CS249537B2 - Method of substituted hexahydropyrrolo(1,2-a)quinolines,hexahydro-1h-pyrido-(182-a)quinolines,hexahydrobenzo(e)-indenes and octahydrophenanthrenes production - Google Patents

Description

(54) A process for the production of substituted hexahydropyrrolof 1,2-a] quinolines, hexahydro-1H-pyrido [1,2-a] quinolines, hexahydrobenzo (e] indenft and octahydrophenanthrenes

The present invention relates to a process for the preparation of certain novel tricyclic compounds with a fused benzene ring, in particular certain hexahydropyrrolo [1,2-a] quinolines, hexahydro-1H-pyrido [1,2-a] quinolines, hexahydrobenzofejindenes and octahydrophenanthrenes corresponding to the general formula I

OH

that there is still no means available to cope with a wide range of pains of varying severity and with minimal side effects. The most commonly used agent - aspirin - has virtually no relevance to alleviating severe pain and is known to have various unwanted side effects. Other, more potent analgesics, such as d-propoxyphene, codeine, and morphine, are addictive. Thus, the need for improved and effective analgesics is evident.

U.S. Pat. No. 4,188,495 discloses analgesically active 1,9-dihydroxyoctahydrophenanthrenes, 1-hydroxyoctahydrophenanthren-9-ones and derivatives thereof, which are prepared from the intermediates of formula (II) and their pharmaceutically acceptable acid addition salts. they are useful as central nervous system agents, particularly as analgesics and antiemetics useful in mammals, including humans.

Despite the constant availability of a variety of analgesic agents, the search for and research for new, better agents continues

in which

_And M represents a group CH 2,

R _a and R _b represent certain alkyl and aralkyl groups a

R _c and Z _a have the meanings given below for R 5 and R 5, respectively. Zi.

U.S. Pat. No. 4,260,764 discloses compounds of the above formula wherein M _a is NR _d , wherein R _d is hydrogen or certain alkyl, aralkyl, carboxy-substituted alkyl or acyl groups and R _a , R b, R _c and Z _and are as defined above.

In our related U.S. patent application, various substituted dodecahydrotrifenylenes, decahydro-1H-cyclopenta [1] phenanthrenes, decahydro-1H-pyridol [1,2-f] phenanthridines and decahydropyrrolo [1,2-f] phenyanthridines having activity on central nervous system.

The nomenclature used herein is based on the IUPAC Nomenclature of Organic Chemistry, Rigaudy and Klesney, 1979 edition, Permangon Press, New York, including the use of the R and S symbols to denote absolute stereochemical configuration and the R * and S * symbols to denote relative stereochemical configurations. Dashed and reinforced lines in some samples generally indicate a relative stereochemical configuration unless otherwise indicated in the text.

It has now been found that certain hexahydropyrrolo [1,2-a] quinolines, hexahydro-1H-pyrido [1,2-a] quinolines, hexahydrobenzo [e] indenes and octahydrophenanthrenes are useful in mammals as tranquilizers, anticonvulsants, diuretics, antidiarrheal agents, antitussives, and as agents for treating glucose.

The compounds are particularly effective as analgesics and as agents for treating and preventing emesis and nausea in mammals, including humans, in particular due to the administration of antineoplastic drugs. These non-narcotic and non-addictive compounds of the invention correspond to formula (I)

OH

and include certain esters, namely, acetates, and pharmaceutically acceptable acid addition salts.

A particularly preferred radical Z 1 is 5-phenyl-2S-pentyloxy, i.e. a group of formula VII

H

CH, (VID

Particularly preferred compounds of formula I wherein M is nitrogen are those of the absolute or relative stereochemical configuration shown in the following formula V

Particularly preferred compounds of formula I wherein M is CH are those of the absolute or relative stereochemical configuration shown in the following formula VI

OH

The ring systems and numbering used for the compounds of the invention herein are as follows:

wherein pyrrolo [1,2-a] quinoline t is a number of 1 or 2,

M is CH or nitrogen and Z 1 is 5-phenyl-2-pentyloxy,

11b ^b 9 pyridine (1,2-a) quinoline benzo [e] indene

Thus, the compounds of formulas V and VI are named as follows:

V, t = 1: 1,2,3,3aS, 4,5R-hexahydro-5- (2-hydroxyethyl) -6- (hydroxy) -8- (substituent Z1) pyrrolo [1,2-a] quinoline,

V, t = 2: 2,3,4,4aS, 5,6R-hexahydro-6- (2-hydroxyethyl) -7- (hydroxy) -9- (substituent Z 1) -ΙΗ-pyridol [1,2-a] ] quinoline,

VI, t = 1: 2,3,3aS, 4,5,9bR-hexahydro-5- (2-hydroxyethyl) -6- (hydroxy) -8- (substituent Z 1) -1 H -benzo [e] indene a

VI, t = 2: 1,2,3,4,4aS, 5,6,10bR-octahydro-6- (2-hydroxyethyl) -7- (hydroxy) -9- (Zijphenanthrene substituent).

By pharmaceutically acceptable acid addition salts is meant addition salts formed from compounds of formula I containing a basic nitrogen atom as moiety M and pharmaceutically acceptable acids. Examples of such acids include:

acetic acid, benzoic acid, hydrobromic acid, hydrochloric acid, citric acid, sulfosalicylic acid, tartaric acid, glycolic acid, malonic acid, maleic acid, fumaric acid, malic acid, 2-hydroxy-3-naphthoic acid, pamoic acid, salic acid , phthalic acid, succinic acid, gluconic acid, mandelic acid, lactic acid, sulfuric acid, phosphoric acid, nitric acid and methanesulfonic acid.

The compounds of formulas (I), (V) and (VI) above have asymmetric centers on the carbons which, together with the moiety M, form a ring connection, the carbon bearing the - (CH 2) 2 OH group and the moiety M representing the CH group.

Another center of asymmetry occurs in the substituent Z 1. The invention includes racemates of formula I, mixtures of diastereomers, pure enantiomers and diastereomers. The applicability of racemic mixtures, mixtures of diastereomers as well as pure enantiomers and diastereomers is determined by the bioassays described below.

As mentioned above, the compounds produced by the process of the invention are particularly useful as analgesics and as antinause agents for administration to mammals, including humans.

The starting materials of the formula II in which R 16 and R 17 are hydrogen atoms can also be represented individually by formulas III, XI and XII below. Methods which can be used to prepare starting materials of formulas III, XI and XII and convert them to therapeutically active compounds of formula I are shown in Reaction Scheme A wherein R 4 is methyl or ethyl, R 15 is hydrogen or a benzyl group and the remaining general symbols are as defined above.

Scheme A

9 ^r ís χχ, X ^coow i ¹ J Γ

L — OCHJ, (Vlil) ^zi

llch _of coor ₄ (IX)

HO CH.COO ^ v f

X X>>.

j 1 'J> r i

...... (ChU ,.

f / '' /

z. _t

CHCOOR,

0 * 15 '' 'M

CHfOOR *

OR, i ^1S j '' - (¾ (X)

C7

L-tHA

Ss

CH..COOR, IOH OH

'Χ' ·?

...... ^řC %

On n

(AND)

The enantiomeric or racemic starting materials of formula VIII, wherein t, M, Ris and Z1 are as defined above and Ris is preferably a benzyl group, are cyclized under dehydration conditions to the corresponding tricyclic ketones of formula IX.

According to a typical reaction, the compound of formula (VIII) is treated at a temperature of about 0 to 100 ° C with a mixture of acetic acid and acetic anhydride or a mixture of trifluoroacetic acid and trifluoroacetic anhydride in molar excess until virtually complete reaction. it usually lasts from a few minutes to several hours. The volatiles are then evaporated under reduced pressure, the product isolated by standard extraction procedures and optionally purified by crystallization or chromatography.

In the second step of this reaction sequence, the ketone of formula (IX) is reacted with an α-haloester in the presence of a zinc metal, but preferably a lithium acetic acid ester of formula (LCH 2 COOR 4) under the conditions of the Reformat reaction. An extensive discussion of the Reformat reaction can be found, for example, in Rathke, Organic Reactions, 22, 423-460 (1975).

Preferred lithiated reagents of the formula LiCH 2 COOR 4 used to prepare intermediates of formula IV can be prepared by any of several methods known in the art [see, for example, Fieser, "Reagents for Organic

Chemistry ”, Wiley-Interscience, New York, Vol. 3 (1972)].

A preferred example is to react lithium dialkylamide with an acetic ester in an inert solvent. A particularly preferred lithium di-alkylamide is lithium dicyclohexylamide. The latter compound is prepared, for example, from equimolar amounts of n-butyllithium and dicyclohexylamine in an inert solvent.

In accordance with a typical embodiment of this reaction, the two reagents are contacted under anhydrous conditions in an inert atmosphere, for example under nitrogen, at a temperature of -80 to -70C in an inert solvent, and an equimolar amount of reagent is added to the resulting suspension. CH3COOR4 at the same temperature.

The resulting lithium derivative of the formula LiCH 2 COOR 4 is then immediately reacted with an intermediate ketone of formula IX in an inert solvent. A particularly preferred lithium-dial-80 to -70 ° C. The reaction is usually complete in about 1 to 10 hours. To decompose the lithium salt of the desired product, an equivalent amount of a weak acid such as acetic acid is added to the reaction mixture. The product is isolated by standard methods and optionally purified as described above.

Examples of useful inert solvents are preferably those mentioned above in connection with the reaction using a halogen ester reagent.

The 5,5- (or 6,6) hydroxy-CH 2 COOR 4 -disubstituted compound of formula (IV) obtained as described above is then subjected to hydrogenolysis and cleavage of the benzyl hydroxyl protecting groups (R 15) to give compounds of formulas (X) and (XI) or their mixtures. Hydro-enolysis of compounds of formula IV is conveniently performed by treatment with hydrogen in the presence of a noble metal catalyst.

Examples of usable noble metals include nickel, palladium, platinum and rhodium. The catalyst is normally used in a catalytic amount, for example in an amount of about 0.01 to 10% by weight, preferably 0.1 to 2.5% by weight, based on the compound of formula IV.

It is often expedient to suspend the catalyst on an inert support, a particularly preferred catalyst being palladium on an inert support such as coal.

One suitable method for carrying out this transformation is by stirring or shaking a solution of the compound of formula IV in a hydrogen atmosphere in the presence of one of the above-mentioned noble metal catalysts. Suitable solvents for this hydrouenolytic reaction are those which substantially dissolve the starting material of formula IV. however, they are not subject to hydrogenation or hydrogenolysis.

Examples of such solvents include lower alkanols such as:

methanol, ethanol and isopropanol;

ethers such as:

diethyl ether, tetrahydrofuran, dioxane and

1,2-dimethoxyethane;

low molecular weight esters such as:

ethyl acetate and butyl acetate;

tertiary amides such as:

N, N-dimethylformamide,

Ν, Ν-dimethylacetamide and

N-methylpyrrolidone, and mixtures thereof.

The introduction of hydrogen gas into the reaction medium is usually ensured by carrying out the reaction in a closed vessel containing a compound of formula IV, a solvent, a catalyst and hydrogen. The pressure inside the reaction vessel may range from about 0.1 to 10 MPa.

The preferred pressure range when the atmosphere inside the reaction vessel is substantially pure hydrogen is from about 0.2 to 5 MPa. The hydrogenolysis is generally carried out at a temperature of about 0 to 60 ° C, preferably about 25 to 50 ° C. When operating at preferred temperatures and pressures, hydrogenolysis is complete in a few hours, for example, in about 2 to 24 hours.

The product is then isolated by standard methods known in the art, for example, by filtration to remove the catalyst, and by evaporation of the solvent or by shaking between water and a water-immiscible solvent, and evaporation of the dried extract.

When the starting compound in hydrogenolysis is a compound of formula IV wherein R15 is hydrogen or benzyl, the resulting product is typically a mixture of the corresponding carboxylic acid or ester of formula XII and the lactone of formula III resulting from the elimination of R4OH elements from the compound of formula XII, XI or X, wherein R 15 represents a hydrogen atom. The mixture thus obtained may be used as such or may be separated by known methods, for example crystallization and / or silica gel chromatography.

The products of formulas XII and III, as well as mixtures thereof, are useful intermediates for the production of the corresponding hydroxy compounds of the formula I using known reducing agents, for example hydrides such as lithium aluminum hydride or lithium borohydride, borane, aluminum hydride and lithiumtriethylborohydride, or via ka249537 talytic hydrogenation catalysts. noble metal base. This reduction is inherent in the invention.

Preferred reducing agents are the above-mentioned hydrides, with lithium aluminum hydride being particularly preferred in view of efficiency and cost. The reduction is carried out under anhydrous conditions and in the presence of a suitable inert solvent, for example ethyl ether, tetrahydrofuran, 1,2-dimethoxyethane or diethylene glycol dimethyl ether.

Typically, a solution of a compound of formula XII, a lactone of formula III, or a mixture of these compounds in any of the above inert solvents is added to a solution of an approximately equimolar amount of a hydride such as lithium aluminum hydride in the same solvent. from -50 to 50 ° C, preferably from about 0 to 30 ° C. Under these conditions, the reduction is virtually complete in about 2 to 24 hours.

Excess reducing agent is then removed, for example by carefully adding wet solvent or ethyl acetate, and the product isolated in a known manner, for example by washing the reaction mixture with water and evaporating the dried organic phase. Purification of the product, if desired, is accomplished, for example, by recrystallization or column chromatography.

The following Reaction Scheme B describes a process for preparing 5- (2-hydroxyethyl) hexahydropyrrolo [1,2-a] quinoline and 6- (2-hydroxyethyl) hexahydropyrido [1,2-a] quinoline compounds of formulas XXIII to XXV and converting them to compounds of formula I wherein M is N. In this scheme, Et is ethyl.

Scheme Β

(yixj ^IXX5

(x X IV)

(XXIII) - (XXV) ----- (I, M = N)

In the initial reaction step of this reaction sequence, the 3-oxoadipic acid diester or 3-oxopimelic acid diester of formula XVI, prepared by reacting succinic or glutaric acid semi-ester with ethyl lithioacetate in the presence of a condensing agent such as dicyclohexylcarbodiimide, is reacted with hydrogen. - (OR 18 -substituted) -5-Z 1 -substituted aniline of general formula (XVII).

Typically, the reactants of Formulas XVI and XVII are contacted in roughly equimolar amounts in the presence of acetic acid, and the mixture is shaken together with a catalytic amount of platinum at room temperature under a hydrogen atmosphere until reduction of the Schiff base formed. After removal of the catalyst and evaporation of most of the acetic acid, the residue is added to a mixture of hydrobromic acid

I, and refluxing acetic acid to effect cyclization and hydrolysis to the acid of formula XVIII or the ketolactam of formula XIX.

If the product is an acid of formula XVIII, it is subjected to further cyclization under dehydration conditions to give the corresponding compound of formula XIX. The ether groups in intermediates of formulas XVIII and XIX, prepared from the starting anilines of formula XVII in which Ris is benzyl and / or Zi is the corresponding alkoxy or benzyloxy group, are cleaved by treatment with hydrobromic acid in acetic acid to give products in which Ris and Zi are hydrogen or hydrogen, respectively. hydroxyl group.

In such a case, it is usually preferred to build a side chain of Z1 by selective esterification, for example by reacting an intermediate of formula XIX in which Ris is a hydrogen atom and Z1 is a hydroxyl group with an appropriate side chain precursor corresponding to the formula Z2X, the oxygen atom forms the radical Z 1 and X represents a leaving group, for example chlorine, bromine, iodine, methanesulfonyloxy or p-toluenesulfonyloxy. A preferred radical X is methanesulfonyloxy.

The remaining reaction steps for the preparation of intermediates of formulas XXI, XXII, XXIII and XXIV are carried out as described above for the corresponding reaction steps in Reaction Scheme A to prepare compounds of formulas IV, X, XI, XII and III. The final step of reducing the lactamdactone of formula XXIV is usually carried out by reduction with hydride, preferably using lithium aluminum hydride, by the methods described above for reducing the lactones of formula III.

One method useful for preparing numerous starting materials of formula VIII wherein M is CH is to first heat cyclohexanone or cyclopentanone with a suitable Grignard reagent containing a substituted phenyl moiety in a high boiling inert solvent to form a compound of formula VIII

in which

Z 1 is methoxy, benzyloxy or 5-phenyl-2-pentyloxy.

Condensation with alkyl acetate, dehydration and hydrolysis of the intermediate ester gives unsaturated acids of formulas

Instead of alkyl acetate, equivalent reagents can be used, such as the corresponding malonate, which, after hydrolysis, decarboxylates to acetate. Reduction of the first product with lithium in liquid ammonia yields the trans-form of the substituted acetic acid derivatives, while catalytic hydrogenation of the latter under the conditions detailed above gives the cis-form of the corresponding acetic acid derivative (with simultaneous debenzylation when Ris is benzyl) ). Finally, cyclization, debenzylation or O-demethylation and alkylation when Z is a phenol ether derivative yields tricyclic ketones of formulas

O OH

respectively.

O OH

t is as defined above,

R 18 is methyl or benzyl and

In which t and Zi are as defined above.

Alternatively, suitably substituted aromatic aldehydes are condensed with nitromethane to form trans-1- (disubstituted phenyl) -2-nibeteethylenes of formula

NO

v nemz

Ris is as defined above and Z? represents methoxy, benzyloxy or the radical Z 1 as defined above.

Condensation of this compound with butadiene under Diels-Alder reaction conditions affords the corresponding 4- (substituted phenyl) -5-nitrocyclohexene. The nephonate reaction is carried out to give the unsaturated cyclohexanone derivative, namely 6- (disubstituted phenyl) -3-cyclohexene-1. -one, which is hydrogenated using the methods detailed above (with simultaneous cleavage of any benzyl group present), demethylates in the presence of a methyl ether moiety (with concomitant dealkylation if Z2 is an alkoxy derivative) and alkylates to form a ketone of formula

in which

Zi has the meaning given to the congregation.

It should be noted that these alkylation reactions invert so that, for example, 5-phenyl-2S-pentyl mesylate gives 5-phenyl-2R-pentyloxy as defined by Z1.

Suitably the corresponding tricyclic nitrogen analogues are prepared from 3, n-dihalo acids and disubstituted anilines, for example according to the following reaction scheme:

t, R 15, Z 1 and Z 2 are as defined above.

This reaction is followed by cyclization, debenzylation or demethylao (accompanied by dealkylation when Z 2 is an alkoxy derivative) and alkylation to give pyrrolo / pyrido [1,2-a] quinolinones of formula

OH

X X f ΪΙ Ί (CH.L.

The getable anilines, aromatic halides or aromatic aldehydes needed as starting materials for the above syntheses are available commercially or are described in the literature. Unless otherwise available, the anilines required for the above reactions are prepared according to the methods of Johnson in U.S. Patent 4,260,764. These anilines are prepared according to the procedure described by Bigelow in Organic Syntheses I, pp. 135-137 (1941). are converted to the corresponding aromatic bromides and chlorides, and then reacted with magnesium to form the corresponding Grignard reagents.

Although a variety of methods are available for synthesizing the aldehydes needed, these are widely available from the anilines described by Johnson in the above-cited patent. The anilines are converted to the corresponding nitriles according to the procedure described by Clarke and Read

Organic Syntheses I, sulfur. 514-516 (1941) and these nitriles are subjected to Stephen reduction to directly obtain aldehydes, alternatively, nitriles can be hydrolyzed to acids, converted to acid chlorides, and hydrogenated under Rosemund reaction conditions.

Acid chlorides can also be converted to thiol esters and then desulfurized to aldehydes according to the procedure described by Wolfram et al. in J. Am. Chem. Soc. 68, pp. 1455-1456. Alternatively, aldehydes are prepared from the corresponding benzylaldehydes by oxidation in dimethylsulfoxide according to Kornberg et al., J. Am. Chem. Soc. 81, pp. 4,113 to 4,114.

Benzyl bromides are prepared by the methods described by Althuis et al. U.S. Pat. No. 4,188,495. Aldehydes can also be obtained by reacting aromatic Grignard reagents with ethyl orthoformate.

The required halide or mesylate, if not commercially available, is readily obtained from the corresponding alcohol using standard chemical reactions and conditions. The alcohols are either commercially available or can be prepared by methods described in the literature. For example, primary alcohols can be obtained by reducing aldehydes, acids or esters with hydrides, while secondary alcohols are prepared by reducing ketones with hydrides.

All kinds of alcohols can be obtained by hydrating olefins or by reacting epoxides with Grignard reagents. Furthermore, numerous halides suitable for side chain introduction can be obtained by direct halogenation of olefins or by addition of hydrogen halides to olefins.

In order to obtain an optically active isomer of one of the compounds according to the invention, the resolution is carried out by preparing, in a manner known per se, the diastereomeric salts of the optically active amine / acid with an intermediate or final acid / base compound and separating them.

Alternatively, intermediate alcohols are resolved by conversion to diastereomeric esters, for example, to optically active amine salts of phthalic acid semi-esters, or individual optically active isomers are prepared directly using optically active starting materials and reagents. It is advantageous to carry out the cleavage in the earlier reaction steps of the process to avoid processing of the undesirable material.

The pharmaceutically acceptable addition salts of the invention are readily prepared by reacting the free base with the appropriate mineral or organic acid, either in aqueous solution or in a suitable organic solvent. The resulting salt can then be obtained by precipitation or evaporation of the solvent. Pharmaceutically acceptable acid addition salts of the compounds of the present invention include, without limitation, salts with hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, sulfuric acid, benzenesulfonic acid, citric acid, laurylsulfonic acid, fumaric acid, oxalic acid, maleic acid, methanesulfonic acid, tartaric acid, p-toluenesulfonic acid and succinic acid.

In the case of polybasic acids, the salt may contain more than 1 mole of base per mole of acid, however, those addition salts which contain the base and acid in a 1: 1 molar ratio are preferred. If desired, these salts may be isolated directly from the reaction mixtures. using an appropriately modified isolation procedure, i.e. without isolation of the intermediate free base.

The analgesic properties of the compounds of formula I and their acetates are determined by the following tests.

Controlling phenylbenzoquinone-induced pain (convulsions) (FBCH)

Groups of five mice (Carwoth Farms CF-1) each receive saline, morphine, codeine or test substance subcutaneously or orally. After 20 minutes (for subcutaneous administration) or 50 minutes (for oral administration), each group of animals is injected with phenylbenzoquinone, known to induce abdomen contractions, by intraperitoneal injection. Five minutes after the injection of phenyl benzoquinone, the test mice are observed for 5 minutes to determine whether or not they experience painful convulsions. The dose of MPE 50 of the test substance blocking these painful cramps by 50% is determined. Tail Tightening (Rat) (SO)

A modification of the procedure described by Haffner in Experimentelle Prufung Schmerzstillender Mittel, Deutsch is used to determine the effects of test substances on the aggressive response of the test animals to the painful clamping of their tail. Copper. Wschr., 55, 731-732 (1929). Male Charles River (Sprague-Dawley) CD rats weighing 50-60 g are used for the test. Before the test substance is applied and at 0.5, 1, 2 and 3 hours after application, the tail of each rat is pinched clamp. This action evokes clearly offensive behavior and biting towards the point of pain, recording the so-called latency of the response, ie the time in seconds that elapses from the stimulus to the offensive response. If there is no response, the staple is removed after 30 seconds and the response latency is recorded for 30 seconds. Morphine is effective in this test when administered intraperitoneally at a dose of 17.8 mg / kg.

The results of the above tests are summarized in the following table:

Test substance

Table I

Analgesic efficacy

FBCH MPE 50 (mg / kg) *]

SO

AND 0.32 - (B) 0.15 • 1 C 0.11 <1.0 D 0.67 6.3 E 0.16 - F 0.28 - 0.76 (p. o.) j—

Legend:

*) all compounds administered subcutaneously except as indicated by the application, oral (p. o.)

The following compounds of the invention were used for the assay:

Compound t (B) Ri Rld Μ N AND 1 N -CH 2 CH 2 OH H /S-.CH3 (B) 1 P-CH 2 CH 2 OH CH3CO ~ CH3 C 1 (3-CH2CH2OCOGH3) CH3CO α-CH 3 D 1 [J-CH2CH2OCOCH3] CH3CO / S-CH 3. E 2 (J-CH 2 CH 2 OH) H ~ GH3, M = CH F 2 H-CH 2 CH 2 OH H ~ .CH3; Preparation of compounds A, C, D, E and F are then ether evaporates in vacuum. It is obtained

written below in the Examples. Compound B was prepared as follows:

1.06 g (2.15 mmol) of dl-6-acetoxy-5-ethoxycarbonylmethyl-8- (5-phenyl-2-pentyloxy) -3,3 and S, 4 are dissolved in anhydrous tetrahydrofuran (25 ml) under anhydrous conditions under a nitrogen atmosphere. 4-tetrahydro (2H) -pyrrolo [1,2-a] quinolin-1-one (diastereomer A) was added dropwise to a mixture of 0.489 g (12.9 mmol) of lithium aluminum hydride in 30 ml of tetrahydrofuran and the reaction mixture was heated for 45 minutes. The reaction mixture was poured into a mixture of 300 ml of 5% (w / v) aqueous acetic acid and 600 ml of ethyl ether, cooled to 0 DEG C. The mixture was stirred for 10 minutes, the resulting emulsion was filtered, and the ether layer was stirred. The combined ether layers were washed three times with 150 ml each of saturated sodium bicarbonate solution and twice with 150 ml of sodium chloride each time, dried over magnesium sulphate with 1.2 g of an orange oil which was taken up in 50 ml. The solution was cooled to -5 ° C under nitrogen and added to němu.0,329. ml (2.37 mmol) of triethylamine, 0.289 g (2.37 mmol) of 4-dimethylaminopyridine and 0.203 ml (2.15 mmol) of acetic anhydride. The resulting mixture was stirred at 0-3 ° C for 30 minutes and then poured into 60 mL of water. The layers are separated, the aqueous phase is extracted with 60 ml of methylene chloride, the extracts are washed with saturated sodium bicarbonate solution and brine, dried over magnesium sulfate, and the solvent is evaporated off under vacuum. The oily residue was purified by silica gel column chromatography using toluene / ethyl ether (7: 3) as eluent to give 374 mg of material which was re-chromatographed on 35 g of silica gel using toluene / ethyl ether. (8: 2) as eluent. 181.6 mg of the desired free base is obtained, which is dissolved in ethyl ether and is converted into dl-6-acetoxy-5R- (2-hydroxyethyl) -8- (5-phenyl-2-pentyloxy) ethyl acetate by adding an ethyl acetate solution of anhydrous chloro. -1,2,3, aS, 4,5-hexahydropyrrolo [1,2-a] quinoline hydrochloride.

Analysis: for C27H35O1N. HCl. 0.5 H2O calculated:

H, 7.68; N, 2.91. found:

% H, 7.74;% N, 2.91.

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

Because of the ability of the compounds of the invention to reduce intraocular pressure, it is contemplated that they may be used to treat glaucoma. The effects of the compounds of the invention on intraocular pressure are determined by dog tests. The test substance is introduced into the eye of the dog in the form of a solution or applied systemically at different times, after which the eye of the test animal is anesthetized with 2 drops of 0.5% tetracaine hydrochloride. A few minutes after this local anesthesia, a mechanical tonometer (Schiotsj is determined for intraocular pressure) and after application of a fluorescein dye, the intraocular pressure is then determined again using a hand tonometer (Holbergj).

mg test substance,

0.05 ml of ethanol, mg of Tween 80 surfactant (polyoxyalkylene sorbitan monooleate and salt solution (make up to 1 ml) or in a more concentrated solution in which the individual components are present in amounts of 10 mg, 0,10 ml. 100 mg and 1 ml.

Alternatively, the compounds of the invention are tested for their ability to reduce intraocular pressure in normal rabbits according to the method of Elsohly et al., J. Clin. Pharmacol. 21, pp. 472S to 478S (1981). In human medicine, the active compounds are used in doses of from 0 01 mg / kg to 10 mg / kg.

The activity of the compounds of the invention as diuretic agents is determined by the procedure described by Lipschitz et al. in J. Pharmacol., 79, 97 (1943) in which rats are used as test animals. The dosage in this use is the same as that described above for the use of the compounds of the invention as analgesic agents.

The anti-emetic properties of the compounds of the invention are determined in non-anesthetized unprotected cats according to the procedure described by McCarthy and Borison, J. Clin. Pharmacol., 21, 30S-37S (1981). The dosage range for this use is also the same as the dosage range described above in describing the use of the compounds of the invention as analgesics.

For administration purposes, the active compounds described above may be formulated as solid or liquid dosage forms suitable for oral or parenteral administration. Capsules containing the active compounds of the formula I are prepared by mixing 1 part by weight of active ingredient with 9 parts of a filler, such as starch or milk sugar, and filling the plug-in gelatin capsules with this mixture so that each capsule contains 100 parts of the mixture. Tablets containing the same active ingredients mentioned above are prepared using mixtures of the active ingredient and standard ingredients used in the preparation of tablets, such as starch, binding agents and glidants, so that each tablet contains from 0.01 to 100 mg of active ingredient.

Suspensions and solutions of the active compounds of the formula I are generally prepared just prior to use in order to avoid problems associated with the instability of the respective compound (e.g. oxidation) or the instability of the respective active ingredient suspension or solution (e.g. precipitation) during storage. Compositions suitable for this purpose are generally dry solid preparations which are reconstituted for injection.

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

Unless an absolute or relative stereochemical configuration (e.g. 5-phenyl-2-pentyl) is specified for a compound containing more than one asymmetric center, such a product is a mixture of two diastereomers or two racemates, usually in a ratio of about 1: 1.

Example 1 dl-6-acetoxy-5- (2-acetoxyethyl) -8- (5-phenyl-2-pentyloxy) -1,2,3,3aS *, 4,5-hexahydropyrrolo [1,2-a] - quinoline hydrochloride (diastereomer A)

Under anhydrous conditions and under a nitrogen atmosphere, 2.235 g (4.53 mmol) of dl-6-acetoxy-5-ethoxycarbonylmethyl-8- (5-phenyl-2-pentyloxy) -3,3aS *, 4,5-tetrahydro - (2H) pyrrolo [1,2-a] quinolin-1-one (diastereomer A) is dissolved in 100 ml of anhydrous tetrahydrofuran, 0.688 g (18.13 mmol) of lithium aluminum hydride is added, the mixture is refluxed for 2 hours. 20 ml of a 10% w / w aqueous solution of sodium hydroxide are added dropwise thereto, and the mixture is filtered, washed five times with 200 ml of ethyl acetate each time, The filtrate was combined with the washings, washed with 500 mL of brine and dried over MgSO 4 to remove the solvent in vacuo to give 1.87 g of off-white foam, which was dissolved in 20 mL of methylene chloride and 2 mL was added. (21.1 mmol of acetic anhydride and 4 ml (28.6 mmol of triethylamine) were added over n After stirring at room temperature, 600 ml of ethyl ether were added and the layers were separated. The ether phase is washed with 250 ml of sodium chloride solution, dried over magnesium sulphate and the ether is evaporated off under vacuum. 2 g of a greenish oily material are obtained which, by column chromatography on 110 g of silica gel (48 to 63 μΐη), eluting with 2 liters of a mixture of toluene and ethyl ether (95: 5) gives 1.65 g of oily product as the free base. The free base is dissolved in 250 ml of ethyl ether, 20 ml of ethyl ether saturated with hydrogen chloride are added, and the precipitated product is isolated by decanting off the pther and washed twice with 25 ml of the same solvent, and the remaining solvent is evaporated under vacuum to give a clear glassy product.

¹ H-NMR of the free base (deuterochloroform, S-values in ppm):

1.27 (doublet, 3H1,

1.38 to 3.54 (multiplet, 18H)

2.03 (singlet, 3H +,

2.29 (sinelet, 3H),

3.88 to 4.40 (multiplet, 3Hj,

5.92 (singlet, 2j,

6.92 to 7.64 (multiplet, 5Hi).

IC (chloroform): 3.45, 5.65, 5.75 μΐη.

High resolution mass spectrum:

(M ⁺ ) for C 29 H 37 O 5 N calculated 479.2738 found 479.2705

Analysis: for C 29 H 37 O 5 N. HCl calculated:

% H, 7.38;% N, 2.72. found:

% H, 7.42;% N, 2.80.

Example 2

Methyl dl-2- [1- (3,5-dimethoxyphenyl) -pyrrolidin-2-yl] acetate

A. 2-Tetrahydrofurfuryl bromide

To a mixture of 20.4 g of 2-tetrahydrofurfuryl alcohol and 58 g of triphenylphosphine was added 32.5 g of N-bromosuccinimide over 1.5 hours. Distillation of the reaction mixture under reduced pressure afforded 20 g of the desired product which, by redistillation, gave 15 g of pure bromide, b.p. 33-40 ° C.

B. 2-Cyanomethyltetrahydrofuran

To a solution of 1.3 g (5 mmol) of 18 crown-6 and 9.05 g (0.05 mol) of 2-tetrahydrofurfrylbromide in 80 ml of acetonitrile was added 16.25 g (0.25 mol) of potassium cyanide. The mixture was heated at 90 ° C for 48 hours, then cooled and filtered. The product on the filter was washed with ethyl ether, the filtrate was combined with the washings and evaporated in vacuo without heating. The residue is distilled to give 4.25 g (77%) of the desired product.

^] H-NMR, (CDCl₃) in ppm:

2.60 (doublet, 2H, 3H2CN).

C. 2-tetrahydrofuran-2-yl) acetic acid

A solution of 90 g (0.81 mol) of 2-cyanomethyltetrahydrofuran, 130 g (3.2 mol) of sodium hydroxide. 250 ml of methanol and 300 ml of water were heated under reflux for 20 hours. The reaction mixture is evaporated in vacuo, the residue is taken up in chloroform and acidified to pH 5 with 6N hydrochloric acid. The organic layer is separated, the aqueous phase is extracted with chloroform, the combined extracts are dried over magnesium sulphate and the solvent is evaporated. 62 g of crude acid are obtained, which is distilled to give 52.6 g of a b.p.

^] H-NMR (CDCl. Δ values in ppm):

2.50 (doublet, 2H CH2 COOH),

11.10 (singlet, 1H, COOH).

D. Methyl 3,6-dibromocaproate

To 800 ml of glacial acetic acid saturated with anhydrous hydrobromic acid, 56 g of 2- (tetrahydro-furan-2-ylacetic acid) was added in one portion and the mixture was heated to 100 ° C for 60 hours. The volatiles were evaporated, the residue was taken up in ethyl ether and washed with water The ether layer was dried over magnesium sulphate and the solvent was evaporated to give 120 g of crude 3,6-dibromocaproic acid which, after distillation, yielded 115 g of product, bp 116-124 ° C.

¹ P-NMR (CDCl3, δ ppm):

3.00 (doublet, 2H, CH2COOH),

3.40 (multiplet, 2H).

4.30 (multiplet, 1H).

118 g of methyl ester are obtained from this acid by esterification with methanolic hydrogen chloride at reflux.

¹ H-NMR (CDCl 3, δ ppm):

2.90 (doublet, 2H),

3.45 (multiplet, 2H).

3.70 (singlet, 3H),

4.30 (multiplet, 1H).

E. A mixture of 52 g (0.340 mol) of 3,5-dimethoxyaniline, 108.8 g (0.378 mol) of methyl-3,6-dibromocaproate, 60 ml of pyridine and 160 ml of tetrahydrofuran was stirred at room temperature overnight under nitrogen. Tetrahydrofuran was distilled off at atmospheric pressure and the remaining mixture was heated at 100 ° C for 2.5 hours. An additional 5.7 g of methyl dl-3,6-dibromocaponate and 3.16 ml of pyridine were added, and heating at 100 ° C was continued for 2.5 hours. The pyridine is evaporated under vacuum, the residue is partitioned between water and methylene chloride, the aqueous phase is extracted four times with 150 ml of methylene chloride each time, the combined organic phases are washed with 75 ml of 1N hydrochloric acid, 75 ml of water and 75 ml of sodium chloride solution, dried. the solvent was evaporated. 57.5 g of an orange-colored solid are obtained.

The aqueous phase was adjusted to pH 9 with 6N sodium hydroxide and extracted four times with 100 ml of methylene chloride each time. The extracts were washed with water and brine and dried over magnesium sulfate and evaporated in vacuo. 16.7 g of an oily residue are obtained.

The orange-colored solid was loaded onto a silica gel column eluting with a mixture of methylene chloride and ethyl acetate. Product containing fractions were combined and evaporated in vacuo to give 53.6 g (56%) of the desired product.

@ ¹ H-NMR (CDCl3) .delta.

3.70 (singlet, 3H, - COOCH 3),

3.70 (singlet, 3H, —COOCH3),

5.80 (singlet, 3H, aromatic protons).

Example 3 dl-2- [1- (3,5-dimethoxyphenyl) pyrrolidin-2-yl] acetic acid

A mixture of 53.6 g (0.192 mol) of methyl-dl-2- [1- (3,5-dimethoxyphenyl) pyrrolidin-2-yl] acetate, 250 ml of methanol and 22.8 g (0.57 mol) of sodium hydroxide The mixture was stirred at room temperature in 200 ml of water for 2.5 hours, then the methanol was evaporated and the aqueous residue was cooled in ice. 48 ml of concentrated hydrochloric acid are added dropwise to this cooled residue, the mixture is extracted four times with 150 ml of methylene chloride each time, the extract is washed with water and, after drying over magnesium sulfate, the solvent is evaporated off. 48.9 g (96%) of the desired product are obtained.

-Ή-NMR (CDCl 3, δ values in ppm):

3.80 (singlet, 6H, OCH 3),

4.10 (multiplet, 1H, J '- CH),

5.82 (singlet, 3H, aromatic protons),

11.0 (singlet, 1 H, COOH).

Mass spectrum (m / e):

206 (basic signal)

265 (M &lt; + &gt;).

Example 4

Resolution to optical isomers via α-methylbenzylamine salt

A. Dextrorotatory salt

A mixture of 52.3 g (0.197 mol) of dl-2- [1- (3,5-dimethoxyphenyl) pyrrolidin-2-yl] acetic acid and 370 ml of ethyl acetate was dissolved by heating and 24.4 g (0.201 mol) were added. d - (- j -) -. alpha.-methylbenzylamine. The resulting mixture was stirred for 10 minutes and then allowed to stand at room temperature for 3 hours to crystallize. After addition of 370 ml of ethyl ether, the mixture is allowed to stand overnight in a refrigerator and then filtered. After washing the filter residue with cold ether, 72.2 g of solid product is obtained. After evaporation of the mother liquors, an additional 4.7 g of a brown solid are obtained.

The first weight of product

72.2 g of ethyl acetate (1440 ml) were added and the mixture was heated until dissolved. The solution was allowed to stand overnight at room temperature, then filtered, the crystals were washed with cold ether and dried in vacuo. 40.9 g of the expected product are obtained, m.p. 129 DEG-130 DEG C. and optical rotation [ _.alpha. ] _D = + 13.5 DEG.

Recrystallization twice from ethyl 249537 acetate yielded 9.7 g of pure salt, m.p. 141-142 ° C and optical rotation [α] _D = + 32 ° C.

B. Levorotatory salt

The mother liquors from the previous reaction were acidified with 167 ml of 1N hydrochloric acid and extracted five times with 125 ml of ethyl acetate each. The extracts were combined, washed with brine, dried (MgSO 4) and the solvent was evaporated. 49 g of residue are obtained, which is dissolved in 350 ml of warm ethyl acetate. After addition of 22.4 g of 1- (.beta.-methylbenzylamine), the solution was cooled to room temperature, 350 ml of ethyl ether was added, and the mixture was cooled in a refrigerator overnight. 44.0 g of salt, which is dissolved in 880 ml of ethyl acetate, is left to stand at room temperature for 6 hours, and 12.4 g of product, m.p. 139 DEG-140 DEG C., are isolated by filtration. overnight, to afford additional product, mp 139-140 ° C, weighing 11.66 grams. the first crop of product having an optical rotation [a] _D = -30.9 °, then a second portion [ «nec = -26.6 ³ (in both cases measured in chloroform.

The above two portions were combined and recrystallized from 480 mL of ethyl acetate. 18.0 g of the desired salt of melting point 141 DEG-142 DEG C. and optical rotation [.alpha.] _D -34.4 DEG are obtained.

Example 5

A. d- (+) -2- [1- (3,5-Dimethoxyphenyl) pyrrolidin-2-yl] acetic acid

Recrystallization of 22.0 g of the dextrorotatory salt prepared in the previous example from 440 ml of ethyl acetate yielded 17.5 g of salt, m.p. - 4- 33.8 °. The salt is treated with 47 ml of 1N hydrochloric acid, extracted four times with 100 ml of ethyl acetate each time, the extracts are washed with brine and dried over magnesium sulphate. Evaporation of the solvent in vacuo gave 12.9 g of d- (4-β-acid) as a green oil, some of which was decoloured by filtration through a short column of silica gel and the product had an optical rotation of [α] _D = + 31.4 °.

B. 1- (-) -? - f - (3,5-Dimethoxyphenyl) pyrrolidin-2-yl] acetic acid

To 18.0 g of the levorotatory salt prepared in the previous example was added 46.5 ml of 1N hydrochloric acid, and the mixture was treated in the same manner as in Part A above. 13.2 g of an optical rotation product are obtained:

[α] _D = -36.4 °.

Example 6 dk d- (+) - and 1- (- j-6,8-dimethoxy-2,3,3a, 4-tetrahydr o-1H-pyrrolo [1,2-a] quinolin-5-one

A. Dextrorotatory isomers

A mixture of 13.2 g (46.5 mmol) of 1- (-) - (1- (3,5-dimethoxyphenyl) pyrrolidin-2-yl] acetic acid, 6.5 g sodium acetate, 100 ml acetic acid and 100 ml The acetic anhydride was heated on a steam bath for 35 minutes, the volatiles were evaporated in vacuo, the residue was stirred with methylene chloride and the organic layer was separated. 2 g (91%) of the crude product, 300 mg of which is crystallized from methylene chloride / hexane, melts at 126 DEG -127 DEG C. and has an optical rotation of:

[ _.alpha. ] _D = + 141 DEG (c = 1, chloroform).

Mass spectrum: m / e = 247 (M &lt; + &gt;).

B. Levorotatory isomers

Using the above procedure using a mixture of 12.9 g (48.6 mmol) of O- (+) -2- (1- (3,5-dimethoxyphenyl) pyrrolidin-2-yl) acetic acid, 6.4 g of sodium acetate Acetic acid (50 ml) and acetic anhydride (50 ml) gave crude product (11.2 g), which was recrystallized from methylene chloride to give the purified isomer, m.p. 129 DEG-130 DEG C. and optical rotation:

[α] _D - 146.2 ° (c = 1, chloroform).

Racemate

In an analogous manner, dl-2- [1- (3,5-dimethoxyphenyl) pyrrolidin-2-yl] acetic acid is converted to dl-6,8-dimethoxy-2,3,3a, 4-tetrahydro-1H- pyrrolo [1,2-a] quinolin-5-one.

Example 7 dl, d- (+ 1 - and 1- (-) -6,8-dihydroxy-2,3,3a,4-tetrahydro-1H-pyrrolo [1,2-a] quinolin-5-one)

A. Dextrorotatory isomer

A mixture of 11.2 g (45.3 mmol) of d- (+) -6,8-dimethoxy-2,3,3a, 4-tetrahydro-1H-pyrrolo [1,2-a] quinolin-5-one, 100 ml of acetic acid and 100 ml of 48% hydrobromic acid were heated at 67 ° C under nitrogen for 2.5 hours. The reaction mixture is concentrated in vacuo, the residue is stirred with water and its pH is adjusted

It is adjusted to 7.0 with sodium bicarbonate solution.

The neutral mixture was extracted six times with 100 ml of ethyl acetate each time, the combined extracts were washed with brine, dried over magnesium sulfate and the solvent was evaporated in vacuo. 9.0 g (91%) of a yellow first product are obtained, from which a 100 mg sample is crystallized from chloroform. The purified product has a melting point of 202-203 ° C and an optical rotation of:

[α] _D = - (-108 ° (c = 1, chloroform)).

Mass spectrum (m / e):

218 (basic signal),

219 (M &lt; + &gt;).

B. Levorotatory isomer

Using an analogous procedure using 50 grams of acid, 10.2 grams of 1- (-) -6,8-dimethoxy-2,3,3a, 4-tetrahydro-1H-pyrrolo [1,2-a] quinolin-5-one. acetic acid and 50 ml of 48% hydrobromic acid gave 9.2 g of product, m.p. 190 DEG-192 DEG C. and optical rotation: [.alpha.] D = -91.4 DEG (c = 1, chloroform).

Racemate

By analogy, dl-6,8-dimethoxy-2,3,3a, 4-tetrahydro-1H-pyrrolo [1,2-a] quinolin-5-one is converted to dl-6,8-dihydroxy-2,3,3 α, 4-tetrahydro-1H-pyrrolo [1,2-a] quinolin-5-one.

Example 7C

6-hydroxy-8- (5-phenyl-2R-pentyloxy) -2,3,3a, 4-tetrahydro-1H-pyrrolo [1,2-a] quinolin-5-one

A mixture of 7.4 g (33.8 mmol) of its - (- (-) -6,8-dihydroxy-2,3,3a, 4-tetrahydr o-1H-pyrrolo [1,2-a] cbiPOhn-5- 9.55 g (69 mmol of powdered potassium carbonate) and 37 ml of dimethylformamide are heated to 80 DEG C. under nitrogen, and 8.391 g (34.6 mmol) of 5-phenyl-2S-pentvl-mesylate are added thereto under heating. The reaction mixture was stirred at 80 DEG C. for a further 90 minutes, the dimethylformamide was evaporated in vacuo, the residue was extracted five times with 50 ml of methylene chloride, the combined extracts were washed with water and brine, and dried over magnesium sulfate.

Evaporation of the solvent in vacuo yielded 13.7 g of crude product which was purified by chromatography on a silica gel column using a mixture of equal volumes of methylene chloride and hexane and a mixture of methylene chloride and ethyl acetate as eluents. The fractions containing the desired product were combined and evaporated to give 8.52 g of product.

¹ H-NMR (CDCl 3, δ ppm):

1.30 (doublet, 3H),

5.35 (multiplet, 1 H),

5.65 (multiplet, 1 H),

7.1 (singlet, 5 H),

12.7 (singlet, 1 H, OH).

Example 7 D

6-Acetoxy-8- (5-phenyl-2R-pentyloxy) -2,3,3a, 4-tetrahydro-1H-pyrrolo [1,2-a] quinolin-5-one

A mixture of 3.138 g (8.6 mmol) of the 6-hydroxy compound obtained in the previous example, 30 ml of pyridine and 9 ml of acetic anhydride was heated at 80 ° C under nitrogen overnight. The pyridine is evaporated in vacuo, the residue is taken up in methylene chloride, the solution is washed with water and dried over magnesium sulphate. The oily residue after evaporation of the solvent was purified by silica gel column chromatography using methylene chloride as eluent.

The product containing fractions were collected and the solvent was evaporated in vacuo to give 2.193 g of the desired product. Reaction of the combined less polar fractions (1.11 g) with fresh acetic anhydride using the procedure described above and after working up as above gives an additional 1.105 g of product.

¹ H-NMR (CDCl 3, <5 ppm):

1.30 (doublet, 3H),

2.30 (singlet. 3H),

5.80 (singlet, 2H, aromatic protons),

7.20 (singlet, 5H, phenyl).

Example 7 E

Lactone ^Hydroxy-6-B 5-carboxymethylene-8- (5-phenyl-2R pentvloxy) 2,3,3a, 4-tetrahydro-lH-pyrrolo [1,2-a) quinoline inu

In a nitrogen atmosphere and under anhydrous conditions, 70 rolls of dry tetrahydrofuran are cooled to -5 ° C! and while keeping the temperature below 0 ° C, 1.490 g (14.76 mmol of 1 diisopropvlamine) was added first, followed by the dropwise addition of 9.22 ml (14.76 mmol) of n-butyl lithium in hexane, after which the mixture was stirred for 30 minutes. 648 mg (7.36 mmol) of ethyl acetate are added dropwise thereto while maintaining the temperature below -67 DEG C. After the addition is complete, the resulting mixture is stirred at -67 DEG for 1 hour. A solution of 1.989 g (4.9 mmol) of the 6-acetoxy derivative prepared in the previous example, 10 ml of tetrahdrofuran, is added thereto, and the mixture is stirred at -74 DEG C. for 3.5 hours. Acetic acid was added in 5, the reaction mixture was allowed to warm to room temperature and extracted with methylene chloride.

The combined extracts were washed with water, dried (MgSO4) and the solvent was dried

243537 evaporated under reduced pressure. The oily residue is chromatographed on silica gel, eluting first with methylene chloride / hexane and then with ethyl acetate. Product containing fractions were combined and evaporated to dryness to give the title lactone (1.13 g).

@ 1 H-NMR (CDCl3, < 5 ppm):

1.30 (doublet, 3H),

5.70 (multiplet, 2H, aromatic protons), 6.05 (multiplet, 1H, olefinic protons),

7.10 (singlet, 5H, phenyl).

Example 7F

2- [6-Hydroxy-8- (5-phenyl-2R-pentyloxy) -1,2,3,3aS, 4,5R-hexahydropyrrolo [1,2-a] quinolin-5-yl] acetic acid lactone

A solution of 1.157 g (2.98 mmol) of the unsaturated lactone obtained in the previous example in 100 ml of methanol is heated to 50 degrees Celsius and 15 ml of 5N sodium hydroxide and 1.41 g of Raney alloy are added thereto. in about 5 minutes. The mixture was stirred at 55 ° C for 3.5 hours, the Rsney alloy was filtered off, the filter cake was washed with methanol, and the solvent was evaporated in vacuo. 75 ml of 1N hydrochloric acid are added to the residue, the precipitated solid is extracted with ethyl acetate, the extracts are dried over magnesium sulphate and evaporated to give 622 mg of crude oil. The oily material was purified by chromatography on silica gel, eluting sequentially with methylene chloride (15 fractions), then ethyl acetate (3 fractions), and finally methanol. Product containing fractions (fractions 2-10) were combined and evaporated in vacuo to give 322 mg of the desired lactone.

@ ¹ H-NMR (CDCl3, .delta. In ppm):

1.30 (doublet, 3H),

4.15 (multiplet, 1H,

5.57 to 5.93 (multiplet, 2Hj,

7.08 (singlet, 5H).

Example 7G

6-hydroxy-5- (2-hydroxyethyl) -8- (5-phenyl-2R-pentyloxy) -1,2,3,3aS *, 4,5R * -hexahydropyrrolo [1,2-a] quinoline

A mixture of 10 ml of dry tetrahydrofuran with 340 mg (0.87 mmol) of saturated lactone obtained in the previous example is dissolved by stirring, 33 mg (0.87 mmol) of lithium aluminum hydride are added and the mixture is stirred at room temperature for 2 hours. drops of water, adjust the pH to 6.0 with 1N hydrochloric acid and extract with ethyl acetate.

The combined extracts were washed with brine, dried (MgSO 4) and the solvent evaporated in vacuo. 344 mg of an oily residue are obtained, which is applied to a silica gel column. The column is eluted first with a mixture of methylene chloride and ethyl acetate and then rinsed with methanol. Fractions containing product were combined and evaporated to dryness in vacuo. 323 mg of an oily product having an optical rotation are obtained:

[α] _D = + 46.5 ° (c = 1, chloroform).

¹ H-NMR (CDCl 3, δ values in ppm):

I, 20 (doublet, 3H),

3.60 (triplet, 2H, CH 2 OH),

4.10 (multiplet, 1 H),

5.65 (multiplet, 2Hj,

7.10 (singlet, 5H).

Example 8

Methyl dl-2- [1- (3,5-dimethoxyphenyl) piperidin-2-yl] acetate

A. 2-Cyanomethyltetrahydropyran

The procedure described in Part B of Example 2 was repeated, substituting 2-chloromethyltetrahydropyran for 2-tetrahydrofurfuryl bromide and heating the reaction for 6 days. The desired product is obtained in a yield of 52%, bp 65-74 ° C / 400 Pa.

¹ H-NMR (CDCl 3, δ values in ppm):

2.50 (doublet, 2H, CH 2 CN).

B. 2- (Tetrahydropyran-2-yl) acetic acid

Alkaline hydrolysis of the above nitrile using the procedure described in Part C of Example 2 affords the desired product in 77% yield, mp 46-50 ° C.

C. Methyl 3,5-dibromoheptanoate

Using the procedure described in Part D of Example 2, 3,7-dibromo-heptanoic acid was obtained in 94% yield by treatment with hydrobromic acid in acetic acid.

¹ H-NMR (CDCl 3, δ ppm):

2.90 (doublet, 2H),

4.30 (multiplet, 1H,

II, 30 (singlet, 1H).

This acid is converted in 95% yield to the desired methyl ester by esterification in methanol saturated with dry hydrogen chloride.

¹ H-NMR (CDCl 3, δ ppm):

3.95 (doublet, 2H, CH2COOCH3),

4.35 (multiplet, 1H, position 3),

4.75 (singlet, 3H, COOCH 3).

D. By analogy to Example 2, 23.7 g (0.155 mole) of 3,5-dimethoxyantline are mixed with 52.3 g (0.173 mole) of methyl, -3,7-dibromoheptanoate, 26.9 g of pyridine and 80 ml. tetrahydrofuran and the mixture was stirred at room temperature overnight. Tetrahydrofuran was distilled off at atmospheric pressure and an additional 5.8 g of 3,7-dibromoheptanoate and 3.3 g of pyridine were added to the residue. The mixture was heated at 100 ° C for 5 hours and then concentrated in vacuo. The residue was dissolved in methylene chloride and treated analogously to Example 2 to give 38 g of crude product.

This crude material was taken up in toluene, loaded onto a 400 g silica gel column and eluted with a mixture of ethyl acetate and methanol. Product containing fractions were combined and evaporated to dryness to give 14.6 g of the desired product.

¹ H-NMR (CDCl 3, δ ppm):

2.58 (doublet, 2H, CH2CO2CH3),

3.64 (singlet, 3H, CO 2 CH 3),

3.78 (singlet, 6H, OCH 3);

4.30 (multiplet, 1H, —NCH — CH2CO2CH3),

6.2 to 5.8 (multiplet, 3H, aromatic protons).

Example 9 d-, l · a dl-2- [1- (3,5-dimethoxyphenyl) piperidin-2-yl] acetic acid

A mixture of 14.5 g (0.049 mol) of methyl-dl-2- [1- (3,5-dimethoxyphenyl) piperidin-2-yl] acetate, 49 ml of 5N sodium hydroxide and 100 ml of methanol is stirred at room temperature overnight, 250 ml of water are then added, the reaction mixture is acidified to pH 5 with 1N hydrochloric acid and extracted with ethyl acetate. The extracts were combined, washed with brine and dried over magnesium sulfate and evaporated in vacuo. It is obtained

12.2 g (90%) of an oily product.

¹ H-NMR (CDCl 3, δ values in PPm):

2. $ 6 (doublet, 2H, CH2CQOH),

3.80 (singlet, 6H);

6.30 to 5.80 (multiplet, 3H)

11.0 (singlet, 1 H, COOH).

Example 10 d-, 1- and dl-3,4,4a, 5-tetrahydro-7,9-dimethoxy-1H, 2H-pyrido [1,2-a] quinolin-6-one

Under a nitrogen atmosphere, a mixture of 12.1 g (0.043 mol) of dl-2- [1- (3,5-dimethoxyphenyl] piperidin-2-yl] acetic acid, 100 ml of glacial acetic acid, 6.0 g of sodium acetate and 100 ml of acetic anhydride are stirred at room temperature overnight, the acetic acid and the acetic anhydride are evaporated in vacuo, the residue is partitioned between methylene chloride and saturated aqueous sodium bicarbonate solution, the organic phase is washed with sodium bicarbonate, water and brine, and dried over magnesium sulfate. .

Evaporation of the extracts to dryness yielded 13 g of a green oil which was purified by chromatography on a 300 g silica gel column eluting with ethyl acetate. Fractions containing product were combined and evaporated to give 5.5 g of the desired dl-product, mp 91-94 ° C.

¹ H-NMR (CDCl 3, δ ppm):

2.50 (multiplet, 2H, CH 2 CO),

3.79 (singlet, 3H);

3.81 (singlet, 3 H],

5.90 (multiplet, 2H).

After recrystallization of the above product from isopropyl ether, 2.6 g of a crystalline substance is obtained, m.p. 92-93 ° C.

Example 11 dl-6-ethoxycarbonylmethyl-6-hydroxy-7,9-dlmethoxy-1,2,3,4,4a, 5-hexahydropyrido [1,2-a] quinoline

To a solution of 5.05 g (0.05 mol) of diisoipropylamine in 100 ml of tetrahydrofuran was added dropwise 31.25 ml (0.05 mol) of 1.6 M n-butyllithium in hexane under anhydrous conditions at 0 ° C under anhydrous conditions. The mixture was stirred at 0 ° C for 20 minutes, then cooled to -78 ° C and a solution of 4.4 g (0.05 mol) of ethyl acetate in 20 mL of tetrahydrofuran was added dropwise.

The resulting mixture was stirred at -78 ° C for 1 hour. A solution of 3.0 g (0.0115 mol) of dl-7,9-dimethoxy-6-oxo-1,2,3 was added dropwise over 30 minutes. 4,4a, 5-hexahydropyrido [1,2-a] quinoline in 20 ml tetrahydrofuran. After the addition was complete, the reaction mixture was stirred for 15 minutes, then 3.6 g of acetic acid was added thereto at -78 ° C and the mixture was poured into water.

After extraction with ether and evaporation of the solvent from the extract, 4.0 g of crude product is obtained, which is purified by chromatography on 200 g of silica gel using ethyl ether as eluent. 3.0 g of purified product are obtained.

¹ H-NMR (CDCl 3, δ ppm):

1.35 (triplet, 3H);

4.20 (quartet, 2H),

4.70 (singlet, 1 H, OH),

5.90 (multiplet, 2H, aromatic protons).

The less polar chromatographic fractions were combined and evaporated to dryness to give 600 mg of olefinic material.

Example 12

IN P

To a suspension of 6 g of florisil in 30 ml of benzene was added 3.0 g of dl-6-ethoxycarbonylmethyl-6-hydroxy-7,9-dimethoxy-1,2,3,4a, 5-hexahydropyrido [1,2-a] quinoline and the mixture was heated under reflux for 2 hours. On chromatography 'frames on thin layer chromatography in a solvent system such as ethyl ether are present on two spots, _Rf 0.7 and 0.5, identical to the less polar fraction (600 mg) obtained in the previous example.

The reaction mixture obtained above was freed of florisil by filtration and the benzene was evaporated. 2.6 g of crude material are obtained, which is combined with the less polar fraction (600 mg) obtained in the previous example. The crude mixture (3.2 g) was applied to a silica gel column. Elution with mixtures of hexane and ethyl ether gave 1.5 g of the less polar product (MP) with R _f = 0.7 in the IR spectrum of the band for the carbonyl group at 1715 cm ^-1, and 1.5 g of more polar product (VP) with R _f = 0.5 in the IR spectrum of the band for the carbonyl group at 1750 ^cm-first

This less polar product was identified as dl-6-ethoxycarbonylmethylene-7,9-dimethoxy-1,2,3,4,4a, 5-hexahydropyridolo [1,2-a] quinoline by ¹ H-NMR spectroscopy.

The more polar product (VP) was similarly identified as dl-6-ethoxycarbonylmethyl-7,9-dimethoxy-2,3,4,4a-tetrahydro- (1H) -pyridolo [1,2-a] quinoline.

Example 13 dl-6-carboxymethyl-7,9-dimethoxy-2,3,4,4a, 5,6-hexahydro-1H-pyrido [1,2-a] quinoline

A flask equipped with a magnetic stirrer, a condenser and a nitrogen inlet was charged with 986 mg (2.97 ml) of dl-6-ethoxycarbonylmethylene-7,9-dimethoxy-1,2,3,4,4a, 5-hexahydropyrido [1,2- a] quinoline and 130 ml of absolute methanol. The mixture is heated to 40 degrees Celsius, 74 ml of 1N sodium hydroxide is added dropwise, the temperature is raised to 45-50 ° C and 1.39 g of Raney alloy are added in portions.

The resulting mixture was stirred for 70 minutes, then allowed to cool, filtered and the filtrate evaporated. The liquid residue was partitioned between water and chloroform, acidified to pH 5 with 1N hydrochloric acid, and the layers were separated after shaking. The aqueous layer was re-extracted with chloroform, the combined organic phases were washed with brine and dried over sodium sulfate. Evaporation of the solvent gave 826 mg of crude product.

Mass spectrum: m / e =

305 (M &lt; + &gt;),

246 (M-CH 2 COOH).

Example 14

COOH

A flask equipped with a magnetic stirrer and a solid carbon dioxide cooled condenser was charged with 826 mg dl-6-carboxymethyl-7,9-dimethoxy-2,3,4,4a, 5,6-hexahydro- (1H) -pyrido [1,2] quinoline, 50 ml glacial acetic acid and 50 ml 48% hydrobromic acid. The flask was heated at 100 ° C for 24 hours, then the reaction mixture was evaporated, the residue diluted with water, adjusted to pH 6-7 with 6N sodium hydroxide, saturated with sodium chloride, and extracted with ethyl acetate.

The extracts were dried over sodium sulfate and the solvent was evaporated under reduced pressure. 702 mg of crude title compound is obtained as an oily foam which is purified by silica gel column chromatography using a mixture of chloroform and ethyl ether as eluent. The product containing fractions were combined and evaporated to give 390 mg of the desired product.

Mass spectrum: m / e = 259 (M &lt; + &gt;).

@ ¹ H-NMR (CDCl3) .delta.

up to 4 (multiplet. 15H, aliphatic protons and

OH),

6.0 (multiplet, 2H, aromatic protons).

Example 15

Lactone dl-6-carboxymethyl-7-hydroxy-9- (5-phenyl-2-pentyloxy) -2,3,4,4a, 5,6-hexahydro- (1 H) -pyrido [1,2- a] quinoline

A flame-dried flask equipped with a magnetic stirrer, condenser and nitrogen capillary was charged with a solution of 390 mg (1.5 mmol) of lactone dl-6-carboxymethyl-7,9-dihydroxy-2,3,4,4a, 5. 6-hexahydro- (1H) -pyrido [1,2-a] quinoline in 3 ml of dimethylformamide and then 500 mg (3.62 mmol) of powdered potassium carbonate, and the resulting mixture is heated at 70 degrees Celsius for 30 min. a solution of 452 mg (1.95 mmol) of dl-5-phenyl-2-methylsulfonyloxypentane in 2 ml of dimethylformamide was added thereto, and the mixture was heated at 80 ° C for 3.5 hours. An additional 135 mg of dl-5-phenyl was added. -2-methylsulfonyloxypentane in 1 mL of dimethylformamide and heating at 80 ° C was continued for an additional 1.8 hours.

The reaction mixture was allowed to cool, stirred at room temperature overnight, reheated to 80 ° C, treated with 250 mg of potassium carbonate powder, heated at 80 ° C for 4 hours, then treated with an additional 135 mg of dl. -5-phenyl-2-methylsulfonyloxypentane in 1 ml of dimethylformamide, heating was continued for 1 hour, then the mixture was again stirred at room temperature. The resulting mixture was stirred with water, extracted with ethyl acetate, the extracts were combined, washed with water and brine, and dried over magnesium sulfate.

Evaporation of the solvent in vacuo gave a brown oily residue which was purified by chromatography on a 50 g silica gel (70-230 mesh) column prepared in chloroform. using the same solvent as the eluent. Product containing fractions were combined and re-chromatographed. Elution with a mixture of isopropyl ether-hexane 2: 1 yielded 263 mg of the desired product, ^X H-NMR was consistent with structure of title compound.

¹ H-NMR (S values in ppmj:

1.30 (doublet, 3H),

4.15 (multiplet, 1 H),

5.95 to 6.25 (multiplet, 2H, aromatic protons),

7.20 (singlet, 2H, phenyl).

Example 16 dl ^J 6- (2-hydroxyethyl) -7-hydroxy-9- (5-phenyl-2-pentyloxy) -2,3,4,4a, 5,6-hexahydro- (1 H) -pyrido [1,2- b] -alquinoline and diacetate

A. To a solution of 263 mg (0.65 mmol) of lactone dl-6-carboxymethyl-7-hydroxy-9- (5-phenyl-2-pentyloxy) -2,3,4,4a, 5,6-hexahydro- ( 1H) -py249337 Rido [1,2-a] quinoline in 20 ml tetrahydrofuran was added portionwise over 3 minutes 25 mg (0.66 mmol) of lithium aluminum hydride under anhydrous atmosphere under anhydrous conditions.

The resulting mixture was stirred at room temperature overnight, then quenched with water, adjusted to pH 6.0 with 1N hydrochloric acid, and partitioned between water and ethyl acetate. The combined organic layers were washed with brine, dried (MgSO 4) and evaporated to dryness. 275 mg of the desired dihydroxy compound are obtained in the form of an oil.

B. 266 mg (0.65 mmol) of the product prepared in Part A above was dissolved in 10 ml of methylene chloride and 1.8 ml of pyridine, 0.6 ml of acetic anhydride was added and the mixture was stirred under nitrogen at room temperature for 48 hours. The reaction mixture was concentrated in vacuo, the residue was dissolved in ethyl acetate, washed with water and brine, and dried over magnesium sulfate. After evaporation of the solvent, 317 mg of crude product is obtained, which is purified by chromatography on a column of 50 g of silica gel (70-230 mesh) eluting with chloroform. Fractions 3-8 are combined and evaporated to dryness to give 215 g of purified diacetate. .

¹ H-NMR (CDCl 3, δ in ppmj):

1.30 (doublet, 3H),

2.05 (slnglet, 3H, acetate),

2.30 (singlet, 3H, phenolic hydroxy acetate,

6.05 (doublet, 1H),

6.20 (broad singlet, 1 H),

7.20 (singlet, 5H).

Mass spectrum: m / e =

493 (M &lt; + &gt;),

406 (M-CH2CH2OCOCH3).

C. To 10 ml of methanol add 0.79 ml of 1N sodium hydroxide solution and 187 mg (0.38 mmol) of the diacetate prepared in Part B above. The reaction mixture is stirred under nitrogen for 2 hours, then neutralized with 1N hydrochloric acid, It is evaporated to dryness, the residue is taken up in ethyl ether and the solution is washed with water and dried over magnesium sulphate. Evaporation of the ether gave 148 mg of the dihydroxy compound.

Mass spectrum: m / e =

409 (M + 1,

364 (M-CH 2 CH 2 OH).

¹ H-NMR (CDCl 3, δ ppm):

1.30 (doublet, 3H),

5.90 (singlet, 2H, aromatic protons),

7.20 (singlet, 5H, phenyl).

Example 17 dl-4a, 10b-trans-7-hydroxy-6β- (2-hydroxyethyl) -9- (5-phenyl-2-pentyloxy) -1,2,3,4,4a, 5,6 , 10b-octahydrophenanthrene

A solution of 2.1 g (5.2 mmol) of dl-4a, 10b-trans-7-hydroxy-6-carboxymethylene-9- (5-phenyl-2-pentyloxy) -2,3 is added to 400 ml of liquid ammonia. 4,4a, 5,10b-hexahydro-1H-phenanthren-lactone in 100 ml of ethyl ether, 84 mg (12 mmol) of lithium metal are added in portions and the blue color is allowed to persist for 2 minutes and then quenched by addition of 2.1 g of ammonium chloride. The ammonia is evaporated under a stream of nitrogen, the residue is taken up in water, the solution is acidified to pH 3 with 1N hydrochloric acid and extracted with ethyl acetate.

The extracts were dried over sodium sulfate and evaporated in vacuo. 2.1 g of crude product are obtained, which is purified by chromatography on silica gel using mixtures of isopropyl ether and hexane as eluents. 440 mg of the title compound are obtained.

¹ H-NMR (CDCl 3, δ ppm):

1.15 (doublet, 3H, CH 3),

3.80 (triplet, 2H, CH 2 OH),

4.25 (multiplet, 1Η00Η),

6.25 to 6.50 (multiplet, 2H, aromatic protons),

7.20 (singlet, 5H, phenyl).

Claims (4)

SUBJECT A process for the production of substituted hexahydropyrrolo [1,2-a] quinolines, hexahydro-1H-pyrido [1,2-a] quinolines, hexahydrobenzo [e] indenes and octahydrophenanthrenes of the general formula wherein: M is CH or nitrogen, t is 1 or 2 and Z 1 is 5-phenyl-2-pentyloxy, their acetates and pharmaceutically acceptable acid addition salts, characterized in that the compound of formula II wherein either W is COOR 6 wherein R 4 is methyl or ethyl, OR 1 represents a hydroxyl group or an OCOCH 3 group, y is 2 and the dotted line bond is absent, or W and ORi together form a grouping O OF THE INVENTION and y is 1, in which case the dashed line represents a bond or y is 2 and the bond indicated by the dashed line is absent, R 16 and R 17 when M represents a nitrogen atom, either represent hydrogen atoms or together represent an oxygen atom of a carbonyl group, or R 16 and R 17 when M represents a CH group represent hydrogen atoms, and M, Z 1 and t are as defined above, reducing in the presence of an inert solvent a reducing agent selected from the group consisting of metal hydrides, preferably lithium aluminum hydride, hydrogen in the presence of a noble metal catalyst, preferably palladium, and metallic lithium in anhydrous liquid ammonia; the product is optionally acetylated and / or converted to its acid addition salt. 2. Method according to claim 1, characterized in that the application of the corresponding starting material, to give a compound of formula I in which Z represents a radical of the formula -C (CH _{Z) 3} C ₆ H ₅ in which one of R and Rt 3 R14 is hydrogen and the other is CH3, and the remaining general symbols are as defined above. 3. A process according to claim 2, wherein the corresponding starting materials are used to form a compound of formula (I) wherein Z1 is a radical of formula (2) wherein R13 is hydrogen and R14 is methyl; the symbols have the meaning given above. 4. The process of claim 1 wherein the solvent is tetrahydrofuran and its reducing agent is lithium aluminum hydride.