as platinum, palladium or rhodium with or without supports and hydrogen pressures from about normal pressure to overpressure, for example 140 kp / cm. In addition to these heterogeneous catalysts, homogeneous catalysts such as Wilkinson's catalyst, tris- (triphenylphenyl) chlorodhodium (I) can be used.

When the protecting group or groups are benzyl or substituted benzyl, catalytic hydrogenation also removes them. Therefore, methyl and ethyl groups are the preferred protecting groups for the 3- and / or 5-hydroxy groups of the reactants of formula VITI.

Alternatively, compounds of formula X may be prepared directly from compounds of formula VIII by reacting compounds of formula VIII with alkyl 3,3-R 2 R 2 acrylate in acetic acid. The reaction is conveniently carried out by reacting equimolar amounts of alkyl 3,3-R 4 R, acrylate and disubstituted aniline (VIII) in 0.1 to 2 equivalents of glacial acetic acid at a temperature between 0 ° C and reflux temperature.

Alternatively, compounds of formula V-B can be prepared directly by condensing equimolar amounts of compounds of formula VIII and the appropriate substituted acrylic acid (R 1 R 2 C = CK-COOH) in pyridine hydrochloride at 150 ° C to 200 ° C.

When both R 1 and R 2 represent alkyl, a compound of formula X is also obtained by treating a compound of formula VIII and alkyl R 4, R 1 acrylate with a mercury acetate in a reaction inert solvent such as tetrahydrofuran, followed by reduction with sodium borohydride.

Direct conversion of compounds of formula VIII to compounds of formula X may also conveniently be accomplished by treating 3,5- (disprotected hydroxy) aniline hydrochloride with an excess of alkyl acetoacetate, for example ethyl acetoacetate, in the presence of sodium cyanoborohydride in a solvent, for example methanol.

The alkyl 3-anilino-3- (R 1) -propionate (X) is then cyclized to the corresponding 2- (R 1) -quinolin-4-one (Formula VA or -B) with a suitable cyclizing agent such as polyphosphoric acid (PPA), with hydrobromic acetic acid, sulfuric acid, oleum (fuming sulfuric acid), hydrogen fluoride, trifluoroacetic acid, phosphoric acid formic acid or other cyclizing agents known to the person skilled in the art. In this variation, the alkyl 3-anilino-3- (R 1) -propionate (X) can be converted to the corresponding acid, for example, by saponifying the i6 641 41 ester and acidifying it before cyclization.

The ether protecting groups of the 3- (and 5-) hydroxy groups can be removed during cyclization by using hydrobromic acid in acetic acid as the cyclizing agent. A 43% aqueous hydrobromic acid solution is generally used because it achieves satisfactory cyclization and deprotection. The reaction is carried out at an elevated temperature, preferably at reflux temperature. But when Z is -O- (for example, polyphosphoric acid or trifluoroacetic acid should be used in the cyclization of the embryo so that the ether is not cleaved to form a thioether bond.

Alternatively, the protecting group (or groups) may be removed after the cyclization reaction. At this stage of the overall synthesis, hydrobromic acid-acetic acid is also the preferred deprotecting agent. The reaction is carried out as described above.

Other reagents such as hydroiodic acid, pyridine hydrochloride or hydrobromide can also be used to remove ether protecting groups such as methyl and ethyl groups. The protecting groups benzyl or substituted benzyl can be removed from the catalytic hydrogenation. Suitable catalysts are palladium and platinum, especially on carbon. Alternatively, they can be removed by preferred hydrolysis with trifluoroacetic acid.

In a preferred process for converting compounds of formula X to compounds of formula V in satisfactory yields and using relatively mild conditions, compounds of formula X are converted to N-carbalkoxy derivatives having 2 to 5 carbon atoms in the N-carbalkoxy group by reacting them with a suitable alkyl or benzyl chloride with. The N-carbalkoxy or carbobenzyloxy derivative of formula X is cyclized with polyphosphoric acid to the corresponding N-carbalkoxy or carbobenzyloxy derivative of the compound of formula V. If desired, N-substituted derivatives of compounds of formula X may be hydrolyzed prior to cyclization to the corresponding 3- (1N-substituted) -3- (protected hydroxy) -5-substituted anilino-3- (R) -propionic acid. Polyphosphoric acid generally achieves maximum cyclization and is a preferred cyclizing agent.

Compounds of formula V in which the hydroxy group or groups are protected and the nitrogen atom is substituted by carbalkoxy are treated with hydrobromic acid-acetic acid to give compounds of formula V-A. When the hydroxy protecting group or groups are benzyl or substituted benzyl, the hydroxy groups are regenerated by

II

17 641 41 by hydrogenation. In this reaction, the possible carbalkoxy group of the nitrogen atom does not change. If desired, it can be subsequently removed by treatment with hydrobromic acid-acetic acid or an acid or base. Removal of the benzyl protecting group with trifluoroacetic acid also removes any N-carbalkoxy group.

When the substituent -ZW of the compounds of formula V is -OH and it is desired that in the compounds of formula II or I said substituent -ZW is a group -O- (alk) -W, where W is as defined above, conversion of the group -OH to a group -O- (alk) -W occurs conveniently and preferably at this point in the overall reaction sequence. Thus, in the Williamson reaction, the 7-OH group of the compound of formula V-B is converted to the group -O- (alk) -w (formula V-C) by the appropriate bromide ^ Br- (alk) -Matila, mesylate or tosylate.

Similarly, a group of the compound of formula V -Z-W 0 O

when - (alk) -X-H, its conversion to the group -X- (alk) -W, where W is other than hydrogen, conveniently occurs at this stage of the reaction sequence by the Williamson reaction.

Various groups, for example those defined for R 9, may be used in place of carbalkoxy or carbobenzyloxy in this preferred method of protecting nitrogen against protonation.

If the group Rg is absent in the compounds of formulas V-A, V-B or V-C, it can be incorporated before reacting the hydroxymethylene derivative (formula VI) by reacting with a suitable Cl-Rg or Br-Rg reactant by known methods. If the compounds of formula I or II are desired as the group Rg is an acyl group, for example an acetyl group, this is generally introduced at the point in the reaction sequence (reaction scheme B) in which the compounds of formula II in which Rg is hydrogen are formed, for example by acylation with a suitable acyl halide.

Esters of compounds of formulas II-IV with alkanoyl or -CO- (CH 2) p -NR 2 R 3 are readily prepared by reacting compounds of formulas II-IV with a suitable alkanoic acid or an acid of formula HOOC- (CH 2) p -NR 2 R 3. such as dicyclohexylcarbodiimide. Alternatively, they are prepared by reacting a compound of formulas II-IV with a suitable alkanoic acid chloride or anhydride, for example acetyl chloride or acetic anhydride in the presence of a base such as pyridine.

Esters of compounds of formula I in which the groups R and 18 641 41 are esterified are prepared by acylation according to the methods described above. Compounds in which only the 9-hydroxy group is acylated are obtained by mild hydrolysis of the corresponding 1,9-diacyl derivative, with the advantage of easier hydrolysability of the phenolic acyl group.

Compounds of formula I in which only one 1-hydroxy group is esterified are obtained by reduction of the corresponding ketone of formula II esterified in the 1-position with borohydride. The compounds of formula I thus formed having a 1-acyl-9-hydroxy or 1-hydroxy-9-acyl substituent can then be further acylated with a different acylating agent to give a di-esterified compound of formula I in the 1- and 9-positions. there are different ester groups.

The presence of a base group in the ester moiety (OR 2) of the compounds of this invention allows the formation of acid addition salts containing said base group. In preparing the basic esters described herein by condensing the appropriate amino acid hydrochloride (or other acid addition salt) with the appropriate compound of formulas I-IV in the presence of a condensing agent, the hydrochloride salt of the basic ester is formed. Careful neutralization gives the free base. The free base can then be converted to other acid addition salts by known methods.

As will be appreciated by those skilled in the art, acid addition salts may, of course, be formed with the nitrogen of the benzo / c / quinoline system. Such salts are prepared by standard methods. Of course, basic ester derivatives can form mono- or diacid addition salts due to their dibasic nature.

The analgesic properties of the compounds of this invention can be determined by experiments using pain-inducing thermal stimuli, e.g., the mouse tail-twitch method, or pain-inducing chemical stimuli, e.g., by measuring the ability of a compound to reduce phenylbenzoquinone-induced vibration in a mouse. These and other experiments are described below.

Experiments with painful thermal stimuli a) Experiments to relieve hot plate pain in mice

The method is modified by Woolfe and MacDonald, J. Pharmacol.

Εκρ. Ther., 80 (1944) 300-307. The feet of the mice are subjected to a thermal stimulus controlled by a 3.2 mm thick aluminum plate. There is a 250 V7 infrared reflector lamp under the aluminum plate. A temperature controller connected to the surface of the plate surface adjusts the heating lamp to a constant temperature of 57 ° C. Each mouse is dropped into a 19 6 41 4 1 glass cylinder (16.5 cm in diameter) on the hot plate and the time is calculated from the time the mouse feet touch the plate. Half an hour as well. two hours after treatment with the test compound, the first "jerk" movements of one or both hind legs of the mouse are observed or until 10 seconds have elapsed without such movements. The maximum potency MT ~ q of morphine is 4-5.6 mg / kg (subcutaneously).

b) Tests to relieve tail pain in the mouse

Mouse tail experiments have been modified by D'Amour and Smith, J. Pharmacol. Exp. Ther., 72 (1941) 74-79 by applying controlled, intense heat to the tail. Each mouse is placed in a suitably narrow space with the tail of a metal cylinder protruding from one end thereof. The cylinder is mounted so that it rests directly on the covered heating lamp. At the start of the test, the Aluminum plate on top of the lamp is pushed aside, focusing the light beam through the gap at the end of the tail. At the same time, the time clock starts. Determine the time delay for the sudden jerk of the tail. Normally, untreated mice respond 3-4 seconds after lamp alignment. The end point of the protection is 10 seconds. Each mouse is tested for one and a half hours after treatment with morphine and test compound. The? 2, -0 of morphine is 3.2-5.6 mgAg (dermal al2e). Experiments with painful chemical stimuli Reduction of phenylbenzoquinone vibration

Groups of five Carwort Farms CF-1 mice were treated subcutaneously or orally with saline, morphine, codeine, and test compound. Twenty minutes (if administered subcutaneously) or fifty minutes (if administered orally) later each, the group was injected intraperitoneally with phenylbenzoquinone, which is known to cause abdominal cramps. Mice were observed for five minutes. ^ After this time, the stimulus injection either caused or did not cause vibration. The est, -g values of the anti-vibration of the drug pretreatment were determined.

The results of the experiments described above were expressed as percentage maximum power (% MT). The% MT values for each group were statistically compared to the% MT values obtained from the standard and control values before medication.5 MT was calculated as follows:% MT = trial time - control time χ 100 end time - control time

In the tables below, the analgesic effect is expressed as MTjjq values, where MT ^ q is the dose at which half of the maximum possible analgesic effect is observed in a given experiment.

The compounds of the present invention are effective analgesics when administered orally and parenterally, and are most conveniently administered in the form of a composition. Such compositions will contain a pharmaceutical carrier selected depending on the mode of administration and standard pharmaceutical practice. The compositions may be administered, for example, as tablets, pills, powders, or granules, which may contain as excipients starch, milk sugar, and certain types of clays. They can be administered as capsules mixed with the same or similar excipients. They may also be administered orally in the form of suspensions, solutions, emulsions, syrups and elixirs, which may contain flavoring and coloring agents. For oral administration as the medicaments of the present invention, tablets or capsules containing from about 0.01 to about 100 mg are most suitable.

The physician will be able to determine the most appropriate dosage for each patient, depending on the the age, weight and condition of the patient and the route of administration. In general, the initial analgesic dose for adults may be 0.01 to 500 mg in one or more daily doses. In many cases, the daily dose of 100 mg must be exceeded. The preferred oral dose is about 0.01 to about 300 mg / day and the recommended dose is about 0.10. 50 mg / day. The preferred parenteral dose is from about 0.01 to about 100 mg / day and the recommended from about 0.01 to about 20 mg / day.

The methods described above can be used to determine the analgesic efficacy of various compounds of this invention and certain prior art compounds.

Abbreviations used in Table I: PBQ = vibration caused by phenylbenzoquinone, TF = tail jerk, HP = hot plate.

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Their antihypertensive utility was determined by their ability to lower the blood pressure of conscious hypertensive rats and dogs at a statistically significant level when orally administering the above doses to said subjects.

Their sedative effect was demonstrated by oral administration to rats of about 0.01 to 50 mg / kg, followed by a decrease in immediate motor activity. The daily dose for mammals is about 0.01 to about 100 mg.

The possible dependence of the pain-numbing compounds according to the invention was investigated by determining the inhibitory effect of benzo / c / quinolines on the binding of JH-dihydromorphine to opium drug receptors in rat brain. The study was performed according to the method described in Pasternak, et al., Molecular Pharmacology, 11 (1375) 340-341. Highly inch 1-phenol tartrate and morphine sulfate, both of which are addictive, were used as controls.

Test compounds were administered to rats as a solution containing 2% ethanol. Based on the results obtained, which are shown in Table II, it was found that the compounds -4 of the invention did not have (at a concentration of 10 M) a pharmacologically detectable activity similar to that of opioid drugs. All of the compounds studied were inactive as binders of opium weathering receptors, so they are not addictive. The negative inhibition values obtained for some compounds are irrelevant and are within the experimental error limits of the experiment.

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er / <£ L <Cl cg, _'_ j 27 6 4 1 4 1 The use of these compounds in the treatment of colic is believed to be due to their ability to lower intraocular pressure. Their effect on intraocular pressure was determined in dog size!} La. The test drug was instilled into the dog's eye as a solution or administered systematically at varying intervals, after which the eye was anesthetized by instilling two drops of 1/2% tetracaine hydrochloride. A few minutes after this local anesthesia, the intraocular pressure was measured with a Schiotz mechanical tonometer and, after the addition of fluorescein, with a Holberg manual tonometer. A suitable solution of the test drug consists of 1 mg of the test drug, 0.05 ml of ethanol, 50 mg of Tween 30 (a polyoxyalkylene derivative of sorbitan monooleate, manufactured by Atlas Powder CO., Wilmington, Delaware 19,899) and 1 ml of saline, or a more concentrated solution of 10 mg. 0.10 ml, 100 mg and 1 :: 1. For human use, the concentration is 0.01 to 10 mg / kg of drug.

Their efficacy as urinary excretory agents was determined according to the method of Lipschitz et al., J. Pharmacol., 79, 97 (1943) using rats as experimental animals. In this case, the dosage range is the same as when using the compounds described above as analgesics.

The compounds of the invention may be used in pharmaceutical compositions and unit dosage forms. As already mentioned above, the administration can take place in one or more doses. to achieve the daily dose effect of the case.

The compounds described herein may be formulated for oral or parenteral administration in solid or liquid form. Capsules containing these compounds are prepared by mixing one part by weight of active ingredient and nine parts of excipient, for example starch or milk sugar, and adding the mixture to gelatin capsules, each capsule containing, for example, 100 parts of mixture. Tablets containing compounds of formula I are prepared by formulating suitable mixtures of the active ingredient with the standard ingredients used in the manufacture of tablets, for example starch, binders and lubricants, each tablet containing 0.01 to 100 mg of active ingredient / tablet.

Suspensions and solutions of these active ingredients, in particular those in which wound I has hydroxy, are generally prepared just before use in order to avoid storage stability problems (e.g. oxidation) or stability problems of suspensions or solutions (e.g. precipitation). In general, suitable compositions are dry solid compositions which are injected.

The preparation of starting materials is described by way of examples from this application in Separated Application 820,202.

Example 1 dl-trans-5,6,6a /? , 7,8,9,10,10a η-octahydro-1-acetoxy-9-hydroxy-6β-methyl-3- (2-heptyloxy) -benzo [c] quinoline To a stirred suspension of 150 at 0 ° C mg (0.39 moles) of dl-trans-5,6,6a β, 7,10,10aβ-hexahydro-1-acetoxy-6 β-methyl-3- (2-heptyloxy) -benzo [c] quinoline- 9 (3H) -one in 10 ml of ethanol was added 40 mg of sodium borohydride. After half an hour the reaction mixture was poured into a mixture of 50 ml of ice-cold 5% acetic acid and 75 ml of ether. After separation of the ether layer, the aqueous phase was extracted with 2 x 50 ml of ether. The combined ether extracts were washed successively with 2 x 50 mL of water, 1 x 50 mL of saturated sodium bicarbonate solution and 1 x 75 mL of brine, dried over magnesium sulfate, filtered, evaporated to give 156 mg of a white foam which was dl-trans. -5,6,6a β, -7,8,9,10,10ac-octahydro-1-acetoxy-9-hydroxy-6β-methyl-3- (2-heptyloxy) -benzo [c] quinoline axial ( a small amount) and a mixture of equatorial (large amount) alcohols. m / e = 389 (m +)

IE (CHCl-O: 5.72, u (estercarbonyl)) TMS

NMR (60 MHz) h CDCl 3: acetate methyl characteristic singlet 2.23 ppm.

The various isomers were separated from the mixture as follows:

180 mg of dl-trans-5,6,6a β, 7,8,9,10,10a b {-octa-hydro-1-acetoxy-9-hydroxy-6 β-methyl-3- (2-heptyloxy) were charged -benzo [c] quinoline alcohols on a column containing 15 g of silica gel and eluted with a solvent mixture of 3 parts benzene and 1 part ether. 15 ml fractions were collected. Fractions 6-8 were combined, evaporated in vacuo to give 13 ml of dl-trans-5,6,5,6,6a / 1,7,8,9,10,10a (X-octahydro-1-acetoxy-9 C hydroxy-6β-methyl-3- (2-heptyloxy) -benzo [c] quinoline.

Fractions 11-16 were combined, evaporated to give 83 mg of dl-trans-5,6,6aβ, 7,3,9,10,10a cis-octahydro-1-acetoxy-9H-hydroxy-si-6 β -methyl-3- (2-heptyloxy) benzo / c / quinoline.

Other compounds prepared according to the above method are prepared from fractions of the friction component:

II

29 64 1 4 1 dl-trans-5,6,6a 0,7,8,9,10,10β-octahydro-1-acetoxy-9-hydroxy-6H? -methyl-3- (5-phenyl-2-pentyloxy) -benzo [d] quinoline m / e = 437 (m +) IR (CHCl3): 5.70 (ester carbonyl)

Conversion of the resulting product to the hydrochloride gave a solid, m.p. 188-190 ° C. Recrystallization from acetone-methanol-ether (25: 1: 100) gave an analytical sample of 9 6-alcohols, m.p. 193-194 ° C.

Analysis for C27H35 ° 4N '

Calculated: C C8.42 H 7.66 N 2.96%

Found: C 63.43 H 7.70 N 2.39%

Conversion of the resulting product to the methanesulfonate (methane with sulfonic acid in dichloromethane) gave a solid which was recrystallized from ethyl acetate to white crystals, m.p. 110-114 ° C.

IR (CHCl 3): 2.95, 3.70, 3.95, 5.60, 6.06, 6.19 and 6.27.

Analysis for C27H35 ° 4N'CH4 ° 3S Calculated: C 63.02 H 7.37 N 2.63%

Found: C 62.90 H 7.31 N 2.74% dl-cis-5,6,6a, R, 7,3,9,10,10 β-octahydro-1-acetoxy-9-hydroxyl- 6 β-methyl-3- (5-phenyl-2-pentyloxy) -benzo [c] quinoline m / e = 437 (m +) IR (CHCl3): 5.71 [u (estercarbonyl)] - 1-trans 5,6,6a β, 7,8,9,10,10a o (-octahydro-1-acetoxy-9,4-hydroxy-6,1-methyl-3- (5-pentyl-2-pentyloxy) -benzo) δ / -quinoline, mp 120-125 ° C (decomposes) as the hydrochloride salt.

[α] 25 D = -93.57 ° (c - 0.3 51, CH 3 OH) m / e = 4 37 (m +)

Analysis for CH 2 Cl 2 / HCl

Calculated: C 68.42 H 7.66 N 2.96%

Found: C 68.24 H 7.68 N 3.00% d-trans-5,6,6a (S, 7,8,9,10,10a t) (- octahydro-1-acetoxy-9H) hydroxy-6H-methyl-3- (5-phenyl-2-pentyloxy) -benzo [q] no., line, mp 120-125 ° C (decomposes) as hydrochloride salt [α] D = +99.33 ° (c = 0.30, CH-OH) m / e = 437 (m +)

Analysis N.HCl

Calculated: C 68.42 H 7.66 N 2.96%

Found: C 63.41 H 7.54 N 2.95%

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C i H N C H N

68.42 7.66 2.96 68.45 7.60 3.08 74.11 8.26 3.20 73.59 8.07 3.24! 67.39 7.45 3.04 67.85 7.37 2.97 70.37 8.86 3.73 69.85 8.87 3.63 70.37 "70.55 8.70 3.71 i __ ^^^ _J______i

Example 2 dl-trans-5,6,6a ft, 7,8,9,10,10a cA-octahydro-1-acetoxy-9/3-hydroxy-6,7-methyl-3- (5-phenyl- 2-Pentyloxy) -benzo [b] quinoline A. Under a nitrogen blanket, 7.57 g (0.20 moles) of sodium borohydrides were added to 200 ml of methanol and cooled in an ascone / ku.1 v. Ice bath to about -75 °. To C. The mixture was stirred for about 90 minutes to dissolve most or all of the sodium borohydride A solution of 8.71 g (0.02 mol) of dl-trans-5,6,6a β, 7,1C, 10ao-hexahydro- 1-Acetoxy-6-n-methyl-3- (5-phenyl-2-pentyloxy) -benzo [c] quinolin-9 (8H) -one in 88 ml of tetrahydrofurar was cooled to about -50 ° C and added dropwise over 5-10 minutes to sodium borohydride solution The reaction mixture was stirred at about -70 ° C for 30 minutes and poured into a mixture of 1000 ml of water, 45 g (0.30 mol) of ammonium chloride , 250 ml of crushed ice and 250 ml of ethyl acetate, the layers were separated and the aqueous phase was extracted with 3 x 200 ml of ethyl acetate. in 1 x 100 ml of water and dried over magnesium sulfone. The dried extract was cooled to about 5 ° C. A solution of 15 ml of ethyl acetate and 0.025 mol of 1.5N hydrochloric acid was added dropwise over 15 minutes. Upon stirring at 0.5 ° C, the hydrochloride salt of the title compound precipitated. The mixture was stirred for half an hour, filtered and the salt dried over 3 2 6 4 1 4 L (25 ° C / 0.055 mmHg) to give 6.378 g (67.3%) of product, m.p. 195-193 ° C (decomposes).

The following compounds were prepared in a similar manner from the appropriate reaction components:

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III III III III III III

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_______i_______4___ li 33 6 4 1 4 1 B. Alternatively, the title compound is prepared as follows: dl-trans-5,6,6a / 7, 7,8,9,10,10a r> (- octahydro-1-acetoxy-9 'j_ ~ __ hydroxy-6R-methyl-3- (5-phenyl-2-pentyloxy) -benzo [q] quinoline

A heterogeneous mixture of 3.0 g (7 mmol) of dl-5,6,6a, 7-tetrahydro-1-acetoxy-6-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 were hydrogenated for three hours in a Parr apparatus at room temperature and pressure at 3.5 kp / cm. The catalyst was removed by filtration, the methanol filtrate was evaporated in vacuo to give the title product.

The product was dissolved in 300 ml of ethyl acetate and the resulting solution was cooled to 0 ° C. an excess of saturated ethyl chloride solution of hydrogen chloride was added to precipitate the hydrochloride salt of the title product as a white solid. Filtered, washed with ethyl acetate and dried.

In a similar manner the following compounds were prepared: 36 6 4141 U ~ i en

<n

L ^ i, -C O oo o O '' O r — I rH ·

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a - - - O I I cm cm ίΊ j j - + 4- l! 6,441 37 dl-5,6,6a, 7-Tetrahydro-1-acetoxy-6β-methyl-3- (5-phenyl-2-pentyloxy) -benzo [c] quinolin-9 (8H) -one was prepared as follows:

To a stirred solution of 4.5 g (0.0115 moles) of dl-5,6,6a, 7-tetrahydro-1-hydroxy-6β-methyl-3- (5-phenyl-2-pentyloxy) benzo [q] Quinolin-9 (8H) -one in 45 ml of pyridine was added at room temperature to 45 ml of acetic anhydride. The resulting solution was stirred for 3.5 hours, poured into 250 ml of ice water and extracted with 2 x 250 ml of diisopropyl ether. The combined extracts were washed with 3 x 200 ml of water, dried over magnesium sulphate and evaporated in vacuo to a yellow-brown oil which solidified on scratching the walls of the flask containing it. Trituration of the solid in n-heptane gave 2.0 g of the 1-acetoxy derivative (yield 40%). It was purified by recrystallization from hot chloroform-n-hexane (1: 4) to give the pure ester, m.p. 136-140 ° C. m / e = 433 (m +) 1 H NMR (60 MHz) δ δ δ (ppm): 7.21 (bs, 5H, aromatic), 6.62 (d, J = 1.5 Hz, 1H, ί = CH ), 5.97 (d, J = 3 Hz, 1H, meta-H), 5.86 (d, J = 3 Hz, 1H, meta-H), 2.27 (s, 3H, CH 3 -C ( = 0)), 1.21 (d, J = 7 Hz, 6H, CH 3 -CN, CH 3 -C-O), 1.49-4.51 (m, 14H, residual protons).

The following tetrahydro-1-acetoxy-3- (5-phenyl-2-pentynyl) -benzo [c] quinolin-9 (8H) -ones were prepared in a similar manner from the appropriate reaction components according to the above procedure: 38 6 4141 33 K Ö 44 Γ-vb c> cö Γ VO r- m 03 rH rH (Tl M (N Ö <V | Γ0 3 - · '' - -P m oo co -m · r ~ · co <j in η ^ r ~~ co tO r ~ r- r- '<ö lii ill lit ill

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40,641 41

Example 3 dl-cis-5,6,6a ft, 7,3,9,10,10a β-octahydro-1-acetoxy-9-hydroxy-6, h-methyl-3- (5-phenyl-2- pentyloxy) -benzo [c] quinoline

To a solution of 1.0 g (2.296 mmol) of dl-cis-5,6,6a, 7,10,10a / 3-hexahydro-1-acetoxy-6 β <-methyl-3 in -7S ° C was (5-Phenyl-2-pentyloxy) -benzo [q] quinolin-9 (8H) -one in 100 mL of dry tetrahydrofuran was added dropwise over 5 minutes with stirring over 4.6 mL (2.296 mmol) of 0.5 M potassium sec. -butyyliboorihydridia. The reaction mixture was stirred for 30 minutes at -78 ° C and poured with stirring to a pre-cooled mixture of 250 ml of 5% acetic acid and 500 ml of ether. The layers were separated and the aqueous layer was extracted with 250 mL of ether. The combined ether extracts were washed successively with 2 x 250 ml of water, 1 x 250 ml of saturated sodium bicarbonate solution and 1 x 250 ml of brine, dried over magnesium sulphate, evaporated in vacuo to give 1.4 g of a yellow oil. The crude oil was chromatographed on 100 g of silica gel using benzene ether (3: 1) as eluent. After elution of less polar impurities, 700 mg of the title compound was isolated as a clear oil. This was dissolved in 35 ml of ether, treated with ether saturated with HCl gas to give 448 mg of the hydrochloride salt of the title compound, m.p. 115-124 ° C from ether-chloroform after recrystallization.

MS (molecular weight) = 437 IR (KBr): 5.58 (ester carbonyl)

Analysis for C27H35O4N.HCl Calculated: C 63.41 H 7.66 N 2.96%

Found: C 63.52 K 7.91 N 2.73%

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

II

41 64141

OH

rs Toch3 L. a.

H 'i'

, 1 V. ' J

.. ^ z-w - i I Rr! 5 R6 J-z-w R4 R P Rg Sp. (° C) i «S (moles-j _________ions)! 5-Phenyl-2-pentyloxy CH, H H IlUH 163-170! «5)" H CII3 "- ^ H oil ''" "" ti ti H "4 37” CH3 H CH3 "159-162x (b) 451

! xII hydrochloride salt I

! \ (a) Analysis for C27H3504N.HCl! Calculated: C 68.41 H 7.66 N 2.96% Yield: C 68.48 H 7.57 N 2.93%; (b) Analysis for C 28 H 37 ° 4N'HCl

Calculated: C 68.88 H 7.85 N 2.87% j

Found: C 68.42 H 7.73 N 2.75% j 42 6 4 1 4 1

Example 4 dl-trans-5,6,6a, R, 7,8,9,10,10a * X -octahydro-1,9-diacetoxy-6-methyl-3- (2-heptyloxy) -benzo [d] quinoline 1.2 g of the dl-trans-5,6,6α / -, 7,10,10acac-hexahydro-1-acetoxy-6 of Example 7 were stirred overnight at room temperature. : '' - un chromatographed reduction product of methyl 3- (2-heptyloxy) -benzo [c] quinolin-9 (SH) -one and excess acetic anhydride and pyridine. The mixture was poured into ice water, the aqueous mixture was extracted with 3 x 100 ml of ether, the combined extracts were washed with water and brine, dried over magnesium sulphate and evaporated. The residue was subjected to column chromatography (40 g of silica gel, eluent benzene-ether (9: 1)) to give 630 mg of the desired dl-trans-5,6,6a /. -octahydro-1,9-diazooxy-6R-methyl-3- (2-heptyloxy) -benzo [c] quinoline which crystallized on addition of hexane and ethyl acetate, mp 36-87 ° C. e = 4 31 (m +) IR (KBr): 5.73 (ester carbonyls)

1 r TMS

"1 H NMR (60 MHz) δ (ppm): 5.88 (bs, H 2, H 4-2H), 2.28 and 2.05 (2 three-proton singlets, CH 3 -C (= O) -) and about 0, 8-5.0 (multiplets, residual protons).

Analysis C25H37 ° 5N

Calculated: C 69.57 H 8.64 N 3.25%

Found: C 69.51 H 3.54 M 3.14%.

By similar treatment for 60 hours at room temperature, 60 mg of dl-trans-5,6,6a / 3,7,8,9,10,10a cis-octahydro-1-acetoxy-9H-hydroxy-6H - "- methyl-3- (4-phenylbutyloxy) -benzo [c] quinoline in 1 ml of pyridine and 1 ml of acetic anhydride gave the desired dl-trans-5,6, -6a Λ ', 7,3,9,10,10a trans-octahydro-1,9,11-diacetoxy-6,3-methyl-3- (4-phenylbutyloxy) benzo [c] quinoline, mp 146-147 ° C from ethyl acetate-hexane (1: 1 ) after recrystallization, m / e = 465 (m +)

Analysis: C23H35 ° 5N

Calculated: C 72.23 H 7.53 N 3.01%

Quality: C 72.17 F 7.61 N 3.08%

Example 5 dl-trans-5,6,6a Λ, 7,8,9,10,10arya-octahydro-1,9-dihydroxy-6 c'-methyl-3- (2-heptyloxy) -benzo / c ' A solution of 130 mg of dl-trans-5,6,6a-0,7, S, 9,10,10a-octydro-1-acetoxy-9-hydroxy-6 m-methyl-3- (2-hootyylioksi) -

II

64141 benzo / q7.jolin and 46 mg of potassium carbonate in 35 ml of methanol were stirred at room temperature. After thirty minutes, the reaction mixture was neutralized with acetic acid and evaporated in vacuo. The residue was dissolved in 100 ml of ether, washed successively with 2 x 35 ml of water, 1 x 35 ml of saturated sodium bicarbonate solution and 1 x 40 ml of brine, dried over magnesium sulphate, evaporated in vacuo to give 96 mg of dl-trans -5,6,6ayi? , 7,8,9,10,10a θ (-octahydro-1,9-dihydroxy-6/3-methyl-3- (2-heptyloxy) -benzo [c] quinoline as an amorphous solid, m.p. 80- 100 ° C (decomposes).

NMR (CDCl 3, 60 MHz) showed no acetate methyl absorption and IR (CHCl 3) showed no ester carbonyl absorption.

In a similar manner, the following compound was prepared from the corresponding 1-acetoxy derivative of Example 1.

dl-trans-5,6,6a (N, 7,8,9,10,10a-octahydro-1,9-dihydroxy-N'-methyl-3- (5-phenyl-2-pentyloxy) -benzo) c7quinoline m / e -395 (m +).

Conversion to the hydrochloride gave a powder, m.p. 151-156 ° C IR (KBr): 3.00, 4.00 (HN =), 6.10 and 6.25.

Similarly, dl-trans-5,6,6a β, 7,10,10a β-hexahydro-1-acetoxy-5-methyl-6H-3- (2-heptyloxy) -benzo [c] quinolin-9 The (3H) -one was hydrolyzed to the corresponding 1-hydroxy compound, m.p. 157-160 ° C. m / e - 359 (m +) / Analysis for C 22 H 13 O 3

Calculated: C 73.50 K 9.25 N 3.90 Found: C 73.16 H 9.14 N 3.85

Example 6 dl-trans-5,6,6a &, 7,8,9,10,10a η-octahydro-1,9-dihydroxy-5-ethyl-6H-methyl-3- (2-heptyloxy) -benzo To a solution of 100 mg of lithium aluminum hydride in 5 ml of dry tetrahydrofuran (cooled in an ice-water bath) was added dropwise a solution of 90 mg of dl-trans-5,6,6a fi, 7, S, 9.10, 10a </, -octahydro-1,9-dihydroxy-5-acetyl-6H-methyl-3- (2-heptyloxy) -benzo [c] quinoline in 3 ml of tetrahydrofuran. After the addition was complete, the reaction mixture was heated at reflux for one hour and then cooled to room temperature. An equivalent amount of water was added followed by 3N potassium hydroxide solution, the precipitate formed was filtered off, the filtrate evaporated in vacuo to give the desired J-ethyl derivative as an oil, m / e - 375 (m +) 6 4141 44

Example 7 dl-trans-5,6,6a, 7,8,9,10,10a o (-octahydro-1-acetoxy-9-hydroxy-5-methyl-3- (5-phenyl-2-pentyloxy) ) -hentso /.o7~ quinoli ini

At room temperature, 1.1 nl of a 37% aqueous formaldehyde solution was added to a solution of dl-trans-5,6,6a, 7,10,10a c-hexahydro-1-acetoxy-3- (5-phenyl-2 -pentyloxy) -benzo [c] quinolin-9 (8H) -one in 15 ml of acetonitrile followed by 0.262 g of sodium cyanoborohydride. The reaction mixture was stirred for one hour, during which time the pH was maintained neutral by the addition of acetic acid as needed. To the reaction mixture were added 0.262 g of sodium cyanoborohydride and 15 ml of methanol, oxidized to pH 3, stirred for two hours and evaporated in vacuo to an oil. This was diluted with 50 ml of water, the pH was adjusted to 9-10 with aqueous sodium hydroxide solution, and the basic mixture was extracted with 3 x 200 ml of ether. The combined ether extracts were washed with brine, dried over sodium sulfate and evaporated in vacuo to a clear oil, the oil was dissolved in ether-hexane (1: 1) and loaded onto a silica gel column. The column was eluted first with 50% ether-hexane and then with 60, 70 and 75% ether-hexane. The eluate was monitored by thin layer chromatography (ether-hexane 10: 1). The first isolated product was 0.125 g of dl-trans-5,6,6a β, 7,10,10a N, N-hexahydro-1-acetoxy-5-methyl-1- (5-phenyl-2-pentyloxy) benzo / c / quinolin-9 (3H) -one. m / e = 435 (m +) 1 ^ vsi Γ1 if Q, N * · "27 33 4

Calculated: C 74.45 H 7.64 N 3.22%

Found: C 74.06 H 7.77 N 3.31%

The second product was 25 mg of the 9'X-hydroxide grade romer of the title compound. m / e = 437 (m +)

Analysis for C 27 H 35 ° 4N

Calculated: C 74.11 H 3.06 N 3.20%

Found: C 73.96 H 3.34 N 3.00%

The third product was 0.7 g of the 9β-hydroxide grade romer of the title compound. m / e - 4 37 (m +)

Analysis

Calculated: C 74.1 1 11 3.06 N 3.20%

Found: C 7 3.56 H 7.36 N 3.21 7,

Similarly, di-trans-5,6,6af (1,7,10,10.-N-hydroxyhydro-1

II

45 6 4141 Acetoxy-3- (2-heptyloxy) -benzo [c] quinolin-9 (8H) -one was treated with sodium cyanoborohydride to give: dl-trans-5,6,6a / 7,10,10a <* - hexahydro 1-acetoxy-5-ethyl-3- (2-heptyloxy) -benzo [c] quinolin-9 (BIT) -one as an oil, m / e = 387 (m +) IR (CHCl 3): 5.80 ( ketonecarbonyl), 5.65 (ester carbonyl) u, /

Analysis for C23H33 ° 4N

Calculated: C 71.29 H 8.58 N 3.61%

Found: C 70.78 K 8.71 N 3.27% dl-trans-5,6,6a β, 7,8,9,10,10a r-octahydro-1-acetoxy-N-hydroxy-5 -methyl-3- (2-heptyloxy) -benzo [c] quinoline as an oil, m / e = 389 (m +) IR (CHCl3): 2.80 (OH), 5.70 (estercarbonyl).

Analysis for C23II3504N

Calculated: C 70.92 H 9.06 N 3.60%

Found: C 70.56 H 8.95 N 3.56% and dl-trans-5,6,6a /? , 7,10,10a nt-hexahydro-1-acetoxy-6H-methyl-3- (5-phenyl-2-pentyloxy) -benzo [c] quinolin-9 (8H) -one was extracted: dl-trans- 5,6,6a / ', 7,10,10a cis-hexahydro-1-acetoxy-5-methyl-6H-methyl-3- (5-phenyl-2-pentyloxy) -benzo [c] quinoline -9 (3R) -one, dl-trans-5,6,6a / ·? , 7,8,9,10,10a oc-octahydro-l-acetoxy-9./? -hydroxy-5-methyl-6/9 -3- (5-phenyl-2-pentylloxy) -benzoic acid quinoline, which was isolated as the hydrochloride salt, m.p. 163-165 ° C. m / e = 451 (n +).

Example 8 dl-trans-5,6,6ap, 7,8,9,10,10ao-4-octahydro-1-acetoxy-9R-hydroxy-5-isobutyryl-3- (5-phenyl-2-pentyloxy) benzo / g7kinoliini

At 5-10 ° C under nitrogen, 38 mg (1.0 mmol) of sodium borohydride were slowly added to a solution of 260 mg (0.529 mmol) of dl-trans-5,6,6a / 9, 7,10,10a cZ-hexahydro- 1-Acetoxy-5-isobutyryl-3- (5-phenyl-2-pentyloxy) -benzo, n-quinolin-9 (8H) -one in 20 ml of absolute ethanol. The reaction mixture was stirred for one hour and acidified with 10% hydrochloric acid. The ethanol was evaporated in vacuo. To the residual solution was added 10 ml of water and extracted with 2 x 50 ml of ethyl acetate. The extracts were combined, washed with brine and dried over magnesium sulfate. Evaporation in vacuo gave the title compound as an amorphous solid (213 mg) which was used without further purification.

46,641 41

Example 9 dl-trans-5,6,6a β, 1,8,9,10,10a N, N-octahydro-1,9,7'-diacetoxy-5-isobutyryl-3- (5-phenyl-2 -pentyloxy) -benzo / c7-quinoline

Under nitrogen and at room temperature, a solution of 213 mg (0.432 mmol) of dl-trans-5,6,6aβ, 7,8,9,10,10a (N-octahydro-1-acetoxy-9β-hydroxy-5- isobutyryl-3- (5-phenyl-2-pentyloxy) -benzo, cis-quinoline in 5 ml of tetrahydrofuran was added to a suspension of 100 mg (2.6 mmol) of lithium aluminum hydride in 5 ml of tetrahydrofuran. , 1 ml of water, 0.1 ml of 15% sodium hydroxide solution and 0.3 ml of water were filtered under a nitrogen blanket and the filter cake was washed with 2x5 ml of tetrahydrofuran The filtrate and washings were combined, evaporated to give 0.174 g of a reddish oil.

the oil was dissolved in 1 ml of pyridine under nitrogen and the solution was cooled to 0 ° C. To the pyridine solution was added 1 ml of acetic anhydride with stirring, and the reaction mixture was stirred for 30 minutes at 0 ° C. It was then poured into 25 ml of water and extracted with 3 x 25 ml of ethyl acetate. The extracts were combined, washed with brine, dried over magnesium sulphate, evaporated to give 184 mg of a brown oil. The oil was purged with nitrogen and chromatographed on 40 g of silica gel using benzene ether (9: 1) as eluent. 10 ml fractions were collected. Fractions 2-10 were combined, evaporated to give 109 mg of an oil, m / e = 521 (m +)

Analysis for C 32 H 43 ° 5N

Calculated: C 73.67 H 8.31 N 2.68%

Found: C 74.33 H 8.89 N 2.23%.

NMR (60 MHz) δ (ppm): 7.22 (s, 5H, · aromatic), 6.05 (d, 1H, aromatic), 5.90 (d, 1H, aromatic), 4.90 (bs, 1H) , 4.30 (bs, 1H), 3.10 (d, 2H, N-CH 2), 2.90 (d, 2H, N-CH 2), 2.70 (bs, 2H), 2.40 and 2 .15 (s, 6H, 2-CH3-COO-), 1.85 (bs, 2H, H7 and Hg), CH3 1.5 (m), 1.05 (d, 6H,, 1.0-3.0 (variable, residual protons).

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Example 10 dl-trans-5,6,6a β, 1,10,10a-hexahydro-1-hydroxy-5-acetyl-6 β-methyl-9-methylene-3- (2-heptyloxy) -benzoic acid c7quinoline A. At 50 ° C, 742 mg (2.12 mmol) of triphenylmethylphosphonium bromide was added to a solution of 0.95 g (2.0 mmol) of sodium hydride in 50 mL of dimethyl sulfoxide. The reaction mixture was heated at 70 ° C for three hours and then 0.858 g (2.0 mmol) of dl-trans-5,6,6a7? , 7,10,10aC * f-Hexahydro-1-acetoxy-5-acetyl-6H-methyl-3- (2-heptyloxy) -benzo [c] quinol-9 (8H) -one 50 ml: in dimethyl sulfoxide. The reaction mixture was heated at 70 ° C overnight, cooled and poured into a mixture of ice and water containing 12.5 g of sodium bicarbonate. The aqueous mixture was extracted with benzene, dried over sodium sulfate, evaporated in vacuo to give the crude product. It was purified by column chromatography on silica gel in hexane-benzene (1: 1).

B. dl-trans-5,6,6a β, 7,10,10a β-hexahydro-5-acetyl-1-hydroxy-6R-methyl-9-methylene-3- (5-enyl-2- pentyloxy) benzo / c7-quinoline 0.94 g (0.039 mol) of sodium hydride obtained by washing 1.87 g of 50% sodium hydride in a mineral oil dispersion with dry pentane and 57 ml of dimethyl sulfoxide together form a slurry which is heated for 2.5 hours at 50 ° C. To the slurry was added 15.32 g (0.043 mol) of triphenylphosphonium bromide, after which the reaction mixture was heated at 60 ° C for 2 hours. To the reaction mixture was added a solution of 1.86 g (0.004 moles) of dl-trans-5,6,6a β, 7,10,10a (N-hexahydro-1-acetoxy-5-acetyl-6 (; -3- (5-phenyl-2-pentyloxy) benzo [c] quinolin-9 (8h) -or in 57 ml of dimethyl sulfoxide, after which the reaction mixture was heated for 30 minutes at 60. The cooled reaction mixture was poured into 200 ml of ice water, to which 20 g of sodium bicarbonate had been added.

This was extracted twice with ethyl acetate (50 ml each), the organic layers were combined and washed with 50 ml of water, 50 ml of saturated brine, dried over magnesium sulphate, filtered and the solvent evaporated to give an orange oil. Purification was performed by chromatography (Brinkman silica gel 125 g, solvent: cyclohexane 3, ether 1) to give 1.251 g of the title product, yield 74%, mp 174-17 ° C.

Analysis 1 C28H35 ° 3N

52 6 4 1 41

Calculated: C 11.56 H 8.14 N 3.23%

Found: C 77.29 H 7.96 N 3.22% IR (KBr): 2.98 (s), 3.34 (m), 3.38 (m), 3.44 (u), 6.10 (u), 6.24 (s), 6.58 (s), 6.90 (s), m / e = 433 (m +) .

1 £ TMS

1 HNMR 10 O MHz) δ CDCl 3: 8.80 (s, 1H, phenol), 7.16 (m, 5H, aroin.), 6.32 (d, 1H, C 2 H), 6.09 (D, 1H, C4H), 4.64 (broad s, 2H, vinyl), 1.96 and 1.93 (2s, 3H, amide-CH3), 1.27 and 1.25 (2d, 3H, C6-CH3), l .02 (d, 3H, side chain CH23), 0.9-4.5 (variable residual protons). In a similar manner, starting from the appropriate starting materials, dl-cis-5,6,6a β, 7,10,10a-N-hexahydro-5-acetyl-1-hydroxy-6β-methyl-9-methylene-3- (5-phenyl) was prepared. -2-pentyloxy) benzo [c] quinoline, m.p. 168-169.5 ° C, 88% yield.

Analysis for C 28 H 35 ° 3N

Calculated: C 77.56 H 8.14 N 3.23%

Found C 77.25 H 8.14 N 3.12%

. f TMS

1 HNMR (60MHz) δ) CDCl 3: 8.82 (s, 1H, phenol), 7.16 (m, 5H, arom.), 6.36 (d, 1H, C 2 H), 6.12 (d, 1H , C (4H), 4.68 (broad s, 2H, vinyl), 2.08 and 2.06 (2s, 3H, amide-CH 3), 1.22 and 1.20 (2d, 3H, C 6 -CH 3), 1, 10 (d, 3H, side chain CH3), 1.50-4.50 (variable residual protons). m / e = 433 (m +) IR (KBr): 2.95 (m), 3.36 (s), 6.10 (s), 6.33 (s), 6.88 fu (s), 7.20 (u), 7.35 [mu] s (s), 8.50 [mu] s (s).

Example 11 dl-trans-5,6,6a / 3,7,8,9,10,10a <N-octahydro-1- (4-N-piperidylbutyryloxy) -9-hydroxy-6/3-methyl -3- (5-phenyl-2-pentyloxy) benzo [c] quinoline hydrochloride in a solution at 25 ° C of 1.0 g (2.53 mmol) of dl-trans-5,6,6a β, 7, 8,9,10,10a-N-octahydro-1,9-dihydroxy-6β-methyl-3- (5-phenyl-2-pentyloxy) -benzo [c] quinoline in 20 ml of methylene chloride was added 0.524 g (2.53 mmol) of 4-N-piperidylbutyric acid hydrochloride and 0.573 g (2.78 mmol) of dicyclohexylcarbodiimide. The reaction mixture was stirred at 25 ° C for six hours, cooled for 12 hours and filtered. Evaporation of the filtrate and trituration of the residue with ether gave 1.3 g of a solid monohydrochloride salt.

IR (KBr): 2.95, 3.70, 5.65 (ester carbonyl), 6.13 and 6.27.

By preparative thin layer chromatography on a portion of this solid on 0.5 mm thick silica gel and eluting with 10%:

II

53 6 4 1 41 11a Methanol-methylene dichloride gave the free base dl-trans-5,6,6a, 7,8,9,10,10a o-octahydro-1- (4-N-piperidylbutyryloxy) -9-hydroxy- 6 β-Methyl-3- (5-phenyl-2-pentyloxy) -benzo [c] quinoline.

i · TMS

1 H NMR (60 MHz) δ CDCl 3 (ppm): 1.12 (d, J = 7Hz, C-3 side chain methyl), 1.25 (d, J = 6 Hz, 6 methyl), 5.84 (s, two ArH) and 7.16 (s, 5H3).

Treatment of this free base with an excess of hydrogen chloride in ether gave the dihydrochloride salt as a hydratable powder.

Example 12

General method for the formation of the hydrochloride salt

Excess hydrogen chloride was passed through a solution of benzo / c / quinoline of formula I and the precipitate formed was isolated and recrystallized from a suitable solvent, for example methanol / ether (1:10).

In this way, the following salt was prepared: dl-trans-5,6,6a β, 7,8,9,10,10a cis-octahydro-1-acetoxy-9 β-hydroxy-6-methyl-3- (5- phenyl-2-pentyloxy) benzo [g] quinoline, m.p. 191-193 ° C. m / e = 437 (m +)

Analysis for C27H3604NC2-

Calculated: C 68.48 H 7.70 N 3.89%

Found: C 68.42 H 7.66 N 2.96%.

Example 13 (2'R, 6S, 6aR, 9R, LOaR) - (-) - 1-Acetoxy-5,6,6a, 7,8,9,10,10a-octahydro-9-hydroxy-5,6- dimethyl-3- (5-phenyl-2-pentyloxy) benzo [g] quinoline

To a stirred solution of 1.0 g (0.0021 moles) of (2'R, 6S, 6aR, 9R, LOaR) - (-) - 1-acetoxy-5,6,6a, 7,8,9,10 , 10α-octahydro-9-hydroxy-6-methyl-3- (5-phenyl-2-pentyloxy) benzo [d] quinoline hydrochloride in 30 ml of CHCl3, 30 ml of saturated NaHCO3 solution were added. and the mixture was stirred for 5 minutes at room temperature. The layers were separated and the aqueous layer was re-extracted with 20 mL of CHCl 3. The chloroform solutions were combined, dried (MgSO 4), filtered and the solvent removed in vacuo to give the free base as a colorless foam.

This foam was dissolved in 40 ml of tetrahydrofuran and combined with 1.0 g of 5% Pd / C, 1.05 ml (0.018 mol = 8.7 eq.) Of glacial acetic acid and 15.8 ml (0.20 moles = 100 eq.) of 37% aqueous formaldehyde. The mixture was placed in a Parr apparatus 2 54 641 41 (pressure 345 kN / m) and hydrogenated for 50 minutes. The catalyst was filtered through diatomaceous earth and washed well with ethyl acetate. The filtrate was diluted to 150 mL with ethyl acetate and then washed successively three times with 100 mL of saturated NaHCO 3 solution, three times with 75 mL of water, once with 75 mL of saturated brine, and dried over MgSO 4. Filter and remove the solvent in vacuo to give a yellow viscous oil which was chromatographed on 50 g of silica gel (0.04-0.63 mm) and extracted with toluene-diethyl ether (1: 1). Similar fractions were combined and the solvent removed in vacuo to give a colorless oil which was redissolved in 50 mL of diethyl ether and treated with dry HCl under nitrogen with stirring. The resulting white solid was filtered under nitrogen and dried in vacuo (0.1 mm) for 24 hours at room temperature to give 0.45 g (44%) of the title product. Mp, 90-95 ° C (decomposes).

Analysis for C23H3.7O4N.HCl Calculated: C 68.90 H 7.85 N 2.87%

Found: C 68.6 H 7.92 N 2.77% N MR (CDCl 3): 2.73 ppm, singlet, 3h (N-CH 3).

IR (KBr): 4.25, u Z, NH (+) Cl, 5.61.

'* O

II

CH 3 mp = -73 ° (C, 1.0, methanol)

Mass spectrum: m / e = 451 (m).

In a similar manner the following compounds were prepared: dl-1-acetoxy-5,6,6a β, 7,8,9,10,10a-octahydro-O / λ-hydroxy-5,6-dimethyl-3- (1.1 -dimethylheptyl) benzo [c] quinoline hydrochloride: m.p. 129-130 ° C (decomposes) m / e = 415 (m +, 100%)

O

W

IR (KBr): 5.67 (-C-CH 3) and

dl-1-acetoxy-5,6,6a.β, 7,8,9,10,10ao <. -octahydro-9β-hydroxy-5-methyl-6H-n-butyl-3- (5-phenyl-2-pentyloxy) benzo [d] quinoline hydrochloride: m.p. 106-103 ° C

m / e = 493

Analysis for C 31 H 43 O 4 N 2 Cl 2 Calculated: C 70.21 H 8.37 N 2.6%

Found: C 71.02 H 8.43 N 2.6% 55 64 1 4 1

Example 14 A.) dl-5,6 / 6a β, 7,8,9 cA, 10,10a 4-Octahydro-1-acetoxy-5-benzoyl-9-benzoyloxy-6 4-methyl-3- (1 -methyl-4-phenylbutoxy) benzo [c] quinoline A stirred suspension of 47.4 g (0.10 moles) of dl-5,6,6α, 7,8,9 oC, 10,10a fA-octahydro-6 β -methyl-3- (1-methyl-4-phenylbutoxy) benzo [d] quinoline hydrochloride and 500 ml of CHCl3 under a nitrogen atmosphere, cooled to 0 ° C and treated first with 250 ml of pyridine and then with 58 ml ( 0.50 moles) of benzoyl chloride mixed with 500 ml of chloroform. The resulting homogeneous solution was then refluxed on a water bath for one hour. The reaction mixture was poured onto crushed ice and extracted with chloroform. The organic extracts were combined, washed successively with water (twice 500 mL), 10% hydrochloric acid, saturated sodium bicarbonate solution (500 mL) and brine (500 mL), dried over MgSO 4, filtered and concentrated to give 119 g of a pale yellow oil. Chromatographed on 2,000 g of silica gel (20% ethyl acetate-cyclohexane) to give 50.5 g (78%) of dl-5,6,6aβ, 7,8,910, -10a c * 1-octahydro-1-acetoxy -5-benzoyl-9-benzoyloxy-6yg-methyl-3- (1-methyl-4-phenylbutoxy) benzo [c] quinoline, m.p. 125-30 ° C.

Analysis for C 41 H 43 O 6 N

Calculated; * C 76.24 H 6.72 N 2.17%

Found: C 76.35 H 6.92 N 2.19% B.) dl-5,6,6a β, 7,8,9pk, 10,10ac-octahydro-1-acetoxy-5-benzoyl-9- Separation of benzoyloxy-6H-methyl-3- (1H-methyl-4-phenylbutoxy) benzo [c] quinoline dl-5,6,6a / 3,7,8,9 ck, 10,10a <λ -octahydro- 50.5 g of 1-acetoxy-5-benzoyl-9-benzoyloxy-6β-methyl-3- (1H-methyl-4-phenylbutoxy) benzo [g] quinoline 50.5 g of dl-5,6,6a, 7,8,9c <10,10α (7C.-Octahydro-1-acetoxy-5-benzoyl-9-benzoyloxy-6β-methyl-3- (1-methyl-4-phenylbutoxy) benzo [d] quinoline was recrystallized from 2 liters 2 -propanol to give 23.8 g of a white crystalline substance (m.p. 136-8 ° C) which was recrystallized twice more from 2-propanol and once from acetonitrile to give 5.7 g of dl-5.6, -6a p, 7,8,9 pc, 10,10a pC-Octahydro-1-acetoxy-5-benzoyl-9-benzoyloxy-6 β-methyl-3- (1/3-methyl-4-phenylbutoxy) benzo] g7-quinoline (m.p. 148-9 ° C).

56 64141 dl-5,6,6a i3, 7,8,9 M,, 10,10 a (X-octahydro-1-aceto-5-benzoyl-9-benzoyloxy-6) The filtrate from the first recrystallization of 6-methyl-3- (1-methyl-4-phenylbutoxy) -benzo [c] quinoline was evaporated to a white foam and triturated with 500 ml of ether to give 12.9 g of a white crystalline solid. (mp 129-132 ° C) These crystals were triturated twice more with ether to give 3.8 g of dl-5,6,63 ^, 7,8,9 ^, 10,10ac-octahydro-1- acetoxy-5-benzoyl-9-benzoyloxy-6β-methyl-3- (1H-methyl-4-phenylbutoxy) benzo [d] quinoline (m.p. 139-141 ° C).

C.) dl-5,6,6a / **, 7,8,9c *, 10,10acac-octahydro-1-acetoxy-9-hydroxy-6H-methyl-3- (1/3-methyl Preparation of 4-phenylbutoxy) -benzo [c] quinoline hydrochloride To a stirred solution of 2.0 g (5.3 mmol) of lithium aluminum hydride in 150 ml of tetrahydrofuran under a nitrogen atmosphere was added dropwise over 5 minutes a solution of 5.7 g (8.8 mmol) dl-5,6,6a / 3,7,8,9c <, 10,10a.X-Octahydro-1-acetoxy-5-benzoyl-9-benzoyloxy-6H-methyl-3 - (1/3-methyl-4-phenylbutoxy) benzo [c] quinoline in 112 ml of tetrahydrofuran. The resulting mixture was heated to reflux for 45 minutes, cooled and carefully poured into an ice-cold mixture of 1125 ml of 5% aqueous acetic acid and 2,250 ml of ether. The mixture containing these two different phases was stirred for ten minutes, after which the layers were separated. The aqueous layer was extracted with 500 mL of ether and the combined ether layers were washed successively with water (three times 500 mL), saturated sodium bicarbonate solution (twice 500 mL) and brine (500 mL), dried over MgSO 4, filtered and evaporated to give 5 g. 4.4 g of dl-5-benzyl-5,6,6a (3,7,8,9 ^ 10,10aO1'-octahydro-1,9-dihydroxy-6H) -methyl-3- (1β'-methyl-4-phenylbutoxy) benzo [c] quinoline as a light purple oil.

dl-5-benzyl-5,6,6a β, 7,8,910,10ao * -octahydro-1,9-dihydroxy-6 β-methyl-3- (1- (3-methyl-4-phenylbutoxy) benzo) c / The quinoline was immediately dissolved in 450 ml of methanol and hydrogenated at atmospheric pressure for three hours using 4.27 g of Pd / c as a catalyst to give, after filtration of the catalyst and evaporation of the methanol, dl-5,6,6a β, 7,8,9 (j-, 10,10a {N-octahydro-1,9-dihydroxy-6 β-methyl-3- (β-methyl-4-phenylbutoxy) benzo [d] quinoline).

Obtained dl-5,6,6aβ, 7,8,9 rl, 10,10a r-octahydro-1,9-dihydroxy-Λ Λ-6-methyl-3- (1p-methyl-4-phenylbutoxy) benzo / c / quinoline ti 64141 was immediately dissolved in 210 ml of methylene chloride, cooled to 0 ° C under a nitrogen atmosphere and treated successively with 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. After stirring for 30 minutes, the reaction mixture was poured into 250 ml of water and the organic layer was separated. The aqueous layer was extracted once more with methylene chloride and the combined methylene layers were washed successively with saturated sodium bicarbonate solution (twice 150 mL), water (150 mL) and brine, dried over MgSO 4, filtered, evaporated using 33% silica gel and chromatographed on 300 g of eluent. ether-toluene solution to give 1.4 g of dl-5,6,6aβ, 7,8,9 <A, 10,10aA-octahydro-1-acetoxy-9-hydroxy-6b-methyl-3 - (1β -methyl-4-phenylbutoxy) benzo [c] quinoline hydrochloride free base, dl-5,6,6a / 3,7,8,9 ok, -10,10α * -octahydro-1-acetoxy-9 Treatment of -hydroxy-6β-methyl-3- (1- (N-methyl-4-phenylbutoxy) benzo [c] quinoline hydrochloride with HCl gas in ether gave, after filtration and trituration with acetone, 795 mg of dl-S N, N-O-octa-hydro-1-acetoxy-9-hydroxy-6H-methyl-3- (1R-methyl-4-phenylbutoxy) benzo [c] quinoline hydrochloride, m.p. 213-215 ° C, m / e = 437 (m +, 100%).

Analysis calculated for C27H35O4N-hc: C, 68.42; H 7.66; N 2.96 Found: C 68.48; H 7.63; N 3.05

In a similar manner starting from 3.8 g of dl-5,6,6a / 2 *, 7,8,9c /> 10,10a <1-octahydro-1-acetoxy-5-benzoyl-9-benzoyloxy-6/3 -methyl-3- (1-N-methyl-4-phenylbutoxy) benzo [c] quinoline was prepared in 1.1 g of dl-5,6,6 [alpha], 1,8,9? -hydroxy-6,6-methyl-3- (1H-methyl-4-phenylbutoxy) benzo [c] quinoline hydrochloride, m.p. 202-205 ° C (decomposes), m / e = 437 (100%, m +).

Analysis calculated for C27H2O-4N .HCl: C, 68.42; H 7.66; N 2.96 Found: C 68.20; H 7.56; N 3.04

Example 15 dl-trans-5,6,6-naphtho, 7,8,9,10,10H-octahydro-1-acetoxy-3- (1,1-dimethylheptyl) -9β-hydroxy-6H-methylbenzo [c] quinoline

A mixture of 446 mg (1.12 mmol) of dl-5,6,6a, 7-tetra-58 6 41 41 hydro-1-acetoxy-6 βτ3- (1,1-dimethylheptyl) benzo [c] quinolin-9 - (8H) -one in 10 ml of methanol and 446 mg of palladium on carbon (5%) was hydrogenated on a Parr apparatus for 1.25 hours at room temperature. The reaction mixture was filtered, the catalyst was washed with methylene chloride, the filtrate and washings were combined and evaporated to give 460 mg of a pink oil, the oil was extracted with 10 ml of ether / petroleum ether (1: 3) to give the title product as crystals, yield 235 mg ( 52%).

Analysis for C25H39NO3

Calculated C 74.77 H 9.79 N 3.49%

Found C 74.54 H 9.68 N 3.42%

Claims (3)

59 64141 A process for the preparation of new therapeutically active benzo / c7-quinoline derivatives of the formula I Π R il fR1 IQ-z-w 5 I R 6 wherein R is hydroxy or alkanoyloxy having 2 to 6 carbon atoms; is hydrogen, alkanoyl having 2 to 6 carbon atoms or -CO- (CH2) p-NR2R3, wherein p is an integer from 1 to 4; R 2 and R 2 together with the nitrogen to which they are attached form a 5- or 6-membered saturated cyclic amino group; R 1 is hydrogen or alkyl of 1 to 6 carbon atoms; Rg is hydrogen, methyl or ethyl; R 1 is hydrogen, alkanoyl of 2 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms, or - (CH 2) -C c H or -CO (CH 2), -C c H c, L X O D Δ X ~ i. O D where x is an integer from 1 to 4; Z is alkylene of 1 to 9 carbon atoms or -O- (alk) -, wherein (alk) is alkylene of 1 to 9 carbon atoms; and W is hydrogen, methyl or phenyl; and for the preparation of their pharmaceutically acceptable acid addition salts, characterized in that a) a compound of formula II 'Λ r,, Λ. <ΙΙ · I «Γ / Ο z-w R 6 where R 1, R 2, R 2, R 9, Z and W are as defined above is reduced by reacting it with a metal hydride, or b) a compound of formula III 0 Λ 7 'km A. (III) N. 'O: 5! R 6 in which R 1, R 4, R 4, R 6, Z and W are as defined above is reduced by catalytic hydrogenation and, if desired, acylated at the 1- and / or 9-position to give a compound in which R 1 and R 2 are hydrogen. , and if it is desired to prepare a compound in which R 1 is not hydrogen, reacting a compound in which R 1 is hydrogen with a form-O aldehyde or an alkyl or acyl halide, and, if desired, reducing the compound thus obtained with an alkali metal borohydride to give a compound having alkyl or phenylalkyl, and if desired, the compound obtained is converted into an acid addition salt. Process according to Claim 1, characterized in that 5,6,6a / E, 7,8,9,10a / 6-octahydro-1-acetoxy-9-hydroxy-6H-methyl-3- ( 5-phenyl-2-pentyloxy) benzoylcycoline. Process according to Claim 1, characterized in that trans-5,6,6a, R-7,8,9,10,10a (X-octahydro-1,9-dihydroxy-5-ethyl-6-ol) is prepared. -methyl-3- (2-heptyloxy) -benzoic acid quinoline I. Process according to Claim 1, characterized in that 5,6,6a / S, 7,8,9,10,10aK-octahydro-1 -acetoxy-9-hydroxy-5,6β-dimethyl-3- (1,1-dimethylheptyl) -benzo [c] 7-mol mol.