FI67701C - FRAMEWORK FOR THERAPEUTIC TREATMENT OF THERAPEUTIC EQUIPMENT TETRACYCLISKA FOERENINGAR - Google Patents

Description

1 67701

A process for the preparation of new therapeutically useful tetracyclic compounds

This invention relates to a process for the preparation of novel biologically active dibenzo-2; 5.6 (cyclohepta-pyridine, dibenzo) 2.3; 6.7, (oxepinopyridine, di-benzo) 2.3; 6, for the preparation of T7-thiepino-pyridine and dibenzo-10 / b, f / pyridoazepine derivatives, their salts and nitrogen oxides.

The formula of the new compounds is R1 »3 15 [a li b J | cl R4 Z \ _: N 4

R c 20 wherein R 1 and R 4 represent hydrogen, hydroxide, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio or trifluoromethyl, is hydrogen or C 1-6 alkylalkyl and X is oxygen, sulfur, NR 9 or wherein R 8 is hydrogen or C 1-6 alkyl.

The compounds of formula I generally have a considerable central nervous system dysfunctional effect which can be exploited in the treatment of stress states, agitation states and anxiety states, and in the treatment of mental illness and syndrome conditions. In addition, the compounds of the invention have excellent antihistamine and antiserotonin activity.

Tetracyclic compounds resembling compounds of formula I are known.

__ - r- 2,67701

Some closely related compounds in which the bond between ring B and ring D is unsaturated and in which the D-ring is 5-membered are described in U.S. Patent 3,636,045 and have a biological mode of action 5 similar to that found for compounds of formula I. However, the compounds of the formula I are generally generally more active and, moreover, in some cases show a tendency towards a neuroleptic effect.

Compounds in which the bond between ring B and ring D is unsaturated and in which the D-ring is 6-membered are described in U.S. Patent 4,002,632. However, these known compounds have the opposite effect, namely a central nervous system stimulating effect, and can be used to treat depressive conditions. .

Compounds of formula I, their salts and nitrogen oxides can be prepared by a) a compound of formula R 1 R 25 wherein Q is ethylene or vinylene, the dashed line indicates a possible bond and R 1, R 2, R 2, R 2, R ^ and X have the same meaning as above, are reduced, or b) an enamine of formula V x w13

fy "Q

35 -¾ R 4 5 3 67701 wherein, R 1, R 2, R 2, R 2 and X have the same meaning as above, or a salt thereof is reduced, or c) a compound of formula h 5 ry ^ χ ^ λ R% a0 ^ 4 V / k_ J.> / 2 w ® a R yx * Δ 1 K2 VN / 4

R, W

5 IV IVa Θ wherein A is an anion of an organic or inorganic acid and R 1, R 2, R 2, R 2 and X are as defined above, are reduced; after which, if desired, the compound obtained is alkylated and / or partitioned into stereo- or optical isomers and / or converted into a salt or nitric oxide.

The process in option a) the reduction is carried out in the manner normally used for the reduction of an amide group. Suitable reducing agents in this process include, in particular, metal hydride complexes such as diisobutyl-aluminum hydride, lithium borohydride, sodium trimethoxyborohydride, and especially lithium aluminum hydride.

If, in addition to the keto group, one or more double bonds have to be reduced in the compound of formula II, it is recommended that the double bonds be reduced first, since in the above reduction method these double bonds, and in particular any double bond between 3- and D-rings, are only partially reduced.

Suitable methods for first reducing these double bonds are catalytic hydrogenation, e.g., treatment of PtCl 2 / magnesium with magnesium in an alcohol, preferably methanol, or Birch reduction (alkali metal) in liquid ammonia, preferably sodium in liquid ammonia).

When reduced so that both the keto group and the double bonds are reduced simultaneously in practically quantitative yields, 4,67701 of diborane, an alkali metal, e.g. sodium, in alcohol, or a mixture of lithium aluminum hydride and aluminum halide, e.g. AlCl 2, are preferably consumed.

The compounds of the formula II required as starting materials are prepared by methods known per se.

One such preparation method is shown in Reaction Scheme 1 below. In process variant b}, the reduction is carried out in a manner commonly used for the reduction of enamine, for example by using metal hydride complexes such as sodium borohydride, lithium borohydride, catalytic hydrogenation, for example by combination. Pd / C / P 2, with alkali metal in liquid ammonia (Birch reduction) or with formic acid.

The starting materials III can be isolated from the reaction mixture obtained by reducing a compound of formula II (having no double bond in the D-ring) as described above with LiAlH 2 m or diborane (see Reaction Scheme 1).

In process variant c) the anion A of the organic or inorganic acid (formula IV) is e.g. a halide, sulphate, phosphate, acetate or propionate anion.

The reduction is carried out with an alkali metal, preferably sodium, in a suitable solvent, preferably an alcohol such as methanol, ethanol or isopropanol.

The compounds of formula IV and IVA required as starting materials are prepared in a manner commonly used for the preparation of analogous compounds. One such preparation method is shown in Reaction Scheme 2.

5,67701

Reaction Scheme 1 Preparation of starting materials II and III & 'Ρ · Μγ \ COOS (' ιΐ / Γ °, <^ X0 COOÄ 5 /I'Cp.A.

v X C; U hr.

ICG ,.

^ n. Na / isoocanol, t \ diborane or χ ^ Ε / εΚ, ΟΗ NSS / AIBN / | LiAlK ^ / ALCi ^ j, v CCI4 1 Π "Τ ^ Ο ^ NBS / Aian / cci.1 t 4.

»'Π ·. jc <X *, j, / «, e.g.

LiAlH. or . ... Na / ispropanol diborane * diborane or

LiAlH / A1C13 _________ TEA. = triety / lamine. DMF = dir.ietwlifonr.ir’icli | 'di, s P.r.A. ^ TSDlvtcsforihapno;

'LI' '^ I

NBS = N-btmisuJtkiniiride J

AIBN = uncoupled β-nonitrile! Y 332 (tadicaol initiator) t .-- '> ✓ l * 67701

Reaction Scheme 2 Prepared starting materials IV 3a IVA: 5 Γ, [I I> J = acetyl)

7 / \ \ _hAs IV

W I

I il tt. ?

l Rs i H

jg j ethanolicuniir.i; ! , r r, or

13j L

'V

ego 15 W.

IV λ 20 The compounds of the formula I can exist in two diastereoisomeric forms, namely as a cis compound or a trans compound. In the cis compound, the hydrogen atoms in the bridge between the B and D rings of the compound of formula I are in the cis position relative to each other. In Trans-25, these hydrogen atoms are on opposite sides of the bond.

Both cis and trans compounds, as well as a mixture of both diastereoisomers, are included in the group of compounds of formula I.

Separate cis and trans isomers can be prepared from the mixture by physicochemical separation methods such as fractionation, column chromatography, preoarative plate chromatography or decomposition according to the countercurrent principle. However, the separate cis and trans isomers 35 can also be prepared directly by the aforementioned 67701 chemical methods if the separation has already been performed at an earlier stage of the synthesis and thus the separated cis or trans isomer starting material can be used.

The cis and trans isomers of formula I are usually obtained as a racemic mixture. However, this racemate can, if desired, be resolved into separate optical antipodes using an optically active acid. Both optical antipodes are included in the group of compounds of the formula. However, in some cases, optically active compounds can also be prepared directly using an optically active starting material. For example, compound II with a saturated D-ring is ideally suited for this direct synthesis.

The term "C 1-8 alkyl" refers to both straight-chain and branched alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl or hexyl. .

Salts of the compounds of the formula I are intended to mean acid addition salts and quaternary ammonium salts.

Acid addition salts are conveniently prepared by reacting the free base with a pharmaceutically acceptable acid. Common acids in this context are hydrochloric acid, bromic acid or hydroiodic acid, phosphoric acid, acetic acid, propionic acid, glycolic acid, maleic acid, malonic acid, succinic acid, tartaric acid, citric acid, salicic acid, ascorbic acid.

Quaternary ammonium salts, and in particular quaternary lower alkyl (1-4C) ammonium compounds, are obtained by reacting compounds of the formula I with an alkyl halide, preferably methyl iodide, methyl bromide or methyl chloride.

Nitrogen oxides of the compounds of formula I are obtained by oxidation of the free base with hydrogen peroxide or per-67701 acid.

Unsubstituted amine of formula I (RC = H)

O

can be alkylated in the usual way, for example by reacting it with an alkyl halide. For this purpose, however, the nitrogen atom in question is usually acylated, for example with an acid chloride or anhydride, and then the keto group of the N-acyl derivative obtained is reduced. To attach the methyl group to the nitrogen atom, Eschwiler-Clarke method 10 (using a mixture of formaldehyde and formic acid) or reaction with formaldehyde and sodium cyanoborohydride in a suitable solvent such as acetonitrile is used.

The compounds of formula I may be administered orally, rectally and parenterally, in an amount such that the daily dose is 0.01 to 10 mg per kilogram of body weight.

When mixed with suitable excipients, the compounds may be formulated into solid dosage forms such as pills, tablets, suppositories, or granules. Optionally, capsules can be mixed with excipients. In the case of suitable liquids, the compounds can also be used as injectable preparations in the form of solutions, emulsions or suspensions.

Preferred compounds of formula I are those compounds wherein X is oxygen or a -C 1-4 group.

Also preferred are compounds of formula I which have no substituents on the benzene rings (R 1, R 2, R 2 and R 2 are all hydrogen) or which have one or two substituents on one or both of the benzene rings.

Further preferred compounds of the formula I are those in which methyl, halogen or methoxy is present as one or two substituents (in one or both benzene rings), in particular in positions 6 and / or 12.

35 677011 why trans-isomers have been identified as compounds of formula I are of pharmacological interest.

Preferred compounds in this respect are the trans isomers of the compounds of the formula I in which X is methylene or oxygen, is methyl and the benzene rings are unsubstituted or have a methyl substituent in the predominantly 6- and / or 12-position.

The pharmacodynamic properties of the compounds of formula I have been determined as follows: Effect on the central nervous system a) Antagonistic effect on reserpine-induced hypothermia, which is a pharmacological property of tricyclic antidepressants, is commonly used to demonstrate possible antidepressant activity. The relief of reserpine-induced hyperthermia, as noted in the present case, is generally considered to be indicative of general CNS depressant activity, and in particular sedative activity.

20 b) The chimney Escape performance test is a simple test to assess the movement coordination of mice. Sedative compounds may be active in this experiment, but in general, strong activity indicates uneven motion coordination.

25 c) Mice treated with compounds with either analgesic or central nervous system depressant (sedative) activity receive significant protection against hot plate thermal irritation. Based on the results from other experiments, the positive effect of the compounds now described in the hot plate assay should be considered to indicate sedative activity rather than analgesic activity.

d) The apomorphine assay (apomorphine-induced mouse climbing) is a well-established assay to demonstrate potential neuroleptic activity. In contrast to the known compounds, all the compounds now described are very active in this experiment.

Antiserotonin and antihistamine effect The superfusion assay is used to determine and compare antihistamine and anti-serotonin activities. The result is expressed as logarithmic values, i.e. pÄ2 ~ value. The higher the pA2 value, the better the antihistamine or antiserotonin activity. Thus, for example, a difference of 1.0 between two compounds means that one compound is 10 times more active than the other. 10 The results are shown in the following tables:

Ofp icfp "-σ i <1 ch3 I ch3

Test compound 4610 8280

A known compound of the formula I

Effect on the central nervous system 20 - - Reserpine antagonism test strong attenuation moderate anthoconistic activity - reserpine reverse test weak attenuation strong antagonistic activity - climbing test in mice EDS0 s.k. mg / kg 2 ^ - hot plate test strong protection inactive

Neurolcptincn activity - strong inhibition of apomorphine test very weakly active

Antihistamine activity i.p. Y / 'kg (body weight) 3 9

Antiserotonin activity ED50 i.p. V / kg (body weight) 2 3

II

11 67701

The following designation and numbering have been used in the examples: 2 to 7 l (2,3,4,4a, 9-3b-hexahydro-1H-dibenzo [* / 1,2; 5,6 / cyclohepta / 3,4- c / pyridine.

f - / / ä (V i) NU /

g? IO

j>, X = O or S

^ 1, t 1,2,3,4,4a, 13b-hexahydro-dibenz-** - [- ^ - 2,3; 6, "Z / oxepino or thiepino [4,5-c] pyridine.

i. 9 - [2,3,4,4a, 9,13b-hexahydro-1H-dibenzothio] [b] f, pyrido [3,4-d] azepine.

i iv

-OF

Example I

2-methyl-l, 2,3,4,4a, 13b-heksahydrodibents / 2.3; 6,7 / oxepino [4,5-c] pyridine maleate Ά. Solution of 35 g of 2-methyl-3,4-dihydrodibenz [2,3; 6,6'-Oxepino [4,5-c] pyridin-1 (2H) -one (m.p. 172-174 ° C) in 2500 ml of dry methanol is heated to boiling, after which 140 g are added in two portions of 70 g. magnesium. The mixture is then boiled for about an hour, after which it is cooled and evaporated to dryness.

1100 ml of 6N hydrochloric acid are then slowly added to the residue under cooling, and the mixture is stirred for some time.

12 67701

The precipitate formed is filtered off and dissolved in methylene chloride. The solution is washed with water until neutral, dried over sodium sulfate and evaporated to dryness. Yield 36.2 g of cis- and trans-2-methyl-3,4,4a, 13b-tetrahydrodibenz [2,3; 6,7 [oxepino] 4,5-c] pyridin-1 (2H) -one, which is then separated and purified by column chromatography on SiO2 using ethyl acetate as eluent.

Yield: 3.6 g of trans compound, m.p. 149-151 ° C, 10 R in ethyl acetate - 0.43 (SiO 2) and 22.4 g of cis, mp 155-157 ° C, in ethyl acetate - 0.31 (S 1 O 2).

B. A solution of 3.6 g of the trans compound obtained in A. in 160 ml of dry ether is slowly added over a period of about 10 minutes to a stirred suspension of 4 g of LiAlH 2 in 400 ml of dry ether.

The reaction mixture is then further stirred for 30 minutes at room temperature and then cooled to about 0 ° C. After adding 16 ml of water, the mixture is filtered and the filtrate is evaporated to dryness in vacuo.

The residue is then dissolved in 45 ml of ethanol and 1.6 g of maleic acid are added to the solution. Maleic acid dissolves after a moment of heating. After cooling and addition of ether, a precipitate is obtained which is separated by filtration and further purified by crystallization or column chromatography.

Yield: .9 g of trans-2-methyl-1,2,3,4,4a, 13b-hexahydro-dibenz [2,3,6,7] oxepino [4,5-c] pyridine maleate , melting point 175 ° C; 30 R 2 in methanol / acetone (9: 1) = 0.40 (S1O2) ·

The corresponding cis compound is obtained in a similar manner using the cis compound obtained in A. as a starting material. The melting point of the maleate salt is 189-192 ° C.

Treatment of the free trans base with methyl iodide 35 affords the corresponding iodomethylate.

Example II

ii 13 67701

The following compounds are obtained as described in Example I: cis -2-methyl-2,3,4,4a, 9,13b-hexahydro-1H-dibenzo '[1,2,5] cyclohepta [3,4-c] pyridine maleate, m.p. 209 ° C; trans-2-methyl-2,3,4,4a, 9,13b-hexahydro-1H-dibenzo-5 / 1,2; 5.6 (cyclohepta) [3,4-c] pyridine maleate, m.p. 177 ° C; cis-2,3,4,4a, 9,13b-hexahydro-lH-dibenzo / l, 2; 5.6 (cyclohepta [3,4-c] pyridine, oil, Rf in methylene chloride / methanol (7: 3) = 0.14 Pigs; Trans-2,3,4,4a, 13b-hexahydro-1H-dibenzo [1,2,5,6] cyclo-10-hepta [3,4-c] pyridine maleate, m.p. 171-173 ° C; 2'-methyl-12-methoxy-2,3,4,4a, 9,13b-hexahydro-1H-dibenzo [1,2]; 5.6 / cyclohepta / mixture of cis and trans forms of 1,4-q7pyridine (oil); cis-2,6-dimethyl-2,3,4,4a, 9,13b-hexahydro-1H-dibenzo [12,5,6] cyclohepta [3,4-c] pyridine, m.p. 142-145 ° C; trans-2,6-dimethyl-2,3,4,4a, 9,13b-hexahydro-lH-dibenzo / 1.2, 5.67-cyclohepta / 3,4-c / pyridine maleate, mp. 182 ° C; 2-methyl-10,11-dimethoxy-l, 2,3,4,4a, 13b-heksahydrodi-benz / 2.3; 6.7 (oxepino / 4,5-c) mixture of cis- and trans-2g forms of pyridine (oil); A mixture of the cis and trans forms of 2,12-dimethyl-1,2,3,4,4a, 13b-hexahydrodibenz [2,3; 6,7] oxepino [4,5-c] pyridine (oil); cis-2,6-dimethyl-1,2,3,4,4a, 13b-hexahydro-dibenzo-25f, 3,3; 6.7 (oxepino / 3,5-q) pyridine maleate, m.p. 177-179 ° C; trans-2,6-dimethyl-l, 2,3,4,4a, 13b-hexahydro-dibenz / 2.3; 6.7 / oxepino / 4,5-c / pyridine maleate. mp. 180 ° C; cis-2,12-dimethyl-l, 2,3,4,4a, 13b-hexahydro-dibenz / 2.3; 6.7 (oxepino) 4,5-c (pyridine maleate, m.p. 181-183 ° C; 30-trans-2,12-dimethyl-1,2,3,4a, 13b-hexahydro-dibenz-E, 3; 6,7-oxepino [4,5-c] pyridine maleate, m.p. 146-149 ° C; cis-2-methyl-12-chloro-l, 2,3,4,4a, 13b-hexahydro-dibenz / 2.3; 6,7β-oxepino [4,5-b] pyridine maleate, m.p. 185 ° C; 67701 14 trans-2-methyl-12-chloro-1,2,3,4,4a, 13b-hexahydro-dibenz / 2,3; 6.7 (oxepino / 3,5-c) pyridine (oil), R 4 -methylene chloride / in methanol (9: 1) = 0.65 Pigs; 2-methyl-6-trifluoromethyl-1,2,3,4,4a, 13b-hexahydro-dibenz 5 / * 2,3; 6,7 (oxepino / 4,5-c) mixture of cis- and trans-forms of pyridine (oil); cis-2-methyl-l, 2,3,4,4a, 13b-hexahydro-dibenzo / 2.3; 6.7 (thiepino) 4,5-c / pyridine (oil), Rf in methanol / acetone (9: 1) = 0.45 Pigs; Trans-2-methyl-1,2,3,4,4a, 13b-hexahydro-dibenzo [2,3] 6,7 / 10-thiepino [* 4,5-o] pyridine maleate, m.p. 181-183 ° C; cis-2,9-dimethyl-2,3,4,4a, 9,13b-hexahydro-1H-dibenzo [h, f] pyrido [3,4-4] azepine (oil);

Trans-2,9-dimethyl-2,3,4,4a, 9,12b-hexahydro-1H-dibenzo [b, f] pyrido [3,4, d] azepine (oil); 2-methyl-12-t, -butyl-1,2,3,4,4a, 13b-hexahydro-dibenz / 2,3; A mixture of cis and trans forms of 6,7-oxepino [4,5-c] pyridine (oil); 2-propyl-1,2,3,4,4a, 13b-hexahydro-dibenz [2, 3; a mixture of cis- and trans-forms of 6,7 / oxepino- (4,5-c) pyridine (oil); 20 cis-2,12-dimethyl-1,2,3,4,4a, 13b- hexahydro-dibenzo [2,3; 6,7] thiepino (4,5-c) pyridine maleate, mp 150 ° C, and the corresponding trans isomer (maleate), mp 170 ° C, cis-2-methyl- 12-Isopropyl-1,2,3,4,4a, 13b-hexahydro-dibenzo [2,3,6,7] oxepino [4,5-c] pyridine maleate, m.p.

136 ° C and the corresponding trans isomer (maleate), m.p. 183 ° C.

Example III

Cis-2-methyl-1,2,3,4,4a, 13b-hexahydro-dibenz [2,3,6,7] oxepino [4,4-c] pyridine

The cis-2-methyl-2,3,4,4a-tetrahydro-dibenz / 2.3; 6.7 / 30 oxepino [4,5-c] pyridine obtained in Example I by reduction with LiAlH4 as a by-product is dissolved in ethanol, then sodium borohydride is added to the solution and the mixture is stirred. CH2CO2 is then added to the reaction mixture. After diluting with water and extracting with methylene chloride, the extracts obtained are evaporated to dryness and the residue is purified graphically on a column of silica gel using a methanol / acetone mixture (9: 1) as eluent to give cis-2-methyl-1,2, 3,4,4a, 13b-Hexahydro-dibenz [2,3,6,7] oxepino [4,5-c] pyridine mp (maleate) 174-175 ° C: 5 In a similar manner cis-2-methyl- 2,3,4,4a, 9,13b-hexahydro-1H-dibenzo [1,2,5,6] cyclohepta [3,4-c] pyridine maleate, mp 207-209 ° C and the corresponding trans isomer (maleate salt), mp 175-176 ° C.

Example IV

Trans-2-methyl-2,3,4,4a, 9,13b-hexahydro-1H-dibenzo [1,2]; 5.6 (cyclohepta) 3,4-c (pyridine maleate).

A mixture of 50 mg of trans-2,3,4,4a, 9,13b-hexahydro-1H-dibenzo [1,2]; 5.6 / cyclohepta / 3,4-c / pyridine,

1 ml of formic acid and 1 ml of 35% aqueous formalde-15 solution are heated on a water bath for 3 hours. The reaction mixture is then made alkaline and extracted with ether. The organic phase is washed with Na 2 SO 4, dried over Na 2 SO 4 and evaporated to dryness, after which the residue is treated with maleic acid. Yield: 48 mg; melting point 175-176 ° C. 20 Example V

2-methyl-2,3,4,4a, 9,13b-hexahydro-1H-dibenzo [1,2]; 5,6 / -cyclohepta [3,4-q] pyridine 4 g of sodium are added with stirring and under nitrogen to a suspension of 0.5 g of 2-methyl-9H-dibenzo [1,2; 5.6 / 25 cyclohepta [3,4-c] pyridinium iodide (formula IV, melting point 300 [deg.] C./50 ml in ethanol, after which the mixture is boiled for 1 hour. The reaction mixture is then poured into H2O and extracted with methylene chloride. The organic phase is washed I O 2, dried over Na 2 SO 4 and evaporated to dryness.

Yield: 260 mg (76%) of cis- and trans-2-methyl-2,3,4,4a, 9,13b-hexahydro-1H-dibenzo [1,2,5,6] cyclohexta / 3,4- q / mixture of pyridines.

in toluene-ethanol (7: 3) = 0.27 for the trans compound and 0.65 for the cis compound.

Isolation of the stereoisomers is carried out by column chromatography on column 16 67701, followed by conversion to the maleate.

Melting point of trans maleate: 177 ° C.

Melting point of cis maleate: 208-209 ° C.

Example VI

The following compounds are prepared as described in Example V: 2-methyl-12-methoxy-2,3,4,4a, 9,13b-hexahydro-1H-dibenzo [1,2]; A mixture of cis- and trans-forms of 5,6 / -cyclohepta [3,4-c] pyridine; 2-methyl-6-chloro-2,3,4,4a, 9.13b-hexahydro-1H-dibenzo [1,2]; A mixture of the cis and trans forms of 5,6 / -cyclohepta [3,4-c] pyridine; cis-2,6-dimethyl-1,2,3,4,4a-13b-hexahydro-dibenz / 2,3; 6.7 / oxepino / 4,5-c / pyridine maleate; trans-2,6-dimethyl-1,2,3,4,4a, 13b-hexahydro-dibenz [2,3,6,7] pepepino [4,5-b] pyridine maleate; 2Q cis-2,12-dimethyl-1,2,3,4,4a, 13b-hexahydro-dibenz / 2,3; 6.7 / oxepino / 4,5-c / pyridine maleate; trans-2,12-dimethyl-1,2,3,4,4a, 13b-hexahydro-dibenz [2,3,6,7] oxepino [4,5-c] pyridine maleate; 2-methyl-12-chloro-1,2,3,4,4a, 13b-hexahydro-dibenz 25 / 2,3; 6,7 (oxepino) / 4,5-c / mixture of cis- and trans-forms of pyridine; cis-2-methyl-l, 2,3,4,4a, 13b-hexahydro-dibenzo / 2.3; 6.7 / tiepiino / 4.5-g / pyridine maleate.

Example VII

30 A.9H-dibenzo [1,2]; 5.6 / cyclohepta / 3,4-c / pyridine

A mixture of 19.9 g of 2-methyl-9H-dibenzo [1,2]; 5.6 [cyclohepta] - [3,4-c] pyridinium iodide (formula IV) and 100 ml of ethanolamine are heated with stirring in an oil bath at 160 DEG C. for 2 hours. The reaction mixture is then poured into CH 2 Cl 2 and extracted with ether. The organic phase is extracted with dilute HCl, then the acidic aqueous layer is made alkaline and extracted with ether. The ether layer is washed with water until neutral, dried over Na 2 SO 4 and evaporated to dryness.

Yield: 7.74 g of 9H-dihydro / 1,2; 5,6 / cyclohepta / 5 [3,4-c] pyridine (formula IVA). The residue is crystallized from ethyl acetate / petroleum ether (1: 2). Sp. 115-117 ° C.

Melting point of the HCl salt obtained by treatment of the free base with HCl: 264-270 ° C.

B. 2,3,4,4a, 9,13b-hexahydro-1H-dibenzo [1,2]; 5.6 / 10 cyclohepta- [3,4-q] pyridine 27 g of sodium are added portionwise with stirring under nitrogen for about 5 hours to a solution of 4.45 g of the free base (obtained in A) in 300 ml of ethanol. The temperature during this process is maintained at 80-90 ° C. After 51/2 hours, all of the sodium has dissolved. 250 ml of CH 2 O are then added, after which the ethanol is distilled off in vacuo. The residue is extracted with ether and the organic phase is washed with water until neutral, dried over Na2SO4 and evaporated to dryness.

Yield: 4.44 g (97.3%) of a mixture of cis and trans isomers of the title compound.

in toluene / ethanol (7: 3) = 0.09 for cis, 0.15 for trans, and in methylene chloride / methanol (7: 3) = 0.14 for SiO 2 for the cis compound, and 0.66 for the trans compound.

Example VIII

2-methyl-1,2,3,4,4a, 13b-hexahydro-dibenz [2,3,6,7] oxepino [4,5-o] pyridine 380 mg of 2-methyl-3,4-dihydro- dibenz / 12.3; Dissolve 6,7 / oxe-30-silino [4,5-c] pyridin-1 (2H) -one in 40 ml of dry tetrahydrofuran.

The solution is boiled under nitrogen with the addition of diborane (gas) through the solution for 30 minutes.

Diborane was obtained by reacting 1.8 ml of BF 3 etherate 35 with 450 mg of sodium borohydride in 5 ml of 18,67701 diglyme. Boiling is continued for 3 hours, after which the solution is cooled and the excess diborane is removed with ethanol. The volume of the mixture is then reduced by evaporation. A mixture of 5 concentrated hydrochloric acid and water (1: 1) is added to the residue and the mixture is heated until a solution is formed. After cooling, the aqueous layer is made alkaline and extracted with ether. The ether extracts are washed with water, dried and evaporated to dryness. Yield: 280 mg of a mixture of cis- and trans-2-methyl-1,2,3,4,4a, 13b-10 hexahydrodibenz [2,3; 6,7] oxepino [4,5-o] pyridines in a ratio of about 1: 1. Methanol / weapon-Toni mixture of the cis compound (9: 1) = 0.30 SiO 2: Ha and the trans compound in the same system = 0.36.

The same mixture of cis and trans isomers is obtained using 2-methyl-dibenz / 2,3 as starting material; 6.7 / Okse-piino / 4,5-o7pyridin-l (2H) -one.

Il

Claims (6)

67701 A process for the preparation of new therapeutically useful tetracyclic compounds of the formula I and their salts and nitrogen oxides, 5 Rl ÄÄ. R 2 W 4 R 11 are R 5, R 2, R 3 and represent hydrogen, hydroxy, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio or trifluoromethyl, R 4 is hydrogen or C 1-6 alkyl -alkyl and X is oxygen, sulfur, NR 9 or CH 2 in the case of hydrogen or C 1-4 alkyl, characterized in that a) a compound of formula R 1 R 3 hx "or R 4 R 4 II Vy-O Rc where Q is ethylene or vinylene, the dashed line indicates a possible bond and R1, R2, R1, R4, R1 and X have the same meaning as above, are reduced, or b) an enamine of the formula 30> cP ·. - R 5 67701 wherein R 1, R 2, R 2, R 2, R 2 and X are as defined above, or a salt thereof is reduced, or c) a compound of formula 5 R 1 R 3 R 1 Ro tal ipiΓΥ3 10 r 5 IV iva wherein A® is an anion of an organic or inorganic acid and R 1, R 2, R 3 / R 2, R 2 and X have the same meaning as reduced above; after which, if desired, the compound obtained is alkylated and / or divided into stereo- or optical isomers and / or converted into a salt or nitric oxide. 67701 5 For use in the preparation of a terra-solid tetracyclic compound having the formula I and a salt and a quaternary oxide, R, R. R 5 is R 1, R 6, R 3 and R 2 is a substituent, hydroxy, halo C 1-6 alkyl, C 3-8 alkoxy, C 1-6 alkylthio or trifluoro-15-methyl, R 5 is hydrogen or C 1-6 alkyl och X är syre, svavel, NRg or CH2, varvid Rg är väte or C 1-4 -alkyl, k-n -netecknat därav, att a) en förening med formuleln 20 1 Vw x "3 r4 ii 25 '" l R5 from Q is ethylene or vinyl, - the striking lines of which are optionally bonded and R1, R2, R1, R1, R3 and X are as defined above, reducing, or b) most of E1 R3 R5