DE2348593A1 - PROCESS FOR PRODUCING NEW HETEROCYCLIC COMPOUNDS - Google Patents

Description

Sandoz AG

Basel Case 100-3875

Traversing s for He rstellxm g re he he teroeyeIischer connections. .

The invention relates to the preparation of new compounds of the formula

■ I /

soft by definition also the optical antipodes of the compounds of formula I. as well as the racemic mixtures of the optical antipodes and where R is hydrogen, alkyl having 1 ~ 5 carbon atoms, Alkenyl or alkynyl with 3-5 carbon atoms, of which the multiple bond is not in a position to the nitrogen atom to which R is bound stands through Cycloalkyl with 3-6 carbon atoms substituted alkyl with 1-4 carbon atoms, hydroxyalkyl 2-5 carbon atoms, phenylalkyl with 7-11 carbon atoms, in the phenyl radical

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with

- 2 - Case iOO-3875

by halogen, alkoxy with 1-4 or alkyl with 1-4 carbon atoms inonosubstituted phenylalkyl with 7-11 carbon atoms or a radical A-CO-R ₃ , in which A stands for alkylene with 1-4 carbon atoms and R stands for alkyl with 1-5 carbon atoms , Phenyl, halogen-substituted phenyl, the hydroxyl or an alkoxy group with 1-4 carbon atoms, R ₁ and R _? can be identical or different and represent hydrogen, halogen or an alkyl group with 1-4 carbon atoms, X and Y either both represent hydrogen, in which case the rings B and C are cis-linked, or X and Y together form an additional bond form, their salts, as well as the compounds of formula I and their salts.

If the radical R or R stands for lower alkyl with 1-5 carbon atoms, it contains in particular 1-4, preferably 1 to 3 carbon atoms.

If R stands for an alkyl group with 1-4 carbon atoms substituted by a cycloalkyl group with 3-6 carbon atoms, so their alkyl group contains in particular 1 or 2, and their cycloalkyl group in particular 3 carbon atoms. A preferred substituent of these Row is e.g. the cyclopropylmethyl group.

If the radical R stands for a hydroxyalkyl group with 2-5 carbon atoms, this contains in particular 2-4, preferably 2 or 3 carbon atoms.

If the radical R stands for a mo-

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- 3 - Case 100-3875

nosubstituted phenylalkyl radical with 7-11 carbon atoms, this phenylalkyl radical contains in particular 7-9, preferably 7 or 8, carbon atoms. The possible halogen substituent of this radical stands in particular for fluorine, chlorine or bromine, preferably for Fluorine or chlorine. Any alkoxy or alkyl substituent With 1-4 carbon atoms this radical contains in particular 1-3, preferably 1 or 2 carbon atoms.

If the radical R stands for a group A-CO-R ₃ , the alkylene group A * contains in particular 1-3, preferably 1 or 2, carbon atoms. .

If R represents phenyl substituted by halogen, then " the halogen substituent is in particular fluorine, chlorine or bromine, preferably fluorine or chlorine.

If the radical R_ stands for an alkoxy group with 1-4 carbon atoms, so it contains in particular 1 or 2, preferably 1 carbon atom.

If the radicals R ₁ and / or R _{0 represent} halogen, they particularly represent fluorine, chlorine or bromine, preferably fluorine or chlorine.

If the radicals R ₁ and / or R "represent an alkyl group with 1-4 carbon atoms, they contain in particular 1 or 2, preferably 1, carbon atoms.

If X stands for hydrogen, this can be in ice or trans position to the one in position 9a Stand for hydrogen.

- if IU is not for a possibly substituted phenyl

stands - ^J

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100-3875

Particularly preferred compounds of the formula I are compounds of the formula

Iw

which by definition also includes the optical antipodes of the compounds of the formula I ₇ and the racemic mixtures of the optical antipodes, and in which X and Y have the above meanings, R is hydrogen, alkyl

with 1-3 carbon atoms, alkenyl or alkynyl with 3-5 carbon atoms, of which the multiple bond is not is in the α-position to the nitrogen atom, from which R

el

is bound, cyclopropylmethyl, hydroxyethyl, phenylalkyl with 7 or 8 carbon atoms, in the phenyl radical by fluorine, chlorine, methyl or methoxy substituted ■

Phenylalkyl of 7 or 8 carbon atoms, acetonyl, 3-oxobutyl, phenacyl, p-fluorophenacyl, 4- (p-fluorophenyl) -4-oxo-butyl and R, and R can be identical or different and represent hydrogen, chlorine, Fluorine or methyl, and their acid addition salts.

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T - Case 100-3875

According to the invention one arrives at the compounds of formula

Yes,

which by definition also includes the optical antipodes of the compounds of the "formula Ia and racemic mixtures of these optical antipodes, and in which R ₁ , R", X and Y have the above meaning and R. alkyl has 1-5 carbon atoms, alkenyl or alkynyl with 3- 5 carbon atoms, of which the multiple bond is not in the α-position to the nitrogen atom to which R _{4 is} bonded, alkyl with 1-4 carbon atoms substituted by cycloalkyl with 3-6 carbon atoms, hydroxyalkyl with 2-5 carbon atoms, phenylalkyl with 7-11 carbon atoms, im Phenyl radical by halogen, alkoxy with 1-4 carbon atoms or alkyl with 1-4 carbon atoms monosubstituted phenylalkyl with 7-11 carbon atoms, or a radical A-CO-R, in which A and R have the above meanings, and their salts by
a) compounds of the formula

409 8 1 5/1 1 3 0

100-3875

Ib,

which, by definition, also represent the optical antipodes of these compounds of the formula Ib, as well as racemic ones Mixtures of these optical antipodes includes, and v.-orin R ,, IC, X and Y have the above meanings, N-alkylated and, if desired, according to methods known per se then any esters of the formula

N-A-COOAIk

Ic,

which by definition comprises the optical antipodes of the compounds of the formula Ic and the racemic mixtures of these optical antipodes and in which R, Ry _1, X, Υ and A have the above meaning and Alk is an alkyl group of 1-4 carbon atoms, to compounds of the formula

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N-A-COOH

Id,

which, by definition, comprises the optical antipodes of the compounds of the formula Id and the racemic mixtures of these optical antipodes and in which R _1, R ₂ , X, Y and A are as defined above, hydrolyzed, or

b) Compounds of the formula Ib reductively to give compounds the formula

Ie,

which by definition also includes the optical antipodes of the compounds of the formula Ie and the racemic mixtures of these optical antipodes, and in which R , R, X and Y have the above meaning and Rj is a primary or secondary alkyl group having 1-5 carbon atoms, alkylated or

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c) compounds of the formula y ο L OC g ο

If,

which by definition also includes the optical antipodes of the compounds of the formula If and the racemic mixtures of these optical antipodes, and in which R _n and R _{n have the} above meaning and R .. alkyl with 1-5 carbon atoms, alkenyl or alkynyl with 3-5 carbon atoms , of which the multiple bond is not in the α-position to the nitrogen atom, on which R ,. bound

den is alkyl with 1-4 carbon atoms substituted by cycloalkyl with 3-6 carbon atoms, Hydroxyalkyl with 2-5 carbon atoms, phenylalkyl with 7-11 carbon atoms, in the phenyl radical by calogen, Alkoxy with 1-4 or alkyl with 1-4 carbon atoms monosubstituted phenylalkyl with 7-11 carbon atoms, or a radical A-CO-R ', where A has the above meaning and R' is alkyl with 1-5 carbon atoms, Phenyl or phenyl substituted by halogen means, among sharp, alkaline ones Conditions for compounds of the formula

ig-

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which, by definition, also includes the optical antipodes of the compounds of the formula Ig as well as the raeemis.chen mixtures of these optical antipodes and where R _r R _? and R _{6 have the} above meaning, converts, or

d) compounds of the formula

You

which by definition are also the optical antipodes of the compounds of the formula Ih and the racemic mixtures of these optical antipodes and in which R, and R have the above meaning and R_ alkyl with 1-5 Carbon atoms, alkyl with 1-4 carbon atoms substituted by cycloalkyl with 3-6 carbon atoms, Phenylalkyl with 7-11 carbon atoms, in the phenyl radical monosubstituted by halogen or alkyl of 1-4 carbon atoms Phenylalkyl with 7-11 carbon atoms, or a radical A-CO-R, in which A and R have the above meaning own means with the help of hydriodic acid / red Phosphorus to compounds of the formula

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NO,

which, by definition, also comprises the optical antipodes of the compounds of the formula Ii and the racemic mixtures of these optical antipodes, and in which R ₁ , R ₃ and R_ have the above meaning, hydrogenated, or

e) compounds of the formula

which, by definition, also include the optical antipodes of the compounds of the formula Ij and the racemic ones Comprises mixtures of these optical antipodes and wherein R 'and Rl can be identical or different and stand for hydrogen, fluorine or alkyl with 1-4 carbon atoms and R * alkyl with 1-5 carbon atoms, alkyl with 1-4 carbon atoms substituted by cycloalkyl with 3-6 carbon atoms, Hydroxyalkyl with 2-5 carbon atoms, phenylalkyl with 8-11 carbon atoms, whose phenyl

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approx. 23 * 8593 • Μ

rest is separated by at least 2 carbon atoms from the nitrogen atom to which it is bonded, in the phenyl radical by halogen, alkoxy with 1-4 carbon atoms
or alkyl with 1-4 carbon atoms monosubstituted phenylalkyl with 8-11 carbon atoms, the phenyl radical of which is separated by at least 2 carbon atoms from the nitrogen atom to which it is bonded,

means "catalytic" to compounds of a formula

Ik,

which by definition are also the optical antipodes
of the compounds of the formula Ik and the racemic mixtures of these optical antipodes, and in which RJ, R £ and IIIj have the above meanings, hydrogenated, or

f) compounds of the formula

II,

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which, by definition, also include the optical antipodes of the compounds of the formula II and the racemic mixtures this includes optical antipodes and in which R 1 and R "have the above meaning and R" is alkyl with 1-5 Carbon atoms, alkyl with 1-4 carbon atoms substituted by cycloalkyl with 3-6 carbon atoms, Hydroxyalkyl with 2-5 carbon atoms, phenylalkyl with 7-11 carbon atoms, in the phenyl radical by halogen, Alkoxy with 1-4 or alkyl with 1-4 carbon atoms monosubstituted phenylalkyl with 7-11 carbon atoms means, by reduction, with the help of a Metallhydri-, des, to compounds of the formula

Iu,

which by definition are also the optical antipodes of the compounds of the formula Iu and the racemic mixtures of these optical antipodes and in which R R "and R" have the above meaning, reduced or g) compounds of the formula

NCOD

IV,

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which by definition are also the optical antipodes of the compounds of the formula IV and the racemic mixtures of these optical antipodes, and in which R, Rp, X and Y have the above meaning and D is hydrogen, Alkyl with 1-4 carbon atoms, cycloalkyl with 3-6 carbon atoms, through cycloalkyl with 3-6 Carbon atoms substituted alkyl with 1-3 carbon atoms, hydroxyalkyl with 1-4 carbon atoms, Phenyl, phenylalkyl with 7-10 carbon atoms, by halogen, alkoxy with 1-4 carbon atoms or alkyl phenyl monosubstituted with 1-4 carbon atoms, or in the phenyl radical by halogen, alkoxy with 1-4 or lower alkyl with 1-4 carbon atoms means monosubstituted phenylalkyl with 7-10 carbon atoms, with the help of metal hydrides to form compounds of the formula

NCH D

In the,

which, by definition, are the optical antipodes of the compounds of the formula Im and the racemic mixtures this includes optical antipodes and where R ,, R ", X, Y and D have the above meaning ,, reduced

and the compounds of the formula Ia thus obtained are obtained as such or as salts.

Salts can be prepared in a known manner from the free bases or acids, and vice versa.

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Case 100-3875

The separation of any racemates of the formula I into their optical Antipodes can be prepared by known methods, for example by fractionated crystallization of the salts of these racemates done with optically active acids.

The following is based on procedural details pointed out, which is useful in the inventive Preparation of the compounds of formula Ia should be taken into account

a) The N-alkylation of the compounds of the formula Ib can e.g. with the help of compounds of the formula

^ER 4. ^V '

where R has the above meaning and E is the acid residue of a reactive ester, or else with the aid of reactive derivatives of the compounds the formula V take place.

In the compounds of the formula V, E denotes, for example, halogen such as chlorine, bromine or iodine or the acid radical an organic sulfonic acid such as an alkyl sulfonyloxy group such as methylsulfonyloxy or an arylsulfonyloxy radical such as phenylsulfonyloxy or p-To-Iylsulfonyloxy.

The N-alkylation of the compounds of the formula Ib with compounds of the formula V is useful in one organic solvent, for example in an amide of an aliphatic carboxylic acid such as dimethylformamide and in the presence of a basic condensing agent v / ie sodium carbonate, N-ethyl-N, N-diisopropylamine carried out.

The reaction temperature can be between room temperature vary up to about 100 °. The reaction time depends in particular on the reaction temperature and the re-

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Case 100-3875

action ability of the compounds of formula V dependent and is about 1 to about 16 hours.

Suitable reactive derivatives of the compounds of formula V are, inter alia, α, β - unsaturated carbonyl compounds, for the introduction of a radical A-COR _r wherein A represents CH ₂ -CH ₂ and R ₃ has the above meanings, and ethylene oxide for the introduction of a hydroxyethyl -Group.

The reaction of the compounds of the formula Ib with cc, β-unsaturated carbonyl compounds such as methyl vinyl ketone, acrylic acid (lower) alkyl esters takes place conveniently in a suitable organic solvent, e.g. a lower alkanol such as methanol, Ethanol, and stirring. The reaction temperature can be between room temperature and reflux temperature vary the reaction mixture; the reaction mixture is preferably heated to about 40-80 °. The reaction time depends in particular on the reaction temperature and the reactivity of the α, β-unsaturated Carbonyl compounds dependent and takes about 1-5 hours.

The reaction of the compounds of the formula Ib with ethylene oxide is also carried out analogously to the known ones Methods and Is illustrated by Example 5. One works in an inert under the reaction conditions Solvent and under cooling. The reaction takes about 10 to 20 hours.

Any hydrolysis of the compounds of the formula Ic can be carried out under acidic conditions, for example with With the help of 2N hydrochloric acid, it is useful

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- W - Case 100-3875

elevated temperature, preferably at reflux temperature take place.

However, the compounds of the formula Ic can also be converted into the compounds of the formula under alkaline conditions Id be hydrolyzed. The alkaline hydrolysis is preferably carried out with the aid of an aqueous, alcoholic Solution of an alkali metal or alkaline earth metal hydroxide, in particular with an aqueous, methanolic or ethanolic solution of sodium. um, potassium or barium hydroxide, useful Room temperature or slightly elevated temperature carried out.

b) The reductive alkylation of the compounds of the formula Ib to give the compounds of the formula Ie can be carried out analogously to known methods'.

For example, the procedure is that the compounds of the formula Ib are alkylated with the corresponding aldehydes or ketones in the presence of formic acid (Leuckart-Wallach method). The reductive alkylation can also be carried out hydrogenolytically, ie with the aid of hydrogen gas in the presence of a noble metal catalyst such as Raney nickel, palladium, etc. In this process variant is well known, but any chlorine bromine τ will, as also at least partially mitreduziert iodo substituent in the compounds of formula Ib in a possible additional bond 3a, 4-position of the compounds of formula Ib. In the reductive alkylation of the latter compounds, it is therefore advisable to use the Leuckart-Wallach method mentioned above.

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Case 100-3875

In the reaction according to Leuckart-Wallach one works in a suitable organic solvent, preferably excess formic acid, at elevated temperature, expediently under reflux.

The catalytic reductive alkylation is carried out in a suitable organic solvent, for example in a lower alkanol such as methanol, conveniently at room temperature.

c) The conversion of the compounds of the formula If into the compounds of the formula Ig takes place under sharp, alkaline conditions, i.e. with the help of strong bases, e.g. potassium hydroxide or potassium tert-butoxide and / or at a higher temperature, for example at about 100 to 200 ° and / or after a longer response time, for example one to seven days.

A particularly suitable reaction medium for this conversion is a saturated solution of potassium hydroxide (about 40%) in n-butanol (1 to 7 days at reflux temperature) or of potassium tert-butoxide in dimethyl sulfoxide. (1 to 7 days at 25 - 80 °)

Method c) is particularly useful for the production of the Compounds of the formula Ig suitable in which the remainder

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R ,. Alkyl with 1-5 carbon atoms, alkenyl or

Alkynyl radicals with 4 or 5 carbon atoms and in which the multiple bond is not in the α- or ß-position to the nitrogen atom to which R ^ is bonded,

by cycloalkyl, with 3-6, preferably with 5- or 6-carbon atoms substituted alkyl with 1-4 Carbon atoms, "hydroxyalkyl with 2-5 carbon atoms, phenylalkyl with 7-11 carbon atoms, in the phenyl radical phenylalkyl monosubstituted by halogen, alkoxy with 1-4, or alkyl with 1-4 carbon atoms having 7-11 carbon atoms, or a radical A-CO-R ', where A has the above meaning and R' is Is phenyl or phenyl substituted by halogen.

d) The hydrogenolysis of the compounds of. Formula Ih to the compounds of the formula Ii with hydriodic acid / red Phosphorus can be carried out analogously to known methods. For example, one proceeds like this that a solution or suspension of a mixture of a compound of formula Ih with red phosphorus in a suitable solvent or suspending agent such as glacial acetic acid, an aqueous solution of hydriodic acid drips. The reaction mixture thus obtained is

, then appropriately heated, for example to 80 to 120 °. The reduction lasts under the above conditions about 4 to 6 hours.

e) The catalytic hydrogenation of the compounds of the formula Ij to the compounds of the formula Ik can be carried out analogously to known methods.

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Noble metal catalysts such as palladium and Raney nickel are suitable as catalysts. The hydrogenation is in an organic solvent / for example a lower alkenol such as methanol or ethanol carried out.

It is preferable to work at a slight excess pressure, for example about 2 to 6 atm and at a higher pressure Temperature, for example about 40 to about 80 °.

According to a preferred embodiment, the hydrogenation in the presence of an in situ - prepared from palladium (II) chloride and sodium borohydride Palladium catalyst carried out.

f) The reduction of the compounds of the formula II with metal hydride can be carried out analogously to for the reduction of imides known methods.

For example, one proceeds in such a way that one can find a solution of compounds of the formula II in an organic solvent which is inert under the reaction conditions, for example a cyclic or open-chain ether such as tetrahydrofuran, with a solution of aluminum hydride or a dialkyl aluminum hydride, preferably the same under the reaction conditions inert organic solvent, added, and for about 20-3O hours at room temperature or higher temperature stirs. The reduction can also be carried out, for example, with a lithium aluminum hydride / aluminum chloride mixture be performed. As far as the compounds of the formula II do not have any chlorine, bromine or iodine substituents

? 348593

wear tuenten, the reduction can also be done with the help of a complex hydride such as a complex aluminum hydride such as lithium aluminum hydride or with the help of the complex lithium aluminum hydride aluminum chloride take place. This process variant can under similar process conditions as described for the reduction with aluminum hydride.

g) The reduction of the amides of the formula IV with metal hydrides can also be carried out analogously to known methods take place.

Examples of metal hydrides are aluminum hydride and dialkyl aluminum hydrides and, insofar as the compounds of the formula IV do not have any chlorine, bromine or iodine substituents carries, also suitable lithium aluminum hydride or lithium aluminum hydride / aluminum chloride.

Suitable solvents are solvents which are inert under the reaction conditions, e.g. cyclic or open-chain ethers such as tetrahydrofuran.

The reduction can be carried out at room temperature and is generally after about 1 1/2-5 Hours completed.

The compounds of the formula obtained by the above processes. Ia can be isolated analogously to known methods and cleaned.

According to the invention, the compounds of the formula Ib are obtained by

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a) of compounds of the formula

NRg

VI,

which by definition also includes the optical antipodes of the compounds of the formula VI and the racemic mixtures of the optical antipodes, and in which R ₁ , R ", X and Y have the above meaning and R- stands for an electron-withdrawing group, the group R _q analogous to known ones Methods, or
b) compounds of the formula

VII ₁

which by definition also includes the optical antipodes of the compounds of the formula VII and the racemic mixtures of the optical antipodes, and in which R _{1 and R 2 have the} above meaning and R, _{Q stands} for the radical R, which has the above meaning, or represents hydrogen, under harsh, alkaline conditions in compounds of the formula 4 0 9 8 15/1130

Case 100-3875

? 348593

In,

JR

which, by definition, also comprises the optical antipodes of the compounds of the formula In as well as the racial mixtures of the optical antipodes and in which R 1 and 'R' have the above meaning, or
, c) compounds of the formula

OK,

which, by definition, also includes the optical antipodes of the compounds of the formula Io and the racemic mixtures of the optical antipodes, and in which RJ and R 'have the above meaning and R ₁ . Means hydrogen or the benzyl group, in the presence of a noble metal catalyst, to give compounds of the formula

4 0 9 8 15/1130

which by definition are also the optical antipodes of the compounds of the formula Ip and the racemic mixtures of the optical antipodes, and wherein R 'and R' have the above meaning, hydrogenated or

d) compounds of the formula

H Q

VIII,

which by definition are also the optical antipodes of the compounds of the formula VIII and the racemic mixtures of the optical antipodes, and where R and R have the above meanings with help of metal hydrides to compounds of the formula

40 9 815/1130

which, by definition, also comprises the optical antipodes of the compounds of the formula Iq and the racemic mixtures of the optical antipodes, and in which R _n and R n have the above meaning, reduced

and the compounds of the formula Ib thus obtained are obtained as bases or as acid addition salts.

Acid addition salts can be prepared in a known manner from the free bases and vice versa.

The following is based on procedural details pointed out, which is useful in the inventive preparation of the compounds of formula Ib should be taken into account.

a) Suitable electron-withdrawing groups R _q are, for example, acyl groups such as the trifluoroacetyl group, the benzoyl group, an aliphatic or aromatic sulfonyl group, for example a tosyl group, a (lower) alkoxycarbonyl group such as the methoxy or ethoxycarbony group, or the phenoxycarbonyl group.

The inventive cleavage of the group R is, for example, by hydrolysis with a 1 to about 5N solution of an alkali metal hydroxide such as sodium or potassium hydroxide in a lower alkanol, preferably Methanol or ethanol carried out.

R _{g stands} for an acyl group that can be easily split off

e.g. the trifluoroacetyl group, see above

can hydrolysis at room temperature or easily

A 0 9 8 1 5/1 1 3 0

increased temperature. The hydrolysis is then complete in about 1/2 to about 3 hours.

If R stands for a less easily cleavable acyl group, e.g. for the Phenoxycarbony1gruppe, so works one expediently with heating, preferably under the reflux temperature of the reaction mixture. The reaction then takes about 10 to about 20 hours.

If R _{g stands} for an aliphatic or aromatic suI-

fonyl group, this group can be

tive conditions - analogous to known methods, for example with sodium ammonia or phenol in 40% hydrobromic acid are split off.

The hydrolysis of the compounds of the formula VI can also be carried out under acidic conditions, for example with With the aid of 2N hydrochloric acid, expediently at elevated temperature, preferably at reflux temperature of the reaction mixture take place.

b) The transformation of the compounds of the. Formula VII into the compounds of formula In can be used as for the ^ conversion the compounds of the formula If described in the compounds of the formula Ig (see method c), take place.

Any group R _q is split off under these severe, alkaline conditions in the presence of nucleophilic anions, for example OH, O- (lower) alkyl ".

c) The catalytic hydrogenation of the compounds of the formula Io can as for the catalytic hydrogenation of the

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Compounds of formula Ij (see method e) described, take place.

If R _{11 stands} for the benzy group, this is also split off under these reaction conditions.

d) The reduction of the compounds of the formula VIII with the aid of metal hydrides can be carried out in the same way as for the reduction of the compounds of the formula II to the compounds of the formula Iu (process f) described, carried out will.

The compounds of the formula II, IV, VI, VIII are also new.

The compounds of the formula VII are partly encompassed by the formula Ib and partly by the formula VI.

The compounds of the formula II can be obtained, for example, by adding compounds of the formula

wherein R ^ and R _{2 have the} above meaning, with compounds of the formula

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χι »

in which R _{0 has the} above meaning, to the compounds

the formula

XII,

vrelche, by definition, also includes the optical antipodes of the compounds of the formula XII and the racemic mixtures of the optical antipodes and in which R 1, R and R _{ß have the} above meaning, condenses and splits off water from the compounds of the formula XII thus obtained.

The condensation of the compounds of the formula X with the compounds of the formula XI is carried out with irradiation Solution of these compounds in a solvent that is inert under the reaction conditions, such as acetone or a chlorinated aliphatic hydrocarbon such as methylene chloride, carried out at room temperature. The reaction takes about 20 to 200 hours.

The compounds of the formula XII can be prepared analogously to known ones Methods using organic or inorganic

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Acids become dehydrated.

Organic acids are e.g. aliphatic or aromatic sulfonic acids, trifluoroacetic acid, trichloroacetic acid, Formic acid as inorganic acids e.g. sulfuric acid, hydrochloric acid, perchloric acid, phosphoric acid etc. suitable.

The reaction time depends on the type and concentration of the acid about 1 to about 15 hours.

While with the help of concentrated, strong acids like Sulfuric acid, trifluoroacetic acid the elimination of water proceeds smoothly at room temperature, it is recommended to warm the reaction mixture when using dilute or weaker acids.

For example, one proceeds in such a way that the compounds of the formula XII are in an organic acid such as trifluoroacetic acid dissolves and the reaction mixture for about 2-5 hours at a temperature of about 20 ~ 40 ° stirs.

The compounds of the formula IV, as well as the compounds of the formula VI, can be prepared according to methods known per se by acylation of the corresponding compounds of the formula Ib, for example with the aid of the corresponding Acid halides, preferably the corresponding chlorides or bromides, or with the corresponding acid anhydrides, getting produced. Any N-formylation is also carried out analogously to known methods.

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The majority of the compounds of the formula VI can - as explained below - directly, by cyclization suitable amides, are synthesized.

a) To compounds of the formula

Via,

which by definition also includes the optical antipodes of the compounds of the formula VIa as well as the racemic mixtures of the optical antipodes and in which R ₁ , R and R_ have the above meaning, can be obtained by using compounds of the formula

XIII,

wherein R ₁ , R ₂ and R _{g have the} above meaning, thermally cyclized.

The thermal cyclization of the compounds of the formula XIII can be carried out in an inert organic solvent

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solvents, preferably with a high boiling point, for example dichlorobenzene. One works expediently with exclusion of oxygen and the reaction mixture is heated to about 160-190 ° during the process about 1 to about 6 hours.

The compounds of the formula VIa thus obtained can, as already described, be converted to the corresponding NH compounds are deacylated and, if desired, catalytically hydrogenated. In the latter case it is to take into account that a possible chlorine, bromine or iodine substituent at least partially with is reduced ..

b) compounds of the formula

NCOOR

VIb,

which, by definition, also include the optical antipodes of the compounds of the formula VIb and the racemic ones Comprises mixtures of the optical antipodes and in which R- and R_ have the same meaning as above, and R ^ is lower alkyl or the phenyl group, can, for example, by reducing the compounds the formula

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N benzyl

Ir-,

which definitxonsgeroass also includes the optical antipodes of the compounds of the formula Ir and the racemic mixtures of the optical antipodes and in which R ₁ and R "have the above meaning, with hydriodic acid / red phosphorus, analogous to known methods, and subsequent substitution of the benzyl group in the so obtained Compounds of the formula

N benzyl

Is,

which, by definition, also include the optical antipodes of the compounds of the formula Is and the racemic ones Mixtures of the optical antipodes comprises where R- and R_ have the above meaning, prepared will

The substitution of the benzyl group in the compounds of the formula Is can also be carried out analogously to known ones Methods, for example by implementing the

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Compounds of the formula Is with the corresponding chlorocarbonic acid ester.

The compounds of the formula VIb thus obtained can, as described (process a or b), in the corresponding tetrahydro compounds of the formula VII (R, = H) / Or into the compounds of the formula To be convicted.

c) By thermal cyclization of the compounds of the formula

XIV,

where R _{g has the} above meaning and either Rl ^{1 is} hydrogen and R ^ is halogen or an alkyl group with one to 4 carbon atoms or R "is halogen or an alkyl group with 1-4 carbon atoms and R ^ is hydrogen, compounds of the formula are obtained

• R "

R "

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VlC,

which, by definition, also includes the optical antipodes of the compounds of the formula VIc and the racemic mixtures of the optical antipodes and in which R ", R- and R _{9 have the} above meaning.

The thermal cyclization of the compounds of the formula XIV can be carried out under those explained for process a Conditions are carried out. The reaction usually takes a little longer (16 to 30 hours).

The compounds of the formula VIII can, as described for the preparation of the compounds of the formula II, starting from the compounds of formula X and using maleimide instead of one Compound of Formula XI.

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The compounds of the formula Ir fall under the general formula Iu. A method of making them is explained, inter alia, under method f.

The compounds prepared by the above process can be isolated in a customary manner and according to known methods Methods to be cleaned.

If the preparation of the starting compounds is not described, these are known or according to methods known per se or analogously to the methods described here or analogously to methods known per se Process producible.

The compounds of formula I and their pharmacologically acceptable acid addition salts have with low toxicity interesting pharmacodynamic properties and can therefore be used as remedies be used.

Animal experiments in particular have found pharmacological effects that are typical of antidepressants are. Thus, at a dose of approximately 2 mg / kg, the compounds according to the invention raise about 30 mg / kg, the cataleptic state (rigid posture), which is caused by the administration of tetra-

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benazine is induced in the rat (tetrabenazine antagonism).

Because of their antidepressant effect, they are suitable for treating depression.

For the above application, the dose to be administered depends on the compound used and the Type of administration as well as the type of treatment. In general, satisfactory results are obtained when administering compounds of the formula I or their physiologically tolerable acid addition salts at a dose of from about 1 to about 30 mg / kg animal body weight. In larger mammals a daily dose of approximately 50 to approximately 500 mg is indicated. These The amount to be administered daily can also be in smaller doses, e.g. 2 to 4 times a day / or administered in sustained release form. A unit dose, for example one for oral administration suitable tablet, may be between about 12.5 and about 250 mg of the active ingredient, along with suitable pharmaceutically indifferent excipients, contain.

They also have analgesic properties. These show up, for example in the tail pinch test on the mouse with doses of approx. 15 to 50 mg / kg body weight see c, in the tail-flick test on the mouse with doses of about 30 to 100 mg / kg body weight s.c, in the hot plate test on the mouse with doses of approx. 30 to 100 mg / kg Body weight ρ., Ο., As well as by inhibition of the phenylbenzoquinone syndrome on the Maxis with doses of approx. 10 to 50 mg / kg Body weight ρ.ο ..

409815/1130

Due to their analgesic effectiveness, the substances can be used to treat Pain of various origins can be used. The doses to be used vary naturally depending on the type of substance, the administration and the one to be treated State. In general, however, satisfactory results are obtained with test animals a dose of about 0.5 to 100 mg / kg body weight. This dose can if necessary, be administered in 2-4 portions or as a sustained release form. For bigger ones In mammals, the daily dose is about 30 to about 300 mg. For example, contain for oral applications the partial doses of about 8 to about 150 mg of the compounds of Formula I in addition to solid or liquid carriers.

The compounds of the formula I or their physiologically acceptable acid addition salts can be used as medicaments administered alone or in a suitable drug form with pharmacologically inert adjuvants will.

The compounds of the formula I form with acids such as hydrogen chloride, hydrogen bromide, Fumaric acid, maleic acid, tartaric acid, naphthalene-1,5-disulfonic acid etc. stable, mostly water soluble salts.

The compounds of the formula I or their physiologically acceptable acid addition salts can be used in a manner known per se, together with suitable auxiliaries commonly used in pharmacy. for oral, rectal or parenteral administration suitable solid or liquid pharmaceutical preparations such as tablets, capsules, coated tablets, drop solutions, Syrups, Svippositorien or sterile solutions can be processed. The active ingredient can mixed with the excipients in the usual way and brought into the desired dosage form. A preferred embodiment represent solid preparations suitable for oral administration, such as tablets, capsules, coated tablets, etc. Suitable auxiliaries and carriers for solid forms are e.g. talc, lactose, sucrose,

409815/1130

Corn starch, polyvinylpyrrolidone, magnesium stearate, dimethyl silicone oil, polyethylene glycol, Silicic acid, stearic acid, microcrystalline cellulose, gelatin, etc. The solid preparations can be per single dose contain the above-mentioned amount of active ingredient.

The preparations can also contain suitable preservatives, stabilizers or wetting agents, Contain solubilizers, sweeteners, colorings, aromas, etc. Another The invention therefore relates to the production of these preparations on known manner, and also the use of the compounds in the above-mentioned indications in the form of the preparations mentioned.

The above-mentioned properties occur in particular with the (3aRS, 4SR, 9aSR) tetrahydrobenz [f] isoindolines of the formula I or Iw. Of the latter compounds, the compounds of the formula

Iz

in which Ra is hydrogen, methyl, 2-propynyl, cyclopropylmethyl or acetonyl and R ^ and

rJ mean hydrogen, methyl or chlorine, a particularly interesting effect.

409815/1130

The following examples, which explain the invention in more detail, do not restrict its scope in any way all temperatures are given in degrees Celsius and are uncorrected.

Example 1:

(Method a)

To a mixture of 10 g (3aRS, 4SR, 9aSR) -3a, 4,9,9a-tetrahydro-4-phenyl-benz [f] isoindoline, 8.5 g sodium carbonate, 0.2 g sodium iodide and 80 ml dimethylformamide a solution of 3.76 g of chloroacetone in 35 ml of dimethylformamide is added dropwise at 100 ° with stirring. That The reaction mixture is conducted at 100 ° for a further 2 hours and then evaporated in a high vacuum. The residue is shaken with methylene chloride / 2N sodium hydroxide solution. The organic Phase is dried and evaporated, the residue in ether is mixed with activated charcoal, the solution filtered and evaporated and the residue crystallized from ether / pentane, the one mentioned in the title Compound of m.p. 106-108 ° obtained. ~~

The preparation of (3aRS, 4SR, 9aSR) -3a, 4, 9,9a-tetra-hydro-4-phenyl-benz [f] isoindoline is described in Example 6, among others.

Analogously to Example 1, using the appropriate starting compounds, alkylation is used of compounds of the formula Ib (according to method a) the following compounds of the formula Ia:

4 0 9 8 15/1130

Casa 100-3875

(3aRS, 4SR, 9aSR) -3a _f 4,9,9a-Tetrahydro-2-methyl-4-phenylbenz [f] isoindoline

M.p. of the hydrochloride ....... 2.07. - 209 °

(3aRS, 4SR, 9aSR) -2-allyl-3a, 4,9,9a-tetrahydro-4-phenylbenz [f] isoindoline

M.p. of the hydrochloride .187-190 °.

(3aRS, 4SR, 9aSR) ^ -Cyclopropylmethyl-Sa, 4, 9,9a-tetrahydro-4-phenyl-benz tf] isoindoline

M.p. 65-68 °

(3aRS, 4SR, 9aSR) -3a, 4,9,9a-tetrahydro-2-isopropyl-4-phenyl-benz [f] isoindoline

M.p. of the hydrogen maleate 150-158 °

(3aRS, 4SR, 9aSR) -3a, 4,9,9a-Tetrahydro-4-phenyl-2- (2-propynyl) -benz [f] isoindoline

M.p. 93-95 °

(3aRS, 4SR, 9aSR) -2- (o-chlorophenethyl) -3a, 4,9,9a-tetrahydro-4-phenyl-benz [f] isoindoline

M.p. of the hydrogen maleate 178-179 °

(3aRS, 4SR, 9aSR) -2- (3a, 4,9,9a-tetrahydro-4-phenyl-benz- [f ] isoindolin-2-.yl) acetophenone ~~

M.p. 120-130 °

(3aRS, 4SR, 9aSR) -p-fluoro-4- (3a, 4,9,9a-tetrahydro-4-phenyl-benztf] isoindolin-2-yl) butyrophenone

M.p. 81-84 °

0 9 8 1 5 / Ί 1 3 0

- CaGi 100-3875

HO

(3aRS, 4SR, 9aSR) -3a, 4,9,9a-tetrahydro-2- (p-methylbenzyl) 4-phenyl-benz [f] isoindoline

M.p. 120-121 °

(3aRS, 4SR, 9aSR) -3a, 4,9,9a-tetrahydro-2- (p-methoxybenzyl) -4-phenyl-benz [f3isoindoline

Snip. 95-100

(3aRS, 4SR, 9aSR) -6-Chlor-Sa, 4,9,9a-tetrahydro-2-methyl-4- (4-chlorophenyl) -benz Ef] isoindoline

133-135 °

(3äRS, 4SR, 9aSR) ~ 6-chloro-4- (4-chlorophenyl) -2-cyclopropylmeth, yl-3a, 4 , 9, 9a-tetrahydro-benz [f] isoindoline

M.p. 124-126 °

(3aRS, 4SR, 9aSR) -2-acetonyl-6-chloro-4- (4-chlorophenyl) -3a, 4,9,9a-tetra-hydrobenz [f] isoindoline

Mp of the bis (base) naphthalene-305-307 ° 1,5-disulfonate

(3aRS, 4SR, 9aSR) -7-chloro-4- (m -chlorophenyl) -3a, 4,9, gate trahydro-2-methyl-benz [f] isoindoline

M.p. of the bis (base) naphthalene-244-248 ° 1,5-disulfonate

(3aRS, 4SR, 9aSR) -2-acetonyl-7-chloro-4- (m -chlorophenyl) -3a, 4,9,9a-tetrahydro-benz tf] isoindoline

Mp of the bis (base) naphthalene-266-269 ° 1,5-disulfonate

(3aRS, 4SR, 9aSR) -7-chloro-4- (m -chlorophenyl) -2-cyclopropylmethyl-3a, 4,9,9a-tetrahydrobenz [f] isoindoline

Mp of bis (base) naphthalene 243-247 ° 1,5-disulfonate

4 0 9 8 15/1130

Case 100-3675

(3aRS, 4SR, 9aSR) -3a, 4,9,9a-tetrahydro-2,6-dimethy1-4 (p-tolyl) benz [f] isoindoline

Mp of the bis (base) naphthalene 195-198 ° 1,5- ^ disulf onates

(3aRS, 4SR, 9aSR) ^ -Cyclopropylmethyl-Sa, 4,9,9a-tetrahydro-'6-methyl-4- (p-tolyl) benz tf] isoindoline

M.p. 98-100 °

(3aRS, 4SR, 9aSR) -3a, 4.9, ga-Tetrahydro-S-methyl ^ - (3-methyl-but-2-enyl) -4-) p-tolyl) -benz [f] isoindoline

M.p. of the hydrochloride 197 - 207 ° (decomp.)

(3aRS, 4SR, 9aSR) -3a, 4,9,9a-tetrahydro-2,6-dimethyl-4-phenyl-benztf] isoindoline

M.p. of the bis (base naphthalene

1,5-disulfonate 280-283

(3aRS, 4SR, 9aSR) -2-acetonyl-3a, 4,9,9a-tetrahydro-6-methyl-4-phenyl-benz tf] isoindoline

M.p. of the bis (base) -naphthalene-

1,5-disulfonate 295-301 °

(3aRS, 4SR, 9aSR) -2-Cyclopropylπlethyl-3a, 4, 9, 9a-tetrahydro-6-methyl-4-phenyl-benz tf] isoindoline

M.p. of the hydrochloride 198-204 ° ~~

{3aRS, 4SR, 9aSR) -3a, 4,9,9a-tetrahydro-2,7-dimethy1-4-pheny1-benz t f] isoindoline

M.p. of the bis (base) -naphthalene-

1,5-disulfonate. 244 - 248 °.

(3aRS, 4SR, 9aSR) -2-acetonyl-3a, 4,9,9a-tetrahydro-7-methyl-4-pheny1-benz [f] isoindoline

M.p. of the bis (base) -naphthalene-

1,5-disulfonate 295-299 °

409815/1130

- 3 ** - 100-3875

HS

(3aRS, 4SR, 9aSR) -3a, 4, 9 _/ 9a-Tetrahydro-2- (3-methylbut-2-enyl) -4-phenyl-benz [f] isoindoline (melting point of the hydrogen maleate: 16 3-168 ° )

(3aRS, 4SR, 9aSR) -3a, 4,9,9a-Tetrahydro-6-methyl-2- (3-methylbut-2-enyl) -4-phenyl-benz [f] isoindoline

OaRS, 4SR, 9aSR) -3a, 4,9 _/ 9a-Tetrahydro-6-methyl-4-phenyl-2- (2-propynyl) -benz [fJ isoindoline

(3aRS, 4SR ^ aSR) -6-011101--2-CyClOPrOPylmethyl-Sa ^, 9, 9a-tetrahydro-4-phenyl-benz [f] isoindoline

(3aRS _/ 4SR _/ 9aSR) -6-chloro-3 _{f 4/9 /} 9a-tetrahydro-4-phenyl-2- (2-propynyl) benz [f] isoindoline

OaRS ^ SR, 9aSR) -6-ChIOr-Sa ^ , 9 ^ a-tetrahydro ^ - (3 methylbut-2-enyl) -4-phenyl-benz [f] isoindoline

(3aRS, 4SR, 9aSR) -2-ethyl-6-chloro-3a _/ 4,9 ^ a-tetrahydro-4-phenyl-benz [f] isoindoline

(3aRS, 4SR ₇ 9aSR) -2-n-Butyl-6-chloro-3a _/ 4,9,9a-tetrahydro-4-phenyl-benz [f] isoindoline

, 9aSR) -6-chloro-2-isopropyl-3a, 4.9 ₇ 9a-tetrahydro-4-phenyl-benz [f] isoindoline

(3aRS, 4SR, 9aSR) -2- (but-2-enyl) -3a, 4,9,9atetrahydro-4-f <ienyl-benz / f / isoindoline

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Case 100-3875

(3aRS, 4SR, 9aSR) -2-cyclopropylraethyl-3a, 4,9,9a-tetrahydro-7-methyl-4-phenyl-benz tf] isoindoline

M.p. 79-82 °

2- (3aRS, 4SR, 9aSR) -3a, 4, 9, 9a-Tetrahyd.ro-7-meth.yl-4-phenyl-benz [f] isoindolin-2-yl) -p-fluoroacetophenone

M.p. of the hydrogen maleate 164 ° -166 °

(3aRS, 4SR, 9aSR) -6-Chlor-Sa, 4,9,9a-tetrahydro-2-methyl-4-phenyl-benz tf] isoindoline

M.p. of the hydrochloride 231-233 °

(3aRS, 4RS, 9aSR) -3a, 4, 9, 9a-Tetrahydro-2-'methyl-4-phenylbenz [f] isoindoline

M.p. of the bis (base) -naphthalene-

1,5-disulfonate 297-303 °

(3aRS, 4RS, 9aSR) -2-acetonyl-3a, 4,9,9a-tetrahydro-4 ~ phenyl-benz [f] isoindoline

M.p. of the bis (base) -naphthalene-

1,5-disulfonate 265-269 °

(3aRS, 4RS, 9aSR) -3a, 4,9,9a-tetrahydro-2,6-dimethy1-4-phenyl-bsnztf] isoindoline

M.p. of the bis (base) -naphthalene-

1,5-disulfonate 183-187 ° ~

(3aRS, 4RS, 9aSR) -3a, 4,9,9a-tetrahydro-2,7-dimethyl-4-phenyl-benz [f] isoindoline

M.p. of the bis (base) -naphthalene-

1,5-disulfonate 204-207 °

(3aRS, 4RS, 9aSR) ^ - Benzyl-δ-chloro-Sa, 4,9,9a-tetrahydro-4-phenyl-benz tf] isoindoline

smp. 4098 15/1130 ' ₁₁₅ _ ₁₁₇

Case 100-3875

(9aRS) -2-Benzyl-9,9a-dihydro-6-methyl-4-phenyl-benz- [f] isoindoline

Mp. 139-143 °

(9aRS) -9,9a-Dihydro-2-methyl-4-phenyl-3H-benz [f] isoindoline

M.p. of the hydrogen maleate 158 - 162 ° (decomp.)

(9aRS) -2-benzyl-9, ga-di
[f] isoindoline

~ 139-142

(9aRS) -2-Benzyl-9,9a-dihydro-4-phenyl-benz [f] isoindoiine 113-115 °

(9aRS) -2-Benzyl-6-chloro-9,9a-dihydro-4-phenyl-benz [f] -isoindoline

M.p. 266-268 °

Processes for the preparation of the required starting compounds are explained in Examples 6, 9, 10, 11, 12, 13 and 20.

The following examples explain further process variants according to procedure a:

4 0 9 8 15/1130

Case 100-3875

Example 2: i 3aRS_,

non (variant method a)

The solution of 7.4 g (3aRS, 4SR ₇ 9aSR) -3a, 4,9,9a-tetrahydro-4-phenylbenz [flisoindoline in 60 ml of ethanol is refluxed for 1 1/2 hours after adding 3 ml of methyl vinyl ketone heated to boiling and then evaporated. The residue is chromatographed on diesel gel with ethyl acetate. On evaporation, the filtrate gives the compound named in the title as an oily residue. Hydrogen maleate: m.p. 121-124 ° (after crystallization from ethanol).

Example 3: i3aRS _x 4SR, 9aSR) -3a, 4, 9 / .9a-TetrahYdro-4-

iIi ^s 2i ⁿ ^ ^o i ^ 2l? ~ grop.ion (variant method a)

A mixture of 15 g (3aRS, 4SR, 9aSR) -3a, 4,9,9a-tetrahydro-4-phenyl-benz [fjisoindoline, 5.9 g of methyl acrylate and 1 ml of 40% strength methanolic solution of Benzyltrimethylammonium hydroxide is stirred for 4 hours at 50 ° and then evaporated. The evaporation residue is slurried with silica gel in benzene / ethyl acetate 9: 1 and filtered. The filtrate gives on evaporation the compound mentioned in the title with a melting point of 75-76 ° (after crystallization from ether / petroleum ether).

409815/1130

Case 100-3875

Example 4:

phen ^ l-benz ^ f3 isoindoline-2-gropionic acid

(Hydrolysis ester process a)

10 g (3aRS, 4SR, 9aSR) -3a, 4,9,9a-tetrahydro-4-phenyl-benz- [f] isoindoline-2-propionic acid methyl ester are refluxed for 5 hours in 50 ml of 2N hydrochloric acid. Then the solution is evaporated, the residue dissolved in water and adjusted to pH = 1 with sodium hydroxide solution and 1 equivalent of 1,5-naphthalenedisulphonic acid added, the bis-1,5-naphthalene disulfonate of the title compound precipitating sticky. You decant from the water and rubs the resin with acetone, whereby it crystallizes; M.p. 193-195 °.

Example 5: i ^^^^ gjg ^ Y

^^ a-tetrahv ^ ro-e ^ methYl-

fe§55l £ li52ii} ^ 2ii2 (variant procedure a)

Into the solution of 4 g of (3aRS, 4SR, 9aSR) -3a, 4,9,9a-tetrahydro-6-methyl-4- (p-tolyl) benz [f] isoindoline in 30 ml of ethanol is 1/3 g of ethylene oxide at -15 ° with stirring initiated. The mixture is left to stand at + 5 ° for 16 hours and then concentrated. The residue results after Chromatography on 30 g of silica gel with methylene chloride / methanol / saturated aqueous ammonia (95: 4.5: 0.5) the compound mentioned in the title of m.p. 128-129 ° (after Crystallization from methylene chloride / petroleum ether).

The compounds described in Examples 2 to 5 can also be prepared analogously to Example 1.

409815/1130

■ - 4 * · - Case 100-3875

Analogously to example 2, the following was produced:

4 - ((9aRS) -9,9a-dihydro-4-phenyl-benz [f] isoindolin-2-yl) butan-2-one

M.p. of the hydrogen maleate: 132-134 °

Analogously to example 3 'and 4, the following was produced:

((9aRS) -9,9a-Dihydro-4-phenyl-benz [f] isoindolin-2-yl) propionic acid

M.p. of bis (base naphthalene-1,5-disulfonate 206-210 °

Example 6:

(Method a)

22.3 g (3aRS, 4SR, 9aSR) -3a, 4,9,9a-tetrahydro-4-phenylbenz [f] isoindoline-2-trifluoroacetamide are dissolved in 3 N methanolic potassium hydroxide solution with heating. The mixture is stirred for 30 minutes at room temperature, then poured into water and extracted with methylene chloride. The extract is dried over sodium sulfate, the solution evaporates and the residue crystallizes from methylene chloride / pentane, giving the compound mentioned in the title, melting point 136-138 °.

The (3aRS, 4SR, 9aSR) -3a, 4,9,9a-tetrahydro-4-phenyl-benz [f] isoindoline-2-trifluoroacetamide required as starting material is obtained e.g. as follows:

0 9 8 15/1130

Case 100-3875

The solution of 310 g of N, N-bis (trans-cinnamyl) trifluoroacetamide in 61 o-dichlorobenzene is refluxed for 16 hours under an argon atmosphere and then evaporated. After crystallization from methylene chloride / pentane (3aRS, 4SR, 9aSR) -3a, 4,9 , 9a-tetrahydro-4-phenylbenz [f] isoindoline-2-trifluoroacetamide with a melting point of 150-153 °. IR (CH ₂ Cl ₂ ) 1690, no band at 950 to 990 cm.

The Ν, Ν-bis (trans-cinnamyl) required as the starting product trifluoroacetamide can be produced as follows:

To slurry 30.2 g of sodium hydride in 540 ml Hexamethylphosphorsäuretriamid is with cooling and Stir.a solution of 275 g of N-cinnamyl-trifluoroacetamide added dropwise in 600 ml of hexamethylphosphoric triamide. After the gas evolution has ended, the Solution of 248.5 g of cinnamyl bromide in 540 ml of hexamethylphosphoric acid triamide added dropwise and the mixture stirred at 25 ° for 16 hours. Then the reaction mixture poured into water and extracted with ether. The ether solution, dried over sodium sulphate, is evaporated and the oily residue is chromatographed on 1.5 kg of silica gel using toluene. _ ^

On evaporation, the piltrate gives the N, N-bis (transcinnamyl) trifluoroacetamide as an oily residue: IR Cl ₂ ) 1690, 968 cm " ¹ .

4098 15/1130

- ^ Sr- Case 100-3875

You can get through under the usual conditions Reduction of (3aRS, 4SR, 9aSR) -3a, 4,9,9a-tetrahydro-4-phenyl-benz [f] isoindoline-2-p-toluenesulfonic acid amide to the title compound. The required starting material (3aRS, 4SR, 9aSR) -3a, 4,9,9a-tetrahydro-4-phenyl-benz- [f] isoindoline-2-p-tpluenesulfonic acid amide is obtained e.g. as follows:

The solution of 2 g of N, N-bis (trans-cinnamyl) -p-toluenesulfonic acid amide in 120 ml of o-dichlorobenzene is refluxed for 48 hours under an argon atmosphere and then evaporated to give (3aRS, 4SR, 9aSR) -3a, 4,9,9a-tetrahydro-4-phenyl-benz [f] isoindoline-2-p-toluenesulfonic acid amide obtained as residue, m.p. 185-187 ° (after crystallization from ether / pentane).

Analogously to Example 6, starting from the corresponding starting compounds using Method a the following compounds of formula Ib:

(3aRS, 4SR, 9aSR) -6-chloro-4- (4-chlorophenyl) -3a, 4,9,9atetrahydro-benz [f] isoindoline

M.p. 133-13 °

(3aRS, 4SR, 9aSR) -6-fluoro-4- (p-fluorophenyl) -3a, 4,9,9atetrahydrobenz [f] isoindoline

M.p. of the hydrogen maleate 134-136 °

(3aRS, 4SR, 9aSR) -7-chloro-4- (m -chlorophenyl) -3a, 4,9,9atetrahydrobenz [f] isoindoline

M.p. of the hydrogen maleate 166-168 °

409815/1130

"OaEG 100-3375

SO

(3aRS, 4SR, 9aSR) -3a, 4,9,9a-tetrahydro-6-methyl-4- (p-tolyl) -benz [f] isoindoline

M.p. 129-132 °

(3aRS, 4SR, 9aSR} -3a, 4,9, ga-Tetrahydro-O-methyl-1-phenylbenz [f] isoindoline

M.p. of the hydrochloride 174-176 °

(3aRS, 4SR, 9aSR) -3a, 4,9,9a-Tetrahydro-7-methyl-4-phenylbenz [f] isoindoline

M.p. of the hydrochloride 225-227 °

(3aRS, 4SR, 9aSR) -6-chloro-Sa ^, 9,9a-tetrahydro-4-phenylbenz [f] isoindoline

M.p. of the hydrochloride 205-207 °

(3aRS, 4RS, 9aSR) -3a, 4,9,9a-tetrahydro-4-phenyl-benz- [f] isoindoline

M.p. of the hydrochloride 256-258 °

(3aRS, 4RS, 9aSR) -3a, 4,9,9a-tetrahydro-6-methyl-4-phenylbenz If] isoindoline

M.p. of the hydrochloride 215-220 °

(3aRS, 4RS, 9aSR) -3a, 4, 9, ga-Tetrahydro ^ -methyl ^ -phenylbenz [f] isoindoline

M.p. of the hydrochloride 226-230 °

(3aRS, 4RS, 9aSR) -6-chloro-3a, 4,9,9a-tetrahydro-4-phenylbenz [f] isoindoline

Mp. 144 - 145 °

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Case 100-3875

$ 4

(9aRS) -9,9a-Dihydro-4-phenyl-benz [f] isoindoline

M.p. of the hydrochloride 238-243 ° (dec.)

Example 7: iSaRS ^^ SR ^^ aSR ^ -Sa ^ 4 _Λ 9 ^^ aiB® £ hYl-4- £ hen
(Method b)

A mixture of 8 g (3aRS, 4SR / 9aSR) -3a, 4,5,9,9a-Tetra ~ hydro-4-phenyl-benz [f] isoindoline, 120 ml of 40% aqueous Solution of formaldehyde and 320 ml of methanol is added to a catalytic amount of Raney nickel under a hydrogen atom until the end of the Gas intake stirred. Then the filtered reaction mixture is evaporated, the residue is mixed with methanol, the insolubles are filtered off and the solution is evaporated, leaving the compound mentioned in the title as a residue receives. The hydrochloride of the title compound melts at 207-209 ° (ethanol / ether).

Example 8: 1 ^ _ii __ig

^ Si ^ S ^ ga-tetrahYdro-g-methYl-benz [f] isoindoline (Method b)

A mixture of 1.5 g of (3aRS, 4SR, 9aSR) -6-chloro-4 - _"(p - _c hlorphenyl) -3a, 4,9,9a-tetrahydro-benz [f] isoindoline, 10 ml of 100% - Formic acid and 10 ml of 40% aqueous formaldehyde solution are refluxed under nitrogen for 2 hours, the mixture is evaporated, the residue is taken up in water, the solution is made alkaline with concentrated sodium hydroxide solution and 4 0 9 8 15/1130

Case 100-3875

extracted with methylene chloride. The dried extracts are mixed with ether until they become turbid, with Hyflo filtered and evaporated to give the title compound as a residue; 133-135 ° (after crystallization from ether).

Analogously to Examples 7 and 8, one obtains from the corresponding Starting compounds, using method b, the following compounds:

(3aRS, 4SR, 9aSR) -3a ,. 4, 9, 9a-tetrahydro-2- -isopropyl-4-phe- nyl-benz [f] isoindoline Of the hydrogen maleate 150-158 ° (3aRS, 4SR, 9aSR) -3a, 4,9,9a-tetrahydro-2 , 6-dimethyl-4- (p-tolyl) benz [f] isoindoline M.p. of the bis (base) -naphthalene- 1,5-disulfonate 195-198 ° (3aRS, 4SR, 9aSR) -3a, 4,9,9a-tetrahydro-2 6-dimethy1-4-phe- nyl-benz [f] isoindoline M.p. of the bis (base) naphthalene 1,5-disulfonate 280 - 283 ° - (3aRS, 4SR, 9aSR) -3a, 4,9,9a-tetrahydro-2 7-dimethy1-4-phe- nyl-benz [f] isoindoline M.p. of the bis (base) naphthalene 1,5-disulfonate 244 - 248 ° (3aRS, 4RS, 9aSR) -3a, 4,9,9a-tetrahydro-2, 6-dimothyl-4-phe- nyl-benz [f] isoindoline M.p. of the bis (base) naphthalene 1,5-disulfonate 18 3 - 187 °

U 0 9 H 1 h / 1 1 3 0

- y »r - Case 100-3875

(3aRS, 4RS, 9aSR) -3a, 4.9, 9a-tetrahydro-2,7-dimethy1-4-phe- 204 - 207 ° 297-303 ° nyl-benz [f] isoindoline 9a-tetrahydro-2-methyl-4-phenyl- M.p. des bis (base) -naphthalene- 1,5-disulfonate -naphthalene- (3aRS, 4RS _f 9aSR) -3a, 4.9, 1, .5-disulf onates benz [f] isoindoline M.p. des bis (base)

Analogously to Example 8, from the appropriate starting compounds and using procedures b the following compounds:

(3aRS, 4SR, 9aSR) -7-chloro-4- (m -chlorophenyl) -3a, 4,9,9a-tetrahydro-2-methyl-benz [f] isoindoline

M.p. of the bis (base) naphthalene

1,5-disulfonate 244-248 °

(3aRS, 4SR, 9aSR) -6-Chlor-Sa, 4,9,9a-tetrahydro-2-methyl-4-pheny1-benz [f 3 isoindoline

. Mp of the hydrochloride 231-233 °

(9aRS) -9,9a-dihydro-2-methyl-4-phenyl-benz tf3 isoindoline, melting point of hydrogen maleate 158 - 162 (decomp.)

409815/1130

100-3875

(3aRS, 4SR, 9aSR) -2-Ethyl-6-chloro-Oa ^, 9, 9a-tetrahydro-4-phenyl-benz [f] isoindoline

(3aRS , 4SR, 9aSR) -2- n -Butyl-6-chloro-3a , 4,9,9a-tetrahydro-4-phenyl-benz [f] isoindoline

(3aRS, 4SR _/ 9aSR) -6-chloro-2-isopropyl-3a _f 4 _# 9,9a-tetrahydro-4-phenyl-benz [f] isoindoline

409815/1130

- # β ~ - Case 100-3875

ST

Example 9: j

(Method c, b)

A solution of 20.2 g (3aRS, 4RS, 9aSR) -3a, 4,9,9a-tetrahydro-6-methyl-4-phenyl-benz [f] isoindoline in 500 ml n-butanol saturated with solid potassium hydroxide
-will reflux for 70 hours under an argon atmosphere
heated to boiling and then evaporated. The residue is partitioned between water / methylene chloride, the organic phase is dried and evaporated and then taken
the residue is dissolved in excess methanolic hydrochloric acid, the solution is evaporated and finally, after crystallization of the residue from methanol / ether, the hydrochloride of the compound mentioned in the title has a melting point of 174 ° -176 ° (decomp.)

Example χα : IS

{/ experience b)

6.4 g (3aRS, 4RS, 9aSR) -6-chloro-3a, 4,9,9a-tetrahydro-2-phenoxycarbonyl-4-phenyl-benz tf] isoindoline v / ground in
320 ml of a saturated solution of potassium hydroxide in n-butanol were heated to boiling under reflux under nitrogen for 70 hours. The reaction mixture is then concentrated, the residue is taken up in water and extracted with methylene chloride. Evaporation of the washed and dried methylene chloride solution gives the compound mentioned in the title; Hydrochloride:
Mp. 205-207 ° (after crystallization from methylene chloride / ether).

/ -09815 / 1130

- 5 * - Case 100-387

SG

Analogously to Example 9 or 10, from the corresponding starting compounds, and using of method b the following compounds:

(3aRS, 4SR, 9aSR) -3a, 4,9,9a-tetrahydro-4-phenyl-benz [fJ isoindoiin

Snip. 136-138 °

(3aRS, -4SR, 9aSR) -6-chloro-4- (4-chlorophenyl) -3a, 4, 9,9atetrahydro-benz [flisoindoiin

133-134 °

(3aRS, 4SR, 9aSR) -6-fluoro-4- (p-fluorophenyl) -3a, 4,9,9atetrahydrobenz [f] isoindoin

M.p. of the hydrogen maleate 134-136 °

(3aRS, 4SR, 9aSR) -7-chloro ~ 4 ~ (m-chlorophenyl) -3a, 4,9,9atetrahydrobenz [f ] isoindoin

Srap. of hydrogen maleate 166 - 168 °

(3aRS, 4SR, 9aSR) -3a, 4,9,9a-tetrahydro-6-methyl-4- (p-to-IyI) -benz [f] isoindoline

M.p. 129-132 ^

(3aRS, 4SR / 9aSR) -3a, 4.9, ga-Tetrahydro-T-methyl-1-phenylbenz [f ] isoindoin

M.p. des Hydrochlorld 225-227 °

409815/1 130

Case 100-3875

Analogously to Example 9, starting from the corresponding starting compounds, and using of method c the following compounds:

(3aRS, 4SR, 9aSR) -3a-4,9,9a-tetrahydro-2-methyl-4-phenylbenzIf] isoindoline

M.p. of the hydrochloride 207-209 °

(3aRS, 4SR, 9aSR) -2-Cyclopropylmethyl ~ 3a, 4,9,9a-tetrahydro-4-phenyl-benz [f] isoindoline .

Mp. _ 65 - 68 '

I O

(3aRS, 4SR, 9aSR) ~ 3a, 4,9,9a-tetrahydro-2-isopropyl-4-phenyl-benz [fjisoindoline

M.p. of the hydrogen maleate - 150-158 °

(3aRS, 4SR, 9aSR} -2- (o-chlorophenethyl) -3ä, 4,9,9a-tetrahydro-4-phenyl-benz [f] isoindoline

Of the hydrogen maleate. 178-179 °

(3aRS, 4SR, 9aSR) -2- (3a, 4, 9, ga-tetrahydro ^ -phenyl-benz [f] isoindolin-2-yl) acetophenone

SmD. 120-130 °

(3aRS, 4SR, 9aSR) -p-fluoro-4- (3a, 4,9,9a-tetrahydro-4-phenyl-benz [f] isoindolin-2-yl) butyrophenone.:

M.p.-81-84 °

. (3aRS, 4SR, 9aSR) -6-chloro-4- (4-chlorophenyl) -3a, 4,9,9a-tetrahydro-2-methyl-benz [f] isoindoline "

133-135 °

(3aRS, 4SR, 9aSR) -6-chloro-4- (4-chlorophenyl) -2-cyclopropylmethyl-3a, 4,9,9a-tetrahydro-benz [f3 isoindoline

M.p. 4098 15/1130 124-126 °

- 57 - 'Case 100-3875

(3aRS, 4SR, 9aSR) -7-chloro-4- (m -chlorophenyl) -3a, 4,9,9atetrahydro-2-methyl-benz [f] isoindoline

* M.p. of the bis (base) naphthalene

1,5-disulfonate 244-248 °

(3aRS, 4SR, 9aSR) -7-chloro-4- (m -chlorophenyl) -2-cyclopropylmethyl-3a, 4,9,9a-tetrahydrobenz [f] isoindoline

M.p. of the bis (base) naphthalene

1,5-disulfonate 243-247 °

(3aRS, 4SR, 9aSR) -3a, 4,9,9a-tetrahydro-2,6-dimethyl-4- (p-tolyl) benz [f3isoindoline

M.p. of the bis (base) naphthalene

1,5-disulfonate 195-198 °

(3aRS, 4SR, 9aSR) ^ - Cyclopropylmethyl-Sa, 4,9,9a-tetrahydro-6-methyl-4- (p-tolyl) -benz [f] isoindoline

M.p. 98-100 °

(3aRS, 4SR, 9aSR) -2- (2-hydroxyethyl) -3a, 4,9,9a-tetrahydro-6-methyl-4- (p-tolyl) -benz [f] isoindoline

M.p. 128-129 °

(3aRS, 4SR, 9aSR) -3a, 4,9,9a-Tetrahydro-2,6-dimethyl-4-phenyl-benz [f] isoindoline

M.p. of the bis (base) naphthalene

1,5-disulfonate 280-283 °

(3aRS, 4SR, 9aSR) ^ - Cyclopropylmethyl-Sa, 4,9,9a-tetrahydro-6-methyl-4-phenyl-benz [f] isoindoline

. Mp of the hydrochloride 198 - 2O4 °

(3aRS, 4SR, 9aSR) -3a, 4,9,9a-tetrahydro-2,7-dimethyl-4-phenyl-benz [f3 isoindoline

M.p. of the bis (base) naphthalene

1,5-disulfonate 244-248 °

409815/1130

100-3875

(3aRS _/ 4SR, 9aSR) -6-chloro-2-cyclopropylmethyl-3a, 4,9 _/ 9a-tetrahydro-4-phenyl-benz [f] isoindoline

(3aRS, 4SR, 9aSR) -2-Ethy1-6-chloro-3a, 4 , 9,9a-tetra ~ hydro-4-phenyl-benz [f] isoindoline

(3aRS, 4SR _f 9aSR) -2-H-BUtYl-G-Chlor-Sa, 4,9,9a-tetrahydro-4-phenyl-benz [f] isoindoline

(3aRS, 4 SR ^ 9 aSR) -6-chloro-2-isopropy1-3a, 4,9,9 a-tetra hydro-4-phenyl-benz [f3 isoindoline

0 9815/1130

- Case 1OO-3875

(3aRS _f 4SR _f 9aSR) -2-Cyclopropylmethyl-3a _/ 4,9,9a-tetrahydro-7-methyl-4-phenyl-benz [f] isoindoline

M.p. 79-82 °

2- ((3aRS, 4SR, 9aSR) -3a, 4,9,9a-tetrahydro-7-methy1-4-phenylbenz [f] isoindolin-2-yl) -p-fluoroacetophenone

M.p. of the hydrogen maleate 164-166 °

(3aRS, 4SR, 9aSR) -6-chloro ~ 3a, 4,9,9a-tetrahydro-2-methyl-4-phenyl-benz Ef] isoindoline

M.p. of the hydrochloride 231-233 °

(3aRS, 4SR, 9aSR) -3a, 4,9,9a-Tetrahydro-2 ~ (p-methylbenzyl) -4-phenyl-benz [f] isoindoline

M.p. 120-121

(3aRS, 4SR, 9aSR) -3a ₇ 4,9,9a-Tetrahydro-2- (p -raethoxybenzyl} -4-phenyl-benz [f] isoindoline

M.p. 95-100 °

Example 11: I3aRS _i 4RS_ _i> 9aSR) _- 3a / .4 _i 9 _i 9a-Tetrahvdro-6-

-4-phenYl2benz [f 2 isoindoline

(Method e, c)

A solution of 0.55 is added at 25 ° to a solution of 35.2 g of (9aRS) -2-benzyl ~ 9,9a-dihydro-6-methyl-4-phenyl-benz [f] isoindoline in 300 ml of ethanol g of palladium (II) chloride and 0.39 g of common salt in 50 ml of water. The mixture is added dropwise at 0 ° with a solution of 2 _f 0 g sodium borohydride in 25 ml of water, stirred for 30 minutes at, tjnd then placed v / ässriger concentrated hydrochloric acid to pH = 2 finally 18 hours at 4 atm / 60 ⁰ hydrogenated. The reaction mixture is filtered, the filtrate is concentrated and the residue is drawn off with hot ethanol

4 0 9 8 15/1130

Case 100-3875

and lets the clear solution cool, with the hydrochloride the compound mentioned in the title with a melting point of 215-220 ° (from methanol / ether) crystallized out.

Example 12:

(Method d, c)

To the suspension of 30 g (9aRS) -2-benzyl-6-chloro-9, 9a ~ dihydro-4-phenyl-benz [f] isoindoline and 46.8 g of red Phosphorus in 400 ml of glacial acetic acid is added dropwise to 190 ml of 57% hydroiodic acid, and the mixture is then added Heated to 110 ° for 5.5 hours, then poured onto ice and made alkaline with sodium hydroxide solution. After extraction with The organic phase is filtered through ethyl acetate, the filtrate is dried and evaporated, whereby the compound mentioned in the title with a melting point of 115-117 ° (after crystallization from pentane) is obtained.

Analogously to Examples 11 and 12, starting from the corresponding starting compounds, and under Using method d or e the following compounds:,

(3aRS, 4RS , 9aSR) -3a, 4.9; 9a-tetrahydro-2 _r 6-dimethyl-4 -phe- nyl-benz [ f] isoindoline M.p. des bis (base; naphthalene- 1,5-disulfonate 183 - 187 °

0 9 8 1 S / 1 1 3 0

Case 100-3875

(3aRS, 4RS, 9aSR) -3a, 4,9,9a-tetrahydro- 2,7-dimethyl-4- 297-303 ° phenyl-benz [f] isoindoline M.p. of the bis (base) naphthalene 1/5 disulfonate 2O4 - 207 ° (3aRS, 4RS, 9aSR) -3a, 4,9,9a-Tetrahydro-2 ~ methyl-4-phe- nyl-benz [f] isoindoline M.p. of the bis (base) naphthalene 1,5-disulfonate

Analogously to Example 11, starting from the corresponding Starting compounds, and using method e or c the following compounds:

(3aRS, 4RS, 9SR) -3a, 4,9,9a-tetrahydro-7 -methy1- 4-phenyl- 265 - 269 ° benz [f] isoindoline M.p. of the hydrochloride 226 - 230 ° (3aRS, 4RS, 9aSR) -3a, 4,9,9a-tetrahydro- 4-phenyl -benz- [f] - isoindoline M.p. of the hydrochloride 256 - 258 ° (3aRS, 4RS, 9aSR) -2-acetonyl-3a, 4,9,9a-tetrahydro-4-phe- nyl-benz [f] isoindoline M.p. of the bis (base) naphthalene
1,5-disulfonate

15/1130

Case 100-3875

Example 13: (3aRS _i 4RS _i 9aSR) _ ^ 6 ~ chlorine-3a _i 4 _i 9 _£ 9a _:: tet; ra2

{Method a)

The mixture of 8.8 g of {3aRS, 4RS, 9aSR) -e-chloro-Sa, 4,9,9atetrahydro-2-phenoxycarbonyl-4-phenyl-benz [f 3 isoindoline, 260 ml of methanol and 42 g of 50% sodium hydroxide solution is under Nitrogen heated to boiling under reflux for 15 hours, then concentrated and diluted with methylene chloride. Evaporation of the washed and dried organic Phap.e gives the compound named in the title from m.p. 144-145 ° {after crystallization from ethanol / pentane) .

The (3aRS, 4RS, 9aSR) -6 ~ used as starting material Chlorine-3a, 4,9,9a-tetrahydro-2-phenoxycarbonyl-4 ~ phenyl ^ benzif3isoindoline can be produced as follows ■:

The solution of 9g (3aRS, 4RS _/ 9aSR) -2-benzyl-6-chlcr-3a, A, 9, 9a ~ tetrahydro-4-phenyl-benz [f 3 isoindoline in 90 ml methylene chloride is at 0 ° with 3, 65 ml of phenyl chloroformate were added, the mixture was stirred for 16 hours at room temperature, then washed with 3N sodium hydroxide solution, 2N hydrochloric acid and water, dried and evaporated. The oily residue is chromatographed on 100 times the amount of silica gel using toluene / ethyl acetate (1: 1), the (3aRS, 4RS, 9aSR) -G-chloro-Sa, 4,9,9a-tetrahydro-2-phenoxycarbonyl -4-phenyl-benz [f3isoindoline of melting point 130 134 ° (after crystallization from ether) is obtained.

4 0 9 a I B / 1 1 3 0

- case 100-3875

Example 14: i9aRS] _ ^ 2-benzyl-9 _i 9a-dih dro-6 _^:; meth2l-

(Method f, d)

To a solution of 27 g of lithium aluminum hydride in 400 ml of tetrahydrofuran, 35 ml of 100% sulfuric acid are added dropwise with stirring under nitrogen at -5 °. The mixture is then stirred for 30 minutes at room temperature, cooled again to -5 ° and within 30 minutes with a solution of 90 g (9aRS> 2-benzyl-9, 9a-dihydro-6-methyl-4-phenyl-benz Ef ] isoindoline-1,3-dione in 1 l of tetrahydrofuran are added.After stirring for 26 hours at room temperature, the reaction mixture is decomposed by adding water and 12% strength sodium hydroxide solution and the precipitate formed is filtered off Methylene chloride was taken up, the filtered solution was evaporated and the residue was crystallized from ether / pentane, giving the compound mentioned in the title with a mp of 139-143 °.

The (9aRS) -2-benzyl ~ used as starting material 9,9a-dihydro-6-methyl-4-phenyl-benz tf] isoindoline-1,3-dione can be produced as follows:

The solution of 35 g of 2,5-dimethylbenzophenone and 317 "5 g of H-Benzylittaleiitiid in 500 ml of acetone or methylene chloride is irradiated with a high pressure mercury lamp through a Pyrex filter until conversion is complete (20 to 130 hours), then filtered and evaporated. The residue after crystallization from ether gives 35 g of 2-benzyl-3a, 4,9,9a-tetrahydro-6-methyl-4-phenyl-benz ~ Ef} isoindolin-4-ol-1 _f 3-dione of melting point 162-164 °, which is dissolved in 170 ml of trifluoroacetic acid. The solution becomes

409815/1130

Case 100-3875

Stirred for 3 hours at 25 ° and evaporated. After crystallization from methylene chloride / Methanol 30 g (9aRS) -2-benzyl-9,9a-dihydro-6-methyl-4-phenyl-benzff] isoindoline-1,3-dione of m.p. 156-158 °.

409 8 15/1 130

Case 100-3875

Analogously to Example 14, starting from the corresponding starting compounds and using method f or d, the following compounds are obtained:

(9aRS) -2-Benzyl-9,9a-dihydro-7-methyl-4-phenyl-benz- [f] isoindoline

M.p. 139-142 °

(9aRS) -2-Benzyl-6-chloro-9,9a-dihydro-4-phenyl-benz- [f3isoindoline

M.p. 266-268 °

(9aRS) -2-Benzyl-9,9a-dihydro-4-phenyl-benz [f] isoin-doline

113-115

(9aRS) -9,9a-Dihydro-4-phenyl-benz [f] isoindoline

M.p. of the hydrochloride 238-243 ° (dec.)

OaRS) -9,9a-Dihydro-2-methyl-4-phenyl-benzC f] isoindoline

M.p. of the hydrogen maleate 158-162 ° (decomp.)

409815/1130

Example 15:

lin (method g)

To the mixture of 7.5 g (3aRS, 4SR, 9aSR) -3a, 4,9,9a-tetrahydro-4-phenyl-benz [f] isoindoline, 7.9 g of pyridine and 100 ml of methylene chloride are 4.7 g of cyclopropylcarboxylic acid chloride at -5 ° added dropwise. The mixture is stirred for 1 hour at room temperature, then one after the other with 10% aqueous citric acid solution and sodium hydrogen carbonate solution shaken over Sodium sulfate dried and evaporated, the residue (3aRS, 4SR, 9aSR) -3a, 4,9,9a-tetrahydro-4-phenyl-benz [f} isoindoline-2-cyclopropylcarboxamide of m.p. 149-151 ° (after crystallization from ether).

To a warm solution of 8.6 g of (3aES, 4SR, 9aSR) -3a, 4, 9,9a-tetrahydro-4-phenyl-benz [f1isoindOlin-2-cyclopropylcarboxamide in 100 ml of tetrahydrofuran, 1 g of lithium aluminum hyärid is added in portions. The mixture is stirred for 1 hour at room temperature, then decomposed with 2N hydroxide solution and filtered. The evaporated FiItrat is with silica gel in benzene / Essigester 1: slurried, filtered and evaporated to 1 to give the title compound, mp 65-68 ⁰ (after crystallization from pentane)..

Analogously to Example 15, one obtains from the corresponding Starting compounds, and using methods g, the following compounds of formula Im:

4 0 9 815/1130

(3aRS, 4SR, 9aSR) -3a, 4.9, Sa-Tetrahydro ^ -methyl- ^ - phenylbenz [f3 isoindoline

M.p. of the hydrochloride 207-209 °

_ (3aRS, 4SR, 9aSR) 7_6-chloro-2-cyclopropyl-methyl-3a, 4,9, 9atetrahydro-4-pheriyl-V) enz7 £ 7is "bindoiiii

M.p. of the hydrogen maleate 150 - 158 *

ι Ο

(3aRS, 4SR, 9aSR) -2- (o-chlorophenethyl) -3a, 4,9,9a-tetra ~ Liydro-4-phenyl-benz [f] isoindoline

M.p. of the hydrogen maleate 178-179 °

(3aRS, 4SR, 9aSR) -ö-chloro - ^ - (4-chlorophenyl) -3a, 4,9,9a-tetrahydro-2-methyl-benz tf] isoindoline

133-135 °

(3aRS, 4SR, 9aSR) -6-chloro-4- (4-chlorophenyl) -2-cyclopropylmethyl-3a, 4,9,9a-tetrahydro-benz [f] isoindoline

M.p. 124-126 °

(3aRS, 4SR ₇ 9aSR) -7-chloro-4- (m-chlorophenyl) -3a, 4,9,9atetrahydro-2-methyl-benz tf] isoindoline

M.p. of the bis (base) naphthalene

1,5-disulfonate 244-248 °

(3aRS, 4SR, 9aSR) -7-chloro-4- (m -chlorophenyl) -2-cyclopropylmethyl-3a, 4,9,9a-tetrahydrobenz [f3isoindoline

M.p. of the bis (base) naphthalene

1,5-disulfonate 243-247 °

(3aRS, 4SR, 9aSR) -3a, 4,9,9a-tetrahydro-2,6-dimethyl-4- (p-tolyl) -benz [f3 isoindoline

M.p. of the bis (base) naphthalene

1,5-disulfonate 195-198 °

40981 R / 1130

(3aRS, 4SR, 9aSR) ^ -Cyclopropylmethyl-Sa, 4,9, 9a-tetrahydro-6-methyl-4- (p-tolyl) -benz [f] isoindoline

M.p. -98-100 °

(3aRS, 4SR, 9aSR) -2- (2-hydroxyethyl) -3a, 4,9,9a-tetrahydro-6-methyl-4- (p-tolyl) ^r -benz [f] isoindoline

M.p. 128-129 °

(3aRS, 4 SR, 9aSR) -3a, 4,9,9a-Tetrahydro-2,6-dimethy1-4-phenyl-benz [f] isoindoline

M.p. of the bis (base) naphthalene

1,5-diuslfonats 280 - 283 °

(3aRS, 4SR, 9aSR) ^ -Cyclopropylmethyl-Sa, 4,9,9a-tetrahydro-6-methyl-4-phenyl-benz [f] isoindoline

. Mp of the hydrochloride 198-204 °

(3aRS, 4SR, 9aSR) -3a, 4,9,9a-tetrahydro-2,7-dimethyl-4-phenyl-benz [f] isoindoline

M.p. of the bis (base) naphthalene

1,5-disulfonate '244-248 °

(3aRS., 4SR, 9aSR) -2-Cyclopropylmethyl-3a, 4,9,9a-tetrahydro-7-methyl-4-phenyl-benz [f] isoindoline

M.p. 79 - 82 ° -

(3aRS, 4SR, 9aSR) -6-chloro-3a, 4,9,9a-tetrahydro-2-methyl-4-phenyl-benz tf] isoindoline

. Mp of the hydrochloride 231-233 °

(3aRS _/ 4SR, 9aSR) -3a, 4,9,9a-tetrahydro-2- (p-methylbenzyl) 4-phenyl-benz [f] isoindoline

M.p. '120 - 121 °

409815/113 0

_x 4SR, 9aSR) -2-ethyl-δ-chloro-Sa, 4,9,9a-tetrahydro-4-phenyl-benz [f] isoindoline

OaRS, 4SR, 9aSR) - ^ - n-Butyl-G-chloro-aa, 4,9,9a-tetrahydro-4-phenyl-benz [£] isoindoline

409815 / 113O

(3aRS, 4SR, 9aSR) -3a, 4,9,9a-Tetrahydro-2-(p-methoxybenzyl) -4-phenyl-benztf] isoindoline

M.p. 95-1OO °

(3aRS, 4RS, 9aSR) -3a, 4,9,9a-Tetrahydro-2-methyl-4-phenyl-benz [f] isoindoline

M.p. of the bis (base) naphthalene

1,5-disulfonate 297-303 °

(3aRS, 4RS, 9aSR) -3a, 4,9,9a-Tetrahydro-2,6-dimethy1-4-phenyl-benz [f] isoindoline

M.p. of the bis (base) naphthalene

1,5-disulfonate 183-187 °

(3aRS, 4RS _r 9a3R) -3a, 4,9,9a-tetrahydro-2,7-dimethyl-4-phenyl-benz [f] isoindoline

M.p. of the bis (base) naphthalene

1,5-disulfate 204-207 °

(3aRS, 4RS, 9aSR) -2 ~ Benzyl-6-chloro-3a, 4,9,9a-tetrahydro-4-phenyl-benz tf] isoindoline

M.p. ■ 115-117 <

(9aRS) -9,9a-Dihydro-2-methyl-4-phenyl-benz [f] isoindoline M.p. of the hydrogen maleate 158-162 ° (-dec.)

(9aRS) -2-Benzyl-9,9a-dihydro-4-phenyl-benz [f] isoindoline M.p. 265-269 °

(9aRS) -2-Benzyl-9,9a-dihydro-6-methyl-4-phenyl-benz [f] -isoindoline

M.p. 139-143 °

(9aRS) -2-Benzyl-9, ga-dihydro ^ -methyl ^ -phenyl-benz- [f] isoindoline

4 0 9 8 15/1130

M.p. 139-142 °

(9aRS) -2-Benzyl-6-chloro-9,9a-dihydro-4-pheny1-benz- [f] isoindoline

M.p. of the hydrochloride: 266-268 '

> O

To illustrate the processes described for the preparation of the required starting compounds, v / ground the following characteristic examples are given:

Example 16:

The solution of 30 g Ν, Ν-bis (trans-p-chlorocinnamyl) -trifluoroacetamide in 600 ml of o-dichlorobenzene is refluxed for 16 hours under an argon atmosphere and then evaporated. Chromatograph the residue on 250 g of silica gel with benzene. The filtrate gives the compound named in the title on evaporation as residue; Mp. 107-112 ° (after crystallization from ether / pentane)

The Ν, Ν-bis (trans-pchlorcinnamyl) used as starting material trif luoroacetamide can be obtained by alkylating N-trans-p-chlorocinnamyl-trifluoroacetamide with transp-chlorocinnamyl bromide be prepared (analogously to Example 6).

0 9 8 1 5/1 1 3 0

Example 17:

3 ^& χ4 _ζ 9 f 9 ^a
isoindoline-2-trifluoroacetamide

The title compound, mp 173 -. {176 ° after crystallization from Äether) as described in Example 6 _r, prepared by thermal cyclization of N, N-bis (trans-pf luorcinnarnyl) trifluoroacetamide.

The Ν, Ν-Bia (trans -pfluorcinnamy.l) required as starting material trif luoracetamide from Srcp. 77 - 79 ° (after crystallization from chloroform) can be based on the example 6 described manner from N-p-Fluoreinnamyl-trifluoroacetainid and p-FTuorcinnamyl bromide.

Example 13?

The compound mentioned in the title is obtained as QeI by thermal cyclization of N _f N-bis (trans-rnr-chlorocinnair.yl5-trifluoroacetamide , as described in Example 6, and obtained by chromatography on silica gel {benzene / ethyl acetate 19: 1) cleaned. The Ν, Ν-Βϊβ (trans-m-chloreinnarayl) -trifluoräeetateid (OeI) required as starting material can be prepared in the manner described in Example 6 from Nm-chlorocinnamyl trifluoroacetamide and m-chlorocinhamyl bromide.

40981 H / 1 13Ö

Example 19:

trifluoroacetamide

The compound mentioned in the title with a melting point of 110-113 ° (after crystallization from ether / pentane) was v / ie in Example 6 described by thermal cyclization of Ν, Ν-bis (trans-p-methylcinnamyl) trifluoroacetamide obtain.

The Ν, Ν-bis (trans-p-irie - thylcinnamyl) trifluoroacetamide (OeI) can be based on the in Example 6 from N-p-methylcinnamyl · · - trifluoroacetamide and p-methylcinnamyl bromide will.

Example 20: I.

Sl2-tr if luoroacetamide

A solution of 218 g of N- (trans-cinnamyl) -N (3-phenyl-2-propynyl) -trif luoroacetamide in 4.4 1 © -dichlorobenzene is refluxed for 5 hours under argon and then evaporated. After crystallization from ether / pentane, the residue gives that described in the title Compound of m.p. 195-197 °.

The N- (trans-cinnamyl) N- (3phenyl-2-propynyl) trifluoroacetamide used as starting material can be obtained by alkylating N- (trans-cinnamyl) -trifluoroacetamide with 1-bromo-3-phenyl-2-propyne getting produced.

4 0 38 15/1130

Example 21:

Example of a pharmaceutical preparation

Tablets

(3aRS, 4SR, 9aSR) -3a, 4,9,9a-Tetrahydro-2-methyl-4-phenyl-benz [f] isoindoline hydrochloride * magnesium stearate
Polyvinyl pyrrolidone talc

Cornstarch
Lactose
Diraethylsxliconol
Polyethylene glycol 6000

* corresponds to 26.3 mg base

The active ingredient is mixed in a known manner with the above auxiliaries and carriers and the mixture is granulated and tabletted in a known manner.

The active ingredient listed for example can be replaced by corresponding amounts of another Active ingredient of the formula I, Iw or Iz, or physiologically acceptable acid addition salts thereof are replaced.

30th , 5 mg 1 , 5 mg 4th mg 5 mg 10 mg 118 mg 0 mg 1 mg 17 0 rag

0 9 8 1 5/1 1 3 0

Claims (1)

Patent claims: 1, Process for the preparation of new compounds of the formula C NO which by definition are also the optical antipodes of the compounds of the formula Ia and also racemic mixtures of these optical antipodes and in which R .. and R, can be identical or different and represent hydrogen, halogen or an alkyl group with 1-4 Carbon atoms represent, X and Y either represent both Are hydrogen, in which case the rings B and C are cis-linked, or X and Y together are an additional Form a bond, and R is alkyl with 1-5 carbon atoms, alkenyl or alkynyl with 3-5 carbon atoms, of which the multiple bond is not in the α-position to the nitrogen atom to which R4 is bonded is substituted by cycloalkyl having 3-6 carbon atoms Alkyl with 1-4 carbon atoms, hydroxyalkyl with 2-5 carbon atoms, phenylalkyl with 7-11 carbon atoms, in the phenyl radical by halogen, alkoxy with 1-4 carbon atoms or alkyl with 1-4 4098 15/113 0 Carbon atoms monosubstituted phenylalkyl with 7-11 carbon atoms, or a radical -A-CO-R ₃ , in which A is alkylene with 1-4 carbon atoms and R _{3 is} alkyl with 1-5 carbon atoms, phenyl, phenyl substituted by halogen, the hydroxy - Or an alkoxy group with 1-4 carbon atoms, means, and their salts, characterized in that one a) compounds of the formula ι Τ ^Λ 2 Ib, The same definitive also includes the optical antipodes of these compounds of the formula Ib, as well as racemic mixtures of these optical antipodes, and in which R, R ₉ , X and Y have the above meaning, N-alkylated by methods known per se and, if desired, all subsequently possible Esters of the formula ~~ 40 98 1 B / 1 1-3-0 N-A-COOAIk Ic, BAD OftiGINAL which clef initionsgemäss the optical antipodes of the compounds of formula Ic sov / ie the re.Gemischen comprises mixtures of these optical antipodes and v.'orin R, R ", X ₁ Y and A have the above meanings and Alk an alky! group of 1- 4 carbon atoms means to compounds of the formula N-A-COOH Id, which, by definition, encompasses the optical antipodes of the compounds of the formula Id as well as the raoeraisehen mixtures of these optical antipodes and in which R,, R ₂ r ^x / ^{Y and A have the} above Beclejutung, hydrolyzed, or b) Compounds of the formula Ib reductively to give compounds the formula ^R 2 4 0 9 8 15/1130 BATH ORIGINAL which by definition also includes the optical antipodes of the compounds of the formula Ie and the racemic mixtures of these optical antipodes, and wherein & _t Rj χ and Y have the above meaning and R _{5 is} a primary or secondary alkyl group with 1-5 carbon atoms, alkyl, or c) compounds of the formula Many, by definition, also have the optical antipodes of the compounds of the formula If and the racemic mixtures of these optical antipodes, and in which R. and R have the above meaning and R is alkyl with 1-5 carbon atoms, alkenyl or alkynyl with 3-5 carbon atoms, of which the multiple bonds are not in ct division to the nitrogen atom stands to which R, Q is linked is, by cycloalkyl of 3-6 carbon atoms substituted alkyl with 1-4 carbon atoms, hydroxyalkyl with 2-5 carbon atoms / Phehylalkyl with 7-11 carbon atoms »in the phenyl radical by halogen, Alkoxy with 1-4 or alkyl with 1-4 carbon atoms monosubstituted phenylalkyl with 7-11 carbon atoms, or a radical A-CO-R ', where A obi- 409815/1130 ge meaning, and Ri, for alkyl with 1-5 carbon atoms, - Phenyl odez * is phenyl substituted by halogen, means, under severe, alkaline ■ conditions to compounds of the formula ^: '-' NO, which, by definition, also represent the optical antipodes of the compounds of the formula Ig as well as the raceric Mixtures of these optical antipodes includes and wherein or Around
2 have the above meaning, transforms, d) compounds of the formula NO. You which by definition are also the optical antipodes
of the compounds of the formula Ih and the racemic ones
Mixtures of these optical antipodes includes and wherein
R ₁ and R _{2 have the} above meaning and R is alkyl with 1-5 carbon atoms, alkyl with 1-4 carbon atoms substituted by cycloalkyl with 3-6 carbon atoms, 4 0 9 815/1130 Phenylalkyl with 7-11 carbon atoms, in the phenyl radical, phenylalkyl with 7-11 carbon atoms monosubstituted by halogen or alkyl with 1-4 carbon atoms, or a radical A-CO-R ₃ , in which A and R _{3 have the} above meanings, means with the aid of Hydroiodic acid / red phosphorus to compounds of the formula Ii, which, by definition, also includes the optical antipodes of the compounds of the formula Ii so; ie the racemic mixtures of these optical antipodes, and in which R ₃ , R ₂ and R are as defined above, hydrogenated, or e) compounds of the formula which, by definition, are the optical antipodes of the compounds of the formula Ij as well as the racemic mixtures of these optical antipodes and in which 4 0 9 8 15/1130 R 'and RI can be identical or different and stand for hydrogen, fluorine or alkyl with 1-4 carbon atoms and R 'alkyl with 1-5 carbon "atoms, alkyl with 1-4 carbon atoms substituted by cycloalkyl with 3-6 carbon atoms, Hydroxyalkyl with 2-5 carbon atoms, Phenylalkyl with 8-11 carbon atoms, the phenyl radical of which is separated by at least 2 carbon atoms from the nitrogen atom, what it is bonded to is separated, in the phenyl radical by halogen, alkoxy with 1-4 carbon atoms or / alkyl monosubstituted with 1-4 carbon atoms Phenylalkyl with 8-11 carbon atoms, whose phenyl radical is replaced by at least 2 carbon atoms from the nitrogen atom, what it is bound to, is separated, means catalytically to compounds of the formula »I-tfÖ Ik, which by definition also the. optical antipodes of the compounds of the formula Ik sov / ie comprises the racemic mixtures of these optical antipodes, and in which Rj, R ^ and R ^ have the above meaning, hydrogenated ,, or 409815/1130 f) compounds of the formula which, by definition, also includes the optical antipodes of the compounds of the formula II as well as the racaric mixtures of these optical antipodes and v / orin R 1 and R 1 have the above meaning and R 1 is alkyl with 1-5. Carbon atoms, alkyl with 1-4 carbon atoms substituted by cycloalkyl with 3-6 carbon atoms, hydroxyalkyl with 2-5 carbon atoms, phenylalkyl with 7-11 carbon atoms ₍ in the phenyl radical with calogen, alkoxy with 1- ^ 4 or alkyl of 1-4 carbon atoms monoüubotituiertes phenylalkyl of 7-11 carbon atoms bedeutetf by reduction / with the aid of a metal _hydride? u compounds of the formula which by definition, also the optical antipodes of the compounds of Formula Iu as well as the racemic mixtures of these optical antipodes and comprises v / orin R, 4 0 9 815/113 0 R “and R _{0 have the} above meaning, reduced or £ ο g) compounds of the formula NCOD IV, v; which, by definition, also includes the optical antipodes of the compounds of the formula IV and the racemic ones Mixtures of these optical antipodes, and where R.J, R, X and Y have the above meanings and D is hydrogen, Alkyl with 1-4 carbon atoms, cycloalkyl with 3-6 carbon atoms, by cycloalkyl ir.it 3-6 Carbon atoms substituted alkyl with 1-3 carbon atoms, Hydroxyalkyl with 1-4 carbon atoms, phenyl, phenylalkyl with 7-10 carbon atoms Halogen, alkoxy with 1-4 carbon atoms or alkyl phenyl monosubstituted with 1-4 carbon atoms, or in the phenyl radical by halogen, alkoxy with 1-4 or lower alkyl with 1-4 carbon atoms .inonosubstituierter Phenylalkyl with 7-10 carbon atoms means, with the help of metal hydrides, to form compounds of the formula NCH D In the, 4 0 9 8 15/1130 which by definition are the optical antipodes of the Compounds of the formula Im and the racemic mixtures this includes optical antipodes and wherein Χ, Y and D have the above meaning, reduced, and the compounds of formula Ia thus obtained as such or as salts wins. 2. Process for the preparation of new compounds of the formula Ib, R. which, by definition, also represent the optical antipodes of these compounds of the formula Ib, as well as racemic Mixtures of these optical antipodes, and wherein R, R-, X and Y are as defined in claim 1 own, and their acid addition salts, characterized in that one ) of compounds of the formula 4 0 9 8 1 5/1 1 3 0 NRg VI, 23Λ8593 which definitionsgeinäss the optical antipodes of the compounds of formula VI as well as the racer African mixtures of the optical antipodes comprises and wherein R, R ', X and Y have the above meaning and R is an electron withdrawing group, di <group R in analogy to known methods splits off, or
b) compounds of the formula "10 VII, which, by definition, also includes the optical antipodes of the compounds of the formula VII as well as the racemic mixtures of the optical antipodes, and in which R _{1 and R 2 have the} above meaning, and R _{10 stands} for the radical R _g , which has the above meaning, or for hydrogen stands, under harsh, alkaline conditions in compounds of the formula 409815/1130 in, which term of definition also includes the optical antipodes of the compounds of the formula In and the racemic units of the optical antipodes and in which R and R have the above meaning, or he converts
c) compounds of the formula R 'H4 which by definition are also the optical 'antipodes of the compounds of the formula Io as well as the racemic mixtures of the optical antipodes, and in which R 'and R' have the meaning given in claim 1 and R. is hydrogen or the benzyl group in the presence of a noble metal catalyst Compounds of the formula Ip, which, by definition, also include the optical antipodes of the compounds of the formula Ip and the racemic ones Mixtures of the optical antipodes. Includes, and 409815/1130 wherein R 'and R' have the above meaning, hydrogenated or
d) compounds of the formula VIII, which by definition are also the optical antipodes of the compounds of ^ Formula VIII and the racemic Comprises mixtures of the optical antipodes, and in which R and R "have the above meaning with the aid of metal hydrides to compounds of the formula which, by definition, also include the optical antipodes of the compounds of the formula Iq and the racemic ones Comprises mixtures of the optical antipodes, and in which R and R_ have the above meaning, reduced and the compounds of the formula Ib thus obtained are obtained as bases or as acid addition salts. 8 15/1130 Process according to claim 1 for the preparation of compounds of the formula Ig, in which R, and R_ have the meaning given in claim 1 and R _ß alkyl with 1-5 carbon atoms, an alkenyl or alkynyl radical with 4 or 5 carbon atoms, the multiple bond of which is not in α - or ß-position, to the nitrogen atom to which R _{ß is} bonded, alkyl with 1-4 carbon atoms substituted by cycloalkyl with 3-6 carbon atoms, hydroxyalkyl with 2-5 carbon atoms, phenyl radical with halogen, alkoxy with 1-4, or alkyl with 1-4 carbon atoms · monosubstituted phenylalkyl 'with 7-11 carbon atoms, or a radical -A-CO-R', in which A has the meaning given in claim 1 and Rl is phenyl or phenyl substituted by halogen, and their Acid addition salts, characterized in that compounds of the formula If, in which R, and R _? have the meaning given in claim 1 and R. has the meaning given in this claim for R _ß , converts, and the compounds of the formula Ig obtained in this way are obtained as a base or as an acid addition salt. 4. The method according to claim 1, characterized in that that one (3aRS, 4SR, 9aSR) -2-acetonyl-3a, 4,9,9atetrahydro-4-phenyl-benz [f] isoindoline or its acid addition salts. 409815/1 1 30 5. The method according to claim 1, characterized in that that one (3aRS, 4SR, 9aSR) -3a, 4,9,9a-tetrahydro-4-phenyl-2- (2-propynyl) -benz [f] iscindoline or its acid addition salts. 6. The method according to claim 1, characterized in that (3aRS, 4SR, 9aSR) -2-cyclopropylmethyl-3a, 4, 9,9a-tetrahydro-6-methyl-4-phenyl-benz [f] isoindoline or its acid addition salts. 7. The method according to claim 1, characterized in that (3aRS, 4SR, 9aSR) -2-cyclopropylraethyl-3a, 4, 9 , 9a-tetrahydro-7-methyl-4-phenyl-benz [f] isoindoline or its Manufactures acid addition salts. 8. The method according to claim 1, characterized in that (3aRS, 4SR, 9aSR) -6-chloro-3a, 4,9,9a-tetrahydro-2-methyl-4-phenyl-benz [f] isoindoline or its acid addition salts. 409815 / 1.130 ?!? 8593 9, compounds of formula C NO I, which by definition are also the optical antipodes of the compounds of the formula I as well as the racial mixtures of the optical antipodes and in which R has hydrogen or the meaning given for R in claim, and R, R, X And Υ have the meaning given in claim 1 and their salts. 10. Compounds of the formula Ig, in which R ₁ , R 1 and R 1. LZ ο have the meaning given in claim 1 and their salts. 11. Medicinal products, characterized in that they contain a compound of the formula I. SANDOZ A.G. 409815 / r 130. / \