FI64142C - FREQUENCY REQUIREMENT FOR THERAPEUTIC THERAPEUTIC ACTIVE BENZY (C) QUINOLINONDERIVAT - Google Patents

Description

64142

Process for the preparation of new therapeutically active benzo / cin / quino-linone derivatives

This invention relates to a process for the preparation of novel benzo / cinquinolone derivatives and their pharmaceutically acceptable acid addition salts. These new compounds are useful as central nervous system agents 10 (CNS agents), especially as analgesics and sedatives, antihypertensive agents in animals including humans, as treatment agents for greenery, and as urinary isolation enhancers. They are also useful as intermediates in the preparation of the benzo-7-quinoline derivatives (I) according to the parent application.

The benzo / c7 quinolinone derivatives of the invention have the formula (II) 0 * * 20 R (ii) R6 wherein hydrogen is alkanoyl having 2 to 6 carbon atoms or -CO- (CH2) p-NR2R3 / wherein p is an integer from 1 to 4 and NR2R ^ represents a 5-6 membered saturated cyclic amino group; R 1 is hydrogen, or alkyl of 1 to 6 carbon atoms? R 1 is hydrogen, methyl or ethyl? 3Q R 9 is hydrogen, alkanoyl of 2 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms, - (CH 2) x -C 6 H 2. or -CO (CH2) _ ^ - CgH ^, where x is an integer from 1 to 4? Z is alkylene of 1 to 9 carbon atoms or -O- (C 1 -C 6 alkylene)? 35 and W is hydrogen, methyl or phenyl.

The process according to the invention for the preparation of these benzo / c7ki-2 64142 nolinone derivatives is characterized in that the compound of formula (III)

O

I 5 O 111 R 5 I R 6 10 wherein R 1, R 1, R 2, Z and W are as defined above is reduced by Birch reduction, and if it is desired to prepare a compound in which R 1 is not hydrogen, the compound obtained is acylated, and if desired, preparing a compound in which Rg is not hydrogen, reacting a compound in which Rg is hydrogen with formaldehyde or an alkyl or acyl halide, and, if desired, reducing the obtained compound with an alkali metal borohydride to a compound in which Rg is alkyl or benzyl, and if desired, converting the obtained compound acid addition salt thereof.

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.

25 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.

9-nor-9β-hydroxyhexahydrocannabinol and others

Q

cannabinoid structures such as N, N-tetrahydrocannabinol

Q. O

The analgesic properties of (<J -THC) and its primary metabolite 11-hydroxy-THC have been described by Wilson and 35 May, Absts. Papers, Am.Chem. Soc., 168 Meet., MEDT 11 (1974), J, Med. Chem., 17, (1974) 475-476 and J. Med. Chem., 18 (1975), 770-703.

U.S. Pat. Nos. 3,641,425,836 and 3,636,058 describe various 1-hydroxy-3-alkyl-6H-dibenzo [5, d] pyranes having 9-position substituents such as oxo, hydrocarbyl, hydroxy, chlorine or hydrocarbylidene, as well as their intermediates.

U.S. Patent No. 3,649,650 discloses a number of tetrahydro-6,6,9-trialkyl-6H-dibenzo [b, d] pyran derivatives having a N-dialkylaminoalkoxy group in the 1-position as psychotherapeutic agents.

DE-A-2 451 934 describes 1,9-dihydroxyhexahydrodibenzo [b, d] pyrans and their certain 1-acyl derivatives having an alkyl group or an alkyl group in the 3-position as antihypertensive, psychoactive, sedative and analgesic agents. The precursors used in their preparation, hexahydro-9H-dibenzo [b, d] pyran-9-ones, which have been reported to be as useful as the corresponding 9-hydroxy compounds, are described in DE Patent 2,451,932.

U.S. Patent No. 3,856,821 describes a group of 3-20 alkoxy-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 7,8,9,10-tetrahydro-3-pentyl-6,6,9-trimethyl-6H-dibenzo [b, d] pyran-1-ol -25 (butoxy, pentyloxy, hexyloxide11a 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 mg / kg. Other ethers were not active even at doses of 20 mg / kg.

30 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-dibenzoyl [b] pyran-1-ols with The 3-substituent is -OCH (CH3), -CH2CH (CH2) or -CH (CHO) C_H. The potency of the ether side chain-containing compound 15 to 35 was 50% lower with respect to the central nervous system than that of the corresponding compound whose alkyl side chain is directly attached to the aromatic ring without an intermediate oxygen atom, 4,641,442 and five times more potent than the compound substituted with oxygen.

Hoop et al., J. Org. Chem., 33 (1968) 2995-2996 describe the preparation of the 5-aza analogue of Δ -tetrahydrocannabinol, which they call 7,8,9,10-tetrahydro-1-hydroxy-5,6,6,9-5 tetramethyl- To 3-n-pentylphenanthridine, but do not mention the utility of the compound. Beil in "Psychomi-metic Drugs," edited by Efron, Raven Press, New York, 1970, p. 336, mentions that the compound was completely ineffective in animal pharmacology.

10 Hardman et al., Proc. West. Pharmacol. Soc., 15 (1971) 14-20 reported 7,8,9,10-tetrahydro-1-hydroxy-6,6,9-trimethyl-3-n-pentylphenanthridine, a 5-aza-N-α tetrahydrocannabinol has some pharmacological effect.

Mechoula and Edery, in "Marijuana", edited by 15 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, Annula Review of Pharmacology, 15 (1975) 192 20 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 / c7-quinolines, namely 1-hydroxyhexahydro-6H-benzo [4-c] quinolin-9 (8H) -ones (II), are particularly effective as analgesic, sedative and antihypertensive agents which do not cause drugs or addiction, to greenery as treatment agents and as agents that increase urinary excretion. In addition, the present invention includes various derivatives of said compounds which are useful dosage forms, as well as intermediates thereof. The above compounds and their derivatives are of formula II. The compounds of formula III are precursors of the compounds of formula II.

The present invention also includes pharmaceutically acceptable acid addition salts of compounds of formula II. Examples of such salts include mineral acid salts such as hydrochloride, hydrobromide, sulfate, nitrate and phosphate, and salts of organic acids such as citrate, acetate, sulfate, sulfate , glycolate, malonate, maleate, fumarate, malate, 2-hydroxy-3-naphthoate, pamoate, salicylate, stearate, phthalate, succinate, gluconate, mandelate, lactate and methanesulfonate.

The compounds of formulas II and III above have centers of asymmetry at the 6a and / or 10a position. Additional centers of symmetry may be present at the 3-position substituent (Z-W) and at the 5-, 6-, and 9-positions. In general, diastereomers having the 9-structure are more preferred than the 9-isomers because they have (quantitatively) higher biological potency.

Of the compounds of formula II in which either or R 1 is other than hydrogen, the 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.

5,6,6a, 7,8,9,10,10a? - (.-Octahydro-1-acetoxy-9/7-hydroxy-6/3-methyl-3- (5-phenyl-2-pentyloxy) - the 1-enantiomer of benzo / c7-quinoline 25 is more preferred than the d-enantiomer and the racemate due to its greater analgesic efficacy.For the sake of simplicity, the above formulas represent racemic compounds.However, the above general formulas are considered to include racemic modifications of the compounds of this invention, diastereomeric mixtures, pure enantiomers and diastereomers The utility of racemic mixtures, diastereomeric mixtures and pure enantiomers and diastereomers can be determined by the biological methods described below.

35 6 64142

Due to the higher biological potency compared to the other compounds described herein, compounds of formula II wherein R 1 is hydrogen or alkanoyl, is hydrogen, methyl or ethyl, R 1 and R 8 are hydrogen or alkyl and Z and W are as follows are preferred: z_ w__ 5 -Alkylene containing -9 carbon atoms H or alkylene containing CH 2 2-5 carbon atoms C 6 H 5 -O- (alkylene) -C 6 H 5 -O- (alkylene) -H or CH 2

In particularly preferred compounds of formula II, R 1 is hydrogen or acetyl; R 1 - is hydrogen; R 1 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-20 (alk) -, where (alk) is alkylene of 4 to 9 carbon atoms, W is hydrogen or phenyl, and when Z is 5 to 9 alkylene containing a carbon atom, W is hydrogen.

Compounds of formula II in which Rg is other than hydrogen, alkyl or - (CH2) x-C8H5 also act as intermediates for compounds of formula II in which Rg is hydrogen, alkyl or - (CHO) -CcH.

£ X D g 7 6414 2

The compounds of formula II are prepared according to the following reaction scheme from the compounds of formula V. JReaktiokaayio A

OH o o «ora 4 Λ4 r l i (V) H 010 (VI) 10 CH3-CO-CH <H2

° O w Base CH.QH

λ «X

I || I KOH O OH

15 lYol <'™ 3ch Ws <«XX ™ ί j o j

(lii) I R4 / M Z-W

B

CHO

20 Li / NHo (VII) / + 1,3-bisformyl derivative female (VII-A) / v ΓΓ ι * vjX-X- 25; H loi RX N -XX Z- «

4 I

B

(II) / + cis isomer / 30. ..

The compounds prepared by the process of the present invention may be further converted to the formula OH OH

\ / "1 1 0Ri” sC Joi R6 8 64142 as described in the parent application.

The ferrous quinolines of formula V are converted to the hydroxymethylene derivatives of formula VI by reaction with ethyl formate and sodium hydride. In this formylation reaction, the bis-formylated derivative (VI) is formed in excellent yields. Treatment of the bis-formylated derivative with methyl ethyl vinyl ketone gives a mixture of the corresponding mono-N-formylated Michael adduct (VII) and 1,3-bis-formylated Michael adduct. Both products are conveniently separable 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-formyloid-Michael adduct is formed as the main product spiro-annation product (III-A). But a compound of formula VII-A can be converted to a compound of formula VII by treatment with an equivalent amount of potassium carbonate in methanol.

20

O

'^' 'l?. ? H 0 CH

h. koh-> YVsA

«O> i; 0 | CH; 0H Yo '

»4 H R> '- N A ^> iz-W

4 I 4 ^ (III-A) »

(VII-A) CHO H

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

The enone of formula III is converted to the compound of formula III by Birch reduction. Both the nocturnal trans isomer is formed. This reduction is conveniently done with lithium metal. Sodium or potassium may also be used. The Re-35 reaction is performed at a temperature between about -35 ° C and -80 ° C. Birch reduction is preferred because it is stereol 641 429 selective 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 R 1 is hydrogen) and the dihydroxy compounds of formula I (R = OR 2 = OH) appear to be quite unstable. When standing, they oxidize, which is evident in a color ranging from purple to red. Colored by-products are formed even upon reduction of hydroxyketone 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 (OR 2) with acetic anhydride in pyridine and formation of acid addition salts, e.g. hydrochlorides. The acetyl derivatives 15 are stable even in further reactions.

The above-mentioned colored by-products are believed to have a quinonoid structure due to the oxidation of the 1-hydroxy group (OR 2) to oxy and the incorporation of another oxo group at the 2- or 4-position. The by-products are themselves effective CNS substances, in particular as analgesics and sedatives and antihypertensives, and are used in the same way and in the same dosage amount as the compounds of the formula II.

Compounds of formulas II-III in which R 1 is alkanoyl or -CO- (C 1-4) p-^ 2 '3' Ester ^ - ^ are readily prepared by reacting compounds of formulas II-III with a suitable alkanoic acid or HOOC- ( CH2) p-NR2R3 in the presence of a condensing agent such as dicyclohexylcarbodiimide. Alternatively, they are prepared by reacting a compound of formulas II-III with a suitable alkanoic acid chloride or anhydride in the presence of a base such as pyridine.

The presence of a base group in the ester moiety (OR · ^) 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 II-IV in the presence of a condensing agent, the basic ester hydrochloride salt 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. Basic ester derivatives can, of course, form mono- or diacid addition salts due to their dibasic nature.

Compounds of formula V are prepared from appropriately substituted anilines, e.g. 3-hydroxy-5- (ZW-substituted) anilines (VIII) or derivatives thereof, in which the 3-hydroxy group is protected by a group (Y · ^) which is easily removed 15 ' to restore the hydroxy group. Suitable protecting groups do not interfere with the further reactions of said 3- (protected hydroxy) -5-substituted anilines and are removable under conditions which do not cause undesired reactions at other sites of said compound or in products prepared therefrom. Examples of protecting groups (Y) are methyl, ethyl, benzyl, substituted benzyl substituted with e.g. alkyl having 1 to 4 carbon atoms, halogen (Cl, Br, F, I) or alkoxy having 1 to 4 carbon atoms.

The precise chemical structure of a 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 the hydroxy-30 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 easily removed by treatment with pyridine hydrochloride. The benzyl-35 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 removed later without interfering with the group Z.

The following page shows an abbreviated reaction scheme B for the preparation of compounds of formula V starting from 3- (protected hydroxy) -5- (ZW-substituted) -aniline (VIII) wherein -ZW is OCH 2: 10 6 41 4 2 12

Reaction Scheme B: (VIII) (IX) 50 ° CH3 I ° CH3 I R4-C-CH2COO R ° I COOR ° jgi * [o] r CH2Cr ^ NH2 CH3O

10 I

B

/ \ r4r5c = ch-coor ° / or / ^ ss ^ 4-COCH2COOR ° H2 / \ + NaCNBH, 15 (VA) / XI (X) / OCH, O OCH, / II (1) ClCOOC-He [/ Αχ flat. Ax ““ 20 / R4 CH30 ^^ A> 4 / COOC2H5 H (R5 = H) \ HBr- / HBr- \ HOAc / HO Ac 25 \ /

\ vlx X

(V-B) \ (V-C)

\ OH O OH O

Ax - = ^ Αχ HO R4 W- (alk2) n-0 ^ "\ ^^ 1jf" ^ VvSR4

H H

35 1! 13 6 414 2

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

The 5-substituent of the compounds of formula VIII may be a desired group of compounds of formula I or II, or a group which can be readily converted to that desired group. When the Z portion of the group -Z-W is -O- (alk) -, the 5-substituent is an OH group or a protected OH 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 in order to obtain satisfactory reactions with alkyl-β-ketoesters, e.g. with acetoacetate, in the presence of acetic acid, to give the corresponding N- (73-protected hydroxy) -5-substituted aniline [- (R) -acrylate (IX). The reaction is carried out in a reaction-inert solvent such as benzene or toluene at a temperature of about 50 ° C to 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 dewatering means can also be used, such as molecular sieves, as well as other solvents suitable for azeotropic dewatering.

Preferred protecting groups for 3-hydroxy-5-substituted anilines are methyl, ethyl and benzyl because ethers 30 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 to convert the more than 35 highly reactive aniline to the most complete corresponding alkyl / γ-anilino / 5- (R) -acrylate. (IX). In order to obtain a satisfactory reaction, an excess of 10 to 20% of alkyl / jeto-keto ester is usually used.

14 64142

Catalytic amounts of acetic acid are used to promote the reaction.

The alkyl N, N-anilino [3- (R)) acrylate (IX) is then reduced to the corresponding alkyl 3-Z- (3-protected hydroxy) -5-5-substituted Anilin <57-3- (R) -propionate (X), e.g. with 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, e.g. below 3.5 kp / cm. Other catalysts can be used, e.g. noble metals such as platinum, palladium or rhodium with or without supports and hydrogen pressures from about normal pressure to overpressure, e.g.

140 kp / cm 2. In addition to these heterogeneous catalysts, homogeneous catalysts such as Wilkinson's catalyst, tris- (triphenylphosphine) 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 preferred protecting groups for the 3- and / or 5-hydroxy groups of the reactive compounds of 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-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 4 acrylate and disubstituted aniline (VIII) in equivalent 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 4 R (-C = CH-COOH)) in pyridine hydrochloride at 150 ° -200 ° C.

When both groups R4 and R ,. are alkyl, the compound of formula X is also obtained by treating the alkyl R 1 R 4 acrylate of formula VIII with mercuric acetate in a reaction-inert solvent such as tetrahydrofuran and then reducing with sodium borohydride.

I! 15 6 414 2

The direct conversion of compounds of formula VIII to compounds of formula X can also be conveniently accomplished by treating 3,5- (disprotected hydroxy) aniline hydrochloride with an excess of alkyl acetoacetate, e.g. ethyl acetoacetate in the presence of sodium cyanoborohydride in a solvent, e.g. 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), 10 hydrobromic acetic acid, sulfuric acid, oleum (fuming sulfuric acid), hydrogen fluoride, trifluoroacetic acid, phosphoric acid formic acid and other cyclizing agents known to those skilled in the art. In this variation, the alkyl 3-anilino-3- (R 1) -propionate (X) can be converted to the corresponding acid, e.g., sap-15 by coupling the ester and adding the acid prior to 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. Generally, a 48% bromohydric acid solution is used because it achieves satisfactory cyclization and deprotection. The reaction is carried out at an elevated temperature and preferably at reflux temperature. But when Z is -O- (alk) -, for example, polyphosphoric acid or trifluoroacetic acid must be used in the cyclization so that the ether is not cleaved to form a thioether bond.

Alternatively, the straight 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 iodic acid, pyridine hydrochloride or hydrobromide may be used to remove ether protecting groups such as methyl and ethyl groups. The protecting groups benzyl or substituted benzyl can be removed catalytically by hydrogenation. Suitable catalysts are palladium and platinum, especially on carbon. Alternatively, they can be removed by solvolysis with trifluoroacetic acid.

1 64142 16

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 the appropriate alkyl. - or with benzyl chloroformate. The β-carbalkoxy or carbobenzyloxy derivative of formula X is then cyclized with polyphosphoric acid to the corresponding N-carbalkoxy or carbobenzyloxy derivative of the compounds of formula V. If desired, the N-substituted derivatives of the compounds of formula X can be hydrolyzed before cyclization to the corresponding 3- / TR- (substituted) -3- (protected hydroxy) -5-substituted aniline p7-3- (R4) -propino acid. Polyphosphoric acid generally achieves maximum cyclization and is the 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 Bent-20 yl or substituted benzyl, the hydroxy groups are catalytically regenerated 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 or an acid or base. Removal of the benzyl protecting group with tri-fluoroacetic acid also removes any N-carbalkoxy group.

If the group Rg is not already present in the compounds of formulas V-A, V-B or V-C, it may be attached prior to formation of the hydroxymethylene derivative (formula VI) by reacting the compound with a suitable Cl-Rg or Br-Rg reactant by known methods. If the compounds of formula II are desired as the group Rg is an acyl group, e.g. acetyl, this is generally introduced at the point in the reaction sequence where the compounds of formula II in which Rg is hydrogen are formed, e.g. by acylation with a suitable acyl halide by known methods. If desired, the resulting acyl derivative can be reduced to the corresponding alkyl compound. If it is desired to prepare a compound in which Rg is methyl, the compound in which Rg is hydrogen may first be reacted with formaldehyde, and then reduced.

The analgesic properties of the compounds of this invention can be determined by experiments using pain-inducing thermal stimuli, e.g., the mouse tail banging 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.

10 Experiments with painful thermal stimuli.

a) Experiments to alleviate hot plate pain in mice

The method is modified by Woolfe and MacDonald, J. Pharmacol. Exp. Ther., 80 (1944) 300-307. The feet of the mice are subjected to a controlled thermal stimulus on a 3.2 mm (1/8 ") thick aluminum plate. Underneath the aluminum plate is a 250 W infrared reflector lamp. A thermostat connected to the surface thermistors 16.5 cm (6 l / 2 "} _ 7 20 and the time is calculated from the time the mouse feet touch the plate. Half and 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 without such movements The maximum MT5Q of morphine is 4 to 5.6 mg / kg (subcutaneously).

25 b) Experiments on the relief of pain in the tail in the mouse.

Mouse tail experiments have been modified by D'Amous and Smith, J. Pharmacol. Exp. Ther., (1941) 74-79 by applying controlled, intense heat to the tail. Each mouse is placed in a so-30 day narrow metal cylinder with the tail protruding from one end thereof. The cylinder is mounted so that it rests directly on the covered heating lamp. At the beginning of the contact, the Aluminum plate on top of the lamp is pushed aside, allowing the light beam to focus through the gap at the end of the tail. In the sauna, the time clock I start is 35. Determine the time delay for the sudden jerk of the tail. Normally, untreated mice respond 3 to 4 seconds after aligning 18,644,142 lamps. 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 MT, -0 of morphine is 3.2 to 5.6 mg / kg (subcutaneously).

5 Experiments with chemical stimuli that cause pain

Reduction of vibration caused by phenylbenzoquinone stimulus

Groups of five Carwort Farms CH-1 mice were treated subcutaneously or orally with saline, morphine, codeine, and test compound. Twenty minutes (in the case of subcutaneous treatment) or fifty minutes (in the case of oral treatment) later, each 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 anti-vibration ΜΤ, - ^ values of the drug pretreatment were determined.

The results of the experiments described above were reported as a 20% 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. The% MT was calculated as follows:. trial time - control time, 25 end time - control time

In the tables below, the analgesic effect is expressed as MT ^ Q values, where MT ^ q is the dose at which half of the maximum 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, e.g., in the form of tablets, pills, powders, or granules, which may contain as excipients, for example, starch, milk sugar 19 641 42, and certain types of clays. They can be administered as capsules mixed with the same or similar excipients. They can 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 recommended oral dose is about 0.01 to about 300 mg / day and the recommended dose is about 0.10 to about 300 mg / day.

15 50 mg / day. The preferred parenteral dose is about 0.01 to about 100 mg / day and the recommended dose is about 0.01 -n. 20 mg / day.

The analgesic efficacy of several compounds of this invention and certain prior art compounds of the art can be determined by the methods described above.

Abbreviations used in the tables: 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 the above 5 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.

10 The use of these compounds in the treatment of green cataracts is believed to be due to their ability to lower intraocular pressure. Their effect on intraocular pressure was determined in dog experiments. 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 instillation of 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 dye, with a Holmberg manual tonometer.

A suitable solution for the test pension consists of 1 mg of test drug, 0.05 ml of ethanol, 50 mg of Tween 80 (a polyoxyalkylene derivative of sorbitan monooleate, manufactured by Atlas Powder CO., Wilmington, Delaware, 19899) and 1 ml of saline, or a more concentrated solution of 10 mg , 0.10 ml, 100 mg 25 and 1 ml. For human use, the concentration is 0.01 to 10 mg / kg of drug.

Their efficacy as urinary secretagogues was determined according to the method of Lipschitz et al., J. Pharmacol., 79, 97 (1943), in which rats are used as experimental animals. In this case, the an-30 lifting range is different from the compounds described above as analgesics.

The compounds of the invention may also be used in pharmaceutical compositions and unit dosage forms. As already mentioned above, the administration can take place in one or more doses of 35. to achieve the daily dose effect of the case.

24 64142 The compounds described herein may be formulated for oral or parenteral administration in solid or liquid form. Capsules containing these compounds of the formula are prepared by mixing one part by weight of active ingredient and nine parts of excipient, e.g. starch or milk sugar, by adding the mixture to gelatin capsules, each capsule containing e.g. 100 parts of mixture. Tablets containing compounds of formula II are prepared by formulating suitable mixtures of the active ingredient with the standard ingredients used in the manufacture of tablets, e.g. starch, binders and lubricants, each tablet containing 0.01 to 100 mg of active ingredient / tablet.

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

The preparation of the starting materials is described below in Examples 1-25, followed by the actual working examples (Examples 26-37).

Example 1

Ethyl dl-3- (3,5-dimethoxyanilino) butyrate A mixture of 95.7 g (0.624 moles) of 3,5-dimethoxyaniline, 87.2 ml (0.670 moles) of ethyl acetoacetate, 535 mL of benzene and 3.3 mL of glacial acetic acid were heated at reflux for 15 hours under a nitrogen blanket, removing water with a Dean-Stark trap. The reaction mixture was cooled to room temperature, decolorized with activated carbon, filtered, evaporated in vacuo to give 168.7 g of ethyl 3 - ((3,4-dimethoxy) -anil-n-7-2-butenoate as an oil.

A mixture of 5.0 g (18.7 mmol) of ethyl 3- (3,5-dimethoxyanilino) -2-butenoate, 42 ml of glacial acetic acid and 250 mg of 35 platinum oxide was hydrogenated in a Parr bomb for 1.5 hours at 3.5 kp / cm2. The reaction mixture was filtered through a filter aid, 50 ml of benzene was added and the solution was evaporated to a vacuum oil, the oil was dissolved in chloroform and the solution was washed successively with saturated sodium bicarbonate solution (2 x 50 ml) and saturated sodium chloride solution. It was dried over magnesium sulfate, filtered and evaporated in vacuo to give 5.1 g of an oil.

By repeating the procedure described above, but using 168.7 g of ethyl 3- (3,5-dimethoxyanilino) -2-butenoate, 320 ml of glacial acetic acid and 2.15 g of platinum oxide, 160.8 g of product were obtained.

Example 2 Ethyl dl-3- (3,5-dimethoxyanilino) butyrate

To a solution of 370 g (1.45 moles) of 3,5-dimethoxyaniline hydrochloride, 4.5 L of analytically pure methanol, and 286.3 g (2.64 moles) of ethyl acetoacetate in a 12-liter three-necked round bottom flask equipped with a mechanical stirrer and reflux condenser were added in one portion. 54 g (0.73 mol) of sodium cyanoborohydride.

After the reflux subsided after 10 minutes, the mixture was heated on a water bath for an additional 20 minutes. To the cooled reaction mixture were added 5.4 g (0.07 mol) of sodium cyanoborohydride and 28.6 g (0.26 mol) of ethyl acetoacetate, and the mixture was heated under reflux for 30 minutes. The latter procedure was repeated once more.

The reaction mixture was isolated in portions by pouring about 500 ml into one liter of ice water and 500 ml of methylene chloride, separating the layers and washing the aqueous phase with 100 ml of methylene chloride. This procedure was repeated in 500 ml portions until the entire reaction mixture was worked up.

The methylene chloride layers were combined, dried over magnesium sulfate, decolorized with activated carbon, filtered and evaporated to give a yellow oil.

Excess ethyl acetoacetate was removed by distillation (oil bath at 130 ° C and 1-5 mm Hg) to leave 376 g (72% yield) of crude 3- (3,5-dimethoxyanilino) butyrate (amber viscous oil) which was used crude.

26 6 414 2

Its Sephrometric Characteristics were: 1 H NMR (60 MHz) (ppm): 5.82-6.0 (m, 3H, aromatic), 4.20 (q, 2H, estrimethylene), 3.80-4.00 ( m, 2H, -NH and -R 1 H-CH 3), 3.78 (s, 6H, -OCH 3) f 2.40-2.55 (m, 2H, 5 -CH 2 COOEt), 1.78 (d, 3H, methyl) and 1.29 (t, 3H, methyl).

Example 3 dl-ethyl 3- (3,5-dimethoxyanilino) hexanoate

Following the procedure of Example 2, condensation of 3,5-dimethoxyaniline hydrochloride and ethyl butyryl acetate 10 gave ethyl d, 1-3- (3,5-dimethoxyanilino) hexanoate.

It was converted to the hydrochloride salt by adding hydrogen chloride to its methylene chloride solution, m.p. 127 ° -129.5 ° C. Recrystallization from cyclohexane-benzene (5: 1) gave an analytical sample, m.p. 126 to 128.5 ° C.

Analysis for C 16 H 25 ° 4N .HCl Calculated: C 57.91 H 7.90 N 4.22%

Found: C 57.89 H 7.74 N 4.40% m / e-295 (m +) 1 H NMR (60 MHz) (ppm): 10.76-11.48 (b, variable, 2H, NH 2 +), 6.77 (d, J 3 = 2 Hz, 2H, meta-H), 6.49, 6.45 (d: nd, J = 2 Hz, 1H, meta-H), 4.08 (q, 2H, OCH 2), 3.77 (s, 6H, ε 5 H 2 O 2), about 3.5-4.8 (m, 1H, CH-N), 2.90 (t, 2H, CH 2 ~ C = O), about 1.4-2.2 (m, 4H,, 1.21 (t, 3H, O-C-CH3), 0.84 (t, 3H, -C-CH3).

Example 4 dl-ethyl 3 - [(3,5-dimethoxy-N-ethoxycarbonyl) -anilino] -butyrate

Method A

71.4 ml (0.75 to 30 moles) of ethyl chloroformate were added dropwise over 45 minutes at 0 ° C under a nitrogen blanket to a mixture of 159.8 g (0.598 moles) of ethyl 3- (3,5-dimethoxyanilino) butyrate. 100 ml of methylene chloride and 100 ml (1.24 moles) of pyridine. The mixture was stirred for 40 minutes, then ethyl chloroformate 35 was added and poured into a mixture of 750 ml of chloroform and 500 ml of ice water. The chloroform layer was isolated, washed successively with 3 x 500 mL of 10% hydrochloric acid, 64142 27 1 x 300 mL of saturated aqueous sodium bicarbonate and 1 x 400 mL of saturated aqueous sodium chloride, and dried over magnesium sulfate. The color was removed with charcoal and evaporated in vacuo to give 5,215 g of an oil. The product was used as such.

Method B

Under a nitrogen overpressure, a mixture of 376 g (1.4 moles) of ethyl 3- (3,5-dimethoxyanilino) butyrate, 1.4 l of methylene chloride and 388 g of ice was stirred and cooled in an ice bath at 0-5 ° C. 8 g (2.81 moles) of anhydrous potassium carbonate. 153 g (1.41 moles) of ethyl chloroformate were added in one portion. The mixture was allowed to warm to room temperature over 1 hour, 153 g (1.41 moles) of ethyl chloroformate were added, and the mixture was heated under reflux for one hour in a water bath. It was then allowed to cool to room temperature and the potassium carbonate was removed by filtration. The red filtrate was washed successively with 2 x 100 mL of water and 1 x 500 mL of brine, dried over magnesium sulfate, decolorized and evaporated in vacuo to give 439 g of crude product which was used without further purification.

1 H NMR (60 MHz) (ppm): 6.2-6.4 (m, 3H, aromatic), 4.65 (sextet, 1H, 3-N-CH-, CH 3), 4.10-4, Δ (2-quartet, 4H, ester methylenes) 3.70 (s, 6H, -OCH 2), 2.30-2.60 (m, 2H, -CH 2 COOEt), 1.00-1.40 (m, 9H, 3-methyl).

Example 5 dl-3- (3,5-Dimethoxy-N-ethoxycarbonyl) -anilino] butyric acid

Method A

202 g (0.595 mol) of ethyl 3 - [(N- (3,5-dimethoxy-N-ethoxycarbonyl) -anilino] -butyrate, 595 ml of 1N aqueous sodium hydroxide solution and 595 ml of ethanol were combined and stirred overnight at room temperature. The reaction mixture was concentrated in vacuo to a volume of about 600 mL, the concentrate was diluted to 1200 mL with water and extracted with 3 x 750 mL of ethyl acetate. The aqueous layer was acidified with 10% hydrochloric acid to pH 2 and re-extracted with 3 x 750 mL of ethyl acetate. The latter extracts were combined, washed with brine, dried over magnesium sulfate and evaporated in vacuo to give 163.5 g (88.2%) of the title product as an oil.

Method B

To a three-liter round-bottomed flask equipped with a 5-liter mechanical stirrer and a reflux condenser was added a solution of 439 g (1.41 moles) of ethyl 3- (N- (3,5-dimethoxy-N-ethoxycarbonyl) -anilino] butyrate in 2 liters of ethanol. 2 liters of 1N aqueous sodium hydroxide-10 solution were added and the mixture was heated under reflux for three hours in a water bath. The reaction mixture was poured into 5 liters of ice water and extracted in one liter portions of 500 ml / portion of diethyl ether. The aqueous layer was cooled by the addition of about 11 ice and acidified with 1.75 ml (2.1 moles) of 15 concentrated hydrochloric acid. Extracted in one liter portions with 250 ml / portion of methylene chloride. The methylene chloride extracts were combined, dried over magnesium sulfate, decolorized with activated carbon and evaporated to dryness to give a viscous yellow oil. Crystallization from ether-cyclohexane (1: 2) gave 224 g (55.3%) of crystalline product, m.p. 78-80 ° C. The material was used in the next step without further purification.

1 H NMR (60 MHz) / cDCl (PPm): 6.24-6.53 (m, 3H, aromatic), 4.65 (sextet, λ max, -N- (COCl 3 H 2 O) CH ) Cl 1.18 (t), 1.28 (d, 6H, methyl), 10.8 (bs, variable, 1H, COOH).

MS (molecular ion) m / e - 311

An analytical sample recrystallized from ethyl acetate-hexane (1: 5) m.p. It was 89-91 ° C.

Analysis for C 15 H 21 O 6 N

Calculated: C 67.86 H 6.80 N 4.50%

Found: C 58.08 H 6.65 N 4.46%

Example 6 35 d- and 1- (3- (3,5-Dimethoxy-4-N-ethoxycarbonyl) anilino) butyric acids li 29 641 42

A mixture of 136.6 g (0.44 mol) of dl-3- (T3,5-dimethoxy-N-ethoxycarbonyl) -anilino-7-butyric acid and 72.5 g (0.44 mol) of 1-ephedrine was dissolved. To 500 ml of methylene chloride. The methylene chloride was then removed in vacuo to give dl-3- [N- (3,5-dimethoxy-N-ethoxycarbonyl) -anilino] -butyric acid 1-ephedrine salt as an oil, = -20.0 (c = 1.0, CHCl 3) · By adding 1500 ml of ether precipitated a white solid which was isolated by filtration and dried, yield 102 g, m.p. 114-116 ° C. Recrystallization from ethyl acetate-10-thihexane (1: 1) gave 71.1 g (34%) of 1-3- (1,3-dimethoxy-N-ethoxycarbonyl) anilino / butyric acid 1- ephedrine salt - laa, sp. 126-127 ° C.

Analysis for C25H36 ° 7N2

Calculated: C 63.00 H 7.61 N 5.88% Found: C 62.87 H 7.64 N 5.88% J = 15.5 ° (c = 1.0, CHCl 3).

The 1-ephecrine salt of the L-isomer was stirred for 10 minutes in 1000 ml of ethyl acetate and 400 ml of 10% hydrochloric acid. The organic phase was isolated, washed with 2 x 400 ml of 10% hydrochloric acid and evaporated in vacuo to an oil. Crystallization of the oil from 400 ml of ethyl acetate-hexane (1: 1) gave 34.6 g of 1-3- ([3,5-dimethoxy-N-ethoxycarbonyl) -anilino] butyric acid, m.p. 96-97 ° C.

Analysis for C 15 H 21 N 6 N

25 Calculated: C 57.86 H 6.80 N 4.50%

Found: C 57.90 H 6.66 N 4.45% -25.4 ° (c = 1.0 CHCl 3).

The mother liquor remaining from the recrystallization of the 1-ephedrine salt of the L-isomer was treated with the usual hydrochloric acid described above to give crude d-3 - [(3,5-dimethoxy-N-ethoxycarbonyl) -anilino] -butyric acid. By treating the crude acid with d -efedtine and crystallization from ether gave the d-ephedrine salt of the d-isomer, mp 124-125 ° C.

35 Analysis for C 25 H 36 O 7 N 2 30 64142

Calculated: C 63.00 H 7.61 N 5.88%

Found: C 62.82 H 7.47 N 5.97% = + 44.0 ° (c = 1.0, CHCl 3).

The D-ephedrine salt was converted to d-3- (1,3,5-dimethoxy-5 (N-ethoxycarbonyl) -anilino] butyric acid in the same manner as described above for the conversion of the 1-ephedrine salt to the free acid. After recrystallization from ethyl acetate-hexane (3: 5), m.p. 019 96-97 ° C.

Analysis for C 15 H 21 O 6 N

10 Calculated: C 57.86 H 6.80 N 4.50%

Found: C 57.95 H 6.57 N 4.35% = + 25.3 ° (c = 1.0, CHCl 3).

Example 7

Methyl 3- (3,5-dimethoxyanilino) propionate A mixture of 114.9 g (0.75 moles) of 3,5-dimethoxyaniline, 69.73 g (0.81 moles) of methyl acrylate and 2 ml of glacial acetic acid, was heated to reflux for 20 hours.

The heating was then stopped, the reaction mixture evaporated and distilled in vacuo to give 106.8 g (73.9%) of the title product, b.p. 174-179 ° C (0.7 mmHg).

Si NMR (60 MHz) (? 1 = (ppm): 5.62-5.95 (m, 3H, aromatic), 4.1 (variable, bs. 1H, -NH), 3.74 (s , 6H, -OCH 3), 3.68 (s, 3H, COOCH 3), 3.41 and 2.59 (two 2H triplets, -NCH 2 CH 2 CO 2).

Example 8 dl-Methyl 3 - ((3-hydroxy) -5- (S-phenyl-4-pentyl) -amino] propionate

A mixture of 1.0 g of 3-hydroxy-5- (5-phenyl-2-pentyl) -aniline, 345 mg of methyl acrylate and 0.1 ml of acetic acid was heated at 106-110 ° C overnight. The cooled residue was dissolved in 100 ml of ethyl acetate and washed twice with 100 ml of saturated sodium bicarbonate solution. The organic phase was dried over magnesium sulphate and evaporated to a crude residue which was chromatographed on 130 g of silica gel using benzene ether (2: 1) as eluent. After elution of less polar impurities, 540 mg (40%) of dl-methyl 3- (β-hydroxy-5- (phenyl-2-pentyl) -anilino) propionate were isolated. M ** 2) cdcj (PPm): 7.14 (s, 5H, aromatic), 5.83-6.13 (m, 3H, aromatic), 3.66 (s, 3H, -COOCH3 ), 3.37 (t, 2H, -NCH 2), 2.16-2.78 (m, 5H, -CH 2 COO and benzyl), 1.28-1.69 (m, 4H, - (CH 2) 2 -). ), 1.11 (d, 3H, CH 3), 4.4-5.2 and 1.28-2.78 (variable, 1H, NH, OH) m / e - 341 (m +).

10 Example 9

Me-3 - [(3,5-dimethoxy-N-ethoxycarbonyl) -anino] -7-propionate

2.0 g (8.4 moles) of ethyl chloroformate were added dropwise over 10 minutes at 0 ° C under a nitrogen blanket to a mixture of 1.0 ml (10.5 mmol) of methyl 3- (3,5-dimethoxyanilino) - propionate, 5 ml of methylene chloride and 5 ml of pyridine. The mixture was stirred for 20 minutes at 0 ° C after the addition of ethyl chloroformate and then for 20 minutes at room temperature and poured into a mixture of 75 ml of methylene chloride and 50 ml of ice water. The methylene chloride layer was isolated, washed successively with 2 x 50 mL of 10% hydrochloric acid, 1 x 30 mL of saturated aqueous sodium bicarbonate and x 40 mL of saturated aqueous sodium chloride, and dried over magnesium sulfate. The color was removed with charcoal, evaporated in vacuo to give 2.72 g of an oil. The product was used as such.

Example 10 3- (73,5-Dimethoxy-N-ethoxycarbonyl) -anilino-7-propionic acid

2.72 g (8.36 moles) of methyl 3 - [(3,5-dimethoxy-N-ethoxycarbonyl) -anilino] -propionate, 8.4 ml of 1N aqueous sodium hydroxide solution and 8.4 ml of ethanol were combined and stirred overnight. over a nitrogen blanket and at room temperature-35 sa. The reaction mixture was concentrated in vacuo to half volume, diluted with 35 mL of water and extracted with 3 x 50 32 64142 mL of methylene chloride. The combined extracts were washed with brine, dried over magnesium sulphate and evaporated to give 2.47 g of product as an oil which was used as such.

Example 11 1-Carbethoxy-5,7-dimethoxy-4-oxo-1,2,3,4-tetrahydroquinoline

A mixture of 1.10 g (3.7 mmol) of 3 - [(3,5-dimethoxy-N-ethoxycarbonyl) -anilino] -propionic acid and 10 g of polyphosphoric acid was heated for 45 minutes at 65 ° C under nitrogen and cooled. then to 0 ° C. It was then dissolved in 200 ml of a mixture of methylene chloride and water (1: 1). The organic layer was isolated and the aqueous phase was extracted with 2 x 100 mL of methylene chloride. The combined extracts were washed with 3 x 100 mL brine and dried over magnesium sulfate. Evaporation of the dried extract gave the product as an oil which crystallized from benzene. Yield 645 mg, m.p. 109-111 ° C.

Analysis for C

20 Calculated: C 60.21 H 6.14 N 5.02%

Found: C 60.11 H 6.14 N 4.80%

Example 12 5,7-Dihydroxy-4-oxo-1,2,3,4-tetrahydroquinoline A mixture of 60 ml of glacial acetic acid, 60 ml of 48% hydrobromic acid and 4.0 g (14.3 mmol) of 1- carbethoxy-5,7-dimethoxy-4-oxo-1,2,3,4-tetrahydroquinoline was heated at reflux overnight and evaporated in vacuo to a dark oil, the oil was dissolved in 50 ml of water and the aqueous solution was neutralized to pH 6-7 1-n with sodium hydroxy-30 dilute solution. 50 ml of saturated brine was added and the resulting mixture was extracted with 3 x 150 ml of ethyl acetate. The extracts were combined, dried over magnesium sulfate and evaporated in vacuo to an oil, the oil was dissolved in benzene-ethyl acetate (1: 1) and the solution was poured onto a silica gel column. The column was eluted with a volume of benzene corresponding to its volume of 64-42 benzene and then with 250 ml of benzene-ethyl acetate (4: 1) and 250 ml of benzene-ethyl acetate (1: 1). 75 ml fractions were collected. Fractions 4-9 were combined and evaporated in vacuo. the oily residue was crystallized from ethanol-hexane (1:10). Yield 1.86 g, mp 166-169 ° C.

Recrystallization of m.p. rose to 171-172.5 ° C. m / e - 179 (m +)

Analysis for C 9 H 18 N 2 O 3

10 Calculated: C 60.33 H 5.05 N 7.82%

Found: C 60.25 H 4.94 N 7.55%

Example 13 dl-1-Carbethoxy-5,7-dimethoxy-2-methyl-4-oxo-1,2,3,4-tetrahydroquinoline A solution of 4.0 g (12.8 mmol) of 3- / 13 (5-Dimethoxy-N-ethoxycarbonyl) -anilino-7-butyric acid in 2 ml of chloroform was added dropwise with stirring to 5.0 g of polyphosphoric acid heated to 60 ° C in a water bath. The reaction mixture was kept at 60-65 ° C for two hours and poured into a mixture of 100 g of ice and 100 ml of ethyl acetate. The aqueous layer was extracted with 2 x 100 mL of ethyl acetate, the combined organic extracts were washed successively with 3 x 100 mL of saturated sodium bicarbonate solution and 1 x 100 mL of brine, and dried over anhydrous magnesium sulfate. Evaporation of the dry product in vacuo gave 2.6 g of crude product.

Purification was performed by column chromatography of 2.5 g of crude product as a benzene solution on 95 g of silica gel. The column was eluted with 30 volumes of benzene and then benzene-ethyl acetate (1: 1). 40 ml fractions were collected.

Fractions 9-18 were combined and evaporated in vacuo to give 1.55 g of product which was purified by recrystallization from petroleum ether, yield 1.33 g, m.p. 92.5 to 94 ° C.

Recrystallization of this product from hot ethyl acetate-hexane (1: 1) gave an analytical sample, m.p. 94-95 ° C.

34 64142

Analysis for C 15 H 19 O 5 N

Calculated: C 61.42 H 6.53 N 4.78%

Found: C 61.54 H 6.55 N 4.94% m / e - 293 (m +) δ IR (KBr): 5.85, 5.95 ("jf 0").

Example 14 dl-5,7-dihydroxy-2-methyl-4-oxo-1,2,3,4-tetrahydroquinoline

Method A

A mixture of 240 ml of glacial acetic acid, 240 ml of 48% hydrobromic acid and 16.0 g (55 mmol) of 1-carbethoxy-5,7-dimethoxy-2-methyl-4-oxo-1,2,3, The 4-tetrahydroquinoline was heated at reflux overnight and evaporated in vacuo to a dark oil, the oil was dissolved in 200 ml of water and the aqueous solution was neutralized to pH 6-7 with 1N sodium hydroxide solution. 200 ml of saturated brine was added and the resulting mixture was extracted with 3 x 500 ml of ethyl acetate. The extracts were combined, dried over magnesium sulphate and evaporated in vacuo to give 12.8 g of a dark oil. Hexane-ethyl acetate (10: 1) was added thereto, and the formed crystals were isolated by filtration. Yield 3.8 g, m.p. 158-165 ° C. Trituration of the crystals in ethyl acetate gave 1.65 g of product, m.p. 165-168 ° C.

On standing the mother liquors precipitated an additional 2.9 g of material, m.p. 168-170 ° C. Column chromatography of the filtrate on silica gel using benzene ether (1: 1) as solvent gave an additional 4.6 g of product, m.p. 167-169 ° C.

Further purified by recrystallization of the product from ethyl acetate, m.p. 173-174 ° C.

Analysis 1 C10H11 ° 3N

Calculated: C 62.16 H 5.74 N 7.25%

Found: C 62.00 H 5.83 N 7.14% m / e - 193 (m +)

35 Method B

A mixture of 100 g (0.32 mol) of dl-3- (X,5,5-dimethoxy-N-ethoxycarbonyl) anilino] butyric acid, 500 ml of 64142 35 of 48% hydrobromic acid and 30 ml of glacial acetic acid was heated for two hours 110 ° C in an oil bath. The temperature of the oil bath was then raised to 145 ° C and heating was continued for two hours. In the final heating step, an azeotropic mixture (about 200-300 ml, b.p. 42-110 ° C) distilled off and the dark red, homogeneous solution was allowed to cool to room temperature. The mixture was poured into 3 liters of ice water and 2 liters of ether, the layers were separated and the aqueous solution was washed with 2 x 100 ml of ether. The ether extracts were combined and washed successively with 2 x 100 mL of water, 1 x 500 mL of brine, 4 x 250 mL of saturated sodium bicarbonate solution and 1 x 500 mL of brine and dried over magnesium sulfate. Color removal with activated carbon and evaporation of the ether gave a yellow foam which was crystallized from about 300 ml of methylene chloride to give 31.3 g (50.4%) of pure 5,7-dihydroxy-2-methyl-4-oxo-1 , 2,3,4-tetrahydroquinoline. Additional product can be isolated from the mother liquor by silica gel chromatography.

1 H NMR (60 MHz) δ fTMS (100 mg sample / 0.3 ml CDCl 3, 0.2 ml CD 3 SOD 3) (ppm): 12.40 (s, 1H, C 5 -OH), 5.72 (d, 2H , meta-H), 5.38-5.60 (bs, 1H, C 2 -OH), 3.50-4.00 (m, 1H, C 2 H), 2.38-2.60 (m, 2H , C3-H2), 1.12 (d, 3H, methyl) m / e - 193 (m +)

25 Analysis c 10 H 11 ° 3N

Calculated: C 62.16 H 5.74 N 7.25%

Found: C 62.01 H 5.85 N 7.02%.

Similarly, methyl dl-3 (β-hydroxy-5- (5-phenyl-2-pentyl) -anilino) propionate was converted to dl-5-30 hydroxy-7- (5-phenyl-2-pentyl ) To 4-oxo-1,2,3,4-tetrahydroquinoline, which was purified by column chromatography on silica gel using benzene ether (5: 1) as eluent, m / e to 309 (m +).

35 1 H NMR (60 MHz) λ max (PPm)! 12> 22 (s, 1H / 50H), 7.14 (s, 5H, 1H, NH), 6.04 (ä, J = 2.5 Hz, 1H, meta-H), 36 64142 5.87 ( d, J = 2.5 Hz, 1H, meta-H), 4.19-4.60 (b, 1H, NH), 3.48 (5.2H, CH 2 N), 2.18-2.89 ( m, 5H, ArCH, ArCH 2, CH 2 -C = O), 1.38-186 (m, 4H, - (CH 2) 2 -), 1.13 (d, 3H, CH 3).

Ethyl dl-3- (3,5-dimethoxyanilino) hexanoate hydrochloride was converted to dl-5,7-dihydroxy-2-propyl-4-oxo-1,2,3,4-tetrahydroquinoline, m.p. 117-119 ° C (from methylene chloride).

m / e - 221 (m +), 135 (base peak, m + -propyl).

1-3- [13,5-Dimethoxy- (N-ethoxycarbonyl) -anil] -7-butyric acid was converted to d-5,7-dihydroxy-2-methyl-4-oxo-1,2,3,4-tetrahydroquinoline, m.p. 167-168 ° C. tpJJ15 = + 167.8 ° (c - 1.0, CH3OH).

m / e - 193 (m +)

Analysis for c 10 H 11 ° 3N

15 Calculated: C 62.16 H 5.74 N 7.25%

Found: C 61.87 H 5.62 N 6.96% d-3 - [(3,5-dimethoxy-N-ethoxycarbonyl) -anilino] butyric acid was converted into 1-5,7-dihydroxy-2-methyl-4 -oxo-1.2.3,4-tetrahydroquinoline, m.p. 166-168 ° C.

20 / b <7 = -168.5 ° (c = 1.0, CH 3 OH) m / e - 193 (m +)

Analysis for c 10 H 11 ° 3N

Calculated: C 62.16 H 5.74 N 7.25%

Found: C 61.82 H 5.83 N 7.22% Example 15 dl-5,7-dihydroxy-2-methyl-4-oxo-1,2,3,4-tetrahydroquinoline

A mixture of 230 g (1.5 moles) of 3,5-dimethoxyaniline, 150 g (1.5 moles) of methyl chrotonate and 90 g of 30 (1.5 moles) of glacial acetic acid was heated under reflux for six hours. IA was adjusted with 90 g (1.5 moles) of glacial acetic acid and the mixture was heated under reflux overnight. To the reaction mixture were added 1000 ml of 48% hydrobromic acid solution and 850 ml of glacial acetic acid and heated under reflux for 4.5 hours. The title product was isolated and purified according to the method of Example 12. Yield 36 g, m.p. 166-170 ° C.

li 64142 37

Example 16 dl-5,7-Dihydroxy-2-methyl-4-oxo-1,2,3,4-tetrahydroquinoline

A mixture of 4.6 g (0.03 moles} of 3,5-dimethoxy-5 cyanaline and 3.0 g (1.26 moles) of pyridine hydrochloride was heated for 45 minutes at 18 to 200 ° C. The reaction mixture was suspended in 500 ml of water (pH ca. 3), the pH was adjusted to 7 and the resulting mixture was stirred for 10 minutes The organic layer was isolated, dried over magnesium sulphate, evaporated to give 3.2 g of a yellow oil.

A mixture of 110 ml of glacial acetic acid, 110 ml of 48% hydrobromic acid and yellow oil was heated at reflux for one hour and evaporated in vacuo to a dark oil. The oil was dissolved in water and the aqueous solution was neutralized with 1 N sodium hydroxide solution to pH 6-7. Saturated brine was added, and the resulting mixture was extracted with ethyl acetate. The extracts were combined, dried over magnesium sulphate, evaporated in vacuo to give 2.8 g of a dark oil. Column chromatography of the crude product on silica gel using benzene ether (4: 1) as eluent gave an additional 510 mg of product, m.p. 163-170 ° C.

Purification was continued by recrystallization from ethyl acetate, m.p. 173-174 ° C.

Calculated: C 62.16 H 5.74 N 7.25%

Found: C 62.00 H 5.83 N 7.14% m / e - 193 (m +), 178 (m + - methyl, base peak).

Similarly, after 3,3-dimethylacrylic acid and 3,5-dimethoxyaniline, purification by silica gel chromatography (eluent benzene ether 1: 1) gave 5,7-dihydroxy-2,2-dimethyl-4-oxo-1,2 , 3,4-tetrahydroquinoline as a yellow oil.

Analysis (MS) 35 Basic peak (m +)

C11H13 ° 3 N

38 64142

Calculated: 207.0895 Found: 207.0895

Base Peak (m + - 15)

C10H10 ° 3 N

5 Calculated: 192.0661

Found: 192.0655

Similarly, condensation of 3,5-dimethoxyaniline and styrylacetic acid gave dl-5,7-dihydroxy-2-benzyl-4-oxo-1,2,3,4-tetrahydroquinoline as an oil after purification with benzene ether as eluent ( 3: 1).

m / e = 269 (m +) and 178 (m + -benzyl, base peak).

NMR (CDCl 3) (ppm): 8.76 (s, 1H, 5-OH), 7.18-7.6 (m, 5H, C 9 H 5), 5.84 (d, J = d Hz, 1H) and 5.62 (d, J = 3 Hz, 1H) for meta-coupled aromatics and 2.14-4.82 (4m, 7H) for residual protons (7-OH, CH-N, CH2-C = O, -CH2- C6H5 and NH).

Example 17 dl-5-Hydroxy-2-methyl-7- (2-heptyloxy) -4-oxo-1,2,3,4-tetrahydroquinoline

325 mg (52 mmol) of potassium hydroxide tablets were added to a solution of 1.0 g (52 mmol) of dl-5,7-dihydroxy-2-methyl-4-oxo-1,2,3,4-tertahydroquinoline. In 10 ml of N, Ν-dimethylformamide. The mixture was slowly heated to 100 ° C and 1.08 g (60 mmol) of dl-2-bromo-25 heptane was added to the resulting solution all at once with good stirring. After ten minutes, 160 mg of potassium hydroxide and 500 mg of dl-2-bromoheptane were added. 80 mg of potassium hydroxide and 250 mg of dl-2-bromoheptane were added twice more. The reaction mixture was stirred for 10 minutes and cooled. 50 ml of chloroform and 25 ml of 30 L of aqueous sodium hydroxide solution were added, the mixture was stirred for 10 minutes, and the layers were separated. The chloroform extract was repeated, the extracts combined, dried over magnesium sulfate and evaporated in vacuo to a dark oil. the oil was chromatographed on 120 g of silica gel 35 using benzene as solvent. Fractions 12-18 were combined, evaporated in vacuo to give 850 mg of pale I! 64142 39 yellow oil which crystallized on standing. The desired product was isolated by filtration and crystallized from hot hexane, m.p. 76-77 ° C.

The above procedure was repeated on a 20-fold 5 scale using benzene-ethyl acetate (9: 1) as the chromatographic solvent. 750 ml fractions were collected. Combining fractions 2-6 gave 32 g of an oil which, on standing and cooling, crystallized into hexane to give 18.2 g of product. An additional 3.2 g of product 10 was obtained by concentrating the mother liquor and allowing it to crystallize in the cold. Total yield 21.4 g.

Analysis c17H25 ° 3N

Calculated: C 70.07 H 8.65 N 4.81%

Found: C 69.82 H 8.67 N 4.83% 15 m / e = 291 (m +), IR (KBr): 6.01 (u)

Similarly, 5,7-dihydroxy-4-oxo-1,2,3,4, -tetrahydroquinoline was converted to dl-5-hydroxy-7- (2-heptyloxy) -4-oxo-1,2,3,4 -tetrahydroquinoline, oil.

1 H-NMR (60 (ppm): 13.3 (s, 1H, phenol), 5.5 and 5.7 (d, 2H, J = 2 Hz, aromatic), 4.6 (bs, 1H, -NH), 4.1-4.6 (m, 1H, -O-CH-), 3.3 (5.2H, J = 7 Hz, -CH2-), 2.6 (t, 2H , J = h Hz, -CH 2 -), 2.0-0.7 (m, residual protons) Example 18 dl-5-hydroxy-2-methyl-7- (5-phenyl-2-pentyl-25-oxy) -4-oxo-l, 2,3,4-tertahydrokinoliini

A mixture of 16.4 g (100 mmol) of 5-phenyl-2- (R, S) -pentanol, 28 ml (200 mmol) of triethylamine and 80 ml of tetrahydrofuran was cooled in a nitrogen-protected ice-water bath. 8.5 ml (110 mmol) of methanesulfonyl chloride in 20 ml of dry tetrahydrofuran were added dropwise at such a rate that the temperature remained almost constant. The mixture was allowed to warm to room temperature and filtered to remove triethylamine hydrochloride. The filter cake was washed with dry tetrahydrofuran and the combined washings and filtrate were evaporated in vacuo to an oil. This was dissolved in 10 ml of chloroform and the solution was washed with 2 x 100 ml of water and 1 x 20 ml of saturated brine. Evaporation of the solvent gave 21.7 g (89.7%) of dl-5-phenyl-2-pentanol mesylate, which was used in the next step without further purification.

A mixture of 1.0 g (5.2 mmol) of dl-5,7-dihydroxy-2-methyl-4-oxo-1,2,3,4-tetrahydroquinoline, 14.35 g (0.104 mol) ) potassium carbonate, 60 ml of N, N-dimethylformamide and 13.68 g (57 mmol) of dl-5-phenyl-2-pentanol mesylate were heated under nitrogen for 1.75 hours at 80-82 ° C. The mixture was cooled to room temperature and poured into 300 ml of ice water. The aqueous solution was extracted with 2 x 50 mL of ethyl acetate, and the combined extracts were washed successively with 3 x 50 mL of water and 1 x 50 mL of saturated brine. The extract was dried over magnesium sulfate, decolorized with activated carbon and evaporated to give the product, m / e = 339 (m +).

The procedure described above was repeated, but using 114.8 g (0.594 moles) of dl-5-hydroxy-2-methyl-7-20 (5-phenyl-2-pentyloxy) -4-oxo-1,2,3,4- tetrahydroquinoline, 612 ml of N, N-dimethylformamide, 174.8 g (1.265 moles) of potassium carbonate and 165.5 g (0.638 moles) of dl-5-phenyl-2-pentanol mesylate. The reaction mixture was cooled, poured into 4 liters of ice water and the aqueous solution was extracted with 2 x 4 liters of ethyl acetate. The combined extracts were washed with 4x2 liters of water and 1 x 2 liters of brine and dried over magnesium sulfate. Evaporation gave 196 g of the title product. It was used crude.

i, TMS

30 n NMR (60 MHzJ / cDCl (PF δ: 12.73 (s, 1H, OH), 7.22 (s, 5H, aromatic), δ 3.80 (d, J = 3 Hz, 1H, meta -H), 5.58 (d, J = d Hz, 1H, meta-H), 1.25 (d, 6H, CH 3 -CH-N and CH 2 -CH-O), 1.41-4, 81 (m, 11H, residual protons).

Example 19 35dl-5-Hydroxy-7- (5-phenyl-2-pentyloxy) -4-oxo-1,2,3,4-tetrahydrocolinoline

By repeating the method of Example 18, but using

B

64142 41 5.7-Dihydroxy-4-oxo-1,2,3,4-tetrahydroquinoline Instead of 5,7-dihydroxy-2-methyl-4-oxo-1,2,3,4-tetrahydroquinoline, dl-5- hydroxy-7- (5-phenyl-2-pentyloxy) -4-oxo-1,2,3,4-tetrahydroquinoline as an oil, yield 74%.

5 m / e = 325 (m +)

Analysis for C 20 H 23 NO 3

Calculated: C 73.70 H 7.12 N 4.31%

Found: C 73.69 H 7.15 N 4.08% ΧΗ NMR (60 MHz) (ppm): 12.6 (bs, 1H, phenol), δ 7.3 (s, 5H, aromatic), δ, Δ (d, 1H, aromatic, J = 2 Hz), 5.6 (d, 1H, aromatic, J = 2 Hz), 4.7-4.1 (m, 2H, NH and O-CH), 3 Δ (5, 2H, CH 2, J = 7 Hz), 3.1-2.1 (m, 4H, 2-CH 2 -), 2.1-1.5 (m, 4H, 2-CH 2 -), 1.3 (d, 3H, -CH-CH-j, J = 6 Hz).

Similarly, 27 g (0.14 moles) of dl-5,7-dihydroxy-2-methyl-4-oxo-1,2,3,4-tetrahydroquinoline was alkylated with 35.2 g (0.154 moles) of 4-phenylbutyl methanesulfonate. and 41.1 g (90%) of the desired dl-5-hydroxy-2-methyl-7- (4-phenylbutyloxy) -4-oxo-1,2,3,4-tetrahydroquinoline were obtained, m.p. 88-90 ° C. Recrystallization from ethyl acetate-hexane (1: 2) gave an analytical sample, m.p. 90-91 ° C.

Analysis for C2q h23o3n

Calculated: C 73.82 H 7.12 N 4.30% Found: C 73.60 H 7.09 N 4.26% m / e = 3.25 (m +) 1 H NMR (60 MHz) / Δ Ci (PPm): 12'58 (s' 1H '~ 0H>' 7.21 (3.5H, C6H5), 5.74 (d, 3J = 2.5 Hz, 1H, meta-H), δ Δ (d, J = 2.5 Hz, 1H, met.aH), 4.36 (bs, 1H, NH), 3.33-4.08 (m, 3H, -O-CH 2, -CH -N), 2.29-2.83 (m, 4H, -CH 2 -C = O) C 9 H 9 -CH 2), 1.51-1.92 (m, 4H, - (CH 2) 2, 1.23 ( d, 3H, -CH 3).

Similarly, alkylation of d-5,7-dihydroxy-4-oxo-1,2,3,4-tetrahydroquinoline with d-2-octyl methanesulfonate gave d-5-hydroxy-2-methyl-7- (2- (R) -octyloxy) -35 4-oxo-1,2,3,4-tetrahydroquinoline, m.p. 64-68 ° C.

42 64142 K725 = + 110.2 ° (C = 1.0, CHCl3).

D J

Alkylation of dl-5,7-dihydroxy-2-propyl-4-oxo-1,2,3,4-tetrahydroquinoline with dl-5-phenyl-2-pentanol mesylate gave dl-5-hydroxy-7- (5-phenyl -2-pentyloxy) -5-propyl-4-oxo-1,2,3,4-tetrahydroquinoline, m / e = 367 (m +).

Example 20 dl-1-Formyl-5-hydroxy-3-hydroxymethylene-2-methyl-7- (5-phenyl-2-pentyloxy) -4-oxo-1,2,3,4-tetrahydro-10-quinoline

A solution of 195 g (ca. 0.58 moles) of dl-5-hydroxy-2-methyl-7- (5-phenyl-2-pentyloxy) -4-oxo-1,2,3,4-tetra- rohydroquinoline in 1140 g (14.6 moles) of ethyl formamide was added dropwise with good stirring to 72 g (3.0 to 15 moles) of sodium hydride (obtained by washing 144 g of 50% sodium hydride in 3 x 500 ml of hexane). ). After about one and a half hours, when 2/3 of the ethyl formate solution had been added, the addition was stopped and the vigorous foam was allowed to settle. 600 ml of diethyl ether were added and the mixture was stirred for 15 minutes before the rest of the ethyl formate solution was added. At the end of the addition, 600 ml of diethyl ether were added, the reaction mixture was stirred for 10 minutes and poured into 2 liters of ice water. Acidification with 10% hydrochloric acid to pH 1, the phase was separated and extracted with 2x2 liters of ethyl acetate. The combined organic solutions were washed successively with 2x2 liters of water and 1 x 1 liter of brine and dried over magnesium sulfate. Evaporation gave 231 g of a red oily oil which was used without further purification.

30 = 0.1 - 0.5 (stretched) thin layer chromatography, silica gel plates, benzene ether (1: 1).

Similarly, dl-5-hydroxy-7- (5-phenyl-2-pentyloxy) -2-propyl-4-oxy-1,2,3,4-tertahydroquinoline was converted to dl-1-formyl-5-hydroxy- To 3-hydroxymethylene-7- (5-phenyl-2-pentyloxy) -2-propyl-4-oxo-1,2,3,4-tetrahydroquinoline. It was used as such in the following examples.

43 64142

EXAMPLE 21 dl-l-formyl-5-hydroxy-3-hydroksimetvleeni-2-methyl-7- (2-heptyloxy) -4-oxo-l, 2,3,4-tetrahydro-market lilni 5 was added dropwise during half an hour 18 , 2 g (0.38 moles) of sodium hydride (obtained by washing with pentane 50% sodium hydride as a mineral oil dispersion) containing a solution of 11.1 g (0.038 moles) of dl-5-hydroxy-2-methyl-7- (2- heptyloxy) -4-oxo-1,2,3,4-tetrahydroquinoline 110 in 10 g (1.48 moles) of ethyl formate. The reaction was exothermic, strongly releasing hydrogen and forming a yellow precipitate. The reaction mixture was cooled, 750 ml of ether were added and the resulting mixture was heated under constant cooling and stirring for three hours. It was then cooled to 0 ° C and neutralized by adding 400 ml of 1N hydrochloric acid. The ether layer was separated and the aqueous phase was extracted with 2 x 150 mL of ether. The ether extracts were combined, washed successively with 2 x 100 mL of saturated sodium bicarbonate solution and 1 x 150 mL of brine, and dried over magnesium sulfate. Evaporation of the dried extract gave 10.8 g of an orange foam. An additional 2.3 g of product was obtained by acidifying the sodium bicarbonate washings with concentrated hydrochloric acid and extracting the acid solution with 2x100 ml of ether. Evaporation after drying of the combined ether extracts gave 2.3 products (13.1 g in total). The product was used as such.

1 H NMR (60 (ppm): 12.27 (bs, 1H, ArOH), 8.8-11.9 (m, 1H, variable, 3 = COH), 8.73 (s, 1H, N-CHO) , 7.41 (s, 1H, = CH), 6.32 (s, 2H, aromatic), 5.52 (q, 1H, -CH-N), 4.18-4.77 (m, 1H , -O-CH), 0.6-2.08 (m, 17H, ch3-c-c5hi; 1 and ch3-cn).

Similarly, dl-5-hydroxy-2-methyl-7- (5-phenyl-2-pentyloxyH-oxo-1,2,3,4-tetrahydroquinoline was converted to 35 dl-1-formyl-5-hydroxy-3- hydroxymethylene-2-methyl-7- (5-phenyl-2-pentyloxy) -4-oxo-1,2,3,4-tetrahydroquinoline.

44 64142 1 H NMR (60 MHz) δ (ppm): 12.22 (bs, 1H, ArOH), 8.8-11.6 variable, 1H, = c 3h), 8.64 (s, 1H, -CHO) , 7.21 (bs, shoulder at 7.30, 6H, aromatic and = CH), 6.23 and 6.17 (two 1H-doublets, j = 2 Hz, meta), 5.42 δ (bq, 1H , N-CH), 4.18-4.70 (m, 1H, -OCH), 2.4-3.0 (m, 2H,

Ar-CH 2), 1.53-2.0 (m, 4H, - (<2) 2 '1/29 (overlapping doublets, 6H, CH 2 -C-N and CH-C-O).

dl-5-hydroxy-7- (2-heptyloxy) -4-oxo-1,2,3,4-tetrahydroquinoline was converted to dl-1-formyl-5-hydroxy-3-hydroxymethylene-7- (2-heptyloxy) To 4-oxo-1,2,3,4-tetrahydroquinoline, oil.

1 H NMR (60 MHz) δ DCI (PP δ: 12 δ (hs, 1H 'phenol), 8.8 (S, 1H, -N-CHO), 8.1 (s, h), 7.3 (s , 1H), 6.1 (s, 2H, aromatic), 4.5 (bs, 2H, -CH 2), 4.2-4.8 (m, -Q-CH 2 * ·), 2.0 -0.7 (residual protons).

dl-5-hydroxy-7- (5-pentyl-2-pentyloxy) -4-oxo-1,2,3,4-tetrahydroquinoline was converted to dl-1-formyl-5-hydroxy-3-hydroxymethylene-7- (5 -phenyl-2-pentyloxy) -4-oxo-1,2,3,4-tetrahydroquinoline.

20 NMR (60 MHz δ cDCl (PE * 1): 12'4 <bs '1H' phenol), 8.5 (s, 1H, CHO), 7.2 (m, 6H? Aromatic and = CH-), 6.2 (m, 2H, aromatic), 4.5 (s, 2H, -CH 2 -), 4.4 (m, 1H, -CH-CH 2 -) / 2.6 (bt, 2H, -CH 2 -) ), 1.7 (m, 5H, residual protons), 1.3 (d, 3H, -CH-CH 3, J = 6 Hz).

25 dl-5-hydroxy-2-methyl-7- (4-phenylbutyloxy) -4-oxo-1,2,3,4-tetrahydroquinoline was converted to dl-1-formyl-5-hydroxy-3-hydroxymethylene-2-methyl -7- (4-phenylbutyloxy) -4-oxo-1,2,3,4-tetrahydroquinoline, m.p. 132-135 ° C (from hexane). Recrystallization from hot methanol gave an analytical sample, m.p. 131-132 ° C.

Analysis for C22H23 ° 5N

Calculated: C 69.27 H 6.08 N 3.67%

Found: C 69.25 H 5.88 N 3.88% m / e = 381 (m +) TMg 35 1 H NMR (60 MHz) δ CDCl 3 (ppm): 12.4-13.6 (m, H, OH ), 12.26 (s, 1H, 5-OH), 8.62 (2H, -C (= O) -H), ca. 7.18-7.48

II

45 64142 (m, 1H, -H), 7.27 (s, 5H, C 9 H 9), 6.26 (bs, 3H, meta-H), 5.46 (q, 1H, CH-N), 3.82-4.23 (ra, 3H, -CH 2 -O), 2.49-2.80 (ra, 3H, ArCH 2), 1.67-2.02 (m, 4H, - (CH 2) 2) -), 1.27 (d, 3H, ch 3).

Example 22 dl-1-Forryl-5-hydroxy-2-methyl-7- (5-phenyl-2-benzyloxy) -4-oxo-3- (3-oxobutyl) -1,2,3,4 tetrahydro-quinoline

To a solution of 229 g (ca. 0.58 moles) of dl-1-for-10-rayyl-3-hydroxymethylene-5-hydroxy-2-methyl-7- (5-phenyl-2-pentyloxy) -4-oxo -1,2,3,4-Tetrahydroquinoline in 880 ml of methanol was added with stirring under nitrogen to 27.2 ml of triethylamine. 97.0 ml of methyl vinyl ketone were then added and the mixture was stirred overnight at room temperature.

The reaction was complete and a mixture of the title compound and dl-1,3, -diformyl-5-hydroxy-2-methyl-7- (5-phenyl-2-pentyloxy) -4-oxo-3 was formed. - (3-oxobutyl), 1,2,3,4-tetrahydroquinoline. In the following steps, the diformyl compound was converted to the desired title compound.

The reaction mixture was diluted with 6 liters of ether, washed successively with 4 x 1700 ml of 10% aqueous sodium carbonate solution and 1 x 2 liters of brine, and dried over magnesium sulfate. Evaporation of the solution gave 238 g of a red-brown oil. This was dissolved in 1920 ml of methanol and the solution was cooled to 0 ° C.

21.2 g of potassium carbonate were added, the mixture was stirred for 3 hours at 0 ° C and treated with 18.7 g of acetic acid.

The methanol was removed in vacuo and the resulting oil, 2 liters of water and 2 liters of ethyl acetate were stirred for 30 minutes. The aqueous phase was separated, extracted with 1x2 liters of ethyl acetate, the combined ethyl acetate solutions were washed with 2x2 liters of water and 1 x 2 liters of brine and dried over magnesium sulfate. Evaporation in vacuo and chromatography of the concentrate on 1.8 kg of silica gel gave 159 g of the title product.

46 64142 m / e = 437 (m +).

Δ NMR (60 MHz) [(ppm): 12.7 (s, 1H, OH), 8.78, (bs, 1H, -CHO), 7.22 (s, 5H, Aromatic), 6.22 ( bs, 2H, meta-Hs), 2.12, 2.07 (s, 3H, -CH 3 -CO-), 1.31 (d, 3H, 5 -CH 2 -CO-) and 1.57 -5.23 (m, 13H, residual protons).

By similar treatment with 35 g (0.09 moles) of dl-1-fornyl-5-hydroxy-3-hydroxymethylene-2-methyl-7- (4-phenylbutyloxy) -4-oxo-1,2,3,4-tetrahydroquinoline 22.7 g (60%) of dl-1-formyl-5-hydroxy-2-methyl-10- (4-phenylbutyloxy) -4-oxo-3- (3-oxobutyl) -1,2,3, 4-tetrahydroquinoline, m.p. 101-103 ° C. An analytical sample was obtained by recrystallization from methanol, m.p. 104-105 ° C;

Analysis C25H29 ° 5N

Calculated: C 70.90 H 6.90 N 3.31% Found: C 70.77 H 6.81 N 3.46%.

Δ NMR (60 MHz) δ δ (ppm): 12.88 (s, 1H, -OH), 9.08 (bs, 1H, -CHO), 7.29 (s, 5H, 3C 6 H 5), δ, 25 (bs, 2H, meta-Hs), 4.88-5.43 (m, 1H, -CHN), 3.86-4.21 (m, 2H, -CH 2 -O-), n. 2.49-3.02 (m, 7H, ArCH 2, - (CH 2) 2 -C (= O) -, -CH-C (= O)), 2.18 δ (s, 3H, CH 3 -C ( = 0)), 1.68-2.03 (m, 4H, - (CH 2) 2 -), 1.13 (d, 3H, CH 3). m / e = 423 (m +).

and treatment of dl-1-formyl-5-hydroxy-3-hydroxymethylene-7- (5-phenyl-2-pentyloxy) -2-propyl-4-oxo-1,2,3,3,4-tetrahydroquinoline gave dl -1-Formyl-5-hydroxy-7- (5-phenyl-2-pentyloxy) -4-oxo-3- (3-oxobutyl) -1,2,3,4-tetrahydroquinoline used as such .

Example 23 dl-1-Formyl-5-hydroxy-4-methyl-β- (2-heptyloxy) -4-oxo-3- (3-oxobutyl) -1,2,3,4-tetrahydroquiniline and dl-1 3, -diformyyli-5-hydroxy-2-methyl-7- (2-heptyyliok-phenoxy) -4-oxo-3- (3-oxobutyl) -1,2,3,4-tetrahydroquinoline

To a solution of 13.1 g (37.7 moles) of dl-5-hydroxy-3-hydroxymethylene-2-methyl-7- (2-heptyloxy) -4-oxo-1,2,3,4 -tetrahydroquinoline in 56 ml of methanol and li 47 64142 5.52 mg (68 mmol) of methyl vinyl ketone, 1.3 ml (9.3 mmol) of triethylamine were added. The mixture was stirred for 18 hours at room temperature under a nitrogen blanket and diluted with 550 ml of ether. The solution was washed with 4 x 60 mL of 10% aqueous sodium bicarbonate and 1 x 100 mL of brine and dried over magnesium sulfate. The ether was removed by evaporation to give 16 g of a dark oil. This was dissolved in as little benzene as possible and the solution was loaded onto a column of 500 g of silica gel. The column was eluted with a volume of benzene corresponding to its volume. The elution solvent was then changed to 15% etherbenzene and 100 ml fractions were collected when the first colored zone began to elute from the column. Fractions 5 to 13 were combined and evaporated in vacuo to give 8.7 g of dl-1,3-diformyl-5-hydroxy-2-methyl-7- (2-heptyloxy) -4-oxo-3- (3 -oxobutyl) -1,2,3,4-tetrahydroquinoline as a yellow oil.

The column was further eluted with 15% ether-benzene-20. Fractions 19-37 were combined and evaporated in vacuo to give 4.6 g of dl-1-formyl-5-hydroxy-2-methyl-7- (2-heptyloxy) -3- (3-oxobutyl) -1.2, 3,4-Tetrahydroquinoline as an oil. An additional monoformyl product was obtained as follows.

1 g of diformyl product and 200 mg of potassium carbonate in 25 ml of methanol were stirred for two hours at 0 ° C.

The solvent was evaporated in vacuo, the residue was suspended in ether and filtered. The filtrate was evaporated and the residue was partitioned between ether and water. The organic layer was separated, the aqueous phase was acidified with 10% hydrochloric acid and extracted with ether. The combined ether extracts were washed successively with saturated sodium bicarbonate solution and brine, and dried over magnesium sulfate. Filtered, evaporated to give 35 more monoformyl products.

641 42 48

The NMR spectrum of the monoformyl derivative was: 1 H NMR (60 MHz) / δ cl (Ppm): 12/72 (s, 1Hp ArOH), 8.87 (s, 1H, N-CHO), 6.12 (s? 2H, aromatic), 4.78-5.50 (m, 1H, N-CH), 4.11-4.72 (m, 1H, -O-CH), 2.21 (s, 3H, C (= O) -), 0.63-3.12 (m, 22H, residual hydrogen).

In a similar manner the following compounds were prepared from the appropriate reactants: dl-1-formyl-5-hydroxy-7- (2-heptyloxy) -4-oxo-3- (3-oxobutyl) -1,2,3,4-tetrahydroquinoline, oil.

1 H NMR (60 MHz) δ coci (ppm): 12'8 (1H 'phenol), 8.7 (s, 1H, N-CHO), 6.1 (s, 1H, aromatic), δ , 1-4.6 (m, 1H, -O-CH), 4.1 (d, 2H, J = 5 Hz, -CH 2 "), 2.3-3.0 (m, 3H, CH 2 and CH -C (= O)), 2.2 (s, 3H, -C (= O) -CH 3), 2.3-0.7 (residual protons).

Dl-1-formyl-5-hydroxy-2-methyl-7- (5-phenyl-2-pentyloxy) -4-oxo-3- (3-oxobutyl) -1,2,3,4-tetrahydroquinoline.

1 H NMR (60 MHz) (ppm): 12.68 (s, 1H, -OH), 8.82 (b, s, 1H, -C (O) H), 7.2 (3, b, s, Δ H, C 9 H 6, 6.18 (b, s, 2 2 H, aromatic), 4.78-5.34 (m, 1H, -N-CH), 4.18-4.68 (m, 1H, - O-CH), 2.17 (s, 3H, -C (O / CH 3), 1.30 (d, 3H, -O-C-CH 3), 1.12 (d, 3H, -NC-CH 3) , 1.4-3.1 (m, 11H, residual hydrogen).

dl-1-formyl-5-hydroxy-7- (5-phenyl-2-pentyloxy) -4-oxo-3- (3-oxobutyl) -1,2,3,4-tetrahydroquinoline.

25 m / e = 423 (m +) -

In all these preparations, the corresponding 1,3-dihydroformyl derivative was also formed as a by-product.

Example 24 dl-5,6,6a-7-Tetrahydro-1-hydroxy-6β-methyl-3-30- (5-phenyl-2-pentyloxy) -benzo [c] quinolin-9 (8H) -one

A solution of 174 g (0.398 mol) of dl-1-formyl-5-hydroxy-2-methyl-7- (5-phenyl-2-pentyloxy) -4-oxo-3- (3-oxobutyl) -1, 2,3,4-Tetrahydroquinoline in 5.9 liters of 2N potassium hydroxide-methanol solution and 5.9 liters of methanol-35 were stirred and heated at reflux overnight under nitrogen. To the cooled solution was added ti- 1! 49 64142 with dropping and stirring for 15 minutes 708 g of acetic acid. The resulting solution was evaporated on a rotary evaporator (vacuum, water suction) to a semi-solid which was isolated by filtration and washed first with water to remove potassium acetate and then with ethyl acetate until the black tar was removed. Yield 68 g (44%) of a yellow solid, m.p. 188-190 ° C. Recrystallization from hot ethyl acetate gave the pure product, m.p. 194-195 ° C. m / e = 391 (m +)

Analysis C25H29 ° 3N

Calculated: C 76.09 H 7.47 N 3.58%

Found: C 76.43 H 7.48 N 3.58%.

NMR (60 MHz) (100 mg dissolved in 0.3 ml CD 3 OD and 0.3 ml CD 3 S (O) CD 3) (ppm): 7.21 (s, 5H, aromatic), δ .80 (s, 2H, meta-Hs), 1.20 (d, 6H, CH 3 -CH-N).

Evaporation of the mother liquors gave a small amount of the corresponding axial methyl derivative. It was purified by column chromatography on silica gel using benzene ether (1: 1) as eluent. Evaporation of the eluate and recrystallization of the residue from ether-hexane (1: 1) gave analytically pure material, m.p. 225-228 ° C.

Thin layer chromatography on silica gel using 2.5% methanol in ether as eluent and visualization with true blue had an Rf value of 0.34. The Rf value of the 6β-methyl-25 derivative was 0.41.

m / e = 391 (m +).

1 H NMR (60 MHz) / TMS (100 mg dissolved in 0.3 mL of CD 2 OD and 0.3 mL of CD 2 SiO 2 CD 2) (ppm): 7.19 (s, 5H, aromatic), δ, 75 (s, 2H, meta-Hs), 1.21 (d, 3H, CH 2 -CHO-) and 0.95 (d, 3H, CH 3 -CH-N).

Similar treatment with 22 g of dl-1-formyl-5-hydroxy-2-methyl-7- (4-phenylbutyloxy) -4-oxo-3- (3-oxobutyl) -1,2,3,4-tetrahydroquinoline gave 17 , 1 g (87%) of dl-5,6,6a, 7-tetrahydro-1-hydroxy-6H-methyl-3-35- (4-phenylbutyloxy) -benzo [c] quinolin-9 (8H) -one, mp.

222-224 ° C. An analytical sample was obtained by recrystallization from methanol, m.p. 224-225 ° C.

50 64142

Analysis ^ 24 ^ 27 ^ 3 ^

Calculated: C 76.36 H 7.21 N 3.71%

Found: C 76.03 H 7.08 N 3.68%.

1 H NMR (60 MHz) (1: 1 mixture of (CD 3) 2 SO and DC 3 OD): δ 1.24 (d, 3H, 6 -CH 3).

m / e = 377 (m +)

Evaporation of the mother liquor gave 2.8 g (m.p. 185-195 ° C) of product which, according to NMR analysis, was a 6 / O-methyl derivative (ca. 40%) and dl-5,6,6a, 7-tetrahydro-1 -mixture of hydroxy-6-10-methyl-3- (4-phenylbutyloxy) -benzo [c] quinolin-9 (8H) -one.

1 H NMR (60 MHz) (1: 1 mixture of (CD 3) 2 SO and CD 3 OD): 1.24 (d, 1.2, H, 6/3> -CH 3) and 0.95 (d, 1 , 8H,.

Example 25 dl-5,6,6a, 7-Tetrahydro-1-hydroxy-6 / O-methyl-3- (2-heptyloxy) -benzo [c] quinolin-9 (8H) -one

A solution of 4.5 g (11.5 mmol) of dl-1-formyl-5-hydroxy-2-methyl-7- (2-heptyloxy) -4-oxo-3- (3-oxo-butyl) - 1,2,3,4-Tetrahydroquinoline in 150 ml of methanol 20 was treated with 150 ml of 2N potassium hydroxide-methanol solution. The mixture was stirred for one hour at room temperature and heated under reflux for 20 hours under nitrogen.

The dark red mixture was allowed to cool to room temperature, neutralized with acetic acid and evaporated in vacuo to about 100 ml. The concentrate was diluted with 400 ml of water, the brown-red solid was isolated by filtration, washed with water, dried to give 6 g. Triturated first in ether and then in methanol, filtered, dried to give 1.96 g, mp 223-229 ° C. Recrystallization from hot methanol gave crystals, m.p. 235-237 ° C.

Analysis for C 21 H 29 O 3 N

Calculated: C 73.43 H 8.51 N 4.08%

Found: C 73.22 H 8.30 N 4.11%.

35 Further material was obtained by evaporating all the mother liquors and extracting with aqueous chloroform to give

II

641 42 51 brown-red impure product, and evaporating the extract. The combined residues were purified by chromatography on silica gel using ether as eluent.

In a similar manner the following compounds were prepared from 5 suitable reactants: dl-5,6,6a, 7-tetrahydro-1-hydroxy-3- (5-phenyl-2-pentyloxy) -benzo [c] quinolin-9 (8H) -one; mp. 170-173 ° C (recrystallized from chloroform) m / e = 377 (m +)

10 Analysis for C24H2? 03N

Calculated: C 76.36 H 7.21 N 3.71%

Found: C 76.38 H 7.21 N 3.85% dl-5,6,6a, 7-tetrahydro-1-hydroxy-3- (2-heptyloxy) -benzo [c] quinolin-9 (8H) - oni, sp. 208-20 ° C 15 m / e = 329 (m +)

Analysis for C 20 H 27 O 3 N

Calculated: C 72.92 H 8.26 N 4.25%

Found: C 72.92 H 8.31 N 4.42%.

dl-5,6,6a, 7-tetrahydro-1-hydroxy-3- (5-phenyl-2-pen-20-yloxy) -6H-propylbenzo [c] quinolin-9 (8H) -one, m.p.

164-166 ° C.

Analysis for C27H33 ^ 3N

Calculated: C 77.29 H 7.93 N 3.34%

Found: C 76.97 H 7.98 N 3.41%.

1-5,6,6a, 7-tetrahydro-1-hydroxy-3- (5-phenyl-2-pentyloxy) -6,3-methylbenzo [c] quinolin-9 (8H) -one, m.p. 176-178 ° C.

Zc * C7q5 = -416.0 ° (C = 0.33, CH3OH) m / e = 391 (m +) 30 Analysis ^ ^ 25 ^ 29 ^ 3 **

Calculated: C 76.69 H 7.47 N 3.58%

Found: C 76.32 H 7.36 N 3.33%.

d-5,6,6a, 7-tetrahydro-1-hydroxy-3- (5-phenyl-2-penylethyloxy) -6,3-methylbenzo [q] quinolin-9 (8H) -one, m.p.

35 17 2-174 ° C.

52 6 4 1 42 £ (J 2 = + 412.9 ° C (c = 1.0, CH 3 OH) m / e = 391 (m +)

Analysis C25H29 ° 3N

Calculated: C 76.69 H 7.47 N 3.58% Found: C 76.40 H 7.39 N 3.51%.

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Example 26 dl-5,6,6a, 71Q, 10a-Hexahydro-1-hydroxy-6H-methyl-3- (2-heptyloxy) -benzo [c] quinolin-9 (8H) -one

Suspension of 1.0 g (2.91 mmol) of dl-5,6,6a, 7-5 tetrahydro-1-hydroxy-6H-methyl-3- (2-heptyloxy) -benzo [c] quinoline -9 (8H) -one in 30 ml of tetrahydrofuran was added dropwise via addition funnel to a vigorously stirred solution of 0.1 g of lithium in 75 ml of liquid ammonia (distilled through potassium hydroxide tablets).

The addition funnel was rinsed with 10 mL of tetrahydrofuran.

The mixture was stirred for 10 minutes and solid ammonium chloride was added to remove the blue color. The excess ammonia was evaporated and the residue was dissolved in 100 ml of water and 50 ml of ethyl acetate. The ethyl acetate layer was separated and the aqueous phase was extracted with 2 x 50 mL of ethyl acetate. The combined extract was washed with brine, dried over magnesium sulfate, evaporated in vacuo to give 1.35 g of a brown, semi-solid product. Trituration of this in pentane-ether (1: 1) gave 0.884 g of a light brown solid, m.p. 130-138 ° C.

The procedure described above was repeated, but using 1.84 g (5.36 mmol) of benzo [c] quinolin-9-one, 0.184 g of lithium, 140 ml of liquid ammonia and 45 ml of tetrahydrofuran. Evaporation of ammonia gave 2.1 g of a residue which was dissolved in benzene and the solution was loaded onto a chromatography column (3.8 x 61 cm) containing 250 g of silica gel. The column was eluted with a volume corresponding to its volume of gasified benzene and then with 1700 ml of gasified benzene ether (9: 1). Continuation of the elution with 1100 ml gave a bright red eluate which was evaporated in vacuo to 580 mg of a light purple solid and triturated in benzene ether (1: 1) to give 370 mg of solid, mp 154-156 ° C. It was stored under nitrogen in the dark.

35 The isolated solids were mixtures of the cis and transm forms of the title product.

58 64142 m / e = 345 (m +).

1 H NMR (100 MHz) (ppm): 6.85 and 7.49 (1H, broad, OH), δ, 7.71, 5.85, 5.93 (D, J = 2Hz, 2H total , cis / trans aromatic hydrogens), δ 0.90 (t, 3H, terminal-CH 2), 1.12-4.43 (m, residual hydrogen).

Example 27

Isomeric 5,6,6a, 7,10,10a-hexahydro-1-acetoxy-64,4-methyl-3- (2-heptyloxy) -benzo [c] quinolin-9 (8h) -ones

Under a nitrogen blanket, 2.2 ml of pyridine was added to a suspension of 222 mg (0.642 mmol) of 5,6,6a, 7,10,10a-hexahydro-1-hydroxy-6,3-methyl-3- ( 2-heptyloxy) -benzo [g] quinolin-9 (8Η) -one in 2.2 ml of acetic anhydride. The mixture was stirred for 1.5 hours at room temperature and poured into 50 ml of ice water. The precipitated gum 15 was extracted with 3 x 50 mL of ether and the combined extracts were washed with 4 x 50 mL of water and 1 x 60 mL of brine. The extract was dried over magnesium sulfate, evaporated in vacuo to give 250 mg of a red oil.

the oil was dissolved in as little moon ether as possible and the solution was applied to a column of 45 g of silica gel and eluted with 200 ml of pentane ether (3: 1). Elution was continued and 10 ml fractions were collected. Fractions 22-32 were combined, evaporated to give 113.5 mg of a foam which was crystallized from petroleum ethers-25 as white crystals, m.p. 112-114 ° C.

Fractions 33-50 were combined, evaporated to give 89.7 mg of a foam which was crystallized from petroleum ether as white crystals, m.p. 78-82 ° C.

The products are isomeric monoacetylated compounds.

Example 28 dl-5,6,6a, 7,10,10a-Hexahydro-1-acetoxy-6H-methyl-3- (2-heptyloxy) -benzo [c] quinolin-9 (8H) -one

The procedure of Example 26 was repeated, but twice the amounts of reactants were used. 2.22 g were obtained

II

641 42 59 products which were acylated. 2.35 g of product were obtained, which was triturated with pentane-ether (3: 1) to give 905 mg of a tan solid, which was recrystallized from ethanol-5 to give 404 mg of pale tan crystals, m.p.

112 to 113.5 ° C.

The mother liquors from which the solids were isolated above were combined and evaporated. The residue was dissolved in as little benzene-ether-methylene chloride-10 (1: 1: 1) as possible and loaded onto a column of 275 g of silica gel (packed with petroleum ether (3: 1) eluted). The column was eluted first with 2 liters of petroleum ether (3: 1), then with 1.5 liters of petroleum ether (2: 1) and with 2 liters of petroleum ether (1: 1). Eluate fractions 2-11 (50 ml each) were collected from a 1: 1 solvent system, evaporated in vacuo to give 496 mg of a foam. Crystallization from petroleum ether gave white crystals, m.p. 100-113 ° C. Recrystallization from ethanol-water (1: 1) gave dl-trans-5,6,6a, <5-7,10,10a -20 hexahydro-1-acetoxy-6/3-methyl-3- (2-heptyloxy) -benzo / c7-quinolin-9 (8H), oni, m.p. 111-112 ° C. m / e = 387 (m +)

Analysis for C23H33 ° 4N

Calculated: C 71.29 H 8.58 N 3.61% Found: C 70.95 H 8.64 N 3.58%.

Fractions 12-18 and 19-27 (50 ml each) were collected and evaporated to give 273 mg and 208 mg of acetylated product, respectively. Crystallization of the residue from fractions 19-27 from petroleum ether gave 119 mg of white crystals, m.p. 84-88 ° C. Crystallization from ethyl acetate-hexane (1:10) gave dl-cis-5,6,6a, 7,10,10a, N-hexahydro-1-acetoxy-3- (2-heptyloxy) -6- methylbenzo / cy-quinolin-9 (8H) -one, m.p. 84-86 ° C.

Analysis for C23H33 ° 4N

35 Calculated: C 71.29 H 8.58 N 3.61%

Found: C 71.05 H 8.48 N 3.56%.

60 641 42

In a similar manner the following compounds were prepared from the appropriate reactants: dl-trans-5,6,6a, N, N-hexahydro-1-acetoxy-6H-methyl-3- (5-phenyl-2-pentyloxy) ) -benzo [c] quinolin-59 (8H) -one, mp 80-82 ° C.

m / e = 435 (m +)

Analysis for C 27 H 33 O 4 N

Calculated: C 74.45 H 7.64 N 3.22%

Found: C 74.43 H 7.73 N 3.28%.

10 dl-cis-5,6,6a / 3,10,10,10a-hexahydro-1-acetoxy-6H-methyl-3- (5-phenyl-2-pentyloxy) benzo [c] quinolin-9 ( 8H) -one, m.p. 172-176 ° C as the hydrochloride salt from acetone-ether (1: 1).

Analysis for C27H3304N.HCl 15 Calculated: C 68.71 H 7.26 N 2.97%

Found: C 68.86 H 7.16 N 2.97%.

dl-trans-5,6,6aβ, 7,10,10a, N-hexahydro-1-acetoxy-3- (5-phenyl-2-pentyloxy) -6 <3-propylbenzo [c] quinolin-9 ( 8H) -one, m.p. 79-80 ° C.

20 m / e = 463 (m +) dl-cis-5,6,6a / E, 7,10,10a, 4-hexahydro-1-acetoxy-3- (5-phenyl-2-pentyloxy) -6 <3 -propylbenzo / q7-quinolin-9 (8H) -one, m.p. 144-146 ° C as the hydrochloride salt. m / e = 463 (m +) 25 d-cis-5,6,6a / 3 / 7,10,10a / 3-hexahydro-1-acetoxy-3- (5-phenyl-2-pentyloxy) -6/3 -methylbenzo [c] quinolin-9 (8H) -one, m.p. 90-94 ° C (decomposes) as the hydrochloride salt.

= + 22.8 ° (c = 0.31, CH 3 OH) m / e = 435 (m +) 30 Analysis for C 27 H 33 O 4 N * HCl

Calculated: C 68.71 H 7.26 N 2.97%

Found: C 69.24 H 7.30 N 3.01% d-trans-5,6,6a / E, 7,10,10a / 3-hexahydro-1-acetoxy-3- (5-phenyl-2- pentyloxy) -6 <3-methylbenzo [c] quinolin-359 (8H) -one, m.p. 90-95 ° C (decomposes) as the hydrochloride salt.

Il 61 641 42

CoO 2 = + 78.46 ° (c = 0.13, CH 3 OH) m / e = 435 (m +)

Analysis for C 70 H 12 O 2 N 2 .HCl Calculated: C 68.71 H 7.26 N 2.97% δ Found: C 70.20 H 7.23 N 3.07% 1-cis-5,6,6ay5 , 17,10,10a-hexahydro-1-acetoxy-3- (5-phenyl-2-pentyloxy) -6,3-methylbenzo [c] quinolin-9 (8H) -one, m.p. 90-92 ° C as the hydrochloride salt.

= -20.5 ° (c = 0.19, CH 3 OH) 10 m / e = 435 (m +)

Analysis for C27H33 ° 4N * HCl Calculated: C 68.7 H 7.26 N 2.97%

Found: C 68.92 H 7.23 N 3.09% 1-trans-5,6,6a <3,7,10,10a / 3-hexahydro-1-acetoxy-15 3- (5-phenyl-2 -pentyloxy) -6f-methylbenzo [c] quinolin-9 (8H) -one, m.p. 92-96 ° C as the hydrochloride.

= -79.0 ° (c = 0.10, CH 3 OH) m / e = 435 (m +)

Analysis for C 27 H 33 ° 4N.HCl 2 O Calculated: C 68.7 H 7.26 N 2.97%

Found: C 68.67 H 7.23 N 3.02 I.

Example 29 dl-5,6,6a, 7,10,10a-Hexahydro-1-acetoxy-6,5-methyl-3- (5-phenyl-2-pentyloxy) -benzo [c] quinolin-9 (8H) -one.

25 trans and cis isomers

Concentrate 1150 mL of ammonia under nitrogen in a direct flame-dried 3-liter three-necked flask equipped with a mechanical stirrer, a 500 mL dropping funnel, and solid CO 2 / acetone cooling (ca. -75 ° C).

30 2.2 lithium wire (6 mm in pieces) was added and a characteristic color formed immediately. To the stirred blue solution at -78 ° C was added dropwise over 10 minutes 21.5 g (0.055 moles) of dl-5,6,6a, 7-tetrahydro-1-hydroxy-6 <5-diethyl-3- ( 5-Phenyl-2-pentyloxy) -benzo [c] quinolin-9 (8H) -one in 250 ml of tetrahydrofuran. After stirring for 5 minutes at -78 ° C, the reaction was quenched by the addition of 20 g of 62 64142 dry ammonium chloride. Cooling was stopped and the reaction mixture was allowed to slowly warm in a water bath to evaporate the ammonia. When the reaction mixture was almost dry, 2 L of ethyl acetate and 1 L of water were added, and the mixture was stirred for 10 minutes. The layers were separated and the aqueous phase was extracted once with 50 ml of ethyl acetate. The combined organic extracts were washed once with 1 liter of water, dried over magnesium sulphate, evaporated to give about 20 g of a brown semi-solid. This residue was immediately dissolved in 200 ml of methylene chloride, 7.5 g (0.061 mol) of 4-dimethylaminopyridine and 6.1 g (0.061 mol) of triethylamine were added, and the stirred mixture was cooled to 0 ° C under nitrogen (ice-water cooling). . 6.1 g (0.061 mol) of acetic anhydride were added dropwise over 5 minutes with good stirring. After stirring for 30 minutes at 0 ° C, the reaction mixture was diluted with 2 liters of ethyl acetate and 1 liter of water and stirred for 10 minutes. The water-soluble material was extracted once more with water and the combined organic extracts were washed successively with 4 x 1 liter of water, 1 x 1 liter of saturated sodium bicarbonate solution and 1 x 1 liter of brine, dried over magnesium sulfate, evaporated to give about 27 g. The residue was chromatographed on 1.8 kg of silica gel using benzene-15-ethyl acetate as eluent. 1 liter fractions were collected.

After elution of less polar impurities, fractions 16-20 were combined and evaporated to a residue which was crystallized from ether-petroleum ether to give 5.6 g (23.4%) of the trans isomer of the title product. Fractions 21-27 were combined to give 7.6 g (31.8%) of a mixture of trans and cis isomers. Fractions 28-32 were combined to give 2.5 g (10.4%) of the cis isomer of the title product.

The trans isomer had the following characteristics: 35 m / e = 435 (m +) 64142 63 ΧΗ NMR (60 MHz) (ppm): 7.24 (s, 5H, aromatic), 5.97 (s, 2H, meta H: ^), 2.28 (s, 3H, CH3-COO), 1.23 (d, 3H, CH3-CH-O-), 1.20 (d, 3H, CH-j-CH-N) , 1.3-4.5 (m, 17H, residual protons).

5 Sp. 81-83 ° C

Analysis for C27H3304N

Calculated: C 74.45 H 7.64 N 3.22%

Found: C 74.15 H 7.68 N 3.18% The characteristic values of this cis isomer were: 10 m / e = 435 (m +)

The hydrochloride salt m.p. 172-176 ° C (decomposes, from acetone-ether).

Analysis for C 27 H 33 O 4 N, HCl

Calculated: C 68.71 H 7.26 N 2.97%

Found: C 68.86 H 7.16 N 2.97%.

Example 30 dl-5,6,6a, 7,10,10a-Hexahydro-1-acetoxy-6/5-methyl-3- (4-phenylbutyloxy) -benzo [c] quinolin-9 (8H) -one, trans and cis isomers

Following the procedure of Example 28 dl-5,6,6a, 7-tetra-20-hydro-1-hydroxy-6- (4-methyl-3- (4-phenylbutyloxy) -benzo) [c] quinolin-9 (8H) - The onion was first reduced with lithium and ammonia and then acylated to the desired hexahydroisomers. * 3-methyl-3- (4-phenylbutyloxy) -benzo [c] quinolin-9 (8H) -one, mp 155-156 ° C, after recrystallization from ethyl acetate-pentane (1: 5).

Analysis for C26H3104N

30 Calculated: C 74.08 H 7.41 N 3.32%

Found: C 74.00 H 7.47 N 3.22% m / e = 421 (m +).

Further purification of the subsequent fractions by column chromatography on silica gel using cyclohexane ether (1: 1) as eluent gave the isomeric dl-cis-5,6,6a, 7,10,10a-hexahydro-1-acetoxy-6H-methyl-3 - (4-phenylbutyloxy) -benzo [c] quinolin-9 (8H) -one, m.p.

64 64142 after recrystallization from 95-96 ° ethyl acetate-hexane (1: 5), m / e = 421 (m +)

Analysis 1 C26H31 ° 4N

5 Calculated: C 74.08 H 7.41 N 3.32%

Found: C 73.95 H 7.51 N 3.31%

In a similar manner, the following compounds were prepared from the appropriate reactants: 65,641 42

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64142 67

Example 31 dl-5,6,6aα, 7,10,10a-hexahydro-1-acetoxy-3- (2-heptyl) oxobenzo [d] quinolin-9 (8H) -one

A solution of 9.0 g of dl-5,6,6a, 7-tetrahydro-1-5-hydroxy-3- (2-heptyloxy) -benzo [g] quinolin-9 (8H) -one in 100 ml of tetrahydrofuran was added dropwise to a vigorously stirred solution of 0.1 g of lithium in 750 ml of liquid ammonia. An additional 0.1 g of lithium was added portionwise to ensure a blue color. The Se-10 was stirred for 10 minutes and the blue color was removed by the addition of excess ammonium chloride. The excess ammonia was evaporated and the residue was dissolved in a mixture of water and ethyl acetate. The combined extracts were washed with water and brine, dried over magnesium sulphate, evaporated to give 8.45 g of crude product as a brown solid.

8.0 g of crude product were suspended in 48 ml of methylene chloride at 0 ° C and treated with 3.24 g of N, N-dimethyl-4-aminopyridine and 3.72 ml of triethylamine. 2.52 ml of acetic anhydride were added to the mixture. , which was stirred for 30 minutes at 0 ° C. Dilute with 300 mL of methylene chloride, separate the methylene chloride layer, wash with 3 x 150 mL of water, 1 x 100 mL of saturated sodium bicarbonate solution, and 1 x 100 mL of brine, and dry over magnesium sulfate. Evaporation of methylene chloride gave 13.7 g of a dark oil which was subjected to column chromatography on 450 g of silica gel. The column was eluted sequentially with ether-hexane (1: 1), ether-hexane (2: 1) and ether. 18 ml fractions were collected. Fractions 306-224 were combined and evaporated to an oil which was crystallized from hexane to give 3.24 g (32%) of the trans isomer of the title compound as pale yellow crystals, m.p. 65.5-68 ° C. m / e = 373 (m +) 35 IR (KBr): 5.82 (ketone C = 0), 5.75 (ester C = 0), 295 (NH) / U · 641 42 68

Fractito 246-290 was combined, evaporated to give 0.55 g (5%) of the crude cis isomer of the title compound as an oil. It was further purified by column chromatography as described above to give pure cis-iso-5 mer as an oil.

m / e = 373 (m +) IR (CHCl 3): 5.82 (ketone C = O), 5.67 (ester C = O), 2.92 (NH) / U.

Analysis for C 22 H 31 ° 4N

10 Calculated: C 70.75 H 8.37 N 3.75%

Found: C 70.90 H 8.54 N 3.79%

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

In a similar manner the following compounds were prepared from dl-5,6,6a, tetrahydro-1-hydroxy-3- (5-phenyl-2-pentyloxy) -benzo [c] quinolin-9 (8H) -one: dl-trans-5 , 6,6a / 3 7,10,10aO-hexahydro-1-acetoxy-3- (5-phenyl-2-pentyloxy) -benzo [c] quinolin-9 (8H) -one, oil.

20 m / e = 421 (m +)

Analysis for C 26 H 31 O 4 N

Calculated: C 74.08 H 7.41 N 3.32%

Found: C 74.16 H 7.59 N 3.20% dl-cis-5,6,6 (), 7.10,10a / O-hexahydro-1-acetoxy-3- (5-25 phenyl-2 -pentyloxy) -benzo [c] quinolin-9 (8H) -one, oil.

m / e = 421 (m +)

Analysis 1 C26H31 ° 4N

Calculated: C 74.08 H 7.41 N 3.32%

Found: C 74.04, H 7.49 N 3.54% 30 and dl-5,6,6a, 7-tetrahydro-1-hydroxy-% / methyl-3- (5-phenyl-2-pentyloxy) -benzo [c] quinolin-9 (8H) -one was converted to dl-trans-5,6,6a7,10,10a-hexahydro-1-acetoxy-N-methyl-3- (5-phenyl-2-pentyloxy) -benzo [c] quinolin-9 (8H) -one, and dl-cis-5,6,6a, E, 7,10,10a-hexahydro-1-35 acetoxy-6β-methyl-3- ( 5-Phenyl-2-pentyloxy) -benzo [c] quinolin-9 (8H) -one.

64142 69

The isomer products were converted to their hydrochloride salts according to the general method of salt formation. The characteristic values of the salts are as follows: 5______

Iso-HCl salt m / e R a) Analysis b) mer (m.p. ° C) (ra +)

C 11 N

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Example 32 dl-trans-5,6,7,10,10a-hexahydro-1-acetoxy-3- (2-heptyloxy) -5-benzoyl-6,3-methylbenzo [c] quinolin-9 (8H) - to a stirred solution of 812 mg of the product of Example 28 dl-trans-5,6,6a, 7,10,10c6 {-hexahydro-1-acetoxy-6β-methyl-3- (2-heptyloxy) -benzo [q] quinolin-9 (8H) -one in 2.5 ml of pyridine, 421 mg of benzoyl chloride in 5 ml of chloroform were added. 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, evaporated and crystallized from ether-petroleum ether to give dl-trans-5,6,6a / 2,7,10,106-hex-15-sahydro-1-acetoxy. -3- (2-heptyloxy) -5-benzoyl-6- (3-methylbenzo [c] quinolin-9 (8H) -one, mp 108-110 ° C m / e = 491 (m +)

By repeating this procedure, but using an equivalent amount of acetyl chloride instead of benzoyl chloride 20 and the appropriate benzo [c] quinoline, the following compound was obtained: dl-trans-5,6,6a <5 / 7,10,10acachexahydro-1-acetoxy - 3- (2-heptyloxy) -5-acetyl-6β-methylbenzo [c] quinolin-9 (8H) -one. m / e = 433 (m +).

Example 33 dl-trans-5,6,6a, N, 7,10,10aPC-hexahydro-1-acetoxy-5-methyl-6- (N-methylethyl-3- (2-heptyloxy) benzo [c] quinoline) -9 (8H) -one

To a stirred solution of 387 mg of dl-trans-30, 5,6,6a, 7,10,10a? (Rhexahydro-1-acetoxy-6H-methyl-3- (2-heptyloxy) -benzo) 9 (8H) -one in 3 ml of acetonitrile cooled to 15 [deg.] C. 0.5 ml of a 37% aqueous solution of formaldehyde and then 100 mg of sodium cyanoborohydride were added, and acetic acid was added to maintain a neutral pH, which was indicated by the completion of the reaction. absence of starting material in thin layer chromatography.

The product was isolated as follows.

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

NMR (60 MHz, CDCl 3) = characteristic absorption of N-CH 2 2.85 ppm.

In a similar manner the following compounds were prepared from the appropriate reactants: dl-trans-5,6,6a, 7,10,10a / 5-hexahydro-1-acetoxy-5-methyl-3- (2-heptyloxy) -benzo [c] quinolin-9 (8H) -one, oil.

dl-trans-5,6,6a, 7,8,9,10,10a-i-octahydro-1,9-diacetoxy-5-methyl-6H-methyl-3- (2-heptyloxy) -benzo / q7ki-20 nolin, oil.

m / e = 445 (m +).

In a similar manner the following compounds were prepared: 75 64142 JL ίβ ° 'r o-c-ch3 ar I 5 R6 m / e

, and R, Re R, R „c„ / -K

- Z-W 4 5 o 8 5p._ (a) f'3 - -O-CH- (CH2) 3CO5 CH3 H CK3 mv.h 94 ° -97 ° C. · 449 Γ3 -O-CH- (CH J, C, Kc CK, H CH, -jH oil 449

I J 0 -> J J

-0- (CHO) .C, H. CH, H CH, "" H 102 ^ 103 ° C. 3,435 t m 0 3 3 3 ^ As the hydrochloride salt

Analysis for C28H3504N.HCl

Calculated: C 69.19 H 7.47 N 2.88%

Found: C 68.72 H 7.18 N 2.74% 2

Analysis for C 28 H 35 O 2 N 2 O 2 CH 2 Calculated: C 74.80 H 7.85 N 3.12%

Found: C 74.66 H 8.05 N 2.66% m.p. 69-75 ° C as the hydrochloride salt

3 Analysis for C27H33 ° 4N

Calculated: C 74, 45 H 7.64 N 3.22

Found: C 73.89 H 7.51 N 3.04%.

64142 76

Example 34 dl-trans-5,6,6a [E, 7,10,10a] -hexahydro-1-acetoxy-5-isobutyryl-3- (5-phenyl-2-pentyloxy) -benzo [c] quino-11-9 (8H) -one 5 A solution of 114 mg (1.07 mmol) of isobutyryl chloride in 20 ml of chloroform was added with stirring at 0 ° C and under nitrogen to a solution of 450 mg (1.07 mmol) of dl-trans-5. , 6,6a, 7,10,10C, 4'-hexahydro-1-acetoxy-3- (5-phenyl-2-pentyloxy) benzo [c] quinolin-9 (8H) -one in 1.5 ml of dry pyridine . The reaction mixture was stirred for five hours and poured into 50 ml of ice-water. The chloroform layer was separated and the aqueous layer was extracted with 2 x 20 ml of chloroform. The chloroform extracts were combined, washed with 2 x 10 mL of 10% hydrochloric acid and 1 x 10 mL of brine and dried over magnesium sulfate. Evaporation of the chloroform solution in vacuo gave a yellow oil which solidified on standing. Trituration of the solid in hexane gave a white crystalline solid which was isolated by filtration, dried to give 400 mg, m.p. 128-129 ° C.

Evaporation of the hexane filtrate gave 121 mg of an oil.

Example 35 - [5- (6,6,6a, 7-Tetrahydro-1- (4-N-piperidyl-butyryloxy-2Si) -6,3-methyl-3- (5-phenyl-2-pentyloxy) -benzo) Quinoline-9 (8K) -one hydrochloride in a solution at 550 ° C of 550 mg (1.41 mmol) of dl-5,6,6a, 7-tetrahydro-1-hydroxy-6'-methyl- 3- (5-Phenyl-2-pentyloxy) -benzo [c] quinolin-9 (8H) -one In 26 mL of methylene chloride was added 291 mg (1.41 mmol) of 4-N-piperidylbutyric acid hydrochloride and 319 mg (1.55 mmol) of methylene chloride. ) dicyclohexylcarbodiimide. The reaction mixture was stirred for 18 hours, cooled to 0 ° C and filtered. Evaporation of the filtrate and trituration of the residue with ether gave 35,800 mg of dl-5,6,6a, 7-tetrahydro-1- (4-N-piperidylbutyryloxy) -6'-methyl-3- (5-phenyl-2-pentyloxy ) -benzo [c] 7-quinolin-9 (8H) -one hydrochloride as a wettable yellow powder.

IR 641 42 77 IR (CHCl 3): 2.92, 4.14 (H & =), 5.69 (ester), 6.00, 6.20 and 6.40

Similarly, dl-trans-5,6,6aβ, 7,8,9,10adj-octahydro-1- (4-N-morpholinobutyryloxy) -9-hydroxy-6 (β-methyl-3-5 (5- Phenyl-2-pentyloxy) -benzo [c] quinoline hydrochloride was prepared from 4-N-morpholinobutyric acid and dl-trans-5,6,6a, 5, -7,8,9,10,10a-octahydro-1, 9-dihydroxy-6- (5-methyl-3- (5-phenyl-2-pentyloxy) benzo [c] quinoline.

IR (KBr). 3.00, 3.75, 5.67 (ester carbonyl, 6.15 and 6.30 10 / U.

Example 36 dl-trans-5,6,6a #, 7,10,10ao-hexahydro-1-acetoxy-5-acetyl-6H-methyl-3- (5-phenyl-2-pentyloxy) benzo [d] / quinolin-9 (8H) -one 2-5 3.49 g (0.008 moles) of dl-trans-5,6,6a, 7,8,9,10,10a, 4-octahydro-1-acetoxy -methyl-3- (5-phenyl-2-pentyloxy) -benzo [c] quinolin-9 (8H) -one was dissolved in 20 ml of (non-alcoholic) chloroform, the solution was cooled in an ice-water bath, and then 14 ml of pyridine (dried potassium) was added. -20 hydroxide tablets) followed by 0.95 ml (0.013 mol) of acetyl chloride dissolved in 5 ml of chloroform. The homogeneous solution was then stirred at ambient temperature for 18 hours. The reaction mixture was poured into 50 ml of an ice-water mixture and extracted twice with 25 ml of chloroform (25 ml each). The combined organic layers were washed with 25 mL of saturated sodium bicarbonate solution, 25 mL of water and 25 mL of saturated brine, dried over MgSO 4, filtered and evaporated to dryness under reduced pressure. Purification was performed by chromatography (200 g of Brinkman silica gel, solvent: cyclohexane 3, ether 1) to give 2.20 g (yield 83.8%) of the title product.

Analysis ^ 29 ^ 35 ^ 5 **

Calculated: C 72.90 R 7.39 N 2.80% 35 Found: C 72.69 H 7.48 N 2.49% IR (KBr): 2.90 (m), 3.38 (s), 3.48 (s), 5.62 (s), 5.78 (s), 6.00 (s), 6.15 (s), 6.30 (p).

78 64142 m / e = 477 (m +).

1 HNMR (60 MHz): 7'2Q 5H 'aromatic), 6.53 (d, 1H, -C_2), 6.39 id, 1H, C_4), 4.71-4.08 (m, 2H, methyl nit), 2.29 (s, 3H, acetate CH 2 Cl 2), 2.02 and 2.04 (2s, 3H, amide CH 2), 1.25 and 1.23 (2d, 3H, C 9 CH 3) , 1.12 (d, 3H, side chain CH3), 3.20-1.36 (variable residual protons).

In a similar manner dl-cis-5,6,6e-7,7,10a-hexahydro-1-acetoxy-6- (5-methyl-3- (5-phenyl-2-pentyloxy) benzo [c] quinolin-9 (8H) - was converted dl-cis-5,6,6,3,7,10aα-hexahydro-10'-acetoxy-5-acetyl-6β-methyl-3- (5-phenyl-2-pentyloxy) benzo / c (7-quinolin-9 (8H) -one, mp 125-128 ° C, yield 82%.

Analysis for C 29 H 35 ° 5N

Calculated: C 72.90 H 7.39 N 2.80% 15 Found: C 72.80 H 7.35 N 2.70% 1 TM 9 HNMR (60: 7.22 (m, 5H, aromatic), 6, 55 (2d, sH, C 2 and C 6), 5.02-6.62 (m, 1H, C 6g methine), 4.52-4.12 (m, 1H, side chain methine), 2.28 (s, 3H, acetate CH3), 2.11 and 2.13 (3H, amide CH3), 1.26 and 1.28 (1H-CH2C3), 1.22 (d, 3H, side chain CH3), 3 , 42-1.65 (alternating residual protons).

IR (KBr): 2.95 (s), 3.43 (s), 5.65 (s), 5.81 (s), 6.02 (s), 6.16 (s), 6.32 (s), 6.70 (s), m / e = 477 (m +) Example 37 dl-5,6,6a, 7,10,10a-hexahydro-1 -acetoxy-6S-methyl-3- (1,1-dimethylheptyl) benzo / quinolin-9 (8H) -one A. Preparation of the final product

Suspension of 2.0 g (5.63 mmol) of dl-5,6,6a, -30 7-tetrahydro-1-hydroxy-6-methyl-3- (1,1-dimethylheptyl) -benzo [c] quinolin-9 (8H) -one in tetrahydrofuran (25 ml) was added dropwise at -78 ° C (carbonic acid-acetone) from a dropping funnel to a vigorously stirred solution of 0.236 g of lithium in liquid ammonia (120 ml, 35 distilled in the presence of potassium hydroxide pellets). . The dropping funnel was rinsed with tetrahydrofuran (10 mL). Reaction-

II

The mixture was stirred for 10 minutes, 24 mg of lithium was added and stirring was continued for another 2 hours.

Solid ammonium chloride (24 g) was then added to remove the blue color. Excess ammonia 5 was allowed to evaporate and the residue was dissolved in a mixture of 50 ml of water and 100 ml of ethyl acetate. The ethyl acetate layer was separated and the aqueous phase was extracted with ethyl acetate (2 x 50 mL). The extracts were combined and washed with brine, dried (MgSO 4) and concentrated under reduced pressure to a brown semi-solid (1.35 g). The residue was dissolved in 25 ml of methylene chloride, cooled to 0 ° C (ice-water bath), followed by the addition of 0.869 ml of triethylamine, 0.762 g of dimethylaminopyridine and 0.588 ml of acetic anhydride over one minute. The reaction mixture was stirred at 0 ° C for half an hour, then diluted with 50 ml of methylene chloride and 25 ml of water. The organic phase was separated and the aqueous phase was extracted with 50 ml of methylene chloride. The organic extracts were combined and washed first with saturated sodium bicarbonate solution (4 x 50 mL) and then with brine (1 x 50 mL), followed by drying (MgSO 4). Evaporation of the solvent under reduced pressure gave a dark brown residue. The residue was dissolved in toluene and poured onto a chromatography column 25 (3.8 x 61 cm) containing 200 g of silica gel. The column was eluted first with a volume of toluene-ether solution (3: 1) corresponding to the volume of the column and then with degassed t-ethylene-ether solution (3: 1). Elution and thin layer chromatography were continued. 30 red eluates were obtained, which were concentrated and then treated with dry HCl. 0.40 g of pink dl-5,6,6a, 7,7 -10,10a-hexahydro-1-acetoxy-6H-methyl-3- (1,1-dimethylheptyl) benzo [c] quinolin-9 (8H) was obtained. ) -one hydrochloride salt.

Yield 17.8%, m.p. 135-137 ° C, 35 MS: m / e 399 (m +), 367, 273.

80 641 42

Analysis for C 18 H 18 N 2 O 3 .HCl

Calculated: C 68.87 H 8.78 N 3.21%

Found: C 67.85 H 8.92 N 3.18%.

B. Preparation of starting material dl-1-formyl-5-hydroxy-7- (1,1-dimethylheptyl) -3- (3-hydroxymethylene) -2-methyl-4-oxo-1,2,3,4-tetra from hydroquinoline (19.7 g; 54.9 mmol) is prepared in the same manner as in Example 22 for dl-1-formyl-5-hydroxy-7- (1,1-dimethylheptyl) -2-methyl-4-oxo-3- (3 -oxobutyl) -10 to 1,2,3,4-tetrahydroquinoline; yield 26.7 g of crude product.

The product obtained above (33.0 g; 862 mmol) is converted in the same manner as in Example 24 with dl-5,6,6a, 7-tetrahydro-1-hydroxy-3- (1,1-dimethylheptyl) -6β-methylbenzo / c Nolin-9 (8H) -one; yield 3.55 g.

15 20 25 30 35 li

Claims (3)

81 641 42 1. A process for the preparation of new therapeutically active benzo / c7 quinolinone derivatives of the formula Wherein R 1 is hydrogen, alkanoyl having 2 to 6 carbon atoms or -CO- (CH 2) o -NR 2 H 2 · P 0 is an integer from 1 to 4 and the group NR 2 R 15 represents 5 -6 membered saturated cyclic amino group; R 4 is hydrogen or alkyl of 1 to 6 carbon atoms; R 1 is hydrogen, methyl or ethyl; R 8 is hydrogen, alkanoyl of 2 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms, "C6H5 or -CO (CH2) x_j_-C8H2, where x is an integer from 1 to 4; Z is alkylene having 1 to 9 carbon atoms or -O- (C1-C8-alkylene); and W is hydrogen, methyl or phenyl, and for the preparation of their pharmaceutically acceptable acid addition salts, characterized in that the compound of formula Λ r I · triot R5 'N 30 J R6 wherein R., R., Rc, Rf, Z and W denote a sauna as above, is reduced by Birch reduction, and if desired to prepare a compound in which R1 is not hydrogen, the compound obtained is acylated, and if desired to prepare a compound in which Rg is not hydrogen, reacting a compound in which Rg is hydrogen with formaldehyde or an alkyl or acyl halide, and if desired, reducing the obtained compound with an alkali metal borohydride to give a compound in which Rg is alkyl or phenylalkyl , and if desired, the compound obtained is converted into an acid addition salt. Process according to Claim 1, characterized in that the compound to be prepared is 5,6,6a, N, N, N-hexahydro-1-acetoxy-β-methyl-3- (5-phenyl- pen-3-pentyloxy) benzo / o / quinolin-9 (8H) -one. 15 aa 6414 2