NO750919L - - Google Patents

Description

Process for the production of new heterocyclic compounds.

The present invention relates to a method for the production of new heterocyclic compounds of formula I

in which R, means hydrogen, alkyl with 1-5 carbon atoms, cycloalkyl with 3-7 carbon atoms, alkenyl or alkynyl with 3-5 carbon atoms, of which the unsaturated bond is not in the cc, |3-position of the nitrogen atom to which R, is attached , with cycloalkyl with 3-6 carbon atoms substituted alkyl with 1-4 carbon atoms, 2-hydroxyethyl, phenylalkyl with 7-11 carbon atoms, in the phenyl residue with halogen, 1-4 alkoxy or alkyl with 1-4 carbon atoms monosubstituted phenylalkyl with 7-11 carbon atoms, a residue A-CO-R^ or a residue (CH2)2-0-CORg, where A stands for alkylene ffied 1-4 carbon atoms, R3 means alkyl with 1-4 carbon atoms, phenyl, with halogen mono- or disubstituted phenyl , hydroxy, alkoxy with 1-4 carbon atoms, or means a residue NR^R^, where R4 and R5 stand for hydrogen or alkyl with 1-4 carbon atoms and R^ means alkyl with 1-4 carbon atoms, and

R2 stands for hydrogen, halogen, alkyl with 1-4 carbon atoms, alkoxy with 1-4 carbon atoms, nitro, hydroxy or a residue NR„RQ, in which R„ means hydrogen or alkyl with 1-4 carbon atoms

loi

and Rg means hydrogen, alkyl of 1-4 carbon atoms or alkanoyl

with 2-4 carbon atoms,

while

if R 1 means a residue (CH 2 ) 2 OCOR 6 , in which R 2 has the above meaning,

(R 2 _does not stand for ..amino or , alkylamino with-1-4 carbon atoms,'

as well as salts thereof.

If the radicals R 1 stand for alkyl with 1-5 carbon atoms and/or

R^ stands for alkyl with 1-4 carbon atoms, these preferably contain 1-3 carbon atoms. R^ means especially methyl,

R 2 means especially methyl or branched alkyl, e.g.

isopropyl.

If the residue R^ stands for cycloalkyl with 3-7 carbon atoms, this preferably contains 3-6, especially 5 carbon atoms.

If R^ stands for the above-defined alkenyl or alkynyl group with 3-5 carbon atoms, it preferably contains 3 carbon atoms.

If R 1 stands for an alkyl group with 1-4 carbon atoms substituted by a cycloalkyl group with 3-6 carbon atoms, its alkyl group especially contains 1 or 2 and its cycloalkyl group especially 3 carbon atoms. A preferred substituent of this series is the cyclopropylmethyl group.

If the residue R^ stands for a phenylalkyl residue with 7-11 carbon atoms optionally monosubstituted with halogen, alkoxy with 1-4 or alkyl with 1-4 carbon atoms, this phenylalkyl residue contains especially 7-9, preferably 7 or 8 carbon atoms. This residue's possible halogen substituent stands for fluorine, chlorine or bromine, preferably for fluorine or chlorine. This residue's possible alkoxy or alkyl substituent; with 1-4 carbon atoms especially contains 1-3, preferably 1 carbon atom.

If the residue R stands for the group A-CO-R^, then the alkylene group A contains, if R^ does not stand for an optionally substituted phenyl group, especially 1-3, preferably 1 or 2 carbon atoms.

If R 1 stands for a halogen mono- or disubstituted phenyl group, this is preferably mono-substituted. This phenyl radical's halogen substituent means by definition fluorine, chlorine or bromine, preferably fluorine or chlorine.

If the residues R 2 , R 4 and/or R 4 constitute an alkyl group with 1-4 carbon atoms, these in particular contain 1 carbon atom.

If R2 stands for alkoxy with 1-4 carbon atoms, this residue especially contains 1 or 2, preferably 1 carbon atom.

If R^ stands for alkoxy with 1-5 carbon atoms, this residue preferably contains 1-4, especially 1 or 2 carbon atoms.

If R7 and/or Rg stand for alkyl with 1-4 carbon atoms, they especially contain 1 or 2, preferably 1 carbon atom.

If Rg stands for alkanoyl with 2-4 carbon atoms, it preferably contains 2 carbon atoms.

If R2 is halogen, this stands for fluorine, chlorine or bromine,

preferred for chlorine.

Rg especially contains 1 or 2, preferably 1 carbon atom.

As can be seen from formula I, the hydrogen atoms in the 3a and 9a positions of the benz/17is°in<^0ls^jelet are in the trans position to each other.

Particularly preferred compounds of formula I are compounds of formula Iw in which R means hydrogen, alkyl with 1-3 carbon atoms, 2-hydroxyethyl, acetonyl or 3-oxobutyl, 2-carboxyethyl, 2-(carbomethoxy)ethyl, 2-(carboethoxy) -ethyl, 2-carbamoylethyl or a group A-CO-R^, in which A has the above-mentioned meaning and R^ means with halogen monosubstituted phenyl and Ra stands for hydrogen, methyl or halogen.

The peculiarity of the method according to the invention for the preparation of the compounds of formula I and their salts is that

a) for the preparation of compounds of formula Ia,

wherein means alkyl with 1-5 carbon atoms, cycloalkyl with 3-7

carbon atoms, alkenyl or alkynyl with 3-5 carbon atoms, of which the unsaturated bond is not in the oe, )3-position to the nitrogen atom to which R* is' bonded, with cycloalkyl with 3-6 carbon atoms substituted alkyl with 1-4 carbon atoms, 2 -hydroxyethyl, phenylalkyl with 7-11 carbon atoms, in the phenyl residue with halogen, alkoxy

with 1-4 or alkyl with 1-4 carbon atoms monosubstituted phenylalkyl with 7-11 carbon atoms, a residue A-CO-R^or a residue (CH2)2-0-COR6, wherein A, R, R^ and R& have the above meaning and R2 stands for hydrogen, halogen, hydroxy, alkyl with 1-4 carbon atoms, alkoxy with 1-4 carbon atoms, nitro or a residue NR^R<g>, in which either Rj means hydrogen or alkyl with 1-4 carbon atoms and Rg means alkanoyl with 2-4 carbon atoms or R^ and Rg means alkyl with 1-4 carbon atoms, compounds of formula Ib are alkylated,

wherein R 2 ; has the above meaning, or

b) for the preparation of compounds of formula Ic

wherein has the above meaning, a reactive derivative of the compound of formula II is reacted with an amine of formula III

wherein R^ has the above meaning or

c) for the preparation of compounds of formula Id

in which R*1 and R^j1 have the meanings given for R^ and R2 with the restriction that they<!>t in the compounds of formula Id at least one primary or secondary amino group is present, R?<1>means hydrogen and/or R2 II means a residue NHR^, in which R7 has the above-mentioned meaning, the protecting group or the protecting groups from compounds of formula IV are removed

where Rg stands for the symbol R^, which has the above meaning,

or stands for a protecting group, and R^q stands for hydrogen,

halogen, alkyl with 1-4 carbon atoms, alkoxy with 1-4 carbon atoms, hydroxy, nitro, a residue NR^Rg or a residue NR^S

in which R^, R^ and R^ have the above meaning and S means a protecting group, with the restriction that at least one protecting group is present, or

d) for the preparation of compounds of formula le

in which

R*11 means hydrogen, alkyl with 1-5 carbon atoms, cycloalkyl

with 3-7 carbon atoms, alkenyl or alkynyl with 3-5 carbon atoms, the unsaturated bond not being in the jac, ^-position to"" the

nitrogen atom to which R<*11> is bonded, with cycloalkyl with 3-6 carbon atoms substituted alkyl with 1-4 carbon atoms, 2-hydrotesy-ethyl, phenylalkyl with 7-11 carbon atoms, in the phenyl residue with halogen or alkyl with 1-4 carbon atoms monosubstituted phenylalkyl with 7-11 carbon atoms or a residue A-COR*, in which A has the above meaning and R^ I stands for alkyl with 1-4 carbon atoms, phenyl, with halogen mono- or disubstituted phenyl, hydroxy or a residue NR^R^ , in which R 4 and R 5 have the above-mentioned meaning, subject to compounds of formula If,

in which R^11 has the above meaning and alk stands for alkyl with 1-4 carbon atoms, an ether cleavage.

And the thus obtained compounds of formula I are recovered in free form or as salts.

From the free bases, acid addition salts can be extracted in a known manner and vice versa.

By definition, alkylation of the compounds of formula Ib means the introduction of a residue R^ in the 2-position of the compounds of formula Ib.

The alkylation of the compounds of formula Ib can be carried out in ways known for the alkylation of secondary amines. Thus, e.g. by reaction with a compound of formula V in which R* has the above meaning and X stands for the acid residue in a reactive ester, or with reactive derivatives of the compounds of formula V.

In the compounds of formula V, X means e.g. halogen such as chlorine,

bromine or iodine, preferably chlorine or bromine, or the acid residue in an organic sulphonic acid, e.g. an alkylsulfonyloxy group such as methylsulfonyloxy, or an arylsulfonyloxy group such as phenylsulfonyloxy or p-tolylsulfonyloxy.

The N-alkylation of the compounds of formula Ib with the compounds of formula V is conveniently carried out in an organic solvent, e.g. in an amide of an aliphatic carboxylic acid such as e.g. dimethylformamide. It is advantageous to work in the presence of a basic condensing agent such as sodium carbonate or N-ethyl-N,N-diisopropylamine. The reaction temperature can vary between room temperature to approximately 100°C.

Suitable reactive derivatives of the compounds of formula V

are among others cc, (3-unsaturated carbonyl compounds, for the introduction of a residue A-COR^, in which A stands for ethylene and R^ has the above-mentioned meaning and ethylene oxide for the introduction of the 2-hydroxyethyl group. The reaction of the compounds of formula Ib with a, (3-unsaturated carbonyl compounds such as methyl vinyl ketone or acrylic acid (lower) alkyl residues 'happens conveniently in a suitable organic solvent, e.g. in glacial acetic acid, a lower alkanol such as methanol, ethanol and under stirring. The reaction temperature can vary

between room temperature and the reflux temperature of the reaction mixture. Preferably, the reaction mixture is heated at about 40-120°C.

The reaction of the compounds of formula Ib with ethylene oxide

also happens analogously to known methods. The reaction temperature can vary between approximately +10 to 100°C.

, R* stands for a primary or secondary alkyl group with 1-4 carbon atoms, for cycloalkyl with 3-7 carbon atoms or gets a cycloalkyl with 3-6 carbon atoms substituted alkyl group with 1-4 carbon atoms, which carries at least one hydrogen atom on the oc-carbon - atom, then this residue can also be introduced by treating the compounds of formula Ib with the corresponding aldehydes or ketones and under reducing conditions.

E.g. one proceeds in such a way that the compounds of formula Ib are alkylated with the corresponding aldehydes or ketones in the presence of formic acid (Leuckart-Wallach method).

The reductive alkylation can also be carried out hydrogenolytically, i.e. by means of hydrogen gas in the presence of a metal catalyst such as Raney nickel, palladium, platinum, etc. However, with this process variant, as is known, a possible chlorine, bromine or nitro substituent in the compounds of formula Ib or a possible cyclopropyl group in at least partially co-reduced. In the presence of this group, the reductive alkylation is therefore appropriately carried out according to the above-mentioned Leuckart-Wallach method.

In the reaction according to Leuckart-Wallach, one works in a suitable organic solvent, preferably in an excess of "" formic acid. It is advantageous to work at an elevated temperature, preferably during reflux.

The catalytic reductive alkylation is carried out in a suitable organic solvent, e.g. in a lower alkanol such as methanol. One works appropriately at room temperature.

Compounds of formula lx

in which X stands for hydrogen, halogen, alkyl with 1-4 carbon atoms, alkoxy with 1-4 carbon atoms, nitro, hydroxy with a residue N(Alk)Alk<1>, in which Alk and Alk' mean alkyl with 1-4 carbon atoms and D means hydrogen, alkyl with 1-4 carbon atoms, cycloalkyl with 3-6 carbon atoms, with cycloalkyl with 3-6 carbon atoms substituted alkyl with 1-3 carbon atoms, phenyl, phenylalkyl with 7-10 carbon atoms, in the phenyl residue with halogen, alkyl with 1 -4 carbon atoms or alkoxy with 1-4 carbon atoms monosubstituted phenyl or in the phenyl residue with halogen, alkyl with 1-4 carbon atoms or alkoxy with 1-4 carbon atoms monosubstituted phenylalkyl with 7-10 carbon atoms, can be obtained by a variant of the alkylation method also by reduction of compounds of formula VI

x

in which R2 has the above-mentioned meaning and D' has the above-mentioned meaning or means lower alkoxy.

The reduction can be carried out with metal hydrides or diborane-alloy with methods known for the reduction of tertamides to tertamines.

As metal hydrides, aluminum hydrides such as e.g. aluminum hydride, dialkyl aluminum hydrides, lithium aluminum hydride or lithium aluminum hydride/aluminum chloride suitable.

Suitable solvents are solvents that are inert under the reaction conditions, e.g. cyclic or open chain ethers such as te tr ahydro fur an.

The reduction can be carried out at room temperature.

If in the compounds of formula VI there is a chlorine

or bromaryl residue, aluminum hydride or a dialkylaluminum hydride is suitably used as the metal hydride, but also diborane. If R<*> in formula VI stands for nitro, then appropriate aluminum hydride or diborane is used as reducing agent and the work is carried out under similar conditions, e.g. at a reaction temperature between +40 and +10°C.

This process variant, the reduction of the compounds of formula VI to the compounds of formula lx, is particularly suitable for the introduction of a cyclopropylmethyl residue in the 2-position of the compounds of formula Ib.

The compounds of formula IV required for use in this process variant can be obtained by acylation of the corresponding compounds of formula Ib, analogously to known methods. One uses e.g. acid halides, preferably the chloride or bromide, or the corresponding acid anhydrides

as an acylating agent. For N formulation apply? one in particular the mixed anhydride of formic acid with a carboxylic acid such as acetic acid.

When the compounds of formula Ib are treated with haloformic acid alkyl esters, the compounds of formula Ib substituted in the 2-position with a carbolic oxy group are obtained. Reduction of these compounds according to the above method variant gives compounds of formula lx, in which D means hydrogen.

in

When using acid anhydrides as an acylating agent, an excess of anhydride can be used as a solvent. Otherwise, it is appropriate to work in an organic solvent that is inert under the reaction conditions. As under the reaction conditions inert organic solvent is e.g. ethers such as dioxane, chlorinated aliphatic hydrocarbons such as methylene chloride, acetonitrile, etc. are suitable.

The reaction temperature is chosen depending on the compounds of formula Ib used and the acylating agent between 0°C and the reflux temperature for the reaction mixture, e.g. about. 80°C. You can usually work at room temperature. It is advantageous to work in the presence of a base such as pyridine, triethylamine, carboxylic acid sodium salts, etc. Pyridine can also be used as a solvent.

If R2 stands for hydroxy, the acylation of the compounds of formula Ib must be carried out under gentle conditions.

Method b) constitutes a condensation to pyrrolidines. It can be carried out analogously to methods known for the production of pyrrolidines by condensation of reactive derivatives of 1,4-butanediols with amines.

As reactive derivatives of the compound of formula II, suitable diesters are used, preferably diesters of the compound of formula II with an aromatic sulphonic acid such as p-toluenesulphonic acid.

Preferably, the reactive derivative of the compound of formula II is reacted with the equivalent amount of the amine of formula III. The reaction can be carried out in the melt or in an organic solvent inert under the reaction conditions such as toluene, methyl chloride or dimethylformamide. A basic condensation agent such as NaOH, sodium carbonate, triethylamine or pyridine is suitably added. Pyridine can also serve as a solvent.

The reaction temperature is about 20 to 200oC, preferred

20 to 120°C. The amine of formula III is preferably used as a base. One works under the exclusion of water.

/

Cleavage of the protecting groups according to the procedure

c) can be carried out analogously to known methods, e.g. in the following way: Suitable protective groups Rg and/or S are e.g. a hydrolytically cleavable group, e.g. an acyl group such as the trifluoroethyl group, a (lower) alkanoyl group, the benzoyl group, a (lower) alkoxycarbonyl group such as the methoxy or (ethoxycarbonyl group or the phenoxycarbonyl group, or a group that can be removed both hydrolytically and also under reducing conditions, e.g. an acid residue of a aliphatic or aromatic sulfonyl acid such as a tosyl residue or a hydrogenolytically or via the carbamate decoupable group such as the benzyl group.

The cleavage of such protecting groups according to the invention takes place analogously to known methods.

If Rg and S both stand for protecting groups, these can be identical. Depending on the nature of the protecting groups and the reaction conditions used, the removal occurs simultaneously, in (arbitrary order (e.g., if one protecting group is hydrolytically and the other hydrogenolytically removable) or in a specific order (if both protecting groups are hydrolytically removable, one easily and the other other less easy.

The hydrolytic separation can be carried out e.g. by means of a 1- to about 5N-16sation of an alkali metal hydroxide such as sodium or potassium hydroxide. A suitable solvent is e.g. a lower alkanol, especially methanol and ethanol are suitable. Does Rg or S stand for an acyl group that can be easily uncoiled, e.g. the trifluoro-<N>acetyl group, then the hydrolysis can take place at room temperature or slightly elevated temperature. The hydrolysis is then complete after about % to about 2 hours. Does Rg or S stand for a less easily cleavable acyl group, e.g. the ethoxycarbonyl group, one conveniently works under heating, preferably at the reflux temperature of the reaction mixture. The reaction then lasts about 10 to about 20 hours.

The hydrolysis of the compounds of formula IV can also take place under acidic conditions, e.g. using 2N hydrochloric acid, suitably at an elevated temperature, preferably at the reflux temperature of the reaction mixture.

Stårr?RQ or S for a group that can be removed hydrogenolytically, e.g., for example 1"for"1'benzyl, is preferably worked in the presence of a catalyst. As catalysts are. precious metal catalysts such as palladium suitable. The hydrogenation is carried out in an organic solvent, e.g. a lower alkanol such as methanol or ethanol. Preferably, you work with weak, overpressure, e.g. approximately 2 to 6 atmospheres and at elevated temperature, e.g. about 40 to about 80°C.

If Rg or S stands for the acid residue in an aliphatic or aromatic sulfonyl group, this group can be cleaved under reducing conditions - analogously to known methods - e.g.

with sodium ammonia.

For the preparation of the compounds of formula Id, which contain an ester or amide group, compounds of formula IV are suitably used, whose protecting group or protective groups are cleavable under hydrogenating conditions or stand for easily hydrolytically cleavable groups. Possible ether groups in the compounds of formula IV are attacked by the use of strong acids.

For the preparation of compounds of formula Id, which contain chlorine, bromine, nitro, an alkenyl-alkynyl, cyclopropyl or •keto group, compounds of formula IV are suitably chosen, whose protecting group or protecting groups are cleavable under hydrolytic conditions.

The ether cleavage of the compounds of formula If (method d) can be carried out analogously to the known methods for cleavage of phenol ethers. Thus, e.g. the compounds of formula If are reacted at ♦80 to 70°C with Lewis acids, e.g. with boron tribromide or aluminum chloride, in an organic solvent inert under the reaction conditions, e.g. a halogenated hydrocarbon such as methylene chloride or carbon tetrachloride, or an aromatic hydrocarbon such as toluene or, benzene. The ether cleavage with aluminum chloride proceeds under relatively energetic conditions. Boron tribromide, on the other hand, allows the ether cleavage to be carried out under very mild conditions and is therefore generally used preferably. if R1 forms a substantial group, e.g.

III

if contains an ester group.

One can also treat compounds of formula If for a short time

with strong mineral acids such as hydrobromic or hydroiodic acid, possibly at an elevated temperature, e.g. at approx. 20-100°C, possibly with the addition of glacial acetic acid. Under the latter conditions, possible amide groups in the compounds can be hydrolysed, aliphatic hydroxy groups eliminated or substituted with halogen or acetoxy. Alkenyl and alkynyl groups as well as cyclopropyl groups also react under these conditions, at least partially. According to a further method, the cleavage of the compounds of formula If can be carried out with alkali metal mercaptide, e.g. potassium thiophenolate in diethyl glycol (mild conditions) or alkali metal respectively alkali metal hydride/mercaptan, e.g. sodium hydride/ ethyl mercaptan in a polar organic solvent inert under the reaction conditions, such as e.g. dimethylformamide by

temperatures between approx. 50 and 150°C. Preferred 80-120°C.

According to a further process variant, lithium iodicL can be allowed to act on the compounds of formula If in the presence of 2,4-6-trimethylpyridine at temperatures between 100 and 150°C.

The compounds of formula I obtained by the above-mentioned methods can be isolated and purified according to methods known per se.

The compounds of formula IV are new.

The compounds of formula IV can e.g. produced in the following manner:

With reaction of compounds of formula VII

in which Ac stands for an acyl group and R-- means hydrogen, halogen, alkyl with 1-4 carbon atoms, alkoxy with 1-4 carbon atoms or a group NR^R^/in which stands for benzyl or alkyl with 1-4 carbon atoms and R^ represent alkyl with 1-4 carbon atoms or a protecting group, with an alkali metal hydride or amide and reaction of the thus obtained alkali metal salt with an allyl halide, compounds of formula VIII are obtained

wherein R^ and Ac have the above meaning.

As acyl group Ac is e.g. aroyl groups such as the benzoyl group or alkanoyl groups such as the acetyl group and especially the trifluoroacetyl group are suitable.

As protecting groups R^ are e.g. those for Rg and S anforte protective groups suitable.

In the thermal cyclization of the compounds of formula VIII, the corresponding compounds of formula IX are formed

wherein R^ and Ac have the above meaning.

The thermal cyclization of the compounds of formula VIII is carried out under heating, e.g. at a reaction temperature of 160-240°C.

You may work in an autoclave. An organic solvent that is inert under the reaction conditions is chosen as the solvent, e.g. an aromatic hydrocarbon such as toluene or a chlorinated, especially aromatic hydrocarbon such as dichlorobenzene. One works appropriately under the exclusion of oxygen. The reaction time varies between 15 hours and approximately 5 days. The reaction mixture thus obtained is evaporated and the residue containing the compounds of formula IX is either worked up and purified or further processed in a crude state. The preparation and purification of the reaction residue can take place according to known methods, e.g. by fractional crystallization or chromatography. The compounds of formula IX, in which R, .. do not stand for hydrogen, are also available by aromatic substitution of corresponding compounds of formula IX, in which R^ stands for hydrogen. E.g. is obtained from the last compound by nitration according to known methods the corresponding compound of formula IX, in which R R^ means the amino group, which by Sandmeyer reaction or further conventional transformation gives other compounds of formula IX.

During the nitriding, you work under relatively mild conditions to avoid dinitration. E.g. a mixture of nitric acid and sulfuric acid is used in a quantity ratio of approximately 40/60. The temperature is approximately +20 to 10°C.

The compounds of formula IX can be analogous to known methods by selective introduction and cleavage of protective groups, N-alkylation and/or introduction of an N-alkanoyl group, and this in a suitable sequence is transferred to compounds of formula IV.

The compounds of formula II are known. The compounds of formula Tf are. 7 included. of the compounds of formula Ia, and the compounds of formula Ib are covered by the compounds of formula Id.

If the preparation of the starting compounds is not described, these are known or can be prepared according to per se known methods, respectively analogous to those described here or analogous to per se known methods.

The compounds of formula I which can be prepared by the method according to the invention, i.e. the compounds of formula I

in free form or in form. of pharmacologically tolerable salts of these compounds, have interesting pharmacodynamic properties.

The compounds can therefore be used as medicine.

With animal experiments, special pharmacological effects were found that are typical for antiaggressive drugs.

The anti-aggressive effect of the compounds which can be produced by the method according to the invention is shown, for example. in an attenuation of the isolation-induced aggressive behavior of mice with doses of 1 to 30 mg/kg p.o. The specific nature of this effect is evident from the fact that the substances exert their aggression-inhibiting effect in doses where a general dampening of the central regulations cannot yet be demonstrated.

Due to their anti-aggressive effect, the substances are suitable for dampening the aggressive behavior of psychopaths and the feeble-minded.

Of particular interest are the compounds of formula I, in which R^ represents hydrogen or alkyl with 1-3 carbon atoms and R2 represents hydrogen, chlorine or methyl, especially trans-3α,4,9,9α-tetrahydrobenz/17isoindoline, trans- 3a,4,9,9a-tetrahydro-6-methylberiz/f7is°in3oline, trans-6-chloro-3a, 4, 9, 9a-tetrahydro-2-isopropylbenz/57is°indoline and trans-3a,4,9, 9a-tetrahydro-2-methylbenz/57is°in<i0lin by a pronounced antiaggressive effect with a high specific character.

Usually, satisfactory results can be obtained with a daily dose of 20 to 1000 mg.

Furthermore, effects typical of analgesics were found in animal experiments for the compounds of formula I.

The analgesic properties showed e.g. in "Tail-fliok" prdven in mice at doses of 30 to 150 mg/kg p.o. as well as in inhibition of the phenylbenzoquinone syndrome in mice at doses of 30 to 100 r ^ mg/kg p.o.

Due to their analgesic properties, the substances can be used to treat pain of various kinds.

The compounds of formula I have been found to be particularly interesting for the latter application, in which R1 stands for alkyl with 1-3 carbon atoms, allyl, propynyl or a group A-CORa3, in which A and R^ have the above meaning, and R^ means hydrogen, chlorine or methyl, especially p-fluoro-4-(trans-3a,4,9,9a,tetrahydrobenz/E7iso;indolin-2-yl)butyrophenone and p-fluoro-4-(branes-6-chloro-3a , 4, 9, 9α-tetrahydrobenz(17isoindolin-2-yl)butyrophenone.

For use as an analgesic, the dose administered also depends on the compound used and the method of administration.

Usually, however, for the latter application, satisfactory results are obtained with a daily dose of 300 to 1000 mg.

The compounds of formula I can be administered alone or in a suitable dosage form. The preparation forms, e.g. a tablet, can be prepared analogously with known methods.

The preparations can be prepared using the usual auxiliary and carrier substances.

In the following examples, which shall illustrate the invention, all room temperature indications are in °C and are uncorrected.

Example 1: trans-3α,_4,~9,9α-tetrahydro-2-methyl-1-benz/f7isoindoline

(method a)

The solution of 4 g of trans-3a,4,9,9a-tetrahydrobenz/f7isoindoline

in a mixture of 60 ml 100% formic acid and 60 ml 40% aqueous formaldehyde solution is heated for 2 hours to boiling under nitrogen and then evaporated. The residue is shaken out with an excess of 2N-NaOH/ether, the ether phase is dried over sodium sulphate and evaporated. The residue is added to a saturated solution of 3.3 g of naphthalene 1,5-disulfonic acid in methanol. On addition of ether, bis[alpha]rans-3a,4,9,9a-tetrahydro-2-methylbenz[f7isoindoline]naphthalene-1,5-disulfnate with a melting point of 296 to 298°C is crystallized.

Example 2: . trans-2-cyclopropylmethyl-3a^4^9^ga-te^ahydrobenz/r7isoindoline

To a solution of 1.98 g of lithium aluminum hydride in 30 ml of tetrahydrofuran is added a solution of 6 g of crude trans-3a,4,9,9a-tetrahydro-2-cyclopropylcarbonylbenz/i:7-isoindoline in 30 ml of tetrahydrofuran prepared while heating. The mixture is stirred for 16

hours at room temperature is then split with saturated ammonium sulfate solution and filtered. The evaporated tartrate is added to a concentrated solution of 2.6 g of naphthalene-1,5-disulfonic acid. After addition of ether, bis/trans-2-cyclopropyl-methyl-3a,4,9,9a-tetrahydrobenz/f"7-isoindoline-7-naphthalene-1,5-disulfonate with melting point 2 93 to 295°C crystallizes out.

The trans-3a,4,9,9a^tetrahydro-2-cyclopropylcarbonylbenz/17isoindoline used as starting material can be prepared in the following way: To a solution of 4.5 g of trans-3a,4,9,9a-tetrahydrobehz/f" 7-isoindoline and 6.2 g of pyridine in 30 ml of methylene chloride are added dropwise at +10° C. to a solution of 3.7 g of cyclopropane carboxylic acid chloride. The mixture is stirred for 1 hour at room temperature, then shaken

then in sequence with 10% citric acid solution (2 times), sodium bicarbonate;. sodium chloride solution, dried over sodium sulfate and evaporated, whereby trans-3a,4,9,9a-tetrahydrobenz/r7isoindoline-2-cyclopropylcarboxylic acid amide is obtained as a crystalline residue.

Example 3: trans-2-cyclopentyl-3a,4,9,9a-tetrahydro-6-methylbenz/f7isoindoline

3.1 g of trans-3a,4,9,9a-tetrahydro-6-methylbenz/f7isoindoline and 1.0 g of cyclopentanone are dissolved in a mixture of 30 ml of ethanol and 3 ml of glacial acetic acid and hydrogenated after the addition of 0.3 g of palladium/ wool for 5 hours at 50°C and 5 ato. After cooling, the catalyst is filtered off, the filtrate is evaporated and the residue dissolved in ether. The ether solution is washed with 2N-NaOH and water, dried and evaporated

The remaining compound mentioned in the title is crystallized as hydrogen maleate, melting point 148-150°C.

Example 4: trans-2-cyclopentyl-3a,4,9,9a-tetrahydrobenz/?7isoindoline

6.5 g of trans-3a,4,9,9a-tetrahydrobenz/r7isoindolirihydrochloride and 0.2 g of benzyl-tri-n-butylammonium bromide are dissolved in 50 ml of methylene chloride. Add 30 ml to the mixture while stirring vigorously

■2N-NaOH and, with continued stirring, 13.5 g of cyclopentyl bromide and a further 30 ml of 2N-NaOH are then added dropwise over the course of 48 hours. The methylene chloride phase is then separated and evaporated. The rest is taken up in ether. The ether solution is extracted with 2N hydrochloric acid, the extract is made alkaline with 2N NaOH and extracted again with ether. After drying over sodium sulfate, the solvent is distilled off and the remaining base is transferred into the hydrogen maleate. By recrystallization from ethanol-ether, one of the salts mentioned in the title compound is obtained. Melting point 169 to 171°C.

Example 5: trans-6-_(N-ethylmethylamino2-3aL4,9,9a-tetrahydro-2-(2-propynyl)benz/r7isoindoline

A mixture of 6 g of trans-6-(N-ethylmethylamino)3a,4,9,9a-tetrahydrobenz/£7isoindoline, 3.4 g of N-ethyl-diisopropylamine and 45 ml of water; dimethylformamide is added at room temperature to 3.4 g of propargyl bromide, stirred for 2 hours and then evaporated. The residue is shaken out with 2N-NaOH/methylene chloride, the organic extract is washed with water and dried with sodium sulphate and evaporated. The compound mentioned in the title is returned (raw).

Example 6: trans-6-acetamido-3a,4,9;9a-tetrahydrobenz/£7isoindoline-2-ethanol

In a solution of 4 g of trans-6-acetamido-3a,4,9,9a-tetrahydrobenz/17is°indoline in 30 ml of ethanol, 1.5 g of ethylene oxide are introduced at +15°C with stirring. The mixture is set aside for 16 hours at 0°C and then evaporated. The compound mentioned in the title is returned (raw).

Example 7: trans-3α,4,9,9α-tetrahydro-6-(N-methylacetamido)

benz/f7i s°i n^°li2-2-propionic acid methyl ester

A mixture of 15 g of trans-3α,4,9,9α-tetrahydro-6-(N-methyl<g>cetamido)

*>enz/17isoindoline, 6 g of acrylic acid methyl ester and 1 ml of a 40% methanolic solution of benzyl trimethylammonium hydroxide are stirred for 4 hours at 50°C and then evaporated. The compound mentioned in the title is returned (raw).

Example ,8-: trans-2-benzyl-3α-4,9,9α-tetrahydrobenz/l/isoindoline

(method b)

10.0 g of trans-2, 3-bis (p-tosyloxymethyl)-1, 2, 3, 4-tetrahydro-naphthalene, 2.1 g of benzylamine and 3.0 g of soda are stirred in 30 ml of dimethylformamide for 6 hours at 100 C. After cooling, filter and evaporate the filtrate. The residue is dissolved in ether, the ether solution is washed twice with water, dried over sodium sulphate and the solvent is distilled off. The remaining compound mentioned in the title is crystallized as hydrochloride. Melting point 240 to 243°C.

The trans-2,3-bis(p-tosyloxymethyl)-1, 2, 3, 4-.tetrahydronaphthalene used as starting material can be prepared in the following way: a) 34.5 igVtrans-1,2,3, 4-tetrahydronaphthalene tallene-2,3-dicarboxylic acid dimethyl ester is reduced in 500 ml of tetrahydrofuran with 19 g of lithium aluminum hydride. It is split while cooling with water, dissolved in dilute hydrochloric acid and trans-2,3-bis(hydroxymethyl)~1,2,3,-4-tetrahydronaphthalene is extracted with isobutanol. After drying the extract, the solvent is distilled off and it is recrystallized from ethanol. Melting point 121 to 123°C. b) 19.2 g of trans-2,3-bis(hydroxymethyl)-1,2,3,4-tetrahydronaphthalene are dissolved in 260 ml of pyridine and at 0°C 40.0 g of p-toluenesulfonic acid chloride are introduced. The portion is stirred for 3 hours at 5°C and then poured onto ice. The desired reaction product separates out crystalline. It is filtered and the dried trans-2,3-bis(p-tosyloxymethyl)-1,2,3,4-tetrahydronaphthalene is recrystallized from ethyl acetate/petroleum ether, melting point 109 to 111°C.

Example 9: ^ans-Ba^^Q^Qa-tetrahydrobenz/f/

isoindoline

(method c)

A solution of 164 g of crude trans-3a,4,9,9a-tetrahydro-2-trifluoro^acetylbenz/r7isoindoline and 168 g of potassium hydroxide in 1.5 1 of methanol is set aside for 1 hour at room temperature under nitrogen, then poured into 1, 2 1 water and extracted 3 times each time with 300 ml of ether. The ether extracts are washed with saturated sodium chloride solution and dried over magnesium sulphate. The oily residue remaining after evaporation of the reaction mixture is worked up by chromatography on 250 g of silica gel with methylene chloride/methanol/25% aqueous ammonia solution, collecting fractions of 1.25 1.

Fractions 6-15 gave, on evaporation, a residue which is evaporated with an excess of methanolic hydrochloric acid. Crystallization of the residue from methanol/ether gives trans-3a,4,9,9a-tetrahydrobenz/f"7-isoindoline hydrochloride with melting point 259 to 266°C.

The trans-3a, 4, 9, 9a-tetrahydro-2;^ trifluoro£acetylbenz/:E7isoindoline used as starting material can be prepared in the following way: a) To an a,; ice bath cooled and stirred suspension of 45 g of 80% sodium hydride (in mineral oil) in 200 ml of hexamethylphosphoric acid triamide is added dropwise to a solution of 343 g of N-cinnamyl-trifluoroP:^acetamide in 600 ml of hexamethylphosphoric acid triamide under nitrogen. After gas evolution has ended (approximately 1 hour), 199 g of allyl bromide are added dropwise over the course of 30 min. at 0-20°C. The mixture is stirred for 16 hours at room temperature, poured into water and then extracted with ether. The ether phase, washed with water and dried over magnesium sulfate, gives, on evaporation, an oily residue which is chromatographed on 2.4 kg of silica gel with toluene/petroleum ether 3:1, the pure N-allyl-N-trans-cinnamyl-trifluoroacetamide being obtained as a colorless oil.

b) A solution of 336 g of N-allyl-N-trans-cinnamyl-trifluracetamide in 3 1 of toluene is heated for 20 hours in a steel autoclave at 235°C

and evaporated. The residue is chromatographed on 2.2 kg of silica gel with 2.2 1 toluene/petroleum ether 4:1 followed by 2.4 1 toluene, whereby fractions of 2.2 1 are collected. The combined fractions 4-21 give on evaporation trans-3α7-4,9,9α-tetrahydro-2-trifluoroacetyl-benz/?7isoindoline as an oily residue. The compound thus obtained is further processed directly without further purification.

Example 10: trans-3α,4,9,9α-tetrahydrobenz/f7

isoindoline

12.0 g of trans-2-benzyl-3a,4,9,9a-tetrahydrobenz/f7isoindoline hydrochloride is dissolved in 100 ml of methanol and hydrogenated after the addition of 0.2 g of palladium charcoal at 50°C and 5 ato for 3 hours . It is filtered off, evaporated and the remaining hydrochloride of the compound mentioned in the title is recrystallized from ethanol/ether (melting point 261 to 263°C).

Example 11: i<ra>2£~^2lZl2l.25li,5t£5^}ZÉ<r>2z^z5itE2z

benz/17isoindoline

30.0 g of trans-2-benzoyl-3a,4,9,9a-tetrahydro-6-nitrobenz/f7-isoindoline are heated with stirring with a mixture of 300 ml of semi-concentrated hydrochloric acid and 50 ml of methanol for 24 hours under reflux. It is then evaporated to half the volume, made alkaline with NaOH and extracted with ether. The ether extract is dried and evaporated and the oily remaining compound mentioned in the title is crystallized as hydrochloride.

(melting point / ~^^ 25Q°C /cleavage/.

The trans-2-benzoyl-3a,4,9,9a-tetrahydro-6-nitrobenz/£7isoindoline used as starting product is obtained in the following way: 30.0 g of trans-2-benzoyl-3a,4,9,9a-tetrahydrobenz /E7isoindoline (melting point 132 to 135°C, prepared from trans-3a,4,9,9a-tetrahydrobenz/f/isoindoline and benzoyl chloride in chloroform in the presence of sodium carbonate) is introduced at +5°C with stirring into a mixture of 76 ml concentrated nitric acid and 38 ml of concentrated sulfuric acid. The mixture is stirred for a further 2 hours at room temperature, then poured onto ice and the separated crystals are filtered off. After recrystallization from ethyl acetate/petroleum ether, trans-2-benzoyl-3α,4,9,α-tetrahydro-6-nitrobenz/β-isoindoline melts at 168 to 170°C. Example 12: t£5n£i3a^4L9^9a-te^ahydro-6- hydroxy-2-methylbenz/r7isoindoline 20 g of 3a,4,9,9a-tetrahydro-6-methoxy-2-methylbenz/r7isoindoline are dissolved in 250 ml of methylene chloride and slowly added while stirring at +75°C 26 g of boron tribromide in the form of a 1-molar solution in methylene chloride. After 5 hours, the solvent is distilled off in vacuo, the residue is heated for 1 hour with 100 ml of ethanol under reflux and evaporated again. The compound mentioned in the title remains as hydrobromide.

The following compounds of formula Ia are obtained by proceeding from their corresponding compounds of formula Ib and using method a): One proceeds analogously to example 8 (method b) and obtains with the reaction of a suitable reactive derivative the compound with II and a compound of formula III, following compounds of formula Ici:

One proceeds analogously to method c and, using the corresponding starting compounds of formula IV, the following compounds of formula Id are obtained:

Claims (8)

1. Process for the preparation of new heterocyclic compounds of formula I in which R1 means hydrogen, alkyl with 1-5 carbon atoms, cycloalkyl with 3-7 carbon atoms, alkenyl, or alkynyl with 3-5 carbon atoms, of which the unsaturated bond is not in a, (3-position to the nitrogen atom to which it is bonded, with cycloalkyl with 3-6 carbon atoms, substituted alkyl with 1-4 carbon atoms, 2-hydroxyethyl, phenylalkyl with 7-11 carbon atoms, in the phenyl residue with halogen alkoxy with 1-4 or alkyl with 1-4 carbon atoms monosubstituted phenylalkyl with 7-11 carbon atoms, a residue A-CO-R3 or a residue (CH2 )2 -0-COR6 , where A stands for the alkylene with 1-4 carbon atoms, R^ means alkyl with 1-4 carbon atoms, phenyl, with halogen mono- or disubstituted phenyl, hydroxy, alkoxy with 1-4 carbon atoms, or a residue NR^ R^ , where R^ and R^ stand for hydrogen or alkyl with 1 -4 carbon atoms and Rg means alkyl with 1-4 carbon atoms and R2 stands for hydrogen, halogen, alkyl with 1-4 carbon atoms, alkoxy with 1-4 carbon atoms, nitro, hydroxy or stands for a residue NR^ Rg, in which R7 means hydrogen or alkyl with 1-4 carbon atoms pg 'Rg means hydrogen, or alkanoyl with 2 to 4 carbon atoms, wherein if R^ means a residue (CH2 )2 OCORg, in which Rg has the above meaning, R2 does not stand for amino or alkylamino with 1-4 carbon atoms, and their salts, characterized in that a) for the preparation of compounds of formula Ia in which R* means alkyl with 1-5 carbon atoms, cycloalkyl with 3-7 carbon atoms, alkenyl or alkynyl with 3-5 carbon atoms, of which the unsaturated bond is not in oc, (3-position to the nitrogen atom to which R <*> is bonded, with cycloalkyl with 3-6 carbon atoms substituted alkyl with 1-4 carbon atoms, 2-hydroxyethyl, phenylalkyl with 7-1T carbon atoms, in the phenyl residue with halogen, 1-4 alkoxy or alkyl with 1-4 carbon atoms monosubstituted phenylalkyl with 7-11 carbon atoms, a residue A-CO-R^ or a residue (CH2 )2~ 0 -C0Rg, wherein A, R^ and R^ have the above meaning and R2 stands for hydrogen, halogen, hydroxy, alkyl with 1-4 carbon atoms, alkoxy with 1-4 carbon atoms, nitro or a residue NR^Rg <1> , in which either R7 means hydrogen or alkyl with 1-4 carbon atoms and R <g > means alkanoyl with 2-4 carbon atoms or R7 and R <g> means alkyl with 1-4 carbon atoms, compounds are alkylated; with formula, Ib in which R^ has the above-mentioned meaning, or b) for the preparation of compounds of formula Ic in which it has the above-mentioned meaning, a reactive derivative of the compound of formula II is reacted With an amine of formula III in which R^ has the above-mentioned meaning, or c) for the preparation of compounds of formula Id in which R*1 and R^ <1> have the meanings given for R^ and R2 with the restriction that in the compounds of formula Id they are present at least one primary or secondary amino group, wherein R?1 means hydrogen and/or R2 II means a residue NHR^ , in which R7 has the above-mentioned meaning, the protecting group or the protecting groups from compounds of formula IV are cleaved off in which Rg stands for the symbol R^ , which has the above meaning, or for a protecting group, and R^ q stands for hydrogen, halogen, alkyl with 1-4 carbon atoms, alkoxy with 1-4 carbon atoms, hydroxy, nitro, a residue NR ^Rg or a residue NR^ S, in which Rij, Rg and R^ have the above meaning and S means a protecting group, with the limitation that there is at least one protecting group, ord) for the preparation of compounds of formula le in which R*11 means hydrogen, alkyl with 1.5 carbon atoms, cycloalkyl with 3-7 carbon atoms, alkenyl or alkynyl with 3-5 carbon atoms, the unsaturated bond not being in a, (3-position to the nitrogen atom to which R is bonded, with cycloalkyl of 3-6 carbon atoms, substituted alkyl of 1-4 carbon atoms, 2-hydroxyethyl, phenylalkyl of 7-11 carbon atoms, in the phenyl residue with halogen or alkyl of 1-4 carbon atoms, monosubstituted phenylalkyl of 7-11 carbon atoms or a residue A-COR <*> , where A has Io has the above meaning and R^ stands for alkyl of 1-4 carbons atoms, phenyl, with halogen mono- or disubstituted phenyl, hydroxy or a residue NR^ R,-, in which R^ and R,- have the above-mentioned meaning, subject to compounds of formula If in which R^ <11> has the above meaning and alk stands for alkyl with 1-4 carbon atoms, an ether cleavage and the thus obtained compounds of formula I are recovered in free form or as salts. 2. Process as stated in claim 1, characterized in that trans-3a,4,9,9a-tetrahydrobenz/E7isoindoline is produced. 3. Process as stated in claim 1, characterized in that trans-2-methyl-3a,4,9,9a-tetrahydrobenz/|7isoindoline is prepared. 4. Method as stated in claim 1, characterized in that trans-2-isopropyl-6-methyl-3a,4,9,9a-tetrahydrobenz/17isoindoline is produced. . 5. Procedure as stated in claim 1, characterized ; v. e d that one prepares trans-6-methyl-3a,4,9,9a-tetrahydrobenz/17isoindoline. 6. Process as stated in claim 1, characterized in that p-fluoro-4-(trans-3a,4,9,9a-tetrahydrobenz/f7isoindolin-2-yl-butyrophenone is prepared). 7. Process as stated in claim 1, characterized in that p-fluoro-4-(trans-6-chloro-3a,4,9,9a-tetrahydrobenz/E7isoindolin-2-yl)butyrophenone is prepared. 8. Process as stated in claim 1, characterized in that trans-6-chloro-2-isopropyl-3a,4,9,9a-tetrahydrobenz/f7isoindoline is prepared.