FI57748B - ANALOGIFICATION OF THE ANTIDPRESSIVE BENS (F) ISOINDOLINER FRAMSTAELLNING AV NYA ANTIDEPRESSIVA BENS (F) - Google Patents

Description

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(32) (33) (31) Pyy * · *** stuelk «« - Bogird prtorftat 29.09.72 Ο3.Ο8.73 Switzerland-Switzerland (CH) 1U250 / 72, 11305/73 Proven-Styrkt (71) Sandoz AG , Basel, Switzerland-Switzerland (CH) (72) Roland Achini, Basel, Wolfgang Ορροίzer, Riehen, Emil Pfenninger,

Therwil, Switzerland-Schweiz (CH) (7U) Oy Kolster Ab (5U) Analog method for the preparation of new anti-depressant benz / X7-isoindolines - Analogifarfarande för framställning av nya antidepresessiva bens / ijisoindoliner

The invention relates to a process for the preparation of new anti-depressant benz / f / isoindolines of the formula

B

R1 —T B C NR I

E2- (Q] in which R represents hydrogen, alkyl having 1 to 5 carbon atoms, alkenyl or alkynyl having 3 to 5 carbon atoms, the double or triple bond of which is not in the 2 57748 n-position relative to the nitrogen atom to which R is attached , Alkyl of 1 to 1 carbon atoms substituted with 3 to 6 carbon atoms, cycloalkyl, hydroxyalkyl of 2 to 5 carbon atoms, phenylalkyl of 7 to 11 carbon atoms, monosubstituted phenylalkyl of 7 to 11 carbon atoms substituted with 1 to 1 in the phenyl residue, halogen, + alkoxy of carbon atom or alkyl of 1-1 + carbon atom or a residue A-CO-R 1, in which A represents alkylene of 1 to 1 carbon atoms and alkyl of 1 to 5 carbon atoms, phenyl, phenyl substituted by halogen, hydroxy- a Si or alkoxy group having 1 to 1 carbon atoms, R 1 and R 2 may be the same or different and represent hydrogen, halogen or an alkyl group having 1 to 1 carbon atoms, X and Y either represent both hydrogen, in which case the rings B and C are bound to cis position, or X and Y together form an additional bond, and to prepare salts thereof. If the radical R and R 1 represent lower alkyl having 1 to 5 carbon atoms, it has in particular 1 to 1, preferably 1 to 3 carbon atoms.

If R represents an alkyl group having 1 to 1 carbon atoms having a cycloalkyl group having 3 to 6 carbon atoms as a substituent, then its alkyl group has 1 or 2 in particular, and its cycloalkyl group has 3 carbon atoms in particular. A preferred substituent in this series is e.g. a cyclopropylmethyl group.

If the residue R represents a hydroxyalkyl group having 2 to 5 carbon atoms, there are in particular 2 to 1 +, preferably 2 or 3 carbon atoms.

If the residue R represents a monosubstituted phenylalkyl residue of 7 to 11 carbon atoms, optionally substituted by halogen, alkoxy of 1 to 1 carbon atoms or alkyl of 1 to 1 carbon atoms, then this phenylalkyl residue has in particular 7 to 9, preferably 7 or 8 carbon atoms. The possible halogen substituent for this residue is in particular fluorine, chlorine or bromine, preferably fluorine or chlorine. The optional 1-1 + carbon atom of the alkoxy or alkyl substituent of this residue has in particular 1-3, preferably 1 or 2 carbon atoms. If the residue R represents a group A-CO-R 1, then the alkylene group has, if R 4 does not correspond to an optionally substituted phenyl group, in particular 1-3, preferably 1 or 2 carbon atoms.

If R 1 represents phenyl containing a halogen substituent, the halogen substituent is in particular fluorine, chlorine or bromine, preferably fluorine or chlorine.

If the residue R1 represents an alkoxy group having 1 to 1 carbon atoms, then there are in particular 1 or 2, preferably 1 carbon atom.

3,57748

If the residues and / or represent halogen, they mainly mean fluorine, chlorine or bromine, preferably fluorine or chlorine.

If the radicals R 1 and / or R 2 represent an alkyl group having 1 to 4 carbon atoms, they have in particular 1 or 2, preferably 1 carbon atom.

If X is hydrogen, then this may be in the cis or trans position relative to the hydrogen in the 9 «(position).

Particularly preferred compounds of formula I are those of formula

B

lv

R

c wherein X and Y have the meanings given above, R represents hydrogen, alkyl of 1 to 3 carbon atoms, alkenyl of 3 to 5 carbon atoms or alkynyl having no double or triple bond in the «(position relative to the nitrogen atom to which R is bonded, a cyclopropylmethyl, hydroxyethyl, phenylalkyl having 7 or 8 carbon atoms, phenylalkyl having 7 or 8 carbon atoms, the phenyl residue being substituted by fluorine, chlorine, methyl or methoxy, acetonyl, 3-oxobutyl, phen acyl, p-fluorophenyl, 4- (p-fluorophenyl) -4-oxobutyl, and R 1 and R c may be the same or different and represent hydrogen, chlorine, fluorine or methyl, and their acid addition salts.

The compounds of the formula I and their salts are obtained according to the invention by: a) compounds of the formula

B

R 2 - (O) U 57748 wherein R 1, R 2, X and Y have the meanings given above and R 2 represents an electron withdrawing group, the group * 9 * is cleaved off by known methods and, if desired, to prepare compounds having the formula is

B

r 'and u and wherein R 1, R 8, X and Y have the meanings given above and represent alkyl of 1 to 5 carbon atoms, alkenyl or alkynyl having 3 to 5 carbon atoms, the double or triple bond of which is not in the R 1 position relative to the nitrogen atom to which R 1 is attached, alkyl of 1 to 4 carbon atoms substituted with cycloalkyl of 3 to 6 carbon atoms, hydroxyalkyl of 2 to 5 carbon atoms, phenylalkyl of 7 to 11 carbon atoms, monosubstituted phenylalkyl of 7 to 11 carbon atoms having - the substituent is halogen, alkoxy of 1 to 4 carbon atoms or alkyl of 1 to 4 carbon atoms, or the residue A-CO-R 1 in which A and R 2 have the meaning given above, compounds of the formula

B

E2-fO) wherein R1, Rail, X and Y have the meanings given above, are N-alkylated by known methods or b) to prepare compounds of formula Ia, alkylate compounds of formula Ib in a manner known per se, 57748 c) alkyl of formula Ib The compounds of formula are alkylated by reduction to compounds of formula

B

ie wherein Re, Rail, X and Y have the meanings given above and R 1 represents a * "primary or secondary alkyl group having 1 to 5 carbon atoms, or e) compounds of the formula

B

-KK if

H 'I H

wherein R 1 and Railia have the meaning given above and R 1 represents hydrogen, alkyl of 1 to 5 carbon atoms, alkenyl or alkynyl having 3 to 5 carbon atoms, the double or triple bond of which is not in the 6t position relative to the nitrogen atom to which R * 6 is bonded, alkyl having 1 to 1 carbon atoms substituted by cycloalkyl having 3 to 6 carbon atoms, hydroxyalkyl having 2 to 5 carbon atoms, phenylalkyl having 7 to 11 carbon atoms, monosubstituted phenylalkyl having 7 to 1 carbon atoms substituted by halogen at the phenyl residue , 1-1 * carbon atom alkoxy or 1-1 * carbon atom alkyl, or a residue A-CO-R '^, wherein A has the meaning given above and R' ^ represents 1-1 * carbon atom alkyl, phenyl, a halogen substituent phenyl or electron-withdrawing group is converted under strong alkaline conditions to compounds of formula 57748 6

ΥΓ \ H

which, by definition, also includes optical antipodes of compounds of formula Ig and racemic mixtures of these optical antipodes, and wherein R 1 and Railia have the above meanings and R 2 has the same meaning as R 8 except for the electron withdrawing group, wherein R 2 is an electron an attractive group, this is cleaved off, or e) compounds of formula

B

__ I

R '<011JR7 is R2- {0] wherein R1 and Rasila are as defined above and R1 is alkyl of 1 to 5 carbon atoms, alkyl of 1 to U carbon atoms substituted by cycloalkyl of 3 to 6 carbon atoms, phenylalkyl of 7 to 11 carbon atoms Monosubstituted phenylalkyl of 7 to 11 carbon atoms in which the phenyl residue is substituted by halogen or alkyl of 1 to U carbon atoms, or a residue A-CO-R 1 in which A and R 1 are as defined above, is hydrogenated with a mixture of hydroiodic acid and red phosphorus to give with the formula

B

R 1 -φΤ φ 11 R 2 ~ (0] 7 57748 wherein R 1, R 8 and R 2 have the meaning given above, or f) compounds of formula

B

»R; 1 R 10) wherein R 1 and R 12 may be the same or different and represent hydrogen, fluorine or alkyl of 1 to 4 carbon atoms and R 1 'represents hydrogen, alkyl of 1 to 5 carbon atoms, alkyl of 1 to 4 carbon atoms having a substituent Cycloalkyl of 3 to 6 carbon atoms, hydroxyalkyl of 2 to 5 carbon atoms, benzyl, phenylalkyl of 8 to 11 carbon atoms having a phenyl residue at least two carbon atoms away from the nitrogen atom to which it is attached, 8 to 11 carbon atoms as monosubstituted phenyl alkyl having 1 to 11 carbon atoms carbon-alkoxy or alkyl having 1 to 4 carbon atoms and having a phenyl residue at least two carbon atoms away from the nitrogen atom to which it is attached is hydrogenated in the presence of a noble metal catalyst to give compounds of formula

B

r 4H01 Ik R * HO) in which R '^, Rasila and R' ^ have the meanings given above, the optionally present benzyl group being cleaved off or 8 57748 g) compounds of the formula H 0 ° in which Ritila and Railia are as defined above said meaning and Rg denotes alkyl having 1 to 5 carbon atoms, alkyl having 1 to U carbon atoms having 3 to 6 carbon atoms as cycloalkyl, hydroxyalkyl having 2 to 5 carbon atoms, phenylalkyl having 7 to 11 carbon atoms, monosubstituted phenylalkyl having 7 to 11 carbon atoms, halogen, 1-U-carbon alkoxy or 1-U-carbon-alkyl as a scavenger, is reduced by means of a metal hydride to give compounds of formula 4j in which R1, R1 and R8 have the meanings given above, or h) compounds of formula

B

9,57748 wherein R 1, R 2, X and Y have the meanings given above and D represents hydrogen, alkyl having 1 to 4 carbon atoms, cycloalkyl having 3 to 6 carbon atoms, alkyl having 1 to 3 carbon atoms having a substituent Cycloalkyl of 3 to 6 carbon atoms, hydroxyalkyl of 1 to 4 carbon atoms, phenyl, phenylalkyl of 7 to 10 carbon atoms, monosubstituted phenyl substituted by halogen, alkoxy of 1 to 4 carbon atoms or alkyl of 1 to 4 carbon atoms monosubstituted by 7 to 10 carbon atoms, monosubstituted halogen, alkoxy of 1 to 4 carbon atoms or lower alkyl of 1 to 4 carbon atoms, is reduced with metal hydrides of the formula

B

R 2 - (O) wherein R, R 1, X, Y and D have the meanings given above, and the compounds of formula I thus obtained are recovered as such or as their salts.

Reference is made below to the methodological details which, for reasons of expediency, must be taken into account in the preparation of the compounds of the formula Ib according to the invention.

a) Suitable electron-withdrawing groups R 1 are, for example, "acyl groups such as a trifluoroacetyl group, a benzoyl group, an aliphatic or aromatic sulfonyl group, for example a tosyl group, a (lower) alkoxycarbonyl residue such as a methoxy or ethoxycarbonyl group, or a phenoxycarbonyl group.

Cleavage of the group according to the invention is carried out, for example, by hydrolysis of an alkali metal hydroxide, such as sodium or potassium hydroxide, with a 1 to about 5 normal solution of a lower molecular alkanol, mainly a methanol or ethanol solution.

If R 1 is a readily cleavable acyl group, for example a trifluoroacetyl group, then the hydrolysis may take place at room temperature or slightly above. The hydrolysis is then complete after about 1/2 to about 3 hours.

10 57748

If there is a less easily cleavable acyl group, for example a phenoxycarbonyl group, it is most conveniently carried out by heating, mainly at a temperature below the boiling point of the reaction mixture. The reaction then takes about 10 to about 20 hours.

If R 1 corresponds to an aliphatic or aromatic sulfonyl group, then this group can be cleaved e.g. under reducing conditions - by known methods e.g. sodium ammonia or phenol in 40% hydrobromic acid.

The hydrolysis of the compounds of formula VI can also take place under acidic conditions, e.g. with 2N hydrochloric acid, most suitably at a higher than normal temperature, mainly at the boiling point of the reaction mixture.

The optional N-alkylation can then be carried out as described in b).

b) The N-alkylation of compounds of formula Ib can be carried out with compounds of formula

ER ^ V

wherein R1 has the meaning given above and E is an acid residue of a reactive ester, or also reactive derivatives of compounds of formula V.

In the compounds of formula V, E denotes, for example, halogen, such as chlorine, bromine or iodine, or an acidic residue of an organic sulphonic acid, for example an alkylsulfonyloxy residue, such as methylsulfonyloxy residue, or an arylsulfonyloxy residue, such as phenylsulfonyloxy or p-tolylsulfonyloxy residue.

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

The reaction temperature may range from room temperature to about 100 ° C. The reaction time depends in particular on the reaction temperature and the reactivity of the compounds of formula V and is from about 1 to about 16 hours.

Suitable reactive derivatives of the compounds of formula V include e.g. , β-unsaturated carbonyl compounds when a residue A-CO-R 2, wherein A is a group CH 8 -CH 2 and Railia has the meaning given above, and ethylene oxide when a hydroxyethyl group is attached thereto.

The reaction of the compounds of formula Ib with β-unsaturated carbonyl compounds such as methyl vinyl ketone, acrylic acid (lower) alkyl ester is most conveniently carried out in a suitable organic solvent, for example a low molecular weight alkanol such as methanol, ethanol, and using stirring. The reaction temperature may vary between room temperature and the boiling point of the reaction mixture, the reaction mixture is preferably heated to about 1 * 0-80 ° C. The reaction time depends in particular on the reaction temperature and the reactivity of the unsaturated carbonyl compounds 57748 and is about 1 to 5 hours.

The reaction of the compounds of formula Ib with ethylene oxide also takes place according to known methods and is clarified in Example 5. The work is carried out under reaction conditions in a neutral solvent and under cooling. The reaction takes about 10-20 hours.

c) Reduction alkylation of compounds of formula Ib to compounds of formula Ie can be carried out according to known methods.

For example, the compounds of formula Ib are alkylated with the corresponding aldehydes or ketones in the presence of formic acid (Leuckart-Wallach method).

The reduction alkylation can also be performed by hydrogenation, i. by means of hydrogen gas in the presence of a noble metal catalyst such as Raney nickel, palladium, etc. In this embodiment, however, the compounds of the formula Ib are known to reduce, at least in part, the possible chlorine, bromine or iodine substituents, as well as in the compounds of the formula Ib 3a, the possible additional bond in the i + position. For the alkylation by reduction of the latter compounds, it is therefore recommended to use the above-mentioned Leuckart-Wallach method.

In the Leuckart-Wallach reaction, the work is carried out in a suitable organic solvent, mainly in excess formic acid, at a higher than normal temperature, most preferably at boiling temperature.

The catalytic reduction alkylation is performed in a suitable organic solvent, for example a low molecular weight alkanol such as methanol, most preferably at room temperature.

d) The conversion of compounds of formula If to compounds of formula Ig takes place under strongly temporal conditions, i. using strong bases, for example potassium hydroxide or potassium tert-butylate and / or at a higher temperature than normal, for example about 100-200 and / or over a long period of time, for example 1-7 days.

Highly suitable reaction media for carrying out this reaction include a saturated solution of potassium hydroxide in n-butanol (about 1% by weight), a boiling point of 1 to 7, or a dimethyl sulfoxide solution of potassium tert-butylate (1 to 7 days at 25 to 30 ° C). .

Process d) is particularly suitable for the preparation of compounds of formula Ig in which the residue Rg represents an alkyl of 1 to 5 carbon atoms, an alkenyl or alkynyl residue of 1 + -5 carbon atoms and in which the multiple bond is not in the o (- or / 4) position relative to the nitrogen atom to which Rg is bonded, 1-U alkyl having 3 to 6 carbon atoms as a substituent, mainly 5 "or 6-carbon cycloalkyl, 2 to 5 carbon atoms hydroxyalkyl, 7 to 11 carbon atoms phenylalkyl, 7 to 11 carbon atoms monosubstituted phenylalkyl having phenyl is substituted by halogen, 1-1 + alkoxy of carbon atom, or alkyl of 1-1 + carbon atom, or a residue A-CO-RJ ^ »wherein Ailia has the meaning given above and R * 2 corresponds to phenyl or phenyl having halogen substituent.

e) The hydrogenation of the compounds of formula Ih to the compounds of formula II with hydroiodic acid and red phosphorus can be carried out by known methods. In this case, for example, an aqueous solution of hydroiodic acid is added dropwise to a solution or suspension of a mixture of a compound of formula Ih and red phosphorus in a suitable solvent or suspension medium, such as acetic acid. The reaction mixture thus obtained is most conveniently heated to, for example, 80-120 ° C. The reduction takes about k-6 hours under the above conditions.

f) The catalytic hydrogenation of the compounds of the formula Ij to the compounds of the formula Ik can take place by known methods. Suitable catalysts are precious metal catalysts such as palladium and Raney nickel. The hydrogenation is carried out in an organic solvent, for example a low molecular weight alkanol such as methanol or ethanol.

The hydrogenation is carried out at a low overpressure, for example at a pressure of about 2 to 6 atoms, and at a higher than normal temperature, for example at about 60 ° C.

In a preferred embodiment, the hydrogenation is carried out in the reaction mixture itself - palladium (II) chloride and sodium borohydride - in the presence of a palladium catalyst.

g) The reduction of the compounds of formula II with a metal hydride can take place by the same known methods used for the reduction of imides.

In this case, for example, a solution of aluminum hydride or dialkylaluminum hydride is preferably added to a solution of compounds of the formula II under reaction conditions in a neutral organic solvent, for example a cyclic or open-chain ether such as tetrahydrofuran, under the same reaction conditions. 20-30 hours at room temperature or higher. The reduction can also be carried out, for example, with a lithium aluminum hydride / aluminum chloride mixture. If the compounds of the formula II have no chlorine, bromine or iodine substituents at all, the reduction can also take place by means of hydride complexes, for example a luminium hydride complex such as lithium aluminum hydride or a lithium aluminum hydride-aluminum chloride complex. These embodiments can be performed under the same process conditions described for reduction with aluminum hydride.

, 3,57748 h) The reduction of amides of the formula IV with metal hydrides can also be carried out by known methods.

Suitable metal hydrides are, for example, aluminum hydride, dialkylaluminum hydride and, if the compounds of the formula IV have no chlorine, bromine or iodine substituents at all, also lithium aluminum hydride or lithium aluminum hydride / aluminum chloride.

Suitable solvents are those which are neutral under the reaction conditions, for example cyclic or open-chain ethers such as tetrahydrofuran.

The reduction can be performed at room temperature and is usually complete after about 1 1 / 2-5 hours.

The compounds of formula Ia obtained by the above-mentioned methods can be isolated and purified by known methods.

The compounds of formulas II, IV and VI are also novel compounds.

Compounds of formula II can be obtained, for example, by condensing compounds of formula

Rr-0 x R2 ~ (0) wherein R and Railia have the above meanings, with compounds of formula 0

A

NRg XI

V

0 wherein Rg has the meaning given above, to compounds of formula 1Π 57748

H O

xn Η ° · ΤΓί wherein Re, Rail and Rg have the above meanings, and by cleaving water from the compounds of formula XII thus obtained.

Condensation of compounds of formula X with compounds of formula XI is accomplished at room temperature by irradiating a solution of these compounds under reaction conditions in a neutral solvent such as acetone or a chlorinated aliphatic hydrocarbon such as methylene chloride. The reaction takes about 20-200 hours.

The compounds of formula XII can be dehydrated by known methods with organic or inorganic acids.

Suitable organic acids include, for example, aliphatic or aromatic sulfonic acids, trifluoroacetic acid, trichloroacetic acid, formic acid and suitable inorganic acids such as sulfuric acid, hydrochloric acid, perchloric acid, phosphoric acid and the like.

Depending on the type and concentrations of acids, the reaction time is from about 1 to about 15 hours. The cleavage of water occurs easily with concentrated strong acids such as sulfuric acid and trifluoroacetic acid at room temperature, with dilute or weaker acids it is recommended that the reaction mixture be heated.

In this case, for example, the compounds of the formula XII are dissolved in an organic acid such as trifluoroacetic acid and the reaction mixture is stirred for about 2 to 5 hours at a temperature of about 20 ° C to 0 ° C.

Compounds of formula IV may be prepared by known methods by acylation of the corresponding compounds of formula Ib, for example using the corresponding acid halides, preferably the corresponding chlorides or bromides, or the corresponding acid anhydrides. Possible N-formylation also takes place by known methods.

15 57748 Most of the compounds of formula VI can be synthesized - as described below - directly by cyclization of the appropriate amides. a1) Compounds of formula

B

R 1 via R 2 - (O) wherein R 1, R 2 and R 2 have the meanings given above can be obtained by thermal cyclization of compounds of the formula. the meaning mentioned above.

The thermal cyclization of the compounds of formula XIII can take place in a neutral organic solvent, preferably a solvent having a high boiling point, for example dichlorobenzene. The work is most conveniently performed under oxygen protection and heating the reaction mixture for about 1 to about 6 hours at about 160-190 ° C.

The compounds of formula Via thus obtained can, as already described, be deacylated to the corresponding NH compounds and, if desired, catalytically hydrogenated. In the latter case, it must be taken into account that at least some of the possible chlorine, bromine or iodine substituents are also reduced.

16 Σ 57748 b) Compounds of formula

B

R 1 -NCOOR 4 VIb v (Ό) wherein R 1 and R 2 have the meaning given above, and R 1 represents a lower alkyl or phenyl group, can be prepared, for example, by benzylating the compounds of formula VIa by known methods, hydrogenating the N-benzyl compounds thus obtained with a mixture of hydroiodic acid / red phosphorus, by known methods, and then substituting a benzyl group with a group COOR 2, in which R 2 represents the same as above.

c1) Compounds of formula

B

where R 1, R 2 and R 2 are as defined above, can be prepared, for example, by modifying the compounds of formula VIb under temporal conditions, i. with strong bases, for example potassium hydroxide or potassium tert-butylate, and / or at an elevated temperature, for example at about 100-200 ° C and / or after a long reaction time, for example after 1-7 days.

Substitution of the benzyl group can also take place according to known methods, for example by reaction with the corresponding chlorocarboxylic acid esters.

17 57748 d) Thermally cyclizing compounds of the formula Ι '^ - Λ

2 NRg XIII

wherein Rg has the meaning given above and either R "1 represents hydrogen and R" 2 represents hydrogen, halogen or an alkyl group having up to U carbon atoms, or R "^ represents halogen or an alkyl group having 1-H carbon atoms and R" represents hydrogen , compounds of formula

B

Β „) θζ ^ 3> 9 VIä

Hs H R 2 which by definition also comprises optical antipodes of the compounds of the formula VId and racemic mixtures of optical antipodes, and in which R ", R 1 and R 8 have the meanings given above.

Thermal cyclization of compounds of formula XIII can be performed under the conditions described in connection with method a. However, the reaction usually requires a little more time (16-30 hours).

The compounds of formulas I, II, IV, VI, and XII by definition also include optical antipodes of these compounds as well as racemic mixtures of optical antipodes.

The compounds prepared by the above method can be isolated in a conventional manner and purified by known methods.

57748 18

Unless the preparation of the starting compounds is described, these are known or can be prepared by known methods or according to the methods described herein or according to methods known per se.

The compounds of formula I and their pharmaceutically acceptable acid addition salts have interesting pharmacodynamic properties and can therefore be used as medicaments.

In animal experiments, in particular, drug effects characteristic of antidepressants were found. Thus, at a dose of about 2 mg / kg to about 30 mg / kg, the compounds of the invention alleviate the cataleptic condition (Haltestarre) induced in rats by administration of tetrahenazine (tetrabenazine antagonism).

Due to their antidepressant effect, they are suitable for the treatment of depressive conditions. The size of the dose to be administered for the above purpose depends on the compound to be used and the mode of administration as well as the mode of treatment. Satisfactory results are generally obtained when the compounds of the formula I or their physiologically acceptable acid addition salts are administered from approximately 1 to about 30 mg / kg (per kilogram of animal weight). For larger mammals, a daily dose of about 50 to about 500 mg is recommended. This daily dose may also be administered in smaller doses, e.g. 2-k times a day, or as a delayed dose. A single dose, e.g., a tablet suitable for oral administration, may contain from about 12.5 to about 250 mg of active ingredient in association with suitable pharmaceutically neutral excipients.

The compounds of the formula I or their physiologically tolerable acid addition salts can be administered as medicaments as such or in a suitable pharmaceutical form in connection with excipients.

The above properties are particularly strong with (3aRS, LSR, 9 & SR) -tetrahydrobenz / f / isoindolines of formula I or Iw. Of the latter compounds, the compounds of the formula have a particularly interesting effect

H, H

P

R

cr 19 57748 wherein R 1 is hydrogen, methyl, 2-propynyl, chloropropylmethyl or a.. I. I. .

acetonyl and R 1 and R 2 are hydrogen, methyl, or chlorine.

In the following examples, which further illustrate the invention, all temperatures are expressed in degrees Celsius and are uncorrected.

Example 1: (3aRS, ltSR, 9aSR) -2-Acetonyl-3a, it, 9, 9a-tetrahydro-it-phenyl-Benz s-Z- [7-isoindoline (method b)

To a mixture of 10 g of (3aRS, itSR, 9aSR) -3a, 4,9,9a-tetrahydro-1-phenyl-benzoisoindoline, 8.5 g of sodium carbonate, 0.2 g of sodium iodide and 80 ml of dimethylformamide are added dropwise 100 A stirred solution of 3.76 g of chloroacetone in 35 ml of dimethylformamide at 0 ° C. The reaction mixture is stirred for a further 2 hours at 100 ° C and then evaporated to dryness under high vacuum. The residue is shaken with methylene chloride and 2N sodium hydroxide. The organic phase is dried and evaporated to dryness, activated carbon is added to the residue dissolved in ether, the solution is filtered and evaporated to dryness and the residue is crystallized from ether / pentane to give the title compound, m.p. is 106-108 °.

The preparation of (3aRS, USR, 9aSR) -3a, 1 *, 9,9a-tetrahydro-U-phenyl-benzo [7] isoindoline has been described e.g. in Example 6.

According to Example 1, using the corresponding starting compounds, compounds of formula Ib are obtained by alkylation (according to method b) of the following formula

Ia corresponding compounds: (3aRS, i + SR, 9aSR) -3a, U, 9,9a-Tetrahydro-2-methyl-U-phenyl-benzo [d] isoindoline hydrochloride m.p. 207-209 °.

(3aRS, 1SR, 9aSR) -2-Allyl-3a, 1,9,9a-tetrahydro-it-phenyl-benzo [f] ioindoline hydrochloride m.p. 187-190 °.

(3aRS, itSR, 9aSR) -2-Cyclopropylmethyl-3a, it, 9,9a-tetrahydro-it-phenyl-benzo [b] isoindoline m.p. 65-68 °.

(3aRS, itSR, 9aSR) -3a, it, 9,9a-Tetrahydro-2-isopropyl-it-phenyl-benzo [thioisoindoline hydrogen maleate m.p. 150-158 °.

(3aRS, itSR, 9aSR) -3a, it, 9,9a-Tetrahydro-t-phenyl-2- (2-propynyl) benzylffolindoline mp 93-95 °.

(3aRS, itSR, 9aSR) -2- (o-Chlorophenethyl) -3a, it, 9,9a-tetrahydro-it-phenyl-benzo {biso-indoline hydrogen maleate m.p. 178-179 ° · (3aRS, itSR, 9aSR) -2- (3a, lt, 9,9a-Tetrahydro-it-phenyl-benzo [7] isoindolin-2-yl) -acetophenone m.p. 120-130 °.

(3aRS, 9aSR) -p-Fluoro-lt- (3a, it, 9,9a-tetrahydro-it-phenyl-benzo [f] isonindolin-2-yl) -butyrophenone m.p. 8l-8it °.

(3aRS, itSR, 9aSR) ~ 3a, it, 9,9a-Tetrahydro-2- (p-methylbenzyl) -N-phenyl-benzoisoindoline m.p. 120-121 °.

(3aRS, 1SR, 9aSR) -3a, It, 9,9a-Tetrahydro-2- (p-methoxybenzyl) -it-phenyl-benzo [b] isoindoline m.p. 95-100 °.

57748 20 (3aRS, USR, 9aSR) -6-chloro-3a, U, 9,9a-tetrahydro-2-methyl-1 '- (U-chlorophenyl) -benz [b] isoindoline m.p. 133-135 °.

(3aRS, 1 + SR, 9aSR) -6-chloro-U- (U-chlorophenyl) -2-cyclopropylmethyl-3a, 1+, 9,9a-tetrahydro-benzo [b] isoindoline m.p. 12 ^ -126 °.

(3aRS, 1 + SR, 9aSR) -2-Acetonyl-6-chloro-1- (U-chlorophenyl) -3a, 9,9a-tetrahydro-benzo [b] isoindoline

Bis (base) naphthalene-1,5-disulfonate m.p. 305-307 °.

(3aRS, SR, 9aSR) -7-Chloro-U- (m-chloro-phenyl) -3a, U, 9,9a-tetrahydro-2-methyl-benzo [C] isoindoline

Bis (base) naphthalene-1,5-disulfonate m.p. 2U1 »-2U8 °.

(3aRS, USR, 9aSR) -2-acetonyl-7-chloro-U- (m-chlorophenyl) -3a, U, 9,9a-tetrahydro-benz / f7isoindoliini

Bis (base) naphthalene-1,5-disulfonate m.p. 266-269 °.

(3aRS, 1 + SR, 9aSR) -7-Chloro-1 + - (m-chlorophenyl) -2-cyclopropylmethyl-3a, U, 9,9a-tetrahydro-benzo [f] isoindoline

Bis (female) naphthalene-1,5 ′ disulfonate m.p. 3-21 * 2 ^ 7 °.

(3aRS, 1 + SR, 9aSR) -3a, b, 9,9a-Tetrahydro-2,6-dimethyl-U- (p-tolyl) benz [7i] indole-line

Bis (base) naphthalene-1,5-disulfonate m.p. 195-198 °.

(3aRS, 1 * SR, 9aSR) -2-Cyclopropylmethyl-3a, U, 9,9a-tetrahydro-6-methyl-1H - (p-tolyl) -benz [f] isoindiline m.p. 98-100 °.

(3aRS.USR ^ aSRj-Sa, *, 9,9a-tetrahydro-6-methyl-2- (3-methyl-but-2-enyl) -U- (p-tolyl) -benz 2C / isoindoline hydrochloride m.p. 197-207 ° (decomposes).

(3aRS, 1 + SR, 9aSR) -3a, 1+, 9,9a-Tetrahydro-2,6-dimethyl-U-phenyl-benzo [f] isoindoline Bis (base) naphthalene-1,5-disulfonate m.p. 280-283 ° · (3a, USR, 9aSR) -2-acetonyl-3a, U, 9,9a-tetrahydro-6-methyl-U-phenyl-benzo [f] isoindoline

Bis (base) naphthalene-1,5-disulfonate m.p. 295-301 °.

(3aRS, 1 * SR, 9aSR) -2-Cyclopropylmethyl-3a, U, 9,9a-tetrahydro-6-methyl-U-phenyl-benzo [7] indoline hydrochloride m.p. 198-200 ° ^.

(3aRS, 1 * SR, 9aSR) -3a, 4,9,9a-Tetrahydro-2,7-dimethyl-U-phenyl-benzo [5-isoindoline] Bis (base) naphthalene-1,5-disulfonate m.p. 2l * U 2lt8 °.

(3aRS, 1SR, 9aSR) -2-Acetonyl-3a, U, 9,9a-tetrahydro-7-methyl-U-phenyl-benzo [f] isoindoline

Bis (base) naphthalene-1,5-disulfonate m.p. 295-299 °.

(3aRS, i + SR, 9aSR) -3a, 4,9,9a-Tetrahydro-2- (3-methyl-but-2-enyl) -U-phenyl-benz7H7-isoindoline (m.p. 163-168 ° of hydrogen maleate).

(3aRS, 4SR, 9aSR) -3a, 4,9,9a-Tetrahydro-6-methyl-2- (3-methylbut-2-enyl) -U-phenyl-benzo [e] isoindoline hydrochloride m.p. 205-207 °.

(3aRS, 1SR, 9aSR) -3a, 1t, 9,9a-Tetrahydro-6-methyl-1 * -phenyl-2- (2-propionyl) -benz [f] isoindoline, m.p. 90-93 °.

21,57748 (3aRS, 1 + SR, 9aSR) -6-Chloro-2-cyclopropylmethyl-3a, 1 +, 9,9a-tetrahydro-1 + -phenyl-benzoisoindoline hydrochloride m.p. 208-210 °.

(3aRS, 1 + SR, 9aSR) -6-chloro-3a, 1 +, 9,9a-tetrahydro-1 + -phenyl-2- (2-propynyl) -benz [f] -isoindoline hydrochloride m.p. 127-130 °.

(3aRS, 1 + SR, 9aSR) -6-chloro-3a, U, 9,9a-tetrahydro-2- (3-methylbut-2-enyl) -1 + -phenyl-benzo [f] isoindoline hydrochloride m.p. 239-21 + 0 °.

(3aRS, 1 + SR, 9aSR) -2-Ethyl-6-chloro-3a, 1 +, 9.9a-tetrahydro-1 + -phenyl-Benz s / E7ioindoline hydrochloride m.p. 198-200 °.

(3aRS, 1 + SR, 9aSR) -2-n-Butyl-6-chloro-3a, 1 +, 9,9a-tetrahydro-U-phenyl-benzo [7] isoindoline fumarate m.p. 161 + -165 degrees.

(3aRS, 1 + SR, 9aSR) -6-Chloro-2-isopropyl-3a, 1 +, 9,9a-tetrahydro-U-phenyl-benzo [7] isoindoline hydrochloride m.p. 21 + 3-21 + 1 +.

(3aRS, 1 + SR, 9aSR) -2- (but-2-ynyl) -3a, 1 +, 9,9a-tetrahydro-1 + -phenyl-Benz s / tisoisoindoline hydrogen maleate m.p. 105-108 °.

(3aRS, 1 + SR, 9aSR) -3a, 1 +, 9,9a-Tetrahydro-2- (p-methoxy-benzyl) -U-phenyl-benzyl-7-isoindoline m.p. 95-100 °.

(3aRS, 1 + SR, 9aSR) -2- (but-2-enyl) ~ 3a, 1 +, 9.9a-tetrahydro-1 + -phenyl-benzo Q] isoindoline (3aRS, 1 + SR, 9aSR ) -2-cyclopropylmethyl-3a, 1 +, 9,9a-tetrahydro-7-methyl-1 + -phenylbenz [E] isoindoline mp · 79-02 °.

2- (3aRS, 1 + SR, 9aSR) -3a, h, 9, 9a-Tetrahydro-7-methyl-1 + -phenyl-benzo [XJ] indol-2-yl) -p-fluoroacetophenone hydrogen maleate m.p. 16i + 166 °.

(3aRS, 1 + SR, 9aSR) -6-Chloro-3a, 1 +, 9,9a-tetrahydro-2-methyl-1 + -phenyl-benzo [f] isoindoline hydrochloride m.p. 231-233 °.

(3aRS, 1 + RS, 9aSR) -3a, 1+, 9,9a-Tetrahydro-2-methyl-1 + -phenyl-benzo [indole] indoline Bis (base) naphthalene-1,5-disulfonate m.p. . 297-303 °.

(3aRS, 1 + RS, 9aSR) -2-Acetonyl-3a, 1 +, 9,9a-tetrahydro-1 + -phenyl-benzo [f] isoindoline Bis (base) naphthalene-1,5-disulfonate m.p. 265-269 °.

(3aRS, 1 + RS, 9aSR) -3a, 1 +, 9.9a-Tetrahydro-2,6-dimethyl-1 + -phenyl-benzo [f] isoindoline Bis (base) naphthalene-1,5-disulfonate m.p. 183-187 °.

(3aRS, 1 + RS, 9aSR) -3a, 1 +, 9,9a-Tetrahydro-2,7-dimethyl-1 + -phenyl-benzo [7] isoindoline Bis (base) naphthalene-1,5-disulfonate m.p. 201 + -207 degrees.

(3aRS, 1 + RS, 9aSR) -2-Benzyl-6-chloro-3a, 1 +, 9,9a-tetrahydro-1 + -phenyl-benzo [f] isoindoline m.p. 115-117 ° · (9aRS) -2-Benzyl-9,9a-dihydro-6-methyl-1 + -phenyl-benzo [f] isoindoline m.p. 139-11 + 3 °.

(9aRS) -9,9a-Dihydro-2-methyl-1 + -phenyl-3H-benzo [f] isoindoline hydrogen maleate m.p. 158-162 ° (decomposes).

57748 22 (9aRS) -2-Benzyl-9,9H-dihydro-7-methyl-1-phenyl-benzo [f] isoindoline m.p. 139-1 ^ 2 °.

(9aRS) -2-Benzyl-9,9a-dihydro-1-phenyl-benzo [a] isoindoline m.p. 113-115 °. (9aRS) -2-Benzyl-6-chloro-9,9a-dihydro-1'-phenyl-benzo [5'-isoindoline m.p. 266-268 °.

Methods for preparing the required starting compounds are described in Examples 6, 9, 10, 11, 12, 13 and 20.

The following examples illustrate other process variants according to method b:

Example 2: (3aRS, USR, 9aSR) -C- (3aβ, 9,9a-Tetrahydro-1H-phenyl-benzo [f] isoindolin-2-yl) -2-butanone (Variation of Method b)

A solution of T, bg (3aRS, USR, 9aSR) -3a, 1 *, 9,9a-tetrahydro-U-phenyl-benzo [c] isoindoline in 60 ml of ethanol is boiled after the addition of 3 ml of methyl vinyl ketone, at reflux for 1 1/2 hours and then evaporated to dryness. The residue is chromatographed on ethyl acetate using silica gel. The filtrate is dried by evaporation of the title compound as an oily residue.

Hydrogen maleate m.p. 121-121 ° (after crystallization from ethanol).

Example 3: (3aRS, 1SR, 9aSR) 3a3a, 1α, α, β-tetrahydro-1-phenyl-benzo [f] isoindoline-2-propionic acid methyl ester (variant of method b)

A mixture of 15 g of (3aRS, 1SR, 9aSR) -3a, 1,9,9a-tetrahydro-1-phenyl-benzo [iso] indoline, 5.9 g of acrylic acid methyl ester and 1 ml of a 10 # solution of benzyltrimethylammonium hydroxide in methanol is stirred. 1 hour at 50 ° C and then evaporated to dryness. The evaporation residue is slurried with silica gel in a benzene / ethyl acetate mixture (9: 1) and filtered. The filtrate is evaporated to dryness to give the title compound, m.p. is 75-76 ° (after crystallization from ether / petroleum ether).

Example k: (3aRS, 1SR, 9aSR) -2- (2-Hydroxyethyl) -3a, 1,9,9a-tetrahydro-6-methyl- (p-tolyl-benzo [e] isoindoline (Variation of Method b))

To a solution of 1 g of (3aRS, 1SR, 9aSR) -3a, 1,9,9a-tetrahydro-6-methyl-1- (p-tolyl) benzo [f] isoindoline in 30 ml of ethanol is introduced at -15 ° with stirring 1.3 g of ethylene oxide. The mixture is allowed to stand for 16 hours at + 5 ° and then evaporated to dryness. The residue is chromatographed on 30 g of silica gel and aqueous ammonia saturated with methylene chloride / methanol (95: 1 → 5: 0.5) to give the title compound, m.p. is 128-129 ° (after crystallization from a mixture of methylene chloride and petroleum ether).

According to Example 1, a) was prepared using ethylene oxide as the epoxide to give: (3aRS, 1SR, 9aSR) -3a, 1,9,9a-tetrahydro-6-methyl-1-phenyl-benzo [f] isoindoline-2-phthanol] hydrochloride m.p. . 160-163 ° - 23,57748 (3aRS, 1 * SR, 9aSR) -3a, k, 9,9a-Tetrahydro-7-methyl-k-phenyl-benzo [f] isoindoline-2-ethanol

Bis (base) naphthalene-1,5-disulfonate m.p. 217-220 °.

(3aRS, USR, 9aSR) -3a, U, 9,9a-Tetrahydro-k-phenyl-benzo [b] isoindoline-2-ethanol Bis (base) naphthalene-1,5-disulfonate m.p. 227-231 °.

b) using 1,1-dimethylethylene oxide as epoxide to give 2-methyl-1 - [(3aRS, USR, 9aSR) -3a, U, 9,9a-tetrahydro-6-methyl-U- (p-tolyl) benzene - [trans-isoindolin-2-yl] -2-propanol hydrogen maleate m.p. 162-165 °.

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

According to Example 2, the following was prepared: 9aRS) -9,9a-dihydro-1-phenyl-benzo [1-isoindolin-2-yl] butan-2-one. Hydrogen maleate m.p. 132-133 ° ^ ·

According to Examples 3 and U, the following were prepared: (T9aRS) -9,9a-dihydro-U-phenyl-benzo [4-isoindolin-2-yl] -propionic acid Bis (base) naphthalene-1,5-disulfonate m.p. 206-210 °.

Example 5 · (3aRS, USR, 9aSR) -3a, 4,9,9a-Tetrahydro-4-phenyl-benzo [7 isoindoline (method a) 22.3 g (3aRS, USR, 9aSR) -3a, lt, 9 » 9α-Tetrahydro-k-phenyl-benzo [b] isoindoline-2-trifluoroacetamide is dissolved in 3N potassium hydroxide in methanol 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 is evaporated to dryness and the residue is crystallized from methylene chloride / pentane to give the title compound, m.p. 136-138 °.

The starting material (3aRS, USR, 9aSR) -3a, 1 +, 9,9a-tetrahydro-1 + -phenyl-benzo [f] 7-isoindoline-2-trifluoroacetamide is obtained, for example, as follows: A solution of 310 g of N, N-bis (trans-cinnamyl) -trifluoroacetamide in 6 liters of o-dichlorobenzene is boiled for 16 hours under argon and then evaporated to dryness. After crystallization from a methylene chloride / pentane mixture, the residue gives (3aRS, 1 + SR, 9aSR) -3a, U, 9,9a-tetrahydro-U-phenyl-benzo [f] isoindoline-2-trifluoroacetamide, m.p. is 150-153 °.

IR (CH 2 Cl 2) 1690, no absorption in the range 950-990 cm -1.

The starting N, N-bis (trans-cinnamyl) trifluoroacetamide can be prepared as follows:

To a slurry of 30.2 g of sodium hydride in 5 x 0 ml of hexamethylphosphoric acid triamide is added dropwise, with cooling and stirring, a solution of 275 g of N-cinnamyl trifluoroacetamide in 600 ml of hexamethylphosphoric acid triamide. At the end of the evolution of gas, a solution of 20.5 g of cinnamyl bromide in 5 ml of hexamethylphosphoric triamide is added dropwise and the mixture is stirred for 16 hours at 25 °. The reaction mixture is then poured into water and extracted with ether. The ether solution, dried over sodium sulphate, is evaporated to dryness and the oily residue 211 57748 is chromatographed using toluene and 1.5 kg of silica gel.

The filtrate is dried to evaporate as an oily residue N, N-bis- (trans-cinnamyl) trifluoroacetamide: IR (CH 2 Cl 2) 1690, 968 cm -1

The title compound is also obtained under conventional conditions by reduction of (3aRS, USR, 9aSR) -3a, β, 9,9a-tetrahydro-U-phenyl-benzo [f] isoindoline-2-p-toluenesulfonic acid amide. The starting material (3aRS, UsR, 9aSR) -3a, U, 9,9a-tetrahydro-U-phenyl-benzo [f] isoindoline-2-p-toluenesulfonic acid amide is obtained, for example, as follows:

A solution of 2 g of N, N-bis (trans-cinnamyl) -p-toluenesulfonic acid amide in 120 ml of o-dichlorobenzene is boiled for i + 8 hours under argon and then evaporated to dryness to give a residue (SaRSjUSR ^ aSiO-SajH ^ ^ a tetrahydro - + - phenyl-benz / £ 7isoindoliini-2-p-tolueenisulfonihappoamidia.

Sp. 185-187 ° (after crystallization from a mixture of ether and pentane).

According to Example 5, using the corresponding starting compounds and method a, the following compounds of formula Ib are obtained: (3aRS, 1SR, 9aSR) -6-chloro-1- (lt-chlorophenyl) -3a, 1 +, 9.9a- tetrahydrobenz / f7isoindoline m.p. 133-13 ** °.

(3aRS, ** SR, 9aSR) -6-Fluoro - ** - (p-fluorophenyl) -3a, 1 *, 9,9a-tetrahydrobenz [e] 7isoindoline hydrogen maleate m.p. 13 ** - 136 °.

(3aRS, i * SR, 9aSR) -7-chloro - * + - (m-chlorophenyl) -3a, * t, 9,9a-tetrahydrobenz / p-isoindoline hydrogen maleate m.p. 166-168 °.

(3aRS, USR, 9aSR) -3a, U, 9,9a-Tetrahydro-6-methyl-U- (p-tolyl) benzo [f] isoindoline mp 129-132 °.

(3aRS, ** SR, 9aSR) ~ 3a, * +, 9,9a-Tetrahydro-6-methyl-**-phenyl-benzo [a] indole hydrochloride m.p. 17 ** - 176 °.

(3aRS, ** SR, 9aSR) -3a, 1+, 9,9a-Tetrahydro-7-methyl-N-phenyl-benzo [b] isoindoline hydrochloride m.p. 225-227 ° · (3aRS, USR, 9aSR) -6-chloro-3a, U, 9,9a-tetrahydro-**-phenyl-benzyl] isoindoline hydrochloride m.p. 205-207 ° · (3aRS, ** RS, 9aSR) -3a, * +, 9,9a-Tetrahydro-**-phenyl-benzo [f] isoindoline hydrochloride m.p. 256-258 °.

(3aRS, ** RS, 9aSR) -3a, 4,9,9a-Tetrahydro-6-methyl-U-phenyl-benzoindoline hydrochloride m.p. 21 ^ -220 °.

(3aRS, ** RS, 9aSR) -3,3 * +, 9,9a-Tetrahydro-7-methyl-U-phenyl-benzo [f] isoindoline hydrochloride m.p. 226-230 · 25 5774 8 (3aRS, URS, 9aSR) -6-chloro-3a, U, 9,9a-tetrahydro-U-phenyl-Benz s / f7i soimlaLi-ni-ni m.p. 1UU-11 + 5 ° - (9aRS) -9,9a-dihydro-U-phenyl-benzo [i] indoline hydrochloride m.p. 238-2 ^ 3 ° (decomposes).

Example 6: (3aRS, USR, 9aSR) -3a, 4,9,9a-Tetrahydro-2-methyl-1H-phenyl-benzo [b] isoindoline (Method c)

A mixture of 8 g of (3aRS, i + SR, 9aSR) -3a, U, 9,9a-tetrahydro-U-phenyl-benz-ixJ isoindoline, 120 ml of a ho% aqueous formaldehyde solution and 320 ml of methanol is stirred in a catalytic Raney after adding nickel in a hydrogen atmosphere until gas binding is complete. The filtered reaction mixture is then evaporated to dryness, methanol is added to the residue, the insoluble matter is filtered off and the solution is evaporated to dryness to give the title compound as a residue. The hydrochloride of the title compound melts at 207-209 ° (ethanol / ether).

Example 7: (3aRS, USR, 9aSR) -6-chloro-U- (p-chlorophenyl) -3a, h, 9,9a-tetrahydro-2-methyl-benzo [f] isoindoline (Method c)

A mixture of 1.5 g of (3aRS, USR, 9aSR) -6-chloro-U- (p-chlorophenyl) -3a, U, 9,9a-tetrahydrobenz [f] isoindoline, 10 ml of 100 # formic acid and 10 ml of 40% aqueous formaldehyde solution are boiled for 2 hours under nitrogen. The mixture is evaporated to dryness, the residue is dissolved in water, the solution is made alkaline with concentrated sodium hydroxide and extracted with methylene chloride. Ether is added to the dried extracts until the solution begins to cloud, filtered through Hyflo and evaporated to dryness to give the title compound as a residue; mp. 133-135 ° (after crystallization from ether).

From the corresponding starting compounds, according to Examples 6 and 7, using method c, the following compounds are obtained: (3aRS, i + SR, 9aSR) -3a, 1 +, 9,9a-Tetrahydro-2-isopropyl-1-phenyl-benzene-isoindoline hydrogen maleate m.p. 150-158 °.

(3aRS, 1 + SR, 9aSR) -3a, U, 9a, 9a-Tetrahydro-2,6-dimethyl-1 * - (p-tolyl) benzo [f] isoindoline

Bis (base) naphthalene-1,5-disulfonate m.p. 195-198 °.

(3aRS, 4SR, 9aSR) -3a, 4,9,9a-Tetrahydro-2,6-dimethyl-U-phenyl-benzo [f] isoindoline Bis (base) naphthalene-1,5-disulfonate m.p. 280-283 °.

(3aRS, USR, 9aSR) -3a, i *, 9,9a-Tetrahydro-2,7-dimethyl-1-phenyl-benzo [e] isoindoline Bis (base) naphthalene-1,5-disulfonate m.p. 2UU-2 ^ + 8 °.

(3aRS, liRS, 9aSR) -3a, 1 *, 9,9a-Tetrahydro-2,6-dimethyl-N-phenyl-benzo [b] ioindoline Bis (base) naphthalene-1,5-disulfonate m.p. 183-187 °.

26 57748 (3aRS, 1 + RS, 9aSR) -3a, k, 9,9a-Tetrahydro-2,7-dimethyl-1 + -phenyl-benzo [f] isoindoline Bis (base) naphthalene-1,5-disulfonate m.p. 201 + -207 degrees.

(3aRS, 1 + RS, 9aSR) -3a, 1 +, 9,9a-Tetrahydro-2-methyl-1 + -phenyl-benzo [f] isoindoline Bis (base) naphthalene-1,5-disulfonate m.p. 297-303 °.

From the corresponding starting compounds, the following compounds are obtained according to Example 7 and using method c: (3aRS, 1 + SR, 9aSR) -7-chloro-1 + - (m-chlorophenyl) -3a, 1 +, 9,9a-tetrahydro-2-methyl-benz cm soindoline

Bis (base) naphthalene-1,5-disulfonate m.p. 2l + l + -2l + 8 °.

(3aRS, 1 + SR, 9aSR) -6-chloro-3a, 1+, 9,9a-tetrahydro-2-methyl-1 + -phenyl-benzo {Yf ioindoline hydrochloride m.p. 231-233 °.

(3aRS) -9,9a-Dihydro-2-methyl-1 + -phenyl-benzo [f] isoindoline hydrogen maleate m.p. 158-1620 (decomposes).

(3aRS, 1 + SR, 9aSR) -2-Ethyl-6-chloro-3a, 1 +, 9,9a-tetrahydro-1 + -phenyl-benz [E] isoindoline hydrochloride m.p. 198-200 °.

(3aRS, 1 + SR, 9aSR) -2-n-butyl-6-chloro-3a, 1 +, 9,9a-tetrahydro-1 + -phenyl-benzo [f] isoindoline, m.p. 161 + - 165 ° · (3aRS, 1 + SR, 9aSR) -6-chloro-2-isopropyl-3a, 1, 9, 9a-tetrahydro-1 + -phenyl-benzo [f] -isoindoline hydrochloride m.p. 3-2l 2l + + I + °.

Example 8: (3aRS, 1 + SR, 9aSR) -3a, 1 +, 9.9a-Tetrahydro-6-methyl-1 + -phenyl-benzZf7-isoindoline (Method d)

A solution of 20.2 g of (3aRS, 1 + RS, 9aSR) -3a, 1 +, 9,9a-tetrahydro-6-methyl-1 + -phenyl-benzo [f] isoindoline in 500 ml of n-butanol saturated with solid potassium hydroxide is boiled for JO hours. protected from argon and then evaporated to dryness. The residue is partitioned between water and methylene chloride, the organic phase is dried and evaporated to dryness, the residue is dissolved in excess methanolic hydrochloric acid solution, the solution is evaporated to dryness and finally the residue is crystallized from methanol / ether to give the title compound. 17 DEG-176 DEG C. (decomposes).

Example 9 · (3aRS, 1 + SR, 9aSR) -6-Chloro-3a, 1 +, 9,9a-tetrahydro-1 + -phenyl-benzZ? 7-isoindoline (Method d)

A mixture of 6.1+ g of (3aRS, 1 + RS, 9aSR) -6-chloro-3a, 1,1 +, 9,9a-tetrahydro-2-phenoxycarbonyl-1 + -phenyl-benzo [3] isoindoline in 320 ml of saturated potassium hydroxide The n-butanol solution is boiled under nitrogen for 70 hours. The reaction mixture is then evaporated to dryness, the residue is dissolved in water and extracted with methylene chloride. Evaporation of the washed and dried methylene chloride solution to dryness gives the title compound; hydrochloride m.p. 205-207 ° (after crystallization from methylene chloride / ether).

27 57748

From the corresponding starting compounds, the following compounds are obtained according to Example 8 or 9 and using method d: (3aRS, 4SR, 9aSR) -3a, 4,9,9a-Tetrahydro-4-phenyl-benzo [f] isoindoline m.p. 136-138 °.

(3aRS, 4SR, 9aSR) -6-chloro-4- (4-chlorophenyl) -3a, 4,9,9a-tetrahydro-benzo [b] isoindoline m.p. 133-134 °.

(3aRS, 4SR, 9aSR) -6-Fluoro-4- (p-fluorophenyl) -3a, 4,9,9a-tetrahydrobenz [s] indole hydrogen maleate m.p. 134-136 °.

(3aRS, 4SR, 9aSR) -7-chloro-4- (m-chlorophenyl) -3a, 4,9,9a-tetrahydrobenz (S] isoindoline hydrogen maleate, mp 166-168 °.

(3aRS, 4SR, 9aSR) -3a, 4,9,9a-Tetrahydro-6-methyl-4- (p-tolyl) -benz [f] isoindoline m.p. 129-132 °.

(3aRS, 4SR, 9aSR) -3a, 4,9,9a-Tetrahydro-7-methyl-4-phenyl-benzo [b] isoindoline hydrochloride m.p. 225-227 °.

Starting from the corresponding starting compounds and using method d, the following compounds are obtained according to Example 8: (3aRS, 4SR, 9aSR) -3a, 4,9,9a-Tetrahydro-2-methyl-4-phenyl-benz Z? 7-isoindoline hydrochloride m.p. 207-209 °.

(3aRS, 4SR, 9aSR) -2-Cyclopropylmethyl-3a, 4,9,9a-tetrahydro-4-phenyl-benzo [7] isoindoline m.p. 65-68 °.

(3aRS, 4SR, 9aSR) -3a, 4,9,9a-Tetrahydro-2-isopropyl-4-phenyl-benzo [f] ioindoline hydrogen maleate m.p. 150-158 °.

(3aRS, 4SR, 9aSR) -2- (o-chlorophenethyl) -3a, 4,9,9a-tetrahydro-4-phenyl-benzo [f] isoindoline hydrogen maleate m.p. 178-179 °.

(3aRS, 4SR, 9aSR) -2- (3a, 4,9,9a-Tetrahydro-4-phenyl-benzo [f] isoindolin-2-yl) -acetophenone, m.p. 120-130 °.

(3aRS, 4SR, 9aSR) -p-Fluoro-4- (3a, 4,9,9a-tetrahydro-4-phenyl-benz [E * 7-isoindolin-2-yl) -butyrophenone, m.p. 81-84 °.

(3aRS, 4SR, 9aSR) -6-chloro-4- (4-chlorophenyl) -3a, 4,9,9'-tetrahydro-2-methyl-benzo] isoindoline, m.p. 133-135 ° · (3aRS, 4SR, 9aSR) -6-chloro-4- (4-chlorophenyl) -2-cyclopropylmethyl-3a, 4,9,9a-tetrahydro-benzo [f] isoindoline, m.p. 124-126 °.

(3aRS, 4SR, 9aSR) -7-chloro-4- (m-chlorophenyl) -3a, 4,9,9a-tetrahydro-2-methyl-benz / f7isoindoliini

Bis (base) naphthalene-1,5-disulfonate m.p. 244-248 °.

(3aBS, kSR, 9aSR) β-Chloro-4- (m-chlorophenyl-2-cyclopropylmethyl-3a, 4,9,9a-tetrahydro-benzo [e] isoindoline

Bis (base) naphthalene-1,5-disulfonate m.p. 243-247 °.

(3aRS, 4SR, 9aSR) -3a, 4,9,9a-Tetrahydro-2,6-dimethyl-4- (p-tolyl) benz [f] indole Bis (base) naphthalene-1,5-disulfonate m.p. 195-198 °.

(3aRS, 4SR, 9aSR) -2-Cyclopropylmethyl-3a, 4,9,9a-tetrahydro-6-methyl-4- (p-tolyl) -benz [f] isoindoline, m.p. 98-100 °.

28 57748 (3aRS, 1 + SR, 9aSR) -2- (2-Hydroxyethyl) -3a,) +, 9,9a-tetrahydro-6-methyl-1 + - (p-tolyl) -2-benzo [7] isoindoline in ethanol mp. 128-129 °.

(3aRS, 1 + SR, 9aSR) -3a,) +, 9,9a-T-tetrahydro-2,6-dimethyl-U-phenyl-benzo [f] isoindoline Bis (base) naphthalene-1,5-disulfonate m.p. 280-283 °.

(3aRS,) + SR, 9aSR) -2-Cyclopropylmethyl-3a, 9,9a-tetrahydro-6-methyl -) - * - phenyl-Benzyl-7-indoindoline hydrochloride m.p. 198-20) + °.

(3aRS,) + SR, 9aSR) -3a, i +, 9,9a-Tetrahydro-2,7-dimethyl-1 + -phenyl-benzo [f] isoindoline Bis (base) naphthalene-1,5-disulfonate m.p. 2bb-2B8 °.

(3aRS,) + SR, 9aSR) -6-chloro-2-cyclopropylmethyl-3a, 1, 9, 9,9a-tetrahydro-U-phenyl-benzo [b] isoindoline hydrochloride m.p. 208-210 °.

(3aRS,) + SR, 9aSR) -2-Ethyl-6-chloro-3a,) +, 9,9a-tetrahydro-) + -phenyl-Benz s / f-isoindoline hydrochloride m.p. 198-200 °.

(3aRS,) + SR, 9aSR) -2-n-Butyl-6-chloro-3a, 1 +, 9,9a-tetrahydro-) + - phenyl-benzo [f] isoindoline fumarate m.p. 16) + - 165 °. ~ (3aRS,) + SR, 9aSR) -6-chloro-2-i-propropyl-3a,) +, 9,9a-tetrahydro -) + - phenyl-Benz s / N-isoindoline hydrochloride m.p. 2b3 ~ 2bb °.

(3aRS, 1 + SR, 9aSR) -3a, 1 +, 9,9a-Tetrahydro-6-methyl-) + - phenyl-benzo [f] isoindoline-2-ethanol hydrochloride m.p. 160-163 °.

(3aRS, 1 + SR, 9aSR) -3a, 1 +, 9,9a-Tetrahydro-7-methyl-1 + -phenyl-benzo [a] 7-isoindoline anionic

Bis (base) naphthalene-1,5-disulfonate m.p. 217 ~ 220 °.

(3aRS,) + SR, 9aSR) -3a,) +, 9,9a-Tetrahydro-1 + -phenyl-benzo [f] isoindoline-2-ethanol Bis (base) naphthalene-1,5-disulfonate m.p. 227-231 °.

2-methyl-1- [(3aRS, 1 + SR, 9aSR) -3a,) +, 9,9a-tetrahydro-6-methyl-) + (p-tolyl) -benz (4-isoindolin-2-yl) -7- 2-propanol hydrogen maleate m.p. 162-165 °.

(3aRS,) + SR, 9aSR) -3a,) +, 9,9a-Tetrahydro-2- (p-methoxy-benzyl) -1 + -phenyl-benzo [f] -isoindoline, m.p. 95-100 °.

(3aRS, 1 + SR, 9aSR) -2-Cyclopropylmethyl-3a,) +, 9,9a-tetrahydro-7-methyl-b-phenyl-benzoisoindoline, m.p. 79-02 °.

2R (3aRS,) + SR, 9aSR) -3a, 1 +, 9,9a-Tetrahydro-7-methyl -) + - phenyl-benzo [£ 7] isoindolin-2-yl] -p-fluoroacetophenone hydrogen maleate m.p. 16) + - 166 °.

(3aRS, 1 + SR, 9aSR) -6-Chloro-3a, 1 +, 9,9a-tetrahydro-2-methyl-1 + -phenyl-benzZ? 7-isoindoline hydrochloride m.p. 231-233 °.

(3aRS, USR, 9aSR) -3a,) +, 9,9a-Tetrahydro-2- (p-methylbenzyl) -1 + -phenyl-benzo [a] isoindoline m.p. 120-121 °.

(3aRS, 1 + SR, 9aSR) -3a, 1 +, 9,9a-Tetrahydro-2- (p-methoxybenzyl) -U-phenyl-Benzyl p-7-isoindoline, m.p. 95-100 °.

57748 29

Example 10: (3aRS, URS, 9aSR) ~ 3a, k, 9,9a-Tetrahydro-6-methyl-U-phenyl-benzo] isoindoline (Method f)

To a solution of 35.2 g of (9aRS) -2-benzyl-9,9a-dihydro-6-methyl-U-phenyl-benzo [f] isoindoline in 300 ml of ethanol is added at 25 ° a solution of 0.55 g of palladium (H) chloride and 0.39 g of common salt in 50 ml of water. A solution of 2.0 g of sodium borohydride in 25 ml of water is added dropwise to the mixture at 0 °, stirred for 30 minutes at 25 °, then the pH is adjusted to 2 with aqueous concentrated hydrochloric acid and finally hydrogenated for 18 hours at 60 ° C under four atmospheres: in. The reaction mixture is filtered, the filtrate is evaporated to dryness, the residue is dissolved in hot ethanol and the clear solution is allowed to cool to give the hydrochloride of the title compound, m.p. is 215-220 ° (crystallized from methanol / ether), crystallizes apart.

Example 11: (3aRS, URS, 9aSR) -2-Benzyl-6-chloro-3a, U, 9,9a-tetrahydro-U-phenyl-benzo [f] isoindoline (Method e)

To a suspension of 30 g of (9aRS) -2-benzyl-6-chloro-9,9a-dihydro-U-phenyl-benzo [X] isoindoline and U6.8 g of red phosphorus in 100 ml of glacial acetic acid is added dropwise 190 ml of 57 #: hydrochloric acid, then the mixture is heated at 110 ° for 5.5 hours, then poured onto ice and made alkaline with sodium hydroxide. After extraction with ethyl acetate, the organic phase is filtered through Celif, the filtrate is dried and evaporated to dryness to give the title compound, m.p. is 115-11T ° (after crystallization from pentane).

Starting from the corresponding starting compounds and using method e or f, according to Examples 10 and 11, the following compounds are obtained: (3aRS, URS, 9aSR) -3a, U, 9,9a-Tetrahydro-2,6-dimethyl-U-phenyl-benzo [f] isoindoline Bis (base) naphthalene-1,5-disulfonate m.p. 183-18 ° - (3aRS, URS, 9aSR) -3a, U, 9,9a-Tetrahydro-2,7-dimethyl-U-phenyl-benzo [f] isoindoline Bis (base) naphthalene-1,5 "disulfonate m.p. 20U-207 ° C.

(3aRS, URS, 9aSR) -3a, U, 9,9a-Tetrahydro-2-methyl-U-phenyl-benzo [f] isoindoline Bis (base) naphthalene-1,5-disulfonate m.p. 297-303 °.

Using the corresponding starting compounds and method f, the following compounds are obtained according to Example 10: (3aRS, URS, 9aSR) “3a, 1 +, 9,9a-Tetrahydro-7-methyl-U-phenyl-benzo [f] isoindoline hydrochloride m.p. 226-230 °.

(3aRS, URS, 9aSR) -3a, U, 9,9a-Tetrahydro-U-phenyl-benz75 / isoindoline hydrochloride m.p. 256-258 °.

Example 12: (3aRS, URS, 9aSR) -6-chloro-3a, U, 9,9a-tetrahydro-U-phenyl-benzo [f] isoindoline (method a)

A mixture of 8.8 g of (3aRS, URS, 9aSR) -6-chloro-3a, U, 9,9a-tetrahydro-2-phenoxycarbonyl-U-phenyl-benzo [7] indoline, 260 ml of methanol and U2 g of 50 Sodium hydroxide is boiled for 15 hours under nitrogen, then evaporated to dryness and diluted with methylene chloride. Evaporation of the washed and dried organic phase to dryness gives the title compound, m.p. is 1HU-1 ^ 5 ° (after crystallization from ethanol / pentane).

The starting material (3aRS, URS, 9aSR) -6-chloro-3a, 1,9,9,9a-tetrahydro-2-phenoxycarbonyl-1-phenyl-benzo [f] isoindoline can be prepared as follows:

To a solution of 9 g of (3aRS, URS, 9aSR) -2-benzyl-6-chloro-3a, 1 +, 9,9a-tetrahydro-U-phenyl-benz [E] isoindoline in 90 ml of methylene chloride is added 0 °: 3.65 ml of chloroformic acid phenyl ester, stirred for 16 hours at room temperature, then washed with 3N sodium hydroxide, 2N hydrochloric acid and water, dried and evaporated to dryness. The oily residue is chromatographed on toluene / ethyl acetate (1: 1) using 100 times the amount of silica gel to give (3aRS, 1 + RS, 9aSR) -6-chloro-3a, U, 9,9a-tetrahydro-2-phenoxycarbonyl-U-phenyl -benz / fisoisoindoline, m.p. is 130-13 ° (after crystallization from ether).

Example 13: (9aRS) -2-Benzyl-9,9a-dihydro-6-methyl-H-phenyl-benzo [f] isoindoline (Method g, h)

To a solution of 2 g of lithium aluminum hydride in 100 ml of tetrahydrofuran is added dropwise and, under nitrogen, at -5 ° with stirring, 35 ml of 100% sulfuric acid. The mixture is then stirred for 30 minutes at room temperature, re-cooled to -5 ° and a solution of 90 g of (9aRS) -2-benzyl-9,9a-dihydro-6-methyl-U-phenyl- benz, n-isoindoline-1,3-dione in 1 liter of tetrahydrofuran. After stirring the reaction mixture for 26 hours at room temperature, water and $ 12 sodium hydroxide are added and the precipitate formed is filtered off. The filtrate is evaporated to dryness, the residue is dissolved in methylene chloride, the filtered solution is evaporated to dryness and the residue is crystallized from ether / pentane to give the title compound, m.p. is 139 ~ 1 ^ 3 °.

The starting material (9aRS) -2-benzyl-9,9a-dihydro-6-methyl-1-phenyl-benzo [f] isoindoline-1,3-dione can be prepared as follows:

A solution of 35 g of 2,5-dimethylbenzophenone and 31.5 g of N-benzylmaleimide in 500 ml of acetone or methylene chloride is irradiated with a high-pressure mercury lamp through a Pyrex filter until the reaction is complete (20-130 hours), then filtered and evaporated to dryness. After crystallization from ether, the residue gives 35 g of 2-benzyl-3,3,1,9,9a-tetrahydro-6-methyl-U-phenyl-benzo [b] isoindolin-U-ol-1,3-dione, m.p. is 162-16U0 and is dissolved in 170 ml of trifluoroacetic acid. The solution is stirred for 3 hours at 25 ° and then evaporated to dryness. After crystallization from a methylene chloride / methanol mixture, 30 g of (9aRS) -2-benzyl-9,9a-dihydro-6-methyl-U-phenyl-benz [X] isoindoline-1,3-dione are obtained, m.p. is 156-156 °.

31 57748

According to Example 13, using the corresponding starting compounds and method g or h, the following compounds are obtained: (9aRS) -2-Benzyl-9,9a-dihydro-T-methyl-U-phenyl-benzo [b] isoindoline m.p. 139-1½0.

(9α-S) -2-Benzyl-6-chloro-9,9a-dihydro-1-phenyl-benzo [7] isoindoline m.p. 266-268 °.

(9aRS) -2-Benzyl-9,9a-dihydro-1 * -phenyl-benzo [e] isoindoline m.p. 113-115 °. (9aRS) -9,9a-Dihydro-U-phenyl-benzo [7] isoindoline hydrochloride m.p. 238-2 ^ 3 ° (decomposes).

(9aRS) -9,9a-Dihydro-2-methyl-U-phenyl-benzo [b] isoindoline hydrogen maleate m.p. 158-162 ° (decomposes).

Example 1U: (3aRS, 4SR, 9aSR) -2-Cyclopropylmethyl-3a, U, 9,9a-tetrahydro-U-phenyl-benzo [7] isoindoline (Method h)

To a mixture of 7 to 5 g of (3aRS, 1 + SR, 9aSR) -3a, U, 9,9a-tetrahydro-1 + -phenyl-4-benzo [f] isoindoline, 7.9 g of pyridine and 100 ml of methylene chloride are added dropwise At -5 ° U, 7 g of cyclopropylcarboxylic acid chloride. The mixture is stirred for 1 hour at room temperature, then shaken successively with 10% aqueous citric acid solution and sodium hydrogen carbonate solution, dried over sodium sulphate and evaporated to dryness to give (3aRS, 4SR, 9aSR) -3a, ^, 9 »9a-en tetrahydro-residue Bent s / E 7iol indoline-2-cyclopropyl-carboxylic acid amide, m.p. is 1 ^ 9-151 ° (after crystallization from ether).

To a warm solution of 8.6 g of (3aRS, USR, 9aSR) -3a, 1 *, 9,9a-tetrahydro-U-phenyl-benzo [7] -indoline-2-cyclopropylcarboxylic acid amide in 100 ml of tetrahydrofuran is added portionwise 1 g of lithium aluminum hydride. The mixture is stirred for 1 hour at room temperature, then 2N sodium hydroxide is added and filtered. The filtrate evaporated to dryness is slurried with silica gel in a mixture of benzene / ethyl acetate (1: 1), filtered and evaporated to dryness to give the title compound, m.p. is 65-68 ° (after crystallization from pentane).

According to Example 1U, using the corresponding starting compounds and method h, the following compounds of formula Im are obtained: (3aRS, USR, 9aSR) -3a, 1 +, 9,9a-tetrahydro-2-methyl-k-phenyl-benz [ isoindoline hydrochloride m.p. 207-209 °.

(3aRS, itSR, 9aSR) -6-chloro-2-cyclopropylmethyl-3a, 4,9,9a-tetrahydro-U-phenyl-benzo [f] isoindoline, hydrochloride m.p. 208-210 °, (3aRG, 1SR, 9aSR) -2- (o-chlorophenethyl) -3a, 1 *, 9,9a-tetrahydro-1 + -phenyl-benzo [f] isoindoline hydrogen maleate m.p. 178-179 °.

(3aRS, USR, 9aSR) -6-chloro-U- (-chlorophenyl) -3a, k, 9,9a-tetrahydro-2-methyl-benzo [e] isoindoline, m.p. 133-135 °.

(3aRS, USR, 9aSR) -6-chloro-N- (1 + -chlorophenyl) -2-cyclopropylmethyl-3a, U, 9,9a-tetrahydro-benzo [f] isoindoline, m.p. 12 i * -126 °.

32 57748 (3aRS, 1 + SR, 9aSR) -7-Chloro-U- (m-chloro-phenyl) -3a, U, 9,9a-tetrahydro-2-methyl-benzo [b] isoindoline

Bis (base) naphthalene-1,5-disulfonate m.p. 21 + 1 ^ + -2 + 8 °.

(3aRS, 1 + SR, 9aSR) -7-Chloro--1 + - (m-chloro-phenyl) -2-cyclopropylmethyl-3a, 1 +, 9, 9a-tetrahydro-benzo [f] isoindoline

Bis (base) naphthalene-1,5-disulfonate m.p. 21 + 3-21 + 7 °.

(3aRS, 1 + SR, 9aSR) -3a, 1 +, 9,9a-Tetrahydro-2,6-dimethyl-1 + - (p-tolyl) benzo [e] isoindoline

Bis (base) naphthalene-1,5-disulfonate m.p. 195-198 °.

(3aRS, 1 + SR, 9aSR) -2-Cyclopropylmethyl-3a, 1 +, 9,9a-tetrahydro-6-methyl-1 + - (p-tolyl) -benz [e] isoindoline »m.p. 93-100 °.

(3aRS, 1 + SR, 9aSR) -2- (2-Hydroxyethyl) -3a, 4,9,9a-tetrahydro-6-methyl-U- (p-tolyl) -benz ££ 7-isoindoline> SP · 128 -129 °.

(3aRS, 1+ SR, 9aSR) ~ 3a, 1+, 9,9a-Tetrahydro-2,6-dimethyl-1 + -phenyl-benzoylindindoline Bis (base) naphthalene-1,5-disulfonate m.p. 280-283 °. ~ 3α (3aRS, 1 + SR, 9aSR) -2-Cyclopropylmethyl-3a, 1, 9, 9a-tetrahydro-6-methyl-1 + -phenyl-benzo [e] isoindoline hydrochloride mp 198-201 + °.

(3aRS, 1 + SR, 9aSR) ~ 3a, 1 +, 9,9a-Tetrahydro-2,7-dimethyl-U-phenyl-benzo [b] oxindoline Bis (base) naphthalene-1,5-disulfonate m.p. 21 + 1 + 8 + -21 °.

(3aRS, 1 + SR, 9aSR) -2-Cyclopropylmethyl-3a, 1 +, 9,9a-tetrahydro-7-methyl-1 + -phenyl-benzo [e] isoindoline, m.p. 79 'at 82 °.

(3aRS, 1 + SR, 9aSR) -6-Chloro-3a, 1 +, 9,9a-tetrahydro-2-methyl-1 + -phenyl-Benz s / 11,7-isoindoline hydrochloride m.p. 231-133 °.

(3aRS, 1 + SR, 9aSR) -3a, k, 9,9a-Tetrahydro-2- (p-methylbenzyl) -N-phenyl-benzoisoindoline, m.p. 120-121 °.

(3aRS, 1 + SR, 9aSR) -2-Ethyl-6-chloro-3a, 1 +, 9,9a-tetrahydro-1 + -phenyl-benz [E] isoindoline hydrochloride m.p. 198-200 °.

(3aRS, 1SR, 9aSR) -2-n-Butyl-6-chloro-3a, U, 9,9a-tetrahydro-U-phenyl-benzo [7] isoindoline, m.p. 161 + -165 degrees.

(3aRS, 1 + SR, 9aSR) -3a, 1 +, 9,9a-Tetrahydro-6-methyl-1 + -phenyl-benzo [e] isoindoline-2-ethanol hydrochloride m.p. 160-163 °.

(3aRS, 1 + SR, 9aSR) -3a, 1 +, 9,9a-Tetrahydro-7-methyl-1 + -phenyl-benzo [7] isoindoline-2-ethanol

Bis (female) naphthalene-1,5-disulfonate m.p. 217-220 °.

(3aRS, I + SR, 9aSR) -3a, I +, 9,9a-tetrahydro-l-phenyl-benz + £ f7isoindoliini-2-ethanol

Bis (base) naphthalene-1,5-disulfonate m.p. 227-231 °.

33 5774 8 (3aRS, USR, 9aSR) -3a, U, 9,9a-Tetrahydro-2- (p-methoxybenzyl) -U-phenyl-benz8-7'-isoindoline, m.p. 95-100 °.

(3aRS, USR, 9aSR) -3a, U, 9,9a-Tetrahydro-2- (p-methoxybenzyl) -U-phenyl-Benzo [f] 7-isoindoline, m.p. 95-100 °.

(3aRS, URS, 9aSR) -3a, U, 9,9a-Tetrahydro-2-methyl-U-phenyl-benzoylindoline Bis (base) naphthalene-1,5-disulfonate m.p. 29T ~ 303 °.

(3aRS, URS, 9aSR) -3a, U, 9,9a-Tetrahydro-2,6-dimethyl-U-phenyl-benzo [f] isoindoline Bis (base) naphthalene-1,5-disulfonate m.p. 183-187 °.

(3aRS, URS, 9aSR) -3a, U, 9,9a-Tetrahydro-2,7-dimethyl-U-phenyl-benzo [b] isoindoline Bis (base) naphthalene-1,5-disulfonate m.p. 20U-207 ° C.

(3aRS, URS, 9aSR) -2-Benzyl-6-chloro-3a, U, 9,9a-tetrahydro-U-phenyl-benzo [7] isoindoline, m.p. 115-117 °.

(9aRS) -9,9a-Dihydro-2-methyl-U-phenyl-benzo [f] isoindoline hydrogen maleate m.p. 158-162 ° (decomposes).

(9aRS) -2-Benzyl-9,9a-dihydro-U-phenyl-benzo] isoindoline, m.p. 265-269 °.

(9aRS) -2-Benzyl-9,9a-dihydro-6-methyl-U-phenyl-benzo [f] isoindoline, m.p. 139-1U30.

(9aRS) -2-Benzyl-9,9a-dihydro-7-methyl-U-phenyl-benzo [7] indoline, m.p. 139-1U20.

(9aRS) -2-Benzyl-6-chloro-9,9a-dihydro-U-phenyl-benzo [f] isoindoline hydrochloride m.p. 266-268 °.

The following typical examples are further illustrated to illustrate the methods of preparation of the required starting materials described above:

Example 15: (3aRS, USR, 9aSR) -6-Chloro-U- (p-chlorophenyl) -3a, U, 9,9a-tetrahydro-benzo [b] indole-2-trifluoroacetamide A solution of 30 g of N, N-bis ( trans-p-chlorocinnamyl) trifluoroacetamide in 600 ml of o-dichlorobenzene is boiled under argon for 16 hours and then evaporated to dryness. The residue is chromatographed on 250 g of silica gel and benzene. The filtrate is dried by evaporation of the title compound as a residue; mp. 107-112 ° (after crystallization from ether / pentane).

The starting N, N-bis (trans-p-chlorocinnamyl) trifluoroacetamide can be prepared by alkylating N-trans-p-chlorocinnamyl trifluoroacetamide with trans-p-cinnamyl bromide (according to Example 5).

Example 16: (3aRS, USR, 9aSR) -6-Fluoro-U- (p-fluorophenyl) -3a, U, 9,9a-tetrahydro-benzo [f] isoindoline-2-trifluoroacetamide The title compound, m.p. was 173-176 ° (after crystallization from ether), was prepared as described in Example 5 by thermal cyclization of N, N-bis (trans-p-fluorocinnamyl) trifluoroacetamide.

3U

5 7 7 4 8 The starting material is N, N-bis (trans-p-fluorocinnamyl) trifluoroacetamide, m.p. is 17-79 ° (after crystallization from chloroform) can be prepared as described in Example 6 from N-p-fluorocinnamyl-trifluoroacetamide and p-fluorocinnamyl bromide.

Example 17: (3aRS, USR, 9aSR) -7-chloro-k- (m-chlorophenyl) -3a, 4,9,9a-tetrahydrobenz [f] isoindoline-2-trifluoroacetamide

The title compound is obtained in the form of an oil by thermal cyclization of N, N-bis (trans-m-chlorocinnamyl) trifluoroacetamide as described in Example 6 and is purified by chromatography on silica gel (benzene / ethyl acetate 19: 1) · N, N-bis ( trans-m-chlorocinnamyl) trifluoroacetamide (oil) can be prepared from Nm-chlorocinnamyl trifluoroacetamide and m-chlorocinnamyl bromide as described in Example 5.

Example 13: (3aRS, USR, 9aSR) -3a, U, 9α, 9α-Tetrahydro-6-methyl-k- (p-tolyl) -benzyl] isoindoline-2-trifluoroacetamide

The title compound, m.p. was 110-113 ° (after crystallization from ether / pentane) was obtained by thermal cyclization of N, N-bis (trans-p-methylcinnamyl) trifluoroacetamide as described in Example 5.

The starting N, N-bis (trems-p-methylcinnamyl) trifluoroacetamide (oil) can be prepared from N-p-methylcinnamyl trifluoroacetamide and p-methylcinnamyl bromide as described in Example 5.

Example 19: (9aRS) -9 <9a-Dihydro-β-phenylbenz / η 7 isoindoline-2-trifluoroacetamide

A solution of 218 g of (N- (trans-cinnamyl) -N- (3-phenyl-2-propynyl) -trifluoroacetamide in 1 liter of o-dichlorobenzene is boiled under argon for 5 hours and then evaporated to dryness. After crystallization from a pentane mixture, the title compound has a mp of 195-197 °.

The starting N- (trans-cinnamyl) -N- (3-phenyl-2-propynyl) -trifluoroacetamide can be prepared by alkylating N- (trans-cinnamyl) trifluoroacetamide with 1-bromo-3-phenyl-2-propyne.

Claims (5)

35 57748 A process for the preparation of new antidepressant benzo [f] isoindolines of the formula H 1 R 2 - (O) wherein and may be the same or different and represent hydrogen, halogen or an alkyl group having 1 to 1 + carbon atoms, X and Y represents either both hydrogen, in which case rings B and C are cis-bonded, or X and Y together form an additional bond, and R represents hydrogen, alkyl of 1 to 5 carbon atoms, or alkenyl or alkynyl of 3 to 5 carbon atoms having a double bond. - or the triple bond is not in the Λ position relative to the nitrogen atom to which R is attached; or alkyl of 1 to 1 carbon atoms substituted by cycloalkyl of 3 to 6 carbon atoms; or 2 to 5 carbon atoms of hydroxyalkyl, 7 to 11 carbon atoms of phenylalkyl, 7 to 11 carbon atoms of monosubstituted phenylalkyl having a halogen substituent on the phenyl group, 1 to 1 carbon atom alkoxy or 1 to 1 carbon atom alkyl; or a group -A-CO-R 1, wherein A represents alkylene of 1-1 + carbon atoms and represents alkyl having 1 to 5 carbon atoms, phenyl, halogen-substituted phenyl, hydroxy or an alkoxy group having 1-1 + carbon atoms, and for the preparation of salts, characterized in that a) compounds of the formula H 36 57748 in which R 1, R 1, X and Y have the abovementioned meaning and R 2 represents an electron-withdrawing group are cleaved by known methods R 1, followed optionally to prepare compounds of formula H 1 R 11a, wherein R 1, R 8, X and Y have the meanings given above and R 1 represents alkyl or alkenyl having 1 to 5 carbon atoms or alkynyl, wherein has 3 to 5 carbon atoms in which the double or triple bond is not in the β-position relative to the nitrogen atom to which R 1 is attached, alkyl of 1 to U carbon atoms substituted by cycloalkyl having 3 to 6 carbon atoms; Hydroxyalkyl of 2 to 5 carbon atoms, phenylalkyl of 7 to 11 carbon atoms, monosubstituted phenylalkyl of 7 to 11 carbon atoms having a halogen substituent on the phenyl group, 1-U carbon alkoxy or 1-U carbon alkyl; or a group of the formula A-CO-R 1 in which A: 11a and R 1 have the above-mentioned meaning, a compound of the formula H 1 R 1 NH 1b in which R, R 8, X and Y have the above-mentioned meaning , N-alkylating by known methods, or b) for the preparation of compounds of formula Ia, N-alkylating compounds of formula Ib in a manner known per se, or c) alkylating compounds of formula Ib by reduction to compounds of formula 37 57748 HE, Re, Railia, X and Y have the meanings given above and denote a primary or secondary alkyl group having 1 to 5 carbon atoms, or d) compounds of the formula? κ, -ίοΓ ^ if H''l H H2- {0} wherein R1 and Railia have the meanings given above and Rg represents hydrogen, alkyl of 1 to 5 carbon atoms or alkenyl or alkynyl of 3 to 5 carbon atoms having the double or triple bond is not in the «position relative to the nitrogen atom to which Rg is attached, alkyl having 1 to 1 carbon atoms substituted by cycloalkyl having 3 to 6 carbon atoms, hydroxyalkyl having 2 to 5 carbon atoms, phenylalkyl having 7 to 11 carbon atoms, 7- 11 carbon atoms of monosubstituted phenylalkyl substituted on the phenyl group by halogen, 1 to 1 carbon atoms alkoxy or 1-U carbon-** atomic alkyl, or a group A-CO-R '^ in which A has the meaning given above and R * 2 denotes alkyl of 1 to 5 carbon atoms, phenyl, halogen-substituted phenyl or an electron-withdrawing group, strongly converted under temporal conditions to compounds of formula 38 57748? ^ - (κΙ) Τ I m6 * H R2HiO] wherein R1 and R11a have the above meanings and R8 has the same meaning as X. υ t. x Rg with the exception of the electron-withdrawing group, in which case, if Rg is an electron-attracting group, this is cleaved off, or e) compounds of the formula H i r2— {O}, in which Re and Railia have the abovementioned meaning and R ^ denotes Alkyl of 1 to 5 carbon atoms, alkyl of 1 to 1 carbon atoms substituted with cycloalkyl of 3 to 6 carbon atoms; Phenylalkyl of 7 to 11 carbon atoms, monosubstituted phenylalkyl of 7 to 11 carbon atoms having a halogen or alkyl of 1 to 1 carbon atom as a substituent on the phenyl group; or the group A-CO-R 2, in which A and Railia have the abovementioned meaning, is hydrogenated with a mixture of hydroiodic acid and red phosphorus to give compounds of the formula H i 39 57748 in which Re and Railia have the abovementioned meaning, or f) compounds of the formula H R ', (n, BR, 7 y E'r-fO) in which R' 1 and R '2 may be the same or different and represent hydrogen, fluorine or alkyl having 1 to 1 carbon atoms, and R 1 'represents hydrogen, alkyl of 1 to 5 carbon atoms, alkyl of 1 to 1+ carbon atoms substituted by cycloalkyl of 3 to 6 carbon atoms; Hydroxyalkyl of 2 to 5 carbon atoms, benzyl, phenylalkyl of 8 to 11 carbon atoms having a phenyl group at a distance of at least two carbon atoms from the nitrogen atom to which the phenyl group is attached; Mono-substituted phenylalkyl of 8 to 11 carbon atoms having a halogen substituent on the phenyl group, alkoxy of 1 to 1 carbon atoms or alkyl of 1 to 1 carbon atoms and having a phenyl group at least two carbon atoms away from the nitrogen atom to which the phenyl group is attached is hydrogenated with a noble metal . wherein R '1, R' 11a and R '1 have the meanings given above, the optionally present benzyl group being cleaved off, or g) compounds of formula 57748 *, 40 ° T NBe 11 H2- [0) wherein R1 and Railia have the meaning given above and R8 represents hydrogen, alkyl having 1 to 5 carbon atoms, alkyl having 1 to U carbon atoms having a cycloalkyl having 3 to 6 carbon atoms as a substituent; Hydroxyalkyl of 2 to 5 carbon atoms, phenylalkyl of 7 to 11 carbon atoms, monosubstituted phenylalkyl of T to 11 carbon atoms having a halogen substituent on the phenyl group, 1-U carbon alkoxy or 1-U carbon alkyl is reduced with a metal hydride "'iSLX me iu wherein Re, Railia and Rg have the meanings given above, or h) compounds of formula H *, 4fO NCOD IV R2- £ 0) m 57748 wherein R, Railia, X and Y has the meaning given above and D represents hydrogen, alkyl having 1 to 1 carbon atoms, cycloalkyl having 3 to 6 carbon atoms, alkyl having 1 to 3 carbon atoms substituted with cycloalkyl having 3 to 6 carbon atoms, hydroxyalkyl having 1 to U carbon atoms, phenyl , T ~ 10 carbon atoms phenylalkyl, mono-substituted phenyl substituted with halogen, 1-1 + carbon atoms alkoxy or 1-1 + carbon atoms alkyl, or 7-10 carbon atoms monosubstituted phenylalkyl having a halogen substituent on the phenyl group ni, 1-1 + carbon atom alkoxy or 1-1 + carbon atom alkyl, is reduced with metal hydrides to compounds corresponding to the formula "" H B1 - ££ 'CD JT BCH2D Im wherein R 1, R 9, X, Y and D has the meaning given above, and the compounds of formula I thus obtained are recovered as such or as salts. Process according to Claim 1, characterized in that the prepared ethanane (3aRS, 1 + SR, 9aSR) -6-chloro-3a, 1 +, 9, 9a-tetrahydro-2-methyl-1 + -phenyl- benz / f / isoindoline or its acid addition salts a. 1.2 57748 1. A compound for the preparation of an antidepressant benz / f / isoindoline with the formula H R1 -C NR I color and R ^ can be a residue or an oil or an alkylate, halogen or alkyl - a group of 1-1 + cholatomer, X and Y betecnar antingen b & da väte, i vilket fall ringarna B oc C C cis-bundna, eller X oc Y Y bildar tillsammans en ytterligare bindning, och R betecknar väte, alkyl med 1-5 kolatomer ellkenen eller alkynyl med 3 ~ 5 kolatomer, i vilka dubbel- eller trippelbindningen icke är i ä-ställningen med hänseende account den kväveatom som R är bunden vid; or alkyl of 1-1 + cholatom, preferably substituted with cycloalkyl of 3-6 cholaters; or hydroxyalkyl of 2-5 cholatomers, phenylalkyl of 7-11 cholaters, monosubstituted phenylalkyl of 7-11 cholaters, hydrogen and phenyl substituents of halogen, alkoxy of 1-1 + cholatomer or alkyl of 1-1 + cholatomers; or a group -A-CO-R 2 »color A alkyl group with 1-1 + cholatom and ochyl alkyl with 1 to 5 cholera, phenyl, halogen substituted phenyl, hydroxyl or alkoxy with 1-1 + cholera, and salter, kännetecknat därav, att a) frän föreningar med formuleln H b, VI R2-liO) viiri H1, KM, X oc Y Y har ovan angiven betydelse och R ^ betecknar en elektroner att-riilHTaride grupp, avspaltas med kända förfaranden Gruppen R ^ , which may be used, for the purpose of obtaining a compound of formula 1 * 3 57748 H r, - {[OT ^ K2 "H [oj vari R1, R ^, X and Y heir are angiven betydelse and R ^ betecknar alkyl med 1-5 kolatomer or alkenyl or alkynyl of 3 to 5 carbon atoms, and a single double or triple bond to a hydrogen atom having an alkyl radical of 1 to 4 carbon atoms, alkyl of 1 to U chelates, one or more substituents of cycloalkyl 6 cholatomers, hydroxyalkyl of 2-5 cholaters, phenylalkyl of T-11 cholatomers, monosubstituted phenylalkyl of 7-11 cholaters, phenyl groups substituted with halogen, alkoxy with 1-U cholatom or alkyl with 1-U cholatom; or a group A-CO-R 2, a variety A and R 2 is an angular lettering, which is given by the form HR * (fQT ^ 1b R 2 - a variation R 1, R 2, X and Y is an angular lettering, N-alkyler with the aid of formula (b) for the preparation of the formulation with the form Ia and the N-alkylation formulation with the formulation Ib at the same time as the formulation, or (c) the formulation with the formulation Ib alkylation of the formulation with the formulation 57748) +1+ H r2- {Oj color R ^, Rg, X och Y y har ovan angiven betydelse och R ,. betecnar en primary or secondary alkyl group with 1-5 colaters, or "d) derivatives of the formula H" ^ - ^ OT NRg If H '' * l H r2- {o) vari R1 och Rg har ovan angiven betydelse och Rg betecknar väte , alkyl of 1-5 cholaters or alkenyl or alkynyl of 3 ~ 5 cholaters, i are a double or triple bond or an array of the same radicals to which Rg is attached; alkyl med 1-1 + cholatomer, preferably substituted with cycloalkyl med 3-6 cholatomer; hydroxyalkyl of 2-5 cholaters, phenylalkyl of 7 "11 cholatomers, monosubstituted phenylalkyl of 7-11 cholaters, hydrogen and phenyl substituents of halogen, alkoxy of 1-1 + cholatomer or alkyl of 1-1 + cholatomer; or groups A-CO-R '^ »vari A with an angular bond and R' ^ betecknar alkyl with 1-5 cholatomers, phenyl, with halogen substituted phenyl or an electron-withdrawing group, optionally under the control of alkaline groups to give formula H · ig r2 ~ (o] 1,5 57748 color och haran angiven betydelse och Rg betecknar decamma som Rg med undantag av en electronically attraherande grupp, varvid, ifall Rg är electron attraherande grupp, denna avspaltas, eller e) föreningar with form HR, - ¢ 01, Γ ® 7 Ih R2- {0] color R ^ och R ^ har ονειη angiven betydelse och R ^ betecknar alkyl med 1-5 kolatomer, alkyl med 1-1 + kolatomer, vilken är substituerad med cycloalkyl with 3-6 cholatomers; phenylalkyl of 7 "11 cholatom, monosubstituted phenylalkyl of 7" 11 cholatom, monocyclic phenyl substituted with halo or alkyl of 1-1 + cholatomer; or the groups A-CO-R ^, color A and R ^ bar ovan angiven betydelse, hydreras med en blandning av iodvätesyra och röd phosphorili föreningar med formuleln H RriOT m7 11 hO! h Ra ^ O) color R 1, R 2 and R 2 have an angular lettering, or if wf) a mixture with the form H. ', - © 1 T ®'T Ij R, 2-fO) U6 57748 color R1 ^ och R' a hydrogen or an alkyl group having 1 to 5 carbon atoms, a fluorine or an alkyl group having 1 to 5 carbon atoms, an alkyl group having 1 to 5 carbon atoms, an alkyl group having 1 to U carbon atoms, an alkyl group having 3 to 6 carbon atoms; hydroxy-alkyl of 2-5 cholatomers, benzyl, phenylalkyl of 8-11 cholatomers, and a phenyl group having a quaternary form of a phenyl group having a phenyl group; monosubstituted phenylalkyl with 8-11 cholatom, hydrogenated with phenyl groups substituted with halogen, alkoxy with 1-U cholester or alkyl with 1-U cholester and waxed phenyl having no collative ring on the phenyl group, hydrates and nerves of a metal catalyst for the preparation of HR, l “i” Oi NR ,? Ik h '\] h color R' ^, R'g and R '^ have an angular lettering, varv in the event that the benzyl group is present, or g) a colorless form R ^ och and R ^ has an angular lettering , alkyl of 1-5 cholaters, alkyl of 1-U cholaters, optionally substituted with cycloalkyl of 3-6 cholaters; hydroxyalkyl of 2-5 cholatomers, phenylalkyl of 7 "11 cholatomers, monosubstituted phenylalkyl of 7 ~ 11 cholatomers, hydrogen and phenyl substituents of halogen, alkoxy of 1-U cholaters or alkyl of 1-cholaters, reducing agents with metal hydrides with the formula 1 * 7 57748 H Η, _ ^ θΧ 2 "8 iu R2— [O] color R, Rg and Rg with an angular betydelse, or h) for example with the formula H i R1" tfOl WC0D IV color R ^, Rg , X and Y are optionally substituted and D is selected from the group consisting of alkyl with 1-U cholatom, cycloalkyl with 3 to 6 cholatomers, alkyl with 1 to 3 cholatomers, fused and substituted with cycloalkyl and 3 to 6 cholatomers; hydroxyalkyl with 1-1 + cholatomer, phenyl, phenylalkyl with T-10 cholatomer, monosubstituted phenyl, fused with halogen, alkoxy with 1-1 + cholatomer or alkyl with 1-1 + cholatomer; "Or monosubstituted phenylalkyl with 7" 10 cholatom, preferably with phenyl groups substituted with halogen, alkoxy with 1-1 + cholatomer or alkyl with 1-1 + cholatom, reducing with metal hydride to form with H R1 '_ [rOl NCH2D m