NO156371B - ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE CYCLOALKA (4,5) -PYRROLO (2,3-G) ISOKINOLINES. - Google Patents

Description

The present invention relates to an analog method

in the preparation of therapeutically active cycloalka[4,5]-pyrrolo[2,3-g]isoquinolines of the general formula

where is hydrogen or benzyl; R 2 is hydrogen,

(Cj-^)-alkyl, hydroxy-(C-^_^)-alkyl, arylhydroxy-

(C1-4)-alkyl, C1-4)-alkoxy-(C1-4)-alkyl, arylcarbonyl-(C1-4)-alkyl, aryl-(C-^)-alkyl or (C2-5)-

alkenyl;

X is 0 or S, and n is 3, 4, 5 or 6, and where

aryl is phenyl optionally substituted with halogen or (C 1-4 )-alkoxy,

optical and geometric isomers of these compounds and pharmaceutically acceptable acid addition salts thereof.

The compounds of the general formula A above can according to

the invention is produced by an analogous method, in which one

a) for the preparation of a compound of the general formula

where R"2 is C(x_4)-alkyl, or (C1_4)<-> alkoxy-(C^_4)-alkyl and n is as previously described, treats a compound of the general formula

where R"2 and n are as previously described,

with formaldehyde or

b) for the preparation of a compound of the general formula Ia above treats a compound of the general formula

formula

where R"2 is as previously described, with a compound of the general formula in the presence of a reducing agent or with a compound of the general formula or a precursor thereof, in which compounds n is as previously described, or c) for the preparation of a connection with the general formula

where n is as previously described,

N-demethylates a compound of formula Ia above where R" 2 is methyl, or

d) for the production of a compound with the general pre-

flour

wherein R"^ is hydrogen or benzyl, R" '2 is hydrogen, (C1-4)-alkyl, (C1-4)-alkoxy-(C1-4)-alkyl, aryl-(<C>1-4)<->alkyl or (C2-5) -alkenyl, and

n is as previously described,

treats a compound with the general formula

in which R"i» R"'2°9 n is as previously described, with phosphorus pentasulphide. or e) for the preparation of a compound of the general formula

where R'2 is (C1-4)-alkyl, hydroxy-(C-L-7)-alkyl,

aryl-hydroxy-(C^_4)-alkyl, (Ci-q)-Alkoxy-(C-L_4)-alkyl, arylcarbonyl-(C1-4)-alkyl, aryl-(C1-4)-alkyl or (C2_ ^)-alkenyl, and X and n are as before

described

substitutes a compound of the general formula

where X and n are as previously described,

on the isoquinoline nitrogen tower, or

f) for the preparation of a compound of the general formula

where R' 1 is benzyl, R<VI> is (C1_4)<->alkyl, (C1_4)-Alkoxy-(Clr4)-alkyl, arylcarbonyl-(C-L_4)-alkyl, aryl-(C^_4)- alkyl or (C2_^)-alkenyl, and X and n are as previously described,

benzylates a compound of the general formula

where r<VI>2' x °9 n is as previously described,

on the pyrrole nitrogen atom 7 or

g) for the production of a compound with the general

formula

where R<IV>2 is hydroxy-(C-^_^)-alkyl or arylhydroxy-(C^__4)-alkyl and X and n are as previously described, reduces the carbonyl group in a compound of the general formula

where R^11 is ^Cl-7^~°xoalkyl or arylcarbonyl-(C^_4)-alkyl, and X and n are as previously described,

or

h) for the preparation of a compound of the general formula

where X, n and R'^ are as previously described,

cleaves the urethane group in a connection with the general

formula

where X, n and R'^ are as previously described and Y is a urethane group, and

if desired, isomerize the mixture of the obtained cis and trans isomers to a final ratio comprising mainly the trans isomer, and/or

;. if desired, separates the transisomer from the mixture obtained, and/or

if desired, a racemic mixture obtained dissolves in the optical antipodes and/or

if desired, converting an obtained compound or a non-pharmaceutically acceptable acid addition salt into a pharmaceutically acceptable acid addition salt thereof.

More specifically, the compounds of formula A above, their optical and geometric isomers and their pharmaceutically acceptable acid addition salts and the various intermediates thereof can be prepared as illustrated below in greater detail.

Thus, e.g. the compounds of formula A where X is 0 characterized by the formula where n, and R2 is as previously described, and can be prepared as indicated in schemes I, II, III and IV and further described.

wherein n and R~" are as previously described.

According to formula I, compounds with formula are prepared

Ia from known compounds of formula IV where ' is (C1-4)-alkyl or (C1-4)-alkoxy-(C-L-4 )-alkyl. Birch reduction of the amine of formula IV with lithium in ammonia containing t-butanol gives the dihydroamine of formula V. Other modifications of the Birch reduction can also be used. Thus, the amine of formula IV can be reacted with an alkali metal such as sodium, lithium, potassium or cesium in ammonia or an amine such as methylamine or ethylamine in the presence of a lower alkanol such as ethanol, butanol or t-butanol. The reaction is generally carried out at the boiling point of the solvent or lower, e.g. from -78° to 15°C. If ammonia is used, the reaction is run at reflux. Optionally, additional solvents such as diethyl ether or tetrahydrofuran are used.

Hydrolysis of the dihydroamine of formula V is easily carried out by usual methods for the hydrolysis of enol ethers, e.g. with aqueous acid. Examples of acids that can be used are hydrochloric acid, hydrogen bromide, formic acid, acetic acid, p-toluenesulfonic acid and perchloric acid. These can be used in aqueous solutions or mixed

ed solvents. Tetrahydrofuran, benzene, diethyl ether, acetone, toluene, dioxane or acetonitrile are examples of the solvents that can be used. E.g. leads to hydrolysis of the dihydroamine of formula V where R2" is methyl in 2N hydrochloric acid at room temperature or higher or in aqueous acetic acid at between 40° and reflux temperature to the diketone of formula VI where R2" is methyl.

The diketone of formula VI is condensed in a Knorr condensation

which gives the methylaminoethyl ketone of formula IX. The Knorr condensation is a well-known method for the production of pyrroles and the method can be used in all well-known modifications [-see e.g. conditions, J.M. Patterson, Synthesis, 281 (1976)

and references therein]. E.g. the reaction of an isonitrosoketone of formula VII in the presence of a reducing agent, e.g. with zinc in aqueous acetic or hydrochloric acid, to proceed

via the aminocarbonyl compound of formula VIII which then condenses with the diketone of formula VI and gives the product methylaminoethyl ketone of formula IX. Alternatively, the condensation can be carried out with an aminocarbonyl compound of formula VIII or precursor thereof such as an aminoketone hydrochloride salt or a ketal derivative of an aminoketone. The use of a precursor of the aminoketone is preferred, as such substances are subject to self-condensation. They can best be used "in situ" where the aminocarbonyl compound is released in the presence of the diketone of formula VI. The aminocarbonyl component reacts immediately and forms the compound of formula IX. It is not necessary to isolate the diketone of formula VI before the Knorr condensation is carried out, as the reaction conditions used are sufficient to hydrolyze the dihydroamine of formula V to the diketone of formula VI. The Knorr condensation is preferably carried out at a pH of from approx. pH 2 to pH 6. Much higher than pH 6, the yield is considerably less due to the formation of self-condensation products of the aminocarbonyl compound of formula VIII.

Preferably, an isonitrosoketone of formula VII and zinc dust are condensed in aqueous acetic acid with a diketone of formula VI where R'<1>2 is methyl which gives the product methylaminoethyl ketone of formula IX where R'^ is methyl.

The Knorr condensation is preferably carried out at a temperature of approx. room temperature to reflux. The isonitroso ketones of formula VII are known compounds or can be easily prepared by nitrosation of the corresponding p-ketoester, e.g. with sodium nitrite. [See e.g. TOE. Geissman and M.J. Schlatter, J. Org. Chem., 11, 771 (1946)].

Examples of isonitroso ketones of formula VII that can be used in the Knorr condensation are:

2-isonitrosocyclopentanone,

2-isonitrosocyclohexanone,

2-isonitrosocycloheptanone, and

2-isonitrosocyclooctanone.

Examples of aminocarbonyl precursor compounds of formula VIII which can be used in the Knorr condensation are: 2-aminocyclohexanone, hydrochloride,

2-aminocyclopentanone, hydrochloride,

2-aminocycloheptanone, hydrochloride, and 2-aminocyclooctanone, hydrochloride.

These compounds are known or can be prepared by reduction of the corresponding isonitrosoketone, e.g. by catalytic hydrogenation in the presence of hydrogen chloride.

The amine of formula IX is transferred to the compound of formula

Ia through an intramolecular Mannich reaction. The Mannich reaction is normally carried out by starting from a ketone and a dialkylamine salt, e.g. dimethylamine hydrochloride and formaldehyde (e.g. as an aqueous solution, as paraformaldehyde or as trioxane)! in an alcoholic solvent such as ethanol at the reflux temperature of the reaction mixture. In the modification described here, an acid addition salt of the methylaminoethyl ketone of formula IX is reacted with formaldehyde added in the form of paraformaldehyde, trioxane, or as aqueous formaldehyde in a solvent. E.g. can a high boiling hydroxyl-containing solvent such as amyl alcohol, octanol, ethylene glycol or diethylene glycol monoethyl ether, a high boiling polar aprotic solvent such as dimethylformamide, N-methyl-pyrrolidinone or diethylene glycol dimethyl ether, a lower boiling polar solvent such as ethanol, butanol or 2-propanol under pressure, or a lower boiling aprotic solvent under pressure such as dioxane or tetrahydrofuran is used at a temperature in the range from approx. 135°C to 200°C, giving cycloalka[4,5]pyrrolo[2,3-g]isoquinolines of formula Ia. The reaction, especially when run at temperatures below 150°C, leads to a mixture of cis and trans isomers, i.e. e.g. when R2" are methyl compounds with the formulas

Prolonged heating of the reaction mixture or separate heating of the isomeric mixture of hydrochloride salts of formulas If and Ig', e.g. in ethylene glycol at reflux 1 2 hours can be used to equilibrate the cis and trans isomers to a final ratio comprising mainly the trans isomer, which is easily isolated by crystallization or chromatographic separation.

When e.g. the hydrochloride salt of the amine of formula IX where 1*2" is methyl is reacted with paraformaldehyde in butanol at 180°C for 2 hours, the product is isolated as the trans isomer If. According to formula scheme II, compounds of formula I'c are prepared by alkylation or acylation of the pyrrole nitrogen in a compound of formula Ia<*> and other N-2-alkyl derivatives by forming the pyrrole anion with a strong base, e.g. sodium amide, potassium hydride, sodium methylsulfinyl carbanion, potassium t-butoxide or butyllithium or with an alkali metal followed by reaction with an alkyl or acyl halide in a solvent such as tetrahydrofuran, dioxane, ethyl ether, dimethylformamide or dimethylsulfoxide. For example, treatment of a compound of formula Ia' where n is 3 with potassium t-butoxide in tetrahydrofuran followed by reaction with methyl iodide 6-methyl derivatives gives , i.e. a compound of formula I'c where n is 3 and ' is methyl. Similarly, reaction of a compound of formula Ia' where n is 4 with butyllithium in tetrahyd rofuran at -3 0° followed by reaction with benzoyl chloride 6-benzoyl derivatives, i.e. a compound of formula I'c where R^' is benzyl and n is 4. Similarly, reaction of a compound of formula Ia<1 > where n is 3 with sodium methylsulfinylcarbanion in dimethylsulfoxide followed by reaction with benzyl chloride 6-benzyl derivatives, i.e. a compound of formula Ic<1> where R^' is benzyl and n is 3.

N-demethylation of the compound of formula Ia<1> can be carried out

by standard N-dealkylation methods such as von Braun's method [H.A. Hageman, Org. Reactions, 7, 198 (1953)], or through acid or base hydrolysis of a urethane derivative such as those indicated in K.C. Rice [J. Org. Chem., 40, 1850 (1975)]. A method for dealkylation of the compound of formula Ia is through the urethane of formula XHIa and. acid hydrolysis to the secondary amine of formula Ib. When e.g. a compound of formula Ia' where n is 4 is refluxed in dioxane with excess ethyl chloroformate and potassium bicarbonate for 6 hours, a compound of formula XIII is obtained where n is 4. Hydrolysis of the preceding compound with 30% aqueous sodium hydroxide in ethanol-dioxane at reflux in 24 hours gives the compound with formula lb where n is 4.

Urethane derivatives can also be used as starting materials for the production of pyrrole-ring substituted derivatives by alkylation or acylation of the pyrrole nitrogen, followed by cleavage of the urethane. The alkylation or acylation is carried out according to methods given for the preparation of compounds of formula I'c, and the urethane derivatives and the methods for cleaving these are indicated as mentioned above in K.C. Rice (ibid). E.g. according to formula II, treatment of the ethoxycarbonyl urethane of formula XHIa where n is 4 with sodium methylsulfinyl carbanion in dimethylsulfoxide followed by treatment with benzyl chloride gives the compound of formula XHIb where n is 4 and R^' is benzyl. Hydrolysis with sodium hydroxide gives 6-benzyl derivatives, i.e. a compound of formula Ih where R^' is benzyl and n is 4.

where R-^ and n are as previously described and R 2'

is (C 14 )-alkyl, hydroxy-(C 14 )-alkyl, arylhydroxy-(C 1-4 )-alkyl, (C 1-4 )-alkoxy-(C 1-4 )-alkyl, arylcarbonyl-(C 1-4 )-alkyl, aryl -(C]__4)-alkyl or (C2-5)-alkenyl.

According to formula scheme III, the compounds of formula Id and Ic are prepared from the secondary amine of formula Ib, the starting material for the preparation of numerous compounds covered by formula I, by substitution on the basic amine nitrogen (N-2) and/or the pyrrole nitrogen (N- 6). E.g. provides treatment of a compound of formula Ib with an alkyl halide such as ethyl bromide, an alkenyl halide such as allyl bromide, a cycloalkylalkyl halide such as chloromethylcyclopropane, an aralkyl halide such as benzyl bromide or an acylalkyl halide such as Y-chloro-p-fluorobutyrophenone in the presence of a base, f .ex. sodium carbonate in acetone, 2-propanone or dimethylformamide, the corresponding substituted compound of formula Id. With reactive halides, the reaction can be carried out at room temperature; unless reactive halides are used, reflux temperatures are used and in some cases the reaction rate can be increased by adding an iodine salt such as lithium iodide to the reaction mixture.

Reaction of a compound of formula Ib with epoxy alkanes gives the hydroxyalkyl substituted compound of formula Id. Treatment with a substituted epoxyalkane gives the 2-substituted-2-hydroxyalkyl analogues of a compound of formula Id,, e.g. reaction of a compound of formula Ib with styrene oxide gives a compound of formula Id, in which R2<1> is 2-phenyl-2-hydroxyethyl. The reaction is normally carried out in the presence of an alcoholic solvent such as methanol at from room temperature to the reflux temperature of the mixture. The epoxy alkane is either commercially available or prepared by epoxidation of the corresponding olefins or by methylenation of a ketone with a sulfonium methylide or sulfoxonium methylide agent, e.g. dimethylsulfonium methylide. Thus gives e.g. treatment of benzaldehyde with dimethylsulfonium methylide styrene oxide.

In some cases where R2' in connection with formula Id does not

contain functional groups that can be alkylated or acylated, the method set forth in formula scheme II for the preparation of compounds of formula Ic' can be used directly to prepare N-6-substituted analogs of formula Ic as set forth in formula scheme III. Alkylations can occur in compounds where R2<1> is hydroxyalkyl or arylhydroxyalkyl. The hydroxyl groups therein must be protected with a base-stable protecting group such as tetrahydropyranyl. After N-6 alkylation, the protecting group is removed by acid hydrolysis.

Alternatively, compounds of formula Id where R2<1> is hydroxyalkyl or aryl hydroxyalkyl can be prepared by the reduction of the corresponding compounds of formula Id where R2' is acylalkyl. More specifically, the preceding reduction can e.g. is carried out with an alkali metal borohydride reducing agent such as sodium borohydride or lithium borohydride by, e.g. room temperature in a solvent, e.g. an alkanol such as ethanol or the like.

In the reactions described in formula schemes I, II and III, both the trans isomers of formula where n, and R2 are as previously described, and the cis iso- and cis isomers of formula

where n, and R2 are as previously described,

of the compounds of formula I are formed, with dominance of the trans isomer. The pure transisomer can be separated by chromatography or crystallization. In addition, mixtures can be isomerized as described for the isomerization of the trans and cis isomers of the oxo compound of formula If and lg<1>, or with base-catalyzed equilibration, e.g. with sodium hydroxide in ethanol.

When the substituent groups R 1 and R 2 in the compounds of formula

In containing additional asymmetric centers, a mixture of diastereomers can be obtained. E.g. is the number of possible isomers 2n when n is the total number of asymmetric centers in the compound. Preferred are the enantiomers and/or diastereomers of compound of formula If as previously described.

where n is as previously described and R,," is ^ ci- 4^~

alkyl or alkoxy-(C-L-4)-alkyl.

An alternative synthesis of the compounds of formula Ia is described in formula IV in which the isoquinoline ring is formed before the formation of the pyrrole ring. According to formula IV, (3,5-dimethoxyphenyl)ethylamine of formula IV is refluxed with aqueous formaldehyde to give the tetrahydroisoquinoline of formula X. Birch reduction of the tetrahydroisoquinoline of formula

X with lithium in liquid ammonia containing t-butanol under essentially the same conditions as described for the Birch reduction of the compound of formula IV affords the hexahydroisoquinoline of formula XI. Hydrolysis of crude hexahydroisoquinoline of formula XI under essentially the same conditions as described for the hydrolysis of the dihydroamine of formula V gives the diketone of formula XII. The compound of formula XII is reacted in a Knorr condensation, as described during the preparation of the methylaminoethyl ketone of formula IX with the isonitroso ketone of formula VII or with the aminocarbonyl compound of formula VIII and gives cycloalka[4,5]pyrrolo-isoquinoline of formula Ia. The sequence of reactions according to formula scheme IV starting from amino of formula IV is preferred in which R2" is methyl, which gives the corresponding N-methyl-cycloalka[4,5]pyrroloisoquinoline of formula Ia as a mixture containing the trans isomer If' and the cis isomer with formula lg' .

The same procedure for isomerizing the mixture of cycloalka[4,5]pyrroloisoquinolines with formulas If and Ig as previously described can be used to prepare mainly the trans isomer with formula If<1>.

The compounds of formula A where X is S are characterized by the formula

where n, and R2 are as previously described,

and can be produced as indicated in formulae V and VI and further described in the following.

where n is as previously described; R 1" is hydrogen, alkyl or benzyl, and R 2"' is hydrogen, (C 1-4 )-alkyl, (C 1-4 )-alkoxy-(C 1-4 )-alkyl, aryl-(C 1-4 )-alkyl or (C 2-5 )-alkenyl .

According to formula V, compounds of formula Ile are prepared by heating compounds of formula le with phosphorus pentasulphide in an inert organic solvent. Preferred solvents are tetrahydrofuran, benzene, toluene or dioxane, and the reaction is generally carried out at reflux temperature.

Further compounds of formula II are prepared as described in formula VI. According to formula VI, a compound of formula Ilb is reacted and gives a compound of formula Ild according to the methods specified in detail in formula III for the preparation of the corresponding oxo compounds of formula Id.

in which n, R^' and R2' are as previously described.

In a similar way, a compound of formula Ild is reacted and gives a compound of formula Ile according to the methods s indicated in scheme III for the preparation of the corresponding oxo compounds of formula Ic.

Further compounds of formula II are prepared according to the methods indicated in detail in formula scheme II for the preparation of corresponding oxo compounds of formula Ih.

In these reactions, both of the trans isomers can have the formula

where n, R, and R^ are as previously described, and the cis isomers with formula

where n, R^ and R^ are as previously described,

of the compounds of formula II are formed, the trans isomer predominating. The pure trans isomer can be separated by chromatography or separation. In addition, the mixture can be isomerized as described for the isomerization of the trans and cis isomers of the oxo compound with formula If<1> and lg<1>.

As described above for compounds of formula I, when the substituent groups R 1 and R 2 in compounds of formula II contain additional asymmetric centers, a mixture of diastereomers can be formed. Preference is given to the enantiomers and/or diastereomers of the compounds of formula IIf as previously described.

The compounds of formula A form acid addition salts with inorganic or organic acids. Thus they form pharmaceutically acceptable acid addition salts with both pharmaceutically acceptable organic and inorganic acids, e.g. with hydrohalic acids such as hydrochloric acid, hydrogen bromide, hydrogen iodide, other mineral acid salts such as sulfuric acid, nitric acid, phosphoric acid or the like, alkyl and monoarylsulfonic acids such as ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid or the like, other organic acids such as acetic acid, tartaric acid, maleic acid, citric acid, benzoic acid, salicylic acid, ascorbic acid and the like. Non-pharmaceutically acceptable acid addition salts of compounds of formula A can be converted into pharmaceutically acceptable acid addition salts through conventional metathetic reactions whereby the non-pharmaceutically acceptable anion is replaced by a pharmaceutically acceptable anion, or alternatively by neutralizing the non-pharmaceutically acceptable acid addition salt and then converting it thus obtained free base with a reagent which gives a pharmaceutically acceptable acid addition salt. The acid addition salts can also form hydrates.

The compounds of the general formula IX and XIII are new and also form part of the present invention.

The compounds of formula A and their pharmaceutically acceptable acid addition salts exhibit neuroleptic activity. Accordingly, the compounds of formula A are useful as antipsychotic agents, for example in the treatment of schizophrenia. The activity of the compounds of formula A, which makes them useful as anti-psychotic agents, can be demonstrated on warm-blooded animals according to known methods.

In a method, e.g. trained rats are placed in experimental chambers equipped with a reaction lever, a steel grid floor that provides electric shock and a loudspeaker that provides auditory stimulation. Each trial consists of a 15-second warning tone (conditioned stimulus), which continues for another 15 seconds followed by an electric shock (unconditioned stimulus” 1.0 mA, 350 V.A.C.). The rats could end the trial at any time by depressing the response lever. A reaction during the initial 15 second warning tone ends the trial before the shock is delivered and is considered an avoidance reaction, while a reaction during the delivery of the shock is an escape reaction. Tests are performed every two minutes during a 1-hour test period (30 tests per period).

Trained rats maintain a reliable control baseline of avoidance behavior (zero to three avoidance errors per group). Compounds are administered at appropriate pretreatment times to a minimum of 3 to 4 rats at each dosage level through a range of dosages. Rats receive excipient alone during control periods. A control and an experimental period alternate each week.

The period is divided into three of the following 20-minute (ten pre-search) sections. Reaction counts are summarized across all subjects at a given dose within each section.

The number of trials in which the rats did not show an avoidance response (avoidance blocking, AB), or did not show an escape response (escape blocking, EB) is determined for each section giving the maximum such effect at each dose. This number is expressed as a percentage of the total trials within the section. The dose estimated to produce a 50% blockade of avoidance (ABD 50) is obtained from the dose-effect regression line fitted to the least squares method. The lowest dosage producing a 20% blockade of the escape response (EBD 20). is replaced by a graphical dose-effect plotting.When these values are reached, the percentage effect is plotted against the log-dose ring.

Antipsychotics can be separated from other types of drugs that affect the behavior of rats in this method by a greater separation between doses that block the avoidance reaction and doses that block the escape reaction. The clinical strength of antipsychotic drugs with known therapeutic uses and properties is clearly and strongly correlated with their strength in this method. Accordingly, the compound of formula A can be used therapeutically in dosage ranges consistent with their potency in the test method.

When 2-methyl-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]-pyrrolo[2,3-g] isoquinolin-10(10H)-one is used as a test compound, a neuroleptic activity is observed at an ABD^q of 0.98 mg/kg p.o.

Likewise, when 2-[4-(4-fluorophenyl)-4-oxobutyl]-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta [4,5]pyrrolo [2,3-g]isoquinolin-10(lOH)-one is used as test substance, neuroleptic activity is observed at an ABD^q of 0.15 mg/kg p.o.

Likewise, when 2-[4-(4-fluorophenyl)-4-oxobutyl]-2,3,4,4a,5,7,8,9,10,lla-decahydro-4a,lla-trans-1H,6H -cyclohexa[4,5]pyrrolo[2,3-g]isoquinolin-11(11H)-one is used as a test substance, neuroleptic activity is observed at an ABD^q of 0.73 mg/kg p.o.

Likewise, when 2-methyl-2,3,4,4a,5,7,8,9,10,11a-decahydro-4a, 11a-trans-1H,6H-cyclohexa[4,5]pyrrolo[2,3 -g]isoquinolin-11 (11H)-one, hydrochloride, 0.75 molar hydrate, which has shown an LDj-q of e.g. 65 0 mg/kg p.o. in mice, used as a test substance, neuroleptic activity is observed at an ABD^Q of 5.5 mg/kg p.o.

Likewise, when 2-methyl-2,3,4,4a,5,7,8,9,10,11,12,13a-dodecahydro-4a,13a-trans-1H,6H-cycloocta[4,5 ]pyrrolo[2,3-g]isoquinolin-13(13H)-one is used as test substance, neuroleptic activity is observed at 8 mg/kg p.o. where avoidance blocking is 63%.

Likewise, when 2-methyl-1,2,3,4,4a,5,7,8,9,10,11,12a-dodecahydro-4a,12a-trans-6H-cyclohepta[4,5]pyrrolo [2,3-g]isoquinolin-12(12H)-one is used as test substance, neuroleptic activity is observed at 16 mg/kg p.o. where avoidance blocking is 50%.

The compounds of formula A and their pharmaceutically acceptable acid addition salts have antipsychotic effects qualitatively similar to haloperidol and trifluoroperazine known for their therapeutic use and properties. Thus, the compounds of formula A show a broad spectrum of activity similar to antipsychotic drugs with known activity and

Safety.

The compounds of formula A and their pharmaceutically acceptable acid addition salts can be used in the form of conventional pharmaceutical preparations. By way of example, suitable oral dosage units that comprise or range from 0.05 to 50 mg and suitable oral dosage sizes in warm-blooded animals comprise or range from approx. 0.001 mg/kg per day to approx. 10 mg/kg per day. For all especially warm-blooded animals, however, the specific dosage may be varied and should be adjusted depending on individual need, and the professional judgment of the person administering and supervising the administration of a compound of formula A or a pharmaceutically acceptable acid addition salt thereof. Furthermore, the frequency with which any such dosage form is given will vary depending on the amount of active drug contained therein and the needs and requirements of the pharmacological situation.

For the described use, the compounds of formula A and their pharmaceutically acceptable acid addition salts are formulated using conventional inert pharmaceutical excipients in dosage forms suitable for oral or parenteral administration. Such dosage forms include tablets, suspensions, solutions etc. Furthermore, the compound of formula A can be introduced into and given in the form of suitable hard or soft capsules. The properties of the inert excipients used in the formulation of the compounds of formula A and their pharmaceutically acceptable acid addition salts for oral and parenteral dosage forms will be apparent to one skilled in the art. These auxiliary materials, whether they are inorganic or organic, include e.g. water, gelatin, lactose, starch, magnesium stearate, talc, vegetable oils, gums, polyalkylene glycols, etc. Further preservatives, stabilisers, wetting agents, emulsifiers, salts for setting osmotic pressure, buffers or the like can, if desired, be taken in such formulations .

As the compounds of formula A and their pharmaceutically acceptable acid addition salts have asymmetric carbon atoms, they are normally obtained as racemic mixtures. If desired, diastereomeric mixtures when such are obtained can be separated. The dissolution of individual racemates in the optically active isomers can be carried out by known methods. Alternatively, optically active isomers can be prepared by using the corresponding optically active starting materials described in the present method. Some racemic mixtures can precipitate as eutectics and can then be separated. However, chemical dissolution is preferred. In this method, diastereomers are formed from the racemic mixture with an optically active solvent, e.g. an optically active acid, such as (+)-tartaric acid, (+)-dibenzoyl-D-tartaric acid, (+)-d-10-camphorsulfonic acid, (-)-3-pinancarboxylic acid and the like to form a diastereomer salt. The diastereomers formed are separated by fractional crystallization and can be transferred into the corresponding optical isomeric base. Thus the invention covers the optically active isomers of the compound of formula A as well as their racemates.

Furthermore, due to the possible different spatial arrangement of the atoms, it should be clear that the compounds produced in the present invention can be obtained in more than one possible geometrically isomeric form. The compounds of formula A as described and claimed are intended to include all such isomeric forms. The examples included here are therefore to be understood as illustrative of particular mixtures of geometric isomers and not as limitations of the scope of the invention.

The examples that follow illustrate the invention. All temperatures are stated in °C unless otherwise stated.

Example 1

Preparation of N-methyl-1,5-dimethoxycyclohexal-1,4-diene-3-ethylamine (Intermediate product)

185.2 g of N-methyl-(3,5-dimethoxyphenyl)-ethylamine hydrochloride was dissolved in 1600 ml of water and the solution was made alkaline with 160 ml of ammonium hydroxide. The mixture was extracted with 3 x 1000 ml of dichloromethane and the combined extracts were washed with 1000 ml of brine and dried over anhydrous sodium sulfate. Evaporation of the solvent on a rotary evaporator at 35 to 40° gave 156.0 g of free base.

1 a 12 liter 3-necked flask equipped with mechanical stirring and

In 2 dry ice coolers, one equipped with a gas inlet and the other with a sodium carbonate drying tube, 4.0 L of anhydrous ammonia was condensed. The ammonia was added to a solution of 15 6 g of the free base in 400 ml of t-butanol and 400 ml of anhydrous ether over 15 minutes. The stirred solution was added over 50 minutes to a total of 3.6 g of lithium wire cut into 6.25 cm lengths. The rate of addition was controlled so that 12.5 cm of wire was added per minute. After all the lithium was added, the deep blue mixture was stirred at reflux for 2 hours. Then 2.8 L of anhydrous ether was added to dilute the mixture, the drying tube was removed to allow the hydrogen to escape, and a total of 280 g of ammonium chloride powder was added slowly over 30 minutes until the blue color had disappeared. The dry ice cooler was removed and the mixture was stirred and the ammonia allowed to evaporate overnight. The remainder was added to 2.8 1 ice water. The mixture was transferred to a separatory funnel, washed with 800 ml of ether and the layers separated. The aqueous layer was extracted with 2 x 1.5 L of dichloromethane and the extracts combined and washed with 1 liter of brine and dried over anhydrous sodium sulfate. Evaporation of the solvents on a rotary evaporator at 40° and finally at 40°/l.0 mm for 1.5 hours gave 150.7 g of crude product as a yellow oil. The crude oil was distilled through a 30 cm Good-loe column (bath 150°) collecting the following fractions:

Fractions 3 and 4 combined gave 120.6 g of N-methyl-1,5-dimethoxycyclohexa-1,4-dien-3-ethylamine as a colorless oil.

Anal. lime. for C^H^NC^: C, 66.97', H, 9.71-, N, 7.10

Found: C, 66.84", H, 9.62; N, 6.93

Example 2

Preparation of 1, 2, 3, 5, 6, 7, 8, 9- octahydro- 2-[ 2-( methylamino) ethyl]- 4H- carbazol- 4-one (Intermediate product)

A mixture of 15.6 g of N-methyl-1,5-dimethoxycyclohexa-1,4-dien-3-ethylamine (79 mmol), 16.7 g of 2-isonitrosocyclohexanone (131 mmol) and 19.5 g of zinc dust ( 300 mg atom) in 300 ml of 70% aqueous acetic acid was heated at reflux for 5 hours, cooled and filtered. The filtrate was concentrated in vacuo and excess dioxane was added. The dioxane-acetic acid azeotrope was distilled off and the process repeated until all the acetic acid had been removed. The residue was chromatographed on alumina III eluting with 10% methanol in dichloromethane which gave 10.7 g of crude 1,2,3,5,6,7,8,9-octahydro-2-[2-(methylamino)ethyl] - 4H-carbazol-4-one. The crude product was dissolved in methanol and treated with methanolic HCl and the solvent evaporated to give 12.2 g of 1,2,3,5,6,7,8,9-octahydro-2-[2-(methylamino)ethyl]-4H- carbazol-4-one hydrochloride.

Example 3

Preparation of 2- methyl- 2, 3, 4, 4a, 5, 7, 8, 9, 10, lla- decahydro-4a, lla- trans- 1H, 6H- cyclohexa-[ 4, 5] pyrrolo[ 2, 3 - g] isoquinoline

- 11( llHl- on (Intermediate product)

A mixture of 2.3 g of 1,2,3,5,6,7,8,9-octahydro-2-[2-(methylamino)ethyl]-4H-carbazol-4-one hydrochloride (8.14 mmol) and 2.3 g paraformaldehyde (76 mmolL in 100 ml n-butanol was heated in a pressure bottle immersed in a 180°C oil bath to an internal pressure of 5.44 atmospheres for one hour. The solution was cooled and the solvent removed under reduced pressure and the residue dissolved in water and washed with dichloromethane (discarded).

The aqueous solution was made alkaline with ammonium hydroxide and extracted with dichloromethane. The extracts were dried over sodium sulfate, filtered and evaporated to a 10 ml<1>s volume. The mixture was slurried with 10 g of alumina, filtered and evaporated to dryness. The residue was chromatographed on 80 g of alumina III eluting with 10% methanol in dichloromethane which gave 2-methyl-2,3,4,4a,5,7,8,9,10,lla-decahydro-4a,lia-trans- 1H,6H-cyclohexa[4,5]pyrrolo-[2,3-g]isoquinolin-11(11H)-one containing a small amount of the corresponding 4a,lla-cis isomer. Crystallization of the crude product from methanol-dichloromethane ether gave 2-methyl-2,3,4,4a,5,7,8,9,10,lla-decahydro-4a,lla-trans-1H,6H-cyclohexa[4, 5]-pyrrolo[2,3-g]isoquinolin-11(11H)-one as an off-white solid. The free base was treated with HCl in methanol and the hydrochloride recrystallized twice from ethanol to give 0.46 g of pure 2-methyl-2,3,4,4a,5,7,8,9,10,lla-decahydro -4a,lla-trans-1H,6H-cyclohexa[4,5]pyrrolo[2,3-g]isoquinolin-11(11H)-one, hydro- i. chloride, 0.75 molar hydrate as crystals, melting point 217 -220° (19% yield).

Anal. lime. for <C>16H22<N>2<0.>HC1.0.75 H20

C, 62.33 > H, 8.01, N, 9.09; Cl, 11.50 Found: C, 62.56; H, 8.11; N, 9.08; Cl, 11.59

Etes. empe 1 4

Preparation of 3, 4- dihydro- 1H- 6, 8- dimethoxy- 2- methyl isoquinoline, hydrochloride (Intermediate product)

A solution of N-methyl-(3,5-dimethoxyphenyl)ethylamine hydrochloride (15.0 g, 64.7 mmol) in 30 mL of water was treated with 35 mL of 2N sodium hydroxide and extracted with dichloromethane. The combined extracts were concentrated on a rotary evaporator and mixed with aqueous formaldehyde (65 mL, 37% solution). The mixture was refluxed for 2 hours, basified with 2N sodium hydroxide (15 mL) and extracted with dichloromethane. The combined extracts were washed with brine and dried over anhydrous magnesium sulfate and concentrated to give the product as a yellow oil (15.5 g). The oil was dissolved in 100 ml of ethanol and treated with ethanolic hydrogen chloride. 75 ml of ether was added and the salt crystallized to give 10.15 g of 3,4 dihydro-1H-6,8-dimethoxy-2-methylisoquinoline hydrochloride (64% yield).

Example 5

Preparation of 1,2,3,4,4a,7-hexahydro-6,8-dimethoxy-2-methylisoquinoline and octahydro-2-methylisoquinoline-6,8-dione (Mellati product) Ammonia (150 ml) was condensed in a flask containing t-butanol (9.1 g, 123 mmol) and diethyl ether (50 mL). To the solution was added 3,4-dihydro-1H-6,8-dimethoxy-2-methyliso-quinoline hydrochloride (1.0 g, 4, 1 mmol).After stirring for 2-3 minutes, lithium wire (0.57 g, 82 mmol) was added in short

ker over 30 minutes. The blue solution was stirred under reflux for 2.5 hours and solid ammonium chloride (4.5 g) added until the blue color disappeared. 100 ml of ether was added and the ammonia allowed to evaporate overnight. 100 ml of ice water was added and the organic phase separated. The aqueous layer was extracted with ethyl acetate and chloroform. The combined extracts were washed with brine and dried over anhydrous magnesium sulfate and concentrated to give 1,2,3,4,4a,7-hexahydro-6,8-dimethoxy-2-methylisoquinoline (0.58 g, crude) as a yellow oil.

The crude product (1.05 g) in 20 ml of 70% aqueous acetic acid was refluxed for 5 hours and the acetic acid removed on a rotary evaporator. The residue was dissolved in water and washed with chloroform. The aqueous phase was concentrated to a 10 ml volume and chromatographed on Dowex AG 50WX8 eluting with 2 M aqueous pyridine to give 0.11 g of octahydro-2-methylisoquinoline-6,8-dione (11.6%, yield) as a pale yellow solid. Treatment with hydrochloric acid in methanol gave the hydrochloride, m.p. 193-196°.

Example 6

Preparation of 2- methyl- 2, 3, 4, 4a, 5, 7, 8, 9, 10, lla- decahydro- 4a, lia- trans- 1H, 6H- cyclohexa-[ 4, 5] pyrrolo[ 2, 3 - g] isoquinolin- 11 ( llH)- one via octahydro- 2- methylisoquinolin- 6, 8-dione A mixture of 72 g crude octahydro-2-methylisoquinolin-6,8-dione (approx. 30% pure, approx. 0, 1 mol), 21.1 g of crude 2-isonitrosocyclohexanone (approx. 60% pure, approx. 0.1 mol) and 19.5 g of zinc dust (0.3 g atom) in 500 ml of 70% aqueous acetic acid were heated at reflux for one hour. A second 10.5 g portion of 2-isonitrosocyclohexanone and 6.5 g of zinc dust were added and the mixture refluxed for a further two hours. The solution was cooled, filtered and concentrated in vacuo, and the residue was dissolved in water and washed with chloroform (discarded). The aqueous solution was made alkaline with ammonium hydroxide and was extracted with chloroform. The extracts were washed with brine, dried over sodium sulfate and concentrated. The crude 2-methyl-2,3,4,4a,5,7,8,9,10,lla-decahydro-4a,lla-trans-1H,6H-cyclohexa[4,5]pyrrolo [2 , 3- g] isoquinolin-11 , llH-one was chromatographed on silica gel (dry column) eluting with the organic phase of a mixture prepared by shaking (by volume) 90 parts chloroform, 30 parts methanol, 10 parts water and 6 parts acetic acid which gave 7.8 g of 2-methyl-2,3,4,4a,5,7,8,9,10,lla-decahydro-4a,lla-trans-1H,6H-cyclohexa[4,5]pyrrolo [2,3-g]isoquinolin-11 ( 11H)-one as a white amorphous solid after slurrying with hot ethanol, mp 273-275°C (dec).

Anal. lime. for C, ,HooN„0: C, 74.38', H, 8.58', N, 10.84

laughed 2.

Found: C, 74.21; H, 8.39; N, 10.61

Example 7

By following the procedure from example 6 and starting from 2-isonitrosocyclopentanone and octahydro-2-methylisoquinoline-6,8-dione, 2-methyl-1,2,3,4-4a,5,7,8,9,10a was obtained -decahydro-4a, 10a-trans-6H-cyclopenta[4,5]pyrrolo[2,3-g]isoquinolin-10(10H)-one, m.p. 296-297°C. (cleavage), crystallized from ethanol-methanol.

Anal. lime. for <C>15H2Q<N>2<0:>C,73,74;H,8,25;N,11,47

Found: C, 73.93; H, 8.41; N, II, 46

The hydrochloride crystallized from water as a hemihydrate, m.p. 256-258°C (decomposition).

Anal. lime. for C15H2()N20.HC1 0.5H2O: C,62,17;H,7,65;N,9,67;C1,12,23 Found: C,62,16;H,7,71;N, 9.54; C1.12.37

Example 8

By following the procedure from example 6 and starting with 2-isonitrosocycloheptanone and octahydro-2-methylisoquinoline-6,8-dione, 2-methyl-1,2,3,4,4a,5,7,8,9,10 was obtained ,11,12a-dodecahydro-4a,12a-trans-6H-cyclohepta[4,5]pyrrolo[2,3-g]-isoquinolin-12(12H)-one, m.p. 293-296°C, crystallized from ethanol.

Anal. lime. for <C>17H24<N>2<0:> C, 74 , 96H,8 ,88>N, 10 ,28 Found: C,74,79JH,8,74;N,10,33

Example 9

By following the procedure from example 6 and starting from 2-isonitrosocyclooctanone and octahydro-2-methylisoquinoline-6,8-dione, 2-methyl-2,3,4,4a,5,7,8,9,10,11 was obtained ,12,13a-dodecahydro-4a,13a-trans-1H,6H-cycloocta[4,5]pyrrolo[2,3-g]-isoquinolin-13(13H)-one, m.p. 298-300°C, crystallized from water-dimethylformamide.

Anal. lime. for <C>18H26<N>2<0:> C,75,48;H,9,15;N,9,78 Found: C,75,29;H,9,04JN,9,70

Example 10

Preparation of 2, 3, 4, 4a, 5, 7, 8, 9, 10, lla- decahydro- 4a, 11a-trans- 1H, 6H- cyclohexa[ 4, 5] pyrrolo[ 2, 3-g] isoquinoline- 11(11H)-one

A mixture of 1.9 g of 2-methyl-2,3,4,4a,5,7,8,9,10,lla-decahydro-4a,lla-trans-1H,6H-cyclohexa[4,5]pyrrolo [2,3-g]isoquinolin-11(11H)-one, 2.6 g ethyl chloroformate and 3.2 g potassium bicarbonate in 100 ml dioxane were heated at reflux for 6 hours, cooled and filtered. The filtrate was concentrated under reduced pressure, dissolved in chloroform and extracted with 5% aqueous hydrochloric acid, washed with water, brine and dried over sodium sulfate. Evaporation of the solvent gave 1.4 g of the a-carbamate 2-ethoxycarbonyl-2,3,4,4a,5,7,8,9,10,lla-decahydro-4a,lla-trans-1H,6H-cyclohexa[4 ,5]pyrrolo[2,3-g]isoquinolin-11(11H)-one. From the aqueous extracts, 0.45 g of starting material was recovered by treatment with ammonium hydroxide and chloroform extraction.

The crude carbamate (1.4 g) was heated to reflux for 24 hours with 15 ml of 30% aqueous sodium hydroxide, a mixture of 15 ml of ethanol and 5 ml of dioxane. The mixture was concentrated in vacuo and the residue was dissolved in 5% aqueous hydrochloric acid and washed with chloroform. The aqueous solution was made alkaline with ammonium hydroxide and extracted with chloroform. The extracts were washed with brine, dried and concentrated to give 0.65 g of 2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-1H,6H-cyclohexa[4 ,5]pyrrolo[2,3-g]isoquinolin-11(11H)-one.

Example 11

By following the procedure from example 10 starting from 2-methyl-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo [2,3-g]isoquinolin-10(10H)-one was obtained via the carbamate 1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-eH-cyclopenta [4,5]pyrrolo[2,3-g]isoquinolin-10(10H)-one, m.p. 242-245°C. (cleavage), crystallized from ethanol-ethyl acetate.

Anal. lime. for C,,H,o<N_0:> C, 73 , 01; H, 7 , 88 ", N, 12 , 16

14 lo z

Found: C , 72 , 84 •, H, 7 , 78 JN, 12 , 30

Example 12

By following the procedure from example 10 and starting from 2-methyl-2,3,4,4a,5,7,8,9,10,11,12,13a-dodecahydro-4a,13a-trans-1H,6H- cycloocta[4,5]pyrrolo[2,3-g]isoquinolin-13(13H)-one, one obtained via the carbamate 1,2,3,4,4a,5,6,7,8,9,10,11 ,12,13a-tetradecahydro-4a,13a-trans-cycloocta[4,5]pyrrolo[2,3-g]isoquinolin-13-one, m.p. 283-5°C, crystallized from ethanol.

Anal. lime. for <C>1?<H>24<N>2<0:> C,74,96;H,8,88;N,10,28 Found: C,74,71;H,8,65;N ,10,24

Example 13

Preparation of 2-[ 4-(4-fluorophenyl)-4-oxobutyl]- 2, 3, 4, 4a, 5, 7, 8, 9, 10, lla- decahydro- 4a, lla- trans- 1H, 6H- cyclohexa[4,5]pyrrolo[2,3-g]isoquinolin-11(11H)-one

A mixture of 0.68 g of 2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-1H,6H-cyclohexa[4,5]pyrrolo[2,3 -g]isoquinolin-11(11 (11H)-one, 1.68 g of γ-chloro-p-fluorobutyrophenone and 1.55 g of potassium carbonate in 15 ml of diethyl ketone were heated to reflux for 24 h. The mixture was cooled, filtered and concentrated The residue was chromatographed (dry column) eluting with the organic phase of a mixture prepared by shaking (in parts by volume) 90 parts chloroform, 30 parts methanol, 10 parts water and 6 parts acetic acid which gave 0.85 g of a crude amine which was recrystallized from ethanol to give 0.42 g of pure 2-[4-(4-fluorophenyl)-4-oxobutyl]-2,3,4,4^5,7,8,9,10,lla-decahydro -4a,lla-trans-1H,6H-cyclohexa[4,5]pyrrolo[2,3-g]isoquinolin-11 ( 11H)-one as a crystalline solid, mp 220-222°.

Anal. lime. for C25H29<N>2<0>2<F:> C,73,50;H,7,16;N,6,86,F,4,65 Found: C, 73 , 46 »H, 7 , 08 ,*N, 7 .16 ;F, 4 .61

Example 14

By following the procedure from Example 13 and alkylating 2,3,4,4a,5,7,8,9,10,lla-decahydro-4a,lla-trans-1H,6H-cyclohexa[4,5] pyrrolo[2, 3-g]isoquinolin-11(11H)-one with (2-bromomethyl)benzene gave 2-(2-phenylethyl)-2,3,4,4a,5,7,8,9,10,lla-decahydro- 4a,11a-trans-1H,6H-cyclohexa[4,5]pyrrolo[2,3-g]isoquinolin-11(11H)-one, m.p. 250-256°C (decomposition), as a crystalline solid after recrystallization from ethanol.

Anal. lime. for C23H2gN20: C, 79 , 27 ;H, 8 ,10 ,'N, 8.04

Found: C,79.29>H,8.40;N,7.97

Example 15

By following the procedure from Example 13 and alkylating 2,3,4,4a,5,7,8,9,10,lla-decahydro-4a,lla-trans-1H,6H-cyclohexa[4,5]pyrrolo[2 ,3-g]isoquinolin-11(11H)-one with benzyl chloride gave 2-benzyl-2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-1H , 6H-cyclohexa[4,5]pyrrolo[2,3-g]isoquinolin-11(11H)-one, m.p. 266-268°C, as a crystalline solid after recrystallization from ethanol.

Anal. lime. for C22H26<N>2<0:> C,79.00;H,7.84;N,8.38

Found: C, 79.27; H, 8.03; N, 8.60

Example 16

By following the procedure from Example 13 and alkylating 1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5] pyrrolo[2,3 -g]isoquinolin-10(10H)-one with benzyl chloride gave 2-benzyl-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta -[4,5]pyrrolo[2,3-g]isoquinolin-10(10H)-one, m.p. 258-260°C (decomposition), as a crystalline solid after recrystallization from ethanol.

Anal. lime. for C21H24<N>2<0:> C , 78 , 71 ',H, 7 , 55 ;N, 8 , 74

Found: C, 78.97; H, 7.54; N, 8.63

Example 17

By following the procedure from Example 13 and alkylating 1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5] pyrrolo[2,3 -g]isoquinolin-10(10H)-one with γ-chloro-p-fluorobutyrophenone gave 2-[4-(4-fluorophenyl)-4-oxobutyl]-1,2,3,4,4a, 5.7 ,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo [2,3-g]isoquinolin-10(10H)-one, m.p. 225-227°C as a crystalline solid after recrystallization from ethanol.

Anal. lime. for C24H27FN2O2: C,73.07;H,6.90;N,7.10 JF,4.82 Found: C,72.76;H,6.86;N,7.24;F,4.71

Example 18

By following the procedure from Example 13 and alkylating 1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5] pyrrolo[2,3 -g]isoquinolin-10(10H)-one with (2-bromomethyl)benzene gave 2-(2-phenylethyl)-1,2,3,4,4a,5,7,8,9,10a-decahydro- 4a,10a-trans-6H-cyclopenta[4,5]pyrrolo[2,3-g]isoquinolin-10 (1OH)-one, m.p. 251-254°C, (dec.), as a crystalline solid after recrystallization from ethanol.

Anal. lime. for C22H2g<N>2<0:> C,79.00;H,7.84;N,8.38

Found: C, 78.68; H, 7.72; N, 8.28

Example 19

By following the procedure from Example 13 and alkylating 1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5] pyrrolo[2,3 -g]isoquinolin-10(10H)-one with 4-methoxybenzyl chloride gave 2-(4-methoxybenzyl)-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a -trans-6H-cyclopenta[4,5]pyrrolo[2,3-g]isoquinolin-10-one, m.p. 236-8° (decomposition), as a crystalline solid after recrystallization from ethanol.

Anal. lime. for C22H26N2<0>2<:><C>,75.40;H,7.48;N,7.99

Found: C, 75.39; H, 7.41 JN, 8.03

Example 20

By following the procedure from example 13 cg alkylate 1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5] pyrrolo[2,3 -g]isoquinolin-10(10H)-one with 4-chlorobenzyl chloride gave 2-(4-chlorobenzyl)-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a -trans-6H-cyclopenta[4,5]pyrrolo[2,3-g]isoquinolin-10 (1OH)-one as a crystalline monohydrate, m.p. 254-6° after recrystallization from ethanol.

Anl. lime. for C21<H>23N20Cl H20:C, 67 , 63 ,'H, 6 , 22 JN, 7 .51*, Cl, 9 , 51 Found: C, 67 .86 ;H, 6 .38 «,N, 7 .50 ;C1.9 , 92

Example 21

By following the procedure from Example 13 and alkylating 1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5] pyrrolo[2,3 -g]isoquinolin-10(10H)-one with allyl bromide gave 2-(2-propenyl)-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans -6H-cyclopenta[4,5]pyrrolo[2,3-g]isoquinolin-10(10H)-one, m.p. 257-9° (decomposition), after recrystallization from ethyl acetate-ethanol.

Anal. lime. for C17H22<N>2<0:> C,75,52;H,8,20;N,10;36

Found: C, 75 , 25 ;H, 8.17JN, 1036

Example 22

By following the procedure from example 12 cg alkylate 1,2,3,4,4a,5,7,8,8,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5] pyrrolo [2 ,3 -g] isoquinolin-10 (10H)_-one with 2-bromomethyl ether gave 2-(2-ethoxyethyl)-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a, 10a-trans-6H-cyclopenta[4,5]pyrrolo[2,3-g]isoquinolin-10 (1OH)-one, m.p. 236-8° (dec) as a crystalline solid after recrystallization from ethanol.

Anal. lime. for <C>18<H>26N2°2: C, 71, 49 ;H, 8 , 67 ,'N, 9 ,26

Found: C, 71.35*, H, 8.47 ; N, 9 , 23

Example 33

Preparation of 2- methyl- L, 2, 3, 4, 4a, 5, 7, 8, 9, 10a- decahydro- 4a, 10a- trans- 6H- cyclopenta-[ 4, 5] pyrrolo[ 2, 3- g ] isoquinoline-10(10H)-thione

A mixture of 244 mg (1.0 mmol) of 2-methyl-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5 ]pyrrolo[2,3-g] isoquinolin-10(10H)-one and 222 mg (1.0 mmol) of phosphorus pentasulfide in 15 ml of dioxane were stirred and refluxed for 17 hours. The dioxane solution was poured off and 20 ml of water and sufficient ammonium hydroxide to bring the pH to 8-9 was added to the residue. The mixture was extracted with chloroform and the extracts washed with brine, dried and evaporated. The crude thione was chromatographed as described in Example 13 and gave 65 mg of pure solid thione which was recrystallized from acetonitrile to give 2-methyl-1,2,3-4,4a,5,7,8,9,10a-decahydro- 4a,lOa-trans-eH-cyclopenta[4,5]pyrrolo[2,3-g]isoquinoline-10(10H)-thione, m.p. 224-227°C (decomposition).

Anal. lime. for C15H2(N2S): C, 69.19; H, 7 , 74N, 10 , 76

Found: C, 68.97; H, 7.59; N, 10.97

Example 2 4

Preparation of 2-(2- hydroxy- 3, 3- dimethylbutyl)- 2, 3, 4, 4a, 5, 7, 8, 9, 10, lla- decahydro- 4a, lla- trans- 1H, 6H- cvclohexa[ 4, 5] pyrrolo [ 2, 3- g ] isoquinolin- 11( 11H)- one

A solution of 488 mg (2.0 mmol) of 2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,lla-trans-1H,6H-cyclohexa[4,5] pyrrolo[2,3-g]isoquinolin-11(11H)-one and 300 mg (3.0 mmol) of 3,3-dimethyl-1,2-epoxybutane in 15 ml of methanol were refluxed for 24 hours and concentrated. The residue was chromatographed and the crude product (350 mg) crystallized from ethanol to give 200 mg of 2-(2-hydroxy-3,3-dimethylbutyl)-2,3,4,4a,5,7,8,9,10,lla- decahydro-4a,11a-trans-1H,6H-cyclohexa[4,5]pyrrolo[2,3-g]isoquinolin-11(11H)-one, m.p. 276-278°C (decomposition).

Anal. lime. for c2iH32N2°2: C' 73'22'H'9'36,N'8'13

Found: C, 73 , 3 9 ;H, 9 , 31 ",N, 8 ,15

Example 25

By following the procedure from Example 24 and alkylating 1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo[2,3 -g]isoquinolin-10(10H)-one with ethylene oxide at room temperature gave 2-(2-hydroxyethyl)-1,2,3,4,4a,5,7,8,9,1Oa-decahydro-4a,10a -trans-6H-cyclopenta[4,5]pyrrolo[2,3-g] isoquinolin-10(1OH)-one, m.p. 237-9° (decomposition) as a crystalline solid after recrystallization from ethanol. Anal. lime. for C-^H^N^: C,70.04;H,8.08;N,10.21

Found: C,69,66>H,8,17;N,10,19

Example 26

By following the procedure from Example 24 and alkylating 1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo[2,3 -g]isoquinolin-10(10H)-one with 3,3-dimethyl-1,2-epoxybutane gave 2-(2-hydroxy-3,3-dimethylbutyl)-1,2,3, 4, 4a, 5 ,7,8,9,10a-decahydro-4a,10a-^trans-6H-cyclopenta[4,5]pyrrolo[2,3-g]isoquinolin-10(10H)-one, m.p. 284-6° (dec) as a crystalline solid after recrystallization from ethanol.

Anal. lime. for C20<H>3Q<N>2<O>2<:> C, 72, 69 «,H, 9 .15 ;N, 8 .48 Found: C,72,80;H,9,02;N ,8.55

Example 2 7

A mixture of 30 mg of sodium hydride dispersion (57%, washed free of oil) and 2 ml of dry dimethylsulfoxide (DMSO) was heated to 65-70° for 1.5 hours. The solution was cooled and a solution of 244 mg of 2-methyl-1,2,3,4,4a,5,7,8,9,10a-decar-hydro-4a,10a-trans-6H-cyclopenta[4,5 ]pyrrolo[2,3-g]isoquinolin-10(10H)-one in 1 ml of dry DMSO was added in portions. The mixture was stirred for 2 hours at room temperature. A solution of 160 mg of benzyl chloride in 1 ml of dry DMSO was added and the mixture stirred for 2.5 hours at room temperature and then poured into ice water. The mixture was extracted with chloroform, the extracts washed with brine, dried and concentrated to give 560 mg of crude solid. Chromatography on silica gel using the system as stated in Example 29 gave 60 mg of 6-benzyl-2-methyl-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a -trans-6H-cyclopenta[4,5]pyrrolo[2,3-g]isoquinolin-10(10H)-one as a crystalline solid, m.p. 169-171° after recrystallization from ethyl acetate-ethanol.

Anal. lime. for C22H2<gN>20: C,79.00;H,7.84;N,8.35

Found: C , 78 , 92 *,H, 7 ,84 ;N, 8 , 55

Example 2 8

To a solution of 2.35 g of rac.-2-methyl-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5 ]pyrrolo[2,3-g]isoquinolin-10 (10H)-one in 20 ml of methanol was added a solution of 3.62 of (+)-dibenzoyl-(D)-tartaric acid monohydrate in 20 ml of methanol. The mixture was concentrated and crystallized from methanol three times and transferred to the free base with ammonium hydroxide. Recrystallization of the base from ethanol gave 0.18 g of (-)-2-methyl-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta [ 4,5]pyrrolo[2,3-g]isoquinolin-10(10H)-one, m.p. 270-2° (decomposition). The hydrochloride salt gave [a]<2>^ - 101.17° in methanol (1%). •

Example 29

Preparation of 2-[4-(4-fluorophenyl)-4-hydroxybutyl]-1,2,3,4)':4a,5,7,8,9,10a-decahydro-6H-4a,10a-trans- cyclopenta[4,5]pyrrolo[2,3-g]isoquinolin-10(10H)-one.

A mixture of 394 mg (1.0 mmol) of 2-[4-(4-fluorophenyl)-4-oxobutyl]-1,2,3,4,4a,5,7,8,9,10a-decahydro- 6H-4a,lOa-trans-cyclopenta[4,5]pyrrolo[2,3-g]isoquinolin-10(10H)-one and 151 mg of sodium borohydride (4.0 mmol) in 15 ml of ethanol were stirred at room temperature for 24 hours . A second portion of sodium borohydride (150 mg, 4.0 mmol) was added and the mixture was further stirred at room temperature for 24 hours. The mixture was poured into 50 ml of water and filtered to remove the white solid containing some starting material. Dry column chromatography on silica gel eluting with the lower phase of a mixture of 90 ml chloroform, 30 ml methanol, 10 ml water and 6 ml glacial acetic acid gave 220 mg of a solid which was recrystallized from dimethylformamide to give 2-[4-( 4-fluorophenyl)-4-hydroxybutyl]-1,2,3,4,4a,5,7,8,9,10a-decahydro-6H-4a,10a-trans-cyclopenta[4,5]pyrrolo [2, 3-g]isoquinolin-10(1OH)-one, m.p. 243-5° as a mixture of diastereomers.

Anal. lime. for <C>24H2g<N>2<0>2<F:> C,72.70;H,7.37;N,7.07

Found: C, 72 , 68H, 7 .56 ;N, 7 .33

Example 30

Following the procedure of Example 29, the sodium borohydride reduction of 2-[4-(4-fluorophenyl)-4-oxobutyl]-2,3,4,4a,5,7,8,9,10,lla-decahydro- 4a,11a-trans-1H,6H-cyclohexa[4,5] pyrrolo [2,3-g] isoquinolin-11(11H)-one 2- [4-(4-fluorophenyl)-4-hydroxybutyl]- 2,3,4,4a,5,7,8,9,10,lla-decahydro-4a,lla-trans-1H,6H-cyclohexa[4,5]pyrrolo[2,3-g]isoquinoline-11( 11H)-one as a mixture of diastereomers, m.p. 239-41°, crystallized from 1,4-dioxane.

Anal. lime. for C25H3]N2<0>2<F:> C,73.14;H,7.61;N,6.82

Found: C, 73 .18 ;H,7 .72 , 6 .82

Example 31

Following the procedure of Example 29, the sodium borohydride reduction of 2-[4-(4-fluorophenyl)-4-oxobutyl]-2,3,4,4a, 5,7,8,9,10,11,12, 13α-dodecahydro-4α,13α-trans-1H,6H-cyclo-octa[4,5]pyrrolo[2,3-g]isoquinolin-13(13H)-one 2-[4-(4-fluoro-phenyl) -4-hydroxybutyl]-2,3,4,4a,5,7,8,9,10,11,12,13a-do-decahydro-4a,13a-trans-1H,6H-cycloocta[4,5] pyrrolo[2,3-g]isoquinolin-13 ( 13H)-one as a mixture of diastereomers, m.p. 249-51°, crystallized from 1,4-dioxane.

Anal. lime. for C27H35N2<0>2<F:> C, 73 , 94',H, 8 , 04 ;N, 6 , 39

Found: C, 73.71; H, 8.05; N, 6.37

Example 32 (Intermediate product)

Preparation of 5-[(2-methylamino)ethyl]-cyclohexane-1,3-dione To a stirred solution of N-methyl-1,5-dimethoxycyclohexa-1,4-dien-3-ethylamine (5,5 g, 27.9 mmol) in 20 ml of tetrahydrofuran, 10 ml of 6N hydrochloric acid was added in one portion. The hot solution was heated for 15 minutes at 50°C and concentrated to a pale yellow oil. The crude oil was dissolved in 25 ml of water and the solution mixed with 50 g of Dowex 50X8 resin (previously washed with 2N HCl and deionized water) in a sintered glass funnel. After a few minutes, the aqueous solution was withdrawn by suction and the resin purified with 4 50 ml portions of water, and then with 8 35 ml portions of 2M aqueous pyridine. Pyridine fractions 3-8 were pooled and concentrated to 3.9 g of 5-[(2-methylamino)ethyl]-cyclohexane-1,3-dione. An analytical sample was crystallized from water and had m.p. 171-4°C.

Anal. lime. for CgH15NC>2: C,63.88;H,8.93;N,8.28

Found: C, 63.50; H, 8.87; N, 8.15

Example 33

Preparation of 6- benzyl- 2, 3, 4, 4a, 5, 7, 8, 9, 10, lla- decahydro-4a, lia- trans- 1H, 6H- cyclohexa[ 4, 5] pyrrolo[ 2, 3- g] isoquinolin-11 (IIH)-one

By following the procedure from Example 2 7, 316 mg of 2-ethoxycarbonyl-2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-1H,6H-cyclohexa[4 ,5]pyrrolo[2,3-g]isoquinolin-11(11H)-one alkylated with 190 mg of benzyl chloride to give 6-benzyl-2-ethoxy-carbonyl-2,3,4,4a,5,7,8, 9,10,11a-decahydro-4a,11a-trans-1H,6H-cyclohexa[4,5]pyrrolo[2,3-g]isoquinolin-11(11H)-one (220 mg), m.p. 54-60°C, which was hydrolyzed according to the procedure from Example 10 with sodium borohydride and gave 6-benzyl-2,3,4,4a,5,7,8,9,10,lla-decahydro-4a,lla-trans- 1H,6H-Cyclohexa[4,5]pyrrolo[2,3-g]isoquinolin-11(11H)-one.

EXAMPLE 34

Preparation of a-(3-chloropropyl)-4-fluorobenzenemethanol:

A mixture of 2 g (10 mmol) of Y-chloro-p-fluorobutyrophenone and 1.5 g (40 mmol) of sodium borohydride in 80 ml of ethanol was stirred at room temperature for 3 1/2 hours. The mixture was cooled on ice/water and 20 ml of 2N hydrochloric acid was slowly added. The solvent was removed under vacuum and 20 ml of water was added to the residue. The mixture was extracted with chloroform and the combined chloroform extracts were dried over sodium sulfate barrel, filtered and concentrated to give an oily residue. The residue was chromatographed on silica gel eluted with hexane-ethyl acetate (9:1) to give 2-(3-chloropropyl)-4-fluorobenzene 3 -methanol.

Preparation of 2-[ 4-( 4- fluorophenyl)- 4- hydroxybutyl]- 1, 2, 3, 4f4a, 5, 7, 8, 9, 10a- decahydro- 6H- 4a, lOa- trans- cyclopenta[ 4, 5]-pyrrolo[2,3g]isoquinoline 10(10H)-one: To a mixture of 115 mg (0.5mmol) 1,2,3,4,4a,5,7,8,9,10a-decahydro- 4a,l0a-trans-6H-cyclopenta[4,5]pyrrolo[2,3-g]isoquinolin-10 (10H)—one and 138 mg (1.0 mmol) potassium carbonate, heated to 100°C in 10 ml n -butanol while stirring was added a solution of 121 mg (0.6 mmol) of α-(3-chloropropyl)-4-fluorobenzenemethanol in 8 ml of n-butanol. After the addition, the mixture was refluxed and stirred for 20 hours. The solvent was removed under vacuum and the residue was added to 15 ml of chloroform. The solution was extracted with 2N hydrochloric acid and the combined acidic extracts were made alkaline with ammonium hydroxide. The mixture was extracted with chloroform and the combined extracts were concentrated to a solid residue. Dry column chromatography of the residue on silica gel eluting with the lower phase of a mixture of 90 ml chloroform, 30 ml methanol, 10 ml water and 6 ml acetic acid gave 14 mg of solid which was boiled in ethanol for a few minutes, cooled and filtered for to give 2-[4-(4-fluorophenyl)-4-hydroxybutyl]-1,2,3,4,4a,5,7,8,9,10a-decahydro-6H-4a,10a-trans-cyclopenta[ 4,5]pyrrolo-[2,3f]isoquinolin-10(10H)-one, m.p. 247-249°C.

Claims (2)

1. Analogous method for the preparation of therapeutically active cycloalka[4,5]-pyrrolo[2,3-g]isoquinolines with the general formula where R 1 is hydrogen or benzyl; R-, is hydrogen, (C2~4^~ alkyl, hydroxy-(C1-7)-alkyl, arylhydroxy-(C1-4)-alkyl, (C-L_4)-alcoc<sy->(C<-> i-<->4)-alkyl, arylcarbonyl-(C1-4)-alkyl, aryl-(C-L-4)-alkyl or (C2-5)-alkenyl; X is 0 or S, and n is 3, 4, 5 or 6 , and where aryl is phenyl optionally substituted with halogen or (C 1-4 )-alkoxy, optical and geometric isomers of these compounds and pharmaceutically acceptable acid addition salts thereof, characterized in that one a) for the preparation of a compound with the general formula where R"2 is (C₁-₄-alkyl or (C₁-₄)-Alkoxy-(C₁-₄)-alkyl, and n is as previously described, treats a compound of the general formula where R"2 and n are as previously described, with formaldehyde, or b) for the preparation of a compound of the general formula Ia above, treat a compound of the general formula where R"2 is as previously described, with a compound of the general formula in the presence of a reducing agent or with a compound of the general formula or a precursor thereof, in which formulas n is as previously described, or c) for the production of a compound with the general formula flour where n is as previously described, N-demethylates a compound of formula Ia above where R'^ is methyl or d) to produce a compound of the general formula flour where R"^ is hydrogen or benzyl, R"<1>2 is hydrogen, (C1_4)-alkyl, (C1_4)-alkoxy-(C1_4)-alkyl, aryl-(C-L_4>-alkyl or (C2_5)_alkenyl, and n is as previously described , treats a compound with the general formula where R"^/ R"'2°9 n is as previously described, with phosphorus pentasulphide, or e) for the preparation of a compound with the general formula where R' 2 is (C 1-4 )-alkyl, hydroxy-(C 1-7 )-alkyl, aryl-hydroxy-(C 1-4 )-alkyl, (C 1-4 )-alkoxy-(C 1-4 )-alkyl, arylcarbonyl-(C-^_4)-alkyl, aryl-(C^_4)-alkyl or (^2-5)-alkenyl, and X and n are as previously described, substitutes a compound of the general formula where X and n are as previously described, on the isoquinoline nitrogen atom, or f) for the preparation of a compound with the general formula flour where R'^ is benzyl, R<VI> is (C 1-4 )-alkyl, (C 1-4 )-alkoxy-(C 1-4 )-alkyl, arylcarbonyl-(C 1-4 )-alkyl, aryl-(C 1-4 )-alkyl or (C2-5)-alkenyl, and X and n are as previously described, benzylates a compound with the general formula where R^1 , X and n are as previously described, at the pyrrole nitrogen atom, or g) for the preparation of a compound with the general formula where R^V is hydroxy-(C-^_7)-alkyl or arylhydroxy-(C^_^)-alkyl and X and n are as previously described, reducing the carbonyl group in a compound with the general formula where R 11 is (C 1-7 )-oxoalkyl or arylcarbonyl-(C 1-4 )-alkyl, and X and n are as previously described, or h) for the preparation of a compound with the general formula where X, n and R 1 is as previously described, cleaves the urethane group in a connection with the general formula where X, n and R-^' are as previously described, and Y is a urethane group, and if desired, the mixture of the obtained cis and trans isomers isomerizes to a final ratio that mainly comprises trans isomers, and/or if desired, separates the trans isomer from the mixture obtained, and/or if desired, dissolves a racemically obtained mixture in the optical antipodes and/or if desired, converting an obtained compound or a non-pharmaceutically acceptable acid addition salt into a pharmaceutically acceptable acid addition salt thereof. 2. Analogous method for the preparation of 2-[4-(4-fluoro-phenyl)-4-oxobutyl]-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a- trans-6H-cyclopenta(4,5)pyrrolo(2,3-g)-isoquinolin-10(10H)-one according to claim 1, characterized in that similarly substituted starting compounds are used.