CH615664A5 - Process for the preparation of novel nitrogen-containing polycyclic compounds - Google Patents

Description

The invention relates to a process for the preparation of the compounds of the formula (I)

R

in the R1 and R2 for hydrogen, lower alkyl, lower alkoxy, hydroxyl, fluorine, chlorine, bromine, trifluoromethyl, 2,2,2-trifluoroethyl, methylthio, trifluoromethylthio, trifluoromethylsulfonyl, methylsulfonyl, carboxyl, methoxycarbonyl, ethoxycarbonyl, carbamoyl, sulfamyl, N- Methylsulfamyl, N, N-dimethylsulfamyl, methylsulfinyl, hydrazinocarbonyl, hydroxylaminocarbonyl, lower alkylcarbonyl, cycloalkylcarbonyl with 4 to 7 carbon atoms or nitro and in which R represents hydrogen, alkyl with up to 10 carbon atoms, alkenyl with 3 to 7 carbon atoms, wherein the alkenyl radical is bonded to the nitrogen atom via a saturated carbon atom, cycloalkyl with 3 to 5 carbon atoms, propargyl, 2,2,2-trifluoroethyl, 2,2,3,3,3-pentafluoropropyl, a-furylmethyl. a-thienylmethyl, - (CH2) nCN, - (CH2) nC02H, - (CH2) qOR3, - (CH2) nC02 (lower alkyl) or -CH (R4) (CH2) pRs with up to 14 carbon atoms, where q is 2 to 6, n 1 to 6, p 0 to 5 mean with R3 lower alkyl, phenyl or lower alkylphenyl, R4 is hydrogen or n-lower alkyl and Rs is a hydrocarbyl group containing at least one ring of

35 3 to 9 carbon atoms bonded to the alkylene group through a ring carbon atom, except that when p is 0, the carbon atom bonded to the -CH (R4) group is not a quaternary carbon atom, and, wherein when R in (I) has a meaning other than H, 40 the nitrogen atom is additionally substituted with oxygen to form a tertiary amine oxide.

The compounds produced according to the invention serve as tranquilizers and analgesics.

There is no prior publication describing compounds of the above 45 class. The closest references describe the following structures, in which one or more features of the compounds according to the invention are missing.

3rd

615 664

U.S. Patent 3,726,897 (Apr 10, 1973)

Ethenanthracenes are prepared by an internal Diels-Alder reaction of propargyl-substituted 9-anthracenemethyleneimines, 9-anthracenemethylamines and 9-anthramids, as can be seen from parallel application US Pat. No. 511,026 dated September 30, 1974.

According to a procedure described therein, a substituted anthracene of the formula

oToTg

• RÉ

The process for the preparation of the compounds of formula (I) is specified in the patent claim.

The term “lower alkyl” means an alkyl group with 1 to 4 carbon atoms including branched alkyl groups.

The term "cycloalkyl group" is used in a limited sense for a residue derived by removing a hydrogen atom from a ring of -CH2 groups.

The term "quaternary carbon atom" refers to a carbon atom that is directly connected to 4 other carbon atoms.

The term “cycloalkenyl” refers to a cyclic hydrocarbon group that contains one or more double bonds and that is formally derived from a cycloalkyl group by removing hydrogen.

20th

wherein R1 and R2 are hydrogen, lower alkyl, lower alkoxy, fluorine, chlorine, bromine, trifluoromethyl, 2,2,2-trifluoroethyl or other partially fluorinated lower alkyl groups, trifluoromethylsulfonyl, methylsulfonyl, carboxyl, alkoxycarbonyl, sulfamyl, Represent N-methylsulfamyl, N, N-dimethylsulfamyl, methylsulfinyl or alkylcarbonyl, reacted with an oxalyl chloride in the presence of a catalyst to give the corresponding 9-anthroyl chloride. The substituted 9-anthroyl chloride is reacted with propargylamine per se or with one which is substituted on the nitrogen atom with the above-mentioned R groups. These compounds are subject to an internal Diels-Alder reaction and provide substituted aether noanthracenes with a 9.12 bridge according to the following equation:

C0N-CHo-C = CH

I e

R

This process can be carried out by heating the alkynyl anthramide, either as such or in a suitable inert solvent, preferably an aromatic hydrocarbon, at 80 to 250 ° C within a sufficient time to effect the cyclization, generally from 1 to 48 hours. depending on the conditions.

The reaction of compounds of formula (II) with bromine leads to a ring rearrangement and to products with the backbone I, substituted with bromine in the 12b and 13 positions, and with a 1-carbonyl group. The bromination can be carried out in an inert solvent, preferably in a chlorinated aliphatic hydrocarbon, with methylene chloride and chloroform as particularly preferred representatives. The reaction temperature should be from about -20 to 100 ° C, preferably 20 to 35 ° C.

The bromine atoms are easily removed from the intermediate by reductive dehalogenation with a trialkyltin hydride, either as such or dissolved in an aromatic hydrocarbon solvent. It is preferred to use tributyltin hydride in benzene or toluene. The reaction is carried out at a temperature in the range from 50 to 180 ° C. and gives compounds having a skeleton structure of the formula (I) which have a 1-carbonyl group.

CO-

NO

II

On the other hand, the bromine atoms can be removed by reaction with zinc and acetic acid at 25 to 120 ° C or with zinc and 45 aqueous dimethylformamide.

Another procedure is based on an ethenoanthracene of the formula

50

55

60

65

III

which can be prepared from the corresponding 9-anthraldehyde by reaction with propargylamine, followed by an internal Diels-Alder reaction, reduction of the carbon-nitrogen double bond and alkylation of the compound of formula (III) (R = H) to the corresponding N-substituted compound. On the other hand, a connection of the

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4th

Formula (111) (R = H) can be acylated in the usual way and the acyl derivatives can then be reduced to the corresponding N-substituted compounds using lithium aluminum hydride.

According to a preferred process for the preparation of compounds of formula (III), as shown in the following reaction equations, the 9-anthraldehyde is reacted with a suitable amine at 25 to 150 ° C in an alcoholic solvent to give an imine. The imine is then treated with a metal hydride reducing agent such as sodium borohydride or sodium cyanoborohydride in an alcohol, e.g. B. methanol, ethanol or isopropanol, the same

Solvent, as used in the manufacture of the imine, can be reduced between 0 and 100 ° C. The secondary amine obtained is mixed with propargyl halide, preferably propargyl bromide, in the presence of an inorganic base, e.g. B. an aqueous solution of an alkali metal carbonate, or an organic base which does not substantially react with propargyl bromide, e.g. B. certain sterically hindered amines including diisopropylethylamine, at 0 to 100 ° C, preferably room temperature, condensed.

The alkynyl-substituted athracenes are then cyclized to give compounds of the formula (III) as described below for the cyclization of alkynyl anthramides.

CH0

CH »N-R

R,

Br-CHp-CsCH «c il

CHgN-R

CH2C * CH

CHg-MH-R

The ring rearrangement takes place in the presence of strong acids such as p-toluosulfonic acid and trifluoroacetic acid at approximately 70 to 200 ° C. and provides products with a skeleton structure of the compound of the formula (I), but with a double bond in the 1-12b position. The rearrangement is preferably carried out with trifluoroacetic acid. This agent can also be used for the rearrangement of compounds of the formula (III) in which R represents an acyl group.

The double bond can be reduced to obtain the desired trans structure on the 3a-12b carbon atoms by means such as sodium cyanoborohydride in acetic acid or by catalytic hydrogenation with a palladium catalyst in acetic acid solution, or a platinum or rhodium catalyst in tetrahydrofuran. All of the above mentioned reductions are usually carried out at room temperature, but temperatures between

0 and 60 ° C are appropriate. Applying the catalytic hydrogenation, the hydrogen pressure should be around

1 to 10 atmospheres.

In this procedure, R should have a different meaning than H and R1 and R2 can be hydrolytically stable groups, including the carboxyl groups, which can then be esterified and converted to alkoxycarbonyl, hydrazinocarbonyl, hydroxylaminocarbonyl, carbamoyl or other corresponding substituents. With

Compounds substituted with methylthio and trifluoromethylthio groups are obtained by reducing the corresponding methylsulfonyl and trifluoromethylsulfonyl compounds in a known manner. The hydroxyl-substituted compounds are obtained by cleavage of the corresponding alkoxy compounds.

The following compounds are examples of suitable anthracenes which can be used as starting materials: 1-methylanthracene, 2-methylanthracene

2,6-dimethylanthracene

2.7-dimethylanthracene 2-isopropylanthracene 2-t-butylanthracene

1,8-dimethylanthracene

1-chloroanthracene

2-chloroanthracene 1,5-dichloroanthracene 1,8-dichloroanthracene 2-methoxyanthracene

1,5-dimethoxyanthracene

1-bromanthracene

2-bromanthracene

3.6-dichloroanthracene 1-fluoroanthracene

55

60

65

5

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2-fluoranthracene, 2,6-dimethoxyanthracene

Trifluoromethylanthracene 2-acetylanthracene

1-propionylanthracene 5

1,5-diacetylanthracene 1,8-diacetylanthracene

1-anthronic acid

2-anthronic acid

1 - Anthracensulfonic acid io

2-anthracene sulfonic acid

1,8-anthracene disulfonic acid

2,6-anthracene disulfonic acid

The pharmacologically active compounds are trans compounds on the 3a-12b ring closure with respect to the

12b hydrogen atom and the 13-methane bridge as shown in structure I. The stereochemistry of the 3a-12b ring compound was determined from the crystal structure of the methiodide salt of the compound of the formula (I) with R = CH3, R1 = R2 = H. The crystals of this compound are monoclinic, space group P2j / c with cell dimensions of a = 10.29 ± 0.008, b = 14.759 ± 0.026, C = 12.902 ± 0.012Â and / 3 = 100.64 ± 0.06 °. The C (1) C (12b) C (3a) C (13) torsion angle is -80.6 ± 1.0 ° and the HC (12b) C (3a) C (13) torsion angle 162.2 + 5 , 0 °, where H is the hydrogen at C (12b). The C (l) C (12b) C (3a) C (13) torsion angle is the angle between the C (12b) -C (l) and C (3a) -C (13) bonds in the C (12b ) -C (3a) projection (clockwise). These data confirm that the 3a-12b ring compound has a trans configuration with respect to the 12b hydrogen atom and the 13-methano bridge.

/ \

CH-

CH.

ro

Racemate mixtures can be separated into the stereoisomerically pure racemates (diastereoisomers) using known physical methods, for example by chromatography or fractional distillation. The pure racemates can be separated into the optical antipodes in a known manner, such as combination with an optically active acid and subsequent separation in a physical manner, such as recrystallization of the salts obtained.

The reduction with sodium cyanoborohydride in acetic acid, the catalytic hydrogenation with palladium in acetic acid or with platinum or rhodium in tetrahydrofuran gives the desired trans structure on the ring compound 3a-12b.

The amine compounds can be converted to the amine oxides by oxidation of the corresponding amine with hydrogen peroxide, peracetic acid, perbenzoic acid or similar agents 35 at room temperature or between about 20 and 60 ° C.

The following examples are provided for illustration only and are not intended to limit the invention. The compounds prepared according to the invention, as described in Examples 40, have a trans configuration on the 3a-12b ring compound with respect to the 12b hydrogen atom and the 13-methano bridge.

example 1

45 2-Methyl-2,3,8,12b-tetrahydro-lH-3a, 8-methanodibenzo- [3,4: 6,7] -cyclohepta [1,2-c] pyrrole by acid-catalyzed rearrangement

* 7 *

oho

\

t

■ no further

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6

">

A mixture of 16.7 g of 9-anthraldehyde, 5 g of propargylamine and 100 ml of ethanol is heated under reflux for 1 hour. The solvent is removed and the residue is crystallized from 100 ml of acetonitrile and gives 16.1 g (82%) of N-propargyl-9-anthracenemethyleneimine (2a) with a melting point of 143 to 144 ° C .; NMR spectrum:

t 0.2 (t, 2 Hz, 1); 1.7 to 3.0 (m, 9); 5.1 (t, 2 Hz, 2) and

7.3 (t, 2 Hz, 1).

Analysis for CiSHi3N:

Calculated: C 88.86 H 5.39 N 5.76 Found: C 88.83 H 5.56 N 5.87

A mixture of 19.4 g of crude N-propargyl-9-anthra-cenemethyleneimine and 200 ml of p-xylene is heated under reflux for 3 hours. After cooling, a precipitate of 14.6 g of 3,5-dihydro-5,9b-o-benzolobenz [e] isoindole (2b) with a melting point of 212 to 214 ° C. is obtained. Others

1.4 g of the product are obtained by removing the solvent from the mother liquor and crystallizing the residue from 50 ml of acetonitrile. NMR spectrum:

t 1.1 (m, 1); 2.5 to 3.5 (m, 9); 4.8 (d, J = 6 Hz, 1) and 5.4 (t, J = 2 Hz, 2).

Analysis for Ci8Hi3N:

Calculated: C 88.86 H 5.39 N 5.76 Found: C 89.10 H 5.58 N 5.66

A mixture of 8.19 g of 3,5-dihydro-5,9b-o-benzolo-benz [e] isoindole, 25 ml of formic acid and 25 ml of aqueous formaldehyde solution is heated under reflux for 3 hours. Concentrated hydrochloric acid (10 ml) is then added and the volatiles removed. The residue is stirred with aqueous sodium hydroxide solution and methylene chloride. After removal of the solvent from the dried methylene chloride extracts and crystallization of the residue from acetonitrile, 5.04 g (58%) of 2-methyl-l, 2,3,5-tetrahydro-5,9b-o-benzolobenz [e ] -isoindole (2c) with a melting point of 196 to 197 ° C; NMR spectrum:

r 2.4 to 3.1 (m, 8); 3.3 (d of t, J =% Hz, 1); 4.8 (d, 6 Hz, 1); 6.1 (s, 2); 6.6 (d, 2 Hz, 2) and 7.3 (s, 3).

Analysis for C19H17N:

Calculated: C 87.99 H 6.61 N 5.40 Found: C 88.05 H 6.91 N 5.32

A sealed Carius bomb tube with 20.0 g of 2-methyl-l, 2,3,5-tetrahydro-5,9b-o-benzolobenz [e] isoindole and 80 ml of trifluoroacetic acid is heated at 150 ° C. for 8 hours. The acid is distilled, the residue dissolved in methylene chloride. The solution is slowly added to a stirred, cooled, excess 15% aqueous sodium hydroxide solution. The layers are separated and the aqueous phase extracted once with methylene chloride. Removal of the solvent from the combined dried extracts gives 19.6 g of 2-methyl-20 2,3-dihydro-8H-3a, 8-methanodibenzo [3,4: 6,7] cyclohepta- [l, 2-c] pyrrole (2d). NMR spectrum:

r 2.5 to 3.3 (m, 8); 3.9 (s, 1); 6.1 (d, 10 Hz, 1); 6.1 (d, 4 Hz, further splitting, 1); 6.9 (d, 10 Hz, 1); 7.3 (s, 3) and 7.4 to 7.9 (AB quartet, J = 9 Hz; the component in the never-25 whose range is split again by 4 Hz; that in the higher range by approximately 1 Hz; 2 ). A sample crystallized twice from isopropyl alcohol melts at 119.5 to 120 ° C.

Analysis for Ci9H17N:

30 Calculated: C 87.99 H 6.61 N 5.40 Found: C 87.66 H 6.74 N 5.45

The above rearrangement can also be carried out with p-toluenesulfonic acid in acetic acid at 165 ° C.

A mixture of 13.6 g of 2-methyl-2,3-dihydro-8H-35 3a, 8-methanodibenzo [3,4: 6,7] cyclohepta [1,2-c] pyrrole,

100 ml of acetic acid and 2 g of 10% palladium-on-charcoal catalyst are shaken under a hydrogen pressure of 2.80 kg / cm2 (40 psi) at room temperature until the pressure remains constant. The filtered mixture is concentrated and the residue is made basic and extracted several times with methylene chloride. Removal of the solvent from the dried extracts gives 13.7 g of 2-methyl-2,3,8,12b-tetra-hydro-lH-3a, 8-methanodibenzo [3,4: 6,7] cyclohepta [1,2 -cj-pyrrole (lc), which is identical on the basis of the NMR spectrum 45 with the product obtained in Example 1.

The hydrogenation of compound 2d to compound lc can also be carried out using a platinum catalyst in tetrahydrofuran. If tetrahydrofuran is used as a solvent together with a palladium catalyst, some stereoisomer lc is also formed.

The reduction of compound 2d to 1c can also be carried out with sodium cyanoborohydride in acetic acid-methanol at room temperature.

55 Example 2

2-Benzyl-2,3,8,12b-tetrahydro-lH-3a, 8-methanodibenzo- [3,4: 6,7] cyclohepta [1,2-c] pyrrole by acid-catalyzed conversion cho

CH = NCH2CeH5 5a

CH2NHCE2CéH £ 5b

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ch2.

-> LO

KCH2CqH5

CHsN ^ CKsCgHg I

CH2CHCK

5s.

ch2

5d

■> LO

5e

A mixture of 100 g of 9-anthraldehyde, 53 g of benzylamine and 300 ml of ethanol is heated under reflux under nitrogen for 2.5 hours. The solution of N-benzyl-9-an-thracenemethyleneimine (5a) is cooled to 60 ° C and 18.78 g of sodium borohydride are added slowly, keeping the temperature at 60 to 65 ° C. After stirring at room temperature overnight, the excess hydride is destroyed by the slow addition of concentrated hydrochloric acid. The mixture is then made basic and extracted several times with methylene chloride. Removal of the solvent from the dried extracts provides 139.9 g of N-benzyl-9-anthracenemethylamine (5b). NMR spectrum:

t 1.8 to 3.0 (m, 14); 5.5 (s, 2); 6.2 (s, 2) and 8.5 (s, 1).

The product is dissolved in 300 ml of methylene chloride, 200 ml of 10% aqueous sodium carbonate solution and 100 ml of propargyl bromide are added and the mixture is stirred vigorously under nitrogen at room temperature for 3 hours. The layers are separated, the aqueous layer extracted once with methylene chloride, the combined extracts washed with concentrated sodium chloride solution and dried. Removal of the solvent gives 153.5 g of N-benzyl-N-propargyl-9-anthracenemethylamine (5c). NMR spectrum:

t 1.5 to 3.0 (m, 14); 5.5 (s, 2); 6.3 (s, 2); 6.9 (d, J = 2.5 Hz, 2) and 7.7 (t, J = 2.5 Hz, 1).

The product is heated under reflux with 11 toluene for 2.25 hours. Removal of the solvent gives crude 2-benzyl-l, 2,3,5-tetrahydro-4,9b-o-benzenobenz [e] isoindole (5d). A sample crystallized from isopropyl alcohol is identical by NMR spectra to the product obtained by benzoylation of 1,2,3,5-tetrahydro-5,9b-o-benzolobenz- [ejisoindole and subsequent reduction (see below) .

A mixture of 48.9 g 2-benzyl-l, 2,3,5-tetrahydro-5,9b-o-benzolobenz [e] isoindole (5d) and 150 ml trifluoroacetic acid in three sealed Carius bomb tubes

35

50

55

60

is heated at 150 ° C for 12 hours. The excess acid is distilled off under vacuum and the residue is dissolved in methylene chloride. The solution is slowly added to a cold, stirred, excess 15% aqueous sodium hydroxide solution. The layers are separated, the aqueous phase is extracted once with methylene chloride and the combined extracts are dried. Removal of the solvent and crystallization of the residue from 150 ml of acetonitrile gives 38.3 g of 2-benzyl-2,3-dihydro-8H-3a, 8-me-thanodibenzo [3,4: 6,7] cyclohepta [1,2 -c] pyrrole (5e). NMR spectrum:

r 2.4 to 3.1 (m, 13); 3.7 (s, 1); 5.7 to 7.8 (m, 7).

An analytical sample obtained by crystallization from acetonitrile has a melting point of 135 to 145 ° C. Analysis for C2SH2iN:

Calculated: C 89.51 H 6.31 N 4.18 Found: C 89.56 H 6.45 N 4.46

A mixture of 37.7 g of finely powdered 2-benzyl-2,3-dihydro-8H-3a, 8-methanodibenzo [3,4: 6,7] cyclohepta- [1,2-c | pyrrole (5e), 300 ml Methanol and 40 ml of acetic acid are cooled with ice and 14.8 g of sodium cyanoborohydride are slowly added with stirring. The mixture is stirred at room temperature for 3 hours, cooled and treated with 50 ml of concentrated hydrochloric acid. After stirring at room temperature for 0.5 hours, the mixture is made basic and extracted several times with methylene chloride. Removal of the solvent from the dried extracts provides 37.5 g of 2-benzyl-2,3,8,12b-tetrahydro-lH-3a, 8-me-thanodibenzo [3,4: 6,7] cyclohepta [1,2 -c] pyrrole, determined by NMR spectrum, is identical to the product according to Example 4. The hydrochloride melts with decomposition at 195 to 200 ° C after crystallization from ethanol.

Analysis for C25H24C1N:

Calculated: C 80.30 H 6.47 N 3.75 Found: C 79.92 H 6.80 N 4.13

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The intermediate, 2-BenzyJ-l, 2,3,5-tetrahydro-5,9b-o-benzolobenz [e] isoindole (5d) can also be prepared as follows:

4.70 g of sodium cyanoborohydride are slowly added with cooling to a slurry of 10.19 g of 3,5-dihydro-5,9b-o-benzolo-benz [e] isoindole (Example 2) in 50 ml of methanol and 10 ml of acetic acid. The mixture is stirred at room temperature overnight and the excess hydride is destroyed with concentrated hydrochloric acid (ice bath), the mixture is made basic and extracted with methylene chloride. After removal of the solvent from the dried extract, 10.14 g of 1,2,3,5-tetrahydro-5,9b-o-benzolobenz [e] isoindole are obtained as an oil; NMR spectrum:

r 2.6 to 3.7 (m, 9) 4.9 (d, 6 Hz, 1) 6.0 (s, 2); 6.5 (d, 2 Hz, 2) and 7.5 (s, 1).

4.19 g of benzoyl chloride are added to a mixture of 4.60 g of l, 2,3,5-tetrahydro-5,9b-o-benzolobenz [e] isoindole, 5 g of magnesium oxide and 20 ml of tetrahydrofuran. After stirring at room temperature overnight, the mixture is filtered, the filtrate concentrated and the residue dissolved in methylene chloride. The solution is washed again with a 10 ml potassium carbonate solution and water and the solvent is removed. The residue, the raw 2-ben-

zoyl-1,2,3,5-tetrahydro-5,9b-o-benzolobenz [e] isoindole is heated under reflux with 2.83 g of lithium aluminum hydride in tetra-hydrofuran for 4 hours. 2.8 ml of water are slowly added to the cooled mixture and then 2.8 ml of 15% aqueous sodium hydroxide solution and finally 8.4 ml of water. The mixture is filtered and the filtrate concentrated to give 5.45 g of crude 2-benzyl-l, 2,3,5-tetra-hydro-5,9b-o-benzolobenz [e] isoindole (5d). Crystallization of 1.06 g of this material from isopropyl alcohol io gives 0.66 g of pure compound 5d with a melting point of 125 to 126 ° C. NMR spectrum:

r2.4 to 3.6 (m, 14); 5.0 (d, 6 Hz, 1); 6.2 (s, 2); 6.3 (s, 2) and 6.7 (d, 2 Hz, 2).

Analysis for C2SH21N:

15 Calculated: C 89.51 H 6.31 N 4.18 Found: C 89.77 H 6.26 N 4.26

Example 3

20 2-Cyclopentylmethyl-2,3,8,12b-tetrahydro-1 H-3a, 8-me-thanodibenzo [3,4: 6,7] cyclohepta [1,2-c] pyrrole by acylation of 2, 3,8,12b-tetrahydro-1 H-3a.8-methanodibenzo [3,4: 6,7] cyclohepta [1,2-c | pyrrole and subsequent reduction.

CHs - ".3

Following the procedure of Example 6, but using cyclopentane carbonyl chloride instead of cyclopropane carbonyl chloride, 2-cyclopentyl-methyl-2,3,8,12b-tetrahydro-lH-3a, 8-methanodibenzo- [3,4: 6,7 ] cyclohepta [l, 2-c] pyrrole as an oil that slowly crystallizes. NMR spectrum:

t 2.5 to 3.0 (m, 8) and 6.0 to 9.0 (m, 19) at 220 MHz, the r 6.0 to 9.0 range dissolves from the lower to the higher field a doublet (J = 4 Hz, 1), a doublet (J = 10 Hz, 1), a doublet of the doublet (J ~ 7 and 8 Hz; 1), a doublet of the doublet (J = 7 and 11 Hz; 1 ), a four-proton multi-plett, a doublet of the doublet (J = 4 and 10 Hz, 1), a doublet (J = 10 Hz; 1) and multiplet (1, 2, 4 and 2 protons). The hydrochloride melts with decomposition at 250 to 253 ° C after crystallization from isopropyl alcohol and drying at 110 to 115 ° C under 0.2 micron pressure for 9 hours.

Analysis for C24H28C1N:

Calculated: C 78.77 H 7.71 N 3.83

Found: C 78.52 H 7.83 N 3.72

The 2-cyclopentylmethyl-2,3,8,12b-tetrahydro-lH-3a, 8-methanodibenzo [3,4: 6,7] cyclohepta [1,2-c] pyrrole-N-oxide is prepared as follows: One A solution of 3.92 g of the free base in 20 ml of chloroform is slowly added to a cooled mixture of 10 ml of 40 cfiger peracetic acid and 2 g of anhydrous sodium acetate. The mixture is stirred at room temperature for 90 minutes, cooled and made basic by adding a 15% aqueous sodium hydroxide solution. The layers are separated and the aqueous layer extracted once with chloroform. The combined organic phases are dried and concentrated to give 3.80 g of crude product which still contains some solvent. The NMR spectrum shows the presence of two isomers. The addition of hot ethyl acetate causes an isomer to crystallize; this is purified by recrystallization from acetonitrile. NMR spectrum (220 MHz) thus from the lower to the higher range: aromatic range r 2.3 to 3.3 (d, J = 7.5 Hz, 1 and m, 7); aliphatic range, r 5.5 to 9.0 (m, 2; d, J = 4.5 Hz + m, 2; d, J = 12 Hz, 1; m, 3; m, l; d / d, J = 4.5 / 10 Hz, l; d, J = 10Hz + m, 3; m, 4 and m, 2).

55 2-Cyclopentylmethyl-2,3,8,12b-tetrahydro-trans-lH-3a, 8-methanodibenzo [3,4: 6,7] cyclohepta [1,2-c] pyrrole is separated into its optical antipodes by fractional Crystallization of the (+) and (-) dibenzoyl (-) tartaric acid salts. The hydrochloride of the (-t -) isomer has an [a] D = 60 +125 ° C (c = 2.21 g / 100 ml chloroform); the hydrochloride of the (-) isomer has an [a] D = -125 ° C (c = 2.00 g / 100 ml chloroform).

Example 4

65 2-Cyclopentylmethyl-2,3,8,12b-tetrahydro-lH-3a, 8-me-thanodibenzo [3,4: 6,7] cyclohepta [1,2-c] pyrrole by acid-catalyzed rearrangement of 2-cyclopentylmethyl l, 2,3,5-trahydro-5,9b-o-benzenobenz [e] isoindole

9

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CKO

CH-N-CH2

8a

CH2C = CH

8b fsj

KCKa

"O

8d

/ vV

8c

/ v /

4V

8f

A /

According to the procedure of Example 5, but using cyclopentylmethylamine instead of benzylamine, the following are obtained:

N-cyclopentylmethyl-9-anthracenemethyleneimine (8a); NMR spectrum:

r 0.9 (t, 1); 1.5 to 2.8 (m, 9); 6.3 (d, further splitting 2) and 7.3 to 9.0 (m, 9).

N-cyclopentylmethyl-9-anthracenemethylamine (8b); NMR spectrum:

r 1.8 to 3.1 (m, 9); 5.6 (s, 2); 7.5 (d, 7 Hz, 2) and 7.8 to 9.3 (m, 10).

N-cyclopentylmethyl-N-propargyl-9-anthracenemethylamine (8c); NMR spectrum:

t 2.3 to 3.0 (m, 9); 5.5 (s, 2); 6.8 (d, 2.5 Hz, 2); 7.5 (m, 2); 7.7 (t, 2.5 Hz, 1) and 7.5 to 9.2 (m, 9).

2-cyclopentylmethyl-l, 2,3,5-tetrahydro-5,9b-o-benzolo-benz [e] isoindole (8d); Melting point 110 to 111 ° C; NMR spectrum:

t 2.6 to 3.2 (m, 8); 3.5 (d / t, 6/2 Hz, 1); 4.9 (d, 6 Hz, 1); 6.2 (s, 2); 6.7 (d, 2 Hz, 2) and 7.3 to 9.0 (m, 11).

Analysis for C24H2SN:

Calculated: C 88.03 H 7.70 N 4.28 Found: C 87.68 H 7.75 N 4.43

2-cyclopentylmethyl-2,3-dihydro-8H-3a, 8-methanodi-benzo [3,4: 6,7] cyclohepta [1,2-c] pyrrole (8e), melting point 103 to 104 ° C; NMR spectrum:

r 2.6 to 3.3 (m, 8); 3.9 (s, 1); 6.0 to 6.3 (d, 4 Hz, 1 and d, so 10 Hz, 1); 6.8 (d, 10 Hz, 1) and 7 to 9 (m, 13).

Analysis for C24H2SN:

Calculated: C 88.03 H 7.70 N 4.28 Found: C 87.83 H 8.06 N 4.34

55 2-Cyclopentylmethyl-2,3,8,12b-tetrahydro-1H-3 a, 8-me-thanodibenzo [3,4: 6,71cyclohepta [1,2-c] pyrrole (8f) is at 220 MHz NMR- spectroscopically identical to the product according to Example 7.

The reduction of compounds 8e to such 8f can be used with hydrogen in acetic acid using palladium-carbon as catalyst, as described in Example 2.

Example 5

65 2-Cyclopentylmethyl-2,3,8,12b-tetrahydro-lH-3a, 8-me-thanodibenzo [3,4: 6,7] cyclohepta [l, 2-c] pyrrole using acid-catalyzed rearrangement of 2-cyclopentane carbonyl l, 2,3,5-tetrahydro-5,9b-o-benzolobenzfe] isoindole

->

9b

8e

<v

A mixture of 12.07 g, 2,3,5-tetrahydro-5,9b-o-benzolobenz [elisoindole (example 5), 70 ml chloroform and 40 35 ml triethylamine is treated with 10.5 g cyclopentane carbonyl chloride and treated with kept at a temperature below 20 ° C. After stirring at room temperature for 2 hours, a 10% aqueous sodium hydroxide solution is added with cooling and the mixture is stirred at room temperature for a further 45 30 minutes. The layers are separated and the aqueous phase extracted once with methylene chloride. Removal of the solvent from the dried extracts and crystallization of the residue from 50 ml of acetonitrile yield 13.14 g2-cyclopentanecarbonyl-l, 2,3,5-tetrahydro-5,9b-o-50 benzolobenz [e] isoindole (9a). NMR spectrum:

r 2.5 to 3.5 (m, 9); 4.8 (d, 6 Hz, 1); 5.1 (s, 2); 5.8 (s, 2 Hz, 2) and 6.7 to 8.7 (m, 9). An analytical sample (acetonitrile) has a melting point of 189 to 190 ° C.

Analysis for C24H23NO: 55

Calculated: C 84.42 H 6.79 N 4.10 Found: C 84.04 H 6.79 N 4.29

A mixture of 11.67 g of the above product and 60 ml of trifluoroacetic acid is heated under reflux for 2 hours. The excess acid is removed under vacuum, the residue is dissolved in methylene chloride and the solution is poured into a cold, stirred, excess aqueous sodium hydroxide solution. The mixture is extracted several times with methylene chloride, the extracts dried, the solvent removed and the residue crystallized from 40 ml of toluene, so that 10.89 g of 2-cyclopentanecarbonyl-2,3-dihydro-8H-3a, 8 -methanodibenzo [3,4: 6,7] cyclohepta [1,2-c] pyrrole (9b). NMR spectrum:

r 2.5 to 3.2 (m, 9); 5.0 to 6.1 (m, 3) and 6.6 to 8.5 (m, 11). An analytical sample (acetonitrile) has a melting point of 185 to 186 ° C.

Analysis for C24H23NO:

Calculated: C 84.42 H 6.79 N 4.10

Found: C 84.60 H 6.93 N 4.55

1.55 g of compound 9b are added to a chilled slurry of 0.40 g of lithium aluminum hydride in 30 ml of ether, and the mixture is stirred at room temperature for 6 hours. The excess hydride is decomposed by adding 0.4 ml of water and then 0.4 ml of 15% aqueous sodium hydroxide solution and 1.2 ml of water. The mixture is filtered and the filtrate concentrated. Crystallization of the residue from isopropyl alcohol yields 0.89 g of 2-cyclo-pentylmethyl-2,3-dihydro-8H-3a, 8-methanodibenzo- [3,4: 6,7] cyclohepta [1,2-c] pyrrole ( 8e), which is identical to the product of Example 8 according to the infrared and NMR spectra.

Reduction of compound 8e as described in Example 8 gives 2-cyclopentylmethyl-2,3,8,12b-tetrahydro-lH-3a, 8-methanodibenzo [3,4: 6,7] cyclohepta [1,2-c ] pyrrole.

Hydrogenate 2-cyclopentane carbonyl-2,3-dihydro-8H-3a, 8-methanodibenzo [3,4: 6,7] cyclohepta [1,2-c] pyrrole (9b) with a palladium on carbon catalyst in Tetra-hydrofuran gives 2-cyclopentane carbonyl-2,3,8,12b-te-trahydro-1 H-3a, 8-methanodibenzo [3,4: 6,7 | cyclohepta- [1,2-c] pyrrole with a cis stereospecificity at the ring condensation site 3a-12b.

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Example 6

2-AllyI-2,3,8,12b-tetrahydro-lH-3a, 8-methanodibenzo- [3,4: 6,7 [cyclohepta [1,2-c] pyrrole.

A mixture of 2.19 g 2,3,8,12b-tetrahydro-lH-3a, 8-methanodibenzo [3,4: 6,7] cyclohepta [1,2-c] pyrrole (example 3), 20 ml chloroform , 20 ml of a 10% potassium carbonate solution and 4 ml of allyl bromide is stirred vigorously under nitrogen at room temperature for 5 hours. The precipitate that forms is brought into solution by adding methanol; the layers are separated and the aqueous phase extracted once with a mixture of methylene chloride and methanol. The solvent is removed from the dried extracts and the residue is heated with 15 ml of methanol and 6 g of trimethylamine in a sealed Carius bomb tube at 110 ° C. for 8 hours. This treatment converts any quaternary salt to the desired tertiary amine. The solvent is removed and the residue is dissolved in methylene chloride. The solution is washed with an aqueous sodium hydroxide solution and dried. Removal of the solvent gives 2-allyl-2,3,8,12b-tetrahydro-lH-3a, 8-methanodibenzo- [3,4: 6,7] cyclohepta [1,2-c] pyrrole. The hydrochloride has a melting point after crystallization from isopropyl alcohol of 208 to 209 ° C (dec.) And weighs 1.60 g.

Analysis for C21H22CIN:

Calculated: C 77.88 H 6.85 N 4.33 Found: C 78.14 H 7.02 N 4.47

The free base has the following NMR spectrum:

t 2.7 to 3.2 (m, 8); 3.7 to 4.4 (m, 1); 4.6 to 5.1 (m, 2) and 6.1 to 7.9 (m, 10).

Example 7

Ethyl 2,3,8,12b-tetrahydro-lH-3a, 8-methanodibenzo [3,4: 6,7 | cyclohepta [1,2-c] pyrrole-2-butyrate.

CHsCHaCEaCOaCaHs

A mixture of 2.35 g of 2,3,8,12b-tetrahydro-lH-3a, 8-methanodibenzo [3,4: 6,7] cyclohepta [1,2-c] pyrrole, 25 ml of dimethylformamide, 4 ml of triethylamine and 2.55 g of ethyl 4-bromobutyrate is heated at 60 to 65 ° C bath temperature under nitrogen for 18 hours. The cooled reaction mixture is diluted with water and extracted twice with methylene chloride. The extracts are washed with a dilute aqueous sodium hydroxide solution, dried and concentrated. 3.07 g of crude ethyl-2,3,8,12b-tetra-hydro-lH-3a, 8-methanodibenzo [3,4: 6,7] cyclohepta [1,2-c] pyrrole-2 are thus obtained -butyrate. NMR spectrum:

r 2.7 to 3.2 (m, 8); 5.9 (quartet J = 7 Hz, 2); 6.0 to 8.5 (m, 14) and 8.8 (t, 7 Hz, 3).

The following derivatives of 2,3,8,12b-tetrahydro-lH-3a.8-methanodibenzo [3,4: 6,7] cyclohepta [1,2-c] pyrrole were prepared according to the procedures of the previous examples. These procedures are identified as follows for identification:

I. Acylation of 2,3,8,12b-tetrahydro-lH-3a, 8-metha-nodibenzo [3,4: 6,71cyclohepta [1,2-c] pyrrole with an appropriate acid chloride and subsequent reduction.

II. Reaction of 9-anthraldehyde, optionally substituted in the benzene ring (s) with a corresponding primary amine, followed by the indicated further steps.

III. Implementation of 9-anthroyl chloride with a corresponding N-substituted propargylamine and subsequent implementation.

IV. Alkylation of 2,3,8,12b-tetrahydro-lH-3a, 8-me-thanodibenzo [3,4: 6,71cyclohepta [1,2-c] pyrrole.

Example 8

2-ethyl-2,3,8,12b-tetrahydro-lH-3a, 8-methanodibenzo [3,4: 6,7] cyclohepta [1,2-c] pyrrole; NMR spectrum:

r 2.5 to 3.2 (m, 8); 6.0 to 8.0 (m, 10) and 8.8 (t, 3).

Example 9

2-n-butyl-2,3,8,12b-tetrahydro-lH-3a, 8-methanodibenzo [3,4: 6,7] cyclohepta [1,2-c] pyrrole; NMR spectrum:

t 2.7 to 3.2 (m, 8) and 6.1 to 9.3 (m, 17).

Example 10

2-n-hexyl-2,3,8,12b-tetrahydro-lH-3a, 8-methanodi-benzo [3,4: 6,7] cyclohepta [1,2-c [pyrrole; NMR spectrum: r 2.7 to 3.2 (m, 8) and 6.0 to 9.4 (m, 21).

Example 11

2-n-heptyl-2,3,8,12b-tetrahydro-lH-3a, 8-methanodi-benzo [3,4: 6,7] cyclohepta [1,2-c] pyrrole; NMR spectrum: t 2.6 to 3.1 (m, 8) and 6.0 to 9.4 (m, 23).

Example 12

2-n-octyl-2,3,8,12b-tetrahydro-lH-3a, 8-methanodibenzo [3,4: 6,7] cyclohepta [1,2-c] pyrrole; NMR spectrum:

r 2.6 to 3.2 (m, 8) and 6.0 to 9.3 (m, 25).

Example 13

2- (2-ethylbutyl) -2,3,8,12b-tetrahydro-lH-3a, 8-methano-dibenzo [3,4: 6,7] cyclohepta [1,2-c] pyrrole; NMR spectrum: t 2.7 to 3.2 (m, 8) and 6.1 to 9.2 (m, 21).

Example 14

2-propargyl-2,3,8,12b-tetrahydro-lH-3a, 8-methanodi-benzo [3,4: 6,7 [cyclohepta [1,2-clpyrrole; NMR spectrum: r 2.5 to 3.1 (m, 8) and 6.0 to 7.8 (m, 11).

Example 15

2-cyclobutylmethyl-2,3,8,12b-tetrahydro-1H-3 a, 8-me-thanodibenzo [3,4: 6,7] cyclohepta [1,2-c] pyrrole;

Hydrochloride: melting point ^ 260 ° C (dec.)

Analysis for C23H28C1N:

Calculated: C 78.49 H 7.45 N 3.98 Found: C 78.31 H 7.31 N 3.93

Example 16

2- (3-methylenecyclobutylmethyl) -2,3,8,12b-tetrahydro-lH-3a, 8-methanodibenzo [3,4: 6,7-lcyclohepta [1,2-c] pyrrole; NMR spectrum:

r 2.7 to 3.3 (m, 8); 5.2 to 5.5 (m, 2) and 6.1 to 8.0 (m, 15).

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Example 17

2- (1-cyclopentenylmethyl) -2,3,8,12b-tetrahydro-1H-3 a, 8-methanodibenzo [3,4: 6,7] cyclohepta [1,2-clpyrrole; NMR spectrum:

r 2.7 to 3.2 (m, 8); 4.3 to 4.5 (m, 1) and 6.0 to 8.3 (m, 16). Example 18

2- (2-CyclopentyIäthyI) -2,3,8,12b-tetrahydro-lH-3a, 8-me-thanodibenzo [3,4: 6,7] cyclohepta [1,2-c] pyrrole; Hydrochloride: melting point 246 to 248 ° C (decomp.)

Analysis for C25H30CIN:

Calculated: C 79.02 H 7.96 N 3.69 Found: C 78.83 H 7.87 N 3.55

Example 19

2- (2-cyclopent-2-enylethyl) -2,3,8,12b-tetrahydro-lH-3a, 8-methanodibenzo [3,4: 6,7] cyclohepta [1,2-c] pyrrole; NMR spectrum:

r 2.7 to 3.1 (m, 8); 4.2 to 4.4 (m, 2) and 6.0 to 9.0 (m, 17). Example 20

2- (3-cyclopentylpropyl) -2,3,8,12b-tetrahydro-lH-3a, 8-methanodibenzo [3,4: 6,7] cyclohepta [1,2-c] pyrrole; Hydrochloride:

Melting point 242 to 243 ° C (decomp.)

Analysis for C26H32C1N:

Calculated: C 79.26 H 8.19 N 3.56 Found: C 79.83 H 8.33 N 3.51

Example 21

2-cyclohexylmethyl-2,3,8,12b-tetrahydro-lH-3a, 8-me-thanodibenzo [3,4: 6,7] cyclohepta [1,2-c] pyrrole; Hydrochloride: melting point 248 to 253 ° C (decomp.)

Analysis for C2sH3oC1N:

Calculated: C 79.02 H 7.96 N 3.69 Found: C 78.69 H 7.91 N 3.79

Example 22

2- (l-cyclohexenylmethyl) -2,3,8,12b-tetrahydro-lH-3a, 8-methanodibenzo [3,4: 6,7] cyclohepta [1,2-c] pyrrole; NMR spectrum:

t 2.7 to 3.2 (m, 8); 4.0 (m, 1) and 5.5 to 8.6 (m, 18).

Example 23

2- (3-cyclohexenylmethyl) -2,3,8,12b-tetrahydro-lH-3a, 8-methanodibenzo [3,4: 6,7] cyclohepta [1,2-c] pyrrole; NMR spectrum:

r 2.6 to 3.1 (m, 8); 4.3 (m, 2) and 6.0 to 9.0 (m, 17).

Example 24

2- (1,4-cyclohexadienylmethyl) -2,3,8,12b-tetrahydro-lH-3a, 8-methanodibenzo [3,4: 6,7] cyclohepta [1,2-clpyrrole; NMR spectrum:

t 2.6 to 3.1 (m, 8); 4.1 to 4.5 (m, 3) and 6.0 to 7.8 (m, 14). Example 25

2- (2-cyclohexylethyl) -2,3,8,12b-tetrahydro-lH-3a, 8-me-thanodibenzo [3,4: 6,7] cyclohepta [1,2-c] pyrrole; Hydrochloride: melting point 234 to 238 ° C (decomp.)

Analysis for C26H32C1N:

Calculated: C 79.26 H 8.18 N 3.56 Found: C 78.77 H 8.26 N 3.40

Example 26

2- (3-cyclohexylpropyl) -2,3,8,12b-tetrahydro-1H-3a, 8-methanodibenzo [3,4: 6,71cycloheptaf 1,2-clpyrrole; NMR spectrum:

r 2.5 to 3.1 (m, 8) and 6.0 to 9.5 (m, 25).

12 •

Example 27

2- (4-cyclohexylbutyl) -2,3,8,12b-tetrahydro-1 H-3a, 8-me-thanodibenzo [3,4: 6,7] cyclohepta [1,2-c] pyrrole; NMR spectrum:

5 t 2.7 to 3.2 (m, 8) and 6.1 to 9.7 (m, 27).

Example 28

2-CycIoheptyImethyI-2,3,8,12b-tetrahydro-lH-3a, 8-me-thanodibenzo [3,4: 6,7] cyclohepta [1,2-c] pyrrole; Hydrochloride: melting point 254 to 256 ° C (dec.)

Analysis for C26H32C1N:

Calculated: C 79.26 H 8.19 N 3.56 Found: C 79.00 H 7.86 N 3.81

The NMR spectrum of the free base obtained as an oil shows bands at r 2.5 to 3.2 (m, 8) and 6.0 to 9.2 (m, 23).

Example 29

2- (4-cycloheptenylmethyl) -2,3,8,12b-tetrahydro-lH-3 a, 8-methanodibenzo [3,4: 6,7] cyclohepta [1,2-c] pyrrole; 20 NMR spectrum:

r 2.7 to 3.1 (m, 8); 4.0 to 4.5 (m, 2) and 6.0 to 9.3 (m, 19).

Example 30

2-cyclooctylmethyl-2,3,8,12b-tetrahydro-1H-3 a, 8-me-25 thanodibenzo [3,4: 6,7] cyclohepta [1,2-c] pyrrole; NMR spectrum:

r 2.7 to 3.3 (m, 8) and 6.1 to 9.2 (m, 25).

Example 31

30 2- (2-Exo-bicyclo [2,2,1] heptylmethyl) -2,3,8,12b-tetra-hydro-lH-3a, 8-methanodibenzo [3,4: 6,7] cyclohepta [l , 2-c] pyrrole; NMR spectrum:

t 2.6 to 3.1 (m, 8) and 6.0 to 9.2 (m, 21).

35 Example 32

2- (2-endo-bicyclo [2,2, l] heptamethyl) -2,3,8,12b-tetra-hydro-lH-3a, 8-methanodibenzo [3,4: 6,7 | cyclohepta [l, 2-c] pyrrole; NMR spectrum:

r 2.6 to 3.1 (m, 8) and 6.0 to 9.3 (m, 21).

40

Example 33

2- (2-Exo-bicyclo [2,2, l] hept-5-enylmethyl) -2,3,8,12b-te-trahydro-lH-3a, 8-methanodibenzo [3,4: 6,7] cyclohepta- [1,2-c] pyrrole; NMR spectrum:

45 r 2.6 to 3.2 (m, 8); 3.8 to 4.1 (m, 2) and 6.0 to 8.9 (m, 17).

Example 34

2- (2-Endo-bicyclo [2,2, l] hept-5-enylmethyl) -2,3,8,12b-tetrahydro-lH-3a, 8-methanodibenzo [3,4: 6,7] cy- 50 clohepta [1,2-c] pyrrole; NMR spectrum:

r 2.6 to 3.3 (m, 8); 3.8 to 4.2 (m, 2) and 6.1 to 9.6 (m, 17).

Example 35

2- (2-phenylethyl) -2,3,8,12b-tetrahydro-lH-3a, 8-me-55 thanodibenzo [3,4: 6,7] cyclohepta [1,2-c] pyrrole; Hydrochloride: melting point 248 to 250 ° C (dec.)

Analysis for C26H26C1N:

Calculated: C 80.49 H 6.76 N 3.61 Found: C 80.71 H 6.82 N 3.59

60 The NMR spectrum of the free base obtained as an oil shows bands at r 2.6 to 3.2 (m, 8) and 6.0 to 7.9 (m, 12).

Example 36

65 2- (2-phenoxyethyl) -2,3,8,12b-tetrahydro-lH-3a, 8-methanediobenzo [3,4: 6,7] cyclohepta [1,2-c] pyrrole; NMR spectrum:

t 2.6 to 3.3 (m, 13) and 5.7 to 8.3 (m, 12).

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Example 37

2- (2-methoxyethyI) -2,3,8,12b-tetrahydro-1 H-3a, 8-me-thanodibenzo [3,4: 6,7] cyclohepta [1,2-c] pyrrole; NMR spectrum:

t 2.7 to 3.1 (m, 8) and 6.1 to 7.9 (m, 15).

Example 38

2- (2-furylmethyl) -2,3,8,12b-tetrahydro-lH-3a, 8-me-thanodibenzo [3,4: 6,7] cyclohepta [1,2-clpyrrole; NMR spectrum:

r 2.6 to 3.2 (m, 9); 3.6 to 3.9 (m, 2) and 6.0 to 8.0 (m, 10). Example 39

5- and ll-chloro-2-methyl-2,3,8,12b-tetrahydro-lH-3a, 8-methanodibenzo [3,4: 6,7] cyclohepta [1,2-c] pyrrole; NMR spectrum:

r 2.6 to 3.2 (m, 7) and 5.9 to 7.8 (m, 11).

Example 40

5- and ll-chloro-2-cyclohexylmethyl-2,3,8,12b-tetrahydro-lH-3a, 8-methanodibenzo [3,4: 6,7] cyclohepta [1,2-c] pyrrole; NMR spectrum:

r 2.5 to 3.1 (m, 7) and 6.0 to 9.5 (m, 21).

Example 41

2-cyclopropyI-2,3,8,12b-tetrahydro-lH-3a, 8-methanodi-benzo [3,4: 6,71cyclohepta [1,2-c] pyrrole; NMR spectrum: r 2.5 to 3.1 (m, 8); 6.0 to 8.4 (m, 9) and 9.4 to 9.8 (m, 4).

Example 42

2-CyclobutyI-2,3,8,12b-tetrahydro-IH-3a, 8-methanodi-benzo [3,4: 6,7] cyclohepta [1,2-c] pyrrole; NMR spectrum: r 2.7 to 3.2 (m, 8) and 6.1 to 8.5 (m, 15).

Example 43

2-cyclopentyl-2,3,8,12b-tetrahydro-lH-3a, 8-methanodi-benzo [3,4: 6,7] cyclohepta [1,2-c] pyrrole; NMR spectrum: r 2.6 to 3.2 (m, 8) and 6.1 to 8.8 (m, 17).

Example 44

2-isopropyl-2,3,8,12b-tetrahydro-lH-3a, 8-methanodi-benzo [3,4: 6,7] cyclohepta [1,2-c] pyrrole; NMR spectrum: r 2.7 to 3.2 (m, 8); 6.1 to 7.9 (m, 9); 8.8 (d.6).

Example 45

2- (1-cyclopentylethyl) -2,3,8,12b-tetrahydro-1H-3a, 8-methanodibenzo [3,4: 6,7] cyclohepta [1,2-c] pyrrole; NMR spectrum:

t 2.7 to 3.1 (m, 8) and 6.1 to 9.1 (m, 21).

Example 46

2- (2-methylcyclopentylmethyl) -2,3,8,12b-tetrahydro-lH-3a, 8-methanodibenzo [3,4: 6,7] cyclohepta [1,2-c] pyrrole; NMR spectrum:

r 2.6 to 3.3 (m, 8) and 6.1 to 9.3 (m, 21).

This compound is a mixture of two isomers in which the methyl group is bound to the cyclopentane ring in the ice and trans positions.

Example 47

2- (3-MethylcyclopentyImethyI) -2,3,8,12b-tetrahydro-1H-3 a, 8-methanodibenzo [3,4: 6,7] cyclohepta [1,2-c] pyrrole; NMR spectrum:

r 2.6 to 3.3 (m, 8) and 6.0 to 9.5 (m, 21).

This compound is a mixture of two isomers in which the methyl group is bound to the cyclopentane ring in the ice and trans positions.

Example 48

2- (2-adamantylmethyl) -2,3,8,12b-tetrahydro-lH-3a, 8-methanodibenzo [3,4: 6,7] cyclohepta [1,2-c] pyrrole; NMR spectrum:

r 2.6 to 3.0 (m, 8) and 6.0 to 8.5 (m, 25).

Example 49

2- (2-thienylimethyl) -2,3,8,12b-tetrahydro-lH-3a, 8-me-thanodibenzo [3,4: 6,7] cyclohepta [1,2-c] pyrrole; NMR spectrum:

r 2.7 to 3.3 (m, 8) and 5.9 to 8.0 (m, 10).

Example 50

2- (trans-2-phenylcyclopropylmethyl) -2,3,8,12b-tetrahy-dro-lH-3a, 8-methanodibenzo [3,4: 6,7] cyclohepta [1,2-c] pyrrole; NMR spectrum:

r 2.7 to 3.2 (m, 13) and 6.0 to 9.3 (m, 14).

Example 51

2-tertiary-butyl-2,3,8,12b-tetrahydro-lH-3a, 8-methanodi-benzo [3,4: 6,7 | cyclohepta [1,2-clpyrrole; Nuclear Magnetic Resonance Spectrum: r 2.6 to 3.0 (m, 8); 6.0 to 7.4 (m, 8); 8.7 (s.9).

Example 52

Nitro-2-methyl-2,3,8,12b-tetrahydro-lH-3a, 8-methanodi-benzo [3,4: 6,7] cyclohepta [1,2-c] pyrrole hydrochloride.

To a solution of 1.5 g (5.06 mmol) of 2-methyl-2,3,8,12b-tetrahydro-lH-3a, 8-methanodibenzo [3,4: 6,71cy-clohepta [1,2 c] pyrrole hydrochloride in 25 l of anhydrous hydrofluoric acid, cooled to -78 ° C., 562 mg (5.06 mmol) of potassium nitrate are added. The reaction mixture is allowed to warm to room temperature and the hydrofluoric acid is evaporated under a stream of nitrogen. The residue is dissolved in methylene chloride and the solution washed with in aqueous sodium hydroxide solution and with water and dried over potassium carbonate. The solvent is removed under vacuum, the residue is dissolved in ether and the insoluble constituents are removed by filtration. The ethereal filtrate is treated with dry hydrogen chloride, so that 1.0 g of nitro-2-methyl-2,3,8,12b-te-trahydro-lH-3a, 8-methanodibenzo [3,4: 6,7] cyclohepta- [l, 2-c] pyrrole hydrochloride as a colorless solid with a melting point of 202 to 207 ° C (with slight decomposition).

Mass spectrum for C19H18N202. '

Calculated: MW 306.174 Found: MW 306.137

NMR spectrum of the free base: ó 2.2 to 4.2 (m, 11); 6.9 to 7.5 (m, 4); 7.8 to 8.3 (m, 3).

Other compounds that fall within the scope of the present invention can be prepared as described above and include compounds of the general formula

7 p

e s

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14

a, with a single substituent on one of the benzene rings such as the 4-, 5-, 6-, 7-, 9-, 10-, 11- and 12-acetyl derivatives, the 4-, 5-, 6-, 7-, 9-, 10-, 11- and 12-t-butyl derivatives, the 4-, 5-, 6-, 7-, 9-, 10-, 11- and 12-methoxy derivatives, the 4-, 5-, 6- , 7-, 9-, 10-, 11- and 12-fluorine derivatives, the 4-, 5-, 6-, 7-, 9-,

10-, 11- and 12-chloro derivatives, the 4-, 5-, 6-, 7-, 9-, 10-, 11- and 12-trifluoromethyl derivatives, the 4-, 5-, 6-, 7-, 9 -, 10-, 11- and 12-2,2,2-trifluoroethyl derivatives, the 4-, 5-, 6-, 7-, 9-, 10-,

11- and 12-methylthio derivatives, the 4-, 5-, 6-, 7-, 9-, 10-, 11- and 12-trifluoromethylsulfonyl derivatives, the 4-, 5-, 6-, 7-, 9-, 10 -, 11- and 12-methylsulfonyl derivatives, the 4-, 5-, 6-, 7-, 9-,

10-, 11- and 12-carboxyl derivatives, the 4-, 5-, 6-, 7-, 9-, 10-,

11- and 12-methoxycarbonyl derivatives, the 4-, 5-, 6-, 7-, 9-, 10-, 11- and 12-ethoxycarbonyl derivatives, the 4-, 5-, 6-, 7-, 9-, 10 -, 11- and 12-carbamoyl derivatives, the 4-, 5-, 6-, 7-,

9-, 10-, 11- and 12-sulfamyl derivatives, the 4-, 5-, 6-, 7-, 9-,

10-, 11- and 12-N-methylsulfamyl derivatives, the 4-, 5-, 6-, 7-, 9-, 10-, 11- and 12-N, N-dimethylsulfamyl derivatives, the 4-, 5-, 6 -, 7-, 9-, 10-, 11- and 12-methylsulfonyl derivatives, the 4-, 5-, 6-, 7-, 9-, 10-, 11- and 12-hydrazinocarbonyl derivatives, the 4-, 5- , 6-, 7-, 9-, 10-, 11- and 12-hydroxylaminocarbonyl derivatives, the 4-, 5-, 6-, 7-, 9-, 10-, 11- and 12-acetyl derivatives,

the 4-, 5-, 6-, 7-, 9-, 10-, 11- and 12-propionyl derivatives, the 4-, 5-, 6-, 7-, 9-, 10-, 11- and 12- Cyclopentylcarbonyl derivatives and the 4-, 5-, 6-, 7-, 9-, 10-, 11- and 12-cyclohexylcarbonyl derivatives.

Compounds of formula (I) wherein R is not a hydrogen atom have an effect on the mammalian central nervous system as clinically useful tranquillizers. You can in pharmaceutical preparations from the active ingredient, i.e. H. the compounds according to the invention can be used in combination with non-toxic pharmaceutical carriers and additives. In each composition of the active pharmaceutical ingredient, this is usually present in an amount of approximately 0.5 to 95%, based on the total weight of the preparation.

Appropriate formulations include injectable and orally administrable dosage forms, such as tablets, hard and soft gelatin capsules, suspensions, syrups, elixirs and others. Additives used in such forms of administration are solvents and diluents, lubricants, binders, disintegrants, preservatives, colors, flavors and other additives which are conventional and known and which cannot form the subject of the invention.

The compounds can be administered as tranquillizers, according to the invention by any type which brings the active ingredient into contact with a reactive part of the warm-blooded body. For example, parenteral administration, e.g. H. Subcutaneously, intravenously, intramuscularly or intraperitoneally. On the other hand or in addition, the administration can also take place orally.

The dose to be administered depends on the age, health and weight of the recipient, the type and severity of the disease, the type of parallel treatment, if any, the frequency of treatment and the nature of the effect desired. In general, the daily dose of the active ingredient will be from 0.01 to 200 mg / kg body weight. Usually a dose of 0.05 to 100 and preferably 0.1 to 50 mg / kg / day, administered one or more times a day, is effective in order to achieve the desired results. For more effective compounds according to the invention, e.g. B. the trans-2-cyclopentylmethyl-2,3,8,12b-tetrahydro-1 H-3a, 8-methanodibenzo (3,4: 6,7) cyclohepta [1,2-c] pyrrole (example 7), the daily dose range is between approximately 0.01 and 100 mg / kg,

preferably 0.05 to 50 mg / kg, and in particular between 0.1 to 25 mg / kg.

The general sedative effect of the compounds according to the invention was determined by tests which were carried out on female white mice, the loss of activity with regard to the study of the environment (exploratory activity), the ptosis, the grasping and lifting reflexes, the catatonia, the muscle tone and the auricular reflex reflex was measured. Experiments carried out on mice allow a prediction of the effects on humans.

A group of female Carworth CFtS mice,

each weighing 16 to 22 g, was fasted 16 to 22 hours before the test. The mice were placed in opaque plastic "shoebox" cages 15 to 30 minutes before injection and then orally with 4, 12, 36, 108 and 324 mg / kg of the compound to be tested as a 13 mg / ml solution in 1% treated aqueous solution of methyl cellulose (Me-thocel®) in distilled water. Each dose was 0.45 ml as the standard volume. The observations were made at 0.5, 2 and 24 hours after the administration. The EDS0 values were calculated for each parameter including death (LDS0). The EDSo and LDS0 values mean the doses at which 50% of the animals should respond.

Exploratory activity

The mouse is placed on a «shoebox» lid (25.4 mm high) with a grid made of stainless steel wire (20.32 x 30.48 cm, 3 meshes per 2.54 cm, 6.35 mm mesh openings) and the normal activities are observed, such as movements of the snout, head movements with an obvious visual inspection of the surroundings and / or walking around on the grid. The absence or noticeable reduction in these activities for 5 seconds represents the loss of expiratory activity.

Ptosis

The mouse is picked up by the tail and placed on the grid with the head facing the observer. A bilateral closure of the eyelids of 50% or more 2 seconds after discontinuation is called ptosis.

catatonia

The mouse is placed with the front legs on the edge of the lid of a “shoe box” made of stainless steel 2.54 cm high, which is covered with an adhesive strip. If the mouse cannot remove both front paws from the edge of the lid within 5 seconds, this means catatonia.

Muscle tone

The observer gently strokes the mouse's abdominal muscles with his thumb and forefinger. Laxity or less often a state of tension is noted.

Gripping and lifting reflexes

The mouse is gently swung at the tail against a horizontal 0.3 mm (12 gauge) wire stretched 25 cm above the vise. After the mouse has gripped the wire with the front paws, its abdomen is held directly under the wire. A normal mouse grabs the wire with its front paws and immediately lifts its rear extremities to the wire. If the mouse does not grasp the wire with the front paws in both attempts, this means that the gripping reflex is lost. If she does not lift the hind limbs to grab the wire with at least one hind paw within 5 seconds, it means the lifting reflex is lost.

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

15

615 664

The ratio of gripping to lifting action is important because the loss of lifting reflex is pronounced in most compounds with a tranquillizer effect.

Ear muscle reflex

The mouse is placed on a stick, 10 to 20 cm horizontally and 9 cm vertically by a Galton pipe, set to 13 kc (5 mm on the pipe scale) and subjected to several short bursts of sound. If the mouse does not twitch or press against the head, the pinna reflex is lost.

An effective tranquillizer should induce little or no tremor. Most compounds induce little tremor in the test mice, as shown in Table 1. The tremor includes fine or coarse and discontinuous or continuous tremor.

Spontaneous motor activity of the mouse (cage activity)

Twenty-four 16 to 20 g or 18 to 22 g female CF, S mice that have been fasting for 16 to 22 hours are paired with the agents at doses of 0.1, 3, 9, 27 and 81 mg / kg in 10 ml / kg of an aqueous 1% methyl cellulose solution intubated. The mice are then placed in separate "shoe box" cages (30.5 x 19.5 x 13.5 cm, plastic with a stainless steel lid with 8.38 mm mesh) and 20 minutes after intubation, the animals are sealed in pairs Woodard brought photoelectric activity chambers (with central light source, floor area = 96 in2). A 5 minute count is made 10 minutes later (30 minutes after administration). The characteristics of the counting chamber are balanced by counting 2 pairs of mice for each dosage level in each of the 6 different counting chambers. Half of the tests were carried out in the morning and the other half in the afternoon in order to minimize the impact of the changes caused by the "biological clock".

Since activity counts do not normally distribute, but their square roots (Irwin, S .; Rev. Canad. Biol. 20, 239 to 50 [1961]), the raw counts are converted to statistics (Student's t-test). The meanings of the square roots are then plotted and an ED50 for stimulation and depression, or both, graphically determined.

With the effects listed above as criteria, the compounds according to the invention show an effective trans-quillizing effect, as shown in Table 1. The ED50 values, i.e. H. the dose that causes a response in 50% of the mice is tabulated. For comparison purposes, the values obtained in the tests for two known commercial tranquillizers, namely chlorpromazine and diazepam, are also entered.

Some compounds according to the invention, in particular those of Examples 7 and 25, show a strong tranquilizing effect (elimination of anxiety states) in addition to their neuroleptic effect. The tranquilizing effect of the compounds was determined by the proximity avoidance test on rats. Tranquillizers such as diazepam were found to be effective in this test, but neuroleptics, such as chlorpromazine, were found to be ineffective at non-sedative doses.

Approach Avoidance Test

Female white Holzman rats weighing 150 to 175 g were used, and the water was withheld for 18 hours. The device consists of two interconnected chambers, the first being the animal and the second containing the stimulus and a water bottle. The second chamber is provided with a floor that can be energized. On the first day, the rats are placed in the first chamber. Let them search for the water bottle in the second chamber for 3 minutes and drink water for at least 2 seconds. After three successful attempts on the first day, a preliminary test is carried out on the animals on the second day. This is followed by a second preliminary experiment, during which the floor of the second chamber is energized 1.5 seconds after the rat has started to drink water. The animals are distributed at random, the agent is administered orally and exposed to the test situation 1, 2 or 4 hours after the shock attempt. The solvent-treated rats usually do not re-enter the second chamber after the shock treatment.

The results of this test are summarized in Table 2 and the ED50 values, i.e. H. the dose that causes 50% of the rats to respond is summarized in a table. The values obtained in this test for the commercial tranquillizers, such as diazepam, are given for comparison purposes.

Compounds of formula (I) in which R is not hydrogen show a useful analgesic effect on the CNS of mammals, which can be demonstrated by tests on female white mice, in which they do the known, by intraperitoneal injection of phenyl-p-benzoquinone Prevent (phenylquinone) curling up. This mouse test suggests analgesic effects in humans (E. Siegmund, R. Cadmus and G. Lee, Proc. Soc. Exp. Biol. Med., 95, 729 [1957]).

A group of five female Carworth CFjS mice, each weighing 18 to 21 g, were fasted for 17 to 21 hours and then with an analgesic compound as an antagonist to phenylquinone at oral doses of 8, 40 and 200 or 0.33, 1 , 3, 9, 27 and 81 mg / kg in 0.20 ml of a 1% methyl cellulose (Methocel®) solution. 30 minutes later, the mice are treated with phenylquinone, 1.1 mg / kg intraperitoneally (dissolved in pure ethanol and diluted with 5% ethanol with distilled water at 40 ° C.). 37 to 47 minutes after the administration of the analgesic compound, the mouse is observed for the appearance of the curvature syndrome. The number of mice that do not curl up during the 10-minute observation is recorded as the quanto index of the analgesic. The ED50 values are obtained graphically from the data.

In view of the blocking of the curvature induced by phenylquinone as a criterion, many compounds according to the invention can be referred to as analgesics. The EDa0 values, i.e. H. the doses by which phenylquinone-induced curling is blocked in 50% of the mice are also shown in Table 1.

5

10th

15

20th

25th

30th

35

40

45

50

55

60

Nb

5

5

5

10th

10th

5

5

5

10th

5

5

5

10th

10th

5

5

5

10th

5

10th

10th

10th

10th

10th

10th

10th

5

Table 1

»

R

example

LD50'1 (mg / kg)

EDso (mg / kg)

Phenyl loss of exploratory-chinoric activity Analgesi-visual cage cum activity ED50 (mg / kg)

Ptosis

catatonia

Muscle tone

Reflexes lifting

gripping

1

150

5.1

50

_

50

30th

100

30th

150

6

300

4.5

20th

-

20th

20th

12

20th

100

19th

> 324

5.0

20th

1.0

7

20th

12

20th

200

7

> 324

2.0

7

0.66

3C

8th

7

11

210

25th

320

6.4

9

4.7

3C

9

8th

8th

450 c

32

> 324

2.9 -

7

-

<4

12

36

20th

200

4th

> 324

9.4

20th

4.6

20th

20th

20th

36

> 324

39

> 324

22.0

200

-

200

100

> 324

100

> 324

10th

> 324

1.9

4.5

-

<3

5

3.2

6

150

11

> 324

26

100

-

100

100

200

> 324

> 324

12

200

4.3

20th

-

12

12

36

12

100

13

> 324

10.5

12

-

7

12

12

7

200

14

> 324

2.6

7

1.3

4.5

5.6

4.1

8.6

187

15

> 324

3.6

3.2c

1.0

<3

5

3C

9

260

16

> 324

12

20 '

-

12

12

12

20th

> 324

17th

> 324

48

200

-

100

36

100

200

> 324

18th

> 324

<135

200

-

200

100

300

200

> 324

20th

> 324

8.2

21st

-

11

13

15

21st

362

21st

> 324

2.9

7

-

7

20th

36

36

300

22

> 324

10th

32

-

3C

18th

3.6

17th

265

23

> 324

15

57

-

46

37

37

88

265

24th

> 324

6

7

-

6

7

6

17th

> 324

26

> 324

6.8

12

0.8

6

10th

7

15

400

27th

> 324

4.2

4.5

0.29

2.9

4.5

4.5

9

97

28

> 324

8.6

29

-

17th

24th

37

57

> 324

29

> 324

28

24th

-

17th

21st

24th

78

290

30th

> 324

7

4th

-

4th

12

7

12

200

4-cyclohexylbutyl

31

> 324

14

21st

-

4-cycloheptenylmethyl

33

> 324

3.3

9

-

Cyclooctylmethyl

34

> 324

6

40

-

2-exobicyclo- [2,2, l] -heptyl-

methyl

35

> 324

6.2

8.6

3.3

2-endobicyclo- [2,2, l] -heptyl-

methyl

36

> 324

9.8

'60

-

2-exobicyclo- [2,2,1] hept-

5-enylmethyl

37

300

2.4

7

-

2-endobicyclo- [2,2,1] -hept-

5-enylmethyl

38

> 324

31

200

-

2-phenoxyethyl

40

> 324

5.3

60

-

2-methoxyethyl

41

300

4.2

20th

-

2-furylmethyl

42

300

26

60

-

2-methyl

43

200

-

7

-

2-cyclohexylmethyl

44

> 324

-

17th

-

Cyclopentylmethyl-N-oxide

7

> 324

24th

12

-

Methyl N-oxide

> 324

-

60

-

Cyclopropyl

46

> 324

90

200

-

Cyclobutyl

47

> 324

9.6

60

-

Cyclopentyl

48

> 324

38

100

-

Isopropyl

49

200

10.8

60

-

1-cyclopentylethyl

50

> 324

23

20th

-

trans-2-phenylcyclopropyl

methyl

55

> 324

48

100

-

2-adamantylmethyl

53

> 324

94

60

-

t-butyl

56

300

45

200

-

2-methylcyclopentylmethyl

51

> 324

10th

100

-

3-methylcyclopentylmethyl

52

> 324

5

12

-

2-thienylmethyl

54

> 324

27th

200

-

2-methylf

57

200

5

20th

-

(-) - Cyclopentylmethyl

7

> 324

1.2

<4

-

(+) - Cyclopentylmethyl

7

> 324

24th

36

-

Chlorpromazine d

850c

-

7

7.3

Diazepam

> 1000

-

87

2.0

a 24-hour value b number of mice L 'extrapolated value d hydrochloride salt, tested on the basis of the free base only in the cage activity test. e Mixture of the 5-chloro and 11-chloro substituted compounds.

f Mix of the nitro-substituted compounds.

17th

26

24th

37

> 324

32

> 324

10th

4th

11

7

19th

> 324

37

> 324

10th

4th

23

21st

62

> 324

97

> 324

10th

5.1

15

12

29

> 324

21st

> 324

10th

20th

60

60

60

> 324

100

> 324

5

g4

7

4th

12

200

20th

> 324

5

60

100

200

200

> 324

> 324

> 324

5

7

12

20th

20th

> 324

12

> 324

5

20th

20th

36

36

200

20th

> 324

5

20th

36

20th

200

> 324

60

> 324

5

20th

100

20th

20th

60

20th

36

5

<3

19th

12

36

> 324

11

> 324

10th

â4

36

12

20th

> 324

7

> 324

5

36

60

100

36

200

60

36

5

60

200

200

200

300

300

> 324

5

36

60

60

60

200

36

> 324

5

60

36

100

60

200

60

> 324

5

12

60

7

36

200

20th

> 324

5

60

20th

36

60

300

36

> 324

5

36

200

100

200

> 324

200

> 324

5

300

36

100

300

> 324

100

> 324

5

100

200

100

60

100

200

200

5

36

60

60

60

300

36

> 324

5

7

12

12

12

200

7

> 324

5

60

200

200

> 324

> 324

200

> 324

5

12

> 324

60

> 324

> 324

12

100

5

<4

7

<4

4th

200

4th

> 324

5

20th

36

60

60

200

20th

> 324

5

7

8th

8th

8th

240

5

> 324

50

79

59

89

4.4

78

63

> 324

50

615 664

18th

Table 2

Active tranquillizer Example dose Number of responsive copies

(mg / kg) IStd. 4 hours EDS0 Na

(mg / kg)

trans-2-cyclopentylmethyl-7 0-2 20

2,3,8,12b-tetrahydro-lH-3a, 8-0.03 - 1 10

methanodibenzo [3.4: 6.7] cyclo-0.1-7 20

hepta [l, 2-c] pyrrole 0.3 - 6 0.2 10

trans-2-cyclohexylmethyl-25 0.1 - 1 10

2,3,8,12b-tetrahydro-lH-3a, 8-0.3-2 10

methanodibenzo [3,4: 6,7] cyclo- 1,0 - 5 0,5 8 hepta [1,2-c] pyrrole

Diazepam - 0 0 - 6

1 0 6

3 2 - 6

10 5 - 6.0 6

a number of rats s

Claims (2)

615 664 2nd PATENT CLAIMS 1. Process for the production of connections of the R in the R1 and R2 for hydrogen, lower alkyl, lower alkoxy, hydroxyl, fluorine, chlorine, bromine, trifluoromethyl, 2,2,2-tri-fluoroethyl, methylthio, trifluoromethylthio, trifluoromethylsulfonyl, methylsulfonyl, carboxyl, methoxycarbonyl, ethoxycarbonyl, Carbamoyl, sulfamyl, N-methylsulfamyl, N, N-dimethylsulfamyl, methylsulfinyl, hydrazinocarbonyl, hydroxylaminocarbonyl, lower alkylcarbonyl, cycloalkylcarbonyl having 4 to 7 carbon atoms or nitro and R in which represents hydrogen, alkyl having up to 10 carbon atoms, alkenyl with 3 to 7 carbon atoms, the alkenyl radical being bonded to the nitrogen atom via a saturated carbon atom, cycloalkyl with 3 to 5 carbon atoms, propargyl, 2,2,2-trifluoroethyl, 2,2,3,3,3-pentafluoropropyl, a- Furylmethyl, a-thienylmethyl, - (CH2) nCN, - (CH2) „C02H, - (CH2) qOR3, - (CH2) nC02 (lower alkyl) or —CH (R4) (CH2) PRS with up to 14 carbon atoms, where q is 2 to 6, n is 1 to 6, p is 0 to 5 with R3 lower alkyl, phenyl or lower alk yl-phenyl, R4 is hydrogen or n-lower alkyl and R5 is a hydrocarbyl group containing at least one ring of 3 to 5 9 carbon atoms which is bonded to the alkylene group via a ring carbon atom, with the exception that when p is 0, that Carbon atom attached to the —CH (R4) group is not a quaternary carbon atom and, when R in (I) has a meaning other than H, the nitrogen atom is additionally substituted with oxygen to form a tertiary one Amine oxide, characterized in that a compound of the formula (XII) wherein R, R1 and R2 are as defined above, reduced to the compound of formula (I). 2. Compounds of formula (I), prepared by the method according to claim I.