DE1770304A1 - Oxazinoisoquinoline derivatives and processes for their preparation - Google Patents

Description

The present invention relates to derivatives of [1,4] oxazino [3,4-a] isoquinoline, Processes for the preparation of these compounds and pharmaceutical compositions of matter comprising them Contain connections.

It has been found that the new compounds of the formula I

(D

in which

R-j ^ hydrogen or a lower alkoxy group,

R_2 and R _{3 are} a lower alkoxy group or, when R is hydrogen, R2 and R- taken together are the methylenedioxy group, and

On the amino group, a lower alkylamino group, a lower dialkylamino group, the morpholino, 1-pyrroiidinyl, Piperidino, 1-piperazinyl, a 4- (lower alkyl) piperazin-1-yl, 4- (hydroxy-lower alkyl) -piperazin-1-yl- or a 4- (lower alkoxy-lower alkyl) -piper-

1 09843/1882

azin-1-yl group means

as well as their acid addition salts with organic or inorganic acids, have valuable pharmacological properties, The Investigations carried out on warm-blooded animals have shown that the compounds according to the invention, in particular those in where the nitrogen atom of the group Am is three times substituted by carbon, on the test animals a calming and have a muscle-relaxing effect in higher doses. the The established tranquillising effect does not affect the vigility, moreover these substances have a favorable effect therapeutic index. These properties characterize the compounds according to the invention as indicated for the treatment of Anxiety, tension and excitement as they occur in neuroses and psychoses,

There are lower alkoxy groups in the compounds of the formula I the methoxy, ethoxy, propoxy or isopropoxy group; the. Methoxy group is preferred, lower alkyl groups such as those in lower alkylamino, dialkylamino or piperazin-1-yl radicals occur, are preferably the methyl and ethyl groups, but can also be the propyl or isopropyl group (hydroxy lower AlkyDpiperazin 1-yl groups and (lower alkoxy- lower Alkyl) piperazin-1-yl groups are in particular the 4-methyl and 4-ethyl, also the 4 ~ (2-hydroxy-ethyl) -, 4 ~ (2-hydroxy-propyl) -, 4- (3-hydroxypropyl) ~ piperazin-l-yl groups and their methyl or Ethyl ether.

109843/1882 ^ D o _{R) G1NAL}

The compounds of the formula I and their acid addition salts are prepared by adding a compound of formula II

(II) COX

in which

X is a halogen atom, in particular chlorine or bromine, a lower alkoxy group or the group -OY in which Y is the Cyanomethyl group, the p-nitrophenyl group, an alkoxycarbonyl group having at most 5 carbon atoms or represents the benzyloxycarbonyl group, and R,, R2 and Ro have the meaning given under formula I, with an amine of the formula III

H-Am (III)

in which Am has the meaning defined under formula I, or an alkali metal derivative thereof, in an inert solvent and, when X is a halogen atom, reacts in the presence of an acid-binding agent and, if desired, the obtained Compound converted into an acid addition salt with an organic or inorganic acid.

The implementation of the functional carboxylic acid derivatives of the Formula II with amines of the formula III can be carried out at room temperature or at an elevated temperature. With strongly exothermic It is advantageous to do the same by cooling under the reaction

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To keep control. The use of inert solvents is particularly appropriate when using carboxylic acid halides of the formula II displayed. Hydrocarbons, especially aromatic hydrocarbons, are suitable as inert solvents, such as benzene, toluene or xylene; however, chlorinated aliphatic hydrocarbons such as 1,2-dichloroethane can also be used or the trichloroethanes, or ethereal solvents such as 1,2-dimethoxy or diethoxy than can be used. When converting carboxylic acid halides of the formula II, it is advantageous to use anhydrous solvents. as Acid-binding agent can contain an at least molar excess Amine of the formula III can be used.

If one starts from a lower alkyl ester according to the formula II, for example a methyl or ethyl ester, this is reacted with the amine of the formula III in aqueous or lower alkanolic solution, for example in ethanol. In Applications of Liquid amines to use ^one of solvents is not necessarily required. Instead of the amines, their alkali metal derivatives can also be used; Lithium amides such as lithium amide, lithium diethyl amide, lithium piperidide and the like are particularly suitable.

The starting materials of the formula II are prepared from the corresponding carboxylic acids of the formula IV by methods known per se

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(IV) COOH

in which R-. , R _? and R- have the meaning given above and can in many cases be used for the reaction with an amine of the formula III without further purification. Sometimes, even after they have been prepared, they are reacted directly with such an amine in the same reaction medium without being isolated.

The carboxylic acid halides corresponding to the formula II are, for example, from the carboxylic acids of the formula IV or from their Alkali metal salts, e.g. from the sodium or potassium salts, or from the acid addition salts of these carboxylic acids with a Mineral acid, e.g. from its hydrochloride, obtained if it is treated with oxalyl chloride or thionyl chloride, if necessary in an inert solvent. As an inert solvent, methylene chloride has proven advantageous, but can also chlorinated ethanes, such as 1,2-dichloroethane, or mononuclear aromatic hydrocarbons, such as benzene or toluene, are used as solvents.

The lower alkyl esters according to the formula II are prepared from the carboxylic acids of the formula IV by esterification, e.g. with a lower alkanol in the presence of a mineral acid such as hydrogen chloride or sulfuric acid.

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Except for the lower alkyl esters according to the formula II so-called "activated esters", for example the cyanomethyl and p-nitrophenyl esters corresponding to formula II, have proven useful proved for the preparation of the compounds of formula I. These esters can be derived from the carboxylic acids of the formula IV known methods. This is how the cyanomethyl esters are formed, if you have a carboxylic acid of the formula IV in an inert solvent, e.g. in ethyl acetate or methylene chloride, in the presence a tertiary amine, such as triethylamine, with chloroaceto-

e.g.

nitrile treated. The p-nitrophenyl esters are / from a carboxylic acid of formula IV and p-nitrophenol in the presence of dicyclohexylcarbodiimide in an inert solvent such as ethyl acetate, tetrahydrofuran or chloroform. Also suitable as reactive functional derivatives of carboxylic acids

NS f

of the formula IVV mixed anhydrides according to the formula II, e.g. the anhydrides of a carboxylic acid of the formula IV with the ethoxy, Isobutoxy- or benzyloxy-formic acid, for the preparation of compounds of the formula I / The implementation of these mixed anhydrides with amines of the formula III takes place under very mild conditions. The mixed anhydrides mentioned are obtained when one Carboxylic acid of the formula IV in the presence of a base, for example triethylamine, with a chloroformic acid ester in an inert Solvent, e.g. methylene chloride, is reacted. The mixed anhydrides formed are not isolated, but by addition of the desired amine of the formula III in the same vessel

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converted to compounds of formula I.

Nitriles of the formula V are advantageously used to prepare the carboxylic acids of the formula IV

(V)

in which R, i 1 * 2 and R _{3 have} the meaning given above, hydrolyzed with aqueous bases, such as sodium or potassium hydroxide. The carboxylic acids formed can be isolated from the hydrolyzates as such or more often than their acid addition salts with a mineral acid. The hydrochlorides of the carboxylic acids of the formula IV have proven to be particularly valuable in that they can be obtained and handled easily.

The nitriles of the formula V are prepared by adding a compound of the formula VI

in which

R denotes the cyano group or the carboxamido group

and

R,, R2 and R. have the meaning given above with a acidic condensing agent, if desired in an inert one Solvent, cyclized and reduced the cyclization product.

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Acid condensing agents of the Lewis acid type can be used for the cyclizations of the compounds of the formula VI such as phosphorus oxychloride, polyphosphoric acid, Boron trifluoride, aluminum chloride and the like. As special valuable condensing agents are phosphorus oxychloride and polyphosphoric acid called. Halogenated lower alkanes, such as di- and trichloroethanes and propanes, can be used as solvents be, the 1,2-dichloroethane is particularly advantageous, has proven liable. It is also possible, if appropriate, to work without a solvent.

During cyclization, the morpholin-5-ones are formed of the formula VI, the 5, llb-dehydro derivatives of the compounds of the formula V, which without further purification to the compounds of Formula V to be reduced. This reduction can be done chemically, e.g. by means of complex hydrides such as sodium borohydride, or catalytically with hydrogen in the presence of a catalyst such as palladium in an inert solvent. In the Reduction does not change the nitrile group. Lower alkenols such as methanol or ethanol are suitable as solvents,

TUkylw'trilt, Wi t tH

y ^

'Or, for the catalytic reduction, also ethyl acetate.

To prepare the morpholin-5-ones of the formula VI, one starts from known phenethylamines which are substituted in the 3-, 4- and 5-positions according to the meaning of R _1, R 1 and R 3. These are 2- (3,4-dimethoxyphenyl) ethylamine, 2- (3,4,5-trimethoxyphenyl) ethylamine and 2- (3,4-methylenedioxyphenyl) ethylamine. Implementation of these phenethylamines with glycidamide leads to

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2-Hydroxy-3- (phenäthylamino) propionamides of the formula VII

R ₃

V CH ₂ -CH ₂ -NH-CH ₂ -CH (Oh) -CONH ₂ (VII)

in which R ₁ , R 2 and R _{3 have} the meaning given above, which with chloroacetic ester in the presence of a base or with chloroacetyl chloride and subsequent treatment with a base give the compounds of the formula VI in which R is the carboxamide group. The compounds of the formula VI, in which R denotes the cyano group, are prepared from these by dehydrating the carboxamido group.

In a second process, the compounds of the formula Ia which come under the formula I are obtained

(Ia) COA on ¹

in which

R, hydrogen or a lower alkoxy group, R2 and Ro a lower alkoxy group or, if R, denotes hydrogen, R ₂ and R ~ taken together are the methylenedi-

oxy group, and
Am 'a lower dialkylamino group, the morpholino, the.

1-pyrrolidinyl, the piperidino or a 4- (lower Alkyl) piperazin-1-yl group,

and their S-Me-addition salts with organic or inorganic ones Acids, if one uses a compound of the formula VIa

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R. 3 / Γ -CH ₂ ι R ₂ -CH ₂ - R. 1 —Ν ( Λ

XIO on ¹

N O (via)

in which R ,, R ₂ , Ro and Am ^{1 have} the meanings given above, cyclized with an acidic condensation agent, if desired in an inert solvent, the cyclization product is reduced and, if desired, a compound thus obtained is converted into an acid addition salt with an organic or inorganic acid caught.

The reaction conditions, condensing agents and solvents suitable for the cyclization are basically the same as those discussed above on the occasion of the cyclization of the compounds of the formula VI. With cyclization of the compounds of formula VIa has the use of phosphorus oxychloride as a condensing agent and working in 1,2-dichloroethane proved to be particularly advantageous. The reduction the cyclization products can also be carried out in a manner analogous to the reduction processes discussed above.

The starting materials of the formula VIa can be in one of the Preparation of the compounds of the formula VI can be obtained in an analogous manner. Assuming one of the substituted ones defined above Phenethylamines and an N, N-di (lower alkyl) glycidamide, e.g. Ν, Ν-diethyl-glycidamide, one obtains an N, N-Di (lower Alkyl) amide analogous to formula VII, e.g. a 2-hydroxy

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the 3- (phenäthylamino) propionic acid diethylamide, the analog / for the Propionamides of the formula VII described manner in a morpholinone the formula VIa can be converted. In addition, a 2-cyano-morpholinone corresponding to the formula VI can be used according to known methods Convert methods into a corresponding morpholinone of formula VIa, e.g. by converting the cyano group into a lower one Alkoxycarbonyl group, e.g. into the methoxy or ethoxycarbonyl group, and reaction of the morpholinone-2-carboxylic acid ester obtained with a lower dialkylamine, morpholine, pyrrolidine, piperidine or 1- (lower alkyl) piperazine.

According to a further process, the compounds of the formula Ib falling under formula I are obtained

(Ib)

in which

R, hydrogen or a lower alkoxy group, R ₂ and RJ a lower alkoxy group or, if R-, denotes hydrogen, R ₂ and R _{3 taken} together denote the methylenedioxy group,

and their acid addition salts with organic or inorganic acids, if a compound of the formula V is used with an alkali metal hydroxide or with an alkali alkanolate in a corresponding lower alkanol and, if desired, the resulting process

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bond in an acid addition salt with an organic or

/ fftni'ofe afet formet Ii l *** nut oteh * rkafrt * tv aw i / tt, A /, fr! / λ, Of ₉ T forme (£ ■ ** · * V *** f <* W * * «

»It t.i. UtTivaffir / ftf /: ' ^f

Sodium and potassium hydroxide are to be mentioned as alkali hydroxides, which are used in a lower alkanolic solution, e.g. in ethanol Application. Lower alkenols come as alkali alkanolates e.g. the sodium and potassium alkanolates. The usage of potassium tert-butoxide in tert-butanol has proven advantageous proven. Alkanols whose carbon number does not exceed 6 are used as lower alkanols.

The compounds of the formula I contain several centers of asymmetry in their skeleton, such as the carbon atoms 3 and 11b. It follows that such compounds can occur in several stereoisomeric optically active forms, each be separated in pairs as racemates from the reaction mixtures. According to the method, two rows are so far more stereoisomeric Racemates, which were designated isomers I and II. It has been found that these isomers I and II are only in relation to the steric position of the substituent in the 3-position differ from each other and that the thermodynamically less stable isomers I under the influence of strong bases can be rearranged into the more stable isomers II. The practical consequences of these conditions are for those skilled in the art is readily apparent and can also be found in a number of the following examples.

To prepare optically active representatives of the compounds of the formula I, use is made of the racemate known per se

109843 / V8 82

cleavage of the optically inactive process products by means of optically active acids, the (+) - and (-) - malic acids as
have proven beneficial.

The following examples illustrate the examples according to the invention Process for the preparation of the compounds according to the invention but without restricting them in any way. The temperatures are given in degrees Celsius.

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example 1

3-cyano-9,10-dimethoxy-1,3,4,6,7, lib-hexahydro- [1,4] oxazino [3,4a] isoquinoline.

(a) A solution of 4.47 g of 2-carboxamido-4- [2- (3,4-dimethoxyphenyl) ethyl] morpholin-5-one in 5.2 ml of freshly distilled phosphorus oxychloride and 122 ml of 1,2 -Dichloroethane was heated under reflux and with exclusion of moisture for 2 hours. The mixture was then ^{evaporated to dryness in vacuo at 80 1} and the residue was dried over potassium hydroxide in vacuo at room temperature for 18 hours , 44 g of sodium borohydride are added in small portions. After the reaction had ended and the solvents had been evaporated off in vacuo, the residue was taken up in 30 ml of 2.5N aqueous hydrochloric acid. This solution was washed with ether, with 4-n. Sodium hydroxide made basic and then extracted 3 times with methylene chloride (20 ml each time). The combined extracts were dried over magnesium sulfate, filtered and the filtrate evaporated to dryness, 3-cyano-9,1O-dimethoxyl, 3,4,6,7, llb-hexahydro- [1,4] oxazino [3,4a] Isoquinoline was obtained which, recrystallized from ethanol with the addition of decolorizing charcoal, gave the product of melting point 182-184 ° (isomer I). Treatment of an ethereal solution of this compound with hydrogen chloride gives the corresponding hydrochloride.

The isomeric 3-nitrile with a melting point of 175-177 'can be obtained from the mother liquors of the crystallization from ethanol just described. (Isomer II) can be obtained.

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Modifying the cycling procedure described under (a) 20 ml of phosphorus oxychloride are added dropwise to the stirred suspension of 9 g of the morpholine in 120 ml of toluene given and the reaction mixture refluxed for 2 hours cooked. Subsequently, the mixture becomes dry in vacuo evaporated, the residue taken up in water and the solution treated with decolorizing charcoal and filtered. The filtrate is made basic with aqueous ammonia and the colorless precipitate is extracted with ethyl acetate. This ethyl acetate extract was for 3 hours with hydrogen over 2 g of 10% Pd-C catalyst hydrogenated. After filtering off the catalyst, the filtrate was evaporated to dryness and the residue from benzene-petroleum ether recrystallized, the nitrile of mp 172-174 "being obtained, recrystallization from benzene increased dt-.n mp, on 178-179. The product was found to be identical to isomer I described under section (a).

The morpholine used as the starting material was prepared as follows:

(b) To a solution of 30.93 g (0.3 mol) of benzonitrile in 150 ml of methanol, 17.7 g of acrylamide was added with stirring. After a homogeneous solution had arisen, one after the other 30 ml (0.3 mol) of 30% strength hydrogen peroxide, 5 ml of a 0.1 M aqueous disodium hydrogen phosphate solution and 5 ml of aqueous. 0.5-n, sodium hydroxide solution added, The. Temperature of the reaction vessel mixture was kept by cooling at about 40 ° and there were a further 20 ml Ο, ^ - η. Sodium hydroxide solution in portions of 5 ml je.de added for half an hour. The mixture was then stirred for a further 30 minutes, then evaporated in vacuo,

109843/1882

BATH ORIGINAL

after removal of the methanol, diluted with 100 ml of water and filtered. The solid filter residue was washed with water and the combined filtrates were evaporated to dryness in vacuo. The oily residue was taken up in 100 ml of acetone, this solution was dried over magnesium sulfate, filtered and the filtrate was evaporated in vacuo, a pale yellow oil being obtained which is the crude glycidamide. This was dissolved in 40 ml of 1,2-dirne thoxyä and the solution immediately for the other conversions are used further. The titer of the glycidamide solution is determined by treating 1 ml of this solution with: 50 ml 0.1-n. Hydrochloric acid in saturated magnesium chloride solution for a period of 30 minutes and titrimetric determination of hydrochloric acid consumption with 0.1-n. Caustic soda determined,

(c) An equimolar amount of an approximately 2 molar solution of 2- (3,4-dimethoxyphenyl) ethylamine in 1,2-dimethoxyethane was added to 39 ml of the cooled solution of glycidamide. The reaction mixture was stirred for 2 hours with cooling and then left at room temperature for 15 hours. The resulting mass was liquefied with ether, the precipitate was filtered off, washed with ether and dried and gave 2-hydroxy-3 ~ [2- (3,4-dimethoxyphenyl) ethylamino] propionamide, which was used directly for the next reaction without further purification can be used, recrystallization of a sample from methanol gave the pure propionamide of melting point 123-128 °.

109843/1182 ^ ⁰ ° » ^l Q / fi / _AL

(d) To 35 ml of a mixture of equal parts abs. Benzene and abs. Dimethylformamide was 1.4 g of a at room temperature Given a 6Ö7oigen dispersion of sodium hydride in mineral oil. then 7 g of 2-hydroxy-3- [2- (3,4-dimethoxyphenyl) ethylamino] propionamide were obtained added, the mixture stirred for 10 minutes, cooled and treated with 2.8 ml of ethyl chloroacetate. To Stirring for 15 minutes at a slightly elevated temperature, the mixture was diluted with 100 ml of dry benzene and kept away from moisture refluxed for 21 hours. It was then evaporated in vacuo and the residue was triturated with acetone. After 16 hours of standing at room temperature, the precipitate was filtered off, washed with a little acetone and im Vacuum dried. The product obtained melted at 159-164 °, recrystallization from acetone gave 2-carboxamido-4- [2 »(3,4-.dimethoxyphenyl) ethyl] morpholin-5-one from m.p. 169-171 °.

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1 ft

Example 2

3-cyano-9,10-methylenedioxy-1,3,4,6,7, llb-hexahydrο- [1,4] oxazine [3,4a] isoquinoline.

(a) A mixture of 4 g of 4-carboxamido-4- [2- (3,4-methylenedioxyphfcnyl) ethyl] morpholin-5-one, 6.3 ml PhcsphcroxychLorid and 40 ml 1,2-dichloroethane for 2 hours with exclusion of moisture boiled on reflux. It was then evaporated in vacuo, the sticky residue in 45 ml of methanol added and 2 ml of 507% sodium hydroxide solution added, after which the solution still reacted acidic. This solution was added with stirring and cooling with ice water, 1.67 g of sodium borohydride in portions. The stirring continued overnight and the next day finely divided, pink precipitate filtered off. The filter residue was suspended in 50 ml of water and the suspension 3 times extracted with 150 ml of methylene chloride each time. The extracts were combined, dried over magnesium sulfate, filtered and the filtrate evaporated in vacuo to give the crude nitrile was obtained in crystalline form.

The methanolic-aqueous filtrate of the borohydride reduction was evaporated and the residue with 30 ml of saturated aqueous ger Sodium bicarbonate solution added. The resulting mixture was extracted 4 times with 20 ml of methylene chloride each time, the combined extracts were dried over magnesium sulfate, filtered and the The filtrate was evaporated in vacuo, a semicrystalline residue being obtained. This was triturated with ethanol and gave a further amount of crystalline, crude nitrile. The GE-

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entire crude nitrile was recrystallized from ethanol and gave the product of melting point 168-183 ° (mixture of isomers I and II). $ „. RaWU« * kr <(tall'ni '<e <«a« ft If fret far üt * «rt tu * / tftt *, -Jfs.tte-rtvijeu *.' ^ ./ Instead/ Jfi _t * i * rtj_ t & u * fa *

The starting material was obtained as follows: ^li ^^

Cb) 3 - [2 - (3,4-methylenedioxyphenyl) ethyl] amino-2-hydroxypropicnamide ,

From a solution of 49.2 g of 2- (3,4-methylenedicxyphenyl) ■ ethylamine hydrochloride with a melting point of 210-212 ° in 1.25 liters of water the base is released by alkalizing to pH 9-10 with soda and the solution by extraction with methylene chloride (3 χ 500 ml) withdrawn. The. combined extracts dried over magnesium sulfate were evaporated to give the amorphous amine. This was dissolved in 25 ml of 1,2-dimethoxyethane and this solution with 96 ml of a 2.56 M solution of glycidamide in 1,2-dimethoxyethane added, this addition being carried out with stirring and cooling. The reaction time was 18 hours, then acetone added and the precipitate filtered off, the filter residue after crystallization from iscpropanol provided the propicnamide, M.p. 141-143.

(c) 2-Carbxamido-4- [2- (3,4-methylenedioxyphenyl) ethyl] -mor pho 1 in ■ - 5 - one .

11 g of anhydrous sodium acetate were added to a solution of 26.2 g of propicnamide in 500 ml of dimethylformamide, prepared with heating, and the mixture with stirring Chilled ice water. At a temperature of 10 was then a solution of 8 ml of chloroacetyl chloride in 80 ml of dimethylformamide added over 2 hours, the mixture for a further

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Stirring with cooling for a further hour and then overnight at room temperature left. Then the reaction mixture became 600 ml Poured water, keeping the temperature below 25 °, and the aqueous mixture extracted with methylene chloride (3 × 100 ml). After drying over magnesium sulfate and filtering, the combined extracts were evaporated in vacuo and left behind sen an oily residue. This residue was dissolved in 200 ml of isopropanol, the solution was cooled in ice water and taken under Stir with 12 ml of a 50% aqueous sodium hydroxide solution added drop by drop. After one hour, the white precipitate was filtered off and suspended in 200 ml of water for 18 hours and filtered off again. After drying, the filter residue was recrystallized from ethanol and gave the morpholinone from m.p. 236-237 °.

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Example 3

3-cyano-9,10,11-trimethoxy-1,3,4,6,7, lib-hexahydro- [1,4] oxazino [3,4a] isoquinoline.

(a) A mixture of 5.01 g of 2-carboxamido-4- [2- (3,4,5-trimethoxyphenyl) ethyl] morpholin-5-one, 7.5 ml of phosphorus oxychloride and 1,2-dichloroethane was refluxed for 1.5 hours boiled and then evaporated in vacuo. The residue was dried in vacuo overnight and then in 75 ml of methanol and 5 ml Water dissolved with cooling (ice water). To this solution, 3.95 g of sodium borohydride were added in portions with stirring. To When the addition was complete, the mixture was stirred for a further 30 minutes and then the colorless precipitate was filtered off and washed with water. The filtrate was extracted with methylene chloride (4 × 10 ml), the extracts combined, dried and evaporated. The residue obtained was combined with the filter residue and the entire material recrystallized from ethanol, the nitrile having a melting point of 151-152 ° (isomer II).

The starting material was obtained as follows:

(b) 3- [2- (3,4,5-trimethoxyphenyl) ethyl] amino-2-hydroxypropionamide .

From a suspension of 45.84 g of 2- (3,4,5-trimethoxyphenyl) ethylamine hydrochloride, Mp. 178-181 °, in 500 ml of water, the base was freed by alkalizing with soda to pH about 9 set and removed from the aqueous phase by extraction with methylene chloride. The dried over magnesium sulfate After evaporation, the extract yielded the amorphous amine, which was dissolved in 20 ml of 1,2-dimethoxyethane. This solution was stirred

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and cooling with 72 ml of a 2.56 M solution of glycidamide in 1,2-dimethoxyethane. After 24 hours a thick crystalline precipitate had formed. Acetone was added to liquefy the mass and then filtered. Crystallization from isopropanol gave the propionamide, / * · * /> · 43 * ~> 3?

(c) 2-carboxamido-4- [2- (3,4,5-trimethoxyphenyl) ethyl] morpholin-5-one .

7.27 g of anhydrous were added to a solution, cooled to 5 °, of 25.2 g of the above propionamide in 350 ml of dimethylformamide Sodium acetate was added and then a solution was slowly added at a temperature not exceeding 5-8 ° of 6.7 ml of chloroacetyl chloride in 67 ml of dimethylformamide. It was stirred for an hour with cooling and one additional hour at room temperature. The mixture was poured into 600 ml of water while cooling, the aqueous mixture with l ™ n. Sodium hydroxide solution neutralized and then extracted 3 times with 100 ml of methylene chloride each time. The combined extracts were dried and then evaporated. The oily residue was dissolved in 250 ml of isopropanol, the solution was cooled in ice water and treated with as much 10.8-n. Sodium hydroxide solution was added until a permanent pH of 8-9 was reached. The deposited precipitate was filtered off and washed by suspension in 200 ml of water for 5 hours. The product filtered off and dried in vacuo at 60 ° was recrystallized from isopropanol and gave the morpholinone, mp. 204.5-206 °.

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Example 4

9, ΙΟ-dimethoxy-1,3,4,6,7, lib-hexahydro- [1,4] oxazino [3,4-a] isoquinoline-3-carboxylic acid hydrochloride,

(a) A suspension of 10 g of 3-cyano-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro- [1,4] oxazine [3,4-a] is4-quineline (Mixture of isomers I and 11) in 75 ml of 1-n. Sodium hydroxide solution and 110 ml Water was refluxed for 2 hours, with one a clear solution resulted, this was evaporated to dryness in vacuo and the residue dissolved in 50 ml of 2.5N hydrochloric acid to give a clear solution Standing has been completed, the crystals are filtered off, with a little 2.5-n. Washed hydrochloric acid, in vacuo dried at 50 for 18 hours to give the carboxylic acid hydrochloride of m.p. 200-205 "(decomp.) (IscmereiKTl).

It was obtained in an analogous manner

(b) from 3-cyano-9,10-methylenedioxy-1,3,4,6,7,11b hexa hydro - [1,4] oxazino [3,4-a] isoquinoline (mixture of isomers I. and ii) the appropriate. Carboxylic acid hydrochloride (isomer II),

(c) dus 3-cyano-9,10, ll ⁱ trimethoxy-1,3,4,6,7, llb-hexahydro- [1,4.! oxazine ·. · [3,4 a] isoquinoline (isomer II ) the corresponding carboxylic acid hydrochloride (isomer II)

10 9 8 4 3/1882 _ßAD

Example 5

3-Ν, N-diethylcarboxamido-9, ΙΟ-dimethoxy-1,3,4,6,7,1Ib-hexahydroll, 4] oxazino [3, 4a! Isoquinoline '

To a suspension of 38.5 g of 9,10-dimethoxy-1, j, 4,6,7,11bhexahydro- [ 1,4] oxazino [3,4a] isoquinoline-S-carboxylic acid hydrochloride 45 ml of oxalyl chloride (prepared according to Ex. 4) were added under nitrogen given. The mixture was then stirred for 30 minutes and then refluxed for 2 hours. After evaporation of the mixture in vacuo, 75 ml of benzene were added to the residue and the mixture was evaporated again. The remaining crude acid chloride hydrochloride was suspended in 100 ml of methylene chloride and 23 g of diethylamine are added dropwise to the suspension with stirring, the temperature being kept at 25 ° by cooling became. After the addition was complete, the mixture was left at room temperature overnight. Then 75 ml of water were added, the organic phase was separated off with 75 ml of water washed, dried over magnesium sulfate, treated with decolorizing charcoal, filtered and the clear filtrate evaporated in vacuo. Recrystallized from ethyl acetate-hexane, the residue gave the Diethyl carboxamide with a melting point of 121-124 ° (Isomer II)

The hydrochloride of diethyl carboxamide can be obtained in the usual way; crystallized from isopropanol shows es m.p. 230-231 °.

To prepare the above acid chloride hydrochloride, thionyl chloride can also be used instead of oxalyl chloride will.

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Example 6

3-piperidinocarbonyl-9,10-dimethoxy-1,3,4,6,7, lib-hexahydro- [Ϊ, 4] oxazino [3,4a] isoquinolines

A mixture of 5 g of 9,10-dimethoxy-l, 3,4,6,7, llb-hexahydro- {l, 4] oxazino [3, 4a] isoquinoline-S-carboxylic acid hydrochloride, Mp. 206-212 °, 5 ml of thionyl chloride and 100 ml of 1,2-dichloroethane was refluxed for 1 hour with exclusion of moisture. It was then evaporated in vacuo, whereby the 9,10-dimethoxy-1,3,4,6,7,1 Ib -hexahydr o-i 1,4] oxazino [3, 4a] isoquinoline-3-carboxylic acid chloride hydrochloride remained as a solid residue. This was taken up in 100 ml of methylene chloride and added to the cooled one Suspension with stirring 5 ml of piperidine slowly added, 5 minutes after the addition was complete, the mixture was in vacuo evaporated. The remaining crystalline residue was suspended in 50 ml of saturated sodium hydrogen carbonate solution and the suspension with 1 100 ml and 2 χ 50 ml of methylene chloride extracted. The combined extracts were dried over magnesium sulfate and evaporated in vacuo and the crystalline Recrystallized residue from ethyl acetate. The piperidide was obtained with a melting point of 200-201.5 ° (isomer II).

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Examples 7-12

Using the 9,10-dimethoxy-1,3,4,6,7, llb-hexahydr produced according to Examples 5 or 6 from 5 g of the carboxylic acid hydrochloride o- [1,4] oxazino [3,4a] isoquinoline-3-carboxylic acid chloride hydrochloride and from the amines mentioned below were obtained in an analogous manner:

7. with 3 ml of morpholine: 3- (morpholin-4-yl) carbonyl-9,10-dimethoxy-1,3,4,6,7, llb-hexahydro-l 1,4] oxazino [3,4a] isoquinoline of m.p. 211-213 ° (from isopropanol);

8. with 5 ml of pyrrolidine: 3- (pyrrolidin-1-yl) carbonyl-9,10-dimethoxy-1,3,4,6,7, IIb-hexahydro41,4] oxazino [3,4a] isoquinoline of m.p. 233-235 ° (from isopropanol);

9. with 5 ml of 1-methylpiperazine: the 3- (4-methylpiperazin-l-yl) carbonyl-9,10-dimethoxy-1,3,4,6,7, llb-hexahydro- [1,4] oxazino [3,4a] isoquinoline of melting point 155-157 ° (from ethyl acetate);

10. with excess ethylamine: the 3-N-ethylcarboxamido-9,10-dimethoxy-l , 3,4,6,7, Ilb-hexahydro41,4] oxazino [3,4a] isoquinoline mp, 153-154 ° (from methanol / ether);

11. with excess 1-benzoyloxycarbonylpiperazine: the 3- (4-benzoyloxycarbonylpiperazin-1-yl) carbonyl-9,10-dimethoxy-1,3,4,6,7, Ilb-hexahydro41,4] oxazino [3,4a] isoquinoline and from this, after treating it with hydrogen bromide in Glacial acetic acid, 3- (piperazin-1-yl) carbonyl-9,10-dimethoxy-1,3, 4,6,7,1 Ib-hexahydro-i 1,4] oxazino [3,4a] isoquinoline of m.p. 213-214 ° (from methylene chloride / ether);

12. with excess l- (2-hydroxyethyl) piperazine: the 3- [4-

109843/1882

(2-hydroxyethyl) piperazin-1-yl] carbonyl-9, ΙΟ-dimethoxy-1,3,4,6,7,1 Ib-hexahydro- [1,4] oxazine »[3,4a] isoquinoline, the a dioxane solvate with a melting point of 76 ° -78 ° was obtained from dioxane.

All of the 3-carboxamides listed in Examples 7-12 belong to the series of isomers II,

Example 13

hydro- [1,4] oxazino [3,4a] isoquinoline.

A mixture of 2.71 g of S-cyano- ^ lO 6,7, llb-hexahydro- {1,4] oxazino [3,4a] isoquinoline (mixture of isomers I and II), 40 ml 0.5-n. Ethanolic potassium hydroxide solution and 8 ml of water were refluxed for 4 hours. Then became evaporated in vacuo and the residue in 15 ml 2.5-n. Dissolved hydrochloric acid. The crystals obtained after scratching were filtered off, dried in vacuo for 8 hours at 50 ° and gave the crude. 9,10-methylenedioxy-l, 3,4,6,7, llb ~ hexahydro4l, 4] oxazino [3,4aJisoquinoline-S-carboxylic acid hydrochloride (isomer II), that was used without further cleaning,

A mixture of 3.22 g of the above carboxylic acid hydrochloride, 5.25 ml of thionyl chloride and 60 ml of 1,2-dichloroethane was The mixture was heated under reflux for 2 hours, then evaporated, the residue was suspended in 60 ml of methylene chloride and added to the suspension 3.2 ml of diethylamine are given. After the reaction had ended, the mixture was evaporated, the residue in 50 ml 0.4-n. Suspended sodium hydroxide solution and the suspension extracted with methylene chloride (4 × 20 ml).

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- 'ZK -

The combined extracts, dried over sodium sulfate, were evaporated and the amorphous, crude product obtained by chromatography Purified on 200 g of neutral aluminum oxide (activity I). The methylene chloride eluates (5 × 150 ml) gave a Oil that crystallized when rubbed with ether. Made from isopropanol recrystallized, the diethyl carboxamide melted at 117-118.5 ° (isomer II).

Example 14

3-N, N-diethylcarboxamido-9,10,11-trimethoxy-1,3,4,6,7, llb-hexahydro41,4] oxazino [3,4a] isoquinoline.

If an equivalent amount of 3-cyano-9,10,11-trimethoxy-1,3,4,6,7, llb-hexahydro- [ 1,4] oxazino [3,4a] isoquinoline, it is done in an analogous manner the 3-N, N-diethylcarboxamido-9,10,11-trimethoxy-1,3,4,6,7, Hbhexahydro- [ 1,4] oxazino [3,4a] isoquinoline of m.p. 91-93 ° (Isomeres II) received.

Example 15

Cleavage of 3-N, N-diethylcarboxamido-9,10-dimethoxy-1,3,4,6,7, Hb-hexahydro-! 1,4] oxazino [3,4a] isoquinoline (Isomer II).

A solution of 11.55 g of rac.-S-NjN-diethylcarboxamido-9,10-dimethoxy-l , 3,4,6,7, llb-hexahydro- (1,4] oxazino [3,4a] isochi -. nolin with a melting point of 121-124 ° and 4.443 g of (-) - apical acid in 50 ml

109843/1882

Isopropanol was produced with heating. After standing for 18 hours at room temperature, a crystalline precipitate had formed, which was filtered off and dried in vacuo at 40 °. After recrystallization from isopropanol, the (-) - apple acid salt of the (-) - base melted at 91-96 °, [Ct] ² Jj = -59.8 ° (c = 2.03 in methanol). The base regenerated from the mother liquor of this crystallization is enriched in relation to the dextrorotatory enantiomer.

The (-) - base released from a solution of this salt in methylene chloride with 10% sodium hydrogen carbonate solution was recrystallized from isopropanol and gave the (-) - 3-N, N-diethylcarboxamido-9,10-dimethoxy-1,3,4, 6.7, llb-hexahydro- [1,4] oxazino [3,4-a] isoquinoline (isomer II) of m.p. 133-135 °, [a] ² Jj - -90.3 ° (c - 1, 68 in methanol).

In an analogous manner, the (+) - malic acid salt of the (+) - base was obtained from the racemic diethyl carboxamide or from a material enriched in relation to the (+) - base and (+) - malic acid. M.p. 87 ° and 91-96 °, Ia] ² Jj = + 58.6 ° (c = 2.09 in methanol). The (+) - 3-N, N-diethylcarboxamido-9,10-dimethoxy-1,3,4,6,7, llb-hexahydro- [1,4] oxazino [3,4-a] isoquinoline ( isomer II) showed mp 132.5 to 134 °, Ia] ² Q -. + 90.8 ° (c = 1.98 in methanol), after crystallization from isopropanol.

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Example 16

3-carboxamido-9,10-dimethoxy-1,3,4,6,7, llb-hexahydro-t 1,4] oxazino [3,4-a] isoquinoline.

A mixture of 0.595 g of 3-cyano-9,10-dimethoxy-1,3,4,6,7, llb-hexahydro- [1,4] oxazino [3,4-a] isoquinoline (mixture of isomers I and II) and 8.5 ml of 0.511-n. ethanolic potassium hydroxide solution was refluxed for 2 hours. After evaporation water (50 ml) was added to the residue in vacuo at 75 ° and the resulting suspension was extracted 3 with 50 ml of chloroform. The combined and dried extracts were evaporated, the residue was recrystallized from ethanol and the carboxamide (Isomer II) of m.p. 237.5-240.5 °.

Example 17

3-carboxamido-9,10,11-trimethoxy-1,3,4,6,7, Ilb-hexahydro41,4] oxazino [3,4-a] isoquinoline.

A mixture of 3.7 g of 3-cyano-9,10,11-trimethoxy-1,3,4,6,7, Ilb-hexahydro41,4] oxazino [3,4-a] isoquinoline, 25 ml of 0.511-n. Potassium tert-butoxide in tert-butanol and 370 ml of tert-butanol were refluxed for 2 hours. Then was im Evaporated in vacuo, the residue with 1-n. Hydrochloric acid adjusted to pH 1-2, the solution with saturated sodium hydrogen carbonate solution neutralized and then extracted with 4 portions of 20 ml of methylene chloride. The combined and dried extracts were evaporated and the crystalline residue from ethanol

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recrystallized. The 3-carboxamide obtained (isomer II) melted at 203.5-205 °.

Example 18

3 -Carboxamido -9,10-methylenedioxy-1,3,4,6,7, lib-hexahydro-! 1.4] oxazino [3,4-a] isoquinoline.

If the procedure described in Example 17 is followed and an equivalent amount of 3-cyano-9,10-methylenedioxy-1 is used , 3,4,6,7, lib-hexahydro-! 1,4] oxazino [3,4-a] isoquinoline so 3-carboxamido-9,10-methylenedioxy-1 is obtained in an analogous manner , 3,4,6,7, lib -hexahydro-! 1,4] oxazino (3,4-a] isoquinoline (Isomer II) of m.p. 226-228 ° (decomp.) After crystallization from ethanol.

Example 19

9,10-Dimethoxy-1,3,4,6,7, Ilb-hexahydro41,4] oxazino [3,4-a] isoquinoline-3-carboxylic acid ethyl ester.

A mixture of 6.33 g of 3-cyano-9, 10-dimethoxy-l, 3,4,6,7, llb-hexahydro-l 1,4] oxazino [3,4-a] isoquinoline (mixture of isomers I and II), 93 ml of 0.5 n, ethanolic potassium hydroxide solution and 21 ml of water was refluxed for 4 hours. It was then evaporated and the residue with methanolic Hydrochloric acid adjusted to pH 1. The inorganic precipitate was filtered off, the filtrate was evaporated in vacuo and the residue

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crystallized from ethanol, the hydrochloride of the 9, lO-dimethoxy-1,3,4,6,7, llb-hexahydro [1,4] oxazino [3,4-a] isoquinoline-3-carboxylic acid ethyl ester received. The corresponding base was obtained from this in the customary manner. Made from isopropanol recrystallized, the 9,10-dimethoxy-1,3,4,6,7, llbhexahydro- { 1,4] oxazino [3,4-a] isoquinoline-S-carboxylic acid ethyl ester (Isomer II) at 111.5-113.5 °.

Example 20

(a) A suspension of 5 g of 3-cyano-9,10-dimethoxy-1,3, 4,6,7,1b-hexahydro- [1,4] oxazino [3,4-a] isoquinoline, melting point 182-184 ° in 83 ml of methanol and 2 ml of water was cooled with ice water and hydrogen chloride gas passed in for 30 minutes with stirring. The resulting solution was still at room temperature Stirred for 90 minutes. After evaporation in vacuo, 100 ml of a saturated sodium hydrogen carbonate solution were added to the residue and extracted 3 χ each with 100 ml of chloroform. The combined and dried extracts gave a residue after evaporation, which crystallized when rubbed with ether. Recrystallized from isopropanol, the 9,10-dimethoxy-1,3,4,6,7, llbhexahydro- [ 1,4] oxazino [3,4-a] isoquinoline-S-carboxylic acid methyl 1-ester (Isomer I) at 108-109 °.

(b) A solution of 6 g of 3-cyano-9,10-dimethoxy-1,3,4, 6,7, llb-hexahydro- (1,4] oxazino [3,4-a] isoquinoline in 15 ml of ethanol and 14 g of concentrated sulfuric acid was added for 18 hours

109843/1882

boiled on reflux. The acidic solution was diluted with 60 ml of water, made basic with potassium carbonate and repeatedly with Ether and benzene extracted. After drying and evaporation, the combined extracts yielded the oily 9,10-dimethoxy-1,3,4, 6,7,1b-hexahydro- {1,4] oxazino [3,4-a] isoquinoline-3-carboxylic acid ethyl ester (Isomer I).

(c) Treating g ^ O-dimethoxy-l ^^ jo ^ jllb-hexahydr o- [1,4] oxazino [3,4-a] isoquinoline-S-carboxylic acid hydrochloride, Mp. 206-212 °, under the conditions given in section (a), the 9,10-dimethoxy-1,3,4, · 6,7, Ilb-hexahydro41,4] oxazino [3,4-a] isoquinoline-3-carboxylic acid methyl ester (Isomer II) of m.p. 123-124.5 °.

Example 21

3-carboxamido-9,10-dimethoxy-1,3,4,6,7, llb-hexahydro-t 1,4] oxazino [3,4-a] isoquinoline (Isomer I).

A suspension of 3 g of 9,10-dimethoxy-1,3,4,6,7, llbhexahydro- [ 1,4] oxazino [3,4-a] isoquinoline-3-carboxylic acid methyl ester (Isomer I) in 100 ml of conc. Ammonium hydroxide solution was filtered and the filter residue was dried over phosphorus pentoxide. Recrystallization from ethanol gave the 3-carboxamide (isomer I), melting point 215-216 °.

to the

Also from / according to Example 20-b produced oily ethyl

ester of the above carboxylic acid is obtained with conc. Ammonia in a similar manner to 3-carboxamide (isomer I) with a melting point of 215-216 °.

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Example 22

3-carboxamido-9,10-dimethoxy-1,3,4,6,7, IIb-hexahydro41,4] oxazino [3,4-a] isoquinoline (Isomer II).

hexahydro-starting from 9,10-diraethoxy-l, 3,4,6,7, llb- / ll, 4] oxazino

{3,4-a] isoquinoline-S-carboxylic acid ethyl ester hydrochloride (Isomeres II) the 3-carboxamide (isomer II) obtained from ethanol is obtained analogously by the procedure described in Example 21 recrystallized at 237.5-240.5 ° melts.

Example 23

3-N-Aethylcarboxamido-9,10-dimethoxy-1,3,4,6,7, Ilb-hexahydro41,4] oxazino [3,4-a] isoquinoline.

A suspension of 24.4 mg of 9,10-dimethoxy-1,3,4,6,7, llbhexahydro- { 1,4] oxazino [3,4-a] isoquinoline-3-carboxylic acid e-methyl ester (Isomer II) in 1 ml of 707oigem aqueous ethylamine was stirred for 5 minutes, a clear solution formed during Was left at room temperature for 18 hours. The residue obtained after evaporation in vacuo was dissolved in 5 ml of chloroform dissolved, the solution dried over magnesium sulfate and evaporated, the crystalline 3-N-ethylcarboxamide (isomer II) was obtained, m.p. 153-154 °.

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Example 24

3-N, N-diethylcarboxamido-9,10-dimethoxy-1,3,4,6,7, llb-hexahydro- [1,4] oxazino [3,4-a] isoquinoline.

To a suspension of 135.1 mg of 9,10-dimethoxy-1,3,4,6,7,1 Ib-hexahydr ο {1,4] oxazino13,4-a] isoquinoline-3-carboxylic acid hydrochloride (Isomer II) in 2.5 ml of methylene chloride was added 0.115 ml of triethylamine, a clear solution being formed. This was mixed with 64.2 mg of isobutyl chloroformate in 1.5 ml of methylene chloride while stirring and cooling (ice water). After a reaction time of 15 minutes, 0.05 ml of diethylamine was added and a further 15 minutes with cooling and a further 15 hours allowed to react at room temperature. It was then extracted by shaking with 5 ml of saturated sodium hydrogen carbonate solution Separated methylene chloride phase and the aqueous. Phase 2 χ extracted with 5 ml of methylene chloride each time. The combined methylene chloride phases gave after drying over magnesium sulfate and evaporation an amorphous residue which crystallized after trituration with ether. The obtained 3-N, N-diethylcarboxamide (isomer II) had the m.p. 121-123 °. The product was with the example 5 received identical »

1098A3 / 1882

Example 25

α-NjN-diethylcarboxamido-g, 10-dimethoxy-1,3,4,6,7, llb-hexahydro- [1,4] oxazino [3,4-a] isoquinoline.

With cooling and in a nitrogen atmosphere, 1 ml of a 22.9% solution of butyllithium was added to 10 ml of diethylamine given in hexane. 1 ml of this solution was added to 48.6 mg of 9,10-dimethoxy-1,3,4,6,7, lib-hexahydro- [1,4] oxazino [3,4-a] isoquinoline-3-carboxylic acid- methyl ester (Isomer II) added and the whole stirred for 24 hours at room temperature. then was evaporated in vacuo, the residue was dissolved in 1 ml 1-n. Hydrochloric acid was added, then 5 ml of saturated sodium hydrogen carbonate solution added and extracted with methylene chloride (3 χ 5 ml). The combined extracts gave over after drying Magnesium sulfate and evaporation of a residue which, in addition to a little starting material, contained the Ν, Ν-diethylcarboxamide (isomer II), such as by comparative thin-layer chromatography and infrared spectroscopy against authentic reference substances was established.

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Example 26

3-N, N-diethylcarboxamido-9,10-dimethoxy-1,3,4,6,7, llb-hexahydro- [1,4] oxazino [3,4-a] isoquinoline.

A mixture of 381.4 mg of 2-N, N-diethylcarboxamido-4- [2- (3,4-dimethoxyphenyl) ethyl] morpholin-5-one, mp. 85-86 °, 0.5 ml of phosphorus oxychloride and 6, 5 ml of 1,2-dichloroethane were refluxed for 2 hours at a bath temperature of 110 ° (exclusion of moisture). It was then evaporated in vacuo and the residue was _{dried over P 3} O ₅ / KOH in a vacuum desiccator for 3 hours.

The dried residue was taken up in 9 ml of methanol and so much 2.5-n. Sodium hydroxide added up a pH of approx. 5 was reached. 131.8 mg of sodium borohydride were added to the solution while cooling with ice water, while stirring became. After the addition had ended, the mixture was stirred for a further 30 minutes and then evaporated in vacuo. The residue was taken up in 10 ml of saturated sodium hydrogen carbonate solution and the mixture was extracted with methylene chloride (3 × 10 ml). The combined and dried extracts were evaporated in vacuo and gave the crude N, N-diethylcarboxamido-9 as residue , 10-dimethoxy-1,3,4,6,7, lib-hexahydro- [1,4] oxazino [3,4-a] isoquinoline, which on the basis of comparative thin-layer chromatography and infrared spectroscopy compared to authentic reference substances is present as a mixture of isomers I and II.

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Example 27

3-cyano-9,10-dimethoxy-1,3,4,6,7, llb-hexahydro- [1,4] oxazino [3,4-a] isoquinoline (isomer II).

A mixture of 946 mg of 3-carboxamido-9,10-dimethoxy-1,3,4,6,7, llb-hexahydro- [1,4] oxazino [3,4-a] isoquinoline (Isomer II) of melting point 237.5-240.5 °, 0.6 ml of phosphorus oxychloride and 15 ml 1,2-dichloroethane was refluxed for 2 hours. After evaporation in vacuo, the residue was taken up in 10 ml of saturated sodium hydrogen carbonate solution and the mixture extracted with chloroform (4 × 10 ml). The combined and dried extracts were evaporated in vacuo and the colorless one crystalline residue taken up in chloroform. This solution was passed through a column of 100 g of neutral aluminum oxide (activity I) filtered. The chloroform eluates contained the nitrile (isomer II), which after crystallization from ethanol at 175-177 ° melted.

Example 28

2-N, N-diethylcarboxamido-4- [2- (3,4-dimethoxyphenyl) ethyl] -morpholin-5-one ..

(a) A suspension of sodium hydride in benzene was made from 8.1 g of a 50% dispersion of sodium hydride in mineral oil prepared by washing it with hexane and taking up the residue in 250 ml of benzene. A solution was added to this suspension of 17.3 g of 2-hydroxy-3- [2- (3,4-dimethoxyphenyl) ethylamino] propionic acid diethylamide given in 100 ml of benzene. The mixture

In an analogous manner, from 3-carboxamido-9,10-kethylene, aioxy-1,3,4,6,7,11b-hexahydro- [1,4-joxazino [3,4-ajisoquinoline, the 3-cyari-9,10- Methylenedioxy-1,3,4,6,7,11b-hexahydro- [1,4-joxazino [3,4-α-isoquinoline (Isomer II) mp. 169-170.5 ° _#

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was refluxed for one hour with exclusion of moisture cooked. After cooling to room temperature, the almost clear solution of excess sodium hydride was decanted and with Washed 10 ml of benzene. The stirred and cooled with ice water benzene solution became a solution of within 20 minutes 6 ml of chloroacetic ester in 25 ml of benzene were added. The mixture was then stirred for a further 45 minutes with cooling and then refluxed for 18 hours. After cooling, the mixture was added with 100 ml of 1-n. Hydrochloric acid, then saturated with 100 ml Washed sodium hydrogen carbonate solution, the benzene phase dried over magnesium sulfate, filtered and evaporated. Covering the oily residue with ether gave crystals, which were recrystallized from ethyl acetate-hexane, m.p. 85-86 °. The starting material was obtained as follows: (b) Ν, Ν-diethylglycidamide.

A mixture of 240 ml of trifluoroacetic anhydride, 40 ml of 90% strength Hydrogen peroxide and 240 ml of methylene chloride were stirred for 30 minutes at a temperature not exceeding 15 °. Then, while stirring, 640 g of disodium hydrogen phosphate and then a solution of 82.1 g of acrylic acid diethylamide in 870 ml of methylene chloride added within 45 minutes, the temperature was kept at about 30 °. After stirring for 2 1/2 hours, the mixture was refluxed for 1 hour. To 1 liter of water was added to cooling, the organic phase was separated off and washed 3 with 100 ml of saturated bicarbonate solution. The dried methylene chloride solution was evaporated

1098A3 / 1882

the crude diethylglycidamide (content: 4.5 mmol / g) remained, which was used for the next reaction without purification, (c) 2-hydroxy-3- [2- (3,4-dimethoxyphenyl) ethylamino] propionic acid diethylamide.

To a boiling and stirring solution of 78 g homoveratrylamine in 220 ml of 1,2-dimethoxyethane were 86.9 g within 30 minutes of the above, crude diethyl glycidamide given. After 3 hours of further boiling, the mixture was evaporated in vacuo. Added to the residue one 300 ml of water and 50 ml of conc. Hydrochloric acid. The mixture was extracted 4 with 150 ml of methylene chloride, the aqueous phase with 150 ml 5-n. Sodium hydroxide solution made basic and extracted 3 χ with 250 ml of methylene chloride. The combined and dried Extracts were evaporated and gave the 2-hydroxy-3- [2- (3,4-dimethoxyphenyl) ethylamino] propionic acid diethylamide, Sdp, 193-196 ° / 0.1 mm. The hydrochloride obtained from it with ethereal hydrochloric acid melted at 131-133 °.

109843/1882

4-2615 / GC 271 *

Example 29

3-N, N-diethylcarboxamido-9, 10-dimethoxy-1,3,4,6,7, llb-hexahydro- [1,4] oxazino [3,4-a] isoquinoline.

A mixture of 287.9 mg of 9,10-dimethoxy-1,3,4,6,7, llb-hexahydro- [1,4] oxazino [3,4-ajisoquinoline-3-carboxylic acid hydrochloride (isomer II), 0.27 ml of triethylamine and 2 ml of chloroacetonitrile were refluxed for 1 hour. After standing at room temperature for 17 hours, a small crystalline precipitate had formed. The mixture was evaporated to dryness and 5 ml of a saturated sodium hydrogen carbonate solution was added to the residue. The mixture was extracted 3 times with 5 ml of methylene chloride, the extracts were combined, dried and evaporated. The residue was taken up in 2 ml of diethylamine and then refluxed for 19 hours. It was then evaporated and the residue triturated under ether, whereupon crystallization occurred. Recrystallized from ethyl acetate-hexane, the product melted at 119 ° -122 °. It was identical to that obtained in Example 5 .

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BATH ORIGINAL

4-2615 / GC 271 *

HS

Example 30 ^τ *

3-N, N-diethylcarboxamido-9, 10-dimethoxy-1,3,4,6,7, llb-hexahydro- [1,4,] oxazino [3,4-a] isoquinoline

A solution of 501.7 mg of 9,10-dimethoxy-1,3,4,6,7, llb-hexahydro- [1,4] oxazino [3,4-a] isoquinoline-3-carboxylic acid hydrochloride (Isomer II) in 5 ml of triethylamine was prepared in the Wäreme. After cooling, 396.1 mg of p-nitrophenyl trifluoroacetate were obtained was added and the mixture was stirred for 2 hours at room temperature. It was then evaporated and the residue was saturated with 10 ml Treated sodium hydrogen carbonate solution. The mixture was made up with a total of 20 ml of methylene chloride in 3 portions pulled out and the dried extracts evaporated. 5 ml of diethylamine were added to the residue, the mixture heated under reflux for 5 hours and then left at room temperature for 18 hours. The one after The residue obtained by evaporation was partitioned between 10 ml of 2.5 N sodium hydroxide solution and 10 ml of methylene chloride aqueous phase extracted twice with 10 ml of methylene chloride each time, the extracts combined and dried. To Removal of the solvent left a residue which crystallized on trituration with ether. From ethyl acetate-hexane recrystallized, the product was obtained from the Snp. 120-123 °, which is identical to that obtained in Example 5 was.

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ÖAP ORIGINAL

The compounds of the formula I and their acid addition salts have, as mentioned at the beginning, valuable pharmacological Properties and can be used therapeutically due to their calming and relaxing effects.

For the application of the compounds according to the invention in unit dose forms, it is advantageous to use pharmaceuticals acceptable acid addition salts, the same with organic and inorganic Acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, Phosphoric acid, methanesulfonic acid, ethanesulfonic acid, acetic acid, Lactic acid, succinic acid, malic acid, maleic acid, aconitic acid, phthalic acid, tartaric acid and embnic acid.

Used as unit dosage forms for oral or parenteral administration of the compounds of the formula I according to the invention man tablets, capsules, dragees, powders, suspensions, syrups and solutions. Oral application and the usual ones Unit dose forms, including sustained release forms thereof, are preferred .

The unit dose forms are manufactured according to methods known per se. To make the one to be used orally In unit dosage forms, pharmaceutically acceptable carriers are used, such as lactose, sucrose, sorbitol or mannitol; Starches such as potato or corn starch or amylopectin; Cellulose derivatives or gelatin, optionally with the addition of lubricants such as magnesium or calcium stearate or polyethylene glycols (Carbowaxen) of suitable molecular weight, and tablets or dragee cores formed from these mixtures. The cores

109843/1882

ORIGINAL INSPECTED

are coated, e.g. with concentrated sugar solutions that e.g. may contain gum arabic, talc and / or titanium dioxide, or with a film-forming polymer used as a solution in volatile organic solvents or mixtures thereof will. Coloring agents can also be added to these coatings, e.g. to distinguish between the different contents of active ingredient to be able to.

Capsules, e.g. gelatine capsules, can contain the active ingredients in the form of their mixtures, with or without additives a pharmaceutically acceptable carrier.

For the production of suppositories that have a Containing active ingredient, for example 3-N, N-diethylcarboxamido-9,10-dimethoxy-1,3,4,6,7, lib-hexahydro- [1,4 j oxazino [3,4-a] isoquinoline in a carrier such as cocoa butter and then forms the suppository from the resulting mass.

Liquid formulations such as suspensions, elixirs, and syrups can also be prepared by methods that are known to the person skilled in the art.

Example A,

Used for the production of push-fit gelatine capsules

(a) 100 g of 3-N, N-diethylcarboxamido-9,10-dimethoxy-1,3,4,6,7, ubhexahydro- [1,4] oxazino [3,4-a] isoquinoline and

(b) 200 grams of corn starch

intimately mixed and this mixture is packed in 1000 gelatin capsules bottled, each containing 100 mg of the active ingredient. '

109843/1882

In an analogous manner, push-fit capsules are prepared which contain the hydrochloride of the active ingredient mentioned under (a) instead of the free base contain.

Example B ,

For the production of tablets is made from

(a) 50 g of a-NjN-diethylcarboxamido-gjlO-dimethoxy-lja ^ jojTjllb-

hexahydro- [1,4] oxazino [3,4-a] isoquinoline,

(b) 130 grams of corn starch

(c) 160 grams of milk sugar

(d) 4 g colloidal silica

(e) 5g gelatin and

(f) 1 gram of magnesium stearate

according to the usual procedure, a granulate is prepared from which 1000 tablets are pressed, each containing 50 mg of active ingredient per tablet contain.

Instead of the free base, the hydrochloride of the active ingredient can also be processed into tablets according to the above recipe,

10964 3/1882

Claims (5)

Claims 1. Compounds of formula I in which R, hydrogen or a lower alkoxy group, IL, and R "is a lower alkoxy group or, when R, is hydrogen means R2 and R-, taken together the methylenedioxy group, and Am the amino group, a lower alkylamino group, a lower dialkylamino group, the morpholino, 1-pyrrolidinyl, Piperidino-. 1-piperazinyl, a 4- (lower alkyl) -piperazin-1-yl-, 4- (hydroxy-lower alkyl) -piperazin-1-yl- or a 4- (lower alkoxy-lower alkyl) piperazin-1-yl group, as well as their acid addition salts with organic and inorganic acids, 2. Process for the preparation of compounds of the formula I. (D COAm 109843/1882 in which R, hydrogen or a lower alkoxy group, R_2 and R ~ a lower alkoxy group or, if R, hydrogen means, R2 and R "taken together the methylenedioxy group, and Am the amino group, a lower alkylamino group, a lower dialkylamino group, the morpholine, 1-pyrrolidinyl, Piperidino-, 1-piperazinyl-, a 4- (lower alkyl) -piperazin-1-yl-, 4- (hydroxy-lower alkyl) -piperazin-1-yl- or <; <ae 4- (lower alkoxy-lower Alkyl) piperazin-1-yl group, as well as their acid addition salts with organic and inorganic Acids, characterized in that a compound of the formula II (ID in which X is a chlorine or bromine atom, a lower alkoxy group or the group -OY in which Y is the cyanomethyl group, the p-nitrophenyl group, an alkoxycarbonyl group with at most Represents 5 carbon atoms or the benzyloxycarbonyl group, means and R-, R ₂ and R3 have the meaning given above, with an amine 109843/1882 ORIGINAL INSPECTED «Η? of formula III H-Am (III) in which Am has the meaning given above, or an alkali metal derivative the same in an inert solvent and, if X is a chlorine or bromine atom, in the presence of one acid-binding agent and, if desired, the obtained Compound converted into an acid addition salt with an organic or inorganic acid. 3. Process for the preparation of compounds of the formula (Ib) CONH, in which R, hydrogen or a lower alkoxy group and Ry and Rj a lower alkoxy group or, when R, denotes hydrogen, R2 and R ~ taken together denote the methylenedioxy group, as well as their acid addition salts with organic and inorganic Acids, characterized in that a compound of the formula V (V) 10 9 8 A 3/1 882 in which R ,, R ₂ and R ~ have the meaning given above, with an alkali metal hydroxide in a lower alkanol or with a lower alkali metal alkanolate in the corresponding alkanol and, if desired, the compound obtained is converted into an acid addition salt with an organic or inorganic acid, 4, Process for the preparation of compounds of the formula Yes (Ia) in which R, hydrogen or a lower alkoxy group, R2 and Ro a lower alkoxy group or, when R ₁ denotes hydrogen, R ₂ and R ~ taken together are the methylenedi- oxy group, and
Am ^{1 is} a lower dialkylamino group which is morpholino, 1-pyrrolidinyl, piperidino or a 4- (lower alkydpiperazin-1-yl group, as well as their acid addition salts with organic and inorganic Acids, characterized in that a compound of the formula VIa OAm ' CH ₂ -CH ₂ -N 0 (VIa) 109843/1882 in which R., R ^, Ro and Am ^{1 have} the meaning given above, cyclized with an acidic condensation agent, if desired in an inert solvent, the cyclization product is reduced and, if desired, a compound thus obtained is converted into an acid addition salt with an organic or inorganic acid . 5. Pharmaceutical compositions, characterized in that that this (a) as active ingredient is a compound according to claim 1 or a pharmaceutically acceptable acid addition salt the same with an organic or inorganic acid and (b) at least one pharmaceutically acceptable carrier contain. J.R. G e i g y A.G. DAP / bm / 2.4.68 109843/1882